Conformational Polymorphism and Isomorphism of Molecular Rotors

Article pubs.acs.org/crystal

Conformational Polymorphism and Isomorphism of Molecular Rotors with Fluoroaromatic Rotators and Mestranol Stators Braulio Rodríguez-Molina,† Ma. Eugenia Ochoa,‡ Margarita Romero,§ Saeed I. Khan,† Norberto Farfán,§ Rosa Santillan,‡ and Miguel A. Garcia-Garibay*,† †

Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States Departamento de Química, Centro de Investigación y de Estudios Avanzados del IPN, México D.F. Apdo. Postal 14-740, 07000, México § Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México D.F., México ‡

S Supporting Information *

ABSTRACT: We report the synthesis and characterization of four molecular rotors 2, 3, 4, and 5 containing 2-fluoro-, 2,3-difluoro-, 2,5-difluoro-, and 2,3,5,6tetrafluoro-substituted 1,4-phenylene rotators, respectively, that are axially linked through the triple bonds of rigid mestranol (3-methoxy-17α-ethynylestradiol) stators. Crystallization experiments using solvent mixtures of hexanes−ethyl acetate and acetonitrile−dichloromethane gave rise to polymorphic, pseudopolymorphic, and isomorphic crystals. Whereas two solids were obtained for compound 2, four were indentified in the cases of compounds 3 and 4, and three for compound 5. The 13 solid forms were characterized by single-crystal and powder X-ray diffraction, infrared spectroscopy, differential scanning calorimetry, and thermogravimetric analysis. Two sets of isomorphous structures were obtained for solvated and solvent-free structures of compounds 3−5. While polymorphic behavior of these compounds arises from their conformational freedom in solution, their isomorphism arises from the closely isosteric relation that exists between hydrogen and fluorine atoms.

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INTRODUCTION Solids that combine long-range molecular order with fast molecular reorientation offer a promising approach for the development of a novel class of functional materials with potential applications in materials science, nanotechnology, and the emergent field of artificial molecular machines.1,2 With a combination of static components to provide an ordered architecture and mobile elements that modulate their function, these materials are also known as amphidynamic crystals.1,3 Collective changes in molecular orientation within the framework of a macroscopic crystalline material have the potential of controlling the transmission, polarization, and frequency of light,4 their dielectric and ferroelectric behavior,5−7 their conductivity,8 and other materials properties.9 Over the past few years, we have designed and synthesized a relatively large number of molecules that form amphidynamic crystals based on structures that possess an axially linked group acting as a rotator (e.g., 1,4-phenylene), which is connected through triple bonds that constitute the rotational axle to a rigid and shielding structure that plays the role of a latticeforming stator.10 Using a combination of variable-temperature solid-state NMR,11 X-ray determined anisotropic displacement parameters,12 and dielectric spectroscopy,13 we have established some of the structure−function relations that determine the dynamics of the rotator. These include the shielding effects of the stator, the axial symmetry order of the rotator,14 and the presence of free volume around the rotator.3,15 © 2013 American Chemical Society

Recently, we reported the synthesis and solid-state characterization of very fast crystalline molecular rotors with phenylene16 (or byciclo[2.2.2]octane)17 rotators linked through the alkyne of two mestranol molecules that act together as the stator (e.g., rotor 1 in Figure 1a, which features the mobile part in red and the static components in blue). In agreement with the low barriers for rotation about C−C sp3−sp single bonds18 connecting the steroid to the alkyne and the phenylene rotator,19 we found that the phenylene−mestranol rotor 1 crystallized in syn- and anti-conformations that included a DMF-solvate in the space group P212121 and a solvent-free structure in the space group P32.20 The latter, termed hereafter as form I, showed the steroidal components adopting a synconformation and was consistently obtained in a large number of solvent and solvent mixtures while the P212121 became a disappearing solvate.21 As shown in Figure 1a, molecular rotors in form I pack in a nested chiral helical array with phenylene rotators stacked in columns with a center-to-center distance of 4.91 Å, which is much greater than the distance between parallel π-stacked aromatic layers (ca. 3.4 Å). The spacing observed is large enough to permit very fast rotation in the solid state (>108 s−1 at 298 K), but short enough for rotational motion to be highly Received: August 26, 2013 Revised: October 3, 2013 Published: October 4, 2013 5107

dx.doi.org/10.1021/cg4012873 | Cryst. Growth Des. 2013, 13, 5107−5115

Crystal Growth & Design

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Our initial efforts are focused on the inclusion of fluorine atoms in the rotator in order to introduce an electric dipole with the polar C−F bond.22 The inclusion of electric dipoles should give rise to molecular analogues of macroscopic compasses,23 with a collective behavior such as that expected for a correlated rotary dipolar array.24,25 At the same time, the replacement of hydrogen (C−H = 0.95 Å) by fluorine (C−F = 1.35 Å) represents the smallest modification in terms of size, which may give the greatest chance for the growth of isomorphic crystals.26 In this paper, we report the synthesis, characterization, and crystallization of molecular rotors 2−5 with fluorine atoms in the central phenylene ring (Scheme 1). Molecular rotors 2 and 3 with one and two fluorine atoms have calculated dipoles of ca. 1.5 and 3.0 D,12,13 respectively. The symmetric molecular rotators in 4 and 5 were synthesized to evaluate the crystallization effects of added fluorine atoms and the potential steric effects on the barriers to rotation. While the fluorine atoms in the para-position of molecular rotor 4 result in zero dipole moment when isolated in the gas phase or in solution, different rotational states between adjacent neighbors in the crystalline helical array are expected to have different dipole− dipole interactions so that dipolar correlations may be expected. On the basis of preliminary solubility experiments, we identified solvent mixtures of hexanes and ethyl acetate or acetonitrile and dichloromethane as the most promising crystallization media. The analysis of single-crystal and powder X-ray diffraction as well as the thermal properties of the various solid forms allowed us to establish the relations that exist between different solid forms and the knowledge necessary to select the structures and required experimental conditions needed to obtain the desirable helical array found in form I.

Figure 1. (a) Phenylene−mestranol molecular rotor 1 with the stator in blue and the rotator in red along with its packing diagram illustrating the formation of helical columns characteristic of form I. (b) The inclusion of dipoles in the central phenylene rotator in compounds 2−5 (in Scheme 1) may generate crystals isomorphous to 1, which would be ideal to study correlated rotation by dipole−dipole interactions.

correlated, as characterized by 2H solid-state NMR.16 The close contacts and dynamic behavior observed in form I of molecular rotor 1 encouraged us to explore analogous molecules that may be able to display correlated rotation influenced by dipole− dipole interactions, as indicated on the right side of Figure 1b. Scheme 1a

a

Reaction conditions: PdCl2(PPh3)2, CuI, (iPr)2NH, dry THF, reflux. The numbering system follows the convention used for steroids. 5108



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RESULTS AND DISCUSSION Synthesis and Characterization. Molecular rotors 2−5 were synthesized by a Sonogashira cross-coupling reaction using Pd(0) and Cu(I) as catalyst and cocatalyst, respectively. The compounds were obtained from moderate to good yields (53−87%) starting from commercially available mestranol, 2fluoro-1,4-diiodobenzene, 2,5-difluoro-1,4-dibromobenzene, and 2,3,5,6-tetrafluoro-1,4-dibromobenzene, as outlined in Scheme 1. In the case of molecular rotor 3, the 1,4-diiodo-2,3difluorobenzene rotator was synthesized as indicated in the Supporting Information. In all cases, the homocoupling product 6 (alkyne−alkyne) was obtained in yields ranging from 10% in the synthesis of compound 3 up to 30% in the case of molecular rotor 5. Fractional recrystallization had to be used occasionally after column chromatography to remove the impurity.27 The characterization and assignment of molecular rotors 2−5 were carried out by using 1D and 2D solution NMR. The chemical shifts of the hydrogen and carbon atoms of the rotators are compiled in Tables S1 and S2, respectively (Supporting Information). It is interesting to note that, in compound 2, the fluorine atom renders the two halves of the molecule nonequivalent, giving rise to a large number of resolved signals in the 1H and 13C NMR spectra. Conversely, the presence of two or four fluorine atoms in compounds 3−5 allows a time-averaged C2 symmetry of the molecules in solution, therefore, showing signals that account only for half of the molecule. In solution 1H NMR, the protons of the central phenyl rings in compounds 2−4 are coupled with the 19F atoms, increasing the multiplicity of the signals, as observed in compound 2 when the hydrogen H24 (δ = 7.13) appears as a doublet of doublets due to the three-bond coupling with fluorine (3JHF = 9.6 Hz) and w-coupling with H26 (J = 1.4 Hz). Similarly, the signal from proton H24 in compound 3 is a doublet of doublets due to the four- and five-bond coupling with the two magnetically nonequivalent fluorine atoms. The 13C NMR signals in solution were also affected by the heteronuclear 13C−19F coupling. This is particularly noticeable in the carbon atoms that bear the halogen, with large C−F coupling values of ca. 250 Hz that agree well with the values reported in the literature.28 The strength of this scalar coupling decreases abruptly with distance, as exemplified in compound 2, where carbon C23 (d, δ = 162.3) has a large coupling constant 1 JCF = 252 Hz, whereas carbons C24 (d, δ = 118.5) and C22 (d, δ = 111.7) also appear as doublets but show coupling constants of only 2JCF = 22.5 Hz and 2JCF = 16.2 Hz, respectively. Because of the time-averaged C2 symmetry in solution, the rotators of compounds 3 and 4 present fewer signals in their 13C spectra than compound 2 did; however, their characteristic chemical shifts and multiplicities can be used to identify them. In compound 3, the signal of carbon C23 (dd, δ = 151.0) interacts with the fluorine atoms at one and two bonds (1JCF = 254 Hz, 2 JCF = 15 Hz), whereas, in compound 4, carbon C23 (dd, δ = 158.3) is coupled at one and four bonds (1JCF = 250 Hz, 4JCF = 3.6 Hz). Finally, in the case of compound 5, carbon atom C23 presents coupling with all the 19F atoms (dddd, δ = 146.7, 1JCF = 254 Hz, 2JCF = 20 Hz, 3JCF = 11 Hz, and 4JCF = 4.3 Hz). Crystallization and Polymorph Screening. Slow evaporation of hexanes/ethyl acetate used in column chromatography29 yielded small transparent needles from compounds 2, 3, and 5, and a white crystalline powder from compound 4. Subsequent crystallizations were explored by dissolving the

desired compounds, typically ca. 5−10 mg in 1 mL of pure solvents or solvent mixtures, and letting them evaporate slowly in small uncapped glass vials. The selection of solvents was based on the solubility of the compounds. Molecular rotors 2− 5 showed good solubility in aromatic solvents (benzene, toluene, xylenes), ethyl acetate, chloroform (CHCl3), and dichloromethane (CH 2Cl2). They were less soluble in dimethylformamide30 and scarcely soluble in acetonitrile, but insoluble in hexanes, methanol, or ethanol. The use of aromatic or halogenated pure solvents afforded amorphous solids in all cases. Mixtures of hexanes−ethyl acetate (4:1) or acetonitrile− dichloromethane (4:1) gave crystalline solids. The resulting solids were analyzed by optical microscopy, infrared spectroscopy, and single-crystal and powder X-ray diffraction (PXRD). Considering their structural similarity, and based on crystallographic information, we labeled the 13 solvates and solvent-free forms obtained from compounds 2−5 in a sequential Roman numeral order, starting from the already reported helical form I up to form VIII. Using this labeling system, we attempted to identify the sets of isomorphic crystals and their crystallization conditions. After the analysis of the results, we were able to develop a correlation scheme for the crystallization of these compounds, which will be discussed in the final section of the article. The first crystal structure of compound 2 was obtained from a specimen resulting from direct evaporation of the column chromatography binary mixture of hexanes/ethyl acetate.31 The colorless crystal was solved in the space group P212121 (mp 230−236 °C), revealing that the molecular rotor adopts a synconformation that is different from that previously observed in compound 1, which was subsequently referred to as form II (Figure 2b). The syn-molecular rotors in this form pack in antiparallel layers propagated by hydrogen bonds between the hydroxyl groups of neighboring molecules, as illustrated in Figure 2d (see the Supporting Information for H-bond distances and angles). While the fluorine atom in the structure is disordered over all four positions in the central phenyl ring, occupancies varied in proportions of 48:33:14:5. By contrast, crystallization of 2 at room temperature using acetonitrile−dichloromethane (4:1) yielded small crystals in the sought-after form I (mp 212−213 °C), as depicted in Figure 2a. The molecular conformation observed in these crystals solved in the space group P32 and the crystallographic parameters in Table 1 confirm that it is isomorphic to the previously reported form I of the phenylene−mestranol rotor 1. A single fluorine atom in the central phenylene of 2 does not alter the desired helical array with the aromatic rotator disordered over two positions with 58:42 occupancies, which is very similar to the 55:45 disorder of the phenylene group in the P32 crystals of 1. In agreement with our expectation, the fluorine atom was also disordered over all eight possible positions in the central phenyl ring with occupancies ranging from 40% to 5%. Given the packing similarity of 2 (Figure 2c) with that of phenylene−mestranol 1, we anticipate that the internal dynamics in crystals of 2 (form I) will be in the fast exchange regime, which is to be corroborated by solid-state NMR. On the basis of the promising results with the monofluoro analogue 2, we explored the crystallization of 2,3-difluorophenylene 3, which features a larger permanent dipole. Colorless needles of 3 (mp 231−235 °C) were obtained after slow evaporation of column chromatography fractions from hexanes−ethyl acetate (4:1), and the X-ray analysis showed 5109



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ray analysis. The crystals grown under these conditions were collected and solved also in the space group P212121, but this time, the molecules of 3 adopted a slightly different synconformation as compared to that observed in the previous structure from hexanes−ethyl acetate. The molecular rotors in this new form, labeled as form III, crystallized with acetonitrile molecules embedded in the lattice through H-bonds with the hydroxyl groups (Figure 4a). This packing array also presents an interaction between the aromatic rings of the steroid framework and the central rotator, with centroid-to-centroid distances ranging from 3.75 to 3.81 Å (Figure 4b). Although a lower temperature in the acetonitrile−dichloromethane solutions was advantageous in order to grow larger crystals of 3, the calculated PXRD did not match the experimental one that had been previously obtained using the same solvent mixture at room temperature. Given that the MeCN solvate crystals of 3 become opaque at room temperature in less than 2 h, we investigated the solid derived from the solvent loss. The dry solid showed a PXRD pattern that is different from both, that of the initial solvate form III, and the one from solvent-free form II, so it was identified as form IV. Analysis of form IV by differential scanning calorimetry showed in the 150−170 °C range an endothermic event, followed by an exothermic process, which was attributed to a melt−crystallization transition. Interestingly, the solid obtained after this heating has a PXRD that matches the one from form II obtained from hexanes/ethyl acetate. This recrystallization could be regarded as the result of two concurrent structural changes: perpendicular layers of molecular rotors in form III slide as the MeCN molecules evolve. At the same time, the two steroids move toward a more eclipsed conformation, resulting in the antiparallel layers that characterize form II (Figure 5). Following this recrystallization, the calorimetric trace of compound 3 showed an endotherm at 232−234 °C that is consistent with the visually determined melting point of form II, ruling out any additional phase transitions. Given the number of solid forms observed in compounds 2 and 3, it was interesting to determine the crystallization of compounds 4 and 5 with two para-related and four fluorine atoms, respectively. We selected the two fluorine atoms in 4 to be in the para-position in order to modify the axial symmetry of the central phenyl ring and reduce the potential distortion caused by the two neighboring fluorine atoms used in rotor 3. Balancing the electronegative and steric effects, we considered that crystallization of 4 might favor form I. However, crystallization of 4 from hexanes−ethyl acetate, either after column chromatography or by redissolving the solid, afforded only a crystalline solid (mp 230−235 °C) with a PXRD pattern that matches that of the solvent-free form II observed in compounds 2 and 3. Conversely, the acetonitrile−dichloromethane mixture (4:1) gave different solids depending on the temperature employed. At low temperature, compound 4 grows in plate-shaped crystals suitable for single-crystal X-ray diffraction studies. The crystals grown at 0−4 °C were solved in the space group P21 with MeCN molecules in the lattice, and this form was identified as V. Although a slightly different crystal symmetry, the molecular rotor 4 in form V adopted the same syn-conformation and packing array observed in form III of compound 3. When the crystallization of 4 was carried out at room temperature, the prisms obtained using acetonitrile−dichloromethane (4:1) were not suitable for single-crystal X-ray diffraction, but the PXRD

Figure 2. Two crystal forms of monofluorinated phenylene rotator 2 with the stator in blue, the rotator in red, and the F atoms in yellow. (a) Molecular structure in form I with syn-conformation from acetonitrile/dichloromethane (4:1) showing the phenyl group and F atom rotationally and positionally disordered. (b) Molecular structure in form II (hexanes/ethyl acetate) also with syn-conformation and the F atom disordered over all four aromatic positions. (c) Helical stack of rotors in form I, space group P32. (d) Parallel layers of rotors in form II, solved in the space group P212121.

that they are isomorphous with form II obtained from compound 2 grown under similar conditions (see Table 1 for crystallographic parameters). In this solvent-free form II, the packing array of 3 is also propagated through hydrogen bonds but no disorder was observed in the position of the fluorine atoms. Experiments intended to grow large batches of 3 in the solvent-free form II yielded mixed results.32 Close analysis revealed that form II was obtained most of the time, but occasionally form I (P32) was formed instead. It is important to note that no concomitant crystallization was detected, as only one form was detected in each of the vials analyzed. So far, form I of compound 3 (mp 223−226 °C) has only been obtained intermittently as a crystalline solid, but it can be easily identified by its attenuated total reflectance Fourier transform infrared spectrum (ATR-FTIR), and its powder X-ray diffraction pattern, which matches that of the original unsubstituted phenylene rotor 1, as illustrated in Figure 3. In addition to the previous crystallization experiments, we seeded concentrated solutions of 3 with small crystallites of compound 1 in its form I, without any change in the resulting crystal forms. Crystallizations of 3 using the same conditions that consistently yielded form I in compound 2 were carried out at 25 °C using a mixture of acetonitrile−dichloromethane (4:1). Very small prisms of 3 belonging to a different crystalline phase were identified by inspection of their PXRD pattern. Hoping to obtain larger crystals, we carried out experiments at 0−4 °C to reduce the evaporation rate of the solvent mixture; after 2 days, we harvested crystals of 3 that were suitable for X5110



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Table 1. Crystallographic Parameters of Compounds 1−3 compound

1

2

2

3

label empirical formula formula weight space group crystal system a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å)3 Z Z′ D (mg/m3) crystal size (mm) wavelength (Å) θ range for data collection (deg) reflns collected unique reflns (Rint) data/restraint/parameters final R indexes R indexes (all data) goodness of fit ρmin (e·Å3) ρmax (e·Å3) temp (K)

form I C48H54O4 694.91 P32 trigonal 14.7945(6) 14.7945(6) 14.7246(4) 90.00 90.00 120.00 2792(2) 3 1 1.24 0.3 × 0.15 × 0.12 0.71073 2.91−27.46 7906 5621(0.0508) 7906/25/501 0.0512/0.0818 0.0875/0.0925 0.981 −0.198 0.23 173(2)

form I C48H53FO4 712.90 P32 trigonal 14.832(3) 14.832(3) 14.751(3) 90.00 90.00 120.00 2810(1) 3 1 1.264 0.40 × 0.20 × 0.20 0.71073 3.89−28.12 9165 6883(0.0477) 9165/140/552 0.0560/0.1174 0.0820/0.1287 1.071 −0.191 0.211 100(2)

form II C48H53FO4 712.90 P212121 orthorhombic 7.077(2) 17.650(4) 30.592(7) 90.00 90.00 90.00 3821(2) 4 1 1.239 0.60 × 0.06 × 0.06 0.71073 3.69−28.26 5376 4281(0.0559) 5376/33/515 0.0435/0.0932 0.0632/0.1009 1.052 −0.179 0.267 100(2)

form II C48H52F2O4 730.90 P212121 orthorhombic 7.037(1) 17.640(3) 31.045(5) 90.00 90.00 90.00 3854(1) 4 1 1.260 0.60 × 0.06 × 0.06 0.71073 3.76−28.41 5449 4628(0.0533) 5449/0/493 0.0395/0.0916 0.0516/0.0978 1.024 −0.168 0.271 100(2)

Figure 3. (a) Calculated powder X-ray diffraction patterns (PXRD) of 2,3-difluorophenylene-substituted rotor 3 from the solvent-free form II first obtained from hexanes−ethyl acetate. (b, c) Experimental PXRD from different crystallizations of 3 from the same solvent mixture as that of the original single crystal. (d) Calculated PXRD from crystals of phenylene rotor 1 in form I, indicating that some crystallizations of 3 with hexanes−ethyl acetate result in formation of the P32 form.

Figure 4. (a) Molecular structure of the form III of compound 3 with syn-conformation, obtained from acetonitrile−dichloromethane at 0−4 °C. The stator is in blue, the rotator in red, and the F atoms in yellow. The hydroxyl groups of the rotor interact with the MeCN molecules, forming O−H...N hydrogen bonds. (b) Perpendicular array of molecules with π−π interactions between phenyl rings of the rotator and neighboring stators.

pattern and the infrared spectrum revealed a new crystalline form VI. Thermogravimetric analysis revealed that this new phase VI loses 4−5% of weight starting at 55 °C, which coincides with a small endotherm between 63 and 85 °C in the differential scanning calorimetric trace. Assuming that only acetonitrile molecules are contained in solid form VI, these transitions are consistent with the loss of ca. one molecule of MeCN (bp 82 °C) per molecular rotor of 4, resulting in a new crystal phase VII (mp 235−240 °C).33 Compared to the

crystallization experiments of compound 3, we did not attempt seeding saturated solutions of 4 with compound 1 in its form I. 5111



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electron-poor rotator and the electron-rich methoxy-aromatic rings in the steroidal stator. Interestingly, subsequent recrystallizations of 5 in hexanes−ethyl acetate resulted in form II with the syn-conformation (mp 225−230 °C), previously identified in molecular rotors 2−4. Complementarily, crystallization of molecular rotor 5 from the acetonitrile− dichloromethane mixture resulted in formation of squareshaped crystals when 4 vol equiv of acetonitrile were added to 1 vol equiv of a concentrated dichloromethane solution at room temperature. The crystals of 5 obtained in this manner contained acetonitrile molecules in the lattice and are isomorphous to form III in compound 3 (Table 2). Although crystals of compound 5 in form III also desolvate, they are stable for up to 1 day at ambient temperature. Thermogravimetric experiments of compound 5 revealed that freshly grown crystals of form III lose 9.5% of their weight in the temperature range of 25−115 °C, which corresponds to the loss of two molecules of acetonitrile (9.7% was calculated from the crystal structure). Calorimetric experiments showed a small endothermic transition at 115 °C in the DSC trace after MeCN evaporation, which was followed by a larger endotherm at 242− 248 °C. PXRD analysis of the solid heated above the first endotherm indicates that, after losing acetonitrile, the solid melts and recrystallizes into the described anti-form VIII (visual mp 241−247 °C), as illustrated in Figure 6. As in the case of compound 4, we did not use seeds of form I from compound 1 to induce its crystallization from saturated solutions of 5. Considering all the results together, in Figure 7, we have established the relation that exists among the crystalline solids obtained from compounds 2−5, which highlights the similarities and differences in the crystallization outcome

Figure 5. View down the crystallographic c axis of the two P212121 crystal forms of compound 3 with slightly different syn-conformations, which appear to be related by the loss of acetonitrile at room temperature. The solvate form III on the left was obtained at low temperature from acetonitrile−dichloromethane. The crystal form II on the right was obtained from hexanes−ethyl acetate. Acetonitrile molecules on the left unit cell were removed for clarity.

In the case of compound 5, with all the hydrogen atoms in the central phenylene replaced by fluorine, slow evaporation of hexanes−ethyl acetate in the column chromatography fractions yielded colorless needles at room temperature. The crystals were also solved in the space group P212121 (mp 247−248 °C), as in the case of rotors 2−4. Unlike the other fluorinated rotors, the molecules of 5 adopt an anti-conformation labeled as form VIII, with interpenetrated layers of rotors connected by hydrogen bonds and aromatic interactions between the Table 2. Crystallographic Parameters of Compounds 3−5 compound

3

4

5

5

label empirical formula formula weight space group crystal system a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) volume (Å)3 Z Z′ D (mg/m3) crystal size (mm) wavelength (Å) θ range for data collection (deg) reflns collected unique reflns (Rint) data/restraint/parameters final R indexes R indexes (all data) goodness of fit ρmin (e·Å3) ρmax (e·Å3) temp (K)

form III C48H52F2O4,2(CH3CN) 813.00 P212121 orthorhombic 12.6657(3) 13.1555(4) 26.4441(7) 90.00 90.00 90.00 4406.2(2) 4 1 1.225 0.75 × 0.5 × 0.375 0.71073 2.71−27.52 9462 8172(0.0531) 9462/0/555 0.0558/0.1322 0.0686/0.1407 1.086 −0.259 0.686 173(2)

form V C48H52F2O4,2(CH3CN) 813.00 P21 monoclinic 13.0753(8) 12.7032(8) 13.5212(8) 90.00 103.593(1) 90.00 2182.9(2) 2 1 1.237 0.38 × 0.20 × 0.20 0.71073 3.49−28.24 5634 4315 (0.0760) 5634/1/568 0.0479/0.0871 0.0710/0.0964 1.070 −0.264 0.233 100(2)

form III C48H50F4O4,2(CH3CN) 848.98 P212121 orthorhombic 12.770(2) 13.057(2) 26.323(4) 90.00 90.00 90.00 4389(1) 4 1 1.285 0.20 × 0.18 × 0.05 0.71073 3.48−27.74 10 815 8741 (0.0499) 10815/0/567 0.0446/0.1103 0.0603/0.1197 1.023 −0.244 0.381 100(2)

form VIII C48H50F4O4 766.88 P212121 orthorhombic 17.386(2) 19.968(2) 22.353(2) 90.00 90.00 90.00 7760(1) 8 2 1.313 0.36 × 0.12 × 0.08 0.71073 3.61−29.20 10 815 9410 (0.0573) 10815/1/1023 0.0401/0.0924 0.0559//0.1001 1.066 −0.264 0.386 100(2)

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solvent free-form II, but form VI from compound 4 gives rise to a new crystalline form VII. Interestingly, crystallization from acetonitrile−dichloromethane at ambient temperature favored the fast crystallization of compound 5 as a MeCN solvate in the space group P212121, which is isomorphous with that of 3 (form III) but more stable at ambient temperature. The acetonitrile molecules in the crystals of form III of the tetrafluorinated compound 5 escape the lattice upon heating and recrystallize in the known solvent-free P212121 anti-form VIII.

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Figure 6. Molecular structures of compound 5 showing the two conformations related by an irreversible phase transition, with the stators in blue, the rotators in red, and the F atoms in yellow. Left: Form III from a mixture of acetonitrile−dichloromethane with the molecular rotor adopting the syn-conformation. Right: Solvent-free form VIII from hexanes−ethyl acetate with the molecular rotor adopting an anti-conformation.

CONCLUSIONS After the successful preparation of molecular rotors analogous to compound 1 with fluorine atoms in the rotator to give compounds 2−5, crystallization experiments indicate that the molecular rotors adopt different conformations and packing arrangements in the solid state depending on the type of solvent, their proportion, and crystallization temperature. Among the several crystalline forms that were detected for molecular rotors 2−5 by different spectroscopic methods, we were able to characterize two solvent-free forms for monofluorinated rotor 2, one of them being isomorphic with the P32 form I of the parent rotor 1, the other one being the solvent-free form II. In the case of difluorinated compound 3, evidence for four crystal forms was identified (forms I, II, III, and IV). Three of those conformational polymorphs/solvates crystallizing in the space group P212121 are related through the loss of acetonitrile from the crystal lattice (III to IV to II), with the fourth one crystallizing intermittently in the desired helical array that characterizes the P32 space group of form I. From these experiments, we concluded that the helical P32 form I can be preferentially obtained in molecular rotor 2 using CH3CN/CH2Cl2 at low temperature. Given the identical packing between the recently crystallized 2 and the parent rotor 1, we anticipate that the internal dynamics in crystals of 2 will be in the fast exchange regime. This will be corroborated in due course using VT 13C CPMAS and 2H solid-state NMR using a deuterated isotopologue. Moreover, the proximity of the fluorinated rotators in this crystal array may enable the study of dipole−dipole interactions and potential ferroelectric/

under the conditions described. It is important to note that the unsubstituted phenylene−mestranol rotor 1 consistently crystallizes in the space group P32 (form I) under all the conditions described, suggesting that it is the most stable crystal structure for that compound. In the right part of Figure 7, we depict the fact that molecular rotors 2−4 first crystallized in the solvent-free P212121 syn-form II right after column chromatography using hexanes−ethyl acetate (4:1). However, compound 5 crystallized in the P212121 anti-form VIII. Dissolving the solids in ethylacetate and adding hexanes to the solution reproduced the solvent-free P212121 syn-form II for compounds 2 through 4, but changed the conformation of 5 from the P212121 anti-form VIII to the P212121 syn-form II. Additionally, compound 3 also crystallized intermittently in the P32 form I under the same conditions. Crystallization experiments at 0−4 °C in acetonitrile− dichloromethane illustrated in the left part of Figure 7, yielded crystals in the P32 form I for compound 2 and gave a related acetonitrile solvate P212121 crystals for compound 3 (form III) and P21 crystals for molecular rotor 4 (form V). These two crystal forms desolvate at room temperature to afford new crystalline phases IV and VI, respectively. Crystalline form IV resulting from 3 changes upon heating toward the P212121

Figure 7. Interrelationships between the different solid forms of molecular rotors 2−5. Notes: a Single crystals obtained after column chromatography. b Disappearing solvate. c Characterized by powder X-ray diffraction, infrared spectroscopy, and calorimetric studies.d Desolvation occurs upon heating above 85 °C. 5113



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the Bruker AV500 acquired with support by National Science Foundation equipment grant CHE1048804.

antiferroelectric transitions, which can be characterized by dielectric spectroscopy. The synthesis of deuterated analogues and the proposed spectroscopic studies are currently underway.

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(1) (a) Vogelsberg, C. S.; Garcia-Garibay, M. A. Chem. Soc. Rev. 2012, 41, 1892. (b) Coskun, A. P.; Banaszak, M.; Astumian, R. D.; Stoddart, J. F.; Grzybowski, B. A. Chem. Soc. Rev. 2012, 41, 19. (2) (a) Kobr, L.; Zhao, K.; Shen, Y. Q.; Comotti, A.; Bracco, S.; Shoemaker, R. K.; Sozzani, P.; Clark, N. A.; Price, J. C.; Rogers, C. T.; Michl, J. J. Am. Chem. Soc. 2012, 134, 10122. (b) Kobr, L.; Zhao, K.; Shen, Y. Q.; Polivkova, K.; Shoemaker, R. K.; Clark, N. A.; Price, J. C.; Rogers, C. T.; Michl, J. J. Org. Chem. 2013, 78, 1768. (3) (a) Garcia-Garibay, M .A. Proc. Natl. Acad. of Sci. U.S.A. 2005, 102, 10793. (b) Khuong, T.-A. V.; Nuñez, J. E.; Godinez, C. E.; GarciaGaribay, M. A. Acc. Chem. Res. 2006, 39, 413. (4) (a) Lemouchi, C.; Iliopoulos, K.; Zorina, L.; Simonov, S.; Wzietek, P.; Cauchy, T.; Rodriguez-Fortea, A.; Canadell, C.; Kaleta, J.; Michl, J.; Gindre, D.; Chrysos, M.; Batail, P. J. Am. Chem. Soc. 2013, 135, 9366. (b) Setaka, W.; Yamaguchi, K. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 9271. (c) Setaka, W.; Yamaguchi, K. J. Am. Chem. Soc. 2012, 134, 12458. (d) Horie, M.; Suzaki, Y.; Hashizume, D.; Abe, T.; Wu, T.; Sassa, T.; Hosokai, T.; Osakada, K. J. Am. Chem. Soc. 2012, 134, 17932. (5) Zhang, W.; Ye, H. Y.; Graf, R.; Spiess, H. W.; Yao, Y. F.; Zhu, R. Q.; Xiong, R.-G. J. Am. Chem. Soc. 2013, 135, 5230. (6) Kao, K. C. Dielectric Phenomena in Solids: With Emphasis on Physical Concepts and Electronic Processes; Elsevier: Amsterdam, 2005. (7) (a) Zhang, W.; Xiong, R.-G. Chem. Rev. 2012, 112, 1163. (b) Tayi, A. S.; Shveyd, A. K.; Sue, A. C.-H.; Szarko, J. M.; Rolczynski, B. S.; Cao, D.; Kennedy, T. J.; Sarjeant, A. A.; Stern, C. L.; Paxton, W. F.; Wu, W.; Dey, S. K.; Fahrenbach, A. C.; Guest, J. R.; Mohseni, H.; Chen, L. X.; Wang, K .L; Stoddart, J .F.; Stupp, S. I Nature 2012, 488, 485. (c) Zhang, Y.; Zhang, W.; Li, S.-H.; Ye, Q.; Cai, H. L.; Deng, F.; Xiong, R.-G.; Huang, S. D. J. Am. Chem. Soc. 2012, 134, 11044. (8) (a) Xue, M.; Wang, K. L. Sensors 2012, 12, 11612. (b) Lemouchi, C.; Mézière, C.; Zorina, L.; Simonov, S.; Rodríguez-Fortea, A.; Canadell, E.; Wzietek, P.; Auban-Senzier, P.; Pasquier, C.; Giamarchi, T.; Garcia-Garibay, M. A.; Batail, P. J. Am. Chem. Soc. 2012, 134, 7880. (9) (a) Ariga, K.; Mori, T.; Ishihara, S.; Kawakami, K.; Hill, J. P. Chem. Mater. dx.doi.org/10.1021/cm401999f. (b) Shustova, N. B.; Ong, T.-C.; Cozzolino, A. F.; Michaelis, V. K.; Griffin, R. G.; Dincă, M. J. Am. Chem. Soc. 2012, 134, 15061. (10) We have adopted the nomenclature proposed by Michl et. al., where the term rotator and stator refer to the moving and static elements within the molecule, respectively, and the term rotor is reserved for the complete molecule. Kottas, G. S.; Clarke, L. I.; Horinek, D.; Michl, J. Chem. Rev. 2005, 105, 1281. (11) Karlen, S. D.; Garcia-Garibay, M. A. Topics Curr. Chem 2006, 262, 179. (12) Khuong, T.-A. V.; Dang, H.; Jarowski, P. D.; Maverick, E.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2007, 129, 839. (13) (a) Horansky, R. D.; Clarke, L. I.; Winston, E. B.; Price, J. C.; Karlen, S. D.; Jarowski, P. D.; Santillan, R.; Garcia-Garibay, M. A. Phys. Rev. B 2006, 74, 054306. (b) Horansky, R. D.; Clarke, L. I.; Price, J. C.; Khuong, T.-A. V.; Jarowski, P. D.; Garcia-Garibay, M. A. Phys. Rev. B. 2005, B72, 014302. (14) Karlen, S. D.; Reyes, H.; Taylor, R. E.; Khan, S. I.; Hawthorne, M. F.; Garcia-Garibay, M. A. Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 14973. (15) (a) Gould, S. L.; Tranchemontagne, D.; Yaghi, O. M.; GarciaGaribay, M. A. J. Am. Chem. Soc. 2008, 130, 3246. (b) Morris, W.; Taylor, R. E.; Dybowski, C.; Yaghi, O. M.; Garcia-Garibay, M. A. J. Mol. Struct. 2011, 1004, 94. (c) Winston, E. B.; Lowell, P. J.; Vacek, J.; Chocholoušová, J.; Michl, J.; Price, J. C. Phys. Chem. Chem. Phys. 2008, 10, 5188. (16) Rodríguez-Molina, B.; Romero, M.; Méndez-Stivalet, J. M.; Farfán, N.; Santillan, R.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2011, 133, 7280.

General Information. Reactions were carried out under an inert atmosphere in oven-dried glassware, unless the reaction procedure states otherwise. All chemicals were purchased from commercial suppliers and used as received. Mestranol 8 is commercially available, and compound 7 was synthesized following the reported procedure.34 Tetrahydrofuran (THF) was distilled from sodium−benzophenone in a continuous still under an atmosphere of argon. Analytical thin-layer chromatography (TLC) was performed using precoated TLC plates with Silica Gel 60 F254 and visualized using a UV lamp. Flash column chromatography was performed using silica gel (230−400 mesh) as the stationary phase. Proton magnetic resonance spectra were recorded at 400 and 500 MHz, and carbon-13 magnetic resonance spectra were recorded at 100 and 125 MHz. All chemical shifts are reported in parts per million (ppm) on the δ-scale relative to TMS (δ 0.0) using residual solvent as reference. Coupling constants J are reported in hertz. Multiplicities are reported as singlet (s), doublet (d), triplet (t), triplet of doublets (td), and multiplet (m). Uncorrected melting points were recorded on a melting point apparatus using open glass capillaries. High-resolution mass spectrometric data were collected using the electrospray ionization technique with a time-offlight detector (ESI-TOF) or a liquid introduction field desorption ionization mass spectrometer with a time-of-flight detector (LIFDITOF). X-ray Single Crystal Diffraction Experiments. The diffraction data were measured at 100(2) K on a Bruker Smart Apex2 CCD-based or at 173(2) K on a Kappa CCD X-ray diffractometer system equipped with Mo−Kα radiation (λ = 0.71073 Å). The structures were solved and refined using the Bruker SHELXTL (Version 6.12) or SIR-2004 software package. The absolute configuration of the compounds was based on the known chiral centers. All atoms were refined anisotropically, and hydrogen atoms were placed at calculated positions. General Methodology for the Synthesis of Compounds 2−5. In a round-bottom flask, 3-methoxy-estra-1,3,5-(10)-trien-17α-yl-17bol (2 equiv) and the corresponding rotator (1 equiv) were dissolved in freshly distilled THF and bubbled with N2 under stirring for 15 min. Afterward, Pd(PPh3)2Cl2 (10 mol %), CuI (10 mol %), and diisopropyl amine (1 mL) in previously degassed THF were added and the solution was refluxed for 8 h. After reflux, the reaction was cooled down to room temperature and quenched with saturated NH4Cl. The organic phase was twice extracted with ethyl acetate or dichloromethane, and the combined organic portions were dried over anhydrous Na2SO4. The solvent was removed at reduced pressure and chromatographed on silica gel. S Supporting Information *

Complete experimental details for all compounds, 1H and 13C NMR spectroscopic data, HRMS, table with hydrogen bonds, melting points, IR spectra, DSC and TGA traces, and crystallographic data as CIF files. This material is available free of charge via the Internet at http://pubs.acs.org.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by National Science Foundation grant DMR1101934. Solution NMR experiments were carried out in 5114



Article

(17) Rodríguez-Molina, B.; Perez-Estrada, S.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2013, 135, 10388. (18) Saebo, S.; Almolof, J.; Bogg, J. E.; Stark, J. G. J. Mol. Struct. (THEOCHEM) 1989, 200, 361. (19) Nuñez, J. E.; Khuong, T.-A. V.; Campos, L. M.; Farfan, N.; Dang, H.; Karlen, S. D.; Garcia-Garibay, M. A. Cryst. Growth Des. 2006, 6, 866. (20) Conformational polymorphism occurs in molecules with a several energetically close conformational minima, which may lead to the formation of different crystal forms made up with different conformers: (a) Bernstein, J. In Solid State Organic Chemistry; Desiraju, G., Ed.; Elsevier: Amsterdam, 1987; pp 471−518. (b) Nangia, A. Acc. Chem. Res. 2008, 41, 595. (c) Kumar, S. S.; Nangia, A. CrystEngComm 2013, 15, 6498. (21) Dunitz, J. D.; Bernstein, J. Acc. Chem. Res. 1995, 28, 193. (22) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (23) Dominguez, Z.; Khuong, T.-A. V.; Sanrame, C. N.; Dang, H.; Nuñez, J. E.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2003, 125, 8827. (24) (a) Kobr, L.; Zhao, K.; Shen, Y.; Shoemaker, R. K.; Rogers, C. T.; Michl, J. Adv. Mater. 2013, 25, 443. (b) Kobr, L.; Zhao, K.; Shen, Y.; Polívková, K.; Shoemaker, R. K.; Clark, N A.; Price, J. C.; Rogers, C. T.; Michl, J. J. Org. Chem. 2013, 78, 1768. (c) Vacek, J.; Michl, J. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 5481. (25) DeLeeuw, S. W.; Solvaeson, D.; Ratner, M. A.; Michl, J. J. Phys. Chem. B 1998, 102, 3876. (26) (a) Nath, N. K.; Nangia, A. Cryst. Growth Des. 2012, 12, 5411. (b) Friscic, T.; Reid, D. G.; Day, G. M.; Duer, M. J.; Jones, W. Cryst. Growth Des. 2011, 11, 972. (c) Cincic, D.; Friscic, T.; Jones, W. New J. Chem. 2008, 32, 1776. (27) Compound 6 crystallizes with two molecules of water in the P21 space group (see the Supporting Information). (28) Pretsch, E.; Buhlmann, P.; Affolter, C. Structure Determination of Organic Compounds: Tables of Spectral Data, 3rd ed.; Springer: Berlin, 2000 (29) Compounds 2−5 were initially purified using hexanes/ethyl acetate (4:1). Afterwards, a better separation of the compounds 4 and 5 from the homocoupling product was achieved using dichloromethane/diethyl ether/hexanes (5:1:4), as indicated in the experimental procedure. (30) A DMF-solvate of compound 4 was obtained by evaporation of dichloromethane−dimethylformamide at room temperature; see the Supporting Information. (31) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112. (32) In these experiments, the solid was dissolved in ethyl acetate and then hexanes were added to reach the proportion used in column chromatography. (33) Given the relatively large number of crystal structures within a small temperature range, the presence of acetonitrile molecules within the lattice does not guarantee the syn-conformation of the molecular rotor 4, although it seems likely that they interact with the rotor through hydrogen bonds with the hydroxyl groups. After desolvation above 115 °C, the resulting solid presented a slightly different powder X-ray diffractogram and infrared spectrum, indicating that the main changes occurred in the O−H stretching region (3600−3200 cm−1), consistent with the H-bonding modification. (34) Rausis, T.; Schlosser, M. Eur. J. Org. Chem. 2002, 3351.

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Conformational Polymorphism and Isomorphism of Molecular Rotors

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