Multiple hydrogen bonds in cytosinium zoledronate trihydrate

The asymmetric unit of the title compound [systematic name: 4-amino-2-oxo-2,3-dihydro­pyrimidin-1-ium 1-hy­droxy-2-(1H,3H-imidazol-3-ium-1-yl)ethylidene­diphosphonate tri­hydrate], C₄H₆N₃O⁺·C₅H₉N₂O₇P₂⁻·3H₂O, contains one cyto­sin­ium cation, one zoledronate anion and three water mol­ecules. The zoledronate anion has a zwitterionic character, in which each phosphonate group is singly deprotonated and an imidazole N atom is protonated. Furthermore, proton transfer takes place from one of the phosphonic acid groups of the zoledronate anion to one of the N atoms of the cytosinium cation. The cytosinium cation forms a C(6) chain, while the zoledronate anion forms a rectangular-shaped centrosymmetric dimer through N—H...O hydrogen bonds. The cations and anions are held together by N—H...O and O—H...O hydrogen bonds to form a one-dimensional polymeric tape. The three water mol­ecules play a crucial role in hydrogen bonding, resulting in a three-dimensional hydrogen-bonded network.

S1. Comment

The interaction of drugs with DNA is among the most important aspects of biological studies in drug discovery and pharmaceutical development processes. A number of clinically important small molecules appear to act by binding directly to DNA, and subsequently inhibiting gene expression or replication by interfering with the enzymes that catalyse these functions (Krugh, 1994). Hydrogen bonding plays a pivotal role in biomolecular structure and functions. In the case of nucleosides, the building blocks of DNA and RNA, hydrogen bonding is one of the most important structural features governing their biological role. Cytosine is well known for its hydrogen-bonding capabilities in DNA and RNA, and several cytosine derivatives have been reported for use in biological applications (Blackburn & Gait, 1996; Kumar & Leonard, 1988).

Zoledronic acid or zoledronate (marketed by Novartis under the trade names Zometa, Zomera, Aclasta and Reclast), a potent bone antiresorptive bisphosphonate drug, is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer. It can also be used to treat osteoporosis, hypercalcaemia of malignancy and pain from bone metastases (Reid, 2002; Black et al., 2007), and to prevent recurring fractures in patients with a previous hip fracture (Lyles et al., 2007). Compared with other bisphosphonate drugs, zoledronic acid has superior potency and pharmacological properties. To the best of our knowledge, we report here for the first time a nucleobase–drug interaction, namely the title compound, cytosinium zoledronate trihydrate, (I), in continuation of our ongoing studies of hydrogen-bond interactions and molecular recognition of nucleobases in the solid state (Sridhar & Ravikumar, 2007, 2008, 2010a,b; Sridhar et al., 2009).

The asymmetric unit of (I) contains one cytosinium cation, one zoledronate anion and three water molecules (Fig. 1). Cytosine is quite a strong base (pK_α1 = 1.6 and pK_α2 = 12.2; Stecher, 1968) and, in the presence of acids, it is readily protonated at the N3 ring position. The cytosinium cation in (I) is protonated at N3, leading to an increase in the internal angle, C2—N3—C4 = 124.1 (3)°, compared with the neutral cytosine molecule [C—N—C = 119.4 (2)°; McClure & Craven, 1973]. Proton transfer is taking place from one of the phosphonic acid groups of the zoledronate molecule to atom N3 of the cytosine molecule.

Zoledronic acid is a bisphosphonic acid, a heterocyclic nitrogen-containing bisphosphonate that has an imidazole-ring side chain. The imidazole ring contains two critically positioned N atoms. The zoledronate group presents its usual zwitterionic character (Vega et al., 1996, 1998), with negative charges in the singly protonated phosphonate groups and a positive charge at protonated imidazole atom N11. The resulting single negative charge is counter-balanced by the protonation of atom N3 of the cytosine molecule. The bond distances and angles are within normal ranges (Allen et al., 1987) and are comparable with the corresponding values observed in zoledronic acid monohydrate (Sanders et al., 2003), zoledronic acid trihydrate (Ruscica et al., 2010), hexa- and pentacoordinated zinc(II)–zoledronate complexes (Freire & Vega, 2009a,b), and potassium and sodium complexes of zoledronate (Freire et al., 2010a,b).

It has already been reported that the P—O bonds in which the O atom is unprotonated are between 1.47 and 1.53 Å long, while in the case of a protonated O atom it increases to 1.54–1.60 Å (Gossman et al., 2003). The P—O distances of (I), as seen in Table 1, are in good agreement with the fact that a protonated P—O bond is slightly longer than an unprotonated P—O bond. The electronic state of the PO₃ group can be seen from the O—P—O bond angles. The O—P—O(H) angles are in the range 108.9–110.8°, while the O—P—O angles are in the range 115.7–116.8° (Table 1). Similar behaviour was observed in previously reported zoledronate structures (Sanders et al., 2003; Ruscica et al., 2010; Freire et al., 2010a,b).

An overlay of the zoledronate molecules (Fig. 2), superimposing the planar imidazole ring, reveals the significant orientational differences between the phosphonate groups. The relative orientations of the imidazole rings can be seen from the C15—C14—N9—C10 torsion angles (Table 1). In (I), it adopts a synclinal orientation, while the previously reported zoledronate structures have either synclinal (±30–90°) or anticlinal (±90–150°) orientations (Table 1). Of these nine reported structures [including (I), Table 1], six molecules exist in a synclinal orientation and the remaining three are in an anticlinal orientation. The orientation of the phosphonate (P1 and P2) groups of the zoledronate anion can be seen from the N9—C14—C15—P1 and N9—C14—C15—P2 torsion angles. It can be seen that the phosphonate groups prefer to adopt either a synclinal (±30–90°) or an antiperiplanar (±150–180°) orientation. In (I), atom P1 is in a synclinal orientation and P2 is in an antiperiplanar orientation. In the case of the hydroxyl group (torsion angle N9—C14—C15—O16), all the structures adopt a synclinal (±30–90°) orientation (Table 1). The above change observed in the conformation of the solid-state structures of zoledronate may be attributed to the different environments of the zoledronic acid: hydrates or metal-coordinated.

In the crystal packing of (I), the component ions are linked into complex three-dimensional networks by a combination of X—H···O (X = N and O) hydrogen bonds (Table 2). A detailed analysis of the hydrogen-bonding scheme reveals that there are 16 potential active H atoms (four from each cation and anion, and eight from water). Five different modes of hydrogen-bonding interaction are observed, viz. cation–cation, anion–anion, cation–anion, cation–water and anion–water.

The cytosinium cations are linked through an N—H···O hydrogen bond, forming a C6 chain (Etter, 1990; Etter et al., 1990; Bernstein et al., 1995) parallel to the b axis. The zoledronate anions form a centrosymmetric dimer [R₂²(16)] through an N—H···O hydrogen bond. The O—H···O hydrogen bonds between symmetry-related dimers of the phosphonate groups of the zoledronate anion form a ribbon parallel to the b axis. These hydrogen bonds form a rather rectangular-shaped centrosymmetric tetramer and produce a characteristic R₄⁴(26) motif (Fig. 3).

The cytosinium cation and zoledronate anion are held together by two N—H···O hydrogen bonds (entries 2 and 3, Table 2), thereby generating an R₂²(10) motif. Intermolecular N—H···O and O—H···O interactions link adjacent R₂²(10) motifs to produce another R₄³(12) motif. Thus, the combination of N—H···O and O—H···O bonds leads to the formation of a one-dimensional polymeric ribbon along the b axis, in which the zoledronate anions are flanked by the cytosinium cations (Fig. 3).

The water molecules (O1W, O2W and O3W) play a dual role as both donors and acceptors in the hydrogen-bonding interactions (Table 2). The two water molecules O1W and O2W, as donors and acceptors, link three zoledronate anions through O—H···O hydrogen bonds, while the third water molecule (O3W) links two zoledronate anions as donor, and acts as acceptor in linking the cytosinium cation via an N—H···O hydrogen bond.

Water molecule O1W, acting as donor, links the two symmetry-related atoms O18(x, y + 1, z) and O20(x, y + 1, z) of the zoledronate anion through three-centred hydrogen bonds (Jeffrey & Saenger, 1991) to form an R₁²(6) motif. As acceptor, it links atom O19(x + 1,y - 1,z) of the anion and forms an infinite anion–water chain along the a axis. The second water molecule, O2W, as donor and acceptor, links the anion–water chain via atoms O21 and O16(x + 1,y,z) to form a tetrameric hydrogen-bonded network of R₄⁴(15) motif. Furthermore, the two water molecules O1W and O2W link the R₄⁴(15) tetramers through O—H···O hydrogen bonds involving atoms O21 and O17(x - 1,y + 1,z) of the anions and form another set of tetrameric hydrogen-bonded networks of R₄³(10) motif. The R₄⁴(15) and R₄³(10) motifs are arranged alternately and aggregate as infinite two-dimensional hydrogen-bonded layers parallel to the (001) plane (Fig.4).

As donor, the third water molecule, O3W, forms hydrogen bonds to atoms O19(-x + 2, -y + 1, -z + 1), O22(-x + 2, -y + 1, -z + 1) and atom O20(-x + 1, -y + 1, -z + 1) of the zoledronate anion, forming an R₁²(6) motif (three-centred hydrogen bonds), resulting in an infinite anion–water chain along the a axis. In addition, atom O3W acts as acceptor in a hydrogen bond from atom N1 of the cytosinium cation. Thus, the water molecule bridges the cation and anion through N—H···O and O—H···O hydrogen bonds and leads to the formation of a one-dimensional chain with alternate cations and anions (Fig. 5).

Thus, the combination of N—H···O and O—H···O hydrogen bonds involving cations, anions and water molecules leads to the formation of three-dimensional hydrogen-bonded networks (Fig. 6). This structure displays segregation of its molecular components.

C—H···O interactions are also observed in the crystal structure of (I). Incidentally, the C—H···O interaction between the imidazole and biphosphonate group [C13—H13···O21(x, -1 + y, z)] is one of the most favourable interactions observed in zoledronate complexes (Freire et al., 2010a,b). It is very interesting to note that there is no water–water interaction in the structure of (I).

Related literature

For related literature, see: Allen et al. (1987); Bernstein et al. (1995); Black (2007); Blackburn & Gait (1996); Etter (1990); Etter, MacDonald & Bernstein (1990); Freire & Vega (2009a, 2009b); Freire et al. (2010a, 2010b); Gossman et al. (2003); Jeffrey & Saenger (1991); Krugh (1994); Kumar & Leonard (1988); Lyles (2007); McClure & Craven (1973); Reid (2002); Ruscica et al. (2010); Sanders et al. (2003); Sridhar & Ravikumar (2007, 2008, 2010a, 2010b); Sridhar et al. (2009); Stecher (1968); Vega et al. (1996, 1998).

S2. Experimental

To obtain crystals of (I) suitable for X-ray study, cytosine (0.111 g, 1 mmol) and zoledronic acid (USV Ltd, Mumbai; 0.272 g, 1 mmol) were dissolved in water (25 ml) and the solution was allowed to evaporate slowly.

S3. Refinement

All H atoms attached to C, N and hydroxyl O atoms were fixed geometrically and treated as riding, with C—H = 0.93 (aromatic) or 0.97 Å (methylene), N—H = 0.86 Å and O—H = 0.82 Å, with U_iso(H) = 1.2U_eq(C,N) or 1.5U_eq(O). Water H atoms were located in a difference Fourier map and included in the subsequent refinement using restraints O—H = 0.85 (1) Å and H···H = 1.40 (2) Å, with U_iso(H) = 1.5U_eq(O). In the last cycle of refinement, they were treated as riding on their parent O atoms.

Computing details

Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: DIAMOND (Brandenburg & Putz, 2005); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008).

Figures

	Fig. 1. The molecular components of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level. Hydrogen bonds are shown as dashed lines.
	Fig. 2. A superposition of the molecular conformation of zoledronate molecules, showing the orientation differences of the phosphonate groups. The overlay was made by making a least-squares fit of the planar imidazole ring atoms with those of (I). Refer to Table 1 for labelling.
	Fig. 3. The one-dimensional polymeric tapes formed by N—H···O and O—H···O interactions involving the cations and anions. For sake of clarity, the three water molecules and H atoms not involved in hydrogen bonding have been omitted. Only atoms involved in hydrogen bonding are labelled. [Symmetry codes: (i) x, y - 1, z; (ii) -x + 2, -y, -z; (v) x, y + 1, z.]
	Fig. 4. Part of the crystal structure of (I), showing the two-dimensional hydrogen-bonded networks built from zoledronate anions and two water molecules (O1W and O2W). For sake of clarity, the cytosinium cation, water molecule O3W and H atoms not involved in hydrogen bonding have been omitted. Only atoms involved in hydrogen bonding are labelled. [Symmetry codes: (iii) x + 1, y, z; (iv) x + 1, y - 1, z; (v) x, y + 1, z; (vi) x - 1, y + 1, z.]
	Fig. 5. Part of the crystal structure of (I), showing the one-dimensional chain formed by water molecule O3W with cytosinium cations and zoledronate anions. For the sake of clarity, the other two water molecules, O1W and O2W, and H atoms not involved in hydrogen bonding have been omitted. Only atoms involved in hydrogen bonding are labelled. [Symmetry codes: (vii) -x + 1, -y + 1, -z + 1; (viii) -x + 2, -y + 1, -z + 1.]
	Fig. 6. Part of the crystal structure of (I), showing the hydrogen-bonding interactions. Hydrogen bonds are shown as dashed lines and H atoms not involved in hydrogen bonding have been omitted for clarity.

4-amino-2-oxo- 2,3-dihydropyrimidin-1-ium 1-hydroxy-2-(1H,3H-imidazol-3-ium-1-yl)ethylidenediphosphonate trihydrate

Crystal data

C4H6N3O^+·C5H9N2O7P2^−·3H2O	Z = 2
Mr = 437.25	F(000) = 456
Triclinic, P1	Dx = 1.662 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 6.7292 (16) Å	Cell parameters from 4828 reflections
b = 6.8032 (16) Å	θ = 3.0–27.9°
c = 19.193 (5) Å	µ = 0.32 mm^−1
α = 89.875 (4)°	T = 294 K
β = 86.747 (5)°	Block, colourless
γ = 84.726 (4)°	0.14 × 0.12 × 0.06 mm
V = 873.5 (4) Å^3

Data collection

Bruker SMART APEX CCD area-detector diffractometer	2805 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	Rint = 0.033
Graphite monochromator	θmax = 25.0°, θmin = 1.1°
ω scans	h = −7→7
7859 measured reflections	k = −8→8
3035 independent reflections	l = −22→22

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)] = 0.060	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.143	H-atom parameters constrained
S = 1.21	w = 1/[σ^2(Fo^2) + (0.0511P)^2 + 1.5176P] where P = (Fo^2 + 2Fc^2)/3
3035 reflections	(Δ/σ)max < 0.001
247 parameters	Δρmax = 0.50 e Å^−3
9 restraints	Δρmin = −0.38 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.

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

	x	y	z	Uiso*/Ueq
P1	0.94429 (14)	0.03787 (12)	0.20340 (5)	0.0218 (2)
P2	0.66606 (14)	0.41161 (12)	0.24243 (5)	0.0225 (2)
O16	0.8769 (4)	0.3519 (4)	0.11825 (12)	0.0278 (6)
H16	0.9828	0.3828	0.1321	0.042*
O17	1.0732 (4)	−0.0474 (4)	0.14326 (13)	0.0335 (6)
O18	0.8167 (4)	−0.1022 (3)	0.24127 (13)	0.0320 (6)
O19	1.0732 (4)	0.1384 (4)	0.25599 (15)	0.0380 (7)
H19	1.1796	0.0710	0.2595	0.057*
O20	0.5988 (4)	0.2830 (4)	0.30150 (12)	0.0294 (6)
O21	0.5096 (4)	0.5515 (4)	0.21253 (13)	0.0325 (6)
O22	0.8447 (4)	0.5239 (4)	0.26582 (14)	0.0322 (6)
H22	0.8358	0.6359	0.2497	0.048*
N9	0.6674 (4)	0.0276 (4)	0.07833 (14)	0.0232 (6)
N11	0.7866 (5)	−0.0766 (5)	−0.02246 (16)	0.0336 (8)
H11	0.8330	−0.0779	−0.0652	0.040*
C10	0.7323 (5)	0.0811 (5)	0.01536 (18)	0.0267 (8)
H10	0.7384	0.2106	0.0003	0.032*
C12	0.7567 (6)	−0.2397 (6)	0.0177 (2)	0.0363 (9)
H12	0.7838	−0.3707	0.0038	0.044*
C13	0.6813 (6)	−0.1757 (5)	0.0807 (2)	0.0321 (9)
H13	0.6456	−0.2533	0.1185	0.038*
C14	0.6019 (5)	0.1652 (5)	0.13577 (18)	0.0255 (8)
H14A	0.5214	0.0984	0.1702	0.031*
H14B	0.5183	0.2753	0.1178	0.031*
C15	0.7772 (5)	0.2448 (5)	0.17136 (17)	0.0207 (7)
O8	0.7341 (6)	0.5225 (4)	0.45878 (17)	0.0607 (10)
N1	0.7579 (5)	0.2882 (5)	0.54241 (16)	0.0346 (8)
H1	0.7661	0.3746	0.5745	0.042*
N3	0.7418 (5)	0.2030 (4)	0.42667 (16)	0.0301 (7)
H3	0.7318	0.2373	0.3838	0.036*
N7	0.7618 (5)	−0.1186 (4)	0.39070 (16)	0.0338 (8)
H7A	0.7596	−0.0775	0.3483	0.041*
H7B	0.7694	−0.2431	0.3993	0.041*
C2	0.7446 (7)	0.3486 (6)	0.4753 (2)	0.0360 (9)
C4	0.7537 (5)	0.0073 (5)	0.44174 (18)	0.0248 (8)
C5	0.7559 (6)	−0.0465 (5)	0.51256 (19)	0.0281 (8)
H5	0.7555	−0.1782	0.5257	0.034*
C6	0.7585 (6)	0.0940 (6)	0.56041 (19)	0.0307 (8)
H6	0.7608	0.0592	0.6073	0.037*
O1W	0.3927 (4)	0.9094 (4)	0.27836 (14)	0.0362 (7)
H1W	0.5046	0.9575	0.2789	0.054*
H2W	0.4060	0.7998	0.2573	0.054*
O2W	0.1989 (4)	0.5602 (4)	0.12357 (16)	0.0410 (7)
H3W	0.2902	0.5443	0.1528	0.061*
H4W	0.1487	0.6796	0.1250	0.061*
O3W	0.7872 (5)	0.5746 (5)	0.64102 (16)	0.0522 (8)
H5W	0.6780	0.6194	0.6623	0.078*
H6W	0.8848	0.5786	0.6669	0.078*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
P1	0.0307 (5)	0.0110 (4)	0.0236 (5)	0.0004 (3)	−0.0052 (4)	0.0008 (3)
P2	0.0317 (5)	0.0130 (4)	0.0226 (5)	0.0015 (4)	−0.0062 (4)	0.0008 (3)
O16	0.0360 (15)	0.0218 (13)	0.0273 (13)	−0.0096 (11)	−0.0046 (11)	0.0061 (10)
O17	0.0447 (17)	0.0205 (13)	0.0341 (15)	0.0044 (12)	−0.0028 (12)	0.0018 (11)
O18	0.0464 (16)	0.0131 (12)	0.0359 (14)	−0.0013 (11)	0.0010 (12)	0.0046 (10)
O19	0.0409 (17)	0.0250 (14)	0.0483 (17)	0.0089 (12)	−0.0216 (13)	−0.0087 (12)
O20	0.0422 (16)	0.0219 (13)	0.0240 (13)	−0.0026 (11)	−0.0004 (11)	0.0017 (10)
O21	0.0391 (15)	0.0230 (13)	0.0344 (14)	0.0074 (11)	−0.0101 (12)	0.0018 (11)
O22	0.0441 (16)	0.0138 (12)	0.0396 (15)	−0.0005 (11)	−0.0133 (12)	0.0007 (11)
N9	0.0306 (16)	0.0179 (14)	0.0222 (15)	−0.0045 (12)	−0.0072 (12)	−0.0010 (11)
N11	0.0370 (19)	0.0389 (19)	0.0256 (16)	−0.0072 (15)	−0.0031 (14)	−0.0062 (14)
C10	0.032 (2)	0.0252 (19)	0.0241 (18)	−0.0066 (15)	−0.0069 (15)	0.0016 (15)
C12	0.042 (2)	0.023 (2)	0.045 (2)	−0.0009 (17)	−0.0117 (19)	−0.0075 (17)
C13	0.045 (2)	0.0197 (18)	0.033 (2)	−0.0061 (16)	−0.0123 (17)	0.0055 (16)
C14	0.031 (2)	0.0224 (18)	0.0235 (18)	−0.0019 (15)	−0.0057 (15)	−0.0014 (14)
C15	0.0275 (18)	0.0113 (15)	0.0233 (17)	−0.0011 (13)	−0.0031 (14)	0.0024 (13)
O8	0.121 (3)	0.0168 (15)	0.0457 (18)	−0.0088 (17)	−0.0110 (19)	0.0054 (13)
N1	0.054 (2)	0.0213 (16)	0.0285 (17)	−0.0027 (15)	−0.0062 (15)	−0.0064 (13)
N3	0.050 (2)	0.0169 (15)	0.0237 (15)	−0.0038 (14)	−0.0061 (14)	0.0027 (12)
N7	0.059 (2)	0.0167 (15)	0.0263 (16)	−0.0038 (14)	−0.0053 (15)	0.0033 (13)
C2	0.055 (3)	0.0192 (19)	0.034 (2)	−0.0023 (17)	−0.0057 (19)	0.0008 (16)
C4	0.0287 (19)	0.0189 (17)	0.0273 (18)	−0.0033 (14)	−0.0035 (15)	0.0038 (14)
C5	0.035 (2)	0.0195 (18)	0.0301 (19)	−0.0042 (15)	−0.0023 (16)	0.0047 (15)
C6	0.036 (2)	0.030 (2)	0.0251 (19)	−0.0018 (16)	−0.0005 (16)	0.0050 (16)
O1W	0.0326 (15)	0.0333 (15)	0.0418 (16)	0.0031 (12)	−0.0050 (12)	−0.0022 (12)
O2W	0.0447 (17)	0.0224 (14)	0.0570 (18)	−0.0013 (12)	−0.0167 (14)	−0.0046 (13)
O3W	0.053 (2)	0.058 (2)	0.0469 (18)	−0.0094 (16)	0.0010 (15)	−0.0255 (16)

Geometric parameters (Å, º)

P1—O17	1.489 (3)	C14—H14A	0.9700
P1—O18	1.500 (3)	C14—H14B	0.9700
P1—O19	1.566 (3)	O8—C2	1.221 (5)
P1—C15	1.846 (3)	N1—C2	1.356 (5)
P2—O21	1.492 (3)	N1—C6	1.364 (5)
P2—O20	1.505 (3)	N1—H1	0.8600
P2—O22	1.569 (3)	N3—C4	1.358 (5)
P2—C15	1.856 (3)	N3—C2	1.365 (5)
O16—C15	1.425 (4)	N3—H3	0.8600
O16—H16	0.8200	N7—C4	1.298 (5)
O19—H19	0.8200	N7—H7A	0.8600
O22—H22	0.8200	N7—H7B	0.8600
N9—C10	1.324 (4)	C4—C5	1.407 (5)
N9—C13	1.378 (5)	C5—C6	1.329 (5)
N9—C14	1.470 (4)	C5—H5	0.9300
N11—C10	1.309 (5)	C6—H6	0.9300
N11—C12	1.373 (5)	O1W—H1W	0.8492
N11—H11	0.8600	O1W—H2W	0.8447
C10—H10	0.9300	O2W—H3W	0.8548
C12—C13	1.342 (6)	O2W—H4W	0.8501
C12—H12	0.9300	O3W—H5W	0.8516
C13—H13	0.9300	O3W—H6W	0.8488
C14—C15	1.537 (5)
O17—P1—O18	115.68 (15)	N9—C14—H14B	109.0
O17—P1—O19	110.34 (16)	C15—C14—H14B	109.0
O18—P1—O19	110.12 (16)	H14A—C14—H14B	107.8
O17—P1—C15	108.43 (15)	O16—C15—C14	104.8 (3)
O18—P1—C15	107.85 (15)	O16—C15—P1	111.1 (2)
O19—P1—C15	103.69 (15)	C14—C15—P1	110.0 (2)
O21—P2—O20	116.77 (16)	O16—C15—P2	111.1 (2)
O21—P2—O22	110.79 (15)	C14—C15—P2	106.6 (2)
O20—P2—O22	108.90 (15)	P1—C15—P2	112.80 (17)
O21—P2—C15	107.97 (15)	C2—N1—C6	121.8 (3)
O20—P2—C15	107.11 (14)	C2—N1—H1	119.1
O22—P2—C15	104.53 (15)	C6—N1—H1	119.1
C15—O16—H16	109.5	C4—N3—C2	124.1 (3)
P1—O19—H19	109.5	C4—N3—H3	117.9
P2—O22—H22	109.5	C2—N3—H3	117.9
C10—N9—C13	108.3 (3)	C4—N7—H7A	120.0
C10—N9—C14	124.6 (3)	C4—N7—H7B	120.0
C13—N9—C14	127.0 (3)	H7A—N7—H7B	120.0
C10—N11—C12	108.3 (3)	O8—C2—N1	122.6 (4)
C10—N11—H11	125.9	O8—C2—N3	121.4 (4)
C12—N11—H11	125.9	N1—C2—N3	116.0 (3)
N11—C10—N9	109.4 (3)	N7—C4—N3	118.7 (3)
N11—C10—H10	125.3	N7—C4—C5	123.9 (3)
N9—C10—H10	125.3	N3—C4—C5	117.4 (3)
C13—C12—N11	107.6 (3)	C6—C5—C4	118.9 (3)
C13—C12—H12	126.2	C6—C5—H5	120.6
N11—C12—H12	126.2	C4—C5—H5	120.6
C12—C13—N9	106.5 (3)	C5—C6—N1	121.5 (3)
C12—C13—H13	126.8	C5—C6—H6	119.2
N9—C13—H13	126.8	N1—C6—H6	119.2
N9—C14—C15	112.9 (3)	H1W—O1W—H2W	110.1
N9—C14—H14A	109.0	H3W—O2W—H4W	109.2
C15—C14—H14A	109.0	H5W—O3W—H6W	111.1
C12—N11—C10—N9	−0.3 (4)	O19—P1—C15—P2	−44.9 (2)
C13—N9—C10—N11	0.0 (4)	O21—P2—C15—O16	63.8 (3)
C14—N9—C10—N11	177.4 (3)	O20—P2—C15—O16	−169.7 (2)
C10—N11—C12—C13	0.5 (4)	O22—P2—C15—O16	−54.2 (3)
N11—C12—C13—N9	−0.4 (4)	O21—P2—C15—C14	−49.8 (3)
C10—N9—C13—C12	0.3 (4)	O20—P2—C15—C14	76.7 (2)
C14—N9—C13—C12	−177.0 (3)	O22—P2—C15—C14	−167.8 (2)
C10—N9—C14—C15	−77.6 (4)	O21—P2—C15—P1	−170.67 (17)
C13—N9—C14—C15	99.3 (4)	O20—P2—C15—P1	−44.1 (2)
N9—C14—C15—O16	62.9 (3)	O22—P2—C15—P1	71.3 (2)
N9—C14—C15—P1	−56.7 (3)	C6—N1—C2—O8	176.3 (4)
N9—C14—C15—P2	−179.3 (2)	C6—N1—C2—N3	−3.1 (6)
O17—P1—C15—O16	−36.7 (3)	C4—N3—C2—O8	179.8 (4)
O18—P1—C15—O16	−162.7 (2)	C4—N3—C2—N1	−0.8 (6)
O19—P1—C15—O16	80.6 (2)	C2—N3—C4—N7	−175.9 (4)
O17—P1—C15—C14	78.9 (3)	C2—N3—C4—C5	4.3 (6)
O18—P1—C15—C14	−47.0 (3)	N7—C4—C5—C6	176.2 (4)
O19—P1—C15—C14	−163.8 (2)	N3—C4—C5—C6	−4.0 (5)
O17—P1—C15—P2	−162.17 (17)	C4—C5—C6—N1	0.4 (6)
O18—P1—C15—P2	71.9 (2)	C2—N1—C6—C5	3.3 (6)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O3W	0.86	1.89	2.747 (4)	177
N3—H3···O20	0.86	1.87	2.675 (4)	155
N7—H7A···O18	0.86	2.07	2.874 (4)	155
N7—H7B···O8^i	0.86	1.98	2.783 (4)	154
O16—H16···O2W^ii	0.82	1.97	2.703 (4)	148
O19—H19···O1W^iii	0.82	1.78	2.592 (4)	172
O22—H22···O18^iv	0.82	1.78	2.578 (3)	163
N11—H11···O17^v	0.86	1.83	2.620 (4)	152
O1W—H1W···O18^iv	0.85	2.18	2.895 (4)	141
O1W—H1W···O20^iv	0.85	2.41	3.050 (4)	133
O1W—H2W···O21	0.84	1.95	2.774 (4)	165
O2W—H3W···O21	0.85	1.92	2.770 (4)	170
O2W—H4W···O17^vi	0.85	1.91	2.746 (4)	168
O3W—H5W···O20^vii	0.85	2.01	2.849 (4)	171
O3W—H6W···O22^viii	0.85	2.34	3.158 (4)	161
O3W—H6W···O19^viii	0.85	2.48	3.027 (4)	123
C5—H5···O8^i	0.93	2.43	3.130 (5)	132
C6—H6···O1W^vii	0.93	2.37	3.203 (5)	148
C13—H13···O21^i	0.93	2.43	3.350 (5)	173
C14—H14A···O1W^i	0.97	2.59	3.534 (5)	165

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