3.1 Impact of ∆pKa value on the occurrence of acid base dimmers
In a reaction, the acid and base involves, the transfer of proton from acid to base gives rise to a salt, whereas the co-crystal arises, when the proton intact with the acid. For a carboxylic acid pyrimidine reaction [41–43], the COO − H···Narom and molecular salts have COO‒ ···H‒N+ arom heterosynthon. The ∆pKa [pKa(base) – pKa(acid)] rule is an empirical indicator which predicts whether a molecular complex will result as a salt [44–46]. The ‘rule of three’ is commonly employed to predict the outcome of a solid resulting from acid-base molecular reactions [42, 43, 47]. As a general rule, ∆pKa < 0 yields a co-crystal while ∆pKa > 3.75 leads to a salt. It is generally believed that the co-crystal or salt or both can appear in the domain between 0 and 3.75 [42, 48]. Furthermore, a report outline that [49], the ∆pKa region can be classified into three zones; in the first zone, the value of ∆pKa < -1, where one can expect the co-crystal; in the second zone the values range ‒1 < ∆pKa < 4, this comprises the co-crystal and salt; while in the third zone, the value of ∆pKa > 4 [50, 51], which is the molecular salt and this is in good agreement with the molecular complexes salicylic acid and pyrimidine derivative. The pKa value of 2A4M6MP, 4-amino salicylic acid and 5-chlorosalicylic acid are 5.77, 3.68 and 2.59 respectively. In the present study, the calculated values of ∆pKa values of acid-base complexes fall in the range 2.0 to 4.0 (Table S9), this confirms the formation of molecular salts.
3.2 Molecular structure and Intermolecular interactions
The molecular structure of salt (I) is shown in Fig. 1. The asymmetric unit of (I) contains a 2-amino-4-methoxy-6-methylpyrimidinium cation and a 4-amino salicylic acid anion. The cation is protonated at N1, which lies between the amine and methoxy groups attached C-atoms. This protonation can be confirmed from the difference of bond angle at the protonated N1 atom [C1‒N1‒C2 = 121.2 (1)°] and the unprotonated atom N2 [C4‒N2‒C1 = 115.9 (1)°] and this also further confirmed from the corresponding reported bond angle of neutral 2-amino-4-methoxy-6-methylpyrimidine [17, 18] which is significantly less [116.0(18)°]. In the salt (I), the 4-aminosalicylate (4AMSA) molecule exhibits an intramolecular O4‒H4···O3 hydrogen bonding interaction (Fig. 1, Table 2). The protonated N-atom (N1) and 2-amino group (N3) of the cation interacts with the O2 and O3 oxygen atoms of the carboxylate anion through a pair of N − H···O hydrogen bonds (Table 2) forming an eight-membered ring motif (8). Inversion-related (8) ring motifs are further bridged by N − H···O hydrogen bonds thereby forming a DDAA tetramer (D stands for hydrogen-bond donor and A stands for hydrogen bond acceptor). This set of fused rings can be represented by the graph-set notations (8), (8) and (8) [50, 52]. This type of motif has been reported previously in the crystal structures of trimethoprim hydrogen glutarate [49, 53] and 2-amino-4-methoxy-6-methylpyridinium trifluoroacetate [54] (Fig. S14). The (8) ring motif is further extended in both sides via N − H···O hydrogen bonding generating a supramolecular chain [49] (Fig. S15). These supramolecular chains are further interconnected via N − H···O hydrogen bonding interactions generating a supramolecular sheet (Fig. S16). The 4-amino salicylate ions form hydrogen bonded supramolecular chain via N − H···O hydrogen bonds involve amino hydrogen N3 and one of the oxygen atoms of the carboxylate group (Fig. S17). Subsequent level of aggregation forms a cyclic heterotetramer preferred stable synthon (Fig. S18). This crystal structure was further stabilized by C − H···π stacking interaction. The C − H···π interaction between the 2A4M6MP cations with the 4-amino salicylate anions (C5 − H5C···Cg(2)v distance of 2.99(1) Å) (Fig. S19). (Symmetry code: 1/2-x,1/2 + y,3/2-z)
Table 2 Hydrogen bonding interactions in the crystal of salt – I and II (Å, °)
D‒H···A
|
D‒H
|
H···A
|
D···A
|
D‒H···A
|
Salt-I
|
N3‒H3A···O2(i)
|
0.94(2)
|
1.88(2)
|
2.815(2)
|
171.7(19)
|
N3‒H3B···O2(ii)
|
0.87(2)
|
2.00(2)
|
2.805(2)
|
154.4(19)
|
O4‒H4···O3
|
1.01(3)
|
1.59(3)
|
2.5322(19)
|
152(3)
|
N4‒H4A···O4(i)
|
0.834(19)
|
2.490(18)
|
3.294(2)
|
162.2(18)
|
N4‒H4B···O2(iii)
|
0.88(3)
|
2.45(3)
|
3.299(2)
|
161.5(18)
|
N1‒H13···O3(i)
|
0.94(2)
|
1.78(2)
|
2.7098(18)
|
173.8(19)
|
C3‒H3···O1(iv)
|
0.938(19)
|
2.423(19)
|
3.313(2)
|
158.3(17)
|
Salt-II
|
N3‒H3B···O3(v)
|
0.86
|
1.99
|
2.848(4)
|
178
|
N3‒H3A···N2(vi)
|
0.86
|
2.27
|
3.118(4)
|
170
|
O4‒H4···O3
|
0.88(4)
|
1.71(4)
|
2.543(3)
|
159
|
N1‒H13···O2(v)
|
0.95(4)
|
1.68(4)
|
2.623(4)
|
173(3)
|
C11‒H11···O2
|
0.92 (3)
|
2.44(3)
|
2.766(4)
|
101(2)
|
Symmetry codes: (i) -1/2+x,1/2-y,1/2+z ; (ii) 1/2-x,1/2+y,1/2-z; (iii) 1/2+x,1/2-y,1/2+z; (iv) 1-x,1-y,-z, (v) -x,1-y,1-z; (vi)1-x,2-y,1-z
The asymmetric unit of salt (II) contains a 2-amino-4-methoxy-6-methylpyrimidinium cation and a 5-chlorosalicylate anion (Fig. 1). The hydroxyl group of the 5-chlorosalicylic acid is deprotonated and proton-transferred to the nitrogen atoms of 2-aminopyrimidine moieties [18, 23, 49, 55]. In the cation, one of the pyrimidine nitrogen atoms (N1) is protonated and this is confirmed from the increase of bond angle at N1 [C2‒N1‒C1: 121.7 (2)°], and this angle is comparable with the unprotonated atom N2 [C4‒N2‒C1: 116.17(19)°] and this also further confirmed from the corresponding reported bond angle of neutral 2-amino-4-methoxy-6-methylpyrimidine [17, 18], which is significantly high [116.0(18)°]. An intramolecular O4 − H4···O3 hydrogen bond in the 5-chlorosalicyclic acid anion generates a S(6) ring motif [56, 57].
The protonated N1-atom and the nitrogen atom of the 2-amino group (N3) are hydrogen-bonded to the carboxylate oxygen atoms (O2 and O3) via a pair of intermolecular N1–H13···O2(i) and N3–H3B···O3(i) hydrogen bonds (symmetry code: (i) -x,1-y,1-z) forming a ring motif R22(8) [18, 56]. The main motif is assembled via complementary hydrogen bonding interaction between the carboxylic acid and the amino pyrimidine moiety to form a dimeric unit (Fig. S20) [49]. Adjacent dimeric units are connected through self-complementary secondary N − H···N hydrogen bonds to form a four component supramolecular networks. Thus, the hydrogen bonds, O − H···N, N − H···O and N − H···N motif combine to form a linear heterotetramer (LHT) motif [49]. This motif is further connected through N–H···N hydrogen bonds involving N2 atom of 2-amino 4-methoxy 6-methyl pyrimidinium cations generating a supramolecular chain (Fig. S21). The C − Cl···π [C10 − Cl···Cg(1)iii distance of 3.856(3) Å; symmetry code: (iii) -1 + x,y,z] type of interaction is also further stabilize the crystal structure (Fig. S22).
3.3 Hirshfeld surface analysis
The three-dimensional dnorm surface is a useful tool for analyzing and visualizing the intermolecular interactions, as it shows negative or positive values depending on whether an intermolecular contact is shorter or longer, respectively, than the sum of the van der Waals radii [18]. The dnorm surface of the salt (I) is shown in Fig. 4, the red points, which represent closer contacts and negative dnorm values correspond to the N‒H···O, O‒H···O, O‒H···N and C‒H···O interactions. The two-dimensional fingerprint plots from the Hirshfeld surface analysis (Fig. 5) provide information about the intermolecular contacts and their percentage of distributions on the Hirshfeld surface. The intermolecular interactions of the salt (I & II) are quantified by using Hirshfeld surface analysis. The mapping of di, de, shape index and curvedness are shown in S24. Figure 5 bar-diagram indicates the contribution of inter-contacts to the Hirshfeld surfaces, H···H (46.1% & 37.1%), N···H (9.6% & 4.5%), C···H (14.3% ,14.9%), O···H (26.6% & 18.0), H···Cl (11.9%) and others (C···C, N···N, C···O, C···Cl ; 3.4 & 13.6%). The important interaction is highlighted by conventional mapping of dnorm on molecular Hirshfeld surfaces as shown in Fig. 4. Hirshfeld surface analyses of synthon, the crystal packing of salts were confirmed by light red spots on the dnorm surfaces of two salts. Further, inter-contacts are plotted with fingerprint plots (Fig. 5). The Fig. 5(a) shows large surfaces for all inter-contacts, Fig. 5(c) shows large surface for H···H interatomic contacts, the N···H contact plot is shown in Fig. 5(d) and the Fig. 5(e) shows the presence of O···H contact with the two characteristic wings and the “butterflies” are identified as a consequence of C‒H interactions reveals the information of intermolecular hydrogen bonding. The fingerprint plot studies have been characterized the non-covalent interaction and their reactive proportions to the present organic salt molecules.
3.4 Interaction energy calculation
To understand the geometric and electronic relationship between the structure of molecules and to predictive structure-property relationship in crystal engineering, energy frameworks offer a powerful path to visualize the supramolecular architecture of molecular crystal structures. The successful calculation of interaction energies with color-coded molecular crystals was performed for both salts (I&II); the values are tabulated (Table S10 & S11). The total energies of all interacting molecules with respect to corresponding reference molecule along with the different symmetry operation and centroid-centroid distance. In the salt I, the total energy for the hetrosynthon is -52.7 kJ/mol and for the homosynthon, the value is -20.5 kJ/mol. Whereas in the salt II, the total energy is -36.2 kJ/mol and − 68.3 kJ/mol for the hetro and homosynthon respectively. On comparing the salts, the total energy values clearly confirm that, in the crystal phase, the salts are forming strong hydrogen bonding interactions. In the energy framework, the strength of intermolecular interactions is directly correlated to the radii of the color-coded cylinders. Figure 6 shows, the energy frameworks of the salt I and II were generated for a cluster of 3×3×3-unit cells to understand the overall topology of the energy distribution in the solid-state phase. In short, by using NCIPLOT the reduced density gradient is plotted as the function of the density (mapped as isosurfaces) over the molecule of interest. Fig S25 shows the sign of the second Hessian eigen value times the electron density (sign of (λ2)ρ in atomic units) enables the identification of attractive/stabilizing or repulsive interactions (Salt–I:-105.90; Salt –II:-114.01 kcal/mole). Overall, the interacting energy topologies of the molecules are concluded that these interacting energies are playing crucial role in the assembly of the molecules in the solid state and in the crystal engineering.
3.5 Topological properties
The QTAIM (Bader's quantum theory of atoms in molecules) analysis is a powerful tool to understand the nature of chemical bonding, reactive nature and intermolecular interactions of the molecular system at electronic level. The topological parameters such as electron density, Laplacian of electron density of both salts obtained from the wave function have carried out to understand the stability of the molecule when it forms together. To visualize the lone pair position and charge accumulation of the salt molecules, deformation electron density map of both salts were plotted, it displays the lone pair position of O-atom of C = O group (Fig. 7a). Similarly, the Laplacian of electron density (Fig. 7b) reveals the charge concentration/depletion at the bond critical point of chemical bonds. On comparing the electronic level information of both salt molecules, the electron density and Laplacian of electron density of C2‒C3 bond is found higher and C2‒C5 is lesser than the other C‒C bonds in the salt molecules [C2‒C3: \({\rho }_{bcp}:\)2.283I/2.223II eÅ−3; \({{\nabla }^{2}{\rho }}_{bcp}\): -24.492I/-23.213II eÅ−5 & C2‒C5: \({\rho }_{bcp}:\) 1.735I/1.731II eÅ−3; \({{\nabla }^{2}{\rho }}_{bcp}\): -15.147I/-15.077II eÅ−5]. And, the \({\rho }_{bcp} \& {{\nabla }^{2}{\rho }}_{bcp}\) of N‒N and C–O bonds of both salt molecules exhibit acceptable values; the C9–N4 and C6–O1 bonds are carrying less electron densities [C9–N4: \({\rho }_{bcp}:\)2.089I eÅ−3; \({{\nabla }^{2}{\rho }}_{bcp}\) -21.651 I eÅ−5 & C6–O1: \({\rho }_{bcp}:\)1.545I/1.598II eÅ−3; \({{\nabla }^{2}{\rho }}_{bcp}\) : -3.969I/-2.723II eÅ−5]. Interestingly, all the C–H bonds possess high electron density and Laplacian of electron density values; Moreover, the \({\rho }_{bcp} \& {{\nabla }^{2}{\rho }}_{bcp}\)of N–H [N1–H13: \({\rho }_{bcp}:\)2.725I/2.61II eÅ−3] bonds are very high which clearly indicates the completion of charge transfer.
The intermolecular interactions between group of salts (I and II) were analyzed to find the strength and type of interactions. In both salt molecules, the N–H∙∙∙O and O–H∙∙∙O type of strong hydrogen bonding intra/intermolecular interactions were observed; in which, the proton of H13 was transferred from the acid O3 atom to base N1 atom. The topological parameters of these intermolecular interactions help us to understand the stability of the cofomers. The electron density and Laplacian of electron density of N2‒H13···O3 bond of salt I is 0.267 eÅ−3 and 3.146 eÅ−5; whereas in the salt II, the \({\rho }_{bcp} \& {{\nabla }^{2}{\rho }}_{bcp}\) of N1‒H13···O2 is 0.343 eÅ−3 and 3.676 eÅ−5 respectively. These are almost similar to the reported experimental values. Moreover, the acid of both salts are forming strong intra-molecular hydrogen bonding, the \({\rho }_{bcp} \& {{\nabla }^{2}{\rho }}_{bcp}\) of O4‒H4···O3 bond is found to higher than the other interactions [O4‒H4···O3: \({\rho }_{bcp}:\)0.426I/0.320II eÅ−3 & \({{\nabla }^{2}{\rho }}_{bcp}\): 3.78I/3.969II eÅ−5]. The small electron density and positive Laplacian of electron density confirms that the interactions are closed-shell interaction. Furthermore, the kinetic energy, potential energy, total energy and dissociation energy of these interactions were calculated and summarized in the Table 3. Figure 7c shows the position of bcp of respective bonds in the molecule, in which the bcp of homo atomic bonds are lies at the middle of the bonds, whereas in hetero atomic bonds, this is not true as it is deviated largely from the middle of the bond. The topological properties of electron density (\({\rho }_{bcp} \& {{\nabla }^{2}{\rho }}_{bcp}\)) at the bond critical point (bcp) provide information about the nature and strength of intermolecular interactions.
Table 3
Topological Properties of the Electron Density for the selected intermolecular interactions in Salt (I & II)
D‒H···A
|
H···A
(Å)
|
ρ(rcp)
(eÅ-3)
|
\({\nabla }^{2}\)ρ(rcp)
(eÅ-5)
|
G(r)
(a.u)
|
V(r)
(a.u)
|
H(r)
(a.u)
|
E(r)
(a.u)
|
De
(KJ/Mol)
|
Salt-I
|
N3‒H3A···O2
|
1.88(2)
|
0.207
|
2.514
|
0.048
|
-0.070
|
-0.022
|
-0.035
|
92.17
|
N1‒H13···O3
|
1.78(2)
|
0.267
|
3.146
|
0.069
|
-0.105
|
-0.036
|
-0.052
|
137.73
|
O4‒H4···O3
|
1.59(3)
|
0.426
|
3.78
|
0.129
|
-0.218
|
-0.089
|
-0.109
|
286.22
|
Salt-II
|
N3‒H3B···O3
|
1.99
|
0.162
|
2.244
|
0.036
|
-0.049
|
-0.012
|
-0.024
|
63.84
|
N1‒H13···O2
|
1.68(4)
|
0.343
|
3.676
|
0.097
|
-0.156
|
-0.059
|
-0.078
|
204.14
|
O4‒H4···O3
|
1.71(4)
|
0.32
|
3.969
|
0.091
|
-0.141
|
-0.050
|
-0.070
|
184.97
|
Electrostatic potential of both salts (I and II) were calculated to understand the characteristic regions of positive (attracting the nucleophiles) and negative (attracting electrophiles) potentials of the cofomers of salt molecules which were clearly visible and well separated. In which, the vicinity of electronegative potential are shown on the acid group of both salts (Fig. 7d). The obtained energy from the HOMO and LUMO of both salts used to determine the band gap and various reactivity descriptors such as electron affinity (A), ionization potential (I), global hardness (Ƞ), electrophilicity (ω) and electronegativity (𝜒) shown in Table 4. The LUMO→ HOMO, ∆E = 2.61 & 3.23eV, The LUMO + 1→ HOMO-1, ∆E = 4.04 & 5eV and LUMO + 2→ HOMO-2, ∆E = 6.36 & 6.26 eV (salt I & II) values are respectively. The Gradient trajectories are originated at the atomic centers and terminated at the bcp. The thick solid lines represent the zero-flux surfaces of atoms in molecules, which defines the boundary of the atomic basin (Fig. 7e).
Table 4
Molecular descriptors of Molecule Salt I & II.
Molecular descriptors
|
Salt – I
|
Salt – II
|
Energy (eV)
|
Electron affinity
A=[-ELUMO]
|
2.079
|
2.188
|
Ionization potential
I=[-EHOMO]
|
4.686
|
5.424
|
Global hardness
Ƞ=(I-A)/2
|
1.304
|
1.618
|
Electro chemical Potential
µ=-(I + A)/2
|
-3.383
|
-3.806
|
Electrophilicity
ω=µ2/2 Ƞ
|
4.388
|
4.476
|
Electronegativity
𝜒=(I + A)/2
|
3.383
|
3.806
|
HOMO energy
|
-4.686
|
-5.424
|
LUMO energy
|
-2.079
|
-2.188
|
Band Gap
=[ELUMO-EHUMO]
|
2.607
|
3.236
|