Science, Faculty of
Chemistry, Department of
DSpace
UBCV
Woods, Nolton Takashi
Master of Science - MSc
University of British Columbia
This thesis outlines the use of a phosphorus containing copolymer as a ligand for gold-catalyzed hydroaminations. Specifically, the phosphine moieties within the backbone of a random copolymer of styrene (S) and methylenephosphine (MP), PMP-co-PS function as P-ligands for gold(I) to afford a pre-catalyst. In Chapter 2, the use of the phosphorus-containing copolymer PMP-co-PS as a ligand for gold(I) is described. The activity of the acquired pre-catalyst PMP(AuCl)-co-PS in the intermolecular hydroamination of alkynes with arylamines (H₂NAr, Ar=Ph,4-NO₂Ph,etc.) is compared with the activity of model pre-catalysts (i.e., Ph₃PAuCl and MesP(AuCl)CHPh₂). Abstraction of the chloride from gold(I) using AgOTf was required for each pre-catalyst to obtain the active catalyst. In hydroaminations of phenylacetylene with arylamines employing pre-catalyst PMP(AuCl)-co-PS and following the above activation process selectively affords the Markovnikov products in good yields. In hydroaminations of diphenylacetylene with arylamines as substrates, the polymer-supported pre-catalyst was not as active; however, moderate yields of the imine and enamine product(s) were formed. Importantly, the polymer support allowed for the isolation of the catalyst from the products. The recovered catalyst could be recycled in additional cycles without the addition of fresh catalyst or AgOTf. It was determined that reducing the amount of gold(I) present to phosphorus in the polymer-supported pre-catalyst resulted in the improved stability of the active catalyst with sustained yields in the recycling reactions. In conclusion, PMP-co-PS was shown to be an effective support in gold catalysis that could be recovered and recycled for further use.
Gold(I) Catalyst Supported by Poly(methylene phosphine)-co-Styrene in the Hydroamination of Alkynes with Arylamines by Nolton Takashi Woods B.Sc., Middle Tennessee State University, 2019 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2023 © Nolton Takashi Woods, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the thesis entitled: Gold(I) Catalyst Supported by Poly(methylene phosphine)-co-Styrene in the Hydroamination of Alkyne with Arylamines submitted by Nolton Takashi Woods in partial fulfilment of the requirements for the degree of Master of Science in Chemistry Examining Committee: Dr. Derek P. Gates, Professor, Department of Chemistry, UBC Supervisor Dr. Laurel L. Schafer, Professor, Department of Chemistry, UBC Supervisory Committee Member Dr. Gregory R. Dake, Professor, Department of Chemistry, UBC Supervisory Committee Member Dr. Parisa Mehrkhodavandi, Professor, Department of Chemistry, UBC Additional Examiner iii Abstract This thesis outlines the use of a phosphorus containing copolymer as a ligand for gold-catalyzed hydroaminations. Specifically, the phosphine moieties within the backbone of a random copolymer of styrene (S) and methylenephosphine (MP), PMP-co-PS function as P-ligands for gold(I) to afford a pre-catalyst. In Chapter 2, the use of the phosphorus-containing copolymer PMP-co-PS as a ligand for gold(I) is described. The activity of the acquired pre-catalyst PMP(AuCl)-co-PS in the intermolecular hydroamination of alkynes with arylamines (H2NAr, Ar=Ph,4-NO2Ph,etc.) is compared with the activity of model pre-catalysts (i.e., Ph3PAuCl and MesP(AuCl)CHPh2). Abstraction of the chloride from gold(I) using AgOTf was required for each pre-catalyst to obtain the active catalyst. In hydroaminations of phenylacetylene with arylamines employing pre-catalyst PMP(AuCl)-co-PS and following the above activation process selectively affords the Markovnikov products in good yields. In hydroaminations of diphenylacetylene with arylamines as substrates, the polymer-supported pre-catalyst was not as active; however, moderate yields of the imine and enamine product(s) were formed. Importantly, the polymer support allowed for the isolation of the catalyst from the products. The recovered catalyst could be recycled in additional cycles without the addition of fresh catalyst or AgOTf. It was determined that reducing the amount of gold(I) present to phosphorus in the polymer-supported pre-catalyst resulted in the improved stability of the active catalyst with sustained yields in the recycling reactions. In conclusion, PMP-co-PS was shown to be an effective support in gold catalysis that could be recovered and recycled for further use. iv Lay Summary Homogeneous catalysts are a powerful tool to effect the synthetic transformations of organic molecules, generally exhibiting greater activity and selectivity than their heterogeneous counterparts. One major drawback is the inability of small-molecule transition metal catalysts to be isolated from the organic products. Functionalization of soluble polymer-supports with the active catalytic species is a promising method to permit the facile separation of homogeneous catalysts from the acquired products. In addition, this methodology offers the exciting prospect to recover and recycle expensive or toxic transition metals used within the catalyst. Herein the use of a polymeric phosphorus support for the homogeneous gold(I)-catalyzed hydroaminations of unsaturated hydrocarbons with nucleophiles is disclosed. This type of reaction being an important route for obtaining precursors of pharmaceuticals. The application of the polymer-support as an effective strategy to recover the catalyst is described in the latter half of the thesis. v Preface All synthetic work was conducted by myself. This thesis is achieved with the help of others. The copolymerization procedure for synthesis PMP-co-PS in Section 2.2.2 was originally developed by Dr. Chi-Wing Tsang. All GPC measurements were run by Henry Walsgrove. The results described in Chapter 2 are intended to be published at a future date. vi Table of Contents Abstract ....................................................................................................................................... iii Lay Summary............................................................................................................................... iv Preface ......................................................................................................................................... v List of Tables ............................................................................................................................. viii List of Figures .............................................................................................................................. ix List of Schemes ........................................................................................................................... xi List of Equations ........................................................................................................................ xii Acknowledgements .................................................................................................................. xiii Chapter 1: Introduction ......................................................................................................... 1 1.1 Polymers ................................................................................................................................ 1 1.1.1 Inorganic Polymers ......................................................................................................... 4 1.2 Phosphaalkene ...................................................................................................................... 6 1.3 Homogenous and Heterogenous Catalysts ......................................................................... 10 1.4 Phosphorus Ligands in Catalysis .......................................................................................... 14 1.5 Polymer-Supported Catalysis .............................................................................................. 16 1.5.1 Separation Techniques for Soluble Polymer-Supports .................................................... 18 1.5.2 Soluble Polymer-Supports with Phosphines .................................................................... 19 1.6 Outline of Thesis .................................................................................................................. 22 Chapter 2: Gold(I) Intermolecular Hydroaminations of Alkynes with Arylamines Utilizing PMP(AuCl)-co-PS ................................................................................................................. 23 2.1 Introduction to Gold Catalysis ............................................................................................. 23 2.2 Results and Discussion ........................................................................................................ 25 2.2.1 Preparation of Pre-catalysts Ph3PAuCl and MesP(AuCl)CHPh2 2-[Au] ......................... 26 2.2.2 Preparation of PMP(AuCl)-co-PS (1-[Au]) ..................................................................... 26 2.3 Selectivity of 1-[Au] and 2-[Au] in the Hydroamination of Alkynes with Arylamines ......... 30 2.3.1 Regioselectivity of Hydroaminations of Phenylacetylene with Arylamines ................. 31 2.3.2 Hydroaminations of Diphenylacetylene with Arylamines ............................................ 36 2.4 Methods to Determine Catalyst Activity ............................................................................. 40 2.4.1 Product Yield Calculation .............................................................................................. 41 vii 2.5 Yield of Hydroaminations with Pre-catalysts 1-[Au], 2-[Au], and Ph3PAuCl at 100 °C........ 44 2.5.1 Role of Silver Triflate .................................................................................................... 44 2.5.2 Yields of the Hydroaminations of Phenylacetylene ..................................................... 45 2.5.3 Product Recovery of 3a and Isolated Yield ................................................................... 47 2.5.4 Yields of the Hydroaminations of Diphenylacetylene .................................................. 49 2.6 Recycling Studies of PMP(AuCl)-co-PS ................................................................................ 51 2.7 Summary ............................................................................................................................. 58 Chapter 3: Conclusions and Future Work ............................................................................. 59 3.1 Conclusion ........................................................................................................................... 59 3.2 Future Work ........................................................................................................................ 60 Chapter 4: Experimental Section .......................................................................................... 62 4.1 Materials and general procedure ........................................................................................ 62 4.2 Preparation of poly(methylenephosphine)-co-styrene polymer PMP-co-PS ..................... 63 4.3 Preparation of Gold(I) Pre-catalysts .................................................................................... 63 4.4 Hydroamination Reaction Procedure via PMP(AuCl)-co-PS ................................................ 64 4.5 Recovery of PMP-co-PS Gold(I) Catalyst ............................................................................. 66 References .......................................................................................................................... 67 Appendices ......................................................................................................................... 85 Appendix A ................................................................................................................................ 85 Appendix B ................................................................................................................................ 94 viii List of Tables Table 1.1 Transition metals applied in organic synthesis featuring phosphorus ligands………….15 Table 1.2 Suzuki Miyaura cross-coupling reactions using 1.15 and homopolymer………………....21 Table 2.1 1H NMR signals of the product(s) formed from the hydroamination of phenylacetylene with arylamines………………………………………………………………………………………………………………………35 Table 2.2 1H NMR signals of the product(s) formed from the hydroamination of diphenylacetylene with arylamines………………………………………………………………………………………..39 Table 2.3 Hydroamination yields of phenylacetylene with arylamines………………………………..….44 Table 2.4 Hydroamination yields of diphenylacetylene with arylamines………………………………...47 ix List of Figures Figure 1.1 Chemical structures of the natural polymers chitin and DNA……..……………………..…....1 Figure 1.2 Cross-linking of polyisoprene by addition of sulfur…………………………………………………..2 Figure 1.3 Common organic polymers with listed global production by tons in 2012…………...….3 Figure 1.4 Polyphosphazene examples in therapeutic applications……………………………...….…..….6 Figure 1.5 Compounds containing P-C multiple bonds……………………………………………………….…....7 Figure 1.6 Polymerization of the C=C and P=C bond…………………………………………………………..…….9 Figure 1.7 Haber-Bosch process schematic of the condensation of ammonia……………………......11 Figure 1.8 Water-soluble rhodium catalysts for hydroformylation……………………………………...….13 Figure 1.9 Dialkylbiaryl phosphine ligands………………………………………………………………………………16 Figure 1.10 Recovery methods of polymer-supports……………………………………………………….….....18 Figure 1.11 Random copolymer of phosphaalkene and styrene………………………………………….….21 Figure 2.1 General Catalytic Cycle of Gold(I) Catalyzed Addition of Nucleophiles (NuH) across the CC Bond of Alkynes…………………………………………………………………………………………………….…….....24 Figure 2.2 Gold(I) pre-catalysts used in this work……………………………………………………………….…..25 Figure 2.3 a) 31P{1H} NMR spectrum (162 MHz, C7D8, 298 K) of 1.15 PMP-co-PS. b) 31P{1H} NMR spectrum (162 MHz, C7D8, 298 K) of 1-[Au]…………………………………………………………………………....28 Figure 2.4 13C Inverse-Gated NMR spectrum (100.6 MHz, CDCl3, 298 K) of PMP-co-PS 1.15......29 Figure 2.5 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination reaction of phenylacetylene and 2,4,6-trimethylaniline utilizing 2-[Au] as pre-catalyst……………………….……32 Figure 2.6 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination of phenylacetylene with arylamines utilizing 1-[Au] at 24 h…….……………………………………………………………………….……34 Figure 2.7 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination reaction of diphenylacetylene with aniline using 2-[Au] as pre-catalyst………………………………………….………..37 Figure 2.8 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination of phenylacetylene with arylamines utilizing 1-[Au] at 24 h………………………………….……………………….…………….….…….38 x Figure 2.9 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination of phenylacetylene and 2,4,6-trimethylaniline using the polymer-supported pre-catalyst 1-[Au] ……………………..….43 Figure 2.10 1H NMR (400 MHz, C7D8, 298 K) spectrum of the isolated products……………..…......46 Figure 2.11 Yield of the hydroamination product with the polymer-supported catalyst, 100% Au(I) coordination (5% mol Au(I)) after 5 successive cycles……………………………………..……..………49 Figure 2.12 Gold mirror formation on NMR tube walls after 24 h of reaction time with 100% Au(I) coordination to PMP-co-PS (1-[Au])……………………………………………………………………...….……50 Figure 2.13 31P{1H} NMR spectrum (162 MHz, C7D8, 298 K) of 1-[Au]-50…………………………..…….51 Figure 2.14 Yield of the hydroamination product with polymer-supported catalyst 1-[Au]-50 (5% mol Au(I)) after 5 successive runs……………………………………………………………………………………………52 Figure 2.15 Absence of gold mirror after 24 h of reaction time with 1-[Au]-50……………………….53 Figure 2.16 Yield of the hydroamination product 3a with polymer-supported catalyst 1-[Au]-20 (5% mol Au(I)) after 5 successive runs………………………………...……………………………..………..………..54 xi List of Schemes Scheme 1.1 Synthesis routes of polysiloxanes………………………………………………………………………….4 Scheme 1.2 Synthesis routes of polyphosphazenes………………………………………………………………….5 Scheme 1.3 Polymerization of cyclic thionylphosphazenes.……………………………………………………..6 Scheme 1.4 Polymerization of phosphaalkene 1.7a………………………………………………………………….9 Scheme 1.5 Functionalizations of the phosphorus moiety of poly(methylene)phosphine………10 Scheme 1.6 Synthesis of a phosphine-containing polymer from monomers 4-styryldiphenylphosphine and styrene…………………………………………………………………………………….20 Scheme 1.7 Suzuki-Miyaura cross-coupling reaction using polymer-support 1.15………………….21 Scheme 2.1 a) Radical polymerization of PMP and styrene and b) metallation of PMP-co-PS with (tht)AuCl……………………………………………………………………………………………………………………………..…27 Scheme 2.2 Hydroamination reaction of phenylacetylene with arylamines using gold(I) pre-catalyst………………………………………………………………………………….……….…………………..…….…...……..31 Scheme 2.3 The intermolecular hydroamination of diphenylacetylene with arylamines….…....36 Scheme 3.1 Hydroamination of alkynes with arylamines employing 1-[Au]……………….….…....…59 xii List of Equations Equation 2.1 Incorporation of PMP units in copolymer 1.15…………………………………………………..29 Equation 2.2 Determining mol of methylene phosphine present in copolymer 1.15……...………30 Equation 2.3 Calculation of mmol of product formed by use of internal standard 1,3-dimethoxybenzene…………………………………………………………………………………………………………………41 Equation 2.4 Determining product yield (%)……………………………………………….……………………...….41 Equation 2.5 Product yield from direct comparison of integrals……………………….....……….……….41 xiii Acknowledgements I appreciate the opportunity I have had to be a part of the UBC chemistry department where I had the chance to meet many incredible people. I would like to thank my supervisor Derek P. Gates for all his help during my studies and his guidance on my research that has allowed me to become a better chemist. I would like to thank all the current and former group members, Dr. Zeyu Han, Henry Walsgrove, Jeffrey Suen, Tian Zhang, Rebecca Yu, Tanvi Garg, Paul Heine, Dr. Ming Li, Aaron, and Zhaoxiang. who have extended their support and expertise during my time here. Special thanks Jeffrey Suen for his thoughts and feedback on my project and Dr. Zeyu Han for mentoring me during my start in the group. For my family and friends I want to thank you for your continuous support during my studies. As for my past mentors Coach Murray, Mr. Doherty, and Dr. Patterson I want to thank you for always pushing me to improve multiple facets of myself and helping me find the confidence to seek out challenges and new experiences. 1 Chapter 1: Introduction A brief history of polymers and phosphaalkenes are discussed in sections 1.1, 1.2 and 1.3 to put the development of a phosphorus-containing polymer into context. To substantiate the appeal of applying a phosphorus-containing polymer support in catalysis, a brief overview of homogeneous catalysis and past developments of phosphorus ligands and polymer-supports are outlined in sections 1.4, 1.5, and 1.6. 1.1 Polymers Polymers are of great significance in our world encompassing a variety of compounds from natural origin such as DNA, chitin, and cellulose to those of synthetic origin such as polystyrene, nylon, and silicone (see Figure 1.1). Before the mechanism and chemical structures of polymers were fully understood they were ubiquitous in the development of human technology. Early uses of natural polymers involved incorporating fibrous materials such as wool, hemp, and silk for textiles.1 Figure 1.1 Chemical structures of the natural polymers chitin and DNA. DNA Chitin 2 The first processed polymer commercially produced was from natural rubber. Natural rubber is comprised of cis-polyisoprene and occurs as a soft and non-conformative material lacking the hardness required for any applicable use. While there were a few uses for natural rubber (e.g., pencil eraser), it was not until Goodyear’s patent on the vulcanization of rubber in 1839 where this polymer realized its economic potential. In Goodyear’s patent, small amounts of sulfur (S8) were added to raw rubber resulting in a tougher and more durable material.2 The sulfur functions as a cross-linking agent in a process called “vulcanization” where covalent bonds are formed between the polyisoprene chains (Figure 1.2). The “vulcanization” process results in rubber that is more rigid and elastomeric than its uncross-linked precursor. cis-polyisoprene Figure 1.2 Cross-linking of polyisoprene by addition of sulfur. The first plastic made entirely from synthetic material was developed by Baekeland in 1907.3 The condensation of formaldehyde and phenol resulted in a rigid thermosetting material. Although combination of these two components was known to form an unusable solid, by controlling the pressure and temperature during condensation Baekeland could produce a moldable resin for commercial use. This useful plastic became known as Bakelite.4 Bakelite quickly found application in the insulation of electronics and other household items that required a material with insulating and fire-resistant properties. While plastics were becoming of significant economic interest, the structure of these materials were not understood until the work of Staudinger. Staudinger first proposed the idea of macromolecules in 1920, theorizing that compounds of high molecular weights exist during his work on cellulose and rubber.5 Previously, it was accepted that high molecular weight molecules consisted of aggregates that resulted in the enhanced material properties. The masses 3 of the single molecule components in the aggregates were suggested to not exceed 5,000 g mol-1.6 Staudinger’s ideas would be contested and not accepted till many years later. For his contribution to polymer science Staudinger was awarded with the Nobel Prize in chemistry in 1953. The present-day use of polymers is extensive, being heavily integrated in consumer goods, industry, and infrastructure. Of these polymers, polyethylene sees the highest production at 85 106 tons in 2012.7 Other polymers such as polypropylene (PP), polyvinylchloride (PVC), and polystyrene (PS) are also produced in significant quantities (Figure 1.3). These polymers can be found in thin films, food packaging, piping, and insulation. The high output of organic polymers can be attributed to the ample availability of the precursors and established manufacturing processes. There are limitations to broader use as many lack modifying groups or possess undesirable properties such as low thermal stability. Polymer Type Global Production in 2012 (tons) PE: HDPE, LDPE, HHDPE 85x106 Polypropylene 54x106 Polyvinylchloride 31x106 Polystyrene 21x106 Figure 1.3 Common organic polymers with listed global production by tons in 2012.7 4 1.1.1 Inorganic Polymers Inorganic polymers, which feature main group elements such as silicon, phosphorus, and related p-block elements in their backbones, offer unique chemical functionality and may possess advantageous properties such as high thermal stability. One notable class of inorganic polymers are polysiloxanes which feature alternating silicon and oxygen atoms in the backbone. The most common polysiloxane is polydimethylsiloxane (PDMS) which is produced for uses such as waterproof sealings and bakeware. The conventional route to obtain PDMS is achieved through the hydrolysis and subsequent polycondensation of dimethyldichlorosilane (Scheme 1.1, a)).8 Ring-opening polymerization (ROP) of cyclic siloxanes is another important route of synthesis as molecular weights and dispersity are more readily controlled in this method.9 An example includes the ROP of hexavinyltrisiloxane catalyzed by dilithio diphenylsilanediolate which affords a poly(divinylsiloxane) (Scheme 1.1, b)).10 Additionally, the anionic ROP of siloxanes has been applied to create macromolecules with interesting morphologies such as star-branched and comb-branched polysiloxanes.11 Siloxane copolymers have been developed as well, such as copoly[1,8-(4,5-dimethylanthraquinonylene)/3,3,5,5-tetramethyl-4-oxa-3,5-disila-1,7-heptanylene] which feature molecular weights up to 60000 g mol-1 and a Tg of 196 °C.12 a) b) ROP of poly(divinyltrisiloxane) Scheme 1.1 Synthesis routes of polysiloxanes. 5 Another well studied class of inorganic polymers are polyphosphazenes, which feature backbones consisting of alternating phosphorus and nitrogen atoms. These polymers can be applied as flame retardants,13 drug delivery systems,14 or cell scaffoldings15. Polyphosphazenes can be prepared from heating hexachlorocyclotriphosphazene (Scheme 1.2, a)).16 A unique route to obtain polyphosphazenes was reported in 2006 by Manners and co-workers with the polymerization of alkyl polyphosphazenes from phosphoranimines at ambient temperature.17 Treatment of phosphoranimines with phosphites yielded polymethylphenylphosphazene with reported molecular weights greater than 400 000 g mol-1 (Scheme 1.2, b)). a) b) Scheme 1.2 Synthesis routes of polyphosphazenes. Modification of the side groups on polyphosphazenes can result in unique properties and applications. The development of polyphosphazenes modified with trifluoroethoxy groups (R=OCH2CF3) 1.1 (Figure 1.4) have been applied as coatings on medical implants to reduce the immune system’s elicited response to the devices.18 Stents coated with 1.1 displayed improved interfacing with cell tissues as a result of the negative surface charge imparted by the trifluoroethoxy groups. Another unique modification of polyphosphazene was reported by Allcock and co-workers where a polyphosphazene was functionalized with p-methyl phenoxy and ethyl glycinato groups 1.2 (Figure 1.4).19 The resultant polymer could be applied as scaffoldings in bone tissue engineering. 6 1.1 1.2 Figure 1.4 Polyphosphazene examples in therapeutic applications. Similar to polyphosphazenes are poly(thionylphosphazenes) whose ROP was first reported by Manners and Liang in 1991.20 Thermolysis of cyclic thionylphosphazenes at 165 °C afforded the polymer 1.3 (Scheme 1.3). The chloro substituents can be readily replaced with a variety of nucleophiles to functionalize 1.3 and fine tune its properties. Reacting 1.3 with Na[OCH2CF3] and substitution with BuNH2 resulted in fluoroalkoxy-substituted polyphosphazenes.21 These polymers possessed molecular weights of 33 000 g mol-1 or greater and Tg’s at -14 °C or lower. 1.3 Scheme 1.3 Polymerization of cyclic thionylphosphazenes. 1.2 Phosphaalkene The formation of stable multiple bonds with heavier elements was considered improbable until the latter part of the 20th century. This belief was held as the classical “double bond rule” excluded the formation of π-bonds that feature elements having a valence principal quantum number of 3 or greater due to repulsion forces.22 One class of compounds that helped refute the “double bond rule” were compounds that featured P=C bonds, most notably phosphaalkenes. The first development of a compound featuring a P-C multiple bond were the phosphamethinine 7 cyanine cations 1.4 (Figure 1.5) reported by Dimroth and Hoffmann in 1964.23 Shortly afterwards, Märkl discovered the synthesis phosphinines 1.5 in 1966.24 Although instrumental in proving the ability of phosphorus to form multiple bonds with other elements, these compounds only featured delocalized P=C bonds. The first localized P=C bond was developed by Becker in 1976.25 Condensation of bis(trimethylsilyl)phosphine with pivaloyl chloride resulted in an acylphosphine which undergoes a 1,3-silatropic rearrangement to the phosphaalkene 1.6 (Figure 1.5). The steric contributions from t-butyl and the siloxy group stabilizes the P=C bond. In 1978, Bickelhaupt and co-workers reported the first phosphaalkene without any heteroatom substituents 1.7a prepared via a base-induced 1,2-elimination.26 Alternative routes of synthesis for phosphaalkenes have been developed since then. One common route to obtain phosphaalkenes is the base-catalyzed phospha-Peterson reaction of di-silylated organophosphines and ketones. This route has been utilized to synthesize phosphaalkenes 1.7a-1.7e in our group.27 Other routes that can be utilized to develop phosphaalkenes are the phospha-Wittig reaction,28 double bond migration,29 and phosphinidene transfer via metal complexes30. Figure 1.5 Compounds containing P-C multiple bonds. A significant component of organic chemistry is the transformations of olefins into functional compounds, polymers, etc. through reactivity of the C=C bond. Analogous to the C=C bond of olefins is the P=C bond of phosphaalkenes. The π-bond of C=C and P=C are noted to be 1.4 1.5 1.6 8 isolobal with the length and polarity of the bonds being similar.31 Thermodynamically, the π-bond energy of P=C is weaker than C=C with bond energies of 43 kcal mol-1 and 65 kcal mol-1 respectively suggesting the tendency of phosphaalkenes to react through this bond.32 This similarity can also be evidenced by NMR studies showing that the tensor elements of the π-bonds are proportional in phosphaalkenes and alkenes.33 Additionally, cyclic phosphaalkenes such as phosphinine and the phospholide anion are noted for sharing similar aromaticity as their carbon counterparts (i.e., benzene and cyclopentadienyl anion).34,35 This observed analogy of P=C and C=C bonds contrasts the expected analogy P=C and N=C bonds which are not isolobal.36 The aforementioned parallel of phosphaalkenes and alkenes through their π-bond is illustrated by the similar reactions displayed by both species (e.g., 1,2-Addition,37 Diels-Alder,38 [2+4]-Cycloadditions,39 and coordination to metal centers40). Significantly, similar to alkenes, phosphaalkenes may be polymerized (Figure 1.6). For the phosphaalkene 1.7a polymerization can be achieved through an anionic or radical mechanism (Scheme 1.4).41 The obtained polymer, poly(methylenephosphine) (PMP), was suggested to be formed from the 1,2-addition of 1.7a to give the structure 1.8. However, the microstructure was revised as addition can occur through a second mechanism beside 1,2-addition. The activation of the methyl group in the ortho-position of mesitylene can occur resulting in a polymer with the structure in 1.9.37 Aside from the homopolymer, copolymers from phosphaalkene 1.7a have been synthesized through radical42 or anionic initiation41b. Block copolymers have been synthesized with styrene,44 isoprene,43 and methyl methacrylate44. 9 Figure 1.6 Polymerization of the C=C and P=C bond. Scheme 1.4 Polymerization of phosphaalkene 1.7a. The unmodified poly(methylenephosphine) is relatively stable but will form the phosphine oxide over time when exposed to air, especially in solution. Controlled functionalization at the phosphorus in the polymer has been reported. Quantitative addition of H2O2 1.10 or S8 1.11 (Scheme 1.5) to PMP results in air- and moisture-stable variants of the polymer.41a Reacting PMP with Me2S·BH3 forms polymer 1.12 which features borane-phosphine adducts imparting air- and moisture-stabiltiy.45 The addition of borane is a reversible process with the addition of diethylamine to remove BH3. Functionalization of the homopolymer and copolymer with coordination to metal centers have also been conducted (1.13). Addition of Pd2(dba)3 to 1.9 and a random copolymer of 1.7a and styrene results in a catalytic species that can be applied in Suzuki couplings.42 Coordination of AuCl to a block copolymer of isoprene and 10 phosphaalkene (PI-b-PMP) has also be achieved resulting in a polymer that, in a block-selective solvent, self-assembles into micellular nanostructures with tunable shapes defined by the relative block lengths.43 Scheme 1.5 Functionalization of the phosphorus moiety of poly(methylene)phosphine. 1.3 Homogenous and Heterogenous Catalysts The chemical sector is the largest consumer of oil and gas, requiring the energy produced as feedstock for chemical production.46 With the target of net-zero emissions by 2050 set under the Paris Agreement, multiple chemical firms have set goals to cut their emissions by then.47 Meeting these goals requires improving atom economy and reducing the energy consumption of synthetic transformations. The development of efficient catalytic transformations has played a key role for the chemical industry in addressing these needs. Namely, an estimated 95% of chemicals are synthesized with the aid of catalysts.48 As a facet of green chemistry, catalysts eliminate the need of additional reagents and minimize waste byproducts.49 While they improve the efficiency of chemical synthesis, it is also desirable that the catalysts themselves are sustainable and non-toxic. However, important questions remain to be answered when 11 developing greener catalysts. Does the catalyst provide the desired product in high selectivity and yield with minimal waste? Can the catalyst be recovered and recycled? Can cheap and readily available base metals be used in catalysts rather than traditional precious metals that require more resources to isolate? These are just a few challenges the work in this thesis seeks to address. Traditionally the field of catalysis is divided into two categories: heterogeneous and homogeneous catalysis. Heterogeneous catalysis is defined as a process where the active catalyst is in a different than the substrates and/or products (typically: solid-gas or solid-liquid). Such systems are noted for the easy recovery and recyclability of the catalyst and are favored in industrial settings with 80% of chemical products being prepared using heterogeneous catalytic processes.50 Application of heterogeneous catalysts in industrial processes commonly entails an immobilized solid state-catalyst where the substrates are flowed over in either the gaseous or liquid phase. An example of this is the Haber-Bosch process where gaseous N2 and H2 are flowed over a solid iron catalyst to synthesize ammonia (Figure 1.7).51 This type of system can be used for multiple cycles before the catalyst loses significant activity. However, some issues are present in heterogeneous catalysis such as difficulty in controlling the selectivity of the products as well as diminished activity compared to homogeneous systems. Figure 1.7 Haber-Bosch process schematic of the condensation of ammonia. 12 In homogeneous systems the catalyst and substrates/products occupy the same phase. The dissolution of the catalyst improves contact with the substrates and permits ready access to the active site of the catalyst. Typically, this results in higher activity compared to analogous heterogeneous processes. In addition to higher activity, homogeneous catalysts tend to be more selective, and the mechanism is easier to study as the active sites are more well defined. However, drawbacks such as difficulty to separate small molecule catalysts from the reaction media limit broader use. To correct this issue, the use of polymer supports,53 multiphase systems,54 or magnetic nanocatalysts55 have been studied. Although not used as frequently in industry compared to heterogeneous systems, significant examples exist such as the Ruhrchemie/Rhone-Poulenc process which utilizes a water-soluble rhodium catalyst in hydroformylation of propene (Figure 1.8).56,57,58 13 L= Figure 1.8 Water-soluble rhodium catalysts for hydroformylation. 14 1.4 Phosphorus Ligands in Catalysis Tuning the capabilities of transition metal complexes in homogenous catalysis requires careful thought in ligand selection. The selectivity, activity, and stability of the complex can be altered significantly depending on the ligands applied. One class of ligands whose use is ubiquitous in homogenous catalysis are tertiary phosphines. The viability of these ligands have been displayed in significant examples such as the hydrogenation of alkenes with Wilkinson’s catalyst59 and olefin metathesis with Grubbs 1st generation catalyst.60,61 The appeal of phosphorus ligands is their ability to stabilize late period transition metals particularly well. This is a result of the strong σ-donor properties of trivalent phosphorus leading to the formation of dative bonds to the metal.62 The stability of these organophosphorus complexes can further be explained by hard and soft acid base theory. Tertiary phosphines are classified as soft bases and the metals they are often coordinated to such as rhodium(I), palladium(II), and gold(I) exist as soft acids.62 While adding stability in organometallic complexes, phosphorus ligands beneficially function as spectator ligands. The capability of tertiary phosphorus ligands in catalytic applications was first demonstrated by Reppe and Schweckendiek in 1948 in the aromatization of acetylene using nickel phosphine complexes.63 Since then a vast library of phosphines in organo-metallic catalysis have been developed. Phosphorus ligands are versatile being applied in processes such as palladium-catalyzed coupling reactions,70-75 nickel catalyzed hydrocyanations,78,79 and other organic transformations (Table 1.1).64-69,76,77 15 Table 2.1 Transition metals applied in organic synthesis featuring phosphorus ligands. Metal Reaction Ligand Rhodium(I) Asymmetric Hydrogenation CAMP64, BINAP65, DIPAMP66 Hydroformylation DIOP67, P(OR)3 (union carbide)68, BISBI69 Palladium(II) Suzuki-Miyaura PPh370, JohnPhos71 Buchwald-Hartwig RuPhos72, BrettPhos72 Negishi Cross-Coupling PPh373, SPhos74, P(2-furyl)375 Gold(I) [4+2] Cycloaddition XPhos76 Hydroazidation WangPhos77 Nickel(I) Hydrocyanation Thixantphos78, Xantphos78, P(OR)379 The functionality of phosphine ligands can be estimated by two parameters: the steric contributions and electronic properties. The steric contributions of the phosphine ligand are determined by its cone angle80 or its solid cone angle81. These measurements describe the size and orientation of the attached groups on the phosphine which can elucidate the imparted selectivity or activity to the active catalyst site at the metal center. The electronic properties refer to the σ-donor and π-accepting capabilities of the ligand. Electron donating substituents such as cyclohexyl or t-butyl increase the σ-donor capabilities, and electron withdrawing substituents such as halides result in greater π-acceptor ability.80,82,83 The electronic properties of the ligand can be determined experimentally through IR84 and NMR85,86 spectroscopies. In addition, theoretical methods such as DFT87 is also used to calculate this parameter. The impact of the electronic properties of the ligand towards the catalyst requires consideration of the transition metal applied and the steps involved in the catalytic cycle. While the two parameters can be measured separately, a change to one will often alter the other. In aryl phosphines, 16 functionalization of aryl substituents with charged or electron withdrawing groups results in large variations of the cone angle.88,89 Triphenylphosphine (PPh3) is a frequently applied phosphine ligand in homogenous catalysis being featured in the development of important reactions such as Suzuki-Miyaura70 and Negishi cross-coupling73. However, PPh3 is not suitable in all applications78,90 and more capable phosphorus ligands have been discovered. Bidentate phosphines, phosphites, and dialkylbiraryl phosphines ligands are some notable classes of P-ligands that have been developed and utilized in homogeneous catalysis. The steric bulk and electron rich nature of dialkylbiaryl phosphine ligands have made them popular in the use of Pd-catalyzed C-N and C-C bond forming cross-coupling reactions. Significant examples, such as BrettPhos and RuPhos (Figure 1.9), are useful in Buchwald-Hartwig aminations to form primary and secondary amines.72,91,92 Fine-tuning the selectivity of catalyst in the applied reactions can be achieved by altering the steric demands of the ligands.93 Figure 1.9 Dialkylbiaryl phosphine ligands. 1.5 Polymer-Supported Catalysis The first application of a polymer-support was described by Merrifield in 1959 in the use of polystyrene cross-linked with divinyl benzene for peptide synthesis.94 The insoluble polymer-support provided as a method to extract growing peptides. Not long after, the use of insoluble polymers were extended as supports for transition metal catalysts as a method of “heterogenizing” homogeneous systems. 17 The recovery of catalysts, especially those containing transition metals, is of importance due to the high cost or inherent toxicity of these complexes.95 However, in homogeneous systems the removal or recovery of small molecule catalysts can prove to be challenging. Separation techniques such as distillation or chromatography often leads to the degradation or poor recovery of the catalyst,95 and thus limits their use in more practical settings. Attaching metal centers to a polymeric ligand via coordinate covalent bonds can facilitate simple and less destructive procedures to recover the catalyst. Aside from recovery, polymer-supports can enhance stability compared to their unsupported counterparts such as aluminum chloride96 and rhodium phosphine complexes97. While the use of insoluble polymer-supports are of interest in supported catalysis, such systems bear disadvantages associated with heterogeneous catalysts e.g. reduced activity compared to homogeneous catalysts and difficulty to characterize the active site.98,99 Soluble polymer-supports, also termed as liquid phase synthesis,100 are the alternative which can be applied for the recovery of the catalyst. The use of soluble polymer-supports in the synthesis of peptides was first described by Bayer and Mutter with the use of polyethylene glycol (PEG) and non-cross-linked polystyrene supports (NCPS) which could recover growing peptide chains more effectively compared to Merrifield’s insoluble supports.100 The development of soluble polymer-supports were further expanded with functionalization of PEG supports101,102 or use of new polymers such as poly(vinyl alcohol) (PVOH)103 and polyacrylamide (PAM)104. Outside of peptide and nucleotide synthesis, the application of soluble supports has been extended to organic synthesis.105,106 In several examples the polymeric catalysts exhibit equivalent or improved activity over the unsupported catalyst while retaining high selectivity.107,108,109 18 1.5.1 Separation Techniques for Soluble Polymer-Supports Figure 1.10 Recovery methods of polymer-supports. Separation of soluble polymer-supports in liquid phase systems was first demonstrated by Bayer through ultrafiltration, which applies a pressure gradient to pass only the products through a membrane.100 Ultrafiltration is still an applicable technique in the recovery of polymer-supports, however, uncoiling of linear polymers can result in the loss of catalyst.110 Efficient recovery of supports through liquid-liquid and solid-liquid separations of polymer-supports have been outlined (Figure 1.10). Liquid-liquid separations involve the use of multiphase systems where phase selectivity of the support may be controlled, this being achieved through either thermoregulated or latent (miscibility upon perturbation) means.111 In thermoregulated separations, miscibility of the support from an aqueous phase into the substrate phase occurs when the system is heated past the polymer’s lower critical solution temperature (LCST).112 Upon cooling below the LCST, the support is expelled to the aqueous phase allowing for the recovery of the catalyst. One such example has been demonstrated by Jin and coworkers in the hydroformylation of 1-decene.113 19 Rhodium/phosphine complexes bound to poly(ethylene oxide) supports were developed featuring cloud points (Cp) ranging from 51-68 °C. Heating the system above the Cp resulted in the catalyst entering the organic phase where hydroformylation proceeded. The process was reversible when the support was cooled to below the Cp. In solid-liquid separations the polymer-support is precipitated out of the solution allowing for the facile recovery of the catalyst. Precipitation of the support can be achieved through thermoregulated means or through the addition of a co-solvent. For polystyrene (PS) supports, the appreciable solubility of PS in organic solvents such as DMF, DCM, toluene, THF and insolubility in hexane, water, or methanol allow for efficient solvent-precipitations. This method may be conducted in air though this carries the risk of catalyst poisoning in air-sensitive systems resulting in diminished recyclability.114,115 1.5.2 Soluble Polymer-Supports with Phosphines Functionalization of polymer-supports with phosphines allow for the anchoring of homogeneous catalysts to promote their recovery. Examples such as PEG functionalized with diphenylphosphine have been applied as catalyst supports for hydrogenation,116,117 hydroformylation,118 diene dimerization,119 and Sonogashira couplings120. In the PEG-supports, functionalization of the hydroxyl end groups with phosphines is applied at one or both termini. Because only the end groups of can support the phosphine, the loading capacity of phosphine compared to the mass of the polymer-support can be low. Use of polymeric carriers featuring multiple sites to support phosphines allow for higher loading capacities such as PS121,122,123,124 or PAM.125 By increasing the number of phosphine ligands as pendant groups in such systems the catalytic activity is akin to that of analogous low molecular weight counterparts.126 Polymer-supports containing phosphines are derived from functionalization of a polymer post-polymerization or from the polymerization of monomers incorporated with phosphine moieties. An example of the latter approach was demonstrated by the Toy group in the synthesis of a copolymer support from a phosphine-containing monomer and styrene via radical initiator.122 Polymerization of 4-styryldiphenylphosphine and styrene in a 1:4.02 mol ratio 20 afforded the polymer 1.14 with an incorporation of 1:3.4 of the monomers respectively (Scheme 1.6). The polymer 1.14 was applied as a reagent in Mitsunobu reactions where, upon completion, the polymer could be separated from the products through precipitation and filtration. Scheme 1.6 Synthesis of a phosphine-containing polymer from monomers 4-styryldiphenylphosphine and styrene. Uniquely, examples of polymers with phosphines incorporated in the backbone have been developed as supports in catalysis. A homogeneous example of a phosphine polymer-supported palladium catalyst used for Suzuki-Miyaura couplings was shown by our group.127 Homopolymer 1.9 of phosphaalkene 1.7a and a random copolymer 1.15 (Figure 1.11) of 1.7a and styrene were prepared with radical initiator VAZO 88 (1% mol). For the copolymer the phosphaalkene was incorporated in a 1:10.1 ratio to styrene. The polymers 1.9 and 1.15 were then applied as supports in the Suzuki-Miyaura cross-coupling of bromobenzene (1 equiv) and phenylboronic acid (1.5 equiv) with Pd2(dba)3 (5% mol) and CsF as base (Scheme 1.7). Pd complexing to the supports was evidenced through 31P NMR spectroscopy though the exact structure of the immobilized catalyst could not be detailed. The copolymer support exhibited superior activity to the homopolymer, with a 62% yield of biphenyl compared to a 23% yield with the homopolymer (Table 1.2). The increased spacing between the phosphines was the suspected reason for the improvement in yield. The effect on yield by increasing the site separation between phosphines has been noted before in polymer-supported catalysts.128,139,130 The palladium supported by copolymer 1.15 was active at a higher temperature of 80 °C with the 21 optimal phosphine to Pd loading at 2.8:1. The support could then be separated from the product through precipitation with the addition of hexanes. 1.15 Figure 1.11 Random copolymer of phosphaalkene and styrene. Scheme 1.7 Suzuki-Miyaura cross-coupling reaction using polymer-support 1.15. Table 1.2 Suzuki Miyaura cross-coupling reactions using 1.15 and homopolymer. Entry Ligand Phosphorus/Pd T(°C) Yield(%) 1 Homopolymer 2.0:1 25 23 2 1.15 1.4:1 25 62 3 1.15 1.4:1 80 83 4 1.15 2.8:1 80 90 5 none N/A 25 22 6 PPh3 1.0:1 25 30 22 1.6 Outline of Thesis As described in the previous sections, the use of polymer-supports in homogeneous catalysis have proven to be an effective strategy in the recovery of catalysts from reaction media. These polymers require the incorporation of functional groups into the polymeric structure in order to coordinate to the metal which is often very difficult to achieve synthetically. Our group has previously synthesized the phosphorus-containing polymer PMP-co-PS as a support for palladium which was applied in Suzuki-Miyaura cross-coupling reactions. This thesis seeks to further explore the use of PMP-co-PS in polymer-supported homogeneous catalysis. Herein the application of PMP-co-PS as a polymer-support for gold(I)-catalyzed hydroaminations is reported. The synthesis of the pre-catalyst PMP(AuCl)-co-PS and analogous pre-catalysts [i.e., Ph3PAuCl and MesP(AuCl)CHPh2] is described at the start of Chapter 2. After which the selectivity of PMP(AuCl)-co-PS and MesP(AuCl)CHPh2 is examined. Subsequently, the intermolecular hydroamination of alkynes (i.e., PhC≡CH and PhC≡CPh) and substituted anilines (H2NAr, Ar = Aryl) conducted at 100 °C employing the three pre-catalysts (5% mol) are discussed with comparisons made on their activity. In the latter portion of Chapter 2, the recyclability of the polymer-supported catalyst was assessed where the support was recovered and applied in multiple cycles without the addition of fresh catalyst or co-catalyst AgOTf. 23 Chapter 2: Gold(I) Intermolecular Hydroaminations of Alkynes with Arylamines Utilizing PMP(AuCl)-co-PS 2.1 Introduction to Gold Catalysis Gold complexes are known to be effective transition metal catalysts for many synthetic transformations. Initially believed to be catalytically inert,131 the use of gold(I) and gold(III) for homogeneous and heterogeneous catalysis have been greatly explored in the past few decades. The first significant example of the use of gold(I) in homogenous catalysis was described by Teles and co-workers in the 1,2-addition of alcohols to alkynes.132 Since then, gold catalysts have been shown to be effective in nucleophilic additions to π-systems such as addition of amines to alkynes and alkenes. The catalytic cycle of the addition of a 1° amine (nucleophile) to an alkyne is described by three main steps: alkyne coordination to cationic gold(I), addition of the amine to the π-complex, and catalyst release via protodeauration (Figure 2.1).133 The favorability of gold(I) to react with carbon-carbon multiple bonds is a result of the π-acidic nature of gold. In the step of alkyne coordination, the primary interaction is believed to occur between the dz2 orbital of gold and the π‖ parallel orbital of the alkyne, with σ donation towards the metal 2.1.134 This interaction accounts for 65% of the bond character, resulting in the electrophilic nature of the alkyne. Consequently, this allows for the favorable addition of nucleophiles to the π-bond of alkynes. The nucleophile will add trans to the metal where a bond slippage event occurs resulting in the hapticity going from ƞ2 to ƞ1 2.2. The ensuing protodeauration process has a proton displacing the gold to release the product, this step often being the rate limiting step in reactions with alkynes.133 The formed enamine product tautomerizes to the imine product frequently. 24 Figure 2.1 General catalytic cycle of gold(I) catalyzed addition of a 1° amine (RNH2) across the CC bond of alkynes. Popular ligands for gold(I) include phosphines and N-heterocyclic carbenes as they form strong bonds with the gold.133 Nevertheless, the presence of reductive substrates (e.g. alkynes) is known to cause the decay of the cationic gold complex.135 Adjustment of the electronic and steric properties of the ligand have been studied to mitigate this problem. In the hydroamination of phenylacetylene with aniline, significant catalyst deactivation was noted with the Ph3PAu+OTf- complex.135 Replacing the PPh3 ligand with bulkier, electron-donating ligands such as dialkylbiaryl phosphines were shown to mitigate catalyst deactivation and give higher conversions of product. The use of PMP-co-PS as a supporting ligand for gold(I) was reported in our group previously as a suitable support for the hydroamination of phenylacetylene and aniline in comparison to PPh3 and a monomolecular model of poly(methylene phosphine).136 The goal of 25 this project is to explore the effectiveness of this system with varying substrates as well as testing the recyclability of the system. 2.2 Results and Discussion To assess the synthetic utility of PMP-co-PS as a support for Au(I) in catalysis, the hydroamination of alkynes with arylamines employing the polymer-supported pre-catalyst were conducted. The activity of the polymer-support was compared to a model ligand of the polymeric system, and the benchmark ligand PPh3 as supports for Au(I). The addition of nitrogen groups to organic molecules such as alkynes is an important synthetic route in the development of pharmaceuticals. In the hydroamination of alkynes, Au(I) has been shown to be an effective metal for catalyzing the formation of carbon-nitrogen bonds.137 The gold(I) catalysts, which utilize phosphines as ligands, have a tolerance for a wide range of amines. With PMP-co-PS applied as a support for gold(I), the hydroamination of phenylacetylene with aniline was reported with the polymer-supported complex exhibiting higher activity than the PPh3 supported complex.136 In this thesis the polymer-supported pre-catalyst was further evaluated in the intermolecular hydroamination of alkynes with arylamines. The regioselectivity and activity of the pre-catalyst PMP(AuCl)-co-PS (1-[Au]) and model pre-catalyst MesP(AuCl)CHPh2 (2-[Au]) were examined and compared to the benchmark pre-catalyst Ph3PAuCl. Ph3PAuCl 2-[Au] MesP(AuCl)CHPh2 1-[Au] PMP(AuCl)-co-PS Figure 2.2 Gold(I) pre-catalysts used in this work. 26 2.2.1 Preparation of Pre-catalysts Ph3PAuCl and MesP(AuCl)CHPh2 2-[Au] Complexes Ph3PAuCl138 and 2-[Au]139 were prepared according to known procedures and their identities were confirmed through 31P{1H} NMR spectroscopy. Molecular model 2-[Au] provides as a comparative ligand to polymeric 1-[Au] as both possess a similar environment of the phosphine moieties. 2.2.2 Preparation of PMP(AuCl)-co-PS (1-[Au]) Preparation of the PMP(AuCl)-co-PS (1-[Au]) pre-catalyst is described as follows. PMP-co-PS was prepared from the random polymerization of the monomers MesP=CPh2 and styrene using VAZO88 as a radical initiator (Scheme 2.1, a)). MesP=CPh2 (3.163 mmol) and VAZO 88 (0.158 mmol) were successfully copolymerized as indicated by 31P{1H} NMR spectroscopy (Figure 2.3, a)). To apply the copolymer as a support for gold(I), the reaction requires stoichiometric addition of (tht)AuCl during metalation as the amount of Au(I) incorporated must be known to determine the mol% loading of Au(I) for the hydroamination reactions. The loading ratio of MesP=CPh2 to Styrene was 20:80, however the ratio of the two moieties in the resultant polymer will vary. Inverse-gated 13C NMR spectroscopy has been reported to accurately determine the incorporation of the MesP=CPh2 units in the copolymer by comparing the ratio of the integrated peaks of the aryl carbons from styrene to the methyl carbons in the mesitylene substituent (Figure 2.4).44 Equation 2.1 was applied to approximate the incorporation of the phosphaalkene units in the copolymer. This is done by comparing the ratio of the methyl carbons on the mesityl group of the phosphaalkene (IMe) to the ratio of the aryl carbons from styrene and phosphaalkene (IAr) present in the system. Using Equation 2.1 to determine monomer incorporation, it was approximated that monomer incorporation (FPA) for 1.15 was 10% incorporation of the monomer MesP=CPh2 (1 methylene phosphine unit per 9 styrene units). The determined FPA is then used to determine the mol of methylene phosphine present (nPA) in the copolymer (Equation 2.2). GPC measurements of 1.15 gave a number average molar mass (Mn) and dispersity (Đ) of: Mn= 6900 g mol-1, Đ= 1.29. 27 b) Scheme 2.1 a) Radical polymerization of PMP and styrene and b) metallation of PMP-co-PS with (tht)AuCl. To synthesize 1-[Au], PMP-co-PS 1.15 (1 equiv (Phosphorus)) and tht(AuCl) (1 equiv) were dissolved in DCM and the reaction mixture was stirred for 24 h at RT (Scheme 2.1, b)). Over this time, the color of the reaction mixture goes from a clear solution to a light purple. The polymer was precipitated by adding the solution dropwise into hexanes and the precipitate was dried in vacuo whereupon a white solid was obtained. 31P{1H} NMR spectroscopy of the polymer indicated the successful coordination of Au(I) to the phosphorus atoms with the downfield shifts of the resonances to δ = 42, 34, 23 (Figure 2.3, b)). a) (tht)AuCl RT 1.15 1-[Au]: Mn= 6900 g mol-1; ĐM= 1.203 28 a) b) Figure 2.3 a) 31P{1H} NMR spectrum (162 MHz, C7D8, 298 K) of 1.15 PMP-co-PS. b) 31P{1H} NMR spectrum (162 MHz, C7D8, 298 K) of 1-[Au]. 29 Figure 2.4 13C Inverse-Gated NMR spectrum (100.6 MHz, CDCl3, 298 K) of PMP-co-PS 1.15. *CDCl3 Equation 2.1 Incorporation of PMP units in copolymer 1.15. 𝐹𝑃𝐴 =2𝐼𝑀𝑒(𝐼𝐴𝑟 − 6𝐼𝑀𝑒) + 2𝐼𝑀𝑒 IAr = Integration of Aryl Carbons IMe = Integration of Methyl and Methylene Carbons of Mesitylene Substituent FPA = Incorporation of MesP=CPh2 Monomer in Copolymer IMe IAr 30 𝐹𝑃𝐴 =2(0.025)(0.643 − 6(0.025)) + 2(0.025) 𝐹𝑃𝐴 = 0.10 Equation 2.2 Determining mol of methylene phosphine present in copolymer 1.15. 𝑛𝑃𝐴 =𝑚𝑃 × 𝐹𝑃𝐴(𝐹𝑃𝐴 × 𝑀𝑊𝑃𝐴) × (𝐹𝑆𝑡𝑦 × 𝑀𝑊𝑆𝑡𝑦) nPA: mol phosphaalkene in copolymer mP: Mass of polymer used MWPA: molecular weight of phosphaalkene monomer MWSty: molecular weight of styrene monomer FSty: Composition of styrene in polymer (FSty = 1-FPA) 𝑛𝑃𝐴 =0.2134 × 0.09(0.09 × 316.4) × (0.91 × 104.2) 𝑛𝑃𝐴 = 1.558 × 10−4 𝑚𝑜𝑙 2.3 Selectivity of 1-[Au] and 2-[Au] in the Hydroamination of Alkynes with Arylamines For complexes 1-[Au] and 2-[Au], the pre-catalysts have only been employed in the hydroamination of phenylacetylene with aniline, both selectively forming the Markovnikov product.136 The selectivity of the two pre-catalysts were not known for the hydroamination of phenylacetylene with various arylamines nor the identity of the product formed from the hydroamination of diphenylacetylene. To identify the formed products and selectivity of 2-[Au] with the substrates applied in this study, preliminary reactions were conducted at RT with progression of the reactions tracked through 1H NMR spectroscopy. Spectra of the RT 31 hydroaminations were compared to the 1H NMR spectra obtained from the hydroaminations conducted at 100 °C utilizing 1-[Au]. Pre-catalyst 2-[Au] was employed rather than the polymer-supported pre-catalyst 1-[Au] for the RT preliminary reactions due to their ease of synthesis, analogy of the phosphine moieties, and quicker reaction times. The RT hydroamination of phenylacetylene with aniline using 1-[Au] requires extensive time to see product conversion (>25%; 192 h), with the pre-catalyst 1-[Au] optimized at 100 °C.136 2.3.1 Regioselectivity of Hydroaminations of Phenylacetylene with Arylamines Scheme 2.2 Hydroamination reaction of phenylacetylene with arylamines using gold(I) pre-catalyst. 32 In the hydroamination of phenylacetylene, the addition of the arylamine to the multiple bond can occur either in a Markovnikov 3 or anti-Markovnikov 3’ fashion (Scheme 2.2).140 Formation of the Markovnikov product 3 can be evidenced by the formation of the methyl group -CH3 resonance (ca. δ = 1.8) in a 1H NMR spectrum. Formation of the anti-Markovnikov product 3’ can be evidenced by 1H resonances associated with the methylene group -CH2- (ca. δ = 3.5) and the imine carbon -CH= (ca. δ = 7.5) in a 1H NMR spectrum. Phenylacetylene (1 equiv), arylamine (1.2 equiv), pre-catalyst (5% mol), co-catalyst AgOTf (5% mol) loading were combined in inert atmospheric conditions. Upon addition of AgOTf the mixture obtains a yellowish hue. The reaction mixture was diluted with C7D8 and transferred to a J-Young tube. No internal standard was added to the RT reactions utilizing 2-[Au] and the yields were not determined. The hydroamination reaction of phenylacetylene and 2,4,6-trimethylaniline is used as a representative reaction to show tracking the formation of the product over 96 h using 1H NMR spectroscopy (Figure 2.5). 33 Figure 2.5 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination reaction of phenylacetylene and 2,4,6-trimethylaniline utilizing 2-[Au] as pre-catalyst (crude reaction mixture). After 96 h the formation of resonances associated with the Markovnikov product (3b) were observed in the 1H NMR spectrum and agrees with the reported literature.141 Resonances of the methyl groups (f) (δ = 2.22) and (e) (δ = 1.97) in the 2,4,6-trimethylaniline moiety of 3b are evident. The resonance at δ = 1.79 is indicative of the protons of the methyl group (g). Downfield in the 1H NMR spectrum the appearance of three new resonances correlating to the 3b are observed. The singlet at δ = 6.81 is representative of the meta-protons (d) of the 2,4,6-trimethylaniline moiety of 3b. The resonances δ 7.17 and δ 7.94 correlate to the protons 34 designated as (a), (b), and (c) in the phenyl moiety of 3b. Resonances correlating to the -CH2- (ca. δ = 3.5) and -CH= (ca. δ = 7.5) groups of the anti-Markovnikov product are not present. For the remaining arylamines, the imine tautomer of the Markovnikov products was selectively formed after 96 h at RT utilizing 2-[Au]. 1H NMR spectra obtained from hydroaminations of phenylacetylene conducted at 100 °C for 24 h utilizing 1-[Au] indicate the formation of identical products (Figure 2.6). 1H NMR resonances associated with the products 3a-3e are listed in Table 2.1. 35 Figure 2.6 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination of phenylacetylene with arylamines utilizing 1-[Au] at 24 h (crude reaction mixture). For full spectra of see Appendix A. List of resonances associated with the products are listed in Table 2.1. 3: CH3 3a 3b 3c 3d 3e 3: Phortho-H 36 Table 2.1 1H NMR signals of the product(s) formed from the hydroamination of phenylacetylene with arylamines. Entry R 1H NMR Markovnikov Product Signals (ppm)a 1 Ph 3a: δ 7.90-7.94 (m, 2H, ArH), δ 7.15-7.21 (m, 5H, ArH), δ 6.91-6.96 (t, 1H, J = 7.4 Hz, ArH), δ 6.70-6.74 (d, 2H, J = 7.2, ArH), δ 1.85 (s, 3H, CH3) 2 2,4,6-Me-Ph 3b: δ 7.94-7.98 (m, 2H, ArH), δ 7.17-7.20 (m, 3H, ArH), δ 6.81 (s, 2H, ArH), δ 2.22 (s, 3H, CH3), δ 1.97 (s, 3H, CH3), δ 1.76 (s, 3H, CH3) 3 2,6-Cl-Ph 3c: δ 7.96-7.99 (m, 2H, ArH), δ 7.16-7.20 (m, 3H, ArH), δ 7.04-7.06 (d, 2H, J = 8.0 Hz, ArH), δ 6.45-6.49 (t, 1H, J = 8.1 Hz, ArH), δ 1.88 (s, 3H, CH3) 4 4-OMe-Ph 3d: δ 7.94-7.97 (m, 2H, ArH), δ 7.17-7.21 (m, 3H, ArH), δ 6.76-6.81 (d, 2H, J = 8.8 Hz, ArH), δ 6.67-6.71 (d, 2H, J = 8.8 Hz, ArH) δ 3.38 (s, 3H, OCH3), δ 1.93 (s, 3H, CH3) 5 4-NO2-Ph 3e: δ 7.86-7.91 (d, 2H, J = 8.8 Hz, ArH), δ 7.80-7.84 (m, 2H, ArH), δ 7.14-7.23 (m, 3H, ArH), δ 6.32-6.37 (d, 2H, J = 8.8 Hz, ArH), δ 1.69 (s, 3H, CH3) aIn C7D8. 2.3.2 Hydroaminations of Diphenylacetylene with Arylamines Regioselectivity of the formed products is not considered with diphenylacetylene as the alkyne is symmetrical. Preliminary reactions at RT were conducted to determine the resonances associated with the product(s) from the hydroamination of diphenylacetylene with arylamines employing 2-[Au]. In this study hydroamination of diphenylacetylene with arylamines employing the pre-catalysts yields imines 4 and/or enamines 4’ (Scheme 2.3). Diagnostic signals associated with the methylene (-CH2-) group of 4 (ca. δ = 4.0) and the amine (NH) and methine (-CH=) groups of 4’ (ca. δ = 5.5; ca. δ = 6.2) were monitored to track formation of the product(s) in the 1H NMR spectra. The hydroamination of diphenylacetylene with arylamines are typically more challenging 3 Markovnikov Product (Imine) 37 due to the increased steric contribution of the alkyne resulting in lower reaction rates.140 With 2-[Au], synthesis of the product(s) was evidenced in the 1H NMR spectra recorded over 744 h of reaction time. Scheme 2.3 The intermolecular hydroamination of diphenylacetylene with arylamine giving the imine 4 and enamine 4’ products. In the presence of the activated pre-catalyst 2-[Au], the hydroamination of diphenylacetylene with aniline forms a mixture of the imine and enamine products 4 and 4’. The resonances correlating to the enamine (δ = 5.41; NH and δ = 6.15; -CH=) and the imine: (δ = 7.97-8.00; ArH2 and δ = 3.85; -CH2-) were observed in the 1H NMR spectrum (Figure 2.7). 1H NMR spectra obtained from hydroaminations of diphenylacetylene conducted at 100 °C utilizing 1-[Au] indicate the formation of identical products (Figure 2.8). The imine tautomer 4 was exclusively formed from the arylamines 2,4,6-trimethylaniline, p-anisidine and 2,6-dichloroaniline. With 4-nitroaniline used as the arylamine only the enamine 4’ was formed. The identifiable signals of the products are listed in Table 2.2. 38 Figure 2.7 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination reaction of diphenylacetylene with aniline using 2-[Au] as pre-catalyst (crude reaction mixture). Resonances associated with the products 4a and 4a’ are labelled in the 1H NMR spectrum recorded at 744 h. *C7D8 4a’: NH 4a’: CH 4a: CH2 1: Diphenylacetylene resonances 2: Aniline resonances 1 1 2 2 2 4a: Phortho-H 39 Figure 2.8 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination of phenylacetylene with arylamines utilizing 1-[Au] at 24 h. For full spectra of see Appendix A. List of resonances associated with the products are listed in Table 2.2. 4: Ph1ortho-H 4: CH2 4’: CH 4’: NH 4a, 4a’ 4b 4c 4d 4e’ 40 Table 2.2 1H NMR signals of the product(s) formed from the hydroamination of diphenylacetylene with arylamines. Entry R 1H NMR Product Signals (ppm)a 1 Ph 4a: δ 7.98 (m, 2H, ArH), δ 6.83 (d, 2H, J = 7.2 Hz, ArH), δ 3.85 (s, 2H, CH2Ph). 4a’: δ 7.35 (m, 2H, ArH), δ 6.44 (d, 2H, ArH), δ 6.15 (s, 1H, CHPh), δ 5.41 (s, 1H, NH). Other ArH resonances of the Imine and Enamine overlap from δ 6.86 - δ 7.15. 2 2,4,6-Me-Ph 4b: δ 8.00 (m, 2H, ArH), δ 7.12 (m, 2H, ArH), δ 6.88 (t, 3H, J = 7.3 Hz, ArH), δ 6.81 (d, 2H, J = 8.0, ArH), δ 6.79 (s, 2H, ArH), δ 3.73 (s, 2H, CH2Ph), δ 2.22 (s, 3H, CH3), δ 1.98 (s, 6H, CH3) 3 2,6-Cl-Ph 4c: δ 8.0 (m, 2H, ArH), δ 6.90-7.08 (m, 12H, ArH), δ 6.43 (t, 1H, J = 8.2 Hz, ArH), δ 3.85 4 4-OMe-Ph 4d: δ 8.02 (m, 2H, ArH), δ 7.09 (m, 5H, ArH), δ 6.98 (m, 2H, ArH), δ 6.80 (d, 3H, J = 8.9 Hz, ArH), δ 6.70 (d, 2H, J = 8.9, ArH), δ 3.93 (s, 2H, CH2Ph), δ 3.32 (s, 3H, CH3) 5 4-NO2-Ph 4e’: δ 7.70 (d, 2H, J = 9.1 Hz ArH), δ 7.30 (m, 2H, ArH), δ 7.25 (d, 2H, J = 7.4 Hz, ArH), δ 7.12 (m, 6H, ArH), δ 6.27 (s, 1H, CHPh), δ 6.06 (d, 2H, J = 9.1 Hz), δ 5.47 (s, 1H, NH) aIn C7D8. 2.4 Methods to Determine Catalyst Activity Frequently applied methods to determine the product yields in catalytic experiments are isolated yield, GC yield, and NMR yields. While isolated yields are preferential as it most accurately describes the amount of product that can be recovered, the procedure can be time consuming and require more material. Alternatively, yields determined by 1H NMR spectroscopy can be determined quickly and be done with small scale setups. Determination of yields using NMR spectroscopy provide a reasonable approximation of the product yield and information about side-products but does not take into account product loss during isolation and purification. 41 Two frequently applied methods for measuring the yield using 1H NMR spectroscopy are determination of yield of product with reference to an internal standard142 or through comparison of the integrations of the product(s) and the reactant(s).143 2.4.1 Product Yield Calculation In the present work, the 1H NMR yields reported via internal standard were determined by comparison of the integrations of specific signals assigned to product(s) to those of an internal standard. Specifically, the yields of products (e.g. Markovnikov vs. anti-Markovnikov addition across the CC bond) that are reported in this study were measured against a known quantity of internal standard (1,3-dimethoxybenzene). For instance, in the hydroamination of phenylacetylene and 2,4,6-trimethylaniline the sole product (3b) results from Markovnikov addition. The mmol of product (nproduct) formed is determined using Equation 2.3 which utilizes the integrals of the signal assigned to the ortho-H of the C-phenyl group (δ = 7.96 in 3b; IProduct) and the signal assigned to the methyl groups of 1,3-dimethoxybenzene (δ = 3.36; IDMB). The yield of the hydroamination from nproduct is determined using Equation 2.4. Figure 2.9 shows the RT 1H NMR spectrum recorded after heating a C7D8 solution of phenylacetylene and 2,4,6-trimethylaniline for 24 h at 100 °C. The key integrals IProduct and IDMB are labelled and the calculation of yield from internal standard is given below the 1H NMR spectrum. For comparison, the product yield was also determined using Equation 2.5 which employs IProduct and the signal assigned to the C–H moiety of phenylacetylene (δ = 2.76 ppm). In the present example, the latter signal is absent suggesting complete conversion of phenylacetylene to product (i.e. 100% yield). 42 Equation 2.3 Calculation of mmol of product formed by use of internal standard 1,3-dimethoxybenzene. 𝐼𝑃𝑟𝑜𝑑𝑢𝑐𝑡𝐼𝐷𝑀𝐵 ×𝑁𝐷𝑀𝐵𝑁𝑃𝑟𝑜𝑑𝑢𝑐𝑡 × 𝑛𝐷𝑀𝐵 (𝑚𝑚𝑜𝑙) = 𝑛𝑃𝑟𝑜𝑑𝑢𝑐𝑡 (𝑚𝑚𝑜𝑙) Iproduct: Integration of product signal IDMB: Integration of 1,3-dimethoxybenzene signal NDMB: Number of nuclei in 1,3-dimethoxybenzene signal NProduct: Number of nuclei in product signal nDMB: mmol of 1,3-dimethoxybenzene nProduct: mmol of product Equation 2.4 Determining product yield (%). 𝑃𝑟𝑜𝑑𝑢𝑐𝑡 𝑌𝑖𝑒𝑙𝑑 (%) =𝑛𝑃𝑟𝑜𝑑𝑢𝑐𝑡 (𝑚𝑚𝑜𝑙)𝑛𝑇ℎ𝑒𝑜𝑟𝑒𝑡𝑖𝑐𝑎𝑙 𝑌𝑖𝑒𝑙𝑑(𝑚𝑚𝑜𝑙) × 100 Equation 2.5 Product yield from direct comparison of integrals. 𝑃𝑟𝑜𝑑𝑢𝑐𝑡 𝑌𝑖𝑒𝑙𝑑 (%) = 𝐼𝑃𝑟𝑜𝑑𝑢𝑐𝑡𝑁𝑃𝑟𝑜𝑑𝑢𝑐𝑡𝐼𝐴𝑙𝑘𝑦𝑛𝑒 + 𝐼𝑃𝑟𝑜𝑑𝑢𝑐𝑡× 100 Iproduct: Integration of product signal IAlkyne: Integration of alkyne signal Nproduct: Number of nuclei in product signal 43 Figure 2.9 1H NMR spectra (400 MHz, C7D8, 298 K) of the hydroamination of phenylacetylene and 2,4,6-trimethylaniline using the polymer-supported pre-catalyst 1-[Au]. Sample calculations of yield using two methodologies is given. Complete consumption of phenylacetylene observed (δ = 2.74). † 1,3-dimethoxybenzene (0.14476 mmol used) Ha Yield determined by Eq. 2.3 and Eq. 2.4 Yield determined by Eq. 2.5 44 2.5 Yield of Hydroaminations with Pre-catalysts 1-[Au], 2-[Au], and Ph3PAuCl at 100 °C To assess the performance of the polymer-supported pre-catalyst 1-[Au] in the hydroamination of alkynes with substituted anilines, the activity of the complex was compared to the pre-catalysts 2-[Au] and Ph3PAuCl. The reactions were performed on an NMR scale for 24 h at 100 °C. Alkyne (1 equiv), arylamine (1.2 equiv), pre-catalyst (5% mol), AgOTf (5% mol), 1,3-dimethoxybenzene (internal standard), and Tol-d8 were combined and transferred to an NMR tube where an initial 1H NMR spectrum was recorded. The reaction mixture was heated at 100 °C for exactly 24 h. After which the reaction was allowed to cool to RT whereupon an 1H NMR spectrum was recorded. 2.5.1 Role of Silver Triflate To obtain the active cationic gold catalysts, the precatalysts were treated with silver triflate (AgOTf). Silver salts role in gold catalysis has primarily been described as removal of a chloride from gold, however it may have a more significant role than this action.144 One issue to consider in the hydroamination experiments conducted in this study is silver triflate’s capability in facilitating the addition of nitrogen compounds across the pi-bond of alkynes.145 The determined yields may be a contribution of the cationic gold complexes and silver. Preliminary reactions were conducted to evaluate the role of AgOTf in this study. Entrya 1-[Au] AgOTf Yieldb 1 none none 0 2 none 5% mol 16 3 5% mol none 0 a1.2 equiv aniline, 1.0 equiv phenylacetylene, ca. 1 mL C7D8 bYield determined by 1H NMR spectroscopy using internal standard 1,3-dimethoxybenzene. 45 In the case where gold(I) catalyst and AgOTf were not present in the reaction mixture, product formation did not occur (entry 1). When silver triflate is added without gold catalyst, product 3a was formed with a marginal yield of 16% (entry 2). Where 1-[Au] was added without AgOTf no product formation detected (entry 3). For comparison the yield of the hydroamination of phenylacetylene with aniline was determined to be 71% with both 1-[Au] and AgOTf present. While the addition of AgOTf to the substrates without precatalyst catalyzes the formation of the product, this capability may not be as apparent with precatalyst present. With the gold precatalyst present AgOTf abstracts the chloride bonded to the gold to form AgCl which precipitates out of solution. AgCl may not be a significant factor in catalyzing addition reactions to alkynes, and is involved in a different role of gold catalyzed reactions.144 2.5.2 Yields of the Hydroaminations of Phenylacetylene In the hydroamination of phenylacetylene with arylamines the pre-catalysts exhibit exclusive regioselectivity of the Markovnikov product(s). The formation of the anti-Markovnikov products, phenylacetylene oligomers or phenylacetylene gold(I) complexes, often observed for gold(I) catalyzed hydroaminations,146 were not evidenced in the 1H NMR spectra. The yield determined from direct comparison of the integrals using Eq. 2.5 is reported for polymer 1-[Au] and model compound 2-[Au]. The yield determined by internal standard (Eq. 2.4) is reported only for the hydroaminations employing 1-[Au]. An isolated yield of entry 1 was obtained using 1-[Au]. All yields reported are representative of multiple trials (2-3 trials per entry). The yields determined using each method were reproducible within the experimental accuracy of NMR integrations (ca. ±15%). For example, repeating the hydroamination of phenylacetylene with aniline using 1-[Au] gave yields using Eq. 2.5 of 95% and 100% compared to that reported 84 % (Table 2.3, entry 1). Repeat runs were performed using a different batch of polymer (Mn = 6,500 g mol-1; Đ = 1.29) thus ensuring that the catalyst performance is independent of batch. Similar data were obtained for the other hydroaminations (Entries 3, 5, 7, 9). 46 Table 2.3 Hydroamination yields of phenylacetylene with arylamines. 3a (R = Ph), 3b (R = 2,4,6-Me), 3c (R = 2,6-Cl), 3d (R = 4-OMe), 3e (R = 4-NO2) Entry (product) R [Au] Yield of 3 (direct comparison (%)a Yield of 3 (vs. Internal Std. (%)b 1 (3a) Ph 1-[Au] 84 80 (74)c 2 (3a) Ph 2-[Au] 50 3 (3b) 2,4,6-Me-Ph 1-[Au] 100 95 4 (3b) 2,4,6-Me-Ph 2-[Au] 94 5 (3c) 2,6-Cl-Ph 1-[Au] 100 97 6 (3c) 2,6-Cl-Ph 2-[Au] 92 7 (3d) 4-OMe-Ph 1-[Au] 70 56 8 (3d) 4-OMe-Ph 2-[Au] 48 9 (3e) 4-NO2-Ph 1-[Au] 100 62 10 (3e) 4-NO2-Ph 2-[Au] 30 aNMR yields determined by direct comparison of integrals (Eq. 2.5) bNMR yields determined from the internal standard 1,3-dimethoxybenzene (Eq. 2.3 and Eq. 2.4). cIsolated yield of imine and acetophenone(hydrolyzed from imine). The hydroamination of phenylacetylene with aniline in the presence of the activated pre-catalyst 1-[Au] gave 3a in 80% yield determined by internal standard (entry 1). Increased steric congestion at the arylamine had no impact on the effectiveness of the polymer-supported catalyst with excellent yields observed for 3b (entry 3). Strong withdrawing groups at the ortho positions with 2,6-dichloroaniline resulted in no impact on the performance of 1-[Au] with a measured yield of 97% of 3c (entry 5). Presence of an electron donating group, -OMe, at the para position notably resulted in deactivation giving 3d in 56% yield (entry 7). The presence of the strong withdrawing group, -NO2, at the para position saw moderate success with a yield of 62% 47 of 3e (entry 9). Strangely though the yield determined by internal standard is much less than yields determined by direct comparison of the integrals. Complete consumption of phenylacetylene is observed during synthesis of 3e. No significant difference in yields determined by Eq. 2.5 were observed for entries 1, 3, and 5. Hydroaminations employing complexes of 1-[Au] proceeded with greater or similar success than 2-[Au] (Table 2.3). Polymer-supported 1-[Au] outperformed Ph3PAuCl in all examples [Yield (%) = 33 (average), range = 6 – 66; see Appendix B, Table B1 for specific yields]. To further illustrate the improved performance of polymer-supported 1-[Au]; in a similar study reporting the intermolecular hydroamination of phenylacetylene with arylamines using Ph3PAuCl, a yield of 52% of 3a and 31% of 3d was obtained.147 In the majority of the trials, complete consumption of phenylacetylene indicated by the integral yields was observed employing complexes of 1-[Au]. Residual phenylacetylene was observed in trials employing 2-[Au] or Ph3PAuCl as pre-catalyst. 2.5.3 Product Recovery of 3a and Isolated Yield An isolated yield of the product(s) from the hydroamination of phenylacetylene with aniline utilizing pre-catalyst 1-[Au] was obtained to compare the accuracy of the measured NMR yields. An upscaled reaction of entry 1 (Table 2.3) was performed. In a Schlenk flask, 1.72 mmol phenylacetylene and 1.92 mmol aniline was combined with pre-catalyst 1-[Au] (5% mol) and AgOTf (5% mol). After 9 h, 1H NMR spectroscopy indicated complete consumption of phenylacetylene, and the reaction was halted. The reaction mixture was added dropwise to hexanes where the catalyst was precipitated. The organic phase was collected, and hexanes were removed in vacuo leaving behind a brown-red oil. To purify and isolate the product, column chromatography was performed using silica as the stationary phase and EtOAc:Hexanes (9:1) as eluent. Volatiles were removed in vacuo and the obtained product was weighed and an 1H NMR spectrum in C7D8 was recorded. The imine is known to be susceptible to hydrolysis where the corresponding ketone is formed.148 Partial hydrolysis of the imine product 3a to acetophenone was observed of the isolated material, with a 4:1 ratio imine to acetophenone determined by direct comparison of the integrals (δ = 7.96 Ph(2H) imine 3a, δ = 8.1 Ph(2H) acetophenone) in the 48 1H NMR spectrum (Figure 2.10). The isolated yield of the product was 74% which is consistent with the NMR yields measured for 3a. Figure 2.10 1H NMR (400 MHz, C7D8, 298 K) spectrum of the isolated products 3a and acetophenone. δ = 7.96 Ph(2H) imine 3a; δ = 8.1 Ph(2H) acetophenone. δ 8.11 δ 7.96 49 2.5.4 Yields of the Hydroaminations of Diphenylacetylene With complexes of 1-[Au] presenting as capable catalysts in the hydroamination of phenylacetylene with arylamines, the transformation of the more encumbered alkyne, diphenylacetylene, was examined. The hydroamination of diphenylacetylene with anilines is noted as more difficult to achieve due to the increased steric demands of the alkyne.140 To further assess the capability of the polymer-supported catalyst in comparison to the monomeric model 2-[Au] and Ph3PAuCl, the hydroamination of diphenylacetylene and arylamines was conducted. The products were found to occur as the imine 4 and enamine 4’ tautomers. To measure the yields of 4, integration of the methylene group -CH2- resonance (δ = 3.8) was used. The yields of 4’ were calculated from the integrations of the -NH resonance (δ = 5.4) or the -CH= resonance (δ = 6.2). Hydroaminations of diphenylacetylene were not as successful as phenylacetylene with moderate to low yields measured. 1H NMR product yields and the ratio of the 4:4’ products (determined from the 1H NMR spectrum) are summarized in Table 2.4. 50 Table 2.4 Hydroamination yields of diphenylacetylene with arylamines. 4a,4a’ (R = Ph), 4b (R = 2,4,6-Me), 4c (R = 2,6-Cl), 4d (R = 4-OMe), 4e’ (R = 4-NO2) Entry (Product) R [Au] NMR Yield (%)a Eq. 2.3 NMR Yield (%)b Eq. 2.2 4:4’c 1 (4a, 4a’) Ph 1-[Au] 63 42d+(19)e 2.2:1 2 (4a, 4a’) Ph 2-[Au] 28 2:1 3 (4b) 2,4,6-Me-Ph 1-[Au] 52 46 4b only 4 (4b) 2,4,6-Me-Ph 2-[Au] 10 4b only 5 (4c) 2,6-Cl-Ph 1-[Au] 68 57 4c only 6 (4c) 2,6-Cl-Ph 2-[Au] 13 4c only 7 (4d) 4-OMe-Ph 1-[Au] 27 27 5.4:1 8 (4d) 4-OMe-Ph 2-[Au] 4 N/A 9 (4e’) 4-NO2-Ph 1-[Au] 80 66 4e’ only 10 (4e’) 4-NO2-Ph 2-[Au] 45 4e’ only aNMR yields determined by direct comparison of integrals (Eq. 2.5) bNMR yields determined from the internal standard 1,3-dimethoxybenzene (Eq. 2.3 and Eq. 2.4). cRatio of imine and enamine tatutomers determined from 1H NMR spectroscopy. dYield of imine. eYield of enamine. Polymeric pre-catalyst 1-[Au] saw the greatest success with aniline as the arylamine giving a mixture of 4a and 4a’. Formation of the imine 4a (42% yield) was favored over the enamine 4a’ (19% yield) (entry 1). Pre-catalyst 1-[Au] was less successful with arylamine 2,4,6-trimethylaniline giving a 46% yield of 4b (entry 3), which may be a result of the increased steric congestion of the substrates. Likewise, 2,6-dichloroaniline only produced a 57% yield of 4c (entry 5) which may be a result of increased steric contribution of the chloro groups. With arylamine p-anisidine, the yield was 27% of 4d (entry 7). With 4-nitroaniline the yield was 66% of 4e’ (entry 9). Pre-catalysts 2-[Au] and Ph3PAuCl were less successful in the hydroamination of diphenylacetylene with arylamines. 2-[Au] gave modest yields of 4a/4a’ (entry 2, 28% yield) and 51 4e’ (entry 10, 45% yield). Yields of 4b, 4c, and 4d were marginal using 2-[Au] (entries 4, 6, 8). Hydroaminations of diphenylacetylene employing Ph3PAuCl gave poor yields in all examples (Appendix B, Table B2). There is ample evidence that utilization of the polymer-supported pre-catalyst 1-[Au] provides a significant advantage over the small-molecule analogous pre-catalysts. 2.6 Recycling Studies of PMP(AuCl)-co-PS Small-molecule transition metal catalysts are often unable to be separated and recovered from the obtained products. Consequently, this results in the contamination of the products or the loss of precious metals. One solution to remedy this issue for homogeneous catalysts is the use of polymer-supports. The use of a polymer-support permits the isolation and recovery of the catalyst for continued use. The application of PMP-co-PS to facilitate the recovery of catalyst was investigated. In the hydroamination reactions described in the previous sections the activated pre-catalyst 1-[Au] could be separated from the crude products through precipitation with hexanes. The precipitated solid was recovered and dried in vacuo resulting in a light-brown solid. To determine if the recovered catalyst was still active, the material was recycled in additional hydroaminations of phenylacetylene with aniline. The reaction conditions were kept consistent as described for synthesis of 3a, with the exception that fresh pre-catalyst or AgOTf was not added. Yields are measured by direct comparison of the integrals using Eq. 2.5. With 1-[Au], the recycling experiments showed that there was a significant decrease in the activity of the catalyst after cycle 1 with the measured yield of 3a at 4% (Figure 2.11). Residual catalytic activity is observed in additional cycles of the recovered catalyst; however, this is minimal and by cycle 5 the measured yield of 3a was 10%. 52 Figure 2.11 Yield of the hydroamination product with the polymer-supported catalyst, 100% Au(I) coordination, after 5 successive cycles. aYield determined by direct comparison of 1H NMR integrals with Eq. 2.5. In gold catalysts the pre-catalyst form of L-Au-Cl is a stable complex, however after chloride abstraction the catalytically active cationic gold complex [L-Au]+ is known to be unstable.137 Varying levels of stability are observed depending on the counteranion applied. In the example of co-catalyst AgOTf employed to activate gold(I) pre-catalyst, the resulting gold complex [Ph3P-Au]+ TfO- is observed to have to poor thermal stability at a temperature of 80 °C.149 The inherent instability of cationic gold complexes results in decomposition that can be evidenced by the formation of a gold mirror or gold nanoparticles.137 In the hydroaminations performed utilizing 1-[Au], this gold mirror was visible as a coating on the NMR tubes at the end 734 610 1001020304050607080901001 (24 h) 2 (24 h) 3 (24 h) 4 (24 h) 5 (24 h)NMR Yield (%)aNumber of Catalytic Uses (Time)* Cycle 1 only 53 of the reactions (Figure 2.12). The gold mirror was visible when pre-catalysts 2-[Au] and Ph3PAuCl were utilized. Figure 2.12 Gold mirror formation observed on NMR tube walls after 24 h of reaction time with 100% Au(I) coordination to PMP-co-PS (i.e. 1-[Au]). 54 In improving the stability of gold catalysts, it has been reported that polymer-supports can impart stability on gold nanoclusters. Multiple coordination sites on a polymer results in the entanglement of the polymer chain around the metal, inhibiting decay.150,151 In gold(I), the use of a mesoporous polymer was found to prevent gold decomposition, with improved stability when the ratio of phosphorus sites to gold was increased.152 To see if adjusting the P:Au ratio has a similar effect on our polymer-support, the ratio of phosphorus to gold was increased. Following the same synthesis procedure described in section 2.2.2, PMP-co-PS copolymer 1.15 is reacted with 0.5 equiv of (tht)AuCl. The partial metalation of the polymer-support can be evidenced by 31P{1H} NMR spectroscopy where signals correlating to the Au-P centers were observed as broad peaks from 41 ppm to 23 ppm (Figure 2.13). These signals match that of the 100% metalated polymer-support indicating similar coordination of the phosphine moieties to gold(I). The uncoordinated phosphine moieties indicated in blue were observed as broad peaks from 10 to -20 ppm. Figure 2.13 31P{1H} NMR spectrum (162 MHz, C7D8, 298 K) of 1-[Au]-50. Resonances correlating to the Au(I) coordinated phosphine moieties are highlighted in red and uncoordinated phosphines are highlighted in blue. With the partially coordinated polymeric pre-catalyst (1-[Au]-50) in hand the recycling experiment was performed (Figure 2.14). A significant improvement was seen in the recyclability of the catalyst as there was no significant drop-off in catalytic activity for the first 3 cycles. The Au-Coordinated Uncoordinated 55 catalyst however started to show signs of sluggishness by cycle 4 with a yield of 74%. By cycle 5 the catalyst only gave a moderate yield of 52% 3a after 24 h. Extension of the reaction time to 72 h in cycle 5 resulted in an improved yield of 83% showing that the catalyst is still active. Visually, the gold mirror on the NMR tubes was not observed after cycle 1 nor in any of the subsequent cycles indicating the increased stability of the partially metalated catalyst (Figure 2.15). Figure 2.14 Yield of the hydroamination product with polymer-supported catalyst 1-[Au]-50 (5% mol Au(I)) after 5 successive runs. aYield determined by direct comparison of 1H NMR integrals with Eq. 2.5. 100859774528301020304050607080901001 (24 h) 2 (24 h) 3 (24 h) 4 (24 h) 5 (24 h) 5 (72 h)NMR Yield (%)Number of Catalytic Uses (Time)* Cycle 1 only 56 Figure 2.15 Absence of gold mirror on NMR tube walls after 24 h of reaction time with 1-[Au]-50. Further attempts to reduce the ratio of phosphine centers to gold(I) was pursued with 0.2 equiv (tht)AuCl added to polymer 1.15 to obtain pre-catalyst 1-[Au]-20. The obtained pre-catalyst was employed in the recycling experiments where a noted decrease in activity was observed after cycle 1. maintain a moderate level of activity for the first 4 cycles (Figure 2.16). By cycle 5, the activity of the catalyst declines giving a yield of 39% of 3a. 57 Figure 2.16 Yield of the hydroamination product 3a with polymer-supported catalyst 1-[Au]-20 (5% mol Au(I)) after 5 successive runs. aYield determined by direct comparison of 1H NMR integrals with Eq. 2.5. The reduction of gold(I) to phosphorus centers displays a positive effect on the stability of the polymer-supported catalyst. For 1-[Au] with 100% Au(I) coordination the activity of the catalyst significantly decreases after the first cycle. For pre-catalysts with only partial coordination of gold(I) to the phosphine moieties (i.e., 1-[Au]-50 and 1-[Au]-20) there was no major decline like that seen of 1-[Au] following cycle 1. 1-[Au]-50 retained a higher level of activity compared to 1-[Au]-20 suggesting that a certain amount of gold(I) needs to be present in the support. The improved stability of the catalysts may be a result of multiple phosphorus sites coordinating to the gold(I) reducing the likelihood of decay. 1007768 663901020304050607080901001 (24 h) 2 (24 h) 3 (24 h) 4 (24 h) 5 (24 h)NMR Yield (%)aNumber of Catalytic Uses (Time)* Cycle 1 only 58 2.7 Summary A random copolymer synthesized from the monomers 1.7a (MesP=CPh2) and styrene was applied as a polymer-support for gold(I). The polymer-supported gold(I) pre-catalyst 1-[Au] was employed in the hydroaminations of alkynes with arylamines with its activity compared to similar pre-catalysts. The polymer-supported catalyst was shown to exhibit superior yields compared to Ph3PAuCl and the monomeric model 2-[Au]. This result may be a result of the increased steric contribution attributed to the polymer-support compared to the model ligand and triphenylphosphine. As discussed earlier, one of the parameters to describe the performance of phosphine ligands is the steric parameter which is measured by its cone angle. Comparing the cone angle for the three precatalysts, the Ph3P ligand has a cone angle of θ = 145°.136 The presence of mesitylene groups (Mes) increases the cone angle significantly with Mes3P having a cone angle of θ = 212°. This suggests 2-[Au] possesses greater bulk than Ph3PAuCl, and 1-[Au] likely having the largest cone angle from the presence of the mesitylene groups and steric contributions from the polymer structure. A larger cone angle is associated with improved stability of gold(I) catalysts.137 This noted effect may explain the improved performance of the polymer-supported system 1-[Au] over 2-[Au] and Ph3PAuCl where more active catalyst is present in the reaction mixture over 24 hours. Aside from the 1-[Au] exhibiting excellent activity, the use of the polymer-support permitted the recovery of the active catalyst from the reaction mixture. The recovered catalyst featuring 100% gold(I) loading to phosphine was observed to be inactive in subsequent hydroamination reactions. Applying the tactic of metalating only a portion of the phosphine sites on the polymer with gold(I) resulted in a recoverable catalyst that remained active in further hydroamination reactions without requiring additional gold or co-catalyst added. This work displays the advantages of the use of PMP-co-PS as support for metal centers to improve catalytic activity and allow for the recycling of the catalyst. 59 Chapter 3: Conclusions and Future Work 3.1 Conclusion In Chapter 2 the development of a polymer-support containing phosphorus moieties in the backbone of the polymer was described. The phosphorus-containing polymer, PMP-co-PS, was coordinated to gold(I) where the obtained catalyst was employed in the intermolecular hydroamination of alkynes with arylamines. The polymer-supported gold(I) was shown to effectively catalyze the hydroamination of phenylacetylene and the more encumbered diphenylacetylene with a variety of arylamines (Scheme 3.1). Compared to the analogous small-molecule pre-catalysts Ph3PAuCl and 2-[Au], the polymer-supported catalyst 1-[Au] outperformed both systems while maintaining regioselectivity for the Markovnikov product when phenylacetylene was the applied alkyne. Hydroaminations of the internal alkyne diphenylacetylene further support the claim that 1-[Au] has greater capability than the small-molecule pre-catalysts. Significantly the polymer-support allowed for facile recovery of the catalyst from the reaction of media through precipitation. However, significant deactivation was displayed upon recycling the recovered catalyst. By reducing the gold(I) loading on the support (i.e. 0.5-0.2 equiv Au(I)) the polymer-supported catalyst was able to maintain improved yields over 5 cycles. 60 Scheme 3.1 Hydroamination of alkynes with arylamines employing 1-[Au] (i.e. PMP(AuCl)-co-PS). 3.2 Future Work The successful use of the PMP-co-PS polymer as a support in gold(I) catalyzed hydroaminations indicates the capability of the support. However, the substrate scope is currently limited to arylalkynes and arylamines. Expanding the library of the substrates as well as conducting intramolecular hydroaminations using these novel phosphorus-containing polymer-supported catalysts may provide better insight on the overall capability of the system. For instance, many molecular gold(I)-phosphine catalysts have been investigated in the construction of nitrogen containing heterocycles which are important for biological products. The gold(I) catalyzed cyclization of chemical precursors featuring alkyne and amine moieties has been applied to construct quinolines (e.g. (-)-quinocarcin),153 indolizinones (e.g. (-)-rhazinilam),154 and spirocycles.155 Comparable syntheses may server as a useful starting point to further catalyst studies with PMP-co-PS. While the present studies have discovered that the reduction of the amount of gold(I) coordinated to the support (i.e. lower Au(I) vs. P ratio) facilitated the recycling of the catalyst, its gradual deactivation with each cycle is observed leading to lower yields of product. The use of 61 micellar polymers has been reported as an effective strategy to stabilize gold(I) catalysts by encapsulating the metal nanoparticles.150 In our group the block copolymer poly(methylenephosphine)-b-poly(isoprene) was shown to exhibit self-assembly properties upon the addition of Au(I) to form micellar structures around the gold center.43 Such a system may provide an alternative strategy to effectively prevent decay of a gold(I) catalyst by trapping the metal ions. Further ways to improve the stability of the polymer-supported pre-catalyst may be achieved by utilizing a different phosphaalkene. Thus, it would be interesting to formally replace the phenyl moieties of monomer 1.7a (i.e. MesP=CPh2) with more sterically hindered groups (e.g. Mes, tBu, etc.), and employ their respective copolymers as gold(I) supports for hydroamination. This change may provide added stability to the Au(I) center. Moreover, it has been previously reported that the introduction of a bulkier group on dialkylbiaryl phosphine ligands had a positive correlation on the stability of a gold(I) catalyst.156 Additionally, adjusting the electronic parameters by replacing the phenyl moieties with electron donating groups may also provide additional stability. 62 Chapter 4: Experimental Section 4.1 Materials and general procedure All manipulations of air- and/or water sensitive compounds were performed under a nitrogen atmosphere using Schlenk line technique or in an MBraun (LabMaster) glovebox. CH2Cl2 was deoxygenated with nitrogen and distilled under reduced pressure and stored over molecular sieves (3 Å) before use. THF was dried over sodium/benzophenone ketyl and distilled before use. Toluene-d8 vials were purchased from Sigma Aldrich and used as received. Styrene was dried over CaH2 and distilled under reduced pressure. Mes-P=CPh2 was prepared following literature procedure. Phenylacetylene (Sigma Aldrich) was distilled under reduced pressure, degassed with nitrogen and stored over 3 Å molecular sieves. Aniline and 2,4,6-trimethylaniline were distilled under reduced pressure, degassed with nitrogen, and stored over 3 Å molecular sieves. p-Anisidine was purified with activated carbon and MgSO4 and recrystallized in CH2Cl2. 2,6-dichloroaniline and 4-nitroaniline were purchased from Sigma Aldrich and used as received. 1,3-dimethoxybenzene was purchased from Cambridge Isotope Laboratories Inc. and used as received. 1H, 13C, and 31P{1H} NMR spectra were recorded at 298 K on a Bruker Advance 400 spectrometer. 1H NMR spectra were referenced to the residual protonated solvent. 13C NMR spectra were referenced to the deuterated solvent. Polymer molecular weights were determined by triple detection gel permeation chromatography (GPC-LLS) using an Agilent liquid chromatograph equipped with an Agilent 1200 series autosampler, Phenomenex Phenogel 5 mm narrow bore columns 515 (4.6 x 300 mm) 104 Å (5000-500000 g mol-1) 500 Å (1000-15000 g mol-1), and 103 Å (1000-75000 g mol-1), Wyatt Optilab T-rEx differential refractometer (λ = 658 nm, 40 °C), Wyatt tristar miniDAWN laser light scattering detector (λ = 690 nm), and a Wyatt ViscoStar viscometer. A flowrate of 0.5 mL min-1 was used and sample were dissolved in THF (ca. 10 mg mL-1). 63 4.2 Preparation of poly(methylenephosphine)-co-styrene polymer PMP-co-PS Monomer MesP=CPh2 (1.000 g, 3.163 mmol) and VAZO 88 (0.039 g, 0.158 mmol) were dissolved in neat styrene (1.318 g, 12.653 mmol) under nitrogen atmosphere. The pale-yellow solution was charged into a sealable pyrex tube and flame sealed. The tube was heated at 140°C for 24 h in an oven equipped with a rocking tray. The tube was subsequently broken in an atmosphere of nitrogen and dissolved in CH2Cl2 and reprecipitated into hexanes three times. The product, a pale-yellow powder, was dried in a vacuum oven at 60°C for 24 h and subsequently characterized by GPC and NMR spectroscopy. Yield = 0.59 g (25.4%). 31P{1H} NMR (162 MHz, CDCl3): δ 5.6 (br), -3.6 (br), -7.0 (br), -9.8 (br), -17.0 (br); 1H NMR (400 MHz, CDCl3): δ 8.0 – 5.7 (br, Ar-H), 2.7 – 0.8 (br, CH3, CH2, CH); 13C NMR (101 MHz, CDCl3): δ 148 – 124 (br, ArC), 55 – 38 (br, CH, CH2), 24 – 20 (CH3) GPC: 1.15 Mn = 6.912 x 103, PDI = 1.29 GPC chromatogram (refractive index trace) collected for 1.15. 4.3 Preparation of Gold(I) Pre-catalysts Preparation of PPh3AuCl and 2-[Au] Model Catalyst 2-[Au] and PPh3AuCl was prepared according to literature procedure. Preparation of 100% Au(I) coordinated PMP(AuCl)-co-PS 10 13 16 19 22Retention time (min)64 A Schlenk flask was charged with PMP-co-PS (0.214 g), (tht)AuCl (50 mg), and CH2Cl2 (ca. 5 mL). The solution was stirred for 24 h at room temperature. The solvent was reduced to half in vacuo leaving a viscous solution. The metalated polymer was purified by reprecipitating the viscous solution into hexanes. After reprecipitation, the polymer was dried in vacuo leaving a grey powder. 31P{1H} NMR (162 MHz, CDCl3): δ 42.3 (br), 34.1 (br), 26.7 (br), 23.7 (br); 1H NMR (400 MHz, CDCl3): δ 8.0 – 5.7 (br, Ar-H), 2.7 – 0.8 (br, CH3, CH2, CH) Preparation of 50% Au(I) coordinated PMP(AuCl)-co-PS Preparation follows that of 100% PMP(AuCl)-co-PS. 0.113 g (0.0825 mmol P) PMP-co-PS, 13 mg (0.0405 mmol) (tht)AuCl combined in CH2Cl2 (ca. 5 mL) 4.4 Hydroamination Reaction Procedure via PMP(AuCl)-co-PS Aniline and phenylacetylene (1.1 – 1.2:1.0 ratio), PMP(AuCl)-co-PS ~5% mol loading, AgOTf ~5% mol loading and deuterated toluene (1 mL) are combined in a vial. ca. 10 uL 1,3-Dimethoxybenzene is used as internal standard. The mixture was quickly transferred to a J-Young or standard NMR tube wrapped in parafilm and electrical tape, and heated in an oil bath at 100 °C for 24h. The reaction was cooled to room temperature and yields were determined through 1H NMR (400 MHz, C7D8). Phenylacetylene and Aniline: 38 μL (0.346 mmol) phenylacetylene, 35 μL (0.383 mmol) aniline (1:1.11 ratio), 30 mg (0.0182 mmol Au, 5.2% mol loading) PMP(AuCl)-co-PS, 6 mg (.0236 mmol) AgOTf, and 1 mL C7D8 were combined and added to an NMR tube. NMR tube was heated in an oil bath at 100 °C for 24 h. 1H NMR (C7D8, 400 MHz) δ 7.95 (m, 2H, ArH), δ 7.27-7.15 (m, 5H, ArH), δ 6.75 (d, J=8.5 Hz, 2H, ArH), δ 1.89 (s, 3H, CH3). Phenylacetylene and 2,4,6-Trimethylaniline: 35 μL (0.318 mmol) phenylacetylene, 51 μL (0.363 mmol) 2,4,6-trimethylaniline (1:1.14 ratio), 29 mg (0.0176 mmol Au, 5.5% mol loading) PMP(AuCl)-co-PS, 5 mg (0.0194 mmol) AgOTf, and 1 mL C7D8 were combined and added to an 65 NMR tube. NMR tube is heated in an oil bath at 100 °C for 24 h. 1H NMR (C7D8, 400 MHz) δ 8.00 (m, 2H, ArH), δ 7.23 (t, J=3.2 Hz, 3H, ArH), δ 6.84 (s, 2H, ArH), δ 2.26(s, 3H, CH3), δ 2.00 (s, 6H, CH3), δ 1.79 (s, 3H, CH3). Phenylacetylene and 2,6-Dichloroaniline: 35 μL (0.318 mmol) phenylacetylene, 60 mg (0.370 mmol) 2,6-dichloraniline (1:1.16 ratio), 29 mg (0.0176 mmol Au, 5.5% mol loading) PMP(AuCl)-co-PS, 5 mg (0.0194 mmol) AgOTf, and 1 mL C7D8 were combined and added to an NMR tube. NMR tube was heated in an oil bath at 100 °C for 24 h. 1H NMR (C7D8, 400 MHz) δ 7.97 (m, 2H, ArH), δ 7.16 (m, 3H, ArH), δ 7.05 (m, 3H, ArH), δ 1.88 (s, 3H, CH3). Phenylacetylene and p-Anisidine: 37 μL (0.337 mmol) phenylacetylene, 47 mg (0.382 mmol) p-anisidine (1:1.13 ratio), 29 mg (0.0176 mmol Au, 5.2% mol loading) PMP(AuCl)-co-PS, 5 mg (0.0194 mmol) AgOTf, and 1 mL C7D8 were combined and added to an NMR tube. NMR tube is heated in an oil bath at 100 °C for 24 h. 1H NMR (C7D8, 400 MHz) δ 8.00 (m, 2H, ArH), δ 7.22 (m, 3H, ArH), δ 6.77 (dd, J=9 Hz, 4H, ArH), δ 3.42 (s, 3H, CH3), δ 1.96 (s, 3H, CH3). Phenylacetylene and 4-Nitroaniline: 35 uL (0.318 mmol) phenylacetylene, 52 mg (0.376 mmol) 4-nitroaniline (1:1.18 ratio), 29 mg (0.0176 mmol Au, 5.2% mol loading) PMP(AuCl)-co-PS, 6 mg (.0236 mmol) AgOTf, and 1 mL C7D8 were combined and added to an NMR tube. NMR tube is heated in an oil bath at 100 °C for 24 h. 1H NMR (C7D8, 400 MHz) δ 8.00 (m, 2H, ArH), δ 7.22 (m, 3H, ArH), δ 6.77 (d, J=9 Hz, 4H, ArH), δ 3.42 (s, 3H, CH3), δ 1.72 (s, 3H, CH3). Diphenylacetylene and Aniline: 60 mg (0.336 mmol) diphenylacetylene, 35 uL (0.383 mmol) aniline (1:1.14 ratio), 30 mg (0.0182 mmol Au, 5.4% mol loading) PMP(AuCl)-co-PS, 5 mg (.0194 mmol) AgOTf, and 1 mL C7D8. 1H NMR (C7D8, 400 MHz) Imine: δ 7.97 (m, 2H, ArH), δ 6.83 (d, 2H, J = 7.2 Hz, ArH), δ 3.85 (s, 2H, CH2Ph). Enamine: δ 7.35 (m, 2H, ArH), δ 6.44 (d, 2H, ArH), δ 6.15 (s, 1H, CHPh), δ 5.41 (s, 1H, NH). Other ArH resonances of the Imine and Enamine overlap from δ 6.86 - δ 7.15. Diphenylacetylene and 2,4,6-Trimethylaniline: 60 mg (0.336 mmol) diphenylacetylene, 52 uL (0.370 mmol) 2,4,6-trimethylaniline (1:1.10 ratio), 30 mg (0.0182 mmol Au, 5.4% mol loading) PMP(AuCl)-co-PS, 5 mg (0.0194 mmol) AgOTf, and 1 mL C7D8. 1H NMR (C7D8, 400 MHz) Imine: δ 66 8.00 (m, 2H, ArH), δ 7.12 (m, 2H, ArH), δ 6.88 (t, 3H, J = 7.3 Hz, ArH), δ 6.81 (d, 2H, J = 8.0, ArH), δ 6.79 (s, 2H, ArH), δ 3.73 (s, 2H, CH2Ph), δ 2.22 (s, 3H, CH3), δ 1.98 (s, 6H, CH3). Diphenylacetylene and 4-Nitroaniline: 60 mg (0.336 mmol) diphenylacetylene, 53 mg (0.384 mmol) 4-nitroaniline (1:1:14 ratio), 29 mg (0.0176 mmol Au, 5.2% mol loading) PMP(AuCl)-co-PS, 5 mg (0.0194 mmol) AgOTf, and 1 mL C7D8. 1H NMR (C7D8, 400 MHz) δ 7.70 (d, 2H, J = 9.1 Hz ArH), δ 7.30 (m, 2H, ArH), δ 7.25 (d, 2H, J = 7.4 Hz, ArH), δ 7.12 (m, 6H, ArH), δ 6.27 (s, 1H, CHPh), δ 6.06 (d, 2H, J = 9.1 Hz), δ 5.47 (s, 1H, NH). Diphenylacetylene and p-Anisidine: 60 mg (0.336 mmol) diphenylacetylene, 46 mg (0.374 mmol) p-anisidine (1:1:11 ratio), 30 mg (0.0182 mmol Au, 5.4% mol loading) PMP(AuCl)-co-PS, 5 mg (0.0194 mmol) AgOTf, and 1 mL C7D8. 1H NMR (C7D8, 400 MHz) δ 8.02 (m, 2H, ArH), δ 7.09 (m, 5H, ArH), δ 6.98 (m, 2H, ArH), δ 6.80 (d, 3H, J = 8.9 Hz, ArH), δ 6.70 (d, 2H, J = 8.9, ArH), δ 3.93 (s, 2H, CH2Ph), δ 3.32 (s, 3H, CH3). Diphenylacetylene and 2,6-Dichloroaniline: 62 mg (0.348 mmol) diphenylacetylene, 64 mg (0.395 mmol) 2,6-dichloroaniline (1:1.13 ratio), 30 mg PMP(AuCl)-co-PS, 6 mg (.0236 mmol) AgOTf, and 1 mL C7D8 were combined and added to an NMR tube. 1H NMR (C7D8, 400 MHz) δ 8.0 (m, 2H, ArH), δ 6.90-7.08 (m, 12H, ArH), δ 6.43 (t, 1H, J = 8.2 Hz, ArH), δ 3.85 (s, 2H, CH2Ph). Isolated Yield of Phenylacetylene and Aniline: 176 mg phenylacetylene, 179 mg aniline, 149 mg PMP(AuCl)-co-PS, 30 mg AgOTf, 4 mL C7D8 combined in Schlenk flask under nitrogen atmosphere and heated for 9 h at 100 °C. The reaction mixture is added to hexanes precipitating out the catalyst. Hexanes was removed under reduced pressure leaving behind a behind a brown-red oil. The oil is dissolved in a minimal amount of hexanes and loaded into a flash column of neutral alumina and ran with 9:1 Hexanes:EtOAc. The volatiles are removed leaving a yellow oil which is subsequently characterized with 1H NMR spectroscopy. 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DOI: https://doi.org/10.1021/acs.organomet.0c00278 85 Appendices Appendix A 1H NMR Spectra of Hydroamination Products with PMP(AuCl)-co-PS Pre-catalyst Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of phenylacetylene with aniline. 86 Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of phenylacetylene with 2,4,6-trimethylaniline. 87 Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of phenylacetylene with 2,6-dichloroaniline. 88 Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of phenylacetylene with p-anisidine. 89 Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of phenylacetylene with 4-nitroaniline. 90 Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of diphenylacetylene with 2,4,6-trimethylaniline. 91 Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of diphenylacetylene with 2,6-dichloroaniline. 92 Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of diphenylacetylene with p-anisidine. 93 Reaction mixture 1H NMR Spectrum (400 MHz, C7D8) of the hydroamination of diphenylacetylene with 4-nitroaniline. 94 Appendix B Yields of Hydroamination Products Utilizing Ph3PAuCl Table B1 R Yield (%) From Eq. 2.3a Product Ph 52 3a 2,4,6-Me-Ph 86 3b 2,6-Cl-Ph 52 3c 4-OMe-Ph 64 3d 4-NO2-Ph 34 3e aDetermined by direct comparison of integrals in 1H NMR spectrum. Table B2 R Yield (%) From Eq. 2.3a Product(s) Ph 15 4a, 4a’ (2:1)b 2,4,6-Me-Ph 2 4b 2,6-Cl-Ph 13 4c 4-OMe-Ph 0 4d 4-NO2-Ph 16 4e’ aDetermined by direct comparison of integrals in 1H NMR spectrum. bRatio of 4:4’ determined in 1H NMR spectrum.
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Gates, Derek P.
Gold(I) catalyst supported by poly(methylene phosphine)-co-styrene in the hydroamination of alkynes with arylamines
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