Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270109027164/fg3114sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270109027164/fg3114Isup2.hkl | |
Portable Document Format (PDF) file https://doi.org/10.1107/S0108270109027164/fg3114sup3.pdf |
CCDC reference: 746095
Codeine phophate was provided by Siegfried Ltd (Zofingen, Switzerland). Suitable single crystals were obtained by slow evaporation of a dimethylformamide (DMF) solution of codeine phosphate on a watch glass. The hemihydrate displays a prismatic habit and forms druses (see Fig. 4 in the Supplementary material). Thermogravimetric analysis of the hemihydrate showed that the dehydration is very slow and proceeds over a wide temperature range, between about 323 and 463 K. The measured total mass loss of about 2.3% confirms the presence of 0.5 mol water per mol codeine dihydrogen phosphate. Gravimetric water vapour sorption experiments indicate that the hemihydrate is stable between 10 and 80% relative humidity (298 K). Over desiccants, the crystals slowly release water. The formation of a dihydrate was observed above 90% relative humidity.
All H atoms were identified in a difference map. Methyl H atoms were idealized and included as rigid groups that were allowed to rotate but not tip (C—H = 0.98 Å) and refined with Uiso(H) = 1.5Ueq(C). H atoms bonded to primary (C—H = 1.00 Å), secondary CH2 (C—H = 0.99 Å) and aromatic C atoms (C—H = 0.95 Å) were positioned geometrically and refined with Uiso(H) = 1.2Ueq(C). H atoms attached to N and O were refined with restrained distances [N—H = 0.86 (2) and O—H = 0.82 (2) Å], and their Uiso parameters were refined freely. The absolute configuration of this structure was known prior to this study and was confirmed by the refined Flack (1983) parameter.
Data collection: CrysAlis CCD (Oxford Diffraction, 2003); cell refinement: CrysAlis RED (Oxford Diffraction, 2003); data reduction: CrysAlis RED (Oxford Diffraction, 2003); program(s) used to solve structure: SIR2002 (Burla et al., 2003); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP/SHELXTL (Sheldrick, 2008) and Mercury (Bruno et al., 2002); software used to prepare material for publication: publCIF (Westrip, 2009).
C18H22NO3+·H2O4P−·0.5H2O | F(000) = 860 |
Mr = 406.36 | Dx = 1.468 Mg m−3 |
Monoclinic, P21 | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: P 2yb | Cell parameters from 8283 reflections |
a = 6.9113 (2) Å | θ = 3.0–29.2° |
b = 33.4470 (9) Å | µ = 0.20 mm−1 |
c = 8.0716 (2) Å | T = 173 K |
β = 99.778 (3)° | Prismatic fragment, colourless |
V = 1838.74 (9) Å3 | 0.32 × 0.16 × 0.16 mm |
Z = 4 |
Oxford Diffraction Gemini-R Ultra diffractometer | 5393 reflections with I > 2σ(I) |
Radiation source: fine-focus sealed tube | Rint = 0.025 |
Graphite monochromator | θmax = 25.5°, θmin = 3.1° |
Detector resolution: 10.3822 pixels mm-1 | h = −8→6 |
ω (1° width) scans | k = −40→33 |
12119 measured reflections | l = −9→9 |
5825 independent reflections |
Refinement on F2 | Secondary atom site location: difference Fourier map |
Least-squares matrix: full | Hydrogen site location: inferred from neighbouring sites |
R[F2 > 2σ(F2)] = 0.046 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.115 | w = 1/[σ2(Fo2) + (0.0799P)2 + 0.6365P] where P = (Fo2 + 2Fc2)/3 |
S = 1.02 | (Δ/σ)max < 0.001 |
5825 reflections | Δρmax = 0.52 e Å−3 |
530 parameters | Δρmin = −0.39 e Å−3 |
12 restraints | Absolute structure: Flack (1983), with how many Friedel pairs? |
Primary atom site location: structure-invariant direct methods | Absolute structure parameter: 0.10 (9) |
C18H22NO3+·H2O4P−·0.5H2O | V = 1838.74 (9) Å3 |
Mr = 406.36 | Z = 4 |
Monoclinic, P21 | Mo Kα radiation |
a = 6.9113 (2) Å | µ = 0.20 mm−1 |
b = 33.4470 (9) Å | T = 173 K |
c = 8.0716 (2) Å | 0.32 × 0.16 × 0.16 mm |
β = 99.778 (3)° |
Oxford Diffraction Gemini-R Ultra diffractometer | 5393 reflections with I > 2σ(I) |
12119 measured reflections | Rint = 0.025 |
5825 independent reflections |
R[F2 > 2σ(F2)] = 0.046 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.115 | Δρmax = 0.52 e Å−3 |
S = 1.02 | Δρmin = −0.39 e Å−3 |
5825 reflections | Absolute structure: Flack (1983), with how many Friedel pairs? |
530 parameters | Absolute structure parameter: 0.10 (9) |
12 restraints |
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. |
x | y | z | Uiso*/Ueq | ||
O1 | 0.7497 (4) | 0.55224 (7) | 0.7220 (3) | 0.0237 (5) | |
O2 | 0.1919 (4) | 0.46152 (7) | 0.8492 (3) | 0.0237 (5) | |
H2 | 0.227 (6) | 0.4847 (7) | 0.845 (5) | 0.028* | |
O3 | 0.5612 (3) | 0.47199 (7) | 0.7674 (3) | 0.0181 (5) | |
N1 | 0.5601 (4) | 0.36418 (8) | 0.2909 (3) | 0.0182 (6) | |
H1 | 0.482 (5) | 0.3467 (9) | 0.327 (4) | 0.022* | |
C1 | 0.7123 (5) | 0.50307 (11) | 0.3123 (4) | 0.0210 (7) | |
H1B | 0.7361 | 0.5101 | 0.2035 | 0.025* | |
C2 | 0.7553 (5) | 0.53014 (10) | 0.4441 (4) | 0.0204 (7) | |
H2B | 0.8135 | 0.5550 | 0.4242 | 0.024* | |
C3 | 0.7160 (4) | 0.52209 (10) | 0.6043 (4) | 0.0168 (7) | |
C4 | 0.6350 (5) | 0.48440 (10) | 0.6283 (4) | 0.0165 (7) | |
C5 | 0.4635 (5) | 0.43353 (9) | 0.7259 (4) | 0.0156 (7) | |
H5B | 0.5102 | 0.4137 | 0.8165 | 0.019* | |
C6 | 0.2380 (5) | 0.43935 (10) | 0.7104 (4) | 0.0183 (7) | |
H6B | 0.1812 | 0.4121 | 0.7187 | 0.022* | |
C7 | 0.1473 (5) | 0.45537 (10) | 0.5439 (4) | 0.0207 (7) | |
H7BA | 0.0526 | 0.4762 | 0.5378 | 0.025* | |
C8 | 0.1963 (5) | 0.44112 (10) | 0.4034 (4) | 0.0193 (7) | |
H8BA | 0.1363 | 0.4511 | 0.2967 | 0.023* | |
C9 | 0.4355 (5) | 0.40152 (10) | 0.2569 (4) | 0.0176 (7) | |
H9B | 0.3244 | 0.3954 | 0.1638 | 0.021* | |
C10 | 0.5523 (5) | 0.43667 (10) | 0.2001 (4) | 0.0218 (7) | |
H10C | 0.6626 | 0.4258 | 0.1501 | 0.026* | |
H10D | 0.4657 | 0.4517 | 0.1112 | 0.026* | |
C11 | 0.6333 (5) | 0.46520 (10) | 0.3395 (4) | 0.0162 (7) | |
C12 | 0.6096 (4) | 0.45709 (10) | 0.5014 (4) | 0.0152 (7) | |
C13 | 0.5219 (4) | 0.41939 (9) | 0.5583 (4) | 0.0142 (6) | |
C14 | 0.3493 (5) | 0.40881 (10) | 0.4174 (4) | 0.0163 (6) | |
H14B | 0.2889 | 0.3833 | 0.4484 | 0.020* | |
C15 | 0.6695 (5) | 0.38424 (10) | 0.5869 (4) | 0.0175 (7) | |
H15C | 0.7860 | 0.3926 | 0.6685 | 0.021* | |
H15D | 0.6078 | 0.3614 | 0.6363 | 0.021* | |
C16 | 0.7352 (5) | 0.37061 (10) | 0.4249 (4) | 0.0188 (7) | |
H16C | 0.8218 | 0.3911 | 0.3877 | 0.023* | |
H16D | 0.8106 | 0.3454 | 0.4454 | 0.023* | |
C17 | 0.6156 (5) | 0.34674 (11) | 0.1355 (4) | 0.0244 (8) | |
H17E | 0.7122 | 0.3641 | 0.0954 | 0.037* | |
H17F | 0.4985 | 0.3446 | 0.0484 | 0.037* | |
H17G | 0.6724 | 0.3201 | 0.1605 | 0.037* | |
C18 | 0.7774 (5) | 0.54043 (11) | 0.8942 (4) | 0.0244 (8) | |
H18D | 0.6518 | 0.5316 | 0.9225 | 0.037* | |
H18E | 0.8270 | 0.5632 | 0.9655 | 0.037* | |
H18F | 0.8723 | 0.5184 | 0.9129 | 0.037* | |
O1A | 0.2322 (4) | 0.54616 (7) | 0.8095 (3) | 0.0265 (6) | |
O2A | −0.3450 (4) | 0.63779 (8) | 0.6868 (4) | 0.0432 (8) | |
H2' | −0.291 (7) | 0.6164 (9) | 0.699 (6) | 0.052* | |
O3A | 0.0512 (4) | 0.62916 (7) | 0.7809 (3) | 0.0242 (5) | |
N1A | 0.2297 (4) | 0.72176 (9) | 1.3122 (4) | 0.0245 (7) | |
H1' | 0.151 (5) | 0.7422 (9) | 1.294 (5) | 0.029* | |
C1A | 0.3185 (6) | 0.58439 (12) | 1.2382 (5) | 0.0292 (8) | |
H1AA | 0.3700 | 0.5741 | 1.3465 | 0.035* | |
C2A | 0.3206 (5) | 0.56109 (11) | 1.0979 (5) | 0.0248 (8) | |
H2A | 0.3800 | 0.5354 | 1.1116 | 0.030* | |
C3A | 0.2394 (5) | 0.57363 (10) | 0.9374 (4) | 0.0185 (7) | |
C4A | 0.1603 (5) | 0.61211 (10) | 0.9217 (4) | 0.0191 (7) | |
C5A | −0.0379 (5) | 0.66622 (10) | 0.8353 (4) | 0.0233 (8) | |
H5A | −0.0199 | 0.6884 | 0.7564 | 0.028* | |
C6A | −0.2585 (5) | 0.65951 (11) | 0.8324 (5) | 0.0311 (9) | |
H6A | −0.3198 | 0.6867 | 0.8203 | 0.037* | |
C7A | −0.3046 (5) | 0.64306 (11) | 0.9930 (5) | 0.0299 (9) | |
H7AB | −0.4030 | 0.6231 | 0.9889 | 0.036* | |
C8A | −0.2119 (5) | 0.65560 (11) | 1.1413 (5) | 0.0282 (8) | |
H8AB | −0.2482 | 0.6457 | 1.2420 | 0.034* | |
C9A | 0.0904 (5) | 0.68707 (10) | 1.3181 (4) | 0.0228 (7) | |
H9A | 0.0092 | 0.6933 | 1.4062 | 0.027* | |
C10A | 0.1994 (6) | 0.64772 (11) | 1.3688 (4) | 0.0267 (8) | |
H10A | 0.3255 | 0.6539 | 1.4424 | 0.032* | |
H10B | 0.1200 | 0.6315 | 1.4348 | 0.032* | |
C11A | 0.2404 (5) | 0.62328 (10) | 1.2219 (4) | 0.0222 (7) | |
C12A | 0.1738 (5) | 0.63628 (9) | 1.0614 (4) | 0.0171 (7) | |
C13A | 0.0772 (5) | 0.67605 (9) | 1.0122 (4) | 0.0182 (7) | |
C14A | −0.0489 (5) | 0.68559 (10) | 1.1484 (4) | 0.0218 (7) | |
H14C | −0.1085 | 0.7127 | 1.1248 | 0.026* | |
C15A | 0.2257 (5) | 0.71002 (10) | 1.0084 (4) | 0.0219 (7) | |
H15A | 0.3112 | 0.7034 | 0.9254 | 0.026* | |
H15B | 0.1540 | 0.7349 | 0.9711 | 0.026* | |
C16A | 0.3526 (5) | 0.71706 (11) | 1.1787 (5) | 0.0269 (8) | |
H16A | 0.4432 | 0.6942 | 1.2067 | 0.032* | |
H16B | 0.4327 | 0.7414 | 1.1738 | 0.032* | |
C17A | 0.3549 (6) | 0.73019 (13) | 1.4793 (5) | 0.0371 (10) | |
H17A | 0.4633 | 0.7109 | 1.4994 | 0.056* | |
H17B | 0.2752 | 0.7278 | 1.5683 | 0.056* | |
H17C | 0.4080 | 0.7574 | 1.4794 | 0.056* | |
C18A | 0.2487 (5) | 0.56154 (11) | 0.6469 (4) | 0.0236 (8) | |
H18A | 0.1249 | 0.5743 | 0.5971 | 0.035* | |
H18B | 0.2773 | 0.5396 | 0.5745 | 0.035* | |
H18C | 0.3551 | 0.5812 | 0.6580 | 0.035* | |
P1 | 0.14829 (13) | 0.30863 (3) | 0.80912 (11) | 0.0224 (2) | |
O1P | 0.0691 (5) | 0.33355 (8) | 0.9366 (3) | 0.0365 (7) | |
O2P | 0.3034 (4) | 0.27828 (9) | 0.8965 (3) | 0.0325 (6) | |
H2P | 0.298 (7) | 0.2735 (14) | 0.995 (3) | 0.039* | |
O3P | −0.0025 (4) | 0.28590 (8) | 0.6872 (3) | 0.0289 (6) | |
O4P | 0.2637 (5) | 0.33724 (8) | 0.7065 (3) | 0.0378 (7) | |
H4P | 0.301 (7) | 0.3274 (13) | 0.623 (4) | 0.045* | |
P2 | 0.20431 (13) | 0.28152 (3) | 0.31333 (10) | 0.0209 (2) | |
O5P | 0.1133 (5) | 0.25202 (9) | 0.4298 (3) | 0.0442 (8) | |
H5P | 0.098 (8) | 0.2635 (14) | 0.516 (4) | 0.053* | |
O6P | 0.2978 (4) | 0.25740 (8) | 0.1937 (3) | 0.0349 (7) | |
O7P | 0.0241 (5) | 0.30399 (15) | 0.2190 (4) | 0.0712 (13) | |
H7P | 0.018 (10) | 0.301 (2) | 0.116 (3) | 0.085* | |
O8P | 0.3404 (4) | 0.30920 (8) | 0.4242 (3) | 0.0335 (6) | |
O1W | −0.0600 (4) | 0.41038 (8) | 1.0012 (4) | 0.0343 (6) | |
H1W | −0.028 (7) | 0.3880 (6) | 0.973 (5) | 0.041* | |
H2W | −0.001 (6) | 0.4278 (8) | 0.959 (5) | 0.041* |
U11 | U22 | U33 | U12 | U13 | U23 | |
O1 | 0.0282 (13) | 0.0159 (12) | 0.0261 (12) | −0.0048 (10) | 0.0025 (10) | −0.0049 (10) |
O2 | 0.0287 (13) | 0.0195 (12) | 0.0269 (13) | −0.0035 (11) | 0.0160 (11) | −0.0051 (11) |
O3 | 0.0241 (12) | 0.0175 (11) | 0.0132 (10) | −0.0072 (9) | 0.0042 (9) | −0.0040 (9) |
N1 | 0.0159 (14) | 0.0204 (14) | 0.0191 (14) | −0.0044 (11) | 0.0050 (11) | −0.0037 (12) |
C1 | 0.0171 (16) | 0.0304 (19) | 0.0154 (16) | 0.0008 (14) | 0.0019 (13) | 0.0078 (15) |
C2 | 0.0133 (15) | 0.0194 (17) | 0.0287 (18) | 0.0000 (13) | 0.0042 (14) | 0.0056 (15) |
C3 | 0.0133 (15) | 0.0153 (16) | 0.0206 (16) | 0.0058 (13) | 0.0000 (13) | −0.0008 (13) |
C4 | 0.0113 (15) | 0.0217 (16) | 0.0154 (15) | 0.0029 (13) | −0.0010 (12) | 0.0002 (13) |
C5 | 0.0215 (17) | 0.0118 (15) | 0.0141 (15) | −0.0054 (13) | 0.0047 (13) | 0.0006 (13) |
C6 | 0.0209 (16) | 0.0158 (16) | 0.0206 (16) | −0.0048 (13) | 0.0102 (13) | −0.0042 (14) |
C7 | 0.0119 (15) | 0.0192 (16) | 0.0319 (18) | 0.0001 (13) | 0.0065 (14) | −0.0053 (15) |
C8 | 0.0118 (15) | 0.0253 (18) | 0.0195 (17) | −0.0037 (14) | −0.0009 (13) | −0.0013 (15) |
C9 | 0.0140 (15) | 0.0220 (17) | 0.0159 (15) | 0.0015 (13) | 0.0004 (12) | −0.0005 (13) |
C10 | 0.0228 (17) | 0.0236 (18) | 0.0200 (16) | 0.0058 (15) | 0.0066 (14) | 0.0015 (15) |
C11 | 0.0140 (15) | 0.0195 (16) | 0.0140 (15) | 0.0018 (13) | −0.0010 (13) | 0.0007 (13) |
C12 | 0.0068 (14) | 0.0216 (17) | 0.0157 (15) | 0.0018 (12) | −0.0025 (12) | −0.0011 (13) |
C13 | 0.0133 (15) | 0.0153 (15) | 0.0137 (15) | −0.0009 (13) | 0.0011 (12) | −0.0023 (12) |
C14 | 0.0145 (15) | 0.0172 (16) | 0.0170 (15) | −0.0023 (13) | 0.0019 (12) | −0.0011 (13) |
C15 | 0.0188 (16) | 0.0143 (15) | 0.0187 (16) | −0.0002 (13) | 0.0006 (13) | 0.0012 (14) |
C16 | 0.0134 (15) | 0.0156 (16) | 0.0261 (17) | 0.0000 (13) | −0.0005 (13) | −0.0011 (14) |
C17 | 0.0210 (18) | 0.0273 (19) | 0.0255 (18) | −0.0020 (15) | 0.0049 (14) | −0.0080 (16) |
C18 | 0.0247 (18) | 0.0280 (19) | 0.0213 (17) | −0.0031 (15) | 0.0064 (15) | −0.0055 (15) |
O1A | 0.0341 (14) | 0.0191 (12) | 0.0273 (13) | 0.0045 (11) | 0.0082 (11) | −0.0026 (11) |
O2A | 0.0375 (17) | 0.0243 (15) | 0.0571 (18) | 0.0065 (13) | −0.0224 (14) | −0.0089 (14) |
O3A | 0.0286 (13) | 0.0166 (12) | 0.0240 (12) | 0.0053 (10) | −0.0056 (10) | −0.0025 (10) |
N1A | 0.0158 (15) | 0.0224 (16) | 0.0340 (17) | 0.0028 (12) | 0.0000 (13) | −0.0068 (13) |
C1A | 0.032 (2) | 0.031 (2) | 0.0251 (19) | 0.0136 (16) | 0.0089 (15) | 0.0088 (17) |
C2A | 0.0258 (18) | 0.0202 (18) | 0.0304 (19) | 0.0103 (15) | 0.0106 (15) | 0.0023 (15) |
C3A | 0.0167 (16) | 0.0187 (17) | 0.0218 (16) | −0.0009 (13) | 0.0080 (13) | −0.0026 (14) |
C4A | 0.0165 (16) | 0.0186 (16) | 0.0217 (17) | −0.0023 (13) | 0.0018 (13) | 0.0053 (14) |
C5A | 0.0268 (18) | 0.0137 (16) | 0.0275 (18) | 0.0047 (14) | −0.0010 (15) | −0.0007 (14) |
C6A | 0.0217 (19) | 0.0173 (19) | 0.047 (2) | 0.0072 (15) | −0.0136 (16) | −0.0085 (17) |
C7A | 0.0124 (16) | 0.0194 (17) | 0.057 (2) | 0.0024 (14) | 0.0044 (16) | −0.0054 (18) |
C8A | 0.0161 (17) | 0.0214 (18) | 0.048 (2) | −0.0001 (14) | 0.0089 (16) | −0.0025 (17) |
C9A | 0.0186 (16) | 0.0217 (17) | 0.0277 (19) | 0.0045 (14) | 0.0026 (14) | −0.0005 (15) |
C10A | 0.0314 (19) | 0.030 (2) | 0.0187 (16) | 0.0105 (17) | 0.0034 (15) | 0.0033 (15) |
C11A | 0.0214 (18) | 0.0248 (19) | 0.0209 (17) | 0.0033 (15) | 0.0055 (14) | 0.0022 (15) |
C12A | 0.0144 (15) | 0.0146 (15) | 0.0235 (17) | 0.0024 (12) | 0.0070 (13) | 0.0003 (14) |
C13A | 0.0140 (16) | 0.0116 (15) | 0.0274 (18) | 0.0020 (12) | −0.0006 (13) | 0.0026 (13) |
C14A | 0.0134 (16) | 0.0140 (16) | 0.037 (2) | 0.0020 (13) | 0.0030 (14) | −0.0009 (15) |
C15A | 0.0203 (17) | 0.0176 (17) | 0.0286 (19) | −0.0016 (14) | 0.0067 (15) | −0.0009 (14) |
C16A | 0.0161 (17) | 0.0236 (19) | 0.042 (2) | −0.0031 (14) | 0.0064 (16) | −0.0036 (16) |
C17A | 0.025 (2) | 0.047 (3) | 0.034 (2) | 0.0026 (18) | −0.0079 (17) | −0.0129 (19) |
C18A | 0.0261 (19) | 0.0268 (19) | 0.0190 (17) | −0.0008 (15) | 0.0070 (14) | −0.0018 (15) |
P1 | 0.0285 (5) | 0.0184 (4) | 0.0216 (4) | −0.0020 (4) | 0.0084 (4) | −0.0007 (4) |
O1P | 0.0549 (18) | 0.0278 (14) | 0.0310 (15) | 0.0114 (13) | 0.0194 (13) | 0.0026 (12) |
O2P | 0.0413 (16) | 0.0394 (15) | 0.0185 (12) | 0.0127 (13) | 0.0104 (11) | −0.0027 (12) |
O3P | 0.0303 (14) | 0.0305 (14) | 0.0259 (12) | −0.0089 (11) | 0.0044 (10) | 0.0040 (11) |
O4P | 0.0580 (19) | 0.0293 (15) | 0.0310 (15) | −0.0236 (14) | 0.0214 (14) | −0.0088 (13) |
P2 | 0.0214 (4) | 0.0231 (5) | 0.0182 (4) | −0.0040 (4) | 0.0036 (4) | 0.0006 (4) |
O5P | 0.071 (2) | 0.0366 (16) | 0.0293 (15) | −0.0330 (16) | 0.0213 (15) | −0.0104 (13) |
O6P | 0.0569 (19) | 0.0252 (14) | 0.0247 (14) | 0.0009 (13) | 0.0132 (13) | −0.0020 (11) |
O7P | 0.050 (2) | 0.138 (4) | 0.0271 (15) | 0.048 (2) | 0.0129 (15) | 0.023 (2) |
O8P | 0.0394 (15) | 0.0362 (15) | 0.0281 (13) | −0.0188 (13) | 0.0143 (12) | −0.0093 (13) |
O1W | 0.0364 (16) | 0.0260 (14) | 0.0457 (17) | −0.0040 (13) | 0.0218 (13) | −0.0025 (14) |
O1—C3 | 1.378 (4) | N1A—C17A | 1.501 (5) |
O1—C18 | 1.427 (4) | N1A—C9A | 1.514 (5) |
O2—C6 | 1.424 (4) | N1A—H1' | 0.868 (19) |
O2—H2 | 0.814 (19) | C1A—C2A | 1.377 (5) |
O3—C4 | 1.374 (4) | C1A—C11A | 1.406 (5) |
O3—C5 | 1.465 (4) | C1A—H1AA | 0.9500 |
N1—C17 | 1.491 (4) | C2A—C3A | 1.386 (5) |
N1—C16 | 1.495 (4) | C2A—H2A | 0.9500 |
N1—C9 | 1.515 (4) | C3A—C4A | 1.396 (5) |
N1—H1 | 0.878 (19) | C4A—C12A | 1.377 (5) |
C1—C2 | 1.390 (5) | C5A—C6A | 1.537 (5) |
C1—C11 | 1.411 (5) | C5A—C13A | 1.547 (5) |
C1—H1B | 0.9500 | C5A—H5A | 1.0000 |
C2—C3 | 1.392 (5) | C6A—C7A | 1.491 (6) |
C2—H2B | 0.9500 | C6A—H6A | 1.0000 |
C3—C4 | 1.406 (5) | C7A—C8A | 1.326 (5) |
C4—C12 | 1.361 (5) | C7A—H7AB | 0.9500 |
C5—C13 | 1.550 (4) | C8A—C14A | 1.502 (5) |
C5—C6 | 1.554 (5) | C8A—H8AB | 0.9500 |
C5—H5B | 1.0000 | C9A—C14A | 1.536 (5) |
C6—C7 | 1.483 (5) | C9A—C10A | 1.537 (5) |
C6—H6B | 1.0000 | C9A—H9A | 1.0000 |
C7—C8 | 1.326 (5) | C10A—C11A | 1.506 (5) |
C7—H7BA | 0.9500 | C10A—H10A | 0.9900 |
C8—C14 | 1.503 (5) | C10A—H10B | 0.9900 |
C8—H8BA | 0.9500 | C11A—C12A | 1.370 (5) |
C9—C14 | 1.535 (4) | C12A—C13A | 1.511 (4) |
C9—C10 | 1.539 (5) | C13A—C15A | 1.535 (5) |
C9—H9B | 1.0000 | C13A—C14A | 1.547 (5) |
C10—C11 | 1.509 (5) | C14A—H14C | 1.0000 |
C10—H10C | 0.9900 | C15A—C16A | 1.518 (5) |
C10—H10D | 0.9900 | C15A—H15A | 0.9900 |
C11—C12 | 1.371 (4) | C15A—H15B | 0.9900 |
C12—C13 | 1.504 (4) | C16A—H16A | 0.9900 |
C13—C14 | 1.543 (4) | C16A—H16B | 0.9900 |
C13—C15 | 1.548 (4) | C17A—H17A | 0.9800 |
C14—H14B | 1.0000 | C17A—H17B | 0.9800 |
C15—C16 | 1.525 (4) | C17A—H17C | 0.9800 |
C15—H15C | 0.9900 | C18A—H18A | 0.9800 |
C15—H15D | 0.9900 | C18A—H18B | 0.9800 |
C16—H16C | 0.9900 | C18A—H18C | 0.9800 |
C16—H16D | 0.9900 | P1—O1P | 1.498 (3) |
C17—H17E | 0.9800 | P1—O3P | 1.511 (3) |
C17—H17F | 0.9800 | P1—O2P | 1.556 (3) |
C17—H17G | 0.9800 | P1—O4P | 1.569 (3) |
C18—H18D | 0.9800 | O2P—H2P | 0.821 (19) |
C18—H18E | 0.9800 | O4P—H4P | 0.829 (19) |
C18—H18F | 0.9800 | P2—O6P | 1.487 (3) |
O1A—C3A | 1.377 (4) | P2—O8P | 1.502 (3) |
O1A—C18A | 1.432 (4) | P2—O7P | 1.541 (3) |
O2A—C6A | 1.424 (5) | P2—O5P | 1.567 (3) |
O2A—H2' | 0.81 (2) | O5P—H5P | 0.816 (19) |
O3A—C4A | 1.377 (4) | O7P—H7P | 0.83 (2) |
O3A—C5A | 1.484 (4) | O1W—H1W | 0.825 (19) |
N1A—C16A | 1.490 (5) | O1W—H2W | 0.817 (19) |
C3—O1—C18 | 116.6 (3) | C2A—C1A—C11A | 120.3 (3) |
C6—O2—H2 | 111 (3) | C2A—C1A—H1AA | 119.9 |
C4—O3—C5 | 107.4 (2) | C11A—C1A—H1AA | 119.9 |
C17—N1—C16 | 111.9 (3) | C1A—C2A—C3A | 122.6 (3) |
C17—N1—C9 | 112.9 (3) | C1A—C2A—H2A | 118.7 |
C16—N1—C9 | 112.2 (2) | C3A—C2A—H2A | 118.7 |
C17—N1—H1 | 106 (2) | O1A—C3A—C2A | 117.1 (3) |
C16—N1—H1 | 109 (2) | O1A—C3A—C4A | 125.7 (3) |
C9—N1—H1 | 104 (3) | C2A—C3A—C4A | 117.0 (3) |
C2—C1—C11 | 120.2 (3) | O3A—C4A—C12A | 112.6 (3) |
C2—C1—H1B | 119.9 | O3A—C4A—C3A | 127.4 (3) |
C11—C1—H1B | 119.9 | C12A—C4A—C3A | 119.7 (3) |
C1—C2—C3 | 122.3 (3) | O3A—C5A—C6A | 109.5 (3) |
C1—C2—H2B | 118.8 | O3A—C5A—C13A | 106.1 (3) |
C3—C2—H2B | 118.8 | C6A—C5A—C13A | 113.5 (3) |
O1—C3—C2 | 117.5 (3) | O3A—C5A—H5A | 109.2 |
O1—C3—C4 | 125.9 (3) | C6A—C5A—H5A | 109.2 |
C2—C3—C4 | 116.5 (3) | C13A—C5A—H5A | 109.2 |
C12—C4—O3 | 113.2 (3) | O2A—C6A—C7A | 114.0 (3) |
C12—C4—C3 | 120.1 (3) | O2A—C6A—C5A | 111.3 (3) |
O3—C4—C3 | 126.5 (3) | C7A—C6A—C5A | 113.5 (3) |
O3—C5—C13 | 106.8 (2) | O2A—C6A—H6A | 105.7 |
O3—C5—C6 | 109.0 (3) | C7A—C6A—H6A | 105.7 |
C13—C5—C6 | 112.0 (2) | C5A—C6A—H6A | 105.7 |
O3—C5—H5B | 109.7 | C8A—C7A—C6A | 121.7 (3) |
C13—C5—H5B | 109.7 | C8A—C7A—H7AB | 119.1 |
C6—C5—H5B | 109.7 | C6A—C7A—H7AB | 119.1 |
O2—C6—C7 | 114.1 (3) | C7A—C8A—C14A | 119.3 (4) |
O2—C6—C5 | 110.9 (3) | C7A—C8A—H8AB | 120.3 |
C7—C6—C5 | 112.4 (3) | C14A—C8A—H8AB | 120.3 |
O2—C6—H6B | 106.3 | N1A—C9A—C14A | 107.6 (3) |
C7—C6—H6B | 106.3 | N1A—C9A—C10A | 112.3 (3) |
C5—C6—H6B | 106.3 | C14A—C9A—C10A | 114.5 (3) |
C8—C7—C6 | 121.0 (3) | N1A—C9A—H9A | 107.4 |
C8—C7—H7BA | 119.5 | C14A—C9A—H9A | 107.4 |
C6—C7—H7BA | 119.5 | C10A—C9A—H9A | 107.4 |
C7—C8—C14 | 118.2 (3) | C11A—C10A—C9A | 113.9 (3) |
C7—C8—H8BA | 120.9 | C11A—C10A—H10A | 108.8 |
C14—C8—H8BA | 120.9 | C9A—C10A—H10A | 108.8 |
N1—C9—C14 | 105.6 (2) | C11A—C10A—H10B | 108.8 |
N1—C9—C10 | 111.9 (3) | C9A—C10A—H10B | 108.8 |
C14—C9—C10 | 115.4 (3) | H10A—C10A—H10B | 107.7 |
N1—C9—H9B | 107.9 | C12A—C11A—C1A | 116.4 (3) |
C14—C9—H9B | 107.9 | C12A—C11A—C10A | 119.6 (3) |
C10—C9—H9B | 107.9 | C1A—C11A—C10A | 123.3 (3) |
C11—C10—C9 | 114.1 (3) | C11A—C12A—C4A | 123.6 (3) |
C11—C10—H10C | 108.7 | C11A—C12A—C13A | 126.2 (3) |
C9—C10—H10C | 108.7 | C4A—C12A—C13A | 109.7 (3) |
C11—C10—H10D | 108.7 | C12A—C13A—C15A | 112.9 (3) |
C9—C10—H10D | 108.7 | C12A—C13A—C14A | 105.8 (3) |
H10C—C10—H10D | 107.6 | C15A—C13A—C14A | 108.7 (3) |
C12—C11—C1 | 116.0 (3) | C12A—C13A—C5A | 101.0 (3) |
C12—C11—C10 | 119.7 (3) | C15A—C13A—C5A | 112.3 (3) |
C1—C11—C10 | 123.8 (3) | C14A—C13A—C5A | 115.8 (3) |
C4—C12—C11 | 124.3 (3) | C8A—C14A—C9A | 114.1 (3) |
C4—C12—C13 | 109.9 (3) | C8A—C14A—C13A | 110.1 (3) |
C11—C12—C13 | 125.2 (3) | C9A—C14A—C13A | 107.3 (3) |
C12—C13—C14 | 105.6 (2) | C8A—C14A—H14C | 108.4 |
C12—C13—C15 | 113.1 (3) | C9A—C14A—H14C | 108.4 |
C14—C13—C15 | 110.1 (2) | C13A—C14A—H14C | 108.4 |
C12—C13—C5 | 100.9 (2) | C16A—C15A—C13A | 112.5 (3) |
C14—C13—C5 | 115.5 (3) | C16A—C15A—H15A | 109.1 |
C15—C13—C5 | 111.4 (3) | C13A—C15A—H15A | 109.1 |
C8—C14—C9 | 114.8 (3) | C16A—C15A—H15B | 109.1 |
C8—C14—C13 | 109.7 (3) | C13A—C15A—H15B | 109.1 |
C9—C14—C13 | 107.2 (3) | H15A—C15A—H15B | 107.8 |
C8—C14—H14B | 108.3 | N1A—C16A—C15A | 111.0 (3) |
C9—C14—H14B | 108.3 | N1A—C16A—H16A | 109.4 |
C13—C14—H14B | 108.3 | C15A—C16A—H16A | 109.4 |
C16—C15—C13 | 112.6 (3) | N1A—C16A—H16B | 109.4 |
C16—C15—H15C | 109.1 | C15A—C16A—H16B | 109.4 |
C13—C15—H15C | 109.1 | H16A—C16A—H16B | 108.0 |
C16—C15—H15D | 109.1 | N1A—C17A—H17A | 109.5 |
C13—C15—H15D | 109.1 | N1A—C17A—H17B | 109.5 |
H15C—C15—H15D | 107.8 | H17A—C17A—H17B | 109.5 |
N1—C16—C15 | 109.9 (3) | N1A—C17A—H17C | 109.5 |
N1—C16—H16C | 109.7 | H17A—C17A—H17C | 109.5 |
C15—C16—H16C | 109.7 | H17B—C17A—H17C | 109.5 |
N1—C16—H16D | 109.7 | O1A—C18A—H18A | 109.5 |
C15—C16—H16D | 109.7 | O1A—C18A—H18B | 109.5 |
H16C—C16—H16D | 108.2 | H18A—C18A—H18B | 109.5 |
N1—C17—H17E | 109.5 | O1A—C18A—H18C | 109.5 |
N1—C17—H17F | 109.5 | H18A—C18A—H18C | 109.5 |
H17E—C17—H17F | 109.5 | H18B—C18A—H18C | 109.5 |
N1—C17—H17G | 109.5 | O1P—P1—O3P | 115.80 (17) |
H17E—C17—H17G | 109.5 | O1P—P1—O2P | 110.82 (15) |
H17F—C17—H17G | 109.5 | O3P—P1—O2P | 108.23 (15) |
O1—C18—H18D | 109.5 | O1P—P1—O4P | 107.52 (16) |
O1—C18—H18E | 109.5 | O3P—P1—O4P | 108.61 (14) |
H18D—C18—H18E | 109.5 | O2P—P1—O4P | 105.34 (17) |
O1—C18—H18F | 109.5 | P1—O2P—H2P | 115 (3) |
H18D—C18—H18F | 109.5 | P1—O4P—H4P | 116 (3) |
H18E—C18—H18F | 109.5 | O6P—P2—O8P | 115.08 (16) |
C3A—O1A—C18A | 116.7 (3) | O6P—P2—O7P | 110.35 (17) |
C6A—O2A—H2' | 103 (4) | O8P—P2—O7P | 111.5 (2) |
C4A—O3A—C5A | 107.3 (2) | O6P—P2—O5P | 108.11 (16) |
C16A—N1A—C17A | 111.0 (3) | O8P—P2—O5P | 107.76 (14) |
C16A—N1A—C9A | 112.7 (3) | O7P—P2—O5P | 103.3 (2) |
C17A—N1A—C9A | 112.9 (3) | P2—O5P—H5P | 110 (4) |
C16A—N1A—H1' | 112 (3) | P2—O7P—H7P | 110 (5) |
C17A—N1A—H1' | 105 (3) | H1W—O1W—H2W | 110 (3) |
C9A—N1A—H1' | 103 (3) |
D—H···A | D—H | H···A | D···A | D—H···A |
O2—H2···O1A | 0.81 (2) | 2.08 (2) | 2.868 (3) | 163 (4) |
N1—H1···O8P | 0.88 (2) | 1.85 (2) | 2.720 (4) | 173 (4) |
O2A—H2′···O1i | 0.81 (2) | 2.17 (3) | 2.938 (4) | 160 (5) |
N1A—H1′···O3Pii | 0.87 (2) | 1.81 (2) | 2.659 (4) | 165 (4) |
O2P—H2P···O6Piii | 0.82 (2) | 1.69 (2) | 2.505 (3) | 172 (5) |
O4P—H4P···O8P | 0.83 (2) | 1.78 (2) | 2.601 (4) | 170 (5) |
O5P—H5P···O3P | 0.82 (2) | 1.81 (2) | 2.609 (4) | 165 (5) |
O7P—H7P···O1Piv | 0.83 (2) | 1.88 (5) | 2.552 (4) | 136 (6) |
O1W—H1W···O1P | 0.83 (2) | 1.98 (2) | 2.798 (4) | 172 (5) |
O1W—H2W···O2 | 0.82 (2) | 2.06 (2) | 2.862 (4) | 167 (4) |
Symmetry codes: (i) x−1, y, z; (ii) −x, y+1/2, −z+2; (iii) x, y, z+1; (iv) x, y, z−1. |
Experimental details
Crystal data | |
Chemical formula | C18H22NO3+·H2O4P−·0.5H2O |
Mr | 406.36 |
Crystal system, space group | Monoclinic, P21 |
Temperature (K) | 173 |
a, b, c (Å) | 6.9113 (2), 33.4470 (9), 8.0716 (2) |
β (°) | 99.778 (3) |
V (Å3) | 1838.74 (9) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.20 |
Crystal size (mm) | 0.32 × 0.16 × 0.16 |
Data collection | |
Diffractometer | Oxford Diffraction Gemini-R Ultra diffractometer |
Absorption correction | – |
No. of measured, independent and observed [I > 2σ(I)] reflections | 12119, 5825, 5393 |
Rint | 0.025 |
(sin θ/λ)max (Å−1) | 0.606 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.046, 0.115, 1.02 |
No. of reflections | 5825 |
No. of parameters | 530 |
No. of restraints | 12 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.52, −0.39 |
Absolute structure | Flack (1983), with how many Friedel pairs? |
Absolute structure parameter | 0.10 (9) |
Computer programs: CrysAlis CCD (Oxford Diffraction, 2003), CrysAlis RED (Oxford Diffraction, 2003), SIR2002 (Burla et al., 2003), SHELXL97 (Sheldrick, 2008), XP/SHELXTL (Sheldrick, 2008) and Mercury (Bruno et al., 2002), publCIF (Westrip, 2009).
D—H···A | D—H | H···A | D···A | D—H···A |
O2—H2···O1A | 0.814 (19) | 2.08 (2) | 2.868 (3) | 163 (4) |
N1—H1···O8P | 0.878 (19) | 1.85 (2) | 2.720 (4) | 173 (4) |
O2A—H2'···O1i | 0.81 (2) | 2.17 (3) | 2.938 (4) | 160 (5) |
N1A—H1'···O3Pii | 0.868 (19) | 1.81 (2) | 2.659 (4) | 165 (4) |
O2P—H2P···O6Piii | 0.821 (19) | 1.69 (2) | 2.505 (3) | 172 (5) |
O4P—H4P···O8P | 0.829 (19) | 1.78 (2) | 2.601 (4) | 170 (5) |
O5P—H5P···O3P | 0.816 (19) | 1.81 (2) | 2.609 (4) | 165 (5) |
O7P—H7P···O1Piv | 0.83 (2) | 1.88 (5) | 2.552 (4) | 136 (6) |
O1W—H1W···O1P | 0.825 (19) | 1.98 (2) | 2.798 (4) | 172 (5) |
O1W—H2W···O2 | 0.817 (19) | 2.06 (2) | 2.862 (4) | 167 (4) |
Symmetry codes: (i) x−1, y, z; (ii) −x, y+1/2, −z+2; (iii) x, y, z+1; (iv) x, y, z−1. |
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Codeine, a natural alkaloid of the opium poppy plant, is used as an analgesic for the treatment of mild to moderate pain, as an antitussive (cough depressant) and as an antidiarrhoeal agent. Codeine is mainly produced from morphine in a semi-synthetic process. It is included in the WHO model list of essential drugs, and it is the most widely used narcotic drug in medical practice. The annual world production (2007) of codeine is 350 tons (1 ton = 1.016 tonne [Please check]), and 45% of this amount is produced in the United Kingdom and the United States (International Narcotics Control Board, 2009). Codeine is a highly addictive substance because the human body metabolizes approximately 10% of administered codeine to form morphine. In fact, codeine cough remedies are among the most commonly abused pharmaceutical drugs.
The most important codeine salts are the phosphate, sulfate and hydrochloride salts. It is known that each of these salts, as well as the base, can exist in at least one hydrated form. In the case of the phosphate, a hemihydrate and a sesquihydrate are specified in individual monographs of the European Pharmacopoeia, and a hemihydrate is mentioned in the United States Pharmacopoeia, but a crystal structure of a codeine phosphate has not been reported so far. Single crystals of the title compound, (I), were produced as part of a comprehensive study of the solid-state properties of codeine.
The asymmetric unit of (I) is composed of two codeine hydrogen cations (c), two dihydrogen phosphate anions (p) and one water molecule (w). A least-squares fit confirms that the two cations have the same geometry (see Fig. 1). They adopt the characteristic T conformation, which is known from related compounds of the opiate family, e.g. morphine monohydrate (Bye, 1976) and morphine derivatives (Reference?), the free base form of codeine (Canfield et al., 1987), codeine monohydrate (Bel'skii et al., 1988), codeine hydrobromide dihydrate (Kartha et al., 1962) and codeine derivatives (Grant et al., 1993; Kolev et al., 2006; Liebman et al., 1978). Using the nomenclature commonly applied to opiates, the mean planes defined by the rings A/B/C and D/E (see the scheme) form angles of 89.36 (5) and 88.66 (5)°, respectively, in the two independent cations of (I).
Adjacent dihydrogen phosphate anions of (I) are joined together by dimeric (p)O—H···O(p) hydrogen bonds to give an infinite ribbon chain with an R22(8) ring motif (Bernstein et al., 1995), as shown in Fig. 2. These phosphate chains run along the c axis. A systematic comparison with chemically related crystal structures reveals that the dimeric ring is the preferred supramolecular synthon in the aggregation of hydrogen phosphate anions. Furthermore, the ribbon chain motif of (I) is present in 34 of the 230 dihydrogen phosphate structures that are included in the current version of the Cambridge Structural Database [Version 5.30 (Allen, 2002), refcodes ACUXIG, BIDPEJ, CEXPAX, CLQUON01, CPAIMZ, DASNUH, DAYHOB, DUNHID, EDUQUP, EJEGAB, FEDMIL, FIJHEL, GEJYEA, GEXXAI, GOLTOQ, HEXRIM, ISUZIF, LELJOC, LELXIJ, MATKAT, MPHAZP, NELVUV, PAMRAX, PIFJAQ, PROCPH, REZNEP, SASBIX, SEGGER, SEPHEB, SODCUJ, XAPRUC, MIKPUS, SIBMUM, SIBQEA]. Among the other R22(8)-based motifs is a second type of ribbon chain, which is topologically distinct from the chain observed in (I).
Independent codeine units are linked to one another through (c)O—H···O(c) hydrogen bonds by employing the hydrogen-bond donor and acceptor functions, respectively, of their hydroxy and methoxy groups. The resulting infinite zigzag chain of codeine molecules is depicted in Fig. 3. It propagates parallel to the a axis and lies approximately perpendicular to the hydrogen-bonded dihydrogen phosphate chains mentioned above. Fig. 3 shows also that these two chain types are (c)N—H···.O(p) hydrogen-bonded to one another via the donor function of the protonated amino group of codeine. Thus, each hydrogen-bonded codeine chain is connected to a multitude of hydrogen-bonded phosphate chains and vice versa, to give a complex three-dimensional hydrogen-bonded network.
The water molecule acts as an additional (c)O···H—O—H···O(p) bridge between the hydroxy group of codeine and a phosphate chain. Additional R34(16) rings are formed due to these bonds (see Fig. 3), but only one independent codeine unit engages in this kind of interaction. Altogether, one unprotonated phosphate O atom accepts two hydrogen bonds, and the other accepts one hydrogen bond.
The crystal structure of (I) differs fundamentally from those of the free base, the monohydrate and the hydrobromide dihydrate of codeine in terms of molecuar packing. This is presumably due to the very specific hydrogen-bonding capabilities of the dihydrogen phosphate anions. The observation that the water molecules of the hemihydrate are firmly bound within a hydrogen-bonded framework is in accordance with the experimentally observed hydration/dehydration behaviour (see below).