Titanocene dichloride

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.[1] It shows antitumour activity and was the first non-platinum complex to undergo clinical trials as a chemotherapy drug.[2]

Titanocene dichloride
Names
IUPAC name
Dichloridobis(η5-cyclopentadienyl)titanium
Other names
titanocene dichloride, dichlorobis(cyclopentadienyl)titanium(IV)
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.013.669
RTECS number
  • XR2050000
UNII
Properties
C10H10Cl2Ti
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
Structure
Triclinic
Dist. tetrahedral
Hazards
R-phrases (outdated) R37, R38
S-phrases (outdated) S36
NFPA 704 (fire diamond)
Flammability (red): no hazard codeHealth code 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformReactivity code 1: Normally stable, but can become unstable at elevated temperatures and pressures. E.g. calciumSpecial hazards (white): no code
2
1
Related compounds
Related compounds
 Ferrocene
Zirconocene dichloride
Hafnocene dichloride
Vanadocene dichloride
Niobocene dichloride
Tantalocene dichloride
Molybdocene dichloride
Tungstenocene dichloride
TiCl4
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YN ?)
Infobox references

Structure

Cp2TiCl2 adopts a distorted tetrahedral geometry (counting Cp as a monodentate ligand). The Ti-Cl distance is 2.37 Å and the Cl-Ti-Cl angle is 95°.[3]

Preparation

The standard preparations of Cp2TiCl2 start with titanium tetrachloride. The original synthesis by Wilkinson and Birmingham uses sodium cyclopentadienide[4] is still commonly used:

2 NaC5H5 + TiCl4 → (C5H5)2TiCl2 + 2 NaCl

It can also be prepared by using freshly distilled cyclopentadiene rather than its sodium derivative:[5]

2 C5H6 + TiCl4 → (C5H5)2TiCl2 + 2 HCl

Reactions

Halide replacement reactions

Cp2TiCl2 is a generally useful reagent that effectively behaves as a source of Cp2Ti2+. A large range of nucleophiles will displace chloride. With NaSH and with polysulfide salts, one obtains the sulfido derivatives Cp2Ti(SH)2 and Cp2TiS5.[6]

The Petasis reagent, Cp2Ti(CH3)2, is prepared from the action of methylmagnesium chloride[7] or methyllithium[8] 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.[9][10]

Reactions affecting Cp ligands

One Cp ligand can be removed from Cp2TiCl2 to give tetrahedral CpTiCl3. This conversion can be effected with TiCl4 or by reaction with SOCl2.[11]

Titanocene itself, TiCp2, is so highly reactive that it rearranges into a TiIII hydride dimer and has been the subject of much investigation.[12][13] 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.[14] The same compound had been reported earlier by a lithium aluminium hydride reduction[15] and sodium amalgam reduction[16] of titanocene dichloride, and studied by 1H NMR[17] prior to its definitive characterisation.[12][13]

"Titanocene" is not Ti(C5H5)2, but rather this isomer with a fulvalene dihydride structure.[13][14]

Reduction

Reduction with zinc gives the dimer of bis(cyclopentadienyl)titanium(III) chloride in a solvent-mediated chemical equilibrium:[18][19]

Cp2TiCl2 is a precursor to TiII derivatives. 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:[20]

Cp2TiCl2 + 2 CO + Mg → Cp2Ti(CO)2 + MgCl2
Cp2TiCl2 + 2 PR3 + Mg → Cp2Ti(PR3)2 + MgCl2

Alkyne derivatives of titanocene have the formula (C5H5)2Ti(C2R2) and the corresponding benzyne complexes are known.[21] One family of derivatives are the titanocyclopentadienes.[22] Rosenthal's reagent, Cp2TiMe3(η2-SiC≡CSiMe3), can be prepared by this method. Two structures are shown, A and B, which are both resonance contributors to the actual structure of Rosenthal's reagent.[23]

Titanocene equivalents react with alkenyl alkynes followed by carbonylation and hydrolysis to form bicyclic cyclopentadienones, related to the Pauson–Khand reaction).[24] A similar reaction is the reductive cyclization of enones to form the corresponding alcohol in a stereoselective manner.[25]

Reduction of titanocene dichloride in the presence of conjugated dienes such as 1,3-butadiene gives η3-allyltitanium complexes.[26] Related reactions occur with diynes. Furthermore, titanocene can catalyze C–C bond metathesis to form asymmetric diynes.[22]

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.[21]

Medicinal research

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.[2][27]

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References
  1. Budaver, S., ed. (1989). The Merck Index (11th ed.). Merck & Co., Inc.
  2. Roat-Malone, R. M. (2007). Bioinorganic Chemistry: A Short Course (2nd ed.). John Wiley & Sons. pp. 19–20. ISBN 978-0-471-76113-6.
  3. Clearfield, Abraham; Warner, David Keith; Saldarriaga Molina, Carlos Hermán; Ropal, Ramanathan; Bernal, Ivan; et al. (1975). "Structural Studies of (π-C5H5)2MX2 Complexes and their Derivatives. The Structure of Bis(π-cyclopentadienyl)titanium Dichloride". Can. J. Chem. 53 (11): 1621–1629. doi:10.1139/v75-228.
  4. Wilkinson, G.; Birmingham, J.G. (1954). "Bis-cyclopentadienyl Compounds of Ti, Zr, V, Nb and Ta". J. Am. Chem. Soc. 76 (17): 4281–4284. doi:10.1021/ja01646a008.
  5. Birmingham, J. M. (1965). "Synthesis of Cyclopentadienyl Metal Compounds". Adv. Organometal. Chem. Advances in Organometallic Chemistry. 2: 365–413. doi:10.1016/S0065-3055(08)60082-9. ISBN 9780120311026.
  6. Shaver, Alan; McCall, James M.; Marmolejo, Gabriela (1990). "Cyclometallapolysulfanes (and Selanes) of Bis(η5-Cyclopentadienyl) Titanium(IV), Zirconium(IV), Molybdenum(IV), and Tungsten(IV)". Inorganic Syntheses. 27: 59–65. doi:10.1002/9780470132586.ch11.
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  10. Straus, D. A. (2000). "μ-Chlorobis(cyclopentadienyl)(dimethylaluminium)-μ-methylenetitanium". Encyclopedia of Reagents for Organic Synthesis. London: John Wiley.
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  14. Troyanov, Sergei I.; Antropiusová, Helena; Mach, Karel (1992). "Direct proof of the molecular structure of dimeric titanocene; The X-ray structure of μ(η5:η5-fulvalene)-di-(μ-hydrido)-bis(η5-cyclopentadienyltitanium)·1.5 benzene". J. Organomet. Chem. 427 (1): 49–55. doi:10.1016/0022-328X(92)83204-U.
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  20. Kuester, Erik (2002). "Bis(η5-2,4-cyclopentadienyl)bis(trimethylphosphine)titanium". Bis(5-2,4-cyclopentadienyl)bis(trimethylphosphine)titanium. Encyclopedia of Reagents for Organic Synthesis. John Wiley. doi:10.1002/047084289X.rn00022. ISBN 0471936235.
  21. Buchwald, S. L.; Nielsen, R. B. (1988). "Group 4 Metal Complexes of Benzynes, Cycloalkynes, Acyclic Alkynes, and Alkenes". Chem. Rev. 88 (7): 1047–1058. doi:10.1021/cr00089a004.
  22. Rosenthal, Uwe; Pellny, Paul-Michael; Kirchbauer, Frank G.; Burlakov, Vladimir V. (2000). "What Do Titano- and Zirconocenes Do with Diynes and Polyynes?". Chem. Rev. 33 (2): 119–129. doi:10.1021/ar9900109. PMID 10673320.
  23. Rosenthal, Uwe; Burlakov, Vladimir V.; Arndt, Perdita; Baumann, Wolfgang; Spannenberg, Anke (2003). "The Titanocene Complex of Bis(trimethylsilyl)acetylene: Synthesis, Structure, and Chemistry". Organometallics. 22 (5): 884–900. doi:10.1021/om0208570.
  24. Hicks, F. A.; et al. (1999). "Scope of the Intramolecular Titanocene-Catalyzed Pauson-Khand Type Reaction". J. Am. Chem. Soc. 121 (25): 5881–5898. doi:10.1021/ja990682u.
  25. Kablaoui, N. M.; Buchwald, S. L. (1998). "Development of a Method for the Reductive Cyclization of Enones by a Titanium Catalyst". J. Am. Chem. Soc. 118 (13): 3182–3191. doi:10.1021/ja954192n.
  26. Sato, F.; Urabe, Hirokazu; Okamoto, Sentaro (2000). "Synthesis of Organotitanium Complexes from Alkenes and Alkynes and Their Synthetic Applications". Chem. Rev. 100 (8): 2835–2886. doi:10.1021/cr990277l. PMID 11749307.
  27. Cini, M.; Bradshaw, T. D.; Woodward, S. (2017). "Using titanium complexes to defeat cancer: the view from the shoulders of Titans" (PDF). Chem. Soc. Rev. 46 (4): 1040–1051. doi:10.1039/C6CS00860G. PMID 28124046.CS1 maint: uses authors parameter (link)

Further reading
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