Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270111052012/sk3425sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270111052012/sk3425Isup2.hkl | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270111052012/sk3425IIsup3.hkl | |
Chemical Markup Language (CML) file https://doi.org/10.1107/S0108270111052012/sk3425Isup4.cml | |
Chemical Markup Language (CML) file https://doi.org/10.1107/S0108270111052012/sk3425IIsup5.cml |
CCDC references: 866760; 866761
Tizanidine hydrochloride was purchased from TCI EUROPE NV Belgium (>98%, purity), used as received and was found to be soluble at room temperature in methanol, ethanol, water, quinoline, morpholine, 2-picoline, N,N'-dimethylformamide, N,N'-dimethylacetamide and dimethyl sulfoxide. Subsequently, different methods of crystallization were employed including: (i) slurry experiments by suspending (II) in different solvents at room temperature; (ii) solvent-assisted grinding experiments by addition of several drops of solvent to the solid of (II) and grinding by hand using a mortar and pestle for several minutes at room temperature; (iii) evaporation crystallization at room temperature and at 353 K; (iv) slow or rapid antisolvent crystallization by overlaying a solution of (II) with an antisolvent (as antisolvents for crystallization experiments a multitude of different organic solvents, e.g. ketones, ethers, esters, alcohols, benzene derivatives and alkanes were used); (v) recrystallization under reflux by subsequent slow or fast cooling; (vi) treatment of a solution or suspension of (II) in an ultrasonic bath at room temperature; (vii) slow or rapid vapour diffusion experiments by diffusion of an antisolvent into a solution of (II) via the gas phase; (viii) thermal treatment using differential scanning calorimetry (DSC) performed on a DSC 131 (SETARAM) device. For the DSC about 25–30 mg of the sample was filled into an aluminium crucible and measured from room temperature to 500 K at a rate of 3 K min-1 under a nitrogen atmosphere to observe phase transitions. All solids thus obtained were analysed by using X-ray powder diffraction data recorded under ambient conditions in transmission mode on a Stoe Stadi-P diffractometer with a Ge(111) monochromator and a linear position-sensitive detector using Cu Kα1 radiation (λ = 1.5406 Å).
The 1H NMR spectra for (I) and (II) were measured on a Bruker Avance 400 device with 400 MHz in tubes filled with d6-DMSO and about 5 mg substance. The elemental analyses (CHNS) were carried out on an Elementar (vario MICRO cube) elemental analyzer. About 1–4 mg of the samples were filled into a tin vessel and measured at 1423 K under a helium atmosphere with addition of oxygen during the measurement.
In order to obtain single crystals of (I), the commercially available compound (II) (60 mg) was dissolved in morpholine (3 ml) in an ultrasonic bath at room temperature. Subsequently, the solution was filtered and diisopropyl ether (7 ml) was added. After 8 d, orange single crystals precipitated. 1H NMR (400 MHz, d6-DMSO): δ 7.64 (d, 3JHH = 9.2 Hz, 1H, H6), 7.52 (d, 3JHH = 9.2 Hz, 1H, H5), 6.33 (s, 2H, H12 and H15), 3.38 (s, 4H, H13A, H13B, H14A and H14B); Elemental analysis calculated for C9H8ClN5S (%): C 42.61, H 3.18, N 27.60, S 12.64; found (%): C 42.48, H 3.07, N 27.43, S 12.92.
For growing crystals of (II), the commercially available compound (II) (340 mg) was dissolved in water (17 ml) in an ultrasonic bath at room temperature. Subsequently, the solution was filtered and the filtrate was allowed to evaporate at room temperature. After 10 d, pale-yellow single crystals precipitated. 1H NMR (400 MHz, d6-DMSO): δ 11.14 (s, 1H, H3), 8.48 (s, 2H, H12 and H15), 8.21 (d, 3JHH = 9.2 Hz, 1H, H6), 7.94 (d, 3JHH = 9.2 Hz, 1H, H5), 3.71 (s, 4H, H13A, H13B, H14A and H14B); Elemental analysis calculated for C9H9Cl2N5S (%): C 37.25, H 3.13, N 24.14, S 11.05; found (%): C 37.31, H 3.23, N 23.92, S 10.88.
All H atoms were located in Fourier difference maps. Nevertheless, H atoms bonded to C atoms were geometrically positioned and refined using a riding model with fixed individual displacement parameters [Uiso(H) = 1.2Ueq(C)] using a riding model with aromatic C—H = 0.95 Å or methylene C—H = 0.99 Å. H atoms bonded to N atoms were refined freely. Only the N15—H15 distance in tizanidine was restrained to 0.88 (1) Å.
For both compounds, data collection: X-AREA (Stoe & Cie, 2001); cell refinement: X-AREA (Stoe & Cie, 2001); data reduction: X-AREA (Stoe & Cie, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009) and publCIF (Westrip, 2010).
C9H8ClN5S | Z = 4 |
Mr = 253.71 | F(000) = 520 |
Triclinic, P1 | Dx = 1.621 Mg m−3 |
Hall symbol: -P 1 | Mo Kα radiation, λ = 0.71073 Å |
a = 7.5935 (6) Å | Cell parameters from 8083 reflections |
b = 10.8712 (9) Å | θ = 3.4–26.0° |
c = 12.8862 (12) Å | µ = 0.55 mm−1 |
α = 95.794 (7)° | T = 173 K |
β = 100.349 (7)° | Block, orange |
γ = 92.125 (7)° | 0.47 × 0.47 × 0.45 mm |
V = 1039.45 (15) Å3 |
Stoe IPDS II two-circle diffractometer | 3872 independent reflections |
Radiation source: fine-focus sealed tube | 3537 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.033 |
ω scans | θmax = 25.6°, θmin = 3.4° |
Absorption correction: multi-scan (MULABS; Spek, 2009; Blessing, 1995) | h = −9→9 |
Tmin = 0.784, Tmax = 0.792 | k = −13→12 |
9426 measured reflections | l = −15→15 |
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)] = 0.029 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.076 | w = 1/[σ2(Fo2) + (0.0395P)2 + 0.3667P] where P = (Fo2 + 2Fc2)/3 |
S = 1.06 | (Δ/σ)max = 0.001 |
3872 reflections | Δρmax = 0.29 e Å−3 |
306 parameters | Δρmin = −0.27 e Å−3 |
1 restraint | Extinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.0305 (18) |
C9H8ClN5S | γ = 92.125 (7)° |
Mr = 253.71 | V = 1039.45 (15) Å3 |
Triclinic, P1 | Z = 4 |
a = 7.5935 (6) Å | Mo Kα radiation |
b = 10.8712 (9) Å | µ = 0.55 mm−1 |
c = 12.8862 (12) Å | T = 173 K |
α = 95.794 (7)° | 0.47 × 0.47 × 0.45 mm |
β = 100.349 (7)° |
Stoe IPDS II two-circle diffractometer | 3872 independent reflections |
Absorption correction: multi-scan (MULABS; Spek, 2009; Blessing, 1995) | 3537 reflections with I > 2σ(I) |
Tmin = 0.784, Tmax = 0.792 | Rint = 0.033 |
9426 measured reflections |
R[F2 > 2σ(F2)] = 0.029 | 1 restraint |
wR(F2) = 0.076 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.06 | Δρmax = 0.29 e Å−3 |
3872 reflections | Δρmin = −0.27 e Å−3 |
306 parameters |
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 | ||
Cl1 | 0.87633 (5) | 0.81691 (4) | 0.35774 (3) | 0.02998 (12) | |
S1 | 0.64157 (6) | 1.12938 (4) | 0.75043 (3) | 0.03014 (13) | |
N1 | 0.61354 (18) | 1.19340 (12) | 0.64090 (11) | 0.0285 (3) | |
N2 | 0.72209 (17) | 0.99966 (12) | 0.71384 (10) | 0.0228 (3) | |
N3 | 0.85938 (16) | 0.80253 (11) | 0.59751 (10) | 0.0196 (3) | |
C1 | 0.6682 (2) | 1.11225 (14) | 0.56883 (13) | 0.0232 (3) | |
C2 | 0.72960 (19) | 1.00099 (13) | 0.61074 (12) | 0.0195 (3) | |
C3 | 0.79219 (18) | 0.90114 (13) | 0.54686 (12) | 0.0184 (3) | |
C4 | 0.79366 (19) | 0.92490 (15) | 0.44363 (12) | 0.0225 (3) | |
C5 | 0.7348 (2) | 1.03598 (16) | 0.40233 (13) | 0.0281 (4) | |
H5 | 0.7399 | 1.0457 | 0.3305 | 0.034* | |
C6 | 0.6716 (2) | 1.12861 (15) | 0.46169 (14) | 0.0278 (4) | |
H6 | 0.6312 | 1.2016 | 0.4324 | 0.033* | |
C11 | 0.81239 (19) | 0.68749 (14) | 0.56164 (11) | 0.0184 (3) | |
N12 | 0.89949 (18) | 0.59355 (12) | 0.60423 (11) | 0.0230 (3) | |
H12 | 0.977 (3) | 0.6061 (18) | 0.6588 (17) | 0.030 (5)* | |
C13 | 0.8035 (2) | 0.47479 (14) | 0.56282 (13) | 0.0252 (3) | |
H13A | 0.7233 | 0.4487 | 0.6102 | 0.030* | |
H13B | 0.8870 | 0.4090 | 0.5516 | 0.030* | |
C14 | 0.6974 (2) | 0.50735 (14) | 0.45782 (13) | 0.0240 (3) | |
H14A | 0.7666 | 0.4946 | 0.3998 | 0.029* | |
H14B | 0.5814 | 0.4587 | 0.4375 | 0.029* | |
N15 | 0.67228 (17) | 0.63892 (12) | 0.48498 (10) | 0.0211 (3) | |
H15 | 0.620 (2) | 0.6844 (16) | 0.4391 (13) | 0.028 (5)* | |
Cl1A | 1.59135 (6) | 0.73702 (4) | 0.77597 (3) | 0.03394 (13) | |
S1A | 1.14534 (6) | 0.30136 (4) | 0.92207 (4) | 0.03389 (13) | |
N1A | 1.3580 (2) | 0.28329 (12) | 0.93078 (11) | 0.0296 (3) | |
N2A | 1.12605 (19) | 0.43135 (13) | 0.87212 (12) | 0.0294 (3) | |
N3A | 1.20243 (19) | 0.65918 (12) | 0.78831 (11) | 0.0266 (3) | |
C1A | 1.4254 (2) | 0.38312 (14) | 0.89417 (12) | 0.0241 (3) | |
C2A | 1.2917 (2) | 0.46815 (14) | 0.86089 (12) | 0.0228 (3) | |
C3A | 1.3382 (2) | 0.58288 (14) | 0.82357 (12) | 0.0230 (3) | |
C4A | 1.5168 (2) | 0.60176 (15) | 0.81929 (12) | 0.0251 (3) | |
C5A | 1.6497 (2) | 0.51658 (15) | 0.85015 (12) | 0.0264 (3) | |
H5A | 1.7704 | 0.5350 | 0.8440 | 0.032* | |
C6A | 1.6067 (2) | 0.40925 (15) | 0.88834 (12) | 0.0262 (3) | |
H6A | 1.6960 | 0.3536 | 0.9104 | 0.031* | |
C11A | 1.1998 (2) | 0.76958 (14) | 0.83723 (12) | 0.0204 (3) | |
N12A | 1.08719 (18) | 0.85375 (12) | 0.79985 (11) | 0.0225 (3) | |
H12A | 1.013 (3) | 0.8373 (18) | 0.7452 (17) | 0.030 (5)* | |
C13A | 1.0908 (2) | 0.95967 (16) | 0.87703 (14) | 0.0311 (4) | |
H13C | 0.9937 | 0.9522 | 0.9184 | 0.037* | |
H13D | 1.0815 | 1.0376 | 0.8433 | 0.037* | |
C14A | 1.2758 (2) | 0.95219 (16) | 0.94604 (14) | 0.0320 (4) | |
H14C | 1.3701 | 0.9979 | 0.9189 | 0.038* | |
H14D | 1.2772 | 0.9843 | 1.0209 | 0.038* | |
N15A | 1.29726 (19) | 0.81865 (13) | 0.93449 (10) | 0.0238 (3) | |
H15A | 1.396 (3) | 0.7939 (18) | 0.9540 (16) | 0.027 (5)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.0270 (2) | 0.0404 (2) | 0.0234 (2) | −0.00064 (16) | 0.00831 (15) | 0.00188 (16) |
S1 | 0.0374 (2) | 0.0235 (2) | 0.0268 (2) | 0.00911 (17) | −0.00057 (17) | −0.00144 (16) |
N1 | 0.0286 (7) | 0.0195 (7) | 0.0340 (8) | 0.0034 (5) | −0.0038 (6) | 0.0033 (6) |
N2 | 0.0258 (7) | 0.0191 (6) | 0.0215 (6) | 0.0032 (5) | −0.0009 (5) | 0.0008 (5) |
N3 | 0.0197 (6) | 0.0190 (6) | 0.0189 (6) | 0.0017 (5) | −0.0002 (5) | 0.0024 (5) |
C1 | 0.0181 (7) | 0.0182 (7) | 0.0306 (8) | −0.0031 (5) | −0.0035 (6) | 0.0063 (6) |
C2 | 0.0160 (7) | 0.0185 (7) | 0.0221 (7) | −0.0026 (5) | −0.0024 (6) | 0.0042 (6) |
C3 | 0.0145 (6) | 0.0192 (7) | 0.0197 (7) | −0.0028 (5) | −0.0019 (5) | 0.0032 (6) |
C4 | 0.0170 (7) | 0.0286 (8) | 0.0215 (7) | −0.0032 (6) | 0.0020 (6) | 0.0049 (6) |
C5 | 0.0227 (8) | 0.0364 (9) | 0.0253 (8) | −0.0053 (7) | 0.0009 (6) | 0.0140 (7) |
C6 | 0.0241 (8) | 0.0257 (8) | 0.0325 (9) | −0.0028 (6) | −0.0033 (7) | 0.0148 (7) |
C11 | 0.0166 (7) | 0.0205 (7) | 0.0188 (7) | 0.0025 (5) | 0.0047 (5) | 0.0024 (6) |
N12 | 0.0218 (6) | 0.0183 (6) | 0.0259 (7) | 0.0039 (5) | −0.0029 (6) | −0.0003 (5) |
C13 | 0.0242 (8) | 0.0186 (8) | 0.0320 (9) | 0.0029 (6) | 0.0043 (6) | 0.0002 (6) |
C14 | 0.0209 (7) | 0.0207 (8) | 0.0287 (8) | 0.0002 (6) | 0.0036 (6) | −0.0039 (6) |
N15 | 0.0187 (6) | 0.0191 (6) | 0.0234 (7) | 0.0011 (5) | −0.0011 (5) | 0.0016 (5) |
Cl1A | 0.0408 (2) | 0.0314 (2) | 0.0329 (2) | 0.00316 (17) | 0.01010 (18) | 0.01310 (17) |
S1A | 0.0350 (2) | 0.0222 (2) | 0.0420 (3) | −0.00166 (17) | 0.00052 (19) | 0.00486 (18) |
N1A | 0.0370 (8) | 0.0194 (7) | 0.0298 (7) | 0.0039 (6) | −0.0016 (6) | 0.0022 (6) |
N2A | 0.0300 (7) | 0.0206 (7) | 0.0335 (8) | 0.0018 (5) | −0.0031 (6) | 0.0002 (6) |
N3A | 0.0306 (7) | 0.0196 (7) | 0.0254 (7) | 0.0064 (5) | −0.0069 (6) | 0.0020 (5) |
C1A | 0.0329 (8) | 0.0178 (7) | 0.0182 (7) | 0.0055 (6) | −0.0030 (6) | −0.0019 (6) |
C2A | 0.0287 (8) | 0.0176 (7) | 0.0185 (7) | 0.0041 (6) | −0.0038 (6) | −0.0026 (6) |
C3A | 0.0300 (8) | 0.0188 (7) | 0.0170 (7) | 0.0055 (6) | −0.0038 (6) | −0.0002 (6) |
C4A | 0.0340 (9) | 0.0224 (8) | 0.0182 (7) | 0.0044 (6) | 0.0024 (6) | 0.0024 (6) |
C5A | 0.0283 (8) | 0.0289 (8) | 0.0211 (7) | 0.0073 (6) | 0.0035 (6) | −0.0016 (6) |
C6A | 0.0309 (8) | 0.0230 (8) | 0.0222 (8) | 0.0115 (6) | −0.0014 (6) | −0.0014 (6) |
C11A | 0.0215 (7) | 0.0212 (7) | 0.0185 (7) | 0.0018 (6) | 0.0012 (6) | 0.0058 (6) |
N12A | 0.0251 (7) | 0.0203 (7) | 0.0191 (6) | 0.0063 (5) | −0.0047 (5) | 0.0010 (5) |
C13A | 0.0293 (8) | 0.0303 (9) | 0.0278 (8) | 0.0109 (7) | −0.0061 (7) | −0.0077 (7) |
C14A | 0.0317 (9) | 0.0273 (9) | 0.0301 (9) | 0.0090 (7) | −0.0089 (7) | −0.0064 (7) |
N15A | 0.0237 (7) | 0.0260 (7) | 0.0193 (6) | 0.0070 (6) | −0.0033 (5) | 0.0020 (5) |
Cl1—C4 | 1.7434 (16) | Cl1A—C4A | 1.7356 (17) |
S1—N2 | 1.6181 (13) | S1A—N2A | 1.6117 (15) |
S1—N1 | 1.6196 (15) | S1A—N1A | 1.6190 (15) |
N1—C1 | 1.347 (2) | N1A—C1A | 1.346 (2) |
N2—C2 | 1.342 (2) | N2A—C2A | 1.343 (2) |
N3—C11 | 1.302 (2) | N3A—C11A | 1.301 (2) |
N3—C3 | 1.3776 (19) | N3A—C3A | 1.388 (2) |
C1—C6 | 1.414 (2) | C1A—C6A | 1.412 (2) |
C1—C2 | 1.434 (2) | C1A—C2A | 1.436 (2) |
C2—C3 | 1.442 (2) | C2A—C3A | 1.435 (2) |
C3—C4 | 1.382 (2) | C3A—C4A | 1.376 (2) |
C4—C5 | 1.423 (2) | C4A—C5A | 1.426 (2) |
C5—C6 | 1.357 (3) | C5A—C6A | 1.362 (2) |
C5—H5 | 0.9500 | C5A—H5A | 0.9500 |
C6—H6 | 0.9500 | C6A—H6A | 0.9500 |
C11—N12 | 1.347 (2) | C11A—N12A | 1.3415 (19) |
C11—N15 | 1.3645 (19) | C11A—N15A | 1.380 (2) |
N12—C13 | 1.461 (2) | N12A—C13A | 1.440 (2) |
N12—H12 | 0.83 (2) | N12A—H12A | 0.82 (2) |
C13—C14 | 1.527 (2) | C13A—C14A | 1.531 (2) |
C13—H13A | 0.9900 | C13A—H13C | 0.9900 |
C13—H13B | 0.9900 | C13A—H13D | 0.9900 |
C14—N15 | 1.4656 (19) | C14A—N15A | 1.462 (2) |
C14—H14A | 0.9900 | C14A—H14C | 0.9900 |
C14—H14B | 0.9900 | C14A—H14D | 0.9900 |
N15—H15 | 0.861 (9) | N15A—H15A | 0.81 (2) |
N2—S1—N1 | 101.09 (7) | N2A—S1A—N1A | 101.29 (8) |
C1—N1—S1 | 105.97 (11) | C1A—N1A—S1A | 106.08 (11) |
C2—N2—S1 | 106.21 (10) | C2A—N2A—S1A | 106.06 (11) |
C11—N3—C3 | 123.23 (12) | C11A—N3A—C3A | 119.65 (13) |
N1—C1—C6 | 126.59 (15) | N1A—C1A—C6A | 126.58 (14) |
N1—C1—C2 | 113.35 (14) | N1A—C1A—C2A | 112.98 (15) |
C6—C1—C2 | 120.06 (15) | C6A—C1A—C2A | 120.43 (15) |
N2—C2—C1 | 113.38 (14) | N2A—C2A—C3A | 124.94 (14) |
N2—C2—C3 | 124.10 (13) | N2A—C2A—C1A | 113.58 (15) |
C1—C2—C3 | 122.52 (14) | C3A—C2A—C1A | 121.44 (15) |
N3—C3—C4 | 128.45 (14) | C4A—C3A—N3A | 125.96 (15) |
N3—C3—C2 | 117.27 (13) | C4A—C3A—C2A | 114.93 (14) |
C4—C3—C2 | 113.87 (13) | N3A—C3A—C2A | 118.92 (15) |
C3—C4—C5 | 123.61 (15) | C3A—C4A—C5A | 123.95 (15) |
C3—C4—Cl1 | 119.70 (12) | C3A—C4A—Cl1A | 119.72 (12) |
C5—C4—Cl1 | 116.67 (12) | C5A—C4A—Cl1A | 116.33 (13) |
C6—C5—C4 | 122.51 (15) | C6A—C5A—C4A | 121.17 (16) |
C6—C5—H5 | 118.7 | C6A—C5A—H5A | 119.4 |
C4—C5—H5 | 118.7 | C4A—C5A—H5A | 119.4 |
C5—C6—C1 | 117.39 (15) | C5A—C6A—C1A | 118.04 (14) |
C5—C6—H6 | 121.3 | C5A—C6A—H6A | 121.0 |
C1—C6—H6 | 121.3 | C1A—C6A—H6A | 121.0 |
N3—C11—N12 | 121.49 (13) | N3A—C11A—N12A | 122.80 (14) |
N3—C11—N15 | 129.87 (13) | N3A—C11A—N15A | 128.51 (14) |
N12—C11—N15 | 108.54 (13) | N12A—C11A—N15A | 108.58 (13) |
C11—N12—C13 | 110.81 (13) | C11A—N12A—C13A | 111.44 (13) |
C11—N12—H12 | 121.2 (14) | C11A—N12A—H12A | 121.2 (14) |
C13—N12—H12 | 125.4 (14) | C13A—N12A—H12A | 126.2 (14) |
N12—C13—C14 | 100.63 (12) | N12A—C13A—C14A | 100.95 (13) |
N12—C13—H13A | 111.6 | N12A—C13A—H13C | 111.6 |
C14—C13—H13A | 111.6 | C14A—C13A—H13C | 111.6 |
N12—C13—H13B | 111.6 | N12A—C13A—H13D | 111.6 |
C14—C13—H13B | 111.6 | C14A—C13A—H13D | 111.6 |
H13A—C13—H13B | 109.4 | H13C—C13A—H13D | 109.4 |
N15—C14—C13 | 100.79 (12) | N15A—C14A—C13A | 101.10 (13) |
N15—C14—H14A | 111.6 | N15A—C14A—H14C | 111.6 |
C13—C14—H14A | 111.6 | C13A—C14A—H14C | 111.6 |
N15—C14—H14B | 111.6 | N15A—C14A—H14D | 111.6 |
C13—C14—H14B | 111.6 | C13A—C14A—H14D | 111.6 |
H14A—C14—H14B | 109.4 | H14C—C14A—H14D | 109.4 |
C11—N15—C14 | 108.98 (12) | C11A—N15A—C14A | 108.15 (12) |
C11—N15—H15 | 120.3 (13) | C11A—N15A—H15A | 118.6 (14) |
C14—N15—H15 | 122.2 (13) | C14A—N15A—H15A | 118.3 (14) |
N2—S1—N1—C1 | 0.07 (12) | N2A—S1A—N1A—C1A | 0.52 (12) |
N1—S1—N2—C2 | −0.34 (12) | N1A—S1A—N2A—C2A | −0.73 (12) |
S1—N1—C1—C6 | −178.86 (13) | S1A—N1A—C1A—C6A | 178.74 (13) |
S1—N1—C1—C2 | 0.22 (15) | S1A—N1A—C1A—C2A | −0.16 (16) |
S1—N2—C2—C1 | 0.51 (15) | S1A—N2A—C2A—C3A | −176.93 (12) |
S1—N2—C2—C3 | −179.27 (11) | S1A—N2A—C2A—C1A | 0.71 (16) |
N1—C1—C2—N2 | −0.50 (18) | N1A—C1A—C2A—N2A | −0.38 (19) |
C6—C1—C2—N2 | 178.65 (13) | C6A—C1A—C2A—N2A | −179.35 (14) |
N1—C1—C2—C3 | 179.28 (13) | N1A—C1A—C2A—C3A | 177.35 (14) |
C6—C1—C2—C3 | −1.6 (2) | C6A—C1A—C2A—C3A | −1.6 (2) |
C11—N3—C3—C4 | −55.7 (2) | C11A—N3A—C3A—C4A | −67.4 (2) |
C11—N3—C3—C2 | 132.12 (15) | C11A—N3A—C3A—C2A | 117.81 (17) |
N2—C2—C3—N3 | −4.6 (2) | N2A—C2A—C3A—C4A | 179.47 (15) |
C1—C2—C3—N3 | 175.66 (13) | C1A—C2A—C3A—C4A | 2.0 (2) |
N2—C2—C3—C4 | −177.91 (14) | N2A—C2A—C3A—N3A | −5.2 (2) |
C1—C2—C3—C4 | 2.33 (19) | C1A—C2A—C3A—N3A | 177.38 (13) |
N3—C3—C4—C5 | −173.98 (14) | N3A—C3A—C4A—C5A | −175.72 (15) |
C2—C3—C4—C5 | −1.6 (2) | C2A—C3A—C4A—C5A | −0.7 (2) |
N3—C3—C4—Cl1 | 4.3 (2) | N3A—C3A—C4A—Cl1A | 5.2 (2) |
C2—C3—C4—Cl1 | 176.77 (10) | C2A—C3A—C4A—Cl1A | −179.80 (11) |
C3—C4—C5—C6 | −0.1 (2) | C3A—C4A—C5A—C6A | −1.1 (2) |
Cl1—C4—C5—C6 | −178.42 (13) | Cl1A—C4A—C5A—C6A | 178.04 (12) |
C4—C5—C6—C1 | 1.0 (2) | C4A—C5A—C6A—C1A | 1.5 (2) |
N1—C1—C6—C5 | 178.87 (15) | N1A—C1A—C6A—C5A | −179.02 (15) |
C2—C1—C6—C5 | −0.2 (2) | C2A—C1A—C6A—C5A | −0.2 (2) |
C3—N3—C11—N12 | 170.07 (14) | C3A—N3A—C11A—N12A | 171.20 (15) |
C3—N3—C11—N15 | −14.0 (2) | C3A—N3A—C11A—N15A | −12.9 (3) |
N3—C11—N12—C13 | 170.34 (14) | N3A—C11A—N12A—C13A | 170.28 (16) |
N15—C11—N12—C13 | −6.37 (17) | N15A—C11A—N12A—C13A | −6.31 (19) |
C11—N12—C13—C14 | 23.74 (16) | C11A—N12A—C13A—C14A | 23.24 (19) |
N12—C13—C14—N15 | −30.12 (14) | N12A—C13A—C14A—N15A | −29.64 (18) |
N3—C11—N15—C14 | 168.37 (15) | N3A—C11A—N15A—C14A | 168.77 (17) |
N12—C11—N15—C14 | −15.28 (17) | N12A—C11A—N15A—C14A | −14.89 (18) |
C13—C14—N15—C11 | 28.97 (16) | C13A—C14A—N15A—C11A | 28.04 (18) |
D—H···A | D—H | H···A | D···A | D—H···A |
N12—H12···N3A | 0.83 (2) | 2.18 (2) | 3.0006 (19) | 171 (2) |
N15—H15···N1i | 0.86 (1) | 2.40 (1) | 3.2078 (18) | 156 (2) |
N12A—H12A···N3 | 0.82 (2) | 2.04 (2) | 2.8489 (19) | 172 (2) |
N15A—H15A···N1Aii | 0.81 (2) | 2.40 (2) | 3.173 (2) | 158.7 (18) |
Symmetry codes: (i) −x+1, −y+2, −z+1; (ii) −x+3, −y+1, −z+2. |
C9H9ClN5S+·Cl− | F(000) = 592 |
Mr = 290.17 | Dx = 1.648 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: -P 2ybc | Cell parameters from 8524 reflections |
a = 8.5321 (7) Å | θ = 3.6–26.7° |
b = 14.0679 (9) Å | µ = 0.72 mm−1 |
c = 10.1266 (8) Å | T = 173 K |
β = 105.856 (6)° | Block, colourless |
V = 1169.24 (15) Å3 | 0.34 × 0.31 × 0.25 mm |
Z = 4 |
Stoe IPDS II two-circle diffractometer | 2383 independent reflections |
Radiation source: fine-focus sealed tube | 1907 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.076 |
ω scans | θmax = 26.4°, θmin = 3.6° |
Absorption correction: multi-scan (MULABS; Spek, 2009; Blessing, 1995) | h = −10→10 |
Tmin = 0.793, Tmax = 0.841 | k = −17→17 |
9834 measured reflections | l = −12→11 |
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)] = 0.032 | H atoms treated by a mixture of independent and constrained refinement |
wR(F2) = 0.080 | w = 1/[σ2(Fo2) + (0.0451P)2] where P = (Fo2 + 2Fc2)/3 |
S = 0.98 | (Δ/σ)max < 0.001 |
2383 reflections | Δρmax = 0.32 e Å−3 |
167 parameters | Δρmin = −0.24 e Å−3 |
0 restraints | Extinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4 |
Primary atom site location: structure-invariant direct methods | Extinction coefficient: 0.0090 (16) |
C9H9ClN5S+·Cl− | V = 1169.24 (15) Å3 |
Mr = 290.17 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 8.5321 (7) Å | µ = 0.72 mm−1 |
b = 14.0679 (9) Å | T = 173 K |
c = 10.1266 (8) Å | 0.34 × 0.31 × 0.25 mm |
β = 105.856 (6)° |
Stoe IPDS II two-circle diffractometer | 2383 independent reflections |
Absorption correction: multi-scan (MULABS; Spek, 2009; Blessing, 1995) | 1907 reflections with I > 2σ(I) |
Tmin = 0.793, Tmax = 0.841 | Rint = 0.076 |
9834 measured reflections |
R[F2 > 2σ(F2)] = 0.032 | 0 restraints |
wR(F2) = 0.080 | H atoms treated by a mixture of independent and constrained refinement |
S = 0.98 | Δρmax = 0.32 e Å−3 |
2383 reflections | Δρmin = −0.24 e Å−3 |
167 parameters |
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 | ||
Cl1 | 0.02346 (7) | 0.76066 (4) | 0.10240 (6) | 0.03510 (16) | |
Cl2 | 0.31350 (6) | 0.55662 (3) | 0.04050 (5) | 0.02433 (14) | |
S1 | 0.35864 (7) | 0.50130 (4) | 0.61467 (6) | 0.03430 (16) | |
N1 | 0.2089 (2) | 0.45298 (12) | 0.50161 (19) | 0.0306 (4) | |
N2 | 0.3675 (2) | 0.60402 (13) | 0.54601 (18) | 0.0289 (4) | |
N3 | 0.3045 (2) | 0.76637 (12) | 0.35886 (19) | 0.0245 (4) | |
H3 | 0.288 (3) | 0.806 (2) | 0.405 (3) | 0.031 (7)* | |
C1 | 0.1570 (2) | 0.51819 (14) | 0.4013 (2) | 0.0242 (4) | |
C2 | 0.2488 (2) | 0.60462 (13) | 0.4276 (2) | 0.0220 (4) | |
C3 | 0.2105 (2) | 0.68171 (13) | 0.3333 (2) | 0.0218 (4) | |
C4 | 0.0821 (2) | 0.66948 (13) | 0.2200 (2) | 0.0229 (4) | |
C5 | −0.0093 (2) | 0.58291 (14) | 0.1926 (2) | 0.0258 (4) | |
H5 | −0.0966 | 0.5775 | 0.1113 | 0.031* | |
C6 | 0.0266 (2) | 0.50853 (14) | 0.2808 (2) | 0.0253 (4) | |
H6 | −0.0343 | 0.4512 | 0.2621 | 0.030* | |
C11 | 0.4458 (2) | 0.77332 (13) | 0.32691 (19) | 0.0215 (4) | |
N12 | 0.5017 (2) | 0.70962 (12) | 0.25494 (18) | 0.0248 (4) | |
H12 | 0.444 (3) | 0.669 (2) | 0.212 (3) | 0.036 (7)* | |
C13 | 0.6536 (3) | 0.74216 (16) | 0.2301 (2) | 0.0328 (5) | |
H13A | 0.6410 | 0.7511 | 0.1308 | 0.039* | |
H13B | 0.7430 | 0.6964 | 0.2672 | 0.039* | |
C14 | 0.6863 (2) | 0.83720 (15) | 0.3069 (2) | 0.0284 (4) | |
H14A | 0.7913 | 0.8359 | 0.3792 | 0.034* | |
H14B | 0.6874 | 0.8904 | 0.2432 | 0.034* | |
N15 | 0.5488 (2) | 0.84520 (13) | 0.36646 (19) | 0.0267 (4) | |
H15 | 0.530 (3) | 0.8892 (18) | 0.404 (3) | 0.027 (6)* |
U11 | U22 | U33 | U12 | U13 | U23 | |
Cl1 | 0.0424 (3) | 0.0251 (3) | 0.0331 (3) | −0.0026 (2) | 0.0024 (2) | 0.0062 (2) |
Cl2 | 0.0299 (2) | 0.0167 (2) | 0.0272 (2) | −0.00025 (17) | 0.00912 (19) | 0.00016 (18) |
S1 | 0.0411 (3) | 0.0291 (3) | 0.0284 (3) | −0.0006 (2) | 0.0024 (2) | 0.0035 (2) |
N1 | 0.0377 (10) | 0.0236 (9) | 0.0299 (9) | −0.0021 (7) | 0.0080 (8) | 0.0021 (7) |
N2 | 0.0314 (9) | 0.0270 (9) | 0.0267 (9) | −0.0011 (7) | 0.0054 (7) | −0.0032 (7) |
N3 | 0.0294 (9) | 0.0176 (8) | 0.0288 (9) | −0.0042 (6) | 0.0117 (7) | −0.0073 (7) |
C1 | 0.0281 (10) | 0.0193 (9) | 0.0285 (10) | −0.0004 (7) | 0.0136 (8) | −0.0023 (8) |
C2 | 0.0233 (9) | 0.0220 (9) | 0.0220 (9) | −0.0006 (7) | 0.0086 (8) | −0.0032 (8) |
C3 | 0.0248 (9) | 0.0175 (9) | 0.0261 (10) | −0.0023 (7) | 0.0122 (8) | −0.0047 (7) |
C4 | 0.0271 (9) | 0.0192 (9) | 0.0240 (9) | 0.0006 (7) | 0.0095 (8) | 0.0011 (8) |
C5 | 0.0248 (10) | 0.0259 (10) | 0.0272 (10) | −0.0034 (8) | 0.0079 (8) | −0.0048 (8) |
C6 | 0.0256 (10) | 0.0214 (9) | 0.0303 (11) | −0.0067 (7) | 0.0100 (8) | −0.0057 (8) |
C11 | 0.0274 (10) | 0.0172 (9) | 0.0187 (8) | −0.0019 (7) | 0.0042 (7) | 0.0010 (7) |
N12 | 0.0258 (8) | 0.0200 (8) | 0.0289 (9) | −0.0046 (7) | 0.0079 (7) | −0.0053 (7) |
C13 | 0.0330 (11) | 0.0310 (11) | 0.0388 (12) | −0.0069 (9) | 0.0170 (10) | −0.0063 (10) |
C14 | 0.0253 (10) | 0.0274 (10) | 0.0313 (11) | −0.0056 (8) | 0.0057 (8) | 0.0006 (9) |
N15 | 0.0329 (9) | 0.0194 (8) | 0.0302 (9) | −0.0091 (7) | 0.0129 (8) | −0.0073 (7) |
Cl1—C4 | 1.728 (2) | C5—H5 | 0.9500 |
S1—N1 | 1.614 (2) | C6—H6 | 0.9500 |
S1—N2 | 1.6143 (19) | C11—N12 | 1.324 (2) |
N1—C1 | 1.351 (3) | C11—N15 | 1.328 (2) |
N2—C2 | 1.342 (3) | N12—C13 | 1.460 (3) |
N3—C11 | 1.334 (3) | N12—H12 | 0.80 (3) |
N3—C3 | 1.420 (2) | C13—C14 | 1.534 (3) |
N3—H3 | 0.76 (3) | C13—H13A | 0.9900 |
C1—C6 | 1.415 (3) | C13—H13B | 0.9900 |
C1—C2 | 1.431 (3) | C14—N15 | 1.463 (3) |
C2—C3 | 1.423 (3) | C14—H14A | 0.9900 |
C3—C4 | 1.363 (3) | C14—H14B | 0.9900 |
C4—C5 | 1.432 (3) | N15—H15 | 0.77 (3) |
C5—C6 | 1.355 (3) | ||
N1—S1—N2 | 101.10 (10) | C1—C6—H6 | 120.8 |
C1—N1—S1 | 106.32 (14) | N12—C11—N15 | 111.91 (17) |
C2—N2—S1 | 106.12 (14) | N12—C11—N3 | 124.71 (17) |
C11—N3—C3 | 121.34 (16) | N15—C11—N3 | 123.37 (18) |
C11—N3—H3 | 114.9 (19) | C11—N12—C13 | 110.69 (17) |
C3—N3—H3 | 122.4 (19) | C11—N12—H12 | 121.4 (19) |
N1—C1—C6 | 127.05 (18) | C13—N12—H12 | 125.1 (19) |
N1—C1—C2 | 112.71 (19) | N12—C13—C14 | 103.46 (16) |
C6—C1—C2 | 120.24 (18) | N12—C13—H13A | 111.1 |
N2—C2—C3 | 125.70 (17) | C14—C13—H13A | 111.1 |
N2—C2—C1 | 113.74 (17) | N12—C13—H13B | 111.1 |
C3—C2—C1 | 120.56 (18) | C14—C13—H13B | 111.1 |
C4—C3—N3 | 122.92 (18) | H13A—C13—H13B | 109.0 |
C4—C3—C2 | 116.95 (17) | N15—C14—C13 | 102.77 (15) |
N3—C3—C2 | 120.13 (17) | N15—C14—H14A | 111.2 |
C3—C4—C5 | 122.69 (18) | C13—C14—H14A | 111.2 |
C3—C4—Cl1 | 120.05 (15) | N15—C14—H14B | 111.2 |
C5—C4—Cl1 | 117.26 (16) | C13—C14—H14B | 111.2 |
C6—C5—C4 | 121.06 (19) | H14A—C14—H14B | 109.1 |
C6—C5—H5 | 119.5 | C11—N15—C14 | 110.89 (17) |
C4—C5—H5 | 119.5 | C11—N15—H15 | 123.7 (18) |
C5—C6—C1 | 118.49 (17) | C14—N15—H15 | 124.6 (18) |
C5—C6—H6 | 120.8 | ||
N2—S1—N1—C1 | −0.22 (15) | C2—C3—C4—C5 | −1.7 (3) |
N1—S1—N2—C2 | 0.20 (14) | N3—C3—C4—Cl1 | −2.0 (3) |
S1—N1—C1—C6 | −179.25 (16) | C2—C3—C4—Cl1 | 178.17 (13) |
S1—N1—C1—C2 | 0.17 (19) | C3—C4—C5—C6 | 1.1 (3) |
S1—N2—C2—C3 | 179.38 (15) | Cl1—C4—C5—C6 | −178.76 (15) |
S1—N2—C2—C1 | −0.12 (19) | C4—C5—C6—C1 | 0.1 (3) |
N1—C1—C2—N2 | 0.0 (2) | N1—C1—C6—C5 | 178.86 (18) |
C6—C1—C2—N2 | 179.43 (16) | C2—C1—C6—C5 | −0.5 (3) |
N1—C1—C2—C3 | −179.57 (16) | C3—N3—C11—N12 | 8.8 (3) |
C6—C1—C2—C3 | −0.1 (3) | C3—N3—C11—N15 | −169.93 (19) |
C11—N3—C3—C4 | −97.5 (2) | N15—C11—N12—C13 | −5.2 (2) |
C11—N3—C3—C2 | 82.3 (2) | N3—C11—N12—C13 | 175.9 (2) |
N2—C2—C3—C4 | −178.29 (17) | C11—N12—C13—C14 | 2.6 (2) |
C1—C2—C3—C4 | 1.2 (2) | N12—C13—C14—N15 | 0.6 (2) |
N2—C2—C3—N3 | 1.9 (3) | N12—C11—N15—C14 | 5.7 (2) |
C1—C2—C3—N3 | −178.62 (16) | N3—C11—N15—C14 | −175.45 (19) |
N3—C3—C4—C5 | 178.10 (17) | C13—C14—N15—C11 | −3.6 (2) |
D—H···A | D—H | H···A | D···A | D—H···A |
N3—H3···Cl2i | 0.76 (3) | 2.35 (3) | 3.0843 (18) | 163 (2) |
N12—H12···Cl2 | 0.80 (3) | 2.39 (3) | 3.1656 (18) | 164 (2) |
N15—H15···Cl2i | 0.77 (3) | 2.70 (2) | 3.3131 (19) | 138 (2) |
N15—H15···Cl2ii | 0.77 (3) | 2.69 (3) | 3.2419 (18) | 131 (2) |
Symmetry codes: (i) x, −y+3/2, z+1/2; (ii) −x+1, y+1/2, −z+1/2. |
Experimental details
(I) | (II) | |
Crystal data | ||
Chemical formula | C9H8ClN5S | C9H9ClN5S+·Cl− |
Mr | 253.71 | 290.17 |
Crystal system, space group | Triclinic, P1 | Monoclinic, P21/c |
Temperature (K) | 173 | 173 |
a, b, c (Å) | 7.5935 (6), 10.8712 (9), 12.8862 (12) | 8.5321 (7), 14.0679 (9), 10.1266 (8) |
α, β, γ (°) | 95.794 (7), 100.349 (7), 92.125 (7) | 90, 105.856 (6), 90 |
V (Å3) | 1039.45 (15) | 1169.24 (15) |
Z | 4 | 4 |
Radiation type | Mo Kα | Mo Kα |
µ (mm−1) | 0.55 | 0.72 |
Crystal size (mm) | 0.47 × 0.47 × 0.45 | 0.34 × 0.31 × 0.25 |
Data collection | ||
Diffractometer | Stoe IPDS II two-circle diffractometer | Stoe IPDS II two-circle diffractometer |
Absorption correction | Multi-scan (MULABS; Spek, 2009; Blessing, 1995) | Multi-scan (MULABS; Spek, 2009; Blessing, 1995) |
Tmin, Tmax | 0.784, 0.792 | 0.793, 0.841 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 9426, 3872, 3537 | 9834, 2383, 1907 |
Rint | 0.033 | 0.076 |
(sin θ/λ)max (Å−1) | 0.607 | 0.625 |
Refinement | ||
R[F2 > 2σ(F2)], wR(F2), S | 0.029, 0.076, 1.06 | 0.032, 0.080, 0.98 |
No. of reflections | 3872 | 2383 |
No. of parameters | 306 | 167 |
No. of restraints | 1 | 0 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.29, −0.27 | 0.32, −0.24 |
Computer programs: X-AREA (Stoe & Cie, 2001), SHELXS97 (Sheldrick, 2008), XP (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009) and publCIF (Westrip, 2010).
D—H···A | D—H | H···A | D···A | D—H···A |
N12—H12···N3A | 0.83 (2) | 2.18 (2) | 3.0006 (19) | 171 (2) |
N15—H15···N1i | 0.861 (9) | 2.401 (12) | 3.2078 (18) | 156.2 (17) |
N12A—H12A···N3 | 0.82 (2) | 2.04 (2) | 2.8489 (19) | 172 (2) |
N15A—H15A···N1Aii | 0.81 (2) | 2.40 (2) | 3.173 (2) | 158.7 (18) |
Symmetry codes: (i) −x+1, −y+2, −z+1; (ii) −x+3, −y+1, −z+2. |
D—H···A | D—H | H···A | D···A | D—H···A |
N3—H3···Cl2i | 0.76 (3) | 2.35 (3) | 3.0843 (18) | 163 (2) |
N12—H12···Cl2 | 0.80 (3) | 2.39 (3) | 3.1656 (18) | 164 (2) |
N15—H15···Cl2i | 0.77 (3) | 2.70 (2) | 3.3131 (19) | 138 (2) |
N15—H15···Cl2ii | 0.77 (3) | 2.69 (3) | 3.2419 (18) | 131 (2) |
Symmetry codes: (i) x, −y+3/2, z+1/2; (ii) −x+1, y+1/2, −z+1/2. |
(Ia) | (Ib) | (II) | |
Cl1—C4 | 1.7434 (16) | 1.7356 (17) | 1.728 (2) |
S1—N1 | 1.6196 (15) | 1.6190 (15) | 1.614 (2) |
S1—N2 | 1.6181 (13) | 1.6117 (15) | 1.6143 (19) |
N1—C1 | 1.347 (2) | 1.346 (2) | 1.351 (3) |
N2—C2 | 1.342 (2) | 1.343 (2) | 1.342 (3) |
N3—C3 | 1.3776 (19) | 1.388 (2) | 1.420 (2) |
N3—C11 | 1.302 (2) | 1.301 (2) | 1.334 (3) |
N12—C11 | 1.347 (2) | 1.3415 (19) | 1.324 (2) |
N12—C13 | 1.461 (2) | 1.440 (2) | 1.460 (3) |
N15—C11 | 1.3645 (19) | 1.380 (2) | 1.328 (2) |
N15—C14 | 1.4656 (19) | 1.462 (2) | 1.463 (3) |
C3—N3—C11 | 123.12 (12) | 119.65 (13) | 121.34 (16) |
The atoms in the second molecule of tizanidine are labelled with the suffix A. |
Diseases like brain or spinal cord injury (BCI and SCI), multiple sclerosis (MS), stroke and traumatic brain injuries are often associated with spasticity and involuntary muscle tension, stiffening, or contraction resulting in abnormal movement of extremities. These movements are caused by excessive motor activity resulting from injured upper motor neurons in the spinal cord sending no longer normal information from the brain to the nerve cells in the muscles. Over 12 million people are affected by spasticity worldwide (Kamen et al., 2008). A huge number of active pharmaceutical ingrediants (APIs) (e.g. tetracepam, flupirtin, baclofen, pridinol, tolperison, eperison, or methocarbamol) for the management of spasticity have been developed over the past few decades, each with its own receptor specificity giving it a unique pharmacological effect. One of these is tizanidine and its currently applied hydrochloride salt.
The free base of tizanidine, (I), was first synthesized by Neumann (1974) in the laboratories of Sandoz–Wander Inc., currently known as Novartis AG. It was patented as an antitremor and antirigor agent together with other 2,1,3-benzothiadiazole derivatives. It can exist in two possible tautomers (Scheme 2 shows the imidazolin-2-amine tautomer on the left and the imidazolidin-2-imine tautomer on the right), but only in the patent a capability of tautomerism from the amino–imidazoline (Ia) to the imino–imidazolidine (Ib) tautomer is mentioned. In the common literature for chemistry and pharmacology (e.g. Falbe & Regitz, 1992; O'Neil, 2006; Mutschler et al., 2008; Bruchhausen et al., 1994; Aktories et al., 2009) and in all related publications only the amino–imidazoline tautomer is mentioned. Also the latest structure determination from single-crystal diffraction data by John et al. (2011) claimed that this tautomer would exist in the solid state. In this context, a recent paper (Cruz-Cabeza & Groom, 2011) reporting on wrong tautomeric assignments in published structures is relevant.
To date the most common and orally administered salt form of tizanidine is its hydrochloride salt, (II), marketed by Novartis AG under the registered trade name SirdaludTM or ZanaflexTM and approved by the US Food and Drug Administration (FDA) in November 1996 for use in adults for spasticity. Tizanidine hydrochloride has been shown to act as an α2-adrenergic agonist (Turski et al., 1986; Kameyama et al., 1986). Its mechanism of action is currently under investigation and has not been fully clarified, but it is believed that the pharmacodynamic effects of tizanidine are linked to its α2-adrenergic agonist properties, albeit its imidazolidine receptor binding may play a role (Bes et al., 1988; Eyssette et al., 1988; Muramatsu & Kigoshi, 1992; Coward, 1994; Milanov & Georgiev, 1994; Landau, 1995; Wagstaff & Bryson, 1997; Mirbagheri et al., 2010; Kaddar et al., 2011).
Polymorph screening on the hydrochloride salt of tizanidine was performed by crystallizing the compound from a variety of different solvents and using various methods. The crystallization experiments resulted in single crystals suitable for X-ray diffraction of the solvent-free compounds (I) and (II). New polymorphs or pseudopolymorphs were not obtained.
Although the free base has already been published, a redetermination was necessary to clarify its tautomeric form in the solid state. Additionally 1H NMR studies were performed to investigate the tautomeric form in the liquid state to give additional impulse to the investigation of the mode of action of tizanidine as a muscle relaxant and the body's response to them during therapy of e.g. multiple sclerosis (MS).
Tizanidine (Fig. 1) crystallizes in P1 with two almost identical molecules in the asymmetric unit (r.m.s. deviation = 0.179 Å for all non-H atoms). Bond lengths in the two molecules show only insignificant differences (see Table 5). Just the acyclic torsion angles differ slightly in both molecules [C4—C3—N3—C11 = -55.7 (2)°, C4A—C3A—N3A—C11A = -67.4 (2)°, C3—N3—C11—N15 = -14.0 (2)° and C3A—N3A—C11A—N15A = -12.9 (3)°]. The molecules are connected by N—H···N hydrogen bonds forming chains running along [211] (Fig. 2). The structure of tizanidine has already been published (John et al., 2011). However, these authors have misplaced the H atoms at two N atoms. Instead of two protonated N atoms in the imidazolidine ring, they have placed only one H atom at one of the imidazolidine N atoms and the other one on the bridging N atom. However, their data show unequivocally that: (i) the bond from the imidazolidine C atom to the bridging N atom is a double bond [1.290 (2) and 1.296 (2) Å]; (ii) in the difference map (Fig. 3) there is no peak indicating an H atom at the bridging N atom; (iii) there are peaks in the difference map indicating that both imidazolidine N atoms are protonated. Additionally a comparison with another ten up-to-date known solvent-free derivatives of (I) in the CSD [Cambridge Structural Database (CSD; Allen, 2002)] revealed that all of them show the imino–imidazolidine tautomer (Ib) [CSD refcode ALALEF (Saczewski et al., 2011), GOLNIE (Elssfah et al., 1999a), HIGGOU (Begum & Vasundhara, 2007), HODQOG (Elssfah et al., 1999b), KIBRAO (Koch et al., 1990), LUVPOH (Varga et al., 2003), QIBBOS (Isobe et al., 2000, VOVCUE01 (Schröder et al., 2003) XERHOS (Kornicka et al., 2006) and ZAYQOF: Dupont et al., 1995)]. Finally, 1H NMR measurements show that (for the –CH2 group), instead of two different signals, as would be expected for the asymmetrical 2-amino–imidazoline tautomer (Ia), only one signal appeared, indicating the symmetrical 2-imino–imidazolidine tautomer (Ib). This proves that the 2-imino–imidazolidine tautomer exists also in the liquid state. As a result, the structure of John et al. (2011) has to be revised.
Tizanidine hydrochloride (Fig. 4) crystallizes with a tizanidium cation (which is protonated at the bridging N atom) and a chloride anion in the asymmetric unit. The only significant structural difference between tizanidine and the protonated molecule are the N—C bond lengths to the bridging N atom (Table 5) which are elongated in the protonated molecule. A least-squares fit of the molecular structures of the two molecules in the asymmetric unit of tizanidine and the tizanidium anion is shown in Fig. 5. The cation and neutral molecule differ in the dihedral angle between the imidazolidine and benzothiadiazole moieties [dihedral angles: 53.89 (4)/67.33 (5) versus. 89.68 (6)°]. Whereas the mean value of the dihedral angle is approximately 60° in the neutral molecule, the ring systems are almost perpendicular in the protonated molecule. Whereas the neutral tizanidine molecules in the crystal are only connected by N—H···N hydrogen bonds, the cations in the structure of tizanidine hydrochloride are not directly connected to each other, but via N—H···Cl hydrogen bonds (Fig. 6). Each Cl anion acts as an acceptor for four N—H hydrogen-bond donors, two of which are from the same cation and the remaining two from two further cations. One of the imidazolidine N—H donors forms a bifurcated hydrogen bond to two different chloride anions, whereas the other two N—H groups are bonded to only one chloride ion each. The hydrogen-bond network leads to a layer parallel to (100).
Although no further polymorph or pseudopolymorph could be obtained from the initial polymorph screening, but the tautomerism of the free base of tizanidine in solid and liquid state could be revealed. The results presented here may give further guiding principles for further examinations on derivatives of tizanidine for developments in this field of study. More to the point, it could support studies dealing with the mechanism of action of tizanidine.