Expeditious Discovery of Small-Molecule Thermoresponsive Ionic Liquid Materials: A Review.

Ionic liquids (ILs) are a class of low-melting molten salts (<100 °C) constituted entirely of ions, and their research has gained tremendous attention in line with their remarkably growing applications (>124,000 publications dated 30 August 2023 from the Web of ScienceTM). In this review, we first briefly discussed the recent developments and unique characteristics of ILs and zwitterionic liquids (ZILs). Compared to molecular solvents and other conventional organic compounds, (zwitter) ionic liquids carry negligible volatility and are potentially recyclable and reusable. For structures, both ILs and ZILs can be systematically tailor-designed and engineered and are synthetically fine-tunable. As such, ionic liquids, including chiral, supported, task-specific ILs, have been widely used as powerful ionic solvents as well as valuable additives and catalysts for many chemical reactions. Moreover, ILs have demonstrated their value for use as polymerase chain reaction (PCR) enhancers for DNA amplification, chemoselective artificial olfaction for targeted VOC analysis, and recognition-based affinity extraction. As the major focus of this review, we extensively discussed that small-molecule thermoresponsive ILs (TILs) and ZILs (zwitterionic TILs) are new types of smart materials and can be expeditiously discovered through the structure and phase separation (SPS) relationship study by the combinatorial approach. Using this SPS platform developed in our laboratory, we first depicted the rapid discovery of N,N-dialkylcycloammonium and 1,3,4-trialkyl-1,2,3-triazolium TILs that concomitantly exhibited LCST (lower critical solution temperature) phase transition in water and displayed biochemically attractive Tc values. Both smart IL materials were suited for applications to proteins and other biomolecules. Zwitterionic TILs are ZILs whose cations and anions are tethered together covalently and are thermoresponsive to temperature changes. These zwitterionic TIL materials can serve as excellent extraction solvents, through temperature change, for biomolecules such as proteins since they differ from the common TIL problems often associated with unwanted ion exchanges during extractions. These unique structural characteristics of zwitterionic TIL materials greatly reduce and may avoid the denaturation of proteins under physiological conditions. Lastly, we argued that both rational structural design and combinatorial library synthesis of small-molecule TIL materials should take into consideration the important issues of their cytotoxicity and biosafety to the ecosystem, potentially causing harm to the environment and directly endangering human health. Finally, we would concur that before precise prediction and quantitative simulation of TIL structures can be realized, combinatorial chemistry may be the most convenient and effective technology platform to discover TIL expeditiously. Through our rational TIL design and combinatorial library synthesis and screening, we have demonstrated its power to discover novel chemical structures of both TILs and zwitterionic TILs. Undoubtedly, we will continue developing new small-molecule TIL structures and studying their applications related to other thermoresponsive materials.

Emerging impacts of ionic liquids on eco-environmental safety and human health.

Owing to their unique physicochemical properties, ionic liquids (ILs) have been rapidly applied in diverse areas, such as organic synthesis, electrochemistry, analytical chemistry, functional materials, pharmaceutics, and biomedicine. The increase in the production and application of ILs has resulted in their release into aquatic and terrestrial environments. Because of their low vapor pressure, ILs cause very little pollution in the atmosphere compared to organic solvents. However, ILs are highly persistent in aquatic and terrestrial environments due to their stability, and therefore, potentially threaten the safety of eco-environments and human health. Specifically, the environmental translocation and retention of ILs, or their accumulation in organisms, are all related to their physiochemical properties, such as hydrophobicity. Based on results of ecotoxicity, cytotoxicity, and toxicity in mammalian models, the mechanisms involved in IL-induced toxicity include damage of cell membranes and induction of oxidative stress. Recently, artificial intelligence and machine learning techniques have been used in mining and modeling toxicity data to make meaningful predictions. Major future challenges are also discussed. This review will accelerate our understanding of the safety issues of ILs and serve as a guideline for the design of the next generation of ILs.

Structural Engineering and Optimization of Zwitterionic Salts for Expeditious Discovery of Thermoresponsive Materials.

This work reported the discovery of N-triflimide (NTf)-based zwitter-ionic liquids (ZILs) that exhibit UCST-type phase transitions in water, and their further structural optimization in fine-tuning polarity to ultimately afford newfangled thermosensitive materials carrying attractive and biocompatible Tc values that clearly demonstrated the true value of the tunability of ZIL structure. This research established that with non-aromatic, acyclic ZILs as small-molecule thermoresponsive materials, their mixing and de-mixing with water triggered by temperatures are entirely reversible.

Reaction-Based Amine and Alcohol Gases Detection with Triazine Ionic Liquid Materials.

We demonstrated in this work the use of affinity ionic liquids, AIL 1 and AIL 2, for chemoselective detection of amine and alcohol gases on a quartz crystal microbalance (QCM). These detections of gaseous amines and alcohols were achieved by nucleophilic aromatic substitution reactions with the electrophilic 1,3,5-triazine-based AIL 1 thin-coated on quartz chips. Starting with inexpensive reagents, bicyclic imidazolium ionic liquids AIL 1 and AIL 2 were readily synthesized in six and four synthetic steps with high isolated yields: 51% and 63%, respectively. The QCM platform developed in this work is readily applicable and highly sensitive to low molecular weight amine gases: for isobutylamine gas (a bacterial volatile) at 10 Hz decrease in resonance frequency (i.e., ΔF = -10 Hz), the detectability using AIL 1 was 6.3 ppb. Our preliminary investigation on detection of the much less nucleophilic alcohol gas by AIL 1 was also promising. To our knowledge, no example to date of reports based on nucleophilic aromatic substitution reactions demonstrating sensitive gas detection in these triazine ionic liquids on a QCM has been reported.

Reaction-Based Detection of Chemical Warfare Agent Mimics with Affinity Ionic Liquids.

We are demonstrating here the successful development of an ionic liquid device based on affinity ionic liquids AIL 1-6 tailored for chemoselective detection of gaseous chemical warfare agent (CWA) mimics on a quartz crystal microbalance (QCM) as well as on disposable filter papers. In the QCM platform, the negligible vapor pressure of ionic liquids ensures that AILs do not dry out on quartz chips and are used free of leakage during the measurements. This lack of vapor pressure makes these ionic liquid devices highly attractive for gas analysis. In the present study, chemoselective CWA mimic vapor detection by QCM occurs when gas rapidly diffuses into the AIL thin film and accordingly the nucleophilic substitution reaction emerges under the experimental conditions developed. Our initial results give credence to three important conclusions: (i) AILs could be prepared in short synthetic steps and are remarkable in detecting CWA mimics, (ii) the analysis of gaseous CWA mimics on QCM is label-free and chemoselective, and (iii) the detection of CWA mimic vapor by AILs on filter paper discs is colorimetric and portable, and, once used, the paper disc can be disposed. To the best of our knowledge, this is the first report in the literature based on the CWA mimic vapor detection in ionic liquids on a QCM.

Affinity Ionic Liquids for Chemoselective Gas Sensing.

Selective gas sensing is of great importance for applications in health, safety, military, industry and environment. Many man-made and naturally occurring volatile organic compounds (VOCs) can harmfully affect human health or cause impairment to the environment. Gas analysis based on different principles has been developed to convert gaseous analytes into readable output signals. However, gas sensors such as metal-oxide semiconductors suffer from high operating temperatures that are impractical and therefore have limited its applications. The cost-effective quartz crystal microbalance (QCM) device represents an excellent platform if sensitive, selective and versatile sensing materials were available. Recent advances in affinity ionic liquids (AILs) have led them to incorporation with QCM to be highly sensitive for real-time detection of target gases at ambient temperature. The tailorable functional groups in AIL structures allow for chemoselective reaction with target analytes for single digit parts-per-billion detection on mass-sensitive QCM. This structural diversity makes AILs promising for the creation of a library of chemical sensor arrays that could be designed to efficiently detect gas mixtures simultaneously as a potential electronic in future. This review first provides brief introduction to some conventional gas sensing technologies and then delivers the latest results on our development of chemoselective AIL-on-QCM methods.

Exploiting Solvate Ionic Liquids for Amine Gas Analysis on a Quartz Crystal Microbalance.

We demonstrated in this work the usefulness of solvate ionic liquids SIL 3 and SIL 4 for chemoselective detection of amine gases on a quartz crystal microbalance. This detection of gaseous amines was achieved by nucleophilic aromatic addition reactions with super electrophilic SIL 3 or SIL 4 thin-coated on quartz chips. Starting with inexpensive reagents, functional SIL 3 and SIL 4 could be readily synthesized in two short steps with high isolated yield (81 and 77%, respectively). The QCM platform developed in this work is readily applicable and highly sensitive to low molecular weight amine gases: for propylamine gas at 10 Hz decrease in resonance frequency, the sensitivity of detection using SIL 4 was 5.4 ppb. This simple and convenient assembly of neutral ligands (e.g., 1a and 1b) with Li+ ion to afford room temperature ionic liquids should be of great importance for a myriad of applications. To the best of our knowledge, no example to date of reports based on nucleophilic aromatic addition reactions demonstrating sensitive amine gas detection in solvate ionic liquids on a QCM has been reported. Furthermore, because of the high color intensity of the Meisenheimer complexes formed, our preliminary result showed that SIL 4 loaded on copier paper can be used not only as a portable amine gas sensor but also as a potential invisible ink that is only revealed by amine vapor.

Quartz Crystal Microbalance Analysis of Diels-Alder Reactions of Alkene Gases to Functional Ionic Liquids on Chips.

We demonstrated here a successful development of the use of functional ionic liquids FIL 1 and FIL 3 for chemoselective detection of alkene gases measured by quartz crystal microbalance. This detection of gaseous alkenes was achieved by the Diels-Alder [4 + 2] cycloadditions with FIL 1 and FIL 3 thin-coated on quartz chips. Our functional ionic liquids could be prepared by straightforward synthetic chemistry in short steps and are superior in alkene gas detection. The QCM platform developed in this work is chemoselective with fast gas diffusion into ionic liquids, readily applicable to low molecular weight alkene gases and insensitive to moisture. To the best of our knowledge, this is the first report based upon the Diels-Alder reactions demonstrating sensitive alkene gas detection in ionic liquids on a QCM. This work is a proof-of-concept inspection of the promising use of a QCM-based sensor method for reaction-directed detection of gas samples, which is part of an ongoing program aimed at studying diseases.

Crowned Ionic Liquids for Biomolecular Interaction Analysis.

On the basis of affinity recognition with positively charged side chains in peptides and proteins, a series of crowned 1,2,3-triazolium ionic liquids (CIL 1-6) was developed and found to be capable of quantitatively extracting peptides and proteins from the aqueous layer into the ionic liquid phase. All of the synthesized CIL 1-6 are liquid at room temperature. This is the first example of biomolecular recognition of both lysine- and arginine-containing peptides and proteins by CILs in pure ionic liquid phase.

Exploiting 1,2,3-Triazolium Ionic Liquids for Synthesis of Tryptanthrin and Chemoselective Extraction of Copper(II) Ions and Histidine-Containing Peptides.

Based on a common structural core of 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyridine, a number of bicyclic triazolium ionic liquids 1-3 were designed and successfully prepared. In our hands, this optimized synthesis of ionic liquids 1 and 2 requires no chromatographic separation. Also in this work, ionic liquids 1, 2 were shown to be efficient ionic solvents for fast synthesis of tryptanthrin natural product. Furthermore, a new affinity ionic liquid 3 was tailor-synthesized and displayed its effectiveness in chemoselective extraction of both Cu(II) ions and, for the first time, histidine-containing peptides.

Exploring silver ionic liquids for reaction-based gas sensing on a quartz crystal microbalance.

Reaction-based, sensitive sensing of aldehyde and ketone gases in real time was effectively achieved on QCM chips thin-coated with silver ionic liquids and , respectively. The method platform developed in this work involves straightforward synthesis of functional silver ionic liquids in water, and is label-free and highly chemoselective with superior gas reactivity for and and, most significantly, totally insensitive to moisture.

Reaction-based azide gas sensing with tailored ionic liquids measured by quartz crystal microbalance.

On the basis of the strain-promoted [3 + 2] cycloaddition reaction performed at ambient temperature, a label-free, online, and chemospecific gas-phase measurement of organic azides in real time was efficiently achieved on QCM chips thin-coated with tailored ionic liquid TIL 1.

Mixture-based combinatorial libraries from small individual peptide libraries: a case study on α1-antitrypsin deficiency.

The design, synthesis and screening of diversity-oriented peptide libraries using a "libraries from libraries" strategy for the development of inhibitors of α1-antitrypsin deficiency are described. The major buttress of the biochemical approach presented here is the use of well-established solid-phase split-and-mix method for the generation of mixture-based libraries. The combinatorial technique iterative deconvolution was employed for library screening. While molecular diversity is the general consideration of combinatorial libraries, exquisite design through systematic screening of small individual libraries is a prerequisite for effective library screening and can avoid potential problems in some cases. This review will also illustrate how large peptide libraries were designed, as well as how a conformation-sensitive assay was developed based on the mechanism of the conformational disease. Finally, the combinatorially selected peptide inhibitor capable of blocking abnormal protein aggregation will be characterized by biophysical, cellular and computational methods.

Biomolecular interactions and tools for their recognition: focus on the quartz crystal microbalance and its diverse surface chemistries and applications.

Interactions between molecules are ubiquitous and occur in our bodies, the food we eat, the air we breathe, and myriad additional contexts. Although numerous tools are available for the recognition of biomolecular interactions, such tools are often limited in their sensitivity, expensive, and difficult to modify for various uses. In contrast, the quartz crystal microbalance (QCM) has sub-nanogram detection capabilities, is label-free, is inexpensive to create, and can be readily modified with a number of diverse surface chemistries to detect and characterize diverse interactions. To maximize the versatility of the QCM, scientists need to know available methods by which QCM surfaces can be modified. Therefore, in addition to summarizing the various tools currently used for biomolecular recognition, explicating the fundamental principles of the QCM as a tool for biomolecular recognition, and comparing the QCM with other acoustic sensors, we systematically review the numerous types of surface chemistries-including hydrophobic bonds, ionic bonds, hydrogen bonds, self-assembled monolayers, plasma-polymerized films, photochemistry, and sensing ionic liquids-used to functionalize QCMs for various purposes. We also review the QCM's diverse applications, which include the detection of gaseous species, detection of carbohydrates, detection of nucleic acids, detection of non-enzymatic proteins, characterization of enzymatic activity, detection of antigens and antibodies, detection of cells, and detection of drugs. Finally, we discuss the ultimate goals of and potential barriers to the development of future QCMs.

A zwitterionic solution for smart ionic liquids to evade cytotoxicity.

By linking the cation and anion motifs of ionic liquids (ILs), zwitterionic liquids (ZILs) exhibit at least 146-2740 and 112-1550 folds less cytotoxicity in human gastric and colon cells than those of the structurally related ILs. Computer simulation shows that ZIL molecules hardly penetrate the cell membranes in contrast to ILs. These findings reveal a novel mechanism for ZILs to evade cytotoxicity, establishing a structure-based design principle for the next generation of sustainable ZILs.

Ultraefficient OG-Mediated Photodynamic Inactivation Mechanism for Ablation of Bacteria and Biofilms in Water Augmented by Potassium Iodide under Blue Light Irradiation.

While photodynamic inactivation (PDI) has emerged as a novel sterilization strategy for drinking water treatment that recently attracted tremendous attention, its efficiency needs to be further improved. In this study, we aimed to clarify the ultraefficient mechanism by which potassium iodide (KI) potentiates octyl gallate (OG)-mediated PDI against bacteria and biofilms in water. When OG (0.15 mM) and bacteria were exposed to blue light (BL, 420 nm, 210 mW/cm2), complete sterilization (>7.5 Log cfu/mL of killing) was achieved by the addition of KI (250 mM) within only 5 min (63.9 J/cm2). In addition, at lower doses of OG (0.1 mM) with KI (100 mM), the biofilm was completely eradicated within 10 min (127.8 J/cm2). The KI-potentiated mechanism involves in situ rapid photogeneration of a multitude of reactive oxygen species, especially hydroxyl radicals (•OH), reactive iodine species, and new photocytocidal substances (quinone) by multiple photochemical pathways, which led to the destruction of cell membranes and membrane proteins, the cleavage of genomic DNA and extracellular DNA within biofilms, and the degradation of QS signaling molecules. This multitarget synergistic strategy provided new insights into the development of an environmentally friendly, safe, and ultraefficient photodynamic drinking water sterilization technology.

Biosafety-inspired structural optimization of triazolium ionic liquids based on structure-toxicity relationships.

Ionic liquids (ILs), owing to their low vapor pressure and excellent solvating ability, are being increasingly applied in various industries to replace highly toxic organic solvents. They mainly pollute aquatic environment and soils, directly endangering eco-environment and human health. Therefore, it is critical to understand and optimize structural motifs of ILs with reduced toxicity. Considering human oral exposure is the major route, our investigations employed a human cell panel (modeling oral exposures) including human stomach (GES-1), intestinal (FHC), liver (HepG2) and kidney (HEK293) cells using a series of experimental and computational approaches to explore the cytotoxicity and molecular mechanism of ILs. We discovered that the cytotoxicity of triazolium and imidazolium ILs was human cell line-dependent with cytotoxicity in an order of FHC > GES-1 > HepG2 > HEK293. For this reason, a toxicity assay using a single cell line was highly inappropriate. Compared to anions (Br-, OTs-, OTMBS-) we tested, the cation of ILs played a major role in causing cytotoxicity. Ionic liquids with cations having longer hydrophobic sidechains (IL09 vs. IL01) readily insert into cell membranes with enhanced membrane and lipidomic perturbations, induce cytotoxicity by triggering cell cycle arrest and apoptosis. Reducing sidechain length and incorporating three nitrogen atoms (triazolium) instead of two (imidazolium) in the cation core alleviated cytotoxicity by reducing cell membrane perturbations and cell function interference. These findings provide important guiding principles for the design of the next-generation of "green" and safe ILs.

Transimination reactions in [b-3C-im][NTf2] ionic liquid.

Compared to conventional molecular solvents, the ionic liquid [b-3C-im][NTf(2)] was found to promote transimination reactions with up to ∼100-fold rate enhancement. This rate effect observed at ambient temperature might be explained by the fact that the ionic liquid displays weak Lewis acidity with very low, if any, nucleophilicity and its imidazolium cation is expected to interact by associating with, and thus electrophilically activating, the C=N bond of the starting imine, leading to increased stabilization of the polar, charged intermediate species and ultimately, rapid product formation. Moreover, the presence of 1 mol% Sc(OTf)(3) in [b-3C-im][NTf(2)] further facilitates the transimination reactions studied.

Total synthesis of asperlicin C, circumdatin F, demethylbenzomalvin A, demethoxycircumdatin H, sclerotigenin, and other fused quinazolinones.

Using scandium triflate and microwaves, the direct double dehydrocyclization of anthranilate-containing tripeptides was achieved, affording the total syntheses of (i) quinazolino[3,2-a]benzodiazepinediones (), (ii) diazepino[2,1-b]quinazolinediones (), and (iii) pyrazino[2,1-b]quinazolinediones () with good overall isolated yields (23-43%, 37-47% and 31-56%, respectively). Among the quinazolino[3,2-a]benzodiazepinediones synthesized, (sclerotigenin), (circumdatin F), and (asperlicin C) are natural products.

Combinatorial discovery of small-molecule 1,2,3-triazolium ionic liquids exhibiting lower critical solution temperature phase transition.

Both lower and upper critical solution temperature (LCST and UCST) systems are two typical phase behaviors of thermoresponsive materials with solvents, in which LCST is far less common than UCST. Recent studies on ionic liquids carrying LCST phase transitions have predominantly focused on quaternary ammonium- and phosphonium-based ionic salts. Based on the 1,2,3-triazole core structure assemblable by azide-alkyne cycloaddition click reaction, this work reports the combinatorial synthesis of 1,3,4-trialkylated 1,2,3-triazolium ionic liquids in three libraries with a total of 160 ionic liquids and demonstrates, for the first time, their values in temperature-switchable phase transition with water. In this work, the successful discovery of a new thermoresponsive ionic liquid b26, based on the structure-and-phase separation study of b8 and b9, perfectly exemplified the true value of the tunability of ionic liquid fine structures. For all 160 ionic liquids synthesized, 155 are liquid at room temperature and 22 room-temperature ionic liquids were found to exhibit thermoresponsive phase transitions having low Tc values in water. To the best of our knowledge, this comprehensive study is the first report of small-molecule 1,2,3-triazolium ionic liquids that exhibit LCST property in water.