Ferrocene

History

Ferrocene was first prepared unintentionally. In 1951, Pauson and Kealy at Duquesne University reported the reaction of cyclopentadienyl magnesium bromide and ferric chloride with the goal of oxidatively coupling the diene to prepare fulvalene. Instead, they obtained a light orange powder of "remarkable stability". A second group at British Oxygen also unknowingly discovered ferrocene. Miller, Tebboth and Tremaine were trying to synthesise amines from hydrocarbons such as cyclopentadiene and ammonia in a modification of the Haber process. They published this result in 1952 although the actual work was done three years earlier. The stability of the new organoiron compound was accorded to the aromatic character of the negatively charged cyclopentadienyls, but they were not the ones to recognize the η⁵ (pentahapto) sandwich structure.

Robert Burns Woodward and Geoffrey Wilkinson deduced the structure based on its reactivity. Independently Ernst Otto Fischer also came to the conclusion of the sandwich structure and started to synthesize other metallocenes such as nickelocene and cobaltocene.

The structure of ferrocene was confirmed by NMR spectroscopy and X-ray crystallography. Its distinctive "sandwich" structure led to an explosion of interest in compounds of d-block metals with hydrocarbons, and invigorated the development of the flourishing study of organometallic chemistry. In 1973 Fischer of the Technische Universität München and Wilkinson of Imperial College London shared a Nobel Prize for their work on metallocenes and other aspects of organometallic chemistry.

Structure and bonding

The carbon–carbon bond distances are 1.40 Å within the five-membered rings, and the Fe–C bond distances are 2.04 Å. Although X-ray crystallography (in the monoclinic space group) points to the Cp rings being in a staggered conformation, it has been shown through gas phase electron diffraction and computational studies that in the gas phase the Cp rings are eclipsed. The staggered conformation is believed to be most stable in the condensed phase due to crystal packing. The Point group of the staggered conformation is D_5d and the point group of the eclipsed conformation is D_5h.

The Cp rings rotate with a low barrier about the Cp_(centroid)–Fe–Cp_(centroid) axis, as observed by measurements on substituted derivatives of ferrocene using ¹H and ¹³C nuclear magnetic resonance spectroscopy. For example, methylferrocene (CH₃C₅H₄FeC₅H₅) exhibits a singlet for the C₅H₅ ring.

In terms of bonding, the iron center in ferrocene is usually assigned to the +2 oxidation state, consistent with measurements using Mössbauer spectroscopy. Each cyclopentadienyl (Cp) ring is then allocated a single negative charge, bringing the number of π-electrons on each ring to six, and thus making them aromatic. These twelve electrons (six from each ring) are then shared with the metal via covalent bonding. When combined with the six d-electrons on Fe²⁺, the complex attains an 18-electron configuration.

Synthesis and handling properties

The first reported syntheses of ferrocene were nearly simultaneous. Pauson and Kealy synthesised ferrocene using iron(III) chloride and a Grignard reagent, cyclopentadienyl magnesium bromide. Iron(III) chloride is suspended in anhydrous diethyl ether and added to the Grignard reagent, which is prepared by reacting cyclopentadiene with magnesium and bromoethane in anhydrous benzene. An iron(III) salt was chosen as they sought to couple the cyclopentadienyl moieties to form dihydrofulvalene and then fullvalene, but ferrocene was formed instead as the oxidative formation of dihydrofulvalene also produced iron(II) by reduction, which in turn reacts with the Grignard.

The other early synthesis of ferrocene was by Miller et al., who reacted metallic iron directly with gas-phase cyclopentadiene at elevated temperature. An approach using iron pentacarbonyl was also reported.

Fe(CO)₅ + 2 C₅H₆(g) → Fe(C₅H₅)₂ + 5 CO(g) + H₂(g)

More efficient preparative methods are generally a modification of the original transmetalation sequence using either commercially available sodium cyclopentadienide or freshly cracked cyclopentadiene deprotonated with potassium hydroxide and reacted with anhydrous iron(II) chloride in ethereal solvents. A modern modification of the Grignard approach is also known:

2 NaC₅H₅ + FeCl₂ → Fe(C₅H₅)₂ + 2 NaClFeCl₂·4H₂O + 2 C₅H₆ + 2 KOH → Fe(C₅H₅)₂ + 2 KCl + 6 H₂O2 C₅H₅MgBr + FeCl₂ → Fe(C₅H₅)₂ + 2 MgBrCl

Even some amine bases can be used for the deprotonation, though the reaction proceeds more slowly than when using stronger bases:

2 C₅H₆ + 2 (CH₃CH₂)₂NH + FeCl₂ → Fe(C₅H₅)₂ + 2 (CH₃CH₂)₂NH₂Cl

Direct transmetalation can also be used to prepare ferrocene from other metallocenes, such as manganocene:

FeCl₂ + Mn(C₅H₅)₂ → MnCl₂ + Fe(C₅H₅)₂

As expected for a symmetric and uncharged species, ferrocene is soluble in normal organic solvents, such as benzene, but is insoluble in water. Ferrocene is an air-stable orange solid that readily sublimes, especially upon heating in a vacuum. It is stable to temperatures as high as 400 °C. The following table gives typical values of vapor pressure of ferrocene at different temperatures:

With electrophiles

Ferrocene undergoes many reactions characteristic of aromatic compounds, enabling the preparation of substituted derivatives. A common undergraduate experiment is the Friedel-Crafts reaction of ferrocene with acetic anhydride (or acetyl chloride) in the presence of phosphoric acid as a catalyst.

Lithiation

Ferrocene reacts readily with butyllithium to give 1,1′-dilithioferrocene, which in turn is a versatile nucleophile. But reaction of ferrocene with t-BuLi produces monolithioferrocene only. These approaches are especially useful methods to introduce main group functionality, e.g. using S₈, chlorophosphines or chlorosilanes. The strained compounds undergo ring-opening polymerization.

Phosphorus derivatives

Many phosphine derivatives of ferrocenes are known and some are used in commercialized processes. Simplest and best known is 1,1′-bis(diphenylphosphino)ferrocene (dppf) prepared from dilithioferrocene. For example, in the presence of aluminium chloride Me₂NPCl₂ and ferrocene react to give ferrocenyl dichlorophosphine, whereas treatment with phenyldichlorophosphine under similar conditions forms P,P-diferrocenyl-P-phenyl phosphine. In common with anisole the reaction of ferrocene with P₄S₁₀ forms a diferrocenyl-dithiadiphosphetane disulfide.

Redox chemistry – the ferrocenium ion

Unlike the majority of organic compounds, ferrocene undergoes a one-electron oxidation at a low potential, around 0.5 V versus a saturated calomel electrode (SCE). This reversible oxidation has itself been used as standard in electrochemistry as Fc⁺/Fc = 0.64 V versus the standard hydrogen electrode. Some electron-rich organic compounds (e.g., aniline) also are oxidized at low potentials, but only irreversibly. Oxidation of ferrocene gives the stable blue-colored iron(III) cation Fe(C
5H
5)+
2 originally called ferricinium, but now more commonly ferrocenium (these terms denote the same ion, contrary to what one would expect from the fact that ferric and ferrous denote different ions of a single iron atom). On a preparative scale, the oxidation is conveniently effected with FeCl₃, to give the ion, which is often isolated as its PF−
6 salt. Alternatively, silver nitrate may be used as the oxidizer.

Ferrocenium salts are sometimes used as oxidizing agents, in part because the product ferrocene is fairly inert and readily separated from ionic products. Substituents on the cyclopentadienyl ligands alters the redox potential in the expected way: electron-withdrawing groups such as a carboxylic acid shift the potential in the anodic direction (i.e. made more positive), whereas electron-releasing groups such as methyl groups shift the potential in the cathodic direction (more negative). Thus, decamethylferrocene is much more easily oxidised than ferrocene and can even be oxidised to the corresponding dication. Ferrocene is often used as an internal standard for calibrating redox potentials in non-aqueous electrochemistry.

Stereochemistry

A variety of substitution patterns are possible with ferrocene including substition at one or both of the rings. The most common substitution patterns are 1-substituted (one substituent on one ring) and 1,1′-disubstituted (one substituent on each ring). Usually the rings rotate freely, which simplifies the isomerism. Disubstituted ferrocenes can exist as either 1,2-, 1,3- or 1,1′- isomers, none of which are interconvertible. Ferrocenes that are asymmetrically disubstituted on one ring are chiral – for example [CpFe(EtC₅H₃Me)] is chiral but [CpFe(C₅H₃Me₂)] is achiral. This planar chirality arises despite no single atom being a stereogenic centre. The substituted ferrocene shown at right (a 4-(dimethylamino)pyridine derivative) has been shown to be effective when used for the kinetic resolution of racemic secondary alcohols.

Applications of ferrocene and its derivatives

Ferrocene and its numerous derivatives have no large-scale applications, but have many niche uses that exploit the unusual structure (ligand scaffolds, pharmaceutical candidates), robustness (anti-knock formulations, precursors to materials), and redox (reagents and redox standards).

Fuel additives

Ferrocene and its derivatives are antiknock agents used in the fuel for petrol engines; they are safer than tetraethyllead, previously used. Petrol additive solutions containing ferrocene can be added to unleaded petrol to enable its use in vintage cars designed to run on leaded petrol. The iron-containing deposits formed from ferrocene can form a conductive coating on the spark plug surfaces.

Pharmaceutical

Ferrocene derivatives have been investigated as drugs. Only one drug has entered the clinic, Ferroquine, an antimalarial.

The anticancer activity of ferrocene derivatives was first investigated in the late 1970s, when derivatives bearing amine or amide groups were tested against lymphocytic leukemia. Some ferrocenium salts exhibit anticancer activity, but no compound has seen evaluation in the clinic. An experimental drug was reported which is a ferrocenyl version of tamoxifen. The idea is that the tamoxifen will bind to the estrogen binding sites, resulting in cytotoxicity. 7-chloro-N-(2-((dimethylamino)methyl)ferrocenyl)quinolin-4-amine Particular success has been seen for antimalarial activity.

As a ligand scaffold

Chiral ferrocenyl phosphines are employed as ligands for transition-metal catalyzed reactions. Some of them have found industrial applications in the synthesis of pharmaceuticals and agrochemicals. For example, the diphosphine 1,1′-bis(diphenylphosphino)ferrocene (dppf) is a valuable ligand for palladium-coupling reactions.

Derivatives and variations

Ferrocene analogues can be prepared with variants of cyclopentadienyl. For example, bisindenyliron and bisfluorenyliron.

Carbon atoms can be replaced by heteroatoms as illustrated by Fe(η⁵-C₅Me₅)(η⁵-P₅) and Fe(η⁵-C₅H₅)(η⁵-C₄H₄N) ("azaferrocene"). Azaferrocene arises from decarbonylation of Fe(η⁵-C₅H₅)(CO)₂(η¹-pyrrole) in cyclohexane. This compound on boiling under reflux in benzene is converted to ferrocene.

Because of the ease of substitution, many structurally unusual ferrocene derivatives have been prepared. For example, the penta(ferrocenyl)cyclopentadienyl ligand, features a cyclopentadienyl anion derivatized with five ferrocene substituents.

In hexaferrocenylbenzene, C₆[(η⁵-C₅H₄)Fe(η⁵-C₅H₅)]₆, all six positions on a benzene molecule have ferrocenyl substituents (R). X-ray diffraction analysis of this compound confirms that the cyclopentadienyl ligands are not co-planar with the benzene core but have alternating dihedral angles of +30° and −80°. Due to steric crowding the ferrocenyls are slightly bent with angles of 177° and have elongated C-Fe bonds. The quaternary cyclopentadienyl carbon atoms are also pyramidalized. Also, the benzene core has a chair conformation with dihedral angles of 14° and displays bond length alternation between 142.7 pm and 141.1 pm, both indications of steric crowding of the substituents.

The synthesis of hexaferrocenylbenzene has been reported using Negishi coupling of hexaiodidobenzene and diferrocenylzinc, using tris(dibenzylideneacetone)dipalladium(0) as catalyst, in tetrahydrofuran:

The yield is only 4%, which is further evidence consistent with substantial steric crowding around the arene core.

Materials chemistry

Ferrocene, a precursor to iron nanoparticles, can be used as a catalyst for the production of carbon nanotubes. The vinylferrocene from ferrocene can be made by a Wittig reaction of the aldehyde, a phosphonium salt and sodium hydroxide. The vinyl ferrocene can be converted into a polymer (polyvinylferrocene, PVFc), a ferrocenyl version of polystyrene (the phenyl groups are replaced with ferrocenyl groups). Another polymer which can be formed is poly(2-(methacryloyloxy)ethyl ferrocenecarboxylate), PFcMA. In addition to using organic polymer backbones, these pendant ferrocene units have been attached to inorganic backbones such as polysiloxanes, polyphosphazenes, and polyphosphinoboranes, (–PH(R)–BH₂–)_n, and the resulting materials exhibit unusual physical and electronic properties relating to the ferrocene / ferrocinium redox couple. Both PVFc and PFcMA have been tethered onto silica wafers and the wettability measured when the polymer chains are uncharged and when the ferrocene moieties are oxidised to produce positively charged groups. The contact angle with water on the PFcMA-coated wafers was 70° smaller following oxidation, while in the case of PVFc the decrease was 30°, and the switching of wettability is reversible. In the PFcMA case, the effect of lengthening the chains and hence introducing more ferrocene groups is significantly larger reductions in the contact angle upon oxidation.