Supporting information
Crystallographic Information File (CIF) https://doi.org/10.1107/S2053229616002643/cu3095sup1.cif | |
Structure factor file (CIF format) https://doi.org/10.1107/S2053229616002643/cu3095Isup2.hkl | |
MDL mol file https://doi.org/10.1107/S2053229616002643/cu3095Isup3.mol | |
Portable Document Format (PDF) file https://doi.org/10.1107/S2053229616002643/cu3095sup4.pdf |
CCDC reference: 1453468
Theophylline (tp) has been used as an active pharmaceutical ingredient (API) for diverse applications since the beginning of the 20t h century (Gremels, 1928; Smith et al., 1935). Recently, tp is used as a powerful bronchodilator and respiratory stimulant treating apnea in infants, as well as acute and chronic asthma (Hendeles & Weinberger, 1983). Due to its low water solubility, this API reveals very poor bioavailability. Based on its different hydrogen-bond donor and acceptor groups, tp is an ideal candidate for the formation of cocrystals (Alhalaweh et al., 2013; Ban et al., 2009; Heiden et al., 2012; Childs et al., 2007; Trask et al., 2006). Cocrystals are multicomponent crystalline systems consisting of uncharged organic compounds stabilized via intermolecular forces, including hydrogen bonds, π–π interactions or halogen bonds (Aakeröy & Salmon, 2005). Cocrystallization with an appropriate coformer allows rendering distinct physicochemical properties of a given API, whereas the molecular structure of the drug and its pharmaceutical affect remains unaffected (McNamara et al., 2006; Good & Rodríguez-Hornedo, 2009; Trask et al., 2005, 2006; Chieng et al., 2009). Cocrystals are of greatinterest in pharmaceutical research to improve the water solubility of an API in order to decrease the required dosages in the tablets. The possibility to tune crystal structures based on crystal-engineering considerations and to broaden the knowledge on structure–property relationships increases the current interest (Sun, 2009). In the present study, we present the crystalline structure of the 1:1 theophylline–benzamide cocrystal determined from synchrotron X-ray powder diffraction data.
Anhydrous theophylline (99%, Sigma–Aldrich, Germany) and benzamide (>=99.5%, Sigma–Aldrich, Germany) were obtained commercially and were used without further purification. Since no single crystals could be obtained by slow evaporation from diverse solvents, the synthesis of the 1:1 cocrystal (in the following abbreviated as the tp:ba cocrystal) was conducted by grinding in a ball mill (MM400, Retsch, Germany) at a frequency of 30 Hz for 25 min. A 10 ml steel vessel with two steel balls (diameter 10 mm) was used for a total load of 1 g. The reactants were neat ground in an equimolar ratio.
Raman measurements were performed on a Raman RXN1™ Analyzer (Kaiser Optical Systems, France). The spectra were collected using a laser with a wavelength of λ = 785 nm and a contactless probe head (working distance 1.5 cm, spot size 1.0 mm). Raman spectra were recorded with an acquisition time of 5 s and 5 accumulations. NIR excitation radiation at λ = 785 nm and an irradiation of 6.6 W cm−2 were performed.
1H MAS NMR measurements were performed on a Bruker AVANCE600 spectrometer using a 2.5 mm double-bearing magic angle spinning (MAS) probe (Bruker Biospin) and applying a spinning speed of 25 kHz. The spectra were recorded with a π/2 pulse length of 2.75 µs, a recycle delay of 300 s and an accumulation number of 32. Existent 1H rotor and probe background signals were suppressed using the EASY experiment (Jaeger & Hemmann, 2014a,b). Adamantane served as secondary field standard with a 1H chemical shift of 1.78 p.p.m.
1H–13C CPMAS experiments were run in a 4 mm rotor with a spinning speed of 12.5 kHz (Hartmann & Hahn, 1962). The cross polarization (CP) contact time was 2 ms and the proton spin-lockfield was ramped linearly (ramped-CP) down to 50% of the initial value (Cook et al., 1996). 1H Two-Pulse Phase Modulation (TPPM) decoupling was applied (Bennett et al., 1995). The 13C chemical shifts were referenced to adamantane with 38.5 p.p.m.
The powder X-ray diffraction (PXRD) pattern of the tp:ba cocrystal used for structure solution was recorded at the Powder diffraction beamline of the Australian Synchrotron (Melbourne, Australia) at an energy of 12.4012 keV and a beam current of 200 mA using a Si (111) double-crystal monochromator. A Mythen one-dimensional microstrip detector was used to record the scattering intensity (Wallwork et al., 2007). The PXRD patterns were recorded for 10 min.
The synchrotron X-ray powder pattern of the tp:ba cocrystal was indexed using the program DICVOL (Boultif & Louër, 1991). The structure was solved using the simulated annealing routine implemented in the DASH program (David et al., 2006). As starting conformation for the tp and ba molecules, the values of the Cambridge Structural Database (CSD; Groom & Allen, 2014) entries BAPLOT01 (Reference?) and BZAMID05 (Reference?) were used. For the initial structure solution, the configurations of the molecules (two molecules of tp and ba) were kept rigid.
Crystal data, data collection and structure refinement details are summarized in Table 1. The structure refinement was carried out by the Rietveld method using the program TOPAS (Rietveld, 1967, 1969; Coelho, 2007). A Pawley refinement was performed including the background, zero-point error, unit-cell parameters, peak-width and peak-asymmetry parameters. For the Rietveld refinements, restraints were applied for all bond lengths, bond angles and planar groups. The data were tested for preferred orientation using the approach of March & Dollase (Dollase, 1986). However, no significant preferred orientation was found. The Rietveld refinement included the atomic coordinates, profile parameters, unit-cell parameters, scale, background,and one overall isotropic displacement parameter for the C, N and O atoms of each molecule. H atoms were included with Biso(H) = 1.2Biso(parent atom).
The crystal structure of the tp:ba cocrystal was optimized by lattice-energy minimizations using dispersion-corrected density functional theory (DFT-D). Calculations were performed by the program GRACE (generation, ranking and charaterization engine; Avant-garde Materials Simulation, 2016) that uses the VASP code for single-point DFT calculations (Dollase, 1986; Kresse & Furthmüller, 1996; Kresse & Hafner, 1993). The PBE functional was combined with an empirical dispersion correction (Neumann & Perrin, 2005). Unit-cell parameters and atomic coordinates of all atoms were optimized without any restraints or constraints. For calculation details, see van de Streek & Neumann (2014).
The solid-state 1H MAS NMR (ssNMR) spectrum of the tp:ba cocrystal presented in Fig. 1 shows that the signal of the acidic proton of tp at 14.5 p.p.m. is high-field shifted in the cocrystal spectrum (Baias et al., 2013). Based on this shift it can be assumed that the proton is bridged weaker to ba in the cocrystal as in pure tp, concluding that a the tp:ba cocrystal consists of neutral molecules without a proton transfer from tp to ba. The observed line broadening in the ssNMR spectrum of the cocrystal indicates that the structure may contain more than one symmetrically independent tp (and ba) molecule, which was proven by 13C NMR investigations (see Fig. S1 in the Supporting information). The splitting of the tp and ba peaks confirms the presence of independent molecules in the cocrystal lattice.
The Raman data depicted in Fig. 2 support the result of the ssNMR investigations. The absorption bands of the carbonyl groups of tp at 1665 and 1707 cm−1 are only slightly shifted in the cocrystal spectrum (1643 and 1690 cm−1). For a salt formation a shift of 30–40 cm−1 to lower frequencies is expected. Additionally, the stretching band of the secondary amino group at 3123 cm−1 would disappear and instead a new absorption band of the ammonium group would occur between 2000 and 2200 cm−1 (Childs et al., 2007). Since this stretching band shifts in the cocrystal by 5 cm−1 only, a salt formation can be ruled out.
Indexing was performed on different laboratory and synchrotron X-ray powder patterns of the tp:ba cocrystal. The X-ray powder diagrams could be indexed unambiguously with a tetragonal unit cell with the figures of merit M(20) = 138.8 and F(20) = 510.6 (de Wolff et al., 1968; Smith & Snyder, 1979). Based on the unit-cell volume of V = 2765 Å3, a value of Z = 8 is reasonable. A Pawley refinement with this unit cell in P4, i.e. without systematic extinctions, led to a χ2 value of 13.9.
The determination of the space group was difficult. Bayesian statistical analysis (Markvardsen et al., 2001) within the program DASH led to P42/n or P41212 as most probably space groups, each with Z' = 1. In both space groups, the tp and ba molecules had to be positioned on a general position, since Wyckoff positions with site symmetry 1 or 2 cannot be occupied by tp or ba molecules, which both have the molecular symmetry m (Cs). However, all attempts to solve the structure in P42/n or P41212 from the synchrotron data by real-space methods with simulated annealing using the programs DASH were unsuccessful. Attempts in several other tetragonal space groups failed too. Using FOX instead of DASH or laboratory data instead of synchrotron data did not help either (Favre-Nicolin & Cerný, 2002). The manual assessment of the systematic extinctions from the visually absent reflections leads to the following reflection conditions:
(1) hkl: none, corresponding to a primitive Bravais lattice
(2) hk0: h + k = 2n, corresponding to an n-glide plane parallel to (001)
(3) 0kl: none, excluding glide planes parallel to (100)
(4) hhl: none, excluding glide planes parallel to (110)
(5) 00l: l = 4n, corresponding to a 41 or 43 screw axis.
(6) 0k0, k = 2n, which is included in (2), but would point to a 21 screw axis parallel to [010], if the n-glide planes were absent.
(7) hh0: ambiguous (one visible reflection only)
However, the determination of systematic extinctions from the X-ray powder data bears uncertainties due to the high peak overlap, especially in the high 2θ region. For example, reflection condition (2) was based only on the absence of three reflections (010, 210 and 030), and for the 00l reflections the condition l = 4n differed from l = 2n only by the reflections 002 and 006, which were visually absent. The only unambiguous observation was the absence of systematic extinctions of the hkl, 0kl and hhl reflections.
Furthermore, the reflection conditions were contradictory to each other. A 41 or 43 screw axis cannot be combined with an n-glide plane perpendicular to it. 1 Obviously, at least one of the observed `reflection conditions' was not due to a systematic extinction, but by reflections with accidentally low intensities. The neglect of condition (2) leads to the extinction symbol P4121–, which corresponds to the space groups P41212 and P43212. (These two space groups cannot be distinguished from each other from powder data of an achiral compound, because all Friedel pairs systematically overlap, hence P43212 was not considered further.) If, on the other hand, reflection condition (5) were only 00l: l = 2n, the space group would be P42/n. Hence, the manual determination of systematic extinctions again led to P41212 (or P43212) and P42/n as the most likely space groups.
We ran further trials in P41212 and P42/n, but without success. We also tested, whether the ba molecule could be situated on the 42 axis with site symmetry 2 in P42/n, which would cause a twofold orientational disorder of the benzamide molecule, with the O atom being disordered with the amino group. However, the DASH runs did not give sensible results. Similarly, a solution trial in P42/n with a disordered ba molecule using two independent molecules with occupancies of 0.5 each, failed.
Although none of the structural models obtained hitherto gave a satisfactory fit to the powder pattern, a visual inspection of the `best of the wrong solutions', i.e. of the models with the lowest χ2 values in each space group, revealed that most structures showed a common packing motif: Along the c axis, the structures consisted of four layers of molecules. Within these layers, all molecules were oriented with their molecular planes parallel to (130) and (310), in some other structures parallel to (30) and (310). However, all structures had χ2 values of more than 200, which indicated that the assumed crystal symmetries were not the correct ones.
Finally, we considered which crystal symmetries are statistically frequent. We used the statistics of structural classes published by Belsky et al., which contains not only the space groups, but also the number of independent molecules and the molecular site symmetries (Chernikova et al., 1990; Belsky et al., 1995). Out of 19642 investigated organic homomolecular structures, 126 were tetragonal with Z = 8. From these structures, the most frequent crystal symmetries were (site symmetries in brackets):
– P41212, Z = 8 (1): 49 structures
– P42/n, Z = 8 (1): 20 structures
– P21c, Z =8 (1): 12 structures
– I, Z = 8 (1): 7 structures
– I41/a, Z = 8 (2): 6 structures
– P41, Z = 8, Z' = 2 (1,1): 5 structures
– I41cd, Z = 8 (2): 5 structures
This statistics again pointed to the space groups P41212 and P42/n, which were incorrect for the tp:ba cocrystal. Since the hkl, 0kl and hhl reflections clearly did not show any systematic extinction, all other space groups could be ruled out, except P41. Hence, we tried to solve the structure of the tp:ba cocrystal in P41, Z = 8 with four independent molecules (two tp and two ba) per asymmetric unit.
In P41, the crystal structure could be solved from the synchrotron powder pattern by simulated annealing with DASH. In order to reach a better statistic, the number of simulated annealing runs was increased from 25 to 100. The best solution was obtained with a profile χ2 value of 33.0 and an intensity χ2 value of 47.5. With slightly higher R values, several structures were obtained, which showed a similar molecular packing, but with one or more molecules rotated by 180° around their long molecular axis.
Subsequently, the structure with the lowest χ2 value was refined by the Rietveld method using the program TOPAS. The molecular geometry was restrained using restraints on bond lengths, bond angles and planar groups. The Rietveld refinement converged with a smooth difference curve and confidence values of Rp = 1.86% and Rwp = 2.41% (see Fig. 3).
1? The combination 41/n is impossible, because the application of a 41 screw operation to a perpendicular n-glide plane generates a second n-glide plane which is parallel to the first one, but shifted by (0, 0, 1/4). If the symmetry operation of the first glide plane is (x', y', z') = (x + 1/2, y + 1/2, −z), that of the second glide plane will be (x', y', z') = (x + 1/2, y + 1/2, −z + 1/2). A consecutive application of both glide planes to an atom on the general position (x, y, z) results in an atom situated at (x + 1, y + 1, z + 1/2), which is equivalent to (y, y, z + 1/2), and denotes a translational copy of the original atom, shifted by (0, 0, 1/2). Hence, every atom has a translational copy shifted by c/2 and the unit cell consists of two identical parts. Thus the unit cell can be transformed by c' = c/2. Thereby the 41 screw axes change to 42 screw axes. The same argumentation holds for the combination 43/n.
A crystal structure of an achiral compound in a chiral space group with Z' ≥ 2 should always be regarded with caution, since it may easily be a case of missed symmetry (Herbstein & Marsh, 1998; Marsh & Spek, 2001; Clemente, 2003). This is especially critical for structures determined from powder data. For example, the low-temperature structure of 4-methylpyridine N-oxide, determined by X-ray powder and neutron powder diffraction, was originally published in 2006 in P41 (Z = 32 and Z' = 8) (Damay et al., 2006). Indeed, the published atomic coordinates do not show any higher symmetry. Later, a rerefinement led to P41212 (Z' = 4) (Palatinus & Damay, 2009). However, for the tp:ba cocrystal there are several facts indicating that the space group is actually correct:
(1) The broadening of the signals in the 1H MAS NMR spectrum indicates Z' > 1.
(2) There are only two translationengleiche supergroups of P41, i.e. P41212 and P4122. However, the clear orientation of the molecular planes parallel to (130) und (310) contradicts the existence of twofold rotation or screw axis parallel to [100] or [110]. Furthermore, extensive structure solution attempts in P41212 failed. Klassengleiche supergroups, such as I41 or P42 (c' = 2c), can be excluded, because the unit-cell parameters are unambiguous, and the Bravais lattice is clearly primitive.
(3) The molecular packing does not show a higher symmetry. The two formula units within the asymmetric unit are clearly symmetrically independent, and not related by any symmetry element, even not a local one. The hydrogen-bond pattern of the two tp molecules is different from each other; the same is valid for the two ba molecules. Also a rotation of one or more molecules around the long molecular axis does not lead to identical hydrogen-bond patterns.
The correctness of the crystal structure was finally proven by a lattice-energy minimization using dispersion-corrected DFT calculations, including an optimization of the lattice parameters. Upon optimization, the protonation state did not change, and the resulting structure did not show any additional symmetry. Lattice parameters and atomic coordinates changed only slightly. A recent survey of 215 crystal structures, which were solved from powder data and published in IUCr journals, revealed, that during a DFT-D optimization under these conditions, the mean deviation of non-H atoms should be less than 0.35 Å. In the case of higher deviations, the structure is likely either to be incorrect or to exhibit special features such as disorder or unusual thermal expansion (van de Streek & Neumann, 2014). For the tp:ba cocrystal, an r.m.s. value of 0.139 Å could be found. Hence, the crystal structure of the tp:ba cocrystal should be correct. The overlay of the solved crystal structure (red) and the DFT-calculated structure (blue) are presented in Fig. 4.
The tp:ba cocrystal crystallizes in the tetragonal space group P41 and reveals a slightly higher density than the reactants. Two crystallographically independent tp and two independent ba molecules are present in the asymmetric unit (tp1, tp2, ba1, and ba2; Fig. 5). Dimers are formed between tp1 and ba1 molecules and tp2 and ba2 molecules. A dimer between ba1 and tp1 is formed including the carbonyl group and amide group and the secondary amino group and carbonyl group of tp1. The ba2 molecule forms a similar dimer to the tp2 molecule.
The dimers are arranged in sheets. The unit cell contains four sheets, with molecules at z ~~1/8, 3/8, 5/8 and 7/8 (Fig. 6). Within each sheet, all molecules are parallel (Fig. 7). The molecules of the first and third sheets are oriented almost exactly in the (310) direction, and those of the second and fourth sheets in the (30) direction. This leads to a hunter's fence arrangement (Fig. 8). The sheets are connected by hydrogen bonds between the molecular dimers: The amino group of the ba1 molecule forms a hydrogen bond to an imidazole N atom of a tp molecule in a neighbouring sheet, whereas the amino group of the ba2 molecule connects to the O atom of a tp molecule in a neighbouring sheet. This leads to a one-dimensional hydrogen-bond network parallel to the [001] direction.
Based on synchrotron powder data, the extraordinary structure of the theophylline–benzamide cocrystal could be solved. Typically, the API theophylline cocrystallizes with benzamide-similar coformers in monoclinic space groups. However, when theophylline is ground under neat conditions with benzamide the tetragonal 1:1 cocrystal is formed in the space group P41. DFT-D calculations proved the correctness of this structure solution. Solid-state NMR investigations and Raman spectroscopy confirm that the cocrystal consists of neutral molecules, thus excluding a salt formation.
Theophylline (tp) has been used as an active pharmaceutical ingredient (API) for diverse applications since the beginning of the 20t h century (Gremels, 1928; Smith et al., 1935). Recently, tp is used as a powerful bronchodilator and respiratory stimulant treating apnea in infants, as well as acute and chronic asthma (Hendeles & Weinberger, 1983). Due to its low water solubility, this API reveals very poor bioavailability. Based on its different hydrogen-bond donor and acceptor groups, tp is an ideal candidate for the formation of cocrystals (Alhalaweh et al., 2013; Ban et al., 2009; Heiden et al., 2012; Childs et al., 2007; Trask et al., 2006). Cocrystals are multicomponent crystalline systems consisting of uncharged organic compounds stabilized via intermolecular forces, including hydrogen bonds, π–π interactions or halogen bonds (Aakeröy & Salmon, 2005). Cocrystallization with an appropriate coformer allows rendering distinct physicochemical properties of a given API, whereas the molecular structure of the drug and its pharmaceutical affect remains unaffected (McNamara et al., 2006; Good & Rodríguez-Hornedo, 2009; Trask et al., 2005, 2006; Chieng et al., 2009). Cocrystals are of greatinterest in pharmaceutical research to improve the water solubility of an API in order to decrease the required dosages in the tablets. The possibility to tune crystal structures based on crystal-engineering considerations and to broaden the knowledge on structure–property relationships increases the current interest (Sun, 2009). In the present study, we present the crystalline structure of the 1:1 theophylline–benzamide cocrystal determined from synchrotron X-ray powder diffraction data.
Raman measurements were performed on a Raman RXN1™ Analyzer (Kaiser Optical Systems, France). The spectra were collected using a laser with a wavelength of λ = 785 nm and a contactless probe head (working distance 1.5 cm, spot size 1.0 mm). Raman spectra were recorded with an acquisition time of 5 s and 5 accumulations. NIR excitation radiation at λ = 785 nm and an irradiation of 6.6 W cm−2 were performed.
1H MAS NMR measurements were performed on a Bruker AVANCE600 spectrometer using a 2.5 mm double-bearing magic angle spinning (MAS) probe (Bruker Biospin) and applying a spinning speed of 25 kHz. The spectra were recorded with a π/2 pulse length of 2.75 µs, a recycle delay of 300 s and an accumulation number of 32. Existent 1H rotor and probe background signals were suppressed using the EASY experiment (Jaeger & Hemmann, 2014a,b). Adamantane served as secondary field standard with a 1H chemical shift of 1.78 p.p.m.
1H–13C CPMAS experiments were run in a 4 mm rotor with a spinning speed of 12.5 kHz (Hartmann & Hahn, 1962). The cross polarization (CP) contact time was 2 ms and the proton spin-lockfield was ramped linearly (ramped-CP) down to 50% of the initial value (Cook et al., 1996). 1H Two-Pulse Phase Modulation (TPPM) decoupling was applied (Bennett et al., 1995). The 13C chemical shifts were referenced to adamantane with 38.5 p.p.m.
The powder X-ray diffraction (PXRD) pattern of the tp:ba cocrystal used for structure solution was recorded at the Powder diffraction beamline of the Australian Synchrotron (Melbourne, Australia) at an energy of 12.4012 keV and a beam current of 200 mA using a Si (111) double-crystal monochromator. A Mythen one-dimensional microstrip detector was used to record the scattering intensity (Wallwork et al., 2007). The PXRD patterns were recorded for 10 min.
The synchrotron X-ray powder pattern of the tp:ba cocrystal was indexed using the program DICVOL (Boultif & Louër, 1991). The structure was solved using the simulated annealing routine implemented in the DASH program (David et al., 2006). As starting conformation for the tp and ba molecules, the values of the Cambridge Structural Database (CSD; Groom & Allen, 2014) entries BAPLOT01 (Reference?) and BZAMID05 (Reference?) were used. For the initial structure solution, the configurations of the molecules (two molecules of tp and ba) were kept rigid.
The crystal structure of the tp:ba cocrystal was optimized by lattice-energy minimizations using dispersion-corrected density functional theory (DFT-D). Calculations were performed by the program GRACE (generation, ranking and charaterization engine; Avant-garde Materials Simulation, 2016) that uses the VASP code for single-point DFT calculations (Dollase, 1986; Kresse & Furthmüller, 1996; Kresse & Hafner, 1993). The PBE functional was combined with an empirical dispersion correction (Neumann & Perrin, 2005). Unit-cell parameters and atomic coordinates of all atoms were optimized without any restraints or constraints. For calculation details, see van de Streek & Neumann (2014).
The solid-state 1H MAS NMR (ssNMR) spectrum of the tp:ba cocrystal presented in Fig. 1 shows that the signal of the acidic proton of tp at 14.5 p.p.m. is high-field shifted in the cocrystal spectrum (Baias et al., 2013). Based on this shift it can be assumed that the proton is bridged weaker to ba in the cocrystal as in pure tp, concluding that a the tp:ba cocrystal consists of neutral molecules without a proton transfer from tp to ba. The observed line broadening in the ssNMR spectrum of the cocrystal indicates that the structure may contain more than one symmetrically independent tp (and ba) molecule, which was proven by 13C NMR investigations (see Fig. S1 in the Supporting information). The splitting of the tp and ba peaks confirms the presence of independent molecules in the cocrystal lattice.
The Raman data depicted in Fig. 2 support the result of the ssNMR investigations. The absorption bands of the carbonyl groups of tp at 1665 and 1707 cm−1 are only slightly shifted in the cocrystal spectrum (1643 and 1690 cm−1). For a salt formation a shift of 30–40 cm−1 to lower frequencies is expected. Additionally, the stretching band of the secondary amino group at 3123 cm−1 would disappear and instead a new absorption band of the ammonium group would occur between 2000 and 2200 cm−1 (Childs et al., 2007). Since this stretching band shifts in the cocrystal by 5 cm−1 only, a salt formation can be ruled out.
Indexing was performed on different laboratory and synchrotron X-ray powder patterns of the tp:ba cocrystal. The X-ray powder diagrams could be indexed unambiguously with a tetragonal unit cell with the figures of merit M(20) = 138.8 and F(20) = 510.6 (de Wolff et al., 1968; Smith & Snyder, 1979). Based on the unit-cell volume of V = 2765 Å3, a value of Z = 8 is reasonable. A Pawley refinement with this unit cell in P4, i.e. without systematic extinctions, led to a χ2 value of 13.9.
The determination of the space group was difficult. Bayesian statistical analysis (Markvardsen et al., 2001) within the program DASH led to P42/n or P41212 as most probably space groups, each with Z' = 1. In both space groups, the tp and ba molecules had to be positioned on a general position, since Wyckoff positions with site symmetry 1 or 2 cannot be occupied by tp or ba molecules, which both have the molecular symmetry m (Cs). However, all attempts to solve the structure in P42/n or P41212 from the synchrotron data by real-space methods with simulated annealing using the programs DASH were unsuccessful. Attempts in several other tetragonal space groups failed too. Using FOX instead of DASH or laboratory data instead of synchrotron data did not help either (Favre-Nicolin & Cerný, 2002). The manual assessment of the systematic extinctions from the visually absent reflections leads to the following reflection conditions:
(1) hkl: none, corresponding to a primitive Bravais lattice
(2) hk0: h + k = 2n, corresponding to an n-glide plane parallel to (001)
(3) 0kl: none, excluding glide planes parallel to (100)
(4) hhl: none, excluding glide planes parallel to (110)
(5) 00l: l = 4n, corresponding to a 41 or 43 screw axis.
(6) 0k0, k = 2n, which is included in (2), but would point to a 21 screw axis parallel to [010], if the n-glide planes were absent.
(7) hh0: ambiguous (one visible reflection only)
However, the determination of systematic extinctions from the X-ray powder data bears uncertainties due to the high peak overlap, especially in the high 2θ region. For example, reflection condition (2) was based only on the absence of three reflections (010, 210 and 030), and for the 00l reflections the condition l = 4n differed from l = 2n only by the reflections 002 and 006, which were visually absent. The only unambiguous observation was the absence of systematic extinctions of the hkl, 0kl and hhl reflections.
Furthermore, the reflection conditions were contradictory to each other. A 41 or 43 screw axis cannot be combined with an n-glide plane perpendicular to it. 1 Obviously, at least one of the observed `reflection conditions' was not due to a systematic extinction, but by reflections with accidentally low intensities. The neglect of condition (2) leads to the extinction symbol P4121–, which corresponds to the space groups P41212 and P43212. (These two space groups cannot be distinguished from each other from powder data of an achiral compound, because all Friedel pairs systematically overlap, hence P43212 was not considered further.) If, on the other hand, reflection condition (5) were only 00l: l = 2n, the space group would be P42/n. Hence, the manual determination of systematic extinctions again led to P41212 (or P43212) and P42/n as the most likely space groups.
We ran further trials in P41212 and P42/n, but without success. We also tested, whether the ba molecule could be situated on the 42 axis with site symmetry 2 in P42/n, which would cause a twofold orientational disorder of the benzamide molecule, with the O atom being disordered with the amino group. However, the DASH runs did not give sensible results. Similarly, a solution trial in P42/n with a disordered ba molecule using two independent molecules with occupancies of 0.5 each, failed.
Although none of the structural models obtained hitherto gave a satisfactory fit to the powder pattern, a visual inspection of the `best of the wrong solutions', i.e. of the models with the lowest χ2 values in each space group, revealed that most structures showed a common packing motif: Along the c axis, the structures consisted of four layers of molecules. Within these layers, all molecules were oriented with their molecular planes parallel to (130) and (310), in some other structures parallel to (30) and (310). However, all structures had χ2 values of more than 200, which indicated that the assumed crystal symmetries were not the correct ones.
Finally, we considered which crystal symmetries are statistically frequent. We used the statistics of structural classes published by Belsky et al., which contains not only the space groups, but also the number of independent molecules and the molecular site symmetries (Chernikova et al., 1990; Belsky et al., 1995). Out of 19642 investigated organic homomolecular structures, 126 were tetragonal with Z = 8. From these structures, the most frequent crystal symmetries were (site symmetries in brackets):
– P41212, Z = 8 (1): 49 structures
– P42/n, Z = 8 (1): 20 structures
– P21c, Z =8 (1): 12 structures
– I, Z = 8 (1): 7 structures
– I41/a, Z = 8 (2): 6 structures
– P41, Z = 8, Z' = 2 (1,1): 5 structures
– I41cd, Z = 8 (2): 5 structures
This statistics again pointed to the space groups P41212 and P42/n, which were incorrect for the tp:ba cocrystal. Since the hkl, 0kl and hhl reflections clearly did not show any systematic extinction, all other space groups could be ruled out, except P41. Hence, we tried to solve the structure of the tp:ba cocrystal in P41, Z = 8 with four independent molecules (two tp and two ba) per asymmetric unit.
In P41, the crystal structure could be solved from the synchrotron powder pattern by simulated annealing with DASH. In order to reach a better statistic, the number of simulated annealing runs was increased from 25 to 100. The best solution was obtained with a profile χ2 value of 33.0 and an intensity χ2 value of 47.5. With slightly higher R values, several structures were obtained, which showed a similar molecular packing, but with one or more molecules rotated by 180° around their long molecular axis.
Subsequently, the structure with the lowest χ2 value was refined by the Rietveld method using the program TOPAS. The molecular geometry was restrained using restraints on bond lengths, bond angles and planar groups. The Rietveld refinement converged with a smooth difference curve and confidence values of Rp = 1.86% and Rwp = 2.41% (see Fig. 3).
1? The combination 41/n is impossible, because the application of a 41 screw operation to a perpendicular n-glide plane generates a second n-glide plane which is parallel to the first one, but shifted by (0, 0, 1/4). If the symmetry operation of the first glide plane is (x', y', z') = (x + 1/2, y + 1/2, −z), that of the second glide plane will be (x', y', z') = (x + 1/2, y + 1/2, −z + 1/2). A consecutive application of both glide planes to an atom on the general position (x, y, z) results in an atom situated at (x + 1, y + 1, z + 1/2), which is equivalent to (y, y, z + 1/2), and denotes a translational copy of the original atom, shifted by (0, 0, 1/2). Hence, every atom has a translational copy shifted by c/2 and the unit cell consists of two identical parts. Thus the unit cell can be transformed by c' = c/2. Thereby the 41 screw axes change to 42 screw axes. The same argumentation holds for the combination 43/n.
A crystal structure of an achiral compound in a chiral space group with Z' ≥ 2 should always be regarded with caution, since it may easily be a case of missed symmetry (Herbstein & Marsh, 1998; Marsh & Spek, 2001; Clemente, 2003). This is especially critical for structures determined from powder data. For example, the low-temperature structure of 4-methylpyridine N-oxide, determined by X-ray powder and neutron powder diffraction, was originally published in 2006 in P41 (Z = 32 and Z' = 8) (Damay et al., 2006). Indeed, the published atomic coordinates do not show any higher symmetry. Later, a rerefinement led to P41212 (Z' = 4) (Palatinus & Damay, 2009). However, for the tp:ba cocrystal there are several facts indicating that the space group is actually correct:
(1) The broadening of the signals in the 1H MAS NMR spectrum indicates Z' > 1.
(2) There are only two translationengleiche supergroups of P41, i.e. P41212 and P4122. However, the clear orientation of the molecular planes parallel to (130) und (310) contradicts the existence of twofold rotation or screw axis parallel to [100] or [110]. Furthermore, extensive structure solution attempts in P41212 failed. Klassengleiche supergroups, such as I41 or P42 (c' = 2c), can be excluded, because the unit-cell parameters are unambiguous, and the Bravais lattice is clearly primitive.
(3) The molecular packing does not show a higher symmetry. The two formula units within the asymmetric unit are clearly symmetrically independent, and not related by any symmetry element, even not a local one. The hydrogen-bond pattern of the two tp molecules is different from each other; the same is valid for the two ba molecules. Also a rotation of one or more molecules around the long molecular axis does not lead to identical hydrogen-bond patterns.
The correctness of the crystal structure was finally proven by a lattice-energy minimization using dispersion-corrected DFT calculations, including an optimization of the lattice parameters. Upon optimization, the protonation state did not change, and the resulting structure did not show any additional symmetry. Lattice parameters and atomic coordinates changed only slightly. A recent survey of 215 crystal structures, which were solved from powder data and published in IUCr journals, revealed, that during a DFT-D optimization under these conditions, the mean deviation of non-H atoms should be less than 0.35 Å. In the case of higher deviations, the structure is likely either to be incorrect or to exhibit special features such as disorder or unusual thermal expansion (van de Streek & Neumann, 2014). For the tp:ba cocrystal, an r.m.s. value of 0.139 Å could be found. Hence, the crystal structure of the tp:ba cocrystal should be correct. The overlay of the solved crystal structure (red) and the DFT-calculated structure (blue) are presented in Fig. 4.
The tp:ba cocrystal crystallizes in the tetragonal space group P41 and reveals a slightly higher density than the reactants. Two crystallographically independent tp and two independent ba molecules are present in the asymmetric unit (tp1, tp2, ba1, and ba2; Fig. 5). Dimers are formed between tp1 and ba1 molecules and tp2 and ba2 molecules. A dimer between ba1 and tp1 is formed including the carbonyl group and amide group and the secondary amino group and carbonyl group of tp1. The ba2 molecule forms a similar dimer to the tp2 molecule.
The dimers are arranged in sheets. The unit cell contains four sheets, with molecules at z ~~1/8, 3/8, 5/8 and 7/8 (Fig. 6). Within each sheet, all molecules are parallel (Fig. 7). The molecules of the first and third sheets are oriented almost exactly in the (310) direction, and those of the second and fourth sheets in the (30) direction. This leads to a hunter's fence arrangement (Fig. 8). The sheets are connected by hydrogen bonds between the molecular dimers: The amino group of the ba1 molecule forms a hydrogen bond to an imidazole N atom of a tp molecule in a neighbouring sheet, whereas the amino group of the ba2 molecule connects to the O atom of a tp molecule in a neighbouring sheet. This leads to a one-dimensional hydrogen-bond network parallel to the [001] direction.
Based on synchrotron powder data, the extraordinary structure of the theophylline–benzamide cocrystal could be solved. Typically, the API theophylline cocrystallizes with benzamide-similar coformers in monoclinic space groups. However, when theophylline is ground under neat conditions with benzamide the tetragonal 1:1 cocrystal is formed in the space group P41. DFT-D calculations proved the correctness of this structure solution. Solid-state NMR investigations and Raman spectroscopy confirm that the cocrystal consists of neutral molecules, thus excluding a salt formation.
Anhydrous theophylline (99%, Sigma–Aldrich, Germany) and benzamide (>=99.5%, Sigma–Aldrich, Germany) were obtained commercially and were used without further purification. Since no single crystals could be obtained by slow evaporation from diverse solvents, the synthesis of the 1:1 cocrystal (in the following abbreviated as the tp:ba cocrystal) was conducted by grinding in a ball mill (MM400, Retsch, Germany) at a frequency of 30 Hz for 25 min. A 10 ml steel vessel with two steel balls (diameter 10 mm) was used for a total load of 1 g. The reactants were neat ground in an equimolar ratio.
Crystal data, data collection and structure refinement details are summarized in Table 1. The structure refinement was carried out by the Rietveld method using the program TOPAS (Rietveld, 1967, 1969; Coelho, 2007). A Pawley refinement was performed including the background, zero-point error, unit-cell parameters, peak-width and peak-asymmetry parameters. For the Rietveld refinements, restraints were applied for all bond lengths, bond angles and planar groups. The data were tested for preferred orientation using the approach of March & Dollase (Dollase, 1986). However, no significant preferred orientation was found. The Rietveld refinement included the atomic coordinates, profile parameters, unit-cell parameters, scale, background,and one overall isotropic displacement parameter for the C, N and O atoms of each molecule. H atoms were included with Biso(H) = 1.2Biso(parent atom).
Cell refinement: TOPAS Academic (Coelho, 2007); data reduction: DASH (David et al., 2006); program(s) used to solve structure: DASH (David et al., 2006); program(s) used to refine structure: TOPAS Academic (Coelho, 2007); molecular graphics: DIAMOND (Crystal Impact, 2014); software used to prepare material for publication: publCIF (Westrip, 2010).
C7H8N4O2·C7H7NO | F(000) = 1264 |
Mr = 301.31 | Dx = 1.446 Mg m−3 |
Tetragonal, P41 | Synchrotron radiation |
Hall symbol: P 4w | µ = 0.11 mm−1 |
a = 10.281404 (12) Å | T = 293 K |
c = 26.15892 (6) Å | Particle morphology: tablet |
V = 2765.19 (1) Å3 | white |
Z = 8 | cylinder, 10 × 0.5 mm |
Australien Synchrotron XRD beamlime diffractometer | Data collection mode: transmission |
Primary focusing, Si 111 monochromator | 2θmin = 2.0°, 2θmax = 82.32°, 2θstep = 0.01° |
Specimen mounting: 0.5 mm glass capillary |
Refinement on Inet | Excluded region(s): none |
Least-squares matrix: full with fixed elements per cycle | 86 parameters |
Rp = 1.86 | 42 restraints |
Rwp = 2.41 | 0 constraints |
Rexp = 1.19 | H-atom parameters constrained |
R(F) = 1.86 | Weighting scheme based on measured s.u.'s w = 1/σ[Yobs]2 |
χ2 = 1.388 | (Δ/σ)max = 0.001 |
21236 data points |
C7H8N4O2·C7H7NO | Z = 8 |
Mr = 301.31 | Synchrotron radiation |
Tetragonal, P41 | µ = 0.11 mm−1 |
a = 10.281404 (12) Å | T = 293 K |
c = 26.15892 (6) Å | cylinder, 10 × 0.5 mm |
V = 2765.19 (1) Å3 |
Australien Synchrotron XRD beamlime diffractometer | Data collection mode: transmission |
Specimen mounting: 0.5 mm glass capillary | 2θmin = 2.0°, 2θmax = 82.32°, 2θstep = 0.01° |
Rp = 1.86 | 21236 data points |
Rwp = 2.41 | 86 parameters |
Rexp = 1.19 | 42 restraints |
R(F) = 1.86 | H-atom parameters constrained |
χ2 = 1.388 |
Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles |
x | y | z | Uiso*/Ueq | ||
C1 | 0.1498 (4) | 0.0405 (3) | 0.83153 (17) | 0.04569 | |
C2 | 0.2867 (4) | 0.0950 (5) | 0.83190 (17) | 0.04569 | |
C3 | 0.0824 (4) | 0.0163 (3) | 0.78716 (16) | 0.04569 | |
C4 | 0.0872 (4) | 0.0125 (3) | 0.87810 (16) | 0.04569 | |
O5 | 0.3562 (7) | 0.0928 (8) | 0.8714 (2) | 0.04569 | |
N6 | 0.3367 (5) | 0.1401 (5) | 0.78775 (16) | 0.04569 | |
C7 | −0.0444 (4) | −0.0346 (3) | 0.78751 (16) | 0.04569 | |
H8 | 0.1232 (17) | 0.0346 (19) | 0.7525 (7) | 0.05483 | |
C9 | −0.0368 (4) | −0.0372 (3) | 0.87881 (16) | 0.04569 | |
H10 | 0.132 (2) | 0.0281 (19) | 0.9107 (7) | 0.05483 | |
H11 | 0.4037 (16) | 0.2066 (18) | 0.7941 (6) | 0.05483 | |
H12 | 0.301 (2) | 0.1603 (17) | 0.7535 (7) | 0.05483 | |
C13 | −0.1038 (4) | −0.0614 (3) | 0.83266 (16) | 0.04569 | |
H14 | −0.0885 (17) | −0.0496 (18) | 0.7539 (7) | 0.05483 | |
H15 | −0.0799 (18) | −0.0560 (18) | 0.9115 (7) | 0.05483 | |
H16 | −0.1916 (17) | −0.0965 (15) | 0.8319 (8) | 0.05483 | |
N17 | 0.7730 (7) | 0.6654 (5) | 0.64541 (16) | 0.04569 | |
C18 | 0.8154 (8) | 0.5652 (5) | 0.61405 (17) | 0.04569 | |
C19 | 0.7909 (5) | 0.6478 (4) | 0.70053 (18) | 0.04569 | |
C20 | 0.7209 (9) | 0.7856 (5) | 0.63011 (17) | 0.04569 | |
N21 | 0.7964 (7) | 0.5792 (4) | 0.56265 (16) | 0.04569 | |
O22 | 0.8566 (8) | 0.4635 (6) | 0.6313 (3) | 0.04569 | |
H23 | 0.842 (2) | 0.572 (2) | 0.7074 (9) | 0.05483 | |
H24 | 0.833 (2) | 0.7219 (16) | 0.7137 (6) | 0.05483 | |
H25 | 0.7094 (18) | 0.6372 (18) | 0.7163 (7) | 0.05483 | |
C26 | 0.7094 (9) | 0.7880 (5) | 0.57544 (17) | 0.04569 | |
O27 | 0.6833 (8) | 0.8667 (6) | 0.6600 (2) | 0.04569 | |
C28 | 0.7514 (9) | 0.6932 (5) | 0.54358 (16) | 0.04569 | |
C29 | 0.8441 (4) | 0.4766 (4) | 0.52873 (15) | 0.04569 | |
N30 | 0.6674 (6) | 0.8883 (4) | 0.54528 (16) | 0.04569 | |
N31 | 0.7320 (8) | 0.7255 (6) | 0.4945 (2) | 0.04569 | |
H32 | 0.8650 (18) | 0.3993 (16) | 0.5481 (6) | 0.05483 | |
H33 | 0.9193 (18) | 0.5080 (19) | 0.5119 (7) | 0.05483 | |
H34 | 0.778 (2) | 0.4566 (19) | 0.5042 (7) | 0.05483 | |
C35 | 0.6858 (8) | 0.8458 (5) | 0.49707 (17) | 0.04569 | |
H36 | 0.6192 (17) | 0.9567 (15) | 0.5552 (7) | 0.05483 | |
H37 | 0.6616 (18) | 0.9010 (18) | 0.4665 (7) | 0.05483 | |
C38 | 0.4621 (3) | 0.6599 (4) | 0.11543 (16) | 0.04569 | |
C39 | 0.4087 (5) | 0.7961 (4) | 0.11160 (17) | 0.04569 | |
C40 | 0.4862 (3) | 0.6035 (4) | 0.16187 (16) | 0.04569 | |
C41 | 0.4870 (3) | 0.5905 (4) | 0.07091 (16) | 0.04569 | |
O42 | 0.4048 (8) | 0.8562 (7) | 0.0695 (2) | 0.04569 | |
N43 | 0.3792 (9) | 0.8545 (5) | 0.15581 (16) | 0.04569 | |
C44 | 0.5347 (3) | 0.4781 (4) | 0.16483 (16) | 0.04569 | |
H45 | 0.470 (2) | 0.652 (2) | 0.1954 (7) | 0.05483 | |
C46 | 0.5354 (3) | 0.4657 (4) | 0.07265 (16) | 0.04569 | |
H47 | 0.4707 (17) | 0.6314 (17) | 0.0377 (7) | 0.05483 | |
H48 | 0.384 (2) | 0.9498 (18) | 0.1531 (7) | 0.05483 | |
H49 | 0.390 (4) | 0.8328 (19) | 0.1928 (6) | 0.05483 | |
C50 | 0.5598 (3) | 0.4082 (4) | 0.12160 (16) | 0.04569 | |
H51 | 0.5510 (18) | 0.4415 (19) | 0.1997 (7) | 0.05483 | |
H52 | 0.5531 (18) | 0.4163 (17) | 0.0405 (7) | 0.05483 | |
H53 | 0.5930 (16) | 0.3202 (19) | 0.1253 (7) | 0.05483 | |
N54 | 0.1707 (5) | 0.7227 (7) | 0.28773 (16) | 0.04569 | |
C55 | 0.0647 (5) | 0.6927 (9) | 0.31895 (17) | 0.04569 | |
C56 | 0.1536 (4) | 0.6994 (4) | 0.23330 (18) | 0.04569 | |
C57 | 0.2901 (5) | 0.7765 (9) | 0.30278 (17) | 0.04569 | |
N58 | 0.0846 (4) | 0.6955 (7) | 0.37094 (16) | 0.04569 | |
O59 | −0.0371 (6) | 0.6510 (9) | 0.3009 (3) | 0.04569 | |
H60 | 0.0681 (18) | 0.6635 (18) | 0.2267 (8) | 0.05483 | |
H61 | 0.163 (2) | 0.7789 (16) | 0.2160 (6) | 0.05483 | |
H62 | 0.2181 (19) | 0.6392 (17) | 0.2224 (6) | 0.05483 | |
C63 | 0.2911 (5) | 0.7926 (8) | 0.35765 (17) | 0.04569 | |
O64 | 0.3734 (6) | 0.8011 (7) | 0.2725 (3) | 0.04569 | |
C65 | 0.1937 (5) | 0.7532 (8) | 0.38978 (16) | 0.04569 | |
C66 | −0.0245 (4) | 0.6597 (4) | 0.40385 (14) | 0.04569 | |
N67 | 0.3892 (5) | 0.8377 (7) | 0.38882 (16) | 0.04569 | |
N68 | 0.2225 (5) | 0.7774 (9) | 0.4390 (2) | 0.04569 | |
H69 | −0.0970 (16) | 0.6329 (17) | 0.3839 (7) | 0.05483 | |
H70 | −0.0488 (17) | 0.732 (2) | 0.4239 (7) | 0.05483 | |
H71 | 0.003 (2) | 0.5886 (17) | 0.4248 (7) | 0.05483 | |
C72 | 0.3439 (5) | 0.8239 (7) | 0.43681 (17) | 0.04569 | |
H73 | 0.4590 (15) | 0.8864 (19) | 0.3792 (7) | 0.05483 | |
H74 | 0.395 (2) | 0.8583 (19) | 0.4671 (9) | 0.05483 |
O22—C18 | 1.215 (9) | C19—H24 | 0.942 (18) |
O27—C20 | 1.207 (8) | C29—H34 | 0.96 (2) |
O59—C55 | 1.226 (9) | C29—H32 | 0.967 (17) |
O64—C57 | 1.194 (9) | C29—H33 | 0.947 (19) |
O5—C2 | 1.257 (7) | C35—H37 | 1.012 (19) |
O42—C39 | 1.263 (7) | C57—C63 | 1.445 (6) |
N17—C19 | 1.465 (6) | C63—C65 | 1.369 (7) |
N17—C20 | 1.405 (8) | C56—H61 | 0.939 (17) |
N17—C18 | 1.387 (7) | C56—H60 | 0.969 (19) |
N21—C29 | 1.463 (6) | C56—H62 | 0.951 (19) |
N21—C28 | 1.355 (7) | C66—H69 | 0.950 (17) |
N21—C18 | 1.366 (6) | C66—H71 | 0.957 (19) |
N30—C35 | 1.348 (6) | C66—H70 | 0.94 (2) |
N30—C26 | 1.368 (7) | C72—H74 | 1.01 (2) |
N31—C35 | 1.327 (9) | C1—C2 | 1.515 (6) |
N31—C28 | 1.341 (7) | C1—C4 | 1.408 (6) |
N30—H36 | 0.899 (17) | C1—C3 | 1.375 (6) |
N54—C57 | 1.403 (8) | C3—C7 | 1.405 (6) |
N54—C55 | 1.396 (7) | C4—C9 | 1.374 (6) |
N54—C56 | 1.455 (6) | C7—C13 | 1.358 (6) |
N58—C66 | 1.462 (6) | C9—C13 | 1.413 (6) |
N58—C65 | 1.361 (8) | C3—H8 | 1.017 (19) |
N58—C55 | 1.376 (6) | C4—H10 | 0.982 (19) |
N67—C72 | 1.347 (6) | C7—H14 | 1.001 (19) |
N67—C63 | 1.377 (7) | C9—H15 | 0.982 (19) |
N68—C72 | 1.338 (8) | C13—H16 | 0.971 (18) |
N68—C65 | 1.344 (7) | C38—C41 | 1.390 (6) |
N67—H73 | 0.911 (18) | C38—C39 | 1.507 (6) |
N6—C2 | 1.347 (6) | C38—C40 | 1.369 (6) |
N6—H12 | 0.990 (19) | C40—C44 | 1.385 (6) |
N6—H11 | 0.985 (18) | C41—C46 | 1.377 (6) |
N43—C39 | 1.338 (6) | C44—C50 | 1.365 (6) |
N43—H49 | 0.999 (17) | C46—C50 | 1.433 (6) |
N43—H48 | 0.984 (19) | C40—H45 | 1.023 (19) |
C20—C26 | 1.435 (6) | C41—H47 | 0.980 (19) |
C26—C28 | 1.353 (8) | C44—H51 | 1.001 (19) |
C19—H23 | 0.96 (2) | C46—H52 | 0.999 (19) |
C19—H25 | 0.940 (19) | C50—H53 | 0.97 (2) |
C18—N17—C19 | 116.8 (5) | N67—C63—C57 | 129.2 (5) |
C18—N17—C20 | 127.2 (4) | N68—C65—C63 | 111.9 (5) |
C19—N17—C20 | 115.9 (4) | N58—C65—N68 | 127.5 (5) |
C18—N21—C28 | 120.1 (4) | N58—C65—C63 | 120.6 (4) |
C18—N21—C29 | 118.2 (5) | N67—C72—N68 | 113.6 (5) |
C28—N21—C29 | 121.0 (4) | N54—C56—H60 | 110.3 (13) |
C26—N30—C35 | 104.5 (4) | N54—C56—H61 | 108.4 (11) |
C28—N31—C35 | 103.6 (5) | N54—C56—H62 | 108.5 (11) |
C35—N30—H36 | 127.0 (13) | H61—C56—H62 | 110.5 (16) |
C26—N30—H36 | 126.7 (12) | H60—C56—H62 | 109.4 (16) |
C55—N54—C57 | 127.3 (4) | H60—C56—H61 | 109.8 (17) |
C55—N54—C56 | 116.2 (4) | N58—C66—H71 | 107.6 (13) |
C56—N54—C57 | 116.5 (4) | N58—C66—H70 | 109.4 (12) |
C55—N58—C66 | 117.6 (4) | H70—C66—H71 | 111.2 (16) |
C65—N58—C66 | 122.0 (4) | H69—C66—H70 | 109.1 (16) |
C55—N58—C65 | 119.3 (5) | N58—C66—H69 | 110.6 (11) |
C63—N67—C72 | 105.3 (5) | H69—C66—H71 | 109.0 (16) |
C65—N68—C72 | 103.3 (5) | N68—C72—H74 | 125.1 (13) |
C72—N67—H73 | 126.0 (13) | N67—C72—H74 | 120.8 (13) |
C63—N67—H73 | 126.8 (12) | C2—C1—C3 | 122.7 (4) |
C2—N6—H11 | 111.2 (10) | C2—C1—C4 | 119.7 (4) |
H11—N6—H12 | 105.4 (15) | C3—C1—C4 | 117.6 (4) |
C2—N6—H12 | 135.0 (13) | O5—C2—N6 | 119.6 (5) |
C39—N43—H48 | 111.9 (12) | N6—C2—C1 | 118.5 (4) |
H48—N43—H49 | 106.7 (16) | O5—C2—C1 | 121.8 (5) |
C39—N43—H49 | 135.4 (16) | C1—C3—C7 | 122.0 (4) |
N17—C18—N21 | 117.3 (5) | C1—C4—C9 | 120.8 (4) |
O22—C18—N17 | 121.9 (5) | C3—C7—C13 | 120.0 (4) |
O22—C18—N21 | 120.4 (6) | C4—C9—C13 | 120.5 (4) |
O27—C20—C26 | 127.4 (6) | C7—C13—C9 | 119.2 (4) |
N17—C20—C26 | 109.3 (5) | C7—C3—H8 | 117.2 (11) |
O27—C20—N17 | 123.1 (5) | C1—C3—H8 | 120.8 (11) |
N30—C26—C20 | 127.8 (5) | C1—C4—H10 | 120.2 (12) |
C20—C26—C28 | 125.1 (5) | C9—C4—H10 | 119.0 (12) |
N30—C26—C28 | 106.8 (4) | C3—C7—H14 | 118.2 (11) |
N31—C28—C26 | 111.3 (6) | C13—C7—H14 | 121.9 (11) |
N21—C28—N31 | 128.1 (5) | C13—C9—H15 | 119.3 (11) |
N21—C28—C26 | 120.3 (4) | C4—C9—H15 | 120.2 (12) |
N30—C35—N31 | 113.6 (5) | C7—C13—H16 | 118.4 (13) |
H23—C19—H24 | 109.8 (18) | C9—C13—H16 | 122.4 (13) |
H24—C19—H25 | 110.1 (17) | C39—C38—C40 | 121.2 (4) |
N17—C19—H23 | 110.8 (15) | C39—C38—C41 | 119.2 (4) |
N17—C19—H24 | 108.5 (10) | C40—C38—C41 | 119.5 (4) |
H23—C19—H25 | 108.2 (18) | O42—C39—N43 | 121.8 (5) |
N17—C19—H25 | 109.5 (12) | O42—C39—C38 | 121.6 (5) |
N21—C29—H34 | 108.9 (13) | N43—C39—C38 | 116.2 (4) |
N21—C29—H32 | 110.5 (10) | C38—C40—C44 | 120.6 (4) |
H32—C29—H34 | 109.4 (16) | C38—C41—C46 | 121.2 (4) |
H33—C29—H34 | 110.0 (17) | C40—C44—C50 | 120.8 (4) |
N21—C29—H33 | 108.1 (12) | C41—C46—C50 | 118.5 (4) |
H32—C29—H33 | 110.0 (16) | C44—C50—C46 | 119.4 (4) |
N31—C35—H37 | 124.8 (11) | C38—C40—H45 | 121.7 (12) |
N30—C35—H37 | 121.5 (12) | C44—C40—H45 | 117.7 (12) |
N54—C55—N58 | 117.2 (5) | C38—C41—H47 | 119.4 (11) |
O59—C55—N54 | 121.2 (5) | C46—C41—H47 | 119.4 (11) |
O59—C55—N58 | 121.0 (6) | C40—C44—H51 | 117.5 (12) |
N54—C57—C63 | 109.3 (4) | C50—C44—H51 | 121.7 (12) |
O64—C57—N54 | 121.7 (5) | C41—C46—H52 | 120.8 (11) |
O64—C57—C63 | 129.0 (6) | C50—C46—H52 | 120.7 (11) |
C57—C63—C65 | 124.8 (5) | C44—C50—H53 | 118.3 (12) |
N67—C63—C65 | 105.8 (4) | C46—C50—H53 | 122.3 (11) |
C19—N17—C18—O22 | 5.3 (11) | C72—N68—C65—N58 | 174.7 (8) |
C20—N17—C18—O22 | −178.4 (8) | C72—N68—C65—C63 | −4.4 (10) |
C19—N17—C18—N21 | 178.5 (6) | O27—C20—C26—N30 | 8.2 (15) |
C20—N17—C18—N21 | −5.3 (12) | O27—C20—C26—C28 | −178.8 (9) |
C19—N17—C20—C26 | 180.0 (6) | N17—C20—C26—N30 | −177.6 (8) |
C18—N17—C20—O27 | 178.2 (9) | N17—C20—C26—C28 | −4.6 (12) |
C19—N17—C20—O27 | −5.5 (12) | C20—C26—C28—N31 | −177.4 (8) |
C18—N17—C20—C26 | 3.7 (12) | N30—C26—C28—N31 | −3.2 (10) |
C29—N21—C18—O22 | −8.6 (11) | C20—C26—C28—N21 | 7.3 (14) |
C28—N21—C18—N17 | 7.2 (11) | N30—C26—C28—N21 | −178.5 (7) |
C29—N21—C18—N17 | 178.1 (6) | N54—C57—C63—C65 | 4.0 (11) |
C28—N21—C18—O22 | −179.5 (8) | O64—C57—C63—N67 | −1.5 (16) |
C18—N21—C28—N31 | 177.2 (9) | O64—C57—C63—C65 | −175.3 (9) |
C29—N21—C28—N31 | 6.6 (13) | N54—C57—C63—N67 | 177.7 (8) |
C18—N21—C28—C26 | −8.4 (12) | N67—C63—C65—N58 | −175.9 (7) |
C29—N21—C28—C26 | −179.0 (7) | C57—C63—C65—N58 | −0.9 (12) |
C26—N30—C35—N31 | 2.0 (9) | C57—C63—C65—N68 | 178.3 (8) |
C35—N30—C26—C20 | 174.7 (9) | N67—C63—C65—N68 | 3.3 (9) |
C35—N30—C26—C28 | 0.7 (9) | C3—C1—C2—O5 | −165.8 (6) |
C35—N31—C28—N21 | 179.1 (9) | C3—C1—C2—N6 | 10.5 (6) |
C28—N31—C35—N30 | −3.9 (10) | C4—C1—C2—O5 | 14.1 (7) |
C35—N31—C28—C26 | 4.3 (10) | C4—C1—C2—N6 | −169.7 (4) |
C56—N54—C55—O59 | −1.1 (12) | C2—C1—C3—C7 | 179.8 (3) |
C56—N54—C57—C63 | −179.7 (6) | C4—C1—C3—C7 | 0.0 (5) |
C56—N54—C57—O64 | −0.4 (12) | C2—C1—C4—C9 | −179.9 (3) |
C57—N54—C55—N58 | −11.5 (13) | C3—C1—C4—C9 | 0.0 (5) |
C55—N54—C57—C63 | 2.5 (12) | C1—C3—C7—C13 | 0.0 (5) |
C57—N54—C55—O59 | 176.8 (9) | C1—C4—C9—C13 | 0.1 (5) |
C56—N54—C55—N58 | 170.6 (6) | C3—C7—C13—C9 | 0.1 (5) |
C55—N54—C57—O64 | −178.2 (8) | C4—C9—C13—C7 | −0.2 (5) |
C55—N58—C65—N68 | 172.3 (8) | C40—C38—C39—O42 | 169.0 (6) |
C66—N58—C55—O59 | −6.2 (12) | C40—C38—C39—N43 | −4.0 (7) |
C66—N58—C65—C63 | −176.1 (6) | C41—C38—C39—O42 | −11.1 (7) |
C66—N58—C55—N54 | −177.9 (6) | C41—C38—C39—N43 | 175.9 (5) |
C55—N58—C65—C63 | −8.7 (11) | C39—C38—C40—C44 | 179.7 (3) |
C65—N58—C55—N54 | 14.2 (11) | C41—C38—C40—C44 | −0.2 (5) |
C65—N58—C55—O59 | −174.1 (8) | C39—C38—C41—C46 | −179.8 (3) |
C66—N58—C65—N68 | 4.9 (12) | C40—C38—C41—C46 | 0.1 (5) |
C72—N67—C63—C65 | −0.7 (8) | C38—C40—C44—C50 | 0.2 (5) |
C63—N67—C72—N68 | −2.1 (9) | C38—C41—C46—C50 | 0.0 (5) |
C72—N67—C63—C57 | −175.4 (8) | C40—C44—C50—C46 | 0.0 (5) |
C65—N68—C72—N67 | 4.0 (10) | C41—C46—C50—C44 | 0.0 (5) |
D—H···A | D—H | H···A | D···A | D—H···A |
N6—H11···O64i | 0.985 (18) | 2.362 (18) | 3.067 (8) | 128.0 (14) |
N6—H12···N68ii | 0.990 (19) | 1.98 (2) | 2.961 (7) | 172.5 (16) |
N30—H36···O42iii | 0.899 (17) | 1.975 (17) | 2.802 (8) | 152.4 (16) |
N43—H48···O27iv | 0.984 (19) | 2.02 (2) | 2.940 (8) | 155.2 (18) |
N43—H49···O64 | 0.999 (17) | 2.117 (18) | 3.102 (9) | 168 (3) |
N67—H73···O5v | 0.911 (18) | 1.923 (17) | 2.751 (9) | 150.4 (17) |
Symmetry codes: (i) −x+1, −y+1, z+1/2; (ii) −y+1, x, z+1/4; (iii) −x+1, −y+2, z+1/2; (iv) −x+1, −y+2, z−1/2; (v) −x+1, −y+1, z−1/2. |
Experimental details
Crystal data | |
Chemical formula | C7H8N4O2·C7H7NO |
Mr | 301.31 |
Crystal system, space group | Tetragonal, P41 |
Temperature (K) | 293 |
a, c (Å) | 10.281404 (12), 26.15892 (6) |
V (Å3) | 2765.19 (1) |
Z | 8 |
Radiation type | Synchrotron |
µ (mm−1) | 0.11 |
Specimen shape, size (mm) | Cylinder, 10 × 0.5 |
Data collection | |
Diffractometer | Australien Synchrotron XRD beamlime |
Specimen mounting | 0.5 mm glass capillary |
Data collection mode | Transmission |
Scan method | ? |
2θ values (°) | 2θmin = 2.0 2θmax = 82.32 2θstep = 0.01 |
Refinement | |
R factors and goodness of fit | Rp = 1.86, Rwp = 2.41, Rexp = 1.19, R(F) = 1.86, χ2 = 1.388 |
No. of parameters | 86 |
No. of restraints | 42 |
H-atom treatment | H-atom parameters constrained |
Computer programs: TOPAS Academic (Coelho, 2007), DASH (David et al., 2006), DIAMOND (Crystal Impact, 2014), publCIF (Westrip, 2010).
O22—C18 | 1.215 (9) | N31—C35 | 1.327 (9) |
O27—C20 | 1.207 (8) | N31—C28 | 1.341 (7) |
O59—C55 | 1.226 (9) | N54—C57 | 1.403 (8) |
O64—C57 | 1.194 (9) | N54—C55 | 1.396 (7) |
O5—C2 | 1.257 (7) | N54—C56 | 1.455 (6) |
O42—C39 | 1.263 (7) | N58—C66 | 1.462 (6) |
N17—C19 | 1.465 (6) | N58—C65 | 1.361 (8) |
N17—C20 | 1.405 (8) | N58—C55 | 1.376 (6) |
N17—C18 | 1.387 (7) | N67—C72 | 1.347 (6) |
N21—C29 | 1.463 (6) | N67—C63 | 1.377 (7) |
N21—C28 | 1.355 (7) | N68—C72 | 1.338 (8) |
N21—C18 | 1.366 (6) | N68—C65 | 1.344 (7) |
N30—C35 | 1.348 (6) | N6—C2 | 1.347 (6) |
N30—C26 | 1.368 (7) | N43—C39 | 1.338 (6) |
C18—N17—C19 | 116.8 (5) | N30—C26—C28 | 106.8 (4) |
C18—N17—C20 | 127.2 (4) | N31—C28—C26 | 111.3 (6) |
C19—N17—C20 | 115.9 (4) | N21—C28—N31 | 128.1 (5) |
C18—N21—C28 | 120.1 (4) | N21—C28—C26 | 120.3 (4) |
C18—N21—C29 | 118.2 (5) | N30—C35—N31 | 113.6 (5) |
C28—N21—C29 | 121.0 (4) | N54—C55—N58 | 117.2 (5) |
C26—N30—C35 | 104.5 (4) | O59—C55—N54 | 121.2 (5) |
C28—N31—C35 | 103.6 (5) | O59—C55—N58 | 121.0 (6) |
C55—N54—C57 | 127.3 (4) | N54—C57—C63 | 109.3 (4) |
C55—N54—C56 | 116.2 (4) | O64—C57—N54 | 121.7 (5) |
C56—N54—C57 | 116.5 (4) | O64—C57—C63 | 129.0 (6) |
C55—N58—C66 | 117.6 (4) | N67—C63—C65 | 105.8 (4) |
C65—N58—C66 | 122.0 (4) | N67—C63—C57 | 129.2 (5) |
C55—N58—C65 | 119.3 (5) | N68—C65—C63 | 111.9 (5) |
C63—N67—C72 | 105.3 (5) | N58—C65—N68 | 127.5 (5) |
C65—N68—C72 | 103.3 (5) | N58—C65—C63 | 120.6 (4) |
N17—C18—N21 | 117.3 (5) | N67—C72—N68 | 113.6 (5) |
O22—C18—N17 | 121.9 (5) | O5—C2—N6 | 119.6 (5) |
O22—C18—N21 | 120.4 (6) | N6—C2—C1 | 118.5 (4) |
O27—C20—C26 | 127.4 (6) | O5—C2—C1 | 121.8 (5) |
N17—C20—C26 | 109.3 (5) | O42—C39—N43 | 121.8 (5) |
O27—C20—N17 | 123.1 (5) | O42—C39—C38 | 121.6 (5) |
N30—C26—C20 | 127.8 (5) | N43—C39—C38 | 116.2 (4) |
D—H···A | D—H | H···A | D···A | D—H···A |
N6—H11···O64i | 0.985 (18) | 2.362 (18) | 3.067 (8) | 128.0 (14) |
N6—H12···N68ii | 0.990 (19) | 1.98 (2) | 2.961 (7) | 172.5 (16) |
N30—H36···O42iii | 0.899 (17) | 1.975 (17) | 2.802 (8) | 152.4 (16) |
N43—H48···O27iv | 0.984 (19) | 2.02 (2) | 2.940 (8) | 155.2 (18) |
N43—H49···O64 | 0.999 (17) | 2.117 (18) | 3.102 (9) | 168 (3) |
N67—H73···O5v | 0.911 (18) | 1.923 (17) | 2.751 (9) | 150.4 (17) |
Symmetry codes: (i) −x+1, −y+1, z+1/2; (ii) −y+1, x, z+1/4; (iii) −x+1, −y+2, z+1/2; (iv) −x+1, −y+2, z−1/2; (v) −x+1, −y+1, z−1/2. |