4-(4-Fluoro­phen­yl)-2-methyl-3-(1-oxy-4-pyridyl)isoxazol-5(2H)-one

Margutti, S.; Schollmeyer, D.; Laufer, S.

doi:10.1107/S1600536807066500

organic compounds

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ISSN: 2056-9890

Volume 64| Part 2| February 2008| Page o504

doi:10.1107/S1600536807066500

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4-(4-Fluorophenyl)-2-methyl-3-(1-oxy-4-pyridyl)isoxazol-5(2H)-one

Simona Margutti,^a Dieter Schollmeyer ^b and Stefan Laufer ^a ^*

^aInstitute of Pharmacy, Department of Pharmaceutical and Medicinal Chemistry, Eberhard-Karls-University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany, and ^bDepartment of Organic Chemistry, Johannes Gutenberg-University Mainz, Duesbergweg 10-14, D-55099 Mainz, Germany
^*Correspondence e-mail: stefan.laufer@uni-tuebingen.de

(Received 6 November 2007; accepted 11 December 2007; online 23 January 2008)

The crystal structure of the title compound, C₁₅H₁₁FN₂O₃, was determined as part of a study on the biological activity of isoxazolone derivatives as p38 mitogen-activated protein kinase (MAPK) inhibitors. The dihedral angles between rings are isoxazole/benzene = 55.0 (3)°, isoxazole/pyridine = 33.8 (2)° and benzene/pyridine = 58.1 (2)°.

Related literature

Isoxazolones as potent inhibitors of p38 MAP kinases were first described by Laughlin et al. (2005 ). For related literature, see: Adams et al. (1998 ); Clark et al. (2002 ); De Laszlo et al. (1998 ); Foster et al. (2000 ); Laufer & Wagner (2002 ); Laufer et al. (2006 ); Ohkawa et al. (2001 ); Revesz et al. (2000 ); Wang et al. (1998 ).

Experimental

Crystal data

C₁₅H₁₁FN₂O₃
M_r = 286.26
Tetragonal, P 4₃ 2₁ 2
a = 10.0828 (6) Å
c = 25.257 (5) Å
V = 2567.6 (6) Å³
Z = 8
Cu Kα radiation
μ = 0.97 mm⁻¹
T = 193 (2) K
0.40 × 0.20 × 0.10 mm

Data collection

Enraf–Nonius CAD-4 diffractometer
Absorption correction: multi-scan (MULABS; Blessing, 1995 ) T_min = 0.60, T_max = 0.88
5114 measured reflections
1488 independent reflections
1129 reflections with I > 2σ(I)
R_int = 0.081
3 standard reflections frequency: 60 min intensity decay: 5%

Refinement

R[F² > 2σ(F²)] = 0.068
wR(F²) = 0.192
S = 1.00
1488 reflections
191 parameters
H-atom parameters constrained
Δρ_max = 0.45 e Å⁻³
Δρ_min = −0.34 e Å⁻³

Data collection: CAD-4 Software (Enraf–Nonius, 1989 ); cell refinement: CAD-4 Software; data reduction: CORINC (Dräger & Gattow, 1971 ); program(s) used to solve structure: SIR92 (Altomare et al., 1994 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997 ); molecular graphics: PLATON (Spek, 2003 ); software used to prepare material for publication: SHELXL97.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536807066500/cf2171sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536807066500/cf2171Isup2.hkl

checkCIF report

Comment top

Compound (II) (Fig. 2) was prepared in the course of our study on isoxazolones derivatives bearing the typical vicinal 4-pyridyl and 4-fluorophenyl pharmacophores of MAP Kinase inhibitors. Isoxazolones are described in the literature as inhibitors for p38 MAP Kinase (Laughlin et al., 2005; Clark et al., 2002).

The prototypical pyridinylimidazole SB 203580 is one of the best studied p38 inhibitors reported until now. Figure 1 shows the most important interactions between the ATP binding sites of p38 kinase and the imidazole inhibitor SB203580 (Wang et al., 1998). The 4-fluorophenyl ring of SB203580 occupies a hydrophobic back pocket, enhancing selectivity. Vicinal to this interaction site, the 4-pyridinyl ring forms a hydrogen bond from the backbone NH group of Met 109 of p38 MAP Kinase (Fig. 1).

However, certain liver toxicities, such as increased liver size and increased cytochrome P450 induction, have been reported (Foster et al., 2000; Adams et al., 1998). In light of this potential toxicity and the risks associated with developing human drugs, a continuing need exists for potent new small-molecule inhibitors of cytokine production with improved pharmacokinetic and safety profiles.

Several research groups have undertaken studies in which the imidazole ring was replaced by other 5- or 6- membered heterocycles (Laufer & Wagner, 2002; De Laszlo et al., 1998; Laufer et al., 2006; Revesz et al., 2000; Ohkawa et al., 2001). Replacement of the core heterocycle represents a strategy to dissect inhibition of p38 from interferences with cytochrome P450 (CYP450).

Accordingly, and based on the research published by Laughlin et al. (2005), we plan to prepare derivatives of isoxazolones in order to obtain more accurate and comparable information about this class of compounds as p38 MAP Kinase inhibitors in terms of biological activity.

The data presented here show the isoxazolone system is almost planar (Fig. 2). It is oriented at a dihedral angle of 55.0 (3)° to the fluorophenyl ring and 33.8 (2)° to the oxy-pyridine system. There are no significant intermolecular interactions.

Related literature top

Isoxazolones as potent inhibitors of p38 MAP kinases were first described by Laughlin et al. (2005). For related literature, see: Adams et al. (1998); Clark et al. (2002); De Laszlo et al. (1998); Foster et al. (2000); Laufer & Wagner (2002); Laufer et al. (2006); Ohkawa et al. (2001); Revesz et al. (2000); Wang et al. (1998).

Experimental top

For the synthesis of 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-N-oxide-propionic acid ethyl ester (see Fig. 3), to a suspension of 10 g (72 mmol) of isonicotinic acid N-oxide in 15 ml of DMF, 19.7 g (121 mmol) of CDI were added. The reaction mixture was stirred at 298 K for 1 h. The limpid solution was then cooled at 273 K and 13.3 g (72 mmol) of (4-fluorophenyl)acetic acid ethyl ester and 4.1 g (168 mmol) of NaH were added. The reaction mixture was stirred at 273 K for 15 min, then the temperature was raised to 298 K and kept under vigorous stirring for 4 h. The reaction mixture was then poured into water/ice, the pH adjusted to 6, and the solution extracted with ethyl acetate. The combined organic layers were then collected, dried over Na₂SO₄ and concentrated under vacuum, affording an oil that was chromatographed over SiO₂ using acetone as eluent, yielding 80% of 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-N-oxide-propionic acid ethyl ester.

For the synthesis of (I), a suspension of 1.0 g (3.3 mmol) of 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-N-oxide-propionic acid ethyl ester and 0.3 g (4.0 mmol) of hydroxylamine hydrochloride in 0.5 ml of H₂O was warmed to 353 K. 3 ml of MeOH were added and the resulting solution refluxed for 4 h. The reaction mixture was then cooled to 298 K and stored at 277 K overnight, whereupon a yellow solid precipitated, yielding 83% of (I).

For the synthesis of (II), a suspension of 0.71 g (2.6 mmol) of (I) in 1 ml of DMF was added to 0.620 ml (4.5 mmol) of Et₃N and refluxed for 2 h. The reaction mixture was then cooled to 298 K, added to 0.231 ml (3.75 mmol) of iodomethane and stirred at 298 K for 2 h. Ethyl acetate was then added and the resulting precipitate separated by filtration and then crystalized from MeOH, yielding 40% of (II).

Computing details top

Data collection: CAD-4 Software (Enraf–Nonius, 1989); cell refinement: CAD-4 Software (Enraf–Nonius, 1989); data reduction: CORINC (Dräger & Gattow, 1971); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: PLATON (Spek, 2003); software used to prepare material for publication: SHELXL97 (Sheldrick, 1997).

Figures top

	Fig. 1. Schematic drawing of important interactions between the prototypical pyridin-4-yl imidazole inhibitor SB 203580 and the ATP binding site of p38.
	Fig. 2. PLATON (Spek, 2003) view of (II). Displacement ellipsoids are drawn at the 50% probability level. H atoms are depicted as circles of arbitrary size.
	Fig. 3. Synthesis of (II).

4-(4-Fluorophenyl)-2-methyl-3-(1-oxy-4-pyridyl)isoxazol-5(2H)-one top

Crystal data top

C₁₅H₁₁FN₂O₃	D_x = 1.481 Mg m⁻³
M_r = 286.26	Cu Kα radiation, λ = 1.54178 Å
Tetragonal, P4₃2₁2	Cell parameters from 25 reflections
Hall symbol: P 4nw 2abw	θ = 20–32°
a = 10.0828 (6) Å	µ = 0.97 mm⁻¹
c = 25.257 (5) Å	T = 193 K
V = 2567.6 (6) Å³	Block, yellow
Z = 8	0.40 × 0.20 × 0.10 mm
F(000) = 1184

Data collection top

Enraf–Nonius CAD-4 diffractometer	1129 reflections with I > 2σ(I)
Radiation source: rotating anode	R_int = 0.081
Graphite monochromator	θ_max = 69.8°, θ_min = 4.7°
θ/2ω scans	h = −12→12
Absorption correction: multi-scan (MULABS; Blessing, 1995)	k = −12→12
T_min = 0.60, T_max = 0.88	l = −23→30
5114 measured reflections	3 standard reflections every 60 min
1488 independent reflections	intensity decay: 5%

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.068	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.192	H-atom parameters constrained
S = 1.00	w = 1/[σ²(F_o²) + (0.149P)²] where P = (F_o² + 2F_c²)/3
1488 reflections	(Δ/σ)_max < 0.001
191 parameters	Δρ_max = 0.45 e Å⁻³
0 restraints	Δρ_min = −0.34 e Å⁻³

Crystal data top

C₁₅H₁₁FN₂O₃	Z = 8
M_r = 286.26	Cu Kα radiation
Tetragonal, P4₃2₁2	µ = 0.97 mm⁻¹
a = 10.0828 (6) Å	T = 193 K
c = 25.257 (5) Å	0.40 × 0.20 × 0.10 mm
V = 2567.6 (6) Å³

Data collection top

Enraf–Nonius CAD-4 diffractometer	1129 reflections with I > 2σ(I)
Absorption correction: multi-scan (MULABS; Blessing, 1995)	R_int = 0.081
T_min = 0.60, T_max = 0.88	3 standard reflections every 60 min
5114 measured reflections	intensity decay: 5%
1488 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.068	0 restraints
wR(F²) = 0.192	H-atom parameters constrained
S = 1.00	Δρ_max = 0.45 e Å⁻³
1488 reflections	Δρ_min = −0.34 e Å⁻³
191 parameters

Special details top

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. Friedel Pairs merged (MERG 3 instruction). 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 (Å²) top

	x	y	z	U_iso*/U_eq
C1	0.4167 (4)	0.0719 (4)	0.3006 (2)	0.0248 (11)
C2	0.3537 (4)	0.1885 (4)	0.2905 (2)	0.0231 (10)
N3	0.2782 (4)	0.1781 (4)	0.24613 (17)	0.0272 (10)
O4	0.2804 (4)	0.0427 (3)	0.23076 (16)	0.0346 (9)
C5	0.3701 (5)	−0.0233 (5)	0.2641 (2)	0.0302 (11)
C6	0.1515 (5)	0.2379 (6)	0.2342 (2)	0.0366 (13)
H6A	0.0806	0.1855	0.2505	0.055*
H6B	0.1387	0.2403	0.1958	0.055*
H6C	0.1493	0.3284	0.2483	0.055*
O7	0.3926 (4)	−0.1402 (4)	0.25595 (18)	0.0409 (10)
C8	0.5231 (4)	0.0446 (4)	0.3400 (2)	0.0262 (11)
C9	0.6393 (5)	0.1185 (5)	0.3410 (2)	0.0290 (11)
H9	0.6499	0.1896	0.3167	0.035*
C10	0.7405 (5)	0.0908 (5)	0.3767 (3)	0.0348 (13)
H10	0.8198	0.1415	0.3774	0.042*
C11	0.7207 (5)	−0.0138 (5)	0.4112 (2)	0.0300 (12)
C12	0.6096 (5)	−0.0891 (5)	0.4118 (2)	0.0315 (12)
H12	0.6000	−0.1598	0.4364	0.038*
C13	0.5100 (5)	−0.0603 (5)	0.3757 (3)	0.0313 (12)
H13	0.4318	−0.1128	0.3752	0.038*
F14	0.8198 (3)	−0.0417 (3)	0.44649 (16)	0.0477 (10)
C15	0.3631 (4)	0.3142 (4)	0.31988 (19)	0.0198 (10)
C16	0.3580 (4)	0.4384 (4)	0.2958 (2)	0.0253 (11)
H16	0.3448	0.4438	0.2586	0.030*
C17	0.3714 (5)	0.5514 (5)	0.3240 (2)	0.0265 (11)
H17	0.3655	0.6347	0.3066	0.032*
N18	0.3934 (4)	0.5467 (4)	0.37729 (18)	0.0253 (9)
C19	0.3954 (5)	0.4264 (5)	0.4021 (2)	0.0270 (11)
H19	0.4076	0.4228	0.4394	0.032*
C20	0.3804 (4)	0.3122 (4)	0.3746 (2)	0.0254 (10)
H20	0.3817	0.2298	0.3929	0.030*
O21	0.4120 (4)	0.6544 (3)	0.40417 (17)	0.0395 (10)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0148 (19)	0.020 (2)	0.039 (3)	0.0011 (17)	0.0004 (19)	0.000 (2)
C2	0.022 (2)	0.021 (2)	0.027 (3)	0.0009 (17)	0.0007 (19)	−0.0004 (19)
N3	0.033 (2)	0.0243 (18)	0.025 (2)	0.0040 (17)	−0.0053 (18)	−0.0087 (17)
O4	0.0338 (19)	0.0286 (17)	0.041 (2)	0.0032 (15)	−0.0063 (17)	−0.0105 (16)
C5	0.025 (2)	0.022 (2)	0.043 (3)	0.0028 (19)	0.004 (2)	−0.004 (2)
C6	0.036 (3)	0.041 (3)	0.033 (3)	0.010 (2)	−0.011 (2)	0.002 (2)
O7	0.040 (2)	0.0289 (18)	0.053 (3)	0.0000 (15)	−0.002 (2)	−0.0161 (18)
C8	0.019 (2)	0.017 (2)	0.042 (3)	0.0062 (17)	−0.002 (2)	−0.005 (2)
C9	0.026 (2)	0.018 (2)	0.042 (3)	0.0040 (17)	−0.002 (2)	−0.002 (2)
C10	0.024 (2)	0.028 (2)	0.053 (4)	0.002 (2)	−0.004 (2)	−0.013 (2)
C11	0.025 (2)	0.024 (2)	0.041 (3)	0.0109 (19)	−0.010 (2)	−0.012 (2)
C12	0.035 (3)	0.023 (2)	0.037 (3)	0.007 (2)	−0.002 (2)	0.001 (2)
C13	0.022 (2)	0.023 (2)	0.048 (3)	0.001 (2)	−0.001 (2)	0.000 (2)
F14	0.0400 (17)	0.0448 (18)	0.058 (2)	0.0099 (15)	−0.0234 (17)	−0.0034 (17)
C15	0.0172 (19)	0.0174 (19)	0.025 (3)	0.0021 (15)	−0.0003 (18)	−0.0017 (18)
C16	0.025 (2)	0.022 (2)	0.028 (3)	0.0062 (18)	0.000 (2)	0.003 (2)
C17	0.029 (2)	0.020 (2)	0.030 (3)	0.0014 (18)	0.003 (2)	0.006 (2)
N18	0.0232 (19)	0.0212 (19)	0.031 (3)	0.0019 (15)	0.0016 (17)	−0.0046 (18)
C19	0.030 (2)	0.025 (2)	0.026 (3)	0.0051 (19)	−0.002 (2)	0.000 (2)
C20	0.025 (2)	0.018 (2)	0.033 (3)	0.0015 (18)	−0.002 (2)	0.0027 (19)
O21	0.049 (2)	0.0213 (17)	0.048 (3)	−0.0046 (15)	−0.0001 (19)	−0.0107 (17)

Geometric parameters (Å, º) top

C1—C2	1.360 (6)	C10—H10	0.950
C1—C5	1.412 (7)	C11—C12	1.354 (7)
C1—C8	1.489 (7)	C11—F14	1.368 (6)
C2—N3	1.359 (6)	C12—C13	1.388 (7)
C2—C15	1.472 (6)	C12—H12	0.950
N3—O4	1.419 (5)	C13—H13	0.950
N3—C6	1.444 (6)	C15—C16	1.393 (6)
O4—C5	1.403 (6)	C15—C20	1.394 (7)
C5—O7	1.218 (6)	C16—C17	1.350 (7)
C6—H6A	0.980	C16—H16	0.950
C6—H6B	0.980	C17—N18	1.364 (7)
C6—H6C	0.980	C17—H17	0.950
C8—C9	1.389 (6)	N18—O21	1.293 (5)
C8—C13	1.395 (7)	N18—C19	1.366 (6)
C9—C10	1.391 (8)	C19—C20	1.352 (7)
C9—H9	0.950	C19—H19	0.950
C10—C11	1.382 (8)	C20—H20	0.950

C2—C1—C5	108.0 (4)	C12—C11—F14	118.8 (5)
C2—C1—C8	128.4 (4)	C12—C11—C10	123.7 (5)
C5—C1—C8	123.5 (4)	F14—C11—C10	117.5 (5)
N3—C2—C1	110.5 (4)	C11—C12—C13	118.3 (5)
N3—C2—C15	121.2 (4)	C11—C12—H12	120.9
C1—C2—C15	128.3 (5)	C13—C12—H12	120.9
C2—N3—O4	106.9 (4)	C12—C13—C8	121.0 (5)
C2—N3—C6	129.5 (4)	C12—C13—H13	119.5
O4—N3—C6	111.0 (4)	C8—C13—H13	119.5
C5—O4—N3	107.6 (4)	C16—C15—C20	116.8 (4)
O7—C5—O4	118.6 (5)	C16—C15—C2	123.5 (4)
O7—C5—C1	134.9 (5)	C20—C15—C2	119.7 (4)
O4—C5—C1	106.5 (4)	C17—C16—C15	121.6 (5)
N3—C6—H6A	109.5	C17—C16—H16	119.2
N3—C6—H6B	109.5	C15—C16—H16	119.2
H6A—C6—H6B	109.5	C16—C17—N18	120.5 (4)
N3—C6—H6C	109.5	C16—C17—H17	119.7
H6A—C6—H6C	109.5	N18—C17—H17	119.7
H6B—C6—H6C	109.5	O21—N18—C17	120.8 (4)
C9—C8—C13	118.4 (5)	O21—N18—C19	120.2 (4)
C9—C8—C1	121.4 (5)	C17—N18—C19	119.0 (4)
C13—C8—C1	120.2 (4)	C20—C19—N18	121.3 (5)
C8—C9—C10	121.5 (5)	C20—C19—H19	119.4
C8—C9—H9	119.2	N18—C19—H19	119.4
C10—C9—H9	119.2	C19—C20—C15	120.7 (4)
C11—C10—C9	117.2 (5)	C19—C20—H20	119.6
C11—C10—H10	121.4	C15—C20—H20	119.6
C9—C10—H10	121.4

C5—C1—C2—N3	−5.8 (6)	C8—C9—C10—C11	0.2 (8)
C8—C1—C2—N3	170.2 (5)	C9—C10—C11—C12	0.0 (8)
C5—C1—C2—C15	176.1 (4)	C9—C10—C11—F14	180.0 (4)
C8—C1—C2—C15	−7.9 (8)	F14—C11—C12—C13	−179.7 (5)
C1—C2—N3—O4	7.4 (5)	C10—C11—C12—C13	0.3 (8)
C15—C2—N3—O4	−174.4 (4)	C11—C12—C13—C8	−0.9 (8)
C1—C2—N3—C6	144.7 (5)	C9—C8—C13—C12	1.1 (8)
C15—C2—N3—C6	−37.1 (7)	C1—C8—C13—C12	178.5 (5)
C2—N3—O4—C5	−6.0 (5)	N3—C2—C15—C16	−33.2 (7)
C6—N3—O4—C5	−151.9 (4)	C1—C2—C15—C16	144.7 (5)
N3—O4—C5—O7	−176.3 (5)	N3—C2—C15—C20	148.1 (5)
N3—O4—C5—C1	2.5 (5)	C1—C2—C15—C20	−34.1 (7)
C2—C1—C5—O7	−179.6 (6)	C20—C15—C16—C17	1.0 (6)
C8—C1—C5—O7	4.1 (10)	C2—C15—C16—C17	−177.8 (5)
C2—C1—C5—O4	1.9 (6)	C15—C16—C17—N18	1.5 (7)
C8—C1—C5—O4	−174.4 (4)	C16—C17—N18—O21	177.0 (4)
C2—C1—C8—C9	−54.3 (8)	C16—C17—N18—C19	−3.1 (7)
C5—C1—C8—C9	121.2 (5)	O21—N18—C19—C20	−177.9 (4)
C2—C1—C8—C13	128.4 (6)	C17—N18—C19—C20	2.2 (7)
C5—C1—C8—C13	−56.1 (7)	N18—C19—C20—C15	0.3 (7)
C13—C8—C9—C10	−0.7 (8)	C16—C15—C20—C19	−1.9 (7)
C1—C8—C9—C10	−178.1 (5)	C2—C15—C20—C19	176.9 (4)

Experimental details

Crystal data
Chemical formula	C₁₅H₁₁FN₂O₃
M_r	286.26
Crystal system, space group	Tetragonal, P4₃2₁2
Temperature (K)	193
a, c (Å)	10.0828 (6), 25.257 (5)
V (Å³)	2567.6 (6)
Z	8
Radiation type	Cu Kα
µ (mm⁻¹)	0.97
Crystal size (mm)	0.40 × 0.20 × 0.10

Data collection
Diffractometer	Enraf–Nonius CAD-4 diffractometer
Absorption correction	Multi-scan (MULABS; Blessing, 1995)
T_min, T_max	0.60, 0.88
No. of measured, independent and observed [I > 2σ(I)] reflections	5114, 1488, 1129
R_int	0.081
(sin θ/λ)_max (Å⁻¹)	0.609

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.068, 0.192, 1.00
No. of reflections	1488
No. of parameters	191
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.45, −0.34

Computer programs: CAD-4 Software (Enraf–Nonius, 1989), CORINC (Dräger & Gattow, 1971), SIR92 (Altomare et al., 1994), SHELXL97 (Sheldrick, 1997), PLATON (Spek, 2003).

Acknowledgements

The authors thank the EU–Craft Program, Project Macrocept (FP6) for funding.

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