supplementary materials


lx2271 scheme

Acta Cryst. (2012). E68, o3358-o3359    [ doi:10.1107/S1600536812046405 ]

Morphine hydrochloride anhydrate

T. Gelbrich, D. E. Braun and U. J. Griesser

Abstract top

In the title molecular salt [systematic name: (5[alpha],6[alpha])-7,8-didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol hydrochloride], C17H20NO3+·Cl-, the conformation of the morphinium ion is in agreement with the characteristics of the previously reported morphine forms [for example, Gylbert (1973). Acta Cryst. B29, 1630-1635]. In the crystal, the cations and chloride anions are linked into a helical chain propagating parallel to the b-axis direction by N-H...Cl and O-H...Cl hydrogen bonds. The title salt and the morphine monohydrate [Bye (1976) Acta Chem. Scand. 30, 549-554] display very similar one-dimensional packing modes of their morphine components.

Comment top

Morphine is the principal alkaloid of opium. Several crystal forms of the free base as well as salts have been investigated in previous studies: a monohydrate (Bye, 1976), a hydrochloride trihydrate (Gylbert, 1973), a hydroiodide dihydrate (Mackay & Hodgkin, 1955), a complex with β–phenylhydracrylic acid (Lutz & Spek, 1998) and a bis(morphininium) dihydrogensulfate pentahydrate (Wongweichintana et al., 1984). The crystal structure of the title salt was previously solved from powder data by Guguta et al. (2008). However, the corresponding atomic coordinates are not available from the Cambridge Structural Database (Allen, 2002) or from supplementary materials accompanying this report.

The asymmetric unit of the title salt contains of one formula unit (Figure 1). The geometry of the molecular morphine scaffold with its five rings agrees with the characteristics of the previously investigated salt and free base structures. The morphinium cation of the title salt is doubly O—H···Cl bonded to the anion so that a R12(10) ring (Etter et al., 1990; Bernstein et al., 1995) is formed. The Cl- ion is additionally N—H···Cl bonded to the protonation site of a second cation, which is related to the first cation by a 21 screw operation parallel to the b–axis. An infinite hydrogen–bonded chain is formed as a result of these interactions, and the chain structure propagates parallel to the b-axis (Figure 2a). The closest intermolecular C—H···O and C—H···π contacts are listed in Table 2 and shown in Figure 2 b.

The program XPac (Gelbrich & Hursthouse, 2005) was used to compare the packing of the morphinium ions with that of the analogous moieties in the five related structures mentioned above (Bye, 1976; Gylbert, 1973; Mackay & Hodgkin, 1955; Lutz & Spek, 1998; Wongweichintana et al., 1984). In this group, the closest similarity relationship involving the title structure is based on a single stack of molecules ('one–dimensional supramolecular construct', Figure 3) that is also present in the monohydrate (Bye, 1976). In both crystals the corresponding stacking vector lies parallel [100] with d = 7.359 Å for the title structure and d = 7.438 Å for the monohydrate. The corresponding XPac dissimilarity index x (Gelbrich et al., 2012) is 8.2, calculated for a cluster comprising a central molecule and its two next neighbours in the stack on the basis of the positions of all 21 non–H atoms. This value confirms that the fundamental geometry of the stack is maintained. However, the geometry of the stack is somewhat affected by its crystal environment, which accomodates the specific hydrogen bond preferences of the second chemical component, i.e. Cl- in the case of the title structure and H2O in the monohydrate.

Related literature top

For related structures, see: Guguta et al. (2008); Gylbert (1973); Mackay & Hodgkin (1955); Bye (1976); Wongweichintana et al. (1984); Lutz & Spek (1998); Scheins et al. (2005). For hysdrogen-bond motifs, see: Bernstein et al. (1995); Etter et al. (1990). For a description of the Cambridge Structural Database, see: Allen (2002). For the program XPac, see: Gelbrich & Hursthouse (2005) and for the corresponding XPac dissimilarity index, see: Gelbrich et al. (2012).

Experimental top

The investigated compound was obtained from Heilmittelwerke Wien, Austria. Block-shaped crystals of the title compound were produced by slow evaporation from an ethanol solution.

Refinement top

The H atoms were identified in a difference map. Methyl H atoms were idealized and included as rigid groups allowed to rotate but not tip (C—H = 0.98 Å). H atoms bonded to tertiary CH (C—H = 0.99 Å), secondary CH2 (C—H = 0.99 Å) and aromatic carbon atoms (C—H = 0.95 Å) were positioned geometrically. Hydrogen atoms attached to O and N atoms were refined with restrained distances [O—H = 0.82 (1) Å] and [N—H = 0.93 (1) Å]. The parameters Uiso of all H atoms were refined freely.

Computing details top

Data collection: CrysAlis PRO (Oxford Diffraction, 2003); cell refinement: CrysAlis PRO (Oxford Diffraction, 2003); data reduction: CrysAlis PRO (Oxford Diffraction, 2003); program(s) used to solve structure: SHELXL97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008) and Mercury (Macrae et al., 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

Figures top
[Figure 1] Fig. 1. Asymmetric unit of the title compound. Displacement ellipsoids are drawn at the 50% probability level, with hydrogen atoms shown as spheres of arbitrary size.
[Figure 2] Fig. 2. a) The hydrogen–bonded chain structure of the title salt. H, O and Cl atoms involved in hydrogen bonding are are drawn as balls and O—H···Cl and N—H···Cl interactions are drawn as dotted lines. H atoms non–participating in hydrogen–bonding were omitted for clarity. b) Impterplay of classical hydrogen bonds (broken lines) and short O—H···X contacts (dotted lines); symmetry codes: (i) -x + 1, y + 1/2, -z + 3/2; (ii) -x + 1/2, -y + 2, z - 1/2; (iii) x + 1/2, -y + 3/2, -z + 1.
[Figure 3] Fig. 3. Common one-dimensional supramolecular construct (SC) of the title structure and the morphine monohydrate (Bye, 1976). a) Stack of molecules related by translation symmetry, viewed perpendicular and parallel to the stacking vector (which lies parallel to the a–axis in both structures); crystal packing of the title structure (b) and the monohydrate (c), viewed paralell to the stacking vector of the common SC; one instance of the SC is highlighted in each strutcure. Hydrogen bonds are indicated by broken lines, H atoms are omitted for clarity, Cl and water O atoms are drawn as balls.
(5α,6α)-7,8-Didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol hydrochloride top
Crystal data top
C17H20NO3+·ClF(000) = 680
Mr = 321.79Dx = 1.411 Mg m3
Orthorhombic, P212121Mo Kα radiation, λ = 0.7107 Å
Hall symbol: P 2ac 2abCell parameters from 4272 reflections
a = 7.3504 (2) Åθ = 3.0–29.2°
b = 12.8524 (5) ŵ = 0.27 mm1
c = 16.0372 (5) ÅT = 173 K
V = 1515.04 (9) Å3Block, colourless
Z = 40.20 × 0.20 × 0.20 mm
Data collection top
Oxford Diffraction Xcalibur (Ruby, Gemini ultra)
diffractometer
2971 independent reflections
Radiation source: Enhance (Mo) X-ray Source2803 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.024
Detector resolution: 10.3575 pixels mm-1θmax = 26.0°, θmin = 3.0°
ω scansh = 99
Absorption correction: multi-scan
(CrysAlis PRO; Oxford Diffraction, 2003)
k = 1215
Tmin = 0.982, Tmax = 1.000l = 1919
7406 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.027H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.069 w = 1/[σ2(Fo2) + (0.0324P)2 + 0.2844P]
where P = (Fo2 + 2Fc2)/3
S = 1.04(Δ/σ)max = 0.001
2971 reflectionsΔρmax = 0.18 e Å3
229 parametersΔρmin = 0.15 e Å3
3 restraintsAbsolute structure: Flack (1983), 1245 Friedel pairs
Primary atom site location: structure-invariant direct methodsFlack parameter: 0.02 (5)
Crystal data top
C17H20NO3+·ClV = 1515.04 (9) Å3
Mr = 321.79Z = 4
Orthorhombic, P212121Mo Kα radiation
a = 7.3504 (2) ŵ = 0.27 mm1
b = 12.8524 (5) ÅT = 173 K
c = 16.0372 (5) Å0.20 × 0.20 × 0.20 mm
Data collection top
Oxford Diffraction Xcalibur (Ruby, Gemini ultra)
diffractometer
2971 independent reflections
Absorption correction: multi-scan
(CrysAlis PRO; Oxford Diffraction, 2003)
2803 reflections with I > 2σ(I)
Tmin = 0.982, Tmax = 1.000Rint = 0.024
7406 measured reflectionsθmax = 26.0°
Refinement top
R[F2 > 2σ(F2)] = 0.027H atoms treated by a mixture of independent and constrained refinement
wR(F2) = 0.069Δρmax = 0.18 e Å3
S = 1.04Δρmin = 0.15 e Å3
2971 reflectionsAbsolute structure: Flack (1983), 1245 Friedel pairs
229 parametersFlack parameter: 0.02 (5)
3 restraints
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
Cl10.96273 (5)0.72090 (4)0.82895 (3)0.03438 (12)
O10.83825 (19)0.64336 (10)0.65098 (8)0.0367 (3)
H1O0.877 (3)0.6586 (18)0.6972 (8)0.051 (7)*
O20.55524 (15)0.77200 (8)0.73074 (6)0.0242 (2)
O30.62377 (17)0.85259 (10)0.88464 (7)0.0294 (3)
H3O0.709 (2)0.8207 (16)0.8625 (13)0.050 (7)*
N10.29227 (19)1.08986 (11)0.56252 (9)0.0242 (3)
H1N0.221 (2)1.1239 (15)0.6013 (10)0.044 (6)*
C10.7896 (2)0.86915 (13)0.51135 (9)0.0243 (4)
H10.84360.89430.46150.042 (6)*
C20.8430 (2)0.77357 (14)0.54336 (10)0.0259 (4)
H20.93080.73380.51390.031 (5)*
C30.7717 (2)0.73423 (12)0.61752 (10)0.0245 (3)
C40.6342 (2)0.79226 (12)0.65458 (9)0.0202 (3)
C50.5554 (2)0.92311 (12)0.82414 (9)0.0227 (3)
H50.46280.96690.85340.019 (4)*
C60.4532 (2)0.86543 (12)0.75454 (9)0.0202 (3)
H60.33010.84460.77530.022 (4)*
C70.6973 (2)0.99708 (13)0.79168 (10)0.0242 (4)
H70.81311.00020.81790.031 (5)*
C80.6628 (2)1.05776 (13)0.72718 (10)0.0232 (4)
H80.75011.10730.70900.027 (5)*
C90.4862 (2)1.09416 (13)0.59477 (10)0.0220 (3)
H90.52111.16910.59990.022 (4)*
C100.6209 (2)1.04229 (14)0.53414 (11)0.0272 (4)
H10A0.57271.04890.47670.029 (5)*
H10B0.73771.08050.53640.048 (6)*
C110.6574 (2)0.92863 (13)0.55164 (9)0.0207 (3)
C120.5743 (2)0.88337 (12)0.61978 (9)0.0188 (3)
C130.43158 (19)0.93188 (12)0.67453 (9)0.0181 (3)
C140.4832 (2)1.04739 (12)0.68285 (9)0.0193 (3)
H140.38751.08360.71630.012 (4)*
C150.2383 (2)0.92357 (13)0.63760 (10)0.0243 (4)
H15A0.20780.84930.62900.033 (5)*
H15B0.14980.95280.67780.017 (4)*
C160.2217 (2)0.98094 (13)0.55534 (11)0.0283 (4)
H16A0.29120.94330.51190.030 (5)*
H16B0.09240.98270.53800.021 (4)*
C170.2666 (3)1.14956 (15)0.48358 (11)0.0349 (4)
H17A0.32411.11200.43740.035 (5)*
H17B0.32251.21840.48920.046 (6)*
H17C0.13631.15740.47230.041 (6)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0245 (2)0.0376 (2)0.0411 (2)0.00496 (19)0.00355 (18)0.0024 (2)
O10.0476 (8)0.0244 (7)0.0383 (8)0.0127 (6)0.0048 (6)0.0009 (6)
O20.0310 (6)0.0171 (5)0.0246 (6)0.0019 (5)0.0063 (5)0.0017 (4)
O30.0345 (7)0.0337 (7)0.0201 (6)0.0081 (6)0.0012 (5)0.0051 (5)
N10.0265 (7)0.0226 (7)0.0236 (7)0.0017 (6)0.0054 (6)0.0008 (6)
C10.0234 (8)0.0297 (9)0.0199 (8)0.0052 (7)0.0032 (7)0.0035 (7)
C20.0240 (8)0.0281 (9)0.0256 (8)0.0007 (8)0.0028 (7)0.0120 (8)
C30.0274 (8)0.0180 (8)0.0282 (8)0.0014 (7)0.0008 (7)0.0051 (7)
C40.0222 (7)0.0190 (8)0.0195 (7)0.0047 (7)0.0005 (6)0.0038 (6)
C50.0258 (8)0.0242 (8)0.0181 (7)0.0037 (7)0.0012 (7)0.0008 (6)
C60.0201 (7)0.0184 (8)0.0221 (7)0.0003 (7)0.0049 (7)0.0008 (6)
C70.0236 (8)0.0250 (8)0.0240 (8)0.0018 (7)0.0044 (7)0.0058 (7)
C80.0245 (8)0.0185 (8)0.0267 (8)0.0063 (7)0.0010 (7)0.0032 (7)
C90.0235 (8)0.0168 (7)0.0258 (8)0.0025 (7)0.0040 (6)0.0029 (6)
C100.0279 (9)0.0268 (9)0.0269 (9)0.0001 (8)0.0029 (7)0.0075 (7)
C110.0201 (8)0.0243 (8)0.0177 (7)0.0042 (7)0.0020 (6)0.0009 (6)
C120.0188 (7)0.0179 (7)0.0198 (7)0.0030 (6)0.0024 (6)0.0041 (6)
C130.0173 (7)0.0177 (7)0.0192 (7)0.0029 (6)0.0002 (6)0.0002 (6)
C140.0204 (7)0.0167 (7)0.0209 (8)0.0008 (6)0.0001 (6)0.0016 (6)
C150.0200 (8)0.0225 (8)0.0303 (9)0.0033 (7)0.0022 (7)0.0012 (7)
C160.0256 (9)0.0268 (9)0.0325 (9)0.0009 (7)0.0096 (7)0.0051 (8)
C170.0449 (11)0.0311 (10)0.0288 (9)0.0037 (9)0.0109 (8)0.0055 (8)
Geometric parameters (Å, º) top
O1—C31.375 (2)C7—H70.9500
O1—H1O0.817 (9)C8—C141.505 (2)
O2—C41.3770 (17)C8—H80.9500
O2—C61.4665 (18)C9—C141.535 (2)
O3—C51.4196 (19)C9—C101.540 (2)
O3—H3O0.831 (10)C9—H91.0000
N1—C171.492 (2)C10—C111.511 (2)
N1—C161.497 (2)C10—H10A0.9900
N1—C91.517 (2)C10—H10B0.9900
N1—H1N0.925 (9)C11—C121.380 (2)
C1—C21.388 (2)C12—C131.503 (2)
C1—C111.395 (2)C13—C141.538 (2)
C1—H10.9500C13—C151.543 (2)
C2—C31.395 (2)C14—H141.0000
C2—H20.9500C15—C161.516 (2)
C3—C41.390 (2)C15—H15A0.9900
C4—C121.370 (2)C15—H15B0.9900
C5—C71.504 (2)C16—H16A0.9900
C5—C61.536 (2)C16—H16B0.9900
C5—H51.0000C17—H17A0.9800
C6—C131.549 (2)C17—H17B0.9800
C6—H61.0000C17—H17C0.9800
C7—C81.320 (2)
C3—O1—H1O105.8 (17)C10—C9—H9107.7
C4—O2—C6106.96 (11)C11—C10—C9114.53 (14)
C5—O3—H3O106.9 (16)C11—C10—H10A108.6
C17—N1—C16111.81 (13)C9—C10—H10A108.6
C17—N1—C9112.91 (14)C11—C10—H10B108.6
C16—N1—C9112.69 (13)C9—C10—H10B108.6
C17—N1—H1N104.8 (14)H10A—C10—H10B107.6
C16—N1—H1N107.3 (14)C12—C11—C1116.35 (15)
C9—N1—H1N106.7 (13)C12—C11—C10118.42 (14)
C2—C1—C11120.71 (15)C1—C11—C10124.55 (15)
C2—C1—H1119.6C4—C12—C11122.73 (14)
C11—C1—H1119.6C4—C12—C13109.92 (13)
C1—C2—C3122.00 (15)C11—C12—C13126.61 (14)
C1—C2—H2119.0C12—C13—C14106.19 (12)
C3—C2—H2119.0C12—C13—C15112.92 (13)
O1—C3—C4123.21 (14)C14—C13—C15109.10 (12)
O1—C3—C2120.45 (15)C12—C13—C6100.58 (12)
C4—C3—C2116.33 (15)C14—C13—C6115.78 (12)
C12—C4—O2112.80 (13)C15—C13—C6111.97 (12)
C12—C4—C3121.21 (14)C8—C14—C9112.77 (13)
O2—C4—C3125.76 (14)C8—C14—C13110.04 (13)
O3—C5—C7113.23 (13)C9—C14—C13107.56 (12)
O3—C5—C6111.20 (13)C8—C14—H14108.8
C7—C5—C6113.13 (12)C9—C14—H14108.8
O3—C5—H5106.2C13—C14—H14108.8
C7—C5—H5106.2C16—C15—C13112.00 (13)
C6—C5—H5106.2C16—C15—H15A109.2
O2—C6—C5109.51 (12)C13—C15—H15A109.2
O2—C6—C13106.75 (11)C16—C15—H15B109.2
C5—C6—C13112.69 (12)C13—C15—H15B109.2
O2—C6—H6109.3H15A—C15—H15B107.9
C5—C6—H6109.3N1—C16—C15111.09 (13)
C13—C6—H6109.3N1—C16—H16A109.4
C8—C7—C5120.73 (15)C15—C16—H16A109.4
C8—C7—H7119.6N1—C16—H16B109.4
C5—C7—H7119.6C15—C16—H16B109.4
C7—C8—C14119.11 (15)H16A—C16—H16B108.0
C7—C8—H8120.4N1—C17—H17A109.5
C14—C8—H8120.4N1—C17—H17B109.5
N1—C9—C14106.60 (12)H17A—C17—H17B109.5
N1—C9—C10111.91 (13)N1—C17—H17C109.5
C14—C9—C10114.89 (13)H17A—C17—H17C109.5
N1—C9—H9107.7H17B—C17—H17C109.5
C14—C9—H9107.7
Hydrogen-bond geometry (Å, º) top
Cg1 is the centroid of the C1–C4/C12/C11 benzene ring.
D—H···AD—HH···AD···AD—H···A
O1—H1O···Cl10.82 (1)2.35 (1)3.1585 (14)173 (2)
O3—H3O···Cl10.83 (1)2.32 (1)3.1416 (13)168 (2)
N1—H1N···Cl1i0.93 (1)2.15 (1)3.0626 (15)169 (2)
C17—H17C···O3ii0.982.383.278 (2)153
C14—H14···O2i1.002.603.2149 (19)120
C2—H2···Cg1iii0.952.713.638 (2)165
Symmetry codes: (i) x+1, y+1/2, z+3/2; (ii) x+1/2, y+2, z1/2; (iii) x+1/2, y+3/2, z+1.
Hydrogen-bond geometry (Å, º) top
Cg1 is the centroid of the C1–C4/C12/C11 benzene ring.
D—H···AD—HH···AD···AD—H···A
O1—H1O···Cl10.817 (9)2.347 (10)3.1585 (14)173 (2)
O3—H3O···Cl10.831 (10)2.324 (11)3.1416 (13)168 (2)
N1—H1N···Cl1i0.925 (9)2.150 (10)3.0626 (15)168.8 (19)
C17—H17C···O3ii0.982.383.278 (2)152.6
C14—H14···O2i1.002.603.2149 (19)119.6
C2—H2···Cg1iii0.952.713.638 (2)165.1
Symmetry codes: (i) x+1, y+1/2, z+3/2; (ii) x+1/2, y+2, z1/2; (iii) x+1/2, y+3/2, z+1.
Acknowledgements top

We thank Volker Kahlenberg for access to the X-ray instrument used in this study. DEB acknowledges financial support from the Hertha Firnberg Programme of the Austrian Science Fund (FWF, project T593–N19).

references
References top

Allen, F. H. (2002). Acta Cryst. B58, 380–388.

Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555–1573.

Bye, E. (1976). Acta Chem. Scand. Ser. B, 30, 549–554.

Etter, M. C., MacDonald, J. C. & Bernstein, J. (1990). Acta Cryst. B46, 256–262.

Flack, H. D. (1983). Acta Cryst. A39, 876–881.

Gelbrich, T. & Hursthouse, M. B. (2005). CrystEngComm, 7, 324–336.

Gelbrich, T., Threlfall, T. L. & Hursthouse, M. B. (2012). CrystEngComm, 14, 5454–5464.

Guguta, C., Peters, T. P. J. & de Gelder, R. (2008). Cryst. Growth Des. 8, 4150–4158.

Gylbert, L. (1973). Acta Cryst. B29, 1630–1635.

Lutz, M. & Spek, A. L. (1998). Acta Cryst. C54, 1477–1479.

Mackay, M. & Hodgkin, D. C. (1955). J. Chem. Soc. pp. 3261–3267.

Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466–470.

Oxford Diffraction (2003). CrysAlis CCD and CrysAlis RED. Oxford Diffraction Ltd, Abingdon, England.

Scheins, S., Messerschmidt, M. & Luger, P. (2005). Acta Cryst. B61, 443–448.

Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122.

Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.

Wongweichintana, C., Holt, E. M. & Purdie, N. (1984). Acta Cryst. C40, 1486–1490.