Two members of the bis­phospho­nate class of drugs: a zwitterion and a molecular compound

The compounds studied in this paper, viz. (1-ammonio-1-phosphono­propyl)­phospho­nate, C₃H₁₁NO₆P₂, (I), and 1-(acetyl­amino)­propyl­idene-1,1-bis­phospho­nic acid dihydrate, C₅H₁₃NO₇P₂·2H₂O, (II), are members of a commonly used family of therapeutic agents. Compound (I) is an inner salt with separated negative (on the ionized PO₃ group) and positive (on the tetrahedral N atom) charges, while (II) possesses neutral phospho­nyl groups and one amide N atom. Both structures have a C—C—C—N backbone, which has comparable geometric parameters in (I) and (II); the main difference was found in one of the N—C—P bond angles, which is lengthened in (II) because of an intramolecular O_PO3—H...O_C=O interaction. The hydrogen-bonding scheme in the crystal of (I) includes all possible donor atoms, namely all the H atoms of the ammonium group and the phospho­nic acid functions. As a result of these interactions, the zwitterions are organized into a plane running along the crystallographic x axis. In (II), the intermolecular interactions include all possible donor atoms, except for the N atom; the packing differs from that of (I) in that the mol­ecules are arranged in a chain running parallel to the x axis. In the chains, the mol­ecules form head-to-head dimers, while the crystallization water mol­ecules contribute to the intra- and interchain cohesion.

S1. Comment

The bisphosphonates constitute a class of compounds that are characterized by the P—C—P bond, the biologically resistent version of the P—O—P bridge of natural pyrophosphate, and which have found a number of practical applications in the human health field. Because of their high tropism to the bone tissue, and their capacity to selectively block the action of the resorbing osteoclasts, several members of this family are currently used for the treatment of skeletal disorders (Compston, 1994; Martin & Grill, 2000; Rodan & Martin, 2000). These compounds have a potential use as drugs for the treatment of neurologic disorders (Atack & Fletcher, 1994), as anti-inflammatory treatments or antiarthritics (Schlachter et al., 1998), as herbicides (Chuiko et al., 1999; Cromartie et al., 1999), as antiparasitics (Docampo, 2001; Urbina, 2002), and as cholesterol-lowering agents (Niesor et al., 2001). Moreover, Fukuda et al. (1999), have reported on the synthesis and therapeutic efficacy of a novel decorporating bisphosphonate to remove radioactive strontium deposited in the bone of contaminated individuals. As an ongoing study aimed at the determination of the structures of biologically active compounds (Vega et al., 2002), a single-crystal X-ray study has been undertaken with the compounds 1-ammoniopropylidene-1,1-bisphosphonate, (I), and 1-(acetylamino)propylidene-1,1-bisphosphonic acid dihydrate, (II), and the results are presented here.

The bisphosphonates (I) and (II) have in common a C—C—C—N backbone and a P—C—P bridge (see Figs. 1 and 2). Compound (I), unlike (II), has zwitterionic character, with one of the phosphonyl H atoms transferred to the N atom and one of the phosphorus groups with a −1 charge. The N atom in (I) possesses pyramidal sp³ hybridization, whereas that in (II) is hybridized planar sp². As can be seen from Tables 1 and 3, the C1—N1 bond is shorter in (II), suggesting that the electronic delocalization could be more important in this bond than in the other C___N bond?. This trend was confirmed in a search in the Cambridge Structural Database (CSD, Version 5.23; Allen, 2002), which retrieved two single-crystal X-ray studies of structures of bisphosphonates containing an acyclic N atom attached to the geminal C atom. In KISROT (Lorberth et al., 1991), the N atom is planar sp² hybridized and the C—N distance is at 1.494 Å; however, this bond is larger in SOPSAR (1.510 Å; Shkol'nikova et al., 1990), where the N atom is sp³ hybridized (note that in both structures the N atom is dimethylated). As can be appreciated from Tables 1 and 3, the lengths of the P—C and C—C bonds shared by the two compounds are very similar, as are those of the P—O bonds. An inspection of the latter clearly indicated the presence of protonated and deprotonated O atoms (Vega et al., 1996): the P—O bonds are in the range 1.4912 (14)–1.505 (3) Å, while the P—O(H) bonds are in the range 1.5283 (15)–1.5614 (14) Å.

The P—C—P bond angle is comparable in both structures, while the O—P—O angles reflect the electronic state of the group. Thus, the neutral PO₃ groups have O—P—O(H) angles in the range 111.99 (8)– 116.31 (8)°, while the (H)O—P—O(H) angles range from 102.72 (8) to 105.90 (18)°. By contrast, the O—P—O angle within the negatively charged phosphorus group is the largest [118.11 (16)°]. The planar 'W' shape delineated by the O—P—C—P—O sequence, which is relevant for the biologic activity of the bisphosphonate (Shkol'nikova et al., 1990), is found in both structures. The O—P—C—P torsion angles that characterize the 'W' are −179.66 (19) and 158.2 (2) [(I)], and −164.05 (9)° and −154.23 (9)° [(II)] (Tables 1 and 3). The C—C—C bond angle in (I) and (II) is larger than the ideal tetrahedral value, suggesting that the sp³ hybridized C2 atom could be deformed because of some conformational freedom associated with thermal motion or disorder. Other bisphosphonates with an aliphatic side chain also display a larger C2 bond angle (Vega et al., 1996; Fernández et al., 2002). As shown by the values of the P—C—C—C torsion angles, the C2—C3 bond is coplanar with C1—P1 but is twisted in relation to C1—P2, the P1—C1—C2—C3 and P2—C1—C2—C3 torsion angles being −175.3 (4) and 59.0 (5)°, respectively, for (I), and −175.27 (14)° and −54.2 (2)°, respectively, for (II). In addition, the C2—C3 bond is twisted towards the N atom, the C3—C2—C1—N1 torsion angles being −58.6 (5) and 67.1 (2)° for (I) and (II), respectively.

The acetyl part of (II) shows the typical planar nature associated with the amide bond, and the bond lengths (Table 3) correspond well to those found in the peptide bond (Lehninger et al., 2000). Therefore, C1/N1/C4/C5/O7 forms a plane, from which atom N1 deviates the most [by 0.008 (2) Å]. Atom P1 deviates more than P2 with respect to the C1/N1/C4/C5/O7 plane [1.7277 (5) Å versus 1.2066 (5) Å]. Such an atomic disposition could enable an intramolecular interaction between O4 and O7 [O4—H4···O7 parameters D···A, H···A and D—H···A are 2.823 (2) Å, 2.41 (3) Å and 108 (2)°], thus forming a seven-membered ring involving atoms O7, C4, N1, C1, P2, O4 and H4. In addition, as a possible cause of this interaction, the N1—C1—P2 bond angle is 5° larger than that in (I), i.e. 111.37 (12)° in contrast to 106.3 (2)°.

The hydrogen-bonding scheme for (I) consists of O(phosphonyl)—H···O(phosphonyl) and N—H···O (phosphonyl) interactions [Table 2]. All the possible donor atoms, namely all the H atoms of the N1 group and of the protonated atoms O3, O4 and O5, are involved in the interactions. The packing in the crystal of (I), as depicted in Fig. 3, can be described as an arrangement of the molecules into planes running parallel to the crystallographic a axis, bound through the O3—H9···O6, O4—H10···O2, O5—H11···O1 and N1— H3···O1 interactions. These planes are stacked along the c axis and are connected by? the remaining N—H···O hydrogen bonds. In (II), intermolecular interactions occur between O atoms, without the participation of the N1 group (Table 4). As shown in Fig. 4, the molecules are dimerized head–to–head through the O3—H3···O1 O(phosphonyl)···O(phosphonyl) interaction; this dimer is joined to others by means of the carbonyl O7 atom and the water O9 atom, thus forming a chain running along the crystallographic a axis. The interchain cohesion is provided by interactions involving the O8 water molecule. It appeared that the molecules in the crystal of (II) are less tight packed than those in (I), possibly because of the lack of interactions of the N1 group. Hence, the interchain cohesion is weakened, preventing the chains from associating and forming a plane; possibly for the same reason, this effect allowed the presence of the crystallization water molecules, which could be retained in (II) but not in (I). As only (II) was used in the biological studies (Fukuda et al., 1999), it could be concluded that this hydrated form of the drug showed better solubility properties than the anhydrous form.

S2. Experimental

Crystals suitable for X-ray diffraction were obtained by slow evaporation from a water solution and were grown at 315 K (I) and 293 K (II).

S3. Refinement

The H atoms in (I) and (II), except those attached to O atoms, were refined using a riding model while constaining their isotropic displacement parameters to 1.3 (H atoms attached to C and N) or 1.5 (H atoms attached to O) times the U_eq values of their carrier atoms. The O– H distances were restrained at 0.85 (3) Å using the DFIX command implemented in SHELXL97 (Sheldrick, 1991).

Computing details

Data collection: MSC/AFC Diffractometer Control Software version 4.3.0 (Molecular Structure Corporation, 1993) for (I); COLLECT (Nonius, 1997–2000) for (II). Cell refinement: MSC/AFC Diffractometer Control Software (Molecular Structure Corporation, 1993) for (I); HKL SCALEPACK (Otwinowski & Minor, 1997) for (II). Data reduction: MSC/AFC Diffractometer Control Software for (I); HKL DENZO (Otwinowski & Minor, 1997) and SCALEPACK for (II). For both compounds, program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XP in SHELXTL/PC (Sheldrick, 1991); software used to prepare material for publication: PARST (Nardelli, 1995) and WinGX (Farrugia, 1999).

Figures

	Fig. 1. : A view of the structure of (I), showing the atom-numbering scheme and displacement ellipsoids at the 30% probabilty level.
	Fig. 2. : A view of the structure of (II), showing the atom-numbering scheme and displacement ellipsoids at the 30% probability level.
	Fig. 3. Partial packing diagram for (I), showing the O—H···O (dotted lines) and some of the N—H···O (dashed lines) hydrogen bonds. Only the H atoms attached to O and N atoms are shown. Atoms labelled with a prime ('), a hash (#) and an ampersand (&) are at symmetry positions (1/2 − x, −y, z − 1/2), (x − 1/2, 1/2 − y, −z) and (1/2 + x, 1/2 − y, −z), respectively.
	Fig. 4. Partial packing diagram for (II), showing the O—H···O (dotted lines) hyrogen bonds. Only the H atoms attached to O and N atoms are shown. Atoms labelled with a dollar sign ($), a hash (#), a pipe (|) and a prime ('), are at symmetry positions (1 − x, −y, −z), (2 − x, y + 1/2, −z − 1/2), (2 − x, −y, −z − 1) and (2 − x, −y, −z), respectively.

(I)

Crystal data

C3H11NO6P2	Dx = 1.687 Mg m^−3
Mr = 219.07	Mo Kα radiation, λ = 0.71073 Å
Orthorhombic, P212121	Cell parameters from 20 reflections
a = 11.666 (3) Å	θ = 10–20°
b = 12.937 (5) Å	µ = 0.50 mm^−1
c = 5.714 (3) Å	T = 293 K
V = 862.4 (6) Å^3	Cubic, colorless
Z = 4	0.2 × 0.15 × 0.15 mm
F(000) = 456

Data collection

Rigaku AFC-6S diffractometer	θmax = 27.5°, θmin = 3.2°
ω–2θ scans	h = 0→15
4140 measured reflections	k = −16→16
1987 independent reflections	l = −7→7
1608 reflections with I > 2σ(I)	3 standard reflections every 300 reflections
Rint = 0.065	intensity decay: 2%

Refinement

Refinement on F^2	H atoms treated by a mixture of independent and constrained refinement
Least-squares matrix: full	w = 1/[σ^2(Fo^2) + (0.0603P)^2] where P = (Fo^2 + 2Fc^2)/3
R[F^2 > 2σ(F^2)] = 0.049	(Δ/σ)max = 0.003
wR(F^2) = 0.119	Δρmax = 0.33 e Å^−3
S = 1.02	Δρmin = −0.24 e Å^−3
1987 reflections	Absolute structure: Flack (1983)
118 parameters	Absolute structure parameter: 0.3 (2)
3 restraints

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
C1	0.3046 (3)	0.1974 (3)	0.2458 (6)	0.0194 (7)
C2	0.3630 (4)	0.3046 (3)	0.2556 (8)	0.0294 (9)
H4	0.4358	0.2965	0.3356	0.038*
H5	0.3799	0.3256	0.0963	0.038*
C3	0.2981 (5)	0.3927 (4)	0.3736 (12)	0.0602 (17)
H6	0.3455	0.4534	0.3767	0.078*
H7	0.2788	0.3731	0.5308	0.078*
H8	0.2292	0.407	0.2876	0.078*
N1	0.2784 (3)	0.1605 (3)	0.4907 (5)	0.0201 (7)
H1	0.2386	0.2088	0.5662	0.026*
H2	0.3437	0.1485	0.5666	0.026*
H3	0.2375	0.1025	0.4837	0.026*
O1	0.3562 (2)	−0.0034 (2)	0.1576 (5)	0.0266 (6)
O2	0.4278 (2)	0.1353 (2)	−0.1309 (5)	0.0251 (6)
O3	0.5133 (2)	0.1115 (2)	0.2768 (5)	0.0270 (6)
H9	0.563 (3)	0.154 (3)	0.249 (9)	0.041*
O4	0.0868 (3)	0.2492 (3)	0.2775 (5)	0.0356 (8)
H10	0.031 (4)	0.284 (4)	0.223 (9)	0.053*
O5	0.1255 (3)	0.0911 (3)	0.0553 (6)	0.0342 (7)
H11	0.133 (5)	0.062 (4)	−0.075 (6)	0.051*
O6	0.1756 (2)	0.2640 (2)	−0.1304 (5)	0.0285 (7)
P1	0.40511 (8)	0.10223 (7)	0.11730 (16)	0.0190 (2)
P2	0.16606 (8)	0.20277 (8)	0.09051 (18)	0.0224 (2)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0202 (17)	0.0254 (19)	0.0125 (16)	−0.0028 (15)	0.0000 (14)	−0.0003 (16)
C2	0.032 (2)	0.0248 (19)	0.031 (2)	−0.0083 (17)	0.0041 (18)	−0.0011 (19)
C3	0.067 (3)	0.031 (2)	0.083 (5)	−0.006 (2)	0.031 (4)	−0.015 (3)
N1	0.0203 (16)	0.0268 (17)	0.0134 (15)	0.0002 (14)	0.0002 (13)	−0.0007 (13)
O1	0.0281 (14)	0.0252 (14)	0.0265 (15)	−0.0021 (12)	−0.0025 (12)	0.0005 (12)
O2	0.0222 (13)	0.0367 (15)	0.0165 (14)	−0.0040 (11)	−0.0007 (12)	0.0020 (11)
O3	0.0192 (14)	0.0362 (16)	0.0256 (15)	−0.0051 (12)	−0.0039 (12)	0.0035 (13)
O4	0.0328 (16)	0.056 (2)	0.0181 (15)	0.0182 (16)	0.0056 (13)	0.0035 (14)
O5	0.0347 (16)	0.0401 (18)	0.0277 (16)	−0.0084 (14)	−0.0068 (14)	0.0006 (14)
O6	0.0297 (15)	0.0386 (16)	0.0173 (14)	0.0121 (12)	0.0013 (12)	0.0040 (12)
P1	0.0175 (4)	0.0234 (4)	0.0162 (4)	−0.0005 (4)	0.0006 (4)	0.0006 (4)
P2	0.0209 (5)	0.0313 (5)	0.0151 (4)	0.0045 (4)	0.0006 (4)	0.0011 (4)

Geometric parameters (Å, º)

C2—C3	1.526 (7)	O3—P1	1.561 (3)
C2—H4	0.97	C1—P1	1.852 (4)
C2—H5	0.97	O3—H9	0.82 (3)
C3—H6	0.96	O4—P2	1.536 (3)
C3—H7	0.96	O4—H10	0.85 (3)
C3—H8	0.96	O5—P2	1.533 (3)
N1—H1	0.89	O5—H11	0.84 (3)
N1—H2	0.89	O6—P2	1.494 (3)
N1—H3	0.89	C1—C2	1.546 (5)
O1—P1	1.498 (3)	C1—P2	1.845 (4)
O2—P1	1.505 (3)	C1—N1	1.510 (5)
N1—C1—C2	109.8 (3)	H1—N1—H2	109.5
N1—C1—P2	106.3 (2)	C1—N1—H3	109.5
C2—C1—P2	111.7 (3)	H1—N1—H3	109.5
N1—C1—P1	106.6 (2)	H2—N1—H3	109.5
C2—C1—P1	109.4 (3)	P1—O3—H9	121 (4)
P1—C1—P2	112.89 (19)	P2—O4—H10	114 (4)
C1—C2—C3	117.9 (4)	P2—O5—H11	121 (4)
C3—C2—H4	107.8	O1—P1—O2	118.11 (16)
C1—C2—H4	107.8	O1—P1—O3	106.74 (16)
C3—C2—H5	107.8	O2—P1—O3	112.71 (16)
C1—C2—H5	107.8	O1—P1—C1	107.72 (17)
H4—C2—H5	107.2	O2—P1—C1	107.21 (17)
C2—C3—H6	109.5	O3—P1—C1	103.24 (16)
C2—C3—H7	109.5	O4—P2—O5	105.90 (18)
H6—C3—H7	109.5	O4—P2—O6	115.17 (17)
C2—C3—H8	109.5	O5—P2—O6	114.29 (18)
H6—C3—H8	109.5	O6—P2—C1	111.16 (17)
H7—C3—H8	109.5	O5—P2—C1	107.32 (18)
C1—N1—H1	109.5	O4—P2—C1	102.01 (18)
C1—N1—H2	109.5
N1—C1—C2—C3	−58.6 (5)	O3—P1—C1—P2	−179.66 (19)
P2—C1—C2—C3	59.0 (5)	N1—C1—P2—O6	164.9 (2)
P1—C1—C2—C3	−175.3 (4)	C2—C1—P2—O6	45.2 (3)
N1—C1—P1—O1	49.3 (3)	O4—P2—C1—P1	158.2 (2)
C2—C1—P1—O1	168.0 (3)	O5—P2—C1—P1	47.1 (3)
O1—P1—C1—P2	−67.0 (2)	O6—P2—C1—P1	−78.6 (2)
N1—C1—P1—O2	177.4 (2)	N1—C1—P2—O5	−69.4 (3)
C2—C1—P1—O2	−63.9 (3)	C2—C1—P2—O5	170.8 (3)
O2—P1—C1—P2	61.1 (2)	N1—C1—P2—O4	41.7 (3)
N1—C1—P1—O3	−63.4 (3)	C2—C1—P2—O4	−78.1 (3)
C2—C1—P1—O3	55.3 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O6^i	0.89	2.01	2.814 (4)	149
N1—H2···O2^i	0.89	1.99	2.796 (4)	149
N1—H3···O1^ii	0.89	1.96	2.740 (4)	146
O3—H9···O6^iii	0.82 (3)	1.82 (3)	2.623 (4)	169 (5)
O4—H10···O2^iv	0.85 (3)	1.68 (3)	2.524 (4)	173 (6)
O5—H11···O1^v	0.84 (3)	1.71 (3)	2.549 (4)	179 (6)

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

(II)

Crystal data

C5H13NO7P2·2H2O	F(000) = 624
Mr = 297.14	Dx = 1.684 Mg m^−3
Monoclinic, P21/c	Mo Kα radiation, λ = 0.71073 Å
a = 11.8880 (3) Å	Cell parameters from 19718 reflections
b = 12.4715 (4) Å	θ = 2.9–28.3°
c = 7.9403 (2) Å	µ = 0.41 mm^−1
β = 95.4986 (13)°	T = 120 K
V = 1171.82 (6) Å^3	Thin plate, colorless
Z = 4	0.26 × 0.11 × 0.06 mm

Data collection

KappaCCD diffractometer	Rint = 0.053
ϕ scans and ω scans with κ offsets	θmax = 28.3°, θmin = 3.1°
9795 measured reflections	h = −15→15
2901 independent reflections	k = −16→16
2417 reflections with I > 2σ(I)	l = −9→10

Refinement

Refinement on F^2	8 restraints
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.043	w = 1/[σ^2(Fo^2) + (0.0579P)^2 + 0.7884P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.113	(Δ/σ)max = 0.007
S = 1.07	Δρmax = 0.34 e Å^−3
2901 reflections	Δρmin = −0.57 e Å^−3
178 parameters

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	0.66692 (4)	0.04953 (4)	0.04122 (6)	0.01592 (14)
P2	0.79657 (4)	−0.05016 (4)	−0.23632 (6)	0.01547 (14)
O1	0.62283 (11)	−0.06218 (11)	0.05360 (18)	0.0191 (3)
O2	0.76103 (12)	0.08260 (12)	0.17587 (18)	0.0207 (3)
H2	0.804 (2)	0.032 (2)	0.212 (3)	0.031*
O3	0.57533 (12)	0.13763 (12)	0.05792 (18)	0.0201 (3)
H3	0.5107 (19)	0.116 (2)	0.016 (3)	0.03*
O4	0.84783 (12)	−0.11407 (11)	−0.08039 (18)	0.0184 (3)
H4	0.9193 (18)	−0.100 (2)	−0.051 (3)	0.028*
O5	0.70358 (12)	−0.12595 (11)	−0.32006 (18)	0.0200 (3)
H5	0.689 (2)	−0.1820 (19)	−0.261 (3)	0.03*
O6	0.87762 (11)	−0.01586 (11)	−0.35802 (17)	0.0194 (3)
O7	0.94424 (11)	0.09220 (11)	−0.03774 (17)	0.0189 (3)
N1	0.78778 (13)	0.16747 (13)	−0.1689 (2)	0.0163 (3)
H1	0.7569	0.2259	−0.215	0.021*
C1	0.71759 (16)	0.06964 (15)	−0.1703 (2)	0.0158 (4)
C2	0.61171 (15)	0.08944 (16)	−0.2967 (2)	0.0175 (4)
H6	0.5579	0.0298	−0.2857	0.023*
H7	0.5746	0.1561	−0.263	0.023*
C3	0.63334 (18)	0.09920 (17)	−0.4829 (2)	0.0218 (4)
H8	0.6532	0.0287	−0.5258	0.028*
H9	0.6957	0.1494	−0.4936	0.028*
H10	0.565	0.1257	−0.5485	0.028*
C4	0.89580 (16)	0.17284 (16)	−0.1015 (2)	0.0170 (4)
C5	0.95426 (18)	0.27870 (18)	−0.1075 (3)	0.0262 (5)
H11	0.9364	0.3112	−0.2193	0.034*
H12	1.0361	0.2682	−0.0867	0.034*
H13	0.9286	0.3261	−0.0206	0.034*
O8	0.64893 (13)	−0.29587 (12)	−0.1788 (2)	0.0251 (3)
H14	0.679 (2)	−0.317 (2)	−0.083 (3)	0.038*
H15	0.651 (2)	−0.343 (2)	−0.256 (3)	0.038*
O9	0.89757 (13)	−0.04504 (12)	0.31393 (19)	0.0221 (3)
H16	0.889 (2)	−0.042 (2)	0.420 (3)	0.033*
H17	0.9653 (19)	−0.030 (2)	0.314 (4)	0.033*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
P1	0.0149 (2)	0.0180 (3)	0.0151 (2)	−0.00030 (17)	0.00300 (18)	−0.00010 (17)
P2	0.0157 (3)	0.0147 (2)	0.0163 (2)	0.00015 (17)	0.00265 (18)	−0.00069 (17)
O1	0.0170 (7)	0.0200 (7)	0.0206 (7)	−0.0012 (5)	0.0032 (5)	0.0034 (5)
O2	0.0182 (7)	0.0258 (8)	0.0181 (7)	−0.0011 (6)	0.0013 (5)	−0.0014 (6)
O3	0.0178 (7)	0.0205 (7)	0.0226 (7)	0.0006 (6)	0.0048 (6)	−0.0028 (6)
O4	0.0162 (6)	0.0167 (7)	0.0220 (7)	−0.0001 (5)	0.0006 (5)	0.0018 (5)
O5	0.0231 (7)	0.0166 (7)	0.0199 (7)	−0.0025 (6)	−0.0007 (5)	−0.0003 (6)
O6	0.0193 (7)	0.0206 (7)	0.0190 (7)	0.0004 (6)	0.0057 (5)	−0.0009 (6)
O7	0.0168 (6)	0.0165 (7)	0.0233 (7)	0.0006 (5)	0.0019 (5)	0.0012 (5)
N1	0.0160 (7)	0.0134 (7)	0.0195 (8)	0.0002 (6)	0.0020 (6)	0.0009 (6)
C1	0.0159 (9)	0.0145 (9)	0.0170 (9)	−0.0006 (7)	0.0014 (7)	0.0005 (7)
C2	0.0141 (8)	0.0202 (9)	0.0178 (9)	0.0002 (7)	−0.0002 (7)	0.0017 (7)
C3	0.0237 (10)	0.0239 (10)	0.0177 (9)	0.0004 (8)	0.0005 (8)	0.0008 (8)
C4	0.0176 (9)	0.0180 (9)	0.0158 (8)	0.0004 (7)	0.0033 (7)	0.0002 (7)
C5	0.0241 (10)	0.0207 (10)	0.0328 (11)	−0.0040 (8)	−0.0026 (9)	0.0044 (8)
O8	0.0318 (8)	0.0196 (7)	0.0235 (7)	−0.0032 (6)	−0.0002 (6)	−0.0016 (6)
O9	0.0202 (7)	0.0275 (8)	0.0188 (7)	−0.0013 (6)	0.0030 (6)	0.0000 (6)

Geometric parameters (Å, º)

O1—P1	1.4950 (14)	C1—C2	1.552 (2)
O2—P1	1.5283 (15)	C2—C3	1.530 (3)
O3—P1	1.5614 (14)	C2—H6	0.99
C1—P1	1.8549 (19)	C2—H7	0.99
O4—P2	1.5476 (14)	C3—H8	0.98
O5—P2	1.5546 (15)	C3—H9	0.98
O6—P2	1.4912 (14)	C3—H10	0.98
C1—P2	1.8662 (19)	C4—C5	1.495 (3)
O2—H2	0.85 (2)	C5—H11	0.98
O3—H3	0.85 (2)	C5—H12	0.98
O4—H4	0.88 (2)	C5—H13	0.98
O5—H5	0.87 (2)	O8—H14	0.86 (2)
C1—N1	1.478 (2)	O8—H15	0.85 (2)
C4—O7	1.242 (2)	O9—H16	0.86 (2)
C4—N1	1.345 (2)	O9—H17	0.83 (2)
N1—H1	0.88
O1—P1—O2	116.31 (8)	P1—C1—P2	111.21 (10)
O1—P1—O3	113.48 (8)	C1—C2—C3	115.87 (15)
O2—P1—O3	102.72 (8)	C3—C2—H6	108.3
O1—P1—C1	109.38 (8)	C1—C2—H6	108.3
O2—P1—C1	108.51 (8)	C3—C2—H7	108.3
O3—P1—C1	105.74 (8)	C1—C2—H7	108.3
O4—P2—O5	103.79 (8)	H6—C2—H7	107.4
O4—P2—O6	115.90 (8)	C2—C3—H8	109.5
O5—P2—O6	111.99 (8)	C2—C3—H9	109.5
O6—P2—C1	109.03 (8)	H8—C3—H9	109.5
O4—P2—C1	110.96 (8)	C2—C3—H10	109.5
O5—P2—C1	104.51 (8)	H8—C3—H10	109.5
P1—O2—H2	114.5 (19)	H9—C3—H10	109.5
P1—O3—H3	111.0 (19)	O7—C4—N1	120.63 (18)
P2—O4—H4	113.9 (17)	O7—C4—C5	121.95 (17)
P2—O5—H5	115.4 (18)	N1—C4—C5	117.42 (17)
C1—N1—C4	124.14 (16)	C4—C5—H11	109.5
C4—N1—H1	117.9	C4—C5—H12	109.5
C1—N1—H1	117.9	H11—C5—H12	109.5
N1—C1—C2	107.22 (15)	C4—C5—H13	109.5
N1—C1—P1	109.68 (12)	H11—C5—H13	109.5
C2—C1—P1	107.04 (12)	H12—C5—H13	109.5
N1—C1—P2	111.37 (12)	H14—O8—H15	112 (3)
C2—C1—P2	110.15 (13)	H16—O9—H17	102 (3)
C4—N1—C1—C2	−166.09 (16)	O4—P2—C1—N1	97.26 (13)
C4—N1—C1—P1	78.01 (19)	O5—P2—C1—N1	−151.46 (12)
C4—N1—C1—P2	−45.5 (2)	O6—P2—C1—C2	87.26 (14)
O1—P1—C1—N1	−165.14 (12)	O4—P2—C1—C2	−143.91 (12)
O2—P1—C1—N1	−37.30 (15)	O5—P2—C1—C2	−32.63 (14)
O3—P1—C1—N1	72.32 (14)	O4—P2—C1—P1	−25.40 (12)
O1—P1—C1—C2	78.86 (14)	O5—P2—C1—P1	85.87 (11)
O2—P1—C1—C2	−153.31 (13)	O6—P2—C1—P1	−154.23 (9)
O3—P1—C1—C2	−43.69 (14)	N1—C1—C2—C3	67.1 (2)
O1—P1—C1—P2	−41.50 (12)	P1—C1—C2—C3	−175.27 (14)
O2—P1—C1—P2	86.33 (11)	P2—C1—C2—C3	−54.2 (2)
O3—P1—C1—P2	−164.05 (9)	C1—N1—C4—O7	1.4 (3)
O6—P2—C1—N1	−31.57 (15)	C1—N1—C4—C5	−178.83 (17)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O2—H2···O9	0.85 (2)	1.62 (2)	2.455 (2)	167 (3)
O3—H3···O1^i	0.85 (2)	1.77 (2)	2.611 (2)	174 (3)
O4—H4···O7	0.88 (2)	2.41 (3)	2.823 (2)	108 (2)
O4—H4···O7^ii	0.88 (2)	1.71 (2)	2.573 (2)	168 (3)
O5—H5···O8	0.87 (2)	1.65 (2)	2.512 (2)	170 (3)
O8—H14···O5^iii	0.86 (2)	2.19 (2)	3.022 (2)	163 (3)
O8—H15···O1^iv	0.85 (2)	1.92 (2)	2.760 (2)	167 (3)
O9—H17···O6^ii	0.83 (2)	1.95 (2)	2.768 (2)	169 (3)
O9—H16···O6^v	0.86 (2)	1.81 (2)	2.663 (2)	171 (3)

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