Aoli Wu  吴奥丽

Aoli Wu received her BS in Applied Chemistry from Central South University in 2014. She is currently a PhD student in Physical Chemistry at Shandong University. Her research focuses on the aggregation behavior and supramolecular self-assembly of imidazolium-based amphiphiles.
Aoli Wu 于 2014 年获得中南大学应用化学学士学位。她目前是山东大学物理化学专业的博士生。她的研究重点是基于咪唑的两亲物的聚集行为和超分子自组装。

Yanan Gao  高亚楠

Yanan Gao obtained his PhD from Shandong University in 2005. He did postdoctoral research in the Max Planck Institute for Dynamics of Complex Technical Systems, the University of Akron, and the University of York, subsequently (2006–2011). He then began his academic career as a professor in Dalian Institute of Chemical Physics, CAS, and was involved in design and synthesis of novel functional ionic liquids. In 2017, he moved to Hainan University and his current research interests include: (1) self-assembly of amphiphiles in ionic liquids; (2) design and synthesis and their properties of covalent organic frameworks (COFs).
高亚楠于 2005 年获得山东大学博士学位。随后（2006-2011 年），他在马克斯普朗克复杂技术系统动力学研究所、阿克伦大学和约克大学进行了博士后研究。随后，他在中国科学院大连化学物理研究所担任教授，开始了他的学术生涯，并参与了新型功能离子液体的设计和合成。2017 年，他移居海南大学，目前的研究兴趣包括：（1） 离子液体中两亲物的自组装;（2） 共价有机框架 （COFs） 的设计合成及其性质。

Liqiang Zheng  郑立强

Liqiang Zheng is a full professor of Physical Chemistry at Shandong University and deputy director of the Key Laboratory of Colloid and Interface Chemistry in the Ministry of Education. He obtained his PhD from Lanzhou Institute of Chemical Physics in 1993. From 1996 to 1999, he undertook postdoctoral studies at the Tsukuba Institute of Industrial Technology Research in Japan. He is mainly engaged in colloid and interfacial science, including the self-aggregation of amphiphiles in solution and their applications in ion-conduction and the preparation of nanomaterials. He has done much research in the field of zwitterionic amphiphiles.
郑立强是山东大学物理化学正教授，胶体与界面化学教育部重点实验室副主任。他于 1993 年在兰州化学物理研究所获得博士学位。1996 年至 1999 年，他在日本筑波工业技术研究所从事博士后研究。主要从事胶体和界面科学，包括两亲物在溶液中的自聚集及其在离子传导和纳米材料制备中的应用。他在两性离子两亲物领域做了大量研究。

Introduction  介绍

Although amphiphiles have been studied over hundreds of years, they still have broad application prospects in the fields of detergents, emulsifiers, nanomaterial preparation, sensors, electrochemical devices and drug delivery.^1–4 Amphiphiles can not only act as a mediator between two completely incompatible media like aqueous and organic solutions, but also self-assemble into abundant well-defined molecular aggregates with dynamic balancing and heterogeneous structures.^5–7 In colloidal systems, amphiphiles decrease the interface tension between the continuous phase and the dispersed phase, preventing unwanted flocculation and coalescence.
尽管两亲物已经研究了数百年，但它们在洗涤剂、乳化剂、纳米材料制备、传感器、电化学器件和药物递送等领域仍具有广阔的应用前景。^1-4两亲物不仅可以作为两种完全不相容的介质（如水溶液和有机溶液）之间的介质，还可以自组装成具有动态平衡和异质结构的丰富、定义明确的分子聚集体。^5-7在胶体系统中，两亲物降低了连续相和分散相之间的界面张力，防止了不必要的絮凝和聚结。

Depending on the charge of the headgroups, amphiphiles can be divided into cationic, anionic, zwitterionic and nonionic structures. Among these are zwitterionic amphiphiles composed of pairs of covalently bonded cations and anions, which are bridged through alkyl or other spacers.^8–10 The first successful synthesis of zwitterionic materials was reported in the 1950s.¹¹ Due to the numerous anionic and cationic groups available from the chemical inventory, zwitterionic amphiphiles with various structures and properties have been designed and investigated. The common structures of zwitterionic amphiphiles are shown in Table 1. The molecules can be roughly divided into five types: sulfobetaine (SB, such as 3-(N,N-dimethyl-alkylammonio)propanesulfonate C_nH_2n+1N⁺(CH₃)₂(CH₂)₃SO₃⁻, denoted SB3-n), carboxybetaine (CB), imidazolium (such as 3-(1-alkyl-3-imidazolio)propanesulfonate (C_nIPS)), phosphonium (such as phosphorylcholine (PC)) and amino acid derivatives. Zwitterionic CB amphiphiles, in which the headgroups are composed of quaternary ammonium and carboxylate groups, and SB amphiphiles, with quaternary ammonium and sulfonate group connected headgroups, are commonly studied and widely used in industry. Their nontoxicity, cleaning and biodegradable properties make them widely used in personal care and cosmetic products.¹² Zwitterionic imidazolium amphiphiles were first reported by Ohno's group and have received extensive attention in recent years due to their special properties caused by the imidazole ring and their outstanding applications in electrochemistry.^13,14 Based on the abovementioned structures, the headgroups, hydrophobic tails, counterions, spacers between cations and anions, and molecular configurations (gemini, bola, wedge-shaped, or dendritic structures) can be further modified to obtain versatile zwitterionic amphiphiles. A slight variation in their structure is expected to cause significant differences in their properties, such as solubility, Krafft temperature, and aggregate structure.
根据头部基团的电荷，两亲物可分为阳离子、阴离子、两性离子和非离子结构。其中包括由共价键合的阳离子和阴离子对组成的两性离子两亲物，它们通过烷基或其他间隔物桥接。^8-10 人据报道，两性离子材料的首次成功合成是在 1950 年代¹¹ 由于化学库存中提供了大量的阴离子和阳离子基团，因此已经设计和研究了具有不同结构和性质的两性离子两亲物。两性离子两亲物的常见结构如表 1 所示。分子大致可分为五种类型：磺基甜菜碱（SB，如3-（N，N-二甲基-烷基锑）丙磺酸盐C_nH_2n+1N⁺（CH₃）₂（CH₂）₃SO₃⁻，表示为SB3-n）、羧基甜菜碱（CB）、咪唑鎓（如3-（1-烷基-3-咪唑啉）丙磺酸盐（C_nIPS））、鏻（如磷酸胆碱 （PC））和氨基酸衍生物。两性离子 CB 两亲物（其中头部基团由季铵和羧酸盐基团组成）和 SB 两亲物（季铵和磺酸盐基团相连）在工业上被广泛研究和广泛使用。它们的无毒、清洁和可生物降解特性使其广泛用于个人护理和化妆品。¹² 两性离子咪唑两亲物最早由 Ohno 小组报道，由于其由咪唑环引起的特殊性质及其在电化学中的突出应用，近年来受到广泛关注。^13,14 基于上述结构，可以进一步修饰头部基团、疏水尾部、反离子、阳离子和阴离子之间的间隔区以及分子构型（双子座、波拉、楔形或树突状结构）以获得多功能两性离子两亲物。预计其结构的微小变化会导致其特性（例如溶解度、Krafft 温度和聚集体结构）出现显著差异。

Carboxybetaine	Sulfobetaine	Imidazolium	Phosphonium/amino acid

Compared with nonionic amphiphiles, although zwitterionic molecules are overall electrically neutral, the coexistence of oppositely charged groups endows them with extremely high polarity. For typical SB-type zwitterions, their dipole moments are calculated as μ ≈ 18–30 D, while the dipole moment of water is only 1.9 D.^15,16 Hence, there are strong binding interactions between the headgroups of zwitterionic amphiphiles. According to molecular dynamics (MD) simulations, water molecules around zwitterionic amphiphiles possess a wider dipole orientation distribution and lower mobility than around nonionic ones. In addition, zwitterionic amphiphiles have demonstrated lower hydration free energies after calculation with the free energy perturbation method, which confirms the stronger hydration of zwitterionic compounds.^17,18 Long et al. investigated the morphologies and thermomechanical properties of n-butyl acrylate-based copolymers composed of zwitterions or cations, respectively.¹⁶ Their experimental results demonstrated that zwitterionomers offered a system with well-defined microphase separation and higher elastomeric properties compared with corresponding cationomers, which can be attributed to the stronger associations among the zwitterionic compounds caused by covalently bonded charged pairs.

According to the MD simulation results reported by Jiang's group, although both SB and CB have strong hydration, there are individual features between them in hydration, ionic interactions, and self-associations (Fig. 1).^19,20 Due to the extra oxygen atoms of SB in the negatively charged groups, the volume of their first coordination shell is larger than that of CB. The obtained coordination numbers of water molecules in the first coordination shell indicate that there are more water molecules around the anionic groups of SB than those of CB. However, the sharper spatial distributions, more preferential dipole orientation, and longer residence time of the water molecules around the anionic groups of CB demonstrate that CB attracts individual water molecules more strongly. Zwitterionic headgroups tend to associate among themselves through the electrostatic interactions between cations and anions, which leads to both lower and upper critical solution temperature, antipolyelectrolyte effects, and even hydrophobic properties for zwitterionic materials.^21,22 Compared with SB, CB molecules with quite different charge densities exhibit fewer self-associations, which causes CB molecules to be fully hydrated and have stronger hydration. In addition, CB is easier to functionalize, and can be widely used in biosensing and targeted drug delivery.²³

With a few exceptions, PC and betaine-type zwitterionic amphiphiles are very soluble in water compared with other zwitterionic amphiphiles. Due to the hydrophilicity of carboxylates being higher than that of sulfonate groups, CB amphiphiles are more soluble than SB amphiphiles. However, after the replacement of the ammonium from SB by an imidazolium group, such as C_nIPS, the solubility decreases sharply. Nome and co-workers found that the temperature at which the solubility of C_nIPS increases rapidly is much higher than that of an SB amphiphile with the same alkyl chain tail.²⁴ The cationic imidazolium ring with its rigid and unsymmetrical nature distinguishes them from other zwitterions. In the crystal state, the rigid and bulky imidazolium ring increases the rigidity of the headgroup and enhances their crystal packing. There are strong interactions between the positively charged imidazolium headgroup of one amphiphile and the negatively charged sulfonate group in another, which is similar to the hydrogen bonding observed for C₁IPS. The C–N–C–C torsion angle of C₁IPS is 100.05°, which allows the formation of a C–H⋯O hydrogen bonding network between the imidazolium cation and the sulfonate anion from neighboring zwitterions. Single crystal data of C₁IPS show that a negative SO₃^– group is surrounded by four cationic imidazolium headgroups accompanied by a six close contact C–H⋯O hydrogen bonding network, which significantly weakens the repulsion between SO₃^– groups.²⁵

The electrostatic potential distributions of SB and C_nIPS are also obviously distinctive.²⁴ For C₁₄IPS and SB3–14, the only difference is the cationic portions. Their zwitterionic headgroups possess similar charge distributions, according to the calculations of natural atomic charges. As shown in Fig. 2, in both cationic imidazolium and ammonium groups, the nitrogen atoms as well as their surrounding carbon atoms are negatively charged, while the hydrogen atoms are positively charged, which maintains the charge balance. Hence, an important difference between the two zwitterionic amphiphiles is that the carbon at the C-2 position of the imidazolium ring carries a considerable positive charge. While the other carbon atoms of C₁₄IPS as well as all the carbon atoms of SB3–14 are negatively charged, consistent with the acidity of the hydrogen bonded to the negative carbon in the imidazolium ring.²⁶ Therefore, the proton of C-2 in the imidazolium ring carries a higher charge than the others, which makes them act as excellent hydrogen bonding donors.^27,28

Another particularity of zwitterions is their ability to interact with salts. Although most zwitterionic amphiphiles are farinose solids with a high melting point and relatively low solubility, their high dipole moment affords them the ability to solvate various ionic compounds.²⁹ For example, 0.01 M C₁₄IPS is readily soluble in 0.08 M NaCl at 25 °C, which indicates that the added electrolytes influence the micellar structures in the system.²⁴ After the addition of salts into the aqueous solution, the ions hinder the interactions between the imidazolium cation and the sulfonate anion, which significantly improves its solubility. Meanwhile, strong ion–dipole interactions arising from the zwitterionic matrix will preclude electrolyte segregation and crystallization.^16,30 More interestingly, a new type of zwitterionic amphiphile with low melting point, high solubility and abundant aggregates can be obtained after mixing zwitterions with equimolar salts. More detailed descriptions are given in section Incorporation of electrolytes.

Based on the above introduction, the structures and properties of zwitterionic amphiphiles can be summarized as: (1) electric neutrality, (2) extremely high polarity, (3) self-association, (4) strong hydration, and (5) a synergistic effect with electrolytes. The special structure of zwitterionic amphiphiles offers the system unique performances, such as no migration under a potential gradient, easy functionalization, inherent stimuli-responsiveness, and antifouling properties, which can be utilized to obtain diverse assembly materials and solve many application problems (shown in Fig. 3).^31–34 Lowe and McCormick reviewed the synthesis and solution properties of zwitterionic polymers.³⁵ Jiang et al. summarized the design and biochemical applications of zwitterionic materials.^18,36 However, in spite of their best known structure and properties, research into and applications of zwitterionic amphiphiles are still less than for other types of amphiphiles. The introduced diversified structures and abundant characteristics help us to gain a better understanding of zwitterionic amphiphiles and provide design principles for broader applications.

Aggregation behavior of zwitterionic amphiphiles

Amphiphiles can form dynamic, heterogeneous and well-defined molecular aggregates like micelles, vesicles, or liquid crystals in solution or other media driven by a variety of noncovalent interactions, such as hydrophobic interaction, electrostatic interaction, hydrogen bonding, π–π stacking and host–guest interaction.^37–41 For zwitterionic amphiphiles, the interactions among anion and cation connected headgroups will endow the aggregates with special assembly structures and properties. Apart from the formation of aggregates as a single compound, the addition of electrolytes or ionic amphiphiles can significantly affect the assembly structure of the system.

Single component

Usually, zwitterionic amphiphiles have lower critical micelle concentration (cmc) values than other ionic analogues due to the overall neutrally charged molecules with relatively weak electrostatic repulsions among the headgroups.²⁴ For imidazolium-based amphiphiles, the presence of the imidazole ring will reinforce the packing ability of zwitterionic micelles, which further decreases their cmc values. According to reports in the literature,^42,43 traditional ionic amphiphiles usually require higher concentrations or additional electrolytes to provide sufficient approach of headgroups with the same charge for packing into wormlike micelles. Zwitterionic amphiphiles like betaines tend to form wormlike micelles without salts or other additives through self-screening effects.^12,44–46 Actually, the behavior of zwitterionic amphiphiles as solutions in water is similar to that of ionic amphiphiles with additional salt. For the 22-carbon-tailed zwitterionic amphiphile erucyl dimethyl amidopropyl betaine (EDAB), the weak electrostatic repulsion between the headgroups and the long hydrophobic tail leads to a low cmc value and Krafft point in water.⁴⁷ Therefore, the small effective headgroup area allows the amphiphile molecules to form cylindrical micelles directly (Fig. 4). In view of their low toxicity and nonfouling nature, isotropic wormlike micelles formed by zwitterionic amphiphiles can be used as thickeners in personal care and cosmetics and even as drug-delivery carriers in biomedicine.⁴⁸ Zwitterionic amphiphiles like SB3-n in aqueous solutions are insensitive to pH and can maintain their zwitterionic state over a wide range of pH values. In addition, these zwitterionic amphiphiles are insensitive to salts and temperature, which makes them more desirable and widely applicable.⁴⁹

Until now, various types of zwitterionic amphiphiles have been designed and investigated, and abundant ordered molecular aggregates can be constructed. Dey et al. synthesized a kind of bola zwitterionic amphiphile (PEGDPC) with l-cysteine as a polar headgroup and poly(ethylene glycol) (PEG) as a spacer.⁵⁰ PEGDPC can form vesicles in aqueous solution. In addition, the walls of the vesicles are composed of a single layer of amphiphilic molecules, which has been confirmed by 2D NOESY experiments. Although the vesicles can be formed in a pH range from 3.0 to 10.0, their size was found to be smaller at a lower or higher pH value compared with that in neutral pH. The reason is that the lower or higher pH will lead to the ionization of the headgroups, which will increase the electrostatic repulsion between the PEGDPC at the surface. As a result, the weak stacking of the amphiphiles induces the decrease in vesicle size. The kinetic and thermodynamic micellization mechanisms of a fluorinated zwitterionic amphiphile polyfluorinated-2-dodecenyl (3-sulfate) propyl dimethyl ammonium (PDSPDA) in ethylammonium nitrate (EAN) were studied by Hao's group.⁵¹ When the concentration of PDSPDA exceeded cmc, two sets of ¹⁹F NMR signals were observed. Due to the long lifetime of the micelles, the exchange of amphiphile molecules between monomers and micelles in EAN was unusually slow. The fluorinated amphiphile, solvated headgroups, and characteristics of EAN are considered to contribute to the phenomenon. In addition, two zwitterionic molecules formed by cysteine-functionalized amphiphiles and sodium 2-mercaptoethanesulfonate (MESNA) oleoyl thioester have been designed to mimic the native precursors of the common phospholipid (Fig. 5).⁵² Both of the raw materials can form micelles in aqueous solution. While, after mixing them, the amidophospholipid products induced tubular vesicles to grow and finally converted them into membrane-bound vesicles. Therefore, such amidophospholipids could be used in applications such as protocells.

Incorporation of electrolytes

Although, the zwitterionic micelles have no net charge, the large dipole moments in the headgroups brought about by covalently bonded opposite charges will induce the micellar interface to interact with both cations and anions, unlike nonionic micelles. Usually, the addition of electrolytes will reduce the cmc values of amphiphiles by interacting with the micellar interface.²⁴ According to studies on the physical and kinetic properties of zwitterionic micelles, they preferentially bind anions to generate negative zeta potential. One of the main reasons is the intrinsic difference in solvation nature between cations and anions. Compared with cations, anions form no clear solvation shell, which is beneficial for them to form ion pairs with the cationic moiety of the headgroup and show greater micellar incorporation. Therefore, zwitterionic micelles become anionoid due to anion binding.⁵³ In addition, the values of zeta potential are related to the binding affinity of zwitterionic micelles and added anions, which follows the Pearson hard–soft classification or the Hofmeister series.^54–57 Although the driving forces for ion binding are not completely clear, it can be ascertained that the binding of a specific anion to zwitterionic micelles is related to the hydration free energies.

Okada et al. investigated the surface potentials of SB3–12 micelles in the presence of various salts by capillary electrophoresis and analyzed the results based on a model derived from the Poisson–Boltzmann equation.⁵⁴ The net charge of single SB3–12 micelles in pure water with inner positive and outer negative charges was almost zero. Therefore, no electrostatic potential can be detected outside the micelles. However, after the addition of electrolytes, this kind of zwitterionic amphiphile accommodates anions better than cations, and a negative electrostatic potential was detected through anion-dominated partition. The nonzero surface potential indicated that there are imbalances between anion and cation partitioning. The results of atomistic MD simulations demonstrated that anion adsorption at the surface of SB3–14 zwitterionic micelle follows the Hofmeister series F⁻ < Cl⁻ < Br⁻ < I⁻ < ClO₄^–, which can be related to the softness and hydration energies of the anions.⁵⁸ Therefore, the binding abilities of anions with low charge densities like PF₆^– and ClO₄^– are much stronger to SB micelles than that with strongly hydrated anions, such as OH⁻ and F⁻. Many investigations have been conducted and also confirmed that the accommodation of anions is dominant in zwitterionic micelle systems with an inner cationic surface and outer anionic surface. In general, the unbalanced distribution of cations and anions in zwitterionic micelles leads to the outer surface potential of micelles having an intrinsic nonzero charge. Emrick et al. prepared supracolloidal fibers composed of oil-in-water emulsion gels which were stabilized by a polymeric zwitterionic surfactant.⁵⁹ Unlike traditional zwitterions, the selected surfactant was sulfur-based cations. The strong dipole–dipole pairing makes the system particularly salt-sensitive. That is, the salt (NaNO₃) concentration in the emulsion and the gel extruded aqueous medium will influence the ability of the emulsions and the supracolloidal fibers.

The nature of the cations can also affect their binding affinity with zwitterionic micelles. In general, the effect of divalent cations on the changing extent is stronger than that of monovalent cations. The effect of CaCl₂ on the solubility, aggregate structure, and rheological property of zwitterionic amphiphile erucyl dimethyl amidopropyl hydroxyl sulfobetaine (EHSB) in aqueous solution has been investigated.⁵³ The electrostatic interaction between the sulfonate groups of EHSB and Ca²⁺ disrupts the inner salt structure of the EHSB headgroups, which increases the solubility of EHSB. The Ca²⁺-improved intermolecular interaction induces an increase in viscosity at lower EHSB concentration, and elasticity at higher EHSB concentration. Therefore, the amphiphiles in aggregates will be stacked compactly, which promotes the growth and entanglement of wormlike micelles (Fig. 6).

Although the solubility of C_nIPS as a single component in water is very low, the incorporation of inorganic or organic salts will significantly increase their solubility and improve the stabilization of a micellized amphiphile. The micellar aggregation number as well as the cmc of C₁₄IPS are only slightly influenced by added salts (such as NaCl or NaBr), but NaClO₄ obviously increases the micelle interface zeta potentials.²⁴ According to the Hofmeister series and Pearson's hard–soft classification, anions with low charge densities, like ClO₄⁻, bind much more strongly to zwitterionic micelles than strongly hydrated anions such as Cl⁻ or Br⁻.

One interesting and promising feature of C_nIPS is that a new type of room-temperature zwitterionic liquid (ZIL) can be constructed by the equimolar addition of inorganic or organic salts. Compared with traditional ionic amphiphiles, this strategy is more convenient for selecting various counterions to tune aggregate structures. The utilization of zwitterionic amphiphiles can effectively avoid a complex and time-consuming ion exchange process, which can suppress the formation of unexpected ion pairs with unfavourable properties.^60,61 It has been demonstrated that a homogeneous liquid matrix can be obtained after mixing solid phosphonium-, imidazolium-, or pyridinium-based zwitterions with sulfonate anions and bis(trifluoromethanesulfonyl)imide (HTFSI).⁶² The soft cations of these zwitterions prefer to form ion pairs with a TFSI⁻ anion according to the soft–hard, acid–base principle. Ohno et al. summarized 45 kinds of zwitterions and discussed the relationship between their structures and thermal and ionic conductivity properties after mixing them with alkali metal salts.⁶³ Most zwitterions possess melting points above 100 °C, suggesting that the tethered cation and anion induce the increase in melting point. In addition, both the increased spacer length between the cation and anion and anion structures with delocalized negative charge will decrease the melting point of the zwitterions. Room-temperature ionic liquids (ILs) can be obtained after mixing equimolar imidazolium-based zwitterionic amphiphiles and lithium salts (LiTFSI, LiOSO₂CF₃, LiBF₄, and LiClO₄). Among these, the imidazolium zwitterion-LiTFSI complex displays the lowest glass transition temperature (T_g) and the highest ionic conductivity. The incorporation of suitable additive ions into zwitterionic amphiphiles is a potential strategy to construct liquid crystal (LC) phases with tunable assembly structures. In general, soft anions such as TFSI⁻ can effectively decrease the T_g of compounds, while hard anions such as Cl⁻ endow organic salts with high crystallinity. It has been demonstrated that the addition of lithium salts with soft and large anions was effective for the induction of nanosegregated aggregates with a circular cone structure, such as bicontinuous cubic (Cub_bi) phase (Fig. 7).⁶⁴ This exhibition can be attributed to the formation of an ion pair, which expands the distance between adjacent zwitterionic headgroups, thus leading to curvature of the interface. Whereas, the addition of hard anions tends to form smectic (Sm) phases.

Our group has explored in detail the aggregation behavior of imidazolium zwitterionic amphiphiles with different counterions, cations, and alkyl chains.⁶⁵ The experimental results demonstrated that more hydrophobic anions and tails are more favorable for micelle formation. In addition, the binding affinity between anions and imidazolium cations also plays important roles in their micellization behavior. For C₁₂IPS, although it has strong hydrophobicity and a high melting point, a hydrophilic zwitterionic amphiphile with a room-temperature IL nature can be easily obtained after mixing C₁₂IPS with equimolar LiTFSI.⁶⁶ According to the soft–hard acid–base theory, the strong interaction affinity between a soft imidazolium cation and a soft TFSI⁻ anion plays an important role in the formation of C₁₂IPS-LiTFSI, which significantly decreases the melting point and increases the solubility of the compound. The nanosegregation between the hydrophilic zwitterion/LiTFSI region and the hydrophobic alkyl chain part prompts the amphiphile to aggregate into wormlike micelles, hexagonal, lamellar, and bicontinuous cubic structures (Fig. 8). After that, a series of soft sulfonic acid containing different substituent groups (CH₃SO₃H, C₆H₅SO₃H, and CF₃SO₃H) were mixed with equimolar C_nIPS (n = 12, 14, 16).⁶¹ The melting temperatures of the complexes increased steadily with alkyl chain length, and among these [C₁₂IPS][CH₃SO₃H] displayed the lowest melting point. In general, a weaker electrostatic interaction with the imidazolium cation brought about by a larger anion radius will cause an increase in melting temperatures. However, the strong hydrogen bonds caused by F atoms from CF₃SO₃H, as well as the additional π–π stacking interactions between imidazole and the phenyl ring, induce the melting point to follow the order: [C₁₂IPS][CF₃SO₃H] > [C₁₂IPS][C₆H₅SO₃H] > [C₁₂IPS][CH₃SO₃H].^67,68 The electrostatic interactions between anions and cations essentially affect their melting points and phase transition behavior. In addition, their hydrophilic headgroup area depends on the effective occupied area of cation and anion, which ultimately influences the critical packing parameter. Based on this, [C₁₂IPS][CH₃SO₃H] with a lower melting point possesses richer liquid crystal phase behavior.³¹ After mixing C₁₆IPS with β-naphthalene sulfonate, the obtained single-tailed zwitterionic amphiphile can self-assemble into micelles, wormlike micelles and a hexagonal liquid crystal with increasing concentration. The introduction of hydrophobic and aromatic β-naphthalene sulfonate promotes π–π stacking between the anion and imidazolium cation, which is conducive to structural transformation.

Zwitterionic/ionic complexes

Zwitterions have excellent synergism with other amphiphiles.⁶⁹ Compared with cationic/anionic amphiphile mixed systems, the attraction forces between the two kinds of amphiphiles in the zwitterionic/anionic systems are also significant.^70,71 The cmc values of zwitterionic/anionic systems, including SB3–12/sodium dodecyl sulfate (SDS), N-dodecyl-N,N-(dimethylammonio)-butyrate (DDMAB)/SDS and SB3–8/sodium octyl sulfate (SOS), demonstrated that there are strong interactions between zwitterionic and anionic amphiphiles.⁷² Among these, the SB3–8/SOS and DDMAB/SDS systems exhibited synergism between the two kinds of amphiphiles at all mole ratios studied. While the SB3–12/SDS system displayed synergistic behavior only when the mole ratio of SB3–12/SDS exceeded 0.30. Dey et al. investigated the interaction between amino acid-based zwitterionic (C₁₂Gly) and SDS.⁷³ The solubility of a single component in water (pH = 6.5) was very poor (ca. 0.6 mM) due to the zwitterionic nature of C₁₂Gly. In comparison with the single component, the C₁₂Gly/SDS mixed system exhibited a much lower cmc and higher surface activity. The synergism caused by strong electrostatic attraction between C₁₂Gly and SDS amphiphiles generated a pseudodouble chain anionic amphiphile. Small mixed micelles, rod-like micelles, threadlike micelles and even vesicles can be produced, depending on the molar ratios and concentrations of the two amphiphiles (Fig. 9). Based on the synergistic effect of zwitterions and anions, supramolecular thermotropic LC structures, such as hexagonal and lamellar phases, were also fabricated by the co-assembly of C_nIPS (n = 12, 14, and 16) and nonmesomorphic dendron 3,4,5-tris(dodecyloxy)benzoic acid (TDBA).⁷⁴

The interactions between zwitterionic amphiphiles (SB3–10, SB3–12, SB3–14) and a cationic amphiphile benzyl dimethylhexadecylammonium chloride (BDHAC) in aqueous solution were also investigated in detail.⁴⁹ A reduction in either surface tension or cmc demonstrates a certain degree of efficiency in mixed micelle formation owing to the interaction between zwitterionic and cationic amphiphiles. The intensity of the electrostatic attraction between SB3-n and BDHAC followed the order: SB3–14 > SB3–12 > SB3–10. The results further showed that a greater synergism was observed when the molar ratio between zwitterionic and cationic amphiphiles was 0.25 : 1 in aqueous solution. Although the zwitterionic amphiphiles are neutrally charged compounds, many of their physical properties are quite different from those of nonionic amphiphiles. In some cases, they behave more like ionic amphiphiles. The cationic partition of the zwitterionic amphiphiles electrically attracts the aryl chloride partition of BDHAC rather than repelling each other, which rationalizes the high surface activity of the systems.

Wang et al. investigated three sets of equimolar binary zwitterionic palmityl sulfobetaine (SNC16)/ionic amphiphile mixed systems. The ionic amphiphiles were anionic sodium hexadecyl sulfate (SHS), anionic SDS, and cationic cetyltrimethylammonium bromide (CTAB), respectively.⁷⁵ The synergistic effects between zwitterionic and ionic amphiphiles on the interfacial water structure at the air–water interfaces were explored by sum frequency generation vibrational spectroscopy (SFGVS). The results indicate that the headgroup–headgroup electrostatic interactions as well as the chain–chain van der Waals attractive interactions in the mixed systems influenced the adsorption of the compounds on the air–water interfaces and enhanced the ordering of water molecules in the interface. Moreover, three-component systems composed of zwitterionic cocamidopropyl betaine (CAPB), anionic sodium lauryl ether sulfate (SLES), and nonionic dodecanoic acid (HC12) were also investigated.⁷⁶ With an increase in HC12 content, synergistic growth was observed from long wormlike micelles to disk-like micelles.

Other additives like small organic molecules and oil can also affect the aggregation behavior of zwitterionic amphiphiles. Tabor et al. selected oleyl amidopropyl betaine (OAPB), which enabled the formation of viscoelastic wormlike aggregates as a single component in aqueous solution.⁴⁸ The effects of additives with different aromaticities and polarities on the structure of OAPB and their aggregation behavior were investigated. The incorporation of non-polar additives induced the evolution from wormlike micelles to microemulsions when the additive concentration exceeded a critical value. Conversely, polar additives can only influence fluid rheological behavior. With the addition of a small amount of polar additives, the viscosity of the OAPB aggregates was significantly increased compared with a pure OAPB system. Polar additives intercalate between the amphiphile headgroups to reduce the molecular packing density, which endows the wormlike micelles with more flexibility. They also studied the assembly structure of erucyl amidopropyl betaine (EAPB) in aqueous solution in the presence of oil, small organic molecules, salts and other amphiphiles by SANS and USANS (Fig. 10).⁴⁴ Wormlike micelles with a radius of about 2.9 nm can be formed even at very low concentration (1 mM). Experimental results demonstrate that salt has little effect on the local micellar aggregation of EAPB. Due to the net neutral charge and large extent of self-screening of headgroups, zwitterionic betaine behaves somewhat more like a nonionic amphiphile under most conditions. Therefore, further addition of excess salts with different valences or hydrophobicity could be expected to have little effect on the system.

Modification of zwitterionic amphiphiles

Designability

Zwitterionic amphiphiles can be easily tailored to exhibit performance-boosting properties. The cation and anion in the headgroup, the hydrophobic tail, as well as additional ionic salts, organic materials or other amphiphiles provide a large number of design possibilities of new zwitterionic materials with various assembly structures and features. The charge densities caused by covalently bonded cationic and anionic groups can also be separated and tuned by controlled distances and spacers. According to the experimental results, the cation sites have little effect on the properties of pure zwitterions. While an increase in spacer chain length between the cation and anion will decrease the melting point of a pure zwitterion.⁷⁷ In addition, the delocalized negatively charged anion will endow the zwitterions with lower melting point values than other anion species. Until now, novel zwitterionic amphiphiles such as gemini, bola, fluorinated, dendritic, and responsive zwitterionic amphiphiles have been skillfully designed (some can be seen in Table 1). For example, the introduction of a gemini structure will prevent the alkyl chains of imidazolium zwitterionic amphiphiles from aligning in an ordered manner, which reduces the crystallinity of the alkyl chain domains.⁷⁸ The unique properties of zwitterionic amphiphiles provide superiority in designing novel building blocks with a tunable packing number, which can self-assemble into more highly ordered hierarchical structures.⁷⁹

Schmuck et al. synthesized a water-soluble guanidiniocarbonyl pyrrole carboxylate zwitterion.⁸⁰ Due to the presence of an extensive hydrogen bonding network accompanied by two mutually interacting ion pairs, the compound tends to form more stable 1 : 1 dimers in water with an extremely high association constant of 170 M⁻¹ compared with a neutral analogue. During the formation of a dimer, the initial large dipole of the zwitterions was almost completely offset due to the mutual interaction between the two ion pairs. When the imidazolium cationic headgroup of the zwitterionic amphiphile (ImH₂ZI) was functionalized by iodine (ImI₂ZI), their self-organization behavior changed significantly.⁸¹ Although both ImI₂ZI and ImH₂ZI display thermotropic smectic (Sm) structures over a wide range of temperature, the ImH₂ZI transformed into the Col phase while the ImI₂ZI transformed into the Cub_bi phase after the addition of HTFSI. The increase in the size of the headgroup and the halogen bonding between the iodine-containing cationic headgroup and the TFSI⁻ anion will influence the assembly behavior. Therefore, the ImH₂ZI/HTFSI mixture displays the columnar (Col) LC structure, while the Cub_bi phase was obtained for the ImI₂ZI/HTFSI mixture. Ohno et al. synthesized gemini zwitterionic amphiphiles G-ZI_m,n. The thermotropic LC phase behavior depends on the spacer structure and the molar ratio between G-ZI_m,n and added HTFSI.⁷⁸ Cub_bi LC phases with a 3D continuous ionic domain have been obtained over a wide range of temperature. Incorporation of a Brønsted acid into the matrix led to the formation 3D continuous Cub_bi or Col_h phases.

The incorporation of large host molecules was a simple and effective method to obtain materials with more properties and functions. Supramolecular hydrogels with excellent mechanical properties were fabricated based on host–guest interaction between β-cyclodextrin (β-CD) and the commercially available zwitterionic amphiphile SB3–14 (Fig. 11).⁸² Compared with SDS@2β-CD microtubes,^83,84 the long and flexible microtubes formed by 2SB3–14@3β-CD can bundle and entangle, and further form into an extensive 3D network, and eventually a strong hydrogel was obtained. For SDS@2β-CD microtubes covered by the anionic headgroups, their surface is highly negative, preventing the microtubes from further bundling or entangling. The electrostatic repulsion among SDS@2β-CD assemblies causes a single microtube with a high inner tension. Therefore, the brittle and inflexible microtubes are unable to deform elastically. For the SB3–14/β-CD microtubes, those unfavorable factors for gel formation are avoided due to the minimized electrostatic repulsion from the zwitterionic headgroup of SB3–14. Liu et al. embedded amphiphilic psulfonatocalix[4]arenes (SC4A) into the liposomal bilayers of zwitterionic phosphoglyceride.⁸⁵ Benefiting from the specific host–guest interaction, high water solubility, and excellent biocompatibility of SC4A, a multifunctional drug-delivery vehicle was obtained. Our group constructed a low molecular weight supramolecular ionogel based on the host–guest interaction between β-CD and the counterion of ZIL in EAN.⁸⁶ Ionogels with different rheological properties can be obtained by adjusting the molar ratio between β-CD and ZIL.

Responsive zwitterionic amphiphiles

Advanced stimuli-responsive amphiphiles endow colloidal systems with the functionality to respond to external stimuli such as temperature, pH, light, and magnetic field.⁸⁷ Due to the presence of pH-sensitive headgroups, most zwitterionic amphiphiles have the ability to undergo protonation and deprotonation to obtain a wide range of net charge densities and form different assemblies by adjusting the pH values of the solution.^88,89 Such unique properties give the building blocks an opportunity to fabricate nanomaterials with a stimuli-responsive and smart character in a reversible and simple pathway. Additionally, zwitterionic amphiphiles are less irritating to the skin and eyes than ionic amphiphiles, which endows them with potential applications as delivery vehicles of pharmaceutical formulations.

Two l-cysteine-based zwitterionic amphiphiles with mPEG as the hydrophobic tail (mPEG300-Cys and mPEG1100-Cys) have been synthesized.⁶⁹ Both can form vesicles over a wide range of pH and can encapsulate hydrophilic and hydrophobic dyes. However, the electrical neutrality of the aggregate surface in neutral pH and the interactions among the vesicles increase the size of the vesicles and make them unstable. The variation of pH in solution will significantly influence the stability of the aggregates through ionizable headgroups. In acidic solution, the change in ionization degree influences the permeability of the vesicles and induces the hydrolysis of the ester linkage, which promotes the release of dye molecules. Due to the biocompatible and eco-friendly advantages of both mPEG and l-cysteine, the self-assembled structures of the amphiphile in aqueous medium are attractive candidates for drug delivery and industrial applications. The zwitterionic gemini amphiphile 2,2′-(1,4-phenylenebis(oxy)) bis(N,N-dimethyl)-N-carboxyethyl-N-(alkylamide propyl) ammonium chloride (C14-B-C14) with two pH-sensitive carboxyl headgroups and a rigid spacer was synthesized by Lu's group.⁹⁰ As shown in Fig. 12, the amphiphile displayed HC14-B-C14H, HC14-B-C14 and C14-B-C14 molecular states at pH values of 2.0, 7.0 and 12.0. A higher cmc and lower efficiency of surfactant adsorption at the air–water interface (pC20) can be obtained with an increase in pH value. In the state of HC14-B-C14H, the amphiphile displayed a cationic property. The strong intermolecular electrostatic repulsion between two cationic headgroups causes the amphiphiles to form a conical structure, and ultimately form spherical micelles. Under nearly neutral conditions, the HC14-B-C14 displayed one anionic and two cationic headgroups. There were intramolecular electrostatic repulsions between the two cationic headgroups that were linked by covalent bonds. The unprotonated carboxylate would be inserted between molecules to shield the inter-molecular electrostatic repulsion. In this case, the amphiphiles tended to exhibit a parallel structure, leading to the formation of wormlike micelles. Under basic conditions, two anionic and two cationic headgroups were present in C14-B-C14. The higher hydrophilic properties decreased the surface activities of the amphiphile. The decrease in intra-molecular and inter-molecular electrostatic repulsions caused the solution to transform into a gel-like fluid. This transition is reversible and can be repeated for at least 4 cycles. The double cationic headgroups of the amphiphile remained constant under different pH conditions, ensuring the good solubility of the amphiphile.

Self-assembled hierarchical nanotubes with stimuli-responsiveness and tunable diameters in aqueous solution were fabricated by the selective attachment of anionic amphiphiles (SDS) to dendrimers (PPIC) with uniquely engineered zwitterionic peripheries.⁷⁹ The diameter of the tubes is responsive to the ionic strength of the solution. In addition, they can reversibly assemble/disassemble under different pH values. At the isoelectric point, there are no interactions between PPIC and SDS due to the zero net charge of PPIC. After reducing the pH to acidic conditions, the net charge of the zwitterionic dendrimers increased to positive values and consequently resulted in the attachment of SDS (Fig. 13). The change in the hydrophilicity and symmetry of the dendrimers transforms them into amphiphilic molecules containing a hydrophilic headgroup (dendrimers) and a hydrophobic tail. Therefore, the electrostatic interaction of the building blocks can be controlled towards the formation of well-ordered nanostructures. Cui et al. prepared pH-responsive Pickering oil-in-water emulsions in the presence of negatively charged silica nanoparticles and a trace amount of zwitterionic amphiphile dodecyldimethylcarboxylbetaine (C12B).⁹¹ The C12B exhibits a cationic property at pH < isoelectric point (pI, 4.9–5.5) while it is zwitterionic at pH values above this. The former can be adsorbed onto particle surfaces; the significant hydrophobization induces the formation of stable emulsions. While it can be demulsified completely at pH > 8.5. Such a phenomenon can be cycled by alternately adding acid and base.

Other types of responsiveness can also be achieved by introducing functional groups or additional organic molecules. Our group designed an asymmetric gemini zwitterionic amphiphile containing azobenzene and TFSI⁻.⁹² The host–guest interaction between β-CD and two kinds of guests and the electrostatic interaction between the zwitterionic headgroup and lithium salt promotes the formation of a supramolecular hydrogel. Both temperature and UV light will destroy the host–guest interaction and thus induce the gel–sol transition. Garcia-Rio et al. prepared supramolecular nanoparticles composed of CB7 and zwitterionic SBs with a negative surface potential.⁹³ The absorption of an additional amount of SB causes the rapid formation of an amorphous aggregate confirmed by the evolution over time of supramolecular nanoparticles and the surface potential. The addition of the competitive cation tetraethylammonium chloride will trigger a supramolecular nanoparticle-to-micelle phase transition. The phase transition from the cubic liquid crystalline phase to the hexagonal liquid crystalline phase can be achieved by changing the temperature for zwitterionic compound [C₁₂IPS][CH₃SO₃H].⁶¹

Zwitterionic amphiphile-based aqueous biphasic systems (ABS), including alkylimidazolium-, phosphonium-, and ammonium-based zwitterions have been widely reported.^60,94,95 Among these, ammonium-based zwitterions with different alkyl chain lengths (N₅₅₅C3S, N₆₆₆C3S, and N₆₆₅C3S) possess thermo-responsiveness (Fig. 14).⁹⁶ Both lower critical solution temperature (LCST)-type and utmost critical solution temperature (UCST)-type phase transitions can be obtained after mixing hydrophilic N₅₅₅C3S and relatively more hydrophobic N₆₆₆C3S at suitable molar ratios in water. The ratio between zwitterions and water molecules will influence their phase transition temperatures.⁶⁰ N₆₆₅C3S with relative high hydrophobicity exhibited reversible temperature-sensitive LCST-type phase transitions after the addition of pure water. While, for N₆₆₆C3S, an LCST-type phase transition was obtained after mixing them with an equimolar amount of trifluoromethanesulfonic acid (HTfO) in the presence of water. Coutinho et al. investigated N₁₁₁C3S, N₁₁₁C4S, N₂₂₂C3S, N₃₃₃C3S, N₅₅₅C3S.⁹⁷ They can form thermo-reversible ABS in the presence of salts (K₃PO₄, K₃C₆H₅O₇, K₂CO₃, K₂HPO₄ and KH₂PO₄). The hydrophobicity of the zwitterion decreases with a decrease in alkyl chain length, which induces interactions between the zwitterions and the water molecules to change from directional hydrogen bonding to non-directional interactions. The thermal behavior of ABS can be used in the separation of amino acids, such as aromatic (l-tryptophan) and aliphatic (glycine) amino acids.

Co-assembly with inorganic nanomaterials

It is well known that a new type of zwitterionic amphiphile can be constructed by mixing equimolar amounts of imidazolium-based zwitterion and inorganic or organic salts. However, most of the selected electrolytes are small in size. Therefore, only electrostatic attractions between zwitterionic headgroups and counterions are considered. Polyoxometalates (POMs) represent a class of nanoscale and well-defined inorganic transition-metal oxide clusters with multiple components and versatility. For traditional covalent modification, complex synthesis is required. While for co-assembly with a cationic amphiphile, the obtained assemblies are commonly insoluble in aqueous media.^98–101 Very recently, we found that organic–inorganic co-assembly using zwitterionic amphiphiles and POMs was a more versatile and promising strategy for fabricating hierarchical and multifunctional supramolecular hydrogels.¹⁰² As shown in Fig. 15, various well-defined aggregates, such as nanofibers, cross-weave, highly parallel-aligned and disordered wormlike micelles, as well as unilamellar vesicles, were fabricated after mixing C₁₆IPS and phosphotungstic acid (HPW) of different molar ratios in water. By balancing the rigidity and flexibility between two assemblies, crystalline and amorphous hydrogel networks that form through a kinetic or thermodynamic controlled gelation process are achieved. The distance between the cation and the anion of the zwitterionic amphiphile C₁₆IPS is about 0.71 nm. While the HPW is roughly spherical with a diameter of approximately 1.0 nm, which is slightly larger than the headgroup of C₁₆IPS. The delocalized negative charge of HPW induces an electrostatic repulsive interaction between the sulfonic anion and the HPW anion in the presence of the electrostatic attraction between the imidazolium cation and the HPW anion. According to a series of comparative experiments and ITC data, the relatively low affinity between the zwitterionic amphiphile and POM is the main driving force for the formation of supramolecular hydrogels. To further investigate the assembly mechanism, the proton on C-2 of the imidazolium ring was replaced by methyl (C₁₆bIPS) and co-assembled with silicotungstic acid (HSiW).¹⁰³ In comparison with C₁₆IPS, the steric effect and hydrogen bonding between the imidazolium cation and HSiW will significantly influence the rheological property of the hydrogel as well as the interactions among the wormlike micelles. Based on this technique, an injectable luminescent hydrogel with excellent temperature and acid/base gas stimuli responsiveness can be obtained through co-assembly with C₂₀IPS and Eu-containing POM (EuW₁₀).¹⁰⁴ In view of the low-level binding affinity between the building blocks, hydrogels with different morphologies, and mechanical and luminescent properties can be flexibly manipulated by adjusting their components. In addition, our group also fabricated transparent and injectable photochromic supramolecular hydrogels with micellar nanostructures by mixing C₁₆IPS and ammonium heptamolybdate (Mo₇).¹⁰⁵ In comparison with pure Mo₇ aqueous solution, the photochromic ability of the hydrogels was enhanced significantly and this material can achieve reversible information writing and erasure by exposure to UV light and air.

Quantum dots (QDs, semiconductor nanocrystals) act as another kind of versatile nanoscale material with an exceptionally narrow size distribution, precisely tunable size and morphology. QDs have attracted wide attention in optoelectronics, sensing, and biomaterials.^106–108 Hao et al. investigated the organic–inorganic co-assembly of the commercially available zwitterionic amphiphile (tetradecyldimethylamine oxide, C₁₄DMAO) and negatively charged carbon quantum dots (CQDs) in water.¹⁰⁹ Before interacting with the CQDs, the amphiphile single component self-assembles into micelles rather than exhibiting a direct binding mode. The reversible protonation or deprotonation of C₁₄DMAO under different pH conditions induces the assemblies to exhibit reversible morphological change, including vesicles and supramolecular polymers (Fig. 16). Based on this feature, rhodamine 6G (R6G) was used as a model drug, and the designed drug delivery system exhibited controllable release by adjusting pH values.

Recently, zwitterionic amphiphiles like SB and PC have been used to encapsulate QDs to reduce their nonspecific interaction with cells. The treated QDs display much smaller diameters, weak nonspecific adsorption with proteins, and strong resistance to salinity and a wide range of pH. Strong interactions between zwitterions and surrounding water molecules offer the modified QDs a high colloidal stability.¹¹⁰ Jiang et al. selected a zwitterionic amphiphile (CBSS) with nonfouling and functionalizable properties that contains a CB headgroup and bidentate thiol end group.¹¹¹ The introduction of CBSS promotes the stability of QDs with targeting capability. Meanwhile, the optical properties and small particle size of QDs are well preserved. After surface modification, the QDs are stable over a wide range of pH values and exhibit low nonspecific adsorption according to surface binding assays and cellular internalization studies. The zwitterionic ligands on the QD surface can also be combined with other functional groups, which provides simple conjugations for highly specific targeting ligands while retaining the advantages of QDs and zwitterions. This QD-based surface chemistry can offer highly specific and sensitive imaging with a considerably low background level. A more detailed introduction into the properties and applications of zwitterionic amphiphile-modified QDs is given in section Antifouling biomaterials.

Application of zwitterionic amphiphiles

Motivated by the unique molecular structures of zwitterionic amphiphiles and their remarkable advantages in the construction of various well-defined aggregates, stimuli-responsive intelligent soft materials, without migration under a potential gradient, and antifouling surfaces with less irritation to biosystems, zwitterionic materials have attracted a wide range of attention in recent years. To highlight the merits of zwitterions over other amphiphiles, in this section we emphasize the roles and applications of zwitterionic amphiphiles in target ion conduction, preparation of noble metal nanomaterials and antifouling biomaterials.

Target ion conduction

The application of zwitterions in electrochemistry was initially inspired by the drawbacks of traditional ILs. High conduction of target ions (like protons, lithium ions, iodide ions) is necessary for corresponding electrochemical systems. The excellent ionic conductivities of ILs (over 10⁻² S cm⁻¹ at room temperature) usually originate from the component ions themselves, which are useless as target ions. Even if the target ions were added to the system, the migration of IL molecules would not be conducive to the electrochemical performance of the cell. Moreover, the increase in T_g and viscosity caused by additional salts can also considerably reduce the ionic conductivity.⁶³ Based on the low target ion transport number and terrible selectivity of traditional ILs, Ohno and co-workers first investigated and pioneered zwitterionic compounds.¹³ As excellent ion dissociators and solvents, zwitterions can effectively liquidize solid salts and strong acids. The overall neutral property of zwitterions endows them with the unique characteristic that the components cannot migrate along the potential gradient, in spite of their high ion density. Therefore, zwitterionic-type molecules can act as an excellent ion conductive matrix to transmit target ions effectively by an applied voltage.^8,14,112

A series of zwitterionic-type molten salts and homologous polymers have been synthesized. After mixing them with an equimolar amount of lithium salts, the complexes display a lower T_g than the original lithium salts due to a decrease in lattice energy. Meanwhile, the obtained conductivity is higher than in other lithium salt mixtures. For this conductive system, only added ions can migrate along the potential gradient. Therefore, zwitterions can act as an excellent matrix in electrochemical applications. Until now, zwitterions with different cation-sites, spacer-chains, and anion-sites have been discussed to investigate the effects of structure on the thermal and ionic conductivity properties of the zwitterions and their mixtures with salts.⁷⁷ It has been confirmed that the SO₃^– groups can facilitate the association or dissociation of lithium ions due to their good exchange sites. Therefore, the groups are excellent exchange sites and play a role in Li⁺ transfer from one site to another. Lin et al. investigated the thermotropic LC structures and ionic conductivities of sulfonate-functionalized imidazolium zwitterionic amphiphiles (C_n-Im-C₃SO₃/C_nIPS and C_n(2-OH)-Im-C₃SO₃).¹¹³ The additional hydrogen bonding caused by hydroxyl makes the melting temperature of [C_n(2-OH)-Im-C₃SO₃] higher than that of [C_n-Im-C₃SO₃]. Due to the presence of hydrogen bonding between the hydrophilic SO₃^– group and the hydroxyl groups on the glass substrate, as well as the high local symmetry around the S atom, the amphiphiles display a highly ordered perpendicular alignment on the glass surface without any approach towards alignment. The addition of lithium salt (LiClO₄) induces the formation of room-temperature LC structures and thus enhances the mesophase ranges. Effective interactions between the oxygen atoms of the sulfonate group and Li⁺ ions as well as well-ordered pathways endow the system with enhanced ionic conductivities.

There are two main kinds of ion transport mechanisms: that is, vehicle and Grotthuss mechanisms.^114–116 The vehicle mechanism with its lower conductivity displays diffusion-controlled transport, while the Grotthuss mechanism with its higher conductivity is controlled by ion hopping. In the zwitterion/LiTFSI system, ion conduction through the diffusion-controlled transport (vehicle) mechanism is generally accepted, and the conduction value is usually about 10⁻⁵–10⁻⁷ S cm⁻¹. People have advocated that ion conduction via the hopping (Grotthuss) mechanism can effectively improve ionic conductivity. For proton-conducting materials, when the transportation of ions occurs on the surface of the cylinder or layer unit, ion hopping through the hydrogen bond networks of the headgroups was the main form.¹¹⁷ While diffusion-controlled transport commonly occurs for ion conduction through the continuous water medium within the cylinder or layer unit. Fixed domains, such as highly viscous media, gels, and solids that allow flexible and successive hydrogen bonds, were usually required for the hopping mechanism. In particular, proton hopping occurs in the hydrogen bonding networks of water molecules. Therefore, it is essential to design a successive hydrogen bonding network with site-specific proton donors and acceptors while allowing rotation for proton hopping.

As a kind of nano-ordered molecular structures, LCs with well-defined periodical structures and anisotropic properties like lamellar, hexagonal, or bicontinuous cubic structures are promising candidates for functional soft materials. A suitable combination of liquid-crystalline structures and a zwitterion/HTFSI compound is a promising technique to fabricate a proton-conduction material with selectivity and anisotropy. It is also expected that the assembled structure would suppress diffusion and generate a suitable field for proton conduction through the hopping mechanism. LC structure materials composed of zwitterionic amphiphiles can be used as ion-conductive channels where the target ion as the counterion of the zwitterion can be efficiently transported in desired directions. Therefore, zwitterionic LC-based materials are attractive candidates for target ion conduction, due to the well-organized channels for ion transportation in the LC structure.^118,119 Ohno et al. prepared phosphonium-type zwitterionic amphiphile PnC4S.¹¹⁷ A hexagonal columnar (Col_h) LC structure was obtained after mixing PnC4S with an equimolar amount of HTFSI in water. In addition, there are hydrophilic nanochannels in the inner part of the columns and the macroscopic orientation of the liquid-crystal domains can be controlled, which exhibits enhanced and anisotropic ion-conduction behavior. The conductivity in the monodomain columnar phases was 8 × 10⁻² S cm⁻¹, almost independent of temperature. The obtained experimental results strongly demonstrated that the conduction proton follows the hopping mechanism.

Among the LC assemblies, thermotropic Cub_bi LCs with two incompatible domains (three-dimensionally (3D) interconnected nanochannels and a surrounding 3D continuous sheath domain) are more interesting.^120–122 They form 3D branched, periodic ionic channel networks that function as alignment-free, ion-conducting pathways. This is also a promising approach for constructing an infinite periodic minimal surface.⁸¹ The amount of additional acid and water will influence LC behavior and proton conductivity. After that, Ohno et al. prepared a series of pyridinium-based zwitterions PyZI-n with different alkyl chains (Fig. 17).¹²³ An amide bond was used to connect the incompatible long alkyl chain part and the pyridinium zwitterionic part and hydrogen bonding networks were thus formed. Cub_bi thermotropic LC structures with a hydrophilic gyroid surface (one kind of periodic minimal surface) have been fabricated through co-assembly with amphiphilic zwitterions and HTFSI in the presence of a small amount of water. The utilization of a gyroid-structured matrix will be an important strategy for achieving proton-conduction pathways with macroscopic continuity.⁷⁸ To explore the importance of LC structures for ionic conductivity, the isotropic liquid formed by 3-sulphopropyl pyridinium betaine and HTFSI was also investigated. For LC mixtures, the assembled structure significantly influences the ion conduction behavior, while the ionic conductivity of the isotropic liquid increases only with temperature. Based on the pathways of 3D continuous ionophilic layers, PyZI-12/HTFSI and PyZI-14/HTFSI transport ions through the vehicular diffusion mechanism. After increasing the component of water, a lyotropic LC structure was formed which significantly increased the ionic conductivity and decreased the activation energy. Due to the proton transport via hydrogen-bonded water networks on the gyroid surface, the conduction mechanism changed from a vehicular to a hopping mechanism.

However, the proton transportation of an LC structure without water usually exhibits lower ionic conductivities than water-containing materials. The presence of enough water to form successive hydrogen-bonded networks is necessary for inducing the hopping conduction of protons.¹²³ Kato et al. successfully fabricated an anhydrous 3D interconnected proton transportation pathway by mixing wedge-shaped SB and benzenesulfonic acid in different ratios (Fig. 18).¹²⁴ A single zwitterion exhibits only a columnar hexagonal phase, while the Cub_bi phase over a wide temperature range can be obtained after mixing it with benzenesulfonic acid in different ratios. The zwitterionic moieties are interlocked in the form of intermolecular ionic pairs in the column center and the alkyl tail chains are interdigitated. In addition, the mixtures do not show hygroscopic behavior, and can efficiently transport protons at over 100 °C without water (10⁻⁴ S cm⁻¹ for Cub_bi phase at 130 °C). The structure, volume, and acidity of the acid molecules play important roles in the formation of the Cub_bi phase. Two types of wedge-shaped imidazolium zwitterions based on dicyanoethenolate or sulfonate were also designed. Both display Col_h LC structures and low ionic conductivities. The addition of LiTFSI and propylene carbonate significantly increases the ionic conductivity. The incorporation of the polar additive propylene carbonate improves the mobility of Li⁺. The carbonyl group of propylene carbonate can coordinate with Li⁺.^125,126 Moreover, Cub_bi LC phases are formed by tuning the components of the zwitterion, LiTFSI and propylene carbonate. The dissociation of LiTFSI by zwitterions, as well as the ion–dipole interaction between Li⁺ and propylene carbonate are essential for the stabilization of LC structures and the enhancement in ionic conductivities.

The rich lyotropic LC phases (H₁, L_α, and V₁) formed by the C₁₂IPS-LiTFSI complex are beneficial for us to understand the lithium-ion conduction mechanism.⁶⁶ The H₁ and L_α structures can provide low-dimensional hydrophilic channels for ion-conductive pathways, while these channels are not continuous on a macroscopic scale. However, a macroscopically continuous lithium-ion conductive pathway can be provided by the V₁ phase even without any orientation control, which fundamentally transforms the conduction mechanism from diffusion to hopping. Our group also fabricated polymeric hexagonal and lamellar LC structures by co-assembly of a zwitterionic amphiphile, which were composed of electrostatically combined polymerizable 3-(1-vinyl-3-imidazolio)-propanesulfonate (VIPS) and 4-dodecyl benzenesulfonic acid (DBSA) (Fig. 19).¹²⁷ Different LC phases can be obtained by adjusting the component concentrations and temperature. Importantly, the LC phases can provide proton pathways which are retained after photo polymerization to obtain proton-conductive films, which generate relatively high ionic conductivity.

Preparation and modification of metal nanomaterials

Amphiphiles have been widely used for the fabrication of morphologically controllable and colloidal metal nanomaterials. Based on various well-known nanoscale assemblies like micelles, vesicles, fibers, and tubes formed by amphiphiles, the introduction of these well-defined aggregates provides feasible soft templates to manipulate metal nanostructures. However, the weak interactions between aggregates and precursors (such as AuCl₄^– anions) were not conducive for morphological replication from soft templates to metal nanomaterials.¹²⁸ It is an effective strategy to design amphiphiles with AuCl₄^– counterions. For an ionic amphiphile, the traditional ionic-exchange method was almost impossible.

Our group selected imidazolium-based zwitterionic amphiphile 3-((11-hydroxyundecyl)imidazolyl)propyl sulfonate (HIPS) (Fig. 20).¹²⁹ AuCl₄^–, as a soft Lewis base, possesses a high affinity with the soft imidazolium cation according to the hard–soft, acid–base theory. The strong interactions between headgroups and precursor anions promote the generation of zwitterionic amphiphiles with AuCl₄^– counterions, and multilamellar vesicles were obtained in aqueous solution. The participation of AuCl₄^– ions in vesicle assemblies is beneficial for morphological replication from soft templates to gold nanostructures. Zwitterionic amphiphiles with reductive counterions can be utilized as reductants to minimize interference on the molecular aggregates. Gold nanoplates with well-defined hexagonal, triangular, and truncated triangular shapes were spontaneously formed at the vesicle bilayers, while gold nanospheres were generated through a stepwise reduction approach. In comparison with C₁₂IPS, no vesicular aggregate was observed. This indicated that the hydrogen bonding networks between the terminal hydroxyl groups of HIPS play an important role in the formation of bilayer vesicles. Based on the above mechanism, wormlike micelles of hundreds of nanometers in length and 5 nm in diameter were also constructed by the assembly of zwitterionic amphiphile 3-(N,N-dimethylpalmitylammonio)propanesulfonate (PAPS) with AuCl₄^– counterions in aqueous solution.¹³⁰ While single PAPS molecules can only form spherical micelles or liquid crystals in aqueous solution. The constructed wormlike micelles act as soft templates for the fabrication of colloidal gold nanowires. AuAg alloy nanowire networks with an adjustable constituent ratio were also obtained using mixed wormlike micelles. This strategy was further implemented to fabricate wormlike micelles with PtCl₆^2– and PdCl₄^2– counterions, and alloyed noble metal like Pt–Au, Pd–Au, and Pt–Pd nanochain networks can also be constructed.³³

To develop a new recovery system for noble metals, it is a promising strategy to develop a new type of amphiphile that can adsorb on the surface of the metal to form highly ordered assembled structures and can even exhibit stimuli responsiveness. It is already known that most betaine amphiphiles possess an ability to respond to pH. Morita-Imura et al. selected the zwitterionic amphiphile 3-[(2-carboxy-ethyl)-hexadecyl-amino]-propionic acid (C16CA), which contains an amine and two carboxyl groups.¹³¹ Reversible structural evolution can be achieved by adjusting the pH of the self-assemblies formed by C16CA (Fig. 21). In phase I (pH > 5), a transparent solution with low viscosity (spherical micelles) was obtained; in phase II (pH between 2 and 5), a phase-separated precipitate (lamellae structure) was observed, and in phase III (pH < 2), a highly viscous solution (wormlike micelles) was formed. The pH-induced transition of the assemblies is beneficial to the recovery of gold nanoparticles (GNPs) through pH-regulated reversible precipitation–redispersion. At pH ≈ 4, the GNPs were dispersed in the lamellar precipitate with a sufficient interparticle distance of C16CA assemblies, which prevents the coagulation of Au NPs. After the pH was adjusted to alkaline, recovery of GNPs was achieved by dissolution of precipitation without additional stirring, heating, or sonication. More importantly, the shape and the diameter of GNPs did not change significantly during the dispersion–redispersion process. After that, C16CA-stabilized silver nanoparticles (AgNPs) were also prepared by the same mechanism based on the strong adsorption between carboxyl groups and AgNPs.¹³² The protonation of the amine groups neutralized the anionic carboxylate groups, which induced the formation of lamellar structures at pH ≈ 4. In addition, C16CA assemblies can not only dissolve in water (at pH > 6) but also in organic solvents such as chloroform and tetrahydrofuran. Therefore, redispersion of the AgNPs can be achieved in different solvents without any additional treatment.

The metal nanoparticles can also be effectively modified by amphiphiles to overcome some inherent defects, such as instability. Empirical guidelines (“Whitesides’ rules”) for good antifouling properties can be summarized as:¹³³ (1) neutrally charged, (2) polar functional groups, that is hydrophilic, (3) hydrogen bonding acceptors, and (4) without hydrogen bonding donors. The utilization of nonionic poly(ethylene glycol) (PEG) is the common method to obtain stable and antifouling nanomaterials. However, the absence of reactive sites in this compound hinders systematic functionalization of PEG-modified metal nanopatricles.¹³⁴ Zwitterionic amphiphiles are other more attractive candidates, and have been extensively investigated due to their stability, biocompatibility, and excellent antifouling features even under complex biological conditions. SBs and CBs are the most commonly used due to their commercial availability and simple synthesis. PC-based materials are FDA (Food and Drug Administration) approved and can be used to enhance the performance of medical devices.^135,136 The high stability and non-fouling properties of zwitterion-modified systems derive from their strong hydration effect due to the strong electrostatic binding between zwitterions and water (rather than hydrogen bonding between PEG and water).¹³⁷ Whitesides’¹³⁸ and Jiang's groups¹³⁹ have demonstrated that the strong resistance of zwitterionic self-assembled monolayers (SAMs) to protein adsorption could be attributed to their strong hydration ability. Similar to zwitterionic phosphorylcholine-stabilized nanoparticles, the zero net charge and antiparallel orientation for dipole minimization were important for their resistance to non-specific interactions on a flat surface.

Thioalkylated zwitterionic PC-modified GNPs have been investigated by Ji's group.¹⁴⁰ The strong Au–S linkage and water solubility of PC endow them with better stability than neutral oligo(ethylene glycol) (OEG). After zwitterionic PC protection, these materials displayed increased stability under various conditions, such as plasma. Furthermore, these materials are amenable to functionalization via Murray's ligand exchange route. They also demonstrated by gel electrophoresis experiments that PC-modified GNPs possess complete non-specific resistant characteristics. The relatively large GNPs in the size ranges between 16 and 50 nm can also be stabilized through thioalkylated zwitterions. By regulating the protonation of the phosphate groups, reversible dispersion agglomeration states can be achieved with different pH values. According to a bead-based platform, Zuilhof's group systematically compared the antifouling performance of five different zwitterion constructed polymer brushes: two sulfobetaines (SBMAA-2 and SBMAA-3 with different methylene groups between opposite charges), a carboxybetaine (CBMAA-2), a phosphocholine (PCMA-2), and a hydroxyl acrylamide (HPMAA).¹⁴¹ Both the nature of the anionic groups and the distance between opposite charges have significant effects on the antifouling performance. The antifouling ability follows HPMAA ≥ CBMAA-2 ≈ PCMA-2 > SBMAA-2 > SBMAA-3 ≫ nonmodified beads.

The utilization of this kind of ligand provides GNPs with colloidal stability, non-fouling characteristics and functionalization capabilities. Through appropriate design, particles with “plug and play” streptavidin connections for ready conjugation were fabricated. Importantly, these ligand-modified GNPs with resistance to freeze-drying and different ionic strengths can be stored as powders for the long-term while still maintaining functionality. The stability and activity of these materials can be well maintained after being freeze-dried, which is beneficial for the functionalization of GNPs with other biomacromolecules or materials. In addition, based on the specific application of avidin, any biotin-functionalized macromolecules (commercially available from the large catalog) can be used to endow AuNPs with desirable biological properties. Amino-acid-derived zwitterions, such as poly(ornithine methacrylamide) (pOrnAA), can also be used to encapsulate GNPs, which gives the nanomaterials ultrastability.¹⁴² Each single GNP is trapped by a cross-linked superhydrophilic zwitterionic hydrogel thin-layer, which resists the aggregation of particles under various conditions, such as PBS buffer, saturated salt solution, lyophilization, extended range of pHs, and human serum. In a biological environment, the zwitterionic hydrogel layer prevents protein adsorption, and keeps the GNPs stable in human blood serum. Furthermore, the pOrnAA endows the nanomaterials with on-demand conjugation sites for biomolecular functionalization. The incorporation of gel did not change the morphology of the GNPs. In addition, the zwitterionic nature and superhydrophilic property of the ligand will ensure quick water penetration when they are redissolved, which will improve the dispersion of GNPs in aqueous solution. The zwitterionic particle surface restrained their interaction with cell membranes through a “stealth” property. Furthermore, functional molecules such as folic acid (FA) can be conjugated onto the GNPs by pOrnAA gel. The obtained FA-pOrn-GNPs exhibited selective internalization in folate receptor overexpressed cancer cells, rather than normal cells, indicating that such functionalization improves the targeting specificity of cancer cell without affecting the particles’ “stealth” property.

Antifouling biomaterials

Zwitterionic amphiphiles with excellent stability, biocompatibility, functionalization, and nonfouling properties are attractive candidates for biomaterials. According to numerous experimental results, zwitterionic biomaterials cause less irritation to the skin and nonspecific resistance to protein in blood serum. In addition, they can effectively stabilize enzymes in urea without affecting their bioactivity, prevent the formation of capsules in vivo, and cause no immune response in blood circulation.^18,139,140 Therefore, a versatile nanoplatform was provided for the application of personal care, household cleaning, and drug-delivery systems in pharmaceutical formulations, and sensitive diagnostic assays. CB and SB have been extensively investigated in biomaterials due to their noticeable antifouling properties (<5 ng cm⁻² adsorbed proteins¹⁴³). Based on numerous simulation studies, Jiang et al. demonstrated the design principles of protein-resistant zwitterions beyond conventional SB and CB (Fig. 22).^18,144 Similar to PEG-based materials, the resistance to the nonspecific protein of zwitterions is attributable to their strong hydration via hydrogen bonding. The zwitterionic materials can serve as excellent implanted materials or therapeutic protein protectants without hampering inherent biological functions.

A series of zwitterions with SB termini and a short OEG spacer as the ligand of nanoparticles have been investigated by Rotello's group (Fig. 23).¹³⁷ The surface hydrophobicity of nanoparticles can be systematically regulated by changing the degree of quaternization of the headgroup. The constructed nanoparticles do not adsorb proteins at moderate serum protein concentrations and do not form a hard corona under physiological serum conditions. This strategy exhibited the potential ability to directly control the interaction between nanomaterials and biosystems while it cannot be affected by protein binding. A series of new ligands composed of short OEG chains and a zwitterionic CB headgroup were also demonstrated. Wei et al. designed two CB and SB dextran (DEX)-based hydrogels that compared their individual properties.¹⁴⁵ Their results demonstrated that the higher hydrophilicity of SB-DEX hydrogels endows them with much higher equilibrium swelling ratios and larger interior pores than CB-DEX hydrogels. The higher water content of SB-DEX makes their rheological storage modulus lower than that of CB-DEX. Additionally, both CB-DEX and SB-DEX had remarkable biocompatibilities. Under acidic conditions (pH 5.0), the SB-DEX and CB-DEX hydrogels can release doxorubicin (DOX) in a sustained manner, which demonstrated their promising application in a drug-delivery system. In comparison to natural dextran, SB-DEX exhibits better resistance to fibrinogen. The CB-DEX has better antiprotein ability than unmodified dextran.¹⁴⁶ In addition, ionic solvation of zwitterions promotes the formation of a hydration layer that prevents the hydrophobic proteins reaching the surface of the hydrogels. Therefore, the SB-DEX exhibits a better protein antifouling property than that of natural dextran. In an acidic environment, the protonation of the –NH₂ group and the increased solubility of DOX are favorable for DOX release. Based on the excellent antifouling performance in human blood caused by the static-induced hydration layer, zwitterionic polymer brushes have exhibited promising applications in stealth coatings.³⁶ For example, zwitterionic polysaccharides can be used to activate CD4⁺ T cells and thus prevent abscess formation. Zwitterionic SB starch-based hydrogels have been fabricated for cell encapsulation and high resistance to nonspecific protein, and cell adhesion has been obtained. Although there are differences in negatively charged headgroups (COO⁻ for CB and SO₃^– for SB), both CB- and SB-modified polysaccharides exhibit excellent resistance to protein adsorption. The differences in anionic groups may induce different hydration properties, as depicted in the work of Jiang's group.^18–20

Self-assembled monolayers (SAMs) formed by zwitterionic PC can also exhibit high resistance to protein adsorption.¹³⁹ According to molecular simulation studies, the headgroups of PC have similar packing densities to membrane lipids and tend to have an antiparallel orientation for dipole minimization. The strong dipole induces the zwitterions to display appropriate packing to minimize their net dipole. Although zwitterions possess a strong hydration layer via electrostatic interactions and have high resistance to protein adsorption, the minimized dipole and balanced charge are the two key factors for their nonfouling properties. Aicart et al. studied the assembly structure and transfection efficiency of lipoplexes fabricated by pEGFP-C3 plasmid DNA (pDNA), cationic gemini amphiphile (C16CnC16), and zwitterionic helper lipid 1,2-dioleoyl-sn-glycero-3-phosphatidylethanolamine (DOPE), which possess fusogenic properties and can decrease the cytotoxicity of a sample.¹⁴⁷ The presence of lipid mixtures made plasmid DNA compact with a large number of Na⁺ counterions. Based on the ability of zwitterionic amphiphiles to form varying assemblies at different pH values, a pH-sensitive zwitterionic bola amphiphile, PEG di(propionyl cysteine), containing the polar headgroup l-cysteine and the spacer PEG was designed.¹⁴⁸

There are several criteria for making nanomaterials (such as QDs and metal nanoparticles) that are water-soluble, and biocompatible in the biological field:¹⁴⁹ (1) stability over a large range of pH values and at relatively high salt concentrations; (2) smallness in size, enabling entry into confined cellular systems; (3) antifouling properties; and (4) easy functionalization. It has been demonstrated that zwitterionic amphiphile modified nanoparticles can overcome some inherent defects of raw materials and endow them with excellent stability, biocompatibility, and ligand exchange ability. The zwitterionic materials can also be further functionalized with highly specific targeting ligands while effectively maintaining their nonfouling properties. Kim et al. fabricated QDs with positive ((+)QDs), negative ((−)QDs), or zwitterionic ((±)QDs) surfaces.¹¹⁰ The hydrodynamic (HD) size of the (±)QDs remains obviously smaller than in the case for PEG decoration due to their resistance to non-specific binding. (−)QDs tend to become unstable and aggregate at low pH due to the decrease in zeta potential (absolute value) caused by the protonation of the carboxylate groups. Similarly, (+)QDs will lose colloidal stability at high pH. While (±)QDs showed excellent stability over a broad pH range. Even at high salt concentrations (saturated NaCl solution), (±)QDs are also more stable than (−)QDs or (+)QDs. In addition, (±)QDs display ignorable cytotoxicity according to the measurement from a HeLa cell mitochondrial activity assay. The (±)QD surface displayed minimal non-specific adsorption onto cells, which is a critical prerequisite for specific cell labeling (Fig. 24). However, QDs must also need conjugation sites that allow post-modification for specific interactions with desired targets. In this system, 1 : 1 primary amine : zwitterions QDs and 1 : 1 carboxylate : zwitterion QDs exhibited enhanced stability. Thus, a mixed QD surface ligand system can allow simple bioconjugations while maintaining the benefits of zwitterions. Lequeux et al. fabricated water-soluble and biocompatible QDs by using bidentate sulfobetaine zwitterionic ligands (DHLA-SB).¹⁴⁹ These DHLA-SB QDs are small in size, and exhibit excellent stability over a large range of pH and salinity, as well as low nonspecific adsorption. These materials can be easily functionalized by mixing DHLA-SB with other functional ligands, such as streptavidin or biotin in specific ratios, allowing specific staining of membrane receptors and tracking them into living cells during recycling. Compared with Cys-QDs or PEG-capped QDs, the fabricated materials were more stable and could be dried, stored, and resuspended in water before utilization. Compared with cysteine, SB possesses the ability to specifically and stably conjugate a wide variety of biomolecules, which make QDs applicable in biological imaging. The inertness of SB to most bioconjugation reaction schemes significantly simplifies subsequent conjugation to biomolecules. Due to their excellent antibiofouling properties, zwitterionic coatings displayed an absence of nonspecific adhesion in live-cell imaging.

Conclusions and future opportunities

Zwitterionic amphiphiles are macroscopically neutral with high polarity and have high stability over a wide range of salinity and pH, a designable structure, as well as stimuli responsiveness. Such special structures and properties give them the ability to construct abundant assembly materials that can be used as interesting candidates to solve various application problems. So far, many zwitterionic amphiphiles have been designed and synthesized, and each of them has exhibited unique features and functions: (1) without electrostatic repulsion from headgroups, zwitterionic amphiphiles such as CB can spontaneously form wormlike micelles at relative low concentration through self-screening effects. While for ionic amphiphiles, high amphiphile concentrations or additional electrolytes are usually required to make headgroups with the same charge accumulate closely to form wormlike micelles. (2) In spite of the electroneutrality of zwitterionic amphiphiles, zwitterionic micelles can adsorb ions, specifically anions. In addition, the competition between adsorbed anions follows the Pearson's hard–soft classification and the Hofmeister series. After anion adsorption, the micelle surfaces generate a negative electrical charge, causing the cations to be incorporated in the micellar pseudophase. (3) Zwitterionic amphiphiles have synergistic effects with electrolyte and even nanoscale inorganic materials, which are different from those of nonionic compounds. Especially for imidazolium zwitterions, novel amphiphiles with more abundant aggregation behaviors can be obtained after mixing with equimolar amounts of salts according to soft–hard, acid–base theory. (4) CB-based amphiphiles intrinsically exhibit pH-dependent assembly properties and are less irritating to the skin and eyes than ionic amphiphiles. In addition, the designability and functionalization of zwitterionic amphiphiles allows for their easy multi-responsive functionality. (5) Since they have zero net charge, zwitterions hardly migrate along the potential gradient, and thus can be proposed as a medium for selective target ion transport. Based on their synergistic effect with electrolytes, the constructed LC structures, especially the Cub_bi phase, provide ion-transport channels and induce the conduction to change from a vehicular to a hopping mechanism. (6) Well-defined aggregates formed by zwitterionic amphiphiles with precursor counterions provide morphological replication from soft templates to metal nanostructures. The pH responsiveness of the amphiphiles makes it possible to recover noble metals with a high colloidal stability. (7) Zwitterionic amphiphile modified nanomaterials exhibit excellent stability, biocompatibility, ligand exchange ability, strong hydration, and minimal non-specific adsorption, which is appealing for their utilization in antifouling biomaterials.

If the structure–function relationships of zwitterionic amphiphiles can be fully understood, it will be feasible to create a construction principle that guides their potential applications in a way never achieved previously. So far, it is still our task to design and modify zwitterionic amphiphiles to obtain aggregates with more diversified structures and versatile functions. In addition, the design and synthesis of phosphonium compounds, amino acid derivatives and other zwitterionic amphiphiles are still rare, which are expected to possess more specific advantages. The summary of this review also provides several future research opportunities using zwitterionic amphiphile-based materials. Abundant inorganic nanomaterials provide a promising selection to co-assemble with zwitterionic amphiphiles. Their application can be expanded to catalysis, optical materials and so on. New electrolytes with 3D continuous ion-transport channels and high target ion conductivity under different conditions are expected to be fabricated that can be applied in energy devices. The ability to resist nonspecific protein adsorption, while easily modified with other desirable functional materials, makes zwitterionic materials excellent platforms for drug-delivery systems in pharmaceutical formulations, personal care, cosmetics, and household cleaning. We hope that more attention will be attracted and excellent ion-transition materials, intelligent soft materials and biomaterials will be developed after the comprehensive examination of structural properties and outstanding applications of zwitterionic amphiphiles in this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors are grateful to the National Natural Science Foundation of China (21573132, 21773141 and 21473196).

References