Advertisement

Remarkable Morphology Transformation from Fiber to Nanotube of a Histidine Organogel in Presence of a Binuclear Iron(III)–Sulfur Complex

  • Shibaji Basak
  • Natashya Falcone
  • Annaleizle Ferranco
  • Heinz-Bernhard KraatzEmail author
Article
  • 80 Downloads

Abstract

Ferrocene (Fc)–peptide conjugates are an interesting class of compounds that have been explored extensively due to the ability of Fc to act as a scaffold to support peptide secondary structural motifs. Fc–peptide conjugates have also displayed self-assembly and gelation behaviour forming an interesting class of new biomaterials. Here, a Fc–phenylalanine–histidine–OMe conjugate has been synthesized and tested for supramolecular gelation. Interestingly, this compound forms a supramolecular gel in the presence of the binuclear iron–sulfur (Fe–S) cluster and displays interesting properties including redox-responsiveness and morphological changes from fibers to spherical vesicles. The gelation in the presence of the Fe–S cluster has future potential to study prebiotic self-assembly, prebiotic cofactor relationships and biomimetic active sites.

Keywords

Organogel Ferrocene Peptides Iron–sulfur Supramolecular 

1 Introduction

Supramolecular gels have attracted a lot of attention over the last several years due to their variety of applications in different fields [1, 2]. They can be studied in materials science, catalysis, drug delivery, environmental studies, as biomimics, and in supramolecular chemistry. The formation of self-assembled gels by low-molecular weight gelators involves non-covalent interactions such as hydrogen bonding, π–π stacking, hydrophobic, and van der Waal interactions [3, 4]. These non-covalent interactions are responsible for forming self-assembled three dimensional nanofibrillar network structures. Hydrogen bonding is stated to be the most significant non-covalent interaction in supramolecular assembly [5, 6, 7]. Gels are also responsive to various external stimuli including heat, light, sonication, and pH [3, 8, 9, 10, 11].

Bio-organometallic ferrocene (Fc) amino acid and peptide conjugates have been explored extensively, largely to study the ability of Fc to act as a scaffold to support peptide secondary structural motifs [12, 13, 14]. More recently, it was discovered that Fc–peptides can also be triggered to form stimuli responsive gels [10, 11, 15, 16]. Many of the reported stable Fc–peptide gels are formed when conjugates have a single podant peptide chain, whereas for di-substituted systems, intramolecular H-bonding interactions between adjacent peptide chains dominate and interfere with effective intermolecular interactions [17]. This subtle interplay between intra- and intermolecular interactions make Fc–peptides an interesting group of conjugates to be studied as small structural and/or environmental changes can influence gelation properties dramatically. The presence of the Fc group also imparts redox responsiveness to Fc–peptide based gels [18]. Fc–peptide derivatives display self-assembly and gelation behaviour, forming a range of nanostructures, including nanofibers, nanotubes, and nanovesicles [10]. For example, Zhang et al. have reported ferrocenoyl phenylalanine as a novel hydrogelator and explored its responsiveness to a series of stimuli including redox reactions, guest–host interactions and pH changes [19]. Fang et al. reported four novel cholesterol-conjugated Fc gelators, which respond to shaking, sonication, heating and redox reactions [20]. In addition, our group has reported multiple Fc–peptide conjugates capable of metal binding and forming organogels [18, 19, 20, 21, 22, 23, 24, 25]. This includes a disubstituted Fc–tryptophan conjugate capable of gel formation and exhibits redox responsiveness [25].

Histidine is an amino acid that is commonly reported as a metal binding site in metalloproteins and nucleases due to the imidazole ring [26, 27]. Histidine’s stabilizing role in complex formation reactions of short oligopeptides has been well recognized and carefully reviewed. Fc–histidine conjugates have been synthesized and explored as active site mimics and for catalysis however, the addition of prebiotic cofactors have not been explored [26]. Histidine residues have the ability to form discrete metal complexes by coordinating divalent metal ions such as Zn, Cd, and Co [27]. To the best of our knowledge Fc–histidine conjugates have not been widely explored as gelators. Histidine gels without Fc have been reported as organogels [28], for example Roy et al. recently explored solely a histidine based peptide amphiphile capable of forming a stable hydrogel at physiological pH [29]. They also investigated metal salts inducing variation in self-assembling behaviour of these amphiphiles as a superior strategy to access diverse nanostructures and physical properties utilizing a single gelator design. Combining the metal binding properties of histidine residues and the redox responsiveness of the Fc into one gelator holds promise for the investigation of interesting morphological and physical properties of novel biomimetic gel materials.

As mentioned, the addition of prebiotic cofactors to Fc–peptide conjugate mimetic models have not been explored. Iron–sulfur (Fe–S) clusters are ubiquitous cofactors composed of iron and inorganic sulfur. They are required for the function of proteins involved in a wide range of activities including electron transport in respiratory chain complexes, regulatory sensing, photosynthesis and DNA repair. They are evolutionary ancient and are present in essentially all organisms including archaea, bacteria, plants, and animals [30]. The high level of evolutionary conservation is consistent with the possibility that Fe–S clusters contributed to the success of early forms of life. Despite their vulnerability to oxidation and degradation, Fe–S clusters are crucial for facilitating enzyme activities in all kingdoms of life because they can bind electron-rich enzymatic substrates, accept or donate single electrons, and stabilize specific protein conformations that are important to the activities of numerous proteins [30]. Constructing enzyme models with the addition of Fe–S clusters present in the system allows the potential to study these enzyme activities and active sites in prebiotic life. Hydrogenase enzymes are a class of enzymes that are reported to achieve electron transfer to or from the active site through a series of Fe–S clusters [31]. One example of a model mimic using a Fc–peptide conjugate and Fe–S cluster was reported by Metzler-Nolte where he constructed a more realistic, peptide-based hydrogenase model covalently attaching a diiron-hexacarbonyl core to two cysteine molecules and are connected via peptide bonds to a Fc moiety [31].

This study reports in fact the first Fc–histidine gel material of its kind. Changes in the rheological properties were observed as a function of metal ions added, and while we reported on metal sensitive gel materials before, the current paper is the first of its kind that reports metal sensitivity in Fc–histidine gel materials. We synthesize and report the properties of a Fc–Phe–His–OMe (G1) conjugate. This compound was found to form an organogel with self-assembling and thixotropic properties. In addition, this compound gels in the presence of the binuclear Fe–S cluster. This can be used to elucidate a biomimetic material that has potential for examining prebiotic self-assembly and as a prebiotic catalytic model through a gel matrix. Recreating the prebiotic world in the laboratory to investigate these very early reactions and the assemblies and aggregates en route to life and materials is not trivial and have required large assumptions [32]. It was found that the addition also allows for a remarkable morphological transformation. Interestingly, the addition of oxidizing and reducing agents also influences the gel’s morphology as there is a change from a typical nanofiber matrix to round vesicles that are interchangeable with the redox agents.

2 Experimental

HCl·H2N–LPhe–OMe, HCl·H2N–LHis–OMe, 6Cl–hydroxybenzotriazole (Cl–HOBt) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC·HCl) were purchased from Advanced Automated Peptide Protein Technologies (AAPPTEC). Fc, trifluoroacetic acid (TFA), triethylsilane and triethyl amine (TEA) were purchased from Sigma Aldrich. All the chemicals were used without further purification. Products were purified by column chromatography, on a column packed with silica gel.

2.1 General Synthesis of FcCO–Phe–His–OMe (G1)

The full synthetic scheme of G1 can be found in the SI, Fig. S1. Ferrocene-monocarboxylic (FcCOOH) acid was synthesized according to modified literature [33], In a 250 mL round bottom flask, 5 mmol of FcCOOH was dissolved in 60 mL of DCM. 10 mmol of EDAC·HCl and 10 mmol of 6Cl–HOBt were added to this solution. This solution was moved to an ice bath with continuous stirring. In another 250 mL round bottom flask, 10 mmol of H2N–(l)Phe–OMe·HCl was dissolved in 50 mL DCM, excess of TEA was added and stirred for 30 min. Excess solvent was evaporated under reduced pressure until a slurry was obtained. This slurry was added to FcCOOH solution and stirred at room temperature for 24 h. After 24 h, the resulting solution was washed with 10% citric acid (30 mL, 3 times), saturated sodium bicarbonate (30 mL, 3 times) and brine solution (30 mL, 3 times), respectively. The resulting organic layer was dried over anhydrous Na2SO4. The resulting solution was filtered and evaporated under reduced pressure and column chromatography was done to purify this mixture to obtain pure FcCO–(l)Phe–OMe.

Fc–CO–(l)Phe–OMe was dissolved in MeOH and 1 N NaOH (20 mL) was added. The reaction mixture was stirred and the progress of saponification was monitored by thin layer chromatography. After 10 h methanol was removed under vacuum, the residue was taken in 50 mL of water, washed with diethyl ether (2 × 50 mL). Then the pH of the aqueous layer was adjusted to 2 using 1 M HCl and it was extracted with ethyl acetate (3 × 50 mL). The extracts were dried over anhydrous Na2SO4, and evaporated in vacuum to yield as a yellow solid Fc–CO–(l)Phe–OH.

In a 250 mL round bottom flask, 3.0 mmol of Fc–CO–(l)Phe–OH was dissolved in 50 mL of DCM by continuous stirring. Once the entire solid dissolved the mixture was cooled to 0 °C in an ice bath. To the cooled mixture, 6 mmol of EDAC·HCl was added following the addition of 6 mmol of 6Cl–HOBt. In the same flask an excess of TEA was added to neutralize the HCl. In another 250 mL round bottom flask, 6 mmol of H2N–(l)His(Trt)–OMe·HCl was dissolved in 25 mL DCM, excess of TEA was added and stirred for 30 min. Excess solvent was evaporated under reduced pressure until a slurry was obtained. This slurry was added to Fc–CO–(l)Phe–OH solution and stirred for 24 h. The resulting solution washed with saturated 10% citric acid (30 mL, 3 times), saturated sodium bicarbonate (30 mL, 3 times) and brine solution (30 mL, 3 times) respectively. The resulting organic layer was dried using anhydrous Na2SO4 and evaporated under reduced pressure. Column chromatography was done to purify this mixture to obtain a pure compound, Fc–CO–(l)Phe–(l)His(Trt)–OMe.

2.2 mmol of Fc–CO–(l)Phe–(l)His(Trt)–OMe was dissolved in DCM and 2.25 mmol of triethylsilane was added. The reaction mixture was stirred under N2 atmosphere. After 15 min, 2 mL of TFA was added to the reaction mixture. After 1 h, the TFA was removed under vacuum. The reaction product was diluted with 3–4 mL water and washed with diethyl ether. DCM was added to the reaction mixture and the clear water part then neutralized by NH4OH solution. The orange product was pulled in DCM layer and dried over anhydrous Na2SO4. Column chromatography was done to purify this mixture to obtain a pure compound, Fc–CO–(l)Phe–(l)His–OMe (G1). 1H NMR (500 MHz, CDCl3): δ 7.38–7.07 (m, 10H, Aromatic Phe), 6.66–6.65 (d, 1H, NH Phe, J = 8.0), 6.43–6.42 (d, 1H, NH Leu, J = 8.0), 5.95–5.93 (d, 1H, NH Phe, J = 6.0), 4.74–4.31 (m, 7H, 3αH and 4H Cp ring which is directly attached to peptide segment), 3.95 (s, 5H, another Cp ring which is not directly attached to peptide segment), 3.71 (s, 3H, OCH3), 3.23–2.96 (m, 4H, βCH2 Phe), 1.61–1.45 (m, 3H, βCH2 and γCH Leu), 0.90–0.87 (t, 6H, 2CH3, Leu, J = 6.75); 13C NMR (126 MHz, CDCl3) δ 138.18, 135.12, 129.19, 129.14, 128.51, 128.47, 126.62, 75.54, 70.39, 70.35, 70.34, 69.52, 69.48, 68.60, 68.57, 67.86, 67.73, 54.54, 54.44, 52.70, 51.71, 36.96, 36.86, 28.61; MS–(ESI) m/z 529.1528 [M+H]+. Yield 1.4 mmol, 63%.

2.2 Nuclear Magnetic Resonance (NMR)

All liquid-phase NMR studies were carried out on a Bruker spectrometer 500 MHz 300 K using CDCl3 maintaining the concentration 10 mM. Chemical shifts (δ) were reported in ppm for all 1D-HNMR. Data processed in MestReNova software.

2.3 Mass Spectrometry

All experiments were performed on Agilent Technologies 6530 Accurate-Mass Q-TOF LC/MS spectrometer.

2.4 Rheology

A small piece of gel sample (10 mM) was placed on Peltier controlled rheology plate (20 mm parallel plate geometry maintaining 500 μm gap) and rheological measurements were carried out using a TA Instruments DHR-1 rheometer. Temperature was kept at 25 °C for all experiments. For frequency sweep experiments, the gels were scanned in the range of frequency 0.1–100 rad s−1.

2.5 Transmission Electron Microscopy

The morphologies of all organogels have been studied by using transmission electron microscopy (TEM) at room temperature (25 °C). 10 mM, 1 mL organogel was prepared freshly for each gelators in toluene (Tol). 20 µL of these gel samples was further diluted to 1 mL of Tol and 5 µL of these dilute solution was placed on a TEM grid (300 mesh size Cu grid) coated with a carbon film. The grid was allowed to dry by slow evaporation in air, and then allowed to dry separately in a vacuum overnight. Images were taken using a Hitachi 7500 transmission EM. The fiber widths were calculated by using ImageJ software.

2.6 Fourier Transform Infrared Spectroscopy (FTIR)

A drop of gel sample was allowed to dry in air and FTIR spectra were recorded using a Bruker ALPHA FTIR spectrometer equipped with a diamond ATR.

2.7 UV–Vis Spectroscopy

Ultraviolet–visible (UV–vis) absorption spectra were acquired on Agilent Technologies Cary 60 UV–vis spectrophotometer in 1 cm quartz cuvette cell at 20 °C. Samples were studied at concentrations of 0.33 mM in the acetonitrile (ACN). The metal salts were added in 0.1 equiv. portions to the gelator solution.

2.8 Gelation Properties

The compound was taken in a glass vial and heated gently to dissolve in organic solvents. After dissolving and cooling to room temperature to form organogels. Gel melting temperature determination was performed by heating gels in an oil bath fitted with a thermometer at a heating rate of 2 °C 5 min−1 until the gel melted. The melting has been confirmed by vial inversion method. The calculated error range in Tgel determination was found to be ± 1 °C.

3 Results and Discussion

3.1 Organogel Formation

The synthesized histidine based Fc derivative, G1, was found to be an organogelator in aromatic hydrocarbon solvents such as Tol and chlorobenzene (Fig. 1). When the hot solution of G1 cools to room temperature (25 °C) it becomes immobilized and turns into a self-supportable organogel. The minimum gelation concentrations (MGCs) were 6 mM and 8 mM for Tol and chlorobenzene, respectively. The gel is thermo-reversible and can undergo sol–gel transformation by multiple heat–cool cycles. The gel melting temperatures (Tgel) where the self-supportable gel becomes solution were found to be 45 °C and 55 °C (at MGC) for Tol and chlorobenzene, respectively. However, the gels obtained from Tol or chlorobenzene were opaque and metastable which formed precipitate after 1–2 h of formation. Addition of a polar solvent such as ACN to the Tol solution of the organogel changes the gelation property dramatically. The addition of ACN to the Tol solution (in a 1:2 ratio respectively) of the compound G1 formed a transparent yellow organogel (Fig. 1d) which is stable in ambient condition for several months. The MGC found to be 8 mM and the Tgel was 52 °C (at MGC) for the organogel obtained from Tol/ACN mixture. The changes observed for the addition of a polar solvent indicates that increase in polarity of the medium assists the formation of a more stable organogel. Interestingly, this organogel also gels in the presence of a binuclear Fe–S cluster, which is the first example of investigating prebiotic self-assembly and is shown in Fig. 1e.
Fig. 1

The chemical structure of a the gelator G1 and b the binuclear iron complex [Fe2S2Cl4]2−. c The organogel obtained from G1 in Tol which is meta-stable and shows opaque appearance. d The organogel obtained from G1 in ACN:Tol (1:2) mixture which is stable (several weeks) and shows transparent appearance. e The organogel obtained from G1 in presence of the binuclear complex of iron in ACN:Tol (1:2) mixture

3.2 Metal-Binding Studies and Its Viscoelastic Properties

We were interested to study the metal binding ability of the gelator G1 through the histidine’s imidazole moiety. The metal binding ability of histidine based di-substituted Fc compound was previously studied in our group [26, 27]. However, in presence of transition metal ions such as Co2+, Ni2+, Cu2+, and Zn2+ in the mixed solvent system (ACN:Tol), the gelator G1 formed solutions. The solution was unable to form any kind of gel over weeks even after prolonged sonication. Interestingly, in presence of the binuclear Fe–S complex, C2, in the mixed solvent system, the gelator formed a black coloured organogel (Fig. 1e). The MGC found to be 10 mM and the Tgel at MGC was 44 °C for the metallogel. UV–vis spectroscopy is a powerful tool to probe the metal binding ability of compound G1. UV–vis spectra were recorded at 0.33 mM concentration of each compound in ACN. 0.1 equiv. of metal solutions in ACN were gradually added until a 1:1.5 ratio of the G1:metal was achieved. The UV–vis spectra for compound G1 in the presence of Co2+, Ni2+, Cu2+, and Zn2+ metal ions showed that the signal at λ = 310 nm gradually increased in intensity by the addition of divalent metal ions (Fig. 2). The UV–vis studies showed that Zn2+ has 1:0.25 binding (G1:metal). The Co2+ and Ni2+ showed 1:0.5 binding respectively (G1:metal). Cu2+ is somewhat unusual and shows 1:1 binding (G1:metal). In case for Cu2+ complex, the peak at 640 nm indicates the Fc (Fe2+) moiety oxidized to ferrocenium (Fe3+) by the addition of Cu2+, followed by the reduction of the Cu2+ to the Cu+. The reduction of the Cu2+ to Cu+ could the probable reason for 1:1 binding to the gelator molecule.
Fig. 2

The metal binding study for G1. a Co2+, b Ni2+, c Cu2+ and d Zn2+. The gelator concentration was 0.33 mM and metal ion concentration was increased gradually by 0.1 equiv. to the gelator concentration. Inset shows the enlarged part at 310 nm region for Co2+, Ni2+ and Zn2+. The inset for Cu2+ shows the enlarged part at 640 nm. The peak at 640 nm for Cu2+ indicates the ferrocene (Fe2+) centre convert to ferrocenium (Fe3+) by the addition of Cu2+

Electrospray ionization–mass spectrometry positive mode (ESI–MS+) in ACN was used to confirm the host–guest binding ratio of the gelator G1 and the metal ions (Figs. 3, S3, S4, S5, S6). High-resolution MS data clearly revealed a [Co + 2G1]2+ peak at m/z = 557.6166 and [Ni + 2G1]2+ peak at m/z = 557.1157 for Co2+ and Ni2+ respectively which indicated a 1:0.5 binding ratio (gelator to metal ions). Additionally, a peak appeared at m/z = 295.5419 for Cu2+ which was assigned for the species [Cu + G1]2+ and a peak appeared for Zn2+ at m/z 1089.7585 which was assigned to the species [Zn + 4G1]2+. The MS data for Cu2+ and Zn2+ indicated a 1:1 and 1:0.25 binding ratio (gelator to metal ions) respectively. The isotope ratio also matched with the calculated pattern and the peaks were separated by 0.5 m/z units indicated a well-defined + 2 charge state of this host–guest binding. The MS data also supports the UV–vis data where the gelator molecule showed the similar binding affinity.
Fig. 3

The ESI–MS confirms the different binding mode of transition metal ions to the gelator G1. a (Co + 2G1)2+, 557.6166, b (Ni + 2G1)2+, 557.1157, c (Cu + G1)2+, 295.5419 and d (Zn + 4G1)2+, 1089.7585 respectively. The above panel shows the measured pattern. The obtained mass showed the binding ratio follows the pattern as G1: Co2+, 1:0.5; G1: Ni2+, 1:0.5; G1: Cu2+, 1:1 and G1: Zn2+, 1:0.25 respectively. The ESI–MS experiments were performed by dissolving the gelator G1 and metal solution of exact molar ratio in ACN

Rheological studies were performed to investigate the mechanical properties of the organogels (Fig. 4). In a frequency sweep (from 0.1 to 100 rad s−1) experiment, the storage (G′) and loss (G″) moduli were monitored as a function of frequency (ω). Both, G′ and G″ were independent of frequency and G′ was found to be larger than G″ which is an inherent property of visco-elastic gel phase material that does not collapse over the entire frequency range tested. The average G′ value of the Tol gel at 8 mM was very poor and found to be 4 (± 2) Pa. However, in presence of polar solvent (1:2, ACN:Tol) the G′ value increased significantly to 1607 (± 224) Pa at the same concentration (8 mM). The high mechanical strength obtained from mixed solvent system supports the formation of highly stable organogel. The metallogel formed in presence of binuclear complex C2 also showed high mechanical strength which was 2087 (± 192) Pa. The elastic behaviour of these organogels measured in the form of tan δ (G″/G′) value. The tan δ value obtained from the Tol gel is 0.274, which was much higher than the tan δ value, 0.129, obtained from the mixed solvent system. The tan δ indicates the gel obtained from mixed solvent system has very high elastic character compared to the Tol gel. Interestingly, the tan δ value for the metallogel was 0.056 which shows an increase in mechanical strength of the gel material.
Fig. 4

The mechanical strength of G1 obtained from frequency sweep rheology experiment. Average G′ = 4 (± 2) and G″ = 1 (± 1) at MGC (8 mM) of the unstable Tol organogel. However, the average G′ and G″ for the organogel obtained in mixed solvent system (ACN:Tol 1:2) increased to 1607 (± 224) Pa and 208 (± 70) Pa respectively. The metallogel in presence of C2 also showed high mechanical strength where G′ was 2087 (± 192) Pa

Organogel obtained from G1 in the mixed solvent system was thixotropic. This property was studied by performing time dependent rheology studies applying an alternating shear force in the form of strain to demonstrate reversible formation of the gels (8 mM) at a constant angular frequency of 10 rad s−1 (Fig. 5). The mechanical strength for the Tol gel was very low and showed a poor result for the recovery study. However, the gel obtained from mixed solvent system undergo gel–sol transition several times in a time sweep experiment by applying alternating oscillatory strain in an order 0.1% (120 s), 100% (120 s), 0.1% (240 s), 100% (120 s), 0.1% (240 s). The G’ value was higher than G″ value at low strain (0.1%) which indicated immobilized gel phase, whereas, at 100% oscillatory strain G″ appeared higher than G′ which essentially indicated sol phase. For the organogel obtained from G1 in mixed solvent system, application of high strain (100%) immediately converts gel phase to sol phase and the gel fully recovered their original strength almost instantly after removal of high strain (100%). However, the metallogel obtained from G1 in presence of C2 showed a decrease in mechanical strength after removal of the high strain in each cycle.
Fig. 5

Alternating strain rheology tests performed for organogels obtained from a the gelator G1 and b in presence of C2 in mixed solvent system (ACN:Tol 1:2). The studies showed organogels were thixotropic and undergo shear-induced breaking and reformation at constant angular frequency of 10 rad s−1. Applied strain: 0.1% (120 s) → 100% (120 s) → 0.1% (240 s) → 100% (120 s) → 0.1% (240 s). The organogel obtained from the gelator G1 fully regained of its original mechanical strength instantly after removal of the high strain. However, the metallogel obtained from G1 in presence of C2 showed a decrease in mechanical strength after removal of the high strain in each cycle

3.3 Redox-Responsiveness Behaviour of Fc–Phe–His–OH

The self-assembled gel was redox active. The redox behaviour was tested by treating the organogel with an oxidizing agent Fe(ClO4)3 in mixed solvent system. By the addition of equimolar Fe(ClO4)3, the gel transformed into a deep blue coloured solution which indicated the Fc-centre converts to Fc+-centre (Fig. 6a, b). However, the blue solution (Fc+) reverse back to a yellow solution (Fc) by the application of a reducing agent such as ascorbic acid. Though the Fc moiety shows a reversible redox behaviour, the self-assembled gel formation is not reversible presumably due to the protonation of the histidine imidazole ring. Interestingly, the gelator compound could be easily recovered from the yellow coloured solution after neutralizing by the addition of aqueous NH4OH solution and subsequent extraction of the gelator compound into an organic layer. The recovered gelator compound is capable of forming the organogel in the above mentioned mixed solvent at the same MGC indicates the quantitative recovery of sample. UV–vis spectroscopic experiments were performed (Fig. S7) to support the redox behaviour of the gelator G1 in ACN. The gelator compound G1 has an absorbance at 445 nm due to the Fc moiety. Upon addition of Fe(ClO4)3, a peak appeared at 640 nm due to the formation of the Fc+ state. However, the signal at 445 nm was not observed to decrease presumably due to the binding of Fe3+ ion to the histidine imidazole ring which has a higher absorbance. However, the spectral pattern reverse back after reduction of the Fe+ moiety by ascorbic acid suggesting that the oxidation and reduction process is completely reversible.
Fig. 6

a Redox activity of the organogel obtained from G1 in mixed solvent system (ACN:Tol 1:2) where the organogel oxidised to a dark blue coloured solution by the addition of a strong oxidiser Fe(ClO4)3 which indicates the Fe3+ (ferrocenium) ion formation. The blue solution transformed into yellow solution after addition of ascorbic acid indicates the ferrocenium (Fe3+) ion reduced to ferrocene (Fe2+) form. However, the reduced state does not form organogel presumably due to the protonation of the histidine imidazole ring. After neutralizing the solution by aqueous NH4OH solution the gelator compound was recovered and formed back the organogel. The morphology study showed a fibrous network for b the organogel obtained from G1. c and d Vesicular morphology for the oxidised solution. The enlarged part showed the larger vesicles entrapped small vesicles. e The fibrous morphology showed by the recovered organogel (after reduction by the application of ascorbic acid and subsequently neutralized by aqueous NH4OH solution)

The morphology of the self-assembled gel obtained from gelator G1 was studied by TEM. The organogel formed a cross-linked fibrous network (Fig. 6b) in mixed solvent system (ACN:Tol 1:2) which is characteristic of supramolecular gels. Average width of the nanofibers obtained from Tol/ACN gel is 28 (± 7) nm at MGC. Remarkably, after oxidation of the self-assembled gel, a vesicular morphology (Fig. 6c, d) was obtained from the blue solution. From the TEM images it is evident that the large vesicles were capable of encapsulating smaller vesicles. The diameters of the vesicles ranged from 1050 to 200 nm. The thickness of the side-wall of the large vesicles appeared to be 110 nm. However, after reduction, the recovered compound formed organogel and the fibrous morphology appeared similar to the organogel before oxidation (Fig. 6e). The average width of the nanofibers appeared 16 (± 3) nm. Moreover, the metallogel obtained from the gelator G1 in presence of the binuclear iron complex C2 showed a nanotubular morphology (Fig. S11) which is remarkably different from any of the organogels. The average diameter of these nano-tubes appeared 24 (± 6) nm.

4 Conclusion

In this work a Fc–peptide conjugate was synthesized and explored for supramolecular gel formation. It was found that this compound formed an organogel in a Tol/ACN mixture with a nanofiber morphology. Interestingly, due to the histidine amino acid residue, this gel was able to self-assemble in the presence of an Fe–S cluster and coordinate to different metals. Incorporating the Fc moiety imparted redox responsiveness, where this gel was responsive to redox agents. Upon addition of an oxidizing agent the supramolecular state was disrupted and reverted the gel into a sol state, while having an effect on the morphology by turning the fibers to spheres. Upon the addition of a reducing agent, the gel can be reformed with a fiber morphology. Combining the metal binding properties of histidine residues and the redox responsiveness of the Fc into one gelator holds promise for interesting morphological and physical properties characterization of novel gel materials. In addition, the gelation in the presence of the Fe–S cluster has future potential to study prebiotic self-assembly, prebiotic cofactor relationships and biomimetic active sites.

Notes

Acknowledgements

We appreciate and gratefully acknowledge the funding from the National Sciences and Engineering Research Council (NSERC) and the University of Toronto.

Supplementary material

10904_2019_1299_MOESM1_ESM.docx (2.4 mb)
Supplementary material 1 (DOCX 2441 kb)

References

  1. 1.
    H.-Q. Peng, B.L.-Y. Niu, Y.-Z. Chen, L.-Z. Wu, C.-H. Tung, Q.-Z. Yang, Biological applications of supramolecular assemblies designed for excitation energy transfer. Chem. Rev. 115(15), 7502–7542 (2015)CrossRefGoogle Scholar
  2. 2.
    J.H. Jung, J.H. Lee, J.R. Silverman, G. John, Coordination polymer gels with important environmental and biological applications. Chem. Soc. Rev. 42(3), 924–936 (2013)CrossRefGoogle Scholar
  3. 3.
    P. Duan, H. Cao, L. Zhang, M. Liu, Gelation induced supramolecular chirality: chirality transfer, amplification and application. Soft Matter 10(30), 5428–5448 (2014)CrossRefGoogle Scholar
  4. 4.
    G. Yu, X. Yan, C. Han, F. Huang, Characterization of supramolecular gels. Chem. Soc. Rev. 42(16), 6697–6722 (2013)CrossRefGoogle Scholar
  5. 5.
    X. Yu, L. Chen, M. Zhang, T. Yi, Low-molecular-mass gels responding to ultrasound and mechanical stress: towards self-healing materials. Chem. Soc. Rev. 43(15), 5346–5371 (2014)CrossRefGoogle Scholar
  6. 6.
    J. Zhang, H. Wang, X. Li, S. Song, A. Song, J. Hao, Two gelation mechanisms of deoxycholate with inorganic additives: hydrogen bonding and electrostatic interaction. J. Phys. Chem. B 120(27), 6812–6818 (2016)CrossRefGoogle Scholar
  7. 7.
    K. Tao, A. Levin, L. Adler-Abramovich, E. Gazit, Fmoc-modified amino acids and short peptides: simple bio-inspired building blocks for the fabrication of functional materials. Chem. Soc. Rev. 45(14), 3935–3953 (2016)CrossRefGoogle Scholar
  8. 8.
    X. Yu, X. Chen, Q. Chai, N. Ayres, Synthesis of polymer organogelators using hydrogen bonding as physical cross-links. Colloid Polym. Sci. 294(1), 59–68 (2016)CrossRefGoogle Scholar
  9. 9.
    T. He, K. Li, N. Wang, Y.X. Liao, X. Wang, X.Q. Yu, A ferrocene-based multiple-stimuli responsive organometallogel. Soft Matter 10(21), 3755–3761 (2014)CrossRefGoogle Scholar
  10. 10.
    S. Basak, J. Nanda, A. Banerjee, Multi-stimuli responsive self-healing metallo-hydrogels: tuning of the gel recovery property. Chem. Commun. 50(18), 2356–2359 (2014)CrossRefGoogle Scholar
  11. 11.
    R. Afrasiabi, H.B. Kraatz, Stimuli-responsive supramolecular gelation in ferrocene–peptide conjugates. Chem. Eur. J. 19(51), 17296–17300 (2013)CrossRefGoogle Scholar
  12. 12.
    S.I. Kirin, H.B. Kraatz, N. Metzler-Nolte, Systematizing structural motifs and nomenclature in 1, n′-disubstituted ferrocene peptides. Chem. Soc. Rev. 35(4), 348–354 (2006)CrossRefGoogle Scholar
  13. 13.
    D.R. van Staveren, N. Metzler-Nolte, Bioorganometallic chemistry of ferrocene. Chem. Rev. 104(12), 5931–5986 (2004)CrossRefGoogle Scholar
  14. 14.
    T. Moriuchi, T. Hirao, Design of ferrocene–dipeptide bioorganometallic conjugates to induce chirality-organized structures. Acc. Chem. Res. 43(7), 1040–1051 (2010)CrossRefGoogle Scholar
  15. 15.
    R. Afrasiabi, H.B. Kraatz, Small-peptide-based organogel kit: towards the development of multicomponent self-sorting organogels. Chem. Eur. J. 19(47), 15862–15871 (2013)CrossRefGoogle Scholar
  16. 16.
    Y. Wang, W. Qi, R. Huang, X. Yang, M. Wang, R. Su, Z. He, Rational design of chiral nanostructures from self-assembly of a ferrocene-modified dipeptide. J. Am. Chem. Soc. 137(24), 7869–7880 (2015)CrossRefGoogle Scholar
  17. 17.
    B. Adhikari, C. Singh, A. Shah, A.J. Lough, H.B. Kraatz, Amino acid chirality of ferrocene conformation guided self-assembly and gelation of ferrocene–peptide conjugates. Chem. Eur. J. 21(32), 11560–11572 (2015)CrossRefGoogle Scholar
  18. 18.
    B. Adhikari, H.B. Kraatz, Redox-triggered changes in the self-assembly of a ferrocene–peptide conjugate. Chem. Commun. 50(42), 5551–5553 (2014)CrossRefGoogle Scholar
  19. 19.
    Z. Sun, Z. Li, Y. He, R. Shen, L. Deng, M. Yang, Y. Lang, Y. Zhang, Ferrocenoyl phenylalanine: a new strategy toward supramolecular hydrogels with multistimuli responsive properties. J. Am. Chem. Soc. 135(36), 13379–13386 (2013)CrossRefGoogle Scholar
  20. 20.
    J. Liu, P. He, J. Yan, X. Fang, J. Peng, K. Liu, Y. Fang, An organometallic supra-gelator with multiple-stimulus responsive properties. Adv. Mater. 20(13), 2508–2511 (2008)CrossRefGoogle Scholar
  21. 21.
    R. Afrasiabi, H.-B. Kraatz, Rational design and application of a redox-active photoresponsive, discrete metallogelator. Chem. Eur. J. 21(21), 7695–7700 (2015)CrossRefGoogle Scholar
  22. 22.
    B. Adhikari, R. Afrasiabi, H.B. Kraatz, Ferrocene–tryptophan conjugate: an example of a redox-controlled reversible supramolecular nanofiber network. Organometallics 32(20), 5899–5905 (2013)CrossRefGoogle Scholar
  23. 23.
    B. Adhikari, A.J. Lough, B. Barker, A. Shah, C. Xiang, H.-B. Kraatz, Bis-amino acid derivatives of 1,1′-ferrocenedicarboxylic acid: structural, electrochemical, and metal ion binding studies. Organometallics 33(18), 4873–4887 (2014)CrossRefGoogle Scholar
  24. 24.
    N. Falcone, H.-B. Kraatz, Chapter 3: ferrocene peptide-based supramolecular gels: current trends and applications, in Advances in Bioorganometallic Chemistry (2019), pp. 57–74.  https://doi.org/10.1016/B978-0-12-814197-7.00003-0 CrossRefGoogle Scholar
  25. 25.
    N. Falcone, S. Basak, B. Dong, J. Syed, A. Ferranco, A. Lough, Z. She, H.-B. Kraatz, A ferrocene–tryptophan conjugate: the role of the indolic nitrogen in supramolecular assembly. ChemPlusChem 82(10), 1282–1289 (2017)CrossRefGoogle Scholar
  26. 26.
    A. Ferranco, S. Basak, A. Lough, H.-B. Kraatz, Metal coordination of ferrocene–histidine conjugates. Dalton Trans. 46(14), 4844–4859 (2017)CrossRefGoogle Scholar
  27. 27.
    A. Ferranco, K. Sun, T. Udaipaul, H.-B. Kraatz, Metal coordination of unsymmetric 1, n′-disubstituted ferrocene histidine peptides. Eur. J. Inorg. Chem. 2018(27), 3213–3233 (2018)CrossRefGoogle Scholar
  28. 28.
    D. Niu, L. Ji, G. Ouyang, M. Liu, Achiral non-fluorescent molecule assisted enhancement of circularly polarized luminescence in naphthalene substituted histidine organogels. Chem. Commun. 54(9), 1137–1140 (2018)CrossRefGoogle Scholar
  29. 29.
    P. Sharma, H. Kaur, S. Roy, Inducing differential self-assembling behaviour in ultrashort peptide hydrogelators using simple metal salts. Biomacromolecules 20(7), 2610–2624 (2019)CrossRefGoogle Scholar
  30. 30.
    T.A. Rouault, Biogenesis of iron–sulfur clusters in mammalian cells: new insights and relevance to human disease. Dis. Model Mech. 5(2), 155–164 (2012)CrossRefGoogle Scholar
  31. 31.
    X. de Hatten, E. Bothe, K. Mera, I. Hug, N. Metzler-Nolte, A ferrocene–peptide conjugate as a hydrogenase model system. Eur. J. Inorg. Chem. 2008(9), 4530–4537 (2008)CrossRefGoogle Scholar
  32. 32.
    S. Basak, I. Singh, A. Ferranco, J. Syed, H.-B. Kraatz, On the role of chirality in guiding the self-assembly of peptides. Angew. Chem. Int. Ed. 56(43), 13288–13292 (2017)CrossRefGoogle Scholar
  33. 33.
    D. Zhang, Q. Zhang, J. Su, H. Tian, A dual-ion-switched molecular brake based on ferrocene. Chem. Commun. 13, 1700–1702 (2009)CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Shibaji Basak
    • 1
  • Natashya Falcone
    • 1
    • 2
  • Annaleizle Ferranco
    • 1
    • 3
  • Heinz-Bernhard Kraatz
    • 1
    • 2
    • 3
    Email author
  1. 1.Department of Physical and Environmental SciencesUniversity of TorontoTorontoCanada
  2. 2.Department of Chemical Engineering and Applied ChemistryUniversity of TorontoTorontoCanada
  3. 3.Department of ChemistryUniversity of TorontoTorontoCanada

Personalised recommendations