N-Phenyl-N'-pyridylureas: stereochemical basis for anti­convulsant activity

4-[N-(2-Chloro-6-methyl­phen­yl)ureido]pyridinium chloride, C₁₃H₁₃ClN₃O⁺·Cl^- (CI-953 hydro­chloride), crystallizes with Z' = 2 in P. In both mol­ecules, the methyl groups and Cl atoms on the benzene rings are disordered. The benzene rings of mol­ecules A and B adopt two conformations, differing by a rotation of 180° about the C-N bond to the ureido group, in an approximate 1:1 ratio. This disorder is further enhanced by the rotation of the methyl groups in both adopted positions. The pyridine and benzene rings inter­sect at angles of 102.1 (1) and 111.3 (1)° for A and B, respectively. Hydrogen bonding is mediated by Cl^- anions, resulting in indirect connectivity between the mol­ecules. Superposition of the mol­ecular structure, after 180° rotation about an amide bond, with that of phenytoin shows that the chemically different mol­ecules possess stereochemical features in common, which may explain their common activities.

S1. Comment

N-Phenyl-N'-pyridinylureas were shown (Lobbestael et al., 1986) to possess anticonvulsant activity in the NIH–NINCDS Antiepileptic Drug Discovery Program. Subsequently, synthesis and testing of a series of over 50 substituted derivatives (Pavia et al., 1990) led to identification of N-(2-chloro-6-methylphenyl)-N'-pyridin-4-ylurea (CI-953) as having the most desirable in vivo profile for a potential anticonvulsant drug. The overall pharmaceutical effects of CI-953 in animal models were similar qualitatively and quantitatively to those of the well known antiepileptic drug phenytoin. These pharmacological similarities led us to determine the crystal and conformational structures of CI-953 in order to ascertain if it possessed stereochemical features in common with the chemically different drug phenytoin, which might be responsible for their similar anticonvulsant properties.

CI-953 hydrochloride crystallizes with Z' = 2 (Fig. 1). The two independent molecules have similar conformations with approximately planar pyridinylurea fragments intersecting the 2,6-disubstituted phenyl ring planes at angles of 69 and 78°. The phenyl rings in both molecules exist in two possible conformations differing by 180° rotation about the C3—N8 bond, resulting in positional disorder of the ortho Cl atoms and methyl groups, with each occupying 50% of each position in the crystal structure. This disorder is further augmented by rotational disorder of the methyl group's H atoms in both positions. Protonation occurs at the pyridinyl atom N15 in both independent molecules. As shown in Fig. 1, the two CI-953 molecules are indirectly linked through hydrogen bonds (Table 1) from the two urea imine groups in each to a chloride anion, a strong intermolecular interaction made possible by/resulting in the cis conformation of the imine H atoms (Fig.2). In addition, a C—H···O hydrogen bond links the type A molecules (Table 1). Van der Waals interactions also contribute to the crystal packing. Intramolecular bond distances and angles are consistent with normal values.

Stereochemical features common to several chemically different types of anticonvulsant drugs, and which are likely determinants of their antiepileptic activity, have been established (Camerman & Camerman, 1980). They consist of two electronegative atoms (hydrogen-bond acceptors) approximately 4.5–5.5 Å apart and at least one hydrophobic group (phenyl ring or equivalent) at a particular location and orientation relative to those atoms. These findings are further supported by a recent study (Thenmozhiyal et al., 2004) of the anticonvulsant properties of a series of phenylmethylenehydantoins, which found that the most important structure–activity descriptor, in essence, was the molecular electronegativity or electron donor capabilities. Although CI-953 is chemically very different from the other drugs studied, we have investigated through molecular superpositions whether similar stereochemical features could exist in CI-953.

Superpositions of CI-953 with phenytoin (Camerman & Camerman, 1971), the best known and conformationally most rigid of the anticonvulsants, maximizing the fit of the two most electronegative atoms, the carbonyl atom O10 and the pyridinal atom N15, with the carbonyl O atoms of phenytoin did not result in a fit of the substituted phenyl group of CI-953 with a phenyl ring of phenytoin even if allowable phenyl ring rotations were invoked. However, as noted above, the observed CI-953 molecular conformation has cis imine H atoms, a conformation favored because of intermolecular hydrogen bonding to the chloride ions. In the absence of this crystallographically imposed feature, a molecular conformation featuring a trans relation of the urea imine H atoms would also be plausible. Accordingly, we produced that conformation by a rotation of 180° about the N8—C9 bond. We then superposed this CI-953 structure with phenytoin by a least-squares maximization of the fit of three atoms in each molecule: O10 and N15 in CI-953 with the carbonyl O atoms in phenytoin, and a phenyl C atom in each (C5 in CI-953 and C11 in phenytoin). The results are shown stereoscopically in Fig. 3. Despite their differences in chemical structure, the two electronegative atoms in each molecule occupy similar positions in space and the disubstituted phenyl ring of CI-953 has a similar position and orientation to a phenyl ring of phenytoin. Since these features are the mediators of anticonvulsant activity in phenytoin, the stereochemical results presented here are persuasive evidence that these features are responsible for the similar anticonvulsant effects of CI-953, and that the two drugs likely involve very similar mechanisms.

It is also noteworthy that in the series of N-phenyl-N'-pyridinylureas synthesized and tested for anticonvulsant activity the most promising analogues, in addition to CI-953, were the 2,6-bismethylphenyl and 2,6-bischlorophenyl compounds. This suggest that the primary function of these groups is to ensure, through steric interactions, that the phenyl plane is roughly perpendicular to the plane of the rest of the molecule, thus maintaining an orientation similar to that of a phenyl ring in phenytoin. The small size of the substituents is also necessary to limit the overall size of the hydrophobic entity in this position.

The efficacy of many antiepileptic drugs is attributed to interactions with ion channels or neurotransmitter systems (Malawska, 2005) but their therapeutic mechanisms at the molecular level are not well understood. Although broad classification of drugs into categories based on a particular mechanistic system is possible, this has limited value because most anticonvulsants possess more than one mechanism of action. The identification of common stereochemical features in chemically different anticonvulsant molecules facilitates new drug design independent of the mechanism(s) of action.

S2. Experimental

Crystals suitable for data collection were obtained by dissolving CI-953 in methanol and subsequently subjected to slow evaporation. Crystals grew in about three weeks. The crystals were small colourless needles. Attempts to grow better crystals in order to avoid disorder proved unsuccessful.

S3. Refinement

All H atoms, except those of the methyl groups, were initially located on a difference map and well behaving during refinement, however, low data to parameters ratio justified placement of H atoms in calculated positions in a riding model approximation. An overall isotropic temperature displacement parameter was refined for all H atoms except for the methyl groups. The final U_iso=0.08 (3) Ų and the range of distances 0.86–0.93 Å. The H atoms from methyl groups were refined as idealized disordered groups with two positions rotated from each other by 60° and the methyl groups C atoms and Cl atoms were refined with partial occupancies set to sum to unity. The C—H distances were fixed at 1.0 Å.

Computing details

Data collection: Picker Operating Manual (Picker, 1967); cell refinement: Picker Operating Manual; data reduction: DATRDN (Stewart, 1976); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. The molecular structure of CI-953, showing 50% probability displacement ellipsoids. H atoms are drawn as small circles of arbitrary radii.
	Fig. 2. A stereodiagram of the molecular packing and hydrogen-bond scheme. Atoms are drawn as circles of arbitrary radii. For clarity, only the H atoms participating in hydrogen bonding are shown.
	Fig. 3. A stereodiagram of the superposition of rotated CI-953 (filled bonds, small circles) and phenytoin. Electronegative atoms are labeled (O is oxygen, N is nitrogen).

4-[N-(2-Chloro-6-methylphenyl)ureido]pyridinium chloride

Crystal data

C13H13ClN3O^+·Cl^−	Z = 4
Mr = 298.16	F(000) = 616
Triclinic, P1	Dx = 1.371 Mg m^−3
a = 8.022 (3) Å	Cu Kα radiation, λ = 1.54178 Å
b = 13.193 (4) Å	Cell parameters from 32 reflections
c = 14.893 (4) Å	θ = 19–45°
α = 69.06 (3)°	µ = 4.01 mm^−1
β = 81.29 (2)°	T = 294 K
γ = 80.60 (3)°	Needle, colourless
V = 1444.9 (9) Å^3	0.52 × 0.12 × 0.08 mm

Data collection

Picker FACS-1 four-circle diffractometer	3375 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.005
Ni-filtered radiation monochromator	θmax = 60.0°, θmin = 3.2°
θ/2θ scans	h = −4→9
Absorption correction: ψ scan (North et al., 1968)	k = −14→14
Tmin = 0.586, Tmax = 0.724	l = −16→16
4418 measured reflections	3 standard reflections every 100 reflections
4272 independent reflections	intensity decay: 2.7%

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.043	H-atom parameters constrained
wR(F^2) = 0.134	w = 1/[σ^2(Fo^2) + (0.0837P)^2 + 0.3467P] where P = (Fo^2 + 2Fc^2)/3
S = 0.94	(Δ/σ)max = 0.003
4272 reflections	Δρmax = 0.27 e Å^−3
385 parameters	Δρmin = −0.15 e Å^−3
7 restraints	Extinction correction: SHELXL97, Fc^*=kFc[1+0.001xFc^2λ^3/sin(2θ)]^-1/4
Primary atom site location: structure-invariant direct methods	Extinction coefficient: 0.0062 (6)

Special details

Experimental. No observed reflections above 60°.

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)
C1A	−0.1968 (5)	0.4567 (3)	−0.0898 (3)	0.0664 (9)
H1A	−0.3126	0.4760	−0.0950	0.081 (4)*
C2A	−0.1406 (5)	0.3730 (2)	−0.0096 (2)	0.0564 (8)
C3A	0.0313 (4)	0.3437 (2)	−0.0020 (2)	0.0489 (7)
C4A	0.1474 (5)	0.4004 (2)	−0.0743 (2)	0.0575 (8)
C5A	0.0879 (6)	0.4843 (3)	−0.1535 (2)	0.0696 (10)
H5A	0.1646	0.5231	−0.2019	0.081 (4)*
C6A	−0.0831 (6)	0.5110 (3)	−0.1614 (3)	0.0703 (10)
H6A	−0.1215	0.5664	−0.2158	0.081 (4)*
C7A	0.344 (2)	0.3784 (18)	−0.078 (3)	0.047 (4)	0.419 (6)
H7A1	0.3770	0.3169	−0.0187	0.114 (16)*	0.209 (3)
H7A2	0.3905	0.4456	−0.0817	0.114 (16)*	0.209 (3)
H7A3	0.3906	0.3583	−0.1365	0.114 (16)*	0.209 (3)
H7A4	0.3951	0.4303	−0.1393	0.114 (16)*	0.209 (3)
H7A5	0.3816	0.3016	−0.0762	0.114 (16)*	0.209 (3)
H7A6	0.3815	0.3889	−0.0214	0.114 (16)*	0.209 (3)
Cl7A	0.3601 (7)	0.3663 (5)	−0.0628 (6)	0.093 (2)	0.581 (6)
N8A	0.0919 (4)	0.25512 (19)	0.07822 (19)	0.0569 (7)
H8A	0.1330	0.2680	0.1226	0.081 (4)*
C9A	0.0852 (4)	0.1504 (2)	0.0853 (2)	0.0470 (7)
O10A	0.0297 (3)	0.12564 (17)	0.02623 (16)	0.0662 (7)
N11A	0.1474 (3)	0.07603 (18)	0.16927 (17)	0.0486 (6)
H11A	0.1826	0.1035	0.2063	0.081 (4)*
C12A	0.1596 (4)	−0.0351 (2)	0.2002 (2)	0.0455 (7)
C13A	0.1199 (5)	−0.0949 (2)	0.1476 (2)	0.0581 (8)
H13A	0.0819	−0.0596	0.0868	0.081 (4)*
C14A	0.1377 (5)	−0.2058 (3)	0.1867 (3)	0.0698 (10)
H14A	0.1094	−0.2461	0.1523	0.081 (4)*
N15A	0.1941 (4)	−0.2580 (2)	0.2723 (2)	0.0667 (8)
H15A	0.2050	−0.3282	0.2947	0.081 (4)*
C16A	0.2343 (5)	−0.2035 (3)	0.3240 (3)	0.0647 (9)
H16A	0.2736	−0.2418	0.3841	0.081 (4)*
C17A	0.2187 (4)	−0.0931 (2)	0.2905 (2)	0.0572 (8)
H17A	0.2472	−0.0557	0.3274	0.081 (4)*
C18A	−0.274 (3)	0.3075 (17)	0.0658 (17)	0.107 (11)	0.581 (6)
H18A	−0.2155	0.2510	0.1201	0.114 (16)*	0.291 (3)
H18B	−0.3351	0.2708	0.0345	0.114 (16)*	0.291 (3)
H18C	−0.3572	0.3583	0.0913	0.114 (16)*	0.291 (3)
H18D	−0.3896	0.3357	0.0438	0.114 (16)*	0.291 (3)
H18E	−0.2701	0.3160	0.1295	0.114 (16)*	0.291 (3)
H18F	−0.2480	0.2285	0.0726	0.114 (16)*	0.291 (3)
Cl1A	−0.2849 (11)	0.3131 (6)	0.0812 (7)	0.0863 (17)	0.419 (6)
C1B	0.7192 (6)	−0.2579 (3)	0.3600 (3)	0.0815 (12)
H1B	0.7411	−0.3191	0.4142	0.080 (4)*
C2B	0.6887 (4)	−0.1550 (3)	0.3675 (3)	0.0580 (8)
C3B	0.6620 (4)	−0.0630 (2)	0.2857 (2)	0.0469 (7)
C4B	0.6565 (5)	−0.0767 (3)	0.1978 (2)	0.0591 (8)
C5B	0.6860 (6)	−0.1799 (3)	0.1924 (3)	0.0827 (12)
H5B	0.6849	−0.1892	0.1335	0.080 (4)*
C6B	0.7171 (7)	−0.2696 (3)	0.2731 (4)	0.0952 (15)
H6B	0.7369	−0.3390	0.2682	0.080 (4)*
C7B	0.638 (3)	0.0211 (16)	0.1086 (14)	0.122 (11)	0.603 (5)
H7B1	0.6117	0.0886	0.1266	0.114 (16)*	0.301 (3)
H7B2	0.5436	0.0154	0.0745	0.114 (16)*	0.301 (3)
H7B3	0.7464	0.0249	0.0650	0.114 (16)*	0.301 (3)
H7B4	0.6561	−0.0026	0.0508	0.114 (16)*	0.301 (3)
H7B5	0.7242	0.0706	0.1029	0.114 (16)*	0.301 (3)
H7B6	0.5214	0.0610	0.1124	0.114 (16)*	0.301 (3)
Cl7B	0.6024 (11)	0.0360 (5)	0.0992 (4)	0.0797 (13)	0.397 (5)
N8B	0.6264 (3)	0.04257 (19)	0.29224 (18)	0.0487 (6)
H8B	0.5312	0.0801	0.2750	0.080 (4)*
C9B	0.7349 (4)	0.0884 (2)	0.3244 (2)	0.0462 (7)
O10B	0.8778 (3)	0.05029 (18)	0.34184 (19)	0.0645 (6)
N11B	0.6573 (3)	0.18678 (19)	0.33408 (18)	0.0479 (6)
H11B	0.5549	0.2070	0.3187	0.080 (4)*
C12B	0.7257 (4)	0.2544 (2)	0.3652 (2)	0.0432 (6)
C13B	0.8944 (4)	0.2432 (3)	0.3830 (2)	0.0554 (8)
H13B	0.9699	0.1848	0.3752	0.080 (4)*
C14B	0.9480 (5)	0.3176 (3)	0.4116 (3)	0.0672 (10)
H14B	1.0618	0.3111	0.4210	0.080 (4)*
N15B	0.8428 (4)	0.3992 (2)	0.4266 (2)	0.0659 (8)
H15B	0.8800	0.4443	0.4464	0.080 (4)*
C16B	0.6799 (5)	0.4130 (3)	0.4116 (2)	0.0612 (9)
H16B	0.6080	0.4707	0.4235	0.080 (4)*
C17B	0.6170 (4)	0.3442 (2)	0.3791 (2)	0.0501 (7)
H17B	0.5042	0.3561	0.3662	0.080 (4)*
C18B	0.701 (4)	−0.144 (3)	0.466 (2)	0.074 (11)	0.397 (5)
H18G	0.6752	−0.0655	0.4608	0.114 (16)*	0.199 (3)
H18H	0.8190	−0.1719	0.4854	0.114 (16)*	0.199 (3)
H18I	0.6182	−0.1878	0.5161	0.114 (16)*	0.199 (3)
H18J	0.7331	−0.2179	0.5141	0.114 (16)*	0.199 (3)
H18K	0.5893	−0.1116	0.4895	0.114 (16)*	0.199 (3)
H18L	0.7900	−0.0956	0.4587	0.114 (16)*	0.199 (3)
Cl1B	0.6720 (9)	−0.1409 (5)	0.4801 (5)	0.0761 (14)	0.603 (5)
Cl1	0.78591 (10)	0.49808 (6)	0.59447 (6)	0.0552 (3)
Cl2	0.29829 (10)	0.21846 (6)	0.26294 (6)	0.0625 (3)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1A	0.076 (2)	0.0475 (19)	0.069 (2)	0.0088 (17)	−0.0277 (19)	−0.0109 (18)
C2A	0.071 (2)	0.0387 (16)	0.0548 (19)	−0.0076 (15)	−0.0162 (17)	−0.0057 (14)
C3A	0.071 (2)	0.0302 (14)	0.0454 (16)	−0.0068 (14)	−0.0215 (15)	−0.0060 (13)
C4A	0.076 (2)	0.0391 (16)	0.0567 (19)	−0.0111 (15)	−0.0050 (16)	−0.0145 (15)
C5A	0.108 (3)	0.0444 (18)	0.0493 (19)	−0.020 (2)	0.0040 (19)	−0.0076 (16)
C6A	0.107 (3)	0.0410 (18)	0.053 (2)	0.0070 (19)	−0.026 (2)	−0.0031 (16)
C7A	0.050 (8)	0.026 (5)	0.075 (10)	−0.005 (5)	−0.009 (7)	−0.027 (6)
Cl7A	0.070 (2)	0.100 (4)	0.114 (4)	−0.0141 (17)	−0.0103 (19)	−0.039 (2)
N8A	0.087 (2)	0.0320 (13)	0.0536 (15)	−0.0050 (12)	−0.0352 (14)	−0.0059 (11)
C9A	0.0598 (18)	0.0332 (15)	0.0455 (16)	−0.0043 (13)	−0.0117 (14)	−0.0085 (13)
O10A	0.109 (2)	0.0392 (11)	0.0547 (13)	−0.0073 (12)	−0.0369 (13)	−0.0099 (10)
N11A	0.0670 (16)	0.0341 (13)	0.0424 (13)	−0.0040 (11)	−0.0207 (12)	−0.0053 (11)
C12A	0.0493 (17)	0.0355 (15)	0.0440 (16)	−0.0013 (12)	−0.0051 (13)	−0.0059 (12)
C13A	0.079 (2)	0.0371 (16)	0.0561 (19)	−0.0065 (15)	−0.0182 (17)	−0.0091 (14)
C14A	0.094 (3)	0.0395 (17)	0.076 (2)	−0.0062 (17)	−0.023 (2)	−0.0149 (17)
N15A	0.080 (2)	0.0331 (14)	0.075 (2)	−0.0024 (13)	−0.0101 (16)	−0.0037 (14)
C16A	0.079 (2)	0.0450 (18)	0.0520 (19)	0.0008 (16)	−0.0153 (17)	0.0053 (15)
C17A	0.073 (2)	0.0398 (17)	0.0489 (18)	−0.0022 (15)	−0.0163 (16)	−0.0016 (14)
C18A	0.063 (9)	0.113 (15)	0.121 (18)	0.011 (8)	−0.033 (10)	−0.013 (10)
Cl1A	0.095 (4)	0.072 (3)	0.077 (2)	−0.031 (2)	0.004 (2)	−0.003 (2)
C1B	0.103 (3)	0.0385 (19)	0.092 (3)	−0.0078 (19)	−0.003 (2)	−0.0125 (19)
C2B	0.064 (2)	0.0428 (17)	0.065 (2)	−0.0061 (15)	−0.0063 (16)	−0.0158 (16)
C3B	0.0503 (17)	0.0332 (15)	0.0563 (18)	−0.0079 (12)	0.0013 (13)	−0.0156 (14)
C4B	0.074 (2)	0.0481 (18)	0.0564 (19)	−0.0160 (16)	0.0026 (16)	−0.0193 (16)
C5B	0.115 (3)	0.066 (2)	0.082 (3)	−0.028 (2)	0.017 (2)	−0.046 (2)
C6B	0.140 (4)	0.043 (2)	0.104 (4)	−0.016 (2)	0.012 (3)	−0.034 (2)
C7B	0.143 (14)	0.123 (13)	0.113 (13)	−0.006 (7)	−0.009 (7)	−0.065 (9)
Cl7B	0.118 (3)	0.075 (2)	0.0488 (17)	−0.034 (2)	−0.0102 (18)	−0.0130 (15)
N8B	0.0533 (15)	0.0362 (13)	0.0603 (15)	−0.0011 (11)	−0.0142 (12)	−0.0193 (11)
C9B	0.0492 (18)	0.0393 (15)	0.0480 (17)	−0.0058 (13)	−0.0012 (13)	−0.0134 (13)
O10B	0.0449 (13)	0.0576 (14)	0.0969 (18)	0.0020 (11)	−0.0106 (12)	−0.0358 (13)
N11B	0.0440 (13)	0.0425 (13)	0.0625 (16)	−0.0035 (11)	−0.0072 (11)	−0.0243 (12)
C12B	0.0477 (16)	0.0366 (15)	0.0442 (15)	−0.0122 (12)	−0.0030 (12)	−0.0102 (12)
C13B	0.0522 (18)	0.0456 (17)	0.072 (2)	−0.0072 (14)	−0.0110 (15)	−0.0214 (16)
C14B	0.068 (2)	0.056 (2)	0.080 (2)	−0.0149 (18)	−0.0260 (19)	−0.0154 (18)
N15B	0.093 (2)	0.0441 (15)	0.0686 (18)	−0.0205 (15)	−0.0270 (16)	−0.0161 (14)
C16B	0.084 (3)	0.0380 (17)	0.060 (2)	−0.0058 (16)	−0.0060 (18)	−0.0154 (15)
C17B	0.0573 (19)	0.0385 (16)	0.0538 (17)	−0.0082 (13)	−0.0029 (14)	−0.0148 (14)
C18B	0.060 (10)	0.051 (10)	0.09 (2)	0.009 (7)	−0.029 (14)	0.009 (11)
Cl1B	0.107 (3)	0.0648 (19)	0.0493 (12)	−0.0180 (18)	−0.0004 (16)	−0.0107 (11)
Cl1	0.0700 (5)	0.0341 (4)	0.0603 (5)	−0.0074 (3)	−0.0128 (4)	−0.0115 (3)
Cl2	0.0624 (5)	0.0558 (5)	0.0780 (6)	0.0086 (4)	−0.0341 (4)	−0.0292 (4)

Geometric parameters (Å, º)

C1A—C6A	1.362 (6)	C1B—C6B	1.360 (6)
C1A—C2A	1.381 (5)	C1B—C2B	1.381 (5)
C1A—H1A	0.9300	C1B—H1B	0.9300
C2A—C3A	1.381 (5)	C2B—C3B	1.393 (5)
C2A—C18A	1.55 (2)	C2B—C18B	1.55 (3)
C2A—Cl1A	1.689 (8)	C2B—Cl1B	1.735 (6)
C3A—C4A	1.391 (5)	C3B—C4B	1.393 (4)
C3A—N8A	1.422 (4)	C3B—N8B	1.410 (3)
C4A—C5A	1.381 (5)	C4B—C5B	1.372 (5)
C4A—C7A	1.551 (18)	C4B—C7B	1.491 (19)
C4A—Cl7A	1.711 (7)	C4B—Cl7B	1.726 (7)
C5A—C6A	1.372 (6)	C5B—C6B	1.372 (6)
C5A—H5A	0.9300	C5B—H5B	0.9300
C6A—H6A	0.9300	C6B—H6B	0.9300
C7A—H7A1	1.0000	C7B—H7B1	1.0000
C7A—H7A2	1.0000	C7B—H7B2	1.0000
C7A—H7A3	1.0000	C7B—H7B3	1.0000
C7A—H7A4	1.0000	C7B—H7B4	1.0000
C7A—H7A5	1.0000	C7B—H7B5	1.0000
C7A—H7A6	1.0000	C7B—H7B6	1.0000
N8A—C9A	1.356 (4)	N8B—C9B	1.362 (4)
N8A—H8A	0.8600	N8B—H8B	0.8600
C9A—O10A	1.204 (3)	C9B—O10B	1.201 (4)
C9A—O10A	1.204 (3)	C9B—O10B	1.201 (4)
C9A—N11A	1.389 (4)	C9B—N11B	1.392 (4)
N11A—C12A	1.362 (4)	N11B—C12B	1.357 (4)
N11A—H11A	0.8600	N11B—H11B	0.8600
C12A—C13A	1.392 (4)	C12B—C13B	1.393 (4)
C12A—C17A	1.400 (4)	C12B—C17B	1.411 (4)
C13A—C14A	1.360 (5)	C13B—C14B	1.349 (4)
C13A—H13A	0.9300	C13B—H13B	0.9300
C14A—N15A	1.323 (5)	C14B—N15B	1.319 (5)
C14A—H14A	0.9300	C14B—H14B	0.9300
N15A—C16A	1.327 (5)	N15B—C16B	1.331 (5)
N15A—H15A	0.8600	N15B—H15B	0.8600
C16A—C17A	1.352 (4)	C16B—C17B	1.361 (4)
C16A—H16A	0.9300	C16B—H16B	0.9300
C17A—H17A	0.9300	C17B—H17B	0.9300
C18A—H18A	1.0000	C18B—H18G	1.0000
C18A—H18B	1.0000	C18B—H18H	1.0000
C18A—H18C	1.0000	C18B—H18I	1.0000
C18A—H18D	1.0000	C18B—H18J	1.0000
C18A—H18E	1.0000	C18B—H18K	1.0000
C18A—H18F	1.0000	C18B—H18L	1.0000
C6A—C1A—C2A	120.2 (4)	C6B—C1B—C2B	119.9 (4)
C6A—C1A—H1A	119.9	C6B—C1B—H1B	120.1
C2A—C1A—H1A	119.9	C2B—C1B—H1B	120.1
C1A—C2A—C3A	120.0 (3)	C1B—C2B—C3B	120.2 (3)
C1A—C2A—C18A	118.3 (8)	C1B—C2B—C18B	118.5 (12)
C3A—C2A—C18A	121.4 (8)	C3B—C2B—C18B	121.1 (12)
C1A—C2A—Cl1A	118.9 (4)	C1B—C2B—Cl1B	119.9 (4)
C3A—C2A—Cl1A	120.9 (4)	C3B—C2B—Cl1B	119.9 (3)
C2A—C3A—C4A	119.8 (3)	C2B—C3B—C4B	119.1 (3)
C2A—C3A—N8A	120.9 (3)	C2B—C3B—N8B	121.1 (3)
C4A—C3A—N8A	119.3 (3)	C4B—C3B—N8B	119.6 (3)
C5A—C4A—C3A	119.1 (3)	C5B—C4B—C3B	119.5 (3)
C5A—C4A—C7A	114.1 (13)	C5B—C4B—C7B	120.6 (9)
C3A—C4A—C7A	126.8 (13)	C3B—C4B—C7B	119.6 (9)
C5A—C4A—Cl7A	121.4 (4)	C5B—C4B—Cl7B	121.3 (4)
C3A—C4A—Cl7A	119.5 (4)	C3B—C4B—Cl7B	119.1 (3)
C6A—C5A—C4A	120.7 (3)	C6B—C5B—C4B	120.7 (4)
C6A—C5A—H5A	119.7	C6B—C5B—H5B	119.6
C4A—C5A—H5A	119.7	C4B—C5B—H5B	119.6
C1A—C6A—C5A	120.3 (3)	C1B—C6B—C5B	120.6 (3)
C1A—C6A—H6A	119.9	C1B—C6B—H6B	119.7
C5A—C6A—H6A	119.9	C5B—C6B—H6B	119.7
C4A—C7A—H7A1	109.5	C4B—C7B—H7B1	109.5
C4A—C7A—H7A2	109.5	C4B—C7B—H7B2	109.5
H7A1—C7A—H7A2	109.5	H7B1—C7B—H7B2	109.5
C4A—C7A—H7A3	109.5	C4B—C7B—H7B3	109.5
H7A1—C7A—H7A3	109.5	H7B1—C7B—H7B3	109.5
H7A2—C7A—H7A3	109.5	H7B2—C7B—H7B3	109.5
C4A—C7A—H7A4	109.5	C4B—C7B—H7B4	109.5
H7A1—C7A—H7A4	141.1	H7B1—C7B—H7B4	141.1
H7A2—C7A—H7A4	56.3	H7B2—C7B—H7B4	56.3
H7A3—C7A—H7A4	56.3	H7B3—C7B—H7B4	56.3
C4A—C7A—H7A5	109.5	C4B—C7B—H7B5	109.5
H7A1—C7A—H7A5	56.3	H7B1—C7B—H7B5	56.3
H7A2—C7A—H7A5	141.1	H7B2—C7B—H7B5	141.1
H7A3—C7A—H7A5	56.3	H7B3—C7B—H7B5	56.3
H7A4—C7A—H7A5	109.5	H7B4—C7B—H7B5	109.5
C4A—C7A—H7A6	109.5	C4B—C7B—H7B6	109.5
H7A1—C7A—H7A6	56.3	H7B1—C7B—H7B6	56.3
H7A2—C7A—H7A6	56.3	H7B2—C7B—H7B6	56.3
H7A3—C7A—H7A6	141.1	H7B3—C7B—H7B6	141.1
H7A4—C7A—H7A6	109.5	H7B4—C7B—H7B6	109.5
H7A5—C7A—H7A6	109.5	H7B5—C7B—H7B6	109.5
C9A—N8A—C3A	120.5 (2)	C9B—N8B—C3B	123.5 (3)
C9A—N8A—H8A	119.8	C9B—N8B—H8B	118.3
C3A—N8A—H8A	119.8	C3B—N8B—H8B	118.3
O10A—C9A—N8A	123.8 (3)	O10B—C9B—N8B	125.4 (3)
O10A—C9A—N8A	123.8 (3)	O10B—C9B—N8B	125.4 (3)
O10A—C9A—N11A	124.4 (3)	O10B—C9B—N11B	124.2 (3)
O10A—C9A—N11A	124.4 (3)	O10B—C9B—N11B	124.2 (3)
N8A—C9A—N11A	111.8 (2)	N8B—C9B—N11B	110.4 (3)
C12A—N11A—C9A	128.0 (2)	C12B—N11B—C9B	127.0 (3)
C12A—N11A—H11A	116.0	C12B—N11B—H11B	116.5
C9A—N11A—H11A	116.0	C9B—N11B—H11B	116.5
N11A—C12A—C13A	124.6 (3)	N11B—C12B—C13B	125.4 (3)
N11A—C12A—C17A	117.6 (3)	N11B—C12B—C17B	117.0 (3)
C13A—C12A—C17A	117.8 (3)	C13B—C12B—C17B	117.5 (3)
C14A—C13A—C12A	118.8 (3)	C14B—C13B—C12B	119.7 (3)
C14A—C13A—H13A	120.6	C14B—C13B—H13B	120.1
C12A—C13A—H13A	120.6	C12B—C13B—H13B	120.1
N15A—C14A—C13A	121.7 (3)	N15B—C14B—C13B	121.6 (3)
N15A—C14A—H14A	119.1	N15B—C14B—H14B	119.2
C13A—C14A—H14A	119.1	C13B—C14B—H14B	119.2
C14A—N15A—C16A	121.0 (3)	C14B—N15B—C16B	121.1 (3)
C14A—N15A—H15A	119.5	C14B—N15B—H15B	119.4
C16A—N15A—H15A	119.5	C16B—N15B—H15B	119.4
N15A—C16A—C17A	120.8 (3)	N15B—C16B—C17B	121.1 (3)
N15A—C16A—H16A	119.6	N15B—C16B—H16B	119.5
C17A—C16A—H16A	119.6	C17B—C16B—H16B	119.5
C16A—C17A—C12A	119.8 (3)	C16B—C17B—C12B	118.9 (3)
C16A—C17A—H17A	120.1	C16B—C17B—H17B	120.5
C12A—C17A—H17A	120.1	C12B—C17B—H17B	120.5
C2A—C18A—H18A	109.5	C2B—C18B—H18G	109.5
C2A—C18A—H18B	109.5	C2B—C18B—H18H	109.5
H18A—C18A—H18B	109.5	H18G—C18B—H18H	109.5
C2A—C18A—H18C	109.5	C2B—C18B—H18I	109.5
H18A—C18A—H18C	109.5	H18G—C18B—H18I	109.5
H18B—C18A—H18C	109.5	H18H—C18B—H18I	109.5
C2A—C18A—H18D	109.5	C2B—C18B—H18J	109.5
H18A—C18A—H18D	141.1	H18G—C18B—H18J	141.1
H18B—C18A—H18D	56.3	H18H—C18B—H18J	56.3
H18C—C18A—H18D	56.3	H18I—C18B—H18J	56.3
C2A—C18A—H18E	109.5	C2B—C18B—H18K	109.5
H18A—C18A—H18E	56.3	H18G—C18B—H18K	56.3
H18B—C18A—H18E	141.1	H18H—C18B—H18K	141.1
H18C—C18A—H18E	56.3	H18I—C18B—H18K	56.3
H18D—C18A—H18E	109.5	H18J—C18B—H18K	109.5
C2A—C18A—H18F	109.5	C2B—C18B—H18L	109.5
H18A—C18A—H18F	56.3	H18G—C18B—H18L	56.3
H18B—C18A—H18F	56.3	H18H—C18B—H18L	56.3
H18C—C18A—H18F	141.1	H18I—C18B—H18L	141.1
H18D—C18A—H18F	109.5	H18J—C18B—H18L	109.5
H18E—C18A—H18F	109.5	H18K—C18B—H18L	109.5

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N8A—H8A···Cl2	0.86	2.48	3.273 (3)	154
N8B—H8B···Cl2	0.86	2.37	3.183 (3)	158
N11A—H11A···Cl2	0.86	2.34	3.173 (3)	163
N11B—H11B···Cl2	0.86	2.30	3.131 (3)	164
N15A—H15A···Cl1^i	0.86	2.26	3.072 (3)	158
N15B—H15B···Cl1	0.86	2.53	3.155 (3)	131
N15B—H15B···Cl1^ii	0.86	2.82	3.397 (3)	126
C13A—H13A···O10A	0.93	2.27	2.864 (4)	121
C13A—H13A···O10A^iii	0.93	2.48	3.186 (4)	133
C13B—H13B···O10B	0.93	2.26	2.850 (4)	121

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