How Solvation Influences the SN2 versus E2 Competition

Computational and Theoretical Chemistry, 2019

The S N 2 reaction of F-+ CH 3 Cl covers a conducive energy domain described by its potential energy surface with varied F-C-Cl and C-F distance. Loci of the potential energy surface produce two reaction wells, one is due to nonconventional F•••H-C hydrogen bonding and the other is due to linear backside attack. The effect of solvent polarity on the PESs leads to (i) a significant increase in the energy barrier of the reaction with increase in the polarity of the solvent, (ii) disappearance of the transition state between the reaction complexes formed due to hydrogen bonding and direct attack on the carbon atom in the polar solvents, and (iii) the formation of reactant complex in cyclohexane due to direct attack of the nucleophile, while in toluene, the complex formation is due to hydrogen bond interaction.

The 23rd International Electronic Conference on Synthetic Organic Chemistry, 2019

Bimolecular nucleophilic substitution (SN2) reaction is one of the most frequently processes chosen as model mechanism to introduce undergraduate chemistry students to computational chemistry methodology. In this work, we performed a computational analysis for the ionic SN2 reaction, where the nucleophile charged (X−; X=F, Cl, Br, I) attacks the carbon atom of the substrate (CH3Cl) through a backside pathway, and simultaneously, the leaving group is displaced (Cl−). The calculations were performed applying DFT methods with the Gaussian09 program, the B3LYP functional, the 6-31+G* basis set for all atoms except iodine (6-311G*), and the solvents effects (acetonitrile and cyclohexane) were evaluated with the PCM model. We evaluated the potential energy surface (PES) for the mentioned reaction considering the reactants, the formation of an initial complex between the nucleophile and the substrate, the transition state, a final complex where the leaving group is still bound to the subst...

Understanding Chemical Reactivity, 2002

This chapter reviews the theoretical background for continuum models of solvation, recent advances in their implementation, and illustrative examples of their use. Continuum models are the most efficient way to include condensed-phase effects into quantum mechanical calculations, and this is typically accomplished by the using self-consistent reaction field (SCRF) approach for the electrostatic component. This approach does not automatically include the non-electrostatic component of solvation, and we review various approaches for including that aspect. The performance of various models is compared for a number of applications, with emphasis on heterocyclic tautomeric equilibria because they have been the subject of the widest variety of studies. For nonequilibrium applications, e.g., dynamics and spectroscopy, one must consider the various time scales of the solvation process and the dynamical process under consideration, and the final section of the review discusses these issues.

Journal of Chemical Theory and Computation, 2007

A new general-purpose reactivity indicator is derived. Unlike existing indicators, this indicator can describe the reactivity of molecules that lie between the electrostatic (or charge) control and electron-transfer (or frontier-orbital) control paradigms. Depending on the parameters in the indicator, it describes electrostatic control (where the electrostatic potential is the appropriate indicator), electron-transfer control (where the Fukui function's potential is the appropriate indicator), and intermediate cases (where linear combinations of the electrostatic potential and the Fukui function's potential are appropriate indicators). Our analysis gives some insight into the origins of the local hard/soft-acid/base principle. The "minimum Fukui function" rule for hard reagents also emerges naturally from our analysis: if (1) a reaction is strongly electrostatically controlled and (2) there are two sites that are equally favorable from an electrostatic standpoint, then the most reactive of the electrostatically equivalent sites is the site with the smallest Fukui function. An analogous electrostatic potential rule for soft reagents is also introduced: if (1) a reaction is strongly electron-transfer-controlled and (2) there are two sites where the Fukui function's potential are equivalent, then the most reactive of the Fukuiequivalent sites will be the one with greatest electrostatic potential (for electrophilic attack on a nucleophile) or smallest electrostatic potential (for nucleophilic attack on an electrophile).

Journal of Chemical Theory and Computation, 2018

Nucleophilic addition onto a carbonyl moiety is strongly affected by solvent, and correctly simulating this solvent effect is often beyond the capability of single-scale quantum mechanical (QM) models. This work explores multiscale approaches for the description of the reversible and highly solvent-sensitive nucleophilic N|•••CO bond formation in an Me 2 N−(CH 2) 3 −CHO molecule. In the first stage of this work, we rigorously compare and test four recent quantum mechanical/molecular mechanical (QM/MM) explicit solvation models, employing a QM description of water molecules in spherical regions around both the oxygen and the nitrogen atom of the solute. The accuracy of the models is benchmarked against a reference QM simulation, focusing on properties of the solvated Me 2 N−(CH 2) 3 − CHO molecule in its ring-closed form. In the second stage, we select one of the models (continuous adaptive QM/MM) and use it to obtain a reliable free energy profile for the N|•••C bond formation reaction. We find that the dual-sphere approach allows the model to accurately account for solvent reorganization along the entire reaction path. In contrast, a simple microsolvation model cannot adapt to the changing conditions and provides an incorrect description of the reaction process.

2020

Solvation effect might have a tremendous influence on chemical reactions. However, precise quantum chemistry calculations are most often done either in vacuum neglecting the role of the solvent or using continuum solvent model ignoring its molecular nature. We propose a new method coupling a quantum description of the solute using electronic density functional theory with a classical grand-canonical treatment of the solvent using molecular density functional theory. Unlike previous work, both densities are minimized self consistently, accounting for mutual polarization of the molecular solvent and the solute. The electrostatic interaction is accounted using the full electron density of the solute rather than fitted point charges. The introduced methodology represents a good compromise between the two main strategies to tackle solvation effect in quantum calculation. It is computationally more effective than a direct quantum-mechanics/molecular mechanics coupling, requiring the explo...

Computation, 2016

An orbital energy-based reaction analysis theory is presented as an extension of the orbital-based conceptual density functional theory. In the orbital energy-based theory, the orbitals contributing to reactions are interpreted to be valence orbitals giving the largest orbital energy variation from reactants to products. Reactions are taken to be electron transfer-driven when they provide small variations for the gaps between the contributing occupied and unoccupied orbital energies on the intrinsic reaction coordinates in the initial processes. The orbital energy-based theory is then applied to the calculations of several S N 2 reactions. Using a reaction path search method, the Cl − + CH 3 I → ClCH 3 + I − reaction, for which another reaction path called "roundabout path" is proposed, is found to have a precursor process similar to the roundabout path just before this S N 2 reaction process. The orbital energy-based theory indicates that this precursor process is obviously driven by structural change, while the successor S N 2 reaction proceeds through electron transfer between the contributing orbitals. Comparing the calculated results of the S N 2 reactions in gas phase and in aqueous solution shows that the contributing orbitals significantly depend on solvent effects and these orbitals can be correctly determined by this theory.

The Journal of Physical Chemistry A, 2001

Car-Parrinello molecular dynamics simulations have been performed to investigate the solvation effects on the prototype S N 2 reaction between Cland CH 3 Cl. The free energy barrier for this reaction in water was calculated using constrained dynamics at a constant temperature of 300 K and constant volume. Calculations on the isolated system (reaction in the gas phase at zero temperature) were performed for reference purposes. Qualitatively, the calculations confirm that the double-well free energy profile of the reaction in the gas phase is converted into a single barrier by solvation and that the height of the barrier increases significantly. Quantitatively, there are two error sources. At the electronic structure side, the Becke-Perdew functional underestimates the barrier height by 8 kcal/mol. At the dynamics side, there is a "hysteresis" effectstoo slow an adaptation of the solvent structure to changes in the reaction coordinatesyielding an estimated error of 3 kcal/mol in the free energy barrier height. After correction for these errors, the calculated value of the free energy barrier is 27 kcal/mol. Considering the accuracy of the solvent-solvent and solvent-reactant interactions of ca. 1 kcal/mol, this compares very well with the experimental estimate of 26.6 kcal/mol. This indicates that the ab initio (DFT) MD very well captures the differential energetic as well as entropic effects of the solvation when going from the (solvated) reactants to the initial ion-dipole complex to the transition state.

The journal of physical chemistry. A, 2017

Anti-, syn-E2 and inv-, ret-SN2 reaction channels for the gas-phase reaction of F- + CH3CH2I were characterized with a variety of electronic structure calculations. A geometrical analysis confirmed the synchronous E2-type transition states for the elimination of current reaction, instead of nonconcerted processes through E1cb-like and E1-like mechanisms. Importantly, the controversy concerning reactant complex for anti-E2 and inv-SN2 paths have been clarified in the present work. A positive barrier of + 19.2 kcal/mol for ret-SN2 shows the least feasibility to occur under the room temperature. Negative activation energies (-16.9, -16.0, and -4.9 kcal/mol, respectively) for inv-SN2, anti-E2, and syn-E2 indicate that inv-SN2 and anti-E2 mechanisms significantly prevail over the eclipsed elimination. Varying the leaving group for a series of reactions F- + CH3CH2Y (Y= F, Cl, Br, and I) leads to a monotonically decreasing barriers, which relates to the gradually looser TS structures foll...

The Journal of Physical Chemistry A, 2019

The prototypical S N 2 reaction of chloride ion with methyl chloride has been reinvestigated in aqueous solution using QM/MM methodology featuring MO6-2X/6-31+G(d) calculations with the TIP4P water model, and partial charges computed with the CM5 method. Though the DFT method yields excellent gas-phase energetics for the reaction, the QM/MM approach is found to yield overestimation of the activation barrier by ca. 12 kcal/mol. The discrepancy is traced to underestimate of the magnitude of the partial charges on the chlorine atoms in the transition structure. When CM1 or CM3 charges based on semiempirical wavefunctions are used instead, the agreement with experiment is much improved. The findings emphasize the sensitivity of the results of QM/MM calculations to the choice of QM method, the MM force field, and implementation of the QM/MM interface.