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Yttrium amidate complexes for the catalytic synthesis of biodegradable polymers and amides Thomson, Jaclyn Alexa 2013

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YTTRIUM AMIDATE COMPLEXES FOR THE CATALYTIC SYNTHESIS OF BIODEGRADABLE POLYMERS AND AMIDES  by  Jaclyn Alexa Thomson B.Sc. (Honours), University of Victoria, 2007  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY  in  The Faculty of Graduate Studies (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) April 2013 © Jaclyn Alexa Thomson, 2013  Abstract Yttrium complexes are highly attractive systems for use in catalysis due to their high activity, low cost, and low toxicity. The highly modular amidate ligand set allows for easy variation of steric and electronic properties and, therefore, the reactive metal complex. This thesis explores the synthesis of yttrium amidate complexes and their use as catalysts in a variety of catalytic transformations. Mono-, bis-, and tris(amidate) complexes of yttrium are highly active initiators for the ring-opening polymerization of rac-lactide, yielding PLA with high molecular weight and narrow polydispersity. Termination of this polymerization is proposed to occur through formation of cyclic PLA with large ring sizes, once the monomer is consumed. Reaction of additional monomer is, therefore, not possible, and the polymerization is not living. The mechanical properties of the poly(ε-caprolactone) synthesized using tris(amidate) complexes of yttrium were determined to be consistent with those of commercially available polymer samples. Rheological testing of prepared poly(ε-caprolactone) suggested the possible formation of polymers with long-chain branching. However, the formation of long-chain branching in the poly(ε-caprolactone), synthesized with the tris(amidate) complex containing the naphthyl substituent, could not be confirmed or wholly refuted based on traditional chemical analyses. One yttrium tris(amidate) complex was also found to initiate the ring-opening polymerization of ε-caprolactone and rac-lactide to form diblock PCL/PLA copolymers. The mono-, bis-, and tris(amidate) complexes of yttrium are also highly active catalysts in the mild amidation of aldehydes with amines. The tris(amidate) complexes were most active, catalyzing the reaction in as little as 5 minutes. The best-performing catalyst can mediate the ii  amidation of alkyl or aryl aldehydes, as well as aryl primary amines and alkyl or aryl secondary amines. This catalyst is also the first example of a rare-earth catalyst capable of tolerating pivalaldehyde in this transformation. The aforementioned class of complexes has been proven to be effective in a number of catalytic transformations. The modular synthesis of the amidate ligand, as well as the facile synthesis of yttrium amidate complexes, provide an easy means for altering the steric and electronic properties of the resulting complexes and, therefore, are ideal for further catalyst development.  iii  Preface The original experimental ideas presented in this thesis are consistent with the research interest of the Schafer group and were conceived in discussion with Dr. Laurel L. Schafer. The research presented herein was performed with supervision and mentoring by Dr. Laurel L. Schafer and assistance from some members of the Schafer group as detailed below. The synthesis of all proligands and complexes were performed by me with the exception of the polymers synthesized in Table 3.2, entries 3-7 which were synthesized by David Le, a 425student working under my supervision. The rheological experiments presented in Chapter 3 were performed by Nazbanoo Noroozi, a collaborating graduate student from the Chemical Engineering Department of UBC in the research group of Dr. Savvas Hatzikiriakos. Rheological data interpretation was done in discussion with Nazbanoo Noroozi, Dr. Savvas Hatzikiriakos, and Dr. Laurel Schafer. 600 MHz NMR spectra were run by Philippa R. Payne of the Schafer group. All other experimental research was executed by me. A portion of Chapter 3 has been published in Rheologica Acta as: Noroozi, N.; Thomson, J. A.; Noroozi, N.; Schafer, L. L.; Hatzikiriakos, S. G. “Viscoelastic behaviour and flow instabilities of biodegradable poly (ε-caprolactone) polyesters” Rheologica Acta 2012, 51, 179192. A portion of Chapter 4 has been published in Dalton Transactions published by RSC Publishing as: Thomson, J. A.; Schafer, L. L. “Yttrium (amidate) complexes for catalytic C–N bond formation. Rapid, room temperature amidation of aldehydes” Dalton Trans. 2012, 41, 7897-7904. Finally, I wrote this thesis with constructive criticism from Dr. Laurel L. Schafer.  iv  Table of Contents Abstract ........................................................................................................................................... ii Table of Contents ............................................................................................................................ v List of Figures ................................................................................................................................ ix List of Schemes ............................................................................................................................ xiii List of Tables ................................................................................................................................ xv List of Abbreviations ................................................................................................................... xvi Foreword ....................................................................................................................................... xx Acknowledgements ...................................................................................................................... xxi Chapter 1. Yttrium Chelates in Catalysis ........................................................................................ 1 1.1  Yttrium Complexes Containing N,N-, N,O-, O,O-, or N,N,O-Chelating Ligands .......... 1  1.1.1  Guanidinate Complexes of Yttrium ...................................................................... 3  1.1.2  Amidinate Complexes of Yttrium ......................................................................... 9  1.1.3  Other N,O-Chelating Complexes of Yttrium ...................................................... 16  1.2  Yttrium Amidate Complexes ......................................................................................... 23  1.3  Scope of Thesis .............................................................................................................. 32  Chapter 2. Yttrium Amidate Complexes as Rapid Initiators for the Ring-Opening Polymerization of rac-Lactide ................................................................................................................................ 34 2.1  Introduction .................................................................................................................... 34  2.1.1 2.2  Scope of Chapter ................................................................................................. 46  Yttrium Amidate Complexes as Initiators ...................................................................... 46  2.2.1  Results and Discussion ........................................................................................ 46  2.2.1.1 Comparison of Mono-, Bis-, and Tris(amidate) Complexes................................. 46 2.2.1.2 Effect of Amidate Ligand on Initiator .................................................................. 53 2.2.1.3 Effect of Monomer to Initiator Ratio[M/I] Investigations .................................... 58 v  2.2.1.4 Effect of Solvent and Temperature on Reactivity................................................. 60 2.2.1.5 Mechanistic Investigations.................................................................................... 67 2.2.1.6 Summary ............................................................................................................. 74 2.3  Conclusions .................................................................................................................... 76  2.4  Experimental .................................................................................................................. 78  2.4.1  Starting Materials and Reagents .......................................................................... 78  2.4.2  Synthesis.............................................................................................................. 79  Chapter 3. Rheological Studies of Poly(ε-caprolactone) Synthesized by the Catalytic RingOpening Polymerization of ε-Caprolactone Using Yttrium Amidate Complexes and the Synthesis of Poly(ε-caprolactone)/Polylactide Copolymers ......................................................................... 85 3.1  Introduction .................................................................................................................... 85  3.1.1  Rheology ............................................................................................................. 87  3.1.2  Copolymers ......................................................................................................... 92  3.1.3  Scope of Chapter ................................................................................................. 99  3.2  Yttrium Amidate Complexes as Initiators .................................................................... 100  3.2.1  Results and Discussion ...................................................................................... 100  3.2.1.1 Rheology of Synthetic Poly(ε-caprolactone) .................................................... 100 3.2.1.2 Effect of Initiator on Poly(ε-caprolactone) Rheology ....................................... 107 3.2.1.3 Analysis of Branched Poly(ε-caprolactone) ...................................................... 114 3.2.1.4 Degradation Analysis of Poly(ε-caprolactone) ................................................. 121 3.2.1.5 Copolymers of Poly(ε-caprolactone) and Poly(lactide) .................................... 126 3.2.1.6 Summary ........................................................................................................... 133 3.3  Conclusions .................................................................................................................. 135  3.4  Experimental ................................................................................................................ 137  3.4.1  Starting Materials and Reagents ........................................................................ 137  3.4.2  Synthesis............................................................................................................ 138 vi  Chapter 4. Yttrium Amidate Complexes as Effective Precatalysts for the Catalytic Synthesis of Amides ........................................................................................................................................ 143 4.1 Introduction ....................................................................................................................... 143 4.1.1 4.2  Scope of Chapter ............................................................................................... 147  Yttrium Amidate Complexes as Precatalysts ............................................................... 149  4.2.1  Results and Discussion ...................................................................................... 149  4.2.1.1 Reaction Conditions and Catalyst Optimization ................................................. 149 4.2.1.2 Substrate Scope ................................................................................................... 153 4.2.1.3 Mechanistic Insight ............................................................................................. 157 4.2.1.4 Summary ............................................................................................................ 165 4.3 Conclusions ....................................................................................................................... 166 4.4 Experimental ..................................................................................................................... 168 4.4.1 Starting Materials and Reagents ................................................................................. 168 4.4.2 Synthesis ..................................................................................................................... 169 Chapter 5. Conclusions and Future Work ................................................................................... 175 5.1  Summary and Conclusions ........................................................................................... 175  5.2  Future Work ................................................................................................................. 177  5.2.1  Stereocontrol in the ROP of rac-Lactide........................................................... 177  5.2.2  Synthesis of Additional PCL/PLA Copolymers ............................................... 180  5.2.3  Rheology of Other Polyesters ........................................................................... 181  5.2.4  Ring-Opening Polymerization of Other Cyclic Monomers .............................. 183  5.2.5  Yttrium (89Y) NMR Spectroscopy .................................................................... 184  References ................................................................................................................................... 187 Appendix A. Statistical Analysis of {1H}1H NMR Spectra ....................................................... 205 Appendix B. Summary of Amidate Complex Numbering.......................................................... 207  vii  Appendix C. Relevant Rheology Equations ............................................................................... 208  viii  List of Figures Figure 1.1 Selected examples of chelating ligands used in the synthesis of yttrium complexes ... 2 Figure 1.2 Typical syntheses of guanidinate proligands and yttrium (guanidinate) complexes .... 4 Figure 1.3 Synthesis of tetra(guanidinate) complex 1.18 and complex 1.20 ................................. 5 Figure 1.4 Synthesis of alkoxide complexes 1.36 and 1.37 ........................................................... 7 Figure 1.5 Polymerization of rac-lactide with complexes 1.36 and 1.37 ...................................... 7 Figure 1.6 Polymerization of rac-β-butyrolactone with complex 1.37.......................................... 8 Figure 1.7 Hydrosilylation of alkenes with complex 1.44 ............................................................. 9 Figure 1.8 Typical syntheses of amidinate proligands and yttrium (amidinate) complexes........ 10 Figure 1.9 Polymerizations of ethylene with complex 1.54 ........................................................ 11 Figure 1.10 Synthesis of mono(amidinate) complex 1.59 ........................................................... 12 Figure 1.11 Reaction of complex 1.59 with AlMe3 ..................................................................... 13 Figure 1.12 Synthesis of tethered bis(amidinate) complex 1.73 .................................................. 14 Figure 1.13 Synthesis of phosphoramidate complex 1.76 ........................................................... 16 Figure 1.14 Hydroamination of aminoalkenes with complex 1.76 .............................................. 17 Figure 1.15 Select examples of phosphoramidate complexes ..................................................... 18 Figure 1.16 Synthesis of amide proligands .................................................................................. 23 Figure 1.17 Binding modes of amidate ligands ........................................................................... 24 Figure 1.18 Solid-state molecular structure of 1.120 (naphthyl group (except for ipso-carbons) omitted for clarity) ........................................................................................................................ 25 Figure 1.19 Polymerization of ε-caprolactone with complex 1.120 ............................................ 26 Figure 1.20 Polymerization of rac-lactide with complexes 1.142 and 1.144 .............................. 29 Figure 1.21 Polymerization of rac-lactide with complexes 1.146 and 1.148 .............................. 31 Figure 1.22 Synthesis of multinuclear complexes 1.156 – 1.159 ................................................ 32 Figure 1.23 Polymerization of ε-caprolactone with complex 1.156 ............................................ 32 ix  Figure 2.1 The ring-opening polymerization of rac-lactide ........................................................ 35 Figure 2.2 The lifecycle of PLA .................................................................................................. 36 Figure 2.3 Coordination-insertion mechanism for the ROP of lactide ........................................ 38 Figure 2.4 The theoretical tacticities of PLA ............................................................................... 42 Figure 2.5 A selection of known yttrium containing initiators for the ROP of lactide ................ 44 Figure 2.6 Tris-, bis-, and mono(amidate) complexes of yttrium ................................................ 48 Figure 2.7 Plot of percentage conversion over time during ROP of rac-lactide using initiators 2.10 – 2.12 ([M]/[I] = 400, room temperature) ............................................................................. 51 Figure 2.8 Plot of percentage conversion over time during the ROP of rac-lactide using initiators 2.13, 2.9, and 2.14 ([M]/[I] = 400, room temperature) ................................................................. 52 Figure 2.9 Yttrium tris(amidate) complexes containing amidate ligands with varying steric and electronic properties ...................................................................................................................... 54 Figure 2.10 Plot of percentage conversion over time during the ROP of rac-lactide using initiators 2.10, 2.13, and 2.15 – 2.17 ([M]/[I] = 400, room temperature) ..................................... 56 Figure 2.11 Mn values of PLA synthesized at different [M]/[I] ratios using complex 2.10 at room temperature in THF ....................................................................................................................... 59 Figure 2.12 Plot of percentage conversion over time during the ROP of rac-lactide using initiator 2.10 ([M]/[I] = 400, room temperature in dichloromethane and THF) ........................... 63 Figure 2.13 Mn values of PLA synthesized at different percent conversions using initiator 2.10 ([M]/[I] = 400, room temperature in dichloromethane and THF) ................................................ 64 Figure 2.14 Plot of percentage conversion over time during the ROP of rac-lactide using initiators 2.10 ([M]/[I] = 400, 0°C, DCM) .................................................................................... 66 Figure 2.15 1H NMR spectrum of PLA (600 MHz, C6D6, 25 °C) ............................................... 68 Figure 2.16 1H NMR spectrum (300 MHz, D8-tol, 25 °C) of Scheme 2.6 reaction a ................. 73 Figure 3.1 Ring-opening polymerization of ε-caprolactone ........................................................ 85 Figure 3.2 Parallel-plate rheometer .............................................................................................. 88 Figure 3.3 Representative time sweep plot .................................................................................. 89 x  Figure 3.4 Representative plot of G′ and G″ vs. shear rate for a viscoelastic liquid ................... 90 Figure 3.5 Representative plot of viscosity vs. shear rate ............................................................ 91 Figure 3.6 Representative plot of zero-shear viscosity vs. molecular weight (Mw) [A = linear, B = long-chain branching, C = star-type branching] ........................................................................ 91 Figure 3.7 Types of copolymers .................................................................................................. 93 Figure 3.8 Representation of the phase separation of PLA and PCL .......................................... 96 Figure 3.9 Known rare-earth and yttrium initiators for PCL/PLA copolymers ........................... 97 Figure 3.10 Yttrium amidate complexes used for the ROP of ε-caprolactone ............................ 99 Figure 3.11 Time sweep measurement of PCL-1 and Capa 6800 at 100 °C ............................. 104 Figure 3.12 Viscosity curves of PCL-1 (Mw = 6.566 x 104 g/mol) at 100 °C ........................... 105 Figure 3.13 Viscosity curves of Capa 6800 (Mw = 8.835 x 104 g/mol) at 100 °C ..................... 106 Figure 3.14 Zero-shear viscosity versus Mw for synthetic (PCL-1) and commercial PCLs...... 107 Figure 3.15 Time sweep measurement of Capa 6800 and PCL-2 at 100 °C ............................. 108 Figure 3.16 Viscosity curves of PCL-2 (Mw = 8.123 x 104 g/mol) at 100 °C ........................... 109 Figure 3.17 Zero-shear viscosity versus Mw for synthetic (PCL-1, PCL-2) and commercial PCL ..................................................................................................................................................... 110 Figure 3.18 Coordination-insertion mechanism for the ROP of ε-caprolactone ....................... 111 Figure 3.19 Linear vs. long-chain branching in PCL................................................................. 114 Figure 3.20 “Branched” PCL tautomerization ........................................................................... 115 Figure 3.21 Deuteration of “branched” PCL ............................................................................. 116 Figure 3.22 Intrinsic Viscosity of “linear” and “branched” PCL .............................................. 119 Figure 3.23 Hydrodynamic Radius of “linear” and “branched” PCL ........................................ 120 Figure 3.24 Radius of Gyration of “linear” and “branched” PCL ............................................. 121 Figure 3.25 Degradation of “linear” PCL (PCL-1) over time ................................................... 123 Figure 3.26 Degradation of “branched” PCL (PCL-2) over time ............................................. 124 Figure 3.27 PCL-1 and PCL-2 .................................................................................................. 125 xi  Figure 3.28 Synthesis of di-block copolymers of PCL/PLA ..................................................... 128 Figure 3.29 1H NMR spectrum of a PCL/PLA di-block copolymer (75:25 PCL:PLA) (600 MHz, C6D6, 25 °C) ................................................................................................................................ 131 Figure 3.30 Proposed synthesis of random copolymers of PCL/PLA ....................................... 132 Figure 4.1 Known rare-earth complexes used as amidation precatalysts .................................. 145 Figure 4.2 Yttrium amidate complexes as precatalysts for the amidation of aldehydes with amines ......................................................................................................................................... 148 Figure 4.3 Amine Substrate Scope ............................................................................................. 154 Figure 4.4 Aldehyde Substrate Scope ........................................................................................ 157 Figure 4.5 Reaction of p-toluidine with benzaldehyde using Y(N(SiMe3)2)3............................ 162 Figure 5.1 Interesting PLA tacticities ........................................................................................ 178 Figure 5.2 New amide proligands for the synthesis of yttrium bis(amidate) complexes........... 179 Figure 5.3 Proposed synthesis of a triblock copolymer of PCL/PLA ........................................ 181 Figure 5.4 Copolymer and homopolymer candidates for rheological analysis.......................... 182 Figure 5.5 Representation of phase separation with and without polymer doping .................... 183 Figure 5.6 Potential cyclic monomers........................................................................................ 184 Figure 5.7 Amide proligands with varying electronic properties .............................................. 185 Figure 5.8 Mono-, bis-, and tris(amidate) complexes of yttrium ............................................... 186  xii  List of Schemes Scheme 1.1 Polymerizations of ε-caprolactone and MMA with complex 1.20 ............................. 5 Scheme 1.2 Syntheses of complexes 1.26 and 1.28 ....................................................................... 6 Scheme 1.3 Polymerizations of ethylene and propylene with complex 1.28 ................................. 6 Scheme 1.4 Synthesis of guanidinate proligand 1.43 and complex 1.44 ....................................... 8 Scheme 1.5 Synthesis of symmetric and asymmetric (amidinate) complexes 1.54 and 1.56 ...... 11 Scheme 1.6 Polymerization of isoprene with complex 1.59 and complex 1.59 plus AlMe3 ....... 12 Scheme 1.7 Synthesis of tethered bis(amidinate) complexes 1.65 and 1.66 ................................ 13 Scheme 1.8 Amidation of aldehydes with amine using complexes 1.65 and 1.66....................... 14 Scheme 1.9 Polymerizations of ε-caprolactone, L-lactide, and rac-lactide with complex 1.73 .. 15 Scheme 1.10 Synthesis of complex 1.94 and associated stoichiometric reactions to prepare complexes 1.95 – 1.98 .................................................................................................................. 20 Scheme 1.11 Synthesis of pyridyl and α-picolyl complexes 1.99 – 1.102 ................................... 21 Scheme 1.12 Synthesis of diamidosilylether complexes 1.104 and 1.106 ................................... 22 Scheme 1.13 Stoichiometric reactions of dimer complex 1.104 .................................................. 22 Scheme 1.14 Synthesis of tris(amidate) complexes ..................................................................... 25 Scheme 1.15 Synthesis of mono- and bis(amidate) complexes ................................................... 27 Scheme 1.16 Hydroamination of aminoalkenes with complexes 1.125 - 1.128 .......................... 28 Scheme 1.17 Synthesis of binaphthyl-based chiral bis(amidate) complexes 1.142 and 1.144 .... 29 Scheme 1.18 Synthesis of biphenyl-based chiral bis(amidate) complexes 1.146 and 1.148 ....... 30 Scheme 1.19 Hydroamination of aminoalkenes with complexes 1.146 and 1.148 ...................... 31 Scheme 2.1 Intramolecular transesterification reactions with poly(lactide) ................................ 37 Scheme 2.2 Synthesis of bis(amidate) complex 2.9 ..................................................................... 47 Scheme 2.3 General synthesis of amide proligands ..................................................................... 54 Scheme 2.4 The ROP of rac-lactide with complex 2.10 .............................................................. 68 xiii  Scheme 2.5 Proposal for the deactivation of initiator 2.10 .......................................................... 70 Scheme 2.6 Possible reactions of complex 2.10 with 1 and 2 equivalents of rac-lactide ............ 72 Scheme 3.2 Proposed mechanism for the synthesis of branched PCL ....................................... 113 Scheme 4.1 The catalytic amidation of alcohols and aldehydes and the Cannizzaro reaction .. 144 Scheme 4.2 Proposed mechanism for the amidation of aldehydes with amines ........................ 158 Scheme 4.3 Tishchenko reaction using precatalyst 4.8 .............................................................. 159 Scheme 4.4 Ligand displacement precatalyst 4.8 by amide product 4.18 .................................. 161 Scheme 4.5 Amide product 4.18 and imine 4.39 stability in presence of precatalyst 4.8 .......... 163 Scheme 4.6 Amide product 4.18 stability in presence of precatalyst 4.8 and substrates or ....... 164 side-products ............................................................................................................................... 164 Scheme 4.7 Amide product 4.18 stability in presence of additional 4.18 or 4.39 ...................... 165  xiv  List of Tables Table 1.1 Summary of select phosphoramidate complexes as initiators for the ROP of rac-lactide ....................................................................................................................................................... 19 Table 2.1 Comparison of yttrium initiators for the ROP of lactide.............................................. 45 Table 2.2 Comparison of initiators for the ROP of rac-lactide using a [M]/[I] of 400................ 49 Table 2.3 Comparison of initiators for the ROP of rac-lactide for tris(amidate) complexes 2.10, 2.13, 2.15, 2.16, and 2.17 using a [M]/[I] of 400 .......................................................................... 55 Table 2.4 Summary of the ROP of rac-lactide for initiator 2.10 ................................................. 58 Table 2.5 Comparison of initiator ability for the ROP of rac-lactide using complex 2.10 in different solvents ........................................................................................................................... 62 Table 2.6 Comparison of initiator ability for the ROP of rac-lactide using complex 2.10 at different temperatures ................................................................................................................... 65 Table 3.1 Comparison of rare-earth and yttrium initiators for the ROP of ε-caprolactone ......... 98 Table 3.2 Scale-up data for the ROP of ε-caprolactone with complex 3.8 ................................ 101 Table 3.3 Synthesis of PCL/PLA di-block copolymers using complex 3.8............................... 130 Table 4.1 Amidation of benzaldehyde with aniline ................................................................... 146 Table 4.2 Reaction optimization for the amidation of benzaldehyde with p-toluidine .............. 150 Table 4.3 Optimized reaction times and isolated product yields of precatalysts 4.8-4.16 for the amidation of benzaldehyde with p-toluidine............................................................................... 152  xv  List of Abbreviations [M]/[I]  monomer to initiator ratio  >  greater than  <  less than  ≥  greater than or equal to  °C  degrees Celsius  Anal.  analysis  b  broad (NMR spectroscopy)  calc  calculated  CL  ε-caprolactone  δ  delta, chemical shift  d  doublet (NMR spectroscopy)  DCM  dichloromethane  DME  dimethoxyethane  ε  epsilon  g  grams  G′  storage modulus  G″  loss modulus  GPC  gel permeation chromatography  h  hours  Hz  Hertz, s-1 xvi  I  initiator  iPr  isopropyl  IR  infrared  J  coupling constant  K  Kelvin  L  ligand  L  levorotatory  LA  lactide  LDA  lithium diisopropylamide  m  multiplet (NMR spectroscopy)  M  metal  M  molar, molL-1  MALDI-TOF  matrix assisted laser desorption ionization – time of flight  mg  milligrams  MHz  megahertz  min  minute  mL  milliliters  MMA  methyl methacrylate  mmol  millimole  Mn  number-averaged molecular weight  mol  mole  xvii  mol%  mole percent  MS  mass spectrometry  Mw  weighted-average molecular weight  NHC  N-heterocyclic carbene  NMR  nuclear magnetic resonance  P  polymer  p  para  PDI  polydispersity index  Ph  phenyl  PCL  poly(ε-caprolactone)  PLA  polylactide  Pm  probability of finding meso diads  Pr  probability of finding racemic diads  ppm  parts per million  R  aryl or alkyl substituent  R  rectus  rac  racemic  ROP  ring-opening polymerization  rt  room temperature  s  singlet (NMR spectroscopy)  s  sinister  xviii  t  triplet (NMR spectroscopy)  TBHP  t-butylhydrogenperoxide  tBu  tert-butyl  temp  temperature  THF  tetrahydrofuran  TMS  trimethylsilyl  η*  viscosity  η0  zero-shear viscosity  xix  Foreword The work reported in this thesis involves the investigation of yttrium (amidate) complexes for a variety of catalytic applications. This thesis has been written as a traditional thesis and thus each chapter is not a stand-alone document. Several compounds are used throughout the entire thesis, however, numbering is consistent within each chapter. Some compounds will be reported as more than one number; a numbering reference for those compounds is available in Appendix B.  xx  Acknowledgements First and foremost I would like to thank Dr. Laurel Schafer for all of her support and guidance throughout the course of my graduate studies. Thank you for being an amazing mixture of super-keen scientist and incredibly caring supervisor, and for never giving up on me. The Schafer group is quite possibly the strangest group of individuals that I have ever been given the opportunity to work with, and I wouldn’t change it for the world. Thank you Schafer group members both past and present, you guys are amazing. I would especially like to thank Dr. Ruth Webster, Dr. Rachel Platel, Ying Lau, and Mitchell Perry for taking the time to read this thesis and give helpful (and comical) comments. I would like to thank my research collaborators Nazbanoo Noroozi, and Dr. Savvas Hatzikiriakos for all of their help with the rheological analysis of my polymers, and their patience in dealing with someone who had never heard the word rheology prior to this project. I would also like to thank Dr. Parisa Mehrkhodavandi for all of her helpful discussions and taking the time to read this thesis. I would like to thank the mechanical shop, electronic shop, glassblower, NMR staff, and analytical staff; especially Ken Love and Milan Coschizza for their endless help with my cheeky glovebox and Brian Ditchburn for saving my behind on numerous occasions. My chemistry ladies (Kadek, Danielle, Jenn, Tulin, Ashlee, and Eszter), thanks for keeping me entertained over the years and reminding me that I wasn’t alone in this. Last, but not least, thank you to all of my friends and family (both the Thomson/Riley’s and Okuda’s). Mom, this one’s for you.  xxi  Chapter 1. Yttrium Chelates in Catalysis 1.1  Yttrium Complexes Containing N,N-, N,O-, O,O-, or N,N,O-Chelating Ligands Yttrium is a highly desirable metal for use in synthesizing new organometallic complexes  due to its low cost and low toxicity.1,2 Yttrium is very similar in reactivity to the lanthanide metals as it has a similar ionic radius (for example, Y3+ = 1.04 Å, Gd3+ = 1.07 Å, Er3+ = 1.00 Å) and exhibits the +3 oxidation state.3 One main difference is that yttrium is diamagnetic, making NMR spectroscopy facile. Cyclopentadienyl-based yttrium complexes have been extensively investigated for many years.4-6 These complexes have been found to be effective catalysts for a number of applications including: hydrosilylation,7-9 hydroamination,4 olefin polymerization,10-15 and polar monomer polymerization.16,17 Despite the obvious applicability of these complexes, the cyclopentadienyl ligand has limitations due to the fact that it is not modular. The synthesis of cyclopentadienyl derivatives can be difficult and therefore, functionalization remains a challenge. Based on these challenges, the organometallic community continues to search for widely applicable ligand sets in which the steric and electronic properties of the ligand can be easily modified. Variations in the steric and electronic properties of the auxiliary ligand result in the ability to tune the reactivity of the metal center, a desirable feature for catalyst development. There are a wide variety of non-cyclopentadienyl ligand scaffolds that have been reported in the synthesis of yttrium complexes. Ligand sets which coordinate in a monodentate, bidentate, tridentate, or tetradentate fashion using N- and O-donor atoms have been reported.18-28 For the 1  purposes of this thesis, the discussion will be limited to bidentate systems. Bidentate ligands have become quite prevalent and include 6-, 5-, and 4-membered chelates. 6-Membered chelating ligands include salicylaldiminates (1.1),29-33 acetylacetonates (1.2),34-37 β-diketiminates (1.3),29,38-46  and  piperazine-phenolates(1.4).47  5-Membered  chelating  ligands  include  aminotroponates (1.5),48 aminotroponimates (1.6),49-51 and iminoquinolates (1.7).52 4-Membered chelating ligands include guanidinates (1.8),53-75 amidinates (1.9),55,56,58,76-92 phosphoramidates (1.10),93-97 alkoxysilylamides (1.11),98-101 and amidates (1.12)102-106 (Figure 1.1). This introduction will focus on 4-membered chelating ligand sets for consistency with the amidate ligands discussed within this thesis.  Figure 1.1 Selected examples of chelating ligands used in the synthesis of yttrium complexes 2  The ligands shown in Figure 1.1 are all monoanionic and exploit the hard-hard Lewis acid-base match of N- and O-donors with yttrium. Each of the ligand sets are modular, containing substituents that can be changed to affect the steric and electronic properties of the ligands, and thus allow for complexes with tunable properties. Yttrium guanidinate (1.8),53 amidinate (1.9),86 phosphoramidate (1.10),95 and alkoxysilylamido complexes (1.11)100 are well known and display structures very similar to the yttrium (amidate) complexes that are discussed in this thesis (vida infra). These complexes provide a benchmark for the reactivity of known and new yttrium amidate complexes in a variety of applications and will be reviewed below.  1.1.1 Guanidinate Complexes of Yttrium The guanidinate ligand is an N,N- bound ligand that forms a 4-membered chelate when coordinated to yttrium. The synthesis begins with reaction of a carbodiimide (1.13) with a lithium amide (1.14) to form the guanidinate lithium salt. Guanidinate complexes of yttrium (1.8) are often formed via salt metathesis (Figure 1.2);55 yttrium mono- and bis(guanidinate) complexes have been shown to support a variety of organometallic complexes including: aryls,65 alkyls,65 alkoxides,53 amidos,71 and chloros.65,67 Homoleptic guanidinate complexes of yttrium have also been reported.55 A vast number of papers have been published reporting the synthesis and application of yttrium (guanidinate) complexes which exhibit large variations in amine backbone and N,N’- substituents.55 Such N-substituents are easily varied and can include: 2,6diisopropylphenyl, isopropyl, cyclohexyl, alkyl tethers, and many others (Figure 1.2). The backbones reported for yttrium (guanidinate) complexes are also quite diverse, including a variety of alkyl substituents. For this reason, only a selection will be discussed below. 3  Figure 1.2 Typical syntheses of guanidinate proligands and yttrium (guanidinate) complexes Yttrium (guanidinate) complexes have been used to promote a variety of catalytic reactions. In general, they have been shown to catalyze olefin polymerization, the polymerization of methylmethacrylate (MMA), the hydrosilylation of alkenes, and the ring-opening polymerization (ROP) of lactide, β-butyrolactone, and ε-caprolactone.55 Specific examples are described below. In 2003, Qi Shen and co-workers reported the synthesis of a dimeric tetra(guanidinate) complex of yttrium (1.18), which was synthesized through salt metathesis of the guanidinate lithium salt (1.17) and yttrium trichloride (Figure 1.3).71 The resulting complex was revealed to be a chloride-bridged dimer which could be reacted with a lithiated amine to generate a mononuclear bis(guanidinate) complex (1.20). Investigations into the catalytic capabilities of the monomeric complex revealed that complex 1.20 was an effective initiator for both the polymerizations of ε-caprolactone and MMA (Scheme 1.1).  4  Figure 1.3 Synthesis of tetra(guanidinate) complex 1.18 and complex 1.2071  Scheme 1.1 Polymerizations of ε-caprolactone and MMA with complex 1.2071 The Trifonov group later reported the use of a similar complex in olefin polymerization.69 Complex 1.26 was synthesized by reaction of a chloro-bridged yttrium-lithium dinuclear complex with (trimethylsilyl)methyllithium (1.25) (Scheme 1.2). Complex 1.26 was then reacted with phenylsilane and a hydride-bridged dimer resulted (1.128). Complex 1.28 was shown to be active in the polymerization of ethylene and propylene (Scheme 1.3), although the formation of 5  polyethylene was slower than other rare earth metal catalysts with the same ligand set, and catalyst activity decreased after 2 hours during the polymerization of propylene.  Scheme 1.2 Syntheses of complexes 1.26 and 1.2869  Scheme 1.3 Polymerizations of ethylene and propylene with complex 1.2869  6  A few years later, in collaboration with the research group of Jean-François Carpentier, the Trifonov group reported the use of two yttrium (guanidinate) alkoxide complexes for the ROP of cyclic esters.53 The alkoxide complexes (1.36 and 1.37) were synthesized by reaction of previously-reported complex 1.33 with KOtBu or NaOiPr (Figure 1.4). Complexes 1.36 and 1.37 were both found to effectively initiate the ROP of rac-lactide, although it was determined that complex 1.36 performed better in toluene, while THF was a better solvent for complex 1.37 (Figure 1.5). In addition, complex 1.37 was found to be an active initiator for the ROP of rac-βbutyrolactone, producing poly(β-butyrolactone) in high yield with a syndiotactic bias (Figure 1.6).  Figure 1.4 Synthesis of alkoxide complexes 1.36 and 1.3753  Figure 1.5 Polymerization of rac-lactide with complexes 1.36 and 1.3753 7  Figure 1.6 Polymerization of rac-β-butyrolactone with complex 1.3753 Lastly, the synthesis of a bis(alkyl) mono(guanidinate) complex was reported in 2008 by Bart Hessen and co-workers.58 The proligand (1.43) was synthesized from reaction of lithium dimethylamide with a 2,6-diisopropylphenyl substituted carbodiimide (1.42) (Scheme 1.4). Subsequent  reaction  with  Y(CH2SiMe3)3(THF)2  resulted  in  complex  1.44.  This  mono(guanidinate) complex was shown to be a highly active catalyst for the hydrosilylation of alkenes, resulting in fast room temperature reactivity (> 5min – 5 h), excellent conversions (> 97 %), and general selectivity for the anti-Markovnikov product (1.47) (Figure 1.7).  Scheme 1.4 Synthesis of guanidinate proligand 1.43 and complex 1.4458  8  Figure 1.7 Hydrosilylation of alkenes with complex 1.4458 In summary, guanidinate complexes of yttrium contain 4-membered metallacycles with hard-hard donor-acceptor interactions, and an amine backbone. The modular nature of the guanidinate ligand allows for easily-tuned steric and electronic properties. Complexes are often synthesized via salt metathesis, and a range of complexes have been reported. These complexes have proven useful in a number of catalytic applications including olefin polymerization, the polymerization of methylmethacryalte (MMA), the hydrosilylation of alkenes, and the ringopening polymerization (ROP) of lactide, β-butyrolactone, and ε-caprolactone.55  1.1.2 Amidinate Complexes of Yttrium The related amidinate ligand is another N,N- bound ligand that forms a 4-membered chelate when coordinated to yttrium. The synthesis of these ligands involves reacting a carbodiimide (1.13) with an alkyl, aryl, or silyl lithium reagent (1.49) (Figure 1.8).55 Yttrium (amidinate) complexes can be formed via three different methods: in situ, through insertion of a carbondiimide into a reactive Y-C bond,107 salt metathesis of yttrium trichloride with the alkali metal salt of the amidinate ligand,108 or protonolysis with the protonated amidinate ligand and an yttrium tris(amido) species.80  9  Figure 1.8 Typical syntheses of amidinate proligands and yttrium (amidinate) complexes Yttrium mono- and bis(amidinate) complexes have been shown to support a variety of organometallic complexes including: alkyls,78,109 alkoxides,76 amidos,76,85,110 and chloros76,111. Homoleptic amidinate complexes of yttrium have also been reported.55,112 As with yttrium (guanidinate) complexes, a vast number of papers have been published reporting the synthesis and application of yttrium (amidinate) complexes which exhibit large variations (eg. 2,6diisopropylphenyl, isopropyl, cyclohexyl, alkyl tethers) in amidinate backbone and Nsubstituents.55 Only a representative selection will be discussed. Yttrium (amidinate) complexes have been used to promote a variety of catalytic reactions, such as olefin polymerization, the amidation of aldehydes with amines, the cyclohydroamination of aminoalkenes, the hydrosilylation of alkenes, and the ROP of cyclic lactones.55 Specific examples are described below. In 2006, the Hessen group from the University of Groningen reported the synthesis of two bis(alkyl) mono(amidinate) complexes (1.54 and 1.56).80 Both complexes were synthesized by protonolysis of Y(CH2SiMe3)3(THF)2 with either a symmetric or asymmetric amidine (Scheme 1.5). Complex 1.54 was found to initiate the polymerization of ethylene, yielding poly(ethylene) with relatively low molecular weights and narrow polydispersity indices at 100 10  °C (Figure 1.9). Interestingly, the asymmetric amidinate complex 1.56 did not initiate polymerization.  Scheme 1.5 Synthesis of symmetric and asymmetric (amidinate) complexes 1.54 and 1.5680  Figure 1.9 Polymerizations of ethylene with complex 1.5480 In 2008, Zhaomin Hou and co-workers reported the use of an yttrium (amidinate) complex for the polymerization of isoprene.92 Complex 1.59 was synthesized by reaction of the amidine 1.58 with an yttrium tris(aminobenzyl) complex (1.57) (Figure 1.10). Investigations into the polymerization of isoprene demonstrated that complex 1.59 is capable of forming iso-3,411  poly(isoprene) rapidly at room temperature, in excellent yield. However, it was reported that the addition of trimethylaluminum drastically changes the selectivity. In fact, the polymer formed from initiation using complex 1.59 and trimethylaluminum was primarily cis-1,4-poly(isoprene) (Scheme 1.6). This was attributed to the formation of a heteronuclear Y-Al complex (1.64) (Figure 1.11).  Figure 1.10 Synthesis of mono(amidinate) complex 1.5992  Scheme 1.6 Polymerization of isoprene with complex 1.59 and complex 1.59 plus AlMe392  12  Figure 1.11 Reaction of complex 1.59 with AlMe392 Yttrium bis- and tris(amidinate) complexes 1.65 and 1.66 were reported by the Shen group in 2009.108 Both complexes were synthesized via salt metathesis of yttrium trichloride and a lithium amidine salt. When yttrium trichloride was reacted with 2 or 1.5 equivalents of proligand, complexes 1.65 and 1.66 were formed, respectively (Scheme 1.7). Both yttrium (amidinate) complexes were found to catalyze the mild amidation of aldehydes with amines, however, only a limited substrate scope was explored (Scheme 1.8).  Scheme 1.7 Synthesis of tethered bis(amidinate) complexes 1.65 and 1.66108  13  Scheme 1.8 Amidation of aldehydes with amine using complexes 1.65 and 1.66108 Recently, Qi Shen and co-workers reported the synthesis of a tethered bis(amidinate) complex of yttrium for use as an initiator in the ROP of cyclic esters.86 Complex 1.73 was prepared through reaction of a tethered bis(amidinate) mono(chloro) species with sodiumborohydrate and dimethoxyethane (DME) (Figure 1.12). Complex 1.73 was found to be a highly active initiator for the ROP of ε-caprolactone, L-lactide, and rac-lactide. In all cases, polymers were formed in good yield with expected molecular weights and narrow PDIs (Scheme 1.9). Also, the polylactide formed using complex 1.73 in combination with rac-lactide displayed a heterotactic bias.  Figure 1.12 Synthesis of tethered bis(amidinate) complex 1.7386  14  Scheme 1.9 Polymerizations of ε-caprolactone, L-lactide, and rac-lactide with complex 1.7386 Much like the guanidinate complexes of yttrium, yttrium (amidinate) complexes contain 4-membered metallacycles with hard-hard donor-acceptor interactions. Amidinate complexes are often synthesized via salt metathesis and a large range of complexes have been reported. These results demonstrate the modular nature of the amidinate ligand and exhibit the facile tuning of ligand steric and electronic properties. These complexes have been proven to be useful in a number of catalytic applications including olefin polymerization, the amidation of aldehydes with amines, the cyclohydroamination of aminoalkenes, the hydrosilylation of alkenes, and the ROP of cyclic lactones and thus reaffirm the stability of 4-membered metallacycles for use in catalytic reactions.55  15  1.1.3 Other N,O-Chelating Complexes of Yttrium In addition to the N,N-bound amidinate and guanidinate 4-membered chelates, a few examples of N,O-bound chelating ligands have been reported for yttrium. These ligands include traditional amidates102-106 as well as phosphorus93-97 and silicon98-101 substituted amidates (Figure 1.1, 1.12, 1.10, and 1.11), all of which will be discussed below. The first example of a phorphorus-containing N,O-bound 4-membered chelate bound to yttrium, phosphoramidate, was reported in 2003 by Livinghouse and co-workers.93 In addition to the thiophosphoramidate complexes, they reported the synthesis of complex 1.76 through protonolysis with proligand 1.74 (Figure 1.13) and Y(SiMe3)2)3. Investigations into the use of complex 1.76 as a catalyst for the intramolecular hydroamination of aminoalkenes revealed that the catalytic activity of the phosphoramidate was virtually non-existent (Figure 1.14).  Figure 1.13 Synthesis of phosphoramidate complex 1.7693  16  Figure 1.14 Hydroamination of aminoalkenes with complex 1.7693 Since this time, the Williams group from Imperial College has reported the synthesis of a number of different dimeric phosphoramidate yttrium complexes.94-97 Following the initial synthesis of complexes 1.80-1.82,94 a variety of other mononuclear and dimeric complexes have been synthesized, varying both the ligand backbone and the other ligand substituents. A selection of examples is shown in Figure 1.15. All of the complexes reported were effective initiators for the ROP of rac-lactide, and the best results of the selected complexes are shown in Table 1.1. Throughout their investigations, the Williams group determined that the alkoxide complexes were the most efficient initiators, showing excellent control and rapid polymerizations.95 It was also determined that stereocontrol could be controlled by the nuclearity of the yttrium complex.96 The mononuclear amido complex 1.88 was found to synthesize heterotactic PLA, while the dimeric isopropoxide complex 1.89 was found to synthesize PLA with a reduced heterotactic bias. This difference in stereocontrol was attributed to the difference in steric bulk surrounding the two phosphoramidate yttrium complexes 1.88 and 1.89 (Figure 1.15).  17  Figure 1.15 Select examples of phosphoramidate complexes94-97  18  Table 1.1 Summary of select phosphoramidate complexes as initiators for the ROP of raclactide94-97  The first examples of a silicon containing N,O-bound 4-membered chelate coordinated to yttrium, alkoxysilylamidos, were reported in 1997 by Tueben and co-workers.100 These complexes were synthesized first by salt metathesis of the lithium salt of the ligand (1.92) and the THF adduct of yttrium trichloride (1.91). Once the initial complex was formed, reaction with a variety of other lithium reagents resulted in a number of new complexes (1.94 – 1.98) (Scheme 1.10). Later in 1997, the Tueben group reported the reaction of either complex 1.94 or complex 1.97 with a variety of pyridine and α-picoline derivatives (Scheme 1.11) to form a number of pyridyl and picolyl complexes (1.99 – 1.102).99  19  Scheme 1.10 Synthesis of complex 1.94 and associated stoichiometric reactions to prepare complexes 1.95 – 1.98100  20  Scheme 1.11 Synthesis of pyridyl and α-picolyl complexes 1.99 – 1.10299 In a slight variation, the Leznoff group from Simon Fraser University has reported the synthesis of diamidosilylether complexes of yttrium.101 The synthesis involves the salt metathesis of one or two equivalents of the lithium salt of the ligand (1.103 or 1.105) with yttrium trichloride to form an yttrium dimer or mononuclear complex, respectively (1.104 or 1.106) (Scheme 1.12). Stoichiometric reactions of the dimer complex 1.104 with additional salts resulted in the generation of two new monomeric yttrium species (1.108 or 1.110) (Scheme 1.13). To date, the application of these complexes has not been reported.  21  Scheme 1.12 Synthesis of diamidosilylether complexes 1.104 and 1.106101  Scheme 1.13 Stoichiometric reactions of dimer complex 1.104101  22  1.2  Yttrium Amidate Complexes Yttrium amidate complexes have recently been reported as effective catalysts for select  catalytic transformations.102-106 Despite their similarities to the other N,N- and N,O- complexes mentioned above, there has been very little research into the synthesis and application of these complexes. In fact, there are only 5 literature reports of the synthesis and application of yttrium (amidate) complexes, a significantly smaller contribution than the >75 reports of amidinate, guanidinate, and other 4-membered N,O-chelates. Amide proligands can be synthesized by reaction of an amine with an acid chloride in the presence of base (Figure 1.16).113 The modular nature of the amide synthesis allows for strategic selection of the amine and acid chloride substituents, providing a means of tuning the steric and electronic properties of the resulting ligand and thus the metal center of the complex to which it is coordinated. Given the variety of amines and acid chlorides available commercially, a number of different amide proligands can be readily synthesized in high yield and at low cost.  Figure 1.16 Synthesis of amide proligands113 Amide proligands are known to exhibit five different binding modes upon coordination to a metal center (Figure 1.17);113 bidentate (κ2) (1.114), monodentate (κ1) through the oxygen (1.115), monodentate (κ1) through the nitrogen (1.116), bridging (μ)through the oxygen and the  23  nitrogen (1.117), and bridging (μ) through only the oxygen (1.118). To date, only bidentate (κ2) and monodentate (κ1) through the oxygen have been reported.  Figure 1.17 Binding modes of amidate ligands113 The synthesis of yttrium tris(amidate) complexes was first reported by the Schafer group in 2008.104 Tris(amidate) complexes of yttrium are easily synthesized by simple protonolysis of three equivalents of amide proligand with Y(N(SiMe3)2)3 (Scheme 1.14). Three novel complexes have been reported, with varying steric and electronic properties (1.120 - 1.122) (Scheme 1.14). NMR spectroscopy and X-ray crystallography indicated that these species were seven coordinate with three κ2-amidate ligands and one neutrally coordinated tetrahydrofuran (THF) (Figure 1.18). 1  H and  13  C NMR spectra demonstrated that the species are fluxional in solution, as the signals  for the three amidate ligands were equivalent.  24  Scheme 1.14 Synthesis of tris(amidate) complexes104  Figure 1.18 Solid-state molecular structure of 1.120 (naphthyl group (except for ipso-carbons) omitted for clarity)104  25  These new complexes were reported to be highly active initiators for the ROP of εcaprolactone with the best results shown in Figure 1.19.104  Figure 1.19 Polymerization of ε-caprolactone with complex 1.120104 In 2009, the Schafer group reported the synthesis and application of yttrium mono- and bis(amidate) complexes.105 Mono- and bis(amidate) complexes of yttrium are also easily prepared though protonolysis, the differences being the use of one vs. two equivalents of amide proligand, and the lower temperature required when synthesizing the mono(amidate) complex (1.123) (Scheme 1.15). Three bis(amidate) complexes were reported with varying electronic properties, in addition to one mono(amidate) complex (1.125 - 1.128) (Scheme 1.15). As with the yttrium tris(amidate) complexes, NMR spectroscopy indicated fluxional species, and combined with X-ray crystallography, it was determined that each complex contained one coordinated molecule of THF.  26  Scheme 1.15 Synthesis of mono- and bis(amidate) complexes105 These mono- and bis(amidate) complexes of yttrium were reported to be highly active precatalysts for the intramolecular hydroamination of aminoalkenes (Scheme 1.16).105 All three bis(amidate) complexes and the mono(amidate) complexes reported were capable of cyclizing a 27  range of terminal and internal aminoalkene substrates, as can be seen below in Scheme 1.16. Reactions were performed at 25, 65, or 110 °C and required anywhere from <15 minutes to 30 hours, depending on substrate and catalyst. All reactions were high yielding (77-99%).  Scheme 1.16 Hydroamination of aminoalkenes with complexes 1.125 - 1.128105 Late in 2011, the Zi group from Beijing Normal University reported the synthesis of binaphthyl-based chiral amidate complexes of yttrium.102 The axially chiral bis(amidate) complex was synthesized through reaction of the bis(amide) proligand 1.141 and Y(N(SiMe3)2)3. Unlike the bis(amidate) complexes reported by the Schafer group, the metal was coordinated by the ligand through one κ2 amidate, and one κ1 amidate bound through the oxygen (Scheme 1.17). Only one amido ligand was substituted, and the resulting complex did not contain coordinating solvent. In addition, a mono(amide) mono(amine) proligand 1.143 was also reacted to form a mono(amidate) mono(amido) complex 1.144 (Scheme 1.17). Complexes 1.142 and 1.144 were  28  reported to initiate the ROP of rac-lactide to form polylactide with an isotactic bias. The best results are shown in Figure 1.20.  Scheme 1.17 Synthesis of binaphthyl-based chiral bis(amidate) complexes 1.142 and 1.144102  Figure 1.20 Polymerization of rac-lactide with complexes 1.142 and 1.144102  29  The Zi group also reported the synthesis of yttrium (amidate) complexes containing chiral biphenyl based amidate ligands.106 Complexes 1.146 and 1.148 were synthesized as shown below (Scheme 1.18), and were found to be catalytically active for both the ROP of rac-lactide, and the intramolecular hydroamination of aminoalkenes (Figures 1.20 and Scheme 1.19). As can be seen below, these catalysts were capable of forming polylactide with an isotactic bias. Also, catalysts 1.146 and 1.148 showed modest enantioselectivity for the hydroamination of aminoalkenes. Reactions were performed at 60 °C for 1.151 and 1.152 and 120 °C for 1.153 and required 16 hours for 1.151 and 1.152 and 24 hours for 1.153.  Scheme 1.18 Synthesis of biphenyl-based chiral bis(amidate) complexes 1.146 and 1.148106  30  Figure 1.21 Polymerization of rac-lactide with complexes 1.146 and 1.148106  Scheme 1.19 Hydroamination of aminoalkenes with complexes 1.146 and 1.148106 Lastly, in 2012 a paper from Carl Redshaw and co-workers reported the synthesis of a series of multinuclear yttrium complexes 1.156 - 1.159 (Figure 1.22).103 These complexes were also found to initiate the ROP of ε-caprolactone, however, polymerizations displayed poor control (Figure 1.23).  31  Figure 1.22 Synthesis of multinuclear complexes 1.156 – 1.159103  Figure 1.23 Polymerization of ε-caprolactone with complex 1.156103  1.3  Scope of Thesis A large number of reports over many years demonstrate the use of yttrium complexes,  with amidinate, guanidinate, and other N,O-chelating support ligands, in a large range of catalytic applications. A similar N,O-chelate, the amidate (Figure 1.16), has been shown to be easily synthesized and simple to modify.113 Additionally, mono-, bis-, and tris(amidate) complexes of yttrium have been reported to be easily accessed through simple protonolysis. 102-106 Despite their ease of preparation, previous to this thesis, very few applications using yttrium 32  (amidate) catalysts have been reported in the literature.102-106 The similar 4-membered metallacycle formed upon coordination of the amidate ligand is analogous to those formed with the amidinate, guanidinate, and other N,O-chelating ligands previously discussed in this chapter. The extensive applications reported by other N,N- and N,O- 4-membered chelate complexes of yttrium encouraged the further investigation of yttrium (amidate) complexes as catalysts. In this thesis, the application of yttrium (amidate) complexes to additional catalytic transformations is investigated. The effectiveness of yttrium (amidate) complexes as initiators for the ROP of rac-lactide will be explored in Chapter 2. The previously studied use of these yttrium complexes as initiators for the ROP of ε-caprolactone104 will be further investigated through rheological analysis of the resulting poly(ε-caprolactone), as well as through their use as initiators for the synthesis of poly(ε-caprolactone)/poly(lactide) copolymers (Chapter 3). Finally, new catalytic application will be presented in the synthesis of amides from amines and aldehydes (Chapter 4).  33  Chapter 2. Yttrium Amidate Complexes as Rapid Initiators for the RingOpening Polymerization of rac-Lactide1 2.1  Introduction Plastics are ubiquitous, being utilized by consumers and industry alike in applications  ranging from commercial packaging to building materials. Although the plastics produced have improved over time, most plastics are still synthesized from petroleum sources, depleting our non-renewable resources. In response to this issue, research into alternative feedstocks for plastic manufacturing has become prevalent. One proposed solution is the use of biodegradable polymers such as polylactide (PLA), which is sourced from renewable feedstocks (Figure 2.2).114,115 PLA is a polyester that can be synthesized through the condensation of lactic acid, or the ring-opening polymerization (ROP) of lactide. Lactic acid is obtained through fermentation of renewable feedstocks like plant sugars and starches. The lactic acid can then be converted to ethyl lactate which can be polymerized followed by depolymerization to form lactide.116 The lactic acid or lactide is then used to synthesize PLA. Once the polymer is discarded it can undergo enzymatic breakdown and biodegradation to ultimately produce CO2 and H2O, these products can then be used to grow more feedstocks (Figure 2.2).114,115 The synthesis of PLA through the condensation of lactic acid often results in low molecular weights due to the limitations inherent in step-growth polymerization.114  1  A version of this chapter will be submitted for publication. Thomson, J. A.; Schafer, L. L. 2013.  34  The ROP of lactide, a chain-growth polymerization, is a more efficient method as chain length can be controlled, high molecular weights can be obtained, and polymerizations can often be performed at modest temperatures.114,115,117 The ROP of lactide is widely used and the resulting polymer has been shown to be applicable in the manufacture of medical products like stents and sutures as well as consumer products like packaging.98,118-120 The manufacture of PLA is now occurring on a 140000 ton scale annually in the US.121  Figure 2.1 The ring-opening polymerization of rac-lactide  35  Figure 2.2 The lifecycle of PLA115,116 Polymerizations can generally be described in three steps: initiation, propagation, and termination. For the ROP of lactide, initiation occurs upon reaction of the initiator with the first coordinated molecule of lactide; propagation is the continuous coordination and ring-opening of monomers forming the growing polymer chain; and termination occurs when propagation is complete and the complete polymer chain is released from the initiator by quenching the reaction. Termination can also occur prior to the full conversion of monomer to polymer by intra-molecular transesterification reactions (Scheme 2.1).  36  Intramolecular transesterification Scheme 2.1 Intramolecular transesterification reactions with poly(lactide) The ROP of lactide using rare-earth complexes as initiators has been reported to proceed via a coordination-insertion mechanism (Figure 2.3).114 This mechanism involves the coordination of one molecule of lactide where the coordination activates the lactide for attack by an oxygen coordinated ligand. The coordinated lactide molecule is ring-opened via cleavage of the acyl bond and a new metal alkoxide species is generated. A second molecule of lactide is then coordinated and ring-opened by the new metal alkoxide, forming a growing polymer chain and a third metal alkoxide species. This process continues until all of the monomer is consumed. The terminus of the growing polymer chain contains the initial ligand used to ring-open the first molecule of lactide that coordinated to the metal center; thus, the terminus is usually an ester or amide group resulting from initiation using an alkoxide or amido ligand.114,117  37  Figure 2.3 Coordination-insertion mechanism for the ROP of lactide114 Of particular interest is living polymerization, which is a chain polymerization from which chain transfer and chain termination are absent. In many cases, the rate of initiation is fast in comparison to the rate of propagation so that the number of chain carriers is consistent throughout the polymerization. As a result, all polymer chains are theoretically the same length and a PDI of close to 1 is obtained. PDI is a measure of the distribution of molecular weights in a given polymer sample. PDI is calculated from the number average molecular weight (Mn) and the weight average molecular weight (Mw) (Equations 1-3).122 Furthermore, these polymerizations provide control over the molecular weights of the resultant polymers, as changes to the monomer to initiator ratio, ([M]/[I]), affect the molecular weight in a predictable and linear 38  fashion. Living polymerizations are of interest because such controlled polymer formation yields narrow PDIs that exhibit unique physical properties. Mn = (Σ Mi Ni) / (Σ Ni)  (1)  Mw = (Σ Mi2 Ni) / (Σ Mi Ni)  (2)  Where: Mi = molecular weight of a polymer chain Ni = number of chains of that molecular weight. PDI = Mw / Mn  (3)  One advantage of PLA over other linear biodegradable polyesters, for example poly(εcaprolactone) (PCL), is the addition of the methyl side chain. This methyl group allows for different tacticities to result from the ROP of racemic lactide (Figure 2.4). Tacticity is the relative stereochemistry of adjacent stereocenters within a polymer.122 Tacticity is important, as PLAs with different tacticities have been shown to exhibit different physical properties; for example, isotactic PLA is crystalline and atactic PLA is amorphous.123 There are four main tacticities that can theoretically result from the ROP of raclactide;122,124 atactic PLA is described as a random distribution of R- and S- configurations within the PLA chains, isotactic PLA is described as chains containing the same configuration at the methine sterocenters throughout the polymer (either R- or S-), heterotactic PLA is assigned when the configuration of the methine stereocenters alternates between two R- and two Sconfigurations, and stereoblock PLA contains chains with alternating blocks of all R- or Sconfiguration.114,115,124 These different tacticities arise from different mechanisms of 39  stereocontrol. The two different types of stereocontrol are site control and chain-end control. Site control occurs when the environment surrounding the active site of the initiator results in a preference for one lactide enantiomer over the other. Chain-end control occurs when the incoming enantiomer of lactide is selected based on the stereochemistry of the last incorporated monomer into the polymer chain.122 Atactic PLA is formed when the incoming monomer is chosen at random. Isotactic PLA can theoretically be produced in three different ways;122 when the monomer is enantiomerically pure, i.e. L- or D-lactide, when the initiator is a mixture of enantiomers, and each complex enantiomer only polymerizes one of the enantiomers of lactide (would follow a site control mechanism), or through a chain-end control mechanism. To date, the formation of isotactic PLA from rac-lactide has not been reported. However, the formation of isotactic-stereoblock PLA has been reported; for example by using a chiral Schiff base aluminum alkoxide initiator which polymerizes through a chain-end control mechanism.125 Heterotactic PLA is also produced through a chain-end control mechanism, where the incoming monomer is selected to have the opposite stereochemistry of the previously ring-opened monomer.114 Finally, stereoblock PLA can also be produced two different ways. The first is when the two enantiomers of lactide are added alternately. The first enantiomer is added and polymerized to completion, then the second enantiomer is added and allowed to polymerize completely before the next addition, and so forth. Secondly, as mentioned above, stereoblock PLA is formed when a chiral initiator is used and errors occur in the chain-end control mechanism.125 The first method can produce stereoblock PLA with consistent block sizing if a living catalyst is used.  40  Within a given polymer sample, there can be regions containing the different tacticities listed above, and these can be found in the polymer to varying degrees. The extent of each tacticity is determined by probability;114,122,126 the probability of isotactic enchainment is designated by Pm and the probability of heterotactic enchainment is designated by P r. These values are determined by statistical analysis of the {1H}1H NMR spectrum of PLA.127 The statistical analysis is based on tetrads within the PLA chains. A tetrad is four adjacent sterocenters. Each adjacent stereocenter pair is assigned to be either a meso (m), (R,R or S,S) or racemic (r) (R,S or S,R) linkage, and each tetrad is then assigned to be either mmm, mmr, mrm, mrr, rmm, rrm, rmr, or rrr (an example can be found in Figure 2.4). Using these assignments and the {1H}1H NMR spectrum, the extent of stereocontrol is determined by Bernoullian statistics (see Appendix A).  41  Figure 2.4 The theoretical tacticities of PLA The ROP of lactide has been studied for decades, and a very large number of initiators have been reported.114,115,117,124,128-135 These initiators span the periodic table and include both inorganic-  115,128,129,131,132,136  and organic-based molecules.134,135 Metal-based initiators include  compounds containing metals from groups 1-14 and the lanthanide series.115,128,129,131,132,136 The ROP of lactide using complexes of rare-earth metals has been an area of great interest in recent 42  years and a large number of complexes have been reported as effective initiators.115,128-130 Rareearth metal complexes are attractive initiators due to their Lewis acidity, high polymerization activity, and low toxicity.137 Selected examples of known N,O- and N,N-chelating yttrium initiators for the ROP of rac-lactide are shown in Figure 2.5 and some of their polymerization results are listed in Table 2.1. The characteristics of polymers resulting from the ROP of rac-lactide, molecular weight and molecular weight distributions as measured by the polydispersity index (PDI), are highly dependent on polymerization conditions. Varying temperature, solvent, monomer to initiator ratio ([M]/[I]) etc. can have a distinct effect and thus the reported examples provide a guide for the use of yttrium initiators in the ROP of rac-lactide.  43  Figure 2.5 A selection of known yttrium containing initiators for the ROP of lactide94,138-141 Compound 2.3 is an N,N chelating yttrium(amidinate) complex containing a phenoxide ligand.138 This complex with one equivalent of benzyl alcohol was reported to polymerize raclactide effectively at high [M]/[I] ratios at room temperature yielding PLA with a high molecular weight, though lower than the theoretical value (Mn (calc)), and a reasonably narrow PDI, PDI ≤ 1.5 (Table 2.1, entry 1). Other yttrium species with N,O chelating ligands such as complexes 2.4 and 2.5 have also been reported for the ROP of rac-lactide.139,141 Bis-alkyl complex 2.4 and phenoxytriamine complex 2.5 are also reported to be effective initiators for this polymerization, resulting in polymers with high molecular weights and PDIs. In fact, the molecular weight obtained for the PLA synthesized with complex 2.5 was very close to the theoretical value. The 44  bis- diamido dimer of yttrium, complex 2.6, was highly active in the ROP of rac-lactide, requiring only 3.7 minutes to reach full conversion.94 In addition, complex 2.6 produced PLA with a molecular weight more than double the calculated value, but with a broader PDI. Finally, the bis-amido species complex 2.7 is an example of a less active initiator, requiring nearly a day (16 hours) to reach a conversion of 81%.140 Although slower reactivity can often impart control, the ROP of rac-lactide with complex 2.7 resulted in PLA with a molecular weight significantly lower than calculated value and a PDI nearing 2. Table 2.1 Comparison of yttrium initiators for the ROP of lactide  It is clear from the results reported for yttrium complexes 2.3 – 2.7 that a number of different systems can initiate the ROP of lactide. The molecular weight, PDI, and yield of PLA have been shown to be influenced by the ligands coordinated to the yttrium metal center. Therefore, a ligand set that is easily accessed and modified is an ideal target for optimization of the synthesis of PLA. This chapter will detail the study of yttrium amidate complexes as rapid initiators for the ROP of rac-lactide. 45  2.1.1 Scope of Chapter Successes achieved by the Schafer group in utilizing yttrium amidate complexes as initiators for the ROP of ε-caprolactone104 as well as reports of other rare-earth complexes as initiators for the ROP of cyclic esters,102,106 inspired the investigation of yttrium amidate complexes for the ROP of rac-lactide. Yttrium amidate complexes are easily synthesized through protonolysis of commercially available Y(NSiMe3)2)3 with a highly modular amide proligand,104,105 which provides a simple means of tuning the steric and electronic properties of resulting complexes. These N,O chelating amidate ligands are very similar to the N,N amidinate and N,N guanidinate chelating ligands whose complexes have been reported as effective initiators for the ROP of rac-lactide.55,56 As mentioned in Section 2.1, a large number of rareearth complexes have been reported for this reaction, employing a range of stoichiometries with respect to the number of coordinated ligands. Based on these findings, yttrium complexes coordinating one, two, or three amidate ligands were tested for their activity in the ROP of raclactide. Investigations into the polymerization mechanism will also be included in this chapter.  2.2  Yttrium Amidate Complexes as Initiators  2.2.1 Results and Discussion 2.2.1.1 Comparison of Mono-, Bis-, and Tris(amidate) Complexes Several mono-, bis-, and tris(amidate) complexes of yttrium (2.9 - 2.14) were synthesized as described in the literature and below (Scheme 2.2).104,105 Complex 2.9 was synthesized through protonolysis of Y(N(SiMe3)2)3 with amide proligand N-(2,6-diisopropylphenyl)t-butyl 46  amide (2.8) in tetrahydrofuran (THF). Two equivalents of amide proligand (2.8) were dissolved in THF and added drop-wise to a stirring solution of Y(N(SiMe3)2)3, also in THF. The mixture was heated at 65 °C for 2 hours. The volatiles were removed and the residue was re-dissolved in toluene and heated at 90 °C for an additional 2 hours. The initial heating in THF resulted in a mixture of tris-, bis-, and mono(amidate) complexes. Additional heating at a higher temperature in toluene forced ligand redistribution to the thermodynamic bis(amidate) complex.105 After work-up, a white crystalline solid was obtained. Complex 2.9 was characterized by 1H NMR spectroscopy where diagnostic signals were found at 1.33 ppm arising from the t-butyl protons and 0.51 ppm from the remaining hexamethyldisilylamide protons. The signals at 3.40 and 1.33 ppm confirmed the presence of the coordinated molecule of THF. Complex 2.9 was also fully characterized by 13C{1H} NMR spectroscopy, mass spectrometry, and elemental analysis.  Scheme 2.2 Synthesis of bis(amidate) complex 2.9 To probe the effect of the number of coordinated amidate ligands on the initiator, two different amide proligands were investigated: N-(2,6-diisopropylphenyl)t-butyl amide (2.8) and N-(2,6-diisopropylphenyl)-1-naphthamide. These two ligands were chosen based on the catalytic activity of their tris-, bis-, and mono(amidate) complexes in the ROP of ε-caprolactone and hydroamination of aminoalkenes.104,105 Complexes 2.10 – 2.14 were synthesized as describe in 47  the literature.104,105 As complexes 2.10, 2.11, and 2.12 contain the same amidate ligand, in addition to complexes 2.13, 2.9, and 2.14, a direct comparison can be made to determine which number of coordinated amidate ligands is ideal to initiate the ROP of rac-lactide.  Figure 2.6 Tris-, bis-, and mono(amidate) complexes of yttrium The experimental procedure used for the initial ROP of rac-lactide with complexes 2.9 – 2.14 was adapted from the procedure for the ROP of ε-caprolactone using yttrium amidate complexes reported in the literature.104 Initial reactions used a monomer to initiator ratio [M]/[I] ratio of 400 to ensure enough PLA was formed for easy isolation (the effect of [M]/[I] ratio will be discussed later in this chapter). In an inert atmosphere, rac-lactide was dissolved in 4 mL of dry THF. A solution of initiator was prepared in THF and 1 mL was added to the rapidly stirring solution of rac-lactide. Generally reactions were stirred vigorously for 15 minutes prior to exposure to air, quenched with a solution of 1:100:600 HCl:CH3OH:CHCl3 and precipitated 48  from cold methanol. The polymerization data for complexes 2.9 – 2.14 are shown in Table 2.2. Data is reported as an average of three runs. Table 2.2 Comparison of initiators for the ROP of rac-lactide using a [M]/[I] of 400  In addition to the general polymerizations mentioned above, the ROP of rac-lactide was also monitored by 1H NMR spectroscopy to observe the progress of the reactions as a function of time. In these reactions, as with the general polymerizations, 1 mL of a solution of initiator was added to 4 mL of rapidly stirring rac-lactide solution. However, in these polymerizations a small aliquot of the reaction mixture (<0.1 mL) was removed at set intervals and quenched by immediate precipitation in hexanes. The volatiles were removed from each sample and the resulting residue was dissolved in CDCl3 and a 1H NMR spectrum collected. The percent conversion can be calculated from the relative integrals of the methine signals of the rac-lactide and PLA (5.07 ppm and 5.20 ppm respectively). When the percent conversion is plotted against time the progress of the reaction can be monitored (Figures 2.7 and 2.8).  49  In the case of the tris-, bis-, and mono(amidate) complexes containing proligand N-(2,6diisopropylphenyl)-1-naphthamide (2.10 – 2.12), polymerizations resulted in near quantitative yield of PLA (Table 2.2). Although the yield of polymer obtained for all three complexes was identical, the molecular weights and PDIs were significantly different. It is shown in Table 2.2 that using tris(amidate) complex 2.10 resulted in the highest molecular weight and narrowest PDI. In fact, the molecular weights of the PLAs resulting from initiation with complexes 2.11 and 2.12 were almost half that observed with complex 2.10, well below the calculated molecular weight of 5.8 x 104 g/mol.142 Despite the large difference in molecular weights and PDIs, it can be seen in Figure 2.7 that there was little difference in the progress of the polymerizations when the number of coordinated amidate ligands was changed. In fact, all three reactions had reached completion within only 5 minutes, which is quite fast for an yttrium system, and fast for the ROP of rac-lactide in general.  50  100 90  % Conversion  80 70 60 50 40 30 20 10 0 0  50  100  2.10  150 200 Time /s 2.11  250  300  350  2.12  Figure 2.7 Plot of percentage conversion over time during ROP of rac-lactide using initiators 2.10 – 2.12 ([M]/[I] = 400, room temperature)  51  100 90  % Conversion  80 70 60 50 40 30 20 10 0 0  200  400 600 Time /s 2.13  2.9  800  1000  2.14  Figure 2.8 Plot of percentage conversion over time during the ROP of rac-lactide using initiators 2.13, 2.9, and 2.14 ([M]/[I] = 400, room temperature) In the case of the mono-, bis-, and tris(amidate) complexes containing proligand N-(2,6diisopropylphenyl)t-butyl amide (2.13, 2.9, and 2.14), polymerizations also resulted in near quantitative yield. As was seen with complex 2.10, tris(amidate) complex 2.13 produced the PLA with the highest molecular weight, and additionally, the PLA with one of the broadest PDIs. Although mono(amidate) complex 2.14 compared well with the results for complex 2.12, bis(amidate) complex 2.9 had a significantly lower molecular weight than complex 2.11 (Table 2.2,entries 2, 3, 5, and 6). As with complexes 2.10 – 2.12, changing the number of coordinated amidate ligands had very little effect on the progress of the polymerizations (Figure 2.8). However, complexes 2.13, 2.9, and 2.14 reacted slightly slower than complexes 2.10 – 2.12; they 52  required 10 minutes and 15 minutes for complete polymerization using complex 2.13 and complexes 2.9 and 2.14 respectively. Tris(amidate) initiators 2.10 and 2.13 were found to have ideal polymer properties (high molecular weights and narrow PDIs). In addition, these initiators completed the polymerizations with the shortest reaction times. Therefore, further optimizations and investigations were performed with the tris(amidate) ligand framework. Further studies included varying the [M]/[I] ratio to find optimized conditions and test for “living” polymerization, and varying the steric and electronic properties of the amidate backbone to potentially tune the initiator activity.  2.2.1.2 Effect of Amidate Ligand on Initiator As has been shown in the literature,114,115,117 both spectator and non-spectator ligands can influence the polymer resulting from the ROP of rac-lactide. Ligands can affect molecular weight, PDI, tacticity, and yield. Having determined that the tris(amidate) coordination environment was the best for initiation of the ROP of rac-lactide, a number of tris(amidate) complexes of yttrium were synthesized to investigate the effect of varying the steric and electronic properties of the amidate ligands. One major advantage of these amidate ligands is that the amide proligand can be synthesized in a modular fashion, through reaction of an acid chloride with a primary amine (Scheme 2.3). This allows for easy variation of the steric and electronic properties of the resulting amidate ligands; five tris(amidate) complexes were synthesized using different amide proligands (Figure 2.9). These amide proligands and their associated complexes were synthesized as described in the literature.104,143  53  Scheme 2.3 General synthesis of amide proligands  Figure 2.9 Yttrium tris(amidate) complexes containing amidate ligands with varying steric and electronic properties It was first noted that the t-butyl substituent of complex 2.13 is slightly more electrondonating than the naphthyl substituent of complex 2.10, thus allowing for the comparison of ligand electronic properties.143 The effect of steric bulk was investigated by comparison of complexes 2.13 and 2.15 due to the decrease in steric bulk on the nitrogen substituent when the 2,6-diisopropylphenyl group was exchanged for a 2,6-dimethylphenyl group. This small adjustment to the steric bulk was proposed to give insight into the effect of protecting the active site during the ROP. Finally, complexes 2.16 and 2.17 were probed for the electron-withdrawing 54  property of the trifluoromethyl substituents on the carbonyl side of their amide proligands. The electron-withdrawing substituents were proposed to draw electron density away from the metal center, thus causing the yttrium metal center to be more Lewis acidic. Each of the complexes listed above (complexes 2.10, 2.13, and 2.15 – 2.17) was used as an initiator in the ROP of rac-lactide and the results are shown in Table 2.3. As with the experiments used to probe the effect of the number of coordinated amidates, each of the initiators was tested using the same conditions as mentioned in Section 2.2.1.1; the polymerizations were also monitored by 1H NMR spectroscopy to determine the conversion of rac-lactide to PLA over time (Figure 2.10). Table 2.3 Comparison of initiators for the ROP of rac-lactide for tris(amidate) complexes 2.10, 2.13, 2.15, 2.16, and 2.17 using a [M]/[I] of 400  Changing from the fairly electron-neutral naphthyl substituent to the more electrondonating t-butyl substituent (complexes 2.10 and 2.13, Table 2.3, entries 1 and 2) had very little effect on the Mn of the resulting polymer. There was a negligible increase in yield accompanying 55  a small increase in both molecular weight and PDI for the PLA synthesized with complex 2.13. It was also shown that there was very little difference in reaction time as both polymerizations were near 100% conversion by 10 minutes.  100 90  % Conversion  80 70 60 50 40 30 20 10  0 0  200  2.10  400 600 Time /s  2.13  2.15  2.16  800  1000  2.17  Figure 2.10 Plot of percentage conversion over time during the ROP of rac-lactide using initiators 2.10, 2.13, and 2.15 – 2.17 ([M]/[I] = 400, room temperature) Comparison of complexes 2.13 and 2.15 as initiators showed more significant differences. Decreasing the steric bulk decreased the molecular weight and increased the PDI although the yield remained very high and the reaction time remained very short (near quantitative conversion in 5 minute). Finally, complexes 2.16 and 2.17 were tested as initiators to investigate the effect of increasing the electron-withdrawing nature of the amidate ligand. The addition of one 56  trifluoromethyl group (2.16) had a large impact on the ROP. Although the PDI and yield were unchanged, the molecular weight of the PLA dropped by a third. Also, monitoring the percent conversion over time (Figure 2.10) showed that the reaction was significantly slower, proceeding to only 56% after the 5 minutes necessary for completing the polymerization with complex 2.10. The addition of a second trifluoromethyl group (2.17) had an even larger impact. The molecular weight increased to 1.5 times that obtained with complex 2.16 as the initiator and a slight narrowing of the PDI was also observed. In addition, the reaction with complex 2.17 was significantly slower than with any other complex. In fact, a maximum of 87% yield was obtained, and only after allowing the polymerization to proceed for 30 minutes. Continued monitoring of the reaction showed no further increase in polymer yield. The results discussed above indicate that complexes 2.10, 2.13, and 2.15 – 2.17 are effective initiators for the ROP of rac-lactide. However, the variations in the steric and electronic properties of the tris(amidate) initiators explored here resulted in modest changes in the resulting polymer. It was demonstrated that using a bulkier diisopropylphenyl substituent rather than a dimethylphenyl substituent provided increased protection of the active site and resulted in a higher molecular weight and narrowed PDI. Also, it was found that the slightly electronwithdrawing nature of the naphthyl substituent resulted in a high yield of PLA with one of the lowest PDIs and highest molecular weights. Consequently, it was determined that complex 2.10 was the preferred initiator for the ROP of rac-lactide, and therefore, further investigations were performed using complex 2.10 as the initiator.  57  2.2.1.3 Effect of Monomer to Initiator Ratio[M/I] Investigations The monomer to initiator ([M]/[I]) ratio used in a polymerization reaction can have a substantial effect on the Mn of the resulting polymer. In the case of living polymerization, the molecular weight of the polymer increases linearly with the [M]/[I] ratio. The [M]/[I] ratio used for the ROP of rac-lactide using complex 2.10 as the initiator was varied to investigate how it affected the polymer produced. The polymerization reactions using varying [M]/[I] ratios were carried out under the same reaction conditions as the experiments comparing the mono-, bis-, and tris(amidate) complexes (Section 2.2.1.1). A large set of [M]/[I] ratios was tested for the ROP and rac-lactide and the polymerization results as shown in Table 2.4. Table 2.4 Summary of the ROP of rac-lactide for initiator 2.10  Entries 1-4 of Table 2.4 showed that the molecular weight obtained for the PLA produced with [M]/[I] ratios of 50 – 300 increased linearly. In fact, the molecular weights obtained for these [M]/[I] ratios were very close to the calculated molecular weights (see Figure 2.11). 58  However, when the [M]/[I] ratio was increased to 400 and 500, there was a break in linearity. The molecular weights of the PLA obtained with the higher [M]/[I] ratios did not follow the previous trend and, therefore, did not match the calculated molecular weights, indicating that the polymerization was not living. Interestingly, the molecular weights obtained from [M]/[I] ratios 300, 400, and 500 also formed a linear trend. The PDIs obtained for the PLA produced at all five [M]/[I] ratios were consistent with what has been reported for these yttrium(amidate) complexes thus far, however there was a slight increase in PDI with the increase in [M]/[I] ratio. This is likely due to an increase in transesterification which might have occurred with the increase in the concentration of lactide and PLA that occured at higher [M]/[I] ratios. The increase in PDI may also be attributed to the increase in yield observed with the increase in [M]/[I] ratio (Table 2.4).  160000  140000  Mn /gmol-1  120000 100000 80000 60000 40000 20000 0 0  100  200  Calculated  300 [M/I]  400  500  600  Experimental Data  Figure 2.11 Mn values of PLA synthesized at different [M]/[I] ratios using complex 2.10 at room temperature in THF 59  It was found that there was no formation of polymer when the [M]/[I] ratio was increased to 600 and above. This result can be accounted for by the decomposition of complex 2.10. It is probable that a minute quantity of impurity, likely deleterious water, was responsible for initiator decomposition during the polymerizations. As the [M]/[I] ratio increased, the amount of impurity increased and thus the amount of decomposition increased. This resulted in an even higher experimental [M]/[I] ratio than calculated and, therefore, an increase in the molecular weight from that of the calculated value. The amount of impurity necessary to decompose all of complex 2.10 was likely present when a [M]/[I] ratio of 600 or higher was tested, resulting in no polymer formation. The polymer obtained using a [M]/[I] ratio of 400 had a high molecular weight, relatively narrow PDI, and high yield. Based on these results, a [M]/[I] ratio of 400 was used for investigations into the effects of polymerization temperature and solvent.  2.2.1.4 Effect of Solvent and Temperature on Reactivity Much like the steric and electronic properties of ligands and the [M]/[I] ratio, polymerization solvent can have a profound effect on the polymer produced. In fact, there can be quite a difference in polymers produced in coordinating versus non-coordinating solvents. Depending on the affinity of the coordinating solvent for the metal center, these solvents can compete with the monomer molecule for the active site. The ROP of rac-lactide with complex 2.10 as the initiator was performed in three different solvents: THF, dichloromethane, and toluene. Polymerization reactions were carried out with the same reaction conditions as the experiments comparing the mono-, bis-, and 60  tris(amidate) complexes (Section 2.2.1.1) with the exception of solvent. The polymerization results can be found in Table 2.5. It was found that PLA produced from polymerizations in THF and dichloromethane had very similar properties including high molecular weights and narrow PDIs. rac-Lactide is only sparingly soluble in toluene, therefore, it was proposed that using toluene as the polymerization solvent would allow the rac-lactide to be added to the reaction in a slow controlled manner. The PLA synthesized from the ROP of rac-lactide in toluene would therefore have a molecular weight consistent with the calculated value and a narrow PDI as monomer would likely be added in a slower more controlled manner. However, the PLA produced in toluene had a molecular weight that was lower than the calculated value (5.76 x 104 g/mol),144 and a much broader PDI indicating that the slow addition did not impart control over the polymerization. In addition to analyzing the polymers by GPC, a {1H}1H NMR spectrum was obtained for each sample. The Pr values listed in Table 2.5 indicated that the ROP of rac-lactide in non-coordinating solvents like dichloromethane and toluene resulted in atactic PLA. Interestingly, the ROP of rac-lactide in coordinating THF resulted in PLA with a slight heterotactic bias. Some THF may be coordinated during all or part of the polymerization and the additional steric bulk present at the metal center is likely responsible for the slight bias in tacticity. As the PLAs resulting from polymerizations performed in THF and dichloromethane had higher yields, higher molecular weights, and narrower PDIs, the effect of these two solvents was explored further.  61  Table 2.5 Comparison of initiator ability for the ROP of rac-lactide using complex 2.10 in different solvents  By monitoring the polymerizations using 1H NMR spectroscopy as mentioned in previous sections, the relative activity of the two solvents could be directly compared. The plot of percent conversion versus time (Figure 2.12) shows that while the polymerization occurs rapidly in both solvents, nearly full conversion occurs faster in dichloromethane, requiring only 2 minutes in comparison to 5 minutes. The slightly slower reaction time obtained with THF was likely due to the competition between the incoming lactide molecule and the surrounding solvent. The samples acquired for 1H NMR spectroscopy were also analyzed by GPC and the molecular weight as a function of percent conversion was plotted for the polymerizations in both solvents (Figure 2.13). As expected, the molecular weights of the polymers obtained using both solvents were higher than the calculated values. This was consistent with the discussion of the effect of [M]/[I] ratio from earlier in the chapter. However, it was noted that the molecular weights of the polymers from both solvents increase linearly with percent conversion. This type of trend is consistent with living-polymerization, however previously discussed results suggest further investigation was necessary and these results will be discussed later in this chapter. 62  100 90  % Conversion  80 70 60 50 40 30 20 10 0  0  200  400 600 Time /s THF  800  1000  DCM  Figure 2.12 Plot of percentage conversion over time during the ROP of rac-lactide using initiator 2.10 ([M]/[I] = 400, room temperature in dichloromethane and THF)  63  100000 90000 80000  Mn /gmol-1  70000 60000  50000 40000 30000 20000 10000 0 0  20  THF (experimental)  40 60 % Conversion DCM (experimental)  80  100  calculated  Figure 2.13 Mn values of PLA synthesized at different percent conversions using initiator 2.10 ([M]/[I] = 400, room temperature in dichloromethane and THF) The polymerization of rac-lactide using complex 2.10 is extremely rapid. It is this high activity that is likely responsible for the broad PDIs obtained for the resulting polymers. Decreasing the rate of polymerization could help in lowering the PDI of the resulting polymer, therefore, to decrease the reaction rate, the polymerizations were performed at 0 °C. Polymerizations were performed using a vacuum manifold; a 1 mL solution of initiator was transferred from a Schlenk tube cooled to 0 °C via cannula to second Schlenk tube cooled to 0 °C containing a rapidly stirring solution of rac-lactide (4 mL) and left to stir for 30 minutes.  64  Polymerizations were performed in THF and dichloromethane and the polymerization results can be found in Table 2.6. Table 2.6 Comparison of initiator ability for the ROP of rac-lactide using complex 2.10 at different temperatures  For the polymerizations performed in dichloromethane at 0 °C, there was little change to the resulting polymer. The PLA showed a slight decrease in molecular weight and a slight increase in PDI, but these results did not indicate that an increase in control was obtained. There was however a large change in the PLA formed in THF at 0 °C. While the PDI changed only slightly, the molecular weight nearly doubled. This is likely due to the competitive binding of the lactide monomer with the THF. If the affinity for the metal center of THF increases with respect to lactide at colder temperatures, it is possible that some of the molecules of complex 2.10 were prevented from coordinating monomer and, therefore, initiating polymerization, resulting in fewer but longer polymer chains. This would account for the increase in molecular weight without a large increase in PDI. These results also did not indicate an increase in control over the polymerization. 65  To investigate the possibility of an induction period, the polymerization in dichloromethane at 0 °C was monitored by 1H NMR spectroscopy. This investigation could not be performed as one single experiment with aliquots removed since catalyst decomposition could not be prevented throughout the full length of the experiment. Instead, an individual experiment was run for each of the aliquots needed. As is shown in Figure 2.14, the results of these experiments are inconsistent. Although the plot of percent conversion vs. time (Figure 2.14) is consistent with that obtained for polymerizations at room temperature, the molecular weights do not follow a general trend. The molecular weights obtained for each percent conversion varied greatly during replicates and thus conclusions could not be made.  90 80  % Conversion  70 60 50 40 30 20 10 0 0  500  1000 Time /s  1500  2000  Figure 2.14 Plot of percentage conversion over time during the ROP of rac-lactide using initiators 2.10 ([M]/[I] = 400, 0°C, DCM)  66  2.2.1.5 Mechanistic Investigations The investigations of yttrium(amidate) complexes in the ROP of rac-lactide shown in the previous sections clearly indicated that these polymerizations are not well-controlled. These initiators are highly active and produce PLA effectively, however improvements could be made with respect to PDIs and stereocontrol; probing the ROP mechanism for these initiators could provide the insight necessary to make improvements. The first step in probing the ROP mechanism of complex 2.10 was to identify the polymer end groups. The fact that complex 2.10 is a homoleptic complex with the exception of a coordinated molecule of THF, proved useful as a non-ligand based end group would indicate that an alternative complex is formed in situ and is responsible for initiation. End group analysis was performed on polymer produced during the ROP of rac-lactide in THF at room temperature using complex 2.10 with a [M]/[I] ratio of 400 (Scheme 2.4). Looking closely at the 1H NMR spectrum of the PLA it was noted that there were no signals present due to the ligand (o-naphthyl proton doublet was absent) or a methylene group next to a hydroxyl functionality, indicating that the polymer had no end groups (Figure 2.15). To confirm the absence of polymer end groups, MALDI-TOF mass spectrometry was employed. A sample of PLA was synthesized with complex 2.10 using a [M]/[I] ratio of 50. This smaller [M]/[I] ratio was necessary due to the molecular weight limits of mass spectrometry. A MALDI-TOF MS was obtained (M = 72 x n) and the molecular weights shown were all multiples of 72 (half a lactide unit) indicating that no end group was present. Based on the MALDI and 1H NMR spectra, a very large PLA ring was proposed (Scheme 2.4). PLA rings have been reported previously by the Chisholm 145,146 and Waymouth147-149 groups as well as a few others.150-152 The Chisholm group reported fairly small 67  ring sizes (eg. 20 x C3H4O2, i.e. 10 rac-lactide units) and the Waymouth group reported significantly larger ring sizes (Mn = 0.5 – 3.0 x 104 gmol-1).  Figure 2.15 1H NMR spectrum of PLA (600 MHz, C6D6, 25 °C) (insert is an expansion of the naphthyl region)  Scheme 2.4 The ROP of rac-lactide with complex 2.10 68  With the proposal of a large PLA ring resulting from these polymerizations, experiments were performed to probe how this occurred. The first experiment was designed to determine if the ring was formed during the quenching procedure or spontaneously once the available monomer was consumed. To test this, complex 2.10 was used to polymerize rac-lactide using the reported conditions. Upon completion of the reaction (15 minutes), a small aliquot was removed and quenched and additional rac-lactide was added to the reaction mixture and left to stir for 15 minutes. The reaction was then quenched and a small aliquot was removed before following the reported isolation procedure. 1H NMR spectra were obtained for the two aliquots once the volatiles were removed, and the residue dissolved in CDCl3. Integration of the methine signals for rac-lactide and PLA showed near quantitative conversion for the initial polymerization and no further reaction when the additional monomer was added. A 79 percent yield was obtained for the overall reaction, confirming that no further polymerization occurred with additional raclactide. These results indicated that once the available monomer was consumed, the initiator was deactivated and thus prevented further polymerization. An alternative proposal for the deactivation of the initiator was the formation of either a four- or five-membered metallacycle (Scheme 2.5). In this case, once the available monomer is converted to polymer, the polymer chain, either coordinated to that complex or that of another complex, could occupy the open coordination site through formation of a four- or five-membered metallacycle. The large polymer chain could then block the coordination of newly added monomer thus deactivating the initiator preventing further polymerization. This proposal accounted for the deactivation of the initiator once the available monomer was consumed placing the polymer chain in a good position to form a large PLA ring.  69  Scheme 2.5 Proposal for the deactivation of initiator 2.10 Additional experiments were conducted to further probe the formation of the PLA ring. The possibility of transesterification was investigated with the first experiment involving analysis of the solvent used in the isolation of PLA for oligomers with end groups. Complex 2.10 was once again used as an initiator to ROP rac-lactide. Once the polymerization was complete, the polymer was isolated as reported above, however the precipitation solvent was retained instead of being discarded as usual. The PLA was re-precipitated multiple times, and in each case the precipitation solvent was retained. Once the volatiles were removed, the residues remaining from each precipitation were analyzed by mass spectrometry. Although small oligomers were present in each of the samples, there were no signals with masses corresponding to an oligomer with a proligand end group. The investigations into the formation of a large PLA ring during the polymerization of rac-lactide using complex 2.10 indicated that the ring formed spontaneously once there was no 70  more available monomer, but prior to quenching. The absence of small oligomers with end groups in the precipitation solvents indicated that the ring formation did not occur via transesterification in the middle of the PLA chain. Future work involving the ROP of lactide with these yttrium amidate initiators should take into account the formation of large cyclic polymers when analyzing polymers and probing mechanisms.145-152 To further investigate the ROP mechanism using complex 2.10, stoichiometric reactions were performed. Complex 2.10 was dissolved in d8-tol and added to two separate J-Young NMR tubes before solutions containing one and two equivalents of rac-lactide were added, one per NMR tube (Scheme 2.6 Reactions a and b). The reactions were shaken for a few minutes before a 1H NMR spectrum was obtained for each. The 1H NMR spectrum of reaction a showed that one of the amidate ligands was displaced (Figure 2.16). The diagnostic ortho-naphthyl signal for tris(amidate) complex 2.10 at 9.26 ppm decreased in size and a new signal appeared at 8.86 ppm which has been reported as the ortho-naphthyl signal of the free ligand.104 In addition, a very small signal appeared at 11.11 ppm which has been reported as the N-H proton of N-(2,6diisopropylphenyl)-1-naphthamide (2.19) when the amide is coordinated through the oxygen, not as the deprotonated N-O chelate.143 For this to have occurred, a proton must have been transferred from the lactide molecule present in the reaction mixture. This indicates the formation of an enolate complex (2.18) which has been proposed previously for this yttrium amidate initiator in the ROP of ε-caprolactone.143 The 1H NMR spectrum of reaction b showed a near complete disappearance of the ortho-naphthyl signal for tris(amidate) complex 2.10 at 9.26 ppm. This indicated the decomposition of complex 2.10. Mass spectra of the products formed in reactions a and b could not be obtained, as removal of the solvent under reduced pressure was shown to also remove rac-lactide. This was confirmed by comparing the 1H NMR spectra of the 71  reaction mixtures before and after the removal of solvent. Attempts to obtain crystals suitable for x-ray crystallography for products formed in reactions a and b were unsuccessful.  Scheme 2.6 Possible reactions of complex 2.10 with 1 and 2 equivalents of rac-lactide  72  Figure 2.16 1H NMR spectrum (300 MHz, D8-tol, 25 °C) of Scheme 2.6 reaction a Although the products formed during reactions a and b could not be fully characterized, the complexes formed in situ could have been formed during initiation of the ROP. Reactions mixtures a and b were, therefore, tested as initiators for the ROP of rac-lactide. These polymerizations were performed by first dissolving rac-lactide in THF followed by direct addition of the entire mixture from either reaction a or b. In both cases, formation of polymer did not occur. These results indicated that the initiation of the ROP either requires more than two equivalents of monomer, or requires immediate propagation to prevent a catalytic resting state from forming.  73  To further investigate the possibility of enolate formation during the ROP of rac-lactide, enantiopure L-lactide was polymerized to search for epimerization. If an enolate complex was being formed and used to initiate polymerization, epimerization of the methyl substituent of Llactide is likely to occur. The polymerization of L-lactide and the isolation of PLLA was performed as reported for the ROP of rac-lactide. A {1H}1H NMR spectrum was obtained for the resulting PLA and the data analyzed as mentioned in Section 2.2.1.4 (See Appendix A). Only a singlet was present in the methine region of the {1H}1H NMR spectrum indicating that no epimerization occurred at the methine carbon of PLA. This provided further evidence that proposed enolate complex is not involved in polymerization.  2.2.1.6  Summary  Overall, yttrium amidate complexes were shown to be good catalysts for the ROP of raclactide. Tris(amidate) complexes of yttrium were found to produce polymer of high molecular weight and narrow PDIs. Although bis(amidate) complexes 2.9 and 2.11 and mono(amidate) complexes 2.12 and 2.14 have been shown to be effective initiators, tris(amidate) complexes 2.10 and 2.13 produced polymer in a slightly higher yield and in a shorter period of time. Investigations into the effect of the amidate backbone indicated that varying the steric bulk of the nitrogen substituent had no effect on the polymerization. However, altering the electronics of the amidate had a profound effect. Comparison of the mildly electron-withdrawing naphthyl substituent with the electronically neutral t-butyl substituent and the electron-withdrawing trifluoromethyl substituted aryl rings showed that increasing the Lewis acidity of the metal center decreased the reactivity of the initiator. The presence of the more electron-withdrawing  74  naphthyl group (complex 2.10) increased the rate of reactivity and yield as well as produced a polymer with more ideal properties (high molecular weight and narrow PDI). Polymerization temperature and solvent were shown to have a significant effect on the polymer produced during the reactions with complex 2.10. Both THF and dichloromethane were effective solvents and facilitated the rapid polymerization of rac-lactide at room temperature. Although polymerizations were effective at 0 °C with complex 2.10, no additional control was obtained and reactions were inconsistent. Polymerizations in THF produced PLA with a heterotactic bias from rac-lactide while polymerizations in non-coordinating solvent resulted in atactic polymer. Probing the effect of the [M]/[I] ratio used during the polymerizations indicated the possibility of living polymerization. Further evidence came from the linear growth of molecular weight with percent conversion. However, investigations into the mechanism showed that complex 2.10 did not initiate the living polymerization of rac-lactide. Finally, end group analysis indicated that the final isolated polymer did not have end groups; therefore, it is likely a very large PLA ring. Observations made after attempting to add more monomer to the reaction once the reaction was complete indicated that the formation of the PLA ring likely occurred before quenching and resulted in deactivation of the initiator. Stoichiometric reaction of complex 2.10 and rac-lactide resulted in the proposal of enolate complex 2.20 with one equivalent of lactide and complex decomposition with the addition of two equivalents.  75  2.3  Conclusions Yttrium amidate complexes were found to be highly active initiators for the ROP of rac-  lactide. The tris(amidate) complexes were found to have greater control over the polymerization than bis- and mono(amidate) complexes. Variation of the steric and electronic properties of the amide proligand was shown to impact the properties of the resulting polymer. The combination of steric bulk on the nitrogen component of the amide proligand and a slight electronwithdrawing substituent on the carbonyl resulted in an initiator capable of synthesizing PLA with high molecular weight and moderate PDI. Therefore, complex 2.10 was determined to be the preferred initiator. Complex 2.10 was a highly active initiator, capable of the ROP of rac-lactide in 5 minutes with [M]/[I] ratios as high as 500. Although very fast in comparison to other reported group 3 and rare-earth complexes, polymerization with complex 2.10 showed little control and does not exhibit living behavior. The ROP of rac-lactide was proposed to follow a coordination-insertion mechanism followed by rapid propagation and termination through formation of cyclic PLA. Stoichiometric reaction of complex 2.10 and rac-lactide indicate that lactide can coordinate to the metal center, supporting the coordination mechanism. There are a number of inherent problems with the use of yttrium amidate complexes for the ROP of rac-lactide. These amidate complexes are highly sensitive to water, molecular oxygen, and high temperatures, therefore, the solvents, glovebox, and monomer used required additional preparations.  76  Overall, yttrium amidate complexes are highly active initiators for the ROP of raclactide, however more robust complexes should be targeted. The highly modular nature of the amide proligands allowed for the specific variation of ligand properties. Future research will take advantage of this tunable ligand set to synthesize more robust yttrium(amidate) complexes for further optimization and investigation of the ROP of rac-lactide.  77  2.4  Experimental  2.4.1 Starting Materials and Reagents All operations were performed under an inert atmosphere of dinitrogen using standard Schlenkline or glovebox techniques. THF, toluene, and hexanes were purified by passage through an alumina column and sparged with nitrogen. Dichloromethane was purified by refluxing over CaH2, distilling, and degassing before storing over molecular sieves. rac-Lactide was purified by subliming three times under reduced pressure. Y(N(SiMe3)2)3 was synthesized as described in the literature.153 Amidate complexes 2.10,104 2.11,105 2.12,105 2.13,143 2.14,143 2.15,104 2.16,104 and 2.17143 were synthesized as described in the literature. Amide proligand 2.8 was synthesized as described in the literature.104 All other chemicals were commercially available and used as received unless already stated. 1H and 13C NMR spectra were recorded on a Bruker AV300 and AV600 spectrometers at 298 K. Chemical shifts are reported in parts per million and referenced to residual solvent. All  13  C NMR spectra were proton-decoupled. Elemental analysis and mass  spectra were performed by the microanalytical laboratory of the Department of Chemistry at the University of British Columbia. Molecular weights were estimated by triple detection gel permeation chromatography using a Waters liquid chromatograph equipped with a Waters 515 HPLC pump, Waters 717 plus autosampler, Waters Styragel columns (4.6 x 300 mm) HR5E, HR4, and HR2, Waters 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 (ca. 4 mg•mL-1).  Absolute molecular weights were  determined using a dn/dc (change in refractive index/change in concentration) of 0.0558 mL•g-1.  78  2.4.2 Synthesis Synthesis of Bis(N-2’,6’-diisopropylphenyl(t-butyl)amidate)mono(trimethylsilylamido) yttrium Mono(tetrahydrofuran) (2.9) Inside a nitrogen filled glovebox, yttrium tris(bis(trimethylsilyl)amide) (0.232 g, 0.408 mmol) was dissolved in 5 mL of tetrahydrofuran with a stirbar in a 100 mL manual chemistry synthesizer tube. Once the solid was dissolved, a solution of N-(2,6-diisopropylphenyl)t-butyl amide 2.8 (0.213 g, 0.815 mmol) dissolved in 5 mL of tetrahydrofuran and was added drop-wise. The solution was stirred within the glovebox for 2 h at 65 °C and then filtered through Celite and concentrated under reduced pressure to give a white solid. The solid was redissolved in toluene and stirred at 90 °C for a subsequent 2 hours. The product was then concentrated again to a white solid and recrystallized by dissolving in hexanes with a few drops of toluene and leaving at -30 °C to give a white crystalline solid. Yield: 0.288 g, 84%. 1H NMR (300 MHz, C6D6): δ 7.20 (broad m, 6H, aryl-H), 3.40 (broad s, 4H, O-CH2), 3.13 (broad m, 4H, CH(CH3)2), 1.33 (overlapping: d, J = 6 Hz, 12H, CH(CH3)2, and broad s, 4H, O-CH2CH2), 1.08 (overlapping d and s, 30H, CH(CH3)2 and C(CH3)3), 0.51(s, 18H N(Si(CH3)3)2). 13C NMR (100.6 MHz, C6D6): δ 182.3(C=O), 141.2, 124.6, 124.5, 123.1 (aryl-C), 69.6 (O-CH2), 42.1 (O-CH2CH2), 23.4 (CH(CH3)2), 28.8 (C(CH3)3), 25.5 (CH3), 24.9 (CH3), 2.39 (N(Si(CH3)3)2). Anal. Found (calcd for C44H78N3O3Si2Y): C 63.11% (62.75%), N 5.30% (4.99%), H 9.22% (9.34%).  79  General Procedure for the Ring-opening Polymerization of rac-Lactide (400:1 Monomer to Initiator Ratio) at Room Temperature in THF, dichloromethane, or Toluene Inside a nitrogen filled glovebox, rac-lactide (0.500 g, 3.47 mmol) was dissolved in 4 mL of solvent and transferred to a 20 mL vial equipped with a stir bar. 1 mL of a solution of an yttrium(amidate) complex (0.00867 M) was transferred by syringe directly into the vigorously stirring solution of rac-lactide. The reaction was stirred for 15 min within the glovebox and then exposed to air and quenched with 1 mL of quenching solution (1/100/600 of HCl/CH3OH/CHCl3). The sample was evaporated to dryness and redissolved in toluene (with the exception of reactions in toluene). The polymer was precipitated from cold methanol and dried overnight in vacuo. General Procedure for the Monitoring the Ring-opening Polymerization of rac-Lactide (400:1 Monomer to Initiator Ratio) at Room Temperature in THF or dichloromethane by 1  H NMR  Inside a nitrogen filled glovebox, rac-lactide (0.500 g, 3.47 mmol) was dissolved in 4 mL of solvent and transferred to a 20 mL vial equipped with a stir bar. 1 mL of a solution of an yttrium(amidate) complex (0.00867 M) was transferred by syringe directly into the vigorously stirring solution of rac-lactide. At set intervals an aliquot was removed and quenched with hexanes. For each aliquot, the volatiles were removed and the sample diluted with CDCl 3 prior to obtaining a 1H NMR spectrum of each.  80  General Procedure for the Ring-opening Polymerization of rac-Lactide (500:1, 400:1, 300:1, 200:1, 100:1, 50:1 Monomer to Initiator ratio) with Complex 2.10 at Room Temperature in THF Inside a nitrogen filled glovebox, complex 2.10 (0.1017 g, 0.0882 mmol) was dissolved in 10 mL of THF in a volumetric flask. rac-Lactide ((500:1; 0.6242 g, 4.331 mmol) (400:1; 0.5005 g, 3.472 mmol) (300:1; 0.3754 g, 2.604 mmol) (200:1; 0.2515 g, 1.745 mmol) (100:1; 0.1250g, 0.8673 mmol) (50:1; 0.0637 g, 0.442 mmol)) was dissolved in 4 mL of THF and transferred to a 20 mL vial equipped with a stir bar. 1 mL of the stock solution of complex 2.10 was transferred directly into the vigorously stirring solution of rac-lactide. The reaction was stirred for 15 min within the glovebox and then exposed to air and quenched with 1 mL of quenching solution (1/100/600 of HCl/CH3OH/CHCl3). The sample was evaporated to dryness and redissolved in toluene. The polymer was precipitated from cold methanol and dried overnight in vacuo. General Procedure for the Ring-opening Polymerization of rac-Lactide (400:1 Monomer to Initiator Ratio) at 0 °C in THF or dichloromethane Inside a nitrogen filled glovebox, rac-lactide (0.500 g, 3.47 mmol) was dissolved in 4 mL of solvent and transferred to a 25 mL Schlenk tube with a stir bar and sealed with a stopper. 1 mL of a solution of complex 2.10 (0.00867 M) was transferred to a second 25 mL Schlenk tube and sealed with a stopper. Both Schlenk tubes were then cooled in an ice bath to 0 °C. Using a vacuum manifold, the solution of complex 2.10 was added as fast as possible to the rapidly stirring solution of rac-lactide. The reaction was stirred for 30 min before the mixture was exposed to air and quenched with 1 mL of quenching solution (1/100/600 of  81  HCl/CH3OH/CHCl3). The sample was evaporated to dryness and redissolved in toluene. The polymer was precipitated from cold methanol and dried overnight in vacuo. General Procedure for the Monitoring the Ring-opening Polymerization of rac-Lactide (400:1 Monomer to Initiator Ratio) at 0 °C in dichloromethane by 1H NMR Inside a nitrogen filled glovebox, rac-lactide (0.500 g, 3.47 mmol) was dissolved in 4 mL of dichloromethane and transferred to a 25 mL Schlenk tube with a stir bar and sealed with a stopper. 1 mL of a solution of complex 2.10 (0.00867 M) was transferred to a second 25 mL Schlenk tube and sealed with a stopper. Both Schlenk tubes were then cooled in an ice bath to 0 °C. Using a vacuum manifold, the solution of complex 2.10 was added as fast as possible to the rapidly stirring solution of rac-lactide. At a set interval, an aliquot was removed and quenched with hexanes. The volatiles of the sample were removed and the residue diluted with CDCl3 prior to obtaining a 1H NMR spectrum. A separate reaction was performed for each time interval shown in Figure 2.12. Procedure for the Ring-opening Polymerization of rac-Lactide (400:1 Monomer to Initiator Ratio) at Room Temperature in THF Followed by the Addition of More rac-Lactide Inside a nitrogen filled glovebox, rac-lactide (0.5094 g, 3.534 mmol) was dissolved in 4 mL of THF and transferred to a 20 mL vial equipped with a stir bar. 1 mL of a solution of complex 2.10 (0.00876 M) was transferred by syringe directly into the vigorously stirring solution of raclactide. The reaction was stirred for 15 min followed by removal of a small aliquot and the addition of additional rac-Lactide (0.1254 g, 0.8700 mmol) dissolved in 1 mL of THF. The mixture was left to stir for an additional 15 min before a second aliquot was removed and the 82  reaction was exposed to air and quenched with 1 mL of quenching solution (1/100/600 of HCl/CH3OH/CHCl3). The sample was evaporated to dryness and redissolved in toluene. The polymer was precipitated from cold methanol and dried overnight in vacuo. The volatiles of the aliquots were removed and the residues diluted with CDCl3 prior to obtaining a 1H NMR spectra. Ring-opening Polymerization of enantiopure S-Lactide (400:1 Monomer to Initiator Ratio) at Room Temperature in THF Inside a nitrogen filled glovebox, S-lactide (0.500 g, 3.47 mmol) was dissolved in 4 mL of THF and transferred to a 20 mL vial equipped with a stir bar. 1 mL of a solution of complex 2.10 (0.00867 M) was transferred by syringe directly into the vigorously stirring solution of S-lactide. The reaction was stirred for 15 min within the glovebox and then exposed to air and quenched with 1 mL of quenching solution (1/100/600 of HCl/CH3OH/CHCl3).  The sample was  evaporated to dryness and redissolved in toluene. The polymer was precipitated from cold methanol and dried overnight in vacuo. Stoichiometric Reaction of Complex 2.10 and 1 or 2 equivalents of rac-Lactide in d8-tol (2.20) Inside a nitrogen filled glovebox, complex 2.10 (0.0102 g, 0.00885 mmol) was dissolved in 0.5 mL of d8-tol and transferred to a J-Young NMR tube. A solution of rac-Lactide (0.0318 g, 0.221 mmol) in d8-tol was made in a 2 mL volumetric flask. The solution of rac-lactide (1 equivalent (0.2 mL plus 0.2 mL of additional C6D6), 2 equivalents (0.4 mL)) was added to the J-Young NMR tube containing the solution of complex 2.10. The mixture was shaken for 5 minutes before a 1H NMR spectrum was obtained. 83  General Procedure for the Ring-opening Polymerization of rac-Lactide (approximately 400:1 Monomer to Initiator Ratio) at Room Temperature in THF with Stoichiometric Reaction Products (Described Above) Inside a nitrogen filled glovebox, rac-lactide (0.500 g, 3.47 mmol) was dissolved in 4 mL of solvent and transferred to a 20 mL vial equipped with a stir bar. The J-Young NMR tube containing the stoichiometric reactions prepared previously (see above) was added directly into the vigorously stirring solution of rac-lactide. The reaction was stirred for 15 min within the glovebox and then exposed to air and quenched with 1 mL of quenching solution (1/100/600 of HCl/CH3OH/CHCl3). The sample was evaporated to dryness and redissolved in toluene. No polymer was formed.  84  Chapter 3. Rheological Studies of Poly(ε-caprolactone) Synthesized by the Catalytic Ring-Opening Polymerization of ε-Caprolactone Using Yttrium Amidate Complexes and the Synthesis of Poly(ε-caprolactone)/Polylactide Copolymers2 3.1  Introduction Much like the PLA discussed in Chapter 2, the synthesis of poly(ε-caprolactone), PCL, is  a sustainable option for replacing plastics that are synthesized from petroleum sources and are currently filling up the world’s landfills.98,118,119,154 Industrially, ε-caprolactone is no longer obtained as a by-product of the petroleum industry, the monomer is now synthesized from the oxidation of cyclohexanone with peracetic acid.155 The resulting polymer, PCL, is biodegradable and can therefore assist in the reduction of the waste associated with current plastic products. PCL is already extensively used in a variety of biomedical applications ranging from drug delivery to stents and dissolving stitches.156  Figure 3.1 Ring-opening polymerization of ε-caprolactone  2  A version of this has been published [Noroozi, N.; Thomson, J.A.; Noroozi, N.; Schafer, L.L.; Hatzikiriakos, S.G. Rheol. Acta 2012, 51, 179.] Reproduced by permission from the Springer Publishing Company.  85  PCL is synthesized through the ring-opening polymerization (ROP) of ε-caprolactone. As with the ROP of rac-lactide, the formation of PCL can follow the coordination-insertion mechanism (see Chapter 2, Figure 2.3).155 Numerous metal-based initiators have been reported for the ROP of ε-caprolactone,155 including alkali157-159 and alkaline earth metals,40,160 tin,161 aluminum,162-164  group  4  metals,165-167  zinc,168,169  and  rare-earth  metals.52,62,71,86,98,103,104,112,119,137,141,170-186 The ROP of ε-caprolactone using yttrium (amidate) complexes was previously investigated by former PhD student Dr. Louisa Stanlake.104,143 Investigations included the comparison of mono-, bis-, and tris(amidate) complexes for the ROP of ε-caprolactone. The PCL formed using mono-, bis-, and tris(amidate) complexes containing the same amidate ligand indicated that tris(amidate) complexes produce PCL with a lower polydispersity, PDI, and higher molecular weight, Mn, than that of the mono- and bis(amidate) complexes. Therefore, tris(amidate) complexes with a variety of amide proligands were investigated. The PCL formed with differing amide backbones showed that the naphthyl substituent produced the polymer with the lowest PDI and one of the highest molecular weights. However, all complexes were highly effective initiators for the ROP of ε-caprolactone and were capable of complete conversion in <15 minutes at room temperature.104,143 Louisa’s investigations into the monomer to initiator ratio, [M]/[I], and temperature revealed that the molecular weights obtained for the polymerizations were significantly higher than the calculated theoretical values at both room temperature and 0 °C for all [M]/[I] investigated. End group analysis was used to confirm the amide proligand as the terminus of the  86  polymer. Stoichiometric experiments were performed to further probe the mechanism of polymerization;143 these will be discussed later in this chapter. In addition to the mechanistic investigations, we were interested in how our synthetic PCL compared to commercially available PCL, with respect to practical application. Analysis of the mechanical properties of the PCL synthesized with yttrium (amidate) complexes is a key step in progressing from synthesis to application. Rheological analyses provide a means to further characterize a polymer on the macromolecule scale.187 These analyses are essential in the development of commercially applicable polymers as traditional chemical analyses cannot provide a clear picture of how small changes to a polymer affect the bulk material properties.187  3.1.1 Rheology Rheology is defined as the science of deformation and flow of matter under controlled testing conditions.187 It is used to study the mechanical properties of both solids and liquids with a rheometer (Figure 3.2). A rheometer is an instrument that measures viscosity over a wide range of shear rates, where shear rate is the angular frequency at which a shear stress is applied. Shear stress is the stress applied parallel to the plane of the material. In the case of a parallel plate rheometer, the sample is placed between a fixed plate and a plate oscillating in a rotational fashion, applying stress parallel to the fixed plate. For the purposes of this thesis, rheology will be discussed in a qualitative manner. Pertinent equations can be found in Appendix C.  87  Figure 3.2 Parallel-plate rheometer Rheological analysis of polymers is important as it provides information relevant to polymer processing and materials properties.187 These in turn inform the potential application/function of the resultant polymers. There are four main terms we have used to investigate the commercially available and synthesized polymers: η*,G′, G″, and η0. η* is defined as the viscosity of a material at a given shear rate; G′ is defined as the storage modulus and is a measure of the elasticity of a material and hence the ability of the material to store energy; G″ is defined as the loss (viscous) modulus and is a measure of the ability of the material to dissipate energy (usually through heat); and η0 is defined as the zero-shear viscosity and represents the value at which the viscosity is independent of shear rate (angular frequency). For the purpose of this thesis, the viscosity of a material, η*, is primarily used to determine the zero-shear viscosity, η0 which can be determined from plots of η* as a function of shear rate. The storage modulus, G′, is useful in determining the thermal stability of the polymer in question, by monitoring as a function of time. Such time sweep measurements (Figure 3.3) are performed by monitoring G′ over time at a constant temperature and shear rate. The variation in G′ represents the thermal stability of the substance. For curve A, the material is stable over the 88  entire course of the experiment. However, for curve B, G′ begins to decrease over time and, therefore, the material is only stable under the testing conditions for a limited time. This analysis is vital in determining the type and duration of rheological analyses that can be performed on the material. It also indicates what types of processing are suitable for a material.  G' (storage modulus) /Pa  10000  1000  100  10  1  10  100 time /s A  1000  10000  B  Figure 3.3 Representative time sweep plot188 G′ as well as G″ can also be used to investigate viscosity. The relative values of G′ and G″ can be used to determine a polymer’s physical state at various shear rates. If G′ > G″ the sample is solid-like and if G′ < G″ then the sample is liquid-like at a given shear rate. Plots of G′ and G″ against the shear rate provide a simple means for analyzing the data (Figure 3.4). For example, the curves in Figure 3.4 indicate that the sample is a viscoelastic-liquid, where the material is solid-like at high shear rates and liquid-like at low shear rates.187 To determine the zero-shear viscosity, η0, η* is monitored over a range of shear rates (Figure 3.5).  89  The zero-shear viscosity, η0, is the value of viscosity when viscosity is independent of angular frequency. Once η0 is determined for a variety of molecular weights, the zero-shear viscosities can be plotted against their respective molecular weights (Figure 3.6). The resulting plot can be used to interpret the morphology of a polymer sample.187 The zero-shear viscosity of linear polymers is proportional to their molecular weights as can be seen for curve A. However, if branching is present in the polymer, the zero-shear viscosity of a polymer will not lie on the linear curve A, it will either lie below, i.e. data point B, as is the case in long-chain branching,187 or above the line, i.e. data point C, as is the case in star-type polymers.187  1000000 100000  G',G" /Pa  10000 1000 100 10 1 0.01  0.1  1 10 100 Angular frequency /rads-1  G' (storage modulus)  1000  10000  G" (loss modulus)  Figure 3.4 Representative plot of G′ and G″ vs. shear rate for a viscoelastic liquid189  90  100000  Viscosity /Pa.s  10000 1000 100 10 1 0.01  0.1  1 10 100 Angular frequency /rads-1  1000  10000  Figure 3.5 Representative plot of viscosity vs. shear rate190  Log (zero-shear viscosity) /Pa.s  5 4.5 4 3.5 3 2.5 2 1.5 1 4.3  4.5  4.7 Log (Mw) /gmol-1 A  B  4.9  5.1  C  Figure 3.6 Representative plot of zero-shear viscosity vs. molecular weight (Mw) [A = linear, B = long-chain branching, C = star-type branching]191 91  All of the experimental analyses introduced above provide important information about polymer structure, materials properties, and processability, thus probing the relationship between the synthesis of polymers and the structure and mechanical properties of these macromolecules and their potential commercial application.  3.1.2 Copolymers A copolymer is a polymer synthesized using more than one type of monomer. Copolymers are important as they exhibit different chemical and mechanical properties than the homo-polymers of their respective monomers; i.e. polymer A and polymer B may have very different properties from each other and from copolymer A/B.187 Copolymerization provides a means for synthesizing new and interesting polymers using well established methods and monomers.  92  Figure 3.7 Types of copolymers There are a number of different types of copolymers. The four main sequences for copolymers containing two different monomers are: alternating, block, random, and graft copolymers (Figure 3.7).122,192 Alternating copolymers consist of linear polymer chains where two different monomers alternate in an -A-B-A-B- fashion through the chains. Block copolymers also consist of linear polymer chains containing two different monomers. These types of polymers contain groupings of either one or the other monomer in an -A-A-A-A- or -B-B-B-Bfashion. Copolymers containing one large block of each monomer are called di-block copolymers. Those polymers consisting of one large block of one monomer, surrounded by two blocks of the other monomer, are called triblocks. Tetrablocks and multiblocks can also be 93  synthesized.122,192 These copolymers with large blocks are usually synthesized by complete polymerization of the first monomer, followed by the addition of the second monomer and subsequent polymerization, and so on for the formation of additional blocks.192 To form block copolymers with blocks of consistent chain length, living polymerization, as described in Chapter 2, is necessary.122 The third type of copolymers is random copolymers.122,192 These polymers also consist of linear chains; however there is no statistical sequence of monomers. The last type of copolymers is graft copolymers.122,192 This type of copolymers is a specific type of branched polymer, where the side chains are different from the main chain. They are formed by first synthesizing a linear chain of one monomer and then attaching chains of a different monomer at branch points along the initial chain. The main chain and side chains can consist of one monomer each or can be copolymers themselves as long as the two types of chains are structurally distinct. As graft copolymers are not usually formed through ring-opening polymerization, they will not be discussed in this Chapter. Polymerizations resulting in polymers containing stereocenters form a specific subgroup of copolymers. These polymers are discussed based on their tacticity, which was mentioned in Chapter 2.114 Using PLA as an example, where A = L-lactide and B = D-lactide, an alternating copolymer is the same as a heterotactic copolymer, a block copolymer is a stereoblock/isotactic copolymer, and a random copolymer is an atactic copolymer (Chapter 2, Figure 2.3).114 As mentioned in Chapter 2 with respect to PLA tacticity, polymers/copolymers can exhibit the sequences discussed above to various extents. For example, a copolymer could be 50% alternating and 50% random.  94  In many cases, the interesting chemical and mechanical properties of two homo-polymers can be combined by simply blending the two polymers together. With some polymers, however, this is not the case. A relevant example is the blending of PCL and PLA. PCL is known to be tough with a high maximum strain while PLA is characterized as hard and brittle with a low maximum strain.114,155 The combination of the mechanical properties of these two polymers is ideal for their use in a number of applications. Unfortunately, the blending of PCL and PLA typically results in phase separation (Figure 3.8).193 As with the separation that occurs when two solvents are immiscible, when two polymers are immiscible they will phase separate. This prevents the formation of homogeneous blends. The development of copolymers of PCL and PLA is attractive to access mechanical properties that would be a combination of their polymer properties.  95  Figure 3.8 Representation of the phase separation of PLA and PCL193 The copolymerization of ε-caprolactone and lactide has become an intense area of research.194 A number of different types of initiators have been developed including both organic alcohol-based,195  and  inorganic  molecules.  The  metal  initiators  reported  for  the  copolymerizations span the periodic table including: magnesium,160,196 aluminum,162-164,197,198 titanium,166,194 zinc,168,169,199 tin,161,200 bismuth,161 and the rare earths.170,173,177,180,183,186,201-203 These initiators have been shown to synthesize block copolymers and/or random copolymers. In  96  most cases, the synthesis of block copolymers results in a di-block and usually the ε-caprolactone must be polymerized first or homo PLA is the only product.204-206 Selected examples of known rare-earth or yttrium initiators for the copolymerization of εcaprolactone and lactide are shown in Figure 3.9 and some of their polymerization results are listed in Table 3.1.  Figure 3.9 Known rare-earth and yttrium initiators for PCL/PLA copolymers170,173,177,180,186  97  Table 3.1 Comparison of rare-earth and yttrium initiators for the ROP of ε-caprolactone and lactide  Complexes 3.3, 3.5, and 3.7 have been reported to polymerize di-block copolymers with PCL as the first block.170,173,177 This result is not surprising, as almost all rare-earth complexes are incapable of polymerizing ε-caprolactone once PLA has already been prepared.204-206 Complex 3.6 is reported to synthesize random copolymers of ε-caprolactone and lactide, one of the very few examples reported for this important transformation.180 It is clear from the results reported for complexes 3.3 - 3.7 that only a few rare-earth systems can be used for the copolymerization of ε-caprolactone and lactide, and they require vastly different polymerization conditions.170,173,177,180,186 This chapter will detail the rheological studies of PCL synthesized using yttrium amidate complexes as well as the study of yttrium amidate complexes as initiators for the copolymerization of ε-caprolactone and lactide. Rheological experiments and discussion were in  98  collaboration with Nazbanoo Noroozi and Dr. Savvas Hatzikiriakos from the Chemical Engineering Department of UBC.  3.1.3 Scope of Chapter The previously reported abilities of yttrium amidate complexes in the ROP of εcaprolactone104,143 have generated interest in the mechanical properties of the resulting polymers. As was mentioned in Chapter 2, yttrium amidate complexes are easily synthesized in high yield.104,105,143 These complexes have been reported to rapidly produce PCL in high yield through the ROP of ε-caprolactone, resulting in polymers with high molecular weights and low PDIs, in comparison to other complexes reported for this reaction.104 One advantage of the amidate backbone is the ease with which the steric and electronic properties of the amidate can be varied.113 Furthermore, initiator structure is known to affect polymer molecular weight and PDI and it is therefore, of interest to compare the effect of amidate electronic properties on the mechanical properties of the resulting PCL. The tris(amidate) complexes discussed in this chapter are shown in Figure 3.10. Investigations into the synthesis of copolymers of PCL and PLA will also be included in this chapter.  Figure 3.10 Yttrium amidate complexes used for the ROP of ε-caprolactone  99  3.2  Yttrium Amidate Complexes as Initiators  3.2.1 Results and Discussion 3.2.1.1  Rheology of Synthetic Poly(ε-caprolactone)  Tris(amidate) complex 3.8 was synthesized as described in the literature,104 through protonolysis of Y(N(SiMe3)2)3 with amide proligand N-(2,6-diisopropylphenyl)t-butyl amide. The experimental procedure used for the ROP of ε-caprolactone with complex 3.8 was adapted slightly from that reported.104 Reactions used a monomer to initiator ratio of 225 and were performed in an inert atmosphere. Complex 3.8 was dissolved in toluene and ε-caprolactone was then added all at once to the rapidly stirring solution of initiator. Reactions were stirred vigorously for 15 minutes prior to exposure to air, quenching with 1 M aqueous HCl and precipitation from cold petroleum ether. The ROP of ε-caprolactone with complex 3.8 has been reported to produce PCL in high yield, with high molecular weight and narrow PDI. Although this was true for polymerizations on a 250 mg scale, experimental scale-up had not been previously investigated. Rheological studies of polymers require a large quantity of product for experiments to be performed (≥2 g) and thus, experiments were performed to facilitate the ROP of ε-caprolactone on a larger scale (2 g). The polymer data for various attempts to scale-up the polymerization are shown in Table 3.2.  100  Table 3.2 Scale-up data for the ROP of ε-caprolactone with complex 3.8  Initial experiments attempted to reproduce the yield and polymer properties of the small scale reactions (Table 3.2, entry 1) while scaling the experimental procedure by a factor of 8. These experiments involved using 8 times the amount of toluene and ε-caprolactone. The first attempt utilized a 100 mL glass jar with a similar shape to the 20 mL vial used in the small scale reactions. As can be seen in Table 3.2, entry 2, the reaction was left for a longer period of time (30 minutes), however only a 50% yield was obtained. After 15 minutes, the mixture became very viscous and manual stirring was required for the remaining reaction time. This increase in viscosity is likely responsible for the low yield, due to mass transfer problems in the reaction milieu. In addition, the polymer molecular weight was more than 20,000 gmol-1 less than the target (Table 3.2, entry 1) and the PDI increased to well above 2. The second attempt (Table 3.2, entry 3) used a 100 mL Schlenk tube to determine if the reaction vessel was responsible for the non-ideal results. However, the use of a Schlenk tube did not increase the % yield and further decreased the molecular weight of the polymer, while maintaining the large PDI of >2. 101  To determine which experimental factors had the greatest impact on the ability to scale up the ROP of ε-caprolactone with yttrium (amidate) complexes, varying conditions were tested for doubling the scale of the reaction. First, the polymerization was performed using the same reaction conditions as the original scale, while doubling the quantity of ε-caprolactone. As is shown in Table 3.2, entry 4, these conditions resulted in a high yield of polymer in 15 minutes with close to the target molecular weight, however the PDI increased significantly. Looking to decrease the PDI obtained with the original conditions, the solvent volume was doubled to 20 mL. The results of this polymerization indicated that 15 minutes was not long enough for the reaction to reach complete conversion, likely due to the decrease in catalyst concentration. This was evident by the 48% yield, as well as the very low molecular weight and PDI >2. Leaving the reaction to stir for an additional 45 minutes (60 minutes total) resulted in near quantitative conversion. However, although the polymer had a PDI close to the target value, the molecular weight had doubled, indicating fewer initiating species. Finally, to investigate the effect of the reaction vessel on the polymerizations, a 50 mL round bottom flask was utilized. Using the increased solvent volume, the polymerization was complete in 15 minutes, resulting in near quantitative conversion. Although the PDI obtained had improved over the ideal value based on the small scale product, the molecular weight obtained was also nearly double the target value (Table 3.2, entry 1). The process of scaling up the ROP of ε-caprolactone using yttrium (amidate) complexes as initiators was found to be very complex, where every condition involved (volume, reaction vessel, time, etc.) had a great impact on the resulting polymer. Experiments thus far have shown conclusively that the ROP of ε-caprolactone on a large scale produces PCL in lower yield with polymer properties (molecular weight and PDI) inconsistent with those produced on a small 102  scale. Therefore, to obtain a large enough quantity of PCL for rheology, the small scale polymerizations (250 mg) were performed multiple times and the resulting polymers combined for rheological analysis. GPC analysis was performed on each individual reaction product to ensure consistency in the final combined sample. This laborious approach was satisfactory for moving forward with rheological investigations. As mentioned previously, the rheological analysis of polymers is a key method to bridge the gap between newly synthesized products and potential industrial applications. The PCL samples synthesized with complex 3.8 (PCL-1) were investigated using a variety of rheological analyses; the results and how they compared to a commercially available high molecular weight PCL (Capa 6800, Mw = 8.835 x 104 gmol-1) are presented below. Initial experiments investigated the thermal stability of the polymer samples. This analysis was vital, as thermal stability is required to perform other rheological experiments. To determine the thermal stability, time sweep measurements were performed at 100 °C. During the experiment, the storage modulus (G′) was monitored and then plotted as a function of time (Figure 3.11). The commercially available polymer, Capa 6800, was found to be thermally stable up to 10,000 seconds, while the synthesized PCL was found to be stable up to 1,700 seconds. This difference in thermal stability is likely due to the stabilizers that are added to commercially available polymers by the suppliers. Thermal stability lasting at least 1,700 seconds was important, as the remaining rheological experiments required heating and a maximum experimental time of 1,500 seconds so thermal decomposition could be avoided.  103  G' (storage modulus) /Pa  10000  1000  100  10 1  10  100 time /s  Capa 6800  1000  10000  PCL-1  Figure 3.11 Time sweep measurement of PCL-1 and Capa 6800 at 100 °C The second set of analyses probed the storage modulus and loss modulus (G′ and G″) and the dynamic viscosity (η*) as a function of angular frequency (ωaT) at 100 °C. The storage modulus and loss modulus indicated that the material is a viscoelastic-liquid. The dynamic viscosity curve of Figure 3.12 clearly indicates that the viscosity became independent of angular frequency as the angular frequency decreased. As the angular frequency decreased, the viscosity reached a constant value. This value of viscosity, known as the zeroshear viscosity, will be discussed below.  104  1000000  100000  100000  G',G" /Pa  1000 1000 100 10  Viscosity /Pa.s  10000  10000  100  1 0.1 0.001  0.01  0.1 1 10 100 Angular frequency /rads-1  G' (storage modulus)  G" (loss modulus)  1000  10 10000  viscosity  Figure 3.12 Viscosity curves of PCL-1 (Mw = 6.566 x 104 g/mol) at 100 °C Figure 3.13 is a plot with the representative curves for the commercially available Capa 6800. When compared to Figure 3.12, it was found that the synthetic PCL behaved in the same manner as the commercial PCL, with respect to the storage modulus, the loss modulus, and the dynamic viscosity.  105  1000000  100000  100000  G',G" /Pa  10000 1000 1000 100 100  Viscosity /Pa.s  10000  10  10 1 0.01  0.1  1 10 100 Angular frequency /rads-1  G' (storage modulus)  G" (loss modulus)  1000  1 10000  viscosity  Figure 3.13 Viscosity curves of Capa 6800 (Mw = 8.835 x 104 g/mol) at 100 °C Finally, the zero-shear viscosity values obtained from the master curves (eg. Figure 3.12 for Mw = 6.566 x 104 g/mol) were plotted as a function of molecular weight for both the different PCLs synthesized with complex 3.8 and various commercially available PCLs (Figure 3.14). The zero-shear viscosities for the commercial PCL and synthesized PCL form a linear curve when plotted as a function of their molecular weights. As mentioned in the introduction, this indicated that the polymers consisted of linear chains with no evidence of branching.  106  Log (zero-shear viscosity) /Pa.s  5 4.5 4 3.5 3 2.5 2 1.5  1 4.4  4.5  4.6  4.7 4.8 Log (Mw) /gmol-1  Synthetic PCL (PCL-1)  4.9  5  5.1  Commercial PCL  Figure 3.14 Zero-shear viscosity versus Mw for synthetic (PCL-1) and commercial PCLs The above data suggests that the PCL synthesized using yttrium (amidate) complex 3.8 is consistent with the PCL that is currently available commercially with respect to basic mechanical properties.  3.2.1.2  Effect of Initiator on Poly(ε-caprolactone) Rheology  Having determined that the mechanical properties of PCL synthesized with yttrium amidate complex 3.8 were consistent with those of commercially available PCL, it was of interest to determine if the structure of the yttrium amidate initiator affected the mechanical properties of the resulting polymers. To investigate the effect of the initiator, PCL was synthesized by the ROP of ε-caprolactone using complex 3.9 as the initiator, and the resulting polymer analyzed for comparison. 107  Rheological analysis of the new PCL samples (PLC-2) was conducted in the same way as the experiments which were performed on the PCL synthesized with complex 3.8 (PCL-1) (Figure 3.15-3.17). Figure 3.15 shows that the new synthesized PCL is stable up to 1500 seconds.  G' (storage modulus) /Pa  10000  1000  100  10 1  10  100 time /s  Capa 6800  1000  10000  PCL-2  Figure 3.15 Time sweep measurement of Capa 6800 and PCL-2 at 100 °C Figure 3.16 shows that the PCL synthesized with complex 3.9 was consistent with the PCL synthesized with complex 3.8. This meant that as with PCL-1, the material was a viscoelastic-liquid. PCL-2 was solid-like at high shear rates (angular frequencies) and liquid-like at low shear rates.  108  1000000  10000  100000  G',G" /Pa  1000 1000 100 100  Viscosity /Pa.s  10000  10 1 0.1 0.001  0.01  0.1 1 10 100 Angular frequency /rads-1  G' (storage modulus)  G" (loss modulus)  1000  10 10000  viscosity  Figure 3.16 Viscosity curves of PCL-2 (Mw = 8.123 x 104 g/mol) at 100 °C Finally, the zero-shear viscosities were determined for the PCL-2 as described for representative example, Figure 3.5. The data was plotted as a function of molecular weight (Figure 3.17) along with the zero-shear viscosities of the initial PCL samples (PCL-1 and the commercially available PCLs). The data points for the PCL synthesized with complex 3.9 were found to lie well below the trend found using the commercially available PCL and the PCL synthesized using complex 3.8., for all four molecular weights. This implied that each sample contained long-chain branching in their structure, as opposed to being a linear polymer.187 Each polymer was synthesized and analyzed numerous times to ensure reproducibility.  109  Log (zero-shear viscosity) /Pa.s  5 4.5 4 3.5 3 2.5 2 1.5  1 4.4  4.6  Synthetic PCL (PCL-1)  4.8 Log (Mw) /gmol-1 Commercial PCL  5  5.2  Synthetic PCL (PCL-2)  Figure 3.17 Zero-shear viscosity versus Mw for synthetic (PCL-1, PCL-2) and commercial PCL The synthesis of branched PCL through the ROP of ε-caprolactone has not been previously reported. The well established coordination-insertion mechanism for the ROP of εcaprolactone155 (Figure 3.18) does not provide an obvious mechanistic pathway to access a branched polymer. Branched PCL has been synthesized through templating reactions.207 Templating reactions involve the synthesis of linear polymer chains before undergoing further reactivity to attach side chains creating branch points (graft polymers).192 See Figure 3.7 for a representation of a graft co-polymer. The synthesis of branched PCL through the ROP of εcaprolactone using complex 3.9 was proposed to occur through initiation by two different yttrium (amidate) species.  110  Figure 3.18 Coordination-insertion mechanism for the ROP of ε-caprolactone In 2008 Louisa Stanlake of the Schafer group proposed the formation of an enolate complex 3.10 during the ROP of ε-caprolactone with complex 3.9.143 The stoichiometric reaction of complex 3.9 and ε-caprolactone shown in Scheme 3.1 suggested the formation of an enolate complex and elimination of protonated ligand.143 However, only the proligand by-product could be fully characterized.143 Such enolate formation has been previously reported by Zhou and coworkers in 2006 as well as Okuda and co-workers in 2007.208,209  111  Scheme 3.1 Formation of enolate complex 3.10143 It was proposed that the reaction to form the enolate complex 3.10 only occurred with some initiator of complex 3.9 in the polymerization mixture.143 The enolate complex 3.10 was initially proposed to be a catalytic resting state and its formation was suggested as being responsible for the high molecular weights obtained during polymerizations.143 If however the enolate complex was not a catalytic resting state, but instead was capable of initiating the ROP of ε-caprolactone, then initiation occurring with both complex 3.9 and enolate complex 3.10 could result in a branched polyester through the mechanism shown below (Scheme 3.2). However, this proposal only accounts for the incorporation of one branch point in the PCL chain. This PCL would be an example of long-chain branching and will be referred to as the “branched” polymer for the remainder of Chapter 3.  112  Scheme 3.2 Proposed mechanism for the synthesis of branched PCL  113  3.2.1.3  Analysis of Branched Poly(ε-caprolactone)  Rheological analyses indicated the presence of a branch point in the PCL chain synthesized through the ROP of ε-caprolactone using complex 3.9. To confirm the presence of this unique feature, the polymer was further investigated using chemical analyses. In should be noted that rheological analyses are more sensitive than molecular characterization techiniques.187 Primary investigations simply involved analysis of the PCL using NMR spectroscopy. 1H NMR spectra were acquired for both the “linear” and “branched” polymers; if a branch point existed in the “branched” polymer, then an additional signal representing hydrogen-A (Figure 3.19) could have been observed in the 1H NMR spectrum. The low abundance of this hydrogen within the long polymer chain, could prove problematic with the sensitivity of NMR spectroscopy, and indeed the 1H NMR spectra of both polymers were found to be identical.  Figure 3.19 Linear vs. long-chain branching in PCL Although the 1H NMR spectra of the “linear” and “branched” polymers were found to be identical, it was proposed that the signal representing the branch point hydrogen-A may not be observed due to tautomerization and ensuing hydrogen bonding (Figure 3.20). Hydrogen  114  bonding is known to broaden signals in the 1H NMR spectra, and the small relative integration of the branched hydrogen (at least 1:500) would likely result in the signal disappearing into the baseline.  Figure 3.20 “Branched” PCL tautomerization It was therefore proposed that reaction of the “branched” polymer with a deuterium source may have aided in the abundance problem associated with the 1H NMR spectra. 2H NMR spectra would not be overwhelmed with signals representing hydrogens of the long polymer chain, and therefore the branch point would be easier to observe. The “branched” polymer was dissolved in diethyl ether and washed with D2O before removing excess D2O with drying agent and removing the diethyl ether under reduced pressure. Without the addition of base, the D 2O wash was proposed to replace only two hydrogen atoms, the branch point hydrogen and the hydrogen of the hydroxy end group. This is due to the greater acidity of those two hydrogens than the other hydrogens on the alky chains. However, the 2H NMR spectrum only contained one signal at 5.88 ppm. A “linear” polymer sample was also washed with D2O and analyzed by 2H NMR spectroscopy. The 2H NMR spectrum of the “linear” polymer contained one signal at 5.88 ppm, confirming the identity of the hydroxyl end group. Therefore, the 2H NMR spectrum did not provide evidence for the existence of a “branched” polymer (Figure 3.21). 115  Figure 3.21 Deuteration of “branched” PCL Further NMR spectroscopy techniques were employed to provide evidence for the existence of the “branched” PCL.  13  C NMR spectra were acquired for both the “linear” and  “branched” samples of PCL, as well as 135-DEPT NMR spectra. The carbon atom at the branch point of the proposed “branched” polymer would have a chemical shift well above those of the other carbons, including the other carbonyl carbons. Also, a linear sample of PCL would only contain methylene carbons and quaternary carbons with the exception of the amide ligand end group. Therefore, the methine carbon of the branch point would be easily shown by 135-DEPT NMR. However, the spectra obtained using both NMR spectroscopy techniques were identical for the two samples tested. Thus, evidence for a branch point in the polymer was not obtained. Finally, infrared (IR) spectroscopy was used to provide evidence for the elusive branch point. IR spectra were acquired for both the “linear” and “branched” polymer samples with the proposal that the carbonyl functionalities of the beta diketone would have different stretching frequencies from the rest of the polyester, thus the IR spectrum for the “branched” polymer sample would have additional carbonyl stretches in comparison to the IR spectrum of the “linear” polymer sample. However, when the two spectra were overlaid, they were found to be identical and thus did not provide evidence for branching in the “branched” PCL sample. Once the use of traditional spectroscopic methods were exhausted for investigations of the full polymer, analysis of “degraded branched” polymer was proposed. The “branched” PCL 116  sample was degraded in a 1M solution of NaOH in 50:50 methanol and water. The mixture was left to reflux for multiple days followed by acidification and extraction. The resulting residue was analyzed by 1H NMR spectroscopy and mass spectrometry. Unfortunately, neither method of analysis provided evidence for the “branched” polymer. Both the 1H NMR spectrum and the mass spectrum only showed the presence of PCL oligomers. As the “branched” PCL may have only one branch point per polymer chain, it was predicted that following degradation, the numerous oligomers of various lengths could make it difficult to observe the signals associated with the single branch point. Thin layer chromatography of the residue resulted in one long spot running from the baseline to the solvent front. Column chromatography was therefore used to separate the degraded sample of “branched” PCL into samples with a smaller variation in the chain length of the oligomers. Once separated, 1H NMR spectroscopy and mass spectrometry were performed on each independent fraction; however, no signals were present representing the branch point. Based on the proposal above for the synthesis of “branched” PCL (Scheme 3.2), there may be only one branch point in a small fraction of the polymer chains. It was unlikely that every polymer produced in the ROP resulted in a chain with a branch point, therefore an increase in the number of chains in the sample with branch points might have increased the spectroscopic signals representing that functionality, and made the branch point easier to characterize. It was previously reported that a decrease in temperature for the ROP of ε-caprolactone resulted in lower molecular weight PCL.143 This was proposed to be due to a decrease in the formation of enolate complex 3.10.143 In an attempt to increase the formation of enolate complex 3.10 and therefore the number of branch points, PCL samples were synthesized with complex 3.9 at higher temperatures (40 °C and 60 °C). These polymerizations were performed using the same 117  method used to synthesize the PCL at room temperature with the exception of temperature and the use of a parallel synthetic tube as the reaction vessel, held at constant temperature, instead of a vial. Full spectroscopic analyses were obtained for the “branched” polymers synthesized at 40 °C and 60 °C; however the spectra did not show any differences to those of the “linear” or “branched” PCLs synthesized at room temperature and, therefore, did not provide evidence for the polymer branch point. As a final attempt to explain the off-linear points on the plot of zero-shear viscosity vs. weighted average molecular weight, the morphology of the “linear” and “branched” PCL samples were compared. Using the laser light scattering detector of the GPC, data for three solution properties of the polymer samples were obtained: intrinsic viscosity, hydrodynamic radius, and radius of gyration. The first property, intrinsic viscosity, describes the effect of a polymer sample on the viscosity of a solution.210 This value is proportional to molecular weight for linear polymers and is therefore often used to determine the molecular weight of a given polymer sample. As this is not always the case for branched polymer samples, this property could therefore provide insight into polymer structure. The second property, the hydrodynamic radius of a polymer, is calculated from the diffusional properties of a particle, taking into account the non-spherical nature of polymers as well as solvation during the analysis.210 This property can therefore help distinguish between different polymer morphologies as long-chain branched polymers, linear polymers, and star-branched polymers would have different hydrodynamic radii. The final property, the radius of gyration, is an additional term used to describe the size of a polymer chain.210 It is based on  118  the moment of inertia of a given mass and can also help distinguish between different polymer morphologies. The data for each property was plotted against the weighted average molecular weight for a number of different “branched” and “linear” polymer samples (Figures 3.22 - 3.24). When polymers have similar morphology, either all linear or all branched chains, the data points will all lie on the same trendline, but much like the zero-shear viscosity plot discussed previously the curves will not overlap. As can be seen in Figures 3.22 - Figures 3.24, the data points for the “linear” and “branched” PCL samples all lie on the same trend. Hence, the morphology of the samples must have been very similar and therefore did not provide evidence for the presence of a branch point.  150 Intrinsic viscosity /mLg-1  140 130 120 110 100 90  80 70 60 50 40000  60000  80000 100000 Mw /gmol-1  "linear" PCL-1  120000  140000  "branched" PCL-2  Figure 3.22 Intrinsic Viscosity of “linear” and “branched” PCL  119  Radius of gyration /nm  24 22 20 18 16 14 12 40000  60000  80000 100000 Mw /gmol-1  "linear" PCL-1  120000  140000  "branched" PCL-2  Figure 3.23 Hydrodynamic Radius of “linear” and “branched” PCL  120  Hydrodynamic radius /nm  16 14 12 10 8 6 4 40000  60000  80000 100000 Mw /gmol-1  "linear" PCL-1  120000  140000  "branched" PCL-2  Figure 3.24 Radius of Gyration of “linear” and “branched” PCL Although none of the methods of analysis mentioned above have shown evidence for the presence of a branch point synthesized during the ROP of ε-caprolactone with complex 3.9, the notion could not be ruled out completely. There may have been so few branch points present that the sensitivity of the instrument could not define a representative signal above the baseline noise. However, if the polymer synthesized with complex 3.9 was not branched, what was causing the discrepancy in the plot of zero-shear viscosity vs. weighted average molecular weight?  3.2.1.4  Degradation Analysis of Poly(ε-caprolactone)  The biodegradable nature of PCL allowed for the proposal of degradation as the cause for the differing data obtained for the PCL synthesized with complexes 3.8 and 3.9 with respect to zero-shear viscosity. Looking back at Figure 3.17, it was shown that the “branched” PCL had 121  zero-shear viscosities significantly lower than necessary to lie on the trend formed by the “linear” PCL data. It was proposed that the “branched” sample of PCL was degrading to a lower molecular weight and thus the lower zero-shear viscosity reported for a specific molecular weight could result from a lower molecular weight. Based on this proposal, the two types of synthetic PCL, “linear” and “branched”, were tested for degradation under typical storage conditions. The conditions were designed to investigate degradation at different temperatures and in the presence or absence of light. Samples of PCL were synthesized using complexes 3.8 and 3.9 and stored in clear glass vials sealed with Teflon caps and left to degrade. The set of vials were separated into three portions, the first was left on the bench top at room temperature in the light, and the second was wrapped in aluminum foil and left in a drawer at room temperature, and the last was stored in the fridge at 4 °C. Each week a sample of polymer from each vial was removed and analyzed by GPC to determine the molecular weight and PDI. Figure 3.25 shows how the molecular weight and PDI of the “linear” PCL changed over the course of a number of weeks and Figure 3.26 shows results for the “branched” PCL. Looking at the data for the “linear” PCL it was clear that the molecular weight and PDI remained constant within error over the five week period for all three storage conditions. Therefore, there was no degradation of the “linear” polymer during the period of testing. However, this was not the case for the “branched” PCL samples. As can be seen in Figure 3.26, the molecular weight of the “branched” PCL decreased significantly and the PDI increased over the 5 week test period for the sample left on the bench at room temperature in natural light. In fact, a significant decrease in molecular weight was observed after only one week. Comparing this data with that of the sample left in the fridge indicated that temperature 122  was not responsible for increasing the rate of degradation, as the sample left in the fridge degraded in a similar fashion. The presence of natural light did not increase the rate of degradation as the sample left in the dark at room temperature also degraded similarly to the other two samples.  100000  4  90000 3.5  80000  3  60000 50000  2.5  PDI  Mn /gmol-1  70000  40000 2  30000  20000  1.5  10000 0  1  0  1  2  3 Time /weeks  4  5  Mn - rt (light)  Mn - fridge (dark)  PDI - rt (light)  PDI - fridge (dark) PDI - rt (dark)  6  Mn - rt (dark)  Figure 3.25 Degradation of “linear” PCL (PCL-1) over time  123  120000 2.4 100000  2.2  2  1.8  60000  PDI  Mn /gmol-1  80000  1.6 40000 1.4  20000  1.2  0  1 0  1  2  3 Time /weeks  4  5  Mn - rt (light)  Mn - fridge (dark)  PDI - rt (light)  PDI - fridge (dark) PDI - rt (dark)  6  Mn - rt (dark)  Figure 3.26 Degradation of “branched” PCL (PCL-2) over time Following the degradation experiments, it was clear that the PCL synthesized using complex 3.9 degraded rapidly under typical storage conditions after as little as a week, while the PCL synthesized using complex 3.8 was stable over a minimum of 5 weeks. The only known difference between the “linear” and “branched” PCL samples was the polymer end groups, as the amide proligand was incorporated into the polymer as the end group (Figure 3.27). As the procedure for the synthesis of PCL was identical for both polymers with the exception of the 124  initiator used, it was unlikely that the difference in degradation resulted from a difference in procedure. However, when the polymerizations were quenched, the tris (amidate) complexes reacted with the hydrochloric acid solution to produce yttrium oxides and free proligand. It was possible that the polymer product was not completely free of amide proligand impurities. Therefore, it was possible that the residual naphthyl substituted amide was aiding in the degradation of the PCL while the t-butyl substituted amide was not.  Figure 3.27 PCL-1 and PCL-2 To test this hypothesis, N-(2,6-diisopropylphenyl)-1-naphthamide was added to the ROP of ε-caprolactone using complex 3.8 after the reaction was quenched. The sample was placed in a clear glass vial with a Teflon cap and left to degrade on the bench at room temperature in natural light. As with the other polymers, a sample was removed every week for GPC analysis to monitor the molecular weight and PDI. As with the original “linear” polymer samples, no degradation occurred over the course of the experiment, indicating that the presence of N-(2,6diisopropylphenyl)-1-naphthamide as an impurity was not responsible for the degradation of the “branched” PCL samples.  125  Although there was no clear explanation for the difference in degradability for the “linear” and “branched” PCL, it was proposed that this was likely responsible for the low zeroshear viscosity values obtained for the “linear” PCL. A closer look at the preparation of samples done by the chemical engineering collaborators provided further evidence. Once the PCL samples had been synthesized and analyzed by GPC, they were immediately passed to the chemical engineering collaborators to minimize time for degradation. However, once obtained by the chemical engineering graduate student, procedure dictates that the sample is dried over multiple days (up to a week) before the polymers are processed for rheological analysis. This drying process allowed ample time for the “branched” PCL to degrade to a significantly lower molecular weight, thus distorting the data towards a lower zero-shear viscosity than was anticipated for PCL of the original molecular weight. Careful examination of Figure 3.26 indicates that the molecular weight of the “branched” PCL appeared to degrade to a fairly constant molecular weight. This implied that there may have been a point in the polymer chain where the bonds were easier to break. Although it was not evident through traditional characterization methods, the aforementioned branch point may have been responsible for the observed degradation.  3.2.1.5  Copolymers of Poly(ε-caprolactone) and Poly(lactide)  Based on the interesting properties of PCL and PLA, there has been significant interest in the field of biodegradable polymer synthesis for the synthesis of copolymers.194 There are two types of copolymers of ε-caprolactone and rac-lactide that were of particular interest, block copolymers and random copolymers.  126  Initial experiments investigated the synthesis of di-block copolymers (Figure 3.28). Due to the degradation observed with tris (amidate) complex 3.9 in the synthesis of PCL, complex 3.8 was chosen to investigate the synthesis of PCL/PLA copolymers. As with the syntheses of PCL and PLA with yttrium (amidate) complexes, the polymerizations were performed under an inert atmosphere. The [M]/[I] ratio was set at 400 to obtain polymer of a large enough molecular weight to provide ease of handling, however the ratio of ε-caprolactone : rac-lactide was varied from 1:2.35 to 1.43:1. rac-Lactide was dissolved in 4.5 - 5 mL of THF and left to stir. A solution of complex 3.8 in THF was added all at once to the stirring solution of monomer and the reaction was left to stir for 15 minutes. Following the stirring, a small aliquot of the reaction mixture (<0.1 mL) was removed and quenched by immediate precipitation in hexanes. The volatiles were removed from the sample and the resulting residue was dissolved in CDCl3 and a 1H NMR spectrum collected. This was to determine if the polymerization had gone to completion. Once the aliquot was removed, ε-caprolactone was added all at once to the stirred reaction mixture and left to stir for an additional 30 minutes. Once the reaction time was complete, a second aliquot was removed for analysis by 1H NMR spectroscopy. The reactions were subsequently exposed to air and quenched with wet hexanes.  127  Figure 3.28 Synthesis of di-block copolymers of PCL/PLA Analysis of the 1H NMR spectrum of the aliquot removed before the addition of εcaprolactone revealed that the rac-lactide was completely converted to PLA before the addition of the second monomer. The 1H NMR spectrum of the second aliquot revealed however, that the ROP of ε-caprolactone did not occur. Further experiments were performed with extended reaction times for the second stage of the di-block synthesis, however no copolymer was ever obtained. Switching from the coordinating solvent THF to the non-coordinating DCM did not alter the results, and again no copolymer was obtained. Analogous results have previously been described in the literature for a number of systems.170,173,177 Given the deactivation of the initiator discussed in Chapter 2, it was proposed that upon complete consumption of the rac-lactide, the initiator was no longer active toward the ROP of cyclic esters. Based on this proposal, the order of addition of monomers was reversed. εCaprolactone was dissolved in 4.5 - 5 mL of THF and left to stir. A solution of complex 3.8 in THF was added all at once to the stirring solution of monomer and the reaction was left to stir for 30 minutes. Following the stirring, a small aliquot of the reaction mixture (<0.1 mL) was removed and quenched by immediate precipitation in hexanes. The volatiles were removed from 128  the sample and the resulting residue was dissolved in CDCl3 and a 1H NMR spectrum collected. Once the aliquot was removed, a solution of rac-lactide was added all at once to the stirring reaction mixture and left to stir. The mixtures immediately became too viscous, and thus the 5 minutes of stirring was done manually. Once the reaction time was complete, a second aliquot was removed for analysis by 1H NMR spectroscopy. The reactions were subsequently exposed to air and quenched with wet hexanes. Analysis of the 1H NMR spectrum of the aliquot removed before the addition of raclactide revealed that the ε-caprolactone was completely converted to PCL before the addition of the second monomer. The 1H NMR spectrum of the second aliquot revealed that the ROP of raclactide did occur, but did not reach full conversion (Table 3.3). The samples used to obtain 1H NMR spectra were also analyzed by GPC. The molecular weight of the second aliquot was found to be significantly higher than that of the first aliquot, therefore indicating that the ROP of raclactide occurred as an addition to the complete PCL chain instead of simply displacing the PCL chain and synthesizing a separate PLA chain (Table 3.3). In addition, the GPC traces were unimodal for both samples. Further experiments were performed with extended reaction times for the second stage of the di-block synthesis, however an increase in % conversion did not occur. Three different di-block copolymers were synthesized using this method and their polymer properties can be found in Table 3.3.  129  Table 3.3 Synthesis of PCL/PLA di-block copolymers using complex 3.8  The identities of the di-block copolymer end groups were investigated by 1H NMR spectroscopy. Looking closely at the 1H NMR spectrum of each of the di-block copolymers it was noted that there were no signals present due to the ligand (o-naphthyl proton doublet was absent) or a methylene group next to a hydroxyl functionality, the only signals present were due to the methyl and methine protons of PLA, and the methylene protons of PCL, indicating that the copolymer had no end groups (Figure 3.29). This is consistent with the lack of end groups observed for the PLA discussed in Chapter 2, and therefore these di-block copolymers are proposed to form large cyclic polymer chains consistent with those proposed in Chapter 2.  130  Figure 3.29 1H NMR spectrum of a PCL/PLA di-block copolymer (75:25 PCL:PLA) (600 MHz, C6D6, 25 °C) (insert is an expansion of the naphthyl region) Once the procedure for the synthesis of PCL/PLA di-blocks was developed, it was of interest to investigate the synthesis of a tri-block of PCL/PLA/PCL. Following the same procedure as with the synthesis of the di-block, an additional aliquot of ε-caprolactone was added after manually stirring, following the addition of the rac-lactide solution. Despite extended 131  reaction times, no tri-block copolymers were ever obtained. This was likely due to the deactivation of the initiator following the ROP of rac-lactide mentioned earlier. Likely the formation of a cyclic di-block copolymer. Once the synthesis of block copolymers was developed, there was interest in synthesizing random copolymers (Figure 3.30). As with the syntheses of PCL, PLA, and PCL/PLA di-blocks with yttrium (amidate) complexes, the polymerizations were performed in an inert atmosphere. The [M]/[I] ratio was set at 400 to obtain polymer of a large enough molecular weight to provide ease of handling, however, the ratio of ε-caprolactone:rac-lactide was varied from 2:1 to 1:2. rac-Lactide and ε-caprolactone were dissolved in 10 mL of DCM and left to stir. A solution of complex 3.8 in DCM was added all at once to the stirring solution of monomers and the reaction left to stir. As with the ROP of rac-lactide in Chapter 2, these reactions were monitored by 1H NMR spectroscopy. During these polymerizations, a small aliquot of the reaction mixture (<0.1mL) was removed at set intervals and quenched by immediate precipitation in hexanes. The volatiles were removed from each sample and the resulting residue was dissolved in CDCl3 and a 1  H NMR spectrum collected. In all attempts at random copolymerization in DCM, the 1H NMR  spectra only showed evidence of the formation of PLA. There were no signals representing PCL.  Figure 3.30 Proposed synthesis of random copolymers of PCL/PLA  132  The ROP of rac-lactide in DCM was significantly faster than the ROP of ε-caprolactone. In addition, the deactivation of the initiator following the complete consumption of rac-lactide would prevent the addition of a growing PCL chain. It was shown in Chapter 2 that the ROP of rac-lactide is significantly slower in THF than DCM. THF was therefore tested as a solvent to prevent the polymerization of only rac-lactide. However, analysis of the 1H NMR spectra showed that as in DCM, no PCL was formed. It can, therefore, be concluded that random copolymers of rac-lactide and ε-caprolactone cannot currently be synthesized by yttrium amidate complexes. This was likely due to the difference in polymerization rate between the ROP of raclactide and ε-caprolactone as a result of increased affinity for rac-lactide over ε-caprolactone by the yttrium amidate complex. Quantitative kinetic data for the polymerizations could not be obtained as the reactions proceed too rapidly. Based on the observations above, the yttrium (amidate) complexes described herein are not capable of preparing multi-block or random copolymers of poly(ε-caprolactone) and poly(lactide) under typical polymerization conditions.  3.2.1.6  Summary  Overall, the PCL synthesized from the ROP of ε-caprolactone using yttrium (amidate) complex 3.8 had mechanical properties consistent with those available commercially. The thermal stability was good, showing degradation after 1700 seconds in comparison to the commercially available PCL Capa 6800, which did not decompose. However, this difference is likely due to the unknown stabilizers present in the commercial sample. The zero-shear viscosity found for all samples synthesized using complex 3.8 lie on the linear trend, indicating that the polymer is linear and shows no evidence of star or long-chain branching. The storage modulus 133  and loss modulus of the PCLs synthesized with complexes 3.8 and 3.9 were found to be consistent with the commercially available Capa 6800 indicating that all three polymers were viscoelastic-liquids. Investigations into the effect of changing the amidate backbone from t-butyl to naphthyl indicated that the change had little effect on the majority of the polymer mechanical properties. The thermal stability showed no difference between the two PCL samples, nor did the storage modulus and loss modulus. Despite these consistencies, the zero-shear viscosity showed a distinct difference; in the case of all three molecular weights (Mw), the zero-shear viscosity was well below the linear trend. This indicated that the polymer likely contained some long-chain branching. 1H, 2H,  13  C, 135-DEPT NMR, and IR spectroscopies showed no evidence of the  proposed branching. Additionally, the solution properties of the different polymers did not indicate branching in either sample. It was proposed that rapid degradation of the “branched” polymer sample was responsible for the zero-shear viscosity data lying below the linear trend. Investigation into this theory confirmed the hypothesis; however it remains unclear as to why the PCL synthesized with complex 3.9 degrades faster than that synthesized with complex 3.8. Complex 3.8 was investigated as an initiator for the synthesis of copolymers of PCL and PLA through the ROP of ε-caprolactone and rac-lactide. Although complex 3.8 was not found to initiate the synthesis of random copolymers, it was shown to produce di-block copolymers. It was determined that additional blocks could not be formed, and the di-blocks must be synthesized starting with the ROP of ε-caprolactone, due to the deactivation of the initiator discussed in Chapter 2.  134  3.3  Conclusions Tris(amidate) complexes of yttrium were confirmed to be highly active initiators for the  ROP of ε-caprolactone. Rheological analysis found that PCL synthesized through the ROP of εcaprolactone using tris(amidate) complex 3.8 as the initiator, had very similar mechanical properties to the PCL produced commercially. Analysis of the polymer indicated good thermal stability for PCL that, unlike commercially available Capa6800, was not blended with known stabilizers. The zero-shear viscosity and the storage and loss modules were consistent with those found for the commercial PCL at comparable molecular weights (Mw). The electronic properties of the amidate ligand were varied by replacing the t-butyl substituent found in complex 3.8 with the naphthyl substituent found in complex 3.9. The mechanical properties were largely unaffected with the exception of the zero-shear viscosity, indicating the presence of branching. Spectroscopic data did not show evidence of branching, but could not conclusively refute its presence. Degradation studies performed on the PCL synthesized with complexes 3.8 and 3.9 as initiators showed that the potentially branched PCL degraded rapidly in comparison with the linear PCL which accounted for the low zero-shear viscosities. However, the cause for the difference in degradation remains unknown and could be caused by the proposed branching. Tris(amidate) complex 3.8 was also found to be an effective initiator for the synthesis of copolymers of PCL and PLA. Although random, multi-block, and alternating copolymers were not obtained using these initiators, di-block copolymers were synthesized through the subsequent ROP of ε-caprolactone and rac-lactide.  135  Overall, tris(amidate) complexes of yttrium are highly active initiators for the synthesis of PCL with good mechanical properties, and for the synthesis of di-block copolymers of PCL and PLA. Future work will involve probing the effects of amidate steric and electronics on the mechanical properties of the resulting PCL, as well as synthesizing different copolymers of PCL and PLA and investigating their mechanical properties.  136  3.4  Experimental  3.4.1 Starting Materials and Reagents All operations were performed under an inert atmosphere of dinitrogen using standard Schlenk-line or glovebox techniques. THF, toluene, and hexanes were purified by passage through an alumina column and sparged with nitrogen. DCM was purified by refluxing over CaH2, distilling, and degassing before storing over molecular sieves. rac-Lactide was purified by subliming three times under reduced pressure. Amidate complexes 3.8 and 3.9 were synthesized as described in the literature.104,143 All other chemicals were commercially available and used as received unless already stated. 1H and 13C NMR spectra were recorded on a Bruker AV300 and AV600 spectrometers at 298 K. Chemical shifts are reported in parts per million and referenced to residual solvent. All 13C NMR spectra were proton-decoupled. Mass spectra were performed by the microanalytical laboratory of the Department of Chemistry at the University of British Columbia. Molecular weights were estimated by triple detection gel permeation chromatography using a Waters liquid chromatograph equipped with a Waters 515 HPLC pump, Waters 717 plus autosampler, Waters Styragel columns (4.6 x 300 mm) HR5E, HR4, and HR2, Waters 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 (ca. 4 mg•mL-1). Absolute molecular weights were determined using a dn/dc (change in refractive index/change in concentration) of 0.079 mL•g-1 for PCL211 and a dn/dc calculated from Astra for the di-block copolymers of PCL/PLA. Rheological analyses were performed by Nazbanoo Noroozi in the Department of Chemical and Biological Engineering at the University of British Columbia. 137  3.4.2 Synthesis General Procedure for the Ring-opening Polymerization of ε-caprolactone ([M]/[I] ratio = 225) at Room Temperature. Inside a dinitrogen filled glovebox, an yttrium (amidate) complex (0.0112 mmol) was dissolved in 10 mL of toluene (measured by volumetric flask). The colorless solution was transferred to a 20 mL vial, equipped with a stir bar. ε-Caprolactone (0.28 mL, 2.5 mmol) was transferred by syringe directly into the rapidly stirring solution of yttrium(amidate) complex. The reaction was stirred for 15 min within the glovebox and then exposed to air and quenched with 1 mL of 1 M aqueous HCl solution. The polymer was precipitated from cold petroleum ether. The polymer was isolated by vacuum filtration, and then dried overnight in vacuo. Yield: 0.274 g, 95%. General Procedure for the 8 x Scale Ring-opening Polymerization of ε-caprolactone ([M]/[I] ratio = 225) at Room Temperature. Inside a dinitrogen filled glovebox, an yttrium (amidate) complex (0.0896 mmol) was dissolved in 25 mL of toluene (measured by volumetric flask). The colorless solution was transferred to a 100 mL reaction vessel equipped with a stir bar, and an additional 55 mL of toluene was added. ε-Caprolactone (2.25 mL, 20.3 mmol) was transferred by syringe directly into the rapidly stirring solution of yttrium(amidate) complex. The reaction was stirred for 30 min within the glovebox and then exposed to air and quenched with 10 mL of 1 M aqueous HCl solution. The polymer was precipitated from cold petroleum ether. The polymer was isolated by vacuum filtration, and then dried overnight in vacuo.  138  General Procedure for the 2 x Scale Ring-opening Polymerization of ε-caprolactone ([M]/[I] ratio = 225) at Room Temperature. Inside a dinitrogen filled glovebox, an yttrium (amidate) complex (0.0225 mmol) was dissolved in 10-20 mL of toluene (measured by volumetric flask). The colorless solution was transferred to a 20-50 mL reaction vessel, equipped with a stir bar. ε-Caprolactone (0.56 mL, 5.0 mmol) was transferred by syringe directly into the rapidly stirring solution of yttrium(amidate) complex. The reaction was stirred for 15-60 min within the glovebox and then exposed to air and quenched with 10 mL of 1 M aqueous HCl solution. The polymer was precipitated from cold petroleum ether. The polymer was isolated by vacuum filtration, and then dried overnight in vacuo. Deuteration of PCL Synthesized with Complex 3.8 with D2O PCL (0.125 g) was dissolved in 20 mL of ethyl ether. The solution was washed with 5 x 20 mL of D2O before drying with magnesium sulfate, filtering, and evaporating to dryness. Yield: 0.122 g, 98%. 2H NMR (CDCl3, 400 MHz, 298 K) δ 5.88 (s, 1D, -OD). Degradation of PCL Synthesized with Complex 3.8 with Base PCL (0.0551 g) was dissolved in 25 mL of 1 M NaOH (50:50 H2O:MeOH). The reaction was stirred for 3 days at reflux. The mixture was acidified to pH 7 with 6 M aqueous HCl and extracted with 5 x 25 mL of ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and evaporated to dryness.  139  General Procedure for the Ring-opening Polymerization of ε-caprolactone ([M]/[I] ratio = 225) at 40 °C or 60 °C. Inside a dinitrogen filled glovebox, an yttrium (amidate) complex (0.0117 mmol) was dissolved in 10 mL of toluene (measured by volumetric flask). The colorless solution was transferred to a parallel synthetic tube, equipped with a stir bar. The solution was heated to 40 °C or 60 °C in a parallel synthetic apparatus and ε-caprolactone (0.28 mL, 2.53 mmol) was transferred by syringe directly into the rapidly stirring solution of yttrium(amidate) complex. The reaction was stirred for 15 min within the glovebox and then exposed to air and quenched with 1 mL of 1 M aqueous HCl solution. The polymer was precipitated from cold petroleum ether. The polymer was isolated by vacuum filtration, and then dried overnight in vacuo. Yield: 0.264 g, 93% (40 °C) and 0.259 g, 90% (60 °C). Monitoring the Degradation of PCLs Synthesized with Complexes 3.8 and 3.9 in Natural Light vs. Dark PCLs (0.250 g) synthesized with complex 3.8 and 3.9 were placed in separate 20 mL vials equipped with Teflon caps. 50% of each type of PCL was placed on a shelf in direct sunlight while the other 50% was wrapped in aluminum foil and placed in a permanent dark location. Once a week a sample was removed from each vial for GPC analysis. Monitoring the Degradation of PCLs Synthesized with Complexes 3.8 and 3.9 at 4 °C PCLs (0.250 g) synthesized with complex 3.8 and 3.9 were placed in separate 20 mL vials equipped with Teflon caps. The vials were placed in the fridge and once a week a sample was removed from each vial for GPC analysis. 140  Monitoring the Degradation of PCLs Synthesized with Complexes 3.8 with the Addition of N-(2,6-diisopropylphenyl)-1-naphthamide Inside a dinitrogen filled glovebox, complex 3.8 (0.0112 mmol) was dissolved in 10 mL of toluene (measured by volumetric flask). The colorless solution was transferred to a 20 mL vial, equipped with a stir bar. ε-Caprolactone (0.28 mL, 2.53 mmol) was transferred by syringe directly into the rapidly stirring solution of complex 3.8. The reaction was stirred for 15 min within the glovebox and then exposed to air and quenched with 1 mL of 1 M aqueous HCl solution. N-(2,6-diisopropylphenyl)-1-naphthamide (0.012 g, 0.012 mmol) was added to the mixture and left to stir for 15 minutes. The polymer was then precipitated from cold petroleum ether. The polymer was isolated by vacuum filtration, and then dried overnight in vacuo. Yield: 0.276 g, 96%. The PCL (0.250 g) was placed in a 20 mL vial equipped with a Teflon cap. The vial was placed on a shelf in direct sunlight and once a week a sample was removed from each vial for GPC analysis. Synthesis of di-block copolymers of PCL/PLA in THF (PCL/PLA final ratio = 40/60, 75/25, 80/20) Inside a dinitrogen filled glovebox, complex 3.8 (0.3056 g, 0.2652 mmol) was dissolved in 50 mL of THF to make a standard solution. 1 mL of the standard solution was then dissolved in more THF (40/60(1.00 mL), 75/25(1.80 mL), 80/20(2.10 mL)) and transferred to a 20 mL vial, equipped with a stir bar. ε-Caprolactone (40/60(0.10 mL, 0.90 mmol), 75/25(0.20 mL, 1.8 mmol), 80/20(0.25 mL, 2.3 mmol)) was transferred by syringe directly into the rapidly stirring solution of complex 3.8. The reaction was stirred for 15 min within the glovebox. A standard solution of rac-lactide (6.1189g, 42.45 mmol) was made in a 50 mL volumetric flask. The rac141  lactide solution 40/60(2.50 mL, 2.12 mmol), 75/25(2.20 mL, 1.87 mmol), 80/20(1.90 mL, 1.61 mmol)) was added all at once to the solution of PCL and left to stir for an additional 15 min. In some cases, manual stirring was required. The mixture was then exposed to air and quenched with 1 mL of 1 M aqueous HCl solution. The polymer was precipitated from cold petroleum ether. The polymer was isolated by vacuum filtration, and then dried overnight in vacuo. Yield: 0.253 g, 62 % (40/60), 0.266 g, 56% (75/25), and 0.304 g, 62% (80/20).  142  Chapter 4. Yttrium Amidate Complexes as Effective Precatalysts for the Catalytic Synthesis of Amides3 4.1 Introduction The synthesis of the amide functionality is a much sought after process desired by chemists and biochemists alike. This functionality can be found in many natural products, pharmaceuticals, polymers, and proteins.212 New synthetic methods for their preparation are essential, as current methodologies typically require acid chlorides or carboxylic acids. While coupling an acid chloride or carboxylic acid to an amine is straightforward, it can be difficult to carry these substituents through a synthetic sequence if other sensitive functionalities are present, and difficult to install the acid at a late stage. In addition, these amide syntheses often involve stoichiometric coupling reagents and produce complex mixtures of side-products that can make isolation of the desired amide product a challenge and often produce large quantities of waste. The development of catalytic routes to obtain amide products with milder, more inexpensive methodologies is an area of intense research.213,214 Recent contributions focus on the synthesis of amides through the amidation of alcohols with amines (Scheme 4.1a).215-218 An alternative approach is the direct amidation of aldehydes with amines (Scheme 4.1b).219 This route is attractive due to the inexpensive nature of the commercially available starting materials.  3  A version of this has been published [Thomson, J. A.; Schafer, L. L. Dalton Trans. 2012, 41, 7897-7904.] Reproduced by permission of The Royal Society of Chemistry.  143  Scheme 4.1 The catalytic amidation of alcohols and aldehydes and the Cannizzaro reaction Catalytic systems for the amidation of aldehydes have attracted significant interest in recent years and a variety of methodologies have been investigated. Several metal-free catalysts have been reported for this transformation, including the use of N-heterocyclic carbenes (NHCs)216,220 as organocatalysts, in combination with varying stoichiometric reagents including t-butylhydrogenperoxide (TBHP) as an oxidant.221,222 Although effective for the transformation, metal free systems do not address the challenge of waste production. A few examples of light and radical mediated amidations have been reported, however these reactions also require either stoichiometric additives or long reactions times.223,224 A number of Cannizzaro type reactions (Scheme 4.1 “c”) have been reported using either catalytic or stoichiometric amounts of nontransition metal reagents such as lithium diisopropylamide (LDA).225 Reactions catalyzed by alkali metal reagents such as sodium hydride or an oxidative mixture of potassium iodide and TBHP have also been reported.226,227 More interestingly, a number of metal-based systems from across the d-block have been investigated. These systems include nickel salts,228 palladium in the presence of hydrogen peroxide,229 ruthenium hydrides in combination with sodium hydride, and copper/silver salts with amine hydrochloride salts.230,231 Although these catalytic systems 144  establish the effective nature of metal-based systems for this transformation, rare-earth metal systems have the added advantage of providing a reduced toxicity profile. The first report of a rare-earth complex catalyzing the amidation of aldehydes was published in 2008 by the Marks group.232 They determined that simple, commercially available rare-earth amido complexes are capable of facilitating this transformation. Recently, the Wang group has shown that the amidation reaction can also be promoted by a variety of other ligated rare-earth systems233 or using rare-earth chlorides in Cannizzaro-type reactions.234,235 The Shen group has reported the use of rare-earth guanidinate,236,237 amidinate,108 and heterobimetallic238240  complexes as well. Most importantly, none of the rare-earth systems reported require the  addition of stoichiometric bases or oxidants.  Figure 4.1 Known rare-earth complexes used as amidation precatalysts232,233,236 Examples of some known rare-earth complexes used as precatalysts for the amidation of aldehydes with amines are shown in Figure 4.1. Lanthanum amido complex 4.1 is a well known starting material for the synthesis of other lanthanum complexes and is comparable to the starting material used in the syntheses of the yttrium (amidate) complexes reported in this thesis. 145  Complex 4.2 is a tris(guanidinate) complex of lanthanum with a coordinated molecule of THF.236 This complex is analogous to the yttrium tris(amidate) complexes discussed in Chapters 2 and 3. Finally, complexes 4.3 and 4.4 are modified amido complexes of yttrium and neodymium and also contain a single coordinated THF molecule.233 Rare-earth complexes 4.1-4.4 are all highly successful precatalysts and their reactivity in the amidation of benzaldehyde (4.5) with aniline (4.6) to form N-phenylbenzamide (4.7) is shown in Table 4.1. It was noted that the reaction time decreased upon coordination of a more complex ligand system (compare complexes 4.1 and 4.2, entries 1 and 2), however, this was accompanied by a decrease in yield. Comparison of neodymium complex 4.3 with analogous yttrium complex 4.4 indicated that the yttrium metal center was more active for this transformation. The highest yield was produced by lanthanum amido complex 4.1. Like most catalytic systems used for this transformation, complexes 4.1 – 4.4 have good substrate scope, however, as with most other reported systems, there are limitations. Table 4.1 Amidation of benzaldehyde with aniline  146  In recent years, the Schafer group and others have demonstrated the vast applicability of early transition metal and rare-earth (amidate) complexes. These complexes have been reported as useful precatalysts in a variety of transformations, especially in catalytic C-N bond forming reactions particularly in the catalytic synthesis of amines. Group 4 and rare-earth(amidate) complexes are effective systems for the intermolecular and intramolecular hydroamination of alkynes,241-243 allenes,244,245 and alkenes.105,106,241,246-252 Tantalum (amidate) complexes have been shown to promote hydroaminoalkylation (the α-alkylation of amines) in an intermolecular fashion and zirconium (pyridonate) complexes have been reported to catalyze the intramolecular version.251,253-256 Finally, rare-earth(amidate) complexes are highly effective initiators in the ROP of ε–caprolactone and rac-lactide, as was reported in Chapters 2 and 3.102,104,106 The success of amidate complexes in such a variety of transformations inspired the investigation of yttrium (amidate) complexes for other catalytic transformations. This chapter will detail the study of yttrium (amidate) complexes as precatalysts for the mild amidation of aldehydes with amines.  4.1.1 Scope of Chapter The notable success of yttrium amidate complexes for the ROP of cyclic esters and the cyclohydroamination of aminoalkenes102,104-106 has generated interest in investigating these yttrium amidate complexes for additional transformations. As was mentioned in the previous chapters, these yttrium amidate complexes are easily synthesized in high yield and high purity.104,105 The modular synthesis of the amide proligands provides a means of easily modifying the amidate backbone, and potentially the precatalyst reactivity. It has been shown that varying the steric and electronic properties of the amidate ligand of these yttrium amidate complexes can have a great impact on hydroamination reaction times, along with molecular 147  weights and PDIs in the ring-opening polymerizations of ε-caprolactone and rac-lactide.104,105 It is of interest to investigate reactivity trends with respect to the number of amidates coordinated. Therefore, mono-, bis-, and tris(amidate) complexes were tested for reactivity in the catalytic synthesis of amides from aldehydes (Figure 4.2). The substrate scope was probed for comparison with known amidation catalysts. Investigations into the amidation mechanism and various byproducts will also be included in this chapter.  Figure 4.2 Yttrium amidate complexes as precatalysts for the amidation of aldehydes with amines 148  4.2  Yttrium Amidate Complexes as Precatalysts  4.2.1 Results and Discussion 4.2.1.1 Reaction Conditions and Catalyst Optimization Initially, to test the reactivity of these yttrium (amidate) complexes for the amidation of aldehydes with amines, we first utilized previously reported reaction conditions.108,236-240 To test the previously reported reaction conditions, complex 4.8 was used to catalyze the reaction of ptoluidine (4.17) and benzaldehyde (4.5) to form N-p-tolylbenzamide (4.18). This combination of substrates was chosen due to the convenient 1H NMR signals resulting from the methyl group of p-toluidine. In CDCl3 the methyl signal of p-toluidine in the 1H NMR spectrum is found at 2.27 ppm and this signal shifts to 2.37 ppm upon coupling to form 4.18. The methyl signals of ptoluidine and N-p-tolylbenzamide are not as well separated in the deuterated version of the reaction solvents, therefore, reactions were monitored by removing sample aliquots from the reaction mixture and quenching before removing volatiles and collecting the 1H NMR spectrum in CDCl3. Reactions were first performed in toluene and were monitored by 1H NMR spectroscopy. It was determined that the reaction went to near completion, in only 5 minutes using complex 4.8. However, it was also determined that leaving the mixture to react longer did not increase the yield of product; in fact the product yield appeared to decrease. Monitoring the reaction for 60 min resulted in a spike in product at 5 min followed by a rapid decrease likely resulting from rapid equilibration of p-toluidine (4.17), benzaldehyde (4.5), and amide product 4.18. Experiments to probe this rapid equilibration, which resulted in a decrease in the yield of 149  product, will be discussed later in this chapter. Insight into this decrease could help prevent the back reaction, thus increasing product yields. In total, three different solvents were investigated to optimize the reaction conditions: THF, DCM, and toluene. As can be seen in Table 4.2, toluene resulted in the highest yield of product with 74% in comparison to 25% and 23% for THF and DCM respectively. The substrate ratio was also optimized, where 3:1 aldehyde:amine is the ideal ratio (Table 4.2). The basis for this result will be discussed later in this chapter. The yttrium (amidate) complex was confirmed to be responsible for catalysis as no reaction occurred in the absence of complex 4.8 or merely in the presence of the amide proligand N-(2,6-diisopropylphenyl)-1-naphthamide. Table 4.2 Reaction optimization for the amidation of benzaldehyde with p-toluidine  Several mono, bis, and tris(amidate) complexes were synthesized, as previously reported104,105 and as mentioned in Chapter 2, and investigated to determine the impact of varying the steric and electronic properties of the amidate ligand. Reactions with complexes 4.8 150  – 4.16 were first monitored by 1H NMR spectroscopy to determine the reaction time necessary to produce the highest yield of product before the mixture equilibrated. Investigations into the reactivity of these yttrium (amidate) complexes revealed very short reaction times (Table 4.3). These reactions occurred incredibly fast; known rare earth amidation catalysts report reactions in terms of hours.219 Looking first at the effect of the number of amidate ligands coordinated, complexes 4.8 – 4.13 were investigated. In the case of the naphthyl substituted amidate complexes (4.8 – 4.10), there was an increase in product yield with an increase in the number of coordinated amidate ligands. It was also shown that the reaction times decreased with the increase in the number of coordinated amidate ligands. With t-butyl-substituted complexes 4.11 – 4.13, while the product yield increases with increasing coordinated amidate ligands, reactions times do not vary significantly. These results indicated that the tris(amidate) complexes are more effective precatalysts in this reaction and that the aryl, somewhat electron-withdrawing naphthyl substituent is preferred over the alkyl t-butyl substituent on the amidate backbone. Once it was determined that the tris(amidate) complexes were the most effective catalysts for the transformation, the steric and electronic properties of the amidate ligand were investigated. To probe the effect of steric bulk on the amidate nitrogen complex 4.14 was investigated; the decrease in steric bulk from complex 4.11 had no effect on either the product yield or reaction time. Varying the electronic properties of the amidate ligand was investigated by incorporation of one and two electron-withdrawing trifluoromethyl substituents in complexes 4.15 and 4.16 respectively. This change in electronic features significantly increased reaction time and decreased the amide product yield. Finally, to confirm the necessity of the amidate 151  ligand, the starting material used to synthesize all the yttrium (amidate) complexes, Y(N(SiMe3)2)3, was tested. While the yield of amide product is comparable to that of precatalyst 4.8, the reaction requires 60 minutes to complete the transformation. Table 4.3 Optimized reaction times and isolated product yields of precatalysts 4.8-4.16 for the amidation of benzaldehyde with p-toluidine  It was determined that yttrium amidate complexes are highly active in the catalytic amidation of aldehydes with amines. The yttrium tris(amidate) scaffold was shown to catalyze the reaction rapidly and in high yield. The steric bulk on the 2,6-diisopropyl substituent on the nitrogen combined with the somewhat electron-withdrawing naphthyl substituent on the carbonyl resulted in the most effective catalyst, complex 4.8.  152  4.2.1.2 Substrate Scope Once the reaction conditions were optimized where the best performing precatalyst was determined to be complex 4.8, the substrate scope was investigated with respect to both the amine and aldehyde components of the amidation reaction. Current rare-earth systems have been shown to be highly effective with aryl substituted aldehydes and amines, however, these reactions require long reaction times (2 to 48 hours) and high temperatures (up to 65°C).108,232234,236-240  Also, there are very few catalysts capable of tolerating alkyl substituents,232,237,239 and  very few that tolerate steric bulk.233,234 The amine substrate scope was probed using a variety of functionalities (Figure 4.3). It was found that a variety of primary aryl amines were tolerated by precatalyst 4.8. Aniline (4.6) and p-toluidine (4.17) reacted with benzaldehyde (4.5) to produce amide products 4.7 and 4.18 in good yields (64% and 74% respectively). 2,6-Dimethylaniline was also reacted with benzaldehyde to investigate the tolerance of sterics on the amine portion of the substrate pair. Amide product 4.19 was formed in 22% yield. Although low yielding, this amine substrate and therefore this substrate pair has rarely been published,234,240 implying that steric bulk on the amine component may not be tolerated by most of the systems that have been reported to date. In addition to probing the effects of steric properties, the electronic properties of the amine were also investigated. It was found that precatalyst 4.8 tolerated electron-withdrawing substituents, as amide product 4.20 was formed in good yield when benzaldehyde was reacted with p-chloroaniline. Electron-donating substituents such as the methoxy functionality were not as effective, as no amide product (4.21) resulted from the reaction of p-anisidine and benzaldehyde. However, it was determined that the electron-donating methoxy functionality could be forced to react by combining the electron-rich amine with an aldehyde containing the 153  highly electron-withdrawing nitro substituent; the result was amide product 4.22. Although functionalized aryl amines were easily tolerated, reactions of the primary alkyl amines cyclohexylamine and t-butylamine did not result in amide products (4.23 and 4.24), which is consistent with the trend of increased reactivity with reduced nucelophilicity.  Figure 4.3 Amine Substrate Scope Inspired by the mechanism proposed by Marks and co-workers in 2008 (vide infra),232 secondary amines were investigated as amine substrates for the formation of tertiary amide products. In this case, alkyl substituents were highly effective substrates producing tertiary amide 154  products 4.25, 4.26, and 4.27 in good yields, using piperidine, N-methylaniline, and Nmethylbenzylamine respectively. The increased yields obtained through reactions with secondary amines may be attributed to the inability of secondary amines to form the competing imine byproduct (vide infra). The formation of imines from aldehydes and amines can be promoted by Lewis acids through Schiff base condensations and will be discussed later in this Chapter.257 The aldehyde substrate scope paralleled that of the amine component with respect to both steric and electronic effects (Figure 4.4). Sterically demanding substrates pivalaldehyde and 2,4,6-trimethylbenzaldehyde were reacted with aniline (4.6) resulting in a 21% yield of amide product 4.28 and no reaction to form amide product 4.29. Nevertheless, this is the first example of a rare earth complex reported for the amidation of pivalaldehyde. The reaction of cyclohexylcarboxaldehyde with aniline and piperidine demonstrated that other alkyl substituted aldehydes were tolerated (4.30 and 4.31), but reaction yields are greatly increased when the aldehyde is combined with a secondary amine. Again, this is likely to be due to the fact that secondary amines cannot form imines through simple Schiff-base condensations.257 The use of cyclocarboxaldehyde as a substrate has rarely been reported for this transformation using a rare earth catalyst.232,236,239 The reaction of 4-chlorobenzaldehyde was initially used to investigate the tolerance of electron-withdrawing substituents by precatalyst 4.8. Performing the reaction in toluene resulted in the immediate formation of insoluble imine by-product. The substrate combination was reinvestigated with THF as the reaction solvent and amide product 4.32 was formed in 19% yield. This low yield is not surprising as mentioned earlier in this chapter, THF is not the ideal solvent for this transformation and this yield is comparable to that of product 4.18 in THF (Table 4.2). 155  To obtain more insight into the effect of electron-withdrawing substituents, 4-nitrobenzaldehyde was reacted with p-toluidine. The reaction resulted in the formation of amide product 4.33 in 87% yield, confirming that aldehyde substrates substituted with electron-withdrawing functionalities are highly effective in the amidation reaction. In fact, when 4-chlorobenzaldehyde and 4-nitrobenzaldehyde were reacted with secondary amine piperidine, the resulting products, 4.34 and 4.35, were formed in two of the highest yields found for this yttrium (amidate) precatalyst. Finally, the effects of electron-donating substituents on the aldehyde component were investigated. It was found that there was no reaction of p-anisaldehyde with aniline (4.36), however, amide product 4.37 was formed upon reaction of the electron-rich aldehyde with piperidine.  156  Figure 4.4 Aldehyde Substrate Scope  4.2.1.3 Mechanistic Insight In a report from 2008, the Marks group proposed a reaction mechanism for the rare-earth catalyzed amidation of aldehydes.232 The mechanism of this transformation using yttrium (amidate) complexes as precatalysts was investigated using this mechanistic proposal as a starting point. Based on this proposal, there are three products produced in this reaction: the desired amide product (boxed) and two side products; an alcohol (B) and an ester (C). In addition to these products, formation of an imine side-product (D) was also observed. Thus the  157  original proposed mechanism has been amended to incorporate a side-reaction involving the formation of imine (Scheme 4.2).  Scheme 4.2 Proposed mechanism for the amidation of aldehydes with amines To probe the mechanism, the substrate pair of p-toluidine (4.17) and benzaldehyde (4.5) was investigated using precatalyst 4.8. The alcohol (B) was first observed while monitoring the reaction to form N-p-tolylbenzamide (4.18) by 1H NMR spectroscopy. Benzyl alcohol was clearly formed as evidenced by the appearance of the diagnostic benzylic protons signal at 4.70 ppm in CDCl3 which is consistent with the 1H NMR spectrum of commercially available benzyl alcohol. Ester side product (C), in this case benzylbenzoate, was also observed during reactions monitored by 1H NMR spectroscopy. The appearance of a diagnostic singlet arising from the benzylic protons at 5.37 ppm indicated the formation of the side product during the reaction. 158  Finally, the formation of two singlets in the 2.30-2.40 ppm region of the 1H NMR spectrum of a crude reaction mixture suggested the formation of imine by-product (D) in addition to amide product. Indeed, the signal arising from the methyl protons of the independently synthesized (E)N-benzylidene-4-methylaniline (D) was observed at 2.32 ppm and additionally the parent mass (M = 196) was present in the mass spectrum of the crude reaction mixture. To further confirm the formation of these side-products, the proposed products were purchased or prepared using standard methods and the spectral data compared directly to those obtained during reaction monitoring. Evidence of the formation of ester side product (C) during the desired transformation and literature precedence19,258 suggested that yttrium (amidate) complexes may be capable of catalytic ester formation from aldehydes, i.e. the Tishchenko reaction.19,258 Indeed, it was found that precatalyst 4.8 was capable of forming benzyl benzoate (4.38) in good yield from benzaldehyde (Scheme 4.3).  Scheme 4.3 Tishchenko reaction using precatalyst 4.8 The formation of imine (D) was only observed by 1H NMR spectroscopy and mass spectrometry in the substrate pairs involving primary aryl amines. The formation of this imine not only consumed the limiting amine reagent, but also results in the formation of water. This water production may be responsible for decomposition of the active yttrium catalyst, resulting 159  in the lower yields observed for many of the primary amine substrates (Figure 4.3). As was mentioned earlier in this chapter, the product yields for the secondary amine substrates are significantly higher. These higher yields are therefore likely due to the prevention of imine formation and, thus, the larger quantity of substrate available and the absence of detrimental water. In addition to the side-products observed when monitoring the catalytic reaction with precatalyst 4.8, it was noted that when the reaction was performed in a sealed NMR tube, by completion only free N-(2,6-diiisopropylphenyl)naphthylamide proligand could be observed. It has been reported that the ortho-naphthyl signal of the free amide proligand shifts significantly from 8.86 ppm to >9 ppm upon complexation. The ortho-naphthyl signals of the yttrium (amidate) complexes are well resolved at 9.16, 9.09, and 9.26 ppm in C6D6 for mono-, bis-, and tris(amidate) complexes respectively, and can, therefore, be used to determine the number of coordinated amidate ligands.104,105 The amide product formed from the catalytic amidation of aldehydes is almost identical structurally to the protonated amidate ligand, therefore experiments were conducted to investigate potential ligand displacement. Six equivalents of amide product 4.18 were reacted with one equivalent of precatalyst 4.8 and monitored by 1H NMR spectroscopy (Scheme 4.4). Indeed, the amide product completely displaced the amidate ligands, as demonstrated by the absence of signals in the >9 ppm region of the 1H NMR spectrum and the appearance of a doublet at 8.86 ppm.  160  Scheme 4.4 Ligand displacement precatalyst 4.8 by amide product 4.18 Looking back to the formation of amide product 4.18 using precatalyst Y(N(SiMe3)2)3, a distinct induction period was observed upon monitoring by 1H NMR spectroscopy (Figure 4.5). Y(N(SiMe3)2)3 is reacted with amide proligands via protonolysis to synthesize the yttrium (amidate) complexes used in this thesis. It is, therefore, possible that yttrium (amidate) complexes were formed in situ as the Y(N(SiMe3)2)3 was surrounded by an excess of amide. This proposal may account for the observed induction period; it has been confirmed that the amidate precatalysts catalyze the transformation in a significantly shorter time (as little as 5 minutes). This is consistent with the increase in reaction time observed with the bis- and mono(amidate) complexes (4.9 and 4.10).  161  100 90 Reaction % Yield  80 70 60 50 40 30 20 10 0 0  10  20  30 40 Time /min  50  60  Figure 4.5 Reaction of p-toluidine with benzaldehyde using Y(N(SiMe3)2)3 Although these yttrium (amidate) complexes have significantly decreased the reaction time, the large yield of amide product was shown to rapidly decrease if the reaction mixture was left to stir beyond the time necessary to obtain the maximum yield. It was observed by 1H NMR spectroscopy that the disappearance of the amide product occurred simultaneously with the appearance of more imine product, indicating that the amide product was first converted back to aldehyde and amine before reacting to form imine. To investigate this process, a number of reactions of p-toluidine (4.17) and benzaldehyde (4.5) were qualitatively monitored by 1H NMR spectroscopy. In each case, the integration of the signal for the methyl protons was compared with that of an internal standard. The first two reactions, amide product 4.18 or imine product 4.39 with precatalyst 4.8, were used to determine if the precatalyst itself was capable of facilitating the reverse reactions. In the first reaction (Scheme 4.5), the precatalyst did not convert the amide product to the  162  starting materials and, therefore, did not form the imine side-product. In the second reaction (Scheme 4,5), the imine did not reform the substrates and, therefore, could not form any amide product. This is likely due to the absence of advantageous water, which would be required to reform the initial substrates from the imine.  Scheme 4.5 Amide product 4.18 and imine 4.39 stability in presence of precatalyst 4.8 Following the initial experiments, a number of reagent combinations were monitored to attempt to observe the disappearance of product. The amide product was first left to stir with the precatalyst 4.8 followed by the addition of one of the starting materials or side-products: aldehyde, amine, alcohol, ester, and imine (Scheme 4.6). Internal standard, 1,3,5trimethoxybenzene, was present in each reaction mixture to allow for the easy quantification of amide product. In all cases, no change was observed in the quantity of amide product present in the 1H NMR spectrum. In addition, no new signals appeared in the 1H NMR spectra and there were no observable changes to the reaction mixtures, therefore, it was concluded that no reactions occurred, with the exception of the aldehyde substrate where precatalyst 4.8 catalyzed the Tishchenko reaction, forming benzyl benzoate.  163  Scheme 4.6 Amide product 4.18 stability in presence of precatalyst 4.8 and substrates or side-products  Lastly, in separate experiments, the amide and imine products were added to equilibrated reaction mixtures and monitored by 1H NMR spectroscopy (Scheme 4.7). As with the experiments described in Scheme 4.6, internal standard was present in each reaction mixture to allow for the easy quantification of the products present in the reaction mixtures. Reaction 164  mixtures were left to react for 60 minutes before the amide and imine products were added, to allow the mixture to reach equilibrium. Surprisingly, with the addition of amide to the reaction mixture, no change was observed throughout 60 minutes of monitoring. The addition of imine to the reaction mixture also resulted in no change after 60 minutes.  Scheme 4.7 Amide product 4.18 stability in presence of additional 4.18 or 4.39 The lack of change observed during reaction monitoring suggests that the reaction pathway responsible for the disappearance of the amide product evolves from a complex mixture of substrates, products, and in situ formed catalytic yttrium species.  4.2.1.4 Summary Overall, yttrium amidate complexes were shown to be good catalysts for the mild amidation of aldehydes with amines. Tris(amidate) complexes of yttrium are more effective precatalysts than bis(amidate) and mono(amidate) complexes of yttrium (complexes 4.8 – 4.13). Variation of the steric bulk on the amidate nitrogen has no effect on the reactivity of these precatalysts (complexes 4.11 and 4.14). However, the addition of electron-withdrawing substituents on the amidate carbon greatly decreased reactivity (complexes 4.15 and 4.16). 165  Reaction conditions have a large effect on the precatalyst activity, showing that yttrium (amidate) complexes are most effective in toluene with a substrate ratio of 3:1 aldehyde:amine. The most effective catalyst for this transformation is complex 4.8 and it is capable of completing the reaction in only 5 minutes. Precatalyst 4.8 has a broad substrate scope capable of tolerating a variety of amines and aldehydes. Mechanistic aspects of the reaction were investigated and it was shown that after the amidation was complete, the reaction rapidly reverses, decreasing the yield of amide product drastically. Reactions of the amide product with combinations of precatalyst, amine and aldehyde substrates, and additional products (alcohol, ester, or imine) gave no insight into the rapid decrease in amide product yield. Insight into this decrease could allow the back reaction (where starting materials are reformed) to be prevented, thus increasing product yields.  4.3 Conclusions Yttrium amidate complexes are easily synthesized in high yield and are good candidates as precatalysts for the mild amidation of aldehydes with amines with the exception of complex 4.8, which is shown to be excellent. Precatalyst 4.8 shows superior activity in comparison to known yttrium and other rare-earth precatalysts and can complete reactions in 5 minutes at room temperature. Induction periods resulting from the use of slower-reacting amido complexes can be avoided by preforming an amidate complex. Precatalyst 4.8 shows excellent substrate scope, tolerating electron-withdrawing and electron-donating functionalities on both the amine and aldehyde components; primary and secondary amines; sterics bulk on both the amine and aldehyde components; and aryl and alkyl 166  substituted aldehydes. Precatalyst 4.8 is one of only a few rare earth complexes capable of tolerating cyclohexylcarboxaldehyde and is the first example of a rare earth complex in combination with pivalaldehyde. Precatalyst 4.8 is also one of the only complexes capable of tolerating steric bulk on the nitrogen. Using precatalyst 4.8, amide product is produced in high yield followed by a rapid decrease to a lower yield. Mechanistic investigations provided evidence to support the mechanism proposed in Scheme 4.2, however, no insight was obtained into the rapid decrease in amide product once formed. Future work would mainly focus on determining the pathway that allows for the rapid disappearance of product once the reaction is complete, and how that pathway might be avoided.  167  4.4 Experimental 4.4.1 Starting Materials and Reagents All operations were performed under an inert atmosphere of nitrogen using standard Schlenk-line or glovebox techniques. THF, toluene, and hexanes were purified by passage through an alumina column and sparged with nitrogen. DCM, benzaldehyde, aniline, 2,6-dimethylaniline, piperidine, N-methylaniline, N-methylbenzylamine, pivalaldehyde, 2,4,6-trimethylbenzaldehyde, benzyl alcohol, cyclohexylamine, t-butylamine, and cyclohexylcarboxaldehyde were purified by distillation and stored over molecular sieves. p-Toluidine, p-chloroaniline, 4-nitrobenzaldehyde, 4-chlorobenzaldehyde, p-anisidine, and p-anisaldehyde were purified by sublimation. Y(N(SiMe3)2)3 was synthesized as described in the literature.153 Complexes 4.8,104 4.9,105 4.10,105 4.11,143 4.13,143 4.14,104, 4.15104, and 4.16143 were prepared according to previously reported procedures. Complex 4.12 was prepared as previously reported in this thesis. (E)-N-benzylidene4-methylaniline was prepared according to a previously reported procedure.259 All other compounds were commercially available and used as received unless otherwise stated. 1H and 13  C NMR spectra were recorded on Bruker AV300, AV400, and AV600 spectrometers at 298 K.  Chemical shifts are reported in parts per million and referenced to residual solvent. All 13C NMR spectra were proton-decoupled. Elemental analysis and mass spectra were performed by the microanalytical laboratory of the Department of Chemistry at the University of British Columbia.  168  4.4.2 Synthesis General Procedure for Catalytic Amidation Inside a nitrogen filled glovebox, a 20 mL vial was charged with yttrium (amidate) complex (0.05 mmol), amine (1.00 mmol), 2.5 mL of toluene, and a stir bar. Benzaldehyde (3.00 mmol) was added by syringe to the stirring solution and the mixture was left to stir before the vial was removed from the glove box and 10 mL of hexanes was added. The volatiles were removed under reduced pressure prior to dissolving in 10 mL of dichloromethane and filtering. Once the dichloromethane was removed under reduced pressure, the product was purified by column chromatography. Tishchenko Reaction with 4.8 (4.38) Inside a nitrogen filled glovebox, a 20 mL vial was charged with 4.8 (0.05 mmol), 2.5 mL of toluene, benzaldehyde (2.00 mmol), and a stir bar and the mixture was left to stir for 1 hour before the vial was removed from the glove box and 10 mL of hexanes was added. The volatiles were removed under reduced pressure prior to dissolving in 10 mL of dichloromethane and filtering. Once the dichloromethane was removed under reduced pressure, the product was purified by column chromatography (20:1 petroleum ether : ethyl acetate) yielding 4.38 as a white solid, 0.142 g (68%). Spectral data matched literature references. Qualitative Monitoring of a Typical Amidation Inside a nitrogen filled glovebox, a 20 mL vial was charged with yttrium (amidate) complex (0.05 mmol), amine (1.00 mmol), 2.5 mL of toluene, and a stir bar and the mixture was left stirring for 30 minutes. Benzaldehyde (3.00 mmol) was added by syringe and the mixture was 169  left to stir. At set intervals (every 5 min) an aliquot was removed and quenched with hexanes. For each aliquot, the volatiles were removed and the sample diluted with CDCl3 prior to obtaining a 1H NMR spectrum of each. Mechanistic Monitoring with 4.8 Inside a nitrogen filled glovebox, a 20 mL vial was charged with 4.8 (0.05 mmol), amide (1.00 mmol), 2.5 mL of toluene, and a stir bar and the mixture was left stirring for 5 minutes. Starting material or side-product (B,C, or D) (3.00 mmol) was added by syringe or dissolved in minimal toluene and added to the mixture and was left to stir. At set intervals (every 5 min) an aliquot was removed and quenched with hexanes. For each aliquot, the volatiles were removed and the sample diluted with CDCl3 prior to obtaining a 1H NMR spectrum of each. or Inside a nitrogen filled glovebox, a 20 mL vial was charged with yttrium (amidate) complex (0.05 mmol), amine (1.00 mmol), 2.5 mL of toluene, and a stir bar. Benzaldehyde (3.00 mmol) was added by syringe to the stirring solution and the mixture was left to stir for 60 min. Sideproduct (C or D) (3.00 mmol) was then added by syringe or dissolved in minimal toluene and added to the mixture and the resulting mixture was left to stir. At set intervals (every 5 min) an aliquot was removed and quenched with hexanes. For each aliquot, the volatiles were removed and the sample diluted with CDCl3 prior to obtaining a 1H NMR spectrum of each.  170  N-phenylbenzamide (4.7) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.124 g (64%). Spectral data matched literature references.234 N-p-tolylbenzamide (4.18) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.151 g (74%). Spectral data matched literature references.260 N-(2,6-dimethylphenyl)benzamide (4.19) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.048 g (22%). Spectral data matched literature references.234 N-(4-chlorophenyl)benzamide (4.20) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.182 g (80%). Spectral data matched literature references.260 N-(4-methoxyphenyl)-4-nitrobenzamide (4.21) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.222 g (84%). Spectral data matched literature references.261  171  phenyl(piperidin-1-yl)methanone (4.25) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.141 g (74%). Spectral data matched literature references.234 N-methyl-N-phenylbenzamide (4.26) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.161 g (83%). Spectral data matched literature references.262 N-benzyl-N-methylbenzamide (4.27) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.163 g (78%). Spectral data matched literature references.263 N-phenylpivalamide (4.28) Purified by column chromatography (started with 1% ethyl acetate in petroleum ether and very slowly increased to 5%) yielding 0.036 g (21%). Spectral data matched literature references.264 N-phenylcyclohexanecarboxamide (4.30) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.071 g (35%). Spectral data matched literature references.265  172  cyclohexyl(piperidin-1-yl)methanone (4.31) Purified by column chromatography (started with 15% ethyl acetate in petroleum ether and slowly increased to 30%) yielding 0.166 g (84%). Spectral data matched literature references.265 4-chloro-N-p-tolylbenzamide (4.32) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.046g (19%). Spectral data matched literature references.233 4-nitro-N-p-tolylbenzamide (4.33) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.220 g (87%). Spectral data matched literature references.260 (4-chlorophenyl)(piperidin-1-yl)methanone (4.34) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.193 g (85%). Spectral data matched literature references.221 (4-nitrophenyl)(piperidin-1-yl)methanone (4.35) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.232 g (98%). Spectral data matched literature references.261 (4-methoxyphenyl)(piperidin-1-yl)methanone (4.37) Purified by column chromatography (8:1 petroleum ether : ethyl acetate) yielding 0.061 g (27%). Spectral data matched literature references.266 173  benzylbenzoate (4.38) Purified by column chromatography (20:1 petroleum ether:ethyl acetate) yielding 0.142 g (68%). Spectral data matched literature references.267  174  Chapter 5. Conclusions and Future Work 5.1  Summary and Conclusions The research presented in this thesis describes investigations into the application of  known and novel yttrium amidate complexes. All complexes were found to be highly active initiators for the ring-opening polymerization of rac-lactide. PLA was formed rapidly, and in near quantitative yield, using almost all of the complexes. The yttrium tris(amidate) complexes were found to synthesize PLA with the highest molecular weight and reasonably narrow polydispersity values (1.277-1.534). As reported for the ring-opening polymerization of εcaprolactone,104,143 the amidate backbone was shown to have a significant effect on the polymerization activity and resulting polymer properties. Complexes with amidate ligands containing the electron-withdrawing trifluoromethyl substituent were found to be less active, while in the case of the complex containing two electron-withdrawing substituents, extremely high molecular weight polymer was obtained in lower yield. Investigation into the mechanism of polymerization resulted in the proposal that the ROP of rac-lactide follows a coordinationinsertion mechanism, with rapid propagation, followed by termination. One proposal for termination was the formation of cyclic PLA. Future work involving the ROP of lactide with these yttrium amidate initiators should take into account the formation of large cyclic polymers when analyzing polymers and probing mechanisms.145-152 The mechanical properties of PCL synthesized using yttrium tris(amidate) complexes were investigated using rheological analyses. Overall, the PCL synthesized from the ROP of εcaprolactone using yttrium tris(amidate) complexes had mechanical properties consistent with 175  commercially available polymers. The thermal stabilities of the synthesized polymers were good, but the samples did show degradation over time, likely due to the lack of stabilizers. Analysis of the storage modulus and loss modulus determined that the synthesized and commercially available PCL were all viscoelastic-liquids. Analysis of the zero-shear viscosity of a variety of samples indicated a difference between PCLs synthesized with yttrium (amidate) complexes containing different amidate backbone substituents, indicating the possible synthesis of a branched PCL when the naphthyl substituent was utilized. The proposal of a branched sample of PCL was neither confirmed nor refuted, as materials properties such as expedited degradation and lower zero-shear viscosities suggest branched polymer formation, yet extensive molecular analytical techniques failed to identify such branch points in the polymeric products. Yttrium tris(amidate) complex, tris(N-2′, 6′-diisopropylphenyl(tert-butyl)amidate)yttrium mono(tetrahydrofuran), was also investigated as an initiator for the synthesis of copolymers of PCL and PLA through the ROP of ε-caprolactone and rac-lactide. Di-block copolymers were synthesized when the ring-opening polymerization of ε-caprolactone was performed first. In addition to the ROP of cyclic esters, the yttrium amidate complexes reported in this thesis were investigated for the catalytic synthesis of amides from aldehydes and amines. Yttrium mono-, bis-, and tris(amidate) complexes were all found to be effective precatalysts for the transformation. The tris(amidate) complexes were found to be most efficient, catalyzing the reaction in as little as 5 minutes. As with the ROP of cyclic esters, the amidate backbone did affect catalytic activity. Although variation of the steric bulk on the amidate nitrogen had no effect on the reactivity of the precatalysts, the addition of electron-withdrawing substituents on the amidate carbon greatly decreased reactivity. The best performing precatalyst had a broad substrate scope capable of tolerating a variety of amines and aldehydes, consistent with catalysts 176  reported in the literature thus far. This yttrium tris(amidate) precatalyst is also one of only a few rare earth complexes capable of tolerating cyclohexylcarboxaldehyde and is the first example of a rare earth complex catalyzing the transformation with pivalaldehyde. This thesis reports the use of yttrium mono-, bis-, and tris(amidate) complexes in new and interesting areas of research, looking into new transformations for the Schafer group. While the reactivity of these complexes shows promise in the applications in which they have been investigated, there are also a number of drawbacks. These yttrium amidate complexes are very sensitive to water, molecular oxygen, and heat, therefore, preparation for catalytic experiments is expensive and time consuming. The development of a set of robust complexes with similar activities is therefore ideal. The investigation of yttrium amidate complexes has remained largely unexplored and there is much left to discover. Recommendations for the development of new yttrium amidate complexes and their use in a variety of applications, as well as some new research directions, are suggested below.  5.2  Future Work  5.2.1 Stereocontrol in the ROP of rac-Lactide In Chapter 2, yttrium mono-, bis-, and tris(amidate) complexes were found to be highly active initiators for the ROP of rac-lactide. By simply altering the polymerization solvent from non-coordinating DCM to coordinating THF, it was shown that the tacticity of the resultant polylactide, PLA, changed from atactic to displaying a modest heterotactic bias (Figure 5.1). Although the heterotactic bias produced when polymerizations were performed in THF was  177  minimal using the conditions presented in Chapter 2, control over polymer tacticity is an ongoing goal in the field of PLA synthesis.128  Figure 5.1 Interesting PLA tacticities In addition to simply optimizing the reaction conditions, modification of the amide proligand could impart substantial changes during the polymerizations and, therefore, on the resulting PLA. Literature precedent for the use of axially chiral268,269 or tethered ligands96,270 for the synthesis of PLA with heterotactic and isotactic biases indicate that the use of a chiral or tethered backbone on an amidate ligand may impart similar biases. The bis(amide) proligands  178  shown in Figure 5.2 represent three possible frameworks with which axially chiral and/or tethered yttrium bis(amidate) complexes could be synthesized.  Figure 5.2 New amide proligands for the synthesis of yttrium bis(amidate) complexes Proligand 5.1 is a bis(amide) tethered through an alkyl chain. The Williams group at Imperial College has shown that the similar class of ligands, phsphoramidates, result in a heterotactic bias in the PLA synthesized using these ligands coordinated to yttrium. 95,96 Proligands 5.2 and 5.3 both contain an axially chiral biphenyl backbone and differ only in the connectivity to the amide functionality. A number of bis(amide) proligands have been investigated in the Schafer group for the hydroamination of aminoalkenes246,249,271,272 and the hydroaminoalkylation of alkenes254,271,272 and have been shown to result in modest to good control over the stereochemistry of the resulting products. The modular nature of the synthesis of amides allows for reasonably easy modifications of the steric and electronic properties of the proposed proligands.113 Reaction of these bis(amide) proligands with one equivalent of Y(N(SiMe3)2)3 could afford new yttrium bis(amidate) mono(amido) complexes which are proposed to exhibit stereocontrol during the ROP of rac-lactide.  179  5.2.2 Synthesis of Additional PCL/PLA Copolymers The synthesis of PLA through the ring-opening polymerization of rac-lactide, using yttrium amidate complexes as initiators, resulted in the formation of very large cyclic polymers. Avoiding the formation of cyclic PLA could provide a means for synthesizing polymers that are thus far inaccessible using yttrium (amidate) initiators. Optimization of the various polymerization conditions provides a good starting point for the prevention of cyclic polymer formation. Decreasing the polymerization activity of these initiators will likely aid in the formation of linear polymers; therefore optimization should include: temperature, solvent, time, concentration, and [M]/[I] ratio. If the cyclization process can be effectively prevented, a number of new types of copolymers can be synthesized using yttrium (amidate) complexes, rac-lactide, and εcaprolactone. In addition to the synthesis of di-blocks, other block copolymers could be prepared including tri-, tetra-, and other multi-blocks (Figure 5.3). Prevention of the cyclization process will also likely improve the yields of the di-block copolymer syntheses as termination, through cyclization, prior to complete conversion is likely responsible for the less than quantitative yields.  180  Figure 5.3 Proposed synthesis of a triblock copolymer of PCL/PLA The decrease in activity predicted with the optimization of the polymerization conditions listed above could also allow for the formation of random copolymers. The synthesis of random copolymers is more likely to occur if the rates of polymerization of the two monomers in the synthesis of their homopolymers are similar;273,274 it has been shown that yttrium amidate complexes polymerize rac-lactide faster than ε-caprolactone.  5.2.3 Rheology of Other Polyesters In Chapter 3, the rheology of poly(ε-caprolactone) was extensively investigated to provide a connection between synthesis and application. As mentioned above, Chapter 2 discussed the use of yttrium amidate complexes for the ROP of rac-lactide. The ease with which the PLA can be synthesized makes these polymers ideal candidates for rheological analysis. The results of the rheological analyses would provide greater insight into the polymers applicability. As was mentioned in Chapter 3, production of polymers on a large scale is ideal for rheological  181  analysis, therefore, investigations into increasing the scale of the ROP of rac-lactide would also be necessary. In addition to the development of the ROP of rac-lactide in Chapter 2, Chapter 3 discussed the synthesis of copolymers of PCL and PLA. The rheological analysis of block copolymers vs. random copolymers vs. homopolymers vs. blends of the homopolymers of PCL and PLA (Figure 5.4, polymers 5.4 - 5.8) would provide unique insight into the effect of copolymer structure on the polymer mechanical properties.  Figure 5.4 Copolymer and homopolymer candidates for rheological analysis As mentioned in Chapter 3, the blending of the homopolymers of PCL and PLA is nontrivial as the polymers phase separate when in the liquid state or when in solution.193 A potential 182  remedy is to dope the polymer blend with a small quantity of either a block copolymer or random copolymer of PCL/PLA (Figure 5.5). Rheological analyses of these doped samples would provide an understanding of how the doping affects the mechanical properties of a sample, and if phase separation can be prevented.  Figure 5.5 Representation of phase separation with and without polymer doping  5.2.4 Ring-Opening Polymerization of Other Cyclic Monomers Yttrium mono-, bis-, and tris(amidate) complexes have been shown to be capable of rapidly initiating the ROP of ε-caprolactone and rac-lactide, indicating the possibility for use in other polymerizations. The ROP of other cyclic monomers (Figure 5.6, monomers 5.9 - 5.14) provides a means for synthesizing interesting polyesters, and a new method for the synthesis of nylon-6 in the case of ε-caprolactam. Initial experiments could involve screening the yttrium amidate complexes discussed in this thesis under typical polymerization conditions reported in the literature for each cyclic monomer.  183  Figure 5.6 Potential cyclic monomers Once the ring-opening polymerizations of the cyclic monomers in Figure 5.6 are sufficiently developed, the methods could then be adjusted to develop the syntheses of new block and random copolymers.  5.2.5 Yttrium (89Y) NMR Spectroscopy A library of yttrium amidate complexes with varied steric and electronic properties have been synthesized, many of which were discussed in this thesis. Of the 11 new complexes reported in the doctoral thesis of Dr. Louisa Stanlake,143 complete characterization, including Xray crystallography, could only be obtained for 5. In addition, X-ray crystallography could not be obtained for a new yttrium bis (amidate) complex reported in this thesis. An alternative method of characterization not yet utilized for yttrium amidate complexes is  89  Y NMR spectroscopy.275,276 This analysis could provide another means of distinguishing 184  between complexes with very similar 1H and  13  C NMR spectra as mass spectrometry is often  difficult to obtain with such air sensitive materials. The chemical environment about a specific atom in a molecule has been shown to greatly affect the chemical shift resulting from that atom in an NMR spectrum. Therefore, in addition, 89  Y NMR could be used to track the electronic properties of the yttrium metal center upon  coordination of various amide proligands (Figure 5.7, 5.15 – 5.19). This technique could also be used to investigate the effect of one, two, or three coordinated amidates by comparing the  89  Y  NMR chemical shifts of yttrium mono-, bis-, and tris(amidate) complexes (Figure 5.8, 5.20 – 5.22). The knowledge of where the electronics of a given complex fits within a series of yttrium amidate complexes affords new insight into catalyst development. This could provide great assistance in tuning complexes for new reactivity in known catalytic transformations.  Figure 5.7 Amide proligands with varying electronic properties  185  Figure 5.8 Mono-, bis-, and tris(amidate) complexes of yttrium Given the extensive capabilities known for yttrium complexes, the future work suggested above is by no means all-inclusive. However, these recommendations provide a suitable starting point to elaborate on the research presented in this thesis.  186  References (1)  Emsley, J. Nature's Building Blocks: An A-Z Guide to the Elements 2003.  (2)  Naumov, A. V. Russ. J. 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PLA tacticity, where Pm + Pr = 1, was calculated using Bernoullian statistics based on the assignments made by Coates and co-workers.126 Pm and Pr values were calculated based on the probability of tetrads and the following formulas: rmr  Pr =  rmm  Pr 2 - Pr +  =0  Pr 2 - Pr + x = 0 Pr = 1  /2  where x = 2(rmm)  mmr  Pr 2 - Pr +  =0  Pr 2 - Pr + x = 0 Pr = 1  /2  where x = 2(mmr)  mmm  Pr2 - 3Pr + 2 -  =0  Pr2 - 3Pr + 2 - 2x = 0 Pr2 - 3Pr + y = 0 Pr = 3  /2  where x = 2(mmr) and y = (2 - 2x)  mrm  Pr = 2(mrm)  The values of rmr, rmm, mmr, mmm and mrm were determined using the equations above with the integrals obtained from analysis of the 1H{1H} NMR spectra.  205  0  JT-5-145_011001r  Representative {1H}1H NMR spectrum:  5  0  mrm r  JT-5-145_011001r  mmm rmr rmm  5  mmr  5  5.45  5.40  5.35  5.30  5.25 5.20 Chemical Shift (ppm)  5.15  5.10  5.05  5.00  5.45  5.40  5.35  5.30  5.25 5.20 Chemical Shift (ppm)  5.15  5.10  5.05  5.00  5  206  Appendix B. Summary of Amidate Complex Numbering  207  Appendix C. Relevant Rheology Equations  stress: τ = F / A shear: γ = x(t) / y0 shear rate: γ = d(x(t)) / y0 d(t )  viscosity, η*: η* = τ / γ  storage modulus, G’: G' = (τ/γ)cosӨ  loss modulus, G”: G" = (τ/γ)sinӨ  208  

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