1,3,5-Benzenetricarboxaldehyde: Building Block for Porous Materials & Supramolecular Polymers

1,3,5-Benzenetricarboxaldehyde is a key building block in the field of materials science, particularly in the synthesis of porous organic materials. Its symmetrical structure, featuring three reactive aldehyde groups on a central benzene ring, makes it an ideal trigonal linker for the construction of highly ordered crystalline structures such as Covalent Organic Frameworks (COFs) and porous organic cages. These materials are of significant interest for applications in gas storage and separation, catalysis, and optoelectronics. The molecular structure of 1,3,5-Benzenetricarboxaldehyde consists of a benzene ring substituted with three formyl groups at the 1, 3, and 5 positions. This C3-symmetric arrangement is crucial for its role in the formation of ordered polymeric frameworks.

Facilitating functionalization of 1,3,5-Benzenetricarboxaldehyde

Nature uses supramolecular interactions to create dynamic and adaptive systems from several structurally diverse building blocks. Synthetic water-compatible supramolecular polymers have recently emerged as potential biomaterials since their structure and dynamics can mimic the fibrous structures found in nature. The use of non-covalent interactions allows control of the number of biological recognition motifs presented on the supramolecular structures by mixing in different functional monomers in the desired ratio. The self-assembly of discotic 1,3,5-Benzenetricarboxaldehyde (BTAs) into supramolecular polymers has been studied extensively in recent years. The amides can be connected to the benzene ring via the carbonyl group or via the nitrogen atom, yielding C-centred and N-centred BTAs, respectively. Although both variants self-assemble in organic media, the aggregation and hydrogen bonding was weaker in case of N-centred BTAs. C-Centred BTAs have been modified to be compatible with water by decorating the core amides with a hydrophobic chain of at least eleven carbon atoms to protect the intermolecular hydrogen bonds from interaction with the solvent. Synthetic water-compatible supramolecular polymers based on 1,3,5-Benzenetricarboxaldehyde have attracted a lot of interest in recent years, as they are uniquely suited to generate functional multicomponent biomaterials.[1]

Their morphologies and intrinsic dynamic behaviour mimic fibrous structures found in nature. Moreover, their modularity allows control of the density of functionalities presented on the surface of the fibres when using functionalized 1,3,5-Benzenetricarboxaldehyde monomers. However, such moieties generally comprise a functionality on only one of three side chains, resulting in lengthy synthetic protocols and limited yields. In this work, we avert the need for desymmetrization of the core by starting from commercially available 5-aminoisophthalic acid. This approach eliminates the statistical reactions and reduces the number of synthetic steps. It also leads to the inversion of the connectivity of one of the amides to the benzene core. By combining spectroscopy, light scattering and cryogenic transmission electron microscopy, we confirm that the inversed amide 1,3,5-Benzenetricarboxaldehydes (iBTAs) form intermolecular hydrogen bonds and assemble into supramolecular polymers, like previously used symmetrical BTAs, albeit with a slight decrease in water solubility. Solubility problems were overcome by incorporating iBTAs into conventional BTA-based supramolecular polymers. These two-component mixtures formed supramolecular fibres with a morphology and dynamic behaviour similar to BTA-homopolymers. Finally, iBTAs were decorated with a fluorescent dye to demonstrate the synthesis of functional monomers, and to visualize their co-assembly with 1,3,5-Benzenetricarboxaldehydes. Our results show that functionality can be introduced into supramolecular polymers with monomers that slightly differ in their core structure while maintaining the structure and dynamics of the fibres.

1,3,5-Benzenetricarboxaldehyde Supramolecular Polymers as Biomaterials

Nature is the source of inspiration for the fabrication of fascinating materials. Although the field of biomaterials has made huge progress in recent years, mimicking Nature remains an extremely challenging task. This is mainly due to the highly dynamic character of natural systems, which is complex to simulate artificially or synthetically. Noncovalent recognition motifs occurring through hydrogen bonding, π–π stacking, metal chelation, van der Waals, and hydrophobic interactions allow natural systems to continuously evolve, reshape and reorganize in time and space to fulfill specific functions. Another example that involves hydrogen bonding and hydrophobic effects is 1,3,5-Benzenetricarboxaldehyde (BTA)-based supramolecular polymers. The increased understanding gathered from fundamental studies on their assembly in water renders this class of materials highly promising for bioapplications. 1,3,5-Benzenetricarboxaldehydes are known to form μm-long 1D fibers via intermolecular 3-fold hydrogen bonding between the amides and hydrophobic effects and they have been proven to be highly dynamic. In this study, we assess the potential of water-compatible BTA derivatives as biomaterials both in the fiber and in the hydrogel state. By applying a fully realistic approach, the stability of different 1,3,5-Benzenetricarboxaldehyde homopolymers (BTA-OEG4, BTA-OEG4-Man, and BTA-Man) and copolymers (BTA-OEG4-Man/BTA-OEG4 and BTA-Man/BTA-OEG4) upon incubation with physiological concentrations of bovine serum albumin (BSA) was investigated.[2]

In particular, 1,3,5-Benzenetricarboxaldehyde-based supramolecular polymers have shown to be highly dynamic through the exchange of monomers within and between fibers, but their suitability as biomaterials has not been yet explored. Herein we systematically study the interactions of BTA supramolecular polymers bearing either tetraethylene glycol or mannose units at the periphery with different biological entities. When 1,3,5-Benzenetricarboxaldehyde fibers were incubated with bovine serum albumin (BSA), the protein conformation was only affected by the fibers containing tetraethylene glycol at the periphery (BTA-OEG4). Coarse-grained molecular simulations showed that BSA interacted with BTA-OEG4 fibers rather than with BTA-OEG4 monomers that are present in solution or that may exchange out of the fibers. Microscopy studies revealed that, in the presence of BSA, BTA-OEG4 retained their fiber conformation although their length was slightly shortened. When further incubated with fetal bovine serum (FBS), both long and short fibers were visualized in solution. Nevertheless, in the hydrogel state, the rheological properties were remarkably preserved. Further studies on the cellular compatibility of all the BTA assemblies and mixtures thereof were performed in four different cell lines. A low cytotoxic effect at most concentrations was observed, confirming the suitability of utilizing functional 1,3,5-Benzenetricarboxaldehyde supramolecular polymers as dynamic biomaterials.

In Situ Covalent Reinforcement of a 1,3,5-Benzenetricarboxaldehyde Supramolecular Polymer

To create a biomimetic, tough, and processable hydrogel, we took inspiration from nature's conjunction of self-assembly and covalent reinforcement. We designed a 1,3,5-Benzenetricarboxaldehyde (BTA) hydrogelator with norbornene (NB) functional handles that we surmised could self-assemble into 1D fibrils. We hypothesized that these biomimetic supramolecular assemblies could be fixed/cross-linked, ultimately leading to a tough hydrogel via intra- and interfiber cross-links. Via rheology and mechanical testing (compression and tensile), we discovered that the toughness, stiffness, and strength of the hydrogels could be tuned in biologically relevant regimes. Ultimately, this supramolecular-co-covalent strategy allowed the creation of remarkably tough 3D bioinks, which were explored for the 3D printing of an in vitro cartilage tissue model.[3]

The NB BTA hydrogel also exhibited room temperature recovery during ramped cyclic loading tests (between 20% and 80% strain), and no softening was observed. These norbornene 1,3,5-Benzenetricarboxaldehyde hydrogels were highly stretchable to ≈550% strain, and exhibited excellent shear-thinning, self-healing, and injectable properties. The NB BTA hydrogel allowed the 3D printing of gradient, yet cohesive, structures with distinct mechanical properties such as stiffness and toughness, and can remove the need to print different materials with different cross-linking mechanisms for each bioink. While tough supramolecular hydrogels have been reported before, this is the first synthetic 1D fibrillar and tough supramolecular hydrogel with the capacity to be bioprinted into complex 3D structures. The norbornene 1,3,5-Benzenetricarboxaldehyde hydrogel exhibited excellent biocompatibility with chondrocytes (ATDC5) and supported hMSC differentiation to produce cartilage-specific proteins. In addition, just like in the natural ECM, we were able to engineer cell-mediated matrix degradation and remodelability by cross-linking with a MMP cleavable peptide cross-linker.

References

[1]Schoenmakers SMC, van den Bersselaar BWL, Dhiman S, Su L, Palmans ARA. Facilitating functionalization of benzene-1,3,5-tricarboxamides by switching amide connectivity. Org Biomol Chem. 2021 Oct 6;19(38):8281-8294. doi: 10.1039/d1ob01587g. PMID: 34518862; PMCID: PMC8494077.

[2]Varela-Aramburu, S., Morgese, G., Su, L., Schoenmakers, S. M. C., Perrone, M., Leanza, L., Perego, C., Pavan, G. M., Palmans, A. R. A., & Meijer, E. W. (2020). Exploring the potential of benzene-1,3,5-tricarboxamide supramolecular polymers as biomaterials. Biomacromolecules, 21(10), 4105–4115.

[3]Hafeez, S., Decarli, M. C., Aldana, A., Ebrahimi, M., Ruiter, F. A. A., Duimel, H., van Blitterswijk, C., Pitet, L. M., Moroni, L., & Baker, M. B. (2023). In situ covalent reinforcement of a benzene-1,3,5-tricarboxamide supramolecular polymer enables biomimetic, tough, and fibrous hydrogels and bioinks. Advanced Materials, 35(35), 2301242.

You may like