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Complexes of transition metal ions with naturally occurring ligands Shuter, Edward M. 1995

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C O M P L E X E S OF TRANSITION M E T A L IONS WITH N A T U R A L L Y OCCURRING LIGANDS  by  E D W A R D M . SHUTER  B . S c , University of British Columbia, 1991  A THESIS SUBMITTED IN P A R T I A L F U L F I L L M E N T OF THE REQUIREMENTS FOR THE D E G R E E OF M A S T E R OF SCIENCE in THE F A C U L T Y OF G R A D U A T E STUDIES (Department of Chemistry)  We accept this thesis as conforming to the required standard  THE UNIVERSITY OF BRITISH C O L U M B I A July 1995 © Edward M . Shuter, 1995.  In presenting this thesis in partial fulfilment  of the requirements for an advanced  degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department  or  by  his or  her  representatives.  It  is understood that copying or  publication of this thesis for financial gain shall not be allowed without my written permission.  Department The University of British Columbia Vancouver, Canada  Date  DE-6 (2/88)  /W  22-  im  11  Abstract Attempts to prepare tris(ligand)metal complexes of technetium in intermediate oxidation states with potentially bidentate oxazoline- and thiazoline-containing ligands were unsuccessful; when pertechnetate was reduced in the presence of excess ligand, T c 0 2 XH2O was produced. Instead, by reaction with pre-formed metal-oxo cores, a series of oxotechnetium(V) and oxorhenium(V) complexes of the formula M O X L 2 ( M = Re, X = Br; M = Tc, X = CI), and H L = 2-(2'-hydro xyphenyl)-2-oxazoline (Hoz), 2-(2'-hydroxy-3-methylphenyl)-2-oxazoline (Hmoz), 2-(2' -hydroxyphenyl)-2-thiazoline (Hthoz), and 2-(2' -hydroxyphenyl)-2-benzoxazole (Hhbo) have been prepared.  These compounds have been characterized by a variety of  techniques, including single crystal X-ray diffraction for two of the complexes, TcOCl(thoz)2 and ReOBr(oz)2- In the two complexes, the geometry around the metals is distorted octahedral with the halide ligands in each bound cis, and one phenolate oxygen from one ligand in each bound trans to the metal-oxo linkage. In ReOBr(oz) , the two oxazoline nitrogens are 2  coordinated trans to one another; in TcOCl(thoz)2, the two thiazoline nitrogens are found cis to one another. In  studies  of  potentially  insulin  mimetic  compounds  analogous  to  bis(maltolato)oxovanadium(IV), the complexes bis(maltolato)oxo(pyridine)vanadium(IV) (VO(ma) (py)), oxobis(picolinato)vanadium(IV) monohydrate, (VO(pic) (H20)), ammonium 2  2  dioxobis(picolinato)vanadate(V) dihydrate, (NH4[VC»2(pic)2]-2H20), and bis(maltolato)dioxomolybdenum(VI), ( M o 0 ( m a ) ) , have been prepared and characterized by elemental 2  2  analysis, infrared spectroscopy, and mass spectrometry. diamagnetic  MoC»2(ma)2 was obtained.  In addition, the H N M R of the l  Bis(maltolato)methoxyoxovanadium(V),  (VO(ma)2(OMe)), was synthesized and was characterized by *H and spectroscopy, and mass spectromerty.  5 1  2  2  2  V N M R infrared  V NMR. X-ray structures were obtained for  N H [ V 0 ( p i c ) ] , VO(ma)2(OCH CH OH), and M o 0 ( m a ) . 2  1  2-hydroxyethoxybis(maltolato)oxovanadium(V),  VO(ma)2(OCH2CH20H), was characterized by 4  5  2  2  Ill  T A B L E OF CONTENTS page Abstract  ii  Table of Contents  iii  List of Figures  iv  List of Tables  vi  List of Schemes  vii  List of Abbreviations  viii  Acknowledgements  xi  Chapter 1.  General Introduction  1  Chapter 2.  Synthesis and Characterization of Bis(ligand)oxorhenium and -technetium Complexes as Potential Radiopharmaceuticals.  Chapter 3.  2.1 Introduction  9  2.2 Synthesis and Characterization  11  2.3 Results and Discussion  15  Synthesis and Characterization of Bis(ligand)oxovanadium and -molybdenum Complexes as Potential Insulin Mimics.  Chapter 4.  3.1 Introduction  23  3.2 Synthesis and Characterization  25  3.3 Results and Discussion  28  Conclusions and Suggestions for Future Work.  39  References  40  Appendix  44  IV  L i s t of Figures page Figure 1.1  Pentagonal bipyramidal structure of VO(C<2)(pic)-2H20.  7  Figure 2.1  Oxazoline and thiazoline based ligands used in this study.  10  Figure 2.2  Two siderophores containing the metal complexing  10  moieties of interest.  Figure 2.3  ORTEP diagram of TcOCl(thoz)2 showing the  18  crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level.  Figure 2.4  ORTEP diagram of ReOBr(oz) showing the 2  20  crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level.  Figure 3.1  Ligands used in this study (see text).  23  Figure 3.2  Comparison of carboxylato and cw-V02 groups.  30  Figure 3.3  ORTEP diagram of NJ^V0 (pic)2-2H 0 showing the  32  +  2  2  crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level.  Figure 3.4  ORTEP diagram of VO(ma)2(OCH CH OH) showing 2  2  the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level.  35  V  Figure 3.5  ORTEP diagram of Mo0 (ma)2 showing the 2  crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level.  38  VI  L i s t of Tables page Table 2.1  Selected bond lengths (A) and angles (°) in TcOCl(thoz) .  17  Table 2.2  Selected bond lengths (A) and angles (") in ReOBr(oz) .  19  Table 3.1  Selected bond lengths (A) and angles (°) in  31  2  2  NH V0 (pic) -2H 0. 4  Table 3.2  2  2  2  Selected bond lengths (A) and angles (°) in  34  VO(ma) (OCH CH OH). 2  Table 3.3  2  2  Bond lengths (A) and angles (°) in Mo0 (ma) . 2  2  37  Vll  L i s t of  Schemes page  Scheme 1.1  Decay scheme of " M o to " T c transition used in the  1  99mT generator. c  Scheme 1.2  Reduction and substitution routes of Tc complex  2  synthesis.  Scheme 1.3  Proposed reaction scheme of vanadium8-hydroxyquinoline complexes according to Floriani and co-workers.  7  vm L i s t of Abbreviations  Abbreviation  Meaning  A  Angstrom(s)  acac  acetylacetonato  ATP  adenosine tripolyphosphate  BM  Bohr magneton  °C  degrees Celsius  cm  -1  wavenumber  cytPTK  cytosolic protein tyrosine kinase  d  doublet (NMR)  D  deuteron  Da  Dalton (mass of one hydrogen atom)  dd  doublet of doublets (NMR)  DMSO  dimethylsulfoxide  EA  elemental analysis  EDTA  ethylenediaminetetraacetate  EI  electron ionization  Et  ethyl  EtOH  ethanol  eV  electron-volt  g  gram(s)  H3apa  N,N-3-azapentane-l,5-diylbis(3-(l-iminoethyl)-6-methyl2#-pyran-2,4-(3fl)-dione)  Hhbo  2-(2' -hydroxyphenyl)benzoxazole  Hma  3-hydroxy-2-methyl-pyrone (maltol)  Hmoz  2-(2' -hydroxy-3' -methylphenyl)-2-oxazoline  ix HM-PAO  3,3,6,6,9,9-hexamethyl-4,8-diazaundecane-2,10-dione dioxime  Hoz  2-(2' -hydroxyphenyl)-2-oxazoline  Hthoz  2-(2' -hydroxyphenyl)-2-thiazoline  Hz  Hertz  i-Pr  isopropyl  IR  infrared  J  coupling constant (in NMR)  k  kilo  K  Kelvin  Ki  first stepwise stability constant for the reaction: M  K2  n+  +  L  m-  — ^  M  L  n  +  m  second stepwise stability constant for the reaction: ML  n +  + L - ^ m  ML  n + m 2  L  ligand; litre(s)  LSIMS  liquid secondary ion mass spectroscopy  m  multiplets (NMR); milli  |J.  micro  M  metal ion; moles per litre; mega  MDP  methylene diphosphonate  Me  methyl  MeOH  methanol  MS  mass spectrum  MW  molecular weight  n  nano  NMR  nuclear magnetic resonance  ORTEP  Oak Ridge Thermal Ellipsoid Plot  pic  pyridine-2-carboxylate (picolinic acid anion)  ppm  parts per million  py  pyridine  R  alkyl group  RT  room temperature  s  singlet (NMR); second  S  Cahn-Ingold-Prelog system of denoting the absolute configuration of a chiral compound (complementary to R)  STZ  streptozotocin  t  triplet (NMR)  ti/2  half-life of a radionuclide  tame  1,1,1 -tris(aminomethyl)e thane  TMS  tetramethylsilane  tren t) . x  X-  y  N,N,N-tris(aminoethyl)amine vibrational stretching mode halide (CI", B r , etc.)  xi Acknowledgements  First and foremost, I would like to thank Professor Chris Orvig for his patience, guidance, and friendship during all my ups and downs at the U.B.C. chemistry department. I wish to thank past and present members of the Orvig team (especially Dr. Hamid Hoveyda, Dr. Lucio Gelmini, Dr. Yan Sun and Peter Caravan) for helping me explore the world of chemistry with them. Dr. Steve Rettig, Prof F.E. Hahn, and Thomas Lugger are to be thanked enormously for their expedient crystal structure determinations. The elemental analysis, N M R , and M S technical staff are thanked for their prompt analyses. Janet M . Jong, Violet G. Yuen, and Dr. J. H . McNeill are to be thanked for providing the biological studies data presented in the appendix. Finally, I wish to thank Grace for her unwavering love and support during the course of my studies. In addition, I thank her for urging me to complete the writing of this thesis.  1 Chapter 1.  General Introduction  Technetium is a Group 7 second row element having a [ K r ] 4 d 5 s electronic 5  2  configuration. Discovered by Perrier and Segre in 1937, technetium is the first of the artificial elements, even though it is present in minute quantities in the earth's crust as a result of on-going natural radioactive decay. While 22 isotopes, 90 to 110 and 99m, are known, the only isotope available in weighable amounts is " T c , which is now produced in kilogram quantities by nuclear fission. The two isotopes of primary usage today are  9 9 m  T c and " T c . 99mT j c  sQ  f widespread  importance in nuclear medicine procedures; its optimal nuclear properties have led to its use in greater than 90% of nuclear medicine scans. " m T c j inexpensive and available to all hospitals s  via the M o / " T c generator, which produces technetium as pertechnetate, 9 9  m  "Mo0  2 4  _J3^  9 m  Tc0 - _ L J  9  4  66 hrs  T c 0  Tc04~.  4  6 hrs  Scheme 1.1 Decay scheme of M o to T c transition used in the 9 9  99m  9 9  9 9 m  Tc  generator.  Pertechnetate is used as a starting material for radiopharmaceuticals, which are compounds containing radioactive nuclides that are useful in the diagnosis or treatment of certain disease states. This decay scheme (Scheme 1.1) illustrates that " m T c j produced from the s  decay of M o as molybdate on an anion exchange column. When pertechnetate is produced, it 9 9  is eluted at a 10" to 1 0 6  -8  M concentration from the column, which retains the more highly  charged "M0O4 ". " m j c has a half-life of 6.0 hours, which is long enough to prepare a 2  radiopharmaceutical and perform a scan, but is short enough to minimize the radiation dose to the patient and to make successive scans on successive days possible. The 140 keV y-ray emitted is strong enough to penetrate tissue and to be imaged by the thin N a l (Tl) crystals of the y-ray camera, but not too high as to overirradiate the patient. The application of technetium and rhenium radioisotopes in diagnostic and therapeutic nuclear medicine (  186  Re,  188  R e , and especially  9 9 m  T c ) , has spawned a widespread interest in the  2 coordination chemistry of these elements. Integral factors that are considered prior to the synthesis of a technetium complex for use as a radiopharmaceutical are the polarity and lipophilicity of the ligand, and of the resulting metal complex, as well as the overall complex charge. A l l these factors in part determine biodistribution properties of the radiopharmaceutical, ' as is evinced by the facts that many lipophilic monocationic 99m r 1 2  r  c  complexes localize in heart muscle and that some neutral complexes accumulate in the brain. " T c is a weak f}- emitter (292 keV, ti/2 = 2.12 x 10 years), which is used for the 5  macroscopic synthesis of coordination compounds. Technetium complexes have been prepared in the oxidation states from -1 to +7.  3  Synthesis of all technetium complexes originally starts  from TCO4-. Salts of TCO4" with various cations have been characterized. 4  5  The crystal  structure of KTCO4 shows that the TCO4" unit is tetrahedral with Tc=0 bond lengths of 1.72  A.  6  A brief overview of the technetium complexes formed in high and intermediate oxidation states is presented with emphasis on Tc(V)-oxo complexes. The synthesis of technetium complexes is by either the reduction or substitution route.  9 9 m  T c 0 " + reductant/ligand  product complex  4  TcOX " + ligand 4  TcX  2 _ 6  »Tc(V) product  + l i g a n d — - Tc(IV) product  Scheme 1.2 Reduction and substitution routes of Tc complex synthesis.  The reduction route can be used with " T c or  9 9 m  T c . The addition of a reducing agent,  such as Sn(II) or sodium dithionate, to a mixture of ligand and pertechnetate produces technetium complexes in an oxidation state lower than +7. Commercial kits most often use Sn(II) as the reductant. Quite often a mixture of products is obtained. The substitution route involves the synthesis of an intermediate technetium complex, onto which ligands can then be added by metathesis.  Compounds of the general formula T C O X 4 " or T c X 6 " , where X is a halide, are the most 2  common intermediates. The H X , and the 7  TCOX4-  TCOX4"  compounds are formed when T c C V is reacted with cold  anion is trapped with a bulky cation, whereas TcX6 ~ is formed when hot 2  H X is reacted with pertechnetate. It is difficult to produce pure 8  9 9 m  TcOX4~  and  9 9 m  TcX6 ~, 2  and so the substitution route is not used with radiopharmaceutical synthesis at present although its use is not completely ruled out.  1  Other Tc(Vn) complexes known are the volatile TC2O7 and TC2S7. TC2O7 is a yellow, crystalline solid consisting of TCO4 tetrahedra linked through linear Tc-O-Tc bonds. There are 9  few Tc(VI) complexes; [(CH3)4N]2Tc04 can be formed by elecrochemical reduction of TCO4- in acetonitrile. TcF6, TcCl6, TCO3, TCOF4, and TcOCU have also been made. TCOF4 is actually a 9  trimer.  10  The Tc(IV) complex [ N H ] T c C l 6 is octahedral with Tc-Cl bond lengths of 2.33 A; 4  2  dissolution of TcX6 ~ compounds in water produces T c 0 x H 2 0 . TCO2 is an impurity in 2  2  commercial TCO4" and, like all Tc complexes, can be oxidized back to TCO4" with H2O2. As " n i T  phosphonates  c  are  bone  scanning  L i ( H 0 ) [ T c ( O H ) ( M D P ) ] - l / 3 H 0 is of interest 2  3  2  11  agents,  the  structure  of  (MDP = methylene diphosphonate); this  complex has infinite polymers of two Tc ions bridged by O H ' and each coordinated to M D P ligands. It is not clear whether the metal ion is in oxidation state +4 or +5. Tc(UI) complexes need good pi-acceptor ligands, such as triphenylphosphine, diarsines, or carbonyls.  Trans-[TcCl(acac)2(PPhi)]  [TcCl3(PMe2Ph)3]  has been synthesized, as has  12  13  mer-  (which was formed from TcCl6 " and PMe2Ph in absolute ethanol). 2  Complexes of the general formula  [TcL2X2] , +  where L is a diphosphine or diarsine, can be  synthesized by mixing TcX6 " + L in acidic ethanol-water mixtures, and at one time showed 2  14  great promise as heart imaging agents.  2  By far, the most important oxidation state is Tc(V) and a large number of Tc(V) complexes have been characterized by X-ray crystallography. Tc(V) centers are d diamagnetic 2  cores usually having at least one oxo group around the metal, although Tc(V) nitrido complexes are known. The T c 0 , T c 0 2 , and T c 2 0 3 3 +  +  4+  cores exist in five, six, and seven coordinated  4 complexes. Ligands of varying denticity, bonding through O, N , S, As, and P atoms, can coordinate to T  c 0  3  +  many  ;  T c 0  3  +  complexes have been characterized. Such species with many  different ligands have proven to be very common; only a very brief survey appears here. Bidentate S,S , 0 15  , 0  1  6  ,  and 0 , S  1 7  donor ligands can bond to T  c 0  3  +  in a five coordinate  square pyramidal geometry. A sixth ligand is sometimes found weakly coordinated in the sixth position trans to the oxo bond. The [  99m  T c O ( H M - P A O ) ] complex,  18  containing the 3,3,6,6,9,9-hexamethyl-4,8-  diazaundecane-2,10-dione dioxime ligand, is used as a brain imaging agent. H M - P A O is a tetradentate trianionic ligand which forms square pyramidal complexes with the T c 0 Some six coordinate Tc(V)  complexes are franHTcO(OCH )(CN)4] 2  19  3  penicillaminato-N,S)(D-penicillaminato-N,0,S)].  20  3 +  core.  and [TcO(D-  Bidentate Schiff base ligands bind through  oxygen and nitrogen to form complexes of the general formula [ T C O X L 2 ] .  The ligand  2 1 , 2 2  H3apa is a 0 , N , N , N , 0 Schiff base donor, which is trianionic and pentacoordinate. [TcO(apa)] has a highly distorted octahedral geometry and the T c = 0 core has a slightly lengthened bond distance of 1.678  A.  23  In T c ( V ) = 0 complexes, the T c = 0 IR stretching frequency has very characteristic values from 890 to 1020 c m . The relative frequency is dependent on the equatorial ligands and on the -1  presence or absence of a sixth ligand trans to the oxo bond. The trans-Tc02  +  core can be  stabilized by nitrogen donating ligands such as pyridine, ethylenediamine, and cyclam. The 1  T c = 0 bond distance of the T c C < 2 unit is about 1.75 +  A compared to 1.61 to 1.68 A for  cores. The greater bond distance leads to lower \)Tc=0 IR stretching frequencies of the  Tc0  3 +  Tc02  +  core of 790 to 834 cm- . 1  Because of the lanthanide contraction, the chemistry of technetium more closely resembles that of its third row congener, rhenium, than its first row Group 7 member, manganese. The similarity of rhenium and technetium complexes in size, shape, charge, and lipophilicity is often exploited. That is, the chemistry of rhenium is often explored as a foundation to help understand the chemistry of technetium. Many technetium complexes have rhenium analogues (see Chapter 2). Rhenium is useful because its natural isotopes are stable and  5 no radioactive safety precautions are required. In addition,  1 8 6  R e has attractive properties for y-  ray imaging and can be used in biological studies with the same y-ray camera instrumentation as 9 9 m  T c . There are some chemical differences between rhenium and technetium complexes, most  notably that rhenium complexes are more difficult to reduce than their technetium analogues.  Vanadium is a first row transition metal discovered in 1831 by the Swede Nils Gabriel Stefstrom  24  and was named for Vanadis, the Norse goddess of love and beauty. Found in  rocks, soil, plants and animals, vanadium has an abundance of 0.014 % in the earth's crust,  25  more concentrated than lead, zinc, copper, and tin. The industrial use of vanadium as a catalyst is gradually increasing the vanadium concentration in the atmosphere.  In nature, neither  vanadium nor any of its compounds exist in a pure form. Having a concentration of 50 n M in the ocean, vanadium is accumulated by certain aquatic organisms. A n order of tunicates (sea 25  squirts) contain 0.15 M vanadium in certain blood cells named vanadocytes.  25  Amavadin is a  low molecular weight bis(ligand) vanadium complex found in the toadstool genus, Amanita. Haloperoxidases  26  from sea algae and lichens, and nitrogenases  27  from the bacterium  Azotobacter chroococcum, were the first proteins discovered with vanadium in the active site. With a concentration of less than 1 u M in mammals, vanadium has been much studied to 28  determine if it is an essential trace element; although evidence suggests that vanadium is essential, this has never been absolutely proven.  29  Complexes in the oxidation states -3,-l,0,+l,+2,+3,44, and +5 have been characterized. Vanadium in the +3, +4, and +5 oxidation states can be found in biological systems, although V(IV) and V(V) are most prevalent. Governed by p H and concentration dependant equilibria, a myriad of vanadium species can exist in aqueous solution. Acidic solutions may contain V , 3 +  V0  2 +  , and cis-V02 , +  although as the pH is increased, oxidation to V(V) is favoured and  hydrolysis to many vanadate monomers and oligomers occurs. At a p H greater than 12, orthovanadate,  VO4 " 3  is the sole V(V) species. When the concentration of vanadium is less than  10 | i M in the physiological pH range from 6 to 8, the predominant species present are monovanadates H2VO4", and HVO4 ", each of which has tetragonally coordinated vanadium. 2  30  6 Other V(V) oligiomeric vanadate species are H 2 V 2 O 7 - , 2  Vanadium(V), or vanadate, binds E D T A ,  31  V 3 O 9 - , HV4O12 -, 3  3  and Vio028 "6  citrate, glycols, catechols and other ligands. 32  Reducing agents such as glutathione and catechols can reduce vanadate to vanadium(IV). The chemistry of vanadium(IV) is centred around the vanadyl ion, V 0 oxocation of the first row transition metals. At low pH, V 0  2 +  2 +  , the most stable  is favored. As the p H is raised,  the vanadyl ion tends to be oxidized. The vanadyl ion forms strong complexes with ligands containing hard donor atoms such as oxygen and nitrogen. Five and six coordinate complexes, usually having octahedral, square pyramidal, or trigonal bipyramidal geometries, are formed with vanadium-oxygen double bond lengths of about 1.6 to 1.7  A.  30  The vanadyl ion is often thought of as a divalent metal ion, competing with C a , M n , 2+  and Z n  2 +  for ligand binding sites.  2 +  Vanadyl forms strong complexes with citrate, A T P ,  pyrophosphate, and amino acids. The flexibility of vanadium complexation can help explain that vanadium binds to the active sites of a number of metalloproteins, having binding constants of up to 10 M . 9  - 1  3 0  Due to its high affinity for small ligands and proteins, it is unlikely that vanadium  exists freely in vivo as vanadyl or vanadate. The complexation of V(IV) and V(V) with human serum transferrin and albumin has been investigated by Chasteen.  33  Both bare V(IV) and V(V) have been stabilized by chelation. Coordinating ligands can stabilize lower oxidation states against oxidation and hydrolysis. Floriani has drawn analogies between carbon functional groups and vanadium centers coordinated to L = 8hydroxyquinolinato.  34  The anhydride analogue L 2 V ( 0 ) - n - 0 - V ( 0 ) L 2 can be esterified to  L V ( 0 ) ( O R ) , base hydrolyzed to L V ( 0 ) - , and acetylated to L V ( 0 ) ( O C ( C H ) 0 ) . Although 2  2  2  2  3  Floriani states the carboxylic acid analogue, L2V(0)(0H) can be synthesized by protonating the carboxylate analogue L V(0)2", research in our group indicates that protonation of (ma)2V(0)2 2  leads to reduction of the metal to V ( I V ) .  35  _  H  L V(0)(OH)-  +  L V(0) " 2  2  2  OH"  L V(0)-u-0-V(0)L  H O  2  0  OH"  2  ROH (CH CO) 0 3  2  \ L V(0)(0C(CH )0) 2  Scheme  L V(0)(OR)  3  2  1.3 Proposed reaction scheme of vanadium-8-hydroxyquinoline complexes according to Floriani and co-workers.  The oxidation of bromide or iodide by  34  H2O2  can be catalyzed by vanadium  bromoperoxidase. It is believed that peroxide coordination to V(V) is intimately involved in this reaction.  Most vanadium peroxide complexes have been shown to be seven coordinate,  pentagonal bipyramidal, such as VO(02)(pyridine-2-carboxylato)-2H20. The oxo group and a 36  water are in the apical positions, while the peroxo, a second water, and the 2-carboxypyridinato (or pic ) groups are in the equatorial plane. -  0 1  r  H 0 H 0  o'  2  2  Figure 1.1 Pentagonal bipyramidal structure of V0(02)(pic)-2H20.  36  Other peroxo V(V) complexes include those of pyridine-3-carboxylic acid, bipyridine, dipicolinic acid, and oxalate. The multiple oxidation states and oxidation-reduction chemistry of vanadium play an integral role in its biochemistry. Anions and cations of vanadium are involved in biological systems. Vanadate,  VO4 -, resembles phosphate 3  and this similarity has ramifications in its  inhibitory, stimulatory, and regulatory functions.  24  Vanadium is known to inhibit both  ribonuclease and the (Na+,K+)-ATPase enzymes. Inhibition of (Na+,K+)-ATPase by vanadyl is  8 much weaker than by vanadate. Absorption of vanadium may be gastrointestinal, respiratory, or through the s k i n .  30  The widespread use of vanadium medicinally at the turn of the century  indicates that oral administration of vanadium is not very toxic.  30  The form of the oxovanadium  compound affecting the body depends on pH, concentration, and oxidation-reduction changes that may occur. Vanadium compounds will bind to the various components of a biological system and assigning the specific oxidation state of vanadium in an organism is often difficult. Vanadium may find use in the treatment of diabetes, a condition of elevated blood glucose. Diabetes is a potentially life-threatening disease and is presently controlled by diet and/or daily injections of the hormone insulin, which acts to uptake glucose, fatty acids, and amino acids for storage as glycogen in muscle and liver, as triglycerides in adipose tissue, and as proteins in muscle. Oral administration of the vanadyl ion has been shown to lower blood glucose in diabetic rats. activity since 1980.  37  37  The vanadate ion, VO4-, has been known to induce insulin-like 3  Pentavalent vanadium, vanadate, is the most toxic form of vanadium;  vanadate must be administered at near toxic concentrations to have an effect and it is poorly absorbed from the gastrointestinal tract. McNeill has shown that vanadyl sulphate acts to reduce blood glucose, but it, too, is poorly absorbed.  This research group has developed  bis(maltolato)oxovanadium(IV), VO(ma)2, an easily prepared complex, containing a bidentate 0 , 0 donor ligand and having low toxicity, that is insulin mimicking and is well absorbed from the gastrointestinal tract. Oral administration of V0(ma)2 to STZ-diabetic rats has shown that it is effective at reducing blood glucose levels and is about 50% more effective that vanadyl sulphate.  38  VO(ma)2 may find use as a diabetes treatment replacing insulin or working in  conjunction with it.  9 Chapter 2.  Synthesis and Characterization of Bis(ligand)oxorhenium and -technetium Complexes as Potential Radiopharmaceuticals.  2.1  Introduction As part of a project to study metal complexes of naturally occurring chelators, bidentate  ligands containing some of the less common binding moieties found in siderophores (microbial iron scavengers) are reported herein to form bis(ligand) complexes with rhenium and technetium. The affinity of siderophores for Fe(rH) is predicated by chelating groups such as catecholates and hydroxamates, and to a lesser extent by derivatives of 2-(2' -hydroxyphenyl)-2-oxazoline (Hoz). 2-(2' -hydroxyphenyl)-2-thiazoline (Hthoz) is to be found in S-desferrithiocin and also forms stable iron(III) complexes.  39  Hoz and 2-(2' -hydroxy-3' -methylphenyl)-2-oxazoline (Hmoz)  contain a binding moiety found in the siderophores mycobactin and agrobactin.  40  While not  found in siderophores, 2-(2'-hydroxyphenyl)benzoxazole (Hhbo) is a more lipophilic and sterically demanding analogue whose Group 13 complexes have recently been reported by our laboratory.  41  The synthesis and characterization of tris(ligand) A l , Ga, and In complexes of the  oxazoline containing ligands have also been reported recently. rhenium and technetium with bidentate Schiff base l i g a n d s  42  21,43  Bis(ligand) complexes of and mono and bis(2-(2 -  hydroxyphenyl)-2-benzothiazolato) complexes of Re(V) and Tc(V) have been reported, have Co, N i , and Zn bis(ligand)metal(II) complexes of H o z . agrobactin was reported in 1980.  40  45  22,44  as  The crystal structure of  10  Figure 2.1  Figure 2.2  Oxazoline and thiazoline based ligands used in this study.  Two siderophores containing the metal complexing moieties of interest.  11 2.2  Synthesis and  Characterization  Materials and Methods.. received. [ ( n - B u ) 4 N ] [ R e O B r ] 4  46  A l l chemicals were reagent grade and were used as  and [ ( n - B u ) 4 N ] [ T c O C l ] were prepared from N H R e 0 (a 7  4  4  4  gift from Johnson Matthey, Inc.) and N H 4 T C O 4 (a gift from the Du Pont Merck Pharmaceutical Company), respectively. The ligands 2-(2'-hydroxyphenyl)-2-oxazoline (Hoz), and 2-(2'hydroxy-3' -methylphenyl)-2-oxazoline (Hmoz) were prepared as previously reported, as was 42  2-(2'-hydroxyphenyl)-2-thiazoline (Hthoz).  47  2-(2'-Hydroxyphenyl)-2-benzoxazole (Hhbo)  was obtained from Aldrich. Caution! " T c is a low energy (0.292 MeV) fj- emitter with a half-life of 2.12 x 10  5  years. A l l manipulations of solutions and solids were performed in a laboratory approved for the handling of low-level radioisotopes, and normal safety procedures must be used at all times to prevent contamination. Instrumentation. N M R spectra were recorded on either a Bruker AC-200E or a Bruker WH-400 instrument. H N M R data are reported as ppm downfield from an external l  TMS reference. Infrared spectra were recorded as KBr discs in the range 4000-400 c n r on a 1  Perkin-Elmer 783 spectrophotometer with polystyrene as a reference.  Mass spectra ( C s  +  LSIMS) were obtained on a Kratos Concept II H32Q instrument with 3-nitrobenzyl alcohol or thioglycerol as the matrix. Expected isotope ratios were observed for all Br, Re, and/or S containing compounds; only the most intense peak in a given isotope pattern is reported. Elemental analyses were performed by Mr. P. Borda using an in-house Carlo Erba instrument, except for the " T c complexes, which were sent to Canadian Microanalytical Services Ltd, Delta, British Columbia.  Bromobis[2-(2' -hydroxyphenyl)-2-oxazolinato]oxorhenium(V), ReOBr(oz)2-H 0 2  To a solution of [(n-Bu) N][ReOBr ] (150 mg, 0.20 mmol) in 30 mL 4  4  ethanol was added Hoz (0.131 g, 0.80 mmol); the solution turned a dark green color. After one hour at reflux, the solution was allowed to cool to room temperature. Slow evaporation of ethanol led to the precipitation of green needles of the monohydrate; these were isolated by  12 filtration, washed with 5 mL ether, and dried in vacuo, yield 0.045 g (37%). X-ray quality crystals were obtained by recrystallization from CH Cl /pentane. Anal. Calcd (found) for 2  2  C i 8 H i B r N 0 R e : C, 34.62 (34.51); H , 2.91 (2.80); N , 4.49 (4.37); Br, 12.8 (12.6). IR: 8  2  6  1625 ft)c=N). 1610 ( D O C ) , 1585 (i>c=c), 1485 (o) =c), 1400, 1260, 1240, 1090, 970 (t)R =o), C  e  860, 755. EIMS: m/z = 527 [ M O L ] , 606 [ M O B r L ] . *H N M R (DMSO-d > 400 M H z ) : +  +  2  2  6  3.78-4.48 (m, 4H), 4.73-5.26 (m, 4H), 6.8-8.1 (m, 8H).  Bromobis[2-(2'  -hydroxyphenyl)-2-thiazolinato]oxorhenium(V),  ReOBr(thoz) . To 25 mL ethanol was added [(n-Bu) N][ReOBr ] (150 mg, 0.20 mmol). 2  4  4  Upon dissolution to form an orange-yellow solution, Hthoz ( 0.075 g, 0.42 mmol) was added and the solution turned a dark green color. Slow evaporation of solvent yielded green needles (0.072 g, 57%). Anal. Calcd (found) for C i H i B r N 0 R e S : C, 33.86 (33.69); H , 2.53 8  6  (2.68); N , 4.39 (4.44); Br, 12.51 (12.33). IR: 1600 0>C=C),  2  3  (\>C=N),  2  1570 0>c=c), 1540 (t>c=c), 1470  1320, 1240, 1225, 1045, 960 (D =o), 850, 765. EIMS: m/z = 559 [MOL ]+, 638 2  Re  [MOBrL ]+. 2  !  H N M R ( D M S O - d , 400 MHz): 3.8-4.10 (m, 4H) 4.18-4.62 (m, 4H) 6.356  7.90 (series of overlapping m, 8H).  Bromobis[2-(2' -hydroxy-3' -methylphenyl)-2-oxazolinato]oxorhenium(V), ReOBr(moz) . To [ ( « - B u ) N ] [ R e O B r ] (153 mg, 0.20 mmol) in 20 2  4  4  mL of 1:1 CHCl3:MeOH was added 2.1 equivalents of Hmoz (0.075 g, 0.42 mmol). Following brief stirring, the green solution was refluxed overnight, and then allowed to cool to room temperature.  After slow evaporation of the solvent, a light green precipitate was isolated,  washed with 10 mL E t 0 and dried in vacuo for 24 hrs to yield 56 mg (46%) ReOBr(moz) . 2  2  Anal. Calcd (found) for C H B r N O R e : C, 37.86 (38.11); H , 3.18 (3.32); N , 4.42 (4.65); 2 0  Br, 12.59 (12.73). IR: 1625  2 0  2  (D =N), C  5  1605 (T) =c)> 1595 (u =c), 1555 (\) =c), 1435, 1400, C  C  C  1265, 1230, 1185, 975 (D =o), 755. EIMS: m/z = 555 [MOL ]+, 634 [MOBrL ]+. *H N M R Re  2  2  (CDCI3, 400 MHz): 1.94 (s, 3H), 2.11 (s, 3H), 4.30 (t, 2H), 4.80-5.10 (m, 6H), 6.69 (t, 1H,  13 7 = 9 Hz), 6.86 (t, 1H, J = 9 Hz), 7.10 (d, 1H, J = 8 Hz), 7.28 (m, 1H, J = 8 Hz), 7.53 (d, 1H, J = 8 Hz), 7.76 (dd, 1H, 7 = 8 Hz).  Bromobis[2-(2' -hydroxyphenyl)benzoxazolato]oxorhenium(V), ReOBr(hbo)2-  This compound was prepared in a procedure analogous to that for  ReOBr(oz) using [(n-Bu)4N]-[ReOBr ] (150 mg, 0.20 mmol) and Hhbo (86 mg, 0.41 mmol) 2  4  to yield 79 mg (56%). Anal. Calcd (found) for C 2 6 H i 6 B r N 0 R e : C, 44.45 (44.33); H , 2.30 2  5  (2.43); N , 3.99 (3.89); Br, 11.37 (11.19). IR: 1610 (\) =N), 1565 (i)c=c), 1520 (v =c), 1475 C  c  (VC=C), 1430, 1325, 1245, 1165, 970 (\)R=o), 870, 810, 755. EIMS: m/z e  623 [ M O L ] + , 702 [ M O B r L ] . *H N M R ( D M S O - d +  2  2  6  , 400 M H z ) :  = 413 [MOL]+,  6.3-8.3 (series of  overlapping m).  Chlorobis[2-(2' -hydroxyphenyl)-2-oxazolinato]oxotechnetium(V), TcOCl(oz) . To [(n-Bu)4N][TcOCl4] (80 mg, 0.16 mmol) in 40 mL methanol was added 2  Hoz (57 mg, 0.35 mmol). The solution, which quickly turned a dark red color, was refluxed overnight. The volume of methanol was reduced to 5 mL by evaporation under reduced pressure. A crystalline red solid was precipitated by layering hexane above the methanol and storing the solution at 0 °C for a week. Following the removal of hexane, additional product was precipitated by the addition of diethyl ether to the solution. The product was isolated by filtration, washed with ether, and dried in vacuo to yield 40 mg (57%). Anal. Calcd (found) for C i H i C l N 0 T c : C, 45.54 (45.67); H , 3.40 (3.61); N , 5.90 (5.84). 8  6  2  5  IR: 1625 (D =N), 1605 C  (v =c), 1580 (x>c=c\ 1545 (D =c), 1410, 1395, 1255, 1240, 1085, 960 (a) =o), 945, 860. C  C  Tc  L S I M S : m/z = 439 [ M O L ^ + . i H N M R ( C D C 1 , 300 MHz): 4.4-5.4 (m, 8H), 6.5-8.2 (series 2  2  of overlapping m, 8H).  Chlorobis[2-(2' -hydroxyphenyl)-2-thiazolinato]oxotechnetium(V), TcOCl(thoz)2 0.5EtOH. -  In 20 mL ethanol, dried over 4 A molecular sieves, was mixed  Hthoz (38 mg, 0.21 mmol) and [(n-Bu) N] [TcOCl ] (50 mg, 0.10 mmol). Refluxing the dark 4  4  14 red solution for 24 hrs then cooling yielded a red precipitate that was isolated, washed with diethyl ether, and dried in vacuo for 18 hrs to yield 50 mg (72%). Anal. Calcd (found) for C19H19CIN2O3.5TCS2: C, 43.07 (42.89); H , 3.61 (3.93); N , 5.29 (5.20). IR: 1600 (\)C=N), 1575 0) =c), 1555 (\> =c), 1540 ( D = C ) . 1525 (\) =c), 1225, 1045, 970 (v =o), 935, 835. C  C  C  C  Tc  L S M S : m/z = 471 [ M O L ] , 506 [ M O C l L ] . +  +  2  2  Chlorobis[2-(2' -hydroxy-3' -methylphenyl)-2-oxazolinato]oxotechnetium(V), TcOCl(moz) 0.5H O. A solution (15 mL) of [ ( « - B u ) N ] [ T c O C l ] 2  2  4  4  (75 mg, 0.15 mmol) and Hmoz (56 mg, 0.31 mmol) in methanol (15 mL) was refluxed for 24 hours. Red crystals were isolated by filtration, washed with diethyl ether, and dried in vacuo to yield 50 mg (65%). Anal. Calcd (found) for C20H21CIN2O5.5TC: C, 46.94 (46.76); H , 4.14 (3.94); N , 5.47 (5.48). IR: 1630 (O) =N), 1605 (T) =c) 1585 (v =c). 1555 (t) =c), 1425, C  C  c  C  1395, 950 (u =o), 755. LSIMS: m/z = 467 [MOL ]+. Tc  2  Chlorobis[2-(2' -hydroxyphenyl)benzoxazolato]oxotechnetium(V), TcOCl(hbo) -1.5H 0. By mixing [(n-Bu) N][TcOCl ] (60 mg, 0.12 mmol) and Hhbo (54 2  2  4  4  mg, 0.26 mmol) in lOmL of methanol, a red product was isolated in a manner identical to that for TcOCl(thoz) (yield 50 mg, 72%). Anal. Calcd (found) for C26H19CIN2O6.5TC: C , 52.24 2  (52.23); H , 3.20 (2.80);N, 4.68 (4.77). IR: 1600 ( D = N ) , 1530, 1470, 1240, 945 C  650.  (D  T C  =O),  LSIMS: m/z = 325 [MOL]+ 535 [ M O L ] , 570 [MOClL ]+. H N M R (CDCI3, 200  MHz): 6.2-8.3 (series of m).  +  2  l  2  15 2.3  Results and  Discussion  Attempts to prepare tris(ligand) technetium complexes by the addition of two to five equivalents of a reducing agent (sodium dithionite or sodium bisulfite) methanol solution containing  NH4TCO4  48,49  to a basic aqueous  and from three to ten equivalents of Hthoz were not  successful. Over the trials performed, the primary product was invariably the black, insoluble T C O 2 X H 2 O  and no reducedmetal-ligandcomplex was ever isolated.  Combination of two equivalents of ligand with pre-formed rhenium or technetium  MOX4"  cores, (X = Br and CI), respectively led to the synthesis of the neutral M O X L 2 compounds. The green rhenium and red technetium compounds formed were all air stable. Elemental analyses for C, H , and N in all samples, and Br for the Re complexes, were consistent with the formulae proposed. The IR spectra of the M O X L 2 compounds each have a characteristicly strong metaloxo band at 960 to 975 c m for the rhenium complexes and from 945 to 970 for the technetium -1  complexes. The t>c=N band in each complex between 1600 and 1630 c m originates from the -1  double bond in the oxazoline or thiazoline ring found in the ligands of each complex. The \>c~c bands come from the aromatic rings of the ligands. The positive LSIMS mass spectra of all the Re complexes as well as TcOCl(thoz)2 and TcOCl(hbo)2 contained the molecular ion, [MOXL2] ; +  for the rest of the complexes, [ M O L 2 ] was the highest mass peak which could be +  assigned. For all spectra, this [ M O L 2 ] was the parent peak, being of greater intensity than the +  molecular ion. The *H N M R spectra of these complexes were indicative of the two ligands in each complex residing in different chemical environments (ie a cis arrangement). For example, the H N M R spectrum of ReOBr(moz)2 had two triplets and four doublets in the aromatic region l  corresponding to the six different hydrogens on the 2 ' -hydroxy-3' -methylphenyl rings of the two ligands; singlet methyl resonances were at 1.94 and 2.11 ppm. This N M R spectrum indicated that there were one equatorial ligand and one axial ligand bound to the metal. ! H N M R spectra of TcOCl(thoz)2 and TcOCl(moz)2 were consistently of poor quality. O R T E P diagrams of TcOCl(thoz) and ReOBr(oz) are in Figures 2.3 and 2.4, 2  2  respectively. These structures are of discrete complexes without significant intermolecular interactions. Both complexes crystallize in a distorted octahedral configuration having two  16 bidentate ligands and one halide about the metal-oxo centers. In each of these complexes, the • metal atom is located 0.19 A above the equatorial plane formed by the two nitrogens, one oxygen, and one halide atoms. In TcOCl(thoz)2, the Tc(l)-0(3) bond distance is 1.661(3) A, close to the average of 1.65 A for a Tc=0 bond. ' In both compounds, phenolate oxygens are 1 2  trans to the M = 0 bonds. The Tc(l)-0(2) bond length of 1.978(3) A is typical of a T c - 0 bond trans to an oxo group. '  1 2  In the equatorial plane of TcOCl(thoz)2, a second phenolate oxygen  atom, the two nitrogen atoms, and the chloride are coordinated to the metal ion. The thiazoline nitrogen atoms, coordinated cis to one another, have Tc-N bond distances of 2.103(4) and 2.115(3) A which are standard for nitrogens singly bound to T c . ' The 0(3)-Tc(l)-0(2) angle 1  2  of 163.7(1)° is below the ideal of 180° for an octahedral complex.  The Tc=0 linkage  significantly opens up the angles to the equatorial oxygen and chloride atoms (0(3)-Tc(l)-0(l) = 103.0(1)°, and 0(3)-Tc(l)-Cl(l) = 102.6(1)°), but not those to the equatorial nitrogen atoms (0(3)-Tc(l)-N(l) = 86.5(1)° and 0(3)-Tc(l)-N(2) = 89.5(1)°). The 0(1)-Tc(l)-N(l) bite angle of the equatorially coordinated ligand is 89.1(1)°, while the 0(2)-Tc(l)-N(2) bite angle for the axial ligand is 82.2(1)°.  17 Table 2.1  Selected bond lengths (A) and angles (°) in TcOCl(thoz)2.  Bond Lengths Tc(l)-Cl(l)  2.362(1)  0(1)-C(5)  1.332(4)  Tc(l)-0(3)  1.661(3)  C(4)-C(5)  1.405(6)  Tc(l)-0(1)  1.977(3)  C(l)-C(4)  1.462(8)  Tc(l)-0(2)  1.978(3)  S(2)-C(10)  1.751(4)  Tcd)-N(l)  2.103(4)  C(10)-N(2)  1.284(5)  Tc(l)-N(2)  2.115(3)  N(2)-C(12)  1.480(5)  Sd)-C(l)  1.747(4)  C(12)-C(ll)  1.482(6)  C(l)-N(l)  1.296(5)  C(ll)-S(2)  1.790(6)  N(l)-C(3)  1.464(6)  0(2)-C(14)  1.328(4)  C(3)-C(2)  1.471(8)  C(14)-C(13)  1.409(5)  C(2)-S(l)  1.808(6)  C(13)-C(10)  1.464(5)  Bond Angles 0(3)-Tc(l)-Cl(l)  102.6(1)  Cl(l)-Tc(l)-N(2)  86.2(1)  0(3)-Tc(l)-0(l)  103.0(1)  Tc(l)-0(1)-C(5)  125.6(3)  0(3)-Tc(l)-0(2)  163.7(1)  Tc(l)-N(l)-C(l)  124.4(3)  0(3)-Tc(l)-N(l)  86.5(1)  0(1)-C(5)-C(4)  126.1(4)  0(3)-Tc(l)-N(2)  89.5(1)  C(5)-C(4)-C(l)  123.2(4)  Nd)-Tcd)-O(l)  89.1(1)  C(4)-C(l)-N(l)  124.8(4)  N(l)-Tc(l)-0(2)  80.4(1)  Tc(l)-0(2)-C(14)  128.5(2)  N(2)-Tc(l)-0(1)  167.0(1)  Tc(l)-N(2)-C(10)  127.8(3)  N(2)-Tc(l)-0(2)  82.2(1)  0(2)-C(14)-C(13)  121.8(3)  Cl(l)-Tcd)-N(l)  170.88(9)  C(14)-C(13)-C(10)  119.7(3)  Cl(l)-Tc(l)-0(1)  87.58(9)  C(13)-C(10)-N(2)  124.9(3)  Cl(l)-Tc(l)-Q(2)  90.94(9)  18  Figure 2.3 ORTEP diagram of TcOCl(thoz)2 showing the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probablity level.  19 Table 2.2  Selected bond lengths (A) and angles (°) in ReOBr(oz)2.  Bond Lengths Re(l)-Br(l)  2.5804(7)  0(2)-C(5)  1.346(6)  Re(l)-0(5)  1.681(4)  C(5)-C(4)  1.412(8)  Re(l)-0(2)  1.988(4)  C(4)-C(l)  1.482(8)  Re(l)-0(4)  2.013(4)  O(3)-C(10)  1.329(7)  Re(l)-N(l)  2.098(5)  C(10)-N(2)  1.311(8)  Re(l)-N(2)  2.045(5)  N(2)-C(12)  1.499(7)  0(1)-C(1)  1.337(6)  C(12)-C(ll)  1.515(9)  C(l)-N(l)  1.284(7)  C(ll)-Q(3)  1.460(8)  N(l)-C(3)  1.484(8)  0(4)-C(14)  1.327(6)  C(3)-C(2)  1.514(9)  C(14)-C(13)  1.419(8)  C(2)-0(l)  1.442(8)  C(13)-C(10)  1.437(8)  Bond Angles 0(5)-Re(l)-Br(l)  90.7(1)  Br(l)-Re(l)-0(4)  169.7(1)  0(5)-Re(l)-0(2)  170.8(2)  Re(l)-0(2)-C(5)  136.7(4)  0(5)-Re(l)-0(4)  98.5(2)  Re(l)-N(l)-C(l)  130.3(5)  0(5)-Re(l)-N(l)  90.9(2)  0(2)-C(5)-C(4)  121.0(6)  0(5)-Re(l)-N(2)  99.5(2)  C(5)-C(4)-C(l)  119.2(5)  N(l)-Re(l)-0(2)  81.5(2)  C(4)-C(l)-N(l)  126.4(6)  N(l)-Re(l)-0(4)  85.9(2)  Re(l)-0(4)-C(14)  127.9(4)  N(2)-Re(l)-0(2)  88.3(2)  Re(l)-N(2)-C(10)  125.5(4)  N(2)-Re(l)-0(4)  90.0(2)  0(4)-C(14)-C(13)  125.3(6)  Br(l)-Re(l)-N(l)  89.3(1)  C(14)-C(13)-C(10)  122.5(5)  Br(l)-Re(l)-N(2)  93.2(1)  C(13)-C(10)-N(2)  127.8(6)  Br(l)-Re(l)-0(2)  84.0(1)  20  H10  Figure  2.4  ORTEP diagram of ReOBr(oz)2 showing the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probablity level.  21 Comparison of the bond lengths and bond angles of Hthoz with the ligand thoz" in 47  TcOCl(thoz)2 shows that there are small changes upon complexation. A l l bond lengths among carbon, nitrogen and sulfur atoms remain within 0.02 A of Hthoz upon complexation to Tc, with the exception of C(2)-C(3) in the thiazoline ring which decreases from 1.522(3) A in Hthoz to 1.471(8) in the equatorial and 1.482(6) A (C(ll)-C(12)) in the axial ligands. The  angles  through the chelate ring portion of Hthoz (0(1)-C(5)-C(4) = 122.1(2)°, C(5)-C(4)-C(l) = 120.0(1)°, and C(4)-C(l)-N(l) = 122.5(1)°) increase in value upon complexation of the equatorial ligand (126.1(4)°, 123.2(4)°, and 124.8(4)°, respectively); in the axial ligand the corresponding values are 121.8(3)°, 119.7(3)°, and 124.9(3)°. This suggests that there is more strain in the equatorial ligand because there are greater deviations from the ideal bond angles of 120° for sp  2  hybridized carbon atoms in the equatorial ligand.  Orthogonal  coordination of the ligands and the cis orientation of the complexed nitrogen atoms about the technetium  center  is  identical to  the  coordination  of the  bidentate  hydroxyphenyl)benzothiazolato (hbf) ligand in the bis(ligand) complex, TcOCl(hbt)2.  2-(2 ' -  22  The crystal structure of ReOBr(oz)2 shows that one ligand coordinates in the equatorial plane with respect to Re=0, while the second ligand has its phenolate oxygen atom bound axially and its oxazoline nitrogen atom bound equatorially with respect to the oxo bond. The Re=0 bond distance is Re(l)-0(5) = 1.681(4) A, typical for a rhenium oxygen double bond.  50  The  Re(l)-0(2) bond length of 1.988(4) A is consistent with the trans influence for an oxygen from an axially bound ligand trans to the Re=0 linkage. In the equatorial plane, the two bound nitrogens coordinate trans to one another (Re(l)-N(l) = 2.098(5) A and Re(l)-N(2) = 2.045(5) A), while the bromide is trans to the equatorial coordinated oxygen (Re(l)-0(4) = 2.013(4) A). The bond angles show that the rhenium complex is closer to a perfectly octahedral complex than the technetium species (for example, 0(5)-Re(l)-0(2) = 170.8(2)°). With an 0(4)-Re(l)-N(2) bite angle of 90.0(2)° for the equatorial ligand and a 0(2)-Re(l)-N(l) angle of 81.5(2)°, the axial and equatorial ligands in ReOBr(oz)2 and TcOCl(thz)2 have very similar bite angles. In conclusion, bis(ligand) rhenium and technetium complexes of ligands containing naturally occurring binding groups derived from siderophores have been prepared and  22 characterized. The crystal structures of the rhenium and technetium complexes show that the two ligands in each complex coordinate in a different orientation to each other. Curiously, we were unsuccessful in preparing tris(ligand) Tc complexes by reduction from pertechnetate, the thermodynamically favoured  T C O 2 X H 2 O  being formed instead.  23 Chapter 3.  Synthesis and Characterization of Bis(ligand)oxovanadium and -molybdenum complexes as Potential Insulin Mimics.  3.1  Introduction This work involves the synthesis of five vanadium complexes with the ligands picolinic  acid and maltol and one molybdenum complex of maltol in order to further the study of potential insulin mimetic effects. Picolinic acid, or pyridine-2-carboxylic acid, is an 0 , N donor, while maltol is a pyrone which has been shown to bind to metals with oc-hydroxyketone donor atoms (ie. an 0 , 0 donor). Upon chelation, these ligands form five membered rings. It is with these naturally occurring binding moieties that bis(ligand) V 0  2 +  , V0  3 +  , VC>2 , and M0O2 " +  24  complexes have been investigated. O  Picolinic Acid Figure 3.1  O  Maltol  Ligands used in this study (see text).  Picolinic acid is found in humans as a metabolite of the amino acid tryptophan. Although potentiometric titrations of vanadium are often complicated by the redox activity of this metal, stable complexes with vanadium are formed as evidenced by its stability constants: log K i = 6.68 and log K2 = 5.31.  51  This ligand has also been tested on humans as a biological carrier of  chromium by oral ingestion of Cr(pic)3 for the treatment of hyperlipidemia.  52  Diperoxo  monopicolinate complexes of vanadium, namely K2[VO(C>2)2(pic)] and K2[VO(02)2(3hydroxypyridine-2-carboxylato)] have been synthesized and tested for insulin mimetic effects at M c G i l l University.  53  24 Biological  studies  from  a collaboration at  U.B.C.  have  bis(maltolato)oxovanadium(IV), VO(ma)2, is an effective insulin mimic. extensive examination of the chemistry of VO(ma)2 in this laboratory.  V0  2 +  + 2Hma  pH = 8.5 py  VO(ma) py\ 0 /MeOH  3  2  HoO  2  r  H  • V0 (ma) ' 2  +  2  /MeOH  0 / MeOH 2  2  35  0 /H 0 2  This has led to an  V 0 - + 2Hma  -VO(ma) ^= " ^ ° H or  2  54  indicated that  VO(ma) (OMe) 2  Scheme 3.1  Reaction scheme of Vanadium-maltolate complexes.  35  The compounds VO(ma)2, VO(ma)2(OMe), and K[V0 (ma)2] have all been characterized 2  by a variety of techniques including X-ray crystallography. 35  55  The interconversion of  VO(ma)2 and K[V02(ma)2] in water and the reaction of each complex in methanol to form the alkoxide, VO(ma)2(OMe) is represented in Scheme 3.1 To further our understanding of this system, V O ( m a ) 2 ( O C H C H O H ) , an analogue of VO(ma) (OMe), and M o 0 2 ( m a ) , a 2  2  2  2  compound similar to K[V02(ma)2], but of neutral charge, have been synthesized and characterized. The high valent chemistry of vanadium and molybdenum is similar. In vitro studies 56  have determined that vanadate, molybdate, and tungstate all activate a 53 kDa enzyme from rat adipocytes, the cytosolic protein tyrosine kinase (cytPTK),  57  which further activates several  insulin mimetic effects. Recently, permolybdate and pertungstate have been tested for their insulin mimetic properties.  58  If the insulin mimetic effects are due to phosphate mimicking by  vanadate, then M 0 O 4 " may act similarly. Mo02(ma)2 is a good compound to test this 2  hypothesis.  25 3.2  Synthesis and  Characterization  Materials and Methods A l l chemicals were reagent grade and were used without further purification. Water was deionized (Barnstead D8902 and D8904 cartridges) and distilled (Corning MP-1 Megapure Still) before use. VO(ma)2 was synthesized by a procedure developed in this laboratory. VOSO43H2O was obtained from Aldrich, NH4VO3 and picolinic acid from 35  Sigma, maltol from Sigma or Pfizer, Na2Mo04'2H20 from Mallinckrodt, and 30% H2O2 from Fisher. Instrumentation. E A , *H N M R , IR and M S instrumentation are as reported in Chapter 2.  5 1  V N M R spectra were recorded on a Varian XL-300 spectrometer operating at  78.864 M H z with a pulse width of 12 (is and a spectral window of 100 kHz, and are referenced to neat VOCI3. Room temperature (293 °K) magnetic susceptibilities were measured on a Johnson-Matthey magnetic susceptibility balance, using Hg[Co(NCS) ] as the susceptibility 4  standard; diamagnetic corrections were estimated by using Pascal's constants.  Oxobis(picolinato)vanadium(IV)  monohydrate,  VO(pic)2(H20).  To  1.069 g (8.68 mmol) picolinic acid in 20 mL water, 0.930 g (4.28 mmol) V O S 0 - 3 H 0 in 20 4  2  mL water was added. The pH was raised from less than 2.5 to 4.4 with dropwise additions of 2 M NaOH. The light blue material that precipitated was isolated by filtration, washed with methanol and ether, and dried in vacuo for a yield of 0.773 g (58% based on V). Anal. Calcd (found) for C i H i N 2 O V : C, 43.79 (43.46); H , 3.06 (3.15); N , 8.51 (8.62). IR (cm" , K B r 1  2  6  0  disk): 3400-3500  (DOH);  1640, 1630, 1600, 1570 (\) =N and \)c=c); 980, 970 (\>v=o). C  LSIMS: m/z = 157 [VOL]+, 312 (M+, [VOL ]+). The solid state magnetic moment was 1.75 2  B M . EPR (RT, H 0 ) : 8-line pattern. Solubility in aerobic water = 3 m M at 60 °C. 2  Ammonium  dioxobis(picolinato)vanadate(V)  dihydrate,  NH [V02(pic)2]-2H20. To a slurry of 0.800 g (6.84 mmol) N H 4 V O 3 in 5 mL water, 4  1.690 g (13.7 mmol) picolinic acid in 3 mL water was added to form a clear yellow solution that was stirred overnight then placed in a fridge for two days. Addition of 50 mL acetone, with  26 stirring, formed yellow crystals that were isolated on a frit and air dried with a yield of 2.043 g (87% based on V). X-ray quality crystals were obtained by recrystallizing the product from water/acetone. Anal. Calcd (found) for C i 2 H i 6 N 0 V : C, 37.81 (38.44); H , 4.23 (4.16); N , 3  11.02 (11.13). IR (cm- , K B r disk): 3400-3500 1  UC=C);  8  (\)OH);  1650, 1640, 1630, 1600 (\) =N and C  920, 890 Cuv=o)- -LSIMS: m/z = 313 [VOL +2]-, 329 [ V 0 L + 2 ] - , 346 (M"+l, 2  [NH4VO2L2+I]-).  5 1  2  2  V N M R ( D 0 ) : -515, -554 ppm. The compound is diamagnetic. 2  Bis(maltolato)oxo(pyridine)vanadium(IV),  VO(py)(ma)2*0.25H2O.  VO(ma) (0.28 g, 0.88 mmol) was dissolved in neat pyridine (2 g, 25 mmol) left to stand for 2  two days. Addition of 20 mL diethyl ether followed by vigorous shaking of the solution led to precipitation of a brown solid, which was isolated by filtration and washed with 20 mL diethyl ether and dried in vacuo to yield a brown powder (0.21 g, 61% based on V ) . Anal. Calcd (found) for C 1 7 H 1 5 . 5 N O 7 . 2 5 V : C, 50.95 (50.98); H , 3.83 (3.90); N , 3.47 (3.50). IR (cm" , 1  K B r disk): 1580 (v =o), 975 (v =o). LSIMS: m/z = 317 [VOL ]+, 398 [ V O L p y + l ] . The +  c  v  2  2  solid state magnetic moment was 1.75 B M .  Bis(maltolato)methoxyoxovanadium(V),  cis-VO(OCH3)(ma)2.  Brown  VO(py)(ma)2 (0.16 g, 0.4 mmol) was dissolved in 30 mL methanol, the clear red solution was stirred in air for two days, and the volume was subsequently reduced to 5 mL by rotary evaporation. Following the addition of 25 mL diethyl ether, the solution was stored at 5 °C for a week. The bright red precipitate was isolated, washed with diethyl ether, and dried in vacuo to yield 0.048 g (34 % based on V). IR (cnr , K B r disk): 1620, 1550, 1480 (\) =o and Dc=c), 1  C  975 (\>v=o)- LSIMS: m/z = 317 [ V O L ] . *H N M R (CD3OD, 200 MHz): 2.45 (s, 6H), 3.34 +  2  (s, 3H), 6.45 (d, 2H, J = 5.5 Hz), 8.18 (d, 2H, J = 5.5 Hz). Sly N M R : -421 ppm (MeOH). 2  2  The compound is diamagnetic.  (2-Hydroxyethoxy)bis(maltolato)oxovanadium(V), VO(ma)2(OCH CH OH). To 0.317 g (5.11 mmol) ethylene glycol in a 50 mL benzene/5 2  2  27 mL acetonitrile solution was added 3.240 g (10.2 mmol) VO(ma)2- To this solution was added 0.341 g (3.0 mmol) of 30% H2O2 turning the solution a dark red colour. B y allowing the solvent to evaporate slowly, crystals suitable for X-ray analysis were obtained.  5 1  V N M R : -426  ppm (reaction solution).  Bis(maltolato)dioxomolybdenum(VI), Mo02(ma)2«  To 1.26 g (10 mmol) of  maltol in 50 mL of acetone, 1.21 g (5mmol) Na2Mo04-2H20 in 25 mL of 5% HC1 was added which immediately turned the solution yellow. After ten minutes stirring, the yellow material that had precipitated was isolated and washed with 40 mL EtOH. The product (0.96 g, 50% yield based on Mo) was dried at 50 °C for three hours. Recrystallization from CH^CVpentane yielded crystals suitable for X-ray analysis. Anal. Calcd (found) for C^H-inMoOg: C, 38.12 (38.07); H , 2.67 (2.67). IR (cm" , K B r disk): 3040 (DC-H); 1625 (\)c=o); 945, 910 (u o=o)- LSIMS: 1  M  m/z = 255 [Mo0 L]+, 364 [ M o O L ] , 381 (M++1, [ M o 0 L + l ] + ) . H N M R (CDCI3, 200 +  2  2  !  2  2  M H z ) 2.51 (s, 6H), 6.62 (d, 2H, 2j = 7.6 Hz), 7.94 (d, 2H, 2j = 7.6 Hz). The compound is diamagnetic.  28 3.3  Results and Discussion With the intent to further understand the vanadium-maltol system, two analogues  containing the picolinate anion were formed: VO(pic)2(H20) and NH4[V02(pic)2]-2H20. Because the pKa's of the deprotonated carboxylic oxygen donor (pKa = 1.03) and pyridinium 59  nitrogen donor (pKa = 5.21) of picolinic acid are much lower than the p K a of the hydroxyl 59  group on maltol (pKa = 8.38) , the pH of the complexation reaction of the vanadyl ion with two 59  equivalents of the ligand requires the pH to be raised to 8.5 in the synthesis of VO(ma) , while 2  the pH need only be raised to 4.4 in the preparation of VO(pic)2(H20). The mixing of the V(V) starting material N H 4 V O 3 with two equivalents of picolinic acid in water formed a clear yellow solution containing the [V02(pic)2]" anion. Acetone was required to precipitate this compound as its ammonium salt because its water solubility is high (> 0.1 M ) . VO(pic)2(H20) has an aerobic water solubility of 3 m M compared to approximately 11 m M for VO(ma)2- Dissolution of the former in common organic solvents, such as acetone or methanol, produces a clear green solution most probably due to the anhydrate VO(pic)2- Solvent and vapour diffusion methods were tried in an effort to obtain X-ray quality crystals of VO(pic)2, with no success. As the biological experiments with VO(pic) (H.20) (described in the appendix) involved dissolving this 2  compound in water, it is clear that it is the monohydrate species that is present during vanadium treatment, so no further attempts were made to isolate the anhydrous complex, although the synthesis of VO(pic)2 from VO(pic)2(H20) by heat treatment has been reported (characterized only by elemental analysis).  60  VO(pic)2(H20) has a d electronic configuration consistent with a magnetic susceptibility 1  of 1.75 B M . Also, considering that vanadium has a nuclear spin of I = 7/2, the eight line EPR spectrum observed confirms the +4 oxidation state of the metal in VO(pic) (H 0). 2  2  The IR spectrum of VO(pic)2(H 0) contains a broad peak from 3300 to 3500 cm"  1  2  attributed to the \)(0-H) of the complexed water molecule and the  i)(C=N)  band at 1640 c m is - 1  from the aromatic coordinating nitrogens. Instead of a single i)(v=0) band, as expected for a pure monooxovanadium(IV) compound, there is a sharp band that has two distinct peaks at 970 and 980 cm" . The two peaks seen may really be one peak split as a solid-state effect in the K B r 1  29 pellet. The hydrated water and ammonium ion of NH4[V02(pic)2]-2H20 have characteristic D(0H) and \)(N-H) bands in the IR spectrum. Peaks attributed to the symmetric and asymmetric i)v=0 stretching frequencies of the d s - V 0 2 moiety are at 875 and 920 c m . +  -1  The mass spectrum of the V(IV) compound has a peak for VO(pic)2 and peaks such as [VO(pic)2]2-pic at m/z = 500, that can be assigned to dimers and trimers formed in the spectrometer  during the analysis.  The mass spectrum of the V ( V ) compound,  NH4[VC»2(pic)2]-2H20, contains a [VO(pic)2]+l peak which is greater in intensity than the [V02(pic)2]+2 peak. Both the *H and  5 1  V N M R spectra of VO(pic)2 contain broad signals,  which are indicative of a paramagnetic  species.  The ! H N M R spectrum  of  NH4[V02(pic)2]-2H.20 shows a singlet at 4.65 ppm due to the ammonium ion and a series of broad peaks from 7.4 to 8.8 ppm due to the aromatic hydrogen resonances. The  5  1  V NMR  spectrum of NH4[VC>2(pic)2]-2H20 (0.1M in H2O) shows a peak at -545 ppm, which is attributed to free vanadate. Based on picolinic acid:metavanadate titration data by Galeffi and Tracey,  61  the peaks at -516 and -554 ppm can be tentatively assigned to octahedral and  pentacoordinate bis(picolinato)vanadium complexes, respectively. The two species assigned in the  5 1  V N M R spectrum may be fluxional, which explains the broad peaks in the aromatic region  of the H N M R spectrum. l  The [V0 (pic) ]- anion consists of a cis-V0 2  2  + 2  center (V(l)-0(5)=1.637(2) A and V ( l ) -  0(6)= 1.638(2) A) with the two picolinate ligands bound with an interplanar angle of 97.25°. The two oxo groups, one hydrogen bonded to an ammonium ion and the second hydrogen bonded to a water molecule, along with the metal center, create a 0(5)-V(l)-0(6) angle of 104.3(1)°, which is typical of other 0 = V = 0 angles.  34  Trans to the ammonium hydrogen  bonded oxo group 0(6) is an oxy group of one picolinate anion 0(3). The nitrogen donor from this ligand N(2) is trans to the carboxylic oxygen donor of the second ligand 0(1). The water hydrogen bonded oxo group is trans to the aromatic nitrogen of the second picolinate molecule. The V(l)-0(3) bond is significantly longer than the V(l)-0(1) bond due to the structural trans influence. For the same reason, the V(l)-N(l) bond is much longer than the V(l)-N(2) bond.  30 The cis-V02  unit can be compared to the structure of the carboxylato group in that they  +  both react with alcohols to form esters.  34  The two oxo groups are each free to bind to an  ammonium ion and a water molecule. The V(l)-0(5) and V(l)-0(6) bond distances (1.637(2) A and 1.638(2) A, respectively) are only slightly greater than the V = 0 bond length of an uncoordinated cis-Y02  +  show that the cis-V02  +  Figure 3.2  oxo group. . A pictoral comparison of these two groups helps to 34  unit is quite analogous to a carboxylate group.  Comparison of carboxylato and cw-VC>2 groups. +  31 Table 3.1  Selected bond lengths (A) and angles (°) in NH V02(pic) -2H20 4  2  Bond Lengths V(l)-0(1)  1.989(2)  0(1)-C(6)  1.288(4)  V(l)-0(3)  2.125(3)  0(3)-C(12)  1.284(4)  V(l)-0(5)  1.637(2)  N(l)-C(l)  1.341(3)  V(l)-0(6)  1.638(2)  N(2)-C(7)  1.344(3)  V(l)-N(l)  2.314(2)  C(l)-C(6)  1.493(4)  V(l)-N(2)  2.126(2)  C(7)-C(12)  1.503(4)  Bond Angles 0(l)-V(l)-0(3)  85.34(8)  0(5)-V(l)-N(2)  97.96(10)  0(l)-V(l)-0(5)  96.41(9)  0(6)-V(l)-N(l)  87.11(10)  0(l)-V(l)-0(6)  104.40(10)  0(6)-V(l)-N(2)  90.42(9)  0(1)-V(1)-N(1)  74.06(8)  N(l)-V(l)-N(2)  88.34(8)  0(1)-V(1)-N(2)  156.10(9)  V(l)-0(1)-C(6)  124.5(2)  0(3)-V(l)-0(5)  93.67(9)  V(l)-0(3)-C(12)  119.6(2)  0(3)-V(l)-0(6)  158.22(9)  V(l)-N(l)-C(l)  111.4(2)  0(3)-V(l)-N(l)  76.75(8)  V(l)-N(2)-C(7)  116.7(2)  0(3)-V(l)-N(2)  74.79(8)  0(1)-C(6)-C(1)  115.4(2)  0(5)-V(l)-0(6)  104.4(1)  N(2)-C(7)-C(12)  114.6(2)  0(5)-V(l)-N(l)  166.82(10)  0(3)-C(12)-C(7)  113.8(2)  32  Figure 3.3  ORTEP diagram of NH4[V02(pic)2]-2H20 showing the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level.  33 The d V(IV) complex VO(ma)2(py)-0.25H2O was easily prepared by the reaction of 1  VO(ma)2 with pyridine for one week. The product precipitated following addition of diethyl ether; the brown powder was characterized by IR spectroscopy, M S , and elemental analysis. The mass spectrum has peaks at m/z = 398 and 317 attributed to VO(ma)2(py)+l and VO(ma)2, respectively. The single D(v=0) band at 975 c m and the good elemental analysis are indicative -1  of a pure compound. Dissolution of VO(ma)2 or NH4[VC<2(ma)2)]-H20 in methanol, ethanol, or isopropanol forms the alkoxide complexes VO(ma)2(OMe), VO(ma)2(OEt), and VO(ma)2(Oi-Pr), respectively.  35  It has been observed that the longer the length of the alkyl chain of the alcohol,  the slower the reaction time to form the VO(ma)2(OR) complexes. Adding 3-6 equivalents of H2O2 to the reaction mixture has been found to increase the reaction time enormously. A second method for the synthesis of VO(ma)2(OMe) involves dissolution of VO(ma)2(py)-0.25H2O in aerobic methanol. It is notable that by visual inspection of the red colour formed in the synthesis of VO(ma)2(OMe), the reaction starting from VO(ma)2 is faster than starting from VO(ma)2(py) 0.25H.2O. -  This is one  example  of a method  stabilizing a  bis(maltolato)oxovanadium(IV) complex in the 44 oxidation state. The complex was precipitated by the addition of diethyl ether. This red crystalline product had a satisfactory elemental analysis and identical spectroscopic data (IR, H N M R , l  reaction of. VQ(ma)2 in aerobic methanol.  35  5 1  V N M R ) as VO(ma) (OMe) formed from the 2  The room temperature H N M R shows one set of !  signals due to the two maltol ligands residing in a single chemical environment.  A low  temperature (-50 °C) K N M R experiment by others in this research group showed two different l  ligand environments indicating a cw-VO(OMe) arrangement.  To  35  synthesize  another  bis(maltolato)oxovanadium(V) alkoxide, one equivalent of ethylene glycol was mixed with two equivalents of VO(ma)2 and 0.6 equivalents of H2O2 in an attempt to synthesize a dimer V(V) complex, [(ma)20V-|i-OCH2CH20-VO(ma)2j.  The combination of 10:1 benzene (as the  precipitating solvent) to acetonitrile (as the reaction solvent) was chosen as these solvents have boiling points within 2 °C of one another, and upon slow evaporation of solvent, the ratio of benzene to acetonitrile will remain approximately the same.  5 1  V N M R spectroscopy of a six  34 hour old reaction solution showed a single peak at -426 ppm. which is in a range similar to VO(ma)2(OMe) (-421 ppm).  35  Evaporation of the solvent led to the formation of red crystals in  an oil at the bottom of a reaction vial. Circumstances permitted that the only characterization method for this product was X-ray crystallography, which showed that the product was VO(ma)2(OCH2CH20H). Further attempts to make this monomer by reacting VO(ma)2 with excess H2O2 in neat ethylene glycol were unsuccessful.  Table 3.2  Selected bond lengths (A) and angles (°) in VO(ma)2(OCH2CH20H).  Bond Lengths V-O(l)  1.56(2)  0(2)-C(l)  1.26(3)  V-0(2)  2.09(2)  0(3)-C(6)  1.35(3)  V-0(3)  1.96(2)  0(4)-C(7)  1.21(3)  V-0(4)  2.27(2)  0(5)-C(12)  1.36(3)  V-0(5)  1.89(2)  C(l)-C(6)  1.44(3)  V-0(8)  1.76(2)  C(7)-C(12)  1.33(3)  Bond Angles 0(l)-V-0(2)  95.5(8)  0(4)-V-0(5)  77.0(7)  0(l)-V-0(3)  99.8(9)  0(4)-V-0(8)  86.2(8)  0(l)-V-0(4)  170.9(8)  0(5)-V-0(8)  102.6(7)  0(l)-V-0(5)  95.1(8)  V-0(2)-C(l)  113(2)  0(l)-V-0(8)  100.2(8)  V-0(3)-C(6)  118.50(15)  0(2)-V-0(3)  78.0(7)  V-0(4)-C(7)  106(2)  0(2)-V-0(4)  79.5(7)  V-0(5)-C(12)  117.10(15)  0(2)-V-0(5)  85.6(7)  V-0(8)-C(13)  131(2)  0(2)-V-0(8)  161.5(8)  0(2)-C(l)-C(6)  120(2)  0(3)-V-0(4)  86.7(7)  0(3)-C(6)-C(l)  111(2)  35 0(3)-V-0(5)  158.8(7)  0(4)-C(7)-C(12)  123(3)  •0(3)-V-0(8)  89.8(8)  0(5)-C(12)-C(7)  116(2)  Figure 3.4  ORTEP diagram of VO(ma) (OCH2CH20H) showing the crystallographic 2  numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level.  36 The crystals of VO(ma)2(OCH2CH20H) were small and diffracted weakly. Only 517 reflections out of 2733 symmetry independent data measured were considered observed and were included into the least-squares refinement.  62  Only the atoms of the vanadyl unit, V and 0(1),  were refined with anisotropic thermal parameters. The geometry around the vanadium atom is nearly identical to that in V0(ma)2(0Me). The alkoxide unit is coordinated cis to the oxo bond. Although the data for the hydrogen atoms were not refined, the 0(l)-0(9) bond distance is 3.76(9) A and the location of these two atoms indicates a hydrogen bond between the hydrogen bound to 0(9) and O(l). The V-O(l) oxo bond is 1.56(2) A, relatively short for a V = 0 bond. The angle formed between the oxo bond, the vanadium atom and the ethylene glycol oxy atom is (0(l)-V-0(8)) 100.2(8)°. The two oxy-vanadium bonds are located trans to one another and have similar lengths (V-0(3) = 1.96(2) A, V-0(5) = 1.89(2) A).  It is the two dative bonds  between the oxo groups of the pyrones to the vanadium center that show variance. The 2.09(2) A V-0(2) bond trans to the alkoxide is significantly shorter than the 2.27(2) A V-0(4) bond. The greater distance of the V-0(4) bond with respect to the other maltol-vanadium bonds can be attributed to the structural trans influence. The synthesis of Mo02(ma)2 was done as previously performed in the synthesis of Mo02(8-hydroxyquinolinato)2.  63  The IR spectrum of Mo02(ma)2, which contains two double  bonded terminal oxygens (Mo=0), showed symmetric and asymmetric stretching frequencies due to the ds-dioxomolybdenum(IV) unit at 945 and 910 c m , respectively. The H N M R -1  l  spectrum of Mo02(ma)2 showed that the methyl protons and the protons on the pyrone ring are more deshielded with respect to those of the free ligand than are those of NH4[V02(ma)2]H20. With an 06 donor set, the Mo02(ma)2 molecule has an approximately octahedral coordination geometry and C symmetry. The ds-oxo atoms are bound with a 0(4)-Mo(l)2  0(4)' bond angle of 104.5(1)°, very similar to the 0=V=0 angle in NH [V0 (pic)2]-2H 0. The 4  2  2  hydroxy groups from the maltol ligands lie trans to one another, while the ketone donor from each ligand lies trans to an oxo bond. The coordination of the ligands is identical as that in K[V0 (ma) ]. 2  2  37  Table 3.3  Bond lengths (A) and angles (°) in Mo02(ma)2.  Bond Lengths Mo(l)-0(2)  1.994(1)  Mo(l)-0(3)  2.243(1)  Mo(l)-0(4)  1.696(1)  0(1)-C(2)  1.363(2)  0(1)-C(5)  1.348(3)  0(2)-C(3)  1.336(2)  0(3)-C(4)  1.257(2)  C(l)-C(2)  1.475(3)  C(2)-C(3)  1.353(2)  C(3)-C(4)  1.436(2)  C(4)-C(5)  1.427(3)  C(5)-C(6)  1.331(3)  Bond Angles 0(2)-Mo(l)-0(2)'  155.46(8)  0(2)-Mo(l)-0(3)  75.11(5)  0(2)-Mo(l)-0(3)'  85.95(5)  0(2)-Mo(l)-0(4)  103.41(6)  0(2)-Mo(l)-0(4)*  91.61(6)  0(3)-Mo(l)-0(3)'  79.17(8)  0(3)-Mo(l)-0(4)  89.29(7)  0(3)-Mo(l)-0(4)'  162.86(6)  0(4)-Mo(l)-0(4)'  104.5(1)  C(2)-0(l)-C(6)  119.9(2)  Mo(l)-0(2)-C(3)  118.68(10)  Mo(l)-0(3)-C(4)  112.4(1)  0(1)-C(2)-C(1)  114.1(2)  0(1)-C(2)-C(3)  119.7(2)  C(l)-C(2)-C(3)  126.2(2)  0(2)-C(3)-C(2)  122.8(2)  0(2)-C(3)-C(4)  115.8(1)  C(2)-C(3)-C(4)  121.4(2)  0(3)-C(4)-C(3)  117.1(2)  0(3)-C(4)-C(5)  126.8(2)  C(3)-C(4)-C(5)  116.1(2)  C(4)-C(5)-C(6)  118.9(2)  0(1)-C(6)-C(5)  124.0(2)•  38  Figure  3.5  ORTEP diagram of Mo02(ma)2 showing the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level.  39 Chapter 4  Conclusions and Suggestions for Future W o r k .  This work consists of the synthesis of bis(ligand)oxorhenium, -oxotechnetium, -oxovanadium, and -dioxomolybdenum complexes. The reduction route of technetium complex synthesis was attempted, but only the substitution route was used successfully to prepare pure rhenium and technetium compounds. Although the stability constants between bidentate oxazolines and technetium would be of interest, the redox activity and hydrolysis of this metal makes potentiometric titrations impossible. To determine if the complexes formed between the oxazoline and thiazoline containing ligands and 99mj  cn a v e  favourable biodistribution properties  for imaging purposes, some in vivo studies should be done. Modification of the Hoz backbone has been performed in this lab and complexes of such ligands may have favourable biodistribution. Potentially tetradentate, pentadentate, and hexadentate ligands formed in the condensation of 2-(2' -hydroxyphenyl)-2-thiazoline-4-carboxylic acid with the amine backbones ethylenediamine, diethylenetriamine, tren, and tame have been prepared in this group and their 64  complexes with rhenium and technetium should be more stable than those of Hthoz due to the chelate effect. The vanadium complexes of picolinic acid reported herein were synthesized in an effort to fully understand the vanadium-maltolate system because VO(ma)2 is an effective insulin mimic. Subsequently, it was determined that VO(pic)2(H20) also has insulin mimetic properties (see Appendix). Studies are presently underway to determine the biodistribution of VO(ma)2 using the y-emitting isotope  4 8  V . Synthesis of lipophilic tetradentate and pentadentate ligands  containing the bidentate picolinic acid and maltol binding moieties could produce other oxovanadium complexes that are insulin mimetic. Recently it has been shown that W O 4 - has 2  insulin mimetic effects and it has been speculated that M 0 O 4 - does too. The compound 2  Mo02(ma) may prove to have blood glucose lowering ability. Animal studies of this compound 2  and its third row congener, W02(ma)2, would be of interest.  40 References  (1)  Deutsch, E.; Libson, K.; Jurisson, S.; Lindoy, L . F. Prog. Inorg. Chem. 1983, 30, 75.  (2)  Clarke, M . J.; Podbielski, L. Coord. Chem. Rev. 1987, 78, 253.  (3)  Clarke, M . J.; Fackler, P. H . Structure and Bonding 1982, 50, 57.  (4)  Schwochau, V . K . Naturforsch 1962,17a, 630.  (5)  McDonald, B . J.; Tyson, G. J. Acta Cryst. 1962,15, 87.  (6)  Krebs, B.; Hasse, K . D. Acta Crystallogr. Sect. B 1976, 25, 925.  (7)  Cotton, F. A.; Davison, A.; Day, V . W.; Gage, L . D.; Trop, H . S. Inorg. Chem. 1979, 18, 3024.  (8)  Thomas, R. W.; Davison, A.; Trop, H . S.; Deutsch, E . Inorg. Chem. 1980,19, 2840.  (9)  Krebs, B . Z. Anorg. Allg. Chem. 1971, 380, 145.  (10)  Peacock, R. 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Inorg. Chem. 1984, 23, 2962.  (22)  Wilcox, B . E.; Cooper, J. N . ; Elder, R. C ; Deutsch, E . Inorg. Chim. Acta. 1988,142, 55.  (23)  Liu, S.; Rettig, S.; Orvig, C. Inorg. Chem. 1991, 30, 4915.  41 (24)  Render, D. Biometals 1992, 5, 3.  (25)  Rehder, D. Angew. Chem. Int. Ed. Engl. 1991, 30, 148.  (26)  deBoer, E.; Weaver, R. / . Biol. Chem. 1988, 263, 12326.  (27)  Smith, B . E.; Eady, R. R.; Lowe, D. J.; Gormal, C. Biochem J. 1988, 250, 299.  (28)  Nechay, B . R. Ann. Rev. Pharmacol. Toxicol. 1984, 24, 501.  (29)  Schwarz, K.; Milne, D. B . Science 1971,174, 426.  (30)  Chasteen, N . D., Ed. Chapterl. Vanadium in Biological Systems; Kluwer Academic Publishers: Dordrecht, 1990.  (31)  Kustin, K.; Toppen, D. L . J. Am. Chem. Soc. 1973, 95, 3564.  (32)  Boyd, D. B . ; Kustin, K. Adv. Inorg. Biochem. 1984, 6, 312.  (33)  Chasteen, N . D.; Grady, J. K.; Holloway, C. E. Inorg. Chem. 1986, 25, 2754.  (34)  Giacomelli, A . ; Floriani, C ; Duarte, A . O. d. S. Inorg. 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Ph.D. thesis, University of British Columbia, 1993.  44 Appendix  The insulin mimetic effects of the vanadyl ion and bis(maltolato)oxovanadium(IV), VO(ma)2, have been previously mentioned in Chapter 1. The Orvig research group, in conjunction with Dr. J.H. McNeill's group in the Faculty of Pharmaceutical Sciences at U.B.C., has also tested the feasibility of using oxobis(picolinato)vanadium(IV) hydrate as a insulin mimicking agent which could be absorbed more effectively than VOSO4 or VO(ma)2 from the gastrointestinal tract thereby reducing the dose of vanadium needed to produce blood glucose lowering effects. Treatment of streptozotocin (STZ) induced diabetic rats with VO(pic)2(H/20) was either by administration in the drinking water (at an initial concentration of 0.5 mg/mL, which was later increased to 0.75 mg/mL) or by intraperitoneal (i.p.) injection at a dose of 0.06 mmol/kg. Treatment of VO(pic)2(H20) in the drinking water resulted in 38% of diabetic rats responding with significant lowering of plasma glucose. Treatment with VO(pic)2(H20) by intraperitoneal injection produced significant lowering of plasma glucose within 2 hours. The peak lowering effect occured at 8 hours and hyperglycemia returned within 24 hours of administration. In conclusion, treatment with VO(pic)2(H20) was able to mimic the actions of insulin by lowering plasma glucose levels, but was less effective than either VOSO4 or VO(ma)2.  

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