Crystal Engineering of Organic Salts: Hydrogen-Bonded Supramolecular Motifs in Trimethoprim Sorbate Dihydrate and Trimethoprim o-Nitrobenzoate S. Baskar Raj,† N. Stanley,† P. Thomas Muthiah,*,† G. Bocelli,‡ R. Olla´,‡ and A. Cantoni‡
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Department of Chemistry, Bharathidasan University, Tiruchirappalli-620 024, India, and IMEM-CNR, Parco Area delle Scineze, 17/a, 1-43100 Parma, Italy Received September 11, 2002
ABSTRACT: In the crystal structures of two organic salts, namely, trimethoprim sorbate dihydrate (1) and trimethoprim o-nitrobenzoate (2), the pyrimidine moieties of trimethoprim are protonated at one of the ring nitrogens. In both the compounds, the carboxylate oxygens are hydrogen-bonded to the protonated pyrimidine rings to form the hydrogen-bonded cyclic bimolecular motif. These motifs further self-organize in two different ways to give different types of hydrogen-bonded networks in the two crystal structures. In compound 1, the two inversion related motifs pair through a pair of N-H‚‚‚N hydrogen bonds involving an unprotonated ring nitrogen and 4-amino group. In addition to this pairing, one of the water oxygens bridges the 2- and 4-amino groups on both sides of pairing to form a complementary DADA (D refers to the hydrogen-bond donor and A refers to the hydrogen-bond acceptor) array of quadruple hydrogen bonds. In compound 2, there is no base-pairing, and the cyclic hydrogen-bonded bimolecular motifs self-assemble into a hydrogen-bonded supramolecular ladder through N-H‚‚‚O and C-H‚‚‚O hydrogen bonds. The o-nitrobenzoate ions form a supramolecular chain, the ions being linked by aromatic C-H‚‚‚O (of the nitro group) hydrogen bonds. Introduction The hydrogen bond, as compared to other forces of interaction, has made it the most important interaction in molecular recognition because of its strength and directionality.1 The crystal itself with the molecules acting as nodes and their interactions acting as the nodal connectivities can act as a supramolecule.2 Crystal engineering,3 a subdiscipline of supramolecular chemistry, deals with the construction of crystalline materials from molecules or ions using noncovalent interactions.4 The intermolecular interactions of these crystalline materials are very much useful as a gas storage device, a sensor, or even as an optical switch, which are attractive materials for use in solar cells. The design of a number of supramolecular nano architectures, layers, ribbons, rosettes, rods, tapes, tubes, sheets, and spheres can be achieved through N-H‚‚‚O and O-H‚‚‚O hydrogen bonds.5,6 Some of the hydrogen-bonded, frequently occurring motifs leading to supramolecular architectures play a significant role in crystal engineering.7,8 In addition to N-H‚‚‚O, N-H‚‚‚N, and O-H‚‚‚O hydrogen bonds, the weak C-H‚‚‚O hydrogen bonds also play an important role in further stabilizing the 3-D network structures. In this paper, we are reporting the hydrogenbonding patterns observed in the crystal structures of two carboxylate complexes of trimethoprim (TMP), a diaminopyrimidine. Trimethoprim [2,4-diamino-5-(3′,4′,5′trimethoxybenzylpyrimidine)] is a very good antifolate drug. It selectively inhibits the bacterial species of the dihydrofolate reductase (DHFR) enzyme.9 The protonated aminopyrimidine moiety of the drug trimethoprim * To whom correspondence
[email protected]. † Bharathidasan University. ‡ Parco Area delle Scineze.
should
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makes a pair of N-H‚‚‚O hydrogen bonds with one of the carboxylate group of the enzyme DHFR.10 The similar type of N-H‚‚‚O hydrogen bonds has also been observed in protein-nucleic acid interactions11 (the protonated cytosine in nucleic acid can interact with the carboxylate group of the protein). Crystal engineering involving diaminopyrimidine-carboxylate interactions are of current interest. The various hydrogen-bonding patterns of trimethoprim (TMP) hydrogen glutarate,12 trimethoprim hydrogen maleate,13 trimethoprim trifluoroacetate,14 trimethoprim salicylate methanol solvate,15 trimethoprim formate,16 trimethoprim perchlorate,17 trimethoprim salicylate dihydrate,18 trimethoprim sulfate trihydrate,19 trimethoprim sulfonates,20 two pseudo-polymorphic forms of trimethoprim m-chlorobenzoate,21 trimethoprim nitrate,22 and trimethoprim terephthalate terephthalic acid23 have already been reported from our laboratory. These studies have advanced our understanding of hydrogen-bonding and interactions for the construction of structures with varied architecture. Experimental Procedures Compounds 1 (trimethoprim sorbate dihydrate) and 2 (trimethoprim o-nitrobenzoate) were prepared by mixing a hot aqueous solution of trimethoprim (Shilpa Antibiotics Ltd., India) with hot aqueous solutions of sorbic acid or o-nitrobenzoic acid (s.d. Fine Chemicals, India) in a 1:1 molar ratio. The resultant mixtures were cooled slowly at room temperature. After a few days, blocks of colorless crystals (1 and 2) were obtained. The crystal data and details of the structure determination are given in Table 1.
Results and Discussion An ORTEP view of the title compounds 1 and 2 are shown in Figure 1. In both the structures, the pyrimi-
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Figure 1. ORTEP view of compound 1 (a) and 2 (b). Ellipsoids are drawn at the 50% probability level. Table 1. Crystallographic Parameters for 1 and 2 properties formula M crystal system space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z radiation (Å) T (K) Dc (g cm-3) µ (mm-1) F (000) reflections collected observed data (I > 2σ(I)) parameters refined final R1 on observed data final wR2 on observed data structure solution structure refinement graphics
1
2
C14H19N4O3‚ C6H7O2‚ 2(H2O) 438.48 triclinic P1 h 10.769(3) 13.308(3) 8.282(2) 90.72(3) 104.93(3) 93.72(2) 1143.9(5) 2 0.71069 293(2) 1.273 0.097 468 6659 2915
C14H19N4O3‚ C7H4NO4 457.44 orthorhombic Pbca 14.499(2) 27.268(3) 10.958(3) 90.00 90.00 90.00 4332.3(14) 8 0.71069 293(2) 1.403 0.107 1920 4720 1462
400 0.0416
390 0.0388
0.0857
0.0653
SHELXS9735 SHELXL9736 PLATON37
SHELXS9735 SHELXL9736 PLATON37
dine moieties are protonated at N1 leading to an enhancement of internal angles at N1 [C-N1-C6, 119.4(9)° for 1 and 119.2(3)° for 2] as compared with the neutral TMP.24 In DHFR-TMP complexes, the drug moiety is also protonated at the N1 position. The dihedral angle between the pyrimidine and the phenyl rings is 81.77(8)° in compound 1, and the corresponding value for compound 2 is 87.2(2)°. The conformation of the TMP moiety can be explained by the two torsion
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angles τ1 (C4-C5-C7-C8) and τ2 (C5-C7-C8-C13). The corresponding angles are 68.2(2) and -154.6(2)° in compound 1 and 72.4(4) and -144.1(3)° in compound 2. The schematic representation of the different types of hydrogen-bonded motifs I-VII observed in this study is shown in Figure 2. Almost in all diaminopyrimidinecarboxylate complexes, the oxygens of the carboxylate group interact with the protonated ring nitrogen (N1) and 2-amino group of the pyrimidine moiety through a pair of N-H‚‚‚O hydrogen bonds as shown in motif I. Both the structures, compounds 1 and 2, have this type of interaction, which is reminiscent of DHFR-TMP complexes.9 This motif I, one of the 24 recurrent hydrogen-bonded cyclic bimolecular motifs,25 self-organizes itself or in association with other hydrogenbonding patterns produces the various hydrogen-bonded molecular architectures (motifs II-IV). [Three kinds of base-pairing patterns (types 1-3) involving N-H‚‚‚N hydrogen bonds are possible in the crystal structures of diaminopyrimidine compounds. Types 1 and 2 are simultaneously present in the crystal structures of TMP24 and pyrimethamine26 resulting in a hydrogenbonded supramolecular ribbonlike pattern. In protonated diaminopyrimidines, type 1 pairing cannot occur since the N1 is the protonation site. Type 3 is present in many of the TMP salts reported from our laboratory.] In addition to the base-pairing, a hydrogen-bonded acceptor X (X ) oxygen of the water molecule in compound 1) bridges the 4- and 2-amino groups on both sides of pairing leading to a complementary linear DADA (D refers to the hydrogen-bond donor and A refers to the hydrogen-bond acceptor) array of quadruple hydrogen bonds with the rings having the graph-set27,28 notations R32(8), R22(8), and R32(8). The motif II occurs in the crystal structure of compound 1. It is interesting to note that the architecture represented by motif II is a recurring motif: X ) O of a methoxy group in TMP perchlorate17 (here perchlorate anion mimics the role of carboxylate anion), X ) O of carboxylate in TMP hydrogen maleate,13 X ) O of methanol in TMP salicylate methanol solvate,15 X ) O of the carboxylate in pyrimethamine hydrogen glutarate,29 X ) O of carboxylate in pyrimethamine formate,29 and X ) O of sulfonate in trimethoprim p-toluenesulfonate.20 Motif I can also self-organize to give the molecular architecture (motif III) where pairing involves the 2-amino group and the ring nitrogen (N3). A hydrogenbond acceptor (X) can bridge the 4-amino group of a pyrimidine and a 2-amino group of another pyrimidine leading to the DADA array of quadruple hydrogen bonds, with R32(8), R22(8), and R32(8) rings. This type of base-pairing leading to the DADA array has been observed in copper(II)-phthalate:trimethoprim(0.5:1:1) complex.30 In motif IV, there is no pairing of the pyrimidine ring, but two of the building motifs I interact sidewise to produce the DDAA array of quadruple hydrogen bonds.31,39 This motif IV has also been identified in TMP hydrogen glutarate12 and TMP formate.16 The three rings in this DDAA array of quadruple hydrogen bonds can be represented by the graph-set notation R22(8), R42(8), and R22(8). Sorbate anion is an antibacterial agent and widely used as a preservative.32 The sorbate moiety lies in the
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Figure 2. Schematic diagram of hydrogen-bonded motifs (CCDC192775 for compound 1 and CCDC192776 for compound 2). (a) Three types of pairing observed in the diaminopyrimidine complexes. (b) Some of the hydrogen-bonded motifs observed in the TMP complexes.
EE configuration. The extended conformation of the sorbate anion can be inferred from the four torsion angles (C17-C18-C19-C20) -179.0(2)°, (C18-C19C20-C21) -178.8(2)°, (C19-C20-C21-C22) -179.6(2)°, and (O5-C17-C18-C19) 176.5(19)°. A supramolecular chain (as shown in motif V) built from a repeating motif made up of a chloride/bromide ion and two water molecules has been already reported from our laboratory.33 Here in compound 1, the carboxylate group of the sorbate anion (O4 and O5) plays the role of the halide ion and interacts with the two water molecules forming a hydrogen-bonded supramolecular chain as shown in motif VI. This supramolecular chain along the c axis as observed in the lattice is shown in Figure 3. In addition to the DADA array of quadruple hydrogen bonds in (motif II) compound 1, the C6 atom of one TMP moiety is hydrogen-bonded to the methoxy oxygen of another TMP in an inversion-related manner forming a dimer-like arrangement. Thus, the combination of an alternative arrangement of a DADA array and hydrogen-bonded dimer leads to the supramolecular network structure as shown in Figure 4. The phenyl rings of the TMP moieties are stacked one over another. The centroid-to-centroid and the interplanar distances are 4.09(14) and 3.49(7) Å, respectively. The slip angle (between the centroid vector and normal to the plane) is 31.3(3)°. A view of the packing is shown in Figure 5. In compound 2, none of the patterns represented by motifs II-IV occur. But a supramolecular ladder is made up of a self-organization of screw-related motifs I through N-H‚‚‚O and C-H‚‚‚O hydrogen bonds [N2H2A‚‚‚O5, 2.824(4) Å and C-H6‚‚‚O4, 3.191(4) Å] as
Figure 3. Hydrogen-bonded supramolecular chain made up of carboxylate groups and water molecules along the c axis.
shown in motif VII. The ladder observed in the lattice is shown in Figure 6. The self-organization of screwrelated motifs I leading to the hydrogen-bonded supramolecular chain has been observed in the crystal structure of 2-aminopyrimidinium trichloroacetate.34 Considering the carboxylate moiety, the oxygen of one side accepts a hydrogen from the carbon (C6) of the pyrimidine ring and oxygen of another side from the 2-amino group. This supramolecular ladders are further cross-linked through a symmetry related (5/2 - x, -1/2 + y, z) C-H‚‚‚O hydrogen bonds involving the C19 and the methoxy oxygen (O3) to give the 2-D sheets (Figure 7). The o-nitrobenzoate ions form a supramolecular
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Figure 4. View of packing along bc plane showing the alternative arrangement DADA array and hydrogen-bonded dimer. Figure 7. Hydrogen-bonded supramolecular 2-D sheet in compound 2 (view along bc plane).
Figure 8. o-Nitrobenzoate ions are extended along a axis through C-H‚‚‚O hydrogen bonds in compound 2. Table 2. Geometries of the Hydrogen Bonds in 1 and 2 compound
D-H‚‚‚A
d(H‚‚‚A) (Å)
d(D‚‚‚A) (Å)
∠(D-H‚‚‚A) (deg)
1
N1-H1‚‚‚O5 N2-H2A‚‚‚O4 N2-H2B‚‚‚O6a N4-H4A‚‚‚N3a N4-H4B‚‚‚O6 O6-H6A‚‚‚O4b O6-H6B‚‚‚O7 O7-H7C‚‚‚O1 O7-H7D‚‚‚O5c C6-H6‚‚‚O2d C1-H14C‚‚‚O2 N1-H1‚‚‚O5 N2-H2A‚‚‚O5e N2-H2B‚‚‚O4 C6-H6‚‚‚O4f C19-H19‚‚‚O1g C20-H20‚‚‚O7h
1.68(2) 1.99(2) 2.19(2) 2.09(2) 2.05(2) 1.89(3) 2.03(3) 2.18(3) 1.78(3) 2.48(19) 2.54(4) 1.61(3) 1.97(3) 1.99(3) 2.32(3) 2.54(3) 2.48(3)
2.634(2) 2.905(2) 3.044(3) 3.013(2) 2.854(3) 2.776(2) 2.845(3) 3.029(3) 2.736(2) 3.355(2) 3.140(3) 2.683(4) 2.824(4) 2.877(4) 3.191(4) 3.528(4) 3.280(4)
172(2) 164(2) 172(2) 167(2) 140.8(17) 175(3) 165(3) 173(2) 171(3) 153.5(14) 118(3) 174(3) 154(3) 170(3) 151(2) 155(2) 138(2)
Figure 5. Another view of packing along bc plane showing the network structure.
2
a 2 - x, 1 - y, -z. b -1 + x, y, z. c -1 + x, y, -1 + z. d 2 - x, -y, -z. e 5/2 - x, -y, 1/2 + z. f 5/2 - x, -y, -1/2 + z. g 5/2 - x, -1/2 + y, z. h 1/2 + x, y, 3/2 - z.
involving DADA, structures with a DDAA array of quadruple hydrogen bonds, and structures lacking these arrays (Table 3). Figure 6. Hydrogen-bonded supramolecular ladder in compound 2 (view along bc plane).
chain along the a axis (Figure 8), the ions being linked by (aromatic) C-H‚‚‚O (of nitro group) hydrogen bonds. The 2-D sheets along with this supramolecular chain form a 3-D network structure. The stacking interactions between the pyrimidine rings and the stacking between the phenyl ring of the TMP moiety and the phenyl ring of the o-nitrobenzoate moiety have been observed. The centroid-to-centroid, interplanar distances and the slip angle for the former are 3.70(2) Å, 3.44(1) Å, and 21.5(7)°, respectively. The corresponding values for the later are 3.94(2) Å, 3.68(1) Å, and 17.3(5)°, respectively. The hydrogen-bonding geometries are given in Table 2. This study shows that motifs I in combination with other hydrogen-bonding functionalities can be organized into supramolecular architectures such as structures
Conclusion Two novel organic salts have been prepared, and the conformations and hydrogen-bonding patterns have been analyzed. In both compounds, the carboxylate anions (O atoms) are hydrogen-bonded to the protonated pyrimidine rings to form a hydrogen-bonded bimolecular motif (motif I). These motifs further self-organize into two different ways to give different types of hydrogenbonding patterns. In compound 1, these motifs, in combination with N-H‚‚‚O and N-H‚‚‚N hydrogen bonds, form a complementary DADA array of quadruple hydrogen bonds (motif II) that have been observed in many 2,4-diaminopyrimidine-carboxylate complexes. This pattern is a potentially recurring synthon. In compound 2, there is no base-pairing, and motifs I are organized into a hydrogen-bonded supramolecular ladder and sheets through N-H‚‚‚O and C-H‚‚‚O hydro-
Crystal Engineering of Organic Salts Table 3. TMP Complexes and the Hydrogen-Bonded Architectures Observed in Them Structures involving DADA array (motif II) of quadruple H-bonding pattern trimethoprim nitrate22 trimethoprim salicylate methanol solvate15 trimethoprim hydrogen maleate13 trimethoprim perchlorate17 trimethoprim p-toluenesulfonate20 trimethoprim trifluoroacetate14 pyrimethamine formate29 pyrimethamine hydrogen glutarate29 pyrimethamine hydrogen maleate38 pyrimethamine hydrogen succinate38 pyrimethamine hydrogen phthalate38 copper(II)-phthalate:trimethoprim30 Structures with DDAA (motif IV) array of quadruple H-bonding pattern trimethoprim formate16 trimethoprim m-chlorobenzoate21 trimethoprim hydrogen glutarate12 Structures lacking such arrays trimethoprim sulfate trihydrate19 trimethoprim terephthalate terephthalic acid23 trimethoprim m-chlorobenzoate dihydrate21 trimethoprim benzenesulfonate monohydrate20 trimethoprim sulfanilate monohydrate20 trimethoprim sulfosalicylate dihydrate20
gen bonds. In addition, the o-nitrobenzoate ions form a supramolecular chain, the ions being linked by the aromatic C-H‚‚‚O (of nitro group) hydrogen bonds. Thus, by employing different carboxylates, varieties of hydrogen-bonding networks can be generated in these series of salts. Acknowledgment. S.B.R. and N.S thank the Council of Scientific and Industrial Research, New Delhi, India for the award of Senior Research Fellowship [ref. 9/475(103)2002, EMR-I for S.B.R. and ref. 9/475(111)2002, EMR-I for N.S]. References (1) Aakero¨y, C. B. Acta Crytallogr. 1997, B53, 569. (2) Desiraju, G. R. Nature 2001, 397. (3) Desiraju, G. R. Crystal Engineering. The Design of Organic Solids; Elsevier: Amsterdam, 1989. (4) Aakero¨y, C. B.; Beatty, A. M. Aust. J. Chem. 2001, 54, 409. (5) Vishweshwar, P.; Naryia, A.; Lynch, V. M. J. Org. Chem. 2002, 67, 556. (6) Aitipamula, S.; Thallapally, P. K.; Thaimattam, R.; Jaskolski, M.; Desiraju, G. R. Org. Lett. 2002, 4, 921. (7) Prabakaran, P.; Murugesan, S.; Muthiah, P. T.; Bocelli, G.; Righi, L. Acta Crystallogr. 2001, E57, o933. (8) Ballbh, A.; Darshak, R. T.; Dastidar, P.; Suresh, E. CrystEngComm. 2002, 4, 135. (9) Hitching, G. H.; Kuyper, L. F.; Baccananari, D. P. Design of Enzyme Inhibitors as Drugs; Sandler, M. and Smith, H. J., Eds.; New York: Oxford University Press, 1988, p 343.
Crystal Growth & Design, Vol. 3, No. 4, 2003 571 (10) Kuyper, L. F. (1990) Crystallographic and Modelling Methods in Molecular Design; Bugg, C. E. and Ealick, S. E., Eds.; Springer-Verlag: New York, 1990, pp 56-79. (11) Vallee, B. L.; Auld, D. S. Acc. Chem. Res. 1993, 26, 543. (12) Robert, J. J.; Baskar Raj, S.; Muthiah, P. T. Acta Crystallogr. 2001, E57, o1206. (13) Prabakaran, P.; Robert, J. J.; Muthiah, P. T.; Bocelli, G.; Righi, L. Acta Crystallogr. 2001, C57, 459. (14) Francis, S.; Muthiah, P. T.; Bocelli, G.; Righi, L. Acta Crystallogr. 2002, E58, o717. (15) Panneerselvam, P.; Stanley, N.; Muthiah, P. T. Acta Crystallogr. 2002, E58, o180. (16) Umadevi, B.; Prabakaran, P.; Muthiah, P. T. Acta Crystallogr. 2002, C58, o510. (17) Muthiah, P. T.; Umadevi, B.; Stanley, N.; Bocelli, G.; Cantoni, A. Acta Crystallogr. 2002, E58, o59. (18) Murugesan, S.; Muthiah, P. T. Academy Discussion Meeting on Frontiers in Structural Chemistry, IIT, Chennai, India, Abstract No. 3.4; 1996. (19) Muthiah, P. T.; Umadevi, B.; Stanley, N.; Shui, X.; Eggleston, D. S. Acta Crystallogr. 2001, E57, o1179. (20) Baskar Raj, S.; Sethuraman, V.; Francis, S.; Hemamalini, M.; Muthiah, P. T.; Bocelli, G.; Cantoni, A.; Rychlewska, U.; Warzajtis, B. CrystEngComm. 2003, 5 (15), 70. (21) Baskar Raj, S.; Muthiah, P. T.; Rychlewska, U.; Warzajtis, B. CrystEngComm. 2003, 5 (9), 48. (22) Murugesan, S.; Muthiah, P. T. Acta Crystallogr. 1997, C53, 763. (23) Hemamalini, M.; Muthiah, P. T.; Bocelli, G.; Cantoni, A. Acta Crystallogr. 2003, E59, o14. (24) Koetzle, T. F.; Williams, G. J. B. J. Am. Chem. Soc. 1976, 98, 4. (25) Allen, F. H.; Raithby, P. R.; Shields, G. P.; Taylor, R. Chem. Commun. 1998, 1043. (26) Sethuraman, V.; Muthiah, P. T. Acta Crystallogr. 2002, E58, o817. (27) Etter, M. C. Acc. Chem. Res. 1990, 23, 120. (28) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem. Int. Ed. Engl. 1995, 34, 1555. (29) Stanley, N.; Sethuraman, V.; Muthiah, P. T.; Luger, P.; Weber, M. Cryst. Growth Des. 2002, 6, 631. (30) Baskar Raj, S.; Muthiah, P. T.; Bocelli, G.; Cantoni, A. Inorg. Chem. Commun. 2003, 6, 748. (31) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.; Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W. Science 1997, 278, 1601. (32) Martindale, W. The Extra Pharmacopoeia, 30th ed.; Pharmaceutical Press: London, 1996. (33) Prabakaran, P.; Murugesan, S.; Robert, J. J.; Panneerselvam, P.; Muthiah, P. T.; Bocelli, G.; Righi, L. Chem. Lett. 2000, 1080. (34) Hu, M.-L.; Ye, M.-D.; Zain, S. M.; Ng, W. S. Acta Crystallogr. 2002, E58, o1005. (35) Sheldrick, G. M. SHELXS97; University of Go¨ttingen, Germany, 1997. (36) Sheldrick, G. M. SHELXL97; University of Go¨ttingen, Germany, 1997. (37) Spek, A. L. PLATON; Utretcht University, The Netherlands, 1997. (38) Sethuraman, V.; Stanley, N.; Muthiah, P. T.; Sheldrick, W. S.; Luger, P.; Weber, M. Cryst. Growth Des. 2003, submitted. (39) Sijbesma, R. P.; Meijer, E. W. Chem. Commun. 2003, 5.
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