bis(cyclopentadienyl)titanium(III) chloride

It was first reported in 1955 by Geoffrey Wilkinson{{cite journal|last1 = Birmingham|first1 = J. M.|last2 = Fischer|first2 = A. K.|last3 = Wilkinson|first3 = G.|authorlink3 = Geoffrey Wilkinson|year = 1955|title = The reduction of bis-cyclopentadienyl compounds|journal = Naturwissenschaften|volume = 42|issue = 4|page = 96|doi = 10.1007/BF00617242|bibcode = 1955NW.....42Q..96B|s2cid = 44523847}} It is commonly prepared by reducing titanocene dichloride with zinc,{{cite book|series = Inorganic Syntheses|title = Inorganic Syntheses|first1 = L. E.|last1 = Manzer|first2 = E. A.|last2 = Mintz|first3 = T. J.|last3 = Marks| chapter=18. Cyclopentadienyl Complexes of Titanium(III) and Vanadium(III) |doi = 10.1002/9780470132524.ch18|volume = 21|year = 1982|pages = 84–86|isbn = 9780470132524}} manganese, or magnesium.{{cite journal|journal = Tetrahedron Letters|volume = 28|issue = 46|year = 1987|pages = 5717–5718|title = A highly stereoselective pinacolization of aromatic and α, β-unsaturated aldehydes mediated by titanium(III)-magnesium(II) complex|first1 = Yuichi|last1 = Handa|first2 = Junji|last2 = Inanaga|doi = 10.1016/S0040-4039(00)96822-9}} For use in organic synthesis, the reagent is often prepared and used directly in situ.{{cite journal|last1 = Nugent|first1 = William A.|last2 = RajanBabu|first2 = T. V.|title = Transition-metal-centered radicals in organic synthesis. Titanium(III)-induced cyclization of epoxy olefins|journal = Journal of the American Chemical Society|volume = 110|issue = 25|pages = 8561–8562|doi = 10.1021/ja00233a051|year = 1988| bibcode=1988JAChS.110.8561N }}

The molecule adopts a dimeric structure with bridging chlorides, though in an appropriate solvent such as THF, exists in a chemical equilibrium with monomeric structures:{{cite journal|title = Structural and magnetic properties of di-μ-chloro-bis[bis(η⁵-cyclopentadienyl)titanium(III)] and di-μ-bromo-bis[bis(η⁵-methylcyclopentadienyl)titanium(III)]|pages = 1645–1655|journal = Inorganic Chemistry|year = 1977|volume = 16|issue = 7|last1 = Jungst|first1 = Rudolph|last2 = Sekutowski|first2 = Dennis|last3 = Davis|first3 = Jimmy|last4 = Luly|first4 = Matthew|last5 = Stucky|first5 = Galen|doi = 10.1021/ic50173a015}}

File:N-RB equilibrium.jpg

File:Cp2TiCl2TiCp2 Spin Density.png

The molecule has been measured to be an open shell singlet with a J-coupling constant of -138 cm⁻¹.

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.{{cite journal|title = The Nugent Reagent: A Formidable Tool in Contemporary Radical and Organometallic Chemistry|first1 = Antonio|last1 = Rosales|first2 = Ignacio|last2 = Rodríguez-Garcia|first3 = Juan|last3 = Muñoz-Bascón|first4 = Esther|last4 = Roldan-Molina|first5 = Natalia M.|last5 = Padial|first6 = Laura P.|last6 = Morales|first7 = Marta|last7 = García-Ocaña|first8 = J. Enrique|last8 = Oltra|doi = 10.1002/ejoc.201500292|year = 2015|volume = 2015|issue = 21|pages = 4567–4591|journal = European Journal of Organic Chemistry}}
This review article was corrected to refer to the "Nugent–RajanBabu Reagent" rather than the "Nugent Reagent" by:
{{cite journal|title = The Nugent–RajanBabu Reagent: A Formidable Tool in Contemporary Radical and Organometallic Chemistry|first1 = Antonio|last1 = Rosales|first2 = Ignacio|last2 = Rodríguez-Garcia|first3 = Juan|last3 = Muñoz-Bascón|first4 = Esther|last4 = Roldan-Molina|first5 = Natalia M.|last5 = Padial|first6 = Laura P.|last6 = Morales|first7 = Marta|last7 = García-Ocaña|first8 = J. Enrique|last8 = Oltra|doi = 10.1002/ejoc.201500761|year = 2015|volume = 2015|issue = 21|page = 4592|journal = European Journal of Organic Chemistry|doi-access = free}}

File: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.{{cite book|title = Encyclopedia of Reagents for Organic Synthesis|last = Nugent|first = William A.|date = January 1, 2001|publisher = John Wiley & Sons|isbn = 9780470842898|doi = 10.1002/047084289x.rn00294}} As can be seen in the above illustration, subsequent reaction proceeds along a pathway determined by added reagents and reaction conditions:

• In the presence of hydrogen atom donors, such as 1,4-cyclohexadiene,{{cite journal|last1 = RajanBabu|first1 = T. V.|last2 = Nugent|first2 = William A.|last3 = Beattie|first3 = Margaret S.|title = Free radical-mediated reduction and deoxygenation of epoxides|doi = 10.1021/ja00173a045|journal = Journal of the American Chemical Society|volume = 112|issue = 17|pages = 6408–6409|year = 1990| bibcode=1990JAChS.112.6408R }} ^tBuSH,{{cite journal|last1 = RajanBabu|first1 = T. V.|last2 = Nugent|first2 = William A.|title = Selective generation of free radicals from epoxides using a transition-metal radical. A powerful new tool for organic synthesis|journal = Journal of the American Chemical Society|year = 1994|volume = 116|issue = 3|pages = 986–997|doi = 10.1021/ja00082a021| bibcode=1994JAChS.116..986R }} water,{{cite journal|last1 = Barrero|first1 = Alejandro F.|last2 = Oltra|first2 = J. Enrique|last3 = Cuerva|first3 = Juan M.|last4 = Rosales|first4 = Antonio|year = 2002|title = Effects of solvents and water in Ti(III)-mediated radical cyclizations of epoxygermacrolides. Straightforward synthesis and absolute stereochemistry of (+)-3α-hydroxyreynosin and related eudesmanolides|journal = Journal of Organic Chemistry|volume = 67|issue = 8|pages = 2566–2571|doi = 10.1021/jo016277e|pmid = 11950302}} the intermediate is protonated to an alcohol product. This transformation provides the complementary regioisomer to that of an epoxide opening using a metal hydride; in particular, the use of lithium aluminium hydride to form the Markovnikov alcohol and particularly axial cyclohexanols from epoxycyclohexanes is well known.{{cite journal|last1 = Rickborn|first1 = Bruce|last2 = Quartucci|first2 = Joe|title = Stereochemistry and mechanism of lithium aluminum hydride and mixed hydride reduction of 4-t-butylcyclohexene oxide|journal = Journal of Organic Chemistry|year = 1964|volume = 29|issue = 11|pages = 3185–3188|doi = 10.1021/jo01034a015}}{{cite journal|title = Reduction of epoxides. II. The lithium aluminum hydride and mixed hydride reduction of 3-methylcyclohexene oxide|first1 = Bruce|last1 = Rickborn|first2 = Wallace E.|last2 = Lamke|year = 1967|volume = 32|issue = 3|pages = 537–539|journal = Journal of Organic Chemistry|doi = 10.1021/jo01278a005}}
• Reaction of the intermediate with a second equivalent of Cp₂TiCl traps the radical as an alkyl-titanium(IV) species which can either undergo β-hydride elimination (favoured for 3° species) or dehydration via β-alkoxy elimination; in both cases an olefin product is generated.
• The radical intermediate can also be trapped intramolecularly when an appropriate acceptor moiety (such as an alkene, alkyne, carbonyl, etc.) is present in the epoxide. Synthesis of natural products with multiple ring systems have taken advantage of this pathway.{{cite journal|last1 = Morcillo|first1 = Sara P.|last2 = Miguel|first2 = Delia|last3 = Campaña|first3 = Araceli G.|last4 = Cienfuegos|first4 = Luis Álvarez de|last5 = Justicia|first5 = José|last6 = Cuerva|first6 = Juan M.|year = 2014|title = Recent applications of Cp₂TiCl in natural product synthesis|journal = Organic Chemistry Frontiers|volume = 1|issue = 1|pages = 15–33|doi = 10.1039/c3qo00024a|url = http://pubs.rsc.org/en/content/articlepdf/2014/qo/c3qo00024a|doi-access = free|hdl = 10481/47295|hdl-access = free}} Intermolecular trapping of acrylates and acrylonitriles with radicals derived from epoxides is possible,{{Cite journal|last1 = RajanBabu|first1 = T. V.|last2 = Nugent|first2 = William A.|title = Intermolecular addition of epoxides to activated olefins: a new reaction|year = 1989|journal = Journal of the American Chemical Society|volume = 111|issue = 12|pages = 4525–4527|doi = 10.1021/ja00194a073| bibcode=1989JAChS.111.4525R }} as well as conjunctive intra-intermolecular variants.{{cite journal|last1 = Gansäuer|first1 = Andreas|last2 = Pierobon|first2 = Marianna|last3 = Bluhm|first3 = Harald|year = 2002|title = Stereoselective synthesis of tri- and tetrasubstituted olefins by tandem cyclization addition reactions featuring vinyl radicals|journal = Angewandte Chemie International Edition|volume = 41|issue = 17|pages = 3206–3208|doi = 10.1002/1521-3773(20020902)41:17<3206::AID-ANIE3206>3.0.CO;2-2|pmid = 12207390}}
• Another pathway intercepts the radical intermediate with nickel catalysis and facilitates enantioselective cross-coupling of opened epoxides with halide and pseudohalide electrophiles.{{cite journal|year = 2015|last1 = Zhao|first1 = Yang|last2 = Weix|first2 = Daniel J.|title = Enantioselective cross-coupling of meso-epoxides with aryl halides|journal = Journal of the American Chemical Society|volume = 137|issue = 9|pages = 3237–3240|doi = 10.1021/jacs.5b01909|pmc = 4415026|pmid = 25716775| bibcode=2015JAChS.137.3237Z }}

File:N-RB ceratopicanol.png

The reagent has been used in the synthesis of over 20 natural products. Ceratopicanol is a naturally-occurring sesquiterpene and its carbon skeleton is incorporated with the structures of both anislactone A and merrilactone A. A regioselective epoxide opening and 5-exo dig radical cyclization to forge the core of ceratopicanol.{{cite journal|title = Cyclopentannulation by an iterative process of sequential Claisen rearrangement and enyne radical closure: Routes to triquinane and propellane systems and use in the synthesis of (±)-ceratopicanol|first1 = D. L. J.|last1 = Clive|first2 = Steven R.|last2 = Magnuson|first3 = Hartford W.|last3 = Manning|first4 = Darrin L.|last4 = Mayhew|journal = Journal of Organic Chemistry|volume = 61|issue = 6|pages = 2095–2108|doi = 10.1021/jo951930h|year = 1996}} Addition of a hydrochloride salt to the reaction facilitates release of the oxygen-bound titanium(IV) intermediate, allowing the reagent to be recycled.{{cite journal|last1 = Gansäuer|first1 = Andreas|last2 = Pierobon|first2 = Marianna|last3 = Bluhm|first3 = Harald|year = 1998|title = Catalytic, highly regio- and chemoselective generation of radicals from epoxides: Titanocene dichloride as an electron transfer catalyst in transition metal catalyzed radical reactions|journal = Angewandte Chemie International Edition|volume = 37|issue = 1–2|pages = 101–103|doi = 10.1002/(sici)1521-3773(19980202)37:1/2<101::aid-anie101>3.0.co;2-w}}

The Madagascan periwinkle Catharanthus roseus L. is the source for a number of important natural products, including catharanthine and vindoline{{cite book|chapter = Catharanthus roseus L. (Periwinkle): Production of Vindoline and Catharanthine in Multiple Shoot Cultures|first1 = K.|last1 = Hirata|first2 = K.|last2 = Miyamoto|first3 = Y.|last3 = Miura|title = Biotechnology in Agriculture and Forestry 26|series = Medicinal and Aromatic Plants|volume = VI|editor-first = Y. P. S.|editor-last = Bajaj|publisher = Springer-Verlag|year = 1994|pages = [https://archive.org/details/medicinalaromati0006unse/page/46 46–55]|chapter-url = https://books.google.com/books?id=e64hCDBddowC&pg=PA47|isbn = 9783540563914|url = https://archive.org/details/medicinalaromati0006unse/page/46}} 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.{{cite book|title = Metal Catalyzed Reductive C—C Bond Formation: A Departure from Preformed Organometallic Reagents|volume = 279|series = Topics in Current Chemistry|pages = 25–52|year = 2007|chapter = Reductive C—C bond formation after epoxide opening via electron transfer|first1 = Andreas|last1 = Gansäuer|first2 = José|last2 = Justicia|first3 = Chun-An|last3 = Fan|first4 = Dennis|last4 = Worgull|first5 = Frederik|last5 = Piestert|doi = 10.1007/128_2007_130|chapter-url = https://books.google.com/books?id=A5xcVmT9iIQC&pg=PA25|editor-first = Michael J.|editor-last = Krische|editor-link1=Michael J. Krische|publisher = Springer Science & Business Media|isbn = 9783540728795}}{{cite book|chapter = Africa's gift to the world|pages = 46–51|chapter-url = https://books.google.com/books?id=aXGmCwAAQBAJ&pg=PA46|title = Botanical Miracles: Chemistry of Plants That Changed the World|first1 = Raymond|last1 = Cooper|first2 = Jeffrey John|last2 = Deakin|publisher = CRC Press|year = 2016|isbn = 9781498704304}}{{cite journal|journal = Molecules|year = 2012|volume = 17|issue = 5|pages = 5893–5914|doi = 10.3390/molecules17055893|title = Modifications on the basic skeletons of vinblastine and vincristine|first1 = Péter|last1 = Keglevich|first2 = Laszlo|last2 = Hazai|first3 = György|last3 = Kalaus|first4 = Csaba|last4 = Szántay|pmid = 22609781|pmc = 6268133|doi-access = free}}{{cite book|last = Raviña|first = Enrique|title = The evolution of drug discovery: From traditional medicines to modern drugs|year = 2011|publisher = John Wiley & Sons|isbn = 9783527326693|pages = 157–159|chapter = Vinca alkaloids|chapter-url = https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA157}} The newer semi-synthetic chemotherapeutic agent vinorelbine is used in the treatment of non-small-cell lung cancer{{cite journal|journal = Clinical Medicine Insights: Oncology|year = 2011|volume = 5|pages = 131–144|doi = 10.4137/CMO.S5074|pmid = 21695100|pmc = 3117629|title = Safety and efficacy of vinorelbine in the treatment of non-small cell lung cancer|first1 = Bryan A.|last1 = Faller|first2 = Trailokya N.|last2 = Pandi}} and is not known to occur naturally. However, it can be prepared either from vindoline and catharanthine{{cite journal|last1 = Ngo|first1 = Quoc Anh|last2 = Roussi|first2 = Fanny|last3 = Cormier|first3 = Anthony|last4 = Thoret|first4 = Sylviane|last5 = Knossow|first5 = Marcel|last6 = Guénard|first6 = Daniel|last7 = Guéritte|first7 = Françoise|title = Synthesis and biological evaluation of Vinca alkaloids and phomopsin hybrids|journal = Journal of Medicinal Chemistry|year = 2009|volume = 52|issue = 1|pages = 134–142|pmid = 19072542|doi = 10.1021/jm801064y}} or from leurosine, in both cases by synthesis of anhydrovinblastine, which "can be considered as the key intermediate for the synthesis of vinorelbine." The leurosine pathway uses the Nugent–RajanBabu reagent in a highly chemoselective de-oxygenation of leurosine.{{cite journal|title = Concise synthesis of anhydrovinblastine from leurosine|first1 = Christophe|last1 = Hardouin|first2 = Eric|last2 = Doris|first3 = Bernard|last3 = Rousseau|first4 = Charles|last4 = Mioskowski|journal = Organic Letters|year = 2002|volume = 4|issue = 7|pages = 1151–1153|doi = 10.1021/ol025560c|pmid = 11922805}} Anhydrovinblastine is then reacted sequentially with N-bromosuccinimide and trifluoroacetic acid followed by silver tetrafluoroborate to yield vinorelbine.

File:Vinorelbine from leurosine and from catharanthine plus vindoline.jpg

Cyclic and benzylic ketones are reduced to their respective alcohols.{{cite journal|last1 = Barrero|first1 = Alejandro F.|last2 = Rosales|first2 = Antonio|last3 = Cuerva|first3 = Juan M.|last4 = Gansäuer|first4 = Andreas|last5 = Oltra|first5 = J. Enrique|year = 2003|title = Titanocene-catalysed, selective reduction of ketones in aqueous media. A safe, mild, inexpensive procedure for the synthesis of secondary alcohols via radical chemistry|journal = Tetrahedron Letters|volume = 44|issue = 5|pages = 1079–1082|doi = 10.1016/S0040-4039(02)02703-X}}

File:N-RB Barbier.jpg-type reaction catalysed by Cp₂TiCl]]

Bis(cyclopentadienyl)titanium(III) chloride also effects both Pinacol{{cite journal|last1 = Gansäuer|first1 = Andreas|year = 1997|title = Pinacol coupling of aromatic aldehydes catalysed by a titanocene complex: A transition metal catalysed radical reaction|journal = Chemical Communications|volume = 1997|issue = 5|doi = 10.1039/A608438I|pages = 457–458}}{{cite journal|last1 = Paradas|first1 = Miguel|last2 = Campaña|first2 = Araceli G.|last3 = Estévez|first3 = Rosa E.|last4 = Cienfuegos|first4 = Luis Álvarez de|last5 = Jiménez|first5 = Tania|last6 = Robles|first6 = Rafael|last7 = Cuerva|first7 = Juan M.|last8 = Oltra|first8 = J. Enrique|title = Unexpected Ti^III/Mn-promoted pinacol coupling of ketones|journal = Journal of Organic Chemistry|volume = 74|issue = 9|pages = 3616–3619|doi = 10.1021/jo9005238|pmid = 19334701|year = 2009}} and McMurry{{cite journal|last1 = Diéguez|first1 = Horacio R.|last2 = López|first2 = Armando|last3 = Domingo|first3 = Victoriano|last4 = Arteaga|first4 = Jesús F.|last5 = Dobado|first5 = José A.|last6 = Herrador|first6 = M. Mar|last7 = Moral|first7 = José F. Quílez del|last8 = Barrero|first8 = Alejandro F.|title = Weakening C—O bonds: Ti(III), a new reagent for alcohol deoxygenation and carbonyl coupling olefination|journal = Journal of the American Chemical Society|volume = 132|issue = 1|pages = 254–259|doi = 10.1021/ja906083c|pmid = 20000601|year = 2010}} couplings of aldehydes and ketones. Barbier-type reactivity is observed between aldehydes or ketones and allyl electrophiles under catalytic conditions.{{cite journal|last1 = Rosales|first1 = Antonio|last2 = Oller-López|first2 = Juan L.|last3 = Justicia|first3 = José|last4 = Gansäuer|first4 = Andreas|last5 = Oltra|first5 = J. Enrique|last6 = Cuerva|first6 = Juan M.|year = 2004|title = Unprecedented Barbier-type reactions catalysed by titanocene(III)|journal = Chemical Communications|volume = 2004|issue = 22|doi = 10.1039/B411173G|pmid = 15543313|pages = 2628–2629}} 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 acrylonitriles to afford Michael type adducts.{{cite journal|last = Streuff|first = Jan|year = 2011|title = A titanium(III)-catalyzed redox Umpolung reaction for the reductive cross-coupling of enones with acrylonitriles|journal = Chemistry – A European Journal|volume = 17|issue = 20|pages = 5507–5510|doi = 10.1002/chem.201100501|pmid = 21488110}} 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.

File:N-RB cat cycle.jpg

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.{{cite journal|last1 = Cangönül|first1 = Asli|last2 = Behlendorf|first2 = Maike|last3 = Gansäuer|first3 = Andreas|last4 = Gastel|first4 = Maurice van|title = Radical-based epoxide opening by titanocenes|journal = Inorganic Chemistry|year = 2013|volume = 52|issue = 20|pages = 11859–11866|doi = 10.1021/ic401403a|pmid = 24112112}} 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.{{cite journal|last1 = Gansäuer|first1 = Andreas|last2 = Barchuk|first2 = Andriy|last3 = Keller|first3 = Florian|last4 = Schmitt|first4 = Martin|last5 = Grimme|first5 = Stefan|last6 = Gerenkamp|first6 = Mareike|last7 = Mück-Lichtenfeld|first7 = Christian|last8 = Daasbjerg|first8 = Kim|last9 = Svith|first9 = Heidi|title = Mechanism of titanocene-mediated epoxide opening through homolytic substitution|journal = Journal of the American Chemical Society|year = 2007|volume = 129|issue = 5|pages = 1359–1371|doi = 10.1021/ja067054e|pmid = 17263420| bibcode=2007JAChS.129.1359G }}

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{{reflist|30em}}

{{Titanium compounds}}

{{Cyclopentadiene complexes}}

Category:Titanocenes

Category:Cyclopentadienyl complexes

Category:One-electron reducing agents

Category:Chloro complexes