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Acta Crystallographica Section C
Structural Chemistry
ISSN 2053-2296
Crystal structures of pyrazinamide-p-amino benzoic acid cocrystal andtheir transamidation reaction product,4-(pyrazine-2-carboxamido)benzoic acid in molten state
Shridhar H. Thorat, Sanjay kumar Sahu and Rajesh G Gonnade*
CONFIDENTIAL – NOT TO BE REPRODUCED, QUOTED NOR SHOWN TO OTHERS
SCIENTIFIC MANUSCRIPT
For review only.
Tuesday 13 October 2015
Category: research papers
Co-editor:
Professor J. WhiteSchool of Chemistry, The University of Melbourne, VIC 3010, Australia
Telephone: 61 8344 2445
Fax: 61 9347 5180Email: whitejm@unimelb.edu.au
Contact author:
Rajesh G Gonnade
IndiaTelephone: 912025902225
Fax: 912025902642Email: rg.gonnade@ncl.res.in
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Crystal structures of pyrazinamide-p-amino benzoic acid cocrystal and their 1
transamidation reaction product, 4-(pyrazine-2-carboxamido)benzoic acid in 2
molten state3
Shridhar H. Thorat, Sanjay kumar Sahu and Rajesh G Gonnade*4
Center for Materials Characterization, CSIR-National Chemical Laboratory, Pune -, 411008,., India5Correspondence email: rg.gonnade@ncl.res.in6
Abstract 7
The 1:1 pharmaceutical cocrystal (1) of anti-tuberculosis drug, pyrazinamide (PZA) and cocrystal former, p-amino 8
benzoic acid (pABA) was successfully synthesized and characterized by relevant solid state characterization methods. 9
The cocrystals crystallized in monoclinic space group P21/n containing one molecule of each component. Both molecules 10
associate via intermolecular O—H···O and N—H···O hydrogen bonds to generate the dimeric acid-amide synthon. The 11
neighboring dimers are linked centrosymmetrically through N—H···O interactions to form the tetrameric assembly 12
supplemented by C—H···N interactions. Linking of the tetrameric assemblies through N—H···N and C—H···O 13
interactions created the two-dimensional packing. Recrystallization of the cocrystals in molten state revealed the 14
formation of carboxamide (2) through transamidation reaction between PZA and pABA. The carboxamide 2 crystallized 15
in triclinic space group P-1 with one molecule in the asymmetric unit. Molecules of 2 forms a centrosymmetric dimeric 16
homo synthon through acid···acid O—H···O hydrogen bond. The neighboring assemblies are connected 17
centrosymmetrically via C—H···N interaction engaging pirazine moieties to generate the linear chain. The adjacent chains 18
are loosely connected via C—H···O interactions to generate the two-dimensional sheet structure. The closely associated 19
two-dimensional sheets in both compounds stacked via aromatic π-stacking interactions engaging pyrazine and benzene 20
rings to create the three-dimensional multi–stack structure.21
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03scheme1.tif
1. Introduction 22
Synthesis of cocrystals and study of their physicochemical properties has developed into a contemporary area of research 23
comprising pharmaceutical solids (Aakeroy et al., 2005; Schulthesiss & Newman, 2009; Vishweshwar et al., 2006), 24
agrochemicals (Nauha & Nissinen, 2011), high energy materials (Bolton et al., 2012; Millar et al., 2012), etc. Constant 25
and consistent endeavour to develop API cocrystals with suitable cocrystal former has gained considerable interest in 26
recent years because of its exploitation in tuning the physicochemical properties of an API that could be economically 27
beneficial and academically inspiring (Babu & Nangia, 2011; Porter et al., 2008; Atipamula et al., 2012). Therefore, 28
synthesis of pharmaceutical cocrystals is a pioneering strategy to enhance the performance of the API without affecting 29
their therapeutic efficiency. Pyrazinamide (PZA) is one of the most important frontline medicines used for the treatment 30
of tuberculosis (TB) (Zhang & Mitchison, 2003). Total four polymorphs of PZA are reported in the literature 31
(Cherukuvada et al., 2010). Several cocrystals of PZA were also reported with cocrystal former that include 4-nitro-32
benzamide (Aakeroy et al., 2004), 2,5-dihydroxybenzoic acid (McMahon et al., 2005), 4-aminosalicylic acid (Grobelny 33
et al., 2011), 2-aminobenzoic acid (Abourahma et al., 2011), succinic acid and fumaric acid (Cherukuvada & Nangia, 34
2012), vanillic acid, gallic acid, 1-hydroxy-2-naphthoic acid, indole-2-carboxylic acid (Adalder et al., 2012), malonic 35
acid and glutaric acid (Luo & Sun, 2013), 3,4-dihydroxybenzoic acid and m-hydroxybenzoic acid (Lou et al., 2013) and 36
hydrochlorothiazide (Wang et al., 2014), . All these cocrystals were thoroughly characterized using appropriate solid-state 37
characterization methods. Abourahma et al. reported the single crystals structures of cocrystals of PZA with ortho, meta 38
isomers of aminobenzoic acid (ABA) as well as meta and para-hydroxybenzoic acids (Abourahma et al. 2011). However, 39
they failed to study the single crystal structure of PZA-p-ABA cocrystals because of its polycrystalline nature.40
Here we report the successful preparation of single crystals of PZA-p-ABA cocrystal 1. The current study also 41
demonstrate interesting transamidation reaction (Rao et al., 2013; Picq et al., 1999) between PZA and pABA in a molten 42
state during hot stage microscopy study to yield corresponding carboxamide 2 in crystalline form. Both the compounds 43
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were thoroughly characterized using single and powder X-ray diffraction, DSC, TGA, 1H NMR and IR spectroscopy. 44
Detailed crystal structure analysis of both compounds has been carried out that revealed the dominance of classical O—45
H···O, N—H···O and N—H···N hydrogen bonding interactions in molecular packing in the crystals. 46
2. Experimental 47
2.1. ′Synthesis and crystallization′ 48
Cocrystallization was carried out from equimolar amounts of commercial samples of PZA and p-ABA by grinding (dry 49
grinding as well solvent assisted grinding) and slow evaporation from the solution under ambient conditions. The 50
grinding experiment was carried out manually using mortar and pestle for about 15 minutes. The 1:1 stoichiometric molar 51
ratio of PZA and p-ABA were grinded using dry (neat) and liquid assisted (or kneading) grinding methods. In liquid 52
assisted grinding small amount ethanol-water mixture (1:1, v:v) was added during grinding. The grinded sample was 53
characterized using powder X-ray diffraction to verify the formation of cocrystal by comparing it with simulated powder 54
pattern from single crystal XRD of molecular cocrystal. The same grinded material was used for solution crystallization. 55
The grinded sample was dissolved in the ethanol-water mixture (1:1, v:v) and heated at 45-50 °C for about 10-15 minutes 56
to dissolve the sample. The hot solution was then filtered into the conical flask to remove the traces of undissolved 57
compound or any foreign material, and the solution was evaporated at room temperature to yield block type crystals of 1. 58
The cocrystallization was also attempted from the various organic solvents such as acetone, ethyl acetate, acetonitrile, 59
methanol, nitromethane, chloroform and acetone-methanol mixture which gave block type cocrystals while crystallization 60
from the 1,4-dioxan, water, tetrahydrofuran and dichloromethane resulted in the separate crystallization of both 61
components. Crystals of carboxamide 2 were obtained by heating the cocrystal 1 till its melting on a hot plate and 62
subsequently cooling the melt. The carboxamide 2 was also been synthesized by heating the physical mixture of PZA and 63
pABA on hot stage till their melting, cooling the melt produced crystals of carboxamide 2 (scheme 1). Both cocrystal 1 64
and carboxamide 2 were characterized by the single crystal X-ray diffraction analysis (SC-XRD), powder X-ray 65
diffraction (PXRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), NMR and IR 66
spectroscopy and hot stage microscopy. Analysis for cocrystal 1: m.p. 452-453 K; IR (Nujol, ν, cm-1): 1595, 1670, 3321, 67
3342, 3414; 1H NMR (200 MHz, DMSO-d6) δ 5.88 (Broad S, 2 H), 6.54 (d, J = 8.6 Hz, 2 H), 7.61 (d, J = 8.6 Hz, 2 H), 68
7.88 (broad S., 1 H), 8.28 (broad S., 1 H), 8.73 (m, 1 H), 8.86 (d, J = 2.40 Hz, 1 H), 9.19 (d, J = 1.4 Hz, 1 H). Analysis for 69
compound 2: m.p. 597-598 K; IR (Nujol, ν, cm-1): 3340,1680;1H NMR (200 MHz, DMSOd6)δ 7.91 - 8.01 (m, 2 H) 8.02 - 70
8.13 (m, 2 H) 8.86 (m, 1 H) 8.97 (d, J= 2.5Hz, 1 H) 9.34 (d,J= 1.5Hz,1 H) 11.05 (s, 1 H,D2O exchangeable) 12.84 (Broad 71
S, 1 H, D2O exchangeable).(see Supporting information for NMR and IR spectra; Figs. S1—S4). 72
2.2. ′DSC Analysis′ 73
DSC analysis: The thermal behavior of cocrystal (1) and carboxamide (2) was investigated by measuring the enthalpy 74
change on a TA Q-100 Differential Scanning Calorimeter instrument. Crystals obtained from crystallization were first air-75
dried before they were used for DSC analysis. Crystals 3-5 mg were placed in a sealed aluminum pan (40 µL) with 76
crimped pan closure and were analyzed from room temperature to 300 oC using an empty pan as the reference. The 77
heating rate was 2 °C min-1 and nitrogen gas was used for purging. DSC analysis of the cocrystal 1 showed two 78
endothermic peaks, first being the sharp whereas the other endotherm is a small hump. The first endotherm centered at 79
179.8 oC indicated their melting followed by formation of carboxamide 2 (as suggested by HSM and single crystals 80
diffraction studies-please see below) and the second endotherm is attributed to the melting of the carboxamide 2. 81
However, DSC analysis of freshly prepared carboxamide 2 revealed a sharp melting endotherm at 326.8 oC (see 82
Supporting information for DSC plots; Figs. S5—S6). 83
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2.3. ′PXRD Analysis′ 84
PXRD analysis: The experimental powder X-ray diffraction patterns were recorded on Rigaku Micromax-007HF 85
instrument (High intensity microfocus rotating anode X-ray Generator) with R-axis detector IV++ at a continuous 86
scanning rate of 2° 2θ/min using Cu Kα radiation (40 kV, 30 mA) with the intensity of the diffracted X-ray being 87
collected at intervals of 0.1° 2θ. A nickel filter was used to remove Cu Kβ radiation. The PXRD patterns of cocrystal 1 88
obtained from solution crystallization and liquid assisted grinding are different than diffractograms of PZA and pABA 89
and matched well with the diffraction pattern of the cocrystal 1 simulated from its single crystal diffraction data (see 90
Supporting information for PXRD patterns; Figs. S7, S8). However, powder diffractogram of cocrystal 1 obtained by dry 91
grinding experiment also reveals the presence of individual diffraction peaks of the PZA and pABA (see Supporting 92
information for PXRD patterns; Figs. S6). Further, the diffraction pattern of the crystals produced from the melt 93
crystallization of cocrystal 1 is different than that of the cocrystal 1, PZA and pABA (see Supporting information for 94
PXRD patterns; Fig. S9). 95
2.4. ′TGA Study′ 96
TGA Study: Thermogravimetric analysis was performed using a TA SDT Q600 TGA instrument. Samples were prepared 97
by placing 7-8 mg of material in a standard 180 µL aluminum pan. It was then heated from ambient temperature (30 °C) 98
to 500 °C with a heating rate 10 oC/min. The nitrogen gas was used for purging with a flow rate of 100 cm3 min-1. TGA 99
analysis of cocrystal 1 revealed weight loss after its melting was attributed to the release of ammonia from the melt 100
reaction. The TGA analysis of carboxamide 2 did not reveal any weight loss on heating (see Supporting information for 101
TGA plots; Figs. S10, S11). 102
2.5. ′IR Spectroscopy′ 103
IR Spectroscopy: The solid-state infrared spectra of the cocrystals (1) and amide (2) were acquired by using BRUKER 104
ALPHA FTIR spectrophotometer at room temperature in Nujol from 500-4000 cm-1 range. see Supporting information 105
for IR spectra; Fig. S4). 106
2.6. ′HSM Analysis′ 107
HSM Analysis: The cocrystals were heated on heating stage P350 and the pictures were grabbed using CCD camera 108
attached to Leica polarizing microscope MZ75. Leica IM 50 software was used for image capture and analysis. The HSM 109
study on cocrystal showed the appearance of thin needles on the surface of big crystals around 170 °C. Unit cell 110
determination of these needles revealed them to be cocrystals. Further, heating cocrystals began to melt at 180 °C and 111
then formed thin plateshaped crystals, which completely melted at 219.2 °C (see Supporting information for crystal 112
photomicrographs; Fig. S12). Determination of the crystal structure of the thin plate confirmed the formation of 113
carboxamide 2. This indicated that the transamidation reaction between the PZA and pABA has occurred in molten state 114
yielding the corresponding carboxamide 2 with the release of ammonia (Figure 1). To confirm the developement of 115
carboxamide 2, HSM studies were carried out couple of additional times and in all the endeavors carboxamide 2 was 116
obtained. HSM studies were also carried out on a physical mixture of PZA and p-ABA around 200 - 210 °C that also 117
revealed the formation carboxamide 2. 118
2.7. Refinement 119
Crystal data, data collection and structure refinement details are summarized in Table 1. For both compounds H-atoms 120
bound to N-atoms (NH~2~ and NH) and hydroxy moiety of carboxyl groups were located in difference Fourier and 121
refined isotropically. Other phenyl hydrogen atoms were placed in geometrically idealized positions (C—H = 0.93 Å) and 122
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constrained to ride on their parent atoms [Uiso(H) = 1.2Ueq(C)]. 123
3. ′Results and discussion′ 124
Crystallization of pyrazinamide (PZA) and p-amino benzoic acid (p-ABA) from various common organic solvents 125
(except 1,4-dioxan, water, tetrahydrofuran, and dichloromethane) yielded block shape cocrystals suitable for single 126
crystal X-ray analysis. Both neat grinding and liquid assisted grinding also lead to cocrystal 1 formation indicated by 127
powder X-ray diffraction studies.128
Cocrystal 1 consists of an equimolar amount of PZA and p-ABA as revealed by 1H NMR spectroscopy and single-129
crystal X-ray diffraction analysis. The DSC profile of cocrystal 1 showed that it is stable up to the melting point, and 130
there was no structural phase change transition prior to its melting. TGA did not reveal any weight loss before melting; 131
however, some weight loss was observed after melting of the crystals corresponding to the release of ammonia after 132
transamidation reaction between PZA and p-ABA. HSM, single crystal and powder X-ray diffraction studies revealed the 133
formation of carboxamide 2 after the transamidation reaction in a molten state. The structure of carboxamide 2 was also 134
confirmed by 1H NMR spectroscopy and single-crystal X-ray diffraction analysis. DSC and TGA studies on carboxamide 135
2did not reveal phase change and weight loss before and after the melting respectively.136
Cocrystal 1 crystallized in monoclinic P21/n space group containing one molecule of each PZA and pABA in the 137
asymmetric unit (Fig.2). Both molecules associated via acid···amide heterodimer synthon (Desiraju, 1995) through 138
conventional O2—H2···O1 and N3—H3A···O3 hydrogen bonds (Fig. 2). In O—H···O hydrogen bond formation the 139
hydroxyl group of the p-ABA donates its H atom to the carbonyl oxygen of the PZA and in turn amine group PZA 140
donates one of the H atoms to the carbonyl oxygen of the carboxyl group of p-ABA to generate the N—H···O hydrogen 141
bond . Neighboring dimers are linked via N3—H3B···O3i [symmetry code: (i) -x+2, -y+1, -z+1] hydrogen bonds 142
involving other H atom of amine group and carbonyl oxygen of carboxylic acid group to generate the tetrameric assembly 143
also supplemented by C8—H8···N2 [symmetry code: (i) -x+2, -y+1, -z+1] interaction (Fig. 3). The adjacent tetramers 144
along the crystallographic 21-screw axis (b-axis) are stitched through N4—H4A···O2ii and C11—H11···O1ii [symmetry 145
code: (ii) -x+1/2, y+1/2, -z+1/2] interactions to form 2D helical sheet structure (Fig. 4). This association also brings the 146
unit-translated tetramers along the b-axis in proximity to make N4—H4B···N1iii [symmetry code: (iii) -x+1/2, y+1/2, -147
z+1/2] hydrogen bond. The neighboring sheets are stacked in centrosymmetric fashion through aromatic π···π interactions 148
between pyrazine and benzene rings (Cg1···Cg2 = 3.6019 (9) Å, dihedral angle = 6.30 (7)°, symmetry code: (v) -x+1, -149
y+1, -z+1, Cg – centroid of the ring, Cg1 = C7—C12 benzene ring, Cg2 = N1—C2 pyrazine ring) to create a wavy 150
pattern on the bc plane supported by weak C4—H4···O1iv [symmetry code: (iv) x+1/2, -y+1/2, z+1/2] contact (Fig. 5).151
Crystal structure of carboxamide 2 belongs to triclinic P-1 space group containing one molecule in the asymmetric unit 152
(Fig. 6). Conformation of the molecule as observed in the crystal structure reveals a planar geometry wherein both 153
pyrazine and benzoic acid moieties are in the same plane. Closely associated molecules form an acid···acid homodimer 154
synthon (Desiraju, 1995) through O2—H2···O1i [symmetry code: (i) -x+1, -y+1, -z+1] hydrogen bond (Fig. 7). The 155
neighboring dimers are further connected by C11—H11···N3ii [symmetry code: (ii) -x+1, -y+2, -z+3] interactions 156
engaging pyrazine moieties across the inversion center to generate the extended molecular string (Fig. 8). The 157
neighboring strings are stitched through C4—H4···O3iii [symmetry code: (ii) x-1, y, z] interactions involving C—H of 158
benzoic acid and the carbonyl oxygen of the carboxamide moiety to create a 2D molecular sheet (Fig. 8). The adjacent 159
sheets are stacked centrosymmetrically via aromatic π···π interactions between pyrazine and benzene rings (Cg1···Cg2 = 160
3.7399 (15) Å, dihedral angle = 8.18 (12)°, symmetry code: (iv) -x+1, -y+2, -z+2, Cg – centroid of the ring, Cg1 = N2—161
C10 pyrazine ring, Cg2 = C2—C7 benzene ring) to create a multiple stack structure (Fig. 9).162
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In conclusion, single crystal structure of cocrystal (1) of pyrazinamide and p-amino benzoic acid has been prepared and 163
its molten state transamidation product carboxamide 2 has been isolated. Both compounds have been thoroughly 164
characterized by relevant solid state characterization methods. As, expected molecules in cocrystal 1 associate via 165
acid···amide heterodimer synthon that further linked to each other through N—H···O hydrogen bond to yield the tetramer. 166
The arrangement of the tetramer through weak interactions led to 2D wavy sheet structure. Conversely, closely linked 167
molecules of carboxamide 2 made acid···acid homodimer synthon (as the obvious choice) and its subsequent association 168
via weak contacts revealed a generation of the 2D planar sheet structure. The occurrence of effective transamidation 169
reaction between pyrazinamide and p-amino benzoic acid in a molten state with better selectivity and complete 170
reproducibility is intriguing. In general, molecular cocrystals provide a good platform for investigating heteromolecular 171
reaction either in a crystalline state or in a molten state with high selectivity and excellent conversion rate not feasible in 172
solution, single component crystal or its melt (MacGillivray et al., 2008; Tamboli et al., 2013). The similar reaction 173
between other carboxamide and amine in molten sate are currently being explored. 174
fig1.tif
Figure 1175
Transamidation reaction between pyrazinamide (PZA) and p-amino benzoic acid (pABA) in a molten state. 176
fig2.tif
Figure 2177
An ORTEP III (Farrugia, 1997) view of 1 displaying dimeric association of pyrazinamide (PZA) and p-amino benzoic 178
acid (pABA) molecules through acid···amide, O2—H2···O1 and N3—H3A···O3 hydrogen bonds. The ORTEP is drawn 179
with 50% probability displacement ellipsoids and H atoms are shown as small spheres of arbitrary radii. 180
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fig3.tif
Figure 3181
Linking of the adjacent dimers through centrosymmetric N3—H3B···O3i and C8—H8···N2i hydrogen bonds to generate 182
tetrameric synthon [Symmetry code: (i) -x + 2, -y + 1, -z + 1]. 183
fig4.tif
Figure 4184
Joining of the neighboring tetramers through N4—H4A···O2ii, N4—H4B···N1iii and C11—H11···O1ii interactions to create 185
two-dimensional helical sheet structure [Symmetry codes: (ii)-x + 1/2, y + 1/2, -z + 1/2; (iii) x, y + 1, z]. 186
fig5a.tif
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fig5b.tif
Figure 5187
(a) Joining of the adjacent sheets through C4—H4···O1ivand aromatic π···πv stacking interactions to generate the wavy 188
pattern in three-dimensional as shown in (b) [Symmetry codes: (iv) x + 1/2, -y + 1/2, z + 1/2; (v) -x + 1, -y + 1, -z + 1]. 189
fig6.tif
Figure 6190
An ORTEP III (Farrugia, 1997) view of 2 drawn with 50% probability displacement ellipsoids and H atoms are shown as 191
small spheres of arbitrary radii. 192
fig7.tif
Figure 7193
Dimeric acid···acid synthon formation through O2—H2···O1i hydrogen bond [Symmetry code: (i) -x + 1, -y + 1, -z + 1]. 194
fig8.tif
Figure 8195
Joining of the adjacent dimeric synthons through C4—H4···O3ii and C11—H11···N3iii contacts to generate the two-196
dimensional sheet pattern on the ac plane [Symmetry codes: (ii) x - 1, y, z; (iii) -x + 1, -y + 2, -z + 3]. 197
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fig9a.tif
fig9b.tif
Figure 9198
Weaving of the adjacent parallel two-dimensional sheets through aromatic π···πiv stacking interactions to generate the 199
multiple stack structure [Symmetry code: (iv) -x + 1, -y + 2, -z + 2]. 200
Table 1201
Experimental details202
203 (1) (2)
204 Crystal data
205 Chemical formula C7H7NO2.C5H5N3O C12H9N3O3
206 Mr 260.26 243.22
207 Crystal system, space group
Monoclinic, P21/n Triclinic, P1
208 Temperature (K) 296 296
209 a, b, c (Å) 7.9293 (8), 15.1231 (16), 10.2490 (12) 6.0535 (5), 7.4159 (6), 13.2548 (10)
210 α, β, γ (°) 90, 100.862 (6), 90 85.612 (5), 81.900 (5), 66.398 (5)
211 V (Å3) 1207.0 (2) 539.69 (7)
212 Z 4 2
213 Radiation type Mo Kα Mo Kα
214 µ (mm−1) 0.11 0.11
215 Crystal size (mm) 0.42 × 0.36 × 0.30 0.36 × 0.28 × 0.21
216
217 Data collection
218 Diffractometer Bruker APEX-II CCD diffractometer
Bruker APEX-II CCD diffractometer
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219 Absorption correction Multi-scan Bruker SADABS
Multi-scan Bruker SADABS
220 Tmin, Tmax 0.957, 0.969 0.961, 0.977
221 No. of measured, independent andobserved [I > 2σ(I)] reflections
9627, 2132, 1756 5721, 1908, 1383
222 Rint 0.019 0.041
223 (sin θ/λ)max (Å−1) 0.595 0.595
224
225 Refinement
226 R[F2 > 2σ(F2)], wR(F2), S0.037, 0.095, 1.05 0.054, 0.134, 1.06
227 No. of reflections 2132 1908
228 No. of parameters 184 164
229 H-atom treatment H atoms treated by a mixture of independent and constrained refinement
H atoms treated by a mixture of independent and constrained refinement
230 ∆ρmax, ∆ρmin (e Å−3) 0.14, −0.18 0.20, −0.31
Computer programs: Bruker APEX2 (Bruker, 2006), Bruker SAINT (Bruker, 2006), SHELXL97 (Sheldrick, 2008), ORTEP-3(Farrugia, 1997), Mercury 231CSD 3.5 (Macrae et al., 2008), SHELXS97 (Sheldrick, 2008), PLATON (Spek, 2003), publCIF(Westrip, 2010). 232
Acknowledgements 233
S·H·T. thanks CSIR (India) for a project fellowship under the ORIGIN program of 12FYP. This work was made possible 234
by financial support from CSIR (ORIGIN)·We gratefully acknowledge Mr. Arun Torris and Ms. Monika Malik for 235
recording the PXRD, DSC, and TGA data.236
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Vishweshwar, P., McMahon, J. A., Bis, J. A. & Zaworotko, M. J. (2006). J. Pharm. Sci. 95, 499-516.269
Wang, J.-R., Ye, V. & Mei, X. (2014). CrystEngComm 16, 6996–7003.270
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925.271
Zhang, Y. & Mitchison, D. (2003). Int. J. Tuberculosis Lung Dis. 7, 6–. 272
checkCIF/PLATON results for paper wq3103checkCIF/PLATON results Ellipsoid plot
checkCIF/PLATON resultsNo syntax errors found. CIF dictionary Interpreting this report
Datablock: 1
Bond precision: C-C = 0.0020 A Wavelength=0.71073Cell: a=7.9293(8) b=15.1231(16) c=10.2490(12) alpha=90 beta=100.862(6) gamma=90Temperature: 296 K
Calculated Reported ---------- --------Volume 1207.0(2) 1207.0(2) Space group P 21/n P2(1)/n Hall group -P 2yn ? Moiety formula C7 H7 N O2, C5 H5 N3 O C7 H7 N1 O2.C5 H5 N3 O1 Sum formula C12 H12 N4 O3 C12 H12 N4 O3 Mr 260.26 260.26 Dx,g cm-3 1.432 1.432 Z 4 4 Mu (mm-1) 0.107 0.107 F000 544.0 544.0 F000’ 544.25 h,k,lmax 9,17,12 9,17,12 Nref 2135 2132 Tmin,Tmax 0.956,0.968 0.957,0.969 Tmin’ 0.956
Correction method= # Reported T Limits: Tmin=0.957 Tmax=0.969 AbsCorr = MULTI-SCANData completeness= 0.999Theta(max)= 25.000R(reflections)= 0.0366( 1756) wR2(reflections)= 0.0954( 2132)S = 1.053 Npar= 184
Alert level CPLAT125_ALERT_4_C No ’_symmetry_space_group_name_Hall’ Given ..... Please Do ! PLAT480_ALERT_4_C Long H...A H-Bond Reported H8 .. N2 .. 2.71 Ang. PLAT480_ALERT_4_C Long H...A H-Bond Reported H11 .. O1 .. 2.69 Ang. PLAT480_ALERT_4_C Long H...A H-Bond Reported H4 .. O1 .. 2.64 Ang. PLAT701_ALERT_1_C Bond Calc 1.316(2), Rep 1.3133(18), Dev.. 1.35 Sigma N3 -C5 1.555 1.555 ............. Bond # 9 PLAT911_ALERT_3_C Missing # FCF Refl Between THmin & STh/L= 0.595 3 ReportPLAT913_ALERT_3_C Missing # of Very Strong Reflections in FCF .... 2 Note PLAT922_ALERT_1_C wR2 in the CIF and FCF Differ by ............... 0.0011 Check PLAT923_ALERT_1_C S values in the CIF and FCF Differ by ....... 0.012 Check
Alert level GPLAT042_ALERT_1_G Calc. and Reported MoietyFormula Strings Differ Please CheckPLAT066_ALERT_1_G Predicted and Reported Tmin&Tmax Range Identical ? CheckPLAT899_ALERT_4_G SHELXL97 is Deprecated and Succeeded by SHELXL 2014 Note PLAT909_ALERT_3_G Percentage of Observed Data at Theta(Max) still 62 %
0 ALERT level A = Most likely a serious problem - resolve or explain 0 ALERT level B = A potentially serious problem, consider carefully 9 ALERT level C = Check. Ensure it is not caused by an omission or oversight 4 ALERT level G = General information/check it is not something unexpected
5 ALERT type 1 CIF construction/syntax error, inconsistent or missing data 0 ALERT type 2 Indicator that the structure model may be wrong or deficient 3 ALERT type 3 Indicator that the structure quality may be low 5 ALERT type 4 Improvement, methodology, query or suggestion 0 ALERT type 5 Informative message, check
Datablock: 2
Bond precision: C-C = 0.0036 A Wavelength=0.71073Cell: a=6.0535(5) b=7.4159(6) c=13.2548(10) alpha=85.612(5) beta=81.900(5) gamma=66.398(5)Temperature: 296 K
Calculated Reported ---------- --------Volume 539.69(8) 539.69(7) Space group P -1 P-1 Hall group -P 1 ? Moiety formula C12 H9 N3 O3 C12 H9 N3 O3 Sum formula C12 H9 N3 O3 C12 H9 N3 O3 Mr 243.22 243.22 Dx,g cm-3 1.497 1.497 Z 2 2 Mu (mm-1) 0.111 0.111 F000 252.0 252.0 F000’ 252.12 h,k,lmax 7,8,15 7,8,15 Nref 1909 1908 Tmin,Tmax 0.963,0.977 0.961,0.977 Tmin’ 0.961
Correction method= # Reported T Limits: Tmin=0.961 Tmax=0.977 AbsCorr = MULTI-SCANData completeness= 0.999Theta(max)= 25.000R(reflections)= 0.0537( 1383) wR2(reflections)= 0.1343( 1908)S = 1.063 Npar= 164
Alert level CPLAT125_ALERT_4_C No ’_symmetry_space_group_name_Hall’ Given ..... Please Do ! PLAT250_ALERT_2_C Large U3/U1 Ratio for Average U(i,j) Tensor .... 2.1 Note PLAT906_ALERT_3_C Large K value in the Analysis of Variance ...... 7.868 Check
Alert level GPLAT002_ALERT_2_G Number of Distance or Angle Restraints on AtSite 2 Note PLAT066_ALERT_1_G Predicted and Reported Tmin&Tmax Range Identical ? CheckPLAT154_ALERT_1_G The su’s on the Cell Angles are Equal .......... 0.00500 DegreePLAT909_ALERT_3_G Percentage of Observed Data at Theta(Max) still 47 % PLAT910_ALERT_3_G Missing # of FCF Reflection(s) Below Th(Min) ... 1 Report
0 ALERT level A = Most likely a serious problem - resolve or explain 0 ALERT level B = A potentially serious problem, consider carefully 3 ALERT level C = Check. Ensure it is not caused by an omission or oversight 5 ALERT level G = General information/check it is not something unexpected
2 ALERT type 1 CIF construction/syntax error, inconsistent or missing data 2 ALERT type 2 Indicator that the structure model may be wrong or deficient 3 ALERT type 3 Indicator that the structure quality may be low 1 ALERT type 4 Improvement, methodology, query or suggestion 0 ALERT type 5 Informative message, check
database duplication summaryDatablock: 1
Chemical name = R factor = 0.037Space group = P2(1)/nFormula = C12 H12 N4 O3a=7.9293 b=15.1231 c=10.249alpha=90 beta=100.862 gamma=90
Datablock: 2
Chemical name = R factor = 0.054Space group = P-1 Formula = C12 H9 N3 O3a=6.0535 b=7.4159 c=13.2548alpha=85.612 beta=81.9 gamma=66.398
No duplication found.
reference checking results
The following reference was not checked in detail as it was not recognized as a journal reference
Bruker (2006). APEX2, SAINT and SADABS. Bruker AXS Inc., Madison, Wisconsin, USA. [software reference?]
All references appear to be cited unambiguously
supporting information
sup-1
supporting information1
Crystal structures of pyrazinamide-p-amino benzoic acid cocrystal and their 2
transamidation reaction product, 4-(pyrazine-2-carboxamido)benzoic acid in 3
molten state4
Shridhar H. Thorat, Sanjay kumar Sahu and Rajesh G Gonnade*5
Computing details 6
For both compounds, data collection: Bruker APEX2 (Bruker, 2006); cell refinement: Bruker SAINT (Bruker, 2006); data 7
reduction: Bruker SAINT (Bruker, 2006); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) 8
used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3(Farrugia, 1997), Mercury CSD 3.5 9
(Macrae et al., 2008); software used to prepare material for publication: SHELXS97 (Sheldrick, 2008), PLATON (Spek, 10
2003), publCIF(Westrip, 2010).11
(1) 12
Crystal data 13
C7H7NO2.C5H5N3O14
Mr = 260.2615
Monoclinic, P21/n16
a = 7.9293 (8) Å17
b = 15.1231 (16) Å18
c = 10.2490 (12) Å19
β = 100.862 (6)°20
V = 1207.0 (2) Å321
Z = 422
F(000) = 544Dx = 1.432 Mg m−3
Mo Kα radiation, λ = 0.71073 ÅCell parameters from 5708 reflectionsθ = 2.4–31.9°µ = 0.11 mm−1
T = 296 KBLOCK, colourless0.42 × 0.36 × 0.30 mm
Data collection 23
Bruker APEX-II CCD 24
diffractometerRadiation source: fine-focus sealed tube25
Graphite monochromator26
φ and ω scans27
Absorption correction: multi-scan 28
Bruker SADABSTmin = 0.957, Tmax = 0.96929
9627 measured reflections2132 independent reflections1756 reflections with I > 2σ(I)Rint = 0.019θmax = 25.0°, θmin = 2.4°h = −9→9k = −16→17l = −10→12
Refinement 30
Refinement on F231
Least-squares matrix: full32
R[F2 > 2σ(F2)] = 0.03733
wR(F2) = 0.09534
S = 1.0535
2132 reflections36
184 parameters37
0 restraints38
Primary atom site location: structure-invariant direct methods
Secondary atom site location: difference Fourier map
Hydrogen site location: inferred from neighbouring sites
H atoms treated by a mixture of independent and constrained refinement
supporting information
sup-2
w = 1/[σ2(Fo2) + (0.0468P)2 + 0.2371P] 39
where P = (Fo2 + 2Fc
2)/3(∆/σ)max < 0.00140
∆ρmax = 0.14 e Å−3
∆ρmin = −0.18 e Å−3
Special details 41
42 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.
43 Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) 44
45 x y z Uiso*/Ueq
46 O1 0.58680 (13) 0.37637 (7) 0.36785 (11) 0.0517 (3)
47 O2 0.49599 (14) 0.53990 (8) 0.31130 (12) 0.0584 (3)
48 O3 0.75052 (13) 0.58388 (7) 0.42341 (11) 0.0547 (3)
49 N1 0.65534 (17) 0.10432 (8) 0.39661 (14) 0.0547 (4)
50 N2 0.89391 (15) 0.22476 (8) 0.53250 (12) 0.0451 (3)
51 N3 0.85200 (18) 0.40066 (10) 0.48778 (14) 0.0488 (4)
52 N4 0.3948 (2) 0.95519 (10) 0.25288 (17) 0.0605 (4)
53 C1 0.7944 (2) 0.07923 (11) 0.48214 (17) 0.0551 (4)
54 H1 0.8129 0.0191 0.4978 0.066*
55 C2 0.6363 (2) 0.19190 (10) 0.38044 (16) 0.0475 (4)
56 H2A 0.5414 0.2134 0.3215 0.057*
57 C3 0.75314 (16) 0.25135 (9) 0.44858 (13) 0.0373 (3)
58 C4 0.9121 (2) 0.13802 (10) 0.54852 (16) 0.0529 (4)
59 H4 1.0076 0.1163 0.6066 0.063*
60 C5 0.72558 (17) 0.34889 (9) 0.43164 (13) 0.0380 (3)
61 C6 0.60904 (18) 0.60223 (9) 0.35883 (14) 0.0406 (4)
62 C7 0.54941 (17) 0.69295 (9) 0.32778 (13) 0.0372 (3)
63 C8 0.65468 (18) 0.76301 (10) 0.37902 (15) 0.0451 (4)
64 H8 0.7618 0.7514 0.4309 0.054*
65 C9 0.60351 (19) 0.84909 (10) 0.35450 (15) 0.0484 (4)
66 H9 0.6759 0.8948 0.3909 0.058*
67 C10 0.44456 (18) 0.86920 (10) 0.27581 (14) 0.0422 (4)
68 C11 0.33981 (19) 0.79880 (10) 0.22312 (15) 0.0460 (4)
69 H11 0.2337 0.8103 0.1696 0.055*
70 C12 0.39059 (18) 0.71314 (10) 0.24887 (14) 0.0426 (4)
71 H12 0.3179 0.6674 0.2131 0.051*
72 H4A 0.298 (3) 0.9642 (13) 0.202 (2) 0.081 (7)*
73 H4B 0.473 (3) 1.0005 (15) 0.2937 (19) 0.082 (6)*
74 H2 0.542 (3) 0.4823 (14) 0.3382 (19) 0.083 (6)*
75 H3B 0.950 (2) 0.3760 (11) 0.5277 (17) 0.060 (5)*
76 H3A 0.837 (2) 0.4591 (13) 0.4714 (17) 0.064 (5)*
supporting information
sup-3
Atomic displacement parameters (Å2) 77
78 U11 U22 U33 U12 U13 U23
79 O1 0.0417 (6) 0.0360 (6) 0.0704 (7) −0.0004 (5) −0.0064 (5) 0.0005 (5)
80 O2 0.0449 (6) 0.0371 (7) 0.0844 (9) −0.0027 (5) −0.0109 (6) 0.0000 (6)
81 O3 0.0421 (6) 0.0372 (6) 0.0755 (8) 0.0038 (5) −0.0117 (6) 0.0005 (5)
82 N1 0.0577 (9) 0.0353 (8) 0.0681 (9) −0.0031 (6) 0.0054 (7) −0.0065 (6)
83 N2 0.0433 (7) 0.0393 (7) 0.0500 (8) 0.0030 (6) 0.0029 (6) −0.0009 (6)
84 N3 0.0412 (7) 0.0333 (7) 0.0669 (9) −0.0011 (6) −0.0042 (6) −0.0042 (6)
85 N4 0.0533 (9) 0.0428 (9) 0.0800 (11) 0.0099 (7) −0.0015 (8) 0.0122 (8)
86 C1 0.0617 (11) 0.0332 (9) 0.0699 (11) 0.0065 (8) 0.0116 (9) −0.0003 (8)
87 C2 0.0448 (9) 0.0380 (9) 0.0567 (10) 0.0015 (7) 0.0018 (7) −0.0016 (7)
88 C3 0.0362 (7) 0.0363 (8) 0.0396 (8) 0.0005 (6) 0.0083 (6) −0.0020 (6)
89 C4 0.0522 (9) 0.0419 (9) 0.0605 (10) 0.0102 (8) 0.0004 (8) 0.0027 (8)
90 C5 0.0368 (8) 0.0352 (8) 0.0410 (8) −0.0006 (6) 0.0055 (6) −0.0023 (6)
91 C6 0.0364 (8) 0.0376 (8) 0.0462 (9) −0.0009 (6) 0.0039 (7) −0.0024 (7)
92 C7 0.0340 (7) 0.0372 (8) 0.0396 (8) 0.0012 (6) 0.0050 (6) 0.0014 (6)
93 C8 0.0355 (8) 0.0402 (9) 0.0544 (9) 0.0042 (6) −0.0040 (7) 0.0013 (7)
94 C9 0.0416 (8) 0.0362 (8) 0.0623 (10) −0.0006 (7) −0.0022 (7) −0.0003 (7)
95 C10 0.0406 (8) 0.0392 (8) 0.0470 (9) 0.0062 (7) 0.0092 (7) 0.0073 (7)
96 C11 0.0343 (8) 0.0499 (10) 0.0500 (9) 0.0045 (7) −0.0014 (7) 0.0092 (7)
97 C12 0.0354 (8) 0.0422 (9) 0.0472 (9) −0.0028 (6) 0.0006 (6) 0.0026 (7)
Geometric parameters (Å, º) 98
99 O1—C5 1.2405 (16) C2—C3 1.383 (2)
100 O2—C6 1.3287 (17) C2—H2A 0.9300
101 O2—H2 0.97 (2) C3—C5 1.496 (2)
102 O3—C6 1.2218 (17) C4—H4 0.9300
103 N1—C1 1.328 (2) C6—C7 1.467 (2)
104 N1—C2 1.340 (2) C7—C8 1.390 (2)
105 N2—C4 1.327 (2) C7—C12 1.396 (2)
106 N2—C3 1.3360 (17) C8—C9 1.372 (2)
107 N3—C5 1.3133 (18) C8—H8 0.9300
108 N3—H3A 0.90 (2) C9—C10 1.396 (2)
109 N3—H3B 0.887 (18) C9—H9 0.9300
110 N4—C10 1.366 (2) C10—C11 1.395 (2)
111 N4—H4A 0.85 (2) C11—C12 1.368 (2)
112 N4—H4B 0.96 (2) C11—H11 0.9300
113 C1—C4 1.373 (2) C12—H12 0.9300
114 C1—H1 0.9300
115
116 C6—O2—H2 109.4 (12) N3—C5—C3 116.92 (12)
117 C1—N1—C2 115.13 (14) O3—C6—O2 121.66 (13)
118 C4—N2—C3 115.82 (13) O3—C6—C7 123.75 (13)
119 C5—N3—H3A 116.1 (11) O2—C6—C7 114.59 (12)
120 C5—N3—H3B 118.6 (11) C8—C7—C12 117.68 (13)
121 H3A—N3—H3B 124.6 (16) C8—C7—C6 119.02 (12)
supporting information
sup-4
122 C10—N4—H4A 117.6 (14) C12—C7—C6 123.31 (13)
123 C10—N4—H4B 117.2 (13) C9—C8—C7 121.20 (13)
124 H4A—N4—H4B 125.2 (19) C9—C8—H8 119.4
125 N1—C1—C4 122.97 (15) C7—C8—H8 119.4
126 N1—C1—H1 118.5 C8—C9—C10 121.07 (14)
127 C4—C1—H1 118.5 C8—C9—H9 119.5
128 N1—C2—C3 122.09 (15) C10—C9—H9 119.5
129 N1—C2—H2A 119.0 N4—C10—C11 121.86 (14)
130 C3—C2—H2A 119.0 N4—C10—C9 120.46 (15)
131 N2—C3—C2 121.90 (14) C11—C10—C9 117.69 (14)
132 N2—C3—C5 117.24 (12) C12—C11—C10 121.06 (14)
133 C2—C3—C5 120.86 (13) C12—C11—H11 119.5
134 N2—C4—C1 122.08 (15) C10—C11—H11 119.5
135 N2—C4—H4 119.0 C11—C12—C7 121.30 (14)
136 C1—C4—H4 119.0 C11—C12—H12 119.4
137 O1—C5—N3 123.92 (13) C7—C12—H12 119.4
138 O1—C5—C3 119.15 (12)
139
140 C2—N1—C1—C4 −0.7 (2) O2—C6—C7—C8 176.59 (13)
141 C1—N1—C2—C3 −0.3 (2) O3—C6—C7—C12 176.98 (14)
142 C4—N2—C3—C2 −1.6 (2) O2—C6—C7—C12 −3.2 (2)
143 C4—N2—C3—C5 177.99 (13) C12—C7—C8—C9 0.8 (2)
144 N1—C2—C3—N2 1.5 (2) C6—C7—C8—C9 −178.96 (14)
145 N1—C2—C3—C5 −178.06 (14) C7—C8—C9—C10 −0.8 (2)
146 C3—N2—C4—C1 0.6 (2) C8—C9—C10—N4 179.57 (15)
147 N1—C1—C4—N2 0.6 (3) C8—C9—C10—C11 0.0 (2)
148 N2—C3—C5—O1 −171.12 (12) N4—C10—C11—C12 −178.90 (15)
149 C2—C3—C5—O1 8.5 (2) C9—C10—C11—C12 0.6 (2)
150 N2—C3—C5—N3 8.25 (19) C10—C11—C12—C7 −0.6 (2)
151 C2—C3—C5—N3 −172.18 (13) C8—C7—C12—C11 −0.2 (2)
152 O3—C6—C7—C8 −3.2 (2) C6—C7—C12—C11 179.60 (14)
Hydrogen-bond geometry (Å, º) 153
154 D—H···A D—H H···A D···A D—H···A
155 O2—H2···O1 0.97 (2) 1.65 (2) 2.6102 (15) 168.3 (19)
156 N3—H3A···O3 0.90 (2) 2.04 (2) 2.9259 (18) 167.7 (16)
157 N3—H3B···O3i 0.887 (18) 2.413 (17) 3.1201 (18) 136.9 (14)
158 C8—H8···N2i 0.93 2.71 3.5277 (19) 147
159 N4—H4A···O2ii 0.86 (2) 2.58 (2) 3.3026 (19) 143.1 (17)
160 C11—H11···O1ii 0.93 2.69 3.5354 (18) 152
161 N4—H4B···N1iii 0.96 (2) 2.26 (2) 3.221 (2) 177.9 (17)
162 C4—H4···O1iv 0.93 2.64 3.312 (2) 130
163 Symmetry codes: (i) −x+2, −y+1, −z+1; (ii) −x+1/2, y+1/2, −z+1/2; (iii) x, y+1, z; (iv) x+1/2, −y+1/2, z+1/2.
supporting information
sup-5
(2) 164
Crystal data 165
C12H9N3O3166
Mr = 243.22167
Triclinic, P1168
a = 6.0535 (5) Å169
b = 7.4159 (6) Å170
c = 13.2548 (10) Å171
α = 85.612 (5)°172
β = 81.900 (5)°173
γ = 66.398 (5)°174
V = 539.69 (7) Å3175
Z = 2F(000) = 252Dx = 1.497 Mg m−3
Mo Kα radiation, λ = 0.71073 ÅCell parameters from 1404 reflectionsθ = 3.1–30.2°µ = 0.11 mm−1
T = 296 KPLATE, colourless0.36 × 0.28 × 0.21 mm
Data collection 176
Bruker APEX-II CCD 177
diffractometerRadiation source: fine-focus sealed tube178
Graphite monochromator179
φ and ω scans180
Absorption correction: multi-scan 181
Bruker SADABSTmin = 0.961, Tmax = 0.977182
5721 measured reflections1908 independent reflections1383 reflections with I > 2σ(I)Rint = 0.041θmax = 25.0°, θmin = 3.0°h = −7→7k = −8→8l = −15→15
Refinement 183
Refinement on F2184
Least-squares matrix: full185
R[F2 > 2σ(F2)] = 0.054186
wR(F2) = 0.134187
S = 1.06188
1908 reflections189
164 parameters190
0 restraints191
Primary atom site location: structure-invariant 192
direct methods
Secondary atom site location: difference Fourier map
Hydrogen site location: inferred from neighbouring sites
H atoms treated by a mixture of independent and constrained refinement
w = 1/[σ2(Fo2) + (0.056P)2 + 0.1999P]
where P = (Fo2 + 2Fc
2)/3(∆/σ)max < 0.001∆ρmax = 0.20 e Å−3
∆ρmin = −0.31 e Å−3
Special details 193
194 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.
195 Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) 196
197 x y z Uiso*/Ueq
198 O1 0.3068 (4) 0.5923 (3) 0.60290 (14) 0.0585 (6)
199 O2 0.7036 (4) 0.5203 (3) 0.58201 (14) 0.0580 (6)
200 O3 0.8121 (3) 0.7531 (3) 1.06954 (13) 0.0507 (5)
supporting information
sup-6
201 N1 0.4345 (4) 0.7768 (3) 1.04650 (15) 0.0356 (5)
202 N2 0.2723 (4) 0.8881 (3) 1.24129 (15) 0.0394 (5)
203 N3 0.5818 (4) 0.9261 (3) 1.36829 (16) 0.0488 (6)
204 C1 0.4945 (5) 0.5782 (4) 0.63617 (18) 0.0393 (6)
205 C2 0.4886 (4) 0.6281 (3) 0.74272 (17) 0.0336 (6)
206 C3 0.2664 (4) 0.7013 (4) 0.80398 (18) 0.0384 (6)
207 H3 0.1254 0.7169 0.7775 0.046*
208 C4 0.2531 (4) 0.7505 (4) 0.90277 (17) 0.0373 (6)
209 H4 0.1030 0.8014 0.9423 0.045*
210 C5 0.4617 (4) 0.7252 (3) 0.94433 (17) 0.0322 (6)
211 C6 0.6860 (4) 0.6489 (4) 0.88418 (17) 0.0359 (6)
212 H6 0.8276 0.6300 0.9111 0.043*
213 C7 0.6960 (4) 0.6017 (4) 0.78455 (17) 0.0369 (6)
214 H7 0.8457 0.5510 0.7447 0.044*
215 C8 0.6007 (4) 0.7877 (3) 1.10190 (17) 0.0338 (6)
216 C9 0.5042 (4) 0.8502 (3) 1.20937 (17) 0.0318 (6)
217 C10 0.1968 (5) 0.9456 (4) 1.33738 (19) 0.0464 (7)
218 H10 0.0360 0.9730 1.3633 0.056*
219 C11 0.3490 (5) 0.9657 (4) 1.39924 (19) 0.0503 (7)
220 H11 0.2867 1.0087 1.4654 0.060*
221 C12 0.6572 (5) 0.8673 (4) 1.27259 (18) 0.0411 (6)
222 H12 0.8191 0.8367 1.2473 0.049*
223 H1 0.296 (5) 0.801 (4) 1.082 (2) 0.043 (8)*
224 H2 0.702 (6) 0.482 (5) 0.5229 (17) 0.092 (12)*
Atomic displacement parameters (Å2) 225
226 U11 U22 U33 U12 U13 U23
227 O1 0.0531 (12) 0.0902 (16) 0.0368 (10) −0.0302 (11) −0.0046 (9) −0.0215 (10)
228 O2 0.0511 (12) 0.0898 (15) 0.0308 (10) −0.0246 (11) 0.0045 (9) −0.0216 (10)
229 O3 0.0382 (11) 0.0790 (14) 0.0387 (10) −0.0269 (10) 0.0037 (8) −0.0181 (9)
230 N1 0.0320 (11) 0.0504 (13) 0.0241 (10) −0.0163 (10) 0.0011 (8) −0.0074 (9)
231 N2 0.0382 (12) 0.0539 (14) 0.0282 (11) −0.0204 (10) 0.0001 (9) −0.0085 (9)
232 N3 0.0513 (15) 0.0691 (16) 0.0323 (12) −0.0294 (13) −0.0030 (10) −0.0110 (11)
233 C1 0.0458 (16) 0.0442 (16) 0.0304 (13) −0.0202 (13) −0.0019 (12) −0.0062 (11)
234 C2 0.0383 (14) 0.0365 (14) 0.0293 (12) −0.0178 (11) −0.0033 (10) −0.0038 (10)
235 C3 0.0339 (14) 0.0518 (16) 0.0334 (13) −0.0203 (13) −0.0053 (11) −0.0026 (11)
236 C4 0.0316 (13) 0.0508 (16) 0.0305 (12) −0.0185 (12) 0.0038 (10) −0.0077 (11)
237 C5 0.0381 (14) 0.0348 (14) 0.0262 (12) −0.0182 (11) 0.0013 (10) −0.0037 (10)
238 C6 0.0310 (13) 0.0449 (15) 0.0319 (13) −0.0141 (12) −0.0028 (10) −0.0091 (11)
239 C7 0.0324 (13) 0.0459 (15) 0.0303 (13) −0.0139 (12) 0.0045 (10) −0.0120 (11)
240 C8 0.0355 (14) 0.0328 (14) 0.0313 (13) −0.0126 (11) 0.0011 (11) −0.0035 (10)
241 C9 0.0357 (13) 0.0333 (13) 0.0268 (12) −0.0146 (11) −0.0009 (10) −0.0034 (10)
242 C10 0.0421 (15) 0.0667 (19) 0.0307 (13) −0.0228 (14) 0.0059 (11) −0.0128 (12)
243 C11 0.0590 (18) 0.072 (2) 0.0274 (13) −0.0330 (16) 0.0018 (12) −0.0142 (13)
244 C12 0.0407 (15) 0.0518 (17) 0.0342 (13) −0.0210 (13) −0.0041 (11) −0.0075 (12)
supporting information
sup-7
Geometric parameters (Å, º) 245
246 O1—C1 1.240 (3) C3—C4 1.369 (3)
247 O2—C1 1.289 (3) C3—H3 0.9300
248 O2—H2 0.855 (19) C4—C5 1.386 (3)
249 O3—C8 1.220 (3) C4—H4 0.9300
250 N1—C8 1.355 (3) C5—C6 1.396 (3)
251 N1—C5 1.406 (3) C6—C7 1.379 (3)
252 N1—H1 0.86 (3) C6—H6 0.9300
253 N2—C9 1.327 (3) C7—H7 0.9300
254 N2—C10 1.333 (3) C8—C9 1.495 (3)
255 N3—C11 1.329 (3) C9—C12 1.381 (3)
256 N3—C12 1.330 (3) C10—C11 1.373 (4)
257 C1—C2 1.479 (3) C10—H10 0.9300
258 C2—C7 1.380 (3) C11—H11 0.9300
259 C2—C3 1.392 (3) C12—H12 0.9300
260
261 C1—O2—H2 113 (2) C7—C6—C5 119.5 (2)
262 C8—N1—C5 129.6 (2) C7—C6—H6 120.2
263 C8—N1—H1 112.3 (17) C5—C6—H6 120.2
264 C5—N1—H1 118.1 (18) C6—C7—C2 121.4 (2)
265 C9—N2—C10 115.9 (2) C6—C7—H7 119.3
266 C11—N3—C12 115.3 (2) C2—C7—H7 119.3
267 O1—C1—O2 123.2 (2) O3—C8—N1 124.8 (2)
268 O1—C1—C2 120.8 (2) O3—C8—C9 120.7 (2)
269 O2—C1—C2 115.9 (2) N1—C8—C9 114.5 (2)
270 C7—C2—C3 118.5 (2) N2—C9—C12 121.8 (2)
271 C7—C2—C1 122.5 (2) N2—C9—C8 118.8 (2)
272 C3—C2—C1 119.0 (2) C12—C9—C8 119.4 (2)
273 C4—C3—C2 120.8 (2) N2—C10—C11 122.0 (2)
274 C4—C3—H3 119.6 N2—C10—H10 119.0
275 C2—C3—H3 119.6 C11—C10—H10 119.0
276 C3—C4—C5 120.6 (2) N3—C11—C10 122.5 (2)
277 C3—C4—H4 119.7 N3—C11—H11 118.7
278 C5—C4—H4 119.7 C10—C11—H11 118.7
279 C4—C5—C6 119.2 (2) N3—C12—C9 122.5 (2)
280 C4—C5—N1 117.5 (2) N3—C12—H12 118.8
281 C6—C5—N1 123.3 (2) C9—C12—H12 118.8
282
283 O1—C1—C2—C7 175.5 (2) C1—C2—C7—C6 −179.8 (2)
284 O2—C1—C2—C7 −4.4 (4) C5—N1—C8—O3 0.3 (4)
285 O1—C1—C2—C3 −3.3 (4) C5—N1—C8—C9 179.4 (2)
286 O2—C1—C2—C3 176.8 (2) C10—N2—C9—C12 0.7 (4)
287 C7—C2—C3—C4 1.6 (4) C10—N2—C9—C8 −179.1 (2)
288 C1—C2—C3—C4 −179.5 (2) O3—C8—C9—N2 179.4 (2)
289 C2—C3—C4—C5 −1.1 (4) N1—C8—C9—N2 0.2 (3)
290 C3—C4—C5—C6 0.1 (4) O3—C8—C9—C12 −0.5 (4)
291 C3—C4—C5—N1 −179.3 (2) N1—C8—C9—C12 −179.7 (2)
supporting information
sup-8
292 C8—N1—C5—C4 −171.8 (2) C9—N2—C10—C11 0.4 (4)
293 C8—N1—C5—C6 8.9 (4) C12—N3—C11—C10 0.7 (4)
294 C4—C5—C6—C7 0.5 (4) N2—C10—C11—N3 −1.2 (5)
295 N1—C5—C6—C7 179.8 (2) C11—N3—C12—C9 0.5 (4)
296 C5—C6—C7—C2 −0.1 (4) N2—C9—C12—N3 −1.3 (4)
297 C3—C2—C7—C6 −1.0 (4) C8—C9—C12—N3 178.6 (2)
Hydrogen-bond geometry (Å, º) 298
299 D—H···A D—H H···A D···A D—H···A
300 O2—H2···O1i 0.86 (2) 1.81 (2) 2.666 (3) 178 (4)
301 C11—H11···N3ii 0.93 2.59 3.365 (3) 142
302 C4—H4···O3iii 0.93 2.38 3.212 (3) 149
303 Symmetry codes: (i) −x+1, −y+1, −z+1; (ii) −x+1, −y+2, −z+3; (iii) x−1, y, z.