Crystal structures of bis[(9S,13S,14S)-3-methoxy-17-methylmorphinanium] tetrachloridocobaltate and tetrachloridocuprate

In the crystal structures of title compounds, two identical protonated dextromethorphan cations are connected to tetrachloridocobaltate (or tetrachloridocuprate) anions via strong N—H⋯Cl hydrogen bonds, forming neutral ion associates

(9S,13S,14S)-3-Methoxy-17-methylmorphinan (dextromethorphan) forms two isostructural salts with (a) tetrachloridocobaltate, namely bis[(9S,13S,14S)-3methoxy- 17-methylmorphinanium] tetrachloridocobaltate, (C 18 [CuCl 4 ]. The distorted tetrahedral anions are located on twofold rotational axes. The dextromethorphan cation can be described as being composed of two ring systems, a tetrahydronaphthalene system A+B and a decahydroisoquinolinium subunit C+D, that are nearly perpendicular to one another: the angle between mean planes of the A+B and C+D moieties is 78.8 (1) for (a) and 79.0 (1) for (b). Two symmetry-related cations of protonated dextromethorphan are connected to the tetrachloridocobaltate (or tetrachloridocuprate) anions via strong N-HÁ Á ÁCl hydrogen bonds, forming neutral ion associates. These associates are packed in the (001) plane with no strong attractive bonding between them. Both compounds are attractive crystalline forms for unambiguous identification of the dextromethorphan and, presumably, of its optical isomer, levomethorphan.

Chemical context
Seemingly innocuous and common over-the-counter drugs have a wide range of uses to treat illness and relieve pain, but they can also lead to long-term abuse and fatalities. Dextromethorphan (systematic name (9S,13S,14S)-3-methoxy-17methylmorphinan) is a member of the Morphinan class of naturally occurring and semi-synthetic psychoactive drugs, chemically similar to morphine, codeine and oxycodone, and differing from these only by a few functional groups. It is commonly found in many cold and cough medicines. In high concentrations, dextromethorphan has effects similar to phencyclidine and ketamine, a dissociative anesthetic, which is known to induce visual hallucinations and a heightened sense of perceptual awareness (Bruera & Portenoy, 2010). The similarity to well-known substances of abuse that are highly controlled makes dextromethorphan an attractive target for recreational ingestion and purification from over-the-counter products.
Cobalt(II) compounds have been employed in color tests for alkaloid detection: e.g., the Scott reagent (Cole, 2003). However, color reactions are usually not very specific and may lead to numerous false positives. To complicate the issue, levomethorphan, an optical isomer of dextromethorphan, is a strong opiate drug and is restricted like morphine in the US and many other countries. Therefore, usual NMR and MS ISSN 2056-9890 identification may be insufficient for clear identification of dextromethorphan and levomethorphan.
We suggest that easy-to-grow crystals of alkaloid metal complexes may provide a suitable analytical approach for unambiguous identification. As a part of this study, we report the crystal structures of two such compounds here.

Structural commentary
The protonated dextromethorphan cations are nearly identical (Figs. 1-3). In both cases, protonation as well as interaction with the tetrachloridocobaltate or tetrachloridocuprate anions does not affect the geometry of the methorphan ring system (Fig. 4), leaving the shape of the organic molecule intact. The derived molecular dimensions within both structures are unexceptional and consistent with those known for similar molecules (Gylbert & Carlströ m, 1977).
There are four six-membered rings in a dextromethorphan molecule. The aromatic ring A is practically planar with deviations less than 0.01 Å in all cases. The cyclohexene ring B can be described as a half-chair shifted towards an envelope conformation: atoms C10, C11, C12 and C13 are adjacent to the aromatic ring and therefore almost planar while C9 and C14 deviate from this plane in opposite directions: C9 À 0.191 (6) Å (a) and À0.173 (8) Å (b); C14 + 0.553 (5) Å (a) and +0.562 (8) Å (b). This half-chair conformation is known (Ibberson et al., 2008) for the unsubstituted cyclohexene molecule in the solid state.
The cyclohexane C and piperidine B rings both have chair conformations. These two rings are nearly coplanar, with the angles between their mean planes being 7.8 (1) (a) and 8.2 (2) (b). As a result, the dextromethorphan cation can be described as two ring systems A+B and C+D, being nearly perpendicular to each other: the angle between the mean planes of the A+B and C+D moieties is 78.8 (1) for (a) and 79.0 (1) for (b).
The tetrachloridocobaltate and tetrachloridocuprate anions both have a distorted tetrahedral geometry. In the cobalt complex, the Cl1-Co1-Cl2 angle is flattened to 116.59 (3) , while in the copper analogue the Cl2-Cu1-Cl1 angle is 129.04 (4) . The larger deviation from tetrahedral geometry in the copper(II) compound is possibly due to the Jahn-Teller effect, as packing effects should be similar in both compounds. The numbering scheme of the dextromethorphan tetrachloridocobaltate complex (a) with displacement ellipsoids drawn at the 50% probability level.

Figure 2
The numbering scheme of the dextromethorphan tetrachloridocuprate complex (b) with displacement ellipsoids drawn at the 50% probability level.

Supramolecular features
The tetrachloridocobaltate and tetrachloridocuprate anions are located on twofold rotational axes. Two identical protonated dextromethorphan cations are connected to tetrachloridocobaltate (or tetrachloridocuprate) anions via strong N-HÁ Á ÁCl hydrogen bonds (Tables 1 and 2), thus forming neutral ion associates (Fig. 5). These associates are packed into layers in the (001) plane ( Fig. 6) with no strong attractive bonding between them. Methyl groups adjacent to the protonated nitrogen atoms separate the tetrachloridometalate anions, thus reducing electrostatic repulsion between them. Close packing and electrostatic interaction with anion results in several short C-HÁ Á ÁCl contacts (Tables 1 and 2 Symmetry codes: (i) x À 1 2 ; y þ 1 2 ; z; (ii) x À 1 2 ; y À 1 2 ; z.

Figure 5
Two dextromethorphan cations forming an ion associate with the tetrachloridocobaltate dianion. Hydrogen bonds are drawn as dashed lines.

Figure 6
Packing diagram of the ion associates in structure (a), viewed along [010].

Figure 4
Overlay of the protonated dextromethorphan cation (a) and the dextromethorphan molecule (refcode XAPTAK01).

Database survey
There are three reported dextromethorphan structures deposited in the Cambridge Structural Database (CSD Version 5.37; Groom et al., 2016). Of these structures, two report structures of the neutral molecule (refcodes XAPTAK and XAPTAK01), one of which (Swamy et al., 2005) refers to a room-temperature measurement and the other (Scheins et al., 2007) a high-quality charge-density investigation performed at 20 K.
A protonated form is also known in a form of the bromide salt (refcode DEXORP), in which one solvate water molecule is connected to a protonated nitrogen atom via a hydrogen bond (Gylbert & Carlströ m, 1977).

Synthesis and crystallization
Dextromethorphan was isolated during the analysis of a proprietary cough syrup using a standard Pharmacopoeia procedure (WHO, 2016). GC-MS assay of the hexane solution shows dextromethorphan to be a main component, with a small admixture of menthol.
Dextromethorphan was positively identified using NMR and FTIR spectra. Slow evaporation of a hexane solution at 274 K yields crystals which were also identified as dextromethorphan (refcode XAPTAK; Swamy et al., 2005). Around 20 mg of the solid residue was treated with two drops of concentrated HCl and an excess of cobalt(II) chloride or copper(II) chloride. Overnight standing in a refrigerator yielded crystals of the title compounds. The colors of the resulting solids were characteristic with the tetrachloridocobaltate(II) salt being blue and the tetrachloridocuprate(II) salt yellow. The bright colors of the crystals make them easy to separate from possible crystalline impurities. We expect that levomethorphan would yield similar crystals with the opposite chirality.
Crystals suitable for X-ray investigation ( Fig. 7) were cut from larger blocks before mounting on Mitigen loops.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 3. In (a), the hydrogen atom H1 of the protonated amine was refined in an isotropic approxima-    (7) À0.005 (6) Computer programs: APEX2 and SAINT (Bruker, 2013), SHELXT (Sheldrick, 2015), SHELXS97 and SHELXL97 (Sheldrick, 2008) and OLEX2 (Dolomanov et al., 2009). tion; idealized methyl groups refined as rotating groups with stretchable bonds and U iso = 1.5U iso (C); all other hydrogen atoms were refined with riding coordinates and stretchable bonds with U iso = 1.2U iso (C). In (b), the hydrogen atom were treated in an similar fashion.

(a) Bis[(9S,13S,14S)-3-methoxy-17-methylmorphinanium] tetrachloridocobaltate
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 )

(b) Bis[(9S,13S,14S)-3-methoxy-17-methylmorphinanium] tetrachloridocuprate
Crystal data (C 18 H 26  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.