Synthesis and solid-state characterisation of 4-substituted methylidene oxindoles

Synthesis

The general reaction scheme outlined below (Scheme 1) was followed, with specific details of the synthesis procedures of all the derivatives of 3 available at http://poc.labtrove.soton.ac.uk/synth_methyl_oxin/group/Condensation%20Products.

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 (ν_max, 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 (ν_max, 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 (ν_max, 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 (ν_max, 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 (ν_max, 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 F_o² 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

Discussion of crystal structures

The molecular structures and numbering schemes for compounds 3a-e are depicted in Figures 1, 2, 3, 4 and 5 below and confirm the expected substitution patterns for this homologous series. The structures of 3a and 3b are isostructural and both contain channels of hydrogen bonded water molecules running parallel to the b-axis. These channels contain water molecules in two alternate orientations so that in each case one H-atom forms a hydrogen bond with the carbonyl O-atom of the oxindole (3a, O^…O distance = 2.815(9)Å, O-H^…O angle = 151(13)°; 3b, O^…O distance = 2.813(3)Å, O-H^…O angle = 171(5)°). Thus in these structures, the carbonyl O-atom acts as a H-bond acceptor to two H-bond donors, the water molecules and the oxindole amine N-H. The remaining H-atom of the water molecule H-bonds to an adjacent water molecule in the structure (3a, O^…O distance = 2.68(3)-2.72(2)Å, O-H^…O angle = 154(8)-167(12)°; 3b, O^…O distance = 2.713(8)-2.718(6)Å, O-H^…O angle = 158(7)°) to form the water channel. The conformation of the molecular structures of these compounds is predominantly defined by rotation about a single methylene group (C9) and all five structures exhibit approximately the same shape (oxindole-benzyl interplanar angle range: 36.11-49.56°). This observation indicates that the different substituents in the para position studied as part of this work do not significantly affect molecular conformation.

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).

In order to discuss the similarity relationships between crystal structures, a method for their graphical representation needs to be described. Each SC provides a connection between at least two crystal structures and a SC may itself be derived from one or more SCs (its sub SCs). Thus in the structure relationship diagram below (Figure 6), each element within a family i.e. crystal structures and SCs is represented by a node and each edge connecting the nodes represents a dependency between these elements. There is a strict vertical hierarchy such that for connected nodes the higher node is a subgroup of the lower node, whilst the horizontal arrangement is arbitrary and simply arranged to provide the least number of crossing lines for ease of readability. The order of elements from bottom to top are 0D SCs < 1D SCs < 2D SCs < 3D SCs < crystal structures, thus to find all the crystal structures that contain a particular SC, all of the branches radiating upwards from its node are followed to the crystal structure level. To find a common SC of two crystal structures the branches radiating downwards from the nodes representing the crystal structures are followed until they meet at a common node.

The XPac analysis of the eight crystal structures reveals some interesting packing features. As one might predict, the dominant packing feature of this set of structures is the N-H^…O dimer formed by the oxindole moieties of the structures, SC A01 (Figure 7). The geometries of the dimers are unremarkable with D^…A distances of 2.844(7)-2.863(4)Å and D-H^…A angles between 167-169° for the Z-conformers and between 2.867(3)-2.904(3)Å and 172-177° for the E-conformers. The larger intermolecular distances and angles of the E-conformers compared with the Z-conformers can be accounted for by steric effects. The dimer motif is robust enough so that the presence of water molecules in the two hydrate structures does not disrupt its formation. The dimer is present in all of the oxindole structures investigated except 3f which forms a catamer structure with a D^…A distance of 2.850(4)Å and a D-H^…A angle of 167°. Also, this is the only structure which exhibits disorder with the benzylidene ring of the molecule adopting two conformations.

SC A11 (Figure 8) is a 1D dimer stack with a translation vector t1 (4.041-4.130Å). It is present in three of the eight oxindole structures investigated: 3a, 3b and 3c. 3a and 3b are isostructural, related by 3D SC A31 and thus this is a subgroup of SC A11. In the structures of 3a and 3b SC A11 propagates along the b-axis whilst in 3c it propagates along the a-axis. Interestingly, there are no direct close contacts less than the sum of the van der Waals (vdW) radii between the dimers comprising SC A11 in any of the structures in which it occurs. However in all the structures studied, close contacts less than the sum of the vdW radii from constituent dimers of the SC to neighboring molecules outside of the SC are observed suggesting that SC A11 arises purely as a result of simple close-packing considerations in these structures.

SC A12 (Figure 9) is best described as a 1D dimer ‘sheared’ tape and is present in the structures of 3c and 3d with a translation vector t2 (13.355-13.449Å). Both 3c and 3d display layer structures with dimer layers parallel to the 120 and 201 planes respectively and SC A12 comprises adjacent dimers from adjacent layers, hence the ‘sheared’ tape description. In the structure of 3c SC A12 propagates along the a-b direction whilst in 3d it propagates along the -a-bc direction. The constituent dimers of SC A12 in 3c exhibit a double close contact less than the sum of the vdW radii between C6 of the oxindole moiety and H12 (of the benzylidene moiety (2.769Å). However, there are no close contacts less than the sum of the vdW radii between the constituent dimers of SC A12 in 3d and so these are not expected to be integral to the SC’s formation.

SC A13 (Figure 10) is a 1D dimer tape and is present in the structures of 3d and 3e with a translation vector t4 (18.457-18.694Å). As previously mentioned, 3d forms a simple layer structure and instances of SC A13 propagate along these layers. The structure of 3e is more complex with adjacent stacks of dimer tapes (SC A13 stacks) rotated 62.7° with respect to each other. Once again one of the structures displaying this SC (3d) also displays short contacts below the sum of the vdW radii between constituent dimers of the SC. These however are very minor, comprising a double contact between C16 of the methyl substituent and H4 of the oxindole (2.899Å) and this along with the fact that the structure of 3e displays no short contacts below the sum of the vdW radii between constituent dimers of the SC suggest that these are not SC forming interactions.

SC B11 (Figure 11) is the only SC amongst this group of structures which is not based on the H-bonded dimer, SC A01. The SC consists of a repeating double-molecule motif forming a 1D tape as shown below. It is displayed in the structures of 3c and 3f where it propagates along a-c axis and a-b axis respectively. In common with structure displaying previously outlined SCs, the structure of 3c displays only a single, minor short contact less than the sum of the vdW amongst constituent molecules of the SC between C16 of the methoxy substituent and H7 of the indole moiety (2.847Å). No such contacts are observed amongst the constituent molecules of the SC in the structure of 3f suggesting that this SC is not directly structure forming.