The last decade has witnessed significant growth in our understanding on intermolecular interactions [1]. Experimental and computational approaches have resulted in obtaining quantitative insights into the underlying nature of different interactions [2]. Non-covalent interactions involving halogens have attracted significant attention. Interactions involving the heavier halogen bromine are ubiquitous and hence an investigation into the electronic features of such interactions is of interest. The existence of the s- hole in bromine-centered interactions have been quantitatively investigated via high resolution electron density analysis in crystals of an ebselen derivative (I). It has been observed that in addition to formation of s-hole centered linear interaction involving bromine, the lone pairs on bromine also interact with the electron deficient region on the π-ring (Fig. 1a) [3]. Thus bromine is associated with both electron donor and acceptor characteristics. Furthermore, this approach has also been utilized to understand carbon-centered π-hole directed O=C...O=C interactions in crystalline fluoroanil (II) and chloranil [4]. The topological characteristics in terms of the MESP, and the electronic features of the interacting atoms will be discussed (Fig. 1b). Such studies establish the subtle yet pivotal role of weak intermolecular interactions in the crystal packing of organic molecules.

Counterions are ubiquitous in solution but the role they play in species formation, stability, and reactivity is not well understood. Inspired by recent work that has shown that consideration of counterions may be important for understanding phase formation and the overall chemical behavior of a metal ion, our group has sought to examine the impact of nonbonding interactions on actinide (An) complex formation and precipitation. Our efforts have focused on the solution and solid‐state structural chemistry of An‐Cl complexes formed from acidic aqueous chloride solutions in the presence of protonated N‐heterocycles. Within this context, a series of seven unique Th^IV compounds that were precipitated from aqueous solution will be presented. The compounds consist of Th^IV metal centers that adopt 8- or 9-coordinate complexes with the general formulas [Th(H₂O)_xCl_8–x]^x–4 (x=2, 4) and [Th(H₂O)_xCl_9–x]^x-5 (x=5–7). While all of the complexes are heteroleptic, bound to Cl^- and H₂O ligand, the structural units vary in composition, charge, and coordination geometry. The complexes range from chloride rich to chloride deficient, with the number of bound chlorides and hence charge on the structural unit showing some dependence on the counterion present in the outer coordination sphere. Our experimental and computational efforts to understand phase formation, the effects of noncovalent interactions, and the energetics that drive the formation of this series of structurally related Th^IV–aquo–chloro compounds will be discussed.

Stacking interactions of aromatic fragments are ubiquitous in many chemical and biological systems [1]. Benzene dimer, as a prototype, has stacking energy of -2.73 kcal/mol, in the most stable parallel-displaced geometry [2]. However, stacking interactions can also be formed by non-aromatic fragments, most notably by metal-chelate rings [3].

Stacking interactions between chelate and aromatic rings were described in crystal structures deposited in the Cambridge Structural Database [3], and were shown to have parallel-displaced geometries (Fig. 1), similar to stacking of aromatic molecules. The study of crystal structures with stacking interactions between aromatic rings and systems that have chelate ring fused with aromatic ring showed that aromatic ring is dominantly closer to chelate than to aromatic ring of the fused system, indicating that chelate-aryl stacking is stronger than aryl-aryl stacking [3]. Calculated CCSD(T)/CBS and DFT interaction energies confirmed this; stacking of benzene with nickel chelate of acac type has the energy of ‑5.52 kcal/mol, while stacking of benzene with zinc chelate of acac type is even stronger, -7.56 kcal/mol [4].

Stacking interactions can be formed between two chelate rings as well. This type of stacking was also described by studying the CSD crystal structures [3]. Geometries of chelate-chelate stacking interactions are mostly parallel-displaced, but there are examples of face-to-face geometries (Fig. 1). Chelate-chelate stacking is even stronger than aryl-aryl and chelate-aryl stacking. Stacking energy between two acac type chelates of nickel is -9.47 kcal/mol [4], while stacking between two dithiolene chelates of nickel is -10.34 kcal/mol [5].

Chelate-aryl and chelate-chelate stacking interactions are much stronger than aryl-aryl stacking due to much stronger electrostatic interactions caused by the presence of metals [4]. Stacking geometries and relative strengths of interactions can be rationalized by observing electrostatic potentials of the complexes that contain metal-chelate rings.

[1] Salonen, L. M., Ellermann, M., Diederich, F. (2011). Angew. Chem. Int. Ed. 50, 4808.

[2] Lee, E. C., Kim, D., Jurečka, P., Tarakeshwar, P., Hobza, P., Kim, K. S. (2007). J. Phys. Chem. A 111, 3446.

[3] Malenov, D. P., Janjić, G. V., Medaković, V. B., Hall, M. B., Zarić, S. D. (2017). Coord. Chem. Rev. 345, 318.

[4] Malenov, D. P., Zarić, S. D. (2019). Dalton. Trans. 48, 6328.

[5] Malenov, D. P., Veljković, D. Ž., Hall, M. B., Brothers, E. N., Zarić, S. D. (2019). Phys. Chem. Chem. Phys. 21, 1198.

In the category of sigma-hole interactions, chalcogen bonding is an interaction between the electropositive surface of a chalcogen atom acting as a chalcogen bond donor and a Lewis-base acting as chalcogen bond acceptor.^[1-2] In today’s date, hydrogen bonding and halogen bonding interactions have been extensively exploited in the field of supramolecular chemistry and crystal engineering owing to the great strength of the interaction, strong directionality, predictability, and profound understanding, whereas the world of chalcogen bonding, in spite of being known for many decades, still struggles to make a mark due to the relatively weaker directionality or predictability and underdeveloped synthetic chemistry of chalcogen compared to the halogens.^[3-4]

Below is a figure demonstrating that when Iodine is attached to acetylene, it generates a strong sigma-hole in the prolongation of the acetylene--I bond which allows this moiety to easily interact with a given nucleophile through halogen bonds. However, what happens when we have a chalcogen (Se/Te) next to acetylene, can we similarly anticipate a strong sigma-hole activation that can favor this moiety to interact with a nucleophile through chalcogen bonds? Herein, we describe the synthesis and solid-state assembly of (methyl Se/Te)ethynyl-substituted derivatives acting as directional chalcogen bond donors in crystal engineering. Directional chalcogen-chalcogen contacts in this series of derivatives allow for a unique molecular helical arrangement in the solid-state assembly of monomer alone. Co-crystallization with various Lewis-bases, fabricate 1D chain motifs with short chalcogen bonds, quite comparable in strength to halogen bond observed with the analogous iodo derivatives.

[1] Aakeroy, C. B., Bryce, D. L., Desiraju, G. R., Frontera, A., Legon, A. C., Nicotra, F., Rissanen, K., Scheiner, S., Terraneo, G., Metrangolo, P., Resnati, G. Definition of the chalcogen bond (IUPAC Recommendation 2019). (2019). Pure Appl. Chem., 91, 1889-1892. [2] Vogel, L., Wonner, P., Huber, S. M. (2019). Angew. Chem. Int. Ed., 58, 1880-1891. [3] Huynh, H.-T., Jeannin, O., Fourmigue, M. (2017). Chem. Commun. 53, 8467. [4] Werz, D. B., Rominger, F., Gleiter, R. (2002). J. Am. Chem. Soc. 124, 10638-10639.

Alcohols and amines can be considered as excellent cocrystal forming agents, due to the compatibility of intermolecular interactions where both compounds act as hydrogen bond donor and acceptor. In such structures different motifs as isolated oligomers (0D), ribbons (1D), layers (2D), etc. can be expected. The main trust of the research was the crystallization and structure determination of cocrystals of allylamine and alcohols followed by the analyses of hydrogen bond architectures, using computational methods.

The examined mixtures are liquid at ambient conditions, therefore, an IR laser-assisted in situ crystallization method has been used directly on the goniometer of the single crystal diffractometer [1]. The X-Ray measurements were complement by DFT periodic calculation in CRYSTAL17.

Among obtained cocrystals, those with three simplest alcohols (methanol, ethanol, and 1-propanol) contain molecules arranged in layers with L4(4)8(8) motif [2] of hydrogen bonds. Further elongation of the aliphatic chain of the alcohol moiety leads to change in hydrogen bonds architecture from 2D to 1D. In consequence, all cocrystals containing C₄ to C₇ alcohols infinite ribbons reveal the T4(2) topology [2]. Further modification appears for 1-octanol cocrystal, where the molecules interact via hydrogen bonds forming layers of the L6(6) type [2]. Thus different topology than for C₁-C₃ alcohols is observed. This structural motif is preserved for cocrystals with C₉ and C₁₀ alcohols.

In the analyzed structures three types of hydrogen bonds motifs occur, depending on the aliphatic chain length of the alcohol molecule. Furthermore, all the systems were analyzed according the binding energy between structural units (ribbons or layers) present in the structures. In addition, the calculations were also performed for simulated structural units (e.g. applying 1D motif for methanol and 2D motif in case of butanol) to show a potential reason for specific architecture type formation in analyzed cocrystals.

The research shows that for ten allylamine – alcohol cocrystals three of structural motifs may exist. Elongation of the aliphatic chain of the alcohol impacts on the change of the motif in a systematic way. This alteration can be used for the rational design of similar systems.

Computational methods for predicting the crystal structures [1] of organic compounds have evolved over the past three decades to the point where they are now used in major pharmaceutical companies to support the solid-form development of new active pharmaceutical ingredients (APIs). More broadly, knowledge of the crystal structure of a compound is fundamental to understanding the mechanical response, charge carrying capacity and porosity of the material. Most crystal structure prediction (CSP) studies produce a static crystal energy landscape (CEL) which depicts the possible polymorphs as a function of lattice energy and crystal density. Although some promising results have recently been reported [2], the challenge of extracting the set of molecular and crystal descriptors from the CEL that will support the targeted crystallization of one polymorph over the many dozens of artefacts on the CEL remains a major unresolved challenge within the CSP community.

Whilst there have been many reports of the application of computational methods to support the discovery of binary cocrystals, very little is known about the accuracy of CSP methods for supporting the discovery of periodic multicomponent crystals that contain > 2 distinct chemical fragments in the crystallographic asymmetric unit. The discovery of such higher-order cocrystals widens the crystal form landscape and allows drug developers to choose the optimal solid dosage form for a particular API. We demonstrate [3] that CSP methods can be adapted to support the discovery of ternary molecular ionic cocrystals comprising many competing intermolecular hydrogen bonding interactions in the crystal. Beyond periodic cocrystals, eutectic composites are an example of aperiodic solid forms, whose discovery is associated with a depression in the melting point of the API. The extent of melting point depression is correlated with a commensurate increase in the solubility of the API. Since a large fraction of pharmaceutical lead compounds are abandoned due to poor solubility profiles, a computational model that can accurately predict eutectic formation is of significant value to the pharmaceutical industry. We demonstrate that the computed mixing energies and binding modes of candidate molecular pairs leads to temperature-dependent interaction parameters that can accurately predict the formation of eutectic composite materials of molecular compounds. Rather than relying on the traditional solid forms of salts, cocrystals, polymorphs or solvates to support the optimization of the solid-state properties of molecular compounds, our results demonstrate that the range of solid forms that may be developed to enhance one or more physicochemical properties of molecular compounds is wider than previously thought. Computational methods remain indispensable in supporting the discovery of new functional crystalline forms of organic compounds.

[1] Reilly, A. M. et al. (2016). Acta Crystallogr., Sect. B: Struct. Sci., Cryst. Eng. Mater. 72, 439-459. [2] Pulido, A. et al. (2017). Nature 543, 657-664. [3] Shunnar, A. F., Dhokale, B., Karothu, D. P., Bowskill, D. H., Sugden, I. J., Hernandez, H. H., Naumov, P. & Mohamed, S. (2020). Chemistry – A European Journal 26, 4752-4765.