Ferrocene Compounds Research Articles

Enhancing the Efficacy of Chiral Ligands and Catalysts: Siloxane-Substituted Oxazoline Ferrocenes as Next-Generation Candidates.

Since the discovery of classical chiral oxazoline ferrocene ligands in 1995, they have become pivotal in transition metal-catalyzed asymmetric transformations. Over the past decade, a notable evolution has been observed with the emergence of siloxane-substituted oxazoline ferrocenes, demonstrating significant potential as chiral ligands and catalysts. These compounds have consistently delivered exceptional results in diverse and mechanistically distinct transformations, surpassing the capabilities of classical oxazoline ferrocene ligands. This review meticulously delineates the research progress on siloxane-substituted oxazoline ferrocene compounds. It encompasses the synthesis of crucial precursors and desired products, highlights their achievements in asymmetric catalysis reactions, and delves into the exploration of the derivatization of these compounds, emphasizing the introduction of ionophilic groups and their impact on the recovery of transition metal catalysts. In addition to presenting the current state of knowledge, this review propels future research directions by identifying potential topics for further investigation concerning the siloxane-tagged derivatives. These derivatives are poised to be promising candidates for the next generation of highly efficient ligands and catalysts.

Synthesis, electrochemistry, and in vitro antileishmanial efficacy of novel ferrocenylazines

Leishmaniasis is a zoonotic disease prevalent in 83–92 countries. This disease's current treatments are unsatisfactory because of a variety of shortcomings, including serious toxicity, variable efficacy, painful administration, and the occurrence of parasite resistance to these antileishmanial agents. The abovementioned limitations have urged the development of novel, reliable, and affordable agents to treat leishmaniasis. Ferrocenylazine derivatives were therefore synthesized for activity screening against Leishmania major and Leishmania donovani cell cultures. This emphasizes the urgent need for new effective antileishmanial agents. In search for such therapeutics, we synthesized and evaluated in vitro the antileishmanial activity of a series of azine derivatives based on the organometallic compound ferrocene. Two ferrocenylaldazines, 2l and 2q, were uncovered as mammalian cell nontoxic antileishmanial early leads, expressing submicromolar activity with IC50 values of 0.78 ± 0.03 and 0.46 ± 0.03 μM, respectively, against amastigote of L. donovani. Ferrocenylazines may therefore act as potential new antileishmanial agents, and the next objective will be the identification of the involved biological targets.

Cation recognition controlled by protonation or chemical reduction: a computational study.

To control biochemical processes, non-covalent interactions involving cations are activated by protons or electrons. In the present study, the bonding situation between: (i) carboxylic acid or (ii) ferrocene-functionalized crown ether derivatives and cations (Li+, Na+ or K+) has been elucidated and, mainly, tuned by the substitution of hydrogen atoms by electron donor (-NH2) or acceptor (-NO2) groups. The deprotonation of the carboxyl groups improves the interaction with the cations through more favorable electrostatic O⋯cation interactions. Reducing the ferrocene structures favors cationic recognition supported by a less unfavorable iron⋯cation binding. The receptors preferably interact with smaller cations because of more attractive electrostatic and orbital (σ or π) O⋯cation interactions. The presence of electron donor or acceptor groups in the carboxylic acid-functionalized crown ethers promotes less attractive interactions with the cations, mainly due to the less favorable electrostatic O⋯Na+ interactions. The -H → -NH2 substitution in the ferrocene framework favors the cationic recognition. It is based on the strengthening of the electrostatic and σ O⋯Na+ and H2N⋯Na+ bonds. The (i) absence of repulsive electrostatic iron⋯cation interactions, or (ii) the presence of oxygen atoms with large electron density, ensures carboxylic acid-functionalized crown ethers have more favorable interactions with cations than ferrocene compounds. Therefore, this work has demonstrated how cation recognition can be improved by structural changes in carboxylic acid- or ferrocene-functionalized crown ethers and has shown that the carboxylic acid molecules appear to be better candidates for cation recognition than ferrocene derivatives.

Ferrocenyl Benzimidazole: A Promising Molecule

Organometallic compound ferrocene formation was a serendipity and due to its "barrel-shape" which grants 3D geometry of the organometallic compound it has an optimal spatial design for better fitting and connection inside the pockets of the dynamic site in natural targets and receptors. The benzimidazole motif has developed to be a significant privileged heterocyclic platform. Ferrocenyl benzimidazole is a complex organic compound having ferrocene an organometallic compound attached to the 2-position of benzimidazole an aromatic heterocyclic compound. Ferrocene benzimidazole derivatives have attracted lots of attention for the construction of new compounds due to their wide applications. By combining ferrocene and benzimidazole produce a vast range of pharmacological actions. Synthetic method and pharmacological effects of various ferrocenyl benzimidazole derivatives were examined. This review gives the medicinal activities of 2- ferrocenyl benzimidazole derivatives like cytotoxic activity, anti-malarial, anti-microbial, anti-fungal etc. were furnished. Keywords: ferrocene, benzimidazole, cyclopentadiene, 2-ferrocenyl benzimidazole, cytotoxic, anti-malarial.

New Strategies for Novel Drugs: Antimicrobial Peptides Containing Ferrocene with Improved Antifungal and Antiplasmodial Biological Activity.

Fungal and parasitic diseases are global health problems, and the available treatments are becoming ineffective, mainly due to the emergence of resistant strains of pathogens. Furthermore, the drugs currently in use exhibit high toxicity and side effects. The scarcity of efficient treatments for fungal and parasitic diseases has motivated the search for new drug candidates, including antimicrobial peptides. The chemokine class RP1 peptide shows inhibitory activity against bacteria, viruses, cancer cells and parasites. In addition, the organometallic compound ferrocene showed antiparasitic activity. Study aimed to assess the effect of conjugation of the RP1 peptide with ferrocene in terms of its structure, biological activity against fungi and parasites and toxicity. Peptides and conjugates were synthesized using solid phase peptide synthesis (SPPS). The Fc-RP1 peptide showed antifungal and antimalarial activities with low toxicity in the U87 and HepG2 cell lines. The mechanism of action of these peptides, analyzed by flow cytometry in the fungus Cryptococcus neoformans, was through membrane permeabilization, with an emphasis on the Fc-RP1 peptide that presented the highest rate of PI-positive cell marking. In conclusion, ferrocene conjugated to antimicrobial peptide RP1 is an attractive biomolecule for drug discovery against fungal and parasitic diseases.

Shock-induced transformation of non-magnetic to magnetic ISM dust analogue

ABSTRACT The fate of organometallic dust subjected to extreme conditions, especially the shock fronts, in the interstellar medium (ISM) has not been explored to date. Iron and cyclopentadiene, which have been found to be present in the ISM, are known to react and produce the organometallic compound ferrocene under terrestrial conditions. In our experiment we subjected ferrocene, a possible proxy of such dust, to ∼5.6 Mach (M) shock commensurate with conditions encountered in the ISM, leading to a temperature rise up to 7300 K within 2 ms. Analysis of the post-shock residue showed the presence of a α-Fe and Fe3C composite that responded to an external magnetic field. These results show that a non-magnetic dust composed of molecules containing transition metals undergoing shock processing in the ISM can dissociate and synthesize dust that is then magnetic. Such drastic transformations from non-magnetic to magnetic dust induced by shocks might be of importance in interstellar polarization.

(Keynote) Zwitterionic Ferrocenes As Redox Flow Battery Components

Ferrocenes play increasingly important roles as cathodic components in redox flow battery designs. Peripheral functionalization has become an key tool in the development of ferrocenes as catholytes, as they can impart significant aqueous solubility. In this talk, two new aqueous soluble ferrocene compounds will be introduced that have zwitterionic functional groups pendant to the cyclopentadienyl ring. These compounds can be produced in one step from commercially available reagents and exhibit good stability and reversible electrochemistry in aqueous solution. We tested two such compounds in redox flow battery devices, and both exhibit superior performance characteristics. Notably, there is an observable difference in stability which corresponds to the length of the aliphatic chain between the cationic and anionic units, and we interrogated the factors behind this difference using computational methods.

Investigation of Copper-64-Based Host-Guest Chemistry Pretargeted Positron Emission Tomography.

Pretargeting is a technique that uses macromolecules as targeting agents for nuclear imaging and therapy with the goal of reducing the radiation toxicity to healthy tissues often associated with directly radiolabeled macromolecules. In pretargeting, a macromolecule is radiolabeled in vivo at the target site using a radiolabeled small molecule (radioligand) that interacts with the macromolecule with high specificity. We report an investigation of host-guest chemistry-driven pretargeting using copper-64 radiolabeled ferrocene (Fc; guest) compounds and a cucurbit[7]uril (CB7; host) molecule functionalized carcinoembryonic antigen targeting hT84.66-M5A monoclonal antibody (CB7-M5A). Two novel ferrocene-based radioligands ([64Cu]Cu-NOTA-PEG3-Fc and [64Cu]Cu-NOTA-PEG7-Fc) were prepared, and their in vitro stability, pharmacokinetic in vivo profile in healthy mice, and pretargeting performance in a subcutaneous BxPC3 human pancreatic cancer cell xenograft mouse model were compared. The antibody dosing was optimized using a zirconium-89 radiolabeled M5A antibody ([89Zr]Zr-DFO-M5A) in a BxPC3 xenograft model, and the dosimetry of [89Zr]Zr-DFO-M5A and the pretargeting approach were compared. Finally, the effects of varying lag times up to 9 days between CB7-M5A and radioligand injection were investigated. In vivo pretargeting studies with both ferrocene radioligands resulted in specific tumor uptake (p = 0.0006 and p = 0.003) and also showed that the host-guest-based pretargeting approach excels with extended lag times up to 9 days with good tumor localization, suggesting that host-guest pretargeting may be suitable for use without clearing agents which have complicated clinical application of this technique. To our knowledge, the reported lag time of 9 days is the longest investigated lag time in any reported pretargeting studies.

In Vitro Anticancer Activity of Two Ferrocene-Containing Camphor Sulfonamides as Promising Agents against Lung Cancer Cells.

The successful design of antitumour drugs often combines in one molecule different biologically active subunits that can affect various regulatory pathways in the cell and thus achieve higher efficacy. Two ferrocene derivatives, DK-164 and CC-78, with different residues were tested for cytotoxic potential on non-small lung cancer cell lines, A549 and H1299, and non-cancerous MRC5. DK-164 demonstrated remarkable selectivity toward cancer cells and more pronounced cytotoxicity against A549. The cytotoxicity of CC-78 toward H1299 was even higher than that of the well-established anticancer drugs cisplatin and tamoxifen, but it did not reveal any noticeable selective effect. DK-164 showed predominantly pro-apoptotic activity in non-small cell lung carcinoma (NSCLC) cells, while CC-78 caused accidental cell death with features characteristic of necrosis. The level of induced autophagy was similar for both substances in cancer cells. DK-164 treatment of A549, H1299, and MRC5 cells for 48 h significantly increased the fluorescence signal of the NFkB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) protein in the nucleus in all three cell lines, while CC-78 did not provoke NFkB translocation in any of the tested cell lines. Both compounds caused a significant transfer of the p53 protein in the nucleus of A549 cells but not in non-cancerous MRC5 cells. In A549, DK-164 generated oxidative stress close to the positive control after 48 h, while CC-78 had a moderate effect on the cellular redox status. In the non-cancerous cells, MRC5, both compounds produced ROS similar to the positive control for the same incubation period. The different results related to the cytotoxic potential of DK-164 and CC-78 associated with the examined cellular mechanisms induced in lung cancer cells might be used to conclude the specific functions of the various functional groups in the ferrocene compounds, which can offer new perspectives for the design of antitumour drugs.

Zwitterionic Ferrocenes: An Approach for Redox Flow Battery (RFB) Catholytes

Herein we present two new ferrocene compounds Fc3 and Fc4 with, respectively, propyl and butyl zwitterionic side chains. These compounds are highly soluble in water (0.66 M for Fc3 and 2.01 M for Fc4). When paired with anthraquinone-2,7-disulfonate as the anolyte, these zwitterionic ferrocenes exhibit excellent performance under neutral aqueous conditions. Voltage and energy efficiencies were ca. 88%, and the Coulombic efficiency was over 99% for both high-concentration redox flow batteries. We observed a difference in stability between the lengths of the zwitterionic chains, with Fc4 showing higher stability than Fc3, and the capacity decreased by ∼5% at the end of 20 cycles (∼1% per day). Density functional theory calculations revealed striking differences in the conformational properties between Fc3 and Fc4, with Fc4 retaining a linear structure of the side chain in solution, while Fc3 favored both linear and curved geometries.

Insights into the thermal decomposition of organometallic compound ferrocene carboxaldehyde as precursor for hematite nanoparticles synthesis

Abstract The paper deals with the thermal decomposition of organometallic compound ferrocene carboxaldehyde [(C5H4CHO)Fe(C5H5)] in oxidative atmosphere, which leads to pure hematite nanoparticles, studied with non-isothermal thermogravimetry (TG) protocol. Deconvolution method with Fraser-Suzuki fit function is adopted to resolve the complex multistep TG profiles into six different reaction steps. Step-wise reaction kinetic parameters (activation energy, reaction mechanism function, reaction rate) are estimated based on the mathematical analysis of the multi-heating rate TG data primarily following model-free (integral isoconversional) approach and using master-plot method. The estimated kinetic parameters are utilised to reconstruct the conversion plots which successfully resemble the experimentally observed ones. A plausible reaction process leading to hematite on thermal decomposition of ferrocene carboxaldehyde as the end product is discussed. A comparative discussion on the thermal decomposition of two ferrocene derivatives have been made. The novelty of the present work lies in successful deconvolution of complex TG profiles and hence obtaining the step-wise reaction kinetic parameters demonstrating different reaction mechanisms involved in the thermal synthesis of hematite nanoparticles starting from ferrocene carboxaldehyde which have no prior reporting. Further, a satisfactory agreement between the reconstructed and experimental decomposition profiles establishes the correctness of the applied modelling approach as well as the methodology adopted.

Palladium-catalyzed disilylation of 2-bromoarylferrocenes: An efficient approach to 1-Trimethylsilyl-2-(2-trimethylsilylaryl)ferrocenes

An unprecedented method for the palladium-catalyzed disilylation of 2-bromoarylferrocenes with hexamethyldisilane has been developed. The catalytic cycle is initiated by oxidative addition of 2-bromoarylferrocenes to Pd(0), followed by CH activation to form a reactive five-membered C,C-palladacycle. By using this protocol, a variety of disilylated ferrocene compounds were obtained in moderate to good yields.

Acid-Responsive Dissociation of Ferrocene Compounds: Diels-Alder Diene Equivalents for Selective Preparation of [60]Fullerene-Fused Bicyclo[2.2.1]hept-5-enes.

Herein, an unprecedented transformation of [60]fullerene with ferrocene compounds giving access to various [60]fullerene-fused bicyclo[2.2.1]hept-5-enes is presented. In the presence of an acid, ferrocene compounds undergo an unusual dissociation process and serve as Diels-Alder diene equivalents to react with [60]fullerene for the selective construction of a class of novel fullerene-fused bridged carbocyclic derivatives. The reaction is easy to perform and has a wide substrate scope as well as excellent functional group compatibility, representing a new application of ferrocene compounds in synthetic chemistry.

Toward Selective Anticancer Agents: Ferrocene‐Steroid Conjugates

AbstractThe medicinal chemistry of ferrocene is a diverse and rapidly growing field. In the search for selective and more efficient anticancer drugs, ferrocene‐steroid conjugates were explored in the past as a tool to target hormone‐dependent cancer cells, notably those of breast and prostate cancers. The mechanisms by which ferrocene compounds induce cytotoxicity are first examined, as well as how they can be exploited to design conjugates of ferrocene with steroid hormones potentially acting as selective antineoplastics. We sought to cover all relevant literature related to ferrocene‐steroid conjugates, from early works published in the 1970s up to now. Particular attention was bestowed upon research where the conjugates were tested for their antitumor potential.

Synthesis and investigation of anti-COVID19 ability of ferrocene Schiff base derivatives by quantum chemical and molecular docking

The recent outbreak of coronavirus disease (COVID-19) has rampaged the world with more than 236 million confirmed cases and over 4.8 million deaths across the world reported by the world health organization (WHO) till Oct 5, 2021. Due to the advent of different variants of coronavirus, there is an urgent need to identify effective drugs and vaccines to combat rapidly spreading virus varieties across the globe. Ferrocene derivatives have attained immense interest as anticancer, antifungal, antibacterial, and antiparasitic drug candidates. However, the ability of ferrocene as anti-COVID-19 is not yet explored. Therefore, in the present work, we have synthesized four new ferrocene Schiff bases (L1-L4) to understand the active sites and biological activity of ferrocene derivatives by employing various molecular descriptors, frontier molecular orbitals (FMO), electron affinity, ionization potential, and molecular electrostatic potential (MEP). A theoretical insight on synthesized ferrocene Schiff bases was accomplished by molecular docking, frontier molecular orbitals energies, active sites, and molecular descriptors which were further compared with drugs being currently used against COVID-19, i.e., dexamethasone, hydroxychloroquine, favipiravir (FPV), and remdesivir (RDV). Moreover, through the molecular docking approach, we recorded the inhibitions of ferrocene derivatives on core protease (6LU7) protein of SARS-CoV-2 and the effect of substituents on the anti-COVID activity of these synthesized compounds. The computational outcome indicated that L1 has a powerful 6LU7 inhibition of SARS-CoV-2 compared to the currently used drugs. These results could be helpful to design new ferrocene compounds and explore their potential application in the prevention and treatment of SARS-CoV-2.

Evaluation of graphene-ferrocene nanocomposite as multifunctional combustion catalyst in AP-HTPB propellant

A novel graphene-ferrocene nanocomposite (G-792-Fe) was designed, prepared and characterized systemically using SEM, EDS, FTIR, XPS and RAMAN methods. The as-synthesized G-792-Fe was used as a multifunctional combustion catalyst in ammonium perchlorate-hydroxyl terminated polybutadiene (AP-HTPB) propellant, and the combustion, anti-migration, safety and mechanical performances of AP-HTPB propellant were revealed. The results showed that anchoring on the surface of graphene can effectively inhibit the migration and volatilization of ferrocene compounds in AP-HTPB propellant. The excellent combustion catalytic performance of G-792-Fe on AP-HTPB propellant (burning rate of AP-HTPB propellant containing G-792-Fe increases from 13.87 mm·s−1 to 17.28 mm·s−1 at 15 MPa) is attributed to its positive effect on AP decomposition, which generates more gas-phase products beneficial to the combustion surface thermal feedback and the gaseous REDOX reaction. Additionally, the G-792-Fe presents positive effects on reducing the electrostatic sensitivity and improving the mechanical properties of AP-HTPB propellant. The ignition energy (E50) and the maximum tensile strength (σm) of AP-HTPB propellant containing G-792-Fe were increased by 24.4 mJ and 0.75 MPa respectively, compared with AP-HTPB propellant containing catocene (156.8 mJ and 1.26 MPa). The positive effects of G-792-Fe on safety and mechanical performances of AP-HTPB propellant can be due the outstanding electrical and mechanical properties of graphene-based material. Results of this study have implications concerning design and application of multifunctional combustion catalyst, which can improve the combustion performance, anti-migration performance, safety performance and mechanical properties of AP-HTPB propellant.

Selenated NHC-Pd(II) catalyzed Suzuki-Miyaura coupling of ferrocene substituted β-chloro-cinnamaldehydes, acrylonitriles and malononitriles for the synthesis of novel ferrocene derivatives and their solvatochromic studies

Suzuki-Miyaura coupling reaction between ferrocenyl/phenyl derivatives of (2-formyl-1-chlorovinyl)ferrocene, 3-chloro-3-ferrocenylacrylonitrile and (3-chloro-3-ferrocenylallylidene)malononitrile and arylboronic acid in the catalytic presence of a selenated NHC-Pd(II) full pincer complex was accomplished. Significantly, the couplings take place in water under normal atmospheric conditions, in contrast to many earlier reported Pd-catalysed reactions requiring inert atmosphere conditions. Solvatochromic studies of new ferrocene compounds revealed some interesting changes. Aggregation studies showed an increase of the absorbance with decrease of water content in the water/DMSO solvent mixture.

The organometallic ferrocene exhibits amplified anti-tumor activity by targeted delivery via highly selective ligands to αvβ3, αvβ6, or α5β1 integrins

High levels of reactive oxygen species (ROS) in tumors have been shown to exert anti-tumor activity, leading to the concept of ROS induction as therapeutic strategy. The organometallic compound ferrocene (Fc) generates ROS through a reversible one-electron oxidation. Incorporation of Fc into a tumor-targeting, bioactive molecule can enhance its therapeutic activity and enable tumor specific delivery. Therefore, we conjugated Fc to five synthetic, Arg-Gly-Asp (RGD)-based integrin binding ligands to enable targeting of the cell adhesion and signaling receptor integrin subtypes αvβ3, α5β1, or αvβ6, which are overexpressed in various, distinct tumors. We designed and synthesized a library of integrin-ligand-ferrocene (ILF) derivatives and showed that ILF conjugates maintained the high integrin affinity and selectivity of their parent ligands. A thorough biological characterization allowed us to identify the two most promising ligands, an αvβ3 (L2b) and an αvβ6 (L3b) targeting ILF, which displayed selective integrin-dependent cell uptake and pronounced ferrocene-mediated anti-tumor effects in vitro, along with increased ROS production and DNA damage. Hence, ILFs are promising candidates for the selective, tumor-targeted delivery of ferrocene to maximize its anti-cancer efficacy and minimize systemic toxicity, thereby improving the therapeutic window of ferrocene compared to currently used non-selective anti-cancer drugs.

Application of capillary electrophoresis technique for the enantioseparation of bioactive ferrocene-based compounds versus DFT calculated data.

Herein, a series of bioactive ferrocene-modified N-heterocycles with alkyl linkers was prepared in good to quantitative yields starting from easy accessible ferrocene alcohols and heterocycles under acidic or neutral (for imidazole) conditions in racemic forms. The analytical resolution of a number of bioactive racemic ferrocene azoles 1-6 (where azole = imidazole, pyrazole, and benzotriazole derivatives) into enantiomers was first carried out by CE using sulfobuthylether-β-CD (captisol) as a chiral selector. The analytical approaches to highly enantiomeric-enriched ferrocene derivatives are based on the formation of their inclusion complexes. The best chiral separation was achieved using zone CE in a quartz capillary. The ACE was used to evaluate the stability constants of captisol complexes with enantiomeric forms of two ferrocene derivatives 1, FcCHMe-imidazole, and 6, FcCHMe-benzotriazole. The optimal conditions for the resolution of the studied (R, S)-ferrocene compounds 1, 2, and 6 were predicted on the basis of the performed quantum chemical calculations and then implemented by the electrophoretic method. A high correlation between density functional theory calculation results and experimental electrophoresis data were obtained. Successful enantioseparation of racemic mixtures is of great importance for the characterization and further applications of drug candidates in enantiopure forms and in the development of clinical treatment. The advantages of the CE procedure make it possible to have important practical value and significance for determining the purity and enantiomeric excess of other ferrocene-containing compounds.

Chiral Oxazolinyl Hydroxyl Ferrocene Catalysts: Synthesis and Applications in Asymmetric Reactions

AbstractChiral oxazolinyl hydroxyl ferrocenes have been demonstrated as representative catalysts in enantioselective nucleophilic addition reactions in the last few decades. They have received much interest from chemists because of not only the numerous substitution patterns at their sandwich backbones, but also their superior catalytic activity in asymmetric transformations. Recent research has revealed that the planar chirality of these catalysts influences the stereochemistry of asymmetric products and the application scope in enantioselective reactions. Herein, we provide an intensive survey of chiral oxazolinyl hydroxyl ferrocene compounds, including the structures of chiral compounds already published, designed synthetic approaches for ferrocenes with different patterns, and their utilization in the enantioselective preparation of secondary alcohols using organozinc reagents.