Open Collections

UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Chiral indium catalysts for the ring-opening polymerization of cyclic esters Aluthge, Dinesh Chinthaka 2014

Your browser doesn't seem to have a PDF viewer, please download the PDF to view this item.

Notice for Google Chrome users:
If you are having trouble viewing or searching the PDF with Google Chrome, please download it here instead.

Item Metadata

Download

Media
24-ubc_2015_february_aluthge_dinesh.pdf [ 5.02MB ]
Metadata
JSON: 24-1.0166078.json
JSON-LD: 24-1.0166078-ld.json
RDF/XML (Pretty): 24-1.0166078-rdf.xml
RDF/JSON: 24-1.0166078-rdf.json
Turtle: 24-1.0166078-turtle.txt
N-Triples: 24-1.0166078-rdf-ntriples.txt
Original Record: 24-1.0166078-source.json
Full Text
24-1.0166078-fulltext.txt
Citation
24-1.0166078.ris

Full Text

CHIRAL INDIUM CATALYSTS FOR THE RING-OPENING POLYMERIZATION OF CYCLIC ESTERS by  Dinesh Chinthaka Aluthge  B.Sc.(Hons.), University of Colombo, Sri Lanka, 2009  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  December 2014  © Dinesh Chinthaka Aluthge, 2014  ii  Abstract The development of highly active and stereoselective catalysts for lactide polymerization is an area of continuing interest in asymmetric catalysis. Aluminum complexes supported by (ONNO), tetradentate, bis(iminophenolate) or salen ligands are the most isoselective catalysts for lactide polymerization reported. However, these are sluggish initiators requiring elevated temperatures and multiple days to achieve high monomer conversion. Recently, indium based catalysts have attracted considerable attention as functional group tolerant catalysts for lactide polymerization.     In this thesis a family of mononuclear and dinuclear chiral indium alkoxide complexes bearing salen ligands was prepared. Solution state and solid state characterization of these complexes were carried out. These were highly active catalysts for the ring-opening polymerization of lactide, to generate the biodegradable polymer, poly(lactic acid)(PLA). Polymerization behavior and the stereoselectivity of these systems showed a well-controlled and isoselective family of catalysts. An investigation into the effects of ligand modifications revealed a profound dependence of the stereoselectivity on the ortho-aryl substituents. A detailed study was carried out to gain insights into the mechanism of polymerization. This provided evidence for a mechanism consistent with a mononuclear propagating species. Modification of the ligand backbone to a binap functionality was carried out to synthesize the first reported indium salbinap complexes. The ligand shows the ability to coordinate in both a κ2 and a κ4 coordination mode to a metal centre. However, these complexes were sluggish initiators with modest stereoselectivity for the ring-opening polymerization of lactide. A dinuclear indium catalyst was used to generate triblock copolymers of PLA and poly(hyroxybutyrate)(PHB) via simple sequential monomer addition. After confirming the iii  formation of these A-B-C type PLA-PHB-PLA triblocks, a series of these copolymers with varying monomer composition were prepared and their thermo-mechanical properties were studies.  iv  Preface The work in chapters 2 and 3 is partially based on the following publication in the journal Chemical Communications: [Aluthge, D.C.]; Patrick, B. O.; Mehrkhodavandi, P. Chem. Commun, 2013, 49, 4295-4297. The results are reproduced by permission of the Royal Society of Chemistry. In chapter 1 the data collection and refinement of two X-ray structures were carried out by Dr. Brian O. Patrick. I carried out the remainder of the X-ray crystallography in this chapter. The synthesis and characterization of the complexes (R,R)-(ONNMeOtBu)InCl and (R,R)-[(ONNMeOtBu)InOEt]2 were carried out in collaboration with Mr. Jun Myun Ahn, an undergraduate researcher. Initial polymerization data for (R,R)-[(ONNMeOtBu)InOEt]2 was also obtained by Mr. Ahn. I carried out the remainder of the synthesis, characterization, polymerizations and other experiments in chapters 2 and 3. Manuscript for publication was written in collaboration with Prof. Parisa Mehrkhodavandi. The intellectual property in this thesis is protected under two patent applications ("Salen indium catalysts and methods of manufacture and use thereof": publication number WO 2013134877 A1 and “Mononuclear Salen Indium Catalysts and Methods of Manufacture and Use Thereof”: U.S. provisional patent application No. 62/021071)         Chapter 4 is based on work reported in a publication in the journal Inorganic Chemistry. The results are reproduced with permission from [Aluthge, D.C.]; Yan, E.-X.; Ahn, J., Mehrkhodavandi, P. Inorg. Chem, 2014, 53, 6828–6836. Copyright 2014 American Chemical Society. The synthesis of the metal complexes with (ONN*OMe)H2 was carried out in collaboration with Ms. Ellen X. Yan and Mr. Jun Myun Ahn, two former undergraduate researchers in the group. I carried out the other syntheses, characterization, all X-ray v  crystallography experiments, all polymerizations and other experiments. Manuscript for publication was written in collaboration with Prof. Parisa Mehrkhodavandi.   The work in Chapter 5 is published in the journal Macromolecules and is reproduced with permission from Aluthge, D. C.; Xu, C.; Othman, N.; Noroozi, N.; Hatzikiriakos, S. G.; Mehrkhodavandi, P. Macromolecules 2013, 46, 3965–3974. Copyright 2013 American Chemical Society. The synthesis of PLA only triblocks discussed were carried out by Ms. Cuiling Xu. The thermo-mechanical properties of these were determined by Dr. Norhayani Othman. I carried out the synthesis of the PHB containing block copolymers, and thermo-mechanical properties were determined in collaboration with Dr. Nazbanoo Noroozi. Manuscript for publication was written in collaboration with Prof. Parisa Mehrkhodavandi and Prof. Savvas Hatzikiriakos.      vi  Table of Contents Abstract .......................................................................................................................................... ii Preface ........................................................................................................................................... iv Table of Contents ......................................................................................................................... vi List of Tables ................................................................................................................................ ix List of Figures ............................................................................................................................... xi List of Schemes ......................................................................................................................... xviii List of Abbreviations and Symbols .......................................................................................... xix Acknowledgements ................................................................................................................... xxii Dedication ................................................................................................................................. xxiii Chapter 1: General introduction ................................................................................................. 1 1.1 Ring-opening polymerization of cyclic esters ............................................................ 1 1.2 Tacticity in PLA .......................................................................................................... 4 1.3 Metal catalysts for the ROP of lactide ........................................................................ 7 1.4 Ligand design in lactide polymerization ................................................................... 10 1.4.1 Tridentate ligands in lactide polymerization......................................................... 10 1.4.2 Tetradentate ligands in lactide polymerization ..................................................... 14 1.4.2.1 Tetradentate tripodal ligands......................................................................... 14 1.4.2.2 Macrocyclic ligands ...................................................................................... 18 1.4.2.3 Salen-type ligands ......................................................................................... 20 1.5 Objectives ................................................................................................................. 33 1.6 Scope of thesis .......................................................................................................... 34  vii  Chapter 2: Synthesis and characterization of chiral salen indium(III) alkoxide complexes 35 2.1 Introduction ............................................................................................................... 35 2.2 Results ....................................................................................................................... 41 2.2.1 Synthesis and characterization of proligands ........................................................ 41 2.2.2 Synthesis and characterization of indium salen chloride complexes .................... 43 2.2.3 Synthesis of dinuclear salen indium ethoxide complexes ..................................... 48 2.2.4 Solution structure of salen indium alkoxide complexes ....................................... 60 2.3 Conclusions ............................................................................................................... 66 2.4 Experimental section ................................................................................................. 67 Chapter 3: Chiral indium salen complexes in lactide polymerization ................................... 82 3.1 Introduction ............................................................................................................... 82 3.2 Results ....................................................................................................................... 85 3.3 Conclusions ............................................................................................................. 104 3.4 Experimental section ............................................................................................... 105 Chapter 4: Synthesis and reactivity of indium salbinap complexes towards lactide polymerization ........................................................................................................................... 108 4.1 Introduction ............................................................................................................. 108 4.2 Results ..................................................................................................................... 110 4.2.1 Synthesis of metal complexes ............................................................................. 110 4.2.2 Polymerization studies ........................................................................................ 122 4.3 Conclusions ............................................................................................................. 129 4.4 Experimental section ............................................................................................... 130 Chapter 5: PLA-PHB-PLA triblock copolymers – synthesis by sequential addition ......... 138 viii  5.1 Introduction ............................................................................................................. 138 5.2 Results ..................................................................................................................... 141 5.3 Conclusion .............................................................................................................. 152 5.4 Experimental section ............................................................................................... 153 Chapter 6: Conclusions and future directions ....................................................................... 156 Bibliography ...............................................................................................................................158 Appendices ..................................................................................................................................165 Appendix A ..................................................................................................................................... 165 Appendix B ...................................................................................................................................... 194 Appendix C ...................................................................................................................................... 197   ix  List of Tables Table 2.1. Selected bond lengths and angles for rac-1 ................................................................ 45 Table 2.2. Selected bond lengths and angles for (R,R)-2 ............................................................. 46 Table 2.3. Selected bond lengths and angles for rac-3 ................................................................ 47 Table 2.4. Selected bond lengths and angles for rac-6 ................................................................ 50 Table 2.5. Selected bond lengths and angles for (R,R)-7 ............................................................. 52 Table 2.6. Selected bond lengths and angles for (R,R)-11 ........................................................... 58 Table 2.7. Selected bond lengths and angles for (R,R)-12 ........................................................... 59 Table 2.8. Dt of compounds calculated using PGSE NMR spectroscopy .................................... 63 Table 3.1. Rate constants for the polymerization of rac-, L- and D-lactide (LA) with rac- and     (R,R)-6 ........................................................................................................................................... 89 Table 3.2. Polymerization of rac-lactide with (R,R)-10 and (R,R)-7 ........................................... 93 Table 3.3. Polymerization of rac-lactide with (R,R)-8 and (R,R)-9 ............................................. 96 Table 3.4. Rate constants for polymerization of rac-, L- and D-lactide (LA) with (R,R)-8 and     (R,R)-9 ........................................................................................................................................... 98 Table 3.5. Polymerization of rac-lactide with (R,R)-12 and (R,R)-13 ....................................... 101 Table 3.6. Rate constants for polymerization of rac-, L- and D-lactide (LA) with (R,R)-11 and     (R,R)-13 ....................................................................................................................................... 103 Table 4.1. Selected bond lengths and angles for 14a ................................................................. 113 Table 4.2. Selected bond lengths and angles for 14b ................................................................. 115 Table 4.3. Selected bond lengths and angles for 15 ................................................................... 119 Table 4.4. Selected bond lengths and angles for 16 ................................................................... 121 Table 4.5. Polymerization of rac-lactide with indium and aluminum salen catalysts. .............. 123 x  Table 5.1. Selected mechanical propertied of commercial PLA and iPP185,186 .......................... 139 Table 5.2. Summary of synthesized lactide triblock copolymers .............................................. 142 Table 5.3. GPC analysis of a PLLA-b-PHB-b-PLLA triblock copolymer with details of polymers formed after each monomer addition .......................................................................................... 146 Table 5.4. Summary of synthesized PLLA-b-PHB-b-PLA copolymers .................................... 148 Table 5.5. The glass transition temperature, Tg, the melting peak temperature, Tm, of the PLA triblock copolymers. ................................................................................................................... 149 Table 5.6. The glass transition temperature, Tg, the melting peak temperature, Tm of triblock copolymers having PHB in the center block. .............................................................................. 150 Table 5.7. Tensile properties of triblock copolymers ................................................................ 151   xi  List of Figures Figure 1.1. Examples of bidegradable polyesters generated via ROP of cyclic esters .................. 2 Figure 1.2. Synthetic routes to PLA ............................................................................................... 3 Figure 1.3. A 1H{1H} NMR spectrum of PLA (methine region) obatined from rac-lactide (600 MHz, CDCl3, 25 °C) ....................................................................................................................... 4 Figure 1.4. Microstructures of PLAs ............................................................................................. 6 Figure 1.5. Homoleptic metal alkoxide catalysts for the ROP lactide ........................................... 7 Figure 1.6. Coordination-insertion mechanism of ROP of lactide38 .............................................. 8 Figure 1.7. In solution equilibrium of Zinc phenolate ethoxide complexes ................................ 11 Figure 1.8. Examples of magnesium and zinc complexes with NNO ligands ............................. 12 Figure 1.9. Dinuclear indium catalyst described by Mehrkhodavandi et al. ............................... 14 Figure 1.10. Metal catalysts bearing tripodal nitrogen donor ligands for lactide polymerization 15 Figure 1.11. Examples of titanatranes for lactide polymerization described by Verkade et al. .. 16 Figure 1.12. Examples of amine bis- and trisphenolate ligand based catalysts for lactide polymerization .............................................................................................................................. 17 Figure 1.13. Examples of metal macrocyclic catalysts in lactide polymerization ....................... 19 Figure 1.14. Examples of salen, salen and salalen ligands .......................................................... 20 Figure 1.15.  Examples of aluminum salen catalysts for lactide polymerization ........................ 21 Figure 1.16. Examples of aluminum catalysts for lactide polymerization with achiral ligands .. 24 Figure 1.17. Examples of aluminum salen and salan catalysts for lactide polymerization by Gibson et al ................................................................................................................................... 25 Figure 1.18. Examples of alumnium catalysts supported by salen-like ligands for lactide polymerization .............................................................................................................................. 26 xii  Figure 1.19. Examples of trivalent metal-based with salen type ligands for lactide polymerization .............................................................................................................................. 27 Figure 1.20. Examples of group 4 salen catalysts in lactide polymerization ............................... 29 Figure 1.21. Variations of salen-type ligands in metal-based lactide polymerization ................. 30 Figure 1.22. Examples of (OSSO) type ligand based catalysts for lactide polymerization ......... 32 Figure 1.23. Reduced and oxidized forms of  thiolphan (n = 1) and thiolphan*(n = 0) based group 4 complexes ........................................................................................................................ 33 Figure 2.1. Achiral indium salen complexes reported by Atwood et al. ..................................... 36 Figure 2.2. Examples of indium catalysts in cyclic ester polymerization .................................... 37 Figure 2.3. Examples of indium complexes with achiral salen ligands for lactide polymerization....................................................................................................................................................... 39 Figure 2.4. Molecular structure of rac-1 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) ........................................................................................................................ 45 Figure 2.5. Molecular structure of (R,R)-2.CH3CN depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity) .................................................................... 46 Figure 2.6. Molecular structure of rac-3 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) ........................................................................................................................ 47 Figure 2.7. Molecular structure of rac-6 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity).................................................................................... 50 Figure 2.8. Atom connectivity for (R,R/S,S) dimer of complex rac-6 ......................................... 51 Figure 2.9. Molecular structure of (R,R)-7 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity).................................................................................... 52 xiii  Figure 2.10. 1H NMR spectra of (R,R)-11 in CDCl3 at temperatures from 25 °C to −20 °C. The methylene resonance of the alkoxide is labelled with (●) ............................................................ 57 Figure 2.11. Molecular structure of (R,R)-11 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity) ......................................................................... 58 Figure 2.12. Molecular structure of (R,R)-12 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) .............................................................................................................. 59 Figure 2.13. Plot of ln(I/I0) vs. γ2δ2G2[Δ−(δ/3)]×10−10  (m−2 s) from PGSE experiments for rac-(ONNtBuOtBu)H2, rac-1 and  rac-6 in CD2Cl2 at 25 °C. I = observed spin echo intensity, I0 = intensity in the absence of a gradient, G = gradient strength, γ = gyromagnetic ratio, δ = length of gradient pulse, Δ = delay between gradient midpoints. The translational diffusion coefficient (Dt) was obtained from the slope of the plots. ..................................................................................... 61 Figure 2.14. Reported diffusion coefficients (Dt) of several dimeric and monomeric complexes67,160 .............................................................................................................................. 62 Figure 2.15. Crossover reaction between (R,R)-6 and (R,R)-8 at in CD2Cl2 at 25 °C. The resonances for the likely crossover product (A) is labelled with (●) ............................................ 65 Figure 2.16. Crossover reaction between (R,R)-6 and (R,R)-10 at in CD2Cl2 at 25 °C. The resonances for the likely crossover product (B) is labelled with (●) ............................................ 66 Figure 3.1. Examples of isoselective catalysts for lactide polymerization with chain-end control....................................................................................................................................................... 83 Figure 3.2. Schematic diagram of the nature of stereoerrors in chain-end control and enantiomorphic site control mechanisms ...................................................................................... 83 Figure 3.3. Substituent effects on isoselectivity in achiral aluminum salen complexes reported by Gibson et al. .................................................................................................................................. 84 xiv  Figure 3.4. rac- or (R,R)-[(ONNtBuOtBu)InOEt]2 (rac- or (R,R)-6) .............................................. 85 Figure 3.5. Plot of observed PLA Mn () and molecular weight distribution (■) as functions of lactide:ethoxide in polymerizations with rac-6 (Mn = number averaged molecular weight, PDI = polydispersity index).  The line indicates calculated Mn values based on the lactide:ethoxide ratio.  All reactions were carried out at room temperature in CH2Cl2 and polymer samples obtained at 99% conversion. ......................................................................................................... 87 Figure 3.6. The ROP plots of 200 equiv. of [lactide (LA)] vs. [initiator].  All reactions were carried out in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. [Catalyst] = 0.0011 M, [LA] = 0.45 M. The value of kobs was determined from the slope of the plots of ln([LA]/[TMB]) vs. time (TMB = 1,3,5-Trimethoxybenzene). ....................................... 88 Figure 3.7. Plot of Pm vs. conversion for polymerization of rac-lactide with a: (top) (R,R)-6; b: (bottom) rac-6.  Depicted with estimated 5% error bars. ............................................................. 90 Figure 3.8. MALDI-TOF mass spectrum of a PLA oligomer grown with (R,R)-6. .................... 91 Figure 3.9. Complexes (R,R)-[(ONNBrOtBu)InOEt]2 (R,R)-10 and (R,R)-[(ONNMeOtBu)InOEt]2 (R,R)-7 ........................................................................................................................................... 92 Figure 3.10. The ROP plots of 200 equiv. of [lactide (LA)] vs. [initiator] for (R,R)-10 (left) and (R,R)-7 (right).  All reactions were carried out in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. [Catalyst] = 0.0011 M, [LA] = 0.45 M. The value of kobs was determined from the slope of the plots of ln([LA]/[TMB]) vs. time (TMB = 1,3,5-Trimethoxybenzene). .................................................................................................................... 94 Figure 3.11. Complexes (R,R)-[(ONNAdOtBu)InOEt]2 (R,R)-8 and (R,R)-[(ONNcumylOcumyl)InOEt]2 (R,R)-9 ................................................................................................. 95 xv  Figure 3.12. The ROP plots of 200 equiv of [lactide (LA)] vs. [initiator] for (R,R)-8 (left) and (R,R)-9 (right).  All reactions were carried out in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. [Catalyst] = 0.0011 M, [LA] = 0.45 M. The value of kobs was determined from the slope of the plots of ln([LA]/[TMB]) vs. time (TMB = 1,3,5-Trimethoxybenzene). .................................................................................................................... 97 Figure 3.13. Mononuclear indium salen alkoxide complexes investigated ................................. 99 Figure 3.14. Plot of observed PLA Mn () and molecular weight distribution (■) as functions of lactide:ethoxide in polymerizations with (R,R)-11 (Mn = number averaged molecular weight, PDI = polydispersity index).  The line indicates calculated Mn values based on the LA:ethoxide ratio.  All reactions were carried out at room temperature in CH2Cl2 and polymer samples obtained at >90% conversion. ......................................................................................................................... 99 Figure 3.15. MALDI-TOF mass spectrum of a PLA oligomer grown with (R,R)-11. .............. 100 Figure 3.16. The ROP plots of 200 equiv. of [lactide (LA)] vs. [initiator] for (R,R)-11 (left) and (R,R)-13 (right).  All reactions were carried out in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. [Catalyst] = 0.0011 M, [LA] = 0.45 M. The value of kobs was determined from the slope of the plots of ln([LA]/[TMB]) vs. time (TMB = 1,3,5-Trimethoxybenzene). .................................................................................................................. 102 Figure 3.17. Proposed catalytic cycle for [(ONNO)InOR] complexes in lactide polymerization..................................................................................................................................................... 104 Figure 4.1. Lactide polymerization catalysts with switchable stereoselectivity ........................ 109 Figure 4.2. Molecular structure of 14a depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity) ........................................................................................ 113 xvi  Figure 4.3. Molecular structure of 14b depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity) ........................................................................................ 115 Figure 4.4. Varible temperature 1H NMR spectra of 14a in toluene-d8 (400 MHz) .................. 116 Figure 4.5. Variable temperature 1H NMR spectra of 14b in toluene-d8 (400 MHz) ................ 116 Figure 4.6. Molecular structure of 15 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity) ........................................................................................ 119 Figure 4.7. Molecular structure of 16 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity) ........................................................................................ 121 Figure 4.8. 1H NMR spectra (CDCl3, 400 MHz, 25 °C) of the reaction of 14a with 200 equiv of rac-lactide, at ~50% conversion. Inset shows a 1H NMR spectrum of 14a overlaid with an expanded region of the spectrum of the reaction. ....................................................................... 124 Figure 4.9. 1H NMR spectra (CDCl3, 400 MHz, 25 °C) of the reaction of 14b with 200 equiv. of rac-lactide at ~83% conversion. Inset shows a 1H NMR spectrum of 14b overlaid with an expanded region of the spectrum of the reaction. ....................................................................... 124 Figure 4.10. Plot of observed PLA Mn and molecular weight distribution (PDI) vs. % conversion for 14b with lactide:initiator ratio of 200:1. The reaction was carried out in refluxing THF and conversions were obtained using 1H NMR spectroscopy. The line represents the theoretically expected Mn value vs. conversion. .............................................................................................. 125 Figure 4.11.  MALDI-TOF mass spectrum of a PLA oligomer grown with 14b. ..................... 126 Figure 4.12. Isoselective chiral aluminum salen catalysts for lactide polymerization .............. 127 Figure 5.1. 1H NMR spectra (400 MHz, 25 °C, CDCl3) showing monomer conversion after each monomer addition during the synthesis of 36PLLA-b-28PHB-b-3PLLA triblock copolymer. Reactions were carried out in THF, 25 °C, [17]o ≈ 1 mM. a) First PLLA block showing ~95% xvii  conversion after 5 hours. b) PLLA-b-PHB diblock showing ~85% rac-BBL conversion after 16 hours. c) Final PLLA-b-PHB-b-PLLA triblock showing an overall L-lactide conversion of ~96% after 8 hours. ............................................................................................................................... 145 Figure 5.2.  Overlap of GPC traces for the synthesis of 27L-46LD-27L.  Right (-----) MA (Mn = 57.1 kDa, PDI = 1.11).  Middle (— —) MA+MB (Mn = 84.2 kDa, PDI = 1.29). Left ( ) MA+MB+MC (Mn = 119.5 kDa, PDI = 1.19). .............................................................................. 147    xviii  List of Schemes Scheme 2.1. Synthesis of known and newly reported (ONNR1OR2)H2 proligands. Yields provided for newly synthesized ligands. ...................................................................................................... 42 Scheme 2.2. Synthesis of (ONNR1OR2)InCl complexes 1-5. ........................................................ 43 Scheme 2.3. Synthesis of dinuclear indium salen alkoxide complexes via the salt metathesis of (ONNO)InCl complexes. .............................................................................................................. 49 Scheme 2.4. One-pot synthesis of indium salen alkoxide complexes .......................................... 54 Scheme 2.5. Synthesis of (R,R)-(ONNR1OR2)InOCH2Pyr complexes via (R,R)-(ONNR1OR2)InCl....................................................................................................................................................... 55 Scheme 2.6. Synthesis of (R,R)-[(ONNBrOtBu)InOEt]2 using a one-pot synthesis ....................... 56 Scheme 2.7. Crossover experiment of (R,R)-6 with (R,R)-8 or (R,R)-10 ..................................... 64 Scheme 3.1. Highly site selective aluminum salen complexes for lactide polymerization .......... 82 Scheme 4.1. Synthesis of indium salbinap complexes ............................................................... 111 Scheme 4.2. Synthesis of complex 15 ........................................................................................ 118 Scheme 4.3. Possible route for synthesis of 16 .......................................................................... 120 Scheme 5.1. Multistep synthesis of PLLA-b-PHB-b-PLLA polymers by Kimura et al. ........... 140 Scheme 5.2. Dinuclear indium catalyst [(NNO)InCl]2(-Cl)(-OEt) (17) for the living homopolymerization of lactide and BBL .................................................................................... 141 Scheme 5.3.  Formation of triblock PLA by sequential addition of lactide ............................... 142 Scheme 5.4. Synthesis of PLA-b-PHB-b-PLA triblock polymers ............................................. 143  xix  List of Abbreviations and Symbols Å   angstrom Anal.   analysis Ar   aromatic  br   broad BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl tBu   tert-butyl, -CMe3 Calcd  calculated d   doublet  δ   chemical shift downfield from tetramethylsilane in ppm  Dt   translational diffusion coefficient  DACH  diaminocyclohexane  (°)   degree(s)  EA   Elemental Analysis  equiv.  equivalent(s)  Et   ethyl Et2O   diethyl ether g  grams  GPC   gel permeation chromatography η  hapticity to describe how a continuous group of atoms on a ligand coordinates a metal center h   hour(s) J   coupling constant in Hertz xx  κ   kappa  k  rate constant  kobs   observed rate constant for reaction LLS   laser light scattering M   molarity m   multiplet(s) Mn   number average molecular weight Me  methyl MS   mass spectroscopy NMR   nuclear magnetic resonance ONNR1OR2 N,N'-(3-R1,5-R2salicylidene)-1,2-cyclohexanediamine   ONN*OR 2,2′-[1,1′-binaphthalene-2,2′-diyl-bis(nitrilomethylidyne)]-bis-4-tert-butyl-6-Rphenol Pm   probability of meso linkages in a polymer chain Pr   probability of racemo linkages in a polymer chain PDI   polydispersity Index PDLA   poly(D-lactic acid) PGSE   pulsed gradient spin-echo Ph   phenyl ppm   parts per million  iPr   iso-propyl, -CHMe2  pyr   pyridine  q   quartet xxi  rac   racemic ±   racemic R   Rectus (Latin for right) ROP   Ring Opening Polymerization S   Sinister (Latin for left) s   singlet salan   a compound synthesized by reduction of a salen compound salen   Bis(iminophenolates) usually prepared by the condensation of a salicylaldehyde with an amine Schiff base  an imine bearing a hydrocarbyl group on the nitrogen atom   t   triplet Tg   glass transition temperature Tm   melting temperature THF   tetrahydrofuran TMB   1,3,5-trimethoxybenzene TMS   trimethylsilyl TMSS   tetrakis(trimethylsilyl)silane VT   variable temperature μ   the prefix given in IUPAC nomenclature for a bridging ligand  xxii  Acknowledgements First and foremost I would like to thank my advisor Prof. Parisa Mehrkhodavandi, for guidance and support throughout the past four year. I will forever cherish the mentorship I received from her. I also wish to thank all the past and present members of the Mehrkhodavandi group, especially Dr. Insun Yu and Kim Osten for the help when I started in the group. I am also grateful to Dr. Paul Kelley for reading and providing helpful comments on my thesis. I wish to thank Dr. Brian Patrick and Ms. Anita Lam for the training and assistance in carrying out X-ray crystallography experiments. I am also thankful to Dr. Maria Ezova for help with NMR experiments and all the support services at the department of chemistry.      I would also like to acknowledge all my collaborators, especially Prof. Savvas Hatzikiriakos and Dr. Nazbanoo Noroozi. I am also grateful to Joe Ahn and Ellen Yan, two amazing undergraduate researchers who worked with me during my time at UBC. I would also like to thank Prof. Jennifer Love for taking the time from her busy schedule to read my thesis.  I also wish to thank my parents for their constant support and encouragement. Finally I would like to thank my partners in crime, Javier Pacheco and Eugene Chong for the good times.    xxiii  Dedication This thesis is dedicated to Piyarathna and Preethie Aluthge.  1  Chapter 1: General introduction The development of commercially useful polymers in the early 20th century ushered in an era where mass produced, organo-polymeric materials have become a ubiquitous part of daily life.1 The Nobel prize-winning discovery by Ziegler and Natta of a titanium based catalyst revolutionized the plastics industry by allowing industry scale production of polyolefins.2 This discovery underscores the importance of metal-based catalysts in modern industry, especially in polymer technology. Sixty years after this discovery, the scale of worldwide polyolefin production is massive. The current estimated annual global production of polyolefins is over 150 million metric tons.3,4 However, the inherent chemical inertness of these substances causes them to persist in the environment centuries after they have been discarded.5,6 The detrimental environmental impact of a man-made waste problem of this scale, has generated an interest in commercially viable, biodegradable alternatives.7-10   1.1 Ring-opening polymerization of cyclic esters The ring-opening polymerization (ROP) of cyclic esters to generate biodegradable polyesters such as poly(caprolactone) (PCL) and poly(lactic acid) (PLA) is a technology currently used in industry to produce commercially available material (Figure 1.1).11,12 Poly(hydroxybutyrate) (PHB), another example of a biodegradable polyester, is biosynthesized by bacteria,13 but also can be generated via the ring-opening polymerization of β-butyrolactone.14,15 Of these polyesters, PLA is the most widely used, for applications ranging  from food packaging to automotive parts.16,17   2   Figure 1.1. Examples of bidegradable polyesters generated via ROP of cyclic esters  Synthetic routes to PLA can be broadly divided in to two categories: ROP of lactide and polycondensation of lactic acid (Figure 1.2).18 PLA is commercially generated from the ROP of bio-sourced lactide, which is the cyclic diester of lactic acid.19 Polycondensation of lactic acid requires the azeotropic distillation of water from the reaction and the maximum molecular weight of polymers is limited to Mn ~ 6500 gmol−1.16 3   Figure 1.2. Synthetic routes to PLA  ROP of lactide affords high molecular weight polymers with better control of the polymerization process relative to polycondensation.18,20_ENREF_18 These advantages can be directly attributed to the fact that ROP can be a living polymerization process. Living polymerization is a chain-growth polymerization where chain termination is absent,21 and is characterized by a linear relationship between the monomer to initiator ratio and the experimental molecular weight and narrow polydispersities (PDIs) (PDIs indicates the molecular weight distribution of the polymers and is the ratio between the weight average (Mw) and the number average molecular weights (Mn)).18,22 With some systems in ROP, an exogenous chain transfer agent such as an alcohol can be added to grow multiple polymer chains; a process known as immortal polymerization.23 This allows the use of lower catalyst loadings and can be used for polymer functionalization.15,24 These advantages make ROP a powerful technique in polymer synthesis.     4  1.2 Tacticity in PLA Three possible isomers of lactide exist; D-, L- and meso-lactide. A racemic mixture of D- and L-lactide is referred to as rac-lactide.25 The stereochemistry of these monomers, when incorporated into a polymer chain, creates material with a certain stereocomplexity or tacticity.26 The tacticity of a given PLA sample may be defined by two parameters: Pm (probability of adjacent stereocentres with the same chirality or a meso (m) linkage) and Pr (probability of adjacent stereocentres with the opposite chirality or a racemo (r) linkage), which can be statistically calculated using 1H and 13C NMR spectroscopy.27,28 Hence, for a perfectly isotactic polymer sample, Pm = 1 and for a perfectly heterotactic sample Pr  = 1. To calculate the Pm and/or Pr value(s) of a PLA sample a homonuclear decoupled 1H{H} NMR spectrum of the methine region of the material is obtained (Figure 1.3). Here the scalar coupling between the methyl and methine protons is removed and five distinguishable resonances corresponding to mmm, mmr(rmm), rmm(mmr), mrm and rmr tetrad sequences (four adjacent linkages) can be observed. The relative integrations of these resonances are substituted to a set of equations derived from Bernoullian statistics to determine Pm and Pr values.29       Figure 1.3. A 1H{1H} NMR spectrum of PLA (methine region) obatined from rac-lactide (600 MHz, CDCl3, 25 °C) 5  The tacticity of the polymer chain has an enormous impact on the bulk properties of the resulting material.30 This fact becomes apparent when taking into account the melting points of PLA polymers with differing tacticities (Figure 1.4). PLA with irregular microstructure, known as atactic PLA, is amorphous and is not very useful for most applications.31 Heterotactic PLA, which is formed through the incorporation of alternating single monomer units of D-lactide and L-lactide, is also amorphous though the polymer chains contain stereoregularity.32 The tacticity of the polymer chain has an enormous impact on the bulk properties of the resulting material.30 Heterotactic PLA can also be generated from meso-lactide.29 Isotactic (PLLA/PDLA) and syndiotactic PLA formed from D-, L-, or meso-lactide respectively, are crystalline and have melting temperatures (Tm) of 180 °C and 152 °C respectively.29-30 Lactide derived from natural sources is composed of > 90% L-lactide with small amounts of D-lactide and meso-lactide.20 Polymerization of this mixture with a simple homoleptic catalyst such as tin(II) octanoate (SnOct)2  or aluminum isopropoxide (Al(OiPr)3)(Figure 1.5) produces isotactic PLA with Tm = 165-170 °C depending on the exact composition of the monomer feedstock.16,33 These initiators do not impart stereoselectivity during polymerization.   6   Figure 1.4. Microstructures of PLAs  7   Figure 1.5. Homoleptic metal alkoxide catalysts for the ROP lactide  Stereoblock PLA (PLLA-b-PDLA), where a single polymer chain contains two distinct regions with opposite stereochemistry, can be generated through coupling of homochiral chains,34 the sequential addition of enantiopure D- and L- lactide,35 or via the polymerization of mixture of D- and L-lactide with a highly stereoselective catalyst.29 Due to stereocomplex formation36 PLLA-b-PDLA microstructures give higher melting points (> 200 °C) than the optically pure isotactic polymers (PDLA/PLLA), and better mechanical properties that are commercially desirable.37 Hence, the ability to control tacticity during the polymerization of lactide represents one of the most important and fundamental aspects of this field.  1.3 Metal catalysts for the ROP of lactide The putative mechanism for the metal-catalyzed ROP of lactide is a coordination-insertion mechanism which was proposed by Dittrich and Schulz (Figure 1.6).38 Here the lactide is activated after coordination to a metal centre through the carbonyl oxygen. Then an initiator, such as an alkoxide attacks the carbonyl carbon, which eventually leads to the ring-opening of the lactide ring and the formation of a new metal-alkoxide bond. This metal-alkoxide bond will act as the initiator for the incoming monomer to turn over the catalytic cycle.32 The 8  thermodynamic driving force for the polymerization reaction is the release of a −23 kJ/mol ring strain in the lactide molecule.39   Figure 1.6. Coordination-insertion mechanism of ROP of lactide38  Stereocontrol in polymerization can arise from either chain-end control, where the stereochemistry of the chain-end determines the configuration of the incoming monomer, or enantiomorphic site control, where the chirality of the ligand imparts stereoselectivity.40,41 However, these two mechanisms are not mutually exclusive, and often act in concert in a given system.42  Numerous metal-based catalysts, bearing a diverse array of ligand architectures have been reported for the ring-opening polymerization of lactide.32,41,43-44 Simple homoleptic complexes such as Sn(Oct)2 and Al(OiPr)3 (Figure 1.5) have been reported to polymerize lactide 9  both in solution (polymerization is carried out in an organic solvent) and melt (the reaction is heated to  temperatures > 130 °C and liquid lactide monomer acts as the reaction medium).45-47 Sn(Oct)2 is the most widely used catalyst for lactide polymerization industrially, due to ease of handling, availability, and solubility in melt lactide.32  Sn(Oct)2 has been approved by the Food and Drug Administration (FDA) as a food additive.48 Though slower than Sn(Oct)2, zinc lactate (Figure 1.5) has also been described as a catalyst for lactide polymerization and is an attractive potential alternative due to low toxicity of zinc, which can be useful in biomedical applications.49 As previously mentioned commercially available lactide with >90% L-lactide polymerized with Sn(Oct)2, will generate isotactic PLA. While this material has commercial applications, the thermal and mechanical properties of this material aren’t suitable for many applications where polyolefins are typically used.50,16 Increasing the isotacticity and stereoblock formation is one way to improve the polymer properties.16  However these simple catalysts are not stereoselective initiators and produce atactic PLA from racemic lactide.32 Since the bulk properties of PLA are highly dependent on the stereoregularity or the tacticity of the polymer,50 research into the development of catalysts for lactide polymerization has largely focused on achieving stereoselectivity.14-16 Numerous organocatalysts such as N-heterocyclic carbenes51 and phosphine-based compounds52 have been investigated for the controlled ROP of lactide. Organocatalysts are an attractive option due to the ability to generate PLA without residual metal contaminants, but a highly stereoselective organocatalyst has remained elusive.18 The vast majority of efforts on developing stereoselective catalysts have been focused on metal-based catalysts with diverse ligand designs.32,41,43-44       10  1.4 Ligand design in lactide polymerization A wide array of ligands with different donors and denticities to support different metal-based initiators has been reported for the ROP of lactide.14-16 As commonly seen in asymmetric catalysis, diverse ligand architectures, with their different donor and stereoelectronic properties, allow for the development of a broad range of catalysts for a given reaction. Ligand modifications can, alter the electrophilicity of the metal centre, enhance or diminish the steric crowding within the catalyst. While examples for bidentate ligand based catalysts can be found in the literature,53-55 tri- and tetradentate ligand supports are more widely used in metal catalyzed ROP of lactide.32,41,43-44   1.4.1 Tridentate ligands in lactide polymerization Although, many tridentate ligand systems with different donor atoms in conjunction with different metals have been reported,18, 26, 28-29 this discussion will focus on NNO-type asymmetric Schiff base and reduced Schiff base ligands commonly known as half salens and half salans respectively (salens and salans are tetradentate, ONNO type, bis(iminophenolate) and bis(aminophenolate) ligands respectively).56 In 2003, Hillmyer and Tolman reported a dinuclear zinc phenolate catalyst with a N-methylated ethylene diamine arm (I.1).57 In this system the monomeric species predominates in solution (Figure 1.7).  This catalyst showed rapid polymerization activity towards lactide, with a propagation rate constant of 2.2 M−1s−1 at 25 °C. However, the catalyst failed to impart any stereoselectivity and generated atactic PLA.   11   Figure 1.7. In solution equilibrium of Zinc phenolate ethoxide complexes  Mehrkhodavandi and coworkers reported a chiral analogue of this ligand system which they used with zinc in an attempt to develop a stereoselective catalyst for lactide polymerization (I.2).58 However, they observed a marked decrease in reactivity compared to the achiral analogue reported by Hillmyer and Tolman, towards lactide polymerization. Furthermore, no stereoselectivity was achieved. The decreased activity was attributed by to a more rigid ligand system with the cyclohexyl diamine back bone opposed to the ethylene diamine analogue which could undergo a facile coordination-decoordination, which promoted higher reactivity.   12    Figure 1.8. Examples of magnesium and zinc complexes with NNO ligands    13  This NNO imino/aminophenolate ligand design has been widely used with divalent metals such as zinc and magnesium (Figure 1.8). These catalysts have attracted considerable interest due to the nontoxic nature of the metal.  Darensbourg et al. used I.3 to generate not only heterotactic PLA but also for the copolymerization of L-lactide and ɛ-caprolactone.59 In an extension of this work, the zinc amide complex (I.3) was treated with 4-fluorophenol to generate the dinuclear phenoxy bridged compound (I.4) which was a more sluggish initiator for lactide polymerization compared to the corresponding amide catalyst.60 However, a very similar zinc Schiff base catalyst with benzyloxide initiators (I.5) polymerized 200 equiv. of rac-lactide within 30 minutes at ambient temperature to generate PLA with a heterotactic bias.61  Similarly magnesium based catalysts with variations of the tridentate NNO ligand design have shown varying degrees of activity and selectivity towards lactide polymerization. Complex I.6 is a highly active catalyst for the ring-opening polymerization of lactide, capable of polymerizing 200 equiv. of L-lactide in under 8 minutes.62 Complex I.7 is a less active catalyst and generates heterotactic PLA (Pr = 0.87)63 while with a dinuclear chiral monoether-salen magnesium catalyst  (I.8) Lin et al. were able to switch between moderate isoselectivity (Pm = 0.67 in CH2Cl2 at −30 °C) to modest heteroselectivity (Pr = 0.58 in THF at 25 °C).64 While the diverse polymerization behavior of these catalysts and the profound impact of subtle ligand modifications on the reactivity and selectivity are noteworthy, limited success has been achieved in developing highly isoselective zinc and magnesium catalysts for lactide polymerization.65 In 2008, Mehrkhodavandi and coworkers used the half salan ligand framework with indium to describe a dinuclear alkoxide complex (Figure 1.9), which is the first reported indium catalyst for lactide polymerization.66 While this initiator was a highly active catalyst capable of 14  living ring-opening polymerization of lactide, only modest isoselectivity (Pm ~ 0.6) was observed.67    Figure 1.9. Dinuclear indium catalyst described by Mehrkhodavandi et al.  While this and many other tridentate ligand designs have had very limited success in generating  isotacticities of Pm > 0.7, tetradentate ligand systems are more effective at addressing this challenge.41  1.4.2 Tetradentate ligands in lactide polymerization This section will discuss metal-based lactide polymerization catalysts with tetradentate ligand architectures. For ease of discussion the ligands will be broadly divided into three categories based on 1) Tripodal ligands 2) macrocycles, and 3) salen-type ligands.  Within each category the discussion will be organized according to the donor atom groups bound to the metal center.   1.4.2.1 Tetradentate tripodal ligands  The facially coordinating, tetradentate, tripodal ligand design with three coordinating linkers attached to a central atom capable of binding to a metal center, has been widely used to 15  support metal-based catalysts in lactide polymerization, especially for group 4 metals.43 The donor atoms of the linkers and the central atom are usually nitrogen or oxygen. Several reports in the literature describe the use of tripodal ligands which exclusively contain nitrogen donors (Figure 1.10). In 2009 Mountford and coworkers reported titanium and zirconium isopropoxide catalysts supported by sulfonamides (I.10, I.11) for the ring-opening polymerization of rac-lactide and ɛ-caprolactone.68 The zirconium catalyst was more active than the titanium analogue for lactide polymerization. However, neither system was stereoselective and generated atactic PLA.    Figure 1.10. Metal catalysts bearing tripodal nitrogen donor ligands for lactide polymerization  Another example describes a five coordinate aluminum alkoxide catalyst (I.12) bearing the same ligand.69 It has been shown spectroscopically that the amine moiety and the pyridyl group compete for the fifth coordination site. The catalyst was less active than the zirconium analogue but showed excellent molecular weight control for melt polymerization of lactide.  An indium analogue was reported by the Mountford et al.70 This catalyst polymerized 300 equiv. of lactide in two hours under melt conditions; however, no stereoselectivity was achieved.     16  Tripodal ligands containing both nitrogen and oxygen donor have been a widely used to support group 4 metal catalysts in lactide polymerization, though other metals have also been investigated. In 2002, Verkade et al. reported the first investigation into the use of titanium alkoxides in the ring-opening polymerization of lactide with a family of aliphatic and aromatic titanatranes (Figure 1.11).71 The authors rationalize the use of this ligand design by evoking possible trans effects by the nitrogen donor to labilize the trans axial alkoxide which would promote high catalytic activity.         Figure 1.11. Examples of titanatranes for lactide polymerization described by Verkade et al.  While all the titanatranes (I.13-I.17) polymerized lactide under melt conditions (130 °C) only the five membered titanatranes I.13, I.14 and I.17 polymerized lactide in solution (toluene, 70 °C). This indicated higher activity in the more strained compounds in this study.  Overall this family of catalysts showed moderate activity requiring ~15 hours under melt conditions to achieve >90% monomer conversion when polymerizing 300 equiv. of lactide.   The same amine trisphenolate ligand design was extended to zirconium by Kol et al. who observed higher activity compared to the titanium analogues for lactide polymerization.72   17   Figure 1.12. Examples of amine bis- and trisphenolate ligand based catalysts for lactide polymerization  Davidson and coworkers reported a family of tetravalent metal catalysts bearing amine trisphenolate  ligands for the ring-opening polymerization of lactide (Figure 1.12: I.18-I.21).73 The authors reported that the titanium complex, which was active only under melt conditions, and polymerized 300 equiv. of lactide in under an hour to generate atactic PLA. The zirconium and hafnium catalysts, while showing similar reactivity, gave heterotactic PLA with Pr values of 0.96 and 0.88 respectively. While both catalysts slowed down considerably in solution (toluene, 25 °C), requiring >48 hours to polymerize 100 equiv. of lactide, the heterotacticity increased in both cases (Pr = 0.97 and 0.98 for hafnium and zirconium respectively). The germanium analogue previously reported by the group was a far more sluggish initiator, requiring up to 24 hours to polymerize 200 equiv. and achieved only moderate heteroselectivity (Pr ~ 0.80) in 18  comparison.74   In another report of group 4 catalysts with amine bisphenolate ligands (I.22-I.24), Davidson et al. reported that while the titanium catalyst was not stereoselective, the zirconium and hafnium systems were able to generate PLA with an isotactic bias reaching up to Pm ~ 0.75 under melt conditions.75  In an extension of this ligand architecture to group 3 and lanthanide catalysts, Mountford et al. reported several yttrium, lanthanum, neodymium and samarium complexes with bridging borohydride and chloride ligands (I.25, I.26).76,77 The yttrium, samarium and neodymium complexes generated heterotactic PLA in THF with the yttrium and samarium catalysts imparting the highest stereoselectivity of Pr = 0.87 and 0.72 respectively. In 2004, Carpentier and coworkers reported several isostructural yttrium (I.27), lanthanum and neodymium complexes with alkoxyaminobisphenolate ligands for the ring-opening polymerization of lactide.78,79 These were highly active catalysts capable of polymerizing 200 equiv. of lactide in 20 minutes. Several of these complexes generated heterotactic PLA with the yttrium complex I.27 generating the highest hetereotacticity (Pr = 0.90). The utility of these catalysts for immortal polymerization of lactide to grow multiple polymer chains by adding an exogenous alcohol has also been demonstrated.80 In addition, Carpentier et al. have successfully extended the use of yttrium alkoxyaminebisphenolates in the stereoselective ring-opening polymerization β-butyrolactone.81   1.4.2.2 Macrocyclic ligands  While macrocycles have not been widely used as ligands in lactide polymerization, several examples of nitrogen and oxygen containing macrocycles used to support metal-based initiators have been reported (Figure 1.13).  The use metal porphyrin catalysts for cyclic ester polymerization, pioneered by Inoue and coworkers represent one of the earliest examples of a 19  macrocyclic ligand in metal catalyzed lactide polymerization.82 This is an extension of the work carried out by the same group where metalloporphyrins were used for the copolymerization of carbon dioxide and epoxides.83  In 1987 an aluminum alkoxide complex supported by a porphyrin ligand (I.28) was described by Inoue et al. for lactide polymerization.84 The authors employ rigorous conditions to facilitate polymerization of lactide (heated to 100 °C in a vacuum sealed tube with the reactants dissolved in CH2Cl2).The polymerizations are well-controlled with good agreement between theoretical and experimental molecular weights and narrow PDIs.  The same research group has shown broad monomer scope for aluminum porphyrin catalysts with other lactones of varying ring sizes. 85-87   Figure 1.13. Examples of metal macrocyclic catalysts in lactide polymerization  In 2011 Okuda and coworkers reported a series of metal catalysts supported by a teradentate cyclen derived ligand (I.29-I.31) for lactide polymerization.88,89  Notably these catalysts were highly active at room temperature for the ROP of meso-lactide and can polymerize 100 equiv. of monomer in 30 minutes. However the reactivity drops considerably when rac- or L-lactide is used; taking up to 24 hours achieve full conversion. The magnesium variant achieved 20  modest isoselectivity with rac-lactide (Pm = 0.64). More detailed investigations have been carried out by Okuda et al. into the scandium system with modifications to the ligand design. However, no data for the ROP of rac-lactide is reported, with the focus  exclusively being on the polymerization of meso-lactide to generate syndiotactic PLA.89  An example of a macrocycle with oxygen donors to support a titanium catalyst for lactide polymerization has been reported by Frediani et al.90  Here the authors describe several titanium chloride complexes bearing calix[4]arene ligands (I.32) which act as solvent free catalysts for lactide polymerization. These complexes act as dual site catalysts with two polymer chains growing from one metal center.  1.4.2.3 Salen-type ligands   Figure 1.14. Examples of salen, salen and salalen ligands   Salen ligands are tetradentate, Schiff base-bis(phenolate) compounds which are traditionally made via the condensation of a diamine and a salicylaldehyde.91 They are widely used in asymmetric transformations, such as enantioselective epoxidations.92 While both tripodal and macrocyclic ligands have been investigated for the stereoselective ROP of rac-lactide with some success, salen type ligands have by far been much more successful in achieving isoselectivity with a variety of metals. Other derivatives of salen ligands, namely the reduced 21  bis(aminophenolate) or salan form and the asymmetrically reduced form (salalen ligands) will also be discussed (Figure 1.14).93 Since many variations of the classic salen ligand architecture incorporating different donor atoms have been reported in literature the discussion on the salen-type ligands will be organized according to donor atoms.  Figure 1.15.  Examples of aluminum salen catalysts for lactide polymerization  The seminal work in using the classic salen ligand design in lactide polymerization was described by Spassky and coworkers who had previously used a series of aluminum salen 22  compounds in the polymerization of epoxides and β-butyrolactone.94,95 Here they describe an aluminum methoxide catalyst supported by an achiral salen ligand (Figure 1.15: I.33) for the ROP of L- and rac- lactide.  Although this system requires elevated temperatures (70-100 °C in toluene) and has poor control over the polymerization process with polydispersities ranging from ~2-4, this nonetheless is an important milestone in catalyst design for lactide polymerization. This report was a prelude to a landmark publication by Spassky et al. which described a highly stereoselective aluminum salbinap (salen ligand with a binap linker) catalyst (I.34) for the ROP of lactide.96 The enantiopure (R)-catalyst was highly competent at chiral resolution of rac-lactide and at ~ 50% conversion at 70 °C in toluene almost exclusively polymerized L-lactide. A kinetics study into the rates of polymerization of L- and D- lactide with the (R) enantiomer of the catalyst showed a kD/kL ~20 which indicated a highly site-selective system. In a subsequent report Spassky et al. showed evidence of extensive transesterfication during polymerization using MALDI-TOF mass spectrometry.97  Subsequent to this work, a series of highly influential publications studied the polymerization of rac-lactide with aluminum salbinap complexes in detail. Coates et al. improved the synthesis of the catalyst by substituting the methoxide ligand with an isopropoxide initiator (1.35) to prevent the formation of an unwanted aggregate.40,29 This catalyst was stereoselective in the ROP of rac-lactide as well as meso-lactide.40,29,98 Though initially thought to form stereocomplex PLA, the polymerization of rac-lactide with racemic aluminum salbinap catalyst was shown to generate isotactic stereoblocks with a melting point of 179 °C.98,99 Duda and coworkers were able to use the same system to generate isotactic stereoblock PLA with a melting point approaching 210 °C through a two-step chiral ligand exchange mechanism.100 In 23  2002, Feijen and coworkers reported an aluminum isopropoxide initiator bearing a Jacobsen salen ligand (1.36) which also generated highly isotactic PLA.101,102 The racemic catalyst generated isotactic stereoblock PLA with rac-lactide in toluene at 70 °C with a Pm ~ 0.93 at 85% monomer conversion. This high isoselectivity was also maintained in melt polymerization at 130 °C to generate PLA with a Pm ~ 0.88.  In a mechanistic study of this system Chisholm and coworkers reported significant solvent effects on isoselectivity and highlight the difficult in assigning the mode of stereocontrol to exclusively enantiomorphic site-control or chain-end control and argues that the chiral environment of the catalyst, the chirality of the chain-end, the helicity of the η4-chelate, λ or δ, and the solvent all affect stereoselectivity in varying degrees.42,103  In a recent report Kol and Lamberti describe an aluminum salalen catalyst (I.37) for lactide polymerization and highlight the contribution of chain-end control to systems with chiral ligands.104 The  mechanistic complexities of stereoselectivity is further evidenced by a recent report by Carpentier et al. who describe a chiral aluminum salen catalyst (1.38) which generates highly isotactic PLA from rac-lactide (Pm ~ 0.90).105 In this example the kinetics indicated a dominant chain-end control mechanism, which contrasts other chiral aluminum salen catalysts where enatiomorphic site control is thought to predominate.98,102  All the previously mentioned chiral aluminum salen alkoxide systems require multiple days at elevated temperatures to polymerize ~200 equiv. of lactide. The low activity of chiral aluminum salen systems towards lactide polymerization is a major drawback of these systems.        24    Figure 1.16. Examples of aluminum catalysts for lactide polymerization with achiral ligands  Several aluminum catalysts supported by achiral salen ligands for isoselective lactide polymerization have been reported (Figure 1.16). After the initial publication which detailed compound I.3394 Spassky et al. reported a series of aluminum salen alkoxide catalysts which were used to generate crystalline PLA with Tm ~ 144 – 159 °C.106 The authors also describe decreased reactivity upon changing the ethylene bridge to a rigid phenyl moiety in one instance (I.39). Profound effects on reactivity and selectivity are observed by Nomura and coworkers when the ethylene linker was changed to a propylene functionality.107 The authors describe compound I.40 which polymerizes 100 equiv. of lactide to 19% conversion (70 °C in toluene) in three days to generate isotactic PLA (Pm ~ 0.79, Tm ~ 163 °C). In contrast the analogue with a propylene linker (I.41) not only achieves 95 % monomer conversion under identical conditions in fourteen hours but also improves the isotacticity of the polymer (Pm ~ 0.92, Tm ~ 192 °C). 25  After a series of incremental modifications to the linker as well as the aromatic substituents, Nomura et al. discovered I.42 which generated isotactic PLA with Pm ~ 0.98 and Tm ~ 210 °C. This is the highest isotacticity reported with an achiral catalyst.108  Several highly isoselective aluminum salen isopropoxide catalysts with the same 2,2-dimethylpropylene linker, but with different aromatic substituents have been described by Chen et al. and more recently by Lin et al.109-111    Figure 1.17. Examples of aluminum salen and salan catalysts for lactide polymerization by Gibson et al  Gibson et al. described a series of aluminum alkyl complexes supported by achiral salen ligands which was used with benzyl alcohol for the ROP of lactide (Figure 1.17).112 The authors observe isoselectivity in many of their catalysts (Example: I.43, Pm = 0.86) and describe the dependency of the degree of isoselectivity on the bridging ligand backbone and the aromatic substituents. A more profound change was observed by Gibson when achiral reduced-salen or salan type ligands were used to prepare several aluminum catalysts.113 When an unsubstituted salen ligand was used (I.44) isotactic PLA with Pm ~ 0.79 is produced. However, the stereoselectivity is completely switched to generate highly heterotactic PLA (Pr ~ 0.96) when 26  chloride substituents are incorporated to the ligand (I.45). A similar observation has been reported by Feijen et al. with chiral aluminum salan complexes.114                  While the classic salen ligand design contains a bis(salicylidene) moiety, several recent examples describe pyrrolic, enolic and alkoxide Schiff base frameworks incorporated to form tetradentate salen-like ligands used to support aluminum catalysts for lactide polymerization (Figure 1.18).  Feijen et al. reported an aluminum isopropoxide catalyst supported by a N,N,N,N salen-type ligand with pyrrole donors (I.46), which generated isotactic PLA (Pm ~ 0.75) from rac-lactide.115 An aluminum salen catalyst with enolate donors (I.47) which showed isoslectivity (Pm ~ 0.80) was reported by Chen and coworkers.116  Figure 1.18. Examples of alumnium catalysts supported by salen-like ligands for lactide polymerization  27  Carpentier et al. described several chiral and achiral aluminum salen-type catalysts with flourinated alkoxide donors coordinating to the metal centre (I.48, 1.49).117 These catalysts gave isotatically enriched PLA (Pm ~ 0.70-0.81) from rac-lactide under melt conditions. The less rigid achiral versions showed higher activity compared to the chiral analogues (30 min vs. 72 h to achieve similar conversions under similar conditions). However no change in selectivity is observed between the two systems, leading the authors to conclude a chain-end control mechanism for the catalysts. The mixed alkoxide-phenolate ligand based aluminum catalyst (I.50) is also capable of isotactic enrichment of PLA in solution (Pm ~0.81 in toluene at 60 °C).118   Figure 1.19. Examples of trivalent metal-based with salen type ligands for lactide polymerization  28  Trivalent metals other than aluminum have also been used with salen/salen-type ligands used for lactide polymerization (Figure 1.19). Mehrkhodavandi et al. have reported several chiral indium salen catalysts which are the subject of this dissertation.119,120 Coates and coworkers reported a dinuclear yttrium salbinap catalyst (I.51) for the ROP of lactide. In stark contrast to the aluminum counterparts no stereocontrol was achieved in polymerization.29 A bismuth alkoxide complex bearing a Jacobsen salen ligand (I.52) was reported by Chisholm, which generates heterotactic PLA (Pr ~ 0.9) from rac-lactide.121 Carpentier et al. have described several indium catalysts bearing salen type ligands. Several examples by the authors (I.53 and I.54) indicate that while the aluminum analogues generate highly isotactic PLA the indium complexes generate atactic polymer.122,105 A recent example by the same group described a bimetallic lithium yttrium catalyst (I.55) bearing a fluorinated salbinap type ligand which generated highly heterotactic PLA (Pr ~ 0.99).123    Group 4 metals have also been widely used in conjunction with salen type ligands (Figure 1.20). In 2006, Gibson et al. reported several chiral and achiral titanium salen alkoxide complexes (I.56) for the ROP of lactide.124 All catalysts reported took over 24 h to polymerize 100 equiv. of lactide in solution and only very modest heterotacticity was obtained (Pr ~ 0.51-0.57). Several achiral titanium and zirconium salan catalysts (I.57, 1.58) were reported by Kol and coworkers for melt polymerization of lactide.72 While no stereoselectivity has been reported for either system, the zirconium complexes were more active towards lactide polymerization than the titanium analogues.   29   Figure 1.20. Examples of group 4 salen catalysts in lactide polymerization  Chakraborty et al. reported zirconium and hafnium alkoxide complexes bearing a Jacobsen salen ligand (I.59, I.60).125 Notably these complexes are bimetallic with each metal centre coordinating to the ligand in a κ2-coordination mode. While these systems were active for melt polymerization of lactide (polymerizes 200 eq. in under 1 h), both generated atactic PLA. Several bimetallic and monometallic achiral zirconium salen catalysts (I.61, I.62) reported by Lin et al. showed polymerization activity but as was the case with other group 4 salen type catalysts, failed to achieve the high stereoselectivity of the aluminum analogues.126          30   Figure 1.21. Variations of salen-type ligands in metal-based lactide polymerization  Several salen-type ligands with novel variations have been reported (Figure 1.21).  Diaconescu et al. reported a family of catalysts supported by ferrocene based bis(phenolate) ligands (I.63, I.64). A cerium (IV) catalyst was highly active for the ROP of lactide with 300 equiv. of L-lactide being polymerized in under 20 minutes at room temperature.127 The yttrium analogue showed a redox controlled polymerization behavior where a change in catalyst activity was observed depending on the oxidation state of ferrocene. A similar behavior had been reported for a titanium salen catalyst by Gibson et al (I.65). 128 In 2012 Williams et al. reported 31  the use of an yttrium based catalyst bearing a phosphorous containing Schiff base ligand, referred to as a phosphasalen ligand (I.66). Catalysts supported by these ligands with an ethylene diamine linker showed high reactivity (polymerizing 1000 eq. of lactide in 45 s at ambient temperature in THF) and high heteroselectivity (Pr ~ 0.9). The authors were able to maintain this reactivity and achieve isoselectivity, (Pm ~ 0.8) by modifying the ligand backbone, to prepare a pentadentate ligand system (I.67).129 This ligand has been shown to achieve isoselectivity with other metals such as lutetium.130      Okuda et al. used a family of 1,ω-dithiaalkanediyl-bridged bisphenolato (OSSO)-type ligands with a range of different metals to develop catalysts for the ROP of lactide (Figure 1.22). While these ligands may not strictly fall into the category of salen-like ligands they coordinate to metals in a similar fashion. Several aluminum alkyl complexes bearing (OSSO) type ligands (I.68, I.69) which were used as catalysts for lactide polymerization with an added alcohol have been described.131 While the complexes with an ethylene diamine backbone generated atactic PLA, the modification of the linker to a –CH2PhCH2- moiety caused modest heteroselectivity (Pr ~ 0.65) to be observed with the system.  Dinuclear indium alkoxide analogues (I.70) were reported to be active in the ROP of L-lactide.132 In contrast group 3 metals such as scandium and yttrium, when used with 1,ω-dithiaalkanediyl-bridged bisphenolato ligands to polymerize rac-lactide were shown to generate highly heterotactic PLA. Compound I.71 polymerized 300 eq. of lactide to 81% conversion in under 8 h (at 25 °C in THF) and generated heterotactic PLA with Pr ~ 0.95.133 A chiral yttrium analogue (I.72) showed higher reactivity towards lactide polymerization albeit with slightly diminished heteroselectivity (Pr ~ 0.88).134 32    Figure 1.22. Examples of (OSSO) type ligand based catalysts for lactide polymerization  When group 4 metals were used with achiral (OSSO) ligands modest isotactic enrichment (Pm ~ 0.6) was observed in the polymerization of rac-lactide.135 In most of work, the authors largely focus on the polymerization of meso-lactide. The titanium complex I.73 and its zirconium analogue I.74 were reported to generate syndiotactic PLA from meso-lactide.      33     Figure 1.23. Reduced and oxidized forms of  thiolphan (n = 1) and thiolphan*(n = 0) based group 4 complexes  In a recent report, Diaconescu et al. describe two sulfur containing bis(phenolate) ligands with ferrocene backbones (Figure 1.23). These ligands are used with zirconium and titanium to form redox switchable catalysts whose polymerization behavior changes based on the oxidation state of the ferrocene.  The zirconium complex I.75 was active for lactide polymerization in its reduced for but inactive the oxidized form and vice versa for ε-caprolactone. While this complex failed to generate block copolymers of PLA and poly(caprolactone) in one a pot synthesis via redox switching, the titanium analogue I.76 was able to successfully carryout the block copolymerization.     1.5 Objectives While numerous metal based catalysts have been reported in the literature, industry still continues to use simple tin compounds such as stannous octanoate for lactide polymerization. 34  This is mainly due to the lack of a catalyst that combines desirable characteristics such as high reactivity, high isoselectivity, robustness and moisture tolerance. In this thesis my attempts to develop an industrially viable, stereoselective catalyst for the ring-opening polymerization of lactide with indium based compounds is described.      1.6 Scope of thesis A survey of scientific literature shows numerous attempts to develop stereoselective metal-based catalysts for lactide polymerization through ligand design.32,41,43-44 Aluminum catalysts supported by salen ligands remain the gold standard for isoselective lactide polymerization due to their ability to generate highly isotactic, stereoblock PLA from rac-lactide.96,40,107 However, sluggish polymerization behavior and high water/air sensitivity preclude their use in an industrial setting.102,29 Recently, indium has emerged as a water tolerant metal in Lewis acid mediated transformations including lactide polymerization.136,137 Having pioneered the use of indium in lactide polymerization,138 the Mehrkhodavandi group is interested in exploiting ligand design to achieve high reactivity, selectivity and control over the polymerization process.67,139-141 In chapter 2 our efforts to synthesize and characterize a family of mononuclear and dinuclear indium salen complexes as catalysts for lactide polymerization is discussed. The polymerization behavior of these catalysts with a detailed kinetic investigation in to the mechanism of polymerization is presented in chapter 3. In chapter 4, several indium salbinap complexes are described and the effects of linker modifications to the selectivity and reactivity in lactide polymerization are presented. Finally, in chapter 5 the synthesis of PLA-PHB-PLA triblocks through sequential monomer additions using a dinuclear indium catalyst is described.           35  Chapter 2: Synthesis and characterization of chiral salen indium(III) alkoxide complexes1  2.1 Introduction Over the past two decades indium(III) species have been used increasingly for Lewis acid-mediated  transformations.142-144 The water and other functional group tolerance of indium is a major advantage in synthetic applications.145 Indium salts and indium salt/ligand combinations have been used in asymmetric allylations,146 Diels-Alder reactions,147 Friedel-Crafts reactions148 and many other catalytic transformations.136  In parallel to this development, the synthesis of discrete indium complexes has gained considerable interest.149  In particular, the use of tetracoordinate bis(iminophenolate) or “salen” type ligands (see chapter 1, page 31) for indium complexes is prevalent. Synthesis of salen indium complexes were pioneered by Atwood et al.(Figure 2.1). Among the compounds reported are several five coordinate indium alkyl/halide complexes (I.78, I.79) bearing achiral salen ligands.150,151 Atwood also reported the first fully-characterized indium salen alkoxide (I.80), which was dinuclear in the solid state with bridging methoxide ligands.150 A similar complex, with tert-butyl groups as substituents on the aromatic rings, was also reported (I.81). These achiral indium salen alkoxide complexes reported by Atwood were not generated cleanly via alcoholysis of indium alkyl analogues. Rather, crystals were isolated and characterized from a mixture of products.150,151 Atwood et al. have also reported indium salen alkoxide dimers, with bridging salen ligands in a κ2 coordination mode at each metal centre                                                  1 This work has been partially published in the Journal Chemical Communications. A manuscript detailing the remainder of the work is in preparation. This work is also patent protected. 36  (I.82).150 While, dinuclear aluminum alkoxides with salen ligands have been reported,152 a vast majority of known aluminum salen alkoxides are mononuclear.42,112,149    Figure 2.1. Achiral indium salen complexes reported by Atwood et al.  The synthesis of discrete indium alkoxide complexes is more challenging than the preparation their aluminum counterparts.153 This is in part due to a much more pronounced aggregation phenomenon seen with indium alkoxides.154 For example, indium isopropoxide is reported to exist in multiple aggregate forms ranging from dimers to hexamers.155 In a further complication, commonly used synthetic routes to generate alkoxides of aluminum, such as alcoholysis of metal alkyl complexes, often generate mixtures of products.132,70 37  In 2006, Huang and coworkers reported several indium catalysts bearing substituted pyrrole ligands (I.82-I.83),156 for the ring opening polymerization (ROP) of ε-caprolactone. Mehrkhodavandi et al. reported the first indium catalyst (17) for lactide polymerization in 2008.66 Since these seminal reports several research groups have reported numerous indium catalysts for the ROP of lactide and other cyclic esters (Figure 2.2, I.84-I.86, see chapter 1 for examples with tetradentate ligands).67,70,105,122,132,139-140,157 While various ligand designs with differing denticities and donors have been investigated as supports for indium-based lactide polymerization catalysts, none of these systems have achieved high isoselectivity in the polymerization of rac-lactide (Pm > 0.7).   Figure 2.2. Examples of indium catalysts in cyclic ester polymerization  38  Due to the success of salen-type ligands in isoselective lactide polymerization, several salen–supported indium complexes have been reported in the literature for cyclic ester polymerization. Diaconescu et al. reported a five-coordinated indium phenoxide complex supported by an achiral, phosphorous containing salen ligand, with a ferrocene backbone (I.87).158 A sulfur containing salen type ligand support for an indium isopropoxide catalysts (I.70) was reported by Okuda et al.132 Sarazin/Carpentier et al. have reported several chiral and achiral indium alkyl/halide complexes bearing salen type ligands (I.53, I.54, I.88).122,105 These complexes have been used with an exogenous alcohol in the ROP of lactide. Attempts to generate indium alkoxide complexes by treating these salen indium alkyl compounds with alcohol resulted in intractable mixtures.122,105  Studies on the synthesis of achiral indium salen complexes are more prevalent than their chiral analogues. Apart from the work in this thesis, two reports by Sarazin/Carpentier et al. 122,105 remain the only literature examples of chiral salen indium complexes.   39   Figure 2.3. Examples of indium complexes with achiral salen ligands for lactide polymerization  A major search focus in the Mehrkhodavandi group involves the development of discrete chiral indium alkoxide catalysts for stereoselective lactide polymerization. With this intention the Jacobsen salen ligand design with a chiral diamino cyclohexane (DACH) backbone is used. Prior to this work an enantiopure indium methyl complex bearing an Jacobsen salen ligand has been reported (I.89).159 However, no further reactivity with this compound was reported.        40  Determination of nuclearity of complexes in solution. As previously discussed, aggregation phenomena dominate the chemistry of indium alkoxide complexes and thus it is necessary to determine the nuclearity of such species.   In many metal complexes, aggregation is usually uncovered in the solid state, typically through single X-ray crystallography.153 However, the solution state nature of these complexes may not necessarily be the same.57,160 Determining the nuclearity of a complex in solution is especially important in homogeoneous catalysis, as it may provide clues regarding the mechanism of catalysis.  Pulsed field gradient spin-echo (PGSE) NMR spectroscopy is a common methodology used to determine the nuclearity of a species in solution by measuring the translational diffusion coefficient (Dt).161 The Dt of the species in question, can be compared with Dt of similar compounds, which have known solution-phase nuclearities.161 This comparison is valid as Dt is related to size and the shape of a species.162 In PGSE NMR spectroscopy applied pulsed magnetic field gradients create a spin-echo, which is attenuated from its initial intensity with time due to the Brownian motion of molecules.163 This can be observed as a decrease in the intensity of 1H NMR resonances of a spectrum obtained. This relationship can be mathematically expressed using equation 2.1; 161,163                                                           ln(I/I0)  = γ2δ2G2Dt[Δ−(δ/3)]                                            (2.1) Here, I = observed spin echo intensity, I0 = intensity in the absence of a gradient, G = gradient strength, γ = gyromagnetic ratio, δ = length of gradient pulse, and Δ = delay between gradient midpoints. A plot of this equation is used to determine Dt.  This technique was used by Hillmyer and Tolman to determine the solution state behaviour of zinc alkoxide catalyst for lactide polymerization (discussed in Chapter 1 - I.1) which was dinuclear in the solid state.57 More recently Mehrkhodavandi et al. have used this 41  technique in a mechanistic investigation of a dinuclear indium catalyst.67 In the following sections, the synthesis and characterization of several indium salen alkoxide complexes will be discussed.  2.2 Results 2.2.1 Synthesis and characterization of proligands A series of known164-168 or newly synthesized tetradentate, Schiff base salen ligands rac- or (R,R)-(ONNR1OR2)H2 were synthesized by treating (±)-1,2-diaminocyclohexane or (R,R)-1,2-diammoniumcyclohexane mono-(+)-tartrate salt with two equiv. of the corresponding salicylaldehydes under basic conditions (Scheme 2.1).  Proligands (R,R)-(ONNtBuOtBu)H2, rac-(ONNtBuOtBu)H2, (R,R)-(ONNBrOtBu)H2, (R,R)-(ONNMeOtBu)H2 and (R,R)-(ONNcumylOcumyl)H2 were prepared using previously published procedures.165-168 Proligands rac- and (R,R)-(ONNAdOtBu)H2 as well as (R,R)-(ONNSiPh3OMe)H2 were not reported in the literature and were prepared and fully characterized in 62 – 93 % yield. The 1H NMR spectra of these all the ligands show one characteristic singlet between 8-9 ppm, which corresponds to the equivalent N=CH resonances. In the 13C{H} spectra, the N=CH resonances appear furthest downfield at chemical shifts of >160 ppm.       42    Scheme 2.1. Synthesis of known and newly reported (ONNR1OR2)H2 proligands. Yields provided for newly synthesized ligands. 43  2.2.2 Synthesis and characterization of indium salen chloride complexes Successful salt metathesis reactions with the family of salen ligands and InCl3 are highly ligand dependent. Deprotonation of racemic or enantiopure rac- or (R,R)-(ONNR1OR2)H2 with two equiv. of PhCH2K or KOtBu followed by addition of one equivalent of InCl3 yields the respective racemic or enantiopure indium chloride derivatives rac- or (R,R)-ONNR1OR2InCl (1-5) (Scheme 2.2).  In contrast, similar reactions with (R,R)-(ONNBrOtBu)H2 form unresolvable mixtures and the 1H NMR spectra of the reactions show the loss of the imine C=NH resonance indicating ligand decomposition.  Scheme 2.2. Synthesis of (ONNR1OR2)InCl complexes 1-5.  The solid state structures of rac-1 (Figure 2.4) and rac-3 (Figure 2.6) determined with single crystals obtained from diethyl ether at −35 °C, contain five coordinate indium centers with 44  a distorted square pyramidal geometry.  In contrast, single crystals of (R,R)-2 grown in acetonitrile gives a structure with a distorted octahedral geometry with an acetonitrile molecule coordinating to the indium trans to the chloride (Figure 2.5). This may be due to the fact that the relatively smaller acetonitrile molecules can undergo more facile coordination to indium compared to diethyl ether. The In-Cl distance in (R,R)-2.CH3CN (Å) is longer than the In-Cl bond distances in either rac-1 or rac-3 and can be attributed to a trans influence from the σ-donation from the coordinating acetonitrile (2.470(1), 2.371(2) and 2.3704(7) Å for 2, 1, and 3 respectively). The 1H NMR spectra of rac- or (R,R)- complexes 1-5 show two singlet resonances corresponding to the N=CH group between 8-9 ppm. Observation of two imine resonances is indicative of the loss of the C2 rotational axis of the ligand after metallation.  The 1H spectra of rac-1 and rac-3 are identical to their enantiopure analogues, (R,R)-1 and (R,R)-3.      45   Figure 2.4. Molecular structure of rac-1depicted with ellipsoids at 50% probability (H atoms omitted for clarity)  Table 2.1. Selected bond lengths and angles for rac-1 rac-1 Bond Lengths (Å) In1-Cl1 2.371(2) In1-N1 2.171(7) In1-O1 2.050(6) In1-N2 2.207(7) In1-O2 2.044(6)   Bond Angles (°) O2-In1-Cl1 106.86(19) O2-In1-N1 150.9(3) N1-In1-Cl1 101.2(2) O1-In1-N1 84.3(3) N2-In1-Cl1 113.40(19) O2-In1-N2 85.8(2) O2-In1-O1 90.0(2) O1-In1-N2 128.6(3)   46   Figure 2.5. Molecular structure of (R,R)-2.CH3CN depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity)  Table 2.2. Selected bond lengths and angles for (R,R)-2 (R,R)-2 Bond Lengths (Å) In1-Cl1 2.470(1) In1-N1 2.213(3) In1-O1 2.066(3) In1-N2 2.181(3) In1-O2 2.071(3) In1-N5 2.521(4) Bond Angles (°) O1-In1-Cl1 95.41(8) O2-In1-N1 157.36(11) O2-In1-Cl1 100.68(8) O1-In1-N1 87.62(11) N1-In1-Cl1 98.59(8) O2-In1-N2 89.52(12) N2-In1-Cl1 96.93(9) O1-In1-N2 161.07(11) O2-In1-O1 102.24(11) N1-In1-N2 76.40(12) Cl1-In1-N5 175.44(9) O1-In1-N5 84.85(11)   47   Figure 2.6. Molecular structure of rac-3 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) Table 2.3. Selected bond lengths and angles for rac-3 rac-3 Bond Lengths (Å) In1-Cl1 2.3704(7) In1-N1 2.194(2) In1-O1 2.0661(16) In1-N2 2.194(2) In1-O2 2.0648(16)   Bond Angles (°) O2-In1-Cl1 112.57(6) O2-In1-N1 133.07(9) N1-In1-Cl1 100.29(7) O1-In1-N1 85.27(7) N2-In1-Cl1 112.57(6) O2-In1-N2 83.93(7) O2-In1-O1 95.88(7) O1-In1-N2 151.87(8)     48  2.2.3 Synthesis of dinuclear salen indium ethoxide complexes As mentioned previously, the synthesis of indium alkoxide complexes is complicated by aggregation and limited synthetic routes. The ligand-dependence of synthetic strategies must also be considered. In order to address these issues, several synthetic strategies were exploited in the synthesis of discrete indium salen alkoxide complexes.  Salt metathesis of (ONNO)InCl complexes. The formation of indium alkoxide complexes via the salt metathesis of an isolable indium halide complex has been previously used by the Mehrkhodavandi group with (NNO) half-salen type ligands systems.67,169 The synthesis of rac/(R,R)-[(ONNtBuOtBu)InOEt]2 (rac-6 and (R,R)-6) was carried out via the salt metathesis of rac/(R,R)-(ONNtBuOtBu)InCl (Scheme 2.3). This methodology can be extended to rac-2, as well as enantiopure (R,R)-2-4, to generate rac-7, (R,R)-7, (R,R)-8 and (R,R)-9 respectively. The reaction of (R,R)-5 with NaOEt generates an unresolvable mixture of products.   49   Scheme 2.3. Synthesis of dinuclear indium salen alkoxide complexes via the salt metathesis of (ONNO)InCl complexes.  The 1H NMR spectra of these complexes show two characteristic C=NH resonances, similar to what was observed in the (ONNO)InCl complexes. Compounds (R,R)-6, (R,R)-7, and  (R,R)-8 contain two diastereotopic multiplet resonances for the –OCH2CH3 protons between 4.0-3.0 ppm, while in the spectrum of (R,R)-9 these methylene protons appear as a quartet at 3.51 ppm. A triplet resonance corresponding to the –OCH2CH3 protons can be observed between 1-2 ppm in the spectra of all indium alkoxide complexes synthesized.   50   Figure 2.7. Molecular structure of rac-6 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity)  Table 2.4. Selected bond lengths and angles for rac-6 rac-6 Bond Lengths (Å) In1-O1 2.080(5) In1-N1 2.171(7) In1-O2 2.128(5) In1-N2 2.207(7) In1-O3 2.121(5)   Bond Angles (°) O1-In1-O3 109.79(19) O1-In1-N1 84.8(2) O1-In1-O2 88.6(2) O3-In1-N1 156.4(2) O3-In1-O2 93.08(19) O2-In1-N1 106.1(2) N2-In1-O1 151.6(2) N2-In1-N1 73.1(2) O3-In1-N2 97.1(2) O2-In1-N2 80.9(2) 51  Single crystals of rac-6 and (R,R)-7 for X-ray crystallography were grown from cyclohexane and acetonitrile respectively by slow evaporation of solvent. Repeated attempts to grow single crystals of complexes 8-9 were unsuccessful. The solid state structures of rac-6 (Figure 2.7), and (R,R)-7 (Figure 2.9) show dinuclear complexes with distorted octahedral indium centers bridged by ethoxide groups. In rac-6, which crystallized in the centrosymmetric space group C2/c, the coordinated cyclohexyldiamine for both indium centers has the same absolute configuration of (SS/SS), implying that the (RR/RR) homochiral dimer also exists.  The (RR/SS) version of the complex can also be isolated from crystals grown under different conditions (in hexanes at −35°C) (Figure 2.8).   Figure 2.8. Atom connectivity for (R,R/S,S) dimer of complex rac-6    52   Figure 2.9. Molecular structure of (R,R)-7 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity)  Table 2.5. Selected bond lengths and angles for (R,R)-7 (R,R)-7 Bond Lengths (Å) In1-O1 2.105(3) In1-N1 2.250(3) In1-O2 2.092(3) In1-N2 2.291(3) In1-O3 2.147(3)   Bond Angles (°) O1-In1-O3 89.73(10) O1-In1-N1 83.33(11) O1-In1-O2 93.90(10) O3-In1-N1 92.75(10) O3-In1-O2 115.12(10) O2-In1-N1 152.03(10) N2-In1-O1 104.00(10) N2-In1-N1 70.94(11) O3-In1-N2 156.88(11) O2-In1-N2 82.89(11)  53  Both rac-6 and (R,R)-7 have similar bond lengths and bond angles (Tables 2.4 and 2.5 respectively) around the indium centre. While 6-coordinate dimeric [(ONNO)Al(OR)]2 complexes are known,152 the most common coordination number for salen aluminum alkoxide complexes is five.170  In contrast, the larger ionic radius of indium(III) often favors 6-coordinate complexes.  In particular, alkoxide complexes are prone to aggregation and can form dimeric [(κ4-ligand)In(OR)]2 complexes such as I.80 or with dithiaalkanediyl-bridged bis(phenolato) (OSSO) complexes of indium (I.70).132 Another notable feature which is particularly prominent in the structure of (R,R)-7 is the distortion shown by the salen ligand itself despite a rigid cyclohexyl backbone.   One-pot synthesis of indium salen alkoxide complexes. While the salt metathesis methodology worked well with many ligands, it is not applicable to systems such as (R,R)-(ONNBrOtBu)H2 where isolation of the indium chloride complex is not possible.  In order to access these indium alkoxide complexes, a one-pot strategy was devised.  The (ONNO)H2 ligands were stirred with InCl3 to form a preliminary adduct, which is then reacted with excess NaOEt.  Although the reaction was not studied in detail, it is possible that this strategy prevents the formation of uncontrolled aggregates through the first Lewis acid/base interaction. The initial absence of a strong base such as KCH2Ph that can have undesirable reactivity with the ligand in use, is an advantage.  This milder procedure was efficiently used to generate (R,R)-6, (R,R)-7, (R,R)-8, (R,R)-9 and (R,R)-10 from their respective proligands (Scheme 2.4).  A similar strategy was used by Mehrkhodavandi et al. to synthesize a dinuclear indium alkoxide complex with a half salen ligand.66 54   Scheme 2.4. One-pot synthesis of indium salen alkoxide complexes  The 1H NMR spectrum of (R,R)-10 shows two C=NH resonances at 8.23 and 7.94 ppm. A triplet corresponding to –CH2CH3 is observed at 1.48 ppm.  It is noteworthy that (R,R)-10 could only be generated using the one-pot synthesis as (R,R)-(ONNBrOtBu)InCl could not be synthesized.  In this route the respective (ONNO)InCl complexes are generated in situ and subsequently undergo salt metathesis with NaOEt to generate the [(ONNO)InOEt]2 complexes. This is supported by the fact that the 1H NMR spectra of incomplete reactions show resonances corresponding the characterized (ONNO)InCl complexes (Appendix, Figure A32).    Repeated attempts at treating (R,R)-5, bearing a salen ligand with bulkier ortho -SiPh3 groups,  with NaOEt as well the one-pot synthesis failed to generate the corresponding indium ethoxide complex. We encountered a similar problem in our attempts to generate bulkier indium salbinap complexes (See chapter 4). Based on our experience we hypothesized that dimerization 55  of indium alkoxide complexes is a necessary thermodynamic minimum which prevents further aggregation and facilitates the formation of discrete compounds. Hence attempts to interfere with this thermodynamic sink only complicate the synthetic outcomes of these reactions. While the issue appears to be prevalent in the literature,70,105,140,153_ENREF_155 to the best of our knowledge no broadly applicable strategy has been put forward to overcome this challenge.  Synthesis of mononuclear salen indium alkoxide complexes. To access a stable mononuclear indium alkoxide complex it was hypothesized that the coordination site that participate in bridging/aggregation had to be blocked. The strategy used to accomplish this was to replace the ethoxide group with a coordinating alkoxide, namely pyridin-2-ylmethoxide. Complexes (R,R)-11 and (R,R)-12 were prepared by treating (R,R)-1 and (R,R)-5 with potassium pyridin-2-ylmethoxide (KOCH2Pyr) (Scheme 2.5).    Scheme 2.5. Synthesis of (R,R)-(ONNR1OR2)InOCH2Pyr complexes via (R,R)-(ONNR1OR2)InCl 56  The ortho-bromo complex was accessed via a one-pot synthesis by treating (ONNBrOtBu)H2 with InCl3 and excess KOCH2Pyr (Scheme 2.6).   Scheme 2.6. Synthesis of (R,R)-[(ONNBrOtBu)InOEt]2 using a one-pot synthesis  In this approach the alkoxide undergoes salt metathesis to form a metal alkoxide bond and the pyridine moiety chelates back to occupy the coordination site which otherwise participates in the dimerization, and forms a stable six-coordinate metal center. In contrast to (R,R)-11 and (R,R)-13, the bulkier complex (R,R)-12 is more challenging to prepare cleanly, with minor impurities observed by 1H NMR spectroscopy after repeated purification attempts. However, it is the major product of the reaction (>90% of the crude reaction).  The 1H NMR spectra of (R,R)-11 and (R,R)-13 show a singlet corresponding to the methylene resonances of pyridin-2-ylmethoxide at 5.03 and 4.77 ppm respectively. However in (R,R)-12 with the more bulkier –SiPh3 groups the methylene resonances appear as two diastereotopic resonances at 4.59-4.54 and 4.05-4.01 ppm. This suggests fluxional behavior of the pyridine moiety in (R,R)-11 and (R,R)-13, which is hindered in the bulkier 12. Variable 57  temperature 1H NMR of (R,R)-11 shows that this singlet resolves into two diastereotopic resonances at −20 °C in CDCl3 (Figure 2.10).   Figure 2.10. 1H NMR spectra of (R,R)-11 in CDCl3 at temperatures from 25 °C to −20 °C. The methylene resonance of the alkoxide is labelled with (●)  Single crystals of (R,R)-11 and (R,R)-12 were grown by slow evaporation from hexanes. The X-ray structures of (R,R)-11 and (R,R)-12 (Figures 2.11 and 2.12) shows mononuclear complexes with a distorted octahedral indium center supported by a chelating pyridyl moiety. Comparison of the In-N bond distances (R,R)-11 shows that the In-NPyridyl bond distance (2.2962(16) Å) is longer than In-NImine bond distances (2.2277(19)and 2.2582(17) Å). In contrast in the X-ray structure of (R,R)-12 the In-N bond distances have similar values, with In-NPyridyl, and the two In-Nimine being 2.242(7), 2.233(7) and 2.234(6) Å respectively.  58        Figure 2.11. Molecular structure of (R,R)-11 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity)  Table 2.6. Selected bond lengths and angles for (R,R)-11 (R,R)-11 Bond Lengths(Å) In1-O1 2.0957(16) In1-N1 2.2582(17) In1-O2 2.1244(15) In1-N2 2.2277(19) In1-O3 2.0855(15) In1-N3 2.2962(16) Bond Angles (°) O1-In1-O3 105.32(6) O1-In1-N1 83.77(6) O1-In1-O2 88.61(6) O3-In1-N1 89.09(6) O3-In1-O2 155.18(6) O2-In1-N1 113.16(6) O1-In1-N2 72.62(6) N2-In1-N1 72.62(6) O3-In1-N2 94.54(6) O2-In1-N2 82.54(6) O1-In1-N3 90.13(6) O2-In1-N3 84.97(6) 59    Figure 2.12. Molecular structure of (R,R)-12 depicted with ellipsoids at 50% probability (H atoms omitted for clarity)  Table 2.7. Selected bond lengths and angles for (R,R)-12 (R,R)-12 Bond Lengths(Å) In1-O1 2.106(6) In1-N1 2.234(6) In1-O2 2.091(5) In1-N2 2.233(7) In1-O3 2.084(5) In1-N3 2.242(7) Bond Angles (°) O1-In1-O3 162.0(2) O1-In1-N1 81.6(2) O1-In1-O2 94.9(2) O3-In1-N1 91.6(2) O3-In1-O2 98.4(2) O2-In1-N1 153.6(2) O1-In1-N2 103.7(2) N2-In1-N1 71.9(2) O3-In1-N2 89.8(2) O2-In1-N2 83.8(2) O1-In1-N3 89.9(3) O2-In1-N3 102.7(2)  60  2.2.4 Solution structure of salen indium alkoxide complexes Insights into the solution structure of the indium salen alkoxide were gained using PGSE NMR spectroscopy.161  The diffusion coefficients of the proligand (ONNtBuOtBu)H2, rac-1, and rac-6 were determined using PGSE NMR spectroscopy (Figure 2.13) at 25 °C with tetrakis(trimethylsilyl)silane (TMSS) as an internal standard.  The diffusion coefficients for rac- (ONNtBuOtBu)H2 and rac-1 were comparable at 9.5(3) × 10–10 m2s–1 and 9.1(2) ×10–10 m2s–1, respectively.  In contrast, rac-6 had a significantly lower diffusion coefficient of 6.5(5) ×10–10 m2s–1. This >20% decrease in the diffusion coefficient going from rac-1 to rac-6 supports a dinuclear solution state structure for rac-6.171 This is similar to what was observed by Mehrkhodavandi et al. for Dt (7.8 × 10–10 m2s–1) of dinuclear indium catalyst (17) when compared to the proligand (I.90, Dt = 12.0 × 10–10 m2s–1) and the mononuclear indium chloride complex (I.91, Dt = 10.0 × 10–10 m2s–1) (Figure 2.13).67 The Dt values reported by Hillmyer and Tolman, for a dinuclear zinc complex (I.93, Dt = 5.7 × 10–10 m2s–1). and its monomeric THF adduct (I.92, Dt = 7.2 × 10–10 m2s–1) also show a similar decrease in the dimer.160   61   Figure 2.13. Plot of ln(I/I0) vs. γ2δ2G2[Δ−(δ/3)]×10−10  (m−2 s) from PGSE experiments for rac-(ONNtBuOtBu)H2, rac-1 and  rac-6 in CD2Cl2 at 25 °C. I = observed spin echo intensity, I0 = intensity in the absence of a gradient, G = gradient strength, γ = gyromagnetic ratio, δ = length of gradient pulse, Δ = delay between gradient midpoints. The translational diffusion coefficient (Dt) was obtained from the slope of the plots.  -4.5-3.5-2.5-1.5-0.50.50.0 0.1 0.2 0.3 0.4(ONNO)H2 (L1)(ONNO)InCl (1)[(ONNO)InOEt]2 (6)γ2δ2G2[Δ−(δ/3)]×10−10  m2s−1 ln(I/I0) 62   Figure 2.14. Reported diffusion coefficients (Dt) of several dimeric and monomeric complexes67,160  The diffusion coefficients for the other salen indium ethoxide complexes (7-10, Table 2.8, entries 5, 6, 8 and 9) were also determined. These when compared to the Dt of rac-(ONNtBuOtBu)H2, rac-1 and rac-6 confirmed their dinuclear nature in solution. Specifically the similarity of Dt values of the ethoxide complexes (7.0 × 10–10 - 6.3 × 10–10 m2s–1) to that of rac-6 supports this. This conclusion is further validated when a comparison is made between the Dt values reported here and values previously published in the literature for molecules of different sizes (Figure 2.14).  PGSE NMR spectroscopy in CD2Cl2 at 25 °C of (R,R)-11 and (R,R)-13 (Table 2.8, entries 3-4) gives Dt values of 8.5(2) × 10–10 m2s–1 and 8.6(5) × 10–10 m2s–1. This is 63  similar to the Dt of rac-1 (9.1(2) × 10–10 m2s–1) which suggests that these alkoxide complexes remain mononuclear in solution.    Table 2.8. Dt of compounds calculated using PGSE NMR spectroscopy Entry Compound Dt(×10–10 m2s–1) 1 (ONNtBuOtBu)H2 9.5(3) 2 (ONNtBuOtBu)InCl (rac-1) 9.1(2) 3 (ONNBrOtBu)InOCH2Pyr((R,R)-13) 8.6(5) 4 (ONNtBuOtBu)InOCH2Pyr((R,R)-11) 8.5(2) 5 [(ONNBrOtBu)InOEt]2 ((R,R)-10) 6.9(4) 6 [(ONNMeOtBu)InOEt]2 ((R,R)-7) 7.0(4) 7 [(ONNtBuOtBu)InOEt]2 ((R,R)-6) 6.5(5) 8 [(ONNAdOtBu)InOEt]2 ((R,R)-8) 6.3(5) 9 [(ONNcumylOcumyl)InOEt]2 ((R,R)-9) 6.0(4)   The stability of the dinuclear structure was studied using complex (R,R)-6. 1H NMR spectrum of this in THF-d8 shows no indication of any dissociation. When (R,R)-6 was stirred under reflux in neat pyridine overnight, and the volatile components evaporated under vacuum, no byproducts in the subsequently obtained 1H NMR spectrum is observed (Appendix, Figure A.33).  However, when (R,R)-6 is stirred in neat ethyl acetate overnight,  ~20% of the compound is converted to other by products (Appendix, Figure A.34). This suggests that while the dinuclear ethoxide complex is very stable it is more reactive towards oxygen donors rather than nitrogen donors.     The relative stability of these complexes were investigated using crossover experiments between (R,R)-6/(R,R)-8 and (R,R)-6/(R,R)-10 (Scheme 2.7). Notably the pair (R,R)-6/(R,R)-8, with bulkier ortho substituents, showed almost complete crossover in 10 minutes (Figure 2.15) while (R,R)-6/(R,R)-10 showed less crossover even after 16 h (Figure 2.16).  This observation 64  suggests that the dinuclear [(ONNO)In(OR)]2 complexes with bulkier ortho substituents are prone to dissociation.            Scheme 2.7. Crossover experiment of (R,R)-6 with (R,R)-8 or (R,R)-10        65       Figure 2.15. Crossover reaction between (R,R)-6 and (R,R)-8 at in CD2Cl2 at 25 °C. The resonances for the likely crossover product (A) is labelled with (●)           66       Figure 2.16. Crossover reaction between (R,R)-6 and (R,R)-10 at in CD2Cl2 at 25 °C. The resonances for the likely crossover product (B) is labelled with (●)    2.3 Conclusions  With this study we have illustrated several synthetic strategies that can be used for the synthesis of indium alkoxides. Simple salt metathesis reactions can be used effectively in many instances to synthesize dinuclear indium alkoxide complexes as the sole product. However, the choice of viable strategy is not only dependent on the general ligand architecture but subtle stereoelectronic differences in substituents as well. Aggregation can be minimized through the judicious selection of synthetic strategies, such as the used of coordinating alkoxides to form 67  mononuclear alkoxide complexes. This shows that through the careful design of synthetic routes a diverse array of indium alkoxide complexes can be prepared. PGSE NMR studies indicate that the dinuclear nature of the indium ethoxides remain intact in solution, while the indium pyridin-2-ylmethoxide complexes remain mononuclear. Studies indicate that these complexes can dissociate in the presence of a suitable donor. Crossover studies indicate that the stability of the dinuclear complexes is dependent on the steric bulk of the ortho substituents.    2.4 Experimental section      General considerations.  Unless otherwise indicated, all air- and/or water-sensitive reactions (synthesis and reactions involving metal complexes) were carried out under dry nitrogen using either an MBraun glove box or standard Schlenk line techniques. Ligands, unless stated otherwise were synthesized without employing air-sensitive techniques.  NMR spectra were recorded on a Bruker Avance 300 MHz, 400 MHz or 600 MHz spectrometer.  1H NMR chemical shifts are reported in ppm versus residual protons in deuterated chloroform; δ 7.27 CDCl3.  13C{1H} NMR chemical shifts are reported in ppm versus residual 13C in the solvent; δ 77.2 CDCl3. Diffraction measurements for X-ray crystallography were made on a Bruker APEX DUO diffractometer with graphite monochromated Mo-Kα radiation. The structures (Table A.1) were solved by direct methods and refined by full-matrix least-squares using the SHELXTL crystallographic software of Bruker-AXS.  Unless specified, all non-hydrogen atoms were refined with anisotropic displacement parameters, and all hydrogen atoms were constrained to geometrically calculated positions but were not refined.  Elemental analysis (C, H, and N) was performed using a Carlo Erba EA1108 elemental analyzer.  The elemental composition of unknown samples was determined by using a calibration factor. The calibration factor was 68  determined by analyzing a suitable certified organic standard (OAS) of a known elemental composition.  Materials.  Solvents (tetrahydrofuran, toluene, hexanes and diethyl ether) were collected from an MBraun solvent purification system whose columns are packed with activated alumina. CD2Cl2, CDCl3, ethyl acetate, pyridine and cyclohexane were dried over CaH2, and degassed through a series of three freeze-pump-thaw cycles. Where dry solvents were not required (i.e. ligand synthesis) solvents were used as received from the manufacturer. Potassium tert-butoxide and NaOEt were purchased from Aldrich and used as received after drying overnight under vacuum. InCl3 was purchased from Strem chemicals and used as received. Rac-/(R,R)-(ONNtBuOtBu)H2, (R,R)-(ONNBrOtBu)H2, (R,R)-(ONNMeOtBu)H2, (R,R)-(ONNcumylOcumyl)H2 and KCH2Ph were synthesized according to previously reported procedures.164-168  Synthesis of (R,R)-(ONNAdOtBu)H2  A 250 mL round-bottom flask was charged with a teflon stir bar, (R,R)-1,2-diammoniumcyclohexane mono-(+)-tartrate (0.390 g, 1.47 mmol) and anhydrous K2CO3 (0.102 g, 0.739 mmol).  To this mixture 15 mL of water was added and stirred until complete dissolution was achieved. In a 250 mL Erlenmeyer flask 3-adamantan-1-yl-5-tert-butyl-2-hydroxybenzaldehyde (0.920 g, 294 mmol) was suspended in 50 mL of ethanol. This was stirred and CH2Cl2 was added drop-wise until complete dissolution of the salicylaldehyde was observed. This solution was then added at once to the stirring aqueous solution in the 250 mL round-bottom flask. Upon mixing a bright yellow solution is observed immediately. A reflux condenser was attached to the round bottom flask and the reaction was heated to reflux (~90 °C) and allowed to stir for 4h. The reaction was then allowed to cool down to room temperature and 69  reaction was concentrated using rotary evaporation until the volume decreased by ~25% this mixture was then cooled down to ~5 °C in a refrigerator for 30 minutes and filtered using suction filtration. The bright yellow solid isolated was repeatedly washed with water. The solid was then dissolved in 25 mL of CH2Cl2 and washed successively with two 25 mL portions of water and a 25 mL portion of a saturated NaCl solution. The organic phase was subsequently dried over anhydrous MgSO4, filtered and the solvent was removed using rotary evaporation to obtain a yellow powder. This was left under vacuum overnight prior to use (yield: 0.960 g, 93%). 1H NMR (400 MHz, CDCl3, 25 °C) : δ 8.30 (2H, s, N=CH), 7.25 (2H, s, ArH), 6.98 (2H, s, ArH), 3.35-3.30 (2H, s, -CH- of DACH), 2.16 (12H, br s, -CH2- of Ad), 2.08 (6H, br s, -CH- of Ad), 1.80 (12H, br s, -CH2- of Ad), 1.92-1.30 (8H, overlapping m, -CH2- of DACH), 1.24 (18 H, br s, Ar-C(CH3)3). 13C NMR (100.63 MHz, CDCl3, 25 °C): δ 166.0, 158.2, 139.9, 136.6, 126.7, 126.0, 117.8, 72.4, 40.3, 37.2, 34.1, 33.3, 31.4, 29.1, 24.4. Anal. calcd (found) for C48H66N2O2: 82.00 (81.42), H 9.68 (9.46), N 3.98 (3.60).   Synthesis of rac-(ONNAdOtBu)H2  The racemic ligand was prepared and purified in an analogous manner to rac-(ONNAdOtBu)H2  (literature procedure)165 from (±)-1,2-diaminocyclohexane and 3-adamantan-1-yl-5-tert-butyl-2- hydroxybenzaldehyde  (yield:  0.210 g, 62%). The compound has NMR signature similar to that of (R,R)-(ONNAdOtBu)H2. Anal. calcd (found) for C48H66N2O2: C 82.00 (82.20), H 9.68 (9.53), N 3.98 (3.00).     70  Synthesis of (R,R)-(ONNSiPh3OMe)H2  This was synthesized in a manner analogous to (R,R)-(ONNAdOtBu)H2 as a yellow solid (yield: 0.126 g, 88% ), 1H NMR (400 MHz, CDCl3, 25 °C) : δ 8.13 (2H, s, N=CH), 7.25 (2H, s, ArH), 7.62-6.92 (34 H, overlapping m, -SiPh3, ArH), 3.24-3.18 (2H, s, -CH- of DACH), 2.18 (6H, s, ArCH3), 1.93-1.75 (4H, overlapping m, -CH2- of DACH), 1.73-1.51 (2H, m, -CH2- ), 1.49-1.25 (2H, m, -CH2-). 13C{H} NMR (100.63 MHz, CDCl3, 25 °C): δ 164.6, 164.0, 141.8, 136.3, 134.8, 134.2, 129.2, 127.6, 127.2, 121.0, 117.7, 72.8, 33.0, 24.2, 20.4. Anal. calcd (found) for C58H54N2O2Si2: C 80.33 (79.65), H 6.28 (6.16), N 3.28 (2.61).   (R,R)-(ONNtBuOtBu)InCl complex ((R,R)-1) A 50 mL round bottom flask was charged with a teflon stir bar, KCH2Ph (0.345 g, 2.65 mmol) and 10 mL of toluene. A solution of (R,R)-(ONNtBuOtBu)H2 (0.725 g, 1.33 mmol) in 15 mL of  toluene was added to the stirring slurry of KCH2Ph (0.345 g, 2.65 mmol). The resulting mixture was stirred at room temperature for 16 h. The solvent was subsequently evaporated under vacuum and the resulting solid was washed with cold hexanes and dried under vacuum to afford a yellow solid (0.781 g). This was dissolved in 15 mL of THF and added to a stirring slurry of InCl3 (0.278 g, 1.26 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 16 h. The mixture was filtered and the solution was dried under vacuum to afford a solid which was washed with cold hexanes and dried in-vacuo to yield (R,R)-1 as a yellow solid (yield: 0.763 g, 83%). 1H NMR (400.19  MHz, CDCl3, 25 °C): δ 8.42 (1H, s, N=CH), 8.21 (1H, s, N=CH), 7.51-7.50 (2H, m, ArH), 6.99 (1H, s, ArH) 6.95 (1H, s, ArH) 3.71-3.64(1H, m, -CH- ) 3.25-3.17(1H, m, -CH- ), 2.68-2.64(1H, m, -CH2-), 2.48-24.5 (1H, m, -CH2-), 2.11-2.08 (2H, m, -CH2-), 1.53-1.43 (4H, m, -CH2-) 1.50 (9H, s, Ar-C(CH3)3), 1.49 (9H, s, Ar-C(CH3)3), 71  1.31 (9H, s, Ar-C(CH3)3), 1.30 (9H, s, Ar-C(CH3)3). 13C{H} NMR (100.63 MHz, CDCl3, 25 °C): δ 171.0, 167.8, 167.0, 142.6, 142.6, 137.7, 137.6, 130.6, 129.5, 117.5, 117.3, 65.0, 63.5, 35.7, 34.0, 31.4, 29.5, 28.6, 26.9, 24.2, 23.7.  Anal. calcd (found) for C36H52N2O2InCl: C 62.21 (62.36), H 7.54 (7.45), N 4.03 (4.04).  Synthesis of rac-( ONNtBuOtBu)InCl complex (rac-1) The racemic complex rac-1 was prepared and purified in an analogous manner to (R,R)-1 from rac-(ONNtBuOtBu)H2 as a yellow solid (yield: 1.134 g,  85%). X-ray quality single crystals were obtained by crystalizing in diethyl ether for four days at –30 °C. The complex has an identical NMR signature to that of (R,R)-1. Anal. calcd (found) for C36H52N2O2InCl: C 62.21 (62.19), H 7.54 (7.50), N 4.03 (4.06).  Synthesis of (R,R)-(ONNMeOtBu)InCl ((R,R)-2) This complex (R,R)-2  was prepared and purified in an analogous manner to (R,R)-1 from (R,R)- (ONNMeOtBu)H2 as a yellow solid (yield: 0.432 g, 82%).  X-ray quality crystals were grown by slow evaporation in acetonitrile. 1H NMR (600 MHz, CDCl3, 25 °C) : δ 8.36 (1H, s, N=CH), 8.18 (1H, s, N=CH), 7.34 (2H, s, ArH), 6.95 (1H, s, ArH), 6.90 (1H, s, ArH), 3.70-3.66 (1H, m, -CH-), 3.11-3.08 (1H, m, -CH-), 2.61-2.57 (1H, m, -CH2-), 2.48-3.44 (1H, m, -CH2-), 2.30 (6H, s, Ar-CH3), 2.09-2.06 (2H, m, -CH2-), 1.57-1.41 (m, 4H, -CH2-), 1.28 (18H, br s, Ar-C(CH3)3). 13C{H} NMR (151 MHz, CDCl3, 25 °C): δ 170.6, 167.0, 166.7, 138.5, 138.3, 134.3, 133.9, 132.1, 129.1, 125.7, 116.5, 116.3, 65.2, 63.4, 33.8, 31.5, 31.5, 31.5, 27.2, 24.3, 23.9, 17.2, 17.2, 2.1. Anal. Calcd (found) for C30H40ClInN2O2:  C, 59.98(58.70); H, 6.60(6.43); N, 4.59(4.85).   72  Synthesis of (R,R)-(ONNAdOtBu)InCl ((R,R)-3)  This complex (R,R)-3 was prepared and purified in an analogous manner (R,R)-1 from (R,R)- (ONNAdOtBu)H2 as a yellow solid (yield: 0.099g, 79%). 1H NMR (600 MHz, CDCl3, 25 °C) : δ 8.43 (1H, s, N=CH), 8.18 (1H, s, N=CH), 7.45 (2H, s, ArH), 6.98 (1H, s, ArH), 6.92 (1H, s, ArH), 3.64-3.60 (1H, m, -CH- of DACH), 3.24-3.20 (1H, m, -CH- of DACH), 2.64-2.61 (1H, m, -CH2- of DACH), 2.48-2.44 (1H, m, -CH2- of DACH), 2.26-2.24 (12H, d (J3 = 6.0 Hz), -CH2- of Ad), 2.16-1.69 (20H, overlapping -CH- and –CH2- resonances of Ad and DACH), 1.52-1.42 (m, 4H, -CH2- of DACH), 1.31 (18H, br s, Ar-C(CH3)3). 13C{H} NMR (151 MHz, CDCl3, 25 °C): δ 171.9, 168.6, 167.8, 166.7, 142.6, 137.9, 137.9, 131.0, 130.5, 129.8, 129.6, 117.5, 68.0, 64.9, 63.2, 40.6, 40.5, 37.3, 37.2, 34.0, 31.3, 29.1, 27.0, 25.3, 24.2, 23.6. Anal. Calcd (found) for C48H64ClInN2O2:  C, 67.72(67.79); H, 7.58(7.75); N, 3.29(3.17).  Synthesis of rac-(ONNAdOtBu)InCl (rac-3) The racemic complex rac-(ONNAdOtBu)H2 was prepared and purified in an analogous manner to (R,R)-1 from rac-(ONNAdOtBu)H2 as a yellow solid (yield:  0.054 g,  74%). X-ray quality single crystals were obtained by crystalizing in diethyl ether for four days at –30 °C. The complex has an identical NMR signature to that of (R,R)-3. Anal. calcd (found) for C48H64ClInN2O2:  C, 67.72(67.64); H, 7.58(7.76); N, 3.29(4.60).  Synthesis of (R,R)-(ONNCumylOcumyl)InCl ((R,R)-4)  This complex (R,R)-4  was prepared and purified in an analogous manner (R,R)-1 from (R,R)- (ONNcumylOcumyl)H2 as a yellow solid (yield: 0.423 g, 79%).  1H NMR (600 MHz, CDCl3, 25 °C) : δ 8.23 (1H, s, N=CH), 8.02 (1H, s, N=CH), 7.32-7.15 (20H, overlapping peaks, ArH), 7.10 73  (2H, s, ArH), 6.88 (1H, s, ArH), 6.85 (1H, s, ArH), 3.49-3.46 (1H, m, -CH-), 3.09-3.06 (1H, m,-CH-), 2.53-2.49 (1H, m, -CH2-), 2.34-2.31 (1H, m, -CH2-), 2.04-2.00 (2H, m, -CH2-), 1.76 (3H, s, -CH3), 1.76 (3H, br s, -CH3), 1.75 (3H, br s, -CH3), 1.72 (3H, br s, -CH3), 1.70 (3H, br s, -CH3), 1.64 (12H, br s, -CH3), 1.41-1.37 (4H, m, -CH2-). 13C{H} NMR (151 MHz, CDCl3, 25 °C): δ 170.5, 166.7, 150.7, 150.6, 133.1, 132.8, 131.5, 128.0, 126.7, 126.7, 126.0, 125.6, 124.9, 124.8, 65.9, 63.1, 42.9, 42.2, 31.0, 30.8, 30.7, 29.4, 28.2, 26.9, 24.1, 23.6, 15.3. Anal. calcd (found) for C56H60ClInN2O2:  C, 71.30(70.94); H, 6.41(6.78); N, 2.97(3.18).  Synthesis of (R,R)-(ONNSiPh3OMe)InCl ((R,R)-5)  This complex (R,R)-5  was prepared and purified in an analogous manner (R,R)-1 from (R,R)- (ONNSiPh3OMe)H2 as a yellow solid (yield: 0.139 g, 79%).  1H NMR (600 MHz, CDCl3, 25 °C) : δ 8.30 (1H, s, N=CH), 8.06 (1H, s, N=CH), 7.40-6.98 (H, overlapping peaks, ArH), 3.70-3.64 (1H, m, -CH-), 3.13-3.11 (1H, m,-CH-), 2.45-2.41 (1H, m, -CH2-), 2.40-2.35 (1H, m, -CH2-),  2.11(3H, s, ArCH3), 2.09(3H, s, ArCH3), 2.06-2.02 (2H, m, -CH2-), 2.01 (2H, m, -CH2-), 1.53-1.40 (m, 4H, -CH2-). 13C{H} NMR (151 MHz, CDCl3, 25 °C): δ 147.4, 136.2, 136.1, 135.9, 134.6, 129.5, 128.2, 127.7, 121.5, 126.9, 126.9, 67.8, 62.4, 51.4, 30.7, 25.0, 23.2, 21.1, 20.2, 19.5. Anal. calcd (found) for C58H62ClInN2O2Si2: C, 68.60(68.25); H, 5.16(5.42); N, 2.76(2.10).  Synthesis of (R,R)-(ONNO)InOEt ((R,R)-6) via the salt metathesis of (R,R)-1 (Representative procedure)  A 50 mL round bottom flask was charged with a Teflon stir bar and NaOEt (0.075 g, 1.10 mmol) in toluene (10 mL). Complex (R,R)-1 (0.763 g, 1.10 mmol) was dissolved in toluene and added to the slurry of NaOEt. The mixture was stirred at room temperature for 16 h. The resulting 74  mixture was filtered through a glass-fiber filter paper and the solution evaporated under vacuum to afford a solid which was washed with cold hexanes and dried to obtain (R,R)-6 as a yellow solid (0.639 g, 82%). The one pot synthesis detailed below for the synthesis of (R,R)-7 was also used to synthesized (R,R)-6 (yield: 0.328 g, 62%)   1H NMR (400.19 MHz, CDCl3, 25 °C): δ 8.19 (1H, s, N=CH), 8.04 (1H, s, N=CH), 7.40-7.39 (1H, s, ArH), 7.38-7.37 (1H, s, ArH), 6.91-6.90 (1H, s, ArH), 6.77-6.76 (1H, s, ArH), 3.90-3.86 (1H, m, -CH-), 3.61-3.40 (2H, m, -CH2- of –OCH2CH3), 3.76-3.72(1H, m, -CH-), 2.31-2.26 (1H, m, -CH2-), 2.07-2.03 (1H, m, -CH2-), 2.00-1.94 (1H, m, -CH2- of DACH), 1.85-1.82 (1H, m, -CH2-), 1.63-1.16 (4H, m, -CH2-) 1.49 (9H, s, ArC(CH3)3), 1.30 (9H, s, ArC(CH3)3), 1.29 (9H, s, ArC(CH3)3), 1.27 (9H, s, ArC(CH3)3), 1.07 (3H, t, -CH3 of –OCH2CH3) 13C{H} NMR (100.63 MHz, CDCl3, 25 °C): δ 170.5, 168.5, 168.2, 162.7, 142.0, 141.9, 135.2, 134.6, 129.3, 129.0, 128.3, 118.1, 117.5, 68.5, 62.8, 59.0, 35.8, 35.5, 33.8, 31.4, 30.7, 29.9, 29.7, 27.3, 24.8, 24.4, 20.9. Anal. calcd (found) for C38H57N2O3In: C 64.77 (64.92), H 8.15 (7.98), N 3.98 (4.09).  Synthesis rac-(ONNtBuOtBu)InOEt (rac-6)  The racemic complex rac-6 was prepared and purified in an analogous manner from rac-1 as a yellow solid (yield: 0.932 g, 81%) Suitable crystals for X-ray diffraction were grown by crystalizing in cyclohexane for three days at -30 0C. The complex has an identical NMR signature to that of (R,R)-6. Anal. calcd (found) for C38H57N2O3In: C 64.77 (64.85), H 8.15 (8.08), N 3.98 (4.02).     75  One-pot synthesis of (R,R)-[(ONNMeOtBu)InOEt]2 ((R,R)-7) (Representative procedure) A 20 mL scintillation vial was charged with the proligand H2(ONNMeOtBu) (0.100 g, 0.216 mmol), InCl3 (0.048 g, 0.216 mmol), 3 mL toluene, and a magnetic stir bar. The mixture was stirred for 30 minutes and a suspension of 6 equiv. NaOEt (0.088 mg, 1.3 mmol) in 4 mL of toluene was added to the reaction. The mixture was allowed to stir at room temperature overnight, and filtered using glass filter paper. The solvent was removed under vacuum to yield a yellow solid (0.087 g, 65%). Salt metathesis of (R,R)-2 was also used in the synthesis of this complex (yield: 0.088 g, 78%).  1H NMR (600 MHz, CDCl3, 25 °C): δ 8.22 (1H, s,  N=CH), 7.97 (1H, m, N=CH), 7.27 (1H, s, ArH), 7.21 (1H, s, ArH), 6.85 (1H, s, ArH), 6.78 (1H, s, ArH), 3.62 (1H, m, -CH2-), 3.37-3.28 (2H,  m, -CH2- of -OCH2CH3), 2.82-2.79 (1H, m, -CH-), 2.26 (3H, s, ArCH3), 2.14 (3H, m, ArCH3), 1.93-1.91 (1H, -CH2-), 1.85-1.83 (1H, m,  -CH2-), 1.77 (1H, -CH2-), 1.44–1.42 (1H, m, -CH2-), 1.33-1.20 (3H, m, -CH2-) 1.32 ( 3H, t(J3 = 6.7 Hz), -OCH2CH3), 1.27 (9H, s, ArC(CH3)3), 1.27 (9H, s, ArC(CH3)3), 1.07–1.03 (1H, m, -CH2-).13C{H} NMR (151 MHz, CDCl3, 25 °C): δ 170.5, 168.2, 167.3, 163.0, 135.9, 135.7, 132.7, 132.2, 131.7, 131.6, 129.2, 128.6, 128.4, 126.9, 125.4, 117.6, 116.4, 68.5, 62.8, 59.9, 33.7, 31.6, 31.6, 27.2, 24.8, 24.7, 20.6, 17.8, 17.2. Anal. Calcd (found) for C32H45InN2O3: C 61.94(60.78); H 7.31(7.27); N 4.51(3.95).                      Synthesis of (R,R)-[(ONNAdOtBu)InOEt]2 ((R,R)-8) (R,R)-8 was synthesized via the salt metathesis of (R,R)-3 as a yellow solid (yield: 0.139 g, 79%) and the one pot synthesis with (R,R)-(ONNAdOtBu)H2 (0.097 g, 56%).  1H NMR (600 MHz, CDCl3, 25 °C): δ 8.13 (1H, s,  N=CH), 8.03 (1H, m, N=CH), 7.43 (1H, s, ArH), 7.31 (1H, s, ArH), 6.90 (1H, s, ArH), 6.78 (1H, s, ArH), 3.88-3.77 (1H, m, -CH-), 3.76-3.61 (2H,  m, -CH2- 76  of -OCH2CH3), 2.74-2.68 (1H, m, -CH-), 2.36-1.15 (38H overlapping signals Ad and –CH2- of DACH), 1.31 (9H, s, Ar(CH3)3), 1.27 (9H, s, ArC(CH3)3), 1.07 ( 3H, t(J 3 = 6.3 Hz), -OCH2CH3). 13C{H} NMR (151 MHz, CDCl3,  25 °C): δ 171.6, 169.3, 168.7, 162.5, 142.3, 141.8, 135.7, 134.5, 130.0, 129.5, 129.0, 128.2, 127.8, 125.3, 118.1, 118.0, 69.8, 62.6, 60.3, 40.6, 40.4, 37.2, 37.1, 33.9, 31.3, 29.1, 27.5, 24.7, 20.7. Anal. Calcd (found) for C50H69InN2O3: C 69.76(66.13); H 8.08(7.98); N 3.39(3.25).  Synthesis of (R,R)-[(ONNCumylOCumyl)InOEt]2 ((R,R)-9) (R,R)-9 was synthesized via the salt metathesis of (R,R)-4 as a yellow solid (yield: 0.256 g, 75%) and the one pot synthesis with (R,R)-(ONNcumylOcumyl)H2 (0.097 g, 59%).  1H NMR (400 MHz, CDCl3, 25 °C): δ 7.86 (1H, s,  N=CH), 7.82 (1H, m, N=CH), 7.38-7.34 (2H, m, ArH), 7.28-7.05 (14H, overlapping signals, ArH), 6.98-6.94 (2H, m, ArH), 6.71 (1H, s, ArH), 6.70-6.64 (2H, m, ArH), 6.62 (1H, s, ArH), 6.54-6.50 (2H, m, ArH), 3.81-3.73 (1H, m, -CH-), 3.51 (2H,  q, -CH2- of -OCH2CH3), 2.46-2.42 (1H, m, -CH-), 2.13 (3H, s, -CH3), 2.05-2.01 (1H, m, -CH2-), 1.93 (3H, s, -CH3), 1.88-1.83 (1H, m, -CH2-), 1.70 (3H, s, -CH3), 1.64 (3H, s, -CH3), 1.64 (3H, s, -CH3), 1.51 (3H, s, -CH3), 1.50 (3H, s, -CH3), 1.45 (3H, s, -CH3)  1.75-1.19 (6H, overlapping signals  -CH2- of DACH), , 1.09 ( 3H, t(J 3 = 3.2 Hz), -OCH2CH3). 13C{H} NMR (151 MHz, CDCl3, 25 °C): δ 171.4, 168.5, 167.7, 161.8, 151.6, 151.2, 150.7, 150.2, 141.8, 141.6, 134.7, 133.7, 131.6, 131.5, 129.4, 127.8, 127.8, 126.6, 126.5, 125.2, 123.6, 118.2, 118.0, 68.9, 62.6, 59.3, 44.2, 42.2, 42.0, 41.7, 31.6, 30.9, 30.7, 30.4, 27.7, 26.4, 24.5, 24.4, 21.1. Anal. Calcd (found) for C58H65InN2O3: C 73.10(71.32); H 6.88(6.36); N 2.94 (2.72).    77  Synthesis of (R,R)-[(ONNBrOtBu)InOEt]2 ((R,R)-10) (R,R)-10 was synthesized using the one pot synthesis with (R,R)-(ONNBrOtBu)H2 as a yellow solid (0.178 g, 69%). 1H NMR (400 MHz, CDCl3, 25 °C):  δ 8.23 (1H, s,  N=CH), 7.94 (1H, m, N=CH), 7.72 (1H, s, ArH), 7.68 (1H, s, ArH), 7.01 (1H, s, ArH), 6.91 (1H, s, ArH), 3.67-3.65 (1H, m, -CH2-), 3.66-3.41 (2H,  m, -CH2- of -OCH2CH3), 2.89-2.85 (1H, m, -CH-), 2.33-2.29 (1H, -CH2-), 1.89-1.83 (3H, m,  -CH2-), 1.50-1.19 (4H, overlapping peaks, -CH2-), 1.48 (3H, t (J3 = 3.6 Hz), -OCH2CH3), 1.29 (9H, s, ArC(CH3)3), 1.26 (9H, s, ArC(CH3)3). 13C{H} NMR (151 MHz, CDCl3, 25 °C): δ 170.4, 164.2, 163.6, 162.8, 137.7, 137.4, 135.3, 130.7, 128.9, 128.2, 119.3, 118.8, 118.4, 117.7, 68.5, 62.8, 60.7, 33.7, 31.3, 31.0, 28.1, 24.5, 24.4, 20.8. Anal. Calcd (found) for C30H39Br2InN2O3: C 48.03 (48.39); H 5.24 (5.16); N 3.73 (3.73).  Synthesis of potassium pyridin-2-ylmethoxide (KOCH2Pyr) A 20 mL scintillation vial was charged was charged with 2-pyridine methanol (0.629 g, 5.76 mmol), 7 mL of THF and a Teflon stir bar. In a separate 20 mL vial KOtBu (0.647 g, 5.76 mmol) was dissolved in 7mL of THF. The KOtBu solution was added slowly to the stirring 2-pyridine methanol solution. After ~10 min of stirring, a light grey precipitate can be observed.  The reaction was allowed to stir for 16 h. The reaction was allowed to settle, and the dark green solution was decanted to isolate a grey colored solid. This solid was repeatedly washed with hexanes, until the washings were colorless. Then the solid was dried in vacuo to give KOCH2Pyr a white powder (yield: 0.780 g, 92%).  1H NMR (600 MHz, THF-d8, 25 °C): δ 8.35 (1H, br s, ArH(Pyr)), 7.52 (1H, t(J3 = 5.6 Hz), ArH(Pyr)), 7.38-7.35 (1H, m, ArH(Pyr)), 6.99-6.97 (1H, m, ArH(Pyr)), 6.98 (1H, br s, -CH2-). We were unable to get 13C{H} data for the compound due to 78  poor solubility in common solvents. Anal. Calcd (found) for C6H6NOK: C 48.95(48.61); H  4.11(4.86); N  9.51(8.78).  Synthesis of (R,R)-[(ONNtBuOtBu)InOCH2Pyr ((R,R)-11) Complex (R,R)-1 (0.124 g, 0.178 mmol) was dissolved in toluene and added to a slurry of potassium pyridin-2-ylmethoxide (0.027 g, 0.183 mmol) in toluene. The mixture was stirred at room temperature for 16 h. The resulting mixture was filtered and the solution evaporated under vacuum to afford a yellow solid (yield: 0.105 g, 77%). Yellow coloured X-ray quality crystals were obtained by crystallizing from hexanes at ambient temperature. 1H NMR (600.15  MHz, CDCl3): δ 8.66-8.65 (1H, d, ArH(pyr)), 8.31 (1H, s, N=CH), 8.14 (1H, s, N=CH), 7.70-7.67 (1H, m, ArH(pyr)), 7.46 (1H, s, ArH), 7.30 (1H, s, ArH), 7.21-7.18 (1H, m, ArH(pyr)), 7.15-7.11 (1H, m, ArH(pyr)), 5.02(2H, s, -CH2- of –OCH2Pyr), 4.29-4.24(1H, m, -CH- ), 3.03-2.98(1H, m, -CH-), 2.54-2.49 (1H, m, -CH2- of DACH), 2.24-2.21 (1H, m, -CH2- of DACH), 2.05-1.98 (2H, m, -CH2- of DACH), 1.74-1.69 (1H, m, -CH2- of DACH), 1.60-1.56 (2H, m, -CH2- of DACH), 1.49 (9H, s, Ar-C(CH3)3),  1.42-1.35 (1H, m, -CH2- of DACH), 1.30 (9H, s, Ar-C(CH3)3), 1.27 (9H, s, Ar-C(CH3)3), 1.19 (9H, s, Ar-C(CH3)3). 13C{H} NMR (150.91 MHz, CDCl3): δ 169.1, 168.7, 168.1, 165.5, 164.6, 147.6, 141.2, 141.1, 138.1, 135.4, 135.0, 129.9, 129.3, 128.8, 128.5, 121.8, 121.4, 118.2, 117.8, 67.4, 64.9, 63.9, 35.8, 35.2, 33.0, 31.4, 30.0, 29.6, 29.3, 27.2, 24.8, 23.8. Anal. calcd (found) for C42H58N3O3In: C 65.71 (66.02), H 7.61(7.78), N 5.47(5.83).  Synthesis of (R,R)-[(ONNSiPh3OMe)InOCH2Pyr ((R,R)-12) Complex (R,R)-12 was synthesized via the salt metathesis of (R,R)-4 (yield: 0.069 g, 51%). The red solid obtained was further purified by washing with acetonitrile and dried under vacuum. 79  However, minor impurities could still be observed in the 1H NMR spectrum. . 1H NMR (600.15  MHz, CDCl3): δ 8.26 (1H, s, N=CH), 7.94 (1H, s, N=CH), 7.80-6.74 (37H, overlapping peaks, ArH(pyr) and ArH (-SiPh3)), 6.22-6.19 (1H, m, ArH(pyr)), 4.56 (1H, d (J2 = 20 Hz), -CH2- of –OCH2Pyr), 4.38-4.34(1H, m, -CH- ), 4.03 (1H, d (J2 = 20 Hz), -CH2- of –OCH2Pyr), 2.92-2.85(1H, m, -CH-), 2.30-1.28.49 (8H, overlapping multiplets , -CH2- of DACH), 2.17 (3H, s, ArCH3), 2.05 (3H, s, ArCH3), 13C NMR (151 MHz, CDCl3, 25 °C): 165.2, 164.0, 159.0, 148.1, 145.8, 141.1, 139.3, 138.0, 137.4, 135.1, 135.9, 135.7, 134.6, 134.4, 128.6, 127.8, 127.2, 126.7, 124.8, 122.0, 121.6, 120.8, 120.4, 120.0, 65.4, 63.6, 32.6, 30.8, 24.4, 23.4, 21.0, 20.1, 20.0, 19.7, 13.7. 13C{H} resonances cannot be identified with great confidence due to the presence of impurities and overlapping signals.     Synthesis of (R,R)-[(ONNBrOtBu)InOCH2Pyr ((R,R)-13) A 20 mL scintillation vial was charged with the proligand H2(ONNBrOtBu) (0.037 g, 0.063 mmol), anhydrous InCl3 (0.019 g, 0.094 mmol), 2 mL toluene and a magnetic stir bar. This was allowed to stir for 30 min and a suspension of 5 equiv. of potassium pyridin-2-ylmethoxide (0.047 g, 0.31 mmol) in 2 mL toluene was added to the reaction. The mixture was stirred at room temperature for 16h, and the remaining salt was filtered off using a glass filter paper. The solution was then evaporated under vacuum to afford a yellow solid. This was further purified with successive washings with hexanes to remove any residual 2-pyridinemethanol and dried in vacuo.  (yield: 0.026 g, 51%).  δ 9.50-9.48 (1H, d, ArH(pyr)), 8.58-8.57 (1H, d, ArH(pyr)) 8.33 (1H, s, N=CH), 8.13 (1H, s, N=CH), 7.75-7.68 (2H, m, ArH(pyr)), 7.65 (1H, s, ArH), 7.57 (1H, s, ArH), 7.04 (1H, s, ArH), 6.99 (1H, s, ArH), 4.77(2H, s, -CH2- of –OCH2Pyr), 4.41-4.35(1H, m, -CH- of DACH), 3.12-3.08(1H, m, -CH- of DACH), 2.37-2.30 (1H, m, -CH2- of DACH), 80  2.09-2.02 (1H, m, -CH2- of DACH), 1.84-1.77 (2H, m, -CH2- of DACH), 1.71-1.44 (4H, m (overlapping), -CH2- of DACH), 1.25(9H, s, ArC(CH3)3), 1.23 (9H, s, ArC(CH3)3). 13C{H} NMR (150.91 MHz, CDCl3): δ 169.1, 164.1, 163.7, 163.2, 148.6, 138.2, 137.9, 137.6, 134.7, 134.5, 130.7, 130.2, 122.3, 120.7, 118.8, 118.2, 117.8, 67.4, 64.5, 63.7, 33.7, 31.3, 29.9, 27.4, 24.7, 23.7. Anal. Calcd (found) for C34H40Br2InN3O3: C 50.21(50.78); H 4.96 (5.06); N 5.17(6.51).  Representative procedure for crossover experiment  In two 20 mL scintillation vials (R,R)-6 (5.2 mg, 3.7×10−3 mmol) and (R,R)-8 (6.3 mg, 3.7× 10−3 mmol) were weighed separately. A volume of 0.3 mL of CD2Cl2 was added to each vial and the contents were mixed inside Teflon sealed J-young tube and taken to the NMR spectrometer immediately to acquire spectra.  Procedure for reaction of pyridine with (R,R)-6 In a 20 mL scintillation vial, (R,R)-6 (10 mg, 7×10−3 mmol) was dissolved in neat pyridine (5 mL) and the solution was transferred to Teflon capped flask with a stir bar. The flask was taken out of the glove box, stirred under reflux for 16 h. Thereafter the reaction was dried under vacuum and a NMR sample was prepared of the contents in CDCl3 and a 1H NMR was acquired.  Procedure for reaction of ethyl acetate with (R,R)-6 A 20 mL scintillation vial was charged with (R,R)-6 (10 mg, 7×10−3 mmol), ethyl acetate and a Teflon stir bar. The reaction was allowed to stir at room temperature for 16 h. Thereafter the 81  reaction was dried under vacuum and a NMR sample was prepared of the contents in CDCl3 and a 1H NMR was acquired.  Representative procedure for sample preparation for PGSE NMR spectroscopy rac-6  In a 1 mL volumetric flask 6.2 mg of (rac-6) (0.0044 mmol, 0.0044 M) was made with a solution of tetrakis(trimethylsilyl)silane (TMSS) (0.94 mM in CD2Cl2). TMSS is used as an internal standard. A 0.5 mL volume of this solution of rac-6 in TMSS was transferred into a NMR tube, which was sealed with a Teflon cap for spectroscopy.           82  Chapter 3: Chiral indium salen complexes in lactide polymerization2  3.1 Introduction As mentioned in chapter 1 the development of industrially relevant, highly isoselective catalysts for the ring-opening polymerization (ROP) of lactide remains a challenge. Site selective aluminum complexes bearing chiral tetradentate salen ligands (I.35 and I.36) are by far the most successful systems in generating desirable, high melting isotactic or isotactic stereoblock poly(lactic acid) (PLA) from racemic lactide (rac-lactide) (Scheme 3.1).29,40,96,98,101-102  Scheme 3.1. Highly site selective aluminum salen complexes for lactide polymerization   The majority of highly active achiral catalysts capable of chain-end control produce low value, amorphous heterotactic PLAs.41,43-44  Notable exceptions are achiral aluminum complexes                                                  2 This work has been partially published in the journal Chemical Communications. A manuscript, detailing the remainder of the work is in preparation. This work is also patent protected.   83  (Example: I.42)108,112-113 as well as organocatalysts172-174 that generate isotactically enriched PLA via chain-end control.  These systems can suffer from low polymerization rates and require elevated temperature. More recently Williams et al. reported several highly active and isoselective rare-earth metal catalysts (Example: I.67) with achiral phosphasalen ligands.129-130   Figure 3.1. Examples of isoselective catalysts for lactide polymerization with chain-end control However, systems with chain-end control inherently propagate stereoerrors that hinders the formation of true block copolymers (Figure 3.2). In contrast, enantiomorphic site control localizes stereoerrors.40,104  Figure 3.2. Schematic diagram of the nature of stereoerrors in chain-end control and enantiomorphic site control mechanisms   Despite their high selectivity, chiral aluminum catalysts suffer from low reactivity and require hours to days at elevated temperatures to achieve high conversions in polymerization 84  reactions.96,101  In response, we have become interested in indium complexes as catalysts for ROP of cyclic esters.66,67  Although indium complexes bearing tetradentate diimino-diol “salen” ligands have been known for a long time,149-150,152 the first indium salen catalyst for the ROP of lactide was reported only recently (See chapter 2, introduction).  These indium complexes, bearing chiral and achiral salen type ligands,105,122 showed low selectivity and sluggish reactivity, compared to aluminum analogues.118,175 The poor results were attributed to the larger ionic radius of indium. However, factors affecting stereoselectivity can be more nuanced with subtle ligand modifications having a profound impact. Studies investigating the impact of aromatic substituents on stereoselectivity and reactivity with achiral aluminum salen catalysts have been reported. In one such study, Gibson et al. found that such substituent effects are highly system dependent and often unpredictable in their impact of stereoselectivity (Figure 3.3).  Figure 3.3. Substituent effects on isoselectivity in achiral aluminum salen complexes reported by Gibson et al.  In compounds I.94-I.95 bulkier substituents improved isoselectivity. However, in compounds 1.96-I.97 which contain a biphenyl backbone, the opposite trend was observed. This suggests 85  that ligand design can play a crucial role in improving the low stereoselectivity for ROP of lactide observed with indium catalysts.      In this chapter we discuss the reactivity of dinuclear and mononuclear indium-ethoxide complexes bearing chiral salen ligands that show an unprecedented combination of site selectivity, high activity, and polymerization control at high molecular weights for the ring opening polymerization of rac-lactide to form isotactic stereogradient PLA. Furthermore, studies into ligand substitution effects on reactivity and selectivity are presented.    3.2 Results Lactide polymerization with rac- and (R,R)-[(ONNtBuOtBu)InOEt]2 complexes. Due to the highly stereoselective catalytic activity of its aluminum analogue towards lactide polymerization, we initially decided to probe the utility of rac- and (R,R)-[(ONNtBuOtBu)InOEt]2 (rac- and (R,R)-6) (Figure 3.4) for the same reaction.  Figure 3.4. rac- or (R,R)-[(ONNtBuOtBu)InOEt]2 (rac- or (R,R)-6) Rac- and (R,R)-6 are highly active catalysts for the ring opening polymerization of rac-lactide.  Reaction of rac-6 (~2 mM) with 200 equiv. of rac-lactide (25 °C, CH2Cl2) results in 97 86  % conversion in under 30 minutes. Polymerizations with (R,R)-6 show full conversions in ~ 1 hour under similar conditions.  Polymerization of up to 1000 equiv. of rac-lactide with rac-6 is complete in less than 4 hours and shows a linear relationship between Mn and added monomer as well as low molecular weight distributions indicative of a controlled system (Figure 3.5). Polymerization can also be done in the melt at 130 °C with 97% conversion obtained in under 10 min.  This is faster, by far, than any known chiral aluminum system, which shows similar conversions at 70 °C in 14 hours to 4 days.29,40,96,98,101-102 The rate of polymerization is first order in lactide concentration (Figure 3.6) with kobs values comparable to the best reported indium complexes (Table 3.1).66-67  The polymer molecular weights correspond to the lactide:ethoxide ratio and thus are consistent with initiation from each alkoxide in complex 6.       87   Figure 3.5. Plot of observed PLA Mn () and molecular weight distribution (■) as functions of lactide:ethoxide in polymerizations with rac-6 (Mn = number averaged molecular weight, PDI = polydispersity index).  The line indicates calculated Mn values based on the lactide:ethoxide ratio.  All reactions were carried out at room temperature in CH2Cl2 and polymer samples obtained at 99% conversion.    Polymerization of rac-lactide with (R,R)-6 (25 °C, CH2Cl2) yields isotactic polymer (Pm > 0.75) as determined by 1H{1H} NMR spectroscopy.  This is the highest selectivity obtained for an indium catalyst to date, leading to crystalline PLA with a melting temperature of 140 °C.  As noted above, other indium catalysts have produced only amorphous polymer.  11.21.41.61.822.22.42.62.830204060801001201401600 200 400 600 800 1000Mn (× 103) g mol-1 (    ) PDI (    ) Monomer/initiator 88   Figure 3.6. The ROP plots of 200 equiv. of [lactide (LA)] vs. [initiator].  All reactions were carried out in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. [Catalyst] = 0.0011 M, [LA] = 0.45 M. The value of kobs was determined from the slope of the plots of ln([LA]/[TMB]) vs. time (TMB = 1,3,5-Trimethoxybenzene).    To probe the mechanism of selectivity further, the rates of polymerization of rac-, D-, and L-lactide with rac- and (R,R)-6 were determined (Table 3.1).  First order plots with respect to lactide concentration show a brief initiation period followed by a linear propagation region (Figure 3.6). There is a five-fold difference in the rate of polymerization of L- and D-lactide with (R,R)-6 (Table 3.1, entries 1 and 2).  The kobs value for ROP of rac-lactide with (R,R)-6 is identical to that of D-lactide, indicating that the polymerization is significantly hampered by the presence of D-lactide.  Polymerization of rac-lactide with rac-6 also yields isotactic polymers (Pm ~ 0.74), however the kobs values for polymerizations of rac-, D- and L-lactide with rac-6 are the same, as expected .  The kL-LA/kD-LA (5) for (R,R)-6 is lower than that for the less active aluminum-salen systems (20), but is nonetheless significant and supports site control as the major contributor to selectivity.101,40  0.511.522.50 2000 4000L-LA vs. (R,R)-6D-LA vs. (R,R)-6Rac-LA vs. (R,R)-6Ln{[LA]/[TMB]} Time (sec.) 00.511.522.50 500 1000D-LA vs Rac-6L-LA vs Rac-6Rac-LA vs Rac-6Ln{[LA]/[TMB]} Time (sec.) 89  Table 3.1. Rate constants for the polymerization of rac-, L- and D-lactide (LA) with rac- and     (R,R)-6 Entry Catalysta Monomerb kobs ( 10–4 s–1) 1 (R,R)-6 D-LA 4.3(9) 2 (R,R)-6 L-LA 22(5) 3 (R,R)-6 rac-LA 4.6(9) 4 rac-6 rac-LA 23(5) 5 rac-6 D-LA 22(5) 6 rac-6 L-LA 26(5) All reactions were carried out with 200 equiv of lactide in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. a [Catalyst] = 0.0011 M, b [Lactide] = 0.45 M.    During the polymerization of rac-lactide with (R,R)-6, the tacticity of the polymer varies in a narrow range (Pm = 0.77 – 0.65) with conversion.  The plot of Pm vs. conversion shows the highest Pm values at <20% and >95% conversion, and the lowest value at 50% conversion (Figure 3.7).  In a site selective catalyst such as (R,R)-6, the preferred monomer (L-lactide) is consumed initially, leading to an L-enriched polymer chain with a high Pm value.  As L-lactide is depleted, more D-lactide is incorporated and the Pm value is lowered.  At higher conversions the concentration of L-lactide is depleted and thus the polymer is composed of predominantly D-lactide, thus the Pm values increase.  This is a clear indication for the formation of a stereogradient polymer. In contrast, when rac-6 is used no significant change in polymer tacticity is observed (Figure 3.7). Both enantiomers of the catalyst are present in rac-6, hence there is no preferential consumption of either D-lactide or L-lactide during any stage of monomer conversion.  This is identical behavior to the aluminum analogues; however, polymerization occurs at much higher rates. 90    Figure 3.7. Plot of Pm vs. conversion for polymerization of rac-lactide with a: (top) (R,R)-6; b: (bottom) rac-6.  Depicted with estimated 5% error bars.   Matrix-assisted laser desorption ionization-time of flight mass spectrometry or MALDI-TOF of oligomeric PLA chains formed with (R,R)-6 shows peaks, separated by m/z ~72 units, indicating extensive transesterification between growing polymer chains (Figure 3.8). This is an explanation for the >1.2 PDIs observed for this system. This is similar to what was observed by Spassky et al. for aluminium salbinap catalysts.97 However it is noteworthy that in the aluminium 0.60.650.70.750.80 20 40 60 80 100% Conversion Pm 0.60.650.70.750.80 20 40 60 80 100Pm     % Conversion  91  analogue bearing a Jacobsen salen ligand showed peaks separated by m/z ~ 144 units indicating minimum chain transfer. 102   Figure 3.8. MALDI-TOF mass spectrum of a PLA oligomer grown with (R,R)-6.  Following this detailed study of lactide polymerization behavior with rac- and (R,R)-6 we decided to investigate the effect of changing the ortho-aryl substituents on polymerization with the (R,R)-[(ONNR1OR2)InOEt]2 complexes discussed in chapter 2.  As previously mentioned, in achiral aluminum salen complexes ligand substitution effects play a crucial role in stereoselectivity. With the potential for similar trends in our indium system we set out to systematically investigate the impact of steric bulk of the ortho substituent compared to (R.R)-6 on lactide polymerization.  92   Figure 3.9. Complexes (R,R)-[(ONNBrOtBu)InOEt]2 (R,R)-10 and (R,R)-[(ONNMeOtBu)InOEt]2 (R,R)-7 Impact of decreased steric hindrance. To investigate the role of decreased hindrance in our system, compounds (R,R)-[(ONNBrOtBu)InOEt]2 ((R,R)-10) and (R,R)-[(ONNMeOtBu)InOEt]2  ((R,R)-7) are used (Figure 3.9). Polymerizations of rac-lactide with these catalysts show a slight decrease in reactivity and a significant drop in selectivity (Table 3.2).            93  Table 3.2. Polymerization of rac-lactide with (R,R)-10 and (R,R)-7  Catalysta Time (h) Convb (%) Mntheo (kDa) MnGPCc (kDa) PDI Pm 1 (R,R)-10 2  97 27.9 52.9 1.15 0.54 2 (R,R)-10 5 99 71.3 97.0 1.35 0.56 3 (R,R)-7 2 98 28.2 47.5 1.19 0.60 4 (R,R)-7 5 99 71.3 91.7 1.29 0.61 aIn CH2Cl2 at 25 °C, [catalyst] ≈ 1 mM. bConversions were determined by 1H NMR spectroscopy. Mntheo = molecular weight of chain-end + 144 gmol–1 × 200 × conversion.  cIn THF (2 mg mL–1) and molecular weights were determined by GPC-LLS (flow rate = 0.5 mLmin–1.) Universal calibration was carried out with polystyrene standards, laser light scattering detector data, and concentration detector. Each experiment is duplicated to ensure accuracy.     Both (R,R)-10 and (R.R)-7 (~1 mM), polymerize 200 equiv. of rac-lactide in ~120 minutes. This is longer than the time required for (R,R)-6 to carry out the same transformation under identical conditions (60 minutes). Furthermore, both catalysts generate polymers with higher than expected molecular weights (Table 3.2). Another difference from (R,R)-6 is the loss of the high isotactic bias. This suggests that the steric bulk at the ortho positions of the salicylaldehyde moieties play a key role in imparting stereoselectivity as decreasing the size of the ortho functionality diminishes isoselectivity. A similar observation was made by Carpentier et al. in a series of aluminum salen catalysts with a chiral diphenyl ethylene backbone for lactide polymerization, where changing the ortho substituent from tert-butyl group to a methyl functionality decreased the isoselectivity from Pm ~0.9 to ~0.8.105 The 500 equiv. polymerizations of lactide appear to have higher PDIs compared to the 200 equiv. polymerizations. This could be due to more extensive transesterification reactions for longer polymerizations. Polymerization reactions that are not quenched after full conversion can undergo depolymerization, which would also affect the molecular weights and PDIs.   94       To probe the polymerization process further, kinetic studies were carried out with (R,R)-7 and (R,R)-10 (Figure 3.10). First order plots for the ROP of L-, D- and rac-lactide with both catalysts show a long initiation period compared to (R,R)-6. While a brief initiation period can be observed in the first order kinetic plots of (R,R)-6, it is much longer in (R,R)-7 and is prolonged further in (R,R)-10. This is consistent with the higher than expected molecular weights of the polymers generated. This initiation period will be discussed in detail in a mechanistic discussion later.   Figure 3.10. The ROP plots of 200 equiv. of [lactide (LA)] vs. [initiator] for (R,R)-10 (left) and (R,R)-7 (right).  All reactions were carried out in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. [Catalyst] = 0.0011 M, [LA] = 0.45 M. The value of kobs was determined from the slope of the plots of ln([LA]/[TMB]) vs. time (TMB = 1,3,5-Trimethoxybenzene).   While no rate constants are calculated due to the curved nature of the plots, (R,R)-10 does not show marked preference for one enantiomer of lactide over the other. This is consistent with the atactic nature of the polymers generated (Pm ~ 0.55). Complex (R,R)-7, which generates PLA 00.511.522.530 5000 10000D-LAL-LArac-LALn{[LA]/[TMB]} 00.511.522.530 2000 4000 6000DLAL-LArac-LALn{[LA]/[TMB]} Time (sec.) 95  with modest isotacticity (Pm ~ 0.60) shows a modest preference for the polymerization of L-lactide.    Figure 3.11. Complexes (R,R)-[(ONNAdOtBu)InOEt]2 (R,R)-8 and (R,R)-[(ONNcumylOcumyl)InOEt]2 (R,R)-9   Impact of increased steric hindrance. To evaluate the impact of increased steric bulk of ligands, compounds (R,R)-[(ONNAdOtBu)InOEt]2 ((R,R)-8) and (R,R)-[(ONNcumylOcumyl)InOEt]2 ((R,R)-9) are used (Figure 3.11).         96  Table 3.3. Polymerization of rac-lactide with (R,R)-8 and (R,R)-9  Catalysta Time (h) Convb (%) Mntheo (kDa) MnGPCc (kDa) PDI Pm 1 (R,R)-8 1 98 28.2 36.3 1.42 0.76 2 (R,R)-8 2 99 71.3 69.4 1.33 0.74 3 (R,R)-9 2 97 27.9 27.9 1.56 0.73 4 (R,R)-9 5 98 70.6 79.0 1.42 0.71 aIn CH2Cl2 at 25 °C, [Catalyst] ≈ 1 mM. bConversions were determined by 1H NMR spectroscopy. Mntheo = molecular weight of chain-end + 144 gmol–1 × 200 × conversion.  cIn THF (2 mg mL–1) and molecular weights were determined by GPC-LLS (flow rate = 0.5 mLmin–1.) Universal calibration was carried out with polystyrene standards, laser light scattering detector data, and concentration detector. Each experiment is duplicated to ensure accuracy.  Catalyst (R,R)-8 shows similar reactivity and isoselectivity (Pm ~ 0.75) to (R,R)-6. The experimental molecular weights of the polymers generated match the experimental molecular weights and molecular weight distributions between 1.3-1.5 are obtained. This indicates a well-controlled system for lactide polymerization. Complex (R,R)-9 requires longer durations for rac-lactide polymerization compared to (R,R)-6 and (R,R)-8. This may be due to a more sterically congested ligand environment which hinders the approach of lactide to the metal centre. Gel permeation chromatographic (GPC) analysis of the polymers show excellent molecular weight control and similar polydispersities to (R,R)-6. PLA generated by (R,R)-9 shows a slight decrease in isotactic enrichment compared to polymers generated with (R,R)-6, which can be due to chain-end control hindering the isoselectivity generated via enantiomorphic site control.           97   Figure 3.12. The ROP plots of 200 equiv of [lactide (LA)] vs. [initiator] for (R,R)-8 (left) and (R,R)-9 (right).  All reactions were carried out in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. [Catalyst] = 0.0011 M, [LA] = 0.45 M. The value of kobs was determined from the slope of the plots of ln([LA]/[TMB]) vs. time (TMB = 1,3,5-Trimethoxybenzene).   The first order kinetics plots of the polymerization process shows (R,R)-8 with a very similar profile to that of (R,R)-6 (Figure 3.12). A brief initiation period followed by a linear propagation region is seen, with (R,R)-8 polymerizing L-lactide rapidly over D-lactide. In contrast, while plots with (R,R)-9 show a similar preference for L-lactide, the initiation period is not observable. This observation, in conjunction with the prolonged initiation periods observed for the least bulky (R,R)-10 and (R,R)-7, suggests that the bulkier complexes undergo more facile initiation. The calculated rate constants show a kL-LA/kD-LA of 4 and 6 respectively for (R,R)-8 and (R,R)-9 (Table 3.4). The kinetics confirm the lower rates of propagation for (R,R)-9 compared to both (R,R)-6 and (R,R)-8.           00.511.522.530 1000 2000 3000L-LAD-LArac-LA00.511.522.50 5000 10000D-LArac-LAL-LA98  Table 3.4. Rate constants for polymerization of rac-, L- and D-lactide (LA) with (R,R)-8 and     (R,R)-9 Entry Catalysta Monomerb kobs ( 10–4 s–1) 1 (R,R)-8 D-LA 9.4(19) 2 (R,R)-8 L-LA 38(8) 3 (R,R)-8 rac-LA 9.4(19) 4 rac-9 D-LA 2.4(5) 5 rac-9 L-LA 14(3) 6 rac-9 rac-LA 2.7(5)  All reactions were carried out with 200 equiv. of lactide in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. a [Catalyst] = 0.0011 M, b [lactide] = 0.45 M.   Nature of catalytically active propagating species. In order to understand polymerization behavior of the dinuclear indium catalysts we needed to determine the nuclearity of the propagating species. We decided to use mononuclear complex (R,R)-(ONNtBuOtBu)InOCH2Pyr ((R,R)-11) (Figure 3.13) to probe this. Our initial hypothesis was that if a dinuclear complex and its mononuclear analogue shows the same reactivity and selectivity this would be consistent with both systems having a similar catalytic species. First we investigated the polymerization behavior of (R,R)-11. The polymerization of up to 1000 equiv. lactide shows experimental molecular weights consistent with expected values (Figure 3.14). This was similar to the dinuclear analogue (R,R)-6, albeit with slightly lower PDIs.     99   Figure 3.13. Mononuclear indium salen alkoxide complexes investigated   Figure 3.14. Plot of observed PLA Mn () and molecular weight distribution (■) as functions of lactide:ethoxide in polymerizations with (R,R)-11 (Mn = number averaged molecular weight, PDI = polydispersity index).  The line indicates calculated Mn values based on the LA:ethoxide ratio.  All reactions were carried out at room temperature in CH2Cl2 and polymer samples obtained at >90% conversion.  11.21.41.61.822.22.42.62.830204060801001201400 200 400 600 800 1000Mn (× 103) g mol-1 (    ) PDI (    ) Monomer/initiator 100   Analysis of these polymers show an isoselectivity of Pm ~ 0.75, which is very similar to what is observed in polymers that are made with (R,R)-6. The MALDI –TOF spectrum of PLA oligomers made with (R,R)-11 shows peaks corresponding to [H(C3H4O)n(OC6H7N)H]+ (i.e. m/z for [H(C3H4O)11(OC6H7N)H]+ ~ 903) separated by m/z ~ 72 (Figure 3.15). This is similar to what was observed in PLA oligomers generated by (R,R)-6. The Polymerization data are consistent with both (R,R)-6 and (R,R)-11 having similar catalytically active propagating species.   Figure 3.15. MALDI-TOF mass spectrum of a PLA oligomer grown with (R,R)-11.  Polymerization of rac-lactide with the mononuclear indium salen alkoxide complex (R,R)-(ONNBrOtBu)InOCH2Pyr ((R,R)-13) shows similar selectivity (Table 3.5, entries 1-2) to (R,R)-[(ONNBrOtBu)InOEt]2 (R,R)-10 (Pm ~ 0.55). In contrast to the higher-than-expected molecular weights observed in (R,R)-10, the molecular weights of polymers made with  (R,R)-13 closely match the expected values (Table 3.5). This is consistent with the mononuclear species 101  having a much shorted initiation period compared to their dinuclear analogues. Complex (R,R)-(ONNSiPh3OMe)InOCH2Pyr ((R,R)-12), which does not have a dinuclear analogue was the slowest catalysts in this series of compounds. While it generates isotatic PLA with Pm ~ 0.75, it takes 24 hours to achieve >90% conversion at 1 mM concentrations. This can be attributed to the bulky –SiPh3 groups hindering the reactivity of the monomer with the metal center.        Table 3.5. Polymerization of rac-lactide with (R,R)-12 and (R,R)-13  Catalysta Time (h) Convb (%) Mntheo (kDa) MnGPCc (kDa) PDI Pm 1 (R,R)-13 0.5 98 28.2 35.8 1.15 0.55 2 (R,R)-13 0.5 98 70.6 70.4 1.25 0.54 3 (R,R)-12 16 75 - - - 0.73 4 (R,R)-12 24 93 26.8 36.7 1.30 0.75 aIn CH2Cl2 at 25 °C, [catalyst] ≈ 1 mM. bConversions were determined by 1H NMR spectroscopy. Mntheo = molecular weight of chain-end + 144 gmol–1 × 200 × conversion.  cIn THF (2 mg mL–1) and molecular weights were determined by GPC-LLS (flow rate = 0.5 mLmin–1.) Universal calibration was carried out with polystyrene standards, laser light scattering detector data, and concentration detector. Each experiment is duplicated to ensure accuracy.   102    Figure 3.16. The ROP plots of 200 equiv. of [lactide (LA)] vs. [initiator] for (R,R)-11 (left) and (R,R)-13 (right).  All reactions were carried out in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. [Catalyst] = 0.0011 M, [LA] = 0.45 M. The value of kobs was determined from the slope of the plots of ln([LA]/[TMB]) vs. time (TMB = 1,3,5-Trimethoxybenzene). Kinetics studies with both (R,R)-11 and (R,R)-13 shows first order relationships with respect to lactide concentration (Figure 3.16). However the initiation periods that can be observed with dinuclear analogous are not observable for the mononuclear catalysts. The ratio of kL-LA/kD-LA (5) and the kobs values (Table 3.3, entries 1-3) are consistent with (R,R)-6 and (R,R)-11 having similar propagating species. Complex (R,R)-13, which lacks the prolonged initiation period of its dinuclear analogue, is more active than any indium salen catalyst investigated (Table 3.3, entries 4-6). However, (R,R)-13 shows no preference for either enantiomer of lactide.       00.511.522.530 2000 4000L-LAD-LArac-LALn{[LA]/[TMB]} Time (sec.) 00.511.522.50 200 400L-LArac-LAD-LALn{[LA]/[TMB]} Time (sec.) 103  Table 3.6. Rate constants for polymerization of rac-, L- and D-lactide (LA) with (R,R)-11 and     (R,R)-13 Entry Catalysta Monomerb kobs ( 10–4 s–1) 1 (R,R)-11 D-LA 6.1(12) 2 (R,R)-11 L-LA 29(6) 3 (R,R)-11 rac-LA 6.9(14) 4 rac-13 D-LA 53(11) 5 rac-13 L-LA 52(10) 6 rac-13 rac-LA 62(12)  All reactions were carried out with 200 equiv of lactide in CD2Cl2 at 25 °C and followed to 90% conversion by 1H NMR spectroscopy. a [Catalyst] = 0.0011 M, b [lactide] = 0.45 M.   Based on these observations we propose a mononuclear, catalytically active species for both the dinuclear and mononuclear systems (Figure 3.17). The initiation periods observed with the dinuclear complexes are attributed to conversion of the dimers to monomers. The prolonged initiation periods observed for the least bulky (R,R)-10 and (R,R)-7 is attributed to the difficulty  a breaking up the dimers, compared to bulkier analogues. This is further evidenced by the more facile crossover shown by bulkier dimers (Chapter 2). The complete disappearance of the initiation period in (R,R)-13, which is very prolonged in the dinuclear analogue, is consistent with the proposed mechanism. This is in contrast to dinuclear propagating species proposed by Mehrkhodavandi et al. for a dinuclear indium catalyst bearing an tridentate half salen ligand.67           104    Figure 3.17. Proposed catalytic cycle for [(ONNO)InOR] complexes in lactide polymerization   3.3 Conclusions  We describe the first chiral indium salen catalysts that display a remarkable combination of high activity and isoselectivity for the polymerization of rac-lactide.  This is in contrast to chiral aluminum salen complexes, which are more selective, yet suffer from low activity.29,96,98-99,101-102  Based on kinetics studies, this system shows a high degree of enantiomorphic site control derived from ligand chirality, resulting in the formation of stereogradient PLA with significant crystallinity. Through ligand modification studies we have demonstrated the profound impact of the aromatic substituents on reactivity and isoselectivity. Furthermore, kinetic studies of dinuclear catalysts and their mononuclear analogues show a polymerization mechanism consistent with a mononuclear propagating species.  105  3.4 Experimental section General considerations.  Unless otherwise indicated, all air- and/or water-sensitive reactions were carried out under dry nitrogen using either an MBraun glove box or standard Schlenk line techniques.  NMR spectra were recorded on a Bruker Avance 300 MHz, 400 MHz and 600 MHz spectrometer. Molecular weights were determined by triple detection gel permeation chromatography (GPC-LLS) using a Waters liquid chromatograph equipped with a Water 515 HPLC pump, Waters 717 plus autosampler, Waters Styragel columns (4.6 × 300 mm) HR5E, HR4 and HR2, Water 2410 differential refractometer, Wyatt tristar miniDAWN (laser light scattering detector) and a Wyatt ViscoStar viscometer. A flow rate of 0.5 mL min-1 was used and samples were dissolved in THF (2 mg mL-1). Narrow molecular weight polystyrene standards were used for calibration purposes. The molar mass was calculated with ASTRA© 5 software using the Mark-Houwink parameters, laser light scattering detector data, and concentration detector.  Distribution and moment procedures of ASTRA© 5 was used calculate molar mass moments Mn, Mw and Mz. Materials.  CH2Cl2 was purified followed by the literature procedures to remove any impurities, dried over CaH2 and degassed through a series of freeze-pump-thaw cycles. CD2Cl2, CDCl3 and cyclohexane were dried over CaH2, and degassed through a series of freeze-pump-thaw cycles. rac-Lactide was a gift from PURAC America Inc. and recrystallized twice from hot dried toluene. 1,3,5-Trimethoxybenzene was purchased from Aldrich and used as received.    Representative procedure for ROP of lactide: In situ kinetics studies All samples for NMR scale polymerization were prepared in NMR tubes that could be sealed with Teflon caps, under an N2 atmosphere. All solutions were added using a syringe. The NMR 106  tube was charged with a stock solution of catalyst ([(ONNO)In(OEt)]2) in CD2Cl2 (0.25 mL, 0.0011 mmol) and frozen. Then a 0.25 mL of CD2Cl2 was added and frozen to create a buffer between the catalyst and the lactide monomer. Finally the stock solution with rac-lactide (0.50 mL, 0.45 mmol) and the internal standard 1,3,5-trimethoxybenzene (5 mg, 0.03 mmol per 0.50 mL) was added and the reaction solution was frozen. The sealed and evacuated NMR tube was immediately taken to the NMR spectrometer (400 MHz Avance Bruker Spectrometer) to monitor the polymerization at 25 °C.   Representative procedure for ROP of lactide: Large scale samples for GPC and 1H{1H} NMR studies In a 20 mL scintillation vial, rac-6 (5 mg, 0.035 mmol) was dissolved in 1 mL of CH2Cl2 and rac-lactide (0.205 g, 1.42 mmol) in 1.5 mL of CH2Cl2 was added and the total volume made to 3 mL. The reaction was allowed to proceed for 4 h after which time the reaction was quenched with a few drops of HCl in ether. A 0.5 mL sample of the reaction mixture was evaporated under vacuum for 3 hours and was dissolved in CDCl3. The monomer conversion was determined using the relative integrations of the methine resonances of PLA and leftover lactide via 1H NMR spectroscopy. 1H{1H} NMR spectrum of the methine region was obtained on a Bruker 600 MHz spectrometer. An analogous procedure was followed for the polymerization of rac-lactide with other catalysts. Thereafter, the mixture was evaporated under vacuum and the polymer was isolated by washing 3 times with cold methanol. The isolated polymer was subsequently dried under vacuum for 4 h prior to GPC analysis.     107  ROP of lactide: In the melt polymerization In a Schlenk flask, (R,R)-6  (5 mg, 0.035 mmol) and rac-lactide (0.202 g, 1.40 mmol) were added and mixed to homogenize the mixture. This was subsequently heated to 130 °C, to obtain slurry which was allowed to react for 10 minutes. The reaction was subsequently quenched with a few drops of HCl in ether.   Determination of melting point (Tm)3  The Tm values of the polymers were obtained using a TA differential scanning calorimeter (DSC) Q 1000. Approximately 2–3 mg of the samples were weighed and sealed in an aluminum pan. The experiments were carried out under a nitrogen atmosphere. The samples were heated at a rate of 10 oC/min from 40 to 200 oC and then held isothermally for 5 min to destroy any residual crystal nuclei before cooling at 5 oC /min. The melting temperatures were obtained from a second heating sequence, performed at 10 oC /min.                                                    3 Carried out by Dr. Norhayani Othman (Department of Chemical and Biological Engineering-University of British Columbia) 108  Chapter 4: Synthesis and reactivity of indium salbinap complexes towards lactide polymerization4     4.1 Introduction With growing interest in stereoselective lactide polymerization, numerous complexes with a diverse array of ligands and metals have been investigated as potential catalysts.32,41,43-44 The effect of changing a single parameter on the reactivity and selectivity of a catalyst can often be profound. These are subtle ligand modifications that can aid in improving the isoselectivity as observed by Nomura et al. and others.107,108,112 However, several examples in the literature describe a complete loss or reversal of isoselectivity to heteroselectivity, which is promoted by minor catalyst modifications. For example, Gibson et al. describes aluminum salan catalysts (Figure 4.1) which can  switch between isoselectivity (I.45) and high heteroselectivity (I.46) with changes in the aromatic substituents of the ligand.113 A similar affect has been reported by Williams and coworkers through the manipulation of the ligand backbone in yttrium phosphasalen complexes (I.66, I.67).129  This switching of stereoselectivity in lactide polymerization has also been observed when the metal is changed while maintaining the same ligand architecture.  Coates and coworkers reported a zinc β-diketiminate complex (I.81) which generates highly heterotactic PLA.53 However, the magnesium analogue (I.82) shows no stereoselectivity. Williams et al. reported yttrium and lutetium catalysts (I.67, I.83) with a pentadentate phosphasalen ligand which shows                                                  4 This work has been published in the journal Inorganic Chemistry. 109  isotactic enrichment (Pm ~ 0.8) in lactide polymerization.130 In the lanthanum analogue (I.84) however, the stereoselectivity switches to generate heteotactic PLA.              Figure 4.1. Lactide polymerization catalysts with switchable stereoselectivity  In the case of phospasalen catalysts, the authors attribute this phenomenon of switchable stereoselectivity, in part to metal size. Larger metals (i.e. lanthanum) having a more open coordination environment, are proposed to disfavor isoselectivity.  This explanation does not appear to be applicable to β-diketiminate catalysts (I.81, I.82) as the high heteroselectivity of the zinc complex can be obtained with a magnesium system by generating mononuclear analogue.176 In this system the dinuclear magnesium motif appears to hinder hetereoselectivity. In this 110  instance, the switch in stereoselectivity can be tentatively attributed to the aggregation state of the catalyst.    In our study, we decided to use the salbinap ligand with indium, which had been used by Spassky96 and Coates29,98 with aluminum alkoxide initiators to generate highly isotactic PLA. The superior rates and stereoselectivity observed with the aluminum salbinap catalysts, with respect to an aluminum initiator bearing a Jacobsen salen ligand, suggested the possibility of improving the stereoselectivity compared to the systems described in chapters 2 and 3.  4.2 Results    4.2.1 Synthesis of metal complexes    The proligand rac-2,2′-[1,1′-binaphthalene-2,2′-diyl-bis(nitrilomethylidyne)]-bis-4-tert-butyl-6-methylphenol, rac-H2(ONN*OMe), can be prepared in 94% yield by condensing rac-1,1′-binaphthyl-2,2′-diamine with two equiv. of 4-tert-butyl-6-methylsalicylaldehyde. The 1H NMR spectrum of rac-H2(ONN*OMe) contains one singlet for the equivalent N=CH protons at 8.60 ppm. The use of a salbinap proligand with unsubstituted salicylaldehyde moieties results in intractable and insoluble metal complex aggregates; these will not be discussed further. Indium complexes are generated by the one-pot reaction of rac-H2(ONN*OMe) (~80 mM) with InCl3 and excess NaOEt at room temperature in toluene.  Analysis of the mixture with 1H NMR spectroscopy after 16 hours shows the formation of two products: 14a and 14b (Scheme 4.1).  Stirring this mixture at room temperature for an additional 4 days forms the dinuclear complex [(µ-2-ONN*OMe)In(µ-OEt)]2 (14a) as the sole product in 67% isolated yield (see below for 14b).  The optimum reaction time for synthesis of 14a is dependent on the reaction concentration; more dilute reactions take longer to reach completion.  111   Scheme 4.1 Synthesis of indium salbinap complexes  The 1H NMR spectrum of 14a contains two singlets at 8.61 and 8.58 ppm corresponding to the N=CH protons.  Due to the highly symmetric nature of the complex only one resonance is observed for the aryl –CH3 and –C(CH3)3 protons at 2.37 and 1.00 ppm, respectively.  The signals for the –OCH2CH3 methylene protons appear as two diastereotopic resonances at ~2.10 and ~2.80 ppm and the OCH2CH3 resonances appear as a triplet at – 0.44 ppm.  Notably, the ethoxide shifts are considerably more upfield than those reported for other indium ethoxide complexes; for example, in (R,R)-6 the –OCH2CH3 protons resonate at 3.61–3.40 ppm and the –112  OCH2CH3 protons resonate at 1.07 ppm.  This upfield shift can be attributed to an induced magnetic field due to the aromatic ring current of the naphthyl moieties directly above each ethoxide.177 Single crystals were obtained from a solution of the 14a in hot acetonitrile and its molecular structure was determined using single crystal X-ray crystallography.  Complex 14a is a dimer with two indium centers bridged by the OEt ligand as well as (ONN*OMe) in a κ2 coordination mode (Figure 4.2).  The D2 symmetric complex contains two slightly distorted octahedral indium metal centers that are coplanar with the bridging oxygen atoms of the ethoxide groups.  The homochiral dimer crystalized in the centrosymmetric P-1 space group, indicating the presence of both the S,S- and R,R- dimers in the unit cell.  The highly symmetric solution structure indicated by the 1H NMR spectrum confirms that 14a is also homochiral in solution.   Complex 14b can be isolated from a 1:1 mixture of 14a and 14b generated in a reaction carried out at room temperature for 16 h.  Complex 14a is then extracted with acetonitrile from this mixture leaving [(κ4-ONN*OMe)In(µ-OEt)]2 (14b) as the insoluble component.  The 1H NMR spectrum of 14b in CDCl3 contains two well-separated signals at 8.33 and 7.93 ppm corresponding to the N=CH protons. The loss of symmetry in 14b, compared to 14a, is clear from the presence of two sets of resonances for the aryl –CH3 (2.01 and 1.87 ppm) and –C(CH3)3 (1.35 and 1.23 ppm) protons.        113   Figure 4.2. Molecular structure of 14a depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity)  Table 4.1. Selected bond lengths and angles for 14a 14a Bond Lengths(Å) In1-O1 2.117(3) In1-N1 2.254(3) In1-O3 2.121(3) In1-N3 2.261(3) In1-O5 2.148(3)   Bond Angles (°) O1-In1-O3 93.12(11) O1-In1-N1 85.68(11) O1-In1-O5 91.91(10) O3-In1-N1 87.90(11) O3-In1-O5 173.94(10) O5-In1-N1 89.10(11) O1-In1-O6 166.84(11) N1-In1-N3 170.33(11) O3-In1-O6 99.93(10) O6-In1-N1 93.06(11) O1-In1-N3 87.05(11) In1-O5-In2 105.41(11)  114  Single crystals of 14b were obtained after slow evaporation in diethyl ether.  The molecular structure of 14b shows two distorted octahedral metal centers with κ4 coordination of the (ONN*OMe) ligand to one indium center (Figure 4.3).  The two metal centers are bridged by ethoxide ligands.  Notably, the In-N bond distances in 14b (2.257(9)-2.318(6) Å) are longer than the corresponding bonds in (R,R)-6 (2.206(6)-2.259(6) Å) and [(κ4-salpen)In(OMe)])2 (I.79)150 (2.222(8)-2.263(7) Å), both of which contain the more electron rich CH-Nimine moiety. The structural motifs we observe for 14a and 14b have been previously reported for aluminum152 and indium150 salen complexes, although a dimeric motif such as 14b is most common with indium complexes.  Complex 14a is structurally similar to the dinuclear aluminum salbinap complex [(µ-κ 2-salbinap)Al(µ-OMe)]2 reported by Coates et al.29 The In-(µ-O) bond distances are longer than the corresponding Al-(µ-O) bond distances (2.142(3)-2.165(3) Å vs. 1.892(4)-1.895(4) Å).  Bond angles around the octahedral cores of the aluminum and indium compounds are similar (Table 4.2).   The solution structures of 14a and 14b, determined using pulsed gradient spin-echo (PGSE) spectroscopy, show that they are dinuclear in solution as well as in the solid state.161  The diffusion coefficients of the proligand H2(ONN*O), determined using PGSE at 25 °C with tetrakis(trimethylsilyl)silane (TMSS) as an internal standard, is 8.9(0.4) × 10–10 m2s–1. In contrast, 14a and 14b had significantly lower diffusion coefficients of 6.2(0.2) × 10–10 m2s–1 and 6.1(0.2) × 10–10 m2s–1. This decrease (~25%) in the diffusion coefficient from the proligand to 14a and 14b supports a dinuclear solution state structure for these complexes.160 Variable temperature 1H NMR spectroscopy for 14a and 14b (toluene-d8, 25 °C – 80 °C) shows no change in the resonances for either complex, indicating that these dimers remain intact at elevated temperature (Figures 4.4 and 4.5). 115   Figure 4.3. Molecular structure of 14b depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity)  Table 4.2. Selected bond lengths and angles for 14b 14b Bond Lengths(Å) In1-O1 2.120(8) In1-O6 2.148(5) In1-O2 2.083(9) In1-N1 2.264(10) In1-O5 2.157(5) In1-N2 2.301(7) Bond Angles (°) O1-In1-O5 159.6(3) O1-In1-N1 160.2(3) O2-In1-O5 100.4(3) O2-In1-N1 97.3(3) O5-In1-O6 74.81(19) O2-In1-N2 82.1(3) O1-In1-N1 80.6(3) N2-In1-N1 79.5(3) O6-In1-N1 104.2(3) O5-In1-N2 98.2(2) O5-In1-N1 89.3(3) In1-O5-In2 105.41(11)  116   Figure 4.4. Varible temperature 1H NMR spectra of 14a in toluene-d8 (400 MHz)  Figure 4.5. Variable temperature 1H NMR spectra of 14b in toluene-d8 (400 MHz)  117  Complex 14a is the thermodynamic product generated from the reaction mixture of 14a and 14b; at elevated temperatures (80 °C in toluene) formation of 14a reaches completion in ~72 h. However, this occurs within a mixture containing an excess of NaOEt. In contrast, heating a pure sample of 14b at 100 °C in toluene-d8 generates <5% of 14a in 96 h (Appendix, Figure C.11).  When an isolated sample of 14b is stirred in toluene with 5 equiv. of NaOEt for 16 h, the 1H NMR spectrum of the reaction shows a 14a:14b ratio of 1:2.75 confirming the accelerated conversion of 14b to 14a in the presence of NaOEt (Appendix, Figure C.7). We also investigated a two-step synthesis via the indium chloride complex to the desired alkoxide complexes in an attempt to avoid a mixture of compounds. The process, as described previously for the synthesis of (R,R)-6, involves the deprotonation of the proligand followed by salt metathesis with InCl3. However, the deprotonation of rac-H2(ONN*OMe) with two equiv KOtBu and the subsequent salt metathesis with InCl3 produces a mixture of two major species (Figure C.8). We were not able to isolate these species for complete characterization; however, the 1H NMR signals of the two compounds suggest that they may be chloro-bridged analogues of 14a and 14b. Treating this mixture with excess NaOEt yields a mixture of 14a and 14b (14a:14b ~1:2.5) (Appendix, Figure C.9).  In an attempt to control or prevent aggregation in our complexes using increased steric hindrance, we synthesized the known proligand rac-H2(ONN*OtBu) in a similar manner to H2(ONN*OMe) (Scheme 4.2).  Deprotonation of rac-H2(ONN*OtBu) with two equiv. of KOtBu and subsequent salt metathesis with 1 equiv. of InCl3 forms (4-ONN*OtBu)InCl (15) exclusively with an isolated yield of 59%.  The 1H NMR spectrum of 15 in CDCl3 shows a broad singlet at 8.48 ppm corresponding to the N=CH resonances.  This is in contrast to rac- or (R,R)-1 which shows two distinct 1H NMR resonances for the imine protons. 118   Scheme 4.2 Synthesis of complex 15 Single crystals of 15 can be grown from a concentrated solution of hexanes at ambient temperature using slow evaporation.  The molecular structure of 15 shows a mononuclear indium complex with distorted trigonal bipyramidal geometry (Figure 4.6).  The In-N bond distances are slightly longer than those of rac-1 (2.191(4)-2.219(3) vs. 2.171(7)-2.207(7) Å), while the In-O bond distances for the two complexes are similar (2.045(3)-2.065(3) for 15 vs. 2.044(6)-2.050(6)). Unfortunately, reactions of 15 with NaOEt under a variety of conditions produce an intractable mixture of products.  One pot reactions of rac-H2(ONN*OtBu) with NaOEt and InCl3 under a variety of conditions also did not yield isolable complexes.  Use of a bulkier alkoxide is a strategy utilized by Coates et al. to prevent the formation of aluminum complexes analogous to 14a.29  However, our attempts to replace NaOEt with NaOiPr in the synthesis of 14a/14b resulted in intractable mixtures of products.  Single crystals isolated from one such reaction after exposure to moisture shows the formation of [(µ-2-ONN*OMe)In]2(µ-Cl)(µ-OH) (16) as one of many products (Figure 4.7).   119   Figure 4.6. Molecular structure of 15 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity)  Table 4.3. Selected bond lengths and angles for 15 15 Bond Lengths (Å) In1-Cl1 2.3823(11) In1-N1 2.219(3) In1-O1 2.045(3) In1-N2 2.191(4) In1-O2 2.065(3)   Bond Angles (°) O2-In1-Cl1 97.64(9) O2-In1-N1 169.10(12) N1-In1-Cl1 93.16(9) O1-In1-N1 85.34(12) N2-In1-Cl1 116.33(9) O2-In1-N2 84.71(12) O2-In1-O1 90.46(12) N1-In1-N2 89.20(14)   120  The molecular structure of 16 shows two octahedral indium centers bridged by two 2-(ONN*OMe) as well as a bridging hydroxide and a bridging chloride. Attempts to use KOCH2Ph instead of NaOEt also resulted in complex mixtures of products.      Scheme 4.3. Possible route for synthesis of 16  Our struggles in the synthesis of isolable dinuclear complexes are a testament to the difficulty of controlling the aggregation phenomenon in indium alkoxide complexes.  We have reported that hydroxyl-bridged complexes are readily generated from the hydrolysis of indium alkoxide groups with trace amounts of water.139,67 Thus, it is possible that [(µ-2-ONN*OMe)In]2(µ-Cl)(µ-OiPr) is one of the metal complexes generated in this reaction and complex 16 forms by the reaction of this species with adventitious water (Scheme 4.3).  However, we have never successfully isolated a pure sample of an indium isopropoxide complex with our proligands. 121   Figure 4.7. Molecular structure of 16 depicted with ellipsoids at 50% probability (H atoms and solvent molecules omitted for clarity)  Table 4.4. Selected bond lengths and angles for 16 16 Bond Lengths(Å) In1-O1 2.094(3) In1-N1 2.234(3) In2-O2 2.105(3) In2-N2 2.249(3) In1-O4 2.120(5) In1-Cl1 2.601(2) Bond Angles (°) O1-In1-O4 162.86(17) O2-In2-N2 85.95(11) O1-In1-N1 86.59(11) O4-In2-N2 91.80(15) O4-In1-N1 92.85(15) O2-In2-Cl1 174.66(9) O1-In1-Cl1 84.67(10) In1-Cl1-In2 87.09(6) O4-In1-Cl1 78.21(16) O4-In2-Cl1 77.93(17) O2-In2-O4 96.93(17) In1-O4-In2 116.8(3  122  It appears that a delicate balance of steric bulk is required to form stable indium dinuclear complexes, which are the thermodynamic products in these systems.  This is further supported by the fact that, as discussed above, unsubstituted salbinap ligands do not form isolable indium species like their aluminum analogues.  Although increasing the steric bulk of the complexes does prevent dimer formation, it also prevents formation of stable dinuclear compounds.  Attempts to deviate from the thermodynamically stable dinuclear complexes only complicate the synthetic outcome of these reactions.  4.2.2 Polymerization studies Compounds 14a and 14b show low activity as catalysts for the ring-opening polymerization of rac-lactide compared to previously reported dinuclear indium complexes from our group (Table 4.5).66-67,119,140 Polymerization of 200 equiv. of rac-lactide catalyzed with 14a (~1 mM, refluxing THF) reaches 23% conversion after 7 days (>90% conversion was achieved in 30 days.)  Complex 14b reaches 86% conversion in 7 days under identical reaction conditions.  Reactions in refluxing toluene occur at a much slower rate with 14a and 14b, reaching ~1% and ~5% conversion, respectively, after 5 days.  In contrast, polymerization of 200 equiv. of rac-lactide with rac-6 reaches >97% conversion in under 30 minutes at room temperature.  The polymer generated by 14b at full conversion has a heterotactic bias (Pr = 0.61).  In contrast, rac-6 generates largely isotactic PLA (Pm ~ 0.74).  The PLA generated by 14a is atactic.    123  Table 4.5. Polymerization of rac-lactide with indium and aluminum salen catalysts.  Catalyst Time (h) Conv (%) Mntheo (kDa) MnGPC (kDa) PDI Pm 1 1a 768 95 27.4 38.5 1.32 0.48 2 1a 696 92 26.5 44.5 1.40 0.47 3 1b 204 92 26.5 24.0 1.82 0.40 4 1b 216 96 27.9 27.3 1.49 0.40 5 I.35a 40 >99 28.7 22.6 1.09 >0.9 6 I.36b 288 85 7.6 7.7 1.06 0.93 7 rac-6c 0.5 >97 28.5 34.9 1.39 0.74 Entries 1-4: In THF, 80 °C, [catalyst] ≈ 1 mM. Conversions were determined by 1H NMR spectroscopy. Mntheo = molecular weight of chain-end + 144 gmol–1 × 200 × conversion.  Entries 2-6; in THF (2 mg mL–1) and molecular weights were determined by GPC-LLS (flow rate = 0.5 mLmin–1.) Universal calibration was carried out with polystyrene standards, laser light scattering detector data, and concentration detector. a In toluene, 70 °C, [catalyst]o ≈ 1 mM, reported by Coates et al.98 In toluene, 70 °C, [catalyst]o ≈ 13 mM, reported by Feijen et al.101  cIn CH2Cl2 25 °C, [catalyst] ≈ 1 mM.   The low reactivity of 14a mimics that of the aluminum analogue [(µ-2-Salbinap)Al(µ-OMe)]2, which is reported to be inactive for lactide polymerization.29  A comparison of the N=CH peaks of 14a and the resulting polymeryl species after monomer additions shows that even at 50% conversion only ~30% of 14a is initiated (Figure 4.8).  Lack of complete initiation is also supported by the higher-than-expected molecular weights observed (Table 4.5, entries 1-2).  The disparity in the initiation rate may also explain the difference between the calculated and observed Mn values for the polymerizations.  Thus, for 14a the rates of initiation and propagation of polymerization are very slow. 124   Figure 4.8. 1H NMR spectra (CDCl3, 400 MHz, 25 °C) of the reaction of 14a with 200 equiv of rac-lactide, at ~50% conversion. Inset shows a 1H NMR spectrum of 14a overlaid with an expanded region of the spectrum of the reaction.   Figure 4.9. 1H NMR spectra (CDCl3, 400 MHz, 25 °C) of the reaction of 14b with 200 equiv. of rac-lactide at ~83% conversion. Inset shows a 1H NMR spectrum of 14b overlaid with an expanded region of the spectrum of the reaction.  125  In contrast to complex 14a, 14b is a well-controlled controlled catalyst for the polymerization of lactide similar to analogous complex 6.  Inspection of a reaction mixture of 14b and 200 equiv. of rac-lactide at ~80% conversion shows that the catalyst is fully initiated (Figure 4.9).  In addition, the theoretical and observed Mn values are in full agreement (Table 4.5, entries 3-4).  GPC analysis of polymerization of 200 equiv. of rac-lactide with 14b at different conversions shows that the experimental and theoretical Mn values are in close agreement and that PDI values range between 1.2 and 1.8 (Figure 4.10).   Figure 4.10. Plot of observed PLA Mn and molecular weight distribution (PDI) vs. % conversion for 14b with lactide:initiator ratio of 200:1. The reaction was carried out in refluxing THF and conversions were obtained using 1H NMR spectroscopy. The line represents the theoretically expected Mn value vs. conversion.     Polymers obtained with 14b are significantly different from those obtained with 6. Matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectroscopy of PLA generated with 14b shows peaks corresponding to the species [H(C6H8O4)n(OC2H5)Na]+ which are separated by m/z = 144 Da apart (Figure 4.11).  No peaks at m/z = 72 Da intervals are 1.01.21.41.61.82.02.22.42.62.83.00100002000030000400000 50 100Mn (Da) ( ) PDI (n) % Conversion 126  observed, which indicates minimal transesterification in the system under these experimental conditions.  In contrast, a MALDI-TOF analysis of polymers generated with 6 show only peaks at m/z = 72 Da indicating extensive transesterification.   Figure 4.11.  MALDI-TOF mass spectrum of a PLA oligomer grown with 14b.  A comparison of the results with indium complexes 14b and 6 shows that their behaviour is very different than the analogous aluminum complexes I.35 and I.36 (Figure 4.12).  Although the salbinap complex, I.35, is significantly more active than I.36 the qualitative polymerization rates are on the same order (Table 4.5 entries 5,6).  In contrast, although complexes 14b and 6 share the same dimeric structure, complex 6 is a highly active catalyst for lactide polymerization, while 14b is orders of magnitude less reactive.  In addition, complexes I.35 and I.36 show 127  different transesterification behavior.  MALDI-TOF mass spectrometry shows peaks at m/z = 72 Da for polymers obtained with the salbinap complex I.35,97 while analogous samples from salen complex, I.36, shows no transesterification.102 This pattern is reversed in the case of the indium complexes:  salbinap complex 14b shows no transesterification, while the salen complex 6 does Most importantly, the aluminum complexes are isoselective for the polymerization of rac-lactide (Pm ~ 0.9) regardless of the ancillary ligand.    Figure 4.12. Isoselective chiral aluminum salen catalysts for lactide polymerization Polymers generated with the two indium complexes show very different microstructures:  14b is heteroselective, while 6 is isoselective. This switch from isoselectivity to heteroselectivity in salbinap systems upon changing the metal centre mirrors a report by Williams et al. with a phosphasalen ligand.130 The switching of isoselectivity of lutetium and yttrium phosphasalen catalysts to heteroselectivity in lanthanum is correlated by the authors to metal size/covalent radius. While covalent radius of an element is not an inherent property, and is highly dependent on the ancillary ligands, a larger metal with greater orbital extension can have a more open coordination environment or promote aggregation that can impact stereoselectivity. We do not observe any evidence of a fundamental change in mechanism between the two indium catalysts, nor between the aluminum and indium complexes as was observed by 128  Carpentier et al.105,178  Most importantly, the compounds under investigation in our study are indium complexes with monodentate alkoxide ligands which are often dimeric.67,119,139,152 The observed discrepancy is likely due to differences in catalyst structure created by different aggregation behavior in indium alkoxide complexes. One possible explanation for the low activity of 14b is that under polymerization conditions, 14b converts to inactive 14a.  However, when individual pure samples of 14a and 14b are heated in refluxing THF-d8 or toluene-d8 for 4 days, complex 14a remains unchanged and complex 14b only degrades by <5% (Appendix, Figures C.10 and C.11).  The low levels of decomposition or conversion of 14b under the reaction conditions indicates that the effects of these processes on the lowered reaction rates are minimal.  Thus the lower rates observed for 14b compared to 6 are likely not caused by a lower initiation rate by the complex.   We investigated the stability of 14b in the presence of ethyl acetate, a possible lactide surrogate, to gain greater information about the mechanism of initiation in the reaction of rac-lactide with 14b. A mixture of complex 14b and 400 equiv. of ethyl acetate was stirred at room temperature in THF for 16 hours.  The 1H NMR spectrum of the mixture, obtained after evaporation of THF and ethyl acetate, shows that 14b remains unchanged (Appendix, Figure C.14).  Under forcing condition, when 14b was stirred for 16 hours in neat ethyl acetate at room temperature, ~50 % 14b converts to other products (Figure C.14). This residue contains a 1:1 mixture of 14b and a new product. Since the N=CH 1H NMR resonances of this product and 14b are well-resolved it is possible to use the 1:1 mixture to determine the diffusion coefficient of this new species. PGSE spectroscopy of the new product in this mixture gives a diffusion coefficient of 6.2(3) × 10−10 m2 s−1, which is the same as the value for 14b suggesting that the dimer remains intact. This study indicates that 14b is a very stable dimer, and the major product 129  from this reaction is also a dimer (Appendix, Figure C.15). We observed similar reactivity with dinuclear indium complexes bearing tridentate ligands.66  4.3 Conclusions Here we have discussed the synthesis, isolation and characterization of dinuclear salbinap indium ethoxide complexes. In addition to the difference in synthetic facility, the rates of polymerization for catalysts 14a and 14b were orders of magnitude slower than the analogous indium complexes with a cyclohexyl backbone.  This result is to be expected for complex 14a with the 2- coordinated ligand, since the analogous aluminum complex is completely unreactive. In contrast, we would have expected complex 14b to show similar reactivity to the corresponding indium complex with a cyclohexyl backbone [(4-ONNtBuOtBu)InOEt]2 (6). We speculate that the increased steric bulk in dinuclear complex 14b is responsible for the sluggish polymerization compared to 6.  The steric argument is supported by the selectivity observed in the ROP of rac-lactide by the two catalysts.  Complex 14b is heteroselective while 6 is isoselective.  This disparity suggests a dominant chain-end control mechanism in 14b, which can be attributed to the increased sterics of the BINAP backbone compared to the cyclohexyl analogue.  This is in marked contrast to what is observed in analogous aluminum catalysts, which produce highly isotactic PLA regardless of the chiral backbone employed. Indium complexes with salen and salbinap ligands behave differently in terms of polymerization activity and selectivity, while nearly identical aluminum analogues behave similarly.  This is due to the fact that the indium complexes are dimers and thus have different coordination environments than the mononuclear aluminum complexes with similar coordination enviroments.  Thus, we conclude that in contrast to aluminum complexes, the larger ionic radius 130  of indium (III) cations which, facilitates and promotes aggregation, is a dominating factor in the chemistry of these species, and must be considered in the development of future stereoselective indium catalysts.  4.4 Experimental section General considerations. Unless otherwise indicated, all air- and/or water-sensitive reactions were carried out under dry nitrogen using either an MBraun glove box or standard Schlenk techniques.  NMR spectra were recorded on a Bruker Avance 400 MHz or 600 MHz spectrometer.  1H NMR chemical shifts are reported in ppm versus residual protons in deuterated chloroform; δ 7.27 CDCl3.  13C1H NMR chemical shifts are reported in ppm versus residual 13C in the solvent: δ 77.2 CDCl3.  Diffraction measurements for X-ray crystallography were made on a Bruker APEX DUO diffractometer with graphite monochromated Mo-Kα radiation. The structures (Table C.1) were solved by direct methods and refined by full-matrix least-squares using the SHELXTL crystallographic software of Bruker-AXS.  Unless specified, all non-hydrogen atoms were refined with anisotropic displacement parameters, and all hydrogen atoms were constrained to geometrically calculated positions but were not refined.  Elemental analysis (C, H, and N) was performed using a Carlo Erba EA1108 elemental analyzer.  The elemental composition of unknown samples was determined by using a calibration factor. The calibration factor was determined by analyzing a suitable certified organic standard (OAS) of a known elemental composition. Molecular weights were determined by triple detection gel permeation chromatography (GPC-LLS) using a Waters liquid chromatograph equipped with a Waters 515 HPLC pump, Waters 717 plus autosampler, Phenomenex Phenogel columns (4.6 × 300 mm) 5u 500A, 5u 10E3A and 10E4A, Waters 2410 differential refractometer, Wyatt tristar miniDAWN© 131  (laser light scattering detector) and a Wyatt ViscoStar II© viscometer. A flow rate of 0.5 mL min-1 was used and samples were dissolved in THF (2 mg mL-1). Narrow molecular weight polystyrene standards were used for calibration purposes. The molar mass was calculated with ASTRA© 6 software using the Mark-Houwink parameters K and a from the ViscoStar, laser light scattering detector data, and concentration detector. Mark-Houwink equation gives the relationship between intrinsic viscosity (η) and molar mass (M). Distribution and moment procedures of ASTRA© 6 was used to calculate molar mass moments Mn, Mw and Mz. Materials. Solvents (tetrahydrofuran (THF), toluene, hexanes and diethyl ether) were collected from an MBraun Solvent Purification System whose columns are packed with activated alumina.  THF was further dried over sodium/benzophenone, distilled under vacuum and degassed. EtOAc, CH2Cl2 and acetonitrile were dried over CaH2, distilled under vacuum and degassed. CDCl3 was dried over CaH2, and degassed through a series of freeze-pump-thaw cycles. Toluene-d8 and THF-d8 from Cambridge Isotope Laboratories, Inc. were dried over sodium/benzophenone, distilled under vacuum and degassed through a series of freeze-pump-thaw cycles. rac-lactide was a gift from PURAC America Inc. and recrystallized thrice from hot dry toluene. rac-1,1'-binaphthyl-2,2'-diamine, potassium tert-butoxide and sodium ethoxide (washed with ethanol and hexanes prior to use) were purchased from Alfa Aesar. InCl3 was purchased from Strem Chemicals Inc. rac-2,2’-[1,1'-binaphthalene-2,2'-diyl-bis(nitrilomethylidyne)]-bis-4,6-ditert-butylphenol and 4-tert-butyl-6-methylsalicylaldehyde were prepared according to literature procedures.179, 167    132  Synthesis of rac-H2(ONN*OMe) A 50 mL round bottomed flask was charged with a racemic mixture of 1,1’-binaphthyl-2,2-diamine (0.222 g, 0.780 mmol), 2 equiv. 4-tert-butyl-6-methylsalicylaldehyde (0.300 mg, 1.56 mmol), 25 mL of ethanol, and a magnetic stir bar. A catalytic amount of formic acid (1 drop) was then introduced to the stirring yellow mixture which was subsequently heated to reflux at 80 °C for 3 h. Heating was discontinued, and the bright yellow precipitate was suction filtered and washed once with cold ethanol (5 mL). The product was subsequently dried under reduced pressure and used without further purification (462 mg, 94%). 1H NMR (600 MHz, CDCl3):  12.00 (1H, s (broad) Ar–OH), 8.60 (1H, s,  Ar–CHN–), 8.04 (1H, d  (J = 8.8 Hz), Ar–H), 7.94 (1H, d, (J = 8.2 Hz),  Ar–H), 7.55 (1H, d (J =8.8 Hz), Ar–H), 7.42 (1H, m, Ar–H), 7.22 (1H, d ( J = 8.3 Hz), Ar–H), 7.11 (1H, s, Ar–H), 7.03 (1H, d (J = 2.1 Hz), Ar–H), 2.05 (3H, s,  Ar–CH3), 1.23 (9H, s, Ar(CH3)3). 13C{H} NMR (151 MHz, CDCl3): 163.3, 157.2, 144.8, 140.7, 133.5, 132.5, 131.6, 129.9, 128.9, 128.3, 127.0, 126.6, 126.3, 125.7, 125.5, 118.0, 118.0, 34.0, 31.6, 15.8. Anal. Calcd for C44H44N2O2: C, 83.51; H, 7.01; N, 4.43. Found: C, 83.17; H, 7.01; N, 4.48.  Synthesis of 14a and 14b  A solution of rac-H2(ONN*OMe) in 10 mL toluene (144 mg, 0.23 mmol) was added to 8 equiv. NaOEt (121 mg, 1.82 mmol) in a 20 mL scintillation vial. A magnetic stir bar was added and the reaction proceeded for 30 minutes at room temperature before addition of 1.3 equiv. anhydrous InCl3 (71 mg, 0.29 mmol). After overnight stirring, the solution was filtered and evaporated under vacuum. The yellow solid was resuspended in 20 mL acetonitrile, filtered, and washed with 1 mL acetonitrile. The resuspension and filtration of the solid precipitate was repeated two 133  more times. The filtrate and wash contained 14a (60 mg, 32%) while the undissolved solid was 14b (35.6 mg, 19%). 14a 1H NMR (400 MHz, CDCl3): δ 8.61 (1H, s, N=CH),8.58 (1H, s, N=CH), 8.05 (2H, s, Ar-H), 7.90-7.81 (4H, m,  Ar-H), 7.52-7.49 (6H, m, Ar-H), 7.06-7.05 (2H, d,  Ar-H), 2.85-2.75 (1H, m, -OCHAHB-), 2.37 (6H, s, Ar-CH3), 2.16-2.05 (1H, m, -OCHAHB-), 1.00 (18H, s, Ar-C(CH3)3), -0.44 (3H, t, -OCH2-CH3). 13C{H} NMR (151 MHz, CDCl3): δ 174.1, 167.4, 149.2, 135.9, 134.7, 133.4, 131.6, 129.1, 128.2, 127.9, 127.0, 126.9, 126.3, 125.31, 124.6, 116.1, 61.0, 32.9, 30.9, 29.5, 18.2. Anal. Calcd for C92H94In2N4O6: C, 69.87; H, 5.99; N, 3.54. Found: C, 72.16; H, 6.28; N, 3.67.  14b 1H NMR (400 MHz, CDCl3): 8.33 (1H, s, N=CH), 7.93 (1H, s, N=CH), 7.84 (1H, s, Ar-H), 7.82 (1H, s, Ar-H), 7.56-7.53 (1H, d (J = 4.8 Hz) Ar-H), 7.40-7.13 (8H, m, Ar-H), 7.07-7.04 (1H, d (J = 4.0 Hz) , Ar-H), 6.75 (1H, m, Ar-H), 6.68 (1H, m, Ar-H), 6.46-6.43 (1H, d(J = 12 Hz), Ar-H), 2.45-2.37 (1H, m, -OCHAHB-), 2.01 (3H, m, Ar-CH3), 1.96-1.92 (1H, m, -OCHAHB-), 1.87 (3H, s, Ar-CH3), 1.35 (9H, s, Ar-C(CH3)3), 1.23 (9H, s, Ar-C(CH3)3), 0.50 (3H, t, -OCH2CH3). 13C{H} NMR (151 MHz, CDCl3): δ 173.5, 172.0, 169.2, 168.6, 147.6, 146.2, 137.0, 135.8, 133.9, 133.8, 132.9, 132.7, 132.6, 132.1, 131.9, 131.7, 129.9, 129.1, 128.3, 128.2, 128.0, 127.5, 127.0, 126.7, 126.6, 126.4, 126.3, 126.0, 125.2, 124.5, 123.7, 118.2, 116.7, 59.7, 33.7, 33.6, 31.5, 31.2, 19.9, 18.7, 16.6. Anal. Calcd for C92H94In2N4O6: C, 69.87; H, 5.99; N, 3.54. Found: C, 69.27; H, 5.86; N, 3.52.   Synthesis of complex 15 A 20 mL scintillation vial was charged with a Teflon stir bar, potassium tert-butoxide (0.651 g, 5.80 mmol) and 2 mL of THF. The mixture was allowed to stir until complete dissolution of KOtBu was achieved. The ligand (±)-H2(ONN*OMe) (0.210 g, 2.93 mmol) was dissolved in 2 mL 134  of THF and added to the stirring solution. The mixture was stirred for 3 h. At this point a suspension of anhydrous InCl3 (0.650 g, 2.94 mmol) in THF 2 mL was added to reaction and stirred for another 6 h. The mixture was then filtered through glass filter paper and the volatile components were evaporated under vacuum to afford a yellow solid. This was redissolved in diethyl ether and allowed to crystallize at −35 °C. The final product was obtained as a yellow crystalline solid (1.50 g, 59%) which was filtered and dried under vacuum. 1H NMR (400 MHz, CDCl3): δ 8.48 (2H, s (broad), N=CH), 8.06-8.05 (2H, d, Ar-H), 7.95-7.94 (2H, d, Ar-H), 7.50-7.42 (6H, m, Ar-H), 7.26-7.24 (2H, m, Ar-H), 6.91 (4H, s (broad),  Ar-H), 1.47 (18H, s, Ar-C(CH3)3), 1.24 (18H, s, Ar-C(CH3)3). 13C NMR (151 MHz, CDCl3): δ 142.9, 138.0, 133.5, 132.4, 130.6, 129.5 127.2, 126.5, 126.1, 124.5, 36.6, 34.0, 31.1, 29.5. Anal. Calcd for C50H54InClN2O2: C, 69.41; H, 6.29; N, 3.24. Found: C, 70.31; H, 6.40; N, 3.07.             Polymerization of lactide (Representative procedure) In a 20 mL scintillation vial (Inside the glove box, Nitrogen atmosphere) 14b (4 mg, 0.0025 mmol) was dissolved in 1 mL of THF and rac-lactide (0.146 g, 1.01 mmol) in 1.5 mL of THF was added. The solution was transferred to Teflon screw-capped dry Schlenk flask. The reaction was removed from the glove box and allowed to stir under reflux in an oil bath at 80 °C for 9 days. The flask was taken back inside the box and a 0.5 mL sample of the reaction mixture was evaporated under vacuum for 3 h and was dissolved in CDCl3. 1H{1H}NMR spectrum of the methine region was obtained on a Bruker 600 MHz spectrometer. Thereafter the mixture was transferred out of the glove box into a 20 mL vial and quenched with two drops of 1M HCl in diethyl ether. The solvent was evaporated under vacuum and the polymer was isolated by 135  washing 3 times with cold methanol. The isolated polymer was subsequently dried under vacuum for 4 h prior to GPC analysis. For the experiments where GPC data was obtained at partial conversions the reaction mixture was taken back into the glovebox, and a sample was withdrawn for analysis.   Monitoring the thermal stability of catalysts (Representative procedure) A Teflon sealed NMR tube was charged with a solution of 14b (5 mg (0.0031 mmol) dissolved in 0.5 mL of THF-d8) and a 1H NMR spectrum was obtained. The tube was allowed to sit in an oil bath at 80 °C and 1H NMR spectra were obtained every 24 h for 4 days.       Convertion of 14b to 14a with NaOEt  A 20 mL scintillation vial was charged with 61 mg (0.038 mmol) of 14b and 13 mg (0.19 mmol) of NaOEt and stirred for 16 h in 1 mL of toluene. The solvent was evaporated under vacuum and a 1H NMR spectrum was obtained of the yellow solid residue.  Reaction of 14b with ethyl acetate A 20 mL scintillation vial was charged with 5 mg (0.0031 mmol) of 14b dissolved in 1 mL of THF and 125 µL (0.63 mmol)of dry EtOAc was added and stirred for 16 h at ambient temperature. The solvent was evaporated under vacuum and a 1H NMR spectrum was obtained of the yellow solid residue. The procedure was similar for the experiment with neat ethyl acetate. However no THF was used and the complex was simply dissolved in 1 mL of ethyl acetate. For PGSE NMR studies a portion of the dry reaction mixture (after a 16 h reaction in neat ethyl 136  acetate and evaporation of volatile components under vaccuum) (3.5 mg, [In]~4mM) was dissolved in a 1 mL volumetric flask with a solution of tetrakis(trimethylsilyl)silane (TMSS) (0.94 mM) in CD2Cl2. The N=CH 1H NMR resonance at 8.41 ppm was used for the analysis.   Representative sample preparation for PGSE studies In a 1 mL volumetric flask 2.8 mg of (ONN*O)H2 (0.0044 mmol, 0.0044 M) was made with a solution of tetrakis(trimethylsilyl)silane (TMSS) (0.94 mM in CD2Cl2) also used as an  internal standard. A 0.5 mL volume was transferred into a Teflon capped sealed NMR tube for spectroscopy.    MALDI-TOF mass spectrometry of PLA oligomers  In a 20 mL scintillation vial (Inside the glove box, Nitrogen atmosphere) 14b (3 mg, 0.0019 mmol) was dissolved in 0.5 mL of THF and rac-lactide (0.014 g, 0.097 mmol) in 0.5 mL of THF was added.  The solution was transferred to Teflon screw-capped dry Schlenk flask. The reaction was removed from the glove box and allowed to stir under reflux in an oil bath at 80 °C for 16 hours. Thereafter the mixture was transferred out of the glove box into a 20 mL vial and quenched with two drops of 1M HCl in diethyl ether. The solvent was evaporated under vacuum and the polymer was isolated by washing 3 times with cold methanol. The isolated polymer was subsequently dried under vacuum for 4 h prior to analysis. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometric analysis was performed on a Bruker Autoflex MALDI-TOF equipped with a nitrogen laser (337 nm). The accelerating potential of the Bruker instrument was 19.5 kV. The polymer samples were dissolved in THF 137  (ca. 1 g/mL). The concentration of a cationization agent, sodium trifluoroacetate, in THF was 1 mM. The matrix used was trans-2-[3-(4-tert-butylphenyl)2-methyl-2-propenylidene]malononitrile (DCTB) at a concentration of 20 mg/mL. A sample solution was prepared by mixing polymer, matrix, and salt in a volume ratio of 5:5:1, respectively. The mixed solution was spotted on a stainless steel target and then left to dry at room temperature. The spectra were collected in a linear mode.                  138  Chapter 5: PLA-PHB-PLA triblock copolymers – synthesis by sequential addition5 In this chapter, I describe the use of a living dinuclear indium catalyst to synthesize poly(lactic acid) (PLA) and poly(hydroxybutyrate) (PHB) PLA-PHB-PLA triblock copolymers. The thermal and mechanical properties of these materials, which were studied in collaboration with the research group of Prof. Savvas Hatzikiriakos (University of British Columbia), will be briefly summarized at the end of the chapter.  5.1 Introduction In recent years, biodegradable polyesters such as poly(lactic acid) (PLA)20 and poly(3-hydroxybutyrate) (PHB)180 have been heavily investigated in a variety of applications such as packaging and drug delivery.181,182  The ring opening polymerization (ROP) of cyclic esters such as lactide and -butyrolactone (BBL), catalyzed by discrete metal complexes has been explored in an attempt to control polymer properties and limit uncontrolled chain transfer / termination events.  However, the brittleness and the relatively weak mechanical properties associated with these crystalline polymers often prohibit processing and wide ranging applications.183   Different parameters are used to evaluate the mechanical properties of a material. Tensile strength is the maximum stress a material can withstand prior to breakage184 The elastic modulus is a measure of the stiffness of a material and is calculated by measuring the slope of a stress-strain curve. Elongation at break is the percent lengthening of a material at breakage, a relatively small elongation at break implies a more brittle material.184                                                   5 This chapter has been published in the journal Macromolecules. 139  A comparison of several mechanical properties of commercial PLA vs. isotactic polypropylene (iPP) (Table 5.1)185,186 shows that while PLA has a higher tensile strength  and a comparable elastic modulus, a much lower elongation at break highlights the problem of brittleness.184   Table 5.1. Selected mechanical propertied of commercial PLA and iPP185,186  PLA iPP Tensile strength (MPa) 50-70 35 Elastic modulus (GPa) 3.7-4.2 5.0 Elongation at break (%) 5.4-3.3 15.6  Blending of various isomeric types of PLA generated from L-lactide (PLLA), D-lactide (PDLA),20 and rac-lactide  (PDLLA) has been implemented to mitigate brittleness and improve other mechanical properties through control of crystallization and morphology.187  Blending of PLLA and PDLA frequently leads to stereocomplex formation with markedly higher melting points than conventional PLAs.188  Another strategy to improve and control mechanical properties is by synthesizing diblock copolymers such as PLLA-b-PDLA which form stereocomplex crystallites of high melting point (above 200 °C).189 These copolymers also exhibit improvement in elongation of break and tensile strength.34 In an attempt to further improve PLA properties such as melting point, elongation at break and tensile strength, copolymers of lactide and other cyclic esters such as glycolide or caprolactone have been developed.190  However, due to the difficulties with the ROP of BBL,180 examples of copolymers of lactide and BBL are rare (Scheme 5.1).191-193 These rare examples show that incorporation of racemic BBL in the middle block of an A-B-A hard-soft-hard triblock produces a biodegradable elastomer, whose mechanical properties can be controlled by the ratio 140  of the hard and soft segments.  In particular, in PLLA-b-PHB-b-PDLA triblocks, the PLLA and PDLA blocks can form stereocomplexes forming a highly crystalline hard segment.   Scheme 5.1. Multistep synthesis of PLLA-b-PHB-b-PLLA polymers by Kimura et al.  In particular, it is very challenging to obtain PHB-containing A-B-C triblocks generated from simple consecutive addition of monomers, in part due to scrambling via transesterification.194  Kimura et al. have reported the formation of PLLA-b-PHB-b-PLLA (A-B-A) polymers through a multistep synthesis (Scheme 5.1) involving the initial tin-catalyzed synthesis of bishydroxy-terminated PHB via ring-opening polymerization of BBL in the presence of 1,4-butanediol, followed by reaction with L-lactide to obtain an (PLLA–PHB–PLLA).195  They found that this triblock exhibited an increased elastic modulus and crystallinity under certain compositions and decrease in its elongation at break compared to pure PLLA and PHB.  These mechanical properties render such materials potentially suitable as biodegradable thermoplastic elastomers.  To our knowledge, there are no examples of well-characterized stereocomplex forming PLLA-PHB-PDLA (A-B-C) triblocks. The Mehrkhodavandi group reported the first example of an indium complex used as an initiator for the living polymerization of rac-lactide to form PLAs with moderate isotactic enrichment and low polydispersity indices (PDIs) (Scheme 5.2).66 We have reported on some properties and applications of these catalysts and the resulting polymers.30,189 The indium catalyst 141  rac-(NNO)InCl]2(-Cl)(-OEt) (17) can catalyze the living homo-polymerization of both lactide and BBL, with very minimal chain transfer / chain termination events.67,141  In particular we have reported on the formation of PLLA-b-PDLA diblocks and studied their rheological and mechanical properties.189 In this chapter, we extend this work to the synthesis and characterization of triblock copolymer containing PLA and PHB via consecutive monomer addition with catalyst 17.   Scheme 5.2. Dinuclear indium catalyst [(NNO)InCl]2(-Cl)(-OEt) (17) for the living homopolymerization of lactide and BBL  5.2 Results PLA-only triblock polymers.  In a previous publication, the Mehrkhodavandi group reported the synthesis of nearly monodispersed diblock copolymers of rac-lactide or D-lactide with L-lactide by sequential living ring-opening polymerization with catalyst 17 (Scheme 5.3).189  142  This technique was also used to synthesize triblock copolymers of different lactide isomers (Table 5.2) by Cuiling Xu, a previous graduate researcher in the group.   Scheme 5.3.  Formation of triblock PLA by sequential addition of lactide  Table 5.2. Summary of synthesized lactide triblock copolymers6 Entry a Wt % LA isomers  (MA-MB-MC) MA : 17 MB : 17 MC : 17 Mn,theob  (kDa) Mn,expt c  (kDa) PDI  1 36L-28DL-36L 423 322 423 168b 169 1.06 2 27L-46DL-27L 294 505 294 157b 190 1.24 3 36L-28DL-36D 426 325 426 170b 152d 1.15d 4 27L-46DL-27D 294 505 294 157b 153d 1.16d a Reactions were carried out in CH2Cl2, 25 °C, [17]o ≈ 1 mM; conversions >98% were observed by 1H NMR spectroscopy after each addition. bCalculated from Mn,theo = (45 gmol–1 + 144 gmol–1 × (MA+MB+MC) × conversion:17). cEntries 1-2 were soluble in THF (2 mg mL–1) and molecular weights were determined by GPC-LLS (flow rate = 0.5 mLmin–1.) Universal calibration was carried out with polystyrene standards.  dSamples were run using a CHCl3 mobile phase (GPC-RI), calibrated with polystyrene standards (flow rate = 1 mLmin–1) with a correction factor of 0.58 for PLA.                                                   6 Data from  MSc dissertation of  Cuiling Xu (University of British Columbia)-2011 143  The triblock polymers (eg. Table 5.2, entry 2) were synthesized in a three-step process. The correlation of the theoretical and expected molecular weights as well as the narrow molecular distributions observed for these triblocks indicated a lack of chain termination events. Triblock copolymers consisting of PLLA and PDLA blocks in each end respectively and a racemic block in the center had not been previously reported.  The ability to generate these triblock polymers can be attributed to the highly controlled nature of ROP with catalyst 17.  PLA-PHB-PLA triblock polymers.  The same strategy was used to synthesize triblock copolymers with different weight percentages of racemic PHB as the middle segment (MB).  The initial goal was to determine whether catalyst 17 was indeed capable of a sequential block polymerization of lactide (MA), BBL (MB), and lactide (MC).  We set out to synthesize a PLLA-b-PHB-b-PLLA triblock with 28 wt% PHB (Scheme 5.4).  The reaction was carried out at 25 °C in dry THF under a nitrogen atmosphere with [17]o ≈ 1 mM with constant stirring.  This is the ideal catalyst concentration under these reaction conditions; a higher concentration (i.e ≥ 1.5 mM) causes polymer precipitation and lower concentrations (~0.75 mM) diminish BBL conversion.     Scheme 5.4. Synthesis of PLA-b-PHB-b-PLA triblock polymers 144  1H NMR spectroscopy was used to determine monomer conversion after each step in the synthesis (Figure 5.1).  The first segment was generated with 426 equiv. of lactide as expected with over >95% conversion.  The second block was generated by addition of 544 equiv. of rac-BBL to the mixture.  Sixteen hours after the addition, the 1H NMR spectrum of the mixture showed that the rac-BBL polymerization had reached ~85% conversion.  Further reaction time did not show any appreciable increase in monomer conversion.  When the in solution concentration of rac-BBL approaches ~80 mM the polymerization ceases under these conditions.  The polymerization of the third and final segment of the triblock was carried out by addition of 426 equiv. L-lactide to the reaction mixture.  After 8 hours, greater than 96% conversion was achieved.  The unreacted BBL monomer showed no appreciable conversion after the addition of the final PLLA block.     145   Figure 5.1. 1H NMR spectra (400 MHz, 25 °C, CDCl3) showing monomer conversion after each monomer addition during the synthesis of 36PLLA-b-28PHB-b-3PLLA triblock copolymer. Reactions were carried out in THF, 25 °C, [17]o ≈ 1 mM. a) First PLLA block showing ~95% conversion after 5 hours. b) PLLA-b-PHB diblock showing ~85% rac-BBL conversion after 16 hours. c) Final PLLA-b-PHB-b-PLLA triblock showing an overall L-lactide conversion of ~96% after 8 hours.    146  Table 5.3. GPC analysis of a PLLA-b-PHB-b-PLLA triblock copolymer with details of polymers formed after each monomer addition Entry a Sample MA : 17 MB : 17 MC : 17 Mn,theo b (kDa) Mn,expt c  (kDa) PDI c 1 PLLA 426 – – 59 57.5 1.11 2 PLLA-b-PHB 426 544 – 101 84.3 1.29 3 PLLA-b-PHB-b-PLLA 426 544 426 159 120 1.19 aReactions were carried out in THF, 25 °C, [17]o ≈ 1 mM. Conversions were determined by 1H NMR spectroscopy with each block. bCalculated from Mn,theo = 45 gmol–1 +144 gmol–1 × (MA+MC):17 × conversion  + 86 gmol–1 × (MB):17  × conversion. cGPC measurements in CHCl3 (GPC-RI), calibrated with polystyrene standards (flow rate = 1 mLmin–1).  The results were multiplied by a correction factor (X), calculated by the X = 0.58 × nPLA + 0.54 × nPHB (nPLA = mole fraction of PLA in sample, nPHB = mole fraction of PHB in sample.) 196   To confirm the synthesis of a triblock copolymer GPC analysis was carried out after formation of each polymer block (Table 5.3).  The diblock and triblock polymers were not soluble in THF, thus GPC analysis was carried out in CHCl3.  Correction factors for PLA (0.58) and PHB (0.54) were used to determine molecular weights obtained from GPC-RI in CHCl3 against polystyrene calibration standards.  For the diblocks and triblocks, correction factors were calculated by considering the amounts of PLA and PHB in the polymers as indicated in the Table 5.3 footnote.196  The GPC data clearly show a stepwise increase in the Mn values with each monomer addition indicating the synthesis of a triblock.  The molecular weight distributions show well-controlled living polymerization of L-lactide in the first block as expected (PDI = 1.11).  However, after the formation of the PLLA-PHB diblock, the PDI increases to 1.29.  This slight increase in molecular weight distribution is apparent in the GPC trace of diblock (Figure 5.2).  The experimental Mn (101 kDa) is 20% higher than the theoretical value (84.3 kDa) and is 147  consistent with some catalyst decomposition as reported previously for the polymerization of BBL with catalyst 17.  Addition of the third block of L-lactide results in an increase in Mn, with the theoretical value (159 kDa) higher than the theoretical value (120 kDa), as expected with decomposition of ~20% of the growing polymer chains after the second addition.  However, it is clear that the [In]-PHB-PLLA chain ends are still living, and after addition of the third block do form the triblock PLLA-b-PHB-b-PLLA in a living fashion and with low polydispersity.    Figure 5.2.  Overlap of GPC traces for the synthesis of 27L-46LD-27L.  Right (-----) MA (Mn = 57.1 kDa, PDI = 1.11).  Middle (— —) MA+MB (Mn = 84.2 kDa, PDI = 1.29). Left ( ) MA+MB+MC (Mn = 119.5 kDa, PDI = 1.19).  -0.200.20.40.60.813 5 7 8 10PLLAPLLA/PHBPLLA/PHB/PLLARefractive index Retention time (min) 148  In order to study the thermal and mechanical properties of these novel polymers, we synthesized a series of PLA-PHB-PLA triblocks with varying PHB content and lactide stereoisomers (Table 5.4).  It should be noted that the rac-BBL was rigorously dried over CaH2 and freshly distilled prior to each polymerization.  Omission of this step resulted in the failure of the catalyst to polymerize the BBL.  During the synthesis, the polymers with the highest PHB content (36L-28BBL-36L) reached the maximum conversion of BBL (~85%), while the 36L-5BBL-36L triblock only achieved ~72% conversion.  This can be attributed to the fact that at a low monomer concentration the catalyst ceases to polymerize.     Table 5.4. Summary of synthesized PLLA-b-PHB-b-PLA copolymers Entrya Mol % LA isomers  (MA-MB-MC) MA : 1 MB : 1 MC : 1 Mn,theo (kDa)b Mn,expt  (kDa)c PDI PHB % 1 36L-28BBL-36L 426 544 426 152 115 1.25 26 2 45L-10BBL-45L 530 197 530 154 126 1.16 8.2 3 47L-5BBL-47L 559 99 559 156 130 1.25 3.9 4 36L-28BBL-36D 426 544 426 157 113 1.32 29 5 45L-10BBL-45D 530 197 530 158 129 1.27 9.3 6 47L-5BBL-47D 559 99 559 156 138 1.22 4.5 a  Reactions were carried out in THF, 25 °C, [1]o ≈ 1 mM at the beginning of the polymerization.  Conversions were determined by 1H NMR spectroscopy with each block. b  Calculated from Mn,theo = 45 gmol–1 +144 gmol–1 × (MA+MC):1 × conversion  + 86 gmol–1 × (MB):1   × conversion. c GPC measurements were in CHCl3 (GPC-RI), calibrated with polystyrene standards (flow rate = 1 mLmin–1)  The results were multiplied by a correcting factor (X), X = 0.58 × nPLA + 0.54 × nPHB (nPLA = mole fraction of PLA in sample, nPHB = mole fraction of PHB in sample.196   149  Thermal study of triblock polymers.7 Our study into properties of copolymers began  with a comparison of the melting temperatures (Tm) and glass transition temperature (Tg, temperature at which an amorphous “glassy” solid becomes  a rubber-like with increased thermal motion of polymer chains) 184 of the PLA-only triblocks (Table 5.5) and those containing PHB in the centre block (Table 5.6).  Triblock copolymers of PLLA-b-PDLLA-b-PLLA with 36% PLLA at each end (Table 5.5, entry 1) show a melting temperature of 168.9 °C.  As the PLLA length decreases to 27% the polymer becomes amorphous as no melting peak is detected during second heating (Table 5.5, entry 2).  In contrast, triblocks incorporating PDLA possess exclusively stereocomplex crystallites with only one melting temperature (Table 5.5, entries 3,4).  As seen above, the melting temperature and crystallinity of the stereocomplex decreases with decreasing the PLLA and PDLA length; 36L-28DL-36D has a higher melting temperature than the triblock with shorter L- and D- blocks.   Table 5.5. The glass transition temperature, Tg, the melting peak temperature, Tm, of the PLA triblock copolymers. Entry wt % of monomers  (MA-MB-MC) Tg  (°C) Tm (°C) 1 36L-28DL-36L 53.3 168.9 2 27L-46DL-27L 57.3 - 3 36L-28DL-36D 62.8 212.8 4 27L-46DL-27D 62.8 208.4                                                     7 The study of thermal and mechanical properties of PLA only triblocks were carried out by Dr. Norhayani Othman (Department of Chemical and Biological Engineering-University of British Columbia)  150  Table 5.6. The glass transition temperature, Tg, the melting peak temperature, Tm of triblock copolymers having PHB in the center block.8 Entry wt % of monomers  (MA-MB-MC) Tg  (°C) Tm  (°C) 1 47L-5BBL-47L 53.2 171.3 2 45L-10BBL-45L 48.6 171.0 3 36L-28BBL-36L 38.71 166.7 4 47L-5BBL-47D 4.5 207.6 5 45L-10BBL-45D 6.4 204.8 6 36L-28BBL-36D 4.8 208.9  Copolymers with atactic PHB as the middle block also display one melting temperature as an indication of stereocomplex crystallites.  The melting temperature of a triblock copolymer of PLLA-b-PHB-b-PLLA with 47% PLLA at each end (Table 5.6, entry 1) is 171.3 °C (typical for crystalline PLA), which is slightly lowered by decreasing the length of the PLLA segments.   Triblocks with PLLA and PDLA at each end (Table 5.6, entries 4, 5 and 6) also show one melting peak at much higher temperatures compared to polymers with PLLA at each end but a lower glass Tg values.  Longer L- and D- blocks result in higher melting temperature.  These melting temperatures are well above 200 °C and correspond to the formation of stereocomplex crystallites, as seen in the PLLA-PDLLA-PDLA triblocks (entries 3 and 4 of Table 5.5).  Similar observations were made by Woo et al. who reported that the crystallization of stereocomplex PLA was significantly hindered in blends with PHB and less perfect crystals were found with increasing PHB content.187                                                    8 The study of thermal and mechanical properties of PHB containing triblocks were carried out in collaboration with Dr. Nazbanoo Noroozi (Department of Chemical and Biological Engineering-University of British Columbia) 151  Tensile properties of triblock copolymers.  The tensile properties of the triblock copolymers were measured (Table 5.7).  For the PLA-only copolymers, the elastic modulus of triblocks remains unchanged regardless of the outer block and block length ratio of PLA (Table 5.7, entries 1-4).  The tensile strength of copolymers PLLA-b-PDLLA-b-PLLA and PLLA-b-PDLLA-b-PDLA with 28% PDLLA are comparable to that of PLLA, whereas the tensile strength of copolymers with 46% PDLLA decreases slightly with the value comparable to the tensile strength of PDLLA.197  Improvements of 85% and 77% were found in the elongation at break for copolymers PLLA-b-PDLLA-b-PLLA as compared to PLLA.  The elongation at break of triblocks PLLA-b-PDLLA-b-PDLA was higher compared to the copolymers without stereocomplex formation.197,198   Table 5.7. Tensile properties of triblock copolymers Entry Samples Tensile strength (MPa) Elastic modulus (MPa) Elongation at break (%) 1 36L-28DL-36L 56±2 2548±124 4.8±0.1 2 27L-46DL-27L 40±4 2674±118 4.6±0.3 3 36L-28DL-36D 58±4 2637±110 3.5±0.1 4 27L-46DL-27D 45±6 2654±102 2.8±0.1 5 47L-5BBL-47L 34±1.5 847±149 9.7±0.1 6 45L-10BBL-45L 40±7.6 729±116 14.2±0.6 7 36L-28BBL-36L 20±1.7 338±2 21.0±1.1 8 47L-5BBL-47D 33±2.1 548±32 10.6±1.7 10 36L-28BBL-36D 15±1.7 431±85 7.3±0.9  In comparison, triblocks incorporating PHB show a significant drop in tensile properties as compared to those having only PLA blocks.  However, the elongation at break of these 152  copolymers improved significantly compared to PLA only triblocks due to the elastomeric nature of atactic PHB.  We observed that shorter blocks of PLLA and PDLA and a longer block of PHB decreases the tensile strength of triblocks.  These results agree with literature reports195 and highlight the elastomeric nature of PLLA-b-PHB-b-PLLA triblocks.  The elongation at break of PLLA-b-PHB-b-PLLA copolymers improved about 10 times compared to pure PLLA.  It should be noted that Kimura et al. studied lower molecular weight PHB (Mn = 31 kDa), which is miscible with PLLA.195  In contrast, high molecular weight PHB blocks used in our study can be phase-separated from PLA.  This could be the reason for the poor tensile properties observed in the present study for triblocks with 28% PHB.  5.3 Conclusion The dinuclear indium catalyst [(NNO)InCl]2(-OEt)(-Cl) (17), previously reported to be highly active for the living ring opening polymerization of cyclic esters, lactide and -butyrolactone, was used to generate a series of triblock copolymers of poly(lactic acid) (PLA) and poly(hydroxybutyrate) (PHB).  Copolymers PLLA-PDLLA-PLLA and PLLA-PDLLA-PDLA, synthesized via sequential monomer addition, showed low molecular weight distributions and excellent correlation between the calculated and experimental molecular weights.  Significantly, triblock copolymers of the type PLA-b-PHB-b-PLA were also synthesized for the first time though a sequential addition technique.  Analysis of the polymers after each monomer addition showed that although only 85% conversion is achieved after addition of BBL, the remaining chains were active and addition of more lactide yields a triblock.  Due to their 153  elastomeric nature, these triblocks exhibited an elongation at break, about five-to-ten times greater than that of corresponding PLLA-b-PDLLA-b-PLDA triblocks.  5.4 Experimental section General considerations. All the air and moisture sensitive manipulations were carried out in an MBraun glove box or using standard Schlenk line techniques. A Bruker Avance 300 MHz or 400 MHz spectrometer was used to record 1H spectra. 1H NMR chemical shifts are given in ppm versus residual protons in deuterated solvents as follows:  7.27 CDCl3.  GPC measurements were done using a CHCl3 mobile phase (GPC-RI), calibrated with monodispersed polystyrene standards (Polymer Laboratories) in the range of 9000 - 233000 g/mol. A flow rate of 1 mL/min with a Waters Styragel column (HR4) was used, and the detection was through a Waters model 2410 refractive index detector. The measurements were carried out at laser wavelength of 690 nm, at 25 °C. The results were multiplied by a correction factor of 0.58 for PLA.199  The data were processed using the Astra software provided by Wyatt Technology Corp. A differential scanning calorimeter (DSC) Q1000 (TA Instruments) was employed to measure the glass transition (Tg) and melting (Tm) temperatures.  Materials. THF was dried over sodium/benzophenone, distilled and degassed prior to use. CDCl3 was dried over CaH2, transferred under vacuum and degassed through three freeze-pump-thaw cycles before use. L- and D-lactide were donated by Purac Biomaterials and recrystallized twice in toluene. β-butyrolactone, purchased from Aldrich, was stirred with CaH2 for 48 hours, distilled under vacuum, degassed through three freeze-pump-thaw cycles and kept in the freezer at −35 °C.  The catalyst [(NNO)InCl]2(-Cl)(-OEt) (17) was prepared according to previously published procedures.66  154  Representative synthesis of lactide/butyrolactone triblock copolymers   Complex 17 (22 mg, 0.020 mmol) was dissolved in THF and transferred to a round bottom flask. While stirring, a solution of L-lactide in THF (1.226 g, 8.514 mmol) was added. Approximately 20 mL of THF was used.  The polymerization was allowed to stir for a four hours and a 1H NMR spectrum was obtained to establish monomer conversion. A volume of 0.5 mL of the reaction mixture was withdrawn for GPC analysis. Then a solution of the second monomer rac-BBL (0.840 mL, 10.3 mmol) in THF (1 mL) was added to the reaction. A 1H NMR spectrum was obtained after 16 hours to establish monomer conversion and 0.5 mL of the reaction mixture was withdrawn for GPC analysis. A solution of the third monomer L-lactide (1.222 g, 8.486 mmol) in THF (5 mL) was added to the reaction mixture. The reaction was allowed to stir for 8 hours and then quenched with 0.5 mL of 1.5 M HCl in Et2O. A few drops of the mixture were removed to check monomer conversion by 1H NMR spectroscopy and the remaining mixture was concentrated under vacuum and the polymer was precipitated with cold MeOH. The resulting polymer was washed with cold MeOH (3 × 3 mL) and dried under vacuum. The polymer was then redissolved in CH2Cl2, a thermal stabilizer tris-nonylphenylphosphite (TNPP) (0.35 wt% of polymer) was added and the solvent was removed under vacuum overnight.  DSC measurement of PLA homopolymers and copolymers  The experiments were carried out under a nitrogen atmosphere.  Approximately 2–3 mg of the samples were weighed and sealed in an aluminum pan. The samples were heated at a rate of 10 °C/min from 40 to 200 °C and held isothermally for 5 min to destroy any residual crystal 155  nuclei before cooling at 5 °C/min. The transition and melting temperatures were obtained from a second heating sequence, performed at 10 °C/min.   Measurement of mechanical properties  Tensile tests were performed using COM-TEN 95 series tensile testing equipment (COM-TEN Industries) at ambient conditions. Tensile specimens were cut from compression-molded films. The films were compressed in a hot press at high temperature before being slowly cooled.  Specimen of 36.6 mm in width and 90 mm in length were cut from the middle portion of the compressed films to avoid edge effects and edge imperfections.  A gage length of 40 mm, crosshead speed of 25 mm/min and a 40 pound (178 N) capacity of load cell was used for testing all samples. To eliminate specimen slippage from the grips, double adhesive masking tape was used to wrap around the top and bottom portions of the sample. For each sample five tests were run. The average modulus, tensile stress and elongation at break were calculated from the resultant stress-strain measurements and these are reported below along with standard deviations shown by the plotted error bars.         156  Chapter 6: Conclusions and future directions In this thesis I attempted to highlight the importance of indium based catalysts for the ROP polymerization of cyclic esters. During my PhD the goals were (1) to synthesize discrete indium complexes as isoselective catalysts for lactide polymerization, (2) to study ligand substitution effects on reactivity and selectivity toward lactide polymerization and to understand the nature of the catalytically active propagating species, and (3) to use indium catalysts to generate different polymer architectures through the sequential polymerization of cyclic esters.   The synthesis of discrete indium alkoxide complexes can be challenging due to pronounced aggregation and a lack of widely applicable synthetic routes. In chapter 2, several synthetic routes to access indium salen alkoxide complexes are described. A two-step route and a one-pot synthesis are reported for the synthesis dinuclear [(ONNR1OR2)InOEt]2 complexes. A salt metathesis route to generate mononuclear (ONNR1OR2)InOCH2Pyr is also described. Notably, the use of a coordinating alkoxide to generate stable mononuclear compounds has the potential to become a broadly applicable strategy to access indium alkoxide compounds. In the future, the use of this strategy with NNO type tridentate ligands and other salen ligands with different substituents can be attempted. This also offers a viable route to functionalize polymer chain-ends with various coordinating alkoxides.  As highlighted in chapter 3, indium salen complexes are highly active and isoselective catalysts for the ROP of lactide.  Evidence for a site selective mechanism in these catalysts to generate isotactic PLA is presented.  Mechanistic investigations have shown evidence consistent with mononuclear propagating species during polymerization. A computational study to investigate the different rates of polymerization observed between these systems and the aluminum analogues would be beneficial in gaining a fundamental understanding about these 157  catalysts. The future work would focus on the development of indium salen catalysts with different ligand backbones and substituents in order to improve the isoselectivity of these systems while maintaining the reactivity.  The work in chapter 4 reported the first synthesis indium salbinap complexes and their activity toward lactide polymerization. In this study we highlight the differences in reactivity and selectivity between aluminum and indium salbinap complexes. These systems were sluggish initiators with modest stereoselectivity for lactide polymerization. The use of a coordinating alkoxide to generate mononuclear analogues would help further our understanding of these systems.      In chapter 5 we describe the use of a dinuclear indium catalyst to generate triblock copolymers of poly(lactide acid) (PLA) and poly(3-hydroxybutyrate) (PHB) using a simple sequential addition method. This is a proof of concept that can be extended to generate diverse arrange of copolymers by using different cyclic esters. This could generate materials with different thermal and mechanical properties that can be fine-tuned by changing the size of each segment in the copolymer.                  158  Bibliography 1. Brydson, J. A., Plastics materials. Butterworth-Heinemann: 1999. 2. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/1963/ Retrieved - August 31, 2014. 3. Kaminsky, W., Macromol. Chem. Phys. 2008, 209, 459-466. 4. Gahleitner, M.; Resconi, L.; Doshev, P., MRS Bull. 2013, 38, 229-233. 5. Environmental impact of polymers. In Polymers and the Environment, Scott, G., Ed. The Royal Society of Chemistry: 1999; pp 19-37. 6. http://www.nytimes.com/2014/08/26/opinion/choking-the-oceans-with-plastic.html Retrieved - August 31, 2014. 7. Gross, R. A.; Kalra, B., Science 2002, 297, 803-807. 8. Amass, W.; Amass, A.; Tighe, B., Polym. Int. 1998, 47, 89-144. 9. http://www.cheminst.ca/magazine/feature-story/many-faces-bioplastics Retrieved - Aug 31, 2014. 10. http://www.cheminst.ca/sites/default/files/pdfs/ACCN/BackIssues/2012%20-%2008%20September.pdf Retrieved - Aug 31, 2014. 11. Garlotta, D., J. Polym. Environ. 2001, 9, 63-84. 12. Woodruff, M. A.; Hutmacher, D. W., Prog. Polym. Sci. 2010, 35, 1217-1256. 13. Qi, Q.; Rehm, B. H. A., Microbiology 2001, 147, 3353-3358. 14. Rieth, L. R.; Moore, D. R.; Lobkovsky, E. B.; Coates, G. W., J. Am. Chem. Soc. 2002, 124, 15239-15248. 15. Xu, C.; Yu, I.; Mehrkhodavandi, P., Chem. Commun. 2012, 48, 6806-6808. 16. Jamshidian, M.; Tehrany, E. A.; Imran, M.; Jacquot, M.; Desobry, S., Comp. Rev.  Food. Sci. F. 2010, 9, 552-571. 17. http://www.purac.com/EN/Bioplastics/PLA-applications.aspx Retrieved - Aug 31, 2014. 18. Kamber, N. E.; Jeong, W.; Waymouth, R. M.; Pratt, R. C.; Lohmeijer, B. G. G.; Hedrick, J. L., Chem. Rev. 2007, 107, 5813-5840. 19. Chen, G.-Q.; Patel, M. K., Chem. Rev. 2011, 112, 2082-2099. 20. Drumright, R. E.; Gruber, P. R.; Henton, D. E., Adv. Mater. 2000, 12, 1841-1846. 21. Jenkins, A. D.; Kratochvíl, P.; Stepto, R. F. T.; Suter, U. W., Pure Appl. Chem. 1996, 68, 2287-2289. 22. Stepto, R. F. T.; Gilbert, R. G.; Hess, M.; Jenkins, A. D.; Jones, R. G.; P., K., Pure Appl. Chem. 2009, 81, 351-353. 23. Asano, S.; Aida, T.; Inoue, S., J. Chem. Soc., Chem. Commun. 1985, 1148-1149. 24. Ajellal, N.; Carpentier, J.-F.; Guillaume, C.; Guillaume, S. M.; Helou, M.; Poirier, V.; Sarazin, Y.; Trifonov, A., Dalton Trans. 2010, 39, 8363-8376. 25. van Hummel, G. J.; Harkema, S.; Kohn, F. E.; Feijen, J., Acta Crystallogr. Sect. B: Struct. Sci. 1982, 38, 1679-1681. 26. Kleine, V. J.; Kleine, H.-H., Die Makromolekulare Chemie 1959, 30, 23-38. 27. Zell, M. T.; Padden, B. E.; Paterick, A. J.; Thakur, K. A. M.; Kean, R. T.; Hillmyer, M. A.; Munson, E. J., Macromolecules 2002, 35, 7700-7707. 28. Chabot, F.; Vert, M.; Chapelle, S.; Granger, P., Polymer 1983, 24, 53-59. 29. Ovitt, T. M.; Coates, G. W., J. Am. Chem. Soc. 2002, 124, 1316-1326. 159  30. Othman, N.; Acosta-Ramírez, A.; Mehrkhodavandi, P.; Dorgan, J. R.; Hatzikiriakos, S. G., J. Rheol.  2011, 55, 987-1005. 31. Perego, G.; Cella, G. D.; Bastioli, C., J. Appl. Polym. Sci. 1996, 59, 37-43. 32. Dechy-Cabaret, O.; Martin-Vaca, B.; Bourissou, D., Chem. Rev. 2004, 104, 6147-6176. 33. David, E. H.; Patrick, G.; Jim, L.; Jed, R., Polylactic Acid Technology. In Natural Fibers, Biopolymers, and Biocomposites, CRC Press: 2005. 34. Silvino, A. C.; Corrêa, P. S.; Dias, M. L., J. Appl. Polym. Sci. 2014, 131, n/a-n/a. 35. Aluthge, D. C.; Xu, C.; Othman, N.; Noroozi, N.; Hatzikiriakos, S. G.; Mehrkhodavandi, P., Macromolecules 2013, 46, 3965-3974. 36. Ikada, Y.; Jamshidi, K.; Tsuji, H.; Hyon, S. H., Macromolecules 1987, 20, 904-906. 37. Fukushima, K.; Hirata, M.; Kimura, Y., Macromolecules 2007, 40, 3049-3055. 38. Dittrich, W.; Schulz, R. C., Angew. Makromol. Chem. 1971, 15, 109. 39. Duda, A.; Penczek, S., Macromolecules 1990, 23, 1636-1639. 40. Ovitt, T. M.; Coates, G. W., J. Am. Chem. Soc. 1999, 121, 4072-4073. 41. Dijkstra, P. J.; Du, H.; Feijen, J., Polym. Chem. 2011, 2, 520-527. 42. Chisholm, M. H.; Patmore, N. J.; Zhou, Z. P., Chem. Commun. 2005, 127-129. 43. Stanford, M. J.; Dove, A. P., Chem. Soc. Rev. 2010, 39, 486-494. 44. Dutta, S.; Hung, W.-C.; Huang, B.-H.; Lin, C.-C., Recent Developments in Metal-Catalyzed Ring-Opening Polymerization of Lactides and Glycolides: Preparation of Polylactides, Polyglycolide, and Poly(lactide-co-glycolide). In Synthetic Biodegradable Polymers, Rieger, B.; Künkel, A.; Coates, G. W.; Reichardt, R.; Dinjus, E.; Zevaco, T. A., Eds. Springer Berlin Heidelberg: 2012; Vol. 245, pp 219-283. 45. Degée, P.; Dubois, P.; Jerôme, R.; Jacobsen, S.; Fritz, H. G., Macromol. Symp. 1999, 144, 289. 46. Kricheldorf, H. R.; Kreiser-Saunders, I.; Stricker, A., Macromolecules 2000, 33, 702-709. 47. Veld, P. J. A. i. t.; Velner, E. M.; Witte, P. v. d.; Hamhuis, J.; Dijkstra, P. J.; Feijen, J., J. Pol. Sci. A 1997, 35, 219-226. 48. Hao, J.; Granowski, P. C.; Stefan, M. C., Macromol. Rapid Commun. 2012, 33, 1294-1299. 49. Schwach, G.; Coudane, J.; Engel, R.; Vert, M., Polym. Bull. 1996, 37, 771-776. 50. Dorgan, J.; Lehermeier, H.; Mang, M., J. Polym. Environ. 2000, 8, 1-9. 51. Connor, E. F.; Nyce, G. W.; Myers, M.; Möck, A.; Hedrick, J. L., J. Am. Chem. Soc. 2002, 124, 914-915. 52. Myers, M.; Connor, E. F.; Glauser, T.; Möck, A.; Nyce, G.; Hedrick, J. L., J. Polym. Sci., Part A: Polym. Chem. 2002, 40, 844-851. 53. Chamberlain, B. M.; Cheng, M.; Moore, D. R.; Ovitt, T. M.; Lobkovsky, E. B.; Coates, G. W., J. Am. Chem. Soc. 2001, 123, 3229-3238. 54. Cheng, M.; Attygalle, A. B.; Lobkovsky, E. B.; Coates, G. W., J. Am. Chem. Soc. 1999, 121, 11583-11584. 55. Drouin, F. d. r.; Oguadinma, P. O.; Whitehorne, T. J. J.; Prud’homme, R. E.; Schaper, F., Organometallics 2010, 29, 2139-2147. 56. Liu, P.; Feng, X.-J.; He, R., Tetrahedron 2010, 66, 631-636. 57. Williams, C. K.; Breyfogle, L. E.; Choi, S. K.; Nam, W.; Young, V. G.; Hillmyer, M. A.; Tolman, W. B., J. Am. Chem. Soc. 2003, 125, 11350-11359. 58. Labourdette, G.; Lee, D. J.; Patrick, B. O.; Ezhova, M. B.; Mehrkhodavandi, P., Organometallics 2009, 28, 1309-1319. 160  59. Darensbourg, D. J.; Karroonnirun, O., Macromolecules 2010, 43, 8880-8886. 60. Darensbourg, D. J.; Karroonnirun, O., Inorg. Chem. 2010, 49, 2360-2371. 61. Chen, H.-Y.; Tang, H.-Y.; Lin, C.-C., Macromolecules 2006, 39, 3745-3752. 62. Tang, H.-Y.; Chen, H.-Y.; Huang, J.-H.; Lin, C.-C., Macromolecules 2007, 40, 8855-8860. 63. Huang, Y.; Hung, W.-C.; Liao, M.-Y.; Tsai, T.-E.; Peng, Y.-L.; Lin, C.-C., J. Polym. Sci., Part A: Polym. Chem. 2009, 47, 2318-2329. 64. Wu, J. C.; Huang, B. H.; Hsueh, M. L.; Lai, S. L.; Lin, C. C., Polymer 2005, 46, 9784-9792. 65. Wang, H. B.; Ma, H. Y., Chem. Commun. 2013, 49, 8686-8688. 66. Douglas, A. F.; Patrick, B. O.; Mehrkhodavandi, P., Angew. Chem. 2008, 120, 2322-2325. 67. Yu, I.; Acosta-Ramirez, A.; Mehrkhodavandi, P., J. Am. Chem. Soc. 2012, 134, 12758-12773. 68. Schwarz, A. D.; Thompson, A. L.; Mountford, P., Inorg. Chem. 2009, 48, 10442-10454. 69. Schwarz, A. D.; Chu, Z. Y.; Mountford, P., Organometallics 2010, 29, 1246-1260. 70. Blake, M. P.; Schwarz, A. D.; Mountford, P., Organometallics 2011, 30, 1202-1214. 71. Kim, Y.; Jnaneshwara, G. K.; Verkade, J. G., Inorg. Chem. 2003, 42, 1437-1447. 72. Gendler, S.; Segal, S.; Goldberg, I.; Goldschmidt, Z.; Kol, M., Inorg. Chem. 2006, 45, 4783-4790. 73. Chmura, A. J.; Davidson, M. G.; Frankis, C. J.; Jones, M. D.; Lunn, M. D., Chem. Commun. 2008, 1293-1295. 74. Chmura, A. J.; Chuck, C. J.; Davidson, M. G.; Jones, M. D.; Lunn, M. D.; Bull, S. D.; Mahon, M. F., Angew. Chem. Int. Edit. 2007, 46, 2280-2283. 75. Chmura, A. J.; Davidson, M. G.; Jones, M. D.; Lunn, M. D.; Mahon, M. F.; Johnson, A. F.; Khunkamchoo, P.; Roberts, S. L.; Wong, S. S. F., Macromolecules 2006, 39, 7250-7257. 76. Bonnet, F.; Cowley, A. R.; Mountford, P., Inorg. Chem. 2005, 44, 9046-9055. 77. Dyer, H. E.; Huijser, S.; Susperregui, N.; Bonnet, F.; Schwarz, A. D.; Duchateau, R.; Maron, L.; Mountford, P., Organometallics 2010, 29, 3602-3621. 78. Cai, C.-X.; Amgoune, A.; Lehmann, C. W.; Carpentier, J.-F., Chem. Commun. 2004, 330-331. 79. Amgoune, A.; Thomas, C. M.; Roisnel, T.; Carpentier, J. F., Chem. Eur. J. 2006, 12, 169-179. 80. Amgoune, A.; Thomas, C. M.; Carpentier, J. F., Macromol. Rapid Commun. 2007, 28, 693-697. 81. Amgoune, A.; Thomas, C. M.; Ilinca, S.; Roisnel, T.; Carpentier, J. F., Angew. Chem. Int. Edit. 2006, 45, 2782-2784. 82. Aida, T.; Inoue, S., Acc. Chem. Res. 1996, 29, 39-48. 83. Aida, T.; Inoue, S., J. Am. Chem. Soc. 1983, 105, 1304-1309. 84. Trofimoff, L.; Aida, T.; Inoue, S., Chem. Lett. 1987, 16, 991-994. 85. Yasuda, T.; Aida, T.; Inoue, S., Die Makromolekulare Chemie, Rapid Communications 1982, 3, 585-588. 86. Shimasaki, K.; Aida, T.; Inoue, S., Macromolecules 1987, 20, 3076-3080. 87. Endo, M.; Aida, T.; Inoue, S., Macromolecules 1987, 20, 2982-2988. 88. Buffet, J.-C.; Davin, J. P.; Spaniol, T. P.; Okuda, J., New J. Chem. 2011, 35, 2253-2257. 89. Buffet, J.-C.; Okuda, J., Dalton Trans. 2011, 40, 7748-7754. 90. Frediani, M.; Sémeril, D.; Mariotti, A.; Rosi, L.; Frediani, P.; Rosi, L.; Matt, D.; Toupet, L., Macromol. Rapid Commun. 2008, 29, 1554-1560. 161  91. Cozzi, P. G., Chem. Soc. Rev. 2004, 33, 410-421. 92. Zhang, W.; Loebach, J. L.; Wilson, S. R.; Jacobsen, E. N., J. Am. Chem. Soc. 1990, 112, 2801-2803. 93. Matsumoto, K.; Saito, B.; Katsuki, T., Chem. Commun. 2007, 3619-3627. 94. Vincens, V.; Le Borgne, A.; Spassky, N., Makromolekulare Chemie. Macromolecular Symposia 1991, 47, 285-291. 95. Le Borgne, A.; Vincens, V.; Jouglard, M.; Spassky, N., Makromolekulare Chemie. Macromolecular Symposia 1993, 73, 37-46. 96. Spassky, N.; Wisniewski, M.; Pluta, C.; LeBorgne, A., Macromol. Chem. Phys. 1996, 197, 2627-2637. 97. Montaudo, G.; Montaudo, M. S.; Puglisi, C.; Samperi, F.; Spassky, N.; LeBorgne, A.; Wisniewski, M., Macromolecules 1996, 29, 6461-6465. 98. Ovitt, T. M.; Coates, G. W., J. Polym. Sci. Pol. Chem. 2000, 38, 4686-4692. 99. Radano, C. P.; Baker, G. L.; Smith, M. R., J. Am. Chem. Soc. 2000, 122, 1552-1553. 100. Majerska, K.; Duda, A., J. Am. Chem. Soc. 2004, 126, 1026-1027. 101. Zhong, Z. Y.; Dijkstra, P. J.; Feijen, J., Angew. Chem. Int. Edit. 2002, 41, 4510-4513. 102. Zhong, Z. Y.; Dijkstra, P. J.; Feijen, J., J. Am. Chem. Soc. 2003, 125, 11291-11298. 103. Chisholm, M. H.; Gallucci, J. C.; Quisenberry, K. T.; Zhou, Z., Inorg. Chem. 2008, 47, 2613-2624. 104. Pilone, A.; Press, K.; Goldberg, I.; Kol, M.; Mazzeo, M.; Lamberti, M., J. Am. Chem. Soc. 2014, 136, 2940-2943. 105. Maudoux, N.; Roisnel, T.; Dorcet, V.; Carpentier, J.-F.; Sarazin, Y., Chem. Eur. J. 2014, 20, 6131-6147. 106. Jhurry, D.; Bhaw-Luximon, A.; Spassky, N., Macromolecular Symposia 2001, 175, 67-79. 107. Nomura, N.; Ishii, R.; Akakura, M.; Aoi, K., J. Am. Chem. Soc. 2002, 124, 5938-5939. 108. Nomura, N.; Ishii, R.; Yamamoto, Y.; Kondo, T., Chem. Eur. J. 2007, 13, 4433-4451. 109. Tang, Z.; Chen, X.; Pang, X.; Yang, Y.; Zhang, X.; Jing, X., Biomacromolecules 2004, 5, 965-970. 110. Tang, Z.; Chen, X.; Yang, Y.; Pang, X.; Sun, J.; Zhang, X.; Jing, X., J. Polym. Sci., Part A: Polym. Chem. 2004, 42, 5974-5982. 111. Chen, H.-L.; Dutta, S.; Huang, P.-Y.; Lin, C.-C., Organometallics 2012, 31, 2016-2025. 112. Hormnirun, P.; Marshall, E. L.; Gibson, V. C.; Pugh, R. I.; White, A. J. P., PNAS 2006, 103, 15343-15348. 113. Hormnirun, P.; Marshall, E. L.; Gibson, V. C.; White, A. J. P.; Williams, D. J., J. Am. Chem. Soc. 2004, 126, 2688-2689. 114. Du, H.; Velders, A. H.; Dijkstra, P. J.; Sun, J.; Zhong, Z.; Chen, X.; Feijen, J., Chem. Eur. J. 2009, 15, 9836-9845. 115. Du, H.; Velders, A. H.; Dijkstra, P. J.; Zhong, Z.; Chen, X.; Feijen, J., Macromolecules 2009, 42, 1058-1066. 116. Pang, X.; Chen, X.; Du, H.; Wang, X.; Jing, X., J. Organomet. Chem. 2007, 692, 5605-5613. 117. Bouyahyi, M.; Grunova, E.; Marquet, N.; Kirillov, E.; Thomas, C. M.; Roisnel, T.; Carpentier, J. F., Organometallics 2008, 27, 5815-5825. 118. Bouyahyi, M.; Roisnel, T.; Carpentier, J. F., Organometallics 2010, 29, 491-500. 119. Aluthge, D. C.; Patrick, B. O.; Mehrkhodavandi, P., Chem. Commun. 2013, 49, 4295-4297. 162  120. Aluthge, D. C.; Yan, E. X.; Ahn, J. M.; Mehrkhodavandi, P., Inorg. Chem. 2014, 53, 6828-6836. 121. Balasanthiran, V.; Chisholm, M. H.; Durr, C. B.; Gallucci, J. C., Dalton Trans. 2013, 42, 11234-11241. 122. Normand, M.; Kirillov, E.; Roisnel, T.; Carpentier, J. F., Organometallics 2012, 31, 1448-1457. 123. Maudoux, N.; Roisnel, T.; Carpentier, J.-F.; Sarazin, Y., Organometallics 2014. 124. Gregson, C. K. A.; Blackmore, I. J.; Gibson, V. C.; Long, N. J.; Marshall, E. L.; White, A. J. P., Dalton Trans. 2006, 3134-3140. 125. Saha, T. K.; Ramkumar, V.; Chakraborty, D., Inorg. Chem. 2011, 50, 2720-2722. 126. Tsai, C.-Y.; Du, H.-C.; Chang, J.-C.; Huang, B.-H.; Ko, B.-T.; Lin, C.-C., RSC Advances 2014, 4, 14527-14537. 127. Broderick, E. M.; Diaconescu, P. L., Inorg. Chem. 2009, 48, 4701-4706. 128. Gregson, C. K. A.; Gibson, V. C.; Long, N. J.; Marshall, E. L.; Oxford, P. J.; White, A. J. P., J. Am. Chem. Soc. 2006, 128, 7410-7411. 129. Bakewell, C.; Cao, T.-P.-A.; Long, N.; Le Goff, X. F.; Auffrant, A.; Williams, C. K., J. Am. Chem. Soc. 2012, 134, 20577-20580. 130. Bakewell, C.; White, A. J. P.; Long, N. J.; Williams, C. K., Angew. Chem. Int. Ed. 2014, 53, 9226-9230. 131. Ma, H. Y.; Melillo, G.; Oliva, L.; Spaniol, T. P.; Englert, U.; Okuda, J., Dalton Trans. 2005, 721-727. 132. Peckermann, I.; Kapelski, A.; Spaniol, T. P.; Okuda, J., Inorg. Chem. 2009, 48, 5526-5534. 133. Ma, H. Y.; Spaniol, T. P.; Okuda, J., Angew. Chem. Int. Edit. 2006, 45, 7818-7821. 134. Ma, H.; Spaniol, T. P.; Okuda, J., Inorg. Chem. 2008, 47, 3328-3339. 135. Buffet, J.-C.; Okuda, J., Chem. Commun. 2011, 47, 4796-4798. 136. Shen, Z.-L.; Wang, S.-Y.; Chok, Y.-K.; Xu, Y.-H.; Loh, T.-P., Chem. Rev. 2012, 113, 271-401. 137. Li, C.-J.; Chan, T.-H., Tetrahedron 1999, 55, 11149-11176. 138. Douglas, A. F.; Patrick, B. O.; Mehrkhodavandi, P., Angew. Chem. Int. Edit. 2008, 47, 2290-2293. 139. Acosta-Ramirez, A.; Douglas, A. F.; Yu, I. S.; Patrick, B. O.; Diaconescu, P. L.; Mehrkhodavandi, P., Inorg. Chem. 2010, 49, 5444-5452. 140. Osten, K. M.; Yu, I. S.; Duffy, I. R.; Lagaditis, P. O.; Yu, J. C. C.; Wallis, C. J.; Mehrkhodavandi, P., Dalton Trans. 2012, 41, 8123-8134. 141. Xu, C. L.; Yu, I. S.; Mehrkhodavandi, P., Chem. Commun. 2012, 48, 6806-6808. 142. Cintas, P., Synlett 1995, 1995, 1087-1096. 143. Ghosh, R.; Maiti, S., J. Mol. Catal. A: Chem. 2007, 264, 1-8. 144. Augé, J.; Lubin-Germain, N.; Uziel, J., Synthesis 2007, 2007, 1739-1764. 145. Loh, T.-P.; Chua, G.-L., Chem. Commun. 2006, 2739-2749. 146. Haddad, T. D.; Hirayama, L. C.; Singaram, B., The Journal of Organic Chemistry 2009, 75, 642-649. 147. Teo, Y.-C.; Loh, T.-P., Org. Lett. 2005, 7, 2539-2541. 148. Nishimoto, Y.; Babu, S. A.; Yasuda, M.; Baba, A., The Journal of Organic Chemistry 2008, 73, 9465-9468. 149. Atwood, D. A.; Harvey, M. J., Chem. Rev. 2000, 101, 37-52. 163  150. Atwood, D. A.; Jegier, J. A.; Rutherford, D., Bull. Chem. Soc. Jpn. 1997, 70, 2093-2100. 151. Hill, M. S.; Atwood, D. A., Main Group Chem. 1998, 2, 191-202. 152. Atwood, D. A.; Jegier, J. A.; Rutherford, D., Inorganic Chemistry 1996, 35, 63-70. 153. Dagorne, S.; Normand, M.; Kirillov, E.; Carpentier, J.-F., Coord. Chem. Rev. 2013, 257, 1869-1886. 154. Carmalt, C. J.; King, S. J., Coord. Chem. Rev. 2006, 250, 682-709. 155. Aldridge, S.; Downs, A. J., The Group 13 Metals Aluminium, Gallium, Indium and Thallium: Chemical Patterns and Peculiarities. Wiley: 2011. 156. Hsieh, I. P.; Huang, C.-H.; Lee, H. M.; Kuo, P.-C.; Huang, J.-H.; Lee, H.-I.; Cheng, J.-T.; Lee, G.-H., Inorg. Chim. Acta 2006, 359, 497-504. 157. Buffet, J.-C.; Okuda, J.; Arnold, P. L., Inorg. Chem. 2010, 49, 419-426. 158. Broderick, E. M.; Guo, N.; Vogel, C. S.; Xu, C. L.; Sutter, J.; Miller, J. T.; Meyer, K.; Mehrkhodavandi, P.; Diaconescu, P. L., J. Am. Chem. Soc. 2011, 133, 9278-9281. 159. Gao, F. X.; Zhu, C. J.; Yuan, F.; Zhu, Y. H.; Pan, Y., Chin. Chem. Lett. 2003, 14, 138-140. 160. Silvernail, C. M.; Yao, L. J.; Hill, L. M. R.; Hillmyer, M. A.; Tolman, W. B., Inorg. Chem. 2007, 46, 6565-6574. 161. Macchioni, A.; Ciancaleoni, G.; Zuccaccia, C.; Zuccaccia, D., Chemical Society Reviews 2008, 37, 479-489. 162. Johnson Jr, C. S., Prog. Nucl. Magn. Reson. Spectrosc. 1999, 34, 203-256. 163. Li, L.; Sotak, C. H., Journal of Magnetic Resonance (1969) 1991, 92, 411-420. 164. Schlosser, M.; Hartmann, J., Angew. Chem. Int. Ed. 1973, 12, 508-509. 165. Jacobsen, E. N.; Zhang, W.; Guler, M. L., J. Am. Chem. Soc. 1991, 113, 6703-6704. 166. Yao, X.; Qiu, M.; Lü, W.; Chen, H.; Zheng, Z., Tetrahedron: Asymmetry 2001, 12, 197-204. 167. Rudzevich, V.; Schollmeyer, D.; Braekers, D.; Desreux, J. F.; Diss, R.; Wipff, G.; Böhmer, V., The Journal of Organic Chemistry 2005, 70, 6027-6033. 168. Cohen, C. T.; Thomas, C. M.; Peretti, K. L.; Lobkovsky, E. B.; Coates, G. W., Dalton Trans. 2006, 237-249. 169. Osten, K. M.; Aluthge, D. C.; Patrick, B. O.; Mehrkhodavandi, P., Inorg. Chem. 2014, 53, 9897-9906. 170. Atwood, D. A.; Harvey, M. J., Chemical Reviews 2001, 101, 37-52. 171. Jiang, Q.; Rüegger, H.; Venanzi, L. M., Inorg. Chim. Acta 1999, 290, 64-79. 172. Zhang, L.; Nederberg, F.; Pratt, R. C.; Waymouth, R. M.; Hedrick, J. L.; Wade, C. G., Macromolecules 2007, 40, 4154-4158. 173. Zhang, L.; Nederberg, F.; Messman, J. M.; Pratt, R. C.; Hedrick, J. L.; Wade, C. G., J. Am. Chem. Soc. 2007, 129, 12610-12611. 174. Dove, A. P.; Li, H.; Pratt, R. C.; Lohmeijer, B. G. G.; Culkin, D. A.; Waymouth, R. M.; Hedrick, J. L., Chem. Commun. 2006, 2881-2883. 175. Boor Jr, J., 1 - Highlights of Ziegler–Natta Catalysts and Polymerizations. In Ziegler–Natta Catalysts Polymerizations, Boor, J., Ed. Academic Press: 1979; pp 1-18. 176. Chisholm, M. H.; Gallucci, J.; Phomphrai, K., Inorg. Chem. 2002, 41, 2785-2794. 177. Abraham, R. J.; Canton, M.; Reid, M.; Griffiths, L., Journal of the Chemical Society, Perkin Transactions 2 2000, 803-812. 178. Normand, M.; Dorcet, V.; Kirillov, E.; Carpentier, J.-F., Organometallics 2013, 32, 1694-1709. 164  179. Bernardo, K. D. S.; Robert, A.; Dahan, F.; Meunier, B., New J. Chem. 1995, 19, 129-131. 180. Carpentier, J.-F., Macromol. Rapid Commun. 2010, 31, 1696-1705. 181. Müller, H.-M.; Seebach, D., Angew. Chem. Int. Ed. 1993, 32, 477-502. 182. Chen, G.-Q., Chem. Soc. Rev. 2009, 38, 2434-2446. 183. Sinha Ray, S.; Bousmina, M., Prog. Mater Sci. 2005, 50, 962-1079. 184. Askeland, D. R.; Phule, P. P., The science and engineering of materials. 5 ed.; Thomson: 2006. 185. George, S.; Joseph, R.; Thomas, S.; Varughese, K. T., Polymer 1995, 36, 4405-4416. 186. Carrasco, F.; Pagès, P.; Gámez-Pérez, J.; Santana, O. O.; Maspoch, M. L., Polym. Degrad. Stab. 2010, 95, 116-125. 187. Woo, E. M.; Chang, L., Polymer 2011, 52, 6080-6089. 188. Sun, J.; Yu, H.; Zhuang, X.; Chen, X.; Jing, X., The Journal of Physical Chemistry B 2011, 115, 2864-2869. 189. Othman, N.; Xu, C. L.; Mehrkhodavandi, P.; Hatzikiriakos, S. G., Polymer 2012, 53, 2443-2452. 190. Hillmyer, M. A.; Tolman, W. B., Acc. Chem. Res. 2014, 47, 2390-2396. 191. Hori, Y.; Takahashi, Y.; Yamaguchi, A.; Nishishita, T., Macromolecules 1993, 26, 4388-4390. 192. Jeffery, B. J.; Whitelaw, E. L.; Garcia-Vivo, D.; Stewart, J. A.; Mahon, M. F.; Davidson, M. G.; Jones, M. D., Chem. Commun. 2011, 47, 12328-12330. 193. Reeve, M. S.; McCarthy, S. P.; Gross, R. A., Macromolecules 1993, 26, 888-894. 194. Kricheldorf, H. R.; Lee, S.-R., Macromolecules 1995, 28, 6718-6725. 195. Hiki, S.; Miyamoto, M.; Kimura, Y., Polymer 2000, 41, 7369-7379. 196. Save, M.; Schappacher, M.; Soum, A., Macromol. Chem. Phys. 2002, 203, 889-899. 197. Sarasua, J. R.; Arraiza, A. L.; Balerdi, P.; Maiza, I., Polymer Engineering & Science 2005, 45, 745-753. 198. Tsuji, H.; Ikada, Y., Polymer 1999, 40, 6699-6708. 199. Save, M.; Schappacher, M.; Soum, A., Macromolecular Chemistry and Physics 2002, 203, 889-899.          165  Appendices Appendix A    Figure A.1. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-(ONNAdOtBu)H2  166   Figure A.2. 13C{1H} NMR spectrum (CDCl3, 25 °C) of (R,R)-(ONNAdOtBu)H2  167   Figure A.3. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-(ONNSiPh3OMe)H2 168   Figure A.4. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-(ONNSiPh3OMe)H2 169   Figure A.5. 1H NMR (CDCl3, 25 °C) spectrum of (R,R)-1  170   Figure A.6. 13C{1H} NMR (CDCl3, 25 °C) spectrum of (R,R)-1  171   Figure A.7. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-2 172   Figure A.8. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-2  173   Figure A.9. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-3   Figure A.10. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-3   174     Figure A.11. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-4  175   Figure A.12. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-4 176   Figure A.13. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-5  Figure A.14. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-5  177   Figure A.15. 1H NMR (CDCl3, 25 °C) spectrum of (R,R)-6.  Figure A.16. 13C{1H} NMR (CDCl3, 25 °C) spectrum of (R,R)-6.   178   Figure A.17. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-7  179   Figure A.18. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-7 180   Figure A.19. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-8 181   Figure A.20. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-8  182   Figure A.21. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-9  Figure A.22. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-9   183    Figure A.23. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-10  184   Figure A.24. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-10  Figure A.25. 1H NMR spectrum (CDCl3, 25 °C) of KOCH2Pyr  185   Figure A.26. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-11 186   Figure A.27. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-11    187   Figure A.28. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-12    Figure A.29. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-12 188   Figure A.30. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-13   189   Figure A.31. 13C{1H} spectrum (CDCl3, 25 °C) of (R,R)-13   190   Figure A.32. 1H NMR spectrum (CDCl3, 25 °C) of a one pot synthesis of (R,R)-7 after 24 h when only 3.5 eq. of NaOEt was used 191   Figure A.33. 1H NMR spectrum (CDCl3, 25 °C) of the reaction between (R,R)-6 and pyridine   192   Figure A.34. 1H NMR spectrum (CDCl3, 25 °C) of the reaction between (R,R)- 6 and ethyl acetate      193  Table A.1. Selected crystallographic parameters of X-ray structures in chapter 2    rac-1 (R,R)-2 rac-3 rac-6 (R,R)-7 (R,R)-11 (R,R)-13 empirical formula C36H52N2O2InCl C34H46N4O2InCl C48H64N2O2InCl C100H162N4O6In2 C73H103.50N8.5O6In2 C42H58N3O3In C64H58N3O3Si2In Fw 695.07 693.02 851.28 1745.98 1425.78 767.73 1088.13 T (K) 90 90 90 100 90 90 90 a (Å) 12.805(3) 36.780(4) 11.7715(13)  29.058(1) 15.0752(9) 9.192(2) 12.019(5) b (Å) 26.307(6) 8.3688(8) 12.7462(15)  17.6316(9) 22.4148(14) 16.465(4) 20.066(9) c (Å) 10.923(3) 24.188(2) 15.4167(17)  20.292(1) 23.2893(13) 25.858(6) 23.278(11)  (deg) 90 90 105.421(2) 90 90 90 90  (deg) 108.242(4) 115.260(2) 96.436(2) 110.009(3) 90 90 90  (deg) 90 90 103.430(2) 90 90 90 90 volume (Å3) 3495(2) 6733.3(11) 2131.3(4) 9768.8(9)  7869.6(8) 3913.6(15) 5614(4) Z 4 8 2 8 4 4 4 crystal system monoclinic monoclinic  Triclinic monoclinic orthorhombic orthorhombic orthorhombic space group P 21/c  (#14) C 2 (#5) P -1(#2) C 2/c (#15) P 21 21 21 P 21 21 21 P 21 21 21 dcalc (g/cm3) 1.321 1.367 1.327 1.187 1.203 1.303 1.287 μ (MoKα) (cm-1) 7.85 8.16 6.57 5.23 6.37 6.44 5.11 2max (deg) 45.1 60.2 60.3 45.0 60 58.6 51 absorption correction (Tmin, Tmax) 0.498,  0.984 0.8152, 0.8705 0.857, 0.900  0.374, 0.990 0.518, 0.846 0.8356, 0.9256 0.7981, 0.8231 total no. of reflections 23431 133172 141946 68784 42732 48390 46482 no. of indep reflections (Rint) 4571 (0.102) 9766 (0.0322) 12569 (0.0310) 6435 (0.141) 21833 (0.0437) 10690 (0.0511) 10262 (0.067) residuals (refined on F2, all data): R1; wR2 0.094; 0.161 0.0228; 0.0487 0.0357; 0.0913 0.094; 0.180 0.1120; 0.0670 0.0572: 0.0388 0.1458: 0.0647 GOF 1.03 1.026 1.392 1.11 1.02 1.023 0.722 no. observations [I > 2s(I)] 3314 18669 12105 4925 8453 9566 8759 residuals (refined on F2): R1a; wR2b 0.059; 0.141  0.0202;0.0473 0.0343;0.0908  0.063; 0.146 0.1033; 0.0469 0.0550; 0.0307 0.1324; 0.0497 a R1 = Σ ||Fo| - |Fc|| / Σ |Fo|; b wR2 = [Σ(w(Fo2 - Fc2)2)/Σ w(Fo2)2]1/2. 194  Appendix B       Figure B.1. 1H{1H} NMR spectra (CDCl3, 25 °C) of methine regions for ROP of rac-lactide with (left) rac-6 at 97% conversion and (right) (R,R)-6 at 96% conversion at 25 °C in CH2Cl2. 195   Figure B.2. 1H{1H} NMR spectra of (CDCl3, 25 °C) the methine region for ROP of rac-lactide with (R,R)-6 after (a) 11% (b) 24% (c) 37% (d) 47% (e) 60% (f) 81% (g) 97%  conversion at 25 °C in CH2Cl2 . 196  Figure B.3. 1H{1H} NMR spectra of (CDCl3, 25 °C) the methine region for ROP of rac-lactide with rac-6 after (a) 11% (b) 24% (c) 37% (d) 47% (e) 60% (f) 81% (g) 97%  conversion at 25 °C in CH2Cl2.   197  Appendix C      Figure C.1. 1H NMR spectrum (CDCl3, 25 °C) of rac-H2(ONN*OMe)  198   Figure C.2. 13C{1H} NMR spectrum (CDCl3, 25 °C) of H2(ONN*OMe)  Figure C.3. 1H NMR spectrum (CDCl3, 25 °C) of [(µ-2-ONN*OMe)In(µ-OEt)]2 (14a)  199   Figure C.4. 13C{1H} NMR spectrum (CDCl3, 25 °C) of [(µ-2- ONN*OMe)In(µ-OEt)]2 (14a) 200   Figure C.5. 1H NMR spectrum (CDCl3, 25 °C) of rac-[(4-ONN*OMe)In(µ-OEt)]2 (14b) 201   Figure C.6. 13C{1H} NMR spectrum (CDCl3, 25 °C) of rac-[(4- ONN*OMe)In(µ-OEt)]2 (14b)   202   Figure C.7. 1H NMR spectrum (CDCl3, 25 °C) of a reaction stirring 14b with 5 equiv. of NaOEt for 16 h.  203   Figure C.8. 1H NMR spectrum (CDCl3, 25 °C) of a mixture of (ONN*OMe)InCl species  204   Figure C.9. 1H NMR spectrum (CDCl3, 25 °C) after reacting the above (ONN*OMe)InCl mixture with excess NaOEt in toluene.  205   Figure C.10. 1H NMR spectra (THF-d8, 25 °C) of 14b refluxed at 80 °C over 4 days in THF-d8 206    Figure C.11. 1H NMR spectra (toluene-d8, 25 °C) of 14b heated at 100 °C over 4 days in toluene-d8. The spectra are overlaid over a spectrum of 14a (toluene-d8, 25 °C)   207   Figure C.12. 1H NMR spectrum (CDCl3, 25 °C) of rac-(ONN*OtBu)InCl (15)  208   Figure C.13. 13C{1H} NMR spectrum (CDCl3, 25 °C) of rac-(ONN*OtBu)InCl (15)    209   Figure C.14. 1H NMR spectra (CDCl3, 25 °C) of 14b, (a) prior to any reaction (b) after reacting with 400 equiv of EtOAc in THF for 16 h (c) after stirring in neat EtOAc for 16 h.     210   Figure C.15. Plot of ln(I/I0) vs. γ2δ2G2[Δ−(δ/3)]×10-10  (m2 s) from PGSE experiment for the internal standard tetrakis(trimethylsilyl)silane (TMSS), rac-(ONN*O)H2 proligand (4 mM), 14a (2 mM) and 14b 2 mM) in CD2Cl2 at 25 °C. The slope from the trend line gives the diffusion coefficient (Dt). I = observed spin echo intensity, I0 = intensity in the absence of a gradient, G = gradient strength, γ = gyromagnetic ratio, δ = length of gradient pulse, Δ = delay between gradient midpoints         y = -14.196x - 0.067 R² = 0.9983 y = -6.1922x - 0.0259 R² = 0.9996 y = -6.088x + 0.0155 R² = 0.9998 y = -8.902x + 0.025 R² = 0.9991 -16-14-12-10-8-6-4-200 0.5 1TMSS14a14b(ONN*O)H2ln(I/I0) γ2δ2G2[Δ−(δ/3)]×10−10  m2 211   Figure C.16. (left) Plot of ln(I/I0) vs. γ2δ2G2[Δ−(δ/3)]×10-10  (m2 s) from PGSE experiment for the major product from the reaction between 14b and EtOAc in CD2Cl2 at 25 °C. Intensities of a well separated peak (Shown in C.16 (right)) was plotted to obtain the above trend line. The slope from the trend line gives the diffusion coefficient (Dt). I = observed spin echo intensity, I0 = intensity in the absence of a gradient, G = gradient strength, γ = gyromagnetic ratio, δ = length of gradient pulse, Δ = delay between gradient midpoints. (right) Identifies the 1H NMR resonance used for this experiment, which is a C=NH peak of the major product formed after the reaction of 14b with neat ethyl acetate at room temperature (CDCl3, 400MHz, 25 °C).         y = -6.207x - 0.0002 R² = 0.9996 -7-6-5-4-3-2-100 0.5 1ln(I/I0) γ2δ2G2[Δ−(δ/3)]×10−10  m2 212  Table C.1. Selected crystallographic parameters of X-ray structures in chapter 4    [In(µ-2-ONN*OMe)(µ-OEt)]2 (14a) [(4-ONN*OMe)In(µ-OEt)]2 (14b) [(µ-2-ONN*OMe)In]2(µ-Cl)(µ-OH) (15) rac-[ONN*OtBu)InCl (16) empirical formula C49.50 H52In N3.75 O3 C46H47N2O3In C48H48N4O2.5InCl0.5 C50H54N2O2InCl Fw 862.39 790.68 853.45 865.22 T (K) 90 90 90 90 a (Å) 19.190(5) 15.445(3) 36.150(3) 14.6190(16) b (Å) 20.468(6) 15.842(3) 12.6645(11) 16.2907(17) c (Å) 26.575(7) 22.983(5) 24.6409(19) 23.505(2)  (deg) 102.203(7) 88.879(4) 90 90.069(2)  (deg) 104.575(7) 75.526(5) 128.044(2) 94.251(2)  (deg) 112.164(6) 80.596(4) 90 114.538(2) volume (Å3) 8793(4) 5371(2) 8884.3(13) 5075.2(9) Z 8 4 8 4 crystal system triclinic triclinic Monoclinic Triclinic space group P -1 (#2) P -1 (#2) C 2/c (#15) P -1 (#2) dcalc (g/cm3) 1.303 0.977 1.276 1.132 μ (MoKα) (cm-1) 5.83 4.71 6.04 5.53 2θmax (deg) 56.9 45.8 61.1 59.6 absorption correction (Tmin, Tmax) 0.7718, 0.9109 0.5448,  0.6638 0.8502, 0.9245 0.801, 0.843 total no. of reflections 320890 57387 77751 35576 no. of indep reflections (Rint)  44121, (0.0782) 14390(0.0665) 13567, (0.0808) 10943, (0.0744) residuals (refined on F2, all data): R1; wR2  0.0989;0.1494 0.1440;0.2939 0.0883;0.1641  0.0770;0.1321 GOF 1.025 1.135 1.063 1.042 no. observations [I > 2s(I)] 30269 8429 9652 7398 residuals (refined on F2): R1a; wR2b 0.0568; 0.1214  0.0970;0.2619 0.0542;0.1445 0.0525;0.1194 a R1 = Σ ||Fo| - |Fc|| / Σ |Fo|; b wR2 = [Σ(w(Fo2 - Fc2)2)/Σ w(Fo2)2]1/2.    

Cite

Citation Scheme:

        

Citations by CSL (citeproc-js)

Usage Statistics

Share

Embed

Customize your widget with the following options, then copy and paste the code below into the HTML of your page to embed this item in your website.
                        
                            <div id="ubcOpenCollectionsWidgetDisplay">
                            <script id="ubcOpenCollectionsWidget"
                            src="{[{embed.src}]}"
                            data-item="{[{embed.item}]}"
                            data-collection="{[{embed.collection}]}"
                            data-metadata="{[{embed.showMetadata}]}"
                            data-width="{[{embed.width}]}"
                            data-media="{[{embed.selectedMedia}]}"
                            async >
                            </script>
                            </div>
                        
                    
IIIF logo Our image viewer uses the IIIF 2.0 standard. To load this item in other compatible viewers, use this url:
https://iiif.library.ubc.ca/presentation/dsp.24.1-0166078/manifest

Comment

Related Items