Synthesis and Vesicle Formation of Ethyl 2-[2′-(F-alkyl)ethyl] 2-alkyl Malonic Acid Disodium Salts

Abstract

A series of new di-anionic perfluoroalkylated amphiphiles with mixed F-alkyl/alkyl long chains and a malonic acid disodium salt head group has been synthesized. Among these new F-alkyl-containing amphiphiles, some were found to self-assemble in stable vesicles by hand shaking in water at room temperature. The vesicular aggregates were viewed by freeze-fracture electron microscopy and measured with photon correlation spectroscopy. Surface-activity of all amphiphiles was also investigated. Their CMCs were in particular determined from curves giving surface tension versus concentration.     

Supramolecular assemblies of nucleoside phosphocholine amphiphiles

A family of new uridine phosphocholine amphiphiles that were prepared using a convenient four-step synthetic route is described. Physicochemical studies (differential scanning calorimetry, small-angle X-ray scattering, UV-vis and circular dichroism spectroscopies, light microscopy, transmission electronic microscopy, and scanning electron microscopy) show that these amphiphiles spontaneously assemble into supramolecular structures including vesicles, fibers, hydrogels, and organogels. In aqueous solution, the amphiphiles possessing saturated alkyl chains self-assemble into DNA-like helical fibers in the crystalline state below T(m) and compact bilayers above the melting temperature (T(m)). The transition from bilayers to fibers is thermally reversible. Above a threshold concentration (>6% w/w), a hydrogel is formed due to an entangled network of the fibers. A therapeutic agent such as DNA can be entrapped within the hydrogel structure. In addition to forming bilayer vesicles and hydrogels in aqueous solution, these nucleoside amphiphiles also form organogels in cyclohexane above T(m). Scanning electron microscopy shows a continuous multilamellar phase in the organogels.     

Re-entrant Photoinduced Morphological Transformation and Temperature-Dependent Kinetic Products of a Rectangular Amphiphilic Diarylethene Assembly

An amphiphilic rectangular-shaped photochromic diarylethene bearing two hydrophobic alkyl chains and two hydrophilic tri(ethylene glycol) chains was synthesized, and its photoinduced morphological transformation in water was investigated. Two unexpected phenomena were revealed in the course of the experiments: a re-entrant photoinduced macroscopic morphological transformation and temperature-dependent kinetic products of supramolecular assembly. When the pure closed-ring isomer was dispersed in water, a re-entrant photoinduced morphological transformation, that is, a photoinduced transition from the hydrated phase to the dehydrated phase and then back to the hydrated phase, was observed by optical microscopy upon irradiation with green light at 20 °C; this was interpreted by the V-shaped phase diagram of the LCST transition. The aqueous assembly of the pure closed-ring isomer was controlled by changing the temperature; specifically, rapid cooling to 15 and 5 °C gave J and H aggregates, respectively, as the kinetic products. The thermodynamic product at both temperatures was a mixture of mostly H aggregate with a small amount of J aggregate. This behavior was rationalized by the temperature-dependent potential energy surface of the supramolecular assembly.     

Oligo(ethylene glycol)/alkyl‐modified Chromophore Assemblies for Photon Upconversion in Water

Molecular self‐assembly is a powerful means to construct nanoscale materials with advanced photophysical properties. Although the protection of the photo‐excited states from oxygen quenching is a critical issue, it still has been in an early phase of development. In this work, we demonstrate that a simple and typical molecular design for aqueous supramolecular assembly, modification of the chromophoric unit with hydrophilic oligo(ethylene glycol) chains and hydrophobic alkyl chains, is effective to avoid oxygen quenching of triplet–triplet annihilation‐based photon upconversion (TTA‐UC). While a TTA‐UC emission is completely quenched when the donor and acceptor are molecularly dispersed in chloroform, their aqueous co‐assemblies exhibit a clear upconverted emission in air‐saturated water even under extremely low chromophore concentrations down to 40 μm . The generalization of this nano‐encapsulation approach offers new functions and applications using oxygen‐sensitive species for supramolecular chemistry.     

Spontaneous crystallization at the air-water interface: an unusual feature of gemini surfactant with a rigid spacer

An unusual feature which involves spontaneous crystallization at the air-water interface from aqueous solution was reported for a water-soluble gemini surfactant with xylyl spacer, (p-phenylenedimethylene) bis(dodecyldimethylammonium) dibromide. Polarizing microscope, in situ confocal microscopic Raman spectroscopy, and powder XRD were used to characterize the structure of the crystal and investigate the driving force for nucleation. It was inferred that, besides the surface enrichment of amphiphiles and the intra- and intermolecular interaction of alkyl chains, the pi-pi stacking interaction of benzene rings plays an extraordinary role in promoting nucleation and stabilizing crystal structure. A mechanism for constructing supramolecular architectures in situ at the air-water interface directly from aqueous solution via water-soluble amphiphiles with groups favorable for pi-pi stacking interaction was proposed.     

Tuneable Transient Thermogels Mediated by a pH‐ and Redox‐Regulated Supramolecular Polymerization

A multistimuli‐responsive transient supramolecular polymerization of β‐sheet‐encoded dendritic peptide monomers in water is presented. The amphiphiles, which contain glutamic acid and methionine, undergo a glucose oxidase catalyzed, glucose‐fueled transient hydrogelation in response to an interplay of pH and oxidation stimuli, promoted by the production of reactive oxygen species (ROS). Adjusting the enzyme and glucose concentration allows tuning of the assembly and the disassembly rates of the supramolecular polymers, which dictate the stiffness and transient stability of the hydrogels. The incorporation of triethylene glycol chains introduces thermoresponsive properties to the materials. We further show that repair enzymes are able to reverse the oxidative damage in the methionine‐based thioether side chains. Since ROS play an important role in signal transduction cascades, our strategy offers great potential for applications of these dynamic biomaterials in redox microenvironments.     

Synthesis and self-assembly of novel oxacalix[2]arene[2]triazine amphiphiles

Heteracalixaromatics are an emerging generation of macrocyclic host molecules in supramolecular chemistry. As a typical example of heteracalixaromatics, oxacalix[2]arene[2]triazine adopts a shape-persistent 1,3-alternate conformation and can be easily functionalized. Taking it as a platform, a series of oxacalix[2]arene[2]triazine-based amphiphiles bearing long alkyl chains were synthesized through post-macrocyclization functionalization or 3+1 fragment coupling protocols. The self-assembly behavior of these amphiphiles in a mixture of tetrahydrofuran (THF) and water was investigated. Dynamic light scattering (DLS) measurements revealed that the size of the self-assembled aggregates is dependent on the structure of the amphiphiles. The long alkyl chain substituents and/or intermolecular hydrogen bonds were found to promote the self-assembly.     

Fabrication of oligo‐glycerol based hydrolase responsive amphiphilic nanocarriers

Herein, we report on the synthesis of a new class of novel non‐ionic amphiphiles using triglycerol as a core, which is further functionalized with hydrophilic units poly(ethylene glycol) monomethyl ether (M_n: 350 and 550) and a pair of hydrophobic alkyl chains (C₁₈ or C₁₅) via chemo‐enzymatic approach. Fluorescence measurements and dynamic light scattering studies showed that all of the synthesized amphiphilic systems spontaneously self‐ assemble in aqueous solution, which is further confirmed by the transmission electron microscopy. Encapsulation of hydrophobic moieties like Nile red and nimodipine was studied using ultraviolet‐visible (UV‐vis) and fluorescence spectrometer techniques. A cytotoxicity study of the amphiphiles using A549, HeLa, and MCF7 cell, which showed that all of the synthesized nanocarriers are well tolerated at the concentrations studied. The release profile of encapsulated Nile red in synthesized amphiphilic system was studied in the presence of the immobilized enzyme (Novozym 435).     

Fabrication of chiral Langmuir-Schaefer films of achiral amphiphilic Schiff base derivatives through an interfacial organization

Supramolecular chirality in the Langmuir-Schaefer (LS) films of two achiral amphiphilic Schiff bases, 2-(2'-benzimidazolyliminomethyl)-4-octadecyloxyphenol (BSC18) and 2-(2'-benzthiazolyliminomethyl)-4-octadecyloxyphenol (TSC18), was investigated. Both of these amphiphiles could form LS films from the water surface or coordinate with Ag(I) in the subphase to form Ag(I)-coordinated LS films. Although both of these amphiphiles were achiral, TSC18 formed a chiral LS film from the water surface, while BSC18 formed a chiral Ag(I)-coordinated LS film from the aqueous AgNO3 subphase. The supramolecular chirality in these LS films was suggested to be due to a cooperative stereoregular pi-pi stacking of the functional groups together with the long alkyl chains in a helical sense. The relationship between the chirality of the LS films and the molecular structures of TSC18 and BSC18 as well as their H-bond or coordination behaviors was discussed. The Schiff base films showed a reversible color change upon exposure to HCl and NH3 gas alternatively; however, the supramolecular chirality was irreversible during these processes.     

Electrospray mass spectrometry: Ethylene glycol as a solvent and its effects on ion desorption

Ethylene glycol solutions of gramicidin S, myoglobin and tetrabutylammonium bromide were analysed by means of electrospray mass spectrometry and their spectra were compared with those of aqueous solutions. The evaporation of water and ethylene glycol droplets, initially at room or elevated temperature, in air at room temperature was modelled. It was found that under conditions where a water droplet's radius would shrink by ～30%, an ethylene glycol droplet shrinks negligibly. Further, droplets that are initially hot (such as those that are ejected from a heated electrospray needle) cool very rapidly owing to evaporation and heat loss to ambient air, and subsequently evaporate much like droplets that are initially at room temperature. For gramicidin S, the ion abundances in ethylene glycol as solvent were ～200 times lower than those in water under room temperature operating conditions. In experiments where the spray probe was heated to ～100°C to reduce the viscosity of ethylene glycol, the gramicidin response difference between the solvents decreased to about a factor of 40. Similar trends were observed for myoglobin and the tetrabutylammonium ion. The gramicidin abundances in ethylene glycol, relative to those in water, are orders of magnitude too large to be accounted for using the conventional solvent evaporation model. It is speculated that decreasing the viscosity increases the velocity of ions drifting in ethylene glycol towards the solution/air interface and increases the total number of analyte ions desorbed at the Taylor cone during electrospray.     

Supramolecular hydrogel formed by glucoheptonamide of l-lysine: simple preparation and excellent hydrogelation ability

We describe the simple preparation of new l-lysine derivatives with a gluconic or glucoheptonic group, their hydrogelation properties, and the thermal and mechanical properties of the supramolecular hydrogels. The l-lysine derivatives with a gluconic group have no hydrogelation ability, while the l-lysine-glucoheptonamide derivatives functioned as hydrogelators. Their hydrogelation abilities increased with the decreasing length of the spacer between the l-lysine segment and the glucoheptonic group. The compound, which has no spacer, formed a supramolecular hydrogel at 0.05 wt % in pure water. The thermal stability and high mechanical strength of the supramolecular hydrogels based on this compound significantly depended on the aqueous solutions. Electron microscopy and FTIR studies demonstrated that the hydrogelators created a three-dimensional network through hydrogen bonding and hydrophobic interactions in the supramolecular hydrogel. In addition, it was found that hydrophobic interactions played an important role in the thermal stability of the supramolecular hydrogel.     

Synthetic Bilayer Membranes: Molecular Design,Self-Organization,and Application

Lipid bilayers are a most central building block of the biological molecular organization. Their two-dimensional self-assembly is essential to the generation of biological shapes and sizes on the molecular level. The observation that a totally synthetic amphiphile in water is spontaneously assembled to a bilayer structure suggested that bilayer formation is a general physicochemical phenomenon that is not restricted to particular structures of biolipid molecules. Bilayer formation is now observed for a large variety of synthetic amphiphiles which contain one, two, three, or four alkyl tails. The flexible alkyl tail may be replaced by perfluoroalkyl chains. The supramolecular structures obtained therefrom can be related to the component's molecular structure in many cases. The structural variety and the ease of molecular design make the synthetic bilayer an attractive vehicle for organizing covalently bound functional units and guest molecules. In addition, stable monolayers on water, planar lipid membranes (BLM), and free-standing cast films are obtainable because of the self-assembling property of bilayer-forming compounds. These molecular organizations display common supramolecular features. The use of the cast film as a molecular template provides exciting potential for the production of novel two-dimensional materials.     

Characterization of Heterogeneous Interaction Behavior in Ternary Mixtures by a Dielectric Analysis: Equi-Molar H–bonded Binary Polar Mixtures in Aqueous Solutions

The heterogeneous associating behavior of the aqueous binary mixtures of ethyl alcohol, ethylene glycol, glycerol and mono alkyl ethers of ethylene glycol, and aqueous ternary mixtures of equi-molar binary systems (i.e., mono alkyl ethers of ethylene glycol with ethyl alcohol, ethylene glycol and glycerol) have been investigated over the entire concentration range using accurately measured dielectric constants at 25 ^∘C. The concentration dependent values of the excess dielectric parameter ε^E and effective Kirkwood correlation factor g ^eff were determined using the measured values of the static dielectric constant, ε_o, at 1 MHz and the high frequency limiting dielectric constant ε_∞ = n _D ². The observed ε^E values in aqueous binary and ternary mixtures are negative over the entire concentration range, which implies the formation of heterogeneous complexes between these molecules that reduces the effective number of dipoles. The stoichiometric ratio corresponding to the maximum interaction in alcohol + water mixtures increases with an increase in the number of hydroxyl groups of the alcohol molecules, but for mono alkyl ethers of ethylene glycol + water mixtures it decreases with the increase in the molecular size of the mono alkyl ethers. In aqueous ternary mixtures the stoichiometric ratio for the maximum extent of heterogeneous interaction is governed by the molecular size of the mono alkyl ethers. It was also found that the strength of the heterogeneous H–bond connectivities in the water + alcohol systems decrease with an increase in the number of hydroxyl groups of the alcohol molecules. However in the case of water + mono alkyl ether binary mixtures and in ternary mixtures, the strength of H–bond connectivities increases with the increase in the molecular size of the mono alkyl ether. An analysis of the g ^eff values confirms that the heterogeneous interaction involves the orientation of molecular dipoles in the studied systems.     

Supramolecular assemblies of DNA with neutral nucleoside amphiphiles

A neutral uridine-based amphiphile is described which condenses plasmid DNA. AFM studies show that the three distinct structural components of the amphiphile (i.e, nucleobase, alkyl chains, and poly(ethylene glycol)) are required for the formation of DNA-amphiphile supramolecular assemblies on a mica surface.     

Mixing Biomimetic Heterodimers of Nucleopeptides to Generate Biocompatible and Biostable Supramolecular Hydrogels

As a new class of biomaterials, most supramolecular hydrogels formed by small peptides require the attachment of long alkyl chains, multiple aromatic groups, or strong electrostatic interactions. Based on the fact that the most abundant protein assemblies in nature are dimeric, we select short peptide sequences from the interface of a heterodimer of proteins with known crystal structure to conjugate with nucleobases to form nucleopeptides. Being driven mainly by hydrogen bonds, the nucleopeptides self‐assemble to form nanofibers, which results in supramolecular hydrogels upon simple mixing of two distinct nucleopeptides in water. Moreover, besides being biocompatible to mammalian cells, the heterodimer of the nucleopeptides exhibit excellent proteolytic resistance against proteinase K. This work illustrates a new and rational approach to create soft biomaterials by a supramolecular hydrogelation triggered by mixing heterodimeric nucleopeptides.     

The structure of mixed nonionic surfactant monolayers at the air-water interface: the effects of different alkyl chain lengths

The structure of mixed nonionic surfactant monolayers of monodecyl hexaethylene glycol (C10E6) and monotetradecyl hexaethylene glycol (C14E6) adsorbed at the air-water interface has been determined by specular neutron reflectivity. Using partial isotopic labeling (deuterium for hydrogen) of the alkyl and ethylene oxide chains of each surfactant, the distribution and relative positions of the chains at the interface have been obtained. The packing of the two different alkyl chain lengths results in structural changes compared to the pure surfactant monolayers. This results in changes in the relative positions of the alkyl chains and of the ethylene oxide chains at the interface. The role of the alkyl chain length is contrasted with that of the ethylene oxide chain length, determined from results reported previously on the nonionic surfactant mixture of monododecyl triethylene glycol (C12E3) and monododecyl octaethylene glycol (C12E8).     

Effects of structural variation on the self-assembly of bis-urea based bolaamphiphiles

We report on the self-assembly in water of a set of bis-urea amphiphiles. A range of techniques, including dynamic light scattering, Cryo-TEM, SAXS, and MS are used to study the effect of structural variation on the morphology of the assemblies. The length, dispersity, and end-group of the ethylene glycol hydrophilic part of the molecule, as well as of the alkyl chain length are varied to tailor the morphology towards soluble wormlike micelles. Slight modification on molecular structures gave a large difference in self-assembly behavior in water, giving guidelines for the design of rodlike supramolecular fibers with novel functionalities, such as strain-stiffening and bioactivity.     

Nonionic Dendritic and Carbohydrate Based Amphiphiles: Self‐Assembly and Transport Behavior

Herein, a new series of non‐ionic dendritic and carbohydrate based amphiphiles is synthesized employing biocompatible starting materials and studied for supramolecular aggregate formation in aqueous solution. The dendritic amphiphiles 12 and 13 possessing poly(glycerol) [G2.0] as hydrophilic unit and C‐10 and C‐18 hydrophobic alkyl chains, respectively, exhibit low critical aggregation concentration (CAC) in the order of 10⁻⁵m and hydrodynamic diameters in the 8–10 nm range and supplemented by cryogenic transmission electron microscopy. Ultraviolet‐visible (UV‐Vis) and fluorescence spectroscopy suggests the effective solubilization of hydrophobic guests by the self‐assembled architectures, with the nanotransporters 12 and 13 possessing the highest encapsulation efficiency of 80.74 and 98.03% for curcumin. Efficient uptake of encapsulated curcumin in adenocarcinomic human alveolar basal epithelial (A549) cells is observed by confocal laser scanning microscopy. Amphiphiles 12 and 13 are non‐cytotoxic at the concentrations studied, however, curcumin encapsulated samples efficiently reduce the viability of A549 cells in vitro. Experimental studies indicate the ability of amphiphile 13 to encapsulate 1‐anilinonaphthalene‐8‐sulfonic acid (ANS) and curcumin with binding constant of 1.16 × 105⁵m ⁻¹ and 1.43 × 10⁶m ⁻¹, respectively. Overall, our findings demonstrate the potential of these dendritic amphiphiles for the development of prospective nanocarriers for the solubilization of hydrophobic drugs.     

低温非水环境中疏水缔合聚丙烯酸钠与两性离子表面活性剂的相互作用

疏水缔合聚合物和表面活性剂是构建黏弹性流体的重要物质, 二者的相互作用对流体性质具有显著影响, 一直是该领域的研究热点, 但此前的研究仅聚焦于水溶液中室温及以上温度范围, 而零下极端低温环境中的相互作用尚未涉及. 本文以疏水缔合聚丙烯酸钠(HMPA)为模型聚合物, 研究了低温(-20~20 ℃)环境中其与两性离子表面活性剂N-(顺-二十二碳-13-烯酸酰胺基丙基)-N,N-二甲基羧酸甜菜碱(EDAB)在乙二醇/水混合溶剂中的相互作用及混合体系的流变性质. 先后考察了HMPA溶解于纯水和乙二醇/水混合溶剂时的流变行为和HMPA-EDAB在乙二醇/水混合溶剂中的流变行为及自组装结构形貌. 研究发现, 加入50%(体积分数)的乙二醇会阻碍HMPA疏水支链形成缔合结构, 减弱其增黏性能, 但同时也会大幅降低体系的冰点. 在HMPA- EDAB混合体系中, HMPA疏水支链会进入EDAB胶束内核自组装形成混合胶束. 混合胶束的形貌取决于 HMPA和EDAB的浓度及环境温度, 进而影响体系的流变行为. 零下的低温有助于EDAB形成蠕虫状胶束, 因此HMPA与EDAB表现出更强的协同增效作用.     

Controlled self-assembly of carbohydrate conjugate rod-coil amphiphiles for supramolecular multivalent ligands

Carbohydrate conjugate rod-coil amphiphiles were synthesized and their self-assembling behavior in aqueous solution was investigated. These amphiphiles were observed to self-assemble into supramolecular structures that differ significantly depending on the molecular architecture. The rod-coil amphiphiles based on a short coil (1) self-assemble into a vesicular structure, while the amphiphiles with a long coil (2) show a spherical micellar structure. In contrast, 3, based on a twin-rod segment, was observed to aggregate into cylindrical micelles with twice the diameter of molecular length scale. As a means to determine the binding activity to protein receptors of these supramolecular objects, hemagglutination inhibition assay was performed. The experiments showed that the supramolecular architecture has a significant effect on the binding activity. In addition, incubation experiments with Escherichia coli showed that mannose-coated objects specifically bind to the bacterial pili of the ORN 178 strain. These results demonstrate that precise control of the nano-objects in shape and size by molecular design can provide control of the biological activities of the supramolecular materials.