A 2:1 sulfamethazine-theophylline cocrystal exhibiting two tautomers of sulfamethazine

In the title cocrystal, 4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide-4-amino-N-(4,6-dimethyl-1,2-dihy­dro­pyrimidin-2-ylidene)benzenesulfonamide-1,3-dimethyl-7H-pur­ine-2,6-dione (1/1/1), C₇H₈N₄O₂·2C₁₂H₁₄N₄O₂S, two sul­fa­methazine mol­ecules cocrystallize with a single mol­ecule of theophylline. Each mol­ecule of sulfamethazine forms a hydrogen-bonded ribbon along the b axis crosslinked by further hydrogen bonding. The two sulfamethazine mol­ecules exhibit a hydrogen-shift isomerization so that the crystal structure contains both tautomeric forms. Calculation of their relative energies showed that the tautomer protonated at the chain N atom is considerably more stable than the one where an N atom in the aromatic ring is protonated. The latter, here observed for the first time, is stabilized through strong intermolecular interactions with the theophylline molecules.

S1. Comment

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 pK_a and pK_b 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 S_LET for the low-energy tautomer and S_HET 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 S_LET (the low-energy tautomer) and S_HET (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. S_HET has the H atom on atom N17 of the ring, whereas S_LET 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 S_HET. In contrast, the longer intra-ring bond from the apex C atom to the H-bearing N atom in S_HET 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. S_HET has a slightly pyramidyl shape at the terminal atom N1 [sum of internal angles 347 (1)°] but S_LET 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; S_HET links together by virtue of the hydrogen bond N1—H1B···O10, and S_LET 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 S_HET, 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 S_HET, and the other side of the theophylline being linked to S_LET 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 S_LET connects directly to ribbon S_HET 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 S_LET (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 S_LET 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 S_HET 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 S_LET tautomer. This energy penalty needed for the observation of the S_HET tautomer in the crystal structure of (I) is compensated by the much better interaction between S_HET and THEO (which involves two strong hydrogen bonds and two weak ones; Fig. 4). The PIXEL interaction energies for the S_HET–THEO and S_LET–THEO dimers were calculated to be -116.5 and -44.2 kJ mol^-1, respectively. Clearly, the interaction between S_HET 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 S_HET 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 S_HET tautomer of sulfamethazine, as verified by PIXEL calculations, has made the observation of the latter in the crystal structure possible for the first time.

Related literature

For related literature, see: Allen (2002); Basak et al. (1983); Basavoju et al. (2008); Bucar et al. (2007); Caira (1992, 2007); Caira et al. (1995); Childs & Hardcastle (2007); Childs, Stahly & Park (2007); Cohen (1975); Cooper et al. (2008); Cossi et al. (2002); Cruz-Cabeza & Groom (2011); Fernandez-Lopez, Kim, Choi, Delgado, Granja, Khasanov, Kraehenbuehl, Long, Weinberger, Wilcoxen & Ghadiri (2001); Frisch (2003); Gavezzotti (2003, 2007); Macrae et al. (2008); Tiwari et al. (1984); Trask et al. (2006); Van Andel, Reisner, Menjoge & Witek (1999); Vishweshwar et al. (2006); Zhang et al. (2007).

S2. Experimental

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, S_LET and S_HET, was calculated using DFT methods with the program GAUSSIAN03 (Frisch et al., 2003). The X-ray molecular geometries for S_LET and S_HET 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 S_LET–THEO and S_HET–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.

S3. Refinement

Aromatic H atoms were positioned geometrically and refined using a riding model, with C—H = 0.93 Å and with U_iso(H) = 1.2 U_eq(C). Methyl H atoms were idealized with tetrahedral angles and refined as a rotating group, with C—H = 0.96 Å and with U_iso(H) = 1.5U_eq(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 U_iso(H) = 1.2U_eq(C).

Computing details

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).

Figures

	Fig. 1. The molecular structures of the two interacting sulfamethazine tautomers (SLET and SHET) and one theophylline (THEO) molecule in the cocrystal, (I). Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. A molecular packing diagram, viewed approximately down the c axis, showing the ribbons of sulfamethazine along the b axis. Atoms involved in hydrogen bonding are labelled and hydrogen bonds are indicated by thin lines. [Symmetry codes: (ii) x, y+1, z; (v) x-1, y, z; (vi) x-1, y-1, z.]
	Fig. 3. A molecular packing diagram, viewed approximately down the b axis, showing the hydrogen-bonding network linking the two ribbons of sulfamethazine together. Atoms involved in hydrogen-bonding are labelled and hydrogen bonds are indicated by thin and dotted lines. [Symmetry codes: (iii) -x+1, y+1/2, -z+1/2; (vii) -x+1, y-1/2, -z+1/2; (viii) -x, y-1/2, -z+1/2.]
	Fig. 4. The relative molecular energies of the two tautomers (SLET and SHET) and the interaction energies of the THEO–SLET and THEO–SHET dimers.

4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide 4-amino-N-(4,6-dimethyl-1,2-dihydropyrimidin-2-ylidene)benzenesulfonamide 1,3-dimethyl-7H-purine-2,6-dione

Crystal data

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) Å^3	0.51 × 0.32 × 0.21 mm
Z = 4

Data collection

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

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.040	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.110	H atoms treated by a mixture of independent and constrained refinement
S = 1.03	w = 1/[σ^2(Fo^2) + (0.0504P)^2 + 1.5617P] where P = (Fo^2 + 2Fc^2)/3
7364 reflections	(Δ/σ)max < 0.001
487 parameters	Δρmax = 0.29 e Å^−3
2 restraints	Δρmin = −0.41 e Å^−3

Special details

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.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	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)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
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)

Geometric parameters (Å, º)

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)

Hydrogen-bond geometry (Å, º)

Cg22 is the centroid of the C22–C27 aromatic ring.

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1B···O10^i	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···O30^ii	0.86 (2)	2.31 (2)	3.008 (2)	137 (2)
N21—H21B···O10^iii	0.87 (2)	2.17 (2)	3.017 (2)	167 (2)
N31—H31A···N50^iv	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···Cg22^i	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.