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Trifluoromethylated zirconium amidate complexes : new directions for the catalytic hydroamination of… Courtney, Sarah Turner 2009

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TRIFLUOROMETHYLATED ZIRCONIUM AMIDATE COMPLEXES: NEW DIRECTIONS FOR THE CATALYTIC HYDROAMINATION OF ALKENES  by COURTNEY SARAH TURNER B. Sc., Mount Allison University, 2006  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  June 2009  © Courtney Sarah Turner 2009  ABSTRACT Hydroamination is the addition of an N–H bond across a C–C multiple bond. Nitrogen containing small molecules, typically accessed through multi-step synthetic pathways, are greatly important to both the pharmaceutical and fine chemical industries. Hydroamination is a rapidly expanding field due to the recent emphasis on sustainable chemistry for industrial applications as it provides an atom economical route to Nheterocycles, imines and amines. Group 4 catalysts have been greatly successful in this area however, intramolecular hydroamination of aminoalkenes typically proceeds only under high temperature reaction conditions. Low temperature reactivity is preferred from a practical perspective and is targeted here as a valuable probe to identify precatalysts most likely to display intermolecular alkene reactivity. The facile synthesis of organic amides provides a desirable means to adjust and optimize the steric and electronic properties of the proligand framework. Trifluoromethyl groups have been identified as desirable electron-withdrawing ligand substituents for the generation of reactive electrophilic zirconium hydroamination precatalysts. Proligand synthetic investigations revealed unforeseen challenges due to the electronic and steric effects imparted by trifluoromethyl substituents and unfortunately, the attractive 2,4,6tris(trifluoromethyl) aryl-amides are of limited practical usefulness.  In complex  synthesis, the structure, bonding and reactivity screening of these novel electrophilic zirconium complexes will be presented as well as challenges associated with increased solubility. Importantly, these fluorinated systems have been shown to enhance reactivity of zirconium bis(amidate)bis(amido) complexes in the intramolecular hydroamination of alkenes. Progress toward low temperature (65 °C) reactivity will be discussed.  ii  TABLE OF CONTENTS Abstract ................................................................................................................................ii Table of Contents ................................................................................................................iii List of Tables .......................................................................................................................v List of Figures .....................................................................................................................vi List of Schemes .................................................................................................................viii List of Abbreviations ..........................................................................................................ix Foreword............................................................................................................................xii Acknowledgements ...........................................................................................................xiii CHAPTER 1: NEW REACTIVITY IN THE HYDROAMINATION OF ALKENES USING GROUP 4 COMPLEXES OF ELECTRONWITHDRAWING AMIDATE LIGANDS..........................................................................1 1.1  Importance of Hydroamination ....................................................................1  1.2  Group 4 Hydroamination Catalysis..............................................................4  1.3  Low Temperature Hydroamination Reactivity ............................................6  1.4  Electronic Ligand Effects.............................................................................7  1.5  Thesis Scope ..............................................................................................11  CHAPTER 2: TRIFLUOROMETHYLATED AMIDE PROLIGAND SYNTHETIC METHODOLOGY .....................................................................................13 2.1  Ligands used in Catalytic Hydroamination................................................13 2.1.1  Amide Proligands ...............................................................15  2.1.2  Electronic and Steric Considerations .................................16  2.2  Proligand Synthesis and Characterization..................................................17  2.3  Synthetic Challenges in the Attempted Formation of Other 2,4,6-Tris(trifluoromethyl)benzamides .......................................25  iii  2.4  Conclusions ................................................................................................27  2.5  Experimental ..............................................................................................27  CHAPTER 3: TRIFLUOROMETHYLATED BIS(AMIDATE)BIS(AMIDO) ZIRCONIUM COMPLEXES: INCREASED ELECTROPHILICITY FOR ENHANCED CATALYTIC ACTIVITY..........................................................................34 3.1  Complexes used for Catalytic Hydroamination .........................................34  3.2  Trifluoromethylated Bis(Amidate)Bis(Amido) Zirconium Complexes ................................................................................35  3.3  Conclusions ................................................................................................47  3.4  Experimental ..............................................................................................47  CHAPTER 4: LOW TEMPERATURE HYDROAMINATION OF ALKENES WITH TRIFLUOROMETHYLATED BIS(AMIDATE) BIS(AMIDO) ZIRCONIUM PRECATALYSTS..............................................................53 4.1  Hydroamination of Alkenes with Group 4 Amidate Complexes .....................................................................53  4.2  Alkene Hydroamination Results: Toward Low Temperature Reactivity .....................................................................55  4.3  Conclusions ................................................................................................61  4.4  Experimental ..............................................................................................61  CHAPTER 5: FUTURE DIRECTIONS AND CONCLUDING REMARKS...................63 5.1  Future Directions........................................................................................63  5.2  Concluding Remarks ..................................................................................66  BIBLIOGRAPHY..............................................................................................................68 APPENDIX A: X-RAY CRYSTALLOGRAPHIC DATA...............................................76  iv  LIST OF TABLES Table 2.1:  Selected bond lengths and angles for proligand 2.5...................................23  Table 2.2:  Selected bond lengths and angles for proligand 2.7...................................24  Table 2.3:  Select bond lengths and angles for non-fluorinated proligand ..................25  Table 3.1:  Select bond lengths and angles for complex 3.2 ........................................40  Table 3.2:  Selected bond lengths and angles for complex 3.3 ....................................42  Table 3.3:  Selected bond lengths and angles for dimer complex (Figure 3.4)............46  Table 4.1:  Aminoalkene hydroamination low temperature reactivity screen using isolated precatalysts ..............................................56  Table 4.2:  Low temperature (65 °C) aminoalkene hydroamination reaction scope, including in situ reactivity for complex 3.6 ......................60  Table A.1:  Crystallographic Data and Refinement Details for Proligand 2.5 .............76  Table A.2:  Crystallographic Data and Refinement Details for Proligand 2.6 .............76  Table A.3:  Cystallographic Data and Refinement Details for Non-fluorinated Proligand (Figure 2.7) ................................................................................76  Table A.4:  Crystallographic Data and Refinement Details for Complex 3.2 (HNMe2 adduct).........................................................................................77  Table A.5:  Crystallographic Data and Refinement Details for Complex 3.3 ..............77  Table A.6:  Crystallographic Data and Refinement Details for Dimer Complex (Figure 3.4) .................................................................................77  v  LIST OF FIGURES Figure 1.1:  Biologically relevant alkaloids containing N-heterocycles .........................2  Figure 1.2:  The first group 4 Cp complex for the hydroamination of alkynes and allenes.......................................................................................4  Figure 1.3:  Non-Cp ligands used for group 4 catalyzed hydroamination ......................6  Figure 1.4:  Josiphos-type ferrocenyl ligand for the palladium-catalyzed asymmetric copolymerization of carbon monoxide and propene ..............10  Figure 2.1:  Brief survey of Cp-type complexes used in the hydroamination of alkenes ...................................................................................................14  Figure 2.2:  Coordination isomers of (N, O) chelating bis(amidate) complexes, L = amido ................................................................................16  Figure 2.3:  Proligands 2.1-2.7 including isolated yields ..............................................17  Figure 2.4:  Solid-state molecular structure of proligand 2.5 (ellipsoid probability at 30%).....................................................................................22  Figure 2.5:  Solid-state molecular structure of proligand 2.7 (ellipsoid probability 30%) ........................................................................................23  Figure 2.6:  Solid-state molecular of non-fluorinated proligand N-(2,6diisopropylphenyl)-2,2-dimethylpropanamide for comparison .................25  Figure 2.7:  Targeted proligands for increasing steric bulk of the nitrogen position of proligand 2.5 framework..........................................................26  Figure 3.1:  Trifluoromethylated bis(amidate)bis(amido) zirconium complexes and their corresponding isolated yields....................................36  Figure 3.2:  Solid-state molecular structure of complex 3.2 with a neutral HNMe2 donor (ellipsoid probability 30%).................................................40  Figure 3.3:  Solid-state molecular structure of complex 3.3 (ellipsoid probability 30%) ........................................................................................42  Figure 3.4:  Solid-state molecular structure of a zirconium mono amidate, amido bridged dimer (proligand 2.6), (ellipsoid probability at 30%) ........45  vi  Figure 5.1:  Proposed proligands, analogues of proligands 2.6 and 2.7, to reduce steric bulk and electron-withdrawing at the carbonyl position of the amide .........................................................63  Figure 5.2:  Proposed CF3 positioning study.................................................................64  Figure 5.3:  Proposed proligand for asymmetric intramolecular hydroamination ..........................................................................................65  Figure 5.4:  Proposed tethered amide proligands ..........................................................65  vii  LIST OF SCHEMES Scheme 1.1:  Intermolecular hydroamination of alkenes and alkynes ..............................3  Scheme 2.1:  Three-step preparation of proligand 2.5.....................................................19  Scheme 4.1:  Proposed mechanism for the intramolecular hydroamination of alkenes with group 4 amidate catalysts. L = ligand; R, R′ = Ph, Me, H...............................................................................................................54  viii  LIST OF ABBREVIATIONS Å  Angstrom  Anal.  Analysis  ArF  Fluorinated aryl group  br  Broad  °C  Degrees Celsius  Calcd.  Calculated  CAr  Aryl carbon  cat.  Catalyst  cm  Centimeter  cm-1  Wavenumber  Cp  Cyclopentadienyl  d  Doublet  DIPHOS  1,2-Bis(diphenylphosphino)ethane  DIPP  2,6-Diisopropylphenyl  DMP  2,6-Dimethylphenyl  E  Molecular moiety shorthand (E = CH or N)  ee  Enantiomeric excess  EI-MS  Electron Impact Mass Spectrometry  eq.  Equation  Et  Ethyl  e.u.  Entropy unit (not SI, e.u. = 4.184 JK-1mol-1)  eV  Electron volt  ix  g  Gram  hr  Hour  Hz  Hertz (s-1)  i  Pr  Isopropyl  J  Joule  K  Kelvin  kJ  Kilojoule  L  Ligand, Liter  Ln  Lanthanide  M  Molar  m  Medium (IR), multiplet (NMR)  m  Meta  max  Maximum  m/z  Mass-to-charge ratio  M+  Molecular ion  Me  Methyl  mg  Milligram  MHz  Megahertz  mL  Milliliter  mol  Mole  mmol  Millimole  n  Number (integer)  NMR  Nuclear magnetic resonance  x  o  Ortho  ov  Overlapping  p  Para  Ph  Phenyl  q  Quartet  R  Organic group  RF  Fluorinated organic group  s  Strong (IR), singlet (NMR)  spt  Septet  t  Triplet  THF  Tetrahydrofuran  w  Weak (IR)  υ  Frequency  δ  Delta, chemical shift (NMR)  Δ  Delta, “change in”, elevated temperature  κ  Kappa, denticity  xi  FOREWARD The work presented herein is a continuation of a project initiated by Robert Thomson of the Schafer research group. This document begins with a literature overview of relevant topics, which provides background material and outlines the relevance of the work to the reader. The introduction also provides a reference point for future members of the Schafer group.  The thesis then continues with the three main chapters, all  beginning with a brief introduction to provide context for the topic, followed by the presentation of results. The final chapter of this thesis contains no experimental data, only proposed future studies and concluding remarks. This is a traditional style thesis and each chapter is meant to flow into the next, making one complete document. Proligand and complex numbering is based on the first chapter in which they appear and is consistent throughout the entire manuscript. Appendix A includes all X-ray crystallographic data and refinement details that were not included in the body of the text for all solid state molecular structures obtained.  xii  ACKNOWLEDGEMENTS Thank you Laurel for your kind patience and support. I am immensely grateful and excited to continue working with you for my next research adventure. I must thank the generous funding sources who supported this research: UBC, NSERC, Boehringer-Ingelheim, Dupont, A. P. Sloan Foundation, BC Knowledge Development Fund, ExxonMobil and the Canadian Foundation for Innovation. Much love and thanks to the Schafer group members (past and present) for your friendship and the generous expense of your time, be it for work or play. Special thanks to Rob for guidance; Ali for models; Louisa for  13  C’s, mtv and lava life; Dave for his  contagious musicality; JM for comic relief; Rashidat for her JM-sass; Pippa for 13C’s and tea time and Neal for X-ray, and being the “student’s champion”. For those of you who exhaustively proof read this thesis, thank you with a big cherry on top. Many thanks to the staff in the chemistry department especially those in the mech shop and electronic shop for helping to keep us up and running. Steve Westcott, thank you. Your support and encouragement will always be most appreciated. Sterics and electronics really are the only two answers in chemistry. Models gals, I look forward to many Wednesday nights to come. Shiv, thanks for morning coffee and exercise motivation. Steph and Yas, thanks for the brain vacations down south of the border. Mike, I love you. Thank you. Mom and Dad and baby brother, thank you for your continuing love and support. Love, light and the magic basement have shaped me into the ridiculous hippie lumberjack chemist that I am. This thesis is for you.  xiii  CHAPTER 1: NEW REACTIVITY IN THE HYDROAMINATION OF ALKENES USING GROUP 4 COMPLEXES OF ELECTRON-WITHDRAWING AMIDATE LIGANDS 1.1 - Importance of Hydroamination Hydroamination is defined as the addition of a nitrogen-hydrogen bond across a carbon-carbon multiple bond, forming new carbon-nitrogen and carbon-hydrogen bonds (eq. 1.1-2).  Amines are vastly important to numerous industries, most notably the  pharmaceutical and agrochemical sectors. Hydroamination is a desirable synthetic tool for the formation of carbon-nitrogen bonds as it is atom-economical. Importantly, it is in contrast to other methods for amine synthesis, which are inefficient multi-step pathways.1 A great deal of work has been done in the field of alkyne hydroamination. These reactions provide an indirect route to amines, by reduction of the imine products. Both intramolecular (eq. 1.1) and intermolecular alkyne reactivity have been accessed and optimized. 2 R' R  R'  R  H 2N  catalyst  n  R  n  (1.1)  N  R  R' R  R  H 2N  R'  catalyst  n  n  R  NH  (1.2)  R  The intramolecular hydroamination reaction of alkenes (eq. 1.2) provides a direct route to cyclic amine products.  Compounds containing one or more nitrogen  heterocycles are prevalent in pharmaceuticals and other bioactive molecules; a few recognizable examples are listed below (Figure 1.1).  1  O O  N nicotine  O  N  N  N  O  N  O  N  N O cocaine  caffeine  HO  O N OH H  N  N  N  O  O  O H  O  HO quinine  morphine  piperine  Figure 1.1: Biologically relevant alkaloids containing N-heterocycles. Intramolecular hydroamination would be an attractive approach in the production of these compounds, as the hydroamination of alkenes allows for regio- and stereoselectivity. Trost and coworkers have successfully used a photochemically-induced hydroamination cyclization as a key last step in the enantioselective synthesis of (-)-codeine and (-)-morphine, demonstrating the potential utility of this reaction. 3 Intermolecular hydroamination can be achieved with alkynes and primary amines to produce enamines, which tautomerize to the more stable imine form (Scheme 1.1). These are important building blocks in organic synthesis as they can be reduced to substituted amines or used as masked carbonyl substituents. This reaction affords either the Markovnikov (branched) or anti-Markovnikov (linear) products, depending on the catalyst used and the steric bulk of the substrates. Group 4 amidate complexes have been shown to selectively produce the anti-Markovnikov product. 4  2  R  H +  NR' cat.  R  NR' +  H  R  red.  NHR' R  H2N R'  H  +  NHR' R  R cat.  + H2N R'  O R  H  Scheme 1.1: Intermolecular hydroamination of alkenes and alkynes. The most difficult transformation, the intermolecular hydroamination of alkenes would provide a method for the direct synthesis of amines (Scheme 1.1). Both regioselective and enantioselective control can be addressed in this transformation. Stereoselectivity is a significant challenge for investigators in this field. Asymmetric hydroamination has been achieved with group 3 metal complexes 5 and there are a few examples of asymmetric hydroamination of aminoalkenes catalyzed by group 4 metal complexes.6 An important example being the cationic zirconium complex developed by Scott and coworkers for secondary aminoalkene substrates. 7 Also, the neutral zirconium amidate complex from the Schafer group for primary amine substrates displays some of the most impressive enantioselectivity reported to date (eq. 1.3). 8 Late transition metals have also had limited success in the asymmetric intermolecular hydroamination of activated alkene substrates. 9  NH2  10 mol% (+)-cat.  H N  cat. =  O NMe N Zr NMe2 2 N O  (1.3)  93% ee  3  1.2 - Group 4 Hydroamination Catalysis Metals capable of catalyzing the hydroamination reaction span the periodic table. Rare earth, late transition and group 4 metal complexes are the three major classes of the most efficient hydroamination catalysts.  They all have distinct advantages and  disadvantages associated with their use, which will be discussed in greater detail in Chapter 3. Group 4 hydroamination catalysts can be grouped into two main categories: metallocenes and non-cyclopentadienyl (Cp) complexes. Importantly, in 1992, Bergman and coworkers published the first zirconocene catalyst (Figure 1.2) for the hydroamination of alkynes and allenes, 10 a field that had been previously dominated by group 3 chemistry at the time. This was a huge advance, as group 4 complexes are typically less air and moisture sensitive than group 3 complexes. This discovery opened up an entirely new field of group 4 catalysis. A brief review of Cp ligand containing complexes and their contributions to hydroamination is included in Chapter 2. This field has since evolved beyond Cp complexes to a wide variety of ligands that will are discussed here.  NH Zr  NH  Figure 1.2: The first group 4 Cp complex for the hydroamination of alkynes and allenes. Interestingly, it was found by the Odom and Schafer groups that Ti(NMe2)4, often used as a starting material for precatalyst synthesis, successfully catalyzes the  4  intermolecular hydroamination of alkynes 11 and the intramolecular hydroamination of alkenes. 12 TiCl4, another common Ti(IV) starting material, was found by Ackermann and coworkers to be an effective catalyst for the intermolecular hydroamination of norbornene. 13 Unfortunately, these precatalysts all suffer from a lack of substrate scope, therefore proligands with easily varied electronic and steric properties can be used to enhance the scope of reactivity and establish general applicability. Non-Cp ligand frameworks for group 4 metal catalyzed hydroamination typically include (N, N) and (N, O) chelating ligands (Figure 1.3). Examples of (N, N) chelating ligands include amidinates,14 guanidinates, 15 and aminotroponiminates,16 bisanilidos, 17 and dipyrrolyl ligands. 18 (N, O/S) chelating ligands include thiophosphinic amidates (N, S),19 sulfonamidos, 20 phenoxyketimines, 21 Schrock (N, O, N) ligands 22 and others. 23 Interestingly, prior to the work in the Schafer group, amidate ligands had been overlooked. This monoanionic, (N, O) chelating ligand motif is central to the work presented in this thesis.  5  R N  R N  N R  N R  N R  amidinates Arnold  guanidinates Richeson  R N R'2N  R'  P  Ar N N Ar  R  N  N  R  N  N P  bisanilidos (NACNAC) Gade  dipyrrolyl ligands Odom  R R  N  O  O  sulfonamidos Bergman  S  R N O  R'  S  R R thiophosphinic amidates Livinghouse  Ar N  S R'  aminotroponiminates Roesky R R  R''  phenoxyketimines Coates  O N R N, O, N Schrock  Figure 1.3: Non-Cp ligands used for group 4 catalyzed hydroamination.  1.3 - Low Temperature Hydroamination Reactivity The hydroamination  reaction  has  inherent kinetic and  thermodynamic  impediments. An illustrative example is the addition of ammonia to ethylene. This reaction is feasible although there are significant obstacles to overcome. The repulsion between the lone pair electrons on nitrogen and the electron density of the double bond creates a large activation barrier making this reaction kinetically unfavorable.  This  activation barrier can be lowered by the use of a catalyst or a highly activated alkene. The reaction is slightly exothermic, with a calculated reaction enthalpy of approximately -97 kJ mol-1, and a calculated Gibbs free energy of -14.7 kJ mol-1. 24 This reaction 6  possesses a negative reaction entropy, meaning that increasing the reaction temperature reduces the spontaneity of the reaction and may shift the equilibrium to favor the starting materials. Hartwig and coworkers performed extensive thermodynamic studies in 2005 to elucidate benchmark thermodynamic values for vinyl arene hydroamination. 25 They confirmed experimentally that the intermolecular hydroamination reactions studied are slightly exothermic, however, they are very nearly thermoneutral. For example, enthalpy and entropy for the reaction between styrene and N-methyl aniline were determined with a Van’t Hoff plot to be -41.9 +/- 3.3 kJ/mol and  -27 +/- 4 e.u. respectively. Thus,  lowering the temperature at which hydroamination occurs will alleviate the inherent thermodynamic dilemma imposed by the negative entropy of the reaction, thus increasing spontaneity and making intermolecular reactivity more accessible. Investigations have shown that modification of the steric and electronic properties of amidate ligands can result in increased reactivity and permit the lowering of reaction temperatures.29  1.4 - Electronic Ligand Effects Ligands exert a dramatic effect on the reactivity of a catalyst centre. They tune reactivity by modulating the steric and electronic environment about the reactive metal center. It is well documented for many different catalyst systems that increasing electron deficiency at the metal center enhances catalytic reactivity. 26 Specifically, for the intramolecular hydroamination of alkynes, allenes and alkenes as well as for intermolecular reaction with alkynes, the reactivity of the catalyst was significantly enhanced with increased electrophilicity of the metal centre. Bergman and coworkers explored this phenomenon using electron-withdrawing sulfonamido  7  ligands for titanium and zirconium. Using this ligand framework, they saw an increase in catalytic activity for the intramolecular hydroamination of alkynes, when compared to results obtained using cyclopentadienyl or disubstituted-amido ligands. 27 An interesting study was undertaken in the Schafer group, which involved tuning the  electronics  of  titanium  and  bis(pyrimidinoxide) ligand (eq. 1.4).  zirconium  complexes  using  a  substituted  The pyrimidonol proligands were designed to  increase the electrophilicity of the metal center in contrast to phenol proligands. Reactivity was greatly enhanced when compared to the unsubstitued bis-(phenoxide) variants, however reduced regioselectivity was observed, presumably due to this enhanced reactivity. 28  N OH N  0.5 Ti(NMe2)4  N  C7H8, rt -2 HNMe2  N  O  Ti(NMe2)2  (1.4)  2  The Schafer group has also studied the electronic effects of amidate ligands on group 4 metals for the hydroamination of alkynes and alkenes. Initial work determined that an electron-withdrawing perfluorophenyl substituent at the carbonyl position of the amidate ligand on a titanium metal center is highly advantageous for intramolecular alkyne hydroamination (eq. 1.5). 29 F Et2N Et2N  Ti  F  Ph  (1.5)  O F  NH2  F  N  F  10 mol% cat., 25 °C, C6D6  2  Ph  N  < 15 min.  8  The perfluorinated proligand shown above (eq. 1.5), N-tert-butyl-2,3,4,5,6pentafluorobenzamide, significantly enhances intramolecular alkyne hydroamination reactivity.  However, once again regioselectivity is substantially decreased for  intermolecular examples. These results led to an optimization study of perfluorophenylsubstituted amide proligands. Increasing the steric bulk at the nitrogen position was found to increase both the regioselectivity and the rate of intermolecular alkyne hydroamination reactions, the optimal proligand having a 2,6-diisopropylphenyl nitrogen substituent. However, attempts to extend the observed reactivity to the intramolecular hydroamination of alkenes were surprisingly unsuccessful. Extensive problem solving by Jason Bexrud of the Schafer group determined that the perfluorinated ligand reacts with the substrate via nucleophilic aromatic substitution at the elevated temperature (110 °C) required to affect intramolecular alkene hydroamination (eq. 1.6). 30 This unexpected reactivity is cited as the probable route for catalyst degradation, thus explaining the reactivity difference between alkyne and alkene hydroamination efforts. Therefore, an electron-withdrawing substituent that would not be susceptible to this type of nucleophilic attack is required. Ph F Ph  Ph NH2 +  Ph  O  F  N H  F  F F  O NH  NH  110 °C, PhCH3 F  (1.6)  F F  F  The trifluoromethyl (CF3) group is a very well established electron-withdrawing substituent.  Interestingly, comparison of the van der Waals volumes of CH3  (13.7 cm3mol-1) versus CF3 (21.3 cm3mol-1) suggests that a CF3 group is the approximate size of an isopropyl substituent, thus imparting steric bulk as well as favorable electronic 9  properties. 31 In 1986, Winter and coworkers published a study on the electronwithdrawing ability of the first CF3-substituted Cp ligand with a variety of different metal centers.  Their findings showed that the single CF3 substituent vastly changed the  electronics of the metal center of interest. 32 Their hypothesis that this would have a great effect on the reactivity of these systems has since been verified as will be shown in the following examples. Togni  and  coworkers  have  demonstrated  a  very  powerful  use  of  trifluoromethylated ligands in catalysis. Their study investigated the electronic ligand effects of modified Josiphos-type ferrocenyl ligands on the palladium-catalyzed asymmetric copolymerization of carbon monoxide and propene. They determined that the highest productivity (measured in grams of polymer per gram Pd per hour) was obtained with a 3,5-bis(trifluoromethyl)phenylphosphane derivative (Figure 1.4). 33,34  CF3  Cy2P  Fe  P  CF3 CF3  F 3C (R, S)  Figure 1.4: Josiphos-type ferrocenyl ligand for the palladium-catalyzed asymmetric copolymerization of carbon monoxide and propene. In 1999, Casey and coworkers published another interesting example showing how significantly CF3 substituents can affect catalytic reactivity. In their study, they found that unsymmetrical DIPHOS ligands with CF3 substituents in the appropriate position increased the regioselectivity of the rhodium catalyzed hydroformylation of  10  1-hexene. This example clearly demonstrated that the position of the CF3 substituents is key to the increased reactivity. They proposed an equilibrium between the equatorial and apical electron-withdrawing unsymmetrical DIPHOS substitution on rhodium, occurring in a 94:6 ratio favoring equatorial CF3 substitution (eq. 1.7). The electron-withdrawing substitution on the equatorial phosphine increased their observed regioselectivity while substitution on the apical phosphine of their catalyst framework had the opposite effect. 35 F 3C  CF3  F 3C  H  H CO P Rh CO P  CO P Rh CO P  (1.7) CF3  F 3C F3C  CF3 CF3  These are only two select examples of the significant impact CF3 groups can have on catalytic reactivity.  Thus CF3 substituted amidate ligands were chosen as an  appropriate target in our study investigating electron-withdrawing amidate ligands and their impact upon group 4 catalyzed low temperature alkene hydroamination reactivity.  1.5 - Thesis Scope The scope of this thesis is presented in the four chapters that follow. Chapter 2 reviews commonly used group 4 ligands for hydroamination of alkenes and concludes with the preferred use of organic amide proligands. Synthesis and characterization of trifluoromethyl containing amides as well as specific synthetic challenges are addressed. Varied electronic and steric properties of these proligands are explored. Bis(amidate)bis(amido) zirconium complexes that are supported by the proligands introduced in Chapter 2 are discussed in Chapter 3.  As well, a brief review of  11  hydroamination precatalysts is presented, followed by synthetic methodology and characterization methods.  Difficulties associated with the complexes containing  trifluoromethyl substituents are also discussed. The use of trifluoromethylated bis(amidate)bis(amido) zirconium complexes as precatalysts for the intramolecular hydroamination of alkenes is discussed in Chapter 4; low temperature reactivity being the focus of this work. Steric and electronic properties are compared and contrasted, leading to conclusions about these features and the observed reactivity of these catalytic systems. Finally, future directions for this work are projected in Chapter 5. Important results are summarized and the conclusions of this investigation are presented.  12  CHAPTER 2: TRIFLUOROMETHYLATED AMIDE PROLIGAND SYNTHETIC METHODOLOGY 2.1 - Ligands used in Catalytic Hydroamination Cyclopentadienyl (Cp) substituted metal complexes are well established in the literature as important catalyst systems for a variety of transformations. In particular, early reports of rare earth and group 4 hydroamination catalysts were based on this ligand set, such as Bergman’s bis(Cp)bis(anilido) zirconium complex, (Cp2 Zr(NH-2,6(CH3)2C6H3)2) discussed in Chapter 1.  This complex successfully catalyzes the  intermolecular hydroamination of alkynes; however it is unable to effect this transformation for alkenes.10 Since then, Cp-type complexes have achieved much success catalyzing alkene hydroamination. Working with group 3 metal catalysts, Marks and coworkers developed chiral organolanthanide Cp complexes (Figure 2.1a), in 1992 that catalyze the intramolecular hydroamination of aminoalkenes both regio- and stereoselectively. 36 Unfortunately, these complexes were found to racemize in the presence of primary amines through reversible loss of a protonated Cp ligand, and therefore displayed limited selectivity. 37 To address this issue, Hultzsch employed a series of more sterically constrained (+)-neomenthyl and (-)-phenylmenthyl indenyl yttrium complexes (Figure 2.1b). These effectively catalyze the hydroamination of primary aminoalkenes but fail to improve enantioselectivities compared to the Marks variant. 38 Moving away from rare earth metals, Doye and coworkers, extending the work of Bergman, have established a series of Group 4 indenyl complexes (Figure 2.1c) that catalyze the intramolecular  13  hydroamination of amino olefins. However, high reaction temperatures and long reaction times (105 °C, 24 - 96 hr) are required. 39 *R (a)  (c)  (b) Si  Y  LnE(SiMe3)2 R*  R* = (+)-neomenthyl E = CH; Ln = La, Nd, Sm, Y, Lu E = N; Ln = La, Sm, Y, Lu  N(Si(Me3)2  M  CH3 CH3  *R R* = (+)-neomenthyl  M = Ti, Zr, Hf  R* = (-)-menthyl E = CH, N; Ln = Sm, Y, Lu R* = (-)-phenylmenthyl E = CH, N; Ln = Y  Figure 2.1: Brief survey of Cp-type complexes used in the hydroamination of alkenes.36,38,39 While the chemistry of Cp complexes is well established, it is difficult to controllably alter catalytic reactivity of these systems using conventional steric and electronic handles, as the variation of the substituents on a Cp ring becomes synthetically challenging beyond a few common examples. 40 In the effort to find a general catalyst system that effects the hydroamination reaction with a more variable ligand set, many modular ligand classes have been studied. As detailed in Chapter 1 (Figure 1.3), these include chelating (N, N/O/S) ligands. However, the easily accessed amidate ligands have been largely overlooked in the literature until recently and are currently being systematically explored by the Schafer group.  14  2.1.1 - Amide Proligands Amide proligands are attractive as they can be easily prepared from a wide range of commercially available acid chloride and primary amine starting materials (eq. 2.1) allowing for a straightforward means of modifying the steric and electronic properties of these proligands. This modularity is extremely useful when trying to optimize a catalyst system for a given reaction. Once deprotonated, the amides form monoanionic chelating amidate ligands where the negative charge is distributed over the nitrogen, carbon and oxygen atoms. These ligands bind well to electropositive metal centers. The hard nitrogen and oxygen donors are a particularly good match for the high valent titanium and zirconium metal centers commonly used in the Schafer group.  R  O  NEt3, CH2Cl2, -78 °C  O Cl  +  H2N R'  R  N H  R'  +  HNEt3Cl  (2.1)  The three main binding modes of amidate ligands when complexed to metal centers include monodentate (with binding through either the nitrogen or the oxygen), bridging, and chelating.1 Thus, attempts to prepare metal complexes using these ligands can potentially result in a mixture of complexes, which likely contributes to why this ligand class has been avoided to date. In the context of catalytic hydroamination, the Schafer group has found the most relevant complexes are the chelating bis(amidate) systems. There are five stereoisomers possible for this chelating (N, O) coordination mode (Figure 2.2).  15  O N N  N L  M O  L  O O  O L  M N  L  N O  L M N  L  N  L  N  N  O  O  M O  L M  L  O N  L  Figure 2.2: Coordination isomers of (N, O) chelating bis(amidate) complexes, L = amido. 2.1.2 - Electronic and Steric Considerations High variability of both electronic and steric properties of a proligand is a desirable feature in the design of any catalytic system, and is the focus of the studies presented in this thesis. To successfully develop a suitable catalyst for the intermolecular hydroamination of alkenes, effective ligand design becomes essential. For the intermolecular hydroamination of alkynes with primary amines, both steric and electronic factors have been investigated for our systems.8,32 A bulky substituent on the nitrogen of the amide proligand was found to give high yields and selectivities while restricting catalyst deactivation pathways, which include metal complex oligomerization.  As discussed in Chapter 1, an electron-withdrawing  perfluorophenyl carbonyl substituent of the amidate increases reactivity of the system, and decreases regioselectivity. 41 Further investigations revealed other problems associated with this group, as it is susceptible to nucleophilic aromatic substitution by primary amine substrates (Chapter 1, eq. 1.6).30 Due to this undesirable side reactivity, a search for a more inert electron-withdrawing substituent was undertaken. The focus of this work then became the use of the sp3-hybridized trifluoromethyl group (CF3), which is not susceptible to nucleophilic attack.  16  2.2 - Proligand Synthesis and Characterization Design of the proligands included in this work involve varying both the number (n = 1, 2, 3) and placement of trifluoromethyl substituents on an aromatic ring (ortho, meta, para) or a tert-butyl moiety on the amide carbonyl, as well as changing the size of the sterically relevant nitrogen substituents (diisopropylphenyl (DIPP), dimethylphenyl (DMP), isopropyl (iPr)). The goal is to determine the most advantageous combination of steric and electronic properties of the proligand to generate the most catalytically reactive system for the hydroamination of alkenes (Figure 2.3). The following trifluoromethylcontaining proligands have been successfully prepared and fully characterized. O  O N H  R F 3C  CF3  N H  R  (F3C)n 2.1 R = DIPP, n = 2 (meta), 83% 2.2 R = DMP, n = 2 (meta), 85% 2.3 R = DIPP, n = 1 (para), 87% 2.4 R = DMP, n = 1 (para), 92% 2.5 R = iPr, n = 3 (ortho/para), 60%  2.6 R = DIPP, 53% 2.7 R = DMP, 63%  Figure 2.3: Proligands 2.1-2.7 including isolated yields.  Proligands 2.1-2.4 are easily synthesized from high yielding reactions using commercially available starting materials with no specialized handling conditions. Proligand 2.2 is prepared using the reaction conditions analogous to those previously reported for the synthesis of 2.1 and 2.3.42 It is important to note that prior to this work, proligands 2.1 and 2.3 had never been exploited in group 4 hydroamination catalyst development. The structure of proligand 2.2 was confirmed by multinuclear NMR spectroscopy. The expected molecular mass was confirmed by mass spectrometry and the  17  calculated quantities of carbon, hydrogen and nitrogen were confirmed by elemental analysis. The 1H NMR spectrum of proligand 2.2 shows two singlets at δ 8.05 and 8.33 (integral ratio of 1:2) that correspond to the para and ortho hydrogens of the CF3substituted aromatic ring. The 13C NMR spectrum contains a diagnostic signal at δ 163, confirming the presence of the carbonyl functional group. The carbon-fluorine for one bond coupled quartet (1JC-F = 275 Hz) appears at δ 122 and the second carbon-fluorine two bond quartet is located at δ 131 (2JC-F = 33 Hz). The expected singlet the chemically equivalent CF3 aryl-substituents appears at δ -63.3 in the 19F NMR spectrum of proligand 2.2. EI-MS gives the expected molecular ion peak at 361 m/z. Elemental analysis is in agreement with the calculated mass for carbon, nitrogen and hydrogen. Proligand 2.4 is prepared using the same synthetic method as 2.2. 1H NMR spectroscopy shows two overlapping signals corresponding to the aryl hydrogens on the CF3 substituted ring at δ 7.91, again the most downfield peak in the spectrum. The broad amide singlet is observed at δ 7.81. In the 13C NMR spectrum the corresponding signals as discussed for 2.2 are visible, with the carbonyl signal at δ 165 and the carbon-fluorine one bond coupled quartet (1J = 275 Hz) at δ 124. The second carbon-fluorine two bond coupled quartet appears at δ 134 (2J = 33 Hz). The  19  F NMR spectrum shows a lone  singlet at δ -63.4, which is similar to the meta CF3 derivative, proligand 2.2. Elemental analysis again confirms the expected carbon, nitrogen and hydrogen content. Proligand 2.5 proved to be the most difficult to access, requiring a modified synthetic route. This amide was prepared in three steps (Scheme 2.1).  18  O Cl  ArF H  1. n-BuLi, Et2O, -5 °C 2. CO2 3. HCl, H2O  ArF COOH  Cl H2N  O cat. DMF DCM, 0 °C ArF COCl  NEt3 DCM, -78 °C  O ArF  N H  F3C ArF =  CF3 F3C  Scheme 2.1: Three-step preparation of proligand 2.5.  2,4,6-Tris(trifluoromethyl)benzoic  acid  was  prepared  from  2,4,6-  tris(trifluoromethyl)benzene as per the literature procedure, starting with the lithiation of the substituted benzene starting material with n-BuLi.  Subsequent reaction of the  mixture with dry CO2, then quenching with HCl and water gives the crude product.19 Benzoic acid, once purified by washing with hexanes is then reacted with oxalyl chloride and DMF to give 2,4,6-tris(trifluoromethyl)benzoyl chloride. This compound is very susceptible to hydrolysis. In order to avoid decomposition, a dry nitrogen atmosphere and rigorously dried reagents, solvents, and glassware are necessary. The preparation of 2,4,6-tris(trifluoromethyl)benzoyl chloride has  been  previously  reported, using  phosphorus(V)chloride (PCl5).43 Initial reactions to secure the acid chloride employed PCl5, however this reaction is found to be problematic for small scale reactions (300 mg versus 50 g scale in reference 19). Complete removal of PCl5 from the reaction mixture is difficult and any excess reagent reacts with the amine in the next step of the synthesis. Oxalyl chloride is a better choice for this transformation as it allows for easy removal of the excess oxalyl chloride in vacuo upon reaction completion and gives a much higher yield for the reaction (60 % over two steps) compared with PCl5 (30% over two steps). 19  Therefore, it has been employed in subsequent attempts to access more sterically bulky derivatives  and  is  the preferred  method  for  the formation  of  the 2,4,6-  tris(trifluoromethyl)benzoyl chloride. Isopropylamine  was  then  successfully  reacted  with  crude  2,4,6-  tris(trifluoromethyl)benzoyl chloride to obtain the desired product, proligand 2.5. The yield of this reaction is moderate, giving 60% isolated yield over the two steps. The signal for the aryl hydrogens appear at δ 8.15 in the 1H NMR spectrum. The amide hydrogen signal is also visible as a broad singlet at δ 5.65. The  13  C NMR spectrum,  shows the expected carbonyl signal at δ 162. The carbon-fluorine one bond coupled quartet (1JC- F = 275 Hz) appears at δ 122 and the second carbon-fluorine two bond quartet is located at δ 131 (2JC-F = 33 Hz). There are two signals in the 19F NMR spectrum at δ -59.6 and -63.7 that integrate in a 1:2 ratio. The larger signal is slightly shifted from the corresponding benzoic acid starting material, making this shift diagnostic for the formation of the amide. The EI-MS shows the expected molecular ion peak at 367 m/z and interestingly, the major mass fragmentation is at 309 m/z. This mass corresponds to the breaking of the C—N amide bond, suggesting that this bond may be especially weak. Elemental analysis confirms the calculated carbon, nitrogen and hydrogen content. The syntheses of proligands 2.6-2.7 were more challenging because of the volatility of both the 2,2-bis(trifluoromethyl)propanoic acid starting material and the corresponding acid chloride.  The acid chloride was prepared by stirring 2,2-  bis(trifluoromethyl)propanoic acid with two equivalents of oxalyl chloride and a catalytic amount of DMF in dry CH2Cl2, and then reacted immediately with the amine in the presence of base without removal of the excess oxalyl chloride. This one-pot method  20  permits ready access to the desired amide that can be easily isolated and purified to give 53% and 62% isolated yields for proligand 2.6 and 2.7 respectively.  Only two  equivalents of oxalyl chloride are required for a reasonable yield in this reaction. Proligand 2.6 is easily recognized from the 1H and 19F NMR spectra. The signal for the methyl of the bis-CF3 substituted tert-butyl moiety appears in the 1H NMR spectrum at δ 1.74. The signals at δ 1.19 and 2.96 correspond to the isopropyl methyl and methyne hydrogens respectively. The amide proton signal appears at δ 7.35. The 13  C NMR spectrum shows the carbonyl carbon signal at δ 159, which is slightly upfield  compared to proligands 2.1-2.5.  The carbon-fluorine one bond coupled quartet  (1JC-F = 259 Hz) appears at δ 123. The second carbon-fluorine two bond quartet is not clearly visible in the spectrum, as the carbon is quaternary and therefore difficult to elucidate from the baseline. There is one signal in the 19F NMR spectrum at δ -68.7. The EI-MS shows a molecular ion of 369 m/z, the molecular mass of proligand 2.6. Elemental analysis agrees with the calculated carbon, nitrogen and hydrogen content. Proligand 2.7 has a broad amide signal in the 1H NMR spectrum at δ 7.30. The DMP methyl signals appear at δ 2.19 and, s imilar to proligand 2.6, the signal at δ 1.76 corresponds to the methyl on the CF3 substituted tert-butyl. The  13  C NMR spectrum  again shows a clear carbonyl signal at δ 158, which is slightly upfield from the other proligands discussed above. The carbon-fluorine one bond coupled quartet (1JC-F = 282 Hz) appears at δ 123 and the second carbon-fluorine two bond quartet is located at δ 57 (2JC-F = 27 Hz). As expected, there is only one signal present in the 19F NMR spectrum at δ -68.8. EI-MS gives the expected molecular ion at 313 m/z. Elemental analysis agrees with the calculated carbon, nitrogen and hydrogen content.  21  We are interested in comparing the bonding in the attainable proligand 2.5 with other known amide proligands, both fluorinated and non-fluorinated, to investigate the effect of trifluoromethyl substituents upon proligand structure and bonding.  X-ray  crystallography is used to obtain the solid-state molecular structure of proligand 2.5 (Figure 2.4); relevant bond lengths and angles are presented for discussion (Table 2.1). The N1-C11 bond is short at 1.323(7) Å, and consistent with significant N—C double bond character due to resonance via through the amide bond. The C1-C11 bond length of 1.512(7) Å is typical for the carbon-carbonyl carbon bond in an amide. The bond angles around the amide carbonyl are interesting, in that the N1-C11-C1 angle of 114.3(4)° is compressed compared with the O1-C11-N1 angle of 124.7(5)° and the O1-C11-C1 angle of 121.0(5)°. The wider O-C-N angle shows the slight tilt of the amide hydrogen back toward the fluorine substituents. It is possible that this is illustrating a mild hydrogen bonding interaction between this hydrogen and the ortho-CF3 fluorines. The sum of these angles is 360.0°, as expected.  Figure 2.4: Solid-state molecular structure of proligand 2.5 (ellipsoid probability at 30%). 22  Table 2.1: Selected bond lengths and angles for proligand 2.5. Angle (°) Distance (Å) C1-C11  1.512(7)  C01-C02-C07  121.4(5)  C2-C7  1.497(8)  C11-N01-C12  122.1(5)  N1-C11  1.323(7)  N01-C11-C01  114.3(4)  N1-C12  1.472(7)  O01-C11-N01  124.7(5)  O1-C11  1.218(6)  O01-C11-C01  121.0(5)  The solid-state molecular structure of proligand 2.7 was also elucidated (Figure 2.5, Table 2.2). The C1-C2 distance of 1.548(3) Å is longer, than the C1-C11 distance for proligand 2.5 of 1.512(7) Å discussed above. Also, as with proligand 2.5, the N1-C1 amide bond distance of 1.327(3) Å is short. The amide bond angles are similar to that for proligand 2.5 as well. Adding to a total of 360° is: the largest bond angle of 123.22(19)° for O1-C1-N1, the O1-C1-C2 bond angle of 119.96(18)° and the N1-C1-C2 bond angle, which is again smaller than the other two at 116.82(16)°. Also similar to the previously discussed proligand, is the slightly larger O1-C1-N1 angle, compared to the O1-C1-C2 angle.  Figure 2.5: Solid-state molecular structure of proligand 2.7 (ellipsoid probability 30%).  23  Table 2.2: Selected bond lengths and angles for proligand 2.7. Angle (°) Distance (Å) C1-C2  1.548(3)  C3-C2-C4  113.8(2)  C2-C3  1.516(3)  N1-C1-C2  116.8(2)  C2-C4  1.525(3)  O1-C1-N1  123.2(2)  N1-C1  1.327(3)  O1-C1-C2  120.0(2)  N1-C6  1.433(3)  O1-C1  1.209(2)  In order to determine the effects of the electron-withdrawing and sterically bulky CF3 groups impose upon the structure and bonding of the amide proligand framework, proligands 2.5 and 2.7 are compared with a non-fluorinated proligand commonly used in the Schafer group.  Previously unpublished, the solid-state molecular structure was  obtained by a former Schafer group member, Zhe Zhang (Figure 2.6). The bond distance between C1-C2 is comparable to that of the fluorinated proligand examples above, at 1.536(2) Å. The amide bond distance between N1-C1 is 1.340(2) Å, which is notably longer than the bond lengths recorded for both fluorinated ligands, which were approximately 1.32 Å. The O1-C1-C2 angle is 121.72(15)° is essentially the same as the O1-C1-N1 angle (121.69(15)). These angles do not display the inequivalency shown by the fluorinated variants. The N1-C1-C2 is smaller than the other two, at 116.58(14) Å, which is comparable to the fluorinated cases discussed previously. Proligands 2.5 and 2.6 have similar solid-state characteristics to the nonfluorinated example given.  Most of the bond lengths and angles are analogous; the  principal difference is the increased amide N—C double bond character bond in the fluorinated proligands.  24  Figure 2.6: Solid-state molecular of non-fluorinated proligand N-(2,6diisopropylphenyl)-2,2-dimethylpropanamide for comparison.  Table 2.3: Select bond lengths and angles for non-fluorinated proligand. Angle (°) Distance (Å) C1-C2  1.536(2)  N1-C1-C2  116.58(14)  N1-C1  1.340(2)  O1-C1-N1  121.69(15)  N1-C6  1.437(2)  O1-C1-C2  121.72(15)  2.3 - Synthetic Challenges In the Attempted Formation of Other 2,4,6-Tris(trifluoromethyl)benzamides  CF3 O  CF3 O  F 3C  N H CF3  F 3C  N H CF3  CF3 O  F 3C  N H CF3  Figure 2.7: Targeted proligands for increasing steric bulk of the nitrogen position of proligand 2.5 framework.  25  As previously mentioned, bulky substituents on the nitrogen of the amide has been shown to increase catalytic reactivity for the Schafer bis(amidate) systems. While the synthesis of proligand 2.5 was successful, attempts to install groups larger than isopropyl on the nitrogen were unsuccessful. 2,6-Diisopropylaniline, 2,6-dimethylaniline, as well as tert-butylamine were each added to the 2,4,6-tris(trifluoromethyl)benzoyl chloride in the same manner as isopropylamine, but none of the desired amide proligands were detected (Figure 2.7).  It is possible that steric crowding due to the ortho-  trifluoromethyl groups of the aromatic ring located on the carbonyl portion of the amide, as well as their electron withdrawing effect, cause the acid chloride and subsequent amide proligand to be especially susceptible to hydrolysis. These effects are likely responsible for the difficulty in achieving this transformation with nitrogen substituents larger than isopropyl. During attempts to install a tert-butyl group on the nitrogen to form N-tert-butyl2,4,6-tris(trifluoromethyl)benzamide, a number of parameters were varied.  To avoid  decomposition of the acid chloride by hydrolysis, reactants, solvents and glassware were rigorously dried before use. Reactions of the acid chloride with tert-butylamine and triethylamine in CH2Cl2 or toluene were heated to various temperatures (65 °C, 90 °C, 115 °C) to no avail. The molar ratio of acid chloride to tert-butylamine was varied; 1:1, 4:1, 10:1 and 20:1 (acid chloride: amine) ratios were attempted, but no amide formation was detected by 1H NMR spectroscopy. The addition order of the reactants was also examined, typically triethylamine and the amine-coupling partner are added to a cooled solution of the crude acid chloride in CH2Cl2. Reverse addition of the acid chloride in CH2Cl2 to a solution of amine and base was attempted, however it did not have an  26  advantageous effect. Consideration was also given to the base used in the reaction. Triethylamine, pyridine and the absence of base were tried, but no desirable reaction was observed. A possible explanation of the difficulty with the preparation this ligand type, is that the electron withdrawing CF3 groups increase the C—N double bond character in the amides. Based upon the consistent observation of 1,3,5-trifluoromethylbenzene in the 1H and 19F NMR spectra, a rearrangement of the desired amides is proposed (eq. 2.3). CF3  CF3 O  F 3C  N H CF3  H F3C  + O C N  (2.3)  CF3  Alternatively, Lopez and coworkers published a computational study in 2005 about the susceptibility of twisted amides to hydrolysis.44 The twisting of the amides studied was imposed by steric bulk and a cyclic structural confinement, which led to a misalignment of the p-orbitals. This disturbs the inherent resonance of the amide bond and causes elongation of the C—N bond, allowing for increased susceptibility to hydrolysis. There is no evidence in the structures discussed herein to support twisting or elongation of the amide C—N bond, but it is reasonable to propose an elongation of this bond in compounds that could not be isolated, perhaps caused by excess steric bulk at the nitrogen.  2.4 - Conclusions A family of amide proligands was prepared with varied steric and electronic properties. The number of the electron-withdrawing CF3 groups at the carbonyl position as well as the steric nature of the nitrogen substituents of the presented amide proligands  27  are reviewed.  In isolable trifluoromethylated proligands, all amides show similar  diagnostic features in the multinuclear NMR spectra, such as the broad amide hydrogen signal in the 1H NMR spectra above δ 7.3 (except for 2.5, NH is at δ 5.7, the carbonyl carbons in the 13C NMR spectra which appear above δ 159 and the fluorine signal(s) in the 19F NMR spectra that appear in the δ -60 to -70 range. Unexpected difficulty was encountered when attempting to install groups larger than isopropyl on the nitrogen of a proposed amide bearing ortho-CF3 substituents potentially due to a sterically induced susceptibility to hydrolysis. Thus, metal complexation and catalysis investigations were restricted to seven proligands (Figure 2.3).  2.5 - Experimental All reactions were carried out under a dry nitrogen atmosphere using standard Schlenk line and glovebox techniques, unless otherwise indicated. NMR spectra were recorded on Bruker 300 MHz, 400 MHz or 600 MHz Avance spectrometers.  Mass  spectrometry was measured using a Kratos MS-50 spectrometer using electron impact ionization (70 eV source). Structural determinations using elemental analysis and single crystal X-ray crystallography were carried out at the University of British Columbia, Department of Chemistry. Chemicals used were purchased from Sigma-Aldrich and used either without further purification or dried before use as indicated. Dichloromethane (CH2Cl2) was dried over calcium hydride and distilled before use. d6-Benzene and  d8-  toluene were degassed and stored over molecular sieves. N-(2,6-diisopropylphenyl)-3,5bis(trifluoromethyl)benzamide,42  N-(2,6-diisopropylphenyl)-4-(trifluoromethyl)benz-  amide,42 2,4,6-tris(trifluoromethyl)benzoic acid43 and 2,4,6-tris(trifluoromethyl)benzoyl  28  chloride43 were prepared as described in the literature, although an alternate preparation of 2,4,6-tris(trifluoromethyl)benzoyl chloride is described herein.  Synthesis of N-(2,6-dimethylphenyl)-3,5-bis(trifluoromethyl)benzamide (2.2) On the bench top in a 100 mL round bottom flask, 2,6-dimethylaniline (0.91 mL, 0.89 g, 7.3 mmol) was  O F3C  N H  dissolved in CH2Cl2 (20 mL) and stirred at room CF3  temperature. Triethylamine (0.51 mL, 0.37 g, 3.7 mmol) was added to this solution via syringe and the colorless solution was stirred for 1 hour before being cooled to -78 °C with a dry ice, isopropanol bath. 3,5-Bis(trifluoromethyl)benzoyl chloride (0.65 mL, 1.0 g, 3.7 mmol) was added drop wise via syringe. The resulting pale yellow solution was allowed to warm to room temperature, and stir overnight. The reaction mixture was then diluted with diethyl ether (20 mL) and washed with 1 M HCl (3 × 30 mL), 1 M NaOH (1 × 30 mL) and saturated brine (1 × 30 mL). The organic fraction was dried over anhydrous MgSO4 and then filtered. The solvent was removed in vacuo, yielding 1.3g (85 % yield) of a crude white solid. Recrystallization from CH2Cl2-hexanes gave 0.90 g (68 % isolated yield) of purified white microcrystalline product. 1H NMR (CDCl3, 25 °C, 600 MHz) δ: 2.22 (s, 6H, Ar-CH3), 7.09 (d, 2H, Ar-H), 7.14 (m, 1H, Ar-H), 7.59 (br s, 1H, N-H), 8.05 (s, 1H, ArF-H), 8.33 (s, 2H, ArF-H).  13  C NMR (CDCl3, 25 °C, 600 MHz)  δ: 18.6, 123.1 (q, Ar-CF3, 1JC-F = 270 Hz), 125.6, 127.7, 128.2, 128.7, 129.3, 132.7 (q, CAr-CF3, 2JC-F = 33 Hz), 133.1, 135.6, 136.7, 163.3. 19F NMR (CDCl3, 25 °C, 300 MHz) δ: -63.3 (s, C-F). EI-MS (m/z): 361 (M+ ). IR (KBr) νmax (cm-1): 1650 (s), 3048 (m), 3238  29  (br, s). Anal. Calcd. for C17H13F6NO: C, 56.52; N, 3.88; H, 3.63. Found: C, 56.22; N, 3.86; H, 3.50.  Synthesis of N-(2,6-dimethylphenyl)-4-(trifluoromethyl)benzamide (2.4) Proligand 2.4 was prepared applying the procedure O  described for 2.2 using 1.8 mL of 4-trifluoromethylbenzoyl chloride (2.5 g, 12 mmol) and 3.0 mL of 2,6-dimethylaniline  N H F3C  (2.9 g, 24 mmol). An isolated yield of 92% was obtained. 1H NMR (CDCl3, 25 °C, 600 MHz) δ: 2.19 (s, 6H, Ar-CH3), 7.07 (m, 2H, Ar-H), 7.13 (m, 1H, Ar-H), 7.63 (d, 2H, ArFH), 7.81 (br s, 1H, NH), 7.91 (d, 2H, ArF-H).  13  C NMR (CDCl3, 25 °C, 600 MHz) δ:  18.6, 123.8 (q, Ar-CF3, 1JC-F = 270 Hz), 125.9, 127.9, 128.5, 133.7 (q, CAr-CF3, 2JC-F = 33 Hz), 133.7, 135.7, 137.7, 165.0.  19  F NMR (CDCl3, 25 °C, 300 MHz) δ: -63.4 (s, CF3).  Anal. Calcd. for C16H14F3NO: C, 65.52; N, 4.78; H, 4.81. Found: C, 65.43; N, 4.80; H, 4.83.  Synthesis of 2,4,6-tris(trifluoromethyl)benzoyl chloride reactive intermediate Under an atmosphere of nitrogen in a 250 mL Schlenk tube, a solution of 2,4,6-tris(trifluoromethyl)benzoic acid (0.40 g, 1.2 mmol) in dry CH2Cl2 (15 mL) was cooled to 0 °C with an ice F3C  CF3 O Cl CF3  water bath. Oxalyl chloride (0.83 mL, 1.2 g, 9.8 mmol) was added to this colorless solution via syringe. A catalytic amount of DMF was injected into the solution, which caused the vigorous evolution of gas. The reaction mixture was allowed to warm to room temperature, and was stirred overnight. Oxalyl chloride and CH2Cl2 were then removed  30  under vacuum, leaving a yellow oily residue. The acid chloride was difficult to isolate and purify, and so was used directly in the synthesis of N-isopropyl-2,4,6tris(trifluoromethyl)benzamide without further purification.  Synthesis of N-isopropyl-2,4,6-tris(trifluoromethyl)benzamide (2.5) To a crude solution of 2,4,6-tris(trifluoromethyl)benzoyl CF3 O  chloride (0.41 g, 1.2 mmol) under a nitrogen atmosphere, dry CH2Cl2 (15 mL) was added and the yellow solution was cooled  F 3C  N H CF3  to -78 °C with a dry ice, isopropanol bath. Approximately 10 equivalents of isopropylamine (1.0 mL, 0.71 g, 12.2 mmol) was added via syringe, resulting in vigorous gas evolution. Triethylamine (0.17 mL, 0.12 g, 1.22 mmol) was then added, and the reaction was allowed to stir while warming to room temperature overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with 1 M HCl (3 × 30 mL), 1 M NaOH (1 × 30 mL) and saturated brine (1 × 30 mL). The organic fraction was dried over anhydrous MgSO4 and then filtered. The solvent was removed in vacuo, yielding 1.25 g (60 % over two steps) of a crude white solid product. Room temperature recrystallization from a CH2Cl2-hexanes mixture, then sublimation at 75 °C gave 30% isolated yield of the colorless, air stable desired product. 1H NMR (CDCl3, 25 °C, 400 MHz) δ: 1.26 (d, 6H, CH3), 4.34 (spt, 1H, CH-(CH3)2) ), 5.65 (br s, 1H, N-H), 8.15 (s, 2H, ArF-H).  13  C NMR  (CDCl3, 25 °C, 600 MHz) δ: 22.2 (CH3), 29.9 (CH-(CH3)2), 42.9, 122.5 (q, CF3, 1JC-F = 275 Hz), 127.3 (CAr), 130.8 (q, 2,6-CAr-CF3, 2JC-F = 33 Hz), 132.5 (q, 4-CAr-CF3, 2  JC-F = 36 Hz), 138.0 (CAr), 161.8 (C=O). 19F NMR (CDCl3, 25 °C, 300 MHz) δ: -63.7  (s, 3F, 4-CF3), -59.6 (s, 6H, 2,6-CF3). EI-MS (m/z): 367 (M+ ). IR (KBr) νmax (cm-1):  31  1650 (s), 3089 (w), 3286 (br s). Anal. Calcd. for C13H10F9NO: C, 42.52; N, 3.81; H, 2.74. Found: C, 42.48; N, 3.74; H, 2.83.  In situ preparation of N-(2,6-diisopropylphenyl)-3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)propanamide (2.6) To a cooled solution (0 °C, ice water bath) of 2,2O  bis(trifluoromethyl)propionic acid (0.50 g, 2.4 mmol) in dry CH2Cl2 (5.0 mL) under an atmosphere of nitrogen, 2 equivalents  F3C  CF3  N H  of oxalyl chloride (0.41 mL, 0.61 g, 4.8 mmol) was added via syringe. The reaction was allowed to warm to room temperature and then was stirred for 6 hours. 2,6Diisopropylaniline (0.90 mL, 0.84 g, 4.8 mmol) was then added to the reaction mixture drop wise via syringe, causing the evolution of HCl gas, followed by triethylamine (0.33 mL, 0.24 g, 2.4 mmol). The pale yellow solution was allowed to react overnight, forming a precipitate that was removed by filtration before the solution was diluted with 30 mL of CH2Cl2 and washed with 1 M HCl (3 × 30 mL), 1 M NaOH (1 × 30 mL) and saturated brine (1 × 30 mL). The organic fraction was dried over anhydrous MgSO4, and then filtered. Solvent was removed in vacuo, and the resulting white powder was purified by sublimation at 90 °C to give a 53% isolated yield. 1H NMR (CDCl3, 25 °C, 600 MHz) δ: 1.19 (d, 12H, CH-(CH3)2), 1.76 (s, 3H, C-CH3), 2.96 (spt, 2H, (CH-(CH3)2), 7.21 (d, 2H, 3,5-ArH), 7.32 (br s, 1H, NH), 7.35 (t, 1H, 4-ArH). 13C NMR (CDCl3, 25 °C, 600 MHz) δ: 12.8, 23.2, 28.1, 123.3 (q, 1JC-F = 284 Hz, CF3), 123.2, 128.7, 129.4, 145.8, 159.0 (C=O)  19  F NMR (CDCl3, 25 °C, 300 MHz) δ: -68.74 (s, CF3). EI-MS (m/z): 369 (M+ ).  32  Anal. Calcd. for C17H21F6NO: C, 55.28; N, 3.79; H, 5.73. Found: C, 55.67; N, 3.82; H, 5.99.  Synthesis  of  N-(2,6-dimethylphenyl)-3,3,3-trifluoro-2-methyl-2-(trifluoromethyl)  propanamide (2.7) Proligand 2.7 was prepared using the same method described for 2.6 with 2,2-bis(trifluoromethyl)propionic acid (0.50 g, 2.4 mmol), 0.41 mL of oxalyl chloride (0.61 g, 4.8 mmol) in the F3C  O  CF3  N H  first step and then 2.9 mL of 2,6-dimethylaniline (2.9 g, 24 mmol) and 0.33 mL triethylamine (0.24 g, 2.4 mmol) in the second step of the in situ reaction. Isolated yield was 62%. 1H NMR (CDCl3, 25 °C, 400 MHz) δ: 1.74 (s, 3H, C-CH3), 2.19 (s, 6H, CArCH3), 7.08-7.15 (m, 3H, ArH), 7.30 (br s, 1H, NH). 13C NMR (CDCl3, 25 °C, 600 MHz) δ: 12.7, 17.5, 56.8 (q, 2JC-F = 27 Hz, C-CF3), 123.2 (q, 1JC-F = 282 Hz, CF3), 127.8, 128.0, 132.0, 135.1, 157.9 (C=O). 19F NMR (CDCl3, 25 °C, 300 MHz) δ: -68.8. EI-MS (m/z): 313 (M+ ). Anal. Calcd. for C13H13F6NO: C, 49.85; N, 4.47; H, 4.18. Found: C, 49.69; N, 4.51; H, 4.56.  33  CHAPTER 3: TRIFLUOROMETHYLATED BIS(AMIDATE)BIS(AMIDO) ZIRCONIUM COMPLEXES: INCREASED ELECTROPHILICITY FOR ENHANCED CATALYTIC ACTIVITY 3.1 - Complexes used for Catalytic Hydroamination An increasing variety of metal complexes are being used for the intramolecular hydroamination of alkenes. Rare earth metals are well suited for this transformation as shown by T. J. Marks, who pioneered this field with lanthocene-based catalysts as discussed in section 2.1.37, 45 Other major contributors to the group 3 catalyzed hydroamination field include Roesky,46 Hessen,47 Hultzch, 48 Trifonov,49 Livinghouse, 50 Scott 51 and Molander. 52 Group 3 metals are known to be extremely air and moisture sensitive and are therefore not typically viewed as ideal catalyst systems. To address these concerns, alternative catalysts are currently being developed. For example, strong acids can be used to catalyze this reaction; 53 however the hydroamination of any aminoalkene substrate bearing an acid sensitive functional group becomes a challenge with this approach. Late transition metals have increased air and moisture stability and improved functional group tolerance, compared to group 3 catalysts.9h-i,m-q However, many of these catalyst systems display limited substrate scope, and require activated alkenes to proceed. 54 There are late transition metal systems that can catalyze the hydroamination of unactivated olefins with secondary amines. 55 However, catalyst systems that are capable of directing reactions of unactivated terminal and internal alkenes with both primary and secondary amines are rare. A rhodium catalyst developed by Hartwig and coworkers56 is one of only two examples, the other being a copper catalyst recently reported by Sawamura and coworkers.57  34  Group 4 metals are celebrated for their low cost, low toxicity, and easily managed handling conditions.  Titanium and zirconium have shown great promise in the  intramolecular catalytic hydroamination of unactivated alkenes.58 Group 4 amidate complexes have displayed excellent functional group tolerance 59 and improved air and moisture stability relative to group 3 catalysts further supporting their application as a usable, efficacious catalyst framework. Notably, a general catalyst system that effects the intermolecular hydroamination reaction with a wide substrate scope remains elusive.  3.2 - Trifluoromethylated Bis(Amidate)Bis(Amido) Zirconium Complexes Thus far, group 4 metal catalyzed intramolecular hydroamination reactions of alkenes require high temperatures (>110 °C) to proceed. From a practical perspective, low temperature reactivity is preferred and as discussed in Chapter 1, is also critical to achieve intermolecular alkene hydroamination reactivity. Ligands can be used to advantage for tuning the electronic nature of a metal centered catalyst.26 Ligands that are derivatized with electron-withdrawing CF 3 substituents pull electron density from the metal center, thereby increasing catalytic reactivity in reactions that are promoted by electrophilic metal centers. As previously noted, increased electrophilicity of the metal centre has been shown to significantly increase the reactivity of hydroamination catalysts as demonstrated by Bergman’s group 4 sulfonamido studies,27 as well as Schafer group studies of electronic effects with amidate29,30 and bis(pyrimidinoxide) ligands.28 Thus, increasing the electrophilicity of the metal center is one way low temperature reactivity may be achieved.  35  Work done by the Schafer group and others has highlighted a disparity in reactivity between the two most commonly used group 4 metals for hydroamination: zirconium and titanium. Titanium, the smaller metal center, is the optimal choice for the hydroamination of alkynes however, zirconium has proven to be more effective for the intramolecular hydroamination of alkenes.58c Thus, zirconium was chosen as the ideal starting point for the pursuit of a low temperature reactive hydroamination catalyst. Bis(amidate)bis(amido) zirconium complexes are easily prepared via a simple protonolysis reaction between commercially available tetrakis(dimethylamido)zirconium and two equivalents of an amide proligand (eq. 3.1 where RF = trifluoromethylated aryl or alkyl groups). The reactants are stirred in hexanes at room temperature under a dry nitrogen atmosphere. Removal of the solvent and the resulting dimethylamine in vacuo gives the desired complex in reasonable yield (ranging from 41% to 81%).  The  following zirconium complexes have been prepared and characterized using a variety of techniques (Figure 3.1). O  2 RF  R  N H  R N  Zr(NMe2)4 hex, rt -2 HNMe2  RF O  R  NMe2  (3.1)  NMe2  2  R  N Zr (CF3)n  Zr  O 2  NMe2 NMe2  3.1 R = DIPP, n = 2 (meta), 72% 3.2 R = DMP, n = 2 (meta), 63% 3.3 R = DIPP, n = 1 (para), 81% 3.4 R = DMP, n = 1 (para), 69% 3.5 R = iPr, n = 3 (ortho/para), 41%  N F3C F3C  Zr O 2  NMe2 NMe2  3.6 R = DIPP, 79% 3.7 R = DMP, 81%  Figure 3.1: Trifluoromethylated bis(amidate) bis(amido) zirconium complexes and their corresponding isolated yields.  36  These trifluoromethylated bis(amidate) complexes display increased solubility in common organic solvents when compared to their non-fluorinated variants. This is an expected phenomenon, as fluorine substituents are known to change solubility properties when incorporated into organic compounds. 60 This enhanced solubility has made purification and recrystallization challenging for the complexes discussed herein. Also, these trifluoromethylated complexes display thermal sensitivity. Complexes stored at -37 °C are stable for months while those kept at room temperature degrade on the same time scale. Non-fluorinated zirconium complexes are significantly more robust as they do not display this type of sensitivity. Many of these trifluoromethylated bis(amidate)bis(amido) zirconium complexes have not been rigorously characterized. At the outset of this project, it was thought prudent to first screen the potential catalytic reactivity and then to rigorously characterize only the catalytically superior complexes. Unfortunately, difficulties in isolation and characterization of these complexes have thus far impeded full characterization of some of the most active precatalysts.  Thus, all crude complexes were characterized by  multinuclear NMR spectroscopy before being used for catalysis. Diagnostic 1H NMR spectral data includes the integral ratio of the dimethylamido signal with the methyl signals for the nitrogen substituent of the amidate (DIPP - 2 iPr Me:1 NMe2, DMP - 1:1, i  Pr 1:1). These integrations indicate that a bis(amidate)bis(amido) zirconium complex  has formed. Also, 19F NMR spectra are obtained before using a complex for catalysis, as 19  F NMR spectra are very indicative of the formation of a single complex. Thus, much  of the information presented herein is preliminary characterization data only, as required  37  for exploratory catalytic studies. Future work on this project will focus on obtaining full characterization data for the most active hydroamination precatalysts. Complex 3.1 is isolated as a yellow solid. In the 1H NMR spectrum, the two isopropyl methyl groups appear as inequivalent doublets (δ 0.871, 1.19), possibly due to hindered rotation about the Caryl-Calkyl bond on the NMR timescale. isopropyl methyne hydrogens appear as a single septet at δ 3.39.  However, the  When considered  together, this data indicates the possible presence of diastereotopic methyl groups. There is a diagnostic dimethylamido signal at δ 3.07, which has equivalent integral ratios with the isopropyl methyl group signals, indicating that the complex is the desired bis(amidate)bis(amido) complex.  The amide proligand hydrogen signal, typically  appearing at δ 7.50 is no longer present. The one and two-bond carbon-fluorine coupled quartets are visible in the 13C NMR spectrum as quartets at δ 124 and 131 with coupling constants of 272 Hz and 33 Hz respectively. The signal attributed to the carbonyl carbon in the 13C NMR spectrum has shifted downfield to δ 173 from δ 160 for the proligand. The  19  F NMR spectrum shows one signal, at δ -63.4, which is not shifted from the  spectrum of the ligand. This is a common feature of the  19  F NMR spectra for all the  complexes presented. This compound is very soluble in pentane, hexanes, toluene and benzene, and crystallization has not been possible. Satisfactory elemental analysis and mass spectrometry could not be obtained due to solubility difficulties and previously mentioned thermal decomposition issues. The crude material is purified by washing with cold hexanes, isolated as a yellow powder and spectroscopically characterized to verify its suitability for catalytic investigations.  38  Complex 3.2 is a pale yellow solid. The 1H NMR spectrum of this complex shows the methyl signals from the dimethylphenyl moiety at δ 2.04. The diagnostic dimethylamido methyl signal appears at δ 3.10.  19  F NMR spectrum contains a single  signal at δ -63.4. The aryl hydrogens are all accounted for in the aryl region of the spectrum.  EI-MS of this complex shows the expected molecular ion at 898 m/z.  Elemental analysis could not be obtained. Interestingly, the 1H NMR spectra of the crude material contains signals corresponding to a neutrally bound dimethylamido ligand at δ 2.34 (1H, HNMe2) and 2.67 (6H, HNMe2). This complex, with the neutral donor was crystallized and the solid-state molecular structure is shown (Figure 3.2). This structure illustrates a useful quality of these ligands: they can change from κ 2 to κ 1. The structure is asymmetric, with a point group of C1. The neutral amine ligand (N3), has a longer bond (2.396(3) Å) to zirconium than the other two amido ligands, N4 and N5 (2.024 Å and 2.126 Å respectively), also the bonds about N3 are pyramidalized, with angles adding up to only 345 °. As with most κ 2 amidate ligands, the nitrogen-zirconium bond distance is longer than the oxygen-zirconium bond: 2.371(2) Å and 2.198(2) Å respectively. The C1-C3 bond distance of 1.488(4) Å, is slightly shorter than the bond distances seen in the proligands (1.5 Å, Chapter 2).  The bite angle of the chelating amidate ligand is  57.51(7)°, also typical for amidate ligands.58c Interestingly, the Zr1-O2-C2 bond angle of the κ 1 bound amidate is almost linear (168.1(3) °).  The neutrally bound HNMe2 is  extremely difficult to remove from this compound. Leaving under vacuum in excess of 6 hours does nothing to remove this neutrally bound ligand. However, when the synthesis of this complex is performed in THF at 60 °C, the HNMe2 can removed. As the boiling point of dimethylamine is very low, it may be displaced from solution into the headspace  39  of the reaction vessel upon heating and then removed in vacuo along with the THF. The material used for the hydroamination catalyst screen was made using the latter method and had no neutrally bound dimethylamine present.  Figure 3.2: Solid-state molecular structure of complex 3.2 with a neutral HNMe2 donor (ellipsoid probability 30%). Table 3.1: Select bond lengths and angles for complex 3.2. Distance (Å) Angle (°) Zr1 - N1 2.371(2) O1 - Zr1 - N1 57.51(7) Zr1 - N3 2.396(3) O1 - Zr1 - N4 118.69(10) Zr1 - N4 2.024(2) O2 - Zr1 - N1 148.28(9) Zr1 - N5 2.126(3) N1 - Zr1 - N4 90.78(9) Zr1 - O1 2.198(2) C2 - O2 - Zr1 168.1(3) Zr1 - O2 2.004(2) C39 - N3 - Zr1 118.2(3) C1 - C3 1.488(4) C40 - N3 - Zr1 116.5(2) N1 - C1 1.303(3) C39 - N3 - C40 110.4(3) N2 - C2 1.266(4) 40  Complex 3.3 can be crystallized from pentane at -37 °C; a solid-state molecular structure has been obtained for this complex (Figure 3.3) and is consistent with the spectral data.  This complex is C2 symmetric and is very similar to non-  trifluoromethylated complexes previously synthesized in the Schafer group.58c The amidate nitrogens are in a trans orientation, thus alleviating the imposed steric strain of the bulky 2,6-diisopropylphenyl substituents.  The amidate ligand bond lengths are  typical, with the Zr1-N1 bond slightly longer at 2.274(2) Å than the Zr1-O2 bond length of 2.260(2) Å. As with complex 3.1, the 1H NMR spectrum of complex 3.3 shows the isopropyl methyl signals in the 2 and 6 positions to be chemically inequivalent, appearing at δ 0.91 and 1.25. The dimethylamido signal at δ 3.14 integrates equally with one isopropyl methyl signal (12:12), thus confirming the solution phase structure of the desired bis(amidate)bis(amido) complex.  The  13  C NMR spectrum shows the  trifluoromethyl group coupling quite clearly as quartets at δ 123 and 132 with 1JC-F = 272 Hz and 2JC-F = 33 Hz respectively. The signal for the carbonyl carbon appears at δ 175. Although single crystals for X-ray crystallography could be acquired from one particular sample, acceptable elemental analysis and mass spectrometry could not be obtained on the bulk material possibly due to thermal decomposition.  41  Figure 3.3: Solid-state molecular structure of complex 3.3 (ellipsoid probability 30%). Table 3.2: Selected bond lengths and angles for complex 3.3. Distance (Å) Angle (°) Zr1 - N3 2.039(2) N1 - Zr1 - O2 53.30(7) Zr1 - N1 2.274(2) N1 - Zr1 - N4 96.77(9) Zr1 - O2 2.260(2) N1 - Zr1 - N2 140.15(7) C1 - C7 1.498(3) N4 - Zr1 - O2 154.56(9) The isolation of complex 3.4 is difficult, as the crude complex exists as a dark green oily residue. Recrystallization of this complex has not been possible. Instead, washing the crude mixture with pentane, filtering the solution through Celite and removing the solvent, purifies this very soluble complex. The 1H NMR spectrum clearly shows the dimethylphenyl methyl signal at δ 2.15 and the dimethylamido signal at δ 3.15,  42  with an equivalent integration ratio (12:12). This supports the formation of the desired bis(amidate)bis(amido) complex. spectrum.  All aryl hydrogen signals are assignable in the  13  C NMR data shows the trifluoromethyl related quartets at δ 122 (1JC-F = 275  Hz) and δ 133 (2JC-F = 33 Hz), as well as the shifted carbonyl signal at δ 176. EI-MS showed the expected molecular ion at 763 m/z. Elemental analysis could not be obtained because of the difficulty with recrystallization. Crude complex 3.5 is a dark brown semi-solid.  Upon precipitation from a  minimal amount of hot hexanes, a light brown solid is obtained in low yield. The 1H NMR spectrum for this complex is simple and displays all of the expected features. The doublet at δ 1.20 (12 hydrogens), as well as the septet at δ 3.09 (2 hydrogens), are due to the methyl and methyne hydrogens of the isopropyl group on the nitrogen of the amidate ligand. The dimethylamido methyl signal is present as a singlet at δ 3.34 (12 hydrogens). The aryl hydrogens signal is shifted slightly upfield from the proligand spectrum (δ 8.20) at δ 7.83 (4 hydrogens). Interestingly, the  13  C NMR spectrum shows two one-bond  coupled quartet signals for the para and or tho CF3 substituents, which overlap and are at δ 121.4 and 122.0 respectively, each with 1JC-F = 272 Hz. Consequently, there are also two two-bond coupled quartets at δ 129.5 and 131.4 with 2JC-F = 33 Hz. The 19F NMR shows the two expected signals with a 1:2 integral ratio, at δ -63.5 and -58.8 respectively. EI-MS showed the expected molecular ion at 911 m/z. Elemental analysis could not be obtained, therefore characterization for further work was determined by multinuclear NMR spectroscopy. Complex 3.6 exists as a colorless, oily semi-solid. It has thus far eluded attempts at recrystallization, as it is extremely soluble in hexanes, pentane and toluene. The 1H  43  NMR is not readily assignable. There is no isopropyl septet peak visible, perhaps having shifted to be overlapping with a broad aliphatic peak. In addition, the peak for the isopropyl methyls is not a doublet.  All signals are very broad, indicating fluxional  behavior in solution on the NMR timescale. Interestingly, there are two signals in the 19F NMR spectrum that have an integral ratio of 1:1. This suggests the two CF3 groups have become inequivalent during complex formation. EI-MS showed the expected molecular ion at 915 m/z. Elemental analysis could not be obtained. Further work used the purest material possible, as determined from multinuclear NMR spectroscopy. A solid-state molecular structure has been obtained from a solution of complex 3.6 in approximately 40 - 50% yield, however it does not match the expected structure of the complex (Figure 3.4). This structure is an amido-bridged mono(amidate)bis(amido) zirconium dimer and is the first Schafer group example of a bridging amido species. Interestingly, previous efforts in the Schafer group to pursue monoamidate Group 4 complexes have been unsuccessful.61 Thus, trifluoromethyl groups play an important role in accessing the monoamidate coordination mode. The amidate ligands are oxobound, with a nearly linear Zr1-O1-C1 bond angle (166.2(2)°), similar to the solid-state molecular structure of complex 3.2 with the neutrally-bound amine donor.  The 5-  coordinate zirconium species appear to have pseudo-trigonal bipyramidal geometry, and the dimer itself is C2 symmetric. The N7-Zr1-N8 bond angle (75.41(8)°) is smaller than the Zr1-N7-Zr2 bond angle (101.4(1)°) making the bridging core a compressed diamond shape that is slightly distorted. The distortion is evident when the bond lengths of the bridging nitrogens are compared to each metal center. The Zr1-N7 bond (2.213(2) Å) is similarly short to the Zr2-N8 bond (2.218(2) Å).  Consequently, the Zr1-N8 bond  44  (2.343(2) Å) and the Zr2-N7 bond (2.329(2) Å) are longer in comparison. The Zr1-Zr2 distance is 3.516(1) Å, longer than the van der Waals radii for zirconium (approximately 2 Å),62 thus there is no Zr—Zr bond. The Zr1-O1 bond is relatively short (2.100(2) Å) when compared to the amidate ligand Zr-O bond of complex 3.3 (2.260(2) Å), this indicates double bond character, again similar to the oxo-bound amidate representation of complex 3.2 discussed above. The very broad signals in the 1H NMR spectra and the solid state molecular structure observed suggest that there may be a mixture of highly fluxional complexes in solution.  Figure 3.4: Solid-state molecular structure of a zirconium mono amidate, amido bridged dimer (proligand 2.6), (ellipsoid probability at 30%).  45  Table 3.3: Bond lengths and bond angles of interest for dimer complex (Figure 3.4). Distance (Å) Angle (°) Zr1 - O1 2.100(2) Zr1 - O1 - C1 166.2(2) Zr1 - N4 2.006(3) N7 - Zr1 - N8 75.41(8) Zr1 - N7 2.213(2) Zr1 - N7 - Zr2 101.4(1) Zr1 - N8 2.343(2) O1 - Zr1 - N8 159.1(1) Zr2 - N7 2.329(2) N4 - Zr1 - N9 113.5(1) Zr2 - N8 2.218(2) O1 - C1 - N1 129.2(3) Zr1 - Zr2 3.516(1) O1 - C1 - C2 115.0(2) C1 - C2 1.567(4) C1 - N1 1.264(4) C36 - N4 1.454(4) C46 - N7 1.479(4) As with complex 3.6, the signals in the 1H NMR spectrum of complex 3.7 are very broad and appear to be time averaged. However, the signals corresponding to the expected complex are present and integrate to the expected values.  The 1H NMR  spectrum shows a signal at δ 2.05, representing the methyl hydrogens on the 2,6dimethylphenyl moiety and integrating to 12 hydrogens.  The signal at δ 2.31 (6  hydrogens) is the signal for the lone methyl on the carbonyl substituent.  The  dimethylamido ligand signal appears at δ 2.60 (12 hydrogens). The aryl hydrogens, contrary to complexes 3.2 and 3.4, show up as two broad signals at δ 6.89 and 7.01. The 19  F NMR spectrum also shows two signals with an integration of 1:1 at δ -68.3 and -67.8,  which are exactly the chemical shifts for complex 3.6. A poorly resolved  13  C NMR  spectrum was obtained for this compound and the data is included in the experimental section. It was not possible to discern carbon-fluorine coupled quartet from the base line and the carbonyl peak could not resolved. EI-MS showed the expected molecular ion at 803 m/z. Elemental analysis could not be obtained. Further work for this complex involved using the most pure sample as characterized by 1H and  19  F NMR spectroscopy  for catalysis. 46  3.3 - Conclusions A series of trifluoromethylated bis(amidate)bis(amido) zirconium complexes have been prepared and characterized. The structure and bonding of these complexes has been discussed. The synthetic route for preparing these complexes is facile, but their isolation and full characterization has proved challenging. The addition of the CF3 groups to the ligands significantly changes the behavior of these complexes compared to the unfluorinated versions; higher solubility in common organic solvents and an oily solid morphology are two of the most common challenges. Fluxional bonding modes have been observed, including and unprecedented mono(amidate)bis(amido) bridging dimer. These trifluoromethylated complexes are both challenging and interesting. However, the overall goal of an improved alkene hydroamination catalyst must provide a balance between reactivity of the catalyst and stability of the precatalyst. In these cases where decomposition is observed at room temperature under inert atmosphere, it is questionable whether these systems will display the desired features necessary for a broadly applicable catalyst.  3.4 - Experimental All reactions were carried out under a dry nitrogen atmosphere using standard Schlenk line and glovebox techniques, unless otherwise indicated. NMR spectra were recorded on Bruker 300 MHz, 400 MHz or 600 MHz Avance spectrometers using J. Young NMR tubes.  Mass spectrometry was performed using a Kratos MS-50  spectrometer using electron impact ionization (70 eV source). Chemicals were purchased from Sigma-Aldrich or Acros and used without further purification. d6-Benzene and d8-  47  toluene were degassed and stored over molecular sieves.  The complexes are titled  according to a shorthand nomenclature for the proligands. For example,  DIPP  (NO)m-CF3  represents a 2,6-diisopropylphenyl substituent on the nitrogen of the amidate, and a 3,5bis(trifluoromethyl)phenyl carbonyl substituent.  Preparation of [(DIPP(NO)m-CF3)2Zr(NMe2)2] (3.1) In the glovebox, a 20 mL sample vial was charged with tetrakis(dimethylamido) zirconium (0.35 g, 1.3  F 3C N Zr O 2  mmol) and two equivalents of proligand 2.1 (1.0 g, 2.5  NMe2 NMe2  F 3C  mmol). Approximately 7 mL of hexanes was added and the reaction was stirred at room temperature for 18 hours. The solvent and the dimethylamine byproduct were removed in vacuo leaving a frothy brown solid that was purified by washing with a minimum amount of cold hexanes giving a yellow solid. An isolated yield of 72% was obtained. 1H NMR (C6D6, 25 °C, 300 MHz) δ: 0.87 (d, 12H, CH-(CH3)2), 1.19 (d, 12H, CH-(CH3)2, 3.07 (s, 12H, N-(CH3)2), 3.39 (spt, 4H, CH-(CH3)2), 7.13-7.24 (ov m, 6H, Ar-H), 7.69 (s, 2H, p ArF-H), 8.20 (s, 4H, o ArF-H).  13  C NMR (C6D6, 25 °C, 600 MHz) δ: 23.2, 23.5,  27.7, 40.9, 122.6 (q, 1JC- F = 272 Hz, CF3), 124.0, 124.4, 126.3, 127.6, 130.0, 131.0 (q, 2  JC-F = 33 Hz) 133.6, 139.5, 140.8, 172.7. 19F NMR (C6D6, 25 °C, 300 MHz) δ: -63.4.  Preparation of [(DM P(NO)m-CF3)2Zr(NMe2)2] (3.2) Using the procedure outlined for complex 3.1, tetrakis(dimethylamido) zirconium (0.39 g, 1.4 mmol)  F 3C N Zr O 2  NMe2 NMe2  F 3C  48  was reacted with proligand 2.2 (1.0 g, 2.8 mmol) in THF, and was heated to 60 °C in a parallel synthetic unit.  The crude product was recrystallized from pentane at room  temperature. Isolated yield was 63%. 1H NMR (C6D6, 25 °C, 300 MHz) δ: 2.04 (s, 12H, Ar-CH3), 3.10 (s, 12H, N-(CH3)2), 6.94 (ov m, 6H, Ar-H), 7.65 (s, 2H, p ArF-H), 8.14 (s, 4H, o ArF-H).  13  C NMR (C6D6, 25 °C, 600 MHz) δ: 17.2, 18.0, 38.4, 40.7, 122.6 (q,  1  JC-F = 272 Hz), 122.6 (ov q, 1JC-F = 271 Hz), 122.0, 122.8, 124.3, 125.2, 125.4, 126.3,  127.6, 128.3, 128.4, 128.7, 128.8, 130.6, 130.9, 131.4 (q, 2JC-F = 33 Hz), 134.2, 139.7, 141.9, 142.2, 147.1, 154.5, 171.5, 172.1.  19  F NMR (C6D6, 25 °C, 300 MHz) δ: -63.4. EI-  MS (m/z): 898 (M+ ).  Preparation of [(DIPP(NO)p-CF3)2Zr(NMe2)2] (3.3) Using the procedure outlined for complex 3.1, tetrakis(dimethylamido) zirconium (0.40 g, 1.4 mmol) was reacted with proligand 2.3 (1.0 g, 2.9 mmol) in  N F3C  Zr O 2  NMe2 NMe2  hexanes. The crude product was recrystallized from pentane at -37 °C to give 81% isolated yield. 1H NMR (C6D6, 25 °C, 300 MHz) δ: 0.911 (d, 12H, CH-(CH3)2), 1.25 (d, 12H, CH-(CH3)2), 3.14 (s, 12H, N-(CH3)2), 3.43 (spt, 4H, CH-(CH3)2), 7.09 (d, 4H, m ArF-H), 7.18-7.24 (ov m, 6H, Ar-H), 7.70 (d, o ArF-H)  13  C NMR (C6D6, 25 °C, 600  MHz) δ: 23.4, 24.1, 27.4, 42.1, 123.2 (q, 1JC-F = 272 Hz, CF3), 123.8, 124.2, 125.9, 130.0, 132.4 (q, 2JC-F = 33 Hz, CAr-CF3), 134.9, 141.0, 142.4, 175.2. 19F NMR (C6D6, 25 °C, 300 MHz) δ: -63.2.  49  Preparation of [(DM P(NO)p-CF3)2Zr(NMe2)2] (3.4) Using the procedure outlined for complex 3.1, tetrakis(dimethylamido) zirconium (0.48 g, 1.7 mmol) was reacted with proligand 2.4 (1.0 g, 3.4 mmol) in hexanes.  N F3C  Zr O 2  NMe2 NMe2  The oily, dark green crude product could not be recrystallized but can be  purified by washing the crude green semi-solid with pentane, filtering the solution through Celite, and removing the solvent in vacuo to give 61% isolated yield. 1H NMR (C6D6, 25 °C, 300 MHz) δ: 2.15 (s, 12H, Ar-CH3), 3.15 (s, 12H, N-(CH3)2), 7.00-7.08 (ov m, 6H, Ar-H), 7.63 (d, 8H, ArF-H).  13  C NMR (C6D6, 25 °C, 600 MHz) δ: 18.5, 41.9,  122.0 (q, 1JC-F = 275 Hz, CF3), 125.7, 129.2, 129.5, 132.1, 133.4 (q, 2JC-F = 33 Hz, CArCF3), 136.7, 143.8, 175.5.  19  F NMR (C6D6, 25 °C, 300 MHz) δ: -63.2. EI-MS (m/z): 763  (M+ ).  Preparation of [( iPr(NO)2,4,6-CF3)2Zr(NMe2)2] (3.5) Using the procedure outlined for complex 3.1, tetrakis(dimethylamido) zirconium (0.068 g, 0.27 mmol) was reacted with proligand 2.5 (0.18 g, 0.54  CF3 N F3C  Zr O 2  NMe2 NMe2  CF3  mmol) in hexanes. The brown crude product was recrystallized from hexanes at -37 °C to yield an off-white solid in 42% isolated yield. 1H NMR (C6D6, 25 °C, 600 MHz) δ: 1.20 (d, 12H, CH-(CH3)2), 3.09 (spt, 2H, CH-(CH3)2), 3.34 (s, 12H, N-(CH3)2), 7.83 (s, 4H, ArF-H).  13  C NMR (C6D6, 25 °C, 600 MHz) δ: 23.1, 42.1, 49.1, 121.4 (q, 1JC-F = 272  Hz, p Ar-CF3 ), 122.0 (q, 1JC-F = 275 Hz, o Ar-CF3), 126.8, 127.6, 129.5 (q, 2JC-F = 33 Hz,  50  CAr-CF3), 131.4 (q, 2JC-F = 35 Hz, CAr-CF3), 134.0, 172.5.  19  F NMR (C6D6, 25 °C, 300  MHz) δ: -63.4 (s, 3F, p CF3), -58.8 (s, 6F, o CF3). EI-MS (m/z): 911 (M+ ).  Preparation of [(DIPP(NO)bis(CF3)tBu)2Zr(NMe2)2] (3.6) Using the procedure outlined for complex 3.1, tetrakis(dimethylamido) zirconium (0.038 g, 0.14 mmol) was reacted with proligand 2.6 (0.10 g, 0.27 mmol) in  F3C F3C  N  NMe2  Zr O 2  NMe2  hexanes. The white crude semi-solid product can be recrystallized from a minimum amount of hot hexanes at -37 °C to give a white solid in 79% isolated yield . 1H NMR (C6D6, 25 °C, 300 MHz) δ: 1.97 (s, 12H, CH-CH3), 2.24 (s, 6H, C-(CF3)2-CH3), 2.51 (s, 12H, N-(CH3)2), 6.80 (br s, 4H, o-Ar-H), 6.94 (br s, 2H, p-Ar-H).  13  C NMR (C6D6, 25  °C, 600 MHz) δ: 11.9, 14.3, 17.4, 17.7, 38.3, 40.9, 123.5 (q, 1JC-F = 272 Hz), 127.6, 128.1, 130.6, 140.4, 145.7. 19F NMR (C6D6, 25 °C, 300 MHz) δ: -68.3 (s, 3F, CF3), -67.8 (s, 3F, CF3). EI-MS (m/z): 915 (M+ ).  Preparation of [(DM P(NO)bis(CF3)tBu)2Zr(NMe2)2] (3.7) Using the procedure outlined for complex 3.1, tetrakis(dimethylamido) zirconium (0.045 g, 0.16 mmol) was reacted with proligand 2.7 (0.10 g, 0.32 mmol) in hexanes.  N F3C F3C  Zr O 2  NMe2 NMe2  The white crude product was recrystallized from hexanes at -37 °C to give an 81% isolated yield. 1H NMR (C6D6, 25 °C, 300 MHz) δ: 2.05 (s, 12H, Ar-CH3), 2.31 (s, 6H, C-(CF3)2-CH3), 2.60 (s, 12H, N-(CH3)2), 6.89-7.00 (br ov m, 6H, Ar-H). 13C NMR (C6D6, 25 °C, 600 MHz) δ: 11.9, 14.3, 17.4, 17.7, 38.3, 40.9, 122.1, 124.9, 127.6, 128.1, 130.6,  51  140.4, 145.7. 19F NMR (C6D6, 25 °C, 300 MHz) δ: -68.3 (s, 3F, CF3), -67.8 (s, 3F, CF3). EI-MS (m/z): 803 (M+ ).  52  CHAPTER 4: LOW TEMPERATURE HYDROAMINATION OF ALKENES WITH TRIFLUOROMETHYLATED BIS(AMIDATE)BIS(AMIDO) ZIRCONIUM PRECATALYSTS 4.1 - Hydroamination of Alkenes with Group 4 Amidate Complexes. Group 4 amidate complexes have shown great promise as hydroamination catalysts.  They are able to perform the hydroamination reactions of alkynes,59, 63  allenes,27,64 and aminoalkenes.58 The currently accepted, imido-mediated mechanism of Group 4 catalyzed intramolecular hydroamination is shown below for alkenes (Scheme 4.1).65 This mechanism is analogous to that originally proposed by Bergman for the group 4 catalyzed hydroamination of allenes 66 and alkynes.67 Upon addition of one equivalent of aminoalkene substrate to the precatalyst, two dimethylamido ligands are released by protonolysis. The resulting imido metal complex is invoked as the active catalyst species and undergoes a [2+2] cycloaddition with the alkene moiety of the substrate, forming a metallacyclobutane intermediate. Upon protonolysis with another equivalent of the aminoalkene substrate, the nitrogen heterocyclic product is eliminated, reforming the active imido species. Bis(amidate)bis(amido) catalytic systems in the Schafer group are thought to proceed via this mechanism as opposed to the σ-bond insertion mechanism proposed for group 3 systems62b, 68 and cationic group 4 systems. 69  53  L2Zr(NMe2)2 R  R  H 2N  R' n  2 HNMe2  R' NH  n  R  R  L2Zr N n  R  R  R'  R  R  H N  N  R  L2Zr N  n  n  R'  R'  ZrL2  R  R  n  R  R' R  L2Zr N n  R  R'  R  H2N  R  R' n  Scheme 4.1: Proposed mechanism for the intramolecular hydroamination of alkenes with group 4 amidate catalysts. L = ligand; R, R′ = Ph, Me, H. Presently, intramolecular alkene hydroamination catalyzed by group 4 complexes require elevated temperatures (>90 °C) to achieve efficient reactivity and unfortunately this disfavours potential intermolecular reactivity. Thus, low temperature reactivity may facilitate intermolecular reactivity and is therefore the focus of the work presented herein. Increasing the electrophilicity of the metal center is one way that higher reactivity may be achieved, as shown by the Schafer group28-30 and others.27 This strategy can be implemented using ligands that are derivatized with electron withdrawing trifluoromethyl 54  groups, which ensure the ligands, do not donate strongly to the metal center. It will be shown that increased reactivity at high temperatures has translated into low temperature reactivity for the trifluoromethylated complexes discussed herein; thereby increasing catalytic reactivity allowing for efficient intramolecular hydroamination reactivity at 65 °C.  4.2 - Alkene Hydroamination Results: Toward Low Temperature Reactivity. The Schafer group and others use the gem-disubstituted 2,2-diphenylpent-4-en-1amine as a standard benchmark substrate. This substrate takes advantage of the gemdisubstituent effect to promote cyclization. 70 The intramolecular hydroamination of this aminoalkene was used as a low temperature screen for the seven complexes discussed in Chapter 3 (Table 4.1). All reactions performed for this screen used isolated precatalysts in the highest obtainable purity and were tested at both 110 °C and 65 °C.  19  F NMR  spectra were taken midway through select hydroamination reactions in an attempt to follow reaction progress. Numerous indistinguishable signals were observed, providing further support to the proposed decomposition problems previously discussed.  55  Table 4.1: Aminoalkene hydroamination low temperature reactivity screen using isolated precatalysts. Ph  5 mol% cat., C6D6  Ph NH2  NH Ph Ph  Entry  Proligand  110 °C  65 °C  yield, time  yield, time  3.1  80%, 18 hr  83%, 116 hr  3.2  73%, 38 hr  45%, 96 hr  3.3  98%, 8 hr  75%, 144 hr  3.4  14%, 42 hr  7%, 19 hr  3.5  96%, 42 hr  73%, 48 hr  3.6  98%, 1 hr  98%, 30 hr  3.7  98%, 1.5 hr  83%, 192 hr  Complex  O  1  F3C  N H CF3 O  2  F3C  N H CF3  O  3  N H F3C O  4  N H F3C  CF3 O  5  N H CF3  F3C  O  6 F3C  7  CF3  N H  O F3C  CF3  N H  *Results reported as 1H NMR yield versus internal standard 1,3,5-trimethoxybenzene.  Subtle modifications to the catalyst framework allowed for the correlation of steric bulk and the electronic nature of the catalyst to the rates of hydroamination reactions. Complex 3.1 (entry 1) has maximized steric bulk at the nitrogen position of the amidate with the large 2,6-isopropyl groups on the phenyl ring. The two meta-CF3 groups on the carbonyl substituent are heavily electron withdrawing, and add steric bulk 56  to the system without over-crowding the metal center, allowing for good reactivity at both  110 °C and 65 °C. However, conversion of the substrate reaches a plateau at 80-  83%. This incomplete reactivity is indicative of either product inhibition or catalyst degradation, both resulting in deactivation of the catalyst. In contrast, complex 3.2 (entry 2) eases the steric bulk at the nitrogen position with the less bulky ortho-methyl substituents. This seemingly small change significantly decreases the reactivity of the precatalyst and is indicative of the trend observed for all of these complexes: 2,6diisopropylphenyl (DIPP) substituted bisamidate complexes consistently perform to a higher standard when compared to the 2,6-dimethylphenyl (DMP) substituted versions. Trifluoromethylated bis(amidate)bis(amido) complexes, in general benefit from increased steric bulk at the nitrogen position, perhaps to offset the increased electrophilicity of the metal center by sterically protecting the active site. Complex 3.3 (entry 3) contains one para-CF3 substituent on the carbonyl position, reducing the electron withdrawing ability of the amidate ligand in comparison to complexes 3.1 and 3.2 discussed above. As with complex 3.1, the sterically bulky DIPP substituent of complex 3.3 is able to suitably protect the metal centre, allowing for higher catalytic reactivity than 3.2. Complex 3.3 is more efficient than complex 3.1 at 110 °C, however lower reactivity of 3.3 was observed at 65 °C. It can be reasoned that increased reactivity at 110 °C should correlate to reactivity at 65 °C, as is the case for the other complexes studied.  This disparity in the results is another indication that catalyst  decomposition is an issue for these trifluoromethylated precatalysts. The lower reaction temperature should reduce decomposition of the precatalyst, however this may be explained by the longer reaction times necessary at 65 °C.  57  Complex 3.4 (entry 4) displays the lowest reactivity for intramolecular hydroamination at both of the temperatures examined. This complex has one para-CF3 group and the less sterically protecting DMP nitrogen substituent. Interestingly, the complex with the least steric bulk at the nitrogen substituent, complex 3.5 (entry 5), performs only modestly at 110 °C with 96% yield in 42 hours, as measured by  1  H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal  standard. However, 3.5 is a lead compound at 65 °C (73% yield in 48 hours). The amidate ligand of 3.5 boasts a total of three CF3 groups in the ortho/para positions of the carbonyl phenyl substituent, however has only an isopropyl nitrogen substituent. It is proposed that in this case, the ortho-CF3 groups contribute to the steric protection of the complex to allow for efficient catalysis. Complex 3.6 (entry 6) is the most impressive precatalyst, as it displays the highest reactivity of all complexes screened at both 110 °C (98% yield in one hour) and 65 °C (98% yield in 30 hours) and is the only example to display quantitative conversions at 65 °C. The metal center in this complex is sterically protected with the DIPP nitrogen substituent. The bis-CF3 substituted t-butyl carbonyl substituent, is also sterically bulky and explores a different electron-withdrawing mode than the complexes previously discussed, through an alkyl carbonyl substituent rather than a phenyl substituent. This change exerts a dramatic effect on catalytic reactivity, greatly improving the efficiency at both 110 °C and 65 °C. Complex 3.7 displays excellent reactivity at 110 °C and is comparable to complex 3.6 in this regard. However, this complex has displayed poor reactivity at 65 °C when compared to the other complexes studied.  58  Two lead compounds were identified, complexes 3.5 and 3.6. A substrate scope analysis was then carried out using these two precatalysts at 65 °C (Table 4.2). Reactivity with the more challenging substrates was observed in some cases, although the substrate scope for both of the precatalysts tested are extremely limited. Complex 3.5 was unable to catalyze the intramolecular hydroamination of 2,2-dimethylpent-4-en-1amine (entry 2) or 2,2-diphenylhex-5-en-1-amine (entry 3). Neither complex was able to catalyze the intramolecular  hydroamination  of  the internal alkene substrate,  2,2-diphenylhex-4-en-1-amine or the intermolecular hydroamination reactions attempted (entries 5 and 6). Complex 3.6 was able to catalyze the intramolecular hydroamination of both 2,2-dimethylpent-4-en-1-amine and 2,2-diphenylhex-5-en-1-amine (entries 2 and 3 respectively).  However, rates of these reactions were slow and 1H NMR spectrum  calculated yields were low.  Overall, complex 3.6 was found to be far superior to  complex 3.5 at effecting these transformations. In situ reactivity of these complexes was also investigated for the hydroamination reactions that proceed with the isolated complex at 65 °C, to compare reactivity. As previously mentioned, possible catalyst stability problems may be providing misguiding results once the catalyst has been isolated and stored. In situ reactions involve preparing the metal catalyst by adding a solution of proligand and tetrakis(amido) zirconium starting material together minutes before addition to the substrate. This method greatly improved the 65 °C hydroamination results with complex 3.6.  However, in situ  preparations showed little to no improvement for complex 3.5 and therefore were not included. This result agrees with the suspected decomposition issues with complex 3.6 as discussed in Chapter 3. Perhaps when the complex is prepared in a concentrated solution  59  many complexes form, or the complexes themselves simply cannot be stored. This is further supported by the interesting structure obtained (Chapter 3, Figure 3.4), however when the complex is formed under the more dilute in situ conditions, the bis(amidate)bis(amido) precatalyst decomposition is less of a concern. The in situ results for complex 3.6 are the most impressive (entries 1, 2, 3). Table 4.2: Low temperature (65 °C) aminoalkene hydroamination reaction scope, including in situ reactivity for complex 3.6. CF3 N  Entry  1  65 oC, C6D6  Ph  3  Ph  4  Ph  Zr O 2  NMe2 NMe2  F3C F3C  CF3  Ph  2  5  F3C  Complex 3.6  yield, time (isolated complex) a (yield, time (in situ))  NH2  5%, 72 hr  Ph NH2  + H2N  NMe2  Complex 3.5 73%, 48 hr  NH2  NMe2  Zr O 2  yield, time (isolated complex)  NH2  Ph  N  98%, 30 hr (98%, 20 hr)a 52%, 120 hr (50%, 38 hr)a 37%, 48 hr (77%, 19 hr)a  0%, 72 hr 0%, 48 hr  0%, 24 hr  0%, 72 hr  0%, 72 hr  Reactions are monitored by 1H NMR, yields are calculated versus internal standard 1,3,5-trimethoxybenzene. a Catalyst was generated immediately prior to substrate addition.  As a probe of mechanism, the intramolecular hydroamination of the secondary aminoalkene substrate, N-methyl-2,2-diphenylpent-4-en-1-amine (eq. 4.4), was attempted at 110 °C and 65 °C. As expected, no reaction was observed for either complex 3.5 or 3.6.  This result suggests that the most probable mechanism is the imido-mediated  version discussed previously.  Ph  Ph H N  5 mol% cat.  N  (4.4) Ph Ph  60  4.3 - Conclusions Low temperature hydroamination reactivity has been screened for a series of trifluoromethylated zirconium bis(amidate)bis(amido) precatalysts. The steric bulk at the nitrogen position played an important role in the observed reactivity, as did the number and position of CF3 substituents on the carbonyl moiety. In general, DIPP is preferable to DMP and increasing the number of CF3 groups leads to higher reactivity at 65 °C. Two lead compounds were deduced from a low temperature screen and were both found to have very limited substrate scope at 65 °C. Neither complexes 3.5 or 3.6 could effect the intermolecular transformations of norbornene or trimethyl(vinyl)silane with aniline. However, in situ reactions greatly improved intramolecular hydroamination results at 65 °C for complex 3.5, which will be a lead compound in future work.  4.4 - Experimental All reactions were carried out under a dry nitrogen atmosphere using standard glovebox techniques. Reactions were monitored using 1H NMR spectroscopy and were recorded on Bruker 300 MHz or 400 MHz Avance spectrometers using J. Young NMR tubes.  Aminoalkene substrates were prepared and dried using standard literature  procedures. 71 Norbornene, trimethyl(vinyl)silane and aniline are known compounds and were distilled before their use. Hydroamination products are known compounds and 1H NMR spectroscopic signals for these compounds match the literature values.17 Other chemicals used were purchased from Sigma-Aldrich.  Norbornene and aniline were  distilled over calcium hydride before use. d6-Benzene and d8-toluene were degassed and stored over molecular sieves.  61  General procedure for hydroamination investigations (2,2-diphenylpent-4-en-1-amine example) In the glovebox, 2,2-diphenylpent-4-en-1-amine (0.050 g, 0.21 mmol), trimethoxybenzene (0.012 g, 0.070 mmol) and 5 mol% complex 3.6 (0.0097 g, 0.11 mmol) were measured into separate vials. d6-Benzene or d8-toluene (approximately 0.70 g) was used to dissolve the reaction components. They were combined and all vials were washed three times with the reaction mixture. The reaction mixture was then transferred to a J. Young NMR tube. A time-zero 1H NMR spectrum was taken before heating. The reaction tube was then placed in a heated oil bath set to the chosen temperature (110 °C or 65 °C). Reaction progress was monitored by 1H NMR spectroscopy.  General procedure for in situ hydroamination investigations (2,2-diphenylpent-4-en-1amine example) In the glovebox, a 0.27 M standard solution of proligand 2.6 (80 µL, 0.021 mmol) is added to a 0.27 M standard solution of Zr(NMe2)4 (40 µL, 0.011 mmol). This mixture was allowed to react for 5 minutes before being added to a mixture of 2,2-diphenylpent4-en-1-amine (0.050 g, 0.21 mmol) and 0.625 M trimethoxybenzene (112 µL, 0.070 mmol). d6-Benzene or d8-toluene (approximately 0.50 g) was used to dilute the solution to the approximate volume for 1H NMR spectroscopy. The reaction mixture was then transferred to a J. Young NMR tube. A time-zero 1H NMR spectrum was taken before heating. The reaction tube was then placed in a heated oil bath set to 65 °C. Reaction progress was monitored by 1H NMR spectroscopy.  62  CHAPTER 5: FUTURE DIRECTIONS AND CONCLUDING REMARKS 5.1 - Future Directions Trifluoromethyl groups have been shown to increase reactivity for the intramolecular hydroamination of alkenes, providing an avenue for low temperature reactivity. In order to obtain a more complete picture of reactivity and to increase the substrate scope of this catalyst framework at low temperatures, there are many avenues of exploration. An appropriate starting point would be to make the titanium and hafnium complexes with the two most successful proligands (2.5 and 2.6) and compare the reactivity with the zirconium analogs presented herein. Also the bis(amidate)bis(alkyl) versions of these precatalyst frameworks would provide an interesting reactivity comparison. A future goal of this project would be to develop complexes with increased stability that are more easily isolated and characterized. Proligands with a more facile synthesis would also help to make more usable catalyst systems. One way to possibly avoid complex decomposition and create a more practical catalyst system is to lessen the electron-withdrawing effect and reduce the steric bulk on the carbonyl position of the amide on proligand 2.6 by using a mono-substituted CF3 derivative (Figure 5.1).  O  CF3  O  N H CF3  N H  Figure 5.1: Proposed proligands, analog of proligands 2.6 and 2.7, to reduce steric bulk and electron-withdrawing at the carbonyl position of the amide.  63  Mechanistic investigations may provide valuable insight.  19  F NMR spectroscopy  could be an interesting handle to follow the catalyst through the reaction progress of more stable catalysts and perhaps gleen some qualitative mechanistic information. As well, kinetic determination of the catalyst order should be performed especially in the case of complex 3.6. Changing the position of the CF3 group from the carbonyl carbon to the nitrogen of the amidate would also be interesting (Figure 5.2). As discussed previously, it is advantageous to have a sterically bulky group in this position. It is possible that CF3 groups in the ortho position would satisfy the steric requirement and also provide an avenue for new reactivity. As well, a meta-CF3 substituted phenyl ring in this position may alleviate steric crowding at the metal, allowing the substrates better access to the catalyst, while still sterically protecting the reactive centre. O R  N H  (CF3)n  R = DIPP, DMP, tBu n = 1, 2, 3  Figure 5.2: Proposed CF3 positioning study.  Also interesting would be the effect of CF3 groups on the asymmetric reactivity currently being studied by Neal Yonson in the Schafer group, following the work of Mark Wood (Chapter 1, eq. 1.4).8 A proposed proligand structure would incorporate the 2,2-bis(trifluoromethyl)tert-butyl moiety into the diphenyl backbone (Figure 5.3).  64  O F3C  CF3  N H  H N  CF CF3 3  O  Figure 5.3: Proposed proligand for asymmetric intramolecular hydroamination.  Another possible study that could be done would involve a tethered system. David Leitch in the Schafer group has developed a tethered ureate system, which has displayed novel reactivity. 72 It would be interesting to compare and contrast the reactivity of these electron donating tethered ureas with electron-withdrawing trifluoromethylated amides.  Following the work of Robert Thomson in the Schafer group, two amide  moieties may be attached together through an alkyl chain, or conversely through an sp2 connector. Probing the reactivity of these systems would be useful (Figure 5.4).61 O F3C F3C  O F3C F3C  N H HN F3C  O CF3  N H  HN  O CF3 CF3  Figure 5.4: Proposed tethered amide proligands.  The guiding objective of this project is to obtain intermolecular reactivity. Intermediate steps to achieve this ambition include room temperature reactivity as well as the use of more appropriate substrates as initial screens. Sluggish reactivity has been observed at 40 °C with all complexes, thus it may be possible to further optimize this class of proligands to obtain room temperature reactivity. Also, successfully catalyzing  65  the intramolecular hydroamination of an unsubstitued aminoalkene substrate is an important step.  This would more accurately mimic intermolecular hydroamination  reactions and would be a preferable reactivity screen. The possible directions this project may take are numerous. These are but a few relevant and interesting proposals that may lead to successes in the future.  5.2 - Concluding Remarks Novel, trifluoromethylated bis(amidate)bis(amido) zirconium complexes have been prepared. It has been found that increasing the electrophilicity of the precatalyst zirconium center increases reactivity of these systems in the catalytic intramolecular hydroamination of alkenes in comparison with non-fluorinated group 4 precatalysts and lowers the temperatures that these reactions have previously required.  Preliminary  screening of low temperature reactivity (65 °C) has been performed, allowing for the discernment of two lead compounds, complex 3.5 and 3.6, which were subjected to an initial substrate scope study. Results from this study as well as other indications of catalyst instability lead us to discover that in situ reactivity for complex 3.6 was enhanced, compared to results of the isolated complex. Thus, catalyst decomposition is an issue that must be addressed in future work. A solid state molecular structure of the first Schafer group example of a bridging-amido, mono(amidate)bis(amido) zirconium dimer was elucidated during the course of this work.  Synthetic challenges in the  synthesis trifluoromethyl proligands have been met and reconciled in the case of proligands 2.6 and 2.7 with the development of a one-pot preparation. However, the case of increasing steric bulk on the framework of proligand 2.5 has remained irreconcilable  66  due to the proposed sterically induced susceptibility to hydrolysis. Electron-withdrawing trifluoromethyl substituents have proven their utility as a means to significantly increase catalytic reactivity. However, it may be inferred from this work that the solution to a general catalyst for intermolecular alkene hydroamination reactivity is more complex than simply adding electron-withdrawing groups. 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Soc. 1992, 114, 275.  72.  D. C. Leitch, J. D. Beard, R. K. Thomson, V. Owright, B. O. Patrick, L. L. Schafer. Eur. J. Inorg. Chem. 2009 In press.  75  APPENDIX A: X-RAY CRYSTALLOGRAPHIC DATA Table A.1: Crystallographic Data and Refinement Details for Proligand 2.5. Empirical Formula C13H10F9NO Crystal system Monoclinic Formula Weight 367.22 Space group P21:b a, b, c (Å) 12.047(7), 4.720(2), 13.173(8) V, Å3 745.4(7) Total reflections 2330 Z 2 Unique reflections 1652 Dcalc , g cm-3 1.636 Parameters 223 -1 a µ(Mo Kα), mm 0.180 R1 0.0656 T, K 173(2) Rwa 0.1726 2θ range (°) 48.1 Goodness-of-fit 1.087 a 2 2 2 2 2 1/2 R1 = Σ Fo-Fc  /Σ Fo ; Rw = Σw(( Fo -Fc  ) /ΣwFo  )  Table A.2: Crystallographic Data and Refinement Details for Proligand 2.6. Empirical Formula C13H13F6NO Crystal system Monoclinic Formula Weight 313.24 Space group P-1 a, b, c (Å) 10.4570(2), 14.2276(3), 14.3268(3) V, Å3 2077.4(1) Total reflections 34026 Z 6 Unique reflections 9453 Dcalc , g cm-3 1.502 Parameters 589 µ(Mo Kα), mm-1 0.150 R1a 0.0703 a T, K 173(2) Rw 0.1588 2θ range (°) 51.3 Goodness-of-fit 1.041 a R1 = Σ Fo-Fc  /Σ Fo ; Rw = Σw(( Fo2-Fc 2 )2/ΣwFo2 2)1/2  Table A.3: Crystallographic Data and Refinement Details for Non-fluorinated Proligand (Figure 2.6). Empirical Formula C17H27NO Crystal system Monoclinic Formula Weight 261.40 Space group P21/c a, b, c (Å) 10.141(2), 18.353(3), 9.887(3) V, Å3 1646.0(4) Total reflections 18263 Z 4 Unique reflections 3956 Dcalc , g cm-3 1.055 Parameters 192 -1 a µ(Mo Kα), cm 0.64 R1 0.097 T, K 173(2) Rwa 0.183 2θ range (°) 56.1 Goodness-of-fit 1.07 a 2 2 2 2 2 1/2 R1 = Σ Fo-Fc  /Σ Fo ; Rw = Σw(( Fo -Fc  ) /ΣwFo  )  76  Table A.4: Crystallographic Data and Refinement Details for Complex 3.2 (HNMe2 adduct). Empirical Formula C40H48F12N5O2Zr Crystal system monoclinic Formula Weight 943.00 Space group P-1 a, b, c (Å) 11.676(1), 11.714(1), 16.133(3) V, Å3 2102.3(1) Total reflections 44471 Z 2 Unique reflections 12562 -3 Dcalc , g cm 1.422 Parameters 562 µ(Mo Kα), mm-1 0.351 R1a 0.0811 a T, K 173(2) Rw 0.1860 2θ range (°) 64.22 Goodness-of-fit 1.091 a 2 2 2 2 2 1/2 R1 = Σ Fo-Fc  /Σ Fo ; Rw = Σw(( Fo -Fc  ) /ΣwFo  )  Table A.5: Crystallographic Data and Refinement Details for Complex 3.3 Empirical Formula C44H54F6N4O2Zr Crystal system Monoclinic Formula Weight 876.13 Space group P-1 a, b, c (Å) 12.604(2), 13.209(2), 14.870(2) V, Å3 2184.3(8) Total reflections 23275 Z 2 Unique reflections 11634 -3 Dcalc , g cm 1.332 Parameters 514 µ(Mo Kα), mm-1 0.317 R1a 0.0809 a T, K 173(2) Rw 0.1209 2θ range (°) 65.1 Goodness-of-fit 1.120 a 2 2 2 2 2 1/2 R1 = Σ Fo-Fc  /Σ Fo ; Rw = Σw(( Fo -Fc  ) /ΣwFo  )  Table A.6: Crystallographic Data and Refinement Details for Dimer Complex (Figure 3.4) Empirical Formula C46H58F12N8O2Zr2 Crystal system Monoclinic Formula Weight 1165.44 Space group P21/c:b1 a, b, c (Å) 16.1382(3), 18.4085(4), 19.6368(4) V, Å3 5509.5(3) Total reflections 36983 Z 4 Unique reflections 9738 -3 Dcalc , g cm 1.405 Parameters 638 µ(Mo Kα), cm-1 0.461 R1a 0.0523 a T, K 173(2) Rw 0.0912 2θ range (°) 46.54 Goodness-of-fit 1.058 a 2 2 2 2 2 1/2 R1 = Σ Fo-Fc  /Σ Fo ; Rw = Σw(( Fo -Fc  ) /ΣwFo  )  77  

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