Design of co-crystals/salts of some Nitrogenous bases and some derivatives of thiophene carboxylic acids through a combination of hydrogen and halogen bonds

Background The utility of N-heterocyclic bases to obtain molecular complexes with carboxylic acids is well studied. Depending on the solid state interaction between the N-heterocyclic base and a carboxylic acid a variety of neutral or ionic synthons are observed. Meanwhile, pyridines and pyrimidines have been frequently chosen in the area of crystal engineering for their multipurpose functionality. HT (hetero trimers) and LHT (linear heterotetramers) are the well known synthons that are formed in the presence of pyrimidines and carboxylic acids. Results Fourteen crystals involving various substituted thiophene carboxylic acid derivatives and nitrogenous bases were prepared and characterized by using single crystal X-ray diffraction. The 14 crystals can further be divided into two groups [1a-7a], [8b-14b] based on the nature of the nitrogenous base. Carboxylic acid to pyridine proton transfer has occurred in 3 compounds of each group. In addition to the commonly occurring hydrogen bond based pyridine/carboxylic acid and pyrimidine/carboxylic acid synthons which is the reason for assembly of primary motifs, various other interactions like Cl…Cl, Cl…O, C–H…Cl, C-H…S add additional support in organizing these supermolecules into extended architectures. It is also interesting to note that in all the compounds π-π stacking occurs between the pyrimidine-pyrimidine or pyridine-pyridine or acid-acid moieties rather than acid-pyrimidine/pyridine. Conclusions In all the compounds (1a-14b) either neutral O–H…Npyridyl/pyrimidine or charge-assisted Npyridinium-H…Ocarboxylate hydrogen bonds are present. The HT (hetero trimers) and LHT (linear heterotetramers) are dominant in the crystal structures of the adducts containing N-heterocyclic bases with two proton acceptors (1a-7a). Similar type supramolecular ladders are observed in 5TPC44BIPY (8b), TPC44BIPY (9b), TPC44TMBP (11b). Among the seven compounds [8b-14b] the extended ligands are linear in all except for the TMBP (10b, 11b, 12b). The structure of each compound depends on the dihedral angle between the carboxyl group and the nitrogenous base. All these compounds indicate three main synthons that regularly occur, namely linear heterodimer (HD), heterotrimer (HT) and heterotetramer (LHT).


Background
The utilization of intermolecular interactions for directed self assembly in order to understand their strength, directionality as well as distance is perhaps the main goal of supramolecular chemistry and crystal engineering [1][2][3][4][5][6]. The identification of various commonly occurring synthons between two functional groups not only adds to knowledge but also simplifies the design and prediction of such supramolecular assemblies [7][8][9]. These interactions involve electrostatic, hydrogen bonding, Van der Waals and pi-pi stacking interactions. The perfect example that emphasizes the importance of hydrogen bonding is provided by Mother Nature in the form of complementary base pairing of the double helix of DNA [10,11]. Recently halogen bonding is a paradigm that complements the role of hydrogen bonding and its importance in formation of crystal structures has also been emphasized [12][13][14]. Also in recent years, the advances in this field have enabled the design and synthesis of molecules of pharmaceutical importance with improved physicochemical properties [15][16][17][18]. The utility of N-heterocyclic bases to obtain molecular complexes with carboxylic acids is well studied [19][20][21][22][23]. Depending on the solid state interaction between the N-heterocyclic base and a carboxylic acid a variety of neural or ionic synthons are observed.
Meanwhile, pyridines and pyrimidines have been frequently chosen in the area of crystal engineering for their multipurpose functionality. HT (hetero trimers) and LHT (linear heterotetramers) are the well known synthons that are formed in the presence of pyrimidines and carboxylic acids (Scheme 1). Especially the bipyridyl species with the robust hydrogen bonding sites and high molecular symmetry make it a versatile building block in building crystalline materials [23][24][25][26]. For the sake of further investigation, it is worthwhile to analyze and compare complex structures based on these pyridines and pyrimidines with rigid building blocks such as TPC, 5-TPC and TDC (TPC = Thiophene 2-carboxylic acid, 5-TPC = 5-Chloro thiophene 2-carboxylic acid, TDC-Thiophene dicarboxylic acid). 5-TPC has been an interesting ligand to us due to its hydrogen bonding ability as well as formation of interesting Cl…Cl and C-H…Cl halogen bonding interactions [23,[27][28][29][30]. Beyond this, the aim of this work is to compare the differences that occur during the interchange of pyridines/pyrimidines and to list out the commonly occurring motifs. In our current investigation, the expected carboxylpyridyl heterosynthon [O-H…N pyridyl ] with graph set notation R 2 2 (7) is completely absent (Scheme 2). Instead of the R 2 2 (7) heterosynthon a single point synthon is observed (Scheme 2). This R 2 2 (7) hetero synthon is the most commonly occuring and the reliable recognition pattern between the carboxyl and pyridyl groups [6,31,32].

Results and discussion
Crystallographic data for the compounds (1a-7a) and (8b-14b) are summarized in (Tables 1 and 2) respectively. The hydrogen bonding parameters for the compounds (1a-7a) and (8b-14b) are listed in (Tables 3 and 4) respectively. ORTEP views of compounds (1a-7a) and (8b-14b) are shown in (Figures 1 and 2) respectively. Detailed structural description of all the co-crystals and salts are given below in succession. The details of the co-formers are given in (Scheme 3).
Crystal structure description of 5TPCAMPY (1a) 5TPCAMPY crystallizes in P2 1 /c monoclinic space group where the asymmetric unit consists of one molecule of AMPY and two crystallographically independent molecules of 5TPC. The desired primary N-H…O and O-H… N hydrogen bonding interactions between the two carboxylic groups of two 5TPC and the AMPY molecule result in the formation of a heterotrimer (HT) (Scheme 1). The commonly occurring R 2 2 (8) synthon by hydrogen bonds in the presence of pyrimidine/carboxylic acid interaction is the primary motif. The carboxylic acid moieties are coplanar with respect to the thiophene ring of the 5TPC resulting in a trimer. Adjacent trimers produced from these two strong hydrogen bonds are connected via two symmetry related hydrogen bonds involving H on the thiophene ring and O on the carboxylic acid, (Figure 3a). This results in the formation of hexameric supermolecule with the formation of R 2 2 (10) synthon ( Figure 3a). All these six molecules lie in the same plane they are connected to similar typed six molecules lying on the same plane by a pair of soft C-H…O hydrogen bonds in between the methyl group of pyrimidine and carboxylic acid group of 5-TPC (Figure 3b). There are Cl-π interactions observed between chlorine of thiophene ring and the thiophene ring of the adjacent hexameric supermolecule. These interactions are observed in between Cl1A → Cg3 [symmetry code: −1 + X,1/2-Y,-1/2 + Z] and Cl2A → Cg2 [symmetry code: 1 + X,1/2-Y,1/2 + Z] (where Cg2 = S1A, C2A → C5A; Cg3 = S2A, C7A → C10A).

Crystal structure description of TPCAMPY (2a)
The TPCAMPY crystallizes in the same P2 1 /c monoclinic space group as that of 5TPCAMPY, but the expected   Figure 4). The secondary synthons involving the N − H · · · N hydrogen bonds are responsible for the formation of the linear heterotetramer (LHT) (Scheme 1). The adjacent heterotetramers next to the carboxylate groups (on both sides) do not lie in the same plane and they are connected by a C-H…O hydrogen bonding interactions between hydrogen of thiophene ring of a LHT and carboxylate oxygen of another LHT ( Figure 4). This gives rise to a chain of hydrogen bonds. The pyrimidine ring of a LHT present in a plane, exhibits stacking interactions with another pyrimidine ring lying in parallel planes.
Crystal structure description of TDCAMPY (3a) As both (1a) and (2a), 3a also crystallizes in the same P2 1 /c monoclinic space group. The asymmetric unit consists of two crystallographically independent TDC (A, B) and AMPY (A, B) molecules. The two molecules adopt similar geometry and supramolecular interactions.
In the crystal two individual trimers are formed as a result of hydrogen-bond interactions between the two carboxylic acid groups and pyrimidine groups (A molecule of TDC with that of A molecule of AMPY, B molecule of TDC with that of B molecule of AMPY) (Figure 5a). Due to the presence of two carboxylic acid groups of the TDC the chain extends along the b axis. There are stacking interactions observed between the AMPY of A chain and AMPY of B chain, similarly, stacking interactions are observed between TDC of A chain and TDC of B chain ( Figure 5a).
Two of the AB chains are again connected to an AB chain which are parallel to each other by stacking interaction between the thiophene ring of A chains. This leads to a wavy sheet like arrangement extending along the b axis ( Figure 5b).

Crystal structure description of 5TPCCYT (4a)
The asymmetric unit of (4a) consists of a cytosine (CYT), a protonated cytosine (CYTH + ) and a carboxylate anion. Usually the cytosine gets protonated at N3 and the protonated form (CYTH + ) can interact with the neutral cytosine (CYT) through a set of three hydrogen bonds generating a (CYTH + …CYT) motif as shown in. In the cytosine molecule, protonation at N3 leads to widening of C4-N3-C2 angle from 120.05°to 123.19° [33,34]. The protonated cytosine (CYTH+), and the cytosine (CYT) are linked via triple hydrogen bonds made up of two N-H…O and a N-H…N hydrogen bond ( Figure 6a). This CYT-CYTH + base pair has also been observed in many crystal structures [35,36]. These CYT-CYTH + base pairs are further linked via N-H…O hydrogen bonds leading to chains of base pairs. Such chains running parallel to one another are stacked to the other chain by a pair of π-π stacking interactions between the protonated cytosine (CYTH+) of one chain and the neutral cytosine (CYT) of the other chain (Figure 6a).
Also a pair of strong N-H…O hydrogen bonds between the carboxylate anion and (CYTH + of one chain as well     Table 4 Hydrogen bond metrics for compounds 8b-14b as neutral cytosine (CYT) of the other chain) hold the chains together. This carboxylate anion plays a major role in connecting the chains together. A Cl…π is observed between chlorine of thiophene ring of a chain and the thiophene ring of the adjacent chain ( Figure 6b).
Crystal structure description of 5TPCBA (5a) The compound (5a) crystallizes in P-1 triclinic spacegroup, where the asymmetric unit consists of one molecule of BA and a molecule of 5TPC. The dihedral angle between the adenine plane and phenyl ring plane is 87.2(3)°. The primary R 2 2 (9) motif is composed of 5TPC and BA which are connected through a couple of strong O-H…N and N-H…O hydrogen bonds (Figure 7a). This motif is very much similar to that observed in the related structures [37][38][39]. Adjacent dimeric units are further connected through self complementary secondary N − H · · · N hydrogen bonds. The hydrogen of the phenyl ring and the carboxylic acid oxygen interact in a C-H…O hydrogen bond (Figure 7a). Thus the primary and secondary hydrogen bonds, O − H · · · N, N − H · · · O, N − H · · · N and C-H…O combine to form a tetrameric super molecule ( Figure 7a). Each of these tetrameric super molecules is linked by C-H…O interactions. As in the (4a), the Cl of the 5-TPC plays a major role in building of the supramolecular architectures. The adjacent chains made of the tetrameric super molecules are linked to one another by the Cl…π interactions between Cl of 5-TPC of one chain and the phenyl ring of BA of another chain (Figure 7b).
Crystal structure description of 5TPC44BIPY and TPC44BIPY (8b, 9b) The ORTEP views of 5TPC44BIPY and TPC44BIPY are shown in (Figure 9a and b). The asymmetric unit of (8b) is composed of one molecule of 5-TPC and half molecule of 44BIPY. Similarly the asymmetric unit of (9b) is composed of one molecule of TPC and half a molecule of 44BIPY. The 44BIPY molecules in both the cases lie about an inversion centre connected by the acid molecules on either side. As expected both the compounds show the three molecules aggregate made up of 44BIPY ligands bridging the two carboxylic acids. Both the compounds reveal supramolecular adducts sustained by symmetric COOH…N arom supramolecular heterosynthon (Scheme 2c) (Figures 10 and 11).
But the expected R 2 2 (7) synthon (Scheme 2a) that is formed predominantly between pyridine and carboxylic acid groups in similar type compounds is completely absent. This may be due to the least twisting of the carboxyl group attached to the thiophene ring. The carboxyl group is twisted with an angle of 2.6(2)°and 4.0(3)°in both compounds respectively, with respect to the least squares plane of the thiophene ring. The dihedral angle between the two pyridine rings is 0.0(7)°, 35.13(12) °(8b and 9b). The three molecule aggregates in (8b) are further linked to similar neighboring aggregates through strong Cl…O and soft C-H…O interactions to generate two dimensional arrays in (8b) and (9b) respectively (Figure 10b). In both the cases the 44BIPY molecules act as rungs between the two chains which serve as uprights of a ladder. In (8b) two of these ladders are linked by weak C-H…S interactions, C7-H7....S1 (Figure 10b). Although both (8b) and (9b) form similar type of ladders, the difference lies in the type of arrangement. In (8b) all the three molecules lie in the same plane thereby shaping it into a planar ladder. But in (9b) the ladder is bridged by 44BIPY molecules and an adjacent acid which is flanked and slightly away from 44BIPY (Figures 10a and 11). The large deviation of 44BIPY in (9b) as well as the presence of Cl of the 5-TPC in (8b) are perhaps responsible for the difference in the higher level of supramolecular organization.
Crystal structure description of 5TPC44TMBP and TPC44TMBP (10b, 11b) The ORTEP views of (10b) and (11b) are shown in (Figure 9c and d). The asymmetric unit of (10b) is composed of one molecule of 5TPC and half molecule of TMBP. The carboxylic acid-aromatic nitrogen heterosynthon is found on both pyridine rings of the TMBP in (10b). The crystal structure of (11b) is sustained by carboxylic acid-aromatic nitrogen heterosynthon (Scheme 2c) on both sides of the TMBP. Thus the three molecule aggregate is found in both cases. In  (O1-C1-C2 = 123.6(8)Å, O2-C1-C2 = 112.9(7)Å) of the carboxyl group confirms that it is really a carboxyl group and not a carboxylate ion. The dihedral angle between the pyridine ring/carboxylic acid is 7.5(16)°, 2.9(4)°a nd 7.9(4)°in (10b) and (11b) respectively. The bipyridine ring is very much bent which can be noted by the very high dihedral angle between the two pyridine rings of the TMBP 78.31 (14)°and 51.7(4)°(10b) and (11b) respectively. As in the case of the (8b) and (9b) the same type of ladders are formed in (10b). In (10b) the ladders are formed by Cl…π interactions between the adjacent 5-TPC molecules (Figure 12a).
Two of these parallel ladders are further linked by weak C-H…O interactions on both sides of the TMBP between the carboxylic acid oxygen and the hydrogen of the TMBP, leading to a herring bone like pattern in (10b) (Figure 12b).
In 11b there is a π-π stacking interaction of two oppositely oriented TMBP molecules and this extends into a chain by consecutive similar type π-π stacking interactions ( Figure 13). Also there is a C-H…π interaction inbetween the H of the pyridine ring and the oppositely oriented thiophene ring.
Crystal structure description of TDC44TMBP (12b) The asymmetric unit of compound (12b) consists of one half of trimethylene dipyridinium cation, half a 2,5thiophenedicarboxylate anion, and half a 2,5-thiophenedicarboxylic acid. The thiophene dicarboxylic acid group possesses two functional groups capable of two-point recognition. But each of the carboxylate groups is involved in two one point supramolecular heterosynthons (Scheme 2c): one with the protonated nitrogen atom of trimethylene dipyridinium (N1-H1A…O2 = 2.5883(19)Å), a second with the adjacent carboxylic acid molecule (O3-H3A…O1 = 2.5439(16)Å). The C-O bond distances are 1.254(2)Å, 1.251(2)Å, and 1.307(2)Å, 1.218(2)Å for the carboxylate and carboxylic acid moiety, respectively. The C-N-C angle of the trimethylene dipyridinium is 121.83(16)°. The combination of these heterosynthons leads to a chain extending along the b axis ( Figure 14). Two of these adjacent chains are linked to each other by stacking interactions between the two TDC rings (carboxylate thiophene ring of one chain and carboxylic acid thiophene ring of another) (Figure 14). Similarly two of these chains are linked to two other chains by soft C11-H11…O1 = 3.201(3) (Symmetry code: −x,1-y,1-z).    (19) [symmetry code: 2-x,1-y,1-z] is observed between the N of the bipiperazinium cation and the oxygen of the carboxylate. The other end of the bipiperazinium cation containing two hydrogens is also involved in the same kind of interactions. Thus this forms a large R 4 4 (12) ring motif ( Figure 15). These rings motifs extend into a chain linked by the bipiperazinium cation ( Figure 15).
The carboxylic acid is linked to the carboxylate anion which is perpendicular to it (involved in formation of R 4 4 (12) ring motif) by a strong O1-H2A…O4 = 2.5202 (17) hydrogen bonding interaction. These carboxylic acids thus lie as pendants on both the sides to the chain made up of bipiperazinium cations. Two of these chains are again linked to one another by the stacking interactions between two carboxylic acids of each chain (Cg1-Cg1 iii where Cg1 = S1,C2,C3,C4,C5 [symmetry code iii = 2-x,1y,1-z]) ( Figure 16).     Crystal structure description of 5TPC44PYNO (14b) Similar to the preceding 44BIPY and TMBP compounds (8b, 9b, and 10b), compound (14b) crystallizes with a 1:2 ratio of acid and bipyridine components. The acid group and the PYNO ring lie on the same plane, the dihedral angle between them being 4.48(16)°. One half of the PYNO ring connects with four other molecules (two 5-TPC molecules and two PYNO molecules) by a series of C-H…O and O-H…O hydrogen bonds. Thus this gives rise to two sets of R 2 2 (8) and R 3 2 (9) on each side of the PYNO ring (Figure 17a). Each of the N + -O − functions plays a significant role by participating in bifurcated interactions to neighboring molecules; hence there is a formation of network. The network is further stabilized by a π-π stacking interaction between the thiophene ring and the PYNO ring (Cg1-Cg2 iv where Cg1 = N1,C6,C7,C8,C9,C10 and Cg2 = S1,C2,C3, C4, C5 [Symmetry code (iv) = −X,1-Y,-Z] (Figure 17b).
As said earlier, carboxyl and pyridyl functional groups are known to form the most robust intermolecular interactions. The occurrence of synthons III and IV are accompanied by a strong N-H…O or O-H…N and weaker C-H…O hydrogen bonds (Scheme 2a, b). This leads to the formation of R 2 2 (7) synthon. Previous reports [40] say that for the formation of this motif, strong geometrical complementarity between base and acid molecules is necessary. Our reports add value to this point, since there is a formation of a noncyclic motif of type V and VI in (4a, 5a, 7a-9a, 8b-13b) (Scheme 2c, d). In compounds (8b, 9b, 12b and 13b) the dihedral angle between the carboxylic acid group and the pyridyl group is relatively large range (Table 5), which may probably be  the reason for the formation of non cyclic single point synthon. Also the conformational flexibility of the molecules (dihedral angles of two pyridine rings) affects the formation of this synthon which is the case in compounds (9b-12b). The value is less for 14b which also explains the reason for non formation of synthon of type V or VI (Scheme 2c, d).
Among the 14 structures reported here, 8 of them are co-crystals while the remainder are salts. Several papers have also reported and used the acid dissociation constant pK a in predicting the formation of salts/cocrystals [41]. In our recent report involving pyrimidine with various other acids we have tried to rationalize the formation of salt/cocrystals in terms of pK a values. Also in our previous report we presented a plot of ΔpKa vs ΔDc-o, where the X-axis corresponding to the ΔpKa and Y-axis corresponding to ΔD C−O [where ΔpKa = pKa(base) − pKa (acid), ΔD C−O = difference between the lengths of the two C − O bonds in a carboxyl group]. Now we present a same kind of plot using the calculated ΔpKa [42] of the molecular compounds (1a-4a, 8b-12b) and measured ΔD C−O thiophene carboxylic acids used here ( Figure 18). The C − N − C bond angle in AMPY and CYT, which involves acid-base interaction, ranges from 116 to 118°in most cases (indicative of co-crystal formation) and increases to a higher range of 119 − 124°indicating the formation of salts ( Table 5). The scattergram indicates the densely populated boxes on the upper side which corresponds to co-crystals having larger ΔD C−O and the scarcely populated blocks on the bottom side which corresponds to formation of salts. Also from the plot it can be seen that each of the populated areas corresponds to each type of base involved in salt/cocrystal formation.
Preparation of compounds (1a-7a,8b-14b) Compounds (1a-3a) were prepared by mixing hot methanolic solution of AMPY with hot methanolic solution of 5-TPC/TPC/TDC in 1:1 molar ratio and were allowed to warm over a water bath for half an hour. The mixtures were cooled slowly and kept at room temperature. After a few days, colorless prismatic crystals of (1a-3a) separated out of the mother liquor. Compounds (4a − 7a) were prepared by mixing hot methanolic solution of 5TPC with hot methanolic solution of CYT/BA/2NPY/ ACR in 1:1 molar ratio and were allowed to warm over Figure 16 Two of the chains linked by π-π stacking interactions between the 5-TPC rings in (13b). a water bath for half an hour. The mixtures were cooled slowly and kept at room temperature. After a few days, colorless prismatic crystals of (4a,5a), yellow prismatic crystals of (6a) and yellow plate like crystals of (7a) separated out of the mother liquor. IR selected bands for (1a) (cm Similarly compounds (8b,9b) were prepared by mixing hot ethanolic solution of 44BIPY with hot ethanolic solution of 5TPC/TPC in 1:1 molar ratio and were allowed to warm over a water bath for half an hour. The mixtures were cooled slowly and kept at room temperature. After a few days, colorless needle typed crystals of (8b,9b) separated out of the mother liquor. IR selected bands for (8b) (cm −1 ): 3425(m), 2924(s), 2374(s),  Table 5 Comparisons of dihedral angles (between carboxylic acid and pyridine) and C-N-C bond angles (involved in acid-base interaction) in compounds 1a-14b