Synthesis and solid-state characterisation of 4-substituted methylidene oxindoles
© Tizzard et al.; licensee Chemistry Central Ltd. 2013
Received: 28 June 2012
Accepted: 25 June 2013
Published: 20 December 2013
4-substituted methylidene oxindoles are pharmacologically important. Detailed analysis and comparison of all the interactions present in crystal structures is necessary to understand how these structures arise. The XPac procedure allows comparison of complete crystal structures of related families of compounds to identify assemblies that are mainly the result of close-packing as well as networks of directed interactions.
Five 4-substituted methylidene oxindoles have been synthesized by the Knoevenagel condensation of oxindole with para-substituted aromatic aldehydes and were characterized in the solid state by x-ray crystallography. Hence, the structures of (3E)-3-(4-Bromobenzylidene)-1,3-dihydro-2H-indol-2-one, 3a, (3E)-3-(4-Chlorobenzylidene)-1,3-dihydro-2H-indol-2-one, 3b, (3E)-3-(4-Methoxybenzylidene)-1,3-dihydro-2H-indol-2-one, 3c, (3E)-3-(4-Methylbenzylidene)-1,3-dihydro-2H-indol-2-one, 3d and (3E)-3-(4-Nitrobenzylidene)-1,3-dihydro-2H-indol-2-one, 3e, were elucidated using single crystal X-ray crystallography.
A hydrogen bonded dimer molecular assembly or supramolecular construct was identified in all the crystal structures examined along with a further four 1D supramolecular constructs which were common to at least two of the family of structures studied. The 1D supramolecular constructs indicate that once the obvious strong interaction is satisfied to form hydrogen bonded dimer it is the conventionally weaker interactions, such as steric bulk and edge-to-face interactions which compete to influence the final structure formation.
Oxindoles are important scaffolds in medicinal chemistry and synthetic and structural studies on this important class of heterocycles are extremely welcome. We have recently described the synthesis of a range of oxindoles  and biological studies on metal-substituted oxindole complexes have revealed impressive kinase inhibition . Supported by solid-state analysis, we have been able to establish structure-activity relationships in the oxindoles reported in these studies. The pharmacological importance of 4-substituted methylidene oxindoles cannot be overemphasized. Many have anticancer properties and inhibit vascular endothelial growth factor receptor-2 (VEGFR-2) and platelet-derived growth factor receptor (PDGFR), linked with angiogenesis [3, 4].
The burgeoning scientific interest in the study of polymorphism, crystal engineering and crystal structure prediction has resulted in the need for systematic analysis protocols to enable the comparison of different crystal structures. In 1998 Nangia and Desiraju  argued that a full understanding of crystal structure and crystal engineering requires a comparison of the entire molecule and all interactions in the crystalline state. The analysis of crystal structures for similarities and differences is one of the key issues facing structural chemists today and to that end a number of methods have been developed in recent years to compare crystal structures [6–11]. Many of these have concentrated on the comparison of subsets of structures i.e. comparing polymorphs of a single compound, or the analysis of directed interactions such as hydrogen bonding. However, crystal structures are assembled by the interplay of a number of forces and thus these methods compare only a subset of the interactions contained within crystal structures. To be of more general utility, an analysis method should be flexible enough to identify components of a structure that may reflect the influence of the more diffuse interactions and thus be able to identify assemblies that are mainly the result of close-packing as well as networks of directed interactions. It should also be able to compare crystal structures of different molecular species to allow the systematic investigation of related families of structures, thus allowing the investigation of the effects of systematic substituent variation. With these points in mind the XPac [12, 13] procedure has been developed in our laboratory, the use of which is explained below.
Herein we report the solid-state study of five 4-substituted benzylidene oxindoles and the XPac analyses of these along with three previously published structures.
Where R1 = Br(3a), InChIKey = INAOSTJXLBNFMV-UKTHLTGXSA-N
Cl (3b) InChIKey = CIXKMQYKNWKSNZ-UKTHLTGXSA-N.
OMe (3c) InChIKey = SOHLANGNFXOOEF-GXDHUFHOSA-N.
Me (3d) InChIKey = JEZSEMYAZZHQIB-GXDHUFHOSA-N.
NO2 (3e) InChIKey = WPZSQSSOBHCYOZ-UKTHLTGXSA-N.
General: A solution of 1 (1.37g, 10mmol) and 2 (10mmol) in propan-2-ol (10ml, 100mmol) and piperidine (0.5ml, 5mmol) was refluxed at 100°C for 3h. On cooling the resultant solid was filtered, dried under reduced pressure and then purified by sublimation to give the product. Full details of experimental processes and observations of the synthesis of 3a-e are available at http://poc.labtrove.soton.ac.uk/synth_methyl_oxin/group/Experimental%20Procedure.
3a: doi:10.5258/poc/lt/r/1 http://dx.doi.org/10.5258/poc/lt/r/1 Yellow solid; yield: 1.62g, 5.40mmol, 54%; mp: 192.5°C; IR (νmax, cm-1) 1700 (C=O stretch); 1H (CDCl3): 6.85-6.90 (2H, m), 7.26-7.29 (2H, m), 7.59-7.62 (4H, m), 7.72 (1H, s), 8.28 (1H, brs). 13C (CDCl3): 110.2, 121.4, 121.8, 122.0, 123.0, 123.8, 127.9, 130.1, 130.2, 130.8, 131.5, 131.9, 133.7, 135.9, 169.7; ESIMS (positive mode) (m/z): 300.1 [M+H]+, 302.1 [M+H]+.
3b: doi:10.5258/poc/lt/r/2 http://dx.doi.org/10.5258/poc/lt/r/2 Yellow solid; yield: 1.93g, 7.56mmol, 76%; mp: 181.5°C; IR (νmax, cm-1) 1700 (C=O stretch); 1H (CDCl3): 6.89-6.92 (2H, m), 7.25-7.28 (2H, m), 7.46 (2H, m), 7.58-7.62 (2H, m), 7.75 (1H, s), 8.53 (1H, brs). 13C (CDCl3): 110.2, 110.4, 121.4, 121.8, 122.0, 122.9, 128.0, 128.9, 130.1, 130.2, 130.6, 133.2, 135.5, 135.8, 169.9; ESIMS (positive mode) (m/z): 256.2 [M+H]+, 258.2 [M+H]+.
3c: doi:10.5258/poc/lt/r/3 http://dx.doi.org/10.5258/poc/lt/r/3 Yellow solid; yield: 1.62g, 6.45mmol, 65%; mp: 152.2°C; IR (νmax, cm-1) 1696 (C=O stretch); 1H (CDCl3): 3.89 (3H, s), 6.89-6.92 (2H, m), 6.98-7.01 (2H, m), 7.25 (1H, m), 7.65-7.68 (2H, m), 7.75 (1H, m), 7.80 (1H, s), 8.51 (1H, brs). 13C (CDCl3): 55.4, 110.1, 114.0, 114.1, 121.7, 122.0, 122.7, 125.6, 127.1, 129.4, 131.5, 137.7, 141.3, 160.9, 170.5; ESIMS (positive mode) (m/z): 252.2 [M+H]+.
3d: doi:10.5258/poc/lt/r/4 http://dx.doi.org/10.5258/poc/lt/r/4 Yellow solid; yield: 1.61g, 6.84mmol, 68%; mp: 187.0°C; IR (νmax, cm-1) 1690 (C=O stretch); 1H (DMSO-d6): 2.43 (3H, s), 6.87-6.92 (2H, m), 7.25-7.29 (2H, m), 7.52 (2H, d, J=7.9), 7.60 (2H, d, J= 7.9), 7.82 (1H, s), 8.23 (1H, s). 13C (CDCl3): 21.5, 110.2, 121.7, 121.8, 122.9, 123.9, 129.1, 129.4, 129.5, 129.6, 131.9, 132.2, 137.8, 140.1, 141.5, 170.7; ESIMS (positive mode) (m/z): 236.3 [M+H]+, 471.5 [2M+H]+.
3e: doi:10.5258/poc/lt/r/5 http://dx.doi.org/10.5258/poc/lt/r/5 Red solid; yield: 1.80g, 6.76mmoml, 68%; mp: 247.0°C; IR (νmax, cm-1) 1697 (C=O stretch); 1H (dmso-d6): 6.81-6.91 (2H, m), 7.21 (1H, pseudo tr, J=7.5), 7.39 (1H, ps tr, J=7.5), 7.68 (1H, s), 7.80 (2H, d, J= 8.6), 8.34 (2H, d, J=8.6), 10.70 (1H, brs). 13C (dmso-d6): 110.7, 121.5, 122.9, 123.8, 129.9, 130.9, 132.4, 141.9, 143.3, 147.7, 161.1, 169.1 (some quaternaries missing, poor solubility); ESIMS (positive mode) (m/z): 265.2 [M+H]+.
Full details of characterisation techniques and data for 3a-e are available at http://poc.labtrove.soton.ac.uk/synth_methyl_oxin/group/Analytical%20Procedures and http://poc.labtrove.soton.ac.uk/synth_methyl_oxin/group/Spectroscopic%20Data.
Single Crystal X-ray crystallography
Single-crystal X-ray diffraction analyses were performed using a Bruker APEXII CCD diffractometer mounted at the window of a Bruker FR591 rotating anode (MoKα = 0.71073 Å) and equipped with an Oxford Cryosystems cryostream device. Data were processed using the Collect package and unit cell parameters were refined against all data. An empirical absorption correction was carried out using SADABS. The structures were solved by direct methods using SHELXS-97 and refined on Fo2 by full-matrix least-squares refinements using SHELXL-97. All non-hydrogen atoms were refined with anisotropic displacement parameters. All hydrogen atoms were added at calculated positions and refined using a riding model with isotropic displacement parameters based on the equivalent isotropic displacement parameter (Ueq) of the parent atom. Figures were produced using OLEX2. A summary of the crystallographic data is shown below (Table 1) and full details of the crystallographic experiment for each of the compounds are available at:
3a doi:10.5258/ecrystals/1505 http://dx.doi.org/10.5258/ecrystals/1505
3b doi:10.5258/ecrystals/1326 http://dx.doi.org/10.5258/ecrystals/1326
3c doi:10.5258/ecrystals/1327 http://dx.doi.org/10.5258/ecrystals/1327
3d doi:10.5258/ecrystals/1324 http://dx.doi.org/10.5258/ecrystals/1324
Crystallographic data for 4-substituted methylidene oxindoles
R1/wR2 (observed data: F2 > 2σ(F2))
R1/wR2 (all data)
Results and discussion
Discussion of crystal structures
Comparison of crystal structures
The different substituents in this series do however affect the potential for the structure-defining formation of intermolecular interactions as evidenced by the different crystal structures exhibited by these molecules. Therefore a study using the XPac approach, an algorithm developed to compare sets of complete crystal structures, has been conducted. With this technique, the comparison of structures is based purely on relative geometric conformations and positions of molecules without bias from perceived chemical effects such as H-bonding or other directional intermolecular interactions. The comparison of a group of crystal structures is carried out in a pairwise fashion and is accomplished by generating a set of neighbouring molecules, analogous to a coordination sphere, around a central molecule from the symmetry operations of the space groups of each structure. Parameter lists are then generated and compared for each crystal structure based on angular, planar and distance relationships between the kernel molecule (at the centre of the cluster) and each molecule in the cluster (the surrounding neighbouring molecules). Any matches (within user defined tolerances) of these sets of parameters equates to matches in the positions of molecules in the clusters for each of the crystal structures (the kernels always match of course) and depending on the number of matches the dimensionality of the similarity may be derived. Thus crystal structures with common discrete assemblies e.g. dimers display 0D similarity, those with common rows or stacks of molecules display 1D similarity, structures in which layers of molecules match display 2D similarity and structures which are isostructural display 3D similarity. These common structural motifs between structures are termed Supramolecular Constructs (SCs).
Similarity relationships amongst oxindoles studied (D = dimensionality, # = number of structures)
N-H…O H-bonded oxindole dimer
A01 dimer ‘stack’
A01 dimer ‘sheared tape’
A01 dimer ‘tape’
t1, t4, t5
ring ‘edge to face’ tape
As can be seen from the analysis above, the only SC which would conventionally be seen as containing structure forming intermolecular interactions is SC A01, the H-bonded dimer. The other SCs, apart from B11, are all based on the A01 dimer as a building block. However, the other SCs do not display any further significant relationships that could be considered to be classical strong hydrogen bonds. Nevertheless, each of these SCs have been identified in at least two different crystal structures suggesting that they are robust enough to have arisen under at least two different sets of crystallisation conditions. Despite possessing a strong and constrained structure-forming motif in the oxindole moiety and a relatively simple substitution pattern in the compound family a variety of SCs are formed. This indicates that once the obvious strong interaction is satisfied to form the primary SC it is the conventionally weaker interactions, such as steric bulk and edge-to-face exhibited here, that compete to influence the final structure formation.
The authors would like to thank EPSRC for funding the UK National Crystallography Service.
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