Head-to-head dimers in the zwitterion of 1-hydroxy-3-(pyrrolidin-1-yl)pro­pyl­idene-1,1-bis­phospho­nic acid (EB 1053)

The title compound, 1-hydroxy-1-phospho­no-3-(1-pyr­rol­idin­io)­propyl­idene-1-phospho­nate, C₇H₁₇NO₇P₂, is a member of the bis­phospho­nate class of drugs. As a zwitterion, it possesses a negative charge on one of the PO₃ groups and a positive charge on the pyrrolidine N atom. A zwitterion makes a contact with a neighbouring ion through the hydroxyl O atom and two phospho­nyl O atoms, one each from two different PO₃ groups. Hydro­gen bonding involves O—H...O and N—H...O interactions; the former are involved in the formation of head-to-head dimers, while the latter join the dimers into a chain running along the crystallographic b axis.

S1. Comment

A number of compounds of the bisphosphonate class are used as therapeutic agents for the treatment of skeletal disorders such as osteoporosis, Paget's disease of the bone and hypercalcaemia associated with malignancy (Compston, 1994; Martin & Grill, 2000; Rodan & Martin, 2000). In this context, it has been shown that the bisphosphonate EB 1053 is a potent inhibitor of bone resorption (van der Pluijm et al., 1992). In other studies, this compound has been tested as a cholesterol-lowering agent (Amin et al., 1992) and as an antitumour drug against breast cancer (Senaratne et al., 2000). This work is a part of our ongoing study of the crystal structures of chemical compounds that affect osseous metabolism and are used as therapeutic agents to treat bone diseases (Vega et al., 1996, 1998; Fernández et al., 2002). We report here the single-crystal X-ray analysis of the bisphosphonate EB 1053, (I).

Compound (I) consists of a P—C—P bridge with a substituted hydroxyl group and a side chain that ends in a pyrrolidinyl ring? (Fig. 1). Like other previously studied amino bisphosphonates (Vega et al., 2002; Van Brussel et al., 2003), (I) possesses zwitterionic character. At one end of the molecule a negative charge is located over one PO₃ group, while at the opposite end there is a positively charged N atom. This conformation? was also found for the structures of the related bisphosphonates pamidronate (anhydrous free acid; unpublished results), hereafter H₃PAM, and olpadronate (monohydrated free acid; CSD refcode FURCAW; Shkol'nikova et al., 1987), hereafter H₃OLP, which possess CH₂–CH₂–NH₃⁺ and CH₂–CH₂–NH(CH₃)₂⁺ side chains, respectively. The P—C bond lengths (Table 1) are in good agreement with those of the related compounds. However, the P—C—P bond angle is larger in (I) [114.23 (9)° versus 110.63 (12)° in H₃PAM and 109.91 (4)° in H₃OLP.] In this work, the C2—C3 bond is gauche with respect to the C1—P1 and C1—P2 bonds, the P1—C1—C2—C3 and P2—C1—C2—C3 torsion angles being −43.6 (2)° and 85.46 (19)°, respectively. The same trend was observed for H₃OLP but not for H₃PAM, in which the C2—C3 bond is further from C1—P2, the P2—C1—C2—C3 torsion angle being 175.46 (17)°. As atom C3 forms an intramolecular contact with atom O2 [C3···O2 = 3.028 (2) Å, H8···O2 = 2.59 (2) Å and C3—H8···O2 = 108 (2)°], it is possible that C3? exerts a steric hindrance on the P—C—P linkage, resulting in the lengthening of the bond. The PO₃ groups are staggered when viewed along the P1···P2 vector, and their mutual orientation defines a 'W'-like shape for the O1—P1—C1—P2—O4 sequence. In the plane of the 'W' there is one protonated and one deprotonated O atom, as shown by the P2—C1—P1—O1 and P1—C1—P2—O4 torsion angles of −179.67 (9)° and −170.55 (9)°, which is in agreement with the situation observed for H₃OLP but differs from H₃PAM, in which both O atoms are protonated. The P—O bond lengths (Table 1) indicate the presence of the single (P1—O3, P2—O4 and P2—O5) and double (P1—O1 and P2—O6) bonds that are generally observed for several members of this class of compounds (Vega et al., 1998). The remaining bond, P1—O2, has an intermediate length, suggesting that the −1 charge could be delocalized.

Hydroxyl atom O7 is trans with respect to the O—C—C—C—N backbone of the molecule, the O7—C1— C2—C3 torsion angle being −162.10 (16)°. This atom is similarly orientated in H₃OLP, but it isdifferently disposed in H₃PAM, where the corresponding torsion angle is −66.3 (3) °. An analysis of the hydrogen bonds in which atom O7 takes part, using the PARST program (Nardelli, 1995), revealed that O7 acts as a donor in comparable interactions in (I) and H₃PAM. However, as an acceptor, it forms a stronger hydrogen bond in the latter [D···A = 2.862 Å, H···A = 1.92 (4) Å and D—H···A = 175°] than in (I) (Table 2). In addition, the N atom is trans in the three structures, the C1—C2—C3—N1 torsion angles being −159.04 (16)° [(I)], 174.54 (6)° [H₃OLP] and 169.6 (2)° [H₃PAM]. Therefore, it can be reasoned that the structures in which a tertiary N atom is present have in common a planar O—C—C—C—N backbone.

In the final model, the disordered pyrrolidinyl ring was refined with a major component (N1—C4—C5—C6—C7) accounting for 75% of the occupancy and a minor component (25%) consisting of N1—C4—C5'—C6—C7. These rings are puckered with respect to the most symmetric conformations observed for five-membered rings (Duax et al., 1976) [the Cremer & Pople (1975) ring puckering parameters are q₂ = 0.323 (3) Å and ϕ₂ = 3.9 (5)° for the sequence C4—C5—C6—C7—N1, and q₂ = 0.350 (7) Å and ϕ₂ = 29.5 (7)° for the sequence C5'–C6– C7–N1–C4. The values of the phase indicate that the conformation of both rings is close to the envelope (Allen et al., 1991), but with a tendency to be twisted (especially for the latter ring). The asymmetry parameters (Nardelli, 1983) for the C4—C5—C6—C7—N1 ring indicate a local pseudo mirror Δ_S(C4) passing on C4 and the midpoint of the C6–C7 bond and a local pseudo twofold axis Δ_S(C7) running along C7 and the midpoint of the C4—C5 bond. For the C5'—C6—C7—N1—C4 ring, the local pseudo symmetry elements Δ_S(C6) and Δ₂(N1) run along C6 and N1 and the midpoint of the C4—N1 and C5—C6 bonds, respectively.

Atoms O3, O5 and O7 function as tridentate ligands (Table 2), and their atomic disposition, as can be seen from Fig. 2, is such that they define the base of a pyramid that has a vertex at atom N1. An analysis using the XP program (Sheldrick, 1991) showed that N1 is 2.644 Å from the centroid (Ct) of the triad of O atoms and forms a Ct—H5—N1 angle of 168.10°; in addition, both P atoms are at the same distance with respect to N1 (ca 2 Å). By comparison with H₃OLP and H₃PAM, it could be concluded that the interactions in which the N atom takes part are different and depend on the environment of the atoms involved in the interactions.

The packing in the crystal of (I) is achieved through hydrogen bonding, which consists of O—H···O and N—H···O type interactions (Table 2). O(phosphonyl)—O(phosphonyl) hydrogen bonds pack pairs of molecules into head-to-head dimers (Fig. 2); note that atoms O2, O3, O5 and O6 are part of an eight-membered P—O—H···O—P—O···H—O ring. A chain running along the crystallographic b axis is generated by N— H···O, O(hydroxyl)—O(phosphonyl) and O(phosphonyl)—O(phosphonyl) interactions. The latter form a nine-membered ring that includes atoms O1, O4, O6 and O7.

S2. Experimental

Crystals suitable for X-ray diffraction were obtained by slow evaporation from an aqueous solution in an oven at 315 K.

S3. Refinement

Atom C5 is disordered over two sites, and the occupancy was refined freely until the last cycles of refinement, at which point it was fixed at 0.75 for C5 and at 0.25 for C5'. The displacement and positional parameters of H atoms attached to the tertiary N atoms and the hydroxyl O atom were freely refined. The U_iso values for the remaining H atoms were kept at 1.2 (for those bonded to C atoms) and 1.5 (for those bonded to phosphonyl O atoms) times larger than the U_eq of their carriers. The positions of H atoms attached to C atoms were refined freely, ?except for H atoms attached to disordered atoms, which were treated as riding with the C—H distance fixed at 0.97 Å. H atoms attached to phosphonyl O atoms were refined with a restrained O—H distance of 0.85 (3) Å using the DFIX command implemented in SHELXL97 (Sheldrick, 1997).

Computing details

Data collection: MSC/AFC Diffractometer Control Software version 4.3.0 (Molecular Structure Corporation, 1993); cell refinement: MSC/AFC Diffractometer Control Software; data reduction: MSC/AFC Diffractometer Control Software; 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: CSD (Allen, 2002), 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% probability level. H atoms of the minor occupancy component (C5') have been omitted for clarity.
	Fig. 2. : Partial packing diagram, showing the hydrogen bonds (thin lines and dotted lines). Only H atoms attached to O atoms are shown. [Symmetry codes: ($) −x + 3/2, y − 1/2, −z + 1/2; (') −x + 2, −y, −z + 1.]

(I)

Crystal data

C7H17NO7P2	F(000) = 608
Mr = 289.16	Dx = 1.63 Mg m^−3
Monoclinic, P21/n	Mo Kα radiation, λ = 0.71073 Å
a = 9.9208 (16) Å	Cell parameters from 20 reflections
b = 10.7754 (19) Å	θ = 10–17.5°
c = 11.4933 (17) Å	µ = 0.39 mm^−1
β = 106.439 (11)°	T = 293 K
V = 1178.4 (3) Å^3	Block, colorless
Z = 4	0.3 × 0.25 × 0.2 mm

Data collection

Rigaku AFC-6S diffractometer	Rint = 0.040
ω–2θ scans	θmax = 28.5°, θmin = 2.9°
Absorption correction: ψ-scan (Molecular Structure Corporation, 1993)	h = −3→13
Tmin = 0.951, Tmax = 1	k = −14→14
8063 measured reflections	l = −15→15
2992 independent reflections	3 standard reflections every 400 reflections
2436 reflections with I > 2σ(I)	intensity decay: 1%

Refinement

Refinement on F^2	3 restraints
Least-squares matrix: full	H atoms treated by a mixture of independent and constrained refinement
R[F^2 > 2σ(F^2)] = 0.037	w = 1/[σ^2(Fo^2) + (0.055P)^2 + 0.191P] where P = (Fo^2 + 2Fc^2)/3
wR(F^2) = 0.103	(Δ/σ)max = 0.004
S = 1.06	Δρmax = 0.38 e Å^−3
2992 reflections	Δρmin = −0.30 e Å^−3
210 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	Occ. (<1)
C1	0.75896 (19)	0.07792 (16)	0.28198 (15)	0.0225 (3)
C2	0.6193 (2)	0.0113 (2)	0.21496 (18)	0.0291 (4)
H6	0.555 (3)	0.078 (2)	0.183 (2)	0.035*
H7	0.635 (3)	−0.036 (2)	0.150 (2)	0.035*
C3	0.5545 (2)	−0.06834 (18)	0.29462 (17)	0.0275 (4)
H8	0.623 (3)	−0.112 (2)	0.355 (2)	0.033*
H9	0.499 (3)	−0.017 (2)	0.332 (2)	0.033*
C4	0.3380 (3)	−0.1132 (3)	0.1194 (2)	0.0485 (6)
H10	0.309 (3)	−0.035 (3)	0.150 (3)	0.058*
H11	0.370 (3)	−0.088 (3)	0.058 (3)	0.058*
C5	0.2243 (4)	−0.2095 (4)	0.1004 (3)	0.0468 (8)	0.75
H12	0.1326	−0.1723	0.0658	0.056*	0.75
H13	0.2382	−0.2743	0.0463	0.056*	0.75
C6	0.2357 (3)	−0.2609 (3)	0.2230 (3)	0.0579 (7)
H14	0.165 (4)	−0.242 (3)	0.256 (3)	0.07*
H15	0.221 (4)	−0.352 (3)	0.207 (3)	0.07*
C7	0.3834 (2)	−0.2364 (2)	0.3021 (2)	0.0360 (5)
H16	0.388 (3)	−0.187 (2)	0.371 (2)	0.043*
H17	0.441 (3)	−0.310 (2)	0.332 (2)	0.043*
N1	0.45500 (17)	−0.16347 (15)	0.22290 (15)	0.0272 (3)
H1	0.502 (3)	−0.213 (2)	0.193 (2)	0.031 (6)*
O1	0.62166 (15)	0.22618 (13)	0.39846 (13)	0.0318 (3)
O2	0.75354 (15)	0.04549 (12)	0.51885 (12)	0.0280 (3)
O3	0.88467 (16)	0.23296 (12)	0.46987 (13)	0.0307 (3)
H3	0.948 (3)	0.198 (2)	0.515 (2)	0.046*
O4	0.90805 (18)	−0.05177 (13)	0.16250 (13)	0.0351 (3)
H4	0.893 (3)	−0.126 (2)	0.142 (3)	0.053*
O5	1.03790 (15)	0.05755 (12)	0.35421 (13)	0.0303 (3)
H5	1.111 (3)	0.013 (2)	0.406 (2)	0.046*
O6	0.90106 (14)	−0.13984 (11)	0.36609 (11)	0.0255 (3)
O7	0.78496 (15)	0.17743 (12)	0.20774 (12)	0.0282 (3)
H2	0.721 (3)	0.227 (2)	0.191 (2)	0.038 (7)*
P1	0.75118 (5)	0.14756 (4)	0.42707 (4)	0.02320 (13)
P2	0.91059 (5)	−0.02418 (4)	0.29530 (4)	0.02260 (13)
C5'	0.2102 (10)	−0.1424 (11)	0.1407 (13)	0.057 (3)	0.25
H12'	0.1393	−0.1587	0.0647	0.068*	0.25
H13'	0.1785	−0.0741	0.1812	0.068*	0.25

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
C1	0.0212 (8)	0.0223 (8)	0.0232 (8)	0.0004 (7)	0.0051 (7)	0.0033 (6)
C2	0.0219 (9)	0.0347 (10)	0.0273 (8)	−0.0019 (8)	0.0013 (7)	0.0007 (8)
C3	0.0233 (9)	0.0297 (9)	0.0279 (9)	−0.0032 (8)	0.0046 (8)	−0.0047 (7)
C4	0.0329 (12)	0.0584 (15)	0.0442 (13)	−0.0082 (12)	−0.0057 (10)	0.0056 (12)
C5	0.0285 (16)	0.054 (2)	0.0513 (19)	−0.0069 (15)	0.0005 (14)	−0.0114 (16)
C6	0.0331 (13)	0.078 (2)	0.0658 (17)	−0.0196 (13)	0.0193 (13)	−0.0078 (15)
C7	0.0349 (11)	0.0402 (11)	0.0376 (11)	−0.0097 (9)	0.0181 (9)	−0.0073 (9)
N1	0.0210 (8)	0.0330 (8)	0.0280 (7)	−0.0013 (7)	0.0075 (6)	−0.0055 (6)
O1	0.0283 (7)	0.0322 (7)	0.0356 (7)	0.0080 (6)	0.0102 (6)	0.0054 (6)
O2	0.0264 (7)	0.0304 (7)	0.0263 (6)	0.0014 (5)	0.0060 (5)	0.0056 (5)
O3	0.0297 (7)	0.0263 (7)	0.0324 (7)	−0.0025 (6)	0.0028 (6)	0.0007 (5)
O4	0.0516 (10)	0.0279 (7)	0.0296 (7)	0.0022 (7)	0.0175 (7)	0.0002 (5)
O5	0.0224 (7)	0.0243 (6)	0.0397 (7)	−0.0008 (5)	0.0011 (6)	0.0054 (6)
O6	0.0254 (7)	0.0220 (6)	0.0265 (6)	−0.0019 (5)	0.0030 (5)	0.0016 (5)
O7	0.0273 (7)	0.0258 (6)	0.0330 (7)	0.0067 (6)	0.0109 (6)	0.0111 (5)
P1	0.0225 (2)	0.0227 (2)	0.0237 (2)	0.00221 (18)	0.00551 (18)	0.00219 (16)
P2	0.0221 (2)	0.0205 (2)	0.0244 (2)	0.00094 (17)	0.00534 (18)	0.00126 (16)
C5'	0.019 (4)	0.058 (7)	0.090 (9)	0.008 (4)	0.009 (5)	−0.005 (6)

Geometric parameters (Å, º)

C1—O7	1.438 (2)	C6—C5'	1.567 (12)
C1—C2	1.557 (3)	C6—H14	0.91 (4)
C1—P1	1.8501 (18)	C6—H15	1.00 (3)
C1—P2	1.8348 (18)	C7—N1	1.522 (3)
C2—C3	1.524 (3)	C7—H16	0.94 (3)
C2—H6	0.97 (2)	C7—H17	0.98 (3)
C2—H7	0.95 (2)	N1—H1	0.85 (2)
C3—N1	1.498 (2)	O1—P1	1.4959 (14)
C3—H8	0.94 (2)	O2—P1	1.5194 (13)
C3—H9	0.96 (3)	O3—P1	1.5729 (15)
C4—C5'	1.394 (11)	O3—H3	0.79 (2)
C4—C5	1.503 (4)	O4—P2	1.5482 (15)
C4—N1	1.508 (3)	O4—H4	0.83 (2)
C4—H10	0.99 (3)	O5—P2	1.5314 (14)
C4—H11	0.90 (3)	O5—H5	0.93 (2)
C5—C6	1.489 (5)	O6—P2	1.5060 (13)
C5—H12	0.97	O7—H2	0.81 (3)
C5—H13	0.97	C5'—H12'	0.97
C6—C7	1.513 (3)	C5'—H13'	0.97
O7—C1—C2	109.50 (14)	C5—C6—H15	103.0 (19)
O7—C1—P2	102.48 (12)	C7—C6—H15	110 (2)
C2—C1—P2	111.03 (13)	C5'—C6—H15	134 (2)
O7—C1—P1	107.01 (11)	H14—C6—H15	102 (3)
C2—C1—P1	112.01 (13)	C6—C7—N1	105.50 (19)
P1—C1—P2	114.23 (9)	C6—C7—H16	114.2 (16)
C3—C2—C1	115.48 (15)	N1—C7—H16	106.7 (15)
C3—C2—H6	107.9 (14)	C6—C7—H17	116.0 (15)
C1—C2—H6	104.1 (14)	N1—C7—H17	107.7 (15)
C3—C2—H7	110.9 (14)	H16—C7—H17	106 (2)
C1—C2—H7	108.6 (15)	C3—N1—C4	115.38 (17)
H6—C2—H7	109 (2)	C3—N1—C7	111.74 (15)
N1—C3—C2	112.29 (15)	C4—N1—C7	105.78 (17)
N1—C3—H8	106.7 (14)	C3—N1—H1	107.8 (16)
C2—C3—H8	112.5 (15)	C4—N1—H1	107.0 (16)
N1—C3—H9	105.4 (14)	C7—N1—H1	108.9 (16)
C2—C3—H9	109.6 (14)	P1—O3—H3	112 (2)
H8—C3—H9	110 (2)	P2—O4—H4	114 (2)
C5'—C4—N1	108.4 (6)	P2—O5—H5	112.3 (16)
C5—C4—N1	104.2 (2)	C1—O7—H2	112.1 (18)
C5'—C4—H10	76.3 (19)	O1—P1—O2	113.96 (8)
C5—C4—H10	111.3 (18)	O1—P1—O3	109.41 (8)
N1—C4—H10	105.1 (18)	O2—P1—O3	111.11 (8)
C5'—C4—H11	139 (2)	O1—P1—C1	106.49 (8)
C5—C4—H11	121 (2)	O2—P1—C1	109.62 (8)
N1—C4—H11	111 (2)	O3—P1—C1	105.84 (8)
H10—C4—H11	103 (3)	O4—P2—O5	109.12 (9)
C6—C5—C4	105.4 (2)	O4—P2—O6	112.81 (8)
C6—C5—H12	110.7	O5—P2—O6	114.02 (7)
C4—C5—H12	110.7	O6—P2—C1	111.47 (8)
C6—C5—H13	110.7	O5—P2—C1	104.26 (8)
C4—C5—H13	110.7	O4—P2—C1	104.40 (8)
H12—C5—H13	108.8	C4—C5'—C6	106.9 (6)
C5—C6—C7	107.8 (2)	C4—C5'—H12'	110.3
C7—C6—C5'	100.6 (4)	C6—C5'—H12'	110.3
C5—C6—H14	117 (2)	C4—C5'—H13'	110.3
C7—C6—H14	116 (2)	C6—C5'—H13'	110.3
C5'—C6—H14	93 (2)	H12'—C5'—H13'	108.6
O7—C1—C2—C3	−162.10 (16)	P2—C1—P1—O1	−179.67 (9)
P2—C1—C2—C3	85.46 (19)	O7—C1—P1—O2	−168.62 (11)
P1—C1—C2—C3	−43.6 (2)	C2—C1—P1—O2	71.36 (14)
C1—C2—C3—N1	−159.04 (16)	P2—C1—P1—O2	−55.95 (12)
N1—C4—C5—C6	33.3 (3)	O7—C1—P1—O3	−48.72 (13)
C4—C5—C6—C7	−22.4 (4)	C2—C1—P1—O3	−168.73 (12)
C5—C6—C7—N1	2.7 (3)	P2—C1—P1—O3	63.95 (11)
C5'—C6—C7—N1	−31.4 (6)	O7—C1—P2—O6	−177.27 (10)
C2—C3—N1—C4	−55.2 (2)	C2—C1—P2—O6	−60.44 (14)
C2—C3—N1—C7	−176.07 (17)	P1—C1—P2—O6	67.38 (11)
C5'—C4—N1—C3	−118.8 (6)	O7—C1—P2—O5	59.27 (12)
C5—C4—N1—C3	−155.7 (2)	C2—C1—P2—O5	176.10 (12)
C5'—C4—N1—C7	5.3 (6)	P1—C1—P2—O5	−56.08 (11)
C5—C4—N1—C7	−31.6 (3)	O7—C1—P2—O4	−55.20 (13)
C6—C7—N1—C3	144.2 (2)	C2—C1—P2—O4	61.63 (14)
C6—C7—N1—C4	17.9 (3)	P1—C1—P2—O4	−170.55 (9)
O7—C1—P1—O1	67.66 (13)	N1—C4—C5'—C6	−25.8 (9)
C2—C1—P1—O1	−52.36 (14)	C7—C6—C5'—C4	35.9 (9)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O7—H2···O6^i	0.81 (3)	1.87 (3)	2.668 (2)	167 (3)
O5—H5···O2^ii	0.93 (2)	1.51 (2)	2.436 (2)	170 (3)
O3—H3···O6^ii	0.79 (2)	1.83 (2)	2.610 (2)	171 (3)
O4—H4···O1^iii	0.83 (2)	1.66 (2)	2.487 (2)	175 (3)
N1—H1···O3^iii	0.85 (2)	2.51 (3)	3.268 (2)	150 (2)
N1—H1···O5^iii	0.85 (2)	2.54 (2)	3.141 (2)	129 (2)
N1—H1···O7^iii	0.85 (2)	2.41 (2)	3.011 (2)	129 (2)

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