Investigation of supramolecular synthons and structural characterisation of aminopyridine-carboxylic acid derivatives

Background Co-crystal is a structurally homogeneous crystalline material that contains two or more neutral building blocks that are present in definite stoichiometric amounts. The main advantage of co-crystals is their ability to generate a variety of solid forms of a drug that have distinct physicochemical properties from the solid co-crystal components. In the present investigation, five co-crystals containing 2-amino-6-chloropyridine (AMPY) moiety were synthesized and characterized. Results The crystal structure of 2-amino-6-chloropyridine (AMPY) (I), and the robustness of pyridine-acid supramolecular synthon were discussed in four stoichiometry co-crystals of AMPY…BA (II), AMPY…2ABA (III), AMPY…3CLBA (IV) and AMPY…4NBA (V). The abbreviated designations used are benzoic acid (BA), 2-aminobenzoic acid (2ABA), 3-chlorobenzoic acid (3CLBA) and 4-nitrobenzoic acid (4NBA). All the crystalline materials have been characterized by 1HNMR, 13CNMR, IR, photoluminescence, TEM analysis and X-ray diffraction. The supramolecular assembly of each co-crystal is analyzed and discussed. Conclusions Extensive N---H · · · N/N---H · · · O/O---H · · · N hydrogen bonds are found in (I-V), featuring different supramolecular synthons. In the crystal structure, for compound (I), the 2-amino-6-chloropyridine molecules are linked together into centrosymmetric dimers by hydrogen bonds to form homosynthon, whereas for compounds (II-V), the carboxylic group of the respective acids (benzoic acid, 2-aminobenzoic acid, 3-chlorobenzoic acid and 4-nitrobenzoic acid) interacts with pyridine molecule in a linear fashion through a pair of N---H · · · O and O---H · · · N hydrogen bonds, generating cyclic hydrogen-bonded motifs with the graph-set notation R228 , to form heterosynthon. In compound (II), another intermolecular N---H · · · O hydrogen bonds further link these heterosynthons into zig-zag chains. Whereas in compounds (IV) and (V), these heterosynthons are centrosymmetrically paired via N---H · · · O hydrogen bonds and each forms a complementary DADA [D = donor and A = acceptor] array of quadruple hydrogen bonds, with graph-set notation R238, R228 and R238.

(II-V), the carboxylic group of the respective acids (benzoic acid, 2-aminobenzoic acid, 3-chlorobenzoic acid and 4-nitrobenzoic acid) interacts with pyridine molecule in a linear fashion through a pair of N-H · · · O and O-H · · · N hydrogen bonds, generating cyclic hydrogen-bonded motifs with the graph-set notation R 2 2 8 ð Þ, to form heterosynthon. In compound (II), another intermolecular N-H · · · O hydrogen bonds further link these heterosynthons into zig-zag chains. Whereas in compounds (IV) and (V), these heterosynthons are centrosymmetrically paired via N-H · · · O hydrogen bonds and each forms a complementary DADA [D = donor and A = acceptor] array of quadruple hydrogen bonds, with graph-set notation R 3 2 8 ð Þ, R 2 2 8 ð Þ and R 3 2 8 ð Þ.

Background
Co-crystal is a structurally homogeneous crystalline material that contains two or more neutral building blocks that are present in definite stoichiometric amounts. The main advantage of co-crystals is their ability to generate a variety of solid forms of a drug that have distinct physicochemical properties from the solid co-crystal components. Such properties include, but are not limited to, solubility, dissolution, bioavailability, hygroscopicity, hydrate/solvate formation, crystal morphology, fusion properties, chemical and thermal stabilities, and mechanical properties. Understanding the knowledge of supramolecular synthons is important for hydrogen bond construction. There are two types of synthons which are supramolecular homosynthon (composed of self-complementary functional groups, as exemplified by the carboxylic acid dimer) and supramolecular heterosynthon [1] (composed of different but complementary functional groups). For instance, the latter includes acid…pyridine [2], acid…amide [3,4], hydroxyl…amine [5] and hydroxyl…pyridine [6] supramolecular synthons with typical distance ranges for  [9] and it is one of the 24-most frequently observed cyclic-hydrogen bonded motifs in organic crystal structures [10]. The various hydrogen-bonding patterns involving aminopyrimidine-carboxylate interactions have been reported in the literatures [11]. Many of the recurring hydrogen-bonded motifs leading to supramolecular architectures play a significant role in crystal engineering [12,13]. The study of co-crystals is of sprouting interest since Active Pharmaceutical Ingredient (API) properties can be modified in a graded manner by revolving into cocrystals [14]. In the present investigation, we have chosen 2-amino-6-chloropyridine (AMPY) (its neutral form) (I), because the molecules of this ligand are self-assembled via N-H · · · N hydrogen bonds to form homosynthon. It also interacts with carboxylic acid molecules through N-H · · · O hydrogen bonds, to form heterosynthon, and paired centrosymmetrically via another N-H · · · O hydrogen bonds, to form a DADA array by multiple hydrogen bonds. The later is a habitually occurring synthon which occurs in amine-carboxylic acid systems. The carboxylic acids referred to in this study, together with their abbreviated designations, are: benzoic acid (BA), 2aminobenzoic acid (2ABA), 3-chlorobenzoic acid (3CLBA) and 4-nitrobenzoic acid (4NBA). The co-crystals were analyzed by IR spectroscopy, 1 HNMR, 13 CNMR, photoluminescence, TEM analysis and X-ray diffraction.

Results and discussion
The targeted molecules, AMPY (I), AMPY…BA (II), AMPY…2ABA (III), AMPY…3CLBA (IV) and AMPY… 4NBA (V), were prepared and their crystal structures were determined. ORTEP views of these compounds (I-V) are shown in Figure 1. The crystal structures of (I-V) have been determined using single-crystal X-ray diffraction. Crystallographic data for compounds (I-V) are presented in Table 1, whereas hydrogen bond geometries are listed in Table 2. The purity of the solid phase of these complexes was characterized by XRPD. All the crystalline materials have been characterized by 1 HNMR, 13 CNMR, IR, photoluminescence and TEM analysis.

Conclusions
In this article, 2-amino-6-chloropyridine and its four cocrystals of benzoic acid derivatives were structurally characterized. It was observed that homosynthon was presented in crystal structure (I), whereas carboxylic acid…pyridine Table 2 Hydrogen-bond geometries for compounds (I-V)  heterosynthon were formed in all four co-crystals structures (II)-(V). DADA arrays were observed in the crystal structures of (IV) and (V). These DADA arrays have been observed in many 2,4-diaminopyrimidine carboxylate complexes as this motif is a potentially recurring synthon.
Common laboratory analytical tools such as 1 H NMR, 13 CNMR, IR, photoluminescence, TEM analysis and XRD were used to understand the supramolecular architectures and to confirm the formation of the co-crystals. All cocrystals display photoluminescence in the solid state. The emission colours of the AMPY-BA derivatives-based building modules are significantly influenced by their incorporation of co-formers into the co-crystals.

Synthesis of (I-V)
Hot methanol solution of 2-amino-6-chloropyridine (AMPY) (I) (57 mg, Aldrich) was warmed over a heating magnetic stirrer for 5 minutes. The resulting solution was allowed to cool slowly at room temperature. Crystals of the compound (I) appeared from the mother liquor after a few days. Compounds (II-V) were prepared by the mixing of hot methanolic solutions of AMPY (Sigma Aldrich, Malaysia) and the corresponding benzoic acid and its derivatives [2-amino benzoic acid, 3-chlorobenzoic acid and 4-nitrobenzoic acid (Sigma Aldrich, Malaysia) in a 1:1 molar ratio. The resultant mixtures were warmed over a water bath at 80˚C for 20 min, allowed to cool slowly and kept at room temperature for crystallization. After a few days, crystals of (II-V) were obtained.

Optical (OM) & Transmission Electron (TEM) Microscopes
An optical microscope (SZII; Olympus, Tokyo, Japan) equipped with a CCD camera (SSC-DC50A; SONY, Tokyo, Japan) was used to take images of crystal habit. Transmission Electron Micrographs (TEM) were obtained using a Philips TEM CM12 with an image analysis system. The specimen was prepared by depositing a drop of the alcholic solution of I-V suspension on the graphite grid sample holder and gently dried.

Photoluminescence (PL)
PL spectra at room temperature of the samples were measured by Jobin Yvon HR 800 UV using 325 nm line of a He-Cd laser and Ar laser as the excitation source respectively. An analyzer was used to select the transverse-electric mode of the scattering light. Polarization-dependent PL spectra were performed at 15 K with a frequency-doubled Nd + -YAG laser at 532 nm as excitation source. The collected PL light was dispersed through a 0.5 m monochromator equipped with a 300 gr/mm grating and detected by an extended-InGaAs detector (detecting range: 0.5-1.1 eV). A linear polarizer was utilized to analyze the polarization of luminescence, and a depolarizer was placed in between the polarizer and monochromator to eliminate the response from the grating. In order to confirm the repeatability, the measurements were carried out for three times. Since the difference between the results was minimum (<0.1%), only one data from each measurement is presented for discussion.
Powder X-ray Diffraction (XRPD) XRPD diffractogram at 25˚C provided another piece of information for the identification and crystallinity of starting materials and co-crystals. Moreover, the powder diffraction patterns generated with the single-crystal data of compounds (I-V) using Mercury [20] matches accurately these experimental XRPD spectra measured using the D5000 powder diffractometer, thereby confirming the purity of the synthesized co-crystals. XRPD diffractograms were collected by SIEMENS D5000 DIFFRACT-OMETER. The source of XRPD was CuKα (1.542 Å) and the diffractometer was operated at 40 kV and 30 mA. The X-ray was passed through a 1 mm slit and the signal a 1 mm slit, a nickel filter, and another 0.1 mm slit. The