Six 1-halobenzoyl-4-(2-methoxyphenyl)piperazines having Z′ values of one, two or four; disorder, pseudosymmetry, twinning and supramolecular assembly in one, two or three dimensions

Among six closely related 1-halobenzoyl-4-(2-methoxyphenyl)piperazines, those with Z′ = 1 form one-dimensional hydrogen-bonded assemblies, those with Z′ = 2 form two-dimensional hydrogen-bonded assemblies, and that with Z′ = 4 forms a three-dimensional hydrogen-bonded assembly. Pseudosymmetry and inversion twinning are apparent when Z′ > 1.


Chemical context
N-(2-Methoxyphenyl)piperazine (2-MeOPP) has been used as a building block in the synthesis of both 5-HT 1A receptor ligands (Orjales et al., 1995) and dopamine D 2 and D 3 ligands (Hackling et al., 2003), and also as a building block for the synthesis of derivatives exhibiting antidepressant-like activity (Waszkielewicz et al., 2015). We have recently reported the structures of a range of salts derived from 2-MeOPP (Harish Chinthal et al., 2020a) and here we report the syntheses and structures of six 1-haloaroyl-4-(2-methoxyphenyl)piperazines, (I)-(VI). The work reported here represents a continuation of an earlier study on the isomeric N-(4-methoxyphenyl)piperazine (4-MeOPP) (Kiran Kumar et al., 2020) and a range of salts and N-aroyl derivatives derived from 4-MeOPP (Kiran In none of the compounds reported here do the molecules exhibit any internal symmetry and hence they are conformationally chiral. The space groups for compounds (II), (III), (IV) and (VI) confirm the presence in the crystal of equal numbers of the two conformational enantiomers. For each of (II), (III) and (V), having Z 0 > 1, there is considerable flex- The structures of the four independent molecules in the selected asymmetric unit of compound (II), viewed approximately along [001], showing the atom-labelling scheme, and the approximate spacial relationships between the molecules. Displacement ellipsoids are drawn at the 30% probability level and, for the sake of clarity, the H atoms have been omitted.

Figure 3
The structures of the two independent molecules in the selected asymmetric unit of compound (III), viewed approximately along [001], showing the atom-labelling scheme, the disorder in one of the molecules and the approximate glide relationship between the two molecules. The major disorder component is drawn using full lines and the minor disorder component is drawn using 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 1
The molecular structure of compound (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. ibility available for the choice of the asymmetric unit: in each case, the asymmetric unit was selected such that the independent molecules in it were linked by C-HÁ Á ÁO hydrogen bonds (Table 1).
For compound (I), which crystallizes in space group P2 1 2 1 2 1 with Z 0 = 1, it was not possible to establish the absolute configuration of the molecules in the crystal selected for data collection (see Section 6). In compound (V), the two independent molecules in the selected asymmetric unit have opposite conformations and they are related by an approximate, but non-crystallographic, inversion close to (0.25, 0.60, 0.25) (cf. Fig. 5), and so (V) may be regarded as a kryptoracemate (Fá biá n & Brock, 2010). Pseudosymmetry is also apparent in compounds (II) and (III). In (III), where Z 0 = 2, molecule 1 containing atom Br14 and the major disorder component of molecule 2 containing atom Br24 are related by an approximate, but non-crystallographic b-glide plane at x = ca 0.62 (cf. Fig. III). The arrangement of the molecules in compound (II) is slightly more complex: molecules 1 and 3, containing atoms Cl14 and Cl34, respectively, are related by an approximate, but non-crystallographic, 2 1 screw axis along (0.56, y, 0.68), as also are molecules 2 and 4, containing atoms Cl24 and Cl44 (cf. Fig. 2). In addition, molecules 1 and 2 are approximately related by the translation (x À 0.25, y + 0.06, z), while molecules 3 and 4 are approximately related by the translation (x + 0.25, y + 0.06, z). Compounds (II), (III) and (V) all exhibit a measure of inversion twinning (Section 6, below) and it seems likely that this is underpinned by the pseudosymmetry in these structures.
In each of (I)-(IV), the methoxy C atom is close to coplanar with the adjacent aryl ring, with displacements from the plane of the ring ranging from 0.024 (7) Å in molecule 4 of (II) to 0.130 (3) Å in (I): for (V) and (VI) the displacements are rather larger, up to 0.447 (1) Å in molecule 2 of (V). However, in every molecule the two exocyclic C-C-O angles differ by ca 10 , as typically found in planar, or near-planar, alkoxyarenes (Seip & Seip, 1973;Ferguson et al., 1996).

Supramolecular features
In assessing the intermolecular interactions, we have discounted hydrogen bonds having D-HÁ Á ÁA angles that are significantly less than 140 , as the interaction energies associated with such contacts are likely to be very low, so that these cannot be regarded as structurally significant (Wood et al., 2009). We have also discounted short contacts involving the H atoms of the methyl groups, as such groups are likely to be undergoing rapid rotation about the adjacent C-O bonds (Riddell & Rogerson, 1996, 1997. The C-HÁ Á Á(arene) contacts have been included only where the HÁ Á ÁCg distances are less than 2.85 Å . It should perhaps be conceded here that these are somewhat arbitrary judgments, made with the primary aim of avoiding over-interpretation of the longer The molecular structure of compound (IV), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 6
The molecular structure of compound (VI), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 5
The structures of the two independent molecules in the selected asymmetric unit of compound (V), showing the atom-labelling scheme and the approximate inversion symmetry relating the two molecules. Displacement ellipsoids are drawn at the 30% probability level. contacts and over-complication of the crystal-structure descriptions. It is convenient to consider first the supramolecular assembly in compounds (I), (IV) and (VI) where Z 0 = 1 and the aggregation is one-dimensional, followed by (III) and (V) where Z 0 = 2 and the aggregation is two-dimensional, and finally (II) where Z 0 = 4 and the aggregation is threedimensional.
The assembly in compounds (I), (IV) and (VI) is very simple. In (I), a single C-HÁ Á ÁO hydrogen bond (Table 1) links molecules which are related by translation to form a C(6) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) chain, which is weakly reinforced by a C-HÁ Á Á(arene) hydrogen bond to form a chain of rings running along (x, 0.25, 0) (Fig. 7). Simple C(6) chains are also formed in compounds (IV) and (VI), although these involve different donors. The chain in (IV) is built from molecules related by the 2 1 screw axis along (0.5, y, 0.25) (Fig. 8), while that in (VI) contains molecules related by translation along [100] (Fig. 9), analogous to that in (I). In none of (I), (IV) and (VI) are there any directionspecific interactions between adjacent chains so that, in each case, the assembly is one-dimensional.
Because of the very low occupancy of the minor disorder component in (III), it is necessary to consider only the interactions involving the major disorder component, where a combination of C-HÁ Á ÁO and C-HÁ Á Á(arene) hydrogen bonds links the molecules into a sheet lying parallel to (100) (Fig. 10). The assembly in (V) is also two-dimensional, but it is Acta Cryst. (2021). E77, 5-13 research communications Table 1 Hydrogen bonds (Å , ).

Figure 7
Part of the crystal structure of compound (I), showing the formation of a hydrogen-bonded chain of rings running parallel to [100]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms not involved in the motif shown have been omitted.

Figure 8
Part of the crystal structure of compound (IV), showing the formation of a hydrogen-bonded chain running parallel to [010]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to the C atoms which are not involved in the motif shown have been omitted.

Figure 9
Part of the crystal structure of compound (VI), showing the formation of a hydrogen-bonded chain running parallel to [100]. Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms which are not involved in the motif shown have been omitted.

Figure 10
Part of the crystal structure of compound (III), showing the formation of a hydrogen-bonded sheet lying parallel to (100). Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the minor disorder component and the H atoms bonded to the C atoms which are not involved in the motif shown have been omitted.

Figure 11
Part of the crystal structure of compound (V), showing the formation of a hydrogen-bonded chain of rings running along (1/2, y, 1/4). Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms which are not involved in the motif shown have been omitted.
rather more complex than that in (III); however, it is possible to analyse the sheet formation in (V) in terms of three simpler sub-structures (Ferguson et al., 1998a,b;Gregson et al., 2000). The first of these sub-structures, which can be regarded as the basic building block in the structure, consists of the two molecules within the selected asymmetric unit (Fig. 5), which are linked by two C-HÁ Á ÁO hydrogen bonds to form a cyclic dimeric unit containing an R 2 2 (22) motif, and dimers of this type are linked to form two types of chains of rings. One of these chains contains dimers which are related by the 2 1 screw axis along (0.5, y, 0.25) (Fig. 11) and the other is built from dimers related by the 2 1 screw axis along (0, y, 0.25) (Fig. 12). Within these two chains, the hydrogen bonds are directed in opposite directions (Table 1), and the combination of the two chains generates a complex sheet lying parallel to (001). There are no direction-specific interactions between adjacent sheets in either (III) or (V).
No fewer than six independent C-HÁ Á ÁO hydrogen bonds, three of them within the selected asymmetric unit, link the molecules of compound (II) into a complex sheet lying parallel to (001) (Fig. 13). In addition, two independent C-HÁ Á Á(arene) hydrogen bonds link molecules related by the 2 1 screw axis along (0.5, 0.5, z) to generate a chain running parallel to the [001] direction (Fig. 14) and chains of this type link the (001) sheets to form a continuous three-dimensional network.

Database survey
Here we briefly compare the structures of compounds (I)-(VI) with those of some analogous compounds. In the structure of 1-(2-fluorobenzoyl)-4-(4-methoxyphenyl)piperazine (VII), Part of the crystal structure of compound (V), showing the formation of a hydrogen-bonded chain of rings running along (0, y, 1/4). Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms which are not involved in the motif shown have been omitted.

Figure 13
Part of the crystal structure of compound (II), showing the formation of a hydrogen-bonded sheet lying parallel to (001). Hydrogen bonds are drawn as dashed lines and, for the sake of clarity, the H atoms bonded to those C atoms which are not involved in the motif shown have been omitted.

Synthesis and crystallization
All reagents were commercially available and all were used as received. For the synthesis of compounds (I)-(VI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (134 mg, 0.7 mmol), 1-hydroxybenzotriazole (68 mg, 0.5 mmol) and triethylamine (0.5 ml, 1.5 mmol) were added to a solution of the appropriately substituted benzoic acid (0.52 mmol) in methanol (10 ml), thus 4-fluorobenzoic acid (73 mg) for (I), 4-chlorobenzoic acid (82 mg) for (II), 4-bromobenzoic acid (103 mg) for (III), 4-iodobenzoic acid (129 mg) for (IV), 3-iodobenzoic acid (129 mg) for (V) and 2-fluorobenzoic acid (73 mg) for (VI). Each mixture was stirred at 323 K for a few minutes and then set aside for two days at room temperature. A solution of N-(2-methoxyphenyl)piperazine (100 mg, 0.52 mmol) in N,Ndimethylformamide (5 ml) was then added to each of the mixtures prepared as above, followed by stirring that was continued overnight at room temperature. When the reactions were confirmed to be complete using thin-layer chromatography, each mixture was then quenched with water (10 ml) and extracted with ethyl acetate (20 ml). Each organic fraction was separated and washed successively with an aqueous hydrochloric acid solution (1 M), a saturated solution of sodium hydrogencarbonate and then with brine. The organic phases were dried over anhydrous sodium sulfate and the solvent was then removed under reduced pressure. The resulting solid products were then crystallized from acetone-

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. One bad outlier reflection (2,0,2) was omitted from the final refinement for compound (IV), and two bad outlier reflections, (1,5,18) and (1,18,15), were omitted from the final refinement for compound (V). All H atoms, apart from those in the minor disorder component of compound (III), were located in difference maps and subsequently treated as riding atoms in geometrically idealized positions, with C-H distances 0.93 Å (aromatic), 0.96 Å (CH 3 ) and 0.97 Å (CH 2 ), and with U iso (H) = kU eq (C), where k = 1.5 for the methyl groups, which were allowed to rotate but not to tilt, and 1.2 for all other H atoms. For the minor disorder component in (III), the bonded distances and the 1,3 nonbonded distances were restrained to be the same as the corresponding distances in the major disorder component, subject to s.u. values of 0.01 and 0.02 Å , respectively. In addition, the anisotropic displacement parameters for pairs of atoms occupying essentially the same physical space were constrained to be identical. Subject to these conditions, the refined disorder occupancies were 0.939 (4) and 0.061 (4). In the absence of significant resonant scattering, it was not possible to determine the absolute configuration of the molecules of (I) in the crystal selected for data collection. The value of the Flack x parameter [Flack (1983), x = À0.2 (8), calculated (Parsons et al., 2013) using 612 quotients of the type [(I + ) À (I À )]/[(I + ) + (I À )], means that the absolute structure is indeterminate (Flack & Bernardinelli, 2000), although this has no chemical significance. For each of (II), (III) and (V), the Flack x parameter indicated the occurrence of inversion twinning (Flack & Bernardinelli, 2000), thus: for (II), x = 0.22 (8) calculated using 1164 quotients; for (III), x = 0.300 (6) calculated using 1164 quotients; and for (V), x = 0.456 (12) calculated using 1728 quotients. The structure of (I) contains two void spaces, each of volume 65 Å 3 and centred close to (0, 0.25, 0) and (0, 0.75, 0.5); however, examination of the refined structure using SQUEEZE (Spek, 2015) showed that these voids contained negligible electron density. There are four small voids in the structure of (II), each of volume ca 32 Å 3 , and all too small to accommodate even a water molecule (Hofmann, 2002).  SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: PLATON (Spek, 2020); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015b) and PLATON (Spek, 2020). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.12 e Å −3 Δρ min = −0.14 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.

1-(4-Fluorobenzoyl)-4-(2-methoxyphenyl)piperazine (I)
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 ) Hydrogen-bond geometry (Å, º)    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.

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 )
x y z U iso */U eq Occ. (      where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max = 0.001 Δρ max = 0.43 e Å −3 Δρ min = −0.91 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq N1 0.3873 (2) 0.4258 (2) (12) 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 )
x y z U iso */U eq N11 0.2358 (9) 0.4763 (4) 0.2308 (2) 0.0432 (17)   where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.17 e Å −3 Δρ min = −0.17 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.