Oriented-External Electric Fields Create Absolute Enantioselectivity in

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Oriented-External Electric Fields Create Absolute Enantioselectivity in Diels−Alder Reactions: Importance of the Molecular Dipole Moment Zhanfeng Wang, David Danovich, Rajeev Ramanan, and Sason Shaik* Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel

J. Am. Chem. Soc. 2018.140:13350-13359. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/17/18. For personal use only.

S Supporting Information *

ABSTRACT: The manuscript studies the enantioselectivity and stereoselectivity of Diels−Alder (DA) cycloadditions between cyclopentadiene (CPD) and a variety of dienophiles (ranging from halo-ethenes to cyanoethenes), under oriented external electric fields (OEEFs). Applying OEEFs oriented in the X/Y directions, perpendicular to the reaction axis (Z), will achieve complete isomeric and enantiomeric discrimination of the products. Unlike the Z-OEEF, which involves charge-transfer from the diene to the dienophile, and thereby brings about catalysis due to increased intramolecular bonding, an OEEF along X, aligned parallel to the C1-C4 atoms of CPD, will lead to R/S enantiomeric discrimination by means of intramolecular-bond polarization. A Y field will discriminate endo/exo stereoisomers in a similar mechanism. The XY field-combination will resolve both R/S and endo/exo. The resolution is complete and can be achieved at will by flipping the direction of the field along the X and Y axes. The preconditions for achieving the enantiomeric and isomeric discrimination are discussed and require fixing of the CPD onto a surface. In so doing the chiral discrimination is achieved by dipole-moment selection rules, such that the field filters out one of the enantiomers, which is highly raised in energy by dipole selection. The dependence of the discrimination on the polarity of the dienophiles leads to a predictive trend. budding field. Earlier theoretical studies1a,3,10,12 provide a glimpse of the wide-ranging potential of OEEF for controlling chemical reactivity and selectivity. Recently, one of these predictions on the Diels−Alder reaction12a was supported in a STM-based experimental study,11 which resolved the dilemma of how to orient the reactants and simultaneously deliver the OEEF along the reaction axis. Our main focus in this manuscript is on the ability of OEEFs to induce enantioselectivity or chiral discrimination, which has become a grail ever since Pasteur13,14 had separated chiral isomers under the microscope. One of the unique prospects of using OEEFs is the ability to create different reactivity and selectivity effects, depending on the directionality of the field.10b,c,11,12,15 As such, we shall specify and formulate the conditions under which uniform OEEFs, which are by definition nonchiral, may still give rise to chiral discrimination and to other selectivity patterns. This articulation of the OEEF tool, is an important goal of theory, which can stimulate further experimentations. The target processes are the Diels−Alder (DA) cycloaddition between cyclopentadiene (CPD) and various substituted ethenes, which are outlined in Chart 1.

1. INTRODUCTION Controlling rate and selectivity of chemical reactions is a major goal in chemistry. Recently, the use of oriented-external electric fields (OEEFs) has been suggested as such means of control.1 Indeed, electric-fields (EFs) are known to bring about a range of effects by interacting with atoms, molecules, and complex matter.2,3 Nature, itself, has harnessed preoriented local-electric-fields (LEF)4 that are responsible for electrostatic catalysis in enzymes.2b,4,5 Furthermore, designed local-electricfields (D-LEFs)6,7 due to embedded6 and/or switchable charges,7 change reactivity, and selectivity,6a affect the dissociation energies of remote bonds7a and enhance H atom transfer (HAT)7b as well as Diels−Alder reactivities.7c Similarly, interfacial-electric-fields (IEF)8 and surface-charging9 induce reaction selectivity and favor a desired mechanism between alternatives. Furthermore, a recent theoretical study mimicked the prebiotic Miller experiment of amino acid generation,10a while others have shown that OEEFs stimulate proton transfer in water and in methanol and bring about efficient transformations of formaldehyde to (D)-erythrose,10b as well as a onestep conversion of methanol to methane and formaldehyde.10c,d Furthermore, pH-switchable charges were reported to lead to diastereomeric selectivity in Diels−Alder reactions.7c The potential is enormous. Harnessing of OEEFs for controlling reactivity and selectivity of nonpolar chemical reactions1,3,8−12 is presently a © 2018 American Chemical Society

Received: August 2, 2018 Published: September 20, 2018 13350

DOI: 10.1021/jacs.8b08233 J. Am. Chem. Soc. 2018, 140, 13350−13359

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Journal of the American Chemical Society

ethene, thus providing a predictive scheme, and at the same time delineating the limits of the chiral discrimination.

Chart 1. Target Diels-Alder Reactions of Cyclopentadiene (CPD) and a Variety of Substituted Ethenes

2. METHODS 2.1. Computational Details for Reactions Without Electric Field. All calculations for the reactions in Chart 1 were performed with Gaussian 09.19 Following our previous calculations on the Diels− Alder (DA) reaction,12a geometries of the reactants complex (RC), transition state (TS), and products (P) were fully optimized at the BP86-D3/6-31+G(d) level (denoted as B1),20 followed by singlepoint energy correction using B3LYP-D3 and the triple ζ basis set, 6-311++G(d,p) (denoted as B2).21 The corresponding energies are labeled as B3LYP-D3/6-311++G(d,p)//BP86-D3/6-31+G(d), briefed to B2//B1. D3 dispersion corrections22 implemented in Gaussian 09 were added to both optimization and single-point calculations. All stationary points were verified by frequency calculations at the B1 level that ascertained that all RC and P species possessed only real frequencies, while all TS species possessed only one imaginary frequency. Zero-point energies (ZPE), thermal corrections to enthalpy, and thermal corrections to Gibbs free energy at T = 298.15 K were obtained from frequency calculations. The B2//B1 level of theory was tested on the reaction of all the cyanoethene molecules with cyclopentadiene. Figure S1 (in the Supporting Information) shows that the computed energy barriers, with inclusion of ZPE correction, exhibit the trends observed in the experimentally determined activation energies.16,23 The solvation free energy was estimated with the single-point calculation at the B1 level. As done previously,16 we also used benzene as solvent to mimic the dioxane used in kinetic studies. Solvation effects were determined using the SMD model.24 2.2. Computational Details for Reactions in the Presence of Electric Fields. The effects of OEEFs were studied using the “Field = M ± N” keyword, which defines in Gaussian 09, the axis of the OEEF, its direction along that axis, and its magnitude. A range of electric field strength (F) was explored, between F = −0.0150 au and F = +0.0150 au (1 au = 51.4 V/Å). A two-directional (2D) OEEF was applied by “Field = Read” keyword. One should note that in Gaussian 09, the positive direction of the electric field vector is defined from the negative to the positive charge, which is opposite to the conventional definition in physics.1b,c As such, whenever the dipole moment (μ) and the field vector (F) are oppositely oriented relative to one another, the OEEF will stabilize the dipole, as exemplified in Scheme 2 for a Z-OEEF. The OEEFs

To avoid a congested manuscript, laden by details, we focus on the reactions of CPD with 1,1-dicyanoethene (1,1-DCE) and acrylonitrile (labeled as MCE; monocyanoethene), henceforth reactions 1 and 2, respectively.16−18 Thus, as shown in Scheme 1, the DA reaction of CPD and 1,1-DCE produces two Scheme 1. (a) Enantiomeric Transition State Complexes for Reaction 1 and (b) exo/endo (EX/EN) Isomers and Their R and S Chirality for Reaction 2

Scheme 2. Definitions of the X, Y, Z Directions, Along with the Definitions of a Positive OEEF (FZ > 0) in Gaussian 09 and the Stabilizing Orientation of the Dipole Moment (−μZ) with FZ > 0a

enantiomers R and S (shorthand notations for [R,R] and [S,S]), while the reaction with MCE gives rise to endo and exo isomers, each having a pair of R and S enantiomers. All other ethenes in Chart 1 have the same isomer/enantiomer entities as MCE, and the details are relegated to the Supporting Information document. As we shall demonstrate, OEEFs lead to complete chiral discrimination, by preferring a single chiral-isomer/enantiomer depending on the directionalities of the OEEF and the molecular dipole. Thus, the OEEF action is a chiral discrimination that filters out all the enantiomers/chiral-isomers except for a single one, which is selected by the field’s directionality. We shall further demonstrate that the chiral discrimination correlates linearly with the dipole moment of the substituted

a QCT is the amount of charge, transferred from the diene to the dienophile (e.g., in the transition state).

were further allowed to be oriented along the X, Y, and Z axes as defined in Scheme 2, where in each case, the Z axis defines the “reaction axis”, which is approximately the direction along which two new C−C bonds are forming. While we applied OEEF in X, Y, and Z axes, our main concern in this manuscript is the chiral and isomeric separation, which does not occur with FZ but rather with FX or/and FY directions for reactions 1 and 2 (Scheme 1) and the analogous reactions in Chart 1. As already mentioned, we focus on reactions 1 and 2, which represent the finding 13351

DOI: 10.1021/jacs.8b08233 J. Am. Chem. Soc. 2018, 140, 13350−13359

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Journal of the American Chemical Society for all other reactions. The detailed results for these other reactions in Chart 1 are collected in the Supporting Information document. The effects of oriented-external electric fields (OEEFs) were calculated initially using single-point calculations at the B2 level on optimized field-free geometries at the B1 level as previously done.12a We subsequently optimized the geometries of stationary points for reaction 1 under X-OEEFs at the B1 level and included other energetic effects (e.g., ZPE), thermal correction to Gibbs free energy, and solvation free energy, on top of the electronic energy, and the field effect. As shall be shown in the Results section, the change of electronic energy based on the single-point calculations on the fieldfree optimized geometries gave good predictions of the effect of OEEFs. Thus, for reaction 2, we only estimated the effect of OEEFs based on the B2 level single-point calculations on the B1 level fieldfree optimized geometries.

Let us consider FX which is aligned along the two carbon atoms of CPD that would form C−C bonds with dienophiles and is approximately parallel to the C1-C4 atoms of CPD. The field along this axis can be aligned in either opposite or parallel manners to the direction of the dipole moment of the cyanoethene. As such, the FX field will create chiral charge distribution in the corresponding stationary species (including RC, TS, and P), and will lead to chiral discrimination, as long as the diene cannot undergo an in plane 180° rotation (around the Z axis), or be attacked from the bottom-side, which will scramble R and S. These degrees of freedom must be somehow controlled in appropriate experimental set ups. Orienting the electric field and the reacting molecules is not a simple task, but chemical and physical ingenuity have already proven that both the reactants and the electric field could be made to align along the reaction axis of a DA reaction, giving rise to observation of its catalysis by the field.11 The Discussion section describes a potential way of restraining the diene on a surface using linkers as done in a few experimental laboratories.8a,9,11 In this manner the diene will not be attacked from the bottom-side and cannot rotate by 180° in plane, and the enantioselectivity will be determined by the direction of the FX field, which will also control the orientation of attack by the dienophile. For the moment, let us assume that such a restraint technique is available and proceed with the description of the results of the study. 3.2. Results for FX Application. 3.2.1. Field-Free Scenario. To appreciate the impact of FX application, let us examine first the energy profile of reaction 1 in the field-free scenario. This is presented in Figure 1, which shows that the

3. RESULTS 3.1. Directionality Effects of OEEFs on the DA Reaction. Our main focus in the manuscript is to delineate the conditions under which OEEF can lead to enantiomeric selection in reactions 1 and 2, and their analogs (Scheme 1 and Chart 1). To this end, it is important to appreciate first the role played by the directionality of OEEF and identify the direction that is likely to create chiral separation and any conditions thereof. Chart 2 shows a DA reaction between a dienophile and CPD Chart 2. Reactivity/Selectivity Patterns of Oriented External Electric Fields

in a Cartesian coordinate system, where Z is the reaction axis,1a,b,12a along which the electron pairing of the reactants evolves to the electron pairing of the product. Y and X are the perpendicular directions to this axis. Indeed, we verified in the present study, in accord with past findings,1a,b,12a,25 that the Z-OEEF (FZ) along the reaction axis catalyzes the DA reaction when the field vector FZ is aligned along the direction in which the diene transfers charge to the dienophile, while flipping the FZ direction will result in inhibition (see Figures S2−S3). These data which verify past findings1a,b,12a are relegated to the Supporting Information. For example, Figure S2 shows that FZ > 0 catalyzed reaction 1 (1,1,-DCE + CPD) by lowering its barrier from 11.0 kcal/mol to ∼7 kcal/mol even for a moderate field of FZ = +0.005 au (0.26 V/Å). At the same time, FZ = +0.005 au causes an increase in the amount of charge transferred (QCT) from CPD to 1,1-DCE, from 0.28 e− to 0.35 e−. Flipping the field to FZ = −0.005 au raises the barrier to ∼15 kcal/mol and lowers QCT to 0.21 e−. However, the R and S enantiomers of reaction 1 respond identically to the application of FZ, showing no chiral discrimination. The same applies to reaction 2 (MCE + CPD), in which FZ causes neither chiral discrimination nor appreciable endo/exo isomeric control (Figure S4). Moreover, in accord with past findings,12a FY is found to control endo/exo selectivity (Figure S5−S6), but again, FY has little ability to induce chiral separation (Figure S7).

Figure 1. B2//B1 energy profile for reaction 1 (CPD and 1,1-DCE) in the field-free situation. The energy profile starts from isolated reactants (RISO). The energy values of RISO are set to zero. The relative energy data (in kcal/mol units) for other species are shown in three lines corresponding, from top to bottom, to Δ(E + ZPE), (ΔG, at T = 298.15 K), and [Δ(G + solvation free energy; denoted as ΔGsol)]. Each data line shows, respectively, the relative energies for the degenerate R/S species. The optimized geometries for the R pathway are shown alongside the profile (bond lengths in Å units).

1,1-DCE and CPD molecules form initially a reaction cluster (RC), which lies 3.5 to 5.2 kcal/mol below the isolated reactants (RISO) and is stabilized by dispersion22 and charge transfer (CT)12a,16 interactions. Subsequently, the reactants establish a transition state (TS), which ultimately leads to the cycloaddition product (P). Note that the energy profiles of the 13352

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Figure 2. Comparison of the field-free relative energies for the degenerate R (blue lines) and S (red lines) pathways (left drawing), in comparison with the same chiral pathways at FX = +0.005 au (right drawing). Note that flipping the field’s direction to FX = −0.0050 au, would switch the ordering of the R and S pathways, with R being the stabilized path. All energies (kcal/mol) are relative to E[RC(S or R)] at F = 0 au. The two values at each entry correspond to (ΔE + ZPE)/[ΔGsol], respectively. Note that the energy profiles of the two chiral pathways undergo significant splitting by the FX field.

two chiral pathways (R and S) are perfectly degenerate, which means no enantioselectivity in the field-free scenario. Inspection of these energy data shows that the relative energies are dominated by the Δ(E + ZPE) species, while free energy terms have minor effects of 0.4−2.9 kcal/mol for the various species. Similarly, solvation correction slightly stabilizes the TS by ∼1 kcal/mol. In fact, as shown in Tables S1 and S2, the relative energies are dominated by the relative electronic energies (ΔE), with smaller contribution from all other terms. 3.2.2. Reaction 1 under Weak FX Field. When the FX field is applied, there occur geometry and relative energy changes for all stationary species, which appear on the energy profiles of the R and S pathways. The major effect however, is the chiral discrimination of the two pathways by the field compared with the degeneracy of these pathways in the absence of the field. Figure 2 exemplifies these changes for reaction 1, displaying the field-free energy profile on the left and on the right the profiles for the R and S pathways in FX = +0.005 au. As both the R and S pathways share the isolated reactants state (RISO), our following analyses start with the RC complex. The energies Δ(E + ZPE) followed by [ΔG + solvation free energy, denoted as ΔGsol)] under the influence of the field are given relative to RC(S, R) at F = 0. Thus for example, RC(S) is stabilized by 6.5 [7.7] kcal/mol relative to the field free RC(S, R) species, and similarly, TS(S) is stabilized relative to the degenerate TS(S, R) species by 5.9 [6.8] kcal/mol, etc. On the other hand, the TS species on the R pathway are destabilized compared to the field-free species by 3.3 [3.8] kcal/mol. Another change occurs in the TS(S) and TS(R) geometries, relative to the field free and degenerate TS(S, R) species; the TS(S) species becomes slightly tighter than the corresponding field-free species, while TS(R) becomes looser. It is interesting to note that the energy barrier on the stabilized S pathway under FX barely changes, and its values 12.6 [12.9] kcal/mol are slightly higher or virtually identical to the values for the field-free reaction, 12.0 [12.0] kcal/mol. It is apparent that in contrast to FZ which lowers the barriers significantly, the FX does not do so. It does not catalyze the reaction. Its effect is entirely different and will be outlined in the discussion section.

The major and most interesting effect in Figure 2 is the chiral discrimination by the field. Thus, for example, a rather weak field, FX = +0.005 au, prefers the entire S pathway by ∼8−13 kcal/mol over the species in the R pathway. The effect of a negative field, FX = −0.005 au, is entirely analogous but now in favor of the R pathway over S (see Figure S8). With such a discrimination, one can get S or R product at will by simply flipping the direction of FX from positive to negative. The energy difference associated with chiral discrimination is not too sensitive to various corrections and/or geometry optimization. Thus, for example, the energy separation of TS(S) versus TS(R) in FX = +0.005 au is 9.2 kcal/mol when E + ZPE is used, 8.8 kcal/mol when G is used, and 10.6 kcal/mol when solvation correction is added to the free energy (see Figures S9, which summarizes the energetics for the various energy types). Furthermore, the main energy difference originates in the electronic energy (E). This is demonstrated in Figure 3, which depicts the energy profile under FX = +0.005 au, using electronic energy only. In part (a), we report the relative electronic energy using single-point calculations in the presence of the field on the field-free geometries, while in part (b) these are relative electronic energies after geometry optimization in the presence of the field. The corresponding energy separation of TS(S) versus TS(R) is 10.0 kcal/mol in the absence of geometry optimization and 9.5 kcal/mol with geometry optimization. These values and all the ones in the above paragraph are essentially similar and almost invariant. The dominance of electronic energies is in line with previous experience7c,11,25,26 and is a sensible result, since the OEEF effect appears in the one-electronic part of the Hamiltonian. For these reasons the effect of field can be well-estimated, in this case, using electronic energies on the field free geometries. These values will be used in the discussion section. In summary, since already an X field of ±0.005 au raises one of the enantiomeric energy profiles by 8−10 kcal/mol, the less stable one for a given field’s direction will have a negligible population. Thus, the stable RC will be stereodetermining. At much weaker X fields (e.g., smaller than ±0.002 au), when the two profiles are separated by ∼2 kcal/mol or less the RCs will be equilibrated, and following the Curtin-Hammett principle, the 13353

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Figure 3. Relative electronic energies (kcal/mol) for the R (blue lines) and S (red lines) pathways using FX = +0.0050 au: (a) single-point calculations on the field-free geometries. (b) Calculations on the optimized geometries in the field. (At FX = −0.0050 au, the R and S pathways are switched, with R being the stabilized path). All energies (kcal/mol) are relative to E[RC(S or R)] at FX = 0 au.

Figure 4. (a) Optimized RC and (b) TS geometries for the S pathway in X-oriented fields (FX) of various intensity. Geometries are represented by the intermolecular C−C distances (Å). At positive values of FX, the S pathway is stabilized and keeps the S orientation of RC(S) and TS(S) all the way to the extreme positive field of FX = +0.0150 au, which is shown on the left-hand side of the figure. In the negative FX regime, the S path is destabilized. It is seen that as the destabilizing field change from −0.0050 au to −0.0075 au, the 1,1-DCE moiety in RC(S) rotates (see red arrow) and the structure collapses to the corresponding conformer of the RC(R) and remains so until FX = −0.0100 au. At the same time, the TS(S) keeps its identity almost until FX = −0.0090 au, but at this field it undergoes a major displacement of the 1,1-DCE moiety, which subsequently undergoes rotation (red arrow) by 180°.

undergoes a major upward shift of the 1,1-DCE moiety that opens the structure, and then 1,1-DCE rotates to avoid the high destabilization energy. Starting from FX < 0, the stabilized path R will have properly optimized RC(R) and TS(R) species, while the destabilized species RC(S) and TS(S) will eventually collapse to the corresponding stabilized R species as soon as the field exceeds −0.0075 au. Thus, intense fields exert a strong orientation effect and will drive the reaction complex toward the stabilized pathway. For reaction 2 (MCE + CPD), the intermolecular interaction between acrolein (MCE) and CPD is weaker than for reaction 1. As a result, the RC species are more fragile during geometry optimization. However, the corresponding TSs are more steadfast, and the phenomenon described in Figure 4 above, in which the destabilized species collapse under intense FX fields to the corresponding ones in the stabilized pathway, ensure that FX can lead to complete chiral discrimination (refer to Figure S10). The same behavior should apply to other dienophiles in Chart 1, especially for the cases when there is a large energy difference between the two pathways. What we are seeing here is an important phenomenon; at high enough FX fields (negative or positive), the destabilized pathways undergo transformation to the stabilized path by a rotation of the cyano-ethene moiety that aligns its dipole

reaction will proceed by passing the lower TS, thus again providing stereoselectivity. 3.2.3. Reaction under Strong FX Field. When the applied field gets stronger than ±0.0050 au, the pathway that undergoes destabilization by the field reveals instability of the geometries of the optimized species, which tend to collapse to the species of the stabilized path. Figure 4 demonstrates these issues for the species in reaction 1 at various fields. For reaction 1, the stabilized pathway at FX > 0 is S, while the destabilized one is R. For the species belonging to the stabilized S path, the geometry optimization proceeds without too many problems, even under the extreme field. This is shown in Figure 4 for FX = +0.0150 au where the geometries for the RC(S) and TS(S), on the left-hand side, undergo successful optimization, which conserve the S chirality and the nature of the species. This behavior changes as we switch the direction of the field to FX < 0, which stabilizes the R path. Initially at FX = −0.0050 au, even though the S pathway is destabilized, still the RC(S) and TS(S) species could be optimized and conserved their chiral identity. However, as the field’s intensity was further increased to FX = −0.0075 au, it is seen that the 1,1-DCE moiety of RC(S) rotated, and the structure collapsed to the stable species RC(R) of the enantiomeric pathway. At the same time, TS(S) 13354

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Journal of the American Chemical Society moment opposite to the direction of the FX field. This basically means that at sufficiently strong FX, the field determines the enantiomeric preference by orienting the cyano-ethylene in the most favorable manner, wherein the dipole moment of the dienophile is opposite to the field vector. This automatic conversion of the destabilized path to the stabilized one during geometry optimization ensures that under strong fields, the high-energy pathway will be completely filtered out. This and all the above results show that, in discussing trends, for these present reactions, we can use single-point energy calculations and compare electronic energies without the need for thermal and solvation terms.

4. DISCUSSION As we mentioned above, a precondition for observing this huge chiral discrimination is the fixation of CPD, so it cannot rotate 180° in plane and cannot be attacked from the bottom-side of the ring. Thus, we imagine a surface loaded with such retrained CPD molecules, while at the same time, the cyano-ethylene will be oriented through the interaction of its dipole moment with the X field in with positive or negative directions. Using reaction 1 as an example, imagine a scenario in which CPDs are assembled and fixed onto a surface (e.g., by linkers) (see Chart 3)

Figure 5. Relative electronic energies (kcal/mol) of the reactant clusters (RC), the transition states (TS), and products (P) for the R (blue lines) and S (red lines) pathways of reaction 1 (1,1-DCE + CPD) depending on the FX directionality (FX = ± 0.015 au). The energy reference is the electronic energy of the RC cluster of the R(or S) pathway at FX = 0 au.

by ∼30 kcal/mol. Similar large effects on barriers were reported by Cassone et al.,10c,d using DFT/metadynamics calculations with OEEF (of the order of 0.55 V/Å) included. As we saw in the results section of the DA reaction, even at much weaker fields of ±0.005 au (0.26 V/Å), the energy difference between the R and S pathways is ∼10 kcal/mol (see Figures 2 and 3, and Figure S11). With such energy differences, the destabilized pathway either collapses to the stabilized one or is much too high to compete with the stabilized path. Clearly, under competition between the pathways, the FX field would bring about absolute enantioselectivity, at will. As we showed in the Results section (Figure 2 and also Figure S11), the energy barrier for the DA reaction in the preferred path under finite FX values is slightly higher than the barrier at FX = 0. A more striking example is the reaction of 1,1,2-tricyanoethene with CPD that is depicted in Figure 6.

Chart 3. CPD Restrained on a Surface by Linkers,8a,9,11 and 1,1-DCE Molecules Approach It in a Manner Controlled by the X Field

of types used before by several groups.8a,9,11 The linkers may either be covalent8,9 or weaker ones like thiolate linkers on gold.11 The covalent linkers may pose a problem to detach the DA adducts, while the thiolate linkers may be more convenient for this purpose. In any event, the three linkers will prevent or inhibit a 180° rotation of CPD (other designs may lower the necessary linkers to two). At the same time, the 1,1-DCE molecule will have the freedom to approach the fixed CPD to an appropriate DA juxtaposition in either R or S orientations, depending on the voltage stimulus, which is delivered in the X direction parallel to the plane of CPD (e.g., in a capacitor cell). Having outlined a potential restraining mechanism, let us discuss now the chiral discrimination results computed in our study. The relative energies of the R and S pathways at a given FX magnitude (±0.015 au) are shown in Figure 5. It is seen that FX > 0 stabilizes the RC(S), TS(S), and P(S) species of the S pathway (in red color), such that the entire energy profile lies ∼30 kcal/mol below the corresponding species of the R pathway, which is destabilized by FX > 0. Recalling that intense fields will also funnel all the RC species to the most stable one, we can be assured that FX > 0 will prefer the S pathway, completely. If we just flip the field to FX < 0, the stability pattern reverses, preferring now the R pathway (in blue) over S

Figure 6. Effect of X-OEEF at +0.0150 au on the electronic energy of RC, TS, and P clusters of the R (blue lines) and S (red lines) pathways in the reaction of CPD + 1,1,2-tricyanoethene (for the endo, EN, stereoisomer).

Note that the energy barrier for the preferred S-enantiomeric path, 16.5 kcal/mol, is higher than the corresponding field-free barrier, 12.9 kcal/mol. In contrast, the barrier for the unfavored R-enantiomeric path, 11.3 kcal/mol, is slightly lower than the field-free barrier. Thus, Figures 2 and 6 show that chiral discrimination is not associated with catalysis relative to the fieldfree situation; the field effect rather filters out the one of the 13355

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Table 1. Relative Energies (kcal/mol)a of the Four Transition States for Reaction 2 (MCE + CPD; Scheme 1b) under the Combination of FX and FY at ±0.015 au Values

enantiomeric pathways. Furthermore, in contrast to FZ, which leads to catalysis and changes QCT significantly during catalysis (in reaction 1, from 0.28 e− to 0.48 e−), under FX the QCT is virtually constant and identical to the field-free value (0.28 e−). The electronic effect by which FX confers this enantioselectivity will be discussed later. Let us turn now to reaction 2 (MCE + CPD). The products of this reaction have R/S pairs for each of the exo (EX) and endo (EN) stereoisomers. The R and S enantiomers for a given stereoisomer will be resolved by the same setup schematized in Chart 3, while the voltage stimulus is being delivered along the X axis. Figure 7 shows the impact of FX on the R and S

FXY

(+,+)

(+,−)

(−,+)

(−,−)

EN(R) EN(S) EX(R) EX(S)

6.7 −8.3 −39.6b −16.2

−17.1 −38.2b −9.9 5.4

−8.5 6.9 −16.3 −39.5b

−38.1b −17.2 5.5 −10.0

a

Energies are relative to the TS complex of EN(R) species at F = 0. These values indicate the most stabilized enantiomer at each field’s combination.

b

FY = −0.015 au, etc.). It is seen that each 2D-combination has a single isomeric preference (Table 1); FXY(+,+) prefers EX(R) by ∼23−46 kcal/mol over all the others, while just flipping to FXY(−,+) this prefers EX(S) by ∼23−46 kcal/mol over all the others, and so on. Therefore, FXY can bring about a complete resolution and isomeric control at a flip. In a similar manner, one could in principle couple FZ to any other field vector and obtain simultaneous control over kinetics and selectivity. For example, applying FXZ for reaction 1 will lead to simultaneous control of catalysis and R/S resolution. The usage of 2D-OEEFs or even three-dimensional (3D)-fields could in principle be very potent. 4.1. What is the Mechanism Whereby the Electric Field Creates Chiral Discrimination? Let us try to comprehend the mechanism whereby the FX and/or FY induce chiral discrimination, without catalyzing the reaction. For the sake of clarity, let us focus on reaction 1 (1,1-DCE + CPD, Scheme 1a) and first consider its catalysis by a Z-OEEF. Thus, the application of FZ along the “reaction axis” transfers charge from the π-system of CPD to that of 1,1-DCE, which increases the mixing of the charge-transfer state (CTS) into the TS, intensifies the intermolecular bonding between the diene and the dienophile, and thereby lowers the reaction barrier.1a,b,12a Flipping FZ achieves the opposite effect, it will decrease QCT(π) and minimize the corresponding mixing of the CTS in the TS, thus raising the barrier and inhibiting the reaction.1a,b,12a However, FZ is unable to distinguish different isomers. The chiral discrimination mechanism is provided, however, by FX that causes intramolecular charge rearrangements in both CPD and 1,1-DCE. This charge-rearrangement increases the X-component of the dipole moment (μX) of the TS, and creates a chiral discrimination (as long as CPD is fixed on a surface). This information is seen in Figure 8, which displays the electron density difference (EDD)27 maps for the R and S TSs of reaction 1 relative to field-free TSs, and the corresponding μX values, in FX = ± 0.015 au. It is apparent that there is a major electron-density rearrangement in the molecular planes that involves also the σ bonds of the two TSs, leading to an overall chiral chargedistribution. This is caused by increased or decreased bondionicity for stabilized or destabilized TSs, respectively,1b which is apparent from the fact that the X dipole moments differ by more than 8 D for the stabilized/destabilized TSs. Thus by fixing CPD and orienting the OEEF, chiral discrimination is achieved by dipole-moment selection rules, such that the field filters out one of the enantiomers, which is highly raised in energy by dipole selection. Electrostatic theory enables us to calculate the relative stabilization energy (ΔΔE, in kcal/mol)1b in a given field due to a change in the dipole moment using eq 1,

Figure 7. Relative electronic energies (kcal/mol) of the clusters RC, the transition states (TS), and products (P) for the R (blue lines) and S (red lines) pathways of the exo pathway (EX) in reaction 2 (MCE + CPD), depending on the FX directionality (FX = ± 0.015 au). The energy reference is the electronic energy of RC cluster of EX(R) pathway at FX = 0 au.

enantiomers of the EX isomer. It is seen that FX = +0.015 au prefers all the species of R pathway by ∼20 kcal/mol compared with the corresponding species in the S pathway. Just flipping the field’s direction, to FX = −0.015 au, prefers now the S pathway over R by the same energy margins. A significant preference (of ∼6 kcal/mol, which corresponds to 104-fold excess S over R) is conserved even at weaker fields of 0.005 au (Figure S12). As such, FX enables one to achieve, at will, complete R or S enantioselectivity of the EX isomer by simply flipping the direction of FX. Precisely the same result is computed for the R and S enantiomers of the EN isomer, but now the R/S preferences is achieved by the opposite FX direction; FX > 0 favors S, while FX < 0 favors R (Figure S13). As we recall,1a,b,12a FY is capable of resolving the EX and EN isomers by flipping the field from a positive to a negative direction but is unable to separate R and S (refer to Figures S5 − S7). A complete separation of the four isomers can in principle be achieved by using a two-directional (2D)-field with X and Y component, FXY. A two-dimensional (2D) field requires three different charge surfaces (e.g., a capacitor which defines the FX component) (Chart 3), while a charged surface in the XZ plane will deliver the FY component. If such a setup could be designed2e (in which CPD is assembled on the XY plane), this would then achieve the desired resolution. It is perhaps necessary to qualify here that a 2D-OEEF is simply a single OEEF vector aligned in between its constituent components. Nevertheless, its two components bring about different effects. Table 1 provides the relative stability of the TS for the four pathways; EN(R), EN(S), EX(R), and EX(S), in all the four FXY combinations (e.g., the + ,− signs indicate FX = +0.015 au and 13356

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Table 2. Field Free Dipole Moment X and Y Componentsa of TSs for reaction 2 EN(R) EN(S) EX(R) EX(S) a

Y

2.4 −2.4 −2.6 2.6

3.6 3.7 −3.5 −3.5

In Debye (D) units.

will stabilize the most the EN(S) pathway, and FXY(−,+) will prefer the EX(S) pathway the most, whereas FXY(−,−) will favor EN(R) the most). These trends correspond to the results in Table 1. These simple applications of the equation help realize also the immense potential of OEEFs as means of reactivity/selectivity control, by interacting with the molecular dipole moment. 4.2. Important Role of the Molecular Dipole. For reactions 1 and 2, we showed above that in sufficiently strong fields, the field controls the orientation of the cyano-ethenes and hence the orientation by which they approach the CPD, and as such also the resulting chiral identity of the corresponding TS. Since CPD does not have much of a dipole moment, this orientation and the emerging chiral discrimination derive primarily from the dipole moment of the dienophile and its preferred interaction by the X-field or by the 2D-(X,Y)-field. To test this simple idea, we examined the chiral discrimination for a variety of dienophiles reacting with CPD, as depicted in Chart 1. These dienophiles exhibit a range of fieldfree dipole moments, which span 5 D. We calculated the corresponding DA reactions and determined the chiral discrimination, ΔE(R,S) at a given field strength of 0.0150 au. The details of these calculations were relegated to the Supporting Information (see pp S14−S17). Figure 9 shows that the correlation between the so calculated ΔE(R,S) and the dipole moment μX of the substituted

Figure 8. Electron-density difference (EDD) maps for the R and S transition states of reaction 1, in FX = ± 0.015 au, relative to field-free TSs. Red color signifies electron density increase, while blue signifies density depletion (iso values are set to ±0.001). The μX values in Debye (D) are noted underneath the EDD maps. For a reference, at F = 0, the value of μX (TS) is 4.1 D and −4.1 D for R and S pathways, respectively. ΔΔE(kcal/mol) = 4.8FX × ΔμX (FX in V/Å and μX in D units) (1)

As the value of ΔμX for the TSs for the R versus S pathways is ∼8 D, within the fields used (from −0.015 au to +0.015 au), when FX = −0.015 au (−0.77 V/Å), we get ΔΔE = 30 kcal/mol in favor of the TS for the R pathway, which possesses a positive X dipole moment (Figure 8). The so calculated value is virtually identical to the computed value (see Figure 5). Just flipping the direction of the field to FX = +0.015 au leads again to ΔΔE = 30 kcal/mol in favor of the S pathway, which possesses a negative X-dipole moment (Figure 8). As such, the absolute enantioselectivity originates in increased σ-ionicity in the TS due to the charge polarization by the FX field. This new charge distribution is chiral and direction-dependent for the two enantiomeric paths. Similar magnitudes of field effects on barriers were reported in other reactions as well.10c,d Eq 1 can be generalized to catalysis/inhibition by FZ, where μZ changes due to variations in the charge transfer quantity QCT(π). It can be applied also to 2D-fields, where two dipole moment components change synchronously. Focusing on the 2D-field in reaction 2, the selectivity exerted by FXY is the sum of component terms in eq 2: ΔΔE(kcal/mol) = 4.8[FX × ΔμX + FY × Δμ Y ]

X

(2)

A 3D-field will simply have an additional term, FZ × ΔμZ, to those already in eq 2. For the 2D-field case, the changes in the X and Y dipole moments and the X,Y-OEEF magnitudes makes it possible to uncover the origins of selectivity in reaction 2 in Table 1. To predict trends in Table 1 in a qualitative manner, we can simply utilize the field free dipole moments of TSs (Table 2) for reaction 2. These are given in Table 2 (see part VI of the Supporting Information). Recall that using the convention of Gaussian 09 (Scheme 2), the OEEF will stabilize the dipole whenever the dipole moment and the field are oppositely oriented relative to one another. Thus, from Table 2 and eq 2, we can rationalize that a FXY(+,+) will stabilize EX(R) pathway more than the other three, as both the X and Y dipole moment components are negative and hence leading to stabilization; all other TSs will be stabilized less by FXY(+,+), or destabilized as EN(R). The same principle applies to the other three cases (e.g., FXY(+,−)

Figure 9. ΔE(R,S) values of chiral discrimination (in kcal/mol) induced by an FX field (±0.0150 au) for a variety of dienophiles reacting with CPD, plotted against the field-free X-dipole moment components (μX in Debye units, D) of the dienophiles. For reactions other than 1,1-dicyanoethene, there are endo/exo stereoisomers, and the chiral discrimination is given as the average value for endo and exo stereoisomers (all relevant data are summarized in the Supporting Information, pp S14−S17).

ethene dienophile. The correlation is practically linear. As this dipole-moment increases, the chiral discrimination is seen to vary between ∼0.2 kcal/mol (for propene) to 30 kcal/mol 13357

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that Cassone et al.,10b obtained enantioselective (D)-erythrose, since in this system, the reaction axis Z may project on the reactants field components in the X and Y directions,25 because the TSs has a complex three-dimensional structure and may not be strictly linear. Finally, while usage of 2D- and/or 3D-fields is potent, it also poses design-challenges to experimentalists. Nevertheless, one can already see prototype setups, which can deliver 2D-fields.2e Achieving chiral discrimination in the DA reactions with CPD requires one to fix this molecule onto a surface and prevent its 180° rotation, in plane. This entails the synthesis of CPD with linkers that can be attached to the surface.8a,9,11 Synthesizing linkers may lower the attractiveness of the experiment. For example, covalent linkers were used8,9 to immobilize their catalysts to a surface throughout the turnover of the catalytic process. Such an approach for the present study would necessitate a way to detach the DA adduct from the surface, thus making the experiment cumbersome and of little practical utility. Weaker linkers like those used by Aragonés et al.11 may be more practical. Nevertheless, at present, the strategy of linkers can be used as a proof of principle that complete enantioselection is achievable using OEEFs, while better techniques may be sought. Indeed, it is not a far-fetched idea that in rather strong fields the field itself will orient the molecules like tweezers28 and enable them to react in a stereoselective manner depending on the directionalities of the 3D-field components. We are actively exploring this option, using a 3D field (FXYZ), in which the Z-component drives the reactants to assume a DA orientation with intermolecular bonding, while the inhibition of the 180° rotation of CPD, and the ensuing chirality are directed by the FXY component. Our preliminary results show that this is realizable, thus leaving room for optimism; further progress of this approach would require, however, going beyond static calculations.10

(for 1,1-dicyanoethene). Thus, while the dipole moments at the TSs are significantly higher due to the polarization induced by the FX field (see Figure 8 above), still what determines this polarization capability of the two chiral TSs is already the dipolar nature of the dienophile in the field-free situation. The larger the dipole moment of the dienophile, the greater will be the chiral discrimination by the electric field. Note that even moderate dipoles in Figure 9 lead to significant chiral selectivity, whereas the limit of chiral discrimination is reached for very nonpolar dienophiles like propene. As such, Figure 9 has some predictive value.

5. CONCLUSION We derived here orientation rules for OEEF effects on chiralselectivity and applied these rules to Diels−Alder (DA) reactions of cyclopentadiene (CPD) and a variety of ethene molecules (Chart 1). The following trends were demonstrated. (a) The application of the OEEFs along the X and/or Y directions (Scheme 2), for the reactions of CPD with cyanoethenes (Scheme 1, panels a and b) will lead to complete isomeric discrimination and notably of R and S enantiomers as well as of the endo and exo isomers. Thus, the X field will control chiral discrimination of the R/S enantiomers, while the Y-OEEF will control the endo/exo ratio. The enantiomeric and/or isomeric discriminations can approach 30 kcal/mol in strong fields (e.g., Figure 5 for CPD + 1,1-DCE in reaction 1; Table 1 for CPD + MCE in reaction 2). The unfavorable pathways are highly destabilized and under strong fields will collapse and reorient automatically to the favorable pathway (Figure 4). (b) The condition upon which the chiral discrimination rests, is that the CPD molecule would not be able to rotate 180° in plane or be attacked from both topside and bottomside of the molecular plane. This can be achieved by linking the CPD to a surface.8a,9,11 By so doing chiral-discrimination is reduced to dipole-selection rules. (c) In contrast to catalysis/inhibition, which is controlled by OEEF along the reaction axis Z (Scheme 2), the application of the fields along the X and/or Y directions will lead to complete isomeric discrimination, without actually catalyzing the DA reaction (see Figures 2 and 6) relative to the field-free situation. The X,Y fields induce the enantioselective discrimination by filtering out one of the enantiomers; the one which gets highly destabilized along the corresponding pathway. (d) Catalysis by FZ application stabilizes the DA transition state (TS) by πcharge transfer from the CPD to the dienophile. This CT(π) is akin to HOMO−LUMO mixing, and it improves the intermolecular bonding between the diene and the dienophile. However, the electronic mechanism that creates chiral discrimination involves intramolecular rearrangement of the electron density (Figure 8), in a manner that increases the X-dipole moment of the TS and create a chiral electron density. (e) The chiral discrimination is accompanied by the distortion of the electron density (without having a CT mechanism to stabilize the TS), the barrier slightly increases for the selected enantiomeric pathway (see e.g., Figures 5 and 6). (f) The discriminating-energetic effect depends linearly on the zero-order dipole moment of the dienophile. This allows making simple predictions about the outcome of the OEEF discrimination in a given DA system. (g) Using a two-directional (2D) field (e.g. X,Y-OEEF will simultaneously control both endo/exo and R/S ratios). 3DFields (right- and left-handed FXYZ fields) may be even more powerful, as they will lead to both catalysis/inhibition and chiral/isomeric discrimination. It is interesting to speculate

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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.8b08233. Energy profiles, relative energies of RC and TS clusters, optimized geometries under FX, calculation details for Figure 9, full citation of Gaussian 09, figures of optimized geometries of the reactions of CPD and different substrates at B1 level, tables of electronic energies, tables of dipole moments, tables of transferred charges and Cartesian coordinates of the optimized geometries (PDF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Zhanfeng Wang: 0000-0001-6722-2298 David Danovich: 0000-0002-8730-5119 Rajeev Ramanan: 0000-0002-5879-0768 Sason Shaik: 0000-0001-7643-9421 Notes

The authors declare no competing financial interest. 13358

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2329. (d) Cassone, G.; Pietrucci, F.; Saija, F.; Guyot, F.; Sponer, J.; Sponer, J. E.; Saitta, A. M. Sci. Rep. 2017, 7 (1−8), 6901. (11) Aragonés, A. C.; Haworth, N. L.; Darwish, N.; Ciampi, S.; Bloomfield, N. J.; Wallace, G. G.; Díez-Peréz, I.; Coote, M. L. Nature 2016, 531, 88. (12) (a) Meir, R.; Chen, H.; Lai, W.; Shaik, S. ChemPhysChem 2010, 11, 301. (b) Shaik, S.; de Visser, S. P.; Kumar, D. J. Am. Chem. Soc. 2004, 126, 11746. (c) Hirao, H.; Chen, H.; Carvajal, M. A.; Wang, Y.; Shaik, S. J. Am. Chem. Soc. 2008, 130, 3319. (13) Pasteur, L. C. R. Acad. Sci. Paris 1848, 26, 535. (14) (a) Walsh, P. J.; Kozlowski, M. C. Fundamentals of Asymmetric Catalysis; University Science Books: Sausalito, CA, 2008. (b) Toste, F. D.; Sigman, M. S.; Miller, S. J. Acc. Chem. Res. 2017, 50, 609. (c) For magnetic resolution, see: Banerjee-Ghosh, K.; Ben Dor, O.; Tassinari, F.; Capua, E.; Yochelis, S.; Capua, A.; Yang, S. H.; Parkin, S. S. P.; Sarkar, S.; Kronik, L.; Baczewski, L. T.; Naaman, R.; Paltiel, Y. Science 2018, 360, 1331. (15) Bhattacharyya, K.; Karmakar, S.; Datta, A. Phys. Chem. Chem. Phys. 2017, 19, 22482. (16) For an earlier treatment of the reactivity of CPD and cyanoethenes, see: Jones, G. O.; Guner, V. A.; Houk, K. N. J. Phys. Chem. A 2006, 110, 1216. (17) For general references on DA reactions, see: (a) Silva, E. M. P.; Rocha, D. H. A.; Silva, A. M. S. Synthesis 2018, 50, 1773. (b) Gandini, A. Prog. Polym. Sci. 2013, 38, 1. (c) Juhl, M.; Tanner, D. Chem. Soc. Rev. 2009, 38, 2983. (18) For modeling and understanding the origins of the barrier in DA reactions, see: Bickelhaupt, F. M.; Houk, K. N. Angew. Chem., Int. Ed. 2017, 56, 10070. (19) Frisch, M. J.; et al.. Gaussian 09, revision D.01; Gaussian, Inc.: Wallingford, CT, 2013. (20) (a) Becke, A. D. Phys. Rev. A: At., Mol., Opt. Phys. 1988, 38, 3098. (b) Perdew, J. P. Phys. Rev. B: Condens. Matter Mater. Phys. 1986, 33, 8822. (c) Perdew, J. P. Phys. Rev. B: Condens. Matter Mater. Phys. 1986, 34, 7406. (d) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56, 2257. (21) (a) Becke, A. D. J. Chem. Phys. 1992, 96, 2155. (b) Becke, A. D. J. Chem. Phys. 1992, 97, 9173. (c) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (d) Lee, C. T.; Yang, W. T.; Parr, R. G. Phys. Rev. B: Condens. Matter Mater. Phys. 1988, 37, 785. (e) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem. Phys. 1980, 72, 650. (22) Grimme, S.; Antony, J.; Ehrlich, S.; Krieg, H. J. Chem. Phys. 2010, 132, 154104. (23) For ethene in gas phase, see: (a) Walsh, R.; Wells, J. M. J. Chem. Soc., Perkin Trans. 2 1976, 52. For cyanoethenes in dioxane, see: (b) Sauer, J.; Wiest, H.; Mielert, A. Chem. Ber. 1964, 97, 3183. (24) Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B 2009, 113, 6378. (25) The effect of the reaction axis is general, see: Ramanan, R.; Danovich, D.; Mandal, D.; Shaik, S. J. Am. Chem. Soc. 2018, 140, 4354. (26) See page 43 in the SI document of ref 11. (27) Electron density differences were calculated with Multiwfn-3.5: Lu, T.; Chen, F. W. J. Comput. Chem. 2012, 33, 580. (28) Friedrich, B. Scientia 2017, 115, 26−31.

ACKNOWLEDGMENTS S.S. is supported by the Israel Science Foundation (ISF 520/18). We are thankful to B. Friedrich (ref 28) for his comments on usage of electric tweezers. The paper is dedicated to Raphael D. Levine on occasion of his 80th birthday.

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