Intramolecular 1,5-S⋯N σ-hole interaction in (E)-N′-(pyridin-4-ylmethylidene)thiophene-2-carbohydrazide

The hydrazide-hydrazone forms inverse dimers via hydrogen bonding, but its conformation is defined by the presence of an intramolecular chalcogen bond. Electrostatic forces dominate in the crystal packing and give rise to a layered supramolecular structure.


Chemical context
Hydrazones are a versatile group of organic structures that have been the subject of numerous studies in chemical (Barluenga & Valdé s, 2011), biomedical (Narang et al., 2012), and materials (Serbutoviez et al., 1995) sciences for decades. For example, hydrazone-based iron chelators have found applications as analytical reagents (Singh et al., 1982) and have been proposed for the treatment of bacterial, fungal, and protozoan infections (Narang et al., 2012;Rzhepishevska et al., 2014), as well as health disorders involving alterations in iron metabolism, such as hemochromatosis (Jansová & Š imů nek, 2019), cancer (Lovejoy & Richardson, 2003), and neurodegenerative diseases (Richardson, 2004). In addition, since iron has been identified as a critical co-factor of bacterial phenazine cytotoxicity to mammalian host cells (Mossine et al., 2016), the application of efficient iron chelators to the infection sites could not only restrict proliferation of the pathogen but also protect the infected tissue from injury caused by toxic bacterial metabolites (Mossine et al., 2018).
As a part of our search for potent inhibitors of cytotoxic virulence factors from drug-resistant Pseudomonas aeruginosa, we have prepared 4-pyridinecarboxaldehyde 2-thienyl hydrazone (I), a structural analog of a series of hydrazidehydrazones that have proved to be pharmacologically active in ISSN 2056-9890 vivo. Here we report on the molecular and crystal structures of (I), with an emphasis on the non-covalent interactions in the structure.

Structural commentary
The molecular structure and atomic numbering are shown in Fig. 1. The molecule is essentially flat, with exception of the H2 and the thiophene ring carbon and hydrogen atoms, which deviate from the molecular plane by more than 0.1 Å ; the dihedral angle between the planes formed by the pyridine and the thiophene rings is only 8.28 (7) . The configuration around the azomethine N1-C6 bond is trans with respect to C2 and N1, as would be expected for the structure. The conformation around the N2-C7 bond, with respect to the N1 and C8 atoms, is cis, however. Such a syn-periplanar conformation is unusual for aromatic hydrazide-hydrazones and indicates the presence of additional intramolecular interactions that could stabilize the energetically unfavorable arrangement around the amide bond. Specifically, the interatomic S1Á Á ÁN1 distance is 2.7971 (11) Å , which is shorter than the sum of the van der Waals radii by 0.55 Å (Table 1), thus indicating the presence of a chalcogen bond (Scilabra et al., 2019). In addition, other geometric features of the molecule are in concord with the definition (Aakeroy et al., 2019) of the bond. The angle between the S1-C11 covalent bond and the S1Á Á ÁN1 suspect is 164.17 (5) , which makes the latter an extension of the former. The S1Á Á ÁN1-C6 angle is 148.48 (8) , the S1 donor is in the molecular plane and approaches the N1 acceptor roughly along the axis of the lone pair. In addition, a comparison of the bond lengths in (I) and its structural analogues, 2-thiophene carboxylic acid (Tiekink, 1989), 2-thiophene carboxamide (Low et al., 2009), or 4-hydroxybenzaldehyde 2-thienylhydrazone (Li et al., 2010), which lack attractive non-covalent interactions at the sulfur atom, revealed that the S1-C11 bond in (I) is longer than similar bonds in the reference molecules, by 0.01-0.02 Å . The chalcogen bond is believed to originate from attractive electrostatic interactions between regions of positive ESP of a donor, such as the S1 atom, and a lone pair (or a region) of the acceptor, such as the N1 atom in (I). In thiophene, two p-electrons of the sulfur atom participate in aromaticbonding, while another lone pair of p-electrons occupies the sp 2 orbital, with the maximum of the electron density localized in the thiophene ring plane. Nevertheless, there are regions of positive electrostatic potential, conventionally named -holes (Scilabra et al., 2019), which are located opposite to the S-C covalent bonds. For illustrative purposes, we have calculated a distribution of the electrostatic potential over the promolecule isosurface of (I), which is shown in Fig. 2 and which exhibits one of the two -holes mapped to the surface. Atomic numbering and displacement ellipsoids at the 50% probability level for (I). The intramolecular chalcogen bond is shown as a dotted line. Table 1 Non-covalent heteroatom interactions geometry (Å , ).

Figure 2
Electrostatic potential mapped on the promolecule 0.002 a.u. isosurface of (I), in the range À0.0750 to +0.0806 a.u., red indicates regions of negative ESP and blue indicates regions of positive ESP. The red arrow points at the region of negative ESP that is consistent with topography of aromatic p-electrons originating from the S1 atom and directed away from the molecular plane. The blue arrow points at the region of positive ESP associated with electronegative S1 (-hole) and located within the molecular plane. Calculations were done using a 6-311 G(d,p) basis set at the B3LYP level of theory.

Supramolecular features
The title compound crystallizes in the monoclinic P2 1 /n space group, with four equivalent molecules per unit cell. The molecules are organized pairwise as flat dimers (Fig. 3), with two hydrogen bonds of the same N2-H2Á Á ÁO1 type (Table 1), which are responsible for 'holding' the dimers together. This hydrogen-bonding arrangement can be described in terms of the graph-set descriptor R 2 2 (8). An additional pair of the short C11-H11Á Á ÁN3 contacts links the dimers into molecular sheets propagating in the [110] and [110] directions. The intermolecular contacts also include thestacking between the pyridine aromatic ring and the azomethine double bond.
To evaluate the contributions of these and other intermolecular contacts to the energetics of the crystal lattice in (I), we calculated pairwise interaction energies for all unique contacts found in the crystal structure. The results are shown in Fig. 4. It follows from these data that electrostatic interactions within the dimers are the major contributors to the packing forces in the crystal of (I). The Crystal Explorer software (Spackman et al., 2008) provides a tool to illustrate the magnitude and directionality of the major interactions within a crystal structure, the energy frameworks builder (Turner et al., 2015). Using the pairwise interaction energies calculated for (I), we obtained energy framework diagrams for the contributions of electrostatic and dispersion forces, as well as for the total energy. The diagrams and crystal packing are shown in Fig. 5. According to the diagrams, the main crystal packing forces are those that form sheets of the dimers, as well as stacks of the sheets. These stacks are organized in layers that are about 10 Å thick and run in parallel to (001). Intermolecular contacts between molecules located in neighboring layers are weak.

Figure 4
Interaction energies in crystal structure of (I). the title compound as a single molecule has not been reported previously. In the same paper, the copper complexes of 2pyridinecarboxaldehyde 2-thienylhydrazone (CCDC 1433200) and 3-pyridinecarboxaldehyde 2-thienylhydrazone (CCDC 1433201) were also reported. In four complexes, molecules of 3-or 4-pyridinecarboxaldehyde 2-thienylhydrazone act as monodentate ligands bound to the copper ion through the pyridine nitrogens, are not ionized and do assume conformations close to that of free (I), thus suggesting that the intramolecular chalcogen bonding is retained if coordination to the metal occurs via a remote part of the molecule. In contrast, 2-pyridinecarboxaldehyde 2-thienylhydrazone was found to chelate Cu + through the pyridine and the imine nitrogen atoms, so that the chalcogen bonding between the thiophene sulfur and the imine nitrogen atoms was disabled. The dimerforming hydrogen bonding did survive in the CCDC 1433201, 1433202 and 1433203 structures as well. Not only a coordinated metal ion, such as the aforementioned copper in CCDC 1433200, but also an opportunistic hydrogen bonding can disable the chalcogen bonding in 2-thiophenecarboxylic acidderived hydrazide-hydrazones. For instance, crystalline Schiff bases of 2-thiophenecarboxylic acid hydrazide and 4-methoxybenzaldehyde (Li & Jian, 2010), or 2-acetylpyridine (Christidis et al., 1995) adopt conformations similar to (I), thus suggesting a general trend of 1,5-SÁ Á ÁN chalcogen-bond formation in structures analogous to (I). In contrast, in hydrazones formed by condensation of 2-thiophenecarboxylic acid hydrazide and 4-hydroxybenzaldehyde (Li et al., 2010) or 2-hydroxyacetophenone (Jiang, 2011;Singh et al., 2013), which have an additional hydrogen-bonding interaction between the aromatic hydroxyl groups and the imine nitrogen, the intramolecular chalcogen bonding is switched to a weaker 1,4-SÁ Á ÁO carbonyl contact.

Synthesis and crystallization
To a suspension of 2-thiophenecarboxylic acid hydrazide (711 mg, 5 mmol) in 15 mL of 70% aqueous EtOH were added 0.536 mg (471 mL, 5 mmol) of 4-pyridinecarboxaldehyde, and the reaction mixture was stirred for 2 h at 343 K. The resulting clear solution was brought to 277 K and left for two days to Energy frameworks for separate (a) electrostatic and (b) dispersion contributions to the (c) total pairwise interaction energies. The cylinders link molecular centroids, and the cylinder thickness is proportional to the magnitude of the energies (see Fig. 4). For clarity, the cylinders corresponding to energies <5 kJ mol À1 are not shown. The directionality of the crystallographic axes is the same for all three diagrams. Only H-atom coordinates refined Á max , Á min (e Å À3 ) 0.44, À0.29 Computer programs: APEX3 and SAINT (Bruker, 2016), SHELXS (Sheldrick, 2008), SHELXL (Sheldrick, 2015), OLEX2 (Dolomanov et al., 2009), Mercury (Macrae et al., 2020) and publCIF (Westrip, 2010).
crystallize as colorless needles. Suitable crystals were then selected for subsequent diffraction studies.

(E)-N′-(Pyridin-4-ylmethylidene)thiophene-2-carbohydrazide
Crystal data Special details Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.