Robust thallium(III) complexes with inorganic and organic multidentate ligands

Robus hallium(III) complexes wi h ino ganic and o ganic mul iden a e ligands PhD hesis Tamás Fodo Supe iso : D . Im e Tó h Uni e si y o Deb ecen Deb ecen, 2016 Ezen é ekezés a Deb eceni Egye em Te mésze udományi Dok o i Tanács Kémiai Dok o i Iskola koo dinációs kémiai p og amja ke e ében készí e em a Deb eceni Egye em e mésze udományi dok o i (PhD) okoza ának elnye ése céljából. Deb ecen, 2016. szep embe 13. a jelöl aláí ása Tanúsí om, hogy Fodo Tamás dok o jelöl 2011.- 2016. közö a en megne eze Dok o i Iskola koo dinációs kémiai p og amjának ke e ében i ányí ásommal égez e munkájá . Az é ekezésben oglal e edményekhez a jelöl önálló alko ó e ékenységé el megha á ozóan hozzájá ul . Az é ekezés el ogadásá ja asolom. Deb ecen, 2016. szep embe 13. a éma eze ő aláí ása A dok o i é ekezés be é lapja Robus hallium(III) complexes wi h ino ganic and o ganic mul iden a e ligands É ekezés a dok o i (Ph.D.) okoza megsze zése é dekében a koo dinációs kémia udományágban Í a: Fodo Tamás okle eles egyész Készül a Deb eceni Egye em Kémiai dok o i iskolája (K/2 koo dinációs kémia p og amja) ke e ében Téma eze ő: D . Tó h Im e A dok o i szigo la i bizo ság: elnök:: D . ………………………… agok: D . ………………………… D . ………………………… A dok o i szigo la időpon ja: 20… . ……………… … . Az é ekezés bí álói: D . …..................................... D …....................................... D . …..................................... A bí álóbizo ság: elnök: D . …...................................... agok: D . ………………………….. D . ………………………….. D . ………………………….. D . ………………………….. Az é ekezés édésének időpon ja: 20… . ……………… … . 1. In oduc ion ................................................................................................................ 4 2. Bibliog aphic e iew .................................................................................................. 9 2.1. Thallium chemis y............................................................................................................9 2.2. Polyoxome alla es.............................................................................................................12 2.3. Mac ocyclic polyamino-polyca boxyla e ligands ..........................................................19 3. Expe imen al sec ion................................................................................................ 22 3.1. Ma e ials and P epa a ion o Solu ions .........................................................................22 3.2.1. pH-po en iome y..................................................................................................... 27 3.2.2. Iodide-selec i e po en iome y ................................................................................28 3.3. Spec opho ome y...........................................................................................................28 3.4. NMR measu emen s ........................................................................................................ 29 3.5. C ys al s uc u e analysis................................................................................................ 30 3.6. DFT calcula ions ..............................................................................................................31 4. Resul s and Discussion ............................................................................................. 33 4.1. De ailed cha ac e iza ion o [Tl(do a)]–..........................................................................33 4.1.1. X- ay c ys al s uc u e.............................................................................................33 4.1.2. Solu ion s uc u e and mixed-complex o ma ion.................................................39 4.1.3. S udies on he s abili y and kine ic ine ness o [Tl(do a)]– by UV- is Spec oscopy....................................................................................................................... 44 4.1.5. Solu ion dynamics s udy wi h 13C-NMR ................................................................ 55 4.2. Cha ac e iza ion o [Tl(cdo2a)]+ and i s iodido mixed-ligand complex.......................64 4.2.1. Backg ound o ligand choice ...................................................................................64 4.2.2. Dissocia ion kine ics o [Tl(cdo2a)]+.......................................................................65 4.2.3. Acid-base p ope ies o [Tl(cdo2a)]+.......................................................................66 4.2.4. In es iga ion o he iodido-mixed ligand complex [Tl(cdo2a)I]............................67 4.2.5. Compa ison wi h a igidi ied open-chain complex [Tl(cd abba)]+.......................69 4.3. S udy o he e na y complex o ma ion be ween [Al(no a)] and F+............................73 4.4. Cha ac e iza ion o [Tl2{B-β-SiW8O30(OH)}2]12–, a newly syn hesised hallium- con aining polyoxome alla e...................................................................................................77 4.4.1. X- ay c ys al s uc u e.............................................................................................77 4.4.2. Solu ion s uc u e s udy...........................................................................................79 4.4.2.1. Simula ion o Tl NMR spec a ............................................................................ 81 4.4.3. Solu ion beha io and o e all obus ness............................................................... 86 4.4.4. An ibac e ial ac i i y................................................................................................ 90 5. Summa y................................................................................................................... 99 6. Össze oglaló............................................................................................................. 106 8. Scien i ic publica ions o Tamás Fodo .................................................................... 125 9. Acknowledgemen .................................................................................................... 130 4 1. In oduc ion Thallium is he hea ies elemen in G oup 13 o he pe iodic able, wi h a omic numbe 81 and ela i e a omic mass o 204.38. I was disco e ed by Si William C ookes in 1861 du ing a sea ch o ellu ium in sulphu ic acid plan esidue. The me allic elemen was named a e he b igh g een colou o i s emission line, de i ed om he g eek wo d „θαλλός” which means „budding wig”. Called he “ o go en elemen ” o he pe iodic able by some, hallium esea ch canno be desc ibed as ei he widesp ead o mains eam. The e a e ew books ha deal mos ly, o exclusi ely wi h ino ganic hallium chemis y and he bulk o scien i ic pape s on he subjec a e om a small numbe o esea che s.1,2,3,4 Indeed o mos people, bo h ou side and wi hin he scien i ic communi y, he mos widely known p ope ies o hallium a e i s oxici y and i s use as poison o oden s and some imes humans. Ongoing ino ganic hallium chemis y is mos ly con ined o i s edox eac ions, high- empe a u e supe conduc o s, me al-me al bonds and coo dina ion chemis y.5,6,7,8,9 The elemen can be ound in he Ea h’s c us in 0.1–3 ppm, mos ly in sulphide o es. I is widely dis ibu ed in na u e and has no comme cially impo an sou ce mine al ( he ew hallium-based mine als such as lo ándi e (TlAsS2), c ookesi e ((Cu,Tl,Ag)2Se), and a icenni e (Tl2O3) a e e y a e). This wide dis ibu ion can be mos ly a ibu ed o Tl+ being able o eplace po assium in a ious mine als.10,11 I is manu ac u ed comme cially as a by-p oduc om lue dus s c ea ed du ing he oas ing o py i e o es, in sulphu ic acid plan s, and om he smel ing o lead, zinc, and coppe . Elemen al hallium is eco e ed by elec oly ic educ ion o Tl(I) sul a e solu ions. 5 Thallium is used in he op ical indus y o inc ease he densi y and e ac i e index o glass, o c ea e IR op ical elemen s om TlB –TlI c ys als. In he ield o elec onics, hallium oxysul ide is used in he so- called ‘Thalo ide cell’, which is highly sensi i e o low-in ensi y, long- wa eleng h ligh and hallium-ac i a ed NaI o NaCl c ys als a e used in some ypes o scin illa ion de ec o s. Thallium-con aining alloys a e also used as good quali y bea ings, ha ing a e y high esis ance o co osion and low ic ion coe icien s. The only cu en medical applica ion o hallium is i s use in he o m o in a enous injec ions o 201Tl (hal -li e = 72.9 hou s) o myoca dial imaging. Thallium is oxic o a a ie y o li e o ms, including humans. The biochemical beha iou o Tl+ is simila o ha o K+, enabling i o eplace po assium o some deg ee and in e e e wi h K+–dependen biological eac ions. The le hal dose o hallium is in he ange o 10– 50mg/kg. Compa ed o (bo h na u al & syn he ic) „ ue” poisons, his means ha one needs o abso b qui e a lo o hallium o a a al dose (600 mg o humans). The symp oms appea in 1–5 days and a e pa es hesia o he ex emi ies, hype sec e ion, hai loss, uncon olled muscle mo emen s, con ulsions, deli ium, coma and ul ima ely, dea h by espi a o y ailu e. The me al accumula es in he body and can be abso bed by inges ion o h ough he skin and memb anes, seemingly ega dless o chemical o m. The mos e ec i e known an ido e is colloidal P ussian Blue, (KFe3+[Fe2+(CN)6]·nH2O), ac ing as an ion exchange o Tl+ in he in es ines and accele a ing i s elimina ion. Al hough i is no an ou s anding poison, hallium has ga ne ed conside able in amy. This is in pa due o he ea ly (1920 o 1970) use o 12 s uc u e, equilib ium, and kine ics ha e been epo ed.31,32,33,34,35Fou dinuclea species ep esen ed by a gene al o mula [(NC)5P – Tl(CN)n−1](n−1)− (n = 1–4) and a inuclea complex [(NC)5P –Tl– P (CN)5]3− a e shown o o m in aqueous solu ion. These a e ue equilib ium complexes, hei solu ions also include he pa en complexes P (CN)42− and Tl(CN)n3–n (n = 0–4), and can be shi ed o ei he side o he equilib ium by changing cyanide concen a ion and/o pH in he solu ion. Mul inuclea NMR- (13C, 195P , 205Tl), IR-, Raman spec oscopy, Elec on Spec oscopy o Chemical Analysis (ESCA), X- ay, and Ex ended X- ay Abso p ion Fine S uc u e (EXAFS) s udies con i m di ec , sho (2.60–2.64 Å) P –Tl bonds. The spin-spin coupling pa e n is consis en wi h 4 + 1 + 1 equi alen 13CN− ligands (I = 1/2), espec i ely and one 195P nucleus (na u al abundance 33.8%, I = 1/2). The compounds a e diamagne ic, and he elec onic s a es and he na u e o he P –Tl bonds ha e been elucida ed by Densi y Func ion Theo y (DFT) calcula ion.36 2.2. Polyoxome alla es Polyoxome ala es 37 , 38 a e polyoxoanions ha a e composed mainly, o comple ely o ansi ion elemen s, dis inguishing hem om hei main g oup analogues (such as silica es), which a e bo h s uc u ally and chemically dis inc . The ypically wa e -soluble polyoxome ala es (POMs) a e mos o en highly symme ical anions wi h molecula s uc u es inco po a ing mul iple me al cen e s, he cu en eco d being 368. Also known as addenda, hese me al cen e s a e mainly ansi ion me als o g oups 5 and 6 in high oxida ion s a es, such as W(VI) and 13 V(V). Addenda a e oc ahed ally coo dina ed o six oxygens, o ming MO6 building blocks ha a e joined by co ne - o edge- ( a ely ace-) sha ing oxygen a oms in a sel –assembly manne . The e minology „polyoxo” is due o he la ge numbe o coo dina ed oxygens, usually p esen as b idging and e minal oxo ligands. Na u al POMs may be ound in mine als such as she woodi e (Ca4.5[AlVIV2VV12O40]·H2O) and mendoza ili e (Na(Ca,Mg)2FeIII(PO4)2[PMo11O39](OH,Cl)10·H2O), as well as in he Mo & W s o age p o eins o Azo obac e inelandii, which con ain ~100 o he espec i e a oms as indi idual clus e s wi h 3–8 me al cen e s.39,40 The polyoxoanions o G oup 5 & 6 a e adi ionally classi ied as ei he isopolyanions, which a e composed solely o addenda and oxygens, o he e opolyanions which inco po a e a numbe o me allic o non- me allic he e oa oms. The he e oa om and i s coo dina ed oxygens cons i u e a he e og oup, which is commonly connec ed o he su ounding MO6 g oups by edges o co ne s. As he coo dina ion en i onmen o he he e oa om mos o en de ines he s uc u al ype o he he e oPOM and i ually any elemen o he pe iodic able can se e as a he e oa om, he numbe o known he e opolyanions is g ea and con inually inc easing. Addenda a oms a e dominan ly oc ahed ally coo dina ed and e ain ei he one o wo (mu ually cis) e minal oxygen a oms ha comp ise he ou e mos laye o he POM s uc u e in nea ly all cases. The i s POMs we e desc ibed by Be zelius41 in 1826 (yellow ammonium–12– molybdophospha e and –a sena e, and hei educed „blue” de i a i es), bu de ailed epo s on he chemis y o many polymolybda es and poly ungs a es only began o eme ge in he la e 19 h 14 cen u y. Keggin in oduced he use o X- ay di ac ion in o POM chemis y in 1933, in es iga ing he s uc u e o H3[(PO4)W12O36]·6H2O.41 The o ma ion o polyoxoanions om mononuclea oxoanions is d i en by acidic condensa ion o MO6 oc ahed a, esul ing in he kine ic and e en ually he he modynamic p oduc s unde he o ma ion condi ions. (Poly ungs a es and some poly anada es usually equilib a e much mo e slowly han molybda es). This also means ha all polyoxoanions unde go dissocia ion in alkaline media. The equi ed pH may, a imes, no be achie able in aqueous solu ions hough. The expec ed ini ial s ep in he polyme iza ion o a e ahed al oxoanion is condensa ion o he monop o ona ed e sion. This is he case o V(V) and C (VI) bu no o Mo(VI) and W(VI). Tha V, Mo, and W can gene a e an ex ensi e chemis y o la ge POMs is a esul o hei abili y o coo dina e a la gely a iable amoun o oxygen a oms (4 – 7) (one may men ion ha C canno ). 15 Figu e 2.2.1 Examples o POM s uc u es. (a) α-[(PO4)W12O36]3− (Keggin). (b) [(TeVIO6)W6O18]6−, [{C III(OH)6}Mo6O18]3− (Ande son– E ans). (c) [(UIVO8)W10O28]8− (Weakley–Yamase). (d) [(CeIVO12)Mo12O30]8− (Dex e –Sil e on). (e) α-[(AsO4)2Mo18O54]6− (Wells–Dawson) 16 Se e al pa ame e s such as pH, empe a u e, ionic s eng h, concen a ion and a io o eagen s g ea ly in luence he esul ing POM s uc u es and can be „ uned” o p o ide a la ge a ie y o polyanions. As men ioned, polyanions a e o med by sel –assembly and in he o ma ion o he e oPOMs, he he e og oup unc ions as an impo an empla e. Closed-shell POMs ha e low su ace–oxygen basici y, making hem chemically ine owa ds elec ophiles, and a e also known as plena y s uc u es. They usually only eac wi h me al ions in e ms o ion pai o ma ion. The Keggin s uc u e (XW12) has become he symbol o POM chemis y and mos published esea ch in his ield deals wi h hese ype o polyanions. Keggin anions may o m many s uc u al isome s, o which he bes known a e hose o C3 symme y, designa ed β, in which one o he ou equi alen edge-sha ed M3O13 iads ound in he o iginal „α” Keggin anion o Td symme y, is o a ed by 60°. Each iad co esponds o h ee edge–sha ed MO6 oc ahed a, which a e co ne – linked by μ4–oxo b idges o he cen al he e oa om. Two, h ee, and all ou edge-sha ed g oups, when o a ed, p oduce γ, δ, and ε s uc u es, espec i ely.42 Each addi ional o a ion des abilizes he Keggin ion, as he numbe o edge–sha ed MO6 connec ions is inc eased. Figu e 2.2.2 S uc u al isome s o XM12O40n– Keggin anions 17 The numbe o possible isome s g ea ly inc eases in „mixed-addenda” POMs, such as [(PO4)V2W10O36]5−, which has i e „posi ional” isome s o α con igu a ion, and 13 β–isome s. The exis ence o hese isome ypes has been well es ablished by NMR spec oscopy. The so-called lacuna y, o acan de i a i es o ce ain polyanions, no ably he Keggin and Wells–Dawson s uc u es, a e also known. These s uc u es can be p epa ed by con olled basic hyd olysis and a e ma kedly mo e eac i e han hei pa en POMs. Fo he e opoly ungs a es, loss o W–cen e s along wi h hei e minal oxo- ligands leads o s uc u es wi h a ying acan si e numbe s (mono– o hexa acan ) (e.g. [GeW11O39]7–, [γ-SiW10O36]8–, [P2W15O56]12–, [H2P2W12O48]12–). Figu e 2.2.3 Some lacuna y anion s uc u es. (a) [(PO4)W11O35]7−. (b) [(PO4)W9O30]9−. (c) [(PO4)2W15O48]14− 18 The emo al o each ca ionic (WO)4+ uni also nega es some o he men ioned ine ness, as he o e all nega i e cha ge o he esul ing lacuna y POM is aised, also inc easing nucleophilici y and hus, eac i i y. Such acan POMs a e, in essence, ino ganic mul iden a e ligands and may be modi ied by inco po a ing addi ional he e oa oms o –g oups in o he acan si es. Figu e 2.2.4 Two lacuna y POM sandwich ype s uc u es (a) [UIV(SiW11O39)2]12−; (b) [PdII2(PW11O39)2]10− and one subs i u ed lacuna y POM (c) [Mo7O24{Os(dmso)3}]3−.43 These seconda y he e oa oms, depending on hei inhe en coo dina ion geome y, may econs uc he o iginal POM s uc u e (such as a Keggin anion), o hey may be sandwiched be ween wo lacuna y POMs. The POMs, being a la ge and highly di e se g oup o compounds, a e applied in a wide a ie y o ields.44,45,46,47 One o he ea lies uses is 19 in analy ical chemis y: ace–le el colo ime ic de e mina ion o elemen s ha a e p one o Keggin–anion o ma ion, namely silica es and phospha es. Phospho ungs ic acid (H3PW12O40) is a gene al s ain o elec on mic oscopy. Mo e ecen o ganic de i a i es allow highly selec i e, a ge ed imaging applica ions. 48 POMs ha e p o en o be success ul phasing agen s in he s uc u al c ys allog aphy o se e al la ge biomolecules, he mos no ewo hy ecen case being [P2W18O62]6– used o he high- es s uc u e o ibosomes (2009 Chemis y Nobel P ize). POMs also ind use as indus ial–g ade ca alys s:49 , 50 , 51 , 52 , 53 molybdophospha es in he oxida ion o me hac olein o me hac ylic acid; ungs ophospho ic acids in he p oduc ion o hyd oxoalkanes ia alkene hyd a ion; molybdo anadophospha es in alkene oxida ion and a oma ic coupling, e c. POMs a e also b eaking g ound in o medicine, as many o hem a e biologically ac i e 54 : smalle anada es and molybda es selec i ely inhibi enzyme unc ion55 and many poly ungs a es ha e been ound o possess an i umo al, an ibac e ial and an i i al ac i i y.56,57,58 2.3. Mac ocyclic polyamino-polyca boxyla e ligands Mac ocyclic amino-ca boxyla e ligands a e widely used in clinical chemis y including medical diagnosis and he apeu ic applica ions in ol ing me al complexes. The ligands consis ing o polyaza- mac ocyclic ings and pendan a ms show high selec i i y i he size o he ing and he adius o he me al ion ma ch pe ec ly. Mo eo e , he na u e o he pendan a m a ached o he N-a oms o he mac ocycle can be used o une he physico-chemical p ope ies (s abili y and selec i i y) o he me al complexes. In case o bi unc ional ligands, he e is also a 20 conjuga ed biological ec o (pep ide, an ibody e c.), i.e. a co alen ly bonded en i y in he molecule, esponsible o he selec i e a ge ing o he complexes in li ing o ganisms.59 The mos widely s udied complexes a e he MRI-con as agen s, whe e he mac ocyclic ligands a e o en he 1,4,7,10- e aazacyclododecane-1,4,7,10- e aace a e (do a) and i s de i a i es, known as he mos e sa ile ligands o medical imaging applica ions. 60 Wi h a sui ably sized ca i y and ou po en ially coo dina ing pendan a ms, his mac ocyclic ligand o ms complexes wi h many ca ions (i.e., Ln3+ ions, Sc3+,61 Y3+,62 Ga3+,63 Bi3+,64 Ca2+,65 S 2+,66 Zn2+,67 and ansi ion me al ions such as Fe3+,68 Co2+,63 Ni2+, and Cu2+).69 The complexes a e usually he modynamically e y s able 70 and kine ically qui e ine .71,72 These beha io s oge he make do a a e y sa e me al-binde because i can ca y he me al componen in biological luids wi hou isk o decomplexa ion, which would esul in uncon olled dis ibu ion o he componen s (i.e., me al ion and ligand) in he biological sys em and may cause oxic e ec s o a dec ease in he signal (e.g., elaxi i y, luminescence, adioac i i y). The ad an ages o p o iding high s abili y and ine ness (o en called kine ic s abili y in medical pape s) a e pa ly coun e balanced by he slow o ma ion o me al−do a complexes.73 While his is ha dly a echnical p oblem o s able me al ions, he long o mula ion ime could be a c ucial poin o sho -li ed adioiso opes.74 Ve y in ensi e esea ch du ing he las 2 o 3 decades has p oduced a o e o chemical knowledge abou do a complexes, i.e., he s abili y cons an s, o ma ion and dissocia ion kine ics, and s uc u e in bo h he solid s a e and solu ion ha e been explo ed o many me al ions.75 A signi ican po ion o he in o ma ion ha has allowed gene al conclusions o be es ablished 21 ega ding do a complexes has been collec ed in lan hanide(III)−do a sys ems, pa icula ly he Gd3+ complex. This is ela ed o he ac ha [Gd(do a)]− is a e y good and sa e gene al (nonselec i e) magne ic esonance imaging (MRI) con as agen (CA) widely used in clinical p ac ice unde he ade name Do a em. Do a complexes a e also o g ea impo ance in o he diagnos ic ields, such as adiology (Single Pho on Emission Compu ed Tomog aphy, SPECT and Posi on Emission Tomog aphy, PET). The use o mac ocyclic complexes, such as do a- de i a i es o a ge ed adioiso ope deli e y is a ela i ely esh and hea ily in es iga ed ield. One example is Do a-oc eo a e, an amide o do a and (Ty 3)-oc eo a e which binds o soma os a in ecep o s and is he e o e selec i e owa ds a numbe o neu oendoc ine umo s. Radionuclides commonly anspo ed wi h DOTATATE ( ade name) a e 68Ga o umo diagnosis wi h PET 76 and 177Lu o ß- adia ion ea men .77 I was also epo ed ecen ly, ha mac ocyclic me al complexes may be used o bind and deli e ce ain adioiso opes in anionic o m: Al(III)-complexes o pep ide-linked amide de i a i es o 1,4,7- iazacyclononane-1,4,7- iace a e (no a) we e shown o bind he PET iso ope 18F wi h p omising in i o esul s.78,79. This ype o adionuclide anspo also o egoes bonding he iso ope o he backbone o he ca ie molecule and mos complica ions associa ed wi h he p ocess. I is he e o e qui e ole an o low hal -li e iso opes and allows i ually any modi ica ion o he ligand o ake place be o e labeling, such as linkage o a a ge ing ec o . 28 a oid KClO4 p ecipi a ion in he memb ane. The pH-me e was calib a ed wi h KH-ph hala e (pH = 4.005) and KH2PO4-Na2HPO4 (pH = 6.865) bu e s and he H+ concen a ions we e calcula ed om he measu ed pH alues by applying he me hod p oposed by I ing e al.82 3.2.2. Iodide-selec i e po en iome y F ee iodide concen a ions we e measu ed using a Me ohm 6.0502.160 iodide–selec i e elec ode wi h an Ag/AgCl elec ode as e e ence. As p e iously s a ed, elec oly es con aining K+ we e eplaced wi h 1M NaCl. Measu emen s we e pe o med a 25 (±0.1) °C, in 1M NaClO4 unde a cons an a gon s eam. Calib a ion o he elec ode was pe o med by i a ing a blank 1 M NaClO4 solu ion wi h NaI. 3.3. Spec opho ome y UV-VIS spec a we e eco ded in qua z cu e es anging om 1.0 mm o 1.0 cm pa h leng h wi h a Va ian Ca y 1E UV-Visible Spec opho ome e a 25 °C in he wa eleng h ange 350-200 nm, wi h da a poin s e e y 0.5 nm and a scan a e o 100 nm/min, unless o he wise s a ed. Sho - e m dissocia ion kine ics was ollowed by epea ed eco dings o spec a, wi h delay imes o 1 hou . The UV-ligh was cu o om he sample du ing he delays o a oid pho ochemical decomposi ion. Long- e m kine ics we e ollowed by sepa a e eco dings, wi h delay imes o 1 day o 1 week. 29 3.4. NMR measu emen s 1H and 13C spec a we e eco ded wi h a B uke DRX 400 spec ome e a 400.1 MHz and 100.6 MHz, espec i ely. In spi e o lacking ma ching NMR p obes capable o 205Tl-measu emen , hallium spec a we e ob ained wi h a B uke AM 360 spec ome e by inse ing a 500 MHz BB p obe and uning he x-channel o he equency o 205Tl (207.8 MHz). This se up does no in e ac wi h 1H o 2H and does no enable locking o 1H-decoupling o be used. P obe empe a u es we e kep a 25 (±0.1) °C i no s a ed o he wise. Calib a ion was pe o med using he signal o D2O (4.79 ppm) o 1H-spec a, e ame hylsilane (0 ppm) o 13C-spec a and wi h 50 mM Tl(I)- and Tl(III)-pe chlo a e solu ions (Tl+: -4.72 ppm, Tl3+: 2039 ppm) o 205Tl-spec a. Line-shape analysis was ca ied ou wi h a home-made p og am w i en in Ma Lab, using he algo i hm de eloped by Ree es and Shaw. 83 This p og am i s a signal-shape unc ion simula ing he change o coupling- ee NMR signals caused by chemical exchange, using modi ied Bloch-equa ions ( he coupling- ee app oxima ion implies ha he same exchange a e is applied o bo h se s o signals). The ela i e posi ion o he wo double signals used o he analysis we e ixed, while he in eg als (popula ions) and he line wid hs wi hin he double s we e assumed o be iden ical. Fi e pa ame e s we e es ima ed: wo o de ine he baseline, one o he in ensi y, he equency speci ic o he posi ion o he signal and he exchange a e cons an . The calcula ed a e cons an s we e hen i ed o he Ey ing-Polanyi equa ion [ln(k/T) = -H/RT + ln(kB/h) + S/R, whe e k is he a e cons an , T is 30 he absolu e empe a u e, kB is he Bol zmann cons an , R is he ideal gas cons an , h is he Planck cons an and H and S a e ac i a ion en halpy and ac i a ion en opy. 376.5 MHz 19F NMR spec a we e collec ed using a B uke DRX 400 NMR spec ome e . Calib a ion was pe o med wi h 10 mM sligh ly basic NaF o 19F spec a (0 ppm). 3.5. C ys al s uc u e analysis The sodium sal o [Tl(do a)] could no be c ys allized in spi e o epea ed ials. Thus, we used he guanidine ca ion, which is known o aid he p epa a ion o single c ys als due o i s s ong abili y o o m hyd ogen bonds.84 Single c ys als o C(NH2)3[Tl(do a)]·H2O could be g own a he in e ace be ween 96% e hanol and a solu ion p epa ed by me hod (c) desc ibed abo e. Di ac ion in ensi y da a collec ion was ca ied ou a 293(2) K on a B uke -Nonius MACH3 di ac ome e equipped wi h a poin de ec o using g aphi e-monoch oma ed Mo-Kα adia ion (λ = 0.71073 Å). The s uc u e was sol ed wi h he SIR-92 p og am85 and e ined by he ull- ma ix leas -squa es me hod on F2. All non-hyd ogen a oms we e e ined wi h aniso opic he mal pa ame e s using he SHELXL-97 package.86 Hyd ogen a oms we e loca ed geome ically and e ined in he igid mode, excep o hyd ogen a oms o wa e molecules, which could be ound in he di e ence elec on densi y map. The emaining elec on densi y peaks we e ound close o he Tl a om. C ys al da a and s uc u e e inemen de ails: Fo mula: C17H32N7O9Tl; MW: 682.87; c ys al sys em: iclinic; space g oup: P-1; a = 7.498(10) Å; b = 12.406(5) Å; c = 31 12.800(4) Å;  = 91.01(1)º;  = 90.86(4)º; γ = 107.31(6)º; V = 1136.3(16) Å3; Z = 2; Dcalc = 1.996 g cm–3; F(000) = 672; μ = 7.17 mm–1; Re lec ions collec ed: 4909; Unique e lec ions wi h I > 2(I): 4117; Pa ame e s e ined: 331; GOF on F2 = 1.09; R[F2 > 2σ(F2)] = 0.057; Rin = 0.046; wR(F2) = 0.156;   max and   min = 3.58 and –4.05 e Å–3. 3.6. DFT calcula ions All calcula ions we e pe o med in aqueous solu ion employing DFT wi hin he hyb id GGA app oxima ion wi h he B3LYP exchange- co ela ion unc ional87 and he Gaussian 09 package (Re ision B.01).88 Full geome y op imiza ions o he [Tl(do a)]- sys em we e pe o med in aqueous solu ion wi hou symme y cons ain s. In hese calcula ions we used he ela i is ic e ec i e co e po en ial (RECP) o Ross. e al o Tl (CRENBL), which includes 68 elec ons in he co e, wi h he alence space (5d, 6s and 6p) ep esen ed by an uncon ac ed (3s3p4d) basis se .89 The ligand a oms we e desc ibed using he s anda d 6-311+G(d,p) basis se . The s a iona y poin s ound on he po en ial ene gy su aces as a esul o geome y op imiza ions we e es ed o ep esen ene gy minima a he han saddle poin s ia equency analysis. The ela i e ee ene gies o he di e en con o ma ions o [Tl(do a)]- complexes we e calcula ed in aqueous solu ion a he B3LYP/CRENBL/6-311+G(d,p) le el, and hey include non-po en ial- ene gy con ibu ions (ze o poin ene gies and he mal e ms) ob ained h ough equency analysis. The a m o a ion and ing in e sion p ocesses o [Tl(do a)]- we e in es iga ed by means o he synch onous ansi - guided quasi-New on me hod a he B3LYP/CRENBL/6-31+G(d,p) 32 le el.90 The na u e o he saddle poin s (one imagina y equency) was cha ac e ized by equency analysis. The ee ene gy ba ie s calcula ed include non-po en ial ene gy con ibu ions ob ained by equency analysis. The NMR shielding enso s o he [Tl(do a)]- sys em we e calcula ed in aqueous solu ion using he B3LYP unc ional and he GIAO me hod.91 In hese calcula ions he mo e ex ended 6-311G+(d,p) basis se was used o he ligand a oms. Fo 13C-NMR chemical shi calcula ion pu poses he NMR shielding enso s o TMS we e calcula ed a he same le el. Th oughou his wo k sol en e ec s we e included by using he pola izable con inuum model (PCM), in which he solu e ca i y is buil as an en elope o sphe es cen e ed on a oms o a omic g oups wi h app op ia e adii. In pa icula , we used he in eg al equa ion o malism (IEFPCM) a ian as implemen ed in Gaussian 09.92 The de aul alues o he in eg a ion g id (75 adial shells and 302 angula poin s) and he SCF ene gy con e gence c i e ia (10-8) we e used in all calcula ions. 33 4. Resul s and Discussion 4.1. De ailed cha ac e iza ion o [Tl(do a)]– 4.1.1. X- ay c ys al s uc u e C ys als o C(NH2)3[Tl(do a)]·H2O con ain he [Tl(do a)]- complex, a guanidinium ca ion and a wa e molecule. A iew o he s uc u e o he complex and bond dis ances o he me al coo dina ion en i onmen is p o ided in Figu e 4.1.1.1. The Tl3+ ion is di ec ly coo dina ed o he eigh dono a oms o he ligand, wi h he me al coo dina ion en i onmen being bes desc ibed as wis ed squa e an ip isma ic (TSAP). The s e eochemis y o eigh - and nine-coo dina e me al complexes o do a is well documen ed; he coo dina ion o he ligand o he me al ion in oduced wo sou ces o chi ali y, one associa ed o he con o ma ion o he cyclen moie y [() o ()], and ano he ela ed o he layou o he ou ace a e pendan a ms [ ep esen ed as  o ]. The combina ion o hese wo sou ces o helici y gi es ise o ou possible s e eoisome s exis ing as wo dias e eoisome ic pai s o enan iome s. These enan iome ic pai s p o ide ei he a squa e an ip isma ic [SAP, ()/()] o a TSAP [()/()] coo dina ion a ound he me al ion.16e, 93 Inspec ion o he s uc u e o C(NH2)3[Tl(do a)]·H2O shows ha c ys als con ain he ()/() enan iome ic pai , he wo enan iome s being cen o- symme ically ela ed in acco dance wi h he cen o-symme ic cha ac e o he space g oup P-1. Bo h he guanidinium ca ions and he wa e 34 molecules a e in ol ed in hyd ogen-bonding in e ac ions wi h he oxygen a oms o he ace a e g oups o he ligand. Figu e 4.1.1.1 View o he s uc u e o he [Tl(do a)]- complex p esen in c ys als o C(NH2)3[Tl(do a)]·H2O. The ORTEP plo is a he 30% p obabili y le el. Bond dis ances (Å): Tl01-N1, 2.454(8); Tl01-N4, 2.497(9); Tl1-N7, 2.443(8); Tl01-N10, 2.458(9); Tl01-O1, 2.322(8); Tl01-O11, 2.438(8); Tl01-O41, 2.383(8); Tl01-O71, 2.316(7) 35 Table 4.1.1.1 S uc u al pa ame e s obse ed o selec ed [M(do a)(H2O)]- and [M(do a)]- complexes in he solid s a e. M La Gd Bi Sc Tm Tl Ionic adius / Åa 1.216 1.107 1.17 0.87 0.994 0.98 M-O / Åb 2.467 2.368 2.538 2.150 2.279 2.365 M-N / Å 2.770 2.663 2.526 2.441 2.529 2.464 M-O / M-N 0.89 0.89 1.00 0.88 0.90 0.96 M-QO / Åc 0.728 0.715 1.112 1.007 1.064 1.252 M-QN / Åd 1.810 1.632 1.434 1.327 1.466 1.324 QO-QN 2.54 2.35 2.55 2.33 2.53 2.58 Twis Angle / ºe 23.2 38.5 25.9 41.1 24.4 25.4 Isome TSAP SAP TSAP’ SAP’ TSAP’ TSAP’ a Ionic adii o coo dina ion numbe 8 (Bi, Sc, Tm and Tl) o coo dina ion numbe 9 (La and Gd) aken om e e ence 94. b A e age bond dis ances be ween he me al ion and he O a oms o he ace a e a ms. c Dis ance be ween he me al ion and he leas squa es plane de ined by he coo dina ed O a oms o ace a e g oups. d Dis ance be ween he me al ion and he leas squa es plane de ined by he N a oms o he mac ocycle. e Calcula ed as he a e age alue o he ou o sion angles N-CN-CO-O, whe e N and O a e he dono a oms de ining a i e- membe ed chela e ing and CN and CO ep esen he cen oids o he QN and QO planes, espec i ely. 36 Figu e 4.1.1.2 Va ia ion o he M-N and M-O bond dis ances wi h he ionic adius in [M(do a)]- (M = Tm, Sc, Bi o Tl) and [Ca(do a)]2- complexes. The solid lines a e he linea i s o he da a epo ed o he Ca2+, Sc3+ and Tm3+ complexes (see ex ) Do a-like complexes wi h he ligh Ln3+ ions a e usually nine- coo dina ed, whe e he ligand ac s as eigh -den a e and one wa e molecule is in he inne coo dina ion sphe e. Eigh -coo dina ion wi h he absence o a coo dina ed wa e molecule is ypical o he hea ie Ln3+ ions such as Tm3+. In bo h sub-g oups SAP (Ln= P , Nd, Sm, Dy) and 37 TSAP (Ln= Ce, Tm) geome ies a e ound. Eigh coo dina e complexes ha lack he apical wa e molecule a e o en labeled as SA’ and TSAP’ o di e en ia e hem om he nine-coo dina e SAP and TSAP complexes.63a [Sc(do a)]- adop s a SAP' geome y,63a in con as wi h he TSAP' coo dina ion obse ed o [Ca(do a)]2-, [Bi(do a)]- and [Tm(do a)]-.63a,65,66 In [Tl(do a)]- he coo dina ion geome y a ound Tl3+ is TSAP’. The dis inc i e s uc u al ea u e ha disc imina es SAP and SAP' e sus TSAP and TSAP' s uc u es is ep esen ed by he wis angle be ween he wo squa e planes o he an ip ism, he basal plane comp ised o he ou ni ogen a oms o he mac ocycle, and he uppe plane con aining he ou coo dina ed oxygen a oms o he pendan a ms. The a e age wis angle obse ed o [Tm(do a)]- (25.4º) is close o ha expec ed o a egula wis ed squa e an i ip ism (22.5º) and also simila o hose ound o o he complexes ha ing TSAP o TSAP’ s uc u es (Table 4.1.1.1). Table 4.1.1.1 p o ides a compa ison o s uc u al pa ame e s epo ed in he li e a u e o [M(do a)]- complexes (M = Sc3+,63a Tm3+,63a and Bi3+,65) wi h hose o he Tl3+ analogue. Addi ionally, we ha e also included he co esponding da a o selec ed [M(do a)(H2O)]- complexes, wi h M = La95 o Gd69 as ep esen a i e membe s o he ea lie and middle membe s o he lan hanide se ies, espec i ely. The a e age M-O bond leng hs a e in he ange o 2.54-2.15 Å, while he M-N dis ances ange be ween 2.44 and 2.77 Å. The dis ances be ween he i ual planes de ined by he ou N a oms o he mac ocycle (QN) and he ou dono oxygen a oms o he pendan a ms (QO) a e ca. 2.53-2.58 Å o he complexes wi h TSAP and TSAP’ coo dina ion and 2.33-2.35 Å o hose wi h SAP and SAP’ geome ies. Thus, he QO-QN dis ances o a gi en coo dina ion polyhed on emain nea ly una ec ed by he na u e o he 44 as cyanide exchange a high pH alues equi ed o he o ma ion o he mixed ligand complex. 4.1.3. S udies on he s abili y and kine ic ine ness o [Tl(do a)]– by UV- is Spec oscopy The s abili y cons an o [Tl(ed a)]– has been de e mined by a compe i ion me hod using la ge excess o bo h halide ligands and H+.105 In case o [Tl(do a)]– an e en g ea e s abili y is expec ed u he mo e he mac ocyclic complex o ms e y slowly in acidic solu ions, which p e en s he use o di ec po en iome y o s abili y cons an de e mina ion. Ins ead, we ha e used a compe i ion me hod in which bo h a halide, namely he b omide, and H+ compe e o Tl3+ and do a4–, espec i ely, acco ding o he ollowing equilib ium cha ac e ized by he equilib ium cons an , Kcomp: (n-1)H+ + [HTl(do a)] + 4 B –TlB 4– + Hndo a(4-n)– (4.1.3.1) Kcomp = [TlB 4–][Hndo a(4-n) –]/[HTl(do a)][H+]n-1[B –]4 (4.1.3.2) Tl3+ beha es as a “so ” acid acco ding o he classi ica ion o Pea son, as he s abili y o halide complexes inc eases om he ligh halide ions o he hea y ones. The e o e, iodide would be he s onges compe ing agen o Tl3+. 45 Figu e 4.1.3.1 Time dependence o UV-spec a a ibu ed o he ligand- exchange eac ion be ween [HTl(do a)] and B - in 1M HClO4: [HTl(do a)] ( ed, eco ded a 0) is slowly con e ed o [Tl(B )4] (blue, eco ded a 450 hou s; he abso bance alue and he shape o he spec um a e in acco dance wi h sepa a e measu emen s o [TlB 4]). In e media e spec a we e eco ded a 1 hou in e als o 19 hou s. Con e sion is ~99% a 240 h (magen a). Howe e one has o conside edox eac ions, i.e. Tl3+ can oxidize iodide o iodine while Tl+ is o med (TlI4– is he only TlIn+3-n species de ec ed in solu ion a high I–/ Tl3+ a ios).3 P elimina y expe imen s ha e con i med he immedia e o ma ion o iodine, and he e o e we ha e selec ed B - o he compe i ion eac ions. 46 Knowing he kine ic ine ness o [M(do a)] complexes, sui able he modynamic da a can only be ex ac ed om p ope ly equilib a ed compe i ion sys ems. Thus, ba ch samples con aining 0.5 mM Tl(do a)–, 0.5 M NaB we e p epa ed, a ying he concen a ion o he acid in he ange o 0.1, 0.3, 0.5, 0.8 and 1M o HClO4 and keeping he o al pe chlo a e concen a ion cons an (a 1M wi h (Na++H+)ClO4). The dissocia ion o he complex, i.e. he o ma ion o [TlB 4]– was ollowed o e ime eco ding spec a in he 200-350 nm ange un il he expec ed equilib a ion o he sys em (Figu e 4.1.3.1). The spec a shown in Figu e 4.1.3.1 clea ly show isosbes ic poin (s), which is in ag eemen wi h he p esence o wo species ([HTl(do a)] and [Tl(B )4]) in equilib ium wi h measu able abso bance du ing he 240 hou s expe imen al ime in he sys em, in acco dance wi h he equa ion 4.1.3.1. Howe e , he eac ion is subs an ially slowe in he less acidic samples, whe e he isosbes ic poin s we e no obse ed. This indica es ha some kind o pa allel side eac ion is occu ing unde hese condi ions. This may be a slow edox eac ion in ol ing b omide ions and he Tl3+ ion in an ou -o -cage in e media e in which he me al ion is coo dina ed only by ca boxyla e g oups (as in he o ma ion/dissocia ion in e media e obse ed o o he do a complexes). We in es ed a high amoun o ime and ene gy ying o a oid his complica ion (exclusion o ai om samples wi h a gon, inc easing empe a u e o sho en he equilib a ion ime by con en ional means and by using a mic owa e eac o ) wi hou any success in measu ing he equilib ium cons an de ined by equa ion 4.1.3.2. Finally we decided o only use spec a eco ded a low con e sion o e alua e he kine ics o ou Tl-mac ocyclic complex by means o he 47 ini ial a e me hod. Assuming ha [Tl(do a)] dissocia es simila ly o [Gd(do a)],73c he ollowing equa ions may be used o e alua e he kine ic da a: –d[Tl(do a)] /d = kobs[HTl(do a)] (4.1.3.3) kobs = k0 + k1[H+] + k2[H+]2 (4.1.3.4) whe e kobs is he obse ed pseudo i s -o de eac ion a e cons an , k0 is he a e cons an o spon aneous (o wa e assis ed) dissocia ion o he monop o ona ed complex, k1 and k2 a e he cons an s o p o on-assis ed dissocia ion. The expe imen al esul s a e shown on Figu e 4.1.3.2. Cu e i ing gi es k0 = 0 ( ixed o 0 as he i ing o he dissocia ion kine ic da a in a ial e u ned a small nega i e alue wi h la ge e o ), k1 = (9±7)10–7 s–1M–1 and k2 = (5±0.8)10–6 s–1M–2 alues. The da a shows quad a ic dependence o kobs on acidi y wi h no de ec able spon aneous dissocia ion, which is no su p ising because spon aneous dissocia ion o he monop o ona ed complex is expec ed o occu slowe by se e al o de s o magni ude, han he acid-ca alyzed dissocia ion (which is he dominan eac ion pa hway in he acid concen a ion ange applied in he cu en s udy). The k1 alue also has a la ge unce ain y, and may be a calcula ion a i ac caused by he limi ed numbe o da a poin s and hei inaccu acy in he lowe cH+ ange ela ed o he abo e-men ioned side eac ions du ing he e y slow compe i ion eac ion. This kind o a e law is in acco dance wi h he ela ed li e a u e o do a-complexes, i.e. he dissocia ion is a dominan ly p o on-assis ed p ocess. (We ha e ound some mino spec al changes ha migh be ela ed o some in e ac ion 48 be ween [HTl(do a)] and he B  ion, bu we could no quan i a i ely measu e his p obably small con ibu ion o he dissocia ion kine ics). Figu e 4.1.3.2 Plo o kobs s. acid concen a ion in Tl(III) - do a4 - H+ - B  sys em Using he kobs = k1[H+] + k2[H+]2 a e law one can calcula e he hal li e o he complex a di e en pH alues. Hal -li e o [Tl(do a)] is 32 h in 1 M HClO4 and app oxima ed o 5▪109 h a pH = 7.4. The la e alue indica es ha he dissocia ion o [Tl(do a)] a physiological pH is negligible. To ou su p ise howe e , he [201Tl(do a)] complex was ound ecen ly o decompose in i o.104 Ou da a sugges s ha his phenomenon is mo e likely o be caused by he bio educ ion o Tl(III) in he samples 49 a he han he dissocia ion o he [Tl(do a)] complex. Tl+ (showing simila i y o K+ bo h in size and complexa ion p ope ies) likely o ms a weak and labile complex wi h DOTA, making he dissocia ion o he educed adioiso ope om he complex easy. 4.1.4. Addi ional solu ion s uc u e da a ob ained by 1H and 13C- NMR spec oscopy The 1H-NMR spec um o [Tl(do a)] p esen s six b oad signals a oom empe a u e: one double can be assigned o he p o ons o he ace a e me hylene g oups and wo double s o hose o he ing (3J1H-205Tl scala coupling spli s hese signals in o double s). The b oadness o hese signals is ela ed o exchange p ocesses occu ing in solu ion. Based on he composi ion o he complex and ha o he solu ion, he exchange is a ibu ed o he in amolecula ea angemen o he complex. A highe empe a u es he signals sha pen and hei s uc u e becomes isible as a consequence o he accele a ion o he exchange p ocesses. This is also suppo ed by 13C-NMR spec a, which a high empe a u es show wo signals in he alipha ic egion: a single assignable o he ace a e me hylene ca bons and a 205Tl coupled double o he ing ca bons (Figu e 4.1.4.1). The ca bon nuclei o he me hylene g oups o he pendan a ms do no show 205Tl–coupling. This is likely caused by he combined e ec o a wo-bond coupling ( h ough he ni ogen) and a h ee-bond coupling ( h ough he ca boxyla e oxygen). These couplings may possess di e ing signs ha p esumably cancel ou . The 1H- and 13C-NMR spec a eco ded a low empe a u e (272 K) a e ela i ely well esol ed, and could be ully assigned wi h he aid o 50 he homonuclea 1H-1H COSY and he e onuclea 1H-13C HSQC spec a (Figu e 4.1.4.2, see Cha 4.1.4.1 o labeling). A his empe a u e he ing ca bon double spli s in o wo, indica ing he p esence o wo di e en chemical en i onmen s o he ca bon nuclei o he mac ocyclic moie y. Figu e 4.1.4.1 100 MHz 13C-NMR spec a o a 0.1 M Na[Tl(do a)] solu ion in D2O eco ded a di e en empe a u es in D2O (pH = 4) The spec um shows ou signals: he 205Tl-coupled double (2J205Tl-13C = 64 Hz) o he ca boxyla e (-C=O) g oups a δ=179.7 ppm (C1), a single due o he -CH2- g oups o he ace a e pendan a ms a 58.8 ppm (C2), and wo 205Tl-coupled double s o he non-equi alen ca bon 51 a oms o he mac ocycle ing cen e ed a δ=49.2 (2J205Tl-13C = 156 Hz) and 53.6 (2J205Tl-13C = 161 Hz) ppm. This pa e n poin s o a C4 symme y o he [Tl(do a)] complex a low empe a u es, while he spec a a empe a u es highe han Figu e 4.1.4.2 400 MHz 1H-1H COSY spec um o 0.1 M [Tl(do a)] eco ded in D2O solu ion (pD eading = 4) a 272.5 K (see Cha 4.1.4.1 o labelling) 52 NN N N COO - COO- -OOC -OOC 1 2 3 4 Cha 4.1.4.1 Ligand H4do a and he numbe ing scheme used o NMR spec al assignmen Figu e 4.1.4.3 400 MHz 1H-13C HSQC spec um o 0.1 M [Tl(do a)] a 272.5 K 53 320 K can be in e p e ed as an e ec i e C4 symme y. The 1H-13C HSQC spec um (Figu e 4.1.4.1) shows ha each o he 3 ca bon nuclei in he alipha ic egion is coupled wi h 4 p o on signals, wo o hem showing e y small chemical shi di e ences. This is clea ly obse ed o he p o on nuclei o he –CH2– g oups o he ace a e a ms (H2). Fo hese p o ons one expec s an AB spin sys em wi h a 2Jax-eq o ~16 Hz. Howe e , he coo dina ion o he ligand o he Tl3+ ion c ea es an AB-X sys em, which spli s each o he componen s o he AB spin sys ems in o double s due o he 3J1H-205Tl coupling. The 1H–1H COSY spec um ela es he signals a 3.19 ppm and 3.68, and hose a 3.16 and 2.24 ppm, while no c oss-peak is obse ed ela ing he signals a 3.68 and 2.24 ppm. All hese ou signals a e howe e co ela ed o he ca bon a om o he ace a e a ms in he HSQC spec um. Thus, he signals a 3.68 and 2.24 ppm a e a ibu ed o a single p o on nucleus whose esonance is spli by he coupling o 205Tl. An analogous easoning allowed us o assign he p o on signals o he mac ocyclic agmen (Table 4.1.4.1). Fu he mo e, he spin pa e n o he signals allowed us o disc imina e be ween axial (ax) and equa o ial (eq) p o on nuclei. Indeed, he di e en H-C-C-H dihed al angles ela ing axial and equa o ial p o ons wi h he p o ons a a h ee bond dis ance esul in di e en coupling pa e ns, as expec ed by he Ka plus ela ionship.106,107 As a esul , he equa o ial p o ons p o ide small 3J coupling cons an s, so ha hei coupling pa e ns a e domina ed by he s ong 2Jeq-ax coupling (~16 Hz). This is o ins ance he case o he signal a 2.00 ppm, which is obse ed as a pseudo-double . On he con a y, axial p o ons gi e wo s ong couplings (2Jax-eq and 3Jax-ax) and a weak one 60 Since he empe a u e dependence o he signals a 53.6 and 49.2 ppm co e s bo h he as exchange and he slow exchange egimes, we used hese esonances o pe o m a quan i a i e band-shape analysis o he exchange p ocess, which p o ides he exchange a es kexch a e e y empe a u e. The ag eemen be ween he expe imen al and simula ed spec a is excellen (Figu e 4.1.5.2). The empe a u e dependence o he e alua ed ime cons an s was subsequen ly used o ob ain he ac i a ion pa ame e s o he exchange p ocess using he Ey ing-Polányi equa ion. The esul s a e compa ed o hose ob ained o ela ed do a4 complexes in Table 4.1.5.1. Table 4.1.5.1 Ac i a ion pa ame e s ob ained o he ()  () in e con e sion in [Tl(do a)]  and ela ed sys ems H (kJ mol1) S (J K1 mol-1) G298 (kJ mol1) [Tl(do a)]- Exp. 66 + 2 +23 + 6 59 + 2 Calcd. 73.2 +19.2 67.5 [Bi(do a)]- Exp. 40 -76 + 15 63 [Lu(do a)]- Exp. 101 +116 66 a Values ob ained o he a m- o a ion p ocess wi h DFT calcula ions in aqueous solu ion a he B3LYP/CRENBL/6-31+G(d,p) le el. The ac i a ion en halpy (H) de e mined o [Tl(do a)] alls be ween he alues epo ed o [Bi(do a)] and [Lu(do a)]. Howe e , he di e en signals o he ac i a ion en opy ob ained o he la e wo complexes and he small posi i e S alue de e mined o [Tl(do a)] esul in ela i ely simila ac i a ion ee ene gies a 298 K (G298). The 61 [Lu(do a)] complex exis s in solu ion as a mix u e o he eigh - coo dina e TSAP’ isome and he nine-coo dina e SAP o m, and ac i a ion pa ame e s o bo h he ing-in e sion and a m- o a ion p ocesses could be ob ained.59b Thus, he la ge posi i e ac i a ion ene gy ob ained o his complex migh be ela ed o he expulsion o he coo dina ed wa e molecule in he ansi ion s a e esponsible o he ()  () in e con e sion. Fo [Tl(do a)] S akes a ela i ely small posi i e alue, which is likely ela ed o he ea angemen o he hyd a ion shell du ing he in e con e sion p ocess. 1.82.02.22.42.62.83.03.23.43.63.84.04.24.4 (ppm) 272.5 K 282.5 K 360.0 K 292.5 K 302.5 K 312.5 K 322.5 K 332.5 K 342.5 K 352.5 K Figu e 4.1.5.3 1H-NMR spec a o 0.1 M [Tl(do a)] a a ying empe a u es 62 To ob ain a mo e de ailed in o ma ion o he mechanism esponsible o he enan iome iza ion p ocess in [Tl(do a)], we pe o med a compu a ional in es iga ion o he ing in e sion and a m o a ion p ocesses. Figu e 4.1.5.4 Rela i e ee ene gies o minima, in e media es (labeled as “I”) and ansi ion s a es (labeled as “TS”) in ol ed in he ()  () in e con e sion p ocess o [Tl(do a)] calcula ed in aqueous solu ion a he B3LYP/CRENBL/6-31+G(d,p) le el Acco ding o ou calcula ions pe o med in aqueous solu ion a he B3LYP/CRENBL/6-31+G(d,p) le el he in e sion o he mac ocyclic ing is a ou -s ep p ocess in ol ing he s epwise in e sion each o he 63 ou i e-membe ed chela e ings o med by he coo dina ion o he mac ocyclic moie y. In each o hese s eps one o he chela e ings changes i s con igu a ion om  o  (o ice e sa) h ough a ansi ion s a e in which he H-C-C-H uni s adop a nea ly eclipsed con o ma ion. Simila ou -s ep p ocesses ha e been ob ained p e iously using HF and DFT calcula ions o di e en Ln3+ complexes wi h cyclen-based ligands.112 Due o he symme y p ope ies o he [Tl(do a)] complex (C4 poin g oup), wo di e en ou es a e possible o he in e sion o he second and hi d chela e ings (Figu e 4.1.5.4). As once he i s chela e is in e ed, he second s ep may p oceed ia in e sion o a chela e ing ei he in opposi e (TS2a & TS3a) o adjacen (TS2b & TS3b) posi ion a he mac ocyclic ing wi h espec o he o me . Acco ding o ou calcula ions he lowes -ene gy pa hway co esponds o ha p oceeding h ough TS3b, which p o ides an ac i a ion Gibbs ee ene gy o he ing-in e sion p ocess o G = 60.8 kJ mol1 a 298 K. Con a y o he ing-in e sion p ocess, he a m o a ion pa hway is a single-s ep p ocess in ol ing he simul aneous o a ion o he ou pendan a ms o he ligand. The s uc u e o he TS (TS5, Figu e 4.1.5.4) is qui e dis o ed, wi h ou di e en Tl-N dis ances in he ange 2.50- 2.75 Å and ou Tl-O dis ances anging be ween 2.30 and 2.37 Å. The ac i a ion ee ene gy o he a m o a ion p ocess amoun s o G298 = 67.5 kJ mol1, and hus he a m- o a ion p ocess likely ep esen s he a e de e mining s ep o he ()  () in e con e sion in [Tl(do a)]. The H and S alues calcula ed o he a m o a ion pa hway (Table 4.1.5.1) show a e y good ag eemen wi h he expe imen al alues, which p o ides addi ional suppo o his 64 hypo hesis. In con as , he ing in e sion pa h p o ides negligible ac i a ion en opy. 4.2. Cha ac e iza ion o [Tl(cdo2a)]+ and i s iodido mixed-ligand complex 4.2.1. Backg ound o ligand choice Al hough [Tl(do a)] has p o en o be qui e obus , i lacks he ee me al coo dina ion si e needed o binding addi ional anions. Logic dic a es and expe ience has shown ha ligands wi h ewe pendan dono si es should lea e he encapsula ed me al mo e accessible o wa e molecule(s) o addi ional small anion(s). To his end, he iodide-binding abili y o a ious Tl(III)-complexes was in es iga ed by 205Tl-NMR, using a numbe o mac ocyclic (and one mesocyclic) ligands. The ligands in es iga ed a e, in descending o de o he numbe o dono si es: do3a (1,4,7,10- e aazacyclododecane-1,4,7- iace ic acid), pc a (3,6,9,15- e aazabicyclo [9.3.1]pen adeca-1(15),11,13- iene-3,6,9- iace ic acid), aaz a (2,2'-(1,4-bis(ca boxyme hyl)-6-me hyl-1,4-diazepan-6- ylazanediyl)diace ic acid), cys- and ans-do2a (1,4,7,10- e aazacyclododecane-1,4-diace ic acid and 1,4,7,10- e aazacyclododecane-1,7-diace ic acid) and do1a (1,4,7,10- e aazacyclododecane-1-ace ic acid). To much o ou su p ise only one o he ligands, cdo2a was ound o bind iodide ions in i s Tl(III)-complex. This ac is especially in e es ing when DFT calcula ions pe o med o bo h do2a isome s a e aken in o conside a ion: no only is [Tl( do2a)]+ expec ed o also o m a e na y complex wi h iodide ions, i was also 65 ound o be ene ge ically mo e a ou able han ha o [Tl(cdo2a)]+. The de ails on why his is no he case a e s ill unknown a his ime, we specula e ha s e ic hind ance may be qui e di e en in he wo complexes. 4.2.2. Dissocia ion kine ics o [Tl(cdo2a)]+ 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 200 220 240 260 280 300 320 340 wa eleng h, nm A Figu e 4.2.2.1 Time dependence o UV-spec a a ibu ed o he ligand- exchange eac ion be ween [Tl(cdo2a)]+ and B - in 1M HClO4: [Tl(cdo2a)B ] (bo om black, eco ded a 0) is slowly con e ed o [Tl(B )4] ( op black, eco ded a 15 hou s; he abso bance alue and he shape o he spec um a e in acco dance wi h sepa a e measu emen s o [TlB 4]) 66 The double compe i ion me hod desc ibed ea lie in case o [Tl(do a)]− was used o also de e mine he dissocia ion p ope ies o [Tl(cdo2a)]+, wi h he la e showing some simila i y o he o me (see Figu e 4.2.2.1). The ini ial abso bance is g ea e , likely as a consequence o [Tl(cdo2a)B ] o ming. The la ges di e ence is he inc eased dissocia ion a e (ob ained in he same manne as o [Tl(do a)]−), eaching o al Tl(III)-displacemen in 1M HClO4 o e nigh , as less dono g oups make he complex less compac and he me al cen e mo e accessible. 4.2.3. Acid-base p ope ies o [Tl(cdo2a)]+ The pa en complex can o m mixed hyd oxo complexes acco ding o he ollowing equa ions: [Tl(cdo2a)]+ + H2O [Tl(cdo2a)OH] + H+ (4.2.3.1) [Tl(cdo2a)OH] + H2O [Tl(cdo2a)(OH)2]– + H+ (4.2.3.2) The s abili y cons an s o [Tl(cdo2a)OH] and [Tl(cdo2a)(OH)2]– we e de e mined ia pH- po en iome y and we e ound o be lgKOH[Tl(cdo2a)] = - 7.37(8) and lgKOH[Tl(cdo2a)OH] = -11.10(9). Wi h wo less dono si es han in do a, his complex may possess up o wo coo dina ed wa e molecules, howe e he signi ican di e ence be ween he wo alues indica es ha he complex mos likely has only one and he second coo dina ed OH– mos likely eplaces a ca boxyla e moie y. 67 4.2.4. In es iga ion o he iodido-mixed ligand complex [Tl(cdo2a)I] Fo ma ion o he mixed iodido complex can be desc ibed by he nex equilib ium: [Tl(cdo2a)]+ + I– [Tl(cdo2a)I] (4.2.4.1) To de e mine he s abili y o he [Tl(cdo2a)I] mixed-ligand complex, shown in eq. 4.2.4.1, po en iome ic and NMR i a ions we e ca ied ou , shown in Figu es 4.2.4.1 and 4.2.4.2. The e ec o OH––compe i ion was a oided by keeping he pH in a ange o 3–4. Po en iome ic i a ions we e pe o med on samples con aining 1 mM [Tl(cdo2a)]+ a pH = 4 in 1 M NaClO4. 205Tl-NMR o [Tl(cdo2a)]+ shows a signal a δ = 2500 ppm, wi h a hal -wid h o w½ = 5500 Hz, simila in chemical shi , bu a he b oad compa ed o [Tl(do a)]− (w½ = 2200 Hz). This may be a ibu ed o lowe o e all igidi y and compac ness. The signal o [Tl(cdo2a)I] appea s a δ = 1230 ppm (mo e han 1200 ppm down ield). Using he same p inciples and me hods as o [Tl(do a)]− he o ma ion cons an o lgKI[Tl(cdo2a)] = 4.1±0.1 was ob ained, making his e na y complex somewha less s able han [Tl(ed a)I]2–. This is o be expec ed o mac ocyclic complexes, as he coo dina ed me al ion is much less accessible han wi h open-chain ligands. E en so, [Tl(cdo2a)I] is ela i ely s able as mixed ligand complexes go. 68 -250 -200 -150 -100 -50 0 2345 -lg cI( o ) E, mV Figu e 4.2.4.1 Po en iome ic i a ion cu e o [Tl(cdo2a)]+ (hollow squa es) and calib a ion poin s (black iangles) using iodide-selec i e elec ode. 1 mM [Tl(cdo2a)]+ a pH = 4 in 1 M NaClO4 69 Figu e 4.2.4.2 205Tl NMR i a ion o 9 mM [Tl(cdo2a)]+ wi h 1.107 M NaI a pH = 4. I = 1 M NaClO4 4.2.5. Compa ison wi h a igidi ied open-chain complex [Tl(cd abba)]+ Al hough he in es iga ion o Tl(III)-complexes o open-chain ligands was no he p ima y goal o his wo k, i is wo h compa ing 76 The o ma ion o [Al(no a)(F)]– was almos 100 % in 50 % e hanol a e 15 min o hea ing acco ding o he 19F-NMR spec um (Fig. 4.3.2). The chemical shi was -48 ppm, sligh ly di e en om he –47 ppm measu ed in wa e likely due o a sol en e ec . The ole o e hanol could be ela ed o he dec eased basici y o he ing ni ogen dono a oms in no a,117 esul ing in as e complex o ma ion due o weake compe i ion be ween he H+ ion and Al(III) o he dono a oms o he mac ocycle. Figu e 4.3.2 376.5 MHz 19F-NMR spec a o samples con aining Al(III), no a and F– in equimola amoun s (4 mM each) a e hea ing in pH = 4 ace a e bu e o a ying imes a 100 °C A de ailed s udy o o ma ion kine ics o me al-mac ocyclic complexes in mixed sol en s is in p og ess in ou labo a o y. P elimina y esul s show ha complex o ma ion kine ics a e ai ly complica ed in he Al(III)–no a–H+–F– ou -componen sys em, u he expe imen s should be pe o med o desc ibe and unde s and he o ma ion kine ics o he mixed ligand complex. 77 4.4. Cha ac e iza ion o [Tl2{B-β-SiW8O30(OH)}2]12–, a newly syn hesised hallium-con aining polyoxome alla e Al hough hallium(I) sal s o con en ional di-, pa a- and me a ungs a es ha e been p epa ed by usual me hods (Tl2O·WO3, Tl2O·2WO3, 5Tl2O·12WO3, Tl2W4O13 and Tl0.3WO3), 118 , 119 hese compounds a e ungs en oxides wi h an ex ended s uc u e and o da e no s uc u ally cha ac e ized disc e e Tl-con aining polyanions ha e been epo ed. In his wo k we also p esen da a on he syn hesis and solu ion cha ac e iza ion o he no el, hallium(III)-con aining 16- ungs o-2- silica e [Tl2{B-β-SiW8O30(OH)}2]12-, which ep esen s he i s s uc u ally cha ac e ized disc e e hallium-con aining me al-oxide. In he polyanion, wo oc ahed ally coo dina ed Tl3+ ions a e sandwiched be ween wo lacuna y {B-β-SiW8} Keggin- ype agmen s (Fig. 4.4.1.1). 4.4.1. X- ay c ys al s uc u e Single c ys al X- ay analysis e ealed ha he compound c ys allizes in a monoclinic c ys al sys em wi h space g oup P21/m. The [Tl2{B-β-SiW8O30(OH)}2]12– a chi ec u e p esen s a polyanion wi h idealized C2h symme y, which consis s o wo hallium(III) cen e s and wo {B-β-SiW8O31} POM uni s. The {B-β-SiW8O31} uni s we e o med om he [γ-SiW10O36]8– p ecu so by o a ional isome iza ion and loss o ungs en. The i s POM comp ising a {B-β-SiW8O31} uni was epo ed in 2005. 120 The {M2(B-β-SiW8O31)2} s uc u e ype has been seen be o e.121 The wo equi alen hallium(III) cen e s in he polyanion a e bo h six-coo dina ed, and each hallium ion is coo dina ed o wo {B-β- 78 SiW8O31} lacuna y POM agmen s ia ou e minal O a oms o he wo comple e ungs en-oxo iads and wo e minal O a oms o wo {SiO4} he e o g oups. The Tl-O bond leng h anges om 2.156(1) o 2.238(1) Å, and he dis ance be ween bo h hallium a oms is 3.338(1) Å. Bond alence sum (BVS) calcula ions122 con i m ha he oxida ion s a e o he wo hallium cen e s is +3. As based on elemen al analysis, he polyanion is dip o ona ed and BVS as well as DFT ( ide in a) sugges ha hey a e loca ed on he wo μ3-O a oms. Figu e 4.4.1.1 Polyhed al ep esen a ion o [Tl2{B-β- SiW8O30(OH)}2]12– (1). Colo legend: WO6 (da k ed) oc ahed a, SiO4 (da k g ey) e ahed a, Tl (ligh blue), O (ligh ed). The mos basic ypes o oxygens a e labeled as OA, OB and OC. The ungs en a oms WA and WB ha e di e en 203/205Tl–183W spin-spin coupling cons an s P elimina y DFT calcula ions we e pe o med in o de o e alua e he mos p obable p o ona ion si es and p o on dis ibu ion in aqueous solu ion. The s uc u e was op imized ini ially o he non-p o ona ed anion [Tl2{B-β-SiW8O31)}2]14– and he mos cha ac e is ic X- ay bond 79 dis ances we e a he well ep oduced: Tl-O(Si) 2.28 Å, W-O(Si) 2.25 - 2.43 Å, W-O(Tl) ca 1.81 Å, and Tl···Tl 3.37 Å. 4.4.2. Solu ion s uc u e s udy [Tl2{B-β-SiW8O30(OH)}2]12– is su icien ly soluble in wa e o eco d 205Tl and 203Tl NMR spec a o easonable quali y (Figu e 4.4.2.1). Bo h iso opes ha e a spin o 1/2, and a na u al abundance o 70.5 % and 29.5%, espec i ely. A i s sigh , bo h spec a appea as pseudo- iple s, a ibu ed o he spin-spin coupling be ween wo s e ically iden ical Tl- a oms. The cen al peaks a e assigned o polyanions wi h homonuclea 205Tl-205Tl o 203Tl-203Tl coupling, whe eas he sa elli e peaks belong o he e onuclea 205Tl-203Tl coupled polyanions, espec i ely. The peak in ensi ies o he pseudo- iple s ag ee e y well wi h he expec ed ones om he iso ope a ios, 29.5/2 : 70.5 : 29.5/2 (205Tl NMR), and 70.5/2 : 29.5 : 70.5/2 (203Tl NMR), see SI o de ails. This inding is in ull ag eemen wi h he solid-s a e s uc u e ha ing wo Tl-a oms in iden ical posi ions, and i p o es unequi ocally ha he dime ic s uc u e is p ese ed in solu ion. The chemical shi di e ence be ween he sa elli e peaks ep esen s he coupling cons an , 2J(205Tl-203Tl) = 2670 Hz. In e es ingly, a close look a he spec a indica es u he ine s uc u e o he eco ded peaks caused by spin-spin coupling wi h 183W a oms (14.3%). The wo di e en alues o 2J(203Tl-183W) a e ca. 470 and 350 Hz, espec i ely, and he co esponding alues o 2J(205Tl-183W) a e ca 1% la ge (see Figu e 4.4.2.1 cap ion o de ails). These alues can be a ionalized by coupling o wo s uc u ally inequi alen ypes o ungs en being wo bonds away om he hallium cen e s. These couplings may 80 ac ually be a e aged e ec s o wo ypes o 183W cen e s (WA, WB) wi h simila chemical en i onmen s. The Tl···W dis ances a e 3.64 and 3.65 Å o WA, and 3.72 and 3.73 Å o WB, espec i ely. Figu e 4.4.2.1 Expe imen al (black) and heo e ically simula ed ( ed) 144.26 MHz 205Tl ( op) and 142.86 MHz 203Tl NMR (bo om) spec a o [Tl2{B-β-SiW8O30(OH)}2]12–, ~6 mM in 0.04 M ace ic acid/sodium ace a e bu e , pH = 4.1. Coupling cons an s shown: a) 2J(205Tl-183WA) ca. 475 Hz, b) 2J(205Tl-183WB) ca. 354 Hz, c) 2J(203Tl-183WA) ca. 470 Hz, d) 2J(203Tl-183WB) ca. 350 Hz and e) 2J(205Tl-203Tl) = 2J(203Tl-205Tl) ca. 2700 Hz (same alue in bo h spec a) 81 Howe e , he ela i ely b oad spec al lines p ohibi such a de ailed in es iga ion. The 1H couplings do no play a ole because o as exchange, and he e ec s o 29Si (I = 1/2, 4.7%) and 17O (I = 5/2, 0.037 %) a e also no de ec able. 4.4.2.1. Simula ion o Tl NMR spec a We ha e also simula ed he Tl NMR spec a conside ing he symme y, he ela i e posi ions o he Tl and W a oms, he na u al abundance o he NMR-ac i e nuclei and he spin-spin coupling cons an s measu ed expe imen ally. The expe imen ally ob ained NMR spec a a e supe posi ions o se e al spec a wi h di e en combina ions o NMR- ac i e nuclei. The NMR model used o simula ion is based on he solid- s a e s uc u e o he polyanion. Th ee (I = 1/2) iso opes, 203Tl, 205Tl and 183W (na u al abundances 0.295, 0.705, and 0.143, espec i ely), and geminal spin-spin couplings a e aken in o conside a ion. The wo Tl a oms in he polyanion a e s e ically iden ical wi h C2h symme y. One Tl may be coupled wi h he o he Tl and a mos ou W nuclei (o wo di e en ypes: wo WA and wo WB). The h ee iden i ied independen coupling cons an alues a e 2J(203Tl, 205Tl) = 2670 Hz, 2J(203Tl, 183WA) = 470 Hz, and 2J(203Tl, 183WB) = 350 Hz. The ou o he coupling cons an s (2J(205Tl-183WA), 2J(205Tl-183WB), 2J(203Tl-203Tl) and 2J(205Tl-205Tl)) used di e only by 1%, because he magne ogy ic a io, which hey a e p opo iona e o, is 1% highe o 205Tl han o 203Tl. I he na u al abundance o he obse ed iso ope equals p (p = 0.295 o p = 0.705), hen he a io o polyanions con aining 2, 1 and 0 obse ed Tl-iso opes is de ined by he binomial dis ibu ion and hei NMR signal in ensi y a io can be calcula ed by mul iplying wi h said numbe s: 2·p2 : 1·2·p·(1-p) : 82 0·(1-p)2 = p : (1-p) : 0. The polyanions wi h wo obse ed Tl iso opes o wo di e en Tl iso opes p oduce di e en NMR signals, which a e sepa a ed because o 2J(Tl-Tl) >> 2J(Tl-183W). In he mul iple s assigned o he e onuclea Tl-Tl coupling (sa elli e signals) all couplings a e i s -o de and he Tl-Tl coupling p oduces a symme ic double . The 183W-couplings a e mo e complica ed, owing o he wo di e en coupling cons an s. Fo each sa elli e, coupling o 1, 2, 3, o 4 183W nuclei esul s in 4, 9, 12, o 9 peaks, espec i ely. I p = 0.143, hen he in ensi y o he sa elli e is sha ed among polyanions con aining 0, 1, 2, 3, and 4 183W couplings wi h p obabili ies o (1-p)4, 4·p·(1-p)3, 6·p2·(1-p)2, 4·p3·(1-p), p4 (0.54, 0.36, 0.09, 0.01 and 0.0004) espec i ely, acco ding o he binomial dis ibu ion (see Table 4.4.2.1.1). The cen al peak will ise o 58.5 % in ensi y, caused by spli ing, he ollowing ou obse able signals will be 9.2% each and he in ensi y le o all o he signals is <5%. The coupling cons an s can be ob ained om he sa elli e peaks. In mul iple s assigned o homonuclea Tl-Tl coupling (cen al signals) wi hou 183W coupling, he wo Tl nuclei a e magne ically equi alen (A2 spin sys em) p o iding a single signal wi h a chemical shi δ = 2206 ppm. The 183W coupling causes magne ic non-equi alence o he wo Tl cen e s, so he simple i s -o de coupling canno be used any u he . Fo mulae used in he case o ABX (mo e p ecisely AA’X in ou case) spin sys ems a e known.123 Tungs en is only coupled o one o he wo halliums (A-A’-X), esul ing in J(A’,X) = 0 o he o he one and esul ing in 4 double s. The dis ance be ween wo double s is g ea e han 5400 Hz and hei in ensi y is a mos 0.4% o all o he s, making hem unobse able (los in he noise). The dis ance o he o he wo double s is 83 hal he coupling cons an (ca. 240 o 180 Hz) and hey a e spli by only ca. 11 Hz o 6 Hz, meaning ha hey a e no su icien ly sepa a ed o be obse able. Table 4.4.2.1.1 B eakdown o he spin sys ems and hei con ibu ion o he in ensi y pa e n obse ed in he Tl NMR spec a o [Tl2{B-β- SiW8O30(OH)}2]12– Cen al peaks (Homonuclea Tl-Tl coupling) No. o coupled 183W nuclei Sa elli e peaks (He e onuclea Tl-Tl coupling) No. o spin sys ems In ensi y con ibu ion No. o spin sys ems In ensi y con ibu ion 1 29.15% 0 1 54.0% 2 38.85% 1 2 36.0% 6 22.65% 2 3 9.0% 8 7.55% 3 2 1.0% 11 1.57% 4 1 0.04% 8 0.21% 5 6 0.017% 6 6 0.00083% 7 1 0.000017% 8 Fou simila double s appea when conside ing bo h coupling cons an s. The coupling o wo 183W cen e s equi es nume ical solu ion o six di e en spin sys ems (34 obse able peaks). Fo una ely, simula ion wi h i s -o de couplings and cons an s o 2J(Tl-183WA)/2 and 2J(Tl-183WB)/2 p oduces an almos iden ical spec um a he used line-wid h o 60 Hz; i.e. his simpli ica ion could be used o polyanions wi h 3, 4, 5, 6, 7, 8 183W 84 iso opes, ha ing almos negligible con ibu ions. The in ensi y o he cen al mul iple is sha ed be ween polyanions con aining 0, 1, 2, 3, …, 8 183W couplings wi h p obabili ies o (1-p)8, 8·p·(1-p)7, …, p8 (0.292, 0.389, 0.227, 0.076, 0.016, …, 1.7×10-7), espec i ely, acco ding o he binomial dis ibu ion (see Table 4.4.2.1.1). Summing up he in ensi ies o close signals aises ha o he cen al signal o 41.1 %, he nex 4 signals will be 11.2 % each (howe e , hei sepa a ion is only 30 Hz pe pai ), and inally “shoulde s” wi h 6.1 % in ensi y each appea on bo h sides. In o de o isualize he complexi y o he nume ous spin sys ems, we ha e simula ed bo h he 205Tl and 203Tl NMR spec a using Lo en zians wi h 5 Hz linewid h and plo ed hem oge he wi h he expe imen al spec a (Figu e 4.4.2.1.1). The simila i y in shape and posi ions o peak maxima is ob ious. 85 Figu e 4.4.2.1.1 Expe imen al (black) and heo e ical (simula ed wi h 5 Hz line-wid h, ed) 144.28 MHz 205Tl and 142.88 MHz 203Tl spec a o [Tl2{B-β-SiW8O30(OH)}2]12-. Calcula ions we e pe o med wi h a home- made MATLAB p og am and a ew spin sys ems we e simula ed wi h WINDNMR The chemical shi alue o ca. 2206 ppm ( he posi ion o he cen alpeaks, e e enced o in ini ely dilu ed TlClO4 as 0 ppm) is consis en wi h a +3 oxida ion s a e o he hallium a oms being six- coo dina ed o O a oms in an oc ahed al geome y in wa e . 124 ,27 92 The MIC alues p esen ed a e p omising, as he polyanion e ec s all es ed o ganisms a simila –and in mos cases, lowe – Tl-concen a ions han ino ganic hallium sal s. Conside ing he solu ion da a ob ained he inhibi o y e ec is unlikely o s em om he elease o hallium om he POM, as he concen a ions used in he biological s udy a e se e al o de s highe (µM) han hose a which he POM would no iceably dissocia e (nM). 93 4.5. Cha ac e iza ion o ano he no el Tl(III)-con aining POM, [Tl2{P2W15O57}2]22– Figu e 4.5.1 Polyhed al ep esen a ion o [Tl2{P2W15O57}2]22– (1). Colo legend: WO6 ( ed) oc ahed a, PO4 (blue) e ahed a, Tl (g een), O (ligh ed), Na (b own) A simila compound o he one desc ibed abo e, [Tl2{P2W15O57}2]22– was also syn hesized in B emen and is e y simila o [Tl2{B-β-SiW8O30(OH)}2]12 wi h a ew key di e ences. This polyanion has a di e en symme y, being based on a lacuna y Wells- Dawson s uc u e and con ains phospha e as a he e og oup ins ead o 94 silica e. Two halliums a e sandwiched be ween wo POM agmen s, simila ly o [Tl2{B-β-SiW8O30(OH)}2]12. As 31P is also a I = ½ nucleus bu wi h 100% na u al abundance, u he peak spli ing is o be expec ed and 31P NMR becomes an addi ional ool o in es iga e i wi h. The 31P NMR spec um in Fig. 4.5.2 was p o ided by ou pa ne s in B emen. Figu e 4.5.2 162.14 MHz 31P NMR spec um o 3.7 mM [Tl2{P2W15O57}2]22– in 0.5 M phospha e bu e pH = 5.8. Bo h 205 and 203Tl NMR spec a we e eco ded om a sample made om 49 mg o he compound in 2.5 ml o wa e . The 31P NMR shows a iple 95 and a single peak, which can be assigned o he wo phospho ous a oms ha a e coupled o bo h Tl-nuclei and he wo ha a e isola ed, espec i ely. The Tl NMR spec a howe e , show one majo and one mino signal which do no syne gize wi h he pa e n seen in he 31P NMR. Making he assump ion ha he majo signal may be mos likely a ibu ed o he i le ion, we ha e ocused on in e p e ing i i s . The ollowing coupling cons an s we e ob ained o es ima ed: 2J(P-Tl) ≈ 225 Hz ( om he 31P spec um, 2J(205Tl-203Tl) ≈ 777 Hz, 2J(Tl-183W) > 500 Hz. The spec a clea ly exhibi di e en peak s uc u es, indica ing ha he examined molecule does indeed con ain wo hallium nuclei wi hin coupling dis ance, as in [Tl2{B-β-SiW8O30(OH)}2]12–. In his case howe e , he sa elli e and cen al signals a e much less sepa a ed and he e a e also wo coupling 31P nuclei in oducing addi ional spli ing and o e lap. E en so, he same p inciples can be applied in his case as well. The majo signals in bo h 203 and 205Tl NMR spec a we e decon olu ed by ea ing each o hem as a sum o cons i uen spec a belonging o molecules wi h only homo- o he e onuclea Tl-Tl coupling (somewha akin o he e alua ion o UV- is spec a). The expe imen ally ob ained spec a can be econs uc ed pe -poin by adding hese cons i uen spec a oge he in di e en p opo ions (de e mined by na u al iso ope abundances), as seen in Fig. 4.5.4. The polyanion clea ly e ains i s s uc u e in solu ion, howe e we cu en ly ha e no da a on wha he mino signal migh be a ibu ed o. 96 Figu e 4.5.3 144.28 MHz 205Tl NMR (abo e) and 142.86 MHz 203Tl NMR (below) spec a o [Tl2{P2W15O57}2]22– (below) 97 Figu e 4.5.4 Decon olu ion o he [Tl2{P2W15O57}2]22– Tl NMR spec a: 205Tl (abo e, black) and 203Tl ( ed, below). Cons i uen spec um 98 in ensi ies a e also shown in each (homonuclea : blue and he e onuclea : g een) 99 5. Summa y This hesis deals wi h Tl(III)-complexes o wo, undamen ally di e en mul iden a e ligand ypes,: o ganic polyaminopolyca boxyla es and ino ganic he e opoly ungs a es, which e en so sha e some simila i ies. We ha e s udied solu ion equilib ium and kine ic p ope ies, as well as s uc u al ai s bo h in solid and solu ion phase, o a ious Tl(III)- complexes. S uc u al p ope ies o [Tl(do a)] ha e been explo ed bo h in solid phase and solu ion. In solid s a e, he Tl3+ ion is di ec ly coo dina ed o he eigh dono a oms o he ligand, wi h he me al coo dina ion en i onmen being bes desc ibed as wis ed squa e an ip isma ic (TSAP); he coo dina ion o he ligand o he me al ion in oduces wo sou ces o s e eoisome ism, one associa ed o he con o ma ion o he cyclen moie y [() o ()], and ano he ela ed o he layou o he ou ace a e pendan a ms [ ep esen ed as  o ]. Inspec ion o he s uc u e shows ha c ys als con ain he ()/() enan iome ic pai , he wo enan iome s being cen o-symme ically ela ed in acco dance wi h he cen o-symme ic cha ac e o he space g oup P-1. The “so ” na u e o Tl3+ (and Bi3+) acco ding o he Pea son classi ica ion p o okes a s eng hening o he coo dina ion bonds wi h he so e N dono a oms, which esul s in a deepe pene a ion o he me al ion in o he mac ocyclic ca i y and he p eclusion coo dina ion o u he wa e molecules o small ions o he me al cen e . 100 The acid–base p ope ies and a ini ies owa ds mixed–complex o ma ion we e in es iga ed o [Tl(do a)]− and [Tl(cdo2a)]+. The coo dina i e sa u a ion a ound he me al cen e and o e all compac ness in [Tl(do a)]− makes u he coo dina ion o small anions –e en hose wi h high a ini y owa ds Tl(III)– un a ou able. [Tl(cdo2a)]+ was ound o o m a ela i ely s able mixed–complex wi h iodide ions. The complexes a e highly esis an owa ds dissocia ion ia p o on– o OH–– assis ed pa hways. [Tl(do a)]− does no dep o ona e in he pH– ange 4– 11, as he e is no oom o a Tl–coo dina ed wa e molecule in he complex, howe e a p o ona ion cons an o pKH[Tl(do a)] = 1.4±0.1 was be ob ained om 205Tl-NMR. This p ocess mos likely in ol es he p o ona ion o one o he ca boxyla e a ms. I is likely ha [Tl(do a)]− may be s o ed on any measu able pH inde ini ely. Con e sely, [Tl(cdo2a)]+ does ha e coo dina ed wa e and can be dep o ona ed wice (lgKOHTl(cdo2a) = –7.37±0.01, lgKOHTl(cdo2aOH) = –11.10±0.01). P o ona ion a low pH has no been measu ed, al hough he complex s ays in ac in he pH– ange 0–12 o mon hs. [Tl(do a)]− does no o m mixed–complexes gene ally, due o he me al being i ually comple ely w apped by he ligand dono g oups. Only he o ma ion o a ain mixed [Tl(do a)(CN)]2– complex could be de ec ed using 205Tl-NMR, wi h Kmix = 6.0 ± 0.8. This is se e al o de s o magni ude lowe han o he cyanido–mixed Tl(III)–complexes (in case o [Tl(ed a)]– lgKmix = 8.7) and e en he p o ona ion o cyanide is enough o i o ins an ly dissocia e. [Tl(cdo2a)]+ eadily o ms halido–mixed ligand complexes, such as [Tl(cdo2a)I] as e idenced by po en iome ic i a ions and Tl NMR. A o ma ion cons an o lgKI[Tl(cdo2a)] = 4.1±0.1 is ob ained om bo h po en iome y wi h an iodide-selec i e elec ode and 101 205Tl NMR i a ions in he pH– ange 3–4 (a oiding he in e e ence o OH–). Dissocia ion kine ics o [Tl(cdo2a)]+ and [Tl(do a)]− we e in es iga ed wi h UV-spec opho ome y. Bo h complexes we e ound o be highly s able and ine agains dissocia ion, equi ing la ge excesses o compe ing agen s –bo h o he me al and he ligand– o he disloca ion o Tl(III) o occu in easonable ime spans. Se e al a emp s we e made o de e mine he s abili y o bo h [Tl(cdo2a)]+ and [Tl(do a)]− using he double compe i ion me hod p e iously desc ibed o [Tl(ed a)]–, using la ge (in some cases, se e al housand– old) excesses o bo h B – and H+ in ba ch samples, ollowed ia UV–spec opho ome y. T ue equilib ia ion could no howe e be eached in case o ei he complex, as some unknown side– eac ion akes place which in e e es wi h he e alua ion o UV–spec a om hen on. Insigh in o he dissocia ion o [Tl(do a)]− was howe e ob ained, showing quad a ic dependence o kobs on acidi y, wi h no de ec able spon aneous dissocia ion. This kind o a e law is in acco dance wi h he ela ed li e a u e o do a-complexes, i.e. he dissocia ion is a dominan ly p o on-assis ed p ocess. Using he kobs = k1[H+] + k2[H+]2 a e law, he hal –li e o he complex a di e en pH alues can be calcula ed. Hal -li e o [Tl(do a)] is 32 h in 1 M HClO4 and app oxima ed o 5▪109 h (mo e han hal millon yea s) a pH = 7.4. The la e alue indica es ha he dissocia ion o [Tl(do a)]− a he physiological pH o blood is negligible. [Tl(cdo2a)]+ beha es simila ly, wi h as e dissocia ion and lowe acid concen a ions needed o ini ia e he p ocess. 108 ha ásá a já szódo le, akko is igen lassan. Nagyszámú kísé le e égez ünk a [Tl(cdo2a)]+ és [Tl(do a)]− s abili ási állandóinak megha á ozásá a, a [Tl(ed a)]––hoz ko ábban sike esen használ ke ős kompe íciós módsze el, nagy (ese enkén öbbeze sze es) eleslegben használ B – és H+ ionokkal. Különmin ás módsze használ a, a ál ozásoka UV–spek o o ome iá al kö e ük. Valódi egyensúly nem é ünk el, mi el hosszabb idő el el é el alamilyen isme e len mellék eakció is elindul és kié ékelhe e lenné eszi a o ábbi ada oka . Sike ül azonban belá ás nye ni a [Tl(do a)]− disszociációs olyama ába, a kezde i sebességek módsze é el. Az illesz e gö be az mu a ja, hogy kobs négyze esen ügg a sa koncen áció ól, spon án disszociáció pedig nem észlelhe ő. Ez a aj a sebességi egyenle egyezik a do a-komplexek ide ona kozó i odalmában leí akkal, a bomlás őkén p o on-asszisz ál olyama , A kobs = k1[H+] + k2[H+]2 egyenle e elhasznál a kiszámí ha ó a komplex elezési ideje különböző pH-kon. A [Tl(do a)] ese ében ez 32 ó a 1 M HClO4–ban és megközelí őleg 5▪109 ó a ( öbb min élmillió é ) pH = 7.4–en. Ez u óbbi é ék az mu a ja, hogy a é iziológiás pH-ján a komplex disszociációja elhangyagolha ó. A [Tl(cdo2a)]+ hasonlóan iselkedik, de gyo sabban disszociál (4 ó a 1 M HClO4–ban és 786 ó a pH = 7.4–en) és a olyama alacsonyabb sa koncen ációknál is megkezdődik. A [Tl(do a)]− olda beli izome -in e kon e ziójának dinamikájá is izsgál uk. A komplex olda ban ké TSAP enan iome (() és ()) egyensúlyi ke e ékekén an jelen. A különböző hőmé sékle eken el e 13C-NMR spek umokban meg igyel jelalak- ál ozás az olda ban jelenle ő, egyenlő populációjú ké izome köz i 109 egysze ű cse e olyama hoz endel ük. A olyama magában oglalja a mak ociklus in e ziójá [()  ()] és a négy ace á ka o ációjá [  ]. Sze encsénk e, a eljes lassú–gyo s cse e á mene égigkö e he ő ol szok ányos hőmé sékle eken és k an i a í jelalak- analízissel minden hőmé sékle e kiszámolha ó a ké lépéses olyama cse esebessége kexch, majd ezekből a olyama ak i álási pa amé e ei. Az így kapo é ékek jó egyezés mu a nak a DFT számolásokból szá mazóakkal. A [Tl(do a)]–hoz sze keze ében és obusz usságában némileg hasonló [Al(no a)] komplex észle es izsgála á el égez ük. (Ilyen Al- komplexeke használnak anionho dozókén 18F PET izsgála okhoz, amelyekben a „kemény” Al(III) kö i meg a „kemény” luo ido . Ez szolgál számunk a alapul „lágy-lágy” kölcsönha áson alapuló Tl(III)- jodid egyeskomplexek e ezésé e.) Az i odalomban leí akkal ellen é ben, egyesligandumú [Al(no a)(F)]– képződése nem igyelhe ő meg sem po enciome iá al, sem 19F NMR–el [Al(no a)] és F– köz e len eakciójában. A e ne komplex Al(III)- , F–- és no a- egyenlő koncen ációban a almazó olda okból, melegí és ha ásá a képződik észlelhe ő mennyiségben, de egyensúlyi ada ok nem szüle ek. Ugyanakko a egyeskomplex szin e k an i a í e képződik 15 pe c melegí és u án, ha oldósze kén 50% e anol álasz unk. Ez alószínűleg egy öbblépéses kompe íciós eakció a különböző Al(III)- luo ido komplexek és a no a köz , melyben a [Al(no a)(F)]– egy in e medie , mi el hosszabb melegí és minden ese ben csökken i a egyeskomplex a ányá és [Al(no a)] képződik. 110 Meg izsgál uk ké allium- a almú POM olda beli sze keze é , a szilá d (NH4)5K7[Tl2{B-β-SiW8O30(OH)}2]·19H2O–ban a [Tl2{B-β- SiW8O30(OH)}2]12- sze keze idealizál C2h szimme iájú polianion, mely ké allium(III) magból és ké {B-β-SiW8O31} POM egységből épí he ő el. A {B-β-SiW8O31} egységek a [γ-SiW10O36]8– p eku zo ból képződnek o ációs izome izáció és wol am esz és so án. A ké allium(III) ha szo osan koo dinál és mindké allium ion ké {B-β-SiW8O31} hiányos POM agmens kö össze, a ké egész wol am-oxo iád 4 e minális oxigénjé el és ké {SiO4} he e ocsopo ké e minális oxigénjé el kapcsolódik. Ez a sze keze ál oza lanul megma ad olda ázisban is és ké skalá isan csa oló allium mago a almaz, ami 205Tl és 203Tl NMR spek umok egyé elműen bizonyí anak. Első ánézés e mindké spek um pszeudo– iple nek űnik, ami a ké sz é ikusan azonos, spin-spin csa olásban lé ő Tl-a omhoz endelhe ünk. A jelek o ábbi inom sze keze e is meg igyelhe ő a 183W a omokkal (14.3%) ö énő csa olások mia . A 2J(203Tl-183W) ké különböző é éke kb. 470 és 350 Hz és az ide a ozó 2J(205Tl-183W) é ékek ~1%–kal nagyobbak. Ezeke az é ékeke ké éle, nem-ek i alens wol am a omokkal aló csa olással lehe magya ázni. A [Tl2{B-β-SiW8O30(OH)}2]12- szimme iájá , a Tl és W magok ela í pozíciói , az NMR-ak í magok e mésze es elő o dulásai és a mé csa olási állandóka igyelembe é e szimulál spek umoka is készí e ünk. Valójában a kísé le ileg kapo spek umok nagy számú ész-spek um szupe pozíciói, melyekben különböző számban és helyen sze epelnek NMR-ak í magok. A szimulál modellünkben csak a Tl-O- Tl és Tl-O-183W csa olásoka e ük igyelembe, így 54 különböző 111 lehe séges spin endsze kap unk. A középpon i és sza eli csúcsok köz i jól lá ha ó alakkülönbség annak udha ó be, hogy a 183W magok homonukleá isan csa ol (A2 spin endsze ) Tl-a omokkal csa olnak, megza a a a ké sz é ikusan azonos 205Tl agy 203Tl mag mágneses ek i alenciájá , ezzel AA’X spin endsze e edményez e. Ilyen ese ben a Tl-W elhasadás pon osan eleakko a, min a sza eli jelekben. Ez a jelenség meg igyelhe ő a [Tl2{P2W15O57}2]22––ban is, iszon ebben az ese ben kisebb a á olság a középpon i és sza eli jelek köz és a ké , csa olási á olságban le ő 31P mag (100% e mésze es elő o dulással) o ábbi elhasadás e edményez minden allium jelben. Ez a együle is jól lá ha óan megő zi sze keze é olda ázisban is, és a kísé le ileg kapo 203Tl és 205Tl NMR jelek jól elépí he őek meg elelő a ányú isz án cen ális és sza elli jelek in enzi ásainak öszegekén . A Tl-NMR spek umokban alálha ó egy o ábbi, kisebb jelcsopo , ami szin én lá ha óan ké Tl(III) mago a almaz, de a jelalakja és a kémiai el olódása is más. A [Tl2{B-β-SiW8O30(OH)}2]12- NMR– i álása, melyben kompe íciós ionkén ace á o használ unk, a együle s abili ásá a enged kö e kez e ni. Nagy ace á elesleg melle , öbb nap ala sem ö én kimu a ha ó eakció. A együle e ké allium és ké {B-β-SiW8O31} egység M2L2 komplexekén kezel e, isme e a Tl(Ac)4– komplex s abili ásá , becsülhe ő egy lgK > 40–es minimum s abili ási állandó. (É demes azonban megjegyezni, hogy a poliwol amá ok eakciói gyak an ex ém lassúak, eha nem zá ha ó ki „me as abilis”, nem egyensúlyi iszonyok kialakulása sem). A lá szólagos s abili ási állandó alapján ex apolálha ó, hogy hígulás mia i disszociáció a együle ben 112 csak szub-nanomolá is koncen ációknál álik jelen őssé. Ezek melle megemlí endő, hogy a [Tl2{B-β-SiW8O30(OH)}2]12- e ősen sa as közegben állás közben poliwol amá ok ke e éké é bomlik, melyek 205Tl NMR izsgála aink sze in má csak egy-egy Tl(III)- a almaznak. Ehhez hónapoka kell á ni és a min ákban disszociál alliumo – aká Tl(III) ak a ionkén , aká Tl2O3 oxidkén , agy ace á o-komplexkén – o ább a sem lehe kimu a ni. 113 7. Re e ences 1 A. G. Lee, ‘The Chemis y o Thallium’, Else ie , Ams e dam, NY, 1971. 2 A. J. Downs ed., ‘Chemis y o Aluminium, Gallium, Indium and Thallium’, Chapman & Hall, London, 1993. 3 J. Glase ’Ad ances Thallium Aqueous Solu ion Chemis y’ Ad ances in Ino ganic Chemis y, 1995, Vol. 43, pp. 1–78. 4 K. 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Poble , and Ul ich Ko z: In oducing Thallium in Disc e e Me al-Oxide Chemis y: The Tl3+-Con aining [Tl2{B-β-SiW8O30(OH)}2]12-, Ino ganic Chemis y (beküld e/submi ed) IF: 4.820 (2015) 2. Tamás Fodo , Is án Bányai, A ila Bényei, Ca los Pla as-Iglesias, Mihály Pu gel, Gábo Ho á h, László Zékány, Gyula Ti csó and Im e Tó h: [TlIII(do a)]: An ex ao dina y obus mac ocyclic complex Ino g. Chem., 2015, 54 (11), pp 5426–5437. IF: 4.762 (2014) 1. Edi Fa kas, Tamás Fodo , Fe enc K. Kálmán*, Gyula Ti csó and Im e Tó h: Equilib ium and Dissocia ion Kine ics o [Al(1,4,7- iazacyclononane-1,4,7- iace a e)] ([Al(no a)]) Complex, Reac ion Kine ics, Mechanisms and Ca alysis, 2015, 116(1), 19-33. IF: 0.983 (2013) 8.2. P esen a ions ela ed o he disse a ion 5. Fodo Tamás, Ayass W. W., Zékány László, Bodo And ea, Ko z U., Tó h Im e: Dime agy monome ? 203/205Tl NMR homo- és he e onukleá is spin-spin csa olások he e opolime allá ok olda aiban 50. Komplexkémiai Kollok ium, Bala on ilágos, 2016. május 30-június 1, 4. T. Fodo , W. W. Ayass, L. Zékány, A. Bodo , U. Ko z and I. Tó h: Homonuclea and he e onuclea Tl-Tl NMR spin-spin coupling as s uc u al ool in solu ion Magya NMR Munkabizo ság 2016. é i ülése, MTA DAB Székház, Deb ecen, 2016. május 20-21. 3. Fodo Tamás, Rozinka Felícia, Ca los Pla as-Iglesias, Zékány László, Bényei A ila, Pu gel Mihály, Kálmán Fe enc K isz ián, Ti csó Gyula, Tó h Im e: Vegyesligandumú Tl(III)-komplexek egyensúlyi és kine ikai izsgála a, 20. Nemze közi Vegyészkon e encia, 2014, No embe 6-9, Kolozs á , Románia. 2. Fodo Tamás, Ga da Zol án, Rozinka Felícia, Kálmán Fe enc K isz ián, Ko ács Zol án, Ti csó Gyula és Tó h Im e: Vegyesligandumú allium(III)-komplexek egyensúlyi és kine ikai izsgála a, XLVIII Komplexkémiai Kollok ium, 2014, Május 28- 30, Sió ok, Magya o szág. 1. Tamás Fodo , Ca los Pla as-Iglesias, Mihály Pu gel, László Zékány, A ila Bényei, Im e Tó h: TlDOTA: an ex ao dina ily s able complex XLVI. Komplexkémiai Kollok ium, 2012, Május 21-23, Má a ü ed, Magya o szág 8.3. Pos e s ela ed o he disse a ion 5. Tamás Fodo , Zol án Ga da, Felícia Rozinka, Gyula Ti csó, Im e Tó h Te na y complexes as anion binde s: a new app oach o adiolabeling Medicinal la o o me al complexes: diagnos ic and he apeu ic applica ions, 2015. decembe 7-9., O leans; F anciao szág 4. Edi Fa kas, Tamás Fodo , Fe enc K. Kálmán, Gyula Ti csó, Im e Tó h Equilib ium and Dissocia ion Kine ics o [Al(no a)] Complex Medicinal la o o me al complexes: diagnos ic and he apeu ic applica ions, 2015. decembe 7-9., O leans; F anciao szág 3. Edi Fa kas, Tamás Fodo , Fe enc K. Kálmán, Gyula Ti csó and Im e Tó h Equilib ium and Dissocia ion Kine ics o [Al(no a)] Complex COST Ac ion TD1004, 2015. szep embe 10-11., Belg ád, Sze bia 2. Fodo Tamás, Fa kas Edi Ca los Pla as Iglesias, Zékány László, Pu gel Mihály, Bényei A ila, Kálmán Fe enc K isz ián, Ti csó Gyula, Tó h Im e: Vegyesligandumú émkomplexek, min lehe séges izo ópho dozók, 19. Nemze közi Vegyészkon e encia, 2013, No embe 21-24, Nagybánya, Románia. 1. Tamás Fodo , Edi Fa kas, Gyula Ti csó, Ca los Pla as Iglesias, Mihály Pu gel, László Zékány, A ila Bényei, Im e Tó h: Mixed ligand me al-complexes modeling anion binding: he ha d aluminum(III) and he so hallium(III) 11 h In e na ional Symposium on he Syn hesis and Applica ions o Iso opes and Iso opically Labelled Compounds, Sep embe 9-13, 2012, Heidelbe g/F eibu g, Ge many 8.4. Pape no in ol ed in he disse a ion 1. Enikő Molná , Na halie Camus, Vé onique Pa inec, Gab iele A. Rolla, Mau o Bo a, Gyula Ti csó*, Fe enc K. Kálmán, Tamás Fodo , Raphaël T ipie * and Ca los Pla as- Iglesias*: Picolina e-Con aining Mac ocyclic Mn2+ Complexes as Po en ial MRI Con as Agen s Ino g. Chem. 2014, 53, 5136−5149 IF: 4.762 (2013) 8.5. P esen a ions no ela ed o he disse a ion 3. Molná Enikő, Na halie Camus, Vé onique Pa inec, Gab iele A. Rolla, Mau o Bo a, Kálmán Fe enc K isz ián, Fodo Tamás, Raphaël T ipie , Ca los Pla as-Iglesias, és Ti csó Gyula: Pikoliná csopo o a almazó mak ociklusos ligandumok Mn(II)- komplexei: egyensúly és kine ika, XXXXVIII Komplexkémiai Kollok ium, 2014, Május 28-30, Sió ok, Magya o szág. 2. Ti csó Gyula, Ga da Zol án, Molná Enikő, Fodo Tamás, Kálmán Fe enc, Tei Lo enzo, Ko ács Zol án, Tó h Im e: Mn2+-komplexek: az MRI kon asz anyag ku a ás jö ője agy zsáku cája? 19. Nemze közi Vegyészkon e encia, 2013, No embe 21-24, Nagybánya, Románia. 1. Ga da Zol án, Kálmán Fe enc K isz ián, Bo á Richá d, Molná Enikő, Fodo Tamás, Ko ács Zol án, Tó h Im e, Ti csó Gyula: 7-, 8-, 10-, és 12- agú (mak o) ciklusos ligandumok Mn2+-komplexeinek egyensúlyi és bomláskine ikai jellemzése XLVII. Komplexkémiai Kollok ium, 2013, Május 29-31, Má aháza, Magya o szág 8.6. Pos e s no ela ed o he disse a ion 2. Zol án Ga da, Enikő Molná , Richá d Bo á , Tamás Fodo , Fe enc K. Kálmán, Zol án Ko ács, Im e Tó h, Gyula Ti csó: Tuning o he he modynamic and kine ic p ope ies o Mn2+ complexes o med wi h cyclododecane de i a i es: he e ec o he na u e o dono a oms 16. In e na ional Con e ence on BioIno ganic Chemis y (ICBIC-16), 22-26 July, 2013, G enoble, F ance. 1. Zol án Ga da, Enikő Molná , Richá d Bo á , Tamás Fodo , Fe enc K. Kálmán, Zol án Ko ács, Im e Tó h, Gyula Ti csó: Tuning o he he modynamic and kine ic p ope ies o Mn2+ complexes o med wi h cyclododecane de i a i es: he e ec o he na u e o dono a oms Deb ecen Colloquium on Ino ganic Reac ion Mechanisms, 11-15 June 2013, Deb ecen, Hunga y. 8.7. Pa en claims no di ec ly ela ed o he disse a ion 4. Bo á R., Ga da Z., Fodo T., Kálmán F., K., Nagy V., Ti csó Gy., Tó h I., Új ciklononán alapú együle ek és alkalmazásuk Mn(II)-alapú MRI kon asz anyagok ligandumaikén Magya szabadalom, P1500563, Benyúj a: 2015. no embe 30. 3. Bo á R., Ga da Z., Fodo T., Kálmán F., K., Nagy V., Ti csó Gy., Tó h I., Új 3,6,9,15- e aaza-bicklo[9.3.1]pen adeka-1(14),11(15),12- ién alapú együle ek és alkalmazásuk Mn(II)-alapú MRI kon asz anyagok ligandumaikén , Magya szabadalom, P1500564, Benyúj a: 2015. no embe 30. 2. Bo á R., Ga da Z., Fodo T., Kálmán F., K., Nagy V., Ti csó Gy., Tó h I., Új 2,11- diaza[3.3](2,6)-pi idino án alapú együle ek és alkalmazásuk Mn(II)-alapú MRI kon asz anyagok ligandumaikén , Magya szabadalom, P1500565, Benyúj a: 2015. no embe 30. 1. Bo á R., Ga da Z., Fodo T., Kálmán F., K., Nagy V., Ti csó Gy., Tó h I., Új 6-oxa- 3,9,15- iaza-biciklo[9.3.1]pen adeka-1(14),11(15),12- ién alapú együle ek és alkalmazásuk Mn(II)-alapú MRI kon asz anyagok ligandumaikén , Magya szabadalom, P1500566, Benyúj a: 2015. no embe 30. 9. Acknowledgemen I would like o exp ess my g a i ude o P o . Im e Tó h o supe ising me all hese yea s, always showing me new ways o ackle obs acles and o all he help he has gi en me. I am g a e ul o D . Gyula Ti csó o deepening my unde s anding o p ac ical syn he ic chemis y and insigh in o ine aspec s o po en iome y and elaxome y. Köszönöm Zékány Lászlónak a bonyolul abb számí ásokban, szimulációkban nyúj o elengedhe e len segí ségé , alamin ö énelmi és ilágpoli ikai isme e eim ki e jesz ésé . I would like o hank D . Is án Bányai o ge ing me acquain ed wi h some lesse -known inne wo kings o NMR and o his help wi h measu emen s. I would like o hank D . Mihály Pu gel o his help wi h in silico calcula ions and in e p e a ion he eo . I am g a e ul o D . A ila Bényei o his help in sol ing c ys al s uc u es and his pa ience when wai ing o said c ys als. Köszönöm Rózsa Bélának a munkában, különösképp a allium- elek olízísben nyúj o segí ségé . I hank P o . E nő B üche o cons an ly p o iding new wisdom and knowledge. I hank my cu en and p e ious colleagues and s uden s a he Dep . o Ino ganic and Analy ical Chemis y, Uni e si y o Deb ecen o hei help and o p o iding a iendly, un a mosphe e. Végül sze e ném megköszönni családomnak, hogy mind égig ámoga ak és meg e em e ék a munkához szükséges a omsz é á . I am g a e ul o he hunga ian Science Resea ch Fund (OTKA, p ojec s K-84291 & K-109029) and COST ac ion TD1004 o inancial suppo .