Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S1600536807044364/bt2499sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S1600536807044364/bt2499Isup2.hkl |
CCDC reference: 237224
Pyrimethamine (62 mg, Shah Pharma Chem, India), adipic acid (36 mg, Merck) were mixed in 1:1 molar ratio in hot methanolic solution. The mixtures were allowed to cool at room temperature. Colourless needle shaped crystals were obtained after a few days.
All the hydrogen atoms were fixed geometrically and were refined using a riding model with C—H = 0.93 Å-0.97 Å, N—H = 0.86 Å and O—H 0.82 Å and with Uiso(H)=1.2Ueq(parent atom).
Pyrimethamine [PMN] is an antimalarial drug widely employed in the chemotherapy of malaria. The drug selectively binds to the bacterial Dihydrofolate reductase enzyme (DHFR) with greater affinity than to the human enzyme inhibiting the synthesis of proteins and nucleic acids (Hitchings & Burchall, 1965). PMN [2,4-diamino-5- (p-chlorophenyl)-6-ethyl-pyrimidine] also used in combination with other drugs for treatment of protozoan disease like toxoplasmosis, bacterial infections and some types of cancer (Zuccotto et al., 1998; Kraut & Matthews, 1987). Adipic acid is used as acidulant in baking powders, in beverages and as a gelatinizing agent. Supramolecular aggregates of adipic acid with amino acids like L– and DL-Lysine(Sharma et al., 2006) and L-and DL-arginine (Roy et al., 2005) have been reported in literature. Adipic acid also forms complexes with metals like Cu, Cd, Ni (Bakalbassis et al., 2001) and co-crystal with caffeine (Bucar et al., 2007). Pyrimidine and aminopyrimidines are biologically important compounds and occur in nature as components of nucleic acid. The diaminopyrimidines PMN and TMP (trimethoprim) are components of many drugs. The carboxyl group and carboxylate anion involve in hydrogen bonding interactions with aminopyrimidines (Vallee & Auld, 1993). These interactions play a vital role in protein-nucleic acid and drug-protein recognition processes (Kuyper, 1990). Crystal structures of pyrimethamine (Sethuraman & Thomas Muthiah, 2002), PMN salts (Sethuraman et al., 2003), PMN hydrogen glutarate and PMN formate (Stanley et al., 2002), PMN 3-chloro benzoate, PMN sulfosalicylate monohydrate (Hemamalini et al., 2005) have been reported in our laboratory. The present study has been undertaken to study the hydrogen bonding patterns involving hydrogen adipate anion with the pyrimethamine cation. An ORTEP (II) view of the compound (I) is shown in Fig (1). The asymmetric unit contains one PMN cation and a hydrogen adipate anion. PMN is protonated at N1 as it is evident from the enhancement of internal angle at N1 from 116.3 (2)° in neutral PMN molecule A and 116.09 (18)° in molecule B (Sethuraman & Thomas Muthiah, 2002) to 121.32 (18)°. The conformation of PMN is described two angles namely dihedral and torsion angles. The dihedral angle between 2, 4 diamino pyrimidine and p-chlorophenyl rings is found to be 79.47 (10)°. The torsion angle C5—C6—C7—C8, which represents the deviation of the ethyl group from the pyrimidine ring is found to be 99.3 (3)°. The values are close to the modeling studies of DHFR-PMN complexes (Sansom et al., 1989). The C5—C9 bond length connecting the pyrimidine and phenyl ring was found to be 1.504 (4) Å. This is in agreement with the reported value (De et al., 1989). Adipic acid tends to deviate from the standard trans (Vanier & Brisse, 1983) conformation. This may be dueto increasing chain length of the lower aliphatic dicarboxylic acids and the flexibility of the bonds to adopt twisted conformations. The actual values of the torsion angles are -174.9 (2)°, -170.8 (2)° and -69.4 (3)° for C15—C16—C17—C18, C16—C17—C18—C19 and C17—C18—C19—C20 respectively. The angles indicate that the hydrogen adipate anion exhibits trans-trans-gauche conformation (Zheng et al., 2000; Zheng et al., 2001), which has been confirmed from CSD search of 46 adipic acid fragments (Allen & Kennard, 1993). The various hydrogen-bonding interactions are shown in Table 1. The protonated N1 cation interacts with the carboxyl ate group of the adipate ion via N—H···O hydrogen bonds forming cyclic hydrogen bonded ring motif represented by graph-set notation R22(8) (Etter, 1990; Bernstein et al., 1995; Lynch & Jones, 2004). The ring motif further self assembles to form a complementary DDAA (D represents hydrogen bond donor and A represents hydrogen bond acceptor) array of quadruple hydrogen bonds. The graph set notation of three fused rings is designated as R22(8), R24(8), R22(8) shown in Fig(2). Similar type of interactions has also been observed in crystal structures of TMP hydrogen adipate (Muthiah et al., 2006), PMN m-chlorobenzoate (Devi et al., 2006), TMP hydrogen glutarate (Robert et al., 2001), and PMN hydrogen glutarate (Stanley et al., 2002). The carboxyl and carboxylate ends of hydrogen adipate anion adopts a folded syn conformation so as to tie the 2-amino and 4-amino groups of the paired PMN cation on either sides to form a large 15 membered ring[R22(15)]. Similar interactions are seen in crystal structure of TMP hydrogen adipate (Muthiah et al., 2006). The hydrogen adipate ions are linked through O—H···O hydrogen bonds with the carboxylate group forming the head and carboxyl group forming the tail portions respectively. The infinite supramolecular chain [graph set: C(9)] is shown in Fig (3). This type of head to tail arrangement of hydrogen bonding has been observed in PMN hydrogen glutarate (Stanley et al., 2002) and TMP hydrogen glutarate (Robert et al., 2001). In adipate ions, the carbonyl O3 atoms of the free carboxyl group interacts with 4-amino groups of the pyrimethamine cations through N—H···O hydrogen bonds forming a quadrilateral ring R24(8), shown in Fig(2). This ring formation has also been observed in the crystal structures of cytosine (Barker & Marsh, 1964), 1-methyl cytosine and 5-fluoro-uracil complex (Voet & Rich, 1970) and cytosine and 5-fluoro-uracil complex (Voet & Rich, 1969).
For related literature, see: Allen & Kennard (1993); Bakalbassis et al. (2001); Barker & Marsh (1964); Bernstein et al. (1995); Bucar et al. (2007); De et al. (1989); Devi et al. (2006); Etter (1990); Hemamalini et al. (2005); Kuyper (1990); Lynch & Jones (2004); Robert et al. (2001); Roy et al. (2005); Sansom et al. (1989); Sethuraman & Thomas Muthiah (2002); Sethuraman et al. (2003); Sharma et al. (2006); Stanley et al. (2002); Vallee & Auld (1993); Voet & Rich (1969, 1970); Zheng et al. (2000, 2001); Hitchings & Burchall (1965); Kraut & Matthews (1987); Muthiah et al. (2006); Vanier & Brisse (1983); Zuccotto et al. (1998).
Data collection: SMART (Bruker, 1997); cell refinement: SMART (Bruker, 1997); data reduction: SAINT (Bruker, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003) and ORTEPII (Johnson, 1976); software used to prepare material for publication: PLATON (Spek, 2003).
C12H14ClN4+·C6H9O4− | Z = 2 |
Mr = 394.85 | F(000) = 416 |
Triclinic, P1 | Dx = 1.291 Mg m−3 |
Hall symbol: -P 1 | Mo Kα radiation, λ = 0.71073 Å |
a = 8.154 (1) Å | Cell parameters from 25 reflections |
b = 11.420 (2) Å | θ = 1.8–27.1° |
c = 12.238 (2) Å | µ = 0.22 mm−1 |
α = 79.38 (2)° | T = 293 K |
β = 71.06 (2)° | Needle, colourless |
γ = 71.20 (2)° | 0.3 × 0.12 × 0.1 mm |
V = 1016 (3) Å3 |
Bruker SMART CCD area-detector diffractometer | 3265 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.017 |
Graphite monochromator | θmax = 27.1°, θmin = 1.8° |
ω–scans | h = −10→10 |
9586 measured reflections | k = −14→14 |
3988 independent reflections | l = −14→15 |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.054 | H-atom parameters constrained |
wR(F2) = 0.155 | w = 1/[σ2(Fo2) + (0.0761P)2 + 0.4803P] where P = (Fo2 + 2Fc2)/3 |
S = 1.03 | (Δ/σ)max < 0.001 |
3988 reflections | Δρmax = 0.75 e Å−3 |
247 parameters | Δρmin = −0.29 e Å−3 |
0 restraints | Extinction correction: SHELXL97 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.004 (2) |
C12H14ClN4+·C6H9O4− | γ = 71.20 (2)° |
Mr = 394.85 | V = 1016 (3) Å3 |
Triclinic, P1 | Z = 2 |
a = 8.154 (1) Å | Mo Kα radiation |
b = 11.420 (2) Å | µ = 0.22 mm−1 |
c = 12.238 (2) Å | T = 293 K |
α = 79.38 (2)° | 0.3 × 0.12 × 0.1 mm |
β = 71.06 (2)° |
Bruker SMART CCD area-detector diffractometer | 3265 reflections with I > 2σ(I) |
9586 measured reflections | Rint = 0.017 |
3988 independent reflections |
R[F2 > 2σ(F2)] = 0.054 | 0 restraints |
wR(F2) = 0.155 | H-atom parameters constrained |
S = 1.03 | Δρmax = 0.75 e Å−3 |
3988 reflections | Δρmin = −0.29 e Å−3 |
247 parameters |
Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All e.s.d.'s are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles |
Refinement. Refinement on F2 for ALL reflections except those flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The observed criterion of F2 > σ(F2) is used only for calculating -R-factor-obs etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. |
x | y | z | Uiso*/Ueq | ||
Cl1 | 0.34022 (11) | 0.32332 (8) | 0.00817 (7) | 0.0860 (3) | |
N1 | 1.1280 (2) | 0.03254 (15) | 0.34090 (15) | 0.0420 (5) | |
N2 | 1.2397 (2) | 0.07015 (18) | 0.47705 (15) | 0.0495 (6) | |
N3 | 0.9774 (2) | 0.21031 (16) | 0.44490 (14) | 0.0436 (5) | |
N4 | 0.7145 (2) | 0.34147 (17) | 0.41299 (16) | 0.0538 (6) | |
C2 | 1.1124 (3) | 0.10668 (18) | 0.42111 (16) | 0.0391 (6) | |
C4 | 0.8543 (3) | 0.24149 (18) | 0.38477 (17) | 0.0396 (6) | |
C5 | 0.8706 (3) | 0.17170 (17) | 0.29244 (17) | 0.0389 (6) | |
C6 | 1.0088 (3) | 0.06442 (18) | 0.27514 (17) | 0.0415 (6) | |
C7 | 1.0468 (3) | −0.0232 (2) | 0.1858 (2) | 0.0616 (9) | |
C8 | 1.1962 (5) | −0.0045 (4) | 0.0776 (3) | 0.1047 (16) | |
C9 | 0.7367 (3) | 0.21222 (17) | 0.22296 (17) | 0.0396 (6) | |
C10 | 0.7511 (3) | 0.3024 (2) | 0.1302 (2) | 0.0596 (8) | |
C11 | 0.6303 (4) | 0.3365 (3) | 0.0632 (2) | 0.0671 (9) | |
C12 | 0.4946 (3) | 0.2799 (2) | 0.09055 (19) | 0.0521 (7) | |
C13 | 0.4764 (3) | 0.1909 (2) | 0.1818 (2) | 0.0597 (8) | |
C14 | 0.5978 (3) | 0.1571 (2) | 0.2481 (2) | 0.0562 (8) | |
O1 | 1.5619 (2) | −0.13053 (15) | 0.39195 (16) | 0.0613 (6) | |
O2 | 1.3938 (2) | −0.18294 (14) | 0.30789 (16) | 0.0594 (6) | |
O3 | 2.3656 (3) | −0.48130 (16) | 0.38775 (17) | 0.0706 (7) | |
O4 | 2.2650 (2) | −0.33732 (15) | 0.25569 (15) | 0.0590 (6) | |
C15 | 1.5422 (3) | −0.1989 (2) | 0.3318 (2) | 0.0494 (7) | |
C16 | 1.7001 (3) | −0.3033 (3) | 0.2752 (3) | 0.0774 (10) | |
C17 | 1.8551 (3) | −0.3532 (2) | 0.3244 (2) | 0.0609 (8) | |
C18 | 2.0095 (3) | −0.4499 (2) | 0.2505 (3) | 0.0633 (9) | |
C19 | 2.1553 (4) | −0.5163 (2) | 0.3095 (3) | 0.0675 (9) | |
C20 | 2.2707 (3) | −0.4429 (2) | 0.3223 (2) | 0.0494 (7) | |
H1 | 1.21400 | −0.03560 | 0.33110 | 0.0500* | |
H2A | 1.23490 | 0.11370 | 0.52890 | 0.0590* | |
H2B | 1.32630 | 0.00310 | 0.46110 | 0.0590* | |
H4A | 0.70540 | 0.38320 | 0.46750 | 0.0650* | |
H4B | 0.63330 | 0.36430 | 0.37670 | 0.0650* | |
H7A | 0.93730 | −0.01070 | 0.16440 | 0.0740* | |
H7B | 1.08080 | −0.10810 | 0.21960 | 0.0740* | |
H8A | 1.16410 | 0.07980 | 0.04440 | 0.1570* | |
H8B | 1.21240 | −0.05990 | 0.02230 | 0.1570* | |
H8C | 1.30670 | −0.02140 | 0.09750 | 0.1570* | |
H10 | 0.84250 | 0.34080 | 0.11240 | 0.0710* | |
H11 | 0.64160 | 0.39670 | 0.00090 | 0.0810* | |
H13 | 0.38420 | 0.15340 | 0.19940 | 0.0720* | |
H14 | 0.58570 | 0.09670 | 0.31010 | 0.0670* | |
H4 | 2.32700 | −0.30130 | 0.26990 | 0.0890* | |
H16A | 1.65360 | −0.37170 | 0.27590 | 0.0930* | |
H16B | 1.74600 | −0.27460 | 0.19450 | 0.0930* | |
H17A | 1.81520 | −0.39120 | 0.40240 | 0.0730* | |
H17B | 1.89920 | −0.28560 | 0.32940 | 0.0730* | |
H18A | 1.96110 | −0.51030 | 0.23500 | 0.0760* | |
H18B | 2.06230 | −0.40890 | 0.17670 | 0.0760* | |
H19A | 2.09780 | −0.54900 | 0.38640 | 0.0810* | |
H19B | 2.23460 | −0.58680 | 0.26670 | 0.0810* |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.0792 (5) | 0.1157 (7) | 0.0790 (5) | −0.0179 (4) | −0.0553 (4) | −0.0043 (4) |
N1 | 0.0379 (9) | 0.0389 (9) | 0.0504 (10) | −0.0029 (7) | −0.0203 (7) | −0.0073 (7) |
N2 | 0.0413 (9) | 0.0595 (11) | 0.0510 (10) | −0.0062 (8) | −0.0222 (8) | −0.0108 (8) |
N3 | 0.0399 (9) | 0.0492 (10) | 0.0424 (9) | −0.0077 (7) | −0.0156 (7) | −0.0077 (7) |
N4 | 0.0514 (10) | 0.0517 (10) | 0.0576 (11) | 0.0059 (8) | −0.0268 (9) | −0.0198 (8) |
C2 | 0.0358 (10) | 0.0458 (11) | 0.0361 (10) | −0.0134 (8) | −0.0111 (8) | 0.0001 (8) |
C4 | 0.0389 (10) | 0.0405 (10) | 0.0390 (10) | −0.0095 (8) | −0.0134 (8) | −0.0013 (8) |
C5 | 0.0391 (10) | 0.0387 (10) | 0.0404 (10) | −0.0094 (8) | −0.0156 (8) | −0.0025 (8) |
C6 | 0.0421 (10) | 0.0399 (10) | 0.0457 (11) | −0.0094 (8) | −0.0186 (9) | −0.0041 (8) |
C7 | 0.0614 (14) | 0.0495 (13) | 0.0829 (17) | 0.0056 (10) | −0.0428 (13) | −0.0257 (12) |
C8 | 0.109 (3) | 0.123 (3) | 0.078 (2) | −0.014 (2) | −0.013 (2) | −0.058 (2) |
C9 | 0.0392 (10) | 0.0390 (10) | 0.0410 (10) | −0.0055 (8) | −0.0160 (8) | −0.0063 (8) |
C10 | 0.0587 (14) | 0.0644 (15) | 0.0657 (15) | −0.0290 (12) | −0.0318 (12) | 0.0168 (12) |
C11 | 0.0696 (16) | 0.0763 (17) | 0.0595 (15) | −0.0255 (14) | −0.0343 (13) | 0.0221 (13) |
C12 | 0.0475 (12) | 0.0641 (14) | 0.0466 (12) | −0.0047 (10) | −0.0231 (10) | −0.0117 (10) |
C13 | 0.0497 (13) | 0.0736 (16) | 0.0654 (15) | −0.0265 (12) | −0.0242 (11) | 0.0012 (12) |
C14 | 0.0548 (13) | 0.0641 (14) | 0.0545 (13) | −0.0247 (11) | −0.0239 (11) | 0.0128 (11) |
O1 | 0.0521 (9) | 0.0558 (9) | 0.0875 (12) | −0.0026 (7) | −0.0383 (9) | −0.0230 (9) |
O2 | 0.0432 (8) | 0.0513 (9) | 0.0935 (12) | −0.0013 (7) | −0.0377 (8) | −0.0186 (8) |
O3 | 0.0766 (12) | 0.0603 (10) | 0.0788 (12) | 0.0042 (9) | −0.0453 (10) | −0.0157 (9) |
O4 | 0.0568 (10) | 0.0590 (10) | 0.0756 (11) | −0.0168 (8) | −0.0378 (9) | −0.0049 (8) |
C15 | 0.0419 (11) | 0.0457 (11) | 0.0665 (14) | −0.0071 (9) | −0.0270 (10) | −0.0076 (10) |
C16 | 0.0483 (14) | 0.0833 (19) | 0.111 (2) | 0.0037 (13) | −0.0370 (15) | −0.0481 (17) |
C17 | 0.0466 (13) | 0.0659 (15) | 0.0725 (16) | −0.0073 (11) | −0.0219 (12) | −0.0183 (12) |
C18 | 0.0436 (12) | 0.0645 (15) | 0.0900 (19) | −0.0100 (11) | −0.0199 (12) | −0.0345 (14) |
C19 | 0.0623 (15) | 0.0556 (14) | 0.0877 (19) | −0.0121 (12) | −0.0227 (14) | −0.0198 (13) |
C20 | 0.0428 (11) | 0.0449 (11) | 0.0579 (13) | 0.0024 (9) | −0.0163 (10) | −0.0213 (10) |
Cl1—C12 | 1.756 (4) | C11—C12 | 1.377 (5) |
O1—C15 | 1.244 (3) | C12—C13 | 1.369 (4) |
O2—C15 | 1.285 (4) | C13—C14 | 1.395 (4) |
O3—C20 | 1.219 (4) | C7—H7A | 0.9706 |
O4—C20 | 1.322 (3) | C7—H7B | 0.9702 |
O4—H4 | 0.8201 | C8—H8A | 0.9606 |
N1—C6 | 1.377 (4) | C8—H8C | 0.9599 |
N1—C2 | 1.361 (3) | C8—H8B | 0.9600 |
N2—C2 | 1.341 (4) | C10—H10 | 0.9302 |
N3—C2 | 1.333 (3) | C11—H11 | 0.9298 |
N3—C4 | 1.352 (4) | C13—H13 | 0.9292 |
N4—C4 | 1.332 (3) | C14—H14 | 0.9293 |
N1—H1 | 0.8601 | C15—C16 | 1.515 (5) |
N2—H2A | 0.8598 | C16—C17 | 1.479 (5) |
N2—H2B | 0.8603 | C17—C18 | 1.535 (4) |
N4—H4A | 0.8602 | C18—C19 | 1.511 (5) |
N4—H4B | 0.8605 | C19—C20 | 1.505 (5) |
C4—C5 | 1.448 (4) | C16—H16A | 0.9697 |
C5—C9 | 1.504 (4) | C16—H16B | 0.9709 |
C5—C6 | 1.366 (4) | C17—H17A | 0.9706 |
C6—C7 | 1.509 (4) | C17—H17B | 0.9694 |
C7—C8 | 1.516 (5) | C18—H18A | 0.9694 |
C9—C14 | 1.391 (4) | C18—H18B | 0.9705 |
C9—C10 | 1.387 (4) | C19—H19A | 0.9705 |
C10—C11 | 1.398 (5) | C19—H19B | 0.9699 |
Cl1···C16i | 3.642 (6) | C16···H4iii | 3.0566 |
Cl1···H16Bi | 2.9746 | C20···H17B | 2.9648 |
O1···N2 | 2.909 (5) | C20···H4Aii | 2.8597 |
O1···N2ii | 2.911 (5) | H1···O2 | 1.8377 |
O2···O4iii | 2.581 (5) | H1···H7B | 2.3844 |
O2···C20iii | 3.386 (6) | H1···C15 | 2.7262 |
O2···N1 | 2.698 (5) | H1···H2B | 2.2429 |
O3···N4ii | 2.941 (5) | H2A···H17Bii | 2.5878 |
O3···N4iv | 2.986 (5) | H2A···O1ii | 2.2442 |
O4···O2v | 2.581 (5) | H2B···O2 | 2.8943 |
O4···C17 | 3.228 (6) | H2B···O1 | 2.0656 |
O1···H2Aii | 2.2442 | H2B···C15 | 2.8008 |
O1···H2B | 2.0656 | H2B···H1 | 2.2429 |
O1···H17B | 2.6982 | H4···H16Av | 2.5434 |
O1···H14v | 2.6486 | H4···O2v | 1.7918 |
O2···H1 | 1.8377 | H4···C15v | 2.7445 |
O2···H2B | 2.8943 | H4···C16v | 3.0566 |
O2···H7B | 2.9078 | H4···H7Bv | 2.5930 |
O2···H4iii | 1.7918 | H4A···O3ii | 2.0919 |
O3···H17Avi | 2.9045 | H4A···C20ii | 2.8597 |
O3···H4Biv | 2.3038 | H4B···C9 | 2.5491 |
O3···H16Av | 2.8515 | H4B···O3viii | 2.3038 |
O3···H4Aii | 2.0919 | H4B···C10 | 2.9983 |
O4···H7Bv | 2.6026 | H7A···C14 | 2.8015 |
O4···H17B | 2.7154 | H7A···C9 | 2.6263 |
O4···H18B | 2.5561 | H7B···O4iii | 2.6026 |
N1···O2 | 2.698 (5) | H7B···O2 | 2.9078 |
N1···C2vii | 3.384 (6) | H7B···H1 | 2.3844 |
N2···O1 | 2.909 (5) | H7B···H4iii | 2.5930 |
N2···O1ii | 2.911 (5) | H8B···C12i | 3.0324 |
N4···O3viii | 2.986 (5) | H8C···N1 | 2.9421 |
N4···O3ii | 2.941 (5) | H13···N1iii | 2.8102 |
N1···H8C | 2.9421 | H13···C2iii | 2.9805 |
N1···H13v | 2.8102 | H14···O1iii | 2.6486 |
C2···C2vii | 3.446 (6) | H16A···O3iii | 2.8515 |
C2···N1vii | 3.384 (6) | H16A···H4iii | 2.5434 |
C7···C14 | 3.483 (6) | H16A···H18A | 2.4417 |
C14···C7 | 3.483 (6) | H16B···H18B | 2.5021 |
C16···Cl1i | 3.642 (6) | H16B···Cl1i | 2.9746 |
C17···O4 | 3.228 (6) | H17A···H19A | 2.3993 |
C20···O2v | 3.386 (6) | H17A···O3vi | 2.9045 |
C2···H13v | 2.9805 | H17B···O1 | 2.6982 |
C9···H7A | 2.6263 | H17B···O4 | 2.7154 |
C9···H4B | 2.5491 | H17B···C20 | 2.9648 |
C10···H4B | 2.9983 | H17B···H2Aii | 2.5878 |
C12···H8Bi | 3.0324 | H18A···H16A | 2.4417 |
C12···H19Bviii | 2.7608 | H18B···O4 | 2.5561 |
C13···H19Bviii | 2.7979 | H18B···H16B | 2.5021 |
C14···H7A | 2.8015 | H19A···H17A | 2.3993 |
C15···H1 | 2.7262 | H19B···C12iv | 2.7608 |
C15···H4iii | 2.7445 | H19B···C13iv | 2.7979 |
C15···H2B | 2.8008 | ||
C20—O4—H4 | 109.48 | H8A—C8—H8C | 109.42 |
C2—N1—C6 | 121.32 (18) | H8B—C8—H8C | 109.49 |
C2—N3—C4 | 117.41 (18) | C7—C8—H8C | 109.50 |
C2—N1—H1 | 119.34 | C11—C10—H10 | 119.54 |
C6—N1—H1 | 119.34 | C9—C10—H10 | 119.45 |
C2—N2—H2A | 120.04 | C10—C11—H11 | 120.32 |
C2—N2—H2B | 120.03 | C12—C11—H11 | 120.46 |
H2A—N2—H2B | 119.93 | C14—C13—H13 | 120.36 |
C4—N4—H4A | 119.98 | C12—C13—H13 | 120.36 |
H4A—N4—H4B | 120.03 | C9—C14—H14 | 119.43 |
C4—N4—H4B | 120.00 | C13—C14—H14 | 119.43 |
N2—C2—N3 | 120.72 (19) | O1—C15—C16 | 120.7 (2) |
N1—C2—N2 | 116.74 (19) | O2—C15—C16 | 115.6 (2) |
N1—C2—N3 | 122.5 (2) | O1—C15—O2 | 123.6 (2) |
N3—C4—C5 | 122.70 (19) | C15—C16—C17 | 118.7 (3) |
N3—C4—N4 | 117.24 (18) | C16—C17—C18 | 111.8 (2) |
N4—C4—C5 | 120.1 (2) | C17—C18—C19 | 112.2 (3) |
C4—C5—C9 | 121.56 (18) | C18—C19—C20 | 117.7 (2) |
C4—C5—C6 | 116.7 (2) | O3—C20—C19 | 121.4 (2) |
C6—C5—C9 | 121.72 (19) | O4—C20—C19 | 115.3 (2) |
N1—C6—C7 | 115.77 (19) | O3—C20—O4 | 123.2 (2) |
C5—C6—C7 | 125.1 (2) | C15—C16—H16A | 107.65 |
N1—C6—C5 | 119.10 (19) | C15—C16—H16B | 107.64 |
C6—C7—C8 | 112.5 (2) | C17—C16—H16A | 107.68 |
C5—C9—C10 | 121.2 (2) | C17—C16—H16B | 107.65 |
C5—C9—C14 | 120.59 (18) | H16A—C16—H16B | 107.01 |
C10—C9—C14 | 118.2 (2) | C16—C17—H17A | 109.25 |
C9—C10—C11 | 121.0 (2) | C16—C17—H17B | 109.32 |
C10—C11—C12 | 119.2 (2) | C18—C17—H17A | 109.22 |
Cl1—C12—C13 | 119.2 (2) | C18—C17—H17B | 109.29 |
Cl1—C12—C11 | 119.66 (19) | H17A—C17—H17B | 107.89 |
C11—C12—C13 | 121.2 (2) | C17—C18—H18A | 109.18 |
C12—C13—C14 | 119.3 (2) | C17—C18—H18B | 109.16 |
C9—C14—C13 | 121.1 (2) | C19—C18—H18A | 109.20 |
C6—C7—H7B | 109.14 | C19—C18—H18B | 109.11 |
C8—C7—H7A | 109.07 | H18A—C18—H18B | 107.90 |
C8—C7—H7B | 109.10 | C18—C19—H19A | 107.82 |
H7A—C7—H7B | 107.83 | C18—C19—H19B | 107.88 |
C6—C7—H7A | 109.10 | C20—C19—H19A | 107.88 |
C7—C8—H8A | 109.47 | C20—C19—H19B | 107.92 |
C7—C8—H8B | 109.50 | H19A—C19—H19B | 107.18 |
H8A—C8—H8B | 109.44 | ||
C2—N1—C6—C5 | −1.1 (3) | C5—C6—C7—C8 | 99.4 (3) |
C2—N1—C6—C7 | 177.32 (19) | N1—C6—C7—C8 | −78.9 (3) |
C6—N1—C2—N2 | −177.18 (19) | C5—C9—C10—C11 | 177.6 (2) |
C6—N1—C2—N3 | 3.4 (3) | C5—C9—C14—C13 | −177.8 (2) |
C4—N3—C2—N1 | −0.8 (3) | C14—C9—C10—C11 | −0.4 (3) |
C2—N3—C4—C5 | −3.9 (3) | C10—C9—C14—C13 | 0.3 (3) |
C4—N3—C2—N2 | 179.81 (19) | C9—C10—C11—C12 | 0.4 (4) |
C2—N3—C4—N4 | 176.57 (19) | C10—C11—C12—C13 | −0.1 (4) |
N3—C4—C5—C6 | 6.0 (3) | C10—C11—C12—Cl1 | 179.2 (2) |
N4—C4—C5—C9 | 2.6 (3) | C11—C12—C13—C14 | 0.0 (4) |
N3—C4—C5—C9 | −176.8 (2) | Cl1—C12—C13—C14 | −179.37 (17) |
N4—C4—C5—C6 | −174.5 (2) | C12—C13—C14—C9 | 0.0 (3) |
C9—C5—C6—N1 | 179.56 (19) | O2—C15—C16—C17 | −161.3 (2) |
C4—C5—C6—C7 | 178.5 (2) | O1—C15—C16—C17 | 22.4 (4) |
C4—C5—C6—N1 | −3.3 (3) | C15—C16—C17—C18 | −174.9 (2) |
C4—C5—C9—C14 | −99.6 (2) | C16—C17—C18—C19 | −170.8 (2) |
C6—C5—C9—C10 | −100.6 (3) | C17—C18—C19—C20 | −69.4 (3) |
C6—C5—C9—C14 | 77.5 (3) | C18—C19—C20—O4 | −16.5 (4) |
C4—C5—C9—C10 | 82.4 (3) | C18—C19—C20—O3 | 165.4 (3) |
C9—C5—C6—C7 | 1.3 (3) |
Symmetry codes: (i) −x+2, −y, −z; (ii) −x+3, −y, −z+1; (iii) x−1, y, z; (iv) x+2, y−1, z; (v) x+1, y, z; (vi) −x+4, −y−1, −z+1; (vii) −x+2, −y, −z+1; (viii) x−2, y+1, z. |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O2 | 0.86 | 1.84 | 2.698 (5) | 178 |
N2—H2A···O1ii | 0.86 | 2.24 | 2.911 (5) | 134 |
N2—H2B···O1 | 0.86 | 2.07 | 2.909 (5) | 166 |
O4—H4···O2v | 0.82 | 1.79 | 2.581 (5) | 161 |
N4—H4A···O3ii | 0.86 | 2.09 | 2.941 (5) | 169 |
N4—H4B···O3viii | 0.86 | 2.30 | 2.986 (5) | 136 |
Symmetry codes: (ii) −x+3, −y, −z+1; (v) x+1, y, z; (viii) x−2, y+1, z. |
Experimental details
Crystal data | |
Chemical formula | C12H14ClN4+·C6H9O4− |
Mr | 394.85 |
Crystal system, space group | Triclinic, P1 |
Temperature (K) | 293 |
a, b, c (Å) | 8.154 (1), 11.420 (2), 12.238 (2) |
α, β, γ (°) | 79.38 (2), 71.06 (2), 71.20 (2) |
V (Å3) | 1016 (3) |
Z | 2 |
Radiation type | Mo Kα |
µ (mm−1) | 0.22 |
Crystal size (mm) | 0.3 × 0.12 × 0.1 |
Data collection | |
Diffractometer | Bruker SMART CCD area-detector |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 9586, 3988, 3265 |
Rint | 0.017 |
(sin θ/λ)max (Å−1) | 0.641 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.054, 0.155, 1.03 |
No. of reflections | 3988 |
No. of parameters | 247 |
H-atom treatment | H-atom parameters constrained |
Δρmax, Δρmin (e Å−3) | 0.75, −0.29 |
Computer programs: SMART (Bruker, 1997), SAINT (Bruker, 1997), SHELXS97 (Sheldrick, 1997), SHELXL97 (Sheldrick, 1997), PLATON (Spek, 2003) and ORTEPII (Johnson, 1976), PLATON (Spek, 2003).
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1···O2 | 0.8600 | 1.8400 | 2.698 (5) | 178.00 |
N2—H2A···O1i | 0.8600 | 2.2400 | 2.911 (5) | 134.00 |
N2—H2B···O1 | 0.8600 | 2.0700 | 2.909 (5) | 166.00 |
O4—H4···O2ii | 0.8200 | 1.7900 | 2.581 (5) | 161.00 |
N4—H4A···O3i | 0.8600 | 2.0900 | 2.941 (5) | 169.00 |
N4—H4B···O3iii | 0.8600 | 2.3000 | 2.986 (5) | 136.00 |
Symmetry codes: (i) −x+3, −y, −z+1; (ii) x+1, y, z; (iii) x−2, y+1, z. |
Pyrimethamine [PMN] is an antimalarial drug widely employed in the chemotherapy of malaria. The drug selectively binds to the bacterial Dihydrofolate reductase enzyme (DHFR) with greater affinity than to the human enzyme inhibiting the synthesis of proteins and nucleic acids (Hitchings & Burchall, 1965). PMN [2,4-diamino-5- (p-chlorophenyl)-6-ethyl-pyrimidine] also used in combination with other drugs for treatment of protozoan disease like toxoplasmosis, bacterial infections and some types of cancer (Zuccotto et al., 1998; Kraut & Matthews, 1987). Adipic acid is used as acidulant in baking powders, in beverages and as a gelatinizing agent. Supramolecular aggregates of adipic acid with amino acids like L– and DL-Lysine(Sharma et al., 2006) and L-and DL-arginine (Roy et al., 2005) have been reported in literature. Adipic acid also forms complexes with metals like Cu, Cd, Ni (Bakalbassis et al., 2001) and co-crystal with caffeine (Bucar et al., 2007). Pyrimidine and aminopyrimidines are biologically important compounds and occur in nature as components of nucleic acid. The diaminopyrimidines PMN and TMP (trimethoprim) are components of many drugs. The carboxyl group and carboxylate anion involve in hydrogen bonding interactions with aminopyrimidines (Vallee & Auld, 1993). These interactions play a vital role in protein-nucleic acid and drug-protein recognition processes (Kuyper, 1990). Crystal structures of pyrimethamine (Sethuraman & Thomas Muthiah, 2002), PMN salts (Sethuraman et al., 2003), PMN hydrogen glutarate and PMN formate (Stanley et al., 2002), PMN 3-chloro benzoate, PMN sulfosalicylate monohydrate (Hemamalini et al., 2005) have been reported in our laboratory. The present study has been undertaken to study the hydrogen bonding patterns involving hydrogen adipate anion with the pyrimethamine cation. An ORTEP (II) view of the compound (I) is shown in Fig (1). The asymmetric unit contains one PMN cation and a hydrogen adipate anion. PMN is protonated at N1 as it is evident from the enhancement of internal angle at N1 from 116.3 (2)° in neutral PMN molecule A and 116.09 (18)° in molecule B (Sethuraman & Thomas Muthiah, 2002) to 121.32 (18)°. The conformation of PMN is described two angles namely dihedral and torsion angles. The dihedral angle between 2, 4 diamino pyrimidine and p-chlorophenyl rings is found to be 79.47 (10)°. The torsion angle C5—C6—C7—C8, which represents the deviation of the ethyl group from the pyrimidine ring is found to be 99.3 (3)°. The values are close to the modeling studies of DHFR-PMN complexes (Sansom et al., 1989). The C5—C9 bond length connecting the pyrimidine and phenyl ring was found to be 1.504 (4) Å. This is in agreement with the reported value (De et al., 1989). Adipic acid tends to deviate from the standard trans (Vanier & Brisse, 1983) conformation. This may be dueto increasing chain length of the lower aliphatic dicarboxylic acids and the flexibility of the bonds to adopt twisted conformations. The actual values of the torsion angles are -174.9 (2)°, -170.8 (2)° and -69.4 (3)° for C15—C16—C17—C18, C16—C17—C18—C19 and C17—C18—C19—C20 respectively. The angles indicate that the hydrogen adipate anion exhibits trans-trans-gauche conformation (Zheng et al., 2000; Zheng et al., 2001), which has been confirmed from CSD search of 46 adipic acid fragments (Allen & Kennard, 1993). The various hydrogen-bonding interactions are shown in Table 1. The protonated N1 cation interacts with the carboxyl ate group of the adipate ion via N—H···O hydrogen bonds forming cyclic hydrogen bonded ring motif represented by graph-set notation R22(8) (Etter, 1990; Bernstein et al., 1995; Lynch & Jones, 2004). The ring motif further self assembles to form a complementary DDAA (D represents hydrogen bond donor and A represents hydrogen bond acceptor) array of quadruple hydrogen bonds. The graph set notation of three fused rings is designated as R22(8), R24(8), R22(8) shown in Fig(2). Similar type of interactions has also been observed in crystal structures of TMP hydrogen adipate (Muthiah et al., 2006), PMN m-chlorobenzoate (Devi et al., 2006), TMP hydrogen glutarate (Robert et al., 2001), and PMN hydrogen glutarate (Stanley et al., 2002). The carboxyl and carboxylate ends of hydrogen adipate anion adopts a folded syn conformation so as to tie the 2-amino and 4-amino groups of the paired PMN cation on either sides to form a large 15 membered ring[R22(15)]. Similar interactions are seen in crystal structure of TMP hydrogen adipate (Muthiah et al., 2006). The hydrogen adipate ions are linked through O—H···O hydrogen bonds with the carboxylate group forming the head and carboxyl group forming the tail portions respectively. The infinite supramolecular chain [graph set: C(9)] is shown in Fig (3). This type of head to tail arrangement of hydrogen bonding has been observed in PMN hydrogen glutarate (Stanley et al., 2002) and TMP hydrogen glutarate (Robert et al., 2001). In adipate ions, the carbonyl O3 atoms of the free carboxyl group interacts with 4-amino groups of the pyrimethamine cations through N—H···O hydrogen bonds forming a quadrilateral ring R24(8), shown in Fig(2). This ring formation has also been observed in the crystal structures of cytosine (Barker & Marsh, 1964), 1-methyl cytosine and 5-fluoro-uracil complex (Voet & Rich, 1970) and cytosine and 5-fluoro-uracil complex (Voet & Rich, 1969).