Six 1-aroyl-4-(4-methoxyphenyl)piperazines: similar molecular structures but different patterns of supramolecular assembly

Six new 1-aroyl-4-(4-methoxyphenyl)piperazines have similar molecular structures, but their supramolecular assembly ranges from simple chains, via a chain of rings, to complex sheets.


Chemical context
Piperazines are found in a wide range of compounds which are active across a number of different therapeutic areas such as antibacterial, antidepressant, antifungal, antimalarial, antipsychotic, and antitumour activity (Brockunier et al., 2004;Bogatcheva et al., 2006), and a number of these areas have recently been reviewed (Elliott, 2011;Kharb et al., 2012;Asif, 2015;Brito et al., 2019). 1-(4-Methoxyphenyl)piperazine has been found to inhibit the re-uptake and accelerate the release of monoamine neurotransmitters such as dopamine and serotonin, with a mechanism of action similar to that of recreational drugs such as amphetamines, but with significantly lower abuse potential (Nagai et al., 2007). With these considerations in mind, we have now synthesized and characterized a series of closely related 1-aroyl-4-(4-methoxyphenyl)piperazines, using a straightforward coupling reaction between N-(4-methoxyphenyl)piperazine and a benzoic acid, promoted by 1-(3-dimethylaminopropyl)-3-ethylcarbodimide as the dehydrating agent. Here we report the molecular and supramolecular structures of compounds (I)-(VI) (Figs. 1-6) which we compare with the structures of some related compounds. As well as these 2-substituted derivatives, we have also synthesized 1-(4-fluorobenzoyl)-4-(4-methoxyphenyl)- ISSN 2056-9890 piperazine (VII), but to date we have been unable to obtain any crystalline material suitable for single crystal X-ray diffraction.

Structural commentary
In the 2-chloro derivative (III), the benzoyl substituent is disordered over two sets of atomic sites having refined occupancies for the crystal selected for data collection of 0.942 (2) and 0.058 (2): in these two disorder forms, the chloro substituents occupy sites on opposite sides of the adjacent aryl ring (Fig. 3). Compounds (III), (IV) and (V) have similar unit-cell dimensions (Table 2)  The molecular structure of compound (IV) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 5
The molecular structure of compound (V) 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 1
The molecular structure of compound (I) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 2
The molecular structure of compound (II) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.

Figure 3
The molecular structure of compound (III) showing the atom-labelling scheme, and the disorder of the 2-chlorobenzoyl unit. 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. each can be refined using the atomic coordinates of another as the starting point. However, these three structures exhibit several minor differences: firstly, the benzoyl group is disordered over two sets of atomic sites in (III), but not in (V); in (IV), the disorder was found to be very minor, ca 1.6%, such that attempted refinement of this small fraction was regarded as unrealistic and thus the ordered model was preferable. Secondly, there is a short intermolecular IÁ Á ÁO contact in (V), which has no ClÁ Á ÁO or BrÁ Á ÁO analogue in (III) and (IV). Hence compounds (III)-(V) can be regarded as isomorphous, but not strictly isostructural (cf. Acosta et al., 2009).
In each of the compounds reported here, the piperazine ring adopts an almost perfect chair conformation with the 4methoxyphenyl substituent occupying an equatorial site: the geometry at atom N1 is effectively planar and only in compound (I) is there a very slight pyramidalization at this site. For each compound, the reference molecule was selected as one having a ring-puckering angle (Cremer & Pople, 1975) for the atom sequence (N1,C2,C3,N4,C5,C6) which was close to zero, as opposed to values close to 180 for the corresponding enantiomers. In all of the compounds, the methoxy carbon atom C441 is very close to being coplanar with the adjacent aryl ring: the maximum displacement of this atom from the ring plane is 0.216 (16) Å in compound (V). Associated with this observation, we note that the two exocyclic O-C-C angles at atom C44 always exhibit differences in the range 8-10 : this behaviour is entirely consistent with the that previously observed in planar or nearly planar alkoxyarenes (Seip & Seip, 1973;Ferguson et al., 1996). It is interesting to note that the methoxy group is oriented transoid to the carbonyl group in compounds (I) and (VI), but cisoid in compounds (II)-(V), suggesting that the methyl group may simply be acting in a space-filling role.

Supramolecular features
The supramolecular assembly in compounds (I)-(V) is dominated by contacts of C-HÁ Á ÁO and C-HÁ Á Á(arene) types (Table 1) and it is thus appropriate to define explicitly the criteria against which these contacts have been regarded as structurally significant hydrogen bonds. For single-atom acceptors, we adopt the distance criteria recommended in PLATON (Spek, 2009), based on the well-established concept of van der Waals radii (Bondi, 1964;Nyburg & Faerman, 1985;Rowland & Taylor, 1996), which provide an upper limit for HÁ Á ÁO contacts of 2.60 Å , combined with the recommended (Wood et al., 2009) lower limit of 140 for the D-HÁ Á ÁA angle. For the C-HÁ Á Á(arene) contacts in the isomorphous compounds (III)-(V), both the HÁ Á ÁCg distances and the C-HÁ Á ÁCg angles are entirely typical of C-HÁ Á Á(arene) hydrogen bonds (Braga et al., 1998). On this basis the C-HÁ Á ÁO contacts in (II) can be regarded as significant, while the nearly linear C-HÁ Á ÁO contacts in (III)-(V), which appear in each case to act cooperatively with a C-HÁ Á Á hydrogen bond should be regarded as of marginal significance in (III) and (V).
The sole direction-specific short intermolecular contact in (I) is between molecules related by a glide plane. The mol- Table 1 Hydrogen bonds and short intermolecular contacts (Å , ) in compounds (I)-(VI).
Cg1 and Cg2 are the centroids of the C11-C16 and C41-C46 rings, respectively. ecules of compound (II) are linked by two independent C-HÁ Á ÁO hydrogen bonds (Table 1) to form a chain of centrosymmetric rings in which R 2 2 (10) (Etter, 1990;Etter et al., 1990;Bernstein et al., 1995) rings involving atom C2 as the donor and centred at (n + 1 2 , 1 2 , 1 2 ) alternate with R 2 2 (10) rings involving atom C16 as the donor and centred at (n, 1 2 , 1 2 ), where n represents an integer in each case (Fig. 7). Chains of this type are linked into sheets by an aromaticstacking interaction: the fluorinated rings in the molecules at (x, y, z) and (2 À x, 2 À y, 1 À z) are parallel with an interplanar spacing of 3.520 (2) Å ; the ring-centroid separation is 3.774 (2) Å and the ring-centroid offset is 1.360 (2) Å . This interaction links the hydrogen-bonded chains into a sheet lying parallel to (001) in the domain 1 4 < z < 3 4 : a second such sheet, related to the first by the translational symmetry operation, lies in the domain À 1 4 < z < 1 4 , but there are no direction-specific interactions between adjacent sheets.
As noted previously (see Section 2), the 2-chlorobenzoyl unit in compound (III) is disordered over two sets of atomic sites: however, the occupancy of the minor disorder component is low, and thus only the major component need be considered here. The supramolecular assembly in each of (III)-(V) is essentially the same. A combination of two C-HÁ Á Á(arene) hydrogen bonds, weakly augmented by a C-HÁ Á ÁO Interaction, links the molecules into sheets, whose formation is readily analysed in terms of two one-dimensional sub-structures (Ferguson et al., 1998a,b;Gregson et al., 2000). In the simpler of the two sub-structures, molecules related by the b-glide at x = 3 4 are linked by a C-HÁ Á Á(arene) hydrogen bond to form a chain running parallel to the [010] direction (Fig. 8). In the second sub-structure, a C-HÁ Á Á(arene) hydrogen bond links molecules which are related by the 2 1 screw axis along (x, 1 4 , 1 2 ) to form a chain running parallel to the [100] direction (Fig. 9). These two chain motifs combine to generate a sheet lying parallel to (001) in the domain 1 4 < z < 3 4 . A second sheet, related to the first by inversion, lies in the domain 3 4 < z < 5 4 , but there are no direction-specific interactions between adjacent sheets. However there is, in (V), a rather short intermolecular IÁ Á ÁO contact where I12Á Á ÁO17 i = 3.362 (7) Å and C12-I12Á Á ÁO17 i = 163.5 (2) [symmetry code: (i) 3 2 À x, 1 2 + y, z], as compared with the sum of van der Waals radii of 3.56 Å (Rowland & Taylor, 1996). This contact lies within the chain along [010] and so does not affect the overall two-dimensional nature of the supramolecular assembly. However, short contacts of this type are not present in the structures of (III) and (IV), where the corresponding ClÁ Á ÁO and BrÁ Á ÁO distances are 3.707 (4) and 3.708 (3) Å , respectively, as compared with the sums of van der Waals radii of 3.30 Å and 3.41 Å respectively. Simple considerations of electronegativity (Allen, 1989) indicate that in carbonhalogen bonds of type (aryl)C-X, the halogen atom carries a Part of the crystal structure of compound (III) showing the formation of a simple chain running parallel to the [010] direction. Hydrogen bonds are shown as dashed lines and, for the sake of clarity, the minor disorder component and the H atoms bonded to those C atoms which are not involved in the motif shown have been omitted.

Figure 9
Part of the crystal structure of compound (III) showing the formation of a simple chain running parallel to the [100] direction. Hydrogen bonds are shown as dashed lines and, for the sake of clarity, the minor disorder component and the H atoms bonded to those C atoms which are not involved in the motif shown have been omitted. residual positive charge when X = I, but a residual negative charge when X = Cl or Br. On this basis (aryl)C-XÁ Á ÁO C interactions are expected to be attractive when X = I, but repulsive when X = Cl or Br, so accounting for the much shorter IÁ Á ÁO distance in (V) as compared with the corresponding distances in (III) and (IV).
The supramolecular assembly in compound (VI) takes the form of simple C(6) chains running parallel to the [100] direction, in which molecules related by the a-glide plane at z = 1 4 are linked by an O-HÁ Á ÁO hydrogen bond (Table 1) (Fig. 10). A second chain of this type, related to the first by inversion, and two further chains related to the first pair by the c-glide planes, pass through each unit cell but there are no direction-specific interactions between adjacent chains.
Thus in summary, the supramolecular assembly takes the form of a simple chain in compound (VI), a chain of rings in compound (II), and sheets in compounds (III), (IV) and (V).

Synthesis and crystallization
For the synthesis of compounds (I)-(VII), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (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 [benzoic acid for (I), 2-fluorobenzoic acid for (II), 2-chlorobenzoic acid for (III), 2-bromobenzoic acid for (IV), 2-iodobenzoic acid for (V), salicylic acid for (VI) and 4-fluorobenzoic acid for (VII)] (0.5 mmol) in N,N-dimethylformamide (5 ml) and the resulting mixtures were stirred for 20 min at 273 K. A solution of N-(4-methoxyphenyl)piperazine (100 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was then added and stirring was continued overnight at ambient 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 mol dm À3 ), a saturated solution of sodium hydrogencarbonate and then with brine. The organic phases were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Crystals suitable for single-crystal X-ray diffraction were grown by slow evaporation, at ambient temperature and in the presence of air, of solutions in ethyl acetate. Compound (I     114.47, 115.44, 118.90, 129.43 131.59, 145.11, 154.41, 162.13, 169.39.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. Two bad outlier reflections, (080) and (186), were omitted from the final refinements for compound (V). For the minor disorder component of compound (III), the bonded distances and the 1,3 non-bonded distances were restrained to be the same as those in the major disorder component, subject to s.u. values of 0.01 and 0.02 Å , respectively. The anisotropic displacement parameters for pairs of partial-occupancy atoms occupying essentially the same physical space were constrained to be the same: in addition it was found desirable to constrain the minor component of the chloroaryl ring to be planar, and to apply a rigid-bond restraint to the bond C32-Cl32 in the minor disorder component. Subject to these conditions, the occupancies of the two disorder components refined to 0.942 (2) and 0.058 (2), respectively. After refinement of (IV) as a fully ordered structure, the difference map contained indications of some slight disorder similar to that found for (III). However, when this structure was refined using a disorder model analogous to that used for (III), the preliminary values of the occupancies were 0.9837 (7) and 0.0163 (7), so that each C atom in the minor disorder component represented less than 0.1 electron: accordingly, it was regarded as unrealistic to pursue this disorder model and that the fully ordered model was preferable. The principal feature in the difference map for (V) is a minimum, À2.24 e Å À3 , located 1.80 Å from atom I2 at (x, y, z) and 1.83 Å from atom O17 at ( 3 2 À x, 1 2 + y, z), although not co-linear with these two atoms, which subtend an angle of 135 at the minimum. All H atoms apart from those in the minor disorder components of compound (III) were located in difference maps. The H atoms bonded to C atoms were all 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 atom bonded to an O atom in compound (VI), the atomic coordinates were refined with U iso (H) = 1.5U eq (O), giving an O-H distance of 0.92 (2) Å . In the absence of significant resonant scattering in (I), it was not possible to determine the correct orientation of the structure of (I) relative to the polar axis directions: however, this has no chemical significance. SHELXL2014 (Sheldrick, 2015b); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015b) and PLATON (Spek, 2009). where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.14 e Å −3 Δρ min = −0.13 e Å −3 Extinction correction: SHELXL, Fc * =kFc[1+0.001xFc 2 λ 3 /sin(2θ)] -1/4 Extinction coefficient: 0.0041 (8) 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 0.46344 (7) 0.2520 (2) 0.4700 (3) 0.0433 (5)  C2 0.41820 (8)     where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.21 e Å −3 Δρ min = −0.27 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 0.7575 (4) 0.5325 (4) 0.41972 (9) 0.0547 (8)    where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.23 e Å −3 Δρ min = −0.45 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 Occ. ( 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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq N1 0.68078 (15)   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 0.6767 (5) 0.2532 (5)   where P = (F o 2 + 2F c 2 )/3 (Δ/σ) max < 0.001 Δρ max = 0.16 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.