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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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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

Datablock 1 - ellipsoid plot

Datablock 2 - ellipsoid plot

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.