Polymorphism in cocrystals is gaining interest because of the increasing interest in pharmaceutical cocrystals [1,2]. In this work, we report a 1:1 cocrystal of a BCS class 2 NSAID drug, niflumic acid (NIF), with caffeine (CAF) which exists in two polymorphic forms. Liquid Assisted Grinding (LAG) was used as a mechanochemical synthetic tool. Attempts to produce cocrystals by LAG led to the formation of polycrystalline material. Both the polymorphs were characterized in the solid state by diffractometric, spectroscopic and thermal methods. Recrystallization by slow solvent evaporation was carried out when the above-referred techniques strongly suggest the formation of a new solid form. In those cases where crystals were obtained, single crystal X-ray diffraction experiments were performed. Crystal structure analysis suggests that the NIF molecules in both polymorphs adopt different conformations but exhibits a common hydrogen bonding motif. Thermal analysis suggests that the polymorphs are related enantiotropically. Our work is completed with additional stability studies performed at controlled relative humidity conditions and followed by PXRD.

[1] Aitipamula, S., Chow, P. S., Tan, R. B. H. (2014) CrystEngComm, 16, 3451.

[2] Prohens, R., Barbas, R., Portell, A., Font-Bardia, M., Alcobé, X., Puigjaner, C. (2016) Cryst. Growth Des., 16, 1063.

Keywords: Cocrystal polymorphism; Niflumic acid; Mechanochemistry; Crystal structure

This research was funded by Spanish Research Agency of the Spanish Ministry of Science and Innovation, cofunded with FEDER (UE): “Bioscaffold project” grant number PGC2018-102047-B-I00 (MCIU/AEI/FEDER, UE).

Halogen bond has been the focus of crystallography and chemical engineering for many decades. The effect of intramolecular halogen bonds on adjacent intramolecular hydrogen bonding has hardly been investigated. O-hydroxy sulfonyl Schiff bases are a suitable class of compounds to shed light on these bonding aspects. Series of halogen bonded sulfonyl Schiff bases were synthesized and characterized spectroscopically using mass, FTIR, and NMR methods. The three-dimensional molecular structures of all the sulfonyl Schiff base compounds were confirmed through single-crystal X-ray diffraction studies. The crystal structures of Schiff bases exhibit both inter and intramolecular hydrogen bond interactions. Packing of the structures shows hydrogen bonded 1D chain and π---π interaction generates 2D supramolecular structure. O–H···N intramolecular interactions form the five-membered pseudo chelate rings. The Schiff base structures are also stabilized by C–O···π, N–O···π, π···π interactions and leads to the 3D network through supramolecular synthons. The intermolecular interactions were then quantified using Hirshfeld surface analysis. Further, the density functional theory calculations were employed using B3LYP hybrid functional with a 6-311+G (d, p) level basis set to optimize the structural coordinates. The chemically active regions of the Schiff base molecules were identified from the plot of the molecular electrostatic potential surface. Furthermore, the atoms in molecules (AIM) and their applications to chemical bonding based on Bader's theory have been studied to understand the molecular interactions.

In the last decades, pharmaceutical cocrystallization has being recognized as an interesting approach to modulate the physicochemical properties of active pharmaceutical ingredients (APIs) [1]. Ethenzamide is an anti-inflammatory and analgesic drug, which major drawback is the low solubility in aqueous medium. On the other hand, polyphenols have been widely studied due to their antioxidant properties and their implication in the prevention of degenerative diseases, particularly cardiovascular diseases. These molecules are also “generally recognized as safe” (GRAS), which gives the opportunity to use them as coformers in pharmaceutical cocrystallization [2].

In this study six new ethenzamide-based cocrystals were obtained by mechanochemical synthesis. A complete solid-state characterization was carried out by X-ray diffraction, spectroscopic and thermal techniques. Accelerated aging conditions (40ºC and 75% of relative humidity) were used to evaluate their stability. To complete the study, in vitro cytotoxicity essays were performed by co-culture of mesenchymal stem cells (MSCs) with the new multicomponent materials. The results will be discussed to evaluate the influence of the position of the -OH groups, in the coformer molecule, on the physicochemical properties of the new cocrystals.

Separation of Lutidine Isomers by Selective Enclathration

Molecular selectivity by host-guest procedures is an increasing method to help in the separation of isomers¹. The separation of a component from a mixture may be carried out by exploiting the physico-chemical properties of the compounds in that mixture. The most common techniques, viz. distillation, crystallization, liquid−liquid extraction, and various forms of chromatography, rely on differences in solubility and vapor pressure of the components. In the case of molecular isomers, their macro-properties are often similar, rendering the traditional separation techniques inefficient. In such cases the process of enclathration by a suitable host compound is a useful technique.^2,3,4

In this study, the host compound 3,3′-bis(9-hydroxy-9-fluorenyl)-2−2′-binaphthyl, H1, has been employed to separate the six isomers of lutidine. Competition experiments showed that the preference for enclathration is in the sequence 3,4-LUT > 2,6-LUT > 2,3-LUT > 2,5-LUT > 2,4-LUT ≈ 3,5-LUT. The structures yielded results that agree with the ¹H NMR analyses and with the thermal analysis. The effects of mixed hosts and vapor-phase competitions were briefly explored with two extra hosts, namely, 2,2′-bis(1-hydroxy-4,5-dihydro-2:3,6:7-dibenzocycloheptadien-1-yl)biphenyl (H2) or 3,3′-bis(di-p-olylhydroxymethyl) -1,1′-binaphthyl (H3). Following this study, 2,2’bis(1-hydroxy-4,5-dihydro-2,3:6,7-dibenzocycloheptatrien-1-yl)-biphenyl, H2, was then employed to discriminate between all the pairs of lutidine isomers. The preference for guest enclathration follows the sequence 3,4-LUT>2,4-LUT≈3,5-LUT>2,5-LUT>2,3-LUT>2,6-LUT. This has been confirmed by guest-release endotherms measured by DSC. Four extra diol host compounds with similar structures were tested on pairs of lutidine isomers which were poorly separated by H2.

References:

[1] Nassimbeni, L. R. In Separations and Reactions in Organic Supramolecular Chemistry; Toda, F., Bishop, R., Eds.; Wiley: Chichester, 2004; Chapter 5.

[2] Yang,Y., Bai, P., Guo, X., Separation of xylene isomers: a review of recent advances in materials Ind. Eng. Chem. Res., 56 (2017), pp. 14725-14753.

[3] B. Barton, E.C., Hosten, P.L., (2016) Tetrahedron, 72, 8099-8105.

[4] Nassimbeni, L.R., Bathori, N.B., Patel, L.D., Su, H. & Weber E. (2015) Chem. Commun., 51, 3627-3629.

The distribution of the electron density on the surface of molecules is typically anisotropic. This leads to regions featuring positive potential that can behave as electrophilic sites in attractive interactions involving regions in surrounding molecules having a negative electrostatic potential. Based on this mindset, a systematic rationalization of intermolecular interactions began in the 1990s, when on the surface of halogen atoms a region of positive electrostatic potential, the so called σ-hole,[1] was identified and explored as a new tool in supramolecular chemistry.

Analogous σ-holes were then found on other elements of p-block of the periodic table (elements of groups 14,[2] 15,[3] and 16[4]), and at the same time the awareness grew that also chemical interactions can be rationalized as periodic properties. Nowadays, the attractive interactions occurring between these positive regions and nucleophilic sites are now topics of intense research.

Although in adducts involving d-block elements the identification of electrophilic and nucleophilic moieties is generally nontrivial, some σ-holes have been identified on metals in some of these adducts. This is the case, for instance, of positive σ-holes on the group 11 metals in respective halides[5].

Here, we report the crystal structures of adducts between nitrogen (pyridine derivatives) or oxygen (pyridine N-oxide derivatives) nucleophiles and tetroxides of osmium, showing short noncovalent contacts involving Os. Theoretical evidences suggest that these contacts are σ-hole interactions, and that similar adducts of other group 8 elements behaves in a similar way.[6] We propose the term “osme bond” (OmB, Om=Os, Ru, Fe) for naming the noncovalent interactions wherein group 8 elements behave as electrophile.

In this work, I have analyzed the distribution of the shortest periods in homomolecular crystals of organic compounds, in which there are aromatic bonds, the influence of halogen atoms on this distribution was revealed, and energy analysis was carried out for several substances belonging to the group of 4 Å-structures, according to the method described in [1]. Сrystal structures investigated at normal pressure were extracted from the CSD version 5.41 (November 2019) + 3 updates using combinations of querries in ConQuest and the pre-defined best room temperature list [2].

As shown in Fig. 1a, at a large bin size, the histogram for reduced cell a values of all crystals under consideration (set I) can be well described by a single normal distribution function. As the bin size decreases, additional maxima begin to appear on the histogram (Fig. 1b), the position of which remains almost constant when the bin size changes from 0.3 to 0.03 Å. Similar distributions were plotted for molecules in which there are halogen atoms in any position (set II) and halogen atoms associated with a non-metal atom forming an aromatic bond (set III).

The position of the minimum following the maximum at 3.9 Å for all the above-mentioned sets corresponds to about 4.3 Å. It turned out that the parts of substances with the shortest period up to 4.3 Å of the total number of substances in each set are 1.9% for I, 2.8% for II, and 3.5% for III. A reliably determined substance with the shortest period (3.6021 Å) in all sets is 1,3,4,5,6,8-hexafluoronaphthalene-2,7-diamine (DAFMUV), in which the contribution of two strongest (E₁) translational molecular contacts to the total packing energy (PE) of the crystal (calculated with Mercury) is 55% (the energy coordination number, N_E, is two). At the other end of all sets is 2-bromo-4-chloro-6-[(2,4-dimethylphenylimino)methyl]phenol (EHUHIZ) with the reduced cell a equal to 4.2995 Å, N_E = 2, 2·E₁/PE = 0.48.

[1] Grineva, O. V. (2017). J. Struct. Chem. 58, 373.

[2] Streek van de, J. (2006). Acta Cryst., B 62, 567.

The work is a part of researches on the theme No. 121031300090-2.

Electrostatic self-assembly of organic crystals from charged macrocycles

K. Kravets¹, M. Kravets¹, V. Sashuk¹, O. Danylyuk¹

¹Institute of Physical Chemistry, Polish Academy of Sciences

kkravets@ichf.edu.pl

Macrocyclic host molecules are versatile building blocks in the supramolecular chemistry and crystal engineering. Depending on their structure and properties, macrocycles have found numerous applications in the host-guest systems, sensing, catalysis, design of porous materials, etc. Here we describe our approach towards design of molecular crystalline assemblies using oppositely charged macrocyclic building blocks, anionic p-sulfonatocalix[4]arene and cationic pillar[n]pyridiniums. P-Sulfonatocalix[4]arene with electron-rich basket-like cavity is well-known water-soluble supramolecular host, capable of forming various types of assemblies, such as bilayer clay-type structures, capsules, nanometer tubules, spheres or Russian-doll assemblies.[1] Pillar[n]pyridiniums are new family of water-soluble inherently cationic host molecules of prismatic electon-deficient cavities.[2] These two types of macrocyclic hosts are complementary in terms of charge, size and shape. Their self-assembly is guided mainly by the electrostatic attraction between anionic sulfonate groups of calix[4]arene and positive charge on the pyridinium rings of the cationic macrocycles. The crystallization in gel and liquid-liquid diffusion methods have been used for the obtaining suitable crystals build from mixed macrocycles for single crystal X-ray diffraction analysis. The structural aspects of the supramolecular architectures and main non-covalent interactions guiding the assembly will be discussed.

[1] Scott, J., Dalgarno, M.J., Hardie, J., Mohamed, M., Colin L. R. (2003). Chem. Eur. J. 9, 2834.

[2] Kosiorek, S., Butkiewicz, H., Danylyuk, O., Sashuk, V. (2018). Chem. Commun. 54, 6316.

Keywords: p-sulfonatocalix[4]arene; pillar[n]pyridinium; complex.

National Science Center for funding the research Grant 2019/35/O/ST4/01865 .

Spin-crossover (SCO) materials can change their spin state in response to a variety of stimuli such as temperature, light and guest molecules. These transitions are accompanied by changes in magnetic properties and often a colour change, making them attractive as smart materials.¹

Octahedral metal complexes containing iron(II) are known to be SCO active when certain ligands, often N-donors, are bound to the metal.² In framework and coordination polymer based spin-crossover materials, the cooperativity of the transition is aided by the covalent interactions present. However, in molecular complexes, the cooperativity of a transition relies on the elastic interactions that are present in the crystal structure.³ Therefore, designing molecular SCO materials with specific properties is very challenging due to the vast number of structure-directing intermolecular interactions that need to be considered. The difficulty of design becomes even more complex due to the potential for solvate and polymorph formation.^4,5

Thus, we have used crystal engineering concepts in the design and syntheses of a series of structurally-related SCO materials. We have used variable temperature single crystal X-ray diffraction analysis to obtain SCO curves, by following the octahedral volume at the Fe(II) center (Fig. 1). This variable temperature analysis has also provided valuable insight into the subtle structural changes such as distortions as well as the more drastic crystallographic symmetry-breaking phase transitions that we have seen in our materials.⁶ This work demonstrates design tools that will greatly benefit and evolve the way in which new and desirable SCO materials will be discovered.

1. A. Bousseksou, G. Molnár, L. Salmon and W. Nicolazzi, Chem. Soc. Rev., 2011, 40, 3313–3335.

2. J. Olguín and S. Brooker, Coord. Chem. Rev., 2011, 255, 203–240.

3. W. Nicolazzi and A. Bousseksou, Comptes Rendus Chim., 2018, 21, 1060–1074.

4. M. Hostettler, K. W. Törnroos, D. Chernyshov, B. Vangdal and H. B. Bürgi, Angew. Chemie - Int. Ed., 2004, 43, 4589–4594.

5. J. Tao, R. J. Wei, R. Bin Huang and L. S. Zheng, Chem. Soc. Rev., 2012, 41, 703–737.

6. L. Birchall and H. Shepherd, Manuscript in Preparation.

The single crystal of barium dihydrogenomonophosphate, Ba(H₂PO₄)₂ was prepared by the direct method. This compound exists in two forms: one orthorhombic, the other triclinic. In this work, we are interested in the triclinic form from the vibrational and crystalline sides too.X-ray crystallography showed that this compound crystallizes in the triclinic centrosymmetric with space group P-1 (Z=2) with a = 6.9917(5)Å,b = 7.1929(5)Å,c = 7.9667(9)Å,α = 104.517(8)°,β = 95.918(7)° and γ = 109.459(6). The structure was solved from 3444 independent reflections with R = 0.0198 with wR= 0.0633.The bands observed in the infrared and Raman spectra of Ba(H₂PO₄)₂ are assigned based on the literature results and the theorical group analyses carried out in the group of factors Ci. We were based on density functional theory (DFT / B3LYP) methods with the LanL2DZ base set for the calculation of Optimal molecular geometry, harmonic vibration frequencies, infrared intensities and Raman scattering activities. The HOMO-LUMO properties and geometries of this compound have been determined and discussed. The computational structural parameters are generally in agreement with the experimental investigations. The theoretical infrared and Raman spectra for the title compound have been constructed.

Le interazioni σ-Hole sono una sottoclasse di interazioni non covalenti in cui un'area di potenziale elettrostatico positivo sull'estensione di un legame covalente forma un'interazione netta attraente con un sito ricco di elettroni. Il legame tetrel (TtB) è un'interazione σ-foro in cui l'atomo elettrofilo è un elemento del gruppo 14 della tavola periodica. Il forte interesse per questa interazione è legato al ruolo fondamentale del carbonio nella chimica organica e bio [1].

Tuttavia, la ridotta polarizzabilità del carbonio rende questo elemento il meno incline nel Gruppo a essere coinvolto nella formazione dei TtB. In relazione al nostro lavoro sui derivati ​​del metonio come donatori di TtBs [2], proponiamo sali di metilene bis -piridinio come secondo sistema modello per studiare le caratteristiche geometriche ed energetiche di questa forza sui derivati -CH ₂ -. Le strutture cristalline ottenute presentano contatti brevi e lineari tra il metilene carbonio e vari nucleofili; la formazione di queste interazioni è interpretata come il risultato del forte effetto di ritiro degli elettroni degli atomi di azoto positivi legati direttamente al carbonio.

Le strutture cristalline sono state studiate con vari strumenti per valutare la natura del contatto, ottenendo la conferma inequivocabile che le interazioni presentate dovrebbero essere considerate TtB, completando così il nostro precedente studio sui derivati ​​dell'acido barbiturico [3]. I TtB su questi composti si sono rivelati abbastanza robusti da essere in grado di guidare l'impaccamento cristallino di addotti specifici e costruire architetture distintive.

A σ-hole interaction can be defined as a net attractive interaction between an area of positive electrostatic potential generated on the outer surface of an atom by one of the covalent σ-bonds it is involved in and an electron rich site (Lewis base, e.g., a lone-pair possessing atom or an anion) in the same or another molecular entity. According to the formalism of naming these interactions from the group of the periodic table the atom bearing the σ-hole belongs to, an interaction between a Lewis base and an atom of the Group 14 functioning as the electrophilic site is dubbed Tetrel Bond (TtB).

The N-methylammonium residue is ubiquitous in biology and chemistry, and many N-methylammonium bearing compounds are often used in crystal engineering for the designed formation of crystal architectures.

We propose here a series of 1,6-bis-trimethylammonium hexane crystal structures displaying a close contact between one carbon atom of an N-methylammonium moiety and a neutral and lone-pair-possessing atom or an anion. The geometrical features of these interactions are those typical for a TtB (i.e., linearity of the N⁺ ̶ C···electron-rich site angle, distance between C and the electron-rich site shorter than the sum of VdW radii of involved atoms) and are maintained when both charged and neutral species approach the N-methylammonium carbon.

Hirschfeld Atom Refinement (HAR) and Atom In Molecules (AIM) computational analyses have also been carried out to asses if the interaction occurring in the crystal packing between the N-methylammonium moiety and the electron rich sites are in fact hydrogen bonds (HB) or TtBs. The latter hypothesis is indeed confirmed by these analyses.

In conclusion, the reported experimental and theoretic results indicate that the close contacts between the carbon atom of an N-methylammonium residue and an electron-rich site are TtBs and that the interaction can be robust enough to be employed as an additional tool in the design of crystalline architectures involving this moiety. It can be expected the interaction plays a role in driving or influencing recognition processes involving biomolecules containing the N-methylammonium residue.