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Volume 67 
Part 12 
Pages o484-o486  
December 2011  

Received 19 September 2011
Accepted 20 October 2011
Online 5 November 2011

Two tautomeric polymorphs of 2,6-dichloropurine

aDepartamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Campus de Cartuja s/n, 18071 Granada, Spain, and bLaboratorio de Estudios Cristalográficos, IACT, CSIC-Universidad de Granada, Avenida de las Palmeras 4, 18100 Armilla, Granada, Spain
Correspondence e-mail: jmcampos@ugr.es

Two polymorphs of 2,6-dichloropurine, C5H2Cl2N4, have been crystallized and identified as the 9H- and 7H-tautomers. Despite differences in the space group and number of symmetry-independent molecules, they exhibit similar hydrogen-bonding motifs. Both crystal structures are stabilized by intermolecular N-H...N interactions that link adjacent molecules into linear chains, and by some nonbonding contacts of the C-Cl...[pi] type and by [pi]-[pi] stacking interactions, giving rise to a crossed two-dimensional herringbone packing motif. The main structural difference between the two polymorphs is the different role of the molecules in the [pi]-[pi] stacking interactions.

Comment

2,6-Dichloropurine is an important pharmaceutical intermediate (Schaefer et al., 1978[Schaefer, H. J., Beauchamp, L., de Miranda, P., Elion, G. B., Bauer, D. J. & Collins, P. (1978). Nature (London), 272, 583-585.]) used in the preparation of purine nucleosides and nucleotides, and other purine derivatives of great importance owing to their biological properties (Nair & Pal, 1998[Nair, V. & Pal, S. (1998). Int. Patent WO 9817781.]; Rao Kode & Phadtare, 2011[Rao Kode, N. & Phadtare, S. (2011). Molecules, 16, 5840-5860.]).

[Scheme 1]

Polymorphism, the ability of a given molecule to crystallize in different crystal structures, is a phenomenon often observed for organics (Bernstein, 2011[Bernstein, J. (2011). Cryst. Growth Des. 11, 632-650.]; Brittain, 2011[Brittain, H. G. (2011). J. Pharm. Sci. 100, 1260-1279.]). The term `tautomeric polymorphs' refers to those tautomers of a given compound that crystallize in different crystal structures and they are very rarely observed (Cruz Cabeza et al., 2011[Cruz Cabeza, A. J. & Groom, C. (2011). CrystEngComm, 13, 93-98.]). We present here the crystal structure of the 9H-, (I)[link], and 7H-, (II)[link], tautomers of 2,6-dichloropurine.

The molecular geometric parameters in the two presented polymorphs are similar, but the structures differ in the finer details of their crystal packing. As shown in Fig. 1[link], polymorph (I)[link] crystallizes with two independent molecules in the asymmetric unit (A and B, top and middle) as the 9H-tautomer, while polymorph (II)[link] crystallizes with one symmetry-independent molecule (bottom) as the 7H-tautomer.

The effect of the different -N(H) position in the tautomeric forms (N9 or N7) gives rise to subtle differences between the relevant bond lengths and angles in both structures in the imidazole ring. In (I)[link], the N=Csp2 bond corresponds to N7-C8 [1.310 (5) Å] and N17-C18 [1.307 (5) Å] for molecules A and B, respectively, while in (II)[link] it is N9-C8 [1.327 (3) Å]. These N=Csp2 bond lengths are comparable with those in related structures with 9H- (Mahapatra et al., 2008[Mahapatra, S., Nayak, S. K., Prathapa, S. J. & Guru Row, T. N. (2008). Cryst. Growth Des. 8, 1223-1225.]; Trávnícek & Rosenker, 2006[Trávnícek, Z. & Rosenker, C. J. (2006). Acta Cryst. E62, o3393-o3395.]; Soriano-Garcia & Parthasarathy, 1977[Soriano-Garcia, M. & Parthasarathy, R. (1977). Acta Cryst. B33, 2674-2677.]) and 7H-tautomers (Bo et al., 2006[Bo, Y., Cheng, K., Bi, S. & Zhang, S.-S. (2006). Acta Cryst. E62, o4174-o4175.]; Ikonen et al., 2009[Ikonen, S., Valkonen, A. & Kolehmainen, E. (2009). J. Mol. Struct. 930, 147-156.]; Watson et al., 1965[Watson, D. G., Sweet, R. M. & Marsh, R. E. (1965). Acta Cryst. 19, 573-580.]). The -N(H) tautomeric position is also evident from the greater ring angle at the site where the H atom is attached, namely N9 [C4-N9-C8 = 105.9 (3)°] and N19 [C14-N19-C18 = 105.6 (3)°] for (I)[link], and N7 [C5-N7-C8 = 105.9 (2)°] for (II)[link], compared with the ring angle involving the -N=C- bond [for (I)[link], C5-N7-C8 = 103.6 (3)° and C15-N17-C18 = 103.8 (3)°; for (II)[link], C4-N9-C8 = 103.6 (2)°]. In both polymorphs, the 2,6-dichloropurine molecules form linear chains along the b axis through intermolecular N-H...N interactions forming C(4) motifs (Bernstein et al., 1995[Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.]).

In polymorph (I)[link], chains built by molecules of type A are linked by intermolecular face-to-face [pi]-[pi] stacking interactions involving the N1/C2/N3/C4-C6 ring and a symmetry-related counterpart at (-x + 1, -y + 1, -z + 1), with a centroid-centroid distance of 3.493 (3) Å. Molecules of type B are not involved in [pi]-[pi] stacking interactions. There are also C-Cl...[pi] interactions involving atom Cl16 and ring N1/C2/N3/C4-C6 (Cg1I), with a Cl...centroid distance of 3.468 (2) Å and a C16-Cl16...Cg1Ii angle of 113.46 (17)° [symmetry code: (i) x, -y + [{1\over 2}], z + [{1\over 2}]], and atom Cl6 and ring N11/C12/N13/C14-C16 (Cg2I), with a Cl...centroid distance of 3.664 (2) Å and a C6-Cl6...Cg2I angle of 94.54 (13)°, resulting in a structure containing a two-dimensional herringbone-like motif of constituent molecules.

The crystal structure of polymorph (II)[link] is similar to that of polymorph (I)[link]. Despite the fact that [pi]-[pi] stacking interactions are not observed in (II)[link], the supramolecular structure features a similar herringbone motif to that in (I)[link], due to the presence of C-Cl...[pi] interactions between atom Cl6 and ring N1/C2/N3/C4-C6 (Cg1II), with a Cl...centroid distance of 3.3471 (15) Å and a C6-Cl6...Cg1IIii angle of 108.45 (10)° [symmetry code: (ii) x - [{1\over 2}], -y + [{3\over 2}], -z + 1]. As a consequence of the absence of stacking interactions in (II)[link], the width of the herringbone motif (12.352 Å) is greater than that of (I)[link] (11.797 Å) (Fig. 2[link]) [the width of the motifs was calculated as the distance between the two planes containing the furthermost atoms in the herringbone motif, corresponding to the Cl atoms of 2,6-dichloropurine; 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.])].

[Figure 1]
Figure 1
The contents of the asymmetric units of polymorph (I)[link] (top and middle) and polymorph (II)[link] (bottom), showing the atom-numbering schemes. Displacement ellipsoids are drawn at the 50% probability level.
[Figure 2]
Figure 2
A view of the crystal packing, showing the herringbone arrangement of 2,6-dichloropurine molecules in polymorph (I)[link] (left) and polymorph (II)[link] (right).

Experimental

Polymorph (I)[link] (m.p. 466.05-466.75 K) was obtained unintentionally in an attempted synthesis of (RS)-2,6-dichloro-9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purine (Díaz-Gavilán et al., 2008[Díaz-Gavilán, M., Conejo-García, A., Cruz-López, O., Núñez, M. C., Choquesillo-Lazarte, D., González-Pérez, J. M., Rodríguez-Serrano, F., Marchal, J. A., Aránega, A., Gallo, M. A., Espinosa, A. & Campos, J. M. (2008). ChemMedChem, 3, 127-135.]). Unreacted 2,6-dichloropurine was recovered using ethyl acetate as eluent. After concentrating the solvent under reduced pressure, suitable crystals of 2,6-dichloropurine were obtained after dissolving the compound in CH2Cl2. A vial with a screw top allowed slow evaporation of the solvent at room temperature to produce colourless crystals. Crystals of polymorph (II)[link] (m.p. 467.95-468.85 K) were obtained by solvent evaporation with commercially available 2,6-dichloropurine using ethanol as solvent. The remarkable similarity of the crystal structures of the reported polymorphs yields minimal differences in the shape and position of the peaks in the FT-IR spectra (polycrystalline samples in KBr disks). Hence, the stretching mode [nu](N-H) (a weak peak at 3210 cm-1) and the in-plane deformation mode [delta](N-H) (1513 cm-1) appear at the same site in (I)[link] and (II)[link].

Polymorph (I)[link]

Crystal data
  • C5H2Cl2N4

  • Mr = 189.01

  • Monoclinic, P 21 /c

  • a = 14.0867 (12) Å

  • b = 9.4898 (7) Å

  • c = 12.2656 (9) Å

  • [beta] = 115.381 (4)°

  • V = 1481.4 (2) Å3

  • Z = 8

  • Cu K[alpha] radiation

  • [mu] = 7.36 mm-1

  • T = 296 K

  • 0.12 × 0.10 × 0.06 mm

Data collection
  • Bruker X8 Proteum diffractometer

  • Absorption correction: multi-scan (SADABS; Bruker, 2001[Bruker (2001). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]) Tmin = 0.377, Tmax = 0.753

  • 18199 measured reflections

  • 2547 independent reflections

  • 1713 reflections with I > 2[sigma](I)

  • Rint = 0.085

Refinement
  • R[F2 > 2[sigma](F2)] = 0.051

  • wR(F2) = 0.154

  • S = 1.10

  • 2547 reflections

  • 199 parameters

  • H-atom parameters constrained

  • [Delta][rho]max = 0.27 e Å-3

  • [Delta][rho]min = -0.29 e Å-3

Table 1
Hydrogen-bond geometry (Å, °) for polymorph (I)[link]

D-H...A D-H H...A D...A D-H...A
N9-H9...N7i 0.86 1.96 2.785 (4) 161
N19-H19...N17ii 0.86 1.94 2.768 (5) 160
Symmetry codes: (i) [-x+1, y+{\script{1\over 2}}, -z+{\script{1\over 2}}]; (ii) [-x+2, y+{\script{1\over 2}}, -z+{\script{3\over 2}}].

Polymorph (II)[link]

Crystal data
  • C5H2Cl2N4

  • Mr = 189.01

  • Orthorhombic, P 21 21 21

  • a = 5.5716 (9) Å

  • b = 9.5820 (16) Å

  • c = 13.159 (2) Å

  • V = 702.5 (2) Å3

  • Z = 4

  • Mo K[alpha] radiation

  • [mu] = 0.85 mm-1

  • T = 120 K

  • 0.12 × 0.10 × 0.08 mm

Data collection
  • Bruker SMART APEX diffractometer

  • Absorption correction: multi-scan (SADABS; Bruker, 2001[Bruker (2001). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.]) Tmin = 0.905, Tmax = 0.935

  • 6847 measured reflections

  • 1243 independent reflections

  • 1156 reflections with I > 2[sigma](I)

  • Rint = 0.041

Refinement
  • R[F2 > 2[sigma](F2)] = 0.033

  • wR(F2) = 0.071

  • S = 1.38

  • 1243 reflections

  • 100 parameters

  • H-atom parameters constrained

  • [Delta][rho]max = 0.33 e Å-3

  • [Delta][rho]min = -0.22 e Å-3

  • Absolute structure: Flack (1983[Flack, H. D. (1983). Acta Cryst. A39, 876-881.]), with 489 Friedel pairs

  • Flack parameter: 0.03 (10)

Table 2
Hydrogen-bond geometry (Å, °) for polymorph (II)[link]

D-H...A D-H H...A D...A D-H...A
N7-H7...N9i 0.94 1.88 2.774 (3) 158
Symmetry code: (i) [-x+1, y+{\script{1\over 2}}, -z+{\script{3\over 2}}].

H atoms on N atoms were located in difference maps and refined as riding, with N-H = 0.86 [in (I)] and 0.94 Å [in (II)], and Uiso(H) = 1.2Ueq(N). Other H atoms were positioned geometrically and treated as riding, with C-H = 0.93-0.95 Å and Uiso(H) = 1.2Ueq(C).

For both compounds, data collection: APEX2 (Bruker, 2010[Bruker (2010). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.]); cell refinement: SAINT (Bruker, 2010[Bruker (2010). APEX2 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: PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]); software used to prepare material for publication: publCIF (Westrip, 2010[Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.]).


Supplementary data for this paper are available from the IUCr electronic archives (Reference: GG3264 ). Services for accessing these data are described at the back of the journal.


Acknowledgements

The project `Factoría de Cristalización, CONSOLIDER INGENIO-2010' provided X-ray structural facilities for this work.

References

Bernstein, J. (2011). Cryst. Growth Des. 11, 632-650.  [CrossRef] [ChemPort]
Bernstein, J., Davis, R. E., Shimoni, L. & Chang, N.-L. (1995). Angew. Chem. Int. Ed. Engl. 34, 1555-1573.  [CrossRef] [ChemPort] [ISI]
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Brittain, H. G. (2011). J. Pharm. Sci. 100, 1260-1279.  [ISI] [CrossRef] [ChemPort]
Bruker (2001). SADABS. Bruker AXS Inc., Madison, Wisconsin, USA.
Bruker (2010). APEX2 and SAINT. Bruker AXS Inc., Madison, Wisconsin, USA.
Cruz Cabeza, A. J. & Groom, C. (2011). CrystEngComm, 13, 93-98.  [ChemPort]
Díaz-Gavilán, M., Conejo-García, A., Cruz-López, O., Núñez, M. C., Choquesillo-Lazarte, D., González-Pérez, J. M., Rodríguez-Serrano, F., Marchal, J. A., Aránega, A., Gallo, M. A., Espinosa, A. & Campos, J. M. (2008). ChemMedChem, 3, 127-135.  [PubMed]
Flack, H. D. (1983). Acta Cryst. A39, 876-881.  [CrossRef] [details]
Ikonen, S., Valkonen, A. & Kolehmainen, E. (2009). J. Mol. Struct. 930, 147-156.  [ISI] [CSD] [CrossRef] [ChemPort]
Mahapatra, S., Nayak, S. K., Prathapa, S. J. & Guru Row, T. N. (2008). Cryst. Growth Des. 8, 1223-1225.  [CSD] [CrossRef] [ChemPort]
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.  [ISI] [CrossRef] [ChemPort] [details]
Nair, V. & Pal, S. (1998). Int. Patent WO 9817781.
Rao Kode, N. & Phadtare, S. (2011). Molecules, 16, 5840-5860.  [PubMed]
Schaefer, H. J., Beauchamp, L., de Miranda, P., Elion, G. B., Bauer, D. J. & Collins, P. (1978). Nature (London), 272, 583-585.  [PubMed] [ISI]
Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.  [CrossRef] [details]
Soriano-Garcia, M. & Parthasarathy, R. (1977). Acta Cryst. B33, 2674-2677.  [CrossRef] [details] [ISI]
Spek, A. L. (2009). Acta Cryst. D65, 148-155.  [ISI] [CrossRef] [details]
Trávnícek, Z. & Rosenker, C. J. (2006). Acta Cryst. E62, o3393-o3395.  [CSD] [CrossRef] [details]
Watson, D. G., Sweet, R. M. & Marsh, R. E. (1965). Acta Cryst. 19, 573-580.  [CrossRef] [ChemPort] [details]
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920-925.  [ISI] [CrossRef] [ChemPort] [details]


Acta Cryst (2011). C67, o484-o486   [ doi:10.1107/S0108270111043575 ]