Synthesis and structure of clozapine N-oxide hemi(hydrochloride): an infinite hydrogen-bonded poly[n]catenane

The recrystallization of clozapine N-oxide hydrochloride from a range of solvents leads to the loss of half an equivalent of HCl and the formation of single crystals of a hydrogen-bond-linked poly[n]catenane of clozapine N-oxide hemihydrochloride.

The structure of the title compound, 2C 18 H 19 ClN 4 OÁHCl or (CNO) 2 ÁHCl (C 36 H 39 Cl 3 N 8 O 2 ), at 100 K has tetragonal (I4/m) symmetry. The dihedral angle between the benzene rings of the fused ring system of the CNO molecule is 40.08 (6) and the equivalent angle between the seven-membered ring and its pendant N-oxide ring is 31.14 (7) . The structure contains a very strong, symmetrical O-HÁ Á ÁO hydrogen bond [OÁ Á ÁO = 2.434 (2) Å ] between two equivalent R 3 N + -O À moieties, which share a proton lying on a crystallographic twofold rotation axis. These units then form a (CNO) 4 Á(HCl) 2 ring by way of two equivalent N-HÁ Á ÁCl hydrogen bonds (Cl À site symmetry m). These rings are catenated into infinite chains propagating along the c-axis direction by way of shape complementarity and directional C-HÁ Á ÁN and C-HÁ Á Á interactions.

Chemical context
Coordination-driven self-assembly of supramolecular structures is a major focus area of materials science. However, hydrogen-bond-driven self-assembly has been less well studied, most likely as a consequence of the weakness of hydrogen bonding relative to coordinate bonding. Nevertheless, the directionality of hydrogen bonding can lend it to the controllable formation of supramolecular networks (Gonzá lez-Rodríguez & Schenning, 2011;Steiner, 2002;Prins et al., 2001). The simplest infinite interlocking systems are the one-dimensional polycatenanes (poly[n]catenanes). Such systems have been described involving interpenetrating metallocycles of silver/bis(2-methylimidazolyl) (Jin et al., 2006(Jin et al., , 2008(Jin et al., , 2018 and mercury/1,2-bis[(pyridin-4-ylthio)methyl]benzene (Xue et al., 2015). However, the lack of many examples beyond these suggests that the self-assembly of this interesting topological architecture is not easily achieved. Here, we report the serendipitous discovery of an infinite onedimensional polycatenane architecture templated by a chloride anion that forms upon the attempted recrystallization of clozapine N-oxide (C 18 H 19 ClN 4 O; hereafter CNO) monohydrochloride, an inactive metabolite of clozapine that is utilized as an actuator of engineered muscarinic acetylcholine receptors (Armbruster et al., 2007;Urban & Roth, 2015;Dong et al., 2010;Gomez et al., 2017).
As part of efforts to develop a water-soluble salt form of CNO (van der Peet et al., 2018) we synthesized CNOÁHBr and CNOÁHCl by formation of the salt in methanol (Scheme 1).
The latter compound has been reported previously (Allen et al., 2019), but its preparation was not described. Elemental analysis of the precipitated CNOÁHCl was consistent with the proposed structure in Scheme 1. Although crystals suitable for single crystal X-ray analysis were not obtained from the crude precipitate, powder X-ray diffraction of the precipitate suggested the material was substantially crystalline. To obtain structural verification and to locate the site of protonation, we attempted to grow single crystals of CNOÁHCl for single crystal X-ray analysis. Slow evaporation of a solution of CNOÁHCl from a variety of solvents, or by diffusion of diethyl ether into a variety of solvents consistently yielded small orange block-shaped crystals of the title hemihydrochloride, which were found to be no longer soluble in water or other solvents (Scheme 2).

Structural commentary
Single-crystal X-ray diffraction analysis of the orange crystals revealed that the CNOÁHCl salt implied by the analysis for the initially formed salt (above) had lost half an equivalent of HCl upon crystallization and crystallized as a hemihydrochloride, (CNO) 2 ÁHCl, in the tetragonal space group I4/m (Scheme 2 and Fig. 1). In this structure, two molecules of CNO, which are related by a crystallographic twofold axis, share a proton, which is located on the rotation axis and forms a strong, essentially linear and apparently symmetric O-HÁ Á ÁO/ OÁ Á ÁH-O hydrogen bond between the two molecules via the N-oxide moieties [O1Á Á ÁO1 i = 2.434 (2) Å ; symmetry code (i) Àx, 1 À y, z]. Within the structure, the chloride counter-ion (Cl2) is located on a crystallographic mirror plane and accepts equivalent N-HÁ Á ÁCl hydrogen bonds [N1Á Á ÁCl2 = 3.3259 (14) Å ] to two mirror-related (CNO) 2 H + moieties resulting in the formation of a cyclic structure templated by the Cl À counter-ions (Fig. 2). The diazepine ring core in (CNO) 2 ÁHCl adopts a boat conformation (Table 1)  The molecular structure of (CNO) 2 ÁHCl showing 50% displacement ellipsoids with C-bound H atoms omitted for clarity. The unlabelled atoms are generated by the symmetry operation Àx, 1 À y, z. Table 1 Selected torsion angles ( ).
40.08 (6) to one another; this represents a less puckered ring to that observed in the (CNO)ÁMeOH solvate in which the aromatic rings are at an angle of 56.2 (van der Peet et al., 2018) demonstrating the flexibility of this ring system. The equivalent angle between the seven-membered diazepine ring and its pendant N-oxide ring is 31.14 (7)

Supramolecular features
The tetrameric cyclic structures are catenated and form infinite chains extending along the z-direction (Figs. 3 and 4) in which adjacent links in the chain are related by a 4 2 screw axis.
The catenated rings form both as a result of general complementarity in the shapes of the internal cavities of the interacting (CNO) 2 dimers related by the symmetry operation ( 1 2 À y, 1 2 + x, 1 2 À z), and further stabilized by four equivalent non-classical hydrogen-bonding interactions involving the polarized C-H bond adjacent to the N-oxide moiety; (C15-H15AÁ Á ÁN1, Table 2) in addition to four equivalent C-HÁ Á Á interactions [H15AÁ Á ÁC8 = 2.706 (2) Å ] (Fig. 5). Solvent voids, which account for approximately 17% of the unit-cell volume, lie between the catenated chains: the disordered solvent was accounted for using the Squeeze procedure in PLATON (Spek, 2015). To establish the relationship between the original material and that obtained after crystallization, powder X-ray diffraction data were obtained for the orange crystals and compared to that for the original material (Fig. 6). The two powder diffraction patterns are substantially different, which is consistent with the combustion analysis of the original material that analysed as (CNO)ÁHCl, whereas the crystallized material is (CNO) 2 ÁHCl. Application of the same approach to CNOÁHBr did not lead to an equivalent polymeric material.

Database survey
The formation of strong hydrogen bonds is predicted to occur when the pK a value for the donor acid matches that for the  Partial structure of (CNO) 2 ÁHCl catenated chain showing two members of the poly[n]catenane; adjacent links in the chain are related by a 4 2 screw axis.

Figure 6
Overlay of powder patterns of the initial precipitate of (CNO)ÁHCl and the recrystallized material (CNO) 2 ÁHCl. acceptor's conjugate acid form (Gilli et al., 2009). In this structure, a strong hydrogen bond between a protonated tertiary amine N-oxide and its conjugate base is predicted.

Preparation of clozapine N-oxide hemihydrochloride (CNO) 2 ÁHCl
The above material (CNOÁHCl) was recrystallized by diffusion of diethyl ether into a methanol solution giving (CNO) 2 ÁHCl as small orange blocks.
Preparation of clozapine N-oxide hydrobromide A 25 ml round-bottom flask was charged with clozapine Noxide (1.00 g, 2.92 mmol, 1 eq.) and methanol (5 ml) and stirred under N 2 . Initially, the solid dissolved but then precipitated as a presumed CNOÁmethanolate adduct. The solution was cooled in an ice-water bath and 48% HBr in water (0.35 ml, 3.07 mmol, 1.05 eq) was added slowly to the suspension. The mixture stirred for 1 h at rt, without formation of a precipitate. The solvent was evaporated and the residue suspended in EtOAc (10 ml). The resulting solid was collected by filtration and washed with EtOAc to afford CNOÁHBr as a yellow solid (1.1 g, 89%). Degradation point: 483-493 K

8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine N-oxide hemi(hydrochloride)
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.