How a Solvent Molecule Affects Competing Elimination and

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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., Just Accepted Manuscript • DOI: 10.1021/jacs.8b04529 • Publication Date (Web): 03 Jul 2018 Downloaded from http://pubs.acs.org on July 3, 2018

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Journal of the American Chemical Society

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

Xu Liu,a Jiaxu Zhang,*,a Li Yang,*,a and William L. Hase*,b

a

State Key Laboratory of Advanced Welding and Joining, School of Chemistry and

Chemical Engineering, Harbin Institute of Technology, Harbin 150001, P. R. China

b

Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas 79409, USA

Author E-mail Address: [email protected], [email protected], [email protected]

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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.

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I. 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 Gas-phase 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).

Scheme 1. SN2 and E2 reaction pathways

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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 non-equilibrium solvation 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

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species (Scheme 1). Accordingly, a number of logical and novel approaches,18 i.e., 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 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

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formation of bare Br-, but selectivity of the SN2 vs 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). 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 near-thermal 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

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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 room temperature 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.

II. 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

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theory (WFT)-based MP2 as well as density function theory (DFT) methods30 paired with 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, i.e. 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 ion-molecule reactions involving competing nucleophilic displacement and elimination pathways.6,24,31,32 For the ECP/d basis,17 the Wadt and Hay effective core potential (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 pseudo-potential (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

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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

III. Results A. 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

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dynamics simulations reported here, is characterized in Figure 1. The energies mirror quite well those of the more demanding CCSD(T) theory.

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 zero-point energy (ZPE). Numbers in parentheses include ZPE, compared with experimental data38,39 in square brackets.

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

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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 postreaction 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 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 H-shift 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 (retSN2) 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 characterize 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 synE2 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

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proposed as ret-SN2

How a Solvent Molecule Affects Competing Elimination and

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