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Volume 70 
Part 1 
Pages 106-114  
February 2014  

Received 14 May 2013
Accepted 7 August 2013
Online 10 December 2013

Formation of isostructural solid solutions in 2,6-disubstituted N-phenylformamides and N-phenylthioamides

aSchool of Chemistry and Physics, Westville Campus, University of KwaZulu Natal, Private Bag X54001, Durban, KwaZulu Natal 4000, South Africa,bMolecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO WITS, Johannesburg, Gauteng 2050, South Africa, and cAnorganische und Analytische Chemie, Westfälische Wilhelms Universität Münster, D-48149 Münster, Germany
Correspondence e-mail: andreas.lemmerer@wits.ac.za, demetrius.levendis@wits.ac.za

In order to investigate possible isostructural solid solutions of disubstituted N-phenylformamides and thioamides, we have studied the re-crystallization of pairs of compounds selected from 2,6-difluoro-N-phenylformamide (I), 2,6-dichloro-N-phenylformamide (II), 2,6-dimethyl-N-phenylformamide (III), 2,6-dichloro-N-phenylthioamide (IV), 2,6-dimethyl-N-phenylthioamide (V), 2,6-diisopropyl-N-phenylformamide (VI) and 2,6-diisopropyl-N-phenylthioamide (VII). For single-component 2,6-disubstituted-N-phenylformamides only the trans form occurs in the pure crystal, while for thioamides the cis form occurs, with only one exception. By forming solid solutions of pairs of these molecules the resulting structures all adopt similar N-H...O/S chains in the crystals. Solid solutions (1), (2) and (3), resulting from the mixing of (I) and (II), (II) and (III), and (IV) and (V), respectively, are all isostructural with each other (space group Pbca). Only co-crystal (1) is isostructural to both starting materials, while (2) is isostructural to only one of the starting pair, (II). Solid solution (3), which adopts the same Pbca structure as (1) and (2), is different to the monoclinic structures of both the reactants. Solid solution (4) is monoclinic, with similar hydrogen-bonded chains, and isostructural to the two components, resulting from the composition from the mixing of (VI) and (VII). Isostructural indices were used to quantify crystal-packing similarities and differences. Occupancy factors of the reactants in each co-crystal differ widely.

1. Introduction

In recent years studies involving the amide group and its relevance to biological and chemical systems have been carried out by several researchers. Amides and particularly formamides and thioamides have been known to be of fundamental chemical (polymorphism and crystal engineering) and biological interest (protein folding) as some of the features of these compounds can be manipulated to obtain useful physical and chemical properties (Zeller et al., 2005[Zeller, M., Wilcox, R. J., Snyder, F. G. III, Seibel, H. A. II, Takas, N. J. & Hunter, A. D. (2005). J. Chem. Cryst, 35, 723-729.]; Tan et al., 2006[Tan, T., Han, J., Pang, M., Song, H., Ma, Y. & Meng, J. (2006). Cryst. Growth Des. 6, 1186-1193.]).

Structural mimicry and co-crystallization continues to gain significance for its application to the design of new supramolecular structures with desired functional properties (Trask et al., 2004[Trask, A. V., Motherwell, W. D. S. & Jones, W. (2004). Chem. Commun. pp. 890-891.]). This has been an effective method, notably in the field of pharmaceuticals, to alter physical properties like solubility (or bioavailability), stability and the melting point of the compounds (Remenar et al., 2003[Remenar, J. F., Morissette, S. L., Peterson, M. L., Moulton, B., MacPhee, J. M., Guzmán, H. R. & Almarsson, O. (2003). J. Am. Chem. Soc. 125, 8456-8457.]; Walsh et al., 2003[Walsh, R. D. B., Bradner, M. W., Fleischman, S., Morales, L. A., Moulton, B., Rodríguez-Hornedo, N. & Zaworotko, M. J. (2003). Chem. Commun. pp. 186-187.]; Oswald et al., 2002[Oswald, I. D. H., Allan, D. R., McGregor, P. A., Motherwell, W. D. S., Parsons, S. & Pulham, C. R. (2002). Acta Cryst. B58, 1057-1066.]), and finally in materials with optoelectronic properties, to alter their conductivity, charge transfer and magnetism in nonporous materials (Zeller et al., 2005[Zeller, M., Wilcox, R. J., Snyder, F. G. III, Seibel, H. A. II, Takas, N. J. & Hunter, A. D. (2005). J. Chem. Cryst, 35, 723-729.]).

An additional crystal engineering strategy to altering physiochemical properties is to prepare solid solutions (Hollingsworth, 2002[Hollingsworth, M. D. (2002). Science, 295, 2410-2413.]), which are defined as a non-stoichiometric multi-component complex, compared with co-crystals, which have a definite stoichiometric ratio (Lemmerer & Fernandes, 2012[Lemmerer, A. & Fernandes, M. A. (2012). New J. Chem. 36, 2242-2252.]; Aakeröy & Salmon, 2005[Aakeröy, C. B. & Salmon, D. J. (2005). CrystEngComm, 7, 439-448.]; Bond, 2007[Bond, A. D. (2007). CrystEngComm, 9, 833-834.]; Dunitz, 2003[Dunitz, J. D. (2003). CrystEngComm, 5, 506.]). Recently, work has been published that refers to both solid solutions and co-crystals contained in one crystalline entity (Chen et al., 2010[Chen, S., Xi, H., Henry, R. F., Marsden, I. & Zhang, G. G. Z. (2010). CrystEngComm, 12, 1485-1493.]; Bucar et al., 2012[Bucar, D.-K., Sen, A., Mariappan, S. V. S. & MacGillivray, L. R. (2012). Chem. Commun. 48, 1790-1792.]; Oliveira et al., 2008[Oliveira, M. A., Peterson, M. L. & Klein, D. (2008). Cryst. Growth Des. 8, 4487-4493.]), although for the purposes of this report we will restrict ourselves to describing our complexes as solid solutions. There are many reports on the synthesis of new materials using co-crystallization methods and in particular taking advantage of the hydrogen bonds in the starting materials to derive specific motifs and architectures and can influence the aggregation of different molecules in crystals, sometimes with predictable connectivity patterns (Etter, 1985[Etter, M. C. (1985). J. Chem. 25, 312-319.]; Etter et al., 1986[Etter, M. C., Urbanczyk-Lipkowska, Z., Jahn, D. A. & Frye, J. S. (1986). J. Am. Chem. Soc. 108, 5871-5876.]; Panunto et al., 1987[Panunto, T. W., Urbanczyk-Lipkowska, Z., Johnson, R. & Etter, M. C. (1987). J. Am. Chem. Soc. 109, 7786-7797.]; Etter & Panunto, 1988[Etter, M. C. & Panunto, T. W. (1988). J. Am. Chem. Soc. 110, 5896-5897.]; Etter & Baures, 1988[Etter, M. C. & Baures, P. W. (1988). J. Am. Chem. Soc. 110, 639-640.]; Aakeröy et al., 2005[Aakeröy, C. B., Desper, J. & Levin, B. (2005). CrystEngComm, 7, 102-107.], 2006[Aakeröy, C. B., Desper, J. & Scott, B. M. T. (2006). Chem. Commun. pp. 1445-1447.]). In this work, which is focused on solid solutions, we aim to use the predictability of intermolecular interactions to facilitate the process of their formation. Another factor is the influence of other substituents on compounds. The most common perhaps is the chloro-methyl exchange, which is due primarily to the similar sizes of the Cl atom and the methyl group (Nath & Nangia, 2012[Nath, N. K. & Nangia, A. (2012). Cryst. Growth Des. 12, 5411-5425.]), where there is possible interchangeability of the two in the final product (Gnanaguru et al., 1985[Gnanaguru, K., Ramasubbu, N., Venkatesan, K. & Ramamurthy, V. (1985). J. Org. Chem. 50, 2337-2346.]; Theocharis et al., 1984[Theocharis, C. R., Desiraju, G. R. & Jones, W. (1984). J. Am. Chem. Soc. 106, 3606-3609.]; Edwards et al., 2001[Edwards, M. R., Jones, W., Motherwell, W. D. S. & Shields, G. P. (2001). Mol. Cryst. Liq. Cryst. 356, 337-353.]; Jones et al., 1981[Jones, W., Ramdas, S., Theocharis, C. R., Thomas, J. M. & Thomas, N. W. (1981). J. Phys. Chem. 85, 2594-2597.], 1983[Jones, W., Theocharis, C. R., Thomas, J. M. & Desiraju, G. R. (1983). Chem. Commun. pp. 1443-1444.]). In one study it was found that co-crystals of chloro and methyl ortho-benzoic acids were not isostructural because of differences in the packing of the ribbons (Polito et al., 2008[Polito, M., D'Oria, E., Maini, L., Karamertzanis, P. G., Grepioni, F., Braga, D. & Price, S. L. (2008). CrystEngComm, 10, 1848-1854.]).

A phenomenon that arises from crystallization of chemically similar molecules, and one that is also known to be common for organic compounds and salts, is isostructurality (Galcera et al., 2013[Galcera, J., Friscic, T., Molins, E. & Jones, W. (2013). CrystEngComm, 15, 1332-1338.]; Wood et al., 2012[Wood, P. A., Oliveira, M. A., Zink, A. & Hickey, M. B. (2012). CrystEngComm, 14, 2413-2421.]; Dabros et al., 2007[Dabros, M., Emery, P. R. & Thalladi, V. R. (2007). Angew. Chem. Int. Ed. 119, 4210-4213.]; James et al., 2012[James, S. L. et al. (2012). Chem. Soc. Rev. 41, 413-447.]). Factors such as the balance between `close-packing effects' and more directional and anisotropic intermolecular interactions during crystallization (Aakeröy et al., 2010[Aakeröy, C. B., Champness, N. R. & Janiak, C. (2010). CrystEngComm, 12, 22-43.]) play an important role in the engineering of isostructural crystals. Experiments involving the crystallization of two different compounds mixed in solution, or ground together without solvent, often result in solid solutions, some containing three or more organic molecules (Dabros et al., 2007[Dabros, M., Emery, P. R. & Thalladi, V. R. (2007). Angew. Chem. Int. Ed. 119, 4210-4213.]) or mixed solid solutions that adopted the structure of one of the pure starting materials. Mechanochemical preparations of co-crystals, conducted by grinding solid reactants together with minimal solvent, have been shown to be one of the most practical and beneficial methods, often yielding products that are not obtainable by solution-based methods (James et al., 2012[James, S. L. et al. (2012). Chem. Soc. Rev. 41, 413-447.]).

Isomorphism, which refers to the similarity of the spatial arrangement of the molecules of different compounds in their crystals, has been studied in some detail and increased interest in the topic has helped in the understanding of the significance of intermolecular interactions in crystals (Dey & Desiraju, 2004[Dey, A. & Desiraju, G. R. (2004). CrystEngComm, 6, 642-646.]; Gelbrich & Hursthouse, 2005[Gelbrich, T. & Hursthouse, M. B. (2005). CrystEngComm, 7, 324-336.]; Braga et al., 2011[Braga, D., D'Agostino, S. & Grepioni, F. (2011). CrystEngComm, 13, 1366-1372.]; Nayak et al., 2012[Nayak, S. K., Reddy, M. K., Chopra, D. & Row, T. N. G. (2012). CrystEngComm, 14, 200-210.]). A number of methods have been used to determine the limits of isomorphism. Some work in the field was carried out by Kálmán and co-workers (Fábián & Kálmán, 1999[Fábián, L. & Kálmán, A. (1999). Acta Cryst. B55, 1099-1108.]; Kálmán et al., 1993[Kálmán, A., Párkányi, L. & Argay, G. (1993). Acta Cryst. B49, 1039-1049.]) on the similarities among related steroids, and recently by Dziubek & Katrusiak (2004[Dziubek, K. F. & Katrusiak, A. (2004). Z. Kristallogr. 219, 1-11.]).

In the design of isostructural crystals the most useful substituents are normally halogen atoms. In most cases the similarity in van der Waals radii of atoms or groups (e.g. a methyl group and a chlorine atom, or a bromine and iodine atom) can lead to isostructurality (Cincic et al., 2008a[Cincic, D., Friscic, T. & Jones, W. (2008a). Chem. Eur. J. 14, 747-753.]; van de Streek & Motherwell, 2005[Streek, J. van de & Motherwell, S. (2005). J. Appl. Cryst. 38, 694-696.]). In other cases, similarity in intermolecular interactions also leads to isostructurality (Cincic et al., 2008b[Cincic, D., Friscic, T. & Jones, W. (2008b). New J. Chem. 32, 1776-1781.]). Recently, a design strategy to construct multi-component crystal forms of an active pharmaceutical ingredient (API), olanzapine, yielded a number of isostructural, quaternary multi-component crystal forms (Clarke et al., 2012[Clarke, H. D., Hickey, M. B., Moulton, B., Perman, J. A., Peterson, M. L., Wojtas, L., Almarsson, Ö. & Zaworotko, M. J. (2012). Cryst. Growth Des. 12, 4194-4201.]). Apart from the size of substituents and similar intermolecular interactions, the overall size of molecules can also lead to this phenomenon. Large molecules often create voids large enough that atoms or groups of atoms that differ greatly in size (e.g. S and O atoms or methyl and ethyl groups) can replace each other without affecting the overall crystal structures of these compounds (Nayak et al., 2012[Nayak, S. K., Reddy, M. K., Chopra, D. & Row, T. N. G. (2012). CrystEngComm, 14, 200-210.]). In earlier work, we have observed that replacement of Cl and methyl groups in a series of 2,6-disubstituted N-phenylformamides result in isostructural crystal structures, some of which undergo reversible thermal phase transformations (Omondi et al., 2005[Omondi, B., Fernandes, M. A., Layh, M., Levendis, D. C., Look, J. L. & Mkwizu, T. S. P. (2005). CrystEngComm, 7, 690-700.]; Omondi, Levendis et al., 2009[Omondi, B., Levendis, D. C., Layh, M. & Fernandes, M. A. (2009). Acta Cryst. C65, o470-o475.]). When similar exchanges of substituents were carried out using the analogous thioamides, isostructural crystals could also be isolated (Omondi, Lemmerer et al., 2009[Omondi, B., Lemmerer, A., Fernandes, M. A., Levendis, D. C. & Layh, M. (2009). CrystEngComm, 11, 1658-1665.]).

This report gives a description of solid solutions grown from selected 2,6-disubstituted N-phenylformamides [(I), (II), (III) and (VI)] and N-phenylthioamides [(IV), (V) and (VII) (Fig. 1[link])]. The solid solutions were grown from sets of compounds that were either isostructural [(I) and (II), (VI) and (VII)] or non-isostructural [(II) and (III), (IV) and (V)] in the solid crystalline state. The formamides or thioamides are linked by hydrogen-bonded chains in one of two possible ways and the possibility of exchanging hydrogen-bonded functional groups has been investigated here. Importantly, the compounds can exist as either cis or trans isomers, depending on their physical state (liquid or solid; Fig. 2[link]), and have been observed to exist as a mixture of cis and trans isomers in solution (Gowda et al., 2000[Gowda, B. T., Paulus, H. & Fuess, H. (2000). Z. Naturforsch. A, 55, 791-800.]; Omondi, Lemmerer et al., 2009[Omondi, B., Lemmerer, A., Fernandes, M. A., Levendis, D. C. & Layh, M. (2009). CrystEngComm, 11, 1658-1665.]; Omondi et al., 2005[Omondi, B., Fernandes, M. A., Layh, M., Levendis, D. C., Look, J. L. & Mkwizu, T. S. P. (2005). CrystEngComm, 7, 690-700.]).

[Figure 1]
Figure 1
Schematic diagrams for the 2,6-disubstituted N-arylformamides and N-arylthioamides [(I)-(VII)] that constitute the formations of solid solutions [(1)-(4)]. The conformations of the amide and thioamide moieties are shown for their pure states only.
[Figure 2]
Figure 2
The two conformations commonly adopted by the hydrogen-bonded functional group for the formamides and thioamides, in this case shown for the formamide case only.

2. Experimental

2.1. Preparation of solid solutions (1)-(4)

2,6-Disubstituted N-phenylformamides and N-phenylthioamides were synthesized using methods reported previously (Omondi et al., 2005[Omondi, B., Fernandes, M. A., Layh, M., Levendis, D. C., Look, J. L. & Mkwizu, T. S. P. (2005). CrystEngComm, 7, 690-700.], Omondi, Levendis et al., 2009[Omondi, B., Levendis, D. C., Layh, M. & Fernandes, M. A. (2009). Acta Cryst. C65, o470-o475.]; Omondi, Lemmerer et al., 2009[Omondi, B., Lemmerer, A., Fernandes, M. A., Levendis, D. C. & Layh, M. (2009). CrystEngComm, 11, 1658-1665.]; Fernandes & Reid, 2003[Fernandes, M. A. & Reid, D. H. (2003). Synlett, pp. 2231-2233.]; Ugi et al., 1965[Ugi, I., Fetzer, U., Eholzer, U., Knupfer, H. & Offermann, K. (1965). Angew. Chem. Int. Ed. 4, 472-484.]). The starting materials, in a 1:1 stoichiometric ratio of the following:1 (Ia) and (IIa) for (1), (IIa) and (III) for (2), (IV) and (V) for (3), and (VI) and (VII) for (4), were then dissolved in an appropriate solvent (a single solvent or a mixture that dissolved both ground compounds equally well), followed by crystallization via slow evaporation. For compound (1), a mixture of ethyl acetate and acetonitrile (in a ratio of 9:1) was used. For compounds (2) and (3), a 1:1 mixture of methanol and chloroform was used, while for compound (4), ethyl acetate was used. Good quality, colourless, block-shaped crystals suitable for analysis by single-crystal X-ray diffraction were obtained.

2.2. Single-crystal X-ray diffraction

All diffraction data were collected on a Bruker SMART 1K CCD area-detector diffractometer (Bruker, 1998[Bruker (1998). SMART-NT. Bruker AXS Inc., Madison, Wisconsin, USA.]) with graphite-monochromated Mo K[alpha]1 radiation (50 kV, 30 mA) at various temperatures using a Kryoflex 2 low-temperature device. The collection method involved [omega]-scans of width 0.3°. Data reduction and cell refinements were carried out using the program SAINT-Plus (Bruker, 1999[Bruker (1999). SAINT-Plus and XPREP. Bruker AXS Inc., Madison, Wisconsin, USA.]), and space groups were determined from systematic absences by XPREP (Bruker, 1999[Bruker (1999). SAINT-Plus and XPREP. Bruker AXS Inc., Madison, Wisconsin, USA.]) and further justified by refinement results. Empirical absorption corrections were performed on all crystals using SADABS (Sheldrick, 1996[Sheldrick, G. M. (1996). SADABS. University of Göttingen, Germany.]). In all cases, the structures were solved in the WinGX suite of programs (Farrugia, 1999[Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837-838.]), using direct methods for all compounds using SHELXS97 (Sheldrick, 2008[Bruker (1998). SMART-NT. Bruker AXS Inc., Madison, Wisconsin, USA.]), and refined using full-matrix least-squares calculations based on F2 using SHELXL97 (Sheldrick, 2008[Bruker (1998). SMART-NT. Bruker AXS Inc., Madison, Wisconsin, USA.]). The substituents in the 2 and 6 positions of the phenyl ring are mutually disordered with occupancies of 0.728 (4):0.272 (4), 0.516 (6):0.484 (6), 0.891 (2):0.109 (2), 0.536 (6):0.464 (6) in (1), (2), (3) and (4), respectively. The disorder was modelled by the use of suitable restraints on C-F, C-Cl and C-CH3 distances during refinement using DFIX, SADI and FLAT SHELX commands for (1)-(3); and restraints on C=S and C=O distances using DFIX and FLAT only for (4). Details of the restraints are given in the CIF files.2 With the exception of the H atoms involved in hydrogen bonding (i.e. H1), all H atoms were positioned geometrically and allowed to ride on their respective parent atoms. H1 was in all structures located in the difference map and refined freely with 1.2 times the isotropic displacement parameter of the parent N atom. All atoms were refined anisotropically, except for O1 in (4). Further crystallographic data are summarized in Table 1[link]. Diagrams and publication material were generated using PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]), ORTEP-3 (Farrugia, 1997[Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.]), DIAMOND (Brandenburg, 1999[Brandenburg, K. (1999). DIAMOND. Crystal Impact GbR, Bonn, Germany.]) and MERCURY (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]). Due to the small amounts of the samples synthesized we were unfortunately unable to record powder X-ray diffractograms of the bulk samples.

Table 1
Experimental details

Experiments were carried out with Mo K[alpha] radiation using a Bruker SMART 1K CCD area detector diffractometer. Absorption was corrected for by multi-scan methods, SADABS (Sheldrick, 1996[Sheldrick, G. M. (1996). SADABS. University of Göttingen, Germany.]). H atoms were treated by a mixture of independent and constrained refinement.

  (1) (2) (3) (4)
Crystal data
Chemical formula C7H5Cl1.46F0.54NO C8.03H8.10Cl0.97NO C8.78H10.35Cl0.22NS C13H19NO0.54S0.46
Mr 181.07 168.95 169.71 213.32
Crystal system, space group Orthorhombic, Pbca Orthorhombic, Pbca Orthorhombic, Pbca Monoclinic, P21/c
Temperature (K) 173 293 123 173
a, b, c (Å) 8.5220 (2), 12.2910 (3), 14.3090 (4) 8.5073 (12), 13.093 (2), 14.448 (2) 9.2080 (1), 13.1420 (2), 14.6170 (3) 9.022 (1), 9.0030 (9), 16.0050 (16)
[beta] (°) 90 90 90 103.170 (5)
V3) 1498.78 (7) 1609.3 (4) 1768.83 (5) 1265.8 (2)
Z 8 8 8 4
[mu] (mm-1) 0.61 0.40 0.37 0.15
Crystal size (mm) 0.45 × 0.19 × 0.18 0.36 × 0.25 × 0.15 0.37 × 0.17 × 0.14 0.43 × 0.18 × 0.14
 
Data collection
Tmin, Tmax 0.765, 0.895 0.89, 0.94 0.673, 0.854 0.940, 0.980
No. of measured, independent and observed [I > 2[sigma](I)] reflections 17 793, 1811, 1706 7672, 1475, 972 21 156, 2133, 1755 15 410, 3055, 1775
Rint 0.052 0.043 0.064 0.095
(sin [theta]/[lambda])max-1) 0.661 0.606 0.660 0.661
 
Refinement
R[F2 > 2[sigma](F2)], wR(F2), S 0.036, 0.090, 1.25 0.045, 0.154, 0.86 0.035, 0.097, 1.07 0.065, 0.200, 1.12
No. of reflections 1811 1475 2133 3055
No. of parameters 122 124 124 144
No. of restraints 26 26 26 4
[Delta][rho]max, [Delta][rho]min (e Å-3) 0.22, -0.22 0.16, -0.20 0.35, -0.23 0.55, -0.61
Computer programs: Bruker SMART-NT (Bruker, 1998[Bruker (1998). SMART-NT. Bruker AXS Inc., Madison, Wisconsin, USA.]), Bruker SAINT-Plus (Bruker, 1999[Bruker (1999). SAINT-Plus and XPREP. Bruker AXS Inc., Madison, Wisconsin, USA.]), SHELXS97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]), ORTEP-3 (Farrugia, 1997[Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.]), DIAMOND (Brandenburg, 1999[Brandenburg, K. (1999). DIAMOND. Crystal Impact GbR, Bonn, Germany.]), WinGX publication routines (Farrugia, 1999[Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837-838.]) and PLATON (Spek, 2009[Spek, A. L. (2009). Acta Cryst. D65, 148-155.]).

3. Results

3.1. Crystal structures of the starting materials (I)-(VII)

The structures of (I)-(V) and (VII) have been reported previously by us (Omondi et al., 2005[Omondi, B., Fernandes, M. A., Layh, M., Levendis, D. C., Look, J. L. & Mkwizu, T. S. P. (2005). CrystEngComm, 7, 690-700.]; Omondi, Levendis et al., 2009[Omondi, B., Levendis, D. C., Layh, M. & Fernandes, M. A. (2009). Acta Cryst. C65, o470-o475.]; Omondi, Lemmerer et al., 2009[Omondi, B., Lemmerer, A., Fernandes, M. A., Levendis, D. C. & Layh, M. (2009). CrystEngComm, 11, 1658-1665.]; Omondi & Levendis, 2012[Omondi, B. & Levendis, D. C. (2012). Acta Cryst. E68, o2604.]). The structure of (VI) has been reported previously by Chitanda et al. (2008[Chitanda, J. M., Quail, J. W. & Foley, S. R. (2008). Acta Cryst. E64, o1728.]). The named compounds are abbreviated indicating the type of atom in the 2,6 positions, for example DiF indicates two F atoms; and the type of amide group, O indicates a formamide and S a thioamide compound.

2,6-DiF-O (I) and 2,6-DiCl-O (II) crystallize as two different polymorphs, (Ia) and (Ib), and (IIa) and (IIb), respectively (Omondi et al., 2005[Omondi, B., Fernandes, M. A., Layh, M., Levendis, D. C., Look, J. L. & Mkwizu, T. S. P. (2005). CrystEngComm, 7, 690-700.]). 2,6-DiMe-O (III), 2,6-DiCl-S (IV) and 2,6-DiiPr-O (VI) have to date only been observed in one form. In all of these N-phenylformamides, the molecules adopt a trans conformation in the solid state. In contrast, the N-phenylthioamides 2,6-DiCl-S (IV) and 2,6-DiMe-S (V) adopt a cis conformation (Fig. 1[link]). Crystallographic details of (I)-(VII) are summarized in Table 2[link].

Table 2
Comparative crystal data for starting materials (I)-(VII)

  (Ia) (Ib) (IIa) (IIb) (III) (IV) (V) (VI) (VII)
Formula C7H5F2NO C7H5F2NO C7H5Cl2NO C7H5Cl2NO C9H11NO C7H5Cl2NS C9H11NS C13H19NO C13H19NS
Mr 157.12 157.12 190.02 190.02 149.2 206.08 165.25 205.29 221.35
T (K) 173 293 293 293 293 173 173 293 293
Crystal system Orthorhombic Monoclinic Orthorhombic Monoclinic Orthorhombic Monoclinic Monoclinic Monoclinic Monoclinic
Space group Pbca P21 Pbca P21/n P212121 P21/c C2/c P21/c P21/c
a (Å) 8.5031 (15) 4.468 (2) 8.6036 (10) 4.3539 (8) 4.5023 (4) 7.873 (2) 14.555 (2) 9.0343 (14) 9.0230 (12)
b (Å) 11.387 (2) 8.486 (3) 12.7431 (15) 13.406 (3) 8.5886 (8) 15.643 (4) 8.0597 (13) 8.8580 (13) 9.3670 (12)
c (Å) 14.075 (3) 8.8810 (10) 14.4016 (16) 14.073 (3) 21.297 (2) 7.991 (2) 16.133 (3) 16.001 (2) 16.269 (2)
[beta] (°) 90 100.698 (5) 90 92.616 (4) 90 117.336 (5) 101.422 (4) 104.896 (3) 101.453 (3)
V3) 1362.8 (4) 330.9 (2) 1578.9 (3) 820.5 (3) 823.5 (1) 874.3 (4) 1855.1 (5) 1237.5 (3) 1347.7 (3)
Z' 1 1 1 1 1 1 1 1 1
Z 8 2 8 4 4 4 8 4 4
Dx (g cm-3) 1.532 1.577 1.599 1.538 1.203 1.566 1.183 1.102 1.091
Conformer trans trans trans trans trans cis cis trans trans
Ref (a) (a) (b) (b) (b) (c) (c) (d) (e)
References: (a) Omondi, Levendis et al. (2009[Omondi, B., Levendis, D. C., Layh, M. & Fernandes, M. A. (2009). Acta Cryst. C65, o470-o475.]); (b) Omondi et al. (2005[Omondi, B., Fernandes, M. A., Layh, M., Levendis, D. C., Look, J. L. & Mkwizu, T. S. P. (2005). CrystEngComm, 7, 690-700.]); (c) Omondi, Lemmerer et al. (2009[Omondi, B., Lemmerer, A., Fernandes, M. A., Levendis, D. C. & Layh, M. (2009). CrystEngComm, 11, 1658-1665.]); (d) Chitanda et al. (2008[Chitanda, J. M., Quail, J. W. & Foley, S. R. (2008). Acta Cryst. E64, o1728.]); (e) Omondi & Levendis (2012[Omondi, B. & Levendis, D. C. (2012). Acta Cryst. E68, o2604.]).

3.2. Hydrogen-bonded chains in the starting materials (I)-(VII)

In all of the structures there are chains of molecules linked via N-H...O=C or N-H...S=C hydrogen bonds. Molecules along these chains are related either by a glide plane or twofold screw axis; for example, in polymorphs (Ia), (IIa) (glide plane) and (VI) (screw axis). A typical arrangement is shown in Fig. 3[link](a); alternatively the hydrogen-bonded molecules are related by translation, for example in (III), as shown in Fig. 3[link](b).

[Figure 3]
Figure 3
The two typical arrangements found in crystals of 2,6-disubstituted N-phenylformamides (and thioamides). (a) Hydrogen-bonded chains of type A [example (IIa] with molecules related by the glide plane in the space group Pbca. (b) Hydrogen-bonded chains of type B [example (III)] with molecules related by translation in the space group P212121.

In the case of (IV) and (V) the molecules, which have a cis conformation, are linked via N-H...S=C hydrogen bonds related to each other by a glide plane (Fig. 4[link]). In (VII) the hydrogen-bonded molecules, which are now in a trans conformation, are similarly related by a glide plane.

[Figure 4]
Figure 4
The typical hydrogen-bonded chain for the cis conformation, shown here for DiCl-S (IV).

3.3. Molecular structures, crystal structures, intermolecular interactions and isomorphism in (1)-(4)

The molecular structures and asymmetric units of solid solutions (1)-(4) are shown in Fig. 5[link]. In all of the solid-solution structures, molecules form chains of type A; (1), (2) and (3) in space groups Pbca and (4) in P21/c, shown in Fig. 6[link].

[Figure 5]
Figure 5
Molecular structures and atom-labelling scheme of the asymmetric units of (1)-(4), showing super-positions of the two molecules in the solid solution. Displacement ellipsoids are shown at the 50% probability level. See Table 1[link] for the relative site occupancies of each molecule. Note the trans conformations of the amide and thioamide moieties in all of the solid solutions.
[Figure 6]
Figure 6
The hydrogen-bonded chains formed by the trans configuration of the formamide, vis thioamide groups in (a) (1), (b) (2), (c) (3) and (d) (4). Note the very similar hydrogen-bonded interactions in (a)-(c), compared with (d), as a result of screw-axis symmetry in the latter case compared with the glide planes in the others.

The molecular geometry of all the N-phenylformamide solid solutions (1) and (2) discussed in this report is such that the amide moiety adopts a trans conformation in which the hydrogen attached to the N atom (H1) is trans to the O atom (Fig. 2[link]). The thioamide solid solution (3) also has the trans conformation, while the solid solution formed by superimposing the N-phenylformamide/N-phenylthioamide compounds continues with the trans conformation. Bond distances and angles for all solid solutions show great similarities and compare well to those of other disubstituted N-phenylformamides (Omondi et al., 2005[Omondi, B., Fernandes, M. A., Layh, M., Levendis, D. C., Look, J. L. & Mkwizu, T. S. P. (2005). CrystEngComm, 7, 690-700.]; Omondi, Levendis et al., 2009[Omondi, B., Levendis, D. C., Layh, M. & Fernandes, M. A. (2009). Acta Cryst. C65, o470-o475.]) and N-phenylthioamides (Omondi, Lemmerer et al., 2009[Omondi, B., Lemmerer, A., Fernandes, M. A., Levendis, D. C. & Layh, M. (2009). CrystEngComm, 11, 1658-1665.]). In all of the crystals, the formamide/thioamide moiety is out of the plane of the phenyl ring. The angle between the two planes defined by the phenyl ring (C1-C6) and the formamide or thioamide moiety (C1-N1-C7-X1, X = S or O) is 62.2 (1), 66.2 (1), 78.3 (1) and 75.0 (1)° for (1)-(4), respectively.

The molecules in the asymmetric units of the four solid solutions are disordered over two positions and we therefore refrain from a discussion of bond distances and angles to the substituents in the 2 and 6 positions. The backbone of the molecule in the two structures is less influenced by the disorder, and bond distances and angles are more reliable and compare well to those of the pure crystalline compounds.

Solid solution (1) crystallizes in the same space group (Pbca) as one of the polymorphs of compounds 2,6-DiF-O (Ia) (Pbca) and 2,6-DiCl-O (IIa) (Pbca) with one disordered molecule in the asymmetric unit. The substituents, both at the 2 and 6 position of the N-phenylformamide, are a Cl atom and a F atom, with occupancies of 0.728 (4) for the Cl atoms and 0.272 (4) for the F atoms. Molecules in the crystal structure that are related by a glide plane are linked together through N-H...O hydrogen bonds [N1...O1 = 2.848 (2) Å] forming chains that run in the crystallographic a direction (see Fig. 6[link]a). The N-phenylformamide molecules along this chain point in alternate directions. Adjacent chains are linked through C-H...O stabilizing short contacts [H4...O1 = 3.540 (3) Å] in the c crystallographic direction (Table 3[link]).

Table 3
Selected hydrogen-bond parameters (Å, °) and short contacts

D-H...A D-H H...A D...A D-H...A
(1)
N1-H1...O1i 0.87 (3) 1.98 (3) 2.848 (2) 172 (2)
C4-H4...O1ii 0.95 2.70 3.540 (3) 148
         
(2)
N1-H1...O1iii 0.84 (4) 2.03 (4) 2.870 (3) 172 (3)
C4-H4...O1iv 0.93 2.78 3.586 (4) 146
         
(3)
N1-H1...S1i 0.858 (16) 2.548 (17) 3.2730 (11) 142.9 (14)
         
(4)
N1-H1...S1v 0.86 (3) 2.19 (3) 3.030 (3) 165 (3)
N1-H1...O1v 0.86 (3) 2.43 (3) 3.291 (4) 172 (2)
Symmetry codes: (i) [x-{1\over 2}, y, -z+{3\over 2}]; (ii) [-x+{3\over 2}, -y+1, z-{1\over 2}]; (iii) [x+{1\over 2}, y, -z+{3\over 2}]; (iv) [-x+{1\over 2}, -y+1, z-{1\over 2}]; (v) [-x+1, y-{1\over 2}, -z+{1\over 2}].

Solid solution (2) crystallizes in the same space group (Pbca) as one of the polymorphs of compound 2,6-DiCl-O (IIa) (Pbca) with one disordered molecule in the asymmetric unit. The substituents, both at the 2 and 6 position of the formamide, are a Cl atom and a methyl group, with occupancies of 0.516 (6) for the Cl atoms and 0.484 (6) for the methyl groups. In the crystal, molecules are linked together by N-H...O hydrogen bonds and C-H...O short contacts similar to (1) (Fig. 6[link]b and Table 3[link]).

Solid solution (3) crystallizes in a different space group (Pbca) than compounds 2,6-DiCl-S (IV) (P21/c) and 2,6-DiMe-S (V) (C2/c) with one disordered molecule in the asymmetric unit. The substituents, both at the 2 and 6 position of the thioamide, are a Cl atom and a methyl group, with occupancies of 0.109 (2) for the Cl atoms and 0.891 (2) for the methyl groups. In the crystal, molecules are linked together by N-H...S hydrogen bonds similar to (1) (Fig. 6[link]c and Table 3[link]).

Solid solution (4) crystallizes in a different space group (Pbca) as compounds 2,6-DiiPr-O (VI) (P21/c) and 2,6-DiiPr-S (VII) (P21/c) with one disordered molecule in the asymmetric unit. The substituents, both at the 2 and 6 position, are isopropyl groups, however, with different hydrogen-bonded functional groups, an O atom (formamide) with an occupancy of 0.536 (6) and a S atom (thioamide) with an occupancy of 0.464 (6). In the crystal, molecules are linked together by N-H...O [H1...O1 = 3.291 (4) Å] and N-H...S [H1...S1 = 3.030 (3) Å] hydrogen bonds similar to (1) (Fig. 6[link]d and Table 3[link]).

4. Discussion

The successful preparation of solid solutions of N-phenylformamides and N-phenylthioamides can be divided into two isostructurality experiments. Firstly, the interchange of F, Cl and methyl substituents on the 2 and 6 positions of the phenyl ring illustrates the exchange of ring substituents, and secondly the interchanges of the hydrogen-bonded functional groups in the related thioamides illustrate how hydrogen-bonded functional groups can be interchanged and yet still remain isostructural. The conformations of the molecules have two important degrees of freedom, being the torsion angle C7-N1-C1-C2 of the formamide or thioamide group to the phenyl rings; and the cis/trans conformations within the formamide or thioamide groups, measured using the C1-N1-C7-O1 torsion angle. To assist us in the comparison of the starting materials (I)-(VII) to the solid solutions (1)-(4), we will use various isostructurality parameters using the solid-state module in MERCURY and Kálmán's unit-cell similarity parameters [pi] and [epsilon] (Fábián & Kálmán, 1999[Fábián, L. & Kálmán, A. (1999). Acta Cryst. B55, 1099-1108.]). A view of the packing diagrams of the four co-crystals is shown in Fig. 7[link].

[Figure 7]
Figure 7
Packing diagrams of filled unit-cell contents of (a) (1), (b) (2), (c) (3) and (d) (4). Noteworthy are the isostructural structures of (a)-(c), illustrating F, Cl and methyl exchange in N-phenylformamides and N-phenylthioamides. The outlier is (4), which crystallizes in a different space group with different unit-cell parameters.

Starting compounds (Ia) and (IIa) are isostructural with respect to their solid solution (1) and to each other. They have similar unit cells and the same space group throughout. The unit-cell similarity indices for the pairs (1)/(Ia), (1)/(IIa) and (Ia)/(IIa) are 0.042, 0.023 and 0.05, respectively. Conformationally, the pairs of (1)/(IIa) and (Ia)/(IIa) are also very similar as they have almost identical torsion angles, being all trans (see Table 4[link]), as well as similar C7-N1-C1-C2 angles. The relative similarities or differences among the three pairs can be quantified by working out the r.m.s. value using the solid-state form module in MERCURY, which superimposes regions of common molecular packing and provides an r.m.s. deviation (Macrae et al., 2008[Macrae, C. F., Bruno, I. J., Chisholm, J. A., Edgington, P. R., McCabe, P., Pidcock, E., Rodriguez-Monge, L., Taylor, R., van de Streek, J. & Wood, P. A. (2008). J. Appl. Cryst. 41, 466-470.]) for a cluster of 15 molecules. A lower value of r.m.s. and a higher proportion of fitted molecules out of 15 indicate higher degrees of similarity. As (1) has a greater contribution of the (IIa) molecule in its crystal structure (in terms of the occupancies), the r.m.s. values for a 15 molecule cluster overlaid between (1) and (IIa) is 0.163, with a value of 0.023 for a single molecule. These are the lowest values of the three pairs (see Table 5[link]).

Table 4
Comparative torsion angles (°) of solid solutions (1)-(4) to their starting materials (I)-(VII)

Torsion angle Co-crystal Starting materials
  (1) (Ia) (IIa)
C1-N1-C7-O1 1.3 (3) 0.3 (3) -1.9 (4)
C7-N1-C1-C2 65.4 (2)# 60.3 (2) 67.3 (3)
  (2) (IIa) (III)
C1-N1-C7-O1 -1.9 (5) -1.9 (4) -4.6 (3)
C7-N1-C1-C2 67.7 (4) 67.3 (3) 69.4 (2)
  (3) (IV) (V)
C1-N1-C7-S1 -5.2 (2) 178.9 (1) 177.0 (2)
C7-N1-C1-C2 81.8 (2) 54.0 (2) 63.9 (3)
  (4) (VI) (VII)
C1-N1-C7-O1 2.2 (3) 1.1 (3) -
C1-N1-C7-S1 -0.9 (4) - -1.3 (4)
C7-N1-C1-C2 105.0 (3)# -102.5 (2) -103.4 (3)
#Measured normalized to the other torsion angles due to the symmetry of the phenyl rings.

Table 5
Various comparative isostructurality parameters

Pair [pi] [epsilon] R.m.s. (No. of molecules fit out of 15 molecule cluster) R.m.s. of asymmetric unit
(Ia)/(IIa) 0.062 0.050 0.507 (15/15) 0.05
(1)/(Ia) 0.034 0.032 0.358 (15/15) 0.042
(1)/(IIa) 0.17 0.018 0.163 (15/15) 0.023
(IIa)/(III) 0.040 0.24 0.03 (1/15) 0.035
(2)/(IIa) 0.0083 0.0063 0.137 (15/15) 0.019
(2)/(III) 0.048 0.25 0.018 (1/15) 0.025
(IV)/(V) 0.026 0.019 -# 0.081
(3)/(IV) 0.19 0.26 -# 0.839
(3)/(V) 0.16 0.24 -# 0.729
(VI)/(VII) 0.025 0.029 0.405 (9/15) 0.336
(4)/(VI) 0.0053 0.0075 0.193 (15/15) 0.7
(4)/(VII) 0.19 0.02 0.632 (15/15) 0.831
(VI)/(VII) 0.025 0.029 0.42 (15/15)+ 0.115+
(4)/(VI) 0.0053 0.0075 0.158 (15/15)+ 0.041+
(4)/(VII) 0.19 0.02 0.277 (15/15)+ 0.071+
(1)/(2) 0.026 0.024 0.276 (15/15) 0.037
(1)/(3) 0.070 0.07 0.538 (15/15) 0.126
(2)/(3) 0.042 0.045 0.488 (15/15) 0.102
#This combination of crystal structures is not isostructural.
+Calculated by removing the isopropyl groups.

Starting compounds (IIa) and (III) are not isostructural with respect to each other, as they have different space groups and unit cells. As such, the resulting solid solution (2) is isostructural with (IIa) only, with again the same space group and similar unit cells [as seen in the case for solid solution (1)]. The isostructurality between (2) and (IIa) is seen in the r.m.s. value of 0.137 for the entire 15 molecule cluster, compared with only a single molecule fit out of 15 molecules for the (IIa)/(III) and (2)/(III) pairs. Conformationally, however, the three molecules are very similar in all three structures (see Tables 4[link] and 5[link]), seen in the almost equal site occupancy of the two starting molecules in the solid solution.

In solid solution (3) we are repeating a similar experiment as in (2), but now using N-phenylthioamide pairs. The three compounds (IV), (V) and (3) are all non-isostructural to each other, with three different space groups and unit-cell values. This is reflected in their high [pi] and [epsilon] values. The lack of isostructurality is observed primarily in the cis conformation of the (IV) and (V) molecules compared with the trans conformation of (3), as seen in Table 5[link]. Due to the different natures of the structures, no overlay of a 15-molecule cluster was calculated.

In solid solution (4), the overlay of similar hydrogen-bonded functional groups is achieved by using an O/S exchange. All three structures are isostructural in terms of unit cells and space groups and have similar torsion angles for C1-N1-C7-X1 (X = S or O) and C7-N1-C1-C2. However, the isopropyl groups have small but significant torsional differences among all three structures, and so the r.m.s. values for the single molecule comparisons are high compared with the previous cases. For example, only 9 out of 15 molecules fit between the starting materials, but 15 out of 15 fit for the combinations between (4) and the starting materials. By removing the isopropyl groups from the overlaid structures, a more realistic fitting of the three pairs is presented with all of them having 15 out of 15 molecules overlaying, showing clearly that (4) has a similar conformation to the starting materials, as expected from the values in Table 5[link].

As stated previously, the solid solutions (1)-(3) are all isostructural, as seen in their comparative unit-cell similarity indices. A contributing factor is the robustness of the N-H...O=C hydrogen bonding observed in this family of compounds (Nayak et al., 2012[Nayak, S. K., Reddy, M. K., Chopra, D. & Row, T. N. G. (2012). CrystEngComm, 14, 200-210.]). In this study only one crystal was selected from each batch. Clearly site occupancies of the solid solutions may change if different crystals are selected. In addition, the effect of solvent on the formation of isostructural solid solutions as well as a computational study of generated isomorphs (Polito et al., 2008[Polito, M., D'Oria, E., Maini, L., Karamertzanis, P. G., Grepioni, F., Braga, D. & Price, S. L. (2008). CrystEngComm, 10, 1848-1854.]) warrants further study.

5. Conclusion

To summarize, the solid solutions (1), (2) and (3) show that both fluoro-chloro and chloro-methyl exchange can occur reliably if that is the only substituent required to exchange, and lead to an isostructural series. This may be a consequence of the comparable size of the three different substituents and as a result can interchange easily without affecting the overall solid-state structures of the different compounds. In solid solution (4), the identity of the hydrogen-bonding acceptor atom is changed, involving a S and O atom exchange. What is noteworthy is that all solid solutions adopt the trans conformation, even though some have two cis starting materials and the solutions all contain a mixture of cis and trans conformations.

Acknowledgements

The authors like to thank the University of the Witwatersrand and the National Research Foundation (GUN: 2067413) for funding and providing the infrastructure to carry out this work. BO thanks the IUCr for a PhD grant.

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Acta Cryst (2014). B70, 106-114   [ doi:10.1107/S2052520613022129 ]