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

Mai, X.; Xia, H.-Y.; Cao, Y.-S.; Lu, X.-S.; Fang, X.-N.

doi:10.1107/S1600536809000622

organic compounds

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ISSN: 2056-9890

Volume 65| Part 2| February 2009| Page o442

doi:10.1107/S1600536809000622

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

Xi Mai,^a Hong-Ying Xia,^b Yu-Sheng Cao,^a ^* Xiao-San Lu ^b and Xiao-Niu Fang ^c

^aSino-German Joint Research Institute of Nanchang University, Nanchang 330006, People's Republic of China, ^bDepartment of Pharmacy, Medical College of Nanchang University, Nanchang 330006, People's Republic of China, and ^cDepartment of Chemistry, Jinggangshan University, Ji'an 343009, People's Republic of China
^*Correspondence e-mail: cmxlf2008@ 163.com

(Received 17 December 2008; accepted 7 January 2009; online 31 January 2009)

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

Experimental

Crystal data

C₁₅H₁₄F₂N₂O₂
M_r = 292.28
Monoclinic, P 2₁ /c
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[F² > 2σ(F²)] = 0.080
wR(F²) = 0.260
S = 1.02
2416 reflections
166 parameters
H-atom parameters constrained
Δρ_max = 0.39 e Å⁻³
Δρ_min = −0.37 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N2—H2C⋯O2ⁱ	0.86	2.05	2.910 (5)	174
N2—H2D⋯O2ⁱⁱ	0.86	2.32	3.079 (5)	148
Symmetry codes: (i) -x+1, -y+1, -z+2; (ii) x-1, y, z.

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

Supporting information

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

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

checkCIF report

Comment top

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).

Related literature top

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

Experimental top

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.

Computing details top

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

Figures top

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

1-(2-fluorobenzyl)-1-(2-fluorobenzyloxy)urea top

Crystal data top

C₁₅H₁₄F₂N₂O₂	F(000) = 608
M_r = 292.28	D_x = 1.401 Mg m⁻³
Monoclinic, P2₁/c	Melting point: 414.0 K
Hall symbol: -P 2ybc	Mo Kα radiation, λ = 0.71073 Å
a = 5.196 (5) Å	Cell parameters from 1260 reflections
b = 30.11 (3) Å	θ = 2.4–19.3°
c = 9.059 (8) Å	µ = 0.11 mm⁻¹
β = 102.110 (16)°	T = 296 K
V = 1386 (2) Å³	Needle, colourless
Z = 4	0.34 × 0.13 × 0.07 mm

Data collection top

Bruker APEXII area-detector diffractometer	1042 reflections with I > 2σ(I)
Radiation source: fine-focus sealed tube	R_int = 0.051
Graphite monochromator	θ_max = 25.0°, θ_min = 2.4°
ϕ and ω scans	h = −6→6
8214 measured reflections	k = −35→35
2416 independent reflections	l = −10→10

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)] = 0.080	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.260	H-atom parameters constrained
S = 1.02	w = 1/[σ²(F_o²) + (0.14P)²] where P = (F_o² + 2F_c²)/3
2416 reflections	(Δ/σ)_max < 0.001
166 parameters	Δρ_max = 0.39 e Å⁻³
0 restraints	Δρ_min = −0.37 e Å⁻³

Crystal data top

C₁₅H₁₄F₂N₂O₂	V = 1386 (2) Å³
M_r = 292.28	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 5.196 (5) Å	µ = 0.11 mm⁻¹
b = 30.11 (3) Å	T = 296 K
c = 9.059 (8) Å	0.34 × 0.13 × 0.07 mm
β = 102.110 (16)°

Data collection top

Bruker APEXII area-detector diffractometer	1042 reflections with I > 2σ(I)
8214 measured reflections	R_int = 0.051
2416 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.080	0 restraints
wR(F²) = 0.260	H-atom parameters constrained
S = 1.02	Δρ_max = 0.39 e Å⁻³
2416 reflections	Δρ_min = −0.37 e Å⁻³
166 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. 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
C10	0.2248 (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	−0.3162	0.3856	0.3175	0.127*
C13	−0.0935 (9)	0.44024 (17)	0.3089 (4)	0.118 (2)
H13	−0.2000	0.4526	0.2235	0.141*
C14	0.1352 (10)	0.46187 (12)	0.3803 (5)	0.119 (2)
H14	0.1818	0.4887	0.3426	0.142*
C15	0.2944 (7)	0.44333 (12)	0.5080 (5)	0.0938 (17)
H15	0.4474	0.4578	0.5557	0.113*
C3	0.1504 (7)	0.31233 (9)	0.9537 (4)	0.0677 (13)
C4	0.3952 (7)	0.29896 (13)	1.0354 (4)	0.0867 (16)
C5	0.4847 (6)	0.25614 (15)	1.0185 (5)	0.108 (2)
H5	0.6484	0.2472	1.0732	0.130*
C6	0.3294 (9)	0.22670 (10)	0.9199 (5)	0.1050 (19)
H6	0.3893	0.1980	0.9086	0.126*
C7	0.0846 (9)	0.24007 (11)	0.8383 (5)	0.113 (2)
H7	−0.0192	0.2204	0.7723	0.135*
C8	−0.0049 (6)	0.28289 (12)	0.8552 (4)	0.0964 (18)
H8	−0.1686	0.2918	0.8005	0.116*
C1	0.3969 (8)	0.43961 (14)	0.9001 (5)	0.0581 (11)
C2	0.0492 (10)	0.35829 (16)	0.9702 (6)	0.0767 (14)
H2A	−0.1322	0.3564	0.9812	0.092*
H2B	0.1512	0.3716	1.0615	0.092*
C9	0.3958 (9)	0.38360 (15)	0.7028 (5)	0.0675 (13)
H9A	0.3850	0.3515	0.6953	0.081*
H9B	0.5769	0.3919	0.7050	0.081*
F1	0.5413 (8)	0.32477 (14)	1.1264 (5)	0.1447 (16)
F2	−0.0789 (8)	0.34425 (11)	0.5430 (4)	0.1243 (13)
N1	0.3293 (6)	0.39708 (11)	0.8446 (4)	0.0594 (10)
N2	0.2206 (7)	0.46056 (11)	0.9610 (4)	0.0693 (11)
H2C	0.2563	0.4863	1.0015	0.083*
H2D	0.0704	0.4485	0.9601	0.083*
O1	0.0624 (5)	0.38636 (9)	0.8448 (3)	0.0635 (9)
O2	0.6157 (6)	0.45452 (10)	0.8966 (4)	0.0719 (10)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C10	0.062 (3)	0.080 (3)	0.062 (3)	0.000 (3)	0.018 (2)	−0.019 (2)
C11	0.080 (4)	0.097 (4)	0.071 (4)	−0.010 (3)	0.014 (3)	−0.025 (3)
C12	0.095 (4)	0.139 (6)	0.080 (4)	−0.020 (4)	0.008 (4)	−0.029 (4)
C13	0.132 (6)	0.145 (6)	0.070 (4)	0.005 (5)	0.006 (4)	0.003 (4)
C14	0.141 (6)	0.123 (5)	0.084 (5)	−0.021 (5)	0.006 (4)	0.016 (4)
C15	0.092 (4)	0.111 (4)	0.080 (4)	−0.015 (3)	0.020 (3)	−0.001 (3)
C3	0.071 (3)	0.072 (3)	0.064 (3)	−0.015 (3)	0.021 (3)	0.002 (2)
C4	0.084 (4)	0.091 (4)	0.077 (4)	−0.011 (3)	−0.003 (3)	0.006 (3)
C5	0.106 (5)	0.111 (5)	0.102 (5)	0.010 (4)	0.007 (4)	0.036 (4)
C6	0.127 (5)	0.083 (4)	0.108 (5)	0.007 (4)	0.031 (4)	0.016 (4)
C7	0.106 (5)	0.097 (5)	0.121 (5)	0.000 (4)	−0.009 (4)	−0.008 (4)
C8	0.108 (4)	0.067 (4)	0.104 (4)	−0.001 (3)	0.000 (3)	−0.011 (3)
C1	0.050 (3)	0.064 (3)	0.059 (3)	0.004 (2)	0.008 (2)	−0.006 (2)
C2	0.075 (3)	0.082 (3)	0.076 (3)	−0.015 (3)	0.023 (3)	−0.006 (3)
C9	0.056 (3)	0.070 (3)	0.080 (3)	0.004 (2)	0.022 (2)	−0.021 (2)
F1	0.140 (3)	0.135 (3)	0.133 (3)	−0.026 (3)	−0.031 (2)	−0.013 (2)
F2	0.134 (3)	0.105 (3)	0.129 (3)	−0.038 (2)	0.016 (2)	−0.019 (2)
N1	0.049 (2)	0.061 (2)	0.069 (2)	−0.0016 (16)	0.0145 (17)	−0.0087 (18)
N2	0.054 (2)	0.063 (2)	0.096 (3)	−0.0041 (18)	0.027 (2)	−0.018 (2)
O1	0.0480 (17)	0.0676 (19)	0.077 (2)	−0.0041 (14)	0.0176 (15)	−0.0076 (15)
O2	0.0490 (18)	0.074 (2)	0.095 (2)	−0.0078 (16)	0.0216 (16)	−0.0186 (16)

Geometric parameters (Å, º) top

C10—C11	1.3900	C5—H5	0.9300
C10—C15	1.3900	C6—C7	1.3900
C10—C9	1.497 (6)	C6—H6	0.9300
C11—F2	1.301 (4)	C7—C8	1.3900
C11—C12	1.3900	C7—H7	0.9300
C12—C13	1.3900	C8—H8	0.9300
C12—H12	0.9300	C1—O2	1.229 (5)
C13—C14	1.3900	C1—N2	1.324 (5)
C13—H13	0.9300	C1—N1	1.394 (5)
C14—C15	1.3900	C2—O1	1.429 (6)
C14—H14	0.9300	C2—H2A	0.9700
C15—H15	0.9300	C2—H2B	0.9700
C3—C4	1.3900	C9—N1	1.457 (6)
C3—C8	1.3900	C9—H9A	0.9700
C3—C2	1.499 (6)	C9—H9B	0.9700
C4—F1	1.264 (4)	N1—O1	1.424 (4)
C4—C5	1.3900	N2—H2C	0.8600
C5—C6	1.3900	N2—H2D	0.8600

C11—C10—C15	120.0	C5—C6—H6	120.0
C11—C10—C9	120.3 (3)	C6—C7—C8	120.0
C15—C10—C9	119.7 (3)	C6—C7—H7	120.0
F2—C11—C12	117.9 (3)	C8—C7—H7	120.0
F2—C11—C10	122.1 (3)	C7—C8—C3	120.0
C12—C11—C10	120.0	C7—C8—H8	120.0
C11—C12—C13	120.0	C3—C8—H8	120.0
C11—C12—H12	120.0	O2—C1—N2	124.2 (4)
C13—C12—H12	120.0	O2—C1—N1	119.4 (4)
C14—C13—C12	120.0	N2—C1—N1	116.4 (4)
C14—C13—H13	120.0	O1—C2—C3	113.0 (4)
C12—C13—H13	120.0	O1—C2—H2A	109.0
C13—C14—C15	120.0	C3—C2—H2A	109.0
C13—C14—H14	120.0	O1—C2—H2B	109.0
C15—C14—H14	120.0	C3—C2—H2B	109.0
C14—C15—C10	120.0	H2A—C2—H2B	107.8
C14—C15—H15	120.0	N1—C9—C10	114.9 (3)
C10—C15—H15	120.0	N1—C9—H9A	108.6
C4—C3—C8	120.0	C10—C9—H9A	108.6
C4—C3—C2	121.0 (3)	N1—C9—H9B	108.6
C8—C3—C2	119.0 (3)	C10—C9—H9B	108.6
F1—C4—C5	118.2 (4)	H9A—C9—H9B	107.5
F1—C4—C3	121.8 (4)	C1—N1—O1	112.3 (3)
C5—C4—C3	120.0	C1—N1—C9	119.0 (4)
C4—C5—C6	120.0	O1—N1—C9	110.4 (3)
C4—C5—H5	120.0	C1—N2—H2C	120.0
C6—C5—H5	120.0	C1—N2—H2D	120.0
C7—C6—C5	120.0	H2C—N2—H2D	120.0
C7—C6—H6	120.0	N1—O1—C2	110.1 (3)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2C···O2ⁱ	0.86	2.05	2.910 (5)	174
N2—H2D···O2ⁱⁱ	0.86	2.32	3.079 (5)	148

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

Experimental details

Crystal data
Chemical formula	C₁₅H₁₄F₂N₂O₂
M_r	292.28
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	296
a, b, c (Å)	5.196 (5), 30.11 (3), 9.059 (8)
β (°)	102.110 (16)
V (Å³)	1386 (2)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.11
Crystal size (mm)	0.34 × 0.13 × 0.07

Data collection
Diffractometer	Bruker APEXII area-detector diffractometer
Absorption correction	–
No. of measured, independent and observed [I > 2σ(I)] reflections	8214, 2416, 1042
R_int	0.051
(sin θ/λ)_max (Å⁻¹)	0.595

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.080, 0.260, 1.02
No. of reflections	2416
No. of parameters	166
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.39, −0.37

Computer programs: APEX2 (Bruker, 2004), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), ORTEP-3 for Windows (Farrugia, 1997), publCIF (Westrip, 2009).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2C···O2ⁱ	0.86	2.05	2.910 (5)	174
N2—H2D···O2ⁱⁱ	0.86	2.32	3.079 (5)	148

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

Acknowledgements

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.

References

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