Desymmetrization via Activated Esters Enables Rapid Synthesis of Multifunctional Benzene-1,3,5-tricarboxamides and Creation of Supramolecular Hydrogelators

Abstract

Supramolecular materials based on the self-assembly of benzene-1,3,5-tricarboxamide (BTA) offer an approach to mimic fibrous self-assembled proteins found in numerous natural systems. Yet, synthetic methods to rapidly build complexity, scalability, and multifunctionality into BTA-based materials are needed. The diversity of BTA structures is often hampered by the limited flexibility of existing desymmetrization routes and the purification of multifunctional BTAs. To alleviate this bottleneck, we have developed a desymmetrization method based on activated ester coupling of a symmetric synthon. We created a small library of activated ester synthons and found that a pentafluorophenol benzene triester (BTE) enabled effective desymmetrization and creation of multifunctional BTAs in good yield with high reaction fidelity. This new methodology enabled the rapid synthesis of a small library of BTA monomers with hydrophobic and/or orthogonal reactive handles and could be extended to create polymeric BTA hydrogelators. These BTA hydrogelators self-assembled in water to create fiber and fibrous sheet-like structures as observed by cryo-TEM, and the identity of the BTA conjugated can tune the mechanical properties of the hydrogel. These hydrogelators display high cytocompatibility for chondrocytes, indicating potential for the use of these systems in 3D cell culture and tissue engineering applications. This newly developed synthetic strategy facilitates the simple and rapid creation of chemically diverse BTA supramolecular polymers, and the newly developed and scalable hydrogels can unlock exploration of BTA based materials in a wider variety of tissue engineering applications.

Advanced supramolecular design for direct ink writing of soft materials

“…Supramolecularly designed inks for DIW started to attract more awareness in chemistry, materials science, and engineering communities due to their highly dynamic and reversible features. 20,69 3D-printed soft materials with self-healing properties, 59,166,167,192 enhanced mechanical strength, 163,193,194 multiple-stimuli responsiveness, 74,78,144,193 and complex shape-morphing capabilities 203,205,209 have been demonstrated and discussed in this review. These exciting features come from the functional motifs that are hydrogen bonded, 253 host–guest bound, 118 metal–ligand coordinated, 131 or assembled via van der Waals forces.…”

“…12(c)). 166 At a concentration of 10 w/v%, BTA(C 6/12 ) 2 -PEG 20k and BTA(C 12/12 ) 2 -PEG 20k formed stable hydrogels with an elastic modulus of ∼10 4 Pa. Step-strain sweeps (Fig. 12(d)) showed that the BTA(C 6/6 ) 2 -PEG 20k and BTA(C 6/12 ) 2 -PEG 20k hydrogels possess good self-healing properties, making them promising for DIW.…”

Supramolecular Biomaterials in the Netherlands

“…(H) BTAs are now starting to be interfaced in biological applications and are well poised to have a rich history in tissue engineering and biomaterial applications. Their multiarm structure and one-dimensional self-assembly can be leveraged to form complex fibrous architectures as seen in the native ECM (Reprinted [adapted] with permission from Hafeez et al 99 Under CC BY 4.0). (I) Dynamic covalent crosslinked hydrogels, although not strictly supramolecular, share many of the same features and properties due to their dynamic hydrogel architectures.…”

“…With a rich history of fundamental supramolecular studies, the recent translation of these architectures to water-soluble derivatives 95,96 bodes well for their ultimate use in tissue engineering, drug delivery, and other biomedical applications. Recent insight into the biocompatibility of these supramolecular polymers, 97 their use in the interfacing with a red blood cell's surface, 98 and improved synthesis toward hydrogels for cellular encapsulation 99 suggests that their use in tissue engineering should be a rich area of exploration in the future.…”

Bis-Pyridine-Based Organogel with AIE Effect and Sensing Performance towards Hg2+

“…In the past thirty years, supramolecular chemistry has become even more sophisticated and quickly developed due to its applications in a variety of disciplines and fields [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. As a typical supramolecular material, low-molecular-weight gels (LMWGs) are a kind of soft material between a solid and liquid which have been developed rapidly and widely used in electrolyte materials [ 12 ], sensors [ 13 , 14 ], drug delivery systems [ 15 ], liquid crystal [ 16 ], supramolecular chirality [ 17 , 18 , 19 ], light-harvesting systems [ 20 , 21 ], surfactants [ 22 ] and other fields [ 23 , 24 , 25 , 26 , 27 , 28 ]. Organic molecules can be self-assembled into organogel or hydrogel under the driving force of noncovalent interactions, such as a hydrogen bond, metal coordination, π–π stacking, hydrophobic effect, electrostatic force and van der Waals force [ 29 , 30 , 31 , 32 , 33 ].…”