Ferrocene-based supramolecular structures and their applications in electrochemical responsive systems

Abstract

Electrochemical stimuli have attracted much attention in recent years as they are simple, clean and can be widely applied in biological systems and material science. As one type of common guest molecules, ferrocene and its derivatives have been well studied with different host molecules, mainly including cyclodextrins, cucurbiturils, pillararenes and calixarenes. This article generally summarizes the recent work on the host–guest interactions between ferrocene derivatives and their host molecules, as well as various supramolecular systems based on these interactions. In addition, the development and outlook of electrochemical responsive systems are also discussed.

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Liao Peng

Ms Liao Peng received her BSc degree from the Department of Chemistry, Tsinghua University in 2013. She is currently a graduate student under the supervision of Prof. Jinying Yuan at the same department. Her current scientific interests lie in the design and development of electrochemical stimuli-responsive systems based on polymers and supramolecules, as well as their related applications.

Anchao Feng

Mr Anchao Feng obtained his BSc degree from the Department of Polymer Science and Engineering, University of Science and Technology of China (USTC) in 2011. Currently, he is a PhD student under the supervision of Prof. Jinying Yuan at the Department of Chemistry, Tsinghua University. His main research interest is focused on stimuli-responsive polymers and supramolecular self-assembly.

Meng Huo

Mr Meng Huo received his BSc from the College of Chemistry, Sichuan University in 2013. He is now studying for his PhD degree under the supervision of Prof. Yen Wei and Prof. Jinying Yuan at the Department of Chemistry, Tsinghua University. His research interests are focused on developing new stimuli for biomedical applications and exploring biomimetic applications of stimuli-responsive polymers and supramolecular systems.

Jinying Yuan

Dr Jinying Yuan received her BSc from the Department of Applied Chemistry, University of Science and Technology of China (USTC) in 1987 and received her PhD from the Department of Polymer Science and Engineering, USTC in 2000. After two years of postdoctoral research at the College of Chemistry and Molecular Engineering, Peking University, she joined the Department of Chemistry, Tsinghua University in 2002, where she became a full-time Professor in 2011. Her research interests are focused on the methodology of polymer synthesis and functional polymer materials, especially on controlled polymerization and stimuli-responsive polymers.

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1. Introduction

Interest in stimuli-responsive systems, which can undergo reversible physical or chemical changes as a response to external stimuli, has grown tremendously over the past several years. The stimuli range from light,^1–6 electrochemistry,^7–25 CO₂^26–28 and redox^11,29–37 to pH,^38–43 temperature^44–48 and so on. These stimuli-responsive systems can be widely applied as biological materials and nano machines,^{9,10,20,21,32,33,49–54} thus drawing more and more attention.

As one type of novel stimuli, electrochemical stimuli can drive the structural changes of the systems through inducing electron transfer reactions.^55,56 Electrochemical stimuli are considered significantly attractive because their mode and magnitude can be readily regulated using a potentiostat. Also, the electron transfer reaction is well understood⁵¹ and the change of potential plays a fundamental role in membrane activities of living organisms, such as membrane fusion and disassembly. Most importantly, electrochemical stimuli are clean and can be realized without adding any extra redox reagents or solutions, which is of significance for their application in biological and material fields, because the accumulation of added substances may affect the viability of cells or the mechanical properties of the materials.

To date, various electrochemical responsive systems have been developed, including systems based on conducting polymers,⁵⁶ polyelectrolytes^23,57,58 and small electroactive molecules, such as tetrathiafulvalene,⁷ metallocenes^8–21 and viologen.^14,15,22,59 In this review, we will discuss the most significant progress in supramolecular systems based on ferrocene (Fc) derivatives.

2. Supramolecular systems based on ferrocene derivative guests

For decades, supramolecular systems have been widely studied due to their dynamic and reversible properties as well as their resulting ability to mimic organisms and to respond to external stimuli. In supramolecular systems based on electroactive guests, the application of a certain magnitude of voltage or current can induce the redox reaction of the guest molecules, thus changing the host–guest interaction in the system. Therefore, we can control the structure of these supramolecular systems by electrochemical method.

Fc is widely investigated in electrochemical responsive supramolecular systems because Fc derivatives exhibit simple electrochemical behaviour, and their electroactivity makes it possible to use cyclic voltammetric (CV) techniques to characterize the host–guest interactions. Many types of Fc derivatives, such as ferrocene carboxylic acid (FcA) and ferrocenylmethanol (FcCH₂OH) are commercially available or can be readily synthesized. The variation of host molecules also contributes to the progress of the related fields, including cyclodextrins (CD), cucurbiturils (CB), calixarenes (CA) and pillararenes (PA). Different features and mechanisms of these host–guest interactions as well as their applications in constructing supramolecular systems will be discussed below.

2.1 Cyclodextrin (CD)

CD is a macrocyclic oligosugar composed of a certain number of glucoside units with a certain size of non-polar cavity. Many CDs are commercially available, and the hydroxyl groups offer them the opportunity to be easily modified. The most studied CDs are CDs with 6, 7 and 8 glucoside units, namely α-, β- and γ-CD, respectively. CDs can interact with many guests with suitable sizes, such as polyethylene glycol (PEG) chain,^60–62 azobenzene,⁶ adamantine⁶³ and pyrene⁶⁴ derivatives. Therefore, different supramolecular systems including vesicles, polyrotaxane,^60–62 micelles⁶³ and hydrogels^6,64 can be constructed based on them.⁶⁵ When interacting with Fc derivatives, CDs in different sizes form inclusion complexes with different structures (Fig. 1).^66–69 Particularly, β-CD has the strongest binding ability under a 1 : 1 molar ratio of β-CD and Fc, which is widely investigated.

Fig. 1 Structures of the inclusion complexes formed from Fc with different sizes of CDs (reproduced from ref. 69).

The basic principle and electrochemical properties of the host–guest interactions between β-CD and Fc were first investigated by Evans et al. in 1985.⁷⁰ Characterization by circular dichroism and ultraviolet-visible absorption spectroscopy demonstrated that β-CD can form a stable inclusion complex with Fc derivatives in the reduction state, with a formation constant of 2200 M⁻¹ and a configuration where the Cp–Fe–Cp axis is parallel to the axis of the β-CD cavity. Whereas, no binding of β-CD with oxidized Fc can be detected. Additionally, the mechanism of the oxidation of the β-CD/Fc complex was also investigated in this study. The CV curves revealed that the complex is oxidized in a CE (chemical-electrical) process where the complex first dissociates into Fc and β-CD (chemical process), followed by the oxidation of free Fc (electrical process). Hence, no direct oxidation of the complex can occur, which is distinct from other hosts that we will discuss later.

Different from Fc, cobaltocenium (Cob) derivatives in their most stable oxidation state (Cob⁺) do not interact with β-CD, while their neutral state achieved from one electron reduction is an excellent guest for β-CD.⁷¹ Therefore, the neutral state of a metallocene with appropriate size can be strongly bound by β-CD, while the charged state of similar size is not. This is the basis why we can electrochemically control the binding affinity between β-CD and Fc or other metallocene guests by electrochemical oxidation or reduction.

Due to the reversible properties of β-CD/Fc linkage, it has been applied in constructing various supramolecular systems with electrochemical responsiveness, as discussed in the following section.

2.1.1 Supramolecular vesicles. Inspired by the abovementioned principles, our group have exploited the β-CD/Fc as a linkage to construct an electrochemical responsive vesicle system. We modified polystyrene with β-CD (PS-β-CD) and polyethylene oxide with Fc (PEO-Fc), respectively. Based on the host–guest interaction between β-CD and Fc, the non-covalent block copolymer PS-β-CD/PEO-Fc formed, which can further assemble in an aqueous solution into supramolecular vesicles (Fig. 2a).⁸

Fig. 2 (a) Schematic illustration of the voltage-responsive controlled assembly and disassembly of PS-β-CD/PEO-Fc supramolecular vesicles (potential was reported vs. a saturated Ag/AgCl reference electrode); (b) controlled release of rhodamine B from the supramolecular vesicles upon various voltage stimuli and in comparison with the free release from the vesicles without stimuli (reproduced from ref. 8).

Therefore, the assembly and disassembly of the vesicles can be reversibly manipulated by voltage as an electrochemical method. Additionally, this system can act as an effective carrier in voltage controlled molecule release with a release rate regulated by the strength of the voltage: when the voltage increases from +1.0 to +4.0 V, the time for complete release of rhodamine B decreases from 450 to 32 min (Fig. 2b). This work proved that the electrochemical method can be applied in supramolecular assemblies as a clean type of stimuli and opened up a way for the β-CD/Fc linkage to be applied in constructing nanomaterials.

2.1.2 Supramolecular nanofibers. After the successful trial of PS-β-CD/PEO-Fc supramolecular vesicles as electrochemical nanocapsules, we focused our attention on utilizing the β-CD/Fc linkage in various systems to further study the features and functions from changing their topological structures. As an example of nanofibers, we synthesized β-CD-OEG-β-CD and Fc-OEG-Fc, in which the oligo(ethylene glycol) group (OEG) was added as a short hydrophilic group. On the basis of the host–guest interaction between β-CD and Fc, they can form the supramolecular polymer β-CD-OEG-β-CD-Fc-OEG-Fc and further assemble in water to form nanofibers, owing to the hydrophilic property of the outer surface of β-CD (Fig. 3).⁹ The nanofibers can reversibly heal and degrade upon applying an alternating voltage, thus has the potential application as a one-dimensional nanomaterial.

Fig. 3 Schematic illustration of the formation of the supramolecular polymer β-CD-OEG-β-CD-Fc-OEG-Fc by β-CD-OEG-β-CD and Fc-OEG-Fc and their fabrication into responsive supramolecular nanofibers with redox-switchable properties. (Potential was reported vs. a saturated Ag/AgCl reference electrode) (reproduced from ref. 69).

2.1.3 Supramolecular micelles. In order to create systems based on the β-CD/Fc linkage with practical and real-life applications as drug carriers, we attempted to develop systems of better biocompatibility, which are composed of a PEG homopolymer modified with β-CD (PEG-β-CD) and a poly(L-lactide) homopolymer modified with Fc (PLLA-Fc). Similarly, they can form the non-covalent copolymer PEG-β-CD-Fc-PLLA, and further self-assemble into supramolecular micelles, which were confirmed by dynamic light scattering and transmission electron microscopy (TEM) (Fig. 4a). The most significant characters of these micelles are that they have good biocompatibility and no obvious cytotoxicity, while voltage controlled drug release can also be realized based on this system (Fig. 4b).¹⁰

Fig. 4 (a) TEM characterization of PEG-β-CD-Fc-PLLA micelles and (b) the dependence on the amount of paclitaxel on time under no stimuli and +1.0 V stimuli. (Potential was reported vs. saturated calomel reference electrode) (reproduced from ref. 10).

Also, we can apply the β-CD/Fc connection as a novel way to get more morphologies of assembly. As an example, micelles with a new type of brush-like supramolecular copolymer topology were recently reported by our group. We synthesized PEG-block-poly(glycidyl methacrylate), decorated with amounts of β-CD pendants (GA-CD) and poly(caprolactone) containing Fc end-capping (L-Fc). Based on the host–guest interactions, they can likewise form a brush-like supramolecular copolymer. The copolymer can further self-assemble in an aqueous solution into micelles with voltage-triggered reversible disassemble and reassemble ability (Fig. 5).¹¹

Fig. 5 Schematic illustration of the formation of electrochemical redox responsive micelles from brush-like supramolecular block copolymers and their controlled assembly and disassembly. (Potential was reported vs. saturated Ag/AgCl reference electrode) (reproduced from ref. 11).

2.1.4 Supramolecular hydrogels. Supramolecular hydrogels are extensively studied due to their unique properties such as stimuli-responsiveness and self-healing ability based on their host–guest interactions. Therefore, supramolecular hydrogels with different structures based on the β-CD/Fc connection were also investigated by different research groups.^12,13,24,36

The first polymeric hydrogel based on the inclusion complex between β-CD and Fc with electrochemical activity and dual responsiveness was reported by Jiang et al.¹²β-CD and Fc were decorated onto quantum dots and block copolymer to obtain β-CD @ quantum dots (β-CD@QDs) and Fc-poly(N,N-dimethylacrylamide-block-N-isopropyl acrylamide) [Fc-P(DMA-b-NIPAM)], respectively. With β-CD@QDs as the core and Fc-P(DMA-b-NIPAM) as the shell, a hybrid supramolecular polymer Fc-hybrid inclusion complex (Fc-HIC) as well as hydrogel were formed, which are thermo reversible and electrochemically active at elevated temperatures (Fig. 6).

Fig. 6 Chemical structure of Fc-P(DMA-b-NIPAM) and schematic illustration of the formation of the supramolecular polymer Fc-HIC by Fc-P(DMA-b-NIPAM) and β-CD@QDs (reproduced from ref. 12).

Harada et al. described another type of hydrogel composed of two polyacrylic acid (PAA)-based polymers and further studied its self-healing ability as a soft material.¹³ They synthesized β-CD with functionalized PAA (PAA-6-β-CD) and Fc with functionalized PAA (PAA-Fc). Supramolecular hydrogel can form based on the host–guest interaction (Fig. 7a), and the sol–gel transition of the hydrogel can be induced by voltage stimuli as well as redox stimuli (Fig. 7b). Moreover, due to the dynamic binding ability of the β-CD/Fc connection, this hydrogel also has excellent self-healing and self-repairing ability, which can be regulated by redox stimuli. This work demonstrated that the electrochemical method not only can switch the microscale structure of supramolecular complexes based on β-CD and Fc, but also change their macroscale morphology. Therefore, in addition to the soft nature and universal application of hydrogel, more functions of these systems are expected, such as stimuli-responsive media for cell culture, vascular embolization materials and injectable drug carriers in biological field.

Fig. 7 (a) Schematic illustration of sol–gel transition and (b) sol–gel transition experiment using electrochemical reactions of PAA-based hydrogel. (Potential was reported vs. a saturated Ag/AgCl reference electrode) (reproduced from ref. 13).

Apart from the above supramolecular systems constructed on the basis of the host–guest interaction, the supramolecular structure containing only host molecules can be applied to grasp and reversibly release Fc guests. To achieve this, we modified β-CD onto biocompatible comb-copolymer ethyl cellulose-graft-poly(e-caprolactone) (EC-g-PCL) to get EC-g-PCL-β-CD, which can form spherical micelles covered with β-CD receptors on the outside surface (Fig. 8).¹⁴ After forming the inclusion complex with FcA, the micelles can reversibly release and grasp FcA under electrochemical stimuli. The study indicated that this self-assembled structure can be a promising vehicle for the delivery and controlled release of various molecules as long as the micelles are modified with Fc moieties.

Fig. 8 Schematic illustration of the micelles formed from EC-g-PCL-β-CD and its reversible release of FcA (reproduced from ref. 14).

2.2 Cucurbituril (CB)

Cucurbit[n]urils, short as CBns, are synthesized macrocyclic host molecules composed of n glycoluril monomers with a certain size of enclosed cavities.⁷² As one of the common type of CBns, CB7 has an internal cavity volume of 279 ų, which is the closest to the 262 ų of β-CD.¹⁵ While β-CD does not interact with Fc or Cob in their charged state but do in their neutral state as stated before, CB7 can interact with Fc in its neutral state or with cationic groups but cannot bind Fc with anionic groups.

The formation of the complex between Fc and CB7, as well as its comparison with β-CD was first investigated by Kaifer et al.¹⁶ For neutral and cationic Fc derivatives with suitable size (such as FcCH₂OH and FcMe⁺ in Fig. 9), their binding constants with CB7 are in the range of 10⁹–10¹⁰ M⁻¹ and 10¹²–10¹⁵ M⁻¹, respectively,¹⁵ which are much greater than 10³ M⁻¹, the constants of the same neutral molecules with β-CD. This is because the regions around the carbonyl oxygens in CBs are significantly negative, resulting in strong affinity with positively charged guest molecules. Thus, the strong binding affinity of CB7 with Fc is the combined result of the steric suitability and hydrophobic interactions, as well as the ion–dipole interactions of the two rims and the inner cavity.⁷³ The highly negative regions around the two cavity entrances also leads to the rejection of anionic guests, which can account for the phenomenon that the negatively charged FcA⁻ was not bound by CB7 at all.

Fig. 9 Ferrocenyl guests with different charge states for binding investigations with CB7.

Applying the high stability of the CB7-Fc linkage, supramolecular velcro for reversible underwater adhesion was constructed by Kim et al.³⁴ They synthesized a “loop” silicon surface modified with CB7 hosts and a “hook” silicon surface with Fc guests, which can adhere in water to form supramolecular velcro (Fig. 10a). Considering the redox activity of Fc, the supramolecular velcro can be fastened or unfastened by adding ascorbic acid or NaClO to the solution (Fig. 10b and c). If this is the case, we can propose that an electrical field may offer a more efficient alternative to a chemical redox agent for switchable underwater adhesion. Further study revealed the different mechanism for the electron transfer reaction of the complex between β-CD and CB7, as shown in Fig. 11. As stated before, the β-CD-Fc complex is oxidized in a CE scheme where the dissociation occurs in advance of the oxidation (Fig. 11a). This process is typical for the oxidation of the inclusion complex at fast scan rate, because the complex cannot dissociate fast enough to produce enough free guests to be oxidized, thus the resulting CV curves are distorted.^70,74 However, the CV curves of the CB7-Fc⁺ complex remained fully reversible at scan rates as fast as 2 V s⁻¹.⁷³ This means that the electron transfer reaction for the oxidation of Fc uncharacteristically proceeded in its encapsulated form (Fig. 11b).

Fig. 10 (a) Schematic illustration of supramolecular velcro for underwater adhesion based on the surface modified with CB7 and Fc moiety, respectively. (b) The detachability of supramolecular velcro with an oxidizing reagent (NaClO, 10 mm) and (c) the reversibility of supramolecular velcro by chemical means (W/O = without any additional reagents) (reproduced from ref. 34).

Fig. 11 Different mechanisms of the electron transfer reaction of Fc in the presence of β-CD and CB7, respectively.

Additionally, the crystal study reveals significant difference in the structure of the complex between β-CD and CB7. For β-CD-Fc inclusion complex, the axes of Cp–Fe–Cp and β-CD cavity are parallel and it is the only configuration. However, two crystallographically independent structures are found to coexist in the CB7-Fc crystal, which differ on the ferrocene orientation inside the host cavity (Fig. 12).¹⁶ In both complexes, the Cp rings of Fc are nearly eclipsed and the Fe atom is located close to the geometric center of the CB7 molecule. The most important difference lies on the angles between the axis of Cp–Fe–Cp and CB7 cavity, which are 22° and 79°, respectively. This crystal study reveals that the Fc enjoys a certain degree of rotational freedom inside the cavity of the CB7 host. This freedom means that any modification or substituents covalently attached to Fc may influence the host guest interactions between the CB7 and Fc guests. For example, attachment to the Fc unit with a single oligoethyleneglycol chain or two substituents as ‘bi-armed’ guests somewhat decreases the binding constants, but the constants remain high and exceed 10⁷ M⁻¹ in all cases.^15,75

Fig. 12 X-Ray crystal structure of the complex between Fc and CB[7] (reproduced from ref. 16).

Another difference between CB7 and β-CD is that the high stability of the inclusion complex still remained after the oxidation between CB7 and Fc guests.^15,17 Even after the oxidation and accompanied decrease of the association constant, the CB7-FcMe⁺ is still extraordinarily stable. This means that the oxidation may not drive enough structural changes, which makes research of the electrochemical control of the complex between the CB7 and Fc guest difficult.

However, Kaifer et al. realized this control through special molecular design. The synthesized guests, Fc₂X₂⁺ and Fc₂H₂⁺, were composed of two terminal ferrocenylmethylammonium groups linked by different groups (Fig. 13a).¹⁸ Upon the addition of 1.0 equiv. of CB7, a stable inclusion complex can form with the CB7 on the terminal Fc residues. However, after one-electron oxidation of both ferrocenes, the host molecule moved to the central binding site on the linker and this change was reversible (Fig. 13b). Therefore, this complex can be seen as stable “pseudorotaxane,” where the position of the host molecules can be accurately and reversibly controlled by electrochemical methods.

Fig. 13 (a) Dinuclear Fc guests for binding to the CB7 host and (b) schematic illustration of the electrochemical control on the CB7 binding location in the pseudorotaxanes formed from CB7 and Fc₂X₂⁺ as well as Fc₂H₂⁺ (reproduced from ref. 18).

Apart from this work, in most studies of electrochemical control of the complex with CB7, the guests are 4,4′-bipyridine and its derivatives, such as viologen,^15,17,22 which we will not discuss here due to the limited space.

2.3 Calixarene (CA)

Calix[n]arenes are synthesized macrocyclic host molecules based on the hydroxyalkylation products of phenols and aldehydes. The hydrophobic internal cavities of the CAs vary by the number of repeated units, and the solubility of the molecules can also be readily adjusted by different modification.⁷⁶ Different from CD and CB, CA has a flexible structure and usually a poorly defined cavity, so modification and the environment can greatly affect the host–guest interactions. On one hand, modification should be cautious and variation in temperature, pH and solvent can significantly affect the study of CA. On the other hand, this means that the host–guest interactions are sensitive and can respond to more types of stimuli. Another difference is that the CA itself can be electro- and redox-active by attaching electroactive substituents or converting the phenolic moieties in the ring to quinone,^77–79 which endows more opportunities as well as challenges for the electrochemical control of Fc guest bound by CAs.

The first research of Fc derivatives with sulfonated C[6]A (SC[6]A, Fig. 14a and b) was conducted by Kaifer et al.²⁰ Electrochemical and ¹H NMR results showed that SC[6]A can bind not only to neutral FcCH₂OH, but also to positively charged FcMe⁺. However, SC[6]A forms a stronger complex with FcMe⁺ than FcCH₂OH, also stronger with the oxidized form Fc⁺ than the reduced form Fc. Through the calculation process the dependence of the apparent diffusion coefficient on CA concentration, the equilibrium binding constants between SC[6]A and FcMe⁺ as well as FcCH₂OH are 10 930 ± 960 dm³ M⁻¹ and 3650 ± 360 dm³ M⁻¹, respectively. The large constant for neutral FcCH₂OH indicates the primary significance of the non-electrostatic interactions, while the distinction between these two guests demonstrates that the electrostatic interactions between FcMe⁺ and the negative charge of the sulfonate ions also plays a secondary role in the binding process.

Fig. 14 (a), (b) Structures of SC[6]A and (c) its 1 : 2 inclusion complex formed with FcMe⁺ (reproduced from ref. 78).

Further study gives more details about the host–guest interactions between SC[6]A and Fc derivatives.⁷⁸ When SC[6]A forms a stable complex with FcMe⁺ in a neutral aqueous solution at room temperature, the SC[6]A is in its 1,2,3-alternate conformation and the molar ratio of FcMe⁺ to SC[6]A is 2 : 1 (Fig. 15c), which is different from the inclusion complex of β-CD and CB7. In this rather rigid conformation, one SC[6]A molecule presents two identical cavities, each with four negative charges, and they are only suitable for two FcMe⁺ guest molecules.

Fig. 15 Selective binding of the oxidized and reduced forms of Cob guest with SC[6]A and β-CD under the control of electrochemical stimuli (reproduced from ref. 81).

Moreover, the influences of solvent, pH and temperature on the conformation as well as the host–guest interactions were studied. The change to dimethyl sulfoxide as solvent can stabilize the inclusion complex because it can lock the SC[6]A in its 1,2,3-alternate conformation, while a decrease in pH from 7.0 to 2.6 or rise in temperature decreases the stability of the complex due to the loss of the 1,2,3-alternate conformation. In addition, other study emphasizes the significance of intermolecular hydrogen bonding in the lower rim of the calixarene in the host–guest interactions,⁸⁰ which is in accordance with the above results.

Considering the distinct binding affinity of Fc or Cob derivatives with CA and β-CD, selective binding of the Cob guest was achieved based on the different electrochemical condition.⁸¹ In the mixed solution of SC[6]A and β-CD, Cob⁺ forms a stable 2 : 1 complex with SC[6]A, while it does not interact with β-CD. However, after one-electron reduction of Cob⁺ to Cob, the binding affinity is reversed. That is, Cob forms a stable 1 : 1 inclusion complex with β-CD but does not bind with SC[6]A (Fig. 15). Though Cob was used here as a representative of a metallone guest because of the stability of the inclusion complex, FcA also has the potential to conduct a similar function. This work presents us a simple example as to how the electrochemical control can be manipulated to realize the selective binding with different hosts.

2.4 Pillararene (PA)

Pillar[n]arenes are macrocyclic host molecules composed of a certain number of hydroquinone units linked by methylene bridges at the para-positions.⁸² They have intrinsically symmetrical and rigid pillar structures and can be easily modified to adjust their solubility in different solvents, which brings advantages to their research. However, their disadvantages are that the suitable guests for P[6]As are limited,^83–85 and the binding constants are usually less than 10⁴ M⁻¹, except in the research of paraquat, a derivative of 4,4′-bipyridine, by Huang et al.^43,86

Moreover, Wang et al. first investigated the host guest interactions between P[6]A and Fc as well as Cob in 2013 (Fig. 16).¹⁹ When the molar ratio of per-butylated P[6]A (BP[6]A) and Fc is 1 : 1, Fc shows extremely low binding ability with BP[6]A (18 ± 0.5 M⁻¹) in a CDCl₃–CD₃CN solution. However, the oxidation status, Fc⁺, can strongly bind with the host molecule, due to the efficient charge transfer from the electron-rich cavity of BP[6]A to Fc. Considering the paramagnetic property of Fc⁺, Cob⁺ was used as the analogue of Fc⁺ to calculate the binding constants, which was about (3.7 ± 1.0) × 10⁴ M⁻¹ in a CDCl₃–DMSO-d₆ solution. The considerable change of three to four orders of magnitude in the binding ability means that the host–guest interactions between Fc and BP[6]A also has the potential to be applied in electrochemical controlled systems.

Fig. 16 Schematic illustration of the formation of a highly stable redox-responsive inclusion complex based on BP[6]A and Fc (reproduced from ref. 19).

To utilize the host–guest interactions of PA and Fc in stimuli responsive systems, water soluble P[6]A (WP[6]A) with carboxylate groups and Fc derivatives with hydrophobic chains were synthesized by the same group (Fig. 17).⁴² The 1 : 1 inclusion complex is stable with a binding constant of (1.27 ± 0.42) × 10⁵ M⁻¹, and it can further assemble into supramolecular vesicles in neutral and alkaline aqueous solutions. As the protonation of the carboxylate group in WP[6]A can be manipulated by a change of pH,⁸⁷ this supramolecular vesicle is also pH responsive and can be applied in pH controlled drug release. When adjusting the solution pH to 6.0, the hydrophilic COO⁻ changes to insoluble COOH, thus resulting in the disassembly of the vesicles and accompanied drug release. Although the interaction in this research reported to be pH-responsive, it has the potential to be electrochemical responsive through appropriate molecular design.

Fig. 17 Schematic illustration of the formation of supramolecular vesicles and their pH-responsive drug release (reproduced from ref. 42).

It is worth mentioning that although the host–guest interactions between CA as well as PA with Fc derivatives are clearly investigated, only a few of them have been introduced to polymer self-assembly or electrochemical supramolecular systems, which means that there is still a wide space for macromolecular scientists to explore.

3. Conclusion and outlook

This article systematically summarizes the recent work on the host–guest interactions between Fc derivatives and various host molecules, namely CD, CB, CA and PA, as well as their applications in constructing various supramolecular systems, especially for electrochemical responsive ones. Different types of host molecules have different interactions with Fc derivatives, which can be summarized in Table 1.

Table 1 The comparison of the host–guest interactions between Fc and Fc⁺ derivatives and different host molecules^{a 8–19,34,42,75–88}

Host molecules		Fc derivatives	Fc^+ derivatives
a Solvent is water when not mentioned. b The results are from SC[6]A. c Molar ratio of formed inclusion complex is 2 : 1 for FcMe^+ and SC[6]A. d Related data have not been reported.
β-CD		Bind neutral, cationic and anionic Fc; the binding constant is about 10^3–10^5 M^−1	Does not bind
CB7		Strongly bind neutral and cationic Fc, does not interact with anionic Fc; the binding constant is about 10^9–10^10 M^−1 for neutral Fc and 10^12–10^15 M^−1 for cationic Fc	Weakly binds the oxidized form Fc^+ than reduced Fc (approx. 1.5 orders of magnitude in the K value) but retain strong
C[6]A		Bind neutral and cationic Fc^c; the binding constant is about 10^5 M^−1 for neutral Fc and 10^3 M^−1 for cationic Fc	Strongly binds the oxidized form Fc^+ than reduced Fc
P[6]A	BP[6]A	Weakly bind neutral Fc; the binding constant is about 10 M^−1 for neutral Fc in CDCl3–CD3CN	Strongly binds Fc^+; the binding constant is about 10^4 M^−1 for Fc^+ in a CDCl3–DMSO-d6 solution
	WP[6]A	Strongly bind Fc; the binding constant is about 10^5 M^−1 for Fc	—^d

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Various host–guest interactions have different advantages that can be applied in various systems. For example, the considerable change of the binding ability between Fc derivatives and β-CD or WP[6]A before and after the oxidation of the Fc moiety endows them great opportunities to be widely utilized in water-soluble electrochemical supramolecular systems. Meanwhile, the system based on hydrophobic P[6]A can be exploited in other solvents, such as CHCl₃ or CH₃CN. The high stability of the inclusion complexes between CB7 and Fc derivatives makes them used less often in electro-controlled systems, except unique molecular design, but this interaction can be applied to stabilize the active oxidation state of Fc or to be used for strong adhesion, such as supramolecular velcro.³⁴ In addition, the difference in various host–guest interactions gives the possibility of selective binding of the guest in complex systems containing various host molecules,⁸¹ or selective binding of the host when containing various guest molecules (Fig. 18).⁸⁸

Fig. 18 (a) Two heterobimetallic guests examples and (b) electrochemical as well as the chemical equilibria involved in the voltammetric behaviour of the heterobimetallic complex (2) in the presence of the β-CD host (reproduced from ref. 88).

These supramolecular structures with electrochemical responsiveness have tremendous potential with applications in numerous fields. As for different supramolecular structures, electrochemical responsive micelles and vesicles can be used as drug delivery vehicles for voltage-controlled drug release,^8,10 while electrochemical responsive hydrogels are able to function as injectable drug carriers, cell culture media and self-healing materials.^6,11,13 More applications, such as energy storage, photovoltaic conversion and chemical sensors can also be expected from these systems. However, many problems are still unsolved for these systems. First, the graft of host molecules and Fc derivatives onto polymers largely affects the solubility of the polymers in an aqueous solution. Therefore, a water-soluble polymer backbone is more likely to be chosen, which limits the applications of the systems. Second, the modification and the grafting efficiency of host molecules and Fc onto polymers are not high enough to be applied in industry and needs to be improved. For example, the current modification methods require many steps, and the yield of the most common reaction of β-CD to mono-6-OTs-β-CD is less than 20%.⁸⁹

As for the applications of current electrochemical stimuli systems, most research has stayed in the primary stage, for example, drug release in vitro. More biological applications have not yet been implemented, perhaps because current experiments for electrochemical stimuli, including high concentration of electrolyte, relatively high potential and the insertion of electrode, may cause damage to cells or tissues. Meanwhile, an electrochemical workstation is necessary for the stimuli experiment, which is not mobile and fast enough to be applied practically. Therefore, further investigation and improvement is needed for practical and real-life applications. Apart from the supramolecular systems based on the interaction between different host molecules and relatively simple Fc derivatives, redox and electrochemical responsive systems based on poly(ferrocenylsilane) (PFS), which contains Fc units in the polymer chain, are also significantly attractive. PFS can be reversibly oxidized and reduced by chemical and electrochemical means, thus can be utilized to construct electroactive materials, such as PFS monolayers on gold,²⁵ composite-wall microcapsules,³⁵PFS polyelectrolyte hydrogels³⁷ and so on.^90–92

In conclusion, considering the advantages of Fc derivatives and different types of host molecules, as well as the superiority of the electrochemical method as a clean and novel type of stimulus, supramolecular systems based on Fc derivatives that can respond to electrochemical stimuli will greatly develop in the near future.

The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (21174076, 21374053) and Tsinghua University Initiative Scientific Research Program (2012z023998).

Notes and references

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