Antidiarrhetic loperamide hydro­chloride

Single crystals of the anhydrous form of the title compound {systematic name: 1-[3-(dimethyl­carbamo­yl)-3,3-diphenyl­prop­yl]-4-hy­droxy-4-(4-chloro­phen­yl)piperidin-1-ium chlor­ide}, C₂₉H₃₄ClN₂O₂⁺·Cl⁻, were obtained by diffusion of acetone into a solution in 2-propanol. In the structure, N—H...Cl⁻ and O—H...Cl⁻ hydrogen bonds connect neighbouring mol­ecules and chloride anions to form chains along the c-axis direction. Neighbouring chains along the b-axis direction are connected by inter­molecular C—H...Cl⁻ con­tacts, defining layers parallel to the (100) planes. The layers are connected by weak inter­molecular C—H...Cl inter­actions only, which may account for the plate-like shape of the crystals.

S1. Comment

Loperamide hydrochloride {systematic name: 1-[3-(dimethylcarbamoyl)-3,3-diphenylpropyl]-4-hydroxy-4-(4-methylphenyl)piperidin-1-ium chloride}, (I), is the most potent active pharmaceutical ingredient known for the treatment of diarrhoea (Garwin, 1989; O'Neil, 2006). It is sold as an over-the-counter drug with the brand name Imodium^TM. Various generica are also known. The compound belongs to the group of opioids but does not show opioid-typical side effects such as analgesia, miosis or respiratory depression (Ruppin, 1987; Steinhilber et al., 2005). Its effects are found only within the intestine by means of lowering intestinal activity. Generally, the compound is well tolerated (Baker, 2007; Hanauer, 2008). Crystal structures of polymorphs and pseudopolymorphs of loperamide are known, including loperamide monohydrate (Germain et al., 1977) and loperamide hydrochloride tetrahydrate (Caira et al., 1995). All of the forms, including the title compound, (I), have been characterized by various spectroscopic and thermal analysis techniques (Van Rompay & Carter, 1990). However, the crystal structure of (I) has not yet been reported.

A polymorph screen was performed for (I) in order to search for other polymorphic forms (including solvates), by using various solvents and solvent mixtures. The compound, which has quite high solubility, was recrystallized in order to obtain either suitable single crystals, or at least a powder of improved crystallinity, or other phases. Two different crystallization methods were used: (i) recrystallization from solvents and (ii) diffusion of an antisolvent via the gas phase into a solution of (I). The solvents used included N-methylpyrrolidone, dimethyl sulfoxide, alcohols, ethers and esters, acetone, chloroform and water. The solvents were not dried before use. Altogether about 200 experiments were carried out. From these experiments, the known tetrahydrate of (I), the monohydrate of loperamide, the anhydrous structure of (I) described here, and an amorphous form were found. For all forms, except the amorphous one, crystals were obtained which were characterized using single-crystal structure analysis. No other solid forms were found.

The molecular structure of (I) is shown in Fig. 1. The central piperidinium ring adopts a chair conformation. The bridging N1—C12 and C7—C1 bonds are in equatorial positions, whereas the hydroxy group is in an axial position with respect to the piperidinium ring. The 4-chlorophenyl ring is almost coplanar with the C7—O1 bond [torsion angle O1—C7—C1—C6 = 18.72 (18)°]. A similar coplanarity is observed in loperamide hydrochloride tetrahydrate (Caira et al., 1995), loperamide hydrate (Germain et al., 1977) and loperamide N-oxide hydrate (Peeters et al., 1996) (Table 2). The geometry around the amide N atom is approximately planar, the sum of the three valence angles about atom N2 being 358.5 (1)°. The chloride anion accepts O—H···Cl^- and N⁺—H···Cl^- hydrogen bonds (Table 1), and connects two symmetry-related loperamide units. The hydrogen bonding results in chains of molecules related by c-glide planes and extended along the c-axis direction, as shown in Fig. 2. In the graph-set notation of Etter (1990) and extended by Bernstein et al. (1995), the hydrogen bonding is described as C₂¹(8). Additionally, the chain exhibits a C—H···Cl^- contact (Table 1, entry 6). Neighbouring chains along the b-axis direction are connected by two additional intermolecular C—H···Cl^- contacts (Table 1, entries 3 and 4), defining layers parallel to the (100) planes (Fig. 3). Neighbouring layers along the a-axis direction exhibit only weak intermolecular phenyl–chlorophenyl C—H···Cl interactions (Table 1, entry 5), which may explain why the compound crystallizes as thin plates.

Comparing the structure of (I) with the structures of loperamide hydrochloride tetrahydrate (Caira et al., 1995), loperamide hydrate (Germain et al., 1977) and loperamide N-oxide hydrate (Peeters et al., 1996) shows the central part of the molecule to have the same conformation in all four structures. The ethane fragment has a trans conformation and also is trans-positioned with respect to one of the N—C bonds of the piperidinium ring (Table 2). The main difference between the molecules results from the orientation of the N,N-dimethylcarboxamide and the two phenyl groups at C14 with respect to the ethane fragment. The ethane-carboxamide C12—C13—C14—C15 torsion angle is 43.81 (15)° in (I), compared to ca 70° for the other three structures (Table 2). The angle between the planes of the two phenyl rings at C14 is 74.7 (1)° in (I), which differs by approximately 20° from the values of 57.4, 51.1 and 57.1° reported for loperamide hydrochloride tetrahydrate, loperamide hydrate and loperamide N-oxide hydrate, respectively.

Differential thermal analysis (DTA) and thermal gravimetry (TG) experiments were carried out to determine the temperature at which the tetrahydrate of (I) transforms to the anhydrate, and the temperature of decomposition of the anhydrate. The tetrahydrate releases water continuously between 313 and 393 K to form the anhydrate, which is stable up to the decomposition point of 483 K.

In the literature, a second anhydrate form of (I) has been described by Van Rompay & Carter (1990). We tried to obtain this phase by using the described procedure and by varying the experimental conditions. However, none of our experiments led to the formation of this second anhydrate, as shown by X-ray powder diffraction.

Related literature

For related literature, see: Baker (2007); Bernstein et al. (1995); Caira et al. (1995); Etter (1990); Garwin (1989); Germain et al. (1977); Hanauer (2008); O'Neil (2006); Peeters et al. (1996); Ruppin (1987); Steinhilber et al. (2005); Van Rompay & Carter (1990).

S2. Experimental

Loperamide hydrochloride was purchased from TCI Europe (lot No. LO154, >98% purity). The solvents were of analytical grade and were not dried before use. Crystals of (I) were grown by gas diffusion. A suspension of 50 mg of (I) in 2-propanol (2 ml) was heated in a beaker to 323 K and subsequently cooled to room temperature. The beaker was placed in a larger beaker and acetone (4 ml) was added to the larger beaker. The larger beaker was sealed and kept for 2 weeks at room temperature, after which time colourless plates of (I) were obtained. The DTA–TG measurements were performed on a TGA 92 (SETARAM) device. About 10–20 mg of the sample were filled into corundum crucibles and heated from room temperature to 498 K at a rate of 3 K min^-1 under a nitrogen atmosphere.

S3. Refinement

H atoms on N and O atoms were taken from a difference Fourier synthesis and refined freely with isotropic displacement parameters. H atoms on C atoms were positioned geometrically and treated as riding, with C—H = 0.95 (aromatic), 0.98 (methyl) or 0.99 Å (methylene), and with U_iso(H) = 1.5U_eq(C) (methyl) or 1.2U_eq(C) otherwise. The torsion angles about the C—N bonds were refined for the methyl groups.

Computing details

Data collection: SMART (Siemens, 1995); cell refinement: SMART (Siemens, 1995); data reduction: SAINT (Siemens, 1995); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. The molecular structure of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level. H atoms are drawn as small spheres of arbitrary radius.
	Fig. 2. A hydrogen-bonded chain of (I). The hydrogen bonds are shown as dashed lines. Displacement ellipsoids are drawn at the 50% probability level. [Symmetry codes: (i) x, -y+1/2, z-1/2; (iv) x, -y+1/2, z+1/2.]
	Fig. 3. The crystal packing of (I), viewed down [010]. Hydrogen bonds are shown as dashed lines and H atoms on C atoms have been omitted for clarity. Displacement ellipsoids are drawn at the 50% probability level.

1-[3-(dimethylcarbamoyl)-3,3-diphenylpropyl]-4-hydroxy- 4-(4-methylphenyl)piperidin-1-ium chloride

Crystal data

C29H34ClN2O2^+·Cl^−	F(000) = 1088
Mr = 513.48	Dx = 1.298 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 301 reflections
a = 16.6542 (16) Å	θ = 3–23°
b = 12.2529 (12) Å	µ = 0.28 mm^−1
c = 13.1410 (12) Å	T = 169 K
β = 101.577 (9)°	Plate, colourless
V = 2627.0 (4) Å^3	0.60 × 0.60 × 0.07 mm
Z = 4

Data collection

Siemens SMART 1K CCD diffractometer	6600 independent reflections
Radiation source: normal-focus sealed tube	4941 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.045
ω scans	θmax = 28.9°, θmin = 2.1°
Absorption correction: multi-scan (SADABS; Sheldrick, 2000)	h = −21→22
Tmin = 0.887, Tmax = 0.981	k = −16→16
30967 measured reflections	l = −16→16

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) = 0.094	H atoms treated by a mixture of independent and constrained refinement
S = 1.06	w = 1/[σ^2(Fo^2) + (0.04P)^2 + 0.6P] where P = (Fo^2 + 2Fc^2)/3
6600 reflections	(Δ/σ)max = 0.001
326 parameters	Δρmax = 0.37 e Å^−3
0 restraints	Δρmin = −0.42 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.

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	0.94963 (2)	0.08733 (4)	0.69738 (4)	0.04610 (13)
Cl2	0.53100 (2)	0.07736 (3)	0.88259 (3)	0.02554 (9)
O1	0.54013 (6)	0.05893 (8)	0.65020 (8)	0.0224 (2)
H1B	0.5405 (11)	0.0647 (14)	0.7166 (15)	0.037 (5)*
O2	0.16474 (6)	0.26899 (8)	0.32241 (8)	0.0276 (2)
N1	0.43695 (7)	0.26888 (9)	0.50273 (9)	0.0187 (2)
H1A	0.4644 (10)	0.3264 (14)	0.4749 (13)	0.034 (5)*
N2	0.14143 (7)	0.27537 (10)	0.48426 (9)	0.0242 (3)
C1	0.67500 (8)	0.13635 (11)	0.64735 (10)	0.0207 (3)
C2	0.72754 (9)	0.22328 (12)	0.64112 (11)	0.0253 (3)
H2A	0.7052	0.2941	0.6255	0.030*
C3	0.81174 (9)	0.20893 (13)	0.65717 (12)	0.0290 (3)
H3A	0.8469	0.2691	0.6528	0.035*
C4	0.84366 (9)	0.10557 (13)	0.67963 (12)	0.0282 (3)
C5	0.79370 (9)	0.01748 (13)	0.68809 (12)	0.0284 (3)
H5A	0.8165	−0.0530	0.7044	0.034*
C6	0.70957 (9)	0.03367 (12)	0.67230 (11)	0.0240 (3)
H6A	0.6749	−0.0264	0.6786	0.029*
C7	0.58200 (8)	0.15019 (11)	0.61715 (11)	0.0196 (3)
C8	0.55087 (8)	0.25654 (11)	0.65738 (11)	0.0207 (3)
H8A	0.5636	0.2562	0.7343	0.025*
H8B	0.5798	0.3192	0.6336	0.025*
C9	0.45889 (8)	0.27079 (11)	0.61947 (10)	0.0200 (3)
H9A	0.4295	0.2114	0.6477	0.024*
H9B	0.4414	0.3411	0.6452	0.024*
C10	0.46656 (8)	0.16588 (11)	0.46034 (11)	0.0220 (3)
H10A	0.4540	0.1687	0.3835	0.026*
H10B	0.4372	0.1026	0.4823	0.026*
C11	0.55807 (8)	0.15073 (11)	0.49817 (11)	0.0211 (3)
H11A	0.5876	0.2105	0.4706	0.025*
H11B	0.5751	0.0809	0.4710	0.025*
C12	0.34656 (8)	0.28045 (11)	0.46110 (11)	0.0214 (3)
H12A	0.3174	0.2191	0.4867	0.026*
H12B	0.3358	0.2763	0.3843	0.026*
C13	0.31327 (8)	0.38810 (11)	0.49373 (11)	0.0202 (3)
H13A	0.3537	0.4466	0.4906	0.024*
H13B	0.3064	0.3820	0.5666	0.024*
C14	0.22965 (8)	0.42046 (11)	0.42382 (10)	0.0178 (3)
C15	0.17515 (8)	0.31589 (11)	0.40645 (11)	0.0196 (3)
C16	0.16286 (10)	0.30300 (14)	0.59467 (12)	0.0318 (4)
H16A	0.2042	0.2517	0.6303	0.048*
H16B	0.1138	0.2985	0.6250	0.048*
H16C	0.1849	0.3774	0.6027	0.048*
C17	0.09195 (10)	0.17640 (12)	0.46011 (13)	0.0311 (4)
H17A	0.0566	0.1836	0.3912	0.047*
H17B	0.0579	0.1662	0.5122	0.047*
H17C	0.1282	0.1132	0.4608	0.047*
C18	0.19021 (8)	0.51422 (11)	0.47458 (10)	0.0194 (3)
C19	0.10527 (9)	0.52974 (12)	0.45298 (12)	0.0239 (3)
H19A	0.0712	0.4806	0.4077	0.029*
C20	0.07022 (9)	0.61572 (13)	0.49671 (13)	0.0297 (3)
H20A	0.0124	0.6250	0.4814	0.036*
C21	0.11885 (10)	0.68827 (13)	0.56259 (13)	0.0307 (4)
H21A	0.0946	0.7470	0.5928	0.037*
C22	0.20288 (10)	0.67471 (12)	0.58406 (12)	0.0270 (3)
H22A	0.2365	0.7247	0.6288	0.032*
C23	0.23851 (9)	0.58839 (11)	0.54058 (11)	0.0221 (3)
H23A	0.2964	0.5798	0.5560	0.027*
C24	0.24086 (8)	0.46113 (11)	0.31597 (11)	0.0193 (3)
C25	0.17224 (9)	0.48900 (12)	0.24025 (11)	0.0243 (3)
H25A	0.1191	0.4813	0.2553	0.029*
C26	0.18019 (10)	0.52746 (12)	0.14393 (12)	0.0294 (3)
H26A	0.1326	0.5465	0.0941	0.035*
C27	0.25701 (11)	0.53858 (13)	0.11936 (12)	0.0323 (4)
H27A	0.2624	0.5643	0.0529	0.039*
C28	0.32535 (10)	0.51159 (13)	0.19326 (13)	0.0325 (4)
H28A	0.3783	0.5187	0.1775	0.039*
C29	0.31732 (9)	0.47418 (12)	0.29051 (12)	0.0258 (3)
H29A	0.3652	0.4572	0.3407	0.031*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.02040 (19)	0.0644 (3)	0.0524 (3)	0.01065 (19)	0.00469 (18)	0.0034 (2)
Cl2	0.02292 (18)	0.03055 (19)	0.02422 (19)	0.00335 (15)	0.00728 (13)	0.00021 (15)
O1	0.0251 (5)	0.0208 (5)	0.0216 (6)	−0.0018 (4)	0.0055 (4)	0.0005 (4)
O2	0.0337 (6)	0.0265 (5)	0.0230 (6)	−0.0072 (5)	0.0070 (4)	−0.0050 (4)
N1	0.0175 (6)	0.0192 (6)	0.0191 (6)	0.0021 (5)	0.0028 (5)	0.0002 (5)
N2	0.0276 (7)	0.0229 (6)	0.0234 (7)	−0.0036 (5)	0.0082 (5)	0.0009 (5)
C1	0.0210 (7)	0.0244 (7)	0.0167 (7)	0.0030 (6)	0.0038 (5)	0.0004 (6)
C2	0.0247 (8)	0.0253 (7)	0.0258 (8)	0.0026 (6)	0.0050 (6)	0.0053 (6)
C3	0.0238 (8)	0.0359 (9)	0.0280 (8)	−0.0014 (6)	0.0069 (6)	0.0038 (7)
C4	0.0179 (7)	0.0426 (9)	0.0236 (8)	0.0075 (6)	0.0028 (6)	0.0014 (7)
C5	0.0289 (8)	0.0303 (8)	0.0247 (8)	0.0105 (6)	0.0024 (6)	0.0018 (6)
C6	0.0249 (7)	0.0234 (7)	0.0234 (8)	0.0029 (6)	0.0039 (6)	0.0000 (6)
C7	0.0195 (7)	0.0185 (6)	0.0208 (7)	0.0017 (5)	0.0043 (5)	0.0015 (5)
C8	0.0202 (7)	0.0214 (7)	0.0196 (7)	0.0012 (5)	0.0021 (5)	−0.0021 (6)
C9	0.0214 (7)	0.0208 (7)	0.0179 (7)	0.0029 (5)	0.0043 (5)	−0.0023 (6)
C10	0.0234 (7)	0.0221 (7)	0.0199 (7)	0.0045 (6)	0.0025 (6)	−0.0041 (6)
C11	0.0218 (7)	0.0220 (7)	0.0198 (7)	0.0047 (5)	0.0052 (5)	0.0008 (6)
C12	0.0167 (7)	0.0218 (7)	0.0244 (7)	0.0006 (5)	0.0008 (5)	−0.0004 (6)
C13	0.0179 (7)	0.0222 (7)	0.0197 (7)	0.0021 (5)	0.0015 (5)	−0.0004 (6)
C14	0.0158 (6)	0.0193 (6)	0.0183 (7)	0.0007 (5)	0.0032 (5)	−0.0002 (5)
C15	0.0174 (7)	0.0189 (6)	0.0219 (7)	0.0020 (5)	0.0026 (5)	0.0014 (6)
C16	0.0380 (9)	0.0365 (9)	0.0223 (8)	−0.0016 (7)	0.0093 (7)	0.0058 (7)
C17	0.0334 (9)	0.0242 (8)	0.0385 (9)	−0.0069 (6)	0.0140 (7)	0.0028 (7)
C18	0.0221 (7)	0.0187 (6)	0.0181 (7)	0.0014 (5)	0.0054 (5)	0.0018 (5)
C19	0.0212 (7)	0.0224 (7)	0.0283 (8)	−0.0011 (6)	0.0058 (6)	0.0009 (6)
C20	0.0225 (8)	0.0286 (8)	0.0407 (9)	0.0042 (6)	0.0132 (7)	0.0031 (7)
C21	0.0375 (9)	0.0246 (8)	0.0339 (9)	0.0071 (7)	0.0163 (7)	−0.0005 (7)
C22	0.0355 (8)	0.0226 (7)	0.0231 (8)	−0.0014 (6)	0.0061 (6)	−0.0026 (6)
C23	0.0217 (7)	0.0228 (7)	0.0216 (7)	0.0001 (6)	0.0038 (6)	0.0013 (6)
C24	0.0212 (7)	0.0161 (6)	0.0209 (7)	0.0003 (5)	0.0049 (5)	−0.0006 (5)
C25	0.0223 (7)	0.0252 (7)	0.0247 (8)	−0.0005 (6)	0.0034 (6)	0.0011 (6)
C26	0.0366 (9)	0.0254 (8)	0.0231 (8)	0.0019 (7)	−0.0014 (6)	0.0037 (6)
C27	0.0469 (10)	0.0284 (8)	0.0237 (8)	−0.0021 (7)	0.0119 (7)	0.0052 (7)
C28	0.0320 (9)	0.0345 (9)	0.0350 (9)	−0.0028 (7)	0.0166 (7)	0.0038 (7)
C29	0.0222 (7)	0.0272 (8)	0.0281 (8)	−0.0001 (6)	0.0054 (6)	0.0033 (6)

Geometric parameters (Å, º)

Cl1—C4	1.7474 (15)	C12—H12B	0.9900
O1—C7	1.4307 (16)	C13—C14	1.5580 (18)
O1—H1B	0.87 (2)	C13—H13A	0.9900
O2—C15	1.2260 (17)	C13—H13B	0.9900
N1—C12	1.5016 (17)	C14—C18	1.5402 (19)
N1—C10	1.5022 (17)	C14—C24	1.5485 (19)
N1—C9	1.5042 (18)	C14—C15	1.5603 (19)
N1—H1A	0.952 (18)	C16—H16A	0.9800
N2—C15	1.3556 (18)	C16—H16B	0.9800
N2—C16	1.4626 (19)	C16—H16C	0.9800
N2—C17	1.4646 (18)	C17—H17A	0.9800
C1—C2	1.391 (2)	C17—H17B	0.9800
C1—C6	1.3951 (19)	C17—H17C	0.9800
C1—C7	1.5292 (19)	C18—C23	1.3948 (19)
C2—C3	1.387 (2)	C18—C19	1.3987 (19)
C2—H2A	0.9500	C19—C20	1.384 (2)
C3—C4	1.382 (2)	C19—H19A	0.9500
C3—H3A	0.9500	C20—C21	1.384 (2)
C4—C5	1.381 (2)	C20—H20A	0.9500
C5—C6	1.389 (2)	C21—C22	1.381 (2)
C5—H5A	0.9500	C21—H21A	0.9500
C6—H6A	0.9500	C22—C23	1.390 (2)
C7—C11	1.5341 (19)	C22—H22A	0.9500
C7—C8	1.5351 (19)	C23—H23A	0.9500
C8—C9	1.5228 (18)	C24—C29	1.389 (2)
C8—H8A	0.9900	C24—C25	1.3986 (19)
C8—H8B	0.9900	C25—C26	1.382 (2)
C9—H9A	0.9900	C25—H25A	0.9500
C9—H9B	0.9900	C26—C27	1.388 (2)
C10—C11	1.5166 (19)	C26—H26A	0.9500
C10—H10A	0.9900	C27—C28	1.380 (2)
C10—H10B	0.9900	C27—H27A	0.9500
C11—H11A	0.9900	C28—C29	1.389 (2)
C11—H11B	0.9900	C28—H28A	0.9500
C12—C13	1.5252 (19)	C29—H29A	0.9500
C12—H12A	0.9900
C7—O1—H1B	109.5 (12)	C12—C13—C14	112.74 (11)
C12—N1—C10	108.90 (10)	C12—C13—H13A	109.0
C12—N1—C9	113.00 (11)	C14—C13—H13A	109.0
C10—N1—C9	111.14 (10)	C12—C13—H13B	109.0
C12—N1—H1A	108.3 (10)	C14—C13—H13B	109.0
C10—N1—H1A	105.1 (10)	H13A—C13—H13B	107.8
C9—N1—H1A	110.1 (10)	C18—C14—C24	107.25 (11)
C15—N2—C16	127.44 (12)	C18—C14—C13	110.05 (11)
C15—N2—C17	116.10 (12)	C24—C14—C13	111.34 (11)
C16—N2—C17	114.91 (12)	C18—C14—C15	112.94 (11)
C2—C1—C6	118.01 (13)	C24—C14—C15	107.69 (11)
C2—C1—C7	121.06 (12)	C13—C14—C15	107.59 (11)
C6—C1—C7	120.65 (12)	O2—C15—N2	120.18 (13)
C3—C2—C1	121.50 (14)	O2—C15—C14	119.31 (12)
C3—C2—H2A	119.2	N2—C15—C14	120.48 (12)
C1—C2—H2A	119.2	N2—C16—H16A	109.5
C4—C3—C2	118.85 (14)	N2—C16—H16B	109.5
C4—C3—H3A	120.6	H16A—C16—H16B	109.5
C2—C3—H3A	120.6	N2—C16—H16C	109.5
C5—C4—C3	121.41 (14)	H16A—C16—H16C	109.5
C5—C4—Cl1	119.87 (12)	H16B—C16—H16C	109.5
C3—C4—Cl1	118.72 (12)	N2—C17—H17A	109.5
C4—C5—C6	118.85 (14)	N2—C17—H17B	109.5
C4—C5—H5A	120.6	H17A—C17—H17B	109.5
C6—C5—H5A	120.6	N2—C17—H17C	109.5
C5—C6—C1	121.35 (14)	H17A—C17—H17C	109.5
C5—C6—H6A	119.3	H17B—C17—H17C	109.5
C1—C6—H6A	119.3	C23—C18—C19	118.12 (13)
O1—C7—C1	111.38 (11)	C23—C18—C14	120.83 (12)
O1—C7—C11	105.66 (11)	C19—C18—C14	121.02 (12)
C1—C7—C11	107.91 (11)	C20—C19—C18	120.85 (14)
O1—C7—C8	109.88 (11)	C20—C19—H19A	119.6
C1—C7—C8	113.54 (11)	C18—C19—H19A	119.6
C11—C7—C8	108.11 (11)	C21—C20—C19	120.41 (14)
C9—C8—C7	111.83 (11)	C21—C20—H20A	119.8
C9—C8—H8A	109.3	C19—C20—H20A	119.8
C7—C8—H8A	109.3	C22—C21—C20	119.50 (14)
C9—C8—H8B	109.3	C22—C21—H21A	120.2
C7—C8—H8B	109.3	C20—C21—H21A	120.2
H8A—C8—H8B	107.9	C21—C22—C23	120.41 (14)
N1—C9—C8	110.75 (11)	C21—C22—H22A	119.8
N1—C9—H9A	109.5	C23—C22—H22A	119.8
C8—C9—H9A	109.5	C22—C23—C18	120.71 (13)
N1—C9—H9B	109.5	C22—C23—H23A	119.6
C8—C9—H9B	109.5	C18—C23—H23A	119.6
H9A—C9—H9B	108.1	C29—C24—C25	117.26 (13)
N1—C10—C11	111.37 (11)	C29—C24—C14	122.83 (12)
N1—C10—H10A	109.4	C25—C24—C14	119.89 (12)
C11—C10—H10A	109.4	C26—C25—C24	121.35 (14)
N1—C10—H10B	109.4	C26—C25—H25A	119.3
C11—C10—H10B	109.4	C24—C25—H25A	119.3
H10A—C10—H10B	108.0	C25—C26—C27	120.60 (14)
C10—C11—C7	111.90 (12)	C25—C26—H26A	119.7
C10—C11—H11A	109.2	C27—C26—H26A	119.7
C7—C11—H11A	109.2	C28—C27—C26	118.78 (15)
C10—C11—H11B	109.2	C28—C27—H27A	120.6
C7—C11—H11B	109.2	C26—C27—H27A	120.6
H11A—C11—H11B	107.9	C27—C28—C29	120.55 (15)
N1—C12—C13	111.94 (11)	C27—C28—H28A	119.7
N1—C12—H12A	109.2	C29—C28—H28A	119.7
C13—C12—H12A	109.2	C28—C29—C24	121.45 (14)
N1—C12—H12B	109.2	C28—C29—H29A	119.3
C13—C12—H12B	109.2	C24—C29—H29A	119.3
H12A—C12—H12B	107.9
C6—C1—C2—C3	1.2 (2)	C16—N2—C15—C14	−14.5 (2)
C7—C1—C2—C3	−172.75 (13)	C17—N2—C15—C14	−179.48 (12)
C1—C2—C3—C4	0.1 (2)	C18—C14—C15—O2	133.56 (13)
C2—C3—C4—C5	−1.1 (2)	C24—C14—C15—O2	15.33 (16)
C2—C3—C4—Cl1	178.81 (12)	C13—C14—C15—O2	−104.79 (14)
C3—C4—C5—C6	0.8 (2)	C18—C14—C15—N2	−48.25 (16)
Cl1—C4—C5—C6	−179.15 (12)	C24—C14—C15—N2	−166.48 (12)
C4—C5—C6—C1	0.6 (2)	C13—C14—C15—N2	73.40 (15)
C2—C1—C6—C5	−1.5 (2)	C24—C14—C18—C23	−93.29 (14)
C7—C1—C6—C5	172.42 (13)	C13—C14—C18—C23	27.98 (17)
C2—C1—C7—O1	−167.51 (13)	C15—C14—C18—C23	148.22 (13)
C6—C1—C7—O1	18.72 (18)	C24—C14—C18—C19	84.42 (15)
C2—C1—C7—C11	76.95 (16)	C13—C14—C18—C19	−154.31 (13)
C6—C1—C7—C11	−96.82 (15)	C15—C14—C18—C19	−34.06 (17)
C2—C1—C7—C8	−42.85 (18)	C23—C18—C19—C20	−0.6 (2)
C6—C1—C7—C8	143.38 (13)	C14—C18—C19—C20	−178.36 (13)
O1—C7—C8—C9	−58.43 (15)	C18—C19—C20—C21	0.2 (2)
C1—C7—C8—C9	176.11 (11)	C19—C20—C21—C22	0.4 (2)
C11—C7—C8—C9	56.42 (15)	C20—C21—C22—C23	−0.5 (2)
C12—N1—C9—C8	178.89 (11)	C21—C22—C23—C18	0.1 (2)
C10—N1—C9—C8	56.10 (14)	C19—C18—C23—C22	0.5 (2)
C7—C8—C9—N1	−57.49 (15)	C14—C18—C23—C22	178.23 (13)
C12—N1—C10—C11	178.93 (11)	C18—C14—C24—C29	115.77 (14)
C9—N1—C10—C11	−55.96 (15)	C13—C14—C24—C29	−4.69 (18)
N1—C10—C11—C7	56.82 (15)	C15—C14—C24—C29	−122.40 (14)
O1—C7—C11—C10	61.63 (14)	C18—C14—C24—C25	−62.65 (15)
C1—C7—C11—C10	−179.13 (11)	C13—C14—C24—C25	176.89 (12)
C8—C7—C11—C10	−55.96 (15)	C15—C14—C24—C25	59.18 (15)
C10—N1—C12—C13	−175.34 (11)	C29—C24—C25—C26	0.3 (2)
C9—N1—C12—C13	60.64 (15)	C14—C24—C25—C26	178.79 (13)
N1—C12—C13—C14	160.53 (11)	C24—C25—C26—C27	0.6 (2)
C12—C13—C14—C18	167.24 (11)	C25—C26—C27—C28	−0.7 (2)
C12—C13—C14—C24	−73.97 (14)	C26—C27—C28—C29	−0.1 (2)
C12—C13—C14—C15	43.81 (15)	C27—C28—C29—C24	1.0 (2)
C16—N2—C15—O2	163.68 (14)	C25—C24—C29—C28	−1.1 (2)
C17—N2—C15—O2	−1.31 (19)	C14—C24—C29—C28	−179.53 (13)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1A···Cl2^i	0.95 (2)	2.15 (2)	3.0802 (12)	165 (2)
O1—H1B···Cl2	0.87 (2)	2.22 (2)	3.0962 (11)	176 (2)
C13—H13A···Cl2^ii	0.99	2.78	3.613 (2)	142
C23—H23A···Cl2^ii	0.95	2.83	3.771 (2)	173
C25—H25A···Cl1^iii	0.95	2.90	3.755 (2)	151
C29—H29A···Cl2^i	0.95	2.74	3.578 (2)	148

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