Post on 15-Jul-2015
La Baule - Pornichet, France 29th sept. - 3rd oct. 2014
8th International Symposium on Technetium and
Rhenium: Science and Utilization
1
8th
International Symposium on Technetium and Rhenium: Science and Utilization.
September 29th
to October 3rd
2014. Proceedings and selected lectures. La Baule -
Pornichet, France. Eds. K.German, F.Poineau, M. Fattahi., Ya. Obruchnikova, A.
Safonov. Nantes Moscow Las Vegas : Granica Publishing House, 2014. 561 p.
IPCE RAS 2014
SUBATEC 2014
GRANITSA PUBLISHING HOUSE 2014
UNLV 2014
UDK 546.718 : 548.736
ISBN
Nantes Moscow Las Vegas
Granica Publishing House
2
Table of Contents
Chemistry of Technetium in the nuclear fuel cycle
Multiple Facets of Technetium and Rhenium Chemistry in Molecular
Imaging and Therapy. Roger Alberto, Samer Ursillo, Henrik
Braband, Michael Benz, Michael Felber, Sebastian Imstepf 10
Techntium behavior in the PUREX process. P. Baron 47
The role of a choice of the target form for 99
Tc transmutation. ..Kozar, K.E. German, V.F. Peretrukhin
61
Complexation and extraction of Pu(IV) in the presence of
pertechnetic acid. L. Venault, L. Abiad and Ph. Moisy 74
The ways of technetium localization at the SNF reprocessing. N.D.
Goletsky, B.Ya. Zilberman, Yu.S. Fedorov, A.S. Kudinov, A.A.
Timoshuk, L.V., Sytniuk, E.A. Puzikov, S.A. Rodionov, A.P.
Krinitsyn, V.I. Ryasantsev, D.V. Ryabkov, T.A. Boytsova
85
The nature of the technetium volatile species formed during
vitrification in borosilicate glass. Bradley Childs, Frederic Poineau,
Kenneth R. Czerwinski, and Alfred P Sattelberger.
102
Electrochemical studies of technetium-ruthenium and rhenium-
ruthenium alloys in nitric acid: implications for the long term
behavior of metallic technetium waste forms. Romina Farmand,
Frederic Poineau, Daniel J. Koury, David G. Kolman, Gordon D.
Jarvinen and Kenneth R. Czerwinski
114
Fundamental chemistry of Technetium and Rhenium
Review on the Tc Chemistry at SUBATECH in Inorganic Media
(Chloride, Sulfate, Carbonate) with or without Radiation Effect.
J. Vandenborre, M. Fattahi
128
Speciation of technetium in acidic media (CF3SO3H, H2SO4): Effect
of alpha radiations. Ibtihel Denden, Jrme Roques, Frdric Poineau, Massoud Fattahi
141
Study induced oxidation/reduction of Tc in carbonate media by and radiolysis. M. Ghalei, J.Vandenborre, G. Blain, F. Haddad, M. Fattahi-Vanani
159
Speciation of Technetium in Sulfuric Acid/Hydrogen Sulfide
Solutions. Maryline Ferrier, Frederic Poineau, Jerome Roques, 176
33
Alfred P. Satteleberger and Kenneth R. Czerwinski
Electrochemical properties of technetium species in acidic media. M.
Chotkowski 190
Aquatic chemistry and thermodynamics of Tc in dilute to
concentrated saline systems. E. Yalcintas, X. Gaona, A. C. Scheinost,
M. Altmaier, H. Geckeis
204
Density and activity of perrhenic and pertechnetic acid aqueous
solutions at 25C. P. Moeyaert, L. Abiad, C. Sorel, J.-F. Dufrche, M. Miguirditchian and P. Moisy
218
Comparative study of several supramolecular TcO4- and ReO4
-
receptors. K.E. German, Ya.A. Obruchnikova, G.V. Kolesnikov,
G.A. Kirakosyan, I.G. Tananaev, B.F. Myasoedov
229
The Chemistry of Technetium Chlorides. A. Sattelberger. 245
Synthesis and Characterization of Binary Technetium Bromides and
Iodides. Erik Johnstone, Frederic Poineau, Paul M. Forster, Alfred P.
Sattelberger and Kenneth R. Czerwinski
258
Dinuclear Technetium complexes with multiple metal-metal bonds.
Poineau F., Forster P.M., Todorova T.K., Johnstone E.V., Kerlin
W.M., Gagliardi L., Czerwinski K.R., Sattelberger A.P.
272
Polynuclear Technetium Iodides Compounds with Multiple Metal-
metal Bonds. W.M. Kerlin, F. Poineau, C. Malliakas, P.M. Forster,
A.P. Sattelberger, K.R. Czerwinski .
284
In-Situ Study Of Minor And Major Phase Formation And
Transformation In Tc Bearing Mineral Analogues with Carbonate
Starting Components. Gordon Thorogood, Brendan Kennedy, Emily
Reynolds, Massey De Los Reyes and Helen Brand.
302
Spectroscopic and Photophysical Properties of
Tetracyanidonitridorhenium(V) and -technetium(V) Complexes.
Takashi Yoshimura, Hayato Ikeda, Akitaka Ito, Eri Sakuda, Noboru
Kitamura, Tsutomu Takayama, Tsutomu Sekine and Atsushi
Shinohara
328
Educational Opportunities Within the UNLV Radiochemistry PhD
Program, J. Wendee. 344
Rhenium complexes of benzothiazoles as models for the diagnosis of
Alzheimer`s disease. T.I.A._Gerber,_X._Schoultz 356
44
Nitrosyltechnetium Complexes with Various P,N Ligands.
Janine Ackermann, Adelheid Hagenbach, Ulrich Abram
374
Fluorido Complexes of Low-valent Technetium. Samundeeswari
Mariappan Balasekaran, Adelheid Hagenbach, Ulrich Abram 390
Formation of nitrosyl-containing o-phenanthroline complex of iron in
presence of TcO4- and HNO3. Tatiana Boytsova, V.A. Babain, A.A.
Lumpov, A.A. Murzin
403
A new method for rapid extraction of rhenium from raw vegetation
with subsequent determination of the metal under field conditions.
Ognyan Bozhkov and Christina Tzvetkova
414
Rhenium in the industry
Sorption separation of Rhenium and associated components of
polymetallic raw materials. I. Troshkina, N.V. Balanovskyi, A.V.
Shilyaev, V.A. Moiseenko, Nway Shwan Oo
424
Ionosilicas for Ion Exchange Reaction. P. Hesemann, M. Gigue, P.
Moisy, B. Prelot, U. D. Thach 442
Study on Rhenium sorption at high rate from washing acid of the
sulphuric acid plant at balkhash copper plant. Sergey Zakharyan, A.B.
Yun, E.I. Gedgagov, I.V.Terentieva
464
Study on Rhenium desorption at high rate from macroporous low
base ionites. S. Zakharyan, A.B. Yun, E.I. Gedgagov, V.A. Chen 467
Technetium and Rhenium in nuclear medicine
Molybdenum-99 production from a thorium target irradiated by light
charged particles up to 70 MeV. C. Duchemin, Arnaud Guertin, Ferid
Haddad, Vincent Mtivier, Nathalie Michel
472
Rhenium-188: application for glioblastoma internal radiotherapy.
Annabelle Cikankowitz 473
Starch based microparticles radiolabelling with 99mTc and 188Re for
diagnostic and therapy of Hepatocellular carcinoma. E.Verger, A.
Cikankowitz, A. Bouvier, N. Lepareur, J. Benoit, J. Deloye, C. Aub, O. Couturier, F. Lacoeuille, R. Hustinx, F. Hindr
474
Rhenium-tricarbonyl with a new tripodal N2O ligand: from structural
investigations to a therapeutic radiopharmaceutical. Romain 475
55
Echeynne, Sihem Guizani, Mariusz Wolff, Eric Benoist, Nicolas
Lepareur
Interdisciplinary consortium collaboration for the development of
radiopharmaceutical approach for effective diagnostics and therapy of
prostate cancer in Russia. K. German, O. Vlasova, V. Petriev, V.
Skvortsov, G. Kodina, A. Maruk, N. Airapetova, N. Epshtein, N.
Nerozin, A. Safonov, V. Lebedev, Ya. Obruchnikova, Yu. Shevko
476
Influence of oxygen isotopes on the NMR parameters of the
pertechnetate anion TcO4- . Use of technetium-99g in PET nuclear
chemistry technology: application of 99gTc-NMR for analysis of O-
18 content in water. K. German, G. Kirakosyan, V. Tarasov
491
Poster session
Technetium and Rhenium sulfides formation: kinetics, structure and properties, K. E. German, A.V. Safonov A.A. Shiryaev, Ya. A.
Obruchnikova, V.A. Ilin, V.P. Tarasov, A. V. Afanasiev, V.E.
Tregubova, S.N. Kalmykov
494
Supramolecular interactions of caffeine molecules with each other,
water molecules and oxygen atoms of tetraoxidoanions in the three
new different compounds Me(H2O)6[ReO4]2.caffeine (Me = Co, Cd,
Mg ). K. German, M.N. Glazkova, M.S. Grigoriev, Ya.A.
Obruchnikova, G.V. Kolesnikov, Yu.A. Ustynyuk, F. Poineau, O.S.
Kryzhovets
503
Biological reduction of pertechnetate ion in the implementation of
technology biobarrer into aquifers contaminated with radioactive
waste. A. Safonov T. Khijniak, V. Ilin, K. German
510
Development of Bio filtration system for cleaning solutions from
uranyl and pertechnetate anions. A. Safonov, O. Gorbunova, T.
Khijniak, K. German
511
Platinum And Rhenium Recovery From PtRe Reforming Catalysts via Plasma Arc Technology. Peter Keeley, Neil Rowson, David
Deegan
512
Technetium and Rhenium Complexes with Heavy
Arylchalcogenolates. Bruno N. Cabral, Ernesto S. Lang, Adelheid
Hagenbach, Lars Kirsten, Ulrich Abram
516
Solvent extraction separation of Rhenium and Molybdenum using
octanols and mixtures of trisooctilamine 2-octanone in acid media. A. 523
66
Petrova, A. Kasikov
Evaluation of Rhenium Production Rates in Tungsten Irradiated in
Fast Reactors by Using Continuous Energy Monte Carlo Code MVP.
Tsugio Yokoyama, Atsunori Terashima and Masaki Ozawa
526
Application of Solvent Extraction Preconcentration methods for
Spectrophotometric Determination of Traces of Molybdenum in
Radiopharmaceutical Preparation using 1,5-Diphenylcarbazide.
Nafisa H. Gmati and M. A. Abuzwida
533
Biosorption processes for radioactive waste purification from Tc, U, Sr and Cs. Alexey Safonov, Varvara Tregubova, Olga Gorbunova,
Kjnstantin German, T. Nazina
537
Measurement of 99
Tc via Cherenkov counting. Mojmr Nmec,Kateina ubov
539
Tc(V) and Re(V) oxido complexes with tetradentate
thiocarbamoylbenzamidines for bioconjugation. Adelhei Hagenbach,
U.Abram
540
Review on Chemical Separation of Tc with Extraction
Chromatographic Resins. A. Bombard, S. Happel 544
Microorganisms from extreme habitats for use in biological
technologies to LRW treatment. A. Safonov, S. Gavrilov, T.
Khijniak, K. German, I. Troshkina
545
Octahedral chalcogenide rhenium cluster complexes with phosphine
and pyridine derivatives : synthesis, structure and properties. A.A.
Ivanov, V.K. Khlestkin, M.. Shestopalov, K.A.Brylev, Y.V. Mironov
550
Prospects of octahedral rhenium cluster complexes in biology and
medicine. Michael A. Shestopalov, Anna A. Krasilnikova, Kristina
E. Zubareva, Konstantin A. Brylev, Yuri V. Mironov
551
Rhenium recovery from secondary raw material. Anna Petrova,
Aleksandr Kasikov 552
77
The 8th
International
Symposium
on Technetium and Rhenium:
Science and Utilization, September 29th to October 3rd 2014
La Baule - Pornichet, France.
The 8th
ISTR aimed at continuing 20 years of tradition on Technetium and Rhenium conferences
and the symposium happening every 3 years. It was originally created in 1993 and has been
successively held in 1993 (Sendai, Japan), 1996 (Moscow, Russia), 1999 (Shizuoka, Japan),
2002 (Dubna, Russia), 2005 (Oarai-Ibaraki, Japan), 2008 (Port-Elizabeth, South Africa) and
2011 (Moscow, Russia).
The aims of the 8th
ISTR was to cover all aspects of Technetium and Rhenium chemistry. The
conference was organized around plenary lectures (30-40 minutes), short lectures (15-20)
minutes and poster sessions. The technical program has covered the following topics :
Chemistry of Technetium in the nuclear fuel cycle (separation, disposal, waste form) Technetium and Rhenium in nuclear medicine (isotopes production, labeling,
coordination chemistry) Radioanalytical chemistry (Measure of Tc an Re in biosphere) Fundamental chemistry of Technetium and Rhenium (synthetic, materials and
coordination chemistry, inorganic and organometallic complexes, properties...)
Rhenium in the industry (mining, metallurgy, catalysis)
88
Committees
International Advisory Committee
R. Alberto (Switzerland)
J. Barbet (France)
B. Bryskin (USA)
K. Czerwinski (USA)
J. R. Dilworth (England)
Y. Fujii (Japan)
T.I.A. Gerber (South Africa)
K.E. German (Russia)
G.E. Kodina (Russia)
Ph. Moisy (France)
M. Ozawa (Japan)
V.F. Peretrukhin (Russia)
A. Sattelberger (USA)
T. Sekine (Japan)
I.D. Troshkina (Russia)
A.Yu. Tsivadze (Russia)
F. Poineau (USA)
Yuezhou WEI (China)
Shuao Wang (China)
Local committee
Massoud Fattahi - Chair, Laboratoire SUBATECH - Ecole des Mines de Nantes La Chantrerie - 4 rue Alfred Kastler - BP 20722
44307 NANTES Cedex 3 - France - together with
:
Sverine Gadeyne Sophie Girault
Bernard Kubica
Tanja Pierret
Pascaline Rtout,
Philippe Moisy Co-chair, CEA MARCOULE - DEN/DRCP/SERA/LCAR - Bt 399,BP17171 30207 BAGNOLS-SUR-CEZE Cedex
Frdric Poineau Co-Chair, Department of Chemistry / University of Nevada, Las Vegas - 4505 S. Maryland Pkwy - Las Vegas, NV 89154
Contact : org_istr2014@subatech.in2p3.fr
Sponsored by :
99
Multiple Facets of Technetium and Rhenium Chemistry in Molecular
Imaging and Therapy
Roger Alberto, Samer Ursillo, Henrik Braband, Michael Benz, Michael Felber, Sebastian Imstepf
Department of Chemistry, University of Zurich, Winterthurerstr. 190, CH-8057 Zurich
PET is becoming more and more important, but 99mTc as a radionuclide for Single Photon Emission Computed Tomography (SPECT) has still the strongest impact on diagnostic health care. Whereas SPECT cameras can compete with PET cameras, chemical research efforts are required for keeping the role of Tc alive. Complementing diagnosis with 99mTc by therapeutic modalities is a clear asset over PET strategies (with 18F). Adapting the theranostic concept, we aim at synthesizing 99mTc complexes which mimic pharmacophores (imaging) with cold Re homologues (therapy), the 99mTc complex is a structural moiety in pharmaceutically active lead structures. This strategy requires demanding organometallic reactions. The preparation of cyclopentadienyl based bioorganometallic compounds is a focus since the Cp-ring can mimic phenyls in pharmaceuticals. Complexes of the type [(Cp-R)99mTc(CO)3] opened the so-called Cp-phenyl analogy.1 The Cp complex can be a tag, as will be shown with peptides (A),2 but also an integral part of structure in which it plays an essential role for receptor recognition. Examples with CA and HDAC inhibitors will be presented.3 Replacing Tc by Re will yield homologues with almost identical, pharmacological properties but with therapeutic potential.
We have extended the approach to cyclopentadienyl derivatives with two carboxylato groups (B) allowing to couple two bioactive functionalities to one 99mTc or Re complex. Finally, for replacing a phenyl ring in a pharmaceutical by a "true" phenyl ring, first insights in arene chemistry will be given. These aspects from low valent, organometallic chemistry will be rounded up by insights from high valent 99mTc and Re chemistry.4
1. Liu, Y.; Spingler, B.; Alberto, R. et al., J. Am. Chem. Soc., 2008, 130, 1554.2. Nadeem, Q.; Can, D.; Alberto, R. et al., Org. & Biomol. Chem., 2014, 12, 1966.3. Can, D.; Spingler, B.; Alberto, R.; et al., Angew. Chem. Int. Edit., 2012, 51, 3354.4. Braband, H., Benz, M., Tooyama, Y. Alberto, R. Chem. Commun., 2014, 50, 4126.
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MultipleFacetsofTechnetiumandRhenium
Chemistry in Molecular Imaging and Therapy
MultipleFacetsofTechnetiumandRhenium
Chemistry in Molecular Imaging and TherapyChemistryinMolecularImagingandTherapyChemistryinMolecularImagingandTherapy
RogerAlberto
D f Ch i
RogerAlberto
D f Ch iDepartmentofChemistryUniversityofZrich
DepartmentofChemistryUniversityofZrich
LaBaule Pornichet,France,September29,2014LaBaule Pornichet,France,September29,2014
OutlineOutline
Abitofhistory
Organometallic Chemistry and Coordination Chemistry
Abitofhistory
Organometallic Chemistry and Coordination ChemistryOrganometallicChemistryandCoordinationChemistry
OrganometallicChemistry andCoordinationChemistry
WhatcanwelearnfromMetalsinMedicine
IntegratedMolecularImagingAgents:Theranostics
Phenyl Cyclopentadienyl Analogy
OrganometallicChemistryandCoordinationChemistry
OrganometallicChemistry andCoordinationChemistry
WhatcanwelearnfromMetalsinMedicine
IntegratedMolecularImagingAgents:Theranostics
Phenyl Cyclopentadienyl Analogy
2
Functionalized Cyclopentadienylcomplexes
MissedOpportunities
Functionalized Cyclopentadienylcomplexes
MissedOpportunities
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Duringthepastfiveyears,therehasbeenadramaticsurgeofactivityintechnetiumchemistry,thisactivityhasbeendriventoalargeextentbythedesireofinorganicchemiststoobtainabasicunderstandingofthislargelyunexploredelement.AnevengreaterdrivingforcehasbeenprovidedbytheextensiveuseofTc99mindiagnosticnuclear
AbitofHistory..AbitofHistory..
e e g eate d g o ce as bee p o ded by t e e te s e use o c 99 d ag ost c uc eamedicineproceduresandthegrowingrealizationthatsignificantadvanceinthisappliedfieldwilldependuponbasicresearchinthefieldofinorganicTechnetiumchemistry
the several oxidation states of technetium exhibit diverse chemistries which will allow Tc99m
E.Deutsch,K.Libson andS.Jurisson,L.F.Lindoy inProgressinInorganicChemistry,1983,30,75
3
theseveraloxidationstatesoftechnetiumexhibitdiversechemistrieswhichwillallowTc 99mtobeincorporatedintoavarietyofformulationsthatarespecificfordifferentorgans,thus,variouschemicalformsofthesingleisotope
E.Deutsch,K.Libson andS.Jurisson,L.F.Lindoy inProgressinInorganicChemistry,1983,30,75
Oneofthereasonsfortheincreasedinterestintechnetiumchemistryduringthelastfewyearsisthewidespreaduseofradiopharmaceuticallabelledwith99mTc.{..}However,Fig.2showsthatthenumberofstudiesreportedonnew99mTcradiopharmaceuticalshasdecreasedfrom1977to1980.Thisfactevidencesastall
i i i di h i l h h ill l b ll i d b h
AbitofHistory..AbitofHistory..
positioninradiopharmaceuticalresearchthatwillonlybealleviatedbyFurtherdevelopmentoftechnetiumchemistry.Fortunatelystudiesonthecoordinationchemistryareexpanding.
JACS,1952
G.Bandoli,U,Mazzi,E.Roncari,Coord.Chem.Rev.1982,44,191
TechnetiumandChemistry
4
112
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Duringthisperiodoftime*,thecoordinationchemistryoftechnetiumplayedasignificantrole.Thesuccessfuldevelopmentof99mTcimagingagentswastotallydependentonthedesignoftechnetiumcomplexes sincethebiodistributionandtargeting capability depend exclusively on their lipophilicity, size and charge.
AbitofHistory..AbitofHistory..
targetingcapabilitydependexclusivelyontheirlipophilicity,sizeandcharge.
Theroleofcoordinationchemistryinthedevelopmentoftargetspecificradiopharmaceuticals
Althoughthefocusofradiopharmaceuticalresearchhasshiftedtowardsbiologicalcharacterizationofradiolabeledreceptorligandsinthelastseveralyears,coordination chemistrystillplaysasignificantroleinthedesignanddevelopmentofnewtargetspecificradiopharmaceuticals.
5
S.Liu, Chem.Soc.Rev.2004,33,445
Muchofthisworkhasbeendirectedtowardtheinvestigationofkineticallyinertcomplexesformedinoxidationstatesthatarereadilyaccessibleinaqueousmediab th d ti f th t h t t i Th t di h d t t d th t
AbitofHistory..AbitofHistory..
bythereductionofthepertechnetateion.ThesestudieshavedemonstratedthatitispossibletoprepareclassesofstablecomplexesinboththeVandtheIIIoxidationstateswiththeappropriatechoiceofligand.
Thisinturnhasenabledus(a)tosynthesizethisclassofair andwaterstablecomplexesattracerconcentrations(ca.108109 M)withmetastable 99mTc(b,)tobegintoevaluatethebiologicaldistributionsofthesecomplexesinanimals,and( )
6
(c)toestablishstructurefunctioncorrelationsonapotentiallylargeclassofwellcharacterizedcomplexes.
SynthesisandCharacterizationofHexakis(alkylisocyanide)andHexakis(arylisocyanide)ComplexesofTechnetium(I)M.J.Abrams,A.Davison,A.G.Jones,C.E.Costello,H.Pang,Inorg.Chem.,1983,22,2798
113
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Forthesynthesisofspecificradiopharmaceuticals,theversatilechemistryofthistransitionelement,apparentfromtheexistenceofcompoundsinalargenumberoftechnetiumoxidationstates,isanadvantage.However the labeling requires the complexing of 99mTc with suitable functional groups
AbitofHistory..AbitofHistory..
However.thelabelingrequiresthecomplexing of99mTcwithsuitablefunctionalgroups.
K.Schwochau,Angew.Chem.Int.Ed.,1994,33,2258
TheearlyhistoryoftechnetiumandtechnetiumradiopharmaceuticalsisbestcharacterizedbythequotefromLouisPasteur:Inthefieldsofobservations,chancefavors onlythepreparedmind
7
UnparalleledcontributionsofTechentium99mtoMedicineover5decadesW.C.Eckelman,CardiovascularImaging,2009,2,364
OrganometallicchemistryandCoordinationchemistryOrganometallicchemistryandCoordinationchemistry
Complexes;noMCbondsCoordinationcompoundsaregenerallythermodynamicallyverystableChelateeffectplaysanimportantrole;entropiccontrolpH dependencies; competition metalbindingH+
Complexes;noMCbondsCoordinationcompoundsaregenerallythermodynamicallyverystableChelateeffectplaysanimportantrole;entropiccontrolpH dependencies; competition metalbindingH+
InTechnetiumcoordinationchemistry:afewbasicligandtypesInTechnetiumcoordinationchemistry:afewbasicligandtypes
pHdependencies;competitionmetal binding HpHdependencies;competitionmetal binding H
8
PnAO,MAMA,MAGs,DADTetcandderivativesPnAO,MAMA,MAGs,DADTetcandderivatives
Designedforthe{Tc=O}3+ andthe{TcN}2+ coreDesignedforthe{Tc=O}3+ andthe{TcN}2+ core
114
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5
DTPA
Ligandsforthe3+family,Ga3+,Lu3+,In3+,Gd3+ etcLigandsforthe3+family,Ga3+,Lu3+,In3+,Gd3+ etc
OrganometallicchemistryandCoordinationchemistryOrganometallicchemistryandCoordinationchemistry
DOTA TETA
NOTA
YDOTAYDOTA YDOTAYDOTA
9
HYNIC,awonderfulcoordinationchemistryapproach..HYNIC,awonderfulcoordinationchemistryapproach..
OrganometallicchemistryandCoordinationchemistryOrganometallicchemistryandCoordinationchemistry
terminaldiazenidoterminaldiazenido
zwitterionicdiazenidozwitterionicdiazenido
bidentatediazenidobidentatediazenido
monodentatediazene
monodentatediazene
bentdiazenidobent
diazenido
O NH
R..butrequiresmultidentatecoligands..butrequiresmultidentatecoligands
10
N
N
N
TcLO
NHN
O
O
H
OH
COOH
tricine tricine tricine +LEDDA
J.Dilworthetal.
115
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6
HYNIC,awonderfulcoordinationchemistryapproach..HYNIC,awonderfulcoordinationchemistryapproach..
OrganometallicchemistryandCoordinationchemistryOrganometallicchemistryandCoordinationchemistry
Modelcomplexes
TcNCl
NH
Cl
Cl
NN
N
N
H
11J.Dilworth J.etal., J.Chem.Soc.DaltonT. 1994,1251;T.Nicholson,J.Zubieta,J.Babich etal., Inorg.Chim.Acta, 1996,252,421;Inorg.Chem., 1998,37,2701.
Organometallicchemistry andCoordinationchemistryOrganometallicchemistry andCoordinationchemistry
oneormoreMCbondsbondsessentiallycovalentstabilityratherkineticthanthermodynamicchelate effect plays a minor role (robustness)
oneormoreMCbondsbondsessentiallycovalentstabilityratherkineticthanthermodynamicchelate effect plays a minor role (robustness)chelateeffectplaysaminorrole(robustness)closedshellcomplexes,diamagnetic,oftenredoxinertrarelypHdependenciesduetocovalentbonds
chelateeffectplaysaminorrole(robustness)closedshellcomplexes,diamagnetic,oftenredoxinertrarelypHdependenciesduetocovalentbonds
OrganometalliccompoundsrelyonafewbasicligandclassesOrganometalliccompoundsrelyonafewbasicligandclasses
OR
R'
12
[Tc2(CO)10]
J.C.Hileman etal.,JACS,1961,83,2953W.Hieber etal.ANIE,1961,73,579
[Tc(5C5H5)(CO)3]Carbonmonoxide Cyclopentadienyl Carbene
[Tc2(CO)9(=C(COMe)R)]
E.O.Fischeretal.,Chem.Ber.,1972,105,3027
Ch.Palmetal.Naturwissenschaften,1962,49,279
areneF.Baumgrtner etal.
Chem.Ber.,1961,94,2198
[Tc(C6H6)2]+
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Organometallicchemistry andCoordinationchemistryOrganometallicchemistry andCoordinationchemistry
oneormoreMCbondsbondsessentiallycovalentstabilityratherkineticthanthermodynamicchelate effect plays a minor role (robustness)
oneormoreMCbondsbondsessentiallycovalentstabilityratherkineticthanthermodynamicchelate effect plays a minor role (robustness)chelateeffectplaysaminorrole(robustness)closedshellcomplexes,diamagnetic,oftenredoxinertrarelypHdependenciesduetocovalentbonds
chelateeffectplaysaminorrole(robustness)closedshellcomplexes,diamagnetic,oftenredoxinertrarelypHdependenciesduetocovalentbonds
OrganometalliccompoundsrelyonafewbasicligandclassesOrganometalliccompoundsrelyonafewbasicligandclasses
otherligands
13
[Tc(CNtBu)6]+
isonitrileM.J.Abrams etal.
J.LabelledComp.Radiopharm.,1982,14,1596
alkyle
[Tc2O4(CH3)4]
W.A.Herrmannetal.ANIE.,1990,29,189
alkenealkine
? ?
Organometallicchemistry andCoordinationchemistryOrganometallicchemistry andCoordinationchemistry
Difficultieswithorganometallic(technetium)compoundsDifficultieswithorganometallic(technetium)compoundslowoxidationsstates;reductionpronetobackoxidationsolubilitiesofligandsinwaterhydrolytic stability of complexes
lowoxidationsstates;reductionpronetobackoxidationsolubilitiesofligandsinwaterhydrolytic stability of complexeshydrolyticstability ofcomplexesStabilityofligandsinwateraccessibilityofligands andderivativesligandcentredreactivities
hydrolyticstability ofcomplexesStabilityofligandsinwateraccessibilityofligands andderivativesligandcentredreactivities
notveryattractiveconditionsforradiopharmaceuticalapproaches!notveryattractiveconditionsforradiopharmaceuticalapproaches!
14
CN-R
Tc
CN-RR-NC CN-R
CN-RR-NC[99mTcO4]-[S2O4]2- Cu+
H2O / 10min 98o C
yield >98%
M.J.Abrams etal. Inorg.Chem.1983,22,2798
arock!!
117
10/7/2014
8
Organometallicchemistry/MetalsinMedicineOrganometallicchemistry/MetalsinMedicine
OrganometalliccompoundsinotherfieldsoflifesciencesOrganometalliccompoundsinotherfieldsoflifesciences
BioorganometallicChemistry:TherapyBioorganometallicChemistry:Therapy
Cyclopentadienyls Carbenes Arenes
15P.J.Dysonetal.J.Med.Chem. 2011,54,3895/G.Savaetal.DaltonT. 2011,40,9069/C.Hartinger etal.Organometallics,2012,31,5677G.Jaouenetal.Chem.Brit.,2001,37,36;J.Med.Chem.2006,48, 3937,M.Tackeetal.Metallomics,2011,3,74.
OrganometalliccompoundsinotherfieldsoflifesciencesOrganometalliccompoundsinotherfieldsoflifesciences
BioorganometallicChemistry:TherapyBioorganometallicChemistry:Therapy
Organometallicchemistry/MetalsinMedicineOrganometallicchemistry/MetalsinMedicine
NH2O
N Peptide
cyclopentadienyl alkines /alkyls arenes
16
Mo
COCO
ONH2N N Peptide
P.KpfMaieretal.,ANIE. 1984,23,456/D.R.vanStaveren etal.Chem.Commun. 2002,1406.G.Jaouen(ed)inBioorganometallics,WileyVCH,2004
carbonyls 3allyl
EssentiallyallorganometallicligandsarefoundinMetalsinMedicineEssentiallyallorganometallicligandsarefoundinMetalsinMedicine
118
10/7/2014
9
OrganometalliccompoundsinotherfieldsoflifesciencesOrganometalliccompoundsinotherfieldsoflifesciences
MetalsinMedicineMetalsinMedicine
C M F C Ni CC M F C Ni C
Organometallicchemistry/MetalsinMedicineOrganometallicchemistry/MetalsinMedicine
Cr Mn Fe Co Ni CuMo Tc Ru Rh Pd Ag
Re Os Ir Pt Au
Cr Mn Fe Co Ni CuMo Tc Ru Rh Pd Ag
Re Os Ir Pt Au
Essentiallynothingwithrhenium, notwithcoldandscarcelywith186/188ReEssentiallynothingwithrhenium, notwithcoldandscarcelywith186/188Re
T h ti Rh i th t h d i diT h ti Rh i th t h d i di
17
didwemisssomething?didwemisssomething?
Technetium Rhenium,thematchedpairparadigmTechnetium Rhenium,thematchedpairparadigm
OrganometalliccompoundsinotherfieldsoflifesciencesOrganometalliccompoundsinotherfieldsoflifesciencesUnderestimatedPotentialofOrganometallicRheniumComplexesasAnticancerAgents*
Organometallicchemistry/MetalsinMedicineOrganometallicchemistry/MetalsinMedicine
18
*GillesGasseretal.ACSChem.Biol.2014,inpress
ManyRecomplexesshowlowmicromolar cytotoxicity againstvarietiesofcancercelllines!ManyRecomplexesshowlowmicromolar cytotoxicity againstvarietiesofcancercelllines!
Rheniumastherapeuticcomplexes areessentiallynotexploredRheniumastherapeuticcomplexes areessentiallynotexplored
119
10/7/2014
10
RecentdevelopmentsinbioorganometallicchemistryRecentdevelopmentsinbioorganometallicchemistry
mostcomplexesinbomc arenontargeting,cisplatinlikemostcomplexesinbomc arenontargeting,cisplatinlike
ExtensionoftheconceptExtensionoftheconcept
Organometallicchemistry/MetalsinMedicineOrganometallicchemistry/MetalsinMedicine
pp
A
D CB
10/7/2014
11
MetalsinMedicine:ComplexmediatedactivityMetalsinMedicine:Complexmediatedactivity
Organometallicchemistry/MetalsinMedicineOrganometallicchemistry/MetalsinMedicine
IC50=130nMPAK1
IC50=130nMPAK1
IC50=70nMMSK1
IC50=70nMMSK1
IC50=40nMPi3K
IC50=40nMPi3K
IC50=0.5nMPim1
IC50=0.5nMPim1
IC50=0.4nMGSK3
IC50=0.4nMGSK3
ProteinKinase InhibitorProteinKinase Inhibitor MLCKinhibitor4.4nMMLCKinhibitor4.4nM Pim1inhibitor0.07nMPim1inhibitor0.07nM
E.Meggersetal., Chem.Commun.2009,1001; JACS.2011,133,5976;ANIE 2011,50,2442
21Rhenium fortherapy Technetium fordiagnosisRhenium fortherapy Technetium fordiagnosis
FinetuningofmetalcomplexguidesaffinityandselectivityFinetuningofmetalcomplexguidesaffinityandselectivity
canweestablishsimilarformatchedpairelementscanweestablishsimilarformatchedpairelements
MetalsinMedicine:ComplexmediatedactivityMetalsinMedicine:Complexmediatedactivity
Structuralmimics ofsteroidhormonesStructuralmimics ofsteroidhormones
Organometallicchemistry/MetalsinMedicineOrganometallicchemistry/MetalsinMedicine
22
J.A.Katzenellenbogen etal.,JACS,1993,115,7045;J.Med.Chem.,1994,37,928; J.Org.Chem.,1997,62,6290;J.Org.Chem.,1996, 61,2624
Denovoinhibitors forreceptorsDenovoinhibitors forreceptors
Challengingfor99mTcchemistrywithcoordinationcompoundsChallengingfor99mTcchemistrywithcoordinationcompounds
2121
10/7/2014
12
Tc vectorTc
bioinactivebioinactive bioactivebioactive bioactivebioactive
M
IntegratedMolecularImagingAgentsIntegratedMolecularImagingAgents
TcessentialperfusionTcessentialperfusion
Tcpendent/BFCtargeting
Tcpendent/BFCtargeting
integratedimagingagentsintegrated
imagingagents
M receptorreceptorvectorvector
lead M
TherapyTherapy
TheranosticsTheranostics
inactiveinactive activeactive Tc receptorreceptorvectorvector
DiagnosisDiagnosisstructuralrecognitionbymetalcomplex
structuralrecognitionbymetalcomplex
23
OrganometallicComplexesarewellsuitedfortheconcept
bioactivebioactive
M
i t t di t t d
IntegratedMolecularImagingAgentsIntegratedMolecularImagingAgents
integratedimagingagentsintegrated
imagingagents
TechnetiumforimaginganditsRheniumhomologuefortherapyTechnetiumforimaginganditsRheniumhomologuefortherapy
since..since..
OrganometallicComplexesarewellsuitedfortheconceptOrganometallicComplexesarewellsuitedfortheconcept
24
..manyleadstructurescompriseorganometallicstructuralmotives..manyleadstructurescompriseorganometallicstructuralmotives
2222
10/7/2014
13
HN OO
TherapyandImagingwithMetalComplexesTherapyandImagingwithMetalComplexes
PracticallimitationsPracticallimitations
Optimizedstructurerecognizingcomplexesb th i d b
Optimizedstructurerecognizingcomplexesb th i d b
N N
OO
ReCORHN
O
inaccessible
25
canbesynthesizedbyanymeanscanbesynthesizedbyanymeans
[99mTcO4] productssaline
3060min/r.t.or100Csaline
3060min/r.t.or100C
TrueTcRe(andMn)homologyonlyinlowoxidationstatesTrueTcRe(andMn)homologyonlyinlowoxidationstates
TherapyandImagingwithMetalComplexesTherapyandImagingwithMetalComplexes
OrganicleadstructureOrganicleadstructure ImagingImaging TherapyTherapy
Aminoacids
Aminoacids
Inhibitor
Inhibitor
Aminoacids
Aminoacids
Inhibitor
Inhibitor
Re
CONH
SOC
OCO
O
SO2NH2
HDAC
HD
AC
CAInhibitor
CAInhibitor
HDAC
HD
AC
CAInhibitor
CAInhibitor
2626
2323
10/7/2014
14
TheCyclopentadienyl PhenylAnalogyTheCyclopentadienyl PhenylAnalogy
Thieles acidThieles acidDielsAlder:DielsAlder:
Synthesisof[(5CpR)99mTc(CO)3]+ complexesfromwaterSynthesisof[(5CpR)99mTc(CO)3]+ complexesfromwater
dienophiledienophiledienedieneT>160 CT>160 C
[(HCpCOOH)2][(HCpCOOH)2]
H2O/95 C/3060minH2O/95 C/3060min[99mTcO4][99mTcO4]allinoneallinone
>97%>97%
27
Liu,Y.etal.J.Am.Chem.Soc.2008, 130,155
TheCyclopentadienyl PhenylAnalogyTheCyclopentadienyl PhenylAnalogy
ReCO
COOH
NH2
Synthesisof[(5CpR)99mTc(CO)3]+ complexesfromwaterSynthesisof[(5CpR)99mTc(CO)3]+ complexesfromwater
OC COCO
therapytherapy diagnosisdiagnosis
OTc
O OO Isolink
98C/30 min
OH2
Tc
COOC CO
OH2H2O
28
2424
10/7/2014
15
OTc
O OO Isolink
98C/30 min
OH2
TcOC CO
OH2H2O
60 min / 90C
TheCyclopentadienyl PhenylAnalogyTheCyclopentadienyl PhenylAnalogy
Synthesisof[(5CpR)99mTc(CO)3]+ complexesfromwaterSynthesisof[(5CpR)99mTc(CO)3]+ complexesfromwater
O 98 C/30 minCO
insituBoc deprotection
60min/90 C
D.Canetal,.Organometallics,2012,31,6880
29
TheCyclopentadienyl PhenylAnalogyTheCyclopentadienyl PhenylAnalogy
Synthesisof[(5CpR)99mTc(CO)3]+ complexesfromwaterSynthesisof[(5CpR)99mTc(CO)3]+ complexesfromwater
0 5 10 15 20 25 30
0.0
0.2
0.4
0.6
0.8
1.0
Inte
nsity
22.30
17.10
UV-trace
labelling
30
Minutes
0 5 10 15 20 25 30
0.0
0.2
0.4
0.6
0.8
1.0
Inte
nsity
UV-trace -trace
22.1921.71
0 5 10 15 20 25 30
0.0
0.2
0.4
0.6
0.8
1.0 UV trace -trace
Inte
nsity
15.67 16.77
99mTcReneutralize
2525
10/7/2014
16
TheCyclopentadienyl PhenylAnalogyTheCyclopentadienyl PhenylAnalogy
Whichisthelabelingsite?Whichisthelabelingsite?
Synthesisof[(5CpR)99mTc(CO)3]+ complexesfromwaterSynthesisof[(5CpR)99mTc(CO)3]+ complexesfromwater
R1R1R2R2
31
D.Canetall,Chem.Biodivers.2012,9,1849
Tworadiopharmaceuticalsfromonesingleprecursor!Tworadiopharmaceuticalsfromonesingleprecursor!
CarbonicAnhydrase(CA)InhibitorsCarbonicAnhydrase(CA)Inhibitors
1 01 0
Labeling
[99mTcO4]Isolink
0 5 10 15 20 25 30
0.0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25 30
0.0
0.2
0.4
0.6
0.8
1.0
32
C.Supuran,Nature,2008,7,168181
Re
99mTc
Ligand
26
10/7/2014
17
IC50 valuesIC50 values
CarbonicAnhydrase(CA)InhibitorsCarbonicAnhydrase(CA)Inhibitors
HC I II III IV VA VB VI VII IX XII XIII XIV XV
BA
CAinhibition (nM affinities)CAinhibition (nM affinities)
AZA
33
A 50 49 5217 624 658 556 647 470 57 69 727 29 585
B 39 15 4600 467 481 305 497 360 43 7 482 20 313
AZA 250 12 20000 74 63 54 11 2 25 6 17 41 72
CarbonicAnhydrase(CA)InhibitorsCarbonicAnhydrase(CA)Inhibitors
IC50 valuesIC50 values
HC I II IV VA VB VI VII IX XII XIII XIV XV
CC DD EE
CAinhibition (nM affinities)CAinhibition (nM affinities)
34
HC I II IV VA VB VI VII IX XII XIII XIV XV
C 4590 35.5 41.1 124 104 22.1 21.3 5.2 6.9 78.5 7.9 36.8
D 2570 25.3 32.9 113 105 10.6 7.6 3.7 4.5 62.1 4.1 28.4
E 2775 27.4 33.8 109 102 14.5 10.1 7.0 4.4 56.8 85.4 12.5
AZA 250 12 74 63 54 11 2 25 6 17 41 72
27
10/7/2014
18
ReceptorSubtypeSpecificitiesReceptorSubtypeSpecificities
CarbonicAnhydrase(CA)InhibitorsCarbonicAnhydrase(CA)Inhibitors
FC5
HN
OSO
ONH2
Re
COOC
OC
DCB40
H
FC5
35
HN
OSO
ONH2
Re
COOC
OC
O
HN
ORe
COOC
OC
SO
O
NH2
DCB41
DCB43
CocrystallizationwithCAIICocrystallizationwithCAII
CarbonicAnhydrase(CA)InhibitorsCarbonicAnhydrase(CA)Inhibitors
36
D.Canetal.Angew.Chem.Int.Ed.2012,51,3354
28
10/7/2014
19
HDACInhibitor,SAHA VorinostatHDACInhibitor,SAHA Vorinostat
IC50 (M)MCF-7 A431 HeLa A375 B16F1
Re-(i7)SAHA 9.47 13.7 14.4 14.7 9.82
IntegratedapproachIntegratedapproach
Re-(i6)SAHA 15.2 17.1 13.3 23.3 12.6Re-SAHA 11.4 17.3 8.34 12.5 15.2(i7)SAHA 1.71 2.51 1.65 2.63 3.10(i6)SAHA 7.19 5.22 5.83 4.85 8.88
SAHA 3.74 4.44 4.45 4.58 3.67
37
ReSAHA Re(i6)SAHA Re(i7)SAHA
(i7)SAHA (i6)SAHA
verylowaffinitywithout phenylorCpringverylowaffinitywithout phenylorCpring
HDACInhibitor,SAHA VorinostatHDACInhibitor,SAHA Vorinostat
IntegratedapproachIntegratedapproach
99mTc(i7)SAHA99mTc(i7)SAHA
[99mTc(OH2)3(CO)3]+[99mTc(OH2)3(CO)3]+
[99mTcO4][99mTcO4]Nr.9
38
Smallyieldonly,oxidationtopertechnetate!!Smallyieldonly,oxidationtopertechnetate!!
Systemlimited bychemicalstabilityof[99mTc(OH2)3(CO)3]+ towardsfunctionalgroupsSystemlimited bychemicalstabilityof[99mTc(OH2)3(CO)3]+ towardsfunctionalgroups
29
10/7/2014
20
Cyclopentadienyl PeptidesCyclopentadienyl Peptides
Pendentvs integratedapproachPendentvs integratedapproach
PeptideTransporter2(PEP2)inhibitors:smalltripeptidesPeptideTransporter2(PEP2)inhibitors:smalltripeptides
Cl
PClCl
Cl
39
Q.Nadeem etal.,Org.&Biomol.Chem.,2014,12,1966;Y.Liuetal.,BioconjugateChem.,2013,24,26
Cyclopentadienyl PeptidesCyclopentadienyl Peptides
Pendentvs.integratedapproachPendentvs.integratedapproach
from[99mTcO4]from[99mTcO4]microwave30 120min3080%yield
microwave30 120min3080%yield
40
30
10/7/2014
21
ExtendingthecyclopentadienylscaffoldExtendingthecyclopentadienylscaffold
dimerizessolubilitydimerizessolubility
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
spacerpK
spacerpKsolubility
derivatizationssolubility
derivatizations dimerizevery slowlydimerizevery slowly
Labeling,30min60C
pKapKa
41
faster,moreefficientthanC0faster,moreefficientthanC0
nolabelingatall!!nolabelingatall!!
IntroducingatargetingfunctionIntroducingatargetingfunction
onepottwopotonepottwopot
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
rearrangement!rearrangement!
activationactivation peptideformationpeptideformation
42
31
10/7/2014
22
IntroducingasecondfunctionalityIntroducingasecondfunctionality
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
Pharmaceuticallyactiveleadstructuresoftencompriseanintegrated andnotaterminalphenylgroup
Pharmaceuticallyactiveleadstructuresoftencompriseanintegrated andnotaterminalphenylgroup
twodifferentfunctionscanbeconjugatedviathemetalcomplex..twodifferentfunctionscanbeconjugatedviathemetalcomplex..
..oronlyasingleoneindifferentmodalities..oronlyasingleoneindifferentmodalities
O
O
N function 1
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
IntroducingasecondfunctionalityIntroducingasecondfunctionality
baseexc.Cpp
isomersisomers
+isomers+isomers
sideproductsideproduct
44
alternativeroutealternativeroute 8MNaOH80C/3d
ca.30%
32
10/7/2014
23
pKa =5pKa =5
existsatpH=7.4inwaterasmonoanionexistsatpH=7.4inwaterasmonoanion
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
Introducingasecondfunctionality:RheniumIntroducingasecondfunctionality:Rhenium
+H++H+aa
tautomerstautomers
1,2and1,3CpasaWernertypeligands?1,2and1,3CpasaWernertypeligands?
45Cpchemistryinwaterwithanyelement?Cpchemistryinwaterwithanyelement?
30 C/120min
Na+
>90%
1,2
>90%
1,3
R
OOCH3
OH3CO
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
Introducingasecondfunctionality:RheniumIntroducingasecondfunctionality:Rhenium
Re
COCOOC
waternoradrenalinwaternoradrenalin HBTUamineHBTUamine
46
HBTUamineHBTUamine
33
10/7/2014
24
LabelinginsalineLabelinginsaline
Na+
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
Introducingasecondfunctionality:TechnetiumIntroducingasecondfunctionality:Technetium
standard conditionspH=10,30min70Cstandard conditionspH=10,30min70C BA
CAC
D
47
D
A
B
OOCH3
OH3CO
Na+
LabelingLabeling
O OH2
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
Introducingasecondfunctionality:TechnetiumIntroducingasecondfunctionality:Technetium
pH=5,15min60CpH=5,15min60C
Tc
COCOOC
OTc
O OO Isolink
98C/30 min
OH2
Tc
COOC CO
OH2H2O
trace(99mTc)
48StartingcompoundformultifunctionalityimagingagentsStartingcompoundformultifunctionalityimagingagents
UVtrace(Re)
34
10/7/2014
25
Rhenium:stepwiseintroductionofbiofunctionsRhenium:stepwiseintroductionofbiofunctions
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
OOCH3
OH3CO
NaOH /H2ONaOH /H2O NaOH /H2ONaOH /H2ORe
COCOOC
HBTU
HBTUHBTU
HBTU
HNNH
49
Re
COCOOC
OO
symmetricsymmetricasymmetricasymmetric
FunctionalizedCpDerivativesFunctionalizedCpDerivatives
Technetium:directlabelingwithaminesinwaterTechnetium:directlabelingwithaminesinwater
Buildingblockfor mono and homo difunctionalized complexes
Buildingblockfor mono and homo difunctionalized complexes R
OOCH3
OH3CO
anyaminewater
formonoandhomodi functionalizedcomplexesformonoandhomodi functionalizedcomplexes Re
COCOOC
anyaminewater
35
10/7/2014
26
TargetingtheNucleusTargetingtheNucleus
NuclearTargetingwithAugerEmittersNuclearTargetingwithAugerEmitters
Doxorubicin,anucleustargeting,fluorescentmoleculeDoxorubicin,anucleustargeting,fluorescentmolecule
51Radiotoxic Doxorubicin Tc99mConjugatesImstepf etal. inpreparation
Nucleus Targeting Bifunctional Tc99mComplexesBioconjugateChem.,2011,22,958.
TargetingtheNucleusTargetingtheNucleus
NuclearTargetingwithAugerEmittersNuclearTargetingwithAugerEmittersAsystematicapproach:Synthesis,PropertiesandinvitroProfilAsystematicapproach:Synthesis,PropertiesandinvitroProfil
ctDNA Titration:DNABinding
5252
IC50:Cytotoxicity
36
10/7/2014
27
TargetingtheNucleusTargetingtheNucleus
NuclearTargetingwithAugerEmittersNuclearTargetingwithAugerEmittersAsystematicapproach:Synthesis,PropertiesandinvitroProfilAsystematicapproach:Synthesis,PropertiesandinvitroProfil
OHOOH
O
OH
OHO OO
O
HN
OH
N
O99mTc
N
N
O
OO
S1
Surviving Fraction @50CiHeLa: 74.5 2.0%A431: 70 0 5 5%
IC50:~14Ci (500kBq)
53
A431: 70.0 5.5%B16F1: 22.5 1.4%
IC50 of coldRecomplex:>100M
Exhibits most significant killingability inmurine melanoma (B16F1)cells.
Radiosensitivity:B16F1>A431>HeLa
TargetingtheNucleusTargetingtheNucleus
NuclearTargetingwithAugerEmittersNuclearTargetingwithAugerEmittersAsystematicapproach:Synthesis,PropertiesandinvitroProfilAsystematicapproach:Synthesis,PropertiesandinvitroProfil
Maxuptake 4hrs:~610%
Maxuptake 4hrs:~3%
54
Maxuptake 4hrs:~67%
Maxuptake 4hrs:~4%
Cellularinternalizationisnotcompleteafter4hrsSomewhathigheruptakeforS1Nosignificantdifferencesbetweencelllines
37
10/7/2014
28
TargetingtheNucleusTargetingtheNucleus
M Nucleus Mitochondria Nucleus MitochondriaRe185 (ICPMS) 71% 1.6% 74% 2.1%Tc99m (activity meter) 81% 1.2% 76% 1.8%
55
majoraccumulationofcompoundsinthenucleus~7080%minoraccumulationinmitochondria~12%good(excellent)agreementbetweenquantificationmodalities
M Nucleus Mitochondria Nucleus MitochondriaRe185 (ICPMS) 80% 1.6% 66% 1.8%Tc99m (activity meter) 82% 1.4% 79% 3.2%
Values:Nuclearandmitochondrialinternalization,respectively,asthepercentageofactivityorRecontentwithrespecttowholecell uptake.
TargetingtheNucleusTargetingtheNucleus
NuclearTargetingwithAugerEmittersNuclearTargetingwithAugerEmittersOHO
OHO OO
OHO
OH
HN
N N
OOH
N
O99mTc
N
N
O
OO
S1
M Nucleus Mitochondria
Re185 (ICPMS) 71% 1.6%Tc99m (activity meter) 81% 1.2%
R di t i it ( 80 M) Ch t i it ( 100 M)
56
Radiotoxicity ( 80nM)>>Chemotoxicity(>100M)ComplexS1 exhibitedmarkedlyradiotoxiceffect:IC50 500kBq (B16F1)Majoraccumulationofallderivativesinnucleus:notvisiblewithfluorescenceimaging
FluorescenceQuenchingbyintercalation!!
Verificationwithtwoquantificationmodalities
38
10/7/2014
29
FromCyclopentadienyltoArenesFromCyclopentadienyltoArenes
Chromocene:FischerHafner Synthesis
attractivesinceitcontainsPhenyls
arenescanbesubstituted
arenesareactivated
Chromocene:FischerHafner Synthesis
attractivesinceitcontainsPhenyls
arenescanbesubstituted
arenesareactivated
Chromocene:FischerHafner Synthesis
attractivesinceitcontainsPhenyls
arenescanbesubstituted
arenesareactivated
metalcentredactivity(Dyson,Sadleretal.)
areneringtendstobelost
introductionoffunctionalities
Multivariationsatmetal(X,Y,Z)
metalcentredactivity(Dyson,Sadleretal.)
areneringtendstobelost
introductionoffunctionalities
Multivariationsatmetal(X,Y,Z)
metalcentredactivity(Dyson,Sadleretal.)
areneringtendstobelost
introductionoffunctionalities
Multivariationsatmetal(X,Y,Z)
S th i d b E O Fi h t l f 99MS th i d b E O Fi h t l f 99M
57
SynthesizedbyE.O.Fischeretal.from99Mo
Chemistryessentiallynotinvestigated
Sourceforhigheroxidationstates
Precursorforlabeling
Rheniumanalogues
SynthesizedbyE.O.Fischeretal.from99Mo
Chemistryessentiallynotinvestigated
Sourceforhigheroxidationstates
Precursorforlabeling
Rheniumanalogues
F.Baumgrtner etal.TetrahedronLett.1962,6,253;Chem.Ber.1961,94,2198
MissedOpportunities(Terachem 2010)MissedOpportunities(Terachem 2010)
Tc
[TcCl4]
Al/AlCl3 C6H6 /135 C
5858FischerE.O.etal.Tetrahedron Lett.,1962
it is water stable
39
10/7/2014
30
Radiopharmaceuticalchemistrybranch4methodsforthepreparationoftheanalogues99mTccomplex
[99mTcO4] (dry)
Basicchemistry branchTc
MissedOpportunities(Terachem 2010)MissedOpportunities(Terachem 2010)
orultrasoundr.t.
Purification HPLC50 95%
Moderatemyocardialuptake
[TcCl4]
Al/AlCl3 C6H6 /135 C
Al/AlCl3 /C6H6135 C60min
59
Wester,D.W.etal.J.Med.Chem. 1991 and this conference
it is water stable
FischerE.O.etal.Tetrahedron Lett. 1962
monocationic99mTcbisarenecomplexesformyocardialimagingmonocationic99mTcbisarenecomplexesformyocardialimaging
[99mTcO4][99mTcO4] Al /AlCl3Al /AlCl3
FromCyclopentadienyltoArenesFromCyclopentadienyltoArenes
arenearene
notenoughheartuptake discarded stableinwaterunderphysiologicalconditions
notenoughheartuptake discarded stableinwaterunderphysiologicalconditions
[99TcCl4][99TcCl4]
R3 E05
[Re(C6H6)2 ]PF6
60
D.W.Wester etal.J.Med.Chem.1991,34,3284D.W.Wester etal.J.Med.Chem.1991,34,3284
[ReO4]Zn /AlCl3arene/810hZn /AlCl3arene/810h
Re
R
2030%4,E05
3,E05
2,E05
1,E05
0,E+00
1,E05
2,E05
3,E05
2,50 2,00 1,50 1,00 0,50 0,00 0,50 1,00 1,50 2,00
40
10/7/2014
31
FromCyclopentadienyltoArenesFromCyclopentadienyltoArenes
ExtendingthechemistrywithRheniummodelcomplexesExtendingthechemistrywithRheniummodelcomplexes
[R O ] Zn / AlCl3Zn / AlCl3BuLi Re
H
Bu
[ReO4]Zn /AlCl3benzene/810hZn /AlCl3benzene/810h
70%
Re
80%
COOH
LDACO2
COOH
61
ReRe
COOH
introductionoftargetingfunctionsintroductionoftargetingfunctions
Technetiumcomplexes?Technetiumcomplexes?
[99T O ][99T O ]Zn /AlCl3Zn /AlCl3
R
Modelcomplexeswith99TcModelcomplexeswith99Tc
FromCyclopentadienyltoArenesFromCyclopentadienyltoArenes
[99TcO4][99TcO4]3
arene/810h3
arene/810hTc
R
2030%2030%
99TcNMR(benzene)99TcNMR(benzene)
62
41
10/7/2014
32
[99T O ][99T O ]Zn /AlCl3Zn /AlCl3
R
Modelcomplexeswith99TcModelcomplexeswith99Tc
XX
FromCyclopentadienyltoArenesFromCyclopentadienyltoArenes
[99TcO4][99TcO4]3
arene/810h3
arene/810hTc
R
XXFriedelCraftsconditionsFriedelCraftsconditions
63
99TcNMR99TcNMR
From99Tcto99mTcFrom99Tcto99mTc
Na[99mTcO4]insaline(0.9%NaCl):Howtotransferintoarenes?Na[99mTcO4]insaline(0.9%NaCl):Howtotransferintoarenes?
ILIL
FromCyclopentadienyltoArenesFromCyclopentadienyltoArenes
[99mTcO4] /0.9%saline[99mTcO4] /0.9%salinefewmgILfewmgIL [99mTcO4] inIL[99mTcO4] inIL
arenearene >95%99mTcdissolvedinarene>95%99mTcdissolvedinarene
[99mTcO4] /arene[99mTcO4] /areneZn /AlCl31h/95 CZn /AlCl31h/95 C
extractintobufferextractintobuffer
64
20 80%yield20 80%yield
stablefrompH=2 12at37C
notairsensitiveatall
stablefrompH=2 12at37C
notairsensitiveatall
arenecomplexesareanoptionformolecularimaging!arenecomplexesareanoptionformolecularimaging!H.Brabandetal.Chem.Sci. 2014,inpress
42
10/7/2014
33
ConclusionsConclusions
imagingneedstobecombinedwiththerapy,orviceversaimagingneedstobecombinedwiththerapy,orviceversa
Forthefuture..Forthefuture..
ClassicalMetalsinMedicineconceptshaverelevancetomolecularimagingClassicalMetalsinMedicineconceptshaverelevancetomolecularimaging
65
cytotoxic,fluorescent imaging,metabolism
Technetium(andRhenium)chemistry....isstillanexcitingfieldforresearchwithimpactforotherelements
Technetium(andRhenium)chemistry....isstillanexcitingfieldforresearchwithimpactforotherelements
ConclusionsConclusions
TheinertnessoflowvalentReandTc complexes enablesnewconceptsintheranosticsTheinertnessoflowvalentReandTc complexes enablesnewconceptsintheranostics
[99mTcO4] /0.9%saline[99mTcO4] /0.9%saline
66
Nothingisimpossible!Nothingisimpossible!
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34
AcknowledgmentsAcknowledgments
99(m)Tc Chemistry99(m)Tc Chemistry
Henrik BrabandMichaelBenz
Sebastian Imstepf
Henrik BrabandMichaelBenz
Sebastian Imstepf
UniversityofZrichUniversityofZrich
ITN,LisbonPortugalITN,LisbonPortugalI.Santos
P.RaposinhoF.Mendes
I.SantosP.RaposinhoF.Mendes
TU MunichTU MunichSebastianImstepfMichaelFelberQaisar NadeemSamer SuliemanAngeloFrei
Guiseppe Meola
SebastianImstepfMichaelFelberQaisar NadeemSamer SuliemanAngeloFrei
Guiseppe Meola
BildungundForschungSBFBildungundForschungSBF
UniversityofFlorence,ItalyUniversityofFlorence,ItalyProf.C.SupuranProf.C.Supuran
SSAJRP JRPSSAJRP JRP0101SSAJRP JRPSSAJRP JRP0101
TUMunichTUMunich
M.SchotteliusH.J.WesterM.SchotteliusH.J.Wester
67
SSAJRPJRPSSAJRPJRP 0101SSAJRPJRPSSAJRPJRP 0101
68
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35
SolutionstoProblemsSolutionstoProblems
Nr.1B.Noll,P.Leibnitz,H.Spies,ForschungszentRossendorf(Ber.)1999,270,153
Nr.2N.Bryson,J.ListerJames,A.G.Jones,W.M.Davis,A.Davison,Inorg.Chem.1990,29,2948.
6969Nr.3U.Mazzi,D.A.Clemente,G.Bandoli,L.Magon,A.A.Orio,Inorg.Chem. 1977,16,1042.
SolutionstoProblemsSolutionstoProblems
C.K.Fair,D.E.Troutner,E.O.Schlemper,R.K.Murmann,M.L.Hoppe,Acta Crystallogr.,Sect.C:Cryst.Struct.Commun.1984,40,1544.Nr.5
Nr.4J.L.Vanderheyden,A.R.Ketring,K.Libson,M.J.Heeg,L.Roecker,P.Motz,R.Whittle,R.C.Elder,E.Deutsch, Inorg.Chem.1984,23,3184.
70Nr.6W.A.Herrmann,R.Alberto,J.C.Bryan,A.P.Sattelberger, Chem.Ber.1991,124,1107.
Nr.7F.A.Cotton,L.Daniels,A.Davison,C.Orvig,Inorg.Chem.1981,20,3051.F.Poineau,E.V.Johnstone,P.M.Forster,Longzou Ma,A.P.Sattelberger,K.R.Czerwinski,Inorg.Chem.2012,51,9563.
45
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36
SolutionstoProblemsSolutionstoProblems
Nr.8C.Bolzati,A.Boschi,L.Uccelli,F.Tisato,F.Refosco,A.Cagnolini,A.Duatti,S.Prakash,G.Bandoli,A.Vittadini,JACS,2002,124,11468
71
Nr.9R.Alberto,R.Schibli,D.Angst,P.A.Schubiger,U.Abram,S.Abram,T.A.Kaden,Trans.Met.Chem. 1997,22,597
46
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1
TECHNETIUMBEHAVIORINTHEPUREX PROCESS
PascalBARONCurrentFuelCycleBackEndProgramy g
CEA,NuclearEnergyDivision
| PAGE 1
ISTR2014 8th INTERNATIONALSYMPOSIUMONTECHNETIUM ANDRHENIUM29th SEPTEMBER 3rd OCTOBER 2014,Pornichet LABAULEFRANCE
THE PUREX PROCESS
SPENT FUEL HNO3
TBPU
Pu
U, Pu, FPs,MAssolution
3 Pu
DISSOLUTION EXTRACTION
HULLS FPs, MAs
47
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2
1ST CYCLE U-Pu WITH U/Pu PARTITIONING
EXTRACTANTCLEANING
TBP
stripping stripping
RaffinateFP, MA
FEEDU,Pu,FP,MA
UPu
RductorU(IV)
Scrubbingstripping. stripping.
INTRODUCTION
Tc is just one FP among many othersYES, BUT:
Tc production yield in reactor is high
on the contrary than most of the others, Tc is
able to be extracted by TBP (multiple mechanisms)
Tc can have deleterious impact on U/Pu REDOX
chemistry in the PUREX process (multiple oxydation
state)
4
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FISSION PRODUCTS YIELD
Tc 99
INTRODUCTION
Tc is just one FP among many othersYES, BUT:
Tc production yield in reactor is high
on the contrary than most of the others, Tc is
able to be extracted by TBP (multiple mechanisms)
Tc can have deleterious impact on U/Pu REDOX
chemistry in the PUREX process (multiple oxydation
state)
6
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TECHNETIUM BEHAVIOR IN THE DISSOLUTION STEP
AMOUNT:About 1kg / ton (burn up dependent)not cooling-time dependent ( 99Tc , half-life= 2,1.105years),
SPECIESTcO2 and poly mtallic compounds
(undissolved species)
TcO4- in the dissolution solution
DISSOLUTION YIELDDISSOLUTION YIELDFuel type dependent at lab scale: UOX ~ 90 %, MOX ~ 60 %, SFR ~ 20 %
Lower yield at industrial scale (rotating dissolver): ~50% for UOX and MOX
7
TECHNETIUM EXTRACTION BY TBP
SIMPLIFIED EXTRACTION MECHANISMS [ ]+ ++ 44 ,3TBPHTcO3TBPTcOH
( )[ ] ( )( )[ ]( )[ ] ( )( )[ ]
++
++
3334443
33424232
NO,2TBPNOTcOPuTcO,2TBPNOPu
NO,2TBPNOTcOUOTcO,2TBPNOUO
( )[ ] ( )( )[ ] ++ 3334443 NO,2TBPNOTcOZrTcO,2TBPNOZrCo-extraction:
Higher for Zr >> Pu > U Reduced at high [NO3-] (competition)
50
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TECHNETIUM BEHAVIOR IN EXTRACTION STEP
ExtractionU + Pu
scrubbingFP
TBP-dodecane ZrTc +U UTc
Zr AcidHNO3Zr, FP
U, Pu, Tc
U u
ZrTc
Zr +Tc
FeedU, Pu, Tc, Zr, FP
HNO3
TECHNETIUM BEHAVIOR IN EXTRACTION STEPOPTIONS TO LIMIT THE IMPACT
CHEMICAL ADJUSTMENTIntroduction of Zr complexing agent: carboxylic acids
Oxalic acid (forgiven / Pu leakage risk)( g g )Other acids (ex.: KMA)
NOT READY FOR UP3
OPERATING ADJUSTMENT / TOPOLOGYAdjunction of a complementary operation the "Tc scrubbing"(allow separate management of Tc / others FPs)( p g )
SOLUTION CHOOSEN FOR UP3 AND UP2-800
10
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TECHNETIUM BEHAVIOR IN EXTRACTION STEP
TBP 30 %
Main FPs U, Pu, Tcextraction
sscrubbing
FeedU, Pu, FPs HNO3 3 M
HNO3 2 M
Secondaryextraction
Tc scrubbing
FPs, ,
TBP 30 %
U, Pu
TcHNO3 10 M HNO3 1,5 M
TECHNETIUM SCRUBBING FOR LA HAGUE
PRINCIPLES:Zr scrubbing at first stepTc back extraction (high acidity)( g y)
DESIGN CONSTRAINT (1985, active start of UP3 1989)Minimization of the impact on upstream/downstream steps(mainly acid effluents)
OPTIMISATION USING PAREX CODE:DF Tc = 2,8 UP3 (1989), ( )
(validated at lab scale on genuine solution and confirmed by UP3)
Today DF > 30 routinely performed at UP2800 and UP3
12
52
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7
1
10
Zr(IV)
Concent
0.001
0.01
0.1
FP scrubbing sectionMain extraction section
Tc(VII)
ration
g/l
N of stage
0.0001
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
FP scrubbing sectionMain extraction section
Aqueous technetium profile: experimental ( ), calculated ( )
Aqueous zirconium profile: experimental ( ), calculated ( .....)
1
T (VII)
Concent
0.1
Secondaryextraction
Technetiumscrubbing
Tc(VII)
section section
ration
g/l
N of stage
0.01
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Profils techntium aqueux: experimental ( ), calcul ( )
53
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8
U/Pu SPLITTING STEP
FUNCTIONAL REACTION : Pu(IV) Reduction
U4+ + 2Pu4+ + 2H2O UO22+ + 2Pu3+ + 4H+U + 2Pu + 2H2O UO2 + 2Pu + 4H
PARASISTIC REACTION : Pu(III) Oxydation
Pu3+ + HNO2 + H+ + 0,5HNO3 Pu4+ + 0,5H2O + 1,5HNO2
USEFULL or STABILIZING REACTION : HNO Destruction USEFULL or STABILIZING REACTION : HNO2 Destruction
N2H5NO3 + HNO2 HN3 + HNO3 + 2H2O
U/Pu SPLITTING STEP
Pu(IV)
Pu(IV)Pu(III)
TBP 30%Loaded solvent
U(VI), Pu(IV) U(VI)
Pu(III)
HNO3 0.2 M hydrazineU(IV), hydrazine
Pu(III)
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9
TECHNETIUM BEHAVIOR IN URANIUM/PLUTONIUM SPLITTING STEP
SIMPLIFIED REDOX MECHANISM
fast)(very ...UOTc...UTc(VII) 22ox4 ++++ ++ ww
reaction) (limiting...HNOTc...HNOTc
fast)(very ...UOTc...UTc
(fast)...Tc...HNTc
2ox3red
22red
4ox
red52ox
++++++++
+++++
+
zz
yy
x
Tcox is for Tc(V) and/or Tc(VI)Tcred is for Tc(IV) (ou Tc(III) ?)
where
Globally Kinetic of first-order versus [ Tc ]With relatively high activation energy (22 kcal/mol)
DELETERIOUS IMPACT OF Tc ON PUREX PROCESS
Pu(IV)
Pu(IV)Pu(III)
TBP 30%Loaded solvent
U(VI), Pu(IV) U(VI)
Pu(IV)
Pu(III)Pu(IV)
HNO3 0.2 M hydrazineU(IV), hydrazine
Pu(III) HNO2
N2H4
Tc
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DELETERIOUS IMPACT OF Tc ON PUREX PROCESS
NHPu
Pu(IV)Pu(III)Pu(III) NHx Pu
Pu(IV)
DELETERIOUS IMPACT OF Tc ON PUREX PROCESS
Pu(IV)Pu(III)Pu(III)x Pu
Pu
Pu(IV)
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11
TECHNETIUM BEHAVIORARRANGEMENT TAKEN FOR U/Pu SPLITTING STEP
OPERATING CONDITIONS Increase excess of hydrazineyLimiting operating temperatureNeutrons on line monitoring
UP3 - UP2 800 RESULTS Outstanding stable operationOutstanding stable operationDF of uranium vs plutonium > 106Good agreement with model predictions
IN CONCLUSION
Tc is just one FP among many others
YES BUT:YES, BUT:
It has an atypical behavior in the PUREX process
That must be taken into account in the fl h t d i tflowsheet design step
Its chemistry needs to be deepen in the frame of FR fuel reprocessing (high Pu)
22
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12
ISTR2014
THANK YOUFOR YOUR ATTENTION !
| PAGE 23
Pornichet LABAULE,FRANCE29TH SEPTEMBER,3RD OCTOBER2014
PascalBARON
58
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____________________________________Family Amount (kg/t)____________________________________
R G (K X ) K 96 Nd 3 (0 3 PB )
FISSION PRODUCTS :AVERAGEDISTRIBUTION (1 ton UOX, 3,5 % 235U ,33 GWj/t)
Rare Gas (Kr, Xe) Kr : 96 Ndm3 (0,3 PBq) Xe : 736 Ndm3
3T & Alkali (Cs, Rb) 3T = 16 TBq ; 3,977Alkaline earth (Sr, Ba) 2,407Yttrium & Lanthanides 10,198Zirconium 3,586Chalcogens (Se, Te) 0,527Molybdenum 3 335Molybdenum 3,335
Technetium 0,814Platinoids (Ru, Rh, Pd) 3,892Ag, Cd, Sn, Sb, etc... 0,216____________________________________
TECHNETIUM BEHAVIOR OF IN NITRIC ACID
INITIATION INDUCTION FAST REACTIONh d i hydrazine hydrazine
Tc(VII) Tc(VI).Tc(V) Tc(IV) Tc(VI)
hydrazine
very slow
hydrazine
fast
hydrazine
fast
slow
NO3-slow
NO3-
very
fast
TERMINATION3NO3
Tc(VII)
J. Garraway and P.D. Wilson, Journal of Less-Common Metals, 97(1984) 191-203
59
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CINTIQUE DE DCOMPOSITION DE L'HYDRAZINE EN PRSENCE DE TECHNTIUM
0,5
0,6
(mol
/L/h
)
0,1
0,2
0,3
0,4
-d[N
2H5+
]/dt
40C
30C
00 100 200 300 400 500
[Tc] (mg/L)
TECHNETIUM BEHAVIOR IN URANIUM/PLUTONIUM SPLITTING STEP
J. Garraway and P.D. Wilson, Journal of Less-Common Metals, 97(1984) 191-203
60
THE ROLE OF A CHOICE OF THE TARGET FORM FOR 99
Tc TRANSMUTATION
.. Kozar, V.F. Peretrukhin, K.E. German
Frumkin Institute of Physical Chemistry and Electrochemistry of RAS, 31/4 Leninsky
prosp., Moscow, 119071, Russia, kozar@ipc.rssi.ru
99Tc transmutation can be the source of artificial stable ruthenium
100102Ru. Such
ruthenium has been received as a result of a neutron irradiation of Tc targets up to 20 70 % burn-up (for 3 different groups of Tc targets) in experiments on SM high-flux reactor. Metal
homogeneous Tc targets had the form of disks in diameter 6 and with thickness of 0.3 mm [1, 2]. They have been irradiated in geometry of a thin plate and consequently occupied
irradiated volume corresponding to the cylinder in diameter and with height of 6 mm.
Artificial ruthenium demanded exposure during 8 10 years for application without restrictions, as it contained fission fragment
106Ru (T1/2 = 369 days) which can not be
removed from this material by chemical methods.
Application of heterogeneous targets with nuclear-inert stuff to reduce a 106
Ru
radioactivity in artificial Ru and to lower its exposure time before application or to exclude a
technological step on additional preliminary purification of commercial Tc from actinide
impurities [3]. Hence, the target form has effect on the artificial ruthenium purity at equal Tc
nuclear density in irradiated volume.
Transformation of disks in cylinders in the conditions of identical irradiated volume
could allow to lower 106
Ru concentration in artificial ruthenium. The minimum fission-
fragment path length in Tc metal makes about 5 microns (average fission-fragment path
length is about 8 microns). The corresponding form of a heterogeneous target is a tablet
consisting of a mix of spherical Tc metal particle in diameter of 5 microns and a nuclear-inert
stuff with Tc average density which in 20 times is less, than Tc metal. In this case all fission-
fragments, including 106
Ru, escape the Tc (Tc-Ru) grains to stuff. The average distance
between Tc spherical grains is about 23 microns, between their surfaces is about 18 microns
at regular distribution of Tc particles in a target.
Fission-fragment path length in the most applicable nuclear-inert materials (such as
ZrO2, Y2O3, MgAl2O4, MgO, Y3Al5O12, SiC, Al2O3, ZrO2-Y2O3, ZrO2-CaO and many others)
makes 12 15 microns, hence hit probability of 106Ru fission-fragments in the next Tc grainis negligibly small. Artificial ruthenium from such target would be almost free from
106Ru
nuclei. Additional purification of commercial Tc from actinide impurities would be not
necessary at a choice of such target form instead of metal disks. In this case artificial
ruthenium could be applied in non-nuclear field through 3 3.5 years after an irradiation, necessary to decay of transmutation product
103Ru (T1/2 = 39.3 days).
References
1. V. Peretroukhine, V. Radchenko, A. Kozar et al. Technetium transmutation andproduction of artifical stable ruthenium. // Comptes Rendus. Ser. Chimie. 2004. Tome 7. Fascicule 12. P. 1215 1218.
2. .. Kozar, V.F. Peretroukhin, K.V. Rotmanov, V.A. Tarasov. The elaboration oftechnology bases for the artificial stable ruthenium preparation from technetium-99
transmutation products. // 7th
International Symposium on Technetium and Rhenium Science and Utilization. Moscow, Russia, July 4 8, 2011. Book of Proceedings. P. 113. Publishing House GRANITSA, Moscow, 2011. 460 p.
3. .. Kozar, V.F. Peretroukhin, K.V. Rotmanov, V.A. Tarasov. The elaboration oftechnology bases for the artificial stable ruthenium preparation from technetium-99
transmutation products. // Ibid. P. 113.
4/73 61
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1
THEROLEOFACHOICEOF THE TARGET FORMOFTHETARGETFORM
FOR99TcTRANSMUTATION
..Kozar, V.F.Peretrukhin, K.E.German FrumkinInstituteofPhysical
ChemistryandElectrochemistryofRAS,
31/4Leninskyprosp.,Moscow,119071,Russia,
kozar@ipc.rssi.ru guerman_k@mail.ru
ITSWELLKNOWN(SINCE2000) 99Tctransmutationcanbethesourceof
artificialstableruthenium100102Ru,thesecondofthemjst interestingelementsj g
ofthePeriodictable.SuchrutheniumhasbeensynthesizedasaresultofaneutronirradiationofTc
targetsupto20 70%burnup(for3differentgroupsofTctargets)
inexperimentsatSMhighfluxreactorin1999 2003.
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2
Russian Tc - Transmutation program (1992-2003)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
99Tc(n,)100Tc()100Ru75,00%
%
P tt (NL)
Dimitrovgrad (Russia)
IPC RAS - NIIAR 65%
2
25,00%
50,00%
netiu
m-9
9 Bu
rnup
, %
Hanford (USA) 1989
Wootan WJordheim DP
Matsumoto WY
Petten (NL) 1994-1998
Konings RJMFranken WMP
Conrad RP et al.
1999 - 2000Kozar AA
Peretroukhine VFTarasov VA et al.
18%
34%
0,00%1 2 3 4 5
Irradiation time, days
Tech
n
6%
10.5 days 193 days 579 days 72 days 260 days
0,67 % = Pessimistic
Tc transmutationexperiment(IPCERAS NIIAR,19992008)InIPCRASasetofmetaldisctargets(10x10x0.3mm)preparedandassembledintwobatcheswithtotalweightupto5g.Transmutationexperimentwascarriedoutathighflux
SM3reactor(NIIAR,Dimitrovgrad )
2nd2nd batchbatch: F: F > 2> 2 10101155 cmcm--22ss--11 1
2
2nd2nd batchbatch: F: Ftt > 2> 2 10101155 cmcm 22ss 111st batch1st batch: F: Ftt=1.3=1.3 10101155 cmcm--22ss--119999TcTc burnupsburnups havemade:havemade:
34 34 6 % and 65 6 % and 65 11 %11 %forthe1stand2ndtargetsbatchesforthe1stand2ndtargetsbatches
TheThe highhigh 9999TcTc burnburnupupss werewerereachedreached andand aboutabout 22 55 gg ofof newnew
1
-3 -1
9 12
465666768696
6575 45558595
425262728292
4151617181
44548494
43538393
43
1912
-2
2
6
3
7
816
-4
-5
17
-6
-10
-9
13
-8
1
19
4
10-7
5
20
11 2118
reachedreached andand aboutabout 22..55 gg ofof newnewmattermatter transmutationtransmutation rutheniumrutheniumwerewere accumulatedaccumulated asas aa resultresult ofofexperimentsexperiments onon SMSM33 reactorreactor
TheseThese valuesvalues areare significantlysignificantlyhigherhigher ofof burnupsburnups 66 andand 1616 %%achievedachieved onon HFRHFR inin PettenPetten earlierearlier
1 ; 2 ;3 ; 4
7 -2 81
91-
4 3
2
6
1415
7
.5.
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3
IRRADIATIONOF99TcMETALTARGETSINNUCLEARHIGHFLUXREACTORS
Petten transmutationexperiment99 l l d d h h h
3
Dimitrovgrad transmutationexperimentonSMhigh
99Tctargets:metalcylinders4.8mmandwithheightof25mm99Tc burnupinPetten reactorare6% (T1) and 1618% (T2).
fluxreactor99Tc targets:metaldisks 6.0 0.3mmandwiththickness of 0.3 0.02mmTotal targetsmassis 10g
99Tc BURNUPANDHALFCONVERSIONPERIOD
of group
Burn-up, % Irradiation time,
eff. days
Half-conversion period ,
eff. days measured calculated 1 192 202 72 7 240
Measured and calculated 99Tc burnup and halfconversion periods in SM reactor.
burnT 2/1
4
1 192 202 72.7 2402 453 505 262.7 305 3 705 707 424.8 245
99Tc burnupinPetten reactorare6% (T1)and 16 18% (T2).99Tchalfconversionperiodb 2160eff.days.burnT 2/1
Fig. 2. Calculated dependence of 99Tc burnup onirradiation time () and its experimental values() for 3 groups of targets.
64
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ARTIFICIALRuACTIVITYDECAY
Activityof 106Ru+106Rh inartificialRu ,371.6days ,29.8 sec
ActinidecontentinTc:5108gAnpergofTc(bettervaluesareexpensive!)Actinidefission product 106Ru(T1/2=371.6days)cantbeseparatedfromartificialRubychemical methods.
5
106Ru(pure radiator, isabsent) 106Rh 106Pd (stable)106Rhhas 2 main lineswithenergies511.8keV and 621.8keVIn 2006106RhactivityinRufrom20%burnuptargetslater 2100days{5.7T1/2 (106Ru)}after irradiationstop:
15 2 Bk/g of Ru total activity of pair 106Ru + 106Rh 30 Bk/g of RuLater10yearsafterirradiationstop: =3.2 0.4Bk/gof Ru
11/23/2014
5
Transformationofdisks6mm 0.3mmincylindricaltargets6mm 6mm
7
Fig.4.RelativepositionofTc(TcRu)grainsinheterogeneoustarget.
Possibletargetchemicalsubstances8
TcMetal Tc
TcCarbide Tc6C TcDioxide TcO2 Tc Disulfide TcS TcDisulfide TcS2
anditsmixtureswithinertmatter
66
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6
Targetsubstances1. Metal
InstrumentationSample type : Starting
9
Instrumentation Furnaces 6%H2|Arindusturialballoonmixture
Sampletype: OrdinaryPowdermetal
Fusedmetal
Startingmaterial:
TcO2 NH4TcO4 R NTcO
Ingots Rollingmill etcetera
Singlecrystal
Foil
R4NTcO4
1. BulkTcmetal
SetupusedforfusionandcastingofTcmetal
11
SinglecrystalTcmetal
67
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7
1. Tcmetal foil,Xraystudy12
d:20micrometers SystematicabsenceofXrayreflex =PreferentialorientationofcrystalliteswithCaxeperpendiculartothefoilsurface
1. Tcmetal foil,assembling13
Spacer gridbushwith99Tctargets(1)andaluminium core (2)ofcapsule forloadinginreactor.
68
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8
1. Tcmetal foilchemicalconsequences
DissolutioninHNO3 dramaticallysloweddowni f 20% T R i
12
startingfrom20%TctoRuconversion
Possibletoincreasethedissolutionratebyaggressiveagentsaddition(Ag2+,IO4)butcorrosionproblemsarises
PossiblythebestreprocessingprocedureburninginO2 notapprovedbyindustrytodate
Targetsubstances2. TcCarbide
OrthorhombicTcmetalisformedatlowCcontent
50
75
100
Grey bars : ref. hcp Tc metalCurves : exp. spectra
%
30 40 50 60 70 80 900
25
50
75
100
30 40 50 60 70 80 900
25B
I, %
2Theta, deg
A
I, %
69
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9
Targetsubstances2. TcCarbide
Tc6C nonstoechiometry6 y Tc6C+nCexcesscarbonforno slowingdown
Tc6C formedby: Tc+Creaction Tc+C6H6 R4NTcO4 thermaldecompositioninAr
Targetsubstances Tccarbide2. Tc6C+nCexcesscarbon
EXAFSstudyofTc6C+nC[1]
waveletpresentation
[1]K.German,Ya.Zubavichus ISTR2011
70
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10
1. Tccarbidechemicalconsequences
Dissolution of Tc is more active as no RuC is known
12
DissolutionofTcismoreactiveasnoRuC isknownandsoitisnt formedduringtransmutationofTccarbidetoRu TcandRubeingstabilizedinseparatephases
Drawback:PossiblemechanicalinclusionsofTcinRu residue at high burnupsRuresidueathighburnups
MixtureswithCexcesscouldbethebestchoicebecauseresonanceenergyneutronsareparticipatingintransmutationduetoenhancedthermolisation insidethetarget
1. Tcdioxidechemicalconsequences
12
Preparationbychemicalreduction highimpuritycontent
PreparationfromNH4TcO4 similartoTcmetal TargetinstabilityduetoexcessOreleased(Ruisstabilised asmetal))
SomeTc2O7formedathighburnup Thistargetmaterialisnotrecommended
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11
PreparationofartificialstableRutheniumbytransmutationofTechnetium
NewRutheniumisalmostz Tctargetmaterial:monoisotopic Ru100,ithasdifferentspectralproperties
Itisavailableonlytoseveralcountriesthatdevelopnuclearindustry
z Tcmetalpowder/Kozar(2008)
z Tc CcompositeTccarbide/German(2005)
z Rotmanov K.etall.Radiochemistry, 50(2008)408:
99Tctransmutationcanbethesourceofartificialstableruthenium100102Ru.
Conclusions
MetalhomogeneousTctargetsarepossible Tccarbidetargetsarefavorabale Artificialrutheniumdemandedexposureduring810yearsforapplicationwithoutrestrictions
Application of heterogeneous targets with nuclear Applicationofheterogeneoustargetswithnuclearinertstufftoreducea106RuradioactivityinartificialRu
ThetargetformeffecttheartificialrutheniumpurityatequalTcnucleardensityinirradiatedvolume.
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12
Transformationofdisksincylindersintheconditionsofidenticalirradiatedvolumecouldallowtolower106Ruconcentrationinartificialruthenium.TheminimumfissionfragmentpathlengthinTcmetalmakesabout5microns(averagefissionfragmentpathlengthisabout8microns).ThecorrespondingformofaheterogeneoustargetisatabletconsistingofamixofsphericalTcmetalparticleindiameterof5micronsandanuclearinertstuffwithTcaveragedensitywhichin20times is less than Tc metal In this case all fission fragments includingtimesisless,thanTcmetal.Inthiscaseallfissionfragments,including106Ru,escapetheTc(TcRu)grainstostuff.TheaveragedistancebetweenTcsphericalgrainsisabout23microns,betweentheirsurfacesisabout18micronsatregulardistributionofTcparticlesinatarget.
Fissionfragmentpathlengthinthemostapplicablenuclearinertmaterials(suchasZrO2,Y2O3,MgAl2O4,MgO,Y3Al5O12,SiC,Al2O3,ZrO2Y2O3,ZrO2CaOandmanyothers)makes12 15microns,hencehitprobabilityof106RufissionfragmentsinthenextTcgrainisnegligiblysmall. Artificial ruthenium from such target would be almost free fromsmall.Artificialrutheniumfromsuchtargetwouldbealmostfreefrom106Runuclei.AdditionalpurificationofcommercialTcfromactinideimpuritieswouldbenotnecessaryatachoiceofsuchtargetforminsteadofmetaldisks.Inthiscaseartificialrutheniumcouldbeappliedinnonnuclearfieldthrough3 3.5yearsafteranirradiation,necessarytodecayoftransmutationproduct103Ru(T1/2 =39.3days).
References 1.V.Peretroukhine,V.Radchenko,A.Kozaretal.Technetium
transmutationandproductionofartificalstableruthenium.//ComptesRendus. Ser.Chimie. 2004. Tome7. Fascicule12. P.12151218.
2 Kozar V F Peretroukhin K V 2...Kozar ,V.F.Peretroukhin,K.V, ,, .Rotmanov,V.A.Tarasov.Theelaborationoftechnologybasesfortheartificialstablerutheniumpreparationfromtechnetium99transmutationproducts.//7th InternationalSymposiumonTechnetiumandRhenium ScienceandUtilization.Moscow,Russia,July4 8,2011. BookofProceedings. P.113. PublishingHouseGRANITSA,Moscow,2011. 460p.
3. .. Kozar, V.F. Peretroukhin, K.V , 3...Kozar ,V.F.Peretroukhin,K.V, ,, .Rotmanov,V.A.Tarasov.Theelaborationoftechnologybasesfortheartificialstablerutheniumpreparationfromtechnetium99transmutationproducts.//Ibid. P.113.
73
Complexation and extraction of Pu(IV) in the presence of pertechnetic acid
L. Abiad, L. Venault and Ph. Moisy
CEA Marcoule, DEN/DRCP, BP 17171, 30207 Bagnols-sur-Cze Cedex, France
The hypothesis that pertechnetate ion can form extractible complexes with actinides at the +IV or
+VI oxidation state in nitric acid is quite commonly pointed out. Therefore, in nitric acid, the
pertechnetate anion could act as a co-ligand with the nitrate ion and then could replace it in the
extracted species. It can be noticed that in the absence of nitric acid a complex of U(VI) with the
pertechnetate anion 2(4)2 . 2 has already been identified in an organic phase made of
TBP. However, even in the presence of nitric acid, a mixed complex can be formed by replacing a
nitrate anion by a pertechnetate one:
2(3)2 . 2 + 4 2 3 4 . 2 + 3
To check the ability of pertechnetate ions to give rise to complexes with actinides, the study of the
complexation of Pu(IV) by TcO4- was carried out by spectrophotometry in perchloric acid media.
Absorption spectra of Pu(IV)-Tc(VII) mixtures, according to the temperature, enable the calculation of
the complexation constant i of the complex present in solution by chemometric treatment. It was
found that for [Tc]/[Pu] ratio up to 1300, two species are present in solution: the aquo ion Pu4+ and a
complex which could either be Pu(TcO4)3+ or Pu(TcO4)4.The complexation constants have been
respectively estimated to 3 ~ 2.3 0.1 and 4 ~ 3.5 0.2 at T = 298 K.
Onthe other hand, some measurements of the distribution of Tc(VII) and Pu(IV) in biphasic system
(HClO4 TBP 30%/cyclohexane) were carried out. Firstly, it has been shown that the extraction of
pertechnetic acid alone involves 2.5 molecules of TBP perpertechnetic acid, indicating that the
extracted species are both 4 . 2and 4 . 3.Secondly, in the presence of Pu(IV), this
latter is highly extracted when the ratio [Tc]/[Pu] is close to 2500 with DPu 10. Therefore, two
extraction equilibria for the extracted neutral complex Pu(TcO4)4 in organic phase are proposed:
84 + 24+ + 3 (4)4 . + (4)4 . 2
84 + 24+ + 3 ((4)4)2. + (4)4. 2
Nevertheless, as the [Tc]/[Pu] ratio becomes lower than 1400, Pu(IV) is then poorly extracted with D-
values not higher than 1. It is in accordance with the spectrophotometric observations and
chemometric calculations assuming that, in these conditions the complex formed is Pu(TcO4)3+. The
thermodynamic characteristics of this complex have thenbeen calculated.
6/73 74
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8thISTR,LaBaule(FRANCE),Spet.29th,Oct.3rd,2014 1
PPuu(IV(IV))COMPLEXATIONCOMPLEXATION ANDANDEXTRACTIONEXTRACTION
INPRESENCEOFINPRESENCEOFPERTECHNETICPERTECHNETIC ACIDACID
L.ABIAD,L.VENAULT,Ph.MOISY
CEAMarcoule
| PAGE 1
NuclearEnergyDivision
RadiochemistryandProcessDepartment
9 Main GoalGoalTo improve knowledge about Tc complexation chemistry with
GOALS & CONTEXT
o p o e o edge about c co p e at o c e st y tactinides
99 IndustrialIndustrial interestinterest:: PUREX process Disturbances in actinide extraction due to Tc Specific Tc scrubbing step
Nuclear Energy DivisionRadioChemistry and Process Department 2
Chemistry of Tc in the process still not well described
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8thISTR,LaBaule(FRANCE),Spet.29th,Oct.3rd,2014 2
Chemical behavior of Tc(VII) with metallic cations (U, Th, Zr, Pu)
LITTERATURE DATA
Many studies only on the distribution of metallic cations between an aqueous and an organic solutions
Sole identified complex in organic phaseQuoted in litterature (but not identified)
Co-extraction of TcO4- with nitrate ion
[ ]TBP2,)TcO(UO 242[Macasek, 1983]
[ ]TBP2),TcO()NO(Th 433[Pruett, 1984]
[ ]TBP2),TcO()NO(Zr 433[Jassim, 1984]
Nuclear Energy DivisionRadioChemistry and Process Department 3
No studies about the complexation Pu(IV) Tc(VII)Can Pu(IV) be complexed by Tc(VII) alone ? ++ + )4(444 )( nnTcOPunTcOPu
Complexation Complexation reactionreaction
EXPERIMENTAL
++ + )4(444 )( nnTcOPunTcOPu[ ][ ][ ]n
nn
nTcOPu
TcOPu+
+=
44
)4(4
.)(
9 Inert acidic medium towards Pu(IV) chemistry : HClO4 Limitation : radiolysis - competiting extraction of HClO4 and HTcO4
9 Preparation of about 50 samples Tc(VII) Pu(IV)
Nuclear Energy DivisionRadioChemistry and Process Department 4
9 R = 0 to 1400 where
9 Temperatures vary from T = 10 C to T = 50 C
[ ][ ]init.
init.
Pu(IV)Tc(VII)R =
8th ISTR,LaBaule(FRANCE),Sept.29th,Oct.3rd,2014
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8thISTR,LaBaule(FRANCE),Spet.29th,Oct.3rd,2014 3
Experimental absorption spectra for 5 mixtures Pu(IV)-Tc(VII)
I = 2 (HClO4 2 M), [Pu]total = 2.10-3M 25C
RESULTS
9 No Pu(VI) at = 830 nm9 No band for HTcO49 Increase and changes in UV bands at < 500 nm as R 9 Pu(III) at = 600 nm due to radiolysis in Pu(IV) sol. subtraction of Pu(III) spectra
Abs
.
0,04
0,06
0,08
0,10
0,12
0,14 HTcO4 2MR = 1308R = 677R = 500R = 346R = 144
[Tc]
830 nm600 nm
Nuclear Energy DivisionRadioChemistry and Process Department 5
Longueur d'onde (nm)
400 500 600 700 800-0,02
0,00
0,02
,
8th ISTR,LaBaule(FRANCE),Sept.29th,Oct.3rd,2014
cm/m
ol)
30
40
50
For For everyevery spectrumspectrum, at , at everyevery TT subtraction of Pu(III) spectrumA() = Atot.() Pu()()
RESULTS
0,14
HTcO4 2M 680 nm
475 nm
Longueur d'onde (nm)400 450 500 550 600 650 700 750 800
(L/
c
0
10
20
Extinction coefficient for a 10-3 M Pu(III) solution in HClO4 2 M at 25C
Increase of Abs. / Changes in bands complexation of Pu(IV) ?
Abs
.
0 02
0,04
0,06
0,08
0,10
0,12 R = 1308R = 677R = 500R = 346R = 144R = 0
655 nm
550 nm
Nuclear Energy DivisionRadioChemistry and Process Department 6
Absorption spectra of Pu(IV)-Tc(VII) mixtures corrected fromPu(III) contribution
I = 2 (HClO4 2 M, [Pu]total = 2.10-3M 35C
p ( )
Changes in hydratation sphere ?
aw and [H+] kept constant Complexation of Pu(IV) withTc(VII)
Longueur d'onde (nm)350 400 450 500 550 600 650 700 750 800
0,00
0,02
8th ISTR,LaBaule(FRANCE),Sept.29th,Oct.3rd,2014
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8thISTR,LaBaule(FRANCE),Spet.29th,Oct.3rd,2014 4
RESULTS
Qualitative Qualitative studystudy9 Changes in spectra Existence of one or several complexes Pu(TcO4)i(4-i)+9 Effect of T determination of thermodynamic data
Quantitative Quantitative studystudy9 Spectrum = 520 760 nm 9 Small changes in spectrum9 Free Pu(IV) & complexes in the same wavelength range9 No reference spectra for the complexes
Direct treatment of spectra impossible Chimiometric method
Nuclear Energy DivisionRadioChemistry and Process Department 7
Chimiometric method Treatment of a lot of data Few hypothesis about the chemical composition
8th ISTR,LaBaule(FRANCE),Sept.29th,Oct.3rd,2014
ProgramRECONS
11stst stepstep:: Principal Component Analysis Number of species
ProgramNBESPECE
CHIMIOMETRIC METHOD
Hypothesis :2species Reconstructionofspectra reconstructed spectra similar to
experimental ones
statistical &empirical tests 2species T
Number of spectra
[Tc]
1st species
Apparitionofa2nd
Nuclear Energy DivisionRadioChemistry and Process Department 8
At T = 40CWavelength (nm)
ln (
i/ i)
species
background
2species
8th ISTR,LaBaule(FRANCE),Sept.29th,Oct.3rd,2014
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8thISTR,LaBaule(FRANCE),Spet.29th,Oct.3rd,2014 5
22ndnd stepstep:: Modeling Factors Analysis (MFA) Complexation constants & reference spectra
Comparison
CHIMIOMETRIC METHOD
Estimationof n
ExperimentalabsorbanceExperimental
conditions
Hypothesis aboutchemical species
EstimationofabsorbanceAbsestim
Comparison
Nuclear Energy DivisionRadioChemistry and Process Department 9
Estimationofn EstimationofconcentrationsCestim IfAbsestim =Absexper Estimated concentrations=real Criterion :calculated reference spectra &relativedeviation
8th ISTR,LaBaule(FRANCE),Sept.29th,Oct.3rd,2014
22ndnd stepstep:: Modeling Factor Analysis (MFA)
Reference spectra for the two Relative deviation
CHIMIOMETRIC METHOD
+3%
on c
oeff
icie
nt
/mol
/cm
)
4050607080 R maximum upper complex
R = 0 [Pu4+] libre 0.002 M
Reference spectra for the twospecies
Relative deviation
Absexp - Absest
Nuclear Energy DivisionRadioChemistry and Process Department 10
-3%
Wavelength (nm)400 450 500 550 600 650 700 750 800
Extin
ctio
(L/
0102030
8th ISTR,LaBaule(FRANCE),Sept.29th,Oct.3rd,2014
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8thISTR,LaBaule(FRANCE),Spet.29th,Oct.3rd,2014 6
Results from MFA calculations[Pu4+]o = 0.002 M, I = 2, et [TcO4-] = 0 to 2 M)
MFA calculations areT 3 4
CHIMIOMETRIC METHOD
( )( )4444
344
4
TcOPuPuTcO4
TcOPuPuTcO3
4
3
+
+
+
++
or
consistent with ML3 & ML410C 2,8 5% 7,3 16%18C 4,8 21% 9,5 21%25C 2,3 4% 3,4 5%35C 3,5 2% 6,2 2%40C 4,5 2% 8,3 4%
Nuclear Energy DivisionRadioChemistry and Process Department 11
50C 7,9 14% 19,1 14%
8th ISTR,LaBaule(FRANCE),Sept.29th,Oct.3rd,2014
Pu(IVPu(IV) Distribution Ration in ) Distribut