Cp2TiCl/H2O as a Sustainable System for the Reduction of Organic Functional Groups: Potential Application of Cp2TiCl/D2O to the Analysis of Bioactive Phenols in Olive Oil

Abstract

Significant efforts have been made toward developing sustainable reduction reactions of organic and bioorganic compounds. In these studies, the selection of reagents and solvents has played a very important role in the development of environment-friendly methodologies. In this context, the reducing agent Cp₂TiCl/H₂O has been introduced as a safe, efficient, selective, and low-cost reagent, and thus as a sustainable alternative for the reduction of organic compounds. To facilitate understanding of the reductions mediated by this system, in this study we focus on describing the intermediates, mechanisms, and representative examples. Finally, a reflection is made on the future perspectives of this reducing agent, including its analog Cp₂TiCl/D₂O as a powerful tool for the preparation of deuterated phenols, which can be successfully used as an internal standard for analyzing bioactive phenols in olive oil.

1. Introduction

The reduction of functional groups in organic compounds is of central importance in biochemistry and organic chemistry. This reaction can be achieved through several methods, including hydride transfer reactions, catalytic hydrogenations, dissolving metal reductions, and organometallic complexes [1]. Although the reduction reaction has been known about for a long time, this reaction is a central focus of modern organic synthesis, with significant efforts directed at developing more sustainable reductions [2,3] in accordance with the principles of green chemistry [4]. In this context, this manuscript summarizes the use of Cp₂TiCl/water as a green system for the reduction of organic functional groups and its analog Cp₂TiCl/D₂O as an efficient system for the synthesis of deuterated compounds, although it is not intended to be a comprehensive review. This system is constituted by Cp₂TiCl, a single-electron transfer (SET) reagent, which has been proposed as a new green reagent that can carry out an important variety of chemical reactions such as C–C and C–O bond-forming reactions, as well as reduction, isomerization, deoxygenation, and polymerization reactions, under mild reaction conditions and with high diastereo- and regioselectivities [5,6,7,8,9,10,11]. This SET reagent fulfills some of the twelve principles of green chemistry, such as catalysis, safer solvents, waste minimization, atom economy, toxicity, and energy efficiency [5,6]. The other reagent is water or heavy water, an environmentally benign solvent because it is nonflammable, abundant, and nontoxic. Furthermore, the chemical nature of water leads to remarkable new reactions that cannot be achieved otherwise [12]. The most relevant mechanisms of the reduction reactions mediated by the Cp₂TiCl/H₂O system will be discussed. Of note is that the analog of this system, the one using heavy water as a deuterium atom source, is an ideal reagent for the efficient synthesis of deuterated compounds, which present chemical and physical properties virtually identical to those of their non-deuterated analogs. These deuterated compounds have many potential applications [13], especially in the food and pharmaceutical industries. For example, in the food industry, deuterated compounds can be used as an internal standard [14,15] in the analysis of bioactive compounds. In this context, compared to other deuteration methodologies [16,17], the Cp₂TiCl/D₂O system [18] is a sustainable and inexpensive reagent, very useful for the preparation of deuterated phenols that can be used as an internal standard in the analysis of some of the bioactive phenolic compounds present in olive oil [15]. In fact, the antioxidant properties of olive oil have been attributed to some of these bioactive phenols, such as tyrosol, and hydroxytyrosol and its derivatives (e.g., oleuropein) [19]. For this reason, the development of analytical methods using deuterated systems as internal standards which allow the quantification of bioactive phenols is an important goal in food and analytical chemistry. Finally, the future perspectives of this system are discussed.

2. Discussion

The use of Cp₂TiCl in reduction reactions of organic compounds using water as a hydrogen atom donor has been known for more than a decade [15,16]. Cp₂TiCl is a single electron transfer reagent obtained by reducing Cp₂TiCl₂ with a nonhazardous metal in dust form, such as Zn or Mn [20]. Alternatively, photoredox catalysis [21], electrochemical reduction [22], and organosilicon reducing agents [23] can be used to obtain Cp₂TiCl from Cp₂TiCl₂. In tetrahydrofuran (THF) or toluene, the Cp₂TiCl solution is lime green. However, it turns dark blue when water is added to the solution [24,25].

The presence of a vacant site and an unpaired d-electron in the inner sphere of this complex allows its coordination to functional groups with heteroatoms with free valence electrons, obtaining different intermediates if the process is energetically favorable. From these intermediates, important chemical synthesis reactions take place, such as C–C and C–O bond-forming reactions, as well as reduction, isomerization, deoxygenation, protection, epoxidation, and decyanation reactions (Scheme 1) [5,6,7,8,9,10,11].

Considering the study of reduction reactions mediated by the Cp₂TiCl/H₂O system, three types of primary intermediates are formed from epoxides, ozonides, carbonyl compounds, activated halides, and transition metals. Initially, the formation of carbon-centered radicals 1 was observed when C–Y is coordinated to Cp₂TiCl after a single-electron transfer (pathway A, Scheme 2). If a carbon radical 1 is trapped by a second molecule of titanocene(III), an alkyl-Ti^IV intermediate 2 is formed (pathway A1, Scheme 2). However, if the carbon radical 1 is hindered, it can be reduced by hydrogen atom transfer from the aqueous complex of titanocene(III) (pathway A2, Scheme 2). The titanaoxirane intermediates 3 are generated from carbonyl groups and Cp₂TiCl/Mn (pathway B, Scheme 2). Hydrolysis of these intermediates 3 generates the reduced compounds. Finally, a dihydro metal complex 4 is obtained when the Cp₂TiCl/water system reacts with a transition metal such as Pd or Rh, allowing the reduction of alkenes or alkynes (pathway C, Scheme 2). All these reaction species are susceptible to producing reductive products through the mechanisms described below.

A breakthrough in the use of the Cp₂TiCl/H₂O system as a new reducing reagent was the development of a catalytic cycle under reductive conditions reported by Gansäuer et al. [26]. In this catalytic cycle, hydrochloride-substituted pyridines (collidine hydrochloride) were employed as versatile acids to protonate the Ti–C or the Ti–O bonds to generate Cp₂TiCl₂ (Scheme 3) [26]. This catalytic cycle has been used successfully for different target functional groups and uses water as a hydrogen source.

The mechanism involved in the reduction of these intermediates and some examples are discussed below.

2.1. Carbon-Centered Radical Intermediates

Homolysis of one epoxide C–O bond, one ozonide O–O bond, or C–halogen bond occurs by inner-sphere electron transfer and results in the generation of a carbon-centered radical intermediate (pathway A, Scheme 2). Under aqueous conditions, the carbon-centered radical intermediate 1 can be reduced through hydrogen atom transfer (HAT) (pathway A, Scheme 4) from an aqua complex of titanocene(III) or by hydrolysis of an organometallic alkyl-Ti^IV intermediate 2 generated when the radical is trapped by a second species of titanocene(III) (pathway B, Scheme 4).

The HAT pathway is only possible because the activation of water by Cp₂TiCl takes place. This activation of water for HAT was initially reported by us in the radical cyclization of epoxygermacrolides [27]. In that paper, we published the following comment: “Contrary to general belief, water can act as a reactive hydrogen atom donor in radical chemistry mediated by Ti(III) species”. The propensity of water to act as a HAT reagent could be explained by a lowering of the dissociation energy of the O–H bond of almost 60 kcal/mol in the presence of Cp₂TiCl. Initially, aqua complex 5 was proposed as a HAT reagent (pathway A, Scheme 5) [17]. However, after extending and refining the theoretical calculations, studies of cyclic voltammetry, mass spectrometric analysis, and electro-paramagnetic resonance techniques suggested that aqua complex 6 is the active HAT reagent (pathway B, Scheme 5) [25,28].

Water as a HAT reagent was rigorously demonstrated in the transannular cyclization of caryophyllene oxide 7 (Scheme 6) [24]. The radical opening of epoxide 7 mediated by Cp₂TiCl generates a hindered primary radical 8. Several experiments were carried out to determine the reduction mechanism of the radical generated. In this way, treating 7 with titanocene(III) in the presence of 1,4-CHD (a hydrogen atom donor) and subsequent addition of D₂O (after consumption of 7 (1 h)) gave a mixture of 9 and 10 (pathway A, Scheme 6). The lack of deuterium labeling in 9 was a result that allowed us to indicate that the reduction of the hindered radical as 8 took place by the transfer of hydrogen atoms from 1,4-CHD and not by the hydrolysis of the organometallic intermediate which may be generated when the radical is trapped by a second molecule of Cp₂TiCl. In another experiment, epoxide 7 was treated with Cp₂TiCl in the presence of D₂O and 1,4-CHD. Under these conditions, the main isolated product was 11 (pathway B, Scheme 6). The presence of deuterium labeling in 11 indicated that deuterium atom transfer from D₂O was faster than hydrogen atom transfer from 1,4-CHD, which in the previous experiment (pathway A, Scheme 6) was observed to be much faster than the formation of an organometallic alkyl-Ti^IV intermediate.

This mechanism of reduction through HAT was also observed with propargyl radicals [29]. Based on deuteration studies, propargyl radicals were reported to be effectively reduced by HAT from H₂O in a process mediated by Cp₂TiCl.

As can be observed, due to their mild experimental conditions and high chemoselectivity, HAT reactions using the Cp₂TiCl/H₂O system represent an excellent methodology for reducing carbon-centered radicals of diverse nature. A deep theoretical and experimental study [30] indicated that the success of this reaction is based on two key features: (a) an excellent binding capacity of H₂O to Cp₂TiCl and (b) a low activation energy for the HAT step. If the activation energy for the HAT step is high, the dimerization of the radicals usually prevails over their reduction.

Alternatively, the carbon-centered radical intermediate 1 can be reduced by a more conventional mechanism that involves the formation of an organometallic alkyl-Ti^IV intermediate 2 and subsequent hydrolysis by water (pathway B, Scheme 4). This other mechanism was demonstrated based on the experimental and theoretical observations we obtained in the radical opening of ozonides [31]. When ozonide 12 is treated with Cp₂TiCl, an unhindered primary radical 13 is formed. Several reactions were carried out to determine the mechanism of reduction of this benzylic radical 13. When ozonide 12 was treated with titanocene(III) and water, a mixture of homocoupling product 14 (62%) and reductive product 15 (38%) was obtained (pathway A, Scheme 7) [32]. This result is reported in Supplementary Materials. In another experiment, ozonide 12 was treated with Cp₂TiCl and, after consumption of 12 (1 h), D₂O was added, observing a mixture of 14 and deuterium-labeled product 16 (pathway B, Scheme 7) [31]. The 45% deuterium incorporation in 16 together with the same relative ratio of homocoupling and reductive products in both experiments indicated that the reduction of the unhindered primary radical could be due to the hydrolysis of an organometallic alkyl-Ti^IV intermediate formed by trapping the radical with a second molecule of titanocene(III).

To decrease the dimerization of radical 13, Cp₂TiCl was added dropwise to ozonide 12 in dry THF, and finally hydrolysis with HCl (2N) resulted in 15 as the main product [32] (see the example in Scheme 8).

Although more computational and experimental studies are being conducted [32] to verify the proposed mechanism of reduction of carbon radicals, as a general rule it can be observed that hindered and tertiary carbon radicals are normally reduced by HAT from water in a process promoted by Cp₂TiCl, while unhindered and primary radicals are generally reduced via hydrolysis of an organometallic alkyl-Ti^IV intermediate. Several examples of the reduction of epoxides and ozonides by the Cp₂TiCl/H₂O system are illustrated in Scheme 8. As can be observed in Scheme 8, the regioselective opening of epoxides mediated by Cp₂TiCl, where water is used as the donor of hydrogen atoms, is a highly green procedure for obtaining anti-Markovnikov alcohols [26,33].

2.2. Titanaoxirane Intermediates

The Cp₂TiCl/H₂O system can also be used to reduce titanaoxirane species 3 (pathway B, Scheme 2) obtained when carbonyl groups are treated with Cp₂TiCl/Mn. Rosales Martínez et al. [34] explored the reduction mechanism of the carbonyl group with titanocene(III) in an aqueous medium. After treating acetophenone 17 with Cp₂TiCl in the absence of manganese, the starting material 17 was recovered unchanged (pathway A, Scheme 9). However, the same reaction in the presence of manganese gave alcohol 18 with a yield of 94% (pathway B, Scheme 9). These results indicated that manganese is required not only for reducing Cp₂TiCl₂ to Cp₂TiCl, but also for generating the intermediate titanaoxirane 20 as the key intermediate (Scheme 10a).

The observations mentioned were explained by the mechanism proposed in Scheme 10a. Coordination between acetophenone 17 and titanocene(III) would provide the reaction intermediate 19 in an equilibrium reaction shifted toward titanocene(III) and acetophenone 17. This equilibrium was proposed because, in the absence of manganese, the starting material 17 was recovered unchanged. Therefore, the manganese present in the reaction medium could reduce the Cp₂TiCl coordinated to acetophenone 17 through an irreversible process leading to the formation of the titanaoxirane intermediate 20. When water is present in the reaction medium, the aqua complex 6 is formed, which would probably be more acidic than the non-coordinated water and, therefore, could promote the hydrolysis of the intermediate 20 to an alkyl-Ti^IV intermediate such as 21, a precursor of alcohol 18. Several examples of the selective reduction of ketones by Cp₂TiCl/H₂O are presented in Scheme 10b.

2.3. Dihydro Metal Complex Intermediates

In the presence of transition metals such as Rh or Pd, the Cp₂TiCl/H₂O system was also used to reduce alkynes and alkenes [36]. The mechanism of this reduction was explained by the formation of the aqua complex 6, which is able to facilitate the transfer of hydrogen atoms from water to late transition metals (Pd or Rh) to give metal hydride intermediates 4. These intermediates could subsequently bring about alkyne (and alkene) hydrogenation as depicted in Scheme 11a. This mechanism was supported by theoretical and experimental evidence. In this way, theoretical calculations suggested an activation energy of only 17.3 kcal/mol for the hydrogen atom transfer. Several examples of the reduction of alkynes/alkenes by the Cp₂TiCl/H₂O system are presented in Scheme 11b.

All these results show that the Cp₂TiCl/H₂O system is an excellent sustainable reagent for reduction reactions. This system avoids the use of traditional hydrogen atom donors, such as trialkyl stannane hydrides, which are toxic and sometimes produce side products. Moreover, the moderate efficiency of HAT from this system compared with the trialkylstannanes results in chemical advantages in the involved radical chain reactions, since the radical species will not be prematurely reduced. Moreover, this system avoids the use of cyclohexadiene, silanes, and related compounds as HAT reagents, which are expensive, toxic, and/or foul-smelling. Another attractive feature of this system is that it can be used with a catalytic amount of Cp₂TiCl, unlike other novel HAT reagents such as borane complex with N-heterocyclic carbenes since these reagents are employed in stoichiometric amounts.

Finally, the analog of this system that uses heavy water as a deuterium source is used to generate complex deuterium-labeled compounds [16], which can be applied as an internal standard in food analysis. The first synthesis of a deuterated sample of tyrosol, using the Cp₂TiCl/D₂O system as a reducing reagent, was used as an internal standard in determining the concentration of bioactive tyrosol in an olive leaf extract [15]. The result given in mg tyrosol/g of dry weight olive leaves was 0.2 ± 0.05 mg/g.

Although the overall yield of deuterated tyrosol (22) was not high (10.5%), this compound was synthesized from commercially available acetoxystyrene (23) in only three steps: (a) epoxidation of 23 with m-chloroperoxybenzoic acid (mCPBA) to give 24; (b) radical opening of epoxide 24 with the Ti(III)/D₂O system to produce deuterated alcohol 25; and (c) deacetylation of 25 to form 22 (Scheme 12). The moderate deuterium incorporation obtained in alcohol 25 may be due to the fact that part of the alkyl-Ti^IV intermediate generated after the opening of the epoxide 24 with titanocene(III) is not hydrolyzed with the heavy water present in the reaction medium due to a high isotope effect. Part of this intermediate could be hydrolyzed after working up the reaction with H₃O⁺.

3. Conclusions and Perspectives

In summary, we have presented an article showing that Cp₂TiCl/H₂O is a novel hydrogen atom donor system. It is characterized by being a sustainable, efficient, selective, and economic system that allows the reduction of ozonides, epoxides, carbonyl compounds, alkenes, and alkynes to be carried out. These reductions occur under mild and environmentally safe reaction conditions avoiding the use of other toxic and relatively expensive hydrogen atom donors, such as 1,4-cyclohexadiene or Bu₃SnH. Moreover, its analog using heavy water has been postulated as a much cheaper and safer alternative compared to the traditional reducing reagents used to obtain deuterated alcohols such as NaBD₄ and LiAlH₄. Despite recent advances in the use of this system as a reducing reagent in radical and organometallic chemistry, many challenges remain: (1) A wide range of other functional groups needs to be further explored with Cp₂TiCl. (2) Asymmetric reduction is another issue due to two factors: the need to use chiral titanocene(III) reagents [37] and that the key intermediate in the reduction process must be organometallic and non-radical in nature. (3) Developing and optimizing the solvent-free reduction process. (4) Extrapolating this system to industrial chemical reductions. (5) Using the Cp₂TiCl/D₂O system as a deuterium source to generate more deuterated compounds of interest in the food industry, such as deuterated isomers of hydroxytyrosol, oleacein, oleocanthal, and oleuropein, some of them of major importance in the olive oil industry. These deuterated compounds can be used as internal standards to quantify their non-deuterated analogs present in olive oil. For this purpose, high-performance liquid chromatography (HPLC) allied with mass spectrometry detection, using electrospray ionization as an interface can be used [15].

Author Contributions

A.R.M.: design and coordination of the project, writing—original draft, and writing—review and editing. J.F.G.-M.: review. I.R.-G.: writing—review. All authors have read and agreed to the published version of the manuscript.

Acknowledgments

Antonio Rosales Martínez and Juan F. García Martín acknowledge the University of Seville for their positions as professors.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Schemes

Scheme 1. Target functional groups of titanocene(III).

Scheme 2. Intermediates generated in the reduction of functional groups with the Cp2TiCl/H2O system.

Scheme 3. Catalytic Cp2TiCl epoxide opening using 2,4,6-collidine as a regenerator and 1,4-cyclohexadiene (1,4-CHD) as a hydrogen source.

Scheme 4. Reduction of carbon-centered radical intermediates. Pathway A: HAT from water to free radicals mediated by an aqua complex of titanocene(III). Pathway B: Hydrolysis of an alkyl-TiIV intermediate.

Scheme 5. Proposed Cp2TiCl aqua complexes.

Scheme 6. Deuteration experiments in the cyclization of 7. (a) Addition of D2O after 1h of reaction; (b) addition of D2O from the beginning.

Scheme 7. Experiments in the radical opening of ozonide 12. (a) Reaction in the absence of deuterium source [32]; (b) Reaction quenched with D2O [31].

Scheme 8. Examples of reductions of epoxides and ozonides with the Cp2TiCl/H2O system [24,27,30,32,33]. a Substoichiometric amount of Cp2TiCl. b Stoichiometric amount of Cp2TiCl.

Scheme 9. Experiments on the reduction of acetophenone 17 with the Cp2TiCl/H2O system.

Scheme 10. (a) Proposed mechanism for the titanocene(III)/Mn-promoted reduction of acetophenone 17 in an aqueous medium [34]. (b) Examples of selective reduction of ketones by Cp2TiCl/H2O [19,35]. a Substoichiometric amount of Cp2TiCl. b Stoichiometric amount of Cp2TiCl.

Scheme 11. (a) Proposed mechanism for the hydrogenation of alkenes or alkynes with Cp2TiCl/H2O in the presence of Pd or Rh catalysts [36]. (b) Examples of the reduction of alkenes and alkynes. a Stoichiometric amount of Cp2TiCl.

Scheme 12. Synthesis of deuterated tyrosol (22).

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/pr11040979/s1, Figure S1: Experimental procedures for reference [25]; Figure S2: ¹H NMR (CDCl₃, 300 MHz) of the reaction of the crude ozonide 12 with Cp₂TiCl₂ and Mn in THF, showing the relative ratio of products 14 and 15; Figure S3: ¹H NMR (CDCl₃, 300 MHz) of 14; Figure S4: DEPT 135 and ¹³C NMR (CDCl₃, 75 MHz) of 14; Figure S5: 1H NMR (CDCl₃, 300 MHz) of 15; Figure S6: DEPT 135 and ¹³C NMR (CDCl₃, 75 MHz) of 15.

References

1. Smith, M.B.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure; 6th ed. John Wiley & Sons: Hoboken, NJ, USA, 2007; pp. 1786-1869.

2. Sheldon, R.A. Green solvents for sustainable organic synthesis: State of the art. Green Chem.; 2005; 7, pp. 267-278. [DOI: https://dx.doi.org/10.1039/b418069k]

3. Álvarez de Cienfuegos, L.; Robles, R.; Miguel, D.; Justicia, J.; Cuerva, J.M. Reduction reactions in green solvents: Water, supercritical carbon dioxide, and ionic liquids. ChemSusChem; 2011; 4, pp. 1035-1048. [DOI: https://dx.doi.org/10.1002/cssc.201100134] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21826799]

4. Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, UK, 2000; 152.

5. Castro Rodríguez, M.; Rodríguez García, I.; Rodríguez Maecker, R.N.; Pozo Morales, L.; Oltra, J.E.; Rosales Martínez, A. Cp₂TiCl: An Ideal Reagent for Green Chemistry?. Org. Process Res. Dev.; 2017; 21, pp. 911-923. [DOI: https://dx.doi.org/10.1021/acs.oprd.7b00098]

6. Rosales Martínez, A.; Castro Rodriguez, M.; Rodríguez-García, I.; Pozo Morales, L.; Rodriguez Maecker, R.N. Titanocene dichloride: A new green reagent in organic chemistry. Chin. J. Catal.; 2017; 38, pp. 1659-1663. [DOI: https://dx.doi.org/10.1016/S1872-2067(17)62894-8]

7. Rosales Martínez, A.; Pozo Morales, L.; Díaz Ojeda, E.; Castro Rodríguez, M.; Rodríguez-García, I. The Proven Versatility of Cp₂TiCl. J. Org. Chem.; 2021; 86, pp. 1311-1329. [DOI: https://dx.doi.org/10.1021/acs.joc.0c01233]

8. Gansäuer, A. From enantioselective to regiodivergent epoxide opening and radical arylation—useful or just interesting?. Synlett; 2021; 32, pp. 447-456. [DOI: https://dx.doi.org/10.1055/s-0040-1706407]

9. Barrero, A.F.; Quílez del Moral, J.F.; Sánchez, E.M.; Arteaga, J.F. Titanocene-mediated radical cyclization: An emergent method towards the synthesis of natural products. Eur. J. Org. Chem.; 2006; pp. 1627-1641. [DOI: https://dx.doi.org/10.1002/ejoc.200500849]

10. Gansäuer, A.; Justicia, J.; Fan, C.-A.; Worgull, D.; Piestert, F. Reductive C–C Bond Formation after Epoxide Opening via Electron Transfer. Top. Curr. Chem.; 2007; 279, pp. 25-52.

11. Botubol-Ares, J.M.; Durán-Peña, M.J.; Hanson, J.R.; Hernández-Galán, R.; Collado, I.G. Cp₂Ti(III)Cl and analogues as sustainable templates in organic synthesis. Synthesis; 2018; 50, pp. 2163-2180.

12. Breslow, R. The principles of and reasons for using water as a solvent for green chemistry. Handbook of Green Chemistry; Chao-Jun, L. Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2010; Volume 5, pp. 1-29.

13. Liu, J.; Liu, X. Deuteride Materials; Springer Nature Singapore Pte Ltd.: Singapore, 2019; pp. 231-284.

14. Stokvis, E.; Rosing, H.; Beijnen Jos, H. Stable isotopically labeled internal standards in quantitative bioanalysis using liquid chromatography/mass spectrometry: Necessity or not?. Rapid Commun. Mass Spectrom.; 2005; 19, pp. 401-407. [DOI: https://dx.doi.org/10.1002/rcm.1790]

15. Jiménez, T.; Campaña, A.G.; Bazdi, B.; Paradas, M.; Arráez-Román, D.; Segura-Carretero, A.; Fernández-Gutiérrez, A.; Oltra, J.E.; Robles, R.; Justicia, J. et al. Radical reduction of epoxides using a titanocene(III)/water system: Synthesis of β-deuterated alcohols and their use as internal standards in food analysis. Eur. J. Org. Chem.; 2010; 2010, pp. 4288-4295. [DOI: https://dx.doi.org/10.1002/ejoc.201000487]

16. Prakash, G.; Paul, N.; Oliver, G.A.; Werz, D.B.; Maiti, D. C–H deuteration of organic compounds and potential drug candidates. Chem. Soc. Rev.; 2022; 51, pp. 3123-3163. [DOI: https://dx.doi.org/10.1039/D0CS01496F]

17. Atzrodt, J.; Derdau, V.; Kerr, W.J.; Reid, M. C-H Functionalisation for hydrogen isotope exchange. Angew. Chem. Int. Ed.; 2018; 57, pp. 3022-3047. [DOI: https://dx.doi.org/10.1002/anie.201708903]

18. Rosales, A.; Rodríguez-García, I. Cp₂TiCl/D₂O/Mn, a formidable reagent for the deuteration of organic compounds. Beilstein J. Org. Chem.; 2016; 12, pp. 1585-1589. [DOI: https://dx.doi.org/10.3762/bjoc.12.154]

19. Marković, A.K.; Tori´c, J.; Barbarić, M.; Brala, C.J. Hydroxytyrosol, tyrosol and derivatives and their potential effects on human health. Molecules; 2019; 24, 2001. [DOI: https://dx.doi.org/10.3390/molecules24102001]

20. Green, M.L.H.; Lucas, C.R. Some d¹ Bis-π-cyclopentadienyl titanium complexes with nitrogen or phosphorus ligands. J. Chem. Soc. Dalton Trans.; 1972; pp. 1000-1003. [DOI: https://dx.doi.org/10.1039/DT9720001000]

21. Zhang, Z.; Richrath, R.B.; Gansäeuer, A. Merging catalysis in single electron steps with photoredox catalysis-efficient and sustainable radical chemistry. ACS Catal.; 2019; 9, pp. 3208-3212. [DOI: https://dx.doi.org/10.1021/acscatal.9b00787]

22. Liedtke, T.; Hilche, T.; Klare, S.; Gansäeuer, A. Condition screening for sustainable catalysis in single-electron steps by cyclic voltammetry: Additives and solvents. ChemSusChem; 2019; 12, pp. 3166-3171. [DOI: https://dx.doi.org/10.1002/cssc.201900344]

23. Saito, T.; Nishiyama, H.; Tanahashi, H.; Kawakita, K.; Tsurugi, H.; Mashima, K. 1,4-Bis(trimethylsilyl)-1,4-diaza-2,5-cyclohexadienes as Strong Salt-Free Reductants for Generating Low-Valent Early Transition Metals with Electron-Donating Ligands. J. Am. Chem. Soc.; 2014; 136, pp. 5161-5170. [DOI: https://dx.doi.org/10.1021/ja501313s]

24. Cuerva, J.M.; Campaña, A.G.; Justicia, J.; Rosales, A.; Oller-Lopez, J.L.; Robles, R.; Cárdenas, D.J.; Buñuel, E.; Oltra, J.E. Water: The ideal hydrogen-atom source in free-radical chemistry mediated by Ti^III and other single-electron-transfer metals?. Angew. Chem. Int. Ed.; 2006; 45, pp. 5522-5526. [DOI: https://dx.doi.org/10.1002/anie.200600831]

25. Rosales Martínez, A.; Enríquez, L.; Jaraíz, M.; Thiessen, T.; Sidhu, J.; McIndoe, J.S.; Rodríguez-García, I. Understanding the color change of the solutions of Cp₂TiCl upon addition of water. Appl. Organomet. Chem.; 2023; 37, e6979.

26. Gansäeuer, A.; Pierobon, M.; Bluhm, H. Catalytic, highly regio- and chemoselective generation of radicals from epoxides: Titanocene dichloride as an electron transfer catalyst in transition metal catalyzed radical reactions. Angew. Chem. Int. Ed.; 1998; 37, pp. 101-103. [DOI: https://dx.doi.org/10.1002/(SICI)1521-3773(19980202)37:1/2<101::AID-ANIE101>3.0.CO;2-W]

27. Barrero, A.F.; Oltra, J.E.; Cuerva, J.M.; Rosales, A. Effects of solvents and water in Ti(III)-mediated radical cyclizations of epoxygermacrolides. straightforward synthesis and absolute stereochemistry of (+)-3α-hydroxyreynosin and related eudesmanolides. J. Org. Chem.; 2002; 67, pp. 2566-2571. [DOI: https://dx.doi.org/10.1021/jo016277e]

28. Gansäuer, A.; Behlendorf, M.; Cangoenuel, A.; Kube, C.; Cuerva, J.M.; Friedrich, J.; van Gastel, M. H₂O Activation for Hydrogen-Atom Transfer: Correct Structures and Revised Mechanisms. Angew. Chem. Int. Ed.; 2012; 51, pp. 3266-3270. [DOI: https://dx.doi.org/10.1002/anie.201107556] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/22337565]

29. Muñoz-Bascón, J.; Sancho-Sanz, I.; Álvarez-Manzaneda, E.; Rosales, A.; Oltra, J.E. Highly selective Barbier-type propargylations and allenylations catalyzed by titanocene(III). Chem. Eur. J.; 2012; 18, pp. 14479-14486. [DOI: https://dx.doi.org/10.1002/chem.201201720]

30. Paradas, M.; Campaña, A.G.; Jiménez, T.; Robles, R.; Oltra, J.E.; Buñuel, E.; Justicia, J.; Cárdenas, D.J.; Cuerva, J.M. Understanding the Exceptional Hydrogen-Atom Donor Characteristics of Water in TiIII-Mediated Free-Radical Chemistry. J. Am. Chem. Soc.; 2010; 132, pp. 12748-12756. [DOI: https://dx.doi.org/10.1021/ja105670h]

31. Rosales, A.; Muñoz-Bascón, J.; Lopez-Sanchez, C.; Alvarez-Corral, M.; Muñoz-Dorado, M.; Rodriguez-Garcia, I.; Oltra, J.E. Ti-catalyzed homolytic opening of ozonides: A sustainable C-C bond-forming reaction. J. Org. Chem.; 2012; 77, pp. 4171-4176. [DOI: https://dx.doi.org/10.1021/jo300344a]

32. Previously unpublished results. Experimental Procedures and NMR Spectra are Reported in Supporting Information.

33. Rosales Martínez, A.; Rodríguez-García, I.; López-Martínez, J.L. Green reductive regioselective opening of epoxides: A green chemistry laboratory experiment. J. Chem. Educ.; 2022; 99, pp. 2710-2714. [DOI: https://dx.doi.org/10.1021/acs.jchemed.2c00409]

34. Rosales, A.; Muñoz-Bascón, J.; Roldan-Molina, E.; Castaneda, M.A.; Padial, N.M.; Gansauer, A.; Rodríguez-García, I.; Oltra, J.E. Selective reduction of aromatic ketones in aqueous medium mediated by Ti(III)/Mn: A revised mechanism. J. Org. Chem.; 2014; 79, pp. 7672-7676. [DOI: https://dx.doi.org/10.1021/jo501141y]

35. Barrero, A.F.; Rosales, A.; Cuerva, J.M.; Gansaeuer, A.; Oltra, J.E. Titanocene-catalyzed, selective reduction of ketones in aqueous media. A safe, mild, inexpensive procedure for the synthesis of secondary alcohols via radical chemistry. Tetrahedron Lett.; 2003; 44, pp. 1079-1082. [DOI: https://dx.doi.org/10.1016/S0040-4039(02)02703-X]

36. Campaña, A.G.; Estevez, R.E.; Fuentes, N.; Robles, R.; Cuerva, J.M.; Buñuel, E.; Cardenas, D.; Oltra, J.E. Unprecedented hydrogen transfer from water to alkenes and alkynes mediated by Ti^III and late transition metals. Org. Lett.; 2007; 9, pp. 2195-2198. [DOI: https://dx.doi.org/10.1021/ol070779i]

37. Gansäuer, A.; Narayan, S.; Schiffer-Ndene, N.; Bluhm, H.; Oltra, J.E.; Cuerva, J.M.; Rosales, A.; Nieger, M. An improved synthesis of Kagan’s menthyl substituted titanocene and zirconocene dichloride, comparison of their crystal structures, and preliminary catalyst evaluation. J. Organomet. Chem.; 2006; 691, pp. 2327-2331. [DOI: https://dx.doi.org/10.1016/j.jorganchem.2005.10.026]