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Examining Ionic Liquid Effects on Mononuclear Rearrangement of Heterocycles using QM/MM Simulations Caley R Allen, Robel Ghebreab, Brian Doherty, Bin Li, and Orlando Acevedo J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.6b07205 • Publication Date (Web): 03 Oct 2016 Downloaded from http://pubs.acs.org on October 7, 2016

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The Journal of Physical Chemistry

Revised version 9/9/16

Examining Ionic Liquid Effects on Mononuclear Rearrangement of Heterocycles using QM/MM Simulations Caley Allen, Robel Ghebreab, Brian Doherty, Bin Li, and Orlando Acevedo* Department of Chemistry, University of Miami, Coral Gables, Florida 33146 E-mail: [email protected]; Telephone: (305) 284-5662 Submitted July 18, 2016 Abstract: The mononuclear rearrangement of heterocycles (MRH) reaction of the Zphenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole into 4-benzoylamino-2,5-diphenyl1,2,3-triazole derives a sizable rate enhancement in the 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4] ionic liquid as compared to the hexafluorophosphate-based [BMIM][PF6] and conventional organic solvents. However, the origin of the rate difference between [BMIM][BF4] and [BMIM][PF6] has proven difficult to rationalize as no experimental trend relates the physical properties of the solvents, e.g., polarity and viscosity, to the rates of reaction. QM/MM calculations in combination with free-energy perturbation theory and Monte Carlo sampling have been carried out for the MRH reaction to elucidate the disparities in rates when using ionic liquids, methanol, and acetonitrile. Activation barriers and solute-solvent interactions have been computed for both an uncatalyzed and a specific base-catalyzed mechanism. Energetic and structural analyses determined that favorable π+−π interactions between the BMIM cation, the substrate phenyl rings, and the bicyclic quasi-aromatic 10π oxadiazole/triazole transition state region imposed a pre-ordered geometric arrangement that enhanced the rate of reaction. An ionic liquid clathrate formation enforced a coplanar orientation of the phenyl rings that maximized the electronic effects exerted on the reaction route. In addition, site-specific electrostatic stabilization between the ions and the MRH substrate was more prevalent in [BMIM][BF4] as compared to [BMIM][PF6].

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Introduction The mononuclear rearrangement of heterocycles (MRH) reaction (also called the Boulton-Katritzky rearrangement) has been a historically efficient method for synthesizing fivemembered heteroaromatic rings.1-5 Heterocycles containing nitrogen atoms are critical in many areas of chemistry including synthesis, medicinal efforts, and materials; extensive reviews are available.6-11 Of specific interest is the MRH of the Z-phenylhydrazone of 3-benzoyl-5-phenyl1,2,4-oxadiazole into 4-benzoylamino-2,5-diphenyl-1,2,3-triazole (Scheme 1) reported by D’Anna and coworkers.12 The MRH reaction’s ring-to-ring interconversion mechanism represents a special case of SN2 displacement that proceeds via an intramolecular nucleophilic substitution (SNi) reaction that features a bicyclic quasi-aromatic 10π transition state.12-19

Scheme 1. Mononuclear rearrangement of heterocycles (MRH) for the Z-phenylhydrazone of 3benzoyl-5-phenyl-1,2,4-oxadiazole into 4-benzoylamino-2,5-diphenyl-1,2,3-triazole. Solvent effects play a significant role in the rearrangement as substantial rate accelerations have been reported when increasing the polarity of the solvent. Intriguingly, the room temperature ionic liquid 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4] was reported to have the highest rate of reaction when compared to conventional organic solvents.12,20 While tempting to attribute a single solvent property, i.e. polarity, to the observed rate

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enhancement, this explanation is often error prone when applied to the molten salts.21,22 For example, the MRH of Z-phenylhydrazone was reported to have a slower rate of reaction in the ionic liquid [BMIM][PF6] compared to methanol, acetonitrile and [BMIM][BF4]. As a quantitative measure of polarity, the two ionic liquids [BMIM][PF6] and [BMIM][BF4] have comparable polarizability (π*) values of 1.032 and 1.047,23 respectively, despite a two orders of magnitude difference in the rate constant.12 In addition, the ETN value for [BMIM][BF4] is lower than that of methanol, 0.670 versus 0.762,23,24 respectively, despite the reaction proceeding faster in the ionic liquid. Kinetic analysis of the MRH reaction in multiple solvent types, e.g. polar protic, polar aprotic, and nonpolar aprotic, suggests a solvent dependence on the reaction pathway as well.12,25-27 For conventional polar solvents, such as acetonitrile or methanol, rearrangement of Zphenylhydrazone using piperidine as the base occurred with different kinetic laws. This implies a combination (or competition) between a base-catalyzed (specific or general) and an uncatalyzed mechanism (Scheme 2).24 In contrast, MRH reactions in low polarity solvents, e.g. benzene, 1,4dioxane, and ethyl acetate, proceeded exclusively via a base-catalyzed pathway. Performing the reaction in a dioxane/water mixture highlighted a potential mechanism difference dependent upon the proton concentration.15 For example, the MRH reaction (where R = H in Scheme 2) found an uncatalyzed pathway within a pS+ range of 3.8-7.0 (an operational scale of proton concentration in the mixed solvent). At a pS+ ≥ 8.0, a base-catalyzed pathway is believed to dominate.15 Density functional theory (DFT) calculations lent further support to the solvent dependence; a supermolecule approach was employed that complexed two explicit water molecules to the transition state in order to reproduce experimental activation energies.15



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Scheme 2. Transition states for the uncatalyzed and the specific and general base-catalyzed mechanisms in the MRH reaction of the Z-phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4oxadiazole (R = Ph).

The MRH reaction (Scheme 1) in the [BMIM][BF4] ionic liquid showed a simple firstorder dependence on piperidine concentration as compared to a mixed first- and second-order dependence for the conventional solvents.12,20 Intriguingly, only a small variation in reactivity was experimentally observed when changing bases, e.g. butylamine, piperidine, and triethylamine, in multiple ionic liquids. Previous work on bimolecular bond-forming reactions has shown a link between the rates of reactions and solvent viscosity, particularly when other solvent properties such as polarity cannot account for the results.28 Ionic liquids are known to be quite viscous; however, experimental data by D’Anna and coworkers on the current MRH reaction did not find good agreement between viscosity and reactivity in the ionic liquids.12 Several more hypotheses have been put forward regarding the ionic liquids influence on the reactivity of the MRH reaction, including an organizing ability derived from π+-π interactions and the chemical nature of the cations and anions. Atomic-level simulations, featuring hundreds of ionic liquid ions interacting with the MRH reaction, should help clarify many of the


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contradictions experimentally observed for the reactivity in the molten salts as compared to conventional solvents. Mixed quantum and molecular mechanical (QM/MM) calculations utilizing Monte Carlo statistical mechanics and free-energy perturbation theory (MC/FEP) have been carried out for the Z-phenylhydrazone rearrangement of 3-benzoyl-5-phenyl-1,2,4-oxadiazole (Scheme 1) in [BMIM][BF4], [BMIM][PF6], acetonitrile, and methanol. Activation barriers and solute-solvent interactions have been computed for the uncatalyzed and specific base-catalyzed mechanisms (Scheme 2) to further explore the effect of solvent upon MRH reaction. This work provides new insights into solvent effects for both conventional organic solvents and ionic liquids upon the rates and reactivity of MRH reactions used to create important five-membered heteroaromatic rings.

Computational Methods QM/MM Method. QM/MM calculations were carried out for the MRH reaction in [BMIM][BF4], [BMIM][PF6], acetonitrile, and methanol. The solutes were treated with the PDDG/PM3 semiempirical QM,29 which has given excellent results for a wide variety of condensed-phase organic reactions.30-33 Potentials of mean force (PMF) calculations coupled to Metropolis Monte Carlo (MC) statistical mechanics were used to build a free-energy profile for the rearrangement reactions at 25 °C and 1 atm. The solvents were represented explicitly using our custom ionic liquid OPLS-AA force field34 and the united-atom OPLS force field for methanol35 and acetonitrile.36 In the current QM/MM methodology, the systems consisted of the reactants plus 395 conventional solvent molecules or 188 ion pairs for the ionic liquids. The



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boxes are periodic and tetragonal with long-range electrostatic interactions handled with Ewald summations. Solutes were inserted into the fully equilibrated ionic liquid boxes and reequilibrated for up to 100 million MC configurations. The computation of the QM energy and atomic charges is performed for each attempted move of the solute, which occurred every 100 configurations. For electrostatic contributions to the solute-solvent energy, CM3 charges37 were obtained for the solute with a scaling factor of 1.14 for neutral molecules38 and unscaled for charged species. In addition, Lennard-Jones interactions between solute and solvent atoms were taken into account using OPLS parameters. The simulations were performed with the BOSS program.39 The [BMIM] cations were fully flexible, i.e. all bond stretching, angle bending, and torsional motions were sampled. The anions were simulated as rigid. The use of rigid anions in OPLS-AA has been shown to provide an accurate representation of ionic liquid physical properties,33 including use as a reaction medium for computed QM/MM Diels-Alder,40 Kemp elimination,34 β-elimination,41 and SNAr42 reaction studies. Solute-solvent and solvent-solvent intermolecular cutoff distances of 12 Å were employed for the tail carbon atom of each side chain (methyl and alkyl), a midpoint carbon on the alkyl chain, and the ring carbon between both nitrogens for imidazolium. Center atoms, e.g., B in BF4-, were used for the anions. If any distance is within the cutoff, the entire solvent-solvent interaction was included. Adjustments to the allowed ranges for rotations, translations, and dihedral angle movements led to overall acceptance rates of about 30% for new configurations. The ranges for bond stretching and angle bending were set automatically by the BOSS program on the basis of force constants and temperature. Density Functional Theory. The transition structures for the MRH reaction were also computed with M06-2X/6-311+G(d,p) geometry optimizations using Gaussian 09.43 The effect 6 ACS Paragon Plus Environment

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of solvent was explored by using the conductor-like polarizable continuum model (CPCM) with the UFF cavity.44 Frequency calculations were performed in order to verify all stationary points as minima for ground states or as saddle points for transition structures. All calculations were run on computers located at the University of Miami and at the Alabama Supercomputer Center.

Results and Discussion Free energy maps were computed using the QM/MM MC/FEP methodology for both the specific base-catalyzed and uncatalyzed reaction pathways (Scheme 2) to identify the minima and the transition states. The ∆G‡ for the MRH reaction was computed by perturbing the bond distances between the nucleophilic nitrogen atom and the nitrogen in the oxadiazole ring denoted RNN using 0.025 Å increments and a second perturbation was necessary, RNO, which entailed the breaking of the oxadiazole ring at the N–O bond in 0.005 Å increments (see Figure 1). Combining the RNN PMF, which runs along one reaction coordinate with the RNO PMF in a second direction produced a two-dimensional (2D) PMF. The computed transition structure RNO and RNN geometries (±0.03 Å error) for the solvated MRH reactions are provided in Table 1. No major solvent dependence was found in either mechanism for the breaking/making distances involving the RNN nucleophilic attack with computed distance range of 1.90-1.99 Å in the ionic liquids and conventional solvents. The opening of the 1,2,4-oxadiazole ring, RNO, was also found to vary somewhat in distance when comparing the uncatalyzed and base-catalyzed mechanisms, and when changing solvents; however, the computed differences in RNO were generally small with a range of 1.73-1.84 Å (Table 1).



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Each 2D-PMF calculation required extensive reorganization of the solvent for the ionic liquids with 60-80 million configurations of equilibration followed by 20 million MC steps of averaging per FEP window. However, 5 and 10 million MC configurations of equilibration and averaging, respectively, sufficed for the methanol and acetonitrile simulations. Uncertainties in the free energy barriers were calculated by propagating the standard deviation (σi) on each individual ∆Gi. Smooth free energy profiles were obtained with statistical uncertainties (σi) of 0.01-0.03 kcal/mol in each window; thus, implying overall uncertainties in the ∆G‡ of ca. 0.4 kcal/mol for the conventional solvents. The error bars in the ionic liquids simulations are estimated at ± 1 kcal/mol. The QM/MM MC/FEP calculated ∆G‡ values for the MRH reactions in methanol, acetonitrile, [BMIM][BF4] and [BMIM][PF6] are provided in Table 2.

Figure 1. Reaction coordinates RNN and RNO for the specific base-catalyzed MRH reaction of the Z-phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole.


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Table 1. QM/MM Calculated RNO and RNN Transition Structure Bond Distances (Å) for the MRH of the Z-phenylhydrazone of 3-Benzoyl-5-phenyl-1,2,4-oxadiazole in Solution.a

Catalyzed Uncatalyzed a

CH3OH RNO RNN

CH3CN RNO RNN

[BMIM][BF4] RNO RNN

[BMIM][PF6] RNO RNN

1.73 1.74

1.76 1.78

1.84 1.73

1.80 1.76

1.99 1.90

1.95 1.93

1.98 1.95

1.98 1.95

PDDG/PM3/OPLS-AA and MC/FEP.

The MRH reaction in the [BMIM][BF4] and [BMIM][PF6] ionic liquids gave computed ∆G‡ values of 19.0 and 20.4 kcal/mol, respectively, for the specific base-catalyzed pathway and 30.8 and 31.8 kcal/mol for the uncatalyzed pathway. For both proposed MRH reaction mechanisms, the BF4-based ionic liquid is predicted to have a lower activation barrier compared to PF6, which is consistent with experiment. For example, experimental ∆G‡ values of 20.6, 21.3, and 21.4 kcal/mol for the MRH reaction in [BMIM][BF4] were reported when utilizing piperidine (Pip), triethylamine (TEA), and butylamine (BuA), respectively.12 Accordingly, larger ∆G‡ energies for the same Pip, TEA, and BuA bases were reported in [BMIM][PF6], i.e., 22.7, 22.6, and 23.8 kcal/mol.12 Base effects are subtle for the MRH reaction in ionic liquids as the experimental ratios of reactivity are 1:1.2:4.1 for BuA/TEA/Pip in [BMIM][BF4], respectively.12 When the mechanism is believed to be general base-catalyzed, i.e., low polarity solvents,27 a much larger reactivity range was observed, for example, in benzene at 313.1 K gave ratios of 1:66:188 for BuA/TEA/Pip.12,20 This may imply that the uncatalyzed mechanism is dominant in ionic liquids over the base-catalyzed route (Scheme 2) as differences in basicity between primary vs. secondary vs. tertiary amines should have a larger effect upon the rates. However,



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enhancement of the amines’ basicity through decreased solvation in the ionic liquids has been reported and may play a key role.20,42,45

Table 2. Free Energies of Activation, ∆G‡ (kcal/mol), at 25 °C for the MHR of the Zphenylhydrazone of 3-Benzoyl-5-phenyl-1,2,4-oxadiazole in Solution.a ∆G‡ Catalyzed Uncatalyzed Exptl. a

CH3OH

CH3CN

20.7 30.1 23b

20.4 29.6 22b

[BMIM][BF4] [BMIM][PF6] 19.0 30.8 20.6c

20.4 31.8 22.7c

PDDG/PM3/OPLS-AA and MC/FEP. bEstimated using rate constants from piperidine-catalyzed

MRH reaction at 40 °C and the Eyring equation.12 cPiperidine-catalyzed MRH reaction at 25 °C.12 The QM/MM MC/FEP computed ∆G‡ for the specific base-catalyzed reaction in CH3OH and CH3CN were 20.7 and 20.4 kcal/mol, respectively, which is comparable to the [BMIM][PF6] activation barrier and greater than in [BMIM][BF4] as reported experimentally.12 The absolute activation free energies for the uncatalyzed mechanism in CH3OH and CH3CN, i.e., ∆G‡ of 30.1 and 29.6 kcal/mol, were once again larger compared to the specific base-catalyzed route. It should be noted that the reported rate in methanol, which is similar to [BMIM][PF6], might be attributed in part to the catalytic effect of methoxide ion, which was significantly present in the basic solution.12 For example, the first-order kinetic rate constant, ka, reported for the MRH reaction in CH3OH (Equation 1) depended on both the concentration of piperidine and methoxide ion.27 This may indicate a competition between two mechanisms, i.e., uncatalyzed and base-catalyzed, as the strong base CH3O- is readily capable of abstracting the proton prior to 10 ACS Paragon Plus Environment

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the nucleophilic attack in the specific base-catalyzed route, but the highly polar nature of CH3OH should provide a significant contribution from the uncatalyzed pathway. ka = ku + kII[Pip] + kMeO[CH3O-]

(1)

Density functional theory calculations were carried out using the M06-2X/6-311+G(d,p) method in methanol and acetonitrile by using the CPCM continuum solvent method. Table 3 provides the DFT/CPCM computed transition structure distances for RNO and RNN and ∆G‡ values for the specific base-catalyzed mechanism. The calculated free energies of activation for the MRH reaction were identical in both methanol and acetonitrile, i.e., 16.9 kcal/mol, and were underestimated relative to experimental values of approximately 23 and 22, respectively (Table 2). The inability of continuum solvent models to differentiate rates when comparing protic and aprotic solvents has been reported for a wide variety of chemical reactions.30,31 A gas-phase DFT mechanistic study of a MHR featuring the Z-hydrazones of 3-acyl-1,2,4-oxadiazoles (R=H instead of R=Ph in Scheme 2) was reported by Bottoni et al. and predicted an activation barrier of 34.2 kcal/mol for the uncatalyzed nucleophilic attack.15 A supermolecule approach of including two discrete water molecules in the transition state calculation that participate via proton transfers lowered the barrier to 26.1 kcal/mol. Bottoni et al. concluded that the rearrangement should proceed through a concerted, asynchronous path where the nucleophilic attack of the hydrazonic nitrogen onto the oxadiozolic nitrogen and a water promoted proton shuffle from the hydrazonic nitrogen occur in the same kinetic step, but not simultaneously.



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Table 3. M06-2X/6-311+G(d,p)/CPCM Computed Free Energies of Activation, ∆G‡ (kcal/mol), and Transition Structure Geometries (Å) at 25 °C for the Specific Base-catalyzed MHR of the Zphenylhydrazone of 3-Benzoyl-5-phenyl-1,2,4-oxadiazole. Catalyzed CH3OH CH3CN

∆G‡ (calc.) 16.9 16.9

RNO 1.81 1.81

RNN 2.10 2.10

The origin of the lower ∆G‡ for the MRH in [BMIM][BF4] compared to [BMIM][PF6] has proven difficult to rationalize as no experimental trend relates the physical properties of the solvents, e.g., polarity and viscosity, to the observed rate enhancement. However, π+−π interactions may play a large role as it has been postulated that π-stacking between the BMIM cation and the aromatic rings on 3-benzoyl-5-phenyl-1,2,4-oxadiazole may impose a pre-ordered geometric arrangement that enhances the rate of reaction.12 Specifically, a coplanar orientation of the phenyl rings at the transition state should maximize the electronic effects exerted on the reaction route, similar to previous ionic liquid studies of a base-induced β-elimination reaction and an SNAr reaction.41,42 The potential π+−π stacking of the MRH substrate phenyl rings and BMIM cations was monitored over the final 20 million MC steps of the simulation by using combined distribution functions (CDF)46,47 that monitor the angle between a reference normal vector from the plane of the phenyl group and the vector between the geometrical centers of the phenyl and imidazolium rings as a function of the distance between the cation and the substrate. Angles near to 0 or 180 degrees indicate that the imidazolium ring and the phenyl ring are stacked parallel to one another. All BMIM-phenyl CDF plots in [BMIM][BF4] and [BMIM][PF6] are given in Supporting Information Figures S2-S13 for the specific base-catalyzed and


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uncatalyzed mechanisms and the ground states and transition states. The CDF plots highlight the significant π+−π stacking occurring in the ionic liquids throughout the MRH reaction. It should be noted that the OPLS-AA force field has been reported to yield excellent agreement with experiment for computed benzene dimer interaction energies and geometries in the gas and liquid phase.48 Molecular dynamics simulations were performed by Fu and Tian on liquid benzene using eight potentials consisting of Lennard-Jones and Coulomb terms and they recommended the OPLS-AA as the best model based on agreement with high-resolution neutron diffraction data.49 Takeuchi also found the OPLS-AA force field to be more reliable than MP2 calculations in reproducing the structures of benzene clusters consisting of up to 30 rings.50 To examine the coplanarity present in the substrate as a consequence of both the π+−π stacking and a cage-like liquid clathrate structure similar to experimental reports of liquid clathrate formation in 1-alkyl-3-methylimidazolium-based ionic liquids with aromatic compounds,51 dihedral angle distributions for the solute phenyl rings were monitored over the final 20 million configurations of the QM/MM MC/FEP simulations for both the specific basecatalyzed and uncatalyzed reactants and transition structures. Examining the three dihedral angles, φ1 = C-C-C-N, φ2 = C-C-C-C, and φ3 = N-N-C-C (see Figures 2 and 3 for definition), for the specific base-catalyzed reactant in [BMIM][BF4] finds the three phenyl rings to be relatively planar, i.e., approximately 0 or 180 degrees, with distribution peaks for φ1, φ2, and φ3 ranging from 0-30 degrees; the transition structure dihedral angles become less planar with the distribution peaks at 50-60 degrees for φ1 and φ2. Figure 2 shows the specific base-catalyzed transition structure in [BMIM][PF6] to be overall less planar than in the [BMIM][BF4] ionic liquid, particularly for the φ1 and φ2 dihedral angles. The same general trend in planarity, i.e., more prevalent coplanarity in BF4 over PF6 ionic liquids, is found for the uncatalyzed route when 13 ACS Paragon Plus Environment


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comparing dihedral angle distribution plots between the reactants and transition structures (Figure 3). This suggests that favorable π+−π interactions between BMIM and phenyl rings may induce a more constructive reaction orientation in the BF4 ionic liquid prior to nucleophilic attack and may therefore help enhance the rate relative to PF6.


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Figure 2. Dihedral distribution plots for the specific base-catalyzed MRH reaction ground state (GS) and transition state (TS) in the ionic liquids. Definition of torsion angles φ1 = C-C-C-N (magenta), φ2 = C-C-C-C (red), and φ3 = N-N-C-C (blue).



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Figure 3. Dihedral distribution plots for the uncatalyzed MRH reaction ground state (GS) and transition state (TS) in the ionic liquids. Definition of torsion angles φ1 = C-C-C-N (magenta), φ2 = C-C-C-C (red), and φ3 = N-N-C-C (blue). 16 ACS Paragon Plus Environment

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In addition to the favorable π+−π interactions between the BMIM cation and the phenyl substituents, π-stacking between BMIM and the bicyclic quasi-aromatic 10π oxadiazole/triazole reacting region should help stabilize the transition state. The orientation of the imidazolium ring with respect to the 10π bicyclic region was assessed by using combined distribution functions that monitor the angle between the normal vector across the oxadiozolic nitrogen and oxygen atoms and the distance between the oxadiozolic N and the geometrical center of BMIM as a function of the distance between the cation and the substrate (Figure 4). Angles near to 0 or 180 degrees indicate that the imidazolium ring and the substrate transition state are stacked parallel to one another. Figure 4 shows significant π+−π stacking occurring between BMIM and the transition structure for the uncatalyzed mechanism in both [BMIM][BF4] and [BMIM][PF6] with an approximate distance of 4.5 Å and an angle near 0°. The specific base-catalyzed mechanism finds π+−π stacking to be present, but not as pronounced as in the uncatalyzed route (Figure 5), suggesting that the full negative charge on the substrate may be better stabilized by specific sitedirected electrostatic interactions with the cation protons.



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Figure 4. Angle (θ) between the normal to the oxadiazole N and O atoms and the line connecting the oxadiazole nitrogen to the geometric ring center of a given imidazolium ring as a function of the distance (r) between BMIM and the substrate transition structure for the uncatalyzed MRH reaction in [BMIM][BF4] (left) and [BMIM][PF6] (right).


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Figure 5. Angle between the normal to the oxadiazole N and O atoms and the line connecting the oxadiazole nitrogen to the geometric ring center of a given imidazolium ring as a function of the distance between BMIM and the substrate transition structure for the specific base-catalyzed MRH reaction in [BMIM][BF4] (left) and [BMIM][PF6] (right).

The distance between the most acidic proton on the BMIM cation, that is, the H located on the 2-position carbon atom bisecting the nitrogen atoms on the imidazolium ring (pKa = 2123),52,53 and the hydrazonic nitrogen, oxadiozolic nitrogen, and oxadiozolic oxygen atoms on the MRH substrate were monitored over the course of the reaction. Radial distribution functions for the ground and transition states from both the specific base-catalyzed and uncatalyzed reaction mechanisms in [BMIM][BF4] and [BMIM][PF6] are reported in Figures 6 and 7. In addition, 19 ACS Paragon Plus Environment


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substrate interactions with the H4 and H5 protons directly attached to the imidazolium carbon ring atoms nearest the side-chains N-butyl and N-methyl, respectively, were also examined (Supporting Information Figures S14-S17). For the specific base-catalyzed reaction in [BMIM][BF4], the most acidic proton on BMIM (labeled H1) gives large peaks centered around 250 pm with the negatively charged hydrazonic nitrogen (N2) atom and the oxadiozolic nitrogen (N1) atom at the ground state. At the transition state the electron density shifts to the oxadiozolic oxygen (O1) and, as a result, a large radial distribution peak forms between H1-O1 as the ionic liquid organizational structure adjusts to stabilize the change in electron distribution. Concurrently, the H1-N2 peak is diminished for the base-catalyzed transition state giving a smaller peak centered at 370 pm, reflecting the reduction in negative charge (Figure 6). The uncatalyzed mechanism in [BMIM][BF4] gives radial distribution functions that greatly differ from the specific base-catalyzed route since the uncatalyzed path begins as a neutral reactant, but forms a charge separated transition structure with a partial positive charge on N2 and a partial negative charge on O1 (Figure 7). Accordingly, the large radial distribution peak centered around 310 pm for the uncatalyzed H1-N2 ground state shifts at the transition state to a distance of 500 pm with a much smaller peak as the N2 becomes more positively charged. The small H1-O1 peak centered around 360 pm for the [BMIM][BF4] ground state becomes much larger and distance decreases to 280 pm as negative charge develops on O1 at the transition structure (Figure 7).


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Figure 6. Radial distribution functions in [BMIM][BF4] (left) and [BMIM][PF6] (right) for the specific base-catalyzed MRH ground and transition states between the most acidic proton on BMIM and the oxadiozolic oxygen (H1-O1, black), oxadiozolic nitrogen (H1-N1, blue), and hydrazonic nitrogen (H1-N2, red).



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Figure 7. Radial distribution functions in [BMIM][BF4] (left) and [BMIM][PF6] (right) for the uncatalyzed MRH ground and transition states between the most acidic proton on BMIM and the oxadiozolic oxygen (H1-O1, black), oxadiozolic nitrogen (H1-N1, blue), and hydrazonic nitrogen (H1-N2, red).


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The radial distribution functions for the MRH reactant and transition state in [BMIM][PF6] are given in Figures 6 and 7 for H1 and the Supporting Information Figures S14S17 for H4 and H5. Visual inspection of the plots finds dramatically smaller peaks between the H1 atom in BMIM and the heterocycle O and N atoms as compared to [BMIM][BF4] for both mechanisms. This suggests that the PF6 anion severely weakens the favorable BMIM electrostatic interactions provided to the transition state. To better assess the solute-solvent interactions occurring over the course of the MRH reaction, nearest neighbor distributions were computed between the H1, H4, and H5 protons and the substrate O1, N1, and N2 atoms (Table 4 and Supporting Information Figures S20-S25). These distributions monitor the distance between the closest cation/anion and the substrate over the final 20 million MC steps. Consistent with the radial distribution functions, the average neighbor distances find much tighter interactions between BMIM and substrate in the BF4 ionic liquid as compared to PF6. Typical distances between the H1 atom and the O1, N1, and N2 atoms are 1 – 2 Å closer in the [BMIM][BF4] and are indicative of greater electrostatic stabilization, particularly at the transition state (Table 4). Figure 8 shows a nearest neighbor distribution plot highlighting the distances between BMIM ring protons and the oxadiozolic oxygen on the MRH substrate for the uncatalyzed transition state. Notably, the [BMIM][BF4] ionic liquid interacts with the transition structure primarily via the most acidic BMIM proton H1, whereas the less acidic H4 proton interaction is dominant in the [BMIM][PF6] solvent (Figure 8).



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Table 4. Average Distance (Å) Calculated using a Nearest Neighbor Distribution Between the Acidic Proton (H1) in BMIM, Boron (B) in BF4, or Phosphorous (P) in PF6 and the Oxadiozolic Oxygen (O1), Oxadiozolic Nitrogen (N1), and Hydrazonic Nitrogen (N2) from the MRH reaction mechanisms.a [BMIM][BF4] H1-O1 H1-N1 H1-N2 3.6 ± 0.2 2.7 ± 0.2 2.7 ± 0.2 3.0 ± 0.3 2.9 ± 0.2 3.7 ± 0.2 H4-O1 H4-N1 H1-N2 GS 4.9 ± 0.4 5.0 ± 0.3 3.8 ± 0.4 TS 4.4 ± 0.3 4.8 ± 0.2 3.8 ± 0.2 H5-O1 H5-N1 H1-N2 GS 4.2 ± 0.8 3.8 ± 0.5 3.1 ± 0.3 TS 2.9 ± 0.3 2.7 ± 0.2 3.4 ± 0.3 B-O1 B-N1 B-N2 GS 5.1 ± 0.4 5.9 ± 0.3 5.6 ± 0.3 TS 5.6 ± 0.3 5.5 ± 0.5 5.5 ± 0.2 a Uncatalyzed H1-O1 H1-N1 H1-N2 GS 4.1 ± 0.3 3.2 ± 0.3 3.2 ± 0.2 TS 3.0 ± 0.3 3.9 ± 0.3 5.2 ± 0.4 H4-O1 H4-N1 H1-N2 GS 4.0 ± 0.8 5.0 ± 0.7 6.7 ± 0.3 TS 4.8 ± 0.3 5.1 ± 0.3 5.3 ± 0.3 H5-O1 H5-N1 H1-N2 GS 3.5 ± 0.4 4.7 ± 0.4 6.1 ± 0.4 TS 3.6 ± 0.3 2.7 ± 0.2 3.0 ± 0.2 B-O1 B-N1 B-N2 GS 4.8 ± 0.3 5.2 ± 0.2 4.3 ± 0.3 TS 5.2 ± 0.2 5.5 ± 0.3 5.9 ± 0.3 a Ground state (GS) and transition state (TS).

Specific base-catalyzeda GS TS

H1-O1 5.6 ± 0.3 3.3 ± 0.3 H4-O1 3.4 ± 0.3 5.3 ± 0.5 H5-O1 4.6 ± 0.3 3.0 ± 0.5 P-O1 6.5 ± 0.2 5.8 ± 0.3 H1-O1 3.7 ± 0.3 5.2 ± 0.4 H4-O1 5.5 ± 0.4 2.7 ± 0.2 H5-O1 4.5 ± 0.3 3.9 ± 0.7 P-O1 5.2 ± 0.3 5.5 ± 0.2


[BMIM][PF6] H1-N1 5.0 ± 0.4 4.3 ± 0.3 H4-N1 3.3 ± 0.3 4.9 ± 0.4 H5-N1 3.6 ± 0.3 2.7 ± 0.2 P-N1 6.3 ± 0.3 5.8 ± 0.3 H1-N1 3.1 ± 0.4 4.9 ± 0.3 H4-N1 5.4 ± 0.4 3.3 ± 0.5 H5-N1 3.6 ± 0.3 3.4 ± 0.6 P-N1 5.6 ± 0.4 6.2 ± 0.2

H1-N2 3.9 ± 0.4 3.7 ± 0.3 H4-N2 4.4 ± 0.3 4.7 ± 0.3 H5-N2 2.8 ± 0.2 3.0 ± 0.3 P-N2 6.3 ± 0.2 5.5 ± 0.3 H1-N2 3.7 ± 0.3 4.0 ± 0.3 H4-N2 5.0 ± 0.2 4.4 ± 0.5 H5-N2 2.8 ± 0.2 3.9 ± 0.4 P-N2 6.1 ± 0.3 6.3 ± 0.2

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Figure 8. Nearest neighbor distribution in [BMIM][BF4] (solid lines) and [BMIM][PF6] (dashed lines) for the uncatalyzed MRH transition states between the ring protons on BMIM (H1, H4, and H5) and the oxadiozolic oxygen (O1).



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Conclusions To summarize, QM/MM MC/FEP simulations were carried out for the MRH reaction of the Z-phenylhydrazone of 3-benzoyl-5-phenyl-1,2,4-oxadiazole into 4-benzoylamino-2,5diphenyl-1,2,3-triazole in multiple solvents. D’Anna and coworkers reported dramatic rate enhancements for the MRH in the ionic liquid reaction medium [BMIM][BF4] as compared to conventional organic solvents, including acetonitrile, methanol, and benzene.12,20 Intriguingly, [BMIM][BF4] also provided a two orders of magnitude rate increase when compared to the ionic liquid [BMIM][PF6] despite their physical similarities in polarity, viscosity, and cation composition. Consequently, our QM/MM methodology was applied to the MRH reaction following two different reaction mechanisms, i.e, uncatalyzed and specific base-catalyzed, to uncover the origin of the rate enhancement. The computed base-catalyzed route yielded lower absolute ∆G‡ energies, although both mechanisms predicted lower energy barriers in the [BMIM][BF4] solvent as compared to [BMIM][PF6], which is consistent with experimental rate trends for the MRH reaction. The π+−π interactions between the ionic liquid cation, BMIM, and the aromatic rings on 3-benzoyl-5-phenyl-1,2,4-oxadiazole have been hypothesized to impose a pre-ordered geometric arrangement that enhances the rate of reaction.12 Accordingly, structural analyses of the simulations using combined distribution functions for the angle and distance of BMIM to the MRH substrate phenyl rings and bicyclic 10π oxadiazole/triazole transition state region confirmed significant π+−π stacking and the formation of a cage-like liquid clathrate structure. Dihedral angle distributions found the MRH reactants and transition structures solvated by [BMIM][BF4] to have a greater coplanar orientation than in [BMIM][PF6], which should help maximize the electronic effects exerted on the reaction route. In addition, closer average distances between the most acidic protons on the BMIM cation and the hydrazonic nitrogen, 26 ACS Paragon Plus Environment

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oxadiozolic nitrogen, and oxadiozolic oxygen atoms were found in [BMIM][BF4] compared to [BMIM][PF6]. The larger PF6– anion appears to reduce the favorable site-specific stabilizing electrostatic interactions at the transition state relative to BF4–, which may be reflected in the larger experimental ∆H‡ values for the MRH in [BMIM][PF6].12 This work provides a better understanding into ionic liquid effects upon the rates and reactivity of MRH reactions used to create important five-membered heteroaromatic rings.

Acknowledgement. Gratitude is expressed to the National Science Foundation (CHE-1562205), Auburn University, and the Alabama Supercomputer Center for support of this research.

Supporting Information Available: Additional figures for combined distribution functions (CDFs); radial distribution functions; nearest neighbor distributions; DFT energies, frequencies, and coordinates of structures; and complete ref. 43. This material is available free of charge via the Internet at http://pubs.acs.org.

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