Synthesis and crystal structure of 1,3-bis{[N,N-bis(2-hydroxyethyl)amino]methyl}-5-{[(4,6-dimethylpyridin-2-yl)amino]methyl}-2,4,6-triethylbenzene

A 1,3,5-trisubstituted 2,4,6-trialkylbenzene derivative with bis(hydroxyethyl)amino and 2,4-dimethylpyridinylamino substituents was synthesized and its structure determined by single-crystal X-ray diffraction. The crystal packing is stabilized by intra- and intermolecular hydrogen bonds and weak C—H⋯π contacts.


Chemical context
The 1,3,5-trisubstituted 2,4,6-trialkylbenzene scaffold has shown to be valuable for the construction of various artificial receptors (Hennrich & Anslyn, 2002). In the course of our research work, we have successfully used this molecular scaffold in the design of acyclic and macrocyclic receptors for neutral (Mazik, 2009(Mazik, , 2012Amrhein et al., 2016;Koch et al., 2016;Amrhein & Mazik, 2021;Kö hler et al., 2020Kö hler et al., , 2021 and ionic substrates (Geffert et al., 2013;Stapf et al., 2015;Schulze et al., 2018). Our studies on the molecular recognition of carbohydrates have shown that the participation of different types of recognition groups in the complexation of the substrate favourably influences the binding process (Stapf et al., 2020a,b;Kaiser et al., 2019). Such a combination of two types of recognition units, namely heterocyclic and hydroxy groups, is realised in the triethylbenzene-based title compound 1 (see also Stapf et al., 2020a). The design of the receptors consisting of the aforementioned recognition units was inspired by the nature of the protein binding sites involved in the interactions stabilizing the crystalline protein-carbohydrate complexes (Quiocho, 1989). For example, 2-aminopyridine can be considered as a heterocyclic analogue of the asparagine/glutamine primary amide side chain. Furthermore, it should be noted that the formation of intramolecular interactions is also one of the factors influencing the binding properties of a receptor molecule (Rosien et al., 2013). Intramolecular interactions can also be observed in the crystal structure of 1.

Structural commentary
In the title molecule, the structure of which is shown in Fig. 1, the functionalized side arms are arranged on one side of the central benzene ring, while the ethyl substituents are oriented in the opposite direction. One of the bis(hydroxyethyl)amino moieties is disordered over two positions [s.o.f. 0.879 (2)/ 0.121 (2)]. The interplanar angle between the aromatic rings is 73.6 (1) . Within the molecule, three hydroxy groups create a continuous pattern of O-HÁ Á ÁO hydrogen bonds [d(HÁ Á ÁO) 1.86-2.12 Å ]. The amino nitrogen atoms N3 and N4 are involved in intramolecular C-HÁ Á ÁN hydrogen bonding [d(HÁ Á ÁN) 2.40, 2.54 Å ]. The crystal structure contains four potentially solvent-accessible voids with a total volume of 110 Å 3 per unit cell (Spek, 2015). The void volume of 27.5 Å 3 and the maximum residual electron density of 0.55 e Å À3 indicate that the voids could be partially occupied by water molecules.

Figure 1
Perspective view of the molecular structure of the title compound including atom numbering. Anisotropic displacement ellipsoids are drawn at a 50% probability level. Dashed lines represent hydrogenbonding interactions. For the sake of clarity, only the major position of the disordered bis(hydroxyethyl)amino moiety is shown.

Figure 3
Packing excerpt of the title compound with numbering of coordinating atoms. Oxygen atoms are displayed as red, nitrogen atoms as blue circles. Hydrogen atoms excluded from intermolecular interactions are omitted for clarity. Hydrogen bonds are shown as broken lines. into layers extending parallel to the crystallographic bc plane (Fig. 4). As the layer surfaces are defined by the ethyl groups of the molecules, interlayer association is restricted to weak C-HÁ Á Á contacts (Nishio et al., 1995). Information regarding non-covalent bonding present in the crystal is found in Table 1.

Figure 4
Packing diagram of the title compound viewed down the c axis. Oxygen atoms are displayed as red, nitrogen atoms as blue circles. Hydrogenbonding interactions are shown as dashed lines. colourless blocks by diffusion of n-hexane into a solution of the compound in THF.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Carbon-bound hydrogen atoms and protons of the minor (12%) positions of the disordered OH groups (H1A, H2A) were positioned geometrically and allowed to ride on their respective parent atoms, with C-H = 0.95 Å (aromatic) and 0.99 Å (methylene) and U iso (H) = 1.2 U eq (C), and O-H = 0.84 Å (OH) and C-H = 0.98 Å (methyl) and U iso (H) = 1.5 U eq (C,O), respectively. The protons of the N-H and O-H (undisordered or the main positions) were located from the residual electron density map and refined with U iso (H) bound to the parent atom (1.2, for NH and 1.5 for OH) with distance restraints for the OH bonds (SADI). The refinement of the disordered N(CH 2 CH 2 OH) 2 group was performed using geometry (SAME) and U ij (SIMU, RIGU) restrains implemented in SHELXL (Sheldrick, 2015). The refined proportion of the two positions is 88:12%. The maximum residual peak of 0.55 e Å À3 is located inside a 27.5 Å 3 void and can be refined as a partially occupied water molecule ($6%); however, due to the low occupancy, it was not included in the final refinement.

Funding information
Open access funding by the Publication Fund of the Technische Universitä t Bergakademie Freiberg is gratefully acknowledged.

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.