Relevance of weak intermolecular forces on the supramolecular structure of free or DMSO solvated 5-(4-X-benzylidene)rhodanines (X = F, Cl, Br, I)
Abstract
The rhodanines of the title (Xp-Rhod, X = F, Cl, Br, I) were synthesized and characterized in solid state and in solution. The crystal structures of the four compounds show different supramolecular organizations. In the F-, Cl- and Br-derivatives, a (CSNH)2 ring forms via N
H⋯S hydrogen bonds between two neighbouring molecules to give dimers. The I-derivative is also dimeric, but exhibits (CONH)2 rings. The two type of dimers are associated in a variety of structures through hydrogen bonding, π-stacking, CH⋯π interactions and halogen bonding. These interactions were analysed from a crystallographic point of view and their relative relevance was explored using DFT calculations. The effect produced on all these interactions by the incorporation of DMSO molecules to the lattice was analysed by comparing the crystal structures of Xp-Rhod compounds and those of corresponding Xp-Rhod⋅DMSO solvates.
Introduction
Rhodanine (2-thioxothiazolidin-4-one) (Scheme 1, a) and derivatives have attracted considerable interest from the medicinal chemistry community due to their wide range of biological activities. Among others, compounds containing the rhodanine ring have shown to inhibit β-lactamase [1], phosphatase of regenerating liver (PRL-3) [2] UDP-N-acetylmuramate/l-arginine ligase [3] or arylamine N-acetyltransferase [4] enzymes. As these enzymes are involved in biochemical processes related to certain diseases, the inhibitory ability of rhodanines give them a potential role as drugs against these diseases, as recent papers have shown [5], [6], [7], [8].
Investigation of structure–activity relationships for this class of compounds is essential in the design of crystalline materials, which not only have improved physicochemical properties, but will be able to properly interact with a selected biological target.
In this line, trying to provide new structural data on the particular group of 5-benzylidene rhodanines, we have described in a previous paper [9] the effect on the structure of the position of the OMe, OH or Br substituents in the phenyl ring. As in free rhodanine, these derivatives dimerize in the crystal through NH⋯O hydrogen bonds, which give rise to a (CONH)2 ring [10] (Scheme 1, b). This synthon is a common structural motif in organic chemistry [11], [12], although in rhodanine derivatives it coexists with the alternative (CSNH)2 synthon (Scheme 1, c) (vide infra). These dimers are associated through weaker interactions such as CH⋯S/O, CH⋯π or Br⋯S/O, although, if solvent molecules are present in the lattice, they can play a significant role in the crystal structure.
Pursuing this research we now select a group of 5-benzylidene rhodanines (Xp-Rhod) for which the position of the substituent on the phenyl ring, the para position, is maintained and the variation is now on the substituent, covering the usual elements of the halogen group (X = F, Cl, Br, I) (Scheme 2).
The structural study of these four compounds show that the association of the rhodanine rings in some cases is of the (CSNH)2 type, but also the (CONH)2 type was detected. Interestingly, the F-derivative included here is a different polymorph to that previously described [13], [14]. As this previous polymorph was obtained [14] by using DMSO as a solvent, we carried out a recrystallization of all Xp-Rhod compounds trying to obtain new polymorphs. However, in all the cases, the liberated crystals were the corresponding rhodanine/DMSO solvates (Xp-Rhod⋅DMSO). This result enables us to compare the structural data of each specific solvent free rhodanine derivative with the corresponding DMSO solvate and to analyse the effect of the solvent in the supramolecular association of Xp-Rhod compounds. This information also has an indirect relevance for the biological studies with rhodanines because these studies very often use DMSO as vehicle [3], [4], [5], [6], [7].
Section snippets
Material and methods
Rhodanine, 4-fluorobenzaldehyde, 4-chlorobenzaldehyde, 4-bromobenzaldehyde and 4-iodobenzaldehyde were used as supplied by Aldrich. Elemental analyses were performed with a Carlo Erba 1108 microanalyser. Melting points were determined with a Büchi apparatus. Mass spectra were recorded on a Kratos MS50TC spectrometer connected to a DS90 system and operating under EI conditions (direct insertion probe, 70 eV, 250 °C). IR spectra (from KBr pellets or Nujol mulls) were registered on a Bruker IFS66V
Computational details
The electronic structure calculations were carried out with the B97D3 functional [22] and the def2-TZVPP basis set [23]. This density functional (DF) includes the D3 version of Grimme’s dispersion with Becke-Johnson damping, and is one of the currently recommended DFs for the evaluation of noncovalent interactions in large and medium-sized systems [24], [25].
Complexation energies for some interacting pairs of molecules were calculated as the difference between the electronic energy of the dimer
Synthesis and spectroscopic characterization
All Xp-Rhod rhodanines have been prepared as described in Ref. [15]. Their MS-EI mass spectra show the [M+H]+ signal together with others which reveal the fragmentation of the rhodanine ring. Their IR spectra show a medium-intensity band around 3100 cm−1 typical of the NH group, a very strong ν(C
O) band around 1690 cm−1, and a medium-intensity ν(CS) band around 1070 cm−1.
The Xp-Rhod⋅DMSO solvates were isolated from the Xp-Rhod solutions in the [D6][DMSO] used in the RMN studies.
Xp-Rhod
The labelling
Conclusions
Condensation of rhodanine with 4-X-benzaldehydes does not significantly modify the structural parameters of the former.
The condensation products Xp-Rhod are dimers in solid state, on the basis of hydrogen bonds in which the rhodanine CS and NH (X = F, Cl, Br) or CO and NH (X = I) groups are involved, thus forming eight-membered (CSNH)2 or (CONH)2 planar rings, respectively. Although theoretical calculations indicated that the dimer with the last type of synthon is the most stable
Acknowledgements
We would like to thank the Spanish Ministry of Education and Innovation (Project CTQ 2009-10738), Xunta de Galicia, Spain [Dirección Xeral de I+D, (IN845B-2010/121) and Rede de Excelencia MetalBIO (R2014/004)] for financial support, and the Centro de Supercomputación de Galicia (CESGA) for computational resources.
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