R22(8) motifs in Aminopyrimidine sulfonate/carboxylate interactions: Crystal structures of pyrimethaminium benzenesulfonate monohydrate (2:2:1) and 2-amino-4,6-dimethylpyrimidinium sulfosalicylate dihydrate (4:2:2)

Background Pyrimethamine [2,4-diamino-5-(p-chlorophenyl)-6-ethylpyrimidine] is an antifolate drug used in anti-malarial chemotherapy. Pyrimidine and aminopyrimidine derivatives are biologically important compounds owing to their natural occurrence as components of nucleic acids. Results In the crystal structures of two organic salts, namely pyrimethaminium benzenesulfonate monohydrate 1 and 2-amino-4, 6-dimethylpyrimidinium 3-carboxy-4-hydroxy benzenesulfonate dihydrate 2, pyrimethamine (PMN) and 2-amino-4,6-dimethylpyrimidine (AMPY) are protonated at one of the nitrogens in the pyrimidine rings. In both the PMN and AMPY sulfonate complexes, the protonated pyrimidine rings are hydrogen bonded to the sulfonate groups, forming a hydrogen-bonded bimolecular ring motif with graph-set notation R22(8). The sulfonate group mimics the carboxylate anion's mode of association, which is more commonly seen when binding with 2-aminopyrimidines. In compound 1, the PMN moieties are centrosymmetrically paired through a complementary DADA array of hydrogen bonds. In compound 2, two types of bimolecular cyclic hydrogen bonded R22(8) motifs (one involving the carboxylate group and the other involving sulfonate group) coexist. Furthermore, this compound is stabilized by intra and intermolecular O-H...O hydrogen bonds. Conclusion The crystal structures of pyrimethaminium benzenesulfonate monohydrate and 2-amino-4,6-dimethylpyrimidinium sulfosalicylate dihydrate have been investigated in detail. In compound 1, the R22(8) motif involving the sulfonate group is present. The role the sulfonic acid group plays in mimicking the carboxylate anions is thus evident. In compound 2, two types of bimolecular cyclic hydrogen bonded R22(8) motifs (one involving the carboxylate group and the other involving sulfonate group) coexist. In both the compounds base pairing also occurs. Thus homo and hetero synthons are present.


Background
Intermolecular interactions and hydrogen bond motifs that occur repeatedly in crystal structures are called supramolecular synthons. Synthons are the recognition motifs between building blocks that can be used to propagate networks or supramolecular assemblies [1]. Hydrogen bonding patterns involving sulfonate groups in biological systems and metal complexes are of current interest [2][3][4][5][6]. Such interactions can be used for designing supramolecular architectures. Numerous hydrogen-bonding patterns of aminopyrimidine-carboxylate interactions [7,8] have been reported in the literature. Recently, different types of hydrogen-bonding motifs in sulfonate salts have been examined using the Cambridge Structural Database (CSD) [9].

Pyrimethamine
[2,4-diamino-5-(p-chlorophenyl)-6ethylpyrimidine] is an antifolate drug [20] used in antimalarial chemotherapy. The drug binds with great affinity to the bacterial enzyme dihydrofolate reductase (DHFR) [21]. PMN is also used along with other drugs for the treatment of opportunistic infections in patients with AIDS [22]. 2-aminopyrimidine and its derivatives are of particular interest as adduct formers because of their ability to form stable hydrogen-bonded chains via their stereochemically associated amine group and the ring N atoms [23]. Hydrogen bonding plays a key role in molecular recognition [24] and crystal engineering [25]. The present study deals with hydrogen bonding, the nature of hydrogen-bonded arrays and the supramolecular synthons present in the aminopyrimidine-sulfonate salts (Scheme 1). Scheme 1: Hydrogen-bonded arrays and the supramolecular synthons present in the aminopyrimidine-sulfonate salts

Results and discussion
The three dimensional supramolecular architectures in such compounds can be analyzed in terms of various components such as motifs, chains, stacking interactions etc. The schematic representation of the hydrogen-bonded motifs observed in this study is shown in Figure 1 [29]. In compounds 1 and 2, the sulfonate group mimics the association of the carboxylate moiety and makes a hydrogen-bonded ring of graphset notation R 2 2 (8) with the PMN and AMPY cations. The hydrogen-bonding geometry of the N-donors to the sulfonate group gave a mean value for the N-H...O hydrogen bond distances involving sulfonates that was slightly longer in range when compared with the carboxylate O atoms indicating that sulfonates form longer and weaker hydrogen bonds with N-donors than carboxylates. These trends are also observed in the present investigation, as indicated in Table 1. The hydrogen bonds formed between the sulfonates and the N-donors were generally linear [30]. In compound 1, the protonated pyrimeth-aminium (N1A and N1B) cations interact with the (O3A and O2B) oxygen atoms of the sulfonate anions through N-H...O hydrogen bonds (Heterosynthon) forming an eight membered ring motif R 2 2 (8) [31][32][33] (motif II). The pyrimethaminium cations are centrosymmetrically paired through N4-H...N3 hydrogen bonds (Homosynthon) involving the 4-amino group and the N3 atom of the unprotonated pyrimidine to form the ring motif R 2 2 (8) (motif III) ( Table 1). In addition to the base pairing, one of the sulfonate oxygen atoms (O1B and O1A) (a hydrogen bond acceptor) bridges the 4-amino and the 2-amino groups on both sides of the pairing. The combination of such base-pairing patterns and the further bridging of the The ORTEP view of the asymmetric unit of the compound 2 (Hydrogen atoms are omitted for clarity) Figure 3 The ORTEP view of the asymmetric unit of the compound 2 (Hydrogen atoms are omitted for clarity).
The schematic diagram for the various hydrogen-bonded motifs observed in compounds 1 and 2 Figure 1 The schematic diagram for the various hydrogen-bonded motifs observed in compounds 1 and 2. The ORTEP view of the asymmetric unit of the compound 1 (Hydrogen atoms are omitted for clarity) Figure 2 The ORTEP view of the asymmetric unit of the compound 1 (Hydrogen atoms are omitted for clarity).
bases involved in the pairing by hydrogen bonds, leads to the formation of a linear array of four hydrogen bonds. This is called a complementary DADA array (motif V) of quadruple hydrogen-bonding patterns (D stands for hydrogen-bond donor, and A stands for hydrogen-bond acceptor). The corresponding graph-set notations are R 3 2 (8), R 2 2 (8) and R 3 2 (8) (Figure 4). This type of DADA array of quadruple hydrogen bonds has been observed in some previously reported crystal structures [12].

Conclusion
The crystal structures of pyrimethamine benzenesulfonate monohydrate and 2-amino-4,6-dimethylpyrimidine sulfosalicylate dihydrate have been investigated in detail. In compound 1, the R 2 2 (8) motif involving the sulfonate group is present. The role the sulfonic acid group plays in mimicking the carboxylate anions is thus evident. In compound 2, two types of bimolecular cyclic hydrogen bonded R 2 2 (8) motifs (one involving the carboxylate group and the other involving sulfonate group) coexist. In both the compounds base pairing also occurs. Thus homo and hetero synthons are present. These synthons combine to form a supramolecular network. This observation is rel- The hydrogen-bonded DADA array in the compound 1 Figure 4 The hydrogen-bonded DADA array in the compound 1.
evant for many supramolecular architectures and crystal engineering.

Experimental
Compounds 1 and 2 were prepared by the mixing of hot methanolic solutions of PMN (62 mg, Shah Pharmachem, India) or AMPY (Aldrich) and the corresponding acids -benzene sulfonic acid (40 mg, Merck) & 3-carboxy-4-hydroxy-benzene sulfonic acid (55 mg, Merck) in 1:1 molar ratio and warming over water bath for 20 min. After a few days blocks of colourless crystals of compound 1 and 2 were obtained.

X-ray Crystallography
X-ray diffraction data were collected on a Bruker Nonius Kappa CCD area detector diffractometer by using MoKα (λ 0.71073 Å) for compounds 1 and 2 at 120(2)K. The structures were solved by direct methods and refined by full-matrix least squares (on F 2 ) SHELXS97 and SHELXL97 [34], with the graphics produced using PLATON97 [35]. All the non-hydrogen atoms were located from a Fourier map and refined anisotropically. All the hydrogen atoms for compounds 1 and 2 were positioned geometrically and refined as riding. In compound 1, the O1 W of water is disordered and the hydrogen atoms are not found. In compound 2, the water (O1 W) hydrogen atoms are located from difference Fourier map. The O2 W of water is disordered, the hydrogen atoms are not found. The crystal data and details of structural determination for the compounds 1 and 2 are given in Table 2. CCDC reference numbers: 611485 and 611479. All CIF information can be found in Additional file 1.
Hydrogen-bonding patterns involving carboxylate/sulfonate groups in compound 2 (I, II, IV and VI indicates hydrogen bonded motifs) Figure 5 Hydrogen-bonding patterns involving carboxylate/sulfonate groups in compound 2 (I, II, IV and VI indicates hydrogen bonded motifs).
A view of the supramolecular chain made up of sulfosalicylate and water molecule in compound 2

Figure 7
A view of the supramolecular chain made up of sulfosalicylate and water molecule in compound 2.
One dimensional chain made up of sulfosalicylate and AMPY molecule in compound 2 Figure 6 One dimensional chain made up of sulfosalicylate and AMPY molecule in compound 2.
A view of π-π stacking interaction between benzenesulfonate anions in compound 1 Figure 8 A view of π-π stacking interaction between benzenesulfonate anions in compound 1.

Additional file 1
Crystallographic Information. Contains all relevant CIF information.