Organic Ionic Ladders Formed by Supramolecular Motifs in

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Isomorphism and Crystal Engineering: Organic Ionic Ladders Formed by Supramolecular Motifs in Pyrimethamine Salts V. Sethuraman,† N. Stanley,† P. Thomas Muthiah,*,† W. S. Sheldrick,‡ M. Winter,‡ P. Luger,§ and M. Weber§

CRYSTAL GROWTH & DESIGN 2003 VOL. 3, NO. 5 823-828

Department of Chemistry, Bharathidasan University, Tiruchirappalli - 620 024, India, Lehrstuhl fu¨ r Analytische Chemie, Ruhr-Universite¨ at Bochum, D-44780 Bochum, Germany, and Institute of Chemistry/Crystallography, Free University of Berlin, Berlin, Germany Received March 28, 2003

ABSTRACT: Pyrimethamine [2,4-diamino-5-(p-chlorophenyl)-6-ethyl-pyrimidine] (PMN) is an antifolate drug. Four new organic salts, namely, PMN hydrogen maleate (1), PMN hydrogen succinate (2), PMN hydrogen phthalate (3), and PMN fumarate (4), have been synthesized and their hydrogen bonding patterns have been analyzed. As expected, in all the structures, the PMN moieties are protonated at one of the nitrogen atoms of the pyrimidine rings. The carboxylate group of the respective anions interacts with the protonated pyrimidine moiety in near linear fashion through a pair of N-H‚‚‚O hydrogen bonds to form a cyclic hydrogen-bonded motif. The crystal structures of compounds 1 and 2 are isomorphous as revealed by the very good agreement among their cell parameters. Interestingly, the hydrogen succinate mimics the hydrogen maleate here. In all three crystal structures (1-3), the hydrogen bonding motifs and their supramolecular patterns are the same, which is significant from a crystal engineering point of view in the building up of organic ionic ladders. In compound 4, the cyclic hydrogen-bonded motifs are self-organized through N-H‚‚‚O, N-H‚‚‚Cl, and C-H‚‚‚N hydrogen bonds to the formation of different types of hydrogen bonding patterns. Introduction Supramolecular chemistry and crystal engineering are closely related fields.1-3 Both involve the noncovalent interactions as their basis and have expanded the frontiers of chemical science dealing with many physical and biological phenomena. Meijer and co-workers developed DDAA arrays (D ) donor and A ) acceptor) or quadruple hydrogen bonding motifs based on the dimerization of 2-ureido-4-pyrimidones.4 Schimdt and coworkers established that the spatial relationship between neighboring molecules plays a dramatic role in determining the crystal structures.5 According to Desiraju, what the chemists can best do is to find recurring packing patterns adopted by certain functional groups and rely on the robustness of such motifs to create new solid-state structures.6,7 Such repetitive motifs are called supramolecular synthons,8 and they hold the key to successful crystal engineering and are responsible for these crystalline materials being used in a variety of functional roles. Using the Cambridge Structural Database (CSD), we can determine the repetitive occurrence of the hydrogen bonding motifs in related structures.9 Pyrimethamine (PMN) is an antimalarial drug.10,11 2,4Diaminopyrimidine-carboxylate interactions are of current interest.12,13 A number of crystal structures of 2,4diaminopyrimidine with monocarboxylic acids have been reported from our lab, and two recurring hydrogen bonding motifs (one consisting of a DADA array and other consisting of a DDAA array) have been identified. * E-mail: [email protected]. † Bharathidasan University. ‡ Ruhr-Universite ¨ at Bochum. § Free University of Berlin.

Among these two motifs, the DADA array motif appears to be the most recurring supramolecular synthon.12-18 To study the interaction of 2,4-diaminopyrimidine with 1,2-dicarboxylic acids from the crystal engineering point of view, the salts of PMN with four 1,2-dicarboxylic acids (namely, maleic acid, fumaric acid, phthalic acid, and succinic acid) have been prepared. Maleic and fumaric acides have rigid configurations as cis and trans. Phthalic acid is the aromatic analogue of maleic acid and has the same cis configuration. Succinic acid is the saturated analogue of maleic or fumaric acid, which unlike maleic and fumaric acids, lacks the configurational rigidity as cis and trans. Thus, these acids have been chosen to study their preferred mode of hydrogen bonding, the nature of the hydrogen-bonded arrays, the supramolecular synthons observed, and the resultant supramolecular architectures present in the crystal structures.19,20 Experimental Section Preparation. Compounds 1-4 were prepared by mixing a hot methanolic solution of PMN (obtained from Lupin Laboratories Ltd., India) with a hot aqueous methanolic solution of maleic acid (s.d. Fine Chemicals, India), succinic acid (LOBA Chemicals, India), phthalic acid (LOBA Chemicals, India), or fumaric acid (s.d. Fine Chemicals, India). The mixtures were cooled slowly and kept at room temperature. After a few days, colorless crystals were obtained. X-ray Crystallography. For compounds 1-3 were collected at 293 K on a Enraf-Nonius CAD4 diffractometer. The data for compound 4 were collected at 293 K on a STOE four circle diffractometer. In all the compounds, non-hydrogen atoms were located from a Fourier map and refined anisotropically. In all the compounds (1-4), the ethyl hydrogen atoms of the PMN moieties were fixed geometrically and refined

10.1021/cg030015j CCC: $25.00 © 2003 American Chemical Society Published on Web 08/19/2003

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Table 1. Crystallographic Parameters for 1-4 empirical form mol wt cryst syst space group a [Å] b [Å] c [Å] R [°] β [°] γ [°] V [Å3] Z final R1/wR2 for obsd data obsd reflns [I > 2σ(I)]

1

2

3

4

C16H17ClN4O4 364.79 monoclinic P21/c 11.068(4) 8.799(4) 18.122(4) 90 90.19(3) 90 1764.8(11) 4 0.0491 1642

C16H19ClN4O4 366.80 monoclinic P21/c 11.1219(18) 8.7520(17) 18.492(5) 90 91.042(17) 90 1799.7(6) 4 0.0468 2244

C20H19ClN4O4 414.84 triclinic P1 h 9.386(2) 10.0384(14) 10.694(2) 88.613(14) 87.498(16) 78.952(14) 987.8(3) 2 0.0428 3218

C28H30Cl2N8O4 613.50 monoclinic P21/n 11.244(8) 10.60(3) 12.480(10) 90 93.14(6) 90 1485(4) 2 0.0649 1365

Figure 1. (a-d) ORTEP view of 1-4. Ellipsoids for non-hydrogen atoms are drawn at the 50% probability level. using a riding model. All other hydrogen atoms were located from the difference Fourier map and were refined isotropically. Structure solution and refinement were carried out using the SHELX28 program. The geometric parameters were calculated by the PLATON9729 program.

Results and Discussion The targeted molecules, PMN hydrogen maleate (1), PMN hydrogen succinate (2), PMN hydrogen phthalate (3), and PMN fumarate (4), were prepared and their crystal structures were determined. The crystal data for the compounds are given in Table 1. ORTEP21 views of the compounds 1-4 are shown in Figure 1. As expected in all the crystal structures, the PMN moieties are protonated at N1 position. The dihedral angle between the 2,4-diaminopyrmidine and the p-chlorophenyl planes is 72.1(2)° in 1, 72.9(1)° in 2, 73.4(1)° in 3, and 79.1(2)° in 4. These values are close to the values observed in the modeling studies on the dihydrofolate reductasepyrimethamine (DHFR-PMN) complexes.22 Modeling studies of the DHFR-PMN complexes indicate that the dihedral angle plays an important role in the proper docking of the drug molecule at the active site of the enzyme.22 The torsion angle (C5-C6-C7-C8) is -91.9-

(4)° in 1, 91.7(1)° in 2, 65.2(1)° in 3, and 67.5(7)° in 4. Here the torsion angle is not very important as it does not affect the overall binding energy of the enzymedrug complex.22 The schematic representation of the three types of hydrogen-bonded motifs I-III observed in this study is shown in Figure 2. In all the compounds (1-3), the carboxylate group of the respective anions (hydrogen maleate, hydrogen succinate, hydrogen phthalate, and fumarate) interacts with the protonated pyrimidine moiety of PMN in a linear fashion through a pair of N-H‚‚‚O hydrogen bonds to form a cyclic hydrogenbonded motif (motif I). This can be designated by the graph-set23,24 notation R22(8). The motif has been observed in modeling studies of DHFR-PMN complexes,22 and it is one of the 24 most frequently observed motifs in organic crystal structures.25 In the crystal structures of compounds 1-3, the pyrimidine moiety of the PMN cations are centrosymmetrically paired through a couple of N-H‚‚‚N hydrogen bonds involving the 4-amino group and the pyrimidine N3 atom forming an eightmembered hydrogen-bonded ring with a graph-set motif R22(8). One of the oxygen atoms of the respective anions (hydrogen maleate, hydrogen succinate, and hydrogen

Organic Ionic Ladders

Figure 2. Schematic representation of the three types of hydrogen-bonded motifs observed in compounds 1-4 (CCDC 202246-202249).

phthalate) bridge the 2-amino and the 4-amino groups on either side of the paired PMN cations forming a hydrogen-bonded ring motif with graph-set notation R32(8). Thus, there is a hydrogen-bonded system of three fused cyclic hydrogen-bonded ring motifs [represented by graph-set notations R32(8), R22(8), and R32(8)]. This motif is called quadruple hydrogen bonding motif or DADA array motif (motif II). The diaminopyrimidinium cations are bridged by an O atom of the carboxylate group or methanol molecule or a water molecule or perchlorate anion or nitrate anion.12,13 Hence, this motif II can be effectively referred to as an O-mediated synthon. The oxygen atom of the carboxyl group of the respective anion (hydrogen maleate, hydrogen succinate, and hydrogen phthalate) forms an intramolecular hydrogen bond with the oxygen atom of the carboxylate group [with graph-set notation S7]. This DADA array motif is flanked on both sides by large hydrogen-bonded

Crystal Growth & Design, Vol. 3, No. 5, 2003 825

ring systems (16-membered ring with graph-set motif R64(16)]. The repeating pattern consisting of a DADA array (motif II), intramolecular hydrogen bonding, and cyclic hydrogen-bonded motif (motif I) gives rise to a hydrogen-bonded supramolecular ladder in the crystal systems (1-3). This type of hydrogen bonding pattern is shown in Figure 3. The structure of PMN hydrogen succinate having the same hydrogen bonding motif as PMN hydrogen maleate is interesting. Succinic acid is the saturated analogue of maleic acid differing from the former only by two hydrogen atoms. It is inferred that because of the robustness and potentially recurring nature of the hydrogen bonding motif II, succinic acid, which generally adopts the fully extended transoid conformation, folds back here, to give the intramolecular hydrogen bond giving perhaps the most stable hydrogen bonding motif. Because of the similarity in the crystal structures and very small difference in the chemical formula, the two crystals, PMN hydrogen succinate and PMN hydrogen maleate are nearly isomorphous as revealed by the very good agreement in their cell parameters.26 The reported crystal structures of succinate moieties have been retrieved from CSD database,27 and the conformation of the succinate moieties have been analyzed (Table 2). They indicate that most of the succinate anions, hydrogen succinate anions, and succinic acids have the fully extended transoid conformation. Very interestingly, in the present study, the hydrogen succinate anion is in a folded (cissoid) conformation. The dihedral angle is still less than that found in other hydrogen succinate crystal structures, the value being around 59°. Hence, it is clear that hydrogen succinate mimics hydrogen maleate in the PMN hydrogen succinate complex, the reason being the robustness of the hydrogenbonded synthon formed. It is probable that the strain energy arising as a result of folding is more than compensated by the intramolecular hydrogen bonding and the thermodynamic stability of the more robust synthon formed. In compound 4, motif I is self-organized to get different types of hydrogen bonding patterns. The 2-amino and 4-amino groups of the PMN moieties are hydrogen-bonded with both the carboxylate ends of the fumarate anion forming a 13-membered ring motif. This can be designated by a graph-set notation R22(13). Figure 4 illustrates that a fumarate anion holds the four PMN cations through the two hydrogen-bonded motifs I and two of the 13-membered hydrogen-bonded ring motifs [R22(13)]. The PMN cations are centrosymmetrially paired through a couple of N-H‚‚‚Cl hydrogen bonds involving a 4-amino group and chlorine atom (Cl1) resulting in the formation of 18-membered ring motif [with graph-set notation R22(18)] (motif III). This motif has also been observed in the crystal structure of neutral PMN.11 The 18-membered hydrogen-bonded motif (motif III) is self-organized or centrosymmetrically paired through a pair of C-H‚‚‚N hydrogen bonds resulting in the formation of a hydrogen-bonded supramolecular helical pattern (Figure 5). The structure of PMN fumarate differs from the other three in that it has a trans configuration and fumarate dianion is involved and not a hydrogen fumarate monoanion. The hydrogen bonding geometries are given in Table 3.

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Figure 3. (a-c) Hydrogen-bonded supramolecular organic ionic ladders in compounds 1-3.

Figure 5. Hydrogen-bonded supramolecular helical pattern in compound 4 (view along ac plane). Figure 4. Fumarate anionis holding the four PMN cations in compound 4 (view along ab plane).

Conclusions In the crystal structures of PMN with different 1,2dicarboxylaic acids, the presence of the predominant supramolecular motif II leads to the design of the same type of supramolecular hydrogen bonding patterns and

architectures, which is interesting and significant from a crystal engineering point of view. Thus, although the crystal structure is a subtle balance between several noncovalent forces, a design strategy based on hydrogen bonding has been presented here. The directionality and the selectivity of its interactions involved have been utilized in the synthesis of structures with predictable supramolecular motifs.

Organic Ionic Ladders

Crystal Growth & Design, Vol. 3, No. 5, 2003 827 Table 2. CSD Search on Succinate Moietiesa

s. no.

a

ref. code

acid part

1 2 3 4 5 6 7 8 9 10

AQSCCA BULGEU BURWEQ BZASUC DEQFUA DPSUCC DURGAY DURGAY01 FOHRAV FUMCEV

S-

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36

FUMQAF FUMNAC GURFAA HENCSC JOSPOW JOTHEF JOTHEF01 JOTHEF02 KFSCCN KFSCCN KHSUCC KHSUCC01 KIXJIK KIXJUW KOBKIV KOHPOM KTHSUC LABZUJ LACBAS LISUCC LOXSUC10 MELNIA NELKAQ NOZPOH NOZQAU NOZQEY

S-S-HSS-S-S-S-S-SA SA HSHSHSHSS-S-HSSA HSS-HSSA S-S-S-S--

37 38 39 40 41

PEWHEE PEWHEE01 PEWHEE02 PEWHEE03 PEWHEE04

HSHSHSHSHS-

torsion angle 180.00 -180.00 180.00 179.96 179.98 -179.97 -179.98 -180.00 180.00 -63.19 A 63.67 B 173.42 173.45 179.82 179.97 179.98 180.00 -180.00 -180.00 180 -180.00 180.00 -180.00 176.48 -168.45 179.98 180.00 -177.07 -179.98 -70.255 180.00 180.00 -179.97 179.98 179.98 180.00 -179.98 A -180.00 B -70.84 -70.44 -70.61 -70.22 -69.85

SA S-SA S-S-S-S-S-S--

s. no.

ref. code

acid part

torsion angle

42 43 44 45 46 47 48 49 50 51 52 53

PEWHEE05 PINNIJ POTREV POTREV01 QIPNAE QIWZEB RIGTAC SERMOR SERMOR10 SIXZOO SIXZUU SOSBAD

HS-

HSS-S-SA S-S-SA SA HSHSS--

54 55 56 57 58

SOVQEZ SUCACB02 SUCACB03 SUCACB06 SUCACB07

SA SA SA SA SA

59 60 61 62 63 64 65 66 67 68 69 70 71 72

SUCACB08 SUCACB09 SUCACB11 SUTPAY SUTPAY01 SUTPEC SUTPEC01 SUTPEC02 TAJVOP TANPON TASUCM01 VEJXAJ VEJXAJ01 VIRSAQ

SA SA SA S-S-S-S-S-SA S-S-S-S-S--

73 74 75 76 77 78

WERCEB WOJHEI WOQBOT XATNEL XELJON YOWDET

79 80

YOWDIX ZUKXIM

S-SA SA S-S-S-SA S-SA

-69.66 174.67 -179.98 180.00 179.98 71.78 180.00 72.35 72.35 180.00 180.00 179.80 A -180.00 B 180.00 179.98 180.00 -179.98 180.00 A 179.97 B -180.00 180.00 -180.00 179.71 -179.90 75.27 74.95 74.20 -79.50 -69.38 174.14 180.00 179.98 180.00 A 180.00 B 179.98 179.98 180.00 180.00 177.96 179.15 179.15 180.00 -180.00

SA ) succinic acid, HS- ) hydrogen succinate, and S-- ) succinate. Table 3. Geometries of the Hydrogen Bonds in 1-4

compound no. 1

2

D-H‚‚‚A

d(H‚‚‚A) (Å)

d(D‚‚‚A) (Å)

∠(D-H‚‚‚A) (°)

compound no.

N1-H1‚‚‚O1 N2-H2A‚‚‚O2 N2-H2B‚‚‚O4a O3-H3′‚‚‚O2 N4-H4A‚‚‚N3b N4-H4B‚‚‚O4c N1-H1‚‚‚O1d N2-H2A‚‚‚O2d N2-H2B‚‚‚O4e O3-H3′‚‚‚O2 N4-H4A‚‚‚N3 N4-H4B‚‚‚O4f C11-H11‚‚‚O2g C14-H14‚‚‚N3b

1.87(3) 1.94(3) 2.08(3) 1.44(4) 2.07(4) 2.14(3) 1.83(3) 1.88(3) 2.10(3) 1.45(3) 2.18(3) 2.13(3) 2.58(3) 2.56(5)

2.760(4) 2.836(3) 2.981(4) 2.432(3) 3.048(4) 2.821(3) 2.720(3) 2.834(3) 2.962(3) 2.449(3) 3.045(3) 2.842(3) 3.509(3) 3.389(11)

171(3) 176(3) 168(3) 178(2) 175(3) 144(3) 174(3) 178.0(18) 166(3) 174(3) 170(3) 139(2) 163(2) 146(4)

3

4

D-H‚‚‚A

d(H‚‚‚A) (Å)

d(D‚‚‚A) (Å)

∠(D-H‚‚‚A) (°)

N1-H1‚‚‚O2h N2-H2A‚‚‚O4i N2-H2B‚‚‚O1h O1-H3‚‚‚O3 N4-H4A‚‚‚O4d N4-H4B‚‚‚N3j C17-H17‚‚‚O4 C20-H20‚‚‚O2 N1-H1‚‚‚O2 N2-H2A‚‚‚O1 N2-H2B‚‚‚O2k N4-H4A‚‚‚O1l N4-H4B‚‚‚Cl1m

1.79(2) 2.06(2) 2.53(2) 1.17(3) 2.36(2) 2.23(2) 2.28(2) 2.22(2) 1.90(5) 1.93(7) 2.31(6) 2.13(5) 2.78(4)

2.653(2) 2.894(2) 3.337(3) 2.400(2) 3.029(2) 3.131(2) 2.693(2) 2.637(3) 2.724(9) 2.814(9) 2.982(10) 2.884(10) 3.372(10)

176.5(18) 157.0(19) 165.0(18) 172(3) 133.1(17) 174.4(18) 104.6(14) 105.5(14) 178(6) 169(6) 136(5) 154(5) 126(3)

a 3 - x, -y, 2 - z. b 2 - x, 1 - y, 2 - z. c -1 + x, 1 + y, z. d -x, 1 - y, 1 - z. e -1 + x, y, z. f 1 - x, -y, 1 - z. g 1 - x, 1 - y, 1 - z. 2 - y, 2 - z. i -1 + x, 2 + y, z. j -1 - x, 3 - y, 1 - z. k 3/2 - x, -1/2 + y, 3/2 - z. l 1/2 + x, -1/2 - y, 1/2 + z. m 3 - x, -y, 2 - z.

Acknowledgment. N.S. thanks the Council of Scientific and Industrial Research, New Delhi, India, for the award of a Senior Research Fellowship [no. 9/475(111) 2002, EMR-I]. P.T.M. thanks Dr. P. Prabakaran for some discussions. A part of the work was carried out during an Exchange Fellowship to P.T.M. under the INSA(India)-DFG(Germany) program.

h

-x,

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