Ferrocenes- Legendary Magic Bullets in Organometallic Chemistry-An Overview

Publication Ref No.: IJPRD/2010/PUB/ARTI/VOV-2/ISSUE-8/OCT/008 ISSN 0974 – 9446

International Journal of Pharma Research and Development – Online

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FERROCENES: LEGENDARY MAGIC BULLETS IN ORGANOMETALL IC CHEMISTRY-AN

OVERVIEW

Shashi Ravi Suman Rudrangi 1*, Dr. Vijaya Kumar. Bontha1,

Dr. Srinivas. Bethi2,Dr. M. Venkata Reddy3

1Department Of Pharmacy Jangaon Institute Of Pharmaceutical Sciences Yeshwanthapur, Jangaon- 506167

Warangal (Dist), Andhra Pradesh, India. 2Department Of Medicinal Chemistry, Talla Padamavathi College Of Pharmacy

Urus, Kareemabad-506002 Warangal (Dist), Andhra Pradesh, India. 3 Director, Sree Dattha Institute Of Pharmacy

(Former Director, Drugs Control Administration, A.P.) Sheriguda, Ibrahimpatnam, R.R (Dist), Andhra Pradesh, India.

Email: [email protected] ABSTRACT The development of organometallic chemistry took its course like an avalanche since the discovery of ferrocene and sandwich-type complexes and became one of the scientific success stories of the second half of the twentieth century. The unique sandwich structure of the ferrocenes has routed to enormous interest in the compounds of the transition metals with the hydrocarbons and also played a great role in the development of the flourishing study of organometallic chemistry. The applications of ferrocene compounds are not only a subject of increasing interest in academia, but also in industry. This work mainly focuses on the applications of ferrocenes and their derivatives in various fields of science.

Key Words: Ferrocenes, Organometallic chemistry, Sandwich compounds, Organo-transition metal chemistry. INTRODUCTION Ferrocenes are considered as one of the most important organometallic compounds that

have attributed to the rapid acceleration of organometallic Chemistry. [ 1] Though it was discovered over 50 years ago, the research into ferrocene-containing compounds continues

S.R.S.Rudrangi



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apace, vastly stimulated by their successful applications in bioorganometallic chemistry, catalysis and materials science. They are credited as the most thoroughly studied compounds in the modern Organo-transition metal chemistry and constitute one of the most important ligand architectures that have embraced a wide range of enantio-selective processes. [2-3] Ferrocene is a sandwich organometallic compound with the chemical formula Fe (C5H5)2. It is a prototypical metallocene that consists of two cyclo-pentadienyl rings that are bound on the opposite sides of the central Iron (Fe) atom. [4] The chemical structure of Ferrocene is illustrated in Fig.1 [5-6]

The redox chemistry of the iron centre and its unique structure is of the particular importance in the study of the chemistry of the ferrocenes. Because of the unique geometry, electronic properties, and the reactivity that the ferrocene provides, the ferrocene moiety has played a very significant role as the backbone of many ancillary ligands. [6]

Ferrocenes have many ideal properties besides their unique structure like the stability to the temperatures, low cost, and very high tolerance to oxygen, moisture, and various types of the reagents. [3]

APPLICATIONS OF FERROCENES: Though the discovery of Ferrocenes dates back to early 1950’s, the research into the ferrocenes and its derivatives continues apace, mainly due to the applications within the catalysis and materials science. [7, 8] The substitution of ferrocenes by various donor hetero atoms resulted in the formation of a gamut of ligands which are found to have a wide range of applications. [9]

1. ASYMMETRIC CATALYSIS: Ferrocene-based ligand catalysts have been credited for their successful application in a wide range of enantioselective processes. The reason behind their success in the asymmetric catalysis is their unique stereo-chemical aspects, their availability, and the vast variety of coordination modes that are used for the fine-tuning of the chemical and electrical properties. [3]

The ferrocene-based ligands have gained a lot of organometallic importance in the asymmetric catalysis due to their unique aspects of stereochemistry, availability, and the wide range of possibility for fine-tuning of various electronic and steric properties. Some examples of the ferrocene based ligands are illustrated in Fig.2. [3] 2. BIO-CHEMICAL APPLICATIONS: Ferrocenes also have a wide range of bio-chemical applications. They have very good redox characteristics. Avidin is a tetrameric glycoprotein found in the oviducts of reptiles, birds, and the amphibians that binds the biotin with a very high affinity. Ferrocene derivatives can be coupled to the glycoprotein Avidin, through a flexible spacer molecule and results in the formulation of a conjugate with the reversible redox characteristic properties of ferrocenes and the biotin-binding properties of the avidin. [10]

These Fc-Av conjugates, Fig.3, combine biochemical and electrochemical properties aiding in biochemical applications. The Fc-Av conjugates would be the vital elements in the electrochemical immunosensors employing enzyme fragments or redox enzymes as the electrochemical label for antibodies. They can be used for stable immobilisation of biotinylated redox enzymes on the electrodes to generate a large range of electrochemical enzyme sensors.



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3. CORROSION INHIBITORS: Ferrocenes are also applied in the field of corrosion science. It is reported that the ferrocene and its derivatives such as 2-benzimidazolylthioacetylferrocene (BIM Fc), 1, 1’-diformylferrocene (Diformyl Fc), and 1, 1’-diacetylferrocene (Diacetyl Fc), Fig.4, are used as the inhibitors of corrosion. By using the impedance and the polarization resistance (Rp) techniques, these compounds were tested for their inhibition property in HCl and H2SO4 solutions. It was found that these derivatives were stable in both solutions, without producing any change in the colour or precipitation. [11]

4. FUEL ADDITIVES: Ferrocenes are widely known for their use in the fuel and the plastic industries as fuel additives. They are used as smoke reducing additives for the hydrocarbon fuels. They have been recently employed in the preparation of the polyvinylchloride plastics as smoke suppression additives. This results in a dramatic reduction in the production of smoke upon the combustion of polyurethane. [12]

Ferrocenes or their derivatives are used in the range 0.25 to 0.5 %, by weight, based on the polyvinyl chloride polymer to get the best results. Some of the examples of the ferrocene derivatives that are used as smoke suppressants include ethyldicyclopentadienyl iron, acetyldicyclopentadienyl iron, butyryl dicyclopentadienyl iron, N, N-dimethylaminomethyl cyclopentadienyl iron. High molecular weight containing ferrocenes like butyldecyl ferrocene, hexadecyl ferrocene, lauroyl ferrocene afford the advantage of lower volatile loss of compound upon storage of polymer product. [12]

5. OPTICAL FIBER GAS SENSING: It is reported that the ferrocene-based polymers are incorporated as gas sensing

elements in the optical fiber devices. Some of the applications of these sensors are in explosive gas monitoring, hazardous waste analysis, pollution detection, and exhaust analysis of the combustion and internal engines. [13]

6. GOLD CHEMISTRY: Ferrocene derivatives are the most widely studied organometallic ligands that provide a convenient route to the synthesis of heterometallic complexes. [9] Ferrocenes are very well known for their versatile building block properties in the synthesis of a huge number of complexes and ligands with many interesting physical and chemical properties. The ferrocene based ligands are very flexible and form a large number of Gold (I) and Gold (III) complexes, Fig.5, with different structural frameworks. Examples include the coordination of ferrocene and mono- or di- substituted diphenylphosphino, diphenylthiophosphoryl dithiocarbamate and thiolate derivatives. [14]

7. DERIVATIZATION IN ANALYTICAL CHEMISTRY: The highly established chemistry of ferrocenes that allows an easy and rapid access to a bank of reagents and derivatives has given them a considerable role in the field of analytical chemistry. Ferrocene-based derivatization of various functional groups and detection techniques is of high interest in particular. [15]

The chemistry of ferrocenes is well explored and a wide range of ferrocene derivatives are easily accessible through the established synthetic routes. The ferrocenes allow the use of a large variety of detection techniques like UV/Visible absorption spectroscopy, atomic spectroscopy, atomic absorption spectroscopy (AAS), inductively coupled plasma (ICP) excitation with optical emission spectroscopy (OES) or mass spectrometry (MS), electron impact or



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electrospray ionization (ESI) MS, and the electrochemical detection (ECD) techniques that include voltammetry or amperometry. [16-18]

The reversible redox behaviour of the ferrocene/ferrocinium couple at low potentials is a unique property and finds widespread application. [16] Electrochemical detection technique is a sensitive technique and detects the minor differences in electrode potentials that allow the analysis of differentially labeled analytes. By ECD, many ferrocene labels can be determined in a single measurement. Detection of DNA and RNA and the immunoassays are to date the main applications of ECD coupled with Capillary electrophoresis, subsequent to the ferrocene-based derivatization. [20-21]

8. BIOORGANOMETALLIC CHEMISTRY: Anti-Cancer Drugs: Breast cancer is the most common cancer among the women and affects about one in eight women in the western countries. Tamoxifen is the primary drug that is used to treat the breast cancers which test positive for the estradiol receptor (ER). Although, Tamoxifen and its congeners are well tolerated over time and increase the survival rate of the patients, it has some troublesome side effects and other drawbacks. For example, resistance to the drug can develop during the long-term therapy. The drug even increases the risks of uterine cancer and blood clotting in the lungs. [22, 23] About one-third of all the breast cancers are caused by hormone independent tumors, but unluckily Tamoxifen is not effective against these tumors. In fact, there are two known estrogen receptors (ERα and ERβ) which act via different mechanisms. ERα involves in proliferation of tumors which respond to Tamoxifen, whereas ERβ is implicated in

proliferation of tumors which do not respond to it. [24] Several hydroxyl-substituted ferrocifens’ effects were studied by the Paris researchers on the proliferation of two lines of breast tumor cells which were mediated by ERα and ERβ respectively. While Tamoxifen was active only against ERα receptor, three of the ferrocifens exhibited a strong antiproliferative effect in the both cell lines. Ferrocifens are the first molecules that are shown to be active against both hormone-dependent and hormone-independent breast cancer cells. In the experiments carried out by Jaouen and his collaborators, they have observed that hydroxyferrocifens strongly inhibit the proliferation of ovarian cells and kidney cancer but slightly lesser antiproliferative effect in the prostate and uterine cancer cells. In contrast, hydroxytamoxifen is inactive in all these types of cells. The most active hydroxyl ferrocifens exhibits less acute toxicity than Tamoxifen. [25]

The structures of Tamoxifen and Ferrocifen are illustrated in the Fig.6 [22, 23] Antimalarial Drugs:

Malaria is the disease caused by a parasite, Plasmodium falciparum. Several drugs like Chloroquine are used against the malarial parasite, but the problem is that there is an increasing resistance to these drugs. As the parasite needs iron for its development inside the red blood cells, Brocard and co-workers, in late 1990’s combined the poison (Chloroquine) and bait (Ferrocene) in the same molecule. They just inserted a ferrocenyl group into the side chain of Chloroquine, producing a hybrid compound called Ferroquine, which is more potent than Chloroquine. Tests have also shown that ferroquine is effective against both Chloroquine-sensitive and Chloroquine-resistant strains of Plasmodium. Ferroquine is a promising analogue of Chloroquine. Fig.7 [26]



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Antibiotics: In 1970’s, E. I. Edward’s research group synthesised a series of antibiotics conjugated with the ferrocenes that include Ferrocenyl-penicillin, Ferrocenyl-cephalosporin, and Ferrocenyl-hybrid of penicillin and cephalosporin, Fig.8 [27-29] CONCLUSION: It would be fair to say that organometallic chemistry still remains a young and lively discipline in spite of the fact that the key discovery of ferrocene, which sparked it all off, was made more than half a century ago. The traditional boundaries between organic and inorganic chemistry gradually disappeared and a rebirth of the current highly important field of homogeneous catalysis occurred, basing on this development. Although many of the ligands and substitution patterns are now well-established, there does seem enormous scope for further growth of the ferrocenyl chemistry.

REFERENCES: 1. Pamela ST, Wayne EJ , Jr., Clifford EM, Stanley MW, The Synthesis and Characterization of Ferrocene, A Modern Iterative approach to a Classical Organometallic Laboratory Experiment, Presented at the 210th National Meeting of the American Chemical Society, Chicago, IL, 1995, paper CHED 51. 2. Bao XY , Yan X, Fei W, Yong F, Mao PS, Synthesis, Structures and electrochemistry of two Schiff base compounds bearing Phenylferrocene, Inorganic Chemistry Communications, 8, 2005, 44-47. 3. Ramon GA, Javier A, Juan CC, Recent Applications of Chiral Ferrocene Ligands in Asymmetric Catalysis, Angew. Chem. Int. Ed. 45, 2006, 7644-7715.

4. R. Dagani, Fifty Years of Ferrocene Chemistry, Chemical and Engineering News, 79, 49, 2001, 37-38. 5. Samuel AM, John AT, John FT, Dicyclopentadienyl-iron, J. Chem. Soc., 114, 1952, 632-635. 6. Robert CJA, Nicholas JL, Monodentate Ferrocene Donor Ligands, Ferrocenes: Ligands, Materials and Biomolecules, John Wiley and Sons, 2008, 3-6. 7. Togni A, Halterman RL, Ed, Metallocenes, Wiley-VCH Verlag GmbH, Weinheim, Germany, 1998. 8. Long NJ, Metallocenes: An Introduction to Sandwich Complexes, Blackwell Science, Oxford, UK, 1998. 9. Togni A, Hayashi T, Ed, Ferrocenes: Homogeneous Catalysis, Organic Synthesis, Materials Science, VCH, Weinheim, Germany, 1995. 10. Celestino P, Andreas G, Louis T, Ferrocene–avidin conjugates for bio-electrochemical applications, Biosensors & Bioelectronics, 15, 2000, 431-438. 11. Morad MS, Sarhan AAO, Application of some ferrocene derivatives in the field of corrosion inhibition, Corrosion Science, 50, 2007, 744-753. 12. John JK, Polyvinyl Chloride Composition Containing Ferrocene Smoke Suppressant Additives, 1977, U. S. Pat. No. 4,049,618. 13. Rafaei Md, Loren IE, Shadaram M, Application of ferrocene-based polymers in optical fiber gas sensing, Chemical and Biological Sensing, Proc, 4036, 2000, 123-131. 14. Concepción MG, Antonio L, Gold Chemistry with Ferrocene Derivatives as Ligands, Gold Bulletin, 32, 3, 1999, 90-95. 15. Bettina S, Uwe K, Ferrocene-based derivatization in Analytical chemistry, Anal Bioanal Chem, 390,2008, 181-200. 16. Cais M, Slovin E, Snarsky L, J Organomet Chem, 160, 1978, 223–230. 17. Wilson R, Schiffrin DJ, Anal Chem, 68, 1996, 1254–1257.



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18. Rosman KJ, Taylor PDP, Pure Appl Chem, 70, 1998, 217–235 19. Bond AM, McLennan EA, Stojanovic RS, Thomas FG, Anal Chem, 59, 1987, 2853–2860 20. Brazill SA, Kim PH, Kuhr WG, Anal Chem, 73, 2001, 4882–4890 21. Lim T-K, Nakamura N, Ikehata M, Matsunaga T Electrochemistry, 68, 2000, 872–874 22. Siden T, Benedicte D, Jacqueline V, Gerard J, Facile route to ferrocifens, 1-[4-(2-dimethylamino-ethoxy)]-1-(phenyl-2-ferrocenyl-but-1-ene), first organometallic analogue of Tamoxifen, by the McMurry reaction. Journal of Organometallic Chemistry, 541, 1997, 355-361. 23. Gérard J, Siden T, Anne V, Leclercq G, Michael JM, The First Organometallic Selective Estrogen Receptor Modulators (SERMs) and

Their Relevance to Breast Cancer, Current Medicinal Chemistry, 11, 2004, 2505-2517. 24. Siden T, Kaloun EB, Vessieres A, Laios I, Leclercq G, Jaouen G, J. Organomet. Chem., 350, 2002, 643-644. 25. Siden T, Vessieres A, Cabestaing C, Laios I, Provot C, Jaouen G, J. Organomet. Chem., 500, 2001, 637-639. 26. Delhaes L, Abessolo H, Biot C, Berry L, Delcourt P, Maciejewski L et al, Parasitol. Res., 87, 2001, 239. 27. Edwards EI, Epton R, Marr G, J. Organomet. Chem. 85, 1975, C23–C25 28. Edwards EI, Epton R, Marr |G, J. Organomet. Chem. 122, 1976, C49–C53 29. Edwards EI, Epton R, Marr G, J. Organomet. Chem. 168, 1979, 259–272

FIGURES:

Fig.1: Chemical Structure of Ferrocene

Fig.2: Some chiral ferrocene ligands with applicati ons in asymmetric catalysis



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Fig.3: Ferrocene-Avidin Conjugate (Fc-Av)

Fig.4: Ferrocenes as corrosion inhibitors

1 2-benzimidazolylthioacetylferrocene

1,1’-diformylferrocene

Fig.5: Gold complexes with Ferrocene ligands



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Fig.6: Structure of Tamoxifen and Ferrocifen

Fig.7: Structure of Chloroquine and Ferroquine

Fig.8: Structures of Ferrocenyl antibiotics



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…End…

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Ferrocenes- Legendary Magic Bullets in Organometallic Chemistry-An Overview