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Coordination chemistry of Group 13, Technetium and Rhenium metal complexes with Hexadentate Amine Phenol… Wong, Ernest Shing Yan 1996

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COORDINATION CHEMISTRY OF GROUP 13, TECHNETIUM A N D RHENIUM M E T A L COMPLEXES WITH HEXADENTATE AMINE PHENOL LIGANDS by Ernest Shing Yan Wong B. Sc. (Hons.), Simon Fraser University, Canada, 1991 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES (Department of Chemistry) We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH C O L U M B I A March 1996 © Ernest Shing Yan Wong, 1996 In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of d V \ € - w v v -\ ^ TX-p^ The University of British Columbia Vancouver, Canada Date < " W o V y 2 6 ; W£> • DE-6 (2/88) Abstract A series of neutral and monocationic group 13 metal complexes with hexadentate tripodal, linear and pyridine amine phenolates were prepared and characterized by elemental analyses and various spectroscopic techniques (IR, U V , LSIMS, NMR). X-ray crystallographic structural analyses of selected A l 3 + , G a 3 + and I n 3 + complexes were also performed. It was observed that the coordination behavior of the amine phenolates and the stability of the resulting metal complexes were closely related to the flexibility of the ligand, the type and spatial organization of the donor atoms, as well as to the electronic and steric demands of the coordinated metal ion. Coordination of tripodal N3O3 tris(aminomethyl)ethane based amine phenolates (XTAM3") to A l 3 + , G a 3 + and I n 3 + resulted in neutral mono-ligand metal complexes. The N3O3 donor set was suitable for coordination to all three group 13 metal ions. As the size of the metal ion increased from A l 3 + to I n 3 + , X T A M 3 - adjusted to the steric demands of the coordinated metal in a subtle fashion, such that no significant identifiable bond angle change was observed. This flexibility allowed it to coordinate to various metals of differing sizes. Paramagnetic Tc(III), Tc(IV) and Re(IV) complexes with X T A M 3 - were prepared via the substitution and reduction/complexation methods. The coordination of X T A M 3 - to Tc and Re demonstrated the potential use of the hexadentate amine phenolates as ligands for coordination to Tc and Re in intermediate oxidation states. Monocationic G a 3 + and I n 3 + complexes with linear amine phenolates (Xbad2~ and Xbadd 2 ) based on triethylenetetraamine and N,N'-(3-aminopropyl)ethylenediamine were prepared; no analytically pure, A l 3 + complex could be isolated. The N4O2 donor set of the linear amine phenolates was softer than the N3O3 set of X T A M 3 - and hence was less suitable for coordination to the harder A l 3 + ion. Structural analyses of [Ga(Brbad)]C104 and [Ga(Brbadd)]C104, and N M R spectral data revealed the mode of coordination of the Xbad 2 -ligand to be different from that of the longer backbone Xbadd 2 -. Increasing the length of the amine phenolate altered the mode of coordination. ii The introduction of pyridine nitrogen atoms into the amine phenol framework reduced the overall hardness of the donor atom set. Monocationic Ga and In complexes with N2N2O2 pyridine amine phenolates (Xbbpen2) were prepared with ease, while no A l complex could be isolated. Only minor differences between the structures of the Ga and In complexes were observed, suggesting that the cavity of Xbbpen2 - was large enough to accommodate ions as large as I n 3 + without causing significant steric strain to be imposed onto its framework. Stability constant study of Ga and In complexes with sulfonated linear amine phenolates (Sbad4 - and Sbadd 4) showed the Ga complexes to be ~3 orders of magnitude more stable than the corresponding In complexes. The selectivity of the linear amine phenolates for G a 3 + over I n 3 + was consistent with the fact that, while the affinity of amine for G a 3 + and I n 3 + was similar, 2-oxybenzyl groups definitely has an affinity for G a 3 + over I n 3 + . In contrast, the stability constants of Ga and In complexes with sulfonated pyridine amine phenolate (Sbbpen4" ) were very similar to each other. The introduction of the pyridine nitrogen atoms into the amine phenolate donor set muted the selectivity of the amine phenol for G a 3 + over In 3 + . The stability constants of the Ga and In complexes with Sbbpen4" were 7-10 orders of magnitude higher than those of the linear amine phenolate complexes. This was due to the donor atoms in Xbbpen2" being more pre-arranged for coordination than those of linear amine phenolates. iii Table of Contents page Abstract i i Table of Contents iv List of Figures vi List of Tables xi List of Abbreviations xv Acknowledgements xxii Dedication xxiii page Chapter 1 Introduction 1.1 General Introduction 1 1.2 References 13 Chapter 2 Group 13 Complexes with Tripodal N3O3 Tame-based Amine Phenolates 2.1 Introduction 20 2.2 Experimental Section 23 2.3 Results and Discussion 33 2.4 References 46 Chapter 3 " T c and Re Complexes with Tripodal N3O3 Tame-based Amine Phenolates 3.1 Introduction 48 3.2 Experimental Section ' 50 3.3 Results and Discussion 55 3.4 References 60 iv page Chapter 4 Chapter 5 Ga and In Complexes with Linear N4O2 Amine Phenolates 4.1 Introduction 62 4.2 Experimental Section 64 4.3 Results and Discussion 79 4.4 References 98 Ga and In Complexes with Linear N2N2O2 Pyridine Amine Phenolates 5.1 Introduction 100 5.2 Experimental Section 102 5.3 Results and Discussion 111 5.4 References 125 Chapter 6 Determination of Stability Constants for Ga and In Complexes with Linear and Pyridine Amine Phenolates 6.1 Introduction 128 6.2 Experimental Section 131 6.3 Results and Discussion 136 6.4 References 152 Chapter 7 General Conclusions and Suggestions for Future Work 7.1 General Conclusions 154 7.2 Suggestions for Future Work 157 7.3 References 159 Appendices Appendix I 160 Appendix II 181 v List of Figures page. Figure 1.1 Coordination of tren-based amine phenolates (XTRN3~) to trivalent 9 group 13 metal ions. Figure 1.2. Tripodal, linear and pyridine amine phenols 11 Figure 2.1. Tame-based tripodal amine phenols (H3XTAM) 21 Figure 2.2. Reaction scheme for the preparation of H 3 X T A M . 33 Figure 2.3. ORTEP drawing of the asymmetric unit {[Al(BrTAM)] 2[Na(H 20)]}- 37 CIO4 in {[Al(BrTAM)]4[Na(H20)]2}(ClC>4)2 showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. Figure 2.4. Average pendant arm angles (A, B and C) in Ga and In X T A M 3 - 40 complexes Figure 2.5. ORTEP drawing of the [Ga(TAM)]-H 20 unit in [Ga(TAM)]-4.4H 20 41 showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. Figure 2.6. ORTEP drawing of the [In(TAM)]-H20 unit in [In(TAM)]-6.2H20 43 showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. ( vi Figure 3.1. Cyclic voltammogram of ["Tc(BrTAM)] in acetonitrile at a scan rate of 100 mV/s. page 57 Figure 4.1. Linear amine phenols, H 2Xbad and H 2Xbadd. 63 Figure 4.2. Reaction scheme for the preparation of H 2Xbad, H 2XbadAc, 80 H 3 Xapi , H3(l,2,4-Xbtt) and H 3(l,l,4-Xbtt). Figure 4.3. ORTEP drawing of H3Clapi with numbering schemes. Thermal 81 ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. Figure 4.4. ! H N M R spectrum (300 MHz) of H 3Clapi in CDC1 3 . 81 Figure 4.5. *H N M R spectra (300 MHz) of H3CIbadd (top), H 2ClbadAc 84 (middle), and H 2Clbad (bottom) in CDC1 3 . Figure 4.6. ORTEP drawing of the [Ga(Brbad)]+cation and DMSO solvate in . 89 [Ga(Brbad)]C104«DMSO showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. Figure 4.7. Potential coordination modes for [M(Xbad)]+ and [M(Xbadd)]+ complexes (M= G a 3 + , In 3 + ) . vii page Figure 4.8. ORTEP drawing of the [Ga(Brbadd)]+ cation in [Ga(Brbadd)]C104 93 showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. Figure 5.1. Xbbpen2-, N2N2O2pyridine amine phenolates. 101 Figure 5.2. Reaction scheme for the preparation of H2Xbbpen pyridine amine 111 phenols. Figure 5.3. *H N M R spectra (300 MHz) of H2Clbbpen (top, in CDCI3), 113 [Ga(Clbbpen)]C104 (middle, in DMSO-d 6 ) and [In(Clbbpen)]C104 (bottom, in DMSO-^ ) -Figure 5.4. i H - i H N M R COSY spectrum (400 MHz) of [Ga(Clbbpen)]C104 in 115 DMSO-cfe Figure 5.5. ORTEP drawing of [Ga(Clbbpen)]+ cation in [Ga(Clbbpen)]C104 117 showing the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level. Figure 5.6. ORTEP drawing of [In(Clbbpen)]+ cation in [In(Clbbpen)]C104 120 showing the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level. Figure 5.7. Angles A , B , C, D, and E in [M(Xbbpen)]+ (M: G a 3 + and In 3 + ) . 123 viii page Figure 6.1. Linear amine phenols (H2Xbad, t^Xbadd), pyridine amine phenols 129 (H2Xbbpen), and their sulfonated analogs (H6Sbad2+, H6Sbadd2+ and H6Sbbpen2+). Figure 6.2. Plot of chemical shift change (A8 in ppm) versus pH for selected 138 ! H N M R resonances in H6Sbad2+ (top), H^Sbadd2* (middle), and H6Sbbpen2+ (bottom). Figure 6.3. Variable pH (pH 2-10) U V spectra (220 - 320 nm) of H 6Sbad 2 +. 139 Figure 6.4. Variable pH (pH 2-10) U V spectra (220 - 320 nm) of H6Sbadd2 +. 140 Figure 6.5. Variable pH (pH 2-10) U V spectra (220 - 320 nm) of H6Sbbpen2+. 142 Figure 6.6. Experimental Ga (——) and In ( ) titration curves for Sbad4- 145 (top), Sbadd4- (middle- see text), and Sbbpen4" (bottom) at ligand:metal ratio 1.2:1. Figure 6.7. Speciation diagram for the Ga3 +/Sbad4 _ system. 146 Figure 6.8. Variable pH (pH 2-6) U V spectra (220 - 320 nm) of the Ga3+/Sbad4" 147 system. Figure 6.9. Variable pH (pH 2, 8, 10, 11.9) U V spectra (220 - 320 nm) of the 147 Ga3 +/Sbad4- system. ix page Figure 7.1. Proposed reaction scheme for the conversion of amine phenols to 158 potentially bifunctional chelating agents (R = amine backbone). Figure II-1 Variable pH (pH 2-7) U V spectra (220 - 320 nm) of the In3+/Sbad4" 181 system. Figure II-2 Speciation diagram for the In3+/Sbad4" system. 181 Figure II-3 Variable pH (pH 2-5.8) U V spectra (220 - 320 nm) of the 182 Ga 3 +/Sbadd 4" system. Figure II-4 Speciation diagram for the Ga3 +/Sbadd4'system. 182 Figure II-5 Variable pH (pH 2-7.6) U V spectra (220 - 320 nm) of the 183 In3 +/Sbadd4" system. Figure II-6 Speciation diagram for the In 3 +/Sbadd 4 _ system. - 183 Figure II-7 Variable pH (pH 2, 4.1, 5.2, 8.5, 11.9) U V spectra (220 - 320 nm) of 184 the Ga 3 +/Sbbpen 4 _ system. Figure II-8.Speciation diagram for the Ga 3 +/Sbbpen 4' system. . 184 Figure II-9 Variable pH (pH 2.3, 2.9, 3.5, 4.1, 11.8) U V spectra (220 - 320 nm) of 185 the In3+/Sbbpen4" system. Figure II-10.Speciation diagram for the In3+/Sbbpen4- system. 185 List of Tables page Table 1.1 Nuclear properties of metal radionuclides used in diagnostic nuclear 3 medicine. Table 1.2. Human serum transferrin binding constants for trivalent metal ions. 6 Table 2.1. *H N M R data (200 MHz) for tame-based amine phenols, H 3 X T A M 26 (5 in ppm from TMS, CDCI3). Table 2.2. 1 3 C N M R data (200 MHz) for tame-based amine phenols, H 3 X T A M 27 (5 in ppm from TMS, CDCI3). Table 2.3. *H N M R data (200 MHz) for [M(XTAM)] complexes (M = A l , Ga, In) 31 (8 in ppm from TMS, DMSO-fifo). Table 2.4. Selected bond lengths (A) and bond angles (°) in {[Al(BrTAM)]4- 38 Na(H 20)2}(C104)2-6.2H 20. Table 2.5. Selected bond lengths (A) and bond angles (°) in [Ga(TAM)]-4.4H20. 42 Table 2.6. Selected bond lengths (A) and bond angles (°) in [In(TAM)]-4.6H20. 44 Table 3.1. Cyclic voltammetric data for [99Tc(XTAM)] and [Re(XTAM)] 58 complexes. Table 4.1. lH N M R data (300 MHz) for the trien-based N4O2 amine phenols, 68 H 2Xbad (5 in ppm from TMS, CDCI3) xi page Table 4.2. 1 3 C N M R data (200 MHz) for the trien-based N4O2 amine phenols, 69 H 2Xbad (8 in.ppm from TMS, CDCI3) Table 4.3. lK N M R data (300 MHz) for the acetone adducts of the trien-based 70 N4O2 amine phenols, H2XbadAc (8 in ppm from TMS, CDCI3) Table 4.4. lH N M R Data (300 MHz) for the tnentn-based N 4 0 2 amine phenols, 71 H 2Xbadd (8 in ppm from TMS, CDCI3). Table 4.5. 1 3 C N M R data (200 MHz) for the tnentn-based N 4 0 2 amine phenols, 72 H 2Xbadd (8 in ppm from TMS, CDCI3). Table 4.6. Selected bond lengths (A) and angles (°) in H3Clapi. 82 Table 4.7. Selected bond lengths (A) and angles (°) for the [Ga(Brbad)]+ cation 89 in [Ga(Brbad)]C10 4DMSO. Table 4.8. Selected bond lengths (A) and angles (°) for the [Ga(Brbadd)]+ 94 cation in [Ga(Brbadd)]C104. Table 5.1. lH N M R data (300 MHz) for pyridine amine phenols, H2Xbbpen, 104 (8 in ppm from TMS, CDCI3). Table 5.2. 1 3 C N M R data (200 MHz) for pyridine amine phenols, H2Xbbpen 105 (8 in ppm from TMS, CDCI3). Table 5.3. *H N M R data (300 MHz) for Ga and In complexes of H2Xbbpen 109 (8 in ppm from TMS, DMSO-^6) xii page Table 5.4. Selected bond lengths (A) and angles (°) for the [Ga(Clbbpen)]+ 118 cation in [Ga(Clbbpen)]C104. Table 5.5. Selected bond lengths (A) and Angles (°) for the [In(Clbbpen)]+ 121 cation in [In(Clbbpen)]C104. Table 6.1. Deprotonation constants (pK as) of various amines and amine phenols 137 (25 °C, \i = 0.16 M NaCl unless otherwise noted). Table 6.2. Log P and p M Values (pH 7.4) of Ga and In complexes with Sbad4", 144 Sbadd4-, Sbbpen4, HBED, EHPG, PLED, NT A , DTPA, E D T A and transferrin. Table 1-1. Selected crystallographic data for [Ga(TAM)]-4.4H20, 160 [In(TAM)]-4.6H20, and {[Al(BrTAM)] 4[Na(H20)2}(C104) 2-6.2H 20. Table 1-2. Final atomic coordinates (fractional) and Beq (A 2 ) a for non-hydrogen 161 atoms in {[Al(BrTAM)] 4[Na(H 20) 2} (C10 4) 2-6.2H 20. Table 1-3. Final atomic coordinates (fractional) and 5 e q (A2) for non-hydrogen atoms in [Ga(TAM)]-4.4H20. Table 1-4. Final atomic coordinates (fractional) and 5 e q (A2) for non-hydrogen atoms in [In(TAM)]-4.6H20. Table 1-5. Selected crystallographic data for HsClapi. 169 165 167 xiii page Table 1-6. Final atomic coordinates (fractional) and 5 e q (A2) for non-hydrogen 170 atoms in H 3Clapi. Table 1-7. Selected crystallographic data for [Ga(Brbad)]C104 DMSO and 171 [Ga(Brbadd)]C104. Table 1-8. Final atomic coordinates (fractional) and 5 e q (A2) for non-hydrogen 172 atoms in [Ga(Brbad)]C104-DMSO. Table 1-9. Final atomic Coordinates (fractional) and 5 e q (A2) for non-hydrogen 174 atoms in [Ga(Brbadd)]C104. Table 1-10. Selected crystallographic data for [Ga(CIbbpen)]C104 and 176 [In(Clbbpen)]C104. Table I-11. Final atomic coordinates (fractional) and 5 e q (A2) for non-hydrogen 177 atoms in [Ga(Clbbpen)]ClC>4. Table 1-12. Final atomic coordinates (fractional) and BQq (A2) for non-hydrogen 179 atoms in [In(Clbbpen)]ClC»4. xiv List of Abbreviations Abbreviation Meaning a an alpha particle, helium nucleus A angstrom, 1 x 10" 1 0 metre APT attached proton test Anal analytical OAc acetate approximate (3 or P" beta particle P + positron particle b broad (spectral) B M Bohr magneton °C degrees Celsius 8 chemical shift in parts per million (ppm) downfield from tetramethylsilane (NMR); vibrational in-plane bending mode (IR) A 8 change in chemical shift in parts per million (ppm) downfield from tetramethylsilane (NMR) Pcalc calculated density Calcd calculated CDCI3 deuterated chloroform cis Latin, "on the side", or the same side cm - 1 wavenumber(s) (IR) in reciprocal centimeter COSY correlated spectroscopy (NMR) CV cyclic voltammetry D deuterium xv d doublet (NMR) dd doublet of doublets (NMR) D2O deuterated water DMSO dimethylsulfoxide DMSO-c?6 deuterated dimethylsulfoxide DTPA N,N,N',N",N"-diethylenetriaminepentaacetic acid e extinction coefficient (UV) E1/2 half-wave potential AEp difference in peak potential (anodic-cathodic) EC electron capture (mode of radioactivity decay); N,N'-ethylene-di-L-cysteine EDDA-SS N,N'-bis(2-mercaptoethyl)ethylenediamine-N,N'-diacetic acid EDTA N,N,N',N'-ethylenetetraacetic acid E H P G N,N'-ethylenebis[2-(o-hydroxyphenyl)glycine] eq equivalent eV electron volt fw formula weight Y gamma photon(s) g gram(s) H 2 bad l,10-bis(2-hydroxybenzyl)-l,4,7,10-tetrazadecane H 2 badAc acetone adduct of H 2bad H 2 Brbad 1,10-bis(5-bromo-2-hydroxybenzyl)-1,4,7,10-tetrazadecane H 2 BrbadAc acetone^adduct of H 2Brbad H 2 Clbad 1,10-bis(5Tchloro-2-hydroxybenzyl)-1,4,7,10-tetrazadecane H 2 ClbadAc acetone adduct of H 2Clbad H 2badd 1,12-bis(2-hydroxybenzyl)-1,5,8,12-tetraazadodecane H 2Brbadd 1,12-bis(5-bromo-2-hydroxybenzyl)-l ,5,8,12-tetraazadodecane H 2 Clbadd l,12-bis(5-chloro-2-hydroxybenzyl)-l,5,8,12-tetraazadodecane xvi H2bben H2Brbben H 2Clbben H2bbpen H2Brbbpen H 2Clbbpen H2salen H2Brsalen H2Clsalen H 2 Xbad H 2Xbadd H2Xbbpen H 3 api H 3 B r a p i H 3 Clapi H3saltame HiBrsaltame H3Clsaltame H 3 T A M H 3 B r T A M H 3 C I T A M l,2,4-H 3Xbtt N,N'-bis(2-hydroxybenzyl)ethylenediamine N,N'-bis(5-bromo-2-hydroxybenzyl)ethylenediamine N,N'-bis(5-chloro-2-hydroxybenzyl)ethylenediamine N,N'-bis(2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)-ethylenediamine N,N'-bis(5-bromo-2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylenediamine N,N'-bis(5-chloro-2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylenediamine N,N'-bis(salicylidene)ethylenediamine N,N'-bis(5-bromoosalicylidene)ethylenediamine N,N'-bis(5-cMorosalicylidene)ethylenediamine linear trien-based amine phenol linear tnentn-based amine phenol pyridine amine phenol 2-(2-hydroxyphenyl)-1,3-di[3-aza-4-(2-hydroxy-5-chlorophenyl)-prop-4-en-l-yl]-l,3-imidazolidine 2-(5-bromo-2-hydroxy-phenyl)-l,3-di[3-aza-4-(5-bromo-2-hydroxy-phenyl)-prop-4-en-1 -yl] -1,3-imidazolidine 2-(5-chloro-2-hydroxy-phenyl)-l,3-di[3-aza-4-(5-chloro-2-hydroxyphenyl)-prop-4-en-l-yl]-l,3-imidazolidine 1,1,1 -tris(((salicylidene)imino)methyl)ethane 1,1,1 -tris(((5-bromosalicylidene)imino)methyl)ethane 1,1,1 -tris(((5-chlorosalicylidene)imino)methyl)ethane 1,1,1 -tris(((2-hydroxybenzyl)amino)methyl)ethane 1,1,1 -tris(((5-bromo-2-hydroxybenzyl)amino)methyl)ethane 1,1,1 -tris(((5-chloro-2-hydroxybenzyl)amino)methyl)ethane N,N',N"'-tris(2-hydroxybenzyl)-triethylenetetramine xvii 1,1,4-H3Xbtt N,N,N'"-tris(2-hydroxybenzyl)triethylenetetrarnine H 3 X T A M tripodal tame-based amine phenol H 3 X T A P tripodal tap-based amine phenol H 3 X T R N tripodal tren-based amine phenol H 6 T R N S sulfonated tren-based amine phenol H 6Sbbpen 2+ N,N'-bis-(2-hydroxy-5-sulfonylbenzyl)-N,N'-bis(2-methylpyridyl)ethylenediamine HgSbad2"1" l,10-bis(2-hydroxy-5-sulfonylbenzyl)-l,4,7,10-tetraazadecane HgSbadd2+ 1,12-bis(2-hydroxy-5-sulfonylbenzyl)-1,5,8,12-tetraazadodecane HBED N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'diacetic acid HETCOR heteronuclear correlation (NMR) h hour(s) HS A B hard and soft acids and bases Hz hertz IR infrared IT internal transition (mode of radioactivity decay) J coupling constant keV kilo-electron volt L litre(s); ligand log |3 stability constant LSEMS liquid secondary ion mass spectrometry |X micro- (10~6); ionic strength (stability constant studies); prefix for a ligand bridging over two metal centers l^ eff magnetic moment in B M D stretching vibration (IR) m milli-(IO- 3); multiplet (NMR); moderate (IR); metastable (isotope) M molarity; mega- (106) xviii mV millivolt m/z mass-to-charge ratio (in mass spectrometry) MeOH methanol min minute(s) mol mole mp melting point nm nanometer N N M R nuclear magnetic resonance (NC>2salH2)3tach triply deprotonated l,3,5-cis-tris((2-hydroxy-5-nitrobenzyl)-amino)cyclohexane NOTA l,4,7-triazacyclononane-l,4,7-triacetic acid NTA nitrilotriacetic acid Q. ohm ORTEP Oak Ridge Thermal Ellipsoid Program pD negative log of the concentration of deuterium ion PET positron emmission tomography penten N,N,N',N'-tetrakis(2-aminoethyl)ethylenediamine p K a negative log of the equibilibrium constant K a pH negative log of the concentration of H+ PLED N,N'-dipyridoxylethylenediamine-N,N'-diacetic acid pM negative log of the concentration of uncomplexed (or free) metal ion at a particular pH ppm parts per million (NMR) s singlet (NMR); strong (IR) (salH2)3tach triply deprotonated l,3,5-cis-tris((2-oxybenzyl)amino)-cyclohexane Sbbpen 4 - sulfonated pyridine amine phenolate with deprotonated phenolate and sulfonyl oxygen atoms, amine, and pyridine, nitrogen atoms xix Sbad 4 - sulfonated trien-based amine phenolate with deprotonated phenolate and sulfonyl oxygen atoms, and amine nitrogen atoms Sbadd 4 - sulfonated tnentn-based amine phenolate with deprotonated v phenolate and sulfonyl oxygen atoms, and amine nitrogen atoms SHBED N,N'-bis(2-hydroxy-5-sulfonylbenzyl)ethylenediamine-N,N'diacetic acid t triplet (NMR) T temperature ti/2 half-life of a radionuclide td triplet of doublets (NMR) Td tetrahedral tame l,l,l-tris(aminomethyl)ethane tap 1,2,3-triaminopropane TEAP tetraethylammonium perchlorate 2.3.2- tet N,N'-bis(2-aminoethyl)-l,3-propanediamine 3.3.3- tet N,N'-bis(3-aminopropyl)-l,3-propanediamine Tf transferrin THF tetrahydrofuran TMS tetramethylsilane tnentn N,N'(3-amihopropyl)ethylenediamine 1 tpen N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine trien triethylenetetraamine tren N,N',N"-tris(aminoethyl)amine T X - T A C N H 3 1,4,7-tris(3,5-dimethyl-2-hydroxybenzyl)-1,4,7-triazacyclo-nonane N-U V ultraviolet vs very strong (IR) VT variable temperature xx X wavelength (UV) ^ m a x wavelength at peak maximum (UV) w weak (IR) X T A M 3 " tame-based amine phenolates XTAP 3 " tap-based amine phenolates X T R N 3 - tren-based amine phenolates Xbad 2 - trien-based amine phenolates Xbadd2" tnentn-based amine phenolates Xbbpen 2 - pyridine amine phenolates xxi Acknowledgments It is with great pleasure that I thank Dr. Chris Orvig for his continuous support, guidance, encouragement, and patience throughout the course of my studies, as well as for fostering independence of thought and freedom of individual action in his research group. His support and encouragement during times of self-doubt was greatly appreciated. I am also particularly grateful to Dr. Shuang Liu for our collaborative research efforts and many helpful discussions about chemistry, and life in general. I also thank Dr. Steven Rettig for his meticulous determination of the majority of the X-ray crystal structures reported herein. Thanks to all members of the Orvig team, past and present, especially to Ying, Martha, Nick and all members of the "harmonious coffee break" crowd (Ashley, Andreas, Ed, Ika, Jolly Roger, Mark, Marco, Paul, Pete, and Yan). A special thank you goes to Dr. Lucio Gelmini for his friendship, and helpful discussion about chemistry, and life. For their time, careful proofreading and helpful suggestions, I would like to thank Ashley, Andreas, Ika, Mark, Marco and Pete. In addition, a special thank you goes to my friends and comrades, who have always stood by me during the good times and the bad. v Acknowledgment is made to Dr. F. Ekkehardt Hahn and Thomas Lugger (Institut fur Anorganische und Analytische Chemie der Freien Universitat Berlin) for the determination of the crystal structure of [Ga(Brbad)]C104-DMSO. Acknowledgment is also made to the department suppport staff, most notably Mrs. Marietta Austria, Mrs. Liane Darge and Mr. Peter Borda as well as the technical staff of the mass spectrometry laboratory. xxii / dedicate this thesis to my parents, my brother and sister, and to my wife, Elizabeth, with much Love xxiii Chapter One Introduction 1.1. General Introduction The beginning of nuclear medicine can be traced back to 1901 when the French physician, Henri Danlos treated skin lesions with naturally occurring radium.1 Several years later, Blumgart et al. used intravenously administered radium to monitor blood circulation times in humans.2 This was the first radiotracer study performed on humans and it heralded the advent of radionuclides in diagnostic medicine. Despite these early activities, nuclear medicine began to develop rapidly only after the construction of cyclotrons and nuclear reactors in the 1930s and 1940s. These facilities artificially produced a variety of nuclides that have potential applications in either diagnostic or therapeutic nuclear medicine. Today, there are approximately 35 radionuclides that are approved for such medical use. Chemical substances containing radionuclides that are suitable for use in nuclear medicine are known as radiopharmaceuticals. They are formulated and administered in a variety of chemical and physical forms so that they can be directed to a specific organ or tissue. The majority of the radiopharmaceuticals available today (-95 %) are designated for use in the diagnosis of disease,3 though a few are available for therapeutic uses. This is most likely because of the less rigid requirements for diagnostic agents compared to those for therapeutic agents. Therapeutic nuclear medicine requires the radiopharmaceutical to either be highly localized in the tissue of interest and/or be secreted from the body completely. This is because therapeutic agents often involve a nuclide that emits a or (3 particles of relatively high energy, and poses a greater radiation hazard to the patient than diagnostic agents, which are usually administered only once for a course of study. 1 Early developments in nuclear medicine were dominated by medical researchers, who were not particularly interested in the chemistry of the radiopharmaceuticals. For many years, the chemical structures and solution chemistry of many of the imaging agents were not well understood and the agents were discovered by trial and error. However, during the past 20 years, chemists, pharmacologists and medical researchers have worked together to improve and develop new radiopharmaceuticals based on a solid foundation of physiology and pharmacology, as well as structural and solution chemistry. The selection of an appropriate radionuclide is the first step in any radiopharmaceutical development. The criteria for its selection are decay half life, modes of decay, energy of the emitted radiation, availability and cost of the nuclides. In diagnostic nuclear medicine, it is desirable to have radionuclides that emit only y rays or X-rays in the energy range of 100-200 keV. Emission of a and (3 particles can cause radiation damage to the patient as a and P particles often do not have sufficient penetration power to escape from the body, and are instead absorbed by the tissue or organ in which the pharmaceutical is localized. In this respect, a and (3 emitting radionuclides are more suited to the treatment of diseases rather than their diagnosis. Gamma rays and X-rays of 100-200 keV are ideal for diagnostic nuclear medicine because the photons have sufficient energy to escape from the body with minimum scattering and absorption but yet they are low enough in energy for detection with an external gamma camera. The half-life of the radionuclide is also an important consideration since it must be sufficiently short to avoid exposing the patient to excessive radiation but yet long enough to allow the imaging procedure to be carried out in a reasonable length of time. Finally, with the rising cost of health care, the availability and cost of the nuclide will also play an important role in the selection of a suitable candidate. Of the elements known to mankind today, there are twenty elements that have isotopes of interest to diagnostic nuclear medicine. 4 3 The most logical approach to designing a radiopharmaceutical is to replace atoms in a naturally occurring biological molecule with suitable radioisotopes. This results in a compound that is physiologically identical to the nonradioactive parent. As biological molecules consist mainly of carbon, hydrogen, nitrogen and oxygen, 2 isotopes of these elements would be ideal candidates. Much effort has been directed at incorporating the positron emitters  nC, 1 3 N , 1 8 F and 1 5 0 into diagnostic radiopharmaceuticals5 - but their short half-lives ( n C , ti/2 = 20.3 min; 1 3 N , ti/2 = 9.97 min; 1 5 0 , t i / 2 = 2.1 min; 1 8 F , ti/2 = 1.8 min) and limited availability restrict their widespread use. Other nuclides with nuclear properties (Table 1.1) that are suitable for use in diagnostic radiopharmaceuticals are the metal isotopes, 6 7 G a , 6 8 G a , m I n , 1 1 3 m I n , 99mxc, I69yb, 5 7 C o , 5 8 C o , 2 0 1 T 1 , and 5 1 C r . It should be noted that 5 8 C o and 6 8 G a are positron ((3+) emitters. They produce two Y photons of 511 keV from positron annihilation and are utilized in positron emission tomography (PET). As most metal radionuclides are not indigenous to the human body, it is usually necessary to coordinate them with appropriate organic ligands or to tag them to carrier molecules such as antibodies. Coordination of these metal with appropriate ligands, or tagging them to carrier molecules, allows them to be directed to a particular organ, receptor or Table 1.1 Nuclear properties of metal radionuclides used in diagnostic nuclear medicine. Radionuclide Decay Mode 3 Half-lifeb Gamma Photon15 (tl/2) Energy (keV) 51Cr EC 27.7 days 320 57Co EC 270.0 days 122,' 136 58Co EC, p+ 71.3 days 811, 511 6 7 G a EC 78.1 h 93, 185, 300 6 8Ga P + 68.3 min 511 99mx c IT 6h 140 U l l n EC 2.8 days 172, 247 113mjn r r 99.4 min 392 169yb EC 32 days 120 201-n EC 73.0 h 69, 71, 80 (X-rays) a EC = electron capture; IT = isomeric transition; p + = positron emission b reference 4b. 3 tissue of interest. Administration of metal complexes as opposed to naked metal ions should also prevent the coordination of the metal by naturally occurring biological molecules, which would alter the biodistribution of the imaging agent. Investigation into the applications of Ga radionuclides to nuclear medicine began in the late 1950s with studies examining the use of 7 2 G a in the diagnosis and therapy of malignant bone lesions;6"9 however, it was not until the late 1960s, with the discovery of 6 7 G a citrate localizing in soft tissue tumors, that research with Ga radionuclides really advanced. l u It is interesting to note that although much work has gone into the development of Ga radiopharmaceuticals, 6 7 G a citrate is still the only commercially available Ga radiopharmaceutical today. 1 1" 1 3 It is widely used in the detection and imaging of tumors and inflammatory lesions. 1 4 - 1 6 In recent years, other possible medical applications of Ga compounds have also been evaluated. G a 3 + metal complexes with ligands possessing N-heterocycles were considered as potential antitumour and antiviral agents,17 and Ga nitrate was recently approved in the United States for the treatment of hypercalcemia of malignancy.18 Interest in the use of In isotopes in nuclear medicine began in the 1960s with the goal of using short-lived nuclides in the administration of radiopharmaceuticals with a larger dose of radioactivity.4 0 m I n and 1 1 3 m I n w e r e considered for such use. At present, 1 1 1 I n - D T P A and 1 1 1In-oxine (tris(8-hydroxyquinolinato)indium(III)) are widely used in the imaging of tumors and inflammatory lesions, 1 9 and for labeling blood cells (leukocytes, erythrocytes and platelets). 4 d> 2 0 U 1 l n radiopharmaceuticals are also used in the covalent attachment of bifunctional chelates to specific monoclonal antibodies directed against tumor associated antigens. 2 1" 2 4 No 1 1 3 m I n radiopharmaceuticals are used in clinics at present; although 1 1 3 m i n has been considered for use in imaging the brain, the liver and cardiac output. Gallium and indium are group 13 metals that are found in only trace quantities in the Earth's crust and are not known to have any natural biochemical functions. Review articles of Q a25-29,30a,3l a n ( j in29,30b,32 chemistry have appeared over the years, and the stability constants of a number of G a 3 + and I n 3 + complexes have been tabulated. 3 3 Although 4 compounds with Ga and In in +1 and +2 oxidation states are known, chemistry relevant to radiopharmaceuticals is limited to the +3 oxidation state. Hexa(aquo)gallium(III) and hexa(aquo)indium(ffl) cations exist in acidic aqueous solution but undergo a complex series of hydrolysis processes to produce monomeric and polymeric oxo/hydroxyl compounds as the pH is raised. 3 4 Unlike In hydroxide, Ga hydroxide is amphoteric, dissolving in alkaline as well as acidic solutions. Ga(OH)3 precipitates as the pH is raised but redissolves as anionic Ga(OH)4" at alkaline pH. In the design of Ga and In diagnostic imaging agents, the hydrolysis of G a 3 + and I n 3 + has a very practical importance in that the pH range at which the compounds can be prepared without precipitation or hydrolysis of Ga and In is very limited. Equally important is that if Ga and In metal complexes are to be used in vivo, they must be kinetically inert toward demetallation and/or thermodynamically stable toward hydrolysis at physiological pH. Another factor that must be considered in the design of Ga and In radiopharmaceuticals is the strong binding of G a 3 + and I n 3 + to transferrin. The transferrins are a class of monomeric glycoproteins that are responsible for the transport of iron in mammalian blood. 3 5 " 3 6 They have two binding sites that bind tightly, but reversibly, to F e 3 + . 3 7 ' 3 8 Crystallographic structural analyses of various transferrins have shown F e 3 + in each site to be coordinated by two tyrosinate residues (phenolate oxygen atoms), one histidine residue (imidazole nitrogen atom), one aspartate residue (carboxylate oxygen atom) and a carbonate ion, which is coordinated in a bidentate manner. 3 9 ' 4 0 Besides F e 3 + , transferrin also has a high binding affinity for a variety of metal ions including the trivalent group 13 metals. Summarized in Table 1.2 are the binding constants of A l 3 + , G a 3 + , I n 3 + and F e 3 + to human serum transferrin,4 1"4 4 plus the ionic radii of these trivalent metal ions. The large binding constants of G a 3 + and I n 3 + with the bilobal two-sited human transferrin, coupled with the high concentration of vacant binding sites in human blood (~ 50 |J.M) make transferrin a powerful scavenger of these metal ions. In vivo, Ga and In metal complexes must be stable with respect to demetallation by transferrin. Hence, in the design of radiopharmaceuticals, competition with transferrin for trivalent metal ions is of utmost importance. 5 Table 1.2. Human serum transferrin binding constants3 for trivalent metal ions. Trivalen Metal Ions F e 3 + A l 3 + G a 3 + I n 3 + Ionic radius (A)f 0.645 0.535 0.62 0.80 log Pi ( [ H C O 3 I , mM) 22.7 (27)b 13.5(5)° 20.3(27)d 18.52 (5)e l o g p 2 22.1b 12.5c 19.3d 16.64« 3 pH = 7.4, 25 °C, b reference 41, c reference 42, d reference 43, e reference 44. f six-coordinate ionic radius, reference 45 Ligand Design As discussed earlier, for metal complexes to be considered as potential diagnostic radiopharmaceuticals, they must be kinetically inert to demetallation and/or thermodynamically stable toward hydrolysis at physiological pH. They must also be stable with respect to demetallation by the human blood serum protein transferrin. To achieve these objectives, multidentate ligands that form 5- and 6-membered chelate rings upon coordination to a metal are utilized. As a general rule, the chelate effect predicts that complexes with one or more 5- and/or 6-membered chelate ring are more stable than similar complexes that lack some or all of these rings. Hence, multidentate chelating ligands have the potential of forming complexes of high stability. It is also well known that the chelate effect weakens as the chelate ring size increases. The decrease in stability of metal complexes with 6-membered chelate rings relative to corresponding complexes with 5-membered rings is well known. In addition, it has been postulated that complex stability is also closely related to the size of chelate rings and the size of the metal i o n . 4 6 - 4 8 The larger the metal ion, the greater the destabilization in the metal complex as the size of the chelate ring increases from five to six. Since G a 3 + (0.62 A ) 4 5 is smaller than I n 3 + (0.80 A ) , 4 5 it may be possible to utilize this concept of metal ion size and chelate ring size to design multidentate ligands that would show selectivity for one metal ion over another. In addition to having the ability to form complexes of high stability, multidentate chelating ligands can also form complexes with slow ligand exchange kinetics. Metal complexes 6 with multidentate ligands tend to undergo slower ligand exchange processes than those with monodentate ligands because the multidentate ligands are coordinated to the metal via two or more donor atoms and the exchange of a multidentate ligand often involves a stepwise unwrapping of the coordinated ligand, and the opening of chelate rings. If the rate of demetallation or ligand exchange is sufficiently slow compared with the time required to perform the medical procedure, a thermodynamically unstable metal complex may still be useful as a radiopharmaceutical. In the past several years, our group has investigated the coordination of a number of bidentate ligands that formed bis- or tris-ligand complexes with group 13 , 4 9 " 5 7 Re, and T c 5 8 " 6 0 metal ions. To broaden the understanding of the coordination of multidentate chelating systems to metals of radiopharmaceutical interest, an investigation into the coordination of potentially hexadentate ligands with trivalent group 13 metal ions has been undertaken. These potential ligands would provide six donor atoms within a single ligand framework and would encapsulate or surround the metal ion to form binary mono ligand metal complexes. As the six donor atoms are within a single framework and would surround or encapsulate the metal ion, the resulting complexes are expected to be less susceptible to hydrolysis, demetallation, or ligand exchange reactions than bis- and tris-ligand complexes. In addition, the binding selectivity of these potentially multidentate ligands can be altered subtly by having the ligand enforce a specific spatial arrangement of donor atoms (i.e. preorganization of the donor atoms).61 Selectivity of multidentate ligands for metal ions, mode of coordination to metal ions and stability of metal complexes are all affected by the type of donor atoms available for coordination. By selecting appropriate donor atoms, ligands can be tailored to a particular metal or group of metals. In accordance with Pearson's HSAB principle, 6 2" 6 5 G a 3 + and I n 3 + are hard metal ions and should coordinate well with ligands having hard donor atoms, such as negatively charged oxygen atoms (carboxylate, phenolate and catecolate oxygen atoms), and neutral nitrogen atoms (amine, imine, pyridine, imidazole, oxazoline and thiazoline nitrogen atoms). G a 3 + and I n 3 + are known to have a strong binding affinity toward anionic oxygen atoms and neutral amine nitrogen atoms. 4 7 > 6 6 , 6 7 The coordination chemistry of G a 3 + and I n 3 + with 7 multidentate ligands incorporating hydroxy, amino, pyridine, carboxylate and catechol moieties has been extensively explored in the pursuit of new radiopharmaceuticals. 2 9 ' 6 8" 8 8 Tris(8-hydroxyquinolinato)indium(III), with a N3O3 coordination sphere, is presently used as a diagnostic radiopharmaceutical. 2 9 ' 8 9 ' 9 0 Tris(8-hydroxyquinolinato)gallium(III), which also has a N3O3 coordination sphere, is being considered in positron emission tomography. 8 9 ' 9 0 Highly stable G a 3 + and I n 3 + complexes with multidentate polyamino polycarboxylate,3 3 polyamino polyphenolate 7 3 ' 9 1" 9 3 and Schiff base 8 5 " 8 7 ' 9 4 " 9 7 ligands have also been reported. These studies all indicate anionic oxygen atoms and neutral nitrogen atoms as good donor atoms for coordination to group 13 metal ions. Hence, anionic phenolate oxygen atoms and neutral amine nitrogen atoms were selected as potential donor atoms in a series of potentially multidentate ligands, which will now be referred to collectively as amine phenols or as the amine phenolates in their deprotonated form. Tripodal and linear amine phenolate were chosen as potential chelating ligands for the preparation of highly stable and/or kinetically inert group 13 metal complexes. Amine phenolate are versatile ligands which provide potential coordination sites via both neutral amine nitrogen atoms and anionic phenolate oxygen atoms. Compared to the imine CH=N linkages in Schiff bases, the C H 2 - N linkages in amine phenols are less susceptible to hydrolytic decomposition and also provide a greater overall flexibility to the molecules. This increased flexibility allows the ligands to adjust to the steric demands of the metal ion and hence to contribute to the overall stability of the metal complexes. Lipophilicity of the metal complexes with amine phenolate can be easily modified by adding substituent groups on the aromatic rings or on the amine backbone. This preserves the coordination environment around the metal, while possibly altering the overall charge and biodistribution of the complexes. Amine phenols may also act as bifunctional chelates since their attachment to antibodies or other biologically important molecules can be made at the aromatic rings or at the amine backbone. Investigations into the coordination chemistry of trivalent group 13 metal ions with multidentate amine phenolates began with the set of potentially heptadentate tripodal tren-based amine phenolates, XTRN 3" (Figure l . l ) . 9 8 XTRN 3" has seven potential coordination sites via 8 X T R N 3 ' (X=H, Br, CI) Ga-N 40 2 I11-N4O3 Figure 1.1. Coordination of tren-based amine phenolate (XTRN 3 - ) to trivalent group 13 metal ions. 9 four amine nitrogen atoms and three phenolate oxygen atoms. The coordination behavior of the group 13 metal ions with XTRN 3 " amine phenolates was affected by the electronic and steric demands of the bound metal ion. The hard A l 3 + ion coordinated to XTRN 3 " amine phenolates via a N3O3 donor atom set, forming a monocationic complex, while G a 3 + was coordinated via a N4O2 donor atom set, also forming a monocationic complex (Figure 1.1). The larger and softer I n 3 + ion coordinated through all seven donor atoms, forming a neutral complex. As an extension of this study, a series of tripodal and linear amine phenols based on different amine backbones was prepared (Figure 1.2). These amine phenols have different donor atom sets and they coordinate to metal ions to form different numbers of 5- and 6-membered chelate rings. These small variations in donor atom set and spatial arrangement of the donor atoms can have subtle effects on the selectivity of multidentate ligands and on the stability of the resulting complexes. In the case of F^Xbbpen amine phenols (Figure 1.2), pyridine nitrogen donor atoms were introduced to examine what effect this would have on the selectivity of the amine phenols and on the stability of the group 13 metal complexes. While this thesis work was in progress, biodistribution studies with 6 7 G a and 6 8 G a Schiff base analogs of XT A M 3 " and Xbadd3" were reported 8 5" 8 7 and showed these complexes to have good myocardial uptake and retention. Green and co-workers have shown these Ga Schiff base complexes to have potential as myocardial imaging agents; however, these complexes may be prone to hydrolytic decomposition, most likely via the imine CH=N linkages in the Schiff base ligands. Metal complexes with amine phenolates should show similar biodistribution patterns as the metal Schiff base complexes but would be less susceptible to hydrolytic decomposition. Although the amine phenols were initially designed for coordination to group 13 metal ions, they may also prove to be good ligands for Tc and Re metal ions. Tc chemistry is of great interest to nuclear medicine because 99mj c n a s n u c i e a r properties (Table 1.1) that are ideal for application to diagnostic nuclear medicine. The short decay half-life and the emission of y photons of 140 keV make it an ideal radionuclide for use in diagnostic radiopharmaceuticals; however, these nuclear properties of 99mT c a r e a hindrance in macroscopic studies of Tc 10 H 3 XTRN H 3 XTAM H Figure 1.2. Tripodal, linear and pyridine amine phenols 11 chemistry. To circumvent this problem, macroscopic studies are performed using the low energy (3-emitting " T c , which has a substantially longer half-life (ti/2 = 2.12 x 10 5 years) than 99nrT/c Reviews of Tc coordination chemistry and Tc radiopharmaceuticals have appeared over the yea r s . 1 8 - 9 9 " 1 0 4 Investigations of Re coordination chemistry are often performed in conjunction with Tc studies since Re possesses similar chemical properties to those of Tc, and Re atoms provide a nonradioactive alternative to Tc isotopes. Re complexes are also of interest to therapeutic nuclear medicine because of the favorable nuclear properties of 1 8 6 R e and 1 8 8 R e . Tc(V) and Re(V) complexes with tetradentate and pentadentate amine phenols have been reported. 1 0 5" 1 1 1 The coordination of Tc and Re metal ions to XT A M 3 " amine phenolates was studied to explore the suitability of amine phenolates for coordination to Tc and Re metal ions in intermediate oxidation states. ' c The main purpose of this project was to study the coordination chemistry of group 13 metals with potentially hexadentate amine phenolates. The possibility of adjusting the selectivity of multidentate amine phenols for various group 13 metal ions by altering the arrangement of the donor atoms and the type of atoms in the donor set was investigated. The feasibility of using the amine phenolates as ligands for coordination to Tc and Re in intermediate oxidation states was also studied by examining their coordination with XT AM 3 " amine phenolates. This project is part of an overall effort by our group to develop Ga, In and Tc complexes that have potential as diagnostic radiopharmaceuticals. Although no A l radionuclides are suitable for use in nuclear medicine, coordination of A l 3 + with amine phenolate was studied as part of a goal to elucidate a relationship between the coordination behaviour of the amine phenolate and the steric arid electronic demands of the metal ions as they vary down the group from A l 3 + to G a 3 + to I n 3 + . Group 13, Tc and Re metal complexes with tripodal tame-based amine phenolate (XTAMC) are described in Chapter 2 and 3, respectively. The Ga and In complexes with linear amine phenolates (F^Xbad2" and Xbadd 2) are described in Chapter 4. Ga and In omplexes with pyridine amine phenolate (Xbbpen2") are described in Chapter 5. Chapter 6 presents the aqueous stability constants and p M values of Ga and In complexes with sulfonated linear and 12 pyridine amine phenolate. General conclusions and suggestions for future work are discussed in Chapter 7. 1.2 References. 1. Grigg, E. R. N . 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Introduction Amine phenolates are versatile multidentate ligands that provide potential coordination sites via both neutral amine nitrogen atoms and anionic phenolate oxygen atoms. The coordination behaviour of amine phenolates is dependent upon the steric and electronic demands of the bound metal ions. This is demonstrated in the coordination of the potentially heptadentate N4O3 tren-based amine phenolates (XTRN3") to trivalent group 131 (Figure 1.1) and lanthanide metal ions. 2- 3 For trivalent lanthanide ions (six-coordinate ionic radii: 1.17 A for L a 3 + t o 1.01 A for Y b 3 + ) , 4 the metals are too large for X T R N 3 - to enclose completely. This results in a number of lanthanide complexes with different coordination geometries and coordination numbers being isolated.2-3 In the case of the smaller A l 3 + and G a 3 + ions (six-coordinate ionic radii: 0.53 A for Al 3 + and 0.62 A for G a 3 + ) , 4 hexacoordinated monocationic A l 3 + and G a 3 + complexes are isolated. The cavity of XTRN 3" appears to be best suited to I n 3 + (six-coordinate ionic radii of 0.80 A); 4 coordination results in neutral heptacoordinated In/N403 complexes. No significant constraints on the coordinated ligand framework are observed in the coordination of I n 3 + by all seven donor atoms of XTRN 3". This is in contrast to A l 3 + and G a 3 + complexes with HXTRN 2" ligands in which the uncoordinated donor atoms may impart certain constraints on the coordinated ligand frameworks: this, in turn lowers the stability of these metal complexes. The aqueous stability constant of the A l 3 + complex with sulfonated tren-based amine phenolate is shown to be lower than those of the G a 3 + and I n 3 + metal complexes.5 Neutral G a 3 + and I n 3 + metal complexes of the macrocyclic-backbone hexadentate N3O3 ligands l,4,7-tris(3,5-dimethyl-2-hydroxybenzyl)-l,4,7-triazacyclononane (TX-TACN) and 20 l,4,7,-triazacyclononane-l,4,7-triacetic acid (NOTA) have been reported. 6 ' 8 These ligands coordinate to the metal via three nitrogen atoms and three pendant anionic oxygen atoms (either phenolate or carboxylate oxygen atoms) to form stable complexes. The stability constants (log p) of the Ga metal complexes with N O T A and T X - T A C N are 30.98(1) and 44.2(1), respectively.9-1 0 The corresponding In metal complexes have stability constants of 26.2(1) and 33.99(3), respectively. 9- 1 0 The N3O3 donor atom sets of T X - T A C N and NOTA satisfy the electronic requirements of the metal ions and contribute to the high thermodynamic stabilities of these metal complexes. A l , Ga and Fe complexes with tripodal N3O3 ligands based on cyclohexanetriamine have also been reported,11 though no stability constants were available for these metal complexes. The uncoordinated donor atoms within A l and Ga metal complexes with HXTRN 2 - may bestow certain steric constraints onto the ligand framework and contribute to the lower stabilities of these complexes compared to the corresponding In complexes. In order to design a ligand that would particularly form very stable complexes with A l 3 + , G a 3 + and I n 3 + , tris(aminomethyl)ethane (tame) is used as the framework for a new series of tripodal amine phenols ( H 3 X T A M , Figure 2.1). Replacing the tertiary N-bridged framework to a C-bridged X H 3 T A M : X=H H 3 C I T A M : X=C1 H3B1-TAM: X=Br Figure 2.1. Tame-based tripodal amine phenols ( H 3 X T A M ) 21 framework releases the constraints impose by the uncoordinated donor atoms and should produce potentially hexadentate N3O3 amine phenolates. H 3 X T A M would have a smaller tripodal cavity than H 3 X T R N and would be better tailored for the smaller group 13 metal ions. Coordination of XT AM 3 " amine phenolates to trivalent group 13 metal ions is expected to yield neutral octahedral complexes. The stereochemical nonrigidity that is characteristic of seven-coordinate complexes 1 2 and was observed in In(XTRN) is not expected in hexacoordinated In(XTAM) complexes. In addition, the replacement of the tertiary N-bridge in H 3 X T R N with a C-bridge in H 3 X T A M will prevent metal complexes with XT A M 3 " amine phenolate from undergoing the intramolecular dissociative inversion process that was present in In (XTRN). Lipophilic neutral G a 3 + complexes with hexadentate Schiff base analogs of XT A M 3 " have been reported. 1 3" 1 5 Biodistribution studies with their 6 7 G a and 6 8 G a complexes show significant myocardial uptake, but potential in vivo decomposition of the Schiff base complexes is a major concern. Compared to the imine CH=N linkages in Schiff bases, the C H - N H functionalities in amine phenols are inert to hydrolytic decomposition and also provide a greater overall flexibility to the ligand. Ga complexes with tame-based amine phenolates are expected to be more stable with respect to hydrolytic decomposition than their Ga Schiff base counterparts but should still show similar biodistribution patterns. The coordination chemistry of tame-based N3O3 Schiff base ligands with transition metals 1 6" 2 0 and group 13 meta l s 1 5 ' 2 1 ' 2 2 have been investigated; however, the amine phenolate ligands, prepared by the reduction of the Schiff bases, have not been previously reported. The following section describes the syntheses, structures and characterization of a series of tame-based tripodal amine phenols ( H 3 X T A M ) and their A l 3 + , G a 3 + and I n 3 + complexes. This investigation into the coordination of tame-based amine phenolates to group 13 metal ions was done in collaboration with Dr. Shuang Liu (NSERC post-doctoral fellow, 1991-1993). 22 2.2. Experimental Section Materials. Potassium borohydride, lithium aluminum hydride, sodium azide, 2-(hydroxymethyl)-2-methyl-l,3-propanediol, salicylaldehyde, 5-chlorosalicylaldehyde, and 5-bromosalicylaldehyde were obtained from Aldrich. Hydrated Ga and In salts were obtained from Alfa. A l l chemicals were used as received without further purification. 1,1,1-Tris(azidomethyl)ethane was prepared according to literature methods.23 Instrumentation. The following instrumentation was used throughout the work presented in this thesis, unless otherwise indicated. N M R spectra were recorded on Bruker A C -200E (!H, lH-lH COSY and 1 3 C APT NMR), Varian X L 300 ( ! H , V T NMR) , Bruker W H -400 (lH and COSY) and Bruker AMX-500 ( ! H - 1 3 C heteronuclear correlation) spectrometers. Mass spectra were obtained with either a Kratos MS 50 (electron-impact ionization, EI) or a Kratos Concept IIH32Q (Cs + LSIMS) instrument in the positive mode with 3-nitrobenzyl alcohol or thioglycerol as the matrix; only the most intense peaks are listed where envelopes from different isotopes were observed. Infrared spectra were recorded as K B r disks in the range of 4000-400 c m - 1 on a Perkin-Elmer PE 783 spectrophotometer and were referenced to polystyrene. Melting points were measured on a Mel-Temp apparatus and are uncorrected. A l l C, H , N , analyses, unless otherwise indicated, were performed by Mr. Peter Borda on a Carlo Erba instrument in this department. Ligand Syntheses. Caution! The handling of polyazides in large quantities may be i { hazardous. A blast shield was used in reactions involving polyazides. l,l,l-Tris(aminomethyl)ethane (tame). Tame was prepared with some modifications to the reported method. 2 3 To a cold solution (on an ice-bath) of l,l,l-tris(azidomethyl)ethane (16.8 g, 86 mmol) in 200 mL of dry THF was added slowly L iAlH4 (14.0 g, 369 mmol) over a period of 30 min. After the addition was complete, the mixture was refluxed for 24 h. The mixture was cooled to 0 °C and then 8 M NaOH (20 mL) was added slowly to quench excess L i A l H 4 . To the resulting white slurry was added diethyl ether (500 mL) and the reaction mixture was stirred for 30 min. The white precipitate was removed and washed with diethyl 23 ether (2 x 200 mL). The combined filtrate and washings were dried bver anhydrous MgS04. Removal of solvent on a rotary evaporator afforded a pale-yellow oil, 8.6 g (85 %). IR and *H N M R spectra of the crude product were identical with those previously reported.23 This crude product was used without further purification. l , l , l -Tr i s ( ( ( sa l icy l idene) imino)methyI )e thane (H^sal tame). To a solution of salicylaldehyde (3.6 g, 29 mmol) in absolute ethanol (5 mL) was added tame (1.17 g, 10 mmol) in the same solvent (5 mL). In five minutes, a yellow precipitate formed. The mixture was left standing at room temperature for 2-3 h and the solid was then filtered out, washed with diethyl ether and dried in air; the yield was 3.3 g (77 %), mp 134.5-135 °C. Anal calcd (found) for C26H27N3O3: C, 72.71 (72.61); H , 6.34 (6.49); H , 9.78 (9.84). Mass spectrum (EI): m/z = 429 ([C 26H27N 303] +). IR (cnr 1, KBr disk): 3200-2000 (b, "Uo-H), 3000-2800 (m or w, i) C-H ) , 1630, 1580 and 1495 (vs, \>c=N and x>c=c)- *H NMR (200 MHz, CDCI3): 1.16 (s, 3 H), 3.62 (s, 6 H), 6.90 (t, 3 H , 3 / H H = 7.6 Hz), 7.00 (d, 3 H , 3 7 H H = 7.2 Hz), 7.25 (dd, 3 H , 3 / H H = 7.2 Hz, 4 / H H = 3.0 Hz), 7.38 (td, 3 H , 3 / H H = 7.4 Hz, 4 7 H H = 3.2 Hz), 8.38 (s, 3 H), 13.4 (b, s, 3 H). l , l , l -Tr i s ( ( (5-bromosa l icy l idene) imino)rne thyI )e thane ( H ^ B r sal tame). The preparation of l,l,l-tris(((5-bromosalicylidene)imino)methyl)ethane (H3BrsaItame) was similar to the procedure for the preparation of H3saltame. The synthesis employed tame (1.17 g, 10 mmol), 5-bromosalicylaldehyde (6.03 g, 30 mmol) and yielded 5.2 g (78 %). Mp 135-136 °C. Anal calcd (found) for C26H24Br 3N 303: C, 46.88 (47.38); H , 3.63 (3.89); N, 6.31 (6.15). Mass spectrum (EI): m/z = 666 ([C26H 24Br 3N303] +). IR (cnr 1, KBr disk): 3600-2000 (w, -OO-H); 3000-2800 (w or m, \)C-H); 1640, 1575 and 1480 (vs, \)C=N and t>c=c)- L H NMR (200 MHz, CDCI3): 1.08 (s, 3 H), 3.62 (s, 6 H), 6.90 (d, 3 H , 3 / H H = 7.0 Hz), 7.20 (d, 3 H , 4 / H H = 3.0 Hz), 7.40 (dd, 3 H , 3 / H H = 7.2 Hz, 4 / H H = 3.0 Hz), 8.30 (s, 3 H), 13.2 (b, s, 3 H). l , l , l -T r i s ( ( (5 -ch lo rosa l i cy l idene ) imino)me thy l )e thane (H3Cl sa l t ame) . The preparation of l,l,l-tris(((5-chlorosalicylidene)imino)methyl)ethane (H3Clsaltame) was similar to the procedure for the preparation of H3saltame. The synthesis employed tame (1.17 24 g, 10 mmol), 5-chlorosalicylaldehyde (4.7 g, 30 mmol) and yielded 4.5 g (85 %). Mp 123-124 °C. Anal calcd (found) for C26H24CI3N3O3: C, 58.61 (58.28); H, 4.54 (4.66); N, 7.89 (7.88). Mass spectrum (EI): m/z = 531 ([C26H24Cl3N303]+). IR (cm"1, KBr disk): 3200-2000 (b, -OO-H); 1635, 1577 and 1480 (vs, \)C=N and vC=c)- *H NMR (200 MHz, CDCI3): 1.08 (s, 3 H), 3.62 (s, 6 H), 6.90 (d, 3 H, 3 / H H = 7.2 Hz), 7.20 (d, 3 H, 4 / H H = 3.0 Hz), 7.38 (dd, 3 H, 3 / H H = 7.4 Hz, 4 / H H = 3.0 Hz), 8.30 (s, 3 H), 13.2 (b, s, 3 H). l,l,l-Tris(((2-hydroxybenzyl)amino)methyI)ethane (H3TAM). To a solution of H3saltame (2.15 g, 5 mmol) in methanol (100 mL) was added K B H 4 (1.08 g, 20 mmol) in small portions at room temperature over 30 min. After the addition was complete, the reaction mixture was stirred at room temperature for an additional 2 h. The solvent was removed under reduced pressure. To the residue was added N H 4 O A C (3 g, 40 mmol) in water (50 mL) and the mixture was extracted with chloroform (3 x 100 mL). The organic phases were combined, washed with water, and dried over anhydrous MgS04. The solution was filtered and chloroform was removed on a rotary evaporator to afford a pale-yellow solid. The solid was dried under vacuum overnight; the yield was 1.9 g (87 %), mp 65-68 °C. Anal calcd (found) for C26H36N3O4.5: C, 67.51 (67.70); H, 7.84 (7.74); N, 9.08 (9.07). LSIMS: m/z = 436 ([C26H34N303]+, [M+l]+). IR (cm"1, KBr disk): 3300 (m, D N H ) ; 3600-2000 (m, \ ) 0 H); 3100-2800 (m or s, \>CH); 1615 and 1592 (s, 5 NH); 1490-1420 (vs, i)c=c)- : H and 1 3 C NMR spectral data are given in Table 2.1 and 2.2, respectively. l,l,l-Tris(((5-bromo-2-hydroxybenzyl)amino)methyI)ethane (H^BrTAM). A procedure similar to that for H 3 T A M was followed using H3Brsaltame (3.33 g, 5 mmol) in hot methanol (150 mL) and K B H 4 (1.08 g, 20 mmol); the yield was 2.50 g (73 %), mp 65-67 °C. Anal calcd (found) for ( ^ 3 4 6 ^ 3 0 5 : C, 44.09 (44.29); H, 4.84 (4.60); N, 5.93 (5.73). LSIMS: m/z = 673 ([C26H3iBr3N303]+, [M+l]+). IR (cm"1, KBr disk): 3320 (m, u N . H ); 3500-2000 (m, 1)0-H); 1612 and 1582 (s, 8N-H); 1490-1420 (vs, v>C=c)- ! H and 1 3 C NMR spectral data are given in Table 2.1 and 2.2, respectively. 25 Table 2.1. *H N M R data (200 MHz) for tame-based amine phenols, H 3 X T A M (5 in ppm from TMS, CDCI3). (H3) (H4) (X=H7 for H 3 TAM) X (H6) >2 assignment H 3 T A M (X=H) H 3 C I T A M (X=C1) H 3 B r T A M (X=Br) H i 0.94 (s, 3 H) 0.95 (s, 3 H) 0.95 (s, 3 H) H 2 2.40 (s, 6 H) 2.50 (s, 6 H) 2.45 (s, 6 H) H 3 3.82 (s, 6 H) 3.90 (s, 6 H) 3.90 (s, 6 H) H4 6.90 (dd, 3 H ) a 7.00 (d, 3 H ) c 7.10 (d, 3H)c H 5 6.80 (d, 3 H)b 6.70 (d, 3 H)t> 6.65 (d, 3 H)b H 6 7.05 (td, 3 H )3 7.10 (dd, 3 H ) a 7.25 (dd, 3 H)* H 7 6.70 (t, 3 H)b A V H H = 6.8-7.0 Hz, 4/HH = 3.0-3.3 Hz B V H H = 6.8-7.0 Hz C 4 ^ H H = 3.0-3.3 Hz 26 Table 2.2. 1 3 C N M R data (200 MHz) for tame-based amine phenols, H 3 X T A M (5 in ppm from TMS, CDCI3). 1CH, 8 assignment H 3 T A M (X=H) H3CITAM (X=C1) H 3 B r T A M (X=Br) C i . 20.8 20.8 20.8 c 2 38.1 38.1 j 38.0 C3 54.9 53.5 53.5 c 4 53.0 52.6 52.4 c 5 122.4 124.1 124.1 c 6 157.6 156.1 156.7 c 7 116.2 117.5 118.0 c 8 129.0 .128.9 131.4 c 9 119.4 123.5 111.2 C10 128.8 128.5 131.8 27 l , l » l -Tr i s ( ( (5 -ch loro-2 -hydroxybenzy l )amino)methy l )e thane ( H 3 C I T A M ) . A procedure similar to that for H 3 T A M was followed using FJ^Clsaltame (2.66 g, 5 mmol) in hot methanol (150 mL) and KBH4 (1.08 g, 20 mmol); the yield was 2.05 g (76 %) mp 61-63 °C. Anal calcd (found) for C26H30CI3N3O3: C, 57.95 (57.60); H , 5.61 (5.74); N , 7.80 (7.28). LSIMS: m/z = 540 ([C26H3iCl 3 N 3 03]+ [M+l]+). IR (cm" 1, K B r disk): 3320 (m, u N _ H ) ; 3600-2000 (m, 1)0-H); 3100-2800 (m or s, U C -H) ; 1615 and 1590 (s, 5N-H); 1490-1420 (vs, i)C=c)- *H and 1 3 C N M R spectral data are given in Table 2.1 and 2.2, respectively. Synthesis of Metal Complexes. Since many of the syntheses were similar to each other, detailed procedures are only given for representative examples. Syntheses of the metal complexes mainly employed the perchlorate and nitrate salts of the respective metal ions. Caution! Perchlorate salts of metal complexes are potentially explosive and should be handled with care. [A1(TAM)]-6H20. To a solution of A1(C104) 3-9H 20 (245 mg, 0.50 mmol) in methanol (25 mL) was added H 3 T A M (239 mg, 0.55 mmol) in the same solvent (10 mL). After the addition of sodium acetate (164 mg, 2.0 mmol) in methanol (10 mL), the resulting mixture was filtered immediately; slow evaporation yielded pink microcrystals, which were collected by filtration, washed successively with water, cold ethanol and diethyl ether. The yield was 200 mg (70 %). Anal. Calcd (found) for C26H42AIN3O9: C, 55.02 (54.51); H , 7.46 (7.04); N , 7.40 (7.34). L S I M S : m/z = 460 ([ML+1]+, [ A 1 C 2 6 H 3 i N 3O 3] + ), 919 ([2(ML)+1]+, [(AlC26H3oN 3 03)(AlC26H3iN 3 03)] + ) . IR (cm"1, K B r disk): 3700-2700 (b,s), 3260 (m) (\)NH); 1600 (s), 1572 (w) (8NH). *H N M R spectral data are given in Table 2.3. [Al(ClTAM)]. A procedure similar to that for [Al (TAM)] was followed using A1(C104)3-9H20 (245 mg, 0.50 mmol), H 3 C I T A M (296 mg, 0.55 mmol) and sodium acetate (164 mg, 2.0 mmol); the yield was 202 mg (72 %). Anal . Calcd (found) for C26H27AICI3N3O3: C, 55.48 (55.11); H , 4.84 (4.97); N , 7.47 (7.17). LSIMS: m/z = 564 ([ML+1] + , [A1C26H 28C1 3N 303] +). IR (cm"1, KBr disk): 3700-2800 (b,s), 3265 (m) ( u N H ) ; 1600 (s), 1570 (w) (8NH)- ! H N M R spectral data are given in Table 2.3. 28 {[Al(BrTAM)]4[Na(H20)]2}(Cl04)2-6CH3OH-2H20. Solutions of A1(C10 4 ) 3 -9H 2 0 (245 mg, 0.50 mmol) in methanol (25 mL) and of H 3 B r T A M (350 mg, 0.52 mmol). in methanol (5 mL) were mixed. After the dropwise addition of 2 M NaOH solution (1 mL), the solution was filtered immediately; evaporation of solvents afforded pink crystals. These were separated, washed successively with water, ethanol and diethyl ether. The yield was 230 mg (61 %). Suitable crystals were selected for X-ray diffraction studies. Anal. Calcd (found) for C 1 ioHi4oAl4Br 1 2Cl 2 N 1 2Na203o: C, 40.11 (40.05); H , 4.28 (4.07); N , 5.10 (5.23). LSIMS: mlz = 697 ([ML+1J+, [ A l C 2 6 H 2 8 B r 3 N 3 0 3 ] + ) . IR (cm"1, K B r disk): 3700-2800 (b,s), 3270 (m) (-ONH); 1595 (s), 1560 (w) (8NH). *H N M R spectral data are given in Table 2.3. [Ga(TAM)]-3.5 H 2 0 . Solutions of G a ( N 0 3 ) 3 - 9 H 2 0 (209 mg, 0.50 mmol) in methanol (25 mL) and of H 3 T A M (239 mg, 0.55 mmol) in the same solvent (10 mL) were mixed. After the addition of sodium acetate (164 mg, 2.0 mmol) in methanol (5 mL), the mixture was filtered immediately. The filtrate was left standing at room temperature to evaporate solvents slowly until pink microcrystals formed. These were separated, washed with ethanol and diethyl ether, and dried in air. The yield was 205 mg (72 %). Anal. Calcd (found) for C26H37GaN3C»6.5: C, 55.24 (55.22); H , 6.60 (6.35); N , 7.43 (7.06). L S I M S : mlz = 503 ([ML+1]+, [ G a C 2 6 H 3 i N 3 0 3 ] + ) , 1005 ([2(ML)+1]+, [(GaC26H3oN303)(GaC26H3iN303)]+). IR (cm - 1 , K B r disk): 3700-3650 (b,s), 3260 (s) (UNH); 1598 (s), 1570 (m) (8NH)- *H N M R spectral data are given in Table 2.3. [Ga(BrTAM)] . A procedure similar to that for [Ga(TAM)] was followed using Ga(N03)3-9H 20 (209 mg, 0.50 mmol), H^BrTAM (370 mg, 0.55 mmol) and sodium acetate (164 mg, 2.0 mmol); the yield was 240 mg (65 %). Anal . Calcd (found) for C 2 6 H 2 7 B r 3 G a N 3 0 3 : C, 42.26 (42.20); H , 3.68 (3.15); N , 5.69 (5.60). LSIMS: m/z = 740 ([ML+1]+; [GaC26H28Br 3 N 3 0 3 ] + ) . IR (cnr*, K B r disk): 3700-3000 (b,m), 3265 (s) (V NH); 1594 (s), 1560 (w) (5NH)- ! H N M R spectral data are given in Table 2.3. [Ga(ClTAM)] . A procedure similar to that for [Ga(TAM)] was followed using G a ( N 0 3 ) 3 - 9 H 2 0 (209 mg, 0.50 mmol), H 3 C1TAM (296 mg, 0.55 mmol) and sodium acetate (164 mg, 2.0 mmol); the yield was 205 mg (68 %). Anal . Calcd (found) for 29 C26H27Cl3GaN 3 0 3 : C, 51.57 (52.00); H , 4.49 (4.63); N , 6.94 (6.73). LSIMS: m/z = 607 ([ML+1]+ [GaC 26H28Cl3N 303] +). IR (cm-1, K B r disk): 3700-3000 (b,m), 3265 (s) (\)NH); 1590 (s), 1560 (w) (6NH). *H N M R spectral data are given in Table 2.3. [In(TAM)]-6H20. Solutions of In(N03)3-6H 20 (204 mg, 0.50 mmol) in methanol (25 mL) and of H 3 T A M H 2 O (239 mg, 0.55 mmol) in the same solvent (10 mL) were mixed. After the addition of sodium acetate (164 mg, 2.0 mmol) in methanol (5 mL), the mixture was filtered immediately. The filtrate was left standing at room temperature to evaporate solvents slowly until pink microcrystals formed. These were separated, washed with ethanol and diethyl ether, and dried in air. The yield was 220 mg (67 %). Anal. Calcd (found) for C 26H42lnN3C»9: C, 47.64 (47.92); H , 6.46 (6.40); N , 6.41 (6.45). L S I M S : m/z = 548 ( [ML+1] + , [InC26H 3iN 303] +), 1095 ([2(ML)+1]+, [(InC26H30N3O3)(InC26H3iN3O3)]+). IR (cnr*, K B r disk): 3700-2800 (b,s), 3265 (s) (\)NH); 1598 (s), 1565 (m) (5NH). x H N M R spectral data are given in Table 2.3. [In (BrTAM ) ] -2H 2 0. A procedure similar to that for [In(TAM)] was followed using In(N03)3-6H 20 (204 mg, 0.50 mmol) , H 3 B r T A M (370 mg, 0.55 mmol) and sodium acetate (164 mg, 2.0 mmol); the yield was 231 mg (56 %). Anal . Calcd (found) for C 2 6 H 3 i B r 3 I n N 3 0 5 : C, 38.08 (38.00); H , 3.81 (3.94); N , 5.12 (5.03). LSIMS: m/z = 785 (ML+1, [InC26H28Br 3N 30 3] +). IR (cnr 1, K B r disk): 3700-2500 (b,m), 3260 (s) (DNH); 1585 (s), 1565 (w) (8NH)- *H N M R spectral data are given in Table 2.3. [In (ClTAM ) ] -3H 2 0. A procedure similar to that for [In(TAM)] was followed using In(N0 3 ) 3 -6H20 (204 mg, 0.50 mmol) , H 3 C 1 T A M (296 mg, 0.55 mmol) and sodium acetate (164 mg, 2.0 mmol); the yield was 204 mg (58 %). Anal . Calcd (found) for C 2 6 H 3 3 C l 3 I n N 3 0 6 : C, 44.31 (44.64); H , 4.72 (4.53); N , 5.96 (5.81). LSIMS: m/z = 652 (ML+1, [InC26H28Cl 3N 303] +). IR (cm - 1 , K B r disk): 3700-3000 (b,m), 3265 (s) CD N H ) ; 1595 (s), 1560 (w) (5NH)- ^ N M R spectral data are given in Table 2.3. 30 X-ray crystallographic analyses of [ G a ( T A M ) ] « 4 . 4 H 2O , [In(TAM)]-4.6H 20, and {[Al(BrTAM)]4[Na(H20)]2}(C104)2-6.2H20. A l l crystal structures presented in this thesis, with the exception of [Ga(Brbad)]C104 were determined by Dr. Steven J. Rettig of the U B C structural chemistry laboratory. ORTEP drawings of the asymmetric unit {[A1(B r T A M ) ] 2 [ N a ( H 2 0 ) ] } C I O 4 in {[Al (BrTAM ) ] 4 [Na(H 2 0)]2}(C104)2, [Ga (TAM ) ] -H 2 0 in [Ga (TAM ) ] -4 .4H 2 0 and [In(TAM)]-H 20 in [In(TAM)]-4.6H 20 are shown in Figure 2.3, 2.4 and 2.5, respectively. Selected bond lengths and bond angles in {[Al(BrTAM)] 4 [Na(H 2 0)]2}(C10 4)2-6.2H20, [ G a ( T A M ) ] - 4 . 4 H 2 0 , and [In(T A M ) ] - 4 . 6 H 2 0 are given in Table 2.4, 2.5 and 2.6, respectively. Crystallographic data and final atomic coordinates (fractional) and Beq (A 2 ) for the non-hydrogen atoms in {[Al(BrTAM)]4[Na(H20)]2}(C104)2-6.2H20, [Ga(TAM)]-4.4H 20 , and [In(TAM)]-4.6H20 are given in Appendix I. 32 2.3. Results and Discussion Tripodal N3O3 Amine Phenols ( H 3 X T A M ) . l,l,l-Tris(aminomethyl)ethane (tame) was prepared in moderate yield according to the previously reported method 2 3 with some modifications. Tripodal N3O3 Schiff bases were prepared from condensation reactions of tame with 3 eq of salicylaldehyde or ring-substituted salicylaldehyde (Figure 2.2). Reduction of these Schiff bases with K B H 4 produced the desired tripodal N3C>3 tame-based amine phenols, H 3 X T A M . These amine phenols were soluble in polar solvents such as chloroform, acetone and methanol, and, unlike the Schiff bases, 1 3 , 1 4 they were hydrolytically stable in solution under both acidic and basic conditions. A l l tame-based amine phenols were characterized by a variety of spectroscopic techniques (IR, N M R and LSIMS) and elemental analyses. Figure 2.2. Reaction scheme for the preparation of H 3 X T A M . The *H and 1 3 C N M R data for H 3 X T A M amine phenols are given in Tables 2.1 and 2.2, respectively. N M R spectral assignments were based on C O S Y and ^ C ^ H HETCOR experiments, 1 3 C APT experiments, and on the N M R spectral data of previously reported amine phenols.1"3 Infrared spectra of the amine phenols showed the disappearance of some bands in the region 1630-1500 cnr 1 , characteristic of the imine C=N bonds in the Schiff bases, and the appearance of two new bands at 1610-1580 cm" 1 from N - H bending vibrations. The lH N M R data showed the disappearance of CH=N hydrogen resonances at ~ 8 ppm and the 33 presence of new benzylic CH2 resonances at ~ 3.8 ppm. These observations confirmed that the reduction of the imine bonds to the CH2 -NH amine linkages had taken place. Elemental analyses and all spectroscopic data were consistent with the proposed tripodal amine phenol formulation. Group 13 Metal Complexes. Neutral A l , Ga and In complexes with XT A M 3 - were easily prepared from reactions of H 3 X T A M with hydrated metal salts in the presence of base (either sodium acetate or sodium hydroxide). The complexes were stable under both basic (no metal hydroxide forms in the presence of sodium hydroxide) and weakly acidic conditions (stable to the acetic acid formed when the metal ion coordinated with the amine phenolate ligand in the presence of sodium acetate). These metal complexes were soluble in DMSO and slightly soluble in methanol. A l l complexes were characterized by spectroscopic techniques (IR, N M R and LSIMS), and elemental analyses. These data were consistent with the proposed formulation of neutral hexacoordinated metal complexes. X-ray crystallographic analyses of {[Al(BrTAM)] 4[Na(H 20)]2}(C104)2-6.2H 20, [Ga(TAM)]-4.4H 20, and [In(TAM)]-4.6H20 were performed and found to be consistent with the proposed formulation (vide infra). In {[Al(BrTAM)]4[Na(H 20)]2}(C104) 2-6.2H20, sodium perchlorate co-crystallizes with the complex [Al(BrTAM)]. A l l complexes showed IR bands in the region 3270-3250 cm" 1 attributable to N - H stretches of the coordinated secondary amine groups, and around 1595-1560 cm" 1 from N - H bending vibrations. Upon coordination to the metal ion, the N - H bending frequencies underwent a general bathochromic shift (-20 cm"1). The observation of broad bands at 3600-2500 cm" 1 suggested the presence of hydrogen bonding in most of these complexes. The IR spectrum of {[Al(BrTAM)] 4[Na(H20)]2}(C104)2 showed split IR bands at -1100 cm" 1 and -650 cm"1 from the hydrogen-bonded perchlorate anions. New bands appeared below 600 cm - 1 in the IR spectra of the metal complexes, most likely due to \>M-0 O R ^M-NJ however, assignments of these bands were inconclusive. Mass spectra of all complexes were obtained in a 3-nitrobenzyl alcohol matrix in the positive ion detection mode. In the mass spectrum of {[Al(BrTAM)]4[Na(H20)] 2}(C104)2 34 molecular ions from [Al(BrTAM)+H]+, [Al(BrTAM)+Na] + , [Al 2(BrTAM)2+H]+ and [Al2(BrTAM)2+Na] + were observed. This was consistent with the solid state structural findings. In the spectra of the [M(TAM)J complexes (M - A l , Ga and In), [M(L)+1] +, and [M2(L)2+1]+ ion peaks were observed. The intensity of the [M2(L)2+1]+ ion peaks were lower than the [M(L)+1] + ion peaks. lH N M R spectral data of A l , Ga and In complexes with XT A M 3 * ligands are given in Table 2.3. Except for differences in the aromatic region of the spectra, all the complexes exhibited similar *H N M R spectra; only that of [Ga(TAM)] is discussed as a representative example. ! H N M R spectral assignments were based on i H - 1 ! ! COSY, l3C-lU HETCOR, and 1 3 C APT experiments, and on N M R spectral data of previously studied metal complexes with amine phenolates.1"3 No specific assignments were made for the resonance signals from methylene hydrogens on C3 and C4 of the coordinated amine phenol ligand. In the *H N M R spectrum of H 3 T A M , the two hydrogen atoms on C3 and on C4 were observed to be chemically equivalent (Table 2.1). Thus, in the spectrum of H 3 T A M , there appeared only a singlet at 3.82 ppm from hydrogens on C4, and a singlet at 2.40 ppm from those on C3. Upon coordination of the amine phenolate, XT A M 3 - , to the metal ion (Ga 3 + ) , the singlet at 3.82 ppm appeared as two broad doublets at 3.18 and 4.10 ppm. The singlet at 2.4 ppm became a multiplet at 2.70 ppm. These changes pointed to the non-equivalency of the hydrogens at C3 and at C4 in the coordinated amine phenol ligand. The signals in the aromatic region remained relatively unchanged with only slight shifts upon coordination. These observations clearly demonstrated that the metal complex in DMSO was highly symmetric; all three chelating arms were equivalent. The C3 symmetry of the complex in solution was consistent with the solid state structural findings and was also supported by 1 3 C N M R data, which showed only 10 distinct resonance signals in the 1 3 C spectrum of [Ga(TAM)]. As the N M R spectra of the Ga and In complexes were very similar, variable temperature lH N M R experiments were performed only for A l , Ga and In complexes with T A M 3 " ligands. Except for some minor shifts and slight broadening of the hydrogen resonance signals, no significant changes in the spectral data were observed. The minor shifts and broadening of the 35 signals were probably caused by the thermal vibrations of the coordinated ligand framework. Variable temperature N M R experiments demonstrated the rigid and intact solution structures of the XTAM 3 " metal complexes, even at elevated temperature. X-ray Crystal Structures of Al, Ga and In XT A M 3 - Complexes. A n O R T E P drawing of {[Al(BrTAM)] 2 [Na(H 2 0)]}(C10 4 ) in {[Al(BrTAM)] 4[Na(H 20)]2}(C10 4)2 is illustrated in Figure 2.3; selected bond lengths and bond angles are listed in Table 2.4. There were four {[Al(BrTAM)]4[Na(H 20)] 2}(C104)2 molecules and many disordered waters of hydration in the orthorhombic unit cell. Each {[Al(BrTAM)]4[Na(H20)]2} (004)2 molecule contained 4 [Al(BrTAM)] complexes, two sodium ions and two bridging waters. The {[Al(BrTAM)]4[Na(H20)]2)(C104)2 molecule was centrosymmetric with two water O atoms bridging its two halves. The N a + ion was coordinated by two phenolate O atoms (Na(l)-O(l) = 2.336 A and Na(l)-0(2) = 2.585 A) from one [Al(BrTAM)] complex, one phenolate O (Na(l)-0(4) = 2.334 A) from the other nearest [Al(BrTAM)] complex, and two bridging water O donor atoms (Na(l)-0(7) = 2.389 A and Na(l)-0(7)* = 2.347 A). The perchlorate anion was hydrogen-bonded with 0(8)—H(5) = 2.26 A. Cavities between the hydrogen bonded ion-pairs were occupied primarily by disordered water molecules which were in partially occupied solvent sites and were involved with one another via possible weak hydrogen bonding. The only fully occupied solvent water site was 0(12) - this atom was involved in a reasonably strong hydrogen bond. The A l atom in [Al(BrTAM)] was coordinated to all six donor atoms (a N3O3 donor atom set) in a slightly distorted octahedral coordination geometry with 0 3 occupying one face of the octahedron and N3 occupying the other. The A l - 0 and A l - N distances in each half of the {[Al(BrTAM)]4[Na(H20)]2}(C104)2 molecule were equivalent within experimental error, averaging 1.83 A and 2.09 A, respectively. These values compare well with those in [A1(HTRN)]+, Al(salH2)3tach, and Al(N0 2 salH 2 ) 3 tach complexes in which the A l 3 + cation are also coordinated by a N3O3 donor set in a distorted octahedral geometry.1'1 1 The average of all 36 B r 5 Figure 2.3. ORTEP drawing of the asymmetric,unit {[Al(BrTAM)]2[Na(H20)]}C104 in {[Al(BrTAM)]4[Na(H20)]2} (004)2 showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. 37 Table 2.4. Selected bond lengths (A) and bond angles (°) in {[Al(BrTAM)] 4[Na(H 20)2}-(C10 4 ) 2 -6.2H 2 0. atom atom distance atom atom distance A l l 01 1.838(4) A l l N l 2.090(6) A l l 02 1.842(5) A l l N2 2.075(5) A l l 03 1.820(4) A l l N3 2.083(5) A12 04 1.850(5) A l l N4 2.118(6) A12 05 1.827(5) A l l N5 2.077(6) A12 06 1.827(5) A l l N6 2.085(6) Nal 01 2.336(5) Nal 07 2.389(5) Nal 02 2.585(5) Nal 07a 2.347(5) Nal 04 2.334(5) atom atom atom angle atom atom atom angle 01 A l l 02 92.1(2) 04 A12 05 92.9(2) O l A l l 03 93.7(2) 04 A12 06 92.9(2) 01 A l l N l 92.6(2) 04 A12 N4 91.5(2) O l A l l N2 88.3(2) 04 A12 N5 174.4(2) 01 A l l N3 174.1(2) 04 A12 N6 89.9(2) 02 A l l 03 94.5(2) 05 A12 06 96.4(2) 02 A l l N l 175.0(2) 05 A12 N4 86.7(2) 02 A l l ' N2 92.9(2) ' 05 A12 N5 91.5(2) 02 A l l N3 89.6(2) 05 A12 N6 170.0(2) 03 A l l N l 87.1(2) 06 A12 N4 174.5(2) 03 A l l N2 172.3(2) 06 A12 N5 90.0(2) 03 A l l N3 91.8(2) 06 A12 N6 93.0(2) 38 Table 2.4 cont. atom atom atom angle atom atom atom angle N l A l l N2 85.4(2) N4 A12 N5 85.4(2) N l A l l N3 85.5(2) N4 A12 N6 83.7(2) N2 A l l N3 85.9(2) N5 A12 N6 85.2(2) 01 Nal 02 64.9(1) 02 Na l 07 89.9(2) 01 Nal 04 157.9(2) 02 Nal 0 7 a 167.0(2) O l Nal 07 86.7(2) 04 Nal 07 114.4(2) 01 Nal 0 7 a 105.6(2) 04 Nal 0 7 a 85.4(2) 02 Nal 04 106.6(2) 07 Nal 0 7 a 80.4(2) CI C2 C3 108.5(6) C27 C28 C29 109.1(6) CI C2 C l l 108.6(6) C27 C28 C37 108.6(6) CI C2 C19 109.0(6) C27 C28 C45 109.3(6) C3 C2 C l l 110.1(6) C29 C28 C37 109.4(7) C3 C2 C19 110.5(6) C29 C28 C45 110.3(6) C l l C2 C19 110.2(6) C37 C28 C45 110.2(6) N l C3 C2 112.0(5) N4 C29 C28 111.7(6) N2 C l l C2 112.5(5) N5 C37 C28 112.5(6) N3 C19 C2 111.8(5) N6 C45 C28 112.2(6) a Symmetry operation: 1 - x, y, 3/2 -1 (here and elsewhere). 39 six trans N-Al -O angles was 174° with the largest deviation in 0(5)-Al(2)-N(6) (170°). Bond angles between the apical methyl carbon atom C(l) and the three chelating arms (Figure 2.4, A = 108.9° within 0.6°) suffered little deviation from 109.5°. The bond angles between the three chelating arms (Figure 2.4, B = 110.1° within 0.6°) also showed no significant deviation from Td values. M v A O B (°) C (°) A l 108.9 110.1 112.1 Ga 107.8 111.1 112.8 In 107.0 111.8 114.5 Figure 2.4. Average pendant arm angles (A, B and C) in Ga and In X T A M 3 - complexes An ORTEP drawing of [Ga(TAM)]-H20 is illustrated in Figure 2.5. The selected bond lengths and bond angles are listed in Table 2.5. The complex was neutral with a triply deprotonated N3O3 amine phenol ligand completely encapsulating the G a 3 + ion. Each N 3 and O3 donor set coordinates to the G a 3 + ion in a facial manner to form a slightly distorted octahedral coordination geometry. The distortion of the coordination sphere was most evident in the compression of N-Ga-N angles (average N-Ga-N = 85.5°) and expansion in the O-Ga-0 angles (average O-Ga-0 = 93.2°) from 90°. As a result, the three trans N-Ga-0 angles were 176.8°, 172.5° and 173.9° for 0(1)-Ga(l)-N(2), 0(2)-Ga(l)-N(3) and 0(3)-Ga(l)-N(l), 40 respectively. The Ga-0 distances were equivalent within experimental error averaging 1.92 A while the Ga-N bond lengths were 2.180, 2.127, 2.086, Ga(l)-N(l), Ga(l)-N(2) and Ga(l)-N(3), respectively, averaging 2.13 A. These values fall in the range of 1.900-1.996 A for Ga-O and of 2.097 -2.221 A for Ga-N found in [Ga(HBrTRN)]"1",1 [Ga(TX-TACN)H]+6.7 and Ga[(5-MeO-sal)tame].15 Bond angles between the carbon atom C(l) and the three chelating arms (Figure 2.4, A = 107.8°, within 0.1°) showed a slight lowering from 109.5°. Conversely, bond angles between the three chelating arms (Figure 2.4, B = 111.1°, within 0.3°) were slightly increased from Td values. Figure 2.5. ORTEP drawing of the [Ga(TAM)]H 20 unit in [Ga(TAM)]-4.4H20 showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. 41 Table 2.5. Selected bond lengths (A) and bond angles (°) in [Ga(TAM)]-4.4H 20. atom atom distance atom atom distance Ga l 01 1.916(2) Gal N l 2.180(3) Ga l 02 1.922(2) Ga l N2 2.127(3) G a l 03 1.923(2) Ga l N3 2.086(3) atom atom atom angle atom atom atom angle 01 Ga l 02 92.0(1) 02 G a l N3 172.5(1) 01 Gal 03 93.5(1) 03 Ga l N l 173.9(1) 01 Gal N l 89.4(1) 03 Gal N2 89.1(1) 01 Gal N2 176.8(1) 03 Ga l N3 92.2(1) O l Ga l N3 91.5(1) N l . Ga l N2 87.9(1) 02 Ga l 03 94.2(1) N l Ga l N3 82.3(1) 02 Gal N l 91.1(1) N2 Ga l N3 86.4(1) 02 Gal N2 89.8(1) C3 C2 C l l 111.0(3) CI C2 C3 107.6(1) C3 C2 C'19 110.7(3) CI C2 C l l 107.4(1) . C l l C2 C19 111.6(3) CI C2 C19 108.3(1) N3 C19 ^ C2 112.9(3) N l C3 C2 113.9(3) N2 C l l C2 111.7(3) [In(TAM)]-H 20 and [Ga (TAM ) ]H 2 0 were isomorphous. An ORTEP drawing of [ In (TAM ) ]H 2 0 is illustrated in Figure 2.6. The selected bond lengths and bond angles are listed in Table 2.6. The complex was neutral with I n 3 + being encapsulated by a triply deprotonated N3O3 amine phenolate ligand in a slightly distorted octahedral geometry with O3 and N3 donors occupying two faces of the octahedron. The In-0 distances in [In(TAM)]-H 20 were 2.098, 2.107 and 2.096 A for In(l)-0(1), In(l)-0(2) and In(l)-0(3) respectively, 1 42 averaging 2.10 A while the In-N bond lengths were 2.330, 2.296, 2.257 A for In(l)-N(l), In(l)-N(2) and In(l)-N(3), respectively, averaging 2.29 A. Both In-O and In-N bond lengths are shorter than those (average: In-0 = 2.169 A and In-N(secondary amine) = 2.330 A) found in [In(TRN)], a complex in which the In atom is coordinated by N4O3 donors.1 Three trans N-In-O angles were 171.6°, 169.6° and 168.7° for 0(1)-In(l)-N(2), 0(2)-In(l)-N(3) and 0(3)-In(l)-N(l), respectively. The average of the O-In-O angles was 95.4° while that of the N-In-N bond angles was 83.2°. Compared with those in [Ga(TAM)]-H20, there were no significant changes in bond angles between the apical carbon atom and the three chelate-bearing arms (Figure 2.4, A = 107.0° within 0.4°) and those at the quaternary carbon atom between chelate arms (Figure 2.4, B = 111.8° within 0.4°); however, the bond angle C in each chelating arm was slightly expanded from Ga complex (Figure 2.4, C = 112.8° within 0.3°) to In complex (Figure 2.4, C = 114.5° within 0.4°). Figure 2.6. ORTEP drawing of the [In(TAM)]H20 unit in [In(TAM)]-6.2H20 showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. 43 Table 2.6. Selected bond lengths (A) and bond angles (°) in [In(TAM)]-4.6H 20. atom atom distance atom atom distance Inl 01 2.098(3) Inl N l 2.330(3) Inl 02 2.107(3) Inl N2 2.296(4) Inl 03 2.096(3) Inl N3 2.257(4) atom atom atom angle atom atom atom angle 01 Inl 02 93.4(1) 02 Inl N3 169.6(1) O l Inl 03 96.4(1) 03 Inl N l 168.7(1) 01 Inl N l 86.9(1) 03 Inl N2 92.0(1) 01 Inl N2 171.6(1) 03 Inl N3 88.2(1) O l Inl N3 95.3(1) N l Inl N2 84.8(1) 02 Inl 03 96.3(1) N l Inl N3 80.6(1) 02 Inl N l 94.4(1) N2 Inl N3 84.3(1) 02 Inl N2 86.2(1) C3 C2 C l l 111.8(4) CI C2 C3 106.5(4) C3 C2 C19 111.2(4) CI C2 C l l 107.3(4) C l l C2 C19 112.3(4) CI C2 C19 107.3(4) N3 C19 C2 114.0(4) N l C3 C2 115.4(4) N2 C l l C2 114.2(4) The bond angles A, B and C (Figure 2.4) can be used as a measure of whether the cavity of the coordinated amine phenol ligand matches the size of the metal ion. In the aluminum complex, these bond angles suffered little deviation from tetrahedral values (within the experimental error). As the six coordinate ionic radii increased from 0.53 A for A l 3 + , to 0.62 A for G a 3 + and 0.80 A for I n 3 + , 4 bond angles between the apical carbon atom and the methylene carbon atoms of the three chelating arms (angles A) were slightly compressed, while the angles 44 B arid C were slightly expanded. Apparently, the cavity in the tame-based N3O3 amine phenolates matched the size of A l 3 + best and the coordinated ligand framework suffered its greatest deformation in the indium complex [In(TAM)]-H20. Stability constant studies will better quantify this fit. The fact that the N3O3 amine phenolates reported in the present study formed six-coordinated complexes with A l 3 + , G a 3 + , and I n 3 + ions suggests that the cavity of tame-based N3O3 amine phenolate was quite flexible through the three chelating arms; this flexibility was evinced by the small changes in the A , B and C angles (Figure 2.4). (There were no significant changes in these angles within the experimental error from the A l complex to the Ga complex and from the Ga complex to the In complex; a slight but significant difference was observed between the A l and In complexes.) The relatively small deformation of the coordinated amine phenol ligand in [In(TAM)]-H20 suggested that coordination to a large metal ion (e.g. In 3 + ) did not impart significant strain on the coordinated ligand framework. This augurs well for the coordination chemistry with tri- or tetravalent first-row (e.g. V 3 + , V 4 + , M n 3 + , F e 3 + and C o 3 + ) and second-row (e.g. T c 3 + and T c 4 + ) transition metal ions. Indeed, the coordination of Tc and Re metal ions with N3O3 X T A M 3 - amine phenolates was investigated and the results are discussed in the next chapter. 45 2.4. References 1. Liu , S.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1992, 31, 5400. 2. Liu , S.; Gelmini, L. ; Rettig, S. J.; Thompson, R. C ; Orvig, C. / . Am. Chem. Soc. 1992,114, 6081. 3. Liu , S.; Yang, L.-W.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1993, 32, 2173. 4. Shannon, R. D. Acta Cryst. 1976, A32, 751. 5. Caravan, P.; Orvig, C. Manuscript in preparation. 6. Moore, D. A . ; Fanwick, P. E.; Welch, M . J. Inorg. Chem. 1989, 28, 1504. 7. Moore, D. A. ; Fanwick, P. E.; Welch, M . J. Inorg. Chem. 1990,29, 672. 8. Craig, A . S.; Parker, D.; Adams, H. ; Bailey, N . A . J. Chem. Soc. Chem. Commun. 1989, 1739 9. Clarke, E. T.; Martell, A . E. Inorg. Chim. Acta 1991,181, 273. 10. Clarke, E. T.; Martell, A . E. Inorg. Chim. Acta 1991,186,103. 11. a)Bollinger, J. E.; Mague, J. T.; Banks, W. A. ; Kastin, A . J.; Roundhill, D. M . Inorg. Chem. 1995,34, 2143. b)Bollinger, J. E.; Mague, J. T.; O' Connor, C. J.; Banks, W. A. ; Roundhill, D. M . J. Chem. Soc. Dalton Trans. 1995, 1677. 12. Greenwood, N . N . ; Earnshaw, A . Chemistry of the Elements; Pergamon Press: Toronto, 1984; p. 1074. 13. Green, M . A. J. Labelled Comp. Radiopharm. 1986,25, 1227. 14. Green, M . A. ; Welch, M . J.; Mathias, C. J.; Fox, A . A . K.; Knabb, R. M . ; Huffman, J. C. / . Nucl. Med. 1985, 26, 170. 15. Green, M . A. ; Welch, M . J.; Huffman, J. C. J. Am. Chem. Soc. 1984,106, 3689. 16. Urushigawa, Y . ; Yuki, M . ; Ishikita, H. ; Inazu, T.; Yoshino, T. Mem. Fac. Sci., Kyushu Univ., Ser. C, 1977,10, 125. 17. Konefal, E.; Loeb, S. J.; Willis, C. J.; Stephan, D. W. Inorg. Chim. Acta 1986, 775, 147. ' 46 18. Flueckiger, J. R.; Schlaepfer, C. W. Helv. Chim. Acta 1978, 61, 1765. 19. Hiraki, K . ; Onishi, M . ; Hamada, K.; Ogata, H . Chem. Lett. 1978, 117. 20. Durham, D. A. ; Hart, F. A. ; Shaw, D. J. Inorg. Nucl. Chem. 1967, 29, 509. 21. Evans, D. F.; Jakubovic, D. A . Polyhedron 1988, 7, 1881. 22. Evans, D. F.; Jakubovic, D. A . / . Chem. Soc. Dalton Trans. 1988, 2927. 23. Fleischer, E. B.; Gebala, A . E.; Tasker, P. A . / . Org. Chem. 1971, 36, 3042. 47 Chapter 3 " T c and Re Complexes with Tripodal N3O3 Tame-based Amine Phenolates 3.1. Introduction Tc complexes with tetradentate, pentadentate and hexadentate Schiff base,1"6 amine oxime 7 ' 8 and amine phenolates9"15 have been reported; neutral nitrogen and anionic phenolate oxygen donor atoms are capable of stabilizing Tc(V), Tc(IV) and Tc(III) metal centers. Crystallographic data show tetradentate amine phenolates based on linear diamines coordinated to Tc(V) to form (i-oxo-bis(oxo) dinuclear complexes 9 The corresponding Re(V) complex also exhibit a similar structure.14 Tc(V) complexes with triamine-based Schiff base ligands are also reported and crystallographic data show the T c 0 3 + moiety coordinated by a N3O2 donor atom set.2 Analogous Re(V) oxo complexes are known but no crystal structures are reported. Tc complexes with amine phenolates are stable in solution for over 24 h. 1 0 " 1 2 > 1 4 ' 1 5 A tren-based potentially heptadentate Schiff base is suspected to coordinate to T c 4 + and R e 4 + metal ions via a N3O3 donor atom set 4 The tertiary apical nitrogen atom is uncoordinated and the Tc(IV) center is reduced to Tc(III) with relative ease (Tc(IV) <-> Tc(ffl), E1/2 = -0.53 V vs Ag/AgN03). Though no crystal structures of either the Tc or Re complexes are available, Hunter et al4 predict a N3O3 octahedral coordination geometry based on the observed crystal structures of analogous G a , 1 6 F e , 1 7 C r 1 8 and M n 1 8 complexes. The crystal structure of [Ga(HXTRN)] + also show a N3O3 distorted octahedral coordination geometry.19 The crystal structure of a Tc(U) complex with a tren-based tripodal ligand 6 possessing pyridine groups also supports the prediction of Hunter et al. Over the past several years, our group has prepared a number of Tc(V) and Re(V) complexes with bidentate ligands containing phosphorus, neutral oxygen and anionic oxygen 48 donor atoms. 2 0 " 2 3 It is our desire to extend our investigation of Tc and Re coordination chemistry by studying the coordination of multidentate amine phenols to lower oxidation state Tc and Re metal centers. Coordination of tame-based amine phenols to group 13 metal ions have shown the tripodal amine phenols to be flexible and able to adjust to the steric demands of the bound metal ions. Considering that the ionic radii of six- coordinate T c 3 + (0.685 A ) 2 4 , T c 4 + (0.645 A ) 2 4 , and R e 4 + (0.63 A ) 2 4 are intermediate to those of G a 3 + (0.62 A ) 2 4 and In3+ (0.80 A ) , 2 4 it is suspected that tame-based amine phenols may coordinate via a N3O3 donor atom set to T c 3 + , T c 4 + , and R e 4 + ions to form stable metal complexes. Preparation of Tc complexes invariably begins with pertechnetate ion (TCO4") as the Tc starting material because both " T c and 99m'xc are commonly available in this form. The oxidation state of Tc in the pertechnetate ion is +7 and preparation of Tc complexes usually requires a reduction of the Tc(VII) center with an appropriate reducing agent. There are two common methods for preparing Tc complexes: the reduction/complexation method and the substitution method. The reduction/complexation method involves the reduction of the Tc(VII) center and the subsequent complexation of the reduced Tc center in a one-pot synthetic reaction. Pertechnetate ions are mixed/heated with excess reducing agent and ligand to produce the desired Tc complex. This method is preferred by the medical community as it requires only a single synthetic step. The substitution method involves two steps: the initial preparation of a simple Tc complex with the Tc center having the desired oxidation state, followed by a ligand exchange reaction to coordinate the new ligand to the pre-reduced Tc center. Tc complexes with precursor monodentate (or weakly bound bidentate) ligands are usually prepared in the first step of the substitution method because these Tc complexes can be easily prepared and the precursor ligands can be substituted easily with the new ligand in the second step of the synthesis. The substitution method is a chemically simple synthetic route compared with the reduction/complexation method. Re complexes can also be prepared via both methods, although it is more difficult to prepare Re complexes via the reduction/complexation method because Re is in general more difficult to reduce than T c . 2 5 49 In this chapter are reported " T c and Re tame-based amine phenolate complexes which were preparedvia both the substitution and the reduction/complexation methods. 3.2. Experimental Section Materials. Tame-based amine phenols ( H 3 X T A M ) were prepared as described previously. 2 6 NH4Re04 was provided by Johnson-Matthey Inc. and NH4 9 9 Tc04 was provided by Du Pont Merck Pharmaceutical Co. K 2 " T c C l 6 2 7 99Tc(S-thiourea)6Cl3 2 8 and K 2 R e C l 6 2 9 were prepared according to previously reported methods. Caution! "Tc is a low-energy (0.292 MeV) emitter with a half-life of 2.12 x 105 years. All manipulations of solutions and solids were performed in a laboratory approved for the handling of low-level radioisotopes, and normal safety procedures were followed at all times to prevent contamination. Instrumentation Microanalyses of the " T c complexes were performed by Canadian Microanalytical Services Ltd, Delta, B.C. A Varian XL300 N M R spectrometer was used in the determination of magnetic susceptibility by the Evans' method 3 0 ' 3 1 in CDCI3 with cyclohexane as the reference compound. The magnetic moment was then calculated from the determined magnetic susceptibility. Cyclic voltammetric data were obtained using a P A R C (Princeton Applied Research Col) Model 264 polarographic analyzer/stripping voltammeter and a P A R C Model RE0089 S-Y recorder. Electrochemical measurements were carried out under an argon atmosphere at room temperature. Solution concentrations were approximately 10"3 M in metal complex and 0.1 M in T E A P (tetraethylammonium perchlorate), which acted as the supporting electrolyte. Voltammograms were recorded using a platinum working electrode, a platinum wire counter electrode, and an Ag/AgCl reference electrode. The electrode was calibrated using a 1.0 x 10"3 M solution of ferrocene in acetonitrile containing 0.1 M T E A P for which the ferrocenium/ferrocene reduction potential was 0.40 V and AE p = 72 mV at a scan rate of 100 mVs" 1. Voltammograms reported in this study were recorded at a scan rate of 100 mVs - 1 . 50 Synthesis of Metal Complexes. 9 9 Tc(III) / and 9 9 T c ( I V ) / X T A M 3 " amine phenolate complexes were prepared using either the substitution method or the reduction/complexation method. R e ( I V ) / X T A M 3 _ amine phenolate complexes were prepared via the substitution method. Because many of the syntheses were similar to one another, detailed procedures are only given for representative examples. Monocationic 9 9 T c and Re complexes were prepared with perchlorate or chloride as the counterion. Caution! Perchlorate salts of metal complexes are potentially explosive and should be handled with care. [99Tc(TAM)] . Reduction/Complexation Method. To a solution of of H 3 T A M (200 mg, 0.459 mmol) and triphenylphosphine (180 mg, 0.686 mmol) in methanol (30 mL) was added NH499TcC>4 (50 mg, 0.276 mmol) in distilled water (5 mL). The solution was refluxed and the color of the solution changed to dark intense purple after ~2 h. The solution was refluxed for a total of 12 h and then allowed to cool to room temperature. Slow evaporation of the solvents over several days yielded a purple precipitate, which was collected by filtration, washed with cold methanol, followed by water and diethyl ether. The precipitate was dried in vacuo at room temperature for 24 h to yield 64 mg (44 %). Anal. Calcd (found) for C 2 6 H 3 0 N 3 O 3 9 9 T c : C, 58.76 (58.91); H , 5.69 (5.79); N , 7.91 (7.74). LSIMS: m/z = 525 ([ML-6]+, [ 9 9 TcC26H24N30 3 ] + ) . IR (cm"1, K B r disk): 3500-3200 (b, s) (DNH); 3150-2800 (w, DCH); 1595 (s), 1575 (m) (8NH); 1515-1375 (s, DC=C). X (cm^mol"1, 25 °C): 3.3 x 10"3. | i e f f ( B M ) : 2 . 8 . [ 9 9 T c ( T A M ) ] . Substitution Method. To a solution of [ 9 9Tc(S-thiourea) 6]Cl3 (140 mg, 0.211 mmol) in methanol (10 mL) was added H 3 T A M (216 mg, 0.495 mmol) and sodium acetate (122 mg, 1.49 mmol) in methanol (25 mL). The solution was refluxed and the color of the solution changed to dark intense purple after being refluxed for ~1 h. The solution was refluxed for a total of 8 h and then allowed to cool to room temperature. Slow evaporation of the solvent yielded a purple precipitate, which was collected by filtration and washed with cold methanol, followed by water and diethyl ether. The precipitate was dried in vacuo at room temperature for 24 h to yield 96 mg (86 %). Anal. Calcd (found) for C 2 6 H 3 o N 3 0 3 9 9 T c : C, 58.76 (58.88); H , 5.69 (5.88); N , 7.91 (7.65). L S I M S : m/z = 525 ( [ M L - 6 ] + , 51 [ 9 9TcC26H24N303] +). IR (cm"1, K B r disk): 3600-3100 (b, s) (DNH); 3260-2825 (w, DCH); 1600 (s), 1585 (m) (5 N H) ; 1525-1425 (s, vC=c)- X ( cm 3 moH, 25 °C): 3.15 x 10"3. u e f f (BM): 2.7. [ 9 9Tc(BrTAM)]. Reduction/Complexation^ Method. A procedure similar to that for preparing [9 9Tc(TAM)] via the reduction/complexation method was followed using NH499TcC»4 (50 mg, 0.276 mmol), H 3 B r T A M (309 mg, 0.459 mmol) and triphenylphosphine (180 mg, 0.686 mmol); the yield was 108 mg (51 %). Anal. Calcd (found) for C26H27Br 3 N 3 03 9 9 Tc: C, 40.66 (40.27); H , 3.54 (3.08); N , 5.47 (5.19); Br, 31.21 (31.30). LSIMS: m/z = 762 ([ML-6]+, [ 9 9TcC26H 2iBr3N303]+). IR (cm"1, K B r disk): 3500-3200 (b, s) (DNH); 3150-2800 (w, DCH);. 1595 (s), 1575 (m) (8NH); 1515-1375 (s, vc=cl X (cm 3 moH, 2 5 O Q : 3.3 x 10"3. u . e f f (BM): 2.8. ["Tc(BrTAM)]. Substitution Method. A procedure similar to that for preparing [ 9 9Tc(TAM)] via the substitution method was followed using [99Tc(S-thiourea)6JCl3 (140 mg, 0.211 mmol), H 3 B 1 T A M (309 mg, 0.459 mmol) and sodium acetate (122 mg, 1.49 mmol); the yield was 116 mg (71 %). Anal. Calcd (found) for C26H27Br 3 N303 9 9 Tc: C, 40.66 (40.47); H , 3.54 (3.23); N , 5.47 (5.38). LSIMS: m/z = 762 ([ML-6] + , [ 9 9 TcC26H2iBr3N 3 0 3 ] + ) . IR (cm-!, K B r disk): 3500-3200 (b, s) (\)NH); 3150-2800 (w, u C H ) ; 1595 (s), 1575 (m) (5NH); 1515-1375 (s, DC=C)- X (cmSmol-1, 25 °C): 3.3 x 10"3. jj.eff (BM): 2.8. [ 9 9Tc(ClTAM)]. Reduction/Complexation Method. A procedure similar to that for preparing [9 9Tc(TAM)] via the reduction/complexation method was followed using NH4 9 9 Tc04 (50 mg, 0.276 mmol), H 3 C I T A M (247 mg, 0.459 mmol) and triphenylphosphine (180 mg, 0.686 mmol); the yield was 95 mg (54 %). Anal. Calcd (found) for C26H27Cl3N 303 9 9Tc: C, 49.20 (49.32); H , 4.29 (4.00); N , 6.62 (6.69). LSIMS: m/z = 629 ( [ M L - 6 ] + , [ 9 9 TcC26H 2 iCl3N 3 03] + ) . IR (cm"1, K B r disk): 3600-3300 (b, s) (UNH); 3065-2800 (w, D CH); 1600 (s), 1585 (m) (5NH); 1515-1375 (s, \>c=c)- X (cm 3 moH, 25 °C): 3.0 x 10"3. ^ e f f (BM): 2.7. ["Tc(ClTAM)]. Substitution Method. A procedure similar to that for preparing [ 9 9Tc(TAM)] via the substitution method was followed using [ 9 9Tc(S-thiourea^]Cl 3 (140 mg, 52 0.211 mmol), H 3 C I T A M (247 mg, 0.459 mmol) and sodium acetate (122 mg, 1.49 mmol); the yield was 97 mg (72 %). Anal. Calcd (found) for C26H27Cl3N 303 9 9Tc: C, 49.20 (49.43); H , 4.29 (4.05); N , 6.62 (6.73). LSIMS: m/z = 629 ([ML-6] + , [ 9 9 TcC 2 6 H2iCl3N303] + ) . IR (cm" K B r disk): 3600-3300 (b, s) (I)NH); 3065-2800 (w, D C H); 1600 (s), 1585 (m) (5 N H ) ; 1515-1375 (s, DC=C). X (cu^mor 1 , 25 °C): 3.0 x 10"3. u«ff (BM): 2.8. [ 9 9 Tc(BrTAM ) ]C10 4 . Substitution Method. To a yellow solution of K 2 9 9 T c C l 6 (122 mg, 0.313 mmol) in methanol (10 mL) was added H 3 B r T A M (526 mg, 0.782 mmol) and sodium acetate (289 mg, 3.52 mmol) in methanol (30 mL). The solution was refluxed and the color of the solution changed to intense purple after ~1 h. The solution was refluxed for a total of 6 h and then allowed to cool to room temperature. NaC10 4 (76 mg, 0.626 mmol) was dissolved in the solution. Slow evaporation of the solvent yielded a purple precipitate, which was collected by filtration, and washed with cold methanol. The precipitate was dried in vacuo at room temperature for 24 h to yield 138 mg (51 %). Anal . Calcd (found) for C26H27Br 3 C l N 3 0 7 9 9 T c : C, 35.99 (35.89); H , 3.14 (3.43); N , 4.84 (4.72). LSIMS: m/z = 762 ([ML-6J+, [ 9 9 TcC26H 2 iBr 3 N303] + ) . IR (cm"1, K B r disk): 3500-3200 (b, s) (I>NH); 3150-2800 (w, -OCH); 1595 (s), 1575 (m) ( 6 N H ) ; 1515-1375 (s, u c =c) ; H00 (b, s, u C i -o ) . X (cm 3 moH, 25 °C): 4.7 x 10"3. ^ e f f (BM): 3.3. [Re(TAM)]Cl. Substitution Method. To a solution of K 2 R e C l 6 (414 mg, 0.868 mmol) in methanol (10 mL) was added a solution of H 3 T A M (552 mg, 1.27 mmol) and sodium acetate (312 mg, 3.80 mmol) in methanol (10 mL). K2ReCl6 was marginally soluble in methanol at room temperature but dissolved more readily at elevated temperature. The solution was refluxed for a total of 24 h and then allowed to cool to room temperature. Slow evaporation of the solvent yielded a precipitate, which was collected by filtration, and washed with cold methanol and diethyl ether. The precipitate was dried in vacuo at room temperature for 24 h to yield 409 mg (72 %). Anal. Calcd (found) for C 2 6H 3 0 ClN3O3Re: C, 47.74 (47.98); H , 4.62 (4.48);' N , 6.42 (6.64). LSIMS: m/z =618 ([ML]+, [ReC 2 6H3oN 3 03] + ) . IR (cm"1, K B r disk): 3650-3300 (b, s) (UNH); 3235-2865 (m, VCR); 1595 (s), 1570 (m) (5 NH); 1480-1345 (s, i)C=c). X (crrAnoH, 25 °C): 4.6 x 10"3. ^ e f f (BM): 3.3. 53 v. [Re(BrTAM)]Cl. Substitution Method. A procedure similar to that for [Re(TAM)] was followed using K2ReCl6 (414 mg, 0.868 mmol), HsBrTAM (855 mg, 1.27 mmol) and sodium acetate (312 mg, 3.80 mmol); the yield was 572 mg (74 %). Anal. Calcd (found) for C26H27Br 3 ClN 3 03Re: C, 35.05 (35.10); H, 3.05 (3.44); N , 4.72 (4.56). LSIMS: m/z = 855 ( [ M L ] + , [ReC 2 6H 2 7Br 3 N303] + ) . IR (cm"1, KBr disk): 3650-3300 (b, m) (DNH); 3250-2800 (m, -UCH); 1600 (s), 1580 (m) (6NH); 1515-1375 (s, vC=c)- X (cm 3 moH, 25 °C): 4.6 x 10"3. Ueff(BM): 3.3. [Re(ClTAM)]Cl. Substitution Method. A procedure similar to that for [Re(TAM)] was followed using K 2 ReCl6 (414 mg, 0.868 mmol), H3CITAM (683 mg, 1.27 mmol) and sodium acetate (312 mg, 3.80 mmol); the yield was 440 mg (67 %). Anal. Calcd (found) for C26H27Cl 4 N 3 0 3 Re: C, 41.22 (41.21); H , 3.59 (3.58); N , 5.55 (5.57). LSIMS: m/z = 722 ([ML]+, [ReC26H 2 7 Cl3N30 3 ] + ). IR (cm"1, K B r disk): 3600-3300 (b, s) (UNH); 3255-2800 (w, UCH); 1595 (s), 1585 (m) (5 N H ) ; 1515-1375 (s, vc=c)- X (cm 3 moH, 25 °C): 4.8 x 10' 3. (Xeff (BM): 3.4. 54 3.3. Results and Discussion Reduction of 9 9 Tc04" with excess triphenylphosphine in the presence of H 3 X T A M amine phenols yielded neutral " T c complexes that were soluble in chloroform, acetonitrile, dimethylsulfoxide and methanol. Although Tc(V) amine phenoiate complexes containing a T c 0 3 + moiety have been previously reported,9"15 it was suspected that the oxidation state of the " T c center was +3, since the complexes were neutral. The absence of the characteristic l)Tc=0 band in the infrared spectra of the complexes ruled out the presence of a T c ( v ) 0 3 + moiety. In addition, widely shifted and broad lH N M R resonances were observed, indicating paramagnetic Tc complexes. Paramagnetic complexes were consistent with a Tc(III) oxidation state, not a Tc(V) oxidation state. Substitution reactions with [99Tc(S-thiourea)6]Cl3 (a Tc(III) complex) and H 3 X T A M amine phenols in the presence of sodium acetate yielded neutral complexes that were identical to the complexes obtained from the reduction method. A l l " T c complexes were characterized by elemental analyses, IR, LSIMS, magnetic susceptibility measurements and cyclic voltammetry. In the LSIMS of the " T c complexes, the molecular ion [ M L ] + was not detected; however, the peak corresponding to [ML-6] + ion was detected. The [ML-6] + ion peak was probably caused by the three CH2-NH linkages in the amine phenolate converting back to the imine CH=N linkages in the mass spectrometer. The loss of the 6 hydrogen atoms from the coordinated ligand would account for the detection of [ML-6] + ion, rather than [ M L ] + . This phenomena was observed in both the neutral Tc(III) and the monocationic Tc(IV) complexes. The oxidative dehydrogenation of secondary amine groups bound to a metal has been previously reported. 3 2- 3 3 Paramagnetic 9 9 T c complexes were prepared via both the substitution and the reduction/complexation methods. Magnetic susceptibilities of the " T c complexes were determined by the Evans' method 3 0 ' 3 1 at ~10"2 M in CDCI3 and cyclohexane was used as the reference compound. Magnetic susceptibilities of the ["Tc(XTAM)] complexes were 3 x 10"3 55 cm 3 moH and fieff was 2.7-2.8 B M . This corresponded well to 2 unpaired electrons and a low spin d 4 Tc metal center. Cyclic voltammograms of ["Tc(XTAM)] were recorded in the potential range 0.5 V to -1.75 V (vs Ag/AgCl) with tetraethylammonium perchlorate as the supporting electrolyte in acetonitrile. Cyclic voltammetry data are listed in Table 3.1, while the cyclic voltammogram of [ " T c ( B r T A M ) ] is shown in Figure 3.1. Two distinct well-defined quasi-reversible one-electron waves were detected in the cyclic voltammograms of the [ " T c ( X T A M ) ] complexes recorded at a scan speed of 100 mV/s. For the [ " T c ( B r T A M ) ] and [ " T c ( C I T A M ) ] complexes, one additional quasi-reversible one-electron transfer was observed at —1.6 V . Under identical conditions, no redox processes were detected for the free amine phenols; hence, the redox processes detected in the cyclic voltammograms of the " T c complexes were due to changes in the oxidation states of the 9 9 T c center. The redox processes detected at approximately -0.04 V , -1.1 V and -1.6 V were tentatively assigned to the one-electron transfers [ T c ( I V ) ( X T A M ) ] + / [ T c ( m ) ( X T A M ) ] , T c ( m ) ( X T A M ) ] / [ T c ( n ) ( X T A M ) ] - , and Tc ( I I ) (XTAM)]7 [Tc ( I ) (XTAM)] 2 " , respectively. The reversibility of these one-electron processes suggested that there were neither significant changes to the coordination sphere nor decomplexation of the complex as the Tc(IU) center was oxidized or reduced to Tc(IV) or Tc(II). The [Tc( I V)(XTAM)]+/[Tc( i n)(XTAM)] potential suggested that the X T A M 3 " amine phenolate may also be capable of stabilizing Tc(IV) and that it should be possible to isolate monocationic Tc(IV) X T A M 3 " complexes. Reaction of H s B r T A M and K 2 9 9 T c Q 6 (a Tc(IV) complex) in the presence of sodium acetate yielded a monocationic Tc(IV) complex. Magnetic susceptibility of [ 9 9 Tc(BrTAM)]C104 was 4.7 x 1 0 3 cm 3 moH and (ieff was 3.3 B M . This corresponded to 3 unpaired electrons and a Tc(IV) metal center. The cyclic voltammogram of [ 9 9 T c ( B r T A M ) ] C 1 0 4 was found to be very similar to that of the Tc(III) complex, [ " T c ( B r T A M ) ] . It was qualitatively observed that it was much more difficult to prepare analytically pure monocationic [Tc(XTAM)] + complexes than their neutral Tc(III) analogues. 56 Part of the difficulty in preparing analytically pure [Tc(XTAM)] + complexes may be due to the Tc(TV) complex undergoing reduction to the neutral Tc(IJJ) complex. Tc(ll)/Tc(l) 0.5 0.0 -0.5 -1.0 -1.5 E (V) vs Ag/AgCl Figure 3.1. Cyclic voltammogram of ["Tc(BrTAM)] in acetonitrile at a scan rate of 100 mV/s. 57 Table 3.1. Cyclic voltammetric data for [ "Tc(XTAM)] and [Re(XTAM)] complexes. complex E1/2 (V vs Ag/AgCl) A E p (mV) Tentative Assignments [99Tc(TAM)] -0.04 69 [Tc( I V)(TAM)]+/[Tc( n i)(TAM)] -1.14 96 Tc( I I I)(TAM)]/[Tc( 1 I)(TAM)]-["Tc(BrTAM)] -0.04 68 [Tc( I V)(BrTAM)]+/[Tc( I n)(BrTAM)] -1.09 99 Tc( I I I)(BrTAM)]/[Tc( I I)(BrTAM)]--1.64 82 Tc( n)(BrTAM)] -/[TcWtBrTAM)] 2-[99Tc(ClTAM)] -0.04 64 [Tc( I V)(ClTAM)]+/[Tc( I I I)(ClTAM)] -1.09 95 Tc( n i)(ClTAM)]/[Tc( n)(ClTAM)]--1.68 84 TcC^CClTAM^VtTcCDCClTAM)] 2-[Re(TAM)] -0.37 82 [Re( I V)(ClTAM)]+/[Re( n i)(ClTAM)] -1.23 Re( n i)(ClTAM)]/[Re( n)(ClTAM)]--1.65 Re( n)(ClT AM)] -/[Re^CClT A M ) ] 2 " [Re(BrTAM)] -0.35 80 [Re( I V)(ClTAM)]+/[Re(m)(ClTAM)] . -1.17 Re( n i)(ClTAM)]/[Re( n)(ClTAM)]--1.63 Re( I I)(ClTAM)]V[Re( I)(CITAM)] 2-[Re(ClTAM)] -0.38 79 [Re( I V)(ClTAM)]+/[Re(m)(ClTAM)] -1.17 Re( n i)(ClTAM)]/[Re( n)(ClTAM)]--1.69 ReWCClTAM^VtReWCClTAM)] 2 -58 Re(IV), [ R e ( X T A M ) ] + complexes were prepared via the substitution method using K^ReCl^ as the source of the pre-reduced Re center. Attempts to prepare Re complexes via the reduction/complexation method were unsuccessful. The Re complexes were characterized by elemental analyses, IR, magnetic susceptibility measurements, and cyclic voltammetry. No URe=0 band was observed in the infrared spectra of the complexes, obviating the presence of a R e 0 3 + moiety. Magnetic susceptibilities of the Re complexes were determined by the Evans' method to be ~ 4.6 x 10 - 3 cm 3 mol _ 1 . u.eff was calculated to be ~ 3.3 B M , which corresponded to 3 unpaired electrons consistent with a d 3 Re(IV) center. Cyclic voltammograms of the [Re(XTAM)] + complexes showed a well-defined quasi-reversible one-electron transfer at ~ -0.35 V at a scan rate of 100 mV/s. Two totally irreversible redox processes were also detected at ~ -1.1 V and —1.33 V. The redox process at ~ -0.35 V was assigned to the one-electron transfer [Re( I V ) (XTAM)]+ / [Re( i n ) (XTAM)] . The two irreversible processes detected at lower potential were mostly likely due to Re undergoing reduction to Re(II) and Re(I). The irreversibility of these redox processess can be attributed to decomposition of the complexes. The Tc complexes were easier to reduce than their Re congeners, consistent with the generally easier reduction of Tc compared to Re. Numerous attempts to prepare X-ray quality crystals of either the Tc or Re X T A M 3 " amine phenolate complexes were unsuccessful; however, from the known structures of metal complexes with tame-based amine phenol 2 6 and Schiff base ligands, 1 6 it was suspected that the Tc and Re metal ions were hexacoordinated by 3 amine nitrogen and three phenolate oxygen donor atoms (a N3O3 donor atom set). As predicted earlier, tripodal tame based amine phenols were capable of coordinating to T c 3 + , Tc4"1" and R e 4 + to form stable complexes. The tame-based amine phenols were able to adjust to the steric demand of the Tc and Re metal ions. Biodistribution studies of [ 9 9 m T c ( X T A M ) ] complexes will be conducted in the near future. 59 3.4. References. 1. Marchi, A. ; Rossi, R.; Magon, L. ; Duatti, A. ; Pasqualini, R.; Ferretti, V. ; Bertolasi, V. J. Chem. Soc. Dalton Trans. 1990, 1411. 2. Refosco, F.; Tisato, F.; Mazzi, U . ; Bandoli, G.; Nicolini, M . J. Chem. Soc. Dalton Trans. 1988, 611. 3. Marchi, A. ; Duatti, A. ; Rossi, R.; Magon, L . ; Pasqualini, R.; Bertolasi, V. ; Ferretti, V. ; Gi l l i , G. J. Chem. Soc. Dalton Trans. 1988, 1743. 4. Hunter, G.; Kilcullen, N . J. Chem. Soc. Dalton Trans. 1989, 2115. 5. Tisato, F.; Refosco, F.; Moresco, A. ; Bandoli, G.; Mazzi, U . ; Nicolini, M . / . Chem. Soc. Dalton Trans. 1990, 2225. 6. Thomas, J. A . ; Davison, A. ; Jones, A . G. Inorg. Chim. Acta 1991,184, 99. 7. Volkert, W. A.; Mckenzie, E. H. ; Hoffman, T. J.; Troutner, D. E.; Holmes, R. A . Int. J. Nucl. Med. Biol. 1984, 11, 243. 8. Ramamoorthy, N . ; Pillai, M . R. A. ; Troutner, D. E. Nucl. Med. Biol. 1993, 20, 307. 9. Pillai, M . R. A. ; John, C. S.; Lo, J. M . ; Schlemper, E. O.; Troutner, D. E. Inorg. Chem. 1990,29, 1850. 10. Corlija, M . ; Volkert, W. A. ; John, C. S.; Pillai, M . R. A . ; Lo, J. M . ; Troutner, D. E.; Holmes, R. A . Nucl. Med. Biol. 1991,18, 167. 11. Kothari, K.; Pillai, M . R. A . Appl. Radiat. hot. 1993, 44, 911. 12. Pillai, M . R. A. ; Kothari, K. ; Schlemper, E. O.; Corlija, M . ; Holmes, R. A . Volkert, W. A . Appl. Radiat. hot. 1993, 44, 1113. 13. Pillai, M . R. A. ; John, C. S.; Lo, J. M . ; Troutner, D. E.; Corlija, M . ; Volkert, W. A. ; Holmes, R. A . Nucl. Med. Biol. 1993, 20, 211. 14. Pillai, M . R. A. ; Barnes, C. L. ; Schlemper, E. O. Polyhedron 1994,13, 701. 15. Ramalingam, K.; Raju, N . ; Nanjappan, P.; Linder, K . E.; Pirro, J.; Zeng, W.; Rumsey, W.; Nowotnik, D. P.; Nunn, A . D. / . Med. Chem. 1994, 37, 4155. 16. Green, M . A. ; Welch, M . J.; Huffman, J. C. / . Am. Chem. Soc. 1984,106, 3689. 60 17. Cook, D. F.; Cummins, D.; McKenzie, E. D.; Worthington, J. M . / . Chem. Soc. Dalton Trans. 1976, 1369. 18. Alcock, N . W.; Cook, D. F.; McKenzie, E. D.; Worthington, J. M . Inorg. Chim. Acta, 1980, 38, 107. 19. Liu , S.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1992, 31, 5400. 20. Liu , S.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1991, 30, 4915. 21. Luo, H. ; Rettig, S. J.; Orvig, C. Inorg. Chem. 1993, 32, 4491. 22. Edwards, D. S.; Liu , S.; Poirier, M . J.; Zhang, Z.; Webb, G. A . ; Orvig, C. Inorg. Chem. 1994, 33, 5607. 23. Luo, H. ; Setyawati, I.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1995, 34, 2287. 24. Shannon, R. D. Acta Cryst. 1976, A32, 751. 25. Deutsch, E.; Libson, K.; Vanderheyden, J.-L.; Ketring, A . R.; Maxon, H . R. Nucl. Med. Biol. 1986, 13, 465. 26. Liu , S.; Wong, E; Karunaratne, V. ; Rettig, S. J.; Orvig, C. Inorg. Chem. 1993, 32, 27. Dalziel, J.; Gi l l , N . S.; Nyholm, R. S.; Peacock, R. D. J. Chem. Soc. 1958, 4012. 28. Abrams, M . J.; Davison, A. ; Faggiani, R.; Jones, A . G.; Lock, C. J. L . Inorg. Chem. 1984, 23, 3284. 29. Watt, G. W.; Thompson, R. J. Inorg. Synth. 1963, 7, 189. 30. Evans, D. F. / . Chem. Soc. 1959, 2003. 31. Sur, S. K. / . Mag. Res. 1989, 82, 169. 1756. 32. Goedken, V . L . ; Busch, D. H. ; J. Am. Chem. Soc, 1972, 94, 7355. 33. Mountford, H . S.; MacQueen, D. B.; L i , A. ; Otvos, J. W.; Calvin, M . ; Frankel, R. B.; Spreer, L . O. Inorg. Chem. 1994, 33, 1748. 61 Chapter Four Ga and In Complexes with Linear N4O2 Amine Phenolates r 4.1. Introduction The coordination of metal ions with tripodal X T R N 3 - , X T A M 3 " and XTAP 3 " amine phenolate (Figure 1.2) is greatly affected by the metal's electronic and steric requirements, as well as by the flexibility of the amine phenolate ligands. 1 - 3 As mentioned earlier, the tripodal cavity of XTRN 3 " matches the size of I n 3 + best, while for A l 3 + and G a 3 + , the cavity is too large for heptacoordination of these smaller group 13 metal ions; hexacoordinated A l and Ga complexes are isolated instead.1 The uncoordinated donor atoms within the A l and Ga complexes are protonated, resulting in monocationic complexes. It is interesting to note that A l 3 + is coordinated via a N3O3 donor atom set while G a 3 + is coordinated by a N4O2 donor atom set. The hard A l 3 + ion has a preference for hard anionic phenolate oxygen atoms over neutral amine nitrogen atoms; hence one of the neutral amine nitrogen atoms remains uncoordinated. The choice of donor atom set is dictated by the electronic demands of A l 3 + . Unlike A l 3 + , G a 3 + has a strong binding affinity for both neutral amine nitrogen and anionic phenolate oxygen atoms.4 Therefore, under the steric constraint impose by the tripodal ligand framework, G a 3 + is coordinated via a N4O2 donor atom set. The choice of donor atom set is governed by the steric constraint of the ligand. I n 3 + , like G a 3 + , has a strong affinity for both phenolate oxygen and amine nitrogen atoms4 and because of its larger size, I n 3 + is coordinated by all seven donor atoms. Studies of the coordination of A l 3 + , G a 3 + , and I n 3 + with N3O3 X T A M 3 " and X T A P 3 ' amine phenolates2 ,3 (Figure 1.2) indicate that these ligands are flexible and are able to adjust their framework to match the size of the coordinated metal ion. Although stable A l , Ga and In complexes are prepared with ease, structural data suggest that the X T A M 3 - amine phenolates are best suited for A l 3 + as there is less adjustment of the ligand framework observed in the A l 62 complex. XTAP 3 " differs from XT A M 3 - by having one of its pendant arms shortened by a single methylene linkage. Structural data suggest that X T A P 3 - are more suitable for G a 3 + . It is interesting to note that the preparation of [Al(XTAP)] complexes is often accompanied by the precipitation of A l hydroxide and attempts to isolate analytically pure A l complexes were unsuccessful. This indicates that X T A P 3 " amine phenolates are not very suitable for coordination to the A l 3 + ion. A l l of the previous investigations into the coordination of multidentate amine phenolates to group 7 and 13 metal ions dealt with tripodal ligands.1"3'5 The suitability of amine phenolates for a particular metal ion is influenced to a degree by the size of the tripodal cavity and how the ligand encloses the bound metal ion. To broaden the investigation into the coordination of multidentate amine phenolates more favorable for G a 3 + and I n 3 + chelation, we prepared two series of linear amine phenols based on triethylenetetraamine and N,N' (3-aminopropyl)ethylenediamine (Figure 4.1). These linear amine phenolates instead of enclosing a metal ion with 3 pendant arms, would span the coordination sites and wrap around the metal ion, and coordinate via four amine nitrogen atoms and two anionic phenolate oxygen atoms Figure 4.1. Linear amine phenols, FL^Xbad and F^Xbadd. The choice of a potential N4O2 donor atom set originated from the coordination of tren-based oxygen atoms and neutral amine nitrogen atoms, should also have good binding affinity for the N4O2 donor atom set. On the other hand, the N 4 0 2 donor atom set of these linear amine X=H H 2bad X=J3r H 2Brbad X=C1 H2CIbad X=H X=Br X=C1 H2badd H2Brbadd H2Clbadd amine phenolates (HXTRN 2 " ) to G a 3 + . I n 3 + , which has a strong affinity for both phenolate 63 phenolates is not expected to be well suited for coordination to A l 3 + . While the investigations into the coordination of these linear amine phenolates to G a 3 + and I n 3 + ions were underway, biodistribution data for Ga complexes with substituted Schiff base analogs of Xbadd2" were reported.6-7 The Ga complexes have significant myocardial uptake and retention for up to 2 h. In addition, the Ga complexes are reported to clear rapidly from the blood and to give excellent heart to blood ratios at 5 min post injection. 6 7 G a and 6 8 G a complexes with these linear N4O2 ligands have the potential to become excellent myocardial imaging agents. In the same manner as X T A M 3 - , the linear amine phenolates will be more stable to hydrolytic decomposition than their Schiff base analogs, while retaining similar biodistribution. With these compounds showing such potential as myocardial imaging agents, it is very important to understand the structures and coordination chemistry of Ga and In complexes with linear amine phenolates. 4.2. Experimental Section Materials. Triethylenetetraamine and N , N'-bis(3-aminopropyl)ethylenediamine were obtained from Aldrich and were used without furthur purification. A l l other chemicals were obtained from Aldrich or Alfa, as described in section 2.2. Instrumentation. In addition to the instrumentations that were outlined in section 2.2, conductance measurements were made with a Yellow Springs YS-1 Model 35 conductance meter with solute concentration of ca. 10"3 M in acetonitrile at 25 °C. Ligand Syntheses. 2-(5-Chloro-2-hydroxyphenyl)-l,3-di[3-aza-4-(5-chloro-2-hydroxyphenyl)-prop-4-en-l-yl]-l,3-imidazolidine (H^Clapi). To a solution of triethylenetetraamine (2 g, 14 mmol) in ethanol (20 mL) was added to a solution of 5-chlorosalicylaldehyde (6.6 g, 42 mmol) in ethanol (20 mL). A yellow precipitate deposited at once. The product was collected by filtration, washed with diethyl ether and dried in vacuo at 60 °C for 24 h yielding 6.5 g (83 %), mp 150-152 °C. Recrystallization from methanol afforded crystals suitable for X-ray crystallographic analysis. Anal, calcd (found) for C27H27CI3N4O3: C, 57.71 (57.93); H , 4.84 64 (4.99); N , 9.97 (9.90). LSIMS: m/z = 563 ([M+l]+ [C27H28C13N403]+). Infrared spectrum (cm- 1, K B r disk): 3600-3300 (b,w, D 0 H and/or D N H ) ; 3000-2600 (s, 1)CH); 1647 (s, DC=N); 1585 (m), 1486 (m), 1455 (m) (i)c=c). X H N M R (200 MHz, CDC1 3): 2.62 (m, 2H), 2.65 (m, 2H), 2.91 (m, 2H), 3.42 (m, 2H), 3.57 (t, 4H, J=l Hz), 3.77 (s, H), 6.65 (d, H , / = 7 Hz), 6.87 (d, 2H, / = 7 Hz), 6.92 (s, H), 7.10 (d, H , / = 7 Hz), 7.16 (s, 2H), 7.22 (d, 2H, / = 7 Hz), 8.15 (s, H), 10.38 (b s, H), 13.10 (b s, 2H). l,10-Bis(2-hydroxybenzyl)-l,4,7,10-tetrazadecane ( H 2 b a d ) . To a hot solution of triethylenetetraamine (2 g, 14 mmol) in ethanol (200 mL) was added a hot solution of salicylaldehyde (3.67 g, 30 mmol) in ethanol (200 mL). While the solution was still hot, K B H 4 (1.66 g, 31 mmol) was added in small quantities over 10 min. The solution was then heated (approximately 50 °C) and stirred for an additional 2 h. The solvent was removed under reduced pressure, leaving a white residue. N H 4 O A C (3 g) in 50 mL water was added to the white residue. The aqueous mixture was then extracted with chloroform (3 X 100 mL) The organic fractions were combined, washed with distilled water (3 X 100 mL) and then dried over anhydrous M g S 0 4 . The solution was filtered and the chloroform removed on a rotary evaporator to give a yellow oil. The oil was dried in vacuo at 60 °C for 24 h, yielding 12 g (84 %). Elemental analysis of the oil was not possible. LSIMS: m/z = 359 ( [ M + l ] + , [ C 2 0 H 3 i N 4 O 2 ] + ) , m/z = 253 ([Ci3H 25N 40]+). ! H and 1 3 C N M R spectral data are listed in Tables 4.1 and 4.2, respectively. Reaction of H2bad with Acetone (H2badAc). H 2bad (3 g, 8.4 mmol) was dissolved in acetone (50 mL) and the solution was refluxed for 3 h. A white precipitate formed as the solution cooled to room temperature. Characterization of the precipitate revealed it to be the amine phenol with two isopropyl groups bridging the first and second, as well as the third and fourth N atoms. The methylene carbon on each propyl group was bonded to one inner secondary and one outer amine nitrogen, thereby forming two imidazolidine rings with the trien backbone (Figure 4.2). Yield: 1.95 g (53 %). Mp: 167-8 °C Anal. Calcd (found) for C 2 6 H 3 8 N 4 0 2 : C, 71.20 (70.90); H , 8.73 (8.83); N , 12.77 (12.70). LSIMS: m/z = 439 ([M+l]+ [C26H 3 9 N 4 02] + ) , m/z = 399 ([C23H 3 5 N 4 02] + ) . Infrared spectrum (cm-1, K B r disk): 65 3600-3300 (b,w, DOH and/or D N H ) ; 3000-2600 (s, DCH); 1610 (m), 1590 (m) (8NH); 1500-1460 (s, \>c=c)- *H N M R spectral data are listed in Table 4.3. l,10-Bis(5-bromo-2-hydroxybenzyl)-l,4,7,10-tetrazadecane ( H 2 B r b a d ) . The preparation of l,10-bis(5-bromo-2-hydroxybenzyl)-l,4-7,10-tetrazadecane (H2Brbad) was similar to the procedure for the preparation of H 2 b a d . The synthesis employed triethylenetetraamine (2 g, 14 mmol), 5-bromosalicylaldehyde (6.03 g, 30 mmol) and K B H 4 (1.66 g, 31 mmol). The yield was 5.51 g (76 %). Elemental analysis of the oil was not possible. LSIMS: m/z = 517 ([M+l]+ [C2oH 2 9Br 2 N 4 02] + ) . lH and 1 3 C N M R spectral data are listed in Tables 4.1 and 4.2, respectively. Reaction of H 2 B r b a d with Acetone ( H 2 B r b a d A c ) . The reaction of H 2 B r b a d (3 g, 5.8 mmol) with acetone (50 mL) was similar to the reaction of H 2 b a d with acetone. Characterization of the product showed the presence of two imidazolidine rings. The yield was 1.94 g (56 %). Mp: 165-6 °C. Anal. Calcd (found) for C26H 36Br2N 402: C, 52.36 (52.22); H , 6.08 (6.00) N , 9.39 (9.41). LSIMS: m/z = 597 ( [M+l] + , [ C 2 6 H 3 7 B r 2 N 4 0 2 ] + ) , m/z=557 ( [ C 2 3 H 3 3 B r 2 N 4 0 2 ] + ) . Infrared spectrum (cnr 1 , K B r disk): 3620-3300 (b,w, v0R and/or D N H ) ; 3000-2600 (s, D C H); 1605 (m), 1580 (m) ( 8 N H ) ; 1500-1440 (s, x>c=c)- *H N M R spectral data are listed in Table 4.3. l,10-Bis(5-chloro-2-hydroxybenzyl)-l,4,7,10-tetrazadecane (rl^Clbad). The preparation of l,10-bis(5-chloro-2-hydroxybenzyl)-l,4,7,10-tetrazadecane (H2Clbad) was similar to the procedure for the preparation of H 2 b a d . The synthesis employed triethylenetetraamine (2 g, 14 mmol), 5-chlorosalicylaldehyde (4.70 g, 30 mmol) and KBFLj. (1.66 g, 31 mmol) and yielded 4.62 g (77 %). Elemental analysis of the oil was not possible. LSIMS: m/z = 428 ([M+l]+ [ C 2 o H 2 9 C l 2 N 4 0 2 ] + ) , m/z = 287 ( [ C i 3 H 2 4 C l i N 4 0 i ] + ) . lH and 1 3 C N M R spectral data are listed in Tables 4.1 and 4.2, respectively. Reaction of H 2Clbad with Acetone (H^ClbadAc). The reaction of H 2 C l b a d (3 g, 7.0 mmol) with acetone (50 mL) was similar to the reaction of H 2 b a d with acetone. Characterization of the product revealed the presence of two imidazolidine rings. The yield was 2.21 g (62%). Mp: 168-9 °C. Anal. Calcd (found) for C26H36C1 2N 40 2: C, 61.53 (61.32); H , 66 7.15 (7.07); N , 11.04 (11.10). LSIMS: m/z = 508 ([M+l]+ [C 2 6H3 7 Cl2N 4 02] + ) , m/z = 467 ([C23H33Cl2N4C»2]+). Infrared spectrum (cnr 1, K B r disk): 3600-3300 (b,w, DOH and/or DNH); 3000-2600 (s, 1)CH); 1610 (m), 1585 (m) (8NH); 1500-1440 (s, \)C=c) ! H N M R spectral data are listed in Table 4.3. l ,12-Bis(2-hydroxybenzyl)-l ,5,8,12- tetraazadodecane (H2badd) . To a hot solution of N , N'-bis(3-aminopropyl)ethylenediamine (2 g, 11.5 mmol) in ethanol (200 mL) was added a hot solution of salicylaldehyde (2.8 g, 23 mmol) in ethanol (200 mL). While the solution was still hot, K B H 4 (1.36 g, 25 mmol) was added in small quantities over 10 minutes. The solution was heated at approximately 50 °C and stirred for an additional 2 h. The solvent was removed under reduced pressure, leaving a white residue. N H 4 O A C (3 g) in 50 mL of water was added to the white residue to form an aqueous mixture which was then extracted with chloroform (3 X 100 mL). The organic fractions were combined, washed with distilled water (3 X 100 mL), and then dried over anhydrous MgSC>4. The solution was filtered and the chloroform removed on a rotary evaporator to give a yellow oil. The oil was dried in vacuo at 60 °C for 24 h, yielding 3.85 g (87%). Elemental analysis of the yellow oil was not possible. LSIMS: m/z = 387 ([M+l]+, [C22H35N 4 0 2 ] + ) , 281 ( [ C i 5 H 2 9 N 4 0 ] + ) . *H and 1 3 C N M R spectral data are listed in Tables 4.4 and 4.5, respectively. l ,12-Bis(5-bromo-2-hydroxybenzyl)-l ,5,8,12-tetraazadodecane ( H 2 B r b a d d ) . The preparation of H2Brbadd was similar to that of H2badd, and employed N , N'-bis(3-aminopropyl)ethylenediamine (2 g, 11.5 mmol), 5-bromosalicylaldehyde (4.62 g, 23 mmol) and K B H 4 (1.36 g, 25 mmol), yielding 5.25 g (84%). Elemental analysis of the resulting oil was not possible. LSIMS: m/z = 545 ([M+l]+ [C22H3 3 Br 2 N 4 02] + ) , 359 ( [ C i 5 H 2 8 B r i N 4 0 i ] + ) . *H and 1 3 C N M R spectral data are listed in Tables 4.4 and 4.5, respectively. 67 j Table 4.1. *H N M R data (300 MHz) for the trien-based N4O2 amine phenols, H 2 X b a d (5 ppm from TMS, CDCI3) assignment H 2 bad (X=H) H 2 C l b a d (X=C1) H 2 B r b a d (X=Br) H1/H2/H3 2.74 (m, 12 H ) a 2.72 (m, 12 H ) a 2.74 (m, 12H) a H4 3.93 (s, 4H) 3.90 (s, 4H) 3.93 (s, 4H) H 5 6.95 (dd, 2H)b 6.92 (d, 2H)d 7.08 (d, 2H)d H 6 7.11 (td, 2H)b 7.06 (dd, 2H)b 7.22 (dd, 2H)b H 7 6.75 (m, 2H)c 6.68 (d, 2H)e 6.67 (d, 2H)e H 8 6.75 (m, 2H)c N H 5.20 (b, s) 5.35 (b, s) 5.30 (b, s) a Signal consists of overlapping multiplets attributed to the 12 hydrogens of H i , H 2 and H 3 . B 3 / H H = 6.8-7.0 Hz, 4/HH = 3.0-3.3 Hz c Multiplet at 6.75ppm is attributed to the 4 hydrogens of H7 and Hg. ( D 4 ^ H H = 3.0-3.3 Hz E 3 ^ H H = 6.8-7.0 Hz, 68 Table 4.2. 1 3 C N M R data (200 MHz) for the trien-based N4O2 amine phenols, H2Xbad (8 in ppm from TMS, CDCI3) assignment H 2 bad (X=H) H 2 C l b a d (X=C1) H 2 B r b a d (X=Br) C i , C2, C3 48.0, 48.5, 49.1 48.0, 48.3, 49.0 48.1, 48.4, 49.1 C4 52.4 51.9 51.9 c 5 122.7 123.4 124.6 c 6 158.3 156.9 157.5 c 7 116.3 117.6 118.2 c 8 128.6 128.4 130.9 c 9 118.9 124.1 110.6 C10 128.4 128.0 131.3 69 Table 4.3. *H N M R data (300 MHz) for the acetone adducts of the trien-based N4O2 amine phenols, H2XbadAc (8 in ppm from TMS, CDCI3) assignment H2badAc H 2 C l b a d A c H 2 B r b a d A c (X=H) (X=C1) (X=Br) Hm 1.16 (s, 12H) 1.15 (s, 12H) 1.14 (s, 12H) H i 2.60 (s, 4H) 2.58 (s, 4H) 2.58 (s, 4H) H 2 / H 3 2.86 (m, 8H) a 2.86 (m, 8H) a 2.86 (m, 8H) a H 4 3.82 (s, 4H) 3.77 (s, 4H) 3.78 (s, 4H) H 5 6.90 (dd,2H)b 6.97 (d,2H)d 7.05 (d,2H)d H 6 7.16 (td,2H)t> 7.11 (dd, 2H)b 7.24 (dd, 2H)b H 7 6.78 (m,2H)c 6.73 (d, 2H)e 6.68 (d, 2H)e Hg 6.78 (m,2H)c a Signal consists of overlapping multiplets attributed to the 8 hydrogens of H2 and H3. B V H H = 6.8-7.0 Hz, 4 / H H = 3.0-3.3 Hz c Multiplet at 6.78ppm is attributed to the 4 hydrogens of H7 and Hg. D 4 / H H = 3.0-3.3 Hz e 3 / H H = 6.8-7.0 Hz 70 Table 4.4. lH N M R Data (300 MHz) for the tnentn-based N4O2 amine phenols, H 2 X b a d d (8 in ppm from TMS, CDCI3). ( H 3 ) 2 Wth (Hl)2 P \ >—- / H 7 assignment H 2badd H 2Clbadd H 2Brbadd (X=H) (X=C1) . (X=Br) H1/H2/H4 2.72 (m, 12 H)a 2.60 (m, 12 H)a 2.67 (m, 12H)a H 3 1 1.63 (t,4H)e 1.60 (t, 4H)e 1.65 (t,4H)e H 5 3.97 (s, 4H) 3.85 (s, 4H) 3.92 (s, 4H) H 6 6.80 (dd, 2H)b 6.67 (d, 2H)d 6.65 (d, 2H)d H 7 7.14 (td, 2H)b 7.05 (dd, 2H)b 7.20 (dd, 2H)b H 8 6.97 (m, 2H)c 6.90 (d, 2H)e 7.07 (d, 2H)e H 9 6.97 (m, 2H)c a Signal consists of overlapping multiplets attributed to the 12 hydrogens of H i , H 2 and H4. b A /HH = 6.8-7.0 Hz, 4 / H H = 3.0-3.3 Hz c Multiplet at 6.97 ppm is attributed to the 4 hydrogens of Hs and H9. D 4>/HH = 3.0-3.3 Hz E 3 / H H = 6.8-7.0 Hz 71 Table 4.5. 1 3 C N M R data (200 MHz) for the tnentn-based N4O2 amine phenols, H2Xbad.fl (8 in ppm from TMS, CDCI3). xio assignment H 2 badd (X=H) H 2 C l b a d d (X=C1) H 2 B r b a d d (X=Br) C i , C 2 , C3 ; C4 c 6 c 7 c 8 c 9 C10 C11 29.7, 47.3, 48.0, 49.4 29.3, 47.2, 49.2, 50.0 29.4, 47.4, 48.1, 49.3 52.7 52.1 52.2 122.6 123.2 124.6 158.3 157.0 157.6 116.3 117.5 118.1 128.6 128.2 130.9 118.9 , 124.1 110.5 128.3 128.0 131.3 72 1,12-Bis(5-chIoro-2-hydroxy benzyl)-1,5,8,12-tetraazadodecane (H 2 Clbadd). The preparation of H 2 C l b a d d was similar to that of Ff2badd and employed N , N'-bis(3-aminopropyl)ethylenediamine (2 g, 11.5 mmol), 5-chlorosalicylaldehyde (3.60 g, 23 mmol) and K B H 4 (1.36 g, 25 mmol), yielding 4.3 g (82%). Elemental analysis of the resulting oil was not possible. LSIMS: m/z = 456 ([M+l]+ [C22H33Cl2N 4 0 2 ] + ), 315 ( [ C i 5 H 2 8 C l i N 4 0 i ] + ) . lH and 1 3 C N M R spectral data are listed in Tables 4.4 and 4.5, respectively. Synthesis of Metal Complexes. As many of the syntheses were similar, detailed synthetic procedures are only given for representative examples. It was not possible to obtain analytically pure products of [Ga(bad)]+ and [In(badd)]+ as precipitation of metal hydroxide interfered with and contaminated the product. Syntheses of the metal complexes mainly employed the perchlorate salts of the respective metal ions but other Ga and In salts were also used. Caution! Perchlorate salts of metal complexes are potentially explosive and should be handled with care. [Ga(Brbad)]C10 4-H 20. To a solution of Ga(C10 4 )3-6H 2 0 (405 mg, 0.85 mmol) and H 2 B r b a d (719 mg, 1.4 mmol) in methanol (15 mL) was added sodium acetate (245 mg, 3.0 mmol) in methanol (5 mL). The mixture was immediately filtered and the'filtrate was left at room temperature. Slow evaporation of the solvent yielded a beige precipitate, which was collected by filtration, washed with cold methanol, followed by diethyl ether. The precipitate was dried in vacuo at 80 °C to yield 441 mg (74%). Recrystallization of the precipitate from methanol afforded crystals suitable for X-ray crystallographic analysis. Anal. Calcd (found) for C 2 o H 2 8 B r 2 C l G a N 4 0 7 : C, 34.25 (34.01); H , 4.02 (3.98); N , 7.99 (7.86). LSIMS: m/z = 583 ([ML]+, [GaC2oH 2 6 Br 2 N 4 02] + ) , 684 ([(ML)(A)]+ [(GaC2oH26Br 2 N 4 0 2 )(C10 4 )] + ) , 1267 ([2(ML)(A)]+ [2(GaC2oH 26Br 2N 402)(C10 4)] +). Molar conductance: 122 Q- imoHcm 2 . IR (cm- 1, K B r disk): 3640-3340 (b,m), 3290 (m), 3240 (m) ( u N H ) ; 2980-2860 (m, D C H); 1590 (m), 1555 (w) (8NH); 1500-1410 (s, u c=c). 2 H N M R (400 MHz, DMSO-of 6): 2.40-3.28 (m), 3.60 (d, / = 7 Hz), 3.76 (m), 4.04 (t, / = 7.2 Hz), 4.30 (m), 4.50 (m), 4.88 (m), 4.96 (m), 5.44 (m) (20 benzylic and backbone methylene H and amine H); 6.44 (d, / = 6.8 Hz), 6.56 (t, / = 7 Hz), 7.18 (m) (6 aromatic H). 73 [Ga(Clbad)]C104-H20. A procedure similar to that for [Ga(Brbad)]ClC«4 was followed using Ga(C10 4 )3-6H 2 0 (405 mg, 0.85 mmol), H 2 Clbad (596 mg, 1.4 mmol) and sodium acetate (245 mg, 3 mmol); the yield was 405 mg (78 %). Anal. Calcd (found) for C 2 0 H 2 8 C l 3 G a N 4 O 7 : C, 39.22 (38.98); H , 4.61 (4.49); N , 9.15 (9.11). LSIMS: m/z = 495 ([ML]+, [GaC 2 oH 2 6Cl 2 N 4 0 2 ]+) , 594 ([(ML)(A)]+, [ (GaC 2 oH 2 6 Cl 2 N 4 0 2 ) (C104) ] + ) , 1089 ([2(ML)(A)]+, [2(GaC 2 oH 2 6 Cl 2 N 4 0 2 ) (C104)] + ) . Molar conductance: 120 Q- imoHcm 2 . IR (cm- 1, K B r disk): 3640-3340 (b,m), 3300 (m), 3250 (m) ( u N H ) ; 2980-2860 (m, D CH); 1590 (m), 1555 (w) (5NH); 1500-1410 (s, \)C=c)- ! H N M R (400 MHz, DMSO-^6): 2.40-3.20 (m), 3.58 (d, / = 7 Hz), 3.72 (m), 4.00 (t, / = 7.2 Hz), 4.26 (m), 4.44 (m), 4.85 (m), 4.95 (m), 5.70 (m) (20 benzylic and backbone methylene H and amine H); 6.44 (d, / = 6.8 Hz), 6.56 (t, J = 7 Hz), 7.04 (m) (6 aromatic H). [In(Clbad)]CI04. To a solution of In(C10 4)3-8H 20 (503 mg, 0.90 mmol) and H 2 Clbad (651 mg, 1.5 mmol) in methanol (15 mL) was added sodium acetate (245 mg, 3.0 mmol) in methanol (5 mL). The mixture was immediately filtered and the filtrate was left to stand at room temperature. Slow evaporation of the solvent yielded a white precipitate, which was collected by filtration and washed with cold methanol, followed by diethyl ether. The precipitate was dried in vacuo at 80 °C to yield 444 mg (77 %). Anal. Calcd (found) for C 2 oH 2 6 Cl 3 InN 4 06 : C, 37.56 (37.88); H , 4.10 (4.30); N , 8.76 (8.59). L S I M S : m/z = 539 ([ML]+, [ InC 2 oH 2 6Cl 2 N40 2 ] + ) . Molar conductance: 123 Q^mol - icm 2 . IR (cm"1, K B r disk): 3640-3340 (b,m), 3250 (m), 3200(m) (U N H) ; 2980-2860 (m, U C H); 1590 (m), 1560 (w) (8 N H); 1500-1400 (s, i)c=c). ! H N M R (400 MHz, DMSO-d 6 ) : 2.40-3.10 (m), 3.52 (d, / = 7 Hz), 3.70 (d, / = 7 Hz), 4.02 (t, / = 7.2 Hz), 4.14 (t, / = 7 Hz), 4.44 (m), 4.58 (m), 4.78 (m), 5.00-4.95 (m) (20 benzylic and backbone methylene H and amine H); 6.46 (d, J = 6.8 Hz), 6.60 (t, J = 7 Hz), 7.10 (m) (6 aromatic H). [In(bad)]TH20. A procedure similar to that for [In(CIbad)]OC>4 was followed using In(ClC>4)3-8H20 (503 mg, 0.90 mmol), H 2bad (501 mg, 1.4 mmol), sodium acetate (245 mg, 3 mmol) and sodium iodide (675 mg, 4.5 mmol); the yield was 405 mg (73 %). Anal. Calcd (found) for C 2 0 H3oIInN 4 03: C, 38.98 (38.76); H , 4.91 (4.86); N , 9.09 (9.02). LSIMS: mlz 74 = 471 ([ML]+, [InC 2oH28N402] +), 599 ([(HML)(A)]+, [(InC 2oH29N 402)(I)] +). Molar conductance: 124 r H m o H c m 2 . IR (cm"1, K B r disk): 3660-3300 (b,s), 3230 (s), 3100 (s) (DNH); 2980-2860 (s, "UCH); 1595 (s), 1568 (m) (SNH); 1480-1430 (s, DC=c). *H N M R (400 M H z , DMSO-^6): 2.40-3.20 (m), 3.72 (m), 4.14 (t, / = 7 Hz), 4.24 (t, / = 7.2 Hz), 4.56 (m), 4.70 (m), 4.86 (m), 4.98 (t, / = 7 Hz), 5.14 (m) (20 benzylic and backbone methylene H and amine H); 6.48 (m), 6.64 (t, / = 7 Hz), 7.04 (m) (8 aromatic H). [In(Brbad)]Cl-2H20. A procedure similar to that for [In(Clbad)]C104 was followed using In(C10 4 ) 3 -8H 2 0 (503 mg, 0.90 mmol), H 2Brbad (722 mg, 1.4 mmol), sodium acetate (245 mg, 3 mmol) and sodium chloride (263 mg, 4.5 mmol); the yield was 465 mg (74 %). Anal. Calcd (found) for C2oH3oBr 2 ClInN 4 04: C, 34.29 (34.42); H , 4.32 (3.96); N , 8.00 (8.29). L S I M S : m/z = 629 ([ML]+, [ I n C 2 o H 2 6 B r 2 N 4 0 2 ] + ), 665 ( [ (HML)(A)]+, [(InC 2oH27Br2N 402)(Cl)]+) 1293 ([2(ML)(A)]+, [2(InC2oH26Br 2N 402)(Cl)]+). Molar conductance: 120 Q ^ m o H c m 2 . IR (cnr 1 , K B r disk): 3660-3300 (b,s), 3240 (s), 3100 (s) (DNH); 2980-2860 (s, D C H ) ; 1590 (s), 1555 (m) (8NH); 1480-1400 (s, vC=c)- *H N M R (400 M H z , D M S O - d 6 ) : 2.45-3.28 (m), 3.60 (d, J = 6.9 Hz), 3.76 (m), 4.04 (t„ / = 7 Hz), 4.30 (m), 4.50 (m), 4.88 (m), 4.96 (m), 5.44 (m) (20 benzylic and backbone methylene H and amine H); 6.42 (d, J = 6.8 Hz), 6.56 (d, J = 7 Hz), 7.10 (m) (6 aromatic H). [Ga(Brbadd)]C10 4 . To a solution of Ga(C104)3-6H20 (405 mg, 0.85 mmol) and H2Brbadd (719 mg, 1.3 mmol) in methanol (15 mL) was added sodium acetate (245 mg, 3.0 mmol) in methanol (5 mL). The mixture was immediately filtered and the filtrate was left at room temperature. Slow evaporation of the solvent yielded a beige precipitate, which was collected by filtration and washed with cold methanol followed by diethyl ether. The precipitate was dried in vacuo at 80 °C to yield 441 mg (73 %). Recrystallization of the precipitate from methanol afforded crystals suitable for X-ray crystallographic analysis. Anal. Calcd (found) for C22H3oBr 2 ClGaN40 6 : C, 37.14 (37.48); H , 4.25 (4.16); N , 7.87 (7.76). LSIMS: m/z = 611 ([ML]+, [GaC22H3oBr2N402]+). Molar conductance: 126 Q-imoHcm 2 . IR (cm"1, K B r disk): 3600-3350 (b,m), 3250 (m) (O>NH); 3000-2860 (m, D C H ) ; 1590 (m), 1560 (w) (8NH); 1500-1420 (s, \)c=c). *H N M R (300 MHz, DMSO-^6): 1.60 (d, / = 7 Hz), 1.84 (m), 2.58 (t, / = 75 7.2 Hz), 2.72 (d, J = 7 Hz), 2.84 (d, J = 1 Hz), 2.92 (m), 3.30 (m), 3.62 (m), 3.96 (d, J = 7 Hz), 4.52 (m) (20 benzylic and backbone methylene H); 6.62(d, / = 6.8 Hz), 7.22 (t, / = 7 Hz), 7.26 (d, / = 6.8 Hz) (6 aromatic H). [Ga(badd)]ClO4-0.5H2O. A procedure similar to that for [Ga(Brbadd)]ClC«4 was followed using Ga(C104)3-6H 20 (405 mg, 0.85 mmol), H 2badd (540 mg, 1.4 mmol) and sodium acetate (245 mg, 3 mmol); the yield was 298 mg (62 %). Anal. Calcd (found) for C 2 2 H 3 3 C l G a N 4 0 6 . 5 : C, 46.96 (47.05); H , 5.91 (5.81); N , 9.96 (10.14). LSIMS: m/z = 453 ( [ M L ] + , [GaC 2 2H 3 2N40 2 ] + ) . Molar conductance: 126 Q - i m o H c m 2 . IR (cm"1, K B r disk): 3620-3300 (b,m), 3240 (m) (\)NH); 3000-2860 (m, V C H); 1600 (m), 1570 (w) (8NH); 1500-1430 (s, i)c=c)- l H N M R (300 M H z , DMSO-d 6 ) : 1-60 (d, / = 6.8 Hz), 1.80 (m), 2.62 (t), 2.74(d, 7 = 7 Hz), 2.84 (d, / = 7.2 Hz), 2.92 (m), 3.32 (m), 3.64 (m), 4.00 (m), 4.38 (m) (20 benzylic and backbone methylene H); 6.66 (d, J =6.8 Hz), 6.80 (t, / = 7.2 Hz), 7.04 (d, J = 1 Hz), 7.16 (t, / = 7.2 Hz) (8 aromatic H). [Ga(Clbadd)]C104. A procedure similar to that for [Ga(Brbadd)]ClC«4 was followed using Ga(C104)3-6H20 (405 mg, 0.85 mmol), H 2Clbadd (636 mg, 1.4 mmol) and sodium acetate (245 mg, 3 mmol); the yield was 389 mg (73 %). Anal. Calcd (found) for C 22H3oCl3GaN 406: C, 42.44 (42.34); H , 4.86 (4.90); N , 9.00 (8.97). L S I M S : m/z = 523 ([ML]+, [GaC22H3oCl2N 402] +). Molar conductance: 125 Q ^ m o H c m 2 . IR (cnr 1 , K B r disk): 3600-3300 (b,m), 3245 (m) (o)N H); 3000-2880 (m, \) CH); 1600 (m), 1570 (w) (5NH); 1500-1430 (s, DC=c)- *H N M R (300 MHz, D M S C M 6 ) : 1-60 (d), 1.84 (q), 2.60 (t), 2.74 (d, / = 7 Hz), 2.86 (d, / = 7 Hz), 2.94 (m), 3.30 (m), 3.62 (m), 3.66 (d, / = 7 Hz), 4.00 (m), 4.48 (m) (20 benzylic and backbone methylene H); 6.68(d, / = 6.8 Hz), 7.14 (t, / = 7 Hz), 7.18 (d, / = 6.8 Hz) (6 aromatic H). [InBrbadd)]Cl04. To a solution of In(C10 4)3-8H 20 (503 mg, 0.90 mmol) and H 2Brbadd (651 mg, 1.2 mmol) in methanol (15 mL) was added sodium acetate (245 mg, 3.0 mmol) in methanol (5 mL). The mixture was immediately filtered and the filtrate was left to stand at room temperature. Slow evaporation of the solvent yielded a white precipitate, which was collected by filtration and washed with cold methanol, followed by diethyl ether. The precipitate was 76 dried in vacuo at 80 °C to yield 444 mg (65 %). Anal. Calcd (found) for C22H3oBr2ClInN406: C, 34.93 (35.06); H , 4.00 (4.36); N , 7.41 (7.19). L S I M S : m/z = 657 ([ML]+, [InC 22H3oBr 2N402] +). Molar conductance: 122 Q- imoHcm 2 . IR (cnr 1 , K B r disk): 3600-3340 (b,s), 3240 (s), 3100 (s) ( v N H ) ; 2980-2860 (s, 1)CH); 1610 (s), 1565 (m) (5NH); 1480-1400 (s, i)c=c)- lK N M R (300 M H z , DMSO-d 6 ) : 1.75 (d, J = 1 Hz), 1.82 (m), 2.05 (m), 2.55 (m), 2.80 (m), 3.00 (m), 3.52 (m), 3.76 (d, / = 7 Hz), 4.20 (m), 4.45 (m) (20 benzylic and backbone methylene H); 6.78 (d, / = 6.8Hz), 7.20 (t, / = 7 Hz), 7.25 (d, / = 6.8 Hz) (6 aromatic H). [In(CIbadd)]ClC>4-1.5H20. A procedure similar to that for [In(Brbadd)]C10 4 was followed using In(C10 4)3-'8H 20 (503 mg, 0.90 mmol), H 2Clbadd (681 mg, 1.5 mmol) and sodium acetate (245 mg, 3 mmol); the yield was 458 mg (73 %). Anal. Calcd (found) for C22H33Cl3lnN 4 0 7 . 5 : C, 38.04 (37.94); H , 4.79 (4.66); N , 8.06 (7.98). LSIMS: m/z = 567 ([ML]+, [ InC 2 2 H3oCl2N 4 0 2 ] + ) . Molar conductance: 124 Q-imol-icm 2 . IR (cm"1, K B r disk): 3620-3340 (b,m), 3250 (m), 3200(m) ( D n h ) ; 2980-2860 (m, D C H) ; 1595 (m), 1560 (w) (5NH); 1500-1400 (s, \)c=c)- ! H N M R (300 MHz, DMSO-cfe): 1-76 (d), 1.82 (m), 2.52 (t, / = 7 Hz), 2.68 (d, J = 7 Hz), 2.86 (d, J = 7 Hz), 2.92 (m), 3.04 (m), 3.50 (m), 3.72 (d, J = 1 Hz), 4.18 (m), 4.48 (m) (20 benzylic and backbone methylene H); 6.72 (d, / = 6.8 Hz), 7.10 (t, / = 7 Hz), 7.18 (d, / = 6.8 Hz) (6 aromatic H). 77 X-ray Crystallographic Analyses of H 3 Clapi , [Ga(Brbad)]Cl0 4 -DMSO and [Ga(Brbadd)]Cl0 4. The crystal structure of [Ga(Brbad)]C10 4DMSO was determined by Prof. Dr. F. Ekkehardt Hahn and Thomas Lugger of the Institut Fur Anorganische und Analytische Chemie der Freien Universitat Berlin. An ORTEP drawing of the [Ga(Brbad)]+ cation and D M S O solvate in [Ga(Brbad)]C104-DMSO is shown in Figure 4.6. Selected bond lengths and bond angles in [Ga(Brbad)]+ are given in Table 4.7. Crystallographic data and final atomic coordinates (fractional) and 2?^ (A2) for non-hydrogen atoms in [Ga(Brbad)]C104 are given in Appendix I. ORTEP drawings of H3Clapi and the [Ga(Brbadd)]+ cation in [Ga(Brbadd)]C104 are shown in Figure 4.3 and 4.8, respectively. Selected bond lengths and bond angles in H^Clapi and [Ga(Brbadd)]+ are given in Table 4.6 and Table 4.8, respectively. Crystallographic data and final atomic coordinates (fractional) and 5eq (A2) for non-hydrogen atoms in H3Clapi and [Ga(Brbadd)]C104 are given in Appendix I. 78 4.3. Resul t s and Discuss ion Linear N 4 O 2 Amine Phenols ( H 2 X b a d and H 2 X b a d d ) . In previous studies, tripodal amine phenols were prepared by reducing their Schiff base analogs with K B H ^ . 1 - 3 - 5 The Schiff base compounds were prepared from condensation reactions of the appropriate tripodal amine backbone with salicylaldehyde or ring substituted salicylaldehydes; however, this method was not suitable for the preparation of the linear amine phenols F^Xbad and H 2 X b a d d . Reaction of salicylaldehyde, or a substituted salicylaldehyde with trien resulted in the production of 2-(2-hydroxyphenyl)-l,3-di[3-aza-4T(2-hydroxyphenyl)-prop-4-en-l-yl]-l,3-imidazolidine (H3api) or its ring substituted analogs (H3Clap i and Ff3Brapi) (Figure 4.2). Regardless of the ratio of aldehyde to amine, the resulting Schiff base incorporated an imidazolidine ring, which was formed by the reaction of a third aldehyde with the two inner adjacent secondary amine nitrogens of trien. This observation is consistent with the results found by other workers. 8 - 1 2 Similar Schiff bases with imidazolidine rings were also observed in the reaction of salicylaldehyde or ring substituted salicylaldehydes with tnentn. A crystallographic analysis of F^Clapi was performed and an ORTEP drawing of F^Clapi is given in Figure 4.3. Selected bond lengths and bond angles in FFjClapi are given in Table 4.6. The crystal structure of F^Clapi clearly showed the imidazolidine ring bridging the two inner amine nitrogen atoms. The solid state structure was consistent with the * H N M R spectrum (Figure 4.4). Reduction of H3api , Ff^Clapi or F^Brapi with K B H 4 resulted in two isomeric products, N,N',N'"-tris(2-hydroxybenzyl)-triethylenetetramine, ( l , 2 , 4 - H 3 X b t t ) and N,N,N"'-tris(2-hydroxybenzyl)triethylenetetramine, ( l , l , 4 -H3Xbt t ) (Figure 4.2). Repeated attempts to separate the two isomeric products were unsuccessful; however, X-ray crystal structures of Yb(l,2,4-btt) and In(l,l,4-btt) were determined.12 Preparation of the desired linear N4O2 amine phenols (F^Xbad, H^Xbadd) involved a modified amine phenol synthesis. Instead of performing the K B H 4 reduction on the isolated Schiff base compound, the modified synthesis involved the direct addition of K B H 4 to hot methanolic solutions of tetraamine and salicylaldehyde, or substituted salicylaldehyde. No uncomplexed Schiff bases were ever isolated. The oily products of the in situ reduction were 79 characterized as the desired linear N4O2 amine phenols. These amine phenols were soluble in polar solvents such as methanol and chloroform, and, unlike Schiff bases, they were hydrolytically stable under both acidic and basic conditions. The linear amine phenols were also water soluble at low pH in millimolar concentration. r N H , N H H N H 2 N K B H , / s j~HW H N - ^ N H H N H O , H2Xbad Acetone H9XbadAc H 3Xapi K B H 4 N ^ H N -N H [ ' | T ~ " N H O H ^ ^ X H O H3(l,2,4-Xbtt) / \ ^ H M H H N ^ N ^ H N O H H O H3(l,l,4-Xbtt) Figure 4.2. Reaction scheme for the preparation of H2Xbad, H2XbadAc, H3Xapi, H 3(l,2,4-Xbtt) and H 3(l,l,4-Xbtt). 80 C 1 2 CIS Figure 4.3. ORTEP drawing of H3Clapi with numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. u T T — r — i — " i — i — i — r i i r~ 9 8 7 6 5 4 3 2 1 0 PPM Figure 4.4. *H NMR spectrum (300 MHz) of H 3Clapi in CDCI3. 81 Table 4.6. Selected bond lengths (A) and angles (°) in H^Clapi. atom atom distance atom atom distance 01 C4 1.353(6) CI C I * 1.504(6) 02 C13 1.346(3) C2 C3 1.507(5) N l CI 1.482(3) C3 C4 1.418(5) > N l C2 1.462(3) C9 CIO 1.511(4) N l C9 1.455(3) C l l C12 1.453(4) N2 CIO 1.456(4) C12 C13 1.404(4) 1 N2 C l l 1.269(3) atom atom atom angle atom atom atom angle CI N l C2 103.4(2) 01 C4 C5 118.4(5) CI N l C9 113.7(2) C3 C4 C5 119.2(5) C2 N l C9 113.7(2) N l C9 CIO 112.8(2) CIO N2 C l l 118.5(3) N2 CIO C9 111.4(2) N l CI C I * 104.6(1) N2 C l l C12 122.8(3) N l C2 N l * 100.8(3) c i i C12 C13 120.9(3) N l C2 C3 113.9(2) C l l C12 C17 120.3(3) C2 C3 C4 120.6(4) C13 C12 C17 118.7(3) C2 C3 C8 120.3(4) 02 C13 C12 121.4(3) C4 C3 C8 118.8(4) 02 C13 C14 119.1(3) 01 C4 C3 122.3(4) C12 C13 C14 119.6(3) * Symmetry operation: x, 1/2-y, z Reaction of the trien-based amine phenols (F^Xbad) with acetone resulted in the formation of the easily characterizable and much more tractable acetone adducts with two imidazolidine rings (Figure 4.2). The imidazolidine rings have also been observed in the acetone adducts of the tap-based amine phenols (H3XTAP) 3 but no adducts were produced for tren-based ( H 3 X T R N ) 1 or tame-based ( H 3 X T A M ) 2 amine phenols. For H 3 X T R N and H 3 X T A M , the parent amines lacked the required H N C H 2 C H 2 N H functionality to form imidazolidine rings. Similar treatment of H 2 X b a d d amine phenols with acetone did not produce any acetone adducts because 5 membered imidazolidine rings were much more stable 82 than 6 membered 1,3-piperazine rings. A l l the linear amine phenols (H2Xbad, H2Xbadd) and the acetone adducts of Ff2Xbad (F^XbadAC) were characterized by a variety of spectroscopic techniques (IR, N M R and LSIMS) and elemental analyses. *H N M R spectra of F^Xbad and F^Xbadd showed them to be symmetric about the central ethylene moiety. lH N M R spectra of F^Clbad, H 2ClbadAc and F^Clbadd are shown in Figure 4.5. The two hydroxylbenzyl groups attached to the tetraamine backbone via the terminal amine nitrogens were chemically equivalent because only a single set of *H resonance signals was observed in the aromatic region of the spectra (6.5-7.5 ppm) (Figure 4.5). This set of *H resonance signals corresponded to the hydrogen atoms on two chemically equivalent hydroxybenzyl groups. The presence of a third group, either bridging two amine nitrogens to form an imidazolidine r i n g 8 ' 1 2 (as in HsClapi; Figure 4.4), or simply attached to one amine nitrogen (as in the isomers l,l,4-H3Xbtt or l,2,4-H3Xbtt),12 would result in a second set of aromatic resonance signals. Additional evidence confirming the absence of a third hydroxybenzyl group was the one singlet observed for the benzylic hydrogens in the *H N M R spectra. This singlet at -3.9 ppm corresponding to the benzylic hydrogens also confirmed the successful reduction of the imine bonds. No imine H singlet was observed at -8.3 ppm . 1 3 C N M R spectral data of H 2Xbad and F^Xbadd confirmed the 2-fold symmetry about the central ethylene moiety of the two linear amine phenols. 1 3 C N M R spectra of H 2Xbad showed only 10 out of a possible 20 1 3 C resonance signals and the spectra of H2Xbadd showed 11 out of a possible 22 resonance signals. The hydrogens on the tetraamine backbone appeared as a complex set of overlapping resonance signals from 2.60 ppm to 2.75 ppm (Figure 4.5, spectra of H 3 CIbad and H3Clbadd). Specific assignments of these resonance signals were not possible; however, integration of the overlapping multiplet, of the signals in the aromatic region, and of the singlet from the benzylic hydrogens, confirmed the formulation of N4O2 amine phenols with two hydroxybenzyl groups attached to the ends of the tetraamine backbone. Mass spectral data were also consistent with this formulation. 83 I _ 1 — j — | — r 9 8 7 6 i 1 r — i — i 1 5 4 3 2 1 0 PPM Figure 4.5. ! H N M R spectra (300 MHz) of H 3Clbadd (top), H 2 ClbadAc (middle), and H2Clbad (bottom) in CDCI3. 84 Acetone, adducts of trien-based N4O2 amine phenols (H2badAc, H 2 C l b a d A c , F^BrbadAc) were prepared by refluxing the amine phenols in acetone. Each adduct contained two imidazolidine rings, which were formed by the reaction of acetone with an inner amine nitrogen and an outer amine nitrogen (Figure 4.2). Elemental analyses and spectroscopic studies were consistent with the proposed formulations. *H N M R spectra of the adducts were similar to the spectra of the corresponding amine phenols with the exception of singlets at -1.15 ppm and at ~2.58 ppm. The singlet at 1.15 ppm corresponded to the twelve methyl hydrogens on the two imidazolidine rings. The singlet at 2.58 ppm was from the four methylene hydrogens (Hi) located between the two inner (now tertiary) amine nitrogen atoms of the trien backbone (Table 4.3). In the *H N M R spectra of the amine phenols (H2bad, H2Clbad, H2 R rbad) , this singlet overlapped with resonance signals from hydrogens H3 and H4 on the outer ethylene groups lying in between the inner amine nitrogen and the terminal amine nitrogen. The formation of two imidazolidine rings in the acetone adduct shifted the signals of H3 and H4 downfield from -2.75 ppm to -2.86 ppm. The four H i ,hydrogens were shifted slightly upfield by the formation of the imidazolidine rings. Hence, it was possible to identify the singlet at 2.58 ppm as the four methylene hydrogens, H i . G a and In Complexes. [Ga(Xbad)] + and [In(Xbad)] + complexes were easily prepared from reactions of H2Xbad amine phenols with hydrated metal salts in the presence of excess sodium acetate. Similar procedures were used to prepare [Ga(Xbadd)] + complexes; however, in analogous reactions it was much more difficult to isolate analytically pure In complexes due to formation of In hydroxide. [Ga(Xbad)] + and [Ga(Xbadd)] + complexes were quite stable under both basic (no metal hydroxide forms in the presence of sodium hydroxide) and weakly acidic conditions (stable to the acetic acid formed when the metal ion coordinated with the amine phenol ligand in the presence of sodium acetate). [In(Xbad)] + complexes were also stable under these conditions; however, [In(Xbadd)]+ complexes were not stable under weakly acidic conditions. Precipitation of In hydroxide often occurred when [In(Xbadd] + complexes were left in methanol for several days at room temperature and pH 5-6; this was not observed for [In(Xbad)]+ complexes. The Ga and In linear amine phenolate complexes were all soluble in 85 D M S O , and slightly soluble in alcohol. A l l the metal complexes were characterized by spectroscopic techniques (IR, N M R and LSIMS), molar conductivity measurements, and elemental analyses, and these data were consistent with the proposed formulation of monocationic, hexacoordinated complexes. X-ray crystallographic analyses of [Ga(Brbad)]ClC«4\DMSO and [Ga(Brbadd)]ClC«4 were performed and found to be consistent with the proposed formulation (vide infra). [Ga(Xbad)]+ and [In(Xbad)]+ complexes were also prepared from the reaction of metal salts with H2XbadAc. During complexation of the metal ion, the two imidazolidine rings open, thereby freeing the amine nitrogens for coordination to the metal ion. In the complexation of the Schiff base, Ff3api and its ring substituted analogs with metal ions such as F e 3 + , A l 3 + , G a 3 + , I n 3 + , M n 3 + and C o 3 + , the imidazolidine ring opens and allows all four amine nitrogens to coordinate to the metal i o n . 9 - 1 5 Similar opening of the imidazolidine rings are also observed in the complexation of G a 3 + and I n 3 + with the acetone adduct of tap-based amine phenols.3 One exception among these metal ions is a dinuclear Fe complex with the phenolate oxygen atom of the middle oxybenzyl group bridging two Fe centers.16 Attempts to isolate A l 3 + complexes with linear amine phenolates were unsuccessful, even in the presence of excess ligand, as precipitation of aluminum hydroxide often interfered with and accompanied the isolation of the complexes. A l and Ga complexes of the sulfonated N4O2 Schiff base analogs of Xbad2" have been studied and the p M value for the A l complex is 10 orders of magnitude less than that for the Ga complex. 8 ' 1 7 These complexes are prepared by a template reaction, in which the Schiff base is synthesized in situ from the sulfonated salicylaldehyde and triethylenetetraamine in the presence of the metal ion; however, the actual complexes are not isolated. Clearly, the A l complex is much less stable than its Ga congener. IR spectral data of the Ga and In complexes showed medium to strong bands in the region 3250-3100 cm" 1 and medium to weak bands in the 1595-1555 cm" 1 region, corresponding to N - H stretching and bending modes of the coordinated amines, respectively. Upon coordination of the amine phenolates, there was a general bathochromic shift of ~20 cm" 1 in the N - H bending modes, which was consistent with observations in previous studies.1"3*5'1 2 86 A comparison of the IR data of H 2 X b a d A c with those of the corresponding metal complexes revealed new bands which appeared below 600 cm" 1 in the spectra of the metal complexes. These additional bands were probably M - 0 or M - N stretches; however, assignments of these bands were not conclusive because of their low energies. For the perchlorate complexes, a strong broad perchlorate band was observed at 1100 cm" 1. Molar conductivity measurements of all the Ga and In complexes in acetonitrile showed values of 120-126 Q ' 1 mol" 1 c m 2 (25 °C); this was consistent with a 1:1 electrolyte, i.e. a monocationic metal complex formulation.1 8 In the LSIMS of the Ga and In complexes, the molecular ion [ M L ] + peaks were detected as well as [ H M L A ] + or [ M L A ] + peaks where A is the anion present in the complex. In the spectra of some of the metal complexes, a [ (ML)2A] + peak was also observed *H N M R spectra of [Ga(Xbad)]+ and [In(Xbad)]+ complexes were recorded in DMSO-^6 and were very similar to each other with the exception of the aromatic region (6.5-7.5ppm). The spectra were extremely complex and detailed assignments of the individual resonances were not carried out, but tentative assignments are given in the experimental section. In the free amine phenols, the two oxybenzyl groups attached to the terminal amine nitrogens were chemically equivalent in both the lH and 1 3 C N M R spectra (Table 4.1 and 4.2). Coordination of the amine phenolates to the metal ions caused a greater complexity of the aromatic resonance signals; this was attributed to the two oxybenzyl groups becoming nonequivalent during complexation. This was supported by the 1 3 C N M R spectra of [Ga(Xbad)]+ which showed twenty 1 3 C resonance signals while the 1 3 C N M R spectra of the free amine phenols showed only ten 1 3 C resonance signals. In addition, the singlet from the benzylic hydrogens and the multiplet from the aliphatic hydrogens on the trien backbone became a complex series of overlapping signals from 2.3 ppm to 5.0 ppm. These complex multiplets were observed as high as 120 °C. Nonequivalence of the oxybenzyl groups was also observed at elevated temperature. This clearly demonstrated the rigid intact structure of the Ga and In complexes in solution. These N M R spectral data were consistent with the solid-state structure of [Ga(Brbad)]+. 87 The ! H and 1 3 C N M R spectra of the [Ga(Xbadd)]+ and [In(Xbadd)]+ complexes were similar in DMSO-fifg. Only one set of *H N M R resonance signals in the aromatic region of the spectra proved that the two oxybenzyl groups of Xbadd2" remained chemically equivalent upon coordination. This was in contrast with the [Ga(Xbad)]+ and [In(Xbad)]+ complexes, which had two chemically nonequivalent oxybenzyl groups. Upon coordination of Xbadd2" to G a 3 + and I n 3 + , the lH N M R signals of the benzylic and the aliphatic H atoms became a complex series of overlapping resonances; however, the degree of complexity of these resonances in the Xbadd 2" complexes was significantly less than that observed in the N M R spectra of the Xbad 2 ' complexes. N M R spectral data showed clearly a two fold symmetry in the Xbadd 2" complexes that was not found in the complexes of the shorter Xbad 2" amine phenolates, indicating that the coordination configuration of metal complexes with the longer chain Xbadd2" was different from the configuration of complexes with Xbad2". 1 3 C N M R spectra supported this assignment because only 11 out of a possible 22 1 3 C resonance signals were observed. 1 3 C N M R spectra of [M(Xbad)]+ complexes (M= G a 3 + , In 3 + ) showed 20 1 3 C resonance signals, corresponding to the 20 nonequivalent carbon atoms of the amine phenol. As the N M R spectra of the Ga and In complexes were very similar, variable temperature lH N M R experiments in D M S O - d ^ w e r e performed only for [Ga(Brbad)]C104, [In(Brbad)]Cl, [In(bad)]I, [Ga(Brbadd)]C104, and [In(Clbadd)]C104. No significant change in the spectral data was observed for [Ga(Brbad)]C104, [In(Brbad)]Cl, [In(bad)]I and [Ga(Brbadd)]C104 as the temperature was raised from room temperature to 120 °C. Minor shifts of hydrogen resonance signals and a slight broadening of the signals were observed. Thermal vibrations of the coordinated ligand at the elevated temperature explained the observed broadening and shift of the *H resonance signals. Similar behavior was observed in the variable temperature *H N M R experiment of [In(Clbadd)]C104, except for decomposition at 120 °C as indicated by the presence of free amine phenol. X-ray Crystal Structure of [Ga(Brbad)]C10 4DMSO. A n ORTEP drawing of the [Ga(Brbad)]+ cation in [Ga(Brbad)]C10 4DMS0 is illustrated in Figure 4.6 while selected bond lengths and angles in the cation are listed in Table 4.7. G a 3 + and I n 3 + were 88 Figure 4.6. ORTEP drawing of the [Ga(Brbad)]+ cation and DMSO solvate in [Ga(Brbad)]C104'DMSO showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. Table 4.7. Selected bond lengths (A) and angles (°) for the [Ga(Brbad)]+ cation in [Ga(Brbad)]C104DMSO. atom atom distance atom atom distance Ga 01 1.911(6) N3 C l l 1.50(1) Ga 02 1.914(6) N3 C12 1.49(1) Ga N l 2.073(7) N4 C13 1.49(1) Ga N2 2.138(8) N4 C14 1.45(1) Ga N3 2.153(8) CI C2 1.43(1) Ga N4 2.085(7) CI C6 1.39(1) Brl C4 1.89(1) C2 C3 1.41(1) Br2 C17 1.913(9) C4 C5 1.38(1) Ol CI 1.31(1) C5 C6 1.37(1) 02 C20 1.33(1) C6 C7 1.53(1) 89 Table 4.7 cont. atom atom distance atom atom distance N l C7 1.48(1) C8 C9 1.53(1) N l C8 1.48(1) CIO C l l 1.53(1) N2 C9 1.48(1) C12 C13 1.49(1) N2 CIO 1.48(1) C14 C15 1.53(1) C15 C16 1.37(1) C15 C20 1.41(1) C16 C17 1.36(1) C17 C18 1.36(1) C18 C19 1.37(1) C19 C20 1.41(1) 07 N l a 2.836 atom atom atom angle atom atom atom angle o r Ga 02 102.4(3) Ga 02 C20 123.7(6) O l Ga N l 90.4(3) Ga N l C7 109.9(6) O l Ga N2 168.8(3) Ga N l C8 106.6(6) 01 Ga N3 92.9(3) C7 N l C8 111.7(7) O l Ga N4 82.5(3) Ga N2 C9 108.8(6) 02 Ga N l / 91.5(3) Ga N2 CIO 110.0(6) 02 Ga N2 86.1(3) C9 N2 CIO 112.6(8) 02 Ga N3 162.0(3) Ga N3 C l l 111.7(6) 02 Ga N4 90.1(3) Ga N3 C12 106.0(6) N l Ga N2 82.2(3) C l l N3 C12 112.9(8) N l Ga N3. 97.9(3) Ga N4 C13 111.0(6) N l Ga N4 172.8(3) Ga N4 C14 116.2(6) N2 Ga N3 80.1(3) C13 N4 • C14 112.6(7) N2 Ga N4 104.9(3) Ga 01 CI 126.5(6) N3 Ga N4 82.4(3) / a 07 is probably hydrogen bonded to the amine hydrogen atom on N l , however, this hydrogen position was not located in the least-squares calculations. expected to coordinate to the Xbad 2 " amine phenolates via the four neutral amine nitrogens and two anionic phenolate oxygens (a N4O2 donor set). Considering the steric constraint of the trien backbone, it was expected that the amine phenolate should span the octahedral positions around the metal center in a manner such that any two adjacent donor atoms would be coordinated cis to 90 each other. (A coordination environment with two adjacent donor atoms coordinated trans to each other would have an extremely strained trien backbone). There were, however, four ways in which the linear Xbad2" amine phenolates may span octahedral positions such that adjacent donor atoms were coordinated cis to one another (Figure 4.7); the mirror image of each was also possible since the structures were all chiral. Space filling models suggest that structure A is the least sterically strained of the four possible structures, which is consistent with an earlier postulation.10 1 N H N H H N H N 4 2 3 N l 02 N l 01 0 2 - 101 N2 |N3 0 1 - 102 N l - 102 \ \ \ \ \ \ \ \ N2, N3 N l -N4 N2, N3 N2, N3 N4 01 N4 N4 A B C D Figure 4.7. Potential coordination modes for [M(Xbad)]+ and [M(Xbadd)]+ complexes (M= G a 3 + , In 3 + ) . Crystallographic analysis of [Ga(Brbad)]C104-DMS0 confirmed the hexa-coordination of the ligand to G a 3 + through four amine nitrogens and two phenolate oxygens. The complex was monocationic with a doubly deprotonated amine phenol ligand coordinated to G a 3 + in a distorted octahedral coordination geometry. N l , N2, 02 occupied one face of the octahedron while N3, N4, O l occupied the other face. Distortion in the octahedral geometry can be attributed to the steric requirements of the trien backbone, coordination of the four amine nitrogens resulted in three five-membered chelate rings. These five-membered rings restricted the cis angles involving two consecutive nitrogens to an average of 81.6° (Nl-Ga-N2 = 82.2(3)°, N2-Ga-N3 = 80.1(3)°, N3-Ga-N4 = 82.4(3)°). Coordination of the phenolate 91 oxygens formed two six-membered chelate rings with cis angles of 90.4 (3)° and 90.1(3)° for O l - G a - N l and 02-Ga-N4, respectively. As illustrated in Figure 4.7, the linear Xbad2" amine phenolates can coordinate a metal center in four possible configurations. Crystallographic analysis of [Ga(Brbad)]C10 4DMSO showed that the metal complex assumed the configuration of structure A . This is consistent with the postulate that structure A is the least sterically demanding of the four possible structures (the two halves of the chelating ligand being mer to each other).1 0 M n , 1 9 N i 1 4 and F e 1 5 complexes with linear hexadentate ligands containing trien backbone also assume configuration A . The two Ga-O bond lengths were 1.911(6) A (Ga-Ol) and 1.914(6) A (Ga-02) while the Ga-Nl and Ga-N4 bond lengths were 2.073(7) A and 2.085(7) A, respectively. These latter distances were shorter than the Ga-N2 and Ga-N3 bond lengths which were 2.138(8) A and 2.153(8) A, respectively. Steric constraints of the trien backbone caused this difference in Ga-N bond lengths; however, the Ga-N and Ga-0 bond lengths were still consistent with the bond lengths observed in other Ga amine phenol complexes,1"3 Ga Schiff base complexes, 7 ' 2 0 and other Ga hexadentate ligand complexes. 2 1" 2 6 Attempts to grow X-ray quality crystals of an In analog were unsuccessful; however, the In complexes would probably show a coordination environment similar to that of [Ga(Brbad)]+. As the ionic radius of I n 3 + in six coordination (0.80 A ) 2 7 is larger than that of G a 3 + (0.62 A) 2 7 there would likely be an even greater steric strain within the trien backbone as the amine phenolate wraps around the larger I n 3 + ion. X-ray Structure of [Ga(Brbadd)]C104. Crystals of [Ga(Brbadd)]C104 suitable for X-ray crystallographic analysis were grown from a methanol solution by slow evaporation of the solvent at room temperature. A n ORTEP drawing of the cation, [Ga(Brbadd)]+ is illustrated in Figure 4.8 while selected bond lengths and bond angles are listed in Table 4.8. The G a 3 + ion was hexacoordinated via four neutral amine nitrogen atoms and two anionic phenolate oxygen atoms (a N 4 0 2 donor atom set) in a distorted octahedral coordination geometry. No suitable crystals of the In complexes were available for crystallographic analyses; however, the I n 3 + ion was also expected to be hexacoordinated by a N 4 0 2 donor atom set. 92 crystallographic analyses; however, the In 3 + ion was also expected to be hexacoordinated by a N4O2 donor atom set. Figure 4.8. ORTEP drawing of the [Ga(Brbadd)]+ cation in [Ga(Brbadd)]C104 showing the crystallographic numbering scheme. Thermal ellipsoids for the non-hydrogen atoms are drawn at 33% probability level. 93 Table 4.8. Selected bond lengths (A) and angles (°) for the [Ga(Brbadd)]+ cation in [Ga(Brbadd)]C104. atom atom distance atom atom distance Ga 01 1.934(4) N3 C6 1.459(9) Ga 02 1.913(4) N3 C5 1.484(10) Ga N l 2.101(6) N4 C8 1.480(9) Ga N2 2.087(6) N4 C16 1.513(8) Ga N3 2.093(6) CI C2 1.52(1) Ga N4 2.146(6) C2 C3 1.50(1) B r l C14 1.918(8) C4 C5 1.50(1) Br2 C21 1.900(7) C6 C7 1.52(1) O l C l l 1327(8) C7 C8 1.51(1) 02 C18 1.345(7) C5 C6 1.367(13) N l CI 1.487(7) C9 CIO 1.505(8) N l C9 1.499(8) CIO C l l 1.406(9) N2 C3 1.484(9) C16 C17 1.495(10) N2 C4 1.46(1) C17 C18 1.394(9) C12 C13 1.39(1) C14 C15 1.384(8) atom atom atom angle atom atom atom angle 01 Ga 02 177.6(2) Ga 02 C18 124.6(4) 01 Ga - N l 91.4(2) Ga N l CI 114.9(5) O l Ga N2 89.9(2) Ga N l C9 113.4(4) 01 Ga N3 88.1(2) CI N l C9 109.9(5) 01 Ga N4 87.9(2) Ga N2 C3 116.7(5) 02 Ga N l 90.5(2) Ga N2 C4 108.1(5) 02 Ga N2 91.5(2) C3 N2 C4 110.9(7) 02 Ga N3 90.2(2) Ga N3 C5 106.6(5) 02 Ga N4 90.6(2) Ga N3 ' C6 118.8(5) N l Ga N2 89.9(3) C5 N3 C6 111.1(7) N l Ga N3 172.6(2) Ga N4 C8 118.5(5) N l Ga N4 93.9(2) Ga N4 C16 111.9(4) N2 Ga N3 82.8(3) C8 N4 C16 111.5(5) N2 Ga N4 175.7(3) N l CI C2 113.1(6) N3 Ga N4 93.4(2) CI C2 C3 114.7(7 94 Table 4.8 cont. atom atom atom angle atom atom atom angle Ga 01 C l l 122.0(4) N2 C3 C2 113.8(7) N2 C4 C5 109.6(7) N l C9 CIO 113.8(5) N3 C5 C4 107.2(7) C9 CIO C l l 117.7(7) N3 C6 C7 . 111.9(7) 01 C l l CIO 121.6(6) C6 C7 C8 114.9(7) N4 C16 C17 112.3(6) N4 C8 C7 116.9(7) C16 C17 C18 119.6(6) 02 C18 C17 120.9(7) By crystallography and N M R spectroscopy, it was shown that Ga and In complexes with Xbad2" amine phenolates assumed configuration A ; 6 however, crystallographic analysis of [Ga(Brbadd)]C104 showed the Brbadd 2" ligand coordinated to G a 3 + according to configuration B (Figure 4.8), the two phenolate oxygen atoms coordinated trans to one another. The four nitrogen atoms of the amine backbone formed a distorted equatorial plane with the phenolate oxygen atoms located above and below the plane of the amine nitrogen atoms. N M R spectral data were consistent with the solid state structure of [Ga(Brbadd)]C104. The difference in the coordination modes of Xbad2" and Xbadd2" has a parallel in metal complexes involving similar hexadentate ligands with trien or tnentn amine backbones. N i ( I I ) , 1 4 Fe(III) 1 5 and M n ( I V ) 1 9 complexes with trien ligand backbones all assume configuration A . Related M n ( I V ) 1 9 and Ga(III)7 complexes with tnentn backbones assume configuration B. For both trien-based and tnentn-based amine phenols, only one coordination configuration was observed for Ga and In complexes. The difference in coordination configuration between the [M(Xbad)]+ and [M(Xbadd]+ complexes (M= G a 3 + , In 3 + ) can be attributed to the increased length of the tetraamine backbone in the latter and the change in the number of 5- and 6-membered chelate rings. Barring any major interference from electronic factors, ligands wil l coordinate via a configuration involving the least steric strain. Configuration A represented the least sterically demanding configuration available for 95 coordination of Xbad2" to a metal center. As the length of the amine backbone was increased by substituting trien with tnentn, configuration B became the preferred configuration for coordination of the linear hexadentate ligand to the metal ion. It would be interesting to see what would be the least sterically demanding configuration for complexes with linear amine phenolates based on N,N'-bis(2-aminoethyl)-l,3-propanediamine (2,3,2-tet) and N,N'-bis(3-aminopropyl)-l,3-propanediamine (3,3,3-tet); 3,3,3-tet based amine phenolates would only have 6-membered chelate rings when coordinated to a metal center. Coordination of Brbadd2" to G a 3 + resulted in the formation of one 5-membered and four 6-membered chelate rings. The cis angles N(l)-Ga-N(2), N(2)-Ga-N(3), N(3)-Ga-N(4) and N(l)-Ga-N(4) were 89.9(3)°, 82.8(3)°, 93.4(2)° and 93.9(2)°, respectively. The N(2)-Ga-N(3) angle was much less than the other three cis angles due to the restriction of the five-membered chelate ring. The trans angles averaged 175°. The cis angles O-Ga-N were close to 90° , ranging from 88.9° to 91°. The degree of distortion in the octahedral geometry of [Ga(Brbadd)]+ was much less than the distortion observed in the octahedral geometry of [Ga(Brbad)]+, suggesting that Brbadd2" was more suited to its coordination configuration (configuration B) than was Brbad2" (configuration A) . The difference in the degree of distortion within the octahedral coordination geometry has a parallel in Mn(IV) complexes with hexadentate ligands containing trien and tnentn backbones.19 The Ga-Ol and Ga-02 bond lengths were 1.934 A and 1.913 A respectively, while Ga-N bonds averaged 2.107 A. Ga-N(2) and Ga-N(3) were shorter than Ga-N(l) and Ga-N(4), most likely due to the restriction of the 5-membered chelate ring formed by N2, C4, C5, N3 and Ga. The other two Ga-N bonds were involved in six-membered chelate rings. The observed Ga-0 and Ga-N bond lengths are comparable with those in [Ga(Brbad)]+, Ga amine phenol,1"3 and Schiff base complexes,7-2 0 and other Ga hexadentate complexes 2 1 - 2 6 It was observed qualitatively that there was a difference between the stabilities of the various [M(Xbad)]+ and [M(Xbadd]+ complexes (M= G a 3 + , In 3 + ) . To quantify the stability of these complexes, stability constants were determined by potentiometric titrations and are 96 presented in Chapter 6. Stability constants of the metal complexes will provide us with insights into the selectivity of these linear amine phenolates for G a 3 + and I n 3 + ions. Three five-membered and two six-membered chelate rings were formed by the coordination of Xbad2" to metal ions. Coordination of Xbadd2* to metal ions resulted in the formation of one five-membered and four six-membered chelate rings. It is postulated that complex stability is closely related to the size of the chelate rings and to the size of the metal i o n . 2 8 " 3 0 As chelate ring size increases from five to six, stability of metal complexes generally decreases. The larger the coordinated metal ion, the greater the destabilization in the metal complex as the chelate ring size increases from five to six. Molecular mechanics calculations have shown that complexes of smaller metal ions and M - N bond lengths of approximately 1.6 A will coordinate with the least strain when the resulting chelate ring is six-membered and that larger metal ions coordinate with the least strain when five-membered chelate rings are formed. 2 8 " 3 0 Xbad2" amine phenolates, which formed three five-membered and two six-membered chelate rings upon complexation, and Xbadd2" amine phenolates, which formed one five-membered and four six-membered chelate rings upon complexation, may form metal complexes of varying stabilities as the size of the metal ion increases from A l 3 + (0.53 A ) 2 7 to G a 3 + (0.62 A ) 2 7 to I n 3 + (0.80 A ) 2 7 ; stability constant studies would clarify this situation. 97 4.4. References 1. Liu , S.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1992,31, 5400. 2. Liu , S.; Wong, E.; Karunaratne, V. ; Rettig, S. J.; Orvig, C. Inorg. Chem. 1993,32, 1756. 3. L iu , S.; Wong; E.; Rettig S. J.; Orvig, C. Inorg. Chem. 1993,32, 4268. 4. Duma, T. W.; Marsicano, F.; Hancock, R. D. / . Coord. Chem. 1991, 23, 221. 5. L iu , S.; Gelmini, L . ; Rettig, S. J.; Thompson, R. C.; Orvig, C. / . Am. Chem. Soc, 1992, 114, 6081. 6. Tsang, B. W.; Mathias, C. J.; Green, M . A . / . Nucl. Med. 1993, 34, 1127. 7 Tsang, B. W.; Mathias, C. J.; Fanwick, P. E.; Green, M . A . / . Med. Chem. 1994,37,4400. 8. Evans, D. F.; Jakubovic, D. A . / . Chem. Soc, Dalton Trans. 1988, 2927. 9. Das Sarma, B.; Bailar, J. C. Jr. / . Am. Chem. Soc. 1954, 76, 4051. 10. Das Sarma, B.; Bailar, J. C. Jr. / . Am. Chem. Soc. 1955, 77, 5476. 11. Das Sarma, B.; Ray, K . R.; Sievers, R. E.; Bailar, J. C. Jr. / . Am. Chem. Soc 1964, 86, 14. 12. Yang, L-W.; Liu , S.; Wong, E.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1995,34, 2164. 13. Dodson, G. G.; Hall, D. J. Inorg. Nucl. Chem. 1961, 23, 33. 14. Cradwick, P. D.; Cradwick, M . E.; Dodson, G. G.; Hall, D.; Waters, T.-N. Acta Cryst. 1972,525,45. 15. Sinn, E.; Sim, G.; Dose, E. V. ; Tweedle, M . F.; Wilson, L . J. J. Am. Chem. Soc. 1978, 100, 3375. 16. Chiari, B.; Piovesana, C. O.; Tarantelli, T.; Zanazzi, P. F. Inorg. Chem. 1982, 21, 2444. 17. Evans, D. F.; Jakubovic, D. A . Polyhedron 1988, 7, 1881. 18. Geary, W. J. Coord. Chem. Rev. 1971, 7, 81. 98 19. Chandra, S. K. ; Chakravorty, A . Inorg. Chem. 1992, 31, 760. 20. Green, M . A . ; Welch, M . J.;.Huffman, J. C. / . Am. Chem. Soc. 1984,106, 3689. 21. Kennard, C. H . L . Inorg. Chim. Acta. 1967,2, 347. 22. Restivo, R.; Palenik, G. J.; / . Chem. Soc. Dalton Trans. 1972, 341. 23. Riley, P. E.; Pecoraro, V . L . ; Carrano, C. J.; Raymond, K . N . Inorg. Chem. 1983, 22, 3096. 24. Moore, D. A. ; Fanwick, P. E.; Welch, M . J. Inorg. Chem. 1989, 28, 1504. 25. Moore, D. A . ; Fanwick, P. E.; Welch, M . J. Inorg. Chem. 1990, 29, 672. 26. Hegetschweiler, K.; Ghisletta, M . ; Fassler, T. F.; Nesper, R.; Schmalle, H . W.; Rihs, G. Inorg. Chem. 1993, 32, 2032. 27. Shannon, R. D. Acta Cryst. 1976, A32, 751. 28. Hancock, R. D. Prog. Inorg. Chem. 1989, 37, 187. 29. Hancock, R. D.; Martell, A . E. Chem. Rev, 1989, 89, 1875. 30. Hancock, R. D. / . Chem. Educ. 1992, 69, 615. 99 Chapter Five Ga and In Complexes with N2N'202 Pyridine Amine Phenolates 5.1 Introduction. In previous studies of group 13 metal complexes with amine phenolate ligands, the binding selectivity of the various amine phenolates for group 13 metal ions was examined by varying the spatial arrangements of the amine nitrogen and phenolate oxygen donor atoms;1"4 however, the binding selectivity of multidentate ligands can also be adjusted by the alteration or incorporation of different donor atoms. Though both G a 3 + and I n 3 + are hard metal ions, I n 3 + is considered to be slightly softer than G a 3 + . 5 Introduction of softer donor atoms into a ligand may increase the binding affinity of the ligand for In 3 + . Therefore in an attempt to lower the overall hardness of the amine phenolate donor atom set and to increase the binding affinity of the potential ligand for In 3 + , we have incorporated pyridine nitrogen atoms into the donor set. Numerous investigations of Cu, Co, Fe, Mn and Zn complexes with multinucleating ligands containing phenolate and/or pyridine pendant groups have been reported.6"1 5 For the most part, the objectives of these investigations were to determine the structure and physical properties of metalloproteins, and to reproduce the coordination of multimetallic sites of metalloproteins. Pyridine and/or phenolate groups are incorporated into the multinucleating ligands used in these metalloprotein modeling studies because phenolate and pyridine groups have the potential to mimic, respectively, the coordinating moieties of the amino acids tyrosine and histidine, which are present in the active sites of metalloproteins. Other pendant groups such as pyrazole and benzimidazole groups are also used as analogs of the histidine imidazole functionality. Besides the interest in metalloproteins, polypyridyl ligands have potential application as medicinal agents and as heavy metal chelators in biochemical studies. N,N,N,N-Tetrakis(2-100 pyridylmethyl)ethylenediamine (tpen) was used as a heavy-metal chelator in studies measuring free cytosolic C a 2 + in Ehrlich and Yoshida ascites carcinomas,16 and in studies on the effect of iron-chelating agents on the toxicity of doxorubicin to MCF-7 human breast cancer cells . 1 7 Pyridine substituted ethylenediamine compounds were also examined for anticholinergic, 1 8- 1 9 antihistaminic, and antispasmodic activities. 2 0 Gallium complexs with ligands possessing N -heterocycles were investigated as potential antitumour and antiviral agents.21 In this chapter, the coordination of G a 3 + and I n 3 + with a series of pyridine amine phenolate (Xbbpen2", Figure 5.1) which possess amine nitrogen, pyridine nitrogen and phenolate oxygen donor atoms are presented. Coordination of this series of potential N2N2O2 ligands (Xbbpen2-) to G a 3 + and I n 3 + is expected to yield monocationic complexes, which have the potential to be of interest in nuclear medicine applications, and in myocardial imaging in particular. It is also of interest to compare the selectivity of Xbbpen2" ligands for G a 3 + and I n 3 + to the selectivity of polyamino polycarboxylate (such as E D T A or DTPA) and polyamino polyphenolate (such as amine phenols or HBED) ligands, which possess a harder donor atom set than Xbbpen2". / \ bbpen2 : X=H Clbbpen2 : X=C1 Brbbpen2: X=Br Figure 5.1. Xbbpen2", N2N2O2pyridine amine phenolates. 101 5.2. Experimental Section Materials. Ethylenediamine, hexadecyltrimethylammonium bromide and 2-picolyl chloride hydrochloride were obtained from Aldrich and were used without furthur purification. A l l other chemicals were obtained from Aldrich or Alfa, as described in section 2.2. Instrumentation. In addition to the instrumentations that were outlined in section 2.2, conductance measurements were made with a Yellow Springs YS-1 Model 35 conductance meter with solute concentration of ca. 10~3 M at 25 °C in acetonitrile. Ligand Syntheses. Schiff Bases. N,N'-Bis(salicylidene)ethylenediamine (H2salen) was prepared according to the method of Diehl and Hach. 2 2 N,N'-bis(5-chlorosalicylidene)ethylenediamine (H2CIsalen) and N,N'-bis(5-bromosalicylidene)ethylenediamine (H2Brsalen) were prepared in a similar manner using 5-chlorosalicylaldehyde and 5-bromosalicylaldehyde, respectively. A l l Schiff base compounds were prepared in excellent yields (93-97%). N,N'-Bis(2-hydroxybenzyl)ethylenediamine ( H 2 b b e n ) . N,N'-Bis(2-hydroxy-benzyl)ethylenediamine was prepared according to reported method with some modification.2 3 K B H 4 (5.40 g, 100 mmol) was added in small portions to a hot suspension of H2salen (13.4 g, 50 mmol) in methanol (50 mL). The yellow H2salen dissolved in methanol as K B H 4 was slowly added to the suspension. After the addition of K B H 4 , the solution was stirred and gently heated for 1 h. A white precipitate formed as the solution cooled to room temperature, and additional precipitate was obtained when an aqueous ammonium acetate solution (15.0 g, 200 mmol in 50 mL) was added to the methanol solution at room temperature. The precipitate was collected by vacuum filtration, washed with cold methanol and diethyl ether. The white powder was then dried under vacuum at 60 °C for 24 h. Yield: 10.6 g (78 %). Anal. Calcd (found) for C i 6 H 2 o N 2 0 2 : C, 70.56 (70.56); H , 7.40 (7.53); N , 10.29 (10.49). N,N'-Bis(5-bromo-2-hydroxybenzyl)ethyIenediamine ( H 2 B r b b e n ) . The preparation of N,N'-bis(5-bromo-2-hydroxybenzyl)ethylenediamine was similar to that of H 2 b b e n and employed H2Brsa len (21.3 g, 50 mmol) and K B H 4 (5.40 g, 100 mmol), 102 yielding 18.2 g (85 %). Anal. Calcd (found) for C i 6 H i 8 B r 2 N 2 0 2 : C, 44.68 (44.79); H , 4.22 (4.32); N , 6.51 (6.45). N , N ' - B is (5 - ch lor o-2-hydroxy ben zyl)ethylenedi amine ( H 2 C l b b e n ) . The preparation of N,N'-bis(5-chloro-2-hydroxybenzyl)ethylenediamine was similar to that of H2bben and employed H2Clsalen (16.9 g, 50 mmol) and K B H 4 (5.40 g, 100 mmol), yielding 14.9 g (87 %). Anal. Calcd (found) for C16H18CI2N2O2: C, 56.32 (56.17); H , 5.32 (5.47); N , 8.21 (8.09). N,N'-Bis(2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)-ethylenediamine (H2bbpen). N,N'-Bis(2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)-ethylenediamine was prepared in excellent yield according to the reported method with some modifications.2 4 A solution of 2-picolyl chloride hydrochloride (10 g, 61 mmol) in 50 mL water was neutralized with 4 M NaOH to a pH between 10 and 11. H2bben (8.15 g, 30 mmol) was then added to the solution. H2bben were insoluble in basic aqueous solution so hexadecyltrimethylammonium bromide (0.36 g, 1 mmol) was added as a phase transfer catalyst. The mixture was stirred at room temperature and pH 10-11 for 24 h during which time a white precipitate formed. The white precipitate was collected by vacuum filtration, and washed with water and diethyl ether. It was then dried in vacuo at 60 °C. Yield: 13.2 g (9,7 %). Mp: 116-7 °C. Anal. Calcd (found) for C28H30N4O2: C, 73.98 (74.16); H , 6.65 (6.90); N , 12.33 (11.86). LSIMS: m/z=455 ([M+l]+, [C28H3iN 4 0 2 ]+). IR (cm"1, K B r disk): 3600-3400 (b,w, \) 0 H); 3100-2800 (m, UCH); 1615 (s), 1598 (s), 1590 (s), 1575 (s) 1500-1440 (s) (UC=H, UC=C). Tables of l H and 1 3 C N M R spectral data are given in Table 5.1 and 5.2, respectively. N,N'-Bis(5-bromo-2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylene-diamine (H2Brbbpen). The preparation of N,N'-bis(5-bromo-2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylenediamine was similar to the procedure for the preparation of H2bbpen. The reaction mixture of 2-(chloromethyl)pyridine hydrochloride (10 g, 61 mmol), H2Brbben (12.9 g, 30 mmol), and hexadecyltrimethylammonium bromide (0.36 g, 1 mmol) in 50 mL water was stirred for 48 h at room temperature and pH 10-11. The white precipitate 103 Table 5.1. *H N M R data (300 MHz) for pyridine amine phenols, H2Xbbpen, (8 in ppm from TMS, CDCI3). (Hb)2 (Hb)2 ./ ^ ^uuii*"*" —_N N^—•..iiiii„,| O H (H6)2 H 9 ^ V ^ H 7 (X=H 4forH 2bbpen)x assignment H2bbpen (X=H) H 2Clbbpen (X=C1) H 2Brbbpen (X=Br) H b 2.70 (s, 4H) 2.70 (s, 4H) 2.70 (s, 4H) H i 3.68 (s, 2H) 3.63 (s, 2H) 3.63 (s, 2H) H 2 6.80 (d, 2H)a 6.72 (d, 2H)a 6.70 (d,2H)a H 3 7.15 (m, 2H) 7.12 (dd, 2H)b 7.14 (dd,2H)b H4 6.75 (m, 2H) H 5 6.85 (dd, 2H)b 6.85 (d, 2H)c 6.98 (d, 2H)c H 6 3.75 (s, 4H) 3.74 (s, 4H) 3.74 (s, 2H) H 7 8.56 (d, 2H)d 8.55 (d, 2H)d 8.56 (d, 2H)d H 8 7.62 (td, 2H)e 7.63 (td, 2H)e 7.65 (td, 2H)e H 9 7.25 (m, 2H) 7.25 (m, 2H) 7.20 (m, 2H) H10 7.17 (m, 2H) 7.18 (m, 2H) 7.20 (m, 2H) A: V H H = 8.2-8.6 Hz; b : 3 / H H = 6.3-6.7 Hz, 4 7 H H = 1.0 Hz; c : 4 / H H = 1-1.2 Hz D : V H H = 4.2-4.6 Hz; e : 3 / H H = 7.4-7.6 Hz, 4 / H H = 1.4-1.6 Hz 104 Table 5.2. 1 3 C N M R data (200 MHz) for pyridine amine phenols, H2Xbbpen (8 in ppm from TMS, CDCI3). 1 .Hi" 1 1 i n . - - N / \ N.—••Minium, I HO. 9 14 13 11 12 assignment H2bbpen H 2 Clbbpen H 2 B r b b p e n (X=H) (X=C1) (X=Br) C i 50.0 49.9 49.8 c 2 57.5 57.0 56.9 c 3 122.4 123.3 124.8 C4 157.6 157.2 157.1 c 5 116.3 117.7 118.2 c 6 128.9 128.7 131.6 C7 118.9 124.2 110.4 c 8 129.5 129.2 132.1 c 9 58.6 59.0 58.6 G10 157.4 156.4 156.9 C n 149.0 148.9 148.9 C12 136.7 136.9 136.9 C13 122.3 122.4 122.4 C14 123.3 123.2 123.2 105 formed during the 48 h period . Yield: 17.0 g (93 %). Mp: 115 °C. Anal. Calcd (found) for C28H28Br 2 N 4 0 2 : C, 54.92 (55.23); H , 4.61 (4.67); N , 9.15 (9.26). LSIMS: m/z=613 ([M+l]+ [ C 2 8 H 2 9 B r 2 N 4 0 2 ] + ) . IR (cnr 1, KBr disk): 3600-3400 (b,w, \) 0H); 3100-2800 (m, \)CH); 1615 (s), 1598 (s), 1590 (s), 1575 (s) 1500-1440 (s) (DC=H, I>C=C)- 1 R A N D 1 3 C N M R spectral data are given in Table 5.1 and 5.2, respectively. N,N'-bis(5-chloro-2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylene-diamine (H2Clbbpen). The preparation of N,N'-bis(5-chloro-2-hydroxybenzyl)-N,N'-bis(2-pyridylmethyl)ethylenediamine was similar to the procedure for the preparation of H2bbpen. The reaction mixture of 2-(chloromethyl)pyridine hydrochloride (10 g, 61 mmol), H2Clbben (10.2 g, 30 mmol), and hexadecyltrimethylammonium bromide (0.36 g, 1 mmol) in r 50 mL water was stirred for 48 h at room temperature and pH 10-11. The white precipitate formed during the 48 h period. Yield: 14.3 g (91%) Mp: 115-6 °C. Anal. Calcd (found) for C 2 8 H 2 8 C 1 2 N 4 0 2 : C, 64.25 (64.23); H , 5.39 (5.19); N , 10.70 (10.43). LSIMS: m/z=524 ([M+l]+, [ C 2 8 H 2 8 C 1 2 N 4 0 2 ] + ) . IR (cm-1, K B r disk): 3600-3400 (b,w, DOH); 3100-2800 (m, DCH); 1615 (s), 1598 (s), 1590 (s), 1575 (s) 1500-1440 (s) (\)c=H, "0C=c)- Tables of lH and 1 3 C N M R spectral data are given in Table 5.1 and 5.2, respectively. Synthesis of Metal Complexes. As many of the syntheses were similar to each other, detailed procedures are only given for representative examples. ! H N M R spectra of all metal complexes were performed in DMSO-rf6- The syntheses of Ga and In complexes described below mainly employed the perchlorate salts of the respective metal ions but other Ga or In salts could also be used. Caution! It should be noted that perchlorate salts of metal complexes are potentially explosive and should be handled with care. [Ga(Clbbpen)]C104. To a solution of Ga(C10 4 )3-6H 2 0 (300 mg, 0.630 mmol) and H2Clbbpen (400 mg, 0.764 mmol) in methanol (15 mL) was added sodium acetate (126 mg, 1.54 mmol) in methanol (5 mL). The mixture was immediately filtered and the filtrate was left to stand at room temperature. Slow evaporation of the solvent yielded a beige crystalline precipitate, which was collected by filtration, washed with cold methanol, followed by diethyl ether, and then dried in vacuo at 80 °C to yield 275 mg (63 %). Recrystallization of this 106 precipitate from methanol, afforded crystals suitable for elemental and X-ray crystallographic analysis. Anal. Calcd (found) for C28H26Cl3GaN406: C, 48.70 (48.74); H , 3.79 (3.87); N, 8.11 (8.15). LSIMS: m/z = 591 ([ML]+, [GaC 2 8H 2 6Cl2N 4 02] + ) , 1281 ([2(ML)(A)]+, [2(GaC28H26Cl2N4Q2)(C104)]+). Molar conductance: 121 Q- imoFcm 2 . IR (cm"1, K B r disk): 3100-2850 (m, \)CH); 1615 (s), 1605 (s), 1575 (m), 1560 (m), 1500-1410 (s, 0)C=N, i>C=c). ! H N M R spectral data are given in Table 5.3. [Ga(bbpen)]C104-2.5H20. A procedure similar to that for [Ga(Clbbpen)]C10 4 was followed using Ga(C10 4)3-6H 20 (300 mg, 0.630 mmol), H2bbpen (347 mg, 0.763 mmol) and sodium acetate (126 mg, 1.54 mmol); the yield was 288 mg (63 %). Anal. Calcd (found) for C 2 8 H 3 3 C l G a N 4 0 8 . 5 : C, 50.44 (50.20); H , 4.99 (4.67); N , 8.40 (8.33). LSIMS: m/z = 522 ([ML]+, [GaC28H 2 8 N 4 0 2 ] + ) , 1143 ([2(ML)(A)]+, [2 (GaC 2 8 H 2 8 N 4 0 2 ) (C10 4 ) ]+ ) . Molar conductance: 119 Q-imoHcm 2 . IR (cnr 1, KBr disk): 3070-2900 (m, 0)CH); 1610 (s), 1600 (s), 1575 (m), 1565 (w) 1500-1400 (s) (\)c=N, vc=c)- - H N M R spectral data are given in Table 5.3. [Ga(Brbbpen)]CI04. A procedure similar to that for [Ga(Clbbpen)]C104 was followed using Ga(C10 4 )3-6H 2 0 (300 mg, 0.630 mmol), H 2Brbbpen (468 mg, 0.764 mmol) and sodium acetate (126 mg, 1.54 mmol); the yield was 353 mg (72 %). Anal. Calcd (found) for C 2 8H26Br 2 ClGaN 4 06: C, 43.14 (43.18); H , 3.36 (3.36); N , 7.19 (7.09). LSIMS: m/z = 680 ([ML]+, [GaC 2 8H 2 6 Cl2N 4 0 2 ] + ) , 1459 ([2(ML)(A)]+, [2(GaC28H 26Cl2N 40 2)(C10 4)] +). Molar conductance: 122 Q - i m o H c m 2 . IR (cm"1, K B r disk): 3120-2800 (m, \)CH); 1610 (s), 1580 (m), 1570 (m), 1550 (m), 1500-1410 (s, x>c=N, VQ=C)- ! H N M R spectral data are given in Table 5.3. [In(Clbbpen)]C104-H20. To a solution of In(C10 4)3-8H 20 (300 mg, 0.538 mmol) and H2Clbbpen (350 mg, 0.669 mmol) in methanol (15 mL) was added sodium acetate (110 mg, 1.34 mmol) in methanol (5 mL). The same workup as for the Ga analog yielded 263 mg (65 %). Recrystallization from methanol afforded crystals suitable for elemental and X-ray crystallographic analysis. Anal. Calcd (found) for C 2 8 H28Cl3 lnN 4 07: C, 44.62 (44.96); H , 3.74 (3.80); N , 7.43 (7.40). LSIMS: m/z = 636 ([ML]+ [ InC28H 2 6Cl2N 4 0 2 ] + ) . Molar 107 conductance: 122 O ^ m o l ^ c m 2 . IR (cm"1, K B r disk): 3100-2800 (m, \>CH); 1615 (s), 1575 (m), 1570 (m), 1500-1410 (s, VC=N, X>C=C). lH N M R spectral data are given in Table 5.3. [In(bbpen)]C104-H20. A procedure similar to that,for [In(Clbbpen)]C104 was followed using In(C104)3-8H20 (300 mg, 0.538 mmol), H2bbpen (304 mg, 0.669 mmol) and sodium acetate (110 mg, 1.34 mmol); the yield was 276 mg (75 %). Anal. Calcd (found) for C 2 8H3oCl InN 4 07: C, 49.11 (49.32); H , 4.42 (4.35); N , 8.18 (7.89). LSIMS: m/z = 567 ([ML]+, [ I n C 2 8 H 2 8 N 4 0 2 ] + ) . Molar conductance: 119 Q ^ m o H c m 2 . IR (cm"1, K B r disk): 3080-2800 (m, D C H ) ; 1610 (s), 1595 (s), 1575 (m), 1565 (w) 1500-1410 (s) (vC=N, vC=c)-! H N M R spectral data are given in Table 5.3. [In(Brbbpen)]ClO4-0.5H2O. A procedure similar to that for [In(Clbbpen)]C104 was followed using In(C10 4)3-8H 20 (300 mg, 0.538 mmol), H2Brbbpen (409 mg, 0.668 mmol) and sodium acetate (110 mg, 1.34 mmol); the yield was 354 mg (79 %). Anal. Calcd (found) for C28H 2 7Br 2 ClInN 4 0 6.5: C, 40.34 (40.35); H , 3.26 (3.37); N , 6.72 (6.63). LSIMS: m/z = 725 ([ML]+, [InC 2 8 H26Cl2N 4 02] + ) . Molar conductance: 123 Q - i m o H c m 2 IR (cm"1, K B r disk): 3100-2800 (m, DCH); 1615 (s), 1575 (m), 1570 (m), 1500-1410 (s, DC=N, UC=C)- *H N M R spectral data are given in Table 5.3. X-ray crystallographic analyses of [Ga(Clbbpen)]C10 4 and [In(Clbbpen)]C104. ORTEP drawings of [Ga(Clbbpen)]+ and [In(Clbbpen)]+ cations in [Ga(Clbbpen)]C104 and [In(Clbbpen)]C104 are shown in Figure 5.5 and 5.6, respectively. Selected bond lengths and bond angles in [Ga(Clbbpen)]+ and [In(Clbbpen)]+ cations are given in Table 5.4 and Table 5.5, respectively. Crystallographic data and final atomic coordinates (fractional) and fieq (A 2 ) for non-hydrogen atoms in [Ga(Clbbpen)]C104 and [In(Clbbpen)]C104 are given in Appendix I. 108 o e a .O u PQ o c o c a. o u 'a a. a o s a U " 3 -o u a a 4J 6 B K CN 3 CO X C N B CN TD" C N TD" CN X CN TD" co CN T D co C N NO CN CN C N CN X CN CN i n CN O 00 00 X CN X CN NO o 00 X CN CN CN o 00 00 X C N o O 00 X C N 00 NO — 00 00 X CN o NO X CN C N T D . 3 is o NO CN ON NO CN O X CN • a TD" - a T D T D TD" CO NO o NO o CN 00 q NO •>* 00 00 X CN i n CN X CN is T D >n NO 4-X CN • 60 CN T 3 CN X CN 60 CN TD" TD" TD" -4-* TD" TD" CN m i n NO co NO 00 >n 00 00 r~ i> 4-CN 60 X CN T 3 CN <u CN 60 X CN TD" TD" TD" TD" TD" 00 ON NO o CN vq oo 00 00 r-^ " N O X X 00 X ON o X N •<* en • CN N 2 - 00 00 N N X X 00 CN o ^> N N" N" ffi K ffi NO in so od oo t> N N 00 £ NO *> t-i » NO x ffi w w ix pc S £ 3 3 3 3 | 3 . co co co co m j r , ' co C3 -C O T 3 <U 4- 60 5.3. Results and Discussion. Ligand Syntheses^  Pyridine amine phenols (F^Xbbpen) were prepared in good yield according to the reported method with some improvements (Figure 5.2). 2 4> 2 5 The first step in the preparation of each pyridine amine phenol involved the condensation reaction of ethylenediamine with the appropriate salicylaldehyde to produce the Schiff base. This was followed by the reduction of the Schiff base with potassium borohydride to produce the corresponding amine phenol. The final step involved the reaction of the amine phenol with 2-(chloromethyl)pyridine at pH 10-11 in the presence of hexadecyltrimethylammonium bromide (which acts as a phase transfer catalyst). FJ^Xbbpen were soluble in polar solvents such as methanol, chloroform and acetone, and were hydrolytically stable under both weakly acidic and basic condition. They were also water soluble (millimolar concentration) in weakly acidic solution. Figure 5.2. Reaction scheme for the preparation of F^Xbbpen pyridine amine phenols. I l l lH and 1 3 C N M R spectral data of F^Xbbpen are listed in Table 5.1 and 5.2, respectively. Assignments of lH and 1 3 C N M R resonances were based on i H - i H COSY and 1 3 C - ! H HETCOR, 1 3 C APT experiments and on N M R spectral data of previously studied amine phenols. 1" 4 N M R spectral data of E^Xbbpen indicated them to be symmetrical about the ethylene moiety of the ethylenediamine backbone. The ! H N M R spectrum of H2Clbbpen in CDCI3 is shown in Figure 5.3 (top). The two hydroxybenzyl groups were spectroscopically equivalent, as were the two pyridylmethyl moieties. A single set of lH resonances in the region 6.5-7.15 ppm was observed for the hydrogen atoms on the two equivalent hydroxybenzyl groups. The set of resonance signals in the 7.15-8.6 ppm region was attributed to the eight hydrogen atoms on the two equivalent pyridine groups. The singlet at 3.65 ppm corresponded to the four benzylic hydrogens, while the singlet at 3.74 ppm corresponded to the four methylene hydrogens on the two equivalent pyridine arms. The four ethylene hydrogens on the ethylenediamine backbone appeared as a singlet at 2.70 ppm. 1 3 C N M R spectra also indicated a symmetry about the ethylene moiety of the ethylenediamine backbone as only 14 out of a possible 28 1 3 C resonance signals were observed. Elemental analyses, infrared, and mass spectral data were consistent with the N M R spectral data. Ga and In Complexes. Monocationic G a 3 + and I n 3 + complexes were easily prepared from reactions of FJ^Xbbpen with hydrated metal salts in the presence of excess sodium acetate. The complexes were found to be stable under both basic (no metal hydroxide formed in the presence of sodium hydroxide) and weakly acidic conditions (stable to acetic acid formed upon the coordination of the metal ion by the ligand in the presence of sodium acetate). The G a 3 + and I n 3 + complexes were soluble in DMSO, and slightly soluble in alcohols and in weakly acidic solution (pH 4-5). The metal complexes were characterized by spectroscopic techniques (IR, N M R and LSIMS), conductivity measurements, and elemental analyses. A l l data were consistent with the proposed formulation of monocationic, hexacoordinated complexes in which the metal ion was coordinated to two amine nitrogen atoms, two pyridine nitrogen atoms and two phenolate oxygen atoms (a N 2 N ' 2 0 2 donor atom set). 112 u lb § 8 7 6 5 4 3 a i 0 ppm Figure 5.3. *H NMR spectra (300 MHz) of H2Clbbpen (top, in CDC1 3), [Ga(Clbbpen)]C104 (middle, in DMSO-^6) and [In(Clbbpen)]C104 (bottom, in DMSO-de). 113 X-ray crystallographic analyses of [Ga(Clbbpen)]C104 and [In(Clbbpen)]C104 were performed and found to be consistent with the proposed formulation (vide infra) Attempts to isolate analytically pure A l 3 + complexes were unsuccessful, even in the presence of excess ligand, as precipitation of aluminum hydroxide often interfered with and accompanied the isolation of the complexes. *H N M R spectra of freshly prepared solutions of A1(C104)3 and H2bbpen showed the presence of an A l complex; however, precipitation of aluminum hydroxide from the solution occurred after an hour at room temperature. Subsequent ! H N M R spectra of the solution showed diminished intensities for the *H resonance signals attributed to the A l complex. This clearly indicated the instability of the A l complexes in solution and the lower stability of the A l complexes compared to their Ga, and In congeners. Infrared spectral data of H2Xbbpen showed strong to medium bands in the 1590-1575 cm - 1 region corresponding to C=N stretching modes of the pyridine groups. Upon coordination to G a 3 + or I n 3 + , there was a general bathochromic shift of -15 c m - 1 and a decrease in the intensity of the C=N stretching modes. Additional bands that were probably due to M-O and M -N stretches were observed; however, assignments of these bands were not conclusive because of their low energies. The infrared spectra of the metal complexes also exhibited strong broad perchlorate bands at -1100 cm"1. Molar conductivity measurements in acetonitrile of the Ga and In complexes showed values of 119-122 Q ^ m o H c n r 1 (25 °C); this was consistent with a 1:1 electrolyte 2 6 i.e. a monocationic metal complex formulation. In the LSIMS of the Ga and In complexes, the molecular ion [ M L ] + peaks were detected as well as the [ ( M L ) 2 A ] + peaks, where A was the anion present in the complexes. lH N M R spectra of the metal complexes were recorded in DMSO-^6 and were very similar to each other with the exception of the aromatic region (6.5-7.5 ppm). *H N M R spectra of [Ga(Clbbpen)]C104 and [In(Clbbpen)]C104 in DMSO-^6 are given in Figure 5.3. Assignments of the N M R resonances were based on C O S Y experiments of [Ga(Clbbpen) ]C10 4 (Figure 5.4), and on N M R spectral data of FFiClbbpen and of previously studied metal complexes with amine phenolates.1"4 The equivalence of the pendant 114 JJULi UUul, • • • { b k . 4 i . i ft r * 1 • A t1 k r - r E 1 . . . . ft 0 f* tl • o at • P 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 9.0 PPM Figure 5.4. ^ H N M R COSY spectrum (400 MHz) of [Ga(Clbbpen)]C10 4 in DMSO-J6 115 arms was maintained in the [Ga(Xbbpen)]+ and [In(Xbbpen]+ complexes. *H N M R spectra of the metal complexes showed two sets of aromatic resonance signals corresponding to the pyridine (7.17-8.56 ppm) and oxybenzyl groups (6.75-7.15 ppm). N M R spectra also showed the symmetrical nature of the metal complexes; only 14 1 3 C resonance signals of a possible 28 were observed. Upon coordination, the singlet at 3.6 ppm due to the four benzylic hydrogens H i became two doublets at ~3.8 and -4.0 ppm. Since the lH N M R spectra of the metal complexes still showed the two oxybenzyl groups as chemically equivalent, the two doublets at -3.8 and -4.0 ppm must correspond to two nonequivalent hydrogens atoms on the same benzylic carbon. The methene hydrogens of the pyridine pendant arms also became nonequivalent upon complexation and appeared as a pair of doublets at -4.3 and -4.4 ppm. The two doublets at -3.0 and -3.25 ppm corresponded to the two nonequivalent hydrogen atoms on each methylene carbon of the ethylenediamine backbone. These assignments were confirmed by i H - 1 ! ! COSY (Figure 5.4), and 1 3 C - ! H HETCOR experiments. The pair of doublets at -3.8 ppm correlated to the methene carbon on the pyridine pendant arms, while the pair of doublets at -4.4 ppm correlated to the methene carbons on the oxybenzyl pendant arm. i H ^ H C O S Y experiments showed the doublets in each pair coupled only to each other. As the N M R spectra of the Ga and In complexes were very similar, variable temperature lH N M R experiments were only performed for [Ga(bbpen)]C104 and [In(bbpen)]C104. No significant changes were observed in the lH N M R spectra of these metal complexes as the temperature was raised from room temperature to 120 °C. This clearly demonstrated the intact and rigid structure of the complexes in solution, minor shifts of the *H resonance signals and a slight broadening of the signals being observed. Thermal vibrations of the coordinated ligand at the elevated temperature would explain the observed broadening and shifts of the *H resonance signals. X-ray Structures of [Ga(Clbbpen)]C104 and [In(Clbbpen)]Cl04. Crystals of [Ga(Clbbpen)]C104 suitable for crystallographic analysis were grown from a methanol solution by slow evaporation of the solvents at room temperature. An ORTEP drawing of 116 drawing of [Ga(Clbbpen)]C104 is shown in Figure 5.5; selected bond lengths and bond angles are listed in Table 5.4. As expected, the G a 3 + ion was coordinated to the Clbbpen2- ligand via two amine nitrogen atoms, two pyridine nitrogen atoms, and two anionic phenolate oxygen atoms (a N2N2O2 donor set), giving monocationic complexes with a distorted octahedral coordination geometry. The donor atoms Nl , N3, 01 occupied one face of the octahedron while N2, N4, 02 occupied the other face. The two amine nitrogen atoms of the ethylenediamine backbone were coordinated cis to each other while the two pyridine nitrogen atoms were coordinated trans to each other. The two phenolate oxygen atoms formed an equatorial plane with the amine nitrogen atoms and were coordinated cis to each other. Figure 5.5. ORTEP drawing of [Ga(Clbbpen)]+ cation in [Ga(Clbbpen)]C104 showing the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level. 117 Table 5.4. Selected bond lengths (A) and angles (°) for the [Ga(Clbbpen)]+ cation in [Ga(Clbbpen)]C104. atom atom distance atom atom distance Ga 01 1.860(2) N3 C l l 1.338(3) Ga 02 1.871(2) N4 C24 1.351(3) Ga N l 2.180(2) CI C2 1.510(3) Ga N2 2.158(2) C3 C4 1.510(3) Ga N3 2.121(2) C4 C5 1.409(3) Ga N4 2.107(2) CIO C l l 1.499(3) 01 C5 1.332(3) C16 C17 1.501(3) 02 C18 1.337(3) C17 C18 1.412(3) N l CI 1.487(3) C23 C24 1.493(3) N l C3 1.498(3) N l CIO 1.489(3) N2 C2 1.491(3) N2 C16 1.496(3) N2 C23 1.492(3) atom atom atom angle atom atom atom angle 01 Ga 02 95.17(6) Ga O l C5 131.2(1) O l Ga N l 90.77(7) Ga 02 C18 130.1(1) 01 Ga N2. 170.22(7) Ga N l CI 106.3(1) O l Ga N3 96.03(7) Ga N l C3 110.3(1) 01 Ga N4 92.98(7) Ga N l CIO 109.5(1) 02 Ga N l 169.97(7) Ga N2 C2 105.9(1) 02 Ga N2 92.30(6) Ga N2 C16 110.9(1) 02 Ga N3 92.14(7) Ga N2 C23 110.1(1) 02 Ga N4 97.92(7) Ga N3 C l l 116.4(2) N l Ga N2 82.81(7) Ga N3 C15 124.0(2) N l Ga N3 78.82(7) Ga N4 C24 116.2(1) N l Ga N4 90.18(7) Ga N4 C28 125.5(2) N2 Ga N3 89.97(7) CI N l C3 110.3(2) N2 Ga N4 79.72(7) CI N l CIO 110.8(2) N3 Ga N4 165.83(7) C2 N2 C23 110.6(2) C3 N l CIO 109.6(2) C16 N2 C23 109.3(2) C2 N2 C16 109.9(2) 118 The three trans angles, N2-Ga-01, N l -Ga -02 and N3-Ga-N4 were 170.22(7)°, 169.67(7)° and 165.83(7)°, respectively. The last angle had the largest deviation from 180° (-15 °), probably caused by the intrinsically small bite angle of the two 5-membered chelate rings. The other two trans angles N2-Ga-01 and Nl -Ga-02 , which each involved one 5-membered and one 6-membered chelate ring, deviated less from 180°. The cis N-Ga-N' angles within the two 5-membered chelate rings, N2-Ga-N4 and Nl-Ga-N3 were 79.72(7)° and 78.82(7)°, respectively. The cis angle formed by the coordination of the two amine nitrogens (Nl-Ga-N2) was 82.81(7)°. Most of the N-Ga-0 angles were in the range 91-93°. The only two exceptions were the angles N3-Ga-01 and N4-Ga-02 which were 96.03(7)° and 97.92(7)°, respectively. N-Ga-N' angles between different chelate rings (N2-Ga-N3 and Nl-Ga-N4) were -90°. The two Ga-0 bond lengths were 1.860(2) A (Ga-Ol) and 1.871(2) A (Ga-02). Ga-Nl and Ga-N2 bond lengths (Ga to amine nitrogen bond lengths) were 2.180(2) and 2.158(2) A, respectively. Bond lengths of 2.121(2) A and 2.107(2) A were observed for the Ga-N3 and Ga-N4 bonds (Ga to pyridine nitrogen bonds). The bond lengths of Ga to phenolate oxygen and Ga to amine nitrogen atom were comparable with bond lengths observed in Ga amine phenol1"4, Ga Schiff base 2 7 and other hexacoordinated Ga complexes. 2 8" 3 2 Bond lengths of Ga to pyridine nitrogen atom were consistent with bond lengths observed in Ga complexes involving heterocyclic ligands. 3 3" 3 6 [In(Clbbpen)]C104 crystals suitable for crystallographic analysis were obtained from a methanol solution by slow evaporation of solvent at room temperature. An ORTEP drawing of [In(Clbbpen)]C104 is illustrated in Figure 5.6; selected bond lengths and bond angles are listed in Table 5.5. The I n 3 + ion was also hexacoordinated by a N2N2O2 donor set, giving a monocationic complex. The distorted octahedral coordination geometry in [In(Clbbpen)]C104 was very similar to the coordination geometry in [Ga(Clbbpen)]C104. Two amine nitrogen and two phenolate oxygen atoms formed the equatorial plane of the octahedral geometry, where atoms of the same type were coordinated cis to each other. The two pyridine nitrogen atoms, mutually trans, occupied the axial positions of the distorted octahedral geometry. One face of 119 the octahedron was again occupied by Nl , N3, Ol while the other face is occupied by N2, N4, 02, and the In-N and In-0 bond lengths were consistent with those observed in hexadentate In amine phenol complexes.1-3 Figure 5.6. ORTEP drawing of [In(Clbbpen)]+ cation in [In(Clbbpen)]C104 showing the crystallographic numbering. Thermal ellipsoids for the non-hydrogen atoms are drawn at the 33% probability level. 120 Table 5.5. Selected bond lengths (A) and Angles (°) for the [In(Clbbpen)]+ cation in [In(Clbbpen)]C104. atom • atom distance atom atom distance In 01 2.064(2) N2 C16 1.506(3) In 02 2.055(2) N2 C23 1.491(4) In N l 2.320(2) N2 C2 1.481(3) In N2 2.306(2) N2 C16 1.506(3) In N3 2.291(2) N2 C23 1.491(4) In N4 2.271(2) N3 C l l 1.341(3) 01 C5 .1.346(3) N4 C24 1.334(3). 02 C18 1.339(3) CI C2 1.530(4) N l CI 1.481(3) C3 C4 1.505(4) N l C3 1.508(3) C4 C5 1.414(4) N l CIO 1.491(4) CIO C l l 1.505(4) N2 C2 1.481(3) C16 C17 1.503(4) C17 C18 1.412(3) C23 C24 1.504(4) atom atom atom angle atom atom atom angle 01 In 02 105.54(7) In 01 C5 121.2(1) 01 In N l 89.83(7) In 02 C18 126.0(2) 01 In N2 160.00(8) In N l CI 104.6(2) 01 In N3 89.42(8) In N l C3 106.1(1) 01 In N4 • 89.12(7) In N l CIO 112.1(2) 02 In N l 158.25(7) In • N2 C2 105.9(2) 02 In N2 89.78(7) In N2 C16 105.5(1) 02 In N3 90.30(8) In N2 C23 111.7(1) 02 In N4 102.83(7) In N3 C l l 114.9(2) N l In N2 79.36(7) In N3 C15 119.3(2) N l In N3 74.26(8) In N4 C24 116.2(1) N l In N4 92.50(8) In N4 C28 122.9(2) N2 In N3 103.54(8) CI N l C3 110.8(2) N2 In N4 74.73(7) CI N l CIO 112.5(2) N3 In N4 166.69(7) C3 N l CIO 110.5(2) C16 N2 C23 111.7(2) C2 N2 C23 111.5(2) C2 N2 C16 110.1(2) 121 As in the G a 3 + ion in [Ga(Clbbpen)]C104, the I n 3 + ion in [In(Clbbpen)]ClC>4 was coordinated in a distorted octahedral geometry; however, a greater degree of distortion was observed in the coordination geometry of [In(Clbbpen)]C104. The trans angles, Nl-In-02 and N2-In-01 in [In(Clbbpen)]C10 4 were 158.25(7)° and 160.00(8)°, respectively. The deviations from 180° for these angles were ~20°, greater than that observed in [Ga(Clbbpen)]C104; however, the trans angle, N3-In-N4 was 166.69(7)°, close to that in [Ga(Clbbpen)]C104 (165.83(7)°). The constraint of the two 5-membered chelate rings associated with the N3-M-N4 (M=Ga, In) angle most likely forced the N3-M-N4 angle to remain at -166°. Larger deviation in the cis N - M - N ' angles were also observed in [In(CIbbpen)]C104 compared to [Ga(Clbbpen)]C104. An average deviation from 90° of-13° was observed for the cis N-In-N' angles, while the corresponding N-Ga-N' angles only had an average deviation of -4°. Another example of the greater distortion in the octahedral geometry of the In complex was the fact that the Ol-In-02 angle was 105.54(7)° while the corresponding Ol-Ga-02 angle was only 95.17(6)°. The greater distortion in the octahedral geometry of [In(Clbbpen)]C104 versus [Ga(Clbbpen)]ClC<4 likely resulted from the six-coordinate ionic radius of In3+ (0.80 A ) 3 7 being greater than that for G a 3 + (0.62 A ) 3 7 . Since the I n 3 + ion is larger than the G a 3 + ion, it was expected that the angles associated with the pendant arms (angles A , B, C, D and E in Figure 5.7) would be different for the [Ga(Clbbpen)]C104 complex and the [In(CIbbpen)]C104 complex; however, no significant difference was observed between the these angles in [Ga(CIbbpen)]ClC«4 versus the corresponding angles in [In(Clbbpen)]ClC«4. For [In(Clbbpen)]C104, the average angles for A , B , C, D, and E were 112.0°, 110.4°, 111.1° , 113.0°, and 113.0° respectively. The average angles for A , B, C, D, and E in the [Ga(Clbbpen)]C104 complex were 110.7°, 110.1°, 109.4°, 112.4°, and 112.6°, respectively. Angles A , B, and C show very minor deviation from tetrahedral values (within the experimental error). Angles D and E in the In complex were slightly larger than those in the Ga complex. The close similarities of the angles in both the Ga and In complexes suggested that, though greater distortion was observed in the octahedral geometry of [In(Clbbpen)]C10 4, the cavity that was formed by the four pendant arms was 122 sufficiently large to encapsulate ions as large as I n 3 + ion (0.80 A ) 3 7 , without significant adjustments of the pendant arms. B ^yjh> M Figure 5.7. Angles A , B, C, D, and E in [M(Xbbpen)]+ (M: G a 3 + and In 3 + ) . The distorted octahedral coordination geometries in [Ga(Clbbpen)]C104 and [ In (Clbbpen ) ]C104 were consistent with the coordination environments in [Mn( n i)(bbpen)]PF 6 2 4 , [V(m)(bbpen)]PF 6 2 5 and [Ru( i n)(bbpen)]PF 6. 3 8 This was not surprising considering that six coordinate ionic radii of V 3 + (0.640 A) 3?, high spin M n 3 + (0.645 A ) 3 7 and Ru (0.685 A ) 3 7 were intermediate to those of G a 3 + (0.62 A ) 3 7 and I n 3 + (0.80 A ) . 3 7 The bond angles and bond lengths in these complexes were consistent with those in the Ga and In complexes. That Xbbpen 2- can form stable hexadentate complexes with both G a 3 + and I n 3 + suggested that the cavity formed by the two pyridine and two oxylbenzyl pendant groups was suitable for metal ions whose ionic radii were within the range of 0.6-0.8 A. This augers well for the coordination chemistry with tri or tetravalent metal ions whose six coordinate ionic radii is similar to the radii of G a 3 + and I n 3 + ions. Preliminary investigation into the coordination of T c 3 + and R e 3 + ions to Xbbpen2 - has shown that Tc and Re complexes with these ligands are accessible. A l complexes with Xbbpen2* were found to be much less stable than the Ga or In congeners. It would be interesting to see if coordination of these ligands to larger metal ions 123 such as the lanthanides, whose ionic radii is greater than 0.8 A, would'result in stable hexacoordinated mononuclear metal complexes. Ga and In Xbbpen 2 " complexes were prepared with ease and were stable in solution. Qualitatively, there appeared to be no significant difference between the stability of the Ga and In complexes. This is in contrast to metal complexes with polyamino polycarboxylate39 (EDTA, DTP A) and polyamino polyphenolate4 0 (amine phenols, HBED) ligands. I n 3 + polyamino polycarboxylate complexes are reported to be more stable than their G a 3 + counterparts, while G a 3 + and I n 3 + polyamino polyphenolate complexes show a reverse trend. Stability constants of the G a 3 + and I n 3 + complexes with sulfonated analog of the pyridine amine phenols were determined and are reported in chapter 6. Comparison of the stability constants of the [ M ( X b b p e n ) ] + (M= G a 3 + , In 3 + ) complexes with the stability constants of polyamino polycarboxylate and polyamino polyphenolate complexes will also presented in chapter 6. 124 1 5.4 References 1. Liu , S.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1992, 31, 5400. 2. L iu , S.; Wong, E.; Karunaratne, V. ; Rettig, S. J.; Orvig, C. Inorg. Chem. 1993, 32, 1756. 3. Liu , S.; Wong, E.; Rettig S. J.; Orvig, C. Inorg. Chem. 1993, 32, 4268. 4. Wong, E.; Liu , S.; Lugger, T.; Hahn, F. E.; Orvig, C. Inorg. Chem. 1995, 34, 93. 5. a) Pearson R. G. / . Am. Chem.. Soc. 1963, 85, 3533. b) Pearson, R. G. 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A . ; Carty, A . J.; Boorman, P. M . Inorg. Chem. 1972,11, 896. 126 35. Rendle, D. F.; Storr, A . ; Trotter, J. / . Chem. Soc. Dalton Trans. 1973, 2252. 36. McPhail, A . T.; Miller, R. W.; Pitt, C. G.; Gupta, G.; Srivastava, S. C. J. Chem. Soc. Dalton Trans. 1976, 1657. 37. Shannon, R. D. Acta Cryst. 1976, A32, 751. 38. Neves, A. ; De Brito, M . A. ; Oliva, G.; Nascimento, 0. R.; Panepucci, E . H. ; Souza, D. H. ; Batista, A . A . Polyhedron, 1995,14, 1307. 39. Martell, A . E.; Smith, R. M . Critical Stability Constants; Plenum Press: New York; Vols. 1-6, 1974-1989. 40. Ma, R.; Motekaitis, R. J.; Martell, A . E. Inorg. Chim. Acta, 1994,224, 151. 127 Chapter Six Stability Constants for the Ga and In Complexes of Linear and Pyridine Amine Phenolates. r 6.1. Introduction. For Ga and In complexes to be considered as potential radiopharmaceuticals, they must be kinetically inert toward demetallation and/or thermodynamically stable toward hydrolysis at physiological pH. In addition, the metal complex must also be stable with respect to demetallation by the blood serum protein transferrin. The large binding constants of G a 3 + arid I n 3 + with the bilobal two-sited transferrin ( G a 3 + , log Pi=19.75, log p2=18.80; I n 3 + , log Pl=18.30, log P2=16.44),1 coupled with the high concentration of vacant transferrin binding sites in human blood (~50 |0.M) make transferrin a powerful scavenger of these metal ions. Hence, in the design of potential Ga and In radiopharmaceuticals, the stabilities of the metal complexes and the abilities of the chelates to compete with transferrin for trivalent metal ions are of utmost importance. In synthetic studies of group 13 metal complexes with amine phenol ligands, it was observed that the modes of coordination and stabilities of the metal complexes were closely related to the flexibility of the ligand, the size of the coordinated metal ion, and the type and spatial organization of the donor atoms.2"7 In the coordination of the linear amine phenolates to G a 3 + and In 3 + , there were four possible ways in which the linear amine phenolate can span the octahedral coordination sites around the metal ion (Figure 4.7). For Xbad 2 ", configuration A represented the least sterically demanding configuration, while configuration B represented the least sterically demanding configuration for the longer Xbadd 2". It was observed qualitatively that there 128 X N H O H N H H N H N HO X X=H H2bad X=Br H2Brbad X=C1 H2Clbad N H N H H N H N O H HO X=H H 2badd X=Br H2Brbadd X=C1 H2Clbadd X o , s X=H H 2bbpen X=Br H 2Brbbpen X=C1 H 2Clbbpen X O.S N H 2 N H 2 H 2 N H 2 N OH HO SO3" HeSbad 2+ T » T T 1 X T T T TT V T ' , T I N H 2 N H 2 H 2 N H 2 N HeSbadd HO 2 + ^ SO3" + / \ + , N H H N V O H H N HgSbbpen 2+ Figure 6.1. Linear amine phenols (H2Xbad , H 2 X b a d d ) , pyridine amine phenols (H2Xbbpen), and their sulfonated analogs (H6Sbad 2 + , H6Sbadd 2 + and H6Sbbpen 2 + ). 129 was a difference between the stability of the Ga and In linear amine phenolate complexes; the amine phenolates seemed to be more suited for G a 3 + than for I n 3 + 4 > 7 In addition, the metal complexes appeared to be stable over slightly different pH ranges. To quantify the stability of all these metal complexes, stability constants (log (3) have been determined. Coordination of hexadentate pyridine amine phenolates to G a 3 + and I n 3 + yielded robust complexes which were resistant to demetallation in both acidic and basic conditions.6 Solid state structures of both the Ga and In complexes revealed no significant differences between the bond lengths and bond angles in the two complexes, suggesting that the Ga and In complexes might have comparable stability. The [M(Xbbpen)]+ (M= G a 3 + , In 3 + ) complexes appeared to be more stable than the corresponding complexes with tripodal and linear amine phenolates,.so a quantitative comparison of the binding constants of these metal complexes was desired. In order to compare the effect of donor atoms on the selectivity of chelating ligands for G a 3 + and In 3 + , a quantitative comparison between stability constants of complexes with ^ N ^ C ^ pyridine amine phenolates and the stability constants of N2O4 polyamino polycarboxylate, and N2020'2 polyamino polyphenolate complexes were made. In this chapter, the stability constants of the Ga and In complexes with sulfonated trien-based (Sbad 4), sulfonated tnentn-based (Sbadd4), and sulfonated pyridine (Sbbpen4-) amine phenolates are presented. "H6" in HgSbad2"1", HgSbadd2"1" and tbjSbbpen2"1" refers to the six H atoms on the protonated amine, phenolate and pyridine moieties (Figure 6.1). Variable pH ! H N M R and U V spectral data were used to assign the observed deprotonation constants (pK a s) of the sulfonated amine phenols and to verify qualitatively the observed stability constants of the corresponding Ga and In complexes. By comparing stability constants and p M values (-log [uncomplexed M 3 + ] at a particular pH), it is possible to rank the relative stability of the various amine phenolate complexes and also the selectivity of the various amine phenolates for G a 3 + and I n 3 + metal ions. Prior to in vivo experiments, the ability of the amine phenolates to compete with transferrin for G a 3 + and I n 3 + ions can also be elucidated from a comparison of p M values at physiological pH. 130 6.2. Experimental Section Materials. Sodium salicylaldehyde-5-sulphonate was prepared according to the method reported in the literature.8 Water was purified, deionized (Barnstead D8904 and D8902 cartridges, respectively), and distilled (Corning MP-1 Megapure still). Instrumentation. U V spectra were recorded on a Shimadzu UV-2100 UV/Visible recording spectrophotometer. A l l potentiometric measurements were made with an automatic titrator system consisting of Fisher Acumet 950 pH meter equipped with Orion Ross research grade glass and calomel reference electrodes, a Metrohm autoburet (Dosimat model 665), water-jacketed titration beakers fitted with a five hole rubber cap, a Julabo circulating constant temperature bath and an I B M compatible computer, which was interfaced to both the pH meter and the autoburet. Ligand Syntheses. l,10-Bis(2-hydroxy-5-sulfonylbenzyl)-l,4,7,10-tetraazadecane dichloride ([H6Sbad]Cl2). To a hot solution of triethylenetetraamine (2 g, 14 mmol) in methanol (500 mL) was added a hot solution of sodium salicylaldehyde-5-sulphonate (7.66 g, 34 mmol) in methanol (1 L) . While the solution was still hot, NaBFLj. (1.32 g, 35 mmol) was added in sm^ll quantities over 10 min. The solution was heated at approximately 50 °C and stirred for an additional 2 h. The solvent was removed under reduced pressure leaving a pinkish while residue. The residue was dissolved in a minimum amount of water. The pH of the solution was approximately 10. The solution was loaded onto a Rexyn 101 (H) cationic exchange column (active group RSO3"; ionic form H + ; mesh size 16-50) and eluted with deionized distilled water. The eluant was acidified with 1 mL of concentrated HC1. The solvent was then removed under reduced pressure at 100 °C, leaving a pink residue which was dried in vacuo at 100 °C for 2 days. Characterization of the residue revealed it to be the hydrochloride salt of the desired sulfonated amine phenol. The yield was 3.76 g (33 %). The compound was extremely hygroscopic and was, therefore, stored in a dry nitrogen environment. N M R and U V spectra of H6Sbad 2 + were pH dependent. Anal. Calcd (found) for C20H36CI2N4O10S2: C, 131 38.28 (38.18); H , 5.78 (6.00); N 8.93 (9.00). LSIMS: m/z = 519 ([C2oH3iN 4 0 8S2] +), 1037 ({2[C2oH3oN 40 8S2]+l}). U V (kmax nm, (e cm-lM-*)): pH 2.1; 274 (6400), 232 (23900); pH 10.0; 288 (7600), 256 (24500). *H N M R (300 MHz, D 2 0 ) : pH 2.0: 3.54 (m, 12 backbone methylene H), 4.34 (s, 4 benzylic H ), 7.05 (dd, 3 / H H = 7.2 Hz, 4 7 H H = 1-0 Hz, 2 aromatic H), 7.80 (m, 4 aromatic H); pH 12.2; 2.66 (s, 4 backbone methylene H), 2.75 (m, 8 backbone methylene H), 3.69 (s, 4 benzylic H), 6.6 (dd, 3 / H H = 7.0 Hz, 4 / H H = 1-0 Hz, 2 aromatic H), 7.48 (m, 4 aromatic H). l,12-Bis(2-hydroxy-5-sulfonylbenzyl)-l,5,8,12-tetraazadodecane dichlor ide ([H(jSbadd]Cl2). The preparation of H 6 S b a d d 2 + was similar to that of H 6 S b a d 2 + and employed N , N'-bis(3-aminopropyl)ethylenediamine (2.00 g, 11.5 mmol), sodium salicylaldehyde-5-sulfonate (6.40 g, 28.6 mmol) and NaBH4 (1.08 g, 23.0 mmol). The yield was 3.91 g (52 %). The compound was also found to be very hygroscopic and was, therefore, stored in a dry nitrogen environment. *H N M R and U V spectra of H 6 S b a d d 2 + were pH dependent. Anal. Calcd (found) for 022^002^01082: C, 40.31 (40.18); H , 6.15 (6.43); N 8.55 (8.24). LSIMS: m/z = 547 ([C22H 3 5N 4 0 8 S2] + ), 1093 ({2[C22H 3 4 N 4 0 8 S 2 ]+1}) . U V ( k m a x nm, (e cm^M" 1 )): pH 2.0; 280 (3100), 232 (22100); pH 11.0; 290 (4900), 256 (26400). *H N M R (300 MHz, D 2 0 ) : pH 2.0, 2.12 (m, 4 backbone methylene H), 3.20 (m, 8 backbone methylene H), 3.42 (m, 4 backbone methylene H), 4.28 (s, 4 benzylic H), 7.03 (dd, 3 / H H = 7.2 Hz, 4 / H H = 1-0 Hz, 2 aromatic H), 7.74 (m, 4 aromatic H); pH 12.0, 1.67 (m, 4 backbone methylene H), 2.57 (m, 8 backbone methylene H), 2.65 (m, 4 backbone methylene H), 3.7 (s, 4 benzylic H), 6.56 (dd, 3 / H H = 7.0 Hz, 4 / H H = 10 Hz, 2 aromatic H), 7.46 (m, 4 aromatic H) . N,N'-Bis - (2 -hydroxy -5 -sul fonylbenzyl) -N,N'-bis (2 -methylpyr idyl)e thylene-diamine dichloride ( [HgSbbpenJC^) . H 2 b b p e n 2 + was prepared as previously reported 6 and was dissolved (5.00 g, 11.0 mmol) in 35 mL of concentrated H 2 S 0 4 . The solution was heated at 70 °C for 7 h. The solution was allowed to cool to room temperature. While cooling in an ice bath, acetone (1 L) was carefully poured into the H 2 S 0 4 acid solution and a white precipitate formed. This white precipitate was collected by vacuum filtration and 132 washed with cold acetone. The precipitate was dissolved in a minimum amount of concentrated HC1 and the acid solution was loaded onto an Amberlite IRA 402 anionic exchange column (ionic form CI"; mesh size 20-50) and eluted with water. The eluant was collected and the volume reduced to 2 mL. The pH was raised to 10 using concentrated NH3. The basic solution was then loaded onto a Rexyn 101 (H) cationic exchange column (active group RSO3"; ionic form H + ; mesh size 16-50) and eluted with water. The solvent was removed under reduced pressure at 100 °C to yield a pink residue. This residue was dried for 3 days at 100 °C under vacuo. Characterization of the residue revealed it to be a hydrochloride salt of the desired product. The yield was 4.18 g (52 %). The compound was hygroscopic and was stored in a dry nitrogen environment. *H N M R and U V spectra of H6Sbbpen 2 + were pH dependent. Anal. Calcd (found) for C28H37CI2N4O10.5S2: C, 45.90 (45.83); H , 5.09 (4.94); N 7.65 (7.58). LSIMS: m/z = 615 ( [ C 2 8 H 3 i N 4 0 8 S 2 ] + ) . U V (Xmax nm, (e cm^M" 1 ) ) : pH 2.4; 280 (7100), 262 (12200), 232 (24400); pH 12.3; 294 (8500), 255 (31000). *H N M R (300 MHz, D2O): pH 2.2, 3.53 (s, 4 backbone ethylene H), 4.14 (s, 4 benzylic H), 4.39 (s, 4 pyridine methylene H), 6.69 (d, 3 / H H = 8.0 Hz, 2 hydroxybenzyl H), 7.46 (dd, 3 / H H = 7.0 Hz, 4 / H H = 1.0 Hz, 2 hydroxybenzyl H), 7.59 (d, 3 7 H H = 7.2 Hz, 2 hydroxybenzyl H), 7.63 (m, 4 pyridine H), 8.09 (td, 3 / H H = 7.4 Hz, 4 / H H = 1.2 Hz, 2 pyridine H), 8.48 (d, 3 / H H = 4.2 Hz, 2 pyridine H); pH 12.4: 2.68 (s, 4 backbone ethylene H), 3.63 (s, 4 benzylic H), 3.66 (s, 4 pyridine methylene H), 6.60 (d, J = 8.0 Hz, 2 hydroxybenzyl H), 7.26 (d, 3 / H H = 7.2 Hz, 2 pyridine H), 7.32 (d, 3 / H H = 7.4 Hz, 2 pyridine H), 7.40 (dd , 3 / H H = 7.0 Hz, 4 / H H = 1.0 Hz, 2 hydroxybenzyl H), 7.62 (d, 3 / H H = 7.2 Hz, 2 hydroxybenzyl H), 7.72 (d, 3 / H H = 7.4 Hz, 2 pyridine H), 8.35 (td, 3 / H H = 7.4 Hz, 4 / H H = 1.2 Hz, 2 pyridine H). Potentiometric Equilibrium Measurements. Potentiometric equilibrium measurements of H6Sbad 2 + , HgSbadd24" and HgSbbpen2"1" in the absence and presence of G a 3 + and I n 3 + metal ions were performed by methods previously used in our group. 9- 1 0 The measurements were performed with a Fisher Acumet 950 pH meter equipped with an Orion Ross glass and calomel reference electrodes, which were calibrated before each titration by 133 titrating a known amount of HC1 with NaOH of known concentration. A working slope and intercept can be obtained from a plot of mV (measured) vs pH (calculated) so that pH can be read as -log [H + ] directly. A Metrohm automatic buret (Dosimat 665) was used to add the standardized NaOH. Throughout all titrations, the temperature was maintained at 25.0 + 0.1 °C with water-jacketed beakers and a Julabo circulating bath. The ionic strengths of all solutions were maintained at 0.16 M NaCl and the solutions were continuously degassed with Ar to exclude carbon dioxide. NaOH solutions were prepared from dilution of 50% NaOH (less than 0.1% Na2C03) with freshly boiled, distilled, deionized water. Potassium hydrogen phthalate (BDH certified) was then used to standardized the NaOH solution. G a 3 + and I n 3 + solutions were prepared from dilution of the appropriate atomic absorption standard solutions (Aldrich). The exact amount of excess acid in the metal ion solutions was determined by a Gran plot 1 1 of ( V 0 + Vt)x 10~PH vs Vt, where V 0 is the initial volume of 1:1 metal-Na2EDTA solution and Vt is the volume of NaOH added. The amount of base added is equal to the excess acid plus the Na 2 EDTA protons. Solutions of H6Sbad 2 + , HgSbadd2"1" and HgSbbpen 2* were degassed with Ar prior to use. Due to the extremely hygroscopic nature of the sulfonated compounds, the exact ligand concentration of each solution was calculated from the mass of the analytically pure ligand sample and was checked potentiometrically using the Gran extrapolation method. 1 1 The accuracy of the determined ligand concentration was also verified by plotting observed U V absorbance at 232 nm versus concentration at pH 2-3. In all cases, the rigorous linearity indicated conclusively that the concentration obtained from the Gran extrapolation method'was correct. The deprotonation constants (pK as) of H^Sbad2"1", H6Sbadd 2 + and HgSbbpen2"1" were determined potentiometrically from a total of 12, 8, and 11 titrations, respectively. For each compound, several different solutions were prepared using products obtained from two or more separate syntheses. Titrations of solutions of varying concentrations were repeated on different days to ensure reproducibility. 134 Potentiometric titrations of H6Sbad 2 + , HgSbadd2* and HgSbbpen2"1" in the presence of G a 3 + and I n 3 + metal ions were performed with the ratio of metal to ligand ranging from 1:1.2 to 1:2. Amine phenol solutions of differing concentrations prepared from different synthetic batches were used in the titrations of each metal-ligand system. Concentrations of the ligand and the metal ion used in each titration ranged from 0.5 m M to 3 mM. A minimum of 7 titrations were performed for each metal-amine phenol system. Potentiometric titrations of HgSbadd2"1" in the presence of each metal ion were performed in two steps in order to prevent the hydrolysis of the metal ion prior to complexation. The first step involved the addition of base until a pH of 3 was attained, and these data were used to check the excess acid concentration. This was followed by a rapid addition of base to a pH of 4.5; the solution was then allowed to equilibrate for 30 minutes and titrated to completion. The deprotonation constants (pK as) for HgSbad2"1", HgSbadd2* and H6Sbbpen 2 + and the stability constants of the corresponding Ga and In complexes were calculated from the titration data using the program B E S T . 1 2 For all Ga and In amine phenol systems, the computations allowed for the presence of M ( O H ) 2 + , M(OH)2 + , M(OH)3 and M(OH)4~; in addition for I n 3 + , I n C l 2 + , InCl2 +, InCl3 and In(OH)Cl + were also included. 1 3 The possibilities of protonated and ternary hydrolysis metal complexes were investigated, but no evidence was found for the presence of such species. Values of p M (-log [ free metal ion]) at physiological pH were calculated with [M] = 1 (iM, [L] = 10 (iM. To verify the observed pK a s and stability constants, variable pH *H N M R and U V spectroscopic studies were conducted. Variable pH lH N M R spectra of the ligands and of the metal complexes were collected in D2O with the pD values being measured by a Fisher Accumet 950 pH meter equipped with an Accumet Ag/AgCl combination microelectrode. pD was converted to pH by adding 0.40. 1 4 *H N M R spectra were recorded on a Varian 300 MHz spectrometer from pH 2 - 12. Variable pH U V spectra (400 nm - 200 nm) of the amine phenols and the metal complexes were recorded on a Shimadzu UV-2100 UV/Visible recording spectrophotometer from pH 2 - 12. The concentrations of the amine phenols and the metal ions in the U V studies were ~ 10"5 M . 135 6.3. Results and Discussion H 6 S b a d 2 + , H 6 S b a d d 2 + and H 6 Sbbpen 2 + . Preparations of H 6 S b a d 2 + and H 6 S b a d d 2 + involved the Schiff base condensation, and subsequent in situ reduction of sulfonated salicylaldehyde and the tetraamine in the presence of NaBH4. Inorganic impurities such as NaCl were removed by ion exchange chromatography. The synthesis of HgSbbpen2+, on the other hand, involved the direct sulfonation of the unsubstituted t^bbpen with concentrated H 2 S O 4 . H 6 S b a d 2 + , H.6Sbadd 2 + and H.6Sbbpen 2 + were all prepared as dihydrochloride salts, the purity of which was checked by lH N M R , mass spectrometry, and elemental analyses. A l l the sulfonated compounds were stored in a dry nitrogen environment because they are extremely hygroscopic. Sulfonated amine phenols were used in the potentiometric titrations because the parent amine phenols were not sufficiently soluble enough in aqueous solution to carry out the titrations from pH 2-12. Sulfonation increases the aqueous solubility of the amine phenolates without significantly altering their binding affinity for metal ions. 1 5 Deprotonation constants (pK as) of H.6Sbad 2 + , H 6 S b a d d 2 + and fbjSbbpen2"1" are listed in Table 6.1. The deprotonation constants of trien, 1 6 tnentn,17 H B E D , 1 8 S H B E D , 1 5 and H 6 T R N S 1 0 are also listed in Table 6.1 for comparison. The observed pK a s are comparable to the pK a s of compounds with similar ionizable moieties. For each sulfonated compound, six p K a s were determined by potentiometric titrations. Although there were eight potentially ionizable groups on each sulfonated compound, the two sulfonic acid moieties on the hydroxybenzyl groups have pK a s « 1. N M R resonance signals were sensitive to the deprotonation of the various groups; hence variable pH lH N M R studies were used to verify and assign observed pK a s to the six ionizable groups on each amine phenol. Variable pH U V studies were also used to verify the observed pK a s since the n —»7t* transition of the aromatic ring was sensitive to the deprotonation of the two phenol moieties (the same also applied to the two pyridine moieties in HgSbbpen2"1"). 136 Table 6.1. Deprotonation constants (pK as) of various amines and amine phenols (25 °C, u, = 0.16 M NaCl unless otherwise noted). compound pKai pKa 2 pKa 3 pKa4 pKa 5 pKa6 H 6 S b a d 2 + 10.35(9) 9.77(5) 8.16(4) 7.19(4) 5.65(6) 2.71(9) H 6 S b a d d 2 + 10.88(8) 10.49(7) 8.59(5) 7.35(6) 5.83(6) 1.95(8) H 6 S b b p e n 2 + 11.33(4) 10.64(7) 9.09(7) 6.87(3) 4.70(3) 2.17(8) Trien a 9.68 9.09 6.58 3.28 Tnentnb 10.66 9.96 8.54 5.84 H B E D C 12.64 11.03 8.34 4.40 2.24 S H B E D d 12.91 10.42 7.90 4.29 1.96 1.2 H 6 T R N S e 11.2 10.6 9.59 8.07 7.29 6.17 a ref 15; fx = 0.1 K N O 3 . B ref 16; fi = 0.5 M K N O 3 . c ref 17; | i = 0 .10MKC1. d ref 18; \i 0.10 M KC1. e ref 10; [1 = 0.16 M N a C l The six observed p K a s of H 6 S b a d 2 + and H g S b a d d 2 + corresponded to the deprotonation of two phenols and four protonated amine moieties. The four amine moieties were of two discrete types, outer and inner. The two sets of linear amine phenols followed the same order of deprotonation. The two highest pK a s were assigned to the deprotonation of the two outer amine moieties, while thex two lowest pK a s were assigned to the deprotonation of the two inner amine moieties. The deprotonation of the two phenols accounted for the two intermediate pK a s. The assignment of the two intermediate pK a s in HgSbad2"1" (7.19 and 8.16) to the two phenols was verified by a plot of chemical shift change (A8) versus pH for the lH N M R resonance a to the hydroxyl moiety (Figure 6.2, top). As the pH was raised from 5.5 to 9.5, 137 Figure 6.2. Plot of chemical shift change (A 8 in ppm) versus pH for selected *H NMR resonances in H6Sbad2 + (top), H6Sbadd2+ (middle), and H6Sbbpen2+ (bottom). 138 deprotonation of the two phenols was noted by a downfield shift of the aromatic lH resonance signals. The deprotonation of the phenols was also observed in the variable pH UV spectra of HgSbad2"1" (Figure 6.3), where a significant change in the UV spectrum was observed between pHs 6 and 9. The *H NMR resonance of the four benzylic hydrogen atoms was also sensitive to the deprotonation of the two phenols, a plot of AS for the benzylic *H NMR resonance versus pH (Figure 6.2, top) showed a drop in A8 between pHs 5 and 9. The deprotonation of the outer amine groups was also observed in the plot of A8 for the benzylic *H resonance versus pH (Figure 6.2, top). At pH > 9, a much sharper drop in A8 was observed with increase in pH. This sharper drop in A8 resulted from the deprotonation of the outer amine moieties - the benzylic H were sensitive to changes in the chemical environment around these outer amine moieties. Therefore, the two highest pKa's (9.77 and 10.35) were assigned to the 3.0-, 1 1 1 I I 220 240 260' . . . 280 300 320 K (nm) Figure 6.3. Variable pH (pH 2-10) UV spectra (220 - 320 nm) of H 6 Sbad 2 + . 139 two outer amine moieties. The large decrease in A8 for the benzylic H between pHs 9 and 12 could not be attributed to the deprotonation of the inner amine moieties because the benzylic H atoms were not sensitive enough (too far away) to significantly detect this deprotonation; however, the benzylic H atoms were sensitive (close) enough to detect the deprotonation of the phenols between pHs 5 and 9. For H 6 S b a d d 2 + , the assignment of the six p K a s paralleled the assignments for H6Sbad 2 + . Plots of A8 versus pH (Figure 6.2, middle) were again used to verify and assign the 6 observed pK a s in H 6 S b a d d 2 + . Variable pH U V spectral data (Figure 6.4) were consistent with the variable pH ! H N M R data in the assignment of the pK a s which were on average higher than those of H6Sbad 2 + , consistent with the parent tetraamines, tnentn and trien. 140 In general, the basicity of amines is comparable with that of phenols; however, the pK a s of the two phenols were higher than those of the two inner amines but were lower than the pK a s of the two outer amines. This was neither uncommon, nor surprising. The high pK a s of the two outer amine moieties can be attributed to strong ion-hydrogen bonds present between the negatively charged oxygen atoms of the phenolate groups and the hydrogen atoms on the protonated outer amine moieties. This phenomenon has been observed previously in other amine phenols1 0 and in ligands with hydroxybenzyl groups attached to amine nitrogen atoms.19 H-bonding also accounted for the significant difference between the pK a s of the two inner amines. After the deprotonation of one inner amine, an H-bond was established between the deprotonated amine nitrogen atom and the hydrogen atom on the other protonated inner amine. Overall, the pK a s of H 6 S B a d d 2 + were higher than the pK a s of H 6 S b a d 2 + , reflecting the overall higher basicity of tnentn compared to trien. The six pK a s determined from the potentiometric titrations of H6Sbbpen 2 + were assigned, in increasing order, to the deprotonation of two pyridinium moieties, two amine moieties, and two phenol moieties. A plot of AS vs pH for the H atom a to the pyridinium nitrogen atom (Figure 6.2, bottom) showed a large increase in AS from pH 2-6, consistent with the deprotonation of the pyridinium moieties. The two lowest pK a s were therefore assigned to the deprotonation of the two pyridinium moieties. From pH 6-10, increases in AS of the ethylene H resonance signified the deprotonation of the two amine moieties (Figure 6.2, bottom) and confirmed the assignment of the two intermediate pK a s to these amine groups. The two highest pK a s were assigned to the deprotonation of the two phenols and were verified between pH 10 and 13 by an increase in the AS of the aromatic H atom a to the hydroxyl groups (Figure 6.2, bottom). Variable pH U V spectral data (Figure 6.5) were consistent with the N M R data in the assignment of the last two pK a ' s to the deprotonation of the two phenols. From Figure 6.2 (bottom), a decrease in AS for the lH N M R resonance a to the hydroxyl moieties was observed in the pH range corresponding to the deprotonation of the amine moieties. The H atoms on the hydroxybenzyl groups were also sensitive to the deprotonation of the amine nitrogen atoms. 141 The order of deprotonation for the amine and phenol moieties in HgSbbpen2"1" was opposite to that in the linear amine phenols. The two intermediate pKas were assigned to the deprotonation of the two amine nitrogen atoms and the two highest pKas were assigned to the deprotonation of the two phenols. The difference in the order of deprotonation for the amine and phenol moieties can be attributed to the nature of the H-bonds present in H6Sbbpen2 + versus those in the linear amine phenols. Figure 6.2 (bottom) shows the H atoms on the hydroxybenzyl groups to be sensitive to the deprotonation of the amine moieties. This suggested that H^bonding similar to that observed in the linear amine phenols was also present in H6Sbbpen2 +. As the amines were deprotonated to amines, H-bonds were established between the amine nitrogen atoms and the H atoms of the hydroxyl groups, with the H atom 142 affiliated more with the phenolate oxygen atom than with the amine nitrogen atom. In the linear amine phenols, the opposite was found, with the H atom affiliated more with the amine nitrogen atom than with the phenolate oxygen atom. Hence, the assignment of the pK a s for the amine and phenol moieties in H6Sbbpen 2 + and the linear amine phenols were opposite to one another. Ga and In Complexes of H 6 S b a d 2 + , H 6 S b a d d 2 + and H 6 S b b p e n 2 + . The formation of the Ga and In complexes with Sbad4", Sbadd 4 - and Sbbpen 4 - in aqueous isotonic saline was studied by potentiometric titrations, and stability constants were determined from these titrations. lU N M R spectra of the Ga and In complexes with Sbad4 -, Sbadd4 - and Sbbpen4 - showed the aqueous solution structures of these complexes to be consistent with both the solid state and solution structures of the metal complexes with the analogous nonsulfonated amine phenolate ligands. 4- 6 ' 7 Stability constants and p M values of Ga and In complexes with Sbad4", Sbadd4" and Sbbpen4- were expected to be slightly different from those of complexes with analogous nonsulfonated amine phenolates; however, the observed trends and differences between metal complexes with sulfonated amine phenolates will also be valid for complexes with nonsulfonated amine phenolate ligands. The effects of SO3 groups on the stability constants and p M values of metal complexes are demonstrated in the stability constants and p M values of Ga and In complexes with H B E D and SHBED ligands (Table 6.2).l 7- 18 Potentiometric titrations were performed with ratios of metal to ligand varying from 1:1.2 to 1:2. In all cases, only 1:1 metahligand complexes were observed. Figure 6.6 shows the titration curves for 1:1.2 solutions of G a 3 + and I n 3 + with H6Sbad 2 + , H 6 S b a d d 2 + and H6Sbbpen 2 + . In all cases, an inflection was observed at a = 6 (a = moles of OH" added/moles, of amine phenol), indicating the formation of hexacoordinated 1:1 metal ligand complexes of the three amine phenols; Sbbpen4- showed complexation occurring at the lowest pH, indicating that the Ga and In Sbbpen 4 - complexes were the most stable of the three types of amine phenolate complexes considered in this study. Titrations of H6Sbadd 2 + in the presence of G a 3 + and I n 3 + 143 Table 6.2. Log (3 and p M Values (pH.7.4) of Ga and In Complexes with Sbad 4 , Sbadd 4 , Sbbpen4", HBED, EHPG, PLED, NT A, DTP A, EDTA and transferrin. logp pM Ligand G a 3 + In3+ G a 3 + I n 3 + Sbad4" 28.33(8) 24.54(2) 22.9 19.2 Sbadd4" 28.27(5) 24.56(5) 21.1 17.4 Sbbpen4 35.33(8) 34.85(5) 27.4 26.9 HBED 38.513 27.76a 29.6 f 18.9f SHBED 37.47h 29.37h 29.4 f 21.2 f rac-EHPG 33.89 b 26.68b 25.3 f 18 . l f PLED 32.02c 26.25c 26.7 f 20.9 f EDTA 20.3§ 24.98 19.9e 23. l e Tf (1 s t binding site) 19.75d 18.80d 20.9 e 18.7d Tf (2 n d binding site) 18.30d 16.44d a ref 17. b ref 20. c ref 19. d r e f 3 . e ref 27. f recalculated for [M] = 1 | j M and [L] = 10 uM. g ref 29. h : ref 18. could not be performed in one continuous experiment because of hydrolysis of the metal ion prior to complexation; complexation began at pH ~5 but hydrolysis occurred at pH 3-4. To circumvent this problem, the titrations of H6Sbadd 2 + in the presence of metal ions were carried out in two steps. Figure 6.6 (middle) illustrates the two step titration of G a 3 + or I n 3 + with H 6 Sbadd 2 + . 144 2-\ , , . \ 1 — — 1 ' 1 • 1 -2 0 2 a 4 6 8 10-8-X 6-4-2--2 T " 0 a "T~ 4 T " 6 1 8 Figure 6.6. Experimental Ga ( ) and In ( ) titration curves for Sbad4" (top), Sbadd4' (middle- see text), and Sbbpen4" (bottom) at ligand:metal ratio 1.2:1. 145 Log P and pM values (at pH = 7.4) of Ga and In complexes with Shad 4 -, Sbadd4" and Sbbpen4- are summarized in Table 6.2. Values for the Ga and In complexes with HBED, 1 7 SHBED, 1 8 P L E D , 1 9 and rac-EHPG 2 0 are also listed in Table 6.2 for comparison, as are the binding constants of G a 3 + and In 3 + with transferrin.1 To verify qualitatively the stability constant, variable pH UV spectral data were compared with the calculated metal complex speciations. For instance, the speciation diagram of the Ga/Sbad 4 - system (Figure 6.7), predicted that complexation should begin at pH 3 and hydrolysis to [Ga(OH)4]- should begin at pH 9. This was borne out by a comparison of the variable pH UV spectra of H6Sbad2 + with (Figure 6.8 and 6.9) and without G a 3 + (Figure 6.3). The magnitude of the binding constant was confirmed for the other Ga and In complexes in an analogous manner. Speciation diagrams for the other Ga and In amine phenol systems are given in Appendix U. Variable pH UV spectra of the amine phenols in the presence of metal ions are given in Appendix n. Figure 6.7. Speciation diagram for the Ga3 +/Sbad4" system. 146 Figure 6.8. Variable pH (pH 2-6) UV spectra (220 - 320 nm) of the Ga 3 +/Sbad 4- system. Figure 6.9. Variable pH (pH 2, 8, 10, 11.9) UV spectra (220 - 320 nm) of the Ga 3 +/Sbad 4 system. 147 The gallium linear amine phenolate complexes (those of Sbad 4" and Sbadd 4 ) were 3 orders of magnitude more stable than the corresponding indium analogs. This selectivity for gallium was expected based on the information available for ligands containing only aliphatic amine and phenolate donor atoms - oxybenzyl 2 1 and o x y p y r i d y l 2 2 derivatives of triazacyclononane, the hexadentate Schiff base saltames 2 3 and the tripodal N3O3 amine phenols based on the amines tap and tame.24 This is not surprising given that Hancock and Martell have shown that the affinity of amines for gallium and indium is of the same order of magnitude,25 and Martell and co-workers have demonstrated that the 2-oxybenzyl group favours complexation with gallium over indium. 2 5 The selectivity of Shad 4 - and Sbadd 4" for gallium is much less than in the cited examples. 2 1 - 2 4 One obvious difference is that the prior literature on gallium and indium amine phenolate complexes- involved ligands with N3O3 donor sets versus the N4O2 donor set in Sbad 4 " and S b a d d 4 - . By substituting an amine for a phenolate, and hence "softening" the donor set, the selectivity for gallium over indium has been muted. The Sbbpen 4" ligand provides an even better example of this effect (vide infra). It has been shown that complex stability is intimately related to the size of the metal ion and the size of the chelate r i ng . 2 5 - 2 8 Stability generally decreases as the chelate ring size changes from five to six; however, this destabilization is generally greater for larger metal ions. Coordination of Xbad 2 " ligands to G a 3 + or I n 3 + produced complexes with three 5- and two 6-membered chelate rings, while Xbadd 2 " complexes contained one 5- and four 6-membered rings. Based on the above criteria, Xbadd 2 " complexes should be less stable than X b a d 2 " complexes, but the difference in stability between [Ga(Xbad)] + and [Ga(Xbadd)] + should be • I less than the difference between the corresponding In complexes. The stability constants and the p M values for Ga and In complexes with Sbad 4 " and Sbadd 4 " did not however show any indication of this effect. The stability constants of metal complexes with Sbad 4" and Sbadd 4" were of equal magnitude and the difference in p M values (Ga-In) for Sbad 4" and Sbadd 4" are approximately the same. This is not to say that the relationship between complex stability and the size of metal ion, and the size of the chelate ring is not valid for linear amine phenolate complexes. The differences in the basicity of Sbad 4" and Sbadd 4", plus the difference in 148 coordination geometry between the Sbad4- and Sbadd4- complexes may be masking the effect of chelate ring size on the stability of the metal complexes. Attempts to isolate analytically pure A l complexes with both the Xbad and Xbadd linear amine phenolates were unsuccessful as the A l linear amine phenolate complexes were not particularly stable. Although no attempt was made to determine the stability constants of the A l complexes, they should be much lower than the stability constants of the Ga and In complexes. This is actually corroborated by the p M values of the A l and Ga complexes with the Schiff base analog of H2bad. 2 3 The p M value for Ga Schiff base complex is ~9 units higher than that for the corresponding A l complex. The linear amine phenolates are not well suited to complexation of the A l 3 + ion because of its small size, relative hardness, and lower affinity for nitrogen donor atoms. The stability constants and p M values of [Ga(Sbbpen)]" and [In(Sbbpen)]" were significantly higher than those of the linear amine phenolate complexes; the Xbbpen2 - amine phenols have a much greater affinity for G a 3 + and I n 3 + than the linear amine phenolates. It is intuitive that the pyridine amine phenolates have a higher affinity for G a 3 + and I n 3 + than the linear amine phenolates because of the preorganization of the Xbbpen2- donor atoms to form a 3-dimensional clamp. The donor atoms are arranged such that they could coordinate to a metal ion simultaneously, not in a linear sequential arrangement. If a metal ion is of appropriate size, the Xbbpen2- amine phenolate could clamp and coordinate to that metal ion simultaneously with all 6 of its donor atoms, which are prearranged into positions ideal for coordination. This is in contrast to the donor atoms of the linear amine phenolates, which would sequentially position themselves for coordination to the metal ion as the ligand wrapped around the metal center. Examples of this are the divalent metal complexes of penten and N,N'-dimethyl-3,6,9,12-tetraazatetradecane-l,14-diamine, in which the stability constants of penten metal complexes2 9 are 3-6 orders of magnitude higher than corresponding linear polyamine metal complexes. 3 0 The preorganization of the Xbbpen2- donor atoms appears to be well suited for coordination to metal ions whose ionic radii are similar to those of G a 3 + and In 3 + . Complexes of M n 3 + (0)645 A ),3 1 V 3 + , (0.64 A ),31 and Ru3+, (0.82 A ) 3 1 with Xbbpen2- have been reported. 3 2 - 3 4 149 The stability constants and p M values of [Ga(Sbbpen)]- and [In(Sbbpen)]- were, respectively, very similar to each other. Sbbpen4- did not discriminate between G a 3 + and I n 3 + , in stark contrast to ligands such as H B E D 1 7 , S H B E D 1 8 , P L E D 1 9 , and E H P G 2 0 which exhibit a significant selectivity for G a 3 + over I n 3 + , approximately 7-10 orders of magnitude (Table 6.2). SHBED, HBED, PLED and EHPG are sterically similar to Xbbpen2 in that they all have 4 pendant arms attached to an ethylenediamine backbone and coordination of these ligands to a metal center results in the formation of three 5-membered and two 6-membered chelate rings; however they do differ in the donor atoms used for coordination. Both Xbbpen2-and H B E D type ligands have two amine and two oxybenzyl moieties, but the Xbbpen2- amine phenols also have two pyridine moieties while HBED type ligands have two carboxyl moieties. By replacing the two hard carboxylate oxygen atoms in HBED type ligands with the two softer pyridine nitrogen atoms in the Xbbpen2 - amine phenolates, the set of donor atoms becomes softer and more suitable for coordination to the slightly softer I n 3 + ion. Multidentate polyamino polycarboxylate ligands (NT A, EDTA and DTP A) have a selectivity for I n 3 + over G a 3 + , while polyamino polyphenolate ligands (amine phenols and HBED) show a selectivity for G a 3 + over In 3 + . The relatively harder donor atom set of polyamino polyphenolate ligands is more suited to the harder G a 3 + ion, while the softer I n 3 + prefers the softer donor atom set of polyamino polycarboxylate ligands. The hardness of the Xbbpen2- donor atom set lies in between those of the amino polycarboxylate and the polyamino polyphenolate ligands. Hence, Xbbpen 2 -amine phenolates showed no selectivity for one metal over another and bind equally well to both G a 3 + and I n 3 + ions. The difference between the selectivity of Xbbpen 2 - , polyamino polycarboxylate and polyamino polyphenolate ligands follows from, and nicely complements, the work of Motekaitis et al.26 Recently, the stability constants of Ga and In complexes with ligands containing mercaptoethyl groups (EC, EDASS) were reported.3 5-3 6 These ligands are like the H B E D type ligands with the exception that the two phenolate groups are now replaced with mercaptoethyl groups, a N2O2S2 donor atom set. The hard phenolate oxygen donor atoms are replaced with softer and larger thiolate sulfur atoms. The reported stability constants of the Ga complexes 150 with these N2O2S2 ligands are comparable with the corresponding In complexes. In some cases, the In complexes were found to be ~2 orders of magnitude more stable than their Ga congeners. Like [M(Xbbpen)]+ complexes (M= G a 3 + , In 3 + ) , these N2O2S2 complexes illustrate how the selectivity of multidentate chelate can be shifted toward I n 3 + from G a 3 + by the introduction of softer donor atoms and the softening of the donor atom set. In order to compare the metal ion sequestering ability of chelating ligands of differing denticities with each other, or with the iron transport protein transferrin at physiological pH, p M values are calculated from observed stability constants; as a p M value increases, so does the affinity of the ligand for the metal ion. From the observed stability constants of these metal complexes, it was not surprising to discover that Sbbpen4" had the highest p M values for both G a 3 + and I n 3 + . Pyridine amine phenolates should be quite capable of competing with transferrin for G a 3 + and I n 3 + . For Sbad 4 -, the p M values of the Ga and In complexes were, respectively, ~2 units greater than the p M values for the binding of G a 3 + and In^+ to transferrin. In solutions where the concentrations of transferrin and amine phenolates are approximately equal, the amine phenolate should be thermodynamically capable of competing with transferrin for these trivalent metal ions. For Sbadd4-, the p M value of the Ga complex was similar to the p M value for the binding of G a 3 + to transferrin, while the p M value of the In complex was lower than the p M value for transferrin; it is doubtful whether Xbadd2 - amine phenolates would be able to compete with transferrin in vivo for G a 3 + and In 3 + ; however, Ga and In complexes with linear amine phenolates may still have potential as diagnostic radiopharmaceuticals if the in vivo demetallation of the complexes is kinetically slow enough to carry out the imaging procedure. Ga complexes with Schiff base analogs of the linear amine phenolate have been considered as myocardial imaging agents.37-38 The lipophilicity of these complexes was altered by placing substituent groups on the aromatic rings and on the amine backbone. These complexes showed significant myocardial uptake and good myocardial retention at 2 hours post-injection. We expect Ga complexes with linear amine phenolates also to exhibit excellent myocardial uptake and retention. We are optimistic about the potential of [M(Xbbpen)]+ 151 complexes (M= G a 3 + , In 3 + ) as diagnostic radiopharmaceuticals; biodistribution studies of [67Ga(bbpen)]+ will be performed. 6.4. References 1. Harris, W. R.; Chen, Y ; Wein, K. Inorg. Chem. 1994, 33, 4991. 2. Liu , S.; Wong, E.; Karunaratne, V. ; Rettig, S. J.; Orvig, C. Inorg. Chem. 1993, 32, 1756. 3. Liu, S.; Wong, E.; Rettig S. J.; Orvig, C. Inorg. Chem. 1993, 32, 4268. 4. Wong, E.; Liu, S.; Lugger, T.; Hahn, F. E.; Orvig, C. Inorg. Chem. 1995, 34 , 93. . 5. Liu, S.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1992, 31, 5400. 6. Wong, E.; Liu, S.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1995, 34, 3057. 7. Wong, E.; Caravan, P.; Liu, S.; Rettig S. J.; Orvig, C. Inorg. Chem. 1996, 35, xxxx. 8. Berry, K. J.; Moya, F.; Murray, K. S.; van den Bergen, A . M . ; West, B . O. / . Chem. Soc, Dalton Trans. 1982, 109. 9. Lutz, T.G.; Clevette, D. J.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1989, 28, 715 10. Caravan, P.; Hedlund, T.; Liu , S.; Sjoberg, S.; Orvig, C. J. Am. Chem. Soc. 1995, 117, 11230. 11. a)Gran, G. Analyst 1952, 77, 661. b) Gran, G. Anal. Chim. Acta 1988, 206 , 111. 12. Motekaitis, R. J.; Martell, A . E. Can. J. Chem. 1982, 60, 2403. 13. _ Baes, C. F. Jr.; Mesmer, R. E. The Hydrolysis of Cations; Wiley: New York, 1976. 14. Glasoe, P. K.; Long, F. A . J. Phys. Chem. 1960, 64, 188. 15. Motekaitis, F. J.; Sun, Y. ; Martell, A . E. Inorg. Chim. Acta 1989,159, 29. 16. Nakon, R.; Martell, A . E. J. Am. Chem. Soc. 1972, 94, 3026. 17. Paoletti, P.; Fabbrizzi, L ; Barbucci, R. Inorg. Chem. 1973,12, 1861. 18. Ma, R.; Motekaitis, R. J.; Martell, A . E. Inorg. Chim. Acta 1994, 224, 151. 19. Taliaferro, C. H. ; Martell, A . E. Inorg. Chem. 1985, 24, 2408. 152 20. Bannochie, C. J.; Martell, A . E. / . Am. Chem. Soc. 1989, 111, 4735. 21. Clarke, E. T.; Martell, A . E. Inorg. Chim. Acta 1991,186, 103. 22. Motekaitis, R. J.; Sun, Y . ; Martell, A; E. Inorg. Chim. Acta 1992,198-200, 421. 23. Evans, D. F.; Jakubovic, D. A. Polyhedron 1988, 7, 1881. 24. Caravan, P.; Orvig, C. Manuscript in preparation. 25. Hancock, R.D.; Martell, A . E. Chem. Rev., 1989, 89, 1875. 26. Motekaitis, R. J.; Martell, A . E.; Welch, M . J. Inorg. Chem. 1990, 29, 1463. 27. Clevette, D. J.; Orvig, C. Polyhedron. 1990, 9, 151. 28. Hancock, R. D. J. Chem. Ed. 1992, 69, 615. 29. Martell, A . E.; Smith, R. M . Critical Stability Constants; Plenum Press: New York; Vols. 1-6, 1974-1989. 30. Aguilar, J. A. ; Bianchi, A. ; Garcia-Espafia, E.; Luis, S. V. ; Llinares, J. M . ; Ramirez, J. A. ; Soriano, C. J. Chem. Soc. Dalton Trans. 1994, 637. 31. Shannon, R. D. Acta Cryst. 1976, A32, 751. 32. Neves, A . ; Erthal, S. M . D.; Vencato, I.; Ceccato, A . S.; Mascarenhas, Y . P.; Nascimento, O. R.; Horner, M . ; Batista, A . A . Inorg. Chem. 1992, 31, 4749. 33. Neves, A . ; Ceccato, A . S.; Erasmus-Buhr, C ; Gehring, S.; Haase, W.; Paulus, H . ; Nascimento, O. R.; Batista, A . A . J. Chem. Soc, Chem. Commun. 1993, 1782. 34. Neves, A. ; De Brito, M . A. ; Oliva, G.; Nascimento, O. R.; Panepucci, E. H . ; Souza, D. H . F.; Batista, A . A. ; Polyhedron, 1995,14, 1307. 35. Anderson, C. J.; John, C. S.; L i , Y . J.; Martell, A . E.; Welch, M . J. Nucl. Med. Biol. 1995,22, 165. 36. Sun, Y . ; Motekaitis, R. J.; Martell, A . E.; Welch, M . J. Inorg. Chim. Acta 1995, 228, 11. 37. Tsang, B. W.; Mathias, C. J.; Green, M . A . J. Nucl. Med. 1993, 34, 1127. 38. Tsang, B . W.; Mathias, C. J.; Fanwick, P. E.; Green, M . A . J. Med. Chem. 1994, 37, 4400. 153 Chapter Seven General Conclusions and Suggestions for Future Work 7.2. General Conclusions The coordination chemistry of group 13 metals with potentially hexadentate amine phenolates was studied as part of an overall effort by our group to develop metal complexes as diagnostic radiopharmaceuticals. The effects of altering the type and spatial organization of the donor atoms on the selectivity of the amino phenolates for metal ions of differing steric and electronic requirements were examined. The feasibility of coordinating hexadentate amine phenolates to Tc and Re ions in intermediate oxidation states was also studied. In this chapter, the results this research project are summarized and suggestions for future work are offered. The idea for the tripodal tame-based amine phenols (H3XTAM, Figure 1.2) originated from the observed coordination behavior of tren-based amine phenolates ( X T R N 3 - , Figure 1.2) to A l 3 + , G a 3 + , and In3"1-.1 Compared to H3XTRN, H 3 X T A M with its smaller tripodal cavity and N3O3 donor atom set was designed to accomodate the differing electronic and steric requirements of all three trivalent group 13 metals. Coordination of X T A M 3 - to trivalent group 13 metal ions yielded neutral 1:1 metal to ligand complexes. Crystallographic structural analyses of the complexes showed that the metal ions coordinated to three neutral amine nitrogen atoms and three anionic phenolate oxygen atoms in a distorted octahedral coordination geometry. Subtle differences between the structures of the three complexes suggested that the X T A M 3 -ligands were flexible enough to adjust the framework to meet the steric demands of all three ions. As the X T A M 3 " ligand framework suffers the least deformation in the A l complex, it appears that the X T A M 3 ' amine phenolates are best suited to A l 3 + . Qualitatively, there was no significant difference between the stability of the three complexes. A stability constant study, which is presently underway by others in our research group, will better quantify this issue. 154 Two series of linear amine phenols (H^Xbad and H^Xbadd) with potential N4O2 donor atom sets were prepared in an effort to design amine phenolates that would be more suitable for coordination to G a 3 + and I n 3 + than for A l 3 + . The N4O2 donor atom set is slightly softer than the N3O3 set of H 3 X T A M and hence is less suitable for coordination to the hard A l 3 + ion (No analytically pure A l complex with any of the linear amine phenolate ligands was isolated). Coordination of Xbad 2 - and Xbadd 2 - to G a 3 + and I n 3 + yielded monocationic complexes. N M R spectral data and crystal structure analyses of [Ga(Brbad)]C104, and [Ga(Brbadd)]ClC<4 confirmed the coordination of G a 3 + by a N4O2 donor atom set; however, the mode of coordination of the Xbad 2 - ligand was different from that of the longer backbone Xbadd 2 - (Figure 4.7). The two linear amine phenolates were coordinated to the metal in the respective mode which was the least sterically demanding; adjusting the length of the linear amine phenols alters the mode of coordination. [Ga(Xbad)]+ and [Ga(Xbadd)]+ complexes were found qualitatively to be more stable than the corresponding In complexes. This was confirmed by a stability constant study, which showed the stability constants of the Ga complexes to be about 3 orders of magnitude greater than those of the In analogs. The selectivity of the linear amine phenolates for G a 3 + over I n 3 + is consistent with the fact that, while the affinity of amine nitrogen donors for G a 3 + and I n 3 + is of the same magnitude, the 2-oxybenzyl groups definitely have a greater affinity for G a 3 + over I n 3 + . Compared to the tripodal and pyridine amine phenolates, the donor atoms of Xbad 2 - and Xbadd 2 -. are not as pre-organized for coordination to a metal ion. The donor atoms in the tripodal and pyridine amine phenolates were arranged such that if a metal ion were of appropriate size, the amine phenolate can coordinate to the metal simultaneously with all six of its donor atoms. This is in contrast with the donor atoms of the linear amine phenolates, which would sequentially position themselves for coordination to the metal ion as the ligand wrapped around the metal center. The stability constants and p M values of complexes with pyridine amine phenolates were found to be significantly higher than those of the linear amine phenolate complexes. 155 The H2Xbbpen ligand precursors were prepared in order to investigate the effect of introducing softer donor atoms into the amine phenolate donor atom set. The softer nature of the Xbbpen 2 - donor atom set made it unsuitable for coordination to A l 3 + ; no analytically pure [Al(Xbbpen)]+ complex was isolated. On the other hand, monocationic G a 3 + and I n 3 + Xbbpen 2 - complexes were prepared with little difficulty. Crystal structure analyses of [Ga(Clbbpen)]C104 and [In(Clbbpen)]C104 showed both metals coordinated by two phenolate oxygen atoms, two amine nitrogen atoms and two pyridine amine nitrogen atoms. Only minor differences were observed between the structures of the two complexes. Stability constants and p M values of [Ga(Sbbpen)]" and [In(Sbbpen)]" were of the same order of magnitude. The hardness of the donor atom set in Xbbpen2" lies in between those of the polyamino polycarboxylate ligands (NT A, EDTA and DTP A), which have a binding affinity for I n 3 + over G a 3 + , 2 and those of the polyamino polyphenolate ligands, which have an affinity for G a 3 + over I n 3 + (HBED, SHBED, EHPG) . 2 " 5 Hence, pyridine amine phenolates showed no selectivity for one metal over another and bind equally well to both G a 3 + and In 3 + . As a preliminary study into the possibility of using hexadentate amine phenolates to stabilize Tc and Re in intermediate oxidation states, coordination of XTAM 3 " amine phenolates to Tc and Re metal ions was examined. Neutral and monocationic Tc(III), Tc(IV) and Re(IV) complexes with X T A M 3 " were prepared via the substitution and the reduction/complexation methods. Although no structural analyses could be performed on the Tc and Re complexes, it is suspected that the metal ions are coordinated by a N3O3 donor atom set. This study of the coordination of XTAM 3 " amine phenolates to Tc and Re metals demonstrates the possible use of the amine phenolates as ligands for coordination to T c 3 + , T c 4 + and R e 4 + metal ions. From the research presented in this thesis, it is clearly obvious that the coordination behavior of the amine phenolates, and of multidentate ligands in general, are greatly affected by the type and spatial arrangements of the donor atoms, the flexibility of the ligand, and the steric and electronic requirements of the metal ions. Using hexadentate amine phenolate ligands and trivalent group 13 metal ions, I have attempted to illustrate the ways in which the binding selectivity of a ligand can be tuned toward a particular metal or group of metals. 156 7.2. Suggestions for Future Work Several of the complexes presented in this thesis appear to have enough potential to be studied as diagnostic radiopharmaceuticals. 6 7 G a and 6 8 G a complexes with Schiff base analogs of Xbadd2" and XTAM 3 " were reported to have excellent myocardial uptake and retention at 2 hour post-injection.6"9 Ga amine phenolate complexes might exhibit similar biodistribution patterns and would certainly be less susceptible to hydrolytic decomposition. It would also be interesting to observe whether or not 9 9 m T c ( I I I ) / X T A M 3 " complexes would have a biodistribution pattern similar to the corresponding Ga complexes. We are also very optimistic about the possible applications of [Ga(Xbppen)]+ and [In(Xbppen)]+ complexes as imaging agents. The lipophilicity of all the metal complexes can be altered by placing appropriate substituent groups either on the aromatic rings or on the backbone of the ligand. Biodistribution studies of these complexes should be performed in order to explore their potential as diagnostic radiopharmaceuticals. Coordination of X T A M 3 " to Tc and Re metals in the +3 and +4 oxidation states has revealed the possibility of using multidentate amine phenolates as ligands for binary Tc and Re complexes. The coordination chemistry of Tc and Re with amine phenolates needs to be examined further. Preliminary investigations into the coordination of Xbppen2" to T c 3 + and R e 3 + have been very promising but further work in this area is definitely required. Amine phenolates may also be used as bifunctional chelating agents in the attachment of metal ions to large naturally occurring compounds such as proteins and antibodies. The localization of a metal radiopharmaceutical to a specific organ or tissue can be achieved by attaching the pharmaceutical onto a biological molecule that would normally localize in the desired region. The difficulties in using the amine phenolates as bifunctional chelating agents lies in the manner in which the amine phenolates can be attached to the biological molecule. Figure 7.1 describes a possible scheme for converting the amine phenols into bifunctional chelates. This method was suggested by Meares 1 0 for attaching metal chelate onto antibodies. 157 Although the nitro moiety in Figure 7.1 is on a hydroxybenzyl group, it can also be located on the R I N H 0 , N 6 R I N H B r C H j C H N i,j6 O H N H , R I N H N H 2 C H 2 C H N O H N a B H 4 H , N O B r C H i C B r N H S C N J L O H R I N H J L O H o H N O , R I N H J* O H Figure 7.1. Proposed reaction scheme for the conversion of amine phenols to potential Afunctional chelating agents (R = amine backbone). backbone of an amine phenol. The reaction scheme begins with the reduction of the nitro group to an amine moiety. This is followed by the reaction of the amine group with either bromoacetamide, nitrous acid or thiophosgene to form, respectively, three different moieties, which can then be used to attach the chelate onto a biological molecule. The bromoacetamide moiety can then react with sulfur and nitrogen nucleophiles on proteins, while the isothiocyanate moiety can react with amino groups, and the diazonium compound can react with several different amino acid residues. The bromoacetamide group can also be converted to a 158 glycinamide moiety, which can then be used for attaching the chelates to synthetic peptides. Utilizing the amine phenolates as bifunctional chelating agents opens the door to a whole new area of research for the amine phenolate complexes. 7.3. References. 1. Liu, S.; Rettig, S. J.; Orvig, C. Inorg. Chem. 1992, 31, 5400. 2. Martell, A . E.; Smith, R. M . Critical Stability Constants; Plenum Press: New York; Vols. 1-6, 1974-1989. 3. Ma, R.; Motekaitis, R. J.; Martell, A. E. Inorg. Chim. Acta 1994, 224, 151. 4. Motekaitis, F. J.; Sun, Y . ; Martell, A . E. Inorg. Chim. Acta 1989,159, 29. 5. Bannochie, C. J.; Martell, A . E. J. Am. Chem. Soc. 1989, 111, 4735. 6. Green, M . A . J. Labelled Comp. Radiopharm. 1986, 23, 1227. 7. Green, M . A. ; Welch, M . J.; Mathias, C. J.; Fox, A . A. ; Knabb, R. M . ; Huffman, J. C. J. Nucl. Med. 1985, 26, 170. 8. Tsang, B. W.; Mathias, C. J.; Green, M . A. J. Nucl. Med. 1993, 34, 1127. 9. Tsang, B . W.; Mathias, C. J.; Fanwick, P. E.; Green, M . A . / . Med. Chem. 1994, 37, 4400. 10. Meares, C. F. Nucl. Med. Biol. 1986,13, 311. 159 Appendices Appendix I Table 1-1. Selected crystallographic data for [Ga(TAM)]-4.4H 20, [In(TAM)]-4.6H 20, and {[Al(BrTAM)] 4 [Na(H 2 0) 2 }(C10 4 ) 2 -6.2H 2 0. complex {[Al(BrTAM)] 4 [Na (H 2 0) 2 ]}(C10 4 ) 2 -6.22H 2 0 [Ga(TAM)]-4.4H 2 0 [In(TAM)]-4.6H 20 formula Cio4Hi 2 o . 4 4AlBri 2 -C l 2 N i 2 0 9 N a 2 0 2 g . 2 2 C26H38.7GaN307.35 C 26H39.i 4InN 307.57 fw 3173.78 580.63 629.69 cryst syst orthorhombic monoclinic monoclinic space group Pbcn CVc CVc a, A 27.226 (2) 32.105 (9) ll.dSA (2) b, A 15.687 (4) 10.559 (2) 10.744 (2) c, A 30.013 (3) 19.626 (5) 19.429 (2) P,deg 90 118.43 (1) 117.842 (4) V, A 3 12818 (3) 5851 (2) 6027 (1) Z 4 8 8 Pca/c g / c m 3 1.644 1.318 1.388 T,°C 21 21 21 radiation (k, A) Cu Ka(l.54178) Cu K a ( 1.54178) Cu K a ( 1.54178) u,, cm' 1 58.36 16.49 67.81 transm factors 0.87 - 1.00 0.78 - 1.00 0.83 - 1.00 R 0.049 0.039 0.038 Rw 0.048 0.046 0.043 .160 Table 1-2. Final atomic coordinates (fractional) and 5 e q (A 2 ) a for non-hydrogen atoms in {[Al(BrTAM)]4[Na(H 20)2} (C10 4) 2-6.2H 20. atom x y z , #eq occ. B r l 0.38242(4) 0.67028(6) 0.70449(5) 7.84(7) Br2 0.50007(5) 0.11209(8.) 0.43776(3) 8.78(7) Br3 0.81652(3) 0.36464(8) 0.70030(4) 7.75(6) Br4 0.56974(3) -0.24058(6) 0.66555(4) 6.91(6) Br5 0.19140(4) 0.10179(8) 0.84451(4) 7.99(7) Br6 0.31309(5) 0.25866(9) 0.45872(4) 10.34(9) C l l 0.2044(2) 0.0856(3) 0.5588(2) 12.0(3) A l l 0.55639(7) 0.3472(1) 0.63792(6) 2.68(9) A12 0.38229(7) 0.0846(1) 0.67205(7) 3.1(1) Na l 0.4850(1) 0.2121(2) 0.6913(1) 3.8(1) 01 0.5035(1) 0.3544(3) 0.6757(1) 2.6(2) 02 0.5418(2) 0.2359(3) 0.6234(1) 3.0(2) 03 0.5991(1) 0.3188(3) 0.6822(1) 3.1(2) 04 0.4492(2) 0.0781(3) 0.6820(1) 3.2(2) 05 0.3701(1) 0.1263(3) 0.7278(2) 3.6(2) 06 0.3871(2) 0.1880(3) 0.6444(2) 3.5(2) 07 0.5549(2) 0.2134(3) 0.7394(1) 4.3(3) 08 0.2426(4) 0.1238(7) 0.5789(3) 17.4(8) 09 0.1832(6) 0.130(1) 0.5279(5) 29.2(2) 010 0.1717(5) 0.052(2) 0.5909(7) 35(2) O i l 0.226(1) 0.014(1) 0.5396(7) 32(2) 012 0.0626(3) 0.0485(7) 0.5798(2) 11.0(5) 013 0.1181(7) 0.231(1) 0.5042(5) 21(2) 161 Table 1-2 (cont'd). atom X y z occ. 013A •0.055(1) 0.160(2) 0.577(1) 22(3) 014 0.297(1) -0.010(3) 0.450(1) 20(1) 0.34 014A 0.322(1) -0.177(3) 0.495(1) 21(1) 0.33 015 0.695(1) 0.070(2) 0.524(1) 20(1) 0.44 N l 0.5763(2) 0.4740(3) 0.6491(2) 2.7(3) N2 0.5121(2) 0.3956(3) 0.5877(2) 2.7(2) N3 0.6122(2) 0.3468(3) 0.5905(2) 2.8(3) N4 0.3714(2) -0.0382(4) 0.6996(2) 3.3(3) N5 0.3077(2) 0.0809(4) 0.6575(2) 3.7(3) N6 0.3909(2) 0.0174(4) 0.6126(2) 3.4(3) CI 0.5948(3) 0.5591(5) 0.5320(3) 5.2(3) -C2 0.5826(3) 0.4905(5) 0.5664(2) 3.5(4) C3 0.5720(2) 0.5341(4) 0.6108(2) 3.2(3) C4 0.5541(2) 0.5079(4) 0.6910(2) 3.3(3) C5 0.4987(2) 0.5040(5) 0.6894(2) 2.8(3) C6 0.4765(2) 0.4245(4) 0.6827(2) 2.8(3) C7 0.4248(2) 0.4206(5) 0.6827(2) 3.5(4) C8 0.3970(2) 0.4939(5) 0.6889(3) 4.1(4) C9 0.4200(3) 0.5694(5) 0.6954(3) 3.8(4) CIO 0.4705(3) 0.5758(4) 0.6959(2) 3.5(4) C l l 0.5373(3) 0.4417(5) 0.5506(2) 3.7(4) C12 0.4756(2) 0.3319(5) 0.5717(2) 3.4(3) C13 0.5003(3) 0.2533(4) 0.5535(2) 3.4(3) 162 Table 1-2 (cont'd). atom X y z C14 0.5335(2) 0.2085(5) 0.581592) 3.2(3) C15 0.5560(3) 0.1365(5) 0.5651(3) 4.3(4) C16 0.5469(3) 0.1073(5) 0.5229(3) 5.1(5) C17 0.5141(3) 0.1505(6) 0.4971(3) 5.2(5) C18 0.4911(3) 0.2231(5) 0.5112(2) 4.3(4) C19 0.6267(2) 0.4296(5) 0.5708(2) 3.6(4) C20 0.6561(3) 0.2963(50 0.6042(20 3.7(4) C21 0.6778(2) 0.3258(4) 0.6479(2) 3.3(4) C22 0.6479(2) 0.3324(4) 0.6853(2) 2.8(3) C23 0.6678(3) 0.3504(5) 0.7266(3) 4.1(4) C24 0.7181(3) 0.3610(5) 0.731193) 5.0(5) C25 0.7473(3) 0.3547(5) 0.6941(3) 4.6(4) . C26 0.7279(3) 0.3386(5) 0.6531(3) 4.2(4) C27 0.2877(3) 00.1468(6) 0.6162(3) 6.4(5) C28 0.3187(3) -0.0735(5) 0.6344(3) 4.4(4) C29 0.3528(3) -0.1075(5) 0.6706(3) 4.2(4) C30 0.4148(3) -0.0675(5) 0.7265(2) 3.9(4) C31 0.4607(2) -0.0675(5) 0.6993(2) 3.1(3) C32 0.4774(2) 0.0071(5) 0.6808(2) 2.9(3) C33 0.5233(2) 0.0102(4) 0.660892) 3.3(3) C34 0.5510(2) -0.062595) 0.6569(2) 3.5(4) C35 0.5332(2) -0.1384(5) 0.6730(2) 3.5(4) C36 0.4880(3) -0.141395) 0.694392) 3.7(4) C37 0.2842(3) -0.0064(5) 0.654593) 4.4(4) 163 T a b l e 1-2 (cont 'd) . atom X y - z C38 0.2783(3) 0.1394(5) 0.6856(3) 4.5(4) C39 0.2831(2) 0.1222(5) 0.7344(3) 3.6(4) C40 0.3301(3) 0.1185(5) 0.7539(3) 3.8(4) C41 0.3345(3) 0.1097(5) 0.7989(3) 4.2(4) C42 0.2938(3) 0.1033(5) 0.8267(3) 5.2(5) C43 0.2486(3) 0.1065(5) 0.8076(3) 4.9(4) C44 0.2422(3) 0.1145(5) 0.7626(3) 4.8(5) C45 0.3489(3) -0.0341(5) 0.5961(2) 4.2(4) C46 0.4123(3) 0.0720(5) 0.5771(2) 4.2(4) C47 0.3816(3) 0.1475(5) 0.5683(3) 3.8(4) C48 0.3717(2) 0.2044(5) 0.6029(3) 3.6(4) C49 0.3462(3) 0.279695) 0.5938(3) 4.6(4) C50 0.3296(3) 0.2955(60 0.5503(4) 6.1(6) C51 0.3386(3) 0.2379(8) 0.5168930 6.3(6) C52 0.3644(3) 0.1632(6) 0.5254(3) 5.1(5) a £ e q = 8/37i2[£iEjUijai*aj*aiaj]. 164 Table 1-3. Final atomic coordinates (fractional) and 5 eq (A 2 ) a for non-hydrogen atoms in [Ga(TAM)]-4.4H 2 0. atom X y . z occ. Gal 0.38391(1) 0.42029(4) 0.37898(2) 3.44(1) 01 0.44383(7) 0.3353(2) 0.4288(1) 3.95(8) 02 0.35090(7) 0.2649(2) 0.3345(1) 3.96(9) 03 0.37465(8) 0.4096(2) 0.4687(1) 4.7(1) 04 0.49561(9) 0.3270(3) 0.5871(1) 6.2(1) 05 0.3577(5) 0.173(1) 0.5055(7) 15.8(6) 0.53 06 0.3593(2) 0.0349(5) 0.4060(4) 12.2(4) 0.72 07 0.434(1) 0.258(4) 0.643(2) 11(1) 0.19 08 0.4025(8) 0.204(2) 0.578(1) 15(1) 0.39 09 0.2788(7) 0.154(2) 0.461(1) 40(1) 0.75 O10 0.4753(9) 0.272(2) 0.703(1) 15(1) 0.27 O i l 0.394(1) 0.083(5) 0.583(2) 21(2) 0.25 012 0.4440(8) 0.175(3) 0.648(1) 10(1) 0.24 N l 0.39435(9) 0.4544(2) ' 0.2786(1) 3.4(1) N2 0.31897(9) 0.5213(3) 0.3205(1) 3.8(1) N3 0.41648(9) 0.5970(3) 0.4123(1) 3.8(1) CI 0.3498(2) 0.7971(4) 0.2303(2) 5.9(2) C2 0.3612(1) 0.6732(3) 0.2774(2) 4.2(1) C3 0.3905(1) 0.5904(3) 0.2528(2) 4.1(1). C4 0.4400(1) 0.4009(3) 0.2886(2) 4.1(1) C5 0.4479(1) 0.2664(3) 0.3172(2) 3.9(1) C6 0.4510(1) 0.2410(1) 0.3891(2) 3.7(1) C7 0.4622(1) 0.1187(4) 0.4190(2) 4.8(1) 165 Table 1-3 (cont'd). atom X y z C8 0.4693(1) 0.0233(4) 0.3776(3) 5.8(2) C9 0.4648(2) 0.0471(4) 0.3056(3) 6.0(2) CIO 0.4544(1) 0.1684(4) 0.2761(2) 5.1(2) C l l 0.3142(1) 0.6100(3) 0.2582(2) 4.5(1) C12 0.2767(1) 0.4363(4) 0.2929(2) 4.6(1) C13 0.2767(1) 0.3394(3) 0.2371(2) 4.1(1) C14 0.3149(1) 0.2552(3) 0.2630(2) 3.8(1) C15 0.3144(1) 0.1607(3) 0.2127(2) 4.6(1) C16 0.2764(2) 0.1510(4) 0.1389(2) 5.8(2) C17 0.2387(2) 0.2351(5) 0.1134(2) 6.1(2) C18 0.2394(1) 0.3287(4) 0.1622(2) 5.2(2) C19 0.3895(1) 0.7064(3) 0.3637(2) 4.5(1) C20 0.4357(1) 0.6226(4) 0.4966(2) 4.7(1) C21 0.3980(1) 0.6184(4) 0.5210(2) 4.6(1) C22 0.3701(1) 0.5101(4) 0.5071(2) 4.4(1) C23 0.3371(1) 0.5053(4) 0.5346(2) 5.3(2) C24 0.3328(1) 0.6079(5) 0.5757(2) 5.8(2) C25 0.3596(2) 0.7125(5) 0.5887(2) 6.4(2) C26 0.3926(1) 0.7188(4) 0.5617(2) 5.7(2) a f i e q = 8/3rc2[ZiZjUijai*aj*aiaj]. 166 Table 1-4. Final atomic coordinates (fractional) and 5 e q ( A 2 ) a for non-hydrogen atoms in [In(TAM)]-4.6H 2 0. atom X y • z occ. Inl 0.38559(1) 0.39876(3) 0.39062(2) 3.84(1) 01 0.4499(1) 0.3084(3) 0.4368(2) 4.8(1) 02 0.3480(1) 0.2330(3) 0.3459(2) 5.1(1) 03 0.3802(1) 0.4007(3) 0.4939(2) 5.9(2) 04 0.533(1) 0.3319(4) 0.5909(2) 6.7(2) 05 0.301(1) 0.129(3) 0.470(2) 24(1) 0.41 06 0.3542(4) 0.029(1) i 0.4332(7) 28.2(9) 07 0.4207(4) 0.229(1) 0.6160(6) 22.5(8) 08 0.3477(2) 0.108(4) 0.536(3) 21(2) 0.25 09 0.4880(9) 0.311(2) 0.720(1) 20(1) 0.47 010 0.421(1) 0.030(3) 0.579(2) 26(2) 0.44 N l 0.3947(1) 0.4384(3) 0.2807(2) 3.8(1) N2 0.3160(1) 0.4997(4) 0.3235(2) 4.3(1) N3 0.4153(1) 0.5928(3) 0.4198(2) 4.3(1) CI 0.3471(2) 0.7695(5) 0.2306(3) 6.0(2) C2 0.3593(2) 0.6505(4) 0.2806(3) 4.3(2) C3 - 0.3904(2) 0.5723(4) 0.2581(2) 4.2(2) C4 0.4401(2) 0.3856(5) 0.2912(3) 4.6(2) C5 0.4472(2) 0.2527(4) 0.3165(3) 4.4(2) C6 0.4531(1) 0.2214(4) 0.3896(3) 4.3(2) C7 0.4622(2) 0.0978(5) 0.4144(3) 5.8(2) C8 0.4649(2) 0.0073(6) 0.3663(4) 6.9(3) C9 0.4586(2) 0.0377(6) 0.2930(4) 7.0(3) 167 Table 1-4 (cont'd). atom X y z CIO 0.4501(2) 0.1593(5) 0.2689(3) 5.7(2) C l l 0.3136(2) 0.5837(4) 0.2613(3) 4.7(2) C12 0.2761(2) 0.4121(5) 0.2952(3) 5.2(2) C13 0.2785(2) 0.3141(5) 0.2432(3) 4.8(2) C14 0.3147(2) 0.2282(5) 0.2721(3) 4.6(2) C15 0.3155(2) 0.1341(5) 0.2230(4) 6.3(3) C16 0.2806(3) 0.1250(7) 0.1478(4) 8.1(4) C17 0.2448(3) 0.2073(8) 0.1193(4) 8.2(4) C18 0.2439(2) 0.3027(6) 0.1663(3) 6.5(3) C19 0.3852(2) 0.6910(4) 0.3663(3) 4.9(2) C20 0.4321(2) 0.6244(5) 0.5031(3) 5.5(2) C21 0.3947(2) 0.6191(5) 0.5368(3) 5.6(2) C22 0.3711(2) 0.5081(6) 0.5217(2) 5.6(2) C23 0.3371(2) 0.5064(7) 0.5465(3) 7.0(3) C24 0.3285(2) 0.6151(8) 0.5791(3) 7.8(3) C25 0.3519(3) 0.7197(8) 0.5842(4) 8.5(4) C26 0.3844(2) 0.7239(6) 0.5581(3) 7.3(3) a Beq = 8/37C2[ZiZjUijai*aj*aiaj]. 168 Table 1-5. Selected crystallographic data for H3Clapi. compound H 3 C l a p i formula C27H27CI3N4O3 fw 561.89 crystal system orthorhombic space group Pnma a, A 11.398(4)(4) b,k 21.486(3) c, A 10.942(4) a, deg 90 p\ deg 90 y, deg 90 v,k 2680(2) ' z 4 PCfl/c» g / c m 3 1.393 T,°C 21(2) radiation (K, A) Cu K a (1.54178) | i , cm"1 34.51 transm factors 0.85-1.00 0.035 Rw (F) a 0.032 a R (F) = IIIF0I-IFCII/XIF0I, Rw (F) = (Iw(IF0l-IFcl)2/IwF02) 169 Table 1-6. Final atomic coordinates (fractional) and Beq ( A 2 ) a for non-hydrogen atoms in H 3 C l a p i . atom X y z #eq occ. C l l 0.60067(12) 0.2631(2) -0.14476(13) 6.6(2) 0.50 C12 -0.09096(7) 0.09054(4) 0.70281(7) 6.52(4) O l 0.2399(3) 0.2226(2) 0.2261(3) 5.8(2) 02 0.2698(2) 0.05291(12) 0.3298(2) 6.8(1) N l 0.0937(2) 0.19756(11) 0.0268(2) 4.3(1) N2 0.1117(2) 0.07719(11) 0.1651(2) 5.0(1) CI -0.0295(2) 0.21500(13) 0.0000(3) 5.3(2) C2 0.1611(3) 1/4 -0.0214(3) 4.3(2) C3 0.2881(3) 1/4 0.0168(3) 3.9(2) C4 0.3203(4) 0.2356(4) 0.1387(4) 3.9(3) 0.50 C5 0.4380(4) 0.2372(6) 0.1716(4) 4.3(4) 0.50 C6 0.5229(3) 1/4 0.0850(4) 4.8(2) C7 0.4922(3) 1/4 -0.0353(4) 4.5(2) C8 0.3761(4) 0.2583(12) -0.0695(4) 3.1(5) 0.50 C9 0.1280(2) 0.1377(2) -0.0240(2) 5.2(2) CIO 0.0701(3) 0.08342(14) 0.0398(3) 5.6(2) C l l 0.0394(3) 0.08602(13) 0.2515(3) 4.9(1) C12 0.0712(2) . 0.07953(13) 0.3795(3) 4.2(1) C13 0.1856(3) 0.0628(2) 0.4138(3) 5.1(2) C14 0.2124(3) 0.0551(2) 0.5372(3) 5.8(2) C15 0.1283(3) 0.0634(2) 0.6240(3) 5.4(2) C16 0.0157(3) 0.08008(14) 0.5905(3) 4.7(2) C17 -0.0124(2) 0.08800(13) 0.4701(3) 4.7(1) fleq = 8/37U2[IiXjUijai*aj*aiaj]. 170 Table 1-7. Selected crystallographic data for [Ga(Brbad)]C104DMSO and [Ga(Brbadd)]C104. compound [Ga(Brbad)]C104DMSO [Ga(Brbadd)][C104] formula C22H32Br 2ClGaN 40 7S C22H3oBr2ClGaN406 fw 761.6 711.48 crystal system oithorhombic oithorhombic space group Pbca(no. 61) P2{l{lx a, A 14.777(4) 12.462(1) b,k 22.221(5) 21.835(2) o c, A 17.410(7) 9.961(2) v,k 5717(5) 2710.6(5) z 8 4 Pcalc g / c m 3 1.770 1.743 T, °C 20(2) 21 radiation (k, A) Mo K„ (0.710 73) Cu K a (1 .54 178) | l , cm"1 39.4 61.79 transm factors 0.63-1.00 0.85-1.00 i? (F) a 0.048 0.031 Rw (F) a 0.052 0.029 a R (F) = IIIF0I-IFCII/IIF0I, Rw (F) = (Iw(IF 0l-IF cl) 2/IwF 0 2) 171 Table 1-8. Final atomic coordinates (fractional) and 5 e q (A 2 ) for non-hydrogen atoms [Ga(Brbad)]C10 4DMSO. atom x y z - B e q a B r l 0.21693(9) -0.00727(5) 0.07218(8) 6.04 Br2 0.32013(9) -0.49413(6) -0.15653(7) 4.05 Ga . 0.55446(7) -0.24658(5) 0.03114(6) 2.89 CI 0.1715(2) 0.1378(1) 0.2351(2) 4.73 S 0.5724(2) -0.0309(2) 0.1526(2) 5.08 O l 0.4296(4) -0.2371(3) 0.0572(4) 3.07 02 0.5483(5) -0.2812(3) -0.0694(4) 3.22 03 0.1304(6) 0.1185(5) 0.1658(6) , 6.62 04A 0.1901(16) 0.1980(11) 0.2294(12) 8.26 05 A 0.2584(14) 0.1094(9) 0.2329(12) 7.49 0 6 A 0.1154(18) 0.1121(11) 0.2859(14) 9.86 04B 0.2645(17) 0.1559(12) 0.2172(13) 9.64 05B 0.1821(15) 0.1017(9) 0.3016(12) 7.51 06B 0.1369(11) 0.1973(7) 0.2625(9) 5.12 07 0.5698(6) -0.0954(3) 0.1260(5) 5.33 N l 0.5571(5) -0.1603(3) -0.0139(4) 3.15 N2 0.6971(5) -0.2404(4) 0.0123(4) 3.67 N3 0.5989(6) -0.2249(4) 0.1457(4) 3.28 N4 0.5349(5) -0.3313(3) 0.0799(4) 2.92 CI 0.3836(6) -0.1866(5) 0.0572(5) 2.58 C2 0.3141(7) -0.1793(5) 0.1135(6) 3.75 C3 0.2630(7) -0.1260(5) . 0.1159(6) 2.82 172 Table 1-8 (cont'd). atom X y z C4 0.2785(7) -0.0817(5) 0.0644(6) 3.48 C5 0.3441(7) -0.0888(5) 0.0088(6) 4.07 C6 0.3959(7) -0.1397(4) 0.0058(5) 2.67 C7 0.4711(7) -0.1475(5) 0.0542(5) 3.91 C8 0.6352(7) -0.1578(5) -0.0666(6) 4.70 C9 0.7176(7) -0.1812(5) -0.0227(6) 4.10 CIO 0.7464(7) -0.2502(5) 0.0855(6) 3.92 C l l 0.6988(6) -0.2146(5) 0.1488(6) 2.99 C12 0.5687(7) -0.2759(5) 0.1953(6) 3.67 C13 0.5793(7) -0.3354(4) 0.1566(6) 3.63 C14 0.5554(7) -0.3826(4) 0.0310(6) 3.50 C15 0.4960(6) -0.3807(4) -0.0409(5) 2.55 C16 0.4408(7) -0.4276(4) -0.0615(6) 3.34 C17 0.3917(6) -0.4260(4) -0.1279(6) 2.61 C18 0.3934(7) -0.3762(5) -0.1738(6) 3.33 C19 0.4438(7) -0.3271(4) -0.1538(5) 3.10 C20 0.4971(7) -0.3283(4) -0.0870(6) 2.68 C21 0.5948(9) -0.0353(6) 0.2525(6) 5.08 C22 0.4686(10) -0.0186(10) 0.1643(8) 11.07 a Disordered O atoms (04A to 06B) were refined with isotropic thermal parameters. The thermal parameter given for anisotropically refined atoms is the isotropic equivalent thermal parameter defined as fieq = 8/37t2[Ej£jUijaj*aj*aiaj]. 173 Table 1-9. Final atomic coordinates (fractional) and Bcq (A2) for non-hydrogen atoms in [Ga(Brbadd)]C10 4. atom X y z #eq B r l 0.20000(7) 0.08485(4) 0.9289(1) 6.90(3) Br2 1.03872(7) 0.00270(5) 0.2601(1) 7.84(3) Ga l s 0.53184(7) 0.16594(4) 0.36108(10) 4.22(2) C l l 0.7158(2) 0.1767(2) -0.1571(3) 9.44(9) 01 0.3828(3) 0.1440(2) 0.3859(6) 4.9(1) 02 0.6803(3) 0.1843(2) 0.3336(5) 4.3(1) 03 0.736(1) 0.1250(5) -0.094(1) 26.4(7) 04 0.7749(7) 0.1878(6) -0.267(1) 21.6(5) 05 0.6132(6) 0.1710(5) -0.2000(8) 15.5(3) 06 0.7341(6) 0.2244(4) -0.0647(8) 12.2(3) N l 0.5304(4) 0.2198(2) 0.5360(6) 4.2(1) N2 0.4851(4) 0.2420(3) 0.2485(8) 5.3(2) N3 0.5258(5) 0.1223(3) 0.1742(6) 5.1(2) N4 0.5736(4) 0.0835(3) 0.4660(6) 4.4(1) C I , 0.5837(6) 0.2804(3) 0.5228(9) 5.8(2) C2 0.5304(7) 0.3217(3) 0.419(1) 6.8(2) C3 0.5415(7) 0.3004(3) . 0.277(1) 6.2(2) C4 0.4935(6) 0.2261(4) 0.1063(10) 6.6(3) C5 0.4582(7) 0.1612(4) 0.0860(9) 6.9(2) C6 0.4920(6) 0.0584(4) 0.1684(9) 6.5(2) C7 0.5623(7) 0.0174(4) 0.255(1) 7.0(3) 174 Table 1-9 (cont'd). atom X y z #eq C8 0.5448(6) 0.0240(3) 0.4048(10) 5.8(2) C9 0.4206(5) 0.2276(3) 0.5952(9) '5.0(2) CIO 0.3620(4) 0.1682(3) 0.6179(8) 4.2(2) C l l 0.3429(5) 0.1307(3) 0.5059(9) 4.3(2) C12 0.2777(5) 0.0793(3) 0.5244(9) 5.0(2) C13 0.2367(5) 0.0655(3) 0.651(1) 5.1(2) C14 0.2587(5) 0.1024(3) 0.7550(9) 4.8(2) C15 0.3216(5) 0.1542(3) 0.7413(8) 4.2(2) C16 0.6891(6) 0:0842(3) 0.5129(8) 5.1(2) C17 0.7664(5) 0.0916(3) 0.3993(8) 4.4(2) C18 0.7574(5) 0.1421(3) 0.3143(8) 4.3(2) C19 0.8310(5) 0.1491(3) 0.2103(8) 4.6(2) C20 0.9139(6) 0.1079(4) 0.1951(8) 5.3(2) C21 0.9235(5) 0.0590(4) 0.2784(9) 5.5(2) C22 0.8490(5) 0.0498(30 0.3809(9) 5.2(2) Beq=(m)Kz(Un(aa*)z + U22(bb*)z + U^icc*)1 + 2Ui2aa*bb*cos y+2Utfaa*cc*cos P + 2U23bb*cc*cos a) 175 Table 1-10. Selected crystallographic data for [Ga(Clbbpen)]C104 and [In(Clbbpen)]C104. Compound [Ga(Clbbpen)]C104 [In(Clbbpen)]C104 Formula C 2 8 H 2 6 C l 3 G a N 4 0 6 C 2 8 H 2 6 C l 3 I n N 4 0 6 fw 690.62 735.72 Crystal system Triclinic Monoclinic Space group PT P2xlc a, A 11.1563(6) 9.693(1) b,k 14.1365(6) 21.821(2) c, A 9.9296(7) 14.428(1) a, deg 98.395(4) 90 P, deg 107.094(5) 109.413(7) y, deg 70.751(4) 90 V, A 3 1411.1(2) 2878.2(5) Z 2 4 Pcalc g/cm 3 1.625 1.698 T, °C 21 21 Radiation M o K a M o K a X,k 0.71069 0.71069 | i , cm - 1 13.10 11.37 Transmission factors - 0.82-1.00 0.84-1.00 R(F) 0.035 0.030 Rw (F) 0.031 0.029 R = SIIF 0 l - IF c l l/ i : iF 0 l , Rw = (Zw(IF 0 l - IF c l ) 2 /EwlF 0 l 2 ) 176 Table 1-11. Final atomic coordinates (Fractional) and fieq (A 2 ) for non-hydrogen atoms in [Ga(Clbbpen)]C10 4. atom X y z Gal 0.37827(3) 0.19882(2) - 0.39109(3) 2.146(5) C l l 0.93307(7) -0.04954(6) 0.09009(8) 4.56(2) C12 -0.17793(6) 0.32092(6) 0.69529(7) 3.98(2) C13 0.76501(7) 0.39886(5) 0.18380(7) 3.66(2) O l 0.4687(2) 0.0787(1) 0.3122(2) 2.82(4) 02 0.2478(1) 0.1507(2) 0.4123(2) 2.64(4) 03 0.8574(2) 0.4535(1) 0.2305(2) 5.20(6) 04 0.6843(4) 0.4335(2) 0.0550(3) 12.3(1) 05 0.8244(3) 0.2952(2) 0.1672(3) 8.19(8) 06 0.6897(3) 0.4157(2) 0.2810(3) 9.44(10) N l 0.5007(2) 0.2759(1) 0.3451(2) 2.37(4) N2 0.3062(2) 0.3399(1) 0.5020(2) 2.26(4) N3 ' 0.2582(2) 0.2616(1) 0.1968(2) 2.53(4) N4 0.5071(2) 0.1708(1) 0.5941(2) 2.38(4) CI 0.4874(2) 0.3693(2) 0.4379(3) 3.01(5) C2 0.3475(2) 0.4144(2) 0.4490(3) 2.88(5) C3 0.6413(2) 0.2112(2) 0.3764(2) 2.61(5) C4 0.6604(2) 0.1134(2) 0.2888(2) 2.40(5) C5 0.5746(2) 0.0548(2) 0.2631(2) 2.41(5) C6 0.6017(2) -0.0353(2) 0.1810(3) 2.92(5) C7 0.7108(3) -0.0677(2) 0.1284(3) 3.32(6) 177 Table M l (cont'd). atom X y • z C8 0.7947(2) -0.0096(2) 0.1558(3) 2.98(5) C9 0.7696(2) 0.0802(2) 0.2339(3) 2.81(5) CIO 0.4531(2) 0.2998(2) 0.1937(3) 3.07(6) C l l 0.3096(2) 0:3105(2) 0.1342(2) 2.82(5 C12 0.2351(3) 0.3663(2) 0.0181(3) 3,76(6) C13 0.1052(3) 0.3686(2) -0.0363(3) 4.36(7) C14 0.0534(3) 0.3147(2) 0.0249(3) 4.04(7) C15 0.1329(2) 0.2626(2) 0.1420(3) 3.22(6) C16 0.1594(2) 0.3715(2) 0.4716(2) 2.45(5) C17 0.1080(2) 0.2972(2) 0.5123(2) 2.32(5) C18 0.1532(2) 0.1931(2) 0.4789(2) 2.35(5) C19 0.0919(2) 0.1312(2) 0.5133(3) 2.98(5) C20 -0.0092(2) 0.1692(2) 0.5779(3) 3.17(6) C21 -0.0504(2) 0.2706(2) 0.6115(2) 2.91(5) C22 0.0074(2) 0.3336(2) • 0.5793(2) 2.76(5) C23 0.3650(2) 0.3311(2) 0.6571(2) 2.93(5) C24 0.4897(2) 0.2466(2) 0.6934(2) 2.50(5) C25 0.5804(2) 0.2438(2) 0.8232(3) 3.22(6) C26 0.6893(3) 0.1590(2) 0.8543(3) 3.64(6) C27 0.7030(2) 0.0800(2) 0.7548(3) 3.44(6) C28 0.6112(2) 0.0886(2) 0.6259(3) 2.72(5) #eq=(8/3)7i2(£/n(aa*)2 + U22(bb*)2 + U^cc*)2 + 2Ui2aa*bb*cosy+2Ui3aa*cc*cos P + 2U23bb*cc*cos a) 178 Table 1-12. Final atomic coordinates (Fractional) and Z?eq (A 2 ) for non-hydrogen atoms in [In(Clbbpen)]C10 4. atom X y z Beq occ. Inl 0.37940(2) - 0.533967(9) 0.31498(1) 2.750(3) C l l -0.02215(9) 0.75982(4) 0.48934(6) 4.72(2) C12 0.87957(9) 0.36259(4) 0.12489(7) 5.72(2) C13 -0.31020(8) 0.64470(4) 0.08925(6) 4.14(2) O l 0.3695(2) 0.56363(9) 0.4485(1) 3.31(4) 02 0.5981(2) 0.52306(9) 0.3354(1) 3.49(4) 03 -0.2285(3) 0.6742(1) 0.1782(2) 6.83(7) 04 -0.292(1) 0.6764(4) 0.0125(5) 8.8(2) 0.70(2) 04a -0.358(4) 0.684(1) 0.012(2) 16.8(7) 0.30 05 -0.4622(7) 0.6453(4) 0.0790(7) 8.1(2) 0.70 05a -0.422(3) 0.617(2) 0.098(2) 16.2(10) 0.30 06 -0.2700(9) 0.5832(2) 0.0880(7) 9.0(2) 0.70 06a -0.205(2) 0.609(1) 0.056(1) 11.5(6) 0.30 N l 0.1388(2) 0.5646(1) 0.2394(2) 3.06(5) N2 0.3222(2) 0.4811(1) 0.1686(1) 3.11(5) N3 0.3909(2) 0.6340(1) , 0.2696(2) 3.36(5) N4 0.3113(2) 0.4391(1) 0.3478(2) 2.95(5) CI 0.0760(3) 0.5177(1) 0.1626(2) 3.82(6) C2 0.1805(3) 0.5064(2) 0.1049(2) 4.28(7) C3 0.0673(3) 0.5617(1) 0.3175(2) 3.23(6) C4 0.1293(3) 0.6100(1) 0.3947(2) 3.01(6) C5 0.2786(3) 0.6091(1) 0.4537(2) 3.08(6) 179 Table 1-12 (cont'd). atom X y z #eq C6 0.3322(3) 0.6573(1) 0.5193(2) 3.71(6) C7 0.2419(3) 0.7039(1) 0.5295(2) 4.10(7) C8 0.0956(3) 0.7027(1) 0.4735(2) 3.68(7) C9 0.0390(3) 0.6570(1) 0.4063(2) 3.39(6) CIO 0.1286(3) 0.6277(1) 0.1983(2) 3.70(6) C l l 0.2644(3) 0.6648(1) 0.2467(2) 3.42(6) C12 0.2607(4) 0.7265(1) 0.2634(2) 4.57(8) C13 0.3894(4) 0.7577(2) 0.3042(3) 5.52(9) C14 0.5197(4) 0.7266(2) 0.3249(3) 5.31(9) C15 0.5176(3) 0.6649(1) 0.3066(2) 4.12(7) C16 0.4412(3) 0.4968(1) 0.1271(2) 3.36(6) C17 0.5871(3) 0.4701(1) 0.1858(2) 3.02(5) C18 0.6555(3) 0.4844(1) 0.2861(2) 3.10(6) C19 0.7895(3) 0.4569(1) 0.3359(2) 3.78(7) C20 0.8579(3) 0.4191(1) 0.2874(2) 4.17(7) C21 0.7921(3) 0.4078(1) 0.1893(2) 4.01(7) C22 0.6571(3) 0.4320(1) 0.1386(2) 3.49(6) C23 0.3130(3) 0.4138(1) 0.1833(2) 3.81(7) C24 0.2881(3) 0.3967(1) 0.2775(2) 3.09(6) C25 0.2457(3) 0.3377(1) 0.2908(2) 4.10(7) C26 0.2244(4) 0.3227(1) 0.3778(3) 4.92(8) C27 0.2471(3) 0.3671(1) 0.4495(2) 4.34(8) C28 0.2907(3) 0.4248(1) 0.4332(2) 3.41(6) #eq=(8/3)7t2(t/i i (aa*)2 + U22(bb*)2 + U^icc* a) 2 + 2Ui2aa*bb*cos j +2U\2,aa*cc*cos P + 2U23bb*cc*cos 180 Appendix II o is * H E o X(nm) Figure II-l Variable pH (pH 2-7) U V spectra (220 - 320 nm) of the In3 +/Sbad4" system. 100-, [ I n L f ; [ l n ( O H ) 3 ] — • [ l n ( 0 H ) 4 f [ I n C l f * [ l n ( C I ) 2 ] * [ I n t C D J [ l n ( C I O H f 2 3 4 5 6 7 p H 8 9 10 11 Figure II-2. Speciation diagram for the In3 +/Sbad4" system. 181 Figure II-3 Variable pH (pH 2-5.8) U V spectra (220 - 320 nm) of the G a 3 + / S b a d d 4 " system. 182 Figure II-5 Variable pH (pH 2-7.6) U V spectra (220 - 320 nm) of the I n 3 + / S b a d d 4 " system. loo-, 2 4 6 pH 8 1 0 1 2 Figure II-6. Speciation diagram for the In 3 + /Sbadd 4 " system. 183 30-, 230 A.(nm) 280 Figure II-7 Variable pH (pH 2, 4.1, 5.2, 8.5, 11.9) U V spectra (220 - 320 nm) of the Ga 3 + /Sbbpen 4 * system. 100-1 80 60 H co o 20H [GaLf [GaOH]J+ [Ga(OH)4r 2 3 4 5 6 7 p H 8 Figure II-8. Speciation diagram for the Ga 3 + /Sbbpen 4 - system. I M 1 1 1 1 i r r ' i 1 1 1 1 [ 9 10 11 12 184 60-, 2 3 4 5 6 7 pH 8 9 10 11 12 Figure 11-10. Speciation diagram for the In 3 + /Sbbpen 4 - system. 185 

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