research papers\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

IUCrJ
Volume 4| Part 4| July 2017| Pages 466-475
ISSN: 2052-2525

Exploring the salt–cocrystal continuum with solid-state NMR using natural-abundance samples: implications for crystal engineering

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aSolid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore, 560 012, India, bRIKEN CLST–JEOL Collaboration Center, RIKEN, Yokohama, Kanagawa 230-0045, Japan, cJEOL RESONANCE Inc., Musashino, Akishima, Tokyo 196-8558, Japan, and dDepartment of Chemistry, Indian Institute of Technology Ropar, Rupnagar, India
*Correspondence e-mail: yunishiy@jeol.co.jp, desiraju@sscu.iisc.ernet.in

Edited by L. R. MacGillivray, University of Iowa, USA (Received 21 February 2017; accepted 8 May 2017; online 5 June 2017)

There has been significant recent interest in differentiating multicomponent solid forms, such as salts and cocrystals, and, where appropriate, in determining the position of the proton in the X—H⋯AY X⋯H—A+Y continuum in these systems, owing to the direct relationship of this property to the clinical, regulatory and legal requirements for an active pharmaceutical ingredient (API). In the present study, solid forms of simple cocrystals/salts were investigated by high-field (700 MHz) solid-state NMR (ssNMR) using samples with naturally abundant 15N nuclei. Four model compounds in a series of prototypical salt/cocrystal/continuum systems exhibiting {PyN⋯H—O—}/{PyN+—H⋯O} hydrogen bonds (Py is pyridine) were selected and prepared. The crystal structures were determined at both low and room temperature using X-ray diffraction. The H-atom positions were determined by measuring the 15N—1H distances through 15N-1H dipolar interactions using two-dimensional inversely proton-detected cross polarization with variable contact-time (invCP-VC) 1H→15N→1H experiments at ultrafast (νR ≥ 60–70 kHz) magic angle spinning (MAS) frequency. It is observed that this method is sensitive enough to determine the proton position even in a continuum where an ambiguity of terminology for the solid form often arises. This work, while carried out on simple systems, has implications in the pharmaceutical industry where the salt/cocrystal/continuum condition of APIs is considered seriously.

1. Introduction

Detection of the H-atom position in an X—H⋯AY hydrogen bond is a matter of fundamental and practical importance (Jeffrey, 1997[Jeffrey, G. A. (1997). In An Introduction to Hydrogen Bonding. Oxford University Press.]; Desiraju & Steiner, 1999[Desiraju, G. R. & Steiner, T. (1999). In The Weak Hydrogen Bond in Structural Chemistry and Biology. Oxford University Press.]). Atomic positions derived for an H atom from an X-ray analysis approximates the centroid of the electron density. Positions derived from neutron diffraction correspond to the nuclei of the atoms. Neutron-derived H-atom positions and the corresponding hydrogen-bond metrics are more accurate but this does not necessarily mean that they are chemically the most meaningful (Aakeröy & Seddon, 1993[Aakeröy, C. B. & Seddon, K. R. (1993). Chem. Soc. Rev. 22, 397-407.]; Cotton & Luck, 1989[Cotton, F. A. & Luck, R. L. (1989). Inorg. Chem. 28, 3210-3213.]). An X—H⋯AY hydrogen bond may also be considered as an extreme of a proton-transfer reaction where the other extreme is X⋯H—A+Y. Situations are known in which this proton-transfer reaction is mediated by a change in tem­per­ature and where the H-atom position varies smoothly between the X and A atoms (Steiner et al., 2001[Steiner, T., Majerz, I. & Wilson, C. C. (2001). Angew. Chem. Int. Ed. 40, 2651-2654.]; Parkin et al., 2004[Parkin, A., Harte, S. M., Goeta, A. E. & Wilson, C. C. (2004). New J. Chem. 28, 718-721.]; Wilson & Goeta, 2004[Wilson, C. C. & Goeta, A. E. (2004). Angew. Chem. Int. Ed. 43, 2095-2099.]; Grobelny et al., 2011[Grobelny, P., Mukherjee, A. & Desiraju, G. R. (2011). CrystEngComm, 13, 4358-4364.]).

In the pharmaceutical industry, there is considerable interest in making multicomponent molecular crystals of drugs or active pharmaceutical ingredients (APIs) in order to achieve better physical, chemical or pharmacological properties (Almarsson & Zaworotko, 2004[Almarsson, Ö. & Zaworotko, M. J. (2004). Chem. Commun. pp. 1889-1896.]; Vishweshwar et al., 2006[Vishweshwar, P., McMahon, J. A., Bis, J. A. & Zaworotko, M. J. (2006). J. Pharm. Sci. 95, 499-516.]; Wouters & Quéré, 2012[Wouters, J. & Quéré, L. (2012). In Pharmaceutical Salts and Co-crystals. Cambridge: RSC Publishing.]). Generally, these crystals involve the formation of a hydrogen bond between the drug molecule, which is usually basic, and another compound, referred to often as a coformer, which is usually acidic. The binary crystal therefore often contains a hydrogen bond of the type (Drug)⋯H—(Coformer) and if the two molecular species are not ionized, the substance is called a `cocrystal'. The definition of this term `cocrystal' is still contentious (Desiraju, 2003[Desiraju, G. R. (2003). CrystEngComm, 5, 466-467.]; Dunitz, 2003[Dunitz, J. D. (2003). CrystEngComm, 5, 506.]; Bond, 2007[Bond, A. D. (2007). CrystEngComm, 9, 833-834.]; Childs et al., 2007[Childs, S. L., Stahly, G. P. & Park, A. (2007). Mol. Pharm. 4, 323-338.]; Aakeröy & Salmon, 2005[Aakeröy, C. B. & Salmon, D. J. (2005). CrystEngComm, 7, 439-448.]; Aitipamula et al., 2012[Aitipamula, S., et al. (2012). Cryst. Growth Des. 12, 2147-2152.]) and is in some aspects incomplete or inadequate. In any event, if the proton-transfer reaction across the hydrogen bond is complete, the multicomponent crystal that is obtained is of the form (Drug)+—H⋯(Coformer) and is called a `salt', whereas the intermediate state of affairs is termed a `continuum' (Fig. 1[link]).

[Figure 1]
Figure 1
Schematic presentation of (a) a cocrystal, (b) a salt and (c) a continuum (where the H-atom position is shared between the two heavy atoms) in a typical O···H···N interaction.

For the patent protection of new multicomponent solid forms of an API, the substance to be patented must be characterized as denoted by the specifications, i.e. whether it is a salt or cocrystal. For example, some APIs were found to exhibit the tendency to transform from one drug form to another due to external forces, such as light, heat, pressure and mechanical grinding (Ikni et al., 2014[Ikni, A., Clair, B., Scouflaire, P., Veesler, S., Gillet, J.-M., El Hassan, N., Dumas, F. & Spasojević-de Biré, A. (2014). Cryst. Growth Des. 14, 3286-3299.]; Pirttimäki et al., 1993[Pirttimäki, J., Laine, E., Ketolainen, J. & Paronen, P. (1993). Int. J. Pharm. 95, 93-99.]; Shakhtshneider & Boldyrev, 1993[Shakhtshneider, T. P. & Boldyrev, V. V. (1993). Drug Dev. Ind. Pharm. 19, 2055-2067.]; Otsuka et al., 1994[Otsuka, M., Otsuka, K. & Kaneniwa, N. (1994). Drug Dev. Ind. Pharm. 20, 1649-1660.]). Therefore, a proper study of the new solid form is of the utmost importance as it is directly related to both patient safety and clinical efficacy. If this issue remains unresolved, the exploration of pharmaceutical solids becomes restricted and the competitive advantage of drug development to launch the product is lost. There are important regulatory and legal implications as to whether or not the marketed form of a drug is the `cocrystal' or `salt' form. What is of relevance here is the so-called ΔpKa rule, which states that a salt is obtained if the pKa difference between the drug and the coformer is greater than 3, while if the difference is less than 1, a cocrystal is obtained (Bhogala et al., 2005[Bhogala, B. R., Basavoju, S. & Nangia, A. (2005). CrystEngComm, 7, 551-562.]; Cruz-Cabeza, 2012[Cruz-Cabeza, A. J. (2012). CrystEngComm, 14, 6362-6365.]; Ramon et al., 2014[Ramon, G., Davies, K. & Nassimbeni, L. R. (2014). CrystEngComm, 16, 5802-5810.]; Mukherjee & Desiraju, 2014[Mukherjee, A. & Desiraju, G. R. (2014). Cryst. Growth Des. 14, 1375-1385.]; US–FDA, 2016[US-FDA (2016). Guidelines, https://www.fda.gov/downloads/Drugs/Guidances/UCM516813.pdf.]). The intermediate region, i.e. 1 < ΔpKa < 3, contains cases where the H atom (proton) is unusually labile and wherein it can move between the drug and coformer species. This gives rise to the so-called `salt–cocrystal continuum', a phenomenon that has been studied using a variety of crystallographic techniques (Aakeröy et al., 2007[Aakeröy, C. B., Fasulo, M. E. & Desper, J. (2007). Mol. Pharm. 4, 317-322.]; Childs et al., 2007[Childs, S. L., Stahly, G. P. & Park, A. (2007). Mol. Pharm. 4, 323-338.]; Schmidtmann et al., 2007[Schmidtmann, M., Gutmann, M. J., Middlemiss, D. S. & Wilson, C. C. (2007). CrystEngComm, 9, 743-745.]; Hathwar et al., 2010[Hathwar, V. R., Pal, R. & Guru Row, T. N. (2010). Cryst. Growth Des. 10, 3306-3310.]; Thomas et al., 2010[Thomas, L. H., Blagden, N., Gutmann, M. J., Kallay, A. A., Parkin, A., Seaton, C. C. & Wilson, C. C. (2010). Cryst. Growth Des. 10, 2770-2774.]; da Silva et al., 2013[Silva, C. C. P. da, de Oliveira, R., Tenorio, J. C., Honorato, S. B., Ayala, A. P. & Ellena, J. (2013). Cryst. Growth Des. 13, 4315-4322.]). Drug⋯coformer systems in the intermediate ΔpKa range are of special significance in regulatory and legal contexts. Over the last decade, crystal engineering has been used extensively to modify the physicochemical properties of APIs by making new solid forms (Desiraju, 2013[Desiraju, G. R. (2013). J. Am. Chem. Soc. 135, 9952-9967.]; Duggirala et al., 2016[Duggirala, N. K., Perry, M. L., Almarsson, Ö. & Zaworotko, M. J. (2016). Chem. Commun. 52, 640-655.]).

Solid-state NMR (ssNMR) methods have always been used in conjugation with diffraction methods, or alone, to determine H-atom positions in hydrogen bonds (Berglund & Vaughan, 1980[Berglund, B. & Vaughan, R. W. (1980). J. Chem. Phys. 73, 2037-2043.]; Rohlfing et al., 1983[Rohlfing, C. M., Allen, L. C. & Ditchfield, R. (1983). J. Chem. Phys. 79, 4958-4966.]; Jeffrey & Yeon, 1986[Jeffrey, G. A. & Yeon, Y. (1986). Acta Cryst. B42, 410-413.]; Wu et al., 1998[Wu, G., Freure, C. J. & Verdurand, E. (1998). J. Am. Chem. Soc. 120, 13187-13193.]; Yazawa et al., 2012[Yazawa, K., Suzuki, F., Nishiyama, Y., Ohata, T., Aoki, A., Nishimura, K., Kaji, H., Shimizu, T. & Asakura, T. (2012). Chem. Commun. 48, 11199-11201.]; Miah et al., 2013[Miah, H. K., Bennett, D. A., Iuga, D. & Titman, J. J. (2013). J. Magn. Reson. 235, 1-5.]). ssNMR has also been used to ascertain the nature of the salt–cocrystal continuum in API systems (Stevens et al., 2014[Stevens, J. S., Byard, S. J., Seaton, C. C., Sadiq, G., Davey, R. J. & Schroeder, S. L. M. (2014). Phys. Chem. Chem. Phys. 16, 1150-1160.]). The use of 15N ssNMR has been documented previously (Li et al., 2006[Li, Z. J., Abramov, Y., Bordner, J., Leonard, J., Medek, A. & Trask, A. V. (2006). J. Am. Chem. Soc. 128, 8199-8210.]). These applications rely on the dependence of chemical shift tensors on H-atom positions. It is obvious that 1H chemical shift tensors are very sensitive to H-atom positions because 1H NMR detects the H atoms directly. In addition, 15N chemical shift tensors are also affected by H-atom positions through changes in the electron distribution, thereby making it also sensitive to H-atom positions. These dependences are further corroborated by quantum chemical calculations. There are several cases where it is very difficult to obtain X-ray-quality single crystals, and powder X-ray methods are often inadequate to accurately determine H-atom positions. In addition, H-atom positions in X-ray diffraction measurements are systematically foreshortened and are at the limit of detection in any case. In such cases, ssNMR is an excellent complementary technique for determining H-atom positions. There is always the fundamental question of whether the X-ray-derived or the neutron-derived position is the more `correct' or indeed if either of these positions is `correct' at all. There are some studies that record differences between the H-atom positions determined by diffraction- and NMR-based methods (Roberts et al., 1987[Roberts, J. E., Harbison, G. S., Munowitz, M. G., Herzfeld, J. & Griffin, R. G. (1987). J. Am. Chem. Soc. 109, 4163-4169.]; Lorente et al., 2001[Lorente, P., Shenderovich, I. G., Golubev, N. S., Denisov, G. S., Buntkowsky, G. & Limbach, H.-H. (2001). Magn. Reson. Chem. 39, S18-S29.]). These disagreements arise partly from the uncertainty in the positions of the H atoms in all X-ray-diffraction-based methods on the one hand, and the fact that the determination of H-atom positions in ssNMR is based on an indirect measurement through chemical shift tensors on the other. Neutron diffraction analysis is very difficult to carry out, compared to X-ray diffraction and ssNMR, because large crystals are needed, which are often impossible to obtain, and also because one needs to collect data over an extended time period in a remote laboratory equipped with a neutron source. Noting that all three methods, i.e. X-ray diffraction, neutron diffraction and ssNMR, may give slightly different results for H-atom positions, and that none of these measurements can, strictly speaking, be used as benchmarks for each other, we embarked on the present study.

Besides the chemical shift tensor, ssNMR is able to measure internuclear N—H distances through 15N-1H dipolar interactions, as the magnitude of the dipolar interaction is inversely proportional to the cube of the internuclear distance. This potentially gives a straightforward solution to the `salt/cocrystal/continuum' problem, while diffraction-based methods provide internuclear distances from the atomic positions themselves. However, the 1H—X distance measure­ments are not easy because of the presence of intense homonuclear 1H-1H dipolar interactions and a very low abundance of 15N (0.4%). While the former obscures the 1H-X dipolar interactions, the latter gives very limited sensitivity, making the measurements practically impossible. These difficulties require isotopic dilution of 1H with 2H and/or isotopic enrichment with 15N nuclei, thus limiting their common application. Moreover, the small 15N-1H dipolar interaction due to the small 15N gyromagnetic ratio (about 10% of 1H) complicates the problem further.

Recent progress in fast magic angle sample spinning (MAS) technology (Nishiyama, 2016[Nishiyama, Y. (2016). Solid State Nucl. Magn. Reson. 78, 24-36.]) has paved a new way for determining 1H-X dipolar interactions (Paluch et al., 2013[Paluch, P., Pawlak, T., Amoureux, J.-P. & Potrzebowski, M. J. (2013). J. Magn. Reson. 233, 56-63.], 2015[Paluch, P., Trébosc, J., Nishiyama, Y., Potrzebowski, M., Malon, M. & Amoureux, J.-P. (2015). J. Magn. Reson. 252, 67-77.]; Park et al., 2013[Park, S. H., Yang, C., Opella, S. J. & Mueller, L. J. (2013). J. Magn. Reson. 237, 164-168.]; Zhang et al., 2015[Zhang, R., Damron, J., Vosegaard, T. & Ramamoorthy, A. (2015). J. Magn. Reson. 250, 37-44.]; Nishiyama et al., 2016[Nishiyama, Y., Malon, M., Potrzebowski, M. J., Paluch, P. & Amoureux, J. P. (2016). Solid State Nucl. Magn. Reson. 73, 15-21.]). Ultrafast MAS > 60 kHz, which is exclusively achieved by a very tiny rotor with a diameter of less than 1.3 mm accompanied by a small sample volume, can overcome the above-mentioned difficulties by suppressing the 1H-1H dipolar interactions to facilitate 1H—X distance measurement. In addition, ultrafast MAS allows direct observation of the NMR signal through the 1H nucleus, which is much more sensitive than 15N because of its high gyromagnetic ratio. The use of high-field magnets, which are now commonly available to researchers, improves the sensitivity further. These combinations allow the observation of 1H-X dipolar interactions in natural-abundance samples with a limited sample volume. The one possible limitation of 1H observation in multicomponent systems is the poor resolution of the 1H chemical shift obtainable in ssNMR even at the maximum attainable MAS rate. However, 15N—1H distance measurements filter out the 1H signals which are not connected to the 15N nuclei, allowing direct measure of 15N-1H dipolar interactions without any overlap of 1H resonances.

This article describes a method where high-field ssNMR is used to determine accurate 15N—1H distances in a series of prototypical salt/cocrystal/continuum systems of the type {PyN⋯H—O—}/{PyN+—H⋯O} at natural abundance without any isotopic dilution/enrichment. Of special significance is that we have used natural-abundance samples throughout. Furthermore, the distances obtained from ssNMR data were compared with the distances obtained from single-crystal X-ray diffraction (SCXRD) data.

2. Experimental section

2.1. General procedures

All reagents were purchased from commercial sources and were used without further purification. Fourier Transform infrared (FT–IR) spectra were recorded in ATR mode with a PerkinElmer (Frontier) spectrophotometer (4000–400 cm−1). Powder X-ray diffraction (PXRD) data was recorded using a Philips X'pert Pro X-ray powder diffractometer equipped with an X'cellerator detector at room temperature with a scan range 2θ = 5–40° and a step size of 0.026°. X'PertHighScore Plus values were used to compare the experimental PXRD pattern with the calculated lines from the crystal structure. Differential scanning calorimetry (DSC) was performed on a Mettler Toledo DSC 823e module with the heating rate of 5 K min−1 under a nitro­gen atmosphere.

2.2. Crystallization method

Crystallization experiments were carried out under ambient conditions for the four model compounds SA1, SA2, CO1 and CNT1.

SA1: N,N-Dimethypyridin-4-amine and 3-nitro­benzoic acid were taken in a 1:1 molar ratio in a conical flask and dissolved in a minimum amount of MeOH. Good-quality crystals, suitable for diffraction, were obtained after 4–5 d.

SA2: 4-Ethyl­pyridine and 3,5-di­nitro­benzoic acid were taken in a 1:1 molar ratio in a conical flask and dissolved in a minimum amount of MeOH. Good-quality crystals, suitable for diffraction, were obtained after 5–6 d.

CO1: 3-Ethyl­pyridine and 4-nitro­benzoic acid were taken in a 1:1 molar ratio in a conical flask and dissolved in a minimum amount of MeOH. Good-quality crystals, suitable for diffraction, were obtained after 6–7 d.

CNT1: 4-Methyl­pyridine and 2,3,4,5,6-penta­chloro­phenol were taken in a 1:1 molar ratio in a conical flask and dissolved in a minimum amount of MeOH. Good-quality crystals, suitable for diffraction, were obtained after 6–7d.

2.3. Single-crystal X-ray diffraction

Single-crystal X-ray diffraction (SCXRD) data were collected on a Rigaku Mercury 375/M CCD (XtaLAB mini) using graphite-monochromated Mo Kα radiation at 298 and 110 K. The data were processed using CrystalClear software (Rigaku, 2009[Rigaku (2009). Crystal Clear-SM Expert. Rigaku Corporation, Tokyo, Japan.]). Some data sets were collected on a Bruker SMART APEX (D8 QUEST) CMOS diffractometer equipped with an Oxford cryosystems N2 open-flow cryostat using Mo Kα radiation. Data integration and data reduction were carried out with the SAINT-Plus program (Bruker, 2006[Bruker (2006). SAINT-Plus. Bruker AXS Inc., Madison, Wisconsin, USA.]). Structure solution and refinement were executed using SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]) embedded in the WinGX suite (Farrugia, 1999[Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837-838.]) and OLEX2 (Dolomanov et al., 2009[Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Howard, J. A. K. & Puschmann, H. (2009). J. Appl. Cryst. 42, 339-341.]). Refinement of the coordinates and anisotropic displacement parameters of non-H atoms were performed using the full-matrix least-squares method. H-atom positions were located from difference Fourier maps or calculated using the riding model. However, the H atoms of the protonated pyridine and –COOH groups were located from difference Fourier maps. PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]) was used to prepare material for publication.

2.4. ssNMR experimental details

The N—H distances/dipolar couplings are measured by two-dimensional inversely proton-detected cross polarization with variable contact-time (invCP-VC) experiments at ultrafast MAS frequencies (60–70 kHz) (Park et al., 2013[Park, S. H., Yang, C., Opella, S. J. & Mueller, L. J. (2013). J. Magn. Reson. 237, 164-168.]; Nishiyama et al., 2016[Nishiyama, Y., Malon, M., Potrzebowski, M. J., Paluch, P. & Amoureux, J. P. (2016). Solid State Nucl. Magn. Reson. 73, 15-21.]). In CP-VC experiments, the oscillatory behaviour during CP build-up is observed by monitoring the NMR signal intensities with various contact times of CP (Paluch et al., 2013[Paluch, P., Pawlak, T., Amoureux, J.-P. & Potrzebowski, M. J. (2013). J. Magn. Reson. 233, 56-63.], 2015[Paluch, P., Trébosc, J., Nishiyama, Y., Potrzebowski, M., Malon, M. & Amoureux, J.-P. (2015). J. Magn. Reson. 252, 67-77.]). The Fourier transformation of the NMR signal intensity with respect to the contact time gives two well-separated narrow peaks/singularities of the Pake-like dipolar powder pattern. Although the overall dipolar powder pattern is very sensitive to experimental imperfections, the separation between two singularities gives a reliable measure of the size of the N—H dipolar interactions (Paluch et al., 2015[Paluch, P., Trébosc, J., Nishiyama, Y., Potrzebowski, M., Malon, M. & Amoureux, J.-P. (2015). J. Magn. Reson. 252, 67-77.]). While MAS averages out all the homonuclear (1H-1H) and heteronuclear (15N-1H) dipolar interactions, the simultaneous rf irradiation during CP on 1H and 15N hinders the averaging, in effect recoupling the 15N-1H dipolar interactions (Hartmann & Hahn, 1962[Hartmann, S. R. & Hahn, E. L. (1962). Phys. Rev. 128, 2042-2053.]). This results in oscillatory magnetization transfer between 1H and 15N during CP (Müller et al., 1974[Müller, L., Kumar, A., Baumann, T. & Ernst, R. R. (1974). Phys. Rev. Lett. 32, 1402-1406.]). Generally, this oscillatory behaviour is only observed at ultrafast MAS, since it is obscured by residual 1H-1H dipolar interactions at moderate MAS rates (Paluch et al., 2015[Paluch, P., Trébosc, J., Nishiyama, Y., Potrzebowski, M., Malon, M. & Amoureux, J.-P. (2015). J. Magn. Reson. 252, 67-77.]). The sensitivity is maximized by the introduction of the 1H indirect detection approach (Müller, 1979[Müller, L. (1979). J. Am. Chem. Soc. 101, 4481-4484.]; Bodenhausen & Ruben, 1980[Bodenhausen, G. & Ruben, D. J. (1980). Chem. Phys. Lett. 69, 185-189.]) into the CP-VC scheme. The initial magnetization is first transferred from 1H to 15N and then back-transferred to 1H magnetization for detection. Since the gyromagnetic ratio of 1H is ∼10 times larger than that of 15N, the initial magnetization of 1H is much greater than that of 15N and, therefore, significant sensitivity enhancement can be achieved. This can be implemented in the invCP-VC scheme as shown in Fig. 2[link]. First, ramped-amplitude cross polarization (RAMP-CP) is used for magnetization transfer from 1H to 15N (Metz et al., 1994[Metz, G., Wu, X. L. & Smith, S. O. (1994). J. Magn. Reson. A, 110, 219-227.]). This prepares the initial 15N magnetization which is indirectly observed at the end of the sequence. It is important to remove the unwanted residual 1H magnetization by the homonuclear rotary resonance recoupling (HORROR) sequence on the 1H channel (Nielsen et al., 1994[Nielsen, N. C., Bildsøe, H., Jakobsen, H. J. & Levitt, M. H. (1994). J. Chem. Phys. 101, 1805-1812.]; Ishii et al., 2001[Ishii, Y., Yesinowski, J. P. & Tycko, R. (2001). J. Am. Chem. Soc. 123, 2921-2922.]), since more than 99% of 1H does not have a 15N neighbour in a natural-abundance sample. During HORROR irradiation, the 15N magnetization is stored along the z axis by a pair of 15N 90° pulses, such that time-evolution and transversal relaxation of 15N are avoided. 15N magnetization is then back-transferred to 1H by the second constant CP with variable contact times. Finally, the 1H signal is acquired under a weak 15N-1H heteronuclear WALTZ decoupling irradiation (Shaka et al., 1983[Shaka, A. J., Keeler, J. & Freeman, R. (1983). J. Magn. Reson. 53, 313-340.]) on 15N (Wickramasinghe et al., 2015[Wickramasinghe, A., Wang, S., Matsuda, I., Nishiyama, Y., Nemoto, T., Endo, Y. & Ishii, Y. (2015). Solid State Nucl. Magn. Reson. 72, 9-16.]). The 1H signal intensity thus obtained is modulated by the 15N-1H dipolar interaction, which is recoupled by the second constant CP, giving dipolar oscillation. The time-domain data thus obtained are Fourier transformed into frequency-domain data in both dimensions. DC correction (subtracting the average of the final one-eighth points from the total data points) in the 1H-15N dipolar dimension should be applied prior to the Fourier transformation to remove the intense central peak. The peak position in the direct dimension represents the 1H chemical shift, whereas the separation of the peaks (Δ) in the indirect dimension reflects the 15N-1H dipolar coupling, which is converted to an 15N—1H distance (d1H - 15N) using the following relationship:

[{d_{{\rm{1H}} - {\rm{15N}}}}\left({\mathop {\rm A}\limits^ \circ } \right) = {\left({{{120.1} \over {\sqrt 2 \Delta \left({{\rm{kHz}}} \right)}}{{{\gamma _{15{\rm{N}}}}} \over {{\gamma _{1{\rm{H}}}}}}} \right)^{{1 \mathord{\left/ {\vphantom {1 3}} \right. \kern-\nulldelimiterspace} 3}}}, \eqno(1)]

where [{\gamma _{{\rm{1H}}\left({{\rm{15N}}} \right)}}] is the gyromagnetic ratio of 1H(15N) and [{{{\gamma _{{\rm{15N}}}}} \mathord{\left/ {\vphantom {{{\gamma _{{\rm{15N}}}}} {{\gamma _{{\rm{1H}}}}}}} \right. \kern-\nulldelimiterspace} {{\gamma _{{\rm{1H}}}}}}] = 0.10136. The equation with the scaling factor of [\sqrt 2] in the invCP-VC experiment is derived from Eq. 2.15 in Schmidt-Rohr & Spiess (1994[Schmidt-Rohr, K. & Spiess, H. W. (1994). In Multidimensional Solid-State NMR and Polymers. New York: Academic Press.]). Because of the inverse cubic relationship between the internuclear distance and the magnitude of the dipolar coupling, even for systems with small variations in a distance, the separation of dipolar splitting is significantly different. Consequently, precise N—H internuclear distances can be measured from the experiment. For example, the separations (Δ) for 1.0 and 1.1 Å N—H distances are 8.6 and 6.5 kHz, respectively. Moreover, for longer N—H distances, Δ becomes smaller (Δ = 0.3 kHz for 3 Å); therefore, only those protons with very short 15N—1H distances show splitting in the indirect dimension and the other protons do not show any splitting.

[Figure 2]
Figure 2
The pulse sequence used to record the two-dimensional inversely proton-detected cross polarization with variable contact-time (invCP-VC) spectra.

All the data were collected on a 700 MHz (JNM-ECA700II, Jeol RESONANCE Inc.) NMR spectrometer. For each experiment, about 0.8 mg samples were packed separately into a zirconia sample rotor with an outer diameter of 1 mm. All the experimental parameters used to record the invCP-VC experiments on CO1, CNT1, SA2 and SA1 are given in Table 1[link]. DQ Hartmann–Hahn CP matching conditions (ν1H + ν15N = νR) were used for all four samples (Laage et al., 2009[Laage, S., Sachleben, J. R., Steuernagel, S., Pierattelli, R., Pintacuda, G. & Emsley, L. (2009). J. Magn. Reson. 196, 133-141.]). Optimization of the DQ CP condition was carried out using 15N3-labelled L-histidine·HCl·H2O or 13C3,15N-labelled L-alanine by maximizing the 1H NMR spectra observed with the sequence shown in Fig. 2[link] with a fixed second contact time (typically 1 ms). The experimental conditions can be further verified by observing the invCP-VC spectra of a 15N3-labelled L-histidine sample. Two N—H protons of the imidazole ring should give splittings of 6.9 and 7.6 kHz if all the experimental conditions are properly adjusted.

Table 1
All the experimental parameters used to record the invCP-VC experiments

Compound Spectrometer frequency (MHz) MAS rate (kHz) 1H 90° (µs) 15N 90° (µs) Scans Recycle delay (s) Contact time (First CP) Contact time (Second CP) Total experiment time (days)
SA1 700 60 0.9 2.2 288 70 1.0 ms 10 µs–0.71 ms (15 increments) 3.5
SA2 700 70 0.9 2.2 736 20 1.5 ms 30 µs–1.02 ms (34 increments) 5.8
CO1 700 70 1 5 320 8 2.0 ms 0 µs–1.52 ms (151 increments) 4.5
CNT1 700 70 0.7 5 136 70 2.0 ms 0 µs–1 ms (51 increments) 5.0

3. Results and discussion

For this study, we have prepared four solid forms composed of 3-nitro­benzoic acid and N,N-dimethypyridin-4-amine (SA1) (Saha et al., 2015[Saha, S., Rajput, L., Joseph, S., Mishra, M. K., Ganguly, S. & Desiraju, G. R. (2015). CrystEngComm, 17, 1273-1290.]), 3,5-di­nitro­benzoic acid and 4-ethyl­pyridine (SA2), and 4-nitro­benzoic acid and 3-ethyl­pyridine (CO1). We also examined the well-studied case of penta­chloro­phenol and 4-methyl­pyridine (CNT1) (Malarski et al., 1987[Malarski, Z., Majerz, I. & Lis, T. (1987). J. Mol. Struct. 158, 369-377.]; Steiner et al., 2001[Steiner, T., Majerz, I. & Wilson, C. C. (2001). Angew. Chem. Int. Ed. 40, 2651-2654.]) (Fig. 3[link]). All the solid forms were crystallized and characterized by DSC, FT–IR spectroscopy, PXRD, SCXRD and ssNMR. In order to confirm the solid form, i.e. the salt/cocrystal/continuum, SCXRD data were collected at room temperature and at 110 K.

[Figure 3]
Figure 3
Schematic representation of the compounds used in the present study, showing (a) SA1 (3-nitro­benzoic acid and N,N-dimethypyridin-4-amine), (b) SA2 (3,5-di­nitro­benzoic acid and 4-ethyl­pyridine), (c) CO1 (4-nitro­benzoic acid and 3-ethyl­pyridine) and (d) CNT1 (penta­chloro­phenol and 4-methyl­pyridine).

The invCP-VC experiment has several advantages com­pared to previously reported heteronuclear distance measurement methods (Ramamoorthy et al., 1999[Ramamoorthy, A., Wu, C. H. & Opella, S. J. (1999). J. Magn. Reson. 140, 131-140.]; Ladizhansky & Vega, 2000[Ladizhansky, V. & Vega, S. (2000). J. Chem. Phys. 112, 7158-7168.]; van Rossum et al., 2000[Rossum, J. van, de Groot, C. P., Ladizhansky, V., Vega, S. & de Groot, H. J. M. (2000). J. Am. Chem. Soc. 122, 3465-3472.]). These include: (i) accurate estimation of N—H distances [due to the larger dipolar scaling factor (Ksc = 1/[\sqrt 2])]; (ii) straightforward experimental settings; (iii) robustness towards experimental imperfections, such as rf inhomogeneity, Hartmann–Hahn mismatch, rf offset and chemical shift anisotropies; (iv) higher sensitivity due to 1H detection; and (v) the small sample volume (typically less than 1 mg). While the 15N—1H distance measurement in a natural-abundance amino acid using the invCP-VC method was demonstrated earlier, the level of difficulty in the measurement is higher for multi­component systems, especially for cocrystals that are associated with longer 15N—1H distances. In multicomponent systems, a larger number of 1H resonances are expected than in a small amino acid. This results in the lower sensitivity and potential signal overlaps. The low sensitivity is partially overcome by the high magnetic field. An additional sensitivity improvement was achieved simply by applying a large number of transients. It typically took four to five days to collect each set of data (Table 1[link]). The limited spectral resolution of 1H nuclei even at an ultrafast MAS rate potentially produces 1H resonance overlaps. Fortunately, invCP-VC experiments on the 15N—1H system filtered out 1H signals from atoms which are not bonded directly to 15N. Thus, the signal overlaps can easily be avoided in salt/cocrystal/continuum systems which typically include only one N—H hydrogen-bonding pair. Longer 15N—1H distances result in smaller 15N-1H dipolar interactions. This may introduce the effect of remote 15N-1H dipolar interactions which are usually suppressed by the strongest 15N-1H dipolar interactions. This effect depends on numerous factors, including the size of each dipolar interaction and the relative orientation of each N—H vector. We calculated the invCP-VC spectrum of CO1, which shows the longest N—H distances, to evaluate the effects of the second and third nearest-neighbour H atoms. It was shown that these remote N-H dipolar interactions only broaden the invCP-VC spectra and do not affect the peak positions, i.e. 15N—1H distances (Fig. S14 in the supporting information). Therefore, we conclude that one may safely rely on dipolar splitting to obtain 1H—15N distances, even for cocrystals.

One of the major requirements of the two-dimensional invCP-VC 1H→15N→1H experiment with natural-abundance samples is to have as short a 1H spin lattice relaxation time (T1) as possible. However, in pharmaceutical cocrystals, T1 is generally long for N—H protons. The long T1 relaxation time results in impractical total experimental times and limits the application of two-dimensional invCP-VC 1H→15N→1H experiments on actual samples. The application of a rotor-synchronized train of 180° pulses (i.e. RFDR or radio-frequency driven recoupling) during the recycle period (Ye et al., 2014[Ye, Y. Q., Malon, M., Martineau, C., Taulelle, F. & Nishiyama, Y. (2014). J. Magn. Reson. 239, 75-80.]) and/or the addition of a paramagnetic dopant (Wickramasinghe et al., 2007[Wickramasinghe, N. P., Kotecha, M., Samoson, A., Past, J. & Ishii, Y. (2007). J. Magn. Reson. 184, 350-356.]) to the system can be used to reduce T1 values somewhat. For our purpose, we have used the RFDR-based approach in three of the samples (CO1, SA1 and SA2) to reduce the T1 relaxation times. Besides, paramagnetic doping was avoided to preserve the sample purity. While the T1 relaxation time for an NH proton in the case of CNT1 is also very long (70 s), the uniform 1H T1 relaxation hampers the application of the RFDR pulse train and data were collected without RFDR irradiation. The one-dimensional 1H→15N→1H-filtered spectra of all four samples under study give isolated N—H resonances (Fig. S15 in the supporting information). All other unwanted peaks are completely suppressed. In other words, this experiment provides a method for the precise assignment of N—H proton resonances in cases where the signals are overlapped with other 1H resonances (C—H protons) and allows a more accurate and reliable measurement of N—H distances. This highlights the additional advantages of invCP-VC experiments for multicomponent systems where severe overlap of 1H resonances is expected.

The two-dimensional invCP-VC spectra were plotted with the horizontal and vertical axes representing the 1H chemical shift and the size of the 15N-1H dipolar couplings, respectively (Fig. 4[link]). The above-mentioned procedure overcomes the difficulties, including low abundance and thus sensitivity of 15N, small 15N-1H dipolar coupling, complex multicomponent systems and long 1H T1 relaxation time, and clearly gives splitting in the indirect dimension. The observed separations between two singularities/15N-1H dipolar splittings for SA1, SA2, CO1 and CNT1 were found to be 5.36, 4.37, 2.01 and 2.96 kHz, respectively, corresponding to 15N—1H distances of 1.17, 1.25, 1.62 and 1.43 Å. From SCXRD at 298 K, the 15N—1H distances were 1.01, 1.20, 1.54 and 0.99 Å (without normalization), and at 110 K, they were 0.99, 1.18, 1.57 and 1.17 Å for SA1, SA2, CO1 and CNT1, respectively (Table 2[link]). Crystal data, data collection and structure refinement details are summarized in Table 3[link].

Table 2
15N—1H distance (Å) measurements by SCXRDa and ssNMR for the four investigated solid forms

Compound SCXRD (298 K) SCXRD (298 K) Normalized SCXRD (110 K) SCXRD (110 K) Normalized ssNMR
SA1 1.01 (3) 1.01 0.99 (2) 1.01 1.17
SA2 1.20 (3) 1.01 1.18 (3) 1.01 1.25
CO1 1.54 (4) 1.65 1.57 (3) 1.64 1.62
CNT1 0.99 (9) 1.01 1.17 (6) 1.01 1.43
Note: (a) data sets were collected on a Rigaku XtaLAB mini diffractometer.

Table 3
Crystallographic parameters of compounds SA1, SA2, CO1 and CNT1

  SA1 (RT) SA1 (LT) SA2 (RT) SA2 (LT) CO1 (RT)
Chemical formula C14H15N3O4 C14H15N3O4 C14H13N3O6 C14H13N3O6 C14H14N2O4
Mr 289.29 289.29 319.27 319.27 274.27
Crystal system Monoclinic Monoclinic Monoclinic Monoclinic Triclinic
Space group C2/c C2/c P21/c P21/c P[\overline{1}]
Temperature (K) 298 110 298 110 298
a (Å) 28.86 (2) 28.685 (2) 8.574 (9) 8.439 (6) 6.730 (2)
b (Å) 6.791 (5) 6.783 (3) 14.346 (2) 14.091 (9) 7.186 (2)
c (Å) 14.243 (1) 13.975 (7) 12.190 (1) 12.167 (8) 14.298 (3)
α (°) 90 90 90 90 88.158 (6)
β (°) 95.410 (1) 94.175 (7) 94.440 (1) 95.500 (1) 88.340 (6)
γ (°) 90 90 90 90 78.636 (5)
V3) 2779 (3) 2712 (2) 1495 (3) 1440.0 (2) 677.4 (3)
Z 8 8 4 4 2
Dcalcd(Mg m−3) 1.383 1.417 1.419 1.472 1.345
μ (mm−1) 0.103 0.106 0.113 0.117 0.100
F(000) 1216 1216 664 664 288
Total reflections 12517 12292 13680 13152 5680
Unique reflections 2729 2662 2936 2815 2634
Observed reflections [I > 2σ(I)] 2388 2507 2597 2683 1543
Rint 0.059 0.060 0.080 0.097 0.040
R1 [I > 2σ(I)] 0.0498 0.0383 0.0555 0.0400 0.0646
wR2 0.1414 0.1119 0.1737 0.1248 0.1894
Completeness (%) 99.6 99.7 99.9 99.6 99.2
Goodness-of-fit 1.081 1.099 1.135 1.143 1.037
CCDC No. 1529544 1529546 1529547 1529545 1529550
Diffractometer Rigaku Rigaku Rigaku Rigaku Rigaku
           
  CO1 (LT) CNT1 (RT) CNT1 (LT) CNT1 (RT) CNT1 (LT)
Chemical formula C14H14N2O4 C12H8Cl5NO C12H8Cl5NO C12H8Cl5NO C12H8Cl5NO
Mr 274.27 359.44 359.44 359.44 359.44
Crystal system Triclinic Triclinic Triclinic Triclinic Triclinic
Space group P[\overline{1}] P[\overline{1}] P[\overline{1}] P[\overline{1}] P[\overline{1}]
Temperature (K) 110 298 110 298 110
a (Å) 6.631 (5) 7.389 (8) 7.316 (6) 7.386 (8) 7.338 (8)
b (Å) 7.032 (6) 8.922 (8) 8.942 (8) 8.920 (1) 8.899 (9)
c (Å) 14.216 (1) 12.014 (1) 11.763 (9) 12.023 (1) 11.825 (1)
α (°) 87.967 (2) 69.82 (3) 70.15 (4) 69.770 (3) 69.945 (5)
β (°) 88.58 (3) 85.61 (4) 84.67 (4) 85.869 (3) 85.055 (5)
γ (°) 80.207 (2) 76.26 (4) 76.24 (4) 76.324 (4) 76.133 (5)
V3) 652.6 (9) 722.1 (1) 703.0 (1) 722.1 (1) 704.2 (1)
Z 2 2 2 2 2
Dcalcd(Mg m−3) 1.396 1.653 1.698 1.653 1.695
μ (mm−1) 0.104 0.993 1.020 0.993 1.018
F(000) 288 360 360 360 360
Total reflections 6144 6793 6521 6870 11629
Unique reflections 2555 2815 2741 2799 2756
Observed reflections [I > 2σ(I)] 2366 2152 2421 1751 2106
Rint 0.071 0.063 0.054 0.039 0.052
R1 [I > 2σ(I)] 0.0427 0.0505 0.0402 0.0466 0.0396
wR2 0.1338 0.1943 0.1513 0.1288 0.1034
Completeness (%) 99.6 99.6 99.4 98.9 99.7
Goodness-of-fit 1.105 1.155 1.299 1.040 1.102
CCDC No. 1529549 1529548 1529542 1529543 1529541
Diffractometer Rigaku Rigaku Rigaku Bruker Bruker
[Figure 4]
Figure 4
The molecular structures and the two-dimensional invCP-VC spectra (15N-1H dipolar couplings versus 1H chemical shift) of SA1, SA2, CO1 and CNT1.

X-ray crystallography is a powerful and widely accepted technique for structure determination. Since X-rays are scattered by the electrons of an atom, the results of an X-ray-based structure determination give the centroids of the electron density, which correspond to the centres of the nuclei in heavier atoms. In securing light-atom positions, and especially H-atom positions, X-ray diffraction has its limitations. The electron density of an H atom is not centred around the H-atom nucleus, but is aspherically displaced towards the covalently bonded heavier atom (X—H⋯AY). As a result, X-ray-determined X−H distances generally appear to be shorter than the true internuclear distance (Desiraju & Steiner, 1999[Desiraju, G. R. & Steiner, T. (1999). In The Weak Hydrogen Bond in Structural Chemistry and Biology. Oxford University Press.]; Lusi & Barbour, 2011[Lusi, M. & Barbour, L. J. (2011). Cryst. Growth Des. 11, 5515-5521.]). This problem can be avoided by the use of neutron diffraction (ND) analysis, in which the positional and anisotropic displacement parameters of the H atoms can be refined. But the distance (X−H) derived from ND analysis corresponds to the internuclear distance, since the scattering centres are the atomic nuclei.

In this regard, a comparison between the ND- and ssNMR-derived X−H distance would appear to be significant. In fact, there are several important reports where the NMR-derived distances of L-histidine·HCl·H2O were compared with the ND-derived distances (Zhao et al., 2001[Zhao, Z., Sudmeier, J. L., Bachovchin, W. W. & Levitt, M. H. (2001). J. Am. Chem. Soc. 123, 11097-11098.]; Paluch et al., 2015[Paluch, P., Trébosc, J., Nishiyama, Y., Potrzebowski, M., Malon, M. & Amoureux, J.-P. (2015). J. Magn. Reson. 252, 67-77.]). We have also demonstrated that the invCP-VC method applied to L-histidine·HCl·H2O gives as reliable an internuclear N—H distance as the ND method (Nishiyama et al., 2016[Nishiyama, Y., Malon, M., Potrzebowski, M. J., Paluch, P. & Amoureux, J. P. (2016). Solid State Nucl. Magn. Reson. 73, 15-21.]). However, ND is expensive and limited by availability. It also requires a large amount of samples or a large-sized crystal, which is often difficult to grow. Therefore, alternatively, a comparison of the neutron-normalized (NN) X-ray distance, in lieu of the neutron-derived distance, with the ssNMR-derived distance can be considered reliably meaningful. It should be noted that the NN X-ray distance is an outcome of the analysis of available XRD and ND crystal structure data in the Cambridge Structural Database (Groom et al., 2016[Groom, C. R., Bruno, I. J., Lightfoot, M. P. & Ward, S. C. (2016). Acta Cryst. B72, 171-179.]), where the X-ray-derived distance is extended by shifting the X−H bond vector to the average neutron-derived distance (Allen & Bruno, 2010[Allen, F. H. & Bruno, I. J. (2010). Acta Cryst. B66, 380-386.]). This is a widely used procedure.

The ssNMR X−H distances of CO1 (1.62 Å) and SA1 (1.17 Å) show a fair agreement with the NN X-ray distances of CO1 (1.65 Å) and SA1 (1.01 Å). The observed differences in the measured 15N—1H distances from the two methods (XRD/ND and ssNMR) could be attributed to: (i) inaccurate proton positions due to a low scattering cross sectional area of the H atoms, (ii) different timescales of measurements (tens of µs in NMR and ps in XRD/ND) and, therefore, averaging of the libratory motions at different timescales, and (iii) dissimilar distance dependence (1/r3 in NMR and 1/r in XRD/ND) which ultimately resulted in a longer distance for NMR compared to XRD (Ishii et al., 1997[Ishii, Y., Terao, T. & Hayashi, S. (1997). J. Chem. Phys. 107, 2760-2774.]). Since the current approach gives the internuclear distances directly, unlike diffraction-based methods, where the distances are calculated from the positions of the nuclei, ssNMR-based approaches are appropriately com­plementary to the other methods.

From ssNMR, the 15N—1H distance in SA1 is 1.17 Å and is the smallest in comparison to the corresponding distances in SA2, CNT1 and CO1. This clearly suggests that SA1 is a `salt' in which complete transfer of the proton across the hydrogen bond from acid to pyridine has taken place. Similarly, the longer distance observed for CO1 (1.62 Å) clearly rules out any possibility of the transfer of the proton from the acid to pyridine, confirming that CO1 is a `cocrystal'. Interestingly, SA2, which is an adduct of a strong acid and a strong base, is a case of a continuum, despite having ΔpKa > 3, with an 15N—1H distance of 1.25 Å from ssNMR, half of the N—O distance (2.54 Å by SCXRD at both temperatures). CNT1 shows the importance of locating accurate proton positions in these classifications. In this example, unlike in the previously discussed continuum scenario, the distance obtained from SCXRD and ssNMR were not comparable. The SCXRD distance was completely misleading due to poor data quality. From the difference Fourier map, the residual electron density is delocalized over a region between the two heavy atoms (O and N) and the proton position had to be fixed at 0.99 Å (SCXRD at 298 K, Rigaku XtaLAB mini). Further refinements were not sustained. Alternatively, the SCXRD measurement was carried out on a Bruker SMART APEX (D8 QUEST) CMOS diffractometer. The N—H distance was 1.65 Å at room temperature, i.e. 0.18 Å longer than obtained by Steiner et al. (2001[Steiner, T., Majerz, I. & Wilson, C. C. (2001). Angew. Chem. Int. Ed. 40, 2651-2654.]). In other words, locating the proton position in a salt–cocrystal continuum is ambiguous from SCXRD data as it is somewhat machine dependent. Neutron normalization of the X-ray distance, in this regard, is also not appropriate since neutron normalization adjusts the H-atom position to an average distance, and practically ignores the polarization effect caused by the acceptor atom in a strongly hydrogen-bonded system. In this regard, a comparative study with ND data of a system where large crystals could be obtained would appear to be the next step. None of the compounds studied here was available in the form of large crystals.

The 15N—1H distance of CNT1 obtained by invCP-VC ssNMR is 1.43 Å at room temperature, which suggests that CNT1 behaves more like a `cocrystal' at room temperature (N⋯O = 2.54 Å by SCXRD). Previous studies on CNT1 with variable-temperature time-of-flight neutron diffraction shows that the N—H distance increases with temperature and that it is 1.306 Å at 200 K (Steiner et al., 2001[Steiner, T., Majerz, I. & Wilson, C. C. (2001). Angew. Chem. Int. Ed. 40, 2651-2654.]). Therefore, at room temperature, the N—H distance is expected to be longer than 1.306 Å. As a result, the N—H distance at room temperature determined by ssNMR can be considered to be as reliable as neutron diffraction data. In this situation, the two-dimensional invCP-VC method turns out to be a significant tool for location of precise proton positions through dipolar coupling, especially in proton-disordered systems. In addition, the present ssNMR technique is advantageous as it can be performed on microcrystalline, or even amorphous, samples with laboratory-based NMR equipment.

4. Conclusions

We have carried out two-dimensional inversely proton-detected CP-VC ssNMR measurements at fast MAS to determine N—H distances with naturally abundant 15N nuclei in multicomponent solid forms. N—H distances vary with the length of the hydrogen bond between the two individual components of a salt, cocrystal or continuum, and these distances were measured through two well-separated singularities of the Pake-like dipolar powder pattern. The measured distances can be easily used to locate the proton positions in such systems and hence a clear distinction between salt, cocrystal and continuum may be established. The technique will be useful where the ΔpKa rule has limitations, especially in the range 1 < ΔpKa < 3. We believe that the method presented in this work will have an impact on the pharmaceutical industry. Further, the method can be utilized for microcrystalline samples where obtaining a single crystal is difficult. Our future studies will be directed towards the implementation of this technique in more complex systems, such as to differentiate polyamorphous solid forms.

Supporting information


Computing details top

For all compounds, program(s) used to refine structure: SHELXL97 (Sheldrick, 2008).

(SA-1-LT) top
Crystal data top
C7H4NO4·C7H11N2Dx = 1.417 Mg m3
Mr = 289.29Melting point: 160-163 K
Monoclinic, C2/cMo Kα radiation, λ = 0.71073 Å
a = 28.685 (15) ÅCell parameters from 5097 reflections
b = 6.783 (3) Åθ = 2.8–33.7°
c = 13.975 (7) ŵ = 0.11 mm1
β = 94.175 (7)°T = 110 K
V = 2712 (2) Å3Block, colorless
Z = 80.22 × 0.19 × 0.18 mm
F(000) = 1216
Data collection top
Rigaku
diffractometer
2662 independent reflections
Radiation source: fine-focus sealed tube2507 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.060
profile data from ω–scansθmax = 26.0°, θmin = 1.4°
Absorption correction: multi-scan
SADABS
h = 3535
Tmin = 0.828, Tmax = 1.000k = 88
12292 measured reflectionsl = 1717
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.038Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.112H atoms treated by a mixture of independent and constrained refinement
S = 1.10 w = 1/[σ2(Fo2) + (0.0601P)2 + 1.1467P]
where P = (Fo2 + 2Fc2)/3
2662 reflections(Δ/σ)max < 0.001
250 parametersΔρmax = 0.27 e Å3
0 restraintsΔρmin = 0.25 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
C10.24504 (4)0.03795 (18)0.10802 (9)0.0239 (3)
C20.20300 (4)0.02431 (18)0.06753 (9)0.0230 (3)
C30.19100 (4)0.22795 (18)0.06892 (8)0.0190 (3)
C40.22451 (4)0.35419 (18)0.11737 (8)0.0218 (3)
C50.26592 (4)0.28117 (18)0.15571 (8)0.0219 (3)
C60.13944 (5)0.5071 (2)0.03136 (10)0.0289 (3)
C70.11823 (5)0.1691 (2)0.02857 (10)0.0310 (3)
C80.09586 (5)0.02538 (18)0.22057 (9)0.0249 (3)
C90.05720 (5)0.11388 (19)0.17238 (10)0.0304 (3)
C100.02023 (5)0.00051 (19)0.13326 (9)0.0253 (3)
C110.02353 (4)0.20199 (18)0.14312 (8)0.0201 (3)
C120.06164 (4)0.29390 (17)0.19095 (8)0.0195 (3)
C130.09842 (4)0.17884 (18)0.23038 (8)0.0195 (3)
C140.14066 (4)0.27671 (18)0.28240 (8)0.0205 (3)
N10.27652 (4)0.08771 (15)0.15117 (7)0.0223 (2)
N20.15095 (3)0.29770 (15)0.02658 (7)0.0230 (3)
N30.01513 (4)0.32432 (16)0.10123 (7)0.0242 (3)
O10.17069 (3)0.16988 (13)0.32505 (7)0.0278 (2)
O20.14200 (3)0.46403 (13)0.27718 (6)0.0251 (2)
O30.01255 (4)0.50377 (14)0.11108 (8)0.0372 (3)
O40.04832 (3)0.24031 (15)0.05862 (8)0.0361 (3)
H10.2560 (5)0.175 (2)0.1070 (10)0.030 (4)*
H1N0.3077 (7)0.040 (3)0.1764 (13)0.049 (5)*
H20.1821 (6)0.069 (2)0.0357 (12)0.035 (4)*
H40.2184 (6)0.490 (3)0.1200 (11)0.029 (4)*
H50.2882 (5)0.368 (2)0.1829 (10)0.025 (4)*
H6A0.1611 (6)0.588 (2)0.0070 (12)0.036 (4)*
H6B0.1074 (7)0.525 (3)0.0043 (13)0.042 (5)*
H6C0.1413 (5)0.553 (2)0.0959 (12)0.033 (4)*
H7A0.1345 (6)0.081 (2)0.0712 (12)0.036 (4)*
H7B0.0971 (7)0.251 (3)0.0668 (13)0.053 (5)*
H7C0.1020 (7)0.086 (3)0.0129 (13)0.043 (5)*
H80.1222 (6)0.107 (2)0.2468 (11)0.029 (4)*
H90.0556 (6)0.259 (3)0.1654 (12)0.045 (5)*
H100.0071 (6)0.058 (2)0.1005 (12)0.036 (4)*
H120.0633 (5)0.435 (2)0.1975 (10)0.026 (4)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0258 (6)0.0183 (6)0.0277 (6)0.0009 (5)0.0024 (5)0.0022 (5)
C20.0226 (6)0.0193 (6)0.0270 (6)0.0028 (5)0.0003 (5)0.0012 (5)
C30.0186 (6)0.0209 (6)0.0178 (5)0.0002 (4)0.0038 (4)0.0017 (4)
C40.0235 (6)0.0175 (6)0.0247 (6)0.0009 (5)0.0034 (5)0.0008 (5)
C50.0207 (6)0.0225 (6)0.0223 (6)0.0034 (5)0.0009 (4)0.0003 (5)
C60.0295 (7)0.0266 (7)0.0302 (7)0.0091 (5)0.0009 (5)0.0036 (5)
C70.0239 (7)0.0376 (8)0.0305 (7)0.0011 (6)0.0037 (5)0.0061 (6)
C80.0276 (7)0.0186 (6)0.0279 (6)0.0022 (5)0.0029 (5)0.0016 (5)
C90.0354 (7)0.0161 (6)0.0385 (7)0.0011 (5)0.0055 (6)0.0009 (5)
C100.0259 (7)0.0214 (6)0.0278 (6)0.0054 (5)0.0041 (5)0.0015 (5)
C110.0190 (6)0.0206 (6)0.0206 (6)0.0012 (4)0.0008 (5)0.0023 (4)
C120.0206 (6)0.0169 (6)0.0213 (6)0.0013 (4)0.0023 (5)0.0008 (4)
C130.0210 (6)0.0192 (6)0.0183 (6)0.0012 (4)0.0017 (4)0.0008 (4)
C140.0199 (6)0.0215 (6)0.0201 (6)0.0010 (4)0.0008 (4)0.0006 (4)
N10.0206 (5)0.0227 (5)0.0234 (5)0.0017 (4)0.0007 (4)0.0031 (4)
N20.0203 (5)0.0239 (6)0.0246 (5)0.0024 (4)0.0006 (4)0.0010 (4)
N30.0212 (5)0.0245 (6)0.0266 (5)0.0005 (4)0.0011 (4)0.0000 (4)
O10.0245 (5)0.0233 (5)0.0344 (5)0.0009 (3)0.0070 (4)0.0038 (4)
O20.0244 (5)0.0182 (4)0.0317 (5)0.0026 (3)0.0050 (4)0.0001 (3)
O30.0335 (5)0.0207 (5)0.0554 (7)0.0044 (4)0.0106 (5)0.0019 (4)
O40.0256 (5)0.0361 (6)0.0443 (6)0.0007 (4)0.0136 (4)0.0053 (4)
Geometric parameters (Å, º) top
C1—N11.3515 (17)C9—C101.3894 (19)
C1—C21.3613 (18)C10—C111.3831 (18)
C2—C31.4241 (18)C11—C121.3871 (17)
C3—N21.3397 (16)C11—N31.4719 (16)
C3—C41.4216 (17)C12—C131.3933 (17)
C4—C51.3606 (18)C13—C141.5194 (16)
C5—N11.3495 (17)C14—O11.2441 (15)
C6—N21.4610 (18)C14—O21.2734 (16)
C7—N21.4596 (17)N3—O41.2261 (14)
C8—C91.3910 (19)N3—O31.2266 (16)
C8—C131.3934 (18)
N1—C1—C2122.19 (12)C12—C13—C8119.01 (11)
C1—C2—C3120.20 (11)C12—C13—C14119.93 (11)
N2—C3—C4121.73 (11)C8—C13—C14121.06 (11)
N2—C3—C2122.48 (11)O1—C14—O2125.86 (11)
C4—C3—C2115.79 (11)O1—C14—C13118.36 (11)
C5—C4—C3120.60 (12)O2—C14—C13115.78 (10)
N1—C5—C4121.91 (11)C5—N1—C1119.26 (11)
C9—C8—C13120.75 (11)C3—N2—C7121.33 (11)
C10—C9—C8120.69 (12)C3—N2—C6120.83 (10)
C11—C10—C9117.76 (11)C7—N2—C6117.81 (11)
C10—C11—C12122.70 (11)O4—N3—O3123.64 (11)
C10—C11—N3118.44 (11)O4—N3—C11117.84 (11)
C12—C11—N3118.87 (11)O3—N3—C11118.51 (10)
C11—C12—C13119.10 (11)
(SA-1-RT) top
Crystal data top
C7H4NO4·C7H11N2Dx = 1.383 Mg m3
Mr = 289.29Melting point: 160-163 K
Monoclinic, C2/cMo Kα radiation, λ = 0.71073 Å
a = 28.86 (2) ÅCell parameters from 4323 reflections
b = 6.791 (5) Åθ = 2.9–33.7°
c = 14.243 (10) ŵ = 0.10 mm1
β = 95.4097 (10)°T = 298 K
V = 2779 (3) Å3Block, colorless
Z = 80.22 × 0.19 × 0.18 mm
F(000) = 1216
Data collection top
Rigaku
diffractometer
2729 independent reflections
Radiation source: fine-focus sealed tube2388 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.059
profile data from ω–scansθmax = 26.0°, θmin = 1.4°
Absorption correction: multi-scan
SADABS
h = 3535
Tmin = 0.835, Tmax = 1.000k = 88
12517 measured reflectionsl = 1717
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.050Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.141H atoms treated by a mixture of independent and constrained refinement
S = 1.08 w = 1/[σ2(Fo2) + (0.0742P)2 + 0.9562P]
where P = (Fo2 + 2Fc2)/3
2729 reflections(Δ/σ)max = 0.001
246 parametersΔρmax = 0.21 e Å3
0 restraintsΔρmin = 0.17 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
C130.40096 (5)0.3197 (2)0.27019 (10)0.0402 (3)
O20.35699 (4)0.03687 (17)0.22487 (9)0.0546 (3)
C120.43787 (5)0.2062 (2)0.30903 (10)0.0405 (3)
C110.47601 (5)0.2981 (2)0.35586 (10)0.0424 (4)
O10.32886 (4)0.32828 (18)0.17595 (10)0.0623 (4)
C30.30883 (5)0.2717 (2)0.43211 (10)0.0397 (3)
C140.35863 (5)0.2224 (2)0.21897 (10)0.0440 (4)
N20.34892 (4)0.2015 (2)0.47438 (9)0.0488 (4)
N30.51479 (5)0.1768 (2)0.39707 (10)0.0534 (4)
C20.27554 (5)0.1472 (2)0.38306 (11)0.0460 (4)
C40.29662 (6)0.4727 (2)0.43461 (12)0.0490 (4)
N10.22393 (5)0.4118 (2)0.34901 (9)0.0479 (4)
C80.40357 (6)0.5229 (3)0.28006 (13)0.0534 (4)
C50.23456 (5)0.2205 (3)0.34415 (12)0.0480 (4)
O30.51270 (5)0.0008 (2)0.38680 (13)0.0841 (5)
C10.25495 (6)0.5354 (3)0.39328 (13)0.0520 (4)
C100.47894 (6)0.4990 (3)0.36560 (13)0.0562 (4)
O40.54797 (5)0.2601 (2)0.43902 (12)0.0813 (5)
C60.36047 (8)0.0062 (3)0.47001 (17)0.0644 (5)
C70.38198 (7)0.3280 (4)0.52967 (17)0.0686 (6)
C90.44213 (7)0.6106 (3)0.32754 (15)0.0660 (5)
H90.44320.74690.33380.079*
H120.4361 (6)0.066 (3)0.3009 (11)0.048 (5)*
H50.2125 (7)0.135 (3)0.3161 (13)0.053 (5)*
H20.2824 (7)0.014 (3)0.3785 (13)0.060 (5)*
H40.3164 (8)0.561 (3)0.4665 (16)0.078 (7)*
H80.3771 (7)0.603 (3)0.2548 (13)0.059 (5)*
H10.2434 (7)0.671 (3)0.3931 (13)0.066 (6)*
H100.5069 (8)0.555 (3)0.3951 (15)0.073 (6)*
H6A0.3581 (8)0.051 (3)0.4071 (19)0.088 (8)*
H6B0.3906 (10)0.028 (4)0.4964 (19)0.096 (8)*
H1N0.1924 (9)0.462 (4)0.3231 (16)0.087 (7)*
H6C0.3367 (9)0.088 (4)0.5087 (18)0.096 (8)*
H7A0.4041 (11)0.247 (5)0.568 (2)0.128 (10)*
H7B0.3963 (10)0.410 (4)0.493 (2)0.101 (9)*
H7C0.3657 (9)0.408 (4)0.5771 (18)0.094 (8)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C130.0410 (8)0.0394 (8)0.0396 (7)0.0016 (6)0.0012 (6)0.0017 (6)
O20.0469 (6)0.0439 (7)0.0696 (8)0.0060 (5)0.0124 (5)0.0008 (5)
C120.0399 (8)0.0344 (8)0.0466 (8)0.0023 (6)0.0008 (6)0.0015 (6)
C110.0376 (8)0.0430 (8)0.0458 (8)0.0000 (6)0.0000 (6)0.0019 (6)
O10.0501 (7)0.0532 (7)0.0792 (8)0.0008 (5)0.0175 (6)0.0094 (6)
C30.0340 (7)0.0449 (8)0.0404 (7)0.0008 (6)0.0051 (6)0.0032 (6)
C140.0386 (8)0.0461 (9)0.0462 (8)0.0017 (6)0.0014 (6)0.0019 (6)
N20.0385 (7)0.0557 (8)0.0510 (8)0.0047 (6)0.0022 (5)0.0027 (6)
N30.0409 (7)0.0563 (9)0.0608 (9)0.0016 (6)0.0068 (6)0.0007 (7)
C20.0452 (8)0.0392 (8)0.0532 (9)0.0013 (6)0.0029 (6)0.0008 (7)
C40.0451 (8)0.0413 (8)0.0592 (10)0.0061 (7)0.0021 (7)0.0032 (7)
N10.0412 (7)0.0504 (8)0.0512 (8)0.0028 (5)0.0002 (5)0.0063 (6)
C80.0568 (10)0.0385 (8)0.0624 (10)0.0041 (7)0.0083 (8)0.0015 (7)
C50.0395 (8)0.0519 (9)0.0516 (9)0.0058 (7)0.0005 (6)0.0018 (7)
O30.0667 (9)0.0506 (8)0.1280 (14)0.0103 (6)0.0278 (9)0.0043 (8)
C10.0514 (9)0.0395 (8)0.0646 (10)0.0029 (7)0.0022 (7)0.0037 (7)
C100.0532 (10)0.0467 (9)0.0656 (11)0.0113 (7)0.0100 (8)0.0040 (8)
O40.0533 (8)0.0825 (10)0.1011 (11)0.0024 (7)0.0302 (7)0.0110 (8)
C60.0604 (12)0.0620 (12)0.0695 (13)0.0209 (9)0.0000 (9)0.0100 (10)
C70.0453 (10)0.0936 (17)0.0641 (12)0.0012 (10)0.0092 (9)0.0131 (11)
C90.0738 (12)0.0341 (9)0.0861 (13)0.0041 (8)0.0145 (10)0.0032 (8)
Geometric parameters (Å, º) top
C13—C121.387 (2)N2—C61.452 (2)
C13—C81.388 (2)N2—C71.459 (2)
C13—C141.5145 (19)N3—O31.216 (2)
O2—C141.2639 (19)N3—O41.2193 (18)
C12—C111.381 (2)C2—C51.353 (2)
C11—C101.373 (2)C4—C11.357 (2)
C11—N31.4672 (19)N1—C51.338 (2)
O1—C141.2376 (18)N1—C11.340 (2)
C3—N21.3406 (18)C8—C91.382 (3)
C3—C41.411 (2)C10—C91.374 (3)
C3—C21.414 (2)
C12—C13—C8118.68 (14)C3—N2—C7121.71 (16)
C12—C13—C14120.24 (14)C6—N2—C7117.02 (16)
C8—C13—C14121.08 (13)O3—N3—O4123.17 (15)
C11—C12—C13119.23 (14)O3—N3—C11118.80 (13)
C10—C11—C12122.45 (14)O4—N3—C11118.02 (15)
C10—C11—N3118.70 (13)C5—C2—C3120.62 (15)
C12—C11—N3118.85 (14)C1—C4—C3120.40 (15)
N2—C3—C4122.68 (14)C5—N1—C1119.08 (14)
N2—C3—C2121.77 (15)C9—C8—C13120.77 (15)
C4—C3—C2115.54 (14)N1—C5—C2122.13 (15)
O1—C14—O2125.70 (14)N1—C1—C4122.20 (16)
O1—C14—C13118.41 (14)C11—C10—C9118.05 (15)
O2—C14—C13115.89 (13)C10—C9—C8120.82 (16)
C3—N2—C6121.22 (15)
(SA-2-LT) top
Crystal data top
C7H3N2O6·C7H10NDx = 1.473 Mg m3
Mr = 319.27Melting point: 119-122 K
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 8.439 (6) ÅCell parameters from 5652 reflections
b = 14.091 (9) Åθ = 2.4–33.8°
c = 12.167 (8) ŵ = 0.12 mm1
β = 95.500 (11)°T = 110 K
V = 1440.0 (17) Å3Block, colorless
Z = 40.21 × 0.16 × 0.13 mm
F(000) = 664
Data collection top
Rigaku
diffractometer
2815 independent reflections
Radiation source: fine-focus sealed tube2683 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.097
profile data from ω–scansθmax = 26.0°, θmin = 2.2°
Absorption correction: multi-scan
SADABS
h = 1010
Tmin = 0.865, Tmax = 1.000k = 1717
13152 measured reflectionsl = 1515
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.040Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.125H atoms treated by a mixture of independent and constrained refinement
S = 1.14 w = 1/[σ2(Fo2) + (0.064P)2 + 0.317P]
where P = (Fo2 + 2Fc2)/3
2815 reflections(Δ/σ)max < 0.001
248 parametersΔρmax = 0.28 e Å3
0 restraintsΔρmin = 0.28 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
H1N0.456 (3)0.2575 (19)0.467 (2)0.076 (7)*
H80.1224 (18)0.3429 (12)0.2389 (13)0.022 (4)*
H100.038 (2)0.1235 (12)0.4386 (15)0.026 (4)*
H120.306 (2)0.0791 (13)0.1781 (15)0.034 (4)*
H10.527 (2)0.1017 (13)0.4854 (15)0.033 (4)*
H20.6808 (19)0.0090 (13)0.3644 (14)0.029 (4)*
H40.707 (2)0.2511 (13)0.1794 (15)0.031 (4)*
H50.5597 (19)0.3312 (12)0.3115 (13)0.022 (4)*
H6A0.871 (2)0.1059 (13)0.1422 (15)0.031 (4)*
H6B0.858 (2)0.0167 (13)0.2149 (15)0.030 (4)*
C140.30472 (14)0.26050 (9)0.10136 (10)0.0192 (3)
C130.22438 (14)0.21815 (9)0.19588 (10)0.0183 (3)
C80.13626 (14)0.27749 (9)0.25878 (10)0.0197 (3)
C90.06869 (14)0.23924 (9)0.34798 (10)0.0196 (3)
C100.08378 (15)0.14480 (9)0.37842 (10)0.0200 (3)
C110.17268 (14)0.08853 (9)0.31377 (10)0.0194 (3)
C120.24314 (14)0.12263 (9)0.22315 (10)0.0190 (3)
N20.02385 (13)0.30238 (8)0.41489 (9)0.0241 (3)
N30.19327 (13)0.01231 (8)0.34342 (9)0.0237 (3)
O10.36156 (12)0.19939 (7)0.03716 (8)0.0244 (2)
O20.31207 (12)0.34760 (7)0.09291 (8)0.0266 (2)
O30.04470 (13)0.38464 (7)0.38489 (9)0.0358 (3)
O40.07647 (13)0.26784 (8)0.49665 (8)0.0354 (3)
O50.09484 (14)0.04888 (8)0.39831 (9)0.0366 (3)
O60.30787 (13)0.05436 (7)0.31190 (9)0.0324 (3)
C10.56982 (16)0.12698 (10)0.42318 (11)0.0231 (3)
C20.65598 (15)0.07589 (10)0.35234 (11)0.0226 (3)
C30.70791 (14)0.12053 (9)0.26002 (10)0.0189 (3)
C40.67219 (15)0.21688 (9)0.24425 (10)0.0207 (3)
C50.58611 (15)0.26418 (9)0.31819 (10)0.0212 (3)
C60.79381 (16)0.06533 (10)0.17825 (11)0.0227 (3)
C70.6767 (2)0.02098 (13)0.08992 (14)0.0411 (4)
H7A0.73420.01380.03870.062*
H7B0.61530.07010.05130.062*
H7C0.60680.02130.12400.062*
N10.53517 (13)0.21897 (8)0.40567 (9)0.0208 (3)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C140.0214 (6)0.0198 (6)0.0164 (6)0.0001 (5)0.0019 (5)0.0011 (4)
C130.0184 (6)0.0215 (6)0.0150 (6)0.0017 (4)0.0017 (5)0.0008 (5)
C80.0207 (6)0.0190 (6)0.0193 (6)0.0003 (5)0.0015 (5)0.0011 (5)
C90.0190 (6)0.0230 (7)0.0172 (6)0.0008 (5)0.0033 (5)0.0052 (5)
C100.0209 (6)0.0235 (7)0.0154 (6)0.0048 (5)0.0017 (5)0.0013 (5)
C110.0217 (6)0.0188 (6)0.0172 (6)0.0029 (5)0.0002 (4)0.0003 (5)
C120.0198 (6)0.0210 (6)0.0162 (6)0.0009 (5)0.0014 (5)0.0019 (5)
N20.0254 (6)0.0252 (6)0.0224 (6)0.0014 (4)0.0063 (4)0.0056 (4)
N30.0318 (6)0.0210 (6)0.0184 (5)0.0031 (5)0.0025 (4)0.0006 (4)
O10.0348 (5)0.0202 (5)0.0198 (5)0.0005 (4)0.0111 (4)0.0001 (3)
O20.0362 (5)0.0193 (5)0.0259 (5)0.0006 (4)0.0113 (4)0.0008 (4)
O30.0443 (6)0.0246 (6)0.0416 (6)0.0056 (4)0.0191 (5)0.0019 (4)
O40.0454 (6)0.0389 (6)0.0250 (5)0.0021 (5)0.0191 (5)0.0019 (4)
O50.0501 (7)0.0284 (6)0.0339 (6)0.0065 (5)0.0172 (5)0.0079 (4)
O60.0400 (6)0.0218 (5)0.0364 (6)0.0054 (4)0.0091 (5)0.0021 (4)
C10.0266 (6)0.0239 (7)0.0194 (6)0.0018 (5)0.0046 (5)0.0031 (5)
C20.0258 (6)0.0196 (7)0.0226 (6)0.0005 (5)0.0037 (5)0.0027 (5)
C30.0174 (6)0.0208 (6)0.0184 (6)0.0028 (4)0.0003 (5)0.0024 (4)
C40.0232 (6)0.0206 (6)0.0188 (6)0.0027 (5)0.0042 (5)0.0007 (5)
C50.0242 (6)0.0185 (7)0.0212 (6)0.0014 (5)0.0041 (5)0.0000 (5)
C60.0251 (6)0.0225 (7)0.0210 (6)0.0013 (5)0.0050 (5)0.0026 (5)
C70.0390 (8)0.0437 (9)0.0392 (9)0.0068 (7)0.0039 (7)0.0226 (7)
N10.0227 (5)0.0221 (6)0.0179 (5)0.0018 (4)0.0035 (4)0.0011 (4)
Geometric parameters (Å, º) top
C14—O21.2338 (18)N2—O41.2280 (17)
C14—O11.2858 (17)N3—O61.2266 (17)
C14—C131.5126 (18)N3—O51.2279 (16)
C13—C121.392 (2)C1—N11.3413 (19)
C13—C81.3953 (18)C1—C21.382 (2)
C8—C91.3828 (19)C2—C31.3942 (19)
C9—C101.384 (2)C3—C41.400 (2)
C9—N21.4785 (17)C3—C61.5029 (18)
C10—C111.3868 (19)C4—C51.3807 (19)
C11—C121.3876 (19)C5—N11.3458 (18)
C11—N31.4721 (19)C6—C71.523 (2)
N2—O31.2228 (18)
O2—C14—O1126.22 (12)O3—N2—O4124.38 (12)
O2—C14—C13119.05 (11)O3—N2—C9118.33 (12)
O1—C14—C13114.72 (12)O4—N2—C9117.29 (12)
C12—C13—C8120.22 (12)O6—N3—O5124.19 (12)
C12—C13—C14120.92 (11)O6—N3—C11117.89 (11)
C8—C13—C14118.81 (12)O5—N3—C11117.92 (11)
C9—C8—C13118.58 (12)N1—C1—C2121.61 (12)
C8—C9—C10123.40 (12)C1—C2—C3119.48 (13)
C8—C9—N2118.48 (12)C2—C3—C4117.89 (12)
C10—C9—N2118.11 (12)C2—C3—C6120.57 (12)
C9—C10—C11116.03 (12)C4—C3—C6121.49 (12)
C10—C11—C12123.30 (13)C5—C4—C3119.91 (12)
C10—C11—N3118.06 (11)N1—C5—C4120.97 (13)
C12—C11—N3118.64 (11)C3—C6—C7110.98 (12)
C11—C12—C13118.47 (12)C1—N1—C5120.11 (11)
(SA-2-RT) top
Crystal data top
C7H3N2O6·C7H10NDx = 1.419 Mg m3
Mr = 319.27Melting point: 119-122 K
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 8.574 (9) ÅCell parameters from 5147 reflections
b = 14.346 (15) Åθ = 1.7–33.6°
c = 12.190 (13) ŵ = 0.11 mm1
β = 94.440 (13)°T = 298 K
V = 1495 (3) Å3Block, colorless
Z = 40.21 × 0.16 × 0.13 mm
F(000) = 664
Data collection top
Rigaku
diffractometer
2936 independent reflections
Radiation source: fine-focus sealed tube2597 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.080
profile data from ω–scansθmax = 26.0°, θmin = 2.2°
Absorption correction: multi-scan
SADABS
h = 1010
Tmin = 0.833, Tmax = 1.000k = 1717
13680 measured reflectionsl = 1515
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.056Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.174H atoms treated by a mixture of independent and constrained refinement
S = 1.14 w = 1/[σ2(Fo2) + (0.0968P)2 + 0.2206P]
where P = (Fo2 + 2Fc2)/3
2936 reflections(Δ/σ)max < 0.001
248 parametersΔρmax = 0.26 e Å3
0 restraintsΔρmin = 0.28 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
H1N0.041 (4)0.255 (2)0.970 (3)0.115 (10)*
H80.628 (2)0.3388 (15)0.7471 (17)0.055 (5)*
H100.538 (3)0.1206 (18)0.940 (2)0.076 (7)*
H120.802 (3)0.0834 (17)0.676 (2)0.066 (6)*
H10.029 (3)0.0985 (18)0.984 (2)0.077 (7)*
H20.172 (3)0.009 (2)0.864 (2)0.080 (7)*
H40.207 (3)0.2468 (17)0.681 (2)0.073 (6)*
H50.063 (2)0.3231 (16)0.8120 (18)0.058 (5)*
H6A0.361 (3)0.1042 (19)0.638 (2)0.085 (8)*
H6B0.356 (3)0.0135 (19)0.709 (2)0.078 (7)*
N10.03790 (17)0.21530 (10)0.90713 (12)0.0497 (4)
C10.0693 (2)0.12469 (14)0.92256 (16)0.0562 (5)
C20.1527 (2)0.07456 (13)0.85079 (16)0.0554 (5)
C30.20643 (18)0.11811 (12)0.75876 (14)0.0461 (4)
C40.1747 (2)0.21284 (12)0.74503 (15)0.0496 (4)
C50.0903 (2)0.25934 (13)0.81997 (15)0.0518 (4)
C60.2904 (2)0.06335 (15)0.67594 (17)0.0576 (5)
C70.1775 (3)0.0194 (2)0.5909 (3)0.1049 (11)
H7A0.23440.01490.53940.157*
H7B0.11650.06710.55260.157*
H7C0.10920.02210.62620.157*
C140.8082 (2)0.26141 (12)0.60483 (14)0.0470 (4)
C130.72647 (18)0.21817 (11)0.69838 (13)0.0430 (4)
C80.63933 (19)0.27516 (12)0.76338 (14)0.0473 (4)
C90.57078 (19)0.23589 (12)0.85189 (14)0.0474 (4)
C100.5843 (2)0.14256 (13)0.87867 (14)0.0482 (4)
C110.67191 (19)0.08839 (12)0.81216 (13)0.0461 (4)
C120.74321 (19)0.12379 (12)0.72273 (13)0.0443 (4)
N20.4801 (2)0.29688 (12)0.92097 (14)0.0619 (4)
N30.6909 (2)0.01154 (12)0.83896 (14)0.0617 (4)
O10.86720 (18)0.20299 (9)0.54057 (11)0.0601 (4)
O20.81357 (18)0.34689 (9)0.59709 (12)0.0670 (4)
O30.4634 (2)0.37841 (12)0.89479 (18)0.0948 (6)
O40.4244 (2)0.26172 (14)1.00048 (14)0.0880 (6)
O50.5973 (3)0.04787 (12)0.89583 (17)0.0982 (7)
O60.7998 (2)0.05327 (11)0.80264 (17)0.0895 (6)
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0529 (8)0.0514 (8)0.0460 (8)0.0025 (6)0.0103 (6)0.0032 (6)
C10.0646 (11)0.0571 (11)0.0485 (9)0.0025 (8)0.0154 (8)0.0070 (8)
C20.0633 (11)0.0449 (9)0.0591 (10)0.0011 (8)0.0125 (8)0.0057 (8)
C30.0431 (8)0.0477 (9)0.0475 (9)0.0055 (6)0.0041 (7)0.0042 (7)
C40.0550 (9)0.0475 (9)0.0474 (9)0.0062 (7)0.0112 (7)0.0021 (7)
C50.0588 (10)0.0440 (9)0.0537 (10)0.0028 (7)0.0119 (8)0.0002 (7)
C60.0590 (11)0.0568 (10)0.0582 (11)0.0015 (8)0.0128 (8)0.0093 (9)
C70.0923 (18)0.119 (2)0.101 (2)0.0176 (16)0.0106 (15)0.0646 (18)
C140.0514 (9)0.0462 (9)0.0440 (8)0.0007 (7)0.0074 (7)0.0023 (7)
C130.0433 (8)0.0466 (9)0.0394 (8)0.0025 (6)0.0052 (6)0.0014 (6)
C80.0478 (9)0.0453 (9)0.0492 (9)0.0004 (7)0.0063 (7)0.0016 (7)
C90.0438 (8)0.0543 (10)0.0447 (8)0.0026 (7)0.0080 (7)0.0093 (7)
C100.0492 (9)0.0550 (10)0.0410 (8)0.0096 (7)0.0066 (7)0.0013 (7)
C110.0504 (9)0.0450 (9)0.0428 (8)0.0049 (7)0.0029 (7)0.0015 (7)
C120.0449 (8)0.0460 (9)0.0421 (8)0.0017 (6)0.0051 (6)0.0033 (6)
N20.0615 (9)0.0644 (10)0.0618 (10)0.0008 (7)0.0187 (8)0.0125 (8)
N30.0814 (11)0.0483 (9)0.0562 (9)0.0052 (8)0.0109 (8)0.0046 (7)
O10.0815 (9)0.0487 (7)0.0536 (7)0.0009 (6)0.0275 (6)0.0007 (5)
O20.0913 (10)0.0442 (7)0.0695 (9)0.0015 (6)0.0322 (8)0.0038 (6)
O30.1151 (15)0.0633 (10)0.1138 (14)0.0146 (9)0.0584 (12)0.0081 (9)
O40.1104 (13)0.0895 (12)0.0709 (10)0.0059 (10)0.0502 (9)0.0063 (9)
O50.1370 (17)0.0657 (10)0.0988 (13)0.0121 (10)0.0539 (12)0.0237 (9)
O60.1100 (14)0.0509 (8)0.1118 (14)0.0155 (8)0.0356 (11)0.0089 (8)
Geometric parameters (Å, º) top
N1—C11.338 (3)C13—C81.395 (2)
N1—C51.343 (2)C8—C91.388 (3)
C1—C21.375 (3)C9—C101.381 (3)
C2—C31.393 (3)C9—N21.477 (2)
C3—C41.393 (3)C10—C111.385 (3)
C3—C61.506 (3)C11—C121.387 (3)
C4—C51.380 (3)C11—N31.477 (3)
C6—C71.502 (3)N2—O31.218 (3)
C14—O21.231 (2)N2—O41.222 (2)
C14—O11.278 (2)N3—O51.218 (2)
C14—C131.517 (2)N3—O61.221 (3)
C13—C121.391 (3)
C1—N1—C5119.49 (16)C9—C8—C13118.78 (17)
N1—C1—C2121.84 (17)C10—C9—C8123.00 (16)
C1—C2—C3119.89 (18)C10—C9—N2118.56 (16)
C4—C3—C2117.41 (16)C8—C9—N2118.44 (17)
C4—C3—C6121.83 (16)C9—C10—C11116.42 (16)
C2—C3—C6120.73 (17)C10—C11—C12123.13 (17)
C5—C4—C3119.96 (16)C10—C11—N3118.07 (16)
N1—C5—C4121.39 (18)C12—C11—N3118.79 (15)
C7—C6—C3111.46 (19)C11—C12—C13118.66 (15)
O2—C14—O1125.98 (16)O3—N2—O4123.99 (18)
O2—C14—C13119.15 (15)O3—N2—C9118.42 (17)
O1—C14—C13114.86 (16)O4—N2—C9117.58 (18)
C12—C13—C8120.01 (16)O5—N3—O6123.58 (19)
C12—C13—C14120.83 (15)O5—N3—C11118.37 (18)
C8—C13—C14119.10 (16)O6—N3—C11118.06 (16)
(CO-1-LT) top
Crystal data top
C7H5NO4·C7H9NZ = 2
Mr = 274.27F(000) = 288
Triclinic, P1Dx = 1.396 Mg m3
a = 6.631 (5) ÅMo Kα radiation, λ = 0.71073 Å
b = 7.032 (6) ÅCell parameters from 2645 reflections
c = 14.216 (12) Åθ = 2.9–33.4°
α = 87.967 (17)°µ = 0.10 mm1
β = 88.58 (3)°T = 110 K
γ = 80.207 (18)°Block, colorless
V = 652.6 (9) Å30.21 × 0.18 × 0.14 mm
Data collection top
Rigaku
diffractometer
2555 independent reflections
Radiation source: fine-focus sealed tube2366 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.071
profile data from ω–scansθmax = 26.0°, θmin = 1.4°
Absorption correction: multi-scan
SADABS
h = 88
Tmin = 0.835, Tmax = 1.000k = 88
6144 measured reflectionsl = 1717
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.043Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.134H atoms treated by a mixture of independent and constrained refinement
S = 1.11 w = 1/[σ2(Fo2) + (0.0749P)2 + 0.0851P]
where P = (Fo2 + 2Fc2)/3
2555 reflections(Δ/σ)max < 0.001
237 parametersΔρmax = 0.33 e Å3
0 restraintsΔρmin = 0.33 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
C10.26950 (18)0.23170 (17)0.23632 (9)0.0198 (3)
C20.19022 (19)0.21745 (17)0.32802 (9)0.0203 (3)
C30.0210 (2)0.27531 (19)0.34036 (9)0.0235 (3)
C40.14047 (19)0.34181 (19)0.26370 (9)0.0252 (3)
C50.04746 (18)0.35406 (18)0.17500 (9)0.0218 (3)
C60.3292 (2)0.14700 (19)0.40875 (9)0.0248 (3)
C70.4014 (2)0.3124 (2)0.45763 (9)0.0284 (3)
C120.56470 (18)0.27960 (18)0.82746 (9)0.0197 (3)
C110.68389 (18)0.27143 (17)0.74498 (9)0.0203 (3)
C100.89479 (18)0.21779 (17)0.75283 (8)0.0187 (3)
C90.99063 (18)0.17221 (18)0.83820 (9)0.0208 (3)
C80.86858 (18)0.18269 (18)0.91965 (9)0.0202 (3)
C130.65621 (17)0.23511 (16)0.91416 (8)0.0174 (3)
C140.53258 (18)0.23554 (17)1.00490 (8)0.0192 (3)
N10.15482 (16)0.29868 (15)0.16176 (7)0.0205 (3)
N21.02244 (16)0.20765 (16)0.66561 (8)0.0237 (3)
O10.33936 (13)0.31896 (13)0.99750 (6)0.0231 (3)
O20.60992 (13)0.16336 (15)1.07743 (6)0.0276 (3)
O30.93613 (16)0.23586 (16)0.58977 (7)0.0346 (3)
O41.20966 (14)0.17185 (16)0.67351 (7)0.0362 (3)
H10.414 (2)0.194 (2)0.2198 (11)0.025 (4)*
H1A0.274 (4)0.315 (3)1.0660 (18)0.069 (7)*
H30.078 (2)0.271 (2)0.4033 (12)0.028 (4)*
H40.290 (3)0.382 (3)0.2710 (14)0.045 (5)*
H50.125 (2)0.400 (2)0.1210 (11)0.019 (3)*
H6A0.257 (3)0.074 (2)0.4564 (13)0.037 (4)*
H6B0.446 (3)0.058 (3)0.3831 (12)0.035 (4)*
H7A0.489 (3)0.265 (3)0.5084 (14)0.044 (5)*
H7B0.286 (3)0.401 (3)0.4846 (13)0.036 (4)*
H7C0.475 (3)0.386 (3)0.4126 (13)0.043 (5)*
H120.416 (3)0.318 (2)0.8213 (12)0.033 (4)*
H110.623 (3)0.304 (2)0.6842 (13)0.032 (4)*
H91.135 (3)0.131 (2)0.8413 (12)0.033 (4)*
H80.930 (2)0.155 (2)0.9806 (12)0.028 (4)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0187 (6)0.0203 (6)0.0201 (6)0.0028 (4)0.0007 (5)0.0003 (5)
C20.0231 (6)0.0177 (6)0.0200 (6)0.0032 (4)0.0002 (5)0.0009 (4)
C30.0232 (6)0.0248 (7)0.0215 (6)0.0019 (5)0.0056 (5)0.0006 (5)
C40.0187 (6)0.0286 (7)0.0273 (7)0.0018 (5)0.0028 (5)0.0010 (5)
C50.0202 (6)0.0241 (6)0.0210 (6)0.0034 (5)0.0024 (5)0.0012 (5)
C60.0260 (6)0.0245 (7)0.0217 (6)0.0009 (5)0.0014 (5)0.0034 (5)
C70.0294 (7)0.0326 (7)0.0231 (7)0.0057 (6)0.0061 (5)0.0051 (6)
C120.0152 (6)0.0215 (6)0.0214 (6)0.0008 (4)0.0004 (5)0.0015 (5)
C110.0206 (6)0.0218 (6)0.0178 (6)0.0021 (5)0.0023 (5)0.0025 (5)
C100.0186 (6)0.0185 (6)0.0189 (6)0.0035 (4)0.0034 (5)0.0003 (5)
C90.0145 (6)0.0217 (6)0.0253 (6)0.0015 (4)0.0001 (5)0.0022 (5)
C80.0186 (6)0.0226 (6)0.0191 (6)0.0026 (5)0.0033 (5)0.0031 (5)
C130.0159 (6)0.0163 (6)0.0195 (6)0.0014 (4)0.0004 (5)0.0022 (4)
C140.0177 (6)0.0208 (6)0.0190 (6)0.0035 (4)0.0018 (5)0.0021 (5)
N10.0191 (5)0.0216 (5)0.0208 (5)0.0040 (4)0.0017 (4)0.0000 (4)
N20.0227 (6)0.0250 (6)0.0231 (6)0.0038 (4)0.0046 (4)0.0002 (4)
O10.0155 (4)0.0317 (5)0.0197 (5)0.0016 (3)0.0010 (3)0.0035 (4)
O20.0204 (5)0.0417 (6)0.0186 (5)0.0007 (4)0.0008 (4)0.0079 (4)
O30.0335 (6)0.0509 (7)0.0186 (5)0.0053 (5)0.0029 (4)0.0014 (4)
O40.0192 (5)0.0544 (7)0.0330 (6)0.0020 (4)0.0077 (4)0.0001 (5)
Geometric parameters (Å, º) top
C1—N11.3440 (18)C11—C101.391 (2)
C1—C21.400 (2)C10—C91.386 (2)
C2—C31.399 (2)C10—N21.4807 (18)
C2—C61.5060 (19)C9—C81.393 (2)
C3—C41.384 (2)C8—C131.397 (2)
C4—C51.396 (2)C13—C141.5109 (19)
C5—N11.3420 (19)C14—O21.2184 (17)
C6—C71.526 (2)C14—O11.3202 (17)
C12—C131.389 (2)N2—O31.2273 (17)
C12—C111.3951 (19)N2—O41.2311 (17)
N1—C1—C2123.68 (12)C10—C9—C8117.90 (12)
C3—C2—C1116.77 (12)C9—C8—C13120.38 (12)
C3—C2—C6122.48 (12)C12—C13—C8120.33 (11)
C1—C2—C6120.74 (12)C12—C13—C14122.11 (12)
C4—C3—C2119.88 (12)C8—C13—C14117.55 (12)
C3—C4—C5119.35 (13)O2—C14—O1124.54 (11)
N1—C5—C4121.60 (12)O2—C14—C13121.12 (12)
C2—C6—C7112.23 (12)O1—C14—C13114.33 (11)
C13—C12—C11120.33 (12)C5—N1—C1118.70 (11)
C10—C11—C12117.91 (12)O3—N2—O4123.75 (11)
C9—C10—C11123.15 (11)O3—N2—C10118.35 (12)
C9—C10—N2118.56 (12)O4—N2—C10117.90 (12)
C11—C10—N2118.29 (12)
(CO-1-RT) top
Crystal data top
C7H5NO4·C7H9NZ = 2
Mr = 274.27F(000) = 288
Triclinic, P1Dx = 1.345 Mg m3
a = 6.7302 (16) ÅMo Kα radiation, λ = 0.71073 Å
b = 7.1859 (17) ÅCell parameters from 4398 reflections
c = 14.298 (3) Åθ = 3.1–27.6°
α = 88.158 (6)°µ = 0.10 mm1
β = 88.340 (6)°T = 298 K
γ = 78.636 (5)°Block, colorless
V = 677.4 (3) Å30.21 × 0.18 × 0.14 mm
Data collection top
Rigaku
diffractometer
2634 independent reflections
Radiation source: fine-focus sealed tube1543 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.040
profile data from ω–scansθmax = 26.0°, θmin = 3.1°
Absorption correction: multi-scan
SADABS
h = 88
Tmin = 0.758, Tmax = 1.000k = 88
5680 measured reflectionsl = 1717
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.065Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.189H atoms treated by a mixture of independent and constrained refinement
S = 1.04 w = 1/[σ2(Fo2) + (0.1009P)2]
where P = (Fo2 + 2Fc2)/3
2634 reflections(Δ/σ)max < 0.001
225 parametersΔρmax = 0.20 e Å3
0 restraintsΔρmin = 0.21 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
C10.2264 (4)0.7625 (4)0.26211 (19)0.0535 (7)
C20.3039 (4)0.7736 (4)0.17196 (18)0.0535 (7)
C30.5118 (4)0.7161 (4)0.1609 (2)0.0609 (8)
C40.6294 (5)0.6531 (4)0.2368 (2)0.0673 (8)
C50.5378 (4)0.6447 (4)0.3235 (2)0.0596 (7)
C60.1675 (6)0.8436 (5)0.0915 (2)0.0688 (9)
C70.1000 (5)0.6857 (5)0.0433 (2)0.0905 (11)
H7A0.01350.73720.00730.136*
H7B0.02680.61890.08720.136*
H7C0.21630.59970.01920.136*
C80.6338 (4)0.8179 (4)0.58116 (19)0.0552 (7)
C90.5153 (4)0.8304 (4)0.66133 (19)0.0557 (7)
C100.6113 (4)0.7895 (3)0.74529 (17)0.0501 (6)
C110.8184 (4)0.7388 (4)0.75120 (18)0.0524 (7)
C120.9337 (4)0.7283 (4)0.67035 (18)0.0517 (7)
C130.8427 (3)0.7682 (3)0.58431 (16)0.0441 (6)
C140.9641 (4)0.7627 (3)0.49399 (18)0.0508 (7)
N10.3398 (3)0.6987 (3)0.33668 (14)0.0532 (6)
N20.4855 (4)0.8009 (3)0.83174 (18)0.0630 (7)
O11.1568 (3)0.6901 (3)0.50124 (13)0.0629 (6)
O20.8841 (3)0.8237 (3)0.42161 (13)0.0797 (7)
O30.5720 (4)0.7746 (4)0.90595 (16)0.0925 (8)
O40.3028 (3)0.8370 (4)0.82532 (16)0.0966 (8)
H10.091 (4)0.794 (3)0.2804 (18)0.059 (8)*
H1A1.222 (6)0.689 (5)0.430 (3)0.118 (12)*
H30.561 (4)0.722 (4)0.100 (2)0.061 (8)*
H40.767 (5)0.618 (4)0.227 (2)0.093 (11)*
H50.614 (4)0.595 (4)0.374 (2)0.070 (9)*
H6A0.238 (5)0.916 (4)0.050 (2)0.083 (10)*
H6B0.043 (6)0.925 (5)0.114 (3)0.109 (12)*
H80.569 (5)0.852 (4)0.523 (2)0.083 (9)*
H90.384 (4)0.863 (4)0.6554 (19)0.065 (8)*
H110.888 (5)0.710 (4)0.808 (2)0.082 (9)*
H121.072 (5)0.709 (4)0.673 (2)0.077 (9)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0511 (16)0.0564 (16)0.0529 (16)0.0109 (13)0.0054 (13)0.0058 (13)
C20.0622 (16)0.0499 (15)0.0478 (15)0.0099 (13)0.0033 (12)0.0018 (12)
C30.0642 (18)0.0679 (19)0.0476 (17)0.0068 (14)0.0097 (14)0.0025 (14)
C40.0534 (18)0.077 (2)0.068 (2)0.0051 (15)0.0096 (15)0.0019 (16)
C50.0553 (17)0.0681 (19)0.0538 (17)0.0080 (14)0.0032 (14)0.0022 (14)
C60.075 (2)0.068 (2)0.0597 (19)0.0061 (18)0.0033 (16)0.0050 (16)
C70.103 (3)0.100 (3)0.074 (2)0.033 (2)0.0269 (19)0.0100 (19)
C80.0509 (16)0.0636 (17)0.0489 (16)0.0066 (13)0.0042 (12)0.0040 (13)
C90.0423 (15)0.0640 (18)0.0595 (17)0.0084 (13)0.0006 (13)0.0028 (14)
C100.0498 (15)0.0468 (14)0.0529 (15)0.0086 (12)0.0091 (12)0.0049 (12)
C110.0535 (16)0.0615 (16)0.0410 (14)0.0079 (13)0.0021 (12)0.0024 (12)
C120.0417 (14)0.0589 (16)0.0519 (15)0.0037 (12)0.0012 (12)0.0004 (12)
C130.0440 (13)0.0411 (13)0.0465 (14)0.0065 (10)0.0006 (10)0.0011 (10)
C140.0553 (16)0.0504 (15)0.0464 (15)0.0103 (13)0.0009 (12)0.0001 (12)
N10.0591 (14)0.0558 (13)0.0455 (12)0.0134 (11)0.0052 (10)0.0055 (10)
N20.0632 (16)0.0665 (16)0.0579 (15)0.0116 (12)0.0168 (12)0.0048 (12)
O10.0472 (11)0.0851 (14)0.0505 (11)0.0005 (9)0.0053 (8)0.0002 (10)
O20.0596 (13)0.1250 (19)0.0480 (12)0.0049 (12)0.0011 (10)0.0155 (12)
O30.0951 (17)0.132 (2)0.0505 (13)0.0240 (15)0.0121 (12)0.0042 (13)
O40.0637 (15)0.133 (2)0.0866 (17)0.0075 (14)0.0265 (12)0.0055 (14)
Geometric parameters (Å, º) top
C1—N11.344 (3)C9—C101.376 (4)
C1—C21.382 (4)C10—C111.374 (3)
C2—C31.385 (4)C10—N21.473 (3)
C2—C61.504 (4)C11—C121.369 (4)
C3—C41.373 (4)C12—C131.386 (3)
C4—C51.373 (4)C13—C141.505 (3)
C5—N11.322 (3)C14—O21.209 (3)
C6—C71.496 (4)C14—O11.305 (3)
C8—C91.372 (4)N2—O41.211 (3)
C8—C131.383 (3)N2—O31.217 (3)
N1—C1—C2124.0 (3)C12—C11—C10118.7 (2)
C1—C2—C3116.1 (2)C11—C12—C13120.5 (2)
C1—C2—C6121.1 (3)C8—C13—C12119.1 (2)
C3—C2—C6122.8 (3)C8—C13—C14118.7 (2)
C4—C3—C2120.4 (3)C12—C13—C14122.2 (2)
C3—C4—C5119.2 (3)O2—C14—O1124.2 (2)
N1—C5—C4122.1 (3)O2—C14—C13120.8 (2)
C7—C6—C2112.5 (3)O1—C14—C13114.9 (2)
C9—C8—C13121.4 (3)C5—N1—C1118.3 (2)
C8—C9—C10117.7 (3)O4—N2—O3123.7 (2)
C11—C10—C9122.6 (2)O4—N2—C10118.6 (2)
C11—C10—N2119.3 (2)O3—N2—C10117.7 (2)
C9—C10—N2118.2 (2)
(CNT-1-LT) top
Crystal data top
C6Cl5O·C6H8NF(000) = 360
Mr = 359.44Dx = 1.698 Mg m3
Triclinic, P1Melting point: 75-79 K
a = 7.316 (6) ÅMo Kα radiation, λ = 0.71073 Å
b = 8.942 (8) ÅCell parameters from 3305 reflections
c = 11.763 (9) Åθ = 2.5–33.6°
α = 70.15 (4)°µ = 1.02 mm1
β = 84.67 (4)°T = 110 K
γ = 76.24 (4)°Needle, colorless
V = 703.0 (10) Å30.25 × 0.16 × 0.14 mm
Z = 2
Data collection top
Rigaku
diffractometer
2741 independent reflections
Radiation source: fine-focus sealed tube2421 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.054
profile data from ω–scansθmax = 26.0°, θmin = 1.8°
Absorption correction: multi-scan
SADABS
h = 99
Tmin = 0.707, Tmax = 1.000k = 1111
6521 measured reflectionsl = 1414
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.040Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.151H atoms treated by a mixture of independent and constrained refinement
S = 1.30 w = 1/[σ2(Fo2) + (0.0743P)2 + 0.0744P]
where P = (Fo2 + 2Fc2)/3
2741 reflections(Δ/σ)max < 0.001
185 parametersΔρmax = 0.58 e Å3
0 restraintsΔρmin = 0.61 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
N10.7730 (4)0.2822 (3)0.0500 (2)0.0199 (6)
Cl11.12019 (11)0.05020 (10)0.16138 (7)0.0219 (2)
Cl51.08069 (11)0.42010 (9)0.35827 (7)0.0222 (2)
Cl41.24737 (11)0.15953 (10)0.59805 (7)0.0216 (2)
Cl21.29877 (12)0.31341 (10)0.39982 (7)0.0255 (2)
Cl31.35552 (11)0.21137 (10)0.62035 (7)0.0235 (2)
C21.1595 (4)0.0078 (4)0.2823 (3)0.0178 (6)
C41.2640 (4)0.0649 (4)0.4871 (3)0.0171 (6)
O11.0406 (3)0.2888 (3)0.16786 (19)0.0210 (5)
C11.1090 (4)0.1753 (4)0.2683 (3)0.0161 (6)
C51.2148 (4)0.1005 (4)0.4770 (3)0.0180 (6)
C100.5843 (4)0.4188 (4)0.1243 (3)0.0204 (7)
C31.2367 (4)0.1106 (4)0.3886 (3)0.0183 (6)
C80.4991 (4)0.1942 (4)0.0311 (3)0.0227 (7)
H80.41880.12330.06380.027*
C61.1404 (4)0.2168 (4)0.3704 (3)0.0173 (6)
C90.4602 (4)0.3145 (4)0.0812 (3)0.0218 (7)
C110.7374 (4)0.4009 (4)0.0570 (3)0.0188 (6)
C120.2926 (5)0.3323 (5)0.1528 (4)0.0341 (9)
H12A0.22150.25300.10800.051*
H12B0.33400.31550.22830.051*
H12C0.21480.43980.16800.051*
C70.6553 (5)0.1798 (4)0.0937 (3)0.0222 (7)
H70.68040.09760.16780.027*
H110.817 (4)0.464 (4)0.083 (3)0.012 (8)*
H100.565 (5)0.494 (5)0.197 (3)0.024 (9)*
H10.897 (8)0.291 (7)0.101 (5)0.083 (18)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0238 (14)0.0206 (14)0.0152 (13)0.0045 (11)0.0029 (11)0.0055 (11)
Cl10.0256 (4)0.0247 (4)0.0197 (4)0.0069 (3)0.0001 (3)0.0119 (3)
Cl50.0299 (4)0.0170 (4)0.0216 (4)0.0062 (3)0.0033 (3)0.0071 (3)
Cl40.0252 (4)0.0274 (4)0.0156 (4)0.0084 (3)0.0016 (3)0.0092 (3)
Cl20.0315 (5)0.0172 (4)0.0284 (5)0.0046 (3)0.0009 (3)0.0085 (3)
Cl30.0246 (4)0.0240 (4)0.0176 (4)0.0043 (3)0.0033 (3)0.0011 (3)
C20.0139 (14)0.0241 (16)0.0195 (15)0.0062 (12)0.0034 (12)0.0120 (13)
C40.0156 (14)0.0164 (15)0.0155 (14)0.0040 (12)0.0001 (12)0.0004 (12)
O10.0240 (11)0.0210 (11)0.0164 (11)0.0070 (9)0.0047 (9)0.0017 (9)
C10.0139 (14)0.0204 (16)0.0158 (15)0.0076 (12)0.0005 (11)0.0059 (12)
C50.0157 (15)0.0264 (17)0.0149 (14)0.0088 (13)0.0019 (12)0.0085 (13)
C100.0245 (16)0.0189 (16)0.0143 (15)0.0001 (13)0.0016 (13)0.0039 (13)
C30.0145 (14)0.0183 (15)0.0227 (16)0.0053 (12)0.0030 (12)0.0070 (13)
C80.0203 (15)0.0241 (17)0.0275 (17)0.0100 (13)0.0063 (13)0.0114 (14)
C60.0166 (15)0.0185 (15)0.0196 (15)0.0081 (12)0.0022 (12)0.0077 (13)
C90.0205 (15)0.0243 (17)0.0248 (17)0.0010 (13)0.0019 (13)0.0156 (14)
C110.0181 (15)0.0186 (15)0.0214 (16)0.0052 (13)0.0020 (12)0.0085 (13)
C120.0227 (17)0.047 (2)0.039 (2)0.0065 (16)0.0080 (16)0.0212 (18)
C70.0314 (17)0.0183 (16)0.0152 (15)0.0041 (13)0.0009 (13)0.0048 (13)
Geometric parameters (Å, º) top
N1—C111.342 (4)C4—C51.402 (5)
N1—C71.348 (4)O1—C11.315 (4)
Cl1—C21.739 (3)C1—C61.425 (4)
Cl5—C61.724 (3)C5—C61.386 (5)
Cl4—C51.731 (3)C10—C111.378 (5)
Cl2—C31.723 (4)C10—C91.396 (5)
Cl3—C41.733 (3)C8—C71.374 (5)
C2—C31.396 (5)C8—C91.393 (5)
C2—C11.410 (5)C9—C121.499 (5)
C4—C31.398 (4)
C11—N1—C7119.4 (3)C11—C10—C9120.4 (3)
C3—C2—C1122.7 (3)C2—C3—C4120.0 (3)
C3—C2—Cl1119.8 (3)C2—C3—Cl2120.6 (2)
C1—C2—Cl1117.6 (2)C4—C3—Cl2119.4 (2)
C3—C4—C5119.1 (3)C7—C8—C9120.4 (3)
C3—C4—Cl3120.3 (2)C5—C6—C1122.4 (3)
C5—C4—Cl3120.6 (2)C5—C6—Cl5120.1 (2)
O1—C1—C2123.5 (3)C1—C6—Cl5117.5 (2)
O1—C1—C6120.9 (3)C8—C9—C10117.0 (3)
C2—C1—C6115.6 (3)C8—C9—C12121.9 (3)
C6—C5—C4120.3 (3)C10—C9—C12121.2 (3)
C6—C5—Cl4119.9 (3)N1—C11—C10121.4 (3)
C4—C5—Cl4119.8 (2)N1—C7—C8121.5 (3)
(CNT-1-RT) top
Crystal data top
C6Cl5O·C6H8NF(000) = 360
Mr = 359.44Dx = 1.653 Mg m3
Triclinic, P1Melting point: 75-79 K
a = 7.389 (8) ÅMo Kα radiation, λ = 0.71073 Å
b = 8.922 (8) ÅCell parameters from 1777 reflections
c = 12.014 (12) Åθ = 2.5–32.9°
α = 69.82 (3)°µ = 0.99 mm1
β = 85.61 (4)°T = 298 K
γ = 76.26 (4)°Needle, colorless
V = 722.1 (12) Å30.25 × 0.16 × 0.14 mm
Z = 2
Data collection top
Rigaku
diffractometer
2815 independent reflections
Radiation source: fine-focus sealed tube2152 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.063
profile data from ω–scansθmax = 26.0°, θmin = 1.8°
Absorption correction: multi-scan
SADABS
h = 99
Tmin = 0.723, Tmax = 1.000k = 1111
6793 measured reflectionsl = 1414
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.051Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.194H atoms treated by a mixture of independent and constrained refinement
S = 1.16 w = 1/[σ2(Fo2) + (0.1071P)2]
where P = (Fo2 + 2Fc2)/3
2815 reflections(Δ/σ)max = 0.039
192 parametersΔρmax = 0.52 e Å3
0 restraintsΔρmin = 0.60 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
H100.930 (6)0.010 (5)0.684 (4)0.054 (13)*
H70.815 (5)0.398 (5)0.344 (4)0.046 (11)*
H110.684 (5)0.047 (5)0.574 (4)0.047 (12)*
H81.068 (7)0.389 (6)0.436 (5)0.080 (15)*
H1N0.643 (13)0.179 (11)0.411 (8)0.19 (4)*
Cl10.42078 (16)0.07870 (12)0.14420 (10)0.0545 (3)
Cl20.25422 (14)0.33695 (14)0.09403 (9)0.0533 (3)
Cl50.37352 (15)0.55455 (14)0.32908 (9)0.0549 (3)
Cl40.19713 (17)0.81558 (13)0.09201 (12)0.0637 (4)
Cl30.14316 (15)0.70894 (14)0.12139 (10)0.0588 (4)
C10.3905 (5)0.3280 (5)0.2269 (3)0.0388 (8)
C30.2856 (5)0.3987 (5)0.0228 (3)0.0390 (8)
C60.3381 (5)0.4953 (5)0.2113 (3)0.0395 (8)
O10.4596 (4)0.2132 (3)0.3269 (2)0.0498 (7)
C40.2345 (5)0.5642 (5)0.0099 (3)0.0399 (8)
C50.2613 (5)0.6128 (5)0.1062 (3)0.0412 (9)
C20.3611 (5)0.2826 (4)0.1290 (3)0.0378 (8)
N10.7232 (5)0.2236 (4)0.4472 (3)0.0483 (8)
C100.9108 (6)0.0877 (5)0.6198 (4)0.0483 (10)
C91.0322 (5)0.1896 (5)0.5784 (4)0.0493 (10)
C80.9945 (6)0.3087 (6)0.4680 (4)0.0543 (11)
C70.8402 (6)0.3221 (6)0.4066 (4)0.0535 (11)
C110.7595 (6)0.1061 (5)0.5523 (4)0.0480 (10)
C121.1992 (7)0.1723 (8)0.6500 (6)0.0852 (17)
H12A1.26710.25370.60670.128*
H12B1.27840.06510.66470.128*
H12C1.15880.18700.72410.128*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
Cl10.0698 (7)0.0401 (6)0.0601 (7)0.0160 (5)0.0071 (5)0.0210 (5)
Cl20.0581 (6)0.0679 (7)0.0440 (6)0.0219 (5)0.0019 (4)0.0259 (5)
Cl50.0637 (7)0.0598 (7)0.0555 (6)0.0187 (5)0.0035 (5)0.0346 (5)
Cl40.0694 (7)0.0400 (6)0.0838 (8)0.0108 (5)0.0024 (6)0.0238 (5)
Cl30.0552 (6)0.0587 (7)0.0503 (6)0.0127 (5)0.0078 (5)0.0014 (5)
C10.0359 (17)0.044 (2)0.043 (2)0.0169 (16)0.0023 (15)0.0178 (17)
C30.0328 (17)0.050 (2)0.0411 (19)0.0198 (16)0.0054 (15)0.0179 (17)
C60.0362 (17)0.047 (2)0.044 (2)0.0163 (16)0.0044 (16)0.0232 (17)
O10.0622 (16)0.0434 (15)0.0445 (15)0.0212 (13)0.0075 (13)0.0080 (12)
C40.0325 (17)0.043 (2)0.041 (2)0.0120 (15)0.0008 (15)0.0084 (16)
C50.0351 (17)0.039 (2)0.053 (2)0.0139 (15)0.0072 (16)0.0177 (17)
C20.0366 (17)0.0376 (19)0.045 (2)0.0144 (15)0.0020 (15)0.0169 (16)
N10.0536 (19)0.050 (2)0.0451 (18)0.0168 (16)0.0050 (15)0.0170 (16)
C100.053 (2)0.044 (2)0.042 (2)0.0029 (19)0.0054 (19)0.0113 (18)
C90.0400 (19)0.056 (2)0.058 (2)0.0003 (18)0.0058 (18)0.032 (2)
C80.051 (2)0.058 (3)0.064 (3)0.025 (2)0.008 (2)0.026 (2)
C70.070 (3)0.050 (2)0.038 (2)0.020 (2)0.000 (2)0.0072 (19)
C110.050 (2)0.043 (2)0.049 (2)0.0110 (19)0.0005 (19)0.0131 (18)
C120.057 (3)0.102 (5)0.108 (4)0.011 (3)0.028 (3)0.050 (4)
Geometric parameters (Å, º) top
Cl1—C21.715 (4)C6—C51.389 (5)
Cl2—C31.724 (4)C4—C51.409 (5)
Cl5—C61.729 (4)N1—C71.326 (5)
Cl4—C51.709 (4)N1—C111.330 (5)
Cl3—C41.719 (4)C10—C91.373 (6)
C1—O11.323 (4)C10—C111.376 (6)
C1—C61.399 (5)C9—C81.382 (6)
C1—C21.415 (5)C9—C121.506 (6)
C3—C41.391 (6)C8—C71.365 (6)
C3—C21.391 (5)
O1—C1—C6124.0 (3)C6—C5—Cl4121.0 (3)
O1—C1—C2119.5 (3)C4—C5—Cl4119.4 (3)
C6—C1—C2116.4 (3)C3—C2—C1121.6 (4)
C4—C3—C2120.7 (3)C3—C2—Cl1120.1 (3)
C4—C3—Cl2119.5 (3)C1—C2—Cl1118.2 (3)
C2—C3—Cl2119.8 (3)C7—N1—C11118.1 (4)
C5—C6—C1122.7 (3)C9—C10—C11120.3 (4)
C5—C6—Cl5119.8 (3)C10—C9—C8117.1 (4)
C1—C6—Cl5117.5 (3)C10—C9—C12121.5 (5)
C3—C4—C5118.9 (3)C8—C9—C12121.4 (5)
C3—C4—Cl3121.1 (3)C7—C8—C9119.7 (4)
C5—C4—Cl3120.0 (3)N1—C7—C8122.9 (4)
C6—C5—C4119.6 (4)N1—C11—C10121.9 (4)
(CNT1-LT) top
Crystal data top
C6HCl5O·C6H7NF(000) = 360
Mr = 359.44Dx = 1.695 Mg m3
Triclinic, P1Melting point: 75-79 K
a = 7.3382 (8) ÅMo Kα radiation, λ = 0.71073 Å
b = 8.8986 (9) ÅCell parameters from 5272 reflections
c = 11.8245 (11) Åθ = 3.2–27.5°
α = 69.945 (5)°µ = 1.02 mm1
β = 85.055 (5)°T = 110 K
γ = 76.133 (5)°Needle, colorless
V = 704.17 (12) Å30.27 × 0.15 × 0.13 mm
Z = 2
Data collection top
Bruker P4
diffractometer
2756 independent reflections
Radiation source: fine-focus sealed tube2106 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.052
ω scansθmax = 26.0°, θmin = 3.4°
Absorption correction: empirical
SADABS
h = 99
Tmin = 0.833, Tmax = 0.876k = 1010
11629 measured reflectionsl = 1414
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.040Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.103H atoms treated by a mixture of independent and constrained refinement
S = 1.10 w = 1/[σ2(Fo2) + (0.0398P)2 + 0.5163P]
where P = (Fo2 + 2Fc2)/3
2756 reflections(Δ/σ)max < 0.001
193 parametersΔρmax = 0.37 e Å3
0 restraintsΔρmin = 0.28 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
C10.3903 (4)0.8268 (4)0.2293 (2)0.0234 (7)
C20.3609 (4)0.7824 (4)0.1299 (3)0.0246 (7)
C30.2860 (4)0.8999 (4)0.0232 (3)0.0243 (7)
C40.2353 (4)1.0648 (4)0.0118 (3)0.0257 (7)
C50.2618 (4)1.1117 (4)0.1086 (3)0.0245 (7)
C60.3396 (4)0.9937 (4)0.2146 (3)0.0241 (7)
C70.8416 (5)0.8215 (4)0.4054 (3)0.0334 (8)
C80.9971 (5)0.8081 (4)0.4679 (3)0.0338 (8)
C91.0356 (4)0.6888 (4)0.5791 (3)0.0311 (7)
C100.9136 (4)0.5841 (4)0.6220 (3)0.0298 (7)
C110.7611 (4)0.6017 (4)0.5552 (3)0.0279 (7)
C121.2035 (5)0.6704 (5)0.6512 (4)0.0537 (11)
H12A1.26490.75880.61160.081*
H12B1.28920.56760.65800.081*
H12C1.16350.67310.73010.081*
N10.7245 (4)0.7202 (3)0.4481 (2)0.0292 (6)
O10.4590 (3)0.7125 (2)0.32955 (18)0.0306 (5)
Cl10.42125 (12)0.57844 (9)0.14310 (7)0.0342 (2)
Cl20.25397 (11)0.83833 (10)0.09585 (7)0.0331 (2)
Cl30.14334 (11)1.21033 (10)0.12073 (7)0.0357 (2)
Cl40.19843 (12)1.31485 (10)0.09655 (8)0.0394 (2)
Cl50.37690 (11)1.05247 (10)0.33437 (7)0.0338 (2)
H10.581 (7)0.720 (5)0.378 (4)0.090 (15)*
H70.807 (4)0.904 (4)0.332 (3)0.019 (7)*
H81.078 (5)0.874 (4)0.434 (3)0.035 (9)*
H100.929 (4)0.499 (4)0.695 (3)0.032 (9)*
H110.677 (4)0.528 (4)0.579 (3)0.028 (8)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0207 (15)0.0276 (16)0.0253 (16)0.0111 (13)0.0003 (12)0.0092 (13)
C20.0215 (16)0.0248 (16)0.0307 (16)0.0110 (13)0.0030 (13)0.0102 (13)
C30.0199 (16)0.0339 (17)0.0246 (15)0.0139 (13)0.0020 (12)0.0119 (13)
C40.0201 (15)0.0280 (17)0.0257 (16)0.0071 (13)0.0031 (12)0.0046 (13)
C50.0223 (15)0.0233 (15)0.0313 (16)0.0093 (13)0.0035 (13)0.0113 (13)
C60.0220 (16)0.0298 (17)0.0265 (16)0.0114 (13)0.0035 (13)0.0138 (13)
C70.044 (2)0.0301 (18)0.0246 (17)0.0097 (16)0.0017 (15)0.0073 (14)
C80.0338 (19)0.036 (2)0.041 (2)0.0173 (16)0.0114 (16)0.0212 (16)
C90.0253 (17)0.0348 (18)0.0399 (19)0.0027 (14)0.0003 (14)0.0237 (15)
C100.0339 (19)0.0272 (17)0.0246 (16)0.0003 (14)0.0023 (14)0.0080 (14)
C110.0301 (18)0.0264 (17)0.0301 (17)0.0098 (14)0.0049 (14)0.0118 (13)
C120.035 (2)0.070 (3)0.065 (3)0.0093 (19)0.0152 (19)0.033 (2)
N10.0302 (15)0.0318 (15)0.0266 (14)0.0079 (12)0.0003 (11)0.0103 (11)
O10.0380 (13)0.0278 (12)0.0275 (11)0.0134 (10)0.0080 (10)0.0050 (9)
Cl10.0448 (5)0.0253 (4)0.0362 (4)0.0102 (4)0.0048 (4)0.0122 (3)
Cl20.0371 (5)0.0415 (5)0.0266 (4)0.0135 (4)0.0016 (3)0.0155 (3)
Cl30.0348 (5)0.0354 (5)0.0302 (4)0.0070 (4)0.0047 (3)0.0018 (3)
Cl40.0467 (5)0.0246 (4)0.0485 (5)0.0071 (4)0.0019 (4)0.0144 (4)
Cl50.0395 (5)0.0375 (5)0.0331 (4)0.0119 (4)0.0011 (3)0.0207 (3)
Geometric parameters (Å, º) top
C1—O11.313 (3)C5—Cl41.713 (3)
C1—C61.394 (4)C6—Cl51.731 (3)
C1—C21.409 (4)C7—N11.338 (4)
C2—C31.388 (4)C7—C81.372 (5)
C2—Cl11.717 (3)C8—C91.378 (5)
C3—C41.386 (4)C9—C101.387 (5)
C3—Cl21.727 (3)C9—C121.503 (4)
C4—C51.388 (4)C10—C111.373 (4)
C4—Cl31.720 (3)C11—N11.339 (4)
C5—C61.391 (4)
O1—C1—C6123.7 (3)C4—C5—Cl4119.7 (2)
O1—C1—C2119.8 (3)C6—C5—Cl4120.4 (2)
C6—C1—C2116.5 (3)C5—C6—C1122.5 (3)
C3—C2—C1121.3 (3)C5—C6—Cl5119.9 (2)
C3—C2—Cl1120.3 (2)C1—C6—Cl5117.7 (2)
C1—C2—Cl1118.4 (2)N1—C7—C8122.1 (3)
C4—C3—C2120.8 (3)C7—C8—C9120.1 (3)
C4—C3—Cl2119.9 (2)C8—C9—C10117.2 (3)
C2—C3—Cl2119.2 (2)C8—C9—C12121.9 (3)
C3—C4—C5119.1 (3)C10—C9—C12120.9 (3)
C3—C4—Cl3120.8 (2)C11—C10—C9120.4 (3)
C5—C4—Cl3120.2 (2)N1—C11—C10121.5 (3)
C4—C5—C6119.8 (3)C7—N1—C11118.8 (3)
(CNT1-RT) top
Crystal data top
C6HCl5O·C6H7NF(000) = 360
Mr = 359.44Dx = 1.653 Mg m3
Triclinic, P1Melting point: 75-79 K
a = 7.3857 (8) ÅMo Kα radiation, λ = 0.71073 Å
b = 8.9202 (10) ÅCell parameters from 2874 reflections
c = 12.0227 (12) Åθ = 3.3–24.8°
α = 69.770 (3)°µ = 0.99 mm1
β = 85.869 (3)°T = 298 K
γ = 76.324 (4)°Needle, colorless
V = 722.10 (13) Å30.27 × 0.15 × 0.13 mm
Z = 2
Data collection top
Bruker P4
diffractometer
2799 independent reflections
Radiation source: fine-focus sealed tube1751 reflections with I > 2σ(I)
Graphite monochromatorRint = 0.039
ω scansθmax = 26.0°, θmin = 3.3°
Absorption correction: empirical
SADABS
h = 99
Tmin = 0.836, Tmax = 0.879k = 1111
6870 measured reflectionsl = 1414
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.047Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.129H atoms treated by a mixture of independent and constrained refinement
S = 1.04 w = 1/[σ2(Fo2) + (0.0638P)2]
where P = (Fo2 + 2Fc2)/3
2799 reflections(Δ/σ)max = 0.001
193 parametersΔρmax = 0.28 e Å3
0 restraintsΔρmin = 0.21 e Å3
Special details top

Geometry. All s.u.'s (except the s.u. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell s.u.'s are taken into account individually in the estimation of s.u.'s in distances, angles and torsion angles; correlations between s.u.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell s.u.'s is used for estimating s.u.'s involving l.s. planes.

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 > 2σ(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) top
xyzUiso*/Ueq
C10.1105 (4)0.6719 (4)0.7737 (3)0.0408 (8)
C20.1617 (4)0.5046 (4)0.7895 (3)0.0404 (8)
C30.2384 (4)0.3884 (4)0.8946 (3)0.0433 (8)
C40.2641 (4)0.4355 (4)0.9899 (3)0.0426 (8)
C50.2141 (4)0.6015 (4)0.9773 (3)0.0406 (8)
C60.1394 (4)0.7166 (4)0.8713 (3)0.0392 (8)
C70.6615 (6)0.6777 (5)0.5939 (3)0.0561 (10)
C80.5069 (5)0.6915 (5)0.5312 (4)0.0572 (10)
C90.4682 (5)0.8100 (4)0.4224 (3)0.0519 (9)
C100.5902 (5)0.9115 (5)0.3811 (3)0.0506 (9)
C110.7408 (5)0.8926 (4)0.4485 (3)0.0506 (9)
C120.3014 (6)0.8296 (6)0.3485 (4)0.0919 (15)
H12A0.20920.78050.39890.138*
H12B0.33960.77670.29060.138*
H12C0.24950.94410.30890.138*
N10.7780 (4)0.7767 (3)0.5533 (2)0.0507 (7)
O10.0424 (4)0.7855 (3)0.6742 (2)0.0537 (6)
Cl10.12723 (13)0.44496 (12)0.67202 (8)0.0598 (3)
Cl20.30288 (14)0.18438 (11)0.90896 (9)0.0686 (3)
Cl30.35693 (13)0.29155 (12)1.12172 (8)0.0633 (3)
Cl40.24580 (12)0.66298 (12)1.09406 (7)0.0579 (3)
Cl50.07913 (13)0.92079 (10)0.85595 (8)0.0585 (3)
H10.059 (7)0.780 (6)0.639 (4)0.124 (19)*
H70.695 (4)0.597 (4)0.668 (3)0.057 (10)*
H80.433 (5)0.617 (4)0.568 (3)0.073 (12)*
H100.567 (4)0.994 (4)0.313 (3)0.045 (10)*
H110.824 (4)0.957 (4)0.424 (2)0.041 (9)*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
C10.0369 (18)0.046 (2)0.043 (2)0.0172 (15)0.0022 (16)0.0147 (18)
C20.0381 (17)0.0447 (19)0.049 (2)0.0168 (15)0.0065 (16)0.0248 (17)
C30.0348 (17)0.0373 (18)0.061 (2)0.0137 (14)0.0064 (16)0.0181 (17)
C40.0334 (17)0.046 (2)0.0466 (19)0.0130 (15)0.0030 (15)0.0113 (16)
C50.0337 (17)0.053 (2)0.0432 (19)0.0214 (16)0.0056 (15)0.0197 (17)
C60.0340 (17)0.0413 (18)0.050 (2)0.0173 (14)0.0080 (15)0.0201 (16)
C70.069 (3)0.052 (2)0.046 (2)0.017 (2)0.001 (2)0.013 (2)
C80.055 (2)0.057 (2)0.067 (3)0.025 (2)0.012 (2)0.025 (2)
C90.048 (2)0.053 (2)0.063 (2)0.0023 (18)0.0047 (19)0.034 (2)
C100.056 (2)0.046 (2)0.043 (2)0.0017 (19)0.0043 (19)0.0133 (19)
C110.051 (2)0.048 (2)0.057 (2)0.0171 (19)0.006 (2)0.0191 (19)
C120.063 (3)0.107 (4)0.115 (4)0.011 (2)0.030 (3)0.050 (3)
N10.0576 (19)0.0523 (18)0.0461 (17)0.0187 (15)0.0022 (15)0.0167 (16)
O10.0664 (17)0.0485 (15)0.0479 (15)0.0234 (13)0.0104 (13)0.0095 (12)
Cl10.0687 (6)0.0658 (6)0.0613 (6)0.0206 (5)0.0060 (5)0.0394 (5)
Cl20.0736 (7)0.0423 (5)0.0915 (8)0.0109 (5)0.0021 (6)0.0256 (5)
Cl30.0578 (6)0.0639 (6)0.0557 (6)0.0133 (5)0.0059 (5)0.0037 (5)
Cl40.0612 (6)0.0757 (7)0.0487 (5)0.0237 (5)0.0005 (4)0.0304 (5)
Cl50.0725 (6)0.0434 (5)0.0672 (6)0.0168 (4)0.0069 (5)0.0243 (4)
Geometric parameters (Å, º) top
C1—O11.312 (4)C5—Cl41.722 (3)
C1—C21.398 (4)C6—Cl51.716 (3)
C1—C61.407 (4)C7—N11.327 (4)
C2—C31.382 (4)C7—C81.371 (5)
C2—Cl11.726 (3)C8—C91.366 (5)
C3—C41.389 (4)C9—C101.374 (5)
C3—Cl21.719 (3)C9—C121.512 (5)
C4—C51.395 (4)C10—C111.367 (5)
C4—Cl31.722 (3)C11—N11.322 (4)
C5—C61.383 (4)
O1—C1—C2123.7 (3)C6—C5—Cl4120.0 (2)
O1—C1—C6119.8 (3)C4—C5—Cl4119.9 (2)
C2—C1—C6116.5 (3)C5—C6—C1121.9 (3)
C3—C2—C1122.2 (3)C5—C6—Cl5119.9 (2)
C3—C2—Cl1120.0 (2)C1—C6—Cl5118.1 (2)
C1—C2—Cl1117.7 (2)N1—C7—C8122.5 (4)
C2—C3—C4120.2 (3)C9—C8—C7120.2 (4)
C2—C3—Cl2120.6 (3)C8—C9—C10116.8 (3)
C4—C3—Cl2119.2 (3)C8—C9—C12122.5 (4)
C3—C4—C5119.0 (3)C10—C9—C12120.7 (4)
C3—C4—Cl3120.6 (3)C11—C10—C9120.2 (3)
C5—C4—Cl3120.4 (3)N1—C11—C10122.6 (4)
C6—C5—C4120.1 (3)C11—N1—C7117.8 (3)
 

Footnotes

These authors contributed equally to this work.

§Present address: Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland

Acknowledgements

LR and SJ thank the DST for a Young Scientist Fellowship. MB thanks the UGC for a Dr D. S. Kothari fellowship. GRD thanks the DST for a J. C. Bose Fellowship.

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IUCrJ
Volume 4| Part 4| July 2017| Pages 466-475
ISSN: 2052-2525