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Metal ion coordination chemistry of medicinal interest Saatchi, Katayoun (Seraji-Bozorgzad) 2005

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METAL ION COORDINATION CHEMISTRY OF MEDICINAL INTEREST by KATAYOUN SAATCHI (SERAJI-BOZORGZAD) B.Sc, Al-Zahra University, 1991 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Medicinal Inorganic Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA February 2005 © Katayoun Saatchi, 2005 Abstract Basic coordination chemistry of metal ions of medicinal interest is investigated and reported. The syntheses of vanadium complexes are reported using the naturally occurring ligating moieties isomaltolate (ima") and allomaltolate (ama"), as well as a newly synthesized, potentially tetradentate diaminodipyrone [en(ama)2]2". Complete characterization of the resulting compounds (trans-VO(ima)2(H20), VO(ama)2, V(ima)3, V(ama)3 and VO(en(ama)2), including X-ray crystallography analyses for trans-VO(ima)2(H20) and V(ima)3, are presented herein. The crystal structure of trans-VO(ima)2(H20) shows a coordinated water trans to vanadyl. Potentiometric titrations (25°C, 1= 0.16 M NaCl) were used to measure stability constants in the V(IV)- ima", V(IV)- ama" and V(V)- ama" systems; these data were compared to previous data collected on the V-maltolate system. In vivo efficacy of these compounds to normalize the blood glucose levels of STZ diabetic rats was tested; all but VO(en(ama)2) produced significant decreases in plasma glucose levels. The results were compared to those of the benchmark compound BMOV (VO(ma)2, bis(maltolato)oxovanadium(IV)), a proven insulin-enhancing agent. Rhenium complexation to [en(ama)2] " is also investigated. The resulting complex ReO(en(ama)2)Cl was characterized by a variety of techniques including ID and 2D NMR spectroscopy. These results clearly point to asymmetric binding of the ligand to the metal centre, leaving O = Re - CI in a cis configuration. Novel complexes of Ga and In were synthesized with a group of hetero donor phosphinophenolate ligands (PO", (or£/zohydroxophenyl)diphenylphosphine; MePO", (2-ii hydroxo-5-methylphenyl)diphenylphosphine). The two metal ions interestingly show diversity in their chelation to phosphinophenolates. The RPO" (R = H, Me) heterodonor ligand binds in a bidentate fashion through both the hard and the soft donor atoms to In; whereas, it only chelates Ga through the hard oxygen donor. Electrochemical synthesis proved to be a practical synthetic approach. In2(PO)3Cl3, In(PO)3 and In(MePO)3 were synthesized by electrolysis. [In(MePO)(H20)Cl2]2 and Ga(HPO)Cl3 were synthesized using MCI3 (M = In and Ga respectively). Both dimetallic indium complexes, [In(MePO)(H20)Cl2]2 and In2(PO)3Cl3, show the phenolate oxygens bridging between the two metal ions. All four In atoms are in a distorted octahedral geometry in both complexes with the former having a coordination sphere of PO3CI2 for both indium metal ions and the latter showing a coordination sphere of PO3CI2 for one indium and P2O3CI for the other. Ga(HPO)Cl3 is a zwitterionic complex, with Ga having a OCI3 coordination core. All these complexes were fully characterized including X-ray crystallography. iii Table of Contents Abstract Table of Contents Lists of Tables Lists of Schemes Lists of Figures Lists of Abbreviations Acknowledgements Dedication 11 iv x xii xiii xviii xxiv xxvi Chapter 1 Metals in Medicine 1.1. Introduction 1.1.1. Bioinorganic Chemistry 1 1.1.2. Remedy or Poison 2 1.2. Metals in Medicine 1.2.1. History and Applications 5 1.2.2. Metal Complexes 7 1.2.3. Inorganic Pharmaceuticals 8 1.3. This Work 14 1.4. References 7 iv Chapter 2 Vanadium Complexes of C6H6O3 Structural Isomers 2.1 Introduction 2.1.1. Vanadium 21 2.1.2. Aqueous Chemistry of Vanadium 22 2.1.3. The Role of Vanadium in Biological Systems 24 2.1.4. Diabetes 26 2.1.5. Vanadium and Diabetes 28 2.2. Experimental 2.2.1. Materials 35 2.2.2. Instrumentation2.2.3. Syntheses of Compounds 2.2.3.1. Isomaltol 36 2.2.3.2. Trans-bis(isomaltolato)aquaoxovanadium(IV) 37 2.2.3.3. Tris(isomaltolato)vanadium(III) 38 2.2.3.4. Bis(allomaltolato)oxovanadium(IV) 39 monohydrate 2.2.3.5. Tris(allomaltolato)vanadium(III) 39 monohydrate 2.2.3.6. Bis(isomaltolato)methoxyoxovanadium(V) 39 2.2.4. Potentiometric pH Titrations 40 2.2.5. Solid State X-ray Crystal Structures 40 2.2.6. In Vivo Animal Studies 41 v 2.3. Results and Discussions 2.3.1. Proligands 42 2.3.2. Vanadium(IV) Complexes 44 2.3.3. Vanadium(III) Complexes 52 2.3.4. Solution Studies 58 2.3.5. Biological Results 63 2.4. Conclusions 66 2.5. References 8 Chapter 3 Vanadium and Rhenium Complexes of a Tetradentate Aminopyrone 3.1. Introduction 3.1.1. Vanadium 75 3.1.2. Rhenium 7 3.2. Experimental 3.2.1. Materials 80 3.2.2. Instrumentation3.2.3. Syntheses of Compounds 3.2.3.1. /v: Af'-Bis(3-hydroxy-6-methyl-2- 81 methylene-4-pyrone)ethylenediamine 3.2.3.2. N, 7V-bis(3-hydroxo-6-methyl-2- 81 methylene-4-pyrone)ethylenediamine oxovanadium(IV) dihydrate vi 3.2.3.3. Chloro-TV, AP-bis(3-hydroxo-6-methyl- 82 2-methylene-4-pyrone)ethylenediamineoxorhenium(V) 3.2.4. In vivo Studies 83 3.3. Results and Discussion 3.3.1. Proligand 83 3.3.2. Vanadium(IV) Complex 84 3.3.3. Rhenium(V) Complex 6 3.3.4. Solid State Structure of [H4(en(ama)2)][(Re04)2] 93 3.3.5. Biological Results 96 3.4. Conclusion 99 3.5. References 100 Chapter 4 Gallium and Indium Complexes of Multidentate PO Donors 4.1. Introduction 4.1.1. Gallium and Indium 103 4.1.2. Coordination Chemistry of Gallium and Indium 105 4.1.2.1. Solution Chemistry of Gallium and Indium 106 4.1.3. Gallium, Indium and Nuclear Medicine 108 4.1.4. Previous Contributions from the Orvig Group 114 4.1.5. Heterodonor Phosphinophenolates 115 4.2. Experimental 4.2.1. Materials 118 4.2.2. Instrumentation 11vii 4.2.3. Electrochemical Synthesis 119 4.2.4. Neutralization of Proligands 4.2.4.1. R-HPO (R = H, Me) 119 4.2.4.2. Me2-H2P02 114.2.4.3. Me4-H4P204 120 4.2.5. Syntheses of Compounds 4.2.5.1. Trischlorotris(p.-0(or£/zohydroxophenyl) 120 diphenylphosphinato)diindium(III) 4.2.5.2. Tris((2-hydroxo-5-methylphenyl)diphenyl 121 phosphinato)indium(III) triacetonitrile 4.2.5.3. Tris((or£/zohydroxophenyl)diphenyl 121 phosphinato)indium(III) 4.2.5.4. Bisaquatetrachlorobis(u.-0 122 (2-hydroxo-5-methylphenyl)diphenylphosphinato) diindium(III) dietherate 4.2.5.5. (CW/zohydroxophenyl)diphenyl 122 phosphoniumtrichlorogallium(III) Hydrochloride 4.3. Results and Discussion 4.3.1. Proligands 123 4.3.2. Metal Complexes 127 4.4. Conclusions 143 4.5. References 5 viii Chapter 5 Conclusions and Ideas for Further Work 5.1. Conclusions 153 5.2. Ideas for Further Work 155 5.3. References 161 Appendix A X-ray Crystallographic Analyses 162 ix Lists of Tables Table Description Page 2.1. Selected IR vibrations (KBr, ± 4 cm"1) in the new complexes. 45 2.2. Selected bond lengths (A) and angles (°) for trans-V(ima)2(H.20). 52 2.3. Selected bond lengths (A) and angles (°) in V(ima)3. 56 2.4. Acidity constants of the three C6H6O3 structural isomers 59 and stability constants of the complexes formed between V(IV) and these ligands (/ = 0.16 M NaCl, 25 °C) and for Hacac and VO(acac)2 (7= 0.1 M NaC104, 25 °C). 3.1. Assignment of the 'H NMR spectrum for ReOCl(en(ama)2). 90 3.2. 13C NMR assignments for ReOCl(en(ama)2) in 92 CD3CN/D20(1:2). 3.3. Selected bond lengths (A) and angles (°) for 95 [H4(en(ama)2)][(Re04)2]. 4.1. Characteristics of selected y, P" and p+emitting radiometals. 109 4.2. 31P NMR chemical shifts of neutralized PO proligands. 126 4. 3. Selected bond lengths (A) and angles (°) in In2(PO)3Cl3. 131 4.4. Selected bond lengths (A) and angles (°) in 138 [In(MePO)(H20)Cl2] 2-2Et20. 4.5. Selected bond lengths (A) and angles (°) in 142 Ga(HPO)Cl3HCl. Al. Selected crystallographic data for trans-VO(ima)2(H20) 169 and V(ima)3. x A2. Hydrogen bond data for VO(ima)2(H20) [A and °]. 170 A3. Selected crystallographic data for [H4(en(ama)2)][Re04]2 171 A4. Selected crystallographic data for In2(PO)3Cl3, 172 [In |a-(MePO)Cl2(H20)]2-2Et2Oand Ga(HPO)Cl3HCl. A5. Hydrogen bond data for 173 [In p.-(MePO)Cl2(H20)]2-2Et20 [A and °]. A6. Selected crystallographic data for [H3P02]GaCl4CH2Cl2. 174 A7. Complete list of bond lengths and bond angles 175 for trans-VO(ima)2(H20). A8. Complete list of bond lengths and bond angles for V(ima)3. 179 A9. Complete list of bond lengths and bond angles for 184 [H4(en(ama)2)][(Re04)2]. A10. Complete list of bond lengths and bond angles for In2(PO)3Cl3. 186 All. Complete list of bond lengths and bond angles for 194 [In p.-(MePO)Cl2(H20)]2-2Et20. A12. Complete list of bond lengths and bond angles for 198 Ga(HPO)Cl3HCl. A13. Complete list of bond lengths and bond angles for 201 [H3P02]GaCl4CH2Cl2. xi Lists of Schemes Scheme Description Page 2.1. Two part synthesis of Hima. 43 2.2. Synthesis of Hama. 44 2.3. Hydrogen-bonded tautomers of Hima; structure 46 of the isomaltolate anion. 3.1. Possible diastereomers for the six coordinate 88 complex of a tetradentate N2O2 ligand relative to Re=0. 4.1. Synthetic route to the phosphinophenol HPO and 124 H2PO2 proligands (x = 1, 2; R = H, CH3, t-Bu). 5.1. Various potential chelators that could be synthesized 156 from H2(en(ama)2) . xii Lists of Figures Figure Description Page 1.1. The periodic table of elements, metals whose atomic symbols 4 are highlighted in white are of importance to biological systems either due to their essentiality or applications (i.e. as metallopharmaceuticals or probes). 1.2. A typical dose-response diagram for an essential element. 5 1.3. Platinum and gold metal complexes used as therapeutic drugs. 10 1.4. Structures of some marketed 99mTc radiopharmaceuticals. 13 1.5. Structures of two Gd complexes used as MRI contrast agents. 14 1.6. C6H6O3 structural isomers: maltol (Hma), allomaltol (Hama) 16 and isomaltol (Hima). 1.7. Structure of the potentially tetradentate aminopyrone, 16 H2(en(ama)2) and the potentially bidentate phosphinophenol, R-HPO. 2.1. Speciation diagram for V(V) as a function of pH, [Vtotal] = 10 uM. 23 2.2. Speciation diagram for V(IV) as a function of pH, [Vtotal] = 10 uM. 23 2.3. Dodecahedral structure of amavadin, a natural nonoxo 25 V(IV) compound. 2.4. Streptozotocin (STZ). 27 xiii 2.5. Structures of vanadate anion [H2VO4]", 30 vanadyl cation in aqueous solution at pH ~ 7 and the vanadium coordination complexes BMOV and BEOV. 2.6. Structures of various vanadyl complexes. 31 2.7. Structures of the C6H6O3 isomers, maltol (Hma), 34 allomaltol (Hama) and isomaltol (Hima). 2.8. IR spectra (KBr disk) in the 500-2000 cm"1 region for 46 trans-VO(ima)2(H20) and VO(ama)2H20. 2.9. Typical electron ionization mass spectrum of VOL2 (L = ima", ama"). 48 2.10. Intermolecular H-bonding between neighbouring molecules of 50 trans-VO(ima)2(H20) (above); ORTEP drawing of trans-VO(ima)2(H20) (below), 50% thermal probability ellipsoids are shown. 2.11. Infrared spectra of isomaltol (top) and V(ima)3 (bottom). 54 2.12. Positive ion detection liquid secondary mass spectrum (LSIMS) 55 of the V(III) complexes, VL3 (L = ima", ama"). 2.13. ORTEP drawing of V(ima)3 (two of the ligands are each shown 57 in one of two disordered orientations), 50% thermal probability ellipsoids are shown. 2.14. Species distribution diagrams for the complexation of V(IV) 60 with Hima (top) and Hama (bottom) (L:V(IV) = 4:1; [V(IV)] = 0.1 mM; /= 0.16 mM; 25 °C). 2.15. Plot of pM vs. pH for the V(IV)-Hma, Hama and Hima systems 62 (L:V(IV) = 4:1; [V(IV) = 0.1 mM; /= 0.16 MNaCl; 25 °C). 2.16. Species distribution diagram for the Hama-V(V) system 62 (L:V(V) = 4:1; [V(V)] = 0.1 mM; 7= 0.16 NaCl; 25 °C). 2.17. Plot of the plasma glucose levels in control (C) and 64 STZ-diabetic rats (D) following a single oral gavage administration of either CMC (1%) (CT) or trans-VO(ima)2(H20) (DDT) in comparison to BMOV (DT). 2.18. Plot of the plasma glucose levels in control (C) and STZ-diabetic 64 rats (D) following a single administration of either CMC (1%) (CT) or V(ima)3 (DDT) in comparison to BMOV (DT), by i.p. injection. 2.19. Plot of the plasma glucose levels in control (C) and STZ-diabetic 65 rats (D) following a single administration of either CMC (1%) (CT) or V(ama)3 (DDT) in comparison to BMOV (DT), by i.p. injection. 2.20. Plasma glucose-lowering (%) of trans-VO(ima)2(H20), V(ima)3 67 and V(ama)3 as compared to BMOV. 3.1. Structures of some potential NO donor proligands. 76 3.2. Infrared spectra of the proligand H2en(ama)2, VO(en(ama)2) 85 and ReO(en(ama)2)Cl (KBr disks, cm"1). 3.3. Electrospray mass spectrum of VO(en(ama)2) in 86 MeOH/1% formic acid. 3.4. (+)LSIMS spectrum of ReO(en(ama)2)Cl 87 (inset shows the simulation). xv 3.5. 'H NMR spectrum and assignments for ReOCl(en(ama)2) 90 in CD3CN/D20(1:2). 3.6. 2D-COSY (bottom) and'H-13C HMQC (top) spectra 91 of ReOCl(en(ama)2) in CD3CN/D20 (1:2). 3.7. ORTEP drawing of [H4(en(ama)2)][(Re04)2] 94 asymmetric unit - half the cation, one anion (50% thermal probability ellipsoids are shown). 3.8. Plot of glucose concentration as a function of time in 96 STZ-diabetic rats (D) and rats treated with a single oral gavage administration of VO(en(ama)2) (DDT) or BMOV (DT). 3.9. Plot of pM vs. pH for the V(IV)-Hma, Hima and H2(en(ama)2) 97 systems (L:V(IV) = 4:1(L = Hima, Hma), L:V(IV) = 2:1 (L = H2(en(ama)2)); [V(IV) = 0.1 mM; 1= 0.16 M NaCl; 25 °C). 3.10. Comparison of % glucose lowering with BMOV compared to 98 that of a strong [(en(ama)2) "] and a weak (ima") chelator. 4.1. Examples of different coordination numbers and geometries 107 for Ga and In. 4.2. Solution speciation diagram for In(III) as a function of pH, 109 [Intotal] = 10"5 M. 4.3. Examples of various proligands for Ga3+ and In3+ metal ions 112 which have been investigated for potential applications in nuclear medicine. xvi 4.4. Chemical structure of the multidentate phosphinophenols. 117 4.5. The set up for electrochemical synthesis. 126 4.6. 3IP NMR (CD2C12, 121.5 MHz) spectra of In2(PO)3Cl3 128 at 25 (top) and -90 °C (bottom). 4.7. ORTEP illustration of In2(PO)3Cl3, 50% thermal ellipsoids 130 are shown. 4.8. 31P NMR spectrum of In(PO)3 (121.5 MHz, CD2C12). 134 4.9. EI mass spectra of In(MePO)3 (top) and In(PO)3 (bottom). 136 4.10. EI mass spectrum of [In(MePO)(H20)Cl2] 2-2Et20. 136 4.11. 3IP NMR spectrum of [In(MePO)(H20)Cl2]2-2Et20. 137 4.12. ORTEP drawing of the indium dimeric complex 137 [In(MePO)(H20)Cl2]2 -2Et20, 50% thermal probability ellipsoids are shown. 4.13. Measured (left) and calculated (right) EI (top) and LSI(-) 140 (bottom) mass spectra of Ga(HPO)Cl3. 4.14. 31P NMR spectrum of Ga(HPO)Cl3 141 (121.5 MHz, CD2C12, JHP = 510 Hz). 4.15. ORTEP drawing of the metal complex in Ga(HPO)Cl3-HCl, 141 50%o thermal probability ellipsoids are shown. 5.1. Mass spectrum of the product of the reaction between 159 H2P02and GaCl3. 5.2. ORTEP drawing of [H3P02] [GaCl4], 50% thermal 159 ellipsoids are shown. xvii Lists of Abbreviations Abbreviation Meaning ~ approximately a alpha particles A angstrom, 1 x 10"10 metre Ajso isotropic hyperfine coupling constant Anal analytical ATPase adenosine triphosphatase P~ beta particles P+ positron /J120 overall stability constant of a bisligand-monometal complex BEOV bis(ethylmaltolato)oxovanadium(IV) B.M. Bohr magneton BMOV bis(maltolato)oxovanadium(IV) C healthy rats (Control) °C degrees centigrade C6H603 empirical formula for the structural isomers maltol, allomaltol and isomaltol Calcd calculated CMC carboxymethylcellulose cm"1 wavenumber(s), reciprocal centimetre COSY correlated spectroscopy (NMR) xviii CT healthy rats treated with BMOV (Control Treated) 8 chemical shift in parts per million (ppm) d day(s); doublet (NMR) D hyperglycemic rats (Diabetic) D dimension DT hyperglycemic rats treated with BMOV (Diabetic Treated) DDT hyperglycemic rats treated with a new compound (Diabetic Drug Treated) DMSO dimethylsulfoxide DTP A N,N,N',N",N" '-diethylenetriaminepentaacetic acid E° standard electromotive force of a half-reaction EC electron caption Ef number of moles of metal dissolved per Faraday of charge in an electrochemical reaction EIMS electron impact ionization mass spectrometry en ethylenediamine EPR electron paramagnetic resonance ESIMS electrospray ionization mass spectrometry eV electron volt(s) fac facial isomer of a complex in Oh geometry FDA Food and Drug Administration (USA) fw formula weight y gamma rays xix g gram(s) giso isotropic g-factor (EPR) GI gastrointestinal GOF goodness of fit (crystallography) h hour(s) H2(en(ama)2) N, A^'-bis(3-hydroxy-6-methyl-2-methylene-4-pyrone) H2PO2 bis(o-hydroxyphenyl)phenylphosphine H2P2O4 P, P, P', P'-tetrakis(o-hydroxyphenyl)diphosphinoethane Hma maltol Hama allomaltol Hima isomaltol HMQC Heteronuclear Multiple Quantum Coherence HPO o-hydroxyphenyldiphenylphosphine HSA human serum albumin HSAB Hard Soft Acid Base Hz hertz (s"1) IDDM insulin dependent diabetes mellitus I ionic strength (potentiometry) i.p. intraperitoneal IR infrared IT isomeric transition (y emission) J coupling constant (NMR) k kilo- (103) xx K Kelvin(s) Ka acidity constant K\\o stability constant of a monoligand-monmetal species K\20 stability constant of a bisligand-monometal species K\2-l stability constant of a hydrolized bisligand-monometal species X wavelength L litre; ligand Ln lanthanide(s) LSIMS liquid secondary ion mass spectrometry micro (10"6) Meff effective magnetic moment in BM u-0 bridging oxygen m milli- (10"3); medium (IR); multiplet (NMR) M molar (moles/litre for concentration); metal MeHPO (2-hydroxy-5-methylphenyl)diphenylphosphine Me2H2P02 bis(2-hydroxy-5-methylphenyl)phenylphosphine Me4H4P204 P, P, P', P'-tetrakis(2-hydroxy-5-methylphenyl)diphosphinoethane min minute(s) mol mole(s) MOM methoxymethyl MPJ magnetic resonance imaging m/z mass to charge ratio (in mass spectrometry) n nano- (10"9); number of samples v stretching frequency NADH nicotineamide adenine dinucleotide, reduced form NIDDM non-insulin dependent diabetes mellitus NMR nuclear magnetic resonance o ortho ORTEP Oak Ridge Thermal Ellipsoid Program PET positron emission tomography PGP percent glucose lowering potency pH negative logarithm of the concentration of H+ (proton) pKa negative logarithm of the acidity constant (Ka) PO phosphinophenolate ppb parts per billion ppm parts per million proligand the organic molecule from which the ligand bound to the metal is derived (usually by deprotonation) p density s second(s); strong (IR); singlet (NMR) SD standard deviation SEM standard error of mean (defined as SD/(n ), where n = number of samples) SPECT single photon emission computed tomography STZ streptozotocin t triplet (NMR) xxii T temperature tj/2 half-life Tf human serum transferrin TMEDA tetramethylehylenediamine TMS tetramethylsilane (NMR) upe unpaired electron V volume V volt(s) Vtotai total volume y year(s) Z number of molecules per unit cell (X-ray crystallography) xxiii Acknowledgements First and foremost I would like to thank Dr. Chris Orvig for his wisdom and knowledge, endless support, patience, optimism and encouragement throughout the duration of my studies and for nurturing independence and individual action for the group members. I would like to acknowledge Dr. Kathie Thompson for all her help and discussions about biological properties of vanadium; her knowledge is a precious asset to the group. I also thank Dr. John McNeill and Violet Yuen for their collaboration in the vanadium project. I am immensely grateful to Dr. Nick Burlinson for the help, discussions and all suggestions for the NMR studies, and to Drs. Brian Patrick and Maren Pink for the X-ray crystallographic studies. My thanks go to Drs. Barry Liboiron and Bin Song for collecting the EPR spectrum of VO(ima)2, and for discussions and suggestions with the potentiometric titrations, respectively. Thank you to all the members of the chemistry department especially the support staff, most notably Marietta Austria, Liane Darge, Peter Borda, Marshall Lapawa, Minaz Lakha and Lina Madilao. My gratitude goes to all the ladies in the office for having a helpful hand and wearing a friendly smile all the time especially Sheri Harbour, Lani Collins, Bev Evans and Judy Wrinskelle. Also thanks to Mike Hatton and everybody in the electronic engineering services for helping me set up for the electrochemistry, to Ron Marwick and all others in the mechanical engineering services for their help and to Brian Ditchburn for all the tiny glassware he made for my work. xxiv For help with proofreading I must thank Dr. Cecilia Stevens and Cheri Barta. My sincere thanks to the Orvig group: Peter Hein, Ika, Leon, Mike, Barry, Dave, Devin, Vishakha, Karycia, Tim, Cara, Cheri, Chuck, Meryn, Lauren, Khosro, Michael, Neil and all other past and present group members for all their help, friendliness and good memories throughout the years. Last, but certainly not least, my most heartfelt thanks are extended to my family who, in a way, were on this long roller coaster ride with me throughout the course of my studies. To my parents who have always been there for me, for their never-ending love and encouragement and their pride in my achievements all through my life; to my mother-in-law for all her heartfelt love and support, to my brother Kambiz for giving me the courage to reach for my dream and for all his love and support; to all my sisters for their love and support, to my children for all the school events I missed and all the practices or parties they missed and finally thanks to my husband for his wholehearted love, endless support and much much more. xxv To my parents, Mr. And Mrs. Akbar and Shokouh Seraji-Bozorgzad, who instilled in me many values including determination and appreciation, reaching for the sky and pride in doing ones best. I will treasure these gifts with all my heart forever. To my husband, Saeed and my children (Armin, Anaheed, Ariana and Artemis) who are the best thing that ever happened to me, with all my love. xxvi Chapter 1 Metals in Medicine "Many have said of Alchemy, that it is for the making of gold and silver. For me such is not the aim, but to consider only what virtue and power may lie in medicines." Paracelsus (1493-1541) 1.1. Introduction 1.1.1. Bioinorganic Chemistry Until the early 1800s, chemistry was divided into two separate and distinct fields known as "organic" and "inorganic", the former representing material isolated from living organisms and the latter referring to the chemistry of "dead matter". By the mid 19th century, the field of biochemistry was introduced as a non-substance based term to signify the chemistry of living organisms; however, it was limited to carbon-based molecules. It took another century before "metals in biology" was recognized as an independent and interdisciplinary field [1,2]. Currently, bioinorganic chemistry is defined as the cross point of biology and inorganic chemistry (i.e. when an inorganic element, ion or compound is shown to have a specific activity in a biological system) [3]. This field has shaped the understanding of the function of metal ions in biology, including their processing, their incorporation into proteins and their nature and role in metalloproteins. 1 References start on page 17 Nature singles out a suitable metal ion for various biological functions relative to life processes. The incorporation of inorganic elements is a vital part of many biochemical processes in living organisms [4]; therefore, there has been increased interest in defining the essentiality of metals in order not only to understand metabolic pathways and mechanisms, but also to use this information in the development of metal-based pharmaceuticals for treatment and diagnosis of disease. Bioinorganic chemistry as a newer field of research has succeeded swiftly in elucidating the role of metal ions in biological systems for the past thirty years. Factors influencing the rapid growth in this field are: advanced analytical approaches, easier preparative methods, applications of various characterization techniques, ability to understand and model the biological systems, applications of metal complexes in therapy and diagnosis and, last but not least, the growing knowledge about the number and significance of trace metals in various biological systems. 1.1.2. Remedy or Poison Some 30 elements including many different metal ions, are known to be essential to animals [5]. The word "essential" is used for an element with a specific biological task whose concentration is controlled by physiological mechanisms. Removal of this element from the biological system should cause deficiency diseases and excess concentration of the element could also lead to serious illness; eventually an extreme at either end could lead to death. Carbon, hydrogen, nitrogen, oxygen, phosphorus and sulphur are the most abundant essential elements of living matter. Bulk metals like sodium, potassium, 2 References start on page 17 magnesium and calcium form about 1% of the human body weight. Trace metals (manganese, iron, cobalt, zinc, molybdenum, copper and chromium) however, constitute < 0.01%. Molybdenum is the only essential non-first row transition metal. Iron is the most abundant essential transition metal in the human body. Hemoglobin ("the pigment of life") and myoglobin are iron-containing proteins that bind oxygen. The former delivers oxygen to all body tissue and the latter is an intracellular oxygen storage site in the muscle. Bone, the scaffold of the human body, is composed mainly of hydroxyapatite, a calcium based mineral [6]. Zinc and copper are a part of metalloenzymes performing various chemical reactions necessary to life. A metalloenzyme is a metal-containing protein that acts as a chemical catalyst in a living system [3]. Some of these metal ions are naturally found in various biological systems while the others are only used as a means of investigation or as therapeutic or diagnostic drugs (Figure 1.1). As Paracelsus, the 16th century Swiss physician stated: "The dose makes the poison." A dose/response graph (Figure 1.2) can be used to interpret the physiological response of an essential element to its concentration. This idea can be generalized to include drugs and their effects on biological systems (the benefit and detriment with respect to dose). The range of concentration in which an element or drug can be advantageous varies for different elements or compounds; therefore the shape of the curve varies with the considered element or compound. This depends on the nature of the element (or the compound), method of administration and interactions with other moieties in the biological system. For example the effects of unbalanced concentrations of many essential trace metals are well studied. Iron overload has been related to several chronic diseases including diabetes [7], cancer [8], cardiovascular problems [9] and liver 3 References start on page 17 Figure 1.1. The periodic table of elements, metals whose atomic symbols are highlighted in white are of importance to biological systems either due to their essentiality or applications (i.e. as metallopharmaceuticals or probes). disease [10] among others. It is also a very severe secondary disease in major thalassemia patients [11]. Iron deficiency would ultimately lead to anemia [12], the most common nutritional deficiency worldwide [13]. Copper is yet another essential transition metal used by enzymes as a catalytic cofactor [14]. While scarcity of copper can lead to growth retardation [15] increased copper concentration can be cytotoxic in cells [16]. Menkes and Wilson's 4 References start on page 17 Deficiency symptoms Toxicity Figure 1.2. A typical dose-response diagram for an essential element. diseases are serious genetic disorders in humans caused by malfunctions in the copper transport system in the cells that causes accumulation of excess copper and therefore, copper overload is considered a sombre health hazard for these patients [17]. A chelating agent capable of complexation with the metal ion to enhance its excretion can treat or help prevent overload cases. Chelation therapy is the most common method of treatment in patients with increased concentrations of metal ions. 1.2. Metals in Medicine 1.2.1. History and applications Understanding the use of metals in living organisms and exploring the structure and function of biological systems using metal-based compounds has allowed the formation of a new area in bioinorganic chemistry: medicinal inorganic chemistry. It is the application of inorganic chemistry in developing new compounds for disease 5 References start on page 17 treatment or diagnosis [18, 19]. There are many inorganic pharmaceuticals currently existing with clinical applications and the field is growing rapidly; however, many areas in this field are still underdeveloped. Application of metals in practicing medicine is not a new concept. It is known that the Egyptians used copper to sterilize water in 3000 BC. Arabs and Chinese used gold in medicine about 2500 BC - it was considered a panacea [20]. However, in ancient times these metals, as well as many others used, were not studied or characterized well. Silver nitrate in 1881 was the first antibiotic used in Europe to treat infant blindness [21, 22]; this treatment is still utilized today. As a diuretic, mercurous chloride was used during the Renaissance period, a common practice until the 1950s [23]. Ehrlich was the first person to study the relationship between structure and activity of the inorganic arsenic compound arsphenamine (also known as Elrich 606 or Salvasaran) that was used with great success for the treatment of syphilis [24]. French physician Forestier used gold compounds in 1929 for the first time to treat rheumatoid arthritis [25], a practice still used today. Lithium, the lightest solid element, with a relatively simple chemistry, was introduced into psychiatric practice in 1949. This discovery of lithium controlling mood was an accident by Cade, an Australian psychiatrist [26]. Currently, L12CO3 is still used for treating manic depression [27, 28]. Even today, there are many unanswered questions in this field. 6 References start on page 17 1.2.2. Metal Complexes Considering the importance of metal ions in biological systems, it is reasonable to look at the medicinal properties of naturally found metal ions and also to be curious about the properties of even those metals not found in nature. Identifying and fine-tuning the purpose of metal ions in biological molecules by examining structure-activity relationships is a foundation of bioinorganic chemistry. Coordination complexes with various organic molecules (ligands) surrounding the metal ion are commonly used (vide infra) to alter the behaviour and toxicity of the metal ion and modify its biodistribution. These compounds all have specific reproducible effects in the biological system. Administration and biolocalization of these compounds are very important issues. One way to fine-tune the delivery of the desired metal is to design a potential metal complex with suitable properties [29]. Syntheses of complexes that are relatively water soluble (since water is the major medium in the body), thermodynamically stable to hydrolysis at physiological pH (since hydrolysis is a major problem for various metal ions), neutral in charge (since metal ions bear positive charge this can be achieved by designing anionic ligands), small in size and somewhat lipophilic (this helps to increase passive diffusion through cell membranes) and also kinetically inert to demetalation (there are various proteins that bind to different metals very strongly therefore the complex should be stable enough not to dissociate, for example transferrin is a competitive metal chelator in the body) has been the goal of many research groups. Also the compound should clear from the body in an appropriate fashion, to decrease toxicity. Toxicity and absorption of a metal ion can be altered by choosing the appropriate ligand. 7 References start on page 17 The metal chelator also has a significant part in the making of these metal-base complexes. It should be reasonably non-toxic and a strong chelator to avoid hydrolysis when administered in vivo. The ability to tailor the ligand in metal complexes is a major advantage of complexes over inorganic metal salts [30]. 1.2.3. Inorganic pharmaceuticals Inorganic metal-based drugs are mainly divided into two groups: therapeutic or diagnostic compounds. The former group encompasses chemotherapy, radiotherapy or chelation therapy. Chemotherapeutic compounds and therapeutic radiopharmaceuticals (vide infra) generally take advantage of the toxicity of a drug by means of either chemical interaction or ionizing radiation. Chelation therapy, as mentioned before, focuses on removal of excess (harmful) metal ions by means of an organic ligand. Diagnostic compounds are mainly used in imaging and they take advantage of the specific properties of the metal ion used for each case. This could be the radioactivity, X-ray absorption or magnetic properties of the desired metal (vide infra). One of the most important and successful metal-based compounds in the history of medicinal chemistry is cisplatin [31]. The cytotoxicity of cw-diamminedichloro platinum(II), an entirely inorganic molecule, was discovered by Rosenberg in 1965. It was approved for the treatment of cancer (testicular and ovarian) in 1979 and by 1983 it was the leading anticancer drug in the USA. Cisplatin has been one of the most widely utilized antitumour compounds ever [32] and it still holds > 90% cure rate in treating testicular cancer. The challenge is to synthesize a compound with fewer side effects than cisplatin, superior and more specific tumour action and, last but not least, activity against 8 References start on page 17 cisplatin resistant cancers. Despite the hundreds of complexes investigated, carboplatin (Paraplatin®, for treating breast and lung cancer) and oxaliplatin (Eloxatin™) are the only other two Pt-based compounds in clinical use [33]. The recently FDA approved (August 2002) oxaliplatin is used for colorectal cancer treatment; structures of these compounds are shown in Figure 1.3. There has been a medicinal aura about gold, the metal congener of platinum, for millennia. In 1890 Koch showed the antibacterial activity of gold salts [34] and later these compounds were subsequently used to treat tuberculosis and syphilis among other diseases. However, in the past thirty years the only gold complex that has reached the clinic is the orally active Auranofin (triethylphosphine(2, 3, 4, 6 tetra-0-acetyl-(3-l-D-thiopyranosato-S)gold(I)) [35, 36]. The structure of this compound is shown in Figure 1.3. This phosphinogold(I) thiolate is a second generation gold drug used for treating rheumatoid arthritis. Both the platinum and gold complexes are examples of chemotherapeutic drugs. Radiopharmaceuticals are compounds incorporating a radioactive atom that has suitable nuclear properties to treat or diagnose disease. The use of a radioactive isotope is driven by practical considerations, such as its availability and cost. The half-life and mode of decay are also salient. Longer or shorter half-lives between different radioisotopes are of importance, depending on the biolocalization and clearance time for various radiopharmaceuticals. Subject to the type of radiation for the radioactive element, its application maybe either diagnostic or therapeutic. Therapeutic radiopharmaceuticals emit a or p~ particles, or Auger electrons, with enough energy to kill diseased cells within a limited range of penetration. Metal isotope containing 9 References start on page 17 CI///i„..pt...,rt\NH3 Cl^" ^NH3 Figure 1.3. Platinum and gold metal complexes used as therapeutic drugs. 10 References start on page 17 complexes are very good candidates for this purpose. Incorporating a radioactive metal isotope into a well-designed ligand opens many possibilities for expanding the application of these therapeutic compounds, since utilization of the elements found in 1^ ni '''ill organic molecules such as JZP or ,J1 I (both P" emitters) is not always suitable. I was the first radioisotope used (in 1946) to treat thyroid cancer [37]. Even though a myriad of metal complexes have been optimized and improved for the treatment or diagnosis of disease, as well as for studying the mechanism of various biological processes, few of these complexes have been approved for commercial medical use. The majority of inorganic drugs approved for clinical use are diagnostic, compounds utilized in the measurement of biological function and diagnosis of disease. X-ray imaging is an older method of diagnosis compared to newer techniques such as MRI, magnetic resonance imaging (vide infra); however, it is still the most frequently used technique and is utilized for > 80% of the cases in diagnostic imaging [38]. One commonly used metal-based contrast agent is "the barium meal" utilized for X-ray contrast of the gastrointestinal tract. The source of the barium ion is barium sulphate (BaS04) administered orally to the patient [39]. Diagnostic radiopharmaceuticals are used for imaging purposes. The administered radiopharmaceutical localizes mainly in the targeted tissue while emitting y radiation. Special cameras and detectors capture decay data to produce an image of the organ. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are two common techniques used for imaging y radiation [40]. Both methods are similar in many aspects; however, its dual opposed photon emission gives PET a much better resolution than SPECT. In PET, the y rays are produced as the result 11 References start on page 17 of positron ((3+) annihilation giving two photons 180° apart with E = 511 keV. Diagnostic compounds number about >90% of the currently used radiopharmaceuticals. Nuclear technology found new applications in medicine after World War II. By OO OOtn __ OO 1959, the first Mo/ Tc generator was built. To date, Tc is the workhorse of nuclear medicine [41, 42]; about 90% of diagnostic radiopharmaceuticals are technetium complexes. Technetium is a transition metal with no stable isotopes; it also has a long-lived isotope (99Tc, tj/2 = 2.1 x 105 y). 99mTc however, has a suitable half-life and suitable energy (ti/2 = 6.02 h, Ey = 140 keV) to permit a reasonable preparation time for the radiopharmaceutical (as compared to many other radioactive nuclides with shorter half-lives) and to minimize the radiation dose to the patient. A few marketed technetium drugs are shown in Figure 1.4. With the chemistry of Tc and Re being highly analogous (close ionic radii and comparable oxidation states) the myriad of technetium diagnostic complexes could be translated into potential rhenium therapeutic compounds [42-44]. Rhenium, the 3rd row congener of technetium, with two radioisotopes (186Re, tj/2 - 90.6 h, Ep. = 1.07, 0.93 MeV and l88Re, t,/2 = 16.9 h, £p. = 2.1 MeV), is a promising candidate, drawing increased attention in therapeutic nuclear medicine (see Chapter 3). These rhenium isotopes not only produce p- particles but also emit y rays allowing for biodistribution studies [45]. Magnetic resonance imaging (MRI) is a growing technique for diagnosis. Among its many benefits are non-ionizing radiation and enhanced soft tissue resolution. The lanthanide elements have been the centre of investigation for their application in MRI as contrast agents. Gadolinium, a mid-series lanthanide metal ion, has several complexes approved for in vivo imaging by MRI due to the unique magnetic properties of 12 References start on page 17 R I N R. O 'N. R' .N' V^NS|| N A "N N 'N, ~R Jjj R = CH2C(CH3)2OCH3 H Ceretec™ Cardiolite™ II N COOH R — CH2CH2OCH2CH3 O /\V\ Technescan TM H. Myoview TM H3CH2COOC^ .N. 9 Nk ^COOCH2CH3 \JI / Jc Neurolite™ Figure 1.4. Structures of some marketed Tc radiopharmaceuticals. 13 References start on page 17 Gd3+ (4f7) [20]. Magnevist™, a Gd-DTPA (DTPA, diethylenetriaminepentaaceticacid) complex was approved as a contrast agent in 1988. To date gadolinium chelates are still the most prominent contrast agents [46]; Figure 1.5 shows two examples [47]. 1.3. This Work To further improve the current treatments or to discover new practices, our group has been conducting research on various projects in the area of medicinal inorganic chemistry. Many non-essential metals have received much attention in the past for their potential applications in treatment or diagnosis of several diseases. This thesis presents some fundamental coordination chemistry of vanadium, gallium, indium and rhenium metal ions with various groups of ligands (vide infra). 14 References start on page 17 Chapter 2 focuses on vanadium and its potential insulin-enhancing behaviour. Since the 1980s, vanadium has been studied for its insulin-enhancing properties and its oral activity in the treatment of diabetes mellitus [48], as well as its other biological activities [49]. The anti-diabetic activity of BMOV, (bis(maltolato)oxovanadium(IV)) has been thoroughly studied [48]. The basic coordination chemistry through to the final biological testing of various vanadium complexes is investigated. Syntheses and complete characterization of many vanadium complexes using two ligands (Figure 1.6) isomaltolate (ima") and allomaltolate (ama) are reported herein (Hima and Hama are both structural isomers to maltol, Hma). Stability constants of vanadium complexes of these ligands as well as biological testing in STZ-rats will also be discussed. Hma Hama Hima Figure 1.6. C6H6O3 structural isomers: maltol (Hma), allomaltol (Hama) and isomaltol (Hima). Chapter 3 presents studies on the complexation of vanadium and rhenium by a newly synthesized aminopyrone (N, A^'-bis(3-hydroxo-6-methyl-2-methylene-4-pyrone)ethylenediamine), a potentially tetradentate, O2N2 donor ligand [en(ama)2] ". 15 References start on page 17 Figure 1.7 shows the structure of the proligand H2(en(ama)2). Complete characterization of the V(IV) complex and studies of anti-diabetic activity are presented. In this chapter complexation of rhenium with this new ligand and the complete characterizations of this complex are also reported. In Chapter 4 the chelation of gallium and indium to mixed PO donor ligands, phosphinophenolates is discussed (the proligand is shown in fig. 1.7). These metal ions are of potential use in nuclear medicine [40] among a myriad of applications. Gallium compounds are of interest as therapeutic drugs [50, 51]; recently, the anticancer properties of gallium have raised new interest and therefore, many older gallium complexes are being reinvestigated as potential anticancer therapeutic drugs [51]. The fundamental coordination chemistry of these mixed donor chelators with gallium and indium is investigated in this chapter. Complexes of gallium and indium with these ligands are reported herein for the first time. H2(en(ama)2) R-HPO Figure 1.7. Structure of the potentially tetradentate aminopyrone, H2(en(ama)2) and the potentially bidentate phosphinophenol, R-HPO. 16 References start on page 17 1.4. References 1. Kaim, W.; Schwederski, B. Bioinorganic Chemistry: Inorganic Elements in the Chemistry of Life, an Introduction and Guide, John Wiley & Sons Ltd.: England, 1994, pi. 2. Eichhorn, G. I. Ed. Inorganic Biochemistry Elsevier Scientific Publishing Company: New York, 1975. 3. Lippard, S. J.; Berg, J. M. Principles of Bioinorganic Chemistry, University Science Books: California, 1994, p 1. 4. Holm, R. H.; Solomon, E. I. Chem. Rev. 1996, 96, 7. 5. Wilkins, P. C; Wilkins, R. G. Inorganic Chemistry in Biology, Oxford University Press Inc,N.Y. 1997, p 1. 6. Larsson, L.; Magnusson, P. Metal Ions Biol. Syst. 2004, 41, 71. 7. Salonen, J. T.; Tuomainen, T. P.; Nyyssonen, K.; Lakka, H. M.; Punnonen, K. Brit. Med. J. 1998, 317, 727. 8. Stevens, R.G.; Jones, D. Y.; Micozzi, M. S.; Taylor, P. R. TV. Engl. J. Med. 1988, 319, 1047. 9. Salonen, J. T.; Nyyssonen, K.; Korpela, H.; Tuomilehto, J.; Seppanen, R.; Salonen, R. Circulation 1992, 86, 803. 10. Brittenham, G. M. Alcohol 2003, 30, 151. 11. Olivier, N. F.; Brittenham, G. M. Blood 1997, 89, 739. 12. van den Broek, N. British Medical Bulletin 2003, 67, 149. 13. Crichton, R. R.; Ward, R. J. Metal Ions Biol. Syst. 2004, 41, 194. 17 References start on page 17 14. Pena, M. M. O.; Lee, J.; Thiele, D. J. J. Nutr. 1999,129, 1251. 15. Lippard, S. J. in Bioinorganic Chemistry, Bertini, I.; Gray, H. B.; Lippard, S. J.; Valentine, J. S. Eds; University Science Books: California, 1994, p 506. 16. Luk, E.; Jensen, L. T.; Cullota, V. C. J. Biol. Inorg. Chem. 2003, 8, 803. 17. Sarkar, B. Chem. Rev. 1999, 99, 2535. 18. Guo, Z.; Sadler, P. J. Angew. Chem. Int. Ed. 1999, 38, 1512. 19. Thompson, K. H.; Orvig, C. Science 2003, 300, 936. 20. Sadler, P. J. in Advances in Inorganic Chemistry, Sykes, A. G. Ed.; Academic Press Inc.: California, 1991, 36, 1. 21. Schneider, G. Can. Med. Assoc. J. 1984, 131, 193. 22. Newell, F. W. Am. J. Ophthal. 1980, 90, 874. 23. Johnston, R. L. J. Lab. Clin. Med. 1942, 27, 303. 24. Albert, A. Selective Toxicity, 7th Ed.; Chapman & Hall: New York, 1985, p 206. 25. Forestier, J. Bull. Mem. Soc. Med. Hop. Paris 1929, 53, 323. 26. Cade, J. F. J. Med. J. Aust. 1949, 36, 349 27. Schou, M. Pharmacol. Rev. 1957, 9,1. 28. (a) Birch, N. J. Metal Ions Biol. Syst. 2004, 41, 305. (b) Chen, G.; Rajkowska, G.; Du, F.; Seraji-Bozorgzad, N.; Manji, H. K. J. Neurochem. 2000, 75, 1729. (c) Birch, N. J. Chem. Rev. 1999, 99, 2659. 29. Thompson, K. H.; Orvig, C. Coord. Chem. Rev. 2001, 219-221, 1033. 30. McNeill, J. H.; Yuen, V. G.; Hoveyda, H. R.; Orvig, C. J. Med. Chem. 1992, 35, 1489. 31. Rosenberg, B.; VanCamp, L.; Krigas, T. Nature 1965, 205, 698. 18 References start on page 17 32. Wong, E.; Giandomenico, C. M. Chem. Rev. 1999, 99, 2451. 33. Barns, K. R.; Lippard, S. J. Metal Ions Biol. Syst. 2004, 42, 143. 34. (a) Benedek, T. G. J. Hist. Med. Allied Sci. 2004, 59, 50. (b) Koch, R. Dtsch. Med. Wochenschr. 1890,16, 756. 35. Nicolini, M.Ed. Platinum and Other Metal Coordination Complexes in Cancer Chemotherapy, Martinus Nijhoff, Boston, MA, 1988. 36. Shaw (III), C. F. Chem. Rev. 1999, 99, 2589. 37. Becker, D. V.; Swain, C. T. Semin. Nucl. Med. 1996, 26, 155. 38. Yu, S.; Watson, A. D. Chem. Rev. 1999, 99, 2353. 39. Reference 20, p 13. 40. Anderson, C. J.; Welch, M. J. Chem. Rev. 1999, 99, 2219. 41. Jurisson, S. S.; Lydon, J. D. Chem. Rev. 1999, 99, 2205. 42. Dilworth, J. R.; Parrott, S. J. Chem. Soc. Rev. 1998, 27, 43. 43. Volkert, W. A.; Hoffman, T. J. Chem. Rev. 1999, 99, 2269. 44. Heeg, M. J.; Jurrison, S. S. Acc. Chem. Res. 1999, 52, 1053. 45. Ginj, M.; Maecke, H. R. Metal Ions Biol. Syst. 2004, 42, 116. 46. Caravan, P.; Cloutier, N. J.; Greenfield, M. T.; McDermid, S. A.; Dunham, S. U.; Blute, J. W. M.; Amedio Jr., J. C; Looby, R. J.; Supkowski, R. M.; Horrocks, Jr.; W. D.; McMurry, T. J.; Lauffer, R. B. J. Am. Chem. Soc. 2002,124, 3152. 47. Caravan, P.; Ellison, J. J.; McMurry, T. J.; Lauffer, R. B. Chem. Rev. 1999, 99, 2293. 48. Thompson, K. H.; Orvig, C. Metal Ions Biol. Syst. 2004, 41, 221. 19 References start on page 17 49. Gresser, M. J.; Tracy, A. S. in Vanadium in Biological Systems: Physiology and Biochemistry; Chasteen, N. D. Ed.; Kluwer Academic Publishers:Dordrecht, 1990, p63. 50. Clarke, M. J.; Zhu, F.; Frasca, D. R. Chem. Rev. 1999, 99, 2511. 51. Jakupec, M. A.; Keppler, B. K. Metal Ions Biol. Syst. 2004, 42, 425. 20 References start on page 17 Chapter 2 Vanadium Complexes of C6H603 Structural Isomers Simple Coordination Chemistry to In Vivo Studies 2.1. Introduction 2.1.1. Vanadium Vanadium, element number 23 and a first row transition metal, was first discovered by Andres del Rio in 1802. He called the new element panchromium and then changed the name to erythronium. The results of his discovery were given to Baron Alexander von Humboldt for publication; however, all the documents were destroyed in a shipwreck. Therefore, the glory of the discovery of the new element came to Nils Sefstrom in 1831. He named it vanadium in honour of Vanadis, the Scandinavian goddess of beauty and love, for its colourful chemistry [1]. Vanadium is a shiny, soft and ductile metal. The earth's crust contains about 100 ppm vanadium. Ranking as the 21st most abundant element in the earth's crust, vanadium is more abundant than are Mo, Cu, Zn or Pb [2]. Vanadium is also the most abundant transition metal in the hydrosphere with a concentration of about 20-35 nM, mainly in the form of [H2V04]" and [HVO4]2" [3]. Metallic vanadium is widely used to harden steel alloys. It is also extensively used in the atomic energy industry, in aircraft construction and in space technology. Due to its various oxidation states, it can form a wide range of stable compounds, many of which have commercial use, e.g. vanadium compounds are used in pigments because of 21 References start on page 68 the various colours they show. Vanadium compounds are commonly used in catalysis [!]• Vanadium is an early transition metal that has an extraordinarily rich chemistry. Because of its many oxidation states, it can take many coordination numbers and geometries. In biological systems however, the oxidation states for vanadium are III, IV and V. Physiological effects of vanadium result from the structural resemblance between phosphate and vanadate, as well as from the fact that vanadium can form cationic and anionic compounds [4]. In the human body, vanadium exists in equilibrium between vanadyl ([VO]ZT - V(IV)) or vanadate ([V04]J" - V(V)). It is the ease of conversion between these two oxidation states by molecular oxygen or biological reducing agents, such as ascorbic acid, glutathione and NADH, which permits and complicates various interactions with biological molecules [5-7]. 2.1.2. Aqueous Chemistry of Vanadium Because of hydrolysis, vanadium has a rather complicated aqueous chemistry. The most common oxidation states in aerobic aqueous solutions are IV and V. Speciation diagrams for V(IV) and V(V) as a function of pH are given in Figures 2.1 and 2.2 (by convention, the vanadium coordination spheres in the indicated species are completed with aqua ligands) [8]. For [V(V)] < 10 uM, similar to the physiological range, vanadate is mainly found as monomeric species, with [HVO4]2" and [H2VO4]" being the species in solution at pH > 7. 22 References start on page 68 Figure 2.1. Speciation diagram for V(V) as a function of pH, [Vtotal] = 10 )lM [8]. Figure 2.2. Speciation diagram for V(IV) as a function of pH, [Vtotal] = 10 uM [8]. 23 References start on page 68 Vanadate ([V04] "), the vanadium analogue of phosphate ([PO4] ) is only present in solution at pH > 13. The most stable oxocation of the first row transition metals is V02+, vanadyl ion. In aqueous acidic solutions it is actually present as [VO(H20)s]2+ with an octahedral geometry [9]. The vanadyl ion is rapidly oxidized to vanadate at pH > 3. At higher concentrations of vanadium (> 1 mM), depending on the pH, polymeric vanadates (V(V)) and vanadyl (V(IV)) hydroxo complexes are formed [8]. At neutral pH, [H2VO4]" and [VO(H20)4OH]+ are, respectively, the most prevalent V(V) and V(IV) species in aqueous solutions; however, lower oxidation states of vanadium at this pH can be formed by complexing vanadium with a suitable ligand. Type and nature of ligand play important roles in the stability of these complexes against hydrolysis and oxidation. 2.1.3. The Role of Vanadium in Biological Systems In the early 1900s it was noticed for the first time that there are high accumulations of vanadium in the blood cells of ascidians (commonly known as sea squirts) [10]. These species convert vanadium(IV, V) from sea water and store it as air sensitive V(III) in a concentration that is 107 times greater than that of vanadium in sea water [11]. This high concentration probably suggests an important physiological function; however, this function is not yet understood [12]. Amavadin (Figure 2.3) is a very stable, eight coordinate, unusually nonoxo V(IV) species that is present in high concentrations in Amanita mushrooms. The role for amavadin in these mushrooms is also not yet clear [13]. 24 References start on page 68 Figure 2.3. Dodecahedral structure of amavadin, a natural nonoxo V(IV) compound. Vanadium is essential to the functioning of some enzymes in simple organisms; it has been found in the active site of haloperoxidases in various algae and lichens [14]. One important biological process is the catalytic reduction (fixation) of N2 to NH3 by nitrogenase enzymes to cycle nitrogen from the atmosphere to the soil. A vanadium nitrogenase was purified from Azotobacter bacteria in 1986 for the first time [15]; a vanadium atom replaces the more common molybdenum in the MoFe7Sg active site of the enzyme. The essentiality of vanadium in higher animals and humans has a long and controversial history. In 1974, Hopkins and Mohr [16] showed that removing vanadium from the diet of rats and chicks caused deficiency diseases but later Nielson [17] deemed the work of Hopkins inconclusive. Vanadium deprivation in goats showed effects on pre-and postnatal mortality rates and skeletal formation [18]. These effects are not yet understood and the effect of vanadium on humans remains to be elucidated. To date, the statement made by Schroeder et al. in the 1960s still holds true: "No other trace metal has so long had many supposed biological activities, without having been proven to be essential" [19]. 25 References start on page 68 Vanadium does have many important biochemical roles that are well documented. The facile redox exchange between V(V) and V(IV) and their respective anionic and cationic species permit vanadium to have various roles in its interactions with biomolecules. As vanadate, it is similar to phosphate in geometry, size, shape and charge [20] and has various regulatory, inhibitory or stimulatory effects on enzymes [21,22]. As vanadyl, vanadium competes with other metals for coordination to biomolecules and can also affect enzyme activities [5, 23]. One of the most interesting discoveries in the history of biological vanadium is the discovery in 1977 that sodium vanadate can inhibit the Na - K - ATPase pump [24]. This finding increased interest in the general biochemistry of vanadium, leading indirectly to the discovery of the insulin-like behaviour of sodium metavanadate (vide infra). 2.1.4. Diabetes Diabetes mellitus is a series of heterogeneous metabolic disorders characterized by hyperglycemia and problems in carbohydrate, fat and lipid metabolism. Every day more and more North Americans are diagnosed with diabetes. The disease is expressed with hyperglycemia (elevated levels of glucose in the blood) as a result of unbalanced glucose metabolism. Diabetes is usually distinguished as two different diseases: type I (insulin dependent diabetes mellitus, IDDM) in which minimum sufficient insulin is not produced, or type II (non insulin dependent diabetes mellitus, NIDDM) where insulin is produced but the peripheral tissues fail to respond to the available insulin. This latter phenomenon is called insulin resistance. 26 References start on page 68 OH Figure 2.4. Streptozotocin (STZ). Insulin is a signaling hormone secreted from the P cells in the pancreas; it stimulates glucose uptake, glycolysis and lipogenesis, and also inhibits lipolysis and gluconeogenesis. The vast majority of diabetics are diagnosed with type II diabetes mellitus, which is often related to life-style, age and obesity [25]. Type I diabetics require regular insulin injections, while there are many different treatments for type II patients, with various side effects. In addition to different hypoglycemic drugs, type II diabetics often require insulin injections as well. Insulin, being a polypeptide, is not orally active and must be administered via intramuscular injection. This can limit patient compliance and therefore oral treatments for this disease remain a continuing goal. To understand the physiology and find a treatment for a disease, various animal model studies are usually employed [26]. The animal model in each case should best represent the physiological properties of that disease. In the case of diabetes, a common model is the chemically induced model that is achieved via the one time injection of streptozotocin (STZ) in rats (Figure 2.4). STZ is an antibiotic that selectively kills >90% of the P cells of the pancreas; thus the concentration of insulin decreases in the blood and 27 References start on page 68 the animals become diabetic. Other than the chemically induced STZ diabetes model, there are both genetic and surgical models for type II and viral induction for type I. 2.1.5. Vanadium and Diabetes Vanadium involvement in the treatment of diabetes mellitus has a long history. The inorganic vanadium salt, sodium metavanadate (NaVOs) was tested for the treatment of diabetes even before the discovery of insulin; Lyonnet and Martin reported that two of three diabetic individuals treated with sodium vanadate excreted less glucose in their urine [27]. Shortly after the ATPase inhibition discovery of Cantley et al. [24], Tolman showed that sodium vanadate increased glucose uptake and stimulated glycogen synthesis in rat diaphragm, liver and fat cells [28]. Many other groups also carried out similar in vitro studies to show the many insulin-like behaviours of vanadium [29-32]. In 1985, for the first time, in vivo studies of sodium vanadate showed that this compound has an oral anti-diabetic effect in rats [33]. However, despite the promising results, this compound was suggested by Domingo et al. [34] to be toxic at close to dose levels and to cause severe gastrointestinal problems. Vanadyl sulphate was subsequently tested and proved to be better tolerated and less toxic than sodium vanadate at comparable doses; however, it was poorly absorbed [35-37]. Vanadyl sulphate reduced blood sugar levels to euglycemic with no increase in the circulating insulin levels in these animals for a long period after the withdrawal of treatment [38]. The toxicity of sodium vanadate and the poor absorption of vanadyl sulphate stimulated a search for alternate vanadium-containing moieties as potential anti-diabetic drugs. Other than the inorganic vanadium salts, two other groups of compounds have 28 References start on page 68 been used as potential candidates for the treatment of diabetes: vanadium coordination complexes and peroxovanadium compounds (the latter contains an oxo group and one or two peroxo groups, plus another bidentate ligand bound to vanadium(V)). The peroxovanadates showed promising in vitro activity; however, when tested in vivo they were inactive [39]. Non-peroxo coordination complexes of vanadium (mostly vanadyl) are the current generation of insulin-enhancing compounds; they can be tailored to optimize the desired properties for a candidate drug. Several of these compounds have been synthesized and tested for their insulin-enhancing actions. Some have shown long-term oral activity and an insulin-like ability to normalize blood glucose levels. In 1992, a significant oral study on the insulin-enhancing behaviour of a vanadium complex BMOV, (bis(maltolato)oxovanadium(IV)) was reported [40]. This compound was better absorbed from the gastrointestinal tract and was about two to three times more potent than was vanadyl sulphate, its parent compound [41, 42]. The structure of this complex and the structures of the vanadium inorganic salts are shown in Figure 2.5. Maltol (2-methyl-3-hydroxy-4-pyrone) is used as the proligand in BMOV; it is a non-toxic, water-soluble and a food additive widely approved in Canada, the USA and many other countries. Two maltolate anions bind vanadyl to form a neutral complex. The complex has the desired properties: water solubility, balanced lipophilicity/ hydrophilicity, neutral charge and thermodynamic stability for a candidate oral drug [43]. An analogue of BMOV, BEOV (bis(ethylmaltolato)oxovanadium(IV)), completed phase I clinical trials in humans in late 2000. Over the past 20 years, various research groups have synthesized and tested many complexes of vanadium for their anti-diabetic activity, both in vivo and/or in vitro [28-30, 44]. Structures of a few of these compounds 29 References start on page 68 + Figure 2.5. Structures of vanadate anion [H2VO4]", vanadyl cation in aqueous solution at pH ~ 7 and the vanadium coordination complexes BMOV and BEOV. are shown in Figure 2.6. As seen from the structures, different donor atom motifs are bound to vanadium. All these complexes have been tested for their anti-diabetic activity. Bis(acetylacetonato)oxovanadium(IV), VO(acac)2 is one of the best known vanadyl complexes (first made almost one hundred years ago) [45]; however, it has only recently been tested both in vivo and in vitro for its anti-diabetic activity [23, 46]. Both studies showed it to be more effective than was vanadyl sulphate. Substituted acac" vanadium complexes have also been tested for this effect [23, 47]. Vanadyl metformin (VO(metf)2) belongs to a series of vanadyl biguanide complexes [48]; a synergistic effect was desired in these studies because biguanides themselves are oral hypoglycemic compounds commercially available. Synergism was not observed in these studies 30 References start on page 68 VO(acac)2 H2N \ \IIA N: X. N N -N NH2 \ VO(metf)2 o VO(pic)2 , _A\\A MA) s s V-P o H2 •\I/N X8H 17 C8H 17 N S H2 O Naglivan VO(thiazolidinedionato)2 Figure 2.6. Structures of various vanadyl complexes. 31 References start on page because there was a large dose difference between the two classes of compounds (the biguanides and the vanadium-biguanide complex); however, VO(metf)2did show glucose lowering as effective as that of BMOV. The picolinato vanadyl complex VO(pic)2 has also shown effectiveness in various studies; however, this was dependant on the dose as well as the method of administration of the compound to the animals [49, 50]. In V-P, vanadyl has an S4 coordination sphere [51]; in vitro studies of this compound showed inhibition of free fatty acid release in fat cells [52]. Naglivan has an N2S2 donor set around the vanadyl moiety [53]; this complex was tested in vivo, and with supplementary insulin administration, it did show anti-diabetic activity. Various BMOV analogues were recently tested and all showed similar levels of glucose lowering activity in vivo [54]. Rosiglitazone and pioglitazone, are thiazolidinediones commercially available as hypoglycemic drugs as treatment for type II diabetes. A series of thiazolidinediones and their vanadyl complexes were recently synthesized and tested with the hope of observing synergism and increased activity [55]. The complexes showed activity comparable to that of BMOV and a more prolonged treatment effect than did the proligands alone. Some V(V) or V(III) complexes have also been synthesized and tested for insulin enhancing behaviour [49, 56-58]. The choice of proligand is critical in the tissue uptake and distribution of vanadium complexes. BMOV has enhanced activity as compared to that of vanadyl sulphate, presumably due to increased absorption from the gastrointestinal tract. Despite the method of administration, BMOV [59] or other vanadyl complexes [56] still show superior activity as compared to the inorganic salt. Vanadium mainly accumulates in bone, liver and kidney [60]; however the accumulation of vanadium in different organs 32 References start on page 68 varies based on the vanadium source [61]. The latest studies, however, have shown that shortly after administration, vanadium complexes dissociate [54]. Is the active species vanadyl, or the complex as a whole? It is believed that the organic moiety behaves as a "delivery shuttle" for vanadium [54]; using 14C labelled ethylmaltol in BEOV, it was clearly shown that the complex rapidly dissociates after administration and that the labelled ligand and the vanadium cleared the blood stream differently [54]. Despite intense investigations of the insulin-enhancing behaviour of BMOV, the mechanism of action has been elusive to date [62, 63]. Interactions of human serum transferrin (Tf) and human serum albumin (HSA) with BMOV have also been examined to understand the transport of this compound in the body [64]. Mohammad et al. researched the effects of BMOV on protein tyrosine phosphatase in rats and showed that although vanadium inhibits this enzyme, other unknown effects also could cause the glucose lowering [63]. Recently it was shown that BMOV is a competitive, reversible intracellular phosphatase inhibitor; vanadate is believed to be the actual active site enzyme inhibitor [62]. Several literature examples of BMOV oxidation to V(V) species corroborate these findings [65-67]. New compounds are being tested continuously to investigate further, and possibly improve, the pharmacological effectiveness of vanadium insulin-enhancing compounds. Increasing the bioavailability of these potential new anti-diabetic drugs is also an important area of research. In our laboratories, we have studied the coordination chemistry, solution thermodynamics and biological activity of many vanadium complexes over the past dozen years. Over time, BMOV, has proven to be the most promising complex of V(IV) and has become the "benchmark" in the field. Experience 33 References start on page 68 has shown our group that major modifications of the structure of maltol have failed to improve the anti-diabetic activity of the analogous vanadyl complexes (overall no obvious advantage was noticed over BMOV). Maltol has two structural isomers, allomaltol (Hama) and isomaltol (Hima), which are also non-toxic natural products and potential ligands after deprotonation for chelation to vanadium (Figure 2.7). Having in mind to stay close to the maltol motif, in this chapter we report the chemical and biological properties of vanadium complexes with these ligands (ima~, ama"). Allomaltol (3-hydroxy-6-methyl-4-pyrone, Hama) has a structure very close to that of maltol (3-hydroxy-2-methyl-4-pyrone, Hma), wherein the methyl group is shifted from the 2 to the 6 position on the ring [67]. Isomaltol (l-(3-hydroxy-2-furanyl) ethanone, Hima) is a p-hydroxyeneone, with a metal binding site analogous to that in acetylacetonate after it is deprotonated [69, 70]. Deprotonated isomaltol has been chelated to group 13 metals for potential application as radiopharmaceuticals [71]. It has also been complexed to sodium, copper Hma Hama Hima Figure 2.7. Structures of the C6H603 isomers, maltol (Hma), allomaltol (Hama) and isomaltol (Hima). 34 References start on page 68 and iron [70, 72]. Vanadium complexes of acetylacetonate (acac") or substituted acetylacetonates have been synthesized and tested for anti-diabetic activity as well [46, 47], therefore investigating the vanadium-isomaltol system was deemed worthwhile. The syntheses and complete characterization of various vanadium(III, IV) complexes with these two ligands are reported along with the determination of acidity and stability constants for these compounds. Biological testing of the anti-diabetic behaviour of these new vanadium compounds is also presented. 2.2. Experimental 2.2.1. Materials All solvents were reagent grade and were used without further purification. All the chemicals were obtained from commercial sources (Aldrich, Sigma, Fisher) and were used without further purification. Reactions were carried out in air unless specified. Water was deionized (Barnstead D8902 and D8904 cartridges), distilled (Corning MP-1 Megapure Still) and degassed by boiling under Ar for 30 minutes. Allomaltol [68] and O-galactosylisomaltol [70] were made according to previously published methods. 2.2.2. Instrumentation Infrared spectra were recorded as KBr disks with a Mattson Galaxy Series 5000 FTIR spectrophotometer in the 4000-400 cm"1 range. Mass spectra were obtained with a Kratos MS 50 (electron-impact ionization, EIMS), a Micromass LCT (electrospray ionization, ESI) or a Kratos Concept II H32Q instrument (Cs+, liquid secondary ion mass spectrometry (LSIMS) with positive ion detection). Elemental analyses were performed 35 References start on page 68 by Mr. Peter Borda in this department or by Delta Microanalytical Services. 'H NMR spectra were recorded on a Bruker AC-200E or a Bruker AV-300 NMR spectrometer at 200 or 300 MHz, respectively. Room temperature magnetic susceptibilities were measured using a Johnson Matthey balance. Diamagnetic corrections were estimated using Pascal's constants [73] and Hg[Co(NCS)4] was used as the susceptibility standard. EPR spectra were recorded on a Bruker ESC-106 EPR spectrometer in 20 uL quartz capillaries in CH2CI2. Simulation of the isotropic EPR spectrum was performed using Bruker's WINEPR/SIMFONIA package. Potentiometric measurements were carried out with an automatic titration system consisting of a Metrohm 713 pH meter with a Metrohm 6.0233.100 electrode, a model 665 Metrohm Dosimat autoburet, water-jacketed titration vessels and a Julabo UC circulating bath. Both the pH meter and the autoburet were controlled with an IBM compatible PC. Titrations were controlled by a locally-written QBASIC program. The concentration of NaOH (1M) (Fisher) used for potentiometric titrations was confirmed by titration with potassium biphthalate (Anachemia Canada Inc.). NaCl was used to control the ionic strength (7= 0.16 M). The electrode was calibrated before each titration using a known amount of HCl(aq) solution titrated with a known amount of NaOH. Plotting mV (calculated) vs. pH gave a working slope and an intercept; therefore the pH could be read as -log [H+] directly. The value of pKw used at 7= 0.16 and T = 25°C was 13.76 [74]. 2.2.3. Syntheses of Compounds 2.2.3.1. Isomaltol, C6H6O3 (Hima). O-galactosyl isomaltol (10 g, 35 mmol) was placed in a Schlenk tube equipped with a cold finger under vacuum. The system was 36 References start on page 68 immersed in a preheated Wood's metal bath at 110 C, and the bath was heated to 210 °C. Sublimation of isomaltol started with caramelization of the galactoside. After the sublimation was finished, the light beige product was collected from the cold finger, recrystallized from acetone/water, and dried in a dessicator under vacuum over P2O5 to yield 3.22 g, 73%, mp 98-100 °C. Anal. Calcd (found) for C6H603: C, 57.14 (57.42); H, 4.80 (4.72). IRfcm"1, KBr disk): vc=0/c=c 1577,1615,1636. 'H NMR (200 MHz, CDC13): 5 2.40 (s, 3H, CH3), 6.27 (d, 1H), 7.27 (d, 1H), 8.50 (s, broad, 1H, OH). LSIMS (+): m/z = 127 [(M+l)+]. 2.2.3.2. Trans-bis(isomaItolato)aquaoxovanadium(IV), BIMOV, trans-(VO(ima)2(H20)). Method [A]. Isomaltol (6.15 g, 35 mmol) was dissolved in water (100 mL). The temperature was increased to 50 °C and the pH adjusted to 6 with 1M NaOH solution. . Vanadyl sulphate tetrahydrate (5.75 g, 25 mmol) was added to the isomaltol solution. The colour changed to green immediately and the pH was then adjusted to 7 with 1M NaOH. After one hour the reaction mixture was filtered and the green precipitate dried under vacuum over P2O5 in a dessicator to yield 7.28 g, 89%> yield. Anal. Calcd (found) for Ci2Hi208V: C, 43.00 (43.29), H, 3.60 (3.56). IR (cm"1, KBr disk): vv=o 967. LSIMS (+): m/z = 318 [(M+H)+]. EPR: 8 line pattern, giso = 1.966 ± 0.001, Aiso = 100.0 ± 0.1 (10"4) cm"1. Solid state magnetic moment u, = 1.76 B.M. Method [B]. Isomaltol (78 mg, 0.62 mmol) and vanadyl sulphate (67 mg, 0.32 mmol) were dissolved in ice cold water (15 mL). Urea (19 mg, 0.32 mmol) was added and the 37 References start on page 68 solution was warmed to RT and left overnight. The resulting green X-ray quality crystals, 35 mg (35% yield), were filtered out and completely characterized to be genuine BIMOV. Method [C]. V(ima)3 (10 mg, 0.023 mmol) was dissolved in 5 mL acetone and placed in a 25 mL vial. The vial containing the red solution was closed and kept still. The red solution started changing colour and eventually became green after a few days. Crystals suitable for X-ray crystal structure analysis were grown by slow diffusion of n-pentane into this solution. The isolated product was characterized to be trans-VO(ima)2(H20). 2.2.3.3. Tris(isomaltolato)vanadium(III), V(ima)3. Under Ar, Hima (188 mg, 1.49 mmol) was dissolved in 50 mL of hot (55 °C) degassed water. Vanadyl sulphate (108 mg, 0.50 mmol) was added to this solution. Sodium dithionite (250 mg, 1.44 mmol) was dissolved in Ar saturated water (10 mL) and added to the reaction solution very slowly. The green solution changed to red upon addition of the dithionite. The system was kept at 55 °C with stirring overnight. The next morning the reaction mixture was filtered and the red precipitate washed with cold water. A red solid (170 mg, 80% yield) was isolated. Crystals suitable for X-ray structure were grown by diffusion of n-pentane into an acetone solution of this complex under dry Ar. Anal. Calcd (found) for C18H1509V: C, 50.72 (50.61); H, 3.54 (3.48). IR (cm"1, KBr disk): vc=c/c=o 1534, 1561, 1629 cm"1. LSIMS (+): m/z = 427 [(M+l)+]. Solid state magnetic moment ja = 2.85 B.M. 38 References start on page 68 2.2.3.4. Bis(allomaItoIato)oxovanadium(IV) monohydrate, VO(ama)2.H20. A solution of VO(acac)2 (50 mg, 0.19 mmol) in 2 mL of CH2CI2 was slowly added to a solution of Hama (54 mg, 0.42 mmol) in 3 mL of CH2CI2 under Ar. The colour changed from light yellow to dark burgundy after a few minutes. The solution was stirred overnight; a burgundy solid was isolated by filtration (47 mg, 78% yield). Anal. Calcd (found) for C,2H1208V: C, 43.00 (42.80), H, 3.60 (3.44). IR (cm"1, KBr disk): vv=o 988. EIMS: m/z = 317 [M]+. Solid state magnetic moment JJ. = 1.78 B.M. 2.2.3.5. Tris(allomaltolato)vanadium(III) monohydrate, V(ama)3.H2<I>. The synthesis of this compound was done by a method similar to that for V(ima)3, except that allomaltol was substituted for isomaltol, 75% yield. Anal. Calcd (found) for CisHnOioV: C, 48.65 (48.45); H, 3.82 (3.68). IR (cm"1, KBr disk): vc=c/c=o 1563, 1610 cm"1. LSIMS (+): m/z = 427 [M+l]+. Solid state magnetic moment \i = 2.84 B.M. 2.2.3.6. Bis(isomaltolato)methoxyoxovanadium(V), VO(ima)2(OCH3). Trans-VO(ima)2(H20) (27.2 mg, 0.08 mmol) was dissolved in 1.5 mL of MeOH. H202 (10 uL) was added to this bright green solution and the colour changed to blood red. The reaction flask was kept at -45 °C for 4 hours and then placed in the freezer overnight. The dark red precipitate was filtered and dried under vacuum (13.1 mg, 47% yield). Anal. Calcd (found) for CsHnOgV: C, 44.85 (45.19); H, 3.76 (3.98). IR (cm"1, KBr disk): vv=o 965. 'HNMR (CD3OD): 8 2.30 (s, 3H, CH3), 3.39 (s, 3H, OCH3), 6.28 (d, 1H), 7.53 (d, 1H). 39 References start on page 68 2.2.4. Potentiometric pH Titrations The acidity constants for Hama and Hima were determined by titrating 50 mL of aqueous 0.6 mM HC1 solution (7= 0.16 M NaCl, T = 25 °C) in the presence of 0.92 - 2.0 mM Hama or Hima under Ar with 1.5 mL 0.11 M NaOH. The calculations were done using the data on an IBM-compatible computer containing a Pentium II processor using a curve fit procedure (a Newton-Gauss nonlinear least-square program). The considered pH ranges were 6.3 < pH < 9.7 and 4 < pH < 7.3 for allomaltol and isomaltol, respectively. This corresponds to about 2% and 98% neutralization for each equilibrium [Hama]/[ama"] and [Hima]/[ima"]. The final results for allomaltol were from averages of 6 independent titrations, and for isomaltol averages of 12 independent titrations. The stability constants of V(IV) and/or V(V) with these ligands were determined under the same conditions, as were the acidity constants, except that the acid (HC1) was partly replaced by the respective metal ion (/= 0.16 M, 25°C). The ligand to metal ratio used was < 4:1 to prevent the hydrolysis of V(IV) or V(V). The calculations were carried using a similar curve-fitting procedure by the same Newton-Gaussian nonlinear least-square program. Each titration was repeated at least 8 times, the final results are the average of the eight. 2.2.5. Solid State X-ray Crystal Structures The crystal structure of VO(ima)2(H20) was determined by Dr. M. Pink at the University of Minnesota X-ray crystallographic laboratory and that of V(ima)3 was determined by Dr. B.O. Patrick here at UBC. Selected crystallographic data and complete lists of bond angles and bond lengths are presented in Appendix A. 40 References start on page 68 2.2.6. In vivo Animal Studies All these studies were undertaken in the laboratories of Prof. J. H. McNeill, UBC Faculty of Pharmaceutical Sciences. Male Wistar rats (Animal Care Unit, UBC) that weighed between 190-210 g were placed two per cage (polycarbonate) on a 12 hour light:dark schedule, at constant temperature and humidity (21°C and 54 ± 2%, respectively). Food (Purina Rat Chow #5001) and tap water were freely available. The rats were cared for according to the guidelines of the Canadian Council for Animal Care. After an acclimatization period of 5 days they were divided into 5 groups randomly: control, control treated with BMOV, diabetic, diabetic treated with BMOV and diabetic treated with the testing complex. A single injection of streptozotocin (STZ), 60 mg kg"1 dissolved in 0.9% NaCl into the tail vein induced diabetes (under light halothane anaesthesia). Diabetes was confirmed 3 days after by measuring the blood glucose in the tail blood (Beckman glucose analyzer 2®). The rats with plasma glucose levels > 13 mM were accepted as diabetic. The compounds to be tested by oral gavage were prepared at a dose of 0.6 mmol kg"1 in a volume of 5 mL kg"1. Those to be tested by intraperitoneal (i.p.) injection were prepared at a dose of 0.1 mmol kg"1. All compounds were prepared as uniform suspensions in 1% carboxymethylcellulose (CMC). Both control and diabetic(untreated) groups received an equivalent volume of 1% CMC alone. Blood samples to be tested for plasma glucose levels were collected immediately before the treatment (t = 0) and at 8, 12, 20, 24, 48 and 72 hours following the administration of the drug. The animals were observed for changes in body weight or behaviour, any gastrointestinal disturbance, or 41 References start on page 68 other signs of side effects. Tail vein blood was collected into heparinized capillary tubes and centrifuged (10,000 g x 25 min). The plasma was collected immediately, and after dilution by 50% in distilled water the plasma glucose levels were measured (Beckman Glucose Analyzer 2®). The animals were sacrificed by an injection of 100 mg kg"1 pentobarbital; and the blood for the 72 hr time point was collected by cardiac puncture. Data were analyzed using Number Cruncher Statistical System® (NCSS). Results are presented as mean ± SEM (The data for the test results were analyzed by using GLM model ANOVA followed by Newman-Keuls test where applicable (p < 0.05)). 2.3. Results and Discussion 2.3.1. Proligands Isomaltol (Hima) was made in high yield by vacuum sublimation of O-galactosylisomaltol at 190 °C. The two-part synthesis of isomaltol has been reported previously by Nelson and Hodge [70]. One glucose sugar from lactose is dehydrated to form O-galactosylisomaltol. Hydrolysis of this product by steam distillation results in the formation of isomaltol. The first part of the synthesis used here followed that reported previously [70], but the second part, the synthesis of isomaltol from this precursor, was modified. Herein is reported a simple, less hazardous and less time-consuming method with similar yield. Scheme 2.1 shows the various steps in the modified synthesis of isomaltol. Routine characterizations of Hima showed that the modified procedure was effective in producing this compound. 42 References start on page 68 The 'H-NMR spectrum of isomaltol in chloroform showed all the peaks expected; the chemical shifts and integrations were also correct. The peaks were assigned as a singlet for the methyl group at 5 2.40, and two doublets further downfield for the two ring hydrogens (8 6.27, 7.27) plus a broad peak for the OH hydrogen at 8 8.50. The elemental analysis agreed with the C6H6O3 empirical formula for isomaltol and the mass spectrum clearly showed the parent peak at m/z = 126. The furan structure of isomaltol shown in Scheme 2.1 was proposed in 1961 [75]. Allomaltol (3-hydroxy-6-methyl-4-pyrone, Hama) was made according to the method published by Ellis et al. [76]. Reacting kojic acid with thionyl chloride produces HO OH 78 °C triethylamine EtOH piperidine acetic acid lactose O-galactosylisomaltol vacuum sublimation isomaltol Scheme 2.1. Two part synthesis of Hima. 43 References start on page 68 chlorokojic acid that is simply reduced with zinc in concentrated hydrochloric acid to produce allomaltol. This compound was completely characterized and the data obtained compared favourably to those in the literature. The synthesis of allomaltol is depicted in Scheme 2.2. kojic acid chlorokojic acid allomaltol Scheme 2.2. Synthesis of Hama. 2.3.2. Vanadium(IV) Complexes, VOL2 (L = ima", ama") Both proligands, when deprotonated, are bidentate Lewis bases [77] and are expected to bind strongly to vanadyl. Combining VOSO4 and the proligand Hima in water produces VO(ima)2(H20) with maximum yield obtained when the pH = 6. The same compound was also prepared by air oxidation of the V(III) complex, V(ima)3, in solution. The same synthetic procedure described above was used for allomaltol, but isolation of pure VO(ama)2 was not possible due to its high solubility in water. Also, if left in aqueous solution or exposed to air, it would oxidize over time. Therefore, VO(ama)2 was synthesized from VO(acac)2 by ligand substitution in methylene chloride. 44 References start on page 68 Infrared spectra of these two complexes show the vy=o at 967 cm"1 and 988 cm"1 for trans-VO(ima)2(H20) and VO(ama)2, respectively. These are within the expected range of 930-1030 cm"1 for the oxovanadium stretch [78]. For both complexes examined here, the peak shifted to lower energy compared to that in BMOV or VO(acac)2, at 995 and 998 cm"1 respectively. The shift is particularly noticeable in the case of trans-VO(ima)2(Ff20). This is due to the effect of the bound water in the sixth coordination site, which causes a reduction in the stretching frequency of V=0 as the electron donation from the water oxygen makes vanadium less accepting of the charge donation from the oxo oxygen, and therefore reduces the V=0 bond order. Infrared spectra of the two V(IV) complexes in the 500-2000 cm"1 region are shown in Figure 2.8. Table 2.1 provides the IR data for the vanadium complexes of isomaltol and allomaltol. Isomaltol has a hydrogen bonded conjugate chelate structure depicted in Scheme 2.3, with the carbonyl band in the 1550-1640 cm"1 region. The C=0 stretch is mixed in with the C=C stretch, causing significant broadening of this band. Table 2.1. Selected IR vibrations (KBr, ± 4 cm"1) in the new complexes. VO(ima)2(H20) VO(ama)2 V(ima)3 V(ama)3 vc=o, c=c 1584 1609 1629 1610 1537 1551 1561 . 1563 1511 • 1534 vv=o 967 988 Vv-0 755 758 750 794 45 References start on page 68 Figure 2.8. IR spectra (KBr disk) in the 500-2000 cm"1 region for trans-VO(ima)2(H20) and VO(ama)2-H20. Scheme 2.3. Hydrogen-bonded tautomers of Hima; structure of the isomaltolate anion. 46 References start on page 68 Once deprotonated, the p-hydroxy enone moiety undergoes delocalisation of the electron density, providing a binding site similar to that of a deprotonated acetylacetone, as shown in Scheme 2.3. After chelation, this broad band resolves into three sharp bands indicative of metal bonding at 1511, 1537 and 1584 cm"1. The bathochromic shift is because of the weakening of the CO bonds as electron donation from the carbonyl oxygen to the metal centres reduces the bond order in the carbonyl moiety. A similar trend is observed for allomaltol upon chelation to the vanadium centre. The pyrone stretching frequencies at 1609 and 1551 cm"1 are shifted to lower energies as compared to those in the free proligand. Again it is not possible to distinguish the C=0 stretch from that of C=C. This behaviour is consistent with that of similar pyrones [43, 79] and P-diketones [46] when complexed to vanadyl. Both bis complexes are paramagnetic in the solid state. Magnetic measurements showed a room temperature magnetic moment of p. = 1.76 B.M. for trans-VO(ima)2(H20) and p. = 1.78 B.M. for VO(ama)2 in the solid state, values very close to the spin only value of p, = 1.73 B.M. for a d1 V(IV) system, and within the accepted range of 1.7 - 1.8 B.M. for such systems [80]. The typical eight-line pattern EPR spectrum was also as expected for a V(IV) system for trans-VO(ima)2(H20) at room temperature. The isotropic g and A values are giso = 1.966 + 0.001, Aiso = 100 ± 0.1 (10"4) cm"1 in CH2C12. These are similar to other reported values for vanadyl complexes [43]. The VOL2 (L = ima", ama") complexes were also studied by electron impact ionization mass spectrometry; for both complexes the parent peak VOL2+ and the fragment ion peaks VOL+ and L+ were observed at m/z = 317, 192 and 126, respectively (the coordinated water molecule was not observed by this method). The parent peak for 47 References start on page 68 trans-VO(ima)2(H20) was observed in the electrospray ionization mass spectrum at m/z = 335. Figure 2.9 shows typical EIMS spectra for the bis complexes. These complexes are oxidized in water or alcoholic solutions if exposed to air, resulting in V(V) complexes. This oxidation process was thoroughly studied for the maltol complexes [43, 65]. A methanol solution of VOL2 (L = ima', ama"), if exposed to air for a few hours, turns red in colour; this is indicative of oxidation, which can be accelerated if excess FbC^ is used (3-6 equivalents). The resulting complex has a six-coordinate V(V) metal centre with an alkoxy group filling in the sixth coordination site. Here only VO(ima)2(OCH3) was isolated and characterized. The *H NMR spectrum of VO(ima)2(OCH3) is diagnostic of a V(V) complex; the ring hydrogens appear as doublets at 8 6.28 and 7.53 (4H) while the ring methyl group 192 192 VOL+ 317 [VOL2]+ 108 S 100 126 L+ 11& 123 120 140 11 r-180 209 2CO 220 <iao -iilL m/z 320 Figure 2.9. Typical electron ionization mass spectrum of VOL2 (L = ima", ama"). 48 References start on page 68 has a chemical shift of 8 2.3 (6H). The methoxy hydrogens are observed at 8 3.39 (3H). The room temperature NMR spectrum of this complex shows that the two ligands are in similar environments; however, as a V(V) d° system, VO(ima)2(OCH3) is very labile, meaning that the cis and trans isomers cannot be resolved at room temperature on the NMR time scale. Previous variable temperature NMR studies of the maltol analogue showed a cis structure at lower temperatures [43]. The mass spectrum of the ima" complex did not show the parent peak but instead delineated the bis complex (m/z = 317, VO(ima)2+; [M - OCH3]+). Elemental analyses for the two V02+ complexes showed that, in addition to the two ligands, there is also a water molecule present. Whether this water molecule was actually coordinated was not clear until the X-ray crystal structure of trans-VO(ima)2(H20) was solved. An ORTEP drawing of the complex is shown in Figure 2.10. The structure is very straightforward; an aqua ligand is seen in the sixth coordination site trans to the oxo group. The two furan ligands are bound in a trans arrangement, similar to that seen for BMOV [43]. The geometry around the vanadium centre is pseudo-octahedral. The asymmetric unit cell consists of a half of a formula unit - the V=0 and the aqua ligand define a two-fold axis of symmetry. VO bond lengths are consistent among this compound, BMOV and VO(acac)2. The V=0 bond distance is 1.596(2) A, exactly as long as that reported for BMOV (1.596(7) A [43]) and slightly longer than that in VO(acac)2 (1.584(2) A [81]). This is similar to the vanadyl bond length in related complexes. Upon coordination of isomaltolato to vanadyl, a six-membered chelate ring is formed. The average V-0 bond length in this ring is 2.075 A as compared to 1.988 A for BMOV [43] and 1.968 A for VO(acac)2 [81]. The bond length 49 References start on page 68 Figure 2.10. Intermolecular H-bonding between neighbouring molecules of trans-VO(ima)2(H20) (above); ORTEP drawing of trans-VO(ima)2(H20) (below), 50% thermal probability ellipsoids are shown. 50 References start on page 68 between the coordinated water and the vanadium ion is significantly longer (2.187 A) as compared to the other V-0 bonds. This could be due to steric strain; the vanadyl moiety is sitting above the plane of the other four equatorial oxygen atoms. The isomaltolato bond lengths are also consistent with those reported for other metal complexes of this ligand [71]. The average CO bond length is 1.286 A, close to the average length in VO(acac)2, in which a typical carbonyl bond length is about 1.25 A whereas a single C-0 bond is about 1.45 A. This is indicative of charge delocalisation in the isomaltolato moiety. There is also intermolecular hydrogen bonding between the hydrogens of the coordinated water molecule and the hydroxo oxygens of the isomaltolato ligands of the neighbouring complexes. This provides a network of H-bonding throughout the extended structure (Figure 2.10). The details of these hydrogen bonding interactions are provided in Appendix A (Table A2). The structure of trans-VO(ima)2(H20) is closely related to that of VO(acac)2 (originally reported in 1961 [81] and redetermined in 1995 [82]); the isomaltolato ligand has a binding site similar to that of the acetylacetonato ligand (vide supra). Bond lengths are comparable between the two structures; however, comparison of bond angles is hard because of the disorder (syn/anti orientation of the ligand) in trans-VO(ima)2(H20) structure. The ligand is disordered over two sites in a ratio of 88:12. The geometry around the vanadium is octahedral as opposed to square pyramidal in VO(acac)2. The vanadium(IV) ion is sitting above the equatorial plane in both complexes. The two isomaltolato ligands are trans to one another, similar to the structure of BMOV. Selected bond lengths and angles are presented in Table 2.2; selected crystallographic data are presented in Appendix A (Table Al). 51 References start on page 68 Table 2.2. Selected bond lengths (A) and angles (°) for trans-V(ima)2(H20) with estimated standard deviation in parentheses. V(l)- 0(2) 2.001 (4) 0(4) -V(l) -0(3) 95.99 (9) V(l)- 0(3) 2.038 (3) . 0(4) -V(l) -O (2) 97.5 (3) V(l)- 0(5) 2.187 (2) 0(2) -V(l) -0(3) 93.02 (8) C(3)- 0(2) 1.297 (3) 0(2) -V(l) -0(5) 82.5 (3) C(5)- 0(3) 1.279 (3) 0(3) -V(l) -0(5) 84.01 (9) C(3)- C(4) 1.401 (4) C(4) -C(3) -C(2) 105.7 (2) C(5)- C(4) 1.384 (4) C(4) -C(5) -C(6) 121.1 (2) C(5)- C(6) 1.495 (4) C(4)- 0(1) 1.408 (3) The crystal structure of VO(ama)2-H20 has not been solved yet; however, based on the results of elemental analysis and solution studies, the water molecule probably is coordinated to the vacant coordination site of this complex as well. 2.3.3. Vanadium(III) Complexes, VL3 (L = ima" and ama") Vanadium(III) tris complexes of deprotonated isomaltol and allomaltol were synthesized via dithionite reduction of aqueous vanadyl solution. Addition of excess sodium dithionite to a 1:3 solution of vanadyl sulphate and the proligand causes the reduction of V(IV) and forms the V(III) complexes. This method has been reported 52 References start on page 68 before in the synthesis of V(III) diketonates [83] and has been used in our labs to make V(III) complexes of deprotonated maltol, ethylmaltol and kojic acid [58]. These V(III) compounds are air sensitive to various degrees, V(ima)3 being more stable in the solid form than is V(ama)3; both complexes are more stable than V(ma)3. Either complex oxidizes in solution if exposed to air over several days. Both complexes were completely characterized in the solid state by elemental analysis, IR, MS, and magnetic measurements as well as by X-ray crystallography for V(ima)3. Elemental analyses for these complexes were consistent with the proposed VL3 structure. Both compounds are hygroscopic and V(ama)3 was isolated with one water of crystallization. Infrared spectroscopy is a useful tool in confirming the complexation of the metal centre to the ligand; upon reacting the proligand with the metal, the OH stretch of the proligand disappears, indicative of chelation. Also, the IR spectra of both tris complexes showed vibrations relevant to the bidentate pyrone or furan rings. The absence of the characteristic V=0 stretch peak was a good indication of the reduction of the V(IV) starting material to V(III). As in the bis complexes, the C=0 band has resolved and shifted to lower energy. The bathochromic shift relative to isomaltol is indicative of metal binding, because electron donation from the oxygen atom to the metal centre weakens the carbonyl bond. Here as well, C=C stretches cannot be distinguished from that of C=0 and the bands are assigned as combination bands. All of these data are recorded in Table 2.1, and Figure 2.11 shows the IR spectrum of V(ima)3 as compared to that of the protonated ligand. Liquid secondary ion mass spectra of both these complexes show the parent peak m/z = 427 [ML3 + 1]+, with a correct isotope distribution; high resolution LSIMS 53 References start on page 68 Energy (cm"1) 4Q0B 3500 30DO Z50D ZDDO 1S» 1000 Figure 2.11. Infrared spectra of isomaltol (top) and V(ima)3 (bottom). confirms the molecular mass and formula. The 100% intensity peak is the VL2+ ion for both complexes, and not the actual parent peak. The V2Ls+ peak is also observed at m/z = 727 for both compounds; this peak is characteristic of the ML3 complexes, in this case VL3 [58, 84] (Figure 2.12). Magnetic moments were measured for V(ima)3 and 54 References start on page 68 [VL2]+1 301 Figure 2.12. Positive ion detection liquid secondary mass spectrum (LSIMS) of the V(III) complexes, VL3 (L = ima", ama") V(ama)3 at room temperature and the data were in agreement with previously reported two-electron d vanadium systems [58]. Selected crystallographic data for V(ima)3 are shown in Table Al (Appendix A). Selected bond lengths and angles are presented in Table 2.4. An ORTEP diagram of this complex is shown in Figure 2.13. Crystals of V(ima)3 were grown from the diffusion of n-pentane into an acetone solution of the complex under anaerobic conditions. The vanadium(III) metal ion is situated in a distorted octahedral 06 coordination sphere. 55 References start on page 68 Table 2.3. Selected bond lengths (A) and angles (°) in V(ima)3 with estimated standard deviation in parentheses. V(l) -0(1) 1.951 (2) 0(2) -V(l) -0(1) 91.23(10) V(l) -0(4) 1.953 (6) 0(4) -V(l) -0(1) 94.9 (2) V(l) - O (7) 1.960(5) 0(7) -V(l) -0(1) 177.20 (18) V(l) -0(5) 1.991 (7) 0(4) -v(i) -0(7) 87.6 (3) V(l) -0(2) 2.033 (3) 0(5) -v(i) -0(1) 91.9 (2) V(l) -0(8) 2.082 (6) 0(4) -V(l) -0(5) 94.6 (3) C(l) -0(1) 1.287(4) 0(7) -v(i) -0(5) 89.0 (3) C(5) -0(2) 1.274 (4) 0(2) -V(l) -0(4) 83.7 (2) C(3) -0(3) 1.367 (4) 0(2) -V(l) -0(7) 87.96 (19) C(2) -0(3) 1.398 (3) 0(2) -V(l) -0(5) 176.6 (2) C(l) -C(2) 1.380 (4) 0(2) -V(l) -0(8) 88.0 (2) C(l) -C(4) 1.442 (4) 0(5) -V(l) -0(8) 93.6 (3) C(2) -C(5) 1.382 (5) 0(8) -V(l) -0(1) 86.86(19) C(3) -C(4) 1.336 (5) C(2) -C(l) -C(4) 106.6 (3) C (3) - 0 (3) - C (2) 104.9(3) C(2) -C(5) -C(6) 121.7 (3) 56 References start on page 68 Figure 2.13. ORTEP drawing of V(ima)3 (two of the ligands are each shown in one of two disordered orientations); 50% thermal probability ellipsoids are shown. Two of the ligands around the vanadium are disordered and they each have two orientations; this phenomenon has been observed previously in Al(ima)3 [71]. Due to the disorder in the structure, detailed comparisons of bond angles are difficult; however, bond lengths are quite comparable. In the ordered ligand, the C-C bonds for the binding site are similar (C1-C2 = 1.380 (4) A, C2-C5 = 1.382 (5) A) within experimental error. The average C-C bond length in V(acac)3 is 1.376 (4). In a similar argument the C-0 bond lengths are 1.274 (4) A for the carbonyl and 1.287 (4) A for the hydroxo, both are slightly longer than those observed in the acac" complex. Overall, the bond lengths in V(ima)3 compared to those in V(acac)3 [85] show derealization of the double bonds in isomaltolate when it is coordinated to the vanadium centre. Mer and fac isomers cannot 57 References start on page 68 be assigned to the structure, due to the structural disorder. The V-0 distance varies from 1.951 to 2.082 A (all consistent with a VO single bond). 2.3.4. Solution Studies Acidity constants (equation 2.1) of both Hima and Hama were determined by potentiometric titrations and the results are presented in Table 2.4, along with the analogous values for maltol and acetylacetone (Hacac) for comparison. Stability constants for complexation of V(IV) with these ligands (ima", ama") were also determined potentiometrically. Table 2.4 also shows the formation constants defined by equations 2.2 - 2.5, with the corresponding values for maltol. HL i* H+ + L" Ka 2.1 V02+ + L" [VOL]+ 2.2 [VOL]+ + L"i? VOL2 2.3 V02+ + 21/ ±5 [VOL2]+ A 20 2.4 VOL2 + OH- i5 [VOL2(OH)]- K\2-\ 2.5 Throughout the titrations no precipitation was observed at any point; all the experimental curves were smooth, indicating that hydrolysis was not a factor. By comparing the acidity constants of the three structural isomers one can easily conclude that isomaltol should be a stronger acid than is allomaltol or maltol, therefore it can be predicted that isomaltolate will not be as strong a binding group for vanadium. The acidity constant for isomaltol had been reported earlier by Lutz et al. (pKa= 5.55(1)) [71]. 58 References start on page 68 Table 2.4. Acidity constants of the three C6H60"3 structural isomers and stability constants of the complexes formed between V(IV) and these ligands (1= 0.16 M NaCl, 25 °C) and for Hacac and VO(acac)2 (7= 0.1 M NaC104, 25 °C) [86]. Ligand log Alio log /?120 P^12-I Hima 5.64(2) 5.97(1) 11.37(4) 7.1(1) Hama 8.04(2) 7.90(12) 14.83(8) 8.8(2) Hma 8.44(2) 8.80(2) 16.29(2) 7.5(1) Hacac 8.83 8.59 16.10 It is possible to form L:V(IV) = 2:1 complexes in solution for these bidentate ligands. A deprotonation from VOL2 (L = ima", ama") was observed at higher pH values (about 7 and 9 for isomaltol and allomaltol, respectively) to form hydrolyzed species. The pKa values for these species are 8.8 ± 0.2 for allomaltolate and 7.1 ±0.1 for isomaltolate, respectively. Previous studies in our lab showed that in aqueous solution, there is a water molecule coordinated to vanadium in six coordinate VOL2(H20) [43]. This water molecule is deprotonated at pH > 7. This observation has also been reported by Buglyo et al. recently, for BMOV [87]. When determining the stability constants, the hydrolysis of vanadyl was included in the model using constants from the literature [9]. Using stability constants and hydrolysis constants, species distribution diagrams can be calculated for both ligands. 59 References start on page 68 Figure 2.14. Species distribution diagrams for the complexation of V(IV) with Hima (top) and Hama (bottom) (L:V(IV) = 4:1; [V(fV)] = 0.1 mM; / = 0.16 mM; 25 °C). 60 References start on page 68 The speciation diagrams of VOL2 complexes as a function of pH are shown in Figure 2.14. According to these diagrams the predominant species in solution at neutral pH (pH ~ 7) is VOL2 for allomaltolate, similar to maltolate. For the isomaltolate system, however, the formation constants are less than those for the other two isomers, or for VO(acac)2 (log A'I = 8.59, log p\ = 16.10) [86]. VO(ima)2 is the predominant species in the range 3 < pH < 6. It is obvious from these diagrams that when L:V(IV) > 4, the hydrolysis of vanadyl can be ignored for all these bidentate ligands, up to pH ~6 for isomaltolate (<!0% hydrolysis at pH = 7) and ~9 for allomaltolate. As the pH elevates, the concentration of hydrolysis species increases, and above pH 7 for isomaltolate and 9 for allomaltolate, hydrolysis dominates the solution. A pM vs pH plot, where pM is defined as the sum of all non-complexed "free" vanadium species (equation 2.6) shows that ma" forms the most stable vanadyl complex, followed by ama" and finally ima" (Figure 2.15). pM = -log([V02+] + [VO(OH)+] + [ (VO)2(OH)2]2+ + [ VO(OH)3]") 2.6 The stability constants for ama" complexation with V(V) were also determined under similar conditions using potentiometric titrations (I - 0.16 mM NaCl, 25 °C). Error limits for these values are all higher because of stronger hydrolysis of V(V) as compared to that of V(IV) [9]. The species distribution diagram (Figure 2.16) shows that hydrolysis products cannot be ignored. As can be seen in this plot, the hydrolysis product 61 References start on page 68 Figure 2.15. Plot of pM vs. pH for the V(IV)-Hma, Hama and Hima systems (L:V(IV) 4:1; [V(IV) = 0.1 mM; / = 0.16 M NaCl; 25 °C). o PH Figure 2.16. Species distribution diagram for the Hama-V(V) system (L:V(V) - 4:1; [V(VVJ = 0.1 mM; /= 0.16 NaCl; 25 °C). 62 References start on page 68 [V02(OH)2r is important over a large pH range. Equations 2.7 -2.9 define the formation constants for the V(V)-allomaltol system. The vanadate-allomaltolate complex is more stable than is the maltolate analogue (log Kuo = 7.37, log /?i2o = 14.39) [66]. V02+ + ama ±5 V02(ama) log Km = 9.55 ±0.2 2.7 V02(ama) + ama" U [V02(ama)2] log Km = 7.31 ±0.12 2.8 V02+ + 2ama U [V02(ama)2] log/3i20 = 16.86 ±0.3 2.9 2.3.5. Biological Results Biological studies of anti-diabetic activity were conducted in different trials for each complex. The effectiveness was compared to that of BMOV as a representative standard. In all trials the rats were divided into five groups: control (C, healthy rats); control treated (CT, healthy rats treated with BMOV); diabetic (D, hyperglcemic rats); diabetic treated (DT, hyperglycemic rats treated with BMOV) and diabetic drug treated (DDT, hyperglycemic rats treated with the new compound). For trans-VO(ima)2(H20) the number of rats in each group were 2, 2, 5, 10 and 10 respectively. The compound was administered by oral gavage in this trial, whereas for the two vanadium(III) complexes the method of administration was i.p. (intraperitoneal) injection and the number of rats in the five groups were 3, 3, 3, 6 and 10, respectively. For all the studies, plasma glucose was monitored at time 0 (immediately before administration) and at 8, 12, 24, 48 and 72 hours post administration of the compound. Plots of plasma glucose levels as a function of time for each compound are presented in Figures 2.17-2.19. The 63 References start on page 68 CL Time (h) Figure 2.17. Plot of the plasma glucose levels in control (C) and STZ-diabetic rats (D) following a single oral gavage administration of either CMC (1%) (CT) or trans-VO(ima)2(H20) (DDT) in comparison to BMOV (DT). CO Q_ VJ.KJ -i —r 1 1 1 —I 0 8 12 24 48 72 Time (h) Figure 2.18. Plot of the plasma glucose levels in control (C) and STZ-diabetic rats (D) following a single administration of either CMC (1%) (CT) or V(ima)3 (DDT) in comparison to BMOV (DT), by i.p. injection. 64 References start on page 68 — 40.0 8 12 24 48 72 Time (h) ~*~ c **" C T D + DT DDT Figure 2.19. Plot of the plasma glucose levels in control (C) and STZ-diabetic rats (D) following a single administration of either CMC (1%) (CT) or V(ama)3 (DDT) in comparison to BMOV (DT), by i.p. injection. diabetic animals in all three studies remained hyperglycemic throughout the experiment (blood glucose concentration >13 mM). The average glucose levels at 24 h after treatment for trans-VO(ima)2(H20), V(ima)3 and V(ama)3 were 16.9 ± 3.0, 16.9 ± 2.8 and 16.1 ± 3.4 mM as compared to the BMOV treated group for each trial (13.7 ± 2.3,11.0 ± 4.0 and 14.3 ± 4.3 mM, respectively). These concentrations are significantly lower than the plasma glucose levels for the diabetic group in each trial (> 30 mM). Diabetic (or hyperglycemic) is defined as plasma glucose levels > 13 mM. For trans-VO(ima)2(H20) treated animals, 40% reached the state of euglycemia (plasma glucose < 9 mM) by the 24 h time point. This was the same for the BMOV-treated rats in the same trial. However, rats in the trans-VO(ima)2(H20) treated group reverted to hyperglycemia by the 48 h time point. Respectively, 40% and 50% of the animals that responded to the treatment with 65 References start on page 68 V(ima)3 and V(ama)3, by i.p. injection were euglycemic after 24 hours. The reference BMOV groups in these trials each had 60% and 50% euglycemic rats in comparison. After 24 hours, trans-VO(ima)2(H20) also produced a mild diarrhea in 20%> of the rats. No side effects were observed for animals treated with either of the V(III) complexes. Despite the fact that a significant reduction in the plasma glucose levels between 12 and 48 hours was observed with all three of the complexes, none of them were found to have any better-sustained effect than did BMOV itself. Figure 2.20 shows the percent glucose lowering potency, PGP (defined by equation 2.10) for the new vanadium complexes and BMOV. Trans-VO(ima)2(Ff20) was as active as BMOV for the first 24 hour however, the activity dropped to about 50%> that of BMOV at the 48 h time point. The same behaviour was observed for the two tris complexes up to the first 24 hours but V(ama)3 was almost inactive after 48 hours (Figure 2.20). %PGP = (PGcontroi - PGtest)/PGControi X 100% (PG = Plasma Glucose) 2.10 2.4. Conclusions Vanadium(III, IV) complexes of the structural isomers of maltolate, allomaltolate and isomaltolate, were synthesized and completely characterized. The acidity constants of the ligands as well as the stability constants of their V(IV) and V(V) complexes were determined using potentiometric titrations. The V(IV)-isomaltol system was the least stable among the three ligands (ima", ama", ma") in the physiological pH range. In vivo efficacy of these compounds to normalize the blood glucose levels of STZ diabetic 66 References start on page 68 60 • VO(ima)2(H20) • V(ama)3 • V(ima)3 • BMOV 12 24 48 Time (h) Figure 2.20. Plasma glucose-lowering potency (%) of trans-VO(ima)2(H20), V(ima)3 and V(ama)3 as compared to BMOV. rats was tested; VO(ima)2 has shown significant insulin-enhancing effects despite the low stability of the complex, supporting the study that the complex acts as a "delivery shuttle". 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Shuter, E.; Rettig, S. J.; Orvig, C. Acta Cryst. 1995, 51, 12. 83. Dili, S.; Patsalides, E. Aust. J. Chem. 1976, 29, 2389. 84. Finnegan, M. M.; Lutz, T. G.; Nelson, W. O.; Smith, W.; Orvig, C. Inorg. Chem. 1987, 2^, 2171. 85. Filgueiras, C. A. L.; Horn, A. Jr.; Howie, R. A.; Skakle, J. M. S.; Wardell, J. L. Acta Cryst. 2001, E57, ml57. 86. Imura, H.; Suzuki, N. Bull. Chem. Soc. Jpn. 1986, 59, 2779. 87. Buglyo, P.; Kiss, E.; Fabian, I.; Kiss, T.; Sanna, D.; Garribba, E.; Micera, G. Inorg. Chim. Acta 2000, 306, 174. 74 References start on page 68 Chapter 3 Vanadium and Rhenium Complexes of a Tetradentate Aminopyrone 3.1. Introduction 3.1.1. Vanadium The importance and applications of vanadium compounds with regards to diabetes and insulin-enhancing behaviour were the topics of Chapter 2. The last two decades have seen much research on insulin substitutes to help in the therapy of diabetes mellitus. In reality of course, no compound can completely replace insulin; however, there is always the hope of further improving the insulin-enhancing behaviour by discovering new active compounds. Showing great insulin-enhancing character, vanadium coordination complexes have been a major candidate in this research area. Vanadium compounds have many physiological and biochemical activities; however, their insulin-enhancing behaviour can be considered the most remarkable effect in humans. The potential of inorganic vanadium in the form of vanadyl [VO] or vanadate [VO4] " has been investigated thoroughly [1,2]. Vanadium complexes have shown anti-diabetic effects when administered in vivo and there is ongoing research to find orally active insulin-enhancing vanadium compounds as a treatment for this disease [3]. The chemistry of vanadium with mixed NO donors has been studied [4-9]; some of these complexes have been tested for insulin-enhancing activity [4-7, 9]. In our group, vanadyl complexes of deprotonated 2-(2'-hydroxyphenyl)-2-oxazoline (Hoz) and deprotonated 75 Reference start on page 100 H2(en(ama)2) Figure 3.1. Structures of some potential NO donor proligands. 2-(2'-hydroxyphenyl)-2-thiazoline (Hthoz), both potentially bidentate NO donors, have been investigated [6]. Structures of some potential NO donor proligands are shown in Figure 3.1. Herein is reported the chemistry of an aminopyrone proligand to probe possible improvements in the biological properties of the vanadium 3-hydroxo-4-pyrone complexes. N, N'- bis(3-hydroxy-6-methyl-2-methylene-4-pyrone)ethylenediamine 76 Reference start on page 100 (H2en(ama)2) is the proligand of a potentially tetradentate N2O2 donor, incorporating two allomaltol moieties bridged by an ethylenediamine backbone. It was hoped that increasing the denticity will improve metal chelation and augment the stability of the resulting complex. This chapter reports the synthesis and characterization of the vanadyl-[en(ama)2]2" complex as well as its anti-diabetic activity. Complete solution studies of V(IV) and V(V) complexes of this potentially multidentate chelator proved it to bind more strongly to vanadium than did its parent bisfbidentate ligand) analogues [10]. This increased stability might increase absorption of this compound and result in an increased anti-diabetic activity. 3.1.2. Rhenium Rhenium (element number 75) is yet another transition metal which is drawing growing interest in its coordination chemistry and medical applications. It was first discovered by Noddack et al. in Germany in 1925 [11] and named after the Rhine River. Rhenium cannot be found as a free element or as a compound of distinct mineral composition in nature; it is found spread throughout the earth's crust at a concentration of about 0.001 ppm. Commercial uses of rhenium include rhenium filaments, which are widely used in mass spectrographs and ion gauges, and Re-W thermocouples that are used for measuring temperatures as high as 2200 °C. Rhenium is a third row transition metal of group VII whose properties are closely related to its second row congener technetium, due to the lanthanide contraction for third row transition elements [12]. Re is widely used as a cold surrogate (non-radioactive substitute) in initial investigations of technetium chemistry in nuclear medicine because 77 Reference start on page 100 technetium has no non-radioactive isotopes. More recently the potential applications of rhenium compounds themselves in therapeutic nuclear medicine are attracting much attention. All Tc diagnostic drugs have the potential to be redesigned as Re-based therapeutic compounds [13, 14]. A therapeutic radiopharmaceutical is a radioactive compound containing a suitable isotope which can kill targeted tissue with ionizing radiation [14]. P-radiation is the preferred emission and the p energy determines the depth of the tissue penetration for these compounds, varying from 2-12 mm. The first therapeutic radiopharmaceutical was 13 ll~ used in the early 1940s for the treatment of thyroid cancer; this treatment is still in use today [15]. Rhenium has two radioisotopes, Re and Re, with half-lives of 90 h and 17 h, respectively. The former has a p emission of 1070 keV and the latter a stronger P emission with an energy of 2100 keV. This phenomenon results in a deeper tissue igo 1Q£ penetration for Re (11 mm) as opposed to Re (5 mm), rendering the former more effective for the treatment of bigger tumours. Oxidation of rhenium compounds is easier than is that of technetium analogues, a potentially beneficial factor for in vivo applications since ReO/f (the ultimate oxidation product of rhenium) is easily cleared through the kidneys [13]. Rhenium is found in the 5+ oxidation state in many of the complexes developed for nuclear medicine, complexes which contain the [Re=0]3+ core [16-19]. Chelation of N2O2 donor sets to rhenium results in the formation of a complex cation, which usually coordinates a halide or an anionic ligand (often cis to the oxo) or dimerizes to Re203L2, resulting in neutral complexes with six coordinate rhenium. Trans-ReO(N202)X complexes of this nature have been reported on occasion; recently many trans Schiff base 78 Reference start on page 100 complexes of Re(V) have been reported by Benny et al. [20]. There is a rich chemistry of N2O2 ligands with rhenium; however, the compounds studied have been mainly Schiff bases [21-24] or aminophenols [25]. Rhenium complexes with bidentate NO donors [26] and a variety of amino backbone multidentate ligands have been previously investigated in our group [27]. These ligands, with neutral nitrogen and anionic oxygen atoms, are capable of stabilizing middle oxidation states of the metal centre. [en(ama)2]2_ is an N2O2 donor and, as such, a potential rhenium chelator. The resulting cationic compound could fill its vacant coordination site with an anionic moiety X- to result in a neutral complex of the general formula [ReO(en(ama)2)X]. In this chapter, rhenium complexation to [en(ama)2]2' is reported to form ReO(en(ama)2)Cl, this compound was prepared via both substitution and reduction/complexation methods. Because Tc04_ and Re04_ are the preferred starting materials for the synthesis of technetium and rhenium complexes in nuclear medicine, the preparation of potentially relevant diagnostic and therapeutic complexes, respectively, invariably starts with one of these two salts. Both metal ions are in the 7+ oxidation state, so the synthesis of their complexes requires initial reduction of the metal ion. This can be achieved via two methods. The first method involves a one-pot synthesis wherein the metal centre is reduced and chelated to the ligand in a single procedure. The second method includes two steps: pertechnetate or perrhenate is reduced to a simple precursor complex after which step the desired ligand is introduced and bound to the metal centre via ligand exchange. The former method is of course the preferred method because it includes fewer synthetic steps and is most applicable to technical use in a hospital radiopharmacy. 79 Reference start on page 100 3.2. Experimental 3.2.1. Materials Vanadyl sulphate was purchased from Fisher and ammonium perrhenate was a gift from Johnson-Matthey; both were used without purification. Mer-[ReOCl3(PPh3)2] was made by a literature preparation [28] and H.2en(ama)2 was synthesized according to our published method, with some modifications [10]. All solvents used were obtained from Fisher and used without further purification unless mentioned. Concentrated HC1 and Et3N and all other routine chemicals used were obtained from commercial suppliers. 3.2.2. Instrumentation Mass spectra were obtained with a Kratos Concept IIH32Q (Cs+-LSIMS with positive ion detection) or a Micromass LCT (Electrospray ionization, ESI) instrument. Microanalyses for C, H, N and CI were performed by Mr. Peter Borda or Mr. Minaz Lakha in this department. IR spectra were recorded on a Mattson Galaxy Series 5000 FTIR spectrophotometer in the 500-4000 cm"1 region as KBr disks. !H NMR spectra were recorded on a Bruker AV-300 NMR spectrometer at 300 MHz. The 2D COSY and HMQC experiments were recorded on a Bruker AV-400 spectrometer at 400 MHz. Room temperature magnetic susceptibilities were measured using a Johnson Matthey balance, and diamagnetic corrections were estimated using Pascal's constants [29]. Water was deionized (Barnstead D8902 & D8904 cartridges) and distilled (Corning MP-1 Megapure still). 80 Reference start on page 100 3.2.3. Syntheses of Compounds 3.2.3.1. N, Ar'-Bis(3-hydroxy-6-methyI-2-methylene-4-pyrone) ethylenediamine, H2en(ama)2. Ethylenediamine (0.3 mL, 4.6 mmol) and formaldehyde (37% in H20, 1.2 mL, 14 mmol) were dissolved in 20 mL of MeOH. The reaction mixture was heated to reflux for 2 hours. The light yellow solution was then cooled to 0 °C and allomaltol (Hama) (1.20 g, 9.5 mmol) was added with stirring. After complete dissolution, the solution was placed in the freezer overnight (-4°C). The resulting white solid was filtered out, washed with MeOH (3x5 mL) and dried under vacuum (1.2 g, 74% yield). Anal. Calcd (found) for Ci6H2oN206: C, 57.14 (57.16); H, 5.99 (5.95); N, 8.33 (7.96). IR (cm-1, KBr disk) vc=c,c=o 1582, 1619. ESIMS (+) m/z = 337 [(M+l)+]. 'H NMR (D20): 5 2.15 (s, 6H), 2.81 (s, 4H), 3.51(s, 2H), 3.70 (s, 4H), 6.08 (s, 2H). 3.2.3.2. TV, 7V-bis(3-hydroxo-6-methyl-2-methylene-4-pyrone)-ethylenediamineoxovanadium(IV) dihydrate, VO(en(ama)2).2H20. Vanadyl sulphate (130 mg, 0.51 mmol) and H2(en(ama)2), (172 mg, 0.52 mmol) were added to 20 mL of water with stirring. The pH of the mixture was increased to 8.5 by the addition of IM NaOH. A clear solution of dark brownish colour was obtained. The temperature was then increased to 55°C with constant stirring for two hours. The reaction flask was cooled to room temperature prior to filtration. A dirty pink (light burgundy) solid was obtained (105 mg, 51% yield). Anal. Calcd (found) for C16H22N2O9V: C, 43.95 (44.24); H, 5.07 (5.00); N, 6.41 (6.53). IR (cm-1, KBr disk) vv=o 951. (+) ESIMS m/z = 402 [(M+l)+]. Solid state magnetic moment, p, = 1.79 B.M. 81 Reference start on page 100 3.2.3.3. Chloro-(N, N'-bis(3-hydroxo-6-methyl-2-methylene-4-pyrone) ethylenediamine)oxorhenium(V), ReO(en(ama)2)CI. Method [A]. ReO(PPh3)2Cl3 (83 mg, 0.1 mmol) and H2en(ama)2 (34 mg, 0.1 mmol) were added to 10 mL of MeOH and the temperature was increased to 90 °C. After 30 minutes the solution had changed colour from light yellowish green to dark green and all solids were dissolved. Et3N (3 drops) was added to the solution one hour after the start of the reaction; the colour changed to brown immediately. The reaction mixture was then refluxed for another hour and then cooled to room temperature. Upon filtration, a bright green solid was isolated, washed with 0.5 mL of ethanol and dried under vacuum to yield 20 mg, 35%. Anal. Calcd (found) for Ci6Hi8ClN207Re: C, 33.60 (33.96); H, 3.17 (3.47); N, 4.90 (4.95); CI, 6.20 (5.79). IR (cm"1, KBr disk) vRe=0 941. (+) LSIMS m/z = 537 [(ReO(en(ama)2))+]. 'H NMR (D20/CD3CN): 8 2.20 (s, 3H), 2.55 (s, 3H), 2.68 (m, 1H), 3.54 (q, 1H), 3.88 (q, 1H), 3.85 (d, 1H), 4.18 (d, 1H), 4.62 (d, 1H), 5.08 (d, 1H), 6.18 (s, 1H), 6.50 (s, 1H). Method [B]. NH4Re04 (13 mg, 0.05 mmol) was added to 3 mL of EtOH. One drop of HC1 (cone.) was added to this solution and then PPh3 (26 mg, 0.1 mmol) was added and the temperature increased to 50 °C. After the reaction mixture was stirred for 30 minutes, H2(en(ama)2) was added (17 mg, 0.05 mmol). The clear colourless solution turned green and the colour darkened. The temperature was increased to 90 °C and the solution was stirred for another 1 hour, after which time the mixture cooled to room temperature. After 20 minutes, a bright green solid had precipitated; it was filtered out and the product 82 Reference start on page 100 was dried over P2O5 in vacuo (10 mg, 32% yield). After complete characterization the product was found identical to that isolated by method A. 3.2.4. In vivo Studies All these studies were performed in the laboratories of Prof. J. H. McNeill in the Faculty of Pharmaceutical Sciences, UBC. VO(en(ama)2), prepared as a uniform suspension in 1% CMC, was administrated by oral gavage at a dose of 0.6 mmol kg"1 in a volume of 5 mL to each rat. Blood samples were collected immediately before treatment (t = 0) and at 4, 8, 12, 20, 24, 48 and 72 hours post administration (details of these studies are similar to those described in section 2.2.6.). 3.3. Results and Discussion 3.3.1 Proligand. The tetradentate aminopyrone chelator was synthesized by Mannich coupling of allomaltol and the imine produced from the reaction of ethylenediamine and formaldehyde as recently reported by our group in the literature [10] (with minor modifications). The second step of the reaction was carried out at 0 °C (as opposed to room temperature in the original synthesis) to slow the process and avoid decomposition. The product was isolated from the reaction mixture in one step in good yield. Complete characterization of the final product ensured the product isolated was Ff2(en(ama)2). 83 Reference start on page 100 3.3.2. Vanadium(IV) complex, VO(en(ama)2). Vanadium complexation to the ligand was carried out by dissolution of vanadyl sulphate and the proligand in water and adjusting the pH to 8.5 with IM NaOH. Isolation of the product was not possible at pH < 8. VO(en(ama)2) precipitates out of solution as a dirty pink solid and was characterized using spectroscopic techniques (IR, ESIMS), magnetic measurements and elemental analysis. All data are in agreement with the proposed vanadium complex. According to the elemental analysis results, there are two waters of crystallization present; whether one of these is coordinated to the sixth coordination site or whether they are both present only in the outer sphere and hydrogen bonded to the actual complex cannot be known for sure until the solid state structure of this compound is examined by X-ray diffraction methods. Attempts to grow crystals of this complex have not been successful to date. The infrared spectrum of VO(en(ama)2) shows the V=0 stretch at 951 cm-1 within the range reported for similar vanadyl complexes in the literature [30]. Figure 3.2. shows the infrared spectra of the proligand and this complex. The pyrone stretching frequencies have not shifted noticeably upon complexation; this can be explained by the fact that the carbonyl is not coordinated to the metal centre and the bond order on the C=0 group has remained intact. Magnetic measurements of VO(en(ama)2) in the solid state at room temperature showed a magnetic moment of 1.79 B.M., in agreement with a V(IV) d1 centre with one unpaired electron (upe) [31]. The spin only value for the magnetic moment of a one upe system is 1.73 B.M. In the mass spectrum, the molecular ion peak [VOL + 1]+ was detected in the positive detection mode (Figure 3.3). 84 Reference start on page 100 Energy (cm"1) 2000 1500 1000 500 cm -1 CD o c CD -4—' -•—' "E CO c CO H2(en(ama)2) eu o c CO E CO c CO 1500 1000 Energy (cm"1) 500 1500 VO(en(ama)2) 1000 500 ReO(en(ama)2)CI Figure 3.2. Infrared spectra of the proligand H2en(ama)2, VO(en(ama)2) and ReO(en(ama)2)Cl (KBr disks, cm"1). 85 Reference start on page 100 100 [VOL + 1f 402 V) c CD so-•4—' c Figure 3.3. Electrospray mass spectrum of VO(en(ama)2) in MeOH/1% formic acid. 3.3.3. Re(V) complex, ReO(en(ama)2)Cl. Binding [en(ama)2]2" to rhenium was carried by the reaction of ReOCl3(PPh3)2 with the proligand under basic conditions, resulting in ligand substitution and chelation of the oxorhenium(V) centre by [en(ama)2]2". The same complex was also successfully made from the reduction of [ReOVT in the presence of proligand and HC1. This second method is important because [186/188Re04]"is the starting material in nuclear medicine applications. The infrared spectrum of the product clearly shows the Re=0 stretch at 941 cm"1 (Figure 3.2), consistent with the values reported in the literature for oxorhenium(V) complexes [25-27]. The IR spectrum also rules out the possibility of a ^rara'-dioxorhenium moiety, often a favoured product of rhenium reactions with N2O2 Schiff bases; no IR absorption 3336 m/z 86 Reference start on page 100 characteristic of a u,-oxo dimer (-700 cm-1) or trans dioxo (-850 cm-1) was observed [20, 25]. The C=0 and C=C stretches of the pyrone ring were resolved compared to those in the free ligand; however, similar to the vanadium complex, there is no major shift, again suggesting that the carbonyls are not bound to the metal centre. The peak at 502 cm"1 could be due to the Re-Cl stretch but this could be not be assigned with any certainty because terminal metal-halide stretches are at the low energy limit for the spectrophotometer used. The mass spectrum (Figure 3.4) clearly shows the m/z 537 peak for the cation [ReO(en(ama)2)]+. This is the complex cation formed once the parent compound has lost a chloro ligand, and is easily detected in the positive ion detection mode. Figure 3.4 shows the the simulation of this spectrum to verify the isotope pattern, demonstrating that 100 I537 c CO 537 519 llllilllllllmllll 557 m/z Figure 3.4. (+)LSIMS spectrum of ReO(en(ama)2)Cl (inset shows the simulation). 87 Reference start on page 100 the actual spectrum has the correct isotope pattern for a monorhenium complex. The presence of CI was also confirmed by elemental analysis. Addition of sodium hexaflurophosphate or silver nitrate to the complex solution resulted in no precipitation, indicating that the CI is directly coordinated to the metal centre and the complex is neutral rather than cationic in solution. For a tetradentate N2O2 donor ligand, there are four different modes of binding to a six coordinate metal centre (Scheme 3.1). Generally the geometry with respect to the Re=0 moiety can be affected by a number of factors including the type of backbone, the carbon chain length in the backbone, and the type and number of oxygen donors [20]. Only in the first structure (Scheme 3.1. a) is the ligand bound symmetrically to the O Q Scheme 3.1. Possible diastereomers for the six coordinate complex of a tetradentate N2O2 ligand relative to Re=0. 88 Reference start on page 100 metal centre. In this case the N2O2 core is in the equatorial plane and the molecule possesses a plane of symmetry going through 0=Re-Cl axis. In all the other options [Scheme 3.1. (b, c, d)], the binding N2O2 ligand is non-planar and as a result all hydrogens will be inequivalent. The H2(en(ama)2) 'H NMR spectrum shows a symmetric structure in which each set of equivalent hydrogens appears as one single peak at a characteristic chemical shift. The backbone ethylene and the two pendant methylene groups show peaks at 8 2.8 and 3.7, respectively; the pyrone ring hydrogens have chemical shifts of 8 2.1 and 6.1, for the CH3 and the single hydrogen respectively, and the NH hydrogen appears at 8 3.5. For ReO(en(ama)2)Cl, the 'H NMR spectrum shows all hydrogens to be inequivalent (Figure 3.5), a feature indicative of asymmetric binding of the multidentate ligand with respect to the oxorhenium moiety. This suggests that the chloro ligand is cis to the oxo. In order to assign different hydrogen peaks, additional experiments were performed. The 'H^H COSY (2D Correlation Spectroscopy), I3C and 2D HMQC (Heteronuclear Multiple Quantum Coherence) NMR experiments were conducted to aid in the assignment of various hydrogens in the 'H NMR spectrum for this complex (Figure 3.6). The results of the analyses are presented in Tables 3.1 and 3.2 for the *H and 13C NMR assignments, respectively. The C spectrum was assigned by comparing the chemical shift values to those of similar compounds in the literature [32, 33] and by information obtained from the HMQC data. In the [H NMR spectrum, as can be seen in Figure 3.5, not only are the two pendant arms inequivalent, but so are the two sets of four 89 Reference start on page 100 a D c -NH HN-g f h g U a AJ Figure 3.5. 'H NMR (300 MHz) spectrum and assignments for ReOCl(en(ama)2) in CD3CN/D20(1:2). Table 3.1. Assignment of the !H NMR spectrum (CD3CN/D20) for ReOCl(en(ama)2). Hydrogen Chemical shift (5, ppm) and multiplicity a, b c, d (overlaps with the water peak) e,f ij k,l (2.68,m), (3.54, q) (3.88, q), (3.85, d), (5.08, d) (4.18, d), (4.62, d) (6.18, s), (6.50,s) (2.20, s), (2.55, s) 90 Reference start on page 100 J 0 II ppm 6 ppm Jl n Ji j. All ~3 © 9 & (9 pprrr BP™ Figure 3.6. 2D-C0SY (bottom) and 'H-^C HMQC (top) spectra of ReOCl(en(ama)2) in CD3CN/D20(1:2). 91 Reference start on page 100 Table 3.2. 13C NMR assignments for ReOCl(en(ama)2) in CD3CN/D20 (1:2). a a' Carbon atom Chemical shifts (5, ppm) a, a' 61.9, 75.7 b, b' 61.5,64.7 c,C . 153.0, 154.3 d,d' 148.5, 152.2 e, e' 177.0, 179.7 f,f 111.2,113.2 &g' 165.9, 170.4 h, h' 17.9, 20.1 92 Reference start on page 100 hydrogens belonging to the ethylene backbone and the methylene groups. It is clear from the spectrum that each hydrogen is in a slightly different environment. This could be due to a rigid complex structure and the twisting of the ethylenediamine backbone. It cannot be concluded for sure which one of the three asymmetric structures from Scheme 3.1 (b, c, d) it obtains. Many attempts were made to crystallize this complex for X-ray diffraction studies; in one of these trials [H4(en(ama)2)][(Re04)2] was isolated instead. ReOCl(en(ama)2) had dissociated and the rhenium metal ion had reoxidized to Re(VII). 3.3.4. Solid State Structure of [H4(en(ama)2)](Re04)2 One of the many attempts to grow crystals of ReO(en(ama)2)Cl yielded [H4(en(ama)2)](Re04)2 and because the crystal structure of H2(en(ama)2) was not known, this structure was solved. Crystallographic data for this compound are presented in the Appendix A. Within 2-3 days after dissolution of ReO(en(ama)2)Cl in MeOH/Me2CO (1:1), the green solution changed colour to orange and yellow platelet crystals precipitated. X-ray diffraction proved them to have a monoclinic crystal system with P 2\ln space group and the compound to be [H4(en(ama)2)](Re04)2. Rhenium has reoxidized to the 7+ oxidation state and the ligand was protonated on each of the two amine nitrogens as well as both hydroxo oxygens. The dication sits on a centre of inversion so that half the ligand and one perrhenate anion make up the asymmetric unit (Figure 3.7). The structure of the aminopyrone moiety is as previously predicted [10]. All the bond lengths and angles are as expected. Table 3.3 contains selected bond lengths and bond angles for this compound. 93 Reference start on page 100 Figure 3.7. ORTEP drawing of [H4(en(ama)2)](Re04)2 asymmetric unit - half the cation, one anion (50% thermal probability ellipsoids are shown). 94 Reference start on page 100 Table 3.3. Selected bond lengths (A) and angles (°) for [H4(en(ama)2)](Re04)2 with estimated standard deviation in parentheses. Re(l)- 0(1) 1.725(6) 0(7)-C(3) 1.24(1) Re(l)--0(3) 1.714(6) N(l)-C(8) 1.481(9) Re(l)--0(2) 1.713(6) C(2) - 0(6) 1.344(9) C(2)- C(3) 1.45(1) 0(l)-Re(l)-0(4) 109.3(3) Re(l)--0(4) 1.724(5) C(l)-0(5)-C(5) 119.7(6) 0(5)- C(l) 1.384(9) C(l)-C(2)-C(3) 120.5(7) 0(6)- C(2) 1.344(9) N(l)-C(7)-C(l) 113.2(6) N(l)- C(7) 1.49(1) N(l)-C(8)-C(8) 111.3(7) C(l)- C(2) 1.34(1) 0(5)-C(l)-C(7) 112.2(6) 95 Reference start on page 100 3.3.5. Biological Results The rats were divided into 3 groups, diabetic (D, hyperglycemic rats), diabetic treated (DT, hyperglycemic rats treated with BMOV) and diabetic potential-drug treated (DDT, hyperglycemic rats treated with VO(en(ama)2). There were 8, 5 and 6 rats in these respective groups. In these studies the results are compared to those of BMOV and the diabetic group for glucose lowering properties. Plasma glucose levels were measured at time 0 (immediately before drug administration) and at 4, 8, 12, 24, 48 and 72 hours post administration. A plot of plasma glucose concentration as a function of time for the three groups of animals is shown in Figure 3.8. The BMOV treated group shows a significantly lower plasma JO 4 8 12 24 48 72 o- Time (h) Figure 3.8. Plot of glucose concentration as a function of time in STZ-diabetic rats (D) and rats treated with a single oral gavage administration of VO(en(ama)2) (DDT) or BMOV (DT). 96 Reference start on page 100 glucose level as compared to the diabetic group; the VO(en(ama)2) treated group does not show any glucose lowering at all as compared to the diabetic group. None of the animals in this potential drug-treated group reached euglycemic glucose concentrations (< 9 mM) post treatment. No significant side effects were observed for the VO(en(ama)2) treated group either. Solution studies of the V(IV)-en(ama)2 system have been investigated and compared to BMOV thoroughly [10]. Plots of pM versus pH, in order to compare the stability constants in these studies, indicated that the tetradentate chelator forms a much stronger complex to vanadyl than do any of the considered bidentate ligands, including maltolate (Figure 3.9). Therefore, although this complex might have been absorbed well enough in the body, the high stability of it may be problematic in that enough dissociation of the vanadyl moiety may not take place to allow any insulin-enhancing behaviour. Figure 3.9. Plot of pM vs. pH for the V(IV)-Hma, Hima and H2(en(ama)2) systems (L:V(lV) = 4:l(L=Hima, Hma), L:V(IV) = 2:1 (L = H2(en(ama)2)); [V(1V) = 0.1 mM; / = 0.16 M NaCl; 25 °C). 97 Reference start on page 100 It was clearly shown in a pharmacokinetic study of ([ethyl- 1-14C] BEOV (bis(ethylmaltolato)oxovanadium(IV)) that shortly after the administration of the compound, the pattern of disappearance for 14C differs substantially from that of vanadium suggesting rapid dissociation of the complex [34]. In a study by Peters et al. soaking protein tyrosine phosphatase in solution with BMOV (VO(ma)2) resulted in vanadate appearing to occupy the active site of the enzyme, which may be critical to BMOV's function as an insulin-enhancing agent [35]. Goldwaser et al. have shown that organic ligands, when bound to vanadium, show anti-diabetic activity attributed to different features including the stability of the vanadium-ligand system [36]. In Figure 3.10, the % glucose-lowering potency of this complex (see Chapter 2, equation 2.10) is shown and compared to that of VO(ima)2(H20) and BMOV. It is very clear from the plot that the new compound has no anti-diabetic activity at all. 60.0 -10.0 Time (h) Figure 3.10. Comparison of % glucose lowering potency with BMOV compared to that of a strong [(en(ama)2)2"] and a weak (ima-) chelator. 98 Reference start on page 100 3.4. Conclusion The reaction of H2(en(ama)2) with vanadyl sulphate afforded VO(en(ama)2). All characterization agrees with the 1:1 complex formation. Biological studies of this compound proved it to show no insulin-enhancing behaviour at all; this may have been related to the high stability of this compound inhibiting the dissociation of the complex in time for the vanadyl moiety to have any anti-diabetic effect. Rhenium was complexed to [en(ama)2]2" by two methods (reduction/complexation and reduction/substitution) to produce ReO(en(ama)2)Cl. This compound was characterized completely by the usual methods including NMR spectroscopy. The 'H NMR spectrum of this complex clearly shows an asymmetric binding of the ligand to the metal centre. Crystals of [H4(en(ama)2)](Re04)2 were grown in attempts to crystallize ReO(en(ama)2)Cl. The structure shows a diprotonated aminopyrone cation and two perrhenate anions. The molecule possesses a centre of inversion; therefore the asymmetric unit is only half of the empirical formula. 99 Reference start on page 100 .5. References 1. 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Pharmacol. 2000, 55, 738. 102 Reference start on page 100 Chapter 4 Gallium and Indium Complexes of Multidentate PO Donors Interesting Diverse Chemistry 4.1. Introduction 4.1.1. Gallium and Indium "Few families of elements in the periodic table are more given to "wild civility" than the members of group 13" [1]. These elements (B, Al, Ga, In and Tl) although in the same group, show great irregularity and diversity that makes it appealing to investigate their chemistry. Other than B (discovered in 1808), all the elements of group 13 were discovered in 1860 - 1880 [2]. Ferdinand Reich and Theodor Richter, working in a mining school in Germany, were the first to isolate indium in 1863. They were testing Zn ores by spectroscopic methods when they noticed an unexpected and never reported indigo blue line [3]. After separating the pure element by reducing the isolated oxide, they named it indium for its flame colouration [4]. Until 1924, only one gram of pure indium represented the world supply of this metal. Indium is in fact not as rare as was thought; it is actually as naturally abundant as silver [5]. Gallium was the last group 13 metal discovered. In 1870, Mendeleev predicted its existence and named it eka-aluminium. It wasn't until 1875 that a French chemist, Lecoq de Boisbaudran, discovered gallium by spectroscopic methods in a process similar to the discovery of indium [6]. Boisbaudran named the element gallium in honour of France. 103 References start on page 145 Despite aluminium being the most common metal found in the earth's crust, gallium and indium are only found in trace quantities.; neither element is the dominant metal ion in any known mineral. The earth's crust contains about 20 ppm of gallium and 50 ppb of indium [7]. Both are mainly found as impurities in sulphide minerals (usually zinc ores) as opposed to oxides; however, gallium is also found associated with aluminium in bauxite and is now a byproduct of the aluminium industry. Canada has been one of the lead producers of indium [8]. Gallium and indium are both shiny silvery metals. Indium is relatively soft while gallium easily melts into a liquid at slightly higher than room temperatures (29.8 °C). Gallium boils at 2403 °C making it the element with the widest liquid range. As a result, gallium has applications in metal thermometers for measuring very high temperatures. Gallium and indium both have widespread applications in industry. Indium was first used commercially in dental alloys [9]. Both metals wet glass, and are widely used in the creation of brilliant mirrors. In the study of semiconductivity these two elements are widely utilized; another major application of group 13 compounds is in organic chemistry. Group 13 metal halides or other organometallic complexes of these metals assist various transformations between organic moieties [10]. Boron, aluminium and gallium halides have long been used as catalysts in organic reactions while indium halides have only been utilized in this field recently. The use of indium in organic synthesis is a rapidly growing application [11,12]. There is no knowledge of any direct biological role for either gallium or indium; however, they both have applications in nuclear medicine as potential radiopharmaceuticals due to their useful radioisotopes (vide infra). Recently InCl3 has 104 References start on page 145 shown embryotoxicity and teratogenicity in mice and rats [13], while Ga(N03)3 has been shown to inhibit bone resorption [14]; currently many gallium complexes are being investigated for their anti-tumour activities [15]. 4.1.2. Coordination Chemistry of Gallium and Indium The understanding of the coordination chemistry of group 13 metals has increased tremendously as experimental techniques have improved over time. Today, countless structures and several coordination numbers are known for these elements; however, there are still areas in this field where our knowledge is far from complete [16]. Group 13 metals, having the ns np electronic configuration, can take 1+, 2+ or 3+ oxidation numbers, although the last is the most common state for all these elements (except for Tl which is subject to the inert pair effect) [17]. This relatively high oxidation state causes the tripositive ions to be strongly acidic; therefore, they typically coordinate electron-rich neutral or anionic moieties. The chemistries of gallium and indium are very similar. Since they are both strong Lewis acids, many of the same ligands (mainly oxygen or nitrogen donors) bind both metals, forming stable complexes. With increasing atomic number, metal ions become softer due to more electron delocalisation; therefore, indium is slightly softer than gallium in the same oxidation state. The most stable oxidation state for both elements is 3+. Ga3+ is very similar to Fe3+ in size and coordination chemistry [18]. There is a variety of stoichiometries and structures known for gallium and indium complexes [19] including monometallic complexes, dimetallic (or multimetallic) clusters 105 References start on page 145 bridged by ligands, and ionic compounds. Both metal ions have shown coordination numbers of 3, 4, 5 and 6 depending on the size, shape and denticity of the ligating moiety relative to the metal centre (Figure 4.1). Six coordinated metal centres possess octahedral geometry and are considered to be the most stable complexes in vivo. Gallium and indium halide ligation is one of the most common and important features of coordination complexes of these metals. Neutral donor ligands can form 1:1, 1:2 and 1:3 derivatives with both gallium and indium trihalides [20], an important trait in the chemistry of these elements. These compounds were used as Lewis acids to catalyze organic syntheses as early as 1942 (GaCL;) [21, 22, 23]. Recently, indium halides are finding more applications in the field of catalysis [24]. Compounds featuring Ga or In and group 15 elements are well recognized due to their potential application in the formation of III-V semiconductors (e.g. GaAs, InP) [19c]. Gallium hydrides have been well investigated as precursors in this field [25] while indium hydrides are still under study [26]. 4.1.2.1. Solution Chemistry of Gallium and Indium A sound understanding of the solution chemistry of gallium and indium is also important in expanding the knowledge of coordination chemistry of these elements. Both gallium and indium hydrolyse easily and form various pH and concentration dependent species [27]. Among the possible oxidation states for these elements, the 3+ oxidation state is the most stable in water and exists as [M(H20)6]3+ (M = Ga, In) in acidic aqueous media. The pKa values of 2.6 and 3.9 are known for the hydrolysis of the hexaaquametal 106 References start on page 145 Cl\, /Cl In CI CI CI//'/,...'. „rt\CI • In, 2-Cl CI Y Y Y M = Ga, In Y = halogen CI////„ PPh3 n CI PPh3 H20////(„,., H20^" OH2 M ..„.tt*OH2 3+ M = Ga, In OH, M = Ga, In = bidentate ligand Figure 4.1. Examples of different coordination numbers and geometries for Ga and In. 107 References start on page 145 complex to [M(H20)5OH] for Ga and In, respectively [27]. The speciation diagrams for the hydrolysis of these metal ions show formation of various monomeric and polymeric species in solution with respect to pH and concentration (Figure 4.2 for indium). The hydrolysis of In3+ as the pH is raised eventually leads to the formation of In(OH)3, the dominant species over a wide pH range [27]. A similar pattern is observed for Ga. In(OH)3 and Ga(OH)3 both have very low solubility products (1 x 10"33 [28] and 36 7.1 x 10" [29], respectively), leading to a narrow pH window before the metal ion in each case precipitates out of solution. Ga(OH)3, however, redissolves at high pH as the [Ga(OH)4]" anion. For indium, the presence of chloride in solution is also problematic. Depending on the concentration, various In3+-chloride species or hydroxo-chloride complexes strongly form [27]. These characteristics are important factors when considering in vivo applications for the complexes of these metal ions, as they have to be kinetically inert to demetallation and thermodynamically stable to hydrolysis at physiological pH. 4.1.3. Gallium, Indium and Nuclear Medicine Nuclear medicine originated in 1901 when natural radium was used to treat skin lesions [30]. When cyclotrons and nuclear reactors were built in the 1940s, this field started a rapid growth due to the sudden availability of a range of isotopes. Today many compounds are developed for use as radiopharmaceuticals owing to a modern understanding of physiology, pharmacology and chemistry [31]. A desirable 108 References start on page 145 Figure 4.2. Solution speciation diagram for In(lll) as a function of pH, [Intotai] = 10-5 M [27]. Table 4.1. Characteristics of selected y, (3~ and p+ emitting radiometals. Isotope ti/2 (h) Production method Decay mode mln 67.9 Cyclotron, lnCd(p,n) EC (100%) 172,245 99mTc 6.0 "Mo/ 99n,Tc generator IT (100%) 141 — 188Re 16.98 188W7 188Re generator P" (100%) 155 2116,1965 68Ga 1.1 68Ge/ 68Ga generator P+(90%) 511 — 67Ga 78.26 Cyclotron, 67Zn(p,n) EC (100%) 91,93, 185,296, 388 — 109 References start on page 145 radiopharmaceutical has a half life sufficient for high and specific uptake in the target tissue, as well as for rapid clearance, low toxicity and minimal accumulation in non-target tissue; furthermore it should be easily available and reasonably priced. Today, the majority of radiopharmaceuticals (~ 90 %) are used for disease diagnosis; however, there are some compounds used for therapeutic purposes as well. Table 4.1 shows examples of y, P" and p+ emitting radiometals, their modes of decay and methods of production. Gallium and indium each have two natural and a myriad of radioactive isotopes, of which a few have suitable properties for use as radiopharmaceuticals. This has awakened great interest in the potential applications of gallium and indium in nuclear medicine [32, 33]. 67Gaand 11'in are the most common radioisotopes of gallium and indium used in nuclear medicine. 67Ga and 11'in are both used in SPECT (single photon emission computed tomography) imaging whereas 68Ga, being a positron emitter, has applications in PET (positron emission tomography). 68Ga is generator produced from 68Ge (tm = 280 d) which eliminates the need for an on-site cyclotron, a great advantage over 18F, which is the most commonly used PET radioisotope today but is cyclotron-produced. This radioactive isotope ( Ga) could be widely applicable to the field after the required chemistry is developed. 66Ga (Un = 9.4 h, p+) is yet another cyclotron produced gallium radioisotope suitable for PET imaging. Despite the many different metal complexes made for use as radiopharmaceuticals, a very limited number of gallium and indium compounds have actual clinical applications. The two major factors contributing to this are the hydrolytic and thermodynamic instabilities of these compounds. At pH > 2.5, these metals easily 110 References start on page 145 undergo hydrolysis that is pH, time and concentration dependent [27]. In addition, any applicable chelator for these metals must be strong enough to compete with human serum transferrin (Tf). Although Fe(III) is the metal ion normally found in the active site of this blood-borne protein, Tf has a high affinity for other metal ions; therefore, the high concentration of this protein (0.25 g/100 mL) favours in vivo exchange. Under normal conditions there are ~ 50 uM vacant Fe(III) binding sites available in Tf [34], therefore it readily binds other 3+ metals such as Ga(III) and In(III). As a result, researchers have focused on the syntheses of very stable complexes (log K > 20) of these two metal ions. Figure 4.3 shows a random selection of proligands that once deprotonated have been complexed to Ga or In for potential applications in nuclear medicine. Citrate and oxine (8-hydroxyquinolinato) complexes of Ga and In are well studied, clinically useful and are used widely in nuclear medicine. There has been a lot of debate as to what the exact structure of the metal-citrate complexes in aqueous solution might be, since citrate is a potential multidentate ligand [35]; recently a solid-state structure of [Ga(cit)2]3" has been reported showing that citrate is bound in a tridentate fashion through one terminal acetate and the central hydroxo and acetate groups [36], corroborating the solution data. Gallium and indium both form very stable [37] trisligand complexes with oxine [38]. 67 Ga-citrate was used for imaging tumours for the first time in the late 1960s [39]. Shortly after its introduction, it was shown that the active species in vivo is the transferrin complex formed from the citrate by transmetallation [40]. Today 67Ga-citrate is still widely used clinically as an agent for diagnosis of various cancers such as Hodgkin's 111 References start on page 145 OH O Hma O OH N I Ph Hppp OH Oxine HOOC-^ / \ ^:OOH X" 'X, fj\^OH HO^/^ Hbed CH2COOH I HO C COOH CH2COOH Citric acid HOOCv / \ / \ /C00H N N N N ' HOOC^ ^COOH COOH DTPA NS3 Figure 4.3. Examples of various Ga and In proligands which have been investigated for potential applications in nuclear medicine. 112 References start on page 145 lymphoma [41], lung cancer and malignant melanoma [33] as well as detecting tumours [42]. 67Ga-citrate is also utilized in detecting inflammation [43, 44]. Another group of promising chelators for Ga and In is the 3-hydroxy-4-pyridinone family. 67Ga complexes of 3-hydroxo-4-pyridinones have shown adequate in vivo stability, quick heart uptake and blood clearance in rabbit and dog models to be useful as a first pass extraction heart imaging agent [45]. Santos et al. have reported on the in vivo stability of Fe3+, Al3+ and Ga3+ complexes of 3-hydroxo-4-pyridinones [46]. Recently in our labs, carbohydrate-bearing complexes of 3-hydroxo-4-pyridinones with gallium and indium have been synthesized; the pendant sugar is used to direct the metal complex in vivo [47]. Facile generator production of 68Ga and its suitable half-life are strong reasons for developing Ga-labeled radiopharmaceuticals. Liu et al. have used tripodal aminophenolates to make six coordinate Ga complexes with potential application as myocardial imaging agents [48, 49]. 68Ga-citrate has been used to quantify vascular permeability using PET imaging [33]. Development of 68Ga complexes has advanced immensely for potential application in myocardial imaging [32, 33]. The first in vivo application of11'in was reported in 1969 [50]. Today many complexes of this radionuclide are used as imaging agents. There are several radiopharmaceuticals utilized in diagnosis of infection but among them 67Ga-citrate and ulIn-oxine maintain their positions [51], helping to combat the 35% mortality due to infections per annum [51]. mIn-oxine has been utilized for imaging inflammation in the kidneys and bladder, and for chronic infection [51]. It has also been used in patients to 113 References start on page 145 study rheumatic heart disease [52] and to label leukocytes [53]. 11 'in-DTPA has been used for renal and brain imaging [18]. mIn ligated by biomolecules (e.g. proteins and peptides) is also used for diagnostic purposes; luIn-OctreoScan®, a radiolabeled form of the somatostatin analogue octreotide (mIn-pentetreotide), detects and binds to specific receptors of tumours. This provides early detection and subsequent treatment of malignancies in early stages. This drug was approved by the FDA in 1994 and is used for imaging neuroendocrine tumours [54-56]. Despite the ongoing research, application of these elements in nuclear medicine has been slow due to the underdevelopment of suitable compounds in this area of main group chemistry. 4.1.4. Previous Contributions from the Orvig Group The coordination chemistry of gallium and indium has been examined extensively in our group. Several complexes were synthesized using simple bidentate proligands [45, 48, 49, 57-64] or more elaborate multidentate chelators [65-72]. Some of these compounds have been investigated further for potential applications in nuclear medicine [45, 48, 49] as possible therapeutic and diagnostic drugs. Ga(ma)3 (first synthesized in our labs in the late 1980s as a potential diagnostic agent) is being revisited today as a potential therapeutic anticancer agent [73]. In order to explore further the basic coordination chemistry of gallium and indium with a group of heterodonors, phosphinophenolate ligands have been investigated and are reported herein. Phosphine complexes of gallium and indium are less common simply because phosphines are considered soft bases and preferably bind soft acids; as a result, group 13 114 References start on page 145 phosphine compounds have been only reported periodically in the literature [74,75]. According to the theory of hard and soft acids and bases (HSAB) [76], hard acids prefer to bind to hard bases and soft acids prefer soft bases. For the former, electrostatic forces stabilize the complex, and for the latter, electron delocalisation and polarizability are behind the interaction. There is not much detailed information available on the coordination complexes of gallium and indium with multidentate heterodonor tertiary phosphines; however, adducts formed between simple phosphines and the trihalides of gallium and indium encompass a significant subset of the coordination chemistry of these elements. These compounds have been investigated mainly due to their precursor applications in the material sciences and semiconductor industry. Recently Sigl et al. investigated the chemistry of gallium and indium trichloride coordinated to multidentate phosphines for their potential applications as III/V semiconductor precursors, as well as in catalysis [77-79]. This chapter reports an exploration of the basic, interesting and diverse coordination chemistry of gallium and indium with potentially multidentate phosphinophenolates (i.e. PO donor) ligands. To our knowledge, the chemistry of these metal ions with mixed PO donors has not been investigated previously. 4.1.5. Hetero Donor Phosphinophenolates Recently there has been increased interest in heterodonor multidentate ligands regarding tertiary phosphine groups combined with a nitrogen, oxygen or sulphur donor. Of these, phosphinothiolates are suitable ligands to chelate a wide range of metal ions 115 References start on page 145 including lanthanides [80, 81]. The history of aminophosphines goes back to the late 1800s; in the past decade, however, there is growing interest for the synthesis of these compounds for new materials [82]. Also, the ligating properties of phosphinophenolates toward transition metals have been investigated extensively for various purposes and applications [83-87]. This latter group of chelators is structurally very similar to triphenylphosphine, with one or more of the phenyl substituents functionalised with a hydroxo group, therefore combining a soft phosphine phosphorus donor with one or more hard phenolic oxygens (Figure 4.4). The general formula HxPyOx describes the number of oxygen donors in these compounds (x = 1, 2; y = 1) or (x = 4; y = 2). These are potential bi-, tri-and multidentate proligands, which deprotonate at the phenolic group to bind different metals. Thiolated analogues of these compounds have been recently reported with In and Fe [81, 88]. A myriad of rhenium and technetium complexes with PO ligands is known [83-85, 89]. These mixed donors stabilize the middle oxidation states (3+, 4+, 5+) of rhenium or technetium. Siefert et al. investigated the coordination chemistry of PO donors with Co, Rh and Ni to examine the reactivity of phenolate compounds towards late transition metals [83]. The palladium-catalyzed silylation of aryl halides has also been reported as more efficient, and with greater yields, using PO ligands as compared to other functionalised phosphines [90]. Various Ni complexes of these mixed donors have also been reported to be useful in catalysis for ethylene polymerization [86, 87]. We decided to explore further the basic coordination chemistry of Ga and In by using these multidentate hetero PO donors. Herein we report the synthesis and further 116 References start on page 145 R = H, CH3, t-Bu Figure 4.4. Chemical structures of the multidentate phosphinophenols. 117 References start on page 145 characterization of new diverse gallium and indium complexes with bidentate phosphinophenolate ligands (PO" and MePO"). 4.2. Experimental 4.2.1. Materials All manipulations were carried under an atmosphere of Ar using Schlenk techniques and dry solvents unless mentioned otherwise. Indium was bought from Aldrich and used as wire. The phosphinophenol proligands were synthesised as previously published [84]. GaC^ and InCh were purchased from Aldrich. Solvents, [(CH3)4N]PF6 and [Bii4N]C104, and all other chemicals were purchased from commercial suppliers. 4.2.2. Instrumentation Elemental analyses were performed by Mr. P. Borda or Mr. M. Lakha from this department. Mass spectra were obtained with a Kratos MS 50 (electron-impact ionization) or a Kratos Concept II H32Q instrument (Cs+, liquid secondary ion mass spectrometry (LSIMS)). *H NMR spectra were recorded on a Bruker AC-200E or a Bruker AV-300 NMR spectrometer at 200 or 300 MHz, respectively. 31P NMR spectra were recorded on the Bruker AC-200E (81 MHz) or Bruker AV-300 (121.5 MHz) NMR spectrometers with 8 referenced to external 85% aqueous phosphoric acid. Single crystal X-ray structure analyses were carried out by Dr. Brian Patrick in this department. 118 References start on page 145 4.2.3. Electrochemical Syntheses The electrochemical procedure used in the syntheses of the indium complexes was similar to that described by Tuck [92]. The cell consisted of an indium anode suspended from a platinum wire in a solution of the proligand and electrolyte in dry acetonitrile under Ar, and a platinum cathode. The cell is summarized as Pt(.)/L + E (CH3CN)/In(+) (L = proligand, E = electrolyte). 4.2.4. Neutralization of the Proligands. All proligands were synthesized according to the published procedures [84]. The isolated compounds however, were partial or complete hydrochloride salts (this was problematic in the InL3 (L = RPO" (R = H, CH3)) syntheses; see page 132); therefore, these compounds were carefully neutralized to produce the pure phosphine in each case. 4.2.4.1. R-HPO (R = H, Me). HPOxHCl (100 mg, 0.36 mmol (based on HPO) or 0.34 mmol (based on MeHPO)) was dissolved in 20 mL of dichloromethane. This solution was washed twice with 5 mL of 1M aqueous NH4OH. The organic phase was collected and dried with anhydrous Na2S04. The mixture was filtered and then the solvent was removed from the filtrate by rotary evaporation to yield the neutral phosphine (86 mg, 85% HPO; 83 mg, 84% MeHPO). Anal. Calcd (found) for CigHisOP: C, 77.69 (77.66); H, 3.43 (3.32). 31P NMR (CD2C12, 121.5 MHz): 5 -27 (s). Anal. Calcd (found) for Ci9H17OP: C, 78.07 (78.09); H, 5.86 (5.79). 31P NMR (CD2C12, 121.5 MHz): 5-27.5 (s) 119 References start on page 145 4.2.4.2. Me2-H2P02. Me2-H2P02-HCl (100 mg, 0.31 mmol) was added to 10 mL water. To this suspension, NaOH (4M) was added dropwise by a syringe. Once the solid was dissolved (pH = 12), CH3COOH (4M) was added dropwise to decrease the pH of the solution; as the pH reached 10, a white solid precipitated out of solution and the pH was further decreased to 8.5. The mixture was filtered and the precipitate was dried under vacuum to yield 90 mg, 89% of the neutralized proligand. Anal. Calcd (found) for C20H19O2P: C, 74.52 (74.38); H, 5.94 (5.85). 31P NMR (DMSO, 121.5 MHz): 5 -26 (s). 4.2.4.3. Me4-H4P204. Me4-H4P204-2HCl (100 mg, 0.17 mmol) was added to 10 mL water. To this suspension, NaOH (4M) was added dropwise using a syringe until the solid was dissolved completely (pH = 12). CH3COOH (4M) was used to decrease the pH of solution. As the pH reached 10, a white precipitate appeared in solution. The pH was decreased to 8.5. The mixture was filtered and the precipitate was dried under vacuum to yield (74 mg, 84%) of the neutralized proligand. Anal. Calcd (found) for C3oH3204P2: C, 69.49 (69.16); H, 6.22 (6.01). 31PNMR (DMSO, 121.5 MHz): 6 -29 (s). 4.2.5. Syntheses of Compounds 4.2.5.1. Trichlorotris(u,-O(or/Aohydroxophenyl)diphenylphosphinato) diindium(III), In2(PO)3Cl3. Electrochemical oxidation of an indium anode under Ar, in a solution of [Me4N]PF6 (100 g, 0.45 mmol) and HPOxHCl (160 mg, 0.58 mmol (based on HPO)), in acetonitrile (50 mL), at 8 V and 3 mA for 4 h, caused 52 mg of indium to be dissolved (Ef= 1.01 mol F1). During the electrolysis, hydrogen gas evolved at the cathode. The solution was cloudy at the end. The mixture was filtered and 120 References start on page 145 the clear colourless filtrate was kept over night. Crystals appeared in the flask, they were filtered off, washed with Et^O and dried under vacuum (60 mg, 26% yield). Anal. Calcd (found) for C54H42Cl3ln203P3: C, 55.45 (55.40); H, 3.62 (3.63). EIMS: m/z = 462 [In(PO)Cl2], 704 [In(PO)2Cl]. 'H NMR (CD2C12, 300 MHz): 5 5.8-7.8 (m, Ar Hs). 31P NMR (CD2CI2, 121.5 MHz): 5 49.2 (s), -26.9 (s). 31P NMR (DMSO, 81 MHz): 8 45.6 (s), 48.6 (s),-15.7 (s). 4.2.5.2. Tris((2-hydroxo-5-methyl)phenyldiphenylphosphinato)indium(III) triacetonitrile, In(MePO)3-3CH3CN. Electrochemical oxidation of an indium anode under Ar, in a solution of [Bu4N]C104 (35 mg, 0.1 mmol) and MeHPO (80 mg, 0.27 mmol) in acetonitrile (30 mL), at 10 V and 2 mA for 4 h, caused 35 mg of indium to be dissolved (Ef = 0.92 mol F_1). During the electrolysis, hydrogen gas evolved at the cathode. A grey cloudy precipitate appeared in the reaction flask that was filtered off. After about 1 h, crystals started to appear in the filtrate flask. Crystals were filtered off the following day and dried under vacuum (42 mg, 41% yield). Anal. Calcd (found) for C63H57N3O3P3: C, 68.05 (68.13); H, 5.17 (5.44); N 3.78 (3.52). EIMS: m/z = 988 [ML3]+, 697 [ML2]+, 406 [ML]+, 291 [L]+. 31P NMR (CD2C12, 121.5 MHz): 5 43 (s). 4.2.5.3. Tris((ort/rohydroxophenyl)diphenylphosphinato)indium(III), In(PO)3. Electrochemical oxidation of an indium anode under Ar, in a solution of [Bu4N]C104 (15 mg, 0.1 mmol) and HPO (20 mg, 0.07 mmol) in acetonitrile (20 mL), at 10 V and 2 mA for 1 h, caused 9 mg of indium to be dissolved (Ef = 1.05 mol F_1). During the electrolysis, hydrogen gas evolved at the cathode. A grey precipitate 121 References start on page 145 produced during the electrolysis was filtered off. After 90 min, crystals appeared in the filtrate flask. Crystals were filtered off the following day and dried under vacuum to yield 11 mg (48% yield). EIMS: m/z = 946 [ML3]+, 661 [ML2]+, 392 [ML]+, 277 [L]+. 31P NMR (CD2C12, 121.5 MHz): 5 41.6 (s). 4.2.5.4. Bisaquatetrachlorobis(u.-0-(2-hydroxo-5-methyl)phenyI diphenylphosphinato)diindium(III) Dietherate, [Inu,-(MePO)CI2(H20)]2-2Et20. Indium trichloride (25 mg, 0.11 mmol) was added to 15 mL of Et20 and stirred overnight until all the solid dissolved. MeHPO (37 mg, 0.13 mmol) was dissolved in 10 mL of Et20 and was added to the previous solution slowly. The clear solution was stirred for 1 h. The volume of solvent was slightly reduced and a white solid precipitated out of the solution. The mixture was filtered and the precipitate was washed with ether (1 mL) and dried under vacuum (35 mg, 27%>). (Repeating the same procedure with minor modifications grew X-ray quality crystals; instead of reducing the volume the system was closed under Ar. After two days, colourless crystals appeared in the flask that were filtered, washed with ether and dried under vacuum.) Anal. Calcd (found) for C46H56Cl2In206P2: C, 48.70 (48.73); H, 4.62 (4.62); CI, 12.50 (12.39). EIMS: m/z = 476 [In(MePO)Cl2]+. 31P NMR (DMSO, 121.5 MHz) 5 45.6 (s), -16.2 (s). 4.2.5.5. (0/*^/rohydroxophenyl)diphenyIphosphoniumtrichIorogallium(III) hydrochloride, Ga(HPO)Cl30.75HCl. HPO (140 mg, 52 mmol) was dissolved in 20 mL of toluene. A solution of anhydrous GaCl3 (9mg, 0.52 mmol) in 5 mL toluene was added dropwise to the HPO solution. The temperature was raised to 85 °C and the 122 References start on page 145 reaction mixture was stirred. In less than 30 min, a white precipitate appeared in the flask. After 2 h the reaction mixture was cooled to room temperature, filtered and the precipitate was dried under vacuum (99 mg, 40% yield). Crystals of this compound were grown by diffusion of n-pentane into a solution of the complex in CH2CI2. Anal. Calcd (found) for C18Hi5.75Cl3.75GaOP: C, 44.88 (44.75); H, 3.30 (3.42); CI, 27.60 (27.83). EIMS: m/z = 418 [Ga(HPO)Cl2]+. LSIMS (-): m/z = 453 [Ga(PO)Cl3]". 'H NMR (CD2C12, 300 MHz): 5 9.5 (s, PH). 31P NMR (CD2C12, 121.5 MHz): 5 2.7 (d, JPH = 510 Hz). 4.3. Results and Discussion 4.3.1. Proligands Different syntheses for phosphinophenols have been reported over the years. The synthesis of HPO, a potentially bidentate proligand was first reported by Empsall et al. [93]. In 1977, a different method was proposed by Rauchfuss [91]. In this procedure phenol is used as the precursor. The phenolic oxygen is MOM (methoxymethyl) protected and the resulting compound is ort/zo-lithiated. A reaction of this protected phenol with chlorodiphenylphosphine results in the MOM-protected phosphinophenol that, upon deprotection with anhydrous HC1, yields the bidentate, heterodonor phosphinophenol proligand HPO (or^ohydroxyphenyl)diphenylphosphine. By adopting this method, our group synthesized other multidentate members of the PO family (H2P02, H2P204) [94,95]. Scheme 4.1 shows the synthetic pathway for R-HPO and R2-H2P02 (R = H, CH3, t-Bu). Synthesis of H2P02 has been previously reported via 123 References start on page 145 R R Scheme 4.1. Synthetic route to the phosphinophenol HPO and H2PO2 proligands (x = 1, 2; R = H, CH3, t-Bu). other methods in the literature [96,97]. In H2PO2, two of the phenyl rings have been funtionalized with the OH group in the ortho position to the phosphine phosphorus, therefore it can act as a potentially tridentate ligand with one soft phosphine phosphorus and two hard phenolic oxygen donor atoms. H2P2O4 is a diphosphine wherein an ethylene (C2H4) group separates the two phosphorus atoms. Two phenol rings are bound to each phosphorus with the OH group in the ortho position to the phosphine phosphorus, making this proligand a potentially hexadentate heterodonor chelator (two phosphine phosphorus donors and four phenolic oxygens). 124 References start on page 145 To vary solubility and help with characterization, new substituted proligands were synthesized [84]. Addition of methyl or t-butyl substituents in the para position to the phenolic group enhanced the solubility of these compounds in organic solvents. The substituent alkyl group is a good NMR probe in NMR studies of these compounds. Herein all proligands were synthesized according to the method described above. Only the last step of synthesis (deprotection of the phenolic oxygen) was slightly modified; anhydrous HC1 was produced in situ by adding acetylchloride to the dry methanolic solution of the protected proligand. This allowed better control over the HC1 production than the traditional method previously used in our labs (addition of H2SO4 (cone.) to NH4CI). All proligands were completely characterized by several techniques and all data were compared to literature values. All proligands were isolated as complete or partial hydrochloride salts that were further neutralized to avoid any unwanted reactions upon complexation to the metal ions (vide infra). For neutralization of the potentially bidentate phosphinophenols (R-HPO, R = H, CH3), the CH2CI2 solution of the compound was washed with a solution of NH4OH. The other multidentate proligands (Me2-H2P02, Me4-H2P204) were neutralized by dissolution of the compound in water and increasing the pH to approximately 11 using NaOH and further reprecipitating the neutralized compound by decreasing the pH to 8.5 using acetic acid. Table 4.2 presents the 31P NMR chemical shift data for these proligands, before and after neutralization. A huge upfield chemical shift is observed for H2PO2 and H4P2O4 that were 100% salts; however, HPO shows no substantial shift in the 31 P NMR spectrum since over 90% of the proligand is already the neutral phosphine upon isolation. 125 References start on page 145 Table 4.2. 31P NMR chemical shifts (121.5 MHz) of the PO proligands before and after neutralization. Compound 8 (ppm) before 8 (ppm) after phosphonium salt neutral phosphine R-HPO -27 (CD2CI2) -27.5 (CD2C12) H2P02 +32 (DMSO) -26 (DMSO) H4P2O4 +42 (DMSO) -29 (DMSO) Pt(-)/ proligand, supporting electrolyte, CH3CN/In(+) Figure 4.5. Experimental apparatus for the electrochemical synthesis, before (left) and after (right) the start of reaction. 126 References start on page 145 4.3.2. Metal Complexes Conventional preparative routes were tried to synthesize gallium and indium-PO complexes; however, using aqueous media under aerobic conditions failed to synthesize these complexes. The two factors contributing to this were hydrolysis of the metal ion and rapid oxidation of the phosphine precursor to the analogous phosphine oxide. Many metal precursors and different bases were tried; however, it seemed oxidation of the phosphine took precedence over complexation to the metal ion. Therefore, electrochemical synthesis was considered as an alternate method. The idea was to develop complexation by exposing the proligand to the pure metal ion. The process is rather simple; oxidation of the desired metal in a solution of the proligand catalyses deprotonation of the proligand and enhances complexation. D. G. Tuck and co-workers investigated this phenomenon for many years [98]. The experimental apparatus is shown in Figure 4.5. A simple round bottom flask with two metal electrodes (the anode is the desired metal; the cathode is Pt), suspended in a solution of proligand and electrolyte in CH3CN under Ar. The cell can be written as Pt(.)/L + E (CH3CN)/M(+) (L = proligand, E = supporting electrolyte, M = Ga or In). In2(PO)3Cl3 was synthesized by electrooxidation of metallic indium into a solution of HPO and [(CH3)4N]PF6 or [Bii4N]C104 as the supporting electrolyte. 'H NMR spectrum of In2(PO)3Cl3 showed signals in the aromatic region as expected; however, disappearance of the signal assigned to the OH hydrogen (a doublet at 8 6 due to coupling to the phosphorus atom) signified possible chelation. The 31P NMR spectrum (81 MHz) of the compound in DMSO showed two peaks down field at 8 45.6 and 48.6 for the complex as well as a peak for the free ligand at 8 -16. 127 References start on page 145 • 111111111 • 11' i • i»• • • i • • • • i • • •' i • • • • i • • •' i • • • • i'' * * i'' • • i' •' • i • • • • i' *'' i'' * * i * * * * i • 60 55 50 45 40 SS 10 25 20 15 10 5 0 -5 -10 -15 -20 -25 -30 Ijppm) Figure 4.6. 31P NMR (CD2C12, 121.5 MHz) spectra of ln2(PO)3Cl3 at 25°C (top) and -90 °C (bottom). Since the appearance of the free ligand points to the dissociation of the complex in solution, the two chemical shifts can be assigned to monometallic-ligand species in solution. In CD2CI2 however, the 31P NMR (121.5 MHz) spectrum shows only one signal at 8 49.2 at room temperature from the complex, and a signal at 5 -27 showing some free ligand in solution. This again points to dissociation of the complex in solution. The single peak can be assigned to a monoindium-monoligand species that forms after the two indium centres detach and one ligand dissociates from the indium which has two phosphinophenolates bound. At -90 °C, three signals are observed, one at the same chemical shift as before and two new peaks. These two new peaks are assigned to the monoindium-bisphosphine species before it loses a ligand. Variable temperature NMR experiments were undertaken to investigate further; however, the results were inconclusive. Adding some free proligand to the solution and observing the increased 128 References start on page 145 intensity of the single peak at 8 -27 confirmed the presence of ligand. Figure 4.6 shows the 3IP NMR spectra for In2(PO)3Cl3 at 25 and -90 °C. The IR spectrum of this complex shows no VOH band, which appears about 3250 cm-1 in the free proligand. Although, all information pointed to the chelation of the ligand, the exact identity of the resulting complex remained a mystery until its X-ray crystal structure was solved. The molecular structure of Iri2(PO)3Cl3 was elucidated by X-ray crystallography. A perspective drawing of this complex is shown in Figure 4.7. Selected crystallographic data are presented in Table A4 in the Appendix. The complex is a dimetallic cofacial bioctahedron. The two indium centres are each six coordinate in a distorted octahedral geometry (the octahedra sharing one face), in which one of the indium metal ions has a coordination environment of O3P2CI and the other 03PCl2. The angles around the octahedral metal centres vary from 73.3(1)° (0(2)-In(l)-0(3)) to 106.86(5)° (Cl(l)-In(l)-P(l)) and 70.5(1) (0(2)-In(2)-0(3)) to 105.02(5) (Cl(2)-In(2)-P(3)) for each indium ion, respectively. From the three phosphinophenolate ligands bound to the two metal ions, one phosphine group is coordinated to the first indium centre and the remaining two phosphines are chelated to the other indium ion. The phenolic oxygens of the three PO ligands are all bridging between the indium metal ions forming the shared face. The remaining three coordination sites are filled with chloro ligands. Examples of dimetallic indium complexes bridged by oxygen donor moieties have been reported before [99-101]. Selected bond angles and bond lengths are presented in Table 4.3. Complete bond angles and bond lengths are presented in Appendix A. The two indium metal ions and the three bridging oxygens form a trigonal bipyramid in which 129 References start on page 145 the average side is 2.226 A. The average In-P bond length is 2.683 A. This is in agreement with the bond lengths observed in many indium phosphine compounds [77-79, 88,102,103]. The average In-0 bond length is 2.226 A. This value is also in agreement with the literature values reported for oxobridging (u-O) dimetallic indium compounds [99-101 ]. The average In-Cl bond length is 2.395 A. This bond length is slightly longer than the ones observed in the phosphine adduct of indium trichloride (average 2.383 A) [102] or other dichloroindium complexes bearing phosphine donors [103]. Figure 4.7. ORTEP illustration of In2(PO)3Cl3, 50% thermal ellipsoids are shown. 130 References start on page 145 Table 4. 3. Selected bond lengths (A) and angles (°) in In2(PO)3Cl3 with estimated standard deviation in parentheses. In(l) - In (2) 3.2230(5) In(l) -0(1)- In(2) 93.4(1) In(l) -P(l) 2.625(2) In(l) -0(2)- In (2) 92.0(1) In(l) -0(1) 2.243(4) In(l) -0(3)- In (2) 92.8(1) In(l) -0(3) 2.197(4) Cl(l) -In(l)- -0(1) 176.8(1) In(l) -P(2) 2.733(2) P(l)- -In(l)- 0(2) 148.1(1) In(l)--Cl(l) 2.384(2) P(2)- -In(l)- 0(3) 144.23(9) In(l) -0(2) 2.193(3) Cl (3) - In (2) --0(2) 159.24(9) In(l) -P(l) 2.193(3) CI (2) - In (2) --0(3) 164.7(1) In (2) -0(1) 2.185(4) P(3)- -In (2)- 0(1) 149.3(1) In (2) --CI (3) 2.421(1) In (2) -0(3). 2.252(3) In (2) -- CI (2) 2.381(1) In (2) -P (3) 2.663(2) In (2) -0(2) 2.287(3) 131 References start on page 145 The chloro ligands bound to indium were unexpected before the structure was solved. The source of chloride must be the proligand phosphine hydrochloride salt, thus dictating neutralization of the proligands to avoid this in the future. Even though the proligand (R-HPO) was completely characterized previous to this experiment (including acceptable elemental analysis), further investigation pointed to HC1 being present in up to 10% of the proligand as the phosphonium salt. The EI mass spectrum of In2(PO)3Cl3 did not show the molecular ion; however, peaks at m/z = 277, 462 and 704 were observed, corresponding to [L]+, [InLCl2]+ and [InL2Cl]+ where L = PO. All peaks showed the appropriate isotope patterns. Other peaks due to the fragmentation of the ligand were also observed. Repetition of the electrochemical synthesis with the completely neutrallized proligand proved successful in isolating the monometallic complex. Electrochemical oxidation of indium into the solution of pure proligand (Me-HPO or HPO) and supporting electrolyte ([Bu4N]C104) yielded InL3 (L = Me-PO, PO). The electrochemical efficiency for the process (Ef, defined as the number of moles of metal dissolved per Faraday of charge) was 0.92 and 1.05 mol F1 for In(MePO)3 and In(PO)3, respectively. This value demonstrates that the anodic oxidation of indium is a one electron process initially leading to an In(I) species that is later oxidized to In(III) in solution. This mechanism of action has previously been observed for other metal complexes, including those of indium, where lower oxidation states are the primary electrochemical products [81]. Hydrogen evolution was also clearly observed at the cathode; therefore, the simple mechanism in equations 1-3 can be suggested. 132 References start on page 145 Cathode: HPO + e" -> PO" + lA H2T 1 Anode: In + PO" -> In(PO) + e" 2 In(PO) + 2HPO -» In(PO)3 + H2t 3 The proligands are deprotonated and the ligand anion reacts with In+, the product of oxidation of the indium metal at the anode, to make a metal-ligand chelate. This indium species in solution [In(PO)] further reacts with the proligand to cause further deprotonation. As a result indium is ultimately oxidized to In3+ in the resulting complex. The excess In+ produced in solution through the electrolysis eventually disproportionates 0 3"r" to In and In and the metallic indium is filtered off after the electrolysis. This phenomenon has been reported for subvalent gallium and indium solutions [104]. The direct oxidation potential of indium to the 3+ oxidation state [18] as well as the stepwise oxidation potentials [18] are shown in equations 4-7. It is clear that the lower oxidation states are unstable with respect to disproportionation [18]. In -> In3+ + 3e E° = 0.34 V In -> In+ + e" In+ -> In2+ + e" E° = 0.25 V E° = 0.35 V In2+ -> In3+ + e" E° = 0.45 V 5 6 7 133 References start on page 145 Similarly the electrochemical efficiency (Ef) was calculated to be close to one for In2(PO)3Cl3, suggesting that metallic indium is originally oxidized to the.1+ oxidation state and then further reacts with the ligand in solution causing additional oxidation of the metal centre to the 3+ oxidation state. Chloro ligands fill the vacant coordination sites because of the high mutual affinity of ln3+ and CI". Crystals collected from the electrolysis experiments for lnL3 (L = PCX, MePO") failed to have the quality necessary for complete X-ray crystallographic analysis; however, preliminary X-ray data for L = MePO" showed the complex to have a fac-In(Me-PO)3 arrangement. The 'H NMR spectrum of this compound also confirmed the presence of CH3CN. The 31P NMR spectra of both tris complexes were collected at 121.5 MHz in CD2CI2 (Figure 4.8). A single peak was observed at about 6 43 ppm for the three phosphine phosphorus nuclei bound to the indium metal ion, corroborating the Figure 4.8. 31P NMR spectrum of In(PO)3 (121.5 MHz, CD2C12). 134 References start on page 145 fac arrangement. Leaving the complex in solution for a short time (minutes) results in complete dissociation and a peak at 8 -27 in the 31P NMR spectrum shows the presence of the free ligand upon decomposition of the complex. EI mass spectra for the tris indium complexes I11L3 (L = PO", MePO") showed all relevant peaks for [ML3]+, [ML2]+ and [ML]+. These spectra are shown in Figure 4.9. MCI3 (M = Ga, In) was used as the precursor for the synthesis of [In(MePO)(H20)Cl2]2 and Ga(HPO)Cl3. The chloro ligands in In2(PO)3Cl3 inspired the idea of using the anhydrous metal halides as precursors to synthesize mixed halide-phosphinophenolate complexes of gallium and indium. Dissolution of InCh in ether and reaction with Me-HPO in a 1:1 ratio yielded [In(MePO)(H20)Cl2] 2-2Et20. This dimeric indium complex was completely characterized including X-ray crystallography. Elemental analysis was in complete agreement with the empirical formula. The EI mass spectrum of this dimeric complex did not show the parent ion; however, [In(MePO)Cl2]+ was observed at m/z = 476 showing the appropriate isotope pattern (Figure 4.10). The 3 *P NMR spectrum of this compound showed a single peak with a chemical shift of 8 45.6 from the phosphine phosphorus and a signal at 8 -16 due to free ligand (Figure 4.11). Similar to what was seen with the previous dimetallic complex (In2(PO)3Cl3), it is believed that dissolution leads to dissociation of the complex, which gives rise to the free ligand. The molecular structure of this dimetallic, dimeric indium complex was solved by X-ray crystallography (Figure 4.12). The crystal data, and selected bond lengths and bond angles are listed in Table A4 (in Appendix A) and Table 4.4, respectively. The ORTEP drawing of this complex is shown in Figure 4.12. Each indium is hexacoordinate 135 References start on page 145 1 80 I 60 f a> 291 250 [ML2]+ 697 [ML]! '406 300 400 [ML3 988 700 1000 m/z 100 "TT" 80 60 40 -20 -t~n—j I'i 11 •' 250 277 [ML]+392 [ML2f 669 400 650 [ML3]+ 946 *15 I m/z 950 Figure 4.9. EI mass spectra of In(MePO)3 (top) and In(PO)3 (bottom). 100r f 80! | 60] g 40 1 201 or 292 290 [ln(Me-PO)CI2]+ 476 ft, •-, illij.,,.fJllu m/z 340 490 Figure 4.10. EI mass spectrum of [In(MePO)(H20)Cl2] 2-2Et20. 136 References start on page 145 I I ' I ! I I ! I I I I I I I I I I I I . I I I I  I I I I  I I I I 55 50 45 40 35 SO 25 20 15 10 5 0 -5 -10 -15 -20 -25 (ppm) Figure 4.11. 31P NMR spectrum of [In(MePO)(H20)Cl2] 2-2Et20 (121.5 MHz, DMSO). Figure 4.12. ORTEP drawing of [In(MePO)(H20)Cl2]2 -2Et20, 50% thermal probability ellipsoids are shown. 137 References start on page 145 Table 4.4. Selected bond lengths (A) and angles (°) in [In(MePO)(H20)Cl2] 2-2Et20 with estimated standard deviation in parentheses. In(l) - In (2) 3.563(5) In(l)--0(1)- In(l*) 105.95(6) In(l) -P(l) 2.6093(5) Cl(l) -In(l) -0(2) 169.30(5) In(l) -0(1) 2.271(1) 0(1)- -In(l)--CI (2) 167.67(4) In(l) -0(2) 2.247(2) P(l)- In(l)- 0(1*) 149.36(4) In CO--Cl(l) 2.4544(5) In (1)--CI (2) 2.4114(6) with a 03PC12 coordination sphere. The structure of the dimer shows two indium metal centres each in a pseudo octahedral environment where the angles around the indiums range from 88.51(5)° (Cl(2)-In(l)-0(2)) to 99.41(2)° (Cl(l)-In(l)-Cl(2)) in the asymmetric unit and from 74.05(6)° (0(1)-In(l)-0(1*)) to 111.06(4)° (Cl(2)-In(l)-0(1*)) in the entire molecule. The phosphinophenolate in this complex is behaving in a bidentate fashion and the phosphine phosphorus is also chelated to the indium metal ion. The remainder of the coordination sites are filled with the one aqua and two chloro ligands for each indium. The phenolic oxygens bridging the indium metal ions were also seen in In2(PO)3Cl3. The In-P bond length is 2.609 A, very close to the same bond length value in In2(PO)3Cl3 (2.683 A) and within the literature range reported for various In-phosphines [77-79, 81, 88,104]. The In-0 bond length is 2.271 A and in agreement with 138 References start on page 145 previous data for similar compounds including In2(PO)3Cl3 [99-101]. The average In-Cl bond length is 2.423 A, longer than the same bond length in Ir^PCbCb. The water molecule chelated to each indium is believed to originate from wet solvent. There is also an ether molecule present in the outer coordination sphere for each indium centre. Hydrogen bonding is observed between the ether oxygen and the hydrogens of the ligated water molecule, details of which are presented in Table A5 in the Appendix. GaCb reacted with HPO in toluene to yield Ga(HPO)Cl3, a very interesting zwitterionic-monometallic complex of gallium, with the potential heterodonor bidentate phosphinophenolate ligand acting only as a hard monodentate ligand towards the metal centre. The soft phosphine donor was not bonded to the metal ion in this complex. The metal trihalide precursor is instead bound to the deprotonated phenolic oxygen and the proton has shifted to the phosphorus atom. Many failed attempts were undertaken to deprotonate the phosphonium centre in this complex or to extract a Cf to produce a neutral gallium complex in which the phosphine phosphorus might have bound to the metal centre. Mass spectra of Ga(HPO)Ci3 are shown in Figure 4.13; in the positive detection mode using EIMS, [Ga(HPO)Cl2]+ is observed at m/z = 418 [M-Cf] and [Ga(PO)Cl]+ is observed at m/z = 381 [M-2CT], while other signals at lower mass are observed due to the fragmentation of the ligand. In the negative ion detection mode using LSIMS, the complex loses a proton to give a peak at m/z = 453. Both mass spectra show diagnostic isotope distribution patterns as compared to the calculated model. The 3IP NMR spectrum of the complex (Figure 4.14) shows a doublet for the phosphine 139 References start on page 145 GO C 0 0 > 0 100 80 60 40 20 0 [Ga(HPO)CI2]+ -418 _ II, III 100-, 75 • 50'^ 25 : 4-~+-416 418 420 • m/z 390 440 100 —i in « c 0 0 > 0 [Ga(PO)CI3]-453 |Ull lilt., .l.ltNll 450 100,! 75 50 25 450 452 454 456 458 Figure 4.13. Measured (left) and calculated (right) EI (top) and LSI(-) (bottom) mass spectra of Ga(HPO)Cl3. 140 References start on page 145 ~i—[ T—r i r |—i—i—(—|—i—rl I ] ' I I ' i i y i 1 i • j • i i i j IT I ' I J ' I" r~lT~T~ I—r? Tf Tl—(—I' \~l—l"T" 1 ~f r t~[ i \ r T~l—I ] I I I 1 | T" I I 1 | I I I I | i J5J JO « <0 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 (ppm) Figure 4.14. 31P NMR spectrum of Ga(HPO)Cl3 (121.5 MHz, CD2C12, JHP = 510 Hz). Figure 4.15. ORTEP drawing of the metal complex in Ga(HPO)Cl3HCl, 50% thermal probability ellipsoids are shown. 141 References start on page 145 Table 4.5. Selected bond lengths (A) and angles (°) in Ga(HPO)Cl3-HCl, with estimated standard deviation in parentheses. Ga(l) -Cl(l) 2.1723(7) CI(1) - Ga(l)- Cl (2) 109.95(3) Ga(l) - CI (3) 2.1634(7) CI(1) - Ga(l)- 0(1) 108.87(6) Ga(l) - CI (2) 2.1674(7) CI (2) - Ga(l)- 0(1) 110.77(6) Ga(l) -0(1) 1.1835(2) CI(3) - Ga(l)- 0(1) 103.54(5) P(l)- -H(l) 1.45(3) phosphorus at 8 2.7 due to coupling with the hydrogen. The coupling constant (JPH = 510 Hz) is within range for 1 JPH previously reported (457-870 Hz) [105]. There was no free ligand observed in the P NMR spectrum of this compound to suggest any further dissociation of this complex in solution. The phosphonium proton was also observed in the 'H NMR spectrum at 8 9.5. X-ray single crystal structure analysis was used to study the solid-state structure of Ga(HPO)Cl3 (Figure 4.15). Gallium is situated in a distorted tetrahedral geometry with OCI3 coordination sphere. Angles making the tetrahedron vary from 103.54° for (Cl(3)-Ga(l)-0(1)) to 112.23° for (Cl(2)-Ga(l)-Cl(3)). The Ga-0 bond length (1.835 A) is in agreement with the literature values 1.911 A and 1.898 A reported for GaCl2(0-L-OH) (L = 1,2-C6H4, l,2-Me2C-CMe2) respectively [106]. The average Ga-Cl bond length was calculated to 2.167 A, with in the range of the Ga-Cl bonds reported for various Ga compounds [107]. 142 References start on page 145 The phosphorus atom has a tetrahedral geometry as well. The P-H bond length was found to be 1.45 A. This is within range for the P-H bonds reported in various Pli3PH+ (triphenylphosphonium) cations reported in the literature [108-111]. General crystallographic data are presented in Table A4 in Appendix A, selected bond lengths and angles are presented in Table 4.5; complete bond lengths and angles are also presented in the Appendix. 4.4. Conclusions Interesting and diverse coordination chemistry of the bidentate heterodonor phosphinophenolate ligands with gallium and indium was uncovered. Novel complexes of these metal ions and phosphinophenolates were synthesized through a variety of routes including electrochemical synthetic procedures. The complexes were fully characterized by EA, 31P NMR spectroscopy, MS and X-ray crystallography. For the indium complexes the hard/soft phosphinophenolate is bound in a bidentate fashion through both hard and soft donor atoms (P and O); however, the same ligand only binds through the one hard phenolate donor (O) in a monodentate approach to gallium. In2(PO)3Cl3, In(Me-PO)3 and In(PO)3 were synthesized by electrolysis of indium metal in an acetonitrile solution of the proligand. Metallic indium is originally oxidized "F 3+ to In that further oxidizes to In in solution. In the dimetallic complex In2(PO)3Cl3, the phenolic oxygens bridge the two metal ions. Preliminary structural data on In(Me-PO)3 showed a fac orientation which agrees with the P NMR spectral evidence. 143 References start on page 145 Electrochemical synthesis proved to be a successful synthetic method for these compounds. 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Conclusions Metal ion coordination chemistry of medicinal interest was investigated and reported in this thesis. Simple curiosity was the momentum behind the different projects reported, in addition to the search for a potent therapeutic or a successful diagnostic agent. Fundamental coordination chemistry of V(III), V(IV), V(V), Re(V), Ga(III) and In(III) with various groups of chelators was described herein. Also, results of biological testing of different V(III) and V(IV) complexes, to determine the insulin-enhancing ability of these compounds as compared to the bench mark compound BMOV (bis(maltolato)oxovanadium(IV)), was discussed. In Chapter 2, complexes of V(III, IV, V) with isomaltolate and allomaltolate were synthesized. The original synthesis of isomaltol was modified to a simple, less hazardous procedure. The acidity and stability constants of these ligands and their V(IV), V(V) complexes were determined, and compared to those for BMOV. The species distribution diagram showed the desired vanadium complexes to be the dominant species in solution around physiological pH. A plot of pM-pH was used to compare the stability of the V(IV) complexes to BMOV, and to one another. Although VO(ama)2 is more stable than is VO(ima)2, both complexes are less stable than is BMOV (VO(ma)2). All synthesized V(III) and V(IV) complexes (except VO(ama)2), were tested for their insulin-enhancing 153 References start on page 161 behaviour relative to that of BMOV; Although these compounds showed significant anti diabetic activity, there was no obvious advantage observed over BMOV. Successful coordination of [en(ama)2]2" to Re(V) and V(IV) was explored in Chapter 3. Both metal complexes showed a 1:1 ligand:metal ratio in their complexes. H2(en(ama)2), a potentially tetradentate aminopyrone, has an ethylenediamine back bone with two allomaltol moieties attached to the amine nitrogens. VO(en(ama)2) was synthesized and completely characterized. Since this complex had shown great stability in aqueous solutions relative to that of BMOV, VO(ima)2, VO(ama)2 or other vanadyl complexes [1], it was interesting to find that it had no glucose lowering behaviour. This corroborated the postulate that the ligand acts only as a "delivery shuttle" and the active species in vivo is not the whole complex [2]. The rhenium complex of [en(ama)2]2" was synthesized by ligand substitution on ReO(PPli3)2Cl3 or by reduction/complexation of NH4Re04 in acidic solution to yield ReO(en(ama)2)Cl. NMR studies showed that the ligand is bound in an asymmetric fashion and that CI" is cis to the [Re=0]3+ core; however, exact prediction of the structure was not possible. An X-ray crystal structure of this compound would resolve this matter. In Chapter 4, basic coordination chemistry of Ga and In with potentially bidentate hetero donor phosphinophenolate ligands was examined. Our hypothesis was that presence of the hard oxygen donor would enhance chelation of the soft phosphine phosphorus to the hard metal ions. To probe the syntheses of In-PO complexes electrochemical synthesis was successfully used to make In2(PO)3Cl3 and InL3 (L = Me-PO", PO"). The former is an interesting dimetallic indium complex with the ligands bound through both soft and hard donors. Neutralization of the proligands was carried 154 References start on page 161 out to purify the phosphenophols in order to synthesize the latter complexes (InLs). Complexes with both PO and CI ligands ([In(MePO)(H20)Cl2Et20] and Ga(HPO)Cl3) were made starting with trihalides of gallium and indium. Gallium intriguingly shows diversity in the coordination to these phosphinophenolates as compared to indium. Ga(HPO)Cl3 is a zwitterionic compound wherein the phosphine is protonated and the heterodonor ligand is bound only through the hard phenolic oxygen to Ga. In all the indium complexes synthesized, the soft phosphine phosphorus is bound to the metal centre in addition to the hard phenolic oxygen. Attempts to abstract HC1 from Ga(HPO)Cl3) were unsuccessful. 5.2. Ideas for Further Work The insulin-enhancing studies of the structural isomers of maltol and their various vanadium complexes is incomplete due to lack of data from the biological testing of VO(ama)2 on STZ diabetic rats. It would be interesting to see the actual results from these tests, although it is anticipated that they would be close to all the other results reported for many vanadyl complexes [3]. Complexation of [en(ama)2] " with vanadium and rhenium was the first step in exploring the chemistry of this ligand with various biologically useful metal ions. Exploring the coordination chemistry of this ligand with rhenium's second row congener 99mTc, or in various Ga or In complexes, could be beneficial for applications in nuclear medicine. H2(en(ama)2) can also be functionalised with other groups to make new potential proligands. Scheme 5.1 shows routes to various groups of new chelators using H2(en(ama)2) as the precursor. To increase water solubility, the amine protons 155 References start on page 161 Scheme 5.1. Various potential chelators that could be synthesized from H2(en(ama)2). 156 References start on page 161 could be replaced with carboxylate functional groups. This would also enhance the chelate effect since the denticity of the ligand would increase. H2(en(ama)2) a potentially tetradentate chelator, could become a potentially hexadentate with the addition of pyridyl donors on the amine back bone. With a larger coordination sphere, the ligand might be able to accommodate Ln ions as well. It has been shown that neutral pyridyls are a suitable group of chelators for lanthanides [4]. 3-Hydroxy-4-pyridinones have been studied extensively and our group has investigated the coordination chemistry of these compounds with Ga and In [5-7]. Conversion of the pyrone rings to pyridinones is another possible modification for this compound. These aminopyridinonecarboxylates or aminopyridinonepyridyl moieties would not only make multidentate ligands suitable to bind various metal ions including the lanthanides, but could also be further tailored to tune the overall charge and lipophilicity of the resulting metal complexes. If the substituent on the pyridinone N is functionalised with a sugar moiety it might assist the transport of the compound in vivo. Pyridinones with pendant sugars have been reported recently [8]. All these chelators are capable of binding metals suitable for diagnosis or therapy, including the lanthanides. Thermodynamic solution studies (using potentiometry) of all these new proposed potential ligands and their metal complexes would afford insight into the stability of these complexes under physiological conditions. Chapter 4 was an initial exploration of the chemistry of Ga and In with the group of phosphinophenolate chelators. Neutralization of these compounds is required to achieve metal-ligand systems with no auxiliary halide ligands. Preliminary experimental 157 References start on page 161 results of chelation of Ga or In and H2PO2 suggested complex formation; however, the product metal complex was never isolated. Reacting GaC^ with H2PO2 in a 1:1 ratio in toluene at 85 °C similar to Ga(HPO)Cl3 synthesis, produced a white solid that was recrystallized from ClrbCb/n-pentane. The mass spectrum of this compound showed a peak at m/z = 398 with a perfect diagnostic isotope distribution pattern for [Ga(P02)Cl]+ and one at m/z = 434 [Ga(HP02)Cl2]+ (Figure 5.1). The 'H NMR spectrum showed residual toluene; however, a signal at 9.4 ppm pointed to the protonated phosphine centre similar to that observed in Ga(HPO)Cl3. 31P NMR studies proved this case (JPH = 527 Hz). The coupling constant is larger than that for Ga(HPO)Cl3. It has been shown that more electronegative substituents on the phenyl ring bound to the phosphine lead to higher J values [9]. This would suggest that Ga is bound to the ligand through the hard phenolic donors as was seen in Ga(HPO)Cl3. GaC^ has lost CI" in addition to the phosphine that is protonated to form a neutral compound. Attempts to grow crystals of this compound were unsuccessful. The crystals collected were [H3P02][GaCl4] and the structure was solved by X-ray crystallography. ORTEP diagram of this compound is presented in Figure 5.2, and crystallographic data are presented in the Appendix (Table A6). A complete list of bond lengths and bond angles is also presented in the Appendix. Both Ga and P possess a tetrahedral geometry. The P-H bond length is 1.33 A, in agreement with the range of bond lengths reported for triphenylphosphonium [10,11]; however, this length is shorter than the bond length reported for Ga(HPO)Cl3. The average Ga-Cl bond length is 2.171 A. 158 References start on page 161 CD > -t—' ro CD 100-80 60 40 1 20 77 Lill(..n 190 it,, 2B1 290 [Ga(P02)CI]+ 398 J> [Ga(HP02)Cl2]+ 434 390 (•10) ........... m/z Figure 5.1. Mass spectrum of the product of the reaction between H2P02 and GaCl Electrochemical syntheses of H2PO2 or H4P2O4 complexes of In would be interesting to pursue. Multidentate functionalised phosphinothiolate complexes have been formed through electrolysis with various metals, including indium [12]. Electrochemical syntheses for complexation of Ga could also be attempted, although preliminary experiments proved Ga to be less conductive and much harder to handle (Ga melts at 29 °C; the reaction flask has to be cooled to stop Ga from melting). Another way to address this problem is to use Pt electrodes as both anode and cathode and add the metallic Ga to the reaction mixture. Upon closing the circuit, gallium should get oxidized and the electrolysis should take place. This method could provide a route to tris (ligand) gallium complexes for PO ligands or bis (ligand) gallium complexes for PO2 ligands. 160 References start on page 161 .3. References 1. Song, B.; Saatchi, K.; Rawji, G. H.; Orvig, C. Inorg. Chim. Acta 2002, 339, 393. 2. Thompson, K. H. ; Liboiron, B. D.; Sun, Y.; Bellman, K.; Setyawati, I. A.; Patrick, B. O.; Karunaratne, V.; Rawji, G.; Wheeler, J.; Sutton, K.; Bhanot, S.; Cassidy, C; McNeill, J. FL; Yuen, V. G.; Orvig, C. J. Biol. Inorg. Chem. 2003, 8, 66. 3. Thompson, K. H.; Orvig, C. Metal Ions Biol. Syst. 2004, 41, 221. 4. Caravan, P.; Mehrkhodavandi, P.; Orvig, C. Inorg. Chem. 1997, 36, 1316. 5. Zhang, Z.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1991, 30, 509. 6. Clevette, D. J.; Lyster, D. M.; Nelson, W. M.; Rihela, T. J.; Webb, G. A.; Orvig, C. Inorg. Chem. 1990, 29, 667. 7. Nelson, W. O.; Karpishin, T. B.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1988, 27, 1045. 8. Green, D. E. Ph. D. Thesis, University of British Columbia, 2004. 9. Nelson, J. H. Nuclear Magnetic Resonance Spectroscopy, Pearson Education Inc. NJ, 2003, p 157. 10. Burke, J. M.; Fox, M. A.; Geota, A. E.; Hughes, A. K.; Marder, T. B. Chem. Commun. 2000, 2217. 11. Himmel, H.; Downs, A. J.; Greene, T. M. Inorg. Chem. 2001, 40, 396. 12. Perez-Lourido P.; Romero, J.; Garcia-Vazquez J. A.; Sousa, A.; Maresca, K.; Zubieta, J. Inorg. Chem. 1999, 38, 1293. 161 References start on page 161 Appendix A X-ray crystallographic analyses Al. trans-VO(ima)2(H20). This structure was solved by Dr. Maren Pink. Teal crystals of excellent quality were mounted on the tip of a glass capillary on a Bruker smart platform CCD system for data collection at 173(2) K using MoKa radiation (graphite monochromator) with a frame time of 10 seconds. The cell constants were based on 7846 reflections with 1577 of them being unique (R,„( = 0.0552). The data set was collected 4.42 < 20 < 55.12. Data were processed and corrected for absorption as well as for Lorentz and polarization effects. The structure was solved [1] and refined [2]. The space group C2/c was determined based on systematic absences and intensity statistics. Full-matrix least square/difference Fourier cycles were performed which located the remaining non-hydrogen atoms and fractional sites of 01 and CI. All non-hydrogen atoms were refined with anisotropic displacement parameters. H5 was found in the difference map and all other hydrogen atoms were placed in ideal positions. The full matrix least squares refinement converged to Ri = 0.0392 and wR2 = 0.1098. The goodness of fit was 1.080. Other than the two ligands and the oxo group, there is also a water molecule coordinated to the metal centre. This water molecule interacts with other oxygens of the neighbouring molecules via hydrogen bonds. The ligand is disordered over two sites that results in a structural trans:cis ratio of 88:12. 162 References start on page 168 A2. V(ima)3. The structure was solved by Dr. Brian Patrick. A red chip crystal was mounted on a glass fiber. Measurements were done on a Rigaku/ADSC CCD area detector with graphite monochromated MoKa radiation. The cell constants were based on 5750 reflections with 5.5 < 29 < 50.0 that corresponds to a C-centred monoclinic cell. Statistical analysis of the intensity distribution, and the successful solution and refinement of the structure determined the space group to be C2/c. Data were collected at 173(1)K in oscillation with 47.00 second exposures. Of the 14139 reflections collected, 3369 were unique (R,-n, = 0.073); equivalent reflections were merged. Data were collected [3], processed and corrected for Lorentz and polarization effects. The structure was solved by direct methods [4] and expanded using Fourier transform techniques [5]. Two of the ligands about vanadium were disordered, each adopting two orientations. The first disordered ligand has relative major: minor fragment population of 68:32 whereas the proportions in the second ligand were 86:14. Restraints were used to make sure that each disordered ligand fragment had roughly the same geometry as the non-disordered ligand. All non-hydrogen atoms in the major fragment were refined anisotropically. Hydrogen atoms were included but not refined. The final cycle of full-matrix least square refinements was based on 3130 observed reflections (I > 0.00 a (I)) and 330 variable parameters converged with unweighted and weighted agreement factors of Ri = 0.086, wR2 = 0.134. Goodness of fit was 0.96. 163 References start on page 168 A3. H4(en(ama)2)(Re04)2. The structure was solved by Dr. Brian Patrick. Yellow platelet crystals were mounted on a glass fibre. Mo-Ka radiation was used to collect 9612 reflections of which 2497 were unique (R,„, = 0.062), equivalent reflections were merged. The data was collected at —100 ± 1 °C to a maximum 26 value of 55.7° using the d*TREK program [3]. The data were corrected for Lorentz and polarization effects. The structure was solved by direct methods [4] and expanded using Fourier techniques [5]. The [H.4(en(ama)2)] dication sits on an inversion centre. Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were included in calculated positions, but were not refined. The final cycle of full-matrix least-square refinement was based on 2410 observed reflections (I > 0.00 CT (I)) and 154 variable parameters converged with unweighted and weighted agreement factors of Ri = 0.088 and wR2 = 0.120. A4. In2(PO)3Cb. The structure was solved by Dr. Brian Patrick. A clear platelet crystal of C54H4203P3ln2Cl3 was mounted on the tip of a glass capillary on a Rigaku/ADSC CCD system for data collection at -100+1 °C using MoKoc radiation (graphite monochromator) with a frame time of 12 seconds. The cell constants were based on 9770 reflections (R,*, = 0.063). The data set were collected 29 = 6.2-55.8°. Data were processed and corrected for absorption as well as Lorentz and polarization effects. The structure was solved by direct methods [4] and expanded using fourier transform techniques [5]. The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included but not refined. The final cycle of full-matrix least 164 References start on page 168 square refinements was based on 9328 observed reflections (I > 0.00 CT (I)) and 586 variable parameters converged with unweighted and weighted agreement factors of Ri = 0.081, wR2 = 0.113. Goodness of fit was 1.13. A5. [In(u-0(MePO))(H20)Cl2]2-2Et20. The structure was solved by Dr. Brian Patrick. A clear prism crystal of C46rl5206P2Cl4ln2 was mounted on the tip of a glass capillary on a Rigaku/ADSC CCD area detector with graphite monochromated MoKct radiation. The data collection was at a temperature of -100 ± 1 °C to a maximum 29 value of 55.8°. The cell constants were based on 4679 reflections (Rj„, = 0.038). Data were collected and processed using the d*TREK [3] program and further corrected for Lorentz and polarization effects. The structure was solved by direct methods [4] and expanded using Fourier techniques [5]. The material crystallizes as a InCl2 dimer residing on a centre of inversion. One water molecule is coordinated to each In, with one solvent molecule (Et20) hydrogen bonded in turn to each water. The final cycle of full-matrix least square refinements was based on 4679 observed reflections (I > 0.00 CT (I)) and 279 variable parameters converged with unweighted and weighted agreement factors of Ri = 0.043, wR2 = 0.068. Goodness of fit was 1.11. A6. Ga(HPO)Cl3HCl. The structure was solved by Dr. Brian Patrick. A clear block crystal of CigHieOPCLjGa was mounted on the tip of a glass fibre. All measurements were made on a Rigaku/ADSC CCD area detector with graphite monochromated MoKa radiation. The data collection was at a temperature of -100 ± 1 165 References start on page 168 °C. The cell constants were based on 4679 reflections (R,„, = 0.038) with 29 = 5.8 -55.8°. Data were collected and processed using the d*TREK [3] program and further corrected for Lorentz and polarization effects. The structure was solved by direct methods [4] and expanded using Fourier techniques [5]. The phosphonium hydrogen atom was refined isotropically. The material appears to crystallize with a molecule of HC1 (disordered over 4 sites) in the asymmetric unit. The final cycle of full-matrix least square refinements was based on 4272 observed reflections (I > 0.00 a (I)) and 257 variable parameters converged with unweighted and weighted agreement factors of Ri = 0.051, wR2 = 0.092. Goodness of fit was 1.31. A7. [H3P02]GaCl4-CH2Cl2. The structure was solved by Dr. Brian Patrick. A clear block crystal was mounted on a glass fibre. All measurements were made on a Rigaku/ADSC CCD area detector with graphite monochromated Mo-Kcc radiation. The data collection was at a temperature of —100 ± 1 °C to a maximum 29 value of 60.1°. Of the 18437 reflections collected, 5118 were unique (R,„, = 0.049); equivallant reflections were merged. Data were collected and processed using the d*TREK [3] program and further corrected for Lorentz and polarization effects. The structure was solved by direct methods [4] and expanded using Fourier techniques [5]. The material crystallizes with one molecule of CH2CI2 in the asymmetric unit. The final cycle of full-matrix least square refinements was based on 5023 observed reflections (I > 0.00 a (I)) and 274 variable parameters converged with 166 References start on page 168 unweighted and weighted agreement factors of Rj = 0.055, wR2 = 0.091. Goodness of fit was 1.06. 167 References start on page 168 References: 1. SIR92, Altomare, A.; Cascamo, G.; Giacovazzo, C.; Gualardi, A. J. Appl. Cryst. 1993, 26, 343. 2. SHELXTL-Plus V5.10, Bruker Analytical X-ray Systems, Madison, WI. 3. d*TREK: Area Detector Software. Version 7.1. Molecular Structure Corporation (2001). 4. SIR97: Altomare, A.; Burla, M. C; Cammali, G.; Cascarano, M.; Giacovazzo, C; Moliterni, A. G. G.; Polidori, G.; Spagna, A.; J. Appl. Cryst. 1999, 32, 115. 5. DIRDIF94: Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.; de Gelder, R.; Israel, R.; Smits, J. M. M.; 1994 The DIRDIF-94 program system, Technical Report of The Crystallography Laboratory, Univrsity of Nijmegen, The Netherlands. 168 References start on page 168 Table Al. Selected crystallographic data for trans-VO(ima)2(H20) and V(ima)3. Compound trans-VO(ima)2(H20) V(ima)3 Empirical formula Ci2Hi20gV Ci8H1509V Crystal color, habit teal, block red, chip Crystal size, mm 0.25x0.21 x 0.19 0.20 x 0.20 x 0.05 Crystal system monoclinic monoclinic Space group C2/c C2/c a, A 12.376 (4) 29.187 (6) b, A 13.879 (5) 8.239(1) c, A 8.011 (3) 15.126 (3) P, deg 96.513(6) 100.734 (8) V, A3 1367.2 (8) 3547 (1) Z 4 8 FW 335.16 426.25 p(g/cm3) 1.628 1.584 Temperature 173 (2)K 100(1)°C e (°) 2.21-27.56 2.75-25 F(000) 684 1744 total reflections 7846 14139 Unique reflections 1577 (R(„, = 0.0552) 3369 (R(„, = 0.073) Ri 0.0392 0.086 WR2 0.1059 0.134 GOF 1.080 0.96 169 Table A2. Hydrogen bond data for VO(ima)2(H20) [A and °]. D-H....A d(D-H) d(H...A) d(D...A) < (DHA) O(5)-H(50)...O(2)#1 0.81 1.95 2.731 (6) 160.2 O(5)-H(50)...O(3")#2 0.81 1.94 2.71 (4) 156.7 Symmetry transformations used to generate equivalent atoms:#1 -x, y, -z + 3/2 #2 x, -y + l,z + '/2 170 Table A3. Selected crystallographic data for [H4(en(ama)2)][(Re04)2]. Compound Empirical formula Crystal color, habit Crystal size, mm Crystal system Space group a, A b, A c, A P, deg v, A3 z FW yo(g/cm3) max. 9 (°) F(000) total reflections Unique reflections R, WR2 GOF [H4(en(ama)2)][(Re04)2] Ci6H22N2014Re2 yellow, platelet 0.40 x 0.20 x 0.05 mm momoclinic Plxln 8.3488(8) 17.097(1) 8.5589(9) 117.086(3) 1087.7(2) 2 838.77 2.56 27.85 788 9612 2497 (Rint = 0.062) 0.088 0.12 0.89 171 Table A4. Selected crystallographic data for In2(PO)3Cl3, [In(u-0(MePO)Cl2 (H20)]2-2Et20 and Ga(HPO)Cl3HCl. Compound In2(PO)3Cl3 [In(u-0(MePO)Cl2 (H20)]2-2Et20 Ga(HPO)Cl3 Empirical formula C54H4203P3In2Cl3 C46H5206P2Cl4In2 Ci8Hi6OPCl4Ga Crystal color, habit clear, platelet clear, prism clear, block Crystal size, mm 0.40x0.25x0.15 0.25x0.15x0.05 0.25 x 0.20 x 0.05 Crystal system triclinic triclinic triclinic Space group P 1" (#2) P 1" (#2) P 1" (#2) a, A; a, ° 11.0558(3); 83.908(2) 10.3320(4); 105.611(2) 9.2856(5); 102.024(3) b, A; p,° 13.2211(7); 117.086(3) 10.5387(4); 103.913(2) 9.8663(7); 108.807(2) c, A; y, ° 18.694(2); 64.939(2) 12.722(2); 103.526(2) 12.5628(5); 94.664(3) v, A3 2459.5(2) 1227.1(2) 1051.8(1) z 2 1 2 FW 1167.84 1134.31 490.83 p(g/cm3) 1.577 1.535 1.550 2 0 max ( ) 55.8 55.8 57.4 F(000) 1168.00 572.00 492.00 total reflections 20441 10523 9559 Unique reflections 9328 (R,„,= 0.063) 4679 (Ra,, = 0.038) 4272 (Ra,, = 0.037) Rh WR2, GOF 0.081,0.113, 1.13 0.043,0.068, 1.31 0.051,0.092, 1.11 172 Table A5. Hydrogen bond data for [In |>(MePO)Cl2(H20)]2-2Et20a [A and °]. D-H....A d(D-H) d(H...A) d(D...A) < (DHA) 0(2)-H(27)...0(3) 0.85 1.83 2.673 (3) 170 0(2)-H(28)...Cl(l)# 0.66 2.53 3.166(2) 162 a) Symmetry transformations used to generate equivalent atoms: 2 -x, -y, 1-z 173 Table A6. Selected crystallographic data for [H3P02]GaCl4CH2Cl2. Compound Empirical formula Crystal color, habit Crystal size, mm Crystal system Space group a, A b, A c, A P,deg V, A3 z FW p(g/cm3) max. 9 (°) 7^(000) total reflections Unique reflections Ri WR2 GOF [H3P02]GaCl4-CH2Cl2 Ci9Hi8Cl6Ga02P clear, block 0.50 x 0.35 x 0.20 mm momoclinic P2xlc 7.7839(3) 29.634(1) 11.0905(6) 109.736(3) 2408.0(2) 4 591.76 1.632 30.05 788 18437 5118(R,„, = 0.049) 0.055 0.091 1.06 174 Table A7. Complete list of bond lengths trans-VO(ima)2(H20). VI -04 1.596(2) VI -02 2.001(4) VI -03#1 2.038(3) VI -02'#1 2.04(2) VI -03' 2.07(3) 05 -H50 0.8125 01 -C4 1.408(3) 03 -C5 1.279(3) CI -HI 0.9500 C2 -H2 0.9500 C4 -C5 1.384(4) C6 -H6A 0.9800 C6 -H6C 0.9800 02' -C3' 1.297(3) CI' -C2' 1.338(4) C2' -C3' 1.426(4) C5' -C6' 1.496(4) C6' -H6'B 0.9800 04 -VI -02#1 97.5(3) 02#1 -VI -02 165.0(6) and bond angles (°) for VI -02#1 2.001(4) VI -03 2.038(3) VI -02' 2.04(2) VI -03'#1 2.07(3) VI -05 2.187(2) 01 -CI 1.340(3) 02 -C3 1.297(3) CI -C2 1.338(4) C2 -C3 1.425(3) C3 -C4 1.401(4) C5 -C6 1.495(4) C6 -H6B 0.9800 or -cr 1.340(4) 03' -C5' 1.279(3) cr -HI' 0.9500 C2' -H2' 0.9500 C6' -H6'A 0.9800 C6' -H6'C 0.9800 04 -VI -02 97.5(3) 04 -VI -03 95.99(9) 175 02#1 -VI -03 85.41(7) 02 -VI -03 93.02(8) 04 -VI -03 #i 95.99(9) 02" -VI -03#1 93.02(8) 02 -VI -03 #i 85.41(7) 03 -VI -03#1 168.03(18) 04 -VI -02' 103.0(9) 02#1 -VI -02' 82.29(16) 02 -VI -02' 94.3(3) 03 -VI -02' 7.4(9) 03#1 -VI -02' 160.9(8) 04 -VI -02,#1 103.0(9) 02#1 -VI -02 94.3(3) 02 -VI -02'#1 82.29(16) 03 -VI -02 160.9(8) 03#1 -VI -02"" 7.4(9) #i 02' -VI -02'#1 154.0(17) 04 -VI -03'#1 100(2) 02#1 -VI -03'#1 4(2) 02 -VI -03'#1 162(2) 03 -VI -03,#1 87.95(17) 03#1 -VI -03 89.9(5) 02' -VI -03 t#i 84.4(4) 02'#1 -VI -03'#l 90.9(7) 04 -VI -03' 100(2) 02#1 -VI -03' 162(2) 02 -VI -03' 4(2) 03 -VI -03' 89.9(5) 03#l -VI -03' 87.95(17) 02' -VI -03' 90.9(7) 02,#1 -VI -03' 84.4(4) 03,#1 -VI -03' 159(5) 04 -VI -05 180.0 02ffl -VI -05 82.5(3) 02 -VI -05 82.5(3) 03 -VI -05 84.01(9) 176 03#l -VI -05 84.01(9) 02' -VI -05 77.0(9) 02,#1 -VI 05 77.0(9) 03,#1 -VI -05 80(2) 03' -VI -05 80(2) VI -05 -H50 120.3 CI -01. -C4 106.0(2) C3 -02 -VI 120.88(19) C5 -03 -VI 126.49(17) C2 -CI -01 112.9(2) C2 -CI -HI 123.5 01 -CI -HI 123.5 CI -C2 -C3 106.9(2) CI -C2 -H2 126.6 C3 -C2 -H2 126.6 02 -C3 -C4 126.8(2) 02 -C3 -C2 127.5(2) C4 -C3 -C2 105.7(2) C5 -C4 -C3 130.5(2) C5 -C4 -01 121.1(2) C3 -C4 -01 108.4(2) 03 -C5 -C4 120.6(2) 03 -C5 -C6 118.3(2) C4 -C5 -C6 121.1(2) C3' -02' -VI 117.5(10) C5' -03' -VI 125.2(13) C2' -CI' -01' 112.9(3) C2' -CI' -HI' 123.5 01' -CI* -HI' 123.5 CI' -C2' -C3' 106.9(3) CI' -C2' -H2' 126.6 C3' -C2' -H2' 126.6 02' -C3' -C2' 127.3(3) 03' -C5' -C6' 118.1(3) C5' -C6' -H6'A 109.5 C5' -C6' -H6'B 109.5 177 H6'A -C6' -H6'B 109.5 H6*A -C6' -H6'C 109.5 C5' -C6' -H6'C 109.5 H6'B -C6' -H6'C 109.5 178 Table A8. Complete list of bond lengths (A) and bond angles (°) for V(ima)3. VI -01 1.951(2) VI -02 2.032(3) VI -04 1.954(6) VI -05 1.991(8) VI -07 1.961(6) VI -08 2.083(6) VI -04B 2.032(16) VI -05B 2.041(17) VI -07B 1.80(4) VI -08B 2.12(4) 01 -CI 1.286(4) 02 -C5 1.275(5) 03 -C2 1.399(4) 03 -C3 1.367(5) 04 -C7 1.290(9) 04B -C7B 1.29(2) 05 -Cll 1.285(13) 05B -CUB 1.28(2) 06 -C9 1.361(11) 06 -C8 1.400(8) 06B -C9B 1.36(2) 09B -C14B 1.40(4) 09B -C15B 1.36(4) CI -C2 1.380(5) CI -C4 1.443(4) C2 -C5 1.381(5) C3 -C4 1.336(6) C5 -C6 1.494(6) C7 -C8 1.386(10) C7 -CIO 1.441(11) C7B -C8B 1.38(2) C7B -CI OB 1.44(2) C8 -Cll 1.392(11) C8B -CUB 1.387(19) C9 -CIO 1.341(14) C9B -CI OB 1.34(3) Cll -C12 1.498(11) CUB -C12B 1.49(3) C13 -C16 1.438(11) C13 -C14 1.384(11) C13B -C16B 1.45(8) C13B -C14B 1.40(8) 179 06B -C8B 07 -C13 07B -C13B 08 -C17 08B -C17B 09 -C15 09 -C14 C4 -H4 C6 -H6A C6 -H6B C6 -H6C C9 -H9A C9B -H9B CIO -H10 CI OB -HI OB C12 -H12A C12 -H12C C12 -H12B C12B -H12E 01 -VI -02 01 -VI -04 01 -VI -05 01 -VI -07 1.40(2) 1.289(10) 1.29(8) 1.280(11) 1.28(6) 1.360(8) 1.399(9) 0.9493 0.9802 0.9804 0.9809 0.9514 0.9519 0.9502 0.9492 0.9809 0.9794 0.9793 0.9757 91.22(11) 94.9(2) 91.9(2) 177.19(19) C14 -C17 1.388(11) C14B -C17B 1.39(5) C15 -C16 1.343(12) C15B -C16B 1.34(6) C17 -C18 1.495(12) C17B -C18B 1.49(4) C3 -H3 0.9502 C12B -H12D 0.9761 C12B -H12F 0.9878 C15 -H15 0.9506 C15B -H15B 0.9528 C16 -HI 6 0.9490 C16B -H16B 0.9379 CI 8 -H18A 0.9793 C18 -H18B 0.9788 C18 -H18C 0.9807 C18B -H18D 0.9808 C18B -H18E 0.9815 C18B -H18F 0.9797 C8 -06 -C9 102.1(7) C8B -06B -C9B 102.6(14) VI -07 -C13 123.2(5) VI -07B -C13B 147(3) 180 01 -VI -08 86.85(19) 01 -VI -04B 83.5(5) 01 -VI -05B 90.5(4) 01 -VI -07B 89.6(10) 01 -VI -08B 168.9(9) 02 -VI -04 83.7(2) 02 -VI -05 176.6(2) 02 -VI -07 87.95(18) 02 -VI -08 88.0(2) 02 -VI -04B 173.1(5) 02 -VI -05B 95.9(4) 02 -VI -07B 89.1(13) 02 -VI -08B 97.3(9) 04 -VI -05 94.6(3) 07 -VI -08 90.4(2) 04B -VI -05B 88.6(6) 07B -VI -08B 83.5(14) VI -01 -CI 124.0(2) VI -02 -C5 128.4(2) C2 -03 -C3 104.8(3) VI -04 -C7 122.1(5) VI -04B -C7B 127.4(13 VI -05 -Cll 126.0(6) VI -08 -C17 125.3(5) VI -08B -C17B 128(3) C14 -09 -C15 104.3(5) C14B -09B -C15B 111(2) 01 -CI -C4 126.3(3) 01 -CI -C2 127.0(3) C2 -CI -C4 106.6(3) 03 -C2 -CI 109.5(3) 03 -C2 -C5 121.6(3) CI -C2 -C5 128.8(3) 03 -C3 -C4 113.7(4) CI -C4 -C3 105.3(3) C2 -C5 -C6 121.7(4) 02 -C5 -C6 118.2(4) 02 -C5 -C2 120.0(3) C8 -C7 -CIO 104.4(6) 04 -C7 -C8 126.4(6) 04 -C7 -CIO 129.0(8) 04B -C7B -C8B 120.8(15) 04B -C7B -C10B 127.6(18) C8B -C7B -C10B 110.6(16) 06 -C8 -C7 112.6(6) 06 -C8 -Cll 117.7(7) 181 VI -05B -CUB 125.5(11) 06B -C8B -C7B 107.9(13) 06B -C8B -CUB 121.4(14) C7B -C8B -CUB 130.7(15) 06 -C9 -CIO 115.4(8) 06B -C9B -CI OB 119.1(16) C7 -CIO • •C9 105.6(8) C7B -CI OB -C9B 99.3(15) 05 -Cll -C12 118.5(8) 05 -Cll •C8 120.9(7) C8 -Cll - C12 120.4(8) 05B -CUB -C8B 123.1(15) 05B -CUB -C12B 113.4(17) C8B -CUB -C12B 122.4(17) 07 -C13 -•C14 127.4(7) 07 -C13 -•C16 127.2(8) C14 -C13 -C16 105.4(7) 07B -C13B -C14B 105(4) 07B -C13B -C16B 132(5) C14B -C13B -C16B 122(6) 09 -C14 - C13 110.6(6) C13 -C14 -C17 127.3(8) 09 -C14 - C17 122.1(7) C7 -C8 -Cll 129.6(6) C13B -C16B -C15B 93(4) 08 -C17 -C14 122.4(8) 08 -C17 -C18 117.1(7) C14 -C17 -C18 120.4(8) 08B -C17B -C14B 116(3) 08B -C17B -C18B 118(4) C14B -C17B -C18B 124(4) 03 -C3 -H3 123.16 C4 -C3 -H3 123.19 CI -C4 -H4 127.31 C3 -C4 -H4 127.37 C5 -C6 -H6A 109.50 C5 -C6 -H6B 109.45 C5 -C6 -H6C 109.42 H6A -C6 -H6B 109.54 H6A -C6 -H6C 109.45 H6B -C6 -H6C 109.46 06 -C9 -H9A 122.32 CIO -C9 -H9A 122.30 06B -C9B -H9B 120.72 CI OB -C9B -H9B 120.13 C7 -CIO -H10 127.26 182 09B -C14B -C17B 120(4) 09B -C14B -C13B 95(3) C13B -C14B -C17B 137(5) 09 -C15 -C16 113.5(6) 09B -C15B -C16B 118(4) C13 -C16 -C15 106.1(7) Cll -C12 -H12C 109.46 H12A -C12 -H12B 109.47 H12A -C12 -H12C 109.43 CUB -C12B -H12F 109.05 H12D -C12B -H12E 110.13 CUB -C12B -H12E 109.64 CUB -C12B -H12D 109.67 H12E -C12B -H12F 109.17 H12D -C12B -H12F 109.16 C16 -C15 -H15 123.16 09 -C15 -H15 123.37 09B -C15B -H15B 121.53 C16B -C15B -H15B 120.96 C13 -C16 -H16 126.97 C15 -C16 -H16 126.91 C9 -CIO -H10 127.13 C7B -C10B -HIOB 130.19 C9B -C10B -HIOB 130.53 Cll -C12 -H12A 109.37 H12B -C12 -H12C 109.59 Cll -C12 -H12B 109.51 C13B -C16B -H16B 132.71 C15B -C16B -H16B 134.71 H18B -C18 -H18C 109.49 C17 -C18 -H18A 109.47 C17 -C18 -H18B 109.41 C17 -C18 -H18C 109.44 H18A -C18 -H18B 109.56 H18A -C18 -H18C 109.46 C17B -C18B -H18D 109.55 C17B -C18B -H18E 109.45 C17B -C18B -H18F 109.67 H18D -C18B -H18E 109.42 H18D -C18B -H18F 109.44 H18E -C18B -H18F 109.31 183 Table A9. Complete list of bond lengths (A) and bond angles (°) for [H4(en(ama)2)](Re04)2. Rel -02 1.714(7) Rel -03 1.716(7) Rel -01 1.725(7) Rel -04 1.723(5) 05 -CI 1.385(9) 05 -C5 1.353(11) 06 -C2 1.345(9) 07 -C3 1.240(11) 06 -H6 0.8230 Nl -C7 1.488(11) Nl -C8 1.481(9) Nl -H1A 0.9809 Nl -H1B 0.9800 CI -C2 1.339(12) 03 -Rel -04 110.6(3) 01 -Rel -03 107.3(4) 01 -Rel -04 109.3(3) 01 -Rel -02 110.9(3) 02 -Rel -04 108.9(3) 02 -Rel -03 109.9(3) CI -C7 C2 -C3 C3 -C4 C4 -C5 C5 -C6 C8 -C8_a C4 -H4 C6 -H6A C6 -H6B C6 -H6C C7 -H7B C7 -H7A C8 -H8 C8 -H9 C4 -C5 05 -C5 05 -C5 Nl -C7 Nl -C8 C5 -C4 184 1.494(13) 1.454(13) 1.449(10) 1.347(12) 1.469(12) 1.531(10) 0.9768 0.9816 0.9782 0.9794 0.9800 0.9816 0.9813 0.9781 -C6 125.3(8) -C4 122.6(8) -C6 112.1(7) -CI 113.2(6) -C8_a 111.2(5) -H4 119.97 CI -05 -C5 C2 -06 -H6 C7 -Nl -C8 C8 -Nl -HI A C7 -Nl -H1A C7 -Nl -H1B C8 -Nl -H1B H1A -Nl -H1B 05 -CI -C7 C2 -CI -C7 05 -CI -C2 CI -C2 -C3 06 -C2 -C3 06 -C2 -CI 07 -C3 -C2 07 -C3 -C4 C2 -C3 -C4 C3 -C4 -C5 119.7(7) 109.33 116.1(6) 107.83 107.76 107.77 107.77 109.48 112.3(7) 126.4(7) 121.3(8) 120.7(7) 118.0(7) 121.3(8) 119.7(7) 124.9(8) 115.4(7) 119.9(8) C3 -C4 -H4 120.11 C5 -C6 -H6A 109.17 C5 -C6 -H6C 109.48 H6A -C6 -H6B 109.55 C5 -C6 -H6B 109.60 H6B -C6 -H6C 109.65 H6A -C6 -H6C 109.37 CI -C7 -H7A 108.49 Nl -C7 -H7B 108.67 Nl -C7 -H7A 108.60 CI -C7 -H7B 108.51 H7A -C7 -H7B 109.33 C8_a -C8 -H9 109.26 Nl -C8 -H8 108.92 Nl -C8 -H9 109.09 H8 -C8 -H9 109.51 C8 a -C8 -H8 108.83 185 Table A10. Complete list of bond lengths (A) and bond angles (°) for In2(PO)3Cl3. Inl -In2 3.2229(6) C3 -C4 1.386(9) Inl -Cll 2.3837(18) C4 -C5 1.374(9) Inl -PI 2.6511(14) C5 -C6 1.398(8) Inl -P2 2.7330(15) C7 -C8 1.378(10) Inl -01 2.243(4) C7 -C12 1.371(10) Inl -02 2.192(4) C8 -C9 1.382(9) Inl -03 2.196(4) C9 -CIO 1.381(11) In2 -C12 2.3819(18) CIO -Cll 1.332(13) In2 -C13 2.4209(14) Cll -C12 1.412(9) In2 -P3 2.6628(15) C13 -C14 1.372(8) In2 -01 2.184(4) C13 -C18 1.387(8) In2 -02 2.287(4) C14 -C15 1.381(11) In2 -03 2.252(4) C15 -C16 1.374(10) PI -CI 1.800(6) C16 -C17 1.371(10) PI -C7 1.815(5) C17 -C18 1.388(10) PI -C13 1.817(6) C19 -C20 1.401(8) P2 -C19 1.802(5) C19 -C24 1.396(8) P2 -C25 1.816(6) C20 -C21 1.377(8) P2 -C31 1.807(6) C21 -C22 1.397(8) P3 -C37 1.799(5) C22 -C23 1.376(9) P3 -C43 1.823(6) C23 -C24 1.399(8) 186 P3 -C49 1.822(5) C25 -C26 1.373(9) 01 -C6 1.350(7) C25 -C30 1.399(9) 02 -C24 1.359(7) C26 -C27 1.417(11) 03 -C42 1.329(7) C27 -C28 L366(14) CI -C2 1.404(9) C28 -C29 1.359(15) CI -C6 1.405(7) C29 -C30 1.374(11) C2 -C3 1.373(8) C31 -C32 1.388(9) C31 -C36 1.387(9) C9 -H6 0.9839 C32 -C33 1.391(10) CIO -H7 0.9769 C33 -C34 1.393(11) Cll -H8 0.9874 C34 -C35 1.347(12) C12 -H9 0.9784 C35 -C36 1.407(10) C14 -H10 0.9845 C37 -C38 1.411(8) C15 -Hll 0.9805 C37 -C42 1.417(8) C16 -H12 0.9819 C38 -C39 1.382(9) C17 -HI 3 0.9811 C39 -C40 1.381(10) C18 -H14 0.9813 C40 -C41 1.381(10) C20 -H15 0.9842 C41 -C42 1.424(9) C21 -H16 0.9753 C43 -C44 1.377(9) C22 -HI 7 0.9786 C43 -C48 1.389(8) C23 -HI 8 0.9792 C44 -C45 1.397(10) C26 -H19 0.9788 C45 -C46 1.370(11) C27 -H20 0.9818 C46 -C47 1.377(11) C28 -H21 0.9807 C47 -C48 C49 -C50 C49 -C54 C50 -C51 C51 -C52 C52 -C53 C53 -C54 C2 -HI C3 -H2 C4 -H3 C5 -H4 C8 -H5 C45 -H34 C46 -H35 C47 -H36 C48 -H37 C50 -H38 In2 -Inl -Cll In2 -Inl -PI In2 -Inl -P2 In2 -Inl -01 In2 -Inl -02 In2 -Inl -03 1.380(10) 1.387(8) 1.393(9) 1.394(9) 1.377(10) 1.375(10) 1.390(9) 0.9797 0.9789 0.9805 0.9805 0.9847 0.9815 0.9799 0.9801 0.9808 0.9841 134.17(4) 105.09(3) 100.67(3) 42.57(9) 45.16(10) 44.26(10) C29 -H22 C30 -H23 C32 -H24 C33 -H25 C34 -H26 C35 -H27 C36 -H28 C38 -H29 C39 -H30 C40 -H31 C41 -H32 C44 -H33 C51 -H39 C52 -H40 C53 -H41 C54 -H42 C12 -In2 -P3 C12 -In2 -01 C12 -In2 -02 0.9782 0.9794 0.9809 0.9819 0.9775 0.9798 0.9805 0.9801 0.9861 0.9792 0.9791 0.9817 0.9783 0.9792 0.9774 0.9810 105.03(5) 101.21(10) 94.19(11) C12 -In2 -03 164.69(11) C13 -In2 -P3 C13 -In2 -01 97.74(5) 91.78(10) 188 Cll -Inl -PI 106.87(6) Cll -Inl -P2 100.60(6) Cll -Inl -Ol 176.74(10) Cll -Inl -02 104.04(11) Cll -Inl -03 102.41(11) PI -Inl -P2 106.71(4) PI -Inl -01 75.31(10) PI -Inl -02 148.09(10) PI -Inl -03 92.33(10) P2 -Inl -01 80.90(10) P2 -Inl -02 74.76(10) P2 -Inl -03 144.23(10) 01 -Inl -02 73.49(14) 01 -Inl -03 74.94(14) 02 -Inl -03 73.32(14) Inl -In2 -C12 124.84(4) Inl -In2 -C13 116.46(3) Inl -In2 -P3 106.48(3) Inl -In2 -01 43.99(10) Inl -In2 -02 42.82(9) Inl -In2 -03 42.88(9) C12 -In2 -C13 102.54(6) In2 -P3 -C49 119.89(19) C13 -In2 -02 159.24(10) C13 -In2 -03 92.46(10) P3 -In2 -01 149.31(10) P3 -In2 -02 89.58(10) P3 -In2 -03 75.52(10) 01 -In2 -02 72.76(13) 01 -In2 -03 74.97(13) 02 -In2 -03 70.51(13) Inl -PI -CI 98.44(19) Inl -PI -C7 113.3(2) Inl -PI -C13 123.14(18) CI -PI -C7 109.9(3) CI -PI -C13 104.1(3) C7 -PI -C13 106.7(3) Inl -P2 -C19 95.32(19) Inl -P2 -C25 112.3(2) Inl -P2 -C31 128.41(19) C19 -P2 -C25 107.8(3) C19 -P2 -C31 105.9(3) C25 -P2 -C31 105.1(3) In2 -P3 -C37 99.09(18) In2 -P3 -C43 117.70(19) C9 -CIO -Cll 121.0(6) C37 -P3 -C43 107.9(3) C37 -P3 -C49 ' 109.0(3) C43 -P3 -C49 102.7(2) Inl -01 -In2 93.43(14) Inl -01 -C6 124.0(3) In2 -01 -C6 131.1(3) Inl -02 -In2 92.02(14) Inl -02 -C24 123.3(3) In2 -02 -C24 132.0(3) Inl -03 -In2 92.86(14) Inl -03 -C42 125.8(3) In2 -03 -C42 124.1(3) PI -CI -C2 121.8(4) PI -CI -C6 118.8(4) C2 -CI -C6 119.4(5) CI -C2 -C3 120.7(5) C2 -C3 -C4 119.6(6) C3 -C4 -C5 120.9(5) C4 -C5 -C6 120.4(5) 01 -C6 -CI 121.4(5) 01 -C6- -C5 119.6(5) CI -C6 -C5 118.9(5) PI -CI -C8 118.4(5) CIO -Cll -C12 119.8(7) C7 -C12 -Cll 120.2(7) PI -C13 -C14 122.7(4) PI -C13 -C18 118.8(4) C14 -C13 -C18 118.4(6) C13 -C14 -C15 121.1(6) C14 -C15 -C16 120.0(6) C15 -C16 -C17 120.1(7) C16 -C17 -C18 119.6(6) C13 -C18 -C17 120.9(6) P2 -C19 -C20 121.1(4) P2 -C19 -C24 119.1(4) C20 -C19 -C24 119.8(5) C19 -C20 -C21 120.6(5) C20 -C21 -C22 .119.6(6) C21 -C22 -C23 120.2(5) C22 -C23 -C24 120.8(5) 02 -C24 -C19 122.0(5) 02 -C24 -C23 119.1(5) C19 -C24 -C23 118.9(5) P2 -C25 -C26 121.7(5) P2 -C25 -C30 117.4(5) C26 -C25 -C30 120.8(6) PI -C7 -C12 122.7(5) C8 -C7 -C12 118.9(5) C7 -C8 -C9 120.7(6) C8 -C9 -CIO 119.4(7) €25 . -C30 -C29 119.3(7) P2 -C31 -C32 121.1(4) P2 -C31 -C36 119.4(5) C32 -C31 -C36 119.5(6) C31 -C32 -C33 121.0(6) C32 -C33 -C34 118.6(7) C33 -C34 -C35 120.9(6) C34 -C35 -C36 121.0(7) C31 -C36 -C35 118.9(6) P3 -C37 -C38 122.2(4) P3 -C37 -C42 117.7(4) C38 -C37 -C42 120.1(5) C37 -C38 -C39 120.9(5) C38 -C39 -C40 119.0(6) C39 -C40 -C41 122.3(6) C40 -C41 -C42 119.9(6) 03 -C42 -C37 123.5(5) 03 -C42 -C41 118.7(5) C37 -C42 -C41 117.8(5) C25 -C26 -C27 117.8(7) C26 -C27 -C28 121.1(8) C27 -C28 -C29 119.9(8) C28 -C29 -C30 121.1(9) P3 -C49 -C54 120.3(4) C50 -C49 -C54 118.6(5) C49 -C50 -C51 120.6(6) C50 -C51 -C52 119.8(6) C51 -C52 -C53 120.3(6) C52 -C53 -C54 119.9(6) C49 -C54 -C53 120.6(6) CI -C2 -HI 119.90 C3 -C2 -HI 119.43 C2 -C3 -H2 120.25 C4 -C3 -H2 120.09 C3 -C4 -H3 119.45 C5 -C4 -H3 119.68 C4 -C5 -H4 119.37 C6 -C5 -H4 120.20 C7 -C8 -H5 119.51 C9 -C8 -H5 119.75 C8 -C9 -H6 120.33 CIO -C9 -H6 120.26 191 P3 -C43 P3 -C43 C44 -C43 C43 -C44 C44 -C45 C45 -C46 C46 -C47 C43 -C48 P3 -C49 C16 -C15 -C44 -C48 -C48 -C45 -C46 -C47 -C48 -C47 -C50 -Hll 123.8(4) 116.7(5) 119.5(6) 120.3(6) 119.7(7) 120.2(7) 120.4(6) 119.9(6) 121.1(5) 119.78 C15 -C16 -H12 119.63 C17 -C16 -H12 120.29 C16 -C17 -H13 120.14 C18 -C17 -H13 120.28 C13 -C18 -H14 119.58 C17 -C18 -H14 119.56 C19 -C20 -H15 120.12 C21 -C20 -HI 5 119.31 C20 -C21 -H16 120.45 C22 -C21 -H16 119.93 C21 -C22 -H17 119.18 C23 -C22 -HI 7 120.61 C22 -C23 -HI 8 119.75 C9 -CIO -H7 120.02 Cll -CIO -H7 119.00 CIO -Cll -H8 120.65 C12 -Cll -H8 119.51 C7 -CI 2 -H9 120.04 Cll -C12 -H9 119.80 C13 -C14 -H10 119.21 C15 -C14 -H10 119.67 C14 -C15 -Hll 120.24 C34 -C33 -H25 120.45 C33 -C34 -H26 119.34 C35 -C34 -H26 119.71 C34 -C35 -H27 118.81 C36 -C35 -H27 120.16 C31 -C36 -H28 120.36 C35 -C36 -H28 120.69 C37 -C38 -H29 119.01 C39 -C38 -H29 120.12 C38 -C39 -H30 120.29 C40 -C39 -H30 120.74 C39 -C40 -H31 119.14 C41 -C40 -H31 118.54 C40 -C41 -H32 120.00 192 C24 -C23 -HI 8 119.40 C42 -C41 -H32 120.05 C25 -C26 -H19 121.28 C43 -C44 -H33 . 120.30 C27 -C26 -HI 9 120.95 C45 -C44 -H33 119.43 C26 -C27 -H20 119.51 C44 -C45 -H34 120.53 C28 -C27 -H20 119.40 C46 -C45 -H34 119.79 C27 -C28 -H21 120.52 C45 -C46 -H35 120.00 C29 -C28 -H21 119.60 C47 -C46 -H35 119.77 C28 -C29 -H22 119.73 C46 -C47 -H36 119.84 C30 -C29 -H22 119.12 C48 -C47 -H36 119.74 C25 -C30 -H23 120.46 C43 -C48 -H37 120.10 C29 -C30 -H23 120.24 C47 -C48 -H37 120.01 C31 -C32 -H24 119.07 C49 -C50 -H38 119.41 C33 -C32 -H24 119.89 C51 -C50 -H38 119.94 C32 -C33 -H25 120.94 C50 -C51 -H39 120.69 C52 -C51 -H39 119.51 C54 -C53 -H41 119.91 C51 -C52 -H40 120.49 C49 -C54 -H42 120.00 C53 -C52 -H40 119.20 C53 -C54 -H42 119.36 C52 -C53 -H41 120.13 193 Table All. Complete list of bond lengths (A) and bond angles (°) for [In u-(MePO)Cl2(H20)]2 2Et20. Inl -Cll 2.4544(8) C14 -C15 1.378(3) Inl -C12 2.4113(8) C15 -C16 1.396(5) Inl -PI - 2.6093(7) C16 -C17 1.380(5) Inl -01 2.2709(12) C17 -C18 1.367(5) Inl -02 2.2478(19) C18 -C19 1.391(5) Inl -01_a 2.1912(14) C2 -HI 0.9799 PI -C6 1.797(2) C3 -H2 0.9809 PI -C8 1.814(2) C5 -H3 0.9801 PI -C14 1.819(2) C7 -H5 0.9851 01 -CI 1.353(3) C7 -H6 0.9800 02 -H27 0.85(4) C7 -H4 0.9775 02 -H28 0.65(3) C9 -H7 0.9820 03 -C22 1.442(4) CIO -H8 0.9831 03 -C21 1.419(4) Cll -H9 0.9804 CI -C6 1.408(3) C12 -H10 0.9799 CI -C2 1.400(3) C13 -Hll 0.9815 C2 -C3 1.380(3) C15 -H12 0.9763 C3 -C4 1.398(4) C16 -HI 3 0.9780 C4 -C5 1.385(3) C17 -H14 0.9780 C4 -C7 1.511(4) C18 -H15 0.9836 C5 -C6 1.407(3) C19 -H16 0.9801 194 C8 -C9 C8 -C13 C9 -CIO CIO -Cll Cll "-C12 C12 -C13 C14 -C19 C22 -H22 C22 -H23 C23 -H24 1.386(4) 1.381(4) 1.395(4) 1.373(5) 1.376(6) 1.389(5) 1.389(4) 0.9793 0.9798 0.9808 C20 -C21 1.490(5) C22 -C23 1.494(5) C20 -H17 0.9779 Cll -Inl Cll -Inl Cll -Inl Cll -Inl Cll -Inl C12 -Inl C12 -Inl C12 -Inl C12 -Inl PI -Inl PI -Inl PI -Inl 01 -Inl -C12 99.42(2) -PI 96.55(2) -01 91.82(5) -02 169.31(4) -01_a 88.53(5) -PI 97.93(2) -01 167.67(6) -02 88.51(5) -01_a 111.07(3) -01 75.61(4) -02 89.39(4) -01_a 149.36(4) -02 81.01(7) C20 -HI 8 C20 -HI 9 C21 -H20 C21 -H21 C23 -H25 C23 -H26 C2 -CI -C6 01 -CI -C6 01 -CI -C2 CI -C2 -C3 C2 -C3 -C4 C3 -C4 -C5 C5 -C4 -C7 C3 -C4 -CI C4 -C5 -C6 PI -C6 -CI CI -C6 -C5 PI -C6 -C5 PI -C8 -C9 0.9811 0.9806 0.9817 0.9796 0.9792 0.9779 117.8(2) 121.84(19) 120.3(2) 120.8(2) 122.1(2) 117.4(2) 122.3(2) 120.4(2) 121.6(2) 118.23(17) 120.2(2) 121.56(17) 117.75(18) 195 01 -Inl 01_a -Inl Inl -PI Inl -PI Inl -PI C6 -PI C6 -PI C8 -PI Inl -01 Inl -01 Inl_a -01 H27 -02 Inl -02 Inl -02 C21 -03 CI -C2 -01_a 74.03(5) -02 81.89(6) -C6 99.44(8) -C8 112.80(8) -C14 122.41(8) -C8 108.26(11) -C14 106.54(10) -C14 106.35(10) -CI 121.90(13) -Inl_a 105.97(6) -CI 128.16(12) -H28 104(4) -H28 115(4) -H27 125(3) -C22 115.8(2) -HI 119.63 C3 -C2 -HI 119.53 C4 -C3 -H2 118.89 C2 -C3 -H2 118.99 C6 -C5 -H3 119.27 C4 -C5 -H3 119.12 C4 -C7 -H4 109.83 C4 -C7 -H6 109.56 C9 -C8 -C13 PI -C8 -C13 C8 -C9 -CIO C9 -CIO -Cll CIO -Cll -C12 Cll -C12 -C13 C8 -C13 -C12 PI -C14 -C15 C15 -C14 -C19 PI -C14 -C19 C14 -C15 -C16 C15 -C16 -C17 C16 -C17 -C18 C17 -C18 -C19 C14 -C19 -C18 C17 -C18 -H15 C19 -C18 -H15 C14 -C19 -H16 C18 -C19 -H16 03 -C21 -C20 03 -C22 -C23 C21 -C20 -H17 C21 -C20 -HI 8 119.4(2) 122.80(19) 120.2(3) 119.7(3) 120.3(3) 120.2(4) 120.1(3) 121.8(2) 119.7(2) 118.48(18) 120.1(3) 119.9(3) 119.9(3) 120.8(3) 119.6(2) 119.78 119.46 120.08 120.37 108.5(3) 112.5(3) 109.62 109.35 196 H4 -C7 -H5 109.31 C21 -C20 -HI 9 109.41 C4 -C7 -H5 109.29 H17 -C20 -H18 109.53 H5 -CI -H6 109.09 H17 -C20 -H19 109.58 H4 -C7 -H6 109.75 H18 -C20 -H19 109.34 C8 -C9 -H7 120.02 03 -C21 -H20 109.45 CIO -C9 -H7 119.75 03 -C21 -H21 109.67 Cll -CIO -H8 120.42 C20 -C21 -H20 109.86 C9 -CIO -H8 119.85 C20 -C21 -H21 110.09 CIO -Cll -H9 119.75 H20 -C21 -H21 109.26 C12 -Cll -H9 119.95 03 -C22 -H22 108.61 C13 -C12 -H10 119.95 03 -C22 -H23 108.69 Cll -C12 -H10 119.87 C23 -C22 -H22 108.70 C8 -C13 -Hll 119.97 C23 -C22 -H23 108.70 C12 -C13 -Hll 119.90 H22 -C22 -H23 109.60 C16 -C15 -H12 119.82 C22 -C23 -H24 109.17 C14 -C15 -H12 120.06 C22 -C23 -H25 109.36 C15 -C16 -H13 120.13 C22 -C23 -H26 109.41 C17 -C16 -H13 119.97 H24 -C23 -H25 109.53 C18 -C17 -H14 120.44 H24 -C23 -H26 109.59 C16 -C17 -H14 119.65 H25 -C23 -H26 109.76 197 Table A12. Complete list of bond lengths (A) and bond angles (°) for Ga(HPO)Cl3HCl. Gal -Cll 2.1722(8) Gal -C12 2.1674(8) Gal -C13 2.1634(8) Gal -01 1.835(2) cue -C14C a 1.98(4) PI -C7 1.789(3) PI -C13 1.777(3) PI -CI 1.781(3) PI -HI 1.45(3) 01 -C18 1.346(3) CI -C6 1.391(3) CI -C2 1.388(4) C2 -C3 1.392(4) C3 -C4 1.376(5) C4 -C5 1.375(4) C5 -C6 1.385(4) C7 -C12 1.403(4) C7 -C8 1.387(4) C8 -C9 1.395(4) C9 -CIO 1.378(5) CIO -Cll 1.387(4) Cll -C12 1.385(4) CI 3 -CI 8 1.406(3) C13 -CI 4 1.404(4) C14 -C15 1.389(4) C15 -C16 1.387(4) C16 -CI 7 1.390(4) C17 -C18 1.389(4) C2 -H2 0.9805 C3 -H3 0.9807 C4 -H4 0.9800 C5 -H5 0.9812 C6 -H6 0.9825 C8 -H7 0.9778 C9 -H8 0.9771 C10 -H9 0.9780 Cll -H10 0.9785 C12 -Hll 0.9776 C14 -H12 0.9800 C15 -H13 0.9816 C16 -H14 0.9793 C17 -H15 0.9804 198 Cll -Gal -C12 109.95(3) C7 -C12 -Cll 119.7(3) Cll -Gal -C13 111.29(3) PI -C13 -C14 123.8(2) Cll -Gal -01 108.85(7) PI -C13 -C18 115.48(17) C12 -Gal -C13 112.23(3) C14 -C13 -C18 120.7(3) C12 -Gal -01 110.77(8) C13 -C14 -CI 5 119.3(3) C13 -Gal -01 103.55(7) C14 -C15 -C16 119.6(3) CI -PI -C7 112.18(13) C15 -C16 -C17 121.6(3) CI -PI -C13 111.88(12) C16 -C17 -C18 119.5(3) C7 -PI -C13 109.10(12) 01 -C18 -C13 115.6(2) C13 -PI -HI 107.5(12) 01 -C18 -C17 125.1(2) CI -PI -HI 105.1(13) C13 -CI 8 -C17 119.3(2) C7 -PI -HI 110.9(13) CI -C2 -H2 120.35 Gal -01 , -C18 126.86(18) C3 -C2 -H2 120.37 PI -CI -C2 119.39(19) C2 -C3 -H3 119.89 PI -CI -C6 120.3(2) C4 -C3 -H3 119.90 C2 -CI -C6 120.2(2) C3 -C4 -H4 119.83 CI -C2 -C3 119.3(2) C5 -C4 -H4 119.62 C2 -C3 -C4 120.2(3) C4 -C5 -H5 119.79 C3 -C4 -C5 120.5(3) C6 -C5 -H5 120.13 C4 -C5 -C6 120.1(3) CI -C6 -H6 120.16 CI -C6 -C5 119.6(3) C5 -C6 -H6 120.19 PI -C7 -C8 122.4(2) C7 -C8 -H7 120.59 PI -C7 -C12 117.3(2) C9 -C8 -H7 120.14 199 C8 -CI -C12 C7 -C8 -C9 C8 -C9 -CIO C9 -CIO -Cll CIO -Cll -C12 C12 -Cll -HIO C7 -C12 -Hll Cll -C12 -Hll C13 -C14 -H12 C15 -C14 -H12 C14 -C15 -H13 120.2(3) 119.3(3) 120.4(3) 120.4(3) 119.9(3) 120.13 120.21 120.12 120.19 120.55 120.34 C8 -C9 -H8 119.84 CIO -C9 -H8 119.72 C9 -CIO -H9 119.67 Cll -CIO -H9 119.88 CIO -Cll -HIO 119.95 C16 -C15 -H13 120.06 C15 -C16 -H14 119.35 C17 -C16 -H14 119.03 C16 -C17 -H15 120.17 C18 -C17 -H15 120.32 200 Table A13. Complete list of bond lengths (A) and bond angles (°) for [H3P02]GaCl4-CH2Cl2. Gal -C13 2.1763(10) Gal -Cll 2.1592(9) Gal -C12 2.1965(8) Gal -C14 2.1523(10) C15 -C19 1.760(4) C16 -C19 1.755(4) PI -CI 1.777(3) PI -C7 1.784(3) PI -C13 1.790(3) PI -HI 1.33(3) 01 -C12 1.359(4) 02 -C6 1.353(4) 01 -H2 0.79(3) 02 -H3 0.75(3) CI -C6 1.404(4) CI -C2 1.395(4) C2 -C3 1.390(4) C3 -C4 1.386(5) C4 -C5 1.378(6) C5 -C6 1.385(4) CIO -Cll 1.383(5) Cll -C12 1.384(4) C13 -C14 1.384(4) C13 -CI 8 1.398(4) C14 -C15 1.389(5) C15 -C16 1.387(4) C16 -C17 1.378(4) C17 -C18 1.386(5) C2 -H4 0.9806 C3 -H5 0.9786 C4 -H6 0.9780 C5 -H7 0.9833 C8 -H8 0.9797 C9 -H9 0.9809 C10 -H10 0.9813 Cll -Hll 0.9835 C14 -H12 0.9790 C15 -H13 0.9785 C16 -H14 0.9794 C17 -H15 0.9804 201 C7 -C12 1.401(4) C7 -C8 1.396(5) C8 -C9 1.391(4) C9 -CIO 1.385(4) Cll -Gal -C13 110.72(4) Cll -Gal -C14 109.72(4) C12 -Gal -C13 106.19(4) C12 -Gal -C14 111.37(4) C13 -Gal -C14 111.01(4) Cll -Gal -C12 107.73(3) C7 -PI -C13 112.12(13) CI -PI -C7 110.20(15) CI -PI -C13 111.00(14) C13 -PI -HI 106.0(14) C7 -PI -HI 110.8(13) CI -PI -HI 106.5(13) C12 -01 -H2 114(3) C6 -02 -H3 116(2) C2 -CI -C6 119.9(3) PI -CI -C6 117.3(2) PI -CI -C2 122.8(2) CI -C2 -C3 119.8(3) C2 -C3 -C4 119.5(3) C18 -H16 0.9793 C19 -H17 0.9781 C19 -H18 0.9794 C8 -C9 -CIO 119.7(3) C9 -CIO -Cll 121.2(3) CIO -Cll -C12 119.6(3) 01 -C12 -Cll 124.0(3) C7 -C12 -Cll 120.0(3) 01 -C12 -C7 116.0(3) PI -C13 -C18 118.5(2) C14 -C13 -C18 120.5(3) PI -C13 -C14 121.0(2) C13 -C14 -C15 119.8(3) C14 -C15 -C16 119.6(3) C15 -C16 -C17 120.6(3) C16 -C17 -C18 120.3(3) C13 -C18 -C17 119.1(3) CI -C2 -H4 120.19 C3 -C2 -H4 119.97 C4 -C3 -H5 120.37 C2 -C3 -H5 120.14 C3 -C4 -H6 119.11 202 C3 -CA -C5 C4 -C5 -C6 02 -C6 -CI 02 -C6 -C5 CI -C6 -C5 PI -C7 -C8 C8 -C7 -C12 PI -C7 -C12 C7 -C8 -C9 C12 -Cll -Hll CIO -Cll -Hll C13 -C14 -H12 C15 -C14 -H12 C14 -C15 -H13 C16 -C15 -H13 C17 -C16 -H14 C15 -C16 -H14 C16 -C17 -H15 121.2(3) 119.9(3) 116.1(3) 124.2(3) 119.7(3) 121.5(2) 119.9(3) 118.5(2) 119.6(3) 120.30 120.13 119.91 120.26 120.28 120.10 119.66 119.74 119.79 C5 -C4 -H6 119.69 C4 -C5 -H7 120.11 C6 -C5 -H7 120.01 C9 -C8 -H8 120.34 C7 -C8 -H8 120.04 C8 -C9 -H9 120.06 CIO -C9 -H9 120.28 C9 -CIO -HIO 119.35 Cll -CIO -HIO 119.44 C18 -C17 -H15 119.89 C17 -C18 -H16 120.42 C13 -C18 -H16 120.44 C15 -C19 -C16 111.56(17) C15 -C19 -H17 108.84 C15 -C19 -H18 108.73 C16 -C19 -H17 109.08 C16 -C19 -H18 108.98 H17 -C19 -H18 109.64 203 

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