The three-dimensional hydrogen-bonded framework structure in the 1:1 proton-transfer compound of the drug quinacrine with 5-sulfosalicylic acid

For the hydrated proton-transfer compound 6-chloro-9-[(4-diethyl­ammonio-2-methyl­butyl)­amino]-2-methoxy­acridinium 3-carboxyl­ato-4-hydroxy­benzene­sulfonate dihydrate, C₂₃H₃₂ClN₃O²⁺·C₇H₄O₆S^2-·2H₂O, (I), the conformational features, specifically those of the extended side chain at the 9-position of the acridine parent, have been compared with those of quinacrinium dichloride dihydrate (the drug atabrine or mepacrine). Racemic compound (I) has a three-dimensional hydrogen-bonded framework structure similar to atabrine but also involves the water mol­ecules and both the carboxyl­ate and sulfonate groups of the anion in structure extension. The comparable conformational features found in this uncommon derivative of quinacrine indicate that (I) has potential as a possible pharmaceutical substitute for atabrine.

S1. Comment

Quinacrine [N'-(6-chloro-2-methoxyacridin-9-yl)-N,N-diethylpentane-1,4-diamine] was synthesized in 1931 by Bayer [Is a reference or patent available?] and, as the dihydrochloride dehydrate (atabrine, mepacrine), introduced as a drug which was the first alternative to quinine for the treatment of malaria and other parasite-borne diseases (e.g. Chaga's disease, giardiasis). Its use in the treatment of malaria has largely been superceded by chloroquine, which has fewer of the undesirable adverse physiological side effects of quinacrine, e.g. aplastic anaemia and hyperpigmentation (Wilson et al., 1991). However, its more recent experimental and sometimes controversial uses include the possible treatment of Creutzfeldt–Jacob disease, where it has been found to inhibit the accumulation of pathogenic prion protein in cultured neuroblastoma cells (Doh-Ura et al., 2000), and for non-surgical female sterilization (Zipper et al., 1980). The crystal structure of the Trypanosoma cruzi trypanothione reducatase (TR) complex with quinacrine (Jacobi et al., 1996) showed that specific sites on the acridine ring system (the hetero N, C2 methoxy O and C6 chloro substituent groups), as well as the two amino groups of the C9 substituent side chain, are fixed at active sites of the TR enzyme.

The crystal structure of racemic atabrine (quinacrine dihydrochloride dihydrate; Courseille et al., 1973) showed the molecule to be protonated at the hetero N atom of the acridine ring and at the tertiary terminal N atom of the C9 side chain. In addition, the acridine ring systems showed interactive π–π stacking effects. Considering the difficulty in obtaining good crystals of atabrine, we have prepared the salts of this base with the strong aromatic organic acids 3,5-dinitrosalicylic acid (DNSA) and 3-carboxy-4-hydroxybenzenesulfonic acid (5-sulfosalicylic acid, 5-SSA) for the purpose of crystallographic examination. This approach has been used previously by us and other research groups with reasonable success since these acids, particularly when used in their anionic forms, are recognized as useful synthons for molecular assembly achieved through hydrogen-bonding interactions involving potentially all interactive substituent functional groups. The method allows the structures of difficult-to-crystallize Lewis base compounds, such as many pharmaceuticals, to be determined.

The crystal structures have been reported of the 1:1 salts of 5-SSA with theophylline (a monohydrate; Madarasz et al., 2002), trimethoprim (a dihydrate; Raj et al., 2003), and pyrimethamine (Hemamalini et al., 2005) and brucine (Smith, Wermuth, Healy & White, 2006) (both anhydrates). With DNSA, the structures of 1:1 anhydrous salts with both brucine (Smith, Wermuth, Healy & White, 2006) and strychnine (Smith et al., 2005) are also known. With the 5-SSA anions formed in the reaction of the acid with Lewis bases, all of the substituent groups provide hydrogen-bonding donor or acceptor atoms with potential for both primary and secondary structure extension. In some examples, particularly those salts with polycyclic heteroaromatic amines (Smith, Wermuth & White, 2004), the structures feature anion–anion or anion–cation π–π interactions. We obtained good crystals of the atabrine salt with 5-SSA from an aqueous ethanol solution but not with the DNSA salt prepared under similar conditions.

The crystal structure of the 5-SSA salt reported here is that of racemic quinacrinium 5-sulfosalicylate dihydrate, C₂₃H₃₂ClN₃O²⁺.C₇H₄O₆S^2-.2H₂O, (I). The quinacrine molecule is protonated at both the acridine N (N10) and the terminal tertiary diethylamino N atom (N141), while generating a 5-SSA dianion by deprotonation of both the sulfonic acid and carboxylic acid groups. Dianionic 5-SSA anions are not common among the known structures in the crystallographic literature but some are known, e.g. the salts with guanidine (Smith, Wermuth & Healy, 2004), benzylamine (Smith, Wermuth & Healy, 2006), 2-aminopyridine (Yang & Qu, 2006) and piperazine (Su & Li, 2007).

In the asymmetric unit of (I) (Fig. 1), the dication has primary hydrogen-bonding interactions involving the protonated tertiary amine N atom (N141) and one of the water molecules (O1W), as well as the secondary amine N atom (N91) and the second water molecule (O2W), while the H atom of the acridinium N atom is involved in secondary interactions with a carboxyl group of the 5-SSA dianion [cyclic three-centre asymmetric, graph set R²₁(4) (Etter et al., 1990)] (Table 1). Other secondary inter-species hydrogen bonds generate a three-dimensional framework structure (Fig. 2), which is also found in the structure of quinacrinium chloride dihydrate (Courseille et al., 1973). However, in that structure, the acridinium H atom has a primary interaction with one of the chloride anions, which is in turn associated with the solvent water molecules in structure extension. Conformationally the two structures are similar, with the C91 side chain adopting a comparable perpendicular attitude with respect to the acridine ring (Table 2), which is also the case in the structures of other C9 extended-chain-substituted 6-chloro-2-methoxyacridines, e.g. in the anti-tumour acridine analogues (Berman & Glusker, 1972; Carrell, 1972; Glusker et al., 1972). The only major difference between (I) and the dichloride is found, not unexpectedly, within the terminal diethylamino group. Also in (I) there are no cation–cation or cation–anion aromatic ring π–π interactions, which are present in the structure of the hydrochloride [minimum centroid separation of the inversion-related six-membered rings N10–C13 and C5–C15 = 4.1834 (13) Å].

With the 5-SSA anion species for (I), similar structural and conformational features to those previously observed (Smith, Wermuth & White, 2004) are found. The usual intramolecular O_phenolic—H···O_carboxyl hydrogen bond is found [series range 2.598 (3)–2.625 (2) Å], giving essentially coplanarity of the carboxylic acid group and the benzene ring [torsion angle C2—C1—C7—O71 = -175.0 (2)°]. In addition, the common aromatic C6A—H6A···O52A_sulfonate interaction [2.879 (2) Å] is present. It may be concluded that the chemically stable and structurally similar 5-sulfosalicylate salt of quinacrine, (I), could be considered a possible alternative to atabrine as a drug.

S2. Experimental

The title compound was synthesized by heating together 1 mmol quantities of quinacrium dichloride dihydrate (atabrine or mepacrine) (O'Neil, 2001) and 3-carboxy-4-hydroxybenzenesulfonic acid (5-sulfosalicylic acid = 5-SSA) in 50% ethanol–water (50 ml) under reflux for 10 min. After concentration to ca 30 ml, partial room-temperature evaporation of the hot-filtered solution gave yellow blocks of (I) (m.p. 523 K).

S3. Refinement

H atoms potentially involved in hydrogen-bonding interactions (aminium, carboxylic, phenolic and water) were located by difference methods and their positional and isotropic displacement parameters were refined. Other H atoms were included in the refinement at calculated positions as riding atoms, with C—H = 0.93 (aromatic) or C—H = 0.96 or 0.97 Å (aliphatic), and with U_iso(I) = 1.2U_eq(C).

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2008); cell refinement: CrysAlis RED (Oxford Diffraction, 2008); data reduction: CrysAlis RED (Oxford Diffraction, 2008); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: PLATON (Spek, 2003).

Figures

	Fig. 1. The molecular conformation and atom-numbering scheme for the quinacrine dication, the 5-sulfosalicylate dianion and the two solvent water molecules in (I). Displacement ellipsoids are drawn at the 30% probability level and H atoms are shown as small spheres of arbitrary size. Inter-species hydrogen-bonding associations are shown as dashed lines.
	Fig. 2. Hydrogen-bonding extensions in the structure of (I), shown in a partial view down the approximate c axial direction. [Symmetry codes: (v) x - 1/2, -y + 3/2, z + 1/2; for other symmetry codes, see Table 1.]

6-chloro-9-[(4-diethylammonio-2-methylbutyl)amino]-2-methoxyacridinium 3-carboxylato-4-hydroxybenzenesulfonate dihydrate

Crystal data

C23H32ClN3O^2+·C7H4O6S^2^−·2H2O	F(000) = 1384
Mr = 654.17	Dx = 1.356 Mg m^−3
Monoclinic, P21/n	Melting point: 523 K
Hall symbol: -P 2yn	Mo Kα radiation, λ = 0.71073 Å
a = 10.1753 (3) Å	Cell parameters from 9373 reflections
b = 30.8461 (7) Å	θ = 2.9–28.9°
c = 10.3671 (2) Å	µ = 0.24 mm^−1
β = 99.966 (3)°	T = 297 K
V = 3204.81 (14) Å^3	Block, yellow
Z = 4	0.20 × 0.20 × 0.15 mm

Data collection

Oxford Diffraction Gemini-S Ultra CCD detector diffractometer	5455 independent reflections
Radiation source: Enhance (Mo) X-ray tube	3568 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.049
ω scans	θmax = 25.0°, θmin = 2.9°
Absorption correction: multi-scan (SADABS; Sheldrick, 1996)	h = −11→11
Tmin = 0.906, Tmax = 0.960	k = −36→36
29865 measured reflections	l = −12→12

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) = 0.100	H atoms treated by a mixture of independent and constrained refinement
S = 0.99	w = 1/[σ^2(Fo^2) + (0.0552P)^2] where P = (Fo^2 + 2Fc^2)/3
5455 reflections	(Δ/σ)max = 0.002
433 parameters	Δρmax = 0.26 e Å^−3
0 restraints	Δρmin = −0.26 e Å^−3

Special details

Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles

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
Cl6	0.73514 (8)	1.07667 (2)	1.02838 (7)	0.0788 (3)
O2	1.37199 (16)	0.93866 (5)	0.46659 (16)	0.0572 (6)
N10	1.1183 (2)	1.02589 (6)	0.81378 (18)	0.0449 (7)
N91	0.91323 (18)	0.92482 (5)	0.61055 (17)	0.0361 (6)
N141	1.10064 (19)	0.78100 (6)	0.88969 (17)	0.0405 (6)
C1	1.1711 (2)	0.94843 (6)	0.5586 (2)	0.0406 (8)
C2	1.3003 (2)	0.95817 (7)	0.5492 (2)	0.0442 (8)
C3	1.3695 (2)	0.99067 (7)	0.6276 (2)	0.0507 (8)
C4	1.3091 (2)	1.01273 (7)	0.7137 (2)	0.0488 (9)
C5	0.9350 (3)	1.04771 (6)	0.9128 (2)	0.0465 (9)
C6	0.8050 (3)	1.04374 (7)	0.9227 (2)	0.0487 (9)
C7	0.7218 (3)	1.01360 (7)	0.8475 (2)	0.0516 (9)
C8	0.7741 (2)	0.98673 (6)	0.7649 (2)	0.0445 (8)
C9	0.9721 (2)	0.95988 (6)	0.66931 (18)	0.0328 (7)
C11	1.1046 (2)	0.97092 (6)	0.64782 (18)	0.0345 (7)
C12	1.1765 (2)	1.00352 (6)	0.7248 (2)	0.0393 (8)
C13	0.9900 (2)	1.02031 (6)	0.82663 (19)	0.0400 (8)
C14	0.9107 (2)	0.98788 (6)	0.75396 (19)	0.0356 (7)
C21	1.3163 (3)	0.90073 (8)	0.3983 (3)	0.0663 (10)
C101	0.8054 (2)	0.89728 (6)	0.64293 (19)	0.0368 (7)
C102	0.6813 (2)	0.90126 (7)	0.5384 (2)	0.0498 (8)
C111	0.8531 (2)	0.85013 (6)	0.65477 (19)	0.0372 (7)
C121	0.9708 (2)	0.84169 (6)	0.7633 (2)	0.0415 (8)
C131	1.0014 (2)	0.79360 (6)	0.77116 (19)	0.0395 (7)
C151	1.0970 (3)	0.73304 (7)	0.9145 (2)	0.0619 (10)
C161	1.1456 (4)	0.70609 (8)	0.8109 (3)	0.0925 (13)
C171	1.2371 (2)	0.79845 (8)	0.8845 (2)	0.0501 (8)
C181	1.3376 (3)	0.78939 (10)	1.0066 (2)	0.0729 (10)
S5A	0.68492 (6)	0.71943 (2)	0.92440 (5)	0.0413 (2)
O2A	0.53028 (18)	0.90192 (5)	0.81392 (17)	0.0557 (6)
O51A	0.73433 (17)	0.70207 (5)	0.81288 (15)	0.0579 (6)
O52A	0.55973 (19)	0.69969 (5)	0.94051 (19)	0.0735 (7)
O53A	0.7816 (2)	0.71921 (5)	1.04214 (15)	0.0764 (7)
O71A	0.82953 (17)	0.87392 (5)	1.12651 (16)	0.0625 (6)
O72A	0.69527 (18)	0.92267 (5)	1.01919 (16)	0.0664 (7)
C1A	0.6696 (2)	0.85020 (6)	0.94699 (18)	0.0336 (7)
C2A	0.5708 (2)	0.86055 (6)	0.83976 (19)	0.0386 (7)
C3A	0.5132 (2)	0.82784 (7)	0.75500 (19)	0.0411 (8)
C4A	0.5496 (2)	0.78537 (6)	0.77900 (18)	0.0362 (7)
C5A	0.6446 (2)	0.77423 (6)	0.88733 (17)	0.0318 (7)
C6A	0.7042 (2)	0.80682 (6)	0.96911 (18)	0.0342 (7)
C7A	0.7363 (2)	0.88417 (7)	1.0383 (2)	0.0446 (8)
O1W	1.0461 (3)	0.82390 (8)	1.10118 (19)	0.0795 (9)
O2W	0.9675 (2)	0.88264 (6)	0.37879 (17)	0.0581 (7)
H1	1.12630	0.92680	0.50590	0.0490*
H3	1.45720	0.99710	0.62040	0.0610*
H4	1.35570	1.03410	0.76600	0.0590*
H5	0.98800	1.06830	0.96240	0.0560*
H7	0.63180	1.01190	0.85380	0.0620*
H8	0.71830	0.96700	0.71430	0.0530*
H10	1.170 (3)	1.0455 (8)	0.863 (3)	0.072 (8)*
H91	0.947 (2)	0.9120 (6)	0.546 (2)	0.047 (6)*
H101	0.78380	0.90660	0.72720	0.0440*
H102	0.61160	0.88340	0.56160	0.0750*
H103	0.70140	0.89190	0.45570	0.0750*
H104	0.65240	0.93090	0.53200	0.0750*
H111	0.77930	0.83200	0.66940	0.0450*
H112	0.87750	0.84140	0.57210	0.0450*
H121	1.04820	0.85760	0.74590	0.0500*
H122	0.95000	0.85170	0.84620	0.0500*
H131	0.91920	0.77780	0.77190	0.0470*
H132	1.03570	0.78500	0.69330	0.0470*
H141	1.076 (2)	0.7959 (7)	0.957 (2)	0.064 (8)*
H151	1.00610	0.72470	0.91930	0.0740*
H152	1.15170	0.72680	0.99870	0.0740*
H161	1.13280	0.67590	0.82780	0.1110*
H162	1.23880	0.71160	0.81270	0.1110*
H163	1.09630	0.71360	0.72640	0.1110*
H171	1.23090	0.82960	0.87090	0.0600*
H172	1.26880	0.78580	0.80990	0.0600*
H181	1.29800	0.79510	1.08240	0.0880*
H182	1.36480	0.75960	1.00690	0.0880*
H183	1.41400	0.80770	1.00800	0.0880*
H211	1.29930	0.87930	0.46040	0.0800*
H212	1.37800	0.88930	0.34660	0.0800*
H213	1.23420	0.90820	0.34200	0.0800*
H2A	0.574 (3)	0.9157 (8)	0.888 (3)	0.086 (10)*
H3A	0.44990	0.83490	0.68210	0.0490*
H4A	0.51040	0.76380	0.72230	0.0430*
H6A	0.76900	0.79950	1.04060	0.0410*
H11W	0.985 (3)	0.8378 (9)	1.107 (3)	0.081 (12)*
H12W	1.101 (3)	0.8184 (10)	1.168 (3)	0.104 (12)*
H21W	0.916 (3)	0.8823 (9)	0.300 (3)	0.105 (11)*
H22W	0.999 (3)	0.8564 (9)	0.394 (3)	0.076 (9)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl6	0.1021 (7)	0.0648 (4)	0.0759 (5)	0.0126 (4)	0.0335 (4)	−0.0225 (3)
O2	0.0417 (11)	0.0654 (10)	0.0662 (11)	−0.0010 (8)	0.0138 (8)	−0.0109 (8)
N10	0.0482 (15)	0.0376 (10)	0.0476 (11)	−0.0108 (10)	0.0048 (10)	−0.0111 (8)
N91	0.0384 (12)	0.0317 (9)	0.0384 (10)	−0.0051 (8)	0.0074 (8)	−0.0066 (8)
N141	0.0402 (13)	0.0499 (11)	0.0320 (9)	0.0121 (9)	0.0078 (8)	0.0050 (8)
C1	0.0428 (16)	0.0341 (11)	0.0428 (12)	−0.0018 (10)	0.0014 (10)	−0.0013 (9)
C2	0.0411 (17)	0.0456 (13)	0.0459 (13)	0.0015 (12)	0.0079 (11)	0.0030 (10)
C3	0.0386 (15)	0.0557 (14)	0.0574 (15)	−0.0116 (12)	0.0072 (12)	0.0034 (12)
C4	0.0428 (17)	0.0448 (13)	0.0573 (15)	−0.0146 (12)	0.0041 (12)	−0.0044 (11)
C5	0.0611 (19)	0.0361 (12)	0.0418 (13)	−0.0022 (11)	0.0077 (12)	−0.0092 (9)
C6	0.064 (2)	0.0366 (12)	0.0471 (13)	0.0098 (12)	0.0145 (12)	−0.0038 (10)
C7	0.0555 (17)	0.0416 (12)	0.0586 (15)	0.0078 (12)	0.0124 (12)	−0.0017 (11)
C8	0.0463 (17)	0.0355 (11)	0.0505 (13)	0.0025 (11)	0.0051 (11)	−0.0066 (10)
C9	0.0413 (14)	0.0250 (10)	0.0295 (10)	0.0023 (9)	−0.0008 (9)	0.0028 (8)
C11	0.0376 (14)	0.0289 (10)	0.0349 (11)	−0.0023 (9)	0.0006 (9)	0.0038 (8)
C12	0.0452 (16)	0.0304 (11)	0.0402 (12)	−0.0023 (10)	0.0018 (10)	0.0013 (9)
C13	0.0495 (17)	0.0309 (11)	0.0380 (12)	−0.0010 (11)	0.0032 (10)	0.0000 (9)
C14	0.0410 (15)	0.0269 (10)	0.0367 (11)	0.0016 (9)	0.0003 (10)	0.0023 (8)
C21	0.0591 (19)	0.0708 (17)	0.0708 (18)	0.0023 (14)	0.0163 (14)	−0.0199 (14)
C101	0.0342 (14)	0.0359 (11)	0.0394 (11)	−0.0016 (10)	0.0042 (10)	−0.0030 (9)
C102	0.0438 (16)	0.0454 (13)	0.0556 (14)	0.0003 (11)	−0.0045 (12)	0.0053 (10)
C111	0.0393 (14)	0.0333 (11)	0.0368 (11)	−0.0010 (9)	0.0005 (10)	−0.0001 (8)
C121	0.0389 (15)	0.0411 (12)	0.0418 (12)	0.0011 (10)	−0.0002 (10)	−0.0014 (9)
C131	0.0392 (14)	0.0430 (12)	0.0347 (11)	0.0054 (10)	0.0022 (10)	0.0032 (9)
C151	0.070 (2)	0.0565 (15)	0.0585 (16)	0.0093 (13)	0.0094 (14)	0.0250 (12)
C161	0.141 (3)	0.0528 (16)	0.080 (2)	0.0324 (18)	0.009 (2)	0.0029 (14)
C171	0.0366 (16)	0.0707 (15)	0.0430 (13)	0.0080 (12)	0.0070 (11)	0.0048 (11)
C181	0.0465 (18)	0.123 (2)	0.0472 (15)	0.0158 (16)	0.0026 (13)	0.0065 (15)
S5A	0.0520 (4)	0.0364 (3)	0.0345 (3)	−0.0019 (3)	0.0051 (2)	−0.0023 (2)
O2A	0.0672 (13)	0.0427 (9)	0.0524 (10)	0.0099 (8)	−0.0032 (9)	0.0021 (8)
O51A	0.0681 (12)	0.0578 (10)	0.0506 (10)	0.0141 (9)	0.0180 (9)	−0.0086 (7)
O52A	0.0761 (14)	0.0456 (9)	0.1081 (15)	−0.0168 (9)	0.0418 (12)	0.0011 (9)
O53A	0.1123 (16)	0.0506 (10)	0.0505 (10)	0.0125 (10)	−0.0304 (10)	0.0000 (8)
O71A	0.0579 (12)	0.0603 (10)	0.0586 (10)	0.0028 (9)	−0.0195 (9)	−0.0249 (8)
O72A	0.0837 (14)	0.0377 (9)	0.0697 (11)	−0.0015 (9)	−0.0094 (10)	−0.0127 (8)
C1A	0.0325 (13)	0.0354 (11)	0.0325 (11)	−0.0048 (9)	0.0045 (9)	−0.0032 (8)
C2A	0.0390 (14)	0.0379 (12)	0.0393 (12)	−0.0004 (10)	0.0081 (10)	0.0026 (9)
C3A	0.0389 (15)	0.0504 (13)	0.0309 (11)	−0.0043 (11)	−0.0024 (10)	0.0031 (9)
C4A	0.0361 (14)	0.0420 (12)	0.0294 (10)	−0.0093 (10)	0.0024 (9)	−0.0060 (9)
C5A	0.0314 (13)	0.0379 (11)	0.0268 (10)	−0.0068 (9)	0.0071 (9)	−0.0036 (8)
C6A	0.0302 (13)	0.0427 (12)	0.0282 (10)	−0.0031 (9)	0.0012 (9)	−0.0039 (8)
C7A	0.0483 (17)	0.0419 (13)	0.0433 (13)	−0.0057 (11)	0.0068 (12)	−0.0095 (10)
O1W	0.0739 (17)	0.1240 (18)	0.0380 (11)	0.0435 (15)	0.0028 (11)	−0.0088 (11)
O2W	0.0767 (14)	0.0510 (11)	0.0422 (10)	0.0128 (10)	−0.0021 (9)	−0.0110 (8)

Geometric parameters (Å, º)

Cl6—C6	1.734 (3)	C3—H3	0.9300
S5A—O53A	1.4290 (18)	C4—H4	0.9300
S5A—C5A	1.7661 (19)	C5—H5	0.9300
S5A—O52A	1.447 (2)	C7—H7	0.9300
S5A—O51A	1.4413 (17)	C8—H8	0.9300
O2—C2	1.358 (3)	C111—C121	1.517 (3)
O2—C21	1.433 (3)	C121—C131	1.515 (3)
O2A—C2A	1.354 (2)	C21—H213	0.9600
O71A—C7A	1.239 (3)	C21—H212	0.9600
O72A—C7A	1.263 (3)	C21—H211	0.9600
O2A—H2A	0.92 (3)	C151—C161	1.508 (4)
O1W—H12W	0.83 (3)	C171—C181	1.509 (3)
O1W—H11W	0.77 (3)	C101—H101	0.9800
O2W—H21W	0.89 (3)	C1A—C2A	1.401 (3)
O2W—H22W	0.88 (3)	C1A—C6A	1.393 (3)
N10—C12	1.366 (3)	C1A—C7A	1.494 (3)
N10—C13	1.346 (3)	C102—H102	0.9600
N91—C9	1.332 (2)	C102—H103	0.9600
N91—C101	1.472 (3)	C102—H104	0.9600
N10—H10	0.90 (3)	C2A—C3A	1.398 (3)
N141—C171	1.499 (3)	C3A—C4A	1.372 (3)
N141—C131	1.500 (3)	C4A—C5A	1.392 (3)
N141—C151	1.503 (3)	C5A—C6A	1.385 (3)
N91—H91	0.90 (2)	C111—H112	0.9700
N141—H141	0.91 (2)	C111—H111	0.9700
C1—C2	1.368 (3)	C121—H121	0.9700
C1—C11	1.418 (3)	C121—H122	0.9700
C2—C3	1.401 (3)	C131—H132	0.9700
C3—C4	1.352 (3)	C131—H131	0.9700
C4—C12	1.403 (3)	C151—H151	0.9700
C5—C13	1.414 (3)	C151—H152	0.9700
C5—C6	1.350 (4)	C161—H162	0.9600
C6—C7	1.400 (3)	C161—H163	0.9600
C7—C8	1.364 (3)	C161—H161	0.9600
C8—C14	1.414 (3)	C171—H171	0.9700
C9—C11	1.445 (3)	C171—H172	0.9700
C9—C14	1.448 (3)	C181—H181	0.9600
C11—C12	1.408 (3)	C181—H182	0.9600
C13—C14	1.417 (3)	C181—H183	0.9600
C101—C102	1.520 (3)	C3A—H3A	0.9300
C1—H1	0.9300	C4A—H4A	0.9300
C101—C111	1.531 (3)	C6A—H6A	0.9300
O52A—S5A—C5A	104.58 (10)	H211—C21—H212	109.00
O53A—S5A—C5A	106.86 (9)	N141—C131—C121	113.62 (16)
O51A—S5A—C5A	106.33 (9)	N141—C151—C161	113.58 (19)
O51A—S5A—O52A	111.87 (10)	N141—C171—C181	113.63 (19)
O51A—S5A—O53A	113.53 (11)	C102—C101—H101	109.00
O52A—S5A—O53A	112.89 (11)	C111—C101—H101	109.00
C2—O2—C21	117.64 (19)	N91—C101—H101	109.00
C2A—O2A—H2A	100.6 (16)	C2A—C1A—C6A	118.43 (17)
H11W—O1W—H12W	119 (3)	C2A—C1A—C7A	121.87 (17)
H21W—O2W—H22W	107 (3)	C6A—C1A—C7A	119.70 (17)
C12—N10—C13	122.91 (18)	H102—C102—H103	109.00
C9—N91—C101	131.19 (17)	C101—C102—H104	109.00
C12—N10—H10	116.3 (19)	C101—C102—H103	109.00
C13—N10—H10	120.8 (19)	C101—C102—H102	109.00
C131—N141—C171	111.96 (16)	H103—C102—H104	110.00
C131—N141—C151	111.23 (17)	H102—C102—H104	109.00
C151—N141—C171	114.21 (19)	O2A—C2A—C3A	118.41 (18)
C9—N91—H91	120.0 (13)	O2A—C2A—C1A	121.62 (17)
C101—N91—H91	108.3 (13)	C1A—C2A—C3A	119.97 (17)
C131—N141—H141	105.2 (13)	C2A—C3A—C4A	120.28 (18)
C171—N141—H141	103.1 (13)	C3A—C4A—C5A	120.65 (18)
C151—N141—H141	110.4 (13)	S5A—C5A—C4A	120.97 (14)
C2—C1—C11	120.78 (18)	C4A—C5A—C6A	118.94 (17)
O2—C2—C1	125.11 (19)	S5A—C5A—C6A	120.05 (14)
O2—C2—C3	114.33 (18)	C1A—C6A—C5A	121.67 (18)
C1—C2—C3	120.55 (19)	O72A—C7A—C1A	117.29 (18)
C2—C3—C4	120.19 (19)	O71A—C7A—C1A	119.63 (19)
C3—C4—C12	120.39 (19)	O71A—C7A—O72A	123.1 (2)
C6—C5—C13	119.6 (2)	C101—C111—H112	109.00
Cl6—C6—C5	120.61 (17)	C101—C111—H111	108.00
Cl6—C6—C7	117.8 (2)	H111—C111—H112	108.00
C5—C6—C7	121.6 (2)	C121—C111—H112	109.00
C6—C7—C8	119.3 (3)	C121—C111—H111	109.00
C7—C8—C14	122.0 (2)	C131—C121—H122	110.00
N91—C9—C14	123.69 (19)	C111—C121—H122	110.00
C11—C9—C14	117.71 (17)	C111—C121—H121	110.00
N91—C9—C11	118.61 (17)	H121—C121—H122	108.00
C9—C11—C12	119.23 (17)	C131—C121—H121	110.00
C1—C11—C12	117.35 (18)	C121—C131—H132	109.00
C1—C11—C9	123.27 (17)	C121—C131—H131	109.00
N10—C12—C11	120.01 (19)	N141—C131—H132	109.00
C4—C12—C11	120.73 (19)	H131—C131—H132	108.00
N10—C12—C4	119.24 (18)	N141—C131—H131	109.00
N10—C13—C5	118.87 (19)	H151—C151—H152	108.00
N10—C13—C14	120.69 (18)	C161—C151—H151	109.00
C5—C13—C14	120.4 (2)	N141—C151—H151	109.00
C8—C14—C9	124.53 (18)	N141—C151—H152	109.00
C8—C14—C13	116.87 (17)	C161—C151—H152	109.00
C9—C14—C13	118.52 (18)	H161—C161—H162	109.00
N91—C101—C111	109.15 (16)	C151—C161—H162	109.00
C102—C101—C111	110.28 (16)	C151—C161—H161	109.00
C11—C1—H1	120.00	H162—C161—H163	109.00
N91—C101—C102	110.55 (16)	H161—C161—H163	110.00
C2—C1—H1	120.00	C151—C161—H163	109.00
C2—C3—H3	120.00	C181—C171—H172	109.00
C4—C3—H3	120.00	N141—C171—H172	109.00
C12—C4—H4	120.00	H171—C171—H172	108.00
C3—C4—H4	120.00	C181—C171—H171	109.00
C6—C5—H5	120.00	N141—C171—H171	109.00
C13—C5—H5	120.00	C171—C181—H183	109.00
C6—C7—H7	120.00	C171—C181—H181	109.00
C8—C7—H7	120.00	C171—C181—H182	109.00
C7—C8—H8	119.00	H182—C181—H183	109.00
C14—C8—H8	119.00	H181—C181—H183	109.00
C101—C111—C121	114.90 (16)	H181—C181—H182	110.00
O2—C21—H212	110.00	C4A—C3A—H3A	120.00
H212—C21—H213	109.00	C2A—C3A—H3A	120.00
C111—C121—C131	109.66 (16)	C3A—C4A—H4A	120.00
H211—C21—H213	110.00	C5A—C4A—H4A	120.00
O2—C21—H211	109.00	C5A—C6A—H6A	119.00
O2—C21—H213	109.00	C1A—C6A—H6A	119.00
O52A—S5A—C5A—C4A	−58.41 (19)	Cl6—C6—C7—C8	−178.98 (16)
O53A—S5A—C5A—C4A	−178.33 (17)	C6—C7—C8—C14	0.9 (3)
O51A—S5A—C5A—C6A	−122.24 (17)	C7—C8—C14—C13	−4.0 (3)
O52A—S5A—C5A—C6A	119.25 (18)	C7—C8—C14—C9	179.25 (19)
O53A—S5A—C5A—C6A	−0.7 (2)	C14—C9—C11—C12	10.2 (3)
O51A—S5A—C5A—C4A	60.10 (19)	N91—C9—C11—C1	5.5 (3)
C21—O2—C2—C3	170.4 (2)	N91—C9—C11—C12	−169.92 (18)
C21—O2—C2—C1	−10.0 (3)	C14—C9—C11—C1	−174.41 (18)
C12—N10—C13—C14	5.0 (3)	N91—C9—C14—C8	−12.8 (3)
C13—N10—C12—C4	177.11 (19)	N91—C9—C14—C13	170.54 (18)
C13—N10—C12—C11	−4.4 (3)	C11—C9—C14—C8	167.09 (18)
C12—N10—C13—C5	−174.21 (19)	C11—C9—C14—C13	−9.6 (3)
C9—N91—C101—C111	−125.0 (2)	C9—C11—C12—C4	174.99 (18)
C101—N91—C9—C11	157.06 (19)	C1—C11—C12—C4	−0.7 (3)
C101—N91—C9—C14	−23.1 (3)	C9—C11—C12—N10	−3.4 (3)
C9—N91—C101—C102	113.6 (2)	C1—C11—C12—N10	−179.10 (18)
C9—N91—C101—C111	−125.0 (2)	N10—C13—C14—C8	−174.69 (18)
N91—C101—C111—C121	62.6 (2)	C5—C13—C14—C9	−178.53 (18)
C101—C111—C121—C131	175.79 (16)	N10—C13—C14—C9	2.2 (3)
C111—C121—C131—N141	−170.13 (16)	C5—C13—C14—C8	4.6 (3)
C121—C131—N141—C151	163.03 (18)	C2A—C1A—C7A—O71A	−175.0 (2)
C121—C131—N141—C171	−67.9 (2)	C2A—C1A—C7A—O72A	3.6 (3)
C131—N141—C151—C161	67.4 (3)	C6A—C1A—C7A—O71A	6.0 (3)
C131—N141—C171—C181	175.61 (19)	C6A—C1A—C7A—O72A	−175.40 (19)
C2—C1—C11—C9	−175.11 (19)	C7A—C1A—C2A—O2A	−0.4 (3)
C11—C1—C2—O2	−179.66 (19)	C7A—C1A—C2A—C3A	178.50 (19)
C11—C1—C2—C3	−0.1 (3)	C2A—C1A—C6A—C5A	0.7 (3)
C2—C1—C11—C12	0.4 (3)	C7A—C1A—C6A—C5A	179.74 (19)
C1—C2—C3—C4	0.1 (3)	C6A—C1A—C2A—O2A	178.64 (19)
O2—C2—C3—C4	179.73 (19)	C6A—C1A—C2A—C3A	−2.5 (3)
C2—C3—C4—C12	−0.4 (3)	O2A—C2A—C3A—C4A	−178.77 (19)
C3—C4—C12—C11	0.7 (3)	C1A—C2A—C3A—C4A	2.3 (3)
C3—C4—C12—N10	179.16 (19)	C2A—C3A—C4A—C5A	−0.3 (3)
C13—C5—C6—Cl6	179.58 (15)	C3A—C4A—C5A—C6A	−1.5 (3)
C6—C5—C13—C14	−2.0 (3)	C3A—C4A—C5A—S5A	176.24 (16)
C13—C5—C6—C7	−1.3 (3)	S5A—C5A—C6A—C1A	−176.46 (16)
C6—C5—C13—N10	177.24 (19)	C4A—C5A—C6A—C1A	1.3 (3)
C5—C6—C7—C8	1.9 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2A—H2A···O72A	0.92 (3)	1.69 (3)	2.554 (2)	156 (3)
N10—H10···O71A^i	0.90 (3)	2.49 (2)	3.178 (2)	134 (2)
N10—H10···O72A^i	0.90 (3)	1.94 (3)	2.825 (3)	168 (2)
N91—H91···O2W	0.90 (2)	2.00 (2)	2.869 (2)	163.6 (19)
N141—H141···O1W	0.91 (2)	1.80 (2)	2.700 (3)	173.3 (19)
O1W—H11W···O71A	0.77 (3)	1.97 (3)	2.740 (3)	179 (3)
O1W—H12W···O51A^ii	0.83 (3)	1.95 (3)	2.770 (3)	172 (3)
O2W—H21W···O71A^iii	0.89 (3)	1.88 (3)	2.759 (2)	170 (3)
O2W—H22W···O52A^iv	0.88 (3)	1.87 (3)	2.744 (2)	175 (3)
C1—H1···O2W	0.93	2.34	3.248 (3)	166
C6A—H6A···O53A	0.93	2.48	2.879 (2)	106

Symmetry codes: (i) −x+2, −y+2, −z+2; (ii) x+1/2, −y+3/2, z+1/2; (iii) x, y, z−1; (iv) x+1/2, −y+3/2, z−1/2.