Molecular Complexes of Some Mono- and Dicarboxylic Acids with trans-1,4-Dithiane-1,4-dioxide V. S. Senthil
Kumar,†
Ashwini
Nangia,*,†
Amy K.
Katz,‡
and H. L.
Carrell‡
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India, and Institute for Cancer Research, Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, Pennsylvania 19111 Received April 19, 2002;
CRYSTAL GROWTH & DESIGN 2002 VOL. 2, NO. 4 313-318
Revised Manuscript Received May 13, 2002
W This paper contains enhanced objects available on the Internet at http://pubs.acs.org/crystal. ABSTRACT: Crystallization of carboxylic acids with molecules containing complementary hydrogen bonding groups, e.g., 4,4′-bipyridine, phenazine, and 2-pyridone, is an active pursuit in crystal engineering. We describe in this paper an addition to this family of spacer ligands, trans-1,4-dithiane-1,4-dioxide 4, a molecule that forms complexes with carboxylic acids via O-H‚‚‚O and C-H‚‚‚O hydrogen bonds. Analysis of hydrogen bonding in the molecular complexes of 5-nitrosalicylic acid 6, 3,5-dinitrosalicylic acid 7, succinic acid 8, and oxalic acid 9 with disulfoxide 4 shows that these crystal structures are stabilized by acid-sulfoxide and sulfoxide-sulfoxide supramolecular synthons XII and XIII. The preference for acid-sulfoxide recognition in crystals is explained through database analysis and energy computation. Introduction The carboxylic acid group is an important hydrogen bonding functional group in crystal engineering.1 Carboxylic acids aggregate in the solid state as dimer I, catemer II, and bridged motifs III and IV (Scheme 1).2 In a recent survey of the Cambridge Structural Database (CSD),3 it was found that the dimer synthon I occurs with a probability of 33% in crystal structures containing the CO2H group.4 Recognition of CO2H functional group with other complementary groups is more frequent, e.g., acid-pyridine O-H‚‚‚N hydrogen bond is found in 90% crystal structures that have the constituent moieties.5 Thus, it is profitable to carry out premeditated crystal design not only with carboxylic acids2d,e but, as recent trends indicate,6 by exploiting the robust recognition of carboxylic acids with Nheterocyclic moieties. In this context, 4,4′-bipyridine 1, phenazine 2, and 2-pyridone 3 (Scheme 2) have emerged as important complementary ligands for the crystal engineering of carboxylic acids. For example, Zaworotko7 and Jones8 have used 4,4′-bipyridine to prepare cocrystals of di- and tricarboxylic acids, Jones9 and Desiraju10 have shown the utility of cocrystallization with phenazine and pyridine to facilitate solubilization of insoluble and intractable compounds, and Aa¨keroy11 and Jones12 have studied hydrogen bond networks in cocrystals of dicarboxylic acids with 2-pyridone. A common theme in the crystal structures of these molecular complexes is that the ligands in Scheme 2 act as hydrophobic spacers and connect carboxylic acid groups via strong O-H‚‚‚O or O-H‚‚‚N hydrogen bonds, usually in centrosymmetric patterns. Some common hydrogen bond synthons13 of carboxylic acid with complementary functional groups, e.g., V-VIII, are displayed in Scheme 3. * To whom correspondence should be addressed. E-mail: ansc@ uohyd.ernet.in. † University of Hyderabad. ‡ Fox Chase Cancer Center.
Scheme 1. Some Common Hydrogen Bond Synthons of the Carboxylic Acid Functional Group
Scheme 2. Some Important N-Heterocycles Used in the Crystal Engineering of Carboxylic Acids
We describe in this paper a novel hydrogen bond spacer ligand for carboxylic acids, trans-1,4-dithiane1,4-dioxide 4.14 The genesis for the design of molecule 4 relates to a recent CSD study on pseudopolymorphism in organic crystals.15 In this analysis, we noted that dimethyl sulfoxide (DMSO) has the second highest tendency for inclusion in crystals, a property that is attributed to multipoint recognition between solvent and solute via synthon IX mediated by strong O/N-H‚‚‚O and weak C-H‚‚‚O hydrogen bonds. Such two-point recognition is particularly common in the DMSO solvates of carboxylic acids, synthon X, as pointed out by Weber many years ago.16 More recent CSD analysis shows that recognition between CO2H and SdO groups via O-H‚‚‚OdS hydrogen bonding is favored in over
10.1021/cg025523s CCC: $22.00 © 2002 American Chemical Society Published on Web 05/25/2002
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Table 1. Crystallographic Data of Complexes (6)(4)0.5
(8)(4)
empirical formula
(C7H5NO5) (C4H8O2S2)0.5
(C4H6O4)0.5 (C4H8O2S2)0.5
(C7H4N2O7) (C4H8O2S2)
crystallized from space group a [Å] b [Å] c [Å] R [deg] β [deg] γ [deg] volume [Å3] Z λ [Å] Dcalc [g/cm3] 2θmax range h range k range l reflns. collected unique reflns. observed reflns. no. of parameters R1 [I > 2σ(I)]a wR2 T [K] diffractometer
dioxane P21/c 6.5864(13) 23.353(5) 7.0345(14) 90 96.07(3) 90 1075.9(4) 4 0.71073 1.600 55.92 0 to 8 0 to 30 -9 to 9 2781 2577 1264 182 0.0448 0.0998 293 Enraf-Nonius MACH-3 1.094 71.2
water P1 h 6.2210(12) 6.5660(13) 7.6850(15) 89.78(3) 79.36(3) 64.55(3) 277.56(9) 2 0.71073 1.617 56.52 0 to 8 -7 to 8 -10 to 10 1335 1335 1278 94 0.0364 0.0967 120 Nonius FAST area detector 1.116 74.0
1:1 water/EtOH P21/n 13.766(3) 6.2818(13) 18.675(4) 90 111.53(3) 90 1502.3(5) 4 0.71073 1.682 54.94 0 to 17 0 to 8 -24 to 22 3578 3438 2691 253 0.0450 0.1199 293 Enraf-Nonius MACH-3 1.041 72.3
goodness of fit Ck *[%]b a
(7)(4)
(9)(4)(dihydrate) (C2H2O4)0.5 (C4H8O2S2)0.5 (H2O) water P1 h 6.2640(13) 6.6570(13) 7.6130(15) 100.12(3) 97.09(3) 114.20(3) 278.22(10) 2 0.71073 1.661 56.54 0 to 8 -8 to 8 -10 to 9 1340 1340 1305 97 0.0383 0.1001 120 Nonius FAST area detector 1.105 74.1
Crystallographic reliability index. b Packing fraction (calculated in PLATON).23
Scheme 3. Hydrogen Bond Synthons of Carboxylic Acids with Complementary Molecules 1-3
75% cases.5 Another common aggregation motif in DMSO solvates is the C-H‚‚‚O hydrogen bonded dimer XI, also found in the crystal structure of pure DMSO.17 The utility of DMSO in promoting crystallization and the specific role of hydrogen bonding in the solvates of DMSO continue to be reported.18 These studies encouraged us to view disulfoxide 4 as a dimer of DMSO and explore its ability to form hydrogen bonded complexes with carboxylic acids. Further, disulfoxide 4 may be viewed as a C-H‚‚‚O surrogate of 2,5-piperazinedione 5, a diketopiperazine that has been used in the literature to prepare complexes with salicylic acid and formic acid.19 We report in this paper molecular complexes of disulfoxide 4 with 5-nitrosalicylic acid 6, 3,5-dinitrosalicylic acid 7,20 succinic acid 8, and oxalic acid 9, as characterized by single-crystal X-ray diffraction.
Experimental Section Synthesis. trans-1,4-Dithiane-1,4-dioxide, 4.14a To a solution of 1,4-dithiane (1.2 g, 10 mmol) in glacial acetic acid (20 mL) was added 30% H2O2 (2.4 mL, 20 mmol). The mixture was allowed to stand at room temperature for 24 h. Removal of acetic acid followed by successive crystallization from 1:1 aq. EtOH yielded pure trans-1,4-dithiane-1,4-dioxide 4. The compound decomposes at 252 °C. IR (KBr) 3485, 1618, 1400, 1014, 628 cm-1. 3,5-Dinitrosalicylic Acid, 7.21 A total of 22.5 g of conc. H2SO4 and 4.5 g of conc. HNO3 were mixed and cooled in ice water. Salicylic acid (4.5 g, 32 mmol) was added in small portions keeping the reaction mixture well cooled. After all the salicylic acid was added, the material was poured into ca. 250 mL of water, cooled in ice, and filtered off by suction. The crude compound was dissolved by heating in dil. Na2CO3 solution, filtered, and salted out by adding a large excess of sat. Na2CO3 solution followed by cooling. The sodium salt was filtered, washed with sat. Na2CO3 solution, dissolved in hot water, any insoluble impurities filtered off, and precipitated as the free acid by adding a large excess of conc. HCl. Suction filtration of 7 and recrystallization from hot water gave the moist acid that was dried at 100 °C. m.p. 169-171 °C; IR (KBr) 1676, 1608, 1533, 1338 cm-1. (5-Nitrosalicylic Acid)(trans-1,4-Dithiane-1,4-dioxide), (6)(4)0.5. A mixture of 3,5-dinitrosalicylic acid hydrate, 7 as prepared above, (61.5 mg, 0.25 mmol) and 1,4-dithiane (15 mg, 0.125 mmol) was dissolved in 5 mL of hot dioxane with the idea of obtaining (7)(dithiane) crystals.20 X-ray diffraction showed these crystals to have the composition (6)(4)0.5. Dithiane is oxidized to disulfoxide 4 in air, which then crystallizes in situ with 5-nitrosalicylic acid 6, present as an impurity in 7. m.p. 231-234 °C. (Succinic Acid)(trans-1,4-Dithiane-1,4-dioxide), (8)(4). A 1:1 mixture of succinic acid (118 mg, 1 mmol) and trans1,4-dithiane-1,4-dioxide (152 mg, 1 mmol) was dissolved in cold water. Platelike, colorless crystals were collected after two weeks. m.p. 198-200 °C; IR (KBr) 3414, 1705, 1402, 1309, 1190, 993 cm-1. (3,5-Dinitrosalicylic Acid)(trans-1,4-Dithiane-1,4-dioxide), (7)(4). A powdered mixture of 3,5-dinitrosalicylic acid
Carboxylic Acids with trans-1,4-Dithiane-1,4-dioxide
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Table 2. Metrics of Hydrogen Bonds complex (6)(4)0.5
(8)0.5(4)0.5
(7)(4)
(9)0.5(4)0.5(H2O)
H-bonda
d (Å)
D (Å)
θ (deg)
(a) O-H‚‚‚O (b) C-H‚‚‚O (c) C-H‚‚‚O (d) C-H‚‚‚O (e) O-H‚‚‚O (a) O-H‚‚‚O (b) C-H‚‚‚O (c) C-H‚‚‚O (d) C-H‚‚‚O (e) C-H‚‚‚O (a) O-H‚‚‚O (b) C-H‚‚‚O (c) C-H‚‚‚O (d) C-H‚‚‚O (e) O-H‚‚‚O (a) O-H‚‚‚O (b) O-H‚‚‚O (c) C-H‚‚‚O (d) O-H‚‚‚O (e) C-H‚‚‚O
1.58 2.97 2.46 2.77 1.73 1.64 2.54 2.23 2.74 2.45 1.58 2.39 2.58 2.40 1.67 1.57 1.73 2.82 1.94 2.27
2.554(3) 3.752(3) 3.479(3) 3.833(4) 2.591(3) 2.625(2) 3.385(2) 3.297(2) 3.512(2) 3.405(2) 2.542(3) 3.346(4) 3.466(4) 3.276(3) 2.543(3) 2.544(2) 2.716(2) 3.494(2) 2.918(2) 3.268(3)
169.7 125.6 154.8 165.9 143.4 176.5 123.9 166.2 127.8 146.0 163.0 145.2 138.2 136.9 145.1 169.9 174.8 120.0 171.0 151.1
a O-H and C-H distance are neutron normalized (0.983, 1.083 Å).
(114 mg, 0.5 mmol) and trans-1,4-dithiane-1,4-dioxide (38 mg, 0.25 mmol) was dissolved in hot water and kept at 80 °C for 2 days to get a pale-yellow solid. Platelike crystals of the complex were obtained when the solid was recrystallized from 1:1 water/EtOH. m.p. 200-204 °C; IR (KBr) 1678, 1601, 1529, 1338, 1261, 1016 cm-1. (Oxalic Acid)(trans-1,4-Dithiane-1,4-dioxide)(dihydrate), (9)0.5(4)0.5(H2O). Colorless, platelike crystals of the complex were obtained upon crystallization of equimolar amounts of oxalic acid (90 mg, 1 mmol) and trans-1,4-dithaine1,4-dioxide (152 mg, 1 mmol) from 5 mL of water. The complex decomposes at 240 °C. IR (KBr) 3489, 1697, 1217, 1018 cm-1. X-ray Crystallography. Data on crystals of (6)(4)0.5 and (7)(4) were collected on Enraf-Nonius MACH-3 diffractometer (Hyderabad) and on crystals of (8)(4) and (9)(4)(dihydrate) on Nonius FAST area detector instrument (Philadelphia). The incident radiation is Mo-KR X-ray (λ ) 0.71073 Å) on both instruments. Data on crystals of (6)(4)0.5 and (7)(4) were collected at 293 K, and crystals of (8)(4) and (9)(4)(dihydrate) were cooled to 120 K with the MSC liquid nitrogen system low-temperature device attached to the diffractometer. Structure solutions and refinements of all crystal structures were performed with the SHELX97.22 Geometrical analysis were carried out with PLATON23 on Silicon Graphics workstation. Selected crystallographic parameters and hydrogen bond metrics in the four crystal structures are summarized in Tables 1 and 2.
Results and Discussion We describe in this paper the crystal structure of the molecular complexes of disulfoxide 4 with 5-nitrosalicylic acid 6, 3,5-dinitrosalicylic acid 7, succinic acid 8, and oxalic acid 9, the last crystal being obtained as a hydrate. It is pertinent to mention here that cocrystallization was attempted with a large number of monoand dicarboxylic acids (e.g., benzoic acid, chloroacetic acid, malonic acid, adipic acid and squaric acid), but diffraction quality crystals were obtained in the above four cases only. Crystals of stoichiometry (7)(4), (8)0.5 (4)0.5, and (9)0.5(4)0.5(H2O) were obtained by crystallization from aqueous medium. Crystals of (6)(4)0.5 composition were obtained in a related experiment on the cocrystallization of 7 with dithiane from dioxane solvent. Instead of the expected (7)(dithiane) complex,20 (6)(4)0.5 crystallized from hot dioxane. We believe that dithiane is air-oxidized to the disulfoxide during
Figure 1. Crystal structure of (5-nitrosalicylic acid)(trans1,4-dithiane-1,4-dioxide)0.5, (6)(4)0.5. Note the role of synthon XII in stabilizing the molecular complex. Hydrogen bonds between CO2H and CH2SdO moieties are shown as bold dotted lines and other O-H‚‚‚O, C-H‚‚‚O bonds as normal dotted lines, in this and subsequent figures. Refer to Table 2 for the metrics of interactions (a), (b), (c), etc. W A 3D rotatable image in PDB format is available.
Scheme 4. trans-1,4-Dithiane-1,4-dioxide 4 Discussed in This Paper, and Hydrogen Bond Synthons Common to Dimethyl Sulfoxide
crystallization and that 4 forms the complex with minor amounts of 6, present as an impurity in 7. Attempted cocrystallization of 6 and 4 in an independent experiment, however, did not yield any crystals (see Experimental Section for details). The exact reason why additives and impurities promote crystallization of elusive forms is not fully understood.24 For example, in a previous study we noted that the 1:1 complex of CCl4 and tetraphenylmethane was obtained when complexation of SnI4 with tetraphenylmethane in CCl4 solvent was carried out; no crystals were obtained when SnI4 was absent.24a (5-Nitrosalicylic Acid)(trans-1,4-Dithiane-1,4dioxide), (6)(4)0.5. The crystal structure of (6)(4)0.5 in space group P21/c is displayed in Figure 1. Interestingly, the expected recognition between the carboxylic acid and disulfoxide via synthon XII is present (Scheme 5). Synthon XII may be viewed as a homologous dimeric extension of synthon X, thereby justifying the rationale for studying disulfoxide 4 based on the hydrogen bond motifs of DMSO (Scheme 4). The metrics of O-H‚‚‚O and C-H‚‚‚O hydrogen bonds in XII are listed in Table 2 (1.58 Å, 169.7°; 2.97 Å, 125.6°; neutron-normalized geometry). Although the auxiliary C-H‚‚‚O interaction is long and bent, it is within the accepted distance-angle limit for weak hydrogen bonds advocated by Desiraju and Steiner.25 The OH donor in 6 is intramolecularly hydrogen bonded to the carbonyl group (1.73 Å, 143.4°).
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Scheme 5. O-H‚‚‚O and C-H‚‚‚O Hydrogen Bond Synthon of Carboxylic Acids with 4 (XII) and between Molecules of 4 (XIII)
The acid-disulfoxide aggregates are held together by C-H‚‚‚O interactions (c) and (d) (see Table 2 and Figure 1). (Succinic Acid)(trans-1,4-Dithiane-1,4-dioxide), (8)0.5(4)0.5. The crystal structure of (8)(4) in space group P1 h contains infinite tapes of diacid and disulfoxide molecules mediated by synthon XII (O-H‚‚‚O: 1.64 Å, 176.5°; C-H‚‚‚O: 2.54 Å, 123.9°; Figure 2). Such tapes are in turn connected by C-H‚‚‚O interactions (c), (d), and (e) (Table 2) in the lateral direction to produce an undulated sheetlike structure. In effect, the finite motif of synthon XII in (6)(4)0.5 is replaced by the infinite 1D tape in this structure by the dicarboxylic acid. The fortuitous size-match between the two components, diacid 8 and disulfoxide 4, is responsible for the regular linear arrays and their extension into 2D hydrogen bond networks. A proper matching of molecular dimensions resulting in unique crystal packing has been noted earlier in some diamides, e.g., succinamide, acetylenedicarboxamide, and fumaramide.26 (3,5-Dinitrosalicylic Acid)(trans-1,4-Dithiane1,4-dioxide), (7)(4). In this complex (space group P21/ n), disulfoxide molecules self-associate via C-H‚‚‚O dimer synthon XIII to form a linear tape. The molecule of 4 occupies a general position, and there are two inversion-related tapes connected via C-H‚‚‚O interactions (c) and (d) (Table 2). Such a zigzag pattern of C-H‚‚‚O hydrogen bonds is found in the crystal structure of pure trans-1,4-dithiane-1,4-dioxide.14b The 1D tapes of 4 act as spacers between molecules of acid 7 such that the CO2H group is hydrogen bonded to different molecules of 4, as displayed in Figure 3 (O-H‚‚‚O: 1.58 Å, 163.0°; C-H‚‚‚O: 2.39 Å, 145.2°).
Figure 2. Crystal structure of (succinic acid)(trans-1,4dithiane-1,4-dioxide), (8)0.5(4)0.5. The finite pattern of synthon XII in Figure 1 is extended into an infinite 1D tape by the dicarboxylic acid. Note the size-match between the two molecular components. W A 3D rotatable image in PDB format is available.
Figure 3. Crystal structure of (3,5-dinitrosalicylic acid)(trans1,4-dithiane-1,4-dioxide), (7)(4). Inversion-related zigzag tapes of disulfoxide molecules (shaded differently) formed via synthon XIII (interactions (c) and (d)) act as spacers between the acid molecules. Note that the O-H‚‚‚O and C-H‚‚‚O hydrogen bonds between CO2H and CH2SdO moieties are made to different molecules of 4. W A 3D rotatable image in PDB format is available.
Figure 4. Crystal structure of (oxalic acid)(trans-1,4-dithiane1,4-dioxide)(dihydrate), (9)0.5(4)0.5(H2O). The acid-sulfoxide recognition is interrupted with a water molecule (bold dotted lines) that plays the dual role of connecting translation-related oxalic acid molecules via hydrogen bond (d). The 1D linear tape of disulfoxide molecules (synthon XIII) connects inversionrelated oxalic acid hydrate molecules into a 2D layer. W A 3D rotatable image in PDB format is available.
This type of acid-disulfoxide recognition is similar to that observed in complexes of 2-pyridone, e.g., synthon VIII. The OH group in 7 is intramolecularly hydrogen bonded (1.67 Å, 145.1°). The 1D tape constructed with synthon XII in (8)(4) and with synthon XIII in this crystal structure may be viewed as linear extensions of finite patterns X and XI. (Oxalic Acid)(trans-1,4-Dithiane-1,4-dioxide)(dihydrate), (9)0.5(4)0.5(H2O). The inclusion of water in this ternary complex (space group P1 h ) is not surprising because oxalic acid crystallizes as a dihydrate.27 Once again, the linear tape of disulfoxide molecules mediated by synthon XIII acts as a hydrophobic spacer between hydrated oxalic acid molecules (Figure 4). Thus, the CO2H group is bonded to water, which in turn is bonded to a sulfoxide group (O-H‚‚‚Ow: 1.57 Å, 169.9°; Ow-H‚‚‚O: 1.73 Å, 174.8°). Translation-related oxalic acid molecules are connected by Ow-H‚‚‚O hydrogen bonds (1.94 Å, 171.0°). This termolecular aggregate is
Carboxylic Acids with trans-1,4-Dithiane-1,4-dioxide
further stabilized by weak C-H‚‚‚O hydrogen bonds (Table 2). The involvement of hydrophobic spacer molecule in the hydrogen bond networks of Figure 4 suggests that solubilization of water-soluble carboxylic acids in organic medium should be possible through complexation with disulfoxide 4. Acid-Sulfoxide Synthon X: Database Analysis and Computation. The occurrence of O-H‚‚‚O and C-H‚‚‚O hydrogen-bonded synthon X between carboxylic acid and methylene sulfoxide groups was examined in the CSD (ConQuest 1.4, April 2002, 257 162 entries).3 A sub-database of organic structures that contain CO2H and CH2SdO moieties with no disorder, 3D coordinates determined, no errors, no ions, not polymeric, and with R factor < 0.10 was created (48 hits, duplicate refcodes removed). A search of these 48 crystal structures was carried out for the occurrence of synthon X in the distance-angle range: 1.5 < O-H‚‚‚O < 2.2 Å, 140 < ∠O-H‚‚‚O < 180° and 2.0 < C-H‚‚‚O < 3.0 Å, 120 < ∠C-H‚‚‚O
