Crystal structures of the recreational drug N-(4-methoxyphenyl)piperazine (MeOPP) and three of its salts

The hydrogen-bonded assemblies in N-(4-methoxyphenyl)piperazine and its 3,5-dinitrobenzoate, picrate, and monohydrated 4-aminobenzoate salts are, respectively, one-, zero-, two- and three-dimensional.


Chemical context
N-(4-Methoxyphenyl)piperazine (MeOPP) has fairly recently emerged as a new addition to the range of designer drugs aimed at recreational use, and considerable effort has consequently been invested in the development of rapid and reliable methods for the detection in human fluids not only of MeOPP itself but also of its primary metabolites N-(4-hydroxyphenyl)piperazine and 4-hydroxyaniline (Staack & Maurer, 2003;Staack et al., 2004). The action of MeOPP on human physiology is similar to that of amphetamines, but it has a significantly lower potential for abuse (Nagai et al., 2007). In view of these observations, coupled with the broad range of biological activities exhibited by piperazine derivatives in general (Asif, 2015;Brito et al., 2019), we have recently initiated a programme of study centred on N-(4-methoxyphenyl)piperazine derivatives. Thus, we have recently reported the synthesis and structures of a range of salts derived from MeOPP (Kiran , as well as those of a range of neutral 1-aroyl-4-(4methoxyphenyl)piperazines (Kiran Kumar, Yathirajan, Sagar et al., 2019). In a continuation of the earlier work, we have now prepared a further series of salts, whose molecular and supramolecular structures we report here, along with that of MeOPP itself: the structures reported here are those of N-(4methoxyphenyl)piperazine (I), 4-(4-methoxyphenyl)piperazin-1-ium 3,5-dinitrobenzoate (II), 4-(4-methoxyphenyl)piperazin-1-ium 2,4,6-trinitrophenolate (III) and 4-(4-methoxyphenyl)piperazin-1-ium 4-aminobenzoate monohydrate (IV) (Figs. 1-4). The salts (II)-(IV) were readily prepared by co-crystallization of MeOPP with the appropriate acidic component in methanol.

Structural commentary
Compound (I) is the neutral N-(4-methoxyphenyl)piperazine (MeOPP), and compounds (II) and (III) are unsolvated 1:1 3,5-dinitrobenzoate and 2,4,6-trinitrophenolate (picrate) salts, respectively, while compound (IV) is the 1:1 4-aminobenzoate salt, which crystallizes as a stoichiometric monohydrate in which the water component is firmly embedded in the overall hydrogen-bonded network (see Section 3, below). In each of (I)-(IV), the 4-methoxyphenyl substituent occupies an equatorial site on the piperazine ring but the MeOPP component exhibits no internal symmetry, so that it is conformationally chiral: the space groups (Table 2) confirm that each compound has crystallized as a conformational racemate. In each compound, the reference MeOPP unit was selected as one having a torsional angle C23-C24-O24-C27 that was close to 180 , as opposed to the alternative value close to zero degrees, and with the ring-puckering angle (Cremer & Pople, 1975), as calculated for the atom sequence (N1,C2,C3,N4,C5,C6) which was close to 0 , as opposed to a value close to 180 for the opposite conformational enantiomer.
In the salt (III), the nitro substituents at atoms C32 and C36 (Fig. 3) are both disordered over two sets of atomic sites The molecular structure of compound (I) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 2
The independent components of compound (II) showing the atomlabelling scheme and the hydrogen bond, drawn as a dashed line, within the selected asymmetric unit. Displacement ellipsoids are drawn at the 30% probability level.

Figure 3
The independent components of compound (III) showing the atomlabelling scheme, the hydrogen bonds, drawn as dashed lines, within the selected asymmetric unit, and the disorder in the nitro groups: the major disorder components are drawn with full lines and the minor disorder components are drawn with broken lines. Displacement ellipsoids are drawn at the 30% probability level.
having refined occupancies of 0.531 (16) and 0.469 (16) for the nitro group at atom C32, and 0.62 (6) and 0.38 (6) for that at atom C36. The major and minor disorder components of both these nitro groups are rotated about the exocyclic C-N bonds: for the C32 substituent, the two components are rotated by similar amounts, 22.6 (5) and 24.2 (5) for the major and minor components, but in opposite senses, so that the dihedral angle between the two components is 46.8 (6) ; by contrast, the rotations at C36 are in the same sense, by 25.2 (8) and 5.0 (3) , with a dihedral angle between the components of 20.7 (18) . The bond distances within this anion show some interesting features: firstly, the distance C31-O31, 1.235 (2) Å , is short for a phenolic bond [mean value (Allen et al., 1987) 1.362 Å , lower quartile value 1.353 Å ] and more reminiscent of the distances observed in ketones (mean value 1.210 Å ); secondly, the two C-C distances flanking this C-O unit, 1.448 (3) and 1.455 (3) Å , are much longer that the other C-C distances in this ring, which lie in the range 1.364 (3)-1.383 (3) Å . These metrical observations support the formulation of the picrate anion here as containing an effectively double C O bond at atom C31, with extensive delocalization of the negative charge over the atoms C32-C36, as indicated in the scheme.
In each compound, the methoxy C atom lies close to the plane of the adjacent aryl ring: the deviations from this plane are 0.176 (5), 0.033 (3), 0.040 (6) and 0.277 (7) Å in (I)-(IV), respectively. Associated with this near co-planarity, the two exocyclic O-C-C angles differ by ca 10 in each case, as is often observed when alkoxyarene systems are planar or nearly so (Seip & Seip, 1973;Ferguson et al., 1996).

Supramolecular features
The supramolecular assembly of compound (I) is extremely simple: a single N-HÁ Á ÁO hydrogen bond (Table 1) links molecules that are related by a 2 1 screw axis to form a C(10) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) chain running parallel to the [001] direction (Fig. 5). However, there are no direction-specific interactions between adjacent chains so that the supramolecular assembly here is one-dimensional.
The assembly in the 3,5-dinitrobenzoate salt (II) is also very simple. Two independent N-HÁ Á ÁO hydrogen bonds (Table 1) link inversion-related ion-pairs to form a cyclic centrosymmetric four-ion aggregate characterized by an R 4 4 (12) motif, and centred at (0.5, 0.5, 0.5) (Fig. 6). There are no direction- The independent components of compound (IV) showing the atomlabelling scheme and the hydrogen bonds, drawn as dashed lines, within the selected asymmetric unit. Displacement ellipsoids are drawn at the 30% probability level.

Figure 5
Part of the crystal structure of compound (I) showing the formation of a hydrogen-bonded chain 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. The atoms marked with an asterisk (*) or a hash (#) are at the symmetry positions (1 À x, 1 À y, 1 2 + z) and (1 À x, 1 À y, À 1 2 + z), respectively.

Figure 6
Part of the crystal structure of compound (II) showing the formation of a cyclic hydrogen-bonded R 4 specific interactions between adjacent aggregates, so that the supramolecular assembly here is finite, or zero-dimensional.
The component ions of compound (III) are linked by a combination of N-HÁ Á ÁO and C-HÁ Á Á(arene) hydrogen bonds to form complex sheets; however, the formation of the sheet structure is readily analysed in terms of two simpler, one-dimensional sub-structures (Ferguson et al., 1998a,b;Gregson et al., 2000). Although two of the nitro groups exhibit positional disorder (see Section 2, above), the hydrogen bonds involving the two sets of disorder components are fairly similar (Table 1), so that it is only necessary here to consider the interactions involving the major disorder components. The two ions within the selected asymmetric unit (Fig. 3) are linked by a markedly asymmetric N-HÁ Á Á(O) 2 three-centre system containing an R 2 1 (6) ring, and ion-pairs of this type, which are related by translation, are linked by a two-centre N-HÁ Á ÁO hydrogen bond to form a C(8)C(11)[R 2 1 (6)] chain of rings running parallel to [100] (Fig. 7). In the second sub-structure, cations, which are related by a 2 1 screw axis, are linked by a C-HÁ Á Á(arene) hydrogen bond, to form a chain running parallel to the [010] direction (Fig. 8). The combination of chains running parallel to the [100] and [010] directions then generates a sheet lying parallel to (001) in the domain 0.5 < z < 1.0. A second sheet of this type, related to the first by inversion, lies in the domain 0 < z < 0.5: although there are no direction-specific interactions between adjacent sheets, so that the supramolecular assembly in (III) is two dimensional, the sheets are, however, strongly interdigitated ( Fig. 9). Part of the crystal structure of compound (III) showing the formation of a hydrogen-bonded chain of rings parallel to [100]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the minor disorder components and 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 + x, y, z) and (À1 + x, y, z), respectively.

Figure 8
Part of the crystal structure of compound (III), showing the formation of a hydrogen-bonded chain of cations along [010]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the unit-cell outline, the minor disorder components and the H atoms not involved in the motif shown have been omitted. The atoms marked with an asterisk (*) or a hash (#) are at the symmetry positions ( 1 2 À x, À 1 2 + y, 3 2 À z) and ( 1 2 À x, 1 2 + y, 3 2 À z), respectively. Table 1 Hydrogen bonds and short intermolecular contacts (Å , ) for compounds (I)-(IV).
For compound (IV), the supramolecular assembly is more complex than for any of compounds (I)-(III), as a result of the presence of both an additional amino substituent in the cation and a water molecule, which acts as both a donor and an acceptor of hydrogen bonds (Table 1). The combination of N-HÁ Á ÁO, O-HÁ Á ÁO and C-HÁ Á Á(arene) hydrogen bonds links the components into a three-dimensional framework structure but, again, this can readily be analysed in terms of fairly simple sub-structures. In the first of these, the ionic components and the water molecules form a chain of centrosymmetric rings running parallel to the [100] direction, in which R 6 6 (16) rings centred at (n, 0.5, 1) alternate with R 4 6 (12) rings centred at (n + 0.5, 0.5, 1), where n represents an integer in each case (Fig. 10). In the second sub-structure, the two N-HÁ Á ÁO hydrogen bonds having atoms O24 and O31 as the acceptors (Table 1)  Part of the crystal structure of compound (IV) showing the formation of a hydrogen-bonded chain of rings parallel to [100]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the unit-cell outline and the H atoms bonded to C atoms have been omitted. The atoms marked with an asterisk (*), a hash (#), a dollar sign ($) or an ampersand (&) are at the symmetry positions (1 À x, 1 À y, 2 À z), (Àx, 1 À y, 2 À z), (1 + x, y, z) and (À1 + x, y, z) respectively.

Figure 9
A projection along [100] of part of the crystal structure of (III), showing the interdigitation of the sheets lying parallel to (001). Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the minor disorder components and the H atoms not involved in the motifs shown have been omitted.

Figure 11
Part of the crystal structure of compound (IV) showing the formation of a hydrogen-bonded chain parallel to [001]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the water molecules and the H atoms bonded to C atoms have been omitted.
There are two C-HÁ Á Á(arene) interactions in the structure of compound (IV): the longer of these, involving atom C22, lies within the chain of rings along [100] but the other, shorter, interaction combines with some of the N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds to generate a complex chain running parallel to the [010] direction (Fig. 12). The combination of chains along [100], [010] and [001] then suffices to generate a three-dimensional supramolecular structure.

Database survey
The first salt of MeOPP to have its structure reported was 4-(4-methoxyphenyl)piperazin-1-ium chloride (V) (Zia-ur-Rehman et al., 2009), in which two N-HÁ Á ÁCl hydrogen bonds link the ions into simple chains. The aggregation in the 3,5dinitrobenzoate salt (II) reported here, where two independent N-HÁ Á ÁO hydrogen bonds generate a cyclic R 4 4 (12) motif, can be contrasted with that in the trichloroacetate salt (VI) (Kiran , where two independent N-HÁ Á ÁO hydrogen bonds generate a continuous C 2 2 (6) chain: the reason for the finite aggregation in (II) versus the continuous aggregation in (VI) is not obvious. The electronic delocalization in the anion of (III) reported here is similar to that in the anion of the 5-hydroxy-3,5-dinitrobenzoate salt (VII) (Kiran , where it is the phenolic hydroxyl group that has ionized rather than the carboxyl group, so forming an anion more reminiscent of a picrate ion than of a 3,5-dinitrobenzoate ion. The aggregation in (VII) takes the form of a chain of rings generated by a combination of N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds, with chains of this type further linked by C-HÁ Á Á(arene) hydrogen bonds to form a three-dimensional structure. The unit-cell dimensions of compound (IV) reported here are similar to those in a series of isomorphous monohydrated benzoate salts containing anions of type (4-C 6 H 4 COO) À , where -= H, F, Cl or Br, compounds (VIII)-(XI), in all of which the 4-methoxyphenyl unit exhibits disorder (Kiran : however, despite the similarity in cell dimensions, the structure of (IV) differs from those of (VIII)-(XI) firstly in showing no disorder and secondly in forming a three-dimensional hydrogen-bonded structure as opposed to the onedimensional assembly in (VIII)-(XI). By contrast with compounds (VIII)-(XI) in space group P1, the 4-iodobenzoate analogue (XII), also a monohydrate (Kiran Kumar, Yathirajan, Harish Chinthal et al., 2020) crystallizes in space group P2 1 /c with Z 0 = 3, but with no disorder, and an extensive series of N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds links the nine independent components into complex sheets.

Synthesis and crystallization
N-[4-Methoxyphenyl]piperazine (I), was purchased from Sigma-Aldrich, and crystals suitable for single-crystal X-ray diffraction were grown by slow evaporation, at ambient temperature and in the presence of air, of a solution in methanol, m.p. 316-318 K. For the preparation of the salts (II)-(IV), solutions of (I) (100 mg, 0.52 mmol) in methanol (10 ml), and of 0.52 mmol of the appropriate acidic component [3,5-dinitrobenzoic acid (110.3 mg) for (II), picric acid (119.1 mg) for (III), and 4-aminobenzoic acid (71.3 mg) for (IV)] also in methanol (10 ml) were mixed and then briefly held at 313 K with stirring. The solutions were allowed to cool to ambient temperature and then set aside to crystallize, giving the products (II)-(IV). The products were collected by filtration, and dried in air: m.p. (II) 393-395 K, (III) 420-422 K, and (IV) 407-409 K. Crystals of the salts (II)-(IV) suitable for single-crystal X-ray diffraction were grown by slow evaporation, at ambient temperature and in the presence of air, of solutions in methanol/ethyl acetate (1:1, v/v).

Refinement
Crystal data, data collection and refinement details are summarized in Table 2. 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 (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. For the H atoms bonded to N atoms in (I) and (II), the atomic coordinates were refined with U iso (H) = 1.2U eq (N) giving the N-H distances shown in Table 1. In (III) and (IV), free refinement of the atomic coordinates for the H atoms bonded to N in the cations, and to O in the water component of (IV) gave N-H and O-H distances which were rather unsatisfactory: hence these H atoms bonded to N were treated as riding atoms with U iso (H) = 1.2U eq (N), while for those bonded to O in (IV), the O-H distances were restrained to a value of 0.84 (2) Å , with U iso (H) = 1.5U eq (O), giving the distances shown in Table 1. In compound (III), two of the nitro groups exhibited disorder over two sets of atomic sites having unequal occupancy. For the minor disorder components, the bonded distances and the 1,3 non-bonded distances were restrained to be the same as the corresponding distances in the major disorder components subject to s. u. values of 0.01 and 0.02 Å , respectively, giving refined occupancies of 0.531 (16) and 0.469 (16) for the nitro group at atom C32, and 0.62 (6) and 0.38 (6) for that at atom C36. In addition, for each of the disordered substituents, the component atoms were restrained to have the same U ij components. In the absence of significant resonant scattering, the correct orientation of the structure of (I) with respect to the polar axis direction could not be established: the value of the Flack x parameter (Flack, 1983), as calculated (Parsons et al., 2013) using 546 quotients of the type [(I + ) À (I À )]/ [(I + ) + (I À )] was À0.5 (8), so that the correct orientation is indeterminate (Flack & Bernardinelli, 2000): however, in the space group Pna2 1 , this parameter does not carry any information of chemical significance.   (2) 7.4365 (4), 10.6276 (6), 13.2700 (6) 8.7568 (6), 6.6292 (5), 34.024 (2) 6.2590 (7), 7.4549 (9) SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics:

Special details
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 )

Special details
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 2,4,6-trinitrophenolate (III)
Crystal data Special details 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 )

4-(4-Methoxyphenyl)piperazin-1-ium 4-aminobenzoate monohydrate (IV)
Crystal data where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.24 e Å −3 Δρ min = −0.20 e Å −3 Special details 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.