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Acta Crystallogr Sect E Struct Rep Online. 2009 February 1; 65(Pt 2): o442.
Published online 2009 January 31. doi:  10.1107/S1600536809000622
PMCID: PMC2968304

1-(2-Fluoro­benz­yl)-1-(2-fluoro­benz­yl­oxy)urea

Abstract

In the title hydroxy­urea derivative, C15H14F2N2O2, the dihedral angle between the two benzene rings is 48.64 (19)°. The urea group forms dihedral angles of 48.1 (2) and 79.2 (2)° with the two benzene rings. In the crystal, inversion dimers linked by pairs of N—H(...)O hydrogen bonds occur, and further N—H(...)O links lead to chains of molecules.

Related literature

For geneal background, see: Krakoff et al. (1968 [triangle]); Young et al. (1967 [triangle]) and Yu et al. (1974 [triangle]). For related structures, see: Howard et al. (1967 [triangle]); Thiessen et al. (1978 [triangle]); Armagan et al. (1976 [triangle]); Berman & Kim (1967 [triangle]); Larsen et al. (1966 [triangle]); Nielsen et al. (1993 [triangle]).

An external file that holds a picture, illustration, etc.
Object name is e-65-0o442-scheme1.jpg

Experimental

Crystal data

  • C15H14F2N2O2
  • M r = 292.28
  • Monoclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-0o442-efi1.jpg
  • a = 5.196 (5) Å
  • b = 30.11 (3) Å
  • c = 9.059 (8) Å
  • β = 102.110 (16)°
  • V = 1386 (2) Å3
  • Z = 4
  • Mo Kα radiation
  • μ = 0.11 mm−1
  • T = 296 (2) K
  • 0.34 × 0.13 × 0.07 mm

Data collection

  • Bruker APEXII area-detector diffractometer
  • Absorption correction: none
  • 8214 measured reflections
  • 2416 independent reflections
  • 1042 reflections with I > 2σ(I)
  • R int = 0.051

Refinement

  • R[F 2 > 2σ(F 2)] = 0.080
  • wR(F 2) = 0.260
  • S = 1.02
  • 2416 reflections
  • 166 parameters
  • H-atom parameters constrained
  • Δρmax = 0.39 e Å−3
  • Δρmin = −0.37 e Å−3

Data collection: APEX2 (Bruker, 2004 [triangle]); cell refinement: SAINT (Bruker, 2004 [triangle]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 [triangle]); software used to prepare material for publication: publCIF (Westrip, 2009 [triangle]).

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809000622/xu2472sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809000622/xu2472Isup2.hkl

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Acknowledgments

This work has been supported by Grand Science and Technology Special Project of Jiangxi Province, China (20041 A0300201). The authors also thank Jinggangshan University for assistance with the data collection and refinement.

supplementary crystallographic information

Comment

The anticancer drug hydroxyurea, which has been used in cancer chemotherapy for many years, has shown to impair DNA synthesis by inhibiting the enzyme ribonucleotide reductase (RNR) (Krakoff et al., 1968). Many hydroxyurea derivates has been designed and synthesized, which inhibit RNR by the same mechanism. We designed and synthesized N'-unsubstituted N-hydroxyure derivative, 1-(2-fluorobenzyl)-1-(2-fluorobenzyloxy)urea. Then we used the compound to make the antitumor activity test in vitro for lymphoid leukemia L1210 through the classic MTT assay. Results show that it has higher inhibition ratios than N-hydroxyurea. This seems to be not much in good agreement with the early structure-activity studies of Young et al. (1967) and Yu et al. (1974). As a serial study of such a complex, the title compound was synthesized and its crystal structure is reported here.

The conformations of the N—H and C=O bonds in the structure of 1-(2-fluorobenzyl)-1-(2-fluorobenzyloxy)urea (Fig. 1) are anti to each other, similar to that observed in N-hydroxyurea (Howard et al., 1967; Thiessen et al., 1978; Armagan et al., 1976; Berman & Kim, 1967; Larsen et al., 1966), 1-hydroxy-1-methylurea (Nielsen et al., 1993), 1-hydroxy-3-methylurea (Nielsen et al., 1993) and other hydroxyurea derivates. The bond parameters in N-(phenylmethoxy)-urea are similar to those in above hydroxyurea derivates, but the length of the carbonyl bond (C=O) is obviously shorter (< 1.25 Å). This may be related with the hydroxy group's etherification. The urea N—(C=O) —N group forms a dihedral angle of 48.1 (2) and 79.2 (2)° with the two benzene rings respectively. Intermolecular N—H···O hydrogen bonding presents in the crystal structure (Table 1).

Experimental

The title compound was prepared by the reaction of 1-(2-fluorobenzyloxy)urea (1.3 mmol) and 1-(chloromethyl)-2-fluorobenzene (1.3 mmol) in methanol (10 ml) in the presence of potassium hydroxide (1.7 mmol). After refluxing for 14 h, the mixture was distilled in the reduced pressure at 308 K. The resulting crude solid was filtered and washed by trichloromethane repeatedly, then recrystallized in acetone and trichloromethane mixture (5:2), filtered. Colorless needle-shaped single crystals used for X-ray structure determination were recrystallized from the mixed solvent acetone and N-hexane (3:13) at room temperature for one week.

Refinement

H atoms were placed in calculated positions with C—H = 0.93 (aromatic), 0.97 Å (methylene) and N—H = 0.86 Å, and were refined in riding mode. The Uiso(H) values were set at 1.2Ueq(C,N).

Figures

Fig. 1.
Molecular structure of the title compound showing the atom labeling scheme. Displacement ellipsoids are drawn at the 50% probability level.

Crystal data

C15H14F2N2O2F(000) = 608
Mr = 292.28Dx = 1.401 Mg m3
Monoclinic, P21/cMelting point: 414.0 K
Hall symbol: -P 2ybcMo Kα radiation, λ = 0.71073 Å
a = 5.196 (5) ÅCell parameters from 1260 reflections
b = 30.11 (3) Åθ = 2.4–19.3°
c = 9.059 (8) ŵ = 0.11 mm1
β = 102.110 (16)°T = 296 K
V = 1386 (2) Å3Needle, colourless
Z = 40.34 × 0.13 × 0.07 mm

Data collection

Bruker APEXII area-detector diffractometer1042 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tubeRint = 0.051
graphiteθmax = 25.0°, θmin = 2.4°
[var phi] and ω scansh = −6→6
8214 measured reflectionsk = −35→35
2416 independent reflectionsl = −10→10

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.080Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.260H-atom parameters constrained
S = 1.02w = 1/[σ2(Fo2) + (0.14P)2] where P = (Fo2 + 2Fc2)/3
2416 reflections(Δ/σ)max < 0.001
166 parametersΔρmax = 0.39 e Å3
0 restraintsΔρmin = −0.37 e Å3

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 (Å2)

xyzUiso*/Ueq
C100.2248 (6)0.40316 (12)0.5643 (3)0.0675 (13)
C11−0.0040 (7)0.38153 (11)0.4930 (4)0.0829 (15)
C12−0.1631 (6)0.40007 (16)0.3653 (4)0.106 (2)
H12−0.31620.38560.31750.127*
C13−0.0935 (9)0.44024 (17)0.3089 (4)0.118 (2)
H13−0.20000.45260.22350.141*
C140.1352 (10)0.46187 (12)0.3803 (5)0.119 (2)
H140.18180.48870.34260.142*
C150.2944 (7)0.44333 (12)0.5080 (5)0.0938 (17)
H150.44740.45780.55570.113*
C30.1504 (7)0.31233 (9)0.9537 (4)0.0677 (13)
C40.3952 (7)0.29896 (13)1.0354 (4)0.0867 (16)
C50.4847 (6)0.25614 (15)1.0185 (5)0.108 (2)
H50.64840.24721.07320.130*
C60.3294 (9)0.22670 (10)0.9199 (5)0.1050 (19)
H60.38930.19800.90860.126*
C70.0846 (9)0.24007 (11)0.8383 (5)0.113 (2)
H7−0.01920.22040.77230.135*
C8−0.0049 (6)0.28289 (12)0.8552 (4)0.0964 (18)
H8−0.16860.29180.80050.116*
C10.3969 (8)0.43961 (14)0.9001 (5)0.0581 (11)
C20.0492 (10)0.35829 (16)0.9702 (6)0.0767 (14)
H2A−0.13220.35640.98120.092*
H2B0.15120.37161.06150.092*
C90.3958 (9)0.38360 (15)0.7028 (5)0.0675 (13)
H9A0.38500.35150.69530.081*
H9B0.57690.39190.70500.081*
F10.5413 (8)0.32477 (14)1.1264 (5)0.1447 (16)
F2−0.0789 (8)0.34425 (11)0.5430 (4)0.1243 (13)
N10.3293 (6)0.39708 (11)0.8446 (4)0.0594 (10)
N20.2206 (7)0.46056 (11)0.9610 (4)0.0693 (11)
H2C0.25630.48631.00150.083*
H2D0.07040.44850.96010.083*
O10.0624 (5)0.38636 (9)0.8448 (3)0.0635 (9)
O20.6157 (6)0.45452 (10)0.8966 (4)0.0719 (10)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C100.062 (3)0.080 (3)0.062 (3)0.000 (3)0.018 (2)−0.019 (2)
C110.080 (4)0.097 (4)0.071 (4)−0.010 (3)0.014 (3)−0.025 (3)
C120.095 (4)0.139 (6)0.080 (4)−0.020 (4)0.008 (4)−0.029 (4)
C130.132 (6)0.145 (6)0.070 (4)0.005 (5)0.006 (4)0.003 (4)
C140.141 (6)0.123 (5)0.084 (5)−0.021 (5)0.006 (4)0.016 (4)
C150.092 (4)0.111 (4)0.080 (4)−0.015 (3)0.020 (3)−0.001 (3)
C30.071 (3)0.072 (3)0.064 (3)−0.015 (3)0.021 (3)0.002 (2)
C40.084 (4)0.091 (4)0.077 (4)−0.011 (3)−0.003 (3)0.006 (3)
C50.106 (5)0.111 (5)0.102 (5)0.010 (4)0.007 (4)0.036 (4)
C60.127 (5)0.083 (4)0.108 (5)0.007 (4)0.031 (4)0.016 (4)
C70.106 (5)0.097 (5)0.121 (5)0.000 (4)−0.009 (4)−0.008 (4)
C80.108 (4)0.067 (4)0.104 (4)−0.001 (3)0.000 (3)−0.011 (3)
C10.050 (3)0.064 (3)0.059 (3)0.004 (2)0.008 (2)−0.006 (2)
C20.075 (3)0.082 (3)0.076 (3)−0.015 (3)0.023 (3)−0.006 (3)
C90.056 (3)0.070 (3)0.080 (3)0.004 (2)0.022 (2)−0.021 (2)
F10.140 (3)0.135 (3)0.133 (3)−0.026 (3)−0.031 (2)−0.013 (2)
F20.134 (3)0.105 (3)0.129 (3)−0.038 (2)0.016 (2)−0.019 (2)
N10.049 (2)0.061 (2)0.069 (2)−0.0016 (16)0.0145 (17)−0.0087 (18)
N20.054 (2)0.063 (2)0.096 (3)−0.0041 (18)0.027 (2)−0.018 (2)
O10.0480 (17)0.0676 (19)0.077 (2)−0.0041 (14)0.0176 (15)−0.0076 (15)
O20.0490 (18)0.074 (2)0.095 (2)−0.0078 (16)0.0216 (16)−0.0186 (16)

Geometric parameters (Å, °)

C10—C111.3900C5—H50.9300
C10—C151.3900C6—C71.3900
C10—C91.497 (6)C6—H60.9300
C11—F21.301 (4)C7—C81.3900
C11—C121.3900C7—H70.9300
C12—C131.3900C8—H80.9300
C12—H120.9300C1—O21.229 (5)
C13—C141.3900C1—N21.324 (5)
C13—H130.9300C1—N11.394 (5)
C14—C151.3900C2—O11.429 (6)
C14—H140.9300C2—H2A0.9700
C15—H150.9300C2—H2B0.9700
C3—C41.3900C9—N11.457 (6)
C3—C81.3900C9—H9A0.9700
C3—C21.499 (6)C9—H9B0.9700
C4—F11.264 (4)N1—O11.424 (4)
C4—C51.3900N2—H2C0.8600
C5—C61.3900N2—H2D0.8600
C11—C10—C15120.0C5—C6—H6120.0
C11—C10—C9120.3 (3)C6—C7—C8120.0
C15—C10—C9119.7 (3)C6—C7—H7120.0
F2—C11—C12117.9 (3)C8—C7—H7120.0
F2—C11—C10122.1 (3)C7—C8—C3120.0
C12—C11—C10120.0C7—C8—H8120.0
C11—C12—C13120.0C3—C8—H8120.0
C11—C12—H12120.0O2—C1—N2124.2 (4)
C13—C12—H12120.0O2—C1—N1119.4 (4)
C14—C13—C12120.0N2—C1—N1116.4 (4)
C14—C13—H13120.0O1—C2—C3113.0 (4)
C12—C13—H13120.0O1—C2—H2A109.0
C13—C14—C15120.0C3—C2—H2A109.0
C13—C14—H14120.0O1—C2—H2B109.0
C15—C14—H14120.0C3—C2—H2B109.0
C14—C15—C10120.0H2A—C2—H2B107.8
C14—C15—H15120.0N1—C9—C10114.9 (3)
C10—C15—H15120.0N1—C9—H9A108.6
C4—C3—C8120.0C10—C9—H9A108.6
C4—C3—C2121.0 (3)N1—C9—H9B108.6
C8—C3—C2119.0 (3)C10—C9—H9B108.6
F1—C4—C5118.2 (4)H9A—C9—H9B107.5
F1—C4—C3121.8 (4)C1—N1—O1112.3 (3)
C5—C4—C3120.0C1—N1—C9119.0 (4)
C4—C5—C6120.0O1—N1—C9110.4 (3)
C4—C5—H5120.0C1—N2—H2C120.0
C6—C5—H5120.0C1—N2—H2D120.0
C7—C6—C5120.0H2C—N2—H2D120.0
C7—C6—H6120.0N1—O1—C2110.1 (3)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N2—H2C···O2i0.862.052.910 (5)174
N2—H2D···O2ii0.862.323.079 (5)148

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: XU2472).

References

  • Armagan, N., Richards, J. P. G. & Uraz, A. A. (1976). Acta Cryst. B32, 1042–1047.
  • Berman, H. & Kim, S. H. (1967). Acta Cryst.23, 180–181. [PubMed]
  • Bruker (2004). APEX2 and SAINT Bruker AXS Inc., Madison, Wisconsin, USA.
  • Farrugia, L. J. (1997). J. Appl. Cryst.30, 565.
  • Howard, W., Shields, P. J., Hamrick, J. & Welby, R. (1967). J. Chem. Phys. 46, 2510-2514.
  • Krakoff, I. H., Brown, N. C. & Reichard, P. (1968). Cancer Res.28, 1559–1565. [PubMed]
  • Larsen, I. K. & Jerslev, B. (1966). Acta Chem. Scand.20, 983–991.
  • Nielsen, B. B., Frydenvang, K. & Larsen, I. K. (1993). Acta Cryst. C49, 1018–1022.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Thiessen, W. E., Levy, H. A. & Flaig, B. D. (1978). Acta Cryst. B34, 2495–2502.
  • Westrip, S. P. (2009). publCIF. In preparation.
  • Young, C. W., Schochetman, G., Hodas, S. & Balls, E. M. (1967). Cancer Res.27, 535–540. [PubMed]
  • Yu, R. J. & van Scott, E. J. (1974). J. Invest. Dermatol.63, 279–283. [PubMed]

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