[(5-Bromo­pyridinium-2-ylamino)(phosphono)meth­yl]phospho­nate

The title compound, C₆H₉BrN₂O₆P₂, a micromolar inhibitor of the farnesyl pyrophosphate synthase, is a Z-isomer zwitterion with one negative phospho­nate group and a protonated pyridine N atom. Two types of ribbons, both parallel to the a axis, formed by several centrosymmetrically related O—H...O and N—H...O hydrogen bonds are generated in the crystal structure. The resulting two-dimensional (001) `double-layered' networks are joined into a three-dimensional network via inversion-related halogen–oxygen inter­actions.

S1. Comment

Nitrogen-containing bisphosphonates are a subject of considerable interest because they have a wide range of potential applications, ranging from agriculture to medicine. It was only recently found that their mode of action in humans, parasites and plants relies on inhibition of the same enzyme of the mevalonate/isoprenoid pathway, namely the farnesyl pyrophosphate synthase (FPPS) (van Beek et al., 1999; Martin et al., 1999; Cheng & Oldfield, 2004; Sanders et al., 2005; Ling et al., 2005; Cromartie et al., 1999).

The title compound, (I), is a member of the N-(2-pyridyl)aminomethane-1,1-diphosphonic acid family. These compounds, first developed by Nissan as herbicides (Suzuki et al., 1979), have recently been shown to rank among highly active inhibitors of FPPS (Ghosh et al., 2004; Sanders et al., 2003). Spectroscopic and X-ray studies have revealed an interesting relationship between the topology of a substituent on the pyridyl ring and conformational preferrences of this subclass of acids (Matczak-Jon et al., 2001, 2006; Matczak-Jon, 2005; Szabo et al., 2002; Sanders et al., 2003). The placement of the substituent at the 4- or 5-position of the ring results in the predominance of the Z over the E geometrical isomer in solution, which affords the predominant form to crystallize in the solid state. By way of contrast, the 3-pyridyl-substituted compounds prefer the opposite E geometry in both solution and solid state (Matczak-Jon et al., 2001; Szabo et al., 2002).

We report here the results of our single-crystal X-ray study of (I), and compare the results with those previously obtained for the N-(5-methyl-2-pyridyl) [Cambridge Structural Database (CSD; Allen, 2002) refcode QURYEH (Matczak-Jon et al., 2001)] and N-(5-chloro-2-pyridyl) (Sanders et al., 2003; CSD Refcode BEKCAW) derivatives, which unlike (I) contain two instead of one crystallographically independent zwitterions in the asymmetric unit.

Compound (I) is a zwitterion with one of the phosphonic group deprotonated and the pyridyl N2 atom protonated (Fig. 1), which is common for this subclass of acids (Matczak-Jon et al., 2001, 2006; Sanders et al., 2003; Szabo et al., 2002). Atoms N1 and C1 are both coplanar with the pyridyl ring, as a result of the formal sp²-hybridization of atom N1. This results in a partial double-bond character of the C2—N1 linkage, which is reflected in its length compared with the value for C1—N1, which is typical for a single C—N bond (Table 1). The C1—N1—C2—N2 torsion angle indicates that atom C1 is only slightly displaced from the pyridyl ring plane [the distance of atom C1 from that plane is 0.09 (2) Å]. As expected, (I) adopts the same Z geometry as the related 5-methyl and 5-chloro derivatives. This is reflected in the C1—N1—C2—C3 torsion angle value (see Table 1), which can be compared with 3.7 (12) and 5.9 (12)°, and 6.5 (11) and 13.4 (11)°, respectively, in the two crystallographically independent molecules of the 5-methyl- and 5-chloro-substituted compounds.

The geometry of the diphosphonate fragment is similar to that observed previously (Matczak-Jon et al., 2001, 2006). The O1—P1—C1—P2—O5 sequence with one protonated and one deprotonated O atom reveals a typical almost planar W conformation. Accordingly, every P atom is oriented antiperiplanar (ap) to one of the O atoms from the adjacent phosphonic/phosphonate group and sc to the remaining O atoms from that group. The orientation of the diphosphonate group in relation to the rest of the molecule is additionally stabilized by an intramolecular N1—H2···O3 hydrogen bond. The formation of such an intramolecular hydrogen bond, observed also in the Z-isomeric 4-methyl derivative (Matczak-Jon et al., 2006) and the E-isomeric 3-methyl (Szabo et al., 2002) and 3-carboxy derivatives (Matczak-Jon et al., 2001), is a common feature of most of the aminomethane-1,1-diphosphonic acids studied to date (Matczak-Jon et al., 2005). As shown by the values of the C2—N1—C1—P1 and C2—N1—C1—P2 torsion angles, both P atoms have an ac orientation with respect to the pyridyl C2 atom.

The geometry of both the phosphonic (PO₃H₂) and the phosphonate (PO₃H⁻) groups deviates significantly from an ideal tetrahedron (Table 1). This deviation is reflected in the values of the phosphonate O1—P1—O2 angles, in which the unprotonated O atoms are involved, but also in the phosphonic O4—P2—O6 angles, involving the formal double P=O bond. This is consistent with what was previously observed for other members of this class of compounds (Matczak-Jon et al., 2001; Szabo et al., 2002; Sanders et al., 2003; Matczak-Jon & Videnova-Adrabińska, 2005; Matczak-Jon et al., 2006).

The crystal packing in (I) is determined mainly by hydrogen bonds involving phosphonic (PO₃H₂) and phosphonate (PO₃H⁻) groups, which is a common feature of all the related compounds. The W conformation of the O1—P1—C1—P2—O5 sequence enables atoms O5 and O1 from adjacent molecules to participate in strong O5—H5···O1ⁱⁱ hydrogen bonds (the geometry and symmetry codes are listed in Table 2). Such direct a-axis translation generates infinite chains of zwitterions, marked in Fig. 2a with solid and open lines, which is a common structural phenomenon for the N-(5-methyl-2-pyridyl)-, (Matczak-Jon et al., 2001), N-(5-chloro-2-pyridyl)- (Sanders et al., 2003), N-(4-methyl-2-pyridyl)- and non-substituted N-(2-pyridyl)aminomethane-1,1-diphosphonic acid (Matczak-Jon et al., 2006), but not for the 3-methyl and 3-carboxyl derivatives and the sodium salt of the 5-chloro-substituted compound (Sanders et al., 2003).

The head-to-head arrangement of the molecules in adjacent chains enables the diphosphonate and diphosphonic groups to interact with each other to form ribbons (Fig. 2). Two different types of ribbons, both parallel to the a axis, can be distinguished in the crystal of (1). Every zwitterion from one chain interacts with two others from the adjacent chain via several different hydrogen bonds. The centrosymmetric O3—H3···O1ⁱ contact with one zwitterion generates an R₂²(8) ring motif. Additional R₂²(10) and R₂¹(6) rings are formed along the ribbon by bifurcated centrosymmetric N1—H2···O4^iv and N2—H4···O4^iv contacts to the same O4 atom of another zwitterion. All these interactions give rise to ribbons (Fig. 2a), which are also observed in N-(4-methyl-2-pyridyl)aminomethane-1,1-diphosphonic acid (Matczak-Jon et al., 2006). On the other hand, pairs of zwitterions from adjacent chains are linked to each other by strong phosphonic–phosphonate O6—H6···O2ⁱⁱⁱ hydrogen bonds. These, in combination with the O5—H5···O1ⁱⁱ chain–forming interactions, give rise to R₂²(12) and R₄⁴(16) rings and another type of ribbons, shown in Fig. 2(b). The arrangement of the molecules within these ribbons is almost identical to that observed in N-(2-pyridyl)aminomethane-1,1-diphosphonic acid (Matczak-Jon et al., 2006).

As a result, a two-dimensional (001) `double-layered' network is formed, which, in turn, interacts with the others via short halogen–oxygen interactions about inversion centres, with Br···O distances of 2.967 (2) Å and angular parameters consistent with the values ususally observed for the halogen bonds (see Fig. 3). This gives rise to a three-dimensional network of zwitterions in the crystal structure of (I). It is worth noting that similar, but much weaker, halogen–oxygen interactions were also observed in the 5-chloro analogue, in which one of the two crystallographically independent zwitterions exhibited a Cl···O distance of about 3.17 Å (Sanders et al., 2003).

S2. Experimental

Compound (I) was synthesized according to previously described procedures (Sołoducho et al., 1997). Crystals of (I) were obtained by recrystallization by slow evaporation of an aqueous solution at room temperature. NMR (D₂O, pH = 4.8); ¹H NMR (p.p.m.): δH(1) 4.08 (³J_PH = 19.2 Hz), δH(31) 6.88, δH(41) 7.48, δH(61) 7.86; ¹³C NMR (p.p.m.): δC(1) 51.39 (³J_PC = 129.0 Hz), δC(2) 152.78 (³J_PC = 4.0 Hz), δC(3) 105.46, δC(4) 137.72, δC(5) 114.11, δC(6) 144.91; ³¹P NMR (p.p.m.): δP 12.89.

S3. Refinement

All H atoms were found in difference Fourier maps. In the final refinement cycles, the H atoms were treated as riding atoms, with O—H distances of 0.84 Å, N—H distances of 0.88 Å, and C—H distances of 0.95 or 1.00 Å, and with U_iso(H) values of 1.5U_eq(O) and 1.2U_eq(N,C).

Computing details

Data collection: CrysAlis CCD (Oxford Diffraction, 2003); cell refinement: CrysAlis RED (Oxford Diffraction, 2003); data reduction: CrysAlis RED; program(s) used to solve structure: SHELXS97 (Sheldrick, 1997); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: XP (Bruker, 1997); software used to prepare material for publication: SHELXL97.

Figures

	Fig. 1. The molecular structure of (1) showing the atom numbering scheme and the intramolecular N—H···O hydrogen bond. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. The arrangement of the zwitterions in (I) within two types of ribbons (both along the a axis) formed by adjacent chains interacting with each other via centrosymmetric O3—H3···O1^i, N1—H2···O4^iv and N2—H4···O4^iv (a) or O6—H6···O2^iii (b) hydrogen bonds. The two chains formed by O5—H5···O1^ii bonds are marked with solid and open lines. The stabilizing N1—H2···O3 interactions are also shown. Symmetry codes are given in Table 2.
	Fig. 3. Adjacent chains from two different ribbons joined by Br···O1^vii interactions (dashed lines) [Br···O1^vii = 2.967 (2) Å, C5—Br···O1^vii = 165.6 (1)°, Br···O1^vii—P1^vii = 126.8 (1)°; symmetry code: (vii) 2 − x, 2 − y, 2 − z].

[(5-Bromopyridinium-2-ylamino)(phosphono)methyl]phosphonate

Crystal data

C6H9BrN2O6P2	Z = 2
Mr = 347.00	F(000) = 344
Triclinic, P1	Dx = 2.017 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 7.224 (2) Å	Cell parameters from 8247 reflections
b = 8.701 (2) Å	θ = 4.9–38.7°
c = 10.382 (3) Å	µ = 3.90 mm^−1
α = 103.51 (3)°	T = 100 K
β = 98.97 (3)°	Plate, colourless
γ = 110.98 (3)°	0.16 × 0.06 × 0.02 mm
V = 571.5 (3) Å^3

Data collection

Xcalibur PX κ-geometry diffractometer with Onyx CCD detector	3016 independent reflections
Radiation source: fine-focus sealed tube	2575 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.037
ω and ϕ scans	θmax = 29.0°, θmin = 4.9°
Absorption correction: analytical CrysAlis RED (Oxford Diffraction, 2003)	h = −7→9
Tmin = 0.643, Tmax = 0.940	k = −11→11
9823 measured reflections	l = −14→14

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)] = 0.034	Hydrogen site location: inferred from neighbouring sites
wR(F^2) = 0.071	H-atom parameters constrained
S = 1.08	w = 1/[σ^2(Fo^2) + (0.0331P)^2] where P = (Fo^2 + 2Fc^2)/3
3016 reflections	(Δ/σ)max = 0.001
157 parameters	Δρmax = 0.91 e Å^−3
0 restraints	Δρmin = −0.45 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
Br	0.80710 (4)	1.23483 (3)	1.10652 (3)	0.01524 (9)
P1	0.79803 (9)	0.32576 (8)	0.58864 (7)	0.00820 (14)
P2	0.37407 (10)	0.26104 (8)	0.64555 (6)	0.00785 (14)
O1	1.0233 (2)	0.4438 (2)	0.6554 (2)	0.0101 (4)
O2	0.7361 (3)	0.1372 (2)	0.5695 (2)	0.0124 (4)
O3	0.7234 (3)	0.3579 (2)	0.4508 (2)	0.0117 (4)
O4	0.2803 (3)	0.2541 (2)	0.5050 (2)	0.0109 (4)
O5	0.2907 (3)	0.3467 (2)	0.7589 (2)	0.0108 (4)
O6	0.3512 (3)	0.0848 (2)	0.6633 (2)	0.0115 (4)
N1	0.6723 (3)	0.5730 (3)	0.6884 (2)	0.0089 (4)
N2	0.7141 (3)	0.8550 (3)	0.7542 (2)	0.0101 (4)
C1	0.6488 (4)	0.4027 (3)	0.6966 (3)	0.0088 (5)
C2	0.6930 (4)	0.7105 (3)	0.7895 (3)	0.0091 (5)
C3	0.6981 (4)	0.7204 (3)	0.9276 (3)	0.0107 (5)
C4	0.7312 (4)	0.8748 (3)	1.0210 (3)	0.0112 (5)
C5	0.7535 (4)	1.0202 (3)	0.9779 (3)	0.0115 (5)
C6	0.7426 (4)	1.0074 (3)	0.8436 (3)	0.0116 (5)
H3	0.8252	0.4222	0.4307	0.018*
H5	0.1993	0.3733	0.7223	0.016*
H6	0.3237	0.0122	0.5860	0.017*
H2	0.6730	0.5873	0.6073	0.011*
H4	0.7088	0.8495	0.6679	0.012*
H1	0.7073	0.4141	0.7940	0.011*
H31	0.6788	0.6208	0.9559	0.013*
H41	0.7390	0.8830	1.1147	0.013*
H61	0.7549	1.1044	0.8129	0.014*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Br	0.01399 (14)	0.01174 (14)	0.01510 (14)	0.00522 (11)	0.00273 (10)	−0.00366 (10)
P1	0.0086 (3)	0.0075 (3)	0.0087 (3)	0.0037 (3)	0.0030 (2)	0.0018 (3)
P2	0.0093 (3)	0.0080 (3)	0.0069 (3)	0.0039 (3)	0.0031 (2)	0.0022 (2)
O1	0.0085 (8)	0.0093 (9)	0.0117 (9)	0.0039 (7)	0.0026 (7)	0.0019 (7)
O2	0.0154 (9)	0.0074 (9)	0.0133 (9)	0.0043 (8)	0.0052 (8)	0.0012 (7)
O3	0.0101 (8)	0.0152 (10)	0.0094 (9)	0.0037 (8)	0.0034 (7)	0.0047 (8)
O4	0.0132 (8)	0.0108 (9)	0.0085 (9)	0.0052 (8)	0.0027 (7)	0.0026 (7)
O5	0.0121 (8)	0.0147 (9)	0.0086 (9)	0.0084 (8)	0.0038 (7)	0.0038 (7)
O6	0.0165 (9)	0.0080 (9)	0.0090 (9)	0.0047 (8)	0.0045 (8)	0.0009 (7)
N1	0.0138 (10)	0.0074 (10)	0.0071 (10)	0.0054 (9)	0.0043 (8)	0.0025 (8)
N2	0.0140 (10)	0.0102 (11)	0.0073 (10)	0.0068 (9)	0.0031 (8)	0.0018 (8)
C1	0.0105 (11)	0.0095 (12)	0.0086 (12)	0.0065 (10)	0.0025 (10)	0.0026 (10)
C2	0.0073 (11)	0.0083 (12)	0.0114 (12)	0.0035 (10)	0.0018 (10)	0.0024 (10)
C3	0.0123 (12)	0.0117 (13)	0.0100 (12)	0.0057 (10)	0.0044 (10)	0.0044 (10)
C4	0.0078 (11)	0.0168 (14)	0.0083 (12)	0.0047 (11)	0.0022 (10)	0.0030 (10)
C5	0.0092 (11)	0.0093 (12)	0.0109 (12)	0.0030 (10)	0.0012 (10)	−0.0035 (10)
C6	0.0114 (11)	0.0084 (12)	0.0145 (13)	0.0046 (10)	0.0021 (10)	0.0030 (10)

Geometric parameters (Å, º)

Br—C5	1.891 (3)	O3—H3	0.840
P1—O1	1.517 (2)	O5—H5	0.840
P1—O2	1.492 (2)	O6—H6	0.840
P1—O3	1.572 (2)	N1—H2	0.880
P1—C1	1.847 (3)	N2—H4	0.880
P2—O4	1.488 (2)	C1—H1	1.000
P2—O5	1.561 (2)	C2—C3	1.410 (4)
P2—O6	1.541 (2)	C3—C4	1.376 (4)
P2—C1	1.832 (3)	C3—H31	0.950
N1—C1	1.454 (3)	C4—C5	1.402 (4)
N1—C2	1.338 (3)	C4—H41	0.950
N2—C2	1.355 (3)	C5—C6	1.361 (4)
N2—C6	1.353 (3)	C6—H61	0.950
O1—P1—O2	116.76 (11)	C6—N2—C2	124.0 (2)
O1—P1—O3	110.28 (10)	C6—N2—H4	118.0
O2—P1—O3	111.44 (11)	C2—N2—H4	118.0
O1—P1—C1	107.20 (11)	N1—C1—H1	108.7
O2—P1—C1	108.16 (11)	P2—C1—H1	108.7
O3—P1—C1	101.82 (11)	P1—C1—H1	108.7
O4—P2—O5	113.59 (10)	N1—C2—N2	115.8 (2)
O4—P2—O6	115.26 (11)	N1—C2—C3	126.8 (2)
O5—P2—O6	106.33 (10)	N2—C2—C3	117.4 (2)
O4—P2—C1	109.63 (11)	C4—C3—C2	119.7 (2)
O5—P2—C1	103.39 (11)	C4—C3—H31	120.1
O6—P2—C1	107.84 (11)	C2—C3—H31	120.1
C1—N1—C2	127.7 (2)	C3—C4—C5	120.0 (2)
P1—C1—P2	114.1 (2)	C3—C4—H41	120.0
P1—C1—N1	107.9 (2)	C5—C4—H41	120.0
P2—C1—N1	108.5 (2)	C6—C5—C4	119.6 (2)
P1—O3—H3	109.5	C6—C5—Br	120.0 (2)
P2—O5—H5	109.5	C4—C5—Br	120.3 (2)
P2—O6—H6	109.5	N2—C6—C5	119.3 (2)
C2—N1—H2	116.1	N2—C6—H61	120.4
C1—N1—H2	116.1	C5—C6—H61	120.4
O1—P1—C1—P2	−172.8 (2)	C1—N1—C2—N2	179.5 (2)
O2—P1—C1—P2	−46.1 (2)	C1—N1—C2—C3	0.5 (4)
O3—P1—C1—P2	71.4 (2)	C6—N2—C2—N1	−178.0 (2)
O4—P2—C1—P1	−63.1 (2)	C6—N2—C2—C3	1.1 (4)
O5—P2—C1—P1	175.5 (2)	N1—C2—C3—C4	176.6 (2)
O6—P2—C1—P1	63.1 (2)	N2—C2—C3—C4	−2.4 (4)
O1—P1—C1—N1	66.6 (2)	C2—C3—C4—C5	1.9 (4)
O2—P1—C1—N1	−166.7 (2)	C3—C4—C5—C6	−0.1 (4)
O3—P1—C1—N1	−49.2 (2)	C3—C4—C5—Br	−178.1 (2)
O4—P2—C1—N1	57.2 (2)	C2—N2—C6—C5	0.7 (4)
O5—P2—C1—N1	−64.2 (2)	C4—C5—C6—N2	−1.2 (4)
O6—P2—C1—N1	−176.6 (2)	Br—C5—C6—N2	176.8 (2)
C2—N1—C1—P1	−141.2 (2)	H2—N1—C2—N2	−0.5
C2—N1—C1—P2	94.7 (3)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
O3—H3···O1^i	0.84	1.80	2.607 (3)	161
O5—H5···O1^ii	0.84	1.72	2.559 (2)	176
O6—H6···O2^iii	0.84	1.70	2.538 (3)	179
N1—H2···O3	0.88	2.44	2.888 (3)	112
N1—H2···O4^iv	0.88	1.98	2.769 (3)	149
N2—H4···O4^iv	0.88	1.84	2.648 (3)	152
C4—H41···O6^v	0.95	2.47	3.382 (3)	160
C4—H41···O5^v	0.95	2.60	3.303 (3)	131
C6—H61···O2^vi	0.95	2.60	3.298 (3)	131

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