Bis(cyclopentadienyl)titanium(III) chloride

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Bis(cyclopentadienyl)titanium(III) chloride
Nugent-RajanBabu-reagent-3D-balls.png
Names
Other names
titanocene monochloride
Nugent–RajanBabu reagent
Identifiers
3D model (JSmol)
PubChem CID
Properties
C20H20Cl2Ti2
Molar mass 427.01 g·mol−1
Appearancegreen solid
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Bis(cyclopentadienyl)titanium(III) chloride, also known as the Nugent–RajanBabu reagent, is the organotitanium compound which exists as a dimer with the formula [(C5H5)2TiCl]2. It is an air sensitive green solid. The complex finds specialized use in synthetic organic chemistry as a single electron reductant.

Contents

In the presence of a suitable solvent that can act as a two-electron donor ("solv"), such as an ether like tetrahydrofuran, the dimer separates and forms a chemical equilibrium between the forms [(C5H5)2TiCl] and [(C5H5)2Ti(solv)Cl]. It is these forms that are responsible for much of the chemical properties of this reagent, which is also the reason that the substance is sometimes written as [(C5H5)2TiCl] or [Cp2TiCl], where Cp represents the cyclopentadienyl anion.

An example of an application of this reagent is in the preparation of vinorelbine, a chemotherapeutic agent which can be prepared in three steps from the naturally-occurring alkaloid leurosine.

Synthesis and structure

It was first reported in 1955 by Geoffrey Wilkinson [1] It is commonly prepared by reducing titanocene dichloride with zinc, [2] manganese, or magnesium. [3] For use in organic synthesis, the reagent is often prepared and used directly in situ . [4]

The molecule adopts a dimeric structure with bridging chlorides, [5] though in an appropriate solvent such as THF, [4] exists in a chemical equilibrium with monomeric structures: [5]

Nugent-RajanBabu reagent synthesis and equilibrium in solution N-RB equilibrium.jpg
Nugent–RajanBabu reagent synthesis and equilibrium in solution

The compound is also known as the Nugent–RajanBabu reagent, after scientists William A. Nugent and T. V. (Babu) RajanBabu, and has found applications in free radical and organometallic chemistry. [6]

Use in organic synthesis

N-RB reaction pathways.jpg

Bis(cyclopentadienyl)titanium(III) chloride effects the anti-Markovnikov opening of epoxides to a free radical intermediate and is tolerant of alcohols and some basic nitrogen functional groups, however it is sensitive to oxidizing functional groups such as nitro groups. [7] As can be seen in the above illustration, subsequent reaction proceeds along a pathway determined by added reagents and reaction conditions: [8]

N-RB ceratopicanol.png

The reagent has been used in the synthesis of over 20 natural products. [6] [7] [14] Ceratopicanol is a naturally-occurring sesquiterpene and its carbon skeleton is incorporated with the structures of both anislactone A and merrilactone A. [8] [14] A regioselective epoxide opening and 5-exo dig radical cyclization to forge the core of ceratopicanol. [14] [18] Addition of a hydrochloride salt to the reaction facilitates release of the oxygen-bound titanium(IV) intermediate, allowing the reagent to be recycled. [19]

The Madagascan periwinkle Catharanthus roseus L. is the source for a number of important natural products, including catharanthine and vindoline [20] and the vinca alkaloids it produces from them: leurosine and the chemotherapy agents vinblastine and vincristine, all of which can be obtained from the plant. [8] [21] [22] [23] The newer semi-synthetic chemotherapeutic agent vinorelbine is used in the treatment of non-small-cell lung cancer [22] [24] and is not known to occur naturally. However, it can be prepared either from vindoline and catharanthine [22] [25] or from leurosine, [26] in both cases by synthesis of anhydrovinblastine, which "can be considered as the key intermediate for the synthesis of vinorelbine." [22] The leurosine pathway uses the Nugent–RajanBabu reagent in a highly chemoselective de-oxygenation of leurosine. [14] [26] Anhydrovinblastine is then reacted sequentially with N-bromosuccinimide and trifluoroacetic acid followed by silver tetrafluoroborate to yield vinorelbine. [25]

Vinorelbine from leurosine and from catharanthine plus vindoline.jpg

Additional reactivity

Cyclic and benzylic ketones are reduced to their respective alcohols. [27]

Example of Barbier-type reaction catalysed by Cp2TiCl N-RB Barbier.jpg
Example of Barbier-type reaction catalysed by Cp2TiCl

Bis(cyclopentadienyl)titanium(III) chloride also effects both Pinacol [28] [29] and McMurry [30] couplings of aldehydes and ketones. Barbier-type reactivity is observed between aldehydes or ketones and allyl electrophiles under catalytic conditions. [31] The proposed mechanism involves titanium(III)-mediated generation of an allyl radical species which intercepts a titanium(III)-coordinated carbonyl. Another application involves the single electron reduction of enones to generate allylic radicals which can undergo intermolecular trapping with acrylonitirles to afford Michael type adducts. [32] Benzylic and allylic alcohols can be de-oxygenated under mild conditions using super-stoichiometric Cp2TiCl, however the reported scope for aliphatic alcohols is currently limited. [30]

Catalytic modification: addition of a mildly acidic HCl salt promotes cleavage of the Ti-O bond and allows regeneration of Cp2Ti Cl using a stoichiometric reductant N-RB cat cycle.jpg
Catalytic modification: addition of a mildly acidic HCl salt promotes cleavage of the TiO bond and allows regeneration of Cp2Ti Cl using a stoichiometric reductant

Mechanism

The dimeric titanium(III) complex reversibly dissociates to the monomer Cp2TiCl. This 15 electron species is Lewis acidic and thus binds epoxides and carbonyl compounds. [33] The complex transfers a single electron to the coordinated substrate generating an alkyl centered radical and an oxygen bound titanium(IV) species. This process is driven by the strength of the titanium-oxygen bond, as well as strain release in the case of epoxides. [34]

Related Research Articles

Epoxide class of chemical compounds

An epoxide is a cyclic ether with a three-atom ring. This ring approximates an equilateral triangle, which makes it strained, and hence highly reactive, more so than other ethers. They are produced on a large scale for many applications. In general, low molecular weight epoxides are colourless and nonpolar, and often volatile.

Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula LiAlH4. It was discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthesis, especially for the reduction of esters, carboxylic acids, and amides. The solid is dangerously reactive toward water, releasing gaseous hydrogen (H2). Some related derivatives have been discussed for hydrogen storage.

Titanium tetrachloride inorganic chemical compound

Titanium tetrachloride is the inorganic compound with the formula TiCl4. It is an important intermediate in the production of titanium metal and the pigment titanium dioxide. TiCl4 is a volatile liquid. Upon contact with humid air, it forms spectacular opaque clouds of titanium dioxide (TiO2) and hydrated hydrogen chloride. It is sometimes referred to as "tickle" or "tickle 4" due to the phonetic resemblance of its molecular formula (TiCl4) to the word.

Sodium borohydride Chemical compound

Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula NaBH4. This white solid, usually encountered as a powder, is a reducing agent that finds application in chemistry, both in the laboratory and on an industrial scale. It has been tested as pretreatment for pulping of wood, but is too costly to be commercialized. The compound is soluble in alcohols, certain ethers, and water, although it slowly hydrolyzes.

Vinorelbine pharmaceutical drug

Vinorelbine (NVB), sold under the brand name Navelbine among others, is a chemotherapy medication used to treat a number of types of cancer. This includes breast cancer and non-small cell lung cancer. It is given by injection into a vein or by mouth.

McMurry reaction

The McMurry reaction is an organic reaction in which two ketone or aldehyde groups are coupled to form an alkene using a titanium chloride compound such as titanium(III) chloride and a reducing agent. The reaction is named after its co-discoverer, John E. McMurry. The McMurry reaction originally involved the use of a mixture TiCl3 and LiAlH4, which produces the active reagent(s). Related species have been developed involving the combination of TiCl3 or TiCl4 with various other reducing agents, including potassium, zinc, and magnesium. This reaction is related to the Pinacol coupling reaction which also proceeds by reductive coupling of carbonyl compounds.

Titanocene dichloride chemical compound

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

Tebbes reagent chemical compound

The Tebbe's reagent is the organometallic compound with the formula (C5H5)2TiCH2ClAl(CH3)2. It is used in the methylenation of carbonyl compounds, that is it converts organic compounds containing the R2C=O group into the related R2C=CH2 derivative. It is a red solid that is pyrophoric in the air, and thus is typically handled with air-free techniques. It was originally synthesized by Fred Tebbe at DuPont Central Research.

Petasis reagent chemical compound

The Petasis reagent is an organotitanium compound with the formula Cp2Ti(CH3)2. It is an orange-colored solid.

<i>Vinca</i> alkaloid group of indole-indoline dimers obtained from the Vinca genus of plants

Vinca alkaloids are a set of anti-mitotic and anti-microtubule alkaloid agents originally derived from the periwinkle plant Catharanthus roseus and other vinca plants. They block beta-tubulin polymerization in a dividing cell.

Aluminium hydride chemical compound

Aluminium hydride (also known as alane or alumane) is an inorganic compound with the formula AlH3. It presents as a white solid and may be tinted grey with decreasing particle size and impurity levels. Depending upon synthesis conditions, the surface of the alane may be passivated with a thin layer of aluminum oxide and/or hydroxide. Alane and its derivatives are used as reducing agents in organic synthesis.

Organotitanium compound any metaloorganic compound having a carbon–titanium bond

Organotitanium compounds in organometallic chemistry contain carbon-to-titanium chemical bonds. Organotitanium chemistry is the science of organotitanium compounds describing their physical properties, synthesis and reactions. They are reagents in organic chemistry and are involved in major industrial processes.

The reduction of nitro compounds is a chemical reactions of wide interest in organic chemistry. The conversion can be effected by many reagents. The nitro group was one of the first functional groups to be reduced. Alkyl and aryl nitro compounds behave differently. Most useful is the reduction of aryl nitro compounds.

Titanocene dicarbonyl chemical compound

Dicarbonylbis(cyclopentadienyl)titanium is the chemical compound with the formula (η5-C5H5)2Ti(CO)2, abbreviated Cp2Ti(CO)2. This maroon-coloured, air-sensitive species is soluble in aliphatic and aromatic solvents. It has been used for the deoxygenation of sulfoxides, reductive coupling of aromatic aldehydes and reduction of aldehydes.

The Kulinkovich reaction describes the organic synthesis of cyclopropanols via reaction of esters with dialkyldialkoxytitanium reagents, generated in situ from Grignard reagents bearing hydrogen in beta-position and titanium(IV) alkoxides such as titanium isopropoxide. This reaction was first reported by Oleg Kulinkovich and coworkers in 1989.

Tributyltin hydride chemical compound

Tributyltin hydride is an organotin compound with the formula (C4H9)3SnH. It is a colorless liquid that is soluble in organic solvents. The compound is used as a source of hydrogen atoms in organic synthesis.

Organozirconium chemistry

Organozirconium compounds are organometallic compounds containing a carbon to zirconium chemical bond. Organozirconium chemistry is the corresponding science exploring properties, structure and reactivity of these compounds. Organozirconium compounds have been widely studied, in part because they are useful catalysts in Ziegler-Natta polymerization.

In organometallic chemistry, bent metallocenes are a subset of metallocenes. In bent metallocenes, the ring systems coordinated to the metal are not parallel, but are tilted at an angle. A common example of a bent metallocene is Cp2TiCl2. Several reagents and much research is based on bent metallocenes.

Titanocene pentasulfide chemical compound

Titanocene pentasulfide is the organotitanium compound with the formula (C5H5)2TiS5, commonly abbreviated as Cp2TiS5. This metallocene exists as a bright red solid that is soluble in organic solvents. It is of academic interest as a precursor to unusual allotropes of elemental sulfur as well as some related inorganic rings.

Zirconocene chemical compound

Zirconocene is a hypothetical compound with 14 valence electrons, which has not been observed or isolated. It is an organometallic compound consisting of two cyclopentadienyl rings bound on a central zirconium atom. A crucial question in research is what kind of ligands can be used to stabilize the Cp2ZrII metallocene fragment to make it available for further reactions in organic synthesis.

References

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