N,N′-[(2,3,5,6-Tetra­methyl-p-phenyl­ene)dimethyl­ene]bis­[2-chloro-N-(2-chloro­ethyl)ethanamine]

Wang, G.-Z.; Zhuang, Y.-Y.; Zhou, C.-H.

doi:10.1107/S1600536809026300

organic compounds

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ISSN: 2056-9890

Volume 65| Part 8| August 2009| Page o1850

doi:10.1107/S1600536809026300

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N,N′-[(2,3,5,6-Tetramethyl-p-phenylene)dimethylene]bis[2-chloro-N-(2-chloroethyl)ethanamine]

Guang-Zhou Wang,^a Ya-Yun Zhuang ^a and Cheng-He Zhou ^a ^*

^aLaboratory of Bioorganic & Medicinal Chemistry, School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, People's Republic of China
^*Correspondence e-mail: zhouch@swu.edu.cn

(Received 1 July 2009; accepted 6 July 2009; online 15 July 2009)

The title molecule, C₂₀H₃₂Cl₄N₂, lies on an inversion center. A weak intramolecular C—H⋯N hydrogen bond may, in part, influence the conformation of the molecule.

Related literature

For a related crystal structure, see: Yin et al. (2006 ). For general background to the pharmacological activity of nitrogen mustards, see: Rachid et al. (2007 ); Duan et al. (2008 ); Zhou et al. (2009 ); Zhuang et al. (2008 ).

Experimental

Crystal data

C₂₀H₃₂Cl₄N₂
M_r = 442.29
Monoclinic, P 2₁ /c
a = 13.6694 (14) Å
b = 9.751 (1) Å
c = 8.3997 (8) Å
β = 93.695 (2)°
V = 1117.27 (19) Å³
Z = 2
Mo Kα radiation
μ = 0.54 mm⁻¹
T = 298 K
0.16 × 0.12 × 0.10 mm

Data collection

Bruker SMART CCD diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick,1996 ) T_min = 0.919, T_max = 0.948
13369 measured reflections
2732 independent reflections
2283 reflections with I > 2σ(I)
R_int = 0.031

Refinement

R[F² > 2σ(F²)] = 0.048
wR(F²) = 0.134
S = 1.04
2732 reflections
120 parameters
H-atom parameters constrained
Δρ_max = 0.46 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C1—H1C⋯N1	0.96	2.43	3.159 (3)	133

Data collection: SMART (Bruker, 2001 ); cell refinement: SAINT-Plus (Bruker, 2001); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL.

Supporting information

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536809026300/lh2858sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536809026300/lh2858Isup2.hkl

checkCIF report

Comment top

Nitrogen mustards such as chlorambucil and melphalan are cytotoxic chemotherapy agents, which are widely used in the treatment of a variety of malignant diseases. As bifunctional DNA-alkylating agents, nitrogen mustards are able to crosslink cellular DNA and thereby interfere with the DNA replication (Rachid et al., 2007; Duan et al., 2008; Zhuang et al., 2008; Zhou et al., 2009). The title compound (I), was obtained by the chlorination of the corresponding diol. Here we present the crystal structure of (I) (Fig. 1).

The title molecule lies on an inversion center. A weak intramolecular C—H···N hydrogen bond may, in part, influence the conformation of the molecule.

Related literature top

For a related crystal structure, see: Yin et al. (2006). For general background to the pharmacological activity of nitrogen mustards, see: Rachid et al. (2007); Duan et al. (2008); Zhou et al. (2009); Zhuang et al. (2008).

Experimental top

To a stirred solution of 1,4-bis(bromomethyl)-2,3,5,6-tetramethylbenzene (6.40g, 20mmol) in absolute alcohol (30mL) at 348K potassium carbonate (5.53g, 40mmol) and 2,2'-azanediyldiethanol (4.21g, 40mmol) were added. The progress of the reaction was monitored by TLC. The mixture was filtered to remove the inorganic salts, the solvent was concentrated under reduced pressure and recrystallization from absolute alcohol gave the intermediate2,2',2'',2'''-(2,3,5,6-tetramethyl-p-phenylene)bis (methylene) bis (azanetriyl)tetraethanol (Yield: 5.23g, 71.0%; white solid; Mp., 417-418K). Sulfonyl chloride (40mL) was added dropwise to the intermediate (3.68g, 10mmol) in an ice-salt bath and then the mixture was stirred slowly at gentle reflux for three hours. Sulfonyl chloride was removed under reduced pressure, after cooling, water was added cautiously, and then the mixture was neutralized with NaHCO₃. The suspension was filtered and washed with chloroform. The organic layer was washed with water, dried over anhydrous Na₂SO₄ and the solvent was removed in vacuo. The resulting residue was recrystallized from chloroform to give the title compound (Yield: 3.83g, 86.7%; white solid; Mp. 389-340K).

Computing details top

Data collection: SMART (Bruker, 2001); cell refinement: SAINT-Plus (Bruker, 2001); data reduction: SAINT-Plus (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXTL (Sheldrick, 2008).

Figures top

Fig. 1. The molecular structure of (I), showing the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level [symmetry code: (a) -x, -y, -z+1].

N,N'-[(2,3,5,6-Tetramethyl-p-phenylene)dimethylene]bis[2- chloro-N-(2-chloroethyl)ethanamine] top

Crystal data top

C₂₀H₃₂Cl₄N₂	F(000) = 468
M_r = 442.29	D_x = 1.315 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 4998 reflections
a = 13.6694 (14) Å	θ = 2.6–28.0°
b = 9.751 (1) Å	µ = 0.54 mm⁻¹
c = 8.3997 (8) Å	T = 298 K
β = 93.695 (2)°	Block, white
V = 1117.27 (19) Å³	0.16 × 0.12 × 0.10 mm
Z = 2

Data collection top

Bruker SMART CCD diffractometer	2732 independent reflections
Radiation source: fine-focus sealed tube	2283 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.031
ϕ and ω scans	θ_max = 28.3°, θ_min = 2.6°
Absorption correction: multi-scan (SADABS; Sheldrick,1996)	h = −17→17
T_min = 0.919, T_max = 0.948	k = −12→12
13369 measured reflections	l = −11→11

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)] = 0.048	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.134	H-atom parameters constrained
S = 1.04	w = 1/[σ²(F_o²) + (0.0809P)² + 0.1826P] where P = (F_o² + 2F_c²)/3
2732 reflections	(Δ/σ)_max = 0.001
120 parameters	Δρ_max = 0.46 e Å⁻³
0 restraints	Δρ_min = −0.25 e Å⁻³

Crystal data top

C₂₀H₃₂Cl₄N₂	V = 1117.27 (19) Å³
M_r = 442.29	Z = 2
Monoclinic, P2₁/c	Mo Kα radiation
a = 13.6694 (14) Å	µ = 0.54 mm⁻¹
b = 9.751 (1) Å	T = 298 K
c = 8.3997 (8) Å	0.16 × 0.12 × 0.10 mm
β = 93.695 (2)°

Data collection top

Bruker SMART CCD diffractometer	2732 independent reflections
Absorption correction: multi-scan (SADABS; Sheldrick,1996)	2283 reflections with I > 2σ(I)
T_min = 0.919, T_max = 0.948	R_int = 0.031
13369 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.048	0 restraints
wR(F²) = 0.134	H-atom parameters constrained
S = 1.04	Δρ_max = 0.46 e Å⁻³
2732 reflections	Δρ_min = −0.25 e Å⁻³
120 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
C1	0.12764 (15)	0.2248 (2)	0.6112 (3)	0.0550 (5)
H1A	0.1026	0.2650	0.7046	0.083*
H1B	0.1296	0.2930	0.5290	0.083*
H1C	0.1926	0.1906	0.6366	0.083*
C2	0.06149 (12)	0.10771 (19)	0.5531 (2)	0.0396 (4)
C3	−0.03006 (12)	0.13651 (18)	0.4753 (2)	0.0400 (4)
C4	−0.06146 (16)	0.2853 (2)	0.4533 (3)	0.0578 (5)
H4A	−0.0419	0.3364	0.5477	0.087*
H4B	−0.1314	0.2897	0.4345	0.087*
H4C	−0.0309	0.3237	0.3637	0.087*
C5	0.09103 (12)	−0.02818 (19)	0.57881 (19)	0.0380 (4)
C6	0.18937 (12)	−0.0575 (2)	0.6671 (2)	0.0426 (4)
H6A	0.1939	−0.0056	0.7658	0.051*
H6B	0.1927	−0.1541	0.6944	0.051*
C7	0.27229 (13)	−0.08753 (18)	0.4172 (2)	0.0381 (4)
H7A	0.2054	−0.1096	0.3803	0.046*
H7B	0.3099	−0.1720	0.4238	0.046*
C8	0.31611 (16)	0.0100 (2)	0.3029 (2)	0.0476 (4)
H8A	0.3821	0.0342	0.3425	0.057*
H8B	0.2774	0.0934	0.2952	0.057*
C9	0.36606 (12)	−0.04271 (19)	0.6687 (2)	0.0403 (4)
H9A	0.4158	−0.0715	0.5986	0.048*
H9B	0.3577	−0.1159	0.7448	0.048*
C10	0.40134 (13)	0.0836 (2)	0.7575 (2)	0.0454 (4)
H10A	0.4551	0.0592	0.8332	0.055*
H10B	0.3487	0.1199	0.8171	0.055*
N1	0.27367 (9)	−0.02246 (15)	0.57401 (16)	0.0353 (3)
Cl1	0.31962 (4)	−0.06609 (6)	0.10972 (6)	0.0624 (2)
Cl2	0.44162 (4)	0.21356 (5)	0.62479 (7)	0.05813 (19)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
C1	0.0412 (10)	0.0543 (12)	0.0691 (14)	−0.0048 (8)	0.0002 (9)	−0.0143 (10)
C2	0.0307 (8)	0.0500 (10)	0.0387 (9)	−0.0023 (7)	0.0059 (6)	−0.0025 (7)
C3	0.0325 (8)	0.0471 (10)	0.0412 (9)	0.0009 (7)	0.0081 (7)	0.0014 (7)
C4	0.0443 (11)	0.0506 (11)	0.0779 (15)	0.0040 (8)	0.0004 (10)	0.0066 (10)
C5	0.0279 (8)	0.0535 (10)	0.0329 (8)	0.0005 (7)	0.0044 (6)	0.0014 (7)
C6	0.0319 (8)	0.0623 (11)	0.0336 (8)	−0.0002 (7)	0.0028 (6)	0.0061 (8)
C7	0.0364 (8)	0.0440 (9)	0.0341 (8)	−0.0054 (7)	0.0033 (6)	−0.0018 (7)
C8	0.0630 (12)	0.0471 (10)	0.0329 (9)	−0.0063 (9)	0.0049 (8)	−0.0025 (8)
C9	0.0309 (8)	0.0485 (10)	0.0410 (9)	0.0037 (7)	−0.0019 (7)	0.0027 (7)
C10	0.0373 (9)	0.0608 (12)	0.0376 (9)	−0.0038 (8)	−0.0024 (7)	−0.0015 (8)
N1	0.0272 (6)	0.0470 (8)	0.0316 (7)	−0.0005 (5)	0.0007 (5)	−0.0014 (6)
Cl1	0.0788 (4)	0.0759 (4)	0.0331 (3)	−0.0251 (3)	0.0084 (2)	−0.0071 (2)
Cl2	0.0622 (3)	0.0514 (3)	0.0611 (3)	−0.0097 (2)	0.0064 (2)	−0.0031 (2)

Geometric parameters (Å, º) top

C1—C2	1.518 (3)	C6—H6B	0.9700
C1—H1A	0.9600	C7—N1	1.461 (2)
C1—H1B	0.9600	C7—C8	1.504 (2)
C1—H1C	0.9600	C7—H7A	0.9700
C2—C5	1.398 (3)	C7—H7B	0.9700
C2—C3	1.402 (2)	C8—Cl1	1.7874 (19)
C3—C5ⁱ	1.403 (2)	C8—H8A	0.9700
C3—C4	1.521 (3)	C8—H8B	0.9700
C4—H4A	0.9600	C9—N1	1.462 (2)
C4—H4B	0.9600	C9—C10	1.503 (3)
C4—H4C	0.9600	C9—H9A	0.9700
C5—C3ⁱ	1.403 (2)	C9—H9B	0.9700
C5—C6	1.520 (2)	C10—Cl2	1.798 (2)
C6—N1	1.473 (2)	C10—H10A	0.9700
C6—H6A	0.9700	C10—H10B	0.9700

C2—C1—H1A	109.5	N1—C7—C8	108.58 (14)
C2—C1—H1B	109.5	N1—C7—H7A	110.0
H1A—C1—H1B	109.5	C8—C7—H7A	110.0
C2—C1—H1C	109.5	N1—C7—H7B	110.0
H1A—C1—H1C	109.5	C8—C7—H7B	110.0
H1B—C1—H1C	109.5	H7A—C7—H7B	108.4
C5—C2—C3	120.14 (16)	C7—C8—Cl1	110.64 (13)
C5—C2—C1	120.23 (16)	C7—C8—H8A	109.5
C3—C2—C1	119.63 (17)	Cl1—C8—H8A	109.5
C2—C3—C5ⁱ	119.59 (16)	C7—C8—H8B	109.5
C2—C3—C4	118.96 (16)	Cl1—C8—H8B	109.5
C5ⁱ—C3—C4	121.45 (16)	H8A—C8—H8B	108.1
C3—C4—H4A	109.5	N1—C9—C10	113.44 (14)
C3—C4—H4B	109.5	N1—C9—H9A	108.9
H4A—C4—H4B	109.5	C10—C9—H9A	108.9
C3—C4—H4C	109.5	N1—C9—H9B	108.9
H4A—C4—H4C	109.5	C10—C9—H9B	108.9
H4B—C4—H4C	109.5	H9A—C9—H9B	107.7
C2—C5—C3ⁱ	120.26 (15)	C9—C10—Cl2	111.79 (13)
C2—C5—C6	119.41 (16)	C9—C10—H10A	109.3
C3ⁱ—C5—C6	120.33 (16)	Cl2—C10—H10A	109.3
N1—C6—C5	113.28 (14)	C9—C10—H10B	109.3
N1—C6—H6A	108.9	Cl2—C10—H10B	109.3
C5—C6—H6A	108.9	H10A—C10—H10B	107.9
N1—C6—H6B	108.9	C7—N1—C9	113.11 (13)
C5—C6—H6B	108.9	C7—N1—C6	114.36 (13)
H6A—C6—H6B	107.7	C9—N1—C6	110.96 (13)

C5—C2—C3—C5ⁱ	−1.1 (3)	C3ⁱ—C5—C6—N1	110.03 (18)
C1—C2—C3—C5ⁱ	179.79 (17)	N1—C7—C8—Cl1	178.35 (12)
C5—C2—C3—C4	178.23 (17)	N1—C9—C10—Cl2	−69.96 (18)
C1—C2—C3—C4	−0.9 (3)	C8—C7—N1—C9	−86.20 (18)
C3—C2—C5—C3ⁱ	1.1 (3)	C8—C7—N1—C6	145.47 (16)
C1—C2—C5—C3ⁱ	−179.79 (17)	C10—C9—N1—C7	138.52 (16)
C3—C2—C5—C6	−178.45 (15)	C10—C9—N1—C6	−91.42 (19)
C1—C2—C5—C6	0.7 (3)	C5—C6—N1—C7	−54.9 (2)
C2—C5—C6—N1	−70.5 (2)	C5—C6—N1—C9	175.66 (15)

Symmetry code: (i) −x, −y, −z+1.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C1—H1C···N1	0.96	2.43	3.159 (3)	133

Experimental details

Crystal data
Chemical formula	C₂₀H₃₂Cl₄N₂
M_r	442.29
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	298
a, b, c (Å)	13.6694 (14), 9.751 (1), 8.3997 (8)
β (°)	93.695 (2)
V (Å³)	1117.27 (19)
Z	2
Radiation type	Mo Kα
µ (mm⁻¹)	0.54
Crystal size (mm)	0.16 × 0.12 × 0.10

Data collection
Diffractometer	Bruker SMART CCD diffractometer
Absorption correction	Multi-scan (SADABS; Sheldrick,1996)
T_min, T_max	0.919, 0.948
No. of measured, independent and observed [I > 2σ(I)] reflections	13369, 2732, 2283
R_int	0.031
(sin θ/λ)_max (Å⁻¹)	0.667

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.048, 0.134, 1.04
No. of reflections	2732
No. of parameters	120
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.46, −0.25

Computer programs: SMART (Bruker, 2001), SAINT-Plus (Bruker, 2001), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008).

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C1—H1C···N1	0.96	2.43	3.159 (3)	132.7

Acknowledgements

We thank Southwest University (SWUB2006018, XSGX0602) and the Natural Science Foundation of Chongqing (2007BB5369) for financial support.

References

Bruker (2001). SAINT-Plus and SMART. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Duan, J. X., Jiao, H., Kaizerman, J., Stanton, T. & Evans, J. W. (2008). J. Med. Chem. 51, 2412–2420. Web of Science CrossRef PubMed CAS Google Scholar
Rachid, Z., Brahimi, F., Qiu, Q., Williams, C., Hartley, J. M., Hartley, J. A. & Jean-Claude, B. J. (2007). J. Med. Chem. 50, 2605–2608. Web of Science CrossRef PubMed CAS Google Scholar
Sheldrick, G. M. (1996). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Yin, L.-N., Liu, Q.-X., Wu, X.-M., Cheng, F.-J. & Guo, J.-H. (2006). Acta Cryst. E62, o2510–o2511. Web of Science CSD CrossRef IUCr Journals Google Scholar
Zhou, C. H., Gan, L. L., Zhang, F. F., Zhang, Y. Y., Wang, G. Z., Jin, L. & Geng, R. X. (2009). Sci. China Ser. Chem. 52, 415–458. Web of Science CrossRef CAS Google Scholar
Zhuang, Y. Y., Zhou, C. H., Wang, Y. F. & Li, D. H. (2008). Chin. Pharm. J. 43, 1281–1287. CAS Google Scholar

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doi:10.1107/S1600536809026300

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organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

N,N′-[(2,3,5,6-Tetra­methyl-p-phenyl­ene)di­methyl­ene]bis­­[2-chloro-N-(2-chloro­ethyl)ethanamine]

Related literature

Experimental

Crystal data

Data collection

Refinement

Supporting information

Acknowledgements

References

organic compounds

N,N′-[(2,3,5,6-Tetramethyl-p-phenylene)dimethylene]bis[2-chloro-N-(2-chloroethyl)ethanamine]