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Neutral and cationic indium complexes for the synthesis of oxygenated copolymers Diaz Lopez, Carlos Andres 2021

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NEUTRAL AND CATIONIC INDIUM COMPLEXES FOR THE SYNTHESIS OF OXYGENATED COPOLYMERS by  Carlos Andres Diaz Lopez  M.Sc., University of Los Andes, 2013  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)  March 2021  © Carlos Andres Diaz Lopez, 2021  ii  The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled:  Neutral and Cationic Indium Complexes for the Synthesis of Oxygenated Copolymers  submitted by Carlos Andres Diaz Lopez  in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry  Examining Committee: Dr. Parisa Mehrkhodavandi, Chemistry, UBC Supervisor  Dr. Derek Gates, Chemistry, UBC Supervisory Committee Member  Laurel Schafer, Chemistry, UBC University Examiner Dr. Glenn Sammis, Chemistry, UBC University Examiner  Additional Supervisory Committee Members: Dr. Stephen Withers, Chemistry, UBC Supervisory Committee Member Dr. Pierre Kennepohl, Chemistry, University of Calgary Supervisory Committee Member iii  Abstract  The development of synthetic polymers that include more sustainable building blocks is an active area of research. Controlled synthesis of copolymers including biobased segments has shown promising results, as the great diversity of functionalities from renewable resources can be used to tune the properties of macromolecules and often allow for post-functionalization.  Herein, a series of discrete cationic indium complexes were synthesized and characterized. The role of counteranions was explored and (±)-[(ONNO)In(THF)2][SbF6] proved a highly active catalyst for the polymerization of epoxides and their co-polymerization with other cyclic ethers such as THF, oxetane and oxepane. This catalyst was also active in the one-pot copolymerization of epichlorohydrin with rac-lactide with good control. Investigation of the role of counteranions and solvent donors on the kinetics of polymerization of epoxides revealed a subtle effect of solvents on initiation rates.  The activity of this cationic system was improved by changing the counterion from [SbF6] to a less coordinating tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (BArF4). In this way, copolymerization of different epoxides and rac-lactide was achieved either through a mixture of monomers or via sequential addition to high molecular weight block copolymers. Mechanistic studies and control experiments indicate that the epoxide is polymerized by a cationic mechanism to yield a neutral alkoxide indium species that subsequently polymerizes the lactide by a coordination-insertion mechanism with no significant interference of the two mechanisms under polymerization conditions. The thermal and tensile properties of different block iv  copolymers were studied, revealing mostly amorphous materials.  It was possible to control the ductility and stiffness of the copolymers by tuning the nature and chain length of the blocks.   Finally, a series of neutral indium complexes with different ligand frameworks containing hemi-labile donors were synthesized and characterized. Alkoxide complexes with iminophenolate ligands bearing morpholine, thiomorpholine and methylpiperazine side donors were active in the polymerization of  rac-lactide with very good control over molecular weights. The role of hemi-labile side donors was explored in the synthesis of block copolymers by sequential and simultaneous addition of rac-lactide and ε-caprolactone. v  Lay Summary  The low recyclability of traditional polymers and their bio-accumulation in the ecosystems make it pressing to develop synthetic alternatives that include more sustainable materials. In order for greener polymers become more prevalent, not only are they expected to exhibit properties comparable to those of traditional plastics, but also they should ideally manifest new properties that open the door to new applications. The controlled synthesis of copolymers including biobased precursors has shown very promising results, as the diversity of building blocks from biomass can be used to tune the properties of the polymeric materials. The main focus of this Ph.D. thesis is to explore the reactivity of different indium catalytic systems in the synthesis of biodegradable copolymers from both bioderived and non-bioderived building blocks. vi  Preface  The thesis introduction shown in chapter 1 as well as part of the introduction of chapters 3, 4 and 5 are based on a review manuscript published in the journal Polymer Chemistry. The manuscript was written by myself and edited by Professor Parisa Mehrkhodavandi:    1. Diaz, C.; Mehrkhodavandi, P. Strategies for the Synthesis of Block Copolymers with Biodegradable Polyester Segments. Polym. Chem., 2021, Advance Article.  The work presented in chapters 2 and 3 is partially based on a manuscript published in the journal Chemical Communications. The manuscript was written by myself and edited by Professor Parisa Mehrkhodavandi. In these chapters, single crystal X-ray crystallography of bimetallic complex (1) was performed by a former student in the group: Dr. Insun Yu. Crystallography of monometallic complex (1') as well as dichloride complexes (7), (8), (8') and (9) was performed by Dr. Brian Patrick. Crystallography of cationic complexes (10'), (13) and (12) was performed by former Ph.D. student Dr. Tannaz Ebrahimi. I carried out the remaining characterization work as well as the syntheses of complexes, polymerizations and other experiments.   2. Diaz, C.; Ebrahimi, T.; Mehrkhodavandi, P. Cationic indium complexes for the copolymerization of functionalized epoxides with cyclic ethers and lactide. Chem. Commun., 2019, 55, 3347.  vii  The work presented in chapters 2 and 4 is based on a manuscript published in the journal Macromolecules. The manuscript was written by myself and edited by Professors Parisa Mehrkhodavandi and Savvas Hatzikiriakos. The thermo-mechanical properties of the polymers were determined by Dr. Tanja Tomkovic. I carried out the remaining characterization work as well as the syntheses of complexes, polymerizations and other experiments.:  3. Diaz, C.; Tomkovic, T.; Goonesinghe, C.; Hatzikiriakos, S. G.; Mehrkhodavandi, P. One-pot Synthesis of Oxygenated Block Copolymers by Polymerization of Epoxides and Lactide Using Cationic Indium Complexes Macromolecules, 2020, 53(20), 8819.  The work presented in chapters 2 and 5 was carried out in collaboration with undergraduate researcher Jane Fu, who worked on the synthesis of the different complexes under my supervision. Synthesis of ligand precursors was carried out in collaboration with previous graduate student in our group, Shazia Soobrattee. Crystals suitable for single-crystal X-ray diffraction were obtained by me and solved by Dr. Brian Patrick. I carried out polymerizations and other experiments. This work is soon to be submitted for publication in Dalton Transactions.  4. Diaz, C., Fu, J.; Soobrattee S.; Nyamayaro K.; Patrick, B.; Mehrkhodavandi, P. Dalton Trans. Manuscript in preparation.     viii  Table of Contents  Abstract ......................................................................................................................................... iii	Lay Summary ................................................................................................................................ v	Preface ........................................................................................................................................... vi	Table of Contents ....................................................................................................................... viii	List of Tables ................................................................................................................................. xi	List of Figures ............................................................................................................................. xiii	List of Symbols and Abbreviations ............................................................................................ xx	Acknowledgements ................................................................................................................... xxvi	Dedication ................................................................................................................................ xxvii	Chapter 1: General introduction ................................................................................................. 1	1.1	 Biobased polymers .......................................................................................................... 1	1.1.1	 Poly(lactic) acid (PLA) ............................................................................................... 3 1.1.2	 Tacticity in PLA .......................................................................................................... 4 1.1.3	 Mechanisms of ring-opening polymerization (ROP) of lactide .................................. 5 1.1.4	 Ring-opening polymerization (ROP) of lactide by Group 13 metal complexes ......... 7 1.2	 Polyethers ...................................................................................................................... 12 1.2.1 Mechanisms of ring-opening polymerization (ROP) of epoxides ............................ 15 1.2.2	 Ring-opening polymerization (ROP) of epoxides by Group 13 metal complexes ... 17 1.3	 Synthesis of oxygenated block copolymers .................................................................. 23	1.3.1	 Synthesis of polyester-polyester block copolymers .................................................. 23	1.3.2	 Synthesis of polyether-polyester block copolymers  ................................................. 28 ix  1.4	 Scope of the thesis ......................................................................................................... 31	Chapter 2: Synthesis and characterization of cationic and neutral indium species ............. 33	2.1	 Introduction ................................................................................................................... 33	2.2	 Results ........................................................................................................................... 38	2.2.1	 Synthesis and characterization of proligands ............................................................ 38 2.2.2	 Synthesis and characterization of neutral indium alkyl complexes .......................... 41 2.2.3	 Synthesis and characterization of neutral indium chloride complexes ..................... 46 2.2.4	 Synthesis and characterization of cationic indium complexes .................................. 56 2.3	 Conclusions ................................................................................................................... 63 2.4	 Experimental ................................................................................................................. 63	Chapter 3: Cationic indium species active in the polymerization of cyclic ethers ................ 76	3.1	 Introduction ................................................................................................................... 76	3.2	 Results ........................................................................................................................... 80	3.2.1	 Reactivity of cationic complexes in the polymerization of epoxides ........................ 80 3.2.2	 Substrate scope in the homopolymerization of epoxides by cationic complex ......... 88 3.2.3	 Copolymerization of epoxides and other cyclic ethers by cationic complex ............ 92 3.2.4	 Kinetics of polymerization of epoxides .................................................................... 94 3.3	 Conclusions ................................................................................................................... 97	3.4	 Experimental ................................................................................................................. 99	Chapter 4: Cationic indium species for the copolymerization of epoxides and lactide ...... 102	4.1	 Introduction ................................................................................................................. 102 4.2	 Results ......................................................................................................................... 106	4.2.1	 One-pot copolymerization by simultaneous addition of epoxides and lactide ........ 106 x  4.2.2	 One-pot copolymerization by sequential addition of epoxides and lactide ............ 111 4.2.3	 Attempts at post-functionalization of block copolymers ........................................ 115 4.2.4	 Lactide polymerization and mechanistic studies ..................................................... 118 4.2.5	 Mechanical and thermal properties of block copolymers ....................................... 124 4.3	 Conclusions ................................................................................................................. 128	4.4	 Experimental ............................................................................................................... 129	Chapter 5: Neutral indium species for the homo- and copolymerization of cyclic esters .. 134	5.1	 Introduction ................................................................................................................. 134 5.2	 Results ......................................................................................................................... 138 5.2.1	 Synthesis and characterization of neutral indium alkoxide complexes ................... 138 5.2.2	 Hemilabile behaviour of neutral indium chloride complexes ................................. 142 5.2.3	 Homopolymerization of cyclic esters by neutral indium complexes ...................... 144 5.2.4	 Copolymerization of cyclic esters by neutral indium complexes ........................... 148 5.3	 Conclusions ................................................................................................................. 152	5.4	 Experimental ............................................................................................................... 153	Chapter 6: Conclusions and future work ................................................................................ 159	Bibliography .............................................................................................................................. 163	Appendices ................................................................................................................................. 174	Appendix A ............................................................................................................................. 174	Appendix B ............................................................................................................................. 211 Appendix C ............................................................................................................................. 247	xi  List of Tables  Table 2.1.  Selected distances (Å) and angles (°) for rac-1 .......................................................... 44	Table 2.2.  Selected distances (Å) and angles (°) for (R,R)-1' ...................................................... 45	Table 2.3.  Selected distances (Å) and angles (°) for 6 ................................................................. 52	Table 2.4.  Selected distances (Å) and angles (°) for 7 ................................................................. 53	Table 2.5.  Selected distances (Å) and angles (°) for 8 ................................................................. 54	Table 2.6.  Selected distances (Å) and angles (°) for 7' ................................................................ 55	Table 2.7.  Selected distances (Å) and angles (°) for rac-11 ........................................................ 60	Table 2.8.  Selected distances (Å) and angles (°) for rac-12 ........................................................ 61	Table 2.9.  Selected distances (Å) and angles (°) for rac-9' .......................................................... 62	Table 3.1.  Polymerization of epoxides employing cationic complex rac-9 ......................... 82	Table 3.2.  Polymerization of different epoxides employing cationic complex rac-11 ....... 89 Table 3.3.  Copolymerization of cyclic ethers and epoxides with rac-11 ............................. 93 Table 4.1.  Copolymerization of ECH and rac-LA with cationic complex rac-11 ............ 108	Table 4.2.  Copolymerization of epoxides and rac-LA using cationic initiators ................ 110	Table 4.3.  Copolymerization of epoxides and rac-LA using cationic initiators ................ 112	Table 4.4.  Copolymerization of epoxides and rac-LA using cationic initiators ................ 114	Table 4.5.  Rates of polymerization of LA isomers with cationic initiators and ECH ...... 121	Table 4.6.  Mechanical properties of block copolymers synthesized with rac-17 ............. 125	Table 5.1.  Homopolymerization of lactide with neutral indium species ............................ 145	Table 5.2.  Homopolymerization of caprolactone with neutral indium species ................. 147	Table 5.3.  Sequential copolymerization of cyclic esters with neutral indium species ...... 149	xii  Table 5.4.  Simultaneous copolymerization of cyclic esters by neutral indium species .... 151	 xiii  List of Figures  Figure 1.1. Examples of bidegradable oxygenated polymers generated via ROP of cyclic esters generated via ROP of cyclic esters .................................................................................................. 2	Figure 1.2. Synthesis of lactide from renewable feedstocks. ......................................................... 3	Figure 1.3. PLA microstructures arising from lactide ROP ........................................................... 4	Figure 1.4. Example of a tetrad and calculation of Pm and Pr using Bernoullian statistics ............ 5	Figure 1.5. Simplified coordination-insertion mechanism of lactide ROP where M represents a metal complex and Nu a nucleophilic group ................................................................................... 6	Figure 1.6. Simplified activated-monomer mechanism of lactide ROP ......................................... 6	Figure 1.7. Examples of chiral and achiral aluminum alkoxide/alkyl complexes active in lactide ROP. ................................................................................................................................................ 9	Figure 1.8. Examples of indium alkoxide complexes active in lactide ROP. .............................. 12	Figure 1.9. Common epoxides used for ROP reactions, including representative glycidyl ethers and amines. .................................................................................................................................... 13	Figure 1.10. Simplified anionic mechanism of polymerization of propylene oxide ...................  15	Figure 1.11. Simplified cationic mechanism of polymerization of propylene oxide. .................. 16	Figure 1.12. Examples of neutral aluminum complexes active in propylene oxide ROP ............ 18	Figure 1.13. Examples of cationic aluminum complexes active in the ROP of PO ..................... 20	Figure 1.14. Examples of cationic aluminum complexes active in the ROP of PO ..................... 22	Figure 1.15.  Aluminum complexes for the block copolymerization of lactide and other cyclic esters .............................................................................................................................................. 25	xiv  Figure 1.16. Aluminum complexes for the block copolymerization of lactide and other cyclic esters .............................................................................................................................................. 27	Figure 1.17. Synthesis of amphiphilic polyether-polyester block copolymers using PEG as a macroinitiator (preformed block) in the ROP or ROCOP of oxygenated monomers ................... 30	Figure 1.18. Synthesis of polyether-polyester block copolymers using sequential ROP of cyclohexene oxide and lactide ....................................................................................................... 31	Figure 2.1. Examples of indium alkoxide reported by Atwood, Mehrkhodavandi and collaborators .................................................................................................................................. 34	Figure 2.2. Some examples of indium alkoxide and alkyl complexes supported by aminophenolate, iminophenolate or phosphiniminophenolate ligands ......................................... 35	Figure 2.3. Some examples of cationic indium complexes .......................................................... 37	Figure 2.4. Synthesis of reported salen (ONNO)H2, salan (ONHNHO)H2 and salophen (ONArNO)H2 proligands ................................................................................................................ 39	Figure 2.5. Synthesis of reported tridentate (NMe2NO)H proligand ............................................. 40	Figure 2.6. Synthesis of tridentate proligands with potentially coordinating side groups. Yields provided in parentheses ................................................................................................................. 41	Figure 2.7. Synthesis of monometallic and bimetallic alkyl indium complexes supported by the salen ligand. Isolated yields are provided in parentheses .............................................................. 42	Figure 2.8. Aromatic and imine region in the 1H NMR spectrum (CDCl3, 25 °C) of the mixture obtained from the reaction of 1 equiv of In(CH2SiMe3)3 and 1 equiv of racemic salen proligand (top). Signals attributed to a monometallic complex are labeled in red. Spectra of bimetallic compound rac-1 (medium) and racemic proligand (bottom) are shown for comparison ............. 43	xv  Figure 2.9. Molecular structure of bimetallic complex rac-1 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) ...................................................................................... 44	Figure 2.10. Molecular structure of monometallic complex (R,R)-1' depicted with ellipsoids at 50% probability (H atoms omitted for clarity) .............................................................................. 45	Figure 2.11. Synthesis of racemic and enantiopure indium chloride complexes supported by the salen ligand. Isolated yields are provided in parentheses .............................................................. 46	Figure 2.12. Synthesis of indium chloride complex (3) supported by the salophen ligand. Isolated yield is provided in parentheses ....................................................................................... 47	Figure 2.13. Indium chloride complexes (4-8) synthesized by salt metathesis of the corresponding potassium ligand salts and InCl3. Isolated yields are provided in parentheses ..... 48	Figure 2.14. Aliphatic region in the 1H NMR spectrum (CDCl3, 25 °C) of racemic dichloride compound rac-4 and achiral dichloride compound 5. Proligand (NMe2N*O)H is shown for comparison .................................................................................................................................... 49	Figure 2.15. Aliphatic region in the 1H NMR spectrum (CDCl3, 25 °C) of achiral dichloride compounds 6-8 showing different splitting patterns for methylene heterocyclic protons and ethylene backbone protons (labeled with green crosses) .............................................................. 50	Figure 2.16. Different coordination modes exhibited by complexes 6 and 7 in the solid state and in solution (CDCl3) ........................................................................................................................ 51	Figure 2.17. Molecular structure of monometallic complex 6 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) ...................................................................................... 52 Figure 2.18. Molecular structure of monometallic complex 7 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) ...................................................................................... 53 xvi  Figure 2.19. Molecular structure of monometallic complex 8 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) ...................................................................................... 54 Figure 2.20. Molecular structure of monometallic complex 7' depicted with ellipsoids at 50% probability (H atoms omitted for clarity) ...................................................................................... 55 Figure 2.21. Synthesis of cationic indium species (9-15). Isolated yields are provided in parentheses .................................................................................................................................... 56 Figure 2.22. Synthesis of cationic indium species (rac-16). Isolated yields are provided in parentheses .................................................................................................................................... 57 Figure 2.23. Synthesis of cationic indium complexes (17-18) supported by the salen and salophen ligand. Isolated yields are provided in parentheses ........................................................ 58 Figure 2.24. Molecular structure of monometallic complex rac-11 depicted with ellipsoids at 30% probability (H atoms omitted for clarity) .............................................................................. 60 Figure 2.25. Molecular structure of monometallic complex rac-12 depicted with ellipsoids at 50% probability (H atoms omitted for clarity) .............................................................................. 61 Figure 2.26. Molecular structure of monometallic complex rac-9' depicted with ellipsoids at 50% probability (H atoms omitted for clarity) .............................................................................. 62 Figure 3.1. Polymerization of oxetane initiated by a cationic initiator (I = initiator, WCA = weakly coordinating anion) can experience significant backbiting leading to depolymerization. Addition of dioxane can significantly decrease backbiting .......................................................... 77	Figure 3.2. Regio-regular and regio-irregular poly(propylene oxide) PPO. Regio-regular microstructure is comprised predominantly of H-T linkages while regio-irregular microstructure has significant portions of H-H and T-T linkages ......................................................................... 79	xvii  Figure 3.3. Polymerization of different epoxides initiated by cationic initiators (I = initiator, WCA = weakly coordinating anion). [cat] = 28.0 mM, [epoxide] = 2.8 M ............................. 80	Figure 3.4. Comparison of activity of different cationic indium species synthesized. Reactions were performed in C6D5Br at 40 °C for 2 h. [cat]0 = 28.0 mM, [1,2-epoxy-5-hexene] = 2.8 M. The ROP reaction was monitored by 1H NMR spectroscopy ................. 81	Figure 3.5. Effect of addition of KPF6 on the polymerization of E5H by rac-11 at 50 °C (top). Effect of different solvents in the polymerization of E5H by rac-11 at 25°C (bottom). The ROP reactions were monitored by 1H NMR spectroscopy ............................................................. 84	Figure 3.6. Activity of cationic indium species rac-16. Reactions were performed in C6D5Br at 25 °C or 80 °C for 2 days. [cat] = 22.0 mM, [1,2-epoxy-5-hexene] = 4.4 M. The ROP reaction was monitored by 1H NMR spectroscopy ................................................ 86	Figure 3.7. Variable Temperature (VT) 1H NMR (top) and 19F NMR (bottom) spectra (C6D5Br) of complex rac-15 ......................................................................................................................... 87	Figure 3.8. MALDI-TOF spectrum of the isolated product from the ROP of 1,2-epoxy-3,3-dimethylbutane with rac-11. The distributions refer to cyclic homopolymerization product, linear product with OH chain end and cyclic homopolymerization product with one ring-opened THF molecule ........................................................................................................................................ 91	Figure 3.9. First order kinetic plot for the polymerization of 1,2-epoxy-5-hexene (E5H) by PF6 complex rac-9, AsF6 complex rac-10 and SbF6 complex rac-11 at 40 °C in C6D5Br. The ROP reaction was monitored by 1H NMR spectroscopy ....................................................................... 95	Figure 3.10. First order kinetic plot for the polymerization of 1,2-epoxy-5-hexene (E5H) by THF complex rac-11, 2-methyl THF complex rac-13 and tetrahydropyran complex rac-14 at 50 °C in C6D5Br. The ROP reaction was monitored by 1H NMR spectroscopy ......................................... 96	xviii  Figure 4.1. Redox-switchable systems active in the copolymerization of cyclohexene oxide (CHO) and lactide in a mixture of monomers. ............................................................................ 103	Figure 4.2. Ring-opening copolymerization (ROCOP) of epoxides and cyclic  anhydrides to give highly alternating polyesters ....................................................................................................... 104	Figure 4.3. Systems active in the ring-opening copolymerization (ROCOP) of epoxides and cyclic anhydrides ......................................................................................................................... 105	Figure 4.4. Cationic indium complexes studied in the copolymerization of epoxides and LA. 107	Figure 4.5. Molecular weights (green circles) and dispersities (blue riangles) of the products from the copolymerization of ECH and LA employing rac-11 (130 °C, 60 min). Theoretical molecular weights (red circles) were determined on the basis of (144 gmol−1 × equiv LA × conv. LA) + (93 gmol−1 × 200 × conv. ECH) ........................................................................................ 109	Figure 4.6. Synthesis of poly(glycidyl amine) from poly(epichlorohydrin) .............................. 116	Figure 4.7. 13C{1H} NMR spectra (CDCl3) of the methylene region in PECH and its post-functionalization reactions with sodium azide at different temperatures .................................... 117	Figure 4.8. Kinetic plots of copolymerization of ECH (260 equiv) and rac-LA (170 equiv) at 25 °C in CD2Cl2 with simultaneous addition of both monomers. [rac-17]0 = 6.0 mM, [ECH]0 = 1.6 M, [rac-LA]0 = 1.0 M ....................................................................................... 118	Figure 4.9. Control reaction of ECH with indium alkoxide complex at room temperature in CD2Cl2. Reaction was monitored after 24 h. [I.18]0 = 4.0 mM ...................................... 120	Figure 4.10. 31P{1H} NMR spectra of reaction mixtures of ECH polymerization (400 equiv.) by cationic initiator rac-17 followed by addition of PPh3 in CD2Cl2 (162 MHz, CD2Cl2, 25 °C). .............................................................................................................................................. 122	xix  Figure 4.11.  Proposed mechanism of copolymerization of epoxides and lactide by cationic initiator rac-17. ........................................................................................................... 123	Figure 4.12. Dynamic mechanical analysis (DMA) of selected diblock copolymers prepared with cationic initiator rac-17. .................................................................................................. 127	Figure 4.13. Dynamic mechanical analysis (DMA) of diblock copolymer prepared with cationic initiator rac-17. .......................................................................................................................... 128 Figure 5.1. Copolymerization of cyclic esters with simultaneous addition of monomers leading to random (top), gradient "blocky" (middle) and block copolymers (bottom) ........................... 135	Figure 5.2.  Redox-switchable system active in the one-pot block copolymerization of LA and ε-CL with simultaneous feeding of monomers. ............................................................................. 137 Figure 5.3. Aromatic, imine and aliphatic region in the 1H NMR spectrum (CDCl3, 25 °C) of the crude product from the reaction of 6 with 1 or 2 equiv of KOtBu .............................................. 139	Figure 5.4.  Synthesis of indium alkoxide chloride complexes (19-22) supported by iminophenolate ligands. Isolated yields are provided in parentheses ......................................... 140	Figure 5.5. Aliphatic and aromatic region in the 1H NMR spectrum (CDCl3, 25 °C) of alkoxide complex 20 and its dichloride precursor 6 showing different splitting patterns for methylene heterocycle protons and ethylene backbone protons ................................................................... 141	Figure 5.6.  Molecular structure of the aggregate complex product of the decomposition of 21 in solution. Depicted with ellipsoids at 50% probability (H atoms omitted for clarity) ................. 142	Figure 5.7. Variable Temperature (VT) 1H NMR spectrum (C6D5Br) of complex 6. Signals assigned to morpholine  methylene protons are assigned in red ................................................. 143	xx  List of Symbols and Abbreviations Å  angstrom AcOH  acetic acid Ad  adamantyl Anal.  analysis Ar   aromatic  BArF4  tetrakis(3,5-bis(trifluoromethyl)phenyl)borate β-BL  β-butyrolactone β-6-HEL β-6-heptenolactone Bn  benzyl BO  butylene oxide (Boc)2O di-tert-butyl dicarbonate Boc  tert-butyloxycarbonyl br   broad Calcd.  calculated COSY  Correlation spectroscopy 13C{1H} proton-decoupled carbon conv.  conversion d   doublet deg  degrees D  dextrorotatory enantiomer Đ  Dispersity ε-DL  ε-decalactone xxi  δ   chemical shift downfield from tetramethylsilane in ppm δ-DL  δ-decalactone   δ-VL  δ-valerolactone Da  Daltons DBU  1,8-diazabicyclo[5.4.0]undec-7-ene DMEB  3,3-dimethyl-1,2-epoxybutane DACH  diaminocyclohexane DCM  dichloromethane DFT  density-functional theory DMSO  dimethyl sulfoxide DNA  deoxyribonucleic acid DOSY  Diffusion ordered spectroscopy DSC  differential scanning calorimetry DXO  1,5-dioxepan-2-one (°)   degree(s) E.A.   Elemental Analysis E5H  1,2-epoxy-5-hexene ECH  epichlorohydrin EOC  1,2-epoxyoctane ε-CL  ε-caprolactone equiv  equivalent(s) Et   ethyl Et2O   diethyl ether xxii  EtOH  ethanol EO  ethylene oxide ζ-HL  ζ-heptalactone g  grams GA  glycolide GI  globalide GPC   gel permeation chromatography 1H{1H} proton-decoupled proton h   hour(s) η-CYL  η-caprylolactone HSQC  Heteronuclear single quantum coherence spectroscopy HMBC Heteronuclear multiple bond correlation spectroscopy iPr  isopropyl IUPAC International Union of Pure and Applied Chemistry J   coupling constant in Hertz κ   kappa or denticity describes number of donors in a ligand binding to a metal  kobs   observed rate constant for reaction kJ  kilo Joule L  levorotatory enantiomer LA  lactide M   molarity m   multiplet(s) Mn   number average molecular weight of polymer xxiii  Mw  weight average molecular weight of polymer MW  molecular weight Me  methyl MeOH  methanol MALDI-TOF  Matrix-assisted laser desorption ionization - time of flight NMR   nuclear magnetic resonance NOESY Nuclear Overhauser enhancement spectroscopy nBu  n-butyl OCA  O-carboxyanhydride Ph  phenyl Pm   probability of meso linkages in a polymer chain Pr  probability of racemo linkages in a polymer chain PECH  poly(epichlorohydrin) PEG  polyethylene glycol (same as PEO) PE5H  poly(1,2-epoxy-5-hexene) PDMEB poly(3,3-dimethyl-1,2-epoxybutane) PEO  poly(ethylene oxide) PEOC  poly(1,2-epoxyoctane) PBO  poly(butylene oxide) PO  propylene oxide PPO  poly(propylene oxide) PPNCl  bis(triphenylphosphoranylidene)imminium chloride PPNOBzF5 bis(triphenylphosphoranylidene)imminium pentafluorobenzoate xxiv  PHA  poly(hydroxy alkanoate) PLA   poly(lactic acid) PCL  poly(caprolactone) PMDETA N,N',N'',N'''-pentamethyldiethylenetriamine PPDL  poly(pentadecanolactone) Ph   phenyl ppm   parts per million PTHF  Poly(tetrahydrofuran) pyr   pyridine q   quartet rac   racemic ±   racemic R   Rectus (Latin for right) in R/S chirality ROP   Ring-opening Polymerization S   Sinister (Latin for left) in R/S chirality s   singlet salan   a compound synthesized by reduction of a salen compound salen   Bisiminophenolate Schiff base  an imine bearing a hydrocarbyl group on the nitrogen atom   t   triplet Tg   glass transition temperature Tm   melting temperature TGA  thermogravimetric analysis xxv  THF   tetrahydrofuran TMB   1,3,5-trimethoxybenzene tol   toluene  TfO  triflate TsO  tosylate tBu   tert-butyl VT   variable temperature WCA  weakly coordinating anion ω-PDL  ω-pentadecanolactone  xxvi  Acknowledgements I would like to thank first and foremost my advisor Prof. Parisa Mehrkhodavandi for the guidance and patience throughout this long journey. I feel truly honored to have worked in her group and to have learned so much from her mentorship over the years. I would also like to thank past colleagues of the Mehrkhodavandi group, especially Dr. Paul Kelley, Dr. Ese Chile, Dr. Tannaz Ebrahimi and Alexandre Kremer for their guidance. A big shout out to all other members of the group (from 2015 until now). Special thanks to Shazia Soobrattee for her friendship during this time. I am grateful to Dr. Brian Patrick, Dr. Maria Ezhova and Dr. Zhicheng (Paul) Xia for their assistance with important X-ray crystallography and NMR experiments. Thanks to all the staff and faculty members in Chemistry, who contribute in one way or another to make this a great department to work in. Special thanks to the NSERC CREATE Sustainable Synthesis Program for the training and funds received during the first two years of my Ph.D.     I would like to acknowledge collaborators from the Chemical and Biological Engineering department, Prof. Savvas Hatzikiriakos and Dr. Tanja Tomkovic. I'm also grateful to undergraduate students Jane Fu and Lirong Cao, who worked for some time with me at UBC. Finally, I wish to thank my family for their emotional support over the years.       xxvii     To Ana Sofía. May you go from strength to strength. 1  Chapter 1: General Introduction  Synthetic polymers are ubiquitous in modern life, with applications ranging from every-day packaging and textiles to more specialized use in biomedicine and electronics. Overwhelmingly, these materials are derived from non-renewable petrochemicals: Despite using less than 5% of total oil and natural gas production,1 the global output of synthetic polymers is now well over 300 million tonnes a year and it's expected to keep growing in the foreseeable future.2 This has brought up serious concerns with their sustainability, in particular with regards to the very low recyclability of most polymers and their bio-accumulation in the ecosystems.3 Moreover, the eventual depletion of petrochemicals makes it pressing to develop synthetic alternatives to traditional polymers that include more sustainable building blocks. In particular, there has been a growing interest in the ring-opening polymerization (ROP) of cyclic monomers such as lactide (LA) and other bioderived cyclic esters as a way to access high molecular weight oxygenated polymers with good biodegradability (Figure 1.1). With the great variety of cyclic monomers available for ROP (both from petrochemical and renewable sources), the development of more active and selective catalytic systems that are tolerant of functional groups can pave a way to the production of new versatile and sustainable materials that are attractive to the industry and find new applications in a variety of fields (e.g. biomedical, electronic).   1.1 Biobased and sustainable polymers According to the International Union of Pure and Applied Chemistry (IUPAC), biobased polymers are macromolecules derived directly from biomass or issued from monomers derived from it.4 The large availability of functionalizable renewable resources has spurred research on 2  more sustainable polymeric materials.5-6 The most common approaches for the utilization of biomass in synthetic polymers are: (i) isolation and/or chemical modification of natural polymers (e.g. bacterial PHA, polyisoprene, modified cellulose), (ii) breakdown of natural carbohydrates and triglycerides with further modification for the synthesis of new monomers (e.g. lactide, succinic acid, ethylene glycol, ethylene) and (iii) direct extraction of monomers from natural oils (e.g. tulipalin A, turpentine, limonene). Another important research direction looks at the use of carbon dioxide (a renewable resource) in a copolymerization with petrochemical- or biomass-derived epoxides.7-9 Since many useful cyclic monomers can be obtained from biomass, ring-opening polymerization (ROP) is an attractive strategy for the synthesis of biobased polymers (Figure 1.1).     Figure 1.1. Examples of biodegradable oxygenated polymers generated via ROP of cyclic esters.  OOOOOnOOOOOnOOOOO nOROPROPROPlactide (LA)!-caprolactone (!-CL)"-pentadecanolactone ("-PDL)poly(lactic acid) (PLA)poly(caprolactone) (PCL)poly(pentadecanolactone) (PPDL)3  Despite the great diversity of renewable feedstocks, currently, only 1% of all synthetic polymers produced yearly are biobased.10 In order for greener polymers to become more prevalent, not only they are expected to exhibit properties comparable to those of traditional plastics, but also ideally bring up new and complementary properties (e.g. tunable biodegradability) that open the door to new applications.   1.1.1 Poly(lactic acid) (PLA) Poly(lactic acid) (PLA) is typically obtained by ring-opening polymerization (ROP) of the biobased monomer lactide (LA), which in turn is obtained from oligomerization of lactic acid (to low molecular weight PLA) followed by depolymerization (Figure 1.2).  High molecular weight PLA can be obtained by ROP with relatively good control over the molecular weight employing homoleptic initiators such as tin(II) octanoate in the presence of an alcohol.11 Depending on the initial stereochemistry of the monomers employed, PLA with different tacticities can be obtained (see below).      Figure 1.2. Synthesis of lactide from renewable feedstocks.  HOOHOOOOHHnoligomerization− H2OOOOOOOOOOOOOL-LA D-LA meso-LAL-(+)-lactic aciddepolymerizationrac-LA (50:50)4  1.1.2 Tacticity in PLA Mechanical and thermal properties of PLA are highly dependent on the tacticity (relative stereochemistry of monomer chiral centers) of the polymer (Figure 1.3).12 An ordered microstructure can be imparted by (1) the use of enantiopure monomer (e.g. L-LA to isotactic PLA), provided there is no epimerization or by (2) the use of a suitable (chiral) initiator in a racemic mixture of monomers (e.g. rac-LA).    Figure 1.3. PLA microstructures arising from lactide ROP.  Isotactic PLA contains on its microstructure sequential stereocenters of the same relative configuration. Such an arrangement makes the polymer highly crystalline with a melting temperature (Tm) of 170-190 °C.13 PLA with an irregular arrangement of stereocenters is known OOOOOOOOL-lactideD-lactiderac-LAOOOOOOOOnOOOOOOOOnOOOOOOOOnS SS SR RR Ratactic PLAheterotactic PLAisotactic stereoblock PLAnPm = 0.5Pm = 1Pr = 1SSRROOOOL-lactideSS OOOOOOOOnS S S Sisotactic PLAPm = 15  as atactic PLA, which is an amorphous material with a glass transition temperature (Tg) of 50-57 °C and poor mechanical properties.14-15 PLA with alternating sequences of L-LA and D-LA is known as heterotactic PLA and it's also highly amorphous despite its regularity.16  Tacticity in PLA is typically determined by 1H{1H} NMR spectroscopy, by comparing the statistical ratio of different tetrads (sequence of 4 stereocenters) in the methine (CH) region of the spectrum. A meso-linkage (m) is defined as the union of two adjacent stereocenters with the same configuration and a racemo-linkage (r) is defined as the union of two adjacent stereocenters with opposite configuration (Figure 1.4). Therefore, a series of 4 consecutive stereocenters resultant from the polymerization of rac-LA can show the following possible tetrads (from 3 linkages): [mmm], [mrm], [rmr] as well as [mmr] and [rmm]. Using Bernoullian statistics,17 the degree of isotacticity can be determined as the probability of finding meso-linkages (Pm) and the degree of heterotacticity can be determined as the probability of finding racemic-linkages (Pr).   Figure 1.4. Example of a tetrad and calculation of Pm and Pr using Bernoullian statistics.  1.1.3 Mechanisms of ring-opening polymerization (ROP) of lactide Metal-mediated polymerization of LA can run through 2 distinct pathways: (1) A coordination-insertion mechanism and (2) an activated-monomer mechanism. The former is typical of metal centers containing nucleophilic initiating groups such as an alkoxide or an amide OOO O OO O OnS SR Rmeso linkage meso linkagePm = [mmm]Pr  = [rmr] + [mrm]rmr mmrrmmmrmmmm1H{1H} spectrum, methine region (5.0-5.30 ppm)racemo linkage[mrm] tetradA  = x + y + z (total integration area)x/A = (Pr)2/2Pr = (2x/A)0.5y/A = (Pr)(Pm)/2Pm = (2y/APr)x yz6  (Figure 1.5),18 while the latter relies on highly electropositive metal centers that allow for initiation with an externally-added alcohol (Figure 1.6).19 Both mechanisms are driven by the release of approximately −23 kJ/mol of ring strain from the monomer20 and can be living in the absence of chain-termination reactions (e.g. backbiting) or significant transesterification (see below).     Figure 1.5. Simplified coordination-insertion mechanism of lactide ROP where M represents a metal complex and Nu a nucleophilic group.    Figure 1.6. Simplified activated-monomer mechanism of lactide ROP. M NuOOOOM NuOOOOMOOONuOMOOOONunew alkoxide nucleophileR O HMOO OOMOOOOR O HRO O OOOHM+MOOOOHROnew alcohol groupH-transfer H-transfer7  1.1.4 Ring-opening polymerization (ROP) of lactide by Group 13 metal complexes Group 13 metal complexes have been reported among the most active and selective initiators for LA polymerization. Most complexes of this group are based on aluminum and indium, but some gallium-based compounds are also known.21-24 Simple homoleptic compound Al(OiPr)3 has been used for polymerization of L-LA in bulk (melt) conditions above 100 °C to give isotactic PLA with excellent activity.25-26 As this species doesn't impart any stereoselectivity during polymerization (giving atactic polymers for rac-LA), multiple aluminum alkoxide complexes supported by ligand frameworks have been developed exhibiting different degrees of control and selectivity.27  One of the first examples was reported in 1987 by Inoue and collaborators, who described a phorphyrin aluminum alkoxide complex (I.1, Figure 1.7) that was active in the living polymerization of 100 equiv of D-LA at 100 °C, giving high conversions to PLA in 96 h with good control over the molecular weights and dispersities (Đ) around 1.1.28 Similarly, a methylenebisphenolate aluminum alkoxide complex (I.2, Figure 1.7) reported by Lin and collaborators was found capable of polymerizing 50 equiv of L-LA in refluxing toluene to high conversions in 48 h yielding products with very low dispersities.29 High degrees of isoselectivity in LA polymerization have been achieved using aluminum complexes with salen-type ligands. One of the first examples was reported by Spassky and collaborators, who employed a salen complex with a chiral R-(+)-binaphtyl diamine linker (I.3, Figure 1.7) for the polymerization of rac-LA at 70 °C to yield stereoblocks. The high selectivity of this complex was due to a higher preference for the D-LA enantiomer, with a kD/kL close to 20.30 The activity of this catalyst was later improved by Coates and collaborators, using a isopropoxide-variant (I.4, Figure 1.7) they accessed isotactic stereo-blocks with higher melting point than the fully-isotactic-enantiopure 8  polymer due to the formation of stereoblocks with higher crystallinity.31-32 Later, Feijen and collaborators employed a chiral salen ligand bearing a chiral diamino-cyclohexane linker to make an aluminum isopropoxide complex (I.5, Figure 1.7) that could also polymerize rac-LA at 70 °C to give stereoblocks with Pm of 0.93 (high isotacticity).33-34 Another chiral variant (I.6, Figure 1.7) reported by Carpentier, Sarazin and collaborators, could polymerize rac-LA at 70 °C to give stereoblocks with Pm of 0.90.35 Interestingly, achiral salen aluminum complexes (I.7, I.8, Figure 1.7) can also induce stereoselective lactide polymerization with Pm values up to 0.98 in the presence of an alcohol.36-37 In such cases where it's not possible to isolate a discrete aluminum alkoxide species, it is often possible to use an aluminum alkyl species that reacts with an alcohol to generate the respective alkoxide species in-situ during polymerization conditions. Such systems are usually ROP-active under immortal conditions (with excess alcohol added as a chain-transfer agent).   Salan aluminum complexes (I.9, I.10, Figure 1.7) reported by Gibson and collaborators showed strikingly different selectivities, as the presence of chloride groups in the phenoxide rings rendered the complex highly heteroselective (Pr of 0.96) in comparison to the unsubstituted complex that showed an isotactic bias.38 In 2005, Okuda and collaborators reported an aluminum alkyl complex (I.11, Figure 1.7) supported by an achiral bisphenolato ligand with thioether linkers (OSSO-type ligand) capable of polymerizing rac-LA in the presence of alcohol at 70 °C to give heterotactically-enriched PLA (P r of 0.64) in a living fashion (Đ around 1.1).39 In 2010, Gao, Mu and collaborators reported a discrete aluminum alkyl species supported by NCN pincer ligand (I.12, Figure 1.7) capable of polymerizing L-LA in an immortal fashion with an excess of alcohol, but with very low productivity even at high temperatures.40   9   Figure 1.7. Examples of chiral and achiral aluminum alkoxide/alkyl complexes active in lactide ROP.  N NNNAlPhPhPhPhO OOOOAl AlOOBnBnPh PhPh PhPhPh PhPhNN OOAl ORR = Me  I.3R = iPr   I.4I.2I.1N NO OtButButButBuAlOiPrMen = 2  I.7n = 3  I.8I.6I.5PhN NPhO OtButButButBuAlOiPrN NO OtButButButBuAlEt(CH2)n+ ROHR = H   I.9R = Cl  I.10N NO ORRRRAlMe+ ROHPh PhS SO OtBuMetBuMeAlMeI.11AlN NEtEtEtEtEt Et+ ROH + ROHI.12OSAlMeMetButBu NNAdOAlMetButBuI.14I.13+ ROH + ROH10  Lamberti, Mazzeo and collaborators reported a phenolato-thioether bidentate aluminum alkyl complex (I.13, Figure 1.7), active in the polymerization of rac-LA, L-LA and ε-caprolactone (ε-CL) in an immortal fashion at 80 °C with very good control, but due to the lack of steric congestion at the metal center, polymerization of rac-LA with this achiral complex yielded atactic PLA.41 More recently, Pang and collaborators reported a tridentate iminophenolate complex bearing an S-(−)-binaphtyl diamine linker (I.14, Figure 1.7) that could polymerize rac-LA to isotactically-enriched PLA (Pm of 0.65), but with a lower selectivity if steric-bulk was reduced around the metal center.42   Despite their outstanding selectivity, aluminum complexes require typically high temperatures and long reaction times to achieve considerable conversions. This limits greatly their applicability in copolymerizations and the range of accessible PLA molecular weights. In sharp contrast to the aluminum complexes here described, many of the indium complexes in the literature reported active in LA ROP display a significantly higher activity at room temperature compared to aluminum complexes. One of the first examples was reported by Hillmyer, Tolman and collaborators in 2009. They described a simple system composed of InCl3, benzyl alcohol and triethylamine that was capable of polymerizing up to 800 equiv of rac-LA to highly heterotactic PLA (Pr up to 0.94 at room temperature and 0.97 at 0 °C) in a matter of hours.43 The high selectivity of system is remarkable taking into account the absence of any chiral inductor and the lack of a supporting ligand framework for the metal center.  Around the same time, Mehrkhodavandi and collaborators reported a dimeric chiral indium initiator supported by a tridentate ligand (NNO) that was highly active in the polymerization of rac-LA to isotactically enriched PLA (Pm up to 0.63) with high control (Đ close to 1.1).44 Interestingly, the dimer shows two asymmetric bridges with only one alkoxide nucleophile for the two metal centers, holding 11  the dimeric structure also in solution (I.15, Figure 1.8). Later DFT studies suggested that the dimeric structure also holds during propagation, allowing for metal-metal cooperation and the growth of a polymer chain per dimer in a coordination-insertion mechanism.45-46 In 2009, Okuda and collaborators re-applied achiral bisphenolato tetradentate ligands with thioether linkers previously used on aluminum to make indium isopropoxide complexes (I.16, I.17, Figure 1.8). Such complexes formed dimeric structures (a common characteristic of indium complexes) that could polymerize L-LA with good activities (slightly faster rates for the bulkier complexes) at room temperature to give isotactic PLA with low dispersities, but showed no selectivity in the ROP of rac-LA.47 Inspired by the high selectivity and good control shown by aluminum salen complexes (see above), Mehrkhodavandi and collaborators reported in 2013 a highly active indium alkoxide dimer supported by a Jacobsen ligand and bridging through two ethoxide groups (I.18, Figure 1.8) that yielded isotactically enriched PLA (Pm of 0.85).48 Increasing or decreasing stereric bulk on this complex by changing the tBu groups decreased significantly its isotactic bias, revealing a delicate steric balance. Also, a monomeric version of this complex could be isolated using 2-pyridine methoxide that could still produce isotactically enriched PLA (Pm of 0.78).49 Later, the same group reported an air- and moisture-stable indium complex supported by a salan ligand (I.19, Figure 1.8). The complex formed dimers in the solid state and in solution by an assymetric ethoxide bridge (in contrast to the salen analogue that formed symmetric bridges with two ethoxide groups).  This very robust system was active in the immortal polymerization of rac-LA to heterotactically-enriched PLA (Pr of 0.72), even after multiple exposures to air and water.50 More recently, Williams and collaborators reported a phosphasalen indium alkoxide complex (I.20, Figure 1.8) that not only shows high rates for rac-LA polymerization, but also shows high levels of isoselectivity (Pm up to 0.92). The combination of high activity and 12  isoselectivity in this system is remarkable when compared to the most stereoselective systems in the literature (based on aluminum). Changing the ethoxide initiator in this complex for a tert-butoxide still afforded fast polymerizations, but about 4-times slower.51          Figure 1.8. Examples of indium alkoxide complexes active in lactide ROP.  1.2 Polyethers Polyethers produced by the ROP of ethylene oxide (EO), propylene oxide (PO) and butylene oxide (BO) constitute an important class of products with several applications. While only these three epoxides make most of commercial polyethers available, other substituted epoxides such as NNOIntButBuClOEttButBuInONNH HCl ClI.15NNOOtButButButBuInNNOOtButButButBuInOOEtEtI.18SSOORRRRInSSOORRRRInOOiPriPrR = tBu          I.16R = CMe2Ph  I.17NN OOIntButButButBuClOEttButButButBuInOO NNHHHHN N PPCMe2PhPhMe2CPhMe2CCMe2PhO OInOEtPhPh PhPhI.19 I.2013  epichlorohydrin, glycidol, substituted glycidyl ethers and glycidyl amines are getting increasing attention from the academia as potential monomers for new functionalized materials (Figure 1.9).  Poly(ethylene oxide) (PEO); also called poly(ethylene glycol) (PEG) for lower molecular weight polymers (up to 30,000 Da), is considered the gold standard for biocompatible polymers (due to its high solubility in water and low immunogenicity and toxicity). Therefore it's highly employed in the biomedical field,52-54 as well as in the cosmetic, pharmaceutical, and food industries.55 PEGylation or the covalent bonding of PEG to drugs or biomolecules is a common method that enhances their stability in vivo by means of the "stealth effect", increasing circulation time and overall improving the pharmacological properties.56    Figure 1.9. Common epoxides used for ROP reactions, including representative glycidyl ethers and amines.  OOOO OOOOHOClOOOEthylene oxidePropylene oxideButylene oxideEpichlorohydrinGlycidolONONAllyl glycidyl etherIsopropylidene glyceryl glycidyl etherN,N-Diallyl glycidyl amineN-Benzyl-N-methyl glycidyl amine14  Unlike PEO, poly(propylene oxide) (PPO) is not soluble in water at room temperature, and due to the additional methyl group in each monomer unit it can have different tacticities. For example, highly atactic PPO is a non-crystalline polymer with a Tg in the range of −75 °C to −67 °C.57 In contrast, isotactic PPO is a semi-crystalline solid with a Tm of 67 °C.58 Atactic PPO is a flexible polymer employed in the production of polyurethane flexible foams and as an ingredient in the composition of lubricants and antifoaming agents.59 Poly(butylene oxide) (PBO) is another polyether produced industrially (though in a far smaller scale compared to PEO and PPO). Having an extra carbon in each monomer unit makes it more hydrophobic compared to PPO, and therefore it is mainly employed for the production of water-proof poly(urethane) sealants. It is also used in copolymers with PEO as polymeric micelles for drug delivery.60 To further broaden the application scope of polyethers, their structure can be modified through the use of functionalized polymerization initiators, through the use of functionalized terminating agents or through the use of functionalized monomers. For example, glycidyl ethers with alkenyl moieties can be polymerized and then be reacted with thiols to form polymers with thioether linkages and new functional groups.61 Overall, several alternatives can be explored for the production of functionalized polyethers with different topologies (e.g. branched or linear) for different purposes.62-63 Particularly, the field of PEGylation of drugs, surfaces or biomolecules like proteins or DNA using functionalized PEG is currently a highly active area of research with a promising future.64-69          15  1.2.1 Mechanisms of ring-opening polymerization (ROP) of epoxides The ROP of epoxides is a type of chain-growth polymerization. The most common mechanisms of metal-catalyzed ROP of epoxides are: (i) anionic ROP, (ii) coordination-insertion ROP and (iii) cationic ROP.  Anionic ROP of epoxides is by far the most accessible method of polymerization for EO and PO.70 It relies on strong bases like hydroxides, alkoxides or amides of alkaline metals to initiate a nucleophilic attack on the epoxide ring (Figure 1.10). Propagation of the polymerization is mediated by an alkoxide group stabilized by the cationic counterion of the initiator (alkaline metal).71-72 The alkoxide chain-end of a growing polymer can be rather stable with respect to termination, and thus, anionic ROP of epoxides can be living.73 Nevertheless, significant chain transfer in the case of PO polymerization can limit severely the maximum molecular weights obtained by this method (Up to 13,000 Da for PPO).74    Figure 1.10. Simplified anionic mechanism of polymerization of propylene oxide.  Polymerization of epoxides by the coordination-insertion mechanism often follows a pathway similar to the one described earlier for LA polymerization (Figure 1.5), but some systems that show high activity in the presence of external cocatalyst; typically bis(triphenylphosphoranylidene)imminium chloride (PPNCl), can also follow an activated-monomer mechanism. The use of a Lewis acid is key to the ring-opening step in the absence of ONuMNu OONuOnOMMO16  strong bases. Trialkyl aluminum-species in the presence of water are known to be very active in the polymerization of PO and some glycidyl ethers.75-76 Other examples of highly active complexes are: aluminum chloride supported by phorphirines,77-78 cobalt(III) acetate supported by salphen ligands58 and chiral bimetallic salen cobalt(III) chloride complexes.79-80 In general, coordination-insertion mechanism provides good control over the polymerization and can be stereoselective. For PPO, molecular weights up to 170,000 Da and low dispersities (close to 1.1) can be obtained.81  Cationic ROP relies on the use of cationic, strong electrophiles to activate epoxides, favoring their ring opening by the nucleophilic attack of other epoxide molecules (Figure 1.11). Thus, the active species in the propagation is an oxonium ion and the counterion initially accompanying the electrophile initiator moves along with the growing chain. Interestingly, the propagation rate constants for the cationic ROP of epoxides are calculated to be up to two orders of magnitude higher than those for anionic ROP, but the productivity of this polymerization method is severely affected by the formation of significant amounts of cyclic polyether and oligomers product of backbiting.82-83    Figure 1.11. Simplified cationic mechanism of polymerization of propylene oxide.  OEOXE O OOXEO OnO X17  1.2.2 Ring-opening polymerization (ROP) of epoxides by Group 13 metal complexes Some of the first neutral aluminum complexes reported to be active in the ROP of epoxides were simple alkyl, alkoxide and chloride precursors (e.g. AlCl3, Al(OiPr)3, AlMe3).84-86 By mixing AlEt3, acetylacetone and water, Vandenberg86 and collaborators developed one of the most active systems for epoxide polymerization, currently employed in industry for the production of high molecular weight polyether elastomers.87 Although the exact structure of Vandenberg's catalyst is still debated, it's high activity is attributed to a bimetallic ROP mechanism favored by the presence of an oxide ion bridging two aluminum centers (I.21, Figure 1.12).88 Later, aluminum systems based on a chiral salen ligand (I.22, Figure 1.12) and porphyrin ligand (I.23, Figure 1.12) would be reported by Le Borgne's research group89-90 and by Inoue's research group77 respectively. Both complexes showed moderate activity towards the ROP of PO with long reaction times and low productivity (oligomerization). Similarly, an aluminum-calixarene complex (I.24, Figure 1.12) reported by Kuran and collaborators showed only modest activity in the same reaction.91     The first example of a discrete cationic group 13 metal complex active in the ROP of epoxides dates back to 1995, when Atwood and collaborators reported the synthesis of a cationic aluminum species with a salen ligand, BPh4− as counterion and the two methanol solvent molecules in the axial positions (I.25, Figure 1.13). This complex could polymerize PO to low molecular weight oligomers (Mn of 1,000 Da), in contrast with same complex bearing a chloride counterion that did not polymerize PO.92 Four years later Atwood and collaborators, reported a similar group of cationic aluminum species with a modified salen ligand and different counterions: BPh4−, TsO− (tosylate) and chloride. A similar counterion effect was reported: only the complex with the less coordinating BPh4− anion showed significant activity in the 18  polymerization of PO.93 Polymerization initiation by protic solvent (methanol) in these compounds was ruled out in a later study involving the synthesis of similar aluminum cationic complexes with coordinating THF molecules (I.26, Figure 1.13). This family of compounds produced high molecular weight PPO (Mn up to 400,000 Da) with low dispersities in what appeared to be a controlled mechanism, but not living.94 On another report, Atwood and collaborators attempted the synthesis of aluminum cationic species supported by a salen-type ligand (with a longer trimethylene diamine linker) in a non-coordinating solvent, obtaining a dinuclear, bis-cationic complex with two µ-O phenolate bridges (I.27, Figure 1.13). This complex produced low-medium molecular weight oligomers when reacted with PO (Mn up to 1,562 Da) with high dispersities.95    Figure 1.12. Examples of neutral aluminum complexes active in propylene oxide ROP.  OO OMetButBu tButBuMeOAlClN NNNAlPhPhPhPhClN NO OAlClO OAlAlO EtEtEtI.21 I.22I.23 I.2419  A different family of five-coordinate cationic aluminum complexes (I.28, Figure 1.13) was also reported by Atwood and collaborators with chelating PMDETA (N,N',N'',N'''- pentamethyldiethylenetriamine). The cationic complexes were not particularly active in the ROP of PO, but yet, another counterion effect was evidenced: While the complex with the Me2AlCl2− counterion was capable of polymerizing PO to oligomeric materials (Mn up to 530 Da), complex with a bromide anion produced very small oligomers that could not be characterized.96 A similar ligand was employed by Bertrand and collaborators for the synthesis of another cationic complex (I.29, Figure 1.13) that polymerized PO to low-medium molecular weight PPO (Mn of 1,416 Da) with a narrow dispersity (Đ of 1.18). 13C{1H} NMR spectroscopy evidenced a regio-regular enchainment of the monomers and the presence chloride ion as initiator was evidenced, indicating a more controlled coordination-insertion mechanism for the polymerization of PO.97 Unfortunately, activity of this system was low and required high initiator loadings and high temperatures to achieve polymerization in two days.  In 2001, Jordan and collaborators reported a series of cationic aluminum species containing an N,N'-diisopropylaminotropoiminate ligand and different alkyl groups bonded to the metal. Only one of these complexes polymerized PO (I.30, Figure 1.13), but molecular weights were not reported. Interestingly, the isobutyl cationic complex could be reacted with acetone to induce a β-H elimination and release of isobutylene gas to yield a cationic aluminum alkoxide (isopropoxide) species whose activity was not further studied.98 Dagorne and collaborators attempted in 2003 the synthesis of three-coordinate cationic aluminum species based on bidentate amino phenolate ligands in a non-coordinating solvent. The resulting cationic species, however were four-coordinate adducts of the cation and neutral precursor, joined together by a µ-O phenolate bridge (I.31, Figure 1.13). The dimers could be broken with addition of THF to 20  form discrete cationic species and the respective neutral species. Their activity towards polymerization of PO was moderate, giving medium molecular weight PPO with atactic microstructure (Mn up to 9,022 Da) with large dispersities (Đ of 1.73).99    Figure 1.13. Examples of cationic aluminum complexes active in the ROP of PO.  NAlO MetBuNAlOMeMetBu [BMe(C6F5)3]NAlN[B(C6F5)4]OAlOAlNNtButBuOtButBu[GaCl4]NtButBuONtButBuNNNSiMe3Me3Si AlClHSiMe3[AlCl4]NNO OAl[BPh4]SSNNNMeAlMeMe[Me2AlCl2]MeMeMe Me2RRR RR = H; S = MeOH    I.25R = tBu; S = THF     I.26I.27I.28 I.29I.30 I.31[GaCl4]21  Later in 2009, the same group explored a different strategy for the synthesis of cationic aluminum complexes. Since most of the previous examples of cationic aluminum complexes were supported by ligands with hard donors (oxygen- and nitrogen-based), they explored the possibility of using L-type soft donors such as phosphines. Despite the apparent hard-soft mismatch that could be detrimental for the stability of the cationic species, bis- (I.32, Figure 1.14) and mono-adduct with coordination of THF (I.33, Figure 1.14) cationic aluminum complexes with phosphino-phenolate ligands were isolated and fully characterized. Both complexes are capable of polymerizing PO to medium molecular weight polymers (Mn up to 8,740 Da) with high relatively dispersities (Đ close to 1.6), but the bis-adduct generally produced higher conversions and higher polymer molecular weight values. Interestingly both cationic complexes also initiated polymerization of ε-CL through a metal-phenoxide insertion (coordination-insertion mechanism).100 Ishii and collaborators also studied the effect of softer donor ligands on the catalytic ROP activity of aluminum cationic complexes. They reported in 2014 a di-nuclear di-cationic aluminum complex with two [OSSO]-type ligands bearing thioether and phenolate groups. Interestingly, the two metals have different geometries, one being square pyramidal and the other trigonal-bipyramidal in a very crowded structure with two µ-O phenolate bridges (I.34, Figure 1.14). Activity of this species in the polymerization of PO at room temperature was rather modest, producing medium molecular weight PPO (Mn of 2,500 Da) with quite low dispersity (Đ of less than 1.1). No analysis of chain-end or mechanism was presented.101 In 2010, Dagorne and Carpentier reported a new cationic aluminum compound with a fluorinated dialkoxide-diimino ligand in diethyl ether, using B(C6F5)3 as an alkyl-abstraction reagent (I.35, Figure 1.14). In contrast to the aluminum complexes with salen-type (dialkoxide-22  diimino) ligands previously reported by Atwood (I.25-I.26, Figure 1.13), the metal center had a distorted trigonal bipyramidal geometry.  ROP of PO with this compound was fast, achieving full conversion of 200 equiv in less than 2 hours at room temperature yielding an oily product composed of low molecular weight oligomers (Mn up to 510 Da) with relatively low dispersities (Đ between 1.1 and 1.3).102    Figure 1.14. Examples of cationic aluminum complexes active in the ROP of PO.  In contrast to the literature based on cationic aluminum species, reports on cationic gallium species active in the ROP of epoxides are scarce. Even so, they are more stable and afford low-O AlONNOCF3CF3CF3CF3 [BMe(C6F5)3]Al OPh2POtButBuMeMePHPh2[BMe(C6F5)3] [BMe(C6F5)3]AlPPh2OtBuMe OMeOAlOAlOSSSStButBuOtButBu tButButButBu[BMe(C6F5)3]2[BMe(C6F5)3]I.32 I.33I.35I.3423  coordination numbers when compared aluminum. For instance, Wehmschulte and collaborators reported in 2003 the synthesis of a stable, linear, two-coordinate gallium complex that was active in the polymerization of cyclohexene oxide.103 In 2005, Dagorne, Bellemin-Laponnaz and collaborators reported different set of cationic gallium complexes incorporating bis(oxazolinato) ligands that were active in the ROP of propylene oxide, producing oligomers (Mn of 448 Da) with atactic microstructure and high dispersities (Đ > 2.0).104          1.3 Synthesis of oxygenated block copolymers Controlled synthesis of copolymers including biodegradable segments has shown promising results, as the diversity of functionalities from both renewable and petrochemical resources can be used to tune thermal and mechanical properties of the macromolecules and often allow for post-functionalization.105 In particular, the use of block copolymers including polyester segments is attractive because of their tunable biodegradation, which has been applied in thermoplastic elastomers, polymeric polyols, phase compatibilizers, gene vectors and other polymer-drug conjugates.106-109 Most commonly, the synthesis of block copolymers including polyester units involves the coupling of a polyester with another block through post-functionalization, or the use of a pre-made block as a macroinitiator for the polymerization of a monomer. Such approaches comprise several steps and have been applied with success to some copolymers.107, 110-113  1.3.1 Synthesis of polyester-polyester block copolymers The controlled ring-opening polymerization (ROP) of lactones is the preferred synthetic method to make polyester blocks. By far, the most common approach is the sequential addition 24  of different cyclic esters in the presence of one or multiple suitable initiators. One of the main challenges to this methodology are inter- and intra-molecular transesterification reactions which can convert block-microstructures intro random copolymers with broad dispersities.114-117 Using tin(II) octoate is not recommended for the synthesis of block architectures as it leads to significant transesterification and scrambling at high temperatures,118-119 but it has been used successfully in block copolymerizations with lactide (LA) and ε-caprolactone (ε-CL) when the temperature was kept below 120 °C.120-123 Other metal initiators have been applied to the controlled synthesis of block polyesters, yielding less dispersed copolymers. In particular, systems based on aluminum have been used the most often,124-126 as well as rare-earth metals,127-128 indium,50, 129-130 zinc131-132 and transition metals.133-135  Most of the aluminum systems reported for ROP of LA and other cyclic esters are based on phenoxy-imine, salen- and salan-type alkyls or alkoxides that give access to different copolymer microstructures.136-141 Zaitsev, Kostjuk and collaborators reported bulky iminophenolate aluminum alkoxides that were relatively controlled in the sequential polymerization of ε-CL or rac-LA at high temperatures (but showed higher dispersities under monomer starved conditions).142 The fluorinated initiator (I.36, Figure 1.15) allowed for a more controlled synthesis of block copolymer, first polymerizing ε-CL and then rac-LA under neat conditions at 130 °C with moderate molecular weight and dispersity (Mn = 13,200 Da; Đ = 1.27). A dinuclear salan aluminium system in the presence of an alcohol (I.37, Figure 1.15) has also been reported to give defined block copolymers of ε-CL and L-LA by sequential addition, but only by the initial polymerization of ε-CL followed by lactide.140 Matsubara and collaborators reported an aluminum isopropoxide complex (I.38, Figure 1.15) bearing half-salen-type ligand that could 25  polymerize first rac-LA and then ε-CL in a sequential manner to form block copolymers (Mn = 11,500 Da; Đ = 1.24) at 70 °C in pyridine (to suppress dimerization of Al complexes).126    Figure 1.15. Aluminum complexes for the block copolymerization of lactide and other cyclic esters.  Pappalardo and collaborators employed a salicylaldiminate aluminum alkyl complex (I.39, Figure 1.15) in the presence of alcohol for the block copolymerization of LA and glycolide (GA) through sequential addition method.143 Under the reaction conditions studied (xylenes, 130 °C), analysis by 13C{1H} NMR spectroscopy showed only homosequence triads, supporting the formation of a block copolymer through a living mechanism (with good agreement between OOOOOOO ORNAlOtBuRO O OO yO HOOxI.38I.38P[LA-b-CL]O ONAlNORI.36F FOOOOROO yxI.36 or I.37P[CL-b-LA]OOO O O HOO!-CL!-CLLALAO ONAlNAlBrBrBrBr+ ROHI.37OOOORO HOx yO OOOI.39P[LA-b-GA]OOOOLAGAONAlFI.39FFFFOOO+ ROH26  experiment and theoretical molecular weight). Interestingly, switching to a simultaneous addition of monomers formed either blocky-structures or totally random copolymers depending on the reaction conditions used (solution or bulk polymerization). Previously, the same group reported a very similar aluminum alkyl complex active in the block copolymerization of rac- or L-LA with ε-CL through a sequential addition method in toluene at 70 °C.141  Mehrkhodavandi and collaborators reported the application of a very active dinuclear indium catalyst (I.15, Figure 1.8) in the synthesis of triblock copolymers of L- and D-LA with rac-β-butyrolactone, rac-β-BL (Figure 1.16).130 The high molecular weight copolymers (Mn = 138,000 Da; Đ = 1.22) were made through three consecutive additions and behaved as thermoplastic elastomers with improved mechanical properties over block copolymers of lactide isomers.130 Later, the same group reported another indium catalyst (I.19, Figure 1.8) supported by a salan ligand that could polymerize LA in an immortal fashion to make linear and star block-copolymers when exposed to air and moisture (Figure 1.16). With this system, diblock copolymers of LA and β-BL were synthesized at room temperature with good control (Mn = 48,600 Da; Đ = 1.01).50 Using Hillmyer and Tolman's simple system43 for the syndio-selective polymerization of rac-LA (indium trichloride, triethylamine and an alcohol), Martín-Vaca, Bourissou and collaborators reported the sequential copolymerization of ε-CL and ε-decalactone (ε-DL) to diblock copolymers with good control (Mn up to 22,000 Da; Đ = 1.24) and no evidence of transesterification regardless of the order of monomer addition order.144 Over the past decade, the ROP of macrolactones has attracted a lot of interest as a result of their long aliphatic backbone that resembles low density poly ethylene (LDPE),145 with the added advantage of a higher biodegradability imparted by the ester group. Despite their limited degradation under physiological conditions, they can be biocompatible146 and their 27  copolymerization with smaller monomers has attracted more attention to tune its physical properties for different applications.117, 147 In 2015, Duchateau and coworkers reported a salen alkyl complex (I.40, Figure 1.16) capable of copolymerizing in a sequential manner ω-pentadecalactone (ω-PDL) and L-LA in p-xylene at 100 °C to high molecular weight block copolymer with moderate dispersity (Mn = 144,000 Da; Đ = 1.50).148 DSC analysis confirmed block microstructure, with two clear melting transitions. Interestingly, block copolymers could only be made if ω-PDL was polymerized first, but not through reverse order of addition, demonstrating the lack of reactivity of a secondary alkoxide group towards macrolactone ROP.   Figure 1.16. Aluminum complexes for the block copolymerization of lactide and other cyclic esters.  OOOOP[LA-b-BL-b-LA]OOOOOO!-BL D-LAL-LAO O O O OOOO OOx y zOOOOOOLA!-BLO O OO OOy zP[BL-b-LA]I.15I.19OOOOOORO HOO x yO OOOI.40P[PDL-b-LA]13L-LAPDLO ONAlNEtI.40+ ROH28  1.3.2 Synthesis of polyether-polyester block copolymers Polyester-polyether block copolymers can be synthesized by ROP of cyclic ethers and lactones. Although multiple metal-based initiators and organocatalysts have been reported to give a controlled polymerization of these molecules, very often a catalytic system optimal for the polymerization of one monomer is inactive or leads to uncontrolled polymerization of the other. Consequently, many of the synthetic procedures reported for the synthesis of polyester-polyether blocks require multiple steps involving different catalytic systems and the purification of intermediates. Some approaches include controlled polycondensation reactions between two preformed polymers149-152 and their linkage through post-functionalization (e.g. click reactions).153-155 By far the most common synthetic strategy involves using commercially available polyethers such as polyethylene glycol/oxide (PEG/PEO), polypropylene oxide (PPO) or poloxamers as a macroinitiators in the ROP of the cyclic ester in the presence of a suitable catalyst. In this fashion, block copolymers of LA,156 ε-CL,157  δ-VL,158-159 β-BL,160-161 ω-PDL162 and different O-carboxyanhydrides (OCAs)163-166 have been accessed. In particular, ROP of OCAs has attracted significant interest due to their straightforward synthesis from different aminoacids or α-hydroxy acids and easy access to functionalized monomers.167 Other functionalized monomers based on ε-CL and LA have also been employed in their copolymerization with PEG macroinitiators to make diblock and triblock copolymers.168-173  The most widely used initiator for these polymerizations is tin(II) octoate, which works well with most common 6- or 7-membered rings in the presence of a hydroxy-capped polyethers, yielding polyether-polyester block copolymers with good control over molecular weight (dispersities as low as 1.1, given that a  monodispersed macroinitiator is used). In order to copolymerize PEG and 4-membered lactones, Gillies and coworkers employed a salen 29  aluminium alkyl complex in the presence of an alcohol (I.41, Figure 1.17), Gillies and collaborators polymerized challenging monomer β-6-heptenolactone (β-6-HEL) with excellent control in the presence of MeO-PEG (Mn 2,000 Da) forming amphiphilic diblocks (Mn = 12,910 Da; Đ = 1.03) that could be subsequently functionalized through the thiol-ene reaction for application in drug delivery (Figure 1.17).174 Another notable exception is the polymerization of OCAs. Using organocatalysts such as DMAP or 4-methoxypyridine, Dove and coworkers have reported the polymerization of OCAs derived from malic acid (L- or D-MalOCA) in the presence of MeO-PEG (Mn = 7,500 Da) to give amphiphilic diblock copolymers (Mn = 9,400 Da; Đ = 1.04) that formed stable stereocomplexed micelles in solution (Figure 1.17).164 Polymerization of macrolactone ω-PDL or bioderived δ-decalactone (δ-DL) has also been achieved using organocatalyst TBD in the presence of diamino- or dihydroxy-capped PEG macroinitiator to give amphiphilic triblock copolymers.162, 175 Other organocatalytic systems such as DBU,158 sparteine/thioureas176-177 and phosphazene base t-BuP2178 have also been employed for the polymerization of cyclic esters in the presence of polyether macroinitiators. Ring-opening copolymerization (ROCOP) of anhydrides and epoxides (a reaction that yields polyesters) has also been performed in the presence of a polyether macroinitiator to make block copolymers. Recently, Xiao, Chen and collaborators employed phosphazene base t-BuP1 (Figure 1.17) in the presence of MeO-PEG (Mn = 5,000 Da) for the polymerization of 2-(methylthio)ethylglycidyl ether and phthalic anhydride (PA) to make an amphiphilic block copolymer (Mn = 12,500 Da; Đ = 1.03) with redox-responsive properties for application in drug delivery (Figure 1.17).179     30    Figure 1.17. Synthesis of amphiphilic polyether-polyester block copolymers using PEG as a macroinitiator (preformed block) in the ROP or ROCOP of oxygenated monomers.   OO!-6-HEL P[EO-b-B6HEL]P[EO-b-MTGEPA]t-BuP1MeO O HMeO O HOOOOMTGEPAO SMeO-PEGMeO-PEGx yMeO O O HOOOOxMeO OyO H2OMeSOOOxMeO OyO H2OSO2x yMeO O O HO S4OROO ONAlNMetBu tButBu tBuI.41 + ROHI.41tBuNP(NMe2)3t-BuP1OOOOCO2BnP[EO-b-MalOCA]MeO O HMeO-PEGx yMeO O O HO4-methoxypyridine CO2BnL-MalOCA31  Using a bimetallic salen aluminum complex in the presence of an alcohol (I.42, Figure 1.18) active in both ROP of cyclohexene oxide (CHO) and cyclic esters, Mazzeo and coworkers synthesized PCHO-b-PCL (Mn = 11,100 Da; Đ = 1.97) and PCHO-b-PLA (Mn = 11,000 Da; Đ = 1.57) through sequential feeding of CHO and ε-CL/L-LA (Figure 1.18). Interestingly, simultaneous feeding of the monomers afforded only the polyester even after prolonged reaction times.180    Figure 1.18. Synthesis of polyether-polyester block copolymers using sequential ROP of cyclohexene oxide and lactide.  1.4 Scope of the thesis While there are numerous examples of neutral and cationic aluminum species active in the ROP of cyclic esters and epoxides, there are only a handful of examples based on indium that are reported for these reactions. Given the functional group tolerance and control shown by indium in different transformations,181 developing and exploring the reactivity of new indium complexes towards different ROP reactions can open the door to more versatile synthetic methodologies for the synthesis of oxygenated polymers. This is particularly relevant for the synthesis of oxygenated block copolymers, where transesterification and uncontrolled polymerization/depolymerization reactions can be detrimental and yield disordered OOOORO OyO O HOxI.42P[CHO-b-LA]L-LAO ONAlNAltButButButBu+ ROHI.42OCHOO32  microstructures. In this thesis, I explore the reactivity of novel cationic and neutral indium species for the synthesis of different homo- and copolymers, including polyether-polyester and polyester-polyester block copolymers.   In chapter 2, the synthesis and characterization of different cationic and neutral indium species active in ROP reactions is discussed. The ROP activity of some of these cationic species is presented in chapter 3. In chapter 4, the synthesis of polyether-polyester block copolymers is described using a cationic indium complex and mechanistic evidence is presented to account for microstructure control. In chapter 5, different neutral indium species are explored for lactide and caprolactone polymerization. Finally, the synthesis of polyester-polyester block copolymers is explored through sequential and simultaneous addition using some of these complexes.        33  Chapter 2: Synthesis and characterization of cationic and neutral indium species   2.1  Introduction Over the years, different indium(III) species have been developed as Lewis acids for a myriad of catalytic and stoichiometric transformations. Interestingly, in comparison to other commonly used Lewis acids such as aluminum(III), magnesium(II) and zinc(II), indium shows a greater stability to air and moisture, even allowing many reactions to be carried out in aqueous media.182-184 Indium has also been used with chiral auxilaries to induce stereoselective transformations.185-187 In particular, indium alkoxides supported by aminophenolate, iminophenolate or phosphiniminophenolate ligands have shown extensive application in ROP reactions. Some of the first examples were reported by Atwood and collaborators (I.43 and I.44 Figure 2.1) by employing the alcoholysis of the respective salen indium alkyl complexes. Unfortunately, these dimeric structures were only obtained in a mixture of products and therefore no ROP activity was reported.188  Years later, Mehrkhodavandi and collaborators reported a phenylamino indium alkoxide complex that also adopted a dimeric structure, both in the solid state and in solution (I.15, Figure 2.1). This complex could polymerize rac-LA and rac-β-butyrolactone (rac-β-BL) in an immortal fashion with excellent control over the molecular weight.44 45, 189 Following contributions of the group explored salen and salan ligands (I.18 and I.19, Figure 2.1), revealing high activities and tunable stereoselectivities.48, 50 This work has opened the door to different contributions exploring similar ligand scaffolds to stabilize indium alkoxide species, which in some cases are 34  generated from the respective alkyl species (Figure 2.2).35, 190-193 A notable constant in these examples is the high tendency of indium alkoxide complexes of forming dimers through bridging (compared to aluminum analogues), which might lead to a fluxional behaviour in solution or during polymerization conditions, making for a more difficult characterization of their structure/activity.49, 194   Figure 2.1. Examples of indium alkoxide reported by Atwood, Mehrkhodavandi and collaborators.  Similarly to aluminum (Figure 1.7), indium alkoxide species can be accesed in situ from the respective alkyl species, using an exogenous alcohol: For instance, Sarazin, Carpentier and NNOORRRRInNNOORRRRInOOEtEtR = H           I.43R = tBu        I.44NNOIntButBuClOEttButBuInONNH HCl ClI.15NNOOtButButButBuInNNOOtButButButBuInOOEtEtI.18NN OOIntButButButBuClOEttButButButBuInOO NNHHHHI.1935  collaborators have shown independently the reactivity of different indium alkyl complexes supported by salen and iminophenolate ligands (I.45, I.46, I.47, I.48, I.49, Figure 2.2) towards the ROP of lactide in the presence of alcohol. Efforts to isolate stable alkoxide species were unsuccessful. Interestingly, for the ligand framework studied, indium complexes showed comparable activity to their aluminum analogues, but significantly lower stereoselectivity. This behavior has been rationalized by the larger size of the indium center compared to aluminum (0.80 Å of the former compared to 0.53 Å of the latter),195 which generates a less sterically crowded active site and is therefore less effective inducing stereocontrol.190    Figure 2.2. Some examples of indium alkoxide and alkyl complexes supported by aminophenolate, iminophenolate or phosphiniminophenolate ligands.  N NCF3OCF3CF3O CF3InMe3Si+ ROHFePh2PPh2POOIntButButButBuNNOPhRNOIn+ ROHtBuO NNIn InOClClN NClClEtI.45I.50 I.51N NO OInMe3Si+ ROHPh PhR2 R2R1R1R1 = H, R2 = H         I.48R1 = Me, R2 = NO2  I.49SiPh3SiMe3SiMe3R = C6H5     I.46R = Pyr        I.4736  Another way to generate indium alkoxides active in lactide ROP involves salt metathesis from the chloride precursors using an alkoxide salt: For instance, Diaconescu and Mehrkhodavandi groups have independently employed indium chloride complexes, which by reaction with sodium phenoxide or ethoxide generate stable alkoxides (I.50, I.51, Figure 2.2).191-192      In contrast to neutral indium species, cationic indium species have been much less studied. Up to date, only a handful of In(III) have been reported in the literature (Figure 2.3) and most of these don't have any reported catalytic activity.196-202 Their synthesis can involve different strategies depending on the initial precursor. For instance, Schmidbaur and collaborators reported the synthesis of an indium cationic species (I.52, Figure 2.3) by the simple reaction of two equiv of indium triiodide with a bulky chelating phosphine, forming an ate complex as a counterion.200  A similar strategy was employed by Neumüller and collaborators by reaction of a cyclohexyl diamine ligand with two equiv of InMe2Cl, affording a cationic complex (I.55, Figure 2.3).196 Starting from a neutral aminotroponiminate dimethyl indium complex, Jordan and collaborators could generate cationic species (I.53, Figure 2.3) by reaction with cationizing agent [CPh3][B(C6F5)4] at high temperatures (methyl abstraction).199  Another common reagent, [NPhMe2H][B(C6F5)4] was employed by Okuda and collaborators for the reaction with a neutral alkyl species in a coordinating solvent, giving a stable cationic species (I.56, Figure 2.3) through protonation of the metal-alkyl bond.197 Mehrkhodavandi and collaborators have reported the same strategy for the synthesis of cationic indium alkyl species (I.58, Figure 2.3).202 Aldridge and collaborators reported the synthesis of a cationic species by salt metathesis of a neutral indium chloride complex and [Na][BArF4] to yield a stable cationic species (I.54, Figure 2.3).198 Exploiting the chelating effect of 1,10-phenanthroline, Corey and 37  collaborators formed a cationic species with a simple iodide counterion (I.57, Figure 2.3) by reaction of two equiv of the ligand with indium triiodide.201    Figure 2.3. Some examples of cationic indium complexes.   InOSi SiOO [B(C6F5)4]NInNMe [B(C6F5)4]iPriPrNInNiPrMeMePPh2InPPh2 IIPPh[InI4] Fe FeInOC COCOCO[BArF4]iPr[Me2InCl2]NNNNInIIIHHONNInPhPhOSiBArF4I.52 I.53 I.54I.55 I.56 I.57I.5838  2.2 Results 2.2.1 Synthesis and characterization of proligands A group of racemic, enantiopure or achiral tetradentate proligands (L2X2) bearing amino- or imino-phenolate groups was synthesized: Proligands rac-(ONNO)H2, (R,R)-(ONNO)H2 and (S,S)-(ONNO)H2 (Jacobsen's ligands) were prepared using reported procedures employing either racemic trans-1,2-diaminocyclohexane or the respective enantiopure monotartrate salt (Figure 2.4).203-205 Salophen ligand (ONArNO)H2 was synthesized in an analogous manner to rac-(ONNO)H2, employing o-phenylenediamine, according to the reported procedures (Figure 2.4).206 Reduced salan proligand rac-(ONHNHO)H2 was synthesized by reaction of the imine precursor rac-(ONNO)H2 with NaBH3CN under acidic conditions according to reported procedure (Figure 2.4).207  Asymmetric tridentate racemic proligand (L2X) bearing iminophenolate groups with a terminal dimethylamine group was also synthesized according to the literature procedure. Using Boc (tert-butyloxycarbonyl) protected racemic trans-1,2-diaminocyclohexane as the starting material (Figure 2.5).208 Reductive amination of this amine and subsequent removal of the protecting group generated the amine used for the coupling with the aldehyde to generate imine tridentate proligand rac-(NMe2NO)H.      39   Figure 2.4. Synthesis of reported salen (ONNO)H2, salan (ONHNHO)H2 and salophen (ONArNO)H2 proligands.   Finally, a family of achiral iminophenolate proligands (L2X or L3X) bearing different potentially coordinating side groups was synthesized by the condensation of an aldehyde with different amines in dry methanol. Namely, N,N-dimethylethylenediamine, 4-(2-aminoethyl)morpholine, 4-(2-aminoethyl)thiomorpholine, 1-(2-aminoethyl)piperazine and 2-(4-OHtButBuN NHOtButBu(±)(±)-(ONNO)H2OHtButBuOH2N NH2(±)+OHtButBuOH3N NH3+COOHOOOCOHH3N NH3COOHOOOCOHOHtButBuN NHOtButBu(R,R)/(S,S)(R,R)/(S,S)-(ONNO)H2K2CO3EtOHEtOH/H2OOHtButBuN NHOtButBu(±)(±)-(ONArNO)H2OHtButBuOH2N NH2+EtOHOHtButBuNH HNHOtButBu(±)(±)-(ONHNHO)H2EtOH/AcOHNaBH3CN40  methylpiperazin-1-yl)-ethylamine were used for the synthesis of (NMe2N*O)H, (NmorN*O)H, (NthioN*O)H, (NpipN*O)H and (NMepipN*O)H proligands respectively (Figure 2.6). These compounds were purified by recrystallization in acetonitrile.   Figure 2.5. Synthesis of reported tridentate (NMe2NO)H proligand.   An important characteristic of this last family of proligands is the presence of a set of methylene signals in their 1H NMR spectra corresponding to the protons in the morpholine, thiomorpholine and methylpiperazine rings. These signals can be used as a diagnostic tool to assess coordination of the terminal heteroatom (O, S or NMe) in solution of the different metal complexes synthesized (see below).  NH2NH2(±)HCl/MeOH NH2HN(±) OO tBu(Boc)2OCH3CN NHN(±) OO tBu1. HCHO2. NaBH3CNMeOH NNH2(±)HCl(±)OHtButBuOOHtButBuN NMeOH(±)-(NMe2NO)H41   Figure 2.6. Synthesis of tridentate proligands with potentially coordinating side groups. Yields provided in parentheses.    2.2.2 Synthesis and characterization of neutral indium alkyl complexes Reacting one equivalent of diprotic salen proligand rac-(ONNO)H2 with one equivalent of In(CH2SiMe3)3 at room temperature in dry diethyl ether (Figure 2.7), yielded a mixture of 3 compounds (as evidenced by the 1H NMR spectrum). The reaction mixture contained free proligand as well as monometallic and bimetallic adducts (Figure 2.8). Reaction in toluene at room temperature or under reflux conditions gave the exact same mixture of products. Employing enantiopure proligand (R,R)-(ONNO)H2 gave the same results as the racemic analogue.   NR =OHtButBuOOHtButBuN RSNR =ONR =(NMe2N*O)H (31%)(NmorN*O)H (88%)(NthioN*O)H (70%)(NmepipN*O)H (59%)MeNNR =25 ℃, MeOHHNNR =(NpipN*O)H (95%)H2N R42   Figure 2.7. Synthesis of monometallic and bimetallic alkyl indium complexes supported by the salen ligand. Isolated yields are provided in parentheses.    In contrast, addition of two equivalents In(CH2SiMe3)3 to one equivalent of rac-(ONNO)H2 gave the bimetallic adduct rac-(ONNO)In2(CH2SiMe3)4 (rac-1) in a clean manner (Figure 2.7). These results agree with those previously reported by Carpentier, Sarazin and collaborators in their synthesis of Group 13 alkyl complexes with similar ligand scaffolds (iminophenolate proligands).35   OHtButBuN NHOtButBuNNOOInSi SiInSiSitButButButBuOtButBuN NOtButBuInSi2 equiv In(CH2SiMe3)31 equiv In(CH2SiMe3)3(±)(±)(±)(±)-(ONNO)In2(CH2SiMe3)4 (rac-1) (81%)(±)-(ONNO)H2Et2Omixture of mono- and bimetallic43   Figure 2.8. Aromatic and imine region in the 1H NMR spectrum (CDCl3, 25 °C) of the mixture obtained from the reaction of 1 equiv of In(CH2SiMe3)3 and 1 equiv of racemic salen proligand (top). Signals attributed to a monometallic complex are labeled in red. Spectra of bimetallic compound rac-1 (medium) and racemic proligand (bottom) are shown for comparison.    The bimetallic nature of compound rac-1 was further confirmed by its solid-state structure (Figure 2.9), showing two indium centers adopting a distorted tetrahedral structure, each coordinating one iminophenolate moiety in the ligand. Fortunately, the monometallic adduct  (R,R)-(ONNO)In(CH2SiMe3) (1') could also be selectively crystallized from its reaction mixture in diethyl ether (Figure 2.10). In this case, the indium center adopts a distorted square pyramidal geometry with similar bond lengths to the bimetallic complex.   44   Figure 2.9. Molecular structure of bimetallic complex rac-1 depicted with ellipsoids at 50% probability (H atoms omitted for clarity)  Table 2.1.  Selected distances (Å) and angles (°) for rac-1 rac-1 Bond Lengths (Å) In1-O1 2.111(7) In2-N2 2.245(2) In2-O2 2.101(8)   In1-N1 2.257(4)   Bond Angles (°) N1-In1-O1 83.21(4)   N2-In2-O2 84.46(0)       45   Figure 2.10. Molecular structure of monometallic complex (R,R)-1' depicted with ellipsoids at 50% probability (H atoms omitted for clarity)   Table 2.2.  Selected distances (Å) and angles (°) for (R,R)-1'  (R,R)-1'  Bond Lengths (Å) In1-C21 2.155(4) In1-N2 2.260(4) In1-N1 2.259(3) In1-O2 2.126(4) In1-O1 2.093(3)   Bond Angles (°) O1-In1-C21 30.91(5)   N1-In1-C21 35.37(9)   O1-In1-N1 47.02(7)   O1-In1-O2 89.24(1)   N1-In1-N2 72.51(1)     46  2.2.3 Synthesis and characterization of neutral indium chloride complexes As the use of an indium alkyl species did not allow the clean synthesis of a monometallic complex with the salen ligand, a different route was explored: Deprotonation of racemic or enantiopure salen ligand using two equivalents of benzyl potassium (PhCH2K) in toluene followed by isolation of the ligand salt and subsequent addition of one equivalent of InCl3 in THF formed racemic or enantiopure monometallic salen indium chloride species (ONNO)InCl (2) in good yields, in agreement with reported procedure (Figure 2.11). Both racemic and enantiopure complexes show the same signatures by 1H NMR spectroscopy, with two characteristic imine resonances expected from the trans configuration of the two imine protons in the presence of a chloride group (loss of C2 rotational axis upon formation of the metal complex).        Figure 2.11. Synthesis of racemic and enantiopure indium chloride complexes supported by the salen ligand.   In a similar fashion, monometallic salophen indium chloride species (ONArNO)InCl (3) could be generated (Figure 2.12) and showed only one characteristic imine signal by 1H NMR OHtButBuN NHOtButBurac-/(R,R)-/(S,S)-(ONNO)H2OtButBuN NOtButBurac-(ONNO)InCl (rac-2) (R,R)-(ONNO)InCl ((R,R)-2)(S,S)-(ONNO)InCl ((S,S)-2)InCl1) 2 equiv PhCH2K2) 1 equiv InCl347  spectroscopy due to its internal plane of symmetry. In contrast, salan proligand rac-(ONHNHO)H2 formed intractable mixtures under these conditions. Using refluxing conditions for this reaction (potassium salt of the salan ligand and InCl3 in THF) during 16 hours yielded the same result. Using InBr3 instead of InCl3 in this case also formed a mixture of products that could not be resolved.    Figure 2.12. Synthesis of indium chloride complex (3) supported by the salophen ligand.   For the racemic tridentate (L2X) or achiral (L2X or L3X) proligands, addition of one equivalent of PhCH2K in toluene followed by isolation of the potassium salt of the ligands and addition of one equivalent of InCl3 in THF yielded different chloride complexes (4-8) in good yields (Figure 2.13). The only exception being the achiral proligand (NpipN*O)H that yielded an intractable mixture under these conditions. Interestingly, closely-related methylated proligand (NmepipN*O)H gave a stable chloride species (8) under the same conditions, which suggests that the presence of additional strongly-coordinating secondary amine groups in the proligand might participate in different coordination modes, giving a mixture of species (this might also be the case for the flexible salan proligand that did not form a stable indium chloride complex).      OHtButBuN NHOtButBu OtButBuN NOtButBuInCl1) 2 equiv PhCH2K2) 1 equiv InCl3(ONArNO)H2 (ONArNO)InCl (3)48   Figure 2.13. Indium chloride complexes (4-8) synthesized by salt metathesis of the corresponding potassium ligand salts and InCl3. Isolated yields are provided in parentheses.    Coordination in solution of the terminal tertiary amine to the indium center in racemic compound rac-4 is evidenced by 1H NMR spectroscopy (CDCl3, 25 °C), where each of the two terminal methyl groups displays a different signal on the spectrum. In contrast, achiral complex 5 (±) OtButBuN Nrac-(NMe2NO)InCl2 (rac-4) (59%)(NMe2N*O)InCl2 (5) (82%) (NmorN*O)InCl2 (6) (87%)(NthioN*O)InCl2 (7) (63%) (NmepipN*O)InCl2 (8) (87%)InCl ClOtButBuN NInCl Cl OtBuNtBuInONClClOtBuNtBuInSNClCl OtBuNtBuInClClNNOtButBuN RIn ClClOHtButBuN R1) 1 equiv PhCH2K2) 1 equiv InCl349  shows on its 1H NMR spectrum only one equivalent methyl signal for the two methyl groups and only two methylene signals for the central ethylene backbone (Figure 2.14). However, coordination of the terminal amine can still be expected in this case due to planar symmetry in this compound. The electronic similarity to rac-4 and comparison to the spectrum of the free proligand (NMe2N*O)H also support coordination in this case.    Figure 2.14. Aliphatic region in the 1H NMR spectrum (CDCl3, 25 °C) of racemic dichloride compound rac-4 and achiral dichloride compound 5. Proligand (NMe2N*O)H is shown for comparison.  Similarly to compound 5, compounds 6-8 show on their 1H NMR spectra only two methylene signals from the central ethylene backbone, which doesn't rule out coordination of the tertiary amine group in solution, but is a consequence of planar symmetry in these complexes. 50  Interestingly, compounds 6 and 7 show splitting of morpholine and thiomorpholine methylene protons respectively by 1H NMR spectroscopy (as evidenced by 2D HSQC and HMBC), indicating a coordination of the ether and thioether moieties to the metal centers (Figure 2.15).    Figure 2.15. Aliphatic region in the 1H NMR spectrum (CDCl3, 25 °C) of achiral dichloride compounds 6-8 showing different splitting patterns for methylene heterocyclic protons and ethylene backbone protons (labeled with green crosses).  In contrast to complexes 6 and 7, complex 8, bearing more sterically-hindered N-methyl piperazine shows only a partial splitting of the methylene ring protons, indicating only partial coordination of the piperazine ring (Figure 2.15). More specifically, methylene protons directly 51  adjacent to the terminal N-methyl group are shown to be all completely equivalent by 1H NMR spectroscopy, ruling out coordination of that terminal nitrogen in solution. The solid state structures of 6 (Figure 2.17), 7 (Figure 2.18) and 8 (Figure 2.19), determined with crystals obtained from hexane and dichloromethane mixtures at room temperature, revealed complexes with planar symmetry around the indium centers in a distorted trigonal bipyramidal geometry. Interestingly, none of the structures shows coordination of the pending sidegroup, in contrast to the solution structure observed for 6 and 7 in CDCl3 (Figure 2.15). Growing crystals of complex 7 in a mixture of THF and hexanes formed a THF adduct (NthioN*O)In(THF)Cl2 (7'), revealing a potential coordination spot upon addition of an external donor. This solid structure revealed the indium center with a distorted octahedral geometry and slightly elongated In-Cl bond distances (Figure 2.20). Nevertheless it is likely that in solution (CDCl3) coordination of the morpholine or thiomorpholine pending sidegroup causes the chloride groups to be trans to each other (as opposed to the cis configuration displayed in the crystal structure of THF adduct 7'), maintaining a planar symmetry in these complexes, hence the equivalency observed by 1H NMR of the ethylene backbone protons (Figure 2.16).        Figure 2.16. Different coordination modes exhibited by complexes 6 and 7 in the solid state and in solution (CDCl3).  OtBuNtBuInCl OtBuNtBuInXNClClClNXsolid state solution (CDCl3)X = O (6), S (7)52   Figure 2.17. Molecular structure of monometallic complex 6 depicted with ellipsoids at 50% probability (H atoms omitted for clarity).   Table 2.3.  Selected distances (Å) and angles (°) for 6  6  Bond Lengths (Å) In1-Cl1 2.377(0) In1-N1 2.164(2) In1-Cl2 2.375(0) In1-N2 2.472(1) In1-O1 2.099(0)   Bond Angles (°) Cl2-In1-N2 101.5(3) O1-In1-N2 159.5(3) Cl2-In1-O1 91.80(3)   N2-In1-Cl1 92.3(3)   O1-In1-Cl1 97.24(3)   N1-In1-Cl1 117.12(3)     53   Figure 2.18. Molecular structure of monometallic complex 7 depicted with ellipsoids at 50% probability (H atoms omitted for clarity).   Table 2.4.  Selected distances (Å) and angles (°) for 7  7 Bond Lengths (Å) In1-Cl1 2.3779(1) In1-N1 2.189(3) In1-Cl2 2.3665(9) In1-N2 2.332(3) In1-O1 2.069(2)   Bond Angles (°) Cl2-In1-N2 92.53(9) O1-In1-N2 155.71(1) Cl2-In1-O1 92.55(7)   N2-In1-Cl1 97.51(1)   O1-In1-Cl1 102.54(8)   N1-In1-Cl1 110.01(9)    54   Figure 2.19. Molecular structure of monometallic complex 8 depicted with ellipsoids at 50% probability (H atoms omitted for clarity).   Table 2.5.  Selected distances (Å) and angles (°) for 8  8 Bond Lengths (Å) In1-Cl1 2.3867(6) In1-N1 2.1939(1) In1-Cl2 2.3716(5) In1-N2 2.3322(1) In1-O1 2.0869(1)   Bond Angles (°) Cl2-In1-N2 92.64(4) O1-In1-N2 157.11(6) Cl2-In1-O1 93.75(4)   N2-In1-Cl1 96.23(4)   O1-In1-Cl1 101.63(5)   N1-In1-Cl1 109.33(5)     55   Figure 2.20. Molecular structure of monometallic complex 7' depicted with ellipsoids at 50% probability (H atoms omitted for clarity).  Table 2.6.  Selected distances (Å) and angles (°) for 7'  7' Bond Lengths (Å) In1-Cl1 2.4620(5) In1-N1 2.2046(1) In1-Cl2 2.4168(5) In1-N2 2.4129(1) In1-O1 2.0869(1) In1-O2 2.3440(1) Bond Angles (°) Cl1-In1-N2 95.28(4)   Cl1-In1-O2 176.58(4)   Cl1-In1-Cl2 94.049(1)   O1-In1-N2 155.58(5)     56  2.2.4 Synthesis and characterization of cationic indium complexes A series of cationic indium complexes can be generated using a salt metathesis route. The reaction of racemic indium chloride complex rac-(ONNO)InCl (rac-2) with different silver salts in THF from −30 to 25 °C  affords the respective solvated racemic cationic species with different counterions rac-[(ONNO)In(THF)2][A], A = PF6 (rac-9), AsF6 (rac-10), SbF6 (rac-11) and BF4 (rac-12) (Figure 2.21).    Figure 2.21. Synthesis of cationic indium species (9-15). Isolated yields are provided in parentheses.   N NO OtBu tButBu tBuIn [A]OtButBuN NOtButBuInClSSAg[A]−30 to 25 ℃, Srac-[(ONNO)In(THF)2][PF6] (rac-9) (85%)rac-[(ONNO)In(THF)2][AsF6] (rac-10) (85%)rac-[(ONNO)In(THF)2][SbF6] (rac-11) (91%)(R,R)-[(ONNO)In(THF)2][SbF6] ((R,R)-11)(92%)rac-[(ONNO)In(THF)2][BF4] (rac-12)rac-[(ONNO)In(Me-THF)2][SbF6] (rac-13) (92%)rac-[(ONNO)In(THP)2][SbF6] (rac-14) (85%)A = PF6, S = THF             A = AsF6, S = THF          A = SbF6, S = THF                                                                                               A = BF4, S = THF             A = SbF6, S = Me-THF     A = SbF6, S = THPN NO OtBu tButBu tBuInOtButBuN NOtButBuInClOTfOAgOTf−30 to 25 ℃, THFrac-(ONNO)In(THF)(OTf) (rac-15) (91%)(ONNO)InCl (2)(ONNO)InCl (2)57  Complexes 9–11 can be obtained in good yields; however, complex 12 was generated as an intractable mixture of products and was only identified from a solid-state structure (Figure 2.25). Reaction of rac-2 with silver triflate (AgOTf) (Figure 2.21) yielded a different species (rac-15) by virtue of the much higher coordinating ability of the triflate ion.93, 209 Choosing hexafluoroantimonate (SbF6) as the counterion of preference, enantiopure variant  (R,R)-[(ONNO)In(THF)2][SbF6] ((R,R)-11) was synthesized in the same fashion, as well as different solvated racemic species rac-[(ONNO)In(S)2][SbF6], S = 2-methyltetrahydrofuran (Me-THF) (rac-13) and tetrahydropyran (THP) (rac-14) (Figure 2.21). Reacting dichloride complexes rac-(NMe2NO)InCl2 (rac-4) with one equivalent of AgSbF6 in THF yielded monocationic species rac-16 in a good yield (Figure 2.22).   Figure 2.22. Synthesis of cationic indium species (rac-16). Isolated yield is provided in parentheses.    The 1H and 13C{1H} NMR spectra (CDCl3, 25 °C) of complexes 9–11 are virtually identical and are characteristic of a highly symmetric indium salen cation with two equivalents of coordinated THF and no evidence for coordination of the counterions. The 1H NMR spectra of the cations show only one imine proton signal, compared to the two peaks in the precursor AgSbF6−30 to 25 ℃, THFrac-[(NMe2NO)In(THF)Cl][SbF6] (rac-16) (99%)(±) OtButBuN Nrac-(NMe2NO)InCl2 (rac-4)InCl Cl (±) OtButBuN NInOCl [SbF6]58  (ONNO)InCl (2), and confirm the planar orientation of the ligand in solution. Moreover, the 19F NMR spectra of compounds rac-9 and rac-11 show additional evidence of the non-coordinating nature of the counterions in solution, with a doublet for 9 due to coupling with 31P (I = 1/2) and two sets of multiplets for 11 due to coupling with 121Sb (I = 5/2) and 123Sb (I = 7/2) for free hexafluoroantimonate counterion.210 NMR spectra of complexes rac-13 and rac-14 show similar spectral profiles with characteristic signals of their solvent donors.   Figure 2.23. Synthesis of cationic indium complexes (17-18) supported by the salen and salophen ligand. Isolated yields are provided in parentheses.    Cationic initiator rac-[(ONNO)In(OEt2)2][BArF4] (rac-17) can be prepared by the reaction of the chloride precursor (ONNO)InCl (2) with [Ag][BArF4] (BArF4 = tetrakis-3,5-bis(trifluoromethyl)phenyl)-borate) in diethyl ether (Figure 2.23). Its 1H NMR spectrum (CDCl3, N NtButButButBuO OInCl BArF4AgBArF4Et2ON NtButButButBuO OInCl BArF4AgBArF4Et2O[(ONArNO)In(OEt2)2][BArF4] (18) (91%)rac/(S,S)-(ONNO)InCl(ONArNO)InClN NInOOOEt2OEt2tBu tButBu tBuN NInOOOEt2OEt2tBu tButBu tBurac-[(ONNO)In(OEt2)2][BArF4] (rac-17) (91%)(S,S)-[(ONNO)In(OEt2)2][BArF4] ((S,S)-17) (90%)59  25 °C) is similar to the previous cationic complexes with additional signals in the aromatic region corresponding to the counterion protons and the characteristic diethyl ether signals. In a similar fashion, the synthesis of the enantiopure variant (S,S)-17 can be achieved using the precursor (S,S)-(ONNO)InCl (Figure 2.23); giving a product with identical NMR signatures to the racemic version. Interestingly, both racemic and enantiopure versions of compound 17 were isolated in good yield from diethyl ether, in contrast to previous results using [Ag][SbF6] that generated stable cationic species only in more coordinating solvents (i.e. tetrahydrofuran, 2-methyltetrahydrofuran, or tetrahydropyran).211 This is expected, as a consequence of the more stabilizing effect of the bulkier perfluorinated [BArF4] counterion that can accommodate less donating donors to stabilize the indium electrophilic center. The 19F NMR spectrum (CD3CN, 25 °C) of 17 supports the non-coordinating nature of the counterion in solution. The reaction of the analogous salophen-supported complex (ONArNO)InCl (3) with [Ag][BArF4] in diethyl ether formed the achiral cationic complex [(ONArNO)In(OEt2)2][BArF4] (18) (Figure 2.23).  The solid-state structures of complexes 11 (Figure 2.24), and 12 (Figure 2.25), disregarding counterions and coordinated solvents, are essentially super- imposable. Recrystallization of 9 in a mixture of acetonitrile (ACN), toluene, and hexanes yields the solvated rac-[(ONNO)In(ACN)(THF)][PF6] (9') (Figure 2.26). All crystal structures reveal the fluorine atoms from the counterions far away from the indium centers (over 5 Å), evidencing the truly cationic nature of these species in the solid-state. Due to the low quality of the crystals obtained for rac-11 and intrinsic disorder, ellipsoids could only be displayed to 30% of probability.     60   Figure 2.24. Molecular structure of monometallic complex rac-11 depicted with ellipsoids at 30% probability (H atoms omitted for clarity).   Table 2.7.  Selected distances (Å) and angles (°) for rac-11  rac-11 Bond Lengths (Å) In1-O1 2.041(5) In1-O4 2.287(5) In1-N1 2.173(6)   In1-O3 2.287(6)   Bond Angles (°) N1-In1-O3 88.8(2)   O3-In1-O4 176.5(2)       61   Figure 2.25. Molecular structure of monometallic complex rac-12 depicted with ellipsoids at 50% probability (H atoms omitted for clarity).   Table 2.8.  Selected distances (Å) and angles (°) for rac-12  rac-12 Bond Lengths (Å) In1-O1 2.042(3) In1-O3 2.272(3) In1-N1 2.146(5) In1-N2 2.4129(1) In1-O4 2.267(4) In1-O2 2.3440(1) Bond Angles (°) N1-In1-O3 87.83(16)   O3-In1-O4 177.34(14)      62   Figure 2.26. Molecular structure of monometallic complex rac-9' depicted with ellipsoids at 50% probability (H atoms omitted for clarity).   Table 2.9.  Selected distances (Å) and angles (°) for rac-9'  rac-9' Bond Lengths (Å) In1-O1 2.061(2) In1-N3 2.353(6) In1-N1 2.169(3)   In1-O3 2.260(2)   Bond Angles (°) N1-In1-O3 86.30(9)   O3-In1-N3 169.9(2)      63  2.3 Conclusion Herein, different strategies have been described for the synthesis of neutral indium alkyl, chloride species (complexes 1-8) as well as different cationic species with a variety of counterions and solvent donors (complexes 9-18). Generally speaking, aminophenolate or iminophenolate proligands can be deprotonated by a strong base and might be followed by salt metathesis with different reagents to produce either neutral or cationic species. Proligands bearing flexible secondary or tertiary amine groups (e.g. salan-type) hardly offered isolable chloride precursors (key intermediates in the synthesis of cationic species), likely due to their different coordination modes available and tendency of indium complexes to aggregate, resulting in a mixture of products.194, 212 Stable cationic species could be afforded with the right combination of counterion and solvent donor.   2.4 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. 1H NMR chemical shifts are reported in ppm versus residual protons in deuterated solvents as follows: δ 7.27 CDCl3, 13C{1H} NMR chemical shifts are reported in ppm versus residual 13C in the solvent: δ 77.2 CDCl3. 19F NMR chemical shifts are reported in ppm and externally referenced to neat CFCl3 at 0 ppm. Diffraction measurements for X-ray crystallography were made on a Bruker X8 APEX II diffraction and a Bruker APEX DUO diffraction with graphite monochromated Mo-Kα radiation. The structures were solved by direct methods and refined by full-matrix least- squares using the SHELXTL crystallographic software 64  of Bruker-AXS. Unless specified, all non- hydrogens were refined with anisotropic displacement parameters, and all hydrogen atoms were constrained to geometrically calculated positions but were not refined. Elemental analysis (E.A.) CHN analysis 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. All ligands were prepared without air-sensitive techniques. Materials. Solvents (THF, 2-Methyl THF, diethyl ether, tetrahydropyran and hexanes) were dried and vacuum- distilled over sodium, using benzophenone as an indicator and degassed through a series of freeze- pump-thaw cycles. Methanol employed in ligand synthesis was dried using 3Å molecular sieves. Toluene and DCM were dried and distilled over CaH2. Deuterated solvents (CDCl3, C6D5Br and CD3CN) were dried over CaH2, collected by vacuum distillation and also degassed. Benzyl potassium was synthesized by the reaction of n-buthyl lithium with potassium tert-butoxide in cold toluene and isolated as a red solid that was washed with hexanes and dried under vacuum, according to published procedures.213 Amines N,N-dimethylethylenediamine, 1-(2-aminoethyl)piperazine and 2-(4-methylpiperazin-1-yl)-ethylamine were obtained from Sigma Aldrich and used without further purification. Amines 4-(2-aminoethyl)morpholine and 4-(2-aminoethyl)thiomorpholine were obtained from Combi-Blocks and used without further purification. Indium trichloride (InCl3) was purchased from Tokyo Chemical Industries (TCI) and used as received. ((trimethylsilyl)methyl)indium (In(CH2SiMe3)3) was prepared according to the reported procedure.214 Silver (tetrakis-3,5-bis- (trifluoromethyl)phenyl)borate (AgBArF4) was synthesized according to reported procedures and recrystallized from dichloromethane/hexanes.215 Silver hexaflurophosphate (AgPF6), silver 65  hexafluroarsenate (AgAsF6), silver hexafluoroantimonate (AgSbF6) and silver tetrafluoroborate (AgBF4) were purchased from Alfa Aesar and used as received. Silver triflate (AgOTf) was purchased from Sigma Aldrich and used as received. Proligands salen,203, 205 salan,207 salophen,206 (NMe2NO)H,208 (NMe2N*O)H,216 and (NmorN*O)H217 were prepared according to published procedures. Indium complexes rac/(R,R)/(S,S)-(ONNO)InCl48 and (ONArNO)InCl188 were prepared according to reported methodologies.  Synthesis of  (NthioN*O)H This proligand was prepared in an analogous manner to reported (NmorN*O)H. A 50 mL round bottom flask was charged with a stirbar and 3,5-ditertbutyl-2-hydroxybenzaldehyde (1.09 g, 4.7 mmol) in dry methanol (15 mL). Then, a solution of 4-(2-aminoethyl)thiomorpholine (0.82 g, 5.6 mmol) in dry methanol (15 mL) was added to it. The reaction mixture was left stirring for 16 hours. Evaporation of the solvent gave a crude solid that was recrystallized in acetonitrile to yield a pale yellow solid (1.19 g, 70%). 1H NMR (300 MHz, CDCl3) δ 8.37 (1H, s, N=CH), 7.39 (1H, d, ArH), 7.09 (1H, d, ArH), 3.71 (2H, t, CH2), 2.83 (4H, m, CH2), 2.77 (2H, t, CH2), 2.70 (4H, m, CH2), 1.45 (9H, s, Ar-C(CH3)3), 1.32 (9H,  s, Ar-C(CH3)3).  13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 166.90, 158.32, 140.25, 136.92, 127.14, 126.01, 118.14, 59.89, 57.05, 55.42, 35.29, 34.37, 31.75, 29.62, 28.28. 19F NMR (376 MHz, CD3CN, 25 °C): δ −110.82, −113.89, −115.97, −119.44, −121.08, −122.24, −125.06, −126.25, −127.84, −131.39, −133.42, −136.51. Anal. Calcd. (found) for C21H34N2OS: C 69.57 (69.71), H 9.45 (8.94), N 7.73 (7.76).  Synthesis of  (NpipN*O)H This proligand was prepared in an analogous manner to reported (NmorN*O)H. A 50 mL round bottom flask was charged with a stirbar and 3,5-ditertbutyl-2-hydroxybenzaldehyde (1.09 g, 4.7 mmol) in dry methanol (15 mL). Then, a solution of 1-(2-aminoethyl)piperazine (0.73 g, 5.7 66  mmol) in dry methanol (15 mL) was added to it. The reaction mixture was left stirring for 16 hours. Evaporation of the solvent gave a crude solid that was recrystallized in acetonitrile to yield a pale yellow solid (1.54 g, 95%). 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, s, N=CH), 7.37 (1H, d, ArH), 7.07 (1H, d, ArH), 3.73 (2H, t, CH2), 2.90 (4H, m, CH2), 2.69 (2H, t, CH2), 2.50 (4H, m, CH2), 1.45 (9H, s, Ar-C(CH3)3), 1.32 (9H,  s, Ar-C(CH3)3).  13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 166.90, 158.17, 140.01, 136.78, 126.92, 125.88, 117.96, 59.59, 56.92, 54.90, 46.18, 35.12, 34.23, 31.57, 29.47. Anal. Calcd. (found) for C21H35N3O: C 73.00 (68.14), H 10.21 (9.95), N 12.16 (14.10).  Synthesis of  (NmepipN*O)H This proligand was prepared in an analogous manner to reported (NmorN*O)H. A 50 mL round bottom flask was charged with a stirbar and 3,5-ditertbutyl-2-hydroxybenzaldehyde (0.86 g, 3.7 mmol) in dry methanol (15 mL). Then, a solution of 2-(4-methyl-piperazin-1-yl)ethylamine (0.66 g, 4.6 mmol) in dry methanol (15 mL) was added to it. The reaction mixture was left stirring for 16 hours. Evaporation of the solvent gave a crude solid that was recrystallized in acetonitrile to yield a pale yellow solid (0.90 g, 68%). 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, s, N=CH), 7.36 (1H, d, ArH), 7.06 (1H, d, ArH), 3.73 (2H, t, CH2), 2.72 (2H, t, CH2), 2.58 (4H, m, CH2) 2.46 (4H, m, CH2), 2.28 (3H, s, CH3), 1.43 (9H, s, Ar-C(CH3)3), 1.30 (9H,  s, Ar-C(CH3)3).  13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 166.76, 158.20, 140.06, 136.81, 126.97, 125.86, 117.99, 58.95, 57.15, 55.27, 53.56, 46.20, 35.08, 34.22, 31.57, 29.52. Anal. Calcd. (found) for C22H37N3O: C 73.49 (73.50), H 10.37 (10.42), N 11.69 (11.68).    67  Synthesis of  rac-(ONO)In2(CH2SiMe3)4 (rac-1) A 20 mL scintillation vial was charged with a stirbar and racemic salen proligand rac-(ONNO)H2 (0.18 g, 0.32 mmol) and diethyl ether (10 mL). In(CH2SiMe3)3 (0.24 g, 0.64 mmol) was added dropwise to the vial and the resulting solution was stirred for 2 days at room temperature, after which the solvent was evaporated yielding a yellow solid that was suspended in hexanes and filtered through celite. Evaporation of the hexanes yielded a yellow solid (0.29 g, 81%). 1H NMR (300 MHz, CDCl3): δ 7.72 (2H, s, N=CH), 7.24 (2H, s, ArH), 6.52 (2H, s, ArH), 3.33 (2H, m, -CH- of DACH), 2.28 (2H, m, -CH2- of DACH), 1.95 (2H, m, -CH2- of DACH), 1.49 (4H, br m, -CH2- of DACH), 1.34 (18H, s, Ar-C(CH3)3), 1.06 (18H, s, Ar- C(CH3)3), 0.19 (18H, s, Si(CH3)3), 0.09 (4H, s, In-CH2), −0.03 (18H, s, Si(CH3)3), −0.13 (4H, s, In-CH2). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 174.41, 167.63, 140.99, 136.19, 130.91, 130.67, 117.67, 73.06, 35.33, 33.75, 33.08, 31.35, 29.87, 24.45, 2.69, 2.36. Anal. Calcd. (found) for C52H96In2N2O2Si4: C 55.60 (54.99), H 8.61 (8.79), N 2.49 (2.68).  Synthesis of rac-(NMe2NO)InCl2 (rac-4) A 20 mL scintillation vial was charged with a stirbar and benzyl potassium (33 mg, 0.25 mmol). Toluene was added to it (4.5 mL) to form a slurry that was constantly stirred as a solution of  racemic proligand rac-(NMe2NO)H (91 mg, 0.25 mmol) in toluene (4.5 mL) was added to it. The reaction mixture was left stirring overnight at room temperature and after removal of the solvent a pale yellow solid was obtained and washed with hexanes. After drying for two hours under vacuum, this solid was suspended in THF (3 mL) and added to a suspension of InCl3 (56 mg, 0.25 mmol) in THF (5 mL). The mixture was stirred overnight at room temperature and then it was filtered through Celite. Filtrate was dried under vacuum giving a crude solid that was suspended in dichloromethane and consequently filtered through Celite. Evaporation of the 68  solvent yielded a yellow solid (81 mg, 59%). 1H NMR (300 MHz, CDCl3) δ 8.44 (1H, s, N=CH), 7.50 (1H, d, ArH), 6.88 (1H, d, ArH), 3.37 (1H, m, CH), 3.00 (1H, m, CH), 2.69 (3H, s, N-CH3), 2.40 (3H, s, N-CH3), 1.90-2.17 (4H, s, CH2 of DACH), 1.48 (2H, m, CH2 of DACH), 1.44 (9H, s, Ar-C(CH3)3), 1.24-1.32 (11H, m, CH2 of DACH and Ar-C(CH3)3).  13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 174.15, 169.71, 142.67, 137.74, 131.82, 129.28, 116.70, 66.49, 60.90, 43.23, 36.57, 35.67, 34.11, 33.12, 31.39, 29.67, 24.90, 24.57, 21.61. Anal. Calcd. (found) for C23H37Cl2InN2O: C 50.85 (49.49), H 6.86 (6.75), N 5.16 (4.93).  Synthesis of (NMe2N*O)InCl2 (5) To a solution of (NMe2N*O)H (304 mg, 1.00 mmol) in toluene, a slurry of benzyl potassium (130.0 mg, 1.00 mmol) in toluene was added. The reaction mixture was stirred at ambient temperature for 16 h. The solvent was subsequently evaporated under vacuum and the pale yellow solid was washed with hexanes. The solid was resuspended in THF (6 mL) and added to a suspension of InCl3 (221 mg, 1.00 mmol) in THF (6 mL). The resulting mixture was stirred at ambient temperature for 16 h and then it was filtered through Celite. Filtrate was dried under vacuum giving a crude solid that was suspended in dichloromethane and consequently filtered through Celite. Evaporation of the solvent yielded a yellow solid (401 mg, 82 %). 1H NMR (300 MHz, CDCl3) δ 8.42 (1H, s, N=CH), 7.51 (1H, d, ArH), 6.90 (1H, d, ArH), 3.83 (2H, d, CH2), 3.00 (2H, d, CH2), 2.68 (6H, s, CH3), 1.47 (9H, s, Ar-C(CH3)3), 1.29 (9H,  s, Ar-C(CH3)3). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 175.7, 169.7, 142.7, 137.8, 132.0, 129.1, 116.4, 56.9, 50.3, 45.5, 35.5, 34.0, 31.4, 29.7. Anal. Calcd. (found) for C19H31Cl2InN2O: C 46.65 (46.44), H 6.39 (6.46), N 5.73 (5.44).   69  Synthesis of (NmorN*O)InCl2 (6) To a solution of (NmorN*O)H (196.8 mg, 0.54 mmol) in toluene, a slurry of benzyl potassium (70.7 mg, 0.54 mmol) in toluene. The reaction mixture was stirred at ambient temperature for 16 h. The solvent was subsequently evaporated under vaccum and the pale yellow solid was washed with hexanes. The solid was resuspended in THF (6 mL) and added to a suspension of InCl3 (121.9 mg, 0.55 mmol) in THF (6 mL). The resulting mixture was stirred at ambient temperature for 16 h and then it was filtered through Celite. Filtrate was dried under vacuum giving a crude solid that was suspended in dichloromethane and consequently filtered through Celite. Evaporation of the solvent yielded a yellow solid that was washed with hexanes two times and dried under vacuum (250 mg, 87%). 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, s, N=CH), 7.50 (1H, d, ArH), 6.84 (1H, d, ArH), 4.16 (2H, t, CH2), 3.91-3.76 (4H, m, CH2), 3.59 (2H, d, CH2), 3.08 (2H, t, CH2), 2.63 (2H, t, CH2), 1.43 (9H, s, Ar-C(CH3)3), 1.27 (9H,  s, Ar-C(CH3)3). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 175.2, 170.1, 142.6, 137.7, 132.2, 129.0, 116.2, 63.6, 56.7, 53.3, 49.9, 35.6, 34.1, 31.3, 29.5. Anal. Calcd. (found) for C21H33Cl2InN2O2: C 47.48 (48.04), H 6.26 (6.48), N 5.27 (5.06). Synthesis of (NthioN*O)InCl2 (7) This complex was prepared in an analogous manner to complex 6, using proligand (NthioN*O)H (371.0 mg, 1.02 mmol), benzyl potassium (133.3 mg, 1.02 mmol) and InCl3 (226.8 mg, 1.03 mmol). The resulting product being a yellow solid (356 mg, 63%). 1H NMR (300 MHz, CDCl3) δ 8.39 (1H, s, N=CH), 7.50 (1H, d, ArH), 6.85 (1H, d, ArH), 3.85-3.79 (4H, m, CH2), 3.25 (2H, t, CH2), 2.98 (2H, t, CH2), 2.65 (2H, t, CH2), 1.43 (9H, s, Ar-C(CH3)3), 1.27 (9H,  s, Ar-C(CH3)3). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 175.7, 170.0, 142.7, 137.9, 132.2, 129.0, 116.3, 70  51.9, 49.1, 35.6, 34.1, 31.3, 30.6, 29.5, 20.6 Anal. Calcd. (found) for C21H33Cl2InN2OS: C 46.09 (46.04), H 6.08 (6.10), N 5.12 (4.74). Synthesis of (NmepipN*O)InCl2 (8) This complex was prepared in an analogous manner to complex 6, using proligand (NmepipN*O)H (151.10 mg, 0.42 mmol), benzyl potassium (54.7 mg, 0.42 mmol) and InCl3 (93.0 mg, 0.42 mmol). The resulting product being a yellow solid (200 mg, 87%). 1H NMR (300 MHz, CDCl3) δ 8.36 (1H, s, N=CH), 7.49 (1H, d, ArH), 6.84 (1H, d, ArH), 3.82-3.77 (2H, m, CH2), 3.69-3.59 (2H, m, CH2), 3.12 (2H, t, CH2), 2.88-2.73 (4H, m, CH2), 3.56-2.47 (2H, m, CH2), 2.32 (3H, s, CH3), 1.42 (9H, s, Ar-C(CH3)3), 1.26 (9H,  s, Ar-C(CH3)3). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 175.2, 169.9, 142.6, 137.6, 132.0, 129.0, 116.4, 68.2, 52.0, 50.2, 49.8, 46.0, 35.6, 34.1, 31.4, 29.6. Anal. Calcd. (found) for C22H36Cl2InN3O: C 48.55 (51.02), H 6.67 (6.80), N 7.72 (7.81).  Synthesis of rac-[(ONNO)In(THF)2][SbF6] (rac-11)  A 20 mL scintillation vial was charged with a stirbar, rac-(ONNO)InCl (0.15 g, 0.22 mmol) and 6 mL of THF, and the resulting solution was cooled down to −30 °C. A suspension of AgSbF6 (0.076 g, 0.22 mmol) in 10 mL of THF was generated, cooled down to −30 °C, and was added to the rac-(ONNO)InCl solution with constant stirring. The formation of a precipitate was observed immediately after this addition addition. The reaction was left stirring in the dark at room temperature for 20 min. The resulting mixture was filtered through Celite and dried under vacuum to produce a pale yellow solid 91% yield, which was used without further purification. Small crystals suitable for X-ray diffraction could be obtained from a THF/toluene solution. 1H NMR (300 MHz, CDCl3, 25 °C): δ 8.48 (2H, s, N=CH), 7.53 (2H, s, ArH), 7.08 (2H, s, ArH), 3.69 (8H, br m, O-CH2 of THF), 3.47 (2H, m, -CH-), 2.68 (2H, m, -CH2-), 2.06 (2H, m, -CH2-), 71  1.82 (8H, br m, -CH2- of THF), 1.61 (4H, br m, -CH2-), 1.46 (18H, s, -C(CH3)3), 1.33 (18H, s, - C(CH3)3). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 170.16, 166.89, 141.47, 138.59, 131.21, 117.36, 69.53, 63.95, 35.63, 34.45, 31.35, 29.43, 27.10, 25.32, 23.46. 19F NMR (376 MHz, CD3CN, 25 °C): δ −110.82, −113.89, −115.97, −119.44, −121.08, −122.24, −125.06, −126.25, −127.84, −131.39, −133.42, −136.51. Anal. Calcd. (found) for C44H68O4N2InSbF6: C 50.84 (50.82), H 6.65 (6.59), N 2.58 (2.69).  Synthesis of (R,R)-[(ONNO)In(THF)2][SbF6] ((R,R)-11)  The enantiopure complex was prepared and purified in an analogous manner to rac-11, employing (R,R)-(ONNO)InCl, in a reaction with AgSbF6 to yield (R,R)-11 in 90% yield. This complex has identical NMR signatures to those of rac-11. Anal. Calcd (found) for C44H68O4N2InSbF6: C 50.84 (50.48), H 6.65 (6.53), N 2.58 (2.67).  Synthesis of rac-[(ONNO)In(THF)2][A] (A = PF6 (rac-9), AsF6 (rac-10)) Complexes 9 and 10 were generated using a similar procedure to complex 11, with additional steps (due to the lower purity of silver salts): the solid products were suspended in dichloromethane, filtered through Celite and then tetrahydrofuran was added to them. Drying under vacuum afforded pale yellow solids, both in 85% yields. Small crystals of the ACN adduct of 1, suitable suitable for X-ray diffraction could be obtained from a THF/toluene/ACN solution. 1H and 13C{1H} NMR spectra of both complexes were identical to those of 11. 19F NMR (rac-9) (376 MHz, CDCl3, 25 °C): δ −70.12, −70.23. Anal. Calcd. (found) for C44H68O4N2InPF6: C 55.70 (55.63), H 7.22 (7.02), N 2.95 (2.99). Anal. Calcd. (found) for C44H68O4N2InAsF6: C 53.23 (53.29), H 6.90 (6.85), N 2.82 (2.88).    72  Synthesis of rac-[(ONNO)In(THF)2][BF4] (rac-12) Complex 12 was generated using a similar procedure to complex 11, but was obtained in a mixture of decomposition products and could not be purified. Small crystals suitable for X-ray diffraction could be obtained from a THF/toluene solution.  Synthesis of rac-[(ONNO)In(Me-THF)2][SbF6] (rac-13)  Synthesized in an analogous manner to 11, using 2-methyl tetrahydrofuran (Me-THF) as a solvent and was obtained as a pale yellow solid in a 92% yield. 1H NMR (300 MHz, CDCl3, 25 °C): δ 8.46 (2H, s, N=CH), 7.54 (2H, s, ArH), 7.08 (2H, s, ArH), 4.22 (2H, br m, O-CH2 of Me-THF), 3.78 (4H, br m, O-CH2 of Me-THF), 1.95 (4H, overlapping m, - CH2- of Me-THF), 1.47 (18H, s, -C(CH3)3), 1.32 (18H, s, -C(CH3)3), 1.05 (6H, d, -CH3 of Me-THF). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 170.61, 166.90, 141.55, 138.97, 131.29, 131.21, 117.49, 77.56, 68.85, 63.86, 35.59, 34.07, 32.34, 31.28, 29.48, 27.41, 24.94, 23.66, 20.88. Anal. Calcd. (found) for C46H72O4N2InSbF6: C 51.75 (51.59), H 6.80 (6.97), N 2.62 (2.53).  Synthesis of rac-[(ONNO)In(THP)2][SbF6] (rac-14) Synthesized in an analogous manner to 11, using tetrahydropyran (THP) as a solvent and was obtained as a pale yellow solid in a 85% yield. 1H NMR (300 MHz, CDCl3, 25 °C): δ 8.48 (2H, s, N=CH), 7.54 (2H, s, ArH), 7.08 (2H, s, ArH), 3.64 (8H, br m, O-CH2 of THP), 1.57 (12H, br overlapping m, -CH2- of THP), 1.49 (18H, s, -C(CH3)3), 1.32 (18H, s, -C(CH3)3). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 170.79, 167.01, 141.77, 139.02, 131.28, 131.11, 117.34, 69.87, 64.03, 35.62, 34.08, 31.27, 29.56, 27.42, 26.17, 23.68, 22.71. Anal. Calcd. (found) for C46H72O4N2InSbF6: C 51.75 (52.48), H 6.80 (7.04), N 2.62 (2.52).    73  Synthesis of rac-(ONNO)In(THF)(OTf) (rac-15) Synthesised in an analogous manner to complex 11, using THF as the reaction solvent and was obtained as a pale yellow solid in a 91% yield. 1H NMR (300 MHz, CDCl3, 25 °C): δ 8.37 (2H, s, N=CH), 7.53 (2H, s, ArH), 6.99 (2H, s, ArH), 3.76 (3H, br m, O- CH2 of THF), 2.60 (2H, m, -CH-), 2.10 (2H, m, -CH2-), 1.84 (3H, br m, -CH2- of THF), 1.47 (18H, s, - C(CH3)3), 1.31 (18H, s, -C(CH3)3). 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 169.9, 167.8, 142.7, 138.3, 130.9, 130.3, 121.7, 117.5, 117.4, 69.5, 63.8, 35.7, 34.1, 31.5, 29.6, 27.6, 25.5, 24.0. Anal. Calcd. (found) for C41H60F3InN2O6S: C 55.91 (55.20), H 6.87 (6.97), N 3.18 (3.05). Synthesis of rac-[(NMe2NO)In(THF)Cl][SbF6] (rac-16) Synthesised in an analogous manner to complex 11, employing rac-(NMe2NO)InCl2 (rac-4) in a reaction with one equiv of AgSbF6 in THF to yield rac-16 as a pale yellow solid in a 99% yield. 1H NMR (300 MHz, CDCl3, 25 °C): δ 8.57 (1H, s, N=CH), 7.54 (1H, d, ArH), 7.02 (1H, d, ArH), 3.91 (4H, br m, O- CH2 of THF), 3.71 (1H, m, -CH-), 2.78 (3H, s, -CH3-), 2.73 (1H, m, -CH-), 2.50 (3H, s, -CH3-), 2.10 (1H, m, -CH2-), 2.01 (2H, m, -CH2-), 1.91 (4H, br m, -CH2- of THF), 1.65 (2H, m, -CH2-), 1.43 (18H, s, - C(CH3)3), 1.32 (18H, s, -C(CH3)3). δ 13C{1H} NMR (101 MHz, CDCl3, 25 °C): δ 173.5, 169.0, 141.8, 138.6, 132.2, 130.7, 117.0, 70.8, 70.3, 68.4, 58.8, 44.8, 37.8, 35.6, 34.2, 31.4, 29.5, 25.4, 24.3, 24.1, 21.8. Anal. Calcd. (found) for C27H45ClF6InN2O2Sb: C 39.76 (40.20), H 5.56 (5.78), N 3.43 (2.89). Synthesis of rac-[(ONNO)In(OEt2)2][BArF4] (rac-17). A 20 mL scintillation vial was charged with a stir bar, rac-(ONNO)InCl (0.15 g, 0.22 mmol), and diethyl ether (6 mL). The resulting solution was cooled down to −30 °C. A solution of AgBArF4 (0.21 g, 0.22 mmol) in 10 mL of diethyl ether was cooled down to −30 °C, and subsequently added to the rac-(ONNO)InCl solution with constant stirring. The formation of a 74  precipitate was observed immediately after this addition. The reaction was left stirring under dark at room temperature for 20 min. The resulting mixture was filtered through Celite and dried under vacuum to produce a pale yellow solid 91% yield, which was used without further purification. 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.43 (2H, s, N=CH), 7.70 (8H, br d, ArH), 7.64 (2H, s, ArH), 7.52 (4H, br m, ArH), 7.07 (2H, s, ArH), 3.63 (8H, q, O−CH2 of Et2O), 3.32 (2H, m, −CH−), 2.56 (2H, m, −CH2−), 1.99 (2H, m, −CH2−), 1.47 (18H, s, −C(CH3)3), 1.42 (4H, br m, −CH2−), 1.31 (18H, s, −C(CH3)3), 1.13 (12H, tr, −CH3 of Et2O). 13C{1H} NMR (100 MHz, CDCl3, 25 °C): δ 171.3, 167.2, 161.9, 142.7, 140.34, 135.0, 132.7, 131.0, 129.10, 66.1, 64.4, 35.8, 34.3, 31.2, 29.7, 27.7, 23.6, 14.2. Anal. Calcd (found) for C76H84BF24InN2O4: C, 54.62 (54.10); H, 5.07 (5.03); N, 1.68 (1.98).  Synthesis of (S,S)-[(ONNO)In(OEt2)2][BArF4] ((S,S)-17)  The enantiopure complex was prepared and purified in an analogous manner to rac-17, employing (S,S)-(ONNO)InCl, in a reaction with AgBArF4 to yield (S,S)-17 in 90% yield. This complex has identical NMR signatures to those of rac-17. Anal. Calcd (found) for C76H84BF24InN2O4: C, 54.62 (54.10); H, 5.07 (4.45); N, 1.68 (2.26).  Synthesis of [(ONArNO)In(OEt2)2][BArF4] (18)  A 20 mL scintillation vial was charged with a stir bar, (ONArNO)InCl (0.063 g, 0.091 mmol), and diethyl ether (4 mL), and the resulting solution was cooled down to −30 °C. A solution of AgBArF4 (0.089 g, 0.091 mmol) in 3 mL of diethyl ether was generated, cooled down to −30 °C, and was added to the (ONArNO)InCl solution with constant stirring. The formation of a precipitate was observed immediately after this addition. The reaction was left stirring under dark at room temperature for 20 min. The resulting mixture was filtered through Celite and dried under vacuum to produce an orange solid 91% yield, which was used without further 75  purification. 1H NMR (400 MHz, CDCl3, 25 °C): δ 8.92 (2H, s, N=CH), 7.73 (2H, d, ArH), 7.68 (10H, br d, ArH), 7.48 (4H, br m, ArH), 7.39 (2H, br m, ArH), 7.21 (2H, d, ArH), 3.63 (8H, q, O−CH2 of Et2O), 1.50 (18H, s, −C(CH3)3), 1.33 (18H, s, −C(CH3)3), 1.13 (12H, tr, −CH3 of Et2O). 13C{1H} NMR (100 MHz, CDCl3, 25 °C): δ 166.1, 161.7, 143.0, 141.0, 135.3, 134.8, 134.2, 131.1, 128.9, 125.9, 123.2, 120.6, 117.9, 117.5, 116.5, 65.8, 35.8, 34.4, 31.2, 29.8, 13.8. Anal. Calcd (found) for C76H78BF24InN2O4: C, 54.82 (55.24); H, 4.72 (4.63); N, 1.68 (2.20).   76  Chapter 3: Cationic indium species active in the polymerization of cyclic ethers  3.1  Introduction As discussed previously, there are different mechanisms by which epoxides (3-membered cyclic ethers) can be polymerized; the most common being anionic, cationic and coordination-insertion mechanisms. While the anionic route (initiated by simple bases) is the simplest and the preferred method in the industrial synthesis of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), it is not suitable for academic applications with reactive epoxides (Fig. 1.9) such as epichlorohydrin (ECH) (where there is a reactive chloride side group) or other substituted epoxides (where chain transfer reactions can be rampant). Coordination-insertion (and activated-monomer by extension) strategies can achieve high levels of control in many cases, with high levels of stereo- and regioselectivity (see below), but they are typically not suitable for the polymerization of higher cyclic ethers (4-, 5- and 7-membered rings).  The polymerization of 4-membered cyclic ethers (oxetanes) is achieved almost exclusively by cationic routes, employing boron trifluoride, cationic species or polyacids as initiators.218-221 Using dioxane as a polymerization solvent has been found to greatly decrease the formation of backbiting side products (Figure 3.1) common to cationic polymerizations (through reversible deactivation of the cationic chain-end by the solvent).222 The coordination-insertion polymerization of oxetane has been reported by Inoue, Aida and collaborators by employing a porphyrin aluminum chloride complex (I.23, Figure 1.12) as an initiator together with an aluminum alkyl species activator at high temperatures.223 More recently, polymerization of 77  oxetane by the same mechanism has been reported (using triisobutylaluminum and a quaternary ammonium salt) to give polymers with good control over the molecular weight and dispersities.224   Figure 3.1. Polymerization of oxetane initiated by a cationic initiator (I = initiator, WCA = weakly coordinating anion) can experience significant backbiting leading to depolymerization. Addition of dioxane can significantly decrease backbiting.  In contrast, polymerization of 5-membered tetrahydrofuran can only be achieved by a cationic mechanism. Examples of initiators include iron trichloride/acetic anhydride system, strong protic acids, triethyl oxonium salts with different counterions and methyl triflate.225-227 In contrast to the polymerization of epoxides and oxetanes, the polymerization of tetrahydrofuran is not significantly affected by backbiting due to the higher basicity of the monomer compared to the aliphatic polymer ether groups, and therefore it can be considered a living polymerization.228-229 Currently, poly(tetrahydrofuran) is industrially produced only in low molecular weights as elastic segments that exhibit excellent hydrolytic stability and are used for the synthesis of [I][WCA]On OOOOWCAInOOOWCAInOOOWCAIOnOOOWCAI OOO78  polyurethanes and polyesters that are particularly useful in the textile industry (in products composed of Spandex or Elastan fibers).230 Similarly, polymerization of 7-membered oxepane has only been reported by cationic initiators,231 but with significantly slower kinetics of polymerization attributed to the formation of a more stable oxonium propagating species in comparison to the more rigid oxetane and tetrahydrofuran monomers.232 For example, using boron trifluoride and epichlorohydrin initiator system at 0 °C the reactivity of oxetane was found to be 35 times that of tetrahydrofuran, which in turn was 270 times more reactive than oxepane.232   Cationic group 13 complexes are interesting for these and other ROP reactions due to the increased electrophilicity and coordinative unsaturation of the metal centers, which create the potential for higher polymerization activity. However, despite the increased reactivity compared to neutral analogues, virtually all known cationic aluminum and gallium systems produce low molecular weight polyethers with broad dispersities (Figures 1.13 and 1.14). Not surprisingly, the ROP of less reactive cyclic ethers such as oxetane, THF, and oxepane are not known for cationic group 13 complexes, with the exception of trialkyl aluminium/water mixtures and simple aluminum and gallium triflates.233 Regio-selective ring-opening polymerization of epoxides. As the cationic ring opening of epoxides occurs by nucleophilic attack on one of the carbons of the epoxide ring, a mixture of regio-isomers can potentially arise when working with monosubstituted epoxides such as PO. The resulting polymer is said to be regio-regular when the attack on only one of the carbons predominates and thus, every pending R group in the resulting polymer chain (e.g. R = CH3 for PPO, R = CH2Cl for PECH) is spaced regularly. If the carbon bearing the R group on the epoxide (methine) is called the head (H), and the other carbon (methylene) is called the tail (T), 79  then regio-regular polymerization is said to provide predominantly head-to-tail linkages (H-T) yielding an equal spacing between the R substituents attached to the main backbone. When errors occur during polymerization, head-to-head (H-H) and (T-T) linkages arise giving unequal spacing between the R substituents attached to the main backbone (Figure 3.2). High levels of regio-errors generally result in amorphous polymers.    Figure 3.2. Regio-regular and regio-irregular poly(propylene oxide) PPO. Regio-regular microstructure is comprised predominantly of H-T linkages while regio-irregular microstructure has significant portions of H-H and T-T linkages.  The most useful method for assessing the regio-chemistry of polyethers is 13C{1H} NMR spectroscopy. Methylene (CH2) and methine (CH) carbons in PPO give characteristic signatures in their spectra that depend on the tacticity. The presence of regio-irregularities (H-H and T-T linkages) can give arise to more peaks, producing a complex pattern. Because each peak in the 13C{1H} NMR spectrum of atactic PPO has been assigned, the degree of stereo- and regio-regularity can be determined for this polymer by comparison with literature values.234  O O OO O OO OOOH-HT-THTT-H80  3.2 Results 3.2.1 Reactivity of cationic complexes in the polymerization of epoxides In order to compare the activities of the catalysts in the polymerization of epoxides, 1,2-epoxyoctane (EOC) (180 equivalents) was added to a suspension of either rac-9, rac-10 and rac-11 in toluene-d8 and then heated to 80 °C (Figure 3.3). The reactions were monitored by 1H NMR spectroscopy to measure conversions to ring opening products (polymers or oligomers) at different times. After only 70 minutes, hexafluoroantimonate complex rac-11 reached full conversion of monomer, while hexafluorophosphate complex rac-9 and hexafluoroarsenate complex rac-10 had reached 50 and 66% conversion respectively. After 24 hours it was evident that both rac-9 and rac-10 did not improve their conversions, showing a visible precipitate after 4 h and 12 h respectively, suggesting decomposition of the catalysts.     Figure 3.3. Polymerization of different epoxides initiated by cationic initiators (I = initiator, WCA = weakly coordinating anion). [cat] = 28.0 mM, [epoxide] = 2.8 M.  Monitoring polymerization of 1,2-epoxy-5-hexene (E5H) at a lower temperature (40 °C) and with a more polar solvent (C6D5Br) to allow for a better solubility of the cationic species revealed hyperbolic curves with information on earlier stages of the polymerization (Figure 3.4). All curves showed very fast propagation rates (with high conversions by the first 7 minutes of xOO RRR = (CH2)5CH3           EOCR = (CH2)2CHCH2   E5HR = C(CH3)3            DMEBR = CH2Cl               ECH[I][WCA]R = (CH2)5CH3           PEOCR = (CH2)2CHCH2   PE5HR = C(CH3)3            PDMEBR = CH2Cl               PECHSolvent, Temperature81  polymerization) followed by the slow deactivation of the cationic active species, as evidenced by the stagnation in conversions. After monitoring the reaction for 2 hours, rac-9 and rac-10 reached maximum conversions of 54 and 67% respectively, similarly to the previous case (EOC polymerization at 80 °C).    Figure 3.4. Comparison of activity of different cationic indium species synthesized. Reactions were performed in C6D5Br at 40 °C for 2 h. [cat]0 = 28.0 mM, [E5H] = 2.8 M. The ROP reaction was monitored by 1H NMR spectroscopy.  As an attempt to improve the polymerization conversions observed with rac-9, polymerization of EOC was attempted using neat conditions (no solvent) at 95 °C, but after 15 hours of reaction a maximum of 57% conversion was achieved. Carrying out the reactions at room temperature 82  under more diluted conditions (in polar and non-polar solvents) resulted in even lower conversions.  Results from the different trials employing rac-9 are summarized below (Table 3.1).  Table 3.1.  Polymerization of epoxides employing cationic complex rac-9    Epoxide equiv. T  (°C) Solvent [cat]  (mM) max. conv.a  (%)  1   (E5H)  100  40  C6D5Br  28  54 2b   (EOC) - 90 - - 57 3 200 80 tol-d8 20 50 4 130 25 CDCl3 4 31 5 130 25 tol-d8 4 32  Maximum conversions were determined by 1H NMR spectroscopy for a period of 2-90 hours. aConversion was monitored by 1H NMR spectroscopy. bReaction was run under neat conditions (no solvent).  A similar counterion effect has been reported before for the metal-catalyzed living radical polymerization of methyl methacrylate with cationic complexes bearing the PF6− and SbF6− counterions.235 Other report on living radical polymerizations with cationic species bearing BF4−, TsO− and TfO− anions also showed a marked counterion effect on the activity (following the order TfO− < TsO− < BF4−), but no explanation to this effect was given.236 The higher activity of cationic species with SbF6− counterions when compared to similar species with PF6− has also xOO RRrac-9OO83  been documented in some metal-catalyzed Diels-Alder reactions with cationic complexes, but with no explanation of the counterion role in those reactions.237-238 In all of these examples, the weakly coordinating anions (WCA) are expected to have a spectator role in the reactions. However, it is known that some WCA can directly coordinate to metal centers,209, 239 and there are known examples of them behaving as true nucleophiles. For instance, Nakajima, Ozawa et al. have reported the non-innocent behavior of PF6− and SbF6− as nucleophiles in the activation of silyl nitriles to silyl fluorides, with a much higher reactivity of the PF6− anion in the nucleophilic attack compared to SbF6−.240 In another study, the interactions of PF6−, AsF6−and SbF6− with macrocycle dodecabenzylbambus[6]uril were predicted by DFT calculations. The host-guest interaction between the different anions and the macrocycle in the optimized molecular geometries revealed different energies of interaction in the order SbF6− (least interacting) < AsF6− < PF6− (most interacting).241  In this case, the counterion effect evidenced in the cationic polymerization of epoxides can be attributed to different degrees of interaction of the cationic chain-end with the anions (Figure 1.11), with higher levels of interaction (and possible nucleophilic attack) of the hexafluorophosphate counterion inhibiting polymerization and leading to faster decomposition in comparison to hexafluoroantimonate counterion. Approximation to the solid-state also reflects this stability in the lattice energy (ELatt) of the "salt-like" compounds. According to the Kaputinskii equation, this energy is inversely proportional to the ionic radii of the ions and therefore larger ions have lower lattice energies with weaker electrostatic interactions. The thermochemical radii follow the order PF6− (2.42 Å) < AsF6−  (2.43 Å) < SbF6− (2.52 Å).242   84    Figure 3.5. Effect of addition of KPF6 on the polymerization of E5H by rac-11 at 50 °C (top). Effect of different solvents in the polymerization of E5H by rac-11 at 25°C (bottom). The ROP reactions were monitored by 1H NMR spectroscopy.  In order to test further the counterion effect in the cationic polymerization of epoxides, a control experiment was run in which hexafluoroantimonate complex rac-11 polymerized E5H at 85  50 °C with and without the addition of one equiv. of hexafluorophosphate ions. Addition of KPF6 to the reaction proceeded to only 58% conversion after 100 min, compared to 83% in the absence of the hexafluorophosphate salt (Figure 3.5). Employing the most active complex of the series; rac-11 for the polymerization of E5H at room temperature also achieved high conversions (> 90%) in about 3 hours in both C6D5Br and tol-d8 (with similar conversion profiles), however the same reaction in CD3CN gave only negligible conversions (Figure 3.5). Complete deactivation of the catalyst in acetonitrile can be attributed to the coordination of this solvent to the metal center, likely leading to an inactive species analogous to rac-9' (Figure 2.25). A similar effect of acetonitrile and other strongly coordinating groups such as amines has been reported before for other cationic polymerizations.98, 243  For comparison, the activity of cationic compound bearing hexafluoroantimonate counterion  rac-16 was also tested in the polymerization of E5H in bromobenzene at either 25 or 80 °C. Reaction at higher temperature reached higher conversion (61%) after 1 hour when compared to the same reaction at lower temperature (34%). Running the reactions for a longer time improved the conversion up to a maximum of 69-77% in two days (Figure 3.6). Despite bearing the same type of counterion and cationic chain-end of rac-11, this cationic species is significantly less active and achieves lower conversions compared to salen-based rac-11. This difference might be explained in part due to the presence of a chloride-metal bond in the cationic complex and subsequent intermediate of polymerization that can participate in the deactivation of cationic chain-ends through nucleophilic attack of the chloride group.   86   Figure 3.6. Activity of cationic indium species rac-16. Reactions were performed in C6D5Br at 25 °C or 80 °C for 2 days. [rac-16]0 = 22.0 mM, [E5H]0 = 4.4 M. The ROP reaction was monitored by 1H NMR spectroscopy.  Reaction of rac-16 with another equivalent of silver hexafluoroantimonate in THF abstracts the chloride group of the cationic species, forming a highly electrophilic biscationic species. This compound could not be isolated as a stable species and triggered the polymerization of THF at room temperature to high molecular weight PTHF (Mn = 336,700 Da; Đ = 1.22). In contrast to the cationic species shown, neutral salen precursor rac-2 is not active in the polymerization of epoxides at room temperature (over 16 hours). Despite reports of similar 87  neutral aluminum chloride species active in the polymerization of propylene oxide (PO), their conversion profile is slow and requires higher temperatures (Figure 1.12). From this, it is evident that the formation of cationic centers from neutral precursors greatly increases their reactivity towards the ROP of cyclic ethers.      Figure 3.7. Variable Temperature (VT) 1H NMR (top) and 19F NMR (bottom) spectra (C6D5Br) of complex rac-15.   88  Interestingly, complex rac-15 bearing a triflate counterion also fails to polymerize epoxides at room temperature: Reaction with E5H in C6D5Br only yields traces of ROP product over 16 hours. This indicates that this species behaves more like a neutral species and not like a true cationic species. 1H NMR spectroscopy also support this hypothesis, as the cationic species 9-11 with the same salen ligand scaffold present identical NMR signatures in their spectra, regardless of their counterion. In contrast, rac-15 shows a different spectrum with a broader imine peak shifted upfield and the presence of only one THF molecule on its solution structure that could be removed with extensive hexane washings without causing decomposition.  Another interesting observation sets apart rac-15 from the previously discussed cationic species. It was observed that the cationic species (rac-9, rac-11) decomposed slowly in CDCl3 (noticeable in a matter of hours) due to the loss of stabilizing tetrahydrofuran molecules in solution (this happened much faster in a suspension with non polar solvents such as hexanes). In contrast to other cationic species, complex rac-15 turned out to be very stable in solution. Heating up a solution of rac-15 in C6D5Br to 120 °C and back to 25 °C did not result in any decomposition or significant change in the 1H or 19F NMR spectra (Figure 3.7).  3.2.2 Substrate scope in the homopolymerization of epoxides by cationic complex  The most active complex with hexafluoroantimonate counterion rac-11 catalyzes the polymerization of a range of functionalized epoxides in bromobenzene or dichloromethane at 25 °C, to afford the respective polyethers with high conversions (Table 3.2). In addition, rac-11 readily polymerizes neat racemic propylene oxide (rac-PO) at 25 °C to form medium to high molecular weight poly(propylene oxide) (Mn = 11,900 Da; Ð = 1.36). Interestingly, this is a 89  higher molecular weight for PPO than most reports of cationic aluminum and gallium species in the literature (Figure 1.13 and 1.14), which typically oligomerize PO to give volatile products.   Table 3.2.  Polymerization of different epoxides employing cationic complex rac-11   Epoxide (E) Conv.a  (%) Mn theob  (Da) Mn expc  (Da) Đc I*d  1  (E5H)  95  18,845  39,220  1.33  0.48  2   (ECH)  99  18,319  36,780  1.27  0.50  3  (DMEB)  99  19,832  16,040  1.30  -  4  (CHO)  99  19,432  52,080  2.06  0.37  5     99  28,546  6,600  2.38  -  Reactions were performed in dichloromethane at 25 °C for 24 h. [rac-11]0 = 32.0 mM, [epoxide] = 6.4 M. [epoxide]/[rac-11] = 200. aConversion was monitored by 1H NMR spectroscopy. bCalculated from 200 x conv. E x MWE gmol-1. cDetermined by GPC measurements in THF. dInitiation efficiency calculated as the ratio of theoretical and experimental molecular weights for the samples with disproportionately high molecular weights.  Overall, the activity and substrate scope of complex rac-11 in these reactions is unprecedented for cationic group 13 systems, given the low molecular weights of polyethers reported for these xOO RRCH2Cl2, 25 ℃OO CltBuOOO O PrO90  species and the limited scope of monomers studied (most reports focus on propylene oxide). Nevertheless, the molecular weight seems to be still greatly affected by backbiting, especially in the case of monomers without much steric hindrance such as PO and EO. Formation of low molecular weight cyclic oligomers by backbiting is characteristic of a cationic mechanism of polymerization and can be detected by mass spectrometry MALDI-TOF.   Complex rac-11 achieves high conversions for the epoxides screened (Table 3.2). For monomers E5H and ECH the initiation efficiency seems to be around 50%, giving polymers with significantly higher than expected molecular weights (based on the monomer to initiator ratio). For the highly reactive monomer CHO, initiation efficient is even lower (around 37%). In sharp contrast, 3,3-dimethyl-1,2-epoxybutane (DMEB) is more controlled by virtue of its steric bulk (higher initiation efficiency and low degrees of backbiting).  Polymerization of an epoxide bearing an ester group (Table 3.2, entry 5) proceeded to high conversions, but only gave low molecular weight products due to the difficulty of precipitating this polymer by addition of methanol. In most cases, the obtained polymers showed monomodal molecular weight distributions by GPC and appeared to be less affected by backbiting than PO (given the high molecular weights obtained). Nevertheless, analysis of a crude polymer sample (PDMEB) by MALDI-TOF, evidences a low molecular weight fraction largely composed of cyclic oligomers (below 3 kDa) despite the steric bulk of the monomer (Figure 3.8). To further rule out a coordination-insertion mechanism in the polymerization of epoxides, PPO obtained by neat polymerization of rac-PO with rac-11 was analyzed by 13C{1H} NMR spectroscopy and it turned out to be a highly regio-irregular product (Appendix, Figure B.5), with several signals in the methine and methylene regions. Carrying out the same reaction with enantiopure version of the catalyst (R,R)-11 did not improve at all the regio-selectivity (Appendix, Figure B.5), giving 91  the same signal pattern. These results indicate no influence of the structure around the metal center in the polymer architecture and are consistent with a cationic mechanism (with an active chain-end far from the metal center) taking place in these polymerizations.         Figure 3.8. MALDI-TOF spectrum of the isolated product from the ROP of 1,2-epoxy-3,3-dimethylbutane with rac-11. The distributions refer to cyclic homopolymerization product, linear product with OH chain end and cyclic homopolymerization product with one ring-opened THF molecule.  Although polymerization of epoxides by rac-11 proceeded in a non-living fashion (molecular weight of products did not increase linearly with conversion), it was found that after full conversion of 100 equivalents of monomer E5H at room temperature, another 100 equivalents 92  could be added and rac-11 would still yield high conversions. However, this did not represent a significant increase in the molecular weight of the products. Repeating this experiment at 80 °C yielded a product with a bimodal distribution, indicating a polymer fraction with a significantly higher molecular weight (Appendix, Figure B.17). This indicates that while the cationic centers can potentially experience a living polymerization, rampant backbiting competes with monomer addition, especially at late stages of polymerization. Increasing the temperature of polymerization seems to be beneficial to tackle these issues.   3.2.3 Copolymerization of epoxides and other cyclic ethers by cationic complex  Catalyst rac-11 is the first indium-based catalyst for the copolymerization of larger cyclic ethers (THF, oxetane and oxepane) with functionalized epoxides such as 1,2-epoxy-5-hexene (E5H) or epichlorohydrin (ECH) (Table 3.3). Oxetane is homopolymerized by rac-11 (25 °C, CH2Cl2, 96 h), however THF and oxepane are not significantly homopolymerizable under these conditions. Copolymerization of epoxides and THF (25 °C, CH2Cl2) is highly dependent on the number of epoxide equivalents. When a 10:100:1 ratio of Epoxide:THF:rac-11 is used, THF conversion is minimal (Table 3.3 entries 1–2). However, with an equimolar mixture of epoxide and THF, up to 85% of the THF converts to produce polyethers with high molecular weights and controlled distributions (Table 3.3, entries 3–4). Other Lewis acid-based systems in the literature capable of THF homo- and co-polymerizations, including rare earth, aluminium or gallium triflates, produce polymers with moderate to high molecular weights but with high dispersities.233, 244 Poorly defined methylalumoxane/AlMe3 mixtures are reported to copolymerize THF and epoxides to form polymers with high dispersities.245  93  Table 3.3.  Copolymerization of cyclic ethers and epoxides with rac-11   epoxide (E) Cyclic ether (CE) [E]: [CE]: [rac-11] time (h)  Solvent Conv. E (%) Conv.  CE (%) yield (%) Mn theo (10-3  Da) Mn (x10-3 Da) Mw (x10-3 Da) Đ 1 ECH THF 10:100:1 48 CD2Cl2 32 19 0 - - - -  2 1,2-epoxy-5- hexene (E5H) THF 10:100:1 48 CD2Cl2 99 0 0 - - - -  3 ECH THF 100:100:1 96 CD2Cl2 69 85 93 12.5 29.9 43.8 1.47 21.4 28.4 1.33 4 1,2-epoxy-5- hexene (E5H) THF 100:100:1 96 CD2Cl2 90 80 86 14.6 17.8 24.7 1.38 13.7 17.4 1.27 5 ECH Oxetane 100:100:1 96 CD2Cl2 90 99 87 14.1 13.5 17.2 1.27  10.4 17.6 1.69  6 ECH Oxepane 100:100:1 96 C6D5Br 92 99 73 18.4 15.0 16.9 1.12  11.4 13.9 1.22 7 - Oxetane 0:100:1 24 CD2Cl2 - 99 66 5.7 13.1 20.6 1.58 8 - Oxepane 0:100:1 24 C6D5Br - 0 0 - - - - 9 ECH - 100:0:1 96 C6D5Br 99 - 45 9.2 4.0 6.6 1.33  5.9 13.5 2.29  Reactions were performed in dichloromethane or bromobenzene at 25 °C. [rac-11]0 = 64.0 mM, [CE]0 = 6.4 M. aConversion was monitored by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. Molecular weights were determined by GPC measurements in THF. Theoretical molecular weights were calculated Calculated from ([E]o/[rac-11] × conv. E × MWE gmol-1) + ([CE]o/[rac-11] × conv. CE × MWCE gmol-1). 94  Similarly, rac-11 catalyzes the copolymerization of oxetane or oxepane with ECH (25 °C, C6H5Br). These reactions reach full conversion for both cyclic ethers and producing high molecular weight copolymers with relatively low dispersities (Table 3.3, entries 5–6). All copolymers generated by simultaneous addition of monomers with rac-11 posses higher molecular weight than the product of the respective epoxide homopolymerization (Appendix, Figures B.13, B.14 and B.15). Their analysis by differential scanning calorimetry (DSC) reveals amorphous materials with only one glass transition temperature, supporting the formation of mostly random copolymers. Analysis by DOSY NMR spectroscopy reveals connectivity of the copolymers, with all polyether groups displaying the same diffusion coefficient in solution ((CDCl3, 25 °C). This rules out a mixture of homopolymers and confirms formation of copolymers (Appendix, Figures B.10, B.11 and B.12).   3.2.4 Kinetics of polymerization of epoxides  In order to explore the role of anion (compare PF6− complex rac-9, AsF6− complex rac-10 and SbF6− complex rac-11) and coordinated solvent (compare THF-solvated complex rac-11, Me-THF-solvated complex rac-13 and THP-solvated complex rac-14) on the reactivity of these systems, the kinetics of polymerization of E5H were studied by 1H NMR spectroscopy.  To test the counterion effect in the kinetics of polymerization, the ROP of 1,2-epoxy-5-hexene (E5H) was monitored in C6D5Br at 40 °C by in situ 1H NMR spectroscopy, employing either rac-9, rac-10 or rac-11. After only 15 minutes of polymerization all complexes show the same conversion of about 40%. However, after 100 min, monomer conversions for these complexes are significantly different: 54, 67, and 83% respectively. Interestingly, during the first stages of polymerization all catalysts show a first order dependence of the rate on epoxide concentration 95  (kobs = 2.1(7) ×10–4 s–1). For each catalyst, there's a period of time after which there is not a further linear first-order dependence, as can be expected by subsequent decomposition of the cationic active centers (Figure 3.9). That initial first-order dependence of the rate on the monomer concentration (without being affected significantly by decomposition rate) indicates that catalysts with different counterions have similar propagation rates (kobs) and also similar initiation rates (as evidenced by similar conversions in the early stages of polymerization).   Figure 3.9. First order kinetic plot for the polymerization of 1,2-epoxy-5-hexene (E5H) by PF6 complex rac-9, AsF6 complex rac-10 and SbF6 complex rac-11 at 40 °C in C6D5Br. The ROP reaction was monitored by 1H NMR spectroscopy.  96  The role of the coordinated solvent is subtler (Figure 3.10). Monitoring rates of polymerization of E5H (C6D5Br, 50 °C) shows slight differences for the differently solvated complexes rac-11 (THF), rac-13 (Me-THF) and rac-14 (THP).    Figure 3.10. First order kinetic plot for the polymerization of 1,2-epoxy-5-hexene (E5H) by THF complex rac-11, 2-methyl THF complex rac-13 and tretrahydropyran complex rac-14 at 50 °C in C6D5Br. The ROP reaction was monitored by 1H NMR spectroscopy.  While all of the reactions are first order in [E5H] with similar rates (kobs = 4.0(7) ×10–4 s–1), their monomer conversions at 40 min are significantly different (rac-11: 68.4(7)%, rac-13: 75(3)%, rac-14: 64(2)%) indicating different initiation rates followed by the same propagation 97  rate (Figure 3.10). As expected, initiation activity of these solvated catalysts correlates inversely with Gutmann donor numbers for their solvent donors (THP > THF > Me-THF).   3.3 Conclusions In summary, we describe a family of different cationic indium complexes supported by different ligand scaffolds.  Cationic indium salen complexes turned out to be the most active in the homopolymerization of epoxides and their copolymerization with higher cyclic ethers: oxetane, tetrahydrofuran and oxepane.  A counterion effect was evidenced in the reactivity of these cationic species with epoxides, with activity increasing in the order rac-9 (PF6 complex) < rac-10 (AsF6 complex) < rac-11 (SbF6 complex). Changing the nature of the coordinated solvents in the cationic species also had an effect in the rates of initiation of polymerization, with activity increasing in the order rac-14 (THP complex) < rac-11 (THF complex) < rac-13 (Me-THF complex).  It must be stressed that the cationic species presented are the first cationic indium compounds reported to be highly active in the polymerization of epoxides. The higher reactivity compared to other cationic Group 13 species in the literature can be attributed to a high Lewis acidity of the indium metal centres in the salen cationic complexes and the presence of labile solvent molecules. The role of the anion and coordinated solvent molecules was examined and shows that modification of the solvent/donor molecules (and counterions) in these systems provides potential for tuning cationic activity.  Characterization of the different polyether products revealed materials with mostly monomodal molecular weight distribution by GPC and only one (broad) glass transition, supporting the formation of random block copolymers with an expected amorphous nature. 98  Connectivity in these copolymers was further confirmed by diffusion ordered spectroscopy (DOSY NMR). Evidence of polymerization by a cationic mechanism in these systems is given: (1) polymerization of tetrahydrofuran is only known to proceed by a cationic mechanism. (2) Polymerization of racemic propylene oxide (PO) with rac-11 gave a regio-irregular product (as evidenced by 13C{1H} NMR spectra) and its enantiopure version (R,R)-11 did not improve at all the regio- or stereo-selectivity. This indicates no influence of the structure around the metal center in the polymer architecture. (3) The counterion effect is in agreement with a cationic mechanism (higher activity for the complex with the more stabilizing counterion). Furthermore, complex formed with a more coordinating triflate anion (OTf), rac-15 is incapable of epoxide polymerization, just like the neutral precursor rac-(ONNO)InCl. (4) MALDI-TOF spectrometry analysis of polymers revealed the presence of cyclic oligomers (no chain-end), which is a consequence of backbiting in cationic mechanisms. In the next chapter, different cationic species with improved stability by virtue of bulkier fluorinated counterion tetrakis(3,5-bis(trifluoromethyl)phenyl)borate will be applied in a more controlled ROP of different epoxides and their copolymerization with racemic lactide (a cyclic ester) to form copolymers either with a mixed-monomer approach or by a more controlled sequential addition method at room temperature. It is anticipated that the bulkier, fluorinated counterion will offer not only better initiation efficiencies (in combination with a suitable coordinating solvent) for the ROP of epoxides, but also decrease the extend of backbiting reactions, overall offering a better match between the theoretical and experimental molecular weight of the copolymers synthesized.  The mechanism of lactide polymerization will be studied and the mechanical properties of the copolymers synthesized will be analyzed.  99  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. 1H NMR chemical shifts are reported in ppm versus residual protons in deuterated solvents as follows: δ 7.27 CDCl3, 13C{1H} NMR chemical shifts are reported in ppm versus residual 13C in the solvent: δ 77.2 CDCl3. 19F NMR chemical shifts are reported in ppm and externally referenced to neat CFCl3 at 0 ppm. For kinetic and conversion measurements TMB (1,3,5-trimethoxybenzene) was used as an internal standard. 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 dn/dc (differential refractive index increment) values of the polymers studied were determined by running external calibration curves or by calculation of the GPC software assuming >90% mass recovery.  Materials. Solvents (THF, Me-THF, THF, diethyl ether and hexanes) were dried and vacuum- distilled over sodium, using benzophenone as an indicator and degassed through a series of freeze- pump-thaw cycles. Toluene and DCM were dried and distilled over CaH2. Deuterated solvents (CDCl3, C6D5Br and CD3CN) were dried over CaH2, collected by vacuum distillation 100  and also degassed. Epoxide monomers were dried over CaH2, distilled and stored under molecular sieves at −30 °C. Representative polymerization of epoxides with complex rac-11 in solution. A Schlenk flask was charged with a solution of complex rac-11 (20.2 mg, 0.019 mmol) in 0.6 mL of C6H5Br. 1,2-Epoxy-5- hexene (0.44 mL, 3.9 mmol) was added directly to the flask by a syringe. The mixture was stirred at 25 °C for 24 h. The resulting solution was concentrated under vaacuum for 3 h and then cold methanol was added to it (0 °C, 15 mL). The polymer precipitated from solution and was isolated by decantation or centrifugation. The isolated polymer was dried under high vacuum for at least 3 h prior to analysis.  Representative polymerization of epoxides with complex rac-11 for NMR monitoring. A J Young NMR tube was charged with a solution of complex rac-11 (20.2 mg, 0.019 mmol) in 0.5 mL of C6D5Br. The solution was frozen with liquid nitrogen and then a solution of 1,3,5-trimethoxybenzene (8.6 mg, 0.051 mmol) in 0.1 mL of C6D5Br was subsequently added to it. The solution was frozen with liquid nitrogen and then a solution of 1,2-Epoxy-5-hexene (0.22 mL, 1.9 mmol) in 0.1 mL of C6D5Br was added to it and frozen with liquid nitrogen. The J Young tube was put under vaccuum and closed and the mixture in the tube was kept frozen under liquid nitrogen prior to analysis. To study the effect of PF6 ions on this system, a similar procedure was employed, but with the addition of KPF6 (3.6 mg, 0.019 mmol) to the 1,3,5-trimethoxybenzene solution in 0.1 mL of C6D5Br.  Representative copolymerization of epoxides and other cyclic ethers with complex rac-11 in solution. A Schlenk flask was charged with a solution of complex rac-11 (40.3 mg, 0.039 mmol) in 0.6 mL C6H5Br and THF (0.31 mL, 3.8 mmol). 1,2-Epoxy-5-hexene (0.44 mL, 3.9 mmol) was added directly to the flask by a syringe. The mixture was stirred at 25 °C for for 4 101  days. The resulting solution was concentrated under vacuum for 3 h and then cold methanol was added to it (0 °C, 15 mL). The polymer precipitated from solution and was isolated by decantation. The isolated polymer was dried under high vacuum for at least 3 h prior to analysis.  DSC measurement of polymers. Approximately 5-10 mg of polymer was weighed and sealed in an aluminum pan. Experiments were carried out under a nitrogen atmosphere. The samples were heated at a rate of 10 °C/min from 25 to 170 °C and held isothermally for 5 min to destroy any residual nuclei before cooling at 5 °C/min. The glass transition and melting temperatures were obtained from the second heating sequence, performed at 10 °C/min.        102  Chapter 4: Cationic indium species for the copolymerization of epoxides and lactide  4.1  Introduction Polyether−polyester block copolymers can be synthesized by ring-opening polymerization (ROP) of epoxides and lactones. Although several catalysts promote a controlled polymerization of these rings (see general introduction), they are typically suitable for just one class of monomers and are inactive or uncontrolled for the other.246 Consequently, many of the synthetic procedures reported for polyether−polyester block copolymers require multiple synthetic steps involving different catalytic systems, purification of intermediates, and removal of unreacted monomers from previous steps. The most common strategy involves using commercially available polyethylene glycol (PEG) as a macroinitiator in the ROP of the cyclic ester in the presence of a Lewis acid.174, 189, 247 However, more recently, some elegant systems have been reported for the one-pot synthesis of these block copolymers.   Some of the most impressive systems capable of selective polymerization of epoxides and LA in a mixture of monomers base their activity on redox switches. Further expanding their work on redox catalysis, Diaconescu and coworkers applied a zirconium alkoxide complex supported by a ferrocene-based ligand in the block copolymerization of CHO and L-LA (Figure 4.1).248 In contrast to previously studied ferrocene-based titanium complexes applied in the block copolymerization of L-LA and ε-CL, this system exhibited a highly orthogonal activity for the epoxide and cyclic ester couple.  Starting from the oxidized version of the catalyst (I.59, Figure 4.1), CHO were polymerized with only trace conversion of LA. Addition of a reductant (CoCp2) 103  activated LA polymerization forming PCHO-b-PLA (Mn = 12,300 Da; Đ = 1.44). Reverse switch starting from the reduced version of the catalyst (I.60, Figure 4.1) was not as controlled due to side reactions of the added oxidant (AcFcBArF) with CHO, but block copolymers with good control could still be formed through sequential addition PLA-b-PCHO-b-PLA (Mn = 16,900 Da; Đ = 1.25).248    Figure 4.1. Redox-switchable systems active in the copolymerization of cyclohexene oxide (CHO) and lactide in a mixture of monomers.  Byers and coworkers also reported a redox switching system based on a bis(imino)pyridine iron complex that could cycle between neutral iron(II) (I.61, Figure 4.1) and cationic iron(III) (I.62, Figure 4.1) with orthogonal activity towards rac-LA and CHO. Interestingly, diblock copolymers (Mn up to 12,500 Da; Đ = 1.40) could be formed with the system switching from FeOOZr(OiPr)2tButButButBu[AcFc][BArF]CoCp2[BArF]I.59 I.60NNFeOOZr(OiPr)2tButButButBuNNNNNFeO OMeO OMe[Fc][PF6]CoCp2NNNFeO OMeO OMe[PF6]I.61 I.62104  both the oxidized and reduced forms, but always with some formation of PCHO homopolymer (which could be removed by selective precipitation). Block copolymers synthesized by sequential addition of monomers had similar properties to those synthesized by simultaneous feeding, further confirming the electivity of the system in a mixture of monomers.249 Some years later, the same group reported an adaptation of their iron system to make it work under electrochemical switches, obviating the need of adding sacrificial redox agents (Mn up to 40,300 Da; Đ = 1.80).250    As the selective formation of block copolymers from monomer mixtures by ROP of epoxides and cyclic esters is not straightforward, much research has focused on the ROCOP of anhydrides and epoxides (Figure 4.2). Nozaki and coworkers251 pioneered this strategy reporting a manganese(III) corrole complex with electron withdrawing substituents  (I.63, Figure 4.3) that in the presence of cocatalyst bis(triphenylphosphoranylidene)iminium pentafluorobenzoate (PPNOBzF5) was active in the ROCOP of glutaric anhydride (GA) and PO to give perfectly alternating polyesters. When the epoxide was added in excess compared to the anhydride, the formation of a polyether block took place right after anhydride consumption, yielding diblock copolymers (Mn = 23,700 Da; Đ = 1.50).251    Figure 4.2. Ring-opening copolymerization (ROCOP) of epoxides and cyclic  anhydrides to give highly alternating polyesters.  ROR’R’OOOO’R R’OOxOR+ ROCOP105  More recently, Williams and coworkers exploited a similar strategy for the well-controlled synthesis of multiblock polyester-polyether macromolecules. Employing a commercial salen chromium(III) chloride catalyst (I.64, Figure 4.3) in the presence of cocatalyst bis(triphenylphosphoranylidene)iminium chloride (PPNCl) and alcohol as a chain-transfer agent, different substituted epoxides could be copolymerized with different anhydrides to give highly alternating polyesters (> 95% polyester linkages). Once the anhydride was totally consumed the system could switch to a ROP mechanism in the presence of excess epoxide to make polyether-polyester block copolymers.   Figure 4.3. Systems active in the ring-opening copolymerization (ROCOP) of epoxides and cyclic anhydrides.  Despite the excellent control provided by some of these systems, the simple synthesis of poly(ester-b-ether) macromolecules still poses important challenges, hindering their more widespread application. These include the need for higher molecular weight products, milder synthetic conditions with simplified initiators (ideally one component), the incorporation of different biosourced monomers, and importantly, more systematic studies of the structure−property relationship of the copolymers.  NNN NC6F5C6F5C6F5 MnI.64N NO OtBu tButBu tBuCrClI.63+ PPNOBzF5 + PPNCl/ROH106  Mechanical and viscoelastic analysis of block copolymers. A tensile test is generally employed for the assessment of different mechanical properties of a material. Most importantly, the Young modulus (E, measure of stiffness of the material at diminishingly small linear strains), the tensile strength (σM, maximum stress the material can withstand) and maximum elongation (εb, maximum lengthening of the material before breakage) of polymers can be determined through this test.252 Dynamic mechanical analysis (DMA) is a technique that measures the storage (E') and loss (E'') moduli of a material as a function of temperature and it can be used as a sensitive tool to detect glass transitions and other transitions corresponding to different interactions between the macromolecules. Detailed analysis of these transitions in block copolymers offers a direct relationship between microstructure and mechanical properties in the material.253   4.2 Results 4.2.1 One-pot copolymerization by simultaneous addition of epoxides and lactide  The neat (no solvent) copolymerization of rac-lactide and epoxides was screened at 130 °C using rac-11 (Figure 4.4) in order to promote solubility of the cationic initiator in both liquid monomers. Interestingly, cationic species rac-11 is inactive towards lactide homopolymerization under these conditions (262 equiv. LA, 130 °C, 60 min), but in the presence of epichlorohydrin (200 equiv. ECH) both monomers are polymerized to high conversions and yield high molecular weight polymers (Table 4.1). Formation of copolymers in this case is confirmed by monomodal molecular weight distributions by GPC and by DOSY NMR spectroscopy, that indicates connectivity of the polyether groups with the polyester groups in the macromolecule as they show the same diffusion coefficient in solution (CDCl3, 25 °C).   107   Figure 4.4. Cationic indium complexes studied in the copolymerization of epoxides and LA.  Interestingly, long-range COSY NMR spectroscopy of a copolymer sample reveals through-bond coupling (5J) of the methine protons in PLA and the methylene/methine protons in PECH, also indicating connectivity of the two polymers (Appendix, Figure B.8). While long-range COSY NMR spectroscopy is not typically employed for the characterization of block copolymers, the presence of an upfield signal between 4.40-4.50 ppm that is attributed to a PLA methine directly attached to a polyether unit254 also is indicative of connectivity in this case (Appendix, Figure B.7). It's important to mention that in the absence of the cationic initiator rac-11, no conversion was observed for either ECH or lactide under the melt conditions explored  (Table 4.1, entry 3), indicating that cationic polymerization of epoxides is a prerequisite for the polymerization of the cyclic ester.        BArF4N NInOOOEt2OEt2tBu tButBu tBurac-[(ONNO)In(OEt2)2][BArF4] (rac-17)(S,S)-[(ONNO)In(OEt2)2][BArF4] ((S,S)-17)BArF4[(ONArNO)In(OEt2)2][BArF4] (18)N NInOOOEt2OEt2tBu tButBu tBuSbF6N NInOOOOtBu tButBu tBurac-[(ONNO)In(THF)2][SbF6] (rac-11)108  Table 4.1.  Copolymerization of ECH and rac-LA with cationic complex rac-11   ECH:LA:rac-11 Conv. ECHa  (%) Conv. LAa  (%) Mnb  (Da) Đb 1 0:262:1 - 0 - - 2c 0:262:1 - 0 - - 3 200:262:0 0 0 - - 4 200:262 92 90 11,720 2.44 5 200:653 92 90 25,000 1.44  Reactions were performed in the melt under a nitrogen atmosphere at 130 °C for 60 min. I0 = 0.012 mmol. aConversion was monitored by 1H NMR spectroscopy. bDetermined by GPC measurements in THF. cReaction run at room temperature with addition of 20 equivalents of benzyl alcohol.  Surprisingly, keeping the equivalents of ECH (200) fixed and further changing the number of equivalents of racemic lactide (176 to 653 equiv), a liner increase in the molecular weight was observed (Figure 4.5) with a corresponding decrease in the molecular weight dispersities with an increase in the equivalents of LA. As lactide does not seem to be polymerized by a cationic mechanism employing rac-11 (Table 4.1, entry 1) or by an activated monomer mechanism255 under these conditions (Table 4.1, entry 2), it is evident that a different mechanism is at play that exerts a higher degree of control (as evidenced by the lower dispersities) compared to the cationic polymerization of epoxides. Despite the linear correlation between the molecular weight and the amount of lactide added, the molecular weights obtained were significantly lower than the theoretical values based on the conversion of each monomer (Figure 4.5). xOO130 ℃OOOO+ Clrac-11ClO OOO y(±) (±)n200 equiv.109    Figure 4.5. Molecular weights (green circles) and dispersities (blue triangles) of the products from the copolymerization of ECH and LA employing rac-11 (130 °C, 60 min). Theoretical molecular weights (red circles) were determined on the basis of (144 gmol−1 × equiv LA × conv. LA) + (93 gmol−1 × 200 × conv. ECH).   In order to curve the side reactions (i.e. backbiting and transesterification/depolymerization) leading to the low experimental molecular weights obtained with rac-11, cationic species bearing a bulkier counterion rac-17 (Figure 4.4) was employed in the neat (no solvent) copolymerization of epoxides and lactide. By changing the counterion from SbF6− to a less coordinating tetrakis(3,5- bis(trifluoromethyl)phenyl)borate (BArF4) and using the less donating diethyl ether as the stabilizing solvent for the cationic species, it is anticipated that backbiting reactions involving the cationic chain-end can be reduced by virtue of the increased steric bulk of the perfluorinated anion and that the initiation efficiency will improve, leading to a more controlled copolymerization of the epoxides and lactide.  The neat (no solvent) copolymerization of 400 equiv of epichlorohydrin (ECH) or 1,2-epoxy-5-hexene (E5H) with 270 equiv of rac-LA catalyzed by rac-17 (130 °C, 60 min) in a one-pot, 110  mixed-monomer (simultaneous addition) procedure reached high conversions, yielding polymers with monomodal distributions (Table 4.2, entries 1−2). In contrast, the analogous reaction using rac-11 yielded monomodal or bimodal distributions, significantly lower molecular weight and higher dispersities (Table 4.2, entries 3−4), and no further increase in the molecular weight compared to the copolymerization of 200 equiv of epoxide and 270 equiv of rac-LA, indicating extensive side reactions (Table 4.2, entries 3− 6).   Table 4.2.  Copolymerization of epoxides and rac-LA using cationic initiators   Initiator (I) epoxide  (E) equiv. E Conv.  Ea  (%) Conv.  LAa  (%) Mn theob  (Da) Mnc  (Da) Đc 1 rac-17 ECH 400:1 75 94 64,447 22,610 1.35 2 rac-17 E5H 400:1 93 99 74,947 25,970 1.47 3 rac-11 ECH 400:1 78 97 66,730 10,130 2.67 4 rac-11 E5H 400:1 94 99 75,339 12,270d 2.69d 5 rac-11 ECH 200:1 96 97 55,570 14,790 2.13 6 rac-11 E5H 200:1 99 72 47,398 13,290 2.12 7e rac-17 E5H 400:1 91 99 74,163 17,960 2.26  Reactions were performed in the melt under a nitrogen atmosphere at 130 °C. I0 = 0.025 mmol. aMonomer conversion determined by 1H NMR spectroscopy. bDetermined on the basis of (144 gmol-1 × 270 × conv. LA) + (MWE gmol-1 × [E]0/[I] × conv. E). cDetermined by GPC measurements in THF. dDisplayed pronounced shoulder in GPC trace. eReaction was carried out for a longer time (6 hours).  OOOO OR(±) (±)130 ºC, 1h+[I]O OOOORx n270 equiv. R = CH2Cl (ECH)R = (CH2)2CHCH2 (E5H)111  The use of a bulkier counterion in rac-17 leads to higher molecular weight polymer, suggesting a decrease in the extent of side reactions such as backbiting, a common feature of cationic polymerization of epoxides. Regardless, transesterification and depolymerization reactions do occur with rac-17 under these reaction conditions, as can be seen by the lower experimental molecular weights (compared to the theoretical values). These reactions are also more prevalent at extended reaction times (Table 4.2, entry 7).   4.2.2 One-pot copolymerization by sequential addition of epoxides and lactide  It is anticipated that carrying the reactions at lower temperature with a sequential addition of monomers approach will significantly decrease the extent of side reactions in the copolymerization of epoxides and lactide using rac-17. In this fashion, addition of 400 equiv. of ECH, E5H, or 3,3-dimethyl-1,2-epoxybutane (DMEB) to a solution of rac-19 in CH2Cl2 at room temperature reaches about 90% conversion and gives the corresponding homopolymers (Table 4.3, entries 1−3). The subsequent addition of increasing amounts of rac-LA after this stage reaches conversions higher than 85% in 1−2 days (Table 4.3, entries 4−11) with a corresponding increase of molecular weight of the block copolymers. In particular, the rac-LA feed for the E5H-b-LA copolymer can be increased up to 545 equiv. and form a monomodal copolymer (Table 4.3, entries 6−9). Without the addition of epoxides, rac-LA cannot be polymerized using rac-17 (Table 4.3, entry 12), as it was previously seen using rac-11 under melt conditions (Table 4.1, entry 1).     112  Table 4.3.  Copolymerization of epoxides and rac-LA using cationic initiators   epoxide  (E) time step I (h) equiv. PPh3 Conv.  Ea  (%) equiv. LA time step II (h) Conv.  LAa  (%) Mn theob  (Da) Mnc  (Da) Đc 1 ECH 48 - 90 0 - - 33,480 20,220 2.12 2 E5H 48 - 90 0 - - 35,280 14,890 1.58 3 DMEB 48 - 86 0 - - 34,400 31,450 1.25 4 ECH 2 - 92 91 24 88 45,756 23,320 1.43 5 ECH 2 - 92 270 60 85 67,272 34,760 1.36 6 E5H 20 - 93 91 24 89 48,119 17,770 1.43 7 E5H 20 - 91 270 48 92 71,442 19,030 1.40 8 E5H 20 - 89 390 48 99 90,486 22,550 1.30 9 E5H 20 - 90 545 48 97 111,406 29,450 1.22 10 DMEB 2 - 86 91 24 99 47,373 40,820 1.39 11 DMEB 2 - 88 270 24 99 73,691 43,860 1.31 12     270 48 0 - - - 13d ECH 48 0.5 0 0 - - - - - 14 ECH 2 0.5 87 270 2 99 70,855 38,500 1.14 15 E5H 20 0.5 90 270 16 95 72,216 38,790 1.42 16 E5H 20 0.5 91 545 20 97 111,798 37,940 1.36 17 DMEB 2 0.5 88 270 4 99 73,691 45,860 1.25 18 ECH 2 1.5 87 270 3 67 58,414 26,730 1.41  All reactions carried out in CH2Cl2 under a nitrogen atmosphere at 25 °C. [rac-17]0 = 8.3 mM, [E]0 = 3.3 M. aMonomer conversion determined by 1H NMR spectroscopy. bDetermined on the basis of (144 gmol-1 × [LA]0/[rac-17] × conv. LA) + (MWE gmol-1 × 400 × conv. E). cDetermined by GPC measurements in THF. dTriphenylphosphine and the epoxide were added at the same time.  ORyOOOOOR(±)(±)DCM, 25 ºC DCM, 25 ºC OOOOORx y n(i)  rac-17(ii) PPh3400 equiv. R = CH2Cl (ECH)R = (CH2)2CHCH2 (E5H)R = C(CH3)3 (DMEB)P[ECH-b-LA]P[E5H-b-LA]P[DMEB-b-LA]113  It is possible to control the reaction further through the addition of triphenylphosphine (PPh3) immediately after the polymerization of epoxides (step I) and allowing it to react for 4 h before the addition of rac-LA (step II). This decreases the dispersity of the copolymers P[ECH-b-LA] (Table 4.3, compare entries 5 and 14) and P[DMEB-b-LA] (Table 4.3, compare entries 11 and 17) and greatly increases the molecular weight of P[E5H-b-LA] up to a maximum of 38,790 Da (Table 4.3, entry 15). Triphenylphosphine is known to react with cationic centers and form stable triphenylphosphonium adducts.244 Therefore, in the polymerization of E5H, it can quench the cationic chain-end and prevent further decrease in the molecular weight during the reaction by precluding extensive backbiting and decreasing the polymerization time for step II. The catalytic effect of different Lewis bases (in particular PPh3) on the polymerization of lactide using tin alkyls has been previously described.256-257 This effect has been ascribed to the coordination of the Lewis bases to the metal center and the polarization of the metal-alkoxide bond, accelerating monomer insertion. Adding more than 1 equiv of PPh3 to the polymerization system had a reverse effect, increasing the polymerization time and also the dispersity of the copolymers (Table 4.3, compare entries 14 and 18). Simultaneous addition of PPh3 and epoxide shuts down the reactivity of the initiator, with no conversion of epoxide over 48 h (Table 4.3, entry 13). This behaviour is in line with a cationic mechanism for the ROP of epoxides using rac-17.   In comparison, using more traditional Lewis acids such as boron trifluoride (BF3•Et2O) for the sequential polymerization of 200 equiv. of epichlorohydrin (step I) and 176 equiv. of rac-lactide (step II) at room temperature produces only low molecular weight products that could not be isolated through regular methanol precipitation (as was done for all polymers obtained with rac-17 and rac-11). Monitoring the conversion for both steps reveals no lactide conversion with this system (Table 4.4, entry 2). Control experiments involving the homopolymerization of 114  epichlorohydrin also yields low molecular weight products with no precipitation in methanol (Table 4.4, entry 1).   Table 4.4.  Copolymerization of epoxides and rac-LA using cationic initiators   Initiator (I) Conv.  ECHa  (%) Mn theob  step I (Da) Mnd  (Da) time step II (h) Conv.  LAa  (%) Mn theoc  step I + II (Da) Mnd  (Da) Đd 1 BF3•Et2O 72 13,392 ~ 2,000e      2 BF3•Et2O   52 0 13,392 - - 3 rac-11  96 17,856 76,500      4 rac-11   52 52 31,035 97,300 1.14 5 rac-11   96 72 36,104 120,100 1.15  Reactions were performed in dichloromethane under a nitrogen atmosphere at 25 °C. [I]0 = 32.0 mM. [ECH] 0 = 6.4 M. [LA] 0 = 5.6 M. aMonomer conversion was determined by 1H NMR spectroscopy. bDetermined on the basis of 93 gmol-1 × 200 × conv. ECH. cDetermined on the basis of (144 gmol-1 × 176 × conv. LA) + (93 × 400 × conv. E). dDetermined by GPC measurements in  THF. eApproximated from MALDI-TOF experiment.  Interestingly, employing rac-11 under the same conditions yields high molecular weight block copolymers (Table 4.4, entries 4 and 5) that are not only higher than those obtained by rac-11, but also much higher than the theoretical molecular weights based on the monomer equivalents and conversions. A closer inspection reveals that the initiation efficiency in step I (ECH polymerization) is only 23%, producing PECH with a much higher molecular weight (Table 4.4, OyOOOOO(±)(±)DCM, 18 h, 25 ºC DCM, 25 ºC OOOOOx y n200 equiv.ClCl[I] 176 equiv. Cl115  entry 3). As the remaining non-reacted catalyst (~ 77%) is not reactive towards lactide ROP, it is expected that high molecular weight block copolymers will form in step II only from the already pre-formed PECH. Due to the high reactivity of the cationic initiators, variations in initiation efficiency might arise from incomplete dissolution of the catalyst in CH2Cl2 before epoxide addition. In general, comparing the results from rac-11 and rac-17 confirms that the latter offers a more controlled copolymerization of epoxides and lactide with a better agreement between the theoretical and experimental molecular weights, especially by sequential addition of monomers at room temperature.  Analysis of the isolated block copolymers by 1H NMR indicates the presence of methine and methyl PLA signals immediately adjacent to a polyether block at 4.39 and 1.52 ppm (Appendix, Figures B.18, B.19 and B.20), respectively which is consistent with the chemical shifts previously found for similar block junctions similar copolymers. Thermogravimetric analysis of the samples shows two clear decomposition steps (Appendix, Figures B.33, B.34 and B.35), corroborating the blocky nature of the copolymers. In addition to the GPC data, diffusion-ordered NMR Spectroscopy (DOSY) is used to confirm the formation of polyether−polyester block copolymers by sequential addition and rule out a mixture of homopolymers (Appendix, Figures B.21, B.22 and B.23).  4.2.3 Attempts at post-functionalization of block copolymers  The synthesis of an amphiphilic block copolymer was attempted through post-functionalization of P[ECH-b-LA] to incorporate primary amine groups in the polyether block. To this end, chloride groups in the polymer can be reacted with sodium azide in a polar solvent and the new azide segments in the polymer can be reduced to amine groups 116  in the polyether block, rendering it water-soluble (Figure 4.6). This post-functionalization strategy has been reported for the synthesis of water-soluble copolymers with glycerol and glycidyl amine units.62     Figure 4.6. Synthesis of poly(glycidyl amine) from poly(epichlorohydrin)        Attempting the first reaction (nucleophilic substitution with sodium azide) on a block P[ECH-b-LA] sample (Mn = 32,240 Da; Đ = 1.29) prepared by the sequential addition method, turned out to be unsuccessful. More specifically, addition of 2 or 3 equivalents of NaN3 per chloride equivalent present in the block copolymer resulted in clear red solutions after 16 h of reaction (110 °C in dry DMF) that did not precipitate any polymers with addition of water or methanol, suggesting depolymerization under those harsh conditions. In order to decrease depolymerization, control reactions were run involving the nucleophilic substitution on PECH homopolymer samples at different temperatures. Monitoring the reactions by 13C{1H} NMR spectroscopy shows quantitative conversion after 16 h at 100 °C in dry DMF as indicated by a shift of the chloromethylene signal from 43-45 ppm to 51-53 ppm (Figure 4.7), indicating formation of poly(glycidyl azide), which could be precipitated by addition of water or methanol. Running the reaction for 2 days at 60 °C in dry DMF only resulted in partial conversion to polyazide (Figure 4.6), exemplifying the inconvenience of decreasing the temperature in the reaction of sodium azide with P[ECH-b-LA] block copolymers. OyDMF, 110 ºCClOyN3NaN3DMF, 25 ºC OyNH2(i)  PPh3(ii) H2O117   Figure 4.7. 13C{1H} NMR spectra (CDCl3) of the methylene region in PECH and its post-functionalization reactions with sodium azide at different temperatures.   Running the reaction of P[ECH-b-LA]  with NaN3 in more polar DMSO-d6 (to ensure a higher solubility of the salt) at room temperature for 24 h does not yield any conversion to a poly(glycidyl azide) block copolymer as indicated by 13C{1H} NMR spectroscopy. Moreover, comparison of the 1H NMR spectra of the starting material and isolated product shows a great decrease in the PLA signals after reaction (Appendix, Figure B.49), indicating that depolymerization reactions are prominent, even at room temperature for this particular reaction.  118  4.2.4 Lactide polymerization and mechanistic studies Initially, the simultaneous (mixed-monomer) copolymerization of rac-LA (170 equiv) and ECH (260 equiv) with rac-17 (6.0 mM in CD2Cl2) was monitored at room temperature in situ using 1H NMR spectroscopy (Figure 4.8). In the first stages of polymerization, lactide is not polymerized (first 9 h), while ECH is converted preferentially (14%). It is evident, however, that the rate of ECH polymerization is greatly affected by the presence of rac-LA and the dilution of the monomer, as the same polymerization in the absence of the cyclic ester and under higher concentrations reaches high conversions in only 2 hours  (Table 4.3, entries 4 and 5).    Figure 4.8. Kinetic plots of copolymerization of ECH (260 equiv) and rac-LA (170 equiv) at 25 °C in CD2Cl2 with simultaneous addition of both monomers. [rac-17]0 = 6.0 mM, [ECH]0 = 1.6 M, [rac-LA]0 = 1.0 M.  To further explore the effect of a non-polymerizable Lewis base in the cationic ROP of epoxides, the diluted polymerization of ECH (392 equivalents) by rac-17 (6.0 mM in CD2Cl2) was monitored in CH2Cl2 with and without the addition of 627 equivalents of diethyl ether (as a 119  Lewis base). After 7 hours conversion in the presence of the Lewis base was only 10% in comparison to 26% without the Lewis base. This can explain in part the lower rate of cationic polymerization of ECH in the presence of lactide (a Lewis base).  After the first 20 h of polymerization in a mixture of ECH and LA, when the conversion of ECH is 19%, the polymerization of lactide ramps up (Figure 4.8). The polymerization of lactide coincides with a slower conversion of ECH in this second stage (Figure 4.8). This reactivity profile indicates that both monomers are polymerized by different mechanisms: while ECH is polymerized first by a more reactive cationic mechanism, lactide is not incorporated in the cationic chain-end (this would be reflected in a concomitant conversion of both monomers at early stages of the polymerization). Therefore, random/statistical copolymers are not formed by simultaneous addition of monomers in this system. This is in line with previous results indicating that rac-LA is not cationically polymerized by rac-17 (Table 4.3, entry 12) and further exemplifies that its polymerization requires the presence of both epoxide and rac-17, with preceding cationic ROP activity taking place.       On the contrary, rac-LA is likely polymerized by a coordination-insertion mechanism involving the other chain-end: a metal-alkoxide intermediate formed after the reaction of the cationic initiator with ECH. Under these conditions (simultaneous monomer addition at room temperature), the rate of lactide insertion is significantly inhibited by a high concentration of epoxide, causing an initial induction period of about 20 h after which conversion increases significantly, reaching 70% in 5 days (Figure 4.8). The rate of epoxide polymerization is even more greatly affected by the presence of the cyclic ester, reaching only 30% conversion in the same time (Figure 4.8). To rule out the polymerization of epoxide by a more controlled coordination-insertion mechanism (involving the indium alkoxide intermediate), a control 120  experiment was run by which indium alkoxide complex I.18 (4.0 mM) was mixed with ECH (400 equiv) in CD2Cl2 at room temperature. Monitoring the reaction after 24 h gave no conversion of epoxide to polyether product (Figure 4.9). This shows that ECH is polymerized mainly by a cationic mechanism in its copolymerization with rac-LA.    Figure 4.9. Control reaction of ECH with indium alkoxide complex at room temperature in CD2Cl2. Reaction was monitored after 24 h. [I.18]0 = 4.0 mM  Interestingly, the polymerization of rac-LA by rac-17/ECH system through sequential addition (Table 4.3, entry 5) reveals some degree of enantiomorphic site control derived from ligand chirality, giving iso-rich PLA block (Pm = 0.72), as determined by 1H{1H} NMR spectroscopy (Appendix, Figure B.44). This is in sharp contrast to the polymerization of rac-LA by the achiral initiator rac-18/ECH under the same conditions (sequential addition, 400 equiv of ECH followed by 270 equiv of rac-LA) that produces completely atactic PLA blocks (Appendix, Figure B.45) of similar molecular weight (Mn = 34,540 Da; Đ = 1.20). Moreover, monitoring the rates of polymerization of rac-, D-, and L-lactide with either rac-17 or (S,S)-17 (after initial neat ECH polymerization) shows a first order dependence of the rate on LA concentration. There is roughly a two-fold difference in the rates of polymerization of D-, and L-lactide using enantiopure OI.18ClCD2Cl2, 25 ºCno reaction NNOOtButButButBuInNNOOtButButButBuInOOEtEtI.18121  complex (S,S)-17 (Table 4.5, entries 5-6), which indicates a kinetic preference of the enantiopure complex for L-LA. The fact that the rate of polymerization of rac-LA is roughly the same as that for D-LA using enantiopure (S,S)-17 shows that the polymerization is greatly inhibited by the presence of D-LA.  Table 4.5.  Rates of polymerization of LA isomers with cationic initiators and ECH  Initiator (I) epoxide  (E) cyclic ester kobs  (10-6 s-1) 1 rac-17 ECH rac-LA 9.67 2 rac-17 D-LA 12.85 3 rac-17 L-LA 14.52 4 (S,S)-17 rac-LA 5.55 5 (S,S)-17 D-LA 7.71 6 (S,S)-17 L-LA 13.98  Reactions were carried out in CH2Cl2 under a nitrogen atmosphere at 25 °C. [I]0 = 4.3 mM, [LA]0 = 0.55 M. ECH was polymerized first (253 equiv.) with the initiator during 2 hours, then a solution of lactide was added. [LA]0 = 0.55 M. 1,2,5-trimethoxybenzene (TMB) was used as internal standard. kobs was determined from the slope of the plots of Ln[LA] vs time.  These results reveal enantiomorphic site control generated from ligand chirality as the main contributor to selectivity in the lactide polymerization, in stark contrast to the epoxide polymerization that proceeds in a cationic mechanism with no regio- or stereo-control: Both rac-17 and (S,S)-17 polymerize enantiopure (R)-(+)-PO in neat (no solvent) conditions to high conversions over 24 h (> 90%), but both initiators yield completely regio-irregular PPO as shown in the 13C{1H} NMR spectra of the products (Appendix, Figure B.6), just like for the samples obtained using rac-11 and (R,R)-11 in the polymerization of rac-PO (vide supra).   122   Figure 4.10. 31P{1H} NMR spectra of reaction mixtures of ECH polymerization (400 equiv.) by cationic initiator rac-17 followed by addition of PPh3 in CD2Cl2 (162 MHz, CD2Cl2, 25 °C).  The role of triphenylphosphine (PPh3) in the sequential polymerization of epoxides and lactide was also studied by 31P{1H} NMR spectroscopy: Polymerization of ECH (400 equiv) using rac-17 during 3 hours, followed by addition of 1 or 3 equiv. of PPh3 in CH2Cl2 revealed a strong signal around 24 ppm in a matter of hours (Figure 4.10), in agreement with the formation of triphenylphosphonium ion in the polymer chain-end. Reaction is slow at room temperature and after 3 h of reaction there is still free triphenylphosphine present in the reaction mixture, which explains why addition of PPh3 also accelerates LA polymerization in the sequential addition experiments.  123  Based on the mechanistic evidence presented, the following mechanism of copolymerization is proposed for rac-17 and similar cationic species. First, cationic initiation occurs by the coordination of epoxide to the cationic center, followed by the cationic propagation with an active cationic chain-end far from the metal center and the corresponding formation of a neutral indium-alkoxide species (Figure 4.11). The addition of triphenylphosphine (PPh3) quenches the cationic chain end and generates a phosphonium chain-end that is no longer active toward epoxides ROP.    Figure 4.11. Proposed mechanism of copolymerization of epoxides and lactide by cationic initiator rac-17 and similar cationic species.   The reaction of lactide follows through a more controlled coordination-insertion mechanism involving the neutral indium alkoxide species, whose propagation runs in an opposite from the cationic polymerization (Figure 4.11). The presence of remaining PPh3 from the previous step can also accelerate the rate of lactide polymerization, presumably by coordination to the indium center and polarization of the indium alkoxide propagating species.  ORInOROEt2(ONNO)In[BArF]− OR OEt2 (ONNO)Initiation I(ONNO)InORPropagation IORnPropagation IImPPh3(ONNO)In OnROOOOmO OnRR+OOOORPPh3(ONNO)InORO OnR[BArF]−[BArF]−[BArF]−RPPh3O[BArF]−124  4.2.5 Mechanical and thermal properties of block copolymers A series of block copolymers with different compositions were made by the copolymerization of either epichlorohydrin (ECH), 3,3-dimethyl-1,2-epoxybutane (DMEB), or 1,2-epoxy-5-hexene (E5H) with racemic lactide (rac-LA) through sequential polymerization employing the most active catalyst rac-17. Block ratios were determined by the integration of polyether and polyester regions in their 1H NMR spectra. Representative tensile results are shown below as the average of different specimens (Table 4.6), where E is the Young modulus, σM is the tensile strength (maximum stress value on the stress−strain curve), and εb is the total linear strain before failure. Stress-strain curves are shown in the appendix (Appendix, Figures B.46 and B.47). While the PLA homopolymer is typically brittle, P[(DMEB)0.55-b-(LA)0.45] and P[(E5H)0.49-b-(LA)0.51] show a great degree of elasticity with linear elongation at break over 500% and 700%, respectively (Table 4.6, entries 3 and 6). In contrast, P[(ECH)0.53-b-(LA)0.47] shows a behaviour more similar to the PLA homopolymer (very low ductility) but with increased stiffness as shown by its much higher E modulus (Table 4.6, entry 1). In this case, the PLA sample analyzed was prepared from rac-lactide using an indium catalyst (I.15, Figure 1.8). This system produces PLA with Pm of 0.61. The sample was prepared in order to have PLA of similar molecular weight to the block copolymers here prepared and allow for accurate comparison of the mechanical properties. Stress-strain analysis of this sample was determined under the same conditions used for the analysis of block copolymer samples. It was noted, however, that this reference PLA sample processed under the same conditions as the copolymers showed a significantly low stiffness (E modulus) besides its particular brittleness (typical of PLA samples).      125  Table 4.6.  Mechanical properties of block copolymers synthesized with rac-17   Copolymer Mna  (kDa) fE/fLAb FE/FLAc E (MPa) σM (MPa) εb (%) Tg DSC (°C) 1 P[(ECH)0.53-b-(LA)0.47] 34.20  0.6/0.4 0.53/0.47 345(6) 4.5(7) 6.4(1.2) −28.4 2 P[(ECH)0.43-b-(LA)0.57] 47.11 0.4/0.6 0.43/0.57 496(4) 18(1) 3.2(4) −30.0/41.9 3 P[(DMEB)0.55-b-(LA)0.45] 45.86  0.6/0.4 0.55/0.45 81(7) 5.1(8) 545(7) 1.9/54.9 4 P[(DMEB)0.41-b-(LA)0.59] 55.31  0.4/0.6 0.41/0.59 512(3) 17(4) 6.9(1.2) 3.2/48.8 5 P[(E5H)0.49-b-(LA)0.51] 38.79 0.6/0.4 0.49/0.51 20(2) 1.8(1) 780(6) −69.6/45.3 6 P[(E5H)0.38-b-(LA)0.62] 43.94 0.4/0.6 0.38/0.62 410(5) 12(2) 7.7(1.7) −74.8/58.7 7 PLA 54.69 - - 9.0(4) 7.0(7) 3.1(7) 55   All measurements represent the average of at least three tests. Samples were prepared by solution casting in PTFE mold at room temperature and atmospheric pressure. Drying was performed in a vacuum oven at 40 °C for 24 h. After drying sample was cut into strips with dimensions 5 mm × 4.5 mm × 0.5 mm. Tensile results are shown as the average of at least 3 different specimens. aDetermined by GPC measurements in THF. bMolar monomer feeding ratio. cMolar composition determined by 1H NMR spectroscopy.  In general, adding a polyether block to PLA increases the stiffness of the material significantly. This was not expected, as the polyether segments are typically considered "softer" blocks compared to lactide, and therefore likely to reduce the mechanical properties of the copolymers at the expense of increasing its elasticity. However, the polyether blocks significantly harden the *O OOO*xOOO yCl*O OOO*tBuxOOO y*O OOO*xOOO yP[ECH-b-LA] P[E5H-b-LA]P[DMEB-b-LA]126  copolymers in the order PECH > PDMEB > PE5H, which could be explained partially by the increased degree of intermolecular forces (dipole-dipole interactions) in PECH compared to PDMEB and PE5H.  In the case of the PDMEB block, the presence of bulkier tert-butyl groups restricts rotational freedom around polymer chains, also increasing overall copolymer stiffness. For the block copolymer with the highest ductility, increasing the proportion of PLA in the block had a detrimental effect on the elongation at break (Table 4.6, entries 5-6), but with a significantly greater modulus and higher stiffness. Similarly, increasing the PLA fraction for the other copolymers also had a corresponding increase in stiffness, up to 500 MPa for both P[(ECH)0.43-b-(LA)0.57] and P[(DMEB)0.41-b-(LA)0.59] (Table 4.6, entries 1-4) with a significant decrease in elasticity. Although it's clear that molecular weight is also a key factor in the overall moderate E modulus of the polymers synthesized and low tensile strength (σM), comparison to PLA of similar molecular weight (Table 4.6, entry 7) reaffirms the important role of the polyether block on the modulation of the mechanical properties of these copolymers (as a semi-hard block).   Dynamic Mechanical Analysis (DMA) was used to study the viscoelastic behaviour of representative block copolymers (Table 4.6, entries 1, 3, 5 and 6) using oscillatory shear measurements; temperature ranging from −80 to 140 °C at a frequency of 0.1 Hz (Figure 4.12). In general, both P[(ECH)0.53-b-(LA)0.47] and P[(DMEB)0.55-b-(LA)0.45] show an initial relaxation process in the range of −20 to 10 °C (Figure 4.10) corresponding to the glass-to-rubber transition of the polyether blocks and characterized by a peak in tanδ curve, where there is a decrease in the storage modulus E' and a small to moderate increase of E''. Temperatures for these transitions correlate with the Tg values found by DSC (Table 4.6, entries 1 and 3). As the corresponding 127  transition for the polyether block in P[(E5H)0.49-b-(LA)0.51] was very close to the lower temperature limit (−80 °C) it could not be observed clearly.    Figure 4.12. Dynamic mechanical analysis (DMA) of selected diblock copolymers prepared with cationic initiator rac-17.  Further heating of the samples shows a second transition in the range of 40-60 °C, characterized by another peak in tanδ curve and an even greater drop in the storage modulus E' that can be attributed to the glass-to-rubber transition of the polyester phase. Also, the higher PLA fraction in P[(E5H)0.38-b-(LA)0.62] compared to P[(E5H)0.49-b-(LA)0.51] resulted in a much 128  higher modulus E' which correlates to its higher stiffness found in the tensile tests (Figure 4.13). Changing the identity of the polyether block also had a profound effect in the storage modulus E' of the material, with PDMEB offering the largest values, followed by PECH and PE5H. In contrast to other samples, block copolymer P[(ECH)0.6-b-(LA)0.4] showed a small peak at 89 °C that likely comes from the melting of small (irregular) crystallites.  Copolymers with PDMEB and PE5H are shown to be more amorphous by DMA, which results in their significantly better mechanical properties.   Figure 4.13. Dynamic mechanical analysis (DMA) of diblock copolymer prepared with cationic initiator rac-17.  4.3 Conclusions In summary, both simultaneous and sequential addition of epoxides and lactide offers a convenient route for the synthesis of polyester-polyether copolymers with cationic initiators rac-11 and rac-17. Generally, cationic complex rac-17 offers the most controlled copolymerizations with a better initiation efficiency and better agreement between experimental and theoretical 129  molecular weights. Polymerization studies and the characterization of products indicate that for the polymerization of both monomers proceeds via two independent mechanisms: a cationic ROP for the epoxides (lactide is not polymerized cationically by these systems, even in the presence of external alcohol) and a coordination-insertion ROP for lactide that can influence the microstructure of the PLA block (display of isotactic bias) through stereoinduction around the metal center. Sequential polymerization of different epoxides using rac-17, followed by deactivation of the cationic chain-end by addition of triphenylphosphine and rac-LA polymerization yielded polyether-block-polyester copolymers with relatively high molecular weight and improved mechanical properties over PLA homopolymer of comparable molecular weight. Tensile test of sample P[(DMEB)0.6-b-(LA)0.4] revealed it to be not only more elastic compared to PLA (εb up to 545%), but also stiffer, with higher E modulus (E of 80.9 MPa). In comparison, P[(DMEB)0.6-b-(LA)0.4]  shows even higher elasticity (εb up to 780%) but with a lower E modulus (E of 19.90 MPa).  The maximum stress obtained for these copolymers is low, although comparable to other thermoplastic elastomers (TPE) based on PLA (ABA triblocks).258 It is expected that increasing the molecular weight and control over the block formation will improve significantly these properties.  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 line techniques. NMR spectra were recorded on a Bruker Avance 300 MHz, 400 MHz and 600 MHz spectrometer. 1H NMR chemical shifts are reported in ppm versus residual protons in deuterated 130  solvents as follows: δ 7.27 CDCl3, 13C{1H} NMR chemical shifts are reported in ppm versus residual 13C in the solvent: δ 77.2 CDCl3. 31P{1H} NMR chemical shifts are reported in ppm and externally referenced to 85% H3PO4 at 0 ppm. For kinetic and conversion measurements TMB (1,3,5-trimethoxybenzene) was used as an internal standard. 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 1.0 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 dn/dc (differential refractive index increment) values of the polymers studied were determined by running external calibration curves or by calculation of the GPC software assuming >90% mass recovery.  Glass transition temperatures of the polymers were obtained using a differential scanning calorimeter (DSC) NETZCH DSC214 Polyma. Approximately 5−10 mg of the samples was weighed and sealed in an aluminum pan with a punctured lid. The experiments were carried out under a nitrogen atmosphere. The samples were heated at a rate of 10 °C/min from −150 to 200 °C. Thermal degradation studies were performed on a NETZCH TG 209 F1 Libra instrument. Samples were placed in an alumina crucible and heated under nitrogen at a rate of 10 °C/min from 25 to 600 °C. Dynamic mechanical measurements were performed using DMA (RSA G2 TA Instruments) in the oscillatory mode. Tensile tests were performed using the RSA G2 (TA Instruments) in axial mode. The Young modulus, E, was determined from the stress, σ, according to the equation σ = Eε, which is eligible only for purely elastic response of the 131  material at diminishingly small linear strains, ε. The linear elongational strain was calculated using ε = [(L − L0)/L0] × 100, where L0 is the initial length of the sample (t = 0), and L is the length of the sample at time t. The tensile strength represents the maximum stress in the stress−strain curve and the ultimate elongation and shows how much the material can elongate before fracture/failure, which was calculated using the equation εu = [(Lf − L0)/L0] × 100, where Lf is the final length of the sample before failure.   Materials. Solvents (THF, diethyl ether and hexanes) were dried and vacuum- distilled over sodium, using benzophenone as an indicator and degassed through a series of freeze- pump-thaw cycles. Toluene and DCM were dried and distilled over CaH2. Deuterated solvents (CDCl3, C6D5Br) were dried over CaH2, collected by vacuum distillation and also degassed. Epoxide monomers were dried over CaH2, distilled and stored under molecular sieves at −30 °C. Racemic, D-, and L-lactide were purchased from Corbion, recrystallized three times from dry toluene, and finally dried under vacuum for three days before use.  Representative polymerization for rate determination of LA polymerization. A vial was charged with rac-17 (10 mg, 0.0060 mmol) and epichlorohydrin (0.12 mL, 1.52 mmol) and left stirring for 2 h. Then, the content was dissolved in 0.2 mL of CD2Cl2, transferred to a J Young NMR tube, and then rinsed and further transferred to the tube with another 0.25 mL of CD2Cl2. The solution in the tube was frozen with liquid nitrogen, and then, a solution of 1,3,5- trimethoxybenzene (8.6 mg, 0.051 mmol) in 0.35 mL of CD2Cl2 was subsequently added to it. The added solution was frozen with liquid nitrogen to make a second layer, and finally, a solution of rac- LA (110 mg, 0.76 mmol) in 0.60 mL of CD2Cl2 was added to the tube and then frozen with liquid nitrogen to make a third layer. The J- Young tube was put under vacuum and closed and the mixture in the tube was kept frozen under liquid nitrogen prior to NMR analysis.  132  Representative copolymerization of epoxides and rac-LA by simultaneous addition of monomers. In a glovebox, a Schlenk flask was charged with rac-17 (20.7 mg, 0.012 mmol), epichlorohydrin (0.40 mL, 5.10 mmol), and rac-lactide (487 mg, 3.38 mmol). The flask was taken out of the glovebox quickly and put in an oil bath to stir at 130 °C. After 1 h, the reaction mixture was left to cool down and dissolved in a minimal amount of dichloromethane. The polymer was precipitated with cold methanol (0 °C, 15 mL) and subsequently washed with more methanol. Representative copolymerization of epoxides and rac-LA by sequential addition of monomers. In a glovebox, a vial was charged with rac-17 (41.4 mg, 0.025 mmol) and epichlorohydrin (0.80 mL, 10.20 mmol), and the reaction was stirred for 2 h. Then, triphenylphosphine (3.2 mg, 0.012 mmol) was added with 1.50 mL of CH2Cl2, and the reaction was further stirred for 4 h. Finally, a solution of rac-lactide in 1.50 mL of CH2Cl2 was added (975.0 mg, 6.76 mmol), and the reaction was stirred for about 3 h. The mixture was concentrated to about 2 mL and the polymer was precipitated with cold methanol (0 °C, 15 mL) and subsequently washed with more methanol. Representative attempt at the post-functionalization of block copolymers. A schlenk flask was charged with a stirbar, a (PECH)0.5-b-(PLA)0.5 sample prepared by the sequential addition method (173.0 mg), DMF (3.0 mL) and sodium azide (180 mg, 0.0027 mol).  The flask was sealed and heated to either 100 °C for 16 hours or to 60 °C for 48 hours. Reaction was allowed to cool to room temperature and cold methanol was added in order to precipitate polymer products. Alternatively, reaction can be carried out on a vial at room temperature using DMSO-d6 instead of DMF for 24 hours. 133  DSC measurement of polymers. Approximately 5-10 mg of polymer was weighed and sealed in an aluminum pan. Experiments were carried out under a nitrogen atmosphere. The samples were heated at a rate of 10 °C/min from 25 to 170 °C and held isothermally for 5 min to destroy any residual nuclei before cooling at 5 °C/min. The glass transition and melting temperatures were obtained from the second heating sequence, performed at 10 °C/min.  Sample preparation for tensile tests and dynamic mechanical analysis. Approximately 600 mg of polymer sample were dissolved in dichloromethane (approx. 10 mL) to make a concentrated, viscous solution. Samples for stress−strain and DMA experiments were prepared by solution casting of this solution in a PTFE mold at room temperature and atmospheric pressure. Drying was performed in a vacuum oven at 40 °C for 24 h. After drying, samples were cut into strips with dimensions of 5 mm x 4.5 mm x 0.5 mm. DMA analysis was carried out in the oscillatory mode of the device to examine the material behaviour in the range of temperatures from −80 to 140 °C at a frequency of 0.1 Hz. Tensile tests were carried out in the axial mode. The sample strips were extended until breakage at room temperature by applying a constant linear strain rate of 0.5 mm/min. For each sample, the data reported correspond to the average and standard deviation of at least three specimens.   134  Chapter 5: Neutral indium species for the homo- and copolymerization of cyclic esters  5.1  Introduction Synthesis of block copolymers with simultaneous addition of monomers that follow the same ROP mechanism can be challenging and requires the monomers to have very different reactivities with a particular catalyst, implying that one gets consumed much faster than the other (kinetic control), but even in that case transesterification in the system can turn blocky structures into random copolymers.  For example, polymerization of unsaturated macrolactones such as macrolactone globalide (GI) and 1,5-dioxepan-2-one (DXO) formed random copolymers in the presence of Novozym 435 as a catalyst (Candida Antarctica Lipase B immobilized). This scrambling occurred despite the different reactivity ratios of those two monomers (Figure 5.1).259  Waymouth and coworkers addressed this issue in 2011, reporting Zwitterionic ROP as a strategy for gradient (block-like) copolymers in the simultaneous copolymerization of ε-caprolactone (ε-CL) and δ-valerolactone (δ-VL) with nucleophilic N-heterocyclic carbenes (Figure 5.1).260 Both linear and cyclic products (obtained in the presence and absence or alcohol respectively) containing a larger fraction of homo-dyads (CL-CL and VL-VL) than hetero-dyads (CL-VL) by 13C{1H} NMR spectroscopy compared to the control experiment with tin (II) octoate, corroborated the blocky-structure of the copolymers.  Recently, Dove and coworkers reported a simple magnesium phenoxide complex (I.65, Figure 5.1) for the block-copolymerization of 3,6-disubstituted lactone menthide (MI) and larger lactones with minimal ring-strain like ζ-heptalactone (ζ-HL, 8-membered ring) or η-135  caprylolactone (η-CYL, 9-membered ring) in toluene at 80 °C (Figure 5.1). In a mixture of monomers, the magnesium complex polymerized the more reactive MI followed by the less strained lactone to give block copolymers (Mn up to 18,400 Da; Đ = 1.50), as evidenced by the presence of major homocoupling carbonyl diads in 13C{1H} NMR spectroscopy (with only a minor presence of heterocoupling diads). Previously, the same group had reported a similar degree of kinetic control in the polymerization of MI and ω-PDL (Figure 5.1) as evidenced by conversion profiles and 13C{1H} NMR spectroscopy (Mn = 13,800 Da; Đ = 2.41).116    Figure 5.1. Copolymerization of cyclic esters with simultaneous addition of monomers leading to random (top), gradient "blocky" (middle) and block copolymers (bottom). 136  Their rationale behind the kinetic control exhibited by this catalyst was that the initial formation of PMI block is "locked" against transesterification side reactions (due to the presence of methyl and isopropyl groups in each monomer unit) and once MI has been depleted, the second block starts forming and can only undergo transesterification mostly within itself. In contrast, reaction of MI with a more reactive lactone (such as ε-CL) forms completely random copolymers as the more reactive small monomer will react first and any incorporation of MI added at the chain end will rapidly be pushed to the middle of the chain by fast transesterification. Random copolymers in this case were evidenced by equal integration of homocoupling and heterocoupling diads in NMR spectroscopy.261 Some of the most exquisite systems offer control in ROP of cyclic esters through external stimuli such as redox-,262-264 allosteric-,265 or thermal-switches.266-267 Diaconescu and coworkers exploited ligand conformational changes through redox switching for the block copolymerization of very similar monomers L-LA and ε-CL.268 The authors tested different zirconium and titanium alkoxide complexes supported by redox-active ferrocene-based ligands. Block copolymerization in a mixture of monomers was achieved by chemical redox switching using a titanium complex (I.66, Figure 5.2) that on its reduced form was active in LA polymerization and on its oxidized form (I.67, Figure 5.2) was much more active for ε-CL polymerization, yielding PLA-b-PCL (Mn = 3,230 Da; Đ = 1.12). Narrow dispersity indicated a controlled polymerization, but only low conversions of monomer were achieved (as an increased in reaction times led to a decrease in substrate selectivity). Formation of multiblock copolymers through several switches was not reported.268   137   Figure 5.2. Redox-switchable system active in the one-pot block copolymerization of LA and ε-CL with simultaneous feeding of monomers.  The need for more versatile and highly controlled metal-based systems active in the synthesis of di- and multiblock polyesters from a diverse range of monomers has spurred studies on systematic catalyst design with relative success.269-272 In particular, the effect of potentially hemilabile coordinating side groups on the ligand scaffold of ROP-active metal complexes has not been extensively studied, but it's been show in some cases to allow for the tuning of cyclic ester ROP activity273 and improve polymerization control through allosteric switches265 and significantly reduced transesterification.274 Other tuning effects of potentially hemilabile coordinating side groups have been described in the ring-opening copolymerization (ROCOP) of epoxides and CO2 to polycarbonates.275-276  FeSSOOTi (OiPr)2tButButButBuFeSSOOTi (OiPr)2tButButButBu[AcFc][BArF]CoCp2[BArF]I.66 I.67I.66OOOOOOO OOOx I.67O OO yOOOxP[LA-b-CL]LAε-CL138  5.2 Results 5.2.1 Synthesis and characterization of neutral indium alkoxides complexes Formation of neutral indium alkoxide species was explored by salt metathesis of the different indium chloride complexes previously synthesized (5-8) with potassium tert-butoxide (KOtBu) in THF. Such a strategy involving indium halides and alkoxide salts has been previously used with success in the Mehrkhodavandi group for the synthesis of different indium alkoxide species with iminophenolate and aminophenolate ligand scaffolds.45, 48, 50 In this case, it was found necessary to carefully optimize the reaction conditions in order to obtain clean reaction products. Due to the presence of two chlorides in the starting material it is theoretically possible to exchange one or two of these groups by tert-butoxide anions. Adding one equivalent of KOtBu to compound 6 in THF yields new monoalkoxide compounds in a matter of minutes (kinetic product) as evidenced by 1H NMR spectroscopy (Figure 5.3). When the reaction was left for 16 hours, this product quickly disappears with the consequent formation of a new compound (thermodynamic product) and reformation of starting dichloride as evidenced by 1H NMR spectroscopy (Figure 5.3). Control experiment involving the addition of 2 equivalents of KOtBu to compound 7 in THF confirms that this second product corresponds to the bisalkoxide compound (Figure 5.3).  As compounds 5-8 exhibited the same behavior (fast formation of mono- with slow formation of bisalkoxide), isolation of monoalkoxides from these dichlorides was challenging and required careful optimization of synthesis and workup conditions in order to obtain the cleanest possible products.     139   Figure 5.3. Aromatic, imine and aliphatic region in the 1H NMR spectrum (CDCl3, 25 °C) of the crude product from the reaction of 6 with 1 or 2 equiv of KOtBu.   Under the best conditions found, new alkoxide chloride compounds (19-22) could be obtained by reaction of dichlorides (5-8) with 1.1 equivalents of KOtBu in THF (Figure 5.4). Fortunately, alkoxide compounds (NMe2N*O)InCl(OtBu) (19) and (NmorN*O)InCl(OtBu) (20) could be separated from their bisalkoxide side-products through extensive washing with non-polar solvents. The other two alkoxides (NthioN*O)InCl(OtBu) (21) and (NmepipN*O)InCl(OtBu) (22) 140  could not be entirely purified and were employed in the polymerization studies with a small fraction (~ 10-20%) of bisalkoxide side-product.    Figure 5.4. Synthesis of indium alkoxide chloride complexes (19-22) supported by iminophenolate ligands. Isolated yields are provided in parentheses.    In contrast to the dichlorides (5-8), the new alkoxide chlorides (19-22) reveal further splitting of signals in their 1H NMR spectra (CDCl3, 25 °C) of the central ethylene backbone protons and the heterocycle methylene protons (Figure 5.5). This is expected as a consequence of the loss of planar symmetry in these compounds by substitution of one chloride group by alkoxide. Compound 22 still shows non-coordination of the terminal N-methyl group, as the methylene OtButBuN RTHFIn OtBuClOtButBuN RIn ClCl1.1 equiv KOtBu(NMe2N*O)InCl(OtBu) (19) (42%) (NmorN*O)InCl(OtBu) (20) (46%)(NthioN*O)InCl(OtBu) (21) (NmepipN*O)InCl(OtBu) (22)OtButBuN NInCl OtBu OtBuNtBuInONClOtBuOtBuNtBuInSNClOtBuOtBuNtBuInClOtBuNN5-8 19-22141  protons directly adjacent to the terminal N-methyl group are shown to be all completely equivalent by 1H NMR spectroscopy, with exact chemical shifts as in the dichloride precursor 8 (Appendix, Figure A.36).    Figure 5.5. Aliphatic and aromatic region in the 1H NMR spectrum (CDCl3, 25 °C) of alkoxide complex 20 and its dichloride precursor 6 showing different splitting patterns for methylene heterocycle protons and ethylene backbone protons.    Attempts to grow single crystals of these alkoxides were largely unsuccessful. Growing crystals of thiomorpholine-based complex 21 over a long period of time from a mixture of hexanes and THF resulted in an aggregate decomposition product (Figure 5.6), further 142  exemplifying the instability of these monoalkoxide chloride complexes (as well as bisalkoxides) in solution over time.       Figure 5.6. Molecular structure of the aggregate complex product of the decomposition of 21 in solution. Depicted with ellipsoids at 50% probability (H atoms omitted for clarity).  5.2.2 Hemilabile behaviour of neutral indium chloride complexes As previously indicated, compounds 6 and 7 show splitting of morpholine and thiomorpholine methylene protons respectively by 1H NMR spectroscopy, indicating a coordination of the ether 143  and thioether moieties to the metal centers. This coordination is labile by temperature and reversible. For example, complex 6 experiences decoordination of the morpholine ring between 85 and 145 °C (Figure 5.7). Similarly, complex 7 displays decoordination of the thiomorpholine ring between 55 and 115 °C (Appendix, Figure C.2).  Figure 5.7. Variable Temperature (VT) 1H NMR spectrum (C6D5Br) of complex 6. Signals assigned to morpholine  methylene protons are assigned in red.    In addition to temperature-induced hemilability, complex 6 also shows solvent-dependent behaviour, as the 1H NMR spectrum showed in d8-THF only two equivalent signals for the 144  morpholine ring methylene signals (just as in the proligand), indicating non-coordination of the terminal ether group in solution due to coordination of d8-THF molecules (Appendix, Figure C.3), indicating great flexibility of the ligand scaffold in the presence of a potentially coordinating monomer. Trying to assert coordination de-coordination of the hemilaabile side-group in the presence of pyridine led to a mixture of decomposition products that could not be resolved.    5.2.3 Homopolymerization of cyclic esters by neutral indium complexes Initially, monoalkoxide compounds 19-22 were studied for the diluted (6.0 mM) polymerization of rac-LA in CD2Cl2 (Table 5.1). Surprisingly, lactide polymerization proceeded in a matter of hours reaching high conversions for all these compounds. Analysis of the polymer products precipitated with cold methanol reveals a good agreement of the experimental and theoretical molecular weights (calculated from conversions and monomer to initiator ratio) in all cases, with very low molecular weight dispersities (Đ ≤ 1.1). This was the case regardless the partial impurity of some of these compounds (~ 10-20% bisalkoxide side-product). The main difference between the alkoxide compounds was their apparent rate of polymerization, with compounds 19 and 22 showing the highest reactivity after 24 hours (Table 5.1, entries 1 and 10), followed by thiomorpholine complex 21 (Table 5.1, entry 8) and then morpholine complex 20 (Table 5.1, entry 3) showing the lowest conversion after the same time. The fact that compounds 19 and 22  show similar reactivity is probably related to the absence of any side coordinating groups in both of these complexes.  Coordination of an ether or thioether side-group on 20 and 21 seems to make the polymerization more sluggish by blocking lactide coordination and ROP, but without affecting 145  the control over the molecular weight or inducing higher transesterification. This blocking effect is more pronounced for an ether group (morpholine in 20) than for a thioether group (thiomorpholine in 21), revealing stronger coordination of the former to the indium center. VT NMR study of the dichloride morpholine precursor 6 and dichloride thiomorpholine precursor 7 also correlates with this observation (see above).    Table 5.1.  Homopolymerization of lactide with neutral indium species   Initiator (I) equiv. LA time (h) Conv.a (%) Mn theob  (Da) Mnc  (Da) Đc 1 19 130 24 99 18,550 16,600 1.05 2 120 100 18,737 17,180 1.10 3   20  124 22 74 13,200 15,250 1.07 4 92 100 17,872 17,200 1.09 5 330 16 46 21,288 22,120 1.06 6 23 60 28,538 27,610 1.05 7 89 98 46,612 40,720 1.04 8 21 139 24 94 18,832 16,850 1.02 9 120 98 19,633 17,360 1.02 10 22 150 24 97 20,971 22,740 1.08 11 67 100 21,620 23,840 1.09 12d 6 60 4 73 8,648 6,437,000 2.51  Reactions were performed in dichloromethane under a nitrogen atmosphere at 25 °C. [I]0 = 5.0 mM. aMonomer conversion was determined by 1H NMR spectroscopy. bDetermined on the basis of 144 gmol-1 × equiv. × conv. LA. c Determined by GPC measurements in  THF. dReaction was run under neat conditions (no solvent) at 130 °C.   CH2Cl2, 25 ℃OOOO(±) OOOOx[I]146  Running the polymerization reactions for longer times does not seem to induce any transesterification or depolymerization in any of the systems (Table 5.1, entries 2, 4, 9 and 11). Dichloride morpholine compound 6 was also tested for LA polymerization under melt (high temperature) conditions (Table 5.1, entry 12). The resulting molecular weight of the product evidenced a very low initiation efficiency (around 1%, as shown by the ratio between theoretical and experimental molecular weights), which is in line with previous findings that metal-alkoxide bonds are better initiators for lactide polymerization than metal-halide bonds.16  Homodecoupling 1H{1H} experiments reveal that the PLA samples generated by neutral indium catalysts 19-22 (Table 5.1) are all basically atactic, evidencing no particular effect of the different potential hemilabile side-groups on the polymerization stereoselectivity (Appendix, Figure B.48).  Homopolymerization of ε-CL with alkoxide complexes turned out to be much faster than LA homopolymerization (Table 5.2), reaching high conversions in 20-40 minutes. However, the control over the ROP was significantly diminished, with molecular weights that were higher than their theoretical values based on conversion and monomer to initiator ratio. In the case of complex 22 a product with bimodal molecular weight distribution was obtained (Table 5.2, entry 6). The reaction of the indium alkoxide species with caprolactone of ε-CL is also significantly affected by transesterification, with a great increase in dispersity after 20 hours of reaction (Table 5.2, entries 2 and 5).     147  Table 5.2.  Homopolymerization of caprolactone with neutral indium species   Initiator (I) equiv. CL time (min) Conv.a (%) Mn theob  (Da) Mnc  (Da) Đc 1 19 407 20 91 43,668 61,070 1.06 2 1,200 99 45,990 69,770 2.34 3 20 137 30 100 15,637 20,470 1.26 4 411 20 78 36,591 60,070 1.03 5 1,200 99 46,442 95,360 1.76 6 22 353 30 100 40,291 64,640d 1.28  Reactions were performed in dichloromethane under a nitrogen atmosphere at 25 °C. [I]0 = 2.5 mM. aMonomer conversion was determined by 1H NMR spectroscopy. bDetermined on the basis of 114 gmol-1 × equiv. × conv. CL. c Determined by GPC measurements in  THF. ddisplayed pronounced shoulder in the GPC trace   Decreasing the number of equivalents of ε-CL and keeping short reaction times improved the control over the polymerization with a better agreement between experimental and theoretical molecular weights (Table 5.2, entry 3). For this reason, the copolymerization experiments between lactide and ε-caprolactone (see below) were set up with less than 200 equivalents of monomer and kept at lower reaction times in order to prevent extensive transesterification affecting the synthesis of block copolymers. The preliminary homopolymerization results suggest that block or "blocky" copolymers of ε-CL and rac-LA should form with either 19 or 21 either by sequential addition of monomers or by simultaneous addition, due to the significantly different reactivity ratio of the monomers.  CH2Cl2, 25 ℃[I]OOO xO148  5.2.4 Copolymerization of cyclic esters by neutral indium complexes To allow for a direct comparison of the effect of a hemilabile side-group on the controlled synthesis of polyester block copolymers, complexes 19 and 20 were employed under the same conditions for the copolymerization of ε-CL and rac-LA by a sequential and simultaneous addition of monomers. These complexes were also chosen for the synthesis of block copolymers because they could be purified and separated from the small fraction of bisalkoxide compound present with the monoalkoxides. To start, the sequential polymerization of cyclic esters was explored (Table 5.3), either with the initial polymerization (M1) of rac-LA or ε-CL and followed by the addition of the opposite monomer (M2). Interestingly, polymerizations that started with ε-CL (forming PCL) in dichloromethane followed by rac-LA addition (also a solution in dichloromethane), gave relatively high sequential conversions for both monomers, resulting in polymer samples with a good agreement between experimental and theoretical molecular weight (Table 5.3, entries 1 and 3). Analysis of the isolated copolymers by quantitative 13C{1H} NMR spectroscopy reveals only signals corresponding to LA-LA and CL-CL diads for both initiators (Appendix, Figures C.8 and C.9), confirming the formation of discrete blocks and no inter-block transesterification, typical of uncontrolled systems. However, analysis by DOSY NMR spectroscopy reveals that initiator 19 produces block copolymers by sequential addition (Appendix, Figure C.4), while initiator 20 produces a mixture of homopolymers (Appendix, Figure C.5). In the later case, this is clearly evidenced by the different diffusion coefficients found for the different polyester segments in solution.       149  Table 5.3.  Sequential copolymerization of cyclic esters with neutral indium species    Initiator  (I) M1 equiv. M1 time  (h) Conv.  M1a  (%) M2 equiv. M2 time   (h) Conv.  M2a   (%) Mn theob  step I + II (Da) Mnc  (Da) Đc 1 19 CL 140 1 100 LA 124 4 87    6 94 32,779 35,580 1.11 2 19 LA 124 24 100 CL 140 20 0 17,872 14,490 1.01 3 20 CL 140 1 100 LA 124 4 17    25 63 27,239 31,870 1.27 4 20 LA 124 96 70 CL 140 20 0 12,510 9,008 1.02  All reactions were carried out under a nitrogen atmosphere in CH2Cl2 at 25 °C. [I]0 = 2.5 mM. aMonomer conversion determined by 1H NMR spectroscopy. bDetermined  on the basis of (144 gmol-1 × 124 × conv. LA) + (114 gmol-1 × 140 × conv. CL). cDetermined by GPC measurements in THF.       150  The reason why complex 20 with morpholine side-group gives a mixture of homopolymers by sequential addition of ε-CL (M1) and rac-LA (M2) may be explained by its relatively low initiation efficiency in the polymerization of caprolactone and subsequent rather slow polymerization of rac-LA (hemilabile side-group blocking lactide coordination and ROP). In comparison, complex 19 is faster at polymerizing both monomers due to the absence of steric hindrance and seems to have a higher initiation efficiency. The sequential polymerization with reverse order: i.e. starting with rac-LA and followed by addition of ε-CL only yielded PLA for both complexes (Table 5.3, entries 2 and 4). This is a common feature of sequential polymerization of lactide and caprolactone with metal-based systems and can be attributed to the formation of a stable lactyl chelate that is not reactive towards the polymerization of other cyclic esters.140, 142, 277    The copolymerization of cyclic esters with simultaneous addition of monomers was also explored (Table 5.4). Interestingly, the presence of the hemilabile group in complex 20 made impossible the formation of block copolymers (Table 5.4, entry 2). Despite the significant rate differences, LA was polymerized first and its conversion plateaued below 60% after 3 days, indicating catalyst decomposition under these conditions. No conversion of CL was detected in those 3 days. In sharp contrast to complex 20, complex 19 had a much higher rate of LA polymerization and once it reached 95%, only a partial conversion of CL was observed (9%). Once LA was fully consumed, CL conversion ramped up quickly, reaching high conversions (Table 5.4, entry 1). This reactivity profile is consistent with the formation of gradient "blocky" copolymers. As expected, analysis of copolymers by quantitative 13C{1H} NMR reveals the presence of small CL-LA triads (Appendix, Figure C.10). Using known formulas,138, 278 the calculated average block lengths were found to be LC = 7 and LL = 14. These values did not 151  change over extended reaction times, indicating no inter block transesterification with this system.  Table 5.4.  Simultaneous copolymerization of cyclic esters by neutral indium species   Initiator (I) equiv. LA equiv. CL time (min) Conv. LAa (%) Conv. CLa (%) Mn theob  (Da) Mnc  (Da) Đc 1 19 124 140 30 54 0    180 95 9    1,560 100 94 32,893 24,400 1.97 4,320 100 96 33,212 20,600 2.11 2 20 30 16 0    180 36 0    1,560 55 0    4,320 55 0 9,830 7,594 1.03  Reactions were performed in dichloromethane under a nitrogen atmosphere at 25 °C. [I]0 = 2.5 mM. aMonomer conversion was determined by 1H NMR spectroscopy. bDetermined on the basis of (144 gmol-1 × 124 × conv. LA) + (114 gmol-1 × 140 × conv. CL). c Determined by GPC measurements in  THF.   Analysis by DOSY NMR spectroscopy (Appendix, Figures C.6 and C.7) reveals that initiator 19 also produces blocky copolymers by simultaneous addition of monomers and this is the case for both the sample run for 26 h and for 3 days (Table 5.4, entry 1). Thermal analysis of these samples by DSC shows a melting temperature typical for PCL, further confirming the blocky structure in this case, but slightly lower compared to the one obtained in the sequential addition experiment (Appendix, Figures C.11 and C.12). OOOOOO(±) +CH2Cl2, 25 ºC[I]O OO yOOOx152  5.3 Conclusions In summary, a series of neutral indium monoalkoxide complexes (19-22) was synthesized by salt methatesis of dichloride precursors with potassium tertbuoxide. The isolation of clean products proved to be difficult due to the presence of a small amount of bisalkoxide side-products that were difficult to remove. Fortunately, monoalkoxide complexes 19 and 20 could be obtained in a clean manner through extensive washings with non-polar solvents. All complexes show activity towards the ROP of rac-LA, displaying good control of the molecular weights. The apparent rates of rac-LA polymerization followed the order 19 (no hemilabile side-group) ≈ 22 (methyl piperazine side-group) > 21 (thiomorpholine side-group) > 20 (morpholine side-group), indicating a higher reactivity of complexes unsupported by side-donors vs those with additional coordinating groups. In comparison to monoalkoxide complexes, dichloride complex 6 displayed a very poor activity in the ROP of rac-LA. Polymerization of ε-CL with monoalkoxides complexes 19, 20 and 22 displayed a higher reactivity at the expense of polymerization control. Employing monoalkoxide complexes 19 and 20 for the synthesis of polyester block copolymers revealed an interesting effect. Only complex 19 allowed the formation of block copolymers through sequential addition of ε-CL (first monomer, M1) and then rac-LA (second monomer, M2) and the formation of gradient block copolymers in a mixed-monomer approach. Despite having similar levels of control in the homopolymerization of monomers, complex 20 could not form block or gradient copolymers by the same methods of addition, presumably due to a less controlled ε-CL and a more sluggish rac-LA polymerization, favoring decomposition and low conversions in the copolymerization.     153  5.4 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. 1H NMR chemical shifts are reported in ppm versus residual protons in deuterated solvents as follows: 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 X8 APEX II diffraction and a Bruker APEX DUO diffraction with graphite monochromated Mo-Kα radiation. The structures were solved by direct methods and refined by full-matrix least- squares using the SHELXTL crystallographic software of Bruker-AXS. Unless specified, all non- hydrogens were refined with anisotropic displacement parameters, and all hydrogen atoms were constrained to geometrically calculated positions but were not refined. Elemental analysis (E.A.) CHN analysis 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. All ligands were prepared without air-sensitive techniques. 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 1.0 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 dn/dc (differential refractive index increment) 154  values of the polymers studied were determined by running external calibration curves or by calculation of the GPC software assuming >90% mass recovery.  Glass transition temperatures of the polymers were obtained using a differential scanning calorimeter (DSC) NETZCH DSC214 Polyma. Approximately 5−10 mg of the samples was weighed and sealed in an aluminum pan with a punctured lid. The experiments were carried out under a nitrogen atmosphere. The samples were heated at a rate of 10 °C/min from −150 to 200 °C. Thermal degradation studies were performed on a NETZCH TG 209 F1 Libra instrument. Samples were placed in an alumina crucible and heated under nitrogen at a rate of 10 °C/min from 25 to 600 °C.  Materials. Solvents (THF, diethyl ether and hexanes) were dried and vacuum- distilled over sodium, using benzophenone as an indicator and degassed through a series of freeze- pump-thaw cycles. Methanol employed in ligand synthesis was dried using 3Å molecular sieves. Toluene and DCM were dried and distilled over CaH2. Deuterated solvents (CDCl3) were dried over CaH2, collected by vacuum distillation and also degassed. Benzyl potassium was synthesized by the reaction of n-buthyl lithium with potassium tert-butoxide in cold toluene and isolated as a red solid that was washed with hexanes and dried under vacuum, according to published procedures.213 Amines N,N-dimethylethylenediamine, 1-(2-aminoethyl)piperazine and 2-(4-methylpiperazin-1-yl)-ethylamine were obtained from Sigma Aldrich and used without further purification. Amines 4-(2-aminoethyl)morpholine and 4-(2-aminoethyl)thiomorpholine were obtained from Combi-Blocks and used without further purification. Indium trichloride (InCl3) was purchased from Tokyo Chemical Industries (TCI) and used as received. Racemic lactide were purchased from Corbion, recrystallized three times from dry toluene, and finally dried 155  under vacuum for three days before use. Caprolactone was purchased from Sigma Aldrich and it was dried over CaH2, then distilled under high vaccuum and stored at −30 °C.  Synthesis of  (NMe2N*O)InCl(OtBu) (19) To a solution of (NMe2N*O)InCl2 (76.0 mg, 0.15 mmol) in THF (2 mL), a suspension of potassium tert-butoxide (20.1 mg, 0.18 mmol) in THF (3 mL) was added quickly. The reaction mixture was stirred at ambient temperature for 40 min. The reaction mixture was then quickly filtered through Celite, the filtrate was dried and washed with hexanes six times times, then with diethyl ether six times, and the redissolved in CH2Cl2, filtered through Celite and dried under vacuum to yield a yellow solid (34 mg, 42%). 1H NMR (300 MHz, CDCl3, 25 °C) δ  8.33 (1H, s, N=CH), 7.49 (1H, d, ArH), 6.85 (1H, d, ArH), 3.84 (1H, m, CH2), 3.63 (1H, m, CH2), 3.00 (1H, m, CH2), 2.81 (1H, m, CH2), 2.69 (3H, s, N-CH3), 2.54 (3H, s, N-CH3), 1.46 (9H, s, Ar-C(CH3)3), 1.38 (9H, s, C(CH3)3), 1.28 (9H, s, Ar-C(CH3)3); 13C{1H} NMR (100 MHz, CDCl3, 25 °C), 175.3, 169.9, 142.5, 136.9, 131.6, 129.5, 116.8, 70.6, 57.1, 51.2, 45.9, 45.4  35.5, 34.7, 34.0, 31.4, 29.7. Anal. Calcd (found) for C23H40InClN2O2: C 52.43 (50.95), H 7.65 (7.20), N 5.32 (5.31). Synthesis of  (NmorN*O)InCl(OtBu) (20) This complex was prepared in an analogous manner to complex 19 and washed extensively with non-polar solvents, using dichloride (NmorN*O)InCl2 (150.0 mg, 0.28 mmol) and potassium tert-butoxide (37.0 mg, 0.33 mmol). The resulting product was a yellow solid (74.5 mg, 46%). 1H NMR (300 MHz, CDCl3, 25 °C) δ  8.32 (1H, s, N=CH), 7.52 (1H, d, ArH), 6.86 (1H, d, ArH), 4.51 (1H, m, O-CH2), 4.22 (1H, m, O-CH2), 3.96 (1H, m, CH2), 3.82 (2H, m, O-CH2), 3.69 (1H, m, N-CH2), 3.59 (1H, m, CH2), 3.42 (1H, m, N-CH2), 2.99 (1H, m, CH2), 2.86 (1H, m, CH2), 156  2.47 (2H, m, N-CH2), 1.47 (9H, s, Ar-C(CH3)3), 1.37 (9H, s, C(CH3)3), 1.28 (9H, s, Ar-C(CH3)3); 13C{1H} NMR (100 MHz, CDCl3, 25 °C), 175.0, 170.2, 142.5, 137.2, 132.1, 129.5, 116.6, 71.1, 64.7, 64.5, 63.6, 58.2, 54.2, 51.1, 35.5, 34.4, 34.0, 31.4, 29.8. Anal. Calcd (found) for C25H42InClN2O3: C 52.78 (52.30), H 7.44 (7.31), N 4.92 (4.94). Synthesis of  (NthioN*O)InCl(OtBu) (21) This complex was prepared in an analogous manner to complex 19, using dichloride (NthioN*O)InCl2 (120.2 mg, 0.22 mmol) and potassium tert-butoxide (29.1 mg, 0.26 mmol). Final product had a small amount of bisalkoxide side-product that could not be removed (10-20%). The resulting product was a yellow solid (28.4 mg, 22%). 1H NMR (300 MHz, CDCl3, 25 °C) δ  8.33 (1H, s, N=CH), 7.51 (1H, d, ArH), 6.86 (1H, d, ArH), 3.95 (1H, m, CH2), 3.83 (1H, m, N-CH2), 3.74 (1H, m, N-CH2),  3.59 (1H, m, CH2), 3.29 (1H, m, S-CH2), 3.16 (1H, m, CH2), 3.07 (1H, m, CH2), 3.03 (1H, m, S-CH2),  2.92 (2H, m, N-CH2), 2.83 (2H, m, S-CH2), 1.47 (9H, s, Ar-C(CH3)3), 1.41 (9H, s, C(CH3)3), 1.29 (9H, s, Ar-C(CH3)3).  Synthesis of  (NmepipN*O)InCl(OtBu) (22) This complex was prepared in an analogous manner to complex 19, using dichloride (NmepipN*O)InCl2 (160.3 mg, 0.29 mmol) and potassium tert-butoxide (37.1 mg, 0.33 mmol).  Final product had a small amount of bisalkoxide side-product that could not be removed (10-20%). The resulting product was a yellow solid (72.6 mg, 42%). 1H NMR (300 MHz, CDCl3, 25 °C) δ  8.30 (1H, s, N=CH), 7.49 (1H, d, ArH), 6.84 (1H, d, ArH), 3.87 (1H, m, CH2), 3.74 (1H, m, N-CH2), 3.59 (1H, m, CH2), 3.48 (1H, m, N-CH2), 3.11 (1H, m, CH2), 3.00 (1H, m, N-CH2) 2.89 (1H, m, CH2), 2.82 (1H, m, N-CH2), 2.57 (4H, m, N-CH2), 2.34 (3H, s, N-CH3), 1.45 (9H, s, Ar-C(CH3)3), 1.37 (9H, s, C(CH3)3), 1.26 (9H, s, Ar-C(CH3)3).  157  Representative procedure for LA or CL homopolymerization. In a glovebox, a vial was charged with either 19, 20, 21 or 22 (12.0 mg, 0.023 mmol) and dichloromethane (1.0 mL). Then, a solution of rac-lactide (428.7 mg, 2.97 mmol) or caprolactone (1.05 g, 9.1 mmol) in dichloromethane (3.0 mL) was added to it. The reaction was stirred for some time until a high conversion was reached. The mixture was concentrated to about 1 mL and the polymer was precipitated with cold methanol (0 °C, 15 mL) and subsequently washed with more methanol. Representative procedure for LA neat homopolymerization. In a glovebox, a vial was charged with 6 (12.0 mg, 0.027 mmol) and rac-lactide (257.7 mg, 1.79 mmol). The flask was taken out of the glovebox and put in an oil bath to stir at 130 °C. After 4 h, the reaction mixture was left to cool down and dissolved in a minimal amount of dichloromethane. The polymer was precipitated with cold methanol (0 °C, 15 mL) and subsequently washed with more methanol. Representative copolymerization of CL and LA by sequential addition of monomers. In a glovebox, a vial was charged with either 19 or 20 (4.0 mg, 0.007 mmol) and dichloromethane (1.0 mL). Then, a solution of either rac-lactide (125.7 mg, 0.87 mmol) or caprolactone (113.1 mg, 1.01 mmol) in dichloromethane (1.0 mL) was added to it. The reaction was stirred for some time until a high conversion was reached. Then, the second monomer was added in dichloromethane (1.0 mL) and the reaction was stirred for a longer time until a high conversion was reached. The mixture was concentrated to about 1 mL and the polymer was precipitated with cold methanol (0 °C, 15 mL) and subsequently washed with more methanol. Representative copolymerization of CL and LA by simultaneous addition of monomers. In a glovebox, a vial was charged with either 19 or 20 (4.0 mg, 0.007 mmol) and dichloromethane (1.0 mL). A mixture of rac-lactide (125.7 mg, 0.87 mmol) and caprolactone (113.1 mg, 1.01 mmol) in dichloromethane (2.0 mL) was added to it. The vial was stirred for 158  several days at room temperature. The solution was concentrated and the polymer sample was precipitated with cold methanol (0 °C, 15 mL) and subsequently washed with more methanol. DSC measurement of polymers. Approximately 5-10 mg of polymer was weighed and sealed in an aluminum pan. Experiments were carried out under a nitrogen atmosphere. The samples were heated at a rate of 10 °C/min from 25 to 170 °C and held isothermally for 5 min to destroy any residual nuclei before cooling at 5 °C/min. The glass transition and melting temperatures were obtained from the second heating sequence, performed at 10 °C/min.      159  Chapter 6: Conclusions and future directions The aim of this thesis was to explore the reactivity of neutral and cationic indium complexes in the ring-opening polymerization (ROP) of oxygenated monomers for the synthesis of homopolymers and copolymers with different architectures. Generally speaking, the main objectives of my research were: (1) to synthesize discrete and monometallic cationic indium complexes, (2) to study their reactivity towards different monomers and understand how their ROP reactivity can be tuned, (3) to study the effect of potentially hemilabile side groups on the ROP of cyclic esters with neutral indium complexes and (4) to explore the controlled, one-pot synthesis of oxygenated block copolymers through the sequential and simultaneous addition of monomers using different indium initiators.  The synthesis of cationic complexes can be challenging due to the high Lewis acidity of the cationic centers that needs adequate stabilization by a combination of ligand and solvent donors. In chapter 2 and 3, the synthesis of several discrete mononuclear cationic complexes bearing different counterions, ligand frameworks and stabilizing solvent donors was described as well as their reactivity towards ROP of cyclic ethers. Remarkably, this has been the first report of cationic indium species with high activity in the ROP of epoxides and their copolymerization with other cyclic ethers and lactide. The tuning of the cationic indium species allowed for the synthesis of high molecular weight copolymers. Future work can explore the induction of regio and stereoselectivity in the highly reactive cationic polymerization of epoxides. Normally, the cationic polymerization of monomers is characterized by (i) extremely fast propagation rates (vs initiation rates) and (ii) achiral active chain-ends, which often results in uncontrolled and regio-irregular polymerizations.279 However, recent progress in the field has exemplified the exertion of stereocontrol through chiral 160  counterions, particularly in the cationic polymerization of vinyl ether monomers.280-281 While the stereoselective polymerization of epoxides by coordination-insertion mechanisms is well known,7 the cationic version of this reaction can open the door to its controlled copolymerization with other monomers (e.g. vinyl ethers) and yield new materials with tailored properties. Employing a bulkier and chiral counterion might also preclude "annoying" backbiting from taking place, significantly improving control over molecular weights.  Similarly, future endeavours can also investigate the reactivity of biscationic indium species with the appropriate stabilizing ligand frameworks as a way of improving initiation efficiency in the cationic polymerization of epoxides and other monomers. The isolation of highly electrophilic biscationic Group 13 complexes and the study of their reactivity should offer interesting routes for the synthesis of different copolymers.  The synthesis of polyester-polyether block copolymers is not a straightforward procedure, requiring typically multiple steps with different catalytic systems. In chapter 4, the optimization of conditions for the synthesis of high molecular weight polyester-polyether block copolymers was presented. Mechanistic evidence was presented that supports the hypothesis of two different mechanisms taking place in the synthesis of poly(lactic acid)-polyether diblock copolymers by employing indium cationic initiators. Employing indium initiators allowed for the synthesis of block copolymers with tunable mechanical properties and potential post-functionalization.  Future efforts should focus on tackling side-reactions in these copolymerizations (i.e. transesterification and backbiting) that preclude these systems from reaching highly controlled and reaching much higher molecular weights. Additionally, the interplay of two different mechanisms with these indium initiators might be exploited for the polymerization of other monomers (e.g. cyclic carbonates, o-carboxyanhydrides), leading to new materials with tunable 161  mechanical and thermal properties. In particular, the synthesis of new amphiphilic block copolymers with biodegradable segments is of great interest in the biomedical field.54  The synthesis of discrete neutral indium complexes can be challenging due to their high tendency to form aggregates. In chapter 5 and part of chapter 2, new discrete neutral indium complexes with potentially hemilabile side groups were reported and their activity towards cyclic ester polymerization was explored. Preliminary results indicate that for this particular family of complexes, the presence of additional coordinating side-groups makes the polymerization more sluggish (with a stronger effect for strongly coordinated donors) and it even precludes the formation of block copolymers by either a sequential addition or mixed-monomer (simultaneous addition) approach.  Future complementary work can make use of PGSE (pulse field gradient spin-echo) NMR spectroscopy to determine nuclearity of these complexes in solution. This will help to better understand differences of reactivity in these systems (i.e. if the differences of reactivity are related to metal complex aggregation involving the hemilabile side-group). The observation in chapter 4 that triphenyl phosphine could accelerate lactide polymerization with a cationic indium initiator, as well as previous literature reports describing the effect of added donors on tin(II) octanoate, suggested that hemilabile donors can potentially accelerate the rate of cyclic ester polymerizations. Although the findings on chapter 5 show this might not be the case, a bigger family of ligand frameworks with more donors should be studied in order to draw a more robust conclusion.    Additionally, the formation of cationic indium alkoxide species can be explored by halide abstraction from the neutral indium alkoxide species here presented. While neutral indium alkoxides are known to be highly active in ROP and ROCOP reactions, it is not clear weather 162  cationic indium alkoxide species will follow a cationic or a coordination-insertion mechanism in the polymerization of different monomers. 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Soc. 2020, 142, 17175-17186.      174  Appendices Appendix A   Figure A.1. 1H NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THF)2][SbF6] (rac-11)    175   Figure A.2. 13C{1H} NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THF)2][SbF6] (rac-11)    176   Figure A.3. 19F{1H} NMR spectrum (CD3CN, 25 °C) of rac-[(ONNO)In(THF)2][SbF6] (rac-11)          177   Figure A.4. 1H NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THF)2][PF6] (rac-9)        178   Figure A.5. 13C{1H} NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THF)2][PF6] (rac-9)    Figure A.6. 19F{1H} NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THF)2][PF6] (rac-9)  179   Figure A.7. 1H NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THF)2][AsF6] (rac-10)        180   Figure A.8. 13C{1H} NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THF)2][AsF6] (rac-10)          181   Figure A.9. 1H NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(Me-THF)2][SbF6] (rac-13)         182   Figure A.10. 13C{1H} NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(Me-THF)2][SbF6] (rac-13)         183   Figure A.11. 1H NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THP)2][SbF6] (rac-14)        184   Figure A.12. 13C{1H} NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(THP)2][SbF6] (rac-14)         185   Figure A.13. 1H NMR spectrum (CDCl3, 25 °C) of (R,R)-[(ONNO)In(THF)2][SbF6] ((R,R)-11)            186   Figure A.14. 1H NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(OEt2)2][BArF4] (rac-17)          187   Figure A.15. 13C{1H} NMR spectrum (CDCl3, 25 °C) of rac-[(ONNO)In(OEt2)2][BArF4] (rac-17)           188    Figure A.16. 19F{1H} NMR spectrum (CH3CN, 25 °C) of rac-[(ONNO)In(OEt2)2][BArF4] (rac-17)             189   Figure A.17. 1H NMR spectrum (CDCl3, 25 °C) of (S,S)-[(ONNO)In(OEt2)2][BArF4] ((S,S)-17)           190   Figure A.18. 1H NMR spectrum (CDCl3, 25 °C) of [(ONArNO)In(OEt2)2][BArF4] (18)            191    Figure A.19. 13C{1H} NMR spectrum (CDCl3, 25 °C) of [(ONArNO)In(OEt2)2][BArF4] (18)            192    Figure A.20. 19F{1H} NMR spectrum (CH3CN, 25 °C) of [(ONArNO)In(OEt2)2][BArF4] (18)          193    Figure A.21. 1H NMR spectrum (CDCl3, 25 °C) of (NMe2N*NO)InCl2 (5)            194   Figure A.22. 13C{1H} NMR spectrum (CDCl3, 25 °C) of (NMe2N*NO)InCl2 (5)           195   Figure A.23. 1H NMR spectrum (CDCl3, 25 °C) of (NmorN*NO)InCl2 (6)            196   Figure A.24. 13C{1H} NMR spectrum (CDCl3, 25 °C) of (NmorN*NO)InCl2 (6)            197   Figure A.25. HSQC NMR spectrum (CDCl3, 25 °C) of (NmorN*NO)InCl2 (6)          198   Figure A.26. HMBC NMR spectrum (CDCl3, 25 °C) of (NmorN*NO)InCl2 (6)          199   Figure A.27. 1H NMR spectrum (CDCl3, 25 °C) of (NthioN*NO)InCl2 (7)           200   Figure A.28. 13C{1H} NMR spectrum (CDCl3, 25 °C) of (NthioN*NO)InCl2 (7)           201    Figure A.29. 1H NMR spectrum (CDCl3, 25 °C) of (NmepipN*NO)InCl2 (8)          202    Figure A.30. 13C{1H} NMR spectrum (CDCl3, 25 °C) of (NmepipN*NO)InCl2 (8)          203   Figure A.31. 1H NMR spectrum (CDCl3, 25 °C) of (NNMe2N*NO)InCl(OtBu) (19)           204   Figure A.32. 13C{1H} NMR spectrum (CDCl3, 25 °C) of (NNMe2N*NO)InCl(OtBu) (19)          205   Figure A.33. 1H NMR spectrum (CDCl3, 25 °C) of (NmorN*NO)InCl(OtBu) (20)            206   Figure A.34. 13C{1H} NMR spectrum (CDCl3, 25 °C) of (NmorN*NO)InCl(OtBu) (20)           207   Figure A.35. 1H NMR spectrum (CDCl3, 25 °C) of (NthioN*NO)InCl(OtBu) (21)           208   Figure A.36. 1H NMR spectrum (CDCl3, 25 °C) of (NmepipN*NO)InCl(OtBu) (22)           209  Table A.1. Selected crystallographic parameters of X-ray structures in chapter 2                          6 7 8 7' empirical formula C21H33N2O2InCl2 C21H33N2OSInCl2 C22H36N3OInCl2 C25H41N2O2SInCl2 Fw 531.23 547.29 544.27 619.40 T (K) 90 173 100 173 a (Å) 9.9999(11) 27.590(3) 28.626(2)  15.6035(18) b (Å) 16.0874(17) 18.283(2) 18.2534(15)  13.8840(17) c (Å) 18.8421(19) 9.6891(11) 9.5987(8)  25.667(3) α (deg) 90 90 90 90 β (deg) 99.016(3) 90 90 90 γ (deg) 90 90 90 90 volume (Å3) 2993.7(5) 4887.5(9) 5015.5(7) 5560.5(11)  Z 4 8 8 8 crystal system monoclinic orthorhombic orthorhombic orthorhombic space group P 21/c  A b a 2 A b a 2 P b c a dcalc (g/cm3) 1.367 1.487 1.442 1.480 μ (MoKα) (cm-1) 11.65 12.85 11.73 11.42 2θmax (deg) 60.188 61.074 61.096 60.102 absorption correction (Tmin, Tmax) 0.705,  0.792 0.779, 0.926 0.800, 0.849  0.735, 0.882 total no. of reflections 74640 44399 38728 8129 no. of indep reflections (Rint) 8778 7466 7603 8129 residuals (refined on F2, all data): R1; wR2 0.0226; 0.0481 0.0378; 0.0587 0.0179; 0.0385 0.0414; 0.0677 GOF 1.085 1.043 1.030 1.097 no. observations [I > 2s(I)] 8156 6471 7367 6501 210  Table A.2. Selected crystallographic parameters of X-ray structures in chapter 2          rac-1 (R,R)-1' rac-11 rac-12 rac-9' empirical formula C52H96In2N2O2Si4 C40H63InN2O2Si C44H68InN2O4 SbF6 C44H68InN2O4 BF4 C41H63InN3O3 PF6 Fw 1123.33 746.86 1039.61 890.66 1013.63 T (K) 296 173 100(2) 100(2) 100(2)  a (Å) 15.976(4) 10.3569(7) 27.115(3) 9.2636(12) 38.279(5)  b (Å) 21.444(5) 14.1857(10) 10.3591(9) 15.978(2) 15.4120(19)  c (Å) 18.444(5) 14.6869(10) 41.932(4) 16.814(2) 17.904(2)  α (deg) 90 95.322(2) 90 78.475(5) 90 β (deg) 102.782(5) 102.051(2) 102.098(6) 85.242(5) 100.866(4)  γ (deg) 90 106.332(2) 90 82.119(5) 90 volume (Å3) 6162(3) 1998.6(2) 11517(2) 2411.7(6) 10373(2)  Z 4 2 8 2 8 crystal system monoclinic triclinic monoclinic triclinic monoclinic space group P 21/c P-1 C2/c  P -1 C2/c  dcalc (g/cm3) 1.211 1.241 1.199 1.326 1.298 μ (MoKα) (cm-1) 8.61 6.55 9.22 5.44 5.42 2θmax (deg) 60.80 61.058 44.956 47.18 55.22 absorption correction  (Tmin, Tmax) 0.856,  0.918 0.835, 0.866 0.666, 0.746 0.673, 0.745 0.388, 0.746 total no. of reflections 92882 58548 60 629 15 110 51 203 no. of indep reflections  (Rint) 18306 22687 7517 (0.0503) 6 891 (0.0528) 11 949 (0.0772) residuals (refined on F2,  all data): R1; wR2 0.094; 0.0515 0.0306; 0.0674 0.1601, 0.3220 0.0871, 0.1733 0.0699, 0.1763 GOF 1.019 1.028 1.031 1.002 1.030 no. observations  [I > 2s(I)] 3314 20999 13282 6099 11 949 211  Appendix B   Figure B.1. 1H NMR spectrum of the copolymerization product of THF and 1,2-epoxy-5-hexene (400 MHz, CDCl3, 25 °C).      212   Figure B.2. 1H NMR spectrum of the copolymerization product of THF and ECH (400 MHz, CDCl3, 25 °C).         213   Figure B.3. 1H NMR spectrum of the copolymerization product of oxetane and ECH (400 MHz, CDCl3, 25 °C).         214   Figure B.4. 1H NMR spectrum of the copolymerization product of oxepane and ECH (400 MHz, CDCl3, 25 °C).         215   Figure B.5. Methine and methylene regions of the 13C{1H}  spectrum (101 MHz, CDCl3, 25°C) of the isolated products from the ROP of racemic propylene oxide in neat conditions at 25 °C with rac-11 (bottom) and with (R,R)-11 (top).    Figure B.6. Methine and methylene regions of the 13C{1H} spectrum (101 MHz, CDCl3, 25°C) of the isolated products from the ROP of R-(+)-propylene oxide in neat conditions at 25 °C with rac-17 (top) and with (S,S)-17 (bottom).   216   Figure B.7. PLA methine and polyether region in the 1H NMR spectrum of the copolymerization product of lactide and ECH by rac-11 under melt conditions (400 MHz, CDCl3, 25 °C).        217   Figure B.8. Long range 1H-1H COSY spectrum of the copolymerization product of lactide and ECH by rac-11 under melt conditions (400 MHz, CDCl3, 25 °C).       218   Figure B.9. DOSY-NMR (400 MHz, CDCl3, 25 °C) of the copolymerization product of rac-lactide and epichlorohydrin by rac-17 under melt conditions.   Figure B.10. DOSY-NMR (400 MHz, CDCl3, 25 °C) of the copolymerization product of THF and epichlorohydrin.  219   Figure B.11. DOSY-NMR (400 MHz, CDCl3, 25 °C) of the copolymerization product of oxetane and epichlorohydrin.   Figure B.12. DOSY-NMR (400 MHz, CDCl3, 25 °C) of the copolymerization product of oxepane and ECH. 220   Figure B.13. GPC traces of the polymers product of homopolymerization of epichlorohydrin (blue) and copolymerization of epichlorohydrin and THF (red).    Figure B.14. GPC traces of the polymers product of homopolymerization of epichlorohydrin (blue) and copolymerization of epichlorohydrin and oxetane (green).  221   Figure B.15. GPC traces of the polymers product of homopolymerization of epichlorohydrin (blue) and copolymerization of epichlorohydrin and oxepane (purple).    Figure B.16. GPC traces of the polymers product of copolymerization of 200 equiv. of ECH with 262 equiv. of rac-LA (orange) and with 653 equiv. of rac-LA (light blue). Polymerizations were carried out with rac-11 under melt conditions. 222   Figure B.17. GPC traces of the polymerization of E5H (100 equiv.) with rac-11 at room temperature (bottom left) and at 80 °C (bottom right). Subsequent addition of another 100 equiv. to the same system still produces conversion, but no change in the molecular weight of the product at room temperature (top left) and a bimodal distribution with higher molecular weight at 80 °C (top right).      223    Figure B.18. 1H NMR spectrum (400 MHz, CDCl3, 25 °C) of isolated polymer product of sequential copolymerization of ECH and rac-LA using initiator rac-17 at room temperature.       224   Figure B.19. 1H NMR spectrum (400 MHz, CDCl3, 25 °C) of isolated polymer product of sequential copolymerization of E5H and rac-LA using initiator rac-17 at room temperature.      225   Figure B.20. 1H NMR spectrum (400 MHz, CDCl3, 25 °C) of isolated polymer product of sequential copolymerization of DMEB and rac-LA using initiator rac-17 at room temperature.      226   Figure B.21. DOSY-NMR (400 MHz, CDCl3, 25 °C) of P[(ECH)0.53-b-(LA)0.47] synthesized by sequential addition using rac-17 at room temperature.    Figure B.22. DOSY-NMR (400 MHz, CDCl3, 25 °C) of P[(DMEB)0.55-b-(LA)0.45] synthesized by sequential addition using rac-17 at room temperature. 227   Figure B.23. DOSY-NMR (400 MHz, CDCl3, 25 °C) of P[(E5H)0.49-b-(LA)0.51] synthesized by sequential addition using rac-17 at room temperature.    228   Figure B.24. DSC thermogram of the polymer product of copolymerization of epichlorohydrin and THF.   Figure B.25. DSC thermogram of the polymer product of copolymerization of epichlorohydrin and oxetane.   229   Figure B.26. DSC thermogram of the polymer product of copolymerization of epichlorohydrin and oxepane.   Figure B.27. DSC thermogram of P[(ECH)0.53-b-(LA) 0.47] synthesized by sequential addition using rac-17 at room temperature.  230   Figure B.28. DSC thermogram of P[(ECH)0.43-b-(LA) 0.57] synthesized by sequential addition using rac-17 at room temperature.  Figure B.29. DSC thermogram of P[(E5H)0.49-b-(LA) 0.51] synthesized by sequential addition using rac-17 at room temperature.  231   Figure B.30. DSC thermogram of P[(E5H)0.38-b-(LA) 0.62] synthesized by sequential addition using rac-17 at room temperature  Figure B.31. DSC thermogram of P[(DMEB)0.55-b-(LA) 0.45] synthesized by sequential addition using rac-17 at room temperature  232   Figure B.32. DSC thermogram of P[(DMEB)0.41-b-(LA) 0.59] synthesized by sequential addition using rac-17 at room temperature  Figure B.33. TGA plot of P[(ECH)0.53-b-(LA)0.47]synthesized by sequential addition using rac-17 at room temperature.  233   Figure B.34. TGA plot of P[(E5H)0.49-b-(LA)0.51] synthesized by sequential addition using rac-17 at room temperature.  Figure B.35. TGA plot of P[(DMEB)0.55-b-(LA)0.45] synthesized by sequential addition using rac-17 at room temperature. 234    Figure B.36. GPC trace of P[(ECH)0.6-b-(LA)0.4] synthesized by sequential addition using rac-17 at room temperature.   Figure B.37. GPC trace of P[(E5H)0.6-b-(LA)0.4] synthesized by sequential addition using rac-17 at room temperature. 235    Figure B.38. GPC trace of P[(DMEB)0.6-b-(LA)0.4] synthesized by sequential addition using rac-17 at room temperature.             236   Figure B.39. First order kinetic plots (3 different replicates) for the polymerization of E5H by [(ONNO)In(THF)2][SbF6] (rac-11) at 50 °C. [I]0 = 27.3 mM, [E5H]0 = 2.73 M. The ROP reaction was monitored by 1H NMR spectroscopy.   237   Figure B.40. First order kinetic plots (3 different replicates) for the polymerization of E5H by [(ONNO)In(Me-THF)2][SbF6] (rac-13) at 50 °C. [I]0 = 27.3 mM, [E5H]0 = 2.73 M. The ROP reaction was monitored by 1H NMR spectroscopy.         238   Figure B.41. First order kinetic plots (3 different replicates) for the polymerization of E5H by [(ONNO)In(THP)2][SbF6] (rac-14) at 50 °C. [I]0 = 27.3 mM, [E5H]0 = 2.73 M. The ROP reaction was monitored by 1H NMR spectroscopy.          239   Figure B.542. First order kinetic plots for the polymerization of LA by (S,S)- [(ONNO)In(Et2O)2][ BArF4] ((S,S)-17) in CD2Cl2 at 25 °C after initial ECH polymerization (255 equiv.). [I]0 = 4.3 mM, [LA]0 = 0.55 M. The ROP reaction was monitored by 1H NMR spectroscopy.           240   Figure B.43. First order kinetic plots for the polymerization of LA by rac- [(ONNO)In(Et2O)2][ BArF4] (rac-17) in CD2Cl2 at 25 °C after initial ECH polymerization (255 equiv.). [I]0 = 4.3 mM, [LA]0 = 0.55 M. The ROP reaction was monitored by 1H NMR spectroscopy.           241   Figure B.44. 1H{1H} spectrum (CDCl3, 25°C) of the methine region for isolated polymer synthesized by sequential copolymerization of ECH and rac-LA using initiator rac-17.  242   Figure B.45. 1H{1H} spectrum (CDCl3, 25°C) of the methine region for isolated polymer synthesized by sequential copolymerization of ECH and rac-LA using initiator 19.          243        Figure B.46. Stress-strain curves at room temperature for PLA and block copolymers with a higher proportion of PLA units than polyether units.      244    Figure B.47. Stress-strain curves at room temperature for PLA and block copolymers with a higher proportion of polyether units than PLA units.       245              Figure B.48. 1H{1H} spectra (CDCl3, 25°C) of the methine region for isolated PLA polymers synthesized by initiators 19 (top left), 20 (top right), 21 (bottom left) and 22 (bottom right).   246   Figure B.49. 1H NMR spectrum (400 MHz, DMSO-d6, 25 °C) of P[(ECH)0.53-b-(LA)0.47] before (bottom) and after (top) 24 h of reaction with NaN3.         247  Appendix C   Figure C.1. 1H NMR spectrum (CDCl3, 25 °C) of rac-[(NMe2NO)In(THF)Cl][SbF6] (rac-16)         248   Figure C.2. VT 1H NMR spectrum (C6D5Br) of (NthioN*O)InCl2 (7)          249   Figure C.3. 1H NMR spectrum (THF-d4, 25 °C) of (NmorN*O)InCl2 (6)           250   Figure C.4. DOSY-NMR (400 MHz, CDCl3, 25 °C) of the copolymer from the sequential polymerization of CL and rac-LA by 19 at room temperature (Table 5.3, entry 1).           251   Figure C.5. DOSY-NMR (400 MHz, CDCl3, 25 °C) of the copolymer from the sequential polymerization of CL and rac-LA by 20 at room temperature (Table 5.3, entry 3).         252   Figure C.6. DOSY-NMR (400 MHz, CDCl3, 25 °C) of the copolymer from the simultaneous polymerization of CL and rac-LA by 19 at room temperature after 26 hours (Table 5.4, entry 1).         253    Figure C.7. DOSY-NMR (400 MHz, CDCl3, 25 °C) of the copolymer from the simultaneous polymerization of CL and rac-LA by 19 at room temperature after 3 days (Table 5.4, entry 1).         254    Figure C.8. Quantitative 13C{1H}  spectrum (101 MHz, CDCl3, 25°C) of the copolymer from the sequential polymerization of CL and rac-LA by 19 at room temperature (Table 5.3, entry 1).  255   Figure C.9. Quantitative 13C{1H}  spectrum (101 MHz, CDCl3, 25°C) of the copolymer from the sequential polymerization of CL and rac-LA by 20 at room temperature (Table 5.3, entry 3).        256    Figure C.10. Quantitative 13C{1H}  spectrum (101 MHz, CDCl3, 25°C) of the copolymer from  the simultaneous polymerization of CL and rac-LA by 19 at room temperature after 26 hours (Table 5.4, entry 1).     257   Figure C.11. DSC thermogram of the copolymer from the sequential polymerization of CL and rac-LA by 19 at room temperature (Table 5.3, entry 1).          258   Figure C.12. DSC thermogram of the copolymer from  the simultaneous polymerization of CL and rac-LA by 19 at room temperature after 26 hours (Table 5.4, entry 1).     

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