Counterion Structure Research Articles

The influence of counterion structure identity on conductivity, dynamical correlations, and ion transport mechanisms in polymerized ionic liquids.

We used equilibrium and non-equilibrium atomistic simulations to probe the influence of anion chemistry on the true conductivity, dynamical correlations, and ion transport mechanisms in polymeric ionic liquids. An inverse correlation was found between anion self-diffusivities, ionic mobilities, and the anion size for spherical anions. While some larger asymmetric anions had higher diffusivities than smaller spherical anions, their diffusivities and mobilities did not exhibit a direct correlation to the anion volumes. The conductivity and anion dynamical correlations also followed the same trends as displayed by the diffusivity and mobility of anions. All the systems we examined displayed positively correlated motion among anions, suggesting a contribution that enhances the conductivity beyond the ideal Nernst-Einstein value. Analysis of ion transport mechanisms demonstrated very similar hopping characteristics among the spherical anions despite differences in their sizes.

Structure and Diffusion of Ionic PDMS Melts.

Ionic polymers exhibit mechanical properties that can be widely tuned upon selectively charging them. However, the correlated structural and dynamical properties underlying the microscopic mechanism remain largely unexplored. Here, we investigate, for the first time, the structure and diffusion of randomly and end-functionalized ionic poly(dimethylsiloxane) (PDMS) melts with negatively charged bromide counterions, by means of atomistic molecular dynamics using a united atom model. In particular, we find that the density of the ionic PDMS melts exceeds the one of their neutral counterpart and increases as the charge density increases. The counterions are condensed to the cationic part of end-functionalized cationic PDMS chains, especially for the higher molecular weights, leading to a slow diffusion inside the melt; the counterions are also correlated more strongly to each other for the end-functionalized PDMS. Temperature has a weak effect on the counterion structure and leads to an Arrhenius type of behavior for the counterion diffusion coefficient. In addition, the charge density of PDMS chains enhances the diffusion of counterions especially at higher temperatures, but hinders PDMS chain dynamics. Neutral PDMS chains are shown to exhibit faster dynamics (diffusion) than ionic PDMS chains. These findings contribute to the theoretical description of the correlations between structure and dynamical properties of ion-containing polymers.

Impact of the anion on electrochemically doped regioregular and regiorandom poly(3‐hexylthiophene)

AbstractChemical and electrochemical doping of π‐conjugated polymers is an important aspect in determining the performance and enabling the operation of many organic electronic devices, from organic light emitting diodes and thermoelectrics to organic electrochemical transistors. In both chemical doping and electrochemical doping an ionized dopant or counterion is present along with the doped π‐conjugated polymer. This dopant or counterion is not a benign spectator, rather, its presence can significantly impact the optical, electronic, and thermoelectric properties of the resulting material. Here, we investigate how counterion structure impacts the electrochemical doping ability, oxidation potential, ionization energy, and polaron absorbance of regioregular (rr) and regiorandom (rra) P3HT. We find that in most cases the anion has a small effect on the polymer oxidation potential, except for in the case of rr‐P3HT with the large tetrakis[3,5‐bis(trifluoromethyl)phenyl]borate anion. We propose that this large anion is excluded from the crystalline regions and thus the oxidation potential is similar to that of rra‐P3HT. The anions also result in significant differences in polaron absorbance and ionization energies, thereby emphasizing the important role of the counterion in determining the optical and electronic properties of doped π‐conjugated polymers.

Investigating how amine structure influences drug-amine ion-pair formation and uptake via the polyamine transporter in A549 lung cells

Transiently associating amines with therapeutic agents through the formation of ion-pairs has been established both in vitro and in vivo as an effective means to systemically direct drug delivery to the lung via the polyamine transport system (PTS). However, there remains a need to better understand the structural traits required for effective PTS uptake of drug ion-pairs. This study aimed to use a structurally related series of amine counterions to investigate how they influenced the stability of theophylline ion-pairs and their active uptake in A549 cells. Using ethylamine (mono-amine), ethylenediamine (di-amine), spermidine (tri-amine) and spermine (tetra-amine) as counterions the ion-pair affinity was shown to increase as the number of protonated amine groups in the counterion structure increased. The mono and diamines generated a single hydrogen bond and the weakest ion-pair affinities (pKFTIR: 1.32 ± 0.04 and 1.43 ± 0.02) whereas the polyamines produced two hydrogen bonds and thus the strongest ion-pair affinities (pKFTIR: 1.93 ± 0.05 and 1.96 ± 0.04). In A549 cells depleted of endogenous polyamines using α-difluoromethylornithine (DFMO), the spermine-theophylline uptake was significantly increased (p < 0.05) compared to non-amine depleted cells and this evidenced the active PTS sequestering of the ion-pair. The mono-amine and di-amine failed to enhance theophylline uptake in these A549 cells, but the tri-amine and tetra-amine both almost doubled the theophylline uptake into the cells when compared to the uptake of free drug. As the data indicated that polyamines with at least 3 amines were required to form ion-pairs that could enhance A549 cell uptake, it suggested that at least two amines were required to physically stabilise the ion-pair and one to interact with the PTS.

Influence of the AOT Counterion Chemical Structure on the Generation of Organized Systems.

The impact of the imidazolium counterion structure on the organized systems formed by the surfactant 1,4-bis-2-ethylhexylsulfosuccinate, AOT, both in aqueous solutions and in nonpolar solvents is investigated. With this in mind, we investigated if the ionic liquid-like (IL-like) surfactant 1-ethyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate, emim-AOT, forms direct micelles or vesicles in water. Dynamic light scattering, zeta potential, conductivity, fluorescence spectroscopy, and UV-visible spectroscopy measurements were performed to characterize the organized systems in aqueous solutions. We also studied the self-aggregation of emim-AOT, 1-butyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate, bmim-AOT, and of 1-hexyl-3-methylimidazolium 1,4-bis-2-ethylhexylsulfosuccinate, hmim-AOT, in nonpolar solvents. The results obtained showed that the IL-like surfactant emim-AOT forms direct micelles in water, as sodium 1,4-bis-2-ethylhexylsulfosuccinate (Na-AOT) does. However, emim-AOT aggregates are larger, have a lower surface charge, are more stable, and have a more polar and less fluid micellar interface than Na-AOT micelles. It was also observed that emim-AOT and hmim-AOT form reverse micelles in nonpolar solvents. The size of the imidazolium cations dramatically influences the size of the reverse micelles and their ability to solubilize water.

Thermodynamic and computational study of isomerism effect at micellization of imidazolium based surface-active ionic liquids: Counterion structure

In this work the influence of benzoate, ortho-, meta- and para-hydroxybenzoate anions, as counterions, on micellization process of 1-dodecyl-3-methyl-imidazolium cation in water is investigated by isothermal titration calorimetry (ITC) in the temeprature range between 278.15 and 318.15 K. ITC experimental data were analyzed by the help of an improved mass-action model, yielding the values of critical micelle concentration, cmc, the degree of counterion binding, β, aggregation number, n, standard heat capacity, ΔMcpθ, enthalpy, ∆MHθ, entropy, ∆MSθ, and Gibbs free energy, ∆MGθ of micellization. It was found that the investigated systems behave mainly like common ionic surfactants and already investigated SAILs: the micellization process of investigated systems is entropically driven at low temperatures, whereas at high temperatures the enthalpic contribution becomes equally important. The last is especially important in the case of ortho-hydroxybenzoate, which incorporates into micellar structure affecting also the entropy-enthalpy compensation. But evidently, the presence and position of –OH group in the counterion influence considerably the micellization process.ΔMcpθ values were further discussed in the light of the removal of water molecules from contact with nonpolar surface area upon micelle formation. All the values are negative, the most in the case of benzoate anion, which could be ascribed to the absence of –OH group.To refine the thermodynamic parameters obtained from ITC, the molecular simulations were performed. First, it is shown that the binding energies between anion and cations increase in the order from benzoate to para-, meta- and ortho-hydroxybenzoate, which coincide with ∆MHθ values. Second, it is demonstrated that water around counterions is strongly perturbed leading to differences in ΔMcpθ.

API ionic liquids: probing the effect of counterion structure on physical form and lipid solubility.

Lipid based formulations (LBFs) are extensively utilised as an enabling technology in drug delivery. The use of ionic liquids (ILs) or lipophilic salts (LS) in drug delivery has also garnered considerable interest due to unique solubility properties. Conversion of active pharmaceutical ingredients (API) to ILs by pairing with an appropriately lipophilic counterion has been shown to decrease melting point of the salt complex and improve solubility in LBFs. However, the relationship between the structure of the counterion, the physicochemical properties of the resulting salts and solubility in LBFs has not been systematically explored. This study investigates the relationship between alkyl sulfate counterion structure and melting temperature (Tm or Tg) in addition to LBF solubility, utilizing cinnarizine and lumefantrine as model weakly basic APIs. Three series of structurally diverse alkyl sulfate counterions were chosen to probe this relationship. Pairing cinnarizine and lumefantrine with a majority of these alkyl sulfate counterions resulted in a reduction in melting temperature and enhanced solubility in model medium chain and long chain LBFs. The chain length of the alkyl sulfate plays a crucial role in performance, and consistently branched alkyl sulfate counterions perform better than straight chain alkyl sulfate counterions, as predicted. Most interestingly, trends in counterion performance were found to be consistent across two APIs with disparate chemical structures. The findings from this study will facilitate the design of counterions which enhance solubility of ionisable drugs and unlock the potential to develop compounds previously restrained by poor solubility.

Influence of Counterion Structure on Conductivity of Polymerized Ionic Liquids.

We performed long-time all-atom molecular dynamics simulations of cationic polymerized ionic liquids with eight mobile counterions, systematically varying size and shape to probe their influence on the decoupling of conductivity from polymer segmental dynamics. We demonstrated rigorous identification of the dilatometric glass-transition temperature (Tg) for polymerized ionic liquids using an all-atom force field. Polymer segmental relaxation rates are presumed to be consistent for different materials at the same glass-transition-normalized temperature (Tg/T), allowing us to extract a relative order of decoupling by examining conductivity at the same Tg/T. Size, or ionic volume, cannot fully explain decoupling trends, but within certain geometric and chemical-specific classes, small ions generally show a higher degree of decoupling. This size effect is not universal and appears to be overcome when structural results reveal substantial coordination delocalization. We also reveal a universal inverse correlation between ion-association structural relaxation time and absolute conductivity for these polymerized ionic liquids, supporting the ion-hopping interpretation of ion mobility in polymerized ionic liquids.

Improved transdermal permeability of ibuprofen by ionic liquid technology: Correlation between counterion structure and the physicochemical and biological properties

The aim of this study was to explore the feasibility of transdermal delivery of ibuprofen using ionic liquid technology. Ibuprofen, a non-steroidal anti-inflammatory drug, was transformed into nine ionic liquids using aromatic, tetraalkylammonium and tetraalkylphosphonium cationic counterions. Both the free drug and synthesized ionic liquids were fully characterized by X-ray Powder Diffractometry (XRPD) analysis, thermal analysis, Fourier Transform Infrared Spectroscopy (FT-IR) analysis and Nuclear Magnetic Resonance Spectrometer analysis (NMR), and the aqueous solubility at 25 °C as well as the octanol-water partition coefficients (LogP) were measured. To evaluate transdermal potential, in vitro skin permeation testing was carried out via Skin Parallel Artificial Membrane Permeability Assays (Skin PAMPA). In addition, the potential skin toxicity of ionic liquids was evaluated by determining their cytotoxicity against HaCaT cells. All the synthesized ibuprofen ionic liquids showed improved skin permeability comparing with the conventional sodium salt. Specifically, ionic liquids with didecyldimethylammonium and tetrahexylammonium counterions were significantly more permeable through artificial skin membrane than the free form of ibuprofen. Conductivity test and 2D NMR nuclear Overhauser effect (NOE) techniques corroborated that ionic liquids with stronger intermolecular intermolecular interaction and higher degree of ion association in aqueous environment crossed the artificial skin membrane more rapidly and efficiently. Taken together, ionic liquids technology could be a versatile platform to turn the physicochemical and biological properties of ionizable drugs and facilitate their transdermal delivery.

Fighting Aggregation-Caused Quenching and Leakage of Dyes in Fluorescent Polymer Nanoparticles: Universal Role of Counterion.

Dye-loaded polymer nanoparticles (NPs) emerge as a powerful tool for bioimaging applications, owing to their exceptional brightness and controlled small size. However, aggregation-caused quenching (ACQ) and leakage of dyes at high loading remain important challenges of these nanomaterials. The use of bulky hydrophobic counterions has been recently proposed as an effective approach to minimize ACQ and dye leakage, but the role of counterion structure is still poorly understood. Here, a systematic study based on ten counterions, ranging from small hydrophilic perchlorate up to large hydrophobic tetraphenylborate derivatives, reveals how counterion nature can control encapsulation and emission of a cationic dye (rhodamine B octadecyl ester) in NPs prepared by nanoprecipitation of a biodegradable polymer, poly-lactide-co-glycolide (PLGA). We found that increase in counterion hydrophobicity enhances dye encapsulation efficiency and prevents dye adsorption at the particle surface. Cellular imaging studies revealed that ≥95 % encapsulation efficiency, achieved with most hydrophobic counterions (fluorinated tetraphenylborates), is absolutely required because non-encapsulated dye species at the surface of NPs are the origin of dye leakage and strong fluorescence background in cells. The size of counterions is found to be essential to prevent ACQ, where the largest species, serving as effective spacer between dyes, provide the highest fluorescence quantum yield. Moreover, we found that the most hydrophobic counterions favor dye-dye coupling inside NPs, leading to ON/OFF fluorescence switching of single particles. By contrast, less hydrophobic counterions tend to disperse dyes in the polymer matrix favoring stable emission of NPs. The obtained structure-property relationships validate the counterion-based approach as a mature concept to fight ACQ and dye leakage in the development of advanced polymeric nanomaterials with controlled optical properties.

Structural motifs in salts of sulfathiazole: implications for design of salt forms in pharmaceuticals APIs

The creation of salts is a frequently used approach to modify physicochemical properties of active pharmaceutical ingredients. This work prepares a collection of sulfathiazole salts to probe the influence of counterion structure on crystal packing.

Polyethylene glycol derivatization of the non-active ion in active pharmaceutical ingredient ionic liquids enhances transdermal delivery

Introducing PEGylated moieties into the counterion structure of API–ILs can significantly enhance the transport through a membrane without a solvent.

Halochromism and protonation-induced assembly of a benzo[g]indolo[2,3-b]quinoxaline derivative.

A new halochromic compound is reported with pronounced UV/Vis spectral responses that depend on the extent of protonation and on the counter-ion structure. The absorption can be controlled over the entire visible spectrum and into the near-IR via a protonation-induced assembly mechanism. Thin-films were used for colorimetric detection of acid vapors.

Effects of counterion structure on the surface activities of anionic fluorinated surfactants whose counterions are organic ammonium ions

The surface tension of dialkylammonium perfluorooctanoate [C7F15COONH2(CnH2n+1)2, n=1–4], dialkylammonium perfluorooctylsulfonate [C8F17SO3NH2(CnH2n+1)2, n=1–4] and trialkylammonium perfluorooctylsulfonate [C8F17SO3NH(CnH2n+1)3, n=1–4] in aqueous solution was measured by drop volume method at 25°C. The critical micelle concentration (cmc), the surface tension at cmc (γcmc), the maximum amount adsorbed (Γmax) and the minimum molecular area (Amin) in the surface adsorption layer were obtained. Because of the limited solubility for C7F15COONH2(C4H9)2, C8F17SO3NH2(C4H9)2 and C8F17SO3NH(C4H9)3 at 25°C, their cmc and γcmc values could not be successfully obtained. Combining with other series in previous works, an overview picture for the effects of organic ammonium counterions on anionic fluorinated surfactants could be drawn. The rules for the interactions between organic ammonium ions and surfactive anions were summarized (including headgroup type, the chain length of fluorinated hydrophobic tail, and the substituent number, the alkyl chain length and the presence of hydroxyl groups in counterion structure). The mechanism behind these rules was discussed in detail, relying on the electrostatic, hydrophobic and steric factors.

Conformations and hydration structure of hydrophobic polyelectrolyte atactic poly(ethacrylic acid) in dilute aqueous solution as a function of neutralisation

Chain conformations, counter-ion structure, intermolecular hydrogen bonding structure and dynamics of atactic polyethacrylic acid (PEA) in salt-free aqueous dilute solution at 25°C are studied via molecular dynamics (MD) simulations with explicit-solvent and explicit-ion description for the first time. The intermolecular structure was analysed by the radial distribution functions (RDF) for specific atom types between PEA chain, water molecules and Na+ counter-ions, as well as by the hydration near the PEA chain in the solvated system. An increase in f provides an increase in 〈Rg〉 of the chain, consistent with the existence of the compact form of PEA. The simulations show expansion for radius-of-gyration with increase in f, as expected for flexible polyelectrolytes under salt-free condition. The extent of intermolecular hydrogen bonds (H-bonds) between PEA and water is enhanced by increase in f. Chains having a higher counter-ion density show higher values of 〈Rg〉, influenced by intermolecular interactions between PEA and water. The coordination of Na+ counter ions and water molecules to carboxyl oxygens of polyacrylic acid (PAA) increases with charge density of the chain. A comparison of the structure aspects is made with PAA and PMA polyelectrolytes in dilute solution, which brings out the hydrophobic effect of the ethyl side-groups in PEA on conformational properties and counter-ion condensation structure.

DNA condensation and size effects of DNA condensation agent

Based on the model of the strong correlation of counterions condensed on DNA molecule, by tailoring interaction potential, interduplex spacing and correlation spacing between condensed counterions on DNA molecule and interduplex spacing fluctuation strength, toroidal configuration, rod-like configuration and two-hole configurations are possible. The size effects of counterion structure on the toroidal structure can be detected by this model. The autocorrelation function of the tangent vectors is found as an effective way to detect the structure of toroidal conformations and the generic pathway of the process of DNA condensation. The generic pathway of all of the configurations involves an initial nucleation loop, and the next part of the DNA chain is folded on the top of the initial nucleation loop with different manners, in agreement with the recent experimental results.

Novel biomimetic systems based on amphiphilic compounds with a diterpenoid fragment: Role of counterions in self-assembly

Novel biomimetic systems are designed based on cationic surfactants composed of an isosteviol moiety and different counterions, namely bromide (S1) and tosylate (S2). The counterion structure is shown to play a crucial role in the surfactant association. A number of methods used provide evidence that only one type of aggregate, i.e., micelles are observed in the S2 systems, while a concentration-dependent association occurs in the case of S1. The DLS and fluorescence anisotropy measurements reveal that the micelle–vesicle–micelle transitions probably occur with the S1 system. The occurrence of small aggregates near the critical micelle concentration with radii of 2.5nm is supported by NMR self-diffusion data. The Orange OT solubilization results strongly support the idea of a second threshold in the S1 system around 0.025mM and provide evidence that hydrophobic domains occur in the aggregates. The latter property and the capacity to integrate with the lipid bilayer make it possible to suggest the newly synthesized surfactants as effective nanocontainers for hydrophobic guests.

Counter-ion effect on surfactant–DNA gel particles as controlled DNA delivery systems

The ability to entrap drugs within vehicles and subsequently release them has led to new treatments for a number of diseases. Based on an associative phase separation and interfacial diffusion approach, we developed a way to prepare DNA gel particles without adding any kind of cross-linker or organic solvent. Among the various agents studied, cationic surfactants offered particularly efficient control for encapsulation and DNA release from these DNA gel particles. The driving force for this strong association is the electrostatic interaction between the two components, as induced by the entropic increase due to the release of the respective counter-ions. However, little is known about the influence of the respective counter-ions on this surfactant–DNA interaction. Here we examined the effect of different counter-ions on the formation and properties of the DNA gel particles by mixing DNA (either single- (ssDNA) or double-stranded (dsDNA)) with the single chain surfactant dodecyltrimethylammonium (DTA). In particular, we used as counter-ions of this surfactant the hydrogen sulfate and trifluoromethane sulfonate anions and the two halides, chloride and bromide. Effects on the morphology of the particles obtained, the encapsulation of DNA and its release, as well as the haemocompatibility of these particles are presented, using counter-ion structure and DNA conformation as controlling parameters. Analysis of the data indicates that the degree of counter-ion dissociation from the surfactant micelles and the polar/hydrophobic character of the counter-ion are important parameters in the final properties of the particles. The stronger interaction with amphiphiles for ssDNA than for dsDNA suggests the important role of hydrophobic interactions in DNA.

Effect of Counterion Structure on Rates and Diastereoselectivities in α,β-Unsaturated Iminium-Ion Diels–Alder Reactions

The use of cyclic α,β-unsaturated iminium-ion dienophiles is documented in two highly diastereoselective Diels-Alder (DA) reactions. The dienophilic counterion was found to have a significant effect on reactivity.

Structure and Thermodynamics of Ionic Dendrimer−Dye Assemblies

In this study, the association ("electrostatic self-assembly") of cationic generation 4 poly(amidoamine) dendrimer with a set of oppositely charged aromatic and aliphatic organic sulfonate counterions was investigated. Aggregate size and shape depend on the counterion structure. Formation of defined assemblies was possible with stiff, mutually interacting aromatic azo-dye counterions (acid red dyes Ar26, Ar44, Ar27, Ar18) but not with flexible or small aliphatic disulfonates and sulfate. Dynamic light scattering yielded sizes in the order of 100 nm. Particle shapes as investigated by small-angle neutron scattering were spherical, ellipsoidal, cylindrical, or of core-shell type. Results revealed that the molar charge ratio of the components is a crucial factor in the aggregation. UV-vis showed a cooperative binding process and yielded twist angles of dye molecules of 15 degrees to 30 degrees according to exciton theory. Isothermal titration calorimetry on dendrimer-dye assembly formation and comparison systems gave information on thermodynamics and contributing interaction energies. The main enthalpic contribution was provided by the mutual interaction of the dye molecules, while electrostatic interaction contributes a maximum of about 1/3 of the total interaction enthalpy.