Structural and energy insights on solid-state complexes with trimethoprim: a combined theoretical and experimental investigation

We present here a new structure of a 1:1 salt of trimethoprim with hemifumarate, highlighted by single-crystal X-ray diffraction and computational conformational studies. This salt was formed during cocrystallization assays conducted to combine trimethoprim and other APIs whose combination exhibits interesting properties. Theoretical in vacuo investigations have been performed on the organic salt through a DFT two-dimensional conformational scan of torsion angles between the two aromatic moieties of trimethoprim. The evaluation of relative energies for hydrogen-bond interactions in the structure has also been performed. Comparison with conformational data from structures implying trimethoprim retrieved from the Cambridge Structural Database (CSD) shows good agreement with theoretical results, proving the validity of vacuum ab initio calculations in describing the energetic landscape of the molecule and thereby gain initial insight into the prediction process for possible new conformations and therefore potential new polymorphs.

Computing details

Data collection: CrysAlis PRO, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET) (compiled May 22 2014,16:03:01); cell refinement: CrysAlis PRO, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET) (compiled May 22 2014,16:03:01); data reduction: CrysAlis PRO, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET) (compiled May 22 2014,16:03:01); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997).

Figures

(I)

Crystal data

C14H19N4O3·C4H3O4	Z = 4
Mr = 406.40	F(000) = 856
Triclinic, P1	Dx = 1.409 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 10.4700 (5) Å	Cell parameters from 6640 reflections
b = 14.6637 (10) Å	θ = 3.0–28.8°
c = 15.0285 (10) Å	µ = 0.11 mm^−1
α = 61.535 (7)°	T = 293 K
β = 83.550 (5)°	Prism, colourless
γ = 71.020 (5)°	0.4 × 0.3 × 0.15 mm
V = 1915.6 (2) Å^3

Data collection

Xcalibur, Ruby, Gemini ultra diffractometer	6752 independent reflections
Radiation source: fine-focus sealed tube	5223 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.028
Detector resolution: 5.1856 pixels mm^-1	θmax = 25.0°, θmin = 2.7°
ω scans	h = −12→12
Absorption correction: multi-scan CrysAlis PRO, Agilent Technologies, Version 1.171.37.34 (release 22-05-2014 CrysAlis171 .NET) (compiled May 22 2014,16:03:01) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −17→17
Tmin = 0.978, Tmax = 1.000	l = −17→17
16621 measured reflections

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)] = 0.044	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.120	H atoms treated by a mixture of independent and constrained refinement
S = 1.04	w = 1/[σ^2(Fo^2) + (0.0561P)^2 + 0.1954P] where P = (Fo^2 + 2Fc^2)/3
6752 reflections	(Δ/σ)max = 0.001
593 parameters	Δρmax = 0.19 e Å^−3
0 restraints	Δρmin = −0.22 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
C1	0.61271 (15)	0.38736 (12)	0.11002 (12)	0.0283 (4)
C2	0.72682 (16)	0.29744 (13)	0.10319 (13)	0.0320 (4)
C3	0.85082 (16)	0.29909 (13)	0.08334 (13)	0.0324 (4)
C4	0.96309 (16)	0.20984 (13)	0.07619 (13)	0.0307 (4)
C5	0.11865 (16)	0.88629 (12)	0.11644 (13)	0.0320 (4)
C6	0.23237 (17)	0.79751 (13)	0.10839 (14)	0.0369 (4)
C7	0.35606 (16)	0.79909 (13)	0.08889 (13)	0.0323 (4)
C8	0.46522 (16)	0.71149 (13)	0.07756 (13)	0.0325 (4)
C9	0.15899 (16)	0.40975 (13)	0.11932 (12)	0.0325 (4)
C11	−0.03401 (16)	0.49566 (13)	0.17210 (12)	0.0309 (4)
C12	0.03922 (16)	0.53913 (12)	0.20899 (12)	0.0313 (4)
C13	0.17243 (17)	0.51564 (13)	0.19324 (13)	0.0337 (4)
H13	0.2247	0.5429	0.2145	0.040*
C14	−0.03083 (18)	0.61316 (14)	0.25435 (13)	0.0394 (4)
H14A	−0.0914	0.6790	0.2022	0.047*
H14B	0.0371	0.6342	0.2724	0.047*
C15	−0.11169 (18)	0.56891 (14)	0.34698 (13)	0.0370 (4)
C16	−0.23083 (19)	0.63986 (14)	0.35654 (14)	0.0428 (5)
H16	−0.2647	0.7099	0.3032	0.051*
C17	−0.30025 (19)	0.60721 (15)	0.44525 (15)	0.0433 (5)
C18	−0.25000 (19)	0.50329 (15)	0.52489 (14)	0.0426 (5)
C19	−0.13568 (19)	0.42945 (14)	0.51280 (14)	0.0422 (4)
C20	−0.06590 (19)	0.46258 (14)	0.42431 (13)	0.0408 (4)
H20	0.0115	0.4134	0.4170	0.049*
C21	−0.4828 (2)	0.77353 (16)	0.37748 (18)	0.0679 (7)
H21A	−0.4262	0.8196	0.3566	0.102*
H21B	−0.5680	0.8081	0.3965	0.102*
H21C	−0.4977	0.7617	0.3225	0.102*
C22	−0.4062 (3)	0.4224 (2)	0.63259 (19)	0.0896 (9)
H22A	−0.4829	0.4717	0.5862	0.134*
H22B	−0.4346	0.3992	0.7009	0.134*
H22C	−0.3673	0.3600	0.6214	0.134*
C23	0.0037 (3)	0.24246 (17)	0.58657 (18)	0.0744 (7)
H23A	−0.0153	0.2361	0.5291	0.112*
H23B	0.0106	0.1751	0.6472	0.112*
H23C	0.0876	0.2584	0.5785	0.112*
C31	0.66032 (16)	0.92351 (12)	0.10837 (12)	0.0311 (4)
C33	0.47925 (16)	1.00526 (12)	0.17511 (12)	0.0303 (4)
C34	0.56370 (16)	1.03973 (12)	0.21362 (12)	0.0298 (4)
C35	0.69486 (16)	1.01285 (12)	0.19287 (13)	0.0338 (4)
H35	0.7540	1.0336	0.2157	0.041*
C36	0.51024 (17)	1.10216 (14)	0.27322 (13)	0.0374 (4)
H36A	0.4932	1.1794	0.2274	0.045*
H36B	0.4244	1.0916	0.2996	0.045*
C37	0.60313 (17)	1.06979 (14)	0.36048 (13)	0.0359 (4)
C38	0.64078 (18)	1.14762 (15)	0.36848 (14)	0.0399 (4)
H38	0.6168	1.2190	0.3163	0.048*
C39	0.71441 (19)	1.11987 (17)	0.45407 (15)	0.0478 (5)
C40	0.75048 (19)	1.01289 (19)	0.53234 (14)	0.0529 (5)
C41	0.7164 (2)	0.93428 (16)	0.52149 (15)	0.0515 (5)
C42	0.64308 (19)	0.96303 (14)	0.43668 (14)	0.0457 (5)
H42	0.6201	0.9101	0.4305	0.055*
C43	0.7160 (3)	1.3025 (2)	0.3906 (2)	0.1008 (10)
H43A	0.7582	1.3059	0.3294	0.151*
H43B	0.7449	1.3459	0.4110	0.151*
H43C	0.6195	1.3301	0.3787	0.151*
C44	0.9517 (3)	0.9365 (4)	0.6369 (2)	0.1404 (17)
H44A	0.9741	0.8690	0.6342	0.211*
H44B	0.9807	0.9221	0.7020	0.211*
H44C	0.9963	0.9837	0.5848	0.211*
C45	0.7174 (3)	0.74947 (19)	0.5971 (2)	0.0951 (10)
H45A	0.6205	0.7693	0.5954	0.143*
H45B	0.7545	0.6808	0.6559	0.143*
H45C	0.7497	0.7433	0.5372	0.143*
N1	0.74417 (14)	0.95647 (11)	0.13979 (11)	0.0347 (3)
N2	0.23291 (15)	0.45310 (11)	0.14707 (11)	0.0346 (3)
N3	0.22090 (18)	0.34339 (14)	0.08010 (13)	0.0473 (4)
N4	−0.16757 (15)	0.51959 (15)	0.17719 (13)	0.0459 (4)
N5	0.71163 (17)	0.86200 (13)	0.06254 (12)	0.0424 (4)
N6	0.34737 (15)	1.02638 (14)	0.18853 (13)	0.0448 (4)
N7	0.52898 (13)	0.94731 (11)	0.12455 (11)	0.0341 (3)
N8	0.02669 (13)	0.42998 (11)	0.13116 (11)	0.0356 (3)
O1	0.63853 (11)	0.47112 (9)	0.09711 (10)	0.0414 (3)
O2	0.50113 (11)	0.37246 (9)	0.12951 (10)	0.0465 (3)
O3	0.94075 (11)	0.11664 (9)	0.11219 (10)	0.0419 (3)
O4	1.06846 (12)	0.22568 (10)	0.03920 (11)	0.0496 (4)
O5	0.00559 (12)	0.87427 (10)	0.12681 (12)	0.0551 (4)
O6	0.14465 (11)	0.96717 (9)	0.11117 (10)	0.0454 (3)
O7	0.57081 (13)	0.72676 (11)	0.04089 (12)	0.0598 (4)
O9	0.44029 (11)	0.61980 (9)	0.10893 (9)	0.0405 (3)
O11	−0.41846 (14)	0.67168 (11)	0.46167 (11)	0.0604 (4)
O12	−0.30967 (15)	0.47548 (12)	0.61707 (10)	0.0572 (4)
O13	−0.10111 (15)	0.32714 (11)	0.59374 (10)	0.0610 (4)
O16	0.75361 (16)	1.19234 (15)	0.46839 (12)	0.0706 (5)
O17	0.80959 (15)	0.98777 (15)	0.62184 (11)	0.0792 (5)
O18	0.75826 (17)	0.83128 (13)	0.60107 (11)	0.0785 (5)
H2	0.7037 (17)	0.2371 (14)	0.1155 (13)	0.037 (5)*
H3	0.8806 (19)	0.3583 (15)	0.0733 (14)	0.050 (5)*
H3M	0.166 (2)	0.3156 (17)	0.0599 (16)	0.061 (6)*
H3N	0.302 (3)	0.3385 (17)	0.0622 (17)	0.066 (7)*
H4M	−0.211 (2)	0.5663 (17)	0.2015 (15)	0.059 (6)*
H4N	−0.212 (2)	0.4963 (16)	0.1498 (15)	0.053 (6)*
H5M	0.653 (2)	0.8363 (17)	0.0426 (16)	0.060 (6)*
H5N	0.793 (2)	0.8538 (16)	0.0422 (15)	0.055 (6)*
H6	0.2051 (19)	0.7381 (15)	0.1163 (14)	0.049 (5)*
H6M	0.312 (2)	1.0579 (17)	0.2223 (16)	0.057 (6)*
H6N	0.297 (2)	1.0006 (16)	0.1595 (16)	0.059 (6)*
H7	0.3852 (18)	0.8579 (14)	0.0794 (14)	0.045 (5)*
H1N	0.838 (2)	0.9362 (16)	0.1299 (15)	0.063 (6)*
H2N	0.322 (2)	0.4371 (16)	0.1377 (15)	0.059 (6)*
H9	0.521 (2)	0.5624 (17)	0.1033 (16)	0.071 (6)*
H4	1.023 (2)	0.0568 (18)	0.1101 (17)	0.078 (7)*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0219 (9)	0.0276 (8)	0.0337 (9)	−0.0027 (7)	0.0002 (7)	−0.0160 (7)
C2	0.0269 (9)	0.0252 (8)	0.0452 (11)	−0.0058 (7)	0.0038 (8)	−0.0194 (8)
C3	0.0262 (9)	0.0292 (9)	0.0452 (11)	−0.0050 (7)	0.0035 (8)	−0.0226 (8)
C4	0.0229 (9)	0.0330 (9)	0.0407 (10)	−0.0047 (7)	0.0026 (8)	−0.0234 (8)
C5	0.0221 (9)	0.0285 (8)	0.0427 (10)	−0.0023 (7)	0.0028 (7)	−0.0185 (8)
C6	0.0279 (9)	0.0283 (9)	0.0571 (12)	−0.0076 (7)	0.0072 (8)	−0.0237 (9)
C7	0.0266 (9)	0.0265 (8)	0.0444 (11)	−0.0058 (7)	0.0047 (8)	−0.0191 (8)
C8	0.0240 (9)	0.0323 (9)	0.0446 (10)	−0.0056 (7)	0.0045 (8)	−0.0231 (8)
C9	0.0265 (9)	0.0347 (9)	0.0327 (9)	−0.0075 (7)	0.0044 (7)	−0.0150 (8)
C11	0.0241 (9)	0.0374 (9)	0.0301 (9)	−0.0081 (7)	0.0041 (7)	−0.0164 (8)
C12	0.0295 (9)	0.0312 (8)	0.0310 (9)	−0.0084 (7)	0.0014 (7)	−0.0136 (7)
C13	0.0308 (9)	0.0327 (9)	0.0364 (10)	−0.0127 (7)	0.0002 (8)	−0.0132 (8)
C14	0.0428 (11)	0.0383 (9)	0.0440 (11)	−0.0165 (8)	0.0100 (9)	−0.0237 (9)
C15	0.0426 (10)	0.0421 (10)	0.0390 (10)	−0.0188 (8)	0.0066 (8)	−0.0262 (9)
C16	0.0499 (12)	0.0386 (10)	0.0423 (11)	−0.0159 (9)	0.0111 (9)	−0.0211 (9)
C17	0.0470 (11)	0.0459 (11)	0.0505 (12)	−0.0207 (9)	0.0154 (9)	−0.0316 (10)
C18	0.0502 (12)	0.0553 (11)	0.0358 (11)	−0.0284 (10)	0.0087 (9)	−0.0255 (9)
C19	0.0510 (12)	0.0434 (10)	0.0375 (11)	−0.0195 (9)	−0.0035 (9)	−0.0186 (9)
C20	0.0440 (11)	0.0425 (10)	0.0430 (11)	−0.0141 (8)	0.0019 (9)	−0.0251 (9)
C21	0.0707 (16)	0.0455 (12)	0.0753 (16)	−0.0101 (11)	0.0225 (13)	−0.0278 (12)
C22	0.092 (2)	0.126 (2)	0.0558 (16)	−0.0756 (19)	0.0142 (14)	−0.0225 (16)
C23	0.0841 (18)	0.0502 (13)	0.0650 (16)	−0.0059 (12)	−0.0069 (13)	−0.0160 (12)
C31	0.0240 (9)	0.0303 (8)	0.0342 (10)	−0.0056 (7)	0.0047 (7)	−0.0139 (8)
C33	0.0233 (8)	0.0335 (8)	0.0326 (9)	−0.0066 (7)	0.0027 (7)	−0.0160 (8)
C34	0.0252 (9)	0.0282 (8)	0.0330 (9)	−0.0061 (7)	0.0012 (7)	−0.0136 (7)
C35	0.0275 (9)	0.0329 (9)	0.0419 (10)	−0.0101 (7)	0.0006 (8)	−0.0174 (8)
C36	0.0316 (9)	0.0381 (9)	0.0458 (11)	−0.0058 (8)	−0.0011 (8)	−0.0249 (9)
C37	0.0308 (9)	0.0420 (10)	0.0362 (10)	−0.0082 (8)	0.0045 (8)	−0.0218 (8)
C38	0.0382 (10)	0.0468 (10)	0.0383 (11)	−0.0140 (8)	0.0051 (8)	−0.0228 (9)
C39	0.0360 (11)	0.0769 (14)	0.0465 (12)	−0.0219 (10)	0.0090 (9)	−0.0397 (12)
C40	0.0325 (11)	0.0889 (16)	0.0326 (11)	−0.0085 (10)	0.0018 (9)	−0.0315 (12)
C41	0.0394 (11)	0.0547 (12)	0.0361 (12)	0.0015 (9)	0.0054 (9)	−0.0136 (10)
C42	0.0445 (11)	0.0411 (10)	0.0450 (12)	−0.0062 (8)	0.0021 (9)	−0.0197 (9)
C43	0.133 (3)	0.095 (2)	0.115 (3)	−0.065 (2)	−0.005 (2)	−0.059 (2)
C44	0.0425 (16)	0.276 (5)	0.071 (2)	−0.012 (2)	−0.0121 (14)	−0.078 (3)
C45	0.100 (2)	0.0458 (14)	0.0776 (19)	0.0059 (14)	0.0209 (16)	−0.0027 (13)
N1	0.0198 (7)	0.0394 (8)	0.0453 (9)	−0.0084 (6)	0.0066 (7)	−0.0216 (7)
N2	0.0212 (8)	0.0363 (8)	0.0441 (9)	−0.0082 (6)	0.0037 (7)	−0.0179 (7)
N3	0.0314 (9)	0.0586 (10)	0.0648 (12)	−0.0128 (8)	0.0172 (9)	−0.0426 (10)
N4	0.0233 (8)	0.0692 (11)	0.0641 (11)	−0.0107 (8)	0.0064 (8)	−0.0490 (10)
N5	0.0267 (9)	0.0518 (9)	0.0551 (10)	−0.0073 (7)	0.0120 (8)	−0.0352 (9)
N6	0.0221 (8)	0.0691 (11)	0.0639 (11)	−0.0116 (7)	0.0101 (8)	−0.0503 (10)
N7	0.0224 (7)	0.0437 (8)	0.0440 (9)	−0.0092 (6)	0.0068 (6)	−0.0282 (7)
N8	0.0250 (8)	0.0471 (8)	0.0424 (9)	−0.0108 (6)	0.0062 (6)	−0.0281 (7)
O1	0.0246 (6)	0.0341 (6)	0.0737 (9)	−0.0040 (5)	0.0035 (6)	−0.0351 (6)
O2	0.0221 (6)	0.0393 (7)	0.0789 (10)	−0.0073 (5)	0.0109 (6)	−0.0314 (7)
O3	0.0269 (7)	0.0308 (6)	0.0692 (9)	−0.0046 (5)	0.0102 (6)	−0.0288 (6)
O4	0.0303 (7)	0.0490 (7)	0.0849 (10)	−0.0152 (6)	0.0240 (7)	−0.0457 (7)
O5	0.0224 (7)	0.0459 (7)	0.1039 (12)	−0.0090 (6)	0.0158 (7)	−0.0439 (8)
O6	0.0264 (7)	0.0348 (6)	0.0831 (10)	−0.0036 (5)	0.0047 (6)	−0.0380 (7)
O7	0.0356 (8)	0.0551 (8)	0.1103 (12)	−0.0194 (6)	0.0326 (8)	−0.0581 (9)
O9	0.0280 (7)	0.0311 (6)	0.0629 (9)	−0.0035 (5)	0.0092 (6)	−0.0275 (6)
O11	0.0619 (9)	0.0524 (8)	0.0597 (9)	−0.0146 (7)	0.0259 (8)	−0.0276 (7)
O12	0.0638 (9)	0.0793 (10)	0.0397 (8)	−0.0374 (8)	0.0137 (7)	−0.0293 (7)
O13	0.0706 (10)	0.0530 (8)	0.0427 (8)	−0.0150 (7)	−0.0017 (7)	−0.0113 (7)
O16	0.0699 (11)	0.1080 (13)	0.0700 (11)	−0.0428 (10)	0.0050 (8)	−0.0602 (11)
O17	0.0464 (9)	0.1414 (15)	0.0431 (9)	−0.0118 (9)	−0.0031 (7)	−0.0480 (10)
O18	0.0759 (12)	0.0664 (10)	0.0440 (9)	0.0056 (9)	−0.0003 (8)	−0.0050 (8)

Geometric parameters (Å, º)

C1—O2	1.2356 (19)	C23—H23A	0.9600
C1—O1	1.2634 (18)	C23—H23B	0.9600
C1—C2	1.501 (2)	C23—H23C	0.9600
C2—C3	1.304 (2)	C31—N7	1.3288 (19)
C2—H2	0.921 (17)	C31—N5	1.331 (2)
C3—C4	1.487 (2)	C31—N1	1.347 (2)
C3—H3	0.956 (19)	C33—N6	1.327 (2)
C4—O4	1.2190 (19)	C33—N7	1.3450 (19)
C4—O3	1.2999 (19)	C33—C34	1.434 (2)
C5—O5	1.2348 (19)	C34—C35	1.344 (2)
C5—O6	1.2658 (19)	C34—C36	1.513 (2)
C5—C6	1.496 (2)	C35—N1	1.358 (2)
C6—C7	1.300 (2)	C35—H35	0.9300
C6—H6	0.954 (19)	C36—C37	1.511 (2)
C7—C8	1.482 (2)	C36—H36A	0.9700
C7—H7	0.949 (18)	C36—H36B	0.9700
C8—O7	1.2176 (19)	C37—C38	1.381 (2)
C8—O9	1.3016 (19)	C37—C42	1.382 (2)
C9—N3	1.329 (2)	C38—C39	1.391 (3)
C9—N8	1.329 (2)	C38—H38	0.9300
C9—N2	1.350 (2)	C39—O16	1.366 (2)
C11—N4	1.329 (2)	C39—C40	1.394 (3)
C11—N8	1.3377 (19)	C40—O17	1.376 (2)
C11—C12	1.432 (2)	C40—C41	1.394 (3)
C12—C13	1.346 (2)	C41—O18	1.367 (2)
C12—C14	1.502 (2)	C41—C42	1.374 (3)
C13—N2	1.361 (2)	C42—H42	0.9300
C13—H13	0.9300	C43—O16	1.422 (3)
C14—C15	1.519 (2)	C43—H43A	0.9600
C14—H14A	0.9700	C43—H43B	0.9600
C14—H14B	0.9700	C43—H43C	0.9600
C15—C16	1.385 (2)	C44—O17	1.420 (3)
C15—C20	1.387 (2)	C44—H44A	0.9600
C16—C17	1.391 (2)	C44—H44B	0.9600
C16—H16	0.9300	C44—H44C	0.9600
C17—O11	1.371 (2)	C45—O18	1.426 (3)
C17—C18	1.383 (3)	C45—H45A	0.9600
C18—O12	1.381 (2)	C45—H45B	0.9600
C18—C19	1.391 (3)	C45—H45C	0.9600
C19—O13	1.367 (2)	N1—H1N	0.95 (2)
C19—C20	1.391 (2)	N2—H2N	0.90 (2)
C20—H20	0.9300	N3—H3M	0.94 (2)
C21—O11	1.422 (2)	N3—H3N	0.85 (2)
C21—H21A	0.9600	N4—H4M	0.90 (2)
C21—H21B	0.9600	N4—H4N	0.88 (2)
C21—H21C	0.9600	N5—H5M	0.95 (2)
C22—O12	1.403 (3)	N5—H5N	0.86 (2)
C22—H22A	0.9600	N6—H6M	0.82 (2)
C22—H22B	0.9600	N6—H6N	0.97 (2)
C22—H22C	0.9600	O3—H4	1.02 (2)
C23—O13	1.405 (2)	O9—H9	1.01 (2)
O2—C1—O1	125.25 (13)	N5—C31—N1	118.82 (15)
O2—C1—C2	117.01 (14)	N6—C33—N7	115.39 (15)
O1—C1—C2	117.73 (14)	N6—C33—C34	122.44 (14)
C3—C2—C1	125.38 (15)	N7—C33—C34	122.15 (14)
C3—C2—H2	120.2 (10)	C35—C34—C33	115.22 (14)
C1—C2—H2	114.4 (10)	C35—C34—C36	121.89 (15)
C2—C3—C4	125.01 (15)	C33—C34—C36	122.89 (14)
C2—C3—H3	123.2 (11)	C34—C35—N1	122.45 (16)
C4—C3—H3	111.8 (11)	C34—C35—H35	118.8
O4—C4—O3	123.77 (13)	N1—C35—H35	118.8
O4—C4—C3	120.49 (14)	C37—C36—C34	114.73 (13)
O3—C4—C3	115.74 (14)	C37—C36—H36A	108.6
O5—C5—O6	125.42 (13)	C34—C36—H36A	108.6
O5—C5—C6	116.20 (14)	C37—C36—H36B	108.6
O6—C5—C6	118.38 (14)	C34—C36—H36B	108.6
C7—C6—C5	125.57 (16)	H36A—C36—H36B	107.6
C7—C6—H6	121.3 (11)	C38—C37—C42	119.51 (17)
C5—C6—H6	113.1 (11)	C38—C37—C36	120.43 (15)
C6—C7—C8	124.19 (16)	C42—C37—C36	119.90 (16)
C6—C7—H7	122.8 (11)	C37—C38—C39	120.40 (17)
C8—C7—H7	113.0 (11)	C37—C38—H38	119.8
O7—C8—O9	123.46 (14)	C39—C38—H38	119.8
O7—C8—C7	120.60 (15)	O16—C39—C38	123.94 (19)
O9—C8—C7	115.94 (14)	O16—C39—C40	116.18 (19)
N3—C9—N8	118.84 (16)	C38—C39—C40	119.88 (18)
N3—C9—N2	118.89 (16)	O17—C40—C41	120.7 (2)
N8—C9—N2	122.26 (14)	O17—C40—C39	120.0 (2)
N4—C11—N8	116.70 (16)	C41—C40—C39	119.08 (18)
N4—C11—C12	120.75 (15)	O18—C41—C42	124.7 (2)
N8—C11—C12	122.56 (14)	O18—C41—C40	115.0 (2)
C13—C12—C11	115.36 (14)	C42—C41—C40	120.33 (18)
C13—C12—C14	122.68 (15)	C41—C42—C37	120.72 (18)
C11—C12—C14	121.78 (14)	C41—C42—H42	119.6
C12—C13—N2	121.90 (16)	C37—C42—H42	119.6
C12—C13—H13	119.0	O16—C43—H43A	109.5
N2—C13—H13	119.0	O16—C43—H43B	109.5
C12—C14—C15	117.43 (13)	H43A—C43—H43B	109.5
C12—C14—H14A	107.9	O16—C43—H43C	109.5
C15—C14—H14A	107.9	H43A—C43—H43C	109.5
C12—C14—H14B	107.9	H43B—C43—H43C	109.5
C15—C14—H14B	107.9	O17—C44—H44A	109.5
H14A—C14—H14B	107.2	O17—C44—H44B	109.5
C16—C15—C20	119.45 (16)	H44A—C44—H44B	109.5
C16—C15—C14	118.23 (15)	O17—C44—H44C	109.5
C20—C15—C14	122.20 (15)	H44A—C44—H44C	109.5
C15—C16—C17	120.52 (17)	H44B—C44—H44C	109.5
C15—C16—H16	119.7	O18—C45—H45A	109.5
C17—C16—H16	119.7	O18—C45—H45B	109.5
O11—C17—C18	115.39 (15)	H45A—C45—H45B	109.5
O11—C17—C16	124.65 (17)	O18—C45—H45C	109.5
C18—C17—C16	119.96 (16)	H45A—C45—H45C	109.5
O12—C18—C17	119.81 (16)	H45B—C45—H45C	109.5
O12—C18—C19	120.58 (17)	C31—N1—C35	119.43 (14)
C17—C18—C19	119.54 (16)	C31—N1—H1N	120.9 (12)
O13—C19—C18	114.35 (16)	C35—N1—H1N	119.5 (13)
O13—C19—C20	125.47 (17)	C9—N2—C13	119.51 (14)
C18—C19—C20	120.18 (17)	C9—N2—H2N	119.2 (13)
C15—C20—C19	120.06 (16)	C13—N2—H2N	121.2 (13)
C15—C20—H20	120.0	C9—N3—H3M	117.1 (12)
C19—C20—H20	120.0	C9—N3—H3N	119.9 (15)
O11—C21—H21A	109.5	H3M—N3—H3N	121.5 (19)
O11—C21—H21B	109.5	C11—N4—H4M	118.4 (13)
H21A—C21—H21B	109.5	C11—N4—H4N	119.5 (13)
O11—C21—H21C	109.5	H4M—N4—H4N	121.6 (19)
H21A—C21—H21C	109.5	C31—N5—H5M	119.0 (12)
H21B—C21—H21C	109.5	C31—N5—H5N	121.2 (13)
O12—C22—H22A	109.5	H5M—N5—H5N	119.0 (18)
O12—C22—H22B	109.5	C33—N6—H6M	120.1 (15)
H22A—C22—H22B	109.5	C33—N6—H6N	117.4 (12)
O12—C22—H22C	109.5	H6M—N6—H6N	122.5 (19)
H22A—C22—H22C	109.5	C31—N7—C33	118.45 (14)
H22B—C22—H22C	109.5	C9—N8—C11	118.21 (14)
O13—C23—H23A	109.5	C4—O3—H4	112.6 (12)
O13—C23—H23B	109.5	C8—O9—H9	111.9 (12)
H23A—C23—H23B	109.5	C17—O11—C21	117.11 (14)
O13—C23—H23C	109.5	C18—O12—C22	115.41 (16)
H23A—C23—H23C	109.5	C19—O13—C23	119.67 (15)
H23B—C23—H23C	109.5	C39—O16—C43	117.38 (18)
N7—C31—N5	118.91 (16)	C40—O17—C44	117.14 (17)
N7—C31—N1	122.24 (14)	C41—O18—C45	117.2 (2)
O2—C1—C2—C3	179.96 (17)	C34—C36—C37—C38	126.38 (16)
O1—C1—C2—C3	−1.2 (3)	C34—C36—C37—C42	−58.2 (2)
C1—C2—C3—C4	−179.66 (16)	C42—C37—C38—C39	−2.2 (2)
C2—C3—C4—O4	166.26 (18)	C36—C37—C38—C39	173.20 (15)
C2—C3—C4—O3	−14.3 (3)	C37—C38—C39—O16	−178.95 (16)
O5—C5—C6—C7	173.97 (19)	C37—C38—C39—C40	0.0 (2)
O6—C5—C6—C7	−5.3 (3)	O16—C39—C40—O17	6.5 (2)
C5—C6—C7—C8	−177.56 (16)	C38—C39—C40—O17	−172.56 (15)
C6—C7—C8—O7	166.05 (19)	O16—C39—C40—C41	−178.47 (16)
C6—C7—C8—O9	−14.0 (3)	C38—C39—C40—C41	2.5 (3)
N4—C11—C12—C13	−175.43 (16)	O17—C40—C41—O18	−6.2 (2)
N8—C11—C12—C13	4.5 (2)	C39—C40—C41—O18	178.72 (16)
N4—C11—C12—C14	−0.2 (3)	O17—C40—C41—C42	172.20 (16)
N8—C11—C12—C14	179.74 (15)	C39—C40—C41—C42	−2.8 (3)
C11—C12—C13—N2	−1.2 (2)	O18—C41—C42—C37	178.93 (16)
C14—C12—C13—N2	−176.41 (15)	C40—C41—C42—C37	0.7 (3)
C13—C12—C14—C15	−125.77 (18)	C38—C37—C42—C41	1.9 (3)
C11—C12—C14—C15	59.3 (2)	C36—C37—C42—C41	−173.54 (15)
C12—C14—C15—C16	−143.39 (17)	N7—C31—N1—C35	2.3 (2)
C12—C14—C15—C20	40.7 (2)	N5—C31—N1—C35	−175.45 (15)
C20—C15—C16—C17	3.8 (3)	C34—C35—N1—C31	−1.6 (2)
C14—C15—C16—C17	−172.26 (16)	N3—C9—N2—C13	−175.86 (15)
C15—C16—C17—O11	179.86 (17)	N8—C9—N2—C13	3.2 (2)
C15—C16—C17—C18	0.3 (3)	C12—C13—N2—C9	−2.4 (2)
O11—C17—C18—O12	−7.5 (3)	N5—C31—N7—C33	176.95 (15)
C16—C17—C18—O12	172.09 (16)	N1—C31—N7—C33	−0.8 (2)
O11—C17—C18—C19	175.59 (16)	N6—C33—N7—C31	179.88 (15)
C16—C17—C18—C19	−4.8 (3)	C34—C33—N7—C31	−1.4 (2)
O12—C18—C19—O13	7.7 (2)	N3—C9—N8—C11	179.04 (16)
C17—C18—C19—O13	−175.49 (16)	N2—C9—N8—C11	0.0 (2)
O12—C18—C19—C20	−171.56 (16)	N4—C11—N8—C9	176.00 (16)
C17—C18—C19—C20	5.3 (3)	C12—C11—N8—C9	−3.9 (2)
C16—C15—C20—C19	−3.3 (3)	C18—C17—O11—C21	−171.92 (18)
C14—C15—C20—C19	172.61 (16)	C16—C17—O11—C21	8.5 (3)
O13—C19—C20—C15	179.61 (17)	C17—C18—O12—C22	95.7 (2)
C18—C19—C20—C15	−1.3 (3)	C19—C18—O12—C22	−87.4 (2)
N6—C33—C34—C35	−179.42 (16)	C18—C19—O13—C23	173.33 (18)
N7—C33—C34—C35	1.9 (2)	C20—C19—O13—C23	−7.5 (3)
N6—C33—C34—C36	0.4 (3)	C38—C39—O16—C43	0.1 (3)
N7—C33—C34—C36	−178.21 (15)	C40—C39—O16—C43	−178.9 (2)
C33—C34—C35—N1	−0.4 (2)	C41—C40—O17—C44	82.9 (3)
C36—C34—C35—N1	179.74 (15)	C39—C40—O17—C44	−102.1 (3)
C35—C34—C36—C37	−38.9 (2)	C42—C41—O18—C45	−2.9 (3)
C33—C34—C36—C37	141.21 (16)	C40—C41—O18—C45	175.50 (18)