How a Solvent Molecule Affects Competing Elimination and Substitution Dynamics. Insight into Mechanism Evolution with Increased Solvation

Abstract

Competiting S2 substitution and E2 elimination reactions are of central importance in preparative organic synthesis. Here, we unravel how individual solvent molecules may affect underlying S2/E2 atomistic dynamics, which remains largely unclear with respective to their effects on reactivity. Results are presented for a prototype microsolvated case of fluoride anion reacting with ethyl bromide. Reaction dynamics simulations reproduce experimental findings at near thermal energies and show that the E2 mechanism dominates over S2 for solvent-free reaction. This is energetically quite unexpected and results from dynamical effects. Adding one solvating methanol molecule introduces strikingly distinct dynamical behaviors that largely promote the S2 reaction, a feature which attributes to a differential solute-solvent interaction at the central barrier that more strongly stabilizes the transition state for substitution. Upon further solvation, this enhanced stabilization of the S2 mechanism becomes more pronounced, concomitant with drastic suppression of the E2 route. This work highlights the interplay between energetics and dynamics in determining mechanistic selectivity and provides insight into the impact of solvent molecules on a general transition from elimination to substitution for chemical reactions proceeding from gas- to solution-phase environments.

A Comparison of QM/MM Simulations with and without the Drude Oscillator Model Based on Hydration Free Energies of Simple Solutes

“…Biological systems are mostly composed of water, and the interactions with water are a central feature of life as we know it [ 1 , 2 , 3 , 4 , 5 ]. Solvation influences a wide variety of processes, including protein folding [ 6 , 7 , 8 , 9 , 10 ], crystal polymorphism [ 11 ], conformational equilibria [ 12 , 13 , 14 , 15 ] and even basic reaction pathways [ 16 ]. Furthermore, water is one of the main actors in the selectivity of biochemical interactions and has a profound influence on both the kinetics and thermodynamics of protein-protein, protein-nucleic acid and protein-ligand binding [ 17 ].…”

Synthesis of bodinieric acids A and B, both C-18 and C-19-functionalized abietane diterpenoids: DFT study of the key aldol reaction

“…S N 2 reactions, increases the energy of the transition state. 19 In our case, this effect would be similar especially for the steric characteristics of TSd, which would hinder the removal of the proton by the base.…”

Tackling Solvent Effects by Coupling Electronic and Molecular Density Functional Theory

“…However, solvent molecules may also be directly involved in the reaction mechanism. For instance, Liu et al have shown that adding a single methanol molecule largely promotes the S N reaction with respect to elimination reaction 2 . Direct involvement of solvent molecules cannot be captured by macroscopic consideration as the ones used in Hughes and Ingold model.…”