Nova Biotechnol Chim (2020) 19(1): 109-115 DOI 10.36547/nbc.v19i1.583  Corresponding author: juraj.cernak@upjs.sk Nova Biotechnologica et Chimica Hydrogen atom disorder in the crystal structure of o-phenylenediacetic acid Lenka Krešáková, Juraj Kuchár and Juraj Černák Department of Inorganic Chemistry, Institute of Chemistry, Faculty of Sciences, P. J. Šafárik University in Košice, Moyzesova 11, 04154 Košice, Slovak Republic Article info Article history: Received: 28th February 2020 Accepted: 5th May 2020 Keywords: o-phenylenediacetic acid Crystal structure Hydrogen atom disorder Hydrogen bonded dimer Abstract H2opda (1) (o-phenylenediacetic acid) was prepared in the form of single crystals. It exhibits molecular crystal structure. The main feature of the supramolecular structure of 1 is formation of hydrogen bonded dimers via a pair of O-HO hydrogen bonds. The hydrogen atoms in COOH groups are disordered in 0.67(2):0.33(2) ratio. The conformation of the free acid is characterized by cis arrangement of the carboxylate groups with respect to the plane of the aromatic ring. The powder diffraction pattern of the bulk sample corroborated the phase identity of the commercial material with that of the studied single crystal.  University of SS. Cyril and Methodius in Trnava Introduction O-phenylenediacetic acid (H2opda) is a dicarboxylic acid which, after partial or full deprotonation, can act, in the form of Hopda(1-) or opda(2-) anions as counter anion in various salts (Imai et al. 2007; García-Zarracino et al. 2008) as well as O-donor anionic ligand in complexes. Within the complexes variable coordination fashions were reported, like terminal Hopda(1-) O-donor ligand in [Co(Hopda)2(pym)2] (pym = H- pyrazol-4-yl)methane) (Sengupta et al. 2012), bridging O,O´-donor ligand in [Cu(opda)(pipm)]4H2O (pipm = (piperazine-1,4- diyl)bis[(pyridin-4-yl)methanone) (Czarnecki et al. 2019) or bis(chelate) bridging ligand in [Cd(opda)(bimb)] (bimb = benzimidazol-1- ylmethyl)benzene) (Yu et al. 2015) to mention few examples. Although the crystal structures containing {o-C6H4(CH2-COO)2} structural fragment are rather numerous, surprisingly, upon the search in CSD (Groom et al. 2016) the crystal structure of the acid alone was not reported up to now. On the other hand, crystal structures of its isomers, namely m-phenylenediacetic acid, H2mpda (Ref-code HOFBOU) and p-phenylenediacetic acid, H2ppda (RIGXOV) were already reported (Fun et al. 2007; Zhu 2008). It is familiar that carboxylate groups, under certain condition, are able to form polymeric-like catemer chains within crystals (D’Ascenzo and Auffinger 2015). Thus comprehensive structure determination and classification of these supramolecular motifs should be of interest in pharmaceutical industry, biomolecular sciences, or crystal engineering. Similar motifs occur in the form of amino acids or motifs involving ligands bearing carboxylate groups (Modec and Klančar 2012). Following our experiments with the aim to prepare single crystals of magnetically active Ce(III) complex with opda(2-) ligand we have unexpectedly obtained single crystals of the free acid. Here we report identification, crystal, molecular and supramolecular structure of H2opda. mailto:juraj.cernak@upjs.sk Nova Biotechnol Chim (2020) 19(1): 109-115 110 Experimental Materials Cerium(III) nitrate, Ce(NO3)3, NaOH, H2pda and ethanol (99.8 %) were purchased from commercial sources and used as received. Synthesis of single crystals of H2pda To the colorless aqueous solution of Ce(NO3)3 (200 mg, 0.46 mmol, 10 mL of H2O) was added a water (15 mL) solution of H2opda (134 mg, 0.69 mmol). The formed solution with pH adjusted to pH = 3 using 0.1 mol.L-1 aqueous solution of NaOH was refluxed 90 min yielding yellow microcrystalline powder which was separated by filtration and the light yellow filtrate was left aside. After one week separated light yellow crystals (LK9) which were separated by filtration, rinsed quickly by small amounts of ethanol and diethylether and dried on air. IR (cm–1): 3065 (w), 3027 (w), 2977 (w), 2939 (w), 2654 (br), 2548 (br), 1682 (s), 1605 (w), 1493 (m), 1453 (m), 1436 (w), 1416 (m), 1394 (m), 1341 (m), 1314 (w), 1284 (w), 1252 (br), 1209 (m), 1191 (w), 1155 (s), 1095 (w), 1050 (w), 910 (br), 812 (m), 758 (m), 742 (s), 701 (s), 667 (m), 650 (m), 626 (m), 543 (m), 500 (m), 445 (m), 413 (w). 1H NMR: [ppm] 3.6 s(4H), 7.21 s(4H-Ar), 12.15 s(2H-OH) 13CNMR: [ppm] 39.5 (2xCH2), 126.9 (C4,C5), 130.6 (C3,C6), 134.09 (C1,C2), 172.4 (COOH) Physical measurements The IR were recorded on a Nicolet 6700 FT-IR spectrophotometer from Thermo Scientific equipped with a diamond crystal Smart Orbit™ in the range 4000 – 400 cm-1. NMR data were collected at room temperature on a Varian VNMRS spectrometer operating at 599.87 MHz for 1H, and 150.84 MHz for 13C. Spectra were recorded in DMSO-d6 and the chemical shifts were referenced to the residual solvent signal (1H NMR 2.50 ppm, 13C NMR 39.5 ppm). The 2D gCOSY, gHSQC and gHMBC (optimized for a long range coupling of 8 Hz) methods were employed. X–ray crystallography X–ray experiments were carried out on a four- circle -axis Xcalibur2 diffractometer equipped with a CCD detector Sapphire2 (Oxford Diffraction). The CrysAlis software package (Oxford Diffraction 2003) was used for data collection and reduction. Analytical absorption corrections using crystal faces were applied (Clark and Reid 1995). The crystal structure of H2opda was solved by direct methods and further refined using the SHELXTL and SHELXL programs (Sheldrick 2015), respectively, incorporated in the WinGX program package (Farrugia 2012). Hydrogen atoms of the aromatic ring and methylene groups were placed in the calculated positions and allowed to ride on the parent atoms with isotropic thermal parameters tied with the parent atoms (U(H) = 1.2U(CH2)). Hydrogen atoms H11 and H31 of the COOH groups involving O1 and O3 atoms, resp. were easily found in the difference map and were included in the refinement first as idealized OH groups riding on the parent O atom; their isotropic thermal parameters were tied with the parent O atoms (U(H) = 1.5U(O)). During last cycles of the refinement it was found that the differences in C-O(H) and C=O distances are rather small (see Discussion) and, in addition, in the difference map were present small maxima at the positions attributable to hydrogen atoms near (C=)O2 and (C=)O4 oxygen atoms. These findings indicated possible disorder, i.e. partial protonation of both oxygen atoms within the respective COOH groups. The adoption of this model allowed to refine occupancy factors for both orientations of protonation which converged to ratio 0.67(2):0.33(2) with refinement of the positions of hydrogen atoms; the O-H distances were restrained to 0.82(1) Å. It should be noted that the refinement program did not indicate splitting of the corresponding oxygen atoms. The structural figures were drawn using the Diamond software (Brandenburg 2008). Some geometric parameters were calculated using the PARST program (Nardelli 1999). Program Mercury CSD 4.2.0 Development (Macrae et al. 2006) was used for comparison of molecular structures. The Hirshfeld surface was calculated using the program CrystalExplorer17 (Turner et al. Nova Biotechnol Chim (2020) 19(1): 109-115 111 Table 1. Crystal data and structure refinement for H2opda. Empirical formula C10 H10 O4 Formula weight 194.18 Temperature [K] 291(2) Wavelength [Å] 0.71073 Å Crystal system Monoclinic Space group P21/n Unit cell dimensions [Å, ] a = 14.5276(15) b = 4.8274(3) c = 14.8183(13)  =118.058(13) Volume [Å3] 917.08(17) Z 4 Density (calculated) [g.cm-3] 1.406 Absorption coefficient [mm-1] 0.110 Crystal dimensions [mm3] 0.867 x 0.193 x 0.057  range for data collection [] 3.116 to 26.493 Index ranges –9  h  17, –5  k  5, –17  l  12 Reflections coll./ obs. 3078/1709 Absorption correction analytical Tmin/Tmax 0.942 / 0.994 Goodness-of-fit on F2 (all/obs.) 1.035/1.034 Final R indices [I>2(I)] R1 = 0.0349, wR2 = 0.0802 R indices (all data) R1 = 0.0508, wR2 = 0.0900 Largest diff. peak and hole [e Å–3] 0.160 and –0.145 2017). Crystal data and final parameters of the structure refinement are summarized in Table 1, while selected geometric parameters are given in Table 2. Possible hydrogen bonds are gathered in Table 3. Results and Discussion Synthesis and spectroscopic characterization Single crystals of the H2opda suitable for single crystal study were obtained unexpectedly by crystallization from the reaction mixture containing cerium nitrate, NaOH and H2opda. We note that our effort to prepare single crystals by simple recrystallization of the commercially obtained H2opda from various solvents were unsuccessful; the “best” results were obtained by recrystallization from acetone but the tiny dendritic needles were not suitable for single crystal study. The obtained single crystals of H2opda were checked by FT-IR, 1H and 13C NMR spectroscopies; the observed absorption bands and positions of the resonance pics are gathered in the experimental part. Crystal structure The crystal structure of H2opda is molecular (Fig. 1) and the unit cell contains 4 molecules of H2opda.There are three points concerning the structural results which merit some comments. The first issue concerns the C-O(H) and C=O bond distances. In H2opda the mean experimental C-O(H) and C=O bond distances are 1.277 Å and 1.248 Å, resp. (Table 2). The search in CSD (Groom et al. 2016) has shown that these values are from the ranges found for corresponding bond Table 2. Selected geometric parameters [Å, ] for H2opda. C8-O1 1.2824(17) C10-O3 1.2695(18) C8-O2 1.2473(17) C10-O4 1.2477(19) C7-C8 1.496(2) C9-C10 1.507(2) C1-C7 1.5123(19) C2-C9 1.516(2) O1-C8-O2 123.51(13) O3-C10-O4 123.50(14) Nova Biotechnol Chim (2020) 19(1): 109-115 112 Table 3. Hydrogen bonds [Å, º] in H2opda; only the thus with higher occupied hydrogen atoms are shown. D-H...A d(D-H) d(H∙∙∙A) d(D∙∙∙A) <(DHA) O1-H11∙∙∙O4i 0.827(10) 1.884(11) 2.7053(15) 172(3) O3-H31∙∙∙O2i 0.819(10) 1.841(10) 2.6598(15) 177(3) Symmetry code: i: 1 - x, 1 - y, 1 - z. distances in structures containing {C6-CH2-COOH} structural fragment (C6 is an aromatic ring with any substituent; organic structures, 198 hits), e.g. similar values of 1.279 Å and 1.247 Å were found in (2,3-dihydro-1H-benzo[b]cyclo- penta[d]furan-8-yl)acetic acid (WIDYAM) (Sun et al. 2018). On the other hand, the mean values of 1.31(2) and 1.22(2) Å for C-O(H) and C=O bonds, resp., in carboxyl-syn structural fragment were reported (D’Ascenzo and Auffinger 2015). Results of our refinement (see the Experimental part) suggest that the rather small observed differences between the C-O(H) and C=O bonds can be explained by hydrogen atom disorder within both COOH groups. Analogous hydrogen atom disorder associated with variation of the corresponding C-O(H) and C=O bonds studied by means of neutron diffraction was reported for benzoic acid (Wilson et al. 1996). The second point worth of discussion is the conformation of the H2opda molecule, more specifically, the positions of the carboxylate groups with respect to the plane of the aromatic ring. While C7 and C9 methylene carbon atoms lie almost in the plane of the aromatic ring (the Fig. 1. Thermal ellipsoid plot of the molecular structure of H2opda along with atoms numbering scheme. The thermal ellipsoids are drawn on 30 % probability level. Hydrogen atoms within the carboxylate groups are disordered (H11/H21 and H31/H41) with occupation factors in the 0.67(2):0.33(2) ratio. distances of these C7 and C9 atoms from the aromatic plane are 0.0055(16) Å (C7) and 0.0140(16) Å (C9), the C8 and C10 atoms of the carboxylate groups are both above the plane formed by the aromatic ring (cis arrangement). These positions of the carboxylate groups can be expressed by torsion angles C6-C1-C7-C8 and C1-C2-C9-C10 with values of 94.61(17) and 75.75(18)°, respectively. We note that the planes formed by carboxylate groups deviate only slightly from co-planarity as can be seen from the value of 10.74(17)° for the angle between the two planes formed by the respective {COO} groups. It may be interesting to compare the conformation of the H2opda molecule, more precisely the positions of the carboxylate groups with respect to the plane of the aromatic ring, with the corresponding structural entities in potassium salt, K(Hopda) (García-Zarracino et al. 2008) and four reported salts containing organic cations (Imai et al. 2007; Modec and Klačnar 2012; Liu et al. 2016; Lin et al. 2017). In the potassium salt, like in the free acid, both COO and COOH groups are placed in cis arrangement with respect to the aromatic plane, like in the free acid, and the Fig. 2. Comparison of the molecular structures of H2opda molecule (green) and Hopda(-) anion in K(Hopda) (red) (left), and H2opda molecule (green) and opda(2-) anion in (dpenH2)(opda)CH3OH (red) (right). The structures were superimposed in such a way that the aromatic rings are overlapped as close as possible. Nova Biotechnol Chim (2020) 19(1): 109-115 113 Fig. 3. View on the supramolecular hydrogen bonded dimers of H2opda. Only hydrogen atoms with higher s.o.f.s are shown for clarity. R1 and R2 are hydrogen bonded rings, both exhibit descriptor . Symmetry code: i: 1 - x, 1 - y, 1 - z. corresponding torsion angles of 97.3(2) and 72.1(3)° are comparable with those found in H2opda; the only difference is the slight rotation of both COO groups around the C-C single bond (see Fig. 2, left). On the other hand, in all four salts with organic cations, the two acetate groups are oriented in the space oppositely, i.e. one is situated above and the second below the plane of the aromatic ring (trans arrangement). As an example we can mention (dpenH2)(opda)CH3OH (dpenH2 2+ = (1R,2R)-1,2- diphenylethylenediammonium dication) (Imai et al. 2007) in which the corresponding torsion angles are 97.83 and -83.12°; the structure overlay of the anion opda(2-) in this salt with H2opda is shown on Fig. 2 (right). It seems the {opda} structural fragment due to its flexibility as to the rotation around methylene group is enough flexible to form in the crystalline state conformation leading to maximization of the lattice energy. The third point to mention is the formed supramolecular structure. Two molecules of H2opda, the asymmetric one and its congener by center of symmetry, are linked by a pair of relatively strong hydrogen bonds of the O-H···O type yielding supramolecular dimers (H2opda)2 (Table 3, Fig. 3); the hydrogen bonded ring systems can be described using descriptor according to Graph Set Analysis (Bernstein et al. 1995). We note that no stacking interactions (the shortest distance between the centers of gravity of the aromatic ring is 4.7856(5) Å) nor Car-H···O weak hydrogen bonds were found, so the formed supramolecular dimers interact only by weak intermolecular interactions of van der Waals nature. The shortest contact is the distance of 2.60 Å between (C7-)H7A hydrogen atom from methylene group and O2ii (ii: x, 1 + y, z) atom from carboxylate group (C7O2 distance is 3.4884(4) Å). Accordingly, the calculated Hirshfeld surface of the supramolecular dimer is featureless and the very weak pink colored circles correspond to the above mentioned contacts (Fig. 4, upper). Fig. 4. Upper: Hirshfeld surface of the hydrogen bonded dimers [H2opda]2. Lower: Hirshfeld surface of the H2opda molecule. The hydrogen bonded congener molecule (ball model) is also shown. Hydrogen bonds leading to dimerization are shown as green dashed lines. Nova Biotechnol Chim (2020) 19(1): 109-115 114 Fig. 5. Packing diagram of H2opda. On the Fig. 4 (lower) is shown the Hirshfeld surface of the H2opda molecule alone clearly displaying the red spots which reflect the formation of O-H···O type hydrogen bonds. The Fig. 5 shows the packing of the supramolecular dimers. Conclusions Single crystals of H2opda crystallized from the reaction mixture formed of cerium(III) nitrate, NaOH and H2opda. Their chemical identity was corroborated by spectroscopic methods. Single crystal X-ray structure analysis confirmed the molecular structure of the free acid with cis arrangement of the two acetate groups with respect to the aromatic plane. Results of the structure analysis indicate hydrogen atom disorder in ratio 33 and 67 % within the carboxylate groups. Two H2opda molecules are linked by a pair of O- H···O type hydrogen bonds yielding supramolecular dimers, which are linked only by weak intermolecular interactions. Supporting Information Crystallographic data for the compound H2opda has been deposited with the Cambridge Crystallographic Data Centre, CCDC 1981160. Copies of the information may be obtained free of charge from The Director, CCDC, 12 Union Road, Cambridge, CB21EZ, UK (fax: +44–1223–336033; e-mail: deposit@ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk). Acknowledgement This work was supported by the Slovak grant agencies APVV-18-0016 and VEGA 1/0063/17. We thank Dr. Vilková for measuring the NMR spectra. 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