The development of Green Chemistry inevitably involves the development of green reagents. In this review, we highlight that Cp2TiCl is a reagent widely used in radical and organometallic chemistry, which shows, if not all, at least some of the 12 principles summarized for Green Chemistry, such as waste minimization, catalysis, safer solvents, toxicity, energy efficiency, and atom economy. Also, this complex has proved to be an ideal reagent for green C–C and C–O bond forming reactions, green reduction, isomerization, and deoxygenation reactions of several functional organic groups as we demonstrate throughout the review.
Cp2TiCl: An Ideal Reagent for Green Chemistry?
† Department of Chemical Engineering, Escuela Politécnica Superior, University of Sevilla, 41011 Sevilla, Spain
‡ Organic Chemistry, ceiA3, University of Almería, 04120 Almería, Spain
§ Petrochemical Engineering, Universidad de las Fuerzas Armadas-ESPE, 050150 Latacunga, Ecuador
∥ Department of Organic Chemistry, Faculty of Science, University of Granada, 18071 Granada, Spain
Org. Process Res. Dev., Article ASAP
Synthesis and Properties of Cp2TiCl
Cp2TiCl is a single-electron-transfer (SET) complex that can be easily prepared from commercial and nontoxic Cp2TiCl2 by using economic and nontoxic reductants such as Mn or Zn. In solution, Cp2TiCl is in an equilibrium between mononuclear and dinuclear species. It has recently been reported that the stoichiometric metal reductant can be replaced by an organic reducing agent.
Although Cp2TiCl is not a renewable feedstock, it is important to say that this SET is a good alternative to them because it is obtained from nonhazardous materials and also because titanium is one of the most abundant and safe transition metals on Earth
- Molecular FormulaC10H10Cl2Ti
- Average mass248.959 Da
Di(2,4-cyclopentadiénide) de dichlorotitane(2+) [French] [ACD/IUPAC Name]
Dichlorotitanium(2+) di(2,4-cyclopentadienide) [ACD/IUPAC Name]
Dichlortitan(2+)di(2,4-cyclopentadienid) [German] [ACD/IUPAC Name]
Titanocene dichloride is the organotitanium compound with the formula (η5-C5H5)2TiCl2, commonly abbreviated as Cp2TiCl2. This metallocene is a common reagent in organometallic and organic synthesis. It exists as a bright red solid that slowly hydrolyzes in air.Cp2TiCl2 does not adopt the typical “sandwich” structure like ferrocene due to the 4 ligands around the metal centre, but rather takes on a distorted tetrahedral shape. It shows antitumour activity and was the first non-platinum complex to undergo clinical trials as a chemotherapy drug.
The standard preparations of Cp2TiCl2 start with titanium tetrachloride. The original synthesis by Geoffrey Wilkinson and Birmingham uses sodium cyclopentadienide is still commonly used:
- 2 NaC5H5 + TiCl4 → (C5H5)2TiCl2 + 2 NaCl
The reaction is conducted in THF. Workup sometimes washing with hydrochloric acid to convert hydrolysis derivatives to the dichloride. Recrystallization from toluene forms acicular crystals.
Cp2TiCl2 can also be prepared by using freshly distilled cyclopentadiene rather than its sodium derivative:
- 2 C5H6 + TiCl4 → (C5H5)2TiCl2 + 2 HCl
This reaction is conducted under a nitrogen atmosphere and by using THF as solvent. The product is purified by soxhlet extractionusing toluene as solvent.
The complex is pseudotetrahedral. Each of the two Cp rings are attached as η5 ligands.
Applications in organic synthesis
Cp2TiCl2 is a generally useful reagent that effectively behaves as a source of Cp2Ti2+. A large range of nucleophiles will displace chloride. Examples:
Application in preparing sulfur allotropes
Titanocene dichloride is used to prepare titanocene pentasulfide, a precursor to unusual alloptropes of sulfur:
- Li2S5 + (C5H5)2TiCl2 → (C5H5)2TiS5 + LiCl
Structure of pentasulfur-The resulting pentasulfur-titanocene complex is allowed to react with polysulfur dichloride to give the desired cyclosulfur of in the series:
Cp2TiCl2 undergoes anion exchange reactions, e.g. to give the pseudohalides. With NaSH and with polysulfide salts, one obtains the sulfido derivatives Cp2Ti(SH)2 and Cp2TiS5.
One Cp ligand can be removed from Cp2TiCl2 to give tetrahedral CpTiCl3. This conversion can be effected with TiCl4 or by reaction with SOCl2.
Reduction with zinc gives the dimer of bis(cyclopentadienyl)titanium(III) chloride in a solvent-mediated chemical equilibrium:
Cp2TiCl2 is a precursor to many TiII derivatives, though titanoce itself, TiCp2, is so highly reactive that it rearranges into a TiIII hydride dimer and has been the subject of much investigation. This dimer can be trapped by conducting the reduction of titanocene dichloride in the presence of ligands; in the presence of benzene, a fulvalene complex, μ(η5:η5-fulvalene)-di-(μ-hydrido)-bis(η5-cyclopentadienyltitanium), can be prepared and the resulting solvate structurally characterised by X-ray crystallography. The same compound had been reported earlier by a lithium aluminium hydride reduction and sodium amalgam reduction of titanocene dichloride, and studied by 1H NMR prior to its definitive characterisation.
“Titanocene” is not Ti(C5H5)2, but rather this isomer with a fulvalene dihydride structure.
Reductions have been investigated using Grignard reagent and alkyl lithium compounds. More conveniently handled reductants include Mg, Al, or Zn. The following syntheses demonstrate some of the compounds that can be generated by reduction of titanocene dichloride in the presence of π acceptor ligands:
- Cp2TiCl2 + 2 CO + Mg → Cp2Ti(CO)2 + MgCl2
- Cp2TiCl2 + 2 PR3 + Mg → Cp2Ti(PR3)2 + MgCl2
- Cp2TiCl2 + 2 Me3SiCCSiMe3 + Mg → Cp2TiMe3SiCCSiMe3 + MgCl2
With only one equivalent of reducing agent, TiIII species such as Cp2TiCl result.
Alkyne and benzyne derivatives of titanocene are well known. One family of derivatives are the titanocyclopentadienes.
Titanocene equivalents react with alkenyl alkynes followed by carbonylation and hydrolysis to form bicyclic cyclopentadienones, related to the Pauson–Khand reaction). A similar reaction is the reductive cyclization of enones to form the corresponding alcohol in a stereoselective manner.
Reduction of titanocene dichloride in the presence of conjugated dienes such as 1,3-butadiene gives η3-allyltitanium complexes. Related reactions occur with diynes. Furthermore, titanocene can catalyze C-C bond metathesis to form asymmetric diynes.
Derivatives of (C5Me5)2TiCl2
Many analogues of Cp2TiCl2 are known. Prominent examples are the ring-methylated derivatives (C5H4Me)2TiCl2 and (C5Me5)2TiCl2. The ethylene complex (C5Me5)2Ti(C2H4) can be synthesised by Na reduction of (C5Me5)2TiCl2 in the presence of ethylene. The Cp compound has not been prepared. This pentamethylcyclopentadienyl (Cp*) species undergoes many reactions such as cycloadditions of alkynes.
Titanocene dichloride was investigated as an anticancer drug. In fact, it was both the first non-platinum coordination complex and the first metallocene to undergo a clinical trial.The mechanism by which it acts is not fully understood; however, it has been conjectured that its activity might be attributable to the compound’s interactions with the protein transferrin.
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Natural product synthesis is an exigent test for newly developed methodologies. Within this context, Rajanbabu and Nugent reported a series of seminal papers about the potential role of Cp2TiCl as a new tool in organic synthesis.1 Soon afterwards, Gansäuer’s group published a collection of relevant papers where a substoichiometric version of this protocol was developed.2Those results were especially important in the development of the corresponding asymmetric reactions using chiral titanocene(III) complexes.3 After these inspiring works, titanocene(III) complexes, essentially titanocene(III) chloride (Cp2TiCl), have recently emerged as a powerful tool in organic synthesis. They are soft single-electron-transfer (SET) reagents capable of promoting different kinds of reactions, such as homolytic epoxide4 and oxetane5 openings, Barbier-type reactions,6 Wurtz-type reactions,7 Reformatsky-type reactions,8 reduction reactions,9 and pinacol coupling reactions (Scheme 1).10
|Scheme 1 General reactivity of Cp2TiCl.
From a practical point of view, titanocene(III) complexes can be prepared and stored. Nevertheless, they are usually highly oxygen-sensitive compounds. Interestingly, they can be easily prepared in situ by simply stirring the corresponding titanocene(IV) precursor and manganese or zinc dust. Another key characteristic of the titanocene(III) chemistry is that whatever the reaction in which it is involved, a catalytic cycle can be closed. In that case, a titanocene(IV) regenerating agent and an electron source, such as manganese or zinc dust, are required. Although some of them have been described in the literature, only two are commonly used: the simple combination of trimethylsilyl chloride and 2,4,6-collidine for aprotic reaction conditions11 and 2,4,6-collidinium hydrochloride for aqueous conditions (see Scheme 2).2
||Scheme 2 Catalytic cycles in titanocene(III) chemistry.
Titanocene(III)-mediated radical processes have been applied to the synthesis of natural products of diverse nature. Beyond simple functional group interconversions, radical cyclizations, mainly from epoxides, have demonstrated their utility to yield (poly)cyclic natural skeletons, which are valuable synthons in organic synthesis. This radical approach has in many cases resulted in better yields and stereoselectivities than the cationic equivalents. In particular, the synthesis at room temperature of stereodefined terpenic skeletons without enzymatic assistance is remarkable. In this context, the main limitation of this bioinspired approach is, in fact, its extraordinary stereoselectivity, which avoids obtaining cis-fused decalins and/or substituents in axial positions. Such stereochemistry is present in many interesting natural terpenes. On the other hand, as can be seen in the first part of the review, the diverse reactivity of titanocene(III) complexes derives in some functional group incompatibilities. It is expected that in near future judicious designs of new titanocene(III) complexes can resolve this drawback. In any case, the evolution of the applications of titanocene(III) in natural product synthesis suggests that these reagents can be a matter of choice in the arsenal of a synthetic organic chemist.