Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence

Abstract

We present a computational study on the enantioselectivity of organocatalytic proline-catalyzed aldol reactions between aldehydes in dimethylformamide (DMF). To explore the free energy surface of the reaction, we apply two-dimensional metadynamics on top of ab initio molecular dynamics (AIMD) simulations with explicit solvent description on the DFT level of theory. We avoid unwanted side reactions by utilizing our newly developed hybrid AIMD (HyAIMD) simulation scheme, which adds a simple force field to the AIMD simulation to prevent unwanted bond breaking and formation. Our condensed phase simulation results are able to nicely reproduce the experimental findings, including the main stereoisomer that is formed, and give a correct qualitative prediction of the change in syn:anti product ratio with different substituents. Furthermore, we give a microscopic explanation for the selectivity. We show that both the explicit description of the solvent and the inclusion of entropic effects are vital to a good outcome—metadynamics simulations in vacuum and static nudged elastic band (NEB) calculations yield significantly worse predictions when compared to the experiment. The approach described here can be applied to a plethora of other enantioselective or organocatalytic reactions, enabling us to tune the catalyst or determine the solvent with the highest stereoselectivity.

Aggregation and support effects in the oxidation of fluxional atomic metal clusters. The paradigmatic Cu5 case

“…Ab Initio molecular dynamics (AIMD) simulations have been carried out using the ORCA MD module written by Brehm and collaborators. [54][55][56] Newton's equations of motion have been solved through numeric integration using the velocity Verlet algorithm within the Canonical Ensemble with time steps of 0.5 and 1.0 fs. The simulations have been accomplished using the Berendsen's thermostat at temperatures of 673, 473, and 573 K for bare Cu 5 -Cu 5 , circumpyrene-supported Cu 5 -(O 2 ) 4 , and circumpyrene-supported Cu 5 -Cu 5 , respectively.…”

Demystifying Solvent Effects on Diels–Alder Reactions in Pure and Mixed Solvents: A Combined Electronic DFT and QM/MM Study

“…However, numerous studies have demonstrated that the dielectric constants of mixed solvents do not combine linearly with those of pure solvents. ,− In explicit solvent models, solvent molecules are treated explicitly, and the free energy is typically evaluated by analyzing the trajectory of time evolution of phase space obtained via MC simulations or molecular dynamics (MD) . Since this approach can provide more molecular details, ab initio MD (AIMD) ,− and mixed QM/MM methods ,− have been extensively applied to get insight into solvent effects on the chemical reaction. For example, Mellmer et al demonstrated that tuning the concentration of hydroxyl groups in aqueous organic solvent mixtures by the AIMD method can greatly increase the rate of various acid-catalyzed reactions by up to 1000-fold.…”

Ethanol Oxidation Reaction Mechanism on Gold Nanowires from Density Functional Theory

“…The spring constant value for NEB calculations was set to 0.02 au. In some cases, the minimum energy path has been quantified using free energy surfaces [54] using well‐tempered metadynamics. The additional parameter that requires well‐tempered metadynamics (polarization temperature) was set to 15000 K. This value proved to be adequate to overcome energy barriers of approximately 30.0 kcal mol −1 .…”