Multidrug‐Containing,Salt‐Based,Injectable Supramolecular Gels for Self‐Delivery,Cell Imaging and Other Materials Applications

Both molecular and crystal‐engineering approaches were exploited to synthesize a new class of multidrug‐containing supramolecular gelators. A well‐known nonsteroidal anti‐inflammatory drug, namely, indomethacin, was conjugated with six different l ‐amino acids to generate the corresponding peptides having free carboxylic acid functionality, which reacted further with an antiviral drug, namely, amantadine, a primary amine, in 1:1 ratio to yield six primary ammonium monocarboxylate salts. Half of the synthesized salts showed gelation ability that included hydrogelation, organogelation and ambidextrous gelation. The gels were characterized by table‐top and dynamic rheology and different microscopic techniques. Further insights into the gelation mechanism were obtained by temperature‐dependent ¹H NMR spectroscopy, FTIR spectroscopy, photoluminescence and dynamic light scattering. Single‐crystal X‐ray diffraction studies on two gelator salts revealed the presence of 2D hydrogen‐bonded networks. One such ambidextrous gelator (capable of gelling both pure water and methyl salicylate, which are important solvents for biological applications) was promising in both mechanical (rheoreversible and injectable) and biological (self‐delivery) applications for future multidrug‐containing injectable delivery vehicles.     

Metal–Organic Gels Derived from Iron(III) and Pyridine Ligands: Morphology,Self‐Healing and Catalysis for Ethylene Selective Dimerization

Metal‐organic gels showing potential application in catalysis have received much concern. In this work, we designed and synthesized two metal‐organic gels based on coordination between Fe^III and pyridine ligands at room temperature. The gels were characterized by X‐ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) to reveal their assembly structures and morphologies, and it was found the metal‐organic gel derived from di‐topic ligand was composed of three‐dimensional network of nanofibers, while the gel derived from tri‐topic ligand was constituted of sponge‐like structure with amorphous phase. Rheological analysis showed the gel consisting of nanofiber networks displayed self‐healing property. The gels were used as catalysts for selective ethylene dimerization, and the optimum catalysis results of the gel with nanofibers reached the maximal catalytic activity of 1.48×10⁵ g/(mol Fe?h) with C₄ yield more than 90 %, whereas the sponge‐like gel only gave 38 % C₄ products at the same condition. The higher dimerization selectivity of the former Fe^III gel was attributed to its regular assembly structure and lower steric hindrance of the surface metal sites. Due to its catalytic activity, high selectivity and preparation simplicity, the Fe^III gel might be potentially applicable for the preparation of C₄ α‐olefins.     

Effect of the Bulkiness of the End Functional Amide Groups on the Optical,Gelation, and Morphological Properties of Oligo(p‐phenylenevinylene) π‐Gelators

Herein, we describe the role of end functional groups in the self‐assembly of amide‐functionalized oligo(p‐phenylenevinylene) (OPV) gelators with different end‐groups. The interplay between hydrogen‐bonding and π‐stacking interactions was controlled by the bulkiness of the end functional groups, thereby resulting in aggregates of different types, which led to the gelation of a wide range of solvents. The variable‐temperature UV/Vis absorption and fluorescence spectroscopic features of gelators with small end‐groups revealed the formation of 1D H‐type aggregates in CHCl₃. However, under fast cooling in toluene, 1D H‐type aggregates were formed, whereas slow cooling resulted in 2D H‐type aggregates. OPV amide with bulky dendritic end‐group formed hydrogen‐bonded random aggregates in toluene and a morphology transition from vesicles into fibrous aggregates was observed in THF. Interestingly, the presence of bulky end‐group enhanced fluorescence in the xerogel state and aggregation in polar solvents. The difference between the aggregation properties of OPV amides with small and bulky end‐groups allowed the preparation of self‐assembled structures with distinct morphological and optical features.     

Peptide Conjugates of a Nonsteroidal Anti‐Inflammatory Drug as Supramolecular Gelators: Synthesis,Characterization, and Biological Studies

Indomethacin ( IND ), which is a well‐known nonsteroidal anti‐inflammatory drug (NSAID), was conjugated with various naturally occurring amino acids. Most of these bioconjugates were capable of gelling pure water, a solution of NaCl (0.9 wt %), and phosphate‐buffered saline (pH 7.4), as well as a few organic solvents. The gels were characterized by table‐top and dynamic rheology, and electron microscopy. Variable‐temperature ¹H NMR spectroscopy studies on a selected gel were performed to gain insights into the self‐assembly process during gel formation. Both 1D and 2D hydrogen‐bonded networks were observed in the single‐crystal structures of two of the gelators. Plausible biological applications of the hydrogelators were evaluated with the ultimate aim of drug delivery in a self‐delivery fashion. All hydrogelators were stable in phosphate‐buffered saline at pH 7.4 at 37 °C, and biocompatible in mouse macrophage RAW 264.7 cell line (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assay). Two of the most biocompatible hydrogelators displayed an anti‐inflammatory response comparable to that of the parent drug IND in prostaglandin E₂ assay. Release of the bioconjugates into the bulk solvent interfaced with the corresponding hydrogels indicated their plausible future application in drug delivery.     

Exploring Orthogonal Hydrogen Bonding towards Designing Organic‐Salt‐Based Supramolecular Gelators: Synthesis,Structures, and Anticancer Properties

A series of primary ammonium monocarboxylate (PAM) salts derived from β‐alanine derivatives of pyrene and naphthalene acetic acid, along with the parent acids, were explored to probe the plausible role of orthogonal hydrogen bonding resulting from amide???amide and PAM synthons on gelation. Single‐crystal X‐ray diffraction (SXRD) studies were performed on two parent acids and five PAM salts in the series. The data revealed that orthogonal hydrogen bonding played an important role in gelation. Structure–property correlation based on SXRD and powder X‐ray diffraction data also supported the working hypothesis upon which these gelators were designed. 3‐(4,5‐Dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) and cell migration assay on a highly aggressive human breast cancer cell line, MDA‐MB‐231, revealed that one of the PAM salts in the series, namely, PAA.B2 , displayed anticancer properties, and internalization of the gelator salt in the same cell line was confirmed by cell imaging.     

Phosphate‐Triggered Self‐Assembly of N‐[(Uracil‐5‐yl)methyl]urea: A Minimalistic Urea‐Derived Hydrogelator

N‐[(Uracil‐5‐yl)methyl]urea is reported as a minimalistic low‐molecular‐weight hydrogelator (LMWHG). The unusual phosphate‐induced assembly of this compound has been thoroughly investigated by IR, UV/Vis, and NMR spectroscopy, electron microscopy, and rheological experiments. This rare example of an anion‐triggered urea‐based LMWHG is the first example of a pyrimidine‐ and urea‐containing molecule that can be forced into self‐assembly in aqueous solution without additional aromatic or lipophilic groups. The gelator/phosphate ratio within the hydrogel was successfully determined by ³¹P MAS NMR spectroscopy. The hydrogel exhibits a very fast and repeatable self‐healing property, and remarkable G′ values. The viscoelastic properties of the hydrogel can easily be tuned by variation of the phosphate ratio.     

Amino Acid Based Low‐Molecular‐Weight Ionogels as Efficient Dye‐Adsorbing Agents and Templates for the Synthesis of TiO2 Nanoparticles

The gelation of ionic liquids is attracting significant attention because of its large spectrum of applications across different disciplines. These ‘green solvents’ have been the solution to a number of common problems due to their eco‐friendly features. To expand their applications, the gelation of ionic liquids has been achieved by using amino acid‐based low‐molecular‐weight compounds. Variation of individual segments in the molecular skeleton of the gelators, which comprise the amino acid and the protecting groups at the N and C termini, led to an understanding of the structure–property correlation of the ionogelation process. An aromatic ring containing amino acid‐based molecules protected with a phenyl or cyclohexyl group at the N terminus were efficient in the gelation of ionic liquids. In the case of aliphatic amino acids, gelation was more prominent with a phenyl group as the N‐terminal protecting agent. The probable factors responsible for this supramolecular association of the gelators in ionic liquids have been studied with the help of field‐emission SEM, ¹H NMR, FTIR, and luminescence studies. It is the hydrophilic–lipophilic balance that needs to be optimized for a molecule to induce gelation of the green solvents. Interestingly, to maximize the benefits from using these green solvents, these ionogels have been employed as templates for the synthesis of uniform‐sized TiO₂ nanoparticles (25–30 nm). Furthermore, as a complement to their applications, ionogels serve as efficient adsorbents of both cationic and anionic dyes and were distinctly better relative to their organogel counterparts.     

Synthesis of Structurally Varied 1,3‐Disiloxanediols and Their Activity as Anion‐Binding Catalysts

A series of new 1,3‐disiloxanediols has been synthesized, including naphthyl‐substituted and unsymmetrical siloxanes, and demonstrated as a new class of anion‐binding catalysts. In the absence of anions, diffusion‐ordered spectroscopy (DOSY) displays self‐association of 1,3‐disiloxanediols through hydrogen‐bonding interactions. Binding constants determined for 1,3‐disiloxanediol catalysts indicate strong hydrogen‐bonding and anion‐binding abilities with unsymmetrical siloxanes displaying different hydrogen‐bonding abilities for each silanol group.     

Oligo(p‐phenylene‐ethynylene)‐Derived Super‐π‐Gelators with Tunable Emission and Self‐Assembled Polymorphic Structures

Linear π‐conjugated oligomers are known to form organogels through noncovalent interactions. Herein, we report the effect of π‐repeat units on the gelation and morphological properties of three different oligo(p‐phenylene‐ethynylene)s: OPE3 , OPE5 , and OPE7 . All of these molecules form fluorescent gels in nonpolar solvents at low critical gel concentrations, thereby resulting in a blue gel for OPE3 , a green gel for OPE5 , and a greenish yellow gel for OPE7 . The molecule–molecule and molecule–substrate interactions in these OPEs are strongly influenced by the conjugation length of the molecules. Silicon wafer suppresses substrate–molecule interactions whereas a mica surface facilitates such interactions. At lower concentrations, OPE3 formed vesicular assemblies and OPE5 gave entangled fibers, whereas OPE7 resulted in spiral assemblies on a mica surface. At higher concentrations, OPE3 and OPE5 resulted in super‐bundles of fibers and flowerlike short‐fiber agglomerates when different conditions were applied. The number of polymorphic structures increases on increasing the conjugation length, as seen in the case of OPE7 with n=5, which resulted in a variety of exotic structures, the formation of which could be controlled by varying the substrate, concentration, and humidity.     

From Nongelating to Gelating: Synthesis and Structural Self‐Assembling Property Relationships of a Homologous Series of Oligo(amide–triazole)s

A homologous series of oligo(amide–triazole)s (OAT) [ OAT‐CO₂H‐2 n and OAT‐COPrg‐(2 n +1) ] with an increasing number of primary amide (CONH) and triazole hydrogen‐bonding functionalities was prepared by an iterative synthetic procedure. It was found that their self‐assembly and thermoreversible gelation strength had a strong correlation to the number of hydrogen‐bonding moieties in the oligomers. There also existed a threshold value of the number of CONH units, above which all the oligomers became organogelators. Hence, oligomers with ≤4 CONH units are devoid of intermolecular hydrogen bonding and also non‐organogelating, whereas those that contain >4 CONH units show intermolecular association and organogelating properties. For the organogelators, the T_gel value increases monotonically with increasing number of CONH units. On the basis of FTIR measurements, both the CONH and triazole C? H groups were involved in the hydrogen‐bonding process. A mixed xerogel that consisted of a 1:1 weight ratio of two oligomers of different lengths ( OAT‐CO₂H‐6 and OAT‐CO₂H‐12 ) was found to show microphase segregation according to differential scanning calorimetry, thus indicating that oligomers that bear a different number of hydrogen‐bonding units exhibited self‐sorting to maximize the extent of intermolecular hydrogen bonding in the xerogel state.     

3‐[4′‐(Diethylboryl)phenyl]pyridine: Exclusive Crystallization of the Cyclic Tetramer

The crystallization of 3‐[4′‐(diethylboryl)phenyl]pyridine ( 1 ), which formed a mixture of oligomers in solution with the cyclic trimer as a major component, in acetone at 0 °C afforded a cyclic tetramer that co‐crystallized with solvent molecules. Similarly, solutions of compound 1 in toluene at 10 °C and in benzene at 8 °C furnished the cyclic tetramer with the incorporation of toluene and benzene molecules, respectively, thus suggesting that the cyclic tetramer was the minor component. ¹³C CP/MAS NMR spectroscopy of precipitates of compound 1 suggested that precipitation from acetone and toluene each afforded mixtures of the cyclic trimer and the cyclic tetramer, whereas precipitation from benzene exclusively furnished the cyclic tetramer. Therefore, it appeared that crystallization readily shifted the equilibrium towards the cyclic tetramer in benzene. The thermodynamic parameters for the equilibrium between these two oligomers in [D₆]benzene, as determined from a van′t Hoff plot, were ΔH°=?8.8 kcal mol^?1 and ΔS°=?23.7 cal mol^?1 K^?1, which were coincident with previously reported calculations and observations.     

Tunable Gel Formation by Both Sonication and Thermal Processing in a Cholesterol‐Based Self‐Assembly System

Sonication‐induced gelation : Adaptive gels that are responsive to ultrasound were prepared and characterized. The self‐assembly of the gelators can be controlled by ultrasound (S‐gel) stimuli and renewed by a thermodynamic process (T‐gel, see images).

     

Self‐Assembly of π‐Conjugated Gelators into Emissive Chiral Nanotubes: Emission Enhancement and Chiral Detection

A series of new π‐conjugated gelators that contain various aromatic rings (phenyl, naphthyl, 9‐anthryl) and amphiphilic L ‐glutamide was designed, and their gel formation in organic solvents and self‐assembled nanostructures was investigated. The gelators showed good gelation ability in various organic solvents that ranged from polar to nonpolar. Those gelator molecules with small rings such as phenyl and naphthyl self‐assembled into nanotube structures in most organic solvents and showed strong blue emission. However, the 9‐anthryl derivative formed only a nanofiber structure in any organic solvent, probably owing to the larger steric hindrance. All of these gels showed enhanced fluorescence in organogels. Furthermore, during the gel formation, the chirality at the L ‐glutamide moiety was transferred to the nanostructures, thus leading to the formation of chiral nanotubes. One of the nanotubes showed chiral recognition toward the chiral amines.     

Gel Sculpture: Moldable,Load‐Bearing and Self‐Healing Non‐Polymeric Supramolecular Gel Derived from a Simple Organic Salt

An easy access to a library of simple organic salts derived from tert‐butoxycarbonyl (Boc)‐protected L ‐amino acids and two secondary amines (dicyclohexyl‐ and dibenzyl amine) are synthesized following a supramolecular synthon rationale to generate a new series of low molecular weight gelators (LMWGs). Out of the 12 salts that we prepared, the nitrobenzene gel of dicyclohexylammonium Boc‐glycinate ( GLY.1 ) displayed remarkable load‐bearing, moldable and self‐healing properties. These remarkable properties displayed by GLY.1 and the inability to display such properties by its dibenzylammonium counterpart ( GLY.2 ) were explained using microscopic and rheological data. Single crystal structures of eight salts displayed the presence of a 1D hydrogen‐bonded network (HBN) that is believed to be important in gelation. Powder X‐ray diffraction in combination with the single crystal X‐ray structure of GLY.1 clearly established the presence of a 1D hydrogen‐bonded network in the xerogel of the nitrobenzene gel of GLY.1 . The fact that such remarkable properties arising from an easily accessible (salt formation) small molecule are due to supramolecular (non‐covalent) interactions is quite intriguing and such easily synthesizable materials may be useful in stress‐bearing and other applications.     

Introducing a Hydrogen‐Bond Donor into a Weakly Nucleophilic Brønsted Base: Alkali Metal Hexamethyldisilazides (MHMDS,M=Li,Na, K,Rb and Cs) with Ammonia

Alkali metal 1,1,1,3,3,3‐hexamethyldisilazide (MHMDSs) are one of the most utilised weakly nucleophilic Brønsted bases in synthetic chemistry and especially in natural product synthesis. Like lithium organics, they aggregate depending on the employed donor solvents. Thus, they show different reactivity and selectivity as a function of their aggregation and solvation state. To date, monomeric LiHMDS with monodentate donor bases was only characterised in solution. Since the first preparation of LiHMDS in 1959 by Wannagat and Niederprüm, all efforts to crystallise monomeric LiHMDS in the absence of chelating ligands failed. Herein, we present ammonia adducts of LiHMDS, NaHMDS, KHMDS, RbHMDS and CsHMDS with unprecedented aggregation motifs: 1) The hitherto missing monomeric key compound in the LiHMDS aggregation architectures. Monomeric crystal structures of trisolvated LiHMDS ( 1 ) and NaHMDS ( 2 ), showing unique intermolecular hydrogen bonds, 2) the unprecedented tetrasolvated KHMDS ( 3 ) and RbHMDS ( 4 ) dimers and 3) the disolvated CsHMDS ( 5 ) dimer with very close intermolecular Si?CH₃???Cs s‐block “agostic” interactions have been prepared and characterised by single‐crystal X‐ray structure analysis.     

Amido‐3‐hydroxypyridin‐4‐ones as Iron(III) Ligands

The synthesis and physicochemical properties of a range of 2‐ and 6‐amido‐3‐hydroxypyridin‐4‐ones are described. All the amido‐substituted 3‐hydroxypyridin‐4‐ones have lower pK_a values than 1,2‐dimethyl‐3‐hydroxypyridin‐4‐one (deferiprone). This is due to the inductive effect of the amido group. Furthermore, the pK_a values of the 3‐hydroxy group in 1‐nonsubstituted pyridinones are dramatically lower than those of the corresponding 1‐alkyl analogues, indicating that a strong hydrogen bond exists between the 2‐amido function and the 3‐oxygen anion, which stabilises the anion. As a result of the decreased competition with protons, the pFe³⁺ values of this group of molecules are higher than that of deferiprone. The distribution coefficients of these molecules are also increased despite the lack of a hydrophobic 1‐alkyl substituent and this is ascribed to the intramolecular hydrogen bond. X‐ray diffraction studies confirm the existence of the intramolecular hydrogen bond.