Smart Polymorphism of Thiacalix[4]arene with Long-Chain Amide

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Smart polymorphism of thiacalix[4]arene with long-chain amide containing substituents Karina V. Gataullina, Marat A. Ziganshin, Ivan I. Stoikov, Alexander E. Klimovitskii, Aidar T. Gubaidullin, Kinga Suwinska, and Valery V. Gorbatchuk Cryst. Growth Des., Just Accepted Manuscript • Publication Date (Web): 25 Apr 2017 Downloaded from http://pubs.acs.org on April 28, 2017

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Crystal Growth & Design

Smart polymorphism of thiacalix[4]arene with longchain amide containing substituents

Karina V. Gataullina,a Marat A. Ziganshin,a Ivan I. Stoikov,a Alexander E. Klimovitskii,a Aidar T. Gubaidullin, b Kinga Suwińska, a,c and Valery V. Gorbatchuk a* a

A.M. Butlerov Institute of Chemistry, Kazan Federal University, Kremlevskaya 18, 420008 Kazan, Russia. E-mail: [email protected]

b

A.E. Arbuzov Institute of Organic and Physical Chemistry, Akad. Arbuzova, 8, 420088 Kazan, Russia. c

Faculty of Mathematics and Natural Sciences, Cardinal Stefan Wyszynski University in Warsaw, K. Woycickiego 1/3, 01-938 Warszawa, Poland

ABSTRACT

A problem of controlled (smart) formation of polymorphs was solved for a set of tertbutylthiacalix[4]arene derivatives with four N-(2-acetoxyethyl)carbamoylmethoxy substituents at lower rim with 1,3-alternate, cone and partial cone conformations. For this, an effective polymorph screening with a reproducible influence of preparation history was achieved using guest vapor inclusion and a standard state of host glass powder. By this procedure with consequent guest release and heating, an ability of the studied calixarenes for polymorphism was investigated and compared as a function of their macrocycle conformation. The data of 1 ACS Paragon Plus Environment

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simultaneous thermogravimetry, differential scanning calorimetry with mass-spectrometry of evolved vapors were determined together with the data of powder X-ray diffraction for the initial host samples, intermediate clathrates and final polymorphs. Besides, single crystal X-ray diffraction data were obtained for four crystalline forms of the studied calixarenes. The results yield a structure-property relationship, where 1,3-alternate calixarene without extended Hbonded supramolecular network at least in one crystalline form has much higher ability for polymorphism than the other two conformations. Thus, 10 polymorphs with essentially different crystal packing were found for this calixarene including a unique tetramorphism with four consecutive melting points of guest-free polymorph and corresponding three crystallization ranges. This ability of 1,3-alternate calixarene is linked with its other smart property: selective crystallization of its compact glass in vapors of binary liquid mixtures, which can be used for visual detection of very small benzene impurities (0.5 % (v/v)) in cyclohexane.

INTRODUCTION Controlled polymorphism of organic compounds depending on small changes in their molecular structure and preparation history is a key problem in the pharmaceutical chemistry1-3 and physical chemistry of organic compounds in the solid state.4,5 The solution of this problem is vital for reproducible preparation of crystalline materials, precluding the phenomenon of disappearing polymorphs.1,3,6,7 To make polymorph formation controllable or smart, one needs to have at least a general assumption on the structure-property relationship for this process. The search of this relationship is extremely complex because formation of any organic polymorph with molecular packing depends not only on its molecular structure but also on its preparation history1,3,6,8-13 including a used solvent3,11,14-20 or adsorbed gas,21 crystallization conditions,3,11,14,22,23 an ability to form solvates3,8,24 and subsequent thermal treatment of crystallization product.3,4,6,25-28 Each factor relates to molecular structure of a target compound in 2 ACS Paragon Plus Environment

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its own way. Consequently, the resulting relationship may be very complicated. It is not surprising that the presence of polymorphophores, which are molecular fragments being flexible or/and capable of hydrogen bonding,29-31 and supramolecular synthons32-35 statistically enable polymorphism with nearly the same probability as their absence.32,36 The problem is how to simplify this search reducing to a minimum the structural differences of compared molecules and the difference in their treatment history. A good approach to this problem is a comparison of the ability to form polymorphs for compounds with polymorphophore groups and having the same molecular composition but different stable conformation. Calixarenes with steric restrictions for rotation of long-chain substituents provide such a possibility.37 In the present work, a relative ability for polymorphism was studied for three derivatives of tert-butylthiacalix[4]arene with four long identical substituents at the lower rim in 1,3-alternate (1), cone (2) and paco (3) conformations (Figure 1). Having the amide and ester fragments, the substituents are capable of H-bonding both as Hdonors and H-acceptors in 1:2 ratio, together with a molecular flexibility, this is enough to expect polymorphism.1,6,8-12 For comparison, high ability for polymorphism was observed for acedapsone, which has the same ratio of H-donor and H-acceptor groups 1:2 and restricted conformational mobility preventing formation of strong intramolecular H-bonds.25 For calixarenes, polymorphism is a typical phenomenon, which occurs not only for flexible molecules,38-43 but also for compounds with rigid macrocycle and without intermolecular hydrogen bonds in the solid state.20-22,44-51 Such a polymorphism is induced by heating3,22,42,43,4951

or guest inclusion/release.3,21,38-41,45-48 In this work, both screening options were studied for

calixarenes 1, 2 and 3.

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Figure 1. Structure of calixarenes 1, 2 and 3. Calixarenes as well as the other substances capable of forming inclusion compounds (clathrates) have an advantage in the study of polymorphism. For these compounds, a standard method may be used for polymorph screening by saturation of the solid host with vapors of various solvents (guests) and subsequent guest removal.1,3,15,52 As a result, the clathrates are prepared at the fixed final thermodynamic activity of guest, which only increases at equilibration.53 This gives a more reproducible preparation of clathrates and, respectively, guestinduced polymorphs just because this saturation process is closer to a reversible one compared with those using a liquid solvent in contact with a target solid compound. Screening of polymorphs induced by solvent vapors is often regarded as the most timeconsuming with a very long vapor/solid equilibration period.1,2,14,16,36,52 Still, for clathrateforming substances this process may be much faster because of the negative Gibbs energy of clathrate formation,54-57 which provides a higher guest affinity for a solid host matrix than for nonporous solids without guest (solvent) inclusion ability.58 To reach equilibrium with calixarene, 40 minutes is enough for ‘guest vapor + solid host’ system, while reproducible vapor sorption results can be obtained after 1-3 days of equilibration.54 4 ACS Paragon Plus Environment

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A property related in some extent to polymorphism is an ability of crystalline compound to exist also in more or less stable amorphous or compact glass form.59 For calixarenes, this issue has a practical dimension.60-62 Amorphous materials are often preferred as a starting point for polymorph screening, where they are used as giving more oversaturated solutions or as suspensions with a possibility to form metastable polymorphs.63 Solvent vapor sorption by amorphous materials with molecular packing may be a part of polymorph preparation procedure.4 For non-calixarene compounds, this technique gives a new solvent-free form in a few reported examples.4,58,64 An amorphous solid may be prepared from a crystalline compound by excessive milling, by various drying methods from its liquid solutions or clathrates (solvates), and by a quench cooling of the one-component melt.4,65 The last method is the simplest but needs a sufficient thermal stability of a studied compound, which decomposition may be a cause of polymorphism.66 Besides, a release of included solvent/guest traces is much easier from a liquid melt. The other factors of preparation history have much lower effect on glass transition point of amorphous solid,67 which is an important characteristic parameter related to the most properties of molecular glass. So, if these conditions of purity and thermal stability are met, a glass formed by cooling melt from above a highest melting point may be chosen as a standard state for preparation of polymorphs,39,65 Such a choice of standard state was made in the present work. The ability of the calixarene to form glasses may be combined with its ability for step-wise guest inclusion with formation of clathrate crystals.56,68,69 This smart property may be used for visual detection of a “good” guest in its mixture with a “bad” one when reaching a threshold concentration as observed for calixarene 3.39 In the present work, much more sensitive detection of small benzene additive in cyclohexane was studied using compact glass of calixarene 1 as related to its wider temperature range of phase transitions. In this work, the ability of calixarene 1 to form numerous polymorphs is linked to the ratio of strong intermolecular and intramolecular H-bonds in the solid state and ability to have free H5 ACS Paragon Plus Environment


donor amide fragments at least in one solid form. For this, single crystal X-ray structural analysis was performed and FTIR spectra were determined for calixarenes 1, 2 and 3 in various forms. A relationship of these data with a thermal behavior of their polymorphs was analyzed including the ability for several consecutive polymorphic transitions with intermediate melting points upon heating. For comparison, a polymorph with non-H-bonded hydroxyl groups is formed from solvate of betamethasone valerate with methanol,27 giving two more polymorphs when heated. The observed structural features of calixarenes 1, 2 and 3, and also effective choice of their initial state and the further treatment conditions provide controlled (smart) formation of new polymorphs.

EXPERIMENTAL SECTION Materials and preparation of samples. Calixarenes 1, 2 and 3 were synthesized as described previously.70 The synthesized compounds were dried under vacuum 100 Pa for 5h at 100 °C for 1 and 2, and at 150 °C for 3. These samples were transformed to the glassy state (g-form) by heating to 170, 160 and 200 °C, respectively, which are 17-19 °C higher than their last melting point, and then by subsequent cooling to room temperature (RT) on the air. Clathrate samples for TG/DSC/MS, IR, PXRD analysis were prepared by equilibration of glassy calixarene powders (10-15 mg) with saturated vapors of organic guests and water in hermetically closed 15-mL vials at 25 °C for 3 days, as described previously.39 The liquid organic guest, 50 µL, was sampled into the open little glass containers placed inside the vials with calixarene samples. For polymorph screening, crystalline samples of guest-free calixarenes 1, 2 and 3 were prepared from various clathrates by drying in vacuum of 100 Pa at RT, with additional heating (10 minutes) in an oven to a point, which is 15-20 °C below the first melting temperature 6 ACS Paragon Plus Environment

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observed for clathrate. For preparation of 1-1 polymorph, clathrate of 1 with ethanol was dried in the same vacuum only at RT. For those clathrates, where a substantial amount of the guest remains in the clathrate phase till the first melting point, their samples were additionally dried under vacuum of 100 Pa for 3 hours at 60 °C. The total drying time under vacuum was 5 hours in all cases. For IR and PXRD experiments, samples of high-temperature polymorphs were prepared by heating initial polymorphs in an oven at the target temperature for 5 minutes and cooling to RT. Single crystals of calixarenes 1, 2 and 3 in hydrate, solvate or guest-free forms were prepared by cooling of their solutions from RT to 4 °C. A solvent used was ethanol in all cases except for 1·H2O crystal, which was grown from water/ethanol mixture. The samples of transparent compact glasses of calixarenes 1 and 2 were prepared by heating of crystalline guest-free calixarene powders (3 mg) on glass plates to the temperature above the last melting point by 17 and 19 °C, respectively, and cooling in the air to RT. The samples on glass plates were equilibrated with saturated vapor (P/P0=1) of water, organic guests or their binary mixtures in hermetically closed 15-ml vials at 25 °C. Then the sample pictures were taken for visual detection of crystallization. Simultaneous TG/DSC/MS experiment. Thermal properties of prepared clathrates and polymorphs were studied by simultaneous method of thermogravimetry (TG), differential scanning calorimetry (DSC) and mass-spectrometry (MS) using thermoanalyzer STA 449 C Jupiter (Netzsch) coupled with quadrupolar mass-spectrometer QMS 403 C Aëolos (Netzsch). All TG/DSC/MS experiments were conducted at a heating rate of 4 °C/min in an argon flow of 75 mL/min. Before the experiment, the studied samples were held for 2–3 min in air and then for 18–20 min in an argon flow inside the thermoanalyzer at 25 °C until their constant weight was reached.



The total mass loss of clathrate, ∆m (% w/w), was determined by TG curve as corresponding to the highest endset point in MS curves of evolved guests. Values of the guest content S (mol guest/mol host) in clathrate samples were determined with an error of 2% but no less than 0.02 mol per 1 mol of host for clathrates with the onset point of elimination of the guest Tonset above 38 °C. This error increases for less stable clathrates, being equal to 0.1 when the Tonset value is below 30 °C. Differential scanning calorimetry (DSC). Phase transitions of calixarene samples were studied using DSC method with a DSC 204 thermoanalyzer F1 Phoenix (Netzsch). These experiments were performed in argon flow of 150 mL/min, with heating and cooling rates of 4 and 10 °C/min, respectively. In the temperature-modulated DSC (TM-DSC) measurements, the heating rate was the same with the oscillation period and amplitude of 60 s and 0.5 °C, respectively. X-ray powder diffraction (XRPD) experiment. X-ray powder diffractograms were determined using Rigaku MiniFlex 600 diffractometer equipped with a D/teX Ultra detector. In this experiment, CuKα (λ = 1.54178 Å) radiation (30 kV, 10 mA) was used, Kβ radiation was eliminated with Ni filter. The diffractograms were determined at RT in the reflection mode, with scanning speed 5 °min-1. Clathrate samples were loaded into a glass holder. Patterns were recorded without sample rotation. To distinguish polymorphs with close or the same type of packing, the diffractograms were determined also with an additive of standard silicon powder SRM 640d, and corresponding corrections were applied to 2θ values. FTIR spectroscopy. IR spectra were collected using Bruker Vertex 70 FTIR spectrometer, which was purged by dry air to remove atmospheric humidity. The interferograms were recorded with 128 scans and a resolution of 2 cm-1. Spectra of solid samples were recorded using attenuated total reflection MIRacle accessory with germanium crystal (PIKE Tech.). A sample


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cell of CaF2 with 0.2 mm spacer was used to obtain spectra of solutions, where calixarene concentration was 0.0125 M. Single-crystal X-ray diffraction experiments. The X-ray diffraction data of single crystals of calixarene 1 were collected on a Bruker AXS Smart Apex II CCD diffractometer in the ω- and

φ-scan modes using graphite monochromator MoKα (λ=0.71073 Å) radiation at 296 K. Data processing was performed using the APEX2 package.71 Data were corrected for the absorption effect using SADABS program.72 The structures were solved by direct methods and refined by the full matrix least-squares using SHELXTL73 and WinGX programs.74 The single crystal X-ray diffraction data for 2·C2H5OH and 3 were collected using a Bruker D8 VENTURE DUO diffractometer in the ω- and φ-scan modes using MoKα (λ = 1.54178 Å) radiation, T = 100 K. Data processing was performed using the APEX3 package.75 Data were corrected for absorption effects using the multi-scan method (SADABS). The structures were solved and refined using the programs XT, VERSION 2014/476 and SHELXL-2014/7,77 respectively. In all structures all non–hydrogen atoms were refined anisotropically. Hydrogen atoms were inserted at calculated positions and refined as riding atoms except for crystals of 1 where the hydrogen atoms of N–H groups and solvent molecules were located from Fourier difference maps and refined as riding atoms. Figures were made using Mercury program.78 Molecular structures and conformations were analyzed by PLATON.79

RESULTS AND DISCUSSION Polymorph screening at host saturation with guest vapors / guest release / heating. To study the influence of differences in molecular structure of 1, 2 and 3 and preparation history on formation of polymorphs, glassy powders (1g, 2g and 3g) of these calixarenes were prepared by heating according to the description given above for use as an initial state for further host 9 ACS Paragon Plus Environment


treatment. The ability of g-form for phase transitions at heating was studied by TM-DSC for calixarenes 1 and 2. DSC curves are shown in Figure 2, Figure S1 in Supporting Information. A specific feature of 1g and 2g is the absence of cold crystallization and melting points (Figures 2, Figure S1). For 3g both these effects are present with onset points Tonset at 118 and 181 °C, respectively.39 The glass transition temperatures Tg of 1g, 2g and 3g are quite close being at 64 °C (Figure 2), 51 °C (Figure S1) and 59 °C,39 respectively. Corresponding changes in heat capacity ∆Cp are equal to 0.131 (Figure 2), 0.214 (Figure S1) and 0.14 J g-1K-1.39

Figure 2. TM-DSC curves for 1g sample. Solid lines correspond to a total DSC signal; dashed and dotted lines indicate reversible and irreversible processes, respectively. For polymorph screening, 1g, 2g and 3g samples were saturated with vapors of water and 16 organic compounds, including C1-C3 aliphatic alcohols, C1-C3 nitriles, acetone, carbon tetrachloride, chloroform, pyridine, benzene, toluene, ethylbenzene, cyclohexane and hexane. To determine the temperature range of guest elimination from clathrates and subsequent polymorphic transitions, simultaneous TG/DSC/MS analysis was performed for saturation products of 1g and 2g. The results with typical DSC curves are shown in Figure 3. Other data of thermal analysis are shown in Figure S2, Figure S3, Figure S4. For calixarene 3, corresponding TG/DSC/MS data were determined earlier.39


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Figure 3. TG/DSC/MS curves for products of 1g and 2g saturation with guest vapors at P/P0=1 and 25°C: (a) 1·0.79C2H5OH, (b) 1·0.91CH3CN, (c) 1·0.43C6H6, (d) 1·0.79(CH3)2CO (e) 1·0.22c-C6H12, (f) 2·0.77C2H5OH, (g) 2·0.61C2H5CN (h) 2·0.38H2O. TG/DSC/MS data show that some clathrates of 1 have more phase transitions at heating than clathrates of 2 (Figure 3) and 3.39 The number of endothermic DSC peaks for clathrates 1 varies from two for saturated products with hexane (Figure S3d) to five for saturated product with 11 ACS Paragon Plus Environment


ethanol (Figure 3a). Besides, almost all saturation products of this host have from one to two exothermic crystallization peaks (Figure 3a-e, Figure S2, Figure S3a-d). The exception is a saturated product of 1g with water vapor, which has no DSC peaks (Figure S2a). For comparison, clathrates of calixarene 2 have no more than three endo-peaks and no more than one exo-peak (3f,g, Figure S3e-h, Figure S4). For clathrates of 3,39 the number of endo- and exopeaks varies in the same range as for 2 with the same set of guests. Similar to the properties of 1g, a sample of 2g saturated with water vapor has only one small endo-peak at 147 °C, which probably corresponds to the melting of an available crystalline fraction (Figure 3h). This correlates with poor water inclusion, which is slightly above experimental errors according to the TG curve (Figure 3h). The samples of 1g (Figure S2a) and 3g39 do not show change in the shape of DSC curves when saturated with water vapor. For host 3, only a shift to lower temperature was observed for peak of cold crystallization.39 Thermal behavior of clathrates prepared from 1g depends much on the guest leaving partially above the first melting point (Figure 3a-e). This is observed for clathrates with ethanol, benzene, acetonitrile, cyclohexane, and in the lesser extent for acetone. These guests are retained in clathrate phase till different temperatures depending on their molecular structure. Respectively, DSC curves of these clathrates have a variety in shape including a number of exo- and endopeaks and their positions. The saturation products of 1 with the other studied guests have DSC curves with shapes (Figure S2, Figure S3a-d) similar to those shown on (Figure 3a-e). The exception is chloroform, which vapors dissolve all three hosts 1, 2 and 3 with formation of the glass forms having with DSC curves the same as for the initial g-form of each of the calixarenes (Figure 2, Figure S1).39 For comparison, the saturation products of 2g with studied guests have much more uniform thermal behavior. All prepared clathrates of 2, except those with water (Figure 3h) and mentioned above chloroform, have DSC curves with two melting peaks and one peak of 12 ACS Paragon Plus Environment

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exothermic crystallization as for the clathrates 2·0.77C2H5OH (Figure 3f) and 2·0.61C2H5CN (Figure 3g). This may be explained by a higher first melting point of this host, 117 °C, so a smaller part of guest remains in host phase and does not complicate further transitions. Calixarene 3 in g-form has intermediate properties in this relation complicated by its ability for cold crystallization.39 For polymorph screening, clathrates having essentially different shapes of DSC curves were chosen. So, 1·0.79C2H5OH, 1·0.91CH3CN, 1·0.43C6H6, 1·0.79(CH3)2CO, 2·0.77C2H5OH, 2·0.61C2H5CN, 3·0.8C2H5OH were taken, from which the guests were removed by heating in a vacuum below onset point of the first phase transition. The exception is ethanol removed from 1·0.79C2H5OH in vacuum at room temperature. To characterize the packing changes in the preparation process of guest-free calixarene samples, XRPD diffractograms were determined for initial 1g and 2g glasses, clathrates of 1, 2 and 3, and corresponding products of guest elimination (Figure 4, Figure 5, Figure S5-21). The XRPD diffractogram of 3g was determined previously.39



Figure 4. XRPD data for clathrates (a) 1·0.79C2H5OH, (g) 1·0.91CH3CN, (j) 1·0.43C6H6, (m) 1·0.79(CH3)2CO, and low-temperature guest-free polymorphs prepared by clathrates drying below the first melting point, and new polymorphs formed at heating of low-temperature polymorphs to designated temperature and cooling to RT. Diffractograms of polymorphs and glass are shown just above diffractogram of clathrate, from which they were obtained. Reflection intensity was multiplied by (h) 1.5, (j, l) 2, (c, d, f) 3, (m, i) 4, (n, o) 5, (e) 7.


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Figure 5. XRPD data for clathrates (a) 2·0.77C2H5OH, (d) 2·0.61C2H5CN, (h) 3·0.8C2H5OH, and low-temperature guest-free polymorphs prepared by clathrates drying below the first melting point, and new polymorphs formed at heating of low-temperature polymorphs to designated temperature and cooling to RT. Diffractograms of polymorphs and glass are shown just above diffractogram of clathrate from which they were obtained. Reflection intensity was multiplied by (a, d, e) 2, (c, f) 2.5, (j) 1.5. According to XRPD data (Figure 4), calixarene 1 forms four different low-temperature polymorphs 1-1, 1-5, 1-5’, 1-7 by removing ethanol, acetonitrile, acetone and benzene, respectively, at temperatures below the first melting point from corresponding clathrates. In polymorph designation N-M, N is a calixarene number, and M shows the polymorph number. Polymorphs 1-5, 1-5’ have very close diffractograms (Figure 4h,n and Figure S10) with coinciding positions of the most peaks, but with different ratio of their intensities. Calixarene 2 forms only two low-temperature polymorphs 2-1 and 2-2 by removing ethanol and propionitrile at 80 °C, respectively, (Figure 5b,e). Clathrate 3·0.8C2H5OH gives polymorph 3-1 at the same 15 ACS Paragon Plus Environment


conditions (Figure 5i). This polymorph has a different packing (Figure 5i) from the previously found β0 form (designated as 3-3 in this work) prepared from 3·1.1CH3CN at 80 °C.39 In most cases, a significant change in packing occurs at removal of guest from the clathrate (Figure 4, Figure 5, Figures S5-7). As an exception, diffractograms of two polymorphs 1-1 and 3-1 (Figure 4b,5i) are almost identical to those of corresponding initial clathrates with ethanol (Figure 4a,5h). Small packing change is observed at the transition from clathrate 2·0.77C2H5OH to polymorph 2-1 (Figure 5a,b). In order to find the other possible polymorphs, the samples 1-1, 1-5, 1-5’, 1-7, 2-1, 2-2 and 3-1 were studied by TG/DSC/MS method. The results are shown in Figure 6. The residual guest contents in these samples do not exceed 0.04, 0.01, 0.02, 0.08, 0.09, 0.04 and 0.04 mol per 1 mol of host, respectively. According to the data obtained (Figure 6), calixarene 1 has significant differences in shape of DSC curves for low-temperature polymorphs (Figure 6a-d) and corresponding initial clathrates (Figure 3a-d) above the point of guest elimination. These differences include a number of phase transition peaks and/or ratio of their thermal effects. For calixarene 2, guest removal gives much smaller changes with only an additional inflection point appearing in DSC curve of polymorph 2-2 between the first melting peak and exo-peak of calixarene crystallization (Figure 6f). Such differences are not observed for polymorph 3-1 (Figure 6g), which has the same shape of DSC curve as the initial clathrate of 3 with ethanol.39 Coinciding shapes of DSC curves were observed also for 3-3 (β0) and its initial clathrate 3·1.1CH3CN.39


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Figure 6. Curves of simultaneous TG/DSC/MS for low-temperature polymorphs (a) 1-1 (b) 1-5, (c) 1-7, (d) 1-5’, (e) 2-1, (f) 2-2, (g) 3-1. Dots (•) denote the points, to which initial polymorphs were heated, kept for 5 min at corresponding temperature and then cooled to RT for XRPD studies. The dots with the same color mark the samples with the same diffractograms. Arrows



show reversible (←) or irreversible (→) transitions at the points indicated by dots. Two arrows at one dot indicate the formation of a mixture of two polymorphs. To follow the changes of calixarenes packing at thermal treatment, XRPD diffractograms were determined for samples of low-temperature polymorphs 1-1, 1-5, 1-5’, 1-7, 2-1, 2-2 and 3-1 heated to the characteristic points on their DSC curves (Figure 6) and cooled to RT. Diffractograms obtained are shown in Figure 4, Figure 5 and Figures S 5-21. This treatment gives 6 more polymorphs for calixarene 1: 1-2, 1-3 and 1-4 from 1-1; 1-3 and 1-6 from 1-5; 1-3 and 1-8 from 1-7; 1-6 and 1-9 from 1-5' (Figure 4, Figures S5, S9-16). The same procedure provides polymorphs 2-3 and 2-4 from 2-1 and 2-2, respectively, (Figure 4b,c,e,f) and 3-2 from 3-1 (Figure 5j). The last transition, 3-1 → 3-2, does not correspond to an observable peak in the DSC curve (Figure 6g), which apparently overlaps with the melting peak. Crystallization of 1-8 from 1-7 goes in two steps probably because this process is accompanied by elimination of residual benzene with a peak on its MS curve (Figure 6c). A specific feature of 2-1 and 2-2 is a minimal change in packing at their phase transition (Figure 5, Figures S17-21). The formation of next polymorphs at heating is accompanied, nevertheless, by thermal effects of melting and crystallization (Figure 5e,f). The melting of 2-1 polymorph at 113 °C and formation of 2-3 from the melt at 130 °C was observed using optical microscopy (Figure S22). A number of polymorphs from clathrates prepared by saturation of 1g and 2g with vapors of various guests and their removal is limited. In particular, methanol gives the same lowtemperature polymorph 1-1 in this procedure (Figure S6), as ethanol (Figure 4b). Treatment of 1g with toluene and cyclohexane gives 1-7 and 1-2, respectively (Figure S6). Polymorph 2-1 is formed also after inclusion/removal of methanol, propyl alcohol, acetonitrile, benzene, hexane, cyclohexane and carbon tetrachloride (Figure S7). Polymorph 2-2 was prepared using acetone and propionitrile, but for the last guest, heating 2-2 gives 2-3, instead of 2-4 (Figure S7). Not 18 ACS Paragon Plus Environment

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much variety of polymorphs was found for 3, giving only three additional ones after treatment with 18 guests.39 In general, the formation of identical polymorphs after host saturation with different guests correlates with an observed similarity in shape of the DSC curves for corresponding clathrates (Figure 3, Figure S23).

Reversibility of polymorphic transitions. Reproducibility of polymorph preparation may depend on their stability linked to a reversibility of corresponding polymorphic transitions.80 So, the reversibility of these transitions was studied by determination and comparison of XRPD diffractograms for samples of low-temperature polymorphs heated to characteristic points, kept for 5 minutes at target temperature and the cooled to RT. According to XRPD diffractograms obtained (Figure 4b-e), the melting of 1-1, 1-2, 1-3 and 1-4 is irreversible in this experiment (Figure 6a), which gives in each case a polymorph or glass formed at higher temperature (Figure 6). The melting at its DSC peak is irreversible also for 1-5, 1-5’, 1-9, 2-1, 3-1, and reversible for 1-6, 1-7, 2-2, 2-3, 2-4 and 3-2 (Figure 4, Figure 5, Figure 6).

Figure 7. Curves of cyclic DSC experiment for initial 1-1 sample with heating to (a) 80 °C, (b) 100 °C, (c) 134 °C, (d) 148 °C, (e) 157 °C and (f) 200 °C. Polymorphs numbers indicate corresponding melting peaks. In addition, reversibility of phase transitions was studied for 1-1 using a separate cyclic heating/cooling DSC experiment (Figure 7, Figure S24). In this experiment, the first cycle of heating to 80 °C was to check the presence of possible guest residues. The next 4 cycles were 19 ACS Paragon Plus Environment


with heating to temperatures of melting peaks of each polymorph and cooling to RT. Cooling curves are shown in Figure S24. The DSC data show the negligibly small contents of glassy phase in the initial 1-1 as it performs glass transition with heat capacity changes ∆Cp = 0.083 J·g-1K-1 only after heating to its first melting peak at 100 °C (Figure 7a-c). In this heating run and in the next three ones, glass transition occurs at nearly the same point of Tg = 62±1 °C, which is lower only by 2°C than Tg value of 1g sample (Figure 2). In the 4th-6th heating curves, the ∆Cp values are different and equal to 0.013, 0.073 and 0.143 J·g-1K-1, respectively, (Figure 7d-f). The higher ∆Cp values observed in the 3rd, 5th and 6th runs are accompanied with broad exo-peaks of cold crystallization with onset points at 100, 100 and near 106 °C, respectively, (Figure 7c,d,f). These peaks are absent in DSC curves for 1g sample prepared by cooling of 1 melt from 170 °C to RT (Figure 2). So, the glassy 1g and glassy components formed at partial melting of polymorphs may have different nature, which may be similar to polyamorphism in partially vitrified solids.81 In 4th and 5th heating runs, DSC curves have two melting peaks including that at the upper point of the previous heating cycle (Figure 7d,e). The final curve (Figure 7f) has a large melting peak of polymorph 1-4 which should be melted in previous 5th run. The presence of such peaks may indicate a partial reversibility of the last transition at heating or/and not complete melting of corresponding polymorph in the previous run. Reversibility of at least the melting of 1-4 may be seen from its unproportionally large enthalpy, 24.6 kJ/mol, which is much higher than the value 4.4 kJ/mol observed in one-run TG/DSC/MS experiment (Figure 6a). The presence of residual crystals of a polymorph at immediate cooling from its melting peak may induce its crystallization in this process according to Ostwald’s rule of stages.3,82 Modification of polymorph by a second guest vapor. Discovered polymorphs of studied calixarenes may be used as an initial state instead of glassy g-form for a further search of new polymorphs. In this work, such a study was performed for 1-5 prepared by drying clathrate of 1 20 ACS Paragon Plus Environment

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with acetonitrile at 60 °C in vacuum. This polymorph was selected because it has a minimal enthalpy of the first melting in the range of 80-110 °C among the found low-temperature polymorphs (Figure 6). Sample 1-5 was heated for 5 minutes at 80 °C, which is a first melting point of clathrate 1·0.91CH3CN (Figure 3b), and cooled to RT. According to XRPD data, the product has a packing which is very close to the packing of initial 1-5 (Figure S25), and no noticeable traces of CH3CN according to TG/DSC/MS data were observed (Figure 8a). So, the thermally treated 1-5 is at least partially a metastable crystalline powder, similar to that described in Ref.47, despite its first endothermic transition with a peak at 110 °C (Figure 8a) is significantly reduced and broadened, while a subsequent exothermic peak at 124 °C has the same enthalpy of ∆H = -12 kJ/mol compared with that of the initial 1-5 (Figure 6b).



Figure 8. Curves of simultaneous TG/DSC/MS for (a) polymorph 1-5 previously heated to 80 °C and cooled to RT (b) hydrate·1·1.54H2O and (c) polymorph 1-10 prepared from hydrate 1·1.54H2O by drying in vacuum at RT over P4O10. For a search of new polymorphs, a sample of 1-5 preliminarily treated by heating at 80 °C was equilibrated with saturated water vapor at 25 °C. This gives hydrate 1·1.54H2O, according to TG/DSC/MS data (Figure 8b). Its XRPD diffractogram (Figure 9a) significantly differs from those of the other studied clathrates of 1 (Figure 4, Figure 5, Figure S6). So, the studied 1-5 sample differs from 1g, which does not sorb water under the same conditions (Figure S2a). Drying of hydrate 1·1.54H2O at room temperature over P4O10 in vacuum gives a new polymorph 1-10 with a powder diffractogram shown in Figure 9b. The polymorph 1-10 does not contain water over trace level according to the obtained TG/DSC/MS curves (Figure 8c). Its water content is less than 0.14 mol per 1 mol of host, which is close to the sensitivity level of the used device. Hydrate 1·1.54H2O and 1-10 perform exothermic peaks at lower temperatures, 105 and 107 °C, respectively, (Figure 8) than the initial 1-5 sample (Figure 6b). Saturation of polymorph 1-10 with ethanol vapor at 25 °C gives ethanol clathrate with the same diffractogram (Figure 9c), as 1·0.79C2H5OH prepared from 1g (Figure 4a). So, consecutive saturation of 1g by vapors of two different compounds with an intermediate and final drying successfully gives a new polymorph. Probably, this approach may increase the number of found polymorphs for 1 much beyond ten.


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Figure 9. XRPD data for (a) hydrate·1·1.54H2O, prepared by saturation with water vapor at 25 °C of 1-5 previously heated to 80 °C and cooled to RT, (b) polymorph 1-10 prepared by prolonged drying in vacuum at RT of 1·1.54 H2O over P4O10, (c) clathrate of 1·with ethanol prepared by saturation of 1-10 with this guest at 25 °C. Diffractograms (a) - (c) were determined with an additive of standard silicon powder SRM 640d. IR data on H-bonding in found polymorphs. To find the cause of the observed calixarene 1 ability to form a large number of polymorphs, IR spectra were determined for solid 1-1, 1-2, 2-1, 2-2 and 3-4, glassy 1g, 2g and 3g, and solutions of calixarenes 1, 2 and 3 in carbon tetrachloride with concentration of 0.0125 M. Figure 10 shows the characteristic areas of the typical spectra obtained. Full spectra are given in the Figure S26-29.



Figure 10. The IR spectra at RT of solid samples (a) 1-1, (b) 1-2, (c) 1g, (d) 2-1, (e) 2-2 and 0.0125 M solutions in CCl4 of the next calixarenes: (f) 1, (g) 2, (h) 3. The spectra are normalized to the peak intensity of C=O stretching vibrations of acyl groups. Analysis of the IR spectra obtained indicates a significant distinction of 1 compared to the other two stable conformations of this compound (Figure 10). The spectrum of calixarene 1 solution in CCl4, 0.0125 M, has a significant band at 3430 cm-1 corresponding to stretching vibrations of free N–H groups, which intensity is 28% from that of H-bonded N–H groups at 3332 cm-1. From the known ratio of extinction coefficients for free and H-bonded N–H groups of amide fragments, 3.4,83 nearly half of N–H groups are free. For comparison, the solution of 3 in CCl4 has only a shoulder at 3440 cm-1 (Figure 10h), while for solution of 2 this shoulder is only on trace level (Figure 10g). Polymorphs 2-1 and 2-2 of this calixarene do not have free N–H groups (Figure 10d,e). The same was observed for glassy 2g and 3g, and for polymorph 3-4 (Figure S29g-i). Specific feature of calixarene 1 is the ability to keep some of its N–H groups free in the solid state. Polymorph 1-1 has the same ratio of free and bonded N–H groups (Figure 10a) as the host 1 solution in CCl4 (Figure 10f). This may provide a high mobility of its structure in the solid phase, compared to 2 and 3, where the fraction of free N–H groups is very low even in dilute solution. Heating of 1-1 gives polymorph 1-2, which has much lower content of free N–H groups 24 ACS Paragon Plus Environment

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(Figure 10b), as well as glassy 1g (Figure 10c). For comparison, a polymorph with three endothermic effects above the endset point of solvent release and also one pronounced exothermic effect of crystallization was observed for betamethasone valerate.27 Thus, solvent (guest) removal from solvate (clathrate) with formation of non-bonded groups, which are both proton donors and proton acceptors, may result in an increased ability for polymorphism. Single crystal X-ray data on H-bonding in calixarene crystals. To determine the structural reasons for different ability of calixarenes 1, 2 and 3 to form polymorphs, their crystal structure was studied using single crystal X-ray diffraction. Two crystalline forms of calixarene 1 were grown by cooling its solutions in water/ ethanol mixture (1·H2O) and ethanol (1·C2H5OH) from RT to 4°C. Hydrate 1·H2O crystals have a shape of prisms (Figure 11a). Solvate 1·C2H5OH crystalizes in the form of plates (Figure 11b). The crystal data, data collection details, and the refinement parameters are given in Table 1.

Figure 11 Crystal habits of calixarene 1: (a) prism of 1·H2O; (b) plate of 1·C2H5OH.

Table 1. Crystal data and results of the structure refinement for 1·H2O, 1·C2H5OH, 2·C2H5OH, and calixarene 3.



1·H2O

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1·C2H5OH

2·C2H5OH

3

Empirical Formula C64H84O16N4S4· H2 O

C64H84O16N4S4· C2H5OH

C64H84O16N4S4· C2H5OH

C64H84O16N4S4

Mr (g·mol−1)

1311.65

1339.65

1339.65

1293.59

Crystal color

colorless

colorless

colorless

colorless

Crystal system

triclinic

monoclinic

monoclinic

monoclinic

Space group

P1

C2/c

P21/n

P21/c

a (Å)

13.033(3)

35.018(3)

18.4569(8)

14.247(3)

b (Å)

14.765(4)

15.0387(14)

21.3208(9)

14.159(3)

c (Å)

18.324(5)

28.362(3)

18.9975(9)

33.363(7)

α (°)

87.779(4)

90

90

90

β (°)

81.648(4)

102.518(5)

110.528(2)

97.23(3)

γ (°)

80.823(4)

90

90

90

V (Å3)

3443.64

14581(2)

7001.11

6676.4

Temperature (K)

296(2)

296(2)

100(2)

100(2)

Crystal size (mm)

0.12 x 0.21 x 0.19 x 0.26 x 0.049 x 0.078 x 0.076 x 0.225 x 0.26 0.61 0.157 0.272

Z

2

8

4

4

ρcalc. (g·cm−3)

1.265

1.221

1.271

1.287

F(000)

1396

5712

2856

2752

µ (cm-1)

2.06

1.96

1.81

1.87

θmin / θmax (°)

1.779 / 29.104

3.083 / 31.611

3.235 / 52.690

3.395 / 78.392

Reflections measured

45142

84212

46270

104085

Independent refl.

17402 0.069]

Number parameters restraints Reflections [I > 2σ(I)]

of 873 / 0 / 6745

[Rint

= 23118 0.139]

[Rint

= 7646 [Rint 0.095]

= 13865 [Rint = 0.051]

898 / 41

838 / 0

847 / 0

5500

5362

11053


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R / wR [> 2σ(I)]

0.066 / 0.146

0.073 / 0.147

0.102 / 0.226

0.043 / 0.098

(all 0.185 / 0.197

0.332/ 0.243

0.146 / 0.248

0.060 / 0.106

Goodness-of-fit on 0.93 F2

0.87

1.04

1.03

ρmax / ρmin (e·Ǻ-3)

0.49 / –0.24

0.66 / –0.41

0.76 / –0.53

R / wR reflections)

0.87 / –0.75

Figure 12. The ORTEP plots of hydrate 1·H2O. Displacement ellipsoids are drawn at the 30% probability level; hydrogen atoms are represented as fixed-size spheres. For clarity only the higher occupancy positions of the disordered fragments are shown. Hydrate 1·H2O crystallizes in a space group P1 with one molecule of calixarene and one molecule of water in an independent part of the unit cell (Figure 12). Two of four tert-butyl groups in a molecule of calixarene 1 are disordered over two positions with the relative occupancies of 0.63: 0.37 and 0.61: 0.39. Also fragments of two long-chain substituents (relative occupancies of 0.58: 0.42 and 0.50: 0.50) are disordered. A calixarene molecule in 1·H2O is in general position of triclinic unit cell and loses its own S4 symmetry in crystal (Figure 12). The reason is in fact that each long-chain substituent has its own conformation described by a specific set of torsion angles (Table S1). Hydrate 1·H2O has a different packing than the hydrate 1·1.54H2O prepared by saturation with water vapor of thermally treated polymorph 1-5 according to corresponding simulated (Figure S30) and experimental (Figure 9a) powder diffractograms. 27 ACS Paragon Plus Environment


Hydrate 1·H2O does not have any cavities with volume of 80 Å3 suitable for ethanol. In this crystal, a water molecule is located outside the calixarene pseudocavities formed by pairs of opposite aromatic fragments. Water links three calixarene molecules by two H-bonds with amide carbonyls of substituents in positions 1 and 4 of two different macrocycles, and by one H-bond with N–H group in position 3 of the third macrocycle (Figure 13, Table S2). There is also a weak intramolecular N–H···O bond between substituents in positions 2 and 4with N…O distance of 3.174(4) Å. So, an H-bonded 2D framework is formed by calixarene and water molecules.

Figure 13. H-bonding in crystal of 1·H2O. View along b crystallographic axis. Only hydrogen atoms of N–H groups and water are shown. Dotted blue and red lines denote the hydrogen bonds. Water molecules are shown in “ball-and-stick” mode. The solvate 1·C2H5OH crystallizes in C2/c space group. The asymmetric part of the unit cell contains one calixarene 1 molecule with one ethanol molecule (Figure 14), as in the case of 1·H2O. Two tert-butyl groups of the molecule (one on each side of calixarene pseudocavities) are disordered over two positions with relative occupancies 0.79:0.21 and 0.53:0.47. Methyl fragment of ethanol molecule is disordered in unit cell over two positions with relative occupancies 0.58:0.42 and ethanol molecule forms only one H-bond with amide CO group of substituent in position 2 of calixarene macrocycle with O…O distance equal to 3.01(2) Å. Unlike water in 1·H2O, ethanol in its solvate with 1 does not link neighboring calixarenes in an extended network. A supramolecular pattern in 1·C2H5OH is restricted to pairs of calixarene molecules linked by two intermolecular N–H···O=C bonds with the N…O distance of 3.13(1) Å 28 ACS Paragon Plus Environment

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between ester and amide groups of substituents in positions 3 and 4, respectively, (Figure 15, Table S3). These pairs form parallel layers with ethanol molecules aggregated in non-bonded pairs with a distance between oxygen atoms of 5.86 Å (Figure 31S).

Figure 14. The ORTEP plots of the solvate (clathrate) 1·C2H5OH. Displacement ellipsoids are drawn at the 20% probability level; hydrogen atoms are represented as fixed-size spheres. For clarity only the higher occupancy positions of the disordered fragments are shown.

Figure 15. H-bonding in 1·C2H5OH crystal. Dotted blue lines denote the hydrogen bonds. Ethanol molecules are given in “ball-and-stick” mode with hydrogen atoms; hydrogen atoms of N–H groups are also shown. Calixarene molecules in 1·C2H5OH have only one classical strong intramolecular N–H···O=C bond between the substituents in positions 1 and 3 of the macrocycle, making fragments OCH2CONHCH2 in these substituents to be practically coplanar (Figure 14). The N…O distance 2.841(5) Å for this H-bond is shorter by 0.33 Å compared to the distance between the same 29 ACS Paragon Plus Environment


atoms in the 1·H2O crystal (Figure 13). Two N–H groups of substituents in positions 2 and 3 are not H-bonded with carbonyls or included solvent. In this respect, 1·C2H5OH is similar to 1-1 polymorph, which has free N–H groups according to IR data (Figure 10). This comparison is rational because simulated XRPD diffractogram of 1·C2H5OH (Figure S32, Figure S33) is close to the experimental diffractograms of 1-1 and clathrate 1·0.79C2H5OH (Figure 4a,b). Less H-bonded structure of 1·C2H5OH results in more symmetrical calixarene molecule than in 1·H2O. This can be seen in a van der Waals representation of 1 from ethanol solvate (Figure 16). Two long-chain substituents in 2,4-positions embrace the disordered tert-butyl group in position 3 of macrocycle in a claw-grip manner. Macrocycle conformation is nearly the same as in hydrate 1·H2O. Dihedral angles between pairs of opposite aromatic rings of calixarene 1 in these crystals are approximately equal: 11.4(1)° and 30.6(1)° - in 1·H2O, and 11.6(2)° and 30.7(2)° - in 1·C2H5OH.

Figure 16. The space-filling representation of calixarene 1 molecule in the crystal of 1·C2H5OH. Central tert-butyl groups is shown as disordered over two positions with relative occupancies 0.53:0.47. As well as in 1·H2O, each long-chain substituent of calixarene 1 has its own conformation (Table S4). Relatively small number of strong intramolecular and intermolecular H-bonds, which 30 ACS Paragon Plus Environment

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stabilizes host conformation, especially in 1·C2H5OH, gives many degrees of freedom to its substituents, which explains the ability of this calixarene to form a large number of polymorphs. For comparison, single crystals of 2·C2H5OH and calixarene 3 without guest were grown under the same conditions from ethanol solution and characterized by X-ray diffraction. Solvate (clathrate) 2·C2H5OH crystallizes in space group P21/n with one host and one ethanol molecule in the asymmetric part of the unit cell (Figure 17). Neighboring host molecules are linked by one H-bond forming infinite 1D chains (Figure 18). Besides, there is one intramolecular H-bond between substituents in positions 1 and 2 of the macrocycle and one H-bond between amide C=O group in position 4 and ethanol. As a result, two of four N–H groups in calixarene 2 molecules remain not H-bonded (Figure 18). Unlike 1·C2H5OH, 2·C2H5OH has a different XRPD diffractogram and, respectively, a different packing than clathrate 2·0.77C2H5OH prepared by saturation of 2g with ethanol vapors (Figure 5a and Figure S34). The same can be concluded from the absence of free N–H groups observed in IR spectra of 2-1 and 2-2 (Figure 10d,e), which XRPD diffractogram is close to that of 2·0.77C2H5OH (Figure 5a-c).

Figure 17. The ORTEP plots of 2·C2H5OH. Displacement ellipsoids are drawn at the 30% probability level; hydrogen atoms are represented as fixed-size spheres.



Figure 18. H-bonding in 2·C2H5OH crystal. Only hydrogen atoms of N–H groups and ethanol molecules are shown. Dotted blue and red lines denote the hydrogen bonds. Ethanol molecules are shown in “ball-and-stick” mode. Single crystals of 3 without guest were grown under the same conditions and characterized by X-ray diffraction. This compound crystallizes in the space group P21/c. A disorder (relative occupancy 0.61:0.39) was observed for CH2OCOCH3 fragment of substituent in position 3 of macrocycle (Figure 19). The powder diffractogram of 3 (Figure S35) simulated from these data indicates formation of the sixth polymorph for this calixarene, being essentially different than experimental diffractograms for polymorphs obtained by host treatment with guest vapors and heating to various temperatures (Ref.39, Figure 5h-j). This is a normal situation for a clathrate forming host, which may form crystals of different guest-free polymorphs depending on its preparation history.84 A unit cell of 3 contains four host molecules aggregated in antiparallel pairs with a small shift of 0.096 Å between average planes of their macrocycles defined by sulfur atoms. These pairs are linked together by two intermolecular N–H···O=C hydrogen bonds (Figure 20, Figure S36). Each pair is linked by four H-bonds with four other such pairs having the average planes of their


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macrocycles inclined to the plane of the first one at an angle of 122.46°. As a result, an Hbonded 2D framework is formed (Figure 20).

Figure 19. The ORTEP plots of crystalline calixarene 3. Displacement ellipsoids are drawn at the 30% probability level; hydrogen atoms are represented as fixed-size spheres. A fragment CH2OCOCH3 of substituent in position 3 is disordered.

Figure 20. Schematic presentation of H-bonded 2D framework in crystals of calixarene 3. Squares represent calixarene molecules. In addition to four intermolecular N–H···O=C hydrogen bonds, each molecule of 3 also forms two intramolecular H-bonds, which connect three amide-containing substituents in positions 1, 2 and 3 of the macrocycle (Figure 20). As a result, calixarene 3 resembles a shape of wheelchair (Figure 19a), where the fourth long-chain substituent in position 4 looks like a backrest and the 33 ACS Paragon Plus Environment


rear handle, tert-butyl groups and benzene rings in positions 1 and 3 are like side armrests, and the benzene ring in position 2 is like a seat with a dihedral angle of 103° to the plane of the benzene ring in position 4. A greater involvement in H-bonding of amide fragments in 3, each involved in two N–H···O=C bonds, can be a reason of its lower tendency to form polymorphs compared with calixarene 1. Smart crystallization in binary vapor mixtures. Smart behavior of calixarene 1 has been studied also in interaction of its compact glass 1g with vapors of binary guest mixtures. Selection of guests for these mixtures was based on the results of 1g crystallization in saturated vapors of organic compounds from various classes: aliphatic alcohols C1-C3, and nitriles C2-C3, acetone, hexane, cyclohexane benzene, toluene, ethylbenzene, pyridine, carbon tetrachloride, chloroform and water. Samples of compact transparent 1g were equilibrated for 24 hours with saturated vapor of each individual compound from this set, and the presence or absence crystallization, and formation of a liquid solution in some cases were observed visually. Pictures of saturation products are given in Figure S37. For the studied set of organic guests, compact 1g crystallizes without formation of liquid solution only in vapors of acetonitrile, propionitrile, butyronitrile, ethanol, propyl alcohol and isopropyl alcohol (Figure S37). The compact 1g does not crystallize in hexane, cyclohexane and water vapors, keeping transparency for 24 hours of equilibration (Figure 21a, Figure S37). All other studied solvents vapors dissolve these 1g samples (Figure S37). So, a binary mixture of a “good” guest, which vapor induces crystallization of calixarene glass, and a “bad” guest, which does not have such ability, may be used to test smart detection of solvent impurities using transparent 1g samples as a sensing material for visual detection. For comparison, 2g does not have such selectivity. It dissolves in methanol vapor with simultaneous crystallization and crystallizes also in all other studied solvent vapors including those of alkanes and water (Figure S38). So, the absence of "bad" guests, which do not initiate 34 ACS Paragon Plus Environment

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crystallization of 2g, makes this host unsuitable for the visual detection of solvent impurities. Besides, both 1g and 2g are less stable in the solvent vapors than previously studied 3g, which forms solutions only with saturated vapors of chloroform and pyridine from the same set of guests and does not crystallize in vapors of alkanes and water.39 The reason of this fact may be a lower first melting point of calixarenes 1 and 2 compared with 3 (Figures 3, 6, S2-4, S23).

Figure 21 Crystallization of molecular glass 1g in saturated vapors of pure c-C6H12 (a) and C6H6/c-C6H12 mixtures with benzene concentration of (b) 0.5 % (v/v), and (c) 1 % (v/v) at 25°C. Equilibration time was 24 h. Lower stability of 1g compared with 3g in vapors of most guests studied supposes a higher sensitivity of 1g layer in visual sensor to the presence of good component in bad solvent. To explore this problem, two pairs of “good” + “bad” solvents were chosen: ethanol-water and benzene-cyclohexane. Compact transparent samples of 1g were exposed to saturated vapors of these mixtures with different compositions for 24 h at 25 °C. The visual changes of 1g samples under these conditions are shown in Figure 21 and Figure S39. A visible crystallization of 1g was observed already at 0.5 % (v/v) benzene in cyclohexane (Figure 21b). At the increase in benzene content to 1 % (v/v), 1g loses its transparency almost completely (Figure 21c). Therefore, the 1g molecular glass can be used as a sensing layer for a visual assessment of



relatively small impurities of good guest in alkane liquid. The same experiment with 1g and vapors of ethanol -water mixture gives a lower threshold concentration of ethanol, 21 % (v/v) (Figure S39), inducing crystallization, instead of 24 % (v/v) observed for 3g.39 This makes possible to create a set of sensors for different concentrations of ethanol in water.

CONCLUSIONS A problem of controlled (smart) formation of polymorphs was solved for a set of tertbutylthiacalix[4]arene derivatives with four N-(2-acetoxyethyl)carbamoylmethoxy substituents at lower rim with the 1,3-alternate, cone and partial cone conformations. For this, an effective polymorph screening was achieved using guest inclusion/release and subsequent heating. This screening is based on a standard method of clathrate preparation by equilibration of solid host with saturated guest vapors. Thus, clathrates are prepared without formation of liquid phase in relatively short time under conditions close to reversible and equilibrium ones. This method together with a suitable choice of a host standard state gives a reproducible influence of preparation history on polymorph formation. Such a standard state is a host glass prepared by cooling the melt formed above the highest melting point where all prehistory of the host sample is wiped out. As a result, an observed structure-property relationship for polymorph formation after guest release is more objective and less complicated by differences in preparation conditions for different polymorphs. The elaborated method of polymorph screening gives a large number of polymorphic forms for a studied calixarene in 1,3-alternate conformation. This can be explained by flexibility of its substituents and a subtle balance of strong intra- and intermolecular H-bonds. Such a balance can be seen from comparison of obtained single crystal X-ray data for the studied calixarenes, which performs their different structural motifs. Intermolecular H-bonds link 1,3-alternate calixarene only in pairs at least in one crystalline form, unlike for calixarenes in cone and partial cone 36 ACS Paragon Plus Environment

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conformations, which have highly H-bonded 1D and 2D networks, respectively, in their single crystals grown under the same conditions. This makes a crystal packing of 1,3-alternate calixarene more flexible and may be a cause of its much higher ability for polymorphism. The number of found polymorphs for this host probably may be increased to an infinite value using a sequential treatment with vapors of two or more different guests and guest release. In particular, a unique tetramorphism was found for this 1,3-alternate calixarene with four consecutive melting points of its crystalline guest-free sample and corresponding three crystallization ranges. A compact glass of this calixarene derivative performs a smart property of selective crystallization in vapors of binary vapor mixture, which can be used for visual detection of very small benzene impurities (0.5 % (v/v)) in cyclohexane.

ASSOCIATED CONTENT Supporting information The Supporting Information is available free of charge on the ACS Publications website at DOI:… TM-DSC curves for 2g sample; TG/DSC/MS curves for clathrates of calixarenes 1 and 2 and their polymorphs; cooling curves of cyclic DSC experiment for 1-1 sample; experimental XRPD data for clathrates of calixarenes 1 and 2, polymorphs of calixarenes 1, 2 and 3; XRPD patterns calculated from single crystal X-ray data for 1·H2O, 1·C2H5OH and 3; IR spectra of solid samples of polymorphs and 1g, 2g and 3g and solutions of calixarenes 1, 2 and 3; two projections of 1·C2H5OH crystal packing; picture of 3 crystal packing; optical microscope pictures of 2-1 and 2-3 samples; pictures of initial 1g and 2g samples and those saturated with vapors of water, organic compounds and their mixtures; torsion angles of calixarene long-chain substituents in 1·H2O, 1·C2H5OH and 3 crystals; parameters of H-bonds in 1·H2O, 1·C2H5OH and 3; TG/DSC/MS data for clathrates prepared from 1g and 2g samples. 37 ACS Paragon Plus Environment


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Accession Codes CCDC 1539674, 1539675, 1540744 and 1540745 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. AUTHOR INFORMATION Corresponding Author E-mail: [email protected] ORCID Valery V. Gorbatchuk: 0000-0002-5347-2066 Notes The authors declare no competing financial interest.

ACKNOWLEDGEMENTS The work was supported by the Russian Government Program of Competitive Growth of Kazan Federal University (KFU) and by RFBR, grant No. 17-03-01311. The work of Alexander E. Klimovitskii was supported by grant №14.Y26.31.0019 from Ministry of Education and Science of Russian Federation. Equipment of the Federal Center of Shared Equipment of KFU was used in this work.


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For Table of Contents Use Only

Smart polymorphism of thiacalix[4]arene with longchain amide containing substituents Karina V. Gataullina, Marat A. Ziganshin, Ivan I. Stoikov, Alexander E. Klimovitskii, Aidar T. Gubaidullin, Kinga Suwińska, Valery V. Gorbatchuk*

TABLE OF CONTENTS GRAPHIC

SYNOPSIS An effective screening procedure reveals a calixarene structure, which has at least 10 guest-free polymorphs and performs a unique tetramorphism with four consecutive melting points. A glass form of this calixarene may be used for visual detection of small additive of benzene in alkane.


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Figure 1. Structure of calixarenes 1, 2 and 3. 87x48mm (300 x 300 DPI)

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Figure 2. TM-DSC curves for 1g sample. Solid lines correspond to a total DSC signal; dashed and dotted lines indicate reversible and irreversible processes, respectively. 80x53mm (300 x 300 DPI)


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Figure 3. TG/DSC/MS curves for products of 1g and 2g saturation with guest vapors at P/P0=1 and 25°C: (a) 1•0.79C2H5OH, (b) 1•0.91CH3CN, (c) 1•0.43C6H6, (d) 1•0.79(CH3)2CO (e) 1•0.22c-C6H12, (f) 2•0.77C2H5OH, (g) 2•0.61C2H5CN (h) 2•0.38H2O. 160x181mm (300 x 300 DPI)



Figure 4. XRPD data for clathrates (a) 1•0.79C2H5OH, (g) 1•0.91CH3CN, (j) 1•0.43C6H6, (m) 1•0.79(CH3)2CO, and low-temperature guest-free polymorphs prepared by clathrates drying below the first melting point, and new polymorphs formed at heating of low-temperature polymorphs to designated temperature and cooling to RT. Diffractograms of polymorphs and glass are shown just above diffractogram of clathrate, from which they were obtained. Reflection intensity was multiplied by (h) 1.5, (j, l) 2, (c, d, f) 3, (m), (i) 4, (n, o) 5, (e) 7. 80x120mm (300 x 300 DPI)


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Figure 5. XRPD data for clathrates (a) 2•0.77C2H5OH, (d) 2•0.61C2H5CN, (h) 3•0.8C2H5OH, and lowtemperature guest-free polymorphs prepared by clathrates drying below the first melting point, and new polymorphs formed at heating of low-temperature polymorphs to designated temperature and cooling to RT. Diffractograms of polymorphs and glass are shown just above diffractogram of clathrate from which they were obtained. Reflection intensity was multiplied by (a, d, e) 2, (c, f) 2.5, (j) 1.5. 80x103mm (300 x 300 DPI)



Figure 6. Curves of simultaneous TG/DSC/MS for low-temperature polymorphs (a) 1-1 (b) 1-5, (c) 1-7, (d) 1-5’, (e) 2-1, (f) 2-2, (g) 3-1. Dots (•) denote the points, to which initial polymorphs were heated, kept for 5 min at corresponding temperature and then cooled to RT for XRPD studies. The dots with the same color mark the samples with the same diffractograms. Arrows show reversible (←) or irreversible (→) transitions at the points indicated by dots. Two arrows at one dot indicate the formation of a mixture of two polymorphs. 160x192mm (300 x 300 DPI)


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Figure 7. Curves of cyclic DSC experiment for initial 1-1 sample with heating to (a) 80 °C, (b) 100 °C, (c) 134 °C, (d) 148 °C, (e) 157 °C and (f) 200 °C. Polymorphs numbers indicate corresponding melting peaks. 80x51mm (300 x 300 DPI)



Figure 8. Curves of simultaneous TG/DSC/MS for (a) polymorph 1-5 previously heated to 80 °C and cooled to RT (b) hydrate 1•1.54H2O and (c) polymorph 1-10 prepared from hydrate 1•1.54H2O by drying in vacuum at RT over P4O10. 80x135mm (300 x 300 DPI)


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Figure 9. XRPD data for (a) hydrate 1•1.54H2O, prepared by saturation with water vapor at 25 °C of 1-5 previously heated to 80 °C and cooled to RT, (b) polymorph 1-10 prepared by prolonged drying in vacuum at RT of 1•1.54 H2O over P4O10, (c) clathrate of 1 with ethanol prepared by saturation of 1-10 with this guest at 25 °C. Diffractograms (a) - (c) were determined with an additive of standard silicon powder SRM 640d. 80x75mm (300 x 300 DPI)



Figure 10. The IR spectra at RT of solid samples (a) 1-1, (b) 1-2, (c) 1g, (d) 2-1, (e) 2-2 and 0.0125 M solutions in CCl4 of the next calixarenes: (f) 1, (g) 2, (h) 3. The spectra are normalized to the peak intensity of C=O stretching vibrations of acyl groups. 80x68mm (300 x 300 DPI)


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Figure 11. Crystal habits of calixarene 1: (a) prism of 1•H2O; (b) plate of 1•C2H5OH. 80x30mm (300 x 300 DPI)



Figure 12. The ORTEP plots of hydrate 1•H2O. Displacement ellipsoids are drawn at the 30% probability level; hydrogen atoms are represented as fixed-size spheres. For clarity only the higher occupancy positions of the disordered fragments are shown. 160x54mm (300 x 300 DPI)


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Figure 13. H-bonding in crystal of 1•H2O. View along b crystallographic axis. Only hydrogen atoms of N–H groups and water are shown. Dotted blue and red lines denote the hydrogen bonds. Water molecules are shown in “ball-and-stick” mode. 80x46mm (300 x 300 DPI)



Figure 14. The ORTEP plots of the solvate (clathrate) 1•C2H5OH. Displacement ellipsoids are drawn at the 20% probability level; hydrogen atoms are represented as fixed-size spheres. For clarity only the higher occupancy positions of the disordered fragments are shown. 160x70mm (300 x 300 DPI)


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Figure 15. H-bonding in 1•C2H5OH crystal. Dotted blue lines denote the hydrogen bonds. Ethanol molecules are given in “ball-and-stick” mode with hydrogen atoms; hydrogen atoms of N–H groups are also shown. 80x42mm (300 x 300 DPI)



Figure 16. The space-filling representation of calixarene 1 molecule in the crystal of 1•C2H5OH. Central tert-butyl groups is shown as disordered over two positions with relative occupancies 0.53:0.47. 80x73mm (300 x 300 DPI)


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Figure 17. The ORTEP plots of 2•C2H5OH. Displacement ellipsoids are drawn at the 30% probability level; hydrogen atoms are represented as fixed-size spheres. 160x59mm (300 x 300 DPI)



Figure 18. H-bonding in 2•C2H5OH crystal. Only hydrogen atoms of N–H groups and ethanol molecules are shown. Dotted blue and red lines denote the hydrogen bonds. Ethanol molecules are shown in “ball-andstick” mode. 80x81mm (300 x 300 DPI)


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Figure 19. The ORTEP plots of crystalline calixarene 3. Displacement ellipsoids are drawn at the 30% probability level; hydrogen atoms are represented as fixed-size spheres. A fragment CH2OCOCH3 of substituent in position 3 is disordered. 160x60mm (300 x 300 DPI)



Figure 20. Schematic presentation of H-bonded 2D framework in crystals of calixarene 3. Squares represent calixarene molecules. 80x68mm (300 x 300 DPI)


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Figure 21. Crystallization of molecular glass 1g in saturated vapors of pure c-C6H12 (a) and C6H6/c-C6H12 mixtures with benzene concentration of (b) 0.5 % (v/v), and (c) 1 % (v/v) at 25°C. Equilibration time was 24 h. 80x72mm (300 x 300 DPI)



Table of Contents/Abstract Graphics 88x31mm (300 x 300 DPI)


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Smart Polymorphism of Thiacalix[4]arene with Long-Chain Amide

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