Titanocene Bis Research Articles

Metallocene-made mad metallacycles in synthesis and catalysis

Metallacycles of transition metals are generally of great interest because of their multifaceted structural chemistry and they are often discussed as key intermediates in multiple catalytic processes, whereupon recent studies are dealing with the participation of metallacycles in polymerization as well as oligomerization reactions. Synthesis and characterization of the titanocene bis(trimethylsilyl)acetylene complex Cp2Ti(η2-Me3SiC2SiMe3) paved the way towards the discovery of three-membered metallacyclopropenes of Group 4 metals (titanium, zirconium, and, later, hafnium) having their own history which is strongly connected with the names of M. E. Vol´pin and his co-workers. Starting from these compounds the very unusual ring-strained “all-C”-five-membered metallacyclocumulenes, metallacyclopentynes, and metalla-cycloallenes of Group 4 metals were obtained and characterized having all their roots in Vol´pin´s chemistry. This mini review gives an overview of these unusual molecules as well as some more common molecules like metallacyclopentanes, metallacyclopentenes, and metalla-cyclopentadienes. Very recently instead of these “all-C”-metallacycles the analogous heteroring systems (with N, S, O atoms instead of C) as well as the smaller four-membered metallacycles became the focus of our interest.

Reactions of Titanocene with Triazines and Dicyandiamide: Formation of Novel Di‐ and Trinuclear Metallacyclic Complexes

AbstractThe titanocene bis(trimethylsilyl)acetylene complex Cp2Ti(η2‐Me3SiC2SiMe3) (1) reacts with different triazines to give trinuclear titanocene compounds. Cleavage of the heterocyclic unit takes place in the reaction with cyanuric chloride, which furnishes a trinuclear cyanide bridged titanocene complex [Cp2Ti(CN)]3 (2). Reaction with cyanuric acid yields the paramagnetic ate complex (Cp2Ti)3(C3N3O3) (3). With melamine the structurally similar amide species (Cp2Ti)3[C3N3(NH)3] (4) is formed. A dinuclear, paramagnetic complex 5 is obtained in the reaction of 1 with dicyandiamide. Complexes 2, 4, and 5 were characterized by X‐ray analyses.

Synthesis and Structures of ansa‐Titanocene Complexes with Diatomic Bridging Units for Overall Water Splitting

The synthesis of a series of ansa-titanocene dichlorides [Cp'2TiCl2] (Cp' = bridged η(5)-tetramethylcyclopentadienyl) and the corresponding titanocene bis(trimethylsilyl)acetylene complexes [Cp'2Ti(η(2)-Me3SiC2SiMe3)] is described. The ethanediyl-bridged complexes [C2H4(C5Me4)2TiCl2] (2-Cl2) and [C2H4(C5Me4)2Ti(η(2)-Me3SiC2SiMe3)] (2-btmsa; btmsa = η(2)-Me3SiC2SiMe3) can be obtained from the hitherto unknown calcocenophane complex [C2H4(C5Me4)2Ca(THF)2] (1). Furthermore, a heterodiatomic bridging unit containing both, a dimethylsilyl and a methylene group was introduced to yield the ansa-titanocene dichloride [Me2SiCH2(C5Me4)2TiCl2] (3-Cl2) and the bis(trimethylsilyl)acetylene complex [Me2SiCH2(C5Me4)2Ti(η(2)-Me3SiC2SiMe3)] (3-btmsa). Besides, tetramethyldisilyl- and dimethylsilyl-bridged metallocene complexes (structural motif 4 and 5, respectively) were prepared. All ansa-titanocene alkyne complexes were reacted with stoichiometric amounts of water; the hydrolysis products were isolated as model complexes for the investigation of the elemental steps of overall water splitting. Compounds 1, 2-btmsa, 2-(OH)2, 3-Cl2, 3-btmsa, 4-(OH)2, 3-alkenyl and 5-alkenyl were characterised by X-ray diffraction analysis.

Titanocene(II)-Catalyzed Hydroboration of Carbonyl Compounds

Titanocene bis(catecholborane), [Cp2Ti(HBcat)2] (1), catalyzes the room-temperature hydroboration of carbonyl compounds by pinacolborane (HBpin) rapidly, cleanly, and chemoselectively. Aryl aldehydes and ketones produced alkoxypinacolboronate esters in moderate to high yields in 2 h, and facile hydrolysis of alkoxypinacolboronate esters over silica occurred cleanly to afford alcohols in good yields. Complex 1 demonstrated a preference for C═O bonds over C═C bonds in both conjugated and nonconjugated enones. Kinetic studies of the catalytic hydroboration of a series of acetophenones showed that electron-poor substrates undergo the reaction more quickly than electron-rich substrates. This result is consistent with the proposed mechanism, in which stronger π-acids should undergo C═O bond cleavage more readily. Computational studies using benzophenone and benzaldehyde showed that the hydroboration is spontaneous and likely proceeds via intermediates that are best described as Ti metallacycles whose structures are not significantly altered by substrate steric differences. This result indicates that similarities in the electronic properties of benzophenone and benzaldehyde supersede their steric differences in determining reaction outcomes.

Experimental and Theoretical Studies of Unusual Four‐Membered Metallacycles from Reactions of Group 4 Metallocene Bis(trimethylsilyl)acetylene Complexes with the Sulfurdiimide Me3SiN=S=NSiMe3 (Eur. J. Inorg. Chem. 4/2012)

AbstractThe cover picture shows the skyline of Rostock at night with a titanocene bis(trimethylsilyl)acetylene complex as well as the unusual metallacyclic complex [Cp2Ti(η2‐Me3SiN=S=NSiMe3)], which can readily be obtained from the former complex by reaction with the sulfurdiimide Me3SiN=S=NSiMe3, rising brightly into the sky. The synthesis and a detailed theoretical study of the structure and bonding of this exotic organometallic compound are described in the article by E. D. Jemmis, A. Schulz, U. Rosenthal et al. on p. 611 ff. magnified image

ChemInform Abstract: Air‐Stable Titanocene Bis(perfluorooctanesulfonate) as a New Catalyst for Acylation of Alcohols, Phenols, Thiols, and Amines under Solvent‐Free Conditions.

AbstractAcyl protection of a wide range of primary, secondary and tertiary aliphatic and aromatic alcohols is efficiently achieved using titanocene bis(perfluorooctanesulfonate) as catalyst under solvent‐free conditions.

Bis(η5:η1-pentafulvene)titanium Complexes: Catalysts for Intramolecular Alkene Hydroamination and Reagents for Selective Reactions with N−H Acidic Substrates

Intramolecular catalytic hydroamination reactions of geminally disubstituted amino alkenes employing the bulky substituted bis(η5:η1-pentafulvene)titanium complexes 1a and 1b and the corresponding benzannelated derivative 2 as catalysts are presented. While all three complexes are competent hydroamination catalysts, best results are achieved with the bis(benzofulvene) derivative 2. In addition, a series of Ti−N-containing compounds became available by stoichiometric reactions of 1 with N−H acidic substrates. In such a way, using aniline derivates (H2N−Ar, Ar: p-tolyl, 1-naphthyl) the bisamides (η5-C5H4−CHR2)2Ti(NHAr)2 (CHR2: adamantyl, Ar: p-tolyl 5a; R: p-tolyl, Ar: p-tolyl 5b; R: p-tolyl, Ar: 1-naphthyl 5c; CHR2: adamantyl, Ar: 1-naphthyl 5d) are prepared in high yields under mild conditions. In contrast to this, the employment of the catalytically relevant amine H2NCH2C(Ph)2CH2CH═CH2 (3a) in a reaction with (η5:η1-C5H4═CR2)2Ti (CR2: adamantylidene, 1a) leads to the titanium monoamide (η5:η1-C5H4═CR2)(η5-C5H4−CHR2)Ti(NHCH2C(Ph)2CH2CH═CH2) (6), characterized by X-ray diffraction. In reaction of 1a and 1b with benzophenone imine the titanocene bis(enamides) (η5-C5H4−CHR2)2Ti(N═CPh2)2 7a and 7b are formed. Titanium nitrogen double bonds are formed by treatment of 1a with 1,1-diphenylhydrazine. In that manner the hydrazido titanocene (η5-C5H4−CHR2)2Ti═N−N(Ph)2 (CHR2: adamantyl) was structurally characterized as the pyridine adduct 9. Three different Ti−N bonds are formed in one step by reaction of (η5:η1-C5H4═CR2)2Ti (R: p-tolyl, 1b) with 1,1-diphenylhydrazine and pyridine (py), leading to (η5-C5H4−CHR2)Ti(═N−NPh2)(−N−NPh2)py 10b (dative Ti−N bond: Ti−py 2.211(2) Ǻ, single Ti−N bond: Ti−NNPh2− 1.968(2) Ǻ, double Ti−N bond: Ti−NNPh22− 1.738(1) Ǻ). The formation of 10b is accompanied by the liberation of one C5H5CHR2 ligand. Generally, the bis(η5:η1-pentafulvene)titanium complexes 1 and 2 are valuable catalysts in hydroamination reactions and reagents in order to prepare Ti−N-containing metallocene-type derivatives.

Air-stable titanocene bis(perfluorooctanesulfonate) as a new catalyst for acylation of alcohols, phenols, thiols, and amines under solvent-free condition

Air-stable titanocene bis(perfluorooctanesulfonate) [Cp 2Ti(OSO 2C 8F 17) 2] that shows high Lewis acidity was prepared from Cp 2TiCl 2 and AgOSO 2C 8F 17. The compound was characterized by different techniques, and examined as a catalyst for acylation reactions. It was found that using equimolar acetic anhydride as acetylating agent and under solvent-free condition, Cp 2Ti(OSO 2C 8F 17) 2 exhibits high activity and selectivity in the acetylation of various alcohols, phenols, thiols, and amines. Also, good catalytic efficiency is observed in the acylation of 2-phenylethanol across various acylating reagents. The catalyst can be reused without loss of activity in a test of ten cycles. The Cp 2Ti(OSO 2C 8F 17) 2 catalyst affords a simple, efficient and general method for the acylation of alcohols, phenols, thiols, and amines.

Metallocene bis(perfluoroalkanesulfonate)s as air-stable cationic Lewis acids

Zirconocene and titanocene bis(perfluorooctanesulfonate)s were synthesized. In contrast to the corresponding triflates and perchlorates, these compounds are air- and water-stable. They were proved to be ionic on the basis of conductivity measurements and X-ray analysis, allowing these complexes to be stored for months. The strong Lewis acidity of these cationic metallocene species, which was proved by ESR study, enabled catalytic glycosylation.

Antitumor Activity of Titanocene Y in Xenografted PC3 Tumors in Mice

Chemotherapeutic options for androgen-independent prostate cancer are extremely limited with minimum survival advantage. The benzyl-substituted unbridged titanocene bis-[(p-methoxybenzyl) cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against the human prostate cancer androgen-independent cell, PC-3, which demonstrated an IC50 value of 56 x 10(-6) mol/L compared to 5.6 x 10(-6) mol/L for cisplatin. Then Titanocene Y was given at the maximum tolerable dose of 40 mg/kg/d on five consecutive days to one cohort of eight PC3 tumor-bearing male NMRI: nu/nu mice, while a second cohort was treated similarly with 3 mg/kg/d of cisplatin. Both of these mouse cohorts showed a statistically significant tumor growth reduction with respect to the third solvent-treated control group, which led to T/C values of 42% for cisplatin and 52% for Titanocene Y at the end of the experiment. This encouraging activity of Titanocene Y against prostate tumors in vivo, which is almost comparable with respect to cisplatin hopefully leads to further development of Titanocene Y in the future.

The synthesis and cytotoxic evaluation of a series of benzodioxole substituted titanocenes

AbstractUsing 6‐benzo[1,3]dioxolefulvene (1a), a series of benzodioxole substituted titanocenes was synthesized. The benzyl‐substituted titanocene bis[(benzo[1,3]dioxole)‐5‐methylcyclopentadienyl] titanium (IV) dichloride (2a) was synthesized from the reaction of Super Hydride with 1a. An X‐ray determined crystal structure was obtained for 2a. The ansa‐titanocene {1,2‐di(cyclopentadienyl)‐1,2‐di‐(benzo[1,3]dioxole)‐ethanediyl} titanium(IV) dichloride (2b) was synthesized by reductive dimerisation of 1a with titanium dichloride. The diarylmethyl substituted titanocene bis(di‐(benzo[1,3]dioxole)‐5‐methylcyclopentadienyl) titanium(IV) dichloride (2c) was synthesized by reacting 1a with the para‐lithiated benzodioxole followed by transmetallation with titanium tetrachloride. When titanocenes 2a–c were tested against pig kidney (LLC‐PK) cells inhibitory concentrations (IC50) of 2.8 × 10−4, 1.6 × 10−4 and 7.6 × 10−5 M, respectively, were observed. These values represent improved cytotoxicity against LLC‐PK, when compared with unsubstituted titanocene dichloride, but are not as impressive as values obtained for titanocenes previously synthesized using the above methods. Copyright © 2006 John Wiley & Sons, Ltd.

Glycol Methyl Ether and Glycol Amine Substituted Titanocenes as Antitumor Agents

Abstract6‐[4‐(2‐Methoxyethoxy)phenyl]fulvene (3a) and 6‐{4‐[2‐(dimethylamino)ethoxy]phenyl}fulvene (3b) were prepared as the starting materials for the synthesis of three different classes of titanocenes, which are ansa‐titanocenes, diarylmethyl‐substituted titanocenes and benzyl‐substituted titanocenes. Because the synthetic possibilities seem to be limited, only ansa‐titanocene {1,2‐bis(cyclopentadienyl)‐1,2‐bis[4‐(2‐methoxyethoxy)phenyl]ethanediyl}titanium dichloride (4a) and benzyl‐substituted titanocene bis‐{[4‐(2‐methoxyethoxy)benzyl]cyclopentadienyl}titanium(IV) dichloride (6a) were obtained and characterised. The change in the substitution pattern of the phenyl moiety from an oxygen atom to a nitrogen atom had such a big influence on the reaction that not one compound of the three titanocene classes could be synthesised, and it was also not possible to obtain diarylmethyl‐substituted titanocenes with the use of either of the fulvenes. When benzyl‐substituted titanocene 6a was tested against pig kidney cells (LLC‐PK), an antiproliferative effect that results in an IC50 value of 43 μM, was observed. This IC50 value is in the lower range of the cytotoxicities evaluated for titanocenes up to now. ansa‐Titanocene 4a surprisingly showed, when tested on the same cell line, a proliferative effect together with a fast rate of hydrolysis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

Anti-tumor activity of Titanocene Y in xenografted Caki-1 tumors in mice

The benzyl-substituted unbridged titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) was tested in vitro against human renal cancer cells (Caki-1), in which it showed an IC50 value of 36 x 10 mol/l. Titanocene Y was then given in vivo in doses of 10, 20, 30, 40 and 50 mg/kg on 5 consecutive days to Caki-1-bearing mice, and it showed concentration-dependent and statistically significant tumor growth reduction with respect to a solvent-treated control cohort. The maximum tolerable dose of Titanocene Y was determined to be 40 mg/kg and it showed significantly better tumor volume growth reduction than cisplatin given at a dose of 2 mg/kg. This superior activity of Titanocene Y with respect to cisplatin will hopefully lead to clinical tests against metastatic renal cell cancer in the near future.

In-vitro anti-tumor activity studies of bridged and unbridged benzyl-substituted titanocenes

The benzyl-substituted ansa-titanocenes [1,2-di(cyclopentadienyl)-1,2-di-(4-N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (Titanocene X) and [1,2-di(cyclopentadienyl)-1,2-bis(m-dimethoxyphenyl)ethanediyl] titanium dichloride (Titanocene Z), and the benzyl-substituted unbridged titanocene bis-[(p-methoxybenzyl)cyclopentadienyl] titanium(IV) dichloride (Titanocene Y) were tested on the growth of a wide variety of tumor cells in vitro on a panel of 36 human tumor cell lines containing 14 different tumor types investigated in a cellular proliferation assay. Titanocene Y with a mean IC50 value of 65.8 x 10 mol/l over the full panel of 36 cancer cell lines reaches the activity of cisplatin with 14.7 x 10 mol/l within a factor of 4, whereas Titanocene X and Z show significantly less cytotoxic activity. Titanocene Y is most effective on pleura mesothelioma, and uterine and renal cell cancer, where the IC50 values are comparable or significantly better than for cisplatin. In particular, in the case of renal cell cancer and pleura mesothelioma there is an obvious lack of chemotherapeutic reagents, which might be filled by Titanocene Y, where a very promising cytotoxic effect in comparison with cisplatin could be shown.

Interaction of bis(trimethylsilyl)acetylene complex of titanocene with mercury trifluoroacetate

The reaction of the bis(trimethylsilyl)acetylene complex of titanocene Cp2Ti(Me3SiC2SiMe3) with mercury trifluoroacetate (NF3COO)2Hg at 20 °C in a THF medium affords titanocene bis(trifluoroacetate) Cp2Ti(OCOCF3)2 and metallic mercury. The structure of Cp2Ti(OCOCF3)2 was established by the analytical and spectroscopic methods and X-ray diffraction analysis.

Reactions of methyl-substituted titanocene–bis(trimethylsilyl)acetylene complexes with acetone azine: crystal structures of (η 5:η 1-C 5HMe 3CH 2CMe 2NH) 2Ti and (C 5Me 5) 2Ti(NCMe 2)

The titanocene–bis(trimethylsilyl)acetylene (BTMSA) complexes Cp′ 2Ti[η 2-C 2(SiMe 3) 2] (Cp′C 5H 5− n Me n ; n=0–5) react with acetone azine Me 2CNNCMe 2 (AA) in two different ways depending on the number of Me substituents at the Cp′ ligands ( n). For n=0–2, BTMSA is replaced by AA, which then undergoes an oxidative addition accompanied by a proton transfer, affording titana-2-isopropyl-4-methyl-2,3-diazacyclopent-3-ene complexes A0– A2. For n=3–5, replacement of the acetylene is followed by the splitting of AA to give either (C 5Me 5) 2Ti(III)(NCMe 2) ( C5) or the Ti(IV) (Cp′A) 2Ti complexes B3 and B4 for n=3 and 4, respectively. The intramolecularly bridging Cp′A ligand 1-(η 5-2,3,5-trimethylcyclopentadienide)-2-(η 1-amide)-2,2′-dimethylethane arises from a formal insertion of the CN bond of isopropylidene amide into a CH bond of one methyl group of the cyclopentadienyl ligands before or after splitting of AA. Crystal structures of C5 and (η 5:η 1-C 5HMe 3CH 2CMe 2NH) 2Ti(IV) ( B4) were determined.

The reaction of titanocene bis(ferrocenylacetylide) and bis(ruthenocenylacetylide) with silver cation: formation of bis(Ti-tweezers) silver complexes

Titanocene bis(acetylide) where the acetylide has ferrocenyl or ruthenocenyl terminal group (C 5H 4R) 2Ti{(CC) n -Mc} 2, reacted with 0.5 equivalent amount of AgPF 6 giving cationic heptanuclear complexes of the form [(C 5H 4R) 4Ti 2{(CC) n -Mc} 4Ag](PF 6) ( 1a: R=SiMe 3, n=1, Mc=ferrocenyl, 2a: R=H, n=2, Mc=ferrocenyl, 3a: R=SiMe 3, n=2, Mc=ferrocenyl, 4a: R=SiMe 3, n=1, Mc=ruthenocenyl) in good yields. Likewise, complex [(C 5H 4SiMe 3) 4Ti 2(CCPh) 4Ag](PF 6) ( 5a) was isolated. The Ti(IV)–Fe(II)–Ag(I) complex 3a was structurally characterized to confirm the solid-state geometry of the first bis(Ti-tweezers) type chelate complex with silver cation in which the silver was coordinated by four triple bonds of the two titanocene bis(acetylide) moieties. The similar Ti(IV)–Ru(II)–Ag(I) complex 4a was also characterized by single-crystal X-ray analysis. Complex 3a reacted with 1.5 equivalents (with respect to Ti) of AgPF 6 to liberate Fc–(CC) 4-Fc (Fc=ferrocenyl) quantitatively.

Reductive coupling reaction induced by remote-site oxidation in titanocene bis(metallocenylacetylide), where metallocenyl = ferrocenyl or ruthenocenyl: a novel route to C n ( n = 4, 6, and 8) wire with the metallocenyl groups at both terminals

The titanocene bis(acetylide) complexes ( ν 5-C 5H 4) 2Ti[C  C) m −Mc)[C  C) n −Mc′] (R  H, SiMe 3: m, n = 1 or 2; Mc, Mc′ = ferroacenyl or ruthenocenyl) have been prepared and found to be easily oxidized with 2 equiv. amount of AgPF 6 liberating a neutral product, Mc−(CC) m (CC) n −Me′. Electrochemical studies indicate that the reaction is induced by initial oxidation of Me and Me′ followed by unprecedented reductive coupling of the two alkynyl carbons bound to titanocene.

Bis(η 5-cyclopentadienyl)bis(hexafluoroarsenato)titan(IV): Synthese, Charakterisierung und Struktur

The reaction of Cp 2TiCl 2 with AgAsF 6 or the reaction of Cp 2TiCl 2 with AsF 5, in SO 2 as the solvent, gives Cp 2Ti(AsF 6)Cp 2TiCl 2 in quantitative yields. The chemical characterization, the solvent equilibria, and the thermal decomposition behaviour are described on the basis of chemical analysis, 1H NMR, IR, Raman, and mass spectral data. The structure of titanocene bis(hexafluoroarsenate) has been determined by an X-ray diffraction study.

Tumor inhibition by titanocene complexes: influence upon two xenografted human lung carcinomas.

The influence of the organometallic complexes titanocene dichloride, titanocene dibromide, titanocene bis(hydrogenmaleinate), and titanocene bis(p-aminothiophenolate) bis(hydrochloride) on the development of a lung adenocarcinoma and a small cell lung carcinoma, both xenografted into athymic mice, was investigated in the present study. The tumors were growing s.c., and the substances administered i.p. as fivefold injections according to a Q2D X 5 (every 2 days X 5) or a Q3D X 5 schedule. In the case of lung adenocarcinoma, titanocene complexes inhibited tumor growth by more than 50% resulting in treated/control values of 20%-50%. The suppression remained stable beyond the end of the treatment period. In the case of small cell lung carcinoma, only those Q2D X 5 schedules, which corresponded to LD10 doses, effected considerable and stable growth inhibition to less than 50% of control values. Titanocene dichloride showed the greatest activity against both human tumors, followed by the p-aminothiophenolate, and hydrogenmaleinate derivatives.