Ferrocenyl Compounds Research Articles

Selective functionalization of ferrocenyl compounds using a novel solvent free synthetic method for the preparation of bioactive unsymmetrical ferrocenyl derivatives

A novel solvent free synthetic method has been designed by using rice husk ash (RHA) as solid support for the selective functionalization of ferrocenyl derivatives and described the synthesis of a 1,1′‐unsymmetrically bi‐functionalized ferrocenyl compounds for their biological evaluation. Single crystal X‐ray structural evaluation showed some interesting intra‐molecular hydrogen bonding interactions across the chains of the ferrocenyl molecule, while DFT calculation revealed the significance of the orientation between the two cyclopentadienyl rings for the hydrogen bonding interaction. Redox and antibacterial properties have been studied to understand the electronic and biological effect of different hydrazone system and their potential for future application.

Differential expression on mitochondrial tryparedoxin peroxidase (mTcTXNPx) in Trypanosoma cruzi after ferrocenyl diamine hydrochlorides treatments

Resistance to benznidazole in certain strains of Trypanosoma cruzi may be caused by the increased production of enzymes that act on the oxidative metabolism, such as mitochondrial tryparedoxin peroxidase which catalyses the reduction of peroxides. This work presents cytotoxicity assays performed with ferrocenyl diamine hydrochlorides in six different strains of T. cruzi epimastigote forms (Y, Bolivia, SI1, SI8, QMII, and SIGR3). The last four strains have been recently isolated from triatominae and mammalian host (domestic cat). The expression of mitochondrial tryparedoxin peroxidase was analyzed by the Western blotting technique using polyclonal antibody anti mitochondrial tryparedoxin peroxidase obtained from a rabbit immunized with the mitochondrial tryparedoxin peroxidase recombinant protein. All the tested ferrocenyl diamine hydrochlorides were more cytotoxic than benznidazole. The expression of the 25.5kDa polypeptide of mitochondrial tryparedoxin peroxidase did not increase in strains that were more resistant to the ferrocenyl compounds (SI8 and SIGR3). In addition, a 58kDa polypeptide was also recognized in all strains. Ferrocenyl diamine hydrochlorides showed trypanocidal activity and the expression of 25.5kDa mitochondrial tryparedoxin peroxidase is not necessarily increased in some T. cruzi strains. Most likely, other mechanisms, in addition to the over expression of this antioxidative enzyme, should be involved in the escape of parasites from cytotoxic oxidant agents.

Biologically Active New N, N', N''-Tri-Substituted Ferrocenyl Phenylguanidines and their Characterization.

Introducing new candidates for various biological targets is a prime characteristic of the present day medicinal research and development. Guanidines are the important bioactive compounds and are well recognized for their diverse biological activities, especially as anticancer, antimicrobial and antioxidant agents. Due to the favorable electronic properties of ferrocene like lipophilicity, redox activity, stability in solution state and its easy derivatization, have made ferrocenyl compounds very popular molecules for biological uses. Keeping in sight, it is valuable to synthesize ferrocenyl guanidines to increase the binding potency with DNA, make them redox active and more lipophilic compounds. Six new ferrocenyl phenylguanidines (F1 - F6) have been synthesized via multi step protocol. The structures of F1 - F6 were established by using elemental analysis, UV-visible, multinuclear (1H and 13C) NMR and FTIR spectroscopy. Solution phase redox behavior, of the synthesized compounds, has been characterized by cyclic voltammetry. Two compounds (F2 & F4) were characterized by single crystal XRD. Due to the biological importance of guanidines; these ferrocenyl guanidiens were screened for different biological activities like antibacterial, antifungal, antioxidant and DNA binding. DNA interaction study was done by using UV-visible spectrometry and cyclic voltammetry revealed good binding capacity of the test compounds. The results revealed that the ferrocene incorporation to guanidines enhances their DNA binding ability. A similar trend was found in antioxidant and antimicrobial studies. Being the bioactive molecules these compounds are potential drug candidates.

“One‐Step” Synthesis of Ionic Ferrocenyl Compounds of Ferrocenylmethyldimethylamine. Characterization, Migration, and Catalytic Properties During Combustion

AbstractAlkylferrocene‐based burning rate catalysts exhibit high migration tendency and volatility during prolonged storage and fabrication process of the solid propellants. To retard the migration problems, eight ionic compounds composed of ferrocenylmethyldimethylammonium cation paired with a common energetic anion, were synthesized by “one‐step” procedure. The compounds were characterized by FT‐IR, NMR, and UV/Vis spectroscopy as well as elementary analysis. Their crystal structures were confirmed by single‐crystal X‐ray diffraction. The TG and DSC analyses indicated that they exhibit high thermal stability. Cyclic voltammetry studies suggested that most of them show reversible or quasi‐reversible redox waves. The anti‐migration results revealed that 1–4 are low‐migratory compounds, but 5 exhibits high migration trends. The TG curves at 70 °C for 24 h showed that all of them have low volatility. They have from high to low impact sensitivity depending on the anions of the compounds. They all exhibit significant effect on the thermal decomposition of ammonium perchlorate (AP) and some of them accelerate the thermal degradation of 1,3,5‐trinitro‐1,3,5‐triazacyclohexane (RDX). Among them 4 is the best one. Unexpectedly, compound 5, with 1H‐tetrazolate as anion, can decompose into its original reactants at the temperature just higher than its melting point and could show smart‐material functionality in solid propellants.

Synthesis of new binuclear ferrocenyl compounds by hydrosilylation reactions

Ferrocenyl silanes are prepared by treatment of Grignard reagents produced from 4-chlorobutylferrocene derivatives and chlorodimethylsilane in THF. Butenylferrocenes are prepared by the elimination reaction of 4-chlorobutylalkylferrocenes by sodium tert-butoxide in DMSO. A hydrosilylation reaction between a butenyl compound and ferrocenylsilane occurred in dry toluene at room temperature in the presence of the Karstedt catalyst to produce the desired binuclear ferrocenyl compound in good to high yields. The electrochemical behavior of new ferrocenyl compounds were studied by cyclic voltammetry in CH3CN/0.1 M LiClO4, and the relation between the peak currents and the square root of the scan rate, showed that the redox process is diffusion-limited.

Substitution of Metallocenes with [2.2]Paracyclophane to Enable Confocal Microscopy Imaging in Living Cells

Bioimaging techniques that allow the visualization of ferrocene in living cells do not exist. This work addresses this challenging problem, and a new indirect approach for the bioimaging of ferrocenyl compounds in living and fixed cells is proposed. It is based on the structural similarity of metallocenyl (ferrocenyl and ruthenocenyl) groups to their metal‐free [2.2]paracyclophanyl congeners. Three adequately designed compounds were obtained. They share a 5‐(1‐ethynylpyrenyl)uracil group as a common structural motif and differ in their three‐dimensional aromatic substituents, namely, [2.2]paracyclophanyl, ferrocenyl and ruthenocenyl. The first substituent allows pyrenyl luminescence to occur, whereas the latter two act as quenchers. The accumulation of the luminescent derivative in the membranes, cytoplasm and mitochondria of living and fixed cells was confirmed by confocal microscopy. Microscopy studies were further correlated with high‐resolution continuum‐source atomic absorption spectroscopy (HR‐CS AAS) measurements of the ruthenocenyl compound that confirmed the uptake of ruthenium into the cells. Thus, taking into account the overall similarity of the compounds under study, it can be hypothesized that the metallocenyl derivatives are localized in the membranes, cytoplasm and mitochondria of the assayed cells. This is the basis for the more general concept of the utilization of luminescent [2.2]paracyclophanes as probes in indirect bioimaging studies of metallocene derivatives.

Progress on the synthesis and catalytic and anti‐migration properties of ferrocene‐based burning rate catalysts

Burning rate catalysts are of great importance in solid composite propellants for their unique property of accelerating combustion speed. Among various kinds of burning rate catalysts, ferrocene and its derivatives exhibit excellent catalytic effects and have become the most widely used burning rate catalysts. However, these simple ferrocenyl compounds trend to migrate in solid composite propellants during storage, which causes great damage to the propellants, equipment and environment and can even affect personal safety. The exploration of novel anti‐migratory ferrocene‐based compounds has become an advanced research hotspot in the field of burning rate catalysis. This review focuses on recent progress on the synthesis and catalytic properties of ferrocene‐based polymers and ferrocene derivatives as burning rate catalysts. Two main aspects of anti‐migratory exploration, i.e. synthesis of ferrocene‐based polymers and modification of the side groups of ferrocene, are summarized. Ferrocene‐based polymers can be obtained via condensation polymerization, addition polymerization, ring‐opening polymerization, polymer reactions, etc. Ferrocenyl compounds with active groups and ferrocene‐based metal coordination compounds were developed instead of the methods of lengthening the carbon chain of side groups and improving molecular polarity. Also, possible mechanisms of burning rate catalytic activity and migration are discussed and analyzed. Finally, the key points of the development of ferrocene‐based burning rate catalysts and solid composite propellants are proposed. Copyright © 2016 John Wiley & Sons, Ltd.

Synthesis and structure–activity relationships of novel hybrid ferrocenyl compounds based on a bicyclic core skeleton for breast cancer therapy

Breast cancer is the most frequent cancer in women worldwide, and incidence is increasing year by year. Although current selective estrogen receptor modulators (SERMs) have clear advantages in the treatment of hormone-responsive breast cancer, they are ineffective for ER(−). In this study, we describe the design and synthesis of a series of dual-acting estrogen receptor (ER) and histone deacetylase (HDAC) inhibitors with incorporation of the ferrocenyl moiety, leading to novel hybrid ferrocenyl complexes (FcOBHS–HDACis) for breast cancer therapy. It is worth to note that these ferrocenyl conjugates could not only potently inhibit HDACs and the proliferation of ERα positive (ER(+)) breast cancer cells (MCF-7), but also show significant antiproliferative effect on ER(−) breast cancer cells (MDA-MB-231). Thus, the FcOBHS–HDACi conjugates represent a novel approach to the development of efficiently dual-acting agents for treatment of breast cancer.

Ferrocenyl compounds derived from the reaction of phenylamines with ferrocenecarbonyl chloride: Synthesis, characterisation and their biological activity

Eight ferrocenyl derivatives were synthesized and characterised by NMR, elemental analyses and X-ray single crystal diffraction analysis. The anticancer activities of the eight compounds were assessed where applicable in the two breast cancer cell lines, MCF-7 and MDA-MB-231. It was found that the cytotoxicity of N-Phenyl-N-(2-Methyl-4-Methoxyphenyl)ferrocenecarboxamide (4) and N,N-bis(4-Methoxyphenyl)ferrocenecarboxamide (8) correlates to their relatively positive reduction potentials, which may suggest that the cytotoxicity stems from their involvement in electron transfer process. Furthermore, comparing the activity of N,N-bis(phenyl)ferrocenecarboxamide (3) to that of compounds 4 and 8 suggest that their methoxyl group may undergo demethylation under physiological conditions to generate biologically active species and thus they exhibited better activity in the two breast cancer cell lines compared to compound 3.

A sensitive electrochemiluminescence immunosensor based on luminophore capped Pd@Au core-shell nanoparticles as signal tracers and ferrocenyl compounds as signal enhancers

In this work, N-(aminobutyl)-N-(ethylisoluminol) (ABEI), an analogue of luminol, is served as both the reductant and luminescence reagent to synthesize ABEI capped Pd@Au core-shell nanoparticles (ABEI-Pd@AuNPs). The nanoparticles not only exhibit inherent electrochemiluminescence (ECL) property, but also possess advantages of noble-metal nanomaterials such as outstanding electronic property, high specific surface area and good biocompatibility. In order to enhance the luminescence efficiency, ferrocene monocarboxylic acid (Fc) as catalyzer is grafted on the surface of ABEI-Pd@AuNPs with the aid of l-cysteine (l-Cys). When the Fc is electrochemically oxidized to ferricinium cation species (Fc+), the decomposition of H2O2 which existed in detection solution can be catalyzed by Fc+ to generate oxygen-related free radicals, resulting effective signal amplification for ABEI-H2O2 system. For potential applications, the Pd@Au core-shell nanoparticles bifunctionalized by ABEI and catalyzer are employed as nano-carriers to immobilize detection antibody (Ab2). Based on sandwiched immunoreactions, a “signal-on” ECL immunosensor is developed for detection of human collagen type IV (Col IV), a potential biomarker associated with diabetic nephropathy. Consequently, the proposed immunosensor provides a wide linear detection ranging from 1pgmL−1 to 10ngmL−1 with a relatively low detection limit of 0.3pgmL−1 (S/N=3).

Assessment of the nematocidal activity of metallocenyl analogues of monepantel

In this study, we present the design, synthesis, characterization and biological evaluation of structurally new ferrocenyl and ruthenocenyl derivatives of the organic anthelmintic monepantel (Zolvix®). All seven metallocenyl derivatives prepared (4a/b, 5a/b, 6a/b and 7) were isolated as racemates and characterized by 1H, 13C and 19F NMR spectroscopies, mass spectrometry, IR spectroscopy and elemental microanalysis. The molecular structures of four compounds (4a/b, 6a and 7) were further confirmed by X-ray crystallography. The biological activities of the organometallic intermediates (4a/b) and organometallic derivatives of monepantel (5a/b, 6a/b and 7) were evaluated in vitro using parasitic nematodes of major importance in livestock, namely Haemonchus contortus and Trichostrongylus colubriformis. Two ferrocenyl compounds (4a and 6a) showed nematocidal activity, while the analogous ruthenocenyl compounds (4b and 6b) were not active at the highest concentration tested (10 μg mL-1). In order to obtain insight into the difference in activity between ferrocenyl and ruthenocenyl derivatives, the potential of the compounds for reactive oxidative species (ROS) production in live cells was assessed. Interestingly, neither the ferrocenyl nor the ruthenocenyl compounds (4a/b and 6a/b) produced significant ROS in HeLa cells when checked after 22 h, potentially indicating a redox-independent activity of 4a and 6a on the parasites. The selectivity of the compounds on parasites was confirmed by investigating their cytotoxicity profiles. None of these compounds was toxic either to HeLa or MRC-5 cells. Thus, 4a and 6a could be considered as interesting leads for further development of new classes of anti-parasitic agents.

Corrigendum to: Ionic binuclear ferrocenyl compounds containing 1,1,3,3-tetracyanopropenide anions – synthesis, structural characterization and catalytic effects on thermal decomposition of main components of solid propellants

Corrigendum to: Ionic binuclear ferrocenyl compounds containing 1,1,3,3-tetracyanopropenide anions – synthesis, structural characterization and catalytic effects on thermal decomposition of main components of solid propellants

Evaluation of the inhibitory effectiveness of three ferrocene derivatives for corrosion of steel XC70 by spectroscopy of electrochemical impedance

In this work, we studied the efficacy of corrosion inhibition of carbon steel X70 in HCl 1M solution using ferrocenyl compounds prepared in VPRS laboratory, these compounds are: N-(ferrocenyl methyl)-2-nitro aniline(Fc12), N-(ferrocenyl methyl)-3-nitro aniline(Fc13) and N-(ferrocenyl methyl)-4-nitro aniline(Fc14). The inhibitory potency of these compounds was determined by the electrochemical impedance spectroscopy (EIS). The overall results show that these compounds have varying percentages of inhibition. The adsorption of these compounds on the surface of the metal is a chemical adsorption. In HCl 1M, the compound Fc12 had the best ability of inhibition at a concentration of 70ppm (R = 91.24%). Keywords: corrosion, carbon steel X70, inhibition, ferrocene derivatives, adsorption isotherms EIS, and acid HCl 1M.

Ionic binuclear ferrocenyl compounds containing 1,1,3,3-tetracyanopropenide anions – synthesis, structural characterization and catalytic effects on thermal decomposition of main components of solid propellants

Abstract Alkyl-substituted ferrocenes are typical burning-rate catalysts in composite solid propellants, but their high migration tendency and volatility has impeded their extensive applications. By introducing the concept of ionic energetic compounds, eight new ionic binuclear ferrocenyl compounds, [FcCH2N(CH3)2(CH2) n N(CH3)2CH2Fc]2+ (X– 2) (Fc = ferrocenyl; X– = 1,1,3,3-tetracyano propenide; n = 3–10; the compounds being numbered consecutively 1–8), were prepared and characterized. The molecular structures of 1, 2, and 4 were determined by single-crystal X-ray diffraction, and their cations were studied by density functional theory calculations (DFT). Compounds 1–5 show high thermal stability but 6–8 are slightly volatile. The results of cyclic voltammetry studies suggest that each salt exhibits a quasireversible redox system. Catalytic effects of the new salts on thermal degradation of ammonium perchlorate (AP), 1,3,5-trinitro-1,3,5-triaza-cyclo-hexane (RDX), and 1,2,5,7-tetranitro-1,3,5,7-tetraazacyclooctane (HMX), have been investigated by DSC and/or TG methods. The results show that the new compounds can bring the peak temperatures of both AP and RDX down significantly and enhance their heat release dramatically, indicating that the ferrocenyl salts possess high catalytic efficiency for the thermal decomposition of AP and RDX. Their catalytic activities are nearly equal to or higher than that of the corresponding nitrates and picrates, as well as their mononuclear counterparts. Compound 6 also efficiently catalyzes the thermal decomposition of hydroxyl-terminated polybutadiene (HTPB) and 1:1 mixtures of HTPB and AP.

Synthesis and in vitro antiplasmodial activity of ferrocenyl aminoquinoline derivatives.

The aim of this study was to synthesize a series of ferrocenyl 4-aminoquinolines and to evaluate their activities against Plasmodium falciparum F32 (chloroquine-sensitive) and FCB1 and K1 (chloroquino-resistant). Some of the ferrocenyl compounds exhibited in vitro antiplasmodial activity in the nM range. In particular, (1R,4R)-N1-(7-chloroquinolin-4-yl)-N4-(ferrocenylmethyl)-N4-methylcyclohexane-1,4-diamine 17 presented the lowest IC50 value (26 nM) against CQ-resistant strains.

Ionic Ferrocenyl Compounds Containing Polycyano Anions. Synthesis, Structures, and Effects on Thermal Decomposition of Core Components of Solid Propellants

AbstractFor lowering high migration tendency of alkyl‐substituted ferrocenes as burning‐rate catalysts in composite solid propellants, eight new ionic ferrocenyl compounds, [FcCH2N(CH3)2(CnH2n+1]+X– (Fc = ferrocenyl; X– = 1,1,3,3‐tetracyanopropenide; n = 3–10; consequently numbered as 1–8), were synthesized and characterized by 1H NMR, 13C NMR, FT‐IR and UV/Vis spectroscopy as well as elementary analysis. In addition, the structures of 1, 3, and 5 were confirmed by single‐crystal X‐ray diffraction analysis and their cations were studied by density functional theory calculations (DFT). 1, 3, and 5 crystallize in the triclinic space group P$\bar{1}$. 1–6 show highly thermal stability (>166 °C), whereas compounds 7 and 8 exhibit volatility to a certain degree. Cyclic voltammetry studies suggested that each salt exhibits a quasi‐reversible redox wave of the ferrocenyl group. The effects of the new compounds on thermal decomposition of ammonium perchlorate (AP), 1,3,5‐trinitro‐1,3,5‐triazacyclohexane (RDX), and 1,2,5,7‐tetranitro‐1,3,5,7‐tetraazacyclooctane (HMX) were investigated by DSC technique. The results show that all the new compounds can catalyze thermal degradation of AP and RDX effectively and are higher in catalytic activity than the corresponding nitrates and picrates, verifying the prospect that relatively high nitrogen content in an ionic ferrocenyl compound is able to enhance its combustion catalytic efficiency.

Ferrocenyl pseudo-dipeptides derived from 1,2-O-isopropylidene-α-D-xylofuranose: Synthesis, electrochemistry and cytotoxicity evaluation

In this article, we describe the synthesis of a new series of ferrocene conjugates of pseudo-dipeptides derived from d-xylose and different l-amino acids. The pseudo-dipeptides (3a–f) were synthesized by the reaction of 5-amino-5-deoxy-1,2-O-isopropylidene-α-D-xylofuranose (1) with different N-Boc-L-amino acids (2a–f). Subsequently, the pseudo-dipeptides were insitu converted to amino-amides (4a–f) and treated with ferrocenoyl chloride to obtain the ferrocenyl xylofuranose pseudo-dipeptide conjugates (5a–f). The structure of the pseudo-dipeptide 3b was determined by X-ray crystallography. Low electrochemical diffusion coefficient (Df) values were obtained for the ferrocenyl compounds (5a–f) in DMSO-buffer solutions. Promising cytotoxicity was observed for the ferrocenyl pseudo-dipeptides (5a–f) as compared to the parent pseudo-dipeptides (3a–f).

Synthesis, characterization, antiparasitic and cytotoxic evaluation of thioureas conjugated to polyamine scaffolds

A series of mono- and multimeric 4-amino-7-chloroquinoline and ferrocenyl thioureas have been prepared by the reaction of a 7-chloroquinoline methyl ester and a ferrocenylimine methyl ester with various amines. These compounds were characterized using standard spectroscopic and analytical techniques. The compounds were evaluated against the NF54 (CQ-sensitive) and Dd2 (CQ-resistant) strains of Plasmodium falciparum. The quinoline compounds show enhanced activity compared to the ferrocene compounds against this parasite. Compound 5 displays the most promising activity against the NF54 strain. Compounds 5 and 6 are effective at inhibiting β-hematin formation perhaps due to an increased number of quinoline moieties. The trimeric (12) and tetrameric (13) ferrocenyl compounds also inhibit β-hematin formation, albeit to a lesser degree compared to the quinoline thioureas. The compounds were also screened against the G3 strain of Trichomonas vaginalis and here the ferrocene-containing compounds show a slightly higher parasite growth inhibition compared to the quinoline thioureas. The quinoline compounds were also found to be more cytotoxic compared to the ferrocenyl compounds. Compound 6 displays good cytotoxicity against WHCO1 oesophageal cancer cells.

Synthesis and characterization of new ferrocenyl compounds with different alkyl chain lengths and functional groups to target breast cancer cells

A new family of organometallic compounds bearing chains of different lengths and with different functional groups was synthesized and evaluated against triple negative MDA-MB-231 and hormone-dependent MCF-7 breast cancer cells. Biological results comparing suberamides (six-methylene chain length) and succinamides (two methylene chain length) showed that chain shortening does not dramatically impact on their antiproliferative effects. Cytotoxicity of primary amides is not dependent on chain length, as suberamide and succinamide showed almost identical activity against both types of breast cancer cells. However, the possibility that some of the cytotoxic activity of hydroxamides could be related to enzyme inhibition, e.g. histone deacetylase (HDAC) inhibition, is not excluded. This is based on the fact that compounds bearing a longer alkyl chain showed IC50 values lower than those with shorter alkyl chains. Succinic and adipic carboxylic acids and a succinimide were also tested and they also showed cytotoxic activity. Interestingly, succinimide was the most active compound against hormone-dependent MCF-7 breast cancer cells, presumably owing to an antagonist effect with the alpha form of the estrogen receptor (ERα). Some new and interesting side chain influences related to antiproliferative effects can therefore be observed.

Friedel-Crafts Reaction of Ferrocenyl Alcohol Catalyzed by [BPy][HSO4] in Water Phase

A novel, environment friendly and efficient methodology for the synthesis of a series of ferrocenyl compounds using the functionalized acid ionic liquid [BPy][HSO4] as catalyst in water under mild conditions is reported. The Friedel-Crafts reaction of ferrocenyl alcohol with nucleophiles could be carried out efficiently in an “aqueous dispersion” and the corresponding ferrocenyl compounds were obtained in good to excellent yields. Suitable crystal of 3i was obtained, and the X-ray diffraction analysis indicated that compound 3i belonged to triclinic, space group P-1. The procedure reported here has the advantages of mild reaction conditions, high yields, operational simplicity and catalyst recyclability.