Crystal Structure and Supramolecular Architecture of Antiallergic Diphenylene Diethyl Dioxalamates

: The crystal structure and the supramolecular architectures of the antiallergic compounds N , N (cid:48) -(4,4 (cid:48) -methanediyl-di-phenyl)-bis-diethyl dioxalamate ( 1 ); N (cid:48) ,N (cid:48) -(4,4 (cid:48) -oxydi- p -phenylene)-bis-diethyl dioxalamate ( 2 ); N,N (cid:48) -(4,4 (cid:48) -biphenylene)-bis- diethyl dioxalamate ( 3 ) are reported. The supramolecular self-assembly in 1-3 is driven by N-H ··· O = C hydrogen bonds and reinforced by C-H ··· O = C, C-H ··· π and C = O ··· C = O interactions. The three compounds preferred to form cross-linked supramolecular architectures. Intermolecular interactions also were studied by the Hirshfeld surface analysis, revealing that the H ··· H, O ··· H, and C ··· H are the more dominant contacts in the three compounds. The knowledge of crystal structure will allow us to perform theoretical studies to evaluate the antiallergic activity of compounds 1-3 .


Introduction
Allergic conjunctivitis is a disease characterized by the ocular conjunctiva inflammation. It is associated with the degranulation of sensitized mast cells, and is caused by dust, smoke, pollens, chemical vapors, solvents, and environmental antigens. Some symptoms of ocular allergy are itching, tearing, lid and conjunctival edema-redness, and photophobia during the acute phase [1,2].
Therapeutic options for treatment of allergic conjunctivitis are topical steroids, antihistamines, and mast cell stabilizers. Lodoxamide is a phenylene bis-oxalamidic compound that acts as mast cell stabilizer by stopping the Ca 2+ flux during the activation of mast cells, inhibiting their degranulation [3].
Allergic reactions start when the allergens bind with the FcεRI receptor of immunoglobulin E (IgE), triggering the signals transduction reaction in mast cells and basophil cells, releasing inflammatory mediators [18,19]. Diphenylene diethyl dioxalamates 1-3 were reported and patented as antiallergic compounds [20][21][22]; however, there is no information about their crystal structure and supramolecular study. In this work, we report the crystal structure and the supramolecular study of three diphenylene bis-diethyl dioxalamates (1-3) (Figure 1). In addition, the intermolecular contacts present in the crystal packing were analyzed by the Hirshfeld surface plots [23]. The knowledge of the molecular structure of 1-3 compounds will allow the development of further studies to evaluate theoretically (docking studies) the antiallergic activity of 1-3 compounds.
Single crystals of 1 were obtained from the evaporation at room temperature of the filtered THF solution obtained after the reaction of 4,4′-diaminodiphenylmethane with ethyl 2-chloro-2oxoacetate, meanwhile, single crystals of 2 and 3 were obtained from de evaporation at room temperature of THF solutions of purified 2 and 3. In the three cases, the THF used was not dried.

X-ray Diffraction
A summary of collection and refinement parameters of 1-3 crystal structures is listed in Table 1. Single crystal X-ray diffraction of 1 and 3 were carried out using a Bruker APEXII with Mo Kα radiation (λ = 0.71073 Å) diffractometer (Bruker, Karlsruhe, Germany), and 2 with a Nonuis Kappa CCD with Mo Kα radiation (λ = 0.71073 Å) (Bruker, Karlsruhe, Germany). The cell refinement and data reduction were carried out with the SAINT V8.34A [24]. The structure was solved by direct methods using SHELXL97 [25]. Mercury software [26] was used to prepare the material for publication. H atoms on C and N were geometrically positioned and treated as riding atoms with C-H 0.95−0.99 Å, Uiso(H) = 1.
Single crystals of 1 were obtained from the evaporation at room temperature of the filtered THF solution obtained after the reaction of 4,4 -diaminodiphenylmethane with ethyl 2-chloro-2-oxoacetate, meanwhile, single crystals of 2 and 3 were obtained from de evaporation at room temperature of THF solutions of purified 2 and 3. In the three cases, the THF used was not dried.

X-ray Diffraction
A summary of collection and refinement parameters of 1-3 crystal structures is listed in Table 1. Single crystal X-ray diffraction of 1 and 3 were carried out using a Bruker APEXII with Mo Kα radiation (λ = 0.71073 Å) diffractometer (Bruker, Karlsruhe, Germany), and 2 with a Nonuis Kappa CCD with Mo Kα radiation (λ = 0.71073 Å) (Bruker, Karlsruhe, Germany). The cell refinement and data reduction were carried out with the SAINT V8.34A [24]. The structure was solved by direct methods using SHELXL97 [25]. Mercury software [26] was used to prepare the material for publication. H atoms on C and N were geometrically positioned and treated as riding atoms with C-H 0.95−0.99 Å, U iso (H) = 1.2 U eq (C) or 1.5 U eq (C); N-H = 0.88 Å, U iso (H) = 1.2 U eq (N). The O-ethyl fragment of compound 2 was disordered over two positions. Both components were refined using restraints applied to the bond distances; the final occupancy factors were 0.612 (18): 0.388 (18) [27].

Computational Details
Geometry optimizations of 1-3 were performed in their anti and syn ( Figure 2) conformations within the framework of the density functional theory in ORCA computational package [28], using a def2-TZVP basis set [29,30]. For the exchange and correlation, the ωB97X-D3 functional [31] was employed. These systems where evaluated in vacuum within the Conductor-like Polarizable Continuum Model (CPCM) [32,33]. All minimal energy states were verified with a calculation of harmonic vibrational frequencies, finding only positive values. The images were rendered by the molecular visualizer Chemcraft [34].

Computational Details
Geometry optimizations of 1-3 were performed in their anti and syn ( Figure 2) conformations within the framework of the density functional theory in ORCA computational package [28], using a def2-TZVP basis set [29,30]. For the exchange and correlation, the ωB97X-D3 functional [31] was employed. These systems where evaluated in vacuum within the Conductor-like Polarizable Continuum Model (CPCM) [32,33]. All minimal energy states were verified with a calculation of harmonic vibrational frequencies, finding only positive values. The images were rendered by the molecular visualizer Chemcraft [34]. The Hirshfeld surfaces and 2D fingerprints calculations were obtained in Crystal Explorer 3.1 [35] using a Thakkar basis set [36] and employing CIF's archives collected of 1-3 crystal structures. The graphs of Hirshfeld's molecular surfaces were mapped with dnorm using a scheme colors, where the red one represents the shortest contacts, the white color indicates intermolecular distances close to the van der Waals contacts with dnorm equal to zero, and the blue color shows the contacts longer than the sum of the van der Waals radii with positive dnorm values [23,37]. The Hirshfeld surfaces and 2D fingerprints calculations were obtained in Crystal Explorer 3.1 [35] using a Thakkar basis set [36] and employing CIF's archives collected of 1-3 crystal structures. The graphs of Hirshfeld's molecular surfaces were mapped with d norm using a scheme colors, where the red one represents the shortest contacts, the white color indicates intermolecular distances close to the van der Waals contacts with d norm equal to zero, and the blue color shows the contacts longer than the sum of the van der Waals radii with positive d norm values [23,37].

Crystal Structure of Compounds 1-3
The two ethyl oxalamate groups in each molecule can adopt the syn or anti conformation, depending on their position relative to the perpendicular plane of the diphenyl rings ( Figure 2). In the Crystals 2020, 10, 1048 4 of 13 crystal structures of 1 and 2 the syn conformation is adopted, whereas in 3 the anti conformation is observed. The ethyl oxalamate side arms are twisted from the mean plane of the phenyl ring showing torsion angles ranging from 152 • to 166 • .
In compounds 1-3, the carbonyl groups of the C=O-C=O fragment adopt the anti conformation usually observed in oxalic acid derivatives [4][5][6][7][8], with torsion angles ranging from 162 • to 178 • (Table S1 Supporting Materials). Intramolecular hydrogen bonding allows the formation of S(5) and S(6) motifs [38] whose geometric parameters are listed in Table S2 of Supporting Materials. Cocrystal In the unit cell, four molecules of 1 co-crystallized with one molecule of oxalic acid and two water molecules. Oxalic acid and water were unexpectedly incorporated into the crystalline lattice from the synthesis residues and the not dried solvent, respectively. The asymmetric unit comprises two independent molecules of 1 (1a and 1b, Figure 3), one molecule of water, and the molecule of oxalic acid lying on the center of symmetry. The torsion angles between the planes of the phenyl rings for the twin independent molecules of 1 are quite different: C4-C13-C17-C16 is −86.4(2) • and C29-C38-C42-C43 is 43.0(3) • around the O=C-C=O group, for 1a and 1b, respectively. Compound 1 is non-linear, with the Ar-CH 2 -Ar angles being 111.1(2) • (C4-C13-C17) for 1a and 115.9(2) • (C29-C38-C42) for 1b. These values are in agreement with the reported values for similar compounds [39,40]. The ethyl oxalamate groups are somewhat twisted out of the plane of the aromatic ring, as can be seen from the torsion angles C2-C1-

Crystal Structure of Compounds 1-3
The two ethyl oxalamate groups in each molecule can adopt the syn or anti conformation, depending on their position relative to the perpendicular plane of the diphenyl rings ( Figure 2). In the crystal structures of 1 and 2 the syn conformation is adopted, whereas in 3 the anti conformation is observed. The ethyl oxalamate side arms are twisted from the mean plane of the phenyl ring showing torsion angles ranging from 152° to 166°.
Cocrystal 12•½(C2H2O4)•H2O crystallized in the triclinic space group P-1. In the unit cell, four molecules of 1 co-crystallized with one molecule of oxalic acid and two water molecules. Oxalic acid and water were unexpectedly incorporated into the crystalline lattice from the synthesis residues and the not dried solvent, respectively. The asymmetric unit comprises two independent molecules of 1 (1a and 1b, Figure 3
The third dimension is extended by lone pair→π interactions (C8-O8···Cg(2) = 3.559 Å; Cg(2) = C1-C6) giving rise to a cross linked supramolecular array. This architecture is similar to the supramolecular arrangement of dimethyl-4,4-methylene-bis(phenylcarbamate) [40]. The presence of oxalic acid and water in the unit cell offer a greater possibility of intermolecular interactions. Despite this, it is worth noting that the characteristic amide-amide R 2 2 (10) motif remains as the driving interaction, in the self-assembly of 1, together with the three centered R 2 1 (5) and R 1 2 (6) interactions. The supramolecular architecture of 2 is given by the self-assembly of 3:1 repetition units of 2, depicting a cross-linked supramolecular array. A central molecule of 2 is perpendicularly interlinked to three parallel molecules by N7-H7···O8 hydrogen bonds, forming C(4) hydrogen bond motifs, (Figure 7a). These interactions are reinforced by C9=O9···C8=O8 carbonyl-carbonyl interactions and C3-H3···Cg(2) interactions (Figure 7b), giving rise to a ribbon propagating along the direction of the b axis. Hydrophobic contacts between the -OEt fragments are given between the ribbons. The whole 2D and 3D supramolecular architecture of 2 is given by the propagation of the ribbons by the N7-H7···O8 hydrogen bond along in the plane ab, contrasting with the related compound 4,4 -oxo-bis(phenylcarbamic acid 1-methylethyl ester) [45] which forms supramolecular tapes of parallel 1:1 units via N-H···O hydrogen bonds showing a C(4) motif. The supramolecular architecture of 2 is given by the self-assembly of 3:1 repetition units of 2, depicting a cross-linked supramolecular array. A central molecule of 2 is perpendicularly interlinked to three parallel molecules by N7-H7···O8 hydrogen bonds, forming C(4) hydrogen bond motifs, (Figure 7a). These interactions are reinforced by C9=O9···C8=O8 carbonyl-carbonyl interactions and C3-H3···Cg(2) interactions (Figure 7b), giving rise to a ribbon propagating along the direction of the b axis. Hydrophobic contacts between the -OEt fragments are given between the ribbons. The whole 2D and 3D supramolecular architecture of 2 is given by the propagation of the ribbons by the N7-H7···O8 hydrogen bond along in the plane ab, contrasting with the related compound 4,4′-oxobis(phenylcarbamic acid 1-methylethyl ester) [45] which forms supramolecular tapes of parallel 1:1 units via N-H···O hydrogen bonds showing a C(4) motif.
The supramolecular architecture of 1-3 is driven by N-H···O=C hydrogen bonds and reinforced by C=O···C=O and C-H···π. It is worth to note the preference of 1 and 3 to form cross-linked supramolecular architectures because of the presence of two independent molecules in the asymmetric unit, as well as co-crystallization with oxalic acid and water molecules, in the case of compound 1.   The first dimensional supramolecular architecture of 3 is given by a supramolecular tape of 3b molecules extended along the (-5 5 -3) plane in which 3b molecules are linked by the N27-H27···O49 hydrogen bond and C22-H22···O49 interaction, forming the three-centered hydrogen bond interaction H22···O49···H27 showing a R 1 2 (6) motif. The second dimension is given by the perpendicular zig-zagging tape of 3a molecules extended along the (4 4 −7) plane. They are linked through C8=O8···C9 carbonyl-carbonyl interactions (O8···C9 = 3.128(3), C8=O8···C9 angle = 111.0(2) • ) and the C12-H12C···Cg(2) interaction, forming an angle with the tape of 3b molecules of 80.61 • (Figure 8). The presence of two different molecules of 3 in the asymmetric unit, pointing to different crystallographic directions lead to the formation of the third dimensional supramolecular array showing cross linked tapes of 3a and 3b, linked through N7-H7···O48 hydrogen bond, and C2-H2···O48 and C32B···Cg(2) interactions ( Figure 8).   The supramolecular architecture of 1-3 is driven by N-H···O=C hydrogen bonds and reinforced by C=O···C=O and C-H···π. It is worth to note the preference of 1 and 3 to form cross-linked supramolecular architectures because of the presence of two independent molecules in the asymmetric unit, as well as co-crystallization with oxalic acid and water molecules, in the case of compound 1.

DFT Calculations and Hirshfeld Surface Analysis
In order to understand the effect of supramolecular interactions in the crystal packing, the geometric optimization of structures 1-3 in anti and syn conformation was carried out (Figure 9). The calculations were performed both in gas phase.

DFT Calculations and Hirshfeld Surface Analysis
In order to understand the effect of supramolecular interactions in the crystal packing, the geometric optimization of structures 1-3 in anti and syn conformation was carried out (Figure 9). The calculations were performed both in gas phase. Theoretical calculations revealed that the anti-conformation is the most favorable for compounds 1-3, being the average energy difference between the syn and anti forms of 5.578 kcal/mol, in the gas phase (Table 3). However, compounds 1 and 2 adopt the energetically unfavorable syn conformation, and compound 3, the anti. Thus, non-covalent interactions determine the conformation adopted by compounds 1-3 and direct the crystal packing. Table 3. Relative energies (kcal/mol) for the syn and anti conformations for 1-3.

Compound
In Gas Phase (kcal/mol) syn anti 1 5.611 0 2 5.617 0 3 5.505 0 The intramolecular hydrogen bonds lengths in syn and anti were also analyzed ( Table 4). All the calculated data are very close to the hydrogen bonding distances found in crystals 1-3 (Table S2 Supporting Materials), obtaining the best results in the optimizations with CPCM, in all systems S(5) motifs were found. Hirshfeld surface study and 2D fingerprints of 1-3 were carried out in order to obtain information about intermolecular contacts and their quantitative contribution the supramolecular Theoretical calculations revealed that the anti-conformation is the most favorable for compounds 1-3, being the average energy difference between the syn and anti forms of 5.578 kcal/mol, in the gas phase (Table 3). However, compounds 1 and 2 adopt the energetically unfavorable syn conformation, and compound 3, the anti. Thus, non-covalent interactions determine the conformation adopted by compounds 1-3 and direct the crystal packing. Table 3. Relative energies (kcal/mol) for the syn and anti conformations for 1-3.

Compound
In The intramolecular hydrogen bonds lengths in syn and anti were also analyzed ( Table 4). All the calculated data are very close to the hydrogen bonding distances found in crystals 1-3 (Table S2 Supporting Materials), obtaining the best results in the optimizations with CPCM, in all systems S(5) motifs were found. Hirshfeld surface study and 2D fingerprints of 1-3 were carried out in order to obtain information about intermolecular contacts and their quantitative contribution the supramolecular self-assembly of 1-3 [35]. Figure 10 shows the Hirshfeld surfaces, shape indexes, and curvednesses of 1-3.

Conclusions
The N-H···O=C hydrogen bond is the interaction that drives the supramolecular assemblies in 1-3, and is reinforced by C-H···O=C, C-H···π and C=O···C=O interactions. The three compounds showed cross-linked supramolecular architecture, caused by the presence of two different molecules in the unit cell of 1 and 3, and the C2 symmetry in 2.
The presence of oxalic acid and water in the unit cell of 1 as consequence of the cocrystal formation, offer a greater possibility of formation of intermolecular interactions.
The syn conformation is preferred in 1 and 2, meanwhile compound 3 adopts the less stable anti conformation, indicating that non-covalent interactions determine the conformation adopted by compounds 1-3 and direct the crystal packing. self-assembly of 1-3 [35]. Figure 10 shows the Hirshfeld surfaces, shape indexes, and curvednesses of 1-3. .

Conclusions
The N-H···O=C hydrogen bond is the interaction that drives the supramolecular assemblies in 1-3, and is reinforced by C-H···O=C, C-H···π and C=O···C=O interactions. The three compounds showed cross-linked supramolecular architecture, caused by the presence of two different molecules in the unit cell of 1 and 3, and the C2 symmetry in 2.
The presence of oxalic acid and water in the unit cell of 1 as consequence of the cocrystal formation, offer a greater possibility of formation of intermolecular interactions.
The syn conformation is preferred in 1 and 2, meanwhile compound 3 adopts the less stable anti conformation, indicating that non-covalent interactions determine the conformation adopted by compounds 1-3 and direct the crystal packing.

Conclusions
The N-H···O=C hydrogen bond is the interaction that drives the supramolecular assemblies in 1-3, and is reinforced by C-H···O=C, C-H···π and C=O···C=O interactions. The three compounds showed cross-linked supramolecular architecture, caused by the presence of two different molecules in the unit cell of 1 and 3, and the C 2 symmetry in 2.
The presence of oxalic acid and water in the unit cell of 1 as consequence of the cocrystal formation, offer a greater possibility of formation of intermolecular interactions.
The syn conformation is preferred in 1 and 2, meanwhile compound 3 adopts the less stable anti conformation, indicating that non-covalent interactions determine the conformation adopted by compounds 1-3 and direct the crystal packing.

Conflicts of Interest:
The authors declare no conflict of interest.