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?
Synthesis and Properties of Cp2TiCl
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
titanocene dichloride, dichlorobis(cyclopentadienyl)titanium(IV)
3D model (JSmol)
|Molar mass||248.96 g/mol|
|Appearance||bright red solid|
|Density||1.60 g/cm3, solid|
|Melting point||289 °C (552 °F; 562 K)|
|sl. sol. with hydrolysis|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
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.
- 2 NaC5H5 + TiCl4 → (C5H5)2TiCl2 + 2 NaCl
Cp2TiCl2 can also be prepared by using freshly distilled cyclopentadiene rather than its sodium derivative:
- 2 C5H6 + TiCl4 → (C5H5)2TiCl2 + 2 HCl
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:
- The Petasis reagent, Cp2Ti(CH3)2, is prepared from the action of methylmagnesium chloride or methyllithium on Cp2TiCl2. This reagent is useful for the conversion of esters into vinyl ethers.
- The Tebbe reagent Cp2TiCl(CH2)Al(CH3)2, arises by the action of 2 equivalents Al(CH3)3 on Cp2TiCl2.
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
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
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
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.