Green reagents reduce or eliminate the use and generation of hazardous substances in the synthesis of chemical compounds [1]. The development of new green reagents is important for the development of a more sustainable chemical industry, based on processes that follow the principles dictated by green chemistry [2]. In this context, the use of green reagents, such as hydrogen peroxide and dimethyl carbonate, in reactions that can be driven by sunlight, have been widely developed over the past twenty years. Alternative methodologies have been implemented in chemical synthesis to catalyze reactions under safe and mild reaction conditions with the use of less harmful solvents and with reduced toxic waste production. Polymer supported reagents[3] have enabled many elegant and efficient strategies for performing a range of different transformations. The main advantage of polymer supported reagents is that excess reagent can be recovered by filtration and reused. However, many previously developed green reagents are applicable only to a very limited number of chemical transformations and substoichiometric amounts must be used.

In this paper, we highlight the effectiveness of Cp₂TiCl as a reagent that fulfils many of the principles of green chemistry, including high catalytic activity, low toxicity, high selectivity, and compatibility with environmentally benign solvents [4].

Cp₂TiCl, is a single electron transfer system (SET) obtained from non-hazardous materials such as Cp₂TiCl₂ and Mn or Zn [5]. Alternatively, organosilicon reducing agents can be used, thus avoiding reductant-derived metal waste [6]. Although, it is not a renewable feedstock, Cp₂TiCl, is derived from titanium, one of the most widely abundant and safe transition metals in the Earth's crust [7]. This reagent has been shown to be capable of promoting and/or catalyzing[8] homolytic cleavage of C-O, C-halogen, and O-O bonds, present in functional groups such as epoxides, ozonides, oxetanes, imines, halides, and carbonyl groups. A breakthrough in the application of this reagent was described by Gansäuer et al.[9] and Oltra et al.[10], with the development of two catalytic cycles, which allowed regeneration of Cp₂TiCl₂ from the titanium derivatives formed in homolytic cleavage of bonds (Figs. 1 and 2). The amount of Cp₂TiCl used in these catalytic cycles ranges between (5 and 20) mol%. Both catalytic cycles for epoxide ring opening are shown in Figs. 1 and 2.

In this context, both catalytic procedures minimize waste generation, contributing to the development of sustainable chemical processes. Although Mn or Zn is used as stoichiometric reagents (2–8 eq) both can be recovered by simple filtration. Furthermore, an economically attractive feature is that the collidine used in both catalytic cycles can be easily recovered during the reaction work-up by simple acid-base extraction [5]. Reactions catalyzed by this SET are conducted at atmospheric pressure and room temperature, which contributes to high energy efficiency. The reactions are also compatible with functional groups including ethers, silanes, and esters. Another aspect to consider in green chemistry is the use of solvents with low risk to human health and low toxicity [11]. In this respect Cp₂TiCl is environmentally friendly, because toluene or tetrahydrofuran [12, 13] can be used to generate Cp₂TiCl from Cp₂TiCl₂ and Mn; these solvents are classified as usable by Pfizer scientists in their practical guide for solvents for medicinal chemists [14]. Finally, Cp₂TiCl is a reagent that has contributed to the development of selective processes with high-step economy [15]. Especially relevant is the cyclization of epoxipolyprenes, catalyzed by Cp₂TiCl, to obtain polycyclic C₁₀, C₁₅, C₂₀ and C₃₀ terpenoids [8]. This reaction mimics their biosynthesis but proceeds through a free radical pathway. This reactivity reinforces the effectiveness of Cp₂TiCl as a green reagent, which complies with the principles of green chemistry as reported by Anastas et al.[2].

The main applications of this new green catalyst are summarized below. A useful feature of Cp₂TiCl is its ability to form carbon-centered radicals by homolytic cleavage of C–X bonds present in several functional groups [8] (Fig. 3).

Reduction reactions of these carbon-centered radicals usually take place in the presence of water, which is a good hydrogen-atom donor. An H atom is transferred from H₂O to the carbon radical [12, 16-18] or to the titanaoxirane intermediate [19] (Fig. 4). This reduction has been postulated to be greener than traditional processes for reducing carbonyl groups and alkenes. In the absence of good hydrogen-atom donors or electron-withdrawing functional groups, epoxides react to yield alkenes or allylic alcohols through a mixed disproportionation process [20]. In this way, tertiary carbon radicals lead to allylic alcohols through a process in which Cp₂TiCl removes a α radical hydrogen atom (isomerization process, Fig. 4) [20]. If the radical is on a di-substituted carbon, a double bond is formed (deoxygenation process, Fig. 4). In this case, the radical is trapped by a second Cp₂TiCl species to form a bimetallic intermediate, which eventually leads to the formation of a double bond.

However, when these carbon-centered radicals form in the absence of a hydrogen-atom donor and in the presence of electron withdrawing groups, a new C–C or C–O bond can be generated, either through intra-or intermolecular C–C and C–O bond forming reactions (Fig. 5) [8]. The C–C bond forming reactions reported in Fig. 5 [21-30] show that Cp₂TiCl is a reagent widely used for this type of reactions and applied to different functional groups, where high diastereoselectivity and high yields can be achieved. The synthesis of natural terpenes from cyclization of monoepoxides of acyclic polyprenes [31] is currently achieved through the use of Cp₂TiCl in C–C bond forming reactions.

Beyond mechanistic considerations, depending on the reaction conditions, Cp₂TiCl has emerged as an excellent green reagent for C–C and C–O bond forming reactions, reduction, deoxygenation, and isomerization reactions. Several examples of this catalytic processes are presented in Figs. 4 and 5.

In summary, Cp₂TiCl is an useful reagent for many different green transformations in chemistry, offering high selectivity, cost effectiveness, high efficiency, and environmental compatibility. This reagent will contribute to developments in green chemistry owing to its wide range of applications in the synthesis of natural products, polymers, and fine chemicals. In this context, Cp₂TiCl might enable new catalytic methodologies that will be useful for environmentally compatible industrial chemical processes.