Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270111024280/ga3166sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S0108270111024280/ga3166Isup2.hkl |
CCDC reference: 842147
Sulfamethazine, theophylline and methanol were purchased from Sigma–Aldrich (Milwaukee, Wisconsin, USA) and used without further purification. A mixture of sulfamethazine (0.056 g, 0.2 mmol) and theophylline (0.018 g, 0.1 mmol) was stirred in methanol (50 ml) with slight warming until dissolution was complete. The filtered solution was kept in a fume hood at room temperature and after several days yellow crystals of (I) were obtained.
The relative stability of the two tautomers, SLET and SHET, was calculated using DFT methods with the program GAUSSIAN03 (Frisch et al., 2003). The X-ray molecular geometries for SLET and SHET were energy minimized in the gas phase at the B3LYP/6-311++G** level of theory, and the torsion angles were constrained to the experimental values. The energy-minimized molecular geometries were then used for a single-point energy calculation at the same level of theory but using a polarizable continuum model (Cossi et al., 2002) with a dielectric constant ε = 3, typical for organic crystals (Cooper et al., 2008). With this simple model, we hoped to take into account the effect of the crystalline environment on the relative stability of the two tautomers.
For the calculation of the intermolecular interactions, we used the PIXEL method as part of the OPIX program developed by Gavezzotti (2003, 2007). We calculated the intermolecular interaction energies of the SLET–THEO and SHET–THEO dimers, as observed in the crystal structure (see Fig. 4). The geometry of the heavy atoms in the two dimers was taken from the crystal structure and H-atom positions were normalized using the program Mercury (Version 2.2; Macrae et al., 2008). Electron densities were calculated using GAUSSIAN03 at the MP2/6-31G** level of theory. The molecular electron density for each molecule was output in a three-dimensional grid with steps of 0.08 Å.
Aromatic H atoms were positioned geometrically and refined using a riding model, with C—H = 0.93 Å and with Uiso(H) = 1.2 Ueq(C). Methyl H atoms were idealized with tetrahedral angles and refined as a rotating group, with C—H = 0.96 Å and with Uiso(H) = 1.5Ueq(C). Three of the methyl groups were refined as idealized disordered methyl groups. The N-bound H atoms were located in a difference map and allowed to refine, with Uiso(H) = 1.2Ueq(C).
Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).
2C12H14N4O2S·C7H8N4O2 | F(000) = 1544 |
Mr = 736.84 | Dx = 1.370 Mg m−3 |
Monoclinic, P21/c | Mo Kα radiation, λ = 0.71073 Å |
Hall symbol: -P 2ybc | Cell parameters from 9971 reflections |
a = 15.8827 (6) Å | θ = 2.6–26.6° |
b = 8.1004 (3) Å | µ = 0.21 mm−1 |
c = 27.7913 (10) Å | T = 293 K |
β = 91.835 (2)° | Block, colourless |
V = 3573.7 (2) Å3 | 0.51 × 0.32 × 0.21 mm |
Z = 4 |
Bruker APEXII CCD area-detector diffractometer | 7364 independent reflections |
Radiation source: fine-focus sealed tube | 5968 reflections with I > 2σ(I) |
Graphite monochromator | Rint = 0.024 |
ϕ and ω scans | θmax = 26.7°, θmin = 1.9° |
Absorption correction: multi-scan (SADABS; Bruker, 2009) | h = −20→20 |
Tmin = 0.900, Tmax = 0.957 | k = −10→10 |
46924 measured reflections | l = −35→34 |
Refinement on F2 | Primary atom site location: structure-invariant direct methods |
Least-squares matrix: full | Secondary atom site location: difference Fourier map |
R[F2 > 2σ(F2)] = 0.040 | Hydrogen site location: inferred from neighbouring sites |
wR(F2) = 0.110 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.03 | w = 1/[σ2(Fo2) + (0.0504P)2 + 1.5617P] where P = (Fo2 + 2Fc2)/3 |
7364 reflections | (Δ/σ)max < 0.001 |
487 parameters | Δρmax = 0.29 e Å−3 |
2 restraints | Δρmin = −0.41 e Å−3 |
2C12H14N4O2S·C7H8N4O2 | V = 3573.7 (2) Å3 |
Mr = 736.84 | Z = 4 |
Monoclinic, P21/c | Mo Kα radiation |
a = 15.8827 (6) Å | µ = 0.21 mm−1 |
b = 8.1004 (3) Å | T = 293 K |
c = 27.7913 (10) Å | 0.51 × 0.32 × 0.21 mm |
β = 91.835 (2)° |
Bruker APEXII CCD area-detector diffractometer | 7364 independent reflections |
Absorption correction: multi-scan (SADABS; Bruker, 2009) | 5968 reflections with I > 2σ(I) |
Tmin = 0.900, Tmax = 0.957 | Rint = 0.024 |
46924 measured reflections |
R[F2 > 2σ(F2)] = 0.040 | 2 restraints |
wR(F2) = 0.110 | H atoms treated by a mixture of independent and constrained refinement |
S = 1.03 | Δρmax = 0.29 e Å−3 |
7364 reflections | Δρmin = −0.41 e Å−3 |
487 parameters |
Experimental. 2 refl'ns behind beamstop (1 0 0;0 0 2) 1 refl'n omitted as partially blocked (9 0 0) missing cusp of data due to crystal mount orientation |
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 | Occ. (<1) | |
N1 | 0.49372 (12) | −0.1004 (2) | 0.14563 (8) | 0.0622 (5) | |
H1A | 0.5357 (14) | −0.093 (3) | 0.1668 (8) | 0.075* | |
H1B | 0.4610 (15) | −0.187 (3) | 0.1451 (9) | 0.075* | |
C2 | 0.45032 (11) | 0.0457 (2) | 0.13886 (7) | 0.0428 (4) | |
C3 | 0.48847 (11) | 0.1971 (2) | 0.14993 (7) | 0.0440 (4) | |
H3A | 0.5433 | 0.1993 | 0.1627 | 0.053* | |
C4 | 0.44564 (11) | 0.3433 (2) | 0.14204 (7) | 0.0418 (4) | |
H4A | 0.4721 | 0.4434 | 0.1489 | 0.050* | |
C5 | 0.36320 (11) | 0.3416 (2) | 0.12385 (6) | 0.0368 (4) | |
C6 | 0.32469 (12) | 0.1920 (2) | 0.11234 (7) | 0.0449 (4) | |
H6A | 0.2696 | 0.1903 | 0.1000 | 0.054* | |
C7 | 0.36822 (12) | 0.0465 (2) | 0.11916 (8) | 0.0483 (5) | |
H7A | 0.3426 | −0.0529 | 0.1105 | 0.058* | |
S8 | 0.30317 (3) | 0.52424 (6) | 0.122565 (16) | 0.03892 (12) | |
O9 | 0.22004 (8) | 0.48197 (18) | 0.13759 (5) | 0.0519 (4) | |
O10 | 0.34959 (9) | 0.64376 (16) | 0.15182 (5) | 0.0475 (3) | |
N11 | 0.28653 (9) | 0.5924 (2) | 0.06838 (5) | 0.0412 (4) | |
C12 | 0.35042 (11) | 0.6519 (2) | 0.04341 (6) | 0.0366 (4) | |
N13 | 0.43223 (9) | 0.63226 (19) | 0.05564 (6) | 0.0415 (4) | |
C14 | 0.48909 (11) | 0.6974 (2) | 0.02669 (7) | 0.0433 (4) | |
C15 | 0.46666 (12) | 0.7852 (3) | −0.01474 (7) | 0.0465 (5) | |
H15A | 0.5078 | 0.8293 | −0.0340 | 0.056* | |
C16 | 0.38302 (12) | 0.8056 (2) | −0.02668 (7) | 0.0412 (4) | |
N17 | 0.32675 (9) | 0.7365 (2) | 0.00264 (5) | 0.0385 (3) | |
H17A | 0.2727 (13) | 0.745 (3) | −0.0046 (7) | 0.046* | |
C18 | 0.57918 (12) | 0.6692 (3) | 0.04168 (9) | 0.0594 (6) | |
H18A | 0.5927 | 0.7326 | 0.0701 | 0.089* | |
H18B | 0.6148 | 0.7027 | 0.0162 | 0.089* | |
H18C | 0.5879 | 0.5541 | 0.0484 | 0.089* | |
C19 | 0.34865 (14) | 0.8958 (3) | −0.06948 (7) | 0.0530 (5) | |
H19A | 0.3274 | 0.8180 | −0.0929 | 0.079* | |
H19B | 0.3925 | 0.9605 | −0.0832 | 0.079* | |
H19C | 0.3038 | 0.9671 | −0.0600 | 0.079* | |
N21 | 0.68580 (16) | 1.1259 (3) | 0.24229 (7) | 0.0668 (6) | |
H21A | 0.7065 (16) | 1.217 (3) | 0.2315 (9) | 0.080* | |
H21B | 0.6680 (16) | 1.124 (3) | 0.2714 (8) | 0.080* | |
C22 | 0.69949 (13) | 0.9810 (3) | 0.21953 (7) | 0.0462 (5) | |
C23 | 0.66990 (13) | 0.8309 (3) | 0.23768 (7) | 0.0510 (5) | |
H23A | 0.6404 | 0.8304 | 0.2661 | 0.061* | |
C24 | 0.68375 (12) | 0.6847 (3) | 0.21424 (7) | 0.0468 (5) | |
H24A | 0.6640 | 0.5864 | 0.2270 | 0.056* | |
C25 | 0.72715 (11) | 0.6830 (2) | 0.17160 (6) | 0.0385 (4) | |
C26 | 0.75680 (13) | 0.8309 (2) | 0.15330 (7) | 0.0469 (5) | |
H26A | 0.7860 | 0.8307 | 0.1248 | 0.056* | |
C27 | 0.74367 (14) | 0.9768 (3) | 0.17659 (7) | 0.0501 (5) | |
H27A | 0.7643 | 1.0744 | 0.1639 | 0.060* | |
S28 | 0.74522 (3) | 0.50000 (6) | 0.140906 (17) | 0.03969 (12) | |
O29 | 0.73683 (8) | 0.52836 (18) | 0.09009 (5) | 0.0496 (3) | |
O30 | 0.69597 (9) | 0.37243 (17) | 0.16176 (5) | 0.0523 (4) | |
N31 | 0.84563 (10) | 0.4548 (2) | 0.14813 (6) | 0.0452 (4) | |
H31A | 0.8754 (14) | 0.481 (3) | 0.1252 (8) | 0.054* | |
C32 | 0.88799 (11) | 0.4232 (2) | 0.19218 (7) | 0.0393 (4) | |
N33 | 0.84206 (10) | 0.4158 (2) | 0.23120 (6) | 0.0455 (4) | |
C34 | 0.88552 (14) | 0.3857 (3) | 0.27267 (7) | 0.0503 (5) | |
C35 | 0.97150 (14) | 0.3617 (3) | 0.27308 (8) | 0.0588 (6) | |
H35A | 1.0011 | 0.3396 | 0.3018 | 0.071* | |
C36 | 1.01314 (13) | 0.3710 (3) | 0.23022 (8) | 0.0527 (5) | |
N37 | 0.97080 (10) | 0.4043 (2) | 0.18862 (6) | 0.0452 (4) | |
C38 | 0.83545 (16) | 0.3830 (4) | 0.31759 (8) | 0.0732 (7) | |
H38A | 0.7868 | 0.4524 | 0.3133 | 0.110* | 0.50 |
H38B | 0.8697 | 0.4230 | 0.3442 | 0.110* | 0.50 |
H38C | 0.8179 | 0.2720 | 0.3240 | 0.110* | 0.50 |
H38D | 0.8628 | 0.3126 | 0.3411 | 0.110* | 0.50 |
H38E | 0.7799 | 0.3419 | 0.3101 | 0.110* | 0.50 |
H38F | 0.8317 | 0.4929 | 0.3303 | 0.110* | 0.50 |
C39 | 1.10624 (14) | 0.3471 (4) | 0.22711 (10) | 0.0797 (8) | |
H39A | 1.1184 | 0.2954 | 0.1970 | 0.119* | |
H39B | 1.1261 | 0.2783 | 0.2532 | 0.119* | |
H39C | 1.1339 | 0.4524 | 0.2291 | 0.119* | |
O41 | 0.16388 (8) | 0.8109 (2) | −0.03003 (5) | 0.0561 (4) | |
C42 | 0.08954 (11) | 0.7884 (2) | −0.01985 (7) | 0.0401 (4) | |
N43 | 0.02429 (9) | 0.84693 (19) | −0.05003 (5) | 0.0408 (4) | |
C44 | 0.04633 (14) | 0.9276 (3) | −0.09525 (7) | 0.0549 (5) | |
H44A | 0.1041 | 0.9627 | −0.0931 | 0.082* | 0.50 |
H44B | 0.0106 | 1.0217 | −0.1008 | 0.082* | 0.50 |
H44C | 0.0388 | 0.8510 | −0.1214 | 0.082* | 0.50 |
H44D | −0.0018 | 0.9275 | −0.1171 | 0.082* | 0.50 |
H44E | 0.0917 | 0.8686 | −0.1094 | 0.082* | 0.50 |
H44F | 0.0635 | 1.0392 | −0.0888 | 0.082* | 0.50 |
C45 | −0.06258 (12) | 0.8313 (2) | −0.04219 (7) | 0.0432 (4) | |
O46 | −0.11434 (9) | 0.8886 (2) | −0.07077 (5) | 0.0615 (4) | |
N47 | −0.08506 (9) | 0.7493 (2) | −0.00133 (5) | 0.0424 (4) | |
C48 | −0.17489 (12) | 0.7296 (3) | 0.00750 (8) | 0.0579 (6) | |
H48A | −0.1975 | 0.8326 | 0.0183 | 0.087* | 0.50 |
H48B | −0.1822 | 0.6469 | 0.0318 | 0.087* | 0.50 |
H48C | −0.2040 | 0.6964 | −0.0217 | 0.087* | 0.50 |
H48D | −0.1916 | 0.6180 | 0.0006 | 0.087* | 0.50 |
H48E | −0.2069 | 0.8037 | −0.0129 | 0.087* | 0.50 |
H48F | −0.1851 | 0.7542 | 0.0406 | 0.087* | 0.50 |
C49 | −0.02381 (11) | 0.6863 (2) | 0.02975 (6) | 0.0375 (4) | |
N50 | −0.03560 (9) | 0.6016 (2) | 0.07120 (6) | 0.0437 (4) | |
C51 | 0.04292 (12) | 0.5703 (3) | 0.08744 (7) | 0.0450 (4) | |
H51A | 0.0551 | 0.5124 | 0.1157 | 0.054* | |
N52 | 0.10207 (10) | 0.6299 (2) | 0.05925 (6) | 0.0429 (4) | |
H52A | 0.1558 (14) | 0.617 (3) | 0.0648 (8) | 0.052* | |
C53 | 0.06002 (11) | 0.7066 (2) | 0.02107 (6) | 0.0380 (4) |
U11 | U22 | U33 | U12 | U13 | U23 | |
N1 | 0.0518 (11) | 0.0418 (10) | 0.0921 (16) | 0.0051 (9) | −0.0099 (10) | 0.0058 (10) |
C2 | 0.0394 (10) | 0.0410 (10) | 0.0481 (11) | 0.0030 (8) | 0.0030 (8) | 0.0053 (8) |
C3 | 0.0323 (9) | 0.0466 (11) | 0.0529 (11) | −0.0001 (8) | −0.0029 (8) | 0.0006 (9) |
C4 | 0.0369 (9) | 0.0399 (10) | 0.0486 (11) | −0.0041 (8) | −0.0010 (8) | −0.0007 (8) |
C5 | 0.0365 (9) | 0.0374 (9) | 0.0366 (9) | 0.0006 (7) | 0.0007 (7) | 0.0045 (7) |
C6 | 0.0373 (9) | 0.0445 (11) | 0.0525 (11) | −0.0039 (8) | −0.0062 (8) | 0.0043 (9) |
C7 | 0.0437 (10) | 0.0379 (10) | 0.0628 (13) | −0.0062 (8) | −0.0039 (9) | 0.0011 (9) |
S8 | 0.0374 (2) | 0.0391 (2) | 0.0405 (2) | 0.00343 (19) | 0.00406 (18) | 0.00590 (19) |
O9 | 0.0421 (7) | 0.0564 (9) | 0.0578 (9) | 0.0051 (6) | 0.0130 (6) | 0.0141 (7) |
O10 | 0.0572 (8) | 0.0409 (7) | 0.0445 (7) | 0.0018 (6) | 0.0016 (6) | −0.0017 (6) |
N11 | 0.0346 (8) | 0.0460 (9) | 0.0428 (8) | 0.0003 (7) | −0.0006 (6) | 0.0095 (7) |
C12 | 0.0362 (9) | 0.0347 (9) | 0.0389 (9) | 0.0018 (7) | −0.0003 (7) | −0.0008 (7) |
N13 | 0.0358 (8) | 0.0438 (9) | 0.0446 (9) | 0.0019 (7) | −0.0013 (7) | 0.0010 (7) |
C14 | 0.0354 (9) | 0.0434 (10) | 0.0511 (11) | −0.0020 (8) | 0.0013 (8) | −0.0094 (9) |
C15 | 0.0394 (10) | 0.0510 (12) | 0.0494 (11) | −0.0067 (9) | 0.0076 (8) | −0.0005 (9) |
C16 | 0.0444 (10) | 0.0397 (10) | 0.0398 (10) | −0.0037 (8) | 0.0064 (8) | −0.0023 (8) |
N17 | 0.0333 (7) | 0.0434 (9) | 0.0388 (8) | 0.0013 (7) | −0.0002 (6) | 0.0051 (7) |
C18 | 0.0372 (10) | 0.0684 (15) | 0.0722 (15) | −0.0001 (10) | −0.0032 (10) | −0.0085 (12) |
C19 | 0.0562 (12) | 0.0580 (13) | 0.0450 (11) | −0.0036 (10) | 0.0040 (9) | 0.0112 (10) |
N21 | 0.1073 (18) | 0.0482 (11) | 0.0456 (11) | 0.0021 (11) | 0.0128 (11) | 0.0007 (9) |
C22 | 0.0550 (11) | 0.0461 (11) | 0.0371 (10) | 0.0050 (9) | −0.0044 (8) | 0.0036 (8) |
C23 | 0.0551 (12) | 0.0568 (13) | 0.0416 (11) | 0.0024 (10) | 0.0110 (9) | 0.0057 (9) |
C24 | 0.0461 (11) | 0.0457 (11) | 0.0491 (11) | −0.0047 (9) | 0.0077 (9) | 0.0087 (9) |
C25 | 0.0358 (9) | 0.0407 (10) | 0.0390 (9) | 0.0021 (8) | −0.0014 (7) | 0.0058 (8) |
C26 | 0.0574 (12) | 0.0453 (11) | 0.0385 (10) | 0.0003 (9) | 0.0077 (9) | 0.0076 (8) |
C27 | 0.0673 (13) | 0.0412 (11) | 0.0418 (11) | −0.0034 (10) | 0.0029 (9) | 0.0098 (8) |
S28 | 0.0361 (2) | 0.0413 (3) | 0.0412 (2) | −0.00011 (19) | −0.00575 (18) | 0.00286 (19) |
O29 | 0.0455 (7) | 0.0608 (9) | 0.0417 (7) | 0.0029 (7) | −0.0102 (6) | 0.0014 (6) |
O30 | 0.0516 (8) | 0.0442 (8) | 0.0607 (9) | −0.0105 (6) | −0.0021 (7) | 0.0026 (7) |
N31 | 0.0393 (8) | 0.0593 (11) | 0.0368 (8) | 0.0094 (8) | −0.0020 (7) | 0.0053 (7) |
C32 | 0.0424 (10) | 0.0361 (10) | 0.0390 (10) | 0.0026 (8) | −0.0047 (8) | 0.0025 (8) |
N33 | 0.0446 (9) | 0.0513 (10) | 0.0404 (9) | −0.0007 (8) | −0.0012 (7) | 0.0039 (7) |
C34 | 0.0569 (12) | 0.0532 (12) | 0.0403 (11) | −0.0106 (10) | −0.0036 (9) | 0.0058 (9) |
C35 | 0.0566 (13) | 0.0746 (16) | 0.0442 (12) | −0.0102 (11) | −0.0138 (10) | 0.0162 (11) |
C36 | 0.0468 (11) | 0.0569 (13) | 0.0538 (12) | −0.0028 (10) | −0.0103 (9) | 0.0135 (10) |
N37 | 0.0404 (8) | 0.0509 (10) | 0.0438 (9) | 0.0032 (7) | −0.0044 (7) | 0.0069 (7) |
C38 | 0.0736 (16) | 0.102 (2) | 0.0441 (12) | −0.0199 (15) | 0.0026 (11) | 0.0076 (13) |
C39 | 0.0443 (12) | 0.116 (2) | 0.0776 (18) | 0.0028 (14) | −0.0124 (12) | 0.0322 (16) |
O41 | 0.0367 (7) | 0.0736 (10) | 0.0582 (9) | 0.0025 (7) | 0.0051 (6) | 0.0165 (8) |
C42 | 0.0388 (9) | 0.0394 (10) | 0.0420 (10) | 0.0024 (8) | 0.0005 (8) | −0.0004 (8) |
N43 | 0.0395 (8) | 0.0423 (9) | 0.0406 (8) | 0.0000 (7) | 0.0000 (7) | 0.0029 (7) |
C44 | 0.0571 (12) | 0.0623 (14) | 0.0451 (11) | 0.0004 (11) | 0.0016 (9) | 0.0112 (10) |
C45 | 0.0404 (10) | 0.0454 (11) | 0.0434 (10) | 0.0003 (8) | −0.0053 (8) | −0.0014 (8) |
O46 | 0.0476 (8) | 0.0788 (11) | 0.0572 (9) | 0.0037 (8) | −0.0119 (7) | 0.0182 (8) |
N47 | 0.0330 (7) | 0.0514 (10) | 0.0425 (9) | −0.0003 (7) | −0.0027 (6) | 0.0026 (7) |
C48 | 0.0349 (10) | 0.0817 (16) | 0.0569 (13) | −0.0015 (10) | −0.0027 (9) | 0.0095 (12) |
C49 | 0.0365 (9) | 0.0379 (10) | 0.0380 (9) | −0.0011 (7) | −0.0020 (7) | −0.0035 (7) |
N50 | 0.0383 (8) | 0.0515 (10) | 0.0412 (9) | −0.0011 (7) | −0.0007 (7) | 0.0046 (7) |
C51 | 0.0421 (10) | 0.0499 (11) | 0.0428 (10) | −0.0003 (9) | −0.0018 (8) | 0.0057 (9) |
N52 | 0.0341 (8) | 0.0504 (10) | 0.0441 (9) | 0.0027 (7) | −0.0021 (7) | 0.0057 (7) |
C53 | 0.0345 (9) | 0.0386 (10) | 0.0408 (10) | 0.0015 (7) | −0.0026 (7) | −0.0006 (8) |
N1—C2 | 1.380 (3) | S28—N31 | 1.6424 (16) |
N1—H1A | 0.877 (19) | N31—C32 | 1.401 (2) |
N1—H1B | 0.873 (19) | N31—H31A | 0.83 (2) |
C2—C3 | 1.398 (3) | C32—N33 | 1.328 (2) |
C2—C7 | 1.398 (3) | C32—N37 | 1.331 (2) |
C3—C4 | 1.380 (3) | N33—C34 | 1.347 (3) |
C3—H3A | 0.9300 | C34—C35 | 1.379 (3) |
C4—C5 | 1.389 (2) | C34—C38 | 1.502 (3) |
C4—H4A | 0.9300 | C35—C36 | 1.383 (3) |
C5—C6 | 1.390 (3) | C35—H35A | 0.9300 |
C5—S8 | 1.7597 (18) | C36—N37 | 1.346 (2) |
C6—C7 | 1.377 (3) | C36—C39 | 1.496 (3) |
C6—H6A | 0.9300 | C38—H38A | 0.9600 |
C7—H7A | 0.9300 | C38—H38B | 0.9600 |
S8—O9 | 1.4387 (13) | C38—H38C | 0.9600 |
S8—O10 | 1.4504 (14) | C38—H38D | 0.9600 |
S8—N11 | 1.6176 (15) | C38—H38E | 0.9600 |
N11—C12 | 1.338 (2) | C38—H38F | 0.9600 |
C12—N13 | 1.342 (2) | C39—H39A | 0.9600 |
C12—N17 | 1.366 (2) | C39—H39B | 0.9600 |
N13—C14 | 1.337 (2) | C39—H39C | 0.9600 |
C14—C15 | 1.390 (3) | O41—C42 | 1.237 (2) |
C14—C18 | 1.495 (3) | C42—N43 | 1.395 (2) |
C15—C16 | 1.369 (3) | C42—C53 | 1.409 (3) |
C15—H15A | 0.9300 | N43—C45 | 1.409 (2) |
C16—N17 | 1.350 (2) | N43—C44 | 1.469 (2) |
C16—C19 | 1.485 (3) | C44—H44A | 0.9600 |
N17—H17A | 0.88 (2) | C44—H44B | 0.9600 |
C18—H18A | 0.9600 | C44—H44C | 0.9600 |
C18—H18B | 0.9600 | C44—H44D | 0.9600 |
C18—H18C | 0.9600 | C44—H44E | 0.9600 |
C19—H19A | 0.9600 | C44—H44F | 0.9600 |
C19—H19B | 0.9600 | C45—O46 | 1.217 (2) |
C19—H19C | 0.9600 | C45—N47 | 1.373 (2) |
N21—C22 | 1.354 (3) | N47—C49 | 1.378 (2) |
N21—H21A | 0.86 (2) | N47—C48 | 1.464 (2) |
N21—H21B | 0.87 (2) | C48—H48A | 0.9600 |
C22—C23 | 1.403 (3) | C48—H48B | 0.9600 |
C22—C27 | 1.404 (3) | C48—H48C | 0.9600 |
C23—C24 | 1.372 (3) | C48—H48D | 0.9600 |
C23—H23A | 0.9300 | C48—H48E | 0.9600 |
C24—C25 | 1.390 (3) | C48—H48F | 0.9600 |
C24—H24A | 0.9300 | C49—N50 | 1.359 (2) |
C25—C26 | 1.390 (3) | C49—C53 | 1.371 (2) |
C25—S28 | 1.7391 (19) | N50—C51 | 1.337 (2) |
C26—C27 | 1.366 (3) | C51—N52 | 1.333 (2) |
C26—H26A | 0.9300 | C51—H51A | 0.9300 |
C27—H27A | 0.9300 | N52—C53 | 1.383 (2) |
S28—O30 | 1.4298 (14) | N52—H52A | 0.87 (2) |
S28—O29 | 1.4329 (14) | ||
C2—N1—H1A | 113.5 (18) | N37—C36—C39 | 116.3 (2) |
C2—N1—H1B | 113.2 (17) | C35—C36—C39 | 122.9 (2) |
H1A—N1—H1B | 120 (3) | C32—N37—C36 | 115.27 (17) |
N1—C2—C3 | 120.76 (17) | C34—C38—H38A | 109.5 |
N1—C2—C7 | 120.87 (18) | C34—C38—H38B | 109.5 |
C3—C2—C7 | 118.33 (17) | H38A—C38—H38B | 109.5 |
C4—C3—C2 | 120.67 (17) | C34—C38—H38C | 109.5 |
C4—C3—H3A | 119.7 | H38A—C38—H38C | 109.5 |
C2—C3—H3A | 119.7 | H38B—C38—H38C | 109.5 |
C3—C4—C5 | 120.25 (17) | C34—C38—H38D | 109.5 |
C3—C4—H4A | 119.9 | H38A—C38—H38D | 141.1 |
C5—C4—H4A | 119.9 | H38B—C38—H38D | 56.3 |
C4—C5—C6 | 119.68 (17) | H38C—C38—H38D | 56.3 |
C4—C5—S8 | 120.20 (14) | C34—C38—H38E | 109.5 |
C6—C5—S8 | 119.61 (14) | H38A—C38—H38E | 56.3 |
C7—C6—C5 | 119.97 (17) | H38B—C38—H38E | 141.1 |
C7—C6—H6A | 120.0 | H38C—C38—H38E | 56.3 |
C5—C6—H6A | 120.0 | H38D—C38—H38E | 109.5 |
C6—C7—C2 | 121.04 (18) | C34—C38—H38F | 109.5 |
C6—C7—H7A | 119.5 | H38A—C38—H38F | 56.3 |
C2—C7—H7A | 119.5 | H38B—C38—H38F | 56.3 |
O9—S8—O10 | 116.80 (9) | H38C—C38—H38F | 141.1 |
O9—S8—N11 | 103.13 (8) | H38D—C38—H38F | 109.5 |
O10—S8—N11 | 111.05 (8) | H38E—C38—H38F | 109.5 |
O9—S8—C5 | 107.20 (8) | C36—C39—H39A | 109.5 |
O10—S8—C5 | 106.53 (8) | C36—C39—H39B | 109.5 |
N11—S8—C5 | 112.21 (8) | H39A—C39—H39B | 109.5 |
C12—N11—S8 | 120.13 (13) | C36—C39—H39C | 109.5 |
N11—C12—N13 | 124.77 (16) | H39A—C39—H39C | 109.5 |
N11—C12—N17 | 114.70 (15) | H39B—C39—H39C | 109.5 |
N13—C12—N17 | 120.53 (16) | O41—C42—N43 | 120.57 (17) |
C14—N13—C12 | 117.90 (16) | O41—C42—C53 | 126.79 (17) |
N13—C14—C15 | 122.69 (17) | N43—C42—C53 | 112.64 (15) |
N13—C14—C18 | 115.52 (18) | C42—N43—C45 | 126.06 (15) |
C15—C14—C18 | 121.79 (18) | C42—N43—C44 | 118.21 (15) |
C16—C15—C14 | 118.91 (17) | C45—N43—C44 | 115.70 (16) |
C16—C15—H15A | 120.5 | N43—C44—H44A | 109.5 |
C14—C15—H15A | 120.5 | N43—C44—H44B | 109.5 |
N17—C16—C15 | 117.37 (17) | H44A—C44—H44B | 109.5 |
N17—C16—C19 | 117.00 (17) | N43—C44—H44C | 109.5 |
C15—C16—C19 | 125.63 (17) | H44A—C44—H44C | 109.5 |
C16—N17—C12 | 122.58 (16) | H44B—C44—H44C | 109.5 |
C16—N17—H17A | 119.4 (13) | N43—C44—H44D | 109.5 |
C12—N17—H17A | 118.0 (13) | H44A—C44—H44D | 141.1 |
C14—C18—H18A | 109.5 | H44B—C44—H44D | 56.3 |
C14—C18—H18B | 109.5 | H44C—C44—H44D | 56.3 |
H18A—C18—H18B | 109.5 | N43—C44—H44E | 109.5 |
C14—C18—H18C | 109.5 | H44A—C44—H44E | 56.3 |
H18A—C18—H18C | 109.5 | H44B—C44—H44E | 141.1 |
H18B—C18—H18C | 109.5 | H44C—C44—H44E | 56.3 |
C16—C19—H19A | 109.5 | H44D—C44—H44E | 109.5 |
C16—C19—H19B | 109.5 | N43—C44—H44F | 109.5 |
H19A—C19—H19B | 109.5 | H44A—C44—H44F | 56.3 |
C16—C19—H19C | 109.5 | H44B—C44—H44F | 56.3 |
H19A—C19—H19C | 109.5 | H44C—C44—H44F | 141.1 |
H19B—C19—H19C | 109.5 | H44D—C44—H44F | 109.5 |
C22—N21—H21A | 120.6 (19) | H44E—C44—H44F | 109.5 |
C22—N21—H21B | 119.0 (18) | O46—C45—N47 | 122.44 (18) |
H21A—N21—H21B | 118 (3) | O46—C45—N43 | 120.61 (18) |
N21—C22—C23 | 121.51 (19) | N47—C45—N43 | 116.95 (16) |
N21—C22—C27 | 120.69 (19) | C45—N47—C49 | 120.04 (15) |
C23—C22—C27 | 117.80 (19) | C45—N47—C48 | 118.17 (16) |
C24—C23—C22 | 121.09 (18) | C49—N47—C48 | 121.79 (16) |
C24—C23—H23A | 119.5 | N47—C48—H48A | 109.5 |
C22—C23—H23A | 119.5 | N47—C48—H48B | 109.5 |
C23—C24—C25 | 120.30 (18) | H48A—C48—H48B | 109.5 |
C23—C24—H24A | 119.8 | N47—C48—H48C | 109.5 |
C25—C24—H24A | 119.8 | H48A—C48—H48C | 109.5 |
C26—C25—C24 | 119.13 (18) | H48B—C48—H48C | 109.5 |
C26—C25—S28 | 119.48 (14) | N47—C48—H48D | 109.5 |
C24—C25—S28 | 121.39 (15) | H48A—C48—H48D | 141.1 |
C27—C26—C25 | 120.87 (18) | H48B—C48—H48D | 56.3 |
C27—C26—H26A | 119.6 | H48C—C48—H48D | 56.3 |
C25—C26—H26A | 119.6 | N47—C48—H48E | 109.5 |
C26—C27—C22 | 120.81 (18) | H48A—C48—H48E | 56.3 |
C26—C27—H27A | 119.6 | H48B—C48—H48E | 141.1 |
C22—C27—H27A | 119.6 | H48C—C48—H48E | 56.3 |
O30—S28—O29 | 118.72 (9) | H48D—C48—H48E | 109.5 |
O30—S28—N31 | 109.33 (9) | N47—C48—H48F | 109.5 |
O29—S28—N31 | 102.45 (8) | H48A—C48—H48F | 56.3 |
O30—S28—C25 | 108.44 (9) | H48B—C48—H48F | 56.3 |
O29—S28—C25 | 109.58 (9) | H48C—C48—H48F | 141.1 |
N31—S28—C25 | 107.77 (9) | H48D—C48—H48F | 109.5 |
C32—N31—S28 | 125.77 (14) | H48E—C48—H48F | 109.5 |
C32—N31—H31A | 116.5 (16) | N50—C49—C53 | 111.76 (16) |
S28—N31—H31A | 114.9 (16) | N50—C49—N47 | 127.20 (16) |
N33—C32—N37 | 128.72 (17) | C53—C49—N47 | 121.03 (16) |
N33—C32—N31 | 117.45 (16) | C51—N50—C49 | 103.28 (15) |
N37—C32—N31 | 113.83 (16) | N52—C51—N50 | 113.59 (17) |
C32—N33—C34 | 115.30 (17) | N52—C51—H51A | 123.2 |
N33—C34—C35 | 120.86 (19) | N50—C51—H51A | 123.2 |
N33—C34—C38 | 116.3 (2) | C51—N52—C53 | 106.36 (16) |
C35—C34—C38 | 122.80 (19) | C51—N52—H52A | 124.0 (14) |
C34—C35—C36 | 119.07 (19) | C53—N52—H52A | 129.6 (14) |
C34—C35—H35A | 120.5 | C49—C53—N52 | 105.01 (16) |
C36—C35—H35A | 120.5 | C49—C53—C42 | 123.27 (17) |
N37—C36—C35 | 120.75 (19) | N52—C53—C42 | 131.72 (16) |
N1—C2—C3—C4 | 178.4 (2) | C24—C25—S28—N31 | −107.55 (17) |
C7—C2—C3—C4 | 0.7 (3) | O30—S28—N31—C32 | −56.24 (19) |
C2—C3—C4—C5 | 1.3 (3) | O29—S28—N31—C32 | 176.97 (17) |
C3—C4—C5—C6 | −1.8 (3) | C25—S28—N31—C32 | 61.43 (19) |
C3—C4—C5—S8 | 170.07 (15) | S28—N31—C32—N33 | 5.9 (3) |
C4—C5—C6—C7 | 0.2 (3) | S28—N31—C32—N37 | −174.23 (15) |
S8—C5—C6—C7 | −171.68 (16) | N37—C32—N33—C34 | 0.3 (3) |
C5—C6—C7—C2 | 1.8 (3) | N31—C32—N33—C34 | −179.84 (18) |
N1—C2—C7—C6 | 180.0 (2) | C32—N33—C34—C35 | −1.2 (3) |
C3—C2—C7—C6 | −2.3 (3) | C32—N33—C34—C38 | 177.7 (2) |
C4—C5—S8—O9 | −137.78 (15) | N33—C34—C35—C36 | 0.8 (3) |
C6—C5—S8—O9 | 34.08 (18) | C38—C34—C35—C36 | −178.1 (2) |
C4—C5—S8—O10 | −12.03 (17) | C34—C35—C36—N37 | 0.6 (3) |
C6—C5—S8—O10 | 159.82 (15) | C34—C35—C36—C39 | 179.9 (2) |
C4—C5—S8—N11 | 109.69 (15) | N33—C32—N37—C36 | 1.0 (3) |
C6—C5—S8—N11 | −78.46 (17) | N31—C32—N37—C36 | −178.85 (18) |
O9—S8—N11—C12 | 176.62 (15) | C35—C36—N37—C32 | −1.4 (3) |
O10—S8—N11—C12 | 50.76 (17) | C39—C36—N37—C32 | 179.3 (2) |
C5—S8—N11—C12 | −68.34 (17) | O41—C42—N43—C45 | −179.08 (18) |
S8—N11—C12—N13 | 13.6 (3) | C53—C42—N43—C45 | 0.6 (3) |
S8—N11—C12—N17 | −167.01 (13) | O41—C42—N43—C44 | 3.3 (3) |
N11—C12—N13—C14 | 179.19 (18) | C53—C42—N43—C44 | −177.04 (17) |
N17—C12—N13—C14 | −0.2 (3) | C42—N43—C45—O46 | 179.33 (19) |
C12—N13—C14—C15 | 0.7 (3) | C44—N43—C45—O46 | −3.0 (3) |
C12—N13—C14—C18 | −179.02 (17) | C42—N43—C45—N47 | −0.8 (3) |
N13—C14—C15—C16 | −0.3 (3) | C44—N43—C45—N47 | 176.91 (18) |
C18—C14—C15—C16 | 179.49 (19) | O46—C45—N47—C49 | 179.75 (19) |
C14—C15—C16—N17 | −0.8 (3) | N43—C45—N47—C49 | −0.1 (3) |
C14—C15—C16—C19 | 179.93 (19) | O46—C45—N47—C48 | 0.5 (3) |
C15—C16—N17—C12 | 1.4 (3) | N43—C45—N47—C48 | −179.35 (18) |
C19—C16—N17—C12 | −179.26 (17) | C45—N47—C49—N50 | −179.50 (18) |
N11—C12—N17—C16 | 179.64 (17) | C48—N47—C49—N50 | −0.3 (3) |
N13—C12—N17—C16 | −0.9 (3) | C45—N47—C49—C53 | 1.2 (3) |
N21—C22—C23—C24 | 179.7 (2) | C48—N47—C49—C53 | −179.64 (19) |
C27—C22—C23—C24 | 0.0 (3) | C53—C49—N50—C51 | −0.2 (2) |
C22—C23—C24—C25 | −0.5 (3) | N47—C49—N50—C51 | −179.65 (19) |
C23—C24—C25—C26 | 0.5 (3) | C49—N50—C51—N52 | 0.3 (2) |
C23—C24—C25—S28 | −179.66 (16) | N50—C51—N52—C53 | −0.2 (2) |
C24—C25—C26—C27 | −0.1 (3) | N50—C49—C53—N52 | 0.1 (2) |
S28—C25—C26—C27 | −179.94 (16) | N47—C49—C53—N52 | 179.56 (16) |
C25—C26—C27—C22 | −0.3 (3) | N50—C49—C53—C42 | 179.19 (17) |
N21—C22—C27—C26 | −179.3 (2) | N47—C49—C53—C42 | −1.4 (3) |
C23—C22—C27—C26 | 0.4 (3) | C51—N52—C53—C49 | 0.1 (2) |
C26—C25—S28—O30 | −169.47 (15) | C51—N52—C53—C42 | −178.9 (2) |
C24—C25—S28—O30 | 10.69 (18) | O41—C42—C53—C49 | −179.85 (19) |
C26—C25—S28—O29 | −38.47 (18) | N43—C42—C53—C49 | 0.5 (3) |
C24—C25—S28—O29 | 141.70 (16) | O41—C42—C53—N52 | −1.1 (4) |
C26—C25—S28—N31 | 72.28 (17) | N43—C42—C53—N52 | 179.27 (18) |
Cg22 is the centroid of the C22–C27 aromatic ring. |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1B···O10i | 0.87 (2) | 2.25 (2) | 3.097 (2) | 163 (2) |
N17—H17A···O41 | 0.88 (2) | 1.92 (2) | 2.780 (2) | 165 (2) |
N21—H21A···O30ii | 0.86 (2) | 2.31 (2) | 3.008 (2) | 137 (2) |
N21—H21B···O10iii | 0.87 (2) | 2.17 (2) | 3.017 (2) | 167 (2) |
N31—H31A···N50iv | 0.83 (2) | 2.31 (2) | 3.131 (2) | 168 (2) |
N52—H52A···N11 | 0.87 (2) | 2.09 (2) | 2.948 (2) | 172 (2) |
N1—H1A···Cg22i | 0.88 (2) | 2.97 (2) | 3.755 (2) | 149 (2) |
Symmetry codes: (i) x, y−1, z; (ii) x, y+1, z; (iii) −x+1, y+1/2, −z+1/2; (iv) x+1, y, z. |
Experimental details
Crystal data | |
Chemical formula | 2C12H14N4O2S·C7H8N4O2 |
Mr | 736.84 |
Crystal system, space group | Monoclinic, P21/c |
Temperature (K) | 293 |
a, b, c (Å) | 15.8827 (6), 8.1004 (3), 27.7913 (10) |
β (°) | 91.835 (2) |
V (Å3) | 3573.7 (2) |
Z | 4 |
Radiation type | Mo Kα |
µ (mm−1) | 0.21 |
Crystal size (mm) | 0.51 × 0.32 × 0.21 |
Data collection | |
Diffractometer | Bruker APEXII CCD area-detector diffractometer |
Absorption correction | Multi-scan (SADABS; Bruker, 2009) |
Tmin, Tmax | 0.900, 0.957 |
No. of measured, independent and observed [I > 2σ(I)] reflections | 46924, 7364, 5968 |
Rint | 0.024 |
(sin θ/λ)max (Å−1) | 0.631 |
Refinement | |
R[F2 > 2σ(F2)], wR(F2), S | 0.040, 0.110, 1.03 |
No. of reflections | 7364 |
No. of parameters | 487 |
No. of restraints | 2 |
H-atom treatment | H atoms treated by a mixture of independent and constrained refinement |
Δρmax, Δρmin (e Å−3) | 0.29, −0.41 |
Computer programs: APEX2 (Bruker, 2009), SAINT (Bruker, 2009), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), PLATON (Spek, 2009), SHELXTL (Sheldrick, 2008).
Cg22 is the centroid of the C22–C27 aromatic ring. |
D—H···A | D—H | H···A | D···A | D—H···A |
N1—H1B···O10i | 0.873 (19) | 2.25 (2) | 3.097 (2) | 163 (2) |
N17—H17A···O41 | 0.88 (2) | 1.92 (2) | 2.780 (2) | 165 (2) |
N21—H21A···O30ii | 0.86 (2) | 2.31 (2) | 3.008 (2) | 137 (2) |
N21—H21B···O10iii | 0.87 (2) | 2.17 (2) | 3.017 (2) | 167 (2) |
N31—H31A···N50iv | 0.83 (2) | 2.31 (2) | 3.131 (2) | 168 (2) |
N52—H52A···N11 | 0.87 (2) | 2.09 (2) | 2.948 (2) | 172 (2) |
N1—H1A···Cg22i | 0.88 (2) | 2.97 (2) | 3.755 (2) | 149.4 (19) |
Symmetry codes: (i) x, y−1, z; (ii) x, y+1, z; (iii) −x+1, y+1/2, −z+1/2; (iv) x+1, y, z. |
S—N | N—C | C—N | C—S—N—C | Interplanar angle | |
SHET | 1.6176 (15) | 1.338 (2) | 1.366 (2) | -68.34 (17) | 62.9 (2) |
SLET | 1.6424 (16) | 1.401 (2) | 1.331 (2) | 61.43 (19) | 86.0 (2) |
Sulfamethazinea | 1.632 (2) | 1.412 (2) | 1.343 (2) | -84.9 (2) | 78.1 (2) |
Reference: (a) Tiwari et al. (1984). |
Cocrystals have been increasingly recognized as an attractive alternative to solid forms of drug products (Vishweshwar et al., 2006). The design of cocrystals containing an active pharmaceutical ingredient (API) with an excipient (Basavoju et al., 2008) or another component (Childs & Hardcastle, 2007; Bucar et al., 2007) can provide an opportunity to design drug-delivery systems at the molecular level. Further, it can improve the pharmaceutical properties of the API (Fernandez-Lopez et al., 2001).
Theophylline is often used in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD) (Van Andel et al., 1999). A derivative of xanthine, theophylline is both weakly acidic and weakly basic, with corresponding pKa and pKb values of 8.6 and 11.5, respectively (Cohen, 1975). Theophylline is expected to have a high potential for cocrystal formation due to the C═O and N—H sites in the molecule (Trask et al., 2006). Indeed, Childs et al. (2007) have summarized the complexes formed between theophylline and both acids (e.g. oxalic acid, malonic acid, gentisic acid, sulfathiazole, acetaminophen etc.) and bases (e.g. urea, benzylamine, phenobarbital etc.). Sulfamethazine is a sulfonamide drug that has been used to treat bacterial diseases in human and veterinary medicine and to promote growth in cattle, sheep, pigs and poultry. Sulfamethazine is known to form cocrystals with aspirin, benzoic acid, trimethoprim and 4-aminosalicylic acid, among others (Caira, 1992, 2007; Caira et al., 1995; Zhang et al., 2007).
In this work, sulfamethazine and theophylline have been cocrystallized in a 2:1 ratio to yield a cocrystal, (I), containing theophylline (hereafter labelled THEO) and two tautomers of sulfamethazine (hereafter labelled SLET for the low-energy tautomer and SHET for the high-energy tautomer). Although observation of both tautomeric forms of a molecule in the solid state is still rare, it is more probable if the tautomers have similar energies. This is highlighted in a paper on tautomers in the Cambridge Structural Database (Cruz-Cabeza & Groom, 2011). In the case of sulfamethazine, however, this is the first time the high-energy tautomer has been observed. Sulfamethazine has been crystallized as a pure substance (Basak et al., 1983; Tiwari et al., 1984), as well as cocrystallizing with carboxylic acids and other solvates, but in every case it was the low-energy stable tautomer that was observed. The observation of both forms in the same structure is rare, especially because of the high energy difference between SLET (the low-energy tautomer) and SHET (the high-energy metastable tautomer) (see below).
The molecular structure of each component in (I) is shown in Fig. 1. The local structure of the theophylline is unremarkable, yielding a planar molecule [mean deviation 0.015 (3) Å]. The two sulfamethazine molecules differ in their geometry and, most importantly, in the position of one of the H atoms. All H atoms involved in hydrogen bonding were located in a difference map and allowed to refine. SHET has the H atom on atom N17 of the ring, whereas SLET has the H atom on atom N31 in the chain. As expected, this affects the bond distances (Table 2), most notably that the chain N atom has shorter bonds to both S and C atoms in SHET. In contrast, the longer intra-ring bond from the apex C atom to the H-bearing N atom in SHET should be noted. Data from sulfamethazine structures in the literature have been included in the table for comparison, representative of the stable tautomer. Also reported are the torsion angle and interplanar spacing but, although they differ between the low- and high-energy tautomers, no trends are observed compared with the published structures. The terminal NH2 group also shows some small differences between the two tautomers of sulfamethazine. SHET has a slightly pyramidyl shape at the terminal atom N1 [sum of internal angles 347 (1)°] but SLET is almost planar, with the sum of internal angles being 358 (1)° for atom N21.
The molecular packing of the cocrystal is presented in Figs. 2 and 3, and the geometry of the hydrogen-bonding interactions is given in Table 1. Fig. 2 is a view approximately down the c axis. It shows two distinct ribbons of sulfamethazine extending along the b axis; SHET links together by virtue of the hydrogen bond N1—H1B···O10, and SLET links together via the hydrogen bond N21—H21A···O30. Both independent ribbons form an infinite chain via a hydrogen bond between the amine and the sulfoxide of the self-same sulfamethazine. The theophylline forms a close interaction with SHET, linked together by two hydrogen-bonding interactions, N17—H17A···O41 and N52—H52A···N11, forming a nine-membered ring. There are three more hydrogen-bonding interactions, which are shown more clearly in Fig. 3. In this case, the view is approximately down the b axis. There are three hydrogen-bonding interactions involving THEO, the two discussed above forming the interaction with SHET, and the other side of the theophylline being linked to SLET via N31—H31A···N50. The two independent ribbons are thus linked to each other through THEO, as well as being linked directly to each other through two other interactions. Ribbon SLET connects directly to ribbon SHET via N21—H21B···O10. The final interaction is the weakest but the most interesting. The `free' atom H1A points towards the centroid Cg22 of aromatic ring C22–C27 of SLET (Fig. 3). Thus, the acceptor is the electron density of an aromatic ring. This link between the two ribbons, the last in Table 1 (entry N1—H1A···π), is certainly a long interaction but still significant in the overall molecular packing scheme.
The SLET tautomer (the tautomer protonated at the chain N atom) was calculated by density functional theory (DFT) methods to be 33.2 kJ mol-1 more stable than the SHET tautomer (the tautomer protonated at the aromatic ring) at the B3LYP/6-311++G** level of theory and using a polarizable continuum model (see Experimental). This large tautomeric energy difference is probably due to the fact that, by protonating the aromatic N atom, some aromaticity of the pyrimidine ring is lost. The observation of pairs of tautomers in the solid state with energy differences greater than 30 kJ mol-1 is still uncommon in crystal structures (Cruz-Cabeza & Groom, 2011). In fact, there are 16 crystal structures containing sulfamethazine in the Cambridge Structural Database (Version 5.32, November 2010; Allen, 2002) and all of them crystallize in the form of the most stable SLET tautomer. This energy penalty needed for the observation of the SHET tautomer in the crystal structure of (I) is compensated by the much better interaction between SHET and THEO (which involves two strong hydrogen bonds and two weak ones; Fig. 4). The PIXEL interaction energies for the SHET–THEO and SLET–THEO dimers were calculated to be -116.5 and -44.2 kJ mol-1, respectively. Clearly, the interaction between SHET and THEO and the extended hydrogen-bonding structure of (I) play an important role in the stabilization and observation of the high-energy tautomer of sulfamethazine. The observation of the SHET tautomer of sulfamethazine is reported here for the first time.
In summary, X-ray diffraction shows that a three-component adduct is formed in (I) between sulfamethazine and theophylline in a 2:1 ratio. In the cocrystal, extensive hydrogen bonding is observed, most notably the theophylline which forms significant hydrogen-bonding interactions to both the sulfamethazine tautomers. The strong interaction between theophylline and the high-energy SHET tautomer of sulfamethazine, as verified by PIXEL calculations, has made the observation of the latter in the crystal structure possible for the first time.