An Easy Access to Organic Salt‐Based Stimuli‐Responsive and Multifunctional Supramolecular Hydrogels

By exploiting orthogonal hydrogen bonding involving supramolecular synthons and hydrophobic/hydrophilic interactions, a new series of simple organic salt based hydrogelators derived from pyrene butyric acid and its β‐alanine amide derivative, and various primary amines has been achieved. The hydrogels were characterised by microscopy, table‐top rheology and dynamic rheology. FTIR, variable‐temperature ¹H NMR and emission spectroscopy established the role of various supramolecular interactions such as hydrogen bonding and π–π stacking in hydrogelation. Single‐crystal X‐ray diffraction (SXRD) studies supported the conclusion that orthogonal hydrogen bonding involving amide–amide and primary ammonium monocarboxylate (PAM) synthons indeed played a crucial role in hydrogelation. The hydrogels were found to be stimuli‐responsive and were capable of sensing ammonia and adsorbing water‐soluble dye (methylene blue). All the hydrogelators were biocompatible (MTT assay in RAW 264.7 cells), indicating their suitability for use in drug delivery.     

Easy Access to Supramolecular Gels of the Nonsteroidal Anti‐inflammatory Drug Diflunisal: Synthesis,Characterization, and Plausible Biomedical Applications

By exploiting salt formation, a new series of primary ammonium monocarboxylate salts of a nonsteroidal anti‐inflammatory drug, namely, diflunisal, was synthesized. The majority of the salts thus synthesized turned out to be good gelators of various solvents, including the solvents (e.g., methyl salicylate and pure water) typically used for topical gel formulation. Single‐crystal X‐ray diffraction studies of a few gelator and nongelator salts in the series revealed details of the hydrogen‐bonding networks present in the salts. Furthermore, one such gelator salt, namely, the diflunisal salt of serinol, was found to be biocompatible (MTT assay), and its anti‐inflammatory (PGE₂ assay) response turned out to be as good as that of the parent drug, which is indicative of its potential in biomedical applications.     

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.     

Remarkable Shape‐Sustaining,Load‐Bearing,and Self‐Healing Properties Displayed by a Supramolecular Gel Derived from a Bis‐pyridyl‐bis‐amide of L‐Phenyl Alanine

A series of bis‐amides decorated with pyridyl and phenyl moieties derived from L ‐amino acids having an innocent side chain (L ‐alanine and L ‐phenyl alanine) were synthesized as potential low‐molecular‐weight gelators (LMWGs). Both protic and aprotic solvents were found to be gelled by most of the bis‐amides with moderate to excellent gelation efficiency (minimum gelator concentration=0.32–4.0 wt. % and gel–sol dissociation temperature T_gel=52–110 °C). The gels were characterized by rheology, DSC, SEM, TEM, and temperature‐variable ¹H NMR measurements. pH‐dependent gelation studies revealed that the pyridyl moieties took part in gelation. Structure–property correlation was attempted using single‐crystal X‐ray and powder X‐ray diffraction data. Remarkably, one of the bis‐pyridyl bis‐amide gelators, namely 3,3‐Phe (3‐pyridyl bis‐amide of L ‐phenylalanine) displayed outstanding shape‐sustaining, load‐bearing, and self‐healing properties.     

Primary Ammonium Monocarboxylate Synthon in Designing Supramolecular Gels: A New Series of Chiral Low‐Molecular‐Weight Gelators Derived from Simple Organic Salts that are Capable of Generating and Stabilizing Gold Nanoparticles

The primary ammonium monocarboxylate (PAM) synthon has been exploited to generate a new series of PAM salts from the free amine of L ‐phenylalanine‐3‐pyridyl amide, (S)‐2‐amino‐3‐phenyl‐N‐(pyridine‐3‐yl)propanamine (designated as “ B ”), and various substituted benzoic acids (designated as “ A(R) ”; R =4‐Me, 4‐Cl, 4‐Br, 4‐NO₂, 3‐Me, 3‐Cl, 3‐Br, 3‐NO₂, 2‐Me, 2‐Cl, 2‐Br, 2‐NO₂). The 4‐ and 3‐substituted benzoate salts showed moderate‐to‐excellent gelation ability with a number of polar and apolar solvents. The gels were characterized by DSC, rheology, SEM and TEM, FTIR spectroscopy, etc. Structure–property studies based on single‐crystal powder X‐ray diffraction (PXRD) and FTIR data provided insights into the role of the PAM synthon in the formation of the gel networks. Interestingly, some of the gels were capable of forming and stabilizing gold nanoparticles at room temperature without the use of any exogenous reducing agents.     

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.     

Tetraalkylammonium Salts as Hydrogen‐Bonding Catalysts

Although the hydrogen‐bonding ability of the α hydrogen atoms on tetraalkylammonium salts is often discussed with respect to phase‐transfer catalysts, catalysis that utilizes the hydrogen‐bond‐donor properties of tetraalkylammonium salts remains unknown. Herein, we demonstrate hydrogen‐bonding catalysis with newly designed tetraalkylammonium salt catalysts in Mannich‐type reactions. The structure and the hydrogen‐bonding ability of the new ammonium salts were investigated by X‐ray diffraction analysis and NMR titration studies.     

Supramolecular Self‐Assembly of Histidine‐Capped‐Dialkoxy‐Anthracene: A Visible‐Light‐Triggered Platform for Facile siRNA Delivery

Supramolecular self‐assembly of histidine‐capped‐dialkoxy‐anthracene (HDA) results in the formation of light‐responsive nanostructures. Single‐crystal X‐ray diffraction analysis of HDA shows two types of hydrogen bonding. The first hydrogen bond is established between the imidazole moieties while the second involves the oxygen atom of one amide group and the hydrogen atom of a second amide group. When protonated in acidic aqueous media, HDA successfully complexes siRNA yielding spherical nanostructures. This biocompatible platform controllably delivers siRNA with high efficacy upon visible‐light irradiation leading up to 90 % of gene silencing in live cells.     

Supramolecular Synthons in Designing Low Molecular Mass Gelling Agents: L‐Amino Acid Methyl Ester Cinnamate Salts and their Anti‐Solvent‐Induced Instant Gelation

Easy access to a class of chiral gelators has been achieved by exploiting primary ammonium monocarboxylate ( PAM ), a supramolecular synthon. A combinatorial library comprising of 16 salts, derived from 5 l ‐amino acid methyl esters and 4 cinnamic acid derivatives, has been prepared and scanned for gelation. Remarkably, 14 out of 16 salts prepared (87.5 % of the salts) show moderate to good gelation abilities with various solvents, including commercial fuels, such as petrol. Anti‐solvent induced instant gelation at room temperature has been achieved in all the gelator salts, indicating that the gelation process is indeed an aborted crystallization phenomenon. Rheology, optical and scanning electron microscopy, small angle neutron scattering, and X‐ray powder diffraction have been used to characterize the gels. A structure‐property correlation has been attempted, based on these data, in addition to the single‐crystal structures of 5 gelator salts. Analysis of the FT‐IR and ¹H NMR spectroscopy data reveals that some of these salts can be used as supramolecular containers for the slow release of certain pest sex pheromones. The present study clearly demonstrates the merit of crystal engineering and the supramolecular synthon approach in designing new materials with multiple properties.     

Supramolecular Gels by Design: Towards the Development of Topical Gels for Self‐Delivery Application

Following a supramolecular synthon approach, simple salt formation has been employed to gain access to a series of supramolecular gelators derived from the well‐known non‐steroidal anti‐inflammatory drug (NSAID) ibuprofen. A well‐studied gel‐inducing supramolecular synthon, namely primary ammonium monocarboxylate (PAM), has been exploited to generate a series of PAM salts by reacting ibuprofen with various primary amines. Remarkably, all of the salts ( S1 – S7 ) thus synthesized proved to be good to moderate gelators of various polar and nonpolar solvents. Single‐crystal and powder X‐ray diffraction studies established the existence of the PAM synthons in the gel network, confirming the efficacy of the supramolecular synthon approach employed. Most importantly, the majority of the salts ( S2 , S3 , S6 , and S7 ) were capable of gelling methyl salicylate (MS), an important ingredient found in many commercial topical gels. In vitro experiments (MTT and PGE₂ assays) revealed that all of the salts (except S3 and S7 ) were biocompatible (up to 0.5 mm concentration), and the most suited one, S6 , displayed anti‐inflammatory ability as good as that of the parent drug ibuprofen. A topical gel of S6 with methyl salicylate and menthol was found to be suitable for delivering the gelator drug in a self‐delivery fashion in treating skin inflammation in mice. Histological studies, including immunohistology, were performed to further probe the role of the gelator drug S6 in treating inflammation. Cell imaging studies supported cellular uptake of the gelator drug in such biomedical application.     

Supramolecular Hydrogels Based on L‐Phenylalanine Derivatives with a Positively Charged Terminal Group

A new hydrogelator based on L ‐phenylalanine with a long hydrophobic chain and positively charged terminus was synthesized, and its gelation behavior in H₂O was investigated. Polarized optical microscopy (POM), field emission scanning electron microscopy (FE‐SEM), and X‐ray diffraction (XRD) results indicate that the hydrogelator self‐assembles into fibres‐like aggregates which then lead to the formation of a hydrogel. ¹H‐NMR and CD spectra of hydrogels and aqueous solution revealed that intermolecular H‐bonding between the amide groups was the driving force for gelation. A luminescence study, in which ANS (8‐anilinonaphthalene‐1‐sulfonic acid) was used as a probe, indicated that the hydrophobic interactions between long chains were the driving force for gelation. Consequently, it was proved that the hydrogelator self‐assembles into fibre‐like aggregates and then forms supramolecular hydrogels through the H‐bonding and hydrophobic interactions.     

Gelation‐Induced Enhanced Fluorescence Emission from Organogels of Salicylanilide‐Containing Compounds Exhibiting Excited‐State Intramolecular Proton Transfer: Synthesis and Self‐Assembly

Self‐assembly structure, stability, hydrogen‐bonding interaction, and optical properties of a new class of low molecular weight organogelators (LMOGs) formed by salicylanilides 3 and 4 have been investigated by field‐emission scanning electron microscopy (FESEM), X‐ray diffraction (XRD), UV/Vis absorption and photoluminescence, as well as theoretical studies by DFT and semiempirical calculations with CI (AM1/PECI=8) methods. It was found that salicylanilides form gels in nonpolar solvents due to π‐stacking interaction complemented by the presence of both inter‐ and intramolecular hydrogen bonding. The supramolecular arrangement in these organogels predicted by XRD shows lamellar and hexagonal columnar structures for gelators 3 and 4 , respectively. Of particular interest is the observation of significant fluorescence enhancement accompanying gelation, which was ascribed to the formation of J‐aggregates and inhibition of intramolecular rotation in the gel state.     

Hydrogen‐bonding‐aided synthesis of novel ladderlike organobridged polysiloxane containing side‐chain naphthyl groups

With a hydrogen‐bonding template, a novel soluble aryl amide‐bridged ladderlike polysiloxane, containing naphthyl as the side‐chain group, has been successfully synthesized via a stepwise coupling polymerization. It is proposed that the monomer, N,N′‐di(3‐naphthyldiethoxylsilyl‐propyl)‐[4,4′‐oxybis(benzyl amide)], prepared by Grignard and hydrosilylation reactions, undergoes self‐assembly first via amido hydrogen bonding and then via hydrolysis, followed by condensation under controlled reaction conditions to yield a high molecular weight, soluble, dark yellow polymer. The analytical results (Fourier transform infrared, ¹H NMR, ²⁹Si NMR, X‐ray diffraction, differential scanning calorimetry, and vapor pressure osmometry) show that the polymer possesses an ordered ladderlike architecture. © 2003 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 41: 636–644, 2003     

Rational Approach Towards Designing Metallogels From a Urea‐Functionalized Pyridyl Dicarboxylate: Anti‐inflammatory,Anticancer, and Drug Delivery

A structural rationale was adopted to design a series of metallogels from a newly synthesized urea‐functionalized dicarboxylate ligand, namely, 5‐[3‐(pyridin‐3‐yl)ureido]isophthalic acid ( PUIA ), that produces metallogels upon reaction with various metal salts (Cu^II, Zn^II, Co^II, Cd^II, and Ni^II salts) at room temperature. The gels were characterized by dynamic rheology and transmission electron microscopy (TEM). The existence of a coordination bond in the gel state was probed by FTIR and ¹H NMR spectroscopy in a Zn^II metallogel (i.e., MG2 ). Single crystals isolated from the reaction mixture of PUIA and Co^II or Cd^II salts characterized by X‐ray diffraction revealed lattice inclusion of solvent molecules, which was in agreement with the hypothesis based on which the metallogels were designed. MG2 displayed anti‐inflammatory response (prostaglandin E₂ assay) in the macrophage cell line (RAW 264.7) and anticancer properties (cell migration assay) on a highly aggressive human breast cancer cell line (MDA‐MB‐231). The MG2 metallogel matrix could also be used to load and release (pH responsive) the anticancer drug doxorubicin. Fluorescence imaging of MDA‐MB‐231 cells treated with MG2 revealed that it was successfully internalized.     

Organo‐ and Hydrogelators Based on Luminescent Monocationic Terpyridyl Platinum(II) Complexes with Biphenylacetylide Ligands

A series of phosphorescent terpyridyl platinum(II) complexes with ancillary biphenylacetylide ligands, namely, [(R₃tpy)PtC≡C(biphenyl)]X (R=tBu, H, or Et₂N; tpy=2,2′;6′,2′′‐terpyridyl; X is an anion) were synthesized and structurally characterized by various spectroscopic techniques and X‐ray diffraction methods. Despite a lack of long alkyl chain(s) or hydrogen‐bonding motif(s), complexes [(tpy)PtC≡C(biphenyl)]Cl and [(tBu₃tpy)PtC≡C(biphenyl)]X (X=Cl, ClO₄, PF₆, or BF₄) were found to gelate water and organic solvents, respectively. The self‐aggregation of these complexes in solutions and the resulting gels were investigated with variable‐temperature (VT) ¹H NMR spectroscopy, polarized optical microscopy, and absorption/emission spectroscopy. SEM micrographs on dry gels revealed entangled nanofibers with diameters of 20–40 nm and lengths of tens of micrometers. Powder X‐ray diffraction (PXRD) study revealed various degrees of crystallinity of these fibrillar nanostructures. The substituents on both the terpyridyl and acetylide ligands and counterion of these complexes play a profound but concerted role in tuning the intermolecular metal???metal and/or π–π interactions, and hence the gelation properties.     

Orthogonal Halogen‐Bonding‐Driven 3D Supramolecular Assembly of Right‐Handed Synthetic Helical Peptides

Peptide‐mediated self‐assembly is a prevalent method for creating highly ordered supramolecular architectures. Herein, we report the first example of orthogonal C?X???X?C/C?X???π halogen bonding and hydrogen bonding driven crystalline architectures based on synthetic helical peptides bearing hybrids of l ‐sulfono‐γ‐AApeptides and natural amino acids. The combination of halogen bonding, intra‐/intermolecular hydrogen bonding, and intermolecular hydrophobic interactions enabled novel 3D supramolecular assembly. The orthogonal halogen bonding in the supramolecular architecture exerts a novel mechanism for the self‐assembly of synthetic peptide foldamers and gives new insights into molecular recognition, supramolecular design, and rational design of biomimetic structures.     

Hydrogen bonding driven self‐assembly of side‐chain amino acid and fatty acid appended poly(methacrylate)s: Gelation and application in oil spill recovery

We report an interesting class of fatty acid appended side‐chain phenylalanine (Phe) containing poly(methacrylate) homopolymers that undergo self‐assembly leading to gelation in selective organic hydrocarbons, due to association among the side‐chain functionalities. Fatty acids of different n‐alkyl chain lengths have been attached to the N‐terminal of the Phe‐based methacrylate and the corresponding homopolymers have been synthesized via reversible addition–fragmentation chain transfer polymerization. These homopolymers undergo gelation in selective organic hydrocarbons. The morphology of these organogels has been characterized by field emission scanning electron microscopy which revealed macroporous structure of the organogels. Viscoelastic properties of organogels and the thermoreversible gel‐to‐sol transition have been investigated by rheological measurements. Powder X‐ray diffraction study has been performed to understand the effect of long n‐alkyl chains on the gelation process. FTIR study reveals inter‐/intra‐chain hydrogen bonding which is the driving force of organogelation of the polymers in suitable solvents. In absence of hydrogen bonding interaction, hydrophobic association fails to direct the self‐assembly process and no gelation is observed. An interesting feature of the homopolymeric gelators is that it can selectively congeal the diesel part from an oil–water biphasic mixture, which might be useful in oil spill treatment. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 511–521     

Thermally Stable 3,6‐Dinitropyrazolo[4,3‐c]pyrazole‐based Energetic Materials

3,6‐Dinitropyrazolo[4,3‐c]pyrazole was prepared using an efficient modified process. With selected cations, ten nitrogen‐rich energetic salts and three metal salts were synthesized in high yield based on the 3,6‐dinitropyrazolo[4,3‐c]pyrazolate anion. These compounds were fully characterized by IR and multinuclear NMR spectroscopies, as well as elemental analyses. The structures of the neutral compounds 4 and its salt 16 were confirmed by single‐crystal X‐ray diffraction showing extensive hydrogen‐bonding interactions. The neutral pyrazole precursor and its salts are remarkably thermally stable. Based on the calculated heats of formation and measured densities, detonation pressures (22.5–35.4 GPa) and velocities (7948–9005 m s^?1) were determined, and they compare favorably with those of TNT and RDX. Their impact and friction sensitivities range from 12 to >40 J and 80 to 360 N, respectively. These properties make them competitive as insensitive and thermally stable high‐energy density materials.     

Formation of Self‐Templated 2,6‐Bis(1,2,3‐triazol‐4‐yl)pyridine [2]Catenanes by Triazolyl Hydrogen Bonding: Selective Anion Hosts for Phosphate

We report the remarkable ability of 2,6‐bis(1,2,3‐triazol‐4‐yl)pyridine ( btp ) compounds 2 with appended olefin amide arms to self‐template the formation of interlocked [2]catenane structures 3 in up to 50 % yield when subjected to olefin ring‐closing metathesis in CH₂Cl₂. X‐ray diffraction crystallography enabled the structural characterization of both the [2]catenane 3 a and the non‐interlocked macrocycle 4 a . These [2]catenanes showed selective triazolyl hydrogen‐bonding interactions with the tetrahedral phosphate anion when screened against a range of ions; 3 a , b are the first examples of selective [2]catenane hosts for phosphate.     

Halide Anion Mediated Dimerization of a meso‐Unsubstituted N‐Confused Porphyrin

The new N‐confused porphyrin (NCP) derivatives, meso‐unsubstituted β‐alkyl‐3‐oxo N‐confused porphyrin (3‐oxo‐NCP) and related macrocycles, were synthesized from appropriate pyrrolic precursors by a [3+1]‐type condensation reaction. 3‐Oxo‐NCP forms a self‐assembled dimer in dichloromethane that is stabilized by complementary hydrogen‐bonding interactions arising from the peripheral amide‐like moieties. The protonated form of 3‐oxo‐NCP was observed to bind halide anions (F^?, Cl^?) through the outer NH and the inner pyrrolic NH groups, thus affording a dimer in dichloromethane. The structure of the chloride‐bridged dimer in the solid state was determined by X‐ray diffraction analysis.