A novel potent non-nucleoside reverse transcriptase inhibitor acyl­thio­carbamate derivative with extensive intra­molecular [pi]-[pi] inter­actions

In the crystal structure of the novel acyl­thio­carbamate derivative O-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)­ethyl] N-(4-methyl­phenyl)-N-(3-nitro­benzoyl)thio­carbamate, C₂₅H₁₉N₃O₆S, intra- and inter­molecular [pi]-[pi] inter­actions occur between the phthalimide and N-benzoyl moieties. The partial atomic charges, calculated by ab initio methods, are consistent with the observed structure.

S1. Comment

Acylthiocarbamates (ATCs) represent a novel chemical class, synthesized through an original highly convergent one-pot three-step procedure that combines, sequentially and covalently, three types of building blocks, namely alcohols, isothiocyanates and acyl chlorides (Ranize et al., 2003). ATCs have proved to be a new class of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), structurally related to N-phenyl-N-thiazolylthiourea derivatives. A structure-based optimization strategy led to the identification of O-(2-phthalimidoethyl) ATCs, which proved to be active at low nanomolar concentrations. Docking simulations suggest that phthalimidoethyl ATCs do not share the bioactive `butterfly like' conformation typical of first-generation NNRTIs. According to this model, the ethyl linker would assume an extended conformation, with the N-phenyl and N-acyl moieties positioned at nearly 90° and located at the top of the allosteric binding site RT, while the phthalimide framework would be positioned at the entrance of the cavity.

In order to characterize this novel class of potent NNRTIs at the atomic level, and to provide insights for further chemical modifications, the crystal structure of (I), O-[2-(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl] N-(4-methylphenyl)-N-(3-nitrobenzoyl)thiocarbamate, one of the most potent ATCs currently available (EC50 = 20 nM; Cesarini et al., 2003), has been determined by single-crystal X-ray analysis and the results are presented here.

The structure of (I) is shown in Fig. 1, where the labels A, B and C are used to specify the ring moieties, as follows: 5A is the five-membered ring defined by atoms C1/N1/C8/C7/C2, 6A is the fused aromatic ring defined by atoms C2/C3/C4/C5/C6/C7, B is the 3-nitro benzoyl ring and C is the methylphenyl ring. The shape of (I) is horseshoe-like, with the phthalimide and 3-nitrobenzoyl groups facing each other. The `linker' connecting these two ring systems is formed by atoms C9/C10/O3/C11/N2/C19 and contains an acylthiocarbamic group. The C11—O3 bond distance is in agreement with the value found in an analogous structure of a secondary N-phenyl thiocarbamate (1.330 Å; Sakamoto et al., 1998), indicating a less marked double-bond character compared with the corresponding value reported for a primary acyl thiocarbamate (1.290 Å; Morales et al., 2000)

Ring C is rotated by a dihedral angle of 83.8 (1)° with respect to ring B. All rings are planar to within 0.01 Å. The thiocarbamic moiety shows a planar conformation, atoms C12, C11, C19 and N2 being coplanar to within 0.004 Å. The molecular fragment N2/C19/(O4)/Ph—NO₂ also shows a certain degree of planarity, the conformation being partially stabilized by weak intramolecular hydrogen bonds. Notably, rings 5A and B (Fig. 1) are in contact through a π–π stacking interaction. The mean planes of rings 5A and B form a dihedral angle of 9.6 (1)° and the centroid–centroid distance between the rings is 3.84 (2) Å.

In order to compare similar geometries, the Cambridge Structural Database (CSD, Version?; Allen, 2002) was searched, retrieving all molecules with similar A and B rings separated by an intramolecular centroid–centroid distance within 4.5 Å. Among the nine compounds found, only three have a dihedral angle between the stacked rings of less than 13°: CSD refcodes GUTTIY (Aldridge et al., 2003), HONXOX (Barrett et al., 1998) and QANWAD (Singh et al., 2000) (Fig 2). In the HONXOX structure, the presence of a bulky carboxylate substituent at the phenyl ring B very close to the linker causes a perturbation in the π–π interaction. In fact, among the four structures considered, it is the only case for which the centroid–centroid distance 6A···B is less than that of 5A···B.

Owing to the importance assumed by aromatic π-systems in chemistry and physics, but mainly in biology, the nature of the π–π interaction has been widely studied (see, for example, Hobza et al., 1994; Hunter & Sanders, 1990). To investigate the contribution of electrostatic components to the 5A···B interaction, an ab initio calculation was performed. Mulliken atomic charges were calculated by single-point methods HF/STO-6–311G*, as implemented in HYPERCHEM (Hypercube, 2005). The same computations were applied on both the title compound and the three molecules selected from the CSD, and the relevant parameters obtained for these four molecules are summarized in Table 2. The charge-distribution analysis in the four molecules shows that atoms C1 and C8 of the phthalimide system have the most positive partial charges, suggesting that the π–π stacked conformation is mainly guided by the electrostatic interactions C1···π and C8···π. Moreover, the variation of the centroid–centroid distance, as well as the relative displacement of the two rings, is surely influenced by a series of parameters, including the nature and number of atoms of the linker, the type and position of the substituent present on the phenyl ring B, and probably the occurrence of (weak) hydrogen-bond interactions.

Even considering the crystal packing (Fig. 3), the molecules tend to arrange in such a way as to realise the A–B π–π interactions. The molecules involved in the intermolecular case are the centrosymmetric pairs, but the interaction is weaker than for the intramolecular case and, therefore, the molecules also appear more shifted. In fact, the centroid–centroid distance between the two A rings is 4.22 (3) Å and the two rings superimpose only partially, as atoms O1/C1–C5 overlap with atoms C5'–C1'/O1' [prime indicates symmetry operator (−1 − x, 1 − y, −1 − z), shortest distance O1···C5' = 3.603 (4) Å]. Apart from two intermolecular contacts, which are appreciably shorter than the sum of the van der Waals radii [C20···S(−x, y − 1/2, −z + 1/2) = 3.405 (2) Å and C21···S(−x, y − 1/2, −z + 1/2) = 3.205 (3) Å], all other intermolecular distances, as well as all bond lengths and bond angles, are in normal ranges (Reference for standard values?).

S2. Experimental

The worked up reaction mixture (Source? Reference?) was dissolved in a dichloromethane–ethanol mixture (Ratio?). The solution was kept at room temperature for 2 d and crystals of (I) grew as colourless rods [Prism below?].

S3. Refinement

The methyl H atoms were treated as an idealized group, with C—H = 0.96 Å, with a global U_iso value fixed at 1.2U_eq(C18). All other H atoms were located in a difference Fourier map and refined freely. [Please check added text] Atom O6 of the nitro group exhibits a large displacement parameter, indicating its tendency to be disordered over two different positions. However, the structural model with the best agreement indexes was that obtained without considering the split positions.

Computing details

Data collection: MACH3 (Nonius, 2000); cell refinement: MACH3; data reduction: NRCVAX (Gabe et al., 1989) and CADABS (local software); program(s) used to solve structure: NRCVAX; program(s) used to refine structure: SHELXL97 (Sheldrick, 1997), PARST95 (Nardelli, 1995) and HYPERCHEM (Hypercube, 2005); molecular graphics: ORTEP-3 for Windows (Version 1.05; Farrugia, 1997) and Mercury (Version 1.3; Bruno et al., 2002); software used to prepare material for publication: Please provide missing details.

Figures

	Fig. 1. A drawing of (I), with the labelling scheme for the atoms and rings. Displacement parameters are drawn at the 50% probability level and H atoms are shown as small spheres of arbitrary radii.
	Fig. 2. Schematic representations and three-dimensional structures of the three molecules selected from the CSD.
	Fig. 3. The crystal packing of (I), viewed along the a axis.

O-[2-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-yl)ethyl] N-(4-methylphenyl)-N-(3-nitrobenzoyl)thiocarbamate

Crystal data

C25H19N3O6S	F(000) = 1016
Mr = 489.49	Dx = 1.399 Mg m^−3
Monoclinic, P21/c	Melting point: 452 K
Hall symbol: -P 2ybc	Mo Kα radiation, λ = 0.71070 Å
a = 7.918 (2) Å	Cell parameters from 16 reflections
b = 10.890 (1) Å	θ = 15.1–18.3°
c = 27.087 (7) Å	µ = 0.19 mm^−1
β = 95.72 (2)°	T = 293 K
V = 2324.0 (9) Å^3	Prism, colourless
Z = 4	0.32 × 0.26 × 0.09 mm

Data collection

Bruker Nonius MACH3 diffractometer	Rint = 0.000
Radiation source: X-Ray	θmax = 27.5°, θmin = 2.6°
Graphite monochromator	h = 0→10
ω/θ scans	k = 0→14
5311 measured reflections	l = −35→34
5311 independent reflections	2 standard reflections every 90 min
2977 reflections with I > 2σ(I)	intensity decay: none

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)] = 0.055	Hydrogen site location: difference Fourier map
wR(F^2) = 0.127	H atoms treated by a mixture of independent and constrained refinement
S = 1.00	w = 1/[σ^2(Fo^2) + (0.0565P)^2] where P = (Fo^2 + 2Fc^2)/3
5311 reflections	(Δ/σ)max = 0.013
381 parameters	Δρmax = 0.23 e Å^−3
0 restraints	Δρmin = −0.21 e Å^−3

Special details

Refinement. The methylic hydrogen atoms have been treated as idealized group (AFIX 137 instruction), with a global U_iso fixed to 1.2 times that of the bonded carbon atom (C18). One of the oxygen atoms (O6) of the nitro group exhibits a large displacement parameter, indicating its tendency to be disordered over two different positions. However, the structural model with the best agreement indexes was that obtained not considering the split positions.

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

	x	y	z	Uiso*/Ueq
C1	−0.3824 (3)	0.5149 (3)	0.42214 (9)	0.0498 (6)
C2	−0.4409 (3)	0.4042 (2)	0.44791 (8)	0.0460 (6)
C3	−0.6017 (4)	0.3618 (3)	0.45431 (11)	0.0621 (8)
C4	−0.6158 (4)	0.2572 (3)	0.48120 (12)	0.0721 (9)
C5	−0.4748 (5)	0.1945 (3)	0.50153 (13)	0.0714 (9)
C6	−0.3104 (4)	0.2353 (3)	0.49532 (11)	0.0600 (7)
C7	−0.2986 (3)	0.3417 (2)	0.46799 (8)	0.0447 (6)
C8	−0.1464 (3)	0.4090 (2)	0.45546 (9)	0.0454 (6)
C9	−0.0989 (4)	0.6132 (3)	0.41576 (10)	0.0545 (7)
C10	−0.0676 (4)	0.6157 (2)	0.36218 (10)	0.0501 (7)
C11	0.1038 (3)	0.5105 (2)	0.30868 (9)	0.0386 (5)
C12	0.3261 (3)	0.4080 (2)	0.26844 (8)	0.0360 (5)
C13	0.4604 (3)	0.4877 (2)	0.27377 (10)	0.0448 (6)
C14	0.5765 (3)	0.4865 (3)	0.23867 (11)	0.0528 (7)
C15	0.5622 (3)	0.4064 (2)	0.19940 (10)	0.0523 (7)
C16	0.4254 (4)	0.3281 (3)	0.19480 (11)	0.0597 (8)
C17	0.3060 (3)	0.3290 (3)	0.22914 (10)	0.0537 (7)
C18	0.6913 (4)	0.4044 (3)	0.16143 (13)	0.0857 (11)
H18A	0.6677	0.4702	0.1382	0.103*
H18B	0.6844	0.3274	0.1441	0.103*
H18C	0.8033	0.4145	0.1780	0.103*
C19	0.1929 (3)	0.2991 (2)	0.33312 (8)	0.0357 (5)
C20	0.0250 (3)	0.25505 (19)	0.34709 (8)	0.0315 (5)
C21	−0.1298 (3)	0.2944 (2)	0.32394 (9)	0.0377 (5)
C22	−0.2790 (3)	0.2390 (2)	0.33466 (10)	0.0488 (6)
C23	−0.2761 (3)	0.1424 (2)	0.36730 (11)	0.0518 (7)
C24	−0.1218 (3)	0.1040 (2)	0.38912 (9)	0.0468 (6)
C25	0.0285 (3)	0.1588 (2)	0.38016 (9)	0.0399 (5)
S	0.06127 (9)	0.60838 (7)	0.26357 (3)	0.0642 (2)
N1	−0.2066 (3)	0.51110 (18)	0.42882 (7)	0.0462 (5)
N2	0.2016 (2)	0.40733 (16)	0.30457 (7)	0.0363 (4)
N3	−0.1162 (4)	−0.0029 (2)	0.42241 (11)	0.0783 (8)
O1	−0.4658 (3)	0.5932 (2)	0.39966 (7)	0.0735 (6)
O2	0.0022 (2)	0.38436 (18)	0.46578 (7)	0.0606 (5)
O3	0.05238 (19)	0.51825 (14)	0.35399 (6)	0.0414 (4)
O4	0.31815 (19)	0.23620 (16)	0.34132 (7)	0.0556 (5)
O5	−0.2464 (3)	−0.0502 (2)	0.43169 (10)	0.1078 (9)
O6	0.0208 (4)	−0.0414 (3)	0.43877 (14)	0.1471 (15)
H3	−0.696 (4)	0.413 (3)	0.4404 (10)	0.067 (9)*
H4	−0.725 (4)	0.222 (3)	0.4898 (12)	0.099 (11)*
H5	−0.480 (4)	0.125 (3)	0.5206 (12)	0.093 (11)*
H6	−0.210 (3)	0.192 (3)	0.5099 (10)	0.066 (9)*
H91	0.015 (3)	0.607 (2)	0.4370 (8)	0.040 (6)*
H92	−0.157 (3)	0.691 (3)	0.4230 (10)	0.074 (9)*
H101	−0.181 (4)	0.597 (2)	0.3395 (10)	0.066 (8)*
H102	−0.016 (3)	0.694 (3)	0.3541 (10)	0.067 (8)*
H13	0.467 (3)	0.544 (2)	0.3003 (9)	0.050 (7)*
H14	0.673 (3)	0.536 (2)	0.2443 (9)	0.065 (8)*
H16	0.415 (4)	0.272 (3)	0.1694 (11)	0.079 (10)*
H17	0.212 (3)	0.272 (3)	0.2262 (10)	0.069 (8)*
H21	−0.132 (3)	0.357 (2)	0.3005 (8)	0.041 (6)*
H22	−0.375 (3)	0.266 (2)	0.3181 (9)	0.058 (8)*
H23	−0.376 (4)	0.108 (3)	0.3785 (10)	0.072 (9)*
H25	0.127 (3)	0.132 (2)	0.3947 (8)	0.032 (6)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0542 (16)	0.0592 (17)	0.0366 (13)	0.0124 (13)	0.0069 (11)	−0.0021 (13)
C2	0.0468 (14)	0.0556 (16)	0.0360 (13)	0.0021 (12)	0.0066 (11)	−0.0036 (11)
C3	0.0442 (16)	0.087 (2)	0.0562 (17)	0.0002 (16)	0.0090 (13)	−0.0083 (17)
C4	0.059 (2)	0.094 (3)	0.066 (2)	−0.0239 (19)	0.0184 (17)	−0.0068 (19)
C5	0.092 (3)	0.062 (2)	0.064 (2)	−0.0190 (19)	0.0274 (19)	0.0059 (17)
C6	0.067 (2)	0.0591 (18)	0.0544 (17)	0.0076 (16)	0.0108 (15)	0.0058 (14)
C7	0.0455 (14)	0.0518 (15)	0.0380 (13)	−0.0002 (12)	0.0108 (11)	−0.0008 (12)
C8	0.0475 (15)	0.0511 (15)	0.0394 (13)	0.0026 (12)	0.0129 (11)	−0.0054 (11)
C9	0.070 (2)	0.0447 (16)	0.0517 (16)	−0.0050 (15)	0.0213 (15)	−0.0040 (13)
C10	0.0618 (18)	0.0364 (14)	0.0558 (16)	0.0047 (13)	0.0246 (14)	0.0033 (12)
C11	0.0360 (12)	0.0387 (13)	0.0428 (13)	−0.0019 (10)	0.0123 (10)	0.0042 (10)
C12	0.0299 (11)	0.0358 (12)	0.0439 (13)	0.0002 (10)	0.0112 (9)	0.0064 (10)
C13	0.0400 (13)	0.0445 (15)	0.0500 (15)	−0.0064 (11)	0.0056 (11)	0.0001 (12)
C14	0.0335 (13)	0.0582 (17)	0.0682 (19)	−0.0114 (13)	0.0123 (12)	0.0120 (15)
C15	0.0503 (15)	0.0451 (15)	0.0658 (17)	0.0101 (12)	0.0277 (13)	0.0131 (13)
C16	0.073 (2)	0.0471 (16)	0.0643 (19)	−0.0070 (14)	0.0314 (15)	−0.0099 (15)
C17	0.0535 (16)	0.0501 (16)	0.0611 (17)	−0.0189 (13)	0.0228 (13)	−0.0077 (14)
C18	0.085 (2)	0.078 (2)	0.105 (3)	0.0091 (18)	0.062 (2)	0.014 (2)
C19	0.0282 (11)	0.0403 (13)	0.0386 (12)	0.0020 (10)	0.0044 (9)	0.0035 (10)
C20	0.0293 (11)	0.0307 (11)	0.0355 (11)	0.0003 (9)	0.0084 (9)	−0.0005 (9)
C21	0.0334 (12)	0.0358 (13)	0.0441 (14)	0.0018 (10)	0.0052 (10)	0.0001 (11)
C22	0.0308 (13)	0.0515 (16)	0.0643 (17)	−0.0002 (12)	0.0061 (12)	−0.0045 (14)
C23	0.0403 (14)	0.0494 (16)	0.0691 (18)	−0.0085 (12)	0.0223 (13)	−0.0040 (14)
C24	0.0524 (15)	0.0367 (13)	0.0550 (15)	−0.0008 (11)	0.0232 (12)	0.0071 (12)
C25	0.0359 (13)	0.0389 (13)	0.0461 (14)	0.0046 (11)	0.0101 (11)	0.0041 (11)
S	0.0685 (5)	0.0675 (5)	0.0615 (4)	0.0283 (4)	0.0304 (4)	0.0314 (4)
N1	0.0490 (13)	0.0476 (12)	0.0440 (12)	0.0016 (10)	0.0145 (9)	0.0011 (10)
N2	0.0320 (9)	0.0351 (10)	0.0438 (11)	0.0007 (8)	0.0132 (8)	0.0057 (9)
N3	0.080 (2)	0.0602 (16)	0.100 (2)	0.0030 (15)	0.0371 (17)	0.0340 (15)
O1	0.0774 (14)	0.0780 (15)	0.0649 (12)	0.0258 (12)	0.0063 (11)	0.0162 (11)
O2	0.0401 (10)	0.0753 (13)	0.0673 (12)	0.0093 (9)	0.0094 (9)	−0.0004 (10)
O3	0.0486 (10)	0.0365 (9)	0.0410 (9)	0.0023 (7)	0.0135 (7)	0.0028 (7)
O4	0.0304 (9)	0.0598 (11)	0.0784 (13)	0.0107 (8)	0.0144 (8)	0.0254 (10)
O5	0.1043 (19)	0.0876 (17)	0.140 (2)	−0.0248 (15)	0.0525 (17)	0.0473 (17)
O6	0.101 (2)	0.135 (3)	0.209 (4)	0.019 (2)	0.034 (2)	0.129 (3)

Geometric parameters (Å, º)

C1—O1	1.205 (3)	C13—C14	1.387 (3)
C1—N1	1.386 (3)	C13—H13	0.95 (2)
C1—C2	1.490 (4)	C14—C15	1.372 (4)
C2—C7	1.381 (3)	C14—H14	0.94 (3)
C2—C3	1.381 (4)	C15—C16	1.374 (4)
C3—C4	1.363 (5)	C15—C18	1.521 (3)
C3—H3	0.98 (3)	C16—C17	1.391 (3)
C4—C5	1.376 (5)	C16—H16	0.92 (3)
C4—H4	1.00 (3)	C17—H17	0.96 (3)
C5—C6	1.401 (4)	C18—H18A	0.9600
C5—H5	0.92 (3)	C18—H18B	0.9600
C6—C7	1.383 (4)	C18—H18C	0.9600
C6—H6	0.97 (3)	C19—O4	1.208 (2)
C7—C8	1.479 (3)	C19—N2	1.415 (3)
C8—O2	1.212 (3)	C19—C20	1.497 (3)
C8—N1	1.384 (3)	C20—C25	1.377 (3)
C9—N1	1.466 (3)	C20—C21	1.388 (3)
C9—C10	1.497 (3)	C21—C22	1.383 (3)
C9—H91	1.02 (2)	C21—H21	0.93 (2)
C9—H92	1.00 (3)	C22—C23	1.373 (4)
C10—O3	1.456 (3)	C22—H22	0.89 (3)
C10—H101	1.06 (3)	C23—C24	1.369 (4)
C10—H102	0.98 (3)	C23—H23	0.95 (3)
C11—O3	1.334 (3)	C24—C25	1.374 (3)
C11—N2	1.375 (3)	C24—N3	1.471 (3)
C11—S	1.632 (2)	C25—H25	0.89 (2)
C12—C17	1.366 (3)	N3—O5	1.201 (3)
C12—C13	1.370 (3)	N3—O6	1.205 (3)
C12—N2	1.456 (3)
O1—C1—N1	125.4 (3)	C13—C14—H14	117.9 (16)
O1—C1—C2	129.0 (2)	C14—C15—C16	117.9 (2)
N1—C1—C2	105.6 (2)	C14—C15—C18	121.6 (3)
C7—C2—C3	120.8 (3)	C16—C15—C18	120.5 (3)
C7—C2—C1	107.7 (2)	C15—C16—C17	121.2 (3)
C3—C2—C1	131.5 (3)	C15—C16—H16	119.5 (19)
C4—C3—C2	118.2 (3)	C17—C16—H16	119.3 (19)
C4—C3—H3	125.4 (16)	C12—C17—C16	119.4 (2)
C2—C3—H3	116.3 (17)	C12—C17—H17	119.8 (16)
C3—C4—C5	121.5 (3)	C16—C17—H17	120.7 (16)
C3—C4—H4	124 (2)	C15—C18—H18A	109.5
C5—C4—H4	114 (2)	C15—C18—H18B	109.5
C4—C5—C6	121.4 (3)	H18A—C18—H18B	109.5
C4—C5—H5	124 (2)	C15—C18—H18C	109.5
C6—C5—H5	115 (2)	H18A—C18—H18C	109.5
C7—C6—C5	116.3 (3)	H18B—C18—H18C	109.5
C7—C6—H6	121.7 (16)	O4—C19—N2	119.27 (19)
C5—C6—H6	122.0 (16)	O4—C19—C20	120.3 (2)
C2—C7—C6	121.9 (2)	N2—C19—C20	119.89 (18)
C2—C7—C8	108.5 (2)	C25—C20—C21	119.2 (2)
C6—C7—C8	129.6 (2)	C25—C20—C19	116.61 (19)
O2—C8—N1	125.0 (2)	C21—C20—C19	123.6 (2)
O2—C8—C7	129.2 (2)	C22—C21—C20	120.3 (2)
N1—C8—C7	105.7 (2)	C22—C21—H21	120.4 (14)
N1—C9—C10	113.9 (2)	C20—C21—H21	119.2 (14)
N1—C9—H91	108.4 (13)	C23—C22—C21	120.7 (3)
C10—C9—H91	109.0 (12)	C23—C22—H22	122.3 (17)
N1—C9—H92	107.8 (16)	C21—C22—H22	116.9 (17)
C10—C9—H92	107.5 (16)	C24—C23—C22	118.0 (2)
H91—C9—H92	110 (2)	C24—C23—H23	118.2 (17)
O3—C10—C9	108.0 (2)	C22—C23—H23	123.4 (17)
O3—C10—H101	107.4 (15)	C23—C24—C25	122.8 (2)
C9—C10—H101	110.4 (14)	C23—C24—N3	118.5 (2)
O3—C10—H102	108.1 (15)	C25—C24—N3	118.6 (2)
C9—C10—H102	110.1 (16)	C24—C25—C20	119.0 (2)
H101—C10—H102	113 (2)	C24—C25—H25	120.9 (14)
O3—C11—N2	110.66 (19)	C20—C25—H25	120.1 (14)
O3—C11—S	126.03 (17)	C8—N1—C1	112.4 (2)
N2—C11—S	123.30 (17)	C8—N1—C9	123.8 (2)
C17—C12—C13	120.7 (2)	C1—N1—C9	123.1 (2)
C17—C12—N2	119.1 (2)	C11—N2—C19	125.25 (17)
C13—C12—N2	120.2 (2)	C11—N2—C12	118.36 (17)
C12—C13—C14	118.9 (3)	C19—N2—C12	116.39 (17)
C12—C13—H13	118.5 (15)	O5—N3—O6	122.3 (3)
C14—C13—H13	122.5 (15)	O5—N3—C24	119.6 (3)
C15—C14—C13	121.9 (2)	O6—N3—C24	118.1 (3)
C15—C14—H14	119.9 (16)	C11—O3—C10	116.77 (18)
O1—C1—C2—C7	179.5 (3)	C21—C22—C23—C24	0.7 (4)
N1—C1—C2—C7	−0.2 (3)	C22—C23—C24—C25	0.8 (4)
O1—C1—C2—C3	−1.6 (5)	C22—C23—C24—N3	−177.3 (2)
N1—C1—C2—C3	178.6 (3)	C23—C24—C25—C20	−1.3 (4)
C7—C2—C3—C4	0.4 (4)	N3—C24—C25—C20	176.8 (2)
C1—C2—C3—C4	−178.3 (3)	C21—C20—C25—C24	0.3 (3)
C2—C3—C4—C5	−0.1 (5)	C19—C20—C25—C24	−171.3 (2)
C3—C4—C5—C6	−0.3 (5)	O2—C8—N1—C1	179.4 (2)
C4—C5—C6—C7	0.3 (4)	C7—C8—N1—C1	−1.2 (3)
C3—C2—C7—C6	−0.3 (4)	O2—C8—N1—C9	−9.5 (4)
C1—C2—C7—C6	178.7 (2)	C7—C8—N1—C9	170.0 (2)
C3—C2—C7—C8	−179.5 (2)	O1—C1—N1—C8	−178.8 (2)
C1—C2—C7—C8	−0.5 (3)	C2—C1—N1—C8	0.9 (3)
C5—C6—C7—C2	−0.1 (4)	O1—C1—N1—C9	9.9 (4)
C5—C6—C7—C8	179.0 (3)	C2—C1—N1—C9	−170.4 (2)
C2—C7—C8—O2	−179.5 (2)	C10—C9—N1—C8	106.3 (3)
C6—C7—C8—O2	1.3 (4)	C10—C9—N1—C1	−83.5 (3)
C2—C7—C8—N1	1.0 (3)	O3—C11—N2—C19	25.5 (3)
C6—C7—C8—N1	−178.1 (2)	S—C11—N2—C19	−155.09 (18)
N1—C9—C10—O3	−74.2 (3)	O3—C11—N2—C12	−153.93 (18)
C17—C12—C13—C14	−0.3 (4)	S—C11—N2—C12	25.5 (3)
N2—C12—C13—C14	−179.7 (2)	O4—C19—N2—C11	−151.3 (2)
C12—C13—C14—C15	−1.2 (4)	C20—C19—N2—C11	36.7 (3)
C13—C14—C15—C16	1.7 (4)	O4—C19—N2—C12	28.1 (3)
C13—C14—C15—C18	−179.1 (3)	C20—C19—N2—C12	−143.9 (2)
C14—C15—C16—C17	−0.7 (4)	C17—C12—N2—C11	−114.9 (3)
C18—C15—C16—C17	−179.9 (3)	C13—C12—N2—C11	64.5 (3)
C13—C12—C17—C16	1.3 (4)	C17—C12—N2—C19	65.6 (3)
N2—C12—C17—C16	−179.3 (2)	C13—C12—N2—C19	−115.0 (2)
C15—C16—C17—C12	−0.8 (4)	C23—C24—N3—O5	−3.7 (4)
O4—C19—C20—C25	16.3 (3)	C25—C24—N3—O5	178.2 (3)
N2—C19—C20—C25	−171.8 (2)	C23—C24—N3—O6	175.0 (3)
O4—C19—C20—C21	−154.9 (2)	C25—C24—N3—O6	−3.2 (5)
N2—C19—C20—C21	17.0 (3)	N2—C11—O3—C10	−173.5 (2)
C25—C20—C21—C22	1.2 (3)	S—C11—O3—C10	7.1 (3)
C19—C20—C21—C22	172.2 (2)	C9—C10—O3—C11	−176.2 (2)
C20—C21—C22—C23	−1.7 (4)