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Article pubs.acs.org/crystal

Synthesis, Structure, and Local Molecular Dynamics for Crystalline Rotors Based on Hecogenin/Botogenin Steroidal Frameworks Izabella Jastrzebska,‡,∇ Tomasz Pawlak,†,∇ Rafael Arcos-Ramos,§ Edwin Florez-Lopez,∥,# Norberto Farfán,∥ Dorota Czajkowska-Szczykowska,‡ Jadwiga Maj,‡ Rosa Santillan,*,⊥ Jacek W. Morzycki,*,‡ and Marek J. Potrzebowski*,† †

Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90-363 Lodz, Sienkiewicza 112, Poland Institute of Chemistry, University of Białystok, Ciołkowskiego 1K, 15-245 Białystok, Poland § Departamento de Química de Radiaciones y Radioquímica, Instituto de Ciencias Nucleares and ∥Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 Ciudad de México, México ⊥ Departamento de Química, Centro de Investigación y de Estudios Avanzados del IPN, Postal 14-740, 07000, Ciudad de México, México ‡

S Supporting Information *

ABSTRACT: The synthesis and solid-state characterization of a series of cyclic/acyclic molecular rotors derived from naturally occurring steroidal 12-oxosapogenins are described. The bridged molecular rotors with rigid steroidal frameworks were obtained by employing ring-closing metathesis (RCM) as a key step. The X-ray diffraction technique was employed for determination and refinement of the crystal and molecular structure of selected models giving good quality single crystals. In the case of the bridged hecogenin molecular rotor 11E for which poor quality crystals were obtained, an NMR crystallography approach was used for fine refinement of the structure. Solid state NMR spectroscopic techniques were applied for the study of local molecular dynamics of the featured acyclic/cyclic molecular rotors. Analysis of 13C principal components of chemical shift tensors and chemical shift anisotropy (CSA) as well as heteronuclear 1H−13C dipolar couplings (DC) unambiguously proved that aromatic rings located in the space within the rigid steroidal framework both for cyclic and acyclic rotors are under kHz exchange regime. Experimental results were confirmed by theoretical calculations of rotation barrier on the density functional theory level. Small distinctions in the values of CSA and DC for the rotors under investigation are explained on the basis of differences in their molecular structures.

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INTRODUCTION The capacity to engineer dynamic processes at the molecular level within rigid frameworks opens new possibilities to develop artificial molecular machines.1−5 Particularly, Loeb and coworkers provided the basic fingerprints to design metal− organic frameworks with dynamic components based on mechanically interlocked molecules (MIMs) for the construction of solid-state molecular machines, such as switches and shuttles.6,7 Within this research field, we have shown that it is possible to engineer molecular rotors with rotational motion of molecular components in the solid state. The molecular design combines a periodic rigid framework created by bulky groups called stators, which are covalently bound by alkynylene moieties to a rotating fragment termed a rotator.8−10 One of our approaches to build up molecular rotors with organic molecules relies on steroidal derivatives as stators; these frameworks are known to produce crystalline solids with different conformations in the solid state.11−13 The combination of 1,4-diethynylphenylene rotators with steroidal frame© 2016 American Chemical Society

works allowed us to reach rotary frequencies in the solid state between the kilohertz to megahertz interval.14−17 An initial strategy based on 17α-ethynylsteroids produced a conformational flexibility that exists as a result of the relatively free rotation of the two steroidal stators around their linking axles. The availability of many different orientations with syn- and anti-fashion modes may result in the formation of different conformational polymorphs, as well as in close intermolecular contacts involving the rotating component.13 In order to control the conformational flexibility reducing the possible crystalline arrays, we recently reported the synthesis of disteroidal macrocyclic molecular rotors applying RCM reactions. In an initial series of macrocyclic molecular rotors derived from androstane derivatives linked by an alkenylene diester bridge, we found that the cis/trans substitution of the Received: May 12, 2016 Revised: August 29, 2016 Published: September 6, 2016 5698

DOI: 10.1021/acs.cgd.6b00726 Cryst. Growth Des. 2016, 16, 5698−5709

Crystal Growth & Design

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employing high resolution 1H−13C cross-polarization magic angle spinning (CP MAS) technique.32−38 This approach is based on the analysis of isochronous and anisochronous carbons when the chemical shifts are averaged due to reorientation of mobile residues. In this work we propose an alternative approach based on the analysis of 13C chemical shift anisotropy (CSA) and CSA averaging related to dynamics processes.39−42 Our analysis is supported by inspection of 1 H−13C dipolar couplings (DC); these values are dependent on molecular dynamics.43 Finally, the NMR crystallography44 strategy can be used for the fine refinement of crystal structure for cases in which the obtained X-ray data are poor quality and provide only a coarse solution.

bridge restricts the conformational degrees of freedom of the stators as conceived; however, this also exposes the rotator to intermolecular interactions in the solid state that affect their internal motion.18 More recently, structural analysis of macrocyclic molecular rotors based on oxosteroid stators revealed that 1,4-diethynylphenylene rotators are close to linearity and comparatively distant from the bridging chain. However, the proximity of the bridging chain to neighboring rotators could restrict the internal rotation in the E isomers.19,20 In this sense, the steroidal 12-oxosapogenins, spirostanic members of the steroidal sapogenins (SS),21 offer the possibility to introduce an alkyne axle at the C-12 position in order to build molecular rotors containing more shielded rotators with conformationally restricted stators with the aim to compare their dynamics and solid state structure with the corresponding bridged analogues. Hecogenin (1) is a steroidal sapogenin obtained from the family Agavaceae, which is used in the treatment of scabies, tumors, pain, inflammatory disorders, as a gastroprotective agent, and also for the synthesis of steroidal hormones. Botogenin (2), in turn, has the structure of the 12-oxodiosgenin, and it has been used as a starting material for the synthesis of cortical steroids; the side chain of this sapogenin can be removed in high yield to form pregn-5-en-3βol-12,20-dione.22−25 With the purpose of controlling the rotational dynamics by modulating the conformational flexibility, herein we report the synthesis and characterization of a novel class of acyclic molecular rotors using steroidal 12oxosapogenins 1 (hecogenin) and 2 (botogenin) (Figure 1).

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EXPERIMENTAL SECTION

All details concerning the synthetic procedures and analysis of obtained compounds are attached as Supporting Information. Single X-ray Diffraction (SXRD) Studies. Crystals of 1,4bis(3β,12β-dihydroxy-25R-5α-spirostan-12α-yl-ethynyl)benzene (5a) were grown during slow evaporation of methylene chloride:hexanes solution in a partially opened glass vial, and the intensity data were collected on an Oxford Diffraction Gemini “A” diffractometer with a CCD area detector (λ MoKα = 0.71073 Å, monochromator: graphite) source equipped with a sealed tube X-ray source at 123 (2) K. CrysAlisPro and CrysAlis RED45 software packages were used for data collection and data integration. Single crystal X-ray diffraction analysis for 8E was performed on a Enraf Nonius Kappa-CCD (λ MoKα = 0.71073 Å, graphite monochromator, T = 298 K-CCD) at 173 (2) K. The crystals were mounted on conventional MicroLoops. The first structure solution was obtained using the SHELXS46 program, and then the SHELXL46 program was applied for refinement and output data. After the structure was completed, it was found using PLATON.47 A high percentage in the total cell volume was filled with disordered solvent molecules. This is a common phenomenon for solvates due to significant molecular mobility, being difficult to locate each solvent molecule within the unit cell. The solvent region was refined using the PLATON module SQUEEZE48 to eliminate the contribution of the electron density in the solvent region from the intensity data, and the solvent-free or solvate model was employed for the final refinement. All software manipulations were done under the WinGX49 environment program set. All heavy atoms were found by Fourier map difference and refined anisotropically. ORTEP-3 for Windows50 and Mercury51 programs were used to prepare artwork representations. Solid-State NMR Experiments. Solid-state cross-polarization magic angle spinning (CP/MAS) NMR and one-pulse 1H MAS experiments were performed on a 600 MHz Avance III spectrometer (operating at 600.13 and 150.90 MHz for 1H and 13C) equipped with a MAS probe head using 4 mm ZrO2 rotors. A sample of 13C-labeled histidine hydrochloride was used to set the Hartmann−Hahn condition for 13C. Conventional 13C CP/MAS spectra were acquired with a proton 90° pulse length of 4 μs, a contact time of 2 ms, a repetition delay of 6 s with a spin rate of 12 kHz, a spectral width of 40 kHz, and a time domain size of 3.5 k data points. Acquisition data were collected with a SPINAL decoupling sequence.52 A 5-π pulse twodimensional (2D) PASS scheme and 1500 and 4000 Hz sample spinning speeds were used in the 2D experiments. The π-pulse length was 8 μs. Sixteen t1 increments using the timings described by Levitt et al. were used in the 2D PASS experiments.53 For each increment, 360 scans were collected. Because the pulse positions in the t1 set returned to their original positions after a full cycle and the t1-FID formed a full echo, the 16-point experimental t1 data were replicated to 256 points (the point 17, 33, 49, etc. is the same as the first point from 16-point experiment, the point 18, 34, 50, etc. is the same as the second point from 16-point experiment). It is standard procedure in the processing of 2D PASS spectra allowing to obtain spectra in F1 dimension with better resolution. Acquisition time was 18 h. After the Fourier transformation in the direct dimension, the 2D spectrum was sheared

Figure 1. Steroidal sapogenins: hecogenin (1) and botogenin (2).

Furthermore, two highly shielded macrocyclic derivatives, in which the two steroidal molecules are linked at C-3 by an alkenylene diester bridge, were prepared from both hecogenin and botogenin, employing olefin metathesis as a key step. The aim of this work is to determine the influence of chemical modifications in stators upon the dynamic processes in the crystal lattice, including a comparison of acyclic and cyclic steroidal molecular rotors. In order to achieve this goal, the use of special tools developed to study structure and dynamics is required. As we highlighted, today the chemistry of molecular rotors is very rich, and different synthetic approaches are used for the synthesis of advanced and sophisticated systems. Similarly, there are techniques that are applied for the analysis of the mode of molecular motion in the solid state. There are only a few methods that allow one to study both the topology and time scale of the dynamic processes in crystalline matter.26,27 Among them, solid state nuclear magnetic resonance (SS NMR) spectroscopy plays a very special role.28−30 This technique gives answers to dynamic processes in the solid state. The most common technique is line-shape analysis of selectively deuterium labeled samples by means of quadrupolar-echo pulse sequences.31 Among others, GarciaGaribay et al. have shown that local molecular motion in rotors with a natural abundance of isotopes can be investigated by 5699



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Scheme 1. Synthesis of the Acyclic Molecular Rotors 5a-b and 6a-b

Figure 2. (A) Molecular structure of 5a, thermal ellipsoids are drawn at 50% probability level for all atoms other than hydrogen. Crystal packing pictures viewed along the crystallographic axis (B) c and (C) a.

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Scheme 2. Synthesis of the Cyclic Molecular Rotor 8E and 8Z

Scheme 3. Synthesis of the Cyclic Molecular Rotors 11E and 11Z

19.23 μs. The maximum t1 evolution time was approximately 1 ms. Only cosine-modulated data were collected. Thus, a real Fourier transformation was performed on the t1 data that yielded spectra with a symmetrized ω1 dimension and dipolar splitting. Because the t1 time signal increases with increasing SEMA contact time, the ω1 dimension was processed using the baseline correction mode “qfill” in the Bruker TopSpin 3.0 program software, which subtracted a constant intensity from the time signals prior to the Fourier transformation and yielded spectra free from the dominant zero-frequency peak that gives the 1 H−13C doublet. The 13C−1H FSLG HETCOR experiments were recorded with a proton 90° pulse length of 2.5 μs, contact time of 0.05 or 1 ms, repetition delay of 6 s, time domain size of 1024 data points in F2, and 64 data points in F1, at a 13 kHz spinning rate.57 All data were processed using the Bruker TopSpin 3.0 program.54 Adamantane (resonances at 38.48 and 29.46 ppm) was used as a secondary 13C chemical-shift reference from external tetramethylsilane (TMS) in all experiments.58

to align all side bands with the center bands in the indirect dimension of the 2D spectrum. One-dimensional chemical shift anisotropy (CSA) spinning sideband patterns were obtained from t1 slices taken at the isotropic chemical shifts in the t2 dimension of the 2D spectrum. The values of the principal elements of the CSA tensor were obtained from the best-fit simulated spinning sideband pattern. Simulations of the spinning CSA sideband spectra were performed on a PC using the Bruker TopSpin 3.0 program.54 The PISEMA MAS experiment55,56 was carried out with an 1H effective field strength of 50 kHz in all of the experiments, and the 13C spin-lock field strengths were adjusted to the first-order sideband condition, ω13C = ω1Heff ± ωr. The spinning speed was 13 kHz and was regulated to ±3 Hz by a pneumatic control unit. The spectra were acquired in 64 rows with 512 scans per row and a recycle delay = 3 s; the acquisition time was 28 h. The 2D PISEMA MAS experiments incremented the SEMA contact time using a step of 16.28 μs. At a spinning speed of 13 kHz, the dwell time for the evolution period was 5701



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Figure 3. (A) Molecular structure of 8E, thermal ellipsoids are drawn at 50% probability level for all atoms other than hydrogen. Crystal packing pictures viewed along the crystallographic axis (B) c and (C) a. Solvent molecules were removed for clarity purposes. DFT Calculations in Periodic Boundary Conditions. The quantum chemical calculations were performed using the CASTEP code.59,60 The geometry optimization was performed using the X-ray diffraction crystal structures of 5a, 8E, and 11E as an input file, and the generalized density approximation DFT functional PBE61 was applied. A comparison of the average forces remaining on the atoms after geometry optimization was carried out for proton-only and all-atom optimizations by using a maximum plane wave cutoff energy of 550 eV and ultrasoft pseudopotential.62 We observed average forces (given as Cartesian components) of ca. 0.005 eV/Å (protons), 1.500 eV/Å (carbons), and 1.200 eV/Å (oxygens) after proton-only optimization of all analyzed structures, which suggested that proton-only optimized structures are not the most preferred structure at the considered level of theory. After all-atom optimizations, the average forces were smaller (especially for heavy atoms) and had a similar magnitude for all atomic species, that is, ca. 0.004 eV/Å (protons), 0.007 eV/Å (carbons), and 0.003 eV/Å (oxygens), which clearly indicated that these structures are much more preferable. The unit cell parameters were taken from the X-ray structures and kept fixed during the optimization of the geometry of the structures, and a Monkhorst−Pack grid63 was used to sample the Brillouin zone. The NMR chemical shifts were computed using the GIPAW method. When calculating the full crystal structure, a planewave basis set with a maximum cutoff energy of 550 eV was used. Finally, we obtained NMR chemical-shielding values in periodic boundary conditions using fully optimized structure. In all cases, the optimization algorithm was BFSG64 with line search. DFT Calculations of Energetic Barrier of Aromatic Ring Rotation. The starting structures for the geometry optimizations were the X-ray geometries (CCDC nos. 1450655 (5a), 1450656 (8E)). The B3LYP65,66 method has been used with the Pople 6-31+G* basis set67−69 for optimization in each of the fixed conformation of torsion angle to the aromatic ring rotation. All of the calculations were performed for a single in vacuo molecule within the Gaussian09 program package.70

Figure 4. 13C SPE for 8E and 11E under 12 kHz spin-rate with relaxation delay 2 s.

Figure 5. 1H VF MAS NMR spectrum of 11E under 50 kHz spin-rate.

synthesized the new acyclic molecular rotors 5a-b and 6a-b in good yields (Scheme 1). Although the C-12 ketone group shows remarkable low reactivity attributed to steric hindrance caused by the angular C-18 and C-19 methyl groups in the β face, no significant preference for the Grignard reagent attack from either of the faces was observed (the 12α- and 12β-ethynylated products were obtained in a 5:4 ratio). The 12β-alcohols (3a and 4a) exhibited lower Rf values compared with 12α-alcohols (3b and 4b). For the steroidal stators 3a-b and 4a-b, the Fourier transform infrared (FT-IR) spectra showed the characteristic broad band for the O−H stretching at 3446−3381 cm−1 and the disappearance of the ketone band at ca. 1700 cm−1 for all compounds. Mass spectrometry (FAB+) confirmed the

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RESULTS AND DISCUSSION Synthesis and Characterization. Using a two-step methodology, which involves the addition of the Grignard reagent over the C-12 ketone followed by a Sonogashira crosscoupling reaction with the corresponding rotator, we 5702



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Figure 6. (A) Crystal and (B) molecular structure of 11E after GIPAW optimization.

Figure 9. 13C CP/MAS for sample (A) 5a, (B) 8E, and (C) 11E under 12 kHz spin rate.

Figure 7. 2D 1H−13C HETCOR MAS spectrum for 11E with mixing time 50 μs.

backbones presented the characteristic signals in the 1H and C NMR spectra, in agreement with previously reported data.71 Only small differences of chemical shifts were present in their 13C NMR spectra (see Supporting Information). Solution 1 H NMR spectra of these compounds presented a singlet at δ (ppm) = 7.33 (5a), 7.35 (5b), 7.35 (6a), and 7.33 (6b) for the phenylene rotator. The 13C NMR spectra showed the corresponding signals at δ (ppm) = 122.6, 131.4 (5a), 122.7, 131.6 (5b), 122.6, 131.4 (6a), and 122.6, 131.5 (6b) for the quaternary and methine carbons, respectively. The molecular structure of compound 5a was confirmed by SXRD studies vide inf ra (Figure 2). Bridged botogenin rotor 8 was obtained from rotor 6a following the sequence previously described (Scheme 2).18−20 Thus, diester 7a was prepared in 66% yield using pent-4-enoic acid and DCC. The 1H NMR spectra of the 3,3′-diester derivative 7a showed signals characteristic of terminal olefinic protons at δ (ppm) = 5.83 and 5.03. The ring-closing metathesis of diester 7a was carried out in the presence of the second generation Grubbs catalyst. Metathesis afforded a mixture of diastereoisomeric compounds 8 in 59% yield (E/Z ratio equal to 20:11). Both isomeric macrocycles were obtained in a pure form by careful HPLC separation. The formation of a macrocycle was confirmed by MS spectra showing molecular ions at m/e 1146.1. The diastereoisomers could not be distinguished by analysis of their 1H NMR spectra. However, the structure of the major product (rotor 8E) was unequivocally proved by a single crystal X-ray diffraction analysis as will be discussed below (Figure 2). Bridged hecogenin molecular rotor 11 (E and Z) was obtained using a reversed order of transformations. The alkynyl derivative 3a was subjected to the Mitsunobu reaction72−75 using pent-4-enoic acid, diethyl azodicarboxylate (DEAD), and 13

Figure 8. Isotropic 13C NMR values correlation (experimental vs theoretical) for 11E.

structures of 3a, 3b, 4a, and 4b. The 1H NMR spectra presented a singlet at δ (ppm) = 2.47 (3a), 2.52 (3b), 2.48 (4a), and 2.52 (4b) for the terminal alkyne. In the 13C NMR spectra of 12β-alcohols, carbon atoms C-12 and C-13 [δ (ppm) = 71.6, 48.4 (3a) and 71.6, 47.6 (4a)] were shielded in comparison with 12α-alcohols [δ (ppm) = 74.8, 52.9 (3b) and 75.0, 48.5 (4b)], which appeared downfield. The signals corresponding to the alkyne group were also affected. Acetylenic carbon signals in the 13C NMR spectra appeared at δ (ppm) = 87.9, 72.6 for 3a, 86.6, 76.1 for 3b, 87.9, 72.6 for 4a, and 86.4, 75.9 for 4b. The subsequent reactions of 3a-b and 4a-b with 1,4-diiodobenzene using the Sonogashira crosscoupling protocol with Pd(0) as a catalyst and CuI as a cocatalyst produced the corresponding molecular rotors 5a-b and 6a-b. HRMS studies confirmed the structures of 5a ([M+] + 1 at 987.6708), 5b ([M+] + 1 at 987.6703), 6a ([M+] + 1 at 983.6389), and 6b ([M+] + 1 at 983.6403). The steroidal 5703



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Figure 10. 2D PASS spectra for (A) 5a, (B) 8E, and (C) 11E recorded with a spinning rate of 4000 Hz after data shearing. Projection along F1 for selected carbon atoms at ca. 92 ppm (D, E, F), ca. 107 ppm (G, H, I) and ca. 122 ppm (J, K, L) for 5a (D, G, J), 8E (E, H, K), and 11E (F, I, L).

unsaturated ester group chains in the RCM substrate close to each other facilitating the final cyclization step. The size of the bridge was designed to obtain the smallest macrocycle with the lowest strain. The bridge consisting of eight carbon atoms was chosen by inspection of Dreiding stereomodels and molecular modeling using the MM+ force-field (HyperChem from HyperCube).76 The Sonogashira cross-coupling of 9a was carried out with 1,4-diiodobenzene, Pd(PPh3)4, CuI, and N,N-diisopropylethylamine, and resulted in acyclic unsaturated diester 10a in high yield. Its structure was proved by its 1H NMR spectrum, which showed a singlet at δ (ppm) = 7.38 for the aromatic protons of the 1,4-diethynylphenylene rotator and the disappearance of the characteristic signal assigned to the proton in the terminal alkyne portion of the starting material. Furthermore, the 13C NMR spectrum exhibited two additional signals, δ (ppm) = 131.6 (CH) and δ (ppm) = 122.8 (ipso C), that unequivocally evidenced the introduction of the aromatic ring between the two steroidal units in compound 9a. In the final step, unsaturated diester 10a was subjected to RCM with the Grubbs second-generation catalyst to afford a diastereoisomeric mixture of macrocyclic products 11 (E/Z ratio equal 5:3). After separation by HPLC, the isomers could not be distinguished by NMR because of negligible spectroscopic differences. Namely, 1 H NMR showed small differences for aromatic signals positioned at δ (ppm) = 7.40 and 7.36 for the isomers E and Z, respectively. Compound 3b was also subjected to similar

Figure 11. Simulated static 13C CSA line shape for 5a (green), 8E (red), and 11E (blue) for experimental (solid line) and GIPAW calculated (dotted line). Picture shows average values for aromatic signals.

triphenylphosphine (Scheme 3). The structure of the resulting ester 9a was confirmed by infrared spectroscopy that revealed a stretching band from the ester group at 1720 cm−1. The presence of a narrow multiplet of 3β-H at δ (ppm) = 5.05 in the 1H NMR spectrum confirmed the esterification of the starting alcohol with inversion of configuration. 13C NMR spectrum showed signals at δ (ppm) = 172.5 for the carbonyl, and δ (ppm) = 136.8 and δ (ppm) = 115.3 for the vinyl carbon atoms. The Mitsunobu esterification was followed by the Sonogashira cross-coupling and the ring-closing metathesis. The inversion of the configuration at C-3 brings the two 5704



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four steroidal units. The macrocyclic tetramers showed molecular ions at m/e 2247.1. Solid-State Characterization of Acyclic Molecular Rotors 5a and 8E. Single Crystal X-ray Diffraction Studies. Crystallization of samples with steroidal frameworks and growing single crystals (SC) with quality suitable for X-ray diffraction (XRD) are always challenging. Fortunately, in the case of 5a and 8E we were able to grow suitable crystals for SXRD studies. The acyclic molecular rotors derived from both hecogenin and botogenin stators showed good solubility in a wide variety of organic solvents (acetone, alcohols, ethyl acetate, acetonitrile, chloroform, methylene chloride, and aromatics). The acyclic molecular rotor 5a crystallized as solvent-free colorless prisms. The crystal structure was solved in the orthorhombic space group P212121 with one molecule per asymmetric unit and Z = 4 (Figure 2). 1,4-Diethynylphenylene axle was almost linear [172°], with the steroidal stators adopting an orthogonal conformation relative to this fragment. As expected, the hydroxyl groups at C-3 and C-12 established several hydrogen-bonding interactions with adjacent molecules [D−H···A distances of ca. 2 Å] forming an interpenetrated bilayer self-assembly similar to our previous macrocyclic molecular rotors with steroidal stators.18−20 The crowded environment around the 1,4-diethynylphenylene rotator (one rotator is surrounded by six different steroidal stators) could restrict the rotational motion in the solid-state. The crystal structure for cyclic molecular rotor 8E was solved in the orthorhombic space group C2221 with Z = 4 as methylene chloride solvate (two solvent molecules). The asymmetric unit contains only half of the molecule, and the other half is generated by an inversion center located on the center of the 1,4-diethynylphenylene rotator. The steroidal stators are relatively close [C3−C3′ distance 7.67 Å], for this reason the two stators acquired a staggered conformation relative to the 1,4-diethynylphenylene axis; this fragment is close to linearity [ca. 175°] and relatively far away from the bridging chain. The crystal packing of 8E was dominated by hydrogen-bonding interactions O(12)−H(12)···Ocarbonyl bridge [2.12 Å], which stacked the molecules in one-dimensional columns, with one of the solvent molecules located inside the formed cavities. The columns are held together by secondary hydrogen-bonding interactions C(21)−H(21)···Obridge [2.64 Å], C(4)−H(4)···O(12) [2.70 Å] and oriented in an antiparallel manner (Figure 3). NMR Crystallography for Sample 11E. When the obtained crystals are bad or of low quality, the refinement of structure is problematic and the solution is ambiguous. In such cases additional tools have to be applied in order to make the obtained results reliable. In this section we show how this problem can be overcome by application of the complementary approach joining X-ray diffraction and NMR crystallography77−79 by discussing the case of 11E. Although no high quality single crystals from compound 11E have been obtained, crystallization attempts with methylene chloride yielded weakly diffracting crystals, which allowed us to confirm the connectivity of the cyclic molecular rotor. Nevertheless, such rough X-ray results are useful constraints for fine refinement of structure employing NMR Crystallography. With this approach, solid state NMR data are supported by theoretical calculations. Experimental and computed data were validated, verified, and compared in order to find the best solution and most reliable structure. Our project was carried out in several steps. The first important issue concerned the

Figure 12. 2D PISEMA MAS spectra for sample (A) 5a, (B) 8E, and (C) 11E. Two example splitting values in them are labeled.

Figure 13. Relative energy dependence on the rotation of phenylene rotators in molecular rotors 5a (green circles), 8E (red triangles), and 11E (blue rhombus). The calculations were performed at the DFT level.

transformations. The Mitsunobu reaction with pent-4-enoic acid afforded the corresponding 3,3′-diester derivative 9b (not shown). It was subjected to the Sonogashira cross-coupling followed by RCM. Interestingly, the reaction did not lead to the cyclic dimer but to a mixture of isomeric products containing 5705



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Figure 14. Molecular structure of (A) 8E and (B) 11E colored by symmetry equivalence indicating by ellipsoids the shape of inner pockets. Two arrows for each molecule are shown, diameter of ellipsoids 7.0 Å and 10.5 Å for 8E and ca. 6.2 Å and 9.9 Å for 11E.

(CRAMPS).81−84 Therefore, the spectra recorded under slow conditions are difficult to analyze, and they do not usually contain subtle structural information. The alternative for CRAMPS techniques is very fast MAS NMR. Because of recent progress in probe-heads manufacturing and reduction of the rotor size, solid-state samples can now be spun very fast. The “very fast” (VF) regime of more than 50 kHz is obtained using commercially available 1.3 mm rotors.85 This frequency exceeds the strength of homonuclear proton dipolar coupling and is therefore expected to enter a new regime for spin dynamics. Figure 5 shows 1H VF MAS NMR spectrum of sample 11E recorded with a spinning rate of 50 kHz. Despite the separation of aromatic and aliphatic signals, the resolution of the spectrum is not sufficient for the assignment of resonances of water molecules. The presence of water was confirmed by employing other techniques (DSC, TGA, and 1H NMR in the liquid phase). In the next step, we have used coarse X-ray data as an input file to compute the structure. For theoretical calculations the GIPAW method was employed.86 In contrast to other theoretical approaches, GIPAW takes into account full crystal structure and periodicity in the solid state. Assuming that the size of the unit cell was correctly established by X-ray diffraction we optimized the positions of heavy atoms and protons. For this purpose we used CASTEP code59 with the generalized density approximation DFT functional PBE.61 During this step a maximum plane wave cutoff energy of 550 eV and ultrasoft pseudopotential were applied.62 The obtained coordinates for the GIPAW optimized structure of 11E are attached as Supporting Information. The crystal and molecular structure for the sample are shown in Figure 6. The striking difference between 8E and 11E is the localization of guest molecules. For the former sample, the solvent molecule is aligned in the inner, closed pocket while the latter water is located in the open space of the outer pocket. In the next step in order to verify the correctness of the structure solution, we compared the theoretical and experimental NMR data. Employing the optimized crystal data for 11E we computed the 13C NMR shielding parameters employing GIPAW. The values of 13C isotropic shifts (σiso) and principal elements of shielding tensors (σii) are shown in Tables S4−S6 attached as Supporting Information. The important point in the strategy of NMR crystallography is unambiguous assignment of the position of diagnostic

crystal contents. As discussed in the previous section, 8E contains methylene chloride in the crystal lattice, and, therefore, the question whether the same or other solvents are incorporated in the network of 11E is justified. The answer to this question is provided by a basic NMR technique, single pulse experiment (SPE) with direct excitation of 13C nuclei and relatively short recycle delay (2 s) in order to identify mobile solvent molecules in the solid phase. Generally speaking, signal arising from the 13C nuclei in solid, crystalline phases are not observed in such experiments, due to their much longer longitudinal (T1) recycle delays. Figure 4 shows 13C SPE spectra for 8E and 11E recorded with 128 scans and a relaxation delay equal to 2 s. As one can see, the differences are apparent. For sample 8E (bottom trace) the sharp signal at δ (ppm) = 38 representing mobile methylene chloride is clearly seen, while for 11E (upper trace) only very weak signals of sample and noise in the baseline are observed. Such results suggest that for the latter case there is no organic solvent in the crystal lattice. Going further with interpretation of data we also considered the case when the guest molecules are trapped inside the host lattice but due to restricted molecular motion and in consequence long T1 relaxation time the detection of guest signal is problematic. Our recent experience clearly proves that in such situation the crosspolarization magic angle spinning technique is very diagnostic and guest molecules are detected.80 In the case of sample 11E both techniques (SPE and CP/MAS) have not confirmed the presence of organic solvent. However, having in mind that the systems under investigation easily form inclusion complexes during crystallization, we can assume that if there is no organic solvent present, then water molecules can play the role of guest. Unfortunately, confirmation of the inclusion of water in crystalline hydrates is not a trivial task. The apparent diagnostic tool, which can confirm or exclude the presence of water, seems to be 1H NMR. However, the assignment of 1H resonances using SS NMR spectroscopy is very challenging due to extremely strong homonuclear dipolar coupling, which in many cases exceeds the range of the chemical shifts for protons. Moreover resolving of the individual peaks is often impossible due to severe broadening. The broadening of proton lines is not removed by slow and medium magic angle spinning without the application of complex pulse sequences like combination of rotation and multi-pulse sequence 5706



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This conclusion is confirmed by PISEMA MAS, which provides information about local molecular motion by analyzing heteronuclear dipolar splitting. Figure 12 shows PISEMA spectra recorded in 2D mode. In such experiment 1 H−13C dipolar splitting for all positions in 13C spectra is reduced by a scaling factor. Moreover, fast molecular motion reduces the principal component of the dipolar tensor by a factor, which is known as the order parameter and ranges from 0.5 to 1. The latter value represents a rigid system. As one can see, splitting between singularities of dipolar Pake doublets, measured as the distance between correlation peaks at specific carbon position, is different. For rigid residues, the value of 1 H−13C dipolar splitting is equal to 14−15 kHz. For residues undergoing reorientation, the dipolar splitting is reduced to 7.4 kHz for sample 5a, 8.2 kHz for sample 8E, and 6.1 kHz for sample 11E. This distinction confirms different rotational barriers for the molecular rotors. It is worthy to highlight that this technique also distinguishes overlapped signals. For sample 8E it is apparent that the signal at ca. 120 ppm, showing two well-separated dipolar doublets, represents two overlapped residues with different dynamics. Finally, we performed energetic barrier calculations for aromatic groups. They were done at DFT level without considering periodicity. Solvent molecules were removed due to the inability of convergence of SCF cycle in the calculation process when they are present. Figure 13 shows a comparison of the energetic barrier for both species. The necessary energies to start these rotations are not very high and are lower for 5a and 11E, which is consistent with previous results (smaller CSA and dipolar coupling for 5a and 11E than 8E). In summary, the acyclic molecular rotor with hecogenin stators 5a crystallized without solvent molecules in their crystal lattice. The cyclic molecular rotors 8E and 11E are structurally similar; however, for 11E the inner closed pocket is rather flat while for 8E it is rather pyramidal. This distinction in pictorial form is shown in Figure 14. Moreover, the guest molecules are located in different places of the host moiety, for 8E in the inner pocket while for 11E in outer pocket.

resonances in the spectrum. For this purpose we employed 1 H−13C 2D HETCOR correlation57 (Figure 7). This experiment carried out with a relatively short mixing time allowed us to assign the position of directly bonded C−H units and separate quaternary signals, which do not show correlation peaks. The assignment of resonances for the overlapped aliphatic region (20−40 ppm) is ambiguous, and these signals were not taken into consideration in further analysis. Experimental values of 13C δiso parameters are collected in Tables S7−S9 (see Supporting Information). Figure 8 shows the correlation between theoretical 13C σiso parameters and experimental 13C δiso. The quality of linear plot and important parameters such as slope, intercept and R2 value (0.9898) suggest that the computed structure very well reflects the real crystal form. A similar analysis was carried for compound 8E with a wellrefined X-ray structure (the 13C σiso versus 13C δiso plot showed very similar parameters). This provides further proof that the solution for 11E is correct. Local Molecular Dynamics of Phenyl Residues Aligned among Steroidal Pincers for Acyclic and Cyclic Molecular Rotors. The 13C CP/MAS solid state (SS) NMR spectra for 5a, 8E, and 11E are shown in Figure 9. By analogy to compounds with a similar structure recently reported by us,18 special attention was paid to the region between 80 and 140 ppm assuming specific molecular dynamics of aromatic residues. For 8E and 11E, this region had to be analyzed with special care because 13C aromatic resonances are partially overlapped by olefinic -CHCH- signals. Such overlapping complicates the analysis of chemical shift tensor (CST) parameters and dipolar couplings (from PISEMA MAS experiment), which are very sensitive to molecular motions in the crystal lattice.55,56 For sample 8E we observed a broadening of signals in the aromatic region during the measurement at ambient temperature, such line-shape suggests local molecular motion or positional disorder. It is well-known that analysis of 13C CST (σii) parameters, in particular span Ω expressed by the equation Ω = σ11 − σ33 (Herzfeld−Berger Convention) is an excellent source of information about local molecular motion.87 As shown elsewhere the correlation of the anisotropic span parameter for calculated and experimental data can be useful for analysis of dynamic processes.88−92 For complex, overcrowded systems, as in the case of the samples under investigation, the extraction of 13C σii parameters from analysis of 1D spectra is not trivial. Hence, we have employed a 2D NMR approach. Figure 10 shows data obtained by means of 2D PASS experiment.53 The 13 C δii parameters are collected in Tables S7−S9. Simulated static spectra shown as purple, yellow, and green dotted lines represent computed data for rigid systems (Figure 11). It has to be stressed that the applied theoretical method in this project does not take into consideration dynamics processes. The powder pattern for experimental spectra, denoted by green, red, and blue solid lines, is considerably narrowed. Such a narrowing effect is related to local molecular motion of the analyzed residue, in this case rotation around the 1−4 axis. It is worthy to express that the apparent narrowing of line-shape for 5a, 8E, and 11E is different. The Ω parameter, which reflects the dynamic process, is smaller for 5a and 11E compared to 8E, suggesting a different rotational barrier for each steroidal molecular rotor. It has to be highlighted that such analysis is only qualitative, and a specific value of energy of rotational barrier cannot be established.

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CONCLUSIONS In conclusion, acyclic and cyclic molecular rotors derived from hecogenin and botogenin stators were synthesized; the title compounds were characterized in solution and in the solid state. Regarding the molecular dynamics of the steroidal molecular rotors, 5a, 8E, and 11E are located under the kHz exchange regime. The molecular motion was proved by using an experimental-theoretical approach. The results revealed that small structural changes influence dynamic processes but do not prevent rotation of the phenylene rotator around its 1,4diethynyl axle. The qualitative experimental data supported by theoretical calculations suggest that the most restricted rotation is found for cyclic rotor 8E. Our work shows that minute topological differences in the structure of molecular rotors can cause significant distinction in the dynamic processes. In this project we proved the power of the solid state NMR approach and revealed the applicability of techniques that were not previously used to study molecular rotors. The analysis of 13 C chemical shift anisotropy and 1H−13C dipolar coupling was found to be a straightforward diagnostic method. Finally, it is worthy to stress that the approach presented in this work can be employed for studying the molecular motion of samples with 5707



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natural abundance without having to label rotors with a 2H isotope.

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(4) Garcia-Garibay, M. A. Nat. Mater. 2008, 7, 431−432. (5) Garcia-Garibay, M. A. Angew. Chem., Int. Ed. 2007, 46, 8945− 8947. (6) Vukotic, V. N.; Harris, K. J.; Zhu, Z.; Schurko, R. W.; Loeb, S. J. Nat. Chem. 2012, 4, 456−460. (7) Zhu, Z.; O’Keefe, C. A.; Vukotic, V. N.; Schurko, R. W.; Loeb, S. J. Nat. Chem. 2015, 7, 514−519. (8) Vogelsberg, C. S.; Garcia-Garibay, M. A. Chem. Soc. Rev. 2012, 41, 1892−1910. (9) Arcos-Ramos, R.; Rodriguez-Molina, B.; Gonzalez-Rodriguez, E.; Ramirez-Montes, P. I.; Ochoa, M. E.; Santillan, R.; Farfán, N.; GarciaGaribay, M. A. RSC Adv. 2015, 5, 55201−55208. (10) Arcos-Ramos, R.; Rodriguez-Molina, B.; Romero, M.; MendezStivalet, J. M.; Ochoa, M. E.; Ramirez-Montes, P. I.; Santillan, R.; Garcia-Garibay, M. A.; Farfán, N. J. Org. Chem. 2012, 77, 6887−6894. (11) Bernstein, J. Polymorphism in Organic Chemistry; Oxford University Press: Oxford, 2002. (12) Bernstein, J. In Organic Solid State Chemistry; Desiraju, G. R., Ed.; Elsevier: Amsterdam, 1987; Vol. 32: Studies in Organic Chemistry. (13) Nangia, A. Acc. Chem. Res. 2008, 41, 595−604. (14) Rodriguez-Molina, B.; Farfán, N.; Romero, M.; Mendez-Stivalet, J. M.; Santillan, R.; Garcia-Garibay, M. A. J. Am. Chem. Soc. 2011, 133, 7280−7283. (15) Rodriguez-Molina, B.; Ochoa, M. E.; Khan, S. I.; Farfán, N.; Santillan, R.; Garcia-Garibay, M. A.; Romero, M. Cryst. Growth Des. 2013, 13, 5107−5115. (16) Jimenez-Garcia, C.; Arcos-Ramos, R.; Mendez-Stivalet, J. M.; Santillan, R.; Farfán, N. Monatsh. Chem. 2015, 146, 1005−1013. (17) Rodriguez-Molina, B.; Pozos, A.; Cruz, R.; Romero, M.; Flores, B.; Farfán, N.; Santillan, R.; Garcia-Garibay, M. A. Org. Biomol. Chem. 2010, 8, 2993−3000. (18) Czajkowska-Szczykowska, D.; Rodriguez-Molina, B.; MagañaVergara, N. E.; Santillan, R.; Morzycki, J. W.; Garcia-Garibay, M. A. J. Org. Chem. 2012, 77, 9970−9978. (19) Czajkowska-Szczykowska, D.; Jastrzebska, I.; Santillan, R.; Morzycki, J. W. Tetrahedron 2014, 70, 9427−9435. (20) Czajkowska-Szczykowska, D.; Aguilar-Granda, A.; Maj, J.; Wilczewska, A. Z.; Witkowski, S.; Santillan, R.; Garcia-Garibay, M. A.; Morzycki, J. W.; Rodriguez-Molina, B. Cryst. Growth Des. 2016, 16, 1599−1605. (21) Jastrzebska, I. Curr. Org. Chem. 2012, 16, 353−372. (22) Ghoghari, A. M.; Rajani, M. Chromatographia 2006, 64, 113− 116. (23) Corbiere, C.; Liagre, B.; Bianchi, A.; Bordji, K.; Dauca, M.; Netter, P.; Beneytout, J. L. Int. J. Oncol. 2003, 22, 899−905. (24) Cerqueria, G. S.; Silva, G. S.; Vasconcelos, E. R.; Freitas, A. P. F.; Moura, B. A.; Macedo, D. S.; Souto, A. L.; Filho, J. M.; Leal, L. K. A.; Brito, G. A. C.; Souccar, C.; Viana, G. S. B. Eur. J. Pharmacol. 2012, 683, 260−269. (25) Peana, A. T.; Moretti, M. D.; Manconi, V.; Desole, G.; Pippia, P. Planta Med. 1997, 63, 199−202. (26) Harada, J.; Ogawa, K. Chem. Soc. Rev. 2009, 38, 2244−2252. (27) Bürgi, H. B. Annu. Rev. Phys. Chem. 2000, 51, 275−296. (28) Nehls, I. Solid State NMR for Chemists, Von Colin A.F.; C.F.C. Press: Ontario, Canada, 1983. (29) Krushelnitsky, A.; Reichert, D. Prog. Nucl. Magn. Reson. Spectrosc. 2005, 47, 1−25. (30) Schmidt-Rohr, K.; Spiess, H. W. Multidimensional Solid-State NMR an Polymers; Academic Press, Ltd.: London, UK, 1994. (31) Spiess, H. W. Colloid Polym. Sci. 1983, 261, 193−209. (32) Pines, A.; Gibby, M. G.; Waugh, J. S. J. Chem. Phys. 1973, 59, 569−590. (33) Sinning, G.; Mehring, M.; Pines, A. Chem. Phys. Lett. 1976, 43, 382−386. (34) O’Brien, Z. J.; Natarajan, A.; Khan, S. I.; Garcia-Garibay, M. A. Cryst. Growth Des. 2011, 11, 2654−2659. (35) O’Brien, Z. J.; Karlen, S. D.; Khan, S. I.; Garcia-Garibay, M. A. J. Org. Chem. 2010, 75, 2482−2491.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b00726. General Information. Synthetic procedures and full analysis of compounds. The DSC and TGA plots for 11E. Single X-ray diffraction studies of compounds 5a and 8E (PDF) Accession Codes

CCDC 1450655−1450656 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*(M.J.P.) Tel. +48 42 680 3240; e-mail: marekpot@cbmm. lodz.pl. *(R.S.) E-mail: [email protected]. *(J.W.M.) E-mail: [email protected]. Present Address

́ Programa de Quimica, Facultad de Ciencias Bás icas, Universidad Santiago de Cali, Pampalinda, Cali, 4102, Colombia.

#

Author Contributions ∇

I.J. and T.P. contributed equally to this work as first authors.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS R.A.-R. (ICN-UNAM) and E.F.L. (FQ-UNAM) thank DGAPA for a postdoctoral fellowship. The authors thank DGAPAUNAM (PAPIIT IN-216616) and CONACYT. Thanks are due to the Polish National Science Centre for the grant support (UMO-2011/02/A/ST5/00459). We would also like to thank Miss Danielle Roth for the excellent editing of this manuscript. The equipment (i.a. HPLC apparatus) for the Center of Synthesis and Analysis BioNanoTechno of the University of Białystok was funded by EU, as a part of the Operational Program Development of Eastern Poland 2007-2013, project: POPW.01.03.00-20-034/09-00. The computational resources were partially provided by the Polish Infrastructure for Supporting Computational Science in the European Research Space (PL-GRID). The authors would like to express their gratitude to Karolina H. Markiewicz (University of Białystok) for DCS and TGA measurements as well as Marco A. Leyvá (CINVESTAV-IPN) for X-ray diffraction experiments, Ramirez crystal structure solution and refinement.

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REFERENCES

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