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Cite This: J. Am. Chem. Soc. 2018, 140, 10995−11005

How a Solvent Molecule Affects Competing Elimination and Substitution Dynamics. Insight into Mechanism Evolution with Increased Solvation Xu Liu,† Jiaxu Zhang,*,† Li Yang,*,† and William L. Hase*,‡

J. Am. Chem. Soc. 2018.140:10995-11005. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 09/14/18. For personal use only.

†

State Key Laboratory of Advanced Welding and Joining, MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, P. R. China ‡ Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409, United States S Supporting Information *

ABSTRACT: Competiting SN2 substitution and E2 elimination reactions are of central importance in preparative organic synthesis. Here, we unravel how individual solvent molecules may affect underlying SN2/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 SN2 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 SN2 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 SN2 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.

1. INTRODUCTION Base-induced elimination (E2) and bimolecular nucleophilic substitution (SN2) are fundamental organic reaction mechanisms and widely used in chemical synthesis, especially for carbon−carbon bond formation and for interchanging functional groups.1 As a result, they continue to be pivotal model systems for chemical reaction dynamics and kinetics.2 Gasphase SN2 reactions are governed by a double-well potential energy surface (PES) where two stable complexes in the reactant entrance (RC) and product exit (PC) channels flank the central barrier (Scheme 1).3 The barrier itself, which represents a transition state corresponding to Walden inversion at the reaction center, as described in organic chemistry textbooks,1 has an essential effect on the reaction kinetics even though it often lies submerged with respect to the reactant asymptote energy. Introducing bulky substituents at the halogenated center carbon atom (α-carbon) is supposed to frustrate Walden inversion and instead promote an E2 process.4 Such an elimination reaction proceeds through a base concerted β-H abstraction, with an α-carbon−Y bond broken, allowing orbital overlap during double-bond formation (Scheme 1). © 2018 American Chemical Society

Scheme 1. SN2 and E2 Reaction Pathways

Gas-phase studies of these processes have enriched our fundamental knowledge of their chemical reaction mechanisms.5−7 However, the dynamics in the liquid-phase may be more complex and different, since nonequilibrium solvation Received: April 30, 2018 Published: July 3, 2018 10995

DOI: 10.1021/jacs.8b04529 J. Am. Chem. Soc. 2018, 140, 10995−11005

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Figure 1. Schematic potential energy surface of the F−(CH3OH)n=0−2 + CH3CH2Br reactions showing stationary points along the inv-SN2 (black) and anti-E2 (pink) pathways at the M06/ECP/d level of theory. The reported energies are relative to the isolated molecules and ions without zeropoint energy (ZPE). Numbers in parentheses include ZPE, compared with experimental data38,39 in square brackets.

finding is a general evolution from SN2 to E2 upon increasing the degree of methyl-substitution. To date, computational studies of the preference for a specific reaction have been frequently inferred indirectly from stationary points on a reaction’s PES and viewed within the context of statistical models such as Rice−Ramsperger− Kassel−Marcus (RRKM) theory and transition-state theory (TST).21 This does not allow one to obtain insight into the underlying dynamics because atomistic details of the reaction mechanism may deviate substantially from those predicted by the intrinsic reaction coordinate (IRC)22 connecting stationary points. Such mechanistic detail is only uncovered by chemical dynamics simulations.3 In particular, important nonstatistical and non-IRC dynamics have been found for both SN2 and E2 reactions.3,23,24 A recent report of microsolvated reactions between fluoride ions and alkyl bromide using the selected ion flow tube (SIFT) technique observed a stepwise SN2 to E2 transition as the alkyl group gets more hindered.25 A negative solvation and temperature dependence of the reactivity was found, resembling a previous prediction for X−(solvent) + RY.12,13 However, the atomic-level dynamics of possible reaction intermediates and intrinsic mechanistic behaviors posed some puzzling issues. Specifically, both the substitution and elimination channels are calculated to be energetically feasible for F−(CH3OH)0,1 + CH3CH2Br reactions, as elaborated below in the energy profile section. The experiments proved the existence of two competing processes and revealed the primary formation of bare Br−, but selectivity of the SN2 versus E2 reaction mechanisms could not be identified by failure to differentiate reaction products. The SN2 and E2 pathways are competitive for the solvent-free F− + CH3CH2Br reaction, but computations indicate that, in accord with what is established for F−(HF)n + C2H5F,26 solvating the reactant F− ion will stabilize the displacement transition state more than that for elimination, thereby favoring the SN2 reaction (Figure 1).

effects may be significant.8,9 Solvent water molecules strongly affect the interaction energetics between the reagents, causing a change in the ion−molecule reaction rate, dropping it by as much as 16 orders of magnitude when undergoing a transition from the gas-phase to solution.10 As a bridge between the two phases, microsolvation with solvent molecules clustered around the reactant ion has received special attention, offering a bottom-up approach to gain details of solute−solvent interactions.11 A decreasing reactivity, upon enhanced ion solvation, has been observed for both substitution and elimination in experiments.10,12,13 These dynamics are understood by the increased stabilization of the reactants by solvation as compared to the transition state, which raises the barrier height and hinders reaction.11,14 Ion-imaging experiments and chemical dynamics simulations for X−(H2O)n + CH3I (X = OH and F) have shown that stepwise hydration of X− alters the reaction dynamics and kinetics quite remarkably from those for the corresponding bare ion.15−17 Steric properties are suggested to be crucial in understanding the influence of solvent molecules in such microsolvated SN2 reactions. In principle, both SN2 and E2 processes may occur as unwanted side reactions for chemical processes, making their competition an intriguing question to be probed.2,4 In past decades, studies have shown that SN2/E2 competition may be significantly influenced by the nature of attacking and leaving groups, substrate characteristics, and environment.2,4,7,9,18−20 However, disentangling these mechanistic effects presents analytical challenges in experiments, considering that both reactions yield the same ionic species (Scheme 1). Accordingly, a number of logical and novel approaches,18 that is, kinetic isotope effects (KIE),7 dianionic nucleophiles that generate diagnostic product ions,19 and ion-imaging,4 have been utilized to estimate the branching ratio between nucleophilic displacement and base-induced elimination. The 10996

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ion−molecule reactions involving competing nucleophilic displacement and elimination pathways.6,24,31,32 For the ECP/d basis,17 the Wadt and Hay ECP was used to represent the core electrons of bromine and an uncontracted 3s,3p basis set for the valence electrons. The valence basis is augmented by a d polarization function set with a 0.384 exponent and diffuse s, p, and d functions with respective exponents of 0.0635, 0.0459, and 0.128.33 The Dunning and Woon’s aug-cc-pVDZ basis was utilized for other atoms. Concerning the PP/t basis set,34 the Peterson aug-cc-pVTZ basis with a pseudopotential (PP) was used for bromine and the aug-cc-pVTZ basis for all others. These basis sets have been shown to successfully represent properties of reactive systems with halides.4,21,33 Overall, the MP2 and M06 methods were found to give the best agreement with available experimental and benchmark CCSD(T) data (see Table S1 and Figure S1 in Supporting Information). Considering both accuracy and computational cost, the M06/ECP/d method was chosen as practical for the direct dynamics calculations. Accordingly, the energy profile of the solvated F−(CH3OH) + CH3CH2Br reaction was characterized with this theory, which also performs well when compared with experimental reaction and solvation energies (Figure 1). Connections of transition states with intermediates on the PES were confirmed by IRC calculations.22 Detailed studies of the F−(CH3OH)0,1 + CH3CH2Br dynamics on the full dimensional M06/ECP/d PES employed a direct dynamics approach, for which the gradient required for the simulations is achieved directly from an electronic structure theory.35 To compare with experiments,25 the simulations were performed at an initial collision energy (Ecoll) of 0.04 eV, the average value for a 300 K collision, with the reactants’ vibrational and rotational energies sampled from their 300 K Boltzmann distributions. Quasiclassical sampling,35,36 which includes zero-point energy (ZPE) of each vibrational mode, was used to determine initial coordinates and momenta for the trajectories. Both CH3CH2Br and F−(CH3OH)n=0,1 had random orientations, and the trajectories were initiated at a specified impact parameter b scanned from 1 Å to the limiting value bmax with a step size of 2 Å; bmax is identified as the value of b for which there are no reactions out of 100 trajectories. The resulting values are ∼17 and 15 Å for the unsolvated and solvated reactions, respectively. 50 or 100 trajectories are computed at each b; thus, the total number of trajectories for the respective n = 0 and 1 are around 600 and 800. All direct dynamics computations were carried out with the VENUS chemical dynamics computer program36 interfaced to the NWChem electronic structure computer program.37

Of interest is how these different SN2 and E2 solvation energetics are manifested in the actual reaction dynamics. Do the SN2 and E2 reactions proceed through unique atomistic mechanisms? What is the impact of the solvating methanol molecule on the competitive dynamics between substitution and elimination? Are there other channels which contribute to the reaction and what are their relative importances? One remarkable finding for F−(CH3OH) + CH3CH2Br at nearthermal energies, as also seen for reactions solely by SN2 mechanism, 13,15 is that formation of the solvated Br−(CH3OH) product is strongly suppressed with respect to its bare Br− counterpart in a 0.15:0.85 ratio. This seems somewhat surprising, since forming the solvated ion is the statistically preferred channel due to the large exoergic binding energy of the Br−(CH3OH) cluster. Understanding this phenomenon requires detailed knowledge of dynamical effects caused by individual solvent molecules, which also provides valuable information of fundamental solvent effects on these prototypical substitution and elimination reactions in solution. Moreover, these model reactions of ethyl bromide are particularly relevant because halogenated hydrocarbons, included in 126 priority pollutants, are known to act as a major pollution source in the groundwater and atmosphere arising from their wide use in electrical insulators, pesticides, organic synthesis, etc.27 Therefore, a thorough characterization of the reactive behavior of these substances is of considerable interest. To address the mentioned questions and the reactivity of ethyl and related alkyl halides, we explored reaction mechanisms for F−(CH3OH)0,1 + CH3CH2Br by means of direct dynamics simulations. The findings agree with roomtemperature experiments and reveal a remarkable chemical system, for which dynamics tightly interplaying with energetics efficiently controls the competition of substitution and elimination and explains the unusual bias toward solvent-free product species. Atomistic behaviors are compared for solvated and unsolvated reactions, shedding light on the intrinsic dynamical features of the two fundamental competing processes. These dynamics remain quite unknown despite the ubiquity and importance of their competition in organic chemistry. Most interestingly, the gas-phase trade-off between E2 and SN2 has been suggested to in general strongly favor elimination, whereas nucleophilic substitution prevails in the condensed phase.26,28,29 The current studies for a microsolvated case provide a detailed atomic-level understanding of such a transformation for these two reactions between two distinctly different realms. The work signifies that a single solvent molecule can greatly affect chemical dynamics where multiple reactions are present and the overlap between them is pronounced.

3. RESULTS 3.1. Potential Energy Profile. Stationary point properties on the F−(CH3OH)0,1 + CH3CH2Br PES were investigated by extensive electronic structure calculations with results presented in detail in the Supporting Information (Table S1 and Figures S1 - S8). A PES profile of the prominent anti-E2 and inv-SN2 pathways at the M06/ECP/d level of theory, chosen for the chemical dynamics simulations reported here, is characterized in Figure 1. The energies mirror quite well those of the more demanding CCSD(T) theory. As illustrated in Figure S1, upon initial encounter of CH3CH2Br with solvent-free F−, either a hydrogen-bonded 0RC1 or ion−dipole 0RC2 complex, with comparable stabilities, is present as a minimum energy structure in the entrance channel. There is a low-energy pathway via 0TS(RC) that interconverts 0RC1 and 0RC2. Elimination, triggered by base abstraction of a β-H of the substrate, proceeds through an anti-E2 [0TS(aE)] or syn-E2 [0TS(sE)] saddle point to the respective post-reaction complexes 0PC(aE) and 0PC(sE), which are followed by product channels with separated 0P1(E) CH2CH2 + Br− + HF or bound species 0P2(E) CH2CH2 + Br−(HF), 0P3(E) CH2CH2(Br−) + HF, and 0P4(E) CH2CH2(HF) + Br−. 0TS(aE) and 0TS(sE) feature

2. METHODS Chemical dynamics simulations require an accurate PES, which governs the atomic motion in the chemical reaction. The PES profile and stationary point characteristics for the unsolvated F− + CH3CH2Br reaction were explored employing the wave function theory (WFT)-based MP2 as well as density function theory (DFT) methods30 paired with effective core potential (ECP)/d basis set. For DFT, various functionals M06, M06-2X, MPW1K, B3LYP, and B97-1 were tested. Higher level coupled cluster theory calculations with triple excitations treated perturbatively, that is, CCSD(T),30 combined with the PP/t basis set were carried out in terms of the MP2/ECP/d optimized geometries to gain benchmark stationary point energies. This approach has served as a reference method for 10997

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Figure 2. Opacity functions Pr(b) of F−(CH3OH)0,1 + CH3CH2Br for the inv-SN2 substitution and anti-E2 and syn-E2 elimination channels and for total reaction at 300 K. For solvated F−(CH3OH) reaction, the O-induced O-inv-SN2 and O-anti-E2 pathways are also identified, but their Pr(b) are negligible; see text.

relative to reagents, which is expected to suppress reactivity as observed in experiment.25 An enlarged energy gap between the inv-SN2 and anti-E2 TSs, upon solvation, is of particular interest and may impact competition between these two pathways. Either solvated product species or the bare ones can be formed with the base solvation. Figure S2 shows that the elimination and substitution products appear to be more stable if the species is solvated by methanol, sharply contrary to the measured 85% yields of free Br−.25 Rationalization of this result requires understanding the reactions’ atomistic dynamics. Furthermore, with methanol bound to the reactant ion, the oxygen atom of F−(CH3OH) may attack either the β-H or α-C of Hβ-CβH2-CαH2-Br, inducing elimination and displacemnet reactions leading to E2 products CH3O-Hβ + CβH2CαH2 + Br− + HF and SN2 products CH3O-CαH2-CβH2-Hβ + Br− + HF (depicted in Figures S3 and S7). Nonetheless, the barriers for these pathways are essentially higher than those for the F− induced E2 and SN2 pathways, and the results of the chemical dynamics simulations given below show that the former are relatively unimportant. 3.2. Reaction Dynamics Simulations. With chemical dynamics trajectory simulations, which follow motions of atoms along the reaction path, one can go much further than predicting reaction mechanisms based on stationary points. In the current study, such simulations for the F−(CH3OH)0,1 + CH3CH2Br reactions were performed by direct dynamics35 on the M06/ECP/d PES for a collision energy Ecoll of 0.04 eV, the value for 300 K experiments.25 3.2.1. Reactivity. At Ecoll of 0.04 eV, the anti-E2, syn-E2, and inv-SN2 reaction channels are open for both the F−(CH3OH)0,1 + CH3CH2Br systems, and their reaction probabilities Pr(b) as a function of the impact prameter b are inspected in Figure 2; Pr(b) is known as the opacity function. For the unsolvated case, Pr(b) extends to large bmax of 17.0 and 15.0 Å for the anti-E2 and inv-SN2 pathways, respectively, which stems from long-range ion−dipole attractive interactions. There is a much higher reaction probability for the former pathway as opposed to the latter over the whole impact parameter range. It is seen that the reaction probability for anti-E2 drops from 1 to 3 Å, then a slight increase appears at 5 Å. An examination of the individual atomistic mechanisms as given below reveals that the unsolvated anti-E2 reaction occurs for more than one-half by indirect dynamics, for which the Pr(b) generally decreases as b is increased. For impact parameters less than ∼9 Å, a direct rebound (DR) mechanism

concerted but also synchronous bonding changes, of prototypic E2 character in a continuous spectrum of elimination transition states.40 This is supported by a quantitative analysis of the elapsed time between the two Hshift and C−Br bond dissociation events, which is normally short and within ∼100 fs for both the unsolvated and solvated trajectory propagations. Substitution happens when a nucleophile attacks the α-C from either the back (inv-SN2) or front (ret-SN2) side eliminating Br−. After surmounting the respective SN2 transition state 0TS(iS) or 0TS(rS), for inversion and retention, the reactive system falls into a deep potential well in the exit channel forming a reaction intermediate 0PC(S) with the CαH2 configuration inverted or retained, whose weak Cα···Br− bond rupture yields 0P(S) CH3CH2F + Br−. Both elimination and substitution are exoergic, and their MEPs generally exhibit the double-well shape which characterizes gas-phase ion−molecule displacement reactions.3 The proximity between the nucleophile and leaving group poses a severe steric repulsion leading to the ret-SN2 0TS(rS) lying much higher in energy than the inv-SN2 0TS(iS). The anti-E2 0TS(aE) has a quite favorable interaction of the developing carbanionic lone pair at Cβ with the backside lobe of the antibonding Cα-Br obital,29 while in contrast the syn-E2 0TS(sE) requires a nearly eclipsed configuration along the Cα−Cβ bond causing about 10 kcal/mol of destabilization. As a result, an energetic preference for the TSs may be proposed as ret-SN2 ≪ syn-E2 < anti-E2 ∼ inv-SN2 and shown in Figure S1, consistent with the respective central barriers of 36.6, 12.9, 2.5, and 1.3 kcal/mol from the reactant complex to TS. This gives rise to the same reactivity trend for the reaction channels as postulated previously for F− + C2H5Y (Y = F, Cl, I).6,21,31 Adding one methanol molecule to F−, the prereaction PES is also characterized by two potential energy minima, that is, a Hbonded one 1RC1 and an ion−dipole one 1RC2, which are connected by a barrier of 1.4 kcal/mol or less. Both the E2 and SN2 pathways for the solvated F−(CH3OH) + CH3CH2Br reaction are described by the typical double-well model, as for free F−, and if the CH3OH molecule is removed from the stationary point configurations, the resulting structures resemble those for the unsolvated case (Figures S2 and S6). Thus, quite similar overall PES profiles are retained upon solvation, but the relative energetics change markedly. In contrast to F− + CH3CH2Br, involvement of one methanol molecule raises energies of stationary points on the PES 10998

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detailed in the following Atomistic Mechanisms section, trajectories that cross the E2 central barrier do not follow the IRC to either the 0PC(aE) or 0PC(sE) post-reaction complex, but instead tend to directly form CH2CH2 + Br− + HF as a result of potential energy release as the reactive system moves from the central barrier to the product asymptote. These non-IRC dynamics, for the observed propensity of the E2 reaction to follow a higher energy pathway, are reminiscent of those for the F− + CH3OOH → HF + CH2O + OH−42 and OH− + CH3F → CH3OH + F−23 reactions, for which the dynamics do not follow the IRC and avoid a deep potential energy minimum in the product exit channel. The total yield of free Br−, resulting from both the elimination and substitution processes, amounts to 98%, in line with room-temperature measurements.25 Solvating the base opens up new reaction pathways, leading to solvated products. For the F−(CH3OH) + CH3CH2Br reaction, seven E2 product channels 1P1(E) to 1P7(E) and three SN2 channels 1P1(S) to 1P3(S) are observed, whose energetic features are indicated in Figure S2. For both the E2 and SN2 pathways, yielding solvated Br−(CH3OH) product is thermodyanmically desired, but, as a matter of fact, the current simulations and experiments25 found it is strongly suppressed with respect to free Br−, as is the case for hydrated SN2 reactions.13,15,17 At a 0.04 eV (300 K) collision energy studied here, the methanol solvated SN2 products 1P2(S) to 1P3(S) and E2 products 1P5(E) to 1P7(E) contribute only ∼10% to the F−(CH3OH) reaction, whereas the channels giving rise to unsolvated 1P1(S) CH3CH2F + Br− + CH3OH and 1P1(E) to 1P4(E) govern, comprising 38 and 51% of the substitution and elimination events, respectively. The atomistic dynamics gained below rationalize the findings as a consequence of the subtle intramolecular vibrational energy redistribution (IVR) as potential energy is released during F−(CH3OH) + CH3CH2Br association,23 so that CH3OH tends to be sheared off without transferring to the leaving Br−. Of the trajectories forming desolvated E2 products, ∼90% follows a complete fragmentation pathway leading to the high-energy 1P1(E) CH2CH2 + Br− + HF + CH3OH, consistent with the postTS non-IRC dynamics found for free F−. Using the SIFT technique, Viggiano et al. investigated solvation effects on the F−(CH3OH) + CH3CH2Br reaction.25 The experiments revealed the fast formation of Br− and Br−(CH3OH) in a 0.85:0.15 (±20%) ratio, and no other product ions could be detected at 300 K. Within statistical uncertainty, our calculations are in reasonable agreement with the experiments, giving a Br−:Br−(CH3OH) ratio of 0.86:0.08 and further suggest ∼50 and 40% of the bare Br− ion are produced via the complete dissociation routes 1P1(E) and 1P1(S), respectively, with minor contributions from other pathways. Trace amounts of product ions Br−(HF) (4%) and Br−(CH2CH2) (2%) via channels 1P2(E) and 1P3(E) are also seen in the simulations, but play an unimportant role in the dynamics. 3.2.2. Atomistic Mechanisms. Different types of reaction mechanisms are identified by performing dynamics simulations and determining details of atomistic motions, and the substitution and elimination reactions may proceed through direct and indirect pathways (see Videos S1−S8 in Supporting Information). Reactive trajectories, for the low 0.04 eV collision energy considered here, are initiated by an internal rotation of the CH3CH2Br molecule due to the long-range ion−dipole interaction to maximize attraction between the

contributes to the anti-E2 products as well. As depicted in Figure 1, the anti-E2 TS shows a relatively extended structure, where F− is localized somewhat away from the center of mass of CH3CH2Br. This allows β-hydrogen abstraction by the base from a relatively large distance and favors a direct rebound reaction with b of around 5 Å over that with b = 1 or 3 Å. A combination of the indirect and direct rebound events results in the observed slight fluctuation of anti-E2 Pr(b) in a b range of 1−5 Å. Despite the fact that the solvated and unsolvated reactions occur for impact parameters up to similar large bmax values, adding a methanol molecule to F− increases the reaction barrier and hinders reactive collision with CH3CH2Br decreasing Pr(b), especially for the anti-E2 pathway. The synE2 Pr(b) shows no marked dependence on the impact parameter and remains low for both the F−(CH3OH)0,1 reactions. For the solvated case, O-anti-E2 and O-inv-SN2 events are observed from the trajectory computations but found to play an insignificant role in the dynamics. They account for only ∼1% of the reactive trajectories, in accordance with their large activation barriers compared to the F-induced counterparts. Using the opacity functions, the integral cross sections bmax

(ICSs) obtained from ∫ Pr(b)2πbdb are much smaller with 0 one methanol bound to the reactant ion. The ICSs for the individual anti-E2, syn-E2, and inv-SN2 pathways are, respectively, 249.6 ± 19.3, 21.2 ± 3.4, and 96.7 ± 9.9 Å2 for F− and 59.1 ± 6.3, 0.6 ± 0.3, and 45.4 ± 5.8 Å2 for F−(CH3OH). Comparison of the ICSs for the different pathways indicates that the anti-E2 dominates independent of solvation or not, while the inv-SN2 becomes more competitive upon CH3OH being involved. In going from F− to F−(CH3OH), the ICSs for anti- and syn-E2 drop by factors of ∼4 and ∼35, respectively, in contrast to a decrease of only a factor of ∼2 for inv-SN2, indicating methanol solvation frustrates the elimination events more than nucleophilic substitution. The reaction rate constant, for the reactants at a 300 K thermal energy and Ecoll of 0.04 eV studied here, is given by k(Ecoll, Tv, Tr) = v(Ecoll)σ(Ecoll, Tv, Tr). The resulting value from the calculated total cross section, including all reaction channels, is (24.9 ± 2.2) × 10−10 and (4.9 ± 0.5) × 10−10 cm3 mol−1 s−1 for the methanol-free and -involved reactions, respectively. The corresponding experimental rates have been measured at 300 K and are approximately (27.0−28.3) × 10−10 and 5.9 × 10−10 cm3 mol−1 s−1,25,41 which compare quite well with the calculated values. Both the experiments and simulations show that F− + CH3CH2Br collisions are about 5 times more reactive than those of F−(CH3OH) + CH3CH2Br, and this suppression of reactivity ascribed to solvation was also found for hydrated X− + CH3Y SN2 dynamics.10,13,17 For solvent-free F− + CH3CH2Br, substitution gives the unique product 0P(S) CH3CH2F + Br−, while four elimination reaction channels 0P1(E) CH2CH2 + Br− + HF, 0P2(E) CH2CH2 + Br−(HF), 0P3(E) CH2CH2(Br−) + HF, and 0P4(E) CH2CH2(HF) + Br− are revealed. As can be seen in Figure S1, although 0P2(E) to 0P4(E) are energetically favored over 0P1(E) due to the complexation energy for the resulting Br−(HF), CH2CH2(Br−), and CH2CH2(HF) clusters, formation of 0P1(E) with separated product species dominates the E2 reaction at a collision energy of 0.04 eV and comprises ∼95% of all of the elimination trajectories. As 10999

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Journal of the American Chemical Society incoming F−(CH3OH)0,1 and the CH3CH2 group. Direct invSN2 reaction occurs by a rebound mechanism (DR) at small impact parameters, that visualizes nucleophilic substitution with Walden inversion in organic chemistry textbooks, whereby F−(CH3OH)0,1 attacks the backside of the Cα−Br bond of CH3CH2Br, directly displaces Br−, and rebounds backward. For larger b values direct stripping (DS) becomes important, in which F−(CH3OH)0,1 approaches α-carbon from the side and strips CH3CH2 off without modifying its direction, causing forward scattering. The indirect reaction is complex mediated with trajectories becoming transiently trapped in the pre- and/or post-reactive potential energy wells, forming a reaction intermediate. It covers a broad impact parameter range approaching bmax and shows isotropic scattering stemming from extensive rotation of the system allowed by its long-time retention in the intermediate region. Similar direct and indirect mechanisms are seen in the baseinduced elimination process, but here F−(CH3OH)0,1 attacks a β-H instead of an α-C. With proper alignment of electron densities, the reactive system undergoes proton transfer and C−Br bond rupture in a synchronous behavior, ensured by overcoming the anti- or syn-E2 central barrier to form products. Detailed dynamics of the methanol molecule for the SN2 and E2 reaction mechanisms are discussed below. Figure 3 compares branching ratios of the atomistic mechanisms for various reaction pathways, signifying essential

the prereaction minimum region of the PES. This results in the indirect pathway prevailing, a finding in line with gas-phase nucleophilic displacement at low collision energies.3 As expected, base solvation introduces pronounced stereodynamic constraints that fundamentally enhances the indirect mechanism. The involvement of methanol molecule blocks direct reactive collisions of CH3CH2Br with F−(CH3OH) clusters, and, thus, the reaction has to proceed via a long-lived collision complex where CH3OH is ultimately pushed aside or sheared off before the F− can attack the substrate. Accordingly, direct events are strongly suppressed upon methanol solvation so that indirect trajectories govern the elimination and substitution dynamics, as evidenced in ion-imaging experiments and predicted theoretically for the microhydrated OH−(H2O)n + CH3I SN2 reactions.15,16 Direct reaction has an unbalanced distribution between rebound and stripping for unsolvated F−, with more DS observed for E2 and more DR for SN2, which becomes exclusively DR for the solvated reaction, but with a very low probability. A large amount of the elimination and substitution indirect events that the F−(CH3OH)0,1 trajectories follow proceed through the hydrogen-bonded (RC1) and ion−dipole (RC2) complexes in the reactant entrance channel and transformations between them occur frequently, as expected given the small barrier for F− migration (Figure 1). Complex formation in the exit channel is found to play a less important role in the dynamics, though solvating F− increases contributions from R0post. This results from the departing CH3OH carrying away an appreciable fraction of the available energy released, after overcoming the E2 or SN2 central barrier and trapping the reactive system in the post-TS potential well of the PES. Preference for indirect dynamics mediated by a prereaction complex was also seen in reactive scatterings of F−(H2O)n with CH3I for a 0.32 eV collision enery.17 Atomistic snapshots illustrating the indirect mechanisms governing the F−(CH3OH)0,1 + CH3CH2Br anti-E2 and inv-SN2 pathways are depicted in Figure 4. The statistical model for the F−(CH3OH) + CH3CH2Br reaction, with equilibrium microsolvation, assumes that CH3OH molecule continues to interact with the reactive system during the course of the SN2 or E2 reaction, forming methanol solvated products which may ultimately dissociate if they contain sufficient energy. Interestingly, the dynamics of solvating methanol found from the trajectories show quite distinct behavior from this model, and the time CH3OH detaches from the reactive system (i.e., CH3OH···F/Br breaking bond ≥2.2 Å)43 versus the time that the basedinduced elimiation or substitution reaction occurs illustrates this point. This information is given as scatter plots in Figure 5 for the prominent anti-E2 and inv-SN2 pathways, which bear similar features. For the direct trajectories, CH3OH departure is simultaneous with F− displacement of Br− for the SN2 reaction (Cα−F forming bond ≤2 Å) or abstraction of β-H for the E2 reaction (F−Hβ forming bond ≤1 Å); that is, CH3OH leaves as the elimination or substitution event occurs. This is the preferential methanol dynamics for the indirect mechanism as well, which amounts to 90% of the solvated reaction. Simulations reveal that for the majority of the indirect trajectories (more than 90%), CH3OH remains attached to F− during the F−(CH3OH) and CH3CH2Br interaction at early stages of the trajectory. The reactive system enters the 1RC1 and/or 1RC2 prereaction potential energy well and then escapes through E2 transition state 1TS(aE)/1TS(sE) or SN2

Figure 3. Branching ratios of atomistic mechanisms for F−(CH3OH)0,1 + CH3CH2Br SN2 and E2 reactions at 300 K. DR and DS, marked by a dark color, are direct reaction pathways denoting rebound and stripping. All indirect processes exhibit lighter colors, where the individual dynamics are characterized by formation of the 0RC1/0RC2 (R0Pre) or 1RC1/1RC2 (R1Pre) prereaction complex and the 0PC(aE)/0PC(S) (R0post) or 1PC(aE)/1PC(S) (R1post) post-reaction complex, and coupling of these events.

differences between the unsolvated and solvated reaction dynamics. Overall, the anti-E2 channel dominates both F−(CH3OH)n=0,1 reactions, with anti-E2, syn-E2, and inv-SN2 yields of 68, 6, and 26% for F− and 56, 1, and 43% for F−(CH3OH). The respective fractional contributions of the anti-E2, syn-E2, and inv-SN2 channels to the direct and indirect events are 0.32:0.36, 0.01:0.05, 0.08:0.18 with n = 0 and 0.02:0.54, 0:0.01, 0.01:0.42 with n = 1. Weak coupling between the low frequency intermolecular and higher frequency intramolecular modes of the prereaction F−(CH3OH)0,1··· CH3CH2Br complexes poses a dynamical bottleneck for transferring energy, required for attaining an E2 or SN2 transition state, causing reactive encounters to tend to trap in 11000

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Figure 4. Atomistic dynamics of representative trajectories illustrating the dominant E2 and SN2 mechanisms for F−(CH3OH)0,1 + CH3CH2Br collisions. Reaction proceeds indirectly by forming a 0RC1/0RC2 or 1RC1/1RC2 complex in the reactant entrance potential energy well (Figure 1).

Figure 5. Distribution of solvating CH3OH departure time as a function of E2 or SN2 occurrence time for the F−(CH3OH) + CH3CH2Br reaction. The CH3OH leaving time is determined when the CH3OH···F/Br breaking bond reaches ∼2.2 Å, the upper bound for a typical hydrogen bond length,43 and the E2 or SN2 occurrence time is recorded once the reactive system crosses the E2 (F−Hβ forming bond ≤1 Å) or SN2 (Cα−F forming bond ≤2 Å) TS (see text for details). Results are illustrated for individual reaction mechanisms: DR, direct rebound; and Ind, indirect. Data for DR are also presented in the inset for clarity.

3.2.3. E2 versus SN2 Competition and Solvation Effects. There exists a controversy for the F− + CH3CH2Cl reaction concerning whether the anti-E2 and inv-SN2 processes share the same minimum energy structure in their entrance channels. Cardini and co-workers conclude that the origin of this discrepancy arises from the role of dispersive and Hbonding interactions in the quantum chemistry calculations,44 which is affirmed by benchmark CCSD(T)-F12b characterizations.6 For the current F− + CH3CH2Br reaction, a single prereaction complex 0RC2 is predicted for both the anti-E2 and inv-SN2 routes (Figure S1), as in the case of F− + CH3CH2I.21 This is ascribed to the use of a large basis and

transition state 1TS(iS) to the product asymptote. Once passing the reaction’s TS dynamical bottleneck and forming the Cα-F or F−Hβ bond, the hydrogen bonding between CH3OH and F (CH3OH···F) becomes weak, and the energy released to the H···F stretch mode tends to break it, resulting in methanol detachment. Thus, CH3OH solvates the TS but not the products. These dynamics for the solvating methanol molecule support the experimental observation that the bare Br− species dominates both the E2 and SN2 outcomes in the F−(CH3OH) + CH3CH2Br reactive collisions, not the energetically favored solvated Br−(CH3OH) complex.25 11001

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complex is not appropriate. Qualitatively, one expects the relative probability of the E2 and SN2 mechanisms to depend upon the range of F− + CH3CH2Br orientations leading to their reactions, which should be reflected by the relative number of vibrational states, that is, microcanonical vibrational entropy, at the E2 and SN2 central barriers.29 However, a quantitative determination of the numbers of these states is difficult, since the vibrational energy at the central barrier depends upon the barrier’s rotational energy which results from the distribution of orbital angular momentum leading to reaction and its projection onto the barrier’s principal rotation axes. This information could be gleaned from the trajectories, but is a particularly challenging problem that poses an open question to be probed both experimentally and computationally. What can be said is that the anti-E2/inv-SN2 relative reaction probability is in good agreement with the reaction path degeneracies for the two mechanisms. It is of interest to compare the solvated and unsolvated F−(CH3OH)0,1 + CH3CH2Br dynamics, accordingly inspecting the influence of solvent molecule on the proceedings of baseinduced elimination and nucleophilic displacement. Upon solvation, the qualitative nature of the E2 and SN2 pathways parallels that for the solvent-free reaction in terms of the stationary points (Figures S5 and S6) and the overall PES structure (Figures S1 and S2), whereas the reaction energetics are substantially modified which may notably change the atomistic dynamics. When CH3CH2Br reacts with solvated F− instead of bare one, both the elimination and displacement channels become less submerged with respect to the reactant asymptote. Interactions between the base and substrate are more efficient in the TS than in the reactants and reactant complexes, which results in lowering the charge on the base and stabilization of its HOMO, as proposed by Bickelhaupt et al. for F− + C2H5F.26 This makes the coupling between base and the solvent CH3OH less favored in the TS, and, thus, the reactants are more strongly stabilized upon solvation as opposed to the TS, thereby enhancing the central barrier height. This effect, together with the steric hindrance by the methanol molecule, contributes to the suppressed reaction efficiency for the solvated case,25 as discussed in the above Reactivity section. Adding one methanol to the base results in the syn-E2 barrier positive, and not submerged, minimizing the yields of this pathway as supported by the trajectory calculations, that is, anti-E2/syn-E2/inv-SN2 in a 0.56:0.01:0.43 ratio is determined for the F−(CH3OH) reaction. The fact that the anti-E2 mechanism remains dominant is expected considering the factors mentioned above for the case without solvation. Nonetheless, a promoted inv-SN2 probability in comparison to anti-E2 is clearly seen in the solvated reaction, suggesting the substitution mechanism to be more competitive upon solvation. The important solute−solvent interactions at reaction’s saddle point might be one reason responsible for this observation, which shift the TS energetics for the anti-E2 versus inv-SN2 that are sufficient to strongly affect the dynamical behavior in E2/SN2 selectivity. A difference in the interaction potential has been found by analyzing the stability of the solvating CH3OH attachment to the anti-E2 and inv-SN2 TSs. Without solvation, these TSs have similar energies. However, as shown in Figure 1, the solvated inv-SN2 transition state 1TS(iS) CH3OH···[FCH2CH3−Br]− is bound by 20 kcal/mol, while the anti-E2 1TS(aE) CH3OH···[F−H−CH2CH2−Br]− is bound by only

sufficient consideration of dispersion. In this ion−dipole complex, F− situates on the opposite side of the C−Br bond, moderately bonded to both Cα and Hβ. Moreover, the syn-E2 and ret-SN2 pathways share the hydrogen-bonded 0RC1 minimum in the reaction’s entrance, in which the base interacts with an α-H instead of α-C and β-H. The barrier between complexes 0RC1 and 0RC2 for F− migration is less than 0.5 kcal/mol, similar to the quite flat prereaction PES found for the homogeneous F− + CH3Y substitution.45 For the unsolvated F− + CH3CH2Br reaction, the saddle point of the front-side attack ret-SN2 channel lies 16.3 kcal/ mol above the reagents, suggesting its negligible contributions at 300 K, as evidenced from the trajectories. In contrast, a submerged barrier is proposed for the remaining three pathways. Particularly, the barrier heights of the energetically most favored anti-E2 and inv-SN2 routes are essentially close, differing by ∼1 kcal/mol regardless of the level of theory used (Table S1). The deviation is only slightly perturbed by varying the leaving group ability from chloride to iodide.6,21 This poses difficulties in distinguishing the preference for the E2 and SN2 pathways and their branching ratio for reactions that can occur by both mechanisms. The chemical dynamics simulations reported here shed light on the selectivity of E2 elimination versus SN2 substitution, which is not identified by experiments and cannot be accounted for simply considering MEPs and their stationary points. The branching found for the three F− + CH3CH2Br mechanisms with submerged barriers is 0.68:0.06:0.26 for antiE2/syn-E2/inv-SN2. The TS’s higher energy and steric disadvantages rationalize the unimportance of the syn-E2 path. The trajectories show that the anti-E2 mechanism governs the reaction, whereas inv-SN2 is suppressed, which is quite interesting since their TSs have similar energetics on the PES (see Figure 1 and above discussion). This anti-E2/inv-SN2 selectivity for the unsolvated reaction probably has multiple origins. An important one is attributed to dynamic control exerted by a stereochemical factor. Despite the fact there are three different targets, namely, Hβ, Hα, and Cα, available for the attacking base when the structure of ethyl bromide is taken into account, the β-hydrogen for anti-E2 is much more accessible allowing F− to approach from large distances and a range of angles. In contrast, the α-carbon has a crowded, restricted environment hindering the inv-SN2 mechanism. This is in accordance with the geometrical character of the respective transition state, where only the anti-E2 TS shows a relatively extended and relaxed configuration. Meanwhile, the E2 elimination has a reaction path degeneracy three times that of SN2 substitution. This 3/1 proportion is close to the ratio of 2.8 for the E2 to SN2 reaction cross sections. Moreover, the lone-pair orbital of the base has a propensity for overlapping with the unoccupied H orbital rather than the occupied sp3 hybrid ones of carbon. Another factor lies in the relative reaction probability of the E2 and SN2 reaction mechanisms, both of which are highly exothermic (Figure 1). TST assumes the E2 and SN2 reactions proceed via their prereaction complexes, but separating the long-range interactions defining the reaction paths for forming these two complexes is not well-defined. Both are expected to be strongly influenced by the long-range F− + CH3CH2Br ion−dipole interaction. In addition, applicability of TST for the E2 and SN2 prereaction complexes is highly questionable since for both the E2 and SN2 mechanisms, ∼50% of the reaction is direct, and, thus, assuming a long-lived prereaction 11002

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Journal of the American Chemical Society ∼16 kcal/mol. This implies solvation lowers the inv-SN2 TS energy more efficiently than it does for the anti-E2 TS, which is assumed to help stabilize the inv-SN2 pathway in the solvated reaction. A shorter CH3OH···F distance of 1.594 Å for the invSN2 TS, as compared to 1.683 Å for the anti-E2 TS, indicates a more compact solvation structure for the former and fits in with its stronger solvation energetics. This picture is in accord with a previous prediction that inefficient solvation of reaction’s saddle point in solution, with respect to reactants, is a consequence of reduction in strength rather than in the number of specific solvent−solute coupling.46 In going from the gas-phase to the monosolvated reaction, the energy gap of the inv-SN2 and anti-E2 TSs enlarges from 1.2 to essentially about 5 kcal/mol. This enhances the importance of inv-SN2 process when the base is methanol solvated, irrespective of its unfavorable steric features relative to anti-E2.4 Upon solvation, the inv-SN2/anti-E2 ratio evolved to 0.43:0.56, in contrast to 0.26:0.68 for the unsolvated case. A correlation of solute−solvent interactions with reaction selectivity was also found qualitatively by Bickelhaupt and co-authors for the HF-solvated reaction of F− with ethyl fluoride,26 in which they focused on the disagreed solvation stabilizations of the SN2 and E2 transition states. The branching ratios of base-induced elimination versus substitution and the atomistic mechanisms obtained from our trajectory simulations allowed us to deduce the underlying intrinsic reaction dynamics under microsolvation. Figure 1 shows that introducing a second methanol molecule further weakens the binding for the reactive system and increases the stationary point energies along the reaction coordinate on the F−(CH3OH)2 + CH3CH2Br PES. The E2 and SN2 barrier heights become even less negative compared to the monosolvated F−(CH3OH) reaction, and a submerged barrier is only observed with the inv-SN2 path (Figure S4). The differential solute−solvent interactions and the resulting distinct solvation stabilizations for the anti-E2 and inv-SN2 TSs appear more pronounced for the disolvated as compared to the monosolvated case. This further increases the energy gap between the two transition states, which makes the TS(inv-SN2) (1.3 kcal/mol below reagents) 8.5 kcal/mol lower in energy than the TS(anti-E2) (7.2 kcal/mol above reagents). As a consequence, the inv-SN2 substitution pathway is much more preferred with two CH3OH bound to the reactant ion and expected to govern the F−(CH3OH)2 + CH3CH2Br reaction dynamics with anti-E2 elimination nearly negligible. Considering Figure 1, one sees that as the base is solvated more, the complex turns less stable and the overall barrier and reaction energies higher, resembling the qualitative potential model proposed by Brauman et al.47 Hence, higher Ecoll is required for reaction to occur with larger solvated F−(CH3OH)n clusters, and the dynamics are expected to feature ejection of solvent methanol molecules in the entrance channel, induced by reactants’ collisions, as seen in the microhydrated F−(H2O)n + CH3I SN2 reactions.17 In this way, the solvation shell of the base is partially stripped away, thereby efficiently facilitating its attack at the substrate. Thus, the succeeding SN2 displacement or E2 elimination reaction avoids the activation barrier with all of the solvent molecules intact and instead proceeds through the less solvated barrier. This occurs even though the latter pathway requires more energy, in agreement with peceding reports that the first few solvent molecules play major roles in the solvation kinetics and dynamics. 10,15,17 As detailed above, the much higher

unsubmerged barrier for the anti-E2 pathway, with respect to inv-SN2, for the reaction with disolvated F−(CH3OH)n=2 already suggests the insignificance of the former in this case for reactants at thermal energies. These systematic trends predict that for higher solvated F− (n ≥ 3), solvation progressively enlarges the inv-SN2 versus anti-E2 energy gap that will quench base-induced elimination events, so that the SN2 substitution dynamics prevail. This mechanistic evolution with increased solvation supports experimental findings in solution-phase conditions.26,28,29

4. CONCLUSIONS Dynamics of the elementary reactions of F−(CH3OH)n with CH3CH2Br which occur by SN2 substitution or E2 elimination are extremely rich and provide us with unforeseen insight into solvation effects on competition between the two processes. Dynamics simulations reveal that both SN2 and E2 reactive scatterings proceed through direct rebound, direct stripping, and indirect mechanisms, which are consistent with the reaction rates and product ion branching ratios measured in experiments.25 The indirect dynamics mediated by entrance channel complex are found to play a decisive role, with the addition of one solvating CH3OH greatly enhancing their contributions. In contrast, the overall large energy release in the exit channel results in a rapid separation of the reaction products without significant post-collision interaction. This is supported by the experimental observation, that is, bare Br− is the dominant product channel, not the energetically favored complexed or methanol solvated Br−.25 Upon increasing solvation of the ionic reactant, blocking by the methanol molecules tends to cease the direct reaction and instead preferentially forces all reactive encounters to transiently trap in the prereaction potential energy well and form an intermediate. This is supposed to be the only mechanism to prevail and poses a critical factor affecting the solvated dynamics. The trajectories reveal a preference of anti-E2 elimination over inv-SN2 substitution in the gas phase with a 0.68:0.26 ratio, which is of interest considering the two processes have similar TS energies. Dynamical and/or steric effects may account for the observed selectivity of reaction channels. Most notably, upon F− solvation with only one CH3OH molecule, subtle discrepancies in the solute−solvent interaction at the saddle point region of the PES change the relative inv-SN2 and anti-E2 TS energetics, enlarging their energy gap and thereby promoting the inv-SN2 mechanism. When more CH3OH molecules are bound to the base and forming a solvent cage, the initial interaction in the entrance channel induces desolvation and the first few solvent molecules are assumed to be crucial in controlling the reaction dynamics.17 The differential solvation of the inv-SN2 and anti-E2 barriers on the PES becomes more pronounced with stepwise addition of methanol, substantially stabilizing the SN2 transition state and accordingly suppressing E2 elimination. Further studies are underway, spanning a wide Ecoll range, to probe the dynamics of larger solvated F−(CH3OH)n clusters as well as the effects of other solvent molecules. This is the first case to our knowledge where atomistic dynamics convoluted with reaction energetics clearly reveal how single solvent molecules affect the mechanistic details for competing substitution versus elimination and determine reaction selectivity. The present results may shed light on one remarkable finding in experiments that the gas-phase reactions 11003

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(12) Eyet, N.; Villano, S. M.; Kato, S.; Bierbaum, V. M. J. Am. Soc. Mass Spectrom. 2007, 18, 1046−1051. (13) Hierl, P. M.; Ahrens, A. F.; Henchman, M.; Viggiano, A. A.; Paulson, J. F.; Clary, D. C. J. Am. Chem. Soc. 1986, 108, 3142−3143. (14) Doi, K.; Togano, E.; Xantheas, S. S.; Nakanishi, R.; Nagata, T.; Ebata, T.; Inokuchi, Y. Angew. Chem., Int. Ed. 2013, 52, 4380−4383. (15) Otto, R.; Brox, J.; Trippel, S.; Stei, M.; Best, T.; Wester, R. Nat. Chem. 2012, 4, 534−538. (16) Xie, J.; Otto, R.; Wester, R.; Hase, W. L. J. Chem. Phys. 2015, 142, 244308. (17) Liu, X.; Xie, J.; Zhang, J. X.; Yang, L.; Hase, W. L. J. Phys. Chem. Lett. 2017, 8, 1885−1892. (18) Wladkowski, B. D.; Brauman, J. I. J. Am. Chem. Soc. 1992, 114, 10643−10644. (19) Gronert, S.; Fagin, A. E.; Wong, L. J. Am. Chem. Soc. 2007, 129, 5330−5331. (20) Gronert, S.; Fagin, A. E.; Okamoto, K.; Mogali, S.; Pratt, L. M. J. Am. Chem. Soc. 2004, 126, 12977−12983. (21) Yang, L.; Zhang, J. X.; Xie, J.; Ma, X. Y.; Zhang, L. Y.; Zhao, C. Y.; Hase, W. L. J. Phys. Chem. A 2017, 121, 1078−1085. (22) Fukui, K. Acc. Chem. Res. 1981, 14, 363−368. (23) Sun, L.; Song, K.; Hase, W. L. Science 2002, 296, 875−878. (24) de Souza, M. A. F.; Correra, T. C.; Riveros, J. M.; Longo, R. L. J. Am. Chem. Soc. 2012, 134, 19004−19010. (25) Eyet, N.; Melko, J. J.; Ard, S. G.; Viggiano, A. A. Int. J. Mass Spectrom. 2015, 378, 54−58. (26) Bickelhaupt, F. M.; Baerends, E. J.; Nibbering, N. M. M. Chem. - Eur. J. 1996, 2, 196−207. (27) U.S. Environmental Protection Agency, Water Quality Regulatory Programs in the Clean Water Act: Toxic and Priority Pollutants, 2013. http://water.epa.gov/scitech/methods/cwa/ pollutants.cfm (accessed November 30, 2013). (28) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry; Plenum Press: New York, 1984; Part A. (29) Bickelhaupt, F. M.; Baerends, E. J.; Nibbering, N. M. M.; Ziegler, T. J. Am. Chem. Soc. 1993, 115, 9160−9173. (30) Cramer, C. J. Essentials of Computational Chemistry - Theories and Models, 2nd ed.; Wiley: New York, 2004. (31) Bento, A. P.; Sola, M.; Bickelhaupt, F. M. J. Chem. Theory Comput. 2008, 4, 929−940. (32) Zhao, Y.; Truhlar, D. G. J. Chem. Theory Comput. 2010, 6, 1104−1108. (33) Hu, W. P.; Truhlar, D. G. J. Am. Chem. Soc. 1995, 117, 10726− 10734. (34) Peterson, K. A.; Shepler, B. C.; Figgen, D.; Stoll, H. J. Phys. Chem. A 2006, 110, 13877−13883. (35) Sun, L.; Hase, W. L. Rev. Comput. Chem. 2003, 19, 79−146. (36) Lourderaj, U.; Sun, R.; Kohale, S. C.; Barnes, G. L.; de Jong, W. A.; Windus, T. L.; Hase, W. L. Comput. Phys. Commun. 2014, 185, 1074−1080. (37) Valiev, M.; Bylaska, E. J.; Govind, N.; Kowalski, K.; Straatsma, T. P.; van Dam, H. J. J.; Wang, D.; Nieplocha, J.; Apra, E.; Windus, T. L.; de Jong, W. A. Comput. Phys. Commun. 2010, 181, 1477−1489. (38) Lemmon, E.; McLinden, M.; Friend, D.; Linstrom, P.; Mallard, W. NIST Chemistry WebBook; National Institute of Standards and Technology: Gaithersburg, MD, 2011. (39) Ruscic, B. Active Thermochemical Tables (ATcT); ATcT.anl.gov, 2016 (40) Ensing, B.; Laio, A.; Gervasio, F. L.; Parrinello, M.; Klein, M. L. J. Am. Chem. Soc. 2004, 126, 9492−9493. (41) Depuy, C. H.; Gronert, S.; Mullin, A.; Bierbaum, V. M. J. Am. Chem. Soc. 1990, 112, 8650−8655. (42) Lopez, J. G.; Vayner, G.; Lourderaj, U.; Addepalli, S. V.; Kato, S.; Dejong, W. A.; Windus, T. L.; Hase, W. L. J. Am. Chem. Soc. 2007, 129, 9976−9985. (43) Jeffrey, G. A. An Introduction to Hydrogen Bonding; Oxford University Press: Oxford, 1977. (44) Mugnai, M.; Cardini, G.; Schettino, V. J. Phys. Chem. A 2003, 107, 2540−2547.

are governed by E2 in general, while SN2 prevails for dynamics in solution.26,28,29

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b04529. Stationary point energies with various methods, potential energy curves, structural views (PDF) Video S1 (AVI) Video S2 (AVI) Video S3 (AVI) Video S4 (AVI) Video S5 (AVI) Video S6 (AVI) Video S7 (AVI) Video S8 (AVI)

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AUTHOR INFORMATION

Corresponding Authors

*[email protected] *[email protected] *[email protected] ORCID

Jiaxu Zhang: 0000-0002-3125-7824 Li Yang: 0000-0002-0143-3524 William L. Hase: 0000-0002-0560-5100 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work is supported by the National Natural Science Foundation of China (no. 21573052), the Fundamental Research Funds for the Central Universities, China, the Natural Science Foundation of Heilongjiang Province of China (no. B2017003), the Open Project of Beijing National Laboratory for Molecular Sciences (no. 20150158), and Robert A. Welch Foundation under grant no. D-0005. Support is also provided by the High Performance Computing Center (HPCC) at Texas Tech University, under the direction of Alan Sill.

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