Ferrocene

Ferrocene is an organometallic compound with the formula Template:Chem2. The molecule is a complex consisting of two cyclopentadienyl rings sandwiching a central iron atom. It is an orange solid with a camphor-like odor that sublimes above room temperature, and is soluble in most organic solvents. It is remarkable for its stability: it is unaffected by air, water, strong bases, and can be heated to 400 °C without decomposition. In oxidizing conditions it can reversibly react with strong acids to form the ferrocenium cation Template:Chem2.<ref name="werner2012" /> Ferrocene and the ferrocenium cation are sometimes abbreviated as Fc and Template:Chem2 respectively.

The first reported synthesis of ferrocene was in 1951. Its unusual stability puzzled chemists, and required the development of new theory to explain its formation and bonding. The discovery of ferrocene and its many analogues, known as metallocenes, sparked excitement and led to a rapid growth in the discipline of organometallic chemistry. Geoffrey Wilkinson and Ernst Otto Fischer, both of whom worked on elucidating the structure of ferrocene, later shared the 1973 Nobel Prize in Chemistry for their work on organometallic sandwich compounds. Ferrocene itself has no large-scale applications, but has found more niche uses in catalysis, as a fuel additive, and as a tool in undergraduate education.

History

Discovery

Ferrocene was discovered by accident twice. The first known synthesis may have been made in the late 1940s by unknown researchers at Union Carbide, who tried to pass hot cyclopentadiene vapor through an iron pipe. The vapor reacted with the pipe wall, creating a "yellow sludge" that clogged the pipe. Years later, a sample of the sludge that had been saved was obtained and analyzed by Eugene O. Brimm, shortly after reading Kealy and Pauson's article, and was found to consist of ferrocene.<ref name=werner2012/><ref name = Pauson2001 />

The second time was around 1950, when Samuel A. Miller, John A. Tebboth, and John F. Tremaine, researchers at British Oxygen, were attempting to synthesize amines from hydrocarbons and nitrogen in a modification of the Haber process. When they tried to react cyclopentadiene with nitrogen at 300 °C, at atmospheric pressure, they were disappointed to see the hydrocarbon react with some source of iron, yielding ferrocene. While they too observed its remarkable stability, they put the observation aside and did not publish it until after Pauson reported his findings.<ref name=werner2012/><ref name=miller/><ref name=laszloRmon/> Kealy and Pauson were later provided with a sample by Miller et al., who confirmed that the products were the same compound.<ref name = Pauson2001 />

In 1951, Peter L. Pauson and Thomas J. Kealy at Duquesne University attempted to prepare fulvalene (Template:Chem2) by oxidative dimerization of cyclopentadiene (Template:Chem2). To that end, they reacted the Grignard compound cyclopentadienyl magnesium bromide in diethyl ether with ferric chloride as an oxidizer.<ref name=werner2012/> However, instead of the expected fulvalene, they obtained a light orange powder of "remarkable stability", with the formula Template:Chem2.<ref name = Pauson2001 /><ref name=pauson/>

Determining the structure

File:Ferrocene kealy.svg

Pauson and Kealy's original (incorrect) notion of ferrocene's molecular structure.<ref name=pauson/>

Pauson and Kealy conjectured that the compound had two cyclopentadienyl groups, each with a single covalent bond from the saturated carbon atom to the iron atom.<ref name=werner2012/> However, that structure was inconsistent with then-existing bonding models and did not explain the unexpected stability of the compound, and chemists struggled to find the correct structure.<ref name=laszloRmon/><ref name=federman/>

The structure was deduced and reported independently by three groups in 1952.<ref name=werner2008/> Robert Burns Woodward, Geoffrey Wilkinson, et al. observed that the compound was diamagnetic and nonpolar.<ref name="wilk52" /> A few months later they described its reactions as being typical of aromatic compounds such as benzene.<ref>Template:Cite journal</ref> The name ferrocene was coined by Mark Whiting, a postdoc with Woodward.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Ernst Otto Fischer and Wolfgang Pfab also noted ferrocene's diamagneticity and high symmetry. They also synthesize nickelocene and cobaltocene and confirmed they had the same structure.<ref name="fischer" /> Fischer described the structure as Doppelkegelstruktur ("double-cone structure"), although the term "sandwich" came to be preferred by British and American chemists.<ref name="okuda" /> Philip Frank Eiland and Raymond Pepinsky confirmed the structure through X-ray crystallography and later by NMR spectroscopy.<ref name="laszloRmon" /><ref name="eiland52" /><ref name="dunitz53" /><ref name="dunitz56" />

The "sandwich" structure of ferrocene was shockingly novel and led to intensive theoretical studies. Application of molecular orbital theory with the assumption of a Fe²⁺ centre between two cyclopentadienide anions Template:Chem2 resulted in the successful Dewar–Chatt–Duncanson model, allowing correct prediction of the geometry of the molecule as well as explaining its remarkable stability.<ref name=mingos/><ref name=mehr/>

Impact

The discovery of ferrocene was considered so significant that Wilkinson and Fischer shared the 1973 Nobel Prize in Chemistry "for their pioneering work, performed independently, on the chemistry of the organometallic, called sandwich compounds".<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Structure and bonding

Mössbauer spectroscopy indicates that the iron center in ferrocene should be assigned the +2 oxidation state. Each cyclopentadienyl (Cp) ring should then be allocated a single negative charge. Thus ferrocene could be described as iron(II) bis(cyclopentadienide), Template:Chem2.

Each ring has six π-electrons, which makes them aromatic according to Hückel's rule. These π-electrons are then shared with the metal via covalent bonding. Since Fe²⁺ has six d-electrons, the complex attains an 18-electron configuration, which accounts for its stability. In modern notation, this sandwich structural model of the ferrocene molecule is denoted as Template:Chem2, where η denotes hapticity, the number of atoms through which each ring binds.

The carbon–carbon bond distances around each five-membered ring are all 1.40 Å, and all Fe–C bond distances are 2.04 Å. 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.<ref>Template:Cite journal</ref>

From room temperature down to 164 K, X-ray crystallography yields the monoclinic space group; the cyclopentadienide rings are a staggered conformation, resulting in a centrosymmetric molecule, with symmetry group D_5d.<ref name=eiland52/> However, below 110 K, ferrocene crystallizes in an orthorhombic crystal lattice in which the Cp rings are ordered and eclipsed, so that the molecule has symmetry group D_5h.<ref name=seiler/> In the gas phase, electron diffraction<ref name=haal68/> and computational studies<ref name=coriani/> show that the Cp rings are eclipsed. While ferrocene has no permanent dipole moment at room temperature, between 172.8 and 163.5 K the molecule exhibits an "incommensurate modulation", breaking the D₅ symmetry and acquiring an electric dipole.<ref>Template:Cite journal</ref>

In solution, eclipsed D_5h ferrocene was determined to dominate over the staggered D_5d conformer, as suggested by both Fourier-transform infrared spectroscopy and DFT calculations.<ref>Template:Cite journal</ref>

Synthesis

Early methods

The first reported syntheses of ferrocene were nearly simultaneous. Pauson and Kealy synthesised ferrocene using iron(III) chloride and cyclopentadienyl magnesium bromide.<ref name=pauson/> A redox reaction produces iron(II) chloride. The formation of fulvalene (the intended outcome), does not occur.<ref name = Pauson2001>Template:Cite journal</ref>

File:Kealy and Pauson synthesis of ferrocene v2.jpg

File:Miller Ferrocen Synthese.svg

The Miller et al.<ref name=miller/> approach to ferrocene

Another early synthesis of ferrocene was by Miller et al.,<ref name=miller/> who treated metallic iron with gaseous cyclopentadiene at elevated temperature.<ref>Template:Cite journal</ref> An approach using iron pentacarbonyl was also reported.<ref>Template:Cite book</ref>

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

Via alkali cyclopentadienide

More efficient preparative methods are generally a modification of the original transmetalation sequence using either commercially available sodium cyclopentadienide<ref name = orgsyn /> or freshly cracked cyclopentadiene deprotonated with potassium hydroxide<ref>Template:Cite book</ref> and reacted with anhydrous iron(II) chloride in ethereal solvents.

Modern modifications of Pauson and Kealy's original Grignard approach are known:

• Using sodium cyclopentadienide: 2 NaC₅H₅ + FeCl₂ → Fe(C₅H₅)₂ + 2 NaCl
• Using freshly-cracked cyclopentadiene: FeCl₂·4H₂O + 2 C₅H₆ + 2 KOH → Fe(C₅H₅)₂ + 2 KCl + 6 H₂O
• Using an iron(II) salt with a Grignard reagent: 2 C₅H₅MgBr + FeCl₂ → Fe(C₅H₅)₂ + 2 MgBrCl

Even some amine bases (such as diethylamine) can be used for the deprotonation, though the reaction proceeds more slowly than when using stronger bases:<ref name=orgsyn>Template:OrgSynth</ref>

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

Direct transmetalation can also be used to prepare ferrocene from some other metallocenes, such as manganocene:<ref>Template:Cite journal</ref>

FeCl₂ + Mn(C₅H₅)₂ → MnCl₂ + Fe(C₅H₅)₂

Properties

File:Ferrocen.jpg

Crystals of ferrocene after purification by vacuum sublimation

Ferrocene is an air-stable orange solid with a camphor-like odor.<ref name=SC06/> As expected for a symmetric, uncharged species, ferrocene is soluble in normal organic solvents, such as benzene, but is insoluble in water. It is stable to temperatures as high as 400 °C.<ref name=SC06>Template:Cite book</ref>

Ferrocene readily sublimes, especially upon heating in a vacuum. Its vapor pressure is about 1 Pa at 25 °C, 10 Pa at 50 °C, 100 Pa at 80 °C, 1000 Pa at 116 °C, and 10,000 Pa (nearly 0.1 atm) at 162 °C.<ref>Template:Cite journal</ref><ref name=fulem2013>Template:Cite journal</ref>

Reactions

File:FcGen'l.png

Important ferrocene reactions

Aromatic substitution

Ferrocene is an aromatic substance. Electrophiles typically substitute onto, rather than add to, the cyclopentadienyl ligands. For example, a common undergraduate experiment performs Friedel-Crafts acylation with acetic anhydride and a phosphoric acid catalyst. Just as this reagent mixture converts benzene to acetophenone, it converts ferrocene to acetylferrocene.<ref>Template:Cite journal</ref>

In the presence of aluminium chloride, Me₂NPCl₂ and ferrocene react to give ferrocenyl dichlorophosphine,<ref>Template:Cite journal</ref> whereas treatment with phenyldichlorophosphine under similar conditions forms P,P-diferrocenyl-P-phenyl phosphine.<ref>Template:Cite journal</ref> Vilsmeier-Haack formylation using formylanilide and phosphorus oxychloride gives ferrocenecarboxaldehyde.<ref name=Rausch/>

Unsubstituted ferrocene undergoes aromatic substitution more easily than benzene, because electrophiles can attack the metal ion before rearranging to the Wheland intermediate.<ref name=GE1287>Template:Greenwood&Earnshaw1st</ref> Thus ferrocene reacts with the weak electrophile P₄S₁₀ to form a diferrocenyl-dithiadiphosphetane disulfide.<ref>Template:Cite journal</ref> Mannich conditions suffice to iminylate ferrocene unto N,N-dimethylaminomethylferrocene.Template:Cn

Superacidic protonation does not complete aromatic substitution, but rather traps the unrearranged bent intermediate hydrido salt, [Cp₂FeH]PF₆.<ref>Template:Cite journal</ref> Strongly oxidizing electrophiles, such as halogens and nitric acid, neither rearrange to a Wheland intermediate nor coordinate to iron, instead generating ferrocenium salts (see Template:Slink).<ref name=GE1287/>

In accordance with cluster compound theory, ferrocene's rings behave as a single delocalized π system. Electronic perturbations to one ring propagate to the other. For example, introduction of a deactivating aldehyde group on one ring inhibits formylation of the other ring as well.<ref name=Rausch>Template:Cite journal</ref>

Metallation

Ferrocene readily metallates. Ferrocene reacts with butyllithium to give [[1,1'-Dilithioferrocene|1,1Template:Prime-dilithioferrocene]], which is a versatile nucleophile. In combination with butyllithiium, tert-butyllithium produces monolithioferrocene.<ref>Template:Cite journal</ref> Likewise ferrocene mercurates to give ferrocendiyl dimercuriacetate.<ref name=GE1288>Template:Greenwood&Earnshaw1st</ref>

Further reaction gives the nitro, halo-, and borono derivatives.<ref name=GE1288/>

Redox chemistry

File:Biferrocene.svg

The one-electron oxidized derivative of biferrocene has attracted much research attention.

Ferrocene undergoes a one-electron oxidation at around 0.4 V versus a saturated calomel electrode (SCE), becoming ferrocenium.<ref name=federman/> This reversible oxidation has been used as standard in electrochemistry as Fc⁺/Fc = 0.64 V versus the standard hydrogen electrode,<ref>Template:Cite journal</ref> however other values have been reported.<ref>Template:Citation</ref><ref>Template:Cite journal</ref> Ferrocenium tetrafluoroborate is a common reagent.<ref>Template:Cite journal</ref> The remarkably reversible oxidation-reduction behaviour has been extensively used to control electron-transfer processes in electrochemical<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and photochemical<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> systems.

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.<ref>Template:Cite journal</ref> Ferrocene is often used as an internal standard for calibrating redox potentials in non-aqueous electrochemistry.

Stereochemistry of substituted ferrocenes

File:Planar chiral ferrocene derivative.svg

A planar chiral ferrocene derivative

Disubstituted ferrocenes can exist as either 1,2-, 1,3- or 1,1Template:Prime- isomers, none of which are interconvertible. Ferrocenes that are asymmetrically disubstituted on one ring are chiral – for example [CpFe(EtC₅H₃Me)]. 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.<ref>Template:Cite journal</ref> Several approaches have been developed to asymmetrically 1,1Template:Prime-functionalise the ferrocene.<ref>Template:Cite journal</ref>

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).

Ligand scaffolds

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|1,1Template:Prime-bis(diphenylphosphino)ferrocene]] (dppf) is a valued ligand for palladium-coupling reactions and Josiphos ligand is useful for hydrogenation catalysis.<ref name="H-U. Blaser 2002">Template:Cite journal</ref> They are named after the technician who made the first one, Josi Puleo.<ref>Template:Cite book</ref><ref name=Stepnicka>Template:Cite book</ref>

File:Josiphos.png

Josiphos ligand.<ref name="H-U. Blaser 2002"/>

Fuel additives

Ferrocene and its derivatives are antiknock agents used in the fuel for petrol engines. They are safer than previously used tetraethyllead.<ref>Template:Cite conference</ref> Petrol additive solutions containing ferrocene can be added to unleaded petrol to enable its use in vintage cars designed to run on leaded petrol.<ref>Template:Cite patent</ref> The iron-containing deposits formed from ferrocene can form a conductive coating on spark plug surfaces. Ferrocene polyglycol copolymers, prepared by effecting a polycondensation reaction between a ferrocene derivative and a substituted dihydroxy alcohol, has promise as a component of rocket propellants. These copolymers provide rocket propellants with heat stability, serving as a propellant binder and controlling propellant burn rate.<ref>Template:Cite patent</ref>

Ferrocene has been found to be effective at reducing smoke and sulfur trioxide produced when burning coal. The addition by any practical means, impregnating the coal or adding ferrocene to the combustion chamber, can significantly reduce the amount of these undesirable byproducts, even with a small amount of the metal cyclopentadienyl compound.<ref>Template:Cite patent</ref>

Pharmaceuticals

File:Ferroceron.svg

Ferrocerone

Ferrocene derivatives have been investigated as drugs,<ref>Template:Cite journal</ref> with one compound Template:Ill approved for use in the USSR in the 1970s as an iron supplement, though it is no longer marketed today.<ref>Template:Cite journal</ref> Only one drug has entered clinical trials in recent years, Ferroquine (7-chloro-N-(2-((dimethylamino)methyl)ferrocenyl)quinolin-4-amine), an antimalarial,<ref name="BiotNosten2011">Template:Cite journal Template:Open access</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> which has reached Phase IIb trials.<ref>Template:Cite journal</ref> Ferrocene-containing polymer-based drug delivery systems have been investigated.<ref>Template:Cite journal</ref>

File:Ferroquine.png

Ferroquine

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.<ref name=":0">Template:Cite journal</ref> Some ferrocenium salts exhibit anticancer activity, but no compound has seen evaluation in the clinic.<ref name=Babin>Template:Cite journal</ref> Ferrocene derivatives have strong inhibitory activity against human lung cancer cell line A549, colorectal cancer cell line HCT116, and breast cancer cell line MCF-7.<ref>Template:Cite patent</ref> An experimental drug was reported which is a ferrocenyl version of tamoxifen.<ref name = top2003 /> The idea is that the tamoxifen will bind to the estrogen binding sites, resulting in cytotoxicity.<ref name=top2003>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Ferrocifens are exploited for cancer applications by a French biotech, Feroscan, founded by Pr. Gerard Jaouen.

Solid rocket propellant

Ferrocene and related derivatives are used as powerful burn rate catalysts in ammonium perchlorate composite propellant.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Derivatives and variations

Ferrocene analogues can be prepared with variants of cyclopentadienyl. For example, bisindenyliron and bisfluorenyliron.<ref name=Stepnicka/>

Various ferrocene derivatives where cyclopentadienyl has been replaced by related ligands

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.<ref>Template:Cite journal</ref> This compound on boiling under reflux in benzene is converted to ferrocene.<ref>Template:Cite journal</ref>

The bis(benzene)iron(II) cation, isoelectronic with bis(benzene)chromium, is unstable against nucleophilic attack, and decomposes "instantaneously" in acetonitrile. It can be observed, however, in metastable nitromethane solution.<ref>Template:Cite journal</ref>

Because of the ease of substitution, many structurally unusual ferrocene derivatives have been prepared. For example, the penta(ferrocenyl)cyclopentadienyl ligand,<ref>Template:Cite journal</ref> features a cyclopentadienyl anion derivatized with five ferrocene substituents.

Penta(ferrocenyl)cyclopentadienyl ligand

File:Hexaferrocenylbenzene-3D-sticks.png

Structure of hexaferrocenylbenzene

In hexaferrocenylbenzene, C₆[(η⁵-C₅H₄)Fe(η⁵-C₅H₅)]₆, all six positions on a benzene molecule have ferrocenyl substituents (R).<ref name = "hexaferrocenylbenzene">Template:Cite journal</ref> 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 hexaiodobenzene and diferrocenylzinc, using tris(dibenzylideneacetone)dipalladium(0) as catalyst, in tetrahydrofuran:<ref name = "hexaferrocenylbenzene" />

Hexaferrocenylbenzene synthesis by Negishi coupling

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

Materials chemistry

File:Wettability of a silica surface with a bound ferrocene-substituted polymer.jpg

Strands of an uncharged ferrocene-substituted polymer are tethered to a hydrophobic silica surface. Oxidation of the ferrocenyl groups produces a hydrophilic surface due to electrostatic attractions between the resulting charges and the polar solvent.<ref name = Pietschnig />

Ferrocene, a precursor to iron nanoparticles, can be used as a catalyst for the production of carbon nanotubes.<ref>Template:Cite journal</ref> Vinylferrocene can be converted to (polyvinylferrocene, PVFc), a ferrocenyl version of polystyrene (the phenyl groups are replaced with ferrocenyl groups). Another polyferrocene 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.<ref name = Pietschnig>Template:Cite journal</ref> 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.<ref name = Pietschnig /><ref>Template:Cite journal</ref>

See also

• Josiphos ligands

References

<references> <ref name="pauson">Template:Cite journal</ref> <ref name="miller">Template:Cite journal</ref> <ref name="wilk52">Template:Cite journal</ref> <ref name="fischer">Template:Cite journal</ref> <ref name="eiland52">Template:Cite journal</ref> <ref name="dunitz53">Template:Cite journal</ref> <ref name="dunitz56">Template:Cite journal</ref> <ref name="haal68">Template:Cite journal</ref> <ref name="seiler">Template:Cite journal</ref> <ref name="coriani">Template:Cite journal</ref> <ref name="laszloRmon">Template:Cite journal</ref> <ref name="werner2012">Template:Cite journal</ref> <ref name="werner2008">Template:Cite book</ref> <ref name="federman">Template:Cite journal</ref> <ref name="mingos">Template:Cite journal</ref> <ref name="mehr">Template:Cite book</ref> <ref name="okuda">Template:Cite journal</ref> </references>

External links

• Ferrocene at The Periodic Table of Videos (University of Nottingham)
• NIOSH Pocket Guide to Chemical Hazards (Centers for Disease Control and Prevention)