Physical and Electrochemical Analysis of N-Alkylpyrrolidinium-Substituted Boronium Ionic Liquids.

In this work, a series of novel boronium-bis(trifluoromethylsulfonyl)imide [TFSI-] ionic liquids (IL) are introduced and investigated. The boronium cations were designed with specific structural motifs that delivered improved electrochemical and physical properties, as evaluated through cyclic voltammetry, broadband dielectric spectroscopy, densitometry, thermogravimetric analysis, and differential scanning calorimetry. Boronium cations, which were appended with N-alkylpyrrolidinium substituents, exhibited superior physicochemical properties, including high conductivity, low viscosity, and electrochemical windows surpassing 6 V. Remarkably, the boronium ionic liquid functionalized with both an ethyl-substituted pyrrolidinium and trimethylamine, [(1-e-pyrr)N111BH2][TFSI], exhibited a 6.3 V window, surpassing previously published boronium-, pyrrolidinium-, and imidazolium-based IL electrolytes. Favorable physical properties and straightforward tunability make boronium ionic liquids promising candidates to replace conventional organic electrolytes for electrochemical applications requiring high voltages.

Correction: Making good on a promise: ionic liquids with genuinely high degrees of thermal stability.

Correction for 'Making good on a promise: ionic liquids with genuinely high degrees of thermal stability' by Brooks D. Rabideau et al., Chem. Commun., 2018, 54, 5019-5031, https://doi.org/10.1039/C8CC01716F.

Correction: Unorthodox crystalline drug salts via the reaction of amine-containing drugs with CO2.

Correction for 'Unorthodox crystalline drug salts via the reaction of amine-containing drugs with CO2' by Mohammad Soltani et al., Chem. Commun., 2019, 55, 13546-13549, https://doi.org/10.1039/C9CC06429J.

Correction: Understanding liquid-liquid equilibria in binary mixtures of hydrocarbons with a thermally robust perarylphosphonium-based ionic liquid.

[This corrects the article DOI: 10.1039/D1RA06268A.].

Correction: Ionic liquids of superior thermal stability. Validation of PPh4+ as an organic cation of impressive thermodynamic durability.

[This corrects the article DOI: 10.1039/D0RA03220D.].

Correction: Tuning the melting point of selected ionic liquids through adjustment of the cation's dipole moment.

Correction for 'Tuning the melting point of selected ionic liquids through adjustment of the cation's dipole moment' by Brooks D. Rabideau et al., Phys. Chem. Chem. Phys., 2020, 22, 12301-12311, https://doi.org/10.1039/D0CP01214A.

Cyclopropane as an Unsaturation "Effect Isostere": Lowering the Melting Points in Lipid-like Ionic Liquids.

The replacement of unsaturation with a cyclopropane motif as a (bio)isostere is a widespread strategy in bacteria to tune the fluidity of lipid bilayers and protect membranes when exposed to adverse environmental conditions, e.g., high temperature, low pH, etc. Inspired by this phenomenon, we herein address the relative effect of the cyclopropanation, both cis and trans configurations, on melting points, packing efficiency, and order of a series of lipid-like ionic liquids via a combination of thermophysical analysis, X-ray crystallography, and computational modeling. The data indicate there is considerable structural latitude possible when designing highly lipophilic ionic liquids that exhibit low melting points. While cyclopropanation of the lipid-like ionic liquids provides more resistance to aerobic degradation than their olefin analogs, the impact on the melting point decrease is not as pronounced. Our results demonstrate that incorporating one or more cyclopropyl moieties in long aliphatic chains of imidazolium-based ionic liquids is highly effective in lowering the melting points of such materials relative to their counterparts bearing linear, saturated, or thioether side chains. It is shown that the cyclopropane moiety effectively disrupts packing, favoring formation of gauche conformer in the side chains, resulting in enhancement of fluidity. This was irrespective of the configuration of the methylene bridge, although marked differences in the effect of cis- and trans-monocyclopropanated ILs on the melting points were observed.

Charge neutralization of the active site glutamates does not limit substrate binding and transport by small multidrug resistance transporter EmrE.

EmrE, a small multidrug resistance transporter from Escherichia coli, confers broad-spectrum resistance to polyaromatic cations and quaternary ammonium compounds. Previous transport assays demonstrate that EmrE transports a +1 and a +2 substrate with the same stoichiometry of two protons:one cationic substrate. This suggests that EmrE substrate binding capacity is limited to neutralization of the two essential glutamates, E14A and E14B (one from each subunit in the antiparallel homodimer), in the primary binding site. Here, we explicitly test this hypothesis, since EmrE has repeatedly broken expectations for membrane protein structure and transport mechanism. We previously showed that EmrE can bind a +1 cationic substrate and proton simultaneously, with cationic substrate strongly associated with one E14 residue, whereas the other remains accessible to bind and transport a proton. Here, we demonstrate that EmrE can bind a +2 cation substrate and a proton simultaneously using NMR pH titrations of EmrE saturated with divalent substrates, for a net +1 charge in the transport pore. Furthermore, we find that EmrE can alternate access and transport a +2 substrate and proton at the same time. Together, these results lead us to conclude that E14 charge neutralization does not limit the binding and transport capacity of EmrE.

Orientation of Cholesterol in Polyunsaturated Lipid Bilayers.

The local normal to the fluid liquid crystalline phase of the lipid membrane is an axis of motional symmetry for the molecules that make up the bilayer. The presence of cholesterol in the membrane increases not only the lipid hydrocarbon chain order but also the strength of the membrane's orienting potential. Cholesterol undergoes rapid reorientation about a diffusion axis that is roughly aligned with the long molecular axis, but there is also a slower reorientation of the diffusion axis, or "wobble", relative to the local bilayer normal. The extent of this second, slower motion depends on the degree of order of the lipids that make up the bilayer. We use 2H nuclear magnetic resonance of deuterium-labeled cholesterol to investigate quantitatively the effect of lipid chain unsaturation on cholesterol orientation in a series of phospholipid bilayers. We find that the hydrocarbon chains in membranes composed of polyunsaturated lipids are much more highly disordered than those in membranes composed of saturated lipids but that cholesterol remains aligned roughly along the bilayer normal.

Shining light on multi-drug resistant Candida auris: Ultraviolet-C disinfection, wavelength sensitivity, and prevention of biofilm formation of an emerging yeast pathogen.

Candida auris is an emerging fungal superbug of worldwide interest. It is associated with high mortality rates and exhibits increased resistance to antifungals. Ultraviolet subtype C (UVC) light can be used to disinfect surfaces to mitigate its spread. The objectives of this study were (1) To investigate UVC disinfection performances and wavelength sensitivity of C. auris. (2) To evaluate the UVC dose required for the prevention of biofilm formation on stainless-steel, plastic (polystyrene), and poly-cotton fabric surfaces. C. auris was grown following standard procedures. The study utilized six different UVC LED arrays with wavelengths between 252 and 280 nm. Arrays were set at similar intensities, to obtain doses of 5-40 mJ cm-2 and similar irradiation time. Disinfection performance for each array was determined using log reduction value (LRV) and percentage reduction by comparing the controls against the irradiated treatments. Evaluation of the ability of 267 nm UVC LEDs to prevent C. auris biofilm formation was investigated using stainless-steel, plastic coupons, and poly-cotton fabric. Peak sensitivity to UVC disinfection was between 267 and 270 nm. With 20 mJ cm-2 , the study obtained ≥LRV3. On stainless-steel coupons, 30 mJ cm-2 was sufficient to prevent biofilm formation, while on plastic, this required 10 mJ cm-2 . A dose of 60 mJ cm-2 reduced biofilms on poly-cotton fabric significantly (R2 = 0.9750, p = 0.0002). The study may allow for the design and implementation of disinfection systems.

Illuminating Human Norovirus: A Perspective on Disinfection of Water and Surfaces Using UVC, Norovirus Model Organisms, and Radiation Safety Considerations.

Human noroviruses (HuNoVs) are a major cause of gastroenteritis and are associated with high morbidity because of their ability to survive in the environment and small inoculum size required for infection. Norovirus is transmitted through water, food, high touch-surfaces, and human-to-human contact. Ultraviolet Subtype C (UVC) light-emitting diodes (LEDs) can disrupt the norovirus transmission chain for water, food, and surfaces. Here, we illuminate considerations to be adhered to when picking norovirus surrogates for disinfection studies and shine light on effective use of UVC for norovirus infection control in water and air and validation for such systems and explore the blind spot of radiation safety considerations when using UVC disinfection strategies. This perspective also discusses the promise of UVC for norovirus mitigation to save and ease life.

Novel boronium salt exhibits substantial antibacterial activity when compared to a commercial quaternary ammonium disinfectant.

Commercial disinfectants are routinely used to decontaminate surfaces where microbes are expected and unwelcome. Several disinfectants contain quaternary ammonium salts, or "quats", all being derived from ammonium. Quaternary alkyl dimethyl benzyl ammonium chloride or bromide disinfectants are widely available. These compounds are effective in reducing or eliminating bacteria on contaminated nonporous surfaces. A unique benzyl derived boronium salt with strong detergent action has been developed. It demonstrated 4-8X greater antibacterial activity against 3 different bacteria when compared to an equal concentration of a commercial quant disinfectant solution containing alkyl dimethyl benzyl ammonium chloride and alkyl dimethyl ethylbenzyl ammonium chloride. Antibacterial effectiveness of each agent was determined by the minimum inhibitory concentration (MIC) method.

Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers.

The dimeric transporter, EmrE, effluxes polyaromatic cationic drugs in a proton-coupled manner to confer multidrug resistance in bacteria. Although the protein is known to adopt an antiparallel asymmetric topology, its high-resolution drug-bound structure is so far unknown, limiting our understanding of the molecular basis of promiscuous transport. Here we report an experimental structure of drug-bound EmrE in phospholipid bilayers, determined using 19F and 1H solid-state NMR and a fluorinated substrate, tetra(4-fluorophenyl) phosphonium (F4-TPP+). The drug-binding site, constrained by 214 protein-substrate distances, is dominated by aromatic residues such as W63 and Y60, but is sufficiently spacious for the tetrahedral drug to reorient at physiological temperature. F4-TPP+ lies closer to the proton-binding residue E14 in subunit A than in subunit B, explaining the asymmetric protonation of the protein. The structure gives insight into the molecular mechanism of multidrug recognition by EmrE and establishes the basis for future design of substrate inhibitors to combat antibiotic resistance.

Understanding liquid-liquid equilibria in binary mixtures of hydrocarbons with a thermally robust perarylphosphonium-based ionic liquid.

Binary mixtures of hydrocarbons and a thermally robust ionic liquid (IL) incorporating a perarylphosphonium-based cation are investigated experimentally and computationally. Experimentally, it is seen that excess toluene added to the IL forms two distinct liquid phases, an "ion-rich" phase of fixed composition and a phase that is nearly pure toluene. Conversely, n-heptane is observed to be essentially immiscible in the neat IL. Molecular dynamics simulations capture both of these behaviours. Furthermore, the simulated composition of the toluene-rich IL phase is within 10% of the experimentally determined composition. Additional simulations are performed on the binary mixtures of the IL and ten other small hydrocarbons having mixed aromatic/aliphatic character. It is found that hydrocarbons with a predominant aliphatic character are largely immiscible with the IL, while those with a predominant aromatic character readily mix with the IL. A detailed analysis of the structure and energetic changes that occur on mixing reveals the nature of the ion-rich phase. The simulations show a bicontinuous phase with hydrocarbon uptake akin to absorption and swelling by a porous absorbent. Aromatic hydrocarbons are driven into the neat IL via dispersion forces with the IL cations and, to a lesser extent, the IL anions. The ion-ion network expands to accommodate the hydrocarbons, yet maintains a core connective structure. At a certain loading, this network becomes stretched to its limit. The energetic penalty associated with breaking the core connective network outweighs the gain from new hydrocarbon-IL interactions, leaving additional hydrocarbons in the neat phase. The spatially alternating charge of the expanded IL network is shown to interact favourably with the stacked aromatic subphase, something not possible for aliphatic hydrocarbons.

Melatonin Alters Fluid Phase Coexistence in POPC/DPPC/Cholesterol Membranes.

The structure and biophysical properties of lipid membranes are important for cellular functions in health and disease. In Alzheimer's disease, the neuronal membrane is a target for toxic amyloid-ß (Aß). Melatonin is an important pineal gland hormone that has been shown to protect against Aß toxicity in cellular and animal studies, but the molecular mechanism of this protection is not fully understood. Melatonin is a small membrane-active molecule that has been shown to interact with model lipid membranes and alter the membrane biophysical properties, such as membrane molecular order and dynamics. This effect of melatonin has been previously studied in simple model bilayers with one or two lipid components. To make it more relevant to neuronal membranes, we used a more complex ternary lipid mixture as our membrane model. In this study, we used 2H-NMR to investigate the effect of melatonin on the phase behavior of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), and cholesterol lipid membranes. We used deuterium-labeled POPC-d31 and DPPC-d62,separately to probe the changes in hydrocarbon chain order as a function of temperature and melatonin concentration. We find that POPC/DPPC/cholesterol at molar proportions of 3:3:2 is close to liquid-disordered/liquid-ordered phase separation and that melatonin can induce phase separation in these ternary mixtures by preferentially incorporating into the disordered phase and increasing its level of disorder. At 5 mol% melatonin, we observed phase separation in samples with POPC-d31, but not with DPPC-d62, whereas at 10 mol% melatonin, phase separation was observed in both samples with either POPC-d31 or DPPC-d62. These results indicate that melatonin can have a strong effect on membrane structure and physical properties, which may provide some clues to understanding how melatonin protects against Aß, and that choice of chain perdeuteration is an important consideration from a technical point of view.

Tuning the melting point of selected ionic liquids through adjustment of the cation's dipole moment.

In previous work with thermally robust salts [Cassity et al., Phys. Chem. Chem. Phys., 2017, 19, 31560] it was noted that an increase in the dipole moment of the cation generally led to a decrease in the melting point. Molecular dynamics simulations of the liquid state revealed that an increased dipole moment reduces cation-cation repulsions through dipole-dipole alignment. This was believed to reduce the liquid phase enthalpy, which would tend to lower the melting point of the IL. In this work we further test this principle by replacing hydrogen atoms with fluorine atoms at selected positions within the cation. This allows us to alter the electrostatics of the cation without substantially affecting the sterics. Furthermore, the strength of the dipole moment can be controlled by choosing different positions within the cation for replacement. We studied variants of four different parent cations paired with bistriflimide and determined their melting points, and enthalpies and entropies of fusion through DSC experiments. The decreases in the melting point were determined to be enthalpically driven. We found that the dipole moment of the cation, as determined by quantum chemical calculations, is inversely correlated with the melting point of the given compound. Molecular dynamics simulations of the crystalline and solid states of two isomers showed differences in their enthalpies of fusion that closely matched those seen experimentally. Moreover, this reduction in the enthalpy of fusion was determined to be caused by an increase in the enthalpy of the crystalline state. We provide evidence that dipole-dipole interactions between cations leads to the formation of cationic domains in the crystalline state. These cationic associations partially block favourable cation-anion interactions, which are recovered upon melting. If, however, the dipole-dipole interactions between cations is too strong they have a tendency to form glasses. This study provides a design rule for lowering the melting point of structurally similar ILs by altering their dipole moment.

Acoustic levitation and infrared thermography: a sound approach to studying droplet evaporation.

Herein we report a new technique combining acoustic levitation and infrared thermography to directly monitor droplet surface temperatures. Using it, temperature profiles were recorded during the evaporation of deionized water, methanol, n-propanol, and isopropanol. Results support the viability of this inexpensive and easily-accessed technique for studying chemical and physical changes in droplets.

2 H NMR of oriented phospholipid/cholesterol bilayers containing an amphiphilic peptide.

Lipid bilayers form the basis of cell membranes and the phase behaviour of the membrane has been linked to proper cell function. Model membranes composed of relatively simple mixtures of phospholipids and cholesterol can already exhibit complex phase behaviour. Specifically, liquid ordered-liquid disordered fluid phase coexistence occurs in mixtures which contain one saturated long chain phospholipid and one unsaturated long chain phospholipid and cholesterol. This fluid-fluid two phase region persists over a broad range of temperatures and sample compositions and can be observed experimentally in various sample preparations including multilamellar dispersions, bicelles, and multi-lamellae stacked on glass slides. In order to explore the practicality of using oriented samples with different concentrations of the peptide, we investigated the effect of the addition of a synthetic 22 residue amphiphilic peptide on the orientability and phase behaviour of the lipid mixtures, as well as the orientation and dynamics of the peptide itself via 2H NMR. Increasing the peptide concentration promoted the formation of the liquid ordered phase, suggesting a preferential interaction of the peptide with the thicker ordered phase. However, higher peptide content (> 4 mol%) had a significant negative effect on the alignment of bicelles with their bilayer normal perpendicular to the external magnetic field. In the stacked bilayer samples, 6 mol% peptide eliminated the two phase coexistence region altogether and a single liquid ordered phase was observed from 285 to 311 K. Even so, 2H spectra of the peptide itself did not reveal any preference for the peptide to partition into either the liquid disordered or liquid ordered phase and we found two populations of the peptide, one which undergoes rapid axial reorientation about the bilayer normal and a second (powder component) which does not.

Ionic liquids of superior thermal stability. Validation of PPh4 + as an organic cation of impressive thermodynamic durability.

Recent work by Wasserscheid, et al. suggests that PPh4 + is an organic molecular ion of truly exceptional thermal stability. Herein we provide data that cements that conclusion: specifically, we show that aliphatic moieties of modified PPh4 +-based cations incorporating methyl, methylene, or methine C-H bonds burn away at high temperatures in the presence of oxygen, forming CO, CO2, and water, leaving behind the parent ion PPh4 +. The latter then undergoes no further reaction, at least below 425 °C.

Unorthodox crystalline drug salts via the reaction of amine-containing drugs with CO2.

Drugs containing amine groups react with CO2 to form crystalline ammonium carbamates or carbamic acids. In this approach, both the cation and anion of the salt, or the neutral CO2 adduct, are derived from the parent drug, generating new crystalline versions in a 'masked' or prodrug form. It is proposed that this approach may serve as a valuable new tool in engineering the physical properties of drugs for formulation purposes.