CRYSTAL GROWTH & DESIGN
Crystal Engineering of Organic Salts: Hydrogen-Bonded Supramolecular Motifs in Pyrimethamine Hydrogen Glutarate and Pyrimethamine Formate
2002 VOL. 2, NO. 6 631-635
N. Stanley,† V. Sethuraman,† P. Thomas Muthiah,*,† P. Luger,‡ and M. Weber‡ Department of Chemistry, Bharathidasan University, Tiruchirappalli-620 024, India, and Institute for Chemistry/Crystallography, Free University of Berlin, D-14195, Berlin, Germany Received July 15, 2002
ABSTRACT: In the crystal structures of the two organic salts, namely, pyrimethamine hydrogen glutarate (1:1) 1 and pyrimethamine formate (1:1) 2, the pyrimethamine moieties are protonated at one of the nitrogen atoms of the pyrimidine rings. The carboxylate group of the respective anions (hydrogen glutarate and formate) interacts with the protonated pyrimidine moiety in a near linear fashion through a pair of N-H‚‚‚O hydrogen bonds. The dihedral angle between the diaminopyrimidine and the p-chlorophenyl plane is 74.8(1)° in compound 1, and the corresponding value in compound 2 is 76.7(1)°. In both compounds, the pyrimidine moieties are centrosymmetrically paired through a pair of N-H‚‚‚N hydrogen bonds. The 2-amino group of the one member of the pair and the 4-amino group of the other member are bridged by an O atom of the carboxylate group, using a pair of N-H‚‚‚O hydrogen bonds. This combination of hydrogen bonds results in the complementary DADA (D ) donor and A ) acceptor in hydrogen bonds) arrays of quadruple hydrogen-bonding patterns. In compound 1, there are chains and ladders made up of the O-H‚‚‚O, N-H‚‚‚O, and C-H‚‚‚N hydrogen bonds whereas compound 2 displays a three-dimensional network of hydrogen bonds. Introduction
Table 1. Crystallographic Parameters for 1 and 2
Crystal engineering1 is a kind of supramolecular (noncovalent) synthesis of target crystal structures with hydrogen bonding as the key recognition element between molecules.2-5 N-H‚‚‚O and O-H‚‚‚O hydrogen bonds have been used in the design of a number of supramolecular nanoarchitectures, layers, ribbons, rosettes, rods, tapes, tubes, sheets, and spheres.6-8 Some of the supramolecular motifs are made up of hydrogenbonding patterns of repetitive occurrence. These patterns are of significance in crystal engineering.9-11 The weak C-H‚‚‚O hydrogen bonds also play an important role in the formation of supramolecular organization.12 We are applying crystal engineering techniques to the study of diaminopyrimidine-carboxylate complexes, especially trimethoprim (TMP) and pyrimethamine (PMN), which are popular antifolate drugs.13 PMN [2,4diamino-5-(p-chlorophenyl)-6-ethylpyrimidine] is used in the treatment of malaria.14 We have already reported the hydrogen-bonding patterns in TMP hydrogen glutarate, TMP hydrogen maleate, TMP salicylate dihydrate, TMP salicylate methanol solvate, and TMP trifluoroacetate.10,15-18 The present study has been carried out in order to study the conformation of the molecules and the hydrogen-bonding patterns present in the crystal structures of PMN hydrogen glutarate 1 and PMN formate 2. Experimental Section Compounds 1 and 2 were prepared by mixing a hot methanolic solution of PMN (obtained from Lupin Laboratories Ltd., India) with a hot methanolic solution of glutaric acid (s.d.Fine * To whom correspondence
[email protected]. † Bharathidasan University. ‡ Free University of Berlin.
should
be
addressed.
E-mail:
properties
1
2
formula M crystal system space group diffractometer a (Å) b (Å) c (Å) β (°) V (Å3) Z radiation (Å) T (K) Dc (g cm-3) µ (mm-1) F(000) reflections collected observed reflections [I > 2σ(I)] parameters refined final R1 on observed data final wR2 on observed data structure solution structure refinement graphics
C12H14ClN4, C5H7O4 380.83 monoclinic P21/c STOE four circle 7.575(2) 14.472(2) 17.423(3) 101.090(10) 1874.3(6) 4 0.71069 293(2) 1.350 0.234 800 4699 3216
C12H14ClN4, CHO2 294.74 monoclinic P21/n Rigaku AFC 13.905(8) 7.514(5) 14.481(5) 106.99(4) 1447.0(14) 4 1.54178 293(2) 1.353 2.4 616 2969 2109
319 0.0415
231 0.0532
0.0558
0.1698
SIR9229 SHELXL9730 PLATON31 ORTEP332
SHELXS9728 SHELXL9730 PLATON31 ORTEP332
Chemicals, India) or formic acid (s.d.Fine Chemicals) in a 1:1 molar ratio. The mixtures were cooled slowly and kept at room temperature. After a few days, blocks of colorless crystals were obtained. The crystal data for the compounds are given in Table 1.
Results and Discussion An ORTEP view of the title compounds 1 and 2 is shown in Figure 2. In both structures, the PMN moieties are protonated at N1, as is evident from the increase
10.1021/cg020027p CCC: $22.00 © 2002 American Chemical Society Published on Web 10/10/2002
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Figure 2. ORTEP view of 1 and 2 (a and b). Ellipsoids for non-H atoms are drawn at the 50% probability level.
Figure 1. Schematic representation of the four types of hydrogen-bonded motifs observed in compounds 1 and 2 (CCDC 187877 for 1 and CCDC 187878 for 2).
in the ring angle at N1 (C2-N1-C6) [from 116.3(2)° (molecule A) and 116.1(2)° (molecule B) in neutral PMN to 121.09(14)° in compound 1 and to 120.8(2)° in compound 2].19 The conformation of the PMN moieties is described by two angles. The first is the dihedral angle between the 2,4-diaminopyrimidine and the p-chlorophenyl planes. The second one is the torsion angle C5C6-C7-C8, which represents the deviation of the ethyl group from the pyrimidine plane. The angle between pyrimidine and phenyl ring is 74.8(1)° in compound 1, and the corresponding angle in 2 is 76.7(1)°. These values are close to the value observed in the modeling studies on the dihydrofolate reductase-PMN (DHFRPMN) complexes.20 The torsion angle [C5-C6-C7-C8] is 96.6(3)° in compound 1, and the corresponding angle in compound 2 is -110.9(3)°. Modeling studies of the DHFR-PMN complexes indicate that the dihedral angle plays an important role in proper docking of the drug molecule in the active site of the enzyme and that the change in the torsion angle representing the orientation of the ethyl group does not affect the overall binding energy of the enzyme-drug complex.20 The bond connecting the pyrimidine and phenyl rings is 1.481(2) Å in compound 1 and 1.492(3) Å in compound 2. These values are in close agreement with those observed in the crystal structure of metoprine (1.495 Å in molecule A and 1.478 Å in molecule B).21 The backbone conformation of the hydrogen glutarate anion can be described
by the two torsion angles C15-C16-C17-C18 of -72.8(2)° and C16-C17-C18-C19 of -175.5(1)°. As evident from the torsion angles, the backbone is in a fully extended conformation.10 The schematic representation of the four types of hydrogen-bonded motifs I-IV observed in this study is shown in Figure 1. In both compounds (1 and 2), the carboxylate group of the respective anions (formate and hydrogen glutarate) interacts with the protonated pyrimidine moiety of PMN in a near linear fashion through a pair of N-H‚‚‚O hydrogen bonds to form a forklike interaction,22 with graph-set R22(8) (motif I). The leastsquares planes passing through the carboxylate group and the pyrimidine ring atoms involved in the specific hydrogen bond interaction make an angle of 17.1° in compound 1, and the corresponding angle in compound 2 is 20.12(1)°. This indicates the near planar interaction of the carboxylate group with the pyrimidine moiety. This motif (I) is one of the 24 most frequently observed bimolecular cyclic hydrogen-bonded motifs in organic crystal structures.23 In compound 1, the hydrogen glutarate anions are further linked through O-H‚‚‚O hydrogen bonds to form a zigzag infinite chain with graph set C(8) (Figure 3), running parallel to the b-axis (motif II). This type of head-to-tail fashion of hydrogen glutarate ions has also been observed in the crystal structure of TMP hydrogen glutarate.10 In both compounds, the PMN cations are centrosymmetrically paired through two N-H‚‚‚N hydrogen bonds involving the 4-amino group and the N3 atom of the PMN moiety [graph set R22(8)]. This kind of pairing has already been observed in many TMP-carboxylate complexes.15-18
Crystal Engineering of Organic Salts
Crystal Growth & Design, Vol. 2, No. 6, 2002 633
Figure 3. Zigzag chain motif made up of hydrogen glutarate anions (carboxyl-carboxylate interaction) in compound 1.
Figure 4. Packing diagram for compound 1 (view along the bc plane). One PMN pair is holding the four zigzag chains of hydrogen glutarate ions.
Figure 5. Packing diagram for compound 1 (view along the a axis). PMN pairs are connected through C-H‚‚‚N hydrogen bonds to form a ladder.
The pairs further interact with hydrogen glutarate chains (motif II) through N-H‚‚‚O hydrogen bonds. This pattern is shown in Figure 4. Such PMN pairs are centrosymmetrically connected through a pair of C-H‚‚‚N interactions involving the methyl and 4-amino groups to form a supramolecular ladderlike pattern along the a-axis. This type of pattern is shown in Figure 5. In both compounds, one of the oxygen atoms [O3 of hydrogen glutarate and O1 of formate] bridges the 2-amino and 4-amino groups on either side of the paired
PMN cations, forming hydrogen-bonded ring motifs with graph set R32(8). This motif is otherwise called a complementary DADA [D ) donor and A ) acceptor] array of quadruple hydrogen bonds as shown in motif III. This type of DADA array has already been observed in many TMP-carboxylate complexes.15-18,24,25 The DADA array of hydrogen-bonding motif can be represented in the form of three fused rings of R32(8), R22(8), and R32(8), in order by using graph set notation.26,27 The other DDAA array of hydrogen-bonding motif (motif IV)
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Figure 6. Packing diagram for compound 2 (view along the ab plane). DADA arrays are connected through N-H‚‚‚O hydrogen bonds. Table 2. Geometries of the Hydrogen Bonds in 1 and 2 compd no. 1
2
D-H‚‚‚A
d(H‚‚‚A) (Å)
d(D‚‚‚A) (Å)
∠(D-H‚‚‚A) (°)
N1-H1‚‚‚O1 O4-H4′‚‚‚O2a N2-H21‚‚‚O2 N2-H22‚‚‚O3b N4-H41‚‚‚N3c N4-H42‚‚‚O3d C11-H11‚‚‚O1e C8-H81‚‚‚N4f N1-H1‚‚‚O2g N2-H2A‚‚‚O1g N2-H2B‚‚‚O1h N4-H4A‚‚‚N3i N4-H4B‚‚‚O1j C11-H11‚‚‚O2k
1.69(2) 1.47(3) 2.21(2) 2.28(2) 2.15(2) 2.26(2) 2.49(2) 2.58(6) 1.61(3) 1.96(3) 2.13(3) 2.18(3) 2.07(3) 2.45(4)
2.599(2) 2.531(2) 3.055(3) 3.081(3) 3.023(2) 2.968(2) 3.339(3) 3.270(4) 2.639(4) 2.869(4) 2.982(3) 3.017(4) 2.846(3) 3.378(5)
174(2) 171(3) 171(2) 163.5(19) 165(2) 138(2) 148.0(19) 129(5) 170(3) 179(2) 162(3) 160(3) 146(3) 159(3)
a -x,-1/2+y,1/2-z. b 1-x,1/2+y,1/2-z. c 2-x,1-y,-z,-1/4+z. 1+x,12-y,-1/2+y. e x,1/2-y,-1/2+z. f -1+x,y,z. g 1-x,-y,1-z.h -1/ 2+x,1/2-y,1/2+z. i -x,1-y,1-z. j 1/2-x,1/2+y,1/2-z. k -1/2+x,1/ 2-y,-1/2+z.
Conclusions Two novel organic salts have been prepared, and the conformations and hydrogen-bonding patterns have been analyzed. In both compounds, the carboxylate group of the respective anions (hydrogen glutarate and formate) interacts with the protonated PMN moieties through a pair of N-H‚‚‚O hydrogen bonds, motif I, and the PMN cations are centrosymmetrically paired through two N-H‚‚‚N hydrogen bonds. In both compounds, one of the oxygen atoms bridges the 2-amino and 4-amino groups on either side of the paired PMN cations, forming a complementary DADA array of quadruple hydrogen bonds (motif III). Because DADA arrays have been observed in many 2,4-diaminopyrimidine-carboxylate complexes, this motif is a potentially recurring synthon.
d
R22(8),
R42(8),
[three fused rings with graph set notation and R22(8)] has also been observed in the crystal structure of TMP hydrogen glutarate.10 As observed in many 2,4-diaminopyrimidine-carboxylate complexes (including the present study), the DADA array of paired hydrogen-bonding motif (motif III) has an important role in stabilizing the crystal structures.15-18,24,25 The diaminopyrimidinium cations are bridged by an O atom of the carboxylate group or methanol molecule or a water molecule.15-18,24,25 Hence, this motif can be effectively referred to as an O-mediated synthon. In compound 2, each formate ion is hydrogen-bonded to three PMN cations (one side forklike interaction and another side bridging the two PMN cations) or the DADA arrays are linked through N-H‚‚‚O hydrogen bonds along the 21 axis. This type of pattern is shown in Figure 6. The hydrogen-bonding geometries are given in Table 2.
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CG020027P
