Titanocene complexes and curcuminoid species have both independently been shown to exhibit a number of biologically relevant properties. While complexes of the type [(η5-cyclopentadienyl)Ti(β-diketonate)]+ have been reported, no curcumin-based analogue has ever been synthesized. Using a straight forward method, several [(η5-cyclopentadienyl)Ti( curc )]+ ( curc  = curcuminoidate) have been prepared using an array of synthetic curcumin analogues. 1H and 13C NMR spectroscopy, mass spectrometry and single crystal X-ray diffractometry have all been utilized to characterize these compounds

Osteraas, Krista L

Stepanova, Valeria A

English

OpenRiver@Winona State University

OpenRiver Student Research and Creative Projects 2022-2023 Student Research & Creative Achievement Projects 9-1-2023 Preparation and Characterization of New Titanocene(IV) Curcuminoid Complexes Krista L. Osteraas Winona State University Valeria A. Stepanova University of Wisconsin, La Crosse Follow this and additional works at: https://openriver.winona.edu/studentgrants2023 Recommended Citation Osteraas, Krista L. and Stepanova, Valeria A., "Preparation and Characterization of New Titanocene(IV) Curcuminoid Complexes" (2023). Student Research and Creative Projects 2022-2023. 12. https://openriver.winona.edu/studentgrants2023/12 This Grant is brought to you for free and open access by the Student Research & Creative Achievement Projects at OpenRiver. It has been accepted for inclusion in Student Research and Creative Projects 2022-2023 by an authorized administrator of OpenRiver. For more information, please contact klarson@winona.edu. Preparation and characterization of new titanocene(IV) curcuminoid complexesKrista L. Osteraas,1 Valeria A. Stepanova,2 and Joseph K. West11 Winona State University, Winona, MN2University of Wisconsin, La Crosse, La Crosse, WII would like to express thanks to the WSU Department of Chemistry, theUndergraduate Student Research and Creative Projects Grant, theUndergraduate Student Research and Creative Presentations Travel SupportGrant, as well as WSU Student Senate for funding the research and making itpossible to execute my project and travel to present.AbstractIntroductionMethodology Results ConclusionAcknowledgementsTitanocene complexes and curcuminoid species have bothindependently been shown to exhibit a number of biologicallyrelevant properties. While complexes of the type [(η5-cyclopentadienyl)Ti(β-diketonate)]+ have been reported, nocurcumin-based analogue has ever been synthesized. Using astraight forward method, several [(η5-cyclopentadienyl)Ti("curc")]+ ("curc" = curcuminoidate) havebeen prepared using an array of synthetic curcumin analogues.1H and 13C NMR spectroscopy, mass spectrometry and singlecrystal X-ray diffractometry have all been utilized tocharacterize these compounds.Curcumin is a chemical compound that is naturally occurring inturmeric and is known to have some bioactive properties.2Curcumin is commonly used for food coloring and flavor, suchas curry powders.Previous research of Titanocene Y (bis-[(p-methoxybenzyl)cyclopentadienyl] titanium dichloride) wasdone. It showed that Titanocene Y was successful in destroyingcancer cells.1 However, further research was required due to itsbroad cytotoxic activity. Titanocene dichloride was used in thisresearch project to develop a compound that is paired with anaturally occurring ligand to offset the broad cytotoxic effectsof Titanocene Y in hopes of synthesizing a potential anti-canceragent.In this study, a new class of titanocene(IV)curcuminoid complexes were explored to gain anunderstanding of their properties and bioactivities. Thisresearch provides a baseline of knowledge for further studiesto address how these complexes can be used and implemented.New compounds of [Cp2Ti(curc)]X were produced andstructures were verified using NMR and crystallography.Approach 1Early synthesis attempts were performed by dissolving 0.5mmol Cp2TiCl2 in a 1:2 solution of H2O/THF in a sealedmicrowave vial. Solution was stirred on stir plate with stir barand purged with N2 for 20 minutes and then placed in an icebath while stirring. 1 mmol of AgNO3 was dissolved in 1 mL ofH2O in a vial and added to the reaction using a needle. The vialwas covered with aluminum foil to protect the AgNO3 due tolight sensitivity. The reaction was stirred for an additional 30minutes. Precipitate was vacuum filtered off using a filter flaskand fritted filter funnel. The precipitate was washed with 2 mLof the H2O/THF solution. Orange liquid in filter flask wastransferred to a round bottom flask with stir bar and returned toan ice bath while stirring. 1 mmol of acac-4-OMe wasdissolved in THF until solution turned clear. The acac-4-OMe/THF solution was added to reaction and stirred in an icebath for 30 more minutes. The reaction vessel was thenremoved from the ice bath and left stirring at room temperaturefor 6 days. Precipitate formed during the 6 day period. Thesolution was filtered using a vacuum flask and fritted filter. Thedry product was transferred to a pre-weighed vial and the crudemass of the product was recorded. The product was thenredissolved in a hexane/DCM solution made from 5 mLhexane/3 mL DCM. The reaction was heated slightly whilestirring. Once fully dissolved, the reaction was removed fromheat and allowed to evaporate. NMR was taken of the dryproduct for characterization.Approach 2Curcuminoid and MeOH were combined in a vial and the solidwas allowed to dissolve. The curcuminoid was deprotonatedusing sodium methoxide (NaOMe). In a separate vessel,Cp2TiCl2 and MeOH were combined to mostly dissolve andthen AgNO3 was added. The Cp2Ti(NO3)2 solution was pipetfiltered into the curcuminoid solution to combine and allowedto stir. The solution was poured over a watch glass toevaporate. The dry product was scraped off of the watch glassand transferred to a pre-weighed vial. The product was thenredissolved in DCM and allowed to evaporate. NMR was takenof the dry product for characterization. Curcuminoids usedwere acac-4-methoxy and acac-4-chloro, as depicted in thescheme below.Approach 1Results yielded a red colored product. During the six days thatthe reaction was sitting, it gradually became darker. NMR wastaken of the final product and showed enol and aldehyde peaks,located around 17 ppm. The texture of the dry product wassticky and oily. The product did not dissolve well in DCM, butdid dissolve well in acetone. Crystallization attempts wereunsuccessful. NMR and an image of the product are depictedbelow.Approach 2Results yielded an orange-colored product. NMR was taken ofthe final product and suggested that the synthesis wassuccessful and the targeted product was acquired. NMR and animage of the products are depicted below.Approach 1The synthesis was unsuccessful in producing the targetedcompound. NMR showed aldehyde peaks, indicating thatstarting material was present. The highly unusual production ofaldehyde likely resulted from our starting curcuminoid. Thisresult, while missing our own target, may prove interesting andfruitful, opening new chemical transformations.Approach 2The synthesis was likely successful in producing the targetedcompound. Crystallization will be vital to verify the structure ofthe final product. Upon successful verification of the structure,many more titanocene-curcuminod complexes will besynthesized. Subsequently, the studies on their bioactivities,especially as cytotoxic agents, will be initiated. Directcomparisons to titanocene dichloride and the curcuminoidprecursors will be necessary to gauge the true capabilities ofthese complexes.(1) Oberschmidt, O.; Hanauske, A. R.; Pampillón, C.; Sweeney, N. J.; Strohfeldt, K.; Tacke, M. Antiproliferative Activity of Titanocene Y against TumorColony-Forming Units. Anticancer. Drugs 2007, 18 (3), 317–321. https://doi.org/10.1097/CAD.0b013e3280115f86.(2) Hartinger, C. G.; Metzler-Nolte, N.; Dyson, P. J. Challenges and Opportunities in the Development of Organometallic Anticancer Drugs.Organometallics 2012, 31, 5677–5685. https://doi.org/10.1021/om300373t.(3) Kuhn, A.; Conradie, J. Orbital Control over the Metal vs. Ligand Reduction in a Series of Neutral and Cationic Bis(Cyclopentadienyl) TI(IV)Complexes. New J. Chem. 2018, 2, 662–670. https://doi.org/10.1039/C7NJ03746E.(4) Lukose, P.; Narula, A. K. Synthesis and Characterisation of Organozirconium(IV) and Organotitanium(IV) - Acid Complexes. Indian J. Chem. 1990,29A (12), 1219–1221.(5) Kuhn, A.; Conradie, J. Electrochemical and Density Functional Theory Study of Bis(Cyclopentadienyl) Mono(β-Diketonato) Titanium(IV) CationicComplexes. Electrochimica Acta 2010, 56 (1), 257–264. https://doi.org/10.1016/j.electacta.2010.08.086.ReferencesFuture DirectionsFuture crystallization attempts should be performed to verifythe structures of the final products of the synthesis. Massspectrometry would also be a helpful tool for characterization.Once the structures are verified, bioactivity tests can be done todetermine if this compound could be useful as an anti-viral oranti-bacterial agent.Alternative synthetic routes (e.g. ligand exchange) may beexplored as well should this Approach 2 also proveunsuccessful. Given the precedent for β-diketonate complexesof the [Cp2Ti]2+ fragment, we would believe there is no reasonthat these complexes are not possible to produce.Eventual bioactivity assays are the primary end goal. Bothinteractions with DNA (via UV-vis and CD spectroscopies) aswell will be explored as will cytotoxicity assays against humancancer cell lines and other infective bacterial and viral agents.

Preparation and Characterization of New Titanocene(IV) Curcuminoid Complexes

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Preparation and Characterization of New Titanocene(IV) Curcuminoid Complexes

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