Twelve 4-(4-methoxyphenyl)piperazin-1-ium salts containing organic anions: supramolecular assembly in one, two and three dimensions

In twelve 4-(4-methoxyphenyl)piperazin-1-ium salts containing organic anions, the hydrogen-bonded supramolecular assembly ranges from simple chains via chains of rings and sheets to three-dimensional framework structures.


Chemical context
In recent years, N-(4-methoxyphenyl)piperazine (MeOPP) has emerged as a new addition to the range of designer recreational drugs, and considerable effort has been invested in the development of methods for the detection both of MeOPP itself and of its metabolites N-(4-hydroxyphenyl)piperazine and 4-hydroxyaniline (Arbo et al., 2012) in human fluids (Staack & Maurer, 2003;Staack et al., 2004). MeOPP has euphoric stimulant properties and its action on human physiology is similar to that of amphetamines (Staack & Maurer, 2005;Wohlfarth et al., 2010), but it has a significantly lower potential for abuse (Nagai et al., 2007). However, no therapeutic applications of MeOPP have been reported to date. In view of the reported properties of MeOPP, coupled with the broad range of biological activities exhibited by piperazine derivatives (Asif, 2015;Brito et al., 2019), we have recently initiated a programme of study centred on N-(4methoxyphenyl)piperazine derivatives, and we have recently reported the synthesis and structures of a series of 1-aroyl-4-(4-methoxyphenyl)piperazines (Kiran Kumar et al., 2019). In a continuation of that work, we have now prepared a series of 4methoxyphenyl)piperazin-1-ium salts of simple organic acids, (I)-(XII), in order to study the various patterns of hydrogenbonding interactions present in these salts, which may eventually be of value in pharmacological and pharmaceutical applications (Kavitha et al., 2014;Kaur et al., 2015;Shaibah, Yathirajan et al., 2017;Shaibah, Sagar et al., 2017;Shaibah et al., 2019). Salts of this type are readily prepared by co-crystallizations of the piperazine and the acids in methanol solution and, in total, 28 different acids representing a wide range of chemical types were investigated (see Section 5): however, only twelve of these provided crystals suitable for singlecrystal X-ray diffraction, and thus we report here the molecular and supramolecular structures of (I)-(XII) (Figs. 1-12).

Figure 2
The independent components of compound (II), showing the atomlabelling scheme, the disorder of the 4-methoxyphenyl group, and the hydrogen bonds within the selected asymmetric unit. The major disorder component is drawn using full lines and the minor disorder component is drawn using dashed lines. Displacement ellipsoids are drawn at the 30% probability level and, for the sake of clarity, a few of the atom labels have been omitted.

Figure 1
The independent components of compound (I), showing the atomlabelling scheme, the disorder of the 4-methoxyphenyl group, and the hydrogen bonds within the selected asymmetric unit. The major disorder component is drawn using full lines and the minor disorder component is drawn using dashed lines. Displacement ellipsoids are drawn at the 30% probability level and, for the sake of clarity, a few of the atom labels have been omitted.

Figure 3
The independent components of compound (III), showing the atomlabelling scheme, the disorder of the 4-methoxyphenyl group, and the hydrogen bonds within the selected asymmetric unit. The major disorder component is drawn using full lines and the minor disorder component is drawn using dashed lines. Displacement ellipsoids are drawn at the 30% probability level and, for the sake of clarity, a few of the atom labels have been omitted.

Figure 4
The independent components of compound (IV), showing the atomlabelling scheme, the disorder of the 4-methoxyphenyl group, and the hydrogen bonds within the selected asymmetric unit. The major disorder component is drawn using full lines and the minor disorder component is drawn dashed broken lines. Displacement ellipsoids are drawn at the 30% probability level and, for the sake of clarity, a few of the atom labels have been omitted.

Figure 6
The independent components of compound (VI), showing the atomlabelling scheme and the hydrogen bonds within the selected asymmetric unit. Displacement ellipsoids are drawn at the 30% probability level.

Figure 7
The independent components of compound (VII), showing the atomlabelling scheme and the hydrogen bond within the selected asymmetric unit. Displacement ellipsoids are drawn at the 30% probability level.

Figure 8
The independent components of compound (VIII), showing the atomlabelling scheme, the disorder of anion, and the hydrogen bonds within the selected asymmetric unit. The major disorder component is drawn using full lines and the minor disorder component is drawn using dashed lines. Displacement ellipsoids are drawn at the 30% probability level.

Figure 12
The independent components of compound (XII), showing the atomlabelling scheme and the hydrogen bonds within the selected asymmetric unit. Displacement ellipsoids are drawn at the 30% probability level, and the atoms marked with the suffix 'a 0 are at the symmetry position (1 À x, 1 À y, Àz)

Figure 11
The independent components of compound (XI), showing the atomlabelling scheme and the hydrogen bond within the selected asymmetric unit. Displacement ellipsoids are drawn at the 30% probability level.

Figure 10
The independent components of compound (X), showing the atomlabelling scheme and the hydrogen bonds within the selected asymmetric unit. Displacement ellipsoids are drawn at the 30% probability level.

Figure 9
The independent components of compound (IX), showing the atomlabelling scheme, the disorder of anion, and the hydrogen bonds within the selected asymmetric unit. The major disorder component is drawn using full lines and the minor disorder component is drawn using dashed lines. Displacement ellipsoids are drawn at the 30% probability level.
While compounds (I)-(IV) are isostructural, compounds (VIII) and (IX) are not, because of both the different configurations of their anions and the different degrees of disorder. Examples have been previously reported of compounds that are isomorphous but not strictly isostructural in terms of their intermolecular interactions (Acosta et al., 2009).
In the anion of compound (VII), the carboxyl group is unionized, with C-O distances of 1.220 (3) and 1.309 (3) Å and it is the phenolic H atom which has been lost (Fig. 7). The C32-O33 distance, 1.280 (3) Å , is closer to that normally found in ketones than to that typical of phenols or phenolates (Allen et al., 1987): in addition, the C31-C32 and C32-C33 distances, 1.437 (4) and 1.430 (4) Å , respectively, are significantly larger than the other C-C distances in this ring, which lie in the rather narrow range 1.370 (3)-1.385 (4) Å , but the C-N and N-O distances are all typical of their types (Allen et al., 1987). These observations indicate that the negative charge in this anion is delocalized over the five atoms C31, C33, C34, C35 and C36, but without any significant delocalization onto the nitro groups, as has been observed in trinitrophenolate (picrate) anions (Kavitha et al., 2006;Sagar et al., 2017;Shaibah et al., 2017a,b).
The anion of compound (X) contains an almost linear and very short (Emsley, 1980;Herschlag & Pinney, 2018) OÁ Á ÁHÁ Á ÁO hydrogen bond, in which the H atom is almost, but not exactly, centred between the two O atoms (Table 1). In the centrosymmetric anion of compound (XII) (Fig. 12), the two independent C-O distances are identical within experimental uncertainty, 1.244 (2) and 1.246 (2) Å , as are the distances C31-C32 and C32-C33, 1.398 (3) and 1.392 (2) Å . However, the remaining C-C distance in this ring, 1.539 (3) Å is typical of a single C-C bond (Allen et al., 1987). These observations indicates the delocalization of a negative charge across each of the O-C-C-C-O units, and that these two units are effectively isolated from each other electronically. Despite the apparent simplicity of this dianion, with its high intrinsic symmetry, it is not possible adequately to describe its electronic structure in a single diagrammatic form, and four forms (A)-(D) (Fig. 13) are required.
There is an intermolecular O-HÁ Á ÁO hydrogen bond in the anion of the unsolvated salt (V). The two anions in the selected asymmetric unit (Fig. 5) are linked by an asymmetric three-centre N-HÁ Á Á(O) 2 hydrogen bond, and the resulting ion pairs, which are related by 2 1 screw axis along ( 1 2 , y, 1 4 ), are Part of the crystal structure of compound (I) showing the formation of a chain of rings parallel to the [100] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the minor disorder component and the H atoms bonded to C atoms have been omitted.

Figure 13
The canonical forms of the anion in compound (XII).

Figure 15
Part of the crystal structure of compound (V) showing the formation of a chain of rings parallel to the [010] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to C atoms have been omitted.

Figure 16
Part of the crystal structure of compound (VI) showing the formation of a sheet of R 6 6 (40) rings lying parallel to (100). Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms not involved in the motifs shown have been omitted. parallel to the [010] direction, and in the second sub-structure, ion pairs which are related by the c-glide plane at y = 3 4 are linked by a C-HÁ Á ÁO hydrogen bond (Table 1) to form a C 2 2 (17) chain running parallel to the [001] direction. The combination of these two simple chain motifs generates a sheet of R 6 6 (40) rings lying parallel to (100) in the domain 1 2 < x < 1.0 (Fig. 16). A second sheet of this type, related to the first by inversion lies in the domain 0 < x < 1 2 , and adjacent sheets are linked by the third sub-structure in which inversionrelated ion pairs are linked by C-HÁ Á ÁN hydrogen bonds into a centrosymmetric R 4 4 (18) ring ( Fig. 17): the action of this interaction is to link all of the (100) sheets into a continuous three-dimensional array.
There is an intermolecular O-HÁ Á ÁO hydrogen bond in the anion of compound (VII) (Fig. 7), but the carboxyl H atom plays no part in the supramolecular assembly. The ions are linked by a combination of N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds to form a chain of centrosymmetric rings running parallel to the [210] direction, in which R 2 2 (10) rings centred at (2n À 1 2 , n, 1 2 ) alternate with R 4 6 (16) rings centred at (2n + 1 2 , n + 1 2 , 1 2 ), where n represents an integer in each case (Fig. 18). Two chains of this type, related to one another by the translational symmetry operations, pass through each unit cell, and a weak C-HÁ Á Á(arene) hydrogen bond links the chains into a three-dimensional framework structure.
For the disordered structure of compound (VIII), the hydrogen bonds formed by the major and minor disorder components are very similar (Table 1) so that only the major disorder form need be considered in detail. Within the selected asymmetric unit (Fig. 8), the component ions are linked by a two-centre N-HÁ Á ÁO hydrogen bond: the ion pairs are linked by a combination of N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds to form sheets, whose formation can readily be analysed in terms of two simple sub-structures. In the simpler of these, anions which are related by the a-glide plane at y = 3 4 are linked by O-HÁ Á ÁO hydrogen bonds into C(7) chains running parallel to the [102] direction (Fig. 19) Part of the crystal structure of compound (VI) showing the formation of the R 4 4 (18) ring which links the (100) sheets. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the unit-cell outline and the H atoms which are bonded to the C atoms not involved in the motif shown have been omitted. The atoms marked with an asterisk (*) are at the symmetry position (1 À x, 2 À y, 1 À z).

Figure 18
Part of the crystal structure of compound (VII) showing the formation of a chain of R 2 2 (10) and R 4 6 (16) rings parallel to the [210] direction. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms which are bonded to the C atoms not involved in the motif shown have been omitted. (Fig. 20). The combination of these two chain motifs generates a sheet lying parallel to (010), and a single C-HÁ Á Á(arene) hydrogen bond links these sheets into a three-dimensional framework structure. The supramolecular aggregation in the isomorphous compound (IX) is similar to that in (VIII). As noted in Section 2 above, the anion in compound (X) contains a very short and nearly symmetrical OÁ Á ÁHÁ Á ÁO hydrogen bond. Within the selected asymmetric unit, the component ions are linked by the three-centre N-HÁ Á Á(O) 2 hydrogen bond and ion pairs which are related by translation are linked by a two-centre N-HÁ Á ÁO hydrogen bond to form a C(9)C(9)[R 2 1 (4)] chain of rings running parallel to the [100] direction (Fig. 21). The C-HÁ Á ÁO contact is at the margin of significance (Wood et al., 2009), but it involves chains related by inversion.
The supramolecular assembly of compound (XI) is extremely simple: two N-HÁ Á ÁO hydrogen bonds link the ions into a C 2 2 (6) chain running parallel to the [100] direction (Fig. 22). In compound (XII), a combination of N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds links all three components into a chain of R 6 6 (18) rings running parallel to the [001] direction (Fig. 23), while a second O-HÁ Á ÁO hydrogen bond links a combination of cations and water molecules into a simple C 2 2 (12) chain running parallel to the [101] direction (Fig. 24) and the combination of these two chain motifs generates a complex sheet lying parallel to (010).
Overall, therefore, the hydrogen-bonded assembly is onedimensional in each of compounds (X) and (XI), twodimensional in compounds (I)-(V) and (XII), and threedimensional in compounds (VI)-(IX). Sub-structures in the Part of the crystal structure of compound (VIII) showing the formation of a C(7) chain of anions, parallel to [102]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to C atoms have been omitted. The atoms marked with an asterisk (*) or a hash (#) are at the symmetry positions ( 1 2 + x, 3 2 À y, À1 + z) and (À 1 2 + x, 3 2 À y, 1 + z), respectively.

Figure 20
Part of the crystal structure of compound (VIII) showing the formation of a C 2 2 (6) chain parallel to [100]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to C atoms have been omitted.

Figure 21
Part of the crystal structure of compound (X) showing the formation of a chain of rings parallel to [100]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to C atoms have been omitted.
form of chains of rings can be identified in compounds (I)-(IV) and in (VII), although (I)-(IV) are all monohydrates, while (VII) is solvent free: within the chain of rings formed by (I)-(IV) it is possible to identify a C 2 2 (6) motif formed by water molecules and anions only (Fig. 14), and a C 2 2 (6) motif built from alternating cations and anions can, in fact, be identified in each of compounds (V), (VI), (VIII), (IX) and (XI) (Figs. 15,16,20,22). By contrast, a C 2 2 (12) motif, built from water molecules and cations can be identified in the structure of compound (XII) (Fig. 24), but sub-structural motifs in the form of simple chains are uncommon in this series (Fig. 19).

Database survey
Compounds (I)-(IV), reported here, are isomorphous across the series of anions 4-XC 6 H 4 COO À , where X = H, F, Cl or Br, despite the rather disparate sizes of the substituents X. A similar, but more extreme, series of isomorphous salts was found in the substituted anilinium 5-nitro(hydrogenphthalate) salts (4-XC 6 H 4 NH 3 ) + Á(C 8 H 4 NO 6 ) À , which are isomorphous for X = H, Cl, Br and I (Glidewell et al., 2005). The structures of a number of salts containing the chloranilate dianion have been reported (Ishida, 2004a,b,c,d;Sovago et al., 2016), and the geometric features previously observed in this anion are fully consistent with the geometry found here in ( Part of the crystal structure of compound (XI) showing the formation of a C 2 2 (6) chain parallel to [100]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to C atoms have been omitted.

Figure 23
Part of the crystal structure of compound (XII) showing the formation of an R 6 6 (18) chain of rings parallel to [001]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to C atoms have been omitted.

Figure 24
Part of the crystal structure of compound (XII) showing the formation of a C 2 2 (12) chain of cations and water molecules parallel to [101]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to C atoms have been omitted. nature of the electronic delocalization has been confirmed in several such salts using a combination of deformation density plots and net atomic charge calculations (Sovago et al., 2016).

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. In each of the isomorphous compounds (I)-(IV), the 4-methoxyphenyl group exhibits disorder over two sets of atomic sites, and in each of (VIII) and (IX), the anion exhibits disorder involving two sets of atomic sites having unequal occupancies. In each case, the bonded distances and the 1,3 non-bonded distances in the minor disorder component were restrained to be the same as the equivalent distances in the major disorder component, subject to s.u. values of 0.01 and 0.02 Å , respectively, and the anisotropic displacement parameters for pairs of partialoccupancy atoms occupying essentially the same physical space were constrained to be equal: in addition, it was found necessary to constrain the minor component of the carboxyl group in (IX) to be planar. The ratio of observed-to-unique data was only 39% for compounds (II) and (III): this is probably a consequence of the ambient temperature data collection allied to the disorder: in both (VII) and (IX), the average U 3 /U 1 ratio was > 4.0: this may be consequence of the disorder. Apart from those in the minor disorder components of (I)-(IV), (VIII) and (IX), all H atoms were located in difference maps. The H atoms bonded to C atoms were then treated as riding atoms in geometrically idealized positions with C-H distances of 0.93 Å (alkenyl and aromatic), 0.96 Å (CH 3 ) or 0.97 Å (CH 2 ), and with U iso (H) = kU eq (C), where k = 1.5 for the methyl groups which were permitted to rotate but not to tilt, and 1.2 for all other H atoms bonded to C atoms: the H atoms bonded to C atoms in the minor disorder components were included on the same basis. The H atoms bonded to O atoms in the disordered components of (VIII) and (IX) were treated as riding atoms with O-H = 0.82 Å and U iso (H) = 1.5U eq (O), For the H atoms bonded to N atoms, and for the H atoms bonded to O atoms in (I)-(V), (VII), (X) and (XII), the atomic coordinates were refined with U iso (H) = 1.2U eq (N) or 1.5U eq (O), leading to the N-H and O-H distances shown in Table 1. The refined occupancies for the disorder components were 0.66 (2) and 0.34 (2) in (I), 0.81 (3) and 0.19 (3) in (II), 0.73 (2) and 0.27 (2) in (III), 0.80 (2) and 0.20 (2) in (IV), 0.660 (15) and 0.340 (15) in (VIII), and 0.906 (9) and 0.094 (9) in (IX). For compound (XI), the correct orientation of the structure relative to the polar axis direction was established using the Flack x parameter (Flack, 1983), x = 0.11 (7). However, for compounds (V), (VIII) and (IX), where there is very little resonant scattering the values of the Flack x parameter were indeterminate (Flack & Bernardinelli, 2000), with values À0.3 (5), À0.6 (7) and À0.3 (4), respectively: hence in these three cases, the correct orientation of the structure with respect to the polar axis direction cannot be established, although this has no chemical significance. The refinement of (XII) was treated as a non-merohedral twin, with twin matrix (À1, 0, 0/0, À1, 0/0.496, 0, 1) and with refined twin fractions 0.2467 (9) and 0.7533 (9).   SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics:

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ.    Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

4-(4-Methoxyphenyl)piperazin-1-ium 2-hydroxy-3,5-dinitrobenzoate (VII)
Crystal data Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq N1 0.6215 (