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

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Di­chloro­phosphinic bis­­(2-chloro­eth­yl)amide

aKey Laboratory of Luminescence and Real-Time Analysis, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chong Qing 400716, People's Republic of China
*Correspondence e-mail: ysong@swu.edu.cn

(Received 29 October 2012; accepted 3 December 2012; online 8 December 2012)

In the title compound, C4H8Cl4NOP, the two chloro­ethyl groups are not related by crystallographic symmetry. The difference in the conformation of the two groups is shown by their N—C—C—Cl torsion angles of 64.57 (15) and 175.62 (10)°.

Related literature

The title compound is a precursor used in the synthesis of the anti­tumor drug cyclo­phosphamide and its analogues. For information on organo­phospho­rus heterocyclic compounds, see: Surendra Babu et al. (2009[Surendra Babu, V. H. H., Krishnaiah, M., Srinivasulu, K., Raju, C. N. & Sreedhar, B. (2009). Acta Cryst. E65, o2700-o2701.]); Srinivasulu et al. (2008[Srinivasulu, K., Babu, B. H., Kumar, K. S., Reddy, C. B., Raju, C. N. & Rooba, D. (2008). J. Heterocycl. Chem. 45, 751-757.]); Krishna et al. (2006[Krishna, J. R., Krishnaiah, M., Stephen Babu, M., Suresh Reddy, C. & Puranik, V. G. (2006). Acta Cryst. E62, o249-o250.]). For the crystal structures of cyclo­phosphamide analogues, see: Camerman & Camerman (1973[Camerman, N. & Camerman, A. (1973). J. Am. Chem. Soc. 95, 5038-5041.]); Jones et al. (1996[Jones, P. G., Thönnessen, H., Fischer, A., Neda, I., Schmutzler, R., Engel, J., Kutscher, B. & Niemeyer, U. (1996). Acta Cryst. C52, 2359-2363.]); Himes et al. (1982[Himes, V. L., Mighell, A. D., Stalick, J. K. & Zon, G. (1982). Acta Cryst. B38, 1009-1012.]); Camerman et al. (1983[Camerman, A., Smith, H. W. & Camerman, N. (1983). J. Med. Chem. 26, 679-683.]); Perales & García-Blanco (1977a[Perales, A. & García-Blanco, S. (1977a). Acta Cryst. B33, 1935-1939.],b[Perales, A. & García-Blanco, S. (1977b). Acta Cryst. B33, 1939-1943.]); Gałdecki & Głowka (1981[Gałdecki, Z. & Głowka, M. L. (1981). Acta Cryst. B37, 1136-1138.]); Boyd et al. (1980[Boyd, V. L., Zon, G. & Himes, V. L. (1980). J. Med. Chem. 23, 372-375.]); Shih et al. (1986[Shih, Y. E. & Wang, J. S. (1986). Heterocycles, 24, 1599-1603.]). For the pharma­cological activity of cyclo­phosphamide analogues, see: Lin et al. (1980[Lin, T. S., Fischer, P. H. & Prusoff, W. H. (1980). J. Med. Chem. 23, 1235-1237.]); Borch & Canute (1991[Borch, R. F. & Canute, G. W. (1991). J. Med. Chem. 34, 3044-3052.]).

[Scheme 1]

Experimental

Crystal data
  • C4H8Cl4NOP

  • Mr = 258.88

  • Monoclinic, P 21 /c

  • a = 9.0723 (15) Å

  • b = 8.4810 (14) Å

  • c = 13.135 (2) Å

  • β = 101.221 (2)°

  • V = 991.4 (3) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 1.30 mm−1

  • T = 298 K

  • 0.16 × 0.12 × 0.10 mm

Data collection
  • Bruker APEXII CCD diffractometer

  • Absorption correction: multi-scan (SADABS; Bruker, 2009[Bruker (2009). APEX2, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]) Tmin = 0.819, Tmax = 0.881

  • 9480 measured reflections

  • 3255 independent reflections

  • 2725 reflections with I > 2σ(I)

  • Rint = 0.020

Refinement
  • R[F2 > 2σ(F2)] = 0.029

  • wR(F2) = 0.090

  • S = 1.05

  • 3255 reflections

  • 101 parameters

  • H-atom parameters constrained

  • Δρmax = 0.57 e Å−3

  • Δρmin = −0.46 e Å−3

Data collection: APEX2 (Bruker, 2009[Bruker (2009). APEX2, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT (Bruker, 2009[Bruker (2009). APEX2, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: SHELXTL (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); software used to prepare material for publication: SHELXTL and local procedures.

Supporting information


Comment top

Cyclophosphamide, a nitrogen mustard alkylating agent, is widely used as an anti-cancer agent. It is converted in the liver to its active form, which is dependent on cytochrome P450 metabolism for its therapeutic effectiveness. During the process of metabolism, a toxic byproduct, acrolein is generated and induces hemorrhagic cystitis. Many cyclophosphamide analogues were developed to reduce this side effect and to find more potent anti-cancer drugs. The title compound is used as an important precursor for the synthesis of cyclophosphamide and its analogues.

In the title molecule (I) (Fig. 1), all bond lengths and angles are within normal ranges and correspond to those observed in related compounds. Atoms C3, N1, P1 and O1 are nearly coplanar, with a dihedral angel of 175.23 (10)° between the C3—N1—P1 and N1—P1—O1 planes. Angles for C3—N—P, P—N—C1 and C1—N—C3 are 120.57 (9)°, 121.02 (9)° and 118.04 (11)°, respectively. It is interesting to notice that two 2-chloroethyls are not symmetry-related, the torsion angle of N1—C1—C2—Cl3is 64.57 (15)°, but the torsion angle of N1—C3—C4—Cl4 is 175.62 (10)°. Although the current compound is conformationally flexible, twist conformation isomers form on closing the phospho-heterocycle, as, for example, in cyclophosphamide (Borch et al., 1991).

Related literature top

The title compound is a precursor used in the synthesis of the antitumor drug cyclophosphamide and its analogues. For information on organophosphorus heterocyclic compounds, see: Surendra Babu et al. (2009); Srinivasulu et al. (2008); Krishna et al. (2006). For the crystal structures of cyclophosphamide analogues, see: Camerman & Camerman (1973); Jones et al. (1996); Himes et al. (1982); Camerman et al. (1983); Perales & García-Blanco (1977a,b); Gałdecki & Głowka (1981); Boyd et al. (1980); Shih et al. (1986). For the pharmacological activity of cyclophosphamide analogues, see: Lin et al. (1980); Borch & Canute (1991).

Experimental top

Bis(2-chloroethyl)amine hydrochloride (20.0 g, 0.112 mol) was added dropwise into a 250 ml round bottom bottle containing POCl3 (52 ml, 0.6 mol). Then the mixture was refluxed for 20 h at 110 °C. The disappearance of solid bis(2-chloroethyl)amine hydrochloride indicated completion of the reaction. To remove excess POCl3, reduced vacuum was used. The crude were dissolved into ethyl acetate and the precipitate was filtered off. The filtrate was concentrated in vacuo and the resulting residue was recrystallized with acetone and hexane (v/v = 1:5), giving white crystals (18.0 g) in a yield of 61%. Single crystals for X-ray diffraction were grown at room temperature by slow evaporation from the solution of the title compound in ethanol.

Refinement top

The H-atoms bonded to C-atoms were positioned geometrically and refined using a riding model, with C—H = 0.93 Å, and with Uiso(H) = 1.2 Ueq(C).

Computing details top

Data collection: APEX2 (Bruker, 2009); cell refinement: SAINT (Bruker, 2009); data reduction: SAINT (Bruker, 2009); 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) and local procedures.

Figures top
[Figure 1] Fig. 1. View of the title compound showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 30% probability level.
[Figure 2] Fig. 2. Crystal packing of title compound, viewed approximately down the a axis, illustrating the stacking of the molecules along the a axis.
Dichlorophosphinic bis(2-chloroethyl)amide top
Crystal data top
C4H8Cl4NOPF(000) = 520
Mr = 258.88Dx = 1.735 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 9.0723 (15) ÅCell parameters from 4728 reflections
b = 8.4810 (14) Åθ = 2.3–31.1°
c = 13.135 (2) ŵ = 1.30 mm1
β = 101.221 (2)°T = 298 K
V = 991.4 (3) Å3Block, colourless
Z = 40.16 × 0.12 × 0.10 mm
Data collection top
Bruker APEXII CCD
diffractometer
3255 independent reflections
Radiation source: fine-focus sealed tube2725 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.020
ϕ and ω scansθmax = 32.2°, θmin = 2.3°
Absorption correction: multi-scan
(SADABS; Bruker, 2009)
h = 1313
Tmin = 0.819, Tmax = 0.881k = 1212
9480 measured reflectionsl = 1913
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)] = 0.029H-atom parameters constrained
wR(F2) = 0.090 w = 1/[σ2(Fo2) + (0.0482P)2 + 0.1876P]
where P = (Fo2 + 2Fc2)/3
S = 1.05(Δ/σ)max = 0.002
3255 reflectionsΔρmax = 0.57 e Å3
101 parametersΔρmin = 0.46 e Å3
0 restraintsExtinction correction: SHELXL97 (Sheldrick, 2008), Fc*=kFc[1+0.001xFc2λ3/sin(2θ)]-1/4
Primary atom site location: structure-invariant direct methodsExtinction coefficient: 0.0064 (13)
Crystal data top
C4H8Cl4NOPV = 991.4 (3) Å3
Mr = 258.88Z = 4
Monoclinic, P21/cMo Kα radiation
a = 9.0723 (15) ŵ = 1.30 mm1
b = 8.4810 (14) ÅT = 298 K
c = 13.135 (2) Å0.16 × 0.12 × 0.10 mm
β = 101.221 (2)°
Data collection top
Bruker APEXII CCD
diffractometer
3255 independent reflections
Absorption correction: multi-scan
(SADABS; Bruker, 2009)
2725 reflections with I > 2σ(I)
Tmin = 0.819, Tmax = 0.881Rint = 0.020
9480 measured reflections
Refinement top
R[F2 > 2σ(F2)] = 0.0290 restraints
wR(F2) = 0.090H-atom parameters constrained
S = 1.05Δρmax = 0.57 e Å3
3255 reflectionsΔρmin = 0.46 e Å3
101 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
xyzUiso*/Ueq
C10.38633 (16)0.82538 (16)0.87493 (12)0.0381 (3)
H1A0.43010.78450.81860.046*
H1B0.46820.85440.93100.046*
C20.2970 (2)0.97152 (18)0.83776 (13)0.0467 (3)
H2A0.21250.94320.78340.056*
H2B0.35991.04470.80870.056*
C30.19521 (15)0.60676 (16)0.83359 (10)0.0353 (3)
H3A0.14290.67690.78020.042*
H3B0.12080.55560.86620.042*
C40.27918 (18)0.48303 (19)0.78420 (13)0.0448 (3)
H4A0.33740.41690.83760.054*
H4B0.34790.53370.74630.054*
Cl10.31341 (5)0.44237 (4)1.05878 (3)0.05244 (12)
Cl30.22968 (5)1.06456 (5)0.94101 (4)0.05789 (13)
Cl20.08981 (4)0.71564 (5)1.05773 (3)0.05103 (12)
Cl40.14781 (6)0.36563 (5)0.69800 (4)0.06145 (14)
N10.29789 (12)0.69934 (13)0.91169 (9)0.0328 (2)
O10.41231 (13)0.76345 (14)1.10623 (8)0.0474 (3)
P10.29887 (4)0.67627 (4)1.03420 (3)0.03356 (10)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0403 (6)0.0353 (6)0.0409 (7)0.0035 (5)0.0131 (5)0.0024 (5)
C20.0600 (9)0.0347 (6)0.0451 (8)0.0025 (6)0.0094 (7)0.0020 (6)
C30.0376 (6)0.0343 (6)0.0330 (6)0.0004 (5)0.0042 (5)0.0035 (5)
C40.0481 (8)0.0409 (7)0.0444 (8)0.0001 (6)0.0067 (6)0.0131 (6)
Cl10.0676 (3)0.03754 (19)0.0523 (2)0.00726 (15)0.01214 (19)0.01047 (15)
Cl30.0608 (3)0.0414 (2)0.0733 (3)0.00801 (16)0.0174 (2)0.01022 (18)
Cl20.04327 (19)0.0641 (3)0.0497 (2)0.00731 (16)0.01884 (16)0.00236 (17)
Cl40.0777 (3)0.0514 (2)0.0521 (3)0.0121 (2)0.0049 (2)0.01980 (19)
N10.0376 (5)0.0315 (5)0.0292 (5)0.0022 (4)0.0062 (4)0.0026 (4)
O10.0479 (6)0.0540 (6)0.0369 (5)0.0032 (5)0.0006 (4)0.0072 (5)
P10.03567 (17)0.03484 (17)0.02971 (16)0.00247 (12)0.00520 (12)0.00150 (12)
Geometric parameters (Å, º) top
C1—N11.4732 (18)C3—H3A0.9700
C1—C21.509 (2)C3—H3B0.9700
C1—H1A0.9700C4—Cl41.7800 (16)
C1—H1B0.9700C4—H4A0.9700
C2—Cl31.7767 (17)C4—H4B0.9700
C2—H2A0.9700Cl1—P12.0100 (6)
C2—H2B0.9700Cl2—P12.0081 (6)
C3—N11.4713 (16)N1—P11.6195 (12)
C3—C41.515 (2)O1—P11.4567 (11)
N1—C1—C2114.16 (12)H3A—C3—H3B108.0
N1—C1—H1A108.7C3—C4—Cl4109.25 (11)
C2—C1—H1A108.7C3—C4—H4A109.8
N1—C1—H1B108.7Cl4—C4—H4A109.8
C2—C1—H1B108.7C3—C4—H4B109.8
H1A—C1—H1B107.6Cl4—C4—H4B109.8
C1—C2—Cl3111.13 (11)H4A—C4—H4B108.3
C1—C2—H2A109.4C3—N1—C1118.04 (11)
Cl3—C2—H2A109.4C3—N1—P1120.57 (9)
C1—C2—H2B109.4C1—N1—P1121.02 (9)
Cl3—C2—H2B109.4O1—P1—N1116.78 (7)
H2A—C2—H2B108.0O1—P1—Cl2112.63 (5)
N1—C3—C4111.43 (11)N1—P1—Cl2108.07 (5)
N1—C3—H3A109.3O1—P1—Cl1112.37 (5)
C4—C3—H3A109.3N1—P1—Cl1105.45 (4)
N1—C3—H3B109.3Cl2—P1—Cl1100.01 (2)
C4—C3—H3B109.3
N1—C1—C2—Cl364.57 (15)C3—N1—P1—O1175.23 (10)
N1—C3—C4—Cl4175.62 (10)C1—N1—P1—O111.87 (13)
C4—C3—N1—C178.71 (15)C3—N1—P1—Cl256.60 (10)
C4—C3—N1—P1108.18 (13)C1—N1—P1—Cl2116.30 (10)
C2—C1—N1—C375.10 (16)C3—N1—P1—Cl149.65 (10)
C2—C1—N1—P197.97 (14)C1—N1—P1—Cl1137.45 (10)

Experimental details

Crystal data
Chemical formulaC4H8Cl4NOP
Mr258.88
Crystal system, space groupMonoclinic, P21/c
Temperature (K)298
a, b, c (Å)9.0723 (15), 8.4810 (14), 13.135 (2)
β (°) 101.221 (2)
V3)991.4 (3)
Z4
Radiation typeMo Kα
µ (mm1)1.30
Crystal size (mm)0.16 × 0.12 × 0.10
Data collection
DiffractometerBruker APEXII CCD
diffractometer
Absorption correctionMulti-scan
(SADABS; Bruker, 2009)
Tmin, Tmax0.819, 0.881
No. of measured, independent and
observed [I > 2σ(I)] reflections
9480, 3255, 2725
Rint0.020
(sin θ/λ)max1)0.749
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.029, 0.090, 1.05
No. of reflections3255
No. of parameters101
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.57, 0.46

Computer programs: APEX2 (Bruker, 2009), SAINT (Bruker, 2009), SHELXS97 (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008), SHELXTL (Sheldrick, 2008) and local procedures.

 

Acknowledgements

This work was supported by the Program for New Century Excellent Talents in Universities (NCET-10–0660), the National Scientific & Technological Special Project – Major Creation of New Drugs (Nos. 2010ZX09401–306-1–4 and 2010ZX09401–306-2–19) and the 211 Project of Southwest University (the Third Term).

References

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First citationBoyd, V. L., Zon, G. & Himes, V. L. (1980). J. Med. Chem. 23, 372–375.  CSD CrossRef CAS PubMed Web of Science
First citationBruker (2009). APEX2, SADABS and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.
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First citationCamerman, A., Smith, H. W. & Camerman, N. (1983). J. Med. Chem. 26, 679–683.  CSD CrossRef CAS PubMed Web of Science
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First citationPerales, A. & García-Blanco, S. (1977b). Acta Cryst. B33, 1939–1943.  CSD CrossRef CAS IUCr Journals Web of Science
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First citationSurendra Babu, V. H. H., Krishnaiah, M., Srinivasulu, K., Raju, C. N. & Sreedhar, B. (2009). Acta Cryst. E65, o2700–o2701.  CrossRef CAS IUCr Journals

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