Solvent Effects on the Symmetric and Asymmetric S_N2 Reactions in the Acetonitrile Solution: A Reaction Density Functional Theory Study

Abstract

Bimolecular nucleophilic substitution (S N 2) reactions are of great importance in chemistry and biochemistry due to their capability of constructing functional groups. In this work, we investigate the solvent effect on the free energy profiles of symmetric and asymmetric S N 2 reactions in the acetonitrile solution using the proposed reaction density functional theory (RxDFT) method. This multiscale method utilizes quantum density functional theory for calculating intrinsic reaction free energy coupled with classical density functional theory for addressing solvation contribution. We find that the presence of acetonitrile brings both the polarization effect and solvation effect on the reaction pathways. For the eight selected symmetric S N 2 reactions, the predicated reaction pathways agree well with the results from the direct and thermodynamic cycle (TC) methods with the SMD-M062X solvation model. In addition, the polarization effect reduces the free energy barriers by about 6 kcal/mol, while the solvation effect increases the barriers by about 18 kcal/mol. For the four selected asymmetric S N 2 reactions, the predicted reaction pathways agree well with the results from the Monte Carlo simulations and experiments. The polarization effect and the solvation effect mutually reduce the free energy barriers, and the solvation effect plays a dominant role.

Steps Forward toward the Substitution of Conventional Solvents in the Heck–Mizoroki Coupling Reaction: Glycerol-Derived Ethers and Deep Eutectic Solvents as Reaction Media

“…Reaction results, conversion, and selectivity are influenced by the solvation of the chemical species of the reaction pathways, namely, reagents, transition states, intermediates, and products. This has been evidenced by DFT calculations and has been presented by Zhao and coworkers for S N 2 or tautomerization reactions. , …”

“…This has been evidenced by DFT calculations and has been presented by Zhao and coworkers for S N 2 or tautomerization reactions. 48,49 We first analyzed this effect on iodobenzene conversions (Table 2). In the case of glycerol, its polarity limited the solubility of the hydrophobic substrates, and its high viscosity provoked diffusion limitations to the reaction components in the medium.…”

Tackling solvent effect by coupling electronic and molecular Density Functional Theory

“…The self-consistent optimisation of electronic density ρ e (r) and the solvent density ρ(r, Ω) when minimising equation 8 allows to account for the mutual polarisation of the solute and the solvent environment. This is a clear improvement with respect to methods that consists in single QM calculation in vacuum followed by a single liquid state theory calculation such as RxDFT [38][39][40]. Indeed, such methods neglect the polarisation of the solute by the solvent density which is properly accounted with the present approach.…”

Tackling Solvent Effects by Coupling Electronic and Molecular Density Functional Theory

“…when minimising equation 9 allows to account for the mutual polarisation of the solute and the solvent environment. This is a clear improvement with respect to methods that consist in a single QM calculation in vacuum followed by a single liquid state theory calculation such 10 as RxDFT [38][39][40] . Indeed, such methods neglect the polarisation of the solute by the solvent density which is properly accounted with the present approach.…”