Ionic Cocrystals of Sodium Chloride with ... - ACS Publications

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Ionic Cocrystals of Sodium Chloride with Carbohydrates Heiko Oertling,*,§ Céline Besnard,† Thibaut Alzieu,§ Mathieu Wissenmeyer,§ Claire Vinay,§ Julien Mahieux,§ and René Fumeaux§ §

Nestec Ltd., Nestlé Research Center, Vers-chez-les-Blanc, 1000 Lausanne 26, Switzerland Laboratory of Crystallography, École de Physique, Université de Genève, 24 quai Ernest-Ansermet, 1211 Genève, Switzerland

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S Supporting Information *

ABSTRACT: Ionic cocrystals of sodium chloride with carbohydrates were investigated from a synthetic as well as from a crystallographic point of view. The syntheses of sodium chloride cocrystals with three different carbohydrates were established and furthermore optimized on a multigram, semitechnical scale. The missing crystal structures of two ionic NaCl cocrystals with a monosaccharide or a disaccharide, e.g., D-(−)-ribose·NaCl and D-(+)-sucrose· NaCl·2H2O, respectively, were elucidated via X-ray diffraction methods using either single crystal diffraction or synchrotron powder X-ray diffraction data applying the Rietveld refinement method. In both structures, sodium chloride contact ion pair formation in the solid state is observed, which represents the only described cases for alkali chloride carbohydrate combinations crystallized from aqueous solutions.

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elucidation has been reported in 1974.1 However, when an aqueous carbohydrate solution containing sodium chloride is evaporated and spontaneous crystallization occurs, commonly, separation happens and the result represents a physical mixture of two well distinguishable crystalline species. As this holds true for the larger part, formation of one new single uniform crystalline phase has been reported if certain conditions and parameters are respected; e.g., salt and sugar cocrystallize and form an ionic cocrystal. For instance, a comparatively large number of carbohydrates readily forms ionic cocrystals with calcium chloride dihydrate; however significantly fewer cases have been reported for the respective alkali metals: ionic cocrystal precipitation has been described for the combinations of ribose, glucose, and sucrose with sodium chloride respectively (see Scheme 1).2 Interestingly, those crystalline sugar salt combinations exhibit different stochiometries: glucose forms a monohydrated cocrystal with two equivalents of the monosaccharide, e.g.,

INTRODUCTION Sodium chloride and carbohydrates, e.g., mono- and disaccharides, are both of pivotal importance for the human diet as they represent a source of sodium and calories, respectively. Sodium serves an essential purpose in the human body as it allows nerves and muscles to operate properly, and it is one key parameter involved in the overall regulation of the physiological water balance. Most of the sodium in the Western diet comes from sodium chloride, e.g., table salt, directly. In foodstuff, this ingredient serves a multitude of purposes (most notably nutrition, preservation, or bulking properties), yet it is consumed foremost and predominantly for its taste. In contrast, mono- and disaccharides, in particular glucose, fructose, and sucrose provide the human body with energy through aerobic respiration and thus constitute an important source of calories. Consequently, all these ingredients are produced and processed in the food and related industries on a very large scale, and therefore their physical, physicochemical, and chemical properties are of fundamental scientific and industrial interest. All of the above ingredients are crystalline materials in their common solid form, however of very different nature: sodium chloride is an ionic salt, its individual atoms held together by Coulombic interactions only. Contrastingly, carbohydrates are molecular solids composed of individual molecules, held together via van der Waals interactions and hydrogen bonds in the crystalline state. Upon dissolution, the carbohydrate molecules are solvated and quickly equilibrate into various isomeric forms. If recrystallized from water at ambient temperature, carbohydrates form one uniform crystalline phase againas is also the case for sodium chloride. Interestingly, if sodium chloride is recrystallized from water at temperatures below 0 °C, sodium chloride dihydrate forms, and its full crystal structure © XXXX American Chemical Society

Scheme 1. Examples of Carbohydrates Forming Ionic Cocrystals with Sodium Chloride

Received: October 17, 2016 Revised: December 4, 2016

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DOI: 10.1021/acs.cgd.6b01521 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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Figure 1. Fit of the calculated powder X-ray diffraction pattern (red) to the observed one (blue) for D-ribose·NaCl. The difference plot (observed− calculated) is depicted in green. An enlarged view of the plot between 6.0 and 20.5° is inserted.

(glucose)2·NaCl·H2O,3−5 whereas sucrose forms an equimolar cocrystal that contains two equivalents of water, e.g., sucrose· NaCl·2H2O.6,7 The ionic cocrystal of ribose with sodium chloride was reported quite recently, displaying the overall anhydrous composition ribose·NaCl.8 It deserves mentioning that to the best of our knowledge only one further carbohydrate-related, sodium chloride ionic cocrystal has been reported: a cyclic acetal derivative of mannitol, e.g., 2,5-Omethylene-D-mannitol, was found to form a crystalline complex with sodium chloride, e.g., 2,5-O-methylene-D-mannitol·NaCl.9 Overall it should be noted however that the phenomenon of ionic cocrystallization is well-explored in the pharmaceutical sciences,10 and for example, the ionic cocrystals of active pharmaceutical ingredients such as piracetam, nicotinamide, and barbituric acid with calcium chloride have been highlighted recently.11 In this context, we felt it was necessary to reinvestigate this field in-depth and explore its full potential, specifically concerning ionic sodium chloride carbohydrate cocrystals. For this purpose, we systematically examined all three ternary systems already mentioned in the literature (e.g., glucose, sucrose, and ribose) and established a targeted, semitechnical synthesis yielding those materials in good yields for the first time. Furthermore, we elucidated the elusive crystal structures of sucrose·NaCl·2H2O and D-ribose·NaCl that were not reported until now.

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glucose molecules in a distorted octahedral manner. Two glucose moieties coordinate the central metal via vicinal hydroxyl groups and two further hexoses are bound via one hydroxyl oxygen atom only. The latter monocoordinated hexoses are hydrogen bonded to one another, and additional hydrogen bonding is observed with the water solvate molecule and the chloride anion. Remarkably, this compound has been investigated as a process intermediate in the industrial production of crystalline glucose in the former Soviet Union.14 In contrast to a direct crystallization of glucose, this alternative process allowed for shorter crystallization times, economy of space, and consequently requiring fewer crystallizers. Also, isolated yields were improved compared to established crystallization procedures. Moreover, the ionic cocrystal of glucose and salt was used for the separation of glucose/fructose mixtures as they occur in inverted sugar solutions, for example, obtained by acidic hydrolysis of sucrose.15 Addition of NaCl allows the cocrystal to precipitate from the mixture, and straightforward filtration permits isolation of the respective carbohydrate. However, in almost all reported cases,3−5 the glucose sodium chloride compound was isolated by serendipity, and very little attention was given to a controlled process that would conveniently allow for the synthesis of larger multigram samples. Also, we found the wealth of literature concerning the industrial production of this compound of limited use for the preparation of lab-scale batches. Eventually, we established a reliable protocol using a standard seeding approach in order to ensure nucleation of the desired crystalline phase yielding the cocrystal in satisfactory yield. Supersaturation was induced via cooling, and filtration of the obtained solid phase successfully achieved as viscosity of the supernatant was suitable to allow for convenient separation. Synthesis of an initial batch of pure seeding crystals was effectuated as nucleation of the ionic cocrystal appears to be strongly favored over the nucleation of the individual pure ingredients under the conditions chosen. Noteworthy, in contrast to the industrial processes described, we made use of a water/ethanol mixture as solvent in order to modify viscosity and furthermore prevent microbial spoilage. Inspired by the results from Rendle and Connett, who obtained the cocrystal by simple dry-mixing,16 an exploratory mechanochemical

RESULTS AND DISCUSSION

(D-Glucose)2·NaCl·H2O. Concerning the ionic cocrystal of glucose with sodium chloride, the correct composition and the corresponding phase diagram of the system water−glucose− sodium chloride were already established in 1927 by Matsuura.12,13 The crystal structure of the compound was published in 1990 by Cho and Honzatko,3 describing the complex as (D-glucose)2·NaCl·0.78H2O. In 1991, a second crystal structure elucidation was reported by Ferguson et al.4 establishing the formula (D-glucose)2·NaCl·H2O, while the anhydrous version of the structure was determined in 2009 by Fun et al.5 In all three structures, the sodium cation and the chloride anion are perfectly separated via glucose molecules. The sodium atom is coordinated by six oxygen atoms from four B



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synthesis was performed, and mechanical treatment of anhydrous glucose and sodium chloride in the presence of equimolar amounts of water in a vibratory ball-mill gave the cocrystal almost quantitatively. However, it should be mentioned that marked corrosion of the steel equipment was clearly visible after only one run, and therefore this approach was not pursued further. D-Ribose·NaCl. The cocrystal of sodium chloride with Dribose, e.g., D-ribose·NaCl, was reported by Czugler et al. in 2011:8 the material obtained displays an anhydrous stoichiometry and was prepared by straightforward precipitation of equimolar amounts of sodium chloride and D-ribose from methanol at room temperature in good yields (84%). The characterization presented comprises melting point determination, elemental analysis, optical rotation measurements, and standard solution NMR experiments; however, no single crystal structure elucidation could be performed. In our hands, we were able to confirm the results of Czugler, but, for the envisioned scale-up of the material, mixtures of water/ethanol were preferred over methanol for reasons of food safety. Synthesis of an initial pure batch of seeding crystals was successfully achieved, as well as scale-up pursuing a standard seeding approach of the supersaturated solution containing ribose and sodium chloride, albeit isolated yields were lower compared to Czugler’s method (e.g., 38%). Also, viscosity of the supernatant in the filtration step was favorable to allow for separation. Unfortunately, all our attempts to obtain crystals of suitable size for single crystal X-ray diffraction analysis were unsuccessful. However, the structure could be solved directly from synchrotron powder X-ray diffraction data, ultimately confirming the formation of the cocrystal. The atomic parameters can be retrieved via CCDC 1510285, which contains the supplementary crystallographic data for this structure (the file can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac. uk/structures). The agreement between the refined structure and the data is very good, as illustrated in Figure 1. Furthermore, the composition and thus purity of the material isolated from seeding crystallization trials were evaluated qualitatively via powder X-ray diffraction (see Figure 2). In both, the initial seeding crystals and the batch material obtained from those seeding crystals, the only crystalline phase detected is the cocrystal. However, the initial seeding crystals do contain a certain amount of amorphous phase as apparent from the uneven baseline. The amount of the amorphous phase is drastically reduced when the seeding crystallization method is used. In the crystal structure (see Figure 3), D-ribose crystallizes in its six-membered pyranose ring form. The sodium cation is coordinated by eight atoms in total, resulting in a distorted square antiprismatic coordination sphere: one chloride anion and seven oxygen atoms from three different ribose molecules supplement the coordination sphere. The sodium cation and the chloride anion thus form a contact ion pair in the sense that there is only one chloride atom in the first coordination sphere of the sodium cation. The bond length of this contact ion pair (2.932 Å) is increased in comparison to the atomic distance in pure sodium chloride (e.g., 2.81 Å). This is in sharp contrast to the overall organization of the individual ions in the cocrystal of glucose and sodium chloride, where the sodium cation and the chloride anion are separated via the carbohydrate. It is however related to the structure of the sucrose sodium chloride cocrystal

Figure 2. Top: powder X-ray diffraction pattern of D-ribose·NaCl obtained from the isolated material using a seeding strategy (in black); bottom: powder X-ray diffraction pattern (in blue) from the seeding crystals obtained via cooling-induced crystallization from water/ ethanol.

discussed later on, as this structure also displays a sodium chloride contact ion pair. Regarding the coordinating carbohydrate, two ribose molecules act as tridentate ligands either coordinating via three vicinal hydroxyl groups or a combination of the ring oxygen atom and two further hydroxyl groups, respectively. Furthermore, one pentose is only attached via the hydroxyl oxygen atom bound to the C3-ring atom. It is worth noting that all these hydroxyl groups are bridging consecutive sodium cations, leading to the formation of a onedimensional chain along the b-axis (see Figure 3). In the crystal, those chains assemble in a two-dimensional arrangement as a result of hydrogen bonding between chloride anions and hydroxyl groups of a neighboring chain (see Figure 4). The Hirshfeld surface of the ribose molecule, with dnorm mapped onto it, is depicted in Figure 5.17,18 Intermolecular interactions that are shorter than the van der Waals radii of the two interacting atoms appear as areas highlighted in red on the corresponding surface. The list of all these interactions, e.g., hydrogen bonds or Na−O interactions, is given in the Supporting Information (Table 1). Various single crystal structures for metal halide complexes of 19 D-ribose have been reported, notably D-ribose·CaCl2·3H2O, in which ribose crystallizes in its five-ring furanose form as a triple hydrate. Moreover, a range of lanthanide complexes exhibiting the overall composition D-ribose·MCl3·5H2O (M = La3+, Ce3+, Pr3+, Nd3+, Sm3+, Eu3+) have been described.20−26 In all of those structures ribose displays its pyranose form and coordinates to the lanthanide metal via three hydroxyl groups. Most importantly, the crystal structure of a further alkali halide complex with D-ribose has been reported, more specifically the ionic cocrystal with cesium chloride, e.g., D-ribose·CsCl.27 Contrastingly, in this structure (CSD reference code PIRTAN), no contact ion pair is observed since the chloride ions are bridging the cesium atoms affording a one-dimensional inorganic network. The coordination sphere of the alkali center is completed by hydroxyl groups and the ribose ring oxygen atom, acting here as a bridge thus allowing an overall 3D organization. Sucrose·NaCl·2H2O. In 1871 Gill correctly suggested the formula sucrose·NaCl·2H2O for this ionic cocrystal and stated C



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Figure 3. Representation of the crystal structure of D-ribose·NaCl showing the one-dimensional chain of bridged sodium atoms. Oxygen atoms are depicted in red, carbon atoms in gray, chlorine atoms in green, sodium atoms in pink, and hydrogen atoms in white.

Figure 4. Representation of the crystal structure of D-ribose·NaCl showing the two-dimensional packing. Oxygen atoms are depicted in red, carbon atoms in gray, chlorine atoms in green, sodium atoms in pink, and hydrogen atoms in white.

Figure 5. dnorm parameter mapped on the Hirshfeld surface for the ribose molecule in the cocrystal (from left to right: side-, front-, and back-view). The different zones are detailed in the Supporting Information (Table 1).

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bromide isomer after several months of standing of the syrup formed upon complete evaporation at room temperature as described by Gilli et al. Single crystal X-ray diffraction analysis confirmed the presence of the desired crystalline phase. Moreover, when crystallizing from a mixture of water and ethanol, the crystallization time could be reduced dramatically to only 4 weeks. As this phase had been described by Cochran and Beevers to be isostructural to its chloride isomer,29,30 we reasoned that seeding of a supersaturated solution of sodium chloride and sucrose should allow for the precipitation of the desired crystalline phase using the crystals of the bromide isomer. Eventually this strategy worked out, and isolation of the pure sucrose sodium chloride cocrystal was accomplished in a rather straightforward fashion: equimolar amounts of sucrose and sodium chloride were dissolved in water and seeded with the bromide isomer crystals at 20 °C. Standard filtration procedures allowed us to isolate the pure cocrystal in good yields. Single crystals were obtained by storing a seeded solution at 4 °C for 1 week, and ultimately the structure could be elucidated using single crystal X-ray diffraction techniques: details on the crystallographic data are given in Table 2 in the Supporting Information, and the structure is shown in Figure 6

that obtaining this material is difficult and reproducibility of the results presents a clear challenge.6 He also commented on the corresponding bromide isomer, proposing the composition sucrose·NaBr·2H2O in analogy with the chloride compound. Schoorl published a synthetic protocol for a larger-scale production of the material,7 yet the strongest evidence for its existence was produced by Cochran and Beevers in 1946.28−30 They elucidated the ionic cocrystal structures of sucrose with sodium chloride as well as sodium bromide by X-ray diffraction methods. Crystals of these materials were grown from aqueous solution over a period of months. The structure of sucrose· NaBr·2H2O is isomorphous to sucrose·NaCl·2H2O according to the authors; the switch from bromide to chloride causes the unit cell to contract. Unfortunately, the crystal structure coordinates for the sucrose·NaCl·2H2O cocrystal were not archived in the Cambridge Structural Database at the time. Some authors conclude that the main obstacle for the cocrystal formation by direct evaporation is the inhibition of nucleation caused by the high viscosity of the supernatant.31−33 Ultimately, the detailed phase diagram of the system sucrose/sodium chloride/water was established in 1962 at 20°, 40°, and 60 °C.34 The sucrose sodium bromide compound was reassessed by Gilli et al. in 1989.35 The asymmetric unit contains a sodium bromide contact ion pair with a bond length that is decreased in comparison to the pure, cubic NaCl-type sodium bromide crystal (2.98 Å): each sodium atom is in contact with one bromine atom, with a distance between them of 2.94 Å, which corresponds well to the sum of the ionic radii (0.98 + 1.95 = 2.93 Å). According to Gilli et al., few examples of sodium halide ion-pairs in crystals are known, and very few have been documented for NaBr, all of which involve a multioxygenated, encapsulating ligand. Furthermore, the coordination sphere is completed by oxygen atoms of sucrose molecules. Encouraged by this exceptionally rich and detailed documentation on the sucrose sodium chloride cocrystal, we envisioned to synthesize this material according to a large variety of different protocols suggested in the literature to produce cocrystals, more specifically crystallization via direct evaporation, cooling a solution using various solvents or solvent mixtures, antisolvent addition to a saturated solution, slurry ripening, freeze-drying, freezing, grinding, liquid-assisted grinding, ball-milling, melting, dry-mixing at different relative humidities, and solvent diffusion experiments. Doing so, some of the parameters that were extensively screened included (i) the ratio of the starting materials, (ii) the nature of the solvent/ cosolvent used, and (iii) the temperature. Eventually none of the above approaches succeeded, and the only crystalline phases repeatedly isolated were those of pure sucrose and sodium chloride. Even when placed in the appropriate region of the reported phase diagram, crystallization did not occur for very extended periods of time.34 Overall, we reckon this pronounced nucleation inhibition of the cocrystalline phase is due to the very high viscosity of the respective solutions in equilibrium, which constitute syrups that become a glassy mass at lower temperatures. Our approaches to overcome this nucleation barrier by modifying the viscosity via either diluting the system (e.g., using alcohols, esters, etc.), crystallizing at higher temperatures or direct mechanochemical synthesis were not successful. Applying the conditions that Gilli et al. described to obtain single crystals of sucrose·NaBr·2H2O did not work out for the chloride isomer.35 The protocol outlined by Schoorl did not produce the desired crystalline phase in our hands.7 However, we were able to obtain crystals of the

Figure 6. Representation of the crystal structure of sucrose·NaCl· 2H2O. Oxygen atoms are depicted in red, carbon atoms in gray, chlorine atoms in green, sodium atoms in pink, and hydrogen atoms in white.

(supplementary crystallographic data are contained in CCDC 1510286, which can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac. uk/structures). As suggested by Cochran and Beevers, the structure is isostructural to the published bromide analogue (CSD reference code DINYOO10). In the structure, sodium is coordinated in a distorted octahedral fashion by two water oxygen atoms, one chloride ion, and three individual sucrose E



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Figure 7. Top: experimental powder X-ray diffraction pattern obtained for the isolated material (in black); bottom: calculated powder X-ray diffraction pattern for sucrose·NaCl·2H2O (in blue) from the structure determined via single crystal X-ray diffraction.

Figure 8. Front and back of the Hirshfeld surface of the sucrose molecule in the cocrystal mapped with dnorm. Red areas represent intermolecular contacts which have been labeled and are detailed in the Supporting Information (Table 3). (≥99.5%), sodium bromide from Sigma-Aldrich (99−100.5%, calc. to the dried substance), and ethanol from alcosuisse (96.1%). (D-Glucose)2·NaCl·H2O. Synthesis of Seeding Crystals. A mixture of 200 mL of ethanol and 128 mL of deionized water was placed at room temperature in a 1.5 L thermostated glass reactor (IKA LR 1000) equipped with anchor stirring, internal temperature control, and a water condenser. While stirring 200 g (1.01 mol) of α-D-glucose monohydrate and 44.0 g (0.75 mol) of sodium chloride were added. The suspension was heated up to 65 °C. After 20 min, a colorless and homogeneous solution was obtained. The external temperature was then set to 40 °C, which allowed for the spontaneous nucleation of crystals. The temperature was maintained at 40 °C, and crystal growth was allowed to continue for 3 h (50 rpm). Stirring was halted and the suspension was subsequently filtered over a glass frit under reduced pressure (borosilicat glass, porosity: 2). The isolated crystals were washed with cold ethanol, dried at 40 °C under a vacuum for 7 h, and 69.0 g (0.158 mol) of cocrystalline (D-glucose)2·NaCl·H2O was obtained as a white powder (yield: 31% with respect to glucose). The identity and phase purity of the obtained material were confirmed by comparison with the reference X-ray diffraction data (CSD reference code VEGLOI01) from the literature4 as well as the reported unit cell parameters. Synthesis via Seeding Crystallization. A mixture of 344 g of deionized water and 489 g of ethanol was placed at room temperature in a 1.5 L thermostated glass reactor (IKA LR 1000) equipped with anchor stirring, internal temperature control, and a water condenser. While stirring 132 g (2.26 mol) of sodium chloride and 600 g (3.03

molecules, via three different hydroxyl oxygen atoms. It is worth emphasizing that, as expected, the organization is further stabilized by hydrogen bonding of the chloride ions, and the sucrose hydroxyl functions both within and between the layers, as well as hydrogen bonding involving the coordinated molecules and the sugar alcohol moieties. The distance between the sodium atom and the chloride anion is shortened compared to the respective ion pair in the ribose structure; e.g., a bond distance of 2.8232 (19) Å is observed. Furthermore, the composition of the powder sample was analyzed via powder X-ray diffraction, and the only crystalline phase in the obtained material is the cocrystal, e.g., sucrose· NaCl·2H2O, as shown in Figure 7. However, a certain amount of amorphous content is visible. The Hirshfeld surface of the sucrose molecule, with the dnorm parameter mapped onto it, is depicted in Figure 8. The full list of all interactions is given in the Supporting Information (Table 3).

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EXPERIMENTAL SECTION

All chemicals were used as purchased without prior purification: sucrose (saccharose) was purchased from Merck KGaA (≥99.0%), D(+)-glucose monohydrate from Sigma-Aldrich (≥99.9%), D-(+)-glucose from Sigma Life Science (≥99.5%, HPLC), D-(−)-ribose from Sigma-Aldrich (≥98.0%), sodium chloride from Merck KGaA F



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mol) of α-D-glucose monohydrate were added, and the temperature was set to 75 °C. A homogeneous, colorless solution was obtained after 75 min of stirring. The temperature was decreased to 40 °C, and the stirring rate was set to 60 rpm. At this point, 500 mg (1.14 mmol) of seeding crystals were carefully added to the solution. Crystallization occurred immediately (formation of a suspension), and the temperature was then decreased to 30 °C; the mixture was maintained under these conditions for 18 h. Finally, stirring was halted and the suspension filtered over a glass frit under reduced pressure (borosilicat glass, porosity: 2). The isolated crystals were washed with 100 mL of cold ethanol, dried at 40 °C under a vacuum for 6 h, and 386 g (884 mmol) of the cocrystalline material were obtained as a white powder (yield: 58% with respect to glucose). Mechanochemical Synthesis. A total of 1.08 g of anhydrous glucose (6.00 mmol), 175 mg of sodium chloride (3.00 mmol), and 54 mg of deionized water (3.00 mmol) were placed in a Retsch MM400 vibratory ball mill and ball-milled at room temperature at a frequency of 5 Hz with one Inox steel ball (diameter 20 mm) for 1.5 h to give 1.22 g (2.79 mmol) of the cocrystalline material in satisfactory purity (yield 93%). Ribose·NaCl. Synthesis of Seeding Crystals. In a thermostated, double-jacketed 250 mL glass reactor with a magnetic stirrer bar, 50.0 g (0.33 mol) of D-(−)-ribose and 19.4 g (0.33 mol) of sodium chloride were added to a mixture of 71.4 mL of deionized water and 114 mL of ethanol at 25 °C (300 rpm). After 30 min the temperature was set to 62 °C, and a clear, homogeneous solution was obtained after 2 h. The solution was cooled to 10 °C which allowed for spontaneous nucleation. Crystal growth was allowed for 20 h. Stirring was halted and the suspension was subsequently filtered over filter paper under reduced pressure. The obtained material was washed with 60 mL of cold ethanol and dried 1 h under a vacuum. A total of 25.5 g (0.12 mol) of cocrystalline D-(−)-ribose·NaCl was isolated as a white powder (yield: 36%). The phase identity and purity were confirmed via powder X-ray diffraction methods. Synthesis via Seeding Crystallization. A mixture of 684 mL of ethanol and 428 mL of deionized water was placed at 30 °C in a 1.5 L thermostated glass reactor (IKA LR 1000) equipped with anchor bottom stirring, internal temperature control, and a water condenser. While stirring 300 g (2.00 mol) of D-(−)-ribose was slowly added over a period of 10 min. When the addition was complete a suspension was obtained at 22 °C. A total of 116 g (2.00 mol) of sodium chloride was added stepwise. In order to obtain a homogeneous solution, the temperature was set to 72 °C, and after 2 h of continued stirring at 100 rpm, a clear solution was formed. The solution was cooled within 45 min to 30 °C, and at this point 10 mg (0.048 mmol) of seeding crystals was carefully added to the solution and the stirring rate was reduced to 80 rpm. Crystallization occurred within minutes, and formation of a suspension was observed. The temperature was set to 10 °C and stirring continued for 15 h to allow crystal growth. Stirring was halted and the suspension subsequently filtered over a glass frit under reduced pressure (borosilicat glass, porosity: 2). The isolated crystals were washed with 120 mL of cold ethanol at room temperature, and remaining humidity was removed from the solid product at 40 °C under a vacuum for 2 h (20 mPa). A total of 158 g (758 mmol) of D-(−)-ribose·NaCl was obtained as a white powder (yield: 38%). X-ray Diffraction Analysis. Structure Solution and Refinement. Samples were loaded in 0.8 mm capillaries and data were collected at the Swiss Norwegian Beamlines BM01A on the Pilatus Dectris M2 detector at a wavelength of 0.8212 Å. Structure indexation and solution via direct-space methods were carried out in the FOX software.36 The Rietveld refinement was performed using the TOPAS Academic software.37 The atoms were refined isotropically and a global isotropic displacement parameter was used for all the carbon and oxygen atoms. The Beq for hydrogen atoms was taken as 1.5 times this one. The hydrogen atoms were placed on the basis of potential Hbonds and allowed to ride on their parent carbon or oxygen atoms, while no other constraints were applied. The fit is shown in Figure 1. The final Rwp factor was 2.42% for a total of 64 parameters refined.

The Rexp for the data is very low, e.g., 0.0029, due to the very low noise level of the 2-dimensional detector. Pattern Comparison and Hirshfeld Surfaces. The samples were loaded in 0.8 mm glass capillaries and X-ray powder diffraction data were collected with copper Kα1 radiation in transmission geometry using a Stoe Stadi-P powder diffractometer equipped with a curved imaging plate detector. Hirshfeld surfaces were generated using the CrystalExplorer software.17 Sucrose·NaCl·2H2O. Initial Synthesis of Isostructural Seeding Crystals of the Composition Sucrose·NaBr·2H2O. 11.09 g (0.032 mol) of D-(+)-sucrose and 5.00 g (0.049 mol) of sodium bromide were dissolved at room temperature in 50 mL of deionized water. The solution was slowly evaporated at room temperature, and the remaining syrup was stored at ambient temperature. After a period of 15 weeks, small crystals appeared and were analyzed via X-ray powder diffraction methods. After additional 6 weeks, the entire batch had solidified and the crystalline material was subsequently used as seeding crystals for the initial seeding crystallization of isostructural sucrose·NaCl·2H2O. The identity and phase purity of the obtained sucrose·NaBr·H2O crystals were confirmed by comparison with the reference X-ray diffraction data from the literature35 (CSD reference code DINYOO10) as well as the reported unit cell parameters. Accelerated Synthesis of Isostructural Seeding Crystals of the Composition Sucrose·NaBr·2H2O. A total of 50.0 g (0.15 mol) of D(+)-sucrose and 22.3 g (0.22 mol) of sodium bromide were added to a mixture of 20 mL of water and 20 mL of EtOH at 70 °C and stirred for 3 h until complete dissolution was achieved. The solution was cooled to room temperature, divided in four equal parts, and transferred into four large Petri-dishes to allow for complete evaporation at room temperature. First crystals of sucrose·NaBr·2H2O started to appear after 27 days. Synthesis via Isostructural Seeding Crystallization. A total of 333 g of deionized water were placed at room temperature in a 1.5 L thermostated glass reactor equipped with mechanical anchor stirring (IKA LR 1000), internal temperature control, and a water condenser. While stirring 848 g (2.48 mol) of D-(+)-sucrose was added over a period of 10 min. Then, the temperature was set to 55 °C and 145 g (2.48 mol) of sodium chloride was added over a period of 7 min. The temperature was set to 95 °C, and a homogeneous, colorless solution was obtained after stirring for 95 min. Afterward, the temperature was set to 20 °C, and the solution was slowly cooled to 20 °C within 135 min. At this point, 300 mg (0.623 mmol) of sucrose·NaBr·2H2O seeding crystals was carefully added to the solution and crystallization started immediately. After 40 min the temperature was set to 15 °C for 2 h. Then, the stirring was reduced to 30 rpm, and the solution was stirred for 3 days and 16 h at 15 °C. Stirring was halted and the suspension filtered over a glass frit under reduced pressure (borosilicat glass, porosity: 1). The solid product was dried at 40 °C for 1 day and 609 g (1.45 mol) of the cocrystalline sucrose·NaCl·2H2O were obtained as a white powder (yield: 58%). Synthesis via Seeding Crystallization. A total of 210 mL of deionized water was placed at room temperature in a 1.5 L thermostated glass reactor equipped with mechanical bottom stirring (IKA LR 1000), internal temperature control, and a water condenser. While stirring 91 g (1.56 mol) of sodium chloride and 504 g (1.47 mol) of D-(+)-sucrose were added over a period of 10 min. Then, the temperature was set to 85 °C, and a colorless, homogeneous solution was obtained after stirring for 45 min. Afterward, the temperature was set to 25 °C and the solution was cooled to 25 °C within 105 min. At this point, the stirring was reduced to 30 rpm, and 500 mg (1.14 mmol) of seeding crystals (sucrose·NaCl·2H2O) were carefully added to the solution. Crystallization (formation of a suspension) occurred within the next minutes. Stirring was continued for 24 h at 25 °C. The suspension was subsequently filtered over a glass frit under reduced pressure (borosilicat glass, porosity: 3). The solid product was dried at 40 °C for 15 h, and 250 g (0.572 mol) of the cocrystalline sucrose· NaCl·2H2O was obtained as a white powder (yield: 39%). The identity and phase purity of the obtained sucrose·NaCl·2H2O crystals were confirmed by powder X-ray diffraction methods. G



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Synthesis of Crystals Suitable for Single Crystal X-ray Diffraction Analysis. Two milliliters of the sucrose sodium chloride solution from the “synthesis via seeding crystallization” was retrieved directly after seeding and stored at 4 °C for a week. X-ray Diffraction Analysis. A single crystal was mounted using perfluoropolyether oil with a MiTeGen MicroLoop on an Agilent SuperNova diffractometer equipped with an Atlas detector. Data collection was carried out using Cu Kα radiation. The sample was kept at 180 K during data collection. The structure was solved with the SIR2011 structure solution program38 applying direct methods and refined with the ShelXL refinement package39 using least-squares minimization within the Olex2 software.40 Hirshfeld surfaces were generated using the CrystalExplorer software.17 Powder Diffraction Analysis. The samples were loaded in 0.8 mm glass capillaries, and X-ray powder diffraction data were collected with copper Kα1 radiation in transmission geometry using a Stoe Stadi-P powder diffractometer equipped with a curved imaging plate detector.

ethanol-accelerated formation of the required seeding crystals permits convenient production of multigram quantities. Until today, the physicochemical properties of this particular ionic cocrystal remained unknown compared to those of its widely studied pure individual ingredientsa fact that does not fail to puzzle as pure salt and sugar are certainly among the most abundant chemicals utilized by mankind, present in every chemistry laboratory as well as every household. It should also be noted that all ingredients used in our investigations are common food-grade materials, and the production of ionic sodium chloride cocrystals under food-grade conditions was thus successfully accomplished. The authors hope to draw the attention of a larger audience toward these underexplored materials, as they constitute novel, inexpensive, nontoxic, and biodegradable crystalline entities, potentially available in bulk quantities on an industrial scale. Ultimately, the century-long scientific debate concerning the existence, the formation, and the composition of the elusive sucrose sodium chloride cocrystal could be concluded and its structure unequivocally established.

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CONCLUSIONS For all three investigated sugar/carbohydrate ionic cocrystals, a reproducible and straightforward synthesis on a multigram scale could be established. Furthermore, the missing crystal structures and therefore the organization of those materials in the solid state could be elucidated for the first time. The synthetic approach makes use of a controlled seeding strategy, which allows one to obtain significant amounts of the desired materials in a reliable manner and will certainly enable further characterization work concerning these to date partly evasive species. The crystal structures of D-(−)-ribose·NaCl and D(+)-sucrose·NaCl·2H2O both exhibit sodium chloride contact ion pairs in the solid state, which sets them apart from the corresponding system (D-glucose)2·NaCl·H2O. Sodium chloride contact ion pair formation in the solid state is rarely observed, in particular when it comes to solid phases constituted of sodium chloride and a purely organic crystallization partner. Only six examples of those contact ion pair complexes have been described so far,41−46 all of them involving elaborate organic ligands that were specifically designed for that purpose commonly involving a multistep ligand synthesis. Those attempts were partly driven by the motivation to create artificial ion pair receptors that could be studied for the transport of ion pairs through biological membranes or for instance salt extraction purposes. Five out of these systems contain crown-ether type macrocycles that accommodate the sodium cation as well as additional coordination sites to stabilize the associated chloride anion. In this respect the two ionic cocrystal structures, e.g., D(−)-ribose·NaCl and sucrose·NaCl·2H2O, are remarkable as no intricate ligand design is required to form a contact sodium chloride ion pair complex. Moreover, the organic scaffolds used are common mono- or disaccharides abundantly found in nature. Interestingly, the formation of an ion pair in the ribose complex has been predicted in 2005 by Ortiz et al., based on NMR-studies of ribose and sodium chloride in D2O-solution.47 Comparing the bond length of the sodium chloride ion pair in pure NaCl (2.81 Å) to sucrose·NaCl·2H2O (2.82 Å) and D(−)-ribose·NaCl (2.93 Å), one can observe an elongation of atomic distance in the ionic cocrystals. Furthermore, it is worth pointing out that the cocrystal of sucrose and table salt was not accessible using standard crystallization techniques: only the utilization of the isomorphous sodium bromide sucrose phase to initiate nucleation allowed for a first synthesis of this otherwise unobtainable species. Applying our outlined protocol, starting with an

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.6b01521. (i) Intermolecular distances between the D-ribose molecule and its respective neighbors (Hirshfeld surface); (ii) crystal data and structure refinement for sucrose·NaCl·2H2O; (iii) intermolecular distances between sucrose and its neighboring molecules (Hirshfeld surface); (iv) sodium atom coordination polyhedron in the crystal structure of ribose·NaCl; (v) sodium atom coordination polyhedron in the crystal structure of sucrose·NaCl·2H2O (PDF) Accession Codes

CCDC 1510285−1510286 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 Author

*Phone +41 21 785 9555. E-mail: [email protected]. com. ORCID

Heiko Oertling: 0000-0001-5278-4140 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Pascal Schouwink for the collection of the powder diffraction data at the S.N.B.L. REFERENCES

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Ionic Cocrystals of Sodium Chloride with ... - ACS Publications

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