Felodipine-diaza­bicyclo­[2.2.2]octa­ne-water (1/1/1)

The title compound, C₁₈H₁₉Cl₂NO₄·C₆H₁₂N₂·H₂O, is a co­crystal hydrate containing the active pharmaceutical ingredient felodipine and diaza­bicyclo­[2.2.2]octane (DABCO). The DABCO and water mol­ecules are linked through O-H...N hydrogen bonds into chains around 2₁ screw axes, while the felodipine mol­ecules form N-H...O hydrogen bonds to the water mol­ecules. The felodipine mol­ecules adopt centrosymmetric back-to-back arrangements that are similar to those present in all of its four reported polymorphs. The dichloro­phenyl rings also form [pi]-stacking inter­actions. The inclusion of water mol­ecules in the cocrystal, rather than formation of N-H...N hydrogen bonds between felodipine and DABCO, may be associated with steric hindrance that would arise between DABCO and the methyl groups of felodipine if they were directly involved in hydrogen bonding.

S1. Comment

Felodipine [systematic name: ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate] is a calcium-channel blocking agent that is widely used for treatment of hypertension and angina (Nussinovitch et al., 1996). The compound belongs to Class II of the Biopharmaceutical Classification Scheme (Amidon et al., 1995) because it is effectively absorbed from the gastro intestine but is practically insoluble in water. One strategy that might be applied to enhance the aqueous solubility of felodipine is to generate alternative solid forms (Hilfiker et al., 2006). To this end, we have recently reported the structures and properties of four felodipine polymorphs (Surov et al., 2012). We have also carried out some cocrystallization trials, and we report here the structure of a hydrated cocrystal of felodipine with diazabicyclo[2.2.2]octane (DABCO), (I).

The asymmetric unit of (I) comprises one molecule of felodipine, one molecule of DABCO and one water molecule (Fig. 1). The conformation of the felodipine molecule is typical for this class of molecule (Goldmann & Stoltefuss, 1991), comprising two approximately planar sections with the dichlorophenyl unit lying perpendicular to the plane of the remainder of the molecule. The 1,4-dihydropyridine (1,4-DHP) ring (N1/C1–C5) adopts a shallow boat conformation, in which atoms N1 and C3 lie 0.135 (4) and 0.293 (4) Å, respectively, from the mean plane defined by C1/C2/C4/C5. These values are consistent with a previous database study for 1,4-DHP rings (Şimşek et al., 2000), which showed that atom C3 typically lies 0.30 Å from the defined plane, while the deviation of atom N1 lies in the range 0.04–0.19 Å. The dihedral angle between the dichlorophenyl ring and the mean plane defined by C1/C2/C4/C5 is 90.00 (8)°. The O atoms of the methyl and ethyl ester groups are approximately in the plane of the 1,4-DHP ring on account of π-electron conjugation between the oxo groups and the double bonds in the ring.

The DABCO and water molecules are linked through O—H···N hydrogen bonds (Table 1) into chains around the 2₁ screw axes in space group P2₁/c (Fig. 2). The felodipine molecules form N—H···O hydrogen bonds to water, adopting pendant positions on alternating sides of the hydrogen-bonded chains. The felodipine molecules in adjacent chains meet in two distinct intermolecular arrangements, both of which are formed across crystallographic inversion centres (Fig. 3). In one interaction, the 1,4-DHP rings of the felodipine molecules adopt a back-to-back arrangement, with a centroid–centroid distance of 4.605 (3) Å [symmetry code: (ii) -x+1, -y, -z+1]. The molecules are offset so that methyl group C18 lies above C3 [C18···C3ⁱⁱ = 3.808 (4) Å] and atom C16 of the methyl ester group lies above atom N1 [N1···C16ⁱⁱ = 3.622 (3) Å]. In the other intermolecular interaction, the dichlorophenyl rings adopt an offset π-stacked arrangement, with a centroid–centroid distance of 4.028 (2) Å [symmetry code: (iii) -x+1, -y+1, -z+1]. The back-to-back arrangement is present in all four felodipine polymorphs (Surov et al., 2012), although the lateral offset of the molecules is variable in each structure. The π-stacked arrangement of dichlorophenyl rings is present only in felodipine polymorph I (Fossheim, 1986).

The Cambridge Structural Database (CSD; Version 5.33 plus updates; Allen, 2002) includes one other cocrystal of felodipine, containing formamide in a 1:1 ratio (Lou et al., 2009). In that structure (Fig. 4), the felodipine molecules form N—H···O hydrogen bonds to formamide and dimeric formamide motifs can be considered to yield a pseudo-2:1 cocrystal in which the formamide dimer constitutes a supramolecular unit that bridges between two felodipine molecules. The CSD also contains three cocrystals of the closely related molecule nifedipine, (II), which has two methyl esters and one nitro group at the 2-position of the phenyl ring. In a 2:1 cocrystal of nifedipine with 1,4-dioxane (Caira et al., 2003), two nifedipine molecules are linked by a 1,4-dioxane molecule into a trimeric hydrogen-bonded unit similar to that described for felodipine–formamide. In the cocrystal of nifedipine with dimethyl sufoxide (DMSO; Klimakow et al., 2010), nifedipine forms an N—H···O hydrogen bond to the O atom of DMSO. The resulting cocrystal is essentially isostructural with nifedipine–1,4-dioxane (2/1), with a pair of dimethyl sufoxide molecules occupying the position of each 1,4-dioxane molecule. The cocrystal of nifedipine with pyrazine (Schultheiss et al., 2010) is unexpected, because nifedipine forms N—H···O hydrogen bonds to the O atoms of the methyl esters, while the pyrazine molecule is not involved in any hydrogen-bonding interaction. In that case, one factor that must contribute to the observed structure is the relative strengths of the N—H···O and N—H···N hydrogen bonds. For felodipine–DABCO, direct N—H···N hydrogen bonding between the two molecules is probably also discouraged by steric constraints resulting from the presence of the two methyl groups on either side of the N—H group in felodipine.

Related literature

For related literature, see: Allen (2002); Amidon et al. (1995); Caira et al. (2003); Fossheim (1986); Goldmann & Stoltefuss (1991); Hilfiker et al. (2006); Klimakow et al. (2010); Lou et al. (2009); Nussinovitch et al. (1996); Schultheiss et al. (2010); Surov et al. (2012); Şimşek et al. (2000).

S2. Experimental

Felodipine (0.1 g, 0.26 mmol) and DABCO (0.03 g, 0.26 mmol) were dissolved in ethanol (10 ml, nominally 99.9%) at room temperature then the solvent was allowed to evaporate at ambient conditions. No precautions were taken to exclude water.

S3. Refinement

H atoms bound to C atoms were included in calculated positions and refined as riding, with C—H = 0.95 (aromatic), 0.98 (methyl) or 0.99 (methylene) Å, and with U_iso(H) = 1.2U_eq(C), or 1.5U_eq(C) for the methyl groups. The methyl groups were allowed to rotate around their local threefold axes. H atoms bound to N or O atoms were located in difference Fourier maps and refined with isotropic displacement parameters, with the following restraints: N1—H1 = 0.88 (1) Å, O1W—H1W and O1W—H2W = 0.84 (1) Å, and H1W···H2W = 1.37 (2) Å.

Computing details

Data collection: APEX2 (Bruker, 2010); cell refinement: SAINT (Bruker, 2010); data reduction: SAINT (Bruker, 2010); program(s) used to solve structure: SHELXTL (Sheldrick, 2008); program(s) used to refine structure: SHELXTL (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures

	Fig. 1. Molecular structure of (I), with displacement ellipsoids drawn at the 50% probability level for non-H atoms.
	Fig. 2. Hydrogen-bonded chains of DABCO and water molecules running along the 21 screw axis parallel to the b axis. The felodipine molecules form hydrogen bonds to water and adopt pendant positions along the hydrogen-bonded chains. H atoms not involved in hydrogen bonding have been omitted.
	Fig. 3. Two types of intermolecular interactions between the felodipine molecules. Cg refers to the centroid of the dichlorophenyl ring. H atoms have been omitted. [Symmetry codes: (ii) -x+1, -y, -z+1; (iii) -x+1, -y+1, -z+1.]
	Fig. 4. Hydrogen-bonded unit in the cocrystal of felodipine with formamide (Lou et al., 2009). The formamide dimer can be viewed as a single supramolecular unit that bridges between the two felodipine molecules.

Ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate– diazabicyclo[2.2.2]octane–water (1/1/1)

Crystal data

C18H19Cl2NO4·C6H12N2·H2O	F(000) = 1088
Mr = 514.43	Dx = 1.330 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 9950 reflections
a = 11.3003 (3) Å	θ = 2.4–25.5°
b = 13.2721 (3) Å	µ = 0.29 mm^−1
c = 17.2019 (4) Å	T = 150 K
β = 95.398 (2)°	Block, colourless
V = 2568.48 (11) Å^3	0.48 × 0.32 × 0.18 mm
Z = 4

Data collection

Bruker–Nonius X8 APEXII CCD diffractometer	4871 independent reflections
Radiation source: fine-focus sealed tube	3789 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.035
ω and ϕ scans	θmax = 25.7°, θmin = 3.6°
Absorption correction: multi-scan (SADABS; Sheldrick, 2003)	h = −13→13
Tmin = 0.818, Tmax = 0.949	k = −14→16
42263 measured reflections	l = −17→20

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)] = 0.053	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.127	H atoms treated by a mixture of independent and constrained refinement
S = 1.10	w = 1/[σ^2(Fo^2) + (0.0389P)^2 + 2.9954P] where P = (Fo^2 + 2Fc^2)/3
4871 reflections	(Δ/σ)max < 0.001
323 parameters	Δρmax = 0.60 e Å^−3
4 restraints	Δρmin = −0.40 e Å^−3

Special details

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.

Least-squares planes (x,y,z in crystal coordinates) and deviations from them (* indicates atom used to define plane)

- 0.4456 (0.0185) x - 11.0659 (0.0089) y + 9.4949 (0.0171) z = 2.7022 (0.0148)

* -0.0119 (0.0012) C1 * 0.0115 (0.0012) C2 * -0.0115 (0.0012) C4 * 0.0119 (0.0012) C5 - 0.1352 (0.0036) N1 - 0.2933 (0.0038) C3

Rms deviation of fitted atoms = 0.0117

- 5.5260 (0.0109) x + 6.5918 (0.0121) y + 13.0716 (0.0122) z = 5.1713 (0.0110)

Angle to previous plane (with approximate e.s.d.) = 90.00 (0.08)

* -0.0109 (0.0017) C6 * 0.0039 (0.0019) C7 * 0.0055 (0.0020) C8 * -0.0079 (0.0020) C9 * 0.0008 (0.0018) C10 * 0.0086 (0.0017) C11

Rms deviation of fitted atoms = 0.0071

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
Cl1	0.83858 (7)	0.50681 (6)	0.49425 (5)	0.0550 (2)
Cl2	0.78131 (6)	0.30671 (6)	0.57566 (4)	0.0459 (2)
O1	0.34343 (18)	0.27372 (16)	0.67063 (11)	0.0448 (5)
O2	0.53921 (17)	0.25585 (16)	0.66623 (10)	0.0440 (5)
O3	0.64778 (19)	0.02210 (16)	0.37398 (12)	0.0499 (5)
O4	0.73064 (17)	0.11377 (16)	0.47348 (12)	0.0475 (5)
N1	0.3166 (2)	0.13692 (17)	0.44478 (13)	0.0347 (5)
H1	0.2467 (14)	0.124 (2)	0.4209 (15)	0.041 (8)*
C1	0.3176 (2)	0.18632 (19)	0.51539 (15)	0.0320 (6)
C2	0.4217 (2)	0.21324 (19)	0.55411 (14)	0.0288 (6)
C3	0.5367 (2)	0.20315 (18)	0.51566 (14)	0.0277 (5)
H3A	0.6010	0.1820	0.5563	0.033*
C4	0.5256 (2)	0.12318 (19)	0.45161 (14)	0.0294 (6)
C5	0.4178 (2)	0.09654 (19)	0.41797 (15)	0.0315 (6)
C6	0.5712 (2)	0.30506 (18)	0.48244 (13)	0.0257 (5)
C7	0.4920 (2)	0.3517 (2)	0.42655 (15)	0.0323 (6)
H7A	0.4177	0.3205	0.4116	0.039*
C8	0.5186 (3)	0.4423 (2)	0.39224 (17)	0.0417 (7)
H8A	0.4628	0.4722	0.3544	0.050*
C9	0.6256 (3)	0.4891 (2)	0.41283 (17)	0.0410 (7)
H9A	0.6449	0.5507	0.3888	0.049*
C10	0.7039 (2)	0.4457 (2)	0.46847 (16)	0.0353 (6)
C11	0.6777 (2)	0.3546 (2)	0.50397 (14)	0.0298 (6)
C12	0.1964 (2)	0.2023 (2)	0.54251 (19)	0.0458 (7)
H12A	0.1837	0.2744	0.5509	0.069*
H12B	0.1906	0.1658	0.5915	0.069*
H12C	0.1357	0.1772	0.5028	0.069*
C13	0.4269 (2)	0.2505 (2)	0.63449 (15)	0.0322 (6)
C14	0.5566 (3)	0.2835 (3)	0.74790 (17)	0.0576 (9)
H14A	0.4939	0.2529	0.7768	0.069*
H14B	0.5528	0.3576	0.7537	0.069*
C15	0.6751 (3)	0.2457 (3)	0.77879 (19)	0.0589 (9)
H15A	0.6875	0.2591	0.8350	0.088*
H15B	0.7367	0.2800	0.7522	0.088*
H15C	0.6795	0.1730	0.7696	0.088*
C16	0.6367 (2)	0.0800 (2)	0.42826 (16)	0.0340 (6)
C17	0.8482 (3)	0.0845 (3)	0.4543 (2)	0.0617 (10)
H17A	0.9072	0.1317	0.4786	0.093*
H17B	0.8505	0.0858	0.3975	0.093*
H17C	0.8661	0.0163	0.4738	0.093*
C18	0.3901 (3)	0.0229 (2)	0.35220 (16)	0.0402 (7)
H18A	0.4635	−0.0105	0.3401	0.060*
H18B	0.3551	0.0590	0.3059	0.060*
H18C	0.3337	−0.0276	0.3678	0.060*
N3	0.0089 (2)	0.45767 (17)	0.23719 (13)	0.0391 (6)
N2	0.0634 (2)	0.29281 (17)	0.30913 (13)	0.0385 (6)
C19	0.1385 (3)	0.4515 (2)	0.25766 (18)	0.0449 (7)
H19A	0.1657	0.5115	0.2886	0.054*
H19B	0.1797	0.4510	0.2094	0.054*
C20	0.1704 (2)	0.3553 (2)	0.30526 (18)	0.0426 (7)
H20A	0.2315	0.3167	0.2804	0.051*
H20B	0.2034	0.3738	0.3587	0.051*
C21	−0.0286 (3)	0.3709 (2)	0.18810 (16)	0.0413 (7)
H21A	0.0055	0.3764	0.1373	0.050*
H21B	−0.1163	0.3707	0.1779	0.050*
C22	0.0127 (3)	0.2722 (2)	0.22839 (17)	0.0435 (7)
H22A	−0.0555	0.2255	0.2292	0.052*
H22B	0.0734	0.2397	0.1989	0.052*
C23	−0.0504 (3)	0.4524 (2)	0.30974 (17)	0.0427 (7)
H23A	−0.1372	0.4606	0.2976	0.051*
H23B	−0.0214	0.5076	0.3453	0.051*
C24	−0.0240 (2)	0.3497 (2)	0.35001 (16)	0.0376 (6)
H24A	0.0076	0.3607	0.4050	0.045*
H24B	−0.0984	0.3104	0.3498	0.045*
O1W	0.09117 (19)	0.10036 (17)	0.36927 (13)	0.0440 (5)
H1W	0.090 (4)	0.1592 (14)	0.350 (2)	0.13 (2)*
H2W	0.062 (4)	0.062 (2)	0.3331 (18)	0.105 (17)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0544 (5)	0.0563 (5)	0.0556 (5)	−0.0274 (4)	0.0124 (4)	−0.0182 (4)
Cl2	0.0391 (4)	0.0602 (5)	0.0366 (4)	−0.0025 (3)	−0.0065 (3)	0.0002 (3)
O1	0.0464 (12)	0.0533 (13)	0.0369 (11)	0.0066 (10)	0.0162 (9)	−0.0019 (9)
O2	0.0438 (12)	0.0630 (13)	0.0252 (10)	0.0135 (10)	0.0030 (8)	−0.0079 (9)
O3	0.0544 (13)	0.0449 (12)	0.0530 (13)	0.0053 (10)	0.0179 (10)	−0.0125 (11)
O4	0.0348 (11)	0.0553 (13)	0.0533 (13)	0.0096 (10)	0.0088 (9)	−0.0109 (11)
N1	0.0303 (13)	0.0341 (13)	0.0393 (13)	−0.0047 (10)	0.0018 (10)	−0.0026 (10)
C1	0.0343 (14)	0.0277 (14)	0.0355 (14)	−0.0019 (11)	0.0119 (11)	0.0046 (11)
C2	0.0335 (14)	0.0262 (13)	0.0275 (13)	0.0000 (11)	0.0080 (11)	0.0048 (11)
C3	0.0332 (14)	0.0255 (13)	0.0250 (12)	0.0037 (11)	0.0064 (10)	0.0030 (10)
C4	0.0375 (15)	0.0246 (13)	0.0269 (13)	−0.0006 (11)	0.0076 (11)	0.0043 (10)
C5	0.0424 (16)	0.0250 (13)	0.0288 (13)	−0.0015 (12)	0.0116 (12)	0.0050 (11)
C6	0.0297 (13)	0.0247 (13)	0.0237 (12)	0.0025 (11)	0.0076 (10)	−0.0016 (10)
C7	0.0316 (14)	0.0291 (14)	0.0362 (14)	−0.0009 (11)	0.0038 (11)	0.0044 (12)
C8	0.0445 (17)	0.0344 (16)	0.0460 (17)	0.0071 (13)	0.0035 (13)	0.0123 (13)
C9	0.0506 (18)	0.0259 (14)	0.0484 (17)	−0.0022 (13)	0.0145 (14)	0.0030 (13)
C10	0.0400 (16)	0.0298 (14)	0.0375 (15)	−0.0102 (12)	0.0118 (12)	−0.0122 (12)
C11	0.0304 (13)	0.0346 (15)	0.0248 (13)	0.0033 (11)	0.0050 (10)	−0.0071 (11)
C12	0.0347 (16)	0.0508 (19)	0.0538 (19)	−0.0051 (14)	0.0135 (14)	−0.0019 (15)
C13	0.0405 (16)	0.0269 (14)	0.0307 (14)	0.0033 (12)	0.0108 (12)	0.0061 (11)
C14	0.061 (2)	0.083 (3)	0.0284 (15)	0.0241 (19)	−0.0003 (14)	−0.0120 (16)
C15	0.056 (2)	0.082 (3)	0.0382 (17)	0.0170 (19)	0.0045 (15)	−0.0073 (17)
C16	0.0423 (16)	0.0255 (14)	0.0364 (15)	0.0039 (12)	0.0158 (12)	0.0047 (12)
C17	0.0389 (18)	0.066 (2)	0.083 (3)	0.0104 (16)	0.0204 (17)	−0.018 (2)
C18	0.0475 (17)	0.0357 (16)	0.0381 (16)	−0.0093 (13)	0.0081 (13)	−0.0054 (12)
N3	0.0473 (14)	0.0345 (13)	0.0356 (13)	0.0019 (11)	0.0053 (10)	0.0003 (10)
N2	0.0455 (14)	0.0321 (13)	0.0368 (13)	0.0044 (11)	−0.0017 (10)	−0.0034 (10)
C19	0.0450 (17)	0.0450 (18)	0.0450 (17)	−0.0105 (14)	0.0053 (13)	−0.0041 (14)
C20	0.0344 (15)	0.0485 (18)	0.0450 (17)	0.0027 (13)	0.0038 (12)	−0.0086 (14)
C21	0.0428 (17)	0.0456 (17)	0.0350 (15)	0.0042 (14)	0.0008 (12)	−0.0068 (13)
C22	0.0531 (18)	0.0354 (16)	0.0413 (16)	−0.0012 (14)	−0.0002 (14)	−0.0097 (13)
C23	0.0524 (18)	0.0375 (16)	0.0391 (16)	0.0071 (14)	0.0095 (13)	−0.0036 (13)
C24	0.0399 (16)	0.0397 (16)	0.0327 (14)	−0.0017 (13)	0.0014 (12)	−0.0002 (12)
O1W	0.0417 (12)	0.0376 (12)	0.0512 (13)	−0.0037 (10)	−0.0036 (10)	0.0012 (11)

Geometric parameters (Å, º)

Cl1—C10	1.745 (3)	C14—H14A	0.9900
Cl2—C11	1.739 (3)	C14—H14B	0.9900
O1—C13	1.217 (3)	C15—H15A	0.9800
O2—C13	1.336 (3)	C15—H15B	0.9800
O2—C14	1.447 (3)	C15—H15C	0.9800
O3—C16	1.225 (3)	C17—H17A	0.9800
O4—C16	1.333 (3)	C17—H17B	0.9800
O4—C17	1.451 (3)	C17—H17C	0.9800
N1—C1	1.379 (3)	C18—H18A	0.9800
N1—C5	1.381 (3)	C18—H18B	0.9800
N1—H1	0.872 (10)	C18—H18C	0.9800
C1—C2	1.344 (4)	N3—C21	1.467 (4)
C1—C12	1.503 (4)	N3—C23	1.472 (4)
C2—C13	1.464 (4)	N3—C19	1.477 (4)
C2—C3	1.519 (3)	N2—C24	1.473 (4)
C3—C4	1.526 (3)	N2—C20	1.473 (4)
C3—C6	1.533 (3)	N2—C22	1.477 (4)
C3—H3A	1.0000	C19—C20	1.541 (4)
C4—C5	1.346 (4)	C19—H19A	0.9900
C4—C16	1.470 (4)	C19—H19B	0.9900
C5—C18	1.505 (4)	C20—H20A	0.9900
C6—C11	1.390 (4)	C20—H20B	0.9900
C6—C7	1.395 (4)	C21—C22	1.534 (4)
C7—C8	1.385 (4)	C21—H21A	0.9900
C7—H7A	0.9500	C21—H21B	0.9900
C8—C9	1.376 (4)	C22—H22A	0.9900
C8—H8A	0.9500	C22—H22B	0.9900
C9—C10	1.368 (4)	C23—C24	1.545 (4)
C9—H9A	0.9500	C23—H23A	0.9900
C10—C11	1.399 (4)	C23—H23B	0.9900
C12—H12A	0.9800	C24—H24A	0.9900
C12—H12B	0.9800	C24—H24B	0.9900
C12—H12C	0.9800	O1W—H1W	0.846 (10)
C14—C15	1.481 (4)	O1W—H2W	0.847 (10)
C13—O2—C14	116.6 (2)	H15A—C15—H15C	109.5
C16—O4—C17	118.2 (2)	H15B—C15—H15C	109.5
C1—N1—C5	122.7 (2)	O3—C16—O4	121.6 (2)
C1—N1—H1	116.0 (19)	O3—C16—C4	127.1 (3)
C5—N1—H1	121 (2)	O4—C16—C4	111.3 (2)
C2—C1—N1	119.8 (2)	O4—C17—H17A	109.5
C2—C1—C12	126.1 (2)	O4—C17—H17B	109.5
N1—C1—C12	114.1 (2)	H17A—C17—H17B	109.5
C1—C2—C13	120.9 (2)	O4—C17—H17C	109.5
C1—C2—C3	120.4 (2)	H17A—C17—H17C	109.5
C13—C2—C3	118.8 (2)	H17B—C17—H17C	109.5
C2—C3—C4	111.1 (2)	C5—C18—H18A	109.5
C2—C3—C6	110.0 (2)	C5—C18—H18B	109.5
C4—C3—C6	110.55 (19)	H18A—C18—H18B	109.5
C2—C3—H3A	108.4	C5—C18—H18C	109.5
C4—C3—H3A	108.4	H18A—C18—H18C	109.5
C6—C3—H3A	108.4	H18B—C18—H18C	109.5
C5—C4—C16	122.8 (2)	C21—N3—C23	108.7 (2)
C5—C4—C3	120.2 (2)	C21—N3—C19	108.7 (2)
C16—C4—C3	117.0 (2)	C23—N3—C19	108.4 (2)
C4—C5—N1	119.9 (2)	C24—N2—C20	108.8 (2)
C4—C5—C18	127.5 (2)	C24—N2—C22	109.0 (2)
N1—C5—C18	112.5 (2)	C20—N2—C22	108.0 (2)
C11—C6—C7	117.2 (2)	N3—C19—C20	110.4 (2)
C11—C6—C3	124.2 (2)	N3—C19—H19A	109.6
C7—C6—C3	118.6 (2)	C20—C19—H19A	109.6
C8—C7—C6	121.9 (3)	N3—C19—H19B	109.6
C8—C7—H7A	119.1	C20—C19—H19B	109.6
C6—C7—H7A	119.1	H19A—C19—H19B	108.1
C9—C8—C7	120.2 (3)	N2—C20—C19	109.8 (2)
C9—C8—H8A	119.9	N2—C20—H20A	109.7
C7—C8—H8A	119.9	C19—C20—H20A	109.7
C10—C9—C8	119.0 (3)	N2—C20—H20B	109.7
C10—C9—H9A	120.5	C19—C20—H20B	109.7
C8—C9—H9A	120.5	H20A—C20—H20B	108.2
C9—C10—C11	121.4 (2)	N3—C21—C22	110.6 (2)
C9—C10—Cl1	118.2 (2)	N3—C21—H21A	109.5
C11—C10—Cl1	120.4 (2)	C22—C21—H21A	109.5
C6—C11—C10	120.4 (2)	N3—C21—H21B	109.5
C6—C11—Cl2	121.6 (2)	C22—C21—H21B	109.5
C10—C11—Cl2	118.0 (2)	H21A—C21—H21B	108.1
C1—C12—H12A	109.5	N2—C22—C21	110.0 (2)
C1—C12—H12B	109.5	N2—C22—H22A	109.7
H12A—C12—H12B	109.5	C21—C22—H22A	109.7
C1—C12—H12C	109.5	N2—C22—H22B	109.7
H12A—C12—H12C	109.5	C21—C22—H22B	109.7
H12B—C12—H12C	109.5	H22A—C22—H22B	108.2
O1—C13—O2	122.0 (2)	N3—C23—C24	109.7 (2)
O1—C13—C2	127.2 (3)	N3—C23—H23A	109.7
O2—C13—C2	110.9 (2)	C24—C23—H23A	109.7
O2—C14—C15	107.3 (2)	N3—C23—H23B	109.7
O2—C14—H14A	110.2	C24—C23—H23B	109.7
C15—C14—H14A	110.2	H23A—C23—H23B	108.2
O2—C14—H14B	110.2	N2—C24—C23	110.4 (2)
C15—C14—H14B	110.2	N2—C24—H24A	109.6
H14A—C14—H14B	108.5	C23—C24—H24A	109.6
C14—C15—H15A	109.5	N2—C24—H24B	109.6
C14—C15—H15B	109.5	C23—C24—H24B	109.6
H15A—C15—H15B	109.5	H24A—C24—H24B	108.1
C14—C15—H15C	109.5	H1W—O1W—H2W	106 (2)
C5—N1—C1—C2	12.4 (4)	C3—C6—C11—Cl2	−3.0 (3)
C5—N1—C1—C12	−166.0 (2)	C9—C10—C11—C6	0.9 (4)
N1—C1—C2—C13	−169.8 (2)	Cl1—C10—C11—C6	−178.90 (19)
C12—C1—C2—C13	8.4 (4)	C9—C10—C11—Cl2	−178.6 (2)
N1—C1—C2—C3	8.7 (4)	Cl1—C10—C11—Cl2	1.6 (3)
C12—C1—C2—C3	−173.0 (2)	C14—O2—C13—O1	4.5 (4)
C1—C2—C3—C4	−24.4 (3)	C14—O2—C13—C2	−174.9 (3)
C13—C2—C3—C4	154.2 (2)	C1—C2—C13—O1	−10.4 (4)
C1—C2—C3—C6	98.4 (3)	C3—C2—C13—O1	171.0 (3)
C13—C2—C3—C6	−83.0 (3)	C1—C2—C13—O2	169.1 (2)
C2—C3—C4—C5	22.0 (3)	C3—C2—C13—O2	−9.5 (3)
C6—C3—C4—C5	−100.5 (3)	C13—O2—C14—C15	157.3 (3)
C2—C3—C4—C16	−159.3 (2)	C17—O4—C16—O3	3.3 (4)
C6—C3—C4—C16	78.2 (3)	C17—O4—C16—C4	−175.2 (3)
C16—C4—C5—N1	177.4 (2)	C5—C4—C16—O3	5.5 (4)
C3—C4—C5—N1	−4.1 (4)	C3—C4—C16—O3	−173.1 (2)
C16—C4—C5—C18	−1.3 (4)	C5—C4—C16—O4	−176.1 (2)
C3—C4—C5—C18	177.3 (2)	C3—C4—C16—O4	5.3 (3)
C1—N1—C5—C4	−14.8 (4)	C21—N3—C19—C20	−62.0 (3)
C1—N1—C5—C18	164.0 (2)	C23—N3—C19—C20	56.0 (3)
C2—C3—C6—C11	121.3 (3)	C24—N2—C20—C19	−62.3 (3)
C4—C3—C6—C11	−115.6 (3)	C22—N2—C20—C19	55.9 (3)
C2—C3—C6—C7	−59.1 (3)	N3—C19—C20—N2	5.9 (3)
C4—C3—C6—C7	64.0 (3)	C23—N3—C21—C22	−63.7 (3)
C11—C6—C7—C8	1.5 (4)	C19—N3—C21—C22	54.1 (3)
C3—C6—C7—C8	−178.0 (2)	C24—N2—C22—C21	54.0 (3)
C6—C7—C8—C9	0.0 (4)	C20—N2—C22—C21	−64.1 (3)
C7—C8—C9—C10	−1.1 (4)	N3—C21—C22—N2	7.8 (3)
C8—C9—C10—C11	0.7 (4)	C21—N3—C23—C24	55.1 (3)
C8—C9—C10—Cl1	−179.5 (2)	C19—N3—C23—C24	−62.8 (3)
C7—C6—C11—C10	−1.9 (3)	C20—N2—C24—C23	55.3 (3)
C3—C6—C11—C10	177.6 (2)	C22—N2—C24—C23	−62.2 (3)
C7—C6—C11—Cl2	177.50 (19)	N3—C23—C24—N2	6.6 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1W	0.87 (1)	1.92 (1)	2.791 (3)	178 (3)
O1W—H1W···N2	0.85 (1)	1.92 (1)	2.763 (3)	172 (5)
O1W—H2W···N3^i	0.85 (1)	1.96 (1)	2.798 (3)	171 (4)

Symmetry code: (i) −x, y−1/2, −z+1/2.