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Oxorhenium(v) and osotechnetium(v) complexes with tetra- and hexadentate polyaminopyridyl molecules Pierreroy, Jason T. 1997

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OXORHENIUMfV) AND OXOTECHNETIUMfV) COMPLEXES WITH TETRA- AND HEXADENTATE POLYAMINOPYRIDYL MOLECULES  by JASON T. PIERREROY  B.Sc, University of British Columbia, Canada, 1995  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Department of Chemistry)  We accept this thesis as conforming to the required standard  The University of British Columbia December 1997 © Jason T. Pierreroy, 1997  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  DE-6 (2/88)  Abstract Complexes with tetra- and hexadentate polyaminopyridyl ligating moieties were prepared and studied as part of a process to understand the coordination chemistry of oxorhenium and oxotechnetium metal centres as potential radiopharmaceuticals. N, N'-bis (2-pyridylmethyl) ethylenediamineoxorheniumfV) perrhenate, [ReO(pmen)][Re0 ], N,N'-bis(2-pyridylmethyl)ethylenediamine- N,N'4  diacetatooxorheniumfV ) bromide, [ReO(bped)lBr, N, N'-bis (2-pyridylmethyl) 7  ethylenediamine-N,N'-diacetatooxotechnetiumfy)  chloride, [TcO(bped)]Cl, were  prepared and characterized. In addition, three new potential ligands: N, N'-bis (methylcarboxymethyl)-N, N'-bis(2-pyridylmethyl) etliylenediamine, pmen-OMe, N,N'-bis(etiiylcarboxymethyl)-N,N'-bis(2-pyridylmethyl)ethylenediamine, pmen-OEt, and N,N'-bis(tert-butylcarboxymethyl)-N,N'bis(2-pyridylmethyl)ethylenediamine, pmen-OBut, were prepared for the first time and characterized. The oxorhenium and oxotechnetium complexes were characterized by mass spectrometry, elemental analyses, infrared spectroscopy, and !H NMR spectroscopy. H pmen and the pmen-esters are oils and elemental analyses 2  were not performed. Crystals suitable for X-ray diffraction studies were not obtained for any of the complexes prepared. Characterization of the oxorhenium(V) and oxotechnetium(V) complexes revealed a number of possible geometries. [ReO(pmen][Re0 ] is proposed to be 4  a 5-coordinate square pyramidal or trigonal bipyramidal complex. The [ReO(bped)]Br and (TcO(bped)JCl complexes were thought to be either 5- or 7-coordinate complexes.  !H NMR of the bped2- complexes showed three  ii  A A ' B B ' patterns i n C D O D indicative of coordinated acetate groups in a 3  7-coordlnate monocapped trigonal prism or pentagonal bipyramidal type configuration. In DaO, [ReO(bped)]+ showed two A A ' B B ' patterns and a singlet i n the i H N M R characteristic of pendant acetate groups. The sirnilarity between the bped - complexes and the pmen - complex suggests that the 2  2  bped - complexes have the same possible 5-coordinate configurations as 2  [ReO(pmen)]+. Based on steric interactions and ring strain associated with the bped complexes, the monocapped trigonal prism or square pyramidal configurations were believed to be favoured. It was not possible to identify the true configuration without an X - r a y diffraction study.  iii  TABLE OF CONTENTS page Abstract  ii  Table of Contents  iv  List of Tables  vi  List of Figures  vii  List of Abbreviations  ix  Acknowledgements  xiii  I.  Introduction  1  II.  Experimental  14  III.  II. 1  Materials and Instrumentation  14  11.2  Syntheses of Ligands  15  11.3  Syntheses of Metal Complexes  17  Results and D i s c u s s i o n  20  III. 1 Ligands: Design and Syntheses  20  111.2  24  Ligands: Characterization 111.2.1  111.3  Mass Spectrometry and Elemental Analysis  25  111.2.2  Infrared Spectroscopy  25  111.2.3  N M R Spectroscopy  29  Metal Complexes: Design and Syntheses  33  111.3.1  H b p e d Complexes  33  111.3.2  H p m e n and H pmen«4HCl Complexes  38  111.3.3  Ester Complexes  39  2  2  2  iv  III.4  Metal Complexes: Characterization 111.4.1  IV.  40  Mass Spectrometry and Elemental Analyses  40  111.4.2  Infrared Spectroscopy  41  111.4.3  NMR Spectroscopy  46  Proposed Structures of [ReO(bped)]Br [TcO(bped)]Cl and [ReO(pmen)][Re0 ] Complexes  53  4  References  66  v  LIST OF TABLES page Table 3.1.  IR stretching frequencies of potential ligands  26  Table 3.2.  i H N M R (200MHz) spectral data for the potential ligands  Table 3.3.  30  13C N M R (50.3 MHz) spectral data for the potential ligands  Table 3.4.  34  IR stretching frequencies for [ReO(pmen)][Re0 ] and 4  [Co(H pmen)Cl )]C104 and [Pd(H pmen)](PF ) complexes.43 2  2  2  6  2  Table 3.5.  IR stretching frequencies of bped - complexes  45  Table 3.6.  i H N M R (200 MHz) spectral data of [ReO(pmen)][Re0 ]  2  4  and cis-oc- and cis-J3-[Co(H pmen)Cl ]C10 complexes 2  2  4  (in D M S O - d )  48  6  Table 3.7.  i H N M R (300 MHz) spectral data for bped2- complexes of ReO(V), TcO(V), and Co(III)  vi  50  LIST OF FIGURES page Figure 1.1.  Radiopharmaceutical chemist's periodic table  5  Figure 1.2.  Some tetra- and hexadentate ethylenediamine derivatives  8  Figure 1.3.  Potential ligands used i n this work  13  Figure 3.1.  IR spectra of H bped (KBr disc), H pmen»4HCl (KBr disc) and 2  2  H p m e n (liquid smear on NaCl plate)  27  Figure 3.2.  IR spectra of H p m e n and pmen-esters  28  Figure 3.3.  i H N M R (200 MHz) spectra of H bped (in D 0 ) , H pmen»4HCl  2  2  2  2  2  (in D 0 ) , and H p m e n (in CDC1 )  31  Figure 3.4.  i H N M R (200 MHz) spectra of the pmen-esters  32  Figure 3.5.  IR spectra of [ReO(pmen)][Re0 ]  42  Figure 3.6.  IR spectra of [ReO(bped)]Br and [TcO(bped)]Cl complexes (KBr  2  2  3  4  disc) Figure 3.7.  44  i H N M R (200 MHz) spectrum of [ReO(pmen)][Re0 ] i n 4  D M S O - d a t pD=5.3  47  6  Figure 3.8.  i H N M R (300 MHz) spectrum of [ReO(bped)lBr i n C D O D (top) at 3  pD=5.5 and D 0 (bottom) at pD=3.3 2  Figure 3.9.  i H N M R (300 MHz) spectrum expansion of [ReO(bped)]Br i n C D O D at pD=5.5  52  3  Figure 4.1.  H p m e n ligand orientation around Co(II)48, Fe(ffl)i4, and 2  Pd(II)48 metal centres Figure 4.2.  49  54  Proposed [ReO(pmen)][Re0 ] structures 4  vii  55  Figure 4.3.  The ligand displacements needed to change a square pyramid into one of trigonal bipyramid geometry  Figure 4.4.  55  Proposed structure of [ReO(bped)]Br using assignments for [Co(bped)]PF from Douglas ? and Caravan40  58  2  6  Figure 4.5.  Proposed bped - complex structures using ! H N M R spectra i n 2  D 0 and C D O D 2  Figure 4.6.  59  3  Proposed structures of [ReO(pmen)][Re0 ], [ReO(bped)]Br, 4  and [TcO(bped)]Cl showing methylene hydrogen orientation  61  Figure 4.7.  Steric interactions i n the Re and Tc complexes  63  Figure 4.8.  Alternating carboxylate group coordination in [ReO(bped)]+  64  Scheme 1.1. Linear tetradentate ligand orientation around a metal centre.... 10 Scheme 3.1. Caravan synthesis of H bped»2HCl  20  Scheme 3.2. Synthesis of H p m e n and H pmen«4HCl  21  2  2  2  Scheme 3.3. Two-step synthesis of H bped«2HCl 2  ..23  Scheme 3.4. Pmen-ester syntheses  23  Scheme 3.5. Bped-metal complex syntheses  35  Scheme 3.6. Liquid-Liquid Diffusion Crystallization (LLD)  37  Scheme 3.7. [ReO(pmen)][Re0 ] synthesis  38  4  viii  LIST OF ABBREVIATIONS Abbreviation  Meaning  OAc  acetate  a  alpha particle  J3~  beta particle  J3+  positron  hbed 4  N,N'-bis(2-hydroxyberizyl)-emylenediairiine-N,N'diacetate  H bped, edampda 2  N,N'-bis(2-pyridylmetJlyl)etbylenediarrline-N,N ,  diacetic acid H bbpen 2  N,N'-bis(2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylenediamine  BFC agent  bifunctional chelating agent  br  broad  calc  calculated  °C  degrees Celsius  CD3OD  deuterated methanol  CH3CN  acetonitrile  CF3SO3-  triflate  cm  wavenumber  1  COSY  correlated spectroscopy (NMR)  8  chemical shift in parts per million (ppm) downfield from tetramethylsilane (NMR); vibrational out-ofplane bending mode (IR)  ix  A  the s p r e a d between the average c h e m i c a l shift of A B patterns (ppm)  D  deuterium  d  doublet (NMR)  dd  doublet of doublets (NMR)  dq  doublet of quartets (NMR)  DMF  N,N'-dimetbylformamide  DMSO DMSO-d  dimethylsulfoxide 6  deuterated dimethylsulfoxide  DTPA -  dietJiylenetriaminepentaacetate  Ey  g a m m a r a y or p h o t o n decay energy  EJJ  b e t a particle decay energy  5  eddass4-  N,N'-bis(2-mercaptoetJiyl)ethylenediamine-N,N'diacetate  edta4-  N , N, N \ N'-ethylenediaminetetraacetate  EDTMP8-  etbylenedianime-N N,N\N'-tetrakis(methylene>  phosphonate) eq  equivalent  eV  electron volt(s)  y  g a m m a ray; p h o t o n  g  gram  GFR  glomerular filtration rate  h  hour(s)  HM-PAO  hexamethylpropylene a m i n e oxime  Hz  Hertz  x  IR  infrared  J  N M R coupling constant between hydrogens a and b  a b  k  kilo (103)  LLD  liquid-liquid diffusion  LSIMS  liquid secondary ion mass spectrometry  m  milli- (10-3); medium (IR); 'metastable' state  M  molarity; metal; mega(10 )  MAG3  mercaptoacetylglycylglycylglycine  mL  rnillilitre  m/z  mass-to-charge ratio (in mass spectrometry)  MeOH  methanol  min  minute(s)  mmol  millimole  mol  mole  MRI  magnetic resonance imaging  VJ  stretching vibration (IR)  NMR  nuclear magnetic resonance  pD  negative log of the concentration of D 0+  pH  negative log of the concentration of H3O+  6  3  pled 4  H p m e n , bispicen 2  pmen-OBut  N,N'-bispyridoxylethylenediamine diacetate N,N'-bis(2-p5rridylmethyl)ethylenediamine N,N'-bis(tert-butylcarboxymethyl)-N, N'-bis (2-pyridylmethyl) ethylenediamine  pmen-OEt  N, N'-bis (ethylcarboxymethyl)-N, N'-bis (2-pyridylmethyl) etJiylenediamine  xi  pmen-OMe  N, N'-bis (metnylcarboxymethyl)-N, N'-bis (2-pyridylmethyl) ethylenediamine  ppm  parts per million (NMR)  [ReO(bped)]Br  N,N'-bis(2-pyridylmemyl)etJiylenediamine-N N'>  diacetatooxorhenium(V) bromide [ReO(pmen)] [Re0 ] 4  N,N'-bis(2-pyridylmetiiyl)ethylenediamineoxorheniumfV) perrhenate  Sbbpen4-  N,N'-bis(2-hydroxy-5-sulfonylberizyl)-N,N'-bis(2pyridylmethy1) ethylenediamine  s  singlet (NMR); strong (IR)  t  triplet (NMR)  td  triplet of doublets (NMR)  tpen  N,N,N'N'-tetra-2-picolylethylenediamine  T1/2  half-life, time for concentration to reach one-half of the initial concentration.  [TcO(bped) ] CI  N,N'-bis(2-pyridylmet±iyl)ethylenediamrne-N,N'diacetatooxotechnetium(V) chloride  vs  very strong (IR)  w  weak (IR)  X-  halide ion  y  year(s)  Y-  bulky counter anion  xii  ACKNOWLEDGMENTS  I would like to thank Dr. Chris Orvlg for his guidance, encouragement, and never ending patience. This appreciation; however, does not extend to Friday hockey where I was often a victim of his unorthodox, mutilative, WWFlike defensive techniques. A special thanks to all the members of the Equipe Orvlg Team, past and present: Ika Setyawati, Lenny Woo, Kathie Thompson, L i Wei Yang, Ernest Wong, Andreas Dittler-rOingemann, Peter Caravan, Mike Kovacs, "Mother" Elisabetta Gobbi, "Father" Nicolas Aebischer, Dave "Huey" Green, Barry "Duey" Liboiron, Devin "Luey" Mitchell, and Peter "Vlad the Inserter" Buglyo. Honourable mentions go to the drunkards: Paul " The E a r l of Lard" Read, Ashley Stephens, Marco Melchior, and Leon X u ("Warrior Princess"), who never ceased to amaze me with their eccentricities and "poetic" vocabulary. Cheers to those outside the Orvig group: Doug and the members of the Sherman group, Rob, Olivier, the Aikidoka people, Maria, and of course my good friend Robyn. The assistance of the departmental support staff is gratefully acknowledged, especially Ms. Liane Darge, Ms. Marietta Austria, and Mr. Borda for their patience. The department is thanked for the T.A. ship and Dupont Merck is thanked for the contributions to the research grant. Thanks goes out to the A.U.S., the E.U.S., The Pit Pub, The Gallery Lounge, The Fringe, and the micro-breweries for supplying the elixir necessary to survive graduate student life.  xiii  3 bebicate tijis t!je"St£f to mp parents, R o b e r t anb g>I)aron, to mp sfeter Cljantelle anb fjer famtlp, C a m , jfflomque, Jlarcus;, to U n c l e H o m e , anb of course to mj> bear beparteb frtenb, Cebrtc.  "fflp brain burtst." -fflontp$ptf)on  xiv  I. Introduction  The research and design of Tc and Re radiopharmaceuticals has greatly expanded over the past twenty years due to the ideal nuclear properties of their radionuclides and their applicability i n the field of nuclear medicine. Radiopharmaceuticals are drugs containing a radionuclide that can be applied either as a diagnostic imaging agent (e.g. 99mTc, I n ) , or as a therapeutic i n  agent (e.g.  186.188  R  e >  1533m).  1  It is possible to monitor biochemical and  physiological properties in vivo by using both the nuclear properties of the radionuclide and the pharmacological properties of the radiopharmaceutical, a n advantage over higher resolution magnetic resonance imaging (MRI) and ultrasound techniques. 1 The use of metals offers a multitude of opportunities i n the design of radiopharmaceuticals. The ability to modify the environment around the metal permits specific in vivo targeting to be incorporated into the molecule. The coordination chemistry of the metal determines the ultimate geometry and stability of the radiopharmaceutical. These properties will decide whether it is suitable for application i n biological systems, where it will encounter a p H of COL 7.4, a temperature of ca. 37°C, and various small molecules, proteins, enzymes, and cells, which could challenge the integrity of the complex. 2,3 1  The commercial development of radiopharmaceuticals flourished i n the 1970's and 80's. Prior to 1980 the focus was on renal and bone imaging, renal and hepatic function, and labelled red blood cells using  99mTc  complexes of  gluconate, glucoheptonate, dimercaptosuccinic acid, phosphonates and diethylenetriaminepentaacetic acid (H DTPA).2 Little was known of the nature 5  1  of the c o m p l e x e s formed a n d the range of a p p l i c a t i o n w a s limited. T o o b t a i n a greater u n d e r s t a n d i n g of t e c h n e t i u m c h e m i s t r y a n d to e x t e n d t h e r a n g e of 99mTc r a d i o p h a r m a c e u t i c a l s i t w a s e s s e n t i a l t h a t n e w l i g a n d s b e d e s i g n e d .  In  the 1980's the m a i n foci of development of n e w r a d i o p h a r m a c e u t i c a l s were i n the areas of cerebral perfusion, m y o c a r d i a l perfusion, k i d n e y f u n c t i o n , a n d liver function.2.3 9 9 m T c O ( d , I - H M - P A O ) (Ceretec™), designed b y T r o u t n e r , 5 , 6  w  a  s the first  c o m m e r c i a l l y available t e c h n e t i u m r a d i o p h a r m a c e u t i c a l for i m a g i n g cerebral b l o o d f l o w (in p a t i e n t s w h o h a v e s u f f e r e d a stroke). 2.3 1  it is also c l a i m e d to be u s e f u l i n  -TNI/  evaluating other cerebral diseases s u c h as h a e m a t o m a s a n d A l z h e i m e r ' s d i s e a s e , b u t it i s not a p p r o v e d for these u s e s .  D e s p i t e its  r  initial intended use, Ceretec's  H' m o s t w i d e s p r e a d u s e i s i n b l o o d c e l l l a b e l l i n g . ~~ T h e c o m p l e x is n e u t r a l a n d lipophilic a n d its  icO  (d I H M P A O ) (Ceretec™)  r e l a t i v e ' i n s t a b i l i t y ' i s t h o u g h t to b e t h e m a i n r e a s o n w h y it c a n b e multifunctional.  T h e e x a c t m e c h a n i s m i s u n k n o w n ; h o w e v e r , it h a s b e e n  s h o w n i n p l a s m a a n d i n vitro t h a t C e r e t e c c r o s s e s t h e c e l l m e m b r a n e a n d r e a c t s w i t h i n t r a - c e l l u l a r c o m p o n e n t s w h i c h c o n v e r t it to a s e c o n d a r y h y d r o p h i l l i c f o r m t h a t c a n n o t r e c r o s s t h e m e m b r a n e t o e x i t t h e c e l l . 3 d,l  and  meso i s o m e r s e x i s t , b u t t h e m e s o i s o m e r i s n o t r e t a i n e d i n t h e b r a i n a s l o n g a n d i s l e s s effective t h a n t h e d a n d I i s o m e r s .  99mTc-sestamibi ( C a r d i o l i t e ™ )  i s a n o c t a h e d r a l c a t i o n i c t e c h n e t i u m (I)  c o m p l e x d e s i g n e d a s a m y o c a r d i a l p e r f u s i o n i m a g i n g agent for e v a l u a t i n g t h e integrity of m y o c a r d i u m ( a b n o r m a l v s . n o r m a l ) .  Unsubstituted alkylisonitriles  and alkylisonitrile esters were investigated initially, but background radiation in the  Cr / (X  liver and lungs and short retention times  O—  N .N  were observed. Complexes with ether 7  groups; however, were retained in the heart and showed better background clearance and longer retention times.  o  .0  /  Tc-sestamibi, (Cardiolite™) ether derivatives improved background clearance due to what was believed to Functionalization of the isonitrile groups with  be metabolism of the lipophilic ethers to hydrophillic hydroxyl groups in the liver which are then subject to further metabolism and elimination.!-3.8 Approval for breast imaging was recently given for 99mTc-sestarnibi as Miraluma™. 99mTcOMAG " (TechneScan-MAG ), by Fritzberg and 3  3  - Davison, is marketed as a renal imaging agent. The anionic oxotechnetate(V) complex consists of  i f  an N S donor atom system exhibiting square 3  N ^ O  COOH TcO(MAG )'  pyramidal geometry with the oxo group in the apical position and the central metal slightly above  3  (TechneScan MAG3)  the basal plane. The uncoordinated carboxylate  group in the deprotonated dianion is important for efficient clearance. 67  Ga-citrate (Neoscan) has been found to be successful in the diagnosis  of primary and metastatic tumours. The exact mechanism is unknown; however, it is known that 67Qa is transchelated to transferrin as soon as it is injected into the blood stream. It mimics the ferric ion in its binding to  3  molecules i n s e r u m a n d a c c u m u l a t e s i n lysosomes b o u n d to intracellular protein.2.3.n G a l l i u m is not r e d u c e d in vivo a n d it does not become incorporated  H  into h a e m o g l o b i n , hence it does not affect the oxygen  2  H c a r r y i n g capacity of r e d blood cells.  Ga—o-  0 — 2  0 ^  T h e exact  I OH  s t r u c t u r e is not k n o w n ; however, there are p r e s u m a b l y  2  Ga - citrate (Neoscan)  three waters filling the r e m a i n i n g coordination s i t e s . 1  2  i53Sm(EDTMP)5- involves a tetraphosphonate ligand a n d shows in vivo localization c o m p a r a b l e to the 9 9 T c - d i p h o s p h o n a t e bone a g e n t s . m  p r i m a r y a p p l i c a t i o n of  15  The  3 S m ( E D T M P ) is as a radiotherapeutic agent for the 5-  o  1 2  p;  palliative treatment of metastatic bone c a n c e r pain.  1 2  S a m a r i u m - 1 5 3 is a beta (£") emitting  radiolanthanide with a near two d a y half-life, w h i c h is ideal for radiotherapeutic applications.  H 0 — - Sm— 2  H Q 2  A low energy g a m m a ray suitable for  o P  ^ p ' o ' \ \  v^o O  o  scintigraphic i m a g i n g is also emitted.  The  complex b i n d s to the hydroxyapatite crystals of  [Sm(EDTMP)«3H 0] 5  2  the bone a n d is retained o n the b o n e while the  u n b o u n d isssm is r a p i d l y cleared b y the blood. T h e a d d e d b o n u s of a g a m m a ray allows the d i s t r i b u t i o n of the c o m p o u n d to be monitored d u r i n g therapeutic application. T h e exact structure is not k n o w n , b u t u s i n g the e m p i r i c a l f o r m u l a it is believed to c o n t a i n three coordinated waters i n a d d i t i o n to the six b o u n d a t o m s of E D T M P 8 - . . 1  2  T h i s complex is not yet approved for c l i n i c a l a p p l i c a t i o n .  Different applications require r a d i o n u c l i d e s with different n u c l e a r properties.  Diagnostic i m a g i n g agents m u s t have r a d i a t i o n w h i c h c a n penetrate  the b o d y w i t h m i n i m a l cell destruction a n d w h i c h c a n be detected b y external  mstTumentation. Radionuclides decaying by gamma ray (y) or positron (S+) emission and having a relatively short half-life (less than 24 hours) are suitable for diagnostic applications. Radiotherapeutic application involves cell 1  destruction, thus decay by particle emission (a, JB", Auger e") and a half-life of from one to ten days are ideal properties. The half-life and mode of decay are dependent on the desired application. Imaging and therapeutic applications have opposite requirements and goals, but both share one common objective, whereby target specificity and a high target-to-background ratio are essential to the success of either directive. The radiopharmaceutical chemist's periodic table (Figure 1.1)i shows the majority of the most medically useful radionuclides, yet some chemical form of  1  18 2  13 14 15 16 17 C 3  4  5  6  7  8  9  10 11 12 Cd  Sc Rt Sr Y  Tc  Lu  Re  Rh Pd  positron  Ga In  Au  I  Tl Pb Bi  Dy Ho  • • beta  O F  P  Src  •  N  gamma  As  Yb  • alpha  Figure 1 . 1 . Radiopharmaceutical chemist's periodic table. Split patterns indicate more than one applicable radioisotope.  99mTc is used i n 90% of all diagnostic scans performed i n nuclear medicine departments i n the North America. Technetium was the first of the artificially 4  produced elements (discovered by Perrier and Segre i n 1937). Twenty-one isotopes of mass number 90 - 110 and several metastable isomers (designated with'm') are known, and technetium metal complexes of oxidation states between -1 and +7 with coordination geometries between 4 and 9 exist. 99Tc is produced i n gram quantities from  235TJ  fusion and is the only isomer used for  macroscopic chemical studies, usually as ammonium pertechnetate, [NH ][Tc0 ], because of its long half-life ( t 4  4  1/2  = 2.11 x 105 y) and m o d e r a t e s -  decay energy of 293 keV. 99Tc is also produced by means of gamma ray decay from its parent,  99mTc,  which is easily obtained from a 9 9 M o / 9 9 m T c generator  via elution through a n anion exchange column with saline solution. 99mTc is widely used because of its ideal nuclear properties ( t i / = 6.02 hr, Ey = 140 2  keV (89%)) and its ease of availability. 1- There are no accompanying J3~ 4  emissions and the gamma ray energy is appropriate for detection by commercial gamma cameras. The half-life is long enough to prepare and administer the radiopharmaceutical, yet short enough to minimize the radiation dose to the patient. In a 1990 estimate, six to seven million administrations of 99mTc  radiopharmaceuticals are performed each year i n the United S t a t e s ,  14  hence the desire to develop new or improved target-specific agents is growing. The high-energy J3- emitting rhenium radionuclides show promise as therapeutic agents. Rhenium is a group VII congener of technetium and the periodic relationship between the two metals enables the design of rhenium radiopharmaceuticals by analogy to already existing technetium diagnostic agents.  1 8 6  R e has a half-life of 90 hours and emits two J3- particles with  6  energies of 1.07 MeV (77%) and 0.934 MeV(23%) as well as a gamma ray (Ey = 137 keV (9.2%)). i88R has a half-life of 17 hours and emits a $ - particle e  (2.1 MeV) and a gamma ray (Ey =155 keV (15%)).! These radionuclides are ideal for therapeutic and diagnostic applications because of their longer halflives and JSparticle emissions, combined with gamma ray emission. A 'localized' high energy radiation dose is delivered to the tissues over a longer, therapeutic period of time, while the additional gamma ray can be used along with a gamma camera as a diagnostic tool. The use of a chelating ligand to form 5- and 6-membered rings upon complexation to a metal is of growing interest i n nuclear medicine and i n the design of radiopharmaceuticals. In designing a potential ligand, the type of donor atom, the size of the metal chelate ring formed upon coordination, and the overall coordination number of the metal ion must be c o n s i d e r e d .  13  Complexes of polyaminocarboxylate ligands have been thoroughly investigated over the past thirty years, whereas complexes with polyaminopyridyl ligands have not been as extensively studied. Of particular interest are tetra- and hexadentate ligands with a single type of donor atom or containing a variety of donor atoms i n various combinations (Figure  1.2).  1 3  -29  EtJiylenediarnine-N,N,N',N'-tetraacetate (edta ") is an example of a 4  polyaminocarboxylate ligand having two nitrogen and four oxygen donor atoms that can form five 5-membered chelate rings around a single metal centre or act as a bridging ligand between two metal c e n t r e s .  14  The initial use of edta 4  was as a synthetic calcium binding additive i n the manufacture of dyes i n the mid 1930's i n G e r m a n y .  3 0 3 2  It was later discovered that its high affinity for  positively charged metal ions was ideal for leeching metal ions from biological and chemical systems. From its early use i n chelation therapy for the 7  Q .O  Q P  T  T  Y  —  0  T  N O bped "  P  2  O O C ^  ^  i  - C O O "  o~o  a  I  N  r  e  n  O O C ^ ,  s  " ,  a  N N  N  r i  OH  tpen  €i . ia 0  ^  0  „  J N  °  ^  R = H:  bbpen*-  R = SO3-:  Sbbpen " 4  ri^°N  eddass " 4  1.2.  t  R  -  Figure  d  - C O O "  XT  R  oKe  -aJ  „^sLP~ HO  N k  2  y S ^TI  T„T N  m  oK>-  S o m e tetra- a n d hexadentate ethylenediamine derivatives  t r e a t m e n t o f l e a d p o i s o n i n g , a p p l i c a t i o n s o f e d t a - g r e w to 4  encompass  t r e a t m e n t s for atherosclerosis, c a r d i a c a i l m e n t s , c o r o n a r y artery disease, h i g h b l o o d p r e s s u r e , a n d a r t h r i t i s b e t w e e n the 1950's a n d 80's.3i.32  its  incorporation into n u c l e a r medicine w a s i n the areas of labelling antibodies a n d m e a s u r i n g the glomerular filtration rate (GFR) i n the k i d n e y s .  1  E d t a - is a 4  b i f u n c t i o n a l c h e l a t i n g (BFC) agent i n the labelling of antibodies b e c a u s e it h a s the a b i l i t y to c o v a l e n t l y b i n d to the a n t i b o d y .  R a d i o n u c l i d e s of i n d i u m a n d  other trivalent metals s u c h as gallium a n d y t t r i u m form the most stable chelates w i t h edta -. 4  A s i C r — e d t a c o m p l e x is u s e d to m e a s u r e the degree of  r e n a l i m p a i r m e n t i n patients w i t h renal disease. 1 T h e G F R is m e a s u r e d b y  8  monitoring the clearance rate of the radiopharmaceutical from the blood. The use of edta - in nuclear medicine decreased due to its lack of metal ion 4  specificity and depletion of essential minerals during application. Hypocalcaemia, acute lead poisoning, insulin shock and nephrotoxic side reactions were common occurrences during treatment.  3032  Newer compounds,  such as DTPA, that formed more stable complexes and had a greater degree of specificity were developed and these eventually replaced edta4-. The ethylenediamine (en) moiety is an ideal unit for constructing a multidentate ligand because the amino group is easily functionalized to incorporate other donor atoms. The most favourable donor atoms for technetium are N, P, S, and O in amine, amide, phosphine, thiol, oxime, and isonitrile functional groups. The N atom is an ideal donor atom for planar 2  chelatering-formingmolecules. If the donor atoms are kept in close proximity to each other, a maximum number of 5- and 6-membered chelate rings can form upon metal ion complexation.33 Hancock notes that larger metal ions coordinate to smaller chelateringswith less ligand strain compared to smaller metal ions.  34  Hexadentate ligands which contain five 5-membered chelate rings  upon coordination, such as edta -, may result in larger metal ions adopting a 4  coordination number of seven by coordinating an additional unidentate ligand.35 The longer M—O and M—N bond lengths in a seven coordinated complex impart less strain in the ligand. Smaller metal ions, which cannot adopt a higher coordination number of seven, may reduce strain by substituting solvent for one of the donor atoms.34  In this research, the ethylenediamine (en) moiety was used in conjunction with 2-pyridylmethyl units to form N,N-bis(2-pyridylmethyl) ,  ethylenediamine (H pmen, bispicen). In H pmen, the picolyl arms provide two 2  2  9  heterocyclic nitrogen atoms in addition to the two basic aliphatic N atoms provided on the en backbone to produce a N tetradentate system. H pmen is 4  2  a linear type molecule with the N atoms linked by 2-carbon chains (a, b, and c) (Scheme 1.1 A).  When complexed to a metal, the molecule is capable of  forming an open-chain tetradentate ligand with three 5-membered chelate rings (x, y, and z) around the central metal ion (Scheme 1.1B). The localized lone pair of electrons on the ethylenediamine and pyridine nitrogens should  b  Scheme 1.1. Linear tetradentate ligand orientation around a metal centre  coordinate easily to the metal centres. In linear type molecules the terminal donor atoms (N ) and the metal atom lie in the coordination plane; however, it py  is not essential that the penultimate donor atoms (N ) lie in the plane also.29 A en  combination of short chain lengths, planarity of the chelate rings, and the N  e n  donor atom's ability to bond to at least three other atoms (including the metal ion) necessitate that the N  e n  atoms and the three attached atoms lie in the  plane of coordination containing the metal ion and the terminal N atoms. Buckling may result across the line of centres of the N  e n  p y  donor  donor atoms  in order to maintain the planarity of the chelate rings (x and z) and to reduce  10  ring strain due to the short chain lengths between the donor atoms (Scheme 1.1C). The neutrality of the compound and the lipophilic pyridyl units may offer potential applications for crossing the blood-brain barrier. The addition of a n acetate group to each amine group i n the en backbone unit produced a potential N 0 system in N,N'-bis(2-pyridylmethyl)ethylenediamine-N,N'4  2  diacetate (bped -, edampda). The bped - molecule should follow the same N 2  2  4  coordination as pmen - with the acetate groups pendant or coordinated. 2  H pmeni3.14,19,20.26,27,47.48,36-39 and H bpedi9.26- 8,40,4i (Figure 1.3) 2  2  2  have been extensively investigated over the past 30 years with di- and trivalent metal ions and have been shown to have planar N configurations. H P m e n 4  has also shown configurations with the N plane of coordination. 8 4  e n  2  donor atoms out of the N - M - N p y p y  No study has been undertaken for group VII metals.  This work focuses on forming complexes with oxorheniumfV) and oxotechnetiumfV) involving pmen - and bped - molecules i n attempts to 2  2  investigate potential applications i n nuclear medicine. The oxo form of the metals are used because of their ease of availability and predominance. Monoand dioxo metals centres are possible from the reduction of the [NH ][M(VII)0 ] 4  4  centre i n the presence of the potential ligand using a reducing agent s u c h as sodium dithionite or stannous chloride i n a one-pot synthesis. Reduced monooxo precursor units, such as [Bu N][ReOBr ] or [ReO(PPh )Cl ] can also be 4  4  2  3  prepared via a variety of synthetic pathways. The [TcO]3+ and [ReO]3+ metal centres tend to prefer square pyramidal and octahedral geometries. Complexation of bped - with the [TcO]3+ and [ReO]3+ metal centres should give 2  rise to a tetra-, penta-, or hexadentate ligand depending on whether none, one, or both of the carboxylates on the acetate arms coordinate to the metal centre.  11  Distortion may occur i n the presence of the hexadentate bped - if the ligand is 2  fully coordinated producing a seven coordinate complex. The possible combinations i n which the donor atoms may coordinate will influence the overall charge on the complex and its applicability as a potential radiopharmaceutical. Attempts to develop a n alternative synthetic route for H b p e d led to the 2  first time synthesis of methyl, ethyl, and tert-butyl ester derivatives of H p m e n 2  (pmen-OMe, pmen-OEt, and pmen-OBut) (Figure 1.3). In attempting to complex the pmen-esters with [TcO]  3+  and [ReO]3+ metal centres it was hoped  that the esters would maintain the same N system coordination characteristics 4  as pmen -, with the ester arms remaining free from coordination. The pendant 2  ester arms i n t u r n could be hydrolysed to produce carboxylate functional groups which might coordinate with the metal centre. The respective p H at which the complex will dissociate and the number of oxo groups on the metal centre are two important considerations that must be taken into account before this occurs. Too low a p H will dissociate the ligand from the metal and a dioxo metal centre may not allow an additional two coordination sites around the metal centre. However, if this idea proves successful, there would be a n alternative pathway to the formation of the metal-bped complex. These tetradentate pmen-ester derivatives' abilities to form complexes with [TcO]  3+  and [ReO] metal centres were also investigated. 3+  Three new complexes were synthesized i n this work: [ReO(pmen)][Re0 ], 4  [ReO(bped)]Br, and [TcO(bped)]Cl. The complexes were difficult to make and no pure samples or x-ray quality crystals were obtained. The elemental analyses were not unambiguous; however, positive LSIMS mass spectroscopy,  12  o o: 2 pmen-OBut  Figure 1.3. Potential ligands used in this work.  infrared spectroscopy, and iH NMR spectroscopy showed strong evidence of the presence of the desired complexed metal centre. Structures of the three complexes were proposed using the spectroscopic results. A considerable amount of effort and time was expended synthesizing the pmen - and bped - complexes. It is hoped that future investigations will 2  2  succeed at improving the purity and determining the structures of the complexes. Once the pure complexes are isolated, the potential of these complexes as radiopharmaceuticals can be investigated. 13  II. Experimental II. 1 Materials and Instrumentation Materials. Et±iylenediamine-N,N'-diacetic acid, etliylenediamine, 2-pyridine carboxaldehyde, 2-(chlorometliyl)pyridine hydrochloride, bromoacetic acid, methylbromoacetate, ethylbromoacetate, tert-butylbromoacetate, tetrabutylammonium bromide, sodium tetraphenylborate, sodium tetrafluoroborate, tetra(n-propyl)ammonium hexafluorophosphate, sodium triflate, sodium perchlorate, and sodium hexafluorophosphate were obtained from Aldrich. Cetyltrimethylammonium bromide and sodium acetate were obtained from BDH and triethylamine was from Fisher. Deuterium oxide (D 0) and deuterated chloroform (CDC1 ) were purchased from Cambridge 2  3  Isotope Laboratory (C.I.L.). Ammonium perrhenate and ammonium pertechnetate were gifts from Johnson-Matthey Pharmaceuticals and Dupont Merck Pharmaceuticals, respectively. All were used without further purification. All solvents were distilled from their.appropriate drying agents.4i [Bu N][ReOBr ]43, [Bu N][ReOBr (H 0)]»PBu 44, [Bu N][TcOCl ]45, and 4  4  4  4  3  2  4  4  N,N'-bis(2-pyildylmetliyl)etliylenedianiine-N,N'-diacetic acid dihydrochloride (H bped»2HCl)40 were all synthesized by published procedures. 2  Caution! 105 years). laboratory safety  Technettum-99  All maniupulations approved  procedures  is a weakJ3-emitter of solutions  for the handling were followed  and solids  of low-level  MeV, T  = 2.12 x  1/2  were  carried  radioisotopes,  at all times to prevent  14  (0.292  and  out in a normal  contamination.  Instrumentation. iH NMR (200 MHz and 300 MHz) and 13C NMR (50.3 MHz) spectra were referenced to TMS and recorded on Bruker AC-200E and Varian XL300 spectrometers. !H COSY spectra were recorded on a Bruker AC-200E spectrometer. Mass spectra were obtained with a Kratos Concept II H32Q (Cs+, LSIMS) instrument. Infrared spectra were obtained as KBr discs (solids) or using NaCl plates (oils) in the range 4000-400 c m on a Galaxy Series FTIR 1  5000 spectrophotometer and referenced to polystyrene. Analyses of C, H, and N were performed by Peter Borda in this department.  II.2  Syntheses of Ligands N,N'-Bis(2-pyridylmethyl)ethylenediamine  prepared by a variation on a literature method.  14  (H pmen). This was 2  Methanol solutions (30 mL) of  ethylenediamine (5.39 g, 89.8 mmol) and 2-pyridine carboxaldehyde (20.27 g, 189 mmol) were combined to give a clear dark amber solution at room temperature. Sodium borohydride (8.49 g, 224 mmol) was added slowly giving rise to a vigorous exothermic effervescence. After two hours, the solvent was removed under reduced pressure and the resultant yellow solid was dissolved in 10% ammonium chloride (90 mL). The crude product was extracted with chloroform (3 x 75 mL) and the combined fractions dried (MgS0 ). The solvent 4  was removed and the yellow-orange oil was dissolved in ethanol and 12 N HC1 was added to produce the HC1 salt. The resulting white precipitate was collected by suction filtration (Anal. Calc (found) for C Hi N »4HCl: C, 43.42 14  8  4  (43.50); H, 5.80 (6.00); N, 14.26 (14.09)), dissolved in water (150 mL), and raised to pH 12 with 5 N NaOH. The product was extracted with chloroform  15  (3 x 75 mL) and dried. The solvent was removed under reduced pressure and the pale yellow oil was dried under vacuum. Yield: 14.6 g (67%). (+LSIMS): m/z 243 ([M+l)+, (Ci H N ]+). 4  19  4  MS  i H N M R (CDC1 ): 5 1.85 (s, 2H), 3  2.34 (s, 4H), 3.48 (s, 4H), 6.65 (t, 2H), 6.89 (d, 2H), 7.13 (t, 2H), 8.05 (d, 2H). Exposure to light turns the oil a darker yellow colour and decomposes the molecule. The oil should be stored i n a cool location away from any light source.  Esters The 'pmen' ester derivatives were all prepared by a similar procedure analogous to one i n the literature46; the preparation is given i n detail only for the methyl ester.  N,N-Bis(methylcarboxymethyl)-N,N-bis(2-pyridylmethyl) ethylenediamine (pmen-OMe). To a 30 m L methylene chloride solution of N,N -bis(2-pyridylmethyl)ethylenediamine (0.988 g, 4.08 mmol) and ,  diisopropylethylamine (1.51 g, 11.7 mmol) was added dropwise methylbromoacetate (1.58 g, 10.4 mmol) i n 15 m L methylene chloride. After stirring the reaction for 24 h, the solvent was removed under reduced pressure and placed under vacuum for 3 h to remove any excess diisopropylethylamine. The crude oil was dissolved i n 50 m L methylene chloride, washed with 0.2 N NaOH (50 mL), water (2 x 15 mL), brine (12 mL), and dried over M g S 0 . The solvent was removed and 10 m L of ethylacetate 4  was added to the red-brown oil to give a clear crimson red solution, which was passed through 5 g of silica gel i n a glass frit and eluted with ethylacetate. The  16  p u r e clear yellow fractions (TLC: M e O H / C H 2 C l 2 :  3/7) were c o m b i n e d a n d t h e  solvent removed under reduced pressure, with several washings  with  m e t h y l e n e c h l o r i d e to r e m o v e a n y r e s i d u a l ethylacetate to give 0 . 6 0 g (41%) a d a r k brown-red oil. Elemental analysis of the oilw a s not done. (+LSIMS):  m/z  3 8 7 ([M+l]+,  [C20H27N4O4H.  of  M S  ! H N M R (CDC13): 5 2 . 1 0 (s, 2 H ) ,  2.75  ( s , 2 H ) , 3 . 4 0 ( s , 2 H ) , 3 . 6 2 ( s , 3 H ) , 3 . 8 5 ( s , 2 H ) , 7 . 0 6 (t, 2 H ) , 7 . 3 9 ( d ,  2H),  7 . 6 2 (t, 2 H ) , 8 . 4 5 ( d , 2 H ) .  The oil should be stored i n a cool place  b e c a u s e t h e colour of the oil d a r k e n s to a b r o w n - b l a c k colour a n d the molecule decomposes over a few weeks.  N,N*-Bis(ethylcarboxymethyl)-N,N -bis(2-pyridylmethyl) ,  ethylenediamine (pmen-OEt).  Substituting ethylbromoacetate for  methylbromoacetate produced a red-brown oil. Yield: 47%. 415  ([M+l]+,  [C 2H31N404]+). 2  i H N M R (CDC13): 5 1.16  M S (+LSIMS):  (t, 6 H ) , 2 . 7 8 ( s , 4 H ) ,  m/z 3.37  ( s , 4 H ) , 3 . 8 6 ( s , 4 H ) , 4 . 0 8 ( q , 4 H ) , 7 . 0 8 (t, 2 H ) , 7 . 3 9 ( d , 2 H ) , 7 . 5 5 (t, 2 H ) , 8 . 4 3 (d.  2H).  N,N -Bis(tert-butylcarboxymethyl)-N,N -bis(2-pyridylmethyl) ,  ,  ethylenediamine ( p m e n - O B u t ) .  Substitution of methylbromoacetate w i t h  butylbromoacetate gave a red-brown oil. Yield: 4 8 % . ([M+l]+,  [C26H39N4O4H.  iH NMR  tert-  M S (+LSIMS): m / z  (CDCI3):  471  8 1 . 3 6 (t, 9 H ) , 2 . 7 5 ( s , 4 H ) , 3 . 2 5  ( s , 4 H ) , 3 . 8 7 ( s , 4 H ) , 7 . 0 5 (t, 2 H ) , 7 . 4 0 ( d , 2 H ) , 7 . 5 3 (t, 2 H ) , 8 . 4 2 ( d , 2 H ) .  II.3  Syntheses of Metal Complexes [ReO(bped)]Br.  To a refluxing solution of H 2 b p e d » 2 H C l (60.5 m g , 0 . 1 4 0  mmol) i n 10 m L of a m e t h a n o l / e t h a n o l mixture ( M e O H / E t O H :  17  2/3) w a s added  sodium acetate (77.1 mg, 0.567 mmol) to produce a clear pale yellow solution. The solution was refiuxed for ten minutes and a red acetonitrile solution (3 mL) of [Bu N][ReOBr ] (100 mg, 0.131 mmol) was added dropwise to give a clear 4  4  green solution. Refluxing was continued for 30 minutes and the solution was then left to stir for 2 days at room temperature. A grey solid was filtered off and the solvent of the filtrate was removed under reduced pressure. The resulting dark green solid was washed with acetone and the insoluble product was collected, dissolved in a minimum amount of methanol, passed through 150 mL of Sephadex LH20, and eluted with methanol. The fractions were collected and the solvent removed. All attempts to crystallize the product failed. Yield: 21 mg (43 %) based on the metal. MS (+LSIMS): m/z 559 ([M]+, [ReO(Ci H N O )]+. Anal. Calc (found) was fitted for ReO(Ci H N O )]Br 8  20  •[Bu NBr] . 4  0  4  4  8  •(NaOAc) .7  45  0  20  4  4  : C, 37.99 (37.90); H, 4.59 (4.51); N, 7.41 (7.47).  IH NMR (CD OD): 8 3.92 (AB, 4H), 3.66 (AB, 4H), 4.90 (AB, 4H) 7.70 (td, 3  2H), 7.78 (d, 2H), 8.09 (t, 2H), 9.12 (d, 2H). [TcO(bped)]Cl. To a clear, pale yellow methanol solution (4 mL) of H bped»2HCl (77.8 mg, 0.182 mmol) and sodium acetate (98.8 mg, 0.726 2  mmol) was added dropwise [Bu N] [TcOCl ] (87.6 mg, 0.176 mmol) in MeOH 4  4  (2 mL). The solution was stirred for 2 days and left to stand for 2 days. A grey precipitate was then filtered out leaving a clear, dark orange-brown filtrate. The solvent was removed under reduced pressure, the crude product was filtered and washed with acetone. The product was dissolved in methanol; the solution was loaded onto 150 mL Sephadex LH20, and eluted with methanol. The brown layer was collected and the solvent removed to produce a brown solid, which was dried under vacuum for 24 hours. All attempts to  18  crystallize with various anions were unsuccessful. Yield: 35 mg (39 %) based on the metal. M S (+LSIMS): m/z 471 ([M]+, [TcO(C H N O )]+). No elemental 18  20  4  4  analysis of the radioactive sample was performed. ! H NMR: (CD OD): 6 3.72 3  (AB, 4H), 3.74 (AB, 4H). 4.82 (AB, 4H), 7.72 (m, 2H), 8.21 (t, 2H), 9.28 (d, 2H). [ReO(pmen)][Re0 ]. To a stirring acetonitrile solution (3 mL) of bis(24  pyridylmethyl)ethylenediamine (205 mg, 0.846 mmol) was added sodium acetate (145 mg, 1.76 mmol) i n methanol (3 mL) to give a clear yellow solution. The solution was degassed with nitrogen for 20 minutes before the dropwise addition of [Bu N][ReOBr ] (430 mg, 0.563 mmol) i n acetonitrile (5 mL), which 4  4  produced a dark purple-black solution. The solution was allowed to stir 24 h at room temperature which yielded a violet precipitate. The violet powder was soluble only in D M S O and D M F , i n which it changed from a cloudy violet solution to a clear yellow-orange solution. Yield: 151 mg (41%) based on metal M S (+LSIMS): m/z  443 ([M]+, [ReO(C Hi N )]+). Anal. Calc (found) was fitted 14  6  4  for [ReO(C H N )](Re0 ]»HCl: C, 23.61 (23.06); H, 2.36 (2.35); N, 7.77 14  16  4  4  (7.68). i H N M R (DMSO-dg): 5 4.18 (AB, 4H), 5.16 (AB, 4H), 7.68 (td, 2H), 7.90 (d, 2H), 8.15 (t, 2H), 9.62 (d, 2H).  19  III. Results and Discussion III. 1 Ligands: Design and Syntheses H bped was originally synthesized by M a r t e l l  20  2  as a mono sodium salt by  means of a multi-step process and later as a dihydrochloride salt by C a r a v a n  40  using a one-pot synthesis with a considerably higher yield. The Caravan synthesis is shown i n Scheme 3.1. D o u g l a s  2 7 2 8  formed a Co(III) complex using  a one pot synthesis by assembling the ligand around the central metal. The potential of b p e d as a ligand for applications i n nuclear medicine is high given 2-  its tendencies to form five 5-membered chelate rings with di- and trivalent transition metals and the l a n t h a n i d e s .  2728  This study attempted to synthesize  and investigate bped - complexes of [ReO]3+ and 2  metal centres as  [TcO]3+  potential radiopharmaceuticals.  HOOC-y N H  1. 0.1 mole eq cetyltrimethylammonium bromide p H ll(NaOH), rt, 36 h C O O H 2. Pass through H c o l u m n 3. Acidify and recrystl. from EtOH-acetone HOOC^ ^ —COOH • N N +  N H edda  +  /  (  CH C1  N  2  /  N-  I  *  2H C 1  ^NH C1 +  H bped»2HCl  picolinyl chloride.HCl  2  Scheme 3.1. Caravan synthesis of H bped»2HCl. 2  There was also interest with the potential N system associated with 4  H pmen. 2  In this study, only H p m e n and H pmen«4HCl were synthesized 2  2  20  (Scheme 3.2) and investigated. Earlier studies on H p m e n conducted with 2  various transition metals have shown both planar and non-planar coordination around the metal c e n t r e .  The neutral H p m e n molecule was ideal  1 4 2 0 2 7 4 7 5 1  2  i n organic solvents for metathesis reactions. H pmen»4HCl was useful i n 2  aqueous conditions where the reduction of [Tc0 ]~ and complexation can be 4  done i n a one-pot synthesis.  O  l.MeOH, rt, 2 h 2.5eqNaBH  HN  2. 10% NH4OH, *  X  4  H N  ^NH  /  2  en  2  o (I  +  y  extract with C H C I 3 f 2-pyridine carboxaldehyde +  H  2  N  \ H  /  NH  +  +  2  /  \  NH y.  ^  ^ H2pmen  +  4C1"  HN"%  E t O H / 1 2 M HC1  H pmen»4HCl 2  Scheme 3.2. Synthesis of H p m e n and H pmen«4HCl. 2  2  The preparation of H bped by means of the C a r a v a n 2  40  method gave  reproducibly low yields and the consistent appearance of a contaminant that transformed the product into a yellow hygroscopic oil. These problems led to the search for alternative means of synthesizing H bped. The Caravan one-pot 2  H b p e d synthesis had a small degree of sodium ions present i n the final 2  product. Some different approaches were tried to improve the yield and increase the purity of the product.  21  Sodium hydroxide (NaOH) was the principal base in the reaction and contamination in the final product was due to the presence of sodium ions as NaCl. H bped was a beige powder when slowly precipitated out of solution. 2  Rapid precipitation of H bped produced a white powder with an increased level 2  of sodium ions in the product. The white H bped gave greater yields, but 2  generally formed a yellow hygroscopic oil when exposed to the atmosphere, due to an additional unknown contaminant. Potassium hydroxide (KOH) was tried in an attempt to eliminate sodium from the product, but the KOH had no affect on the overall yield and purity of the product. The yellow hygroscopic oily product was again present upon recrystallization and exposure to the atmosphere. A second approach (Scheme 3.3) was to add the acetate groups separately to the N,N'-bis(2-pyridylmethyl)ethylenediamine (H pmen) unit using 2  bromoacetic acid and follow the exact same procedure as the one-pot Caravan synthesis. Similar results were obtained from this synthesis with the appearance of the hygroscopic yellow oil. The yields were low and the small amount of product obtained showed evidence of sodium ion contamination. Different solvents of recrystallization were tried; however, there was no change in the overall appearance of the final product.  22  l.MeOH, rt, 2 h 2.5eqNaBH  / HN  4  H N  /  NH  2  2  +  _ 2  |  J  2.  1 0 %  •  NH4OH,  (  extract with CHCI3 en  2-pyridine carboxaldehyde  \ NH  )  r  1  H pmen 2  I 1. 2 mole eq B r C H C O O H  P "O"  (  NH  +  C  + +  mole eq cetyltrimethylammonium  HN ~CT \ bromide, p H 11 (NaOH), rt, 36 h I. »2C1" •2™HN^S ^' P through H column  +  I  NH  2  2. 01 .  a s s  il H bped«2HCl  4  +  - Acidify and recrystal. from EtOH-acetone  2  Scheme 3.3. Two step synthesis of H b p e d » 2 H C l . 2  The formation and hydrolysis of an ester was tried.  Acetate ester  derivatives were attached to H p m e n in place of the acetate groups. Methyl-, 2  ethyl-, and t-butyl-ester derivatives of H p m e n were prepared for the first 2  time. All three pmen-ester products existed as red-brown oils (Scheme 3.4).  ROOC—x HN (  NH ]  1. C H C 1 , diisopropylethylamine 2  2  2. B r C H C O O R 2  H pmen  |  , N  C^J  ^COOR  v  N  ]  I  pmen-ester  2  R= Me, Et, Bu* Scheme 3.4. Pmen-ester synthesis.  23  Base hydrolysis of the esters was tried using K O H or b a r i u m hydroxide, Ba(OH) , i n a warm methanol solution. Within five minutes the K O H hydrolysis 2  produced a salt which precipitated out of solution. Ba(OH)2 did not give a salt immediately, but the Ba + was eliminated as a white B a S 0 salt with the 2  4  addition of concentrated H S 0 . ! H N M R spectroscopy confirmed that H b p e d 2  2  4  was not produced via either of the base hydrolysis techniques. Acid hydrolysis using 6M H C l was mildly successful. A flaky brown solid was obtained after the solvent was removed and the product was dried under vacuum. The pmen-OBut ester was the most successful of the three pmen-ester derivatives. ! H N M R spectroscopy confirmed the ester was hydrolysed to H b p e d ; however, there were unknown impurities present. 2  Recrystallizing from methanol-acetone or ethanol-acetone solvent combinations produced a white precipitate, but the solid rapidly turned yellow and transformed into a yellow oily residue when exposed to air. The hygroscopic residue was recoverable by dissolving it i n methanol, ethanol, or water, but numerous attempts at recrystallization routinely resulted i n the reproduction of the hygroscopic oily product. The use of anionic and cationic exchange columns before attempting to recrystallize the product were unsuccessful i n removing the unknown impurity that caused the product's moisture sensitivity.  III.2 Ligands: Characterization A characterization profile, consisting of mass spectroscopy, elemental analysis, infrared spectroscopy, and ! H and 1 3 C N M R spectroscopies, was performed on all the potential ligands.  24  111.2.1  Mass Spectroscopy a n d E l e m e n t a l A n a l y s i s . Positive(+) LSIMS  mass spectral studies showed strong parent peaks for [M+l]+ with the expected isotope patterns. No distinctive impurities or molecular fragments were visible with any significant intensity i n any of the spectra. Elemental analyses were conducted only on H bped and H pmen»4HCl. 2  2  H p m e n and the pmen-ester derivatives were oils so C,H,N analyses were not 2  performed. The H bped analysis showed the presence of three hydrochlorides 2  present due to a protonated carboxylate as a result of excess H C l used during the protonation process. H p m e n * 4 H C l showed a n elemental analysis within 2  a n experimental error of + 0.3%. 111.2.2  Infrared Spectroscopy. Studies were performed with K B r discs  for the salts (H bped»2HCl, H pmen»4HCl) and with NaCl plates for the oils 2  2  (H pmen, pmen-OMe, pmen-OEt, pmen-OBut). Table 3.1 lists the infrared 2  resonances and the appropriate assignments for the spectra shown i n Figure 3.1 and Figure 3.2. Given the similarities among all the potential ligands, consistent absorption frequencies were observed i n all the product spectra. A l l molecules showed strong absorptions for the (N—H) and (C—H) stretching modes i n the 3200-2400 cm"i region. H bped»2HCl and H pmen»4HCl 2  2  showed a pronounced broadening of the (N—H) and (C—H) signal characteristic of strong intramolecular hydrogen bonding of the protonated N atoms. Strong carbonyl (C=0) stretching frequencies were evident i n H bped»2HCl and the 2  pmen-ester derivatives within the expected region of 1750-1730 cm-i. Pyridine (C=N) and (C=C) ring deformations were consistently observed within 1626-1434 cm-i for all the molecules. H p m e n and its ester derivatives 2  25  ring  778 m  s s s s  758 m  1591 1568 1474 1434  s s s s s vs 762 m  1675 1591 1574 1474 1434 1203  1740 vs  3100-2800 m, br  3386 w  pmen-OMec  1  s s s s s vs 761 m  1659 1591 1574 1474 1434 1194  1738 vs  3100-2800 m, br  3396 m, br  pmen-OEtc  s s s s s vs 759 m  1660 1591 1574 1474 1434 , 1154  1735 vs  3000-2800 m, br  3395 w, br  pmen OBut c  Abbrev.: s= strong, m= medium, w= weak, br= broad, vs= very strong, b Sample analyzed as K B r disc.  765 m  s s s s  c Samples analyzed as liquid smear on NaCl disc.  a  8(C—H) out-of-plane  U(C=N)  1616 1545 1514 1468  —  —  1728 vs  U(C=0) s m m m  3100-2800 s, br  3100-2300 s, br  3000-2500 s, br  D(C—H)  1612 1548 1521 1463  3301 s, br  3255 s, br  3500-3200 s, br  c  1)(N—H)  2  H pmen  2  H pmen»4HClb  2  H bped»2HClb  Assignment  3  Table 3.1. IR stretching frequencies (cm ) of potential ligands.  'I  4000  I  I  I  3000  I  2000  ""I  •'  I  1000  W a v e n u m b e r s (cm-i)  Figure 3.1. IR spectra of H bped»2HCl (KBr disc), H pmen«4HCl (KBr disc), and H pmen (liquid smear on NaCl plate). 2  2  2  27  pmen-OMe  pmen-OEt  pmen-OBut  4000  3000  2000  1000  Wavenumbers (cm-i)  Figure 3.2. IR spectra of H2pmen and pmen-esters. A l l samples analyzed as a liquid smear on a NaCl plate.  28  showed very strong correlation among themselves and with previous studies of H pmen.  A number of common absorptions were visible i n the 1387-757  1 4 3 8  2  cm  1  regions for all of the products. Out-of-plane C — H bending of the 2  methylene on the picolyl group occured i n the 781-740 c m region^ for all the 1  2  samples. III.2.3 NMR  Spectroscopy. i H N M R studies were done in two  solvents: deuterium oxide (D 0) for H bped and H pmen»4HCl, and deuterated 2  2  2  chloroform {CDCI3) for H p m e n and the pmen-ester derivatives. H p m e n and 2  2  H pmen«4HCl were used as references for the chemical shifts between 2  H bped»2HCl and the pmen-esters i n different solvents. C D O D dissolved all 2  3  the samples, but the solvent peaks masked some of the backbone signals. The i H N M R assignments are listed i n Table 3.3 and referenced to Figure 1.3. The i H N M R spectra are shown i n Figures 3.3 and 3.4. The i H N M R spectrum is divided into two sections: the backbone region, (0.0 - 6.0 ppm) and the pyridine region (6.5 - 9.0 ppm). The number of signal resonances and splitting patterns for each species in the backbone region were as expected. Singlets were observed for the methylene hydrogens on the ethylenediamine (H ) and 7  the methylene hydrogens on the picolyl (H ) and methylene hydrogens on the 6  acetate (H ) arms. 8  The four pyridine hydrogen signals represent two symmetry-equivalent sets of four pyridine hydrogens. Two doublets and two triplets were expected from the splitting of each pyridine hydrogen by its adjacent hydrogen(s).  H  x  was split into a doublet by H , and H was split into a doublet by H . The 2  4  3  more downfield doublet was assigned to Hi based on increased shielding i n the space between the two pyridine r i n g s  27  and previous assignments of pyridine  29  o  3  3  3  3  J  3  J  N —H  J l l - 1 0  H(ll)  J l O - l l  c  —  —  2  —  —  —  —  H(10)  1.83 s  —  —  —  —  3.78 s  H(8)  c  2.36 s  3.64 s  3.46 s  —  —  2.77 s  3.37 s  3.58 s  3.84 s  7.37 d 7.8  6.87 d 7.8  8.09 d 8.0  3.34 s  c  H(7)  3  4.68 s  4  4.49 s  3J  —  1.17 t 7.1  4.06 q 7.1  3.36 s  2.79 s  3.86 s  7.42 d 7.7  7.55 td 7.0, 1.8  7.54 td 7.6, 1.8  7.15 td 7.6, 1.6  8.51 td 7.3, 1.5  8.43 td 7.9, 1.6  8.44 dq 4.9,0.70,(0.90) 7.07 tdd 6.1, 1.3  6.66 tdd 6.5, 1.3  7.97 tdd 7.1, 1.0  7.89 tdd 6.7, 1.0  8.43 d 4.2  pmen-OEt  7.06 tdd 6.2, 1.0  8.08 dd 4.5, 0.49  8.76 dd 5.3, 0.76  8.65 dd 5.8, 0.92  H(6)  C  C  14) c  7.99 d 8.0  J 3 4  2  4  H(4)  3  H(3)  < J 3 2 .  3  (  H(2)d  J l 3  H(l)  J 2 i ,  J i 2 -  3  pmen-OMe  —  1.40 s  —  3.29 s  2.79 s  3.88 s  7.45 d 7.8  7.58 td 7.5, 1.8  7.09 tdd  8.47 d, sh 4.8  pmen-OBut  doublets, t= triplet, td= triplet of doublets, q= quartet, dq= doublet of quartets, sh= shoulders.  overlapping dd that gives rise to shoulders in the central peak; Abbrev.: s= singlet, d= doublet, dd= doublet of  a For labelling, see Figure 1.3; b D 0 solvent; c coupling constants (J) in Hz. d Resonance appears to be a pair of  3  2  H pmen  2  H pmen«4HCl  2  H bped«2HCl  3  Table 3.2. iH NMR (200 MHz) spectral dataa for the potential ligands (solvent is CDC1 unless specified) b  H bped»2HCl 2  1  8  HOD  3  LUJUJJ  H pmen«4HCl 2  HOD  H2pmen  TY  i i i i i i i i i i i i i i i i i i  8.5  8.0  7.5  7.0  6.5  /  I  I  I I "I 4.5  I  I  I I I 4.0  I  i '. •  3.5  1  1  i • •  3.0  1  1  i  1  1  2.5  1  "  2.0  ppm Figure 3.3. i H N M R (200 MHz) spectra of H bped»2HCl (in D 0 ) , H pmen-4HC1 (in D O ) , and H p m e n (in CDC1 ). For labelling, refer to Figure 1.3. 2  z  2  3  31  2  2  pmen-OMe 8  7  U pmen-OEt 10  J  .1 pmen-OBu*  ii  1  L  •5  111' 11 * 11 • 111 8.0 7.5 7.0  Figure 3.4.  •»  4.0  3.5  •  1  3.0  2.5  i • • • • i >• • • i  2.0  1.5  1  1  1.0  i H N M R (200 MHz) spectra of the pmen-esters i n C D O D . For labelling refer to Figure 1.3. 3  32  hydrogens i n [(NH ) Ru(py)]2+ and 3  H  3  5  [(NH ) Co(py)]3+.53,54 3  5  H was split by H i and 2  to form a triplet, and H was split by H and H to form a triplet. H was 3  2  4  3  assigned as the downfield triplet based on a greater stabilization of electron withdrawal i n a para position, compared to a meta position, assignments of pyridine hydrogens i n [(NH ) Ru(py)] + and 2  3  5  27  and previous  [(NH ) Co(py)]3+.53,54 3  5  The methylene hydrogen singlets and ester group resonances were assigned using standard *H N M R chemical shift charts and comparison of the H bped 2  and the pmen-ester spectra with those of the H p m e n and H pmen»4HCl. 2  2  i s c N M R spectra of the potential ligands showed half (7-11) of the expected (14-22) resonances. The observed number of peaks was indicative of the molecules possessing two-fold symmetry and equivalent pairs of carbon atoms. The assignments are listed i n Table 3.3.  III.3 Metal Complexes: Design and Syntheses  Three reaction pathways were followed i n attempting to complex the metals and the potential ligands: metathesis, liquid-liquid diffusion crystallization55 (a variation of metathesis), and reduction. A l l three pathways were conducted under a variety of conditions and performed both i n the presence and absence of a base.  III.3.1 H b p e d 2  Complexes  In past experiments, H bped complexation reactions were conducted 2  under aqueous c o n d i t i o n s .  2 6 2 7 4  o . 4 i The use of [ReO] + and [TcO] + precursor 3  reactants such as [Bu N][ReOBr ], [Bu N][ReOBr (H 0)]«PBu 4  4  4  33  4  2  3  3>  and  4*  49.0  — — — —  44.4  — — — —  52.3 55.1 172.7  — —  C(7)  C{8)  C(9)  C(10)  C(ll)  For labelling, see Figure 1.3;  2  55.1  48.6  56.2  C(6)  D 0 solvent.  159.2  159.9  147.9  149.5  C(5)  b  121.8  121.8  128.6  127.8  C(4)  a  159.1  136.3  136.4  144.3  143.6  C(3)  —  60.2  171.6  52.0  51.2  54.8  121.9  122.9  122.2  128.8  128.7  C(2)  14.0  60.1  171.1  52.0  49.6  54.9  136.4  122.9  148.7  148.8  pmen-OEt  149.2  pmen-OMe  145.3  2  147.3  2  C(l)  2  H pmen  3  >  13  28.1  80.8  170.7  56.2  52.3  60.5  159.8  121.8  136.4  122.9  148.9  pmen-OBu  C N M R (50.3 MHz) spectral dataa for the potential ligands (solvent is CDC1 unless specified).  H pmen»4HClb  1 3  H bped«2HClb  Table 3.3.  1  [Bu N][TcOCl ] require non-aqueous conditions due to their hygroscopic nature 4  4  and relative ease of hydrolysis to the unreactive and insoluble Re0 or T c 0 . 2  2  The choice of suitable solvents was limited given the sensitivity of the metal precursor reactants. Methanol was the only solvent that could be used for H bped, but the metal precursors could use methanol, acetone, acetonitrile, 2  chloroform, and methylene chloride. Water can only be used during the reduction of [Re0 ]~ and [Tc0 ]~ because they are not moisture sensitive. 4  4  Metathesis. The precursor reactants were employed in basic and nonbasic conditions (Scheme 3.5). The most successful reactions were with the metal-acetonitrile  (CH3CN)  O [Bu N] 4  +  xJI yf  and the ligand-methanol (MeOH) solutions.  HOOC- —  -COOH  T  N  X  x  M=Re, Tc X=Br, CI  +  f  N  4 NaOAc  1 N  «2HC1  N*Si  •  [MO(bped)]X  CH CN/MeOH 3  H bped»2HCl 2  Scheme 3.5. Bped-metal complex syntheses.  In the absence of base, a precipitate formed rapidly upon the combination of the two reactants. A blue-green powder was produced with Re and an olive green powder was produced with Tc. The powders were only sparingly soluble in DMSO and no crystals of these products were produced. The presence of sodium acetate or triethylamine as a base gave a clear solution. The addition of a bulky counter anion (Y~), such as hexafluorophosphate, perchlorate, triflate, tetrafluoroborate, and tetraphenylborate, to the reaction mixture produced a  35  powder that was a mixture of [Bu N][Y] and [MO(bped)][Y]. 4  Removal of most of the tetrabutylammonium (TBA+) from solution was done using Sephadex LH-20 resin. [MO(bped)]+X- was collected and dried to give a green solid for Re (X=Br) and a light brown powder for Tc (X=C1). Crystallization of the [MO(bped)][Y] salt was attempted with several bulky anions, but all attempts produced a fine white precipitate which consisted mainly of a TBA+Y" salt. Different solvent combinations were tried, but there was no success i n obtaining any of the desired [MO(bped)][Y] product. The [ReO(bped)]Br metathesis reaction employed either [Bu N][ReOBr ] 4  4  or [Bu N][ReOBr (H 0)]PBu as a starting material. The products from either 4  4  2  3  starting material gave spectroscopically identical compounds, however, the solubility of the [Bu N][ReOBr (H 0)]PBu product was m u c h less than that of 4  4  2  3  the [Bu N][ReOBr ] product once the solvent of the reaction mixture was 4  4  removed. The [Bu N][ReOBr ] product was readily soluable i n M e O H and 4  4  water, but the [Bu N][ReOBr (H 0)]PBu was only soluable when heated and 4  4  2  3  formed a n agglomerated white precipitate when the solution cooled to room temperature. The [Bu N] [ReOBr ] product was preferred due to the poor 4  4  solubility of the [Bu N][ReOBr (H 0)]PBu product and difficulty i n removing 4  4  2  3  [TBA]+ from the crude product. Since the metathesis reactions occured very rapidly at room temperature, the same reactions were performed ca. 4°C i n a n ice water bath. The mixtures were slowly warmed to room temperature after the reactants were combined. There was no change i n the overall outcome of the reactions and the same products were obtained.  36  Liquid-liquid Diffusion Crystallization (LLP). The process of diffusion was thought to be slow enough to bring the reactants together at a rate that would induce crystal formation (Scheme 3.6). The experiments were performed at room temperature and at 4°C. A variety of solvent combinations were tried i n either two or three phase L L D systems. Methanol and acetonitrile  glass wool  were the most successful at generating H bped-MeOH  products by layering a clear, yellow  2  intersolvent menisus  H bped-methanol solution on top of a 2  clear, red [Bu N][ReOBr ]-acetonitrile 4  [ReOBr r-CH CN  4  4  solution. In the absence of base, a green  3  Scheme 3.6. L L D  intersolvent meniscus formed within 15 minutes of layering the two solvents. The solution turned a clear blue and produced a royal blue microcrystalline powder i n 24 hours. The Tc analogue gave a green solution and a green microcrystalline powder. Small rectangular prisms were visible when viewed under the microscope for both complexes, but the crystals formed i n clusters and were unsuitable for X-ray analysis. The crystals were only sparingly soluble i n D M S O . The presence of base gave a green solution for Re and a clear brown solution for Tc. No crystals were formed at room temperature or at 4°C. The addition of bulky counter anions (Y) produced a fine white TBA+Y- precipitate. Reduction. The reduction reactions of perrhenate ([Re0 ]") and 4  pertechnetate ([Tc0 ]") were performed i n the presence of the potential ligand 4  under aqueous conditions with sodium dithionite ( N a S 0 ) or stannous 2  37  2  4  chloride dihydrate (SnCl »2H 0) as the reducing agent. The p H of the solution 2  2  was adjusted with NaOH and the reactions were carried out i n either a n acidic or alkaline environment. Changing the temperature, the reducing agent, or the base had no affect i n producing any complexes. The reduction of Re is very difficult. Tc is m u c h easier to reduce than Re, but tends to form a n insoluble black powder, T c 0 . The basicity of the pyridine groups was believed to 2  promote the hydrolysis of the Tc to T c 0 . 2  III.3.2 H p m e n a n d H p m e n » 4 H C l C o m p l e x e s 2  Metathesis  2  The same three precursor metals were used for H p m e n 2  and H pmen«4HCl and the same conditions used i n the H b p e d metathesis 2  2  reactions were followed. The solubility of H p m e n i n organic solvents allowed 2  C H C I 3 and C H 2 C 1 2 to be used i n addition to those used i n the H 2 b p e d  reactions. In the absence of base, no reaction between pmen2- and the [MO]3+ species occured. When two equivalents of base were added to H p m e n , only 2  the reaction with [ReO]3+ was successful, producing a violet powder (Scheme 3.7). There was no reaction with the [TcO] + analogue. The two Re 3  precursors, [Bu N][ReOBr ] and [Bu N][ReOBr (H 0)]«PBu gave products with 4  4  4  4  2  3  identical i H N M R which were only soluble in D M S O and D M F .  O  S c h e m e 3 . 7 . [ReO(pmen)][Re04l synthesis.  38  Liquid-liquid Diffusion Crystallization. Two and three phase L L D systems were set up with MeOH, C H C N , CHC1 3  3>  and C H C 1 as solvents. In 2  2  all cases, the Re reaction with base succeeded i n producing a violet powder. The product was identical to that of the metathesis reaction and there was no TBA+ contamination visible i n the ! H N M R spectrum. No crystals formed i n any of the L L D systems. Reduction.  Reactions of H pmen»4HCl with [NH ] [Re0 ] and 2  4  4  [NH ][Tc0 ] were unsuccessful. Changing the reducing agents and the p H of 4  4  the solution had no effect on the reaction system. The same results were observed as i n the reduction reactions with H bped. 2  III.3.3 Ester Complexes The three pmen-ester derivatives (pmen-OMe, pmen-OEt, and pmen-OBut) were reacted with Re and Tc i n the three proposed synthetic pathways, but did not yield any of the desired products. Changes i n the reaction conditions, such as temperature and the equivalents of base, had no effect on the outcome. A brown oil similar i n appearance to the ester starting material was obtained i n all cases. A black powder was isolated i n some cases when the oil was washed with chloroform or acetone. It was believed to be R e 0 or T c 0 because of its lack of solubility and it showed no signal i n the ! H 2  2  NMR. Infrared and i H N M R spectra showed only the presence of the starting materials and no formation of new products. It appeared that the pmen-ester derivatives easily hydrolyse the metals and are too basic to complex under the experimental conditions.  39  III.4 M e t a l Complexes: C h a r a c t e r i z a t i o n  A total of three complexes were successfully made and characterized i n this thesis: [ReO(bped)]Br, [TcO(bped)]Cl, and [ReO(pmen)][Re0 ]. 4  No crystal  structures were obtained for any of the complexes. Characterization was based o n mass spectrometry, elemental analysis, infrared spectroscopy, a n d i H N M R spectroscopy.  III.4.1 Mass Spectrometry and Elemental Analysis. The reaction of H b p e d with four equivalents of sodium acetate and Re and Tc showed strong 2  parent peaks of m/z 559 and 471 i n the positive LSIMS spectra, corresponding to [ReO(bped)]+ and [TcO(bped)]+ , respectively. There were no other peaks showing the corresponding metal isotope ratios, but TBA+ was present i n both of the spectra at m/z 242. Elemental analysis of the Re complex showed evidence of TBA+ and sodium acetate contamination. The calculated C,H,N analysis was not unabiguous, but one possible formulation was for [ReO(bped)]Br»[TBA+Br-] .4 (NaOAc)o.7 (found): C, 37.99 (37.90); H, 0  5  4.59 (4.51); N, 7.41 (7.47). No elemental analysis was obtained for the Tc complex. Positive(+) LSIMS for the Re reaction without base gave three strong patterns at m/z 623, 659, and 703. A less intense pattern at m / z 559 corresponding to [ReO(bped)]+ was observed, but the more intense peaks, even though they showed Re isotope ratios did not represent any plausible formulation. The reaction without NaOAc was not pursued any further i n favour of the reaction with four equivalents of NaOAc. Pmen - only complexed with Re to form [ReO(pmen)][Re0 ]. 2  4  Positive  LSIMS spectra showed a strong parent peak at m/z 443 corresponding to  40  [ReO(pmen)]+.  Negative LSIMS was also performed and showed the presence  of [Re0 ]" at m/z 252 and its presence was further confirmed by elemental 4  analysis. Again the elemental analysis was not unabiguous, but one possible analysis was calculated for [ReO(C Hi N )][Re0 ]«HCl: C, 23.06; H, 2.35; N, 14  6  4  4  7.68 and the found values were: C, 26.61; H, 2.36; N, 7.77. A trace amount of C H C N (0.2 eq) may also be present if solvent was retained from the reaction 3  mixture.  Calculated: C, 23.46; H. 2.41; N, 7.99.  III.4.2 Infrared Spectroscopy. The infrared spectrum of [ReO(pmen)][Re0 ] is shown i n Figure 3.5 and the assignments are listed i n 4  Table 3.4. The degree of hydrogen bonding within the ligand was greatly reduced upon complexation. The characteristic resonances between 1610-1000 c m - were still present in the complex, but they were dwarfed i n 1  comparison to the two large signals at 908 and 785 c m . The absorption at 1  785 c m - was characteristic of trans dioxo Re complexes and of perrhenate, 1  [Re0 ]~. 4  4,56.57  Since the possibility of a trans dioxo complex was eliminated by  elemental analysis and mass spectrometry, the absorbance was assigned to the 0=Re=0 stretch of the of perrhenate. The large absorption at 908 c m  1  was  assigned to the Re=0 stretch of [ReO(pmen)]+. The absorption was 40-50 c m lower than some characteristic complex Re=Q stretch absorbances.56,57  41  1  4  Figure 3.5. IR spectrum of [ReO(pmen)][Re0 ] (KBr disc).  Table 3.4. IR stretching frequencies (cm-i) for [ReO(pmen)][Re0 ]a 6  4  and [Co(H pmen)Cl ]C10 b.d and [Pd(H pmen)](PF ) 2  2  2  4  6  complexes.  b 2  Assign.  H pmen  D(N—H)  3315 s  3260 s 3215 s  U(C—H)  3100-2800 s, br  —  —  3100-2800 w, br  1610 s 1570 w  1612 1570 w  1608 m 1478 m 1444 m  c  [Co(H pmen)Cl ]+b.d 2  2  m m m m  2  [Pd(H pmen)]+ b ReO(pmen)][Re0 ] 2  4  3250 s  3435 s, br  D(C=N) D(C=C)  1612 1548 1521 1463 m  5 (CH )  1299 w  —  —  1281 w  D(M=0)  —  —  —  908 vs  D(0=M=0)  —  —  —  785 vs  2  a K B r disc, b Complex data taken from ref. 48 and spectra refer to hexachlorobutadiene and parafin oil mulls, c Sample analysed as liquid smear on NaCl disc, d cis-a-[Co(H pmen)Cl ]C10 . e Abbr. s= strong, m= medium, w= 2  2  4  weak, br= broad, vs= very strong.  The IR spectra from the bped - complexes are shown i n Figure 3.6 and 2  the assignments are listed i n Table 3.5. Complexation decreased the N—H, C=0, and M=0 stretching frequencies by 5-25 cm-i. The bands i n the Tc complex were also lower that the corresponding frequencies i n the Re complex, which was expected.  4  The C=0 stretch decreased i n frequency by 20-25  cm-i and the broad N—H and C — H stretching region narrowed and decreased i n intensity, due to the reduction of the intermolecular hydrogen bonding. The M=0 stretching frequency was decreased by 100 cm-i to 925 cm-i with  43  70  60T  50f  40r  75  [TcO(bped)]Cl  ft  70  65  60f 4000  3000  2000  IO'OO  Wavenumber Figure 3.6. IR spectra of [ReO(bped)]Br and [TcO(bped)]Cl complexes (KBr disc). 44  —  —  m m m m  925 m  1241 s  1612 1547 1436 1380  3  925 m,  1244 w  1608m 1478m 1444w 1358w  1691 vs  3100-2800 w  3404 s, br  (TcOfbped)JCl  s=strong, m= medium, w= weak, vs= very strong, br= broad.  [Co(bped)jPF analyzed as K B r disc from ref. 39. c Abbrev.  1303  *  1387 m  a A l l samples analysed as K B r discs.  D(M=0)  2  5 (CH )  ring  ring  6  1614 m 1467 m  1612 1548 1512 1463  D(C=N) D(C=C)  b  1675 s  1728 vs  D(C=0) s m m m  3100-2800 w  —  3000-2500 s, br  D(C—H) 1705 vs  3424 s, br  —  3500-3200 s, br  V(N—H)  [ReO(bped)]Br  6  [Co(bped)]PF b  2  H bped  Assign.  0  Table 3.5. IR stretching frequencies (cm-i) of bped complexes.  complexation and the addition of NaOAc. The Re- and Tc-bped complexes showed a weak signal between 770-780 c m which is characteristic of trans 1  dioxo stretching ( 0 = M = 0 ) .  4 5 6 5 7  This may be due to a small amount of trans  dioxo complex, or to the presence of [M0 ]~, one of the hydrolysis products of 4  [BU4NHMOX4]" (where M=Re, Tc, and X= Br, CI). III.4.3 i H NMR Spectroscopy. The i H N M R spectrum of [ReO(pmen)][Re0 ] at pD=5.5 is shown i n Figure 3.7 and the data are reported 4  i n Table 3.6 along with those for some other pmen-metal complexes.48 A splitting pattern similar to that demonstrated by [Co(H pmen)Cl ]C10 was 2  observed with the [ReO(pmen)][Re0 ].  2  4  The methylene hydrogens, H and H ,  4  6  7  were split into A A ' B B ' patterns that overlap i n the 6.2 - 3.8 p p m region. A i H C O S Y experiment was used to correlate the A B signals. The more downfield A B pattern was assigned to H 6 and the upheld A B pattern was assigned to H  7  i n agreement with the [Co(H pmen)Cl ]C10 . The pyridine hydrogen splitting 2  2  4  patterns remained as two doublets, a triplet, and a triplet of doublets (H ). The 3  pyridine hydrogens follow the same splitting pattern as the free H p m e n . One 2  noticeable difference was the large downfield shift of FL to 9.71 ppm. This large shift may be a result of the solvent coordination and the proximity of FL to the lower axial coordinating position occupied by the solvent molecule. The pyridine hydrogen assignments were referenced and assigned i n accordance with those for [Co(bped)]PF by D o u g l a s and C a r a v a n 27  6  40  and  [Co(H pmen)Cl ]C10 by Goodwin and L i o n s , and Gibson and McKenzie 4 8. 29  2  2  4  46  4  6  Figure 3.7. *H NMR (200 MHz) spectrum of [ReO(pmen))[Re0 ] in DMS0-d at pD=5.3.  Table 3.6. i H N M R (200 MHz) spectral dataa.b of [ReO(pmen)][Re0 ]c 4  and associated [Co(H pmen)Cl2]C10 c o m p l e x e s 2  de  4  (see  Figure 4.1) (in DMSO-d ). 6  cis-a-[Co(H pmen)Cl ] 2  H(l) ( Jl2) 3  H(2) (3J  2 1 >  3J  2 3  + d  f  cis-p-[Co(H pmen)Cl ]+ e.f [ReO(pmen)][Re0 ] 2  2  9.33 d (5.5)  9.35 d ; 9.14 d (6) (6)  9.71 d (5.0)  7.4 - 7.6 br  6.92  7.78 td (6.0. 0.79)  )  H(3)  8.2 t  ( J32' J34) 3  4  2  8.24 td (8.3, 1.3)  3  H(4)  7.6 - 8.4  7.6 d  8.03 d (7.8)  (^43)  H(6)  2.4 br  ( Jab)  5.30 A B (20.9) A =1.53ppm  2  A (ppm) H(7) ( Jab) 2  2.2 - 5.2 4.47 A B (17. 7)  4.28 A B (8.0) A = 0.58ppm  A (ppm)  a  A is the spread between the average chemical shifts of the A B patterns.  b  Numbers i n parentheses refer to coupling (J) i n Hz. c [ReO(pmen)][Re0 ] at 4  pD=5.5. d cis-a-[Co(H pmen)Cl ]C10 . 2  2  e  4  cis-p-[Co(pmen)Cl ]C10 . f Reference 2  4  48. Abbrev.: d= doublet, t= triplet, td= triplet of doublets, br= broad.  i H N M R measurements were done i n C D O D and D 0 for 3  2  [ReO(bped)]Br, b u t only with C D O D for the [TcO(bped)]Cl complex. The 3  spectra are shown i n Figure 3.8 and the assignments are listed i n Table 3.7. The [ReO(bped)]Br and [TcO(bped)]Cl splitting patterns i n C D O D were identical 3  with minor differences i n chemical shifts. The pyridine hydrogen splitting 48  2  3  Figure 3.8. iH NMR (300 MHz) spectra of IReO(bped)]Br in CD OD (top) at pD=5.5 and in D 0 (bottom) at pD=3.3.  Table 3.7. i H N M R (300 MHz) spectral dataa.b for bped - complexes of 2  ReO(V)c.d,  TcO(V)e, and Co(III)fg. Solvents are given i n parentheses.  [Co(bped)]PF (D 0) 2  [ReO(bped)]Br (D 0) 2  [ReO(bped)]Br (MeOD)  [TcO(bped)]Cl (MeOH)  8.95 d 5.9  9.12 d 5.9  9.13 d 4.9  9.27 d 6.9  3  7.84 t 5.4, 7.5  7.73 t 7.4, 7.4  7.68 t 6.0, 6.0  J32> <J34  8.30 t 7.5, 8.0  8.03 td 7.18, 1.4  8.06 t 6.0, 6.0  7.80 d 8.0  7.73 d 8.0  7.75 d 9.3  H(6) A (ppm) 2 J b  4.53 A B 0.36 15.0  4.87 A B 0.65 16.2  4.85 A B 0.73 10.3  4.66 A B 0.51 16.2  H(7) A (ppm)  3.73 A B 0.38 9.4  3.99 A B 0.49 17.4  3.92 A B 0.53 11.8  3.76 A B 0.43 17.3  3.76 A B 0.45 17.9  3.71 s  3.71 A B 0.12 7.6  3.75 A B 0.21 9.9  H(l) 3J  1 2  H(2) 3  J2i,  3  J  2  H(3) 3  3  H(4) 3  J  4  3  a  2  J  a  b  H(8) A (ppm) 2  Jab  6  7.71  e  8.20 t 6.9, 6.9 7.71  h  a A is the spread between the average chemical shifts of the A B patterns. b Coupling constants (J) are i n Hz. c [ReO(bped)]Br i n D 0 at pD=3.3. 2  d ReO(bped)lBr i n C D O D at pD=5.3. e [TcO(bped)]Cl i n C D O D at pD=5.3. 3  3  f [Co(bped)]PF (at 500 MHz) i n D 0 at pD=3.2. g Reference 40. 6  2  h Resonances were overlapping and undefined. Abbrev.: s= singlet, d= doublet, t= triplet, td= triplet of doublets.  patterns remained as two doublets, a triplet, and a triplet of doublets (H ) i n 3  D 0 and C D O D . The backbone region splits the H b p e d H , H , and H 2  3  2  50  6  7  8  singlets into three A A ' B B ' patterns i n C D O D . A n expansion of the backbone 3  region is shown i n Figure 3.9. The complex is rigid on the N M R time scale. Low temperature i H N M R experiment i n C D O D on the [ReO(bped)]Br complex 3  showed no change i n the shape of the signals i n the backbone region indicative of the existence of only one species. The [ReO(bped)]Br and [TcO(bped)]Cl complexes appear to be symmetric with the plane of symmetry or a C axis of 2  rotation bisecting the en ring and the central metal atom. H COSY N M R was l  used to correlate the A B patterns. A ! H N M R spectrum was also r u n on the [ReO(bped)]+ complex i n D 0 . 2  The pyridine region remained unchanged; however, the backbone region showed two A A ' B B ' patterns for H and H , and a singlet for H . The chemical 6  7  8  shifts between the C D O D and D 0 experiments were similar, yet the 3  2  difference i n signal patterns between the D 0 and C D O D spectra indicate two 2  3  different configurations. The pD difference between the D 0 and C D O D 2  3  solutions may play a role i n the different signal patterns; however, there was not enough time to investigate this possibility. The assignments made by Douglas  27  and C a r a v a n  40  on [Co(bped)]PF cannot be applied directly to the Re 6  and Tc complexes. The problem lies with the unrestricted ligand orientation around the binary cobalt system versus the ternary ReO and TcO systems containing an oxo atom that restricts the ligand's orientation about the metal atom. The ! H N M R and proposed structures will be discussed i n Chapter 4.  51  I I I  i | I I  l l | l l  4.8  r  i i |llii | l i ii ,  T  rr| l l i  i  4.4  ppm  1  4.0  I I i i i | l r l i | i M i | i i i i | ' i i | i i 11  | I '  l  l |li l  I | I  i I i|l  3.6  I I  3  l | l l l l | l l  3.2  l l| i i li | li li |i i ll|  iH NMR (300 MHz) spectrum (expansion) of [ReO(bped)]Br in CD OD at pD=5.5.  5.2  " " I ' '" r T i|  Figure 3.9.  I  IV. Proposed Structures of [ReO(bped)]Br, [TcO(bped)]Cl, and [ReO(pmen)][Re04] Complexes The infrared spectra and * H N M R spectra of the bped - and pmen 2  2  complexes had multitudes of similarities. The absorptions i n the IR spectra showed strong shifts of the M=0 stretching signals to lower frequencies upon complexation. The i H N M R spectra of the [ReO(bped)]Br and [TcO(bped)]Cl complexes i n C D O D showed nearly identical splitting patterns for the pyridine 3  and backbone regions. The assignments of the pyridyl hydrogens for the bped - and pmen - complexes were i n agreement with earlier s t u d i e s . 2  2  2 7 4 0 4 7  .  4 8  Despite having almost superposable ! H N M R spectra, a discrepancy with the assignments proposed by Douglas and Caravan arose for the backbone region among the [Co(bped)Cl ]C10 , [ReO(bped)]Br, and [TcO(bped)]Cl complexes. The 2  4  assignments made for the binary [Co(bped)Cl ] system could not be applied to +  2  the ternary [ReO(bped)]+ and [TcO(bped)]+ systems. The presence of the oxo group on the [ReO(bped)]Br and [TcO(bped)]Cl complexes reduced the freedom of orientation of bped - around the [ReO]3+ and [TcO]3+ metal centres a n d 2  eliminated the probability of a [Co(bped)Cl ]+ configuration. 2  In attempting to determine the structure from the *H N M R spectra, it is easier to begin with the [ReO(pmen)][Re0 ] complex and correlate the spectrum 4  with the [ReO(bped)]Br spectra i n D 0 and C D O D when assigning the 2  3  backbone resonances. Gibson and M c K e n z i e  48  identified four likely  orientations of some H p m e n and pmen - transition metal complexes, which are 2  2  shown i n Figure 4.1. Both cis-oc- and cis-p - configurations of [Co(H pmen)Cl ]C10 2  2  48 4  and [Fe(H pmen)Cl ]Cl»H Oi complexes have been 4  2  2  53  2  firmly established by earlier studies. ! H N M R on the cis-oc- and cis-P[Co(H pmen)Cl ]C104 configurations showed discrete differences i n splitting 2  2  patterns. The cis-cc-configuration showed four signals i n the pyridine region, characteristic of equivalent pyridyl units, and two A A ' B B ' patterns i n the backbone region. The cis-(3 configurations had eight signals i n the pyridine region, indicative of two inequivalent pyridyl units, and a complex series of signals i n the backbone region. A third possibility is a square planar p m e n 2 - or octahedral H p m e n configuration of the complex. Pd(II) 8 and Fe(III) have 4  14  2  been shown to maintain these configurations at the expense of significant steric effects i n the ligand. i H N M R studies of the square planar and octahedral configurations contained equivalent pyridyls, showing four signals, and the methylene hydrogens produced two singlets i n the backbone region due to the C  2 v  symmetry of the complexes. The IR data of the square planar  [Pd(H pmen)][PF ] complex was similar to those of the [Co(H pmen)Cl ]C10 2  6  HN  0  M  2  1—X  2  \  —X  HN X  (\  \  M  H  Py  X  cis-a (A)  cis-B (A)  trans  M = Co(III), Fe(III) _ l  x  M = Pd(II)(NoX) (square planar) M = Fe(III),X=Cl  C  Figure 4.1.  H2pmen  2  ligand orientation around Co(III) , 48  Fe(III) and Pd(II) metal centres. 14  48  54  4  and [ReO(pmen)][Re0 ] complexes. 4  Goodwin and L i o n s  note that the coordination covalency of N atoms of  29  pyridine rings i n open-chain planar quadridentate molecules is directed along the axes of the pyridine rings. The resultant pyridyl chelate rings are directed to a planar orientation around the metal centre with the two methylene units of the en both above (or below) the plane of coordination. A buckling of the en chelate ring across the line of centres of the N  e n  atoms is likely to occur i n  reducing strain within the ring. The ! H N M R of the [ReO(pmen)][Re0 ] complex showed a spectrum 4  identical to the cis-a-[Co(H pmen)Cl ]C10 configuration with four pyridine 2  2  4  signals and two A A ' B B ' patterns i n the backbone region. The presence of the oxo group creates a five coordinate complex. Using a combination of the above results, two possible deviations of the octahedral [Co(H pmen)Cl ]C10 2  2  4  geometries that could produce the observed i H N M R spectra for [ReO(pmen)][Re0 ] are the square pyramidal (spy) and trigonal bipyramidal (tbp) 4  configurations (Figure 4.2).  +  Figure 4.2.  Proposed [ReO(pmen)][Re0 ] structures. 4  55  The spy configuration has the four N atoms occupying the basal plane and the oxo group i n the apical position i n accord with Goodwin and L i o n s .  29  It is impossible to determine whether the metal centre is i n or slightly above the basal plane without a crystal structure. A C plane of symmetry bisects the s  en ring and the metal-oxo centre. The presence of the apical oxo group creates two different environments for the methylene hydrogens and accounts for the observation of two A A ' B B ' patterns i n the ! H NMR. The en and oxo group are i n the equatorial plane of the tbp, while the pyridyls occupy the trans axial positions i n a similar fashion to the cis-cc-[Co(H2pmen)Cl2]C104 complex. A C axis of rotation bisects the en ring 2  and the metal centre producing four pairs of symmetry-equivalent pyridyl hydrogens and three pairs of symmetry-equivalent methylene hydrogens. Two enantiomers are possible with this structure, unlike the spy structure. A two-fold symmetry is observed i n both the spy and tbp configurations of [ReO(pmen)][Re0 ]. 4  Interconversion between spy and tbp geometries has  been demonstrated for some complexes,60 but the orientations of the p m e n 2  ligand i n the proposed spy and tbp geometries for [ReO(pmen)][Re0 ] cannot 4  produce the interconversions with the necessary symmetry. Figure 4.3 shows  l  spy  tbp  Figure 4 . 3 . The ligand displacements needed to change a square pyramid into a trigonal bipyramid.  56  that interconversion from spy to tbp produces a n unsymmetiical tbp with cis oriented pyridyl groups. Distortion from one or the other of the two prototype structures is likely to occur and it is uncertain which is taken as the idealized geometry. The strong similarities with the IR and ! H N M R data between [Co(H pmen)Cl ]Cl04 and [ReO(pmen)][Re0 ] assigned the more downfield 2  2  4  A A ' B B ' pattern to the methylene protons on the picolyl group (H ) and the 6  upheld A A ' B B ' pattern was assigned to the methylene protons on the en (H ) i n 7  agreement with Gibson and M c K e n z i e .  48  [ReO(bped)]Br showed the two A A ' B B ' patterns already seen i n the [ReO(pmen)][Re0 ] (Figure 3.9) complex and an additional singlet i n D 0 or 4  2  A A ' B B ' pattern i n C D O D solvents (Figure 3.10) for the methylene hydrogens 3  (H ) when the acetate arms are present. Douglas based the assignments made 8  for the A A ' B B ' patterns of [Co(bped)]C10 on the coupling constants of A A ' B B ' 4  patterns from referenced symmetry-equivalent sets of methylene hydrogen atoms. If these assignments are followed i n the [ReO(bped)]Br complex, the third signal would be assigned to H , the methylene hydrogens on the picolyl 6  group. In this case, the N  e n  atoms are not coordinated i n D 0 solvent and the 2  [ReO(bped)]Br complex is a N 0 system of coordinated N 2  2  O atoms. In the C D O D spectrum, the N 3  e n  p y  atoms and acetate  atoms were coordinated trans to  the apical oxo group below the coordination plane via very long M—N bonds. The structures are shown i n Figure 4.4. Neither of these configurations correlate with the observed [ReO(pmen)][Re0 ] i H N M R spectrum and are 4  unlikely to occur.  57  o  ^  6  O  8  J  8  7  O  Figure 4.4. Proposed structure for [ReO(bped)]Br using assignments for [Co(bped)]PF6 from D o u g l a s and Caravan 27  The i H N M R splitting patterns of H and H i n the [ReO(bped)]Br and 6  7  [ReO(pmen)][Re0 ] spectra were near identical. The third signal i n the 4  [ReO(bped)]Br spectra, a singlet i n D 0 and an A A ' B B ' pattern i n C D O D , was 2  3  assigned to the methylenes on the acetate arms (H ) on the basis that its 8  absence i n [ReO(pmen)][Re0 ] generated no signal (Figure 3.9) and its presence 4  i n the [ReO(bped)]Br complex produced a signal (Figure 3.10). The strong similarity of the [ReO(bped)]Br and [Co(bped)]PF i H N M R spectra showing 6  three A A ' B B ' patterns strongly suggested that a N coordination plane also 4  exists i n the [ReO(bped)]Br complex. The H signal, A A ' B B ' pattern i n C D O D 8  3  or singlet i n D 0 , suggests that the acetate arms are coordinated i n methanol 2  and pendant i n water. Pendant acetate arms will give rise to a spy or tbp geometry. The apical oxo group above the basal plane i n the spy may force the acetate arms to reside below the coordination plane to minimize steric interactions. Free rotation of the acetate arms would create symmetryequivalent methylene hydrogens on the acetate arms to give rise to a singlet i n  58  D 0 . Free rotation of the acetate arms i n the tbp geometry would also 2  possible, but may be restricted due to steric interactions with the pyridyl Hi protons. The coordination of the acetate O atoms produces a n N 0 system and 4  2  adds two additional five-membered chelate rings giving rise to a seven coordinate pentagonal bipyramid (pbp) or a monocapped trigonal prism (mtp) configuration. A monocapped octahedron is a third seven-coordinate geometry; however, it does not give the necessary symmetry required. Figure 4.5 shows the proposed bped - complexes with pendant and coordinated acetate arms. 2  pentagonal bipyramidal  D 0  CD3OD  2  Figure 4 . 5 . Proposed [ReO(bped)] structures using *H N M R +  in D 0 and CD3OD. 2  59  A pbp orients the pyridyl groups i n the trans axial positions, while the en ring and acetate groups are i n the equatorial plane. The structure exhibits C symmetry with a n axis of rotation bisecting the en ring and metal centre. 2  The mtp contains the en and pyridyl N atoms in the equatorial plane and coordinated O atoms of the acetate groups underneath the plane i n close proximity to the central metal ion. To accommodate the acetate arms oriented below the plane, the methylene groups i n the en ring are elevated above the coordination plane. The configuration contains C symmetry with a plane of s  symmetry bisecting the en ring and the metal centre. The pbp and mtp both give rise to equivalent pyridyl groups and three sets of symmetry-equivalent methylene hydrogen pairs i n the i H N M R spectrum. The analogous [TcO(bped)]Cl complex takes the same configurations as its Re congener given the similarities i n the i H N M R between the [ReO(bped)]Br and [TcO(bped)]Cl spectra. The methylene groups i n the ligands were oriented either above, below, or i n the coordination plane i n the proposed structures of the bped - and 2  pmen - complexes. Axial and equatorial orientations of the methylene 2  hydrogens were present i n all the structures. Each methylene unit had two symmetry-inequivalent protons (i.e. a.b). Complementary methylenes gave rise to two pairs of symmetry-equivalent protons (i.e. 6a,6a'), which produced the A A ' B B ' patterns observed i n the backbone region. Figure 4.6 shows the orientations of the methylene hydrogens in the proposed complex structures.  60  Figure 4.6. Proposed structures of [ReO(pmen)][Re0 ], [ReO(bped)]Br, and [TcO(bped)]Cl showing methylene hydrogen orientation. 4  The proposed bped - and pmen - complex structures all contain 2  2  elements of strain i n ball-and-stick models. Conformational strain is experienced i n all the structures because of the shorter bond lengths and bond angles of the heterocyclic N atoms. Steric repulsion between the two pyridyl rings' substituents is pronounced i n the spy conformation of the bped - and pmen - complexes. The Hi protons 2  2  interact when the pyridyl rings are within the coordination plane of the spy and mtp. To accommodate this interaction, a twist i n the pyridyl rings to orient the Hi protons by placing them either above or below the plane.48 As a result of  61  the twist, the corresponding methylenes i n the picolyl groups are oriented above and below the basal plane opposite to the pyridyl. In other words, if the Hi is twisted below the plane, the corresponding methylene i n the picolyl group is oriented above the plane, and visa versa. The tbp and pbp avoid the H i interactions between the pyridyl groups by orienting them trans to one another i n the axial positions. However, there are H interactions with the methylene x  hydrogens (He) and the carboxylates of the pendant and coordinated acetate arms i n the bped complex. The free rotation of the pendant acetate arms is hindered and a n increase i n ring strain with the coordinated acetate arms is a result of their close proximity to the H i protons. This strong steric interaction makes the tbp and pbp configurations for the bped - complexes unfavourable 2  compared to the spy and mcp configurations. The H interactions are shown i n x  Figure 4.7. Cumulative ring strain is common i n planar polypyridyl ligands that give rise to systems of linked consecutive five-membered rings. Crystal structures of some aliphatic systems show the N — M — N e n  e n  bond angle within an en  chelate ring on the order of 87° compared to the favourable angle of 90° for octahedral and spy geometries.59.60 The en ring shows evidence of strain i n all the modelled complexes. The spy and mtp geometries appear to have bond angles slightly less than the ideal 90° i n the en ring. The tbp has an en ring i n the equatorial plane less than the expected 120°, and the N — M — N p y  p y  bond  angle appears to be slightly greater than 180°. The size of the central metal ion and the donor atom may affect the stability of the structure. Hoard notes that the size of the metal will affect the conformation and cumulative ring strain i n ligands involving five-membered  62  R  c>  /  R  Pyridyl rings H i interaction for spy and mtp M: Re :R = - C H C O O " , H Tc : R = - C H C O O " 2  2  H i interaction with methylene protons (H6) and carboxylate of pendant and coordinated acetate arm of tbp and pbp. Figure 4.7. Steric interactions in the Re and Tc complexes.  rings.6i Hancock has also noted that hexadentate ligands that form fivemembered rings tend to coordinate to larger metal ions with an additional unidentate ligand.62 The increase i n coordination number results i n longer M—N bond lengths which decreases the strain on the N—M—N bond angle. No evidence was found for the coordination of additional ligands to the metal centres, but the ligands should coordinate with less strain to the larger Re metal centre according to arguments proposed by Hoard and Hancock. The larger metal ion will increase the separation between the Hi pyridyl groups and decrease the degree of steric interaction. A n increase i n the size of the donor  63  atom has the same effect as metal size and also enhances steric constraints i n multidentate chelate complexes. A six coordinate octahedral configuration of [ReO(bped)]Br and [TcO(bped)]Cl may also be possible. The carboxylate groups on the acetate arms could alternate i n coordination to the [ReO]3+ centre in a fashion similar to that shown i n Figure 4.8. At room temperature the picolyl methylenes produce two pairs of symmetry-equivalent sets of methylene hydrogens. If the swinging action of the acetate arms is faster than the N M R time scale, the methylene  Figure 4.8. Alternating carboxylate group coordination i n [ReO(bped)] . +  hydrogens of the picolyl group would be equivalent and a singlet would be observed i n the ! H N M R spectrum. Low temperature ! H N M R studies of the [ReO(bped)]Br complex were performed i n C D O D in attempting to slow down 3  any rate of exchange that may be taking place. No change i n the third A A ' B B ' pattern associated with the picolyl methylene protons (H ) was observed, thus 8  64  eliminating the possibility of a six coordinate octahedral configuration. These proposed structures are all possibilities; however, the tbp and pbp configurations are not strongly favoured bped - complex configurations due 2  to the proposed steric interactions and the tendency of oxorheniumfV) and oxotechnetiumfV) to form square planar and octahedral complex. No evidence i n the form of a n X-ray diffraction study was available at this time to confirm a definite configuration of the bped - and pmen - complexes. A l l the proposed 2  2  structures were based on evidence derived from mass spectrometry, elemental analysis, IR spectroscopy, and ! H N M R spectroscopy.  65  References 1.  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