Glutathione peroxidase (GPX) [1] is a selenoenzyme containing multiple selenocysteine units in its active site. It catalyses the reduction of harmful peroxides, thus protecting cells from oxidative stress. High concentrations of active peroxides results in an alternative path of the catalytic cycle of GPX, where selenenic acid residues (R–SeOH) undergo oxidation to the corresponding seleninic (R–SeO₂H) and selenonic acids (R-SeO₃H). In general, synthetic seleninic acids and their sulfurated analogues sulfinic acids (R-SO₂H) have been reported as key component in redox regulation [2], exerting in some cases a surprising anticancer activity [3].

The reactivity of these moieties may be related to the electrophilic behaviour of selenium and, to a lesser extent, of sulphur. The propensity of an electron rich atom to act as an electrophile is related to the presence of regions of positive electrostatic potential (σ-holes) on its surface, located on the back-end of the covalent bonds formed by the considered atom. σ-hole interactions are named from the group of the periodic table to which the element behaving as an electrophile belongs; based on this, interactions given by atoms of group 16 are dubbed as Chalcogen Bonds (ChB) [4].

Here, we report the controlled oxidation of L-selenocystine (C₆H₁₂N₂O₄Se₂) in selenocysteine seleninic acid, which is a simple mimic of GPX activity. This compound was isolated and single crystals suitable for X-ray diffraction allowed to an insight at the atomic level of the electrophilic behaviour of selenium. This crystal structure suggests the possible involvement of ChB in the redox regulation activity of the seleninic acid moiety. A survey of the Cambridge Structural Database (CSD) and some computational studies on a small library of these class of compounds may confirm the propensity of seleninic (and sulfinic) acids to act as ChB donors.

The decomposition of the crystal contacts on the Hirshfeld surface between pairs of interacting chemical species enables to derive a contact enrichment ratio [1,2,3]. This descriptor yields information on the propensity of chemical species to interact with themselves and other species. The enrichment ratio is obtained by comparing the actual and equiprobable contacts. H∙∙∙N, H∙∙∙O and H∙∙∙S as well as weak H∙∙∙halogen hydrogen bonds appear generally more or less enriched, depending on the context. Larges series of molecules made of a set of chemical groups and retrieved from the Cambridge Structural Database can be investigated to find trends in the propensity of interactions to form.

The electrostatic energy of between atoms in contact was also computed using a multipolar atom model after electron density database transfer. The mean energy values of different contact types between multipolar pseudoatoms were compared statistically to the contact enrichment ratios.

The analyses suggest that hydrogen bonds are often the most enriched and attractive interactions and are therefore a driving force in the crystal packing formation for organic molecules. The methodology also enables to compare different types of hydrogen bonds which are in competition within a crystal packing. The behavior of weaker interactions such as halogen bonds is less contrasted. The methodology is a way to rank the occurrence of given synthons and the impact in crystal engineering will be discussed

The tenoxicam (4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno(2,3-e)-1,2-thiazine-3-carboxamide 1,1-dioxide), is a non-steroidal anti-inflammatory drug (NSAID), member of oxicam family, widely used in the treatment of osteoporosis. Tenoxicam (TXM) could be present in the β-keto-enolic form (BKE) or β-diketone (BDK) and in a zwitterionic form (ZWC) (Figure 1). However, in solid form (more than 20 different compounds including polymorphic modifications, co-crystals, and solvates) [1 and present work] TXM has predominantly found in the zwitterionic form (ZWC). While in a dissolved form, keto-enolic equilibrium is observed since recorded by us experimental absorption and fluorescence spectra for various TXM solutions show presence two forms of TXM (called A and B) in solvents with high polarity and only A form of TNX in low polar solvents (cyclohexane, toluene, chloroform, dioxane). This led us to think about the possibility to obtain solid forms of tenoxicam contain it in BKE or BDK form.

A set of NMR measurements using various 1D- and 2D- techniques were used to assign which of TXM keto-enolic form (see Figure 1) belong to the A and B forms observed in a liquid environment. As a result, form A observed by optical methods assigns to BKE form and the form B – to ZWC. ¹H NMR spectra of tenoxicam in CDCl₃ detected at various temperatures from -55 to 25 °C show almost 100% TXM in form of BKE at 25 °C and almost 100% TXM in ZWC form at -55°C.

Taking into account optical and NMR data about the domination of BKE form in low polar solvents at room temperature, we tried to obtain solid forms of TNX containing TXM in BKE form by its crystallization from cyclohexane, toluene, dioxane, and chloroform. These experiments showed no crystal phase from cyclohexane and powder of TXM polymorph I from dioxane and toluene. Crystallization from chloroform gave single crystals of three different solvates so called TXM-CHCl₃-I (grow up at room temperature), TXM-CHCl₃-II (grow up at -18°C) and TXM-CHCl₃-III (grow up at -18°C). But in all these solvates TXM presents in ZWC form.

For understanding why TNX exists in BKE form in solution, but crystallize in ZWC form, DFT calculations in vacuo were made. It shows that BKE to be the most thermodynamically stable form, ZWC is less stable and BDK is the least stable (ΔG between BKE and these two forms of 2.20 kcal/mol and 12.49 kcal/mol, respectively). But BKE form is characterized by a large twist between A 2-pyridyl ring and TXM backbone with respect to almost flat ZWC form. Planarization of BKE form diminishes the energy difference between flatten BKE and ZWC forms almost to 0.15 kcal/mol that indicates a presence of another thin interaction within TXM molecule predisposing it to crystallization in ZWC form. This thin interaction was showed to be S-bond between thiophenil ring and carbonyl oxygen according to the analysis of intramolecular interactions within natural bond orbital theory [4]. This S-bond is significantly stronger for ZWC form as compared with flatten BKE form and it should be considered as the driving force of TXM crystallization

The authors would like to thank Dr. Anatoly A. Politov for useful discussion. SGA would like to thank Prof. Dr. Elena V. Boldyreva for her ongoing support. CT would like to thank his former supervisor Prof. Dr. Elena V. Boldyreva and his present supervisor Prof. Dr. Artem R. Oganov for their ongoing support.

SGA is indebted to Ministry of Science and Higher Education of the Russian Federation (project АААА-А19-119020890025-3).

PSS and ASK thank Ministry of Science and Higher Education of the Russian Federation for access to optical and NMR equipment (АААА-А16-116121510087-5).

Halogen bonding (XB) interactions are defined as those involving electrophilic sites (σ-holes) associated to a covalently bonded atom of group-17 with nucleophilic sites from either the same or a different molecule¹. These σ-hole regions are expected to exhibit along the extension of covalent bonds and can be finely tuned by the electronic nature of substituents in the molecule bearing the halogen atom.

In a previous study involving donor-acceptor complexes, we have succeeded to co-crystallize iodine substituted imide derivatives with pyridine derivatives. In these systems, we have pointed out a strong halogen bonding motif where the halogen atom is significantly shifted towards the acceptor moiety. For one of them, which is leading to an ionic crystal rather than a co-crystal², an electrostatic secondary interaction of C=O^δ-···I ^δ+ type has been discussed as one of the reasons behind such a halogen atom shift towards the acceptor. In our work, we are actually investigating the evolution of such XB interactions in an organic binary adduct composed of N-Iodosaccharin and Pyridine (NISac.Py) via X-ray diffraction experiments under pressure. These experiments were undertaken with a Membrane Diamond Anvil Cell (MDAC) under external pressure ranging from 0 GPa to 4.5 GPa, by using an in-house set-up (with the in-situ measurement of pressure from time to time) developed in our laboratory and adapted to the diffractometer (Bruker D8 venture) that was used to collect high-pressure X-ray diffraction data.

Aiming to analyse the influence of the molecular environment on the XB motif of NISac.Py, X-ray diffraction studies have permitted to follow the evolving behaviour of the N_sac-I···N’_py interactions as a function of pressure, which results in the shifting of the halogen atom position between donor and acceptor moieties. This trend might be linked to a potential change of state from co-crystal to ionic crystal form under pressure. The study also opens up an opportunity to understand the modification of secondary interactions as a function of pressure. Another interesting finding resulting from this work is the occurrence of a mechanical twinning and its behaviour as a function of pressure, which is analysed in detail. Periodic theoretical calculations were also carried out by applying isotropic external pressures. They were followed by the analyses of the Equation of State (EOS), molecular environments and non-covalent interactions, all of them showing good agreements with experimental results. In summary, this work illustrates the possibility of working with pressure as another thermodynamic variable that permits to alter weak intermolecular interactions and therefore to explore phase transformation or polymorphic phases in other donor-acceptor systems formed by similar interactions.

[1] Cavallo, G., Metrangolo, P., Milani, R., Pilati, T., Priimagi, A., Resnati, G. & Terraneo, G. (2016). Chem. Rev. 116, 2478–2601. [2] Makhotkina, O., Lieffrig, J., Jeannin, O., Fourmigué, M., Aubert, E. & Espinosa, E. (2015). Cryst. Growth Des. 15, 3464–3473.

Keywords: High-pressure X-ray diffraction; Membrane Diamond Anvil Cells; Halogen bonding; Mechanical Twinning

V.V.S. thanks the French ANR and the Region Grand-Est for a PhD fellowship. We thank PMD²X X-ray diffraction facility of the Institut Jean Barriol, Université de Lorraine, for X-ray diffraction measurements and ERDF for funding high-pressure experimental set-up. High-performance computing resources were partially provided by the EXPLOR center hosted by Université de Lorraine

Controlling supramolecular synthetic output, with the aim to achieve targeted macroscopic properties, is the main goal of crystal engineering.[1] Mechanical flexibility, as one of the highly desired properties of functional materials, has recently become a feature of a growing number of crystalline compounds.[2-5] Plastic deformation, together with elastic response, is frequently observed among organic molecular crystals,[3] but quite rarely noticed among crystalline metal-organic compounds.[4,5] Since the introduction of metal cations to organic systems allow us to achieve specific properties such as magnetic and electric ones, and therefore opens a wide range of possible applications, it is clear that there is a need for determining structural requirements that need to be fulfilled to equip metal-organic crystals with mechanical flexibility.Recently, it was shown that cadmium(II) coordination polymers equipped with halopyrazine ligands adaptably respond to applied external stimuli, displaying elastic flexibility.[5] It was observed that introducing a slight structural changes, simply by exchanging bridging halide anion or halogen atom on halopyrazine ligand, changes the extent of elastic response significantly, while the quantification of their mechanical behaviour clearly showed that they can be categorized into three main subgroups, highly, moderately and slightly elastic. To get an invaluable insight into the phenomenon, we decided to systematically examine similar classes of coordination polymers by introducing slight structural differences through the exchange of supramolecular functionalities only. Herein we opted for pyridine-based ligands decorated with cyano functionality to explore their impact on macroscopic mechanical output. It was determined that the position of cyano group on pyridine ring, as well as used bridging halide anion, dictate the nature and extent of mechanical response. For crystals that displayed elastic behaviour, the responses were quantified and correlated with structural features, primarily the strength and geometry of supramolecular interactions, and compared with the mechanical behaviour of similar metal-containing systems.

[1] Desiraju, G. R. (2007) Angew. Chem. Int. Ed. 46, 8342.

[2] Commins, P., Tilahun Desta, I., Prasad Karothu, D., Panda, M. K., Naumov, P. (2016) Chem. Commun. 52, 13941.

[3] Saha, S., Mishra, M. K., Reddy, C. M., Desiraju, G. R. (2017) Acc. Chem. Res. 51, 2957.

[4] Worthy, A., Grosjean, A., Pfrunder, M. C., Xu, Y., Yan, C., Edwards, G., Clegg, J. K., McMurtrie, J. C. (2018) Nat. Chem. 10, 65.

[5] Đaković, M., Borovina, M., Pisačić, M., Aakeröy, C. B., Soldin, Ž., Kukovec, B.-M., Kodrin, I. (2018) Angew. Chem. Int. Ed. 57, 14801.

This work has been fully supported by Croatian Science Foundation under the project IP-2019-04-1242.

Strong intermolecular interactions serve as vital tools in cocrystal assembly. Halogen bonding (XB) [1], a highly directional interaction, is most often observed between a halogen-atom donor and electron-rich acceptors, such as oxygen or nitrogen. However, XBs can also be used for the organization of arenes in the solid state through interactions with aromatic p-systems, as previously explored in the dichroic and pleochroic cocrystals of naphthalene or azulene, respectively. [2]

This presentation will outline our study of XB cocrystal structures containing various polycyclic aromatic hydrocarbons (PAHs), and evaluate the reliability of halogen bonding to carbon as an overlooked tool for crystal engineering.

[1] Christopherson, J. C.; Topić, F.; Barrett, C. J.; Friščić, T. (2018). Crystal Growth & Design, 18, 1245-1259.

[2] Vainauskas, J.; Topić, F.; Bushuyev, O. S.; Barrett, C. J.; Friščić, T. (2020) Chemical Communications 56, 15145-15148.