Dispersion and Halogen-Bonding Interactions: Binding of the Axial

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Dispersion and Halogen-Bonding Interactions: Binding of the Axial Conformers of Monohalo- and (±)-trans-1,2-Dihalocyclohexanes in Enantiopure Alleno-Acetylenic Cages Cornelius Gropp,† Tamara Husch,‡ Nils Trapp,† Markus Reiher,*,‡ and François Diederich*,† †

Laboratorium für Organische Chemie, ETH Zurich, Vladimir-Prelog-Weg 3, 8093 Zurich, Switzerland Laboratorium für Physikalische Chemie, ETH Zurich, Vladimir-Prelog-Weg 2, 8093 Zurich, Switzerland

‡

S Supporting Information *

ABSTRACT: Enantiopure alleno-acetylenic cage (AAC) receptors with a resorcin[4]arene scaffold, from which four homochiral alleno-acetylenes converge to shape a cavity closed by a four-fold OH-hydrogen-bonding array, form a highly ordered porous network in the solid state. They enable the complexation and co-crystallization of otherwise non-crystalline small molecules. This paper analyzes the axial conformers of monohalo- and (±)-trans-1,2-dihalocyclohexanes, bound in the interior cavity of the AACs, on the atomic level in the solid state and in solution, accompanied by accurate calculations. The dihedral angles ϑa,a (X−C(1)−C(2)−X/H) of the axial/diaxial conformers deviate substantially from 180°, down to 144°, accompanied by strong flattening of the ring dihedral angles. Structure optimization of the isolated guest molecules demonstrates that the non-covalent interactions with the host hardly affect the dihedral angles, validating that the host is an ideal means to study the elusive axial/diaxial conformers. X-ray co-crystal structures of AACs further allowed for a detailed investigation, both experimentally and theoretically, on the interplay between space occupancy, guest conformation, and chiral recognition based purely on dispersion forces and weak CX···π (X = Cl, Br, I) and CX···||| (acetylene) contacts (X = Cl, Br). The theoretical analysis of the non-covalent interactions between host and guest confirmed the high shape complementarity with fully enveloping dispersive interactions between the binding partners, rationalizing the high degree of enantioselectivity in the previously communicated complexation of (±)-trans-1,2dimethylcyclohexane. This study also showed that (±)-trans-1,2-dihalocyclohexanes (X = Cl, Br) engage in significant halogen bonding (XB) interactions CX···||| with the hosts. Slow host−guest exchange on the NMR time scale enabled the characterization of the encapsulated guests in solution, demonstrating that the complexes have identical geometries to those seen in the solid state, with the guests bound in axial/diaxial conformations.

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INTRODUCTION Molecular recognition in its modern definition implies that two molecules interact with each other in a specific way, with the result that their overall potential energy decreases more significantly than in any other interaction mode.1 Understanding processes in nature, where molecular recognition plays a crucial role, requires the study of interactions at the molecular level. The development of model systems with confined cavities has enabled the investigation of intermolecular interactions and molecular conformations of guests entrapped in their inner phase.2 Among the broad spectrum of non-covalent interactions, the weaker ones, such as dispersion interactions3 and the interactions between dipoles,1c,4 remain a challenge for identification and quantification.5 Nonetheless, the importance of halogen bonds (XB)6 has been recognized in many areas of chemistry7 and led to their application as a new tool in medicinal chemistry.8 Exploiting the molecular recognition properties of chiral hosts has yielded significant insight into enantioselective © 2017 American Chemical Society

binding of chiral substrates in chemical and biological systems, thereby establishing fundamental concepts, such as three-point binding and Fischer’s shape complementarity.9 Following the leads by Cram et al.10 and Prelog et al.11 on the design of artificial enantioselective receptors, chiral covalent2b,12 and supramolecular assemblies13 have been investigated to bind optically active guests. Examples of capsular enantioselective ligand binding based purely on shape complementarity and weak intermolecular interactions, nevertheless, remain scarce. X-ray crystallography is the most important tool to provide accurate information on the structures of molecular complexes in the solid state.1a,14 Co-crystallization in porous complexes and crystalline sponges has recently emerged to facilitate the elucidation of non-crystalline small-molecule structures.15 Additionally, theoretical chemistry provides efficient and accurate methods for the structural and physicochemical Received: June 1, 2017 Published: August 15, 2017 12190

DOI: 10.1021/jacs.7b05461 J. Am. Chem. Soc. 2017, 139, 12190−12200

Article

Journal of the American Chemical Society

Mono- and (±)-1,2-trans-dihalocyclohexanes have previously been the subject of much research, suggesting that for monosubstituted cyclohexanes the equatorial conformations are generally favored.21 In clathrate-type inclusion complexes, Toda and co-workers observed both equatorial and axial conformers of bound monohalocyclohexanes15b,c and reported the enantioselective complexation of diequatorial (R,R)-trans1,2-dichlorocyclohexane by an optically active clathrate host.15a X-ray analyses confirm that all guests are bound in axial conformations by the AAC hosts. Comparisons between experimental and calculated dihedral angles for axial and 1,2diaxial conformers are provided. The conformations of the guest observed in the host are in close agreement with the theoretically predicted conformations of the isolated guests. This demonstrates that the interior of the AACs is ideal to capture and study the dihedral angles of their axial/diaxial conformations. We further report on the chiral recognition in the complexation of the (±)-trans-1,2-dihalocyclohexanes. The host−guest interactions are discussed in detail and evidence for CX···||| (acetylene) halogen bonding is provided.22 We also investigate the complexes in solution, using 1D and 2D NMR, ECD and Raman spectroscopies, which confirm similar conformational preferences to those seen in the solid state. This study confirms the outstanding ability of AACs to form porous networks in the solid state, complexing non-crystalline small molecules in their interior at room temperature, allowing for high-resolution X-ray diffraction (Figure 2A; see Supporting Information, Section S4.2 for details).17 They show highly ordered packing in a head-to-tail fashion with numerous dispersive contacts between the n-hexyl chains and the allenoacetylenic arms (Figure 2A).

characterization of molecular aggregates that complement insights obtained by experimental techniques.16 We recently reported on an enantiomerically pure allenoacetylenic cage (AAC) receptor that undergoes solvent-induced binary conformational switching between an open and a closed state, featuring very different chiroptical responses in the electronic circular dichroism (ECD) spectra (Figure 1).17 The

Figure 1. (A) Molecular structure of (P)4-AAC. (B) X-ray co-crystal structure of (P)4-AAC⊃(R,R)-trans-1,2-dimethylcyclohexane.17

(P)4-configured receptor underwent enantioselective inclusion complex formation with (R,R)-trans-1,2-dimethylcyclohexane, based purely on dispersive interactions and optimal spacefilling.18 Complete chiral resolution of (±)-trans-1,2-dimethylcyclohexane was observed in the X-ray crystal structures of the complexes of the (P)4-host with the (R,R)-guest and the (M)4host with the (S,S)-guest.17 The enantioselectivity was attributed to the structural rigidity and preorganization of the cage induced by the circular hydrogen-bonding array,19 which seals the top of the cavity.13b,20 The enantiomers of trans-1,2-dimethylcyclohexane bind in a higher-energy chair conformation with both methyl groups in a diaxial alignment. The dihedral angles Me−C(1)− C(2)−Me were measured as −148° for the (R,R)-guest and +144° for the (S,S)-guest (Figure 1). This substantial deviation from 180° without any apparent repulsive host−guest contacts called for more detailed studies on the dihedral angles in substituted cyclohexanes, both experimentally and theoretically.17 Here, we report comprehensive experimental and theoretical investigations on the conformational preferences of mono- and (±)-1,2-trans-dihalocyclohexanes (Figure 2), when bound in the interior of the AACs.

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METHODOLOGY Synthesis and X-ray Co-Crystal Structures. (P)4-AAC and (M)4-AAC were each synthesized as previously reported.17 To obtain single crystals suitable for X-ray diffraction, AACs (∼1 mg) were dissolved in 9:1 acetonitrile:H2O (1 mL) and the non-crystalline cyclohexane derivative was added (∼1−2 mg). The vial (1 mL) was placed into a second vial (2 mL) containing H2O, which was then sealed. By slow diffusion of H2O at room temperature (25 °C), crystallization occurred over 1−3 days. The single crystals were studied by single crystal X-ray diffraction; a detailed description is provided in the Supporting Information, Section S4. Eleven X-ray co-crystal structures of (P)4-AAC and (M)4-AAC with monosubstituted and trans-1,2-disubstituted cyclohexanes were obtained for this study. Theoretical Methodology. Guest structures were optimized with the Perdew−Burke−Ernzerhof density functional (PBE) 23 in combination with empirical D3 dispersion corrections24 (PBE-D3) and with spin-component scaled Møller−Plesset perturbation theory (SCS-MP2).25 (P)4AAC⊃guest structures were optimized with PBE-D3. A def2TZVPPD basis set26 on the halogen atoms and a def2-TZVPP basis set26 on all other atoms was chosen for all PBE-D3 and SCS-MP2 calculations in combination with the corresponding Ahlrichs’s density-fitting bases. Subsequent single-point energy evaluations incorporated counterpoise corrections27 (their effect is discussed in the Supporting Information). Additionally, we calculated single-point energies for the guest structures with explicitly correlated density-fitting local coupled cluster theory with single and double excitations and perturbative triple excitations (DF-LCCSD(T0)-F12b)28 in combination with a

Figure 2. (A) Crystal packing of (P)4-AAC⊃trans-1,2-dibromocyclohexane. Ellipsoids are shown at 50% probability at 100 K. The complexed guest is shown in the space-filling representation. (B) Summary of studied guests. 12191

DOI: 10.1021/jacs.7b05461 J. Am. Chem. Soc. 2017, 139, 12190−12200

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Journal of the American Chemical Society

Figure 3. X-ray co-crystal structures of (P)4-AAC⊃X-cyclohexane: X = fluoro (A), chloro (B), bromo (C), iodo (D). Complexed guests are in a higher-energy axial conformation, and ellipsoids are set at a 50% probability at 100 K. Dihedral angles (ϑa,a) are given for X−C(1)−C(2)−H. X = F, cyan; Cl, green; Br, brown; I, purple. See Supporting Information, Section S4 for details.

Figure 4. X-ray co-crystal structures of (P)4-AAC⊃trans-1,2-disubstituted cyclohexanes. (A) (P)4-AAC⊃(±)-trans-1,2-dichlorocyclohexane, with (R,R):(S,S) ratio 3:2. (B) (P)4-AAC⊃(±)-trans-1,2-dibromocyclohexane, with (R,R):(S,S) ratio 3:1. (C) (P)4-AAC⊃(R,R)-trans-1,2dimethylcyclohexane, with (R,R):(S,S) > 95:5.17 (M)4-AAC⊃trans-1,2-disubstituted cyclohexanes show counterclockwise orientation of the Hbonding array and inversion of the (R,R):(S,S) ratios. Complexed guests are in a higher-energy diaxial conformation, and ellipsoids are set at 50% probability at 100 K. (R,R)-Enantiomers are solid, and (S,S)-enantiomers transparent. Dihedral angles (ϑa,a) are given for R−C(1)−C(2)−R.

cc-pVTZ-F12 basis set.29 The calculation of a single-point energy with one method (e.g., DF-LCCSD(T0)-F12b) for a structure optimized with another method (e.g., SCS-MP2) is denoted by a double slash (e.g., DF-LCCSD(T0)-F12b//SCSMP2). Note that we present electronic energy differences at 0 Kelvin and without vibrational and temperature corrections in the gas phase for host−guest complexes. We additionally assessed Gibbs free energies for the isolated guest molecules according to the standard protocol (non-interacting molecules, rigid-rotor-harmonic-oscillator approximation; for details, see the Supporting Information). Details of the theoretical methodology and an assessment of its accuracy are also provided in the Supporting Information. NMR, FT-Raman, and Electronic Circular Dichroism (ECD) Spectroscopies. A detailed description of all methods is provided in the Supporting Information (see Sections S2 for binding experiments and Section S3 for guest complexation studies in solution).

the halogen to these rings decrease from 4.0 Å for the C Cl···π contact to 3.9 Å for the CBr···π and 3.8 Å for the C I···π contact (see Figure 3). The distance of the fluorine to the resorcin[4]arene core increases substantially (4.6 Å) and the guest shows disorder over two positions (Figure 3A). The decreasing distance of the CX···π contact progressing from F, Cl, Br to I, despite the increasing size of the halogen substituent, demonstrates the increasing strength of the interaction of the halogen with the aromatic resorcin[4]arene core. PBE-D3-optimized (P)4-AAC⊃halocyclohexanes confirm a decrease in the distance of the CX···π contact with an increasing atomic number of the halogen substituent from 4.4 Å (CF···π) to 4.0 Å (CI···π). The calculated interaction of iodocyclohexane with (P)4-AAC is 6.7 kcal mol−1 stronger than the corresponding interaction of fluorocyclohexane with the (P)4-AAC host, which is in agreement with our interpretation of the experimental results. Dihedral Angles of Halocyclohexanes Bound to AACs in the Solid State, ϑa,a. The existence of both the equatorial and the axial conformation of monosubstituted cyclohexanes was demonstrated in solution by IR spectroscopy at room temperature and by low temperature NMR spectroscopy, and led to a quantitative determination of the conformational energies (A-values).21e,33 Low temperature, near −150 °C, was required to separate the spectral features of the two conformers. However, no conformational isomer of monohalo- or (±)-trans-1,2-dihalocyclohexanes has ever been isolated at room temperature and only few X-ray crystal structures have been reported.15a−c,21e,34 All X-ray co-crystal structures of

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RESULTS AND DISCUSSION Halocyclohexanes Bound to AACs in the Solid State. It has recently been recognized in theoretical and experimental studies on CX···π contacts that aromatic groups can serve as halogen bond acceptors.30 The interaction strength increases with the polarizability of the halogen (Cl < Br < I).31 In our study of halocyclohexanes complexed in the AACs, the halogens are in close distance to the four electron-rich resorcinol rings of the cavitand core.32 Average distances of 12192

DOI: 10.1021/jacs.7b05461 J. Am. Chem. Soc. 2017, 139, 12190−12200

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of Cl and Br, as compared to the “harder” Me group,36 which enables better accommodation of both enantiomers in the cages. To further rationalize the enantioselective binding observed in the solid state theoretically, we determined the electronic energy differences (see Theoretical Methodology) between the diastereoisomeric complexes formed by (P)4-AAC with the enantiomers of the trans-1,2-dihalocyclohexanes (Cl, Br I). In agreement with the experimental results, the complex of (R,R)1,2-dichlorocyclohexane is 0.6 kcal mol−1 more stable than that of the (S,S)-isomer. This energy difference increases to 1.1 kcal mol−1 for the dibromo analogue, for which the complex of (R,R)-trans-1,2-dibromocyclohexane is more stable than the complex of the (S,S)-isomer. For trans-1,2-diiodocyclohexane, which could not be examined experimentally due to its instability, we predict an even larger enantioselectivity, with the complex of the (R,R)-enantiomer being 2.8 kcal mol−1 more stable than that of the (S,S)-enantiomer. Figure 5 visualizes the non-covalent interactions between guest and host for (P)4-AAC⊃(R,R)-trans-1,2-dibromocyclo-

halocyclohexanes in the AAC show the guest in the higherenergy axial conformation allowing for a detailed analysis of their dihedral angles. The axial dihedral angle ϑa,a (X−C(1)− C(2)−H) decreases from −173° in fluorocyclohexane to −165° for the chloro, bromo, and iodo derivatives, accompanied by a flattening of the ring dihedral angles (Supporting Information, Figure S64). (±)-trans-1,2-Disubstituted Halocyclohexanes Bound to AACs in the Solid State. In contrast to monosubstituted cyclohexanes, trans-1,2-disubstituted cyclohexanes are chiral.21e If complexed in the diaxial conformation, the two halogens could form two halogen bonds by CX···π interactions with the aromatic resorcin[4]arene core and CX···||| interactions to the alleno-acetylenic functionality of the host.22 Applying the above-described crystallization method with racemic trans-1,2dihalocyclohexanes and both (P)4- and (M)4-configured AACs, we obtained six co-crystal structures. Similar to trans-1,2-dimethylcyclohexane,17 both the trans1,2-dichloro and trans-1,2-dibromo derivatives are bound in their diaxial conformation (Figure 4). Comparing the occupancies of the two enantiomers of the chiral guests encapsulated in the AACs enabled us to approximate the enantioselectivity of the complexation in the solid state. The enantiomeric ratio (R,R):(S,S) of trans-1,2-dichlorocyclohexane bound to the (P)4-AAC was 3:2. By increasing the size of the substituents from trans-1,2-dichloro- to trans-1,2-dibromocyclohexane, the (R,R):(S,S) ratio increased to 3:1. With (M)4AAC, the inverse enantiomeric ratios were obtained. In both co-crystal structures, one halogen is directed toward the aromatic surface while the second halogen is oriented toward the acetylene moiety of one alleno-acetylenic arm of the receptor (Figure 4). The CX···π contacts of the trans-1,2dihalocyclohexanes with the aromatic resorcin[4]arene core are 0.3 Å shorter compared to those seen in the corresponding monohalocyclohexane analogues (Figure 3), revealing stronger CX···π contacts. In the complex of the (P)4-AAC with (R,R)trans-1,2-dichlorocyclohexane, the distance of the second chloride to the acetylene (Cl···|||) is 3.4 Å, with a CCl··· CC angle of 167°. The bound (S,S)-enantiomer shows a Cl···||| distance of 3.4 Å with a CCl···CC angle of 154°. With trans-1,2-dibromocyclohexane, the CBr ···||| distance in the (P)4-AAC⊃(R,R)-guest complex is decreased to 3.3 Å (C Br···CC angle of 169°) while the minor populated (S,S)enantiomer gives d(Br···|||) = 3.2 Å and a CBr···CC angle of 154°. All halogen-bonding contacts to the π-system of the acetylene occur at distances below the sum of their van der Waals radii.35 For trans-1,2-bromofluorocyclohexane, the fluorine faces away from the acetylenic backbone (see Supporting Information, Section S4.6). In this case, the AAC optimizes space-filling and shape complementarity (see Supporting Information, Section S4.9, for calculated packing coefficients)18 by rotating one methyl group of one of the four tertiary alcohol termini into the cavity, allowing for close contacts of the fluorine with this endo-methyl group (observed both for the (P)4- and (M)4-configured AACs). While enantiomers with the same absolute configuration are preferred by the optically active AACs ((P)4-AAC prefers (R,R)-configured guests), the enantioselectivity in the inclusion complexation of the (±)-trans-1,2-dihalocyclohexanes is lower than that observed in the case of (±)-trans-1,2-dimethylcyclohexane,17 despite the absence of directional interactions such as CX···π and CX···||| in the complex of the latter. We rationalized this observation with the much higher polarizability

Figure 5. Isosurface of the reduced density gradient s(r) of density functional theory for s(r) = 0.5 revealing the interaction between (R,R)-trans-1,2-dibromocyclohexane and (P)4-AAC within a radius of 4.5 Å around the centroid of the guest molecule. The surfaces are colored on a blue-green-red scale according to values of sign(λ2)ρ(r), ranging from −0.05 to 0.05 au. Blue indicates strongly attractive interactions such as hydrogen-bonding, and green indicates dispersive interactions; red would indicate steric clashes, but no such red regions emerged in the analysis. The definitions for s(r), λ2, and ρ(r) are given in the Supporting Information. Element color code: carbon in host, light gray; carbon in guest, dark gray; oxygen, red; bromine, dark red; hydrogen, white. Hydrogen atoms of the host are omitted for clarity.

hexane evaluated in terms of the reduced density gradient as proposed by Yang and co-workers.37 Note that separation of the host and guest emerged automatically from the calculation on the full host−guest compound and did not have to be introduced in the analysis a priori. The analysis uncovers that no major steric clashes between the guest and the host are present, further illustrating the perfect shape complementarity in the ensemble. The guest instead exhibits allover enveloping dispersive interactions (indicated in green and light blue) with the host. Variable-Temperature X-ray Diffraction. To further visualize the stronger binding of one enantiomer, a single crystal of (P)4-AAC⊃trans-1,2-dibromocyclohexane ((R,R): 12193

DOI: 10.1021/jacs.7b05461 J. Am. Chem. Soc. 2017, 139, 12190−12200

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Journal of the American Chemical Society (S,S) ratio = 3:1) was measured at temperatures between 100 and 280 K in increments of 20 K (Figure 6 and Supporting

Figure 6. X-ray co-crystal structure of (P)4-AAC⊃trans-1,2-dibromocyclohexane measured at 100, 160, 220, and 260 K. Ellipsoids are set at 50% probability. The weaker binding (S,S)-enantiomer shows a stronger increase in ellipsoids size and a second population appears at 220 K.

Information, Section S4.5). We expected the stronger binding (R,R)-enantiomer to show suppressed thermal motion visualized in the size of the thermal ellipsoid compared to the weaker binding (S,S)-enantiomer (ellipsoids were set at 50% probability). Relative to the host, the weaker binding (S,S)-enantiomer showed significantly stronger disorder and a second population, rotated 90° clockwise, already appeared at 220 K (Figure 6). This qualitative comparison of the thermal motion of the two enantiomers at variable temperatures gives further evidence of the selectivity toward one enantiomer in the solid state.38 Theoretical Analysis of the Geometrical Requirements for CX···||| Halogen Bonding. Riley et al.30f studied the orientation dependence of the strength of the C Br···π halogen bond. They concluded that tilting and shifting a halocarbon bond relative to a benzene molecule has a minor effect on the halogen bond strength, which implies low geometric requirements for this type of bond. While these results can be transferred straightforwardly to the interaction of the halogenated guest molecules with the four aromatic rings of the resorcin[4]arene core, no information can be deduced for the geometric requirements of CX···||| contacts. Therefore, we set up a model for the interaction in the host: a halomethane molecule interacting with a 2-butyne molecule (Figure 7). The 2-butyne molecule serves as a model for the acetylenic bond of the alleno-acetylenic arm of the receptor and the halomethane molecule as a model for the guest. Fluoromethane does not exhibit halogen bonding and is not considered in the following. All other halomethanes display a X···||| distance of 3.4−3.5 Å and a CX···CC angle of 179− 180° at their minimum energy structures (Figure 7). As calculated for CX···π interactions,30a,c,d,f,h the halogen bond strength increases with the atomic number of the halogen substituent (X = Cl, 0.9 kcal mol−1; X = Br, 1.3 kcal mol−1; X = I, 2.0 kcal mol−1). To study the geometric requirements of C X···||| halogen bonds, we evaluated the energies required for modifications of the distance of the X···||| contact and the C X···CC angle (Figure 7). Varying the X···||| distance at a fixed CX···CC angle of 180° leads to a slight decrease of the halogen bond strength in the range of 3.3−3.9 Å for all X (at most by 0.5 kcal mol−1). Keeping the distance fixed at 3.5 Å and tilting the halomethane also results in a slow decrease of the halogen bond strength. It decreases by 0.3 kcal mol−1 when tilting to 145° for X = Cl, by 0.7 kcal mol−1 for X = Br, and by 1.4 kcal mol−1 for X = I. For all halogen substituents, the interactions become repulsive for

Figure 7. SCS-MP2 potential energy surface [kcal mol−1] for variations of X···||| distances [pm] and CX···CC angles [°] for X = Cl (top) and X = Br (bottom). For X = I, see Supporting Information, Figure S80.

small distances (