Crystal structures, thermal stabilities, and dissolution behaviours of tinidazole and the tinidazole–vanillic acid cocrystal: insights from energy frameworks

The crystal structures of the anti­microbial drug tinidazole [TNZ; systematic name: 1-(2-ethyl­sulfonyl­eth­yl)-2-methyl-5-nitro­imidazole, C₈H₁₃N₃O₄S] and the 1:1 cocrystal of TNZ with the naturally occurring com­pound vanillic acid (VA; systematic name: 4-hy­droxy-3-meth­oxy­benzoic acid, C₈H₈O₄), namely, the TNZ–VA cocrystal, were determined by single-crystal X-ray analysis at 100 K. The supra­molecular structure of the TNZ–VA cocrystal is com­posed of a carb­oxy­lic acid dimer and an O—H...N(heterocycle) synthon in the form of layers made up of O—H...N and O—H...O hydrogen bonds. The layers are joined via C—H...O hydrogen bonds, π–π stacking and C—H...π inter­actions. The energy framework analysis, together with inter­action energy calculations using the DLPNO-CCSD(T) method, indicates that the TNZ–VA cocrystal inherits strong inter­actions from the TNZ and VA crystals, which accounts for the enhanced thermal stability and reduced dissolution rate. To the best of our knowledge, this is the first example of a cocrystal containing TNZ.

Computing details

For both structures, data collection: APEX3 (Bruker, 2012); cell refinement: SAINT (Bruker, 2012); data reduction: SAINT (Bruker, 2012); program(s) used to solve structure: SHELXT2018 (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2018 (Sheldrick, 2015b); molecular graphics: Mercury (Macrae et al., 2020); software used to prepare material for publication: SHELXL2018 (Sheldrick, 2015b).

1-(2-Ethylsulfonylethyl)-2-methyl-5-nitroimidazole (TNZ)

Crystal data

C8H13N3O4S	Dx = 1.523 Mg m^−3
Mr = 247.27	Melting point: 399 K
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 11.8658 (7) Å	Cell parameters from 5399 reflections
b = 5.4786 (3) Å	θ = 2.3–27.7°
c = 16.7291 (9) Å	µ = 0.30 mm^−1
β = 97.296 (2)°	T = 100 K
V = 1078.72 (10) Å^3	Prism, colorless
Z = 4	0.23 × 0.20 × 0.18 mm
F(000) = 520

Data collection

Bruker APEX II CCD area detector diffractometer	2491 independent reflections
Radiation source: fine-focus sealed tube	2233 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.034
phi and ω scans	θmax = 27.7°, θmin = 2.3°
Absorption correction: multi-scan (SADABS2016; Krause et al., 2015)	h = −15→15
Tmin = 0.678, Tmax = 0.746	k = −7→5
9021 measured reflections	l = −21→21

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F^2 > 2σ(F^2)] = 0.032	H-atom parameters constrained
wR(F^2) = 0.082	w = 1/[σ^2(Fo^2) + (0.0346P)^2 + 0.605P] where P = (Fo^2 + 2Fc^2)/3
S = 1.05	(Δ/σ)max = 0.001
2491 reflections	Δρmax = 0.43 e Å^−3
147 parameters	Δρmin = −0.36 e Å^−3

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

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

	x	y	z	Uiso*/Ueq
C1	0.18385 (11)	0.6154 (3)	0.37337 (8)	0.0164 (3)
C2	0.08810 (12)	0.3127 (3)	0.41070 (9)	0.0206 (3)
H2	0.040670	0.172723	0.409400	0.025*
C3	0.13837 (11)	0.4256 (3)	0.47923 (8)	0.0181 (3)
C4	0.23880 (12)	0.7875 (3)	0.32185 (8)	0.0213 (3)
H4A	0.320832	0.757079	0.328146	0.032*
H4B	0.224598	0.955544	0.337991	0.032*
H4C	0.207265	0.763610	0.265355	0.032*
C5	0.27293 (11)	0.7923 (2)	0.50549 (8)	0.0161 (3)
H5A	0.235540	0.843307	0.552434	0.019*
H5B	0.286552	0.939841	0.473906	0.019*
C6	0.38598 (11)	0.6673 (2)	0.53444 (8)	0.0146 (3)
H6A	0.428646	0.643197	0.487893	0.018*
H6B	0.370681	0.504307	0.556254	0.018*
C7	0.41331 (13)	0.7879 (3)	0.70109 (8)	0.0215 (3)
H7A	0.451262	0.899037	0.742774	0.026*
H7B	0.331581	0.830563	0.692789	0.026*
C8	0.42595 (14)	0.5268 (3)	0.73203 (9)	0.0274 (3)
H8A	0.382826	0.416677	0.693351	0.041*
H8B	0.396798	0.515085	0.784141	0.041*
H8C	0.506375	0.480516	0.738516	0.041*
N1	0.19924 (9)	0.6225 (2)	0.45531 (6)	0.0150 (2)
N2	0.11645 (10)	0.4317 (2)	0.34507 (7)	0.0200 (3)
N3	0.12955 (10)	0.3601 (2)	0.55971 (7)	0.0218 (3)
O1	0.07275 (11)	0.1769 (2)	0.57015 (7)	0.0340 (3)
O2	0.17735 (10)	0.4849 (2)	0.61553 (6)	0.0335 (3)
O3	0.45683 (9)	1.09379 (19)	0.58949 (6)	0.0240 (2)
O4	0.58437 (8)	0.7360 (2)	0.61700 (6)	0.0240 (2)
S1	0.47108 (3)	0.83740 (6)	0.60972 (2)	0.01619 (10)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0154 (6)	0.0183 (7)	0.0151 (6)	0.0021 (5)	0.0000 (5)	−0.0005 (5)
C2	0.0187 (6)	0.0200 (7)	0.0229 (7)	−0.0032 (5)	0.0019 (5)	−0.0002 (6)
C3	0.0166 (6)	0.0187 (7)	0.0189 (6)	0.0002 (5)	0.0020 (5)	0.0023 (5)
C4	0.0251 (7)	0.0215 (7)	0.0173 (7)	−0.0036 (6)	0.0027 (5)	0.0010 (5)
C5	0.0166 (6)	0.0152 (6)	0.0159 (6)	0.0008 (5)	−0.0005 (5)	−0.0025 (5)
C6	0.0150 (6)	0.0142 (6)	0.0141 (6)	0.0005 (5)	−0.0003 (5)	−0.0024 (5)
C7	0.0270 (7)	0.0237 (7)	0.0135 (6)	0.0011 (6)	0.0014 (5)	−0.0031 (5)
C8	0.0368 (9)	0.0280 (8)	0.0169 (7)	0.0001 (7)	0.0013 (6)	0.0029 (6)
N1	0.0133 (5)	0.0165 (6)	0.0147 (5)	0.0001 (4)	−0.0001 (4)	0.0003 (4)
N2	0.0193 (6)	0.0212 (6)	0.0189 (6)	−0.0019 (5)	0.0004 (4)	−0.0014 (5)
N3	0.0181 (6)	0.0271 (7)	0.0202 (6)	0.0008 (5)	0.0028 (5)	0.0041 (5)
O1	0.0429 (7)	0.0295 (6)	0.0311 (6)	−0.0101 (5)	0.0104 (5)	0.0083 (5)
O2	0.0313 (6)	0.0517 (8)	0.0171 (5)	−0.0129 (6)	0.0015 (4)	0.0011 (5)
O3	0.0324 (6)	0.0156 (5)	0.0233 (5)	−0.0031 (4)	0.0010 (4)	−0.0012 (4)
O4	0.0165 (5)	0.0299 (6)	0.0242 (5)	−0.0009 (4)	−0.0023 (4)	−0.0039 (4)
S1	0.01731 (17)	0.01577 (18)	0.01475 (16)	−0.00152 (13)	−0.00083 (12)	−0.00202 (12)

Geometric parameters (Å, º)

C1—N2	1.3345 (18)	C6—S1	1.7753 (13)
C1—N1	1.3603 (17)	C6—H6A	0.9900
C1—C4	1.4830 (19)	C6—H6B	0.9900
C2—N2	1.3553 (19)	C7—C8	1.522 (2)
C2—C3	1.370 (2)	C7—S1	1.7736 (14)
C2—H2	0.9500	C7—H7A	0.9900
C3—N1	1.3853 (18)	C7—H7B	0.9900
C3—N3	1.4101 (18)	C8—H8A	0.9800
C4—H4A	0.9800	C8—H8B	0.9800
C4—H4B	0.9800	C8—H8C	0.9800
C4—H4C	0.9800	N3—O1	1.2337 (17)
C5—N1	1.4658 (17)	N3—O2	1.2355 (17)
C5—C6	1.5292 (18)	O3—S1	1.4497 (11)
C5—H5A	0.9900	O4—S1	1.4452 (10)
C5—H5B	0.9900
N2—C1—N1	112.12 (12)	H6A—C6—H6B	107.8
N2—C1—C4	124.15 (12)	C8—C7—S1	113.86 (10)
N1—C1—C4	123.71 (12)	C8—C7—H7A	108.8
N2—C2—C3	109.53 (13)	S1—C7—H7A	108.8
N2—C2—H2	125.2	C8—C7—H7B	108.8
C3—C2—H2	125.2	S1—C7—H7B	108.8
C2—C3—N1	107.29 (12)	H7A—C7—H7B	107.7
C2—C3—N3	127.36 (13)	C7—C8—H8A	109.5
N1—C3—N3	125.35 (12)	C7—C8—H8B	109.5
C1—C4—H4A	109.5	H8A—C8—H8B	109.5
C1—C4—H4B	109.5	C7—C8—H8C	109.5
H4A—C4—H4B	109.5	H8A—C8—H8C	109.5
C1—C4—H4C	109.5	H8B—C8—H8C	109.5
H4A—C4—H4C	109.5	C1—N1—C3	105.11 (11)
H4B—C4—H4C	109.5	C1—N1—C5	126.09 (11)
N1—C5—C6	109.41 (11)	C3—N1—C5	128.61 (11)
N1—C5—H5A	109.8	C1—N2—C2	105.94 (12)
C6—C5—H5A	109.8	O1—N3—O2	123.35 (13)
N1—C5—H5B	109.8	O1—N3—C3	116.76 (13)
C6—C5—H5B	109.8	O2—N3—C3	119.89 (13)
H5A—C5—H5B	108.2	O4—S1—O3	118.14 (7)
C5—C6—S1	112.74 (9)	O4—S1—C7	109.02 (7)
C5—C6—H6A	109.0	O3—S1—C7	107.63 (7)
S1—C6—H6A	109.0	O4—S1—C6	107.29 (6)
C5—C6—H6B	109.0	O3—S1—C6	107.70 (6)
S1—C6—H6B	109.0	C7—S1—C6	106.49 (7)
N2—C2—C3—N1	0.51 (16)	N1—C1—N2—C2	−0.82 (16)
N2—C2—C3—N3	179.45 (13)	C4—C1—N2—C2	177.31 (13)
N1—C5—C6—S1	−169.50 (9)	C3—C2—N2—C1	0.17 (16)
N2—C1—N1—C3	1.12 (15)	C2—C3—N3—O1	2.1 (2)
C4—C1—N1—C3	−177.02 (13)	N1—C3—N3—O1	−179.15 (13)
N2—C1—N1—C5	176.50 (12)	C2—C3—N3—O2	−177.75 (14)
C4—C1—N1—C5	−1.6 (2)	N1—C3—N3—O2	1.0 (2)
C2—C3—N1—C1	−0.96 (15)	C8—C7—S1—O4	−48.58 (13)
N3—C3—N1—C1	−179.93 (13)	C8—C7—S1—O3	−177.85 (11)
C2—C3—N1—C5	−176.18 (12)	C8—C7—S1—C6	66.88 (12)
N3—C3—N1—C5	4.9 (2)	C5—C6—S1—O4	−165.64 (9)
C6—C5—N1—C1	−98.36 (15)	C5—C6—S1—O3	−37.48 (11)
C6—C5—N1—C3	75.93 (16)	C5—C6—S1—C7	77.74 (11)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
C8—H8A···O2	0.98	2.64	3.331 (2)	128
C2—H2···O1^i	0.95	2.39	3.3311 (19)	171
C6—H6A···O3^ii	0.99	2.46	3.2362 (17)	135
C6—H6B···O3^iii	0.99	2.50	3.3511 (17)	143
C8—H8A···O3^iii	0.98	2.70	3.4161 (19)	130
C7—H7A···N2^iv	0.99	2.60	3.5353 (19)	157
C8—H8B···O1^v	0.98	2.58	3.4082 (19)	143
C6—H6A···O4^vi	0.99	2.71	3.4133 (17)	128
C5—H5A···O1^vii	0.99	2.70	3.4500 (18)	133

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

1-(2-Ethylsulfonylethyl)-2-methyl-5-nitroimidazole; 4-hydroxy-3-methoxybenzoic acid (TNZ-VA)

Crystal data

C8H13N3O4S·C8H8O4	F(000) = 872
Mr = 415.42	Dx = 1.498 Mg m^−3
Triclinic, P1	Melting point: 404 K
a = 11.1206 (5) Å	Mo Kα radiation, λ = 0.71073 Å
b = 12.6519 (6) Å	Cell parameters from 9002 reflections
c = 13.6042 (6) Å	θ = 2.4–27.5°
α = 98.078 (1)°	µ = 0.23 mm^−1
β = 97.793 (1)°	T = 100 K
γ = 99.780 (1)°	Prism, yellow
V = 1842.42 (15) Å^3	0.57 × 0.35 × 0.25 mm
Z = 4

Data collection

Bruker APEXII CCD area detector diffractometer	8425 independent reflections
Radiation source: fine-focus sealed tube	7034 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.031
phi and ω scans	θmax = 27.5°, θmin = 2.1°
Absorption correction: multi-scan (SADABS2016; Krause et al., 2015)	h = −14→14
Tmin = 0.678, Tmax = 0.746	k = −14→16
16552 measured reflections	l = −16→17

Refinement

Refinement on F^2	0 restraints
Least-squares matrix: full	Hydrogen site location: mixed
R[F^2 > 2σ(F^2)] = 0.039	H-atom parameters constrained
wR(F^2) = 0.106	w = 1/[σ^2(Fo^2) + (0.0476P)^2 + 0.7942P] where P = (Fo^2 + 2Fc^2)/3
S = 1.03	(Δ/σ)max = 0.001
8425 reflections	Δρmax = 0.39 e Å^−3
511 parameters	Δρmin = −0.48 e Å^−3

Special details

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

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

	x	y	z	Uiso*/Ueq
C1	−0.46056 (14)	0.86128 (12)	0.26200 (12)	0.0181 (3)
C2	−0.36794 (14)	0.80378 (13)	0.27192 (12)	0.0196 (3)
H2	−0.303525	0.815954	0.328133	0.024*
C3	−0.48290 (14)	0.73672 (13)	0.12877 (12)	0.0188 (3)
C4	−0.52869 (16)	0.67038 (14)	0.02743 (13)	0.0255 (4)
H4A	−0.519630	0.716963	−0.023929	0.038*
H4B	−0.616105	0.637473	0.022657	0.038*
H4C	−0.480551	0.612898	0.016672	0.038*
C5	−0.64659 (13)	0.85083 (12)	0.12261 (12)	0.0172 (3)
H5A	−0.696638	0.872518	0.174146	0.021*
H5B	−0.697934	0.789346	0.073279	0.021*
C6	−0.60737 (13)	0.94607 (12)	0.06971 (11)	0.0165 (3)
H6A	−0.575349	0.918946	0.008476	0.020*
H6B	−0.538864	0.998278	0.114686	0.020*
C7	−0.73585 (17)	1.10524 (15)	0.14532 (13)	0.0283 (4)
H7A	−0.755094	1.063089	0.199162	0.034*
H7B	−0.655148	1.155129	0.169154	0.034*
C8	−0.83651 (19)	1.17061 (17)	0.12190 (17)	0.0411 (5)
H8A	−0.815246	1.214412	0.070539	0.062*
H8B	−0.843111	1.218652	0.183242	0.062*
H8C	−0.915777	1.120736	0.096896	0.062*
N1	−0.53583 (11)	0.81701 (10)	0.17062 (10)	0.0163 (3)
N2	−0.38173 (12)	0.72649 (11)	0.18929 (10)	0.0201 (3)
N3	−0.47884 (12)	0.94978 (11)	0.33122 (10)	0.0210 (3)
O1	−0.39776 (11)	0.98249 (10)	0.40576 (9)	0.0293 (3)
O2	−0.57235 (11)	0.98869 (10)	0.31472 (9)	0.0278 (3)
O3	−0.84376 (10)	0.93943 (9)	0.00736 (9)	0.0272 (3)
O4	−0.68905 (12)	1.07976 (11)	−0.03874 (10)	0.0326 (3)
S1	−0.72785 (3)	1.01561 (3)	0.03492 (3)	0.01782 (10)
C9	0.01626 (14)	0.47902 (12)	0.29301 (12)	0.0176 (3)
C10	−0.01500 (14)	0.43286 (12)	0.19089 (12)	0.0178 (3)
H10	0.026078	0.378217	0.163946	0.021*
C11	−0.10512 (14)	0.46637 (12)	0.12932 (12)	0.0180 (3)
C12	−0.16802 (14)	0.54533 (13)	0.17106 (12)	0.0201 (3)
C13	−0.13652 (15)	0.58994 (13)	0.27226 (12)	0.0224 (3)
H13	−0.179388	0.642736	0.300050	0.027*
C14	−0.04333 (14)	0.55866 (13)	0.33361 (12)	0.0198 (3)
H14	−0.020594	0.591259	0.402434	0.024*
C15	0.11253 (14)	0.43973 (13)	0.35574 (12)	0.0196 (3)
C16	−0.07432 (15)	0.35336 (13)	−0.01673 (12)	0.0213 (3)
H16A	0.014440	0.384254	−0.003279	0.032*
H16B	−0.102977	0.337225	−0.089567	0.032*
H16C	−0.089379	0.286175	0.011607	0.032*
O5	0.15118 (11)	0.35713 (10)	0.32573 (9)	0.0287 (3)
O6	0.15317 (11)	0.49796 (10)	0.44539 (8)	0.0255 (3)
H6	0.218012	0.476315	0.474978	0.038*
O7	−0.14007 (10)	0.42987 (9)	0.02857 (8)	0.0210 (2)
O8	−0.25695 (11)	0.57457 (10)	0.10785 (9)	0.0292 (3)
H8	−0.294480	0.621059	0.139295	0.044*
C17	0.94304 (16)	−0.07560 (14)	0.59092 (13)	0.0244 (4)
C18	0.85017 (16)	−0.01837 (15)	0.59093 (14)	0.0287 (4)
H18	0.776949	−0.033059	0.542351	0.034*
C19	0.98849 (15)	0.05546 (13)	0.72037 (13)	0.0218 (3)
C20	1.05196 (17)	0.12934 (15)	0.81456 (14)	0.0297 (4)
H20A	1.020283	0.197275	0.819536	0.044*
H20B	1.141145	0.145242	0.813689	0.044*
H20C	1.036305	0.094225	0.872592	0.044*
C21	1.15235 (14)	−0.05841 (13)	0.70510 (13)	0.0219 (3)
H21A	1.208835	0.004903	0.748481	0.026*
H21B	1.189875	−0.078320	0.644839	0.026*
C22	1.13687 (14)	−0.15361 (13)	0.76226 (12)	0.0187 (3)
H22A	1.073486	−0.214209	0.721798	0.022*
H22B	1.107962	−0.131091	0.826266	0.022*
C23	1.27814 (15)	−0.30524 (13)	0.68857 (12)	0.0224 (3)
H23A	1.204977	−0.363532	0.684181	0.027*
H23B	1.273367	−0.277331	0.623995	0.027*
C24	1.39617 (18)	−0.35043 (16)	0.70807 (15)	0.0340 (4)
H24A	1.468193	−0.292072	0.713354	0.051*
H24B	1.397172	−0.408358	0.652373	0.051*
H24C	1.399039	−0.379924	0.771038	0.051*
N4	1.03218 (12)	−0.02863 (11)	0.67403 (10)	0.0204 (3)
N5	0.87873 (13)	0.06310 (12)	0.67142 (11)	0.0261 (3)
N6	0.95208 (15)	−0.16613 (13)	0.51980 (11)	0.0317 (4)
O9	0.87115 (15)	−0.19110 (14)	0.44492 (11)	0.0552 (5)
O10	1.03764 (14)	−0.21426 (12)	0.53472 (11)	0.0448 (4)
O11	1.27991 (11)	−0.24272 (10)	0.88032 (9)	0.0270 (3)
O12	1.37899 (10)	−0.11068 (9)	0.78510 (10)	0.0280 (3)
S2	1.27955 (3)	−0.19896 (3)	0.78827 (3)	0.01716 (9)
C25	0.50219 (14)	0.32744 (13)	0.55299 (12)	0.0195 (3)
C26	0.55642 (14)	0.39283 (13)	0.64589 (12)	0.0189 (3)
H26	0.522721	0.453611	0.670389	0.023*
C27	0.65868 (14)	0.36881 (12)	0.70163 (12)	0.0185 (3)
C28	0.70904 (14)	0.27939 (13)	0.66395 (12)	0.0180 (3)
C29	0.65570 (15)	0.21639 (13)	0.57145 (12)	0.0202 (3)
H29	0.690715	0.156907	0.545781	0.024*
C30	0.55186 (15)	0.23925 (13)	0.51603 (12)	0.0210 (3)
H30	0.515016	0.194962	0.453315	0.025*
C31	0.38976 (15)	0.35374 (13)	0.49928 (12)	0.0224 (3)
C32	0.66986 (16)	0.51617 (14)	0.83451 (13)	0.0270 (4)
H32A	0.680275	0.571157	0.790708	0.040*
H32B	0.715997	0.546457	0.902031	0.040*
H32C	0.581919	0.494700	0.838347	0.040*
O13	0.34422 (12)	0.29145 (10)	0.41124 (9)	0.0306 (3)
H13A	0.279267	0.318603	0.384668	0.046*
O14	0.34167 (12)	0.42777 (11)	0.53397 (9)	0.0328 (3)
O15	0.71543 (11)	0.42347 (9)	0.79447 (9)	0.0242 (3)
O16	0.80696 (10)	0.25822 (9)	0.72288 (8)	0.0226 (2)
H16	0.831837	0.197997	0.697200	0.034*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0164 (7)	0.0188 (7)	0.0173 (7)	0.0013 (6)	−0.0003 (6)	0.0027 (6)
C2	0.0182 (7)	0.0213 (8)	0.0189 (7)	0.0043 (6)	−0.0012 (6)	0.0051 (6)
C3	0.0191 (7)	0.0191 (7)	0.0189 (7)	0.0054 (6)	0.0015 (6)	0.0049 (6)
C4	0.0292 (9)	0.0252 (8)	0.0207 (8)	0.0107 (7)	−0.0036 (7)	−0.0002 (7)
C5	0.0121 (6)	0.0191 (7)	0.0206 (7)	0.0043 (6)	−0.0006 (6)	0.0058 (6)
C6	0.0128 (6)	0.0189 (7)	0.0180 (7)	0.0042 (6)	0.0008 (6)	0.0034 (6)
C7	0.0298 (9)	0.0274 (9)	0.0246 (9)	0.0096 (7)	0.0011 (7)	−0.0080 (7)
C8	0.0375 (11)	0.0366 (11)	0.0460 (12)	0.0203 (9)	0.0002 (9)	−0.0140 (9)
N1	0.0146 (6)	0.0176 (6)	0.0164 (6)	0.0038 (5)	−0.0003 (5)	0.0038 (5)
N2	0.0202 (6)	0.0213 (7)	0.0185 (6)	0.0060 (5)	−0.0014 (5)	0.0047 (5)
N3	0.0228 (7)	0.0203 (7)	0.0200 (7)	0.0046 (5)	0.0031 (5)	0.0029 (5)
O1	0.0299 (6)	0.0308 (7)	0.0214 (6)	0.0042 (5)	−0.0046 (5)	−0.0048 (5)
O2	0.0258 (6)	0.0288 (6)	0.0298 (6)	0.0120 (5)	0.0039 (5)	0.0012 (5)
O3	0.0175 (5)	0.0254 (6)	0.0343 (7)	0.0068 (5)	−0.0045 (5)	−0.0044 (5)
O4	0.0369 (7)	0.0386 (7)	0.0329 (7)	0.0200 (6)	0.0117 (6)	0.0203 (6)
S1	0.01769 (18)	0.01863 (19)	0.01722 (19)	0.00720 (14)	0.00008 (14)	0.00144 (14)
C9	0.0158 (7)	0.0174 (7)	0.0184 (7)	0.0025 (6)	0.0000 (6)	0.0026 (6)
C10	0.0167 (7)	0.0169 (7)	0.0197 (8)	0.0046 (6)	0.0020 (6)	0.0020 (6)
C11	0.0183 (7)	0.0172 (7)	0.0171 (7)	0.0028 (6)	0.0004 (6)	0.0012 (6)
C12	0.0192 (7)	0.0199 (8)	0.0210 (8)	0.0068 (6)	−0.0005 (6)	0.0032 (6)
C13	0.0239 (8)	0.0210 (8)	0.0225 (8)	0.0096 (6)	0.0018 (6)	0.0003 (6)
C14	0.0207 (7)	0.0208 (8)	0.0164 (7)	0.0044 (6)	0.0005 (6)	−0.0002 (6)
C15	0.0183 (7)	0.0218 (8)	0.0174 (7)	0.0032 (6)	0.0008 (6)	0.0020 (6)
C16	0.0228 (8)	0.0213 (8)	0.0185 (8)	0.0053 (6)	0.0026 (6)	−0.0014 (6)
O5	0.0311 (6)	0.0300 (7)	0.0228 (6)	0.0164 (5)	−0.0073 (5)	−0.0040 (5)
O6	0.0249 (6)	0.0306 (6)	0.0189 (6)	0.0130 (5)	−0.0058 (5)	−0.0031 (5)
O7	0.0236 (6)	0.0232 (6)	0.0152 (5)	0.0084 (5)	−0.0019 (4)	0.0002 (4)
O8	0.0323 (7)	0.0338 (7)	0.0217 (6)	0.0213 (5)	−0.0063 (5)	−0.0021 (5)
C17	0.0249 (8)	0.0266 (9)	0.0204 (8)	0.0092 (7)	−0.0033 (7)	0.0008 (7)
C18	0.0266 (9)	0.0312 (9)	0.0264 (9)	0.0116 (7)	−0.0063 (7)	0.0009 (7)
C19	0.0214 (8)	0.0208 (8)	0.0244 (8)	0.0080 (6)	0.0011 (6)	0.0050 (7)
C20	0.0270 (9)	0.0272 (9)	0.0315 (10)	0.0092 (7)	−0.0036 (7)	−0.0030 (8)
C21	0.0167 (7)	0.0218 (8)	0.0283 (9)	0.0074 (6)	0.0005 (6)	0.0065 (7)
C22	0.0148 (7)	0.0210 (8)	0.0204 (8)	0.0053 (6)	0.0003 (6)	0.0040 (6)
C23	0.0227 (8)	0.0218 (8)	0.0201 (8)	0.0050 (6)	0.0012 (6)	−0.0039 (6)
C24	0.0344 (10)	0.0325 (10)	0.0347 (10)	0.0177 (8)	0.0032 (8)	−0.0070 (8)
N4	0.0183 (6)	0.0210 (7)	0.0215 (7)	0.0075 (5)	−0.0019 (5)	0.0026 (5)
N5	0.0238 (7)	0.0267 (7)	0.0276 (8)	0.0119 (6)	−0.0025 (6)	0.0022 (6)
N6	0.0347 (8)	0.0355 (9)	0.0232 (7)	0.0154 (7)	−0.0049 (6)	−0.0025 (7)
O9	0.0505 (9)	0.0680 (11)	0.0361 (8)	0.0292 (8)	−0.0209 (7)	−0.0233 (8)
O10	0.0528 (9)	0.0478 (9)	0.0327 (8)	0.0337 (7)	−0.0094 (7)	−0.0101 (7)
O11	0.0317 (6)	0.0328 (7)	0.0186 (6)	0.0145 (5)	−0.0004 (5)	0.0056 (5)
O12	0.0187 (6)	0.0204 (6)	0.0406 (7)	0.0014 (5)	−0.0038 (5)	0.0024 (5)
S2	0.01659 (18)	0.01639 (18)	0.01694 (18)	0.00511 (14)	−0.00258 (14)	0.00034 (14)
C25	0.0218 (8)	0.0205 (8)	0.0171 (7)	0.0076 (6)	0.0012 (6)	0.0038 (6)
C26	0.0202 (7)	0.0173 (7)	0.0201 (8)	0.0066 (6)	0.0021 (6)	0.0032 (6)
C27	0.0188 (7)	0.0180 (7)	0.0178 (7)	0.0026 (6)	0.0017 (6)	0.0028 (6)
C28	0.0164 (7)	0.0212 (8)	0.0182 (7)	0.0053 (6)	0.0033 (6)	0.0070 (6)
C29	0.0238 (8)	0.0212 (8)	0.0185 (7)	0.0105 (6)	0.0057 (6)	0.0038 (6)
C30	0.0244 (8)	0.0233 (8)	0.0156 (7)	0.0074 (6)	0.0018 (6)	0.0023 (6)
C31	0.0256 (8)	0.0229 (8)	0.0185 (8)	0.0084 (6)	−0.0006 (6)	0.0020 (6)
C32	0.0294 (9)	0.0227 (8)	0.0258 (9)	0.0068 (7)	0.0000 (7)	−0.0040 (7)
O13	0.0322 (7)	0.0367 (7)	0.0213 (6)	0.0194 (6)	−0.0076 (5)	−0.0051 (5)
O14	0.0341 (7)	0.0365 (7)	0.0256 (6)	0.0216 (6)	−0.0094 (5)	−0.0064 (5)
O15	0.0238 (6)	0.0242 (6)	0.0214 (6)	0.0084 (5)	−0.0045 (5)	−0.0035 (5)
O16	0.0209 (6)	0.0256 (6)	0.0221 (6)	0.0110 (5)	−0.0016 (5)	0.0033 (5)

Geometric parameters (Å, º)

C1—C2	1.361 (2)	C17—C18	1.358 (2)
C1—N1	1.3865 (19)	C17—N4	1.386 (2)
C1—N3	1.419 (2)	C17—N6	1.419 (2)
C2—N2	1.355 (2)	C18—N5	1.356 (2)
C2—H2	0.9500	C18—H18	0.9500
C3—N2	1.3374 (19)	C19—N5	1.334 (2)
C3—N1	1.3542 (19)	C19—N4	1.355 (2)
C3—C4	1.484 (2)	C19—C20	1.486 (2)
C4—H4A	0.9800	C20—H20A	0.9800
C4—H4B	0.9800	C20—H20B	0.9800
C4—H4C	0.9800	C20—H20C	0.9800
C5—N1	1.4719 (18)	C21—N4	1.4728 (19)
C5—C6	1.520 (2)	C21—C22	1.521 (2)
C5—H5A	0.9900	C21—H21A	0.9900
C5—H5B	0.9900	C21—H21B	0.9900
C6—S1	1.7716 (15)	C22—S2	1.7850 (15)
C6—H6A	0.9900	C22—H22A	0.9900
C6—H6B	0.9900	C22—H22B	0.9900
C7—C8	1.527 (2)	C23—C24	1.524 (2)
C7—S1	1.7724 (17)	C23—S2	1.7671 (16)
C7—H7A	0.9900	C23—H23A	0.9900
C7—H7B	0.9900	C23—H23B	0.9900
C8—H8A	0.9800	C24—H24A	0.9800
C8—H8B	0.9800	C24—H24B	0.9800
C8—H8C	0.9800	C24—H24C	0.9800
N3—O2	1.2311 (18)	N6—O10	1.2234 (19)
N3—O1	1.2329 (17)	N6—O9	1.2295 (19)
O3—S1	1.4410 (12)	O11—S2	1.4385 (12)
O4—S1	1.4408 (13)	O12—S2	1.4418 (12)
C9—C14	1.389 (2)	C25—C30	1.389 (2)
C9—C10	1.401 (2)	C25—C26	1.406 (2)
C9—C15	1.474 (2)	C25—C31	1.473 (2)
C10—C11	1.379 (2)	C26—C27	1.382 (2)
C10—H10	0.9500	C26—H26	0.9500
C11—O7	1.3636 (18)	C27—O15	1.3645 (18)
C11—C12	1.412 (2)	C27—C28	1.409 (2)
C12—O8	1.3555 (18)	C28—O16	1.3502 (18)
C12—C13	1.386 (2)	C28—C29	1.388 (2)
C13—C14	1.387 (2)	C29—C30	1.387 (2)
C13—H13	0.9500	C29—H29	0.9500
C14—H14	0.9500	C30—H30	0.9500
C15—O5	1.2344 (19)	C31—O14	1.225 (2)
C15—O6	1.3113 (19)	C31—O13	1.3217 (19)
C16—O7	1.4306 (18)	C32—O15	1.4235 (19)
C16—H16A	0.9800	C32—H32A	0.9800
C16—H16B	0.9800	C32—H32B	0.9800
C16—H16C	0.9800	C32—H32C	0.9800
O6—H6	0.8811	O13—H13A	0.9048
O8—H8	0.8742	O16—H16	0.8956
C2—C1—N1	107.11 (13)	C18—C17—N4	107.55 (15)
C2—C1—N3	127.29 (14)	C18—C17—N6	127.90 (15)
N1—C1—N3	125.59 (13)	N4—C17—N6	124.54 (14)
N2—C2—C1	109.55 (13)	N5—C18—C17	109.08 (15)
N2—C2—H2	125.2	N5—C18—H18	125.5
C1—C2—H2	125.2	C17—C18—H18	125.5
N2—C3—N1	111.38 (13)	N5—C19—N4	111.28 (14)
N2—C3—C4	124.02 (14)	N5—C19—C20	123.58 (15)
N1—C3—C4	124.57 (14)	N4—C19—C20	125.14 (14)
C3—C4—H4A	109.5	C19—C20—H20A	109.5
C3—C4—H4B	109.5	C19—C20—H20B	109.5
H4A—C4—H4B	109.5	H20A—C20—H20B	109.5
C3—C4—H4C	109.5	C19—C20—H20C	109.5
H4A—C4—H4C	109.5	H20A—C20—H20C	109.5
H4B—C4—H4C	109.5	H20B—C20—H20C	109.5
N1—C5—C6	109.35 (12)	N4—C21—C22	110.82 (13)
N1—C5—H5A	109.8	N4—C21—H21A	109.5
C6—C5—H5A	109.8	C22—C21—H21A	109.5
N1—C5—H5B	109.8	N4—C21—H21B	109.5
C6—C5—H5B	109.8	C22—C21—H21B	109.5
H5A—C5—H5B	108.3	H21A—C21—H21B	108.1
C5—C6—S1	113.92 (10)	C21—C22—S2	110.80 (11)
C5—C6—H6A	108.8	C21—C22—H22A	109.5
S1—C6—H6A	108.8	S2—C22—H22A	109.5
C5—C6—H6B	108.8	C21—C22—H22B	109.5
S1—C6—H6B	108.8	S2—C22—H22B	109.5
H6A—C6—H6B	107.7	H22A—C22—H22B	108.1
C8—C7—S1	109.14 (13)	C24—C23—S2	108.84 (11)
C8—C7—H7A	109.9	C24—C23—H23A	109.9
S1—C7—H7A	109.9	S2—C23—H23A	109.9
C8—C7—H7B	109.9	C24—C23—H23B	109.9
S1—C7—H7B	109.9	S2—C23—H23B	109.9
H7A—C7—H7B	108.3	H23A—C23—H23B	108.3
C7—C8—H8A	109.5	C23—C24—H24A	109.5
C7—C8—H8B	109.5	C23—C24—H24B	109.5
H8A—C8—H8B	109.5	H24A—C24—H24B	109.5
C7—C8—H8C	109.5	C23—C24—H24C	109.5
H8A—C8—H8C	109.5	H24A—C24—H24C	109.5
H8B—C8—H8C	109.5	H24B—C24—H24C	109.5
C3—N1—C1	105.70 (12)	C19—N4—C17	105.48 (13)
C3—N1—C5	125.06 (13)	C19—N4—C21	125.99 (13)
C1—N1—C5	129.15 (13)	C17—N4—C21	128.48 (14)
C3—N2—C2	106.23 (13)	C19—N5—C18	106.61 (14)
O2—N3—O1	124.08 (14)	O10—N6—O9	123.71 (15)
O2—N3—C1	119.59 (13)	O10—N6—C17	119.87 (14)
O1—N3—C1	116.33 (13)	O9—N6—C17	116.42 (15)
O4—S1—O3	117.56 (8)	O11—S2—O12	117.34 (8)
O4—S1—C6	107.18 (7)	O11—S2—C23	108.82 (8)
O3—S1—C6	109.72 (7)	O12—S2—C23	108.23 (8)
O4—S1—C7	108.38 (9)	O11—S2—C22	107.58 (7)
O3—S1—C7	107.94 (8)	O12—S2—C22	108.17 (7)
C6—S1—C7	105.41 (8)	C23—S2—C22	106.16 (8)
C14—C9—C10	120.52 (14)	C30—C25—C26	120.32 (14)
C14—C9—C15	121.30 (14)	C30—C25—C31	121.99 (14)
C10—C9—C15	118.17 (14)	C26—C25—C31	117.65 (14)
C11—C10—C9	120.32 (14)	C27—C26—C25	120.07 (14)
C11—C10—H10	119.8	C27—C26—H26	120.0
C9—C10—H10	119.8	C25—C26—H26	120.0
O7—C11—C10	125.34 (14)	O15—C27—C26	125.13 (14)
O7—C11—C12	115.45 (13)	O15—C27—C28	115.31 (13)
C10—C11—C12	119.21 (14)	C26—C27—C28	119.52 (14)
O8—C12—C13	123.13 (14)	O16—C28—C29	123.28 (14)
O8—C12—C11	117.04 (14)	O16—C28—C27	116.85 (14)
C13—C12—C11	119.82 (14)	C29—C28—C27	119.85 (14)
C12—C13—C14	121.00 (15)	C30—C29—C28	120.78 (14)
C12—C13—H13	119.5	C30—C29—H29	119.6
C14—C13—H13	119.5	C28—C29—H29	119.6
C13—C14—C9	119.08 (14)	C29—C30—C25	119.45 (15)
C13—C14—H14	120.5	C29—C30—H30	120.3
C9—C14—H14	120.5	C25—C30—H30	120.3
O5—C15—O6	122.59 (14)	O14—C31—O13	122.42 (15)
O5—C15—C9	121.99 (14)	O14—C31—C25	122.36 (15)
O6—C15—C9	115.42 (13)	O13—C31—C25	115.21 (14)
O7—C16—H16A	109.5	O15—C32—H32A	109.5
O7—C16—H16B	109.5	O15—C32—H32B	109.5
H16A—C16—H16B	109.5	H32A—C32—H32B	109.5
O7—C16—H16C	109.5	O15—C32—H32C	109.5
H16A—C16—H16C	109.5	H32A—C32—H32C	109.5
H16B—C16—H16C	109.5	H32B—C32—H32C	109.5
C15—O6—H6	110.6	C31—O13—H13A	106.3
C11—O7—C16	116.75 (12)	C27—O15—C32	117.33 (12)
C12—O8—H8	112.1	C28—O16—H16	113.0
N1—C1—C2—N2	0.99 (18)	N4—C17—C18—N5	0.1 (2)
N3—C1—C2—N2	−179.26 (15)	N6—C17—C18—N5	−178.96 (18)
N1—C5—C6—S1	−165.63 (10)	N4—C21—C22—S2	173.86 (11)
N2—C3—N1—C1	1.63 (18)	N5—C19—N4—C17	0.1 (2)
C4—C3—N1—C1	−176.71 (15)	C20—C19—N4—C17	179.02 (17)
N2—C3—N1—C5	178.45 (13)	N5—C19—N4—C21	177.60 (15)
C4—C3—N1—C5	0.1 (2)	C20—C19—N4—C21	−3.5 (3)
C2—C1—N1—C3	−1.56 (17)	C18—C17—N4—C19	−0.1 (2)
N3—C1—N1—C3	178.68 (15)	N6—C17—N4—C19	179.01 (17)
C2—C1—N1—C5	−178.21 (14)	C18—C17—N4—C21	−177.57 (16)
N3—C1—N1—C5	2.0 (3)	N6—C17—N4—C21	1.6 (3)
C6—C5—N1—C3	−94.54 (17)	C22—C21—N4—C19	100.69 (18)
C6—C5—N1—C1	81.51 (19)	C22—C21—N4—C17	−82.4 (2)
N1—C3—N2—C2	−1.04 (18)	N4—C19—N5—C18	0.0 (2)
C4—C3—N2—C2	177.31 (16)	C20—C19—N5—C18	−178.95 (17)
C1—C2—N2—C3	0.00 (19)	C17—C18—N5—C19	−0.1 (2)
C2—C1—N3—O2	−174.86 (16)	C18—C17—N6—O10	−174.3 (2)
N1—C1—N3—O2	4.8 (2)	N4—C17—N6—O10	6.8 (3)
C2—C1—N3—O1	4.8 (2)	C18—C17—N6—O9	6.1 (3)
N1—C1—N3—O1	−175.50 (15)	N4—C17—N6—O9	−172.85 (19)
C5—C6—S1—O4	−163.08 (11)	C24—C23—S2—O11	−62.57 (15)
C5—C6—S1—O3	−34.38 (13)	C24—C23—S2—O12	65.97 (15)
C5—C6—S1—C7	81.61 (13)	C24—C23—S2—C22	−178.11 (13)
C8—C7—S1—O4	64.52 (16)	C21—C22—S2—O11	150.14 (11)
C8—C7—S1—O3	−63.80 (16)	C21—C22—S2—O12	22.48 (14)
C8—C7—S1—C6	179.01 (14)	C21—C22—S2—C23	−93.49 (13)
C14—C9—C10—C11	0.3 (2)	C30—C25—C26—C27	−0.8 (2)
C15—C9—C10—C11	179.54 (15)	C31—C25—C26—C27	177.05 (15)
C9—C10—C11—O7	177.72 (14)	C25—C26—C27—O15	−176.95 (15)
C9—C10—C11—C12	−1.9 (2)	C25—C26—C27—C28	0.9 (2)
O7—C11—C12—O8	1.2 (2)	O15—C27—C28—O16	−0.3 (2)
C10—C11—C12—O8	−179.13 (15)	C26—C27—C28—O16	−178.35 (14)
O7—C11—C12—C13	−178.05 (14)	O15—C27—C28—C29	178.07 (14)
C10—C11—C12—C13	1.6 (2)	C26—C27—C28—C29	0.0 (2)
O8—C12—C13—C14	−178.90 (16)	O16—C28—C29—C30	177.21 (15)
C11—C12—C13—C14	0.3 (3)	C27—C28—C29—C30	−1.0 (2)
C12—C13—C14—C9	−1.9 (3)	C28—C29—C30—C25	1.1 (3)
C10—C9—C14—C13	1.6 (2)	C26—C25—C30—C29	−0.2 (2)
C15—C9—C14—C13	−177.60 (15)	C31—C25—C30—C29	−177.97 (16)
C14—C9—C15—O5	167.39 (16)	C30—C25—C31—O14	176.00 (17)
C10—C9—C15—O5	−11.9 (2)	C26—C25—C31—O14	−1.8 (3)
C14—C9—C15—O6	−12.1 (2)	C30—C25—C31—O13	−3.7 (2)
C10—C9—C15—O6	168.64 (14)	C26—C25—C31—O13	178.44 (15)
C10—C11—O7—C16	−2.3 (2)	C26—C27—O15—C32	−3.7 (2)
C12—C11—O7—C16	177.37 (14)	C28—C27—O15—C32	178.38 (14)