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Crystal structure of (3S*,4R*)-4-fluoro-3-(4-meth­­oxy­phen­yl)-1-oxo-2-phenyl-1,2,3,4-tetra­hydro­iso­quinoline-4-carb­­oxy­lic acid

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aInstitute of Pharmacy and Food Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany, and bInstitute of Inorganic Chemistry, University of Wuerzburg, Am Hubland, 97074 Wuerzburg, Germany
*Correspondence e-mail: ulrike.holzgrabe@uni-wuerzburg.de

Edited by H. Stoeckli-Evans, University of Neuchâtel, Switzerland (Received 25 April 2017; accepted 15 May 2017; online 23 May 2017)

The title compound, C23H18FNO4, crystallized as a racemate. It exhibits a cis conformation with respect to the F atom and the methine H atom. The piperidine ring has a screw-boat conformation. The meth­oxy­phenyl ring and the phenyl ring are inclined to the mean plane of the iso­quinoline ring system by 89.85 (4) and 46.62 (5)°, respectively, and by 78.15 (5)° to one another. In the crystal, mol­ecules are linked by an O—H⋯O hydrogen bond forming chains propagating along the a-axis direction. The chains are linked by C—H⋯F hydrogen bonds, forming layers lying parallel to the ab plane.

1. Chemical context

Several decades ago, Cushman et al. (1977[Cushman, M., Gentry, J. & Dekow, F. W. (1977). J. Org. Chem. 42, 1111-1116.]) described a general synthesis of 4-carb­oxy-3,4-di­hydro­isoquinolin-1(2H)-ones by a condensation reaction of various aldimines with homophthalic anhydride. In most cases, a mixture of trans and cis diastereomers was obtained. As the trans isomer is the thermodynamically more stable product, it was possible to epimerize the cis compound completely to the more stable isoform. Accordingly, Haimova et al. (1977[Haimova, M. A., Mollov, N. M., Ivanova, S. C., Dimitrova, A. I. & Ognyanov, V. I. (1977). Tetrahedron, 33, 331-336.]) reported the isolation of the pure thermodynamic product after the treatment of the reaction mixture with 10% NaOH solution.

Combined synthesis conditions resulted in isolation of stereopure trans compound (±) 3 (Fig. 1[link]). First of all, the imine derivative 1 was synthesized by condensation of 4-meth­oxy­benzaldehyde and aniline. Conversion of homophthalic anhydride 2 with 1 in conc. HOAc gave a diastereomeric cis/trans mixture, which was completely converted to the pure trans enanti­omers by treatment with 8 M NaOH solution. The cis/trans isomers can be differentiated by the proton-coupling constants JAB between H-3 and H-4, being JAB 1.5 Hz for the trans compounds and JAB 6.0 Hz for the cis isomers.

[Figure 1]
Figure 1
Synthesis scheme to obtain the trans-isomer (±) 3. Reagents and conditions: (a) EtOH, r.t., 3 h; (b) homophthalic anhydride (2), conc. HOAc, 393 K, 5 h; EtOH, 8 M NaOH, r.t., 24 h.

To prevent epimerization during subsequent synthesis steps, e.g. an amide formation, the isosteric substitution of the acidic proton H-4 by a fluorine atom was investigated (Fig. 2[link]). First, the carb­oxy­lic acid (±) 3 was protected by tert-butyl ester to obtain the ester (±) 4 (Takeda et al., 1994[Takeda, K., Akiyama, A., Nakamura, H., Takizawa, S., Mizuno, Y., Takayanagi, H. & Harigaya, Y. (1994). Synthesis, pp. 1063-1066.]). Fluorination to (±) 5 was achieved by deprotonation with lithiumbis(tri­methyl­sil­yl)amide (LiHMDS) and addition of N-fluoro­benzene­sulfonimide (NFSI) (Differding & Ofner, 1991[Differding, E. & Ofner, H. (1991). Synlett, pp. 187-189.]; Davis et al., 1995[Davis, F. A., Han, W. & Murphy, C. K. (1995). J. Org. Chem. 60, 4730-4737.]). Finally, the fluorinated product was deprotected using mild conditions (Li et al., 2006[Li, B., Berliner, M., Buzon, R., Chiu, C. K., Colgan, S. T., Kaneko, T., Keene, N., Kissel, W., Le, T., Leeman, K. R., Marquez, B., Morris, R., Newell, L., Wunderwald, S., Witt, M., Weaver, J., Zhang, Z. & Zhang, Z. (2006). J. Org. Chem. 71, 9045-9050.]) to obtain the pure diastereomer (±) 6.

[Scheme 1]
[Figure 2]
Figure 2
Synthesis scheme to obtain the fluorinated cis-enanti­omers (±) 6. Reagents and conditions: (a) absolute THF, DMAP, di-tert-butyl dicarbonate, r.t., 24 h; (b) absolute THF, LiHMDS, NFSI, 201 K–r.t., 42 h; (c) CH3CN, 85% (w/w) H3PO4, 323 K, 4 d.

2. Structural commentary

Compound (±) 6 exhibits a cis-conformation with respect to the fluorine atom F12 and the H atom H10, as shown in Fig. 3[link]. The piperidine ring (N1/C2/C3/C8–C10) has a screw-boat conformation [puckering amplitude Q = 0.3812 (11) Å, θ = 64.50 (17)°, φ = 279.15 (18)°]. The meth­oxy­phenyl ring (C16–C21) and the phenyl ring (C24–C29) are inclined to the mean plane of the iso­quinoline ring system (N1/C1–C10) by 89.85 (4) and 46.62 (5)°, respectively, and by 78.15 (5)° to one another.

[Figure 3]
Figure 3
The mol­ecular structure of compound (±) 6, with atom labelling and 50% probability displacement ellipsoids.

3. Supra­molecular features

In the crystal, mol­ecules are linked by an O—H⋯O hydrogen bond, between the carb­oxy­lic OH group (OH14) and amide oxygen atom (O11), forming chains propagating along the a-axis direction (Fig. 4[link] and Table 1[link]). The chains are linked by C—H⋯F hydrogen bonds, forming layers parallel to the ab plane (Fig. 4[link] and Table 1[link]). Individual chains are homo-chiral, with adjacent molecules related by translation only. It is interesting that carboxylate inversion dimers are not observed. It is supposed that the formation of such dimers is hindered by the quite strong F⋯ H interactions, causing a fixed arrangement between the chain layers.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
O14—H14⋯O11i 0.84 1.75 2.5645 (11) 163
C23—H23C⋯F12ii 0.98 2.50 3.2435 (14) 133
Symmetry codes: (i) x+1, y, z; (ii) [-x+1, y+{\script{1\over 2}}, -z+{\script{3\over 2}}].
[Figure 4]
Figure 4
A view along the c axis of the crystal packing of compound (±) 6, with hydrogen bonds drawn as dashed lines (see Table 1[link]). For clarity, only H atoms H14 and H23C (grey balls) have been included.

4. Synthesis and crystallization

The synthesis of the title compound, (±) 6, is outlined in Figs. 1[link] and 2[link].

1-(4-Meth­oxy­phen­yl)-N-phenyl­methanimine (1): Synthesized according to the procedure reported by Torregrosa et al. (2005[Torregrosa, R., Pastor, I. M. & Yus, M. (2005). Tetrahedron, 61, 11148-11155.]). The imine was prepared by condensation of 4-meth­oxy­benzaldehyde (5.00 g, 36.7 mmol) and aniline (3.40 ml, 36.7 mmol) in EtOH (20 ml) at room temperature to obtain colourless crystals (yield 7.20 g, 34.0 mmol, 92%). The NMR spectra and melting point corresponds to reported data (Torregrosa et al., 2005[Torregrosa, R., Pastor, I. M. & Yus, M. (2005). Tetrahedron, 61, 11148-11155.]).

trans-3-(4-Meth­oxy­phen­yl)-1-oxo-2-phenyl-1,2,3,4-tetra­hydro­iso­quinoline-4-carb­oxy­lic acid, (±) 3: Synthesized according to the procedure reported by Guy et al. (2013[Guy, R. K., Zhu, F., Clark, J. A., Guiguemde, W. A., Floyd, D., Knapp, S., Stein, P. & Castro, S. (2013). PCT/IB2012/054305.]). Homophthalic anhydride (3.50 g, 21.5 mmol) was dissolved in conc. HOAc, 1 (6.00 g, 28.4 mmol) was added and the reaction mixture stirred for 4 h at 393 K. Afterwards, the mixture was adjusted to neutral pH value with NaOH solution and extracted with CHCl3, the organic phase dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel chromatography (CHCl3/EtOH/FA 10/0.3/0.1) to isolate mixture of cis/trans-diastereomers. The solid was dissolved in EtOH (10 ml), 8 M NaOH solution (2.30 ml) was added and the reaction mixture stirred for 24 h at room temperature. After adjusting the pH value to acidic conditions, the mixture was extracted with CHCl3, dried over Na2SO4 and concentrated in vacuo to obtain a racemic mixture of trans-enanti­omers as a colourless amorphous solid (yield 6.50 g, 17.3 mmol, 77%; m.p. 443–444 K). 1H NMR (CDCl3, 400 MHz): δ 8.27–8.22 (m, 1H), 7.49–7.44 (m, 2H), 7.27–7.16 (m, 6H), 7.05–7.01 (m, 2H), 6.75–6.72 (m, 2H), 5.52 (s, 1H), 3.97 (d, J = 1.4 Hz, 1H), 3.72 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 174.5, 163.7, 159.4, 142.2, 132.7, 132.2, 130.9, 129.6, 129.5, 129.1, 128.8, 128.6, 127.7 (2C), 127.3, 126.9, 114.3 (2C), 64.4, 55.3, 51.6. IR 1723, 1602, 1510, 1491, 1462, 1247, 1172, 1027, 828, 730, 693, 628 cm−1. ESI–MS: m/z 374.2 [M + H+].

tert-Butyl-trans-3-(4-meth­oxy­phen­yl)-1-οxo-2-phenyl-1,2,3,4-tetra­hydro­iso­quinoline-4-carboxyl­ate, (±) 4: 2.50 g of 3 (6.70 mmol) were dissolved in abs. THF (70 ml). After the addition of di-tert-butyl­dicarbonate (1.40 ml, 6.00 mmol) and DMAP (81.5 mg, 0.70 mmol) the reaction mixture stirred for 24 h at room temperature. Afterwards the reaction was quenched with water (100 ml), extracted with CHCl3, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by MPLC (petroleum ether/EtOAc 1/0 to 0/1) to isolate 4 as a colourless amorphous solid (yield 1.60 g, 3.70 mmol, 55%; m.p. 421–422 K). 1H NMR (CDCl3, 400 MHz): δ 8.25–8.21 (m, 1H), 7.45–7.41 (m, 2H), 7.33–7.32 (m, 4H), 7.24–7.19 (m, 1H), 7.17–7.15 (m, 1H), 7.08–7.05 (m, 2H), 6.75–6.71 (m, 2H), 5.54 (d, J = 1.4 Hz, 1H), 3.89 (d, J = 1.7 Hz, 1H), 3.71 (s, 3H), 1.38 (s, 9H). 13C NMR (CDCl3, 100 MHz): δ 169.9, 163.5, 159.2, 142.6, 133.4, 132.3, 131.6, 129.6, 129.4, 129.0, 128.4, 128.3, 127.7 (2C), 126.9, 126.6, 114.2 (2C), 82.5, 64.7, 55.3, 53.2, 28.0. IR 2975, 1730, 1661, 1510, 1399, 1300, 1244, 1139, 1028, 826 cm−1. ESI–MS: m/z 430.1 [M + H+].

tert-Butyl-cis-4-fluoro-3-(4-μeth­oxy­phen­yl)-1-oxo-2-phen­yl-1,2,3,4-tetra­hydro­iso­quinoline-4-carboxyl­ate, (±) 5: 500 mg of compound 4 (1.20 mmol) were dissolved in abs. THF (38 ml) under an argon atmosphere and cooled to 301 K. After the addition of 1 M LiHMDS solution (1.40 ml, 1.40 mmol), the mixture was stirred for 1 h while cooling. Afterwards, NFSI (511 mg, 1.60 mmol) was added and the mixture stirred for a further 30 min at 301 K and then 40 h at room temperature. The reaction mixture was extracted with CHCl3, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by MPLC (petroleum ether/EtOAc 1/0 to 0/1) to isolate (±) 5 as colourless crystals (yield 320 mg, 0.70 mmol, 62%; m.p. 452–453 K). 1H NMR (CDCl3, 400 MHz): δ 8.41–8.39 (m, 1H), 7.69–7.60 (m, 2H), 7.51–7.48 (m, 1H), 7.34–7.29 (m, 2H), 7.27–7.23 (m, 1H), 7.11–7.07 (m, 2H), 6.92–6.88 (m, 2H), 6.72–6.68 (m, 2H), 5.21 (d, J = 15.7 Hz, 1H), 3.73 (s, 3H), 1.26 (s, 9H). 13C NMR (CDCl3, 100 MHz): δ 165.8 (d, JCF = 26.8 Hz), 162.0 (d, JCF = 1.3 Hz), 160.1, 141.3, 132.6 (d, JCF = 2.9 Hz), 132.3, 130.9 (d, JCF = 3.9 Hz), 130.3 (d, JCF = 3.2 Hz), 130.1 (2C), 129.3, 129.2 (d, JCF = 2.7 Hz), 128.4 (d, JCF = 3.5 Hz), 127.8, 127.7, 126.9 (d, JCF = 8.9 Hz), 114.1 (2C), 92.5 (d, JCF = 189.9 Hz), 84.4, 70.9 (d, JCF = 28.3 Hz), 55.3, 27.8. 19F NMR (CDCl3, 188 MHz): δ −123.4. IR 2929, 1737, 1664, 1513, 1458, 1416, 1306, 1250, 1156, 1031 cm−1. ESI–MS: m/z 448.1 [M + H+].

Synthesis of the title compound: cis-4-fluoro-3-(4-meth­oxy­phen­yl)-1-oxo-2-phenyl-1,2,3,4-tetra­hydro­iso­quinoline-4-carb­oxy­lic acid, (±) 6: 68.5 mg of 5 (0.20 mmol) were dissolved in CH3CN (1.2 ml), 85% (w/w) H3PO4 (86.5 µl, 0.80 mmol) was added and the mixture stirred at 323 K for 4 d. Afterwards, the mixture was extracted with CHCl3, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by MPLC (EtOAc to EtOAc+0.1% FA) to isolate (±) 6 as colourless crystals (yield 21.3 mg, 54.0 mmol, 36%; m.p. 461–462 K). 1H NMR (DMSO-d6, 400 MHz): δ 8.22–8.17 (m, 1H), 7.75–7.70 (m, 2H), 7.59–7.55 (m, 1H), 7.34–7.31 (m, 2H), 7.24–7.20 (m, 1H), 7.13–7.10 (m, 2H), 7.00–6.69 (m, 2H), 6.77–6.74 (m, 2H), 5.53 (d, J = 14.0 Hz, 1H), 3.66 (s, 3H). 13C NMR (DMSO-d6, 100 MHz): δ 167.6 (d, JCF = 26.6 Hz), 161.6, 159.2, 140.8, 132.9 (d, JCF = 1.5 Hz), 132.5 (d, JCF = 19.3 Hz), 130.7 (d, JCF = 3.0 Hz), 129.7, 129.2 (d, JCF = 3.6 Hz), 128.8, 128.3, 127.5, 127.4, 127.0, 125.9 (d, JCF = 6.6 Hz), 113.7 (2C), 92.6 (d, JCF = 188.0 Hz), 68.7 (d, JCF = 28.1 Hz), 55.0. 19F NMR (CD3OD, 188 MHz): δ −130.0. IR 2834, 2594, 1737, 1617, 1511, 1464, 1281, 1219, 1036 cm−1. ESI–MS: m/z 392.0 [M + H+].

5. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2[link]. The H atoms were included in calculated positions and treated as riding: O—H = 0.84 Å, C–H = 0.95–1.00 Å with Uiso(H) = 1.5Ueq(O-hydroxyl,C-meth­yl) and 1.2Ueq(C) for other H atoms.

Table 2
Experimental details

Crystal data
Chemical formula C23H18FNO4
Mr 391.38
Crystal system, space group Monoclinic, P21/c
Temperature (K) 100
a, b, c (Å) 8.4849 (11), 15.407 (3), 14.157 (2)
β (°) 102.598 (16)
V3) 1806.1 (5)
Z 4
Radiation type Mo Kα
μ (mm−1) 0.11
Crystal size (mm) 0.28 × 0.20 × 0.18
 
Data collection
Diffractometer Bruker D8 Quest
Absorption correction Multi-scan (SADABS; Bruker, 2014[Bruker (2014). APEX2, SAINT-Plus, and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.])
Tmin, Tmax 0.718, 0.746
No. of measured, independent and observed [I > 2σ(I)] reflections 48705, 3697, 3509
Rint 0.024
(sin θ/λ)max−1) 0.625
 
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.032, 0.081, 1.05
No. of reflections 3697
No. of parameters 264
H-atom treatment H-atom parameters constrained
Δρmax, Δρmin (e Å−3) 0.38, −0.21
Computer programs: APEX2 and SAINT-Plus (Bruker, 2014[Bruker (2014). APEX2, SAINT-Plus, and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXT (Sheldrick, 2015a[Sheldrick, G. M. (2015a). Acta Cryst. A71, 3-8.]), SHELXL2014 (Sheldrick, 2015b[Sheldrick, G. M. (2015b). Acta Cryst. C71, 3-8.]), SHELXLE (Hübschle et al., 2011[Hübschle, C. B., Sheldrick, G. M. & Dittrich, B. (2011). J. Appl. Cryst. 44, 1281-1284.]) and Mercury (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]).

Supporting information


Computing details top

Data collection: APEX2 (Bruker, 2014); cell refinement: SAINT-Plus (Bruker, 2014); data reduction: SAINT-Plus (Bruker, 2014); program(s) used to solve structure: SHELXT (Sheldrick, 2015a); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015b); molecular graphics: SHELXLE (Hübschle et al., 2011) and Mercury (Macrae et al., 2008); software used to prepare material for publication: SHELXL2014 (Sheldrick, 2015b).

(3S*,4R*)-4-Fluoro-3-(4-methoxyphenyl)-1-oxo-2-phenyl-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid top
Crystal data top
C23H18FNO4F(000) = 816
Mr = 391.38Dx = 1.439 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 8.4849 (11) ÅCell parameters from 9581 reflections
b = 15.407 (3) Åθ = 2.8–28.3°
c = 14.157 (2) ŵ = 0.11 mm1
β = 102.598 (16)°T = 100 K
V = 1806.1 (5) Å3Block, colourless
Z = 40.28 × 0.20 × 0.18 mm
Data collection top
Bruker D8 Quest
diffractometer
3697 independent reflections
Radiation source: microfocus sealed tube (Incoatec ImS)3509 reflections with I > 2σ(I)
Multi-layer mirror monochromatorRint = 0.024
Detector resolution: 10.24 pixels mm-1θmax = 26.4°, θmin = 2.6°
φ and ω scansh = 1010
Absorption correction: multi-scan
(SADABS; Bruker, 2014)
k = 1919
Tmin = 0.718, Tmax = 0.746l = 1717
48705 measured reflections
Refinement top
Refinement on F2Secondary atom site location: difference Fourier map
Least-squares matrix: fullHydrogen site location: inferred from neighbouring sites
R[F2 > 2σ(F2)] = 0.032H-atom parameters constrained
wR(F2) = 0.081 w = 1/[σ2(Fo2) + (0.0355P)2 + 1.0295P]
where P = (Fo2 + 2Fc2)/3
S = 1.05(Δ/σ)max = 0.001
3697 reflectionsΔρmax = 0.38 e Å3
264 parametersΔρmin = 0.21 e Å3
0 restraintsExtinction correction: (SHELXL2016; Sheldrick, 2015b), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0347 (17)
Special details top

Experimental. The crystal was immersed in a film of perfluoropolyether oil, mounted on a polyimide microloop (MicroMounts of MiTeGen) and transferred to stream of cold nitrogen (Bruker Kryoflex2).

Melting points were determined on a Melting point meter MPM-H2 (Schorpp Geraetetechnik, Ueberlingen, Germany) and were not corrected. IR spectra were obtained using a JASCO FT/IR-6100 spectrometer (JASCO, Gross-Umstadt, Germany). TLC was performed on pre-coated aluminium sheets with silica gel 60 F254 (Macherey-Nagel, Dueren, Germany). 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded on a Bruker AV 400 instrument (Bruker Biospin, Ettlingen, Germany). 19F (188 MHz) NMR spectra were recorded on a Bruker Advance 200Hz Spektrometer (Bruker Biospin, Bremen, Germany) at 298 K. Chemical shifts are given in ppm and were calibrated on residual solvent peaks as internal standard (CDCl3: 1H 7.26 ppm, 13C 77.1 ppm; DMSO-d6: 1H 2.50 ppm, 13C 39.52 ppm; CD3OD: 1H 3.31 ppm, 13C 49.00 ppm (Gottlieb et al., 1997)). NMR signals are specified as s (singlet), d (doublet), m (multiplet). Coupling constants J are given in Hz. Medium pressure liquid chromatography (MPLC) was performed on puriFlash®430 system (Interchim, Montluçon, France) using pre-packed silica gel 50 µ columns from Interchim (Montluçon, France). MS data were obtained using an Agilent 1100 Series LC/MSD Trap (Agilent Technologies, Boeblingen, Germany). Commercial available chemicals were used without further purification. Gottlieb, H. E., Kotlyar, V. & Nudelman, A. (1997). J. Org. Chem. 62, 7512-7515.

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.33200 (10)0.61320 (6)0.66591 (6)0.01065 (19)
C20.24318 (12)0.57637 (7)0.72408 (7)0.0111 (2)
C30.32751 (12)0.51757 (7)0.80230 (7)0.0111 (2)
C40.24489 (13)0.48959 (7)0.87212 (8)0.0137 (2)
H40.1399820.5113080.8717970.016*
C50.31679 (13)0.42986 (7)0.94204 (8)0.0159 (2)
H50.2623560.4118390.9906460.019*
C80.48373 (12)0.48743 (7)0.80421 (7)0.0110 (2)
C70.55226 (13)0.42559 (7)0.87261 (8)0.0146 (2)
H70.6566070.4031500.8727990.018*
C60.46852 (14)0.39665 (7)0.94054 (8)0.0167 (2)
H60.5153020.3537820.9863870.020*
C90.56834 (12)0.51784 (7)0.72743 (7)0.0104 (2)
C100.50982 (12)0.60708 (7)0.68386 (7)0.0103 (2)
H100.5382440.6096580.6189800.012*
O110.09652 (9)0.59098 (5)0.71148 (6)0.01599 (18)
F120.53273 (7)0.45825 (4)0.64999 (4)0.01453 (16)
C130.75401 (12)0.52245 (7)0.76088 (8)0.0113 (2)
O140.82294 (9)0.51358 (6)0.68636 (6)0.01713 (18)
H140.9190810.5307690.7018300.026*
O150.82280 (9)0.53632 (6)0.84323 (6)0.01743 (19)
C160.59280 (12)0.68403 (7)0.74097 (7)0.0108 (2)
C170.55319 (13)0.71191 (7)0.82625 (8)0.0133 (2)
H170.4692880.6833260.8488580.016*
C180.63400 (13)0.78083 (7)0.87914 (8)0.0142 (2)
H180.6066920.7984200.9378670.017*
C190.75537 (12)0.82394 (7)0.84538 (8)0.0125 (2)
C200.79674 (13)0.79631 (7)0.76033 (8)0.0139 (2)
H200.8805070.8249020.7376090.017*
C210.71594 (13)0.72720 (7)0.70881 (8)0.0131 (2)
H210.7447160.7089090.6507390.016*
O220.83760 (9)0.89465 (5)0.88880 (6)0.01602 (18)
C230.81993 (14)0.91544 (8)0.98427 (8)0.0175 (2)
H23A0.8838760.9672231.0073490.026*
H23B0.8578660.8666331.0276710.026*
H23C0.7059120.9267260.9832780.026*
C240.25598 (12)0.67125 (7)0.58933 (8)0.0124 (2)
C250.16993 (13)0.74324 (7)0.60909 (9)0.0174 (2)
H250.1600060.7549050.6734290.021*
C260.09829 (14)0.79821 (8)0.53368 (10)0.0239 (3)
H260.0385070.8472100.5467620.029*
C270.11357 (15)0.78197 (8)0.43966 (10)0.0257 (3)
H270.0652210.8198730.3885970.031*
C280.19975 (15)0.71015 (9)0.42085 (9)0.0236 (3)
H280.2104600.6988980.3565660.028*
C290.27096 (13)0.65417 (8)0.49529 (8)0.0167 (2)
H290.3292960.6047240.4818660.020*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0066 (4)0.0132 (4)0.0116 (4)0.0003 (3)0.0007 (3)0.0019 (3)
C20.0094 (5)0.0113 (5)0.0128 (5)0.0010 (4)0.0025 (4)0.0019 (4)
C30.0101 (5)0.0109 (5)0.0119 (5)0.0024 (4)0.0017 (4)0.0015 (4)
C40.0118 (5)0.0154 (5)0.0143 (5)0.0033 (4)0.0039 (4)0.0023 (4)
C50.0180 (5)0.0176 (5)0.0127 (5)0.0070 (4)0.0045 (4)0.0002 (4)
C80.0101 (5)0.0106 (5)0.0121 (5)0.0027 (4)0.0019 (4)0.0013 (4)
C70.0118 (5)0.0131 (5)0.0178 (5)0.0010 (4)0.0009 (4)0.0007 (4)
C60.0185 (5)0.0149 (5)0.0148 (5)0.0033 (4)0.0006 (4)0.0040 (4)
C90.0088 (5)0.0108 (5)0.0111 (5)0.0006 (4)0.0015 (4)0.0023 (4)
C100.0071 (5)0.0133 (5)0.0110 (5)0.0001 (4)0.0028 (4)0.0014 (4)
O110.0079 (4)0.0188 (4)0.0215 (4)0.0009 (3)0.0038 (3)0.0035 (3)
F120.0135 (3)0.0146 (3)0.0154 (3)0.0022 (2)0.0030 (2)0.0051 (2)
C130.0096 (5)0.0095 (5)0.0150 (5)0.0006 (4)0.0034 (4)0.0017 (4)
O140.0087 (4)0.0271 (4)0.0165 (4)0.0028 (3)0.0047 (3)0.0019 (3)
O150.0109 (4)0.0258 (4)0.0146 (4)0.0015 (3)0.0005 (3)0.0002 (3)
C160.0090 (5)0.0102 (5)0.0126 (5)0.0014 (4)0.0010 (4)0.0022 (4)
C170.0118 (5)0.0135 (5)0.0156 (5)0.0010 (4)0.0052 (4)0.0015 (4)
C180.0152 (5)0.0144 (5)0.0137 (5)0.0004 (4)0.0048 (4)0.0005 (4)
C190.0108 (5)0.0102 (5)0.0148 (5)0.0002 (4)0.0009 (4)0.0012 (4)
C200.0107 (5)0.0148 (5)0.0166 (5)0.0015 (4)0.0040 (4)0.0032 (4)
C210.0126 (5)0.0148 (5)0.0125 (5)0.0008 (4)0.0039 (4)0.0016 (4)
O220.0173 (4)0.0146 (4)0.0162 (4)0.0053 (3)0.0036 (3)0.0024 (3)
C230.0171 (5)0.0191 (5)0.0152 (5)0.0036 (4)0.0015 (4)0.0036 (4)
C240.0078 (4)0.0129 (5)0.0150 (5)0.0030 (4)0.0009 (4)0.0031 (4)
C250.0122 (5)0.0151 (5)0.0230 (6)0.0011 (4)0.0002 (4)0.0002 (4)
C260.0144 (5)0.0142 (6)0.0383 (7)0.0008 (4)0.0046 (5)0.0042 (5)
C270.0196 (6)0.0217 (6)0.0287 (7)0.0075 (5)0.0102 (5)0.0134 (5)
C280.0228 (6)0.0285 (7)0.0162 (6)0.0091 (5)0.0026 (5)0.0069 (5)
C290.0152 (5)0.0183 (6)0.0157 (5)0.0032 (4)0.0012 (4)0.0021 (4)
Geometric parameters (Å, º) top
N1—C21.3560 (14)C16—C211.3960 (15)
N1—C241.4444 (13)C17—C181.3907 (15)
N1—C101.4774 (12)C17—H170.9500
C2—O111.2386 (13)C18—C191.3946 (15)
C2—C31.4878 (14)C18—H180.9500
C3—C41.3987 (15)C19—O221.3655 (13)
C3—C81.3992 (15)C19—C201.3923 (15)
C4—C51.3912 (16)C20—C211.3847 (15)
C4—H40.9500C20—H200.9500
C5—C61.3899 (17)C21—H210.9500
C5—H50.9500O22—C231.4282 (13)
C8—C71.3920 (15)C23—H23A0.9800
C8—C91.5023 (14)C23—H23B0.9800
C7—C61.3880 (16)C23—H23C0.9800
C7—H70.9500C24—C251.3895 (16)
C6—H60.9500C24—C291.3899 (16)
C9—F121.4112 (12)C25—C261.3940 (17)
C9—C101.5440 (14)C25—H250.9500
C9—C131.5445 (14)C26—C271.388 (2)
C10—C161.5187 (14)C26—H260.9500
C10—H101.0000C27—C281.384 (2)
C13—O151.2036 (14)C27—H270.9500
C13—O141.3202 (13)C28—C291.3935 (16)
O14—H140.8400C28—H280.9500
C16—C171.3901 (15)C29—H290.9500
C2—N1—C24119.90 (8)C21—C16—C10119.43 (9)
C2—N1—C10123.43 (9)C16—C17—C18121.29 (10)
C24—N1—C10116.15 (8)C16—C17—H17119.4
O11—C2—N1120.70 (10)C18—C17—H17119.4
O11—C2—C3121.52 (9)C17—C18—C19119.57 (10)
N1—C2—C3117.78 (9)C17—C18—H18120.2
C4—C3—C8120.18 (10)C19—C18—H18120.2
C4—C3—C2118.68 (9)O22—C19—C20115.65 (9)
C8—C3—C2121.08 (9)O22—C19—C18124.66 (10)
C5—C4—C3119.81 (10)C20—C19—C18119.67 (10)
C5—C4—H4120.1C21—C20—C19120.09 (10)
C3—C4—H4120.1C21—C20—H20120.0
C6—C5—C4119.78 (10)C19—C20—H20120.0
C6—C5—H5120.1C20—C21—C16120.96 (10)
C4—C5—H5120.1C20—C21—H21119.5
C7—C8—C3119.39 (10)C16—C21—H21119.5
C7—C8—C9121.58 (9)C19—O22—C23117.14 (8)
C3—C8—C9118.86 (9)O22—C23—H23A109.5
C6—C7—C8120.17 (10)O22—C23—H23B109.5
C6—C7—H7119.9H23A—C23—H23B109.5
C8—C7—H7119.9O22—C23—H23C109.5
C7—C6—C5120.53 (10)H23A—C23—H23C109.5
C7—C6—H6119.7H23B—C23—H23C109.5
C5—C6—H6119.7C25—C24—C29120.38 (10)
F12—C9—C8107.70 (8)C25—C24—N1120.76 (10)
F12—C9—C10105.86 (8)C29—C24—N1118.85 (10)
C8—C9—C10113.83 (8)C24—C25—C26119.43 (11)
F12—C9—C13107.42 (8)C24—C25—H25120.3
C8—C9—C13114.13 (9)C26—C25—H25120.3
C10—C9—C13107.41 (8)C27—C26—C25120.57 (12)
N1—C10—C16112.29 (8)C27—C26—H26119.7
N1—C10—C9110.66 (8)C25—C26—H26119.7
C16—C10—C9114.28 (8)C28—C27—C26119.51 (11)
N1—C10—H10106.3C28—C27—H27120.2
C16—C10—H10106.3C26—C27—H27120.2
C9—C10—H10106.3C27—C28—C29120.63 (12)
O15—C13—O14125.92 (10)C27—C28—H28119.7
O15—C13—C9123.50 (9)C29—C28—H28119.7
O14—C13—C9110.50 (9)C24—C29—C28119.48 (11)
C13—O14—H14109.5C24—C29—H29120.3
C17—C16—C21118.42 (10)C28—C29—H29120.3
C17—C16—C10122.12 (9)
C24—N1—C2—O111.02 (15)F12—C9—C13—O15148.60 (10)
C10—N1—C2—O11172.43 (10)C8—C9—C13—O1529.28 (14)
C24—N1—C2—C3179.57 (9)C10—C9—C13—O1597.91 (12)
C10—N1—C2—C38.16 (15)F12—C9—C13—O1434.57 (11)
O11—C2—C3—C410.34 (15)C8—C9—C13—O14153.90 (9)
N1—C2—C3—C4170.26 (9)C10—C9—C13—O1478.92 (10)
O11—C2—C3—C8166.87 (10)N1—C10—C16—C1750.04 (13)
N1—C2—C3—C812.53 (15)C9—C10—C16—C1777.06 (12)
C8—C3—C4—C51.71 (16)N1—C10—C16—C21131.70 (10)
C2—C3—C4—C5175.53 (10)C9—C10—C16—C21101.20 (11)
C3—C4—C5—C61.68 (16)C21—C16—C17—C180.31 (16)
C4—C3—C8—C73.75 (15)C10—C16—C17—C18177.98 (9)
C2—C3—C8—C7173.41 (9)C16—C17—C18—C191.09 (16)
C4—C3—C8—C9179.22 (9)C17—C18—C19—O22176.94 (10)
C2—C3—C8—C92.05 (15)C17—C18—C19—C201.42 (16)
C3—C8—C7—C62.42 (16)O22—C19—C20—C21177.51 (9)
C9—C8—C7—C6177.76 (10)C18—C19—C20—C210.99 (16)
C8—C7—C6—C50.97 (17)C19—C20—C21—C160.21 (16)
C4—C5—C6—C73.03 (17)C17—C16—C21—C200.14 (15)
C7—C8—C9—F1284.49 (12)C10—C16—C21—C20178.47 (9)
C3—C8—C9—F1290.87 (11)C20—C19—O22—C23169.09 (9)
C7—C8—C9—C10158.47 (9)C18—C19—O22—C2312.49 (15)
C3—C8—C9—C1026.17 (13)C2—N1—C24—C2554.81 (14)
C7—C8—C9—C1334.68 (14)C10—N1—C24—C25117.20 (11)
C3—C8—C9—C13149.96 (9)C2—N1—C24—C29125.51 (11)
C2—N1—C10—C1693.63 (11)C10—N1—C24—C2962.48 (12)
C24—N1—C10—C1678.07 (11)C29—C24—C25—C260.14 (16)
C2—N1—C10—C935.38 (13)N1—C24—C25—C26179.82 (10)
C24—N1—C10—C9152.92 (9)C24—C25—C26—C270.58 (17)
F12—C9—C10—N175.45 (10)C25—C26—C27—C280.49 (18)
C8—C9—C10—N142.65 (11)C26—C27—C28—C290.05 (18)
C13—C9—C10—N1170.02 (8)C25—C24—C29—C280.38 (16)
F12—C9—C10—C16156.62 (8)N1—C24—C29—C28179.30 (10)
C8—C9—C10—C1685.28 (11)C27—C28—C29—C240.48 (17)
C13—C9—C10—C1642.08 (11)
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
O14—H14···O11i0.841.752.5645 (11)163
C23—H23C···F12ii0.982.503.2435 (14)133
Symmetry codes: (i) x+1, y, z; (ii) x+1, y+1/2, z+3/2.
 

Acknowledgements

Financial support to UH for this work was provided by: Deutsche Forschungsgemeinschaft (CRU216).

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