5-Phenyl­uridine trihydrate

In the title compound, C₁₅H₁₆N₂O₆·~3H₂O, the substituted uracil ring is oriented in the anti position relative to the ribose ring, and the phenyl and uracil rings are oriented in a noncoplanar fashion. The furanose ring adopts a conformation close to 3'-endo, in contrast to the furanose conformation seen in the crystal structure of the synthetic precursor 5-bromo­uridine, which is close to 2'-endo. The mol­ecule is involved in an extensive hydrogen-bonding network with several water mol­ecules, some of which are disordered.

S1. Comment

The shape of nucleosides depends mainly on three conformational parameters: (i) the glycosyl torsion angle, which determines the syn or anti orientation of the base relative to the ribose; (ii) the orientation of the primary hydroxy group; and (iii) the conformation of the furanose ring (Blackburn & Gait, 1996). Analogues of naturally occurring nucleosides are sought after as biological tools and enzyme inhibitors, e.g. for anti-viral therapy, and insights into structural modifications that allow manipulation of the conformation of nucleosides are therefore highly valuable.

5-Phenyluridine was prepared from 5-bromouridine and phenylboronic acid via Suzuki–Miyaura cross-coupling. Clear, colourless prisms of the 3.06-hydrate, (I), were obtained after recrystallization from dry ethanol at room temperature. The structure determined for (I) provides, for the first time, insights into the conformational preferences of a 5-arylated uridine derivative. In 5-phenyluridine (Fig. 1), the substituted uracil ring is oriented in the anti position relative to the ribose ring, i.e. the O4—C1—N11—C12 torsion angle is -170.0 (4)°; viewed down the N11—C1 bond, the C22—H22 bond is above, and pointing towards, atom O5 of the CH₂OH group of the sugar moiety, and the N13—H13 bond points away from O5. The furanose ring adopts a conformation close to 3'-endo, an envelope shape with atom C3 displaced 0.601 (8) Å from the mean-plane of the other four ring atoms. This conformation is similar to the conformation seen in the crystal structure of the native parent nucleoside uridine (Green et al., 1975). In contrast, most previously reported uridine derivatives with additional substituents at position 5, including 5-bromouridine (Cervi et al., 1991), preferentially adopt a furanose conformation close to 2'-endo. For the present study, 5-bromouridine was prepared as a synthetic precursor for the title compound and its structure solved (data not shown). Our crystallographic data for 5-bromouridine indeed confirmed the preference of this uridine derivative for the 2'-endo conformation, as previously described (Cervi et al., 1991). The furanose conformational differences between 5-phenyluridine and other 5-substituted uridine derivatives suggest that the conformation of furanose in uridine nucleosides can be modulated by the nature of the substituent in position 5. This finding may have important implications for the design of bioactive nucleoside analogues. The biological activity of nucleoside anti-virals, for example, hinges on their recognition by several virus-encoded enzymes (e.g. thymidine kinase, DNA polymerase). The substrate specificity of these enzymes is at least partly controlled by the conformation of the furanose (Choi et al., 2003), and the role of substituents in position 5 for the furanose conformation therefore warrants further investigation.

To date, no structural information has been available for uridine derivatives with an aryl or heteroaryl substituent in position 5. However, the structures of four 2'-deoxyuridine derivatives with a heterocyclic substituent (thienyl, thiazolyl, oxazolyl or thiazolyl) in position 5 have been reported (Creuven et al., 1996; Srivatsan & Tor, 2007; Greco & Tor, 2007). All of these known 5-heteroaryl-2'-deoxyuridines show a coplanar, or near coplanar, orientation of the heterocyclic substituent and the uracil base (Creuven et al., 1996; Srivatsan & Tor, 2007; Greco & Tor, 2007). In stark contrast, the phenyl and uracil rings in 5-phenyluridine are oriented in a noncoplanar fashion. The torsion angles about the C15—C21 bond show a rotation of ca 37.5° between the planes of the uracil and phenyl rings. These conformational differences have implications for stacking and packing. In our crystal structure, molecules of 5-phenyluridine are stacked along a twofold screw symmetry axis which passes close to the mid-point of the C15—C21 bond; the aromatic rings are arranged so that the phenyl and uracil rings lie overlapping, alternately, on each side of the axis and essentially parallel, about 3.42 Å apart, in infinite stacks (Fig. 2). Additionally, the molecules in a stack are connected in a spiral arrangement through hydrogen bonds through the fully occupied water molecules (O5···H31A—O31—H31B···O14^4a; symmetry code as in Fig. 1). Each stack is linked to its four neighbours through further hydrogen bonds, either directly or through the O31 water molecules. The disordered water molecules lie in zigzag chains, parallel to the a axis and between the stacks, and it is estimated that they are linked to each other and to the uridine molecules through further hydrogen bonds, some of which are not well defined since the H atoms were not located or well refined. A listing of the recognized hydrogen bonds is given in Table 1.

Of the previously reported 5-heteroaryl-2'-deoxyuridines, only the structure of 5-(thien-2-yl)-2'-deoxyuridine shows an alternating stacking arrangement of the uracil base and the 5-substituent similar to that observed in 5-phenyluridine (Creuven et al., 1996). However, in the 5-(thien-2-yl)-2'-deoxyuridine crystal, the molecules are stacked with offset overlap of the planar systems; in a pair of the two independent molecules, the inter-ring bonds overlap the thiophene ring of the opposite molecule. These pairs, repeated by translation along the c axis, then overlap with the inter-ring bonds above the edge of the uracil rings, and the overall stacking is a continuation of these stepwise, offset pairings. In summary, the different substituents in position 5 of 5-(thien-2-yl)-2'-deoxyuridine and 5-phenyluridine induce substantially different stacking patterns. These differences may be exploited for the generation of specific supramolecular architectures, and further studies into the differential effects different substituents in position 5 have on packing and stacking of 5-(hetero)aryluridines are currently underway.

Related literature

The synthetic precursor 5-bromouridine (Cervi et al., 1991) and three structurally related uridine derivatives with heterocyclic substituents at position 5 (Srivatsan & Tor, 2007) have been reported.

S2. Experimental

For the preparation of 5-phenyluridine, 5-bromouridine (50 mg, 0.155 mmol), phenylboronic acid (34 mg, 0.280 mmol) and K₂CO₃ (43 mg, 0.311 mmol) were suspended in degassed water (5 ml). The mixture was stirred under nitrogen for 10 min at room temperature. TPPTS [define] (6 mg, 0.011 mmol) and Na₂Cl₄Pd (1 mg, 0.005 mmol) were added, and the reaction was stirred under nitrogen for 4 h at 313 K. Once all starting material had been consumed, the reaction was cooled to room temperature. 0.05 M aqueous TEAB [define] (50 ml) was added, and the pH was adjusted to pH 7 with 1% aqueous HCl. The aqueous solution was filtered through celite and the filtrate was evaporated. The crude product was purified by column chromatography (silica, 5–10% methanol in CHCl₃) to give the title compound as a white amorphous powder (22.4 mg, 45%). This material was recrystallized from dry ethanol at room temperature to give crystals suitable for diffraction experiments.

S3. Refinement

The analysis shows that, in addition to the 5-phenyluridine molecule, there is a well defined water molecule, and two other water molecules each split over two (or perhaps more) sites. The H atoms of the hydroxy groups of the 5-phenyluridine molecule and of the ordered water molecule were located in difference maps and were refined with distance constraints. Other H atoms in the uridine molecule were included in idealized positions and their U_iso values were set to ride on the U_eq values of the parent C and N atoms.

The partially occupied O atoms were refined isotropically, initially varying the site-occupancy-factor and U_iso values in alternate cycles. A few H-atom sites were identified from difference maps, but these did not refine satisfactorily and were not included in the model.

The Flack parameter was not a reliable indicator of the absolute configuration, and the Friedel equivalent reflections were then merged. Since the crystals were prepared from uridine, the results shown were set to conform to the known configuration of that molecule.

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2005); cell refinement: CrysAlis RED (Oxford Diffraction, 2005); data reduction: CrysAlis RED (Oxford Diffraction, 2005); program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEP (Johnson, 1971); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).

Figures

Fig. 1. A view of the molecule of 5-phenyluridine and its hydrogen-bonded neighbours, indicating the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level. [Symmetry codes: (2a) 3/2 - x, -y, z - 1/2; (2b) 3/2 - x, -y, 1/2 + z; (2c) ???????; (3a) 2 - x, 1/2 + y, 1/2 - z; (3b) 1 - x, 1/2 + y, 1/2 - z; (3c) 2 - x, y - 1/2, 1/2 - z; (3d) 1 - x, y - 1/2, 1/2 - z; (4a) x - 1/2, 1/2 - y, 1 - z; (4b) 1/2 + x, 1/2 - y, 1 - z.] The site occupancies of the disordered O atoms are as follows: O41 0.487, O42 0.410, O43 0.12, O51 0.465, O52 0.462, O53 0.12.

Fig. 2. A view of the packing down the a axis. A 21 symmetry axis (parallel to the a axis) passes close to the mid-point of the C15—C21 bond, and the stacking of phenyl/uracil rings in infinite columns about this axis can be seen.

5-Phenyluridine 2.06-hydrate

Crystal data

C15H16N2O6·3.06H2O	F(000) = 792
Mr = 371.02	Dx = 1.450 Mg m^−3
Orthorhombic, P212121	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: P 2ac 2ab	Cell parameters from 4688 reflections
a = 7.2144 (3) Å	θ = 3.4–30.0°
b = 14.0623 (6) Å	µ = 0.12 mm^−1
c = 16.7536 (8) Å	T = 140 K
V = 1699.67 (13) Å^3	Prism, colourless
Z = 4	0.52 × 0.09 × 0.07 mm

Data collection

Oxford Diffraction Xcalibur 3 CCD diffractometer	1731 independent reflections
Radiation source: Enhance (Mo) X-ray Source	1363 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.092
Detector resolution: 16.0050 pixels mm^-1	θmax = 25.0°, θmin = 3.4°
Thin slice ϕ and ω scans	h = −8→8
Absorption correction: multi-scan (CrysAlis RED; Oxford Diffraction, 2005) Empirical absorption correction using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm.	k = −16→16
Tmin = 0.544, Tmax = 0.997	l = −19→19
17587 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)] = 0.058	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.111	H atoms treated by a mixture of independent and constrained refinement
S = 1.12	w = 1/[σ^2(Fo^2) + (0.0312P)^2 + 2.0481P] where P = (Fo^2 + 2Fc^2)/3
1731 reflections	(Δ/σ)max = 0.002
281 parameters	Δρmax = 0.22 e Å^−3
5 restraints	Δρmin = −0.23 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	Occ. (<1)
C1	0.9940 (7)	0.0672 (4)	0.3118 (3)	0.0179 (11)
H1	1.0961	0.0221	0.3192	0.022*
C2	0.8460 (7)	0.0217 (3)	0.2609 (3)	0.0194 (12)
H2	0.7501	−0.0098	0.2928	0.023*
O2	0.9391 (5)	−0.0423 (2)	0.2085 (2)	0.0204 (8)
C3	0.7717 (7)	0.1071 (4)	0.2150 (3)	0.0219 (12)
H3	0.6880	0.1442	0.2490	0.026*
O3	0.6787 (5)	0.0796 (3)	0.1435 (2)	0.0256 (9)
C4	0.9509 (8)	0.1631 (4)	0.1999 (3)	0.0210 (12)
H4	1.0154	0.1341	0.1545	0.025*
O4	1.0597 (5)	0.1476 (2)	0.2702 (2)	0.0229 (8)
C5	0.9291 (9)	0.2687 (3)	0.1835 (3)	0.0282 (13)
H5A	1.0506	0.2975	0.1779	0.034*
H5B	0.8625	0.2777	0.1338	0.034*
O5	0.8307 (5)	0.3144 (2)	0.2470 (2)	0.0282 (9)
N11	0.9226 (6)	0.0974 (3)	0.3918 (2)	0.0184 (10)
C12	0.8807 (7)	0.0258 (3)	0.4449 (3)	0.0199 (12)
O12	0.8926 (5)	−0.0581 (2)	0.4259 (2)	0.0257 (9)
N13	0.8284 (6)	0.0551 (3)	0.5187 (2)	0.0205 (10)
H13	0.7973	0.0112	0.5518	0.025*
O14	0.7687 (5)	0.1617 (2)	0.6166 (2)	0.0219 (8)
C14	0.8196 (7)	0.1480 (4)	0.5469 (3)	0.0174 (11)
C15	0.8685 (7)	0.2199 (3)	0.4890 (3)	0.0179 (12)
C16	0.9216 (7)	0.1912 (3)	0.4156 (3)	0.0212 (12)
H16	0.9596	0.2371	0.3792	0.025*
C21	0.8655 (7)	0.3227 (4)	0.5103 (3)	0.0190 (12)
C22	0.8084 (7)	0.3888 (3)	0.4540 (3)	0.0239 (13)
H22	0.7672	0.3679	0.4044	0.029*
C23	0.8114 (8)	0.4859 (4)	0.4703 (4)	0.0333 (15)
H23	0.7747	0.5292	0.4314	0.040*
C24	0.8693 (8)	0.5182 (4)	0.5448 (4)	0.0315 (14)
H24	0.8707	0.5829	0.5561	0.038*
C25	0.9247 (7)	0.4529 (4)	0.6020 (3)	0.0298 (14)
H25	0.9642	0.4738	0.6518	0.036*
C26	0.9212 (8)	0.3558 (4)	0.5849 (3)	0.0242 (12)
H26	0.9567	0.3125	0.6239	0.029*
O31	0.4545 (7)	0.3345 (4)	0.2315 (3)	0.0462 (12)
O41	0.1487 (16)	0.2570 (8)	0.0101 (8)	0.044 (3)	0.49
O42	0.252 (2)	0.2800 (9)	0.0081 (8)	0.038 (3)	0.41
O51	0.3718 (15)	0.1755 (7)	0.1388 (6)	0.045 (3)	0.46
O52	0.4580 (15)	0.2261 (8)	0.1031 (7)	0.038 (2)	0.46
O43	0.325 (6)	0.274 (3)	0.054 (3)	0.051 (11)*	0.12
O53	0.365 (11)	0.215 (6)	0.092 (5)	0.10 (3)*	0.12
H2O	0.880 (10)	−0.067 (5)	0.172 (3)	0.08 (3)*
H3O	0.599 (7)	0.116 (4)	0.128 (4)	0.06 (2)*
H5O	0.885 (7)	0.363 (3)	0.263 (3)	0.037 (18)*
H31A	0.566 (4)	0.331 (7)	0.242 (5)	0.11 (4)*
H31B	0.412 (14)	0.307 (7)	0.270 (4)	0.08 (4)*	0.75

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.018 (3)	0.014 (3)	0.022 (3)	−0.001 (2)	0.004 (2)	−0.002 (2)
C2	0.018 (3)	0.013 (2)	0.027 (3)	0.001 (2)	0.003 (2)	−0.001 (2)
O2	0.0234 (19)	0.0160 (18)	0.022 (2)	0.0051 (16)	−0.0007 (17)	−0.0062 (16)
C3	0.018 (3)	0.020 (3)	0.028 (3)	0.005 (2)	0.004 (2)	−0.007 (2)
O3	0.023 (2)	0.021 (2)	0.032 (2)	0.0040 (18)	−0.0125 (18)	−0.0089 (18)
C4	0.031 (3)	0.019 (3)	0.013 (3)	0.003 (2)	−0.001 (2)	0.001 (2)
O4	0.0223 (19)	0.0242 (19)	0.0222 (19)	−0.0035 (17)	−0.0004 (17)	0.0008 (16)
C5	0.038 (3)	0.015 (3)	0.031 (3)	0.000 (3)	0.002 (3)	−0.004 (2)
O5	0.027 (2)	0.016 (2)	0.042 (3)	−0.0036 (17)	0.0026 (19)	−0.0079 (18)
N11	0.023 (2)	0.015 (2)	0.017 (2)	−0.003 (2)	0.003 (2)	−0.0024 (18)
C12	0.024 (3)	0.016 (3)	0.021 (3)	−0.003 (2)	−0.002 (2)	0.000 (2)
O12	0.036 (2)	0.0154 (19)	0.026 (2)	−0.0034 (17)	0.0015 (17)	−0.0032 (17)
N13	0.028 (3)	0.012 (2)	0.021 (2)	0.002 (2)	0.000 (2)	0.0051 (19)
O14	0.026 (2)	0.0186 (18)	0.021 (2)	0.0019 (16)	0.0020 (16)	0.0011 (17)
C14	0.011 (3)	0.023 (3)	0.018 (3)	−0.002 (2)	−0.001 (2)	−0.005 (2)
C15	0.023 (3)	0.016 (3)	0.015 (3)	−0.004 (2)	−0.001 (2)	−0.002 (2)
C16	0.022 (3)	0.016 (3)	0.026 (3)	−0.004 (2)	−0.004 (2)	0.001 (2)
C21	0.021 (3)	0.016 (3)	0.020 (3)	−0.005 (2)	0.002 (2)	−0.003 (2)
C22	0.026 (3)	0.019 (3)	0.027 (3)	−0.005 (3)	0.006 (3)	0.001 (2)
C23	0.036 (4)	0.023 (3)	0.041 (4)	0.001 (3)	0.006 (3)	0.006 (3)
C24	0.023 (3)	0.020 (3)	0.052 (4)	−0.004 (2)	0.008 (3)	−0.007 (3)
C25	0.024 (3)	0.026 (3)	0.040 (4)	−0.005 (3)	0.004 (3)	−0.012 (3)
C26	0.023 (3)	0.020 (3)	0.030 (3)	−0.006 (3)	−0.001 (3)	0.000 (2)
O31	0.043 (3)	0.056 (3)	0.040 (3)	0.016 (3)	0.002 (2)	0.004 (3)
O41	0.027 (6)	0.045 (7)	0.061 (7)	0.002 (5)	−0.009 (6)	−0.029 (5)
O42	0.063 (9)	0.030 (7)	0.022 (6)	0.016 (7)	−0.019 (8)	−0.004 (5)
O51	0.043 (6)	0.044 (6)	0.049 (6)	0.019 (6)	−0.013 (6)	−0.005 (6)
O52	0.032 (6)	0.035 (6)	0.047 (7)	0.008 (5)	−0.005 (6)	0.006 (5)

Geometric parameters (Å, º)

C1—O4	1.411 (6)	C12—N13	1.357 (6)
C1—N11	1.497 (6)	N13—C14	1.391 (6)
C1—C2	1.509 (7)	N13—H13	0.8600
C1—H1	0.9800	O14—C14	1.239 (6)
C2—O2	1.426 (6)	C14—C15	1.445 (7)
C2—C3	1.524 (7)	C15—C16	1.349 (7)
C2—H2	0.9800	C15—C21	1.490 (7)
O2—H2O	0.82 (6)	C16—H16	0.9300
C3—O3	1.427 (6)	C21—C22	1.387 (7)
C3—C4	1.535 (7)	C21—C26	1.393 (7)
C3—H3	0.9800	C22—C23	1.392 (7)
O3—H3O	0.81 (5)	C22—H22	0.9300
C4—O4	1.433 (6)	C23—C24	1.393 (8)
C4—C5	1.518 (7)	C23—H23	0.9300
C4—H4	0.9800	C24—C25	1.386 (8)
C5—O5	1.431 (6)	C24—H24	0.9300
C5—H5A	0.9700	C25—C26	1.395 (7)
C5—H5B	0.9700	C25—H25	0.9300
O5—H5O	0.83 (5)	C26—H26	0.9300
N11—C12	1.376 (6)	O31—H31A	0.83 (2)
N11—C16	1.378 (6)	O31—H31B	0.82 (2)
C12—O12	1.225 (6)
O4—C1—N11	109.3 (4)	C16—N11—C1	122.2 (4)
O4—C1—C2	107.4 (4)	O12—C12—N13	123.3 (5)
N11—C1—C2	112.5 (4)	O12—C12—N11	121.4 (5)
O4—C1—H1	109.2	N13—C12—N11	115.3 (4)
N11—C1—H1	109.2	C12—N13—C14	127.4 (4)
C2—C1—H1	109.2	C12—N13—H13	116.3
O2—C2—C1	106.4 (4)	C14—N13—H13	116.3
O2—C2—C3	110.6 (4)	O14—C14—N13	118.7 (5)
C1—C2—C3	101.5 (4)	O14—C14—C15	126.6 (5)
O2—C2—H2	112.5	N13—C14—C15	114.7 (4)
C1—C2—H2	112.5	C16—C15—C14	118.2 (4)
C3—C2—H2	112.5	C16—C15—C21	120.8 (5)
C2—O2—H2O	119 (6)	C14—C15—C21	121.0 (4)
O3—C3—C2	112.1 (4)	C15—C16—N11	123.5 (5)
O3—C3—C4	113.3 (4)	C15—C16—H16	118.3
C2—C3—C4	101.0 (4)	N11—C16—H16	118.3
O3—C3—H3	110.0	C22—C21—C26	118.2 (5)
C2—C3—H3	110.0	C22—C21—C15	119.5 (4)
C4—C3—H3	110.0	C26—C21—C15	122.3 (5)
C3—O3—H3O	116 (5)	C21—C22—C23	121.3 (5)
O4—C4—C5	110.7 (4)	C21—C22—H22	119.4
O4—C4—C3	104.4 (4)	C23—C22—H22	119.4
C5—C4—C3	116.4 (5)	C22—C23—C24	120.0 (6)
O4—C4—H4	108.4	C22—C23—H23	120.0
C5—C4—H4	108.4	C24—C23—H23	120.0
C3—C4—H4	108.4	C25—C24—C23	119.4 (5)
C1—O4—C4	110.1 (4)	C25—C24—H24	120.3
O5—C5—C4	110.9 (4)	C23—C24—H24	120.3
O5—C5—H5A	109.5	C24—C25—C26	120.1 (5)
C4—C5—H5A	109.5	C24—C25—H25	120.0
O5—C5—H5B	109.5	C26—C25—H25	120.0
C4—C5—H5B	109.5	C21—C26—C25	121.1 (5)
H5A—C5—H5B	108.0	C21—C26—H26	119.5
C5—O5—H5O	112 (4)	C25—C26—H26	119.5
C12—N11—C16	120.8 (4)	H31A—O31—H31B	100 (9)
C12—N11—C1	116.5 (4)
O4—C1—C2—O2	87.4 (4)	C1—N11—C12—N13	175.6 (4)
N11—C1—C2—O2	−152.3 (4)	O12—C12—N13—C14	176.6 (5)
O4—C1—C2—C3	−28.3 (5)	N11—C12—N13—C14	−2.6 (8)
N11—C1—C2—C3	92.0 (5)	C12—N13—C14—O14	−179.9 (5)
O2—C2—C3—O3	46.3 (5)	C12—N13—C14—C15	1.5 (8)
C1—C2—C3—O3	158.9 (4)	O14—C14—C15—C16	179.7 (5)
O2—C2—C3—C4	−74.7 (5)	N13—C14—C15—C16	−1.7 (7)
C1—C2—C3—C4	37.9 (5)	O14—C14—C15—C21	1.4 (8)
O3—C3—C4—O4	−155.5 (4)	N13—C14—C15—C21	180.0 (5)
C2—C3—C4—O4	−35.4 (5)	C14—C15—C16—N11	3.4 (8)
O3—C3—C4—C5	82.3 (6)	C21—C15—C16—N11	−178.2 (5)
C2—C3—C4—C5	−157.7 (4)	C12—N11—C16—C15	−4.7 (8)
N11—C1—O4—C4	−116.2 (4)	C1—N11—C16—C15	−175.9 (5)
C2—C1—O4—C4	6.1 (5)	C16—C15—C21—C22	38.3 (8)
C5—C4—O4—C1	144.7 (4)	C14—C15—C21—C22	−143.4 (5)
C3—C4—O4—C1	18.8 (5)	C16—C15—C21—C26	−140.7 (6)
O4—C4—C5—O5	−63.0 (6)	C14—C15—C21—C26	37.6 (8)
C3—C4—C5—O5	55.9 (6)	C26—C21—C22—C23	1.9 (8)
O4—C1—N11—C12	−170.0 (4)	C15—C21—C22—C23	−177.1 (5)
C2—C1—N11—C12	70.8 (5)	C21—C22—C23—C24	−1.2 (9)
O4—C1—N11—C16	1.6 (6)	C22—C23—C24—C25	0.4 (9)
C2—C1—N11—C16	−117.6 (5)	C23—C24—C25—C26	−0.3 (8)
C16—N11—C12—O12	−175.2 (5)	C22—C21—C26—C25	−1.8 (8)
C1—N11—C12—O12	−3.6 (7)	C15—C21—C26—C25	177.2 (5)
C16—N11—C12—N13	4.0 (7)	C24—C25—C26—C21	1.0 (9)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N13—H13···O3^i	0.86	2.00	2.822 (5)	158
O2—H2O···O14^ii	0.82 (6)	1.95 (4)	2.727 (5)	158 (7)
O3—H3O···O51	0.81 (5)	1.85 (4)	2.594 (10)	152 (7)
O3—H3O···O52	0.81 (5)	1.90 (3)	2.690 (11)	164 (7)
O3—H3O···O53	0.81 (5)	2.27 (9)	3.08 (8)	176 (7)
O5—H5O···O2^iii	0.83 (5)	1.90 (3)	2.716 (5)	166 (6)
O31—H31A···O5	0.83 (2)	1.92 (3)	2.741 (6)	170 (9)
O31—H31B···O14^iv	0.82 (2)	2.20 (7)	2.878 (6)	140 (9)

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