research papers Acta Crystallographica Section C
Structural Chemistry ISSN 2053-2296
The first polymorph in the family of nucleobases: a second form of cytosine Balasubramanian Sridhar,* Jagadeesh Babu Nanubolu and Krishnan Ravikumar X-ray Crystallography Division, CSIR–Indian Institute of Chemical Technology, Hyderabad 500 007, India Correspondence e-mail:
[email protected] Received 17 November 2014 Accepted 9 January 2015
A new polymorph of cytosine, C4H5N3O, is reported half a century after the report of its first known crystal structure [Barker & Marsh (1964). Acta Cryst. 17, 1581–1587]. Cytosine thus provides the first polymorphic example in the category of parent nucleobases. The new form, denoted (Ib), was observed unexpectedly during an attempt to cocrystallize cytosine with catechol. Form (Ib) crystallizes in the orthorhombic centrosymmetric space group Pccn with two molecules in the asymmetric unit. The previously known form, denoted (Ia), crystallizes in the orthorhombic noncentrosymmetric space group P212121. The cytosine molecule is planar in both forms. Hydrogen-bonding interactions are also similar for both forms. Infinite one-dimensional ribbons composed of cytosine base-pair dimers in R22(8) arrangements are observed in both (Ia) and (Ib). However, the way that the ribbons are packed differs in (Ia) and (Ib). This appears to guide the centrosymmetric versus noncentrosymmetric space-group selection through the formation of an inversion-related motif in polymorph (Ib) and a helical propagation in polymorph (Ia). A few selected polymorphic systems have been gathered from the Cambridge Structural Database to understand possible structural features responsible for achiral molecules adopting centro- and noncentrosymmetric space groups. Keywords: polymorphism; nucleobases; cytosine; crystal structure; 4-aminopyrimidin-2(1H)-one; RNA/DNA building blocks; genetic information.
1. Introduction Polymorphism is the existence of two or more different crystal structures for the same compound. Gavezzotti (2007) has described the concept of polymorphism in more detail. According to his view, it is sets of crystals having (a) identical chemical compositions, (b) the same molecular connectivity
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which may differ in its conformations and (c) different intermolecular interactions. In addition to routine crystal structure analysis of polymorphic systems, studies have been carried out at different pressures and temperatures to understand their solid-state phase transformations and stability. Different polymorphic forms can lead to significant changes in physical properties, such as colour, solubility, bioavailability and thermodynamic stability (Timofeeva et al., 2003; Price et al., 2003; Vrcelj et al., 2003). One of the popular examples is glycine, which exhibits different physical and chemical properties. The - and -forms exhibit piezoelectric properties (Iitaka, 1958, 1960), whereas the -form shows pyroelectricity near room temperature (Chilcott et al., 1999). According to McCrone (1965), the number of polymorphic modifications of a particular compound is in direct proportion to the time and money spent on the search for them. Recently, we have published several research articles on multicomponent crystals of cytosine with carboxylic acid. This has allowed us to study their supramolecular hydrogenbonded interactions and molecular recognition of nucleobases in the solid state (Sridhar & Ravikumar, 2008, 2010a,b; Sridhar et al., 2012). In continuation of this work, attempts were made to grow cocrystals of nucleobases and different hydroxycontaining co-formers like catechol, resorcinol and hydroquinone. Unexpectedly, a new form of cytosine was observed. Attempted cocrystallization leading to the discovery of new forms is not unprecedented (Rafilovich & Bernstein, 2006; Babu et al., 2008). Cytosine is one of the nucleobases in the building blocks of RNA and DNA, which store and transport genetic information within the cell. The first crystal structure of cytosine [referred to as polymorph (Ia)] was determined in 1964 by the photographic method (Barker & Marsh, 1964) and the structure was later redetermined using X-ray diffraction (McClure & Craven, 1973). Now, after half a century, a second polymorph of cytosine [referred to as polymorph (Ib)] has been identified in our laboratory.
No polymorphic forms have been reported for any of the parent nucleobases until now. Cytosine is the first polymorphic example. Notably, all the crystal structures of nucleobases crystallize in centrosymmetric space groups, with the exception of the cytosine system, which crystallizes in both centroand noncentrosymmetric space groups. Adenine, thymine and guanine crystallize in the monoclinic space group P21/c (Ozeki et al., 1969; Guille & Clegg, 2006; Mahapatra et al., 2008), as does uracil, although it was reported using the P21/a setting (Stewart & Jensen, 1967), whereas polymorph (Ia) of cytosine crystallizes in the orthorhombic P212121 space group and polymorph (Ib) of cytosine crystallizes in the orthorhombic Pccn space group.
doi:10.1107/S2053229615000492
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research papers 2. Experimental
Table 1 Experimental details.
2.1. Synthesis and crystallization
Cytosine (Sigma–Aldrich India) and catechol (Himedia Laboratories, Hyderabad) were used as received for the attempted preparation of cocrystals in a methanol–water mixture. Cytosine (0.025 g, 0.23 mmol) and catechol (0.025 g, 0.23 mmol) were dissolved in a mixture of methanol and water (20 ml, 4:1 v/v). The resulting solution was warmed and allowed to stand for slow evaporation at room temperature. On completion of the evaporation of the solvent, we found that most of the material (black in colour) had deposited on the walls of the container, leaving a few transparent crystals at the bottom, which were later found to be the new form of cytosine, (Ib), by single-crystal X-ray diffraction. Despite several attempts, it was not possible to obtain crystals of (Ib) again. A powder X-ray diffraction (PXRD) spectrum could not be measured for the cytosine single crystals due to an insufficient quantity of crystals, but it was possible to record NMR and ESI–MS spectra using the few available crystals of (Ib). 2.2. Mass spectrometry analysis
Electrospray ionization (ESI) mass spectrometry analyses were carried out in both positive and negative ion modes using an Exactive Orbitrap mass spectrometer (Thermo Scientific, Waltham, Massachusetts, USA). The samples were dissolved in methanol and infused directly into the source of the mass spectrometer at a flow rate of 5 ml min1. ESI mass spectra were recorded for pure cytosine, pure catechol, cytosine crystals and the black material (residue). Pure cytosine was detected as a protonated molecule ion, [M + H] + (m/z 112.05053), under positive ion mode, and pure catechol was detected as a deprotonated molecule ion, [M H] (m/z 109.02808), under negative ion mode. The accurate mass values of these pseudomolecular ions match well with their exact mass values (m/z 112.05054 and 109.02841, respectively) to within 3 p.p.m. The spectrum recorded for the cytosine crystals showed a peak at m/z 112.05036 matching with the spectrum of pure cytosine. The black material showed the presence of cytosine (m/z 112.05075) and catechol (m/z 109.02823) under positive and negative ion modes of analysis, respectively.
Crystal data Chemical formula Mr Crystal system, space group Temperature (K) ˚) a, b, c (A ˚ 3) V (A Z Radiation type (mm1) Crystal size (mm) Data collection Diffractometer Absorption correction Tmin, Tmax No. of measured, independent and observed [I > 2(I)] reflections Rint ˚ 1) (sin /)max (A Refinement R[F 2 > 2(F 2)], wR(F 2), S No. of reflections No. of parameters H-atom treatment ˚ 3) max, min (e A
C4H5N3O 111.11 Orthorhombic, Pccn 294 15.104 (1), 15.1212 (10), 9.2948 (6) 2122.8 (2) 16 Mo K 0.11 0.21 0.12 0.08
Bruker SMART APEX CCD areadetector diffractometer Multi-scan (SADABS; Bruker, 2001) 0.97, 0.99 20913, 2137, 1933 0.029 0.622
0.052, 0.136, 1.20 2137 169 H atoms treated by a mixture of independent and constrained refinement 0.25, 0.18
Computer programs: SMART (Bruker, 2001), SAINT (Bruker, 2001), SHELXS97 (Sheldrick, 2015), SHELXL2014 (Sheldrick, 2015), DIAMOND (Brandenburg & Putz, 2005) and SHELXL97 (Sheldrick, 2015).
black material corresponds to a mixture of cytosine and catechol. 2.4. Powder X-ray diffraction (PXRD)
PXRD patterns were recorded for pure cytosine, pure catechol and the black material at room temperature using a Bruker D8 Advance diffractometer with Cu K radiation ( = ˚ ), running at 40 kV and 30 mA. The 2 range covered 1.5406 A from 2 to 50 , with a step size of 0.0005 and a step time of 13.6 s. The PXRD spectrum clearly confirms the presence of both cytosine and catechol crystalline materials in the black residue.
2.3. NMR analysis
The NMR studies were carried out in DMSO-d6 solvent at 298 K using a Bruker AVANCE 500 MHz spectrometer. 1 H NMR spectrum of cytosine: 10.50 (bs, 1H), 7.30 (d, 1H, J = 6.89 Hz), 7.06 (bs, 2H), 5.57 (d, 1H, J = 6.89 Hz); 1H NMR spectrum of catechol: 8.80 (bs, 2H), 6.72 (m, 2H), 6.60 (m, 2H); 1 H NMR spectrum of cytosine crystals: 10.33 (bs, 1H), 7.30 (d, 1H, J = 6.9 Hz), 6.9–7.1 (bd, 2H), 5.56 (d, 1H, J = 6.9 Hz); 1 H NMR spectrum of black material (residue): 10.47 (bs, 1H), 8.80 (bs, 2H), 7.32 (d, 1H, J = 6.9 Hz), 7.09 (bs, 2H), 6.72 (m, 2H), 6.59(m, 2H), 5.60 (d, 1H, J = 6.9 Hz). From these NMR analyses, the transparent crystals match pure cytosine and the Acta Cryst. (2015). C71, 128–135
Figure 1 The molecular structure of cytosine polymorph (Ib), showing the atomlabelling scheme. Displacement ellipsoids are drawn at the 30% probability level. The dashed line indicates a hydrogen bond. Sridhar et al.
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Figure 2 Part of the crystal structure of polymorph (Ib), showing the hydrogen-bonding interactions. Adjacent inversion-related ribbons formed by cytosine molecules A and B are interlinked by N—H O hydrogen bonds, forming a hexameric hydrogen-bonded cavity with an R66 (30) motif. Hydrogen bonds are shown as dashed lines and H atoms not involved in hydrogen bonding have been omitted for clarity. Only atoms involved in hydrogen bonding are labelled. [Symmetry codes: (i) x, y + 12, z 12; (ii) x, y + 12, z + 12; (iii) x + 12, y, z 12; (iv) x + 12, y, z + 12; (v) x 12, y + 12, z + 1.]
2.5. Refinement
Crystal data, data collection and structure refinement details are summarized in Table 1. All N-bound H atoms were located in a difference density map and were refined isotropically. C-bound H atoms were also located in difference density maps but were positioned geometrically and included ˚ and Uiso(H) = 1.2Ueq(C). as riding atoms, with C—H = 0.93 A
3. Results and discussion The asymmetric unit of polymorph (Ib) contains two crystallographically independent molecules (labelled with the suffixes A and B), whereas polymorph (Ia) has only one molecule in the asymmetric unit. The molecular structure of polymorph (Ib), together with the atom-numbering scheme, is shown in Fig. 1. The molecules have very similar geometries in the two polymorphs. Bond lengths and angles are all within normal ranges and the molecules are flat [the r.m.s. deviation ˚ for molecule A and from planarity is 0.0042 (14) A ˚ 0.0117 (15) A for molecule B for the non-H atoms in polymorph (Ib)]. The two molecules are perpendicular to each other, with a dihedral angle between the mean planes of 81.67 (6) . It is known from the literature that neutral cytosine
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can exist in six tautomeric forms. However, the 2H-enol and the 1H-keto–amino forms are the predominant species in the gas phase (Szczesniak et al., 1988), whereas in the solid state, only the 1H-keto–amino tautomer is observed in both polymorphs. Cytosine has been extensively studied for its self-assembling ability arising from its multiple complementary hydrogen bonds. Polymorphs (Ia) and (Ib) are both stabilized by N— H N and N—H O hydrogen bonds [Table 2 gives data for (Ib)]. In polymorph (Ib), each cytosine molecule is held together with its glide-related molecule (i.e. A–A and B–B) through N—H O and N—H N hydrogen bonds, forming Table 2 ˚ , ). Hydrogen-bond geometry (A D—H A
D—H
H A
D A
D—H A
N1A—H1N N3Ai N7A—H2N O8Aii N7A—H3N O8B N1B—H4N N3Biii N7B—H5N O8Biv N7B—H6N O8Av
0.91 (2) 0.87 (3) 0.86 (2) 0.88 (2) 0.92 (2) 0.86 (2)
1.90 (2) 2.12 (3) 2.16 (2) 1.94 (2) 2.12 (3) 2.19 (3)
2.811 (2) 2.991 (2) 3.002 (2) 2.821 (2) 3.030 (2) 3.023 (2)
175.9 (18) 176 (2) 168 (2) 176.3 (18) 173 (2) 166 (2)
Symmetry codes: (i) x; y þ 12; z 12; (ii) x; y þ 12; z þ 12; (iii) x þ 12; y; z 12; (iv) x þ 12; y; z þ 12; (v) x 12; y þ 12; z þ 1.
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Figure 3 Part of the crystal structure of polymorph (Ia), showing the onedimensional ribbons formed by the R22 (8) dimer. Further adjacent screwrelated ribbons are interconnected through N—H O hydrogen bonds, thereby forming a hexameric hydrogen-bonded cavity with an R66 (30) motif. Hydrogen bonds are shown as dashed lines and H atoms not involved in hydrogen bonding have been omitted for clarity.
an R22 (8) dimer (Etter, 1990; Etter et al., 1990; Bernstein et al., 1995). Similarly, polymorph (Ia) forms an R22 (8) dimer with its screw-related cytosine molecule. In polymorph (Ib), the R22 (8) dimers are propagated as two independent infinite onedimensional hydrogen-bonded ribbons (A–A–A and B—B— B) along the c axis (Fig. 2), whereas in polymorph (Ia) the dimers form an infinite one-dimensional hydrogen-bonded ribbon along the b axis. In polymorph (Ib), ribbon A connects to ribbon B through an N7A—H3N O8B hydrogen bond, thereby forming a hexameric hydrogen-bonded cavity which can be described in graph-set notation as an R66 (30) motif. In turn, ribbon B connects a symmetry-related [at (x 12, y + 12, z + 1)] ribbon A through an N7B—H6N O8Av hydrogen bond and forms another set of hexameric hydrogen-bonded cavities with the R66 (30) motif. Thus, the two infinite ribbons formed by molecules A and B are interlinked with each other through N—H O hydrogen bonds, thereby forming a threedimensional hydrogen-bonded network (Fig. 2). Also in polymorph (Ia), the screw-related ribbons are interlinked by N3—H3 O1(x + 12, y + 12, z 1) hydrogen bonds to form a similar hexameric hydrogen-bonded cavity, i.e. R66 (30) (Fig. 3). In both polymorphs (Ia) and (Ib), the combination of N— H N and N—H O hydrogen bonds is responsible for the formation of supramolecular three-dimensional hydrogenbonded networks. However, the arrangements of molecules in the crystal packing of polymorphs (Ia) and (Ib) are different.
Figure 4 (a) Part of the crystal structure of polymorph (Ib), showing the perpendicular orientation of the R22 (8) dimers formed by molecules A and B. The inversion relationship is also seen between the pairs of dimers, which form a square-grid network. (b) Part of the crystal structure of polymorph (Ia), showing the helical arrangement of the molecules in the crystal packing. Hydrogen bonds are shown as dashed lines and H atoms not involved in hydrogen bonding have been omitted for clarity. Acta Cryst. (2015). C71, 128–135
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Figure 5 Partial packing diagrams showing the same hydrogen-bonding interactions among polymorphic forms having different molecular arrangements in the crystal packing. (a) Ribbons formed by R22 (8) dimers are arranged in a helical fashion in the noncentrosymmetric form of 5-fluorocytosine (CSD refcode MEBQEQ01; Hulme & Tocher, 2006). (b) Centrosymmetrically related ribbons are observed in the centrosymmetric form of 5-fluorocytosine (MEBQEQ; Hulme & Tocher, 2006). (c) Inversion-related molecules are linked by O—H O catemers in the centrosymmetric form of methyl paraben (CEBGOF03; Nath et al., 2011). (d) Glide-related molecules are connected by O—H O catemers in the noncentrosymmetric form of methyl paraben (CEBGOF05; Gelbrich et al., 2013).
In polymorph (Ib), two ribbons formed by molecules A and B are perpendicular to each other [dihedral angle = 89.58 (8) ], whereas in polymorph (Ia), the corresponding angle between the symmetry-related ribbons is 56.88 . The arrangement of molecules can be described as a square-grid network in polymorph (Ib) (Fig. 4a) and as a helical arrangement in the crystal packing of polymorph (Ia) (Fig. 4b). The stability of polymorphs can be correlated with their densities Dx and their packing coefficients. According to the ‘density rule’ (Bernstein et al., 1999; Gavezzotti & Filippini, 1995), the higher the density of a polymorph, the higher is its stability. The crystal density of polymorph (Ib) is significantly less than that of polymorph (Ia) (1.391 versus 1.562 Mg m3). Similarly, the packing coefficient of polymorph (Ib) is less than that of polymorph (Ia) (65.7 versus 74.5%). From these values one can assume that form (Ia) is more stable than form (Ib). Within systems exhibiting polymorphism with different Z0 values, many researchers (Anderson & Steed, 2007; Sarma et
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al., 2006) have shown that higher Z0 forms are frequently (but not always) less stable, exhibiting low densities. Cytosine falls into this category. In the crystallization process, the formation of the ‘nuclei’ starting with the first interacting pair seems to be critical in deciding the outcome of the polymorph, as exemplified by the two polymorphic forms of hexa-o-benzyl-myo-inositol (Gonnade et al., 2004). This compound crystallizes in both centrosymmetric (space group P1) and noncentrosymmetric (space group P61) systems. The first interacting molecular pair in the former is related by centrosymmetry, while the same is predisposed for helical propagation in the latter. A similar feature is also seen in the present study. The cytosine base pair (dimer) can be considered as the first interacting pair, which is the same in both of polymorphs (Ia) and (Ib), but the way the dimers are arranged in the crystal structures appears to guide the centrosymmetric versus noncentrosymmetric space-group selection through the formation of an inversion-related motif Acta Cryst. (2015). C71, 128–135
research papers in polymorph (Ib) and the helical propagation in polymorph (Ia). Achiral molecules crystallizing in noncentrosymmetric space groups are not uncommon. Recently, Pidcock revealed that about 15.2% of achiral molecules crystallize in noncentrosymmetric space groups (Pidcock, 2005), but how often an achiral compound shows polymorphism through centroversus noncentrosymmetric space-group selection has not been established so far. To accomplish this task, a systematic search was performed of the Cambridge Structural Database (CSD, Version 5.35 with May 2014 updates; Groom & Allen, 2014). Our search criteria included the keywords ‘polymorph’ and/or ‘form’, structures with three-dimensional coordinates well defined, no errors, no polymeric, no powder, no ions, number of chemical unit = 1 and only organic restrictions, and resulted in 7290 hits. Using the chiral algorithm of Eppel & Bernstein (2008), the 7290 hits were segregated into four categories, viz. achiral (6021), chiral (549), meso (127) and racemic (411). The remaining 182 structures were excluded due to errors. Among the 6021 achiral structures, 4796 crystallize in centrosymmetric space groups, while the remaining 1225 structures crystallize in noncentrosymmetric space groups. The statistics clearly show that the percentage of
achiral compounds crystallizing in noncentrosymmetric space groups (approximately 20%) is slightly higher in polymorphic systems than in the general class of molecules (15.2%), as shown earlier by Pidcock. We then examined achiral polymorphic systems which crystallize in both centrosymmetric and noncentrosymmetric systems and concluded that there are 516 such systems. Our next idea was to understand possible structural features responsible for achiral molecules crystallizing in centro- and noncentrosymmetric space groups. We analysed these examples and classified them under four different categories. A few representative examples are discussed in each case. (i) Polymorphs with the same hydrogen-bonding interactions but different crystal packing. 5-Fluorocytosine (MEBQEQ; Hulme & Tocher, 2006) has two polymorphic forms. Infinite hydrogen-bonded ribbons formed by the fluorocytosine base-pair dimer with the R22 (8) motif are observed in both forms. The way the ribbons are arranged in the crystal packing creates the difference between the forms. In the noncentrosymmetric form, adjacent ribbons are arranged in a helical fashion (Fig. 5a), while in the centrosymmetric form the corresponding ribbons are packed in an inversion-related fashion (Fig. 5b). Methyl paraben
Figure 6 Partial packing diagrams showing the different hydrogen-bonding interactions and different molecular arrangements in the crystal packing of some polymorphic forms. (a) Helical chain of the D(2) type in the noncentrosymmetric form of 5-nitrouracil (CSD refcode NIMFOE02; Srinivasa Gopalan et al., 2000). (b) Centrosymmetric R22 (8) dimers in the centrosymmetric form of 5-nitrouracil (NIMFOE01; Srinivasa Gopalan et al., 2000). (c) Inversionrelated chains interconnected by R22 (8) dimers in the centrosymmetric form of 5-fluorouracil-1-acetic acid (WEFVIN; Qu et al., 2006). (d) Helical arrangement of R22 (8) dimers in the noncentrosymmetric form of 5-fluorouracil-1-acetic acid (WEFVIN02; Zhang et al., 2007). Acta Cryst. (2015). C71, 128–135
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Figure 7 Partial packing diagrams showing the different conformations and different molecular arrangements in the crystal packing of some polymorphic forms. (a) The butyl chain is in an extended conformation and inversion-related molecules are interlinked by a urea tape motif in the centrosymmetric form of tolbutamide (CSD refcode ZZZPUS10; Nath & Nangia, 2011). (b) The folded conformation of the butyl chain and the screw-related molecules are held together by the urea tape motif in the noncentrosymmetric form of tolbutamide (ZZZPUS02; Donaldson et al., 1981). (c) The formation of an amide dimer in the centrosymmetric form of aripiprazole (MELFIT06; Nanubolu et al., 2012). (d) Amide catemer formation in the noncentrosymmetric form of aripiprazole (MELFIT02; Braun et al., 2009).
(CEBGOF; Nath et al., 2011; Gelbrich et al., 2013) is reported with four polymorphic forms. The catemer motif is preserved in all the forms. In the centrosymmetric form, inversionrelated molecules are interlinked by catemers (Fig. 5c), while in the noncentrosymmetric form, the corresponding catemer interlinks the glide-related molecules (Fig. 5d). Interestingly, cytosine falls into this category. (ii) Polymorphs with different hydrogen-bonding interactions and different crystal packing. 5-Nitrouracil (NIMFOE; Kennedy et al., 1998; Srinivasa Gopalan et al., 2000) has three polymorphic forms. The centrosymmetric form has centrosymmetric R22 (8) dimers (Fig. 6a), while the noncentrosymmetric form has D(2)-type helical chains (Fig. 6b). 5-Fluorouracil-1-acetic acid (WEFVIN; Qu et al., 2006; Zhang et al., 2007) has two polymorphic forms. In the centrosymmetric form, adjacent inver-
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sion-related chains are interlinked by R22 (8) dimers (Fig. 6c), whereas only one R22 (8) dimer is observed in the noncentrosymmetric form and these are arranged in a helical fashion (Fig. 6d). (iii) Polymorphs with different conformations and the same hydrogen-bonding interactions. The antidiabetic drug tolbutamide (ZZZPUS; Donaldson et al., 1981; Nath & Nangia, 2011) is reported with five polymorphic forms. The orientations of the phenyl and alkyl chains are different for the five forms. Although the five forms have a similar urea tape motif and similar hydrogen bonding to a sulfonyl group, the molecular orientations in the hydrogen bonding are different due to conformational differences. In the centrosymmetric form, the butyl chain is in an extended conformation and inversion-related molecules are interlinked by the urea tape motifs (Fig. 7a), whereas in the noncentroActa Cryst. (2015). C71, 128–135
research papers symmetric form, the butyl chain is in a folded conformation and screw-related molecules are linked by the urea tape motif (Fig. 7b). (iv) Polymorphs with different conformations and different hydrogen-bonding interactions. The antipsychotic drug aripiprazole (MELFIT; Braun et al., 2009; Nanubolu et al., 2012) is the most structurally characterized, with seven polymorphs reported in the CSD in this category. Very recently, a low-temperature phase with an eighth polymorphic form has been reported (Delaney et al., 2014). The existence of eight polymorphic forms of aripiprazole can be attributed to a very high degree of conformational freedom, significant differences in the hydrogen bonding and the influence of crystal-packing effects (Nanubolu et al., 2012). Centrosymmetric forms have the amide dimer (Fig. 7c), while the noncentrosymmetric forms exist as amide catemers (Fig. 7d). From the above discussion, polymorphism and centrosymmetric versus noncentrosymmetric space-group selections may be attributed to differences in hydrogen bonding, molecular arrangements and conformational flexibility.
4. Conclusions A second polymorphic form of cytosine is reported for the first time, half a century after the first report of its known form (Ia). The new form (Ib) crystallizes in the centrosymmetric orthorhombic space group Pccn, while form (Ia) crystallizes in the noncentrosymmetric orthorhombic space group P212121. Both forms show similar hydrogen-bonding interactions but differ with respect to the molecular arrangements in their crystal structures. Inversion-related motifs are seen in polymorph (Ib), while helical propagation is observed in polymorph (Ia), and this might contribute to the different space-group selections. 516 polymorphic systems from the CSD crystallize in both centrosymmetric and noncentrosymmetric space groups, and these were analysed for strutural insights. Four possible categories are seen, based on the features responsible for deciding the space-group selections within the polymorphic systems, viz. (i) the same hydrogen-bonding interactions but different molecular arrangements, (ii) different hydrogenbonding interactions and different crystal packing, (iii) different conformations and the same hydrogen-bonding interactions, and (iv) different conformations and different hydrogen-bonding interactions. The present structure falls into the first category. The authors acknowledge the CSIR, New Delhi, for financial support as part of the XII five-year plan programme under the titles AARF (grant No. CSC0406) and ORIGIN (grant No. CSC0108). The director, Dr M. Lakshmi Kantam, is thanked for her kind encouragement. Mr Sivanarayan from the X-ray Crystallography Division is thanked for his support with the PXRD data. We also express our gratitude to Dr S. Prabhakar and Mr G. Sai Krishna from the National Centre for Mass Spectrometry Analytical Division, and Dr T. PrabActa Cryst. (2015). C71, 128–135
hakar from the Centre for NMR and Structural Chemistry of the IICT, for their kind support.
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C4H5N3O
135
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supporting information Acta Cryst. (2015). C71, 128-135
[doi:10.1107/S2053229615000492]
The first polymorph in the family of nucleobases: a second form of cytosine Balasubramanian Sridhar, Jagadeesh Babu Nanubolu and Krishnan Ravikumar Computing details Data collection: SMART (Bruker, 2001); cell refinement: SAINT (Bruker, 2001); data reduction: SAINT (Bruker, 2001); program(s) used to solve structure: SHELXS97 (Sheldrick, 2015); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: DIAMOND (Brandenburg & Putz, 2005); software used to prepare material for publication: SHELXL97 (Sheldrick, 2015). 4-Aminopyrimidin-2(1H)-one Crystal data C4H5N3O Mr = 111.11 Orthorhombic, Pccn a = 15.104 (1) Å b = 15.1212 (10) Å c = 9.2948 (6) Å V = 2122.8 (2) Å3 Z = 16 F(000) = 928
Dx = 1.391 Mg m−3 Mo Kα radiation, λ = 0.71073 Å Cell parameters from 6012 reflections θ = 2.7–26.7° µ = 0.11 mm−1 T = 294 K Needle, colourless 0.21 × 0.12 × 0.08 mm
Data collection Bruker SMART APEX CCD area-detector diffractometer Radiation source: fine-focus sealed tube Absorption correction: multi-scan (SADABS; Bruker, 2001) Tmin = 0.97, Tmax = 0.99 20913 measured reflections
2137 independent reflections 1933 reflections with I > 2σ(I) Rint = 0.029 θmax = 26.2°, θmin = 1.9° h = −18→18 k = −18→18 l = −11→11
Refinement Refinement on F2 Least-squares matrix: full R[F2 > 2σ(F2)] = 0.052 wR(F2) = 0.136 S = 1.20 2137 reflections 169 parameters 0 restraints
Acta Cryst. (2015). C71, 128-135
Hydrogen site location: mixed H atoms treated by a mixture of independent and constrained refinement w = 1/[σ2(Fo2) + (0.0623P)2 + 0.5633P] where P = (Fo2 + 2Fc2)/3 (Δ/σ)max < 0.001 Δρmax = 0.25 e Å−3 Δρmin = −0.18 e Å−3
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supporting information 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. Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2)
C2A C4A C5A H5A C6A H6A N1A H1N N3A N7A H2N H3N O8A C2B C4B C5B H5B C6B H6B N1B H4N N3B N7B H5N H6N O8B
x
y
z
Uiso*/Ueq
0.36076 (9) 0.35442 (10) 0.34746 (12) 0.3433 0.34720 (12) 0.3423 0.35402 (9) 0.3531 (13) 0.36037 (9) 0.35521 (12) 0.3593 (14) 0.3487 (13) 0.36800 (8) 0.24228 (12) 0.10553 (12) 0.06004 (13) −0.0014 0.11022 (13) 0.0832 0.19912 (10) 0.2326 (15) 0.19336 (9) 0.06063 (12) 0.0916 (16) 0.0043 (17) 0.32430 (8)
0.25736 (11) 0.39365 (11) 0.43885 (12) 0.5002 0.38950 (12) 0.4167 0.30049 (10) 0.2657 (14) 0.30577 (9) 0.43858 (12) 0.4080 (17) 0.4947 (15) 0.17532 (8) 0.63787 (10) 0.64706 (10) 0.64921 (13) 0.6519 0.64711 (13) 0.6490 0.64229 (10) 0.6443 (13) 0.64050 (9) 0.65109 (11) 0.6474 (14) 0.6539 (13) 0.63072 (8)
0.33348 (16) 0.44934 (18) 0.31544 (19) 0.3112 0.19591 (19) 0.1065 0.20392 (15) 0.123 (2) 0.45595 (15) 0.57286 (18) 0.652 (3) 0.567 (2) 0.33514 (12) 0.50619 (16) 0.62079 (18) 0.4864 (2) 0.4816 0.3671 (2) 0.2772 0.37604 (16) 0.298 (2) 0.62792 (14) 0.74390 (18) 0.829 (3) 0.736 (2) 0.50888 (12)
0.0354 (4) 0.0396 (4) 0.0464 (5) 0.056* 0.0444 (4) 0.053* 0.0395 (4) 0.058 (6)* 0.0388 (3) 0.0516 (4) 0.069 (7)* 0.054 (6)* 0.0444 (3) 0.0363 (4) 0.0398 (4) 0.0511 (5) 0.061* 0.0506 (5) 0.061* 0.0438 (4) 0.060 (6)* 0.0383 (3) 0.0508 (4) 0.066 (7)* 0.059 (6)* 0.0446 (3)
Atomic displacement parameters (Å2)
C2A C4A C5A C6A N1A N3A N7A O8A C2B
U11
U22
U33
U12
U13
U23
0.0337 (8) 0.0399 (9) 0.0624 (11) 0.0529 (10) 0.0475 (8) 0.0458 (8) 0.0750 (12) 0.0573 (8) 0.0457 (9)
0.0425 (9) 0.0433 (9) 0.0368 (9) 0.0469 (10) 0.0446 (8) 0.0422 (8) 0.0428 (9) 0.0391 (7) 0.0338 (8)
0.0299 (8) 0.0357 (9) 0.0400 (10) 0.0334 (9) 0.0265 (7) 0.0283 (7) 0.0372 (9) 0.0368 (7) 0.0294 (8)
0.0019 (7) 0.0033 (7) 0.0033 (8) 0.0031 (8) 0.0012 (6) 0.0028 (6) 0.0060 (8) 0.0034 (5) 0.0014 (7)
−0.0012 (6) 0.0016 (7) 0.0035 (8) 0.0016 (7) 0.0012 (6) −0.0010 (6) −0.0010 (8) −0.0040 (5) −0.0008 (7)
0.0005 (7) −0.0004 (7) 0.0046 (7) 0.0084 (7) 0.0000 (6) 0.0016 (6) −0.0044 (7) 0.0002 (5) 0.0021 (6)
Acta Cryst. (2015). C71, 128-135
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supporting information C4B C5B C6B N1B N3B N7B O8B
0.0454 (9) 0.0413 (10) 0.0517 (11) 0.0487 (9) 0.0444 (8) 0.0449 (9) 0.0416 (7)
0.0386 (9) 0.0707 (13) 0.0666 (12) 0.0552 (9) 0.0430 (8) 0.0699 (11) 0.0553 (8)
0.0353 (9) 0.0412 (10) 0.0335 (9) 0.0275 (7) 0.0274 (7) 0.0376 (9) 0.0370 (7)
0.0037 (7) 0.0065 (9) 0.0067 (9) 0.0031 (7) 0.0034 (6) 0.0100 (8) 0.0027 (5)
0.0006 (7) −0.0059 (8) −0.0078 (8) 0.0018 (6) −0.0003 (5) 0.0043 (7) 0.0012 (5)
0.0014 (7) 0.0019 (9) 0.0007 (8) 0.0012 (6) 0.0026 (6) 0.0025 (7) 0.0001 (6)
Geometric parameters (Å, º) C2A—O8A C2A—N3A C2A—N1A C4A—N3A C4A—N7A C4A—C5A C5A—C6A C5A—H5A C6A—N1A C6A—H6A N1A—H1N N7A—H2N N7A—H3N
1.245 (2) 1.353 (2) 1.373 (2) 1.333 (2) 1.334 (2) 1.424 (2) 1.338 (3) 0.9300 1.352 (2) 0.9300 0.91 (2) 0.87 (3) 0.86 (2)
C2B—O8B C2B—N3B C2B—N1B C4B—N7B C4B—N3B C4B—C5B C5B—C6B C5B—H5B C6B—N1B C6B—H6B N1B—H4N N7B—H5N N7B—H6N
1.244 (2) 1.352 (2) 1.376 (2) 1.332 (2) 1.332 (2) 1.426 (2) 1.343 (3) 0.9300 1.347 (3) 0.9300 0.88 (2) 0.92 (2) 0.86 (2)
O8A—C2A—N3A O8A—C2A—N1A N3A—C2A—N1A N3A—C4A—N7A N3A—C4A—C5A N7A—C4A—C5A C6A—C5A—C4A C6A—C5A—H5A C4A—C5A—H5A C5A—C6A—N1A C5A—C6A—H6A N1A—C6A—H6A C6A—N1A—C2A C6A—N1A—H1N C2A—N1A—H1N C4A—N3A—C2A C4A—N7A—H2N C4A—N7A—H3N H2N—N7A—H3N
121.92 (14) 119.36 (14) 118.71 (15) 117.86 (16) 121.58 (15) 120.56 (17) 117.27 (17) 121.4 121.4 120.60 (16) 119.7 119.7 121.79 (15) 121.8 (13) 116.4 (13) 120.04 (14) 117.2 (16) 116.9 (14) 126 (2)
O8B—C2B—N3B O8B—C2B—N1B N3B—C2B—N1B N7B—C4B—N3B N7B—C4B—C5B N3B—C4B—C5B C6B—C5B—C4B C6B—C5B—H5B C4B—C5B—H5B C5B—C6B—N1B C5B—C6B—H6B N1B—C6B—H6B C6B—N1B—C2B C6B—N1B—H4N C2B—N1B—H4N C4B—N3B—C2B C4B—N7B—H5N C4B—N7B—H6N H5N—N7B—H6N
122.02 (15) 119.59 (15) 118.38 (16) 117.90 (16) 120.42 (17) 121.68 (16) 116.78 (17) 121.6 121.6 120.85 (17) 119.6 119.6 121.94 (16) 121.1 (14) 116.9 (14) 120.33 (14) 118.5 (15) 115.6 (16) 126 (2)
N3A—C4A—C5A—C6A N7A—C4A—C5A—C6A C4A—C5A—C6A—N1A C5A—C6A—N1A—C2A
−0.1 (3) 179.90 (17) −0.5 (3) 0.5 (3)
N7B—C4B—C5B—C6B N3B—C4B—C5B—C6B C4B—C5B—C6B—N1B C5B—C6B—N1B—C2B
178.36 (18) −2.0 (3) 0.7 (3) 1.1 (3)
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supporting information O8A—C2A—N1A—C6A N3A—C2A—N1A—C6A N7A—C4A—N3A—C2A C5A—C4A—N3A—C2A O8A—C2A—N3A—C4A N1A—C2A—N3A—C4A
−179.12 (15) 0.1 (2) −179.32 (15) 0.6 (2) 178.55 (15) −0.7 (2)
O8B—C2B—N1B—C6B N3B—C2B—N1B—C6B N7B—C4B—N3B—C2B C5B—C4B—N3B—C2B O8B—C2B—N3B—C4B N1B—C2B—N3B—C4B
177.75 (16) −1.5 (2) −178.74 (15) 1.6 (2) −179.12 (15) 0.1 (2)
Hydrogen-bond geometry (Å, º) D—H···A i
N1A—H1N···N3A N7A—H2N···O8Aii N7A—H3N···O8B N1B—H4N···N3Biii N7B—H5N···O8Biv N7B—H6N···O8Av
D—H
H···A
D···A
D—H···A
0.91 (2) 0.87 (3) 0.86 (2) 0.88 (2) 0.92 (2) 0.86 (2)
1.90 (2) 2.12 (3) 2.16 (2) 1.94 (2) 2.12 (3) 2.19 (3)
2.811 (2) 2.991 (2) 3.002 (2) 2.821 (2) 3.030 (2) 3.023 (2)
175.9 (18) 176 (2) 168 (2) 176.3 (18) 173 (2) 166 (2)
Symmetry codes: (i) x, −y+1/2, z−1/2; (ii) x, −y+1/2, z+1/2; (iii) −x+1/2, y, z−1/2; (iv) −x+1/2, y, z+1/2; (v) x−1/2, y+1/2, −z+1.
Acta Cryst. (2015). C71, 128-135
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