Urszula Rychlewska2 and Beata Warżajtis2 Beilstein Journal of Organic Chemistry Open Access

Background: Trimethoprim

The hydrogen-bonding networks in the crystal structures of TMP/pyrimethamine salts of various dicarboxylic acids have been investigated in our laboratory [13,21]. Recently we have also reported a novel isomorphism [21]. The crystal structures of pyrimethamine hydrogen maleate [21] and pyrimethamine hydrogen succinate [21] are isomorphous since the hydrogen succinate is the saturated analogue of hydrogen maleate. The hydrogen succinate ion adopts a folded conformation with an intramolecular hydrogen bond (mimicking the hydrogen maleate ion) leading to identical hydrogen-bonded networks in both the crystal structures. In the present work, crystal structures of TMP hydrogen phthalate and TMP hydrogen adipate have been investigated in order to identify the hydrogen bonding networks and compare them with those in the aliphatic analogue, TMP hydrogen maleate [22] and the homolog, TMP hydrogen glutarate [17] respectively.

Results and discussion
The schematic diagram of the hydrogen-bonded motifs observed in these crystal structures (see Additional file 1) is shown in fig. 1 &2. An ORTEP 3 view of the compounds 1 & 2 is shown in fig. 3 &4. In the compounds 1 (trimethoprim hydrogen phthalate) and 2 (trimethoprim hydrogen adipate)(see Additional file 2) one of the nitrogen atoms (N1) of the pyrimidine ring is protonated. The protonated pyrimidine ring interacts with the carboxylate oxygens through a pair of parallel N-H...O (Table 2) hydrogen bonds to form a fork-like interaction (motif I). This is reminiscent of the trimethoprim(TMP)-carboxylate interaction observed in the DHFR-TMP complexes [24]. This hydrogen bonded motif is one among the 24 most frequently observed bimolecular cyclic hydrogen-bonded motifs in organic crystal structures [25]. This has also been observed in the crystal structures of trimethoprim carboxylates such as trimethoprim salicylate monohydrate [26], trimethoprim acetate [9], trimethoprim salicylate methanol solvate [19], trimethoprim benzoate [10] etc,. This fork-like hydrogen-bonded interaction (motif I) has further self assembled in combination with other hydrogenbonded motifs to form different types of networks. The planes of the carboxylate group and the pyrimidine ring (involved in the fork-like interaction) make a dihedral angle of 9.8° in compound 1 and 6.3° in compound 2 respectively.  [22]. The same type of DADA array has also been observed in the other crystal structures of trimethoprim-salicylate methanol solvate [18], trimethoprim-trifluoroacetate [15], pyrimethamine-hydrogen phthalate [21] etc,. The characteristic hydrogen-bonded rings observed in the structure aggregate into a supramolecular ladder consisting of a pair of chains, each of which is built up of alternate TMP and hydrogen phthalate ions (motif III & IV) as shown in fig. 5 [28]. The one of the hydrogen atoms of the 2-amino group is also involved in The ORTEP 3 view of the asymmetric unit of the compound 1 Figure 3 The ORTEP 3 view of the asymmetric unit of the compound 1.
The schematic diagram for the various hydrogen-bonded motifs observed in compound (1) Figure 1 The In the compound 2 (Table 1), in motif V, two TMP cations and two hydrogen adipate anions are arranged about an inversion center so that the complementary DDAA arrays of quadruple hydrogen-bonding patterns are formed. This has also been observed in TMP m-chlorobenzoate [11], TMP-hydrogen glutarate [17] and TMP succinate [29]. In motif VI, the hydrogen atoms of 2-and 4-amino groups of the TMP cation are hydrogen-bonded to the carboxylate and carboxyl ends, respectively, of the same hydrogen adi-pate ion. Thus, the hydrogen adipate bridges the 2-amino and 4-amino groups of TMP. These hydrogen-bonded interactions are almost identical with TMP-dicarboxylate salts such as TMP-hydrogen glutarate [17] and TMP-succinate [29] but differ only in the number of carbon atoms of the chain. Such cyclic hydrogen-bonded ring formation blocks the base-pairing interaction between the pyrimidine moieties. Hence base-pairing has not been observed in the crystal structures of trimethoprim-hydrogen glutarate [17] and TMP-succinate [29] and compound 2. The supramolecular sheet structure for this compound 2 is shown in fig. 6. The carboxyl group (O7-H) of the hydrogen adipate is hydrogen-bonded to the carboxylate group The ORTEP 3 view of the asymmetric unit of the compound 2    (3) 168 (2) Symmetry Codes : a = -1+x, 1+y, z, b = 1+x, y, z, c = -x, 1-y, 1-z, d = 1-x, -y, 1-z, e = 2-x, 1-y, -z, f = -1+x, y, z (O4) of the neighbouring hydrogen adipate ion(motif VII). This head-to-tail arrangement (carboxyl-carboxylate interaction) of the hydrogen adipate ions leads to hydrogen-bonded supramolecular chain. This is shown in fig. 7.
The internal angles at N1 (C2-N1-C6) in the protonated pyrimidine ring of the compounds 1 and 2 are 119.9(1)°a nd 119.6(2)° respectively, the corresponding angle in the neutral trimethoprim(TMP) molecule [31] being 115.5°. Such an enhancement of internal angle at the site of protonation of pyrimidine ring is very characteristic. In the compounds 1 and 2 the dihedral angles between the plane of the pyrimidine and phenyl rings are 74.0(7)°a nd 88.8° respectively. These values are closer to the crystal structures of TMP-sulfate trihydrate [20] (75.8(9)°) and TMP 4-hydroxybenzoate dihydrate [30] (89.1(1)°).
The major (77%) and minor (23%) components in the disordered hydrogen adipate molecule adopt quite unu-sual bent carbon chain conformations: the gauche-gauchetrans (ggt) and the gauche-trans-trans (gtt) forms, respectively. Of the 46 adipic acid fragments present in the Cambridge Crystallographic Data Base [32] there is only one example of the ggt conformation [33] and two cases in which the acid adopts the gtt form [34,35]. The adoption of the bent carbon chain conformation by adipic acid seems necessary in order to place the two terminal carboxyl functions in mutual syn orientation so that they can fasten the 2-and 4-amino groups of the TMP molecule. The disorder, on the other hand, might result from incompatible dimensions between the adipic acid and the two amino groups of the TMP molecule. Much better fit between the 2-and 4-amino groups of the TMP molecule on one side, and aliphatic dicarboxylic acid on the other side is achieved in the case of glutaric acid [17]. This is for two reasons: firstly, in the energetically preferred extended carbon chain conformation an odd number of carbon atoms in a chain implicates the syn orientation of the ter-The hydrogen-bonded supramolecular ladder in the compound 1 Figure 5 The hydrogen-bonded supramolecular ladder in the compound 1.
minal carboxyl functions and, secondly, the carbon chain is identical in length as the N2-C2-N3-C4-N4 fragment of the TMP. The observation that, irrespective on the number of carbon atoms constituting the dicarboxylic acid chain, the TMP/dicarboxylic acid interactions are represented by the same motif VI is quite unusual.
The TMP molecule can be regarded as having a rigid frame, built on the methyl group, on which the substituted phenyl and pyrimidine six-membered rings are free to rotate. An arbitrary conformation of this molecule can be described by the torsion angles of the two rings to the frame. We define these torsion angles as C4-C5-C7-C8 and C5-C7-C8-C9, i.e. with respect to one of the rings the other can rotate around the C5-C7 or around the C7-C8. Figure 8 shows the distribution of these torsion angles in 37 TMP fragments deposited in the Cambridge Structural Data Base [32]. The points mostly cluster around the plus/ minus (80°, 30°) and (160°, 70°) regions. The points representing the (80°, 30°) combination predominantly lie in the region where both torsion angles have the same sign, which is the condition for a propeller conformation. In the presented crystal structures 1 and 2 the correspond-ing torsion angles adopt the values -161.4(1) and 63.5°, and 69.1(2) and 36.5(3)°, respectively. Hence the observed TMP conformations match the two most densely populated conformations observed in other crystal structures containing the TMP moieties.