SYNTHESIS OF TEREPHTHALIC, ISOPHTHALIC AND PHTHALIC ACIDS FROM METHANE AND CARBON DIOXIDE By Van Nguyen A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of Chemistry – Doctor of Philosophy 2020 ABSTRACT SYNTHESIS OF TEREPHTHALIC, ISOPHTHALIC, AND PHTHALIC ACIDS FROM METHANE AND CARBON DIOXIDE By Van Nguyen Terephthalic, isophthalic and phthalic acids are commodity chemicals valuable in the syntheses of a variety of different polymers. Current production of these benzenedicarboxylic acids relies on petroleum-derived xylenes as chemical feedstocks via Amoco-MidCentury oxidation, a process that releases sizeable amount of carbon dioxide and methane and poses other environmental challenge. Rather than generating greenhouse gases, this investigation focuses on using the single carbon (C1) greenhouse gases methane (CH4) and carbon dioxide (CO2) as synthetic starting materials. Proof-of-concept syntheses of terephthalic, isophthalic and phthalic acids are elaborated from acetylenemonocarboxylic acid, which is obtained by reaction of carbon dioxide with methane-derived acetylene. Acetylenemonocarboxylic acid was first employed as a dienophile in a cycloaddition reaction with isoprene to afford terephthalic and isophthalic acids. A more versatile synthetic approach employed metal-catalyzed or Bronsted acid-catalyzed hydration of acetylenemonocarboxylic acid to afford malonic acid semialdehyde and pyruvic acid. Proposed reaction of malonic acid semialdehyde with two equivalents of acetylenemonocarboxylic acid leads to terephthalic and isophthalic acids via intermediacy of coumalic acid. Proposed reaction of pyruvic acid with two equivalents of acetylenemonocarboxylic acid leads to phthalic and isophthalic acids via intermediacy of isocoumalic acid. Copyright by VAN NGUYEN 2020 This dissertation is dedicated to my parents For their love, understanding, and support In memory of Nguyen Mai Quan iv ACKNOWLEDGEMENTS Words cannot describe how grateful I am to my advisor, Dr. John W. Frost. From the first meeting I had in his office with Dr. Karen Draths, for the last five years, between research and teaching, John has taught me how to tackle a problem by asking the right question and paying attention to details. John’s patience with our “miscommunication” problem and his tolerance of my peculiarity have helped me complete the work described in this thesis. I would also like to thank the members of my thesis committee: Dr. Babak Borhan, Dr. James Geiger, and Dr. Kevin Walker for their guidance and support during my time in the graduate program. I have also had the opportunity to work with Dr. Milton R. Smith, III whose perspective in organometallics has been invaluable to my work for the last three years. I am thankful for the support and guidance that Dr. Karen Draths has given to me during toughest moments of my graduate career. Karen and her group’s acceptance of my aloofness yet unwavering effort to make me feel included has become one of the most cherished memories during my time at MSU. I am also thankful for the opportunity to work in the same research group with Swetha Nisthala, David Walls and Kiyoto Tanemura. David’s work during his time in the Frost group has helped point me to the right direction in my mechanistic work. Kio and I have become best friends throughout our time at MSU; his friendship is one of the few precious things that keep my sanity in check. I am also indebted to Dr. Tayeb Kakeshpour for his constant support during and after his time at MSU. His dedication to science has been an inspiration and a reminder to me that being a scientist is the path we chose, and now is the time to give the best effort to our work. v I would like to thank my mother and father who have been patient and understanding of my absence from home for the last five years. They inspired me to continue their paths as chemists, and their love and support help me get up in the morning to go to the lab and finish what I set out to do. I am grateful to my friends and family in Vietnam who are half the world away yet never stop reaching out to me and understand my absence in the milestones of their lives. I wrote this dissertation in memory of my grandfather, who, for the first six years of my life and last of his, took care of me when parents were busy, walked me to school, picked me up every day, and taught me how to read before I could even form a proper sentence. Through his eyes I learned that there is no limit to curiosity when looking at the world full of wonders waiting to be discovered. vi TABLE OF CONTENTS LIST OF TABLES ......................................................................................................................... ix LIST OF FIGURES ........................................................................................................................ x LIST OF SCHEMES..................................................................................................................... xii KEY TO ABBREVIATIONS ...................................................................................................... xiv CHAPTER 1: INTRODUCTION ................................................................................................... 1 1. Amoco-MidCentury oxidation of xylenes to terephthalic, isophthalic and phthalic acids ..... 3 2. Methane and carbon dioxide as C1 chemical feedstocks ....................................................... 6 3. Synthesis of biobased starting materials to terephthalic, isophthalic and phthalic acids ....... 7 3.1. Glucose-derived starting materials to terephthalic acid ................................................... 7 3.2. The Alder route to terephthalic and isophthalic acids ..................................................... 7 3.3. The Propiolate route to terephthalic and isophthalic acids .............................................. 9 3.4. The Pyrone route to terephthalic, isophthalic and phthalic Acids ................................. 11 4. Synthesis of isoprene and acetylenemonocarboxylic acid from methane and carbon dioxide....................................................................................................................................... 12 4.1. Synthesis of isoprene from methane .............................................................................. 12 4.2. Synthesis of AMCA from methane and carbon dioxide ................................................ 12 REFERENCES ............................................................................................................................. 14 CHAPTER 2: THE PROPIOLATE ROUTE TO TEREPHTHALIC & ISOPHTHALIC ACIDS ....................................................................................................................................................... 19 1. Introduction ........................................................................................................................... 19 2. Cycloaddition of isoprene and acetylenemonocarboxylic acid ............................................ 20 2.1. Effect of temperature ..................................................................................................... 20 2.2. Effect of concentration on cycloaddition of isoprene and AMCA ................................ 21 2.3. The impact of isoprene and AMCA mole ratios on cycloaddition yield ....................... 22 2.4. Tetraborylacetate and TiCl4-catalyzed cycloaddition of isoprene and AMCA ............. 23 REFERENCES ............................................................................................................................. 27 CHAPTER 3: THE PYRONE ROUTE FROM ACETYLENEMONOCARBOXYLIC ACID .. 29 1. Introduction ........................................................................................................................... 29 2. Acid catalyzed conversion of AMCA to terephthalic, isophthalic and phthalic acids ......... 32 3. Cycloaddition of pyrones and acetylenemonocarboxylic acid 19 ........................................ 36 3.1. Computational results .................................................................................................... 36 3.2. Cycloaddition of isocoumalic acid and AMCA ............................................................. 37 3.3. Cycloaddition of coumalic acid and AMCA ................................................................. 41 REFERENCES ............................................................................................................................. 43 CHAPTER 4: THE PYRONE ROUTE: MECHANISTIC INSIGHTS ....................................... 45 vii 1. Introduction ........................................................................................................................... 45 2. Formation of coumalic acid and trimesic acid in TfOH catalysis ........................................ 48 3. Formation of coumalic, isocoumalic, and muconic acids in Ru- and Mo-catalysis ............. 50 4. RuCl3 - catalyzed 1,3-hydration of AMCA – Synthesis of pyruvic acid ............................. 54 REFERENCES ............................................................................................................................. 59 CHAPTER 5: EXPERIMENTAL................................................................................................. 62 1. General .................................................................................................................................. 62 2. Product Analyses .................................................................................................................. 62 3. 4-Methyl-1,4-cyclohexadiene-1-carboxylic acid 16 from cycloaddition of AMCA 19 with isoprene 13 ................................................................................................................................ 64 4. Solvent-free conversion of AMCA 19 catalyzed by AuCl/AgSbF6 ..................................... 64 5. Conversion of AMCA 19 catalyzed by AuCl/AgSbF6 in TCE ............................................ 65 6. Solvent-free conversion of AMCA 19 catalyzed by MoCl5/AgSbF6 ................................... 66 7. Conversion of AMCA 19 catalyzed by MoCl5/AgSbF6 in dioxane ..................................... 67 8. Conversion of AMCA 19 catalyzed by RuCl2(p-cymene)]2/AgSbF6 in dioxane/PvOH ...... 67 9. Conversion of AMCA 19 catalyzed by RuCl2(p-cymene)]2/AgSbF6 in HOAc ................... 68 10. Solvent-free conversion of AMCA 19 catalyzed by TfOH ................................................ 69 11. Isolation of terephthalic acid 1 and isophthalic 2 from the solvent-free conversion of AMCA 19 catalyzed by TfOH .................................................................................................. 69 12. Conversion of AMCA 19 to coumalic acid 22 catalyzed by TfOH in TCE ....................... 70 13. Conversion of AMCA 19 to diacrylic ether 50 catalyzed by TfOH in TCE ...................... 70 14. Uncatalyzed cycloaddition of isocoumalic acid 23 and AMCA 19 .................................... 71 15. TiCl4-catalyzed cycloaddition of isocoumalic acid 23 and AMCA 19............................... 71 16. Isolation of phthalic acid 3 and isophthalic acid 2 from the TiCl4-catalyzed cycloaddition of isocoumalic 23 and AMCA 19 ............................................................................................. 72 17. Uncatalyzed cycloaddition of coumalic acid 22 and AMCA 19 ........................................ 72 19. Synthesis of methyl 4-carbomethoxy-5-methoxy-penta-2E, 4Z-dienoate 45 ..................... 73 20. Cycloaromatization of methyl 4-carbomethoxy-5-methoxy-penta-2E, 4Z-dienoate 45 and methyl acetylenemonocarboxylate to trimethyl trimesate 48 ................................................... 74 21. Solvent-free conversion of diacrylic ether 50 to coumalic acid 22 catalyzed by TfOH ..... 74 22. Synthesis of isocoumalic acid 23 from diethyl oxalate and ethyl crotonate ....................... 74 22.a. Diethyl-2-hydroxy-2,4-hexadien-1,6-dioate ................................................................ 75 22.b. Isocoumalic acid 23 ..................................................................................................... 75 23. General procedure for screening of metal catalysts for conversion of AMCA 19 to terephthalic 1, isophthalic 2, coumalic 22, and isocoumalic 23 acids ...................................... 76 24. General procedure for solvent screening for hydration of acetylenemonocarboxylic acid 19 catalyzed by RuCl3 .................................................................................................................... 76 25. Isolation of pyruvic acid 53 from the hydration of AMCA 19 catalyzed by RuCl3 ........... 77 APPENDICES .............................................................................................................................. 78 APPENDIX A: CATALYST SCREENING DATA ................................................................ 79 APPENDIX B: NMR Spectra ................................................................................................. 124 REFERENCES ........................................................................................................................... 144 viii LIST OF TABLES Table 2.1. Effect of temperature on cycloaddition of isoprene and AMCA ................................. 20 Table 2.2. Effect of concentration of AMCA on cycloaddition of isoprene and AMCA ............. 22 Table 2.3. Isoprene/AMCA ratio on cycloaddition of isoprene and AMCA ................................ 23 Table 2.4. Effect of TiCl4 and BOB(OAc)4 on cycloaddition of isoprene and AMCA ................ 25 Table 3.1. Acids catalyzed conversion of acetylenemonocarboxylic acid ................................... 34 Table 3.2. Lewis acid-catalyzed cycloaddition of isocoumalic and acetylenemonocarboxylic acids .............................................................................................................................................. 39 Table 3.3. Cycloaddition of coumalic and acetylenemonocarboxylic acids ................................. 41 Table 4.1. Impact of pyruvic acid and diacrylic ether on Lewis acid catalysis of AMCA ........... 53 Table 4.2. RuCl3-catalyzed hydration of AMCA in various solvents .......................................... 56 Table 5.1. Acid catalyzed conversion of AMCA to pyrone and aromatic products ..................... 80 ix LIST OF FIGURES Figure 1.1. Oxidation of petroleum-derived xylenes to terephthalic, isophthalic and phthalic acids ......................................................................................................................................................... 2 Figure 3.1. 1H-NMR spectrum of BOB(OAc)4-catalyzed cycloaddition of isocoumalic acid and AMCA........................................................................................................................................... 31 Figure 3.2. Catalysts screened to optimize conversion of acetylenemonocarboxylic acid with color coding based on total yield of pyrones and aromatic products ............................................ 33 Figure 4.1. NMR studies of diacrylic ether in D2O at 0, 15, and 22 h and 100˚C ........................ 50 Figure 5.1. 1H - NMR spectrum of solated 4-methyl 1,4-cyclohexadiene carboxylic acid 20 ... 125 Figure 5.2. 13C- NMR spectrum of solated 4-methyl 1,4-cyclohexadiene carboxylic acid 20 . 126 Figure 5.3.1H-NMR spectrum of isolated terephthalic acid 1 .................................................... 127 Figure 5.4. 13C-NMR spectrum of isolated terephthalic acid 1 .................................................. 128 Figure 5.5. 1H-NMR spectrum of coumalic acid 22 ................................................................... 129 Figure 5.6. 13C-NMR spectrum of coumalic acid 22 .................................................................. 130 Figure 5.7. 1H-NMR spectrum of trans-diacrylic ether 50 ......................................................... 131 Figure 5.8. 13C-NMR spectrum of trans-diacrylic ether 50 ........................................................ 132 Figure 5.9. 1H-NMR spectrum of isolated isophthalic acid 2 ..................................................... 133 Figure 5.10. 13C-NMR spectrum of isolated isophthalic acid 2 .................................................. 134 Figure 5.11. 1H-NMR spectrum of isolated phthalic acid 3 ....................................................... 135 Figure 5.12. 13C-NMR spectrum of isolated phthalic acid 3 ...................................................... 136 Figure 5.13. 1H-NMR spectrum of methyl 4-carbomethoxy-5-methoxy-penta-2E,4Z-dienoate 45 ..................................................................................................................................................... 137 Figure 5.14. 13C-NMR spectrum methyl 4-carbomethoxy-5-methoxy-penta-2E,4Z-dienoate 45 ..................................................................................................................................................... 138 x Figure 5.15. 1H spectrum of isolated isocoumalic acid 23 ......................................................... 139 Figure 5.16. 13C-NMR spectrum of isolated isocoumalic acid 23 .............................................. 140 Figure 5.17. 1H-NMR spectrum of pyruvic acid 59.................................................................... 141 Figure 5.18. 13C-NMR spectrum of pyruvic acid 59 .................................................................. 142 xi LIST OF SCHEMES Scheme 1.1. Amoco-MidCentury oxidation of p-xylene and purification of terephthalic acid ..... 3 Scheme 1.2. Propagation and catalytic cycle of p-xylene oxidation to terephthalic acid ............... 4 Scheme 1.3. Glucose-derived starting material to bio-based terephthalic acid. ............................. 7 Scheme 1.4. Alder route to terephthalic and isophthalic acid......................................................... 8 Scheme 1.0.5. The Propiolate Route to Terephthalic and Isophthalic Acids ............................... 10 Scheme 1.6. The Pyrone route to terephthalic, isophthalic and phthalic Acids ............................ 11 Scheme 1.7. Isoprene from methane ............................................................................................. 12 Scheme 1.8. AMCA from methane and carbon dioxide ............................................................... 12 Scheme 2.1. The Alder and Propiolate routes to terephthalic acid ............................................... 19 Scheme 2.2. Cycloaddition of isoprene and AMCA ..................................................................... 20 Scheme 2.3. Synthesis of BOB(OAc)4 ......................................................................................... 24 Scheme 2.4. TiCl4 and BOB(OAc)4 complexes with acrylic acid ................................................ 24 Scheme 3.1. Isocoumalate to phthalate and isophthalate .............................................................. 29 Scheme 3.2. The Pyrone route to terephthalic, isophthalic, and phthalic acids ............................ 31 Scheme 3.3. AuCl/AgSbF6-catalyzed AMCA to coumalic acid, isophthalic, and terephthalic acids .............................................................................................................................................. 32 Scheme 3.4. HOMO-LUMO gaps and orbital coefficient of coumalic, isocoumalic and acetylenemonocarboxylic acids .................................................................................................... 37 Scheme 4.1. Ruthenium catalysis of ethyl acetylenemonocarboxylate ........................................ 46 Scheme 4.2. Au-catalyzed annulation and dimerization of acetylenemonocarboxylic acid ......... 46 Scheme 4.3. Trimerization of sodium acetylenemonocarboxylate catalyzed by Ni(cod)2 .......... 47 Scheme 4.4. Ruthenium catalysis of AMCA in HOAc ................................................................ 48 xii Scheme 4.5. TfOH-catalyzed AMCA in TCE .............................................................................. 48 Scheme 4.6. Formation of trimethyl trimesate from coumalic acid and methyl acetylenemonocarboxylate under acidic condition ....................................................................... 49 Scheme 4.7. 1,4-hydration of AMCA leading to coumalic acid ................................................... 50 Scheme 4.8. RuCl3-catalyzed 1,4- and 1,3- hydration of acetylene compounds .......................... 51 Scheme 4.9. Ru-catalyzed 1,3-hydration of AMCA to pyruvic acid ............................................ 51 Scheme 4.10. Proposed mechanism: 1,3- vs. 1,4-hydration of AMCA ........................................ 52 Scheme 4.11. Mechanism to muconic and hydroxymuconic acid in Mo catalysis ...................... 54 Scheme 4.12. Hydration of AMCA catalyzed by RuCl3 .............................................................. 54 Scheme 4.13. Mechanistic analysis of Ru-catalyzed hydration of AMCA .................................. 57 Scheme 4.14. The pyrone route leading to terephthalic, isophthalic and phthalic acids from methane and carbon dioxide ......................................................................................................... 58 Scheme 5.1. Conversion of AMCA to pyrone and aromatic products ......................................... 79 xiii KEY TO ABBREVIATIONS AMCA BOB(OAc)4 CBA DCE DBU DEHP DINCH Exp. HOAc h HPLC IPA NADH NMR PA PET PLA PTA PVC PvOH p. acetylenemonocarboxylic acid tetraborylacetate 4-carboxybenzaldehyde 1,2-dichloroethane 1,8-diazabicyclo[5.4.0]undec-7-ene di(2-ethylhexyl)phthalate diisononyl cyclohexane 1,2-dicarboxylate Experiment acetic acid hour high pressure liquid chromatography isophthalic acid nicotinamide adenine dinucleotide, reduced nuclear magnetic resonance phthalic acid poly(ethylene terephthalate) poly(lactic acid) purified terephthalic acid poly(vinyl chloride) pivalic acid page xiv TCE TfOH 1,1,2,2-tetrachloroethane triflic acid xv CHAPTER 1: INTRODUCTION Terephthalic 1, isophthalic 2 and phthalic 3 acids are large volume commodity chemicals manufactured from the Amoco-MidCentury oxidation of petroleum-derived xylenes.1 Annually, an estimate of 50 × 109 kg of terephthalic acid 1 are globally manufactured from p-xylene and polymerized with ethylene glycol to form poly(ethylene terephthalate), PET.2 Approximately 1.5 × 109 kg of isophthalic acid (IPA) 2 is produced globally each year from m-xylene.1 The reaction conditions for oxidation of terephthalic acid and isophthalic acid are similar and enable production facilities to be used interchangeably for these two oxidations. Whereas terephthalic acid is the “straight” monomer that dominates PET formulations, isophthalic acid is the “bent” co-monomer that is typically added in much smaller concentrations.1 The content of IPA in PET is typically only 5-7% of purified terephthalic acid (PTA). However, the “bent” IPA is critical to lowering melt process temperatures and inhibiting crystallinity in route to achieving clear, transparent PET. Phthalic acid (PA) 3, obtained from oxidation of o-xylene, has been dominantly esterified to yield di(2-ethylhexyl)phthalate (DEHP) for plasticizer applications, up to 6.0 × 109 kg annually.3 Plasticizers are not covalently attached to poly(vinyl chloride) (PVC), they can diffuse through and volatize out of the polymer. Claims have been made linking DEHP to damaged sexual development in neonatal infants and reproductive problem in rodents. This has led to replacement of phthalate esters in plasticizer applications with diisononyl cyclohexane 1,2-dicarboxylate (DINCH), which is obtained by hydrogenating diisononyl phthalate. Not only that current manufacture of terephthalic, isophthalic, and phthalic acids are using nonrenewable xylenes, the Amoco-MidCentury oxidations to produce aromatic diacids from xylenes are also high carbon footprint processes which will be addressed later in this chapter. As 1 part of a larger effort to address the issue of increasing atmospheric concentration of greenhouse gases, an alternate strategy is to replace the use of petroleum-derived xylenes with abundant C1- chemical feedstock such as methane and carbon dioxide. CO2H CO2H 1 CO2 terephthalic acid TPA CO2H p-xylene m-xylene CO2 2 CO2H isophthalic acid IPA CO2H CO2H CO2 o-xylene 3 phthalic acid PA parafinnic oil naphthenic oil Current synthesis from petroleum-derived xylenes O O O O O O O O Poly(ethylene terephthalate) PET O O O O di-(2-ethylhexyl) phthalate DEHP O O O O diisononyl cyclohexane-1,2-dicarboxylate DINCH Figure 1.1. Oxidation of petroleum-derived xylenes to terephthalic, isophthalic and phthalic acids The work carried out in this thesis focused on developing concise syntheses of terephthalic, isophthalic, and phthalic acids from methane and CO2-derived starting materials such as isoprene and acetylenemonocarboxylic acid (AMCA). Previous work in the Frost group explored the Alder Route as a xylene-free three-step synthesis of terephthalic and isophthalic acids using isoprene and acrylic acid as C1-derived starting materials (Scheme 1.4). The Propiolate Route, presented in chapter 2, while still using isoprene as a starting material, explored AMCA instead of acrylic acid, resulted in a straightforward two-step synthesis to C-8 terephthalic and isophthalic acids. AMCA can be synthesized in two steps directly from methane and CO2, while acrylic acid requires a multi- step synthesis. Chapter 3 presents the Pyrone Route which focuses on catalyzed conversion of 2 AMCA as a single starting material to all three C-8 terephthalic, isophthalic and phthalic acids via two pyrone intermediates – coumalic and isocoumalic acids. Cycloadditions of pyrones and AMCA to selectively form terephthalic and phthalic acids are also included in Chapter 3. With AMCA as the starting material, virtually all terephthalic, isophthalic and phthalic acids can be derived from methane and carbon dioxide, the Pyrone Route not only eliminates petroleum-derived xylenes as chemical feedstocks to targeted aromatic products but also eliminates the high-carbon footprint Amoco-MidCentury oxidation. Mechanistic studies of catalyzed conversion of AMCA to pyrone intermediates and byproducts trimellitic and trimesic acids via 1,3- and 1,4-hydration pathways are presented in Chapter 4. As part of an application of the 1,3-hydration pathway, synthesis of pyruvic acid from AMCA afford a pathway to lactic acids as monomers of biodegradable poly(lactic acid) (PLA). 1. Amoco-MidCentury oxidation of xylenes to terephthalic, isophthalic and phthalic acids Terephthalic acid industrially comes from the Amoco-MidCentury oxidation of p- xylene.1 The same process can be used to produce isophthalic acid from m-xylene.1 Phthalic acid and phthalate anhydride can be obtained via oxidation of o-xylene, either based on the Amoco- MidCentury oxidation or V2O5 oxidation.10 Scheme 1.1. Amoco-MidCentury oxidation of p-xylene and purification of terephthalic acid 3 Scheme 1.2. Propagation and catalytic cycle of p-xylene oxidation to terephthalic acid The Amoco-Midcentury oxidation is a radical process using Br radical as the radical initiator to abstract a H atom from the arylmethyl of p-xylene to from a p-xylene radical. Upon reacting with oxygen, p-xylene formed peroxide 5 which generates another p-xylene radical and peroxide 6. p-Tolualdehyde 7 is formed as peroxide 6 collapsed to generate hydroxy radical and oxidize Co2+ to Co3+. As Br radical abstract the aldehydic proton of 7 followed by reacting with oxygen, peroxide radical 9 is formed. Peroxide 9 abstracts a H atom from p-xylene to form a p- xylene radical and peracid 10. p-Tolualdehyde 7 and peracid 10 reacts in a Baeyer-Villiger reaction to form two molecules of p-toluic acid which can go through another cycle of oxidation to form terephthalic acid. In order to regenerate Co2+, Mn2+ is oxidized by Co3+ and formed Mn3+, which in turn can be reduced by Br anion to regenerate Br radical initiator and Mn2+. 4 Synthesis of PTA from p-xylene highlights many of the challenges inherent in selective oxidation of xylene arylmethyl groups. Amoco-MidCentury oxidations are radical chain reactions employing NaBr and CBr4 as chain propagators in HOAc as solvent.1 Use of halide reagents in the process leads to metal corrosion and therefore requires that pressure reactors required for the oxidation to be constructed from Ti0.1 During the catalytic oxidation of p-xylene, 165 kg of CO2 is generated for each 1000 kg of purified terephthalic acid produced (Scheme 1).4 Of this CO2, 40% comes from over-oxidation of p-xylene and 60% comes from oxidation of the HOAc used as solvent.4a Decarboxylation of HOAc solvent leads to generation of copious quantities of CH4, which has a 25-fold greater impact on climate change relative to CO2 on a wt/wt basis.4b The Amoco-MidCentury oxidation therefore has a sizable carbon footprint. Oxidation of terephthalic acid is never a complete process, which leads to contamination by the partially oxidized 4-carboxybenzaldehyde (CBA) (Scheme 1). In order to form high molecular weight PET, purified terephthalic acid participating in the polycondensation with ethylene glycol has to be 99.99% pure with a maximum of 25 ppm of CBA.5 Removing CBA contamination, therefore, requires an extra step to hydrogenate CBA to p-toluic acid in a pressurized, continuous flow trickle bed reactor containing immobilized Pd/C with a counter flow of H2.11 Crude terephthalic acid solution in water is passed through the reactor, allowing purified terephthalic acid to recrystallize while p-toluic acid remains in solution (Scheme 3).5 Prior to elaboration of CBA hydrogenation/selective crystallization of terephthalic acid from water to obtain PTA, crude terephthalic acid was converted to its methyl ester, which was purified by distillation. Polymerization of dimethyl terephthalate with ethylene glycol to produce PET led to generation of flammable CH3OH. Byproduct CH3OH had to be collected, purified, and reused, which is problematic from an atom economy and process chemistry perspective. 5 Generation of nonflammable H2O during polymerization of the free acid PTA with ethylene glycol quickly displaced use of dimethyl terephthalate in polymerization with ethylene glycol to form PET. 2. Methane and carbon dioxide as C1 chemical feedstocks The U.S. has 16 × 1012 m3 of proven dry natural/shale gas reserves and an estimated 474 × 1012 m3 of total CH4 reserves.6 The amount of methane hydrate off the U.S. coast is estimated at 1500 × 1012 m3. For comparison, the U.S. annually consumes 0.74 × 1012 m3 of CH4.7-9 Renewable biogas production from landfill, wastewater treatment, and industrialized livestock facilities has the potential of supplying 6.0 × 1010 m3/year of CH4, which could serve as a source of the 4.6 × 103 m3/year of methane consumed by the U.S. chemical industry.4 Human activities also introduce 22 × 1012 m3 of CO2 into the atmosphere annually.4 As carbon dioxide concentration continues to rise, one of the consequential impacts is global food security.10 The elemental chemical composition of a plant balances between carbon from atmospheric CO2 and the remaining nutrients from soil.10 Projected increases of CO2 can result in an ionomic imbalance for most plant species which in turns will have critical consequences for human nutrition including protein and other micronutrients, especially in rice-dependent populations.10 Given their abundances and impacts on global climate change, CH4 and CO2 are attractive C1 chemical feedstocks in place of petroleum derived- xylenes for synthesis of large volume commodity chemicals such as terephthalic, isophthalic and phthalic acids. 6 3. Synthesis of biobased starting materials to terephthalic, isophthalic and phthalic acids 3.1. Glucose-derived starting materials to terephthalic acid As commercial production of PTA and IPA relies on fossil fuel cost, there has been alternative routes to bio-based PTA and IPA using glucose-derived starting materials to extend the variety of available chemical feedstocks and avoid xylene intermediacy.11-36 Scheme 1.3. Glucose-derived starting material to bio-based terephthalic acid. However, as global population expected to reach 9.5-13 billion people by 2100, it is predicted that 1 out of 9 people on Earth is or will be starving.37 Additionally, the U.S. will turn 5 billion bushels of corn into ethanol which is enough food to feed 412 million people for an entire year. As a result, converting glucose-derived starting materials to commodity chemicals was problematic consequences. 3.2. The Alder route to terephthalic and isophthalic acids In the early 1950’s, Kurt Alder investigated the electrocyclic ring-opening reaction of methylenecyclobutane 12.38 A cycloaddition trapping reaction using acrylic acid 14 was employed 7 to establish isoprene 13 as the ring-opened product. Research in the Frost group prior to the work in this thesis has established the Alder route to TPA and IPA based on the cycloaddition of isoprene 13 and acrylic acid 14 (Scheme 1.4). Scheme 1.4. Alder route to terephthalic and isophthalic acid a (a) TiCl4 or BOB(OAc)4, (2 mol%), neat, rt, 15(89%),16(4%). (b)/(b’) 5 wt% Pd on C, 240°C, 0.11 bar, p-toluic acid (77%), 17a(12%), 17b(9%),m-toluic acid (69%), 18a(10%), 18b(13%). (c)/(c’) Co(OAc)2 (0.5 mol%), Mn(Oac)2 (0.5 mol%), N-hydroxysuccinimide, O2, HOAc, 100°C, 1(94%), 2(88%). TiCl4-catalyzed cycloaddition of isoprene 13 and acrylic acid afforded 14 para- cycloadduct 15 and meta-cycloadduct 16, which undergo a dehydrogenative aromatization to form p-toluic acid and m-toluic acid, subsequently. An Amoco-Midcentury Oxidation of toluic acids yielded terephthalic and isophthalic acids, respectively. The Alder route has a number of advantageous features. (a) Acrylic acid can be synthesized via a microbial synthesis from glucose while isoprene comes from a steam reforming of methane followed by methanol to olefin (MTO) catalysis.39-42 (b) The Alder route enables access to both PTA and IPA, with high selectivity toward higher-demanded PTA. (c) The Alder route entails a Lewis acid-catalyzed solvent free cycloaddition of unprotected acrylic acid, which leads to free acid product that is ready for polymerization with ethylene glycol to form PET. Catalyzing reaction of unesterified carboxylic acids has remained a problem in synthetic chemistry, often necessitating the use of an ester derivative in place of the free acid. However, no PET is currently produced from polymerization of diesterified terephthalate with ethylene glycol. This follows from the need to capture and recycle byproduct alcohol, which is problematic from an atom economy and process 8 chemistry perspective. By contrast, polymerization of PTA and with ethylene glycol produces nonflammable water, which does not require capture and recycling. With both acrylic acid and isoprene are methane-derived starting materials, the Alder route therefore is the first synthesis to terephthalic and isophthalic acids from the greenhouse gases CH4 and CO2. One significant challenge with the Alder route is the formation of byproduct cyclohexanedicarboxylic acid 17ab and 18ab during the aromatization of cycloadducts 15 and 16. Formation of the cyclohexanedicarboxylic acid siphons away 20-25% of cycloadducts.3 Loss of the activated allylic H atom for Pd(0) insertion means that aromatization of cyclohexanedicarboxylic acid likely requires cracking temperature (>500 ˚C) rather than the relatively mild temperatures required (240˚C) for aromatization of cyclohexenyl cycloadducts.3 Aromatization of cyclohexenes is a long standing problem in synthetic chemistry.43-45 Another challenge of the Alder route is the use of Amoco-MidCentury Oxidation to convert toluic acids to terephthalic and isophthalic acids. With the Amoco-MidCentuty process as a high- carbon footprint due to overoxidation of starting material and decomposition of HOAc to methane and CO2, as well as formation of byproduct cyclohexanedicarboxylic acids, the Propiolate route was developed in the Frost group to avoid these challenges. 3.3. The Propiolate route to terephthalic and isophthalic acids The Propiolate route to PTA and IPA was explored based on the cycloaddition of methane- and carbon dioxide-derived AMCA 19 and isoprene 13.46 The more reactive 1,4- and 1,3- cyclohexadiene 20 and 21 were designed to undergo aromatization without competing formation of a cyclohexane byproduct. Trace amounts of p-toluic acid was detected, which promoted examination of catalyst-free oxidative aromatization of cyclohexadienes and the discovery that heating cyclohexadiene 20 with HOAc at 100˚C under O2 led to p-toluic acid.46 Accordingly, 9 reaction of cyclohexadiene 20 under O2 using N-hydroxysuccinimide as the chain carrier catalyzed by Co(OAc)2 and Mn(OAc)2 lead to terephthalic acid. Synthesis of terephthalic and isophthalic acids becomes a two-step route without cyclohexanedicarboxylic acids byproduct. The cycloaddition of AMCA and isoprene will be discussed in detail in Chapter 2. Scheme 1.0.5. The Propiolate Route to Terephthalic and Isophthalic Acids (a) toluene, 60°C, 67%. (b) Co(OAc)2 (5 mol%), Mn(Oac)2 (5 mol%), N-hydroxy-succinimide (20 mol%), O2, HOAc, 100°C, 85%. While the Propiolate route is one step shorter than the Alder route, it still requires a dehydrogenative aromatization and oxidation of the methyl group derived from isoprene. Both the Alder and Propiolate Routes were not able to eliminate the use Amoco-MidCentury Oxidation and are not a route to phthalic acid. As we were exploring new route to all three C-8 diacids, the Pyrone Route was discovered which does not require oxidation of an arylmethyl group. With the Pyrone Route, terephthalic, isophthalic, and phthalic acids are all derived from a single starting material – AMCA 19. 10 3.4. The Pyrone route to terephthalic, isophthalic and phthalic Acids Scheme 1.6. The Pyrone route to terephthalic, isophthalic and phthalic Acids (a) MoCl5, 0.8 mol%, AgSbF6, 4.0 mol%, dioxane, 100 ˚C, 12h or [RuCl2(p-cymene)]2, 5.0 mol%, AgSbF6, 20 mol%, HOAc, 80 ˚C, 12 h. (b) TiCl4, 5.0 mol%, toluene, 110 ˚C, 12 h. With AMCA as the single starting materials, the Pyrone Route eliminates the use of isoprene. With all carboxylic acids come from AMCA, no Amoco-MidCentury Oxidation process is required, leaving this route as a lower carbon footprint synthesis than the Alder and Propiolate Routes. Catalyzed conversion of AMCA generates all three C-8 diacids via 2 pyrone intermediates: coumalic and isocoumalic acids. The Pyrone route entails two steps: (1) conversion of AMCA to coumalic and isocoumalic acids and (2) cycloaddition of pyrone intermediate with AMCA to form terephthalic, isophthalic and phthalic acids. Screening of catalysts to optimize the pyrone route will be included in detail in Chapter 3, and mechanistic studies leading to coumalic and isocoumalic acids will be discussed in Chapter 4. 11 4. Synthesis of isoprene and acetylenemonocarboxylic acid from methane and carbon dioxide 4.1. Synthesis of isoprene from methane Scheme 1.7. Isoprene from methane (a) Ni on Al2O3 800 °C, 35 bar. (b) CuO/ZnO on Al2O3, 250 °C, 50 bar. (c) SAPO-34, 460 °C, 1 bar. (d) WO3/SiO2 260 °C, 35 bar. (e) Fe2O3/Cr2O3/ K2CO3, 600 °C. Synthesis of renewable isoprene 13 from biogas methane with steam-reforming of biogas methane to CO and reduction to MeOH. Propylene 24 and isopropylene 25 derived from MeOH using methanol to olefin (MTO) catalysis undergo cross metathesis to produce 2-methyl-2-butene 26.41,42 This cross metathesis is a modification of the original Phillips Triolefin Process and the currently practiced OCT routes to synthesis of propylene from 2-butene and ethylene.43 Byproduct ethylene can conceivably be converted into the ethylene glycol 27 required for polymerization with terephthalic acid to form PET. 4.2. Synthesis of AMCA from methane and carbon dioxide Scheme 1.8. AMCA from methane and carbon dioxide (a) 1,500-1,900 °C. (b) Cu+ or DBU. (c) PbO anodic oxidation. (d) Na2Cr2O7, H2SO4. 12 The work completed in this thesis mainly used AMCA purchased from Sigma-Millipore. Prior to 2018, commercial AMCA were isolated as a byproduct of an anodic oxidation of 1,4- butynediol 28 using a PbO anode.47 Main contaminants of AMCA during that period were water and HOAc, which can be removed via distillation under reduced pressure. More recently, commercial AMCA is synthesized from oxidation of propargyl alcohol 29 using Cr(VI) oxide in sulfuric acid.48 Aside from H2O contamination, propargyl aldehyde 30 is generated as a contaminating byproduct. The amount of aldehyde 30 contaminating AMCA varies from batch to batch. After distillation AMCA usually is contaminated with 2 mol% aldehyde. Other sources of commercial AMCA contained 10-25% ethyl acetate which poses a challenge in obtaining pure AMCA due to formation of other byproducts such as ethanol, HOAc, and ethyl acetylenemonocarboxylate during distillation. Conversion of methane into acetylene followed by carboxylation of acetylene leads to AMCA. A variety of different approaches for synthesis of acetylene from methane have been commercialized.40 A recently described dehydrodimerization route employs a supersonic reactor to achieve yields up to 95% for methane to acetylene conversion. Carboxylation of acetylene has been reported using (4,7-diphenylphenanthroline)-bis(triphenylphosphine) copper (I) nitrate or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst.49 Two-step synthesis of AMCA from methane and carbon dioxide potentially avoid byproducts such as propargyl aldehyde, HOAc, and ethyl acetate. At high concentrations, these byproducts result in low yielding of aromatic products from the catalyzed conversion of AMCA. 13 REFERENCES 14 REFERENCES 1. (a) Park, C. –H.; Sheehan, R. J. Phthalic acids and other benzenepolycarboxylic acids. Kirk- Othmer Encyclopedia of Chemical Technology 2000. (b) Partenheimer, W. Methodology and scope of metal/bromide autoxidation of hydrocarbons. Catalysis Today 1995, 23, 69-157. (c) Tomás, R. A. F.; Bordado, J. C.M.; Gomes, J. F. P. p-Xylene oxidation to terephthalic acid: a literature review oriented toward process optimization and development. Chemical Reviews 2013, 113, 7421-7469. 2. Bizzari, S. N.; Blagoev, M.; Kishi, A. 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Process for preparing propiolic acid or a derivative thereof. U. S. Patent 9,073,844 July 7, 2015. (b) Wang, X.; Lim, Y. N.; Lee, C.; Jang, H. -Y.; Lee, B. Y. 1,5,7-Triazabicyclo[4.4.0]dec-1-ene-mediated acetylene decarboxylation and alkyne carboxylation using carbon dioxide. Eur. J. Org. Chem. 2013, 1867-1871. 18 CHAPTER 2: THE PROPIOLATE ROUTE TO TEREPHTHALIC & ISOPHTHALIC ACIDS 1. Introduction Elevation in atmospheric concentrations of greenhouse gases as well large reserves of both methane and methane hydrates could pave the way for carbon dioxide and methane to become the dominanting C-1 feedstocks in chemical synthesis and manufacture. Synthesis of large-volume, economically-important chemicals such as terephthalic acid and isophthalic acid from C-1 feedstocks CH4 and CO2 avoids petroleum and glucose-derived starting materials. Inspired by the challenge in the dehydrogenative aromatization of cycloadduct 15 to p-toluic acid in the Alder route due to loss of 20-25% formation of cyclohexane byproduct, the Propiolate Route was developed based on substitution of acetylenemonocarboxylic acid (AMCA) 19 for acrylic acid 14 to lead to cycloadduct 20 that was more reactive toward aromatization relative to cycloadduct 15 (Scheme 2.1).1 Scheme 2.1. The Alder and Propiolate routes to terephthalic acid A one-pot cascade oxidation of the intermediate cyclohexadiene cycloadduct 20 in HOAc using O2 as oxidant with N-hydroxysuccinimide as the chain carrier catalyzed by Co(OAc)2 and 19 Mn(OAc)2 led to terephthalic acid 1 with no cyclohexane formation.1 Some earlier problems encountered in the Propiolate Route were conversion and selectivity of cycloadducts 20 and 21 (Scheme 2.2) and respectively terephthalic and isophthalic acids. Isophthalic acid are only at 5- 7% of PET, it is necessary for the cycloaddition of isoprene and AMCA to be more selective toward p-cycloadduct 20. The work described in this chapter focuses on optimization to increase selectivity in cycloadduct 20 formation via manipulation of different conditions: temperature, concentration of AMCA in solvent, and isoprene/AMCA ratios. Scheme 2.2. Cycloaddition of isoprene and AMCA 2. Cycloaddition of isoprene and acetylenemonocarboxylic acid 2.1. Effect of temperature As part of optimizing the cycloaddition of isoprene and AMCA, variation of reaction temperature was explored. Due to the reactive nature of AMCA and to avoid runaway polymerization in solvent-free conditions, the cycloaddition was run in a titanium vessel under nitrogen atmosphere. The Initial concentration of AMCA was chosen at 5% wt/wt in toluene (0.6M), and the relative mol/mol ratio of isoprene and AMCA was 1:1. Table 2.1. Effect of temperature on cycloaddition of isoprene and AMCA aEntry 1 2 3 Reaction Temp. % Yield b (˚C) 120 21 60 para – 20 meta - 21 43c 0 30d 24 0 9 a 5% wt/wt of AMCA in toluene, 0.6M, 1:1 mol/mol ratio of isoprene 13 to AMCA 19, 24 h. b Determined by GC. c 15% isolated yield. d 21% isolated yield. 20 At 120 ˚C, cycloaddition of isoprene and AMCA reached 67% total yield of both 20 and 21 with 1.8:1 para 20/meta 21-selectivity. (Table 2.1, entry 1). However, purified para- cycloadduct isolated from the product mixture by recrystallization from toluene afforded only a 15% yield. At 21 ˚C, no product was formed in the reaction (Table 2.1, entry 2). While total yield of para 20 and meta 21 was only 39%, at a reaction temperature of 60 ˚C, the para 20/meta 21- selectivity increased to 3.3:1 with 21% of para 20 being isolated from the product mixture by recrystallization from toluene (Table 2.1, entry 3). Further optimization of the cycloaddition therefore was done at 60 ˚C where the para-selectivity and isolated yield of purified para 20 were improved. 2.2. Effect of concentration on cycloaddition of isoprene and AMCA The next parameter to be evaluated in the cycloaddition of isoprene and AMCA is the concentration of starting materials in toluene. While isoprene is miscible in nonpolar solvents such as toluene, hexane, and xylenes, there is however a limit to solubility of AMCA in such solvents. At the same time, Diels-Alder cycloadditions favored by highest possible concentrations with solvent-free reaction conditions frequently being ideal. Therefore, concentration of AMCA in toluene was utilized as a parameter to optimize the cycloaddition. Two boundary conditions were set: (1) solvent-free and (2) 50% wt/wt of AMCA in toluene, where AMCA and toluene appeared to be immiscible at room temperature at the beginning and end of the reaction. The molar ratio of isoprene and AMCA was maintained at 1:1. Solvent-free cycloaddition of isoprene and AMCA showed promising results, with a total yield of 52% and para 20/meta 21-selectivity of 3.7:1 (Table 2.2, entry 1). However, the product mixture appeared to be a red tacky solid from which 20 was unable to be isolated by recrystallization in toluene. Solvent-free cycloaddition of isoprene and AMCA therefore was not 21 pursued any further. The increase para 20/meta 21-selectivity in solvent-free reaction can be explained by better overlapping of HOMO-isoprene and LUMO-AMCA without interference of solvent. While there were no significant difference going from 5 to 10 wt.% of AMCA in toluene in terms of yield and para 20/meta 21-selectivity, at 25% wt/wt, total yield of 20 and 21 increased to 60% while maintaining para 20/meta 21-selectivity of 3:1 (Table 2.2, entries 2-4). Table 2.2. Effect of concentration of AMCA on cycloaddition of isoprene and AMCA Entrya 1 2 3 4 5 AMCA in tol % Yieldb M -- 0.6 1.2 3 6 wt.% para – 20 meta - 21 solvent-free 5 10 25 50 41c 30 30 45 19 11 9 10 15 5 a 1:1 mol/mol ratio of isoprene 13 to AMCA 19, 24 h reaction. b Determined by GC. c Unable to isolate 20 from product mixture. At 50 wt.% of AMCA in toluene, while the para 20/meta 21-selectivity, the total yield of the reaction suffered (24%). AMCA precipitated from the reaction mixture and formed a thick red liquid. Therefore, 25 wt.% was chosen as the concentration of AMCA in toluene for further optimization of the cycloaddition. 2.3. The impact of isoprene and AMCA mole ratios on cycloaddition yield In order to improve the yield of the cycloaddition, different molar ratios of isoprene and AMCA were explored. Mole ratios including a 1:1 isoprene:AMCA, 5:1 isoprene:AMCA and 1:5 isoprene:AMCA. The temperature of the reaction was set at 60 ˚C and the concentration of AMCA in toluene throughout different molar ratios was maintained at 25 wt.%. 22 Table 2.3. Isoprene/AMCA ratio on cycloaddition of isoprene and AMCA Entrya Isoprene:AMCA % Yield (mol/mol)b (mol/mol) para – 20 meta – 21 1 2 3 4 5 6 1:1 1:2.5 1:5 2.5:1 5:1 5:1 45 33 40 43 66 72c 15 9 10 20 22 24 a 25 wt.% of AMCA in toluene, 24 h reaction. b Determined by GC. c 67% isolated yield, 36h reaction. With a 1:2.5 (mol/mol) isoprene:AMCA ratio, the para 20/meta 21-selectivity reached 3.8:1 (mol/mol ratio) at a lower total yield of para 20 and meta 21 compared to the total yield of the reaction using equimolar of isoprene and AMCA (Table 2.3, entries 1-2). A 1:5 (mol/mol) isoprene:AMCA improved para 20/meta 21-selectivity further and total yield increased to 50% (Table 2.3, entry 3). With a 2.5:1 (mol/mol) isoprene:AMCA ratio, the para 20/meta 21-selectivity lowered to 2.1:1 while total yield remained unchanged compared to the equimolar reaction (Table 2.3, entries 1 and 4). A 5:1 (mol/mol) isoprene:AMCA ratio led to a significant improvement observed in both total yield (88%) of cycloadducts para 20 and meta 21. (Table 2.3, entry 5). Extended reaction time (36 h) at 5:1 (mol/mol) isoprene:AMCA ratio led to a 96% total yield of para 20 and meta 21, with 67% isolated yield of 20. 2.4. Tetraborylacetate and TiCl4-catalyzed cycloaddition of isoprene and AMCA Polymerization reactions encountered during Lewis acid catalyzed cycloaddition involving substrates having an unesterified carboxylic acid has generally required esterification of carboxylic acid. However, during developing the Alder route to terephthalic and isophthalic acids from 23 isoprene and acrylic acid, TiCl4 and tetraborylacetate (BOB(OAc)4) were discovered to catalyze the cycloaddition without polymerization of isoprene, leading to high the para:meta-selectivity in the cycloadditions.2-4 BOB(OAc)4 was synthesized from boric acid and acetic anhydride in toluene in gram-scale.4 HCl is a common byproduct which is corrosive to stainless steel reactors and generates halide waste in in industrial manufacture when metal halides are employed as catalyst. By contrast, BOB(OAc)4 catalysis results in no halide formation while leading to yield and para/meta selectivity in cycloaddition of isoprene and acrylic acid comparatable to the para/meta selectivity and total yield of cycloaddition products observed with TiCl4-catalysis.4 Scheme 2.3. Synthesis of BOB(OAc)4 While uncatalyzed cycloaddition of isoprene and AMCA led to a high total yield of cycloaddition products in toluene, could a catalyst be used to improve para 20/meta 21-selectivity? Given the established impact of TiCl4 and BOB(OAc)4 catalysis the total yield of cycloaddition products and para/meta selectivity of acrylic acid reaction with isoprene, each catalyst was employed in the reaction at optimized conditions of uncatalyzed cycloaddition of isoprene and AMCA with TiCl4 and BOB(OAc)4 concentration of 5 mol% relative to AMCA concentration initially. Scheme 2.4. TiCl4 and BOB(OAc)4 complexes with acrylic acid 24 TiCl4 catalysis was unable to lead to formation of product. As isoprene was added into the TiCl4-AMCA complex in isoprene, the reaction mixture rapidly darkened with the formation of a black precipitate and consumption of all starting materials (Table 2.4, entry 1). Higher loading of TiCl4 therefore was not investigated. BOB(OAc)4 catalysis at 5 mol% led to promising 6.5:1 (mol/mol) para 20/meta 21- selectivity but the catalyzed reaction was low yielding. Increasing catalyst loading to 100 mol% only lead to a 36% total yield of 20 and 21 (Table 2.4, entry 4). Table 2.4. Effect of TiCl4 and BOB(OAc)4 on cycloaddition of isoprene and AMCA Entrya Catalystc % Yield (mol/mol)b para – 20 meta - 21 1 2 3c 4d uncatalyzed TiCl4 BOB(OAc) BOB(OAc)d 66 0 13 31 22 0 2 5 a 25 wt.% of AMCA in toluene (1.2M) isoprene/AMCA (5:1 mol/mol), 24 h reaction. b Determined by GC. c 5 mol%. d 100 mol%. Even though BOB(OAc)4 catalysis led to improved p/m selectivity, the uncatalyzed reaction was able to achieve a significantly higher total yield (96%) (Table 2.3, entry 5). A reason could be that due to BOB-AMCA complex has low solubility in toluene and precipitated out of reaction, sequestering away AMCA needed to react with isoprene, leading to low yielding. BOB and TiCl4 catalysis of isoprene and AMCA provided preliminary knowledge of dealing with catalyzed conversion of AMCA in the Pyrone Route presented in Chapter 3. Substituting AMCA for acrylic acid as the dienophile in the reaction with isoprene eliminates formation of cyclohexane byproducts during cycloadduct aromatization in the Alder route. Aromatization and oxidation of the methylaryl group are also conveniently accomplished in a one-pot, cascade oxidation of the cyclohexadienes 20 and 21. With both AMCA and isoprene 25 derived from CH4 and CO2, the Propiolate Route established a concise synthesis of terephthalic and isophthalic acids from abundant C-1 chemical feedstocks. 26 REFERENCES 27 REFERENCES 1. Zhang, P.; Nguyen, V.; Frost, J. W. Synthesis of terephthalic acid from methane. ACS Sustainable Chem. Eng. 2016, 4, 5998-6001. 2. Barrow, H.; Brown, D. A.; Alcock, N. W.; Errington, W.; Wallbridge, M. G. H. Titanium oxo carboxylate compounds. Crystal and molecular structures of [{TiCl2(O2CEt)(EtCO2H)}2O] and [Ti3Cl3O2(O2CEt)5 and an Unusual Quantitative Conversion of a Ti2O to a Ti3O2 Oxo Derivative. Chem. Soc. Dalton Trans. 1994, 3533-3538. 3. Miller, K. K.; Zhang, P.; Nishizawa-Brennen, Y.; Frost, J. W. Synthesis of biobased terephthalic acid from cycloaddition of isoprene with acrylic acid. ACS Sustainable Chem. Eng. 2014, 2, 2053-2056. 4. Zhang, P.; Kriegel, R. M.; Frost, J. W. B-O-B catalyzed cycloadditions of acrylic acids. ACS Sustainable Chem. Eng. 2016, 4, 6991-6995. 28 CHAPTER 3: THE PYRONE ROUTE FROM ACETYLENEMONOCARBOXYLIC ACID Catalyzed Conversion of Acetylenemonocarboxylic Acid to Terephthalic, Isophthalic and Phthalic Acids via Pyrone Intermediacy 1. Introduction While the Propiolate route formally established a strategy for synthesis of terephthalic and isophthalic acids from methane and CO2-derived isoprene and acetylenemonocarboxylic acid, there are a few shortcomings in this approach: (1) An Amoco-MidCentury oxidation step in HOAc is required to convert the 4-methyl-1,4-cyclohexandiene-1-carboxylic acid 20 and 5-methyl-1,4- cyclohexadiene-1-carboxylic acid 21 to terephthalic and isophthalic acids, respectively; and (2) No phthalic acid can be produced from methane and CO2 using the Propiolate route. To develop an approach that can access all three aromatic diacids and avoid employing an oxidation to introduce a carboxylic acid, different diene starting materials were explored that can ensure: (1) A cyclohexadiene is the product of a cycloaddition with AMCA; (2) Aromatization of the cyclohexadiene cycloadducts is spontaneous. Scheme 3.1. Isocoumalate to phthalate and isophthalate (a) potassium metal, t-BuOH, diethyl ether, 4 ˚C, 12 h.2 (b) H2O:H2SO4:HOAc ratio of 5:1:4 (v/v), 90 ˚C, 6 h.2 (c) [RuCl2(p-cymene)]2 (5 mol%), AgSbF6 (20 mol%), dioxane, PvOH, 110 ˚C, 12 h. (d) toluene, 140 ˚C, 16 h.3 29 To address synthesis of phthalic acid 3, isoprene is replaced with isocoumalic acid 23. Literature precedent showed that methyl isocoumalate 32 reacted with methyl acetylenemonocarboxylate 33 in toluene at 140 ˚C resulted in 63% yield of dimethyl phthalate and 37% yield of dimethyl isophthalate via proposed intermediacy of bicyclohexadienes 34 and 35, respectively.1 The conditions of esterified reaction indicates that uncatalyzed cycloaddition of isocoumalic acid 23 and AMCA will be slow and require higher temperature. However, bicyclohexadienes can undergo decarboxylative aromatization spontaneously and were not reported as part of the product mixture.1 Therefore, utilizing isocoumalic acid 23 will eliminate the use of Amoco-MidCentury oxidation entirely. Chemical synthesis of 23 started with aldol condensation of diethyl oxalate and ethyl crotonate using potassium t-butyl alkoxide in diethyl ether to form diethyl hydroxymuconate.2 Hydrolysis and lactonization of hydroxymuconate formed isocoumalic acid 23 under acidic condition.2 It was also reported that [RuCl2(p- cymene)]2/AgSbF6-catalyzed ethyl acetylenemonocarboxylate formed ethyl isocoumalate 31 in 45% yield.3 However, the NMR reported indicates that the product is actually ethyl coumalate. Therefore, it was unclear which was the right product of the reaction. Replacing ethyl acetylenemonocarboxylate by AMCA resulted in a mixture of both isocoumalic and coumalic acids, among other aromatic products which will be discussed in Section 2 of this Chapter. During catalyst screening to improve the yield and o/m- selectivity of cycloaddition of isocoumalic acid and AMCA, trace amounts of terephthalic acid 1 was observed in NMR spectra of BOB(OAc)4, CuCl2, and Cu(OTf)2-catalyzed reaction (Fig. 3.1). 30 a b d c Figure 3.1. 1H-NMR spectrum of BOB(OAc)4-catalyzed cycloaddition of isocoumalic acid and AMCA In theory, the reaction was supposed to only give meta- and ortho- bicyclic cycloadducts, which subsequently undergo decarboxylation to give isophthalic acid 2 and phthalic acid 3. The presence of terephthalic acid in the reaction mixture indicated that catalyzed conversion of AMCA directly to terephthalic acid in one step is possible. Based on what was observed in the Ru-catalysis, it was hypothesized that AMCA was converted to coumalic acid 23, which subsequently undergoes a cycloaddition with AMCA to form terephthalic and isophthalic acids. A wide range of catalysts were screened to optimize conversion of AMCA to coumalic, terephthalic, isophthalic acids, starting with AuCl based on a report indicating Au-catalyzed annulation [4+2] of AMCA and substituted alkenes to form pyrones.4 Scheme 3.2. The Pyrone route to terephthalic, isophthalic, and phthalic acids 31 This chapter will include two parts: (1) catalyzed conversion of AMCA 19 to terephthalic, isophthalic and phthalic acids, focusing on catalysts that can achieve higher than 50% total yield of products, and (2) cycloadditions of pyrone intermediates and AMCA. 2. Acid catalyzed conversion of AMCA to terephthalic, isophthalic and phthalic acids It was discovered in our lab that AMCA 19 as a single starting material, catalyzed by AuCl/AgSbF6, rapidly formed terephthalic and isophthalic acids (24% yield, 5:1 ratio) at 100˚C, along with coumalic acid 22 (5%) (Scheme 3.3a). Trimellitic 39 and trimesic 40 acids were also formed as byproducts (1% each). With AMCA formed in only 2 steps from methane and CO2, this reaction opens a promising avenue to synthesize terephthalic acid 1 from abundant chemical feedstock. Au-catalyzed reaction of AMCA is an intumescent reaction. Upon complexation with Au, a 1,4-C,O-dipole intermediate 37 is formed,4 which can decarboxylate to form a Au-acetylide 38 (Scheme 3.3b). Au-acetylide 38 can be protodemetalated to form acetylene, which can decompose upon heating to release H2 gas and C. The combination of evolved gas (CO2 and H2), heat, and carbonization could lead to the observed intumescence. Scheme 3.3. AuCl/AgSbF6-catalyzed AMCA to coumalic acid, isophthalic, and terephthalic acids. Catalysts across the periodic table in different solvents and temperatures were explored to optimize conversion of AMCA in high yield and selectivity. Metal catalysts were screened beyond AuCl, with the exception of Group V metals. Besides coumalic, isocoumalic, terephthalic, 32 isophthalic acids, trimellic 39 and trimesic 40 acids were often observed at the end of reaction as byproducts. Muconic acid 41 is another byproduct only observed in using Mo and Au catalysis. Figure 3.2. Catalysts screened to optimize conversion of acetylenemonocarboxylic acid with color coding based on total yield of pyrones and aromatic products Aside from AuCl, other metal chlorides in Group IX to Group XII that were screened were low yielding (1-20%) of pyrones and aromatic products. MoCl5 and [RuCl2(p-cymene)]2 are metal catalysts with highest reactivity in terms of total yield of pyrones and aromatic products. TiCp2Cl2, ZrCp2Cl2, and HfCp2Cl2 showed moderate activity with total yield of pyrones and aromatic products ranging from 20-50%. Super acids such as fluorosulfonic, triflic (TfOH), perfluorosulfonic, and hexafluoroantimonic acids (pKa -12 to -24) showed higher reactivity compared to weaker organic acids, with the best catalyst being TfOH. Hetereogeneous catalysts had low reactivity, with the exception of Dowex-50, which is sulfonic acid with polystyrene backbone. Data obtained from catalyst screening is included in Appendix A. 33 Table 3.1. Acids catalyzed conversion of acetylenemonocarboxylic acid Entry Catalyst 1a 20 4 19 1 0 3 1 0 2a 4 2 20 6 0 12 1 0 % Yield (mol/mol) 22a 5 0 15 60h 6 16 24 30 23b 0 8 1 0 24 24 12 20 39a 1 1 0 0 1 13 11 10 40a 1 1 6 7 1 12 2 2 41a 0 12 0 0 0 0 11 6 19b 13 10 9 12 0 0 7 9 Rxn Cond. dneat eTCE fneat gTCE cAuCl cAgSbF6 TfOH i[RuCl2(p- cymene)]2 jAgSbF6 kdioxane PvOH k,lHOAc cMoCl5 mAgSbF6 nneat odioxane 1 2 3 4 5 6 7 8 a Determined by HPLC. b Yield determined by HPLC. c 0.8 mol%. d 100 ˚C,1 h. e 100 ˚C, 12 h, under N2, TCE: 1,1,2,2-tetrachloroethane. f 15 mol%, 100 ˚C, 4 h; then 110 ˚C, 12 h. g 20 mol%, 25 wt%, 80 ˚C, 28 h. h Yield after isolation and recrystallization from MeOH. i 5 mol%. j 20 mol%. k 80˚C, 12 h. l 6% yield of benzoic acid. m 4.0 mol%. n 50 ˚C, 1 h. o 100 ˚C, 4 h. Yield of products in each reaction using other metal and organo-catalysts compared to AuCl is summarized in Table 3.1. With TCE as solvent and AuCl/AgSbF6 as catalyst (Table 1, entry 2), formation of terephthalic acid 1 diminished while muconic acid 41 emerged as a significant product. Higher selectivity in formation of terephthalic acid 1 in the solvent-free reaction of AMCA catalyzed by AuCl/AgSbF6 could come from cycloaromatization of muconic acid 41 and acetylene. The highest combined yield (39%) of terephthalic 1 and isophthalic 2 acids was achieved using TfOH as the catalyst under solvent-free condition (Table 3.1, entry 3). In TCE as solvent, TfOH catalysis afforded a 60% yield of coumalic acid 22 after isolation (Table 3.1, entry 4). A recent report of dimerization of ethyl acetylenemonocarboxylate affording ethyl isocoumalate in 45% yield employed [RuCl2(p-cymene)]2/AgSbF6 as catalysts.3 However, 1H- NMR and 13C-NMR reported of the product were identical to ethyl coumalate, making it uncertain 34 which product was formed in the reaction.3 Duplication of the reported reaction conditions led to a mixture of products using AMCA as substrate (Table 3.1, entries 5 &6). [RuCl2(p- cymene)]2/AgSbF6 catalysis in dioxane/pivalic acid formed isocoumalic acid 23 selectively over coumalic acid 22 (6.5:1 ratio, 30% yield) (Table 3.1, entry 5). Byproducts trimellic 39 and trimesic 40 acids, not reported in literature,3 were also observed (1:1 mol/mol ratio, 2% yield) (Table 3.1, entry 2). [RuCl2(p-cymene)]2/AgSbF6 was particularly sensitive to the solvent conditions used. In HOAc, [RuCl2(p-cymene)]2/AgSbF6 led to isocoumalic 23 and coumalic 22 acids (1.5:1 mol/mol ratio, 40%) (Table 3.1, entry 5). Terephthalic 1 and isophthalic 2 acids, neither observed in dioxane/PvOH reaction nor reported in literature,3 were formed in the reaction selectively toward isophthalic acid (1:4 mol/mol ratio, 15% yield) (Table 3.1, entry 6). Significant amount of trimellitic 39 and trimesic 40 acids were also observed (1:1 mol/mol ratio, 25% yield) while no muconic acid 41 was detected in the reaction (Table 3.1, entry 6). MoCl5 was reported to catalyze polymerization of poly(acetylenemonocarboxylic acid) in dioxane via a metathesis mechanism.6 MoCl5/AgSbF6 catalysis in solvent-free condition led to formation of coumalic 22 and isocoumalic 23 acids (2/1 mol/mol ratio, 36% yield) (Table 3.1, entry 7). Trimellitic 39 and trimesic 40 acids were also formed in the reaction (5/1 mol/mol ratio, 13% yield). Muconic acid 41 is a byproduct of the MoCl5/AgSbF6 and AuCl/AgSbF6 reactions not observed in [RuCl2(p-cymene)]2/AgSbF6 catalysis. 13C-NMR of trans,trans-muconic acid, however, is identical with reported poly(acetylenemonocarboxylic acid).6 Duplication of the reported reaction conditions catalyzed by MoCl5 to polymerize AMCA only resulted in muconic acid 41 and trace amounts of pyrones 22 and 23, confirming that there was no poly(acetylenemonocarboxylic acid) in the reaction. MoCl5/AgSbF6 catalysis in dioxane increased the yield of coumalic 22 and isocoumalic 23 acids (1.5:1 mol/mol ratio, 50% yield) while reducing 35 the amount of muconic acid 41 (6% yield) (Table 3.1, entry 8). Formation of 22 and 23 using [RuCl2(p-cymene)]2 versus MoCl5 catalysis is associated with formation of triacids 39 and 40. Proposed mechanisms leading to different product distribution will be discussed in Chapter 4. 3. Cycloaddition of pyrones and acetylenemonocarboxylic acid 19 3.1. Computational results HOMO-LUMO gap and orbital coefficients of methyl coumalate and methyl propiolate have also been reported, indicating that there should be no regioselectivity, same as experimental results.9 It was unclear whether these computational results have taken in the effect of different temperatures and solvents. However, there has been no reports in terms of reactivity, regioselectivity and HOMO- LUMO energy gap of the unesterified pyrones and AMCA. These calculations were done by Gaussian’09, at the HF/STO-3G//B3LYP/6-31G* level of theory (Scheme 9). The energy gap between HOMO-LUMO of dienes and dienophiles indicated that in the gas phase, without any adjustment in terms of temperature and solvation effects, cycloadditions of coumalic and isocoumalic with AMCA are normal electron demand Diels-Alder. 36 Scheme 3.4. HOMO-LUMO gaps and orbital coefficient of coumalic, isocoumalic and acetylenemonocarboxylic acids Orbital coefficients also indicated that for isocoumalic acid 23, there should be a slight selectivity toward ortho-cycloadduct, since the absolute value of C-1 is marginally higher than C4 (0.45 vs. 0.38) (Scheme 3.4). Coumalic acid 22, on the other hand, should have higher selectivity toward meta-cycloadduct, due to a greater difference in terms of orbital coefficients of C-1 (0.46) vs. C-4 (0.35) (Scheme 3.4). 3.2. Cycloaddition of isocoumalic acid and AMCA Diels-Alder reactions often require Lewis acid catalysis to increase para selectivity and reduce cycloaddition reaction temperatures. Solvent-free cycloadditions often lead to increased cycloaddition yields and eliminate toxicity, flammability and cost issues associated with solvent use and recycling. A list of Lewis acids screened and the best yielding condition for each catalyst is summarized in Table 3.2. 37 Isocoumalic acid 23 has a high melting point (232 ˚C) and low solubility in AMCA at rt. Therefore, either elevated temperatures or use of a solvent was necessary. Uncatalyzed Diels- Alder reactions of isocoumalic acid and AMCA with or without solvent showed limited regioselectivity (entries 1-3, Table 3.2), as expected from computational results. Cycloaddition proceeded at a much slower rate in solvent (entry 1, Table 3.2). At 150 ˚C, under solvent-free conditions, there was only a 52% conversion, with a 2/3 (mol/mol), ortho/meta selectivity (entry 2, Table 3.2). Full conversion of isocoumalic acid was achieved at an elevated temperature of 200 ˚C with 100% conversion and a 3/2 (mol/mol) ratio (entry 3, Table 3.2). Elevated temperature (150- 200 ˚C) and longer reaction time (3-6 h) also dehydrated phthalic acid to form phthalic anhydride. 38 Table 3.2. Lewis acid-catalyzed cycloaddition of isocoumalic and acetylenemonocarboxylic acids %Yield (mol/mol) Entry Catalyst Solvent Temp. (˚C) Rxn time 1a 2b 3a 4a 5b 6b 7a 8b 9b 10a 11b 12b 13b 14a Uncatalyzedf toluene Uncatalyzed Uncatalyzed TiCl4 f ZrCl4 HfCl4 TiBr4 f BOB(OAc)4 CuOTf Cu(OTf)2 f neat neat toluene neat neat toluene neat neat 1,4- dioxane 110 150 200 110 150 150 110 150 150 200 PhB(OH)2 neat 150 o- BrPhB(OH)2 neat 150 BH3.THF neat 150 12 h 6 h 6 h 12 h 3 h 12 h 12 h 6 h <1 h 6 h 6 h 6 h 6 h BCl3 f toluene 110 12 h 3c 0 0 9 75 5 2 20 1 23 20 23 2 8 4 42d 0 19 51 2 39 22 2 44 0 7 20 10 20 35 23d 94 48 0 8 18 58 60 0 58 65 15 70 40 20 2c 4 30 40 14 37 18 5 45 11 3 40 15 25 33 Isocoumalic acid 23 : AMCA 19 1:7 (mol/mol), 5 mol % catalyst. aReaction in Ti vessel. bReaction at 1atm N2. cDetermined by HPLC. dDetermined by NMR. f 0.2 M Pyrone. TiCl4 at 2 mol% catalyst loading led to a 23:1 para/meta selectivity and a 94% cycloadduct yield for the solvent-free cycloaddition of unesterified acrylic acid and isoprene at rt.23a Solvent- free cycloaddition of isocoumalic acid and AMCA catalyzed by TiCl4 led to no detectable product formation attendant with decomposition of the starting material. Results changed when the reaction was run with TiCl4 in a pressurized reactor with toluene as solvent (entry 4, Table 3.2). 39 The ortho/meta selectivity improved to 5.5:1, with a 94% total yield of aromatized products. Zr4+ and Hf4+ belong to the same group of near transition metals as Ti4+ but did not lead to the same selectivity. Both catalysts showed a slight improvement compared to the uncatalyzed reaction at the same condition but had no effect on ortho- versus meta- selectivity (entry 5, entry 6, Table 3.2). TiBr4–catalyzed reaction was run under the same conditions as entry 4 to compare with TiCl4. Good selectivity (ortho/meta; 6/1, mol/mol) was observed, but conversion was low in this reaction (entry 7, Table 3.2). BOB(OAc)4 is a less corrosive alternative to TiCl4 for para selective cycloaddition of acrylic acid and isoprene.7 BOB(OAc)4-catalyzed reaction afforded a 90% yield, and 1/1 (mol/mol) ortho/meta selectivity. Boron catalysts (entries 11-14, Table 3.2) leading to acyloxyborane and acylboronate intermediacy can enhance para selectivity in the cycloaddition of isoprene and acrylic acid.8,9 However, except PhB(OH)2, boron catalysts only resulted in low yields (entries 16 and 17, Table 3.2). PhB(OH)2-catalyzed reaction afforded 83% yield with a 1.1:1 (mol/mol) ortho/meta selectivity (entry 15, Table 3.2). Overall, TiCl4 is a catalyst that showed the best selectivity toward phthalic acid 3 formation. Even though none of the screened catalysts showed meta-selectivity, BOB(OAc)4 was the only catalyst found to increase isophthalic acid 2 to 45%. Extended reaction time for TiCl4-catalyzed reaction to 24 h under the same conditions resulted in 94% yield with a 5.7:1 ortho/meta selectivity. At a higher load of TiCl4 (20 mol%) relative to isocoumalic acid, after 12 h, the reaction resulted in 98% yield with a 4.2/1 (mol/mol), ortho/meta selectivity. 40 3.3. Cycloaddition of coumalic acid and AMCA Cycloaddition of coumalic acid 22 and AMCA required a lower mole ratio of pyrone 22 to AMCA (1:3) and lower temperature (Table 3.3). Table 3.3. Cycloaddition of coumalic and acetylenemonocarboxylic acids Entry Catalystc Solvent Temp. (˚C) %Yield (mol/mol) 1a 2b 3a 4b - - TiCl4 toluene neat toluene BOB(OAc)4 neat 110 100 110 100 1d 20 44 48 40 2d 15 40 20 25 5d 60 10 16 30 aReaction in Ti vessel. bReaction at 1 atm. c5 mol% catalyst; coumalic acid 22: AMCA 19: 1:3 (mol/mol), 12 h. dDetermined by HPLC. Compared to uncatalyzed cycloaddition of coumalic acid and AMCA in the pressurized reactor, TiCl4 catalysis showed higher para-selectivity. The reaction afforded a total 68% yield of terephthalic and isophthalic acids with a 2.4:1 (mol/mol) para/meta selectivity. Uncatalyzed reaction in solvent-free conditions resulted in an 84% yield and a 1.1:1 (mol/mol) para/meta selectivity (entry 2, Table 3.3), similar to computational results. BOB(OAc)4–catalyzed reaction (entry 4, Table 3.3), resulted in an 65% yield but only 1.6:1 (mol/mol) para/meta selectivity. A previous study of methyl coumalate and methyl acetylenemonocarboxylate/AMCA reported a 64% and 58% yield respectively with a 1:1 (mol/mol) para/meta selectivity in both cases.10 Using toluene as solvent, the reaction resulted in a 35% yield with a 1.2:1 (mol/mol) para/meta selectivity (entry 1, Table 3.3). It was reported that cycloadditions of methyl coumalate and the two alkynes were run at 140 ˚C,10 which was higher than the reaction temperature of entry 41 1 (Table 3.3). The difference in temperatures of the two reactions (110 ˚C vs. 140 ˚C) could be responsible for the difference in conversion of coumalic acid. 42 REFERENCES 43 REFERENCES 1. Effenberger, F.; Ziegler, T. Diels-alder-reaktionen mit 2h-pyran-2-onen: reaktivität und selektivität. Chem. Ber. 1987, 120, 1339-1346. 2. (a) Metanis, N.; Keinan, E.; Dawson, P. A designed synthetic analogue of 4-OT is specific for a non- natural substrate. J. Am. Chem. Soc. 2005, 127, 5862-5868. (b) Wiley, R. H.; Hart, A. J. 2-Pyrones. IX. 2-Pyrone-6-carboxylic acid and its derivatives. J. Am. Chem. Soc. 1954, 77, 1942-1944. (c) Lapworth, A. CXXXIV. The form of change in organic compounds, and the function of the α-meta- orientating groups. J. Chem. Soc. 1901, 79, 1265-1284. 3. Manikandan, R.; Jeganmohan, M. Ruthenium-catalyzed dimerization of propiolates: a simple route to α-pyrones. Org. Lett. 2014, 16, 652-655. 4. Yeom, H. –S.; Koo, J.; Park, H. –S.; Wang, Y.; Liang, Y.; Yu, Z.-X.; Shin, S. Gold-catalyzed intermolecular reactions of propiolic acids with alkenes: [4+2] annulation and enyne cross metathesis. J. Am. Chem. Soc. 2012, 134, 208-211. 5. Zhang, P.; Frost, J. W. B-O-B catalyzed cycloadditions of acrylic acids. ACS Sustainable Chem. Eng. 2016, 4, 6991-6995. 6. Masuda, T.; Kawai, M.; Higashimura, T. Polymerization of propiolic acid and its derivatives catalysed by MoCl5. Polymer 1982, 23, 744-747. 7. (a) Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Direct and waste-free amidations and cycloadditions by organocatalytic activayion of carboxylic acids at room temperature. Angew. Chem., Int. Ed. 2008, 47, 2876-2879. (b) Hall, D.; Marion, O.; Al-Zoubi, R. Method for the organocatalytic activation of carboxylic acids for chemical reactions using orthosubstituted arylboronic acids. WO Patent 2009030022 A1, 2009. 8. Miles, W. H.; Cohen, E. M.; Naimoli, B. J. Diels-alder reactions of β-acylacrylic acids. Synth. Commun. 2013, 43, 1980-1991. 9. Kraus, G. A.; Pollock III, G. R.; Beck, C. L.; Palmer, K. Winter, A. H. Aromatics from pyrones: esters of terephthalic acid and isophthalic acid from methyl coumalate. RSC Advances 2013, 3, 12721-2172 44 CHAPTER 4: THE PYRONE ROUTE: MECHANISTIC INSIGHTS 1,3- vs. 1,4-Hydration of Acetylenemonocarboxylic Acid 1. Introduction The pyrone route established a concise synthesis to terephthalic, isophthalic and phthalic acids from methane- and CO2-derived AMCA. An interesting aspect of catalyzed conversion of a thermogenic material such as AMCA1 is that the process produced multiple products, and different catalytic systems can remarkably change the selectivity in formation of products. MoCl5/AgSbF6 catalysis in dioxane lead to total 50% yield of coumalic and isocoumalic acids which can be selectively converted to terephthalic and phthalic acids under TiCl4 catalytic condition. On the other hand, [RuCl2(p-cymene)]2/AgSbF6 catalysis led to the highest yields of trimellitic and trimesic acids. Meanwhile, using TfOH catalysis, the major products of the process are terephthalic and isophthalic acids in one step. The numerous products formed during catalyzed reactions of AMCA point to the challenges in improving the conversions and selectivities to increase efficiency of the pyrone route. The products also could shed light into the underlying mechanism responsible for the transformation of AMCA. This chapter focueses on possible mechanisms of the key reactions leading to coumalic, isocoumalic, trimellic, trimesic and muconic acids. The dimerization of ethyl acetylenemonocarboxylate 42 to form ethyl isoucoumalate via a [RuCl2(p-cymene)]2/AgSbF6 catalyzed reaction has been reported in literature (Scheme 4.1).2 This reaction proceeds via an oxidative cyclometallation to form intermediate metallacycles which can then undergo a reductive elimination of the metal to yield ethyl esters of coumalate 43 and isocoumalate 44 (Scheme 4). The reported yield of ethyl isocoumalate was 45%.2 Ethyl coumalate 43 has also been observed by the Frost group although this was not reported in the literature 45 account. However, ethyl acetylenemonocarboxylate 42 will lead to esterified isophthalates, phthalates or terephthalate. Virtually no PET is produced from polymerization of diesterified terephthalate with ethylene glycol. This follows from the need to capture and recycle byproduct ethyl alcohol, which is problematic from an atom economy and process chemistry perspective. Accordingly, elaboration of the dimerization of the unesterified propiolic acid is the focus of this project. Scheme 4.1. Ruthenium catalysis of ethyl acetylenemonocarboxylate (a) M = Ru, [RuCl2(p-cymene)]2 (5.0 mol %), AgSbF6 (20 mol%), PvOH, dioxane, 110 ˚C. Recent literature evidence indicates a route to synthesize coumalic and isocoumalic acids via a metal-catalyzed dimerization of derivatives of AMCA.3 An example of this strategy includes Au-catalyzed annulation of AMCA (Scheme 5).3 Scheme 4.2. Au-catalyzed annulation and dimerization of acetylenemonocarboxylic acid (a) Au(t-BuP(o-biphenyl))Cl/AgSbF6, CHCl3, rt. 46 Annulation of AMCA is catalyzed by Au(t-BuP(o-biphenyl))Cl/AgSbF6 at ambient temperature (Scheme 4.2).3 A 1,4-C,O-dipole intermediate formed upon complexation of AMCA by Au(t-BuP(o-biphenyl))Cl/AgSbF6 can undergo dimerization with another AMCA molecule to form coumalic and isocoumalic acids (Scheme 4.2). This can be an alternative route to dimerize AMCA without intermediacy of metallacycles (Scheme 4.1). Trimerization, or Reppe mechanism, of AMCA can be a competing process with dimerization and is reported in literature (Scheme 4.3).4 Trimellitic 39 and trimesic 40 acids (Scheme 4.3) in a 6:1 ratio results from a Ni(cod)2-catalyzed trimerization of sodium acetylenemonocarboxylate.4 Upon decarboxylation with a stochiometric amount of Cu2O, these triacids can be converted to terephthalic and isophthalic acids in a 94:6 ratio (Scheme 4.3).4 The use of sodium acetylenemonocarboxylate not only requires two steps from propiolic acid 4 to terephthalic acid 1 and isophthalic 2 but also results in a salt stream which can be costly in industrial settings. Scheme 4.3. Trimerization of sodium acetylenemonocarboxylate catalyzed by Ni(cod)2 R = Na+, M = Ni, (a) 2 mol % Ni(cod)2, P(Ph)3, NaH, THF, 23 ˚C, 1h. (b) Cu2O, 1 equiv., 180 ˚C The results of uncatalyzed cycloaddition of coumalic acid 22 and AMCA and TfOH- catalysis in chapter 3 showed consistent 1:1 (mol/mol ratio) of terephthalic and isophthalic acids, indicating that coumalic acid is the key intermediate leading to 1 and 2 in the pyrone route. 47 Reppe-type trimerization of acetylenic compounds often employed metal catalysis, such as Co, Ni, and Rh.4-6 The presence of trimesic and trimellitic acids in [RuCl2(p-cymene)]2/AgSbF6 – catalysis suggests that Reppe process is a possible pathway to form the triacids. Scheme 4.4. Ruthenium catalysis of AMCA in HOAc However, trimesic acid was formed in the TfOH catalyzed reaction in 6% yield even in the absence of any catalytic metal, indicating that (1) a Reppe mechanism is not necessary required for the direct formation of trimesic acid 40, and (2) formation of coumalic acid 22 is associated with 40. Scheme 4.5. TfOH-catalyzed AMCA in TCE 2. Formation of coumalic acid and trimesic acid in TfOH catalysis The presence of trimesic acid 40 as a byproduct was proposed to follow from the decomposition of coumalic acid 22.7 It was reported that under acidic condition, coumalic acid 22 can undergo a ring-opening methylation esterification to form 45.8 Base-catalyzed cycloaromatization of 45 and 46 in MeOH leads to 28 (91% yield) (Scheme 4.6).8 Under similar condition of solvent-free TfOH catalysis of AMCA, 45 reacted with methyl acetylenemonocarboxylate 35 to form trimethyl trimesate 48 (40% yield). 48 Scheme 4.6. Formation of trimethyl trimesate from coumalic acid and methyl acetylenemonocarboxylate under acidic condition (a)MeOH:HC(OCH3) (1:3), H2SO4 (5%), rf, 48h, 71% yield.8 (b) Na2CO3, 10 mol%, MeOH, rt, 91% yield.8 (c)TfOH, 15 mol%,100˚ C, neat, N2, 40% yield. Commercial coumalic acid 22 is synthesized from malic acid under acidic conditions.9 A key intermediate leading to formation of coumalic acid is malonic semialdehyde 49 which has never been isolated in enol form,9 but was observed by 1H NMR in TfOH catalysis. In wet TCE, TfOH catalysis results in the conversion of AMCA into trans-diacrylic ether 50, which is the dimer of malonic semialdehyde. NMR studies of diacrylic ether 50 catalyzed by TfOH (20 mol%) in D2O showed conversion of diacrylic either to trimesic acid, isophthalic acid, malonic semialdehyde-keto form, and acetaldehyde (Fig. 4.1). In wet TCE, conversion of AMCA to diacrylic ether 50 (85% isolated yield) was achieved by employing a stoichiometric amount of TfOH in diluted concentration (1 wt% or 0.13M). TfOH- catalyzed reaction of trans-diacrylic ether 50 yielded 55% coumalic acid 22, which is consistent malonic semialdehyde 49 formed via acid-catalyzed 1,4-hydration of AMCA (Scheme 4.7), being an intermediate in coumalic acid formation. 49 Scheme 4.7. 1,4-hydration of AMCA leading to coumalic acid (a) TfOH (2.0 equiv.), 1 mol% H2O, 100 ˚C, TCE, 1 wt%, N2, 28h, 85% yield of 35. (b) TfOH (15 mol%), neat, 100 ˚C, N2, 6 h, 55% yield. HA HB HO2C HB O HA CO2H TSP reference 100 ˚C 0 h 100 ˚C 15 h O CO2H HF OH HO HO2C HG O HH CO2H HD CO2H CO2H HE HC CO2H HO2C CO2H CO2H HG HH HF HD 100 ˚C 22 h HC HE Figure 4.1. NMR studies of diacrylic ether in D2O at 0, 15, and 22 h and 100˚C 3. Formation of coumalic, isocoumalic, and muconic acids in Ru- and Mo-catalysis Similar to trimesic acid and coumalic acid being indicative of a 1,4-hydration pathway, formation of isocoumalic and trimellitic acid in Ru and Mo catalysis was proposed to proceed via 1,3- hydration of AMCA. Ru-catalyzed hydration of acetylenic compounds has been studied 50 extensively, however, there are only two relevant examples that employed free acid acetylenic substrates11,12 (Scheme 4.7). The first example described RuCl3-catalyzed 1,4-hydration of phenylpropiolic acid 51 in acidic condition. Decarboxylation of the hydrate product led to acetophenone 52 without reported yield.11 Scheme 4.8. RuCl3-catalyzed 1,4- and 1,3- hydration of acetylene compounds The second example described 1,3-hydration of AMCA which led to pyruvic acid 53 at 90% yield.10 Scheme 4.9. Ru-catalyzed 1,3-hydration of AMCA to pyruvic acid Replacing RuCl3 by [RuCl2(p-cymene)]2 in hydration of AMCA also led to a 40% yield of pyruvic acid in water, which indicated that pyruvic acid could play intermediacy role leading to formation of isocoumalic acid as well as trimellitic acid. 51 Scheme 4.10. Proposed mechanism: 1,3- vs. 1,4-hydration of AMCA When the metal complex of AMCA is formed in the presence of a catalytic amount of H2O in the reaction, hydration can occur via a 1,4- or 1,3- hydration pathway to form 1,3-hydrate or 1,4-hydrate respectively (Scheme 4.9A). Following the 1,3-hydration pathway, addition of AMCA to 1,3-hydrate forms hydroxymuconic acid 54 which after intramolecular cyclization/esterification forms isocoumalic acid 23. On the other hand, addition of AMCA to the 1,4-hydrate forms seco- coumalic acid 55, which can cyclize to form coumalic acid 22. Trimellitic 39 and trimesic 40 acids formation are side reactions of the main pathways leading to isocoumalic and coumalic acids. The 1,4-hydrate can undergo protodemetallation in the case of [RuCl2(p-cymene)]2/AgSbF6 and MoCl5/AgSbF6 catalysis to form malonic acid semialdehyde 49. A Michael addition-cyclization of and 49 and 55 form cyclohexene 57 which can undergo a dehydration aromatization to form trimesic acid 40 (Scheme 4.9B). Similarly, the 1,3-hydrate can undergo a protodemetallation step to form pyruvic acid 53 (Scheme 6C). Cyclization of pyruvic acid 53 and hydroxymuconic acid 54 formed cyclohexene 56 followed by a dehydration aromatization step to form trimellitic acid 40. 52 Addition of diacrylic ether 50 to RuCl2(p-cymene)]2/AgSbF6 catalysis elevated yield of coumalic acid from 16% to 24% (Table 4.1, entries 1 and 2), which is consistent with malonic acid semialdehyde 49 in a 1,4-hydration pathway and formation of coumalic acid 22 (Scheme 6A). Additional pyruvic acid 53 in RuCl2(p-cymene)]2/AgSbF6 catalysis undergoes Michael addition-cyclization with hydroxymuconic acid 54, increasing formation of trimellitic acid 9 from 13% to 23% (Table 3, entry 3) while diminishing the yield of 22 and 23. Table 4.1. Impact of pyruvic acid and diacrylic ether on Lewis acid catalysis of AMCA Entry Cat. 1d 2 3 4d 5 6 e[RuCl2(p- cymene)]2 fAgSbF6 gMoCl5 hAgSbF6 Reaction Condition Starting Materials HOAc 80˚C, N2 12h dioxane 100˚C, N2 4h 19 19 + 50f 19 + 53f 4 19 + 50f 19 + 53f 22b,i 16 24 8 30 35 15 %Yield (mol/mol) 23c,i 24 24 16 20 17j 22 39b,i 13 12 23 10 6 4 40b,i 12 16 9 2 7k 1k aTriplicate run of each entry; yield of 1, 2, 9 and 10 unaffected by addition of 28 and 35 under conditions mentioned above. bYield determined by HPLC. c Yield determined by 1H NMR. d Data taken from Chapter 3, Table 3.1 for comparison. e 5 mol%. f 20 mol%. g 0.8 mol%. h 4.0 mol%. i ±1%. j ±2%. k ±0%. In MoCl5/AgSbF6 catalysis, addition of diacrylic ether 50 improves the yield of coumalic acid and trimesic acid while slightly inhibiting formation of isocoumalic and trimellitic acids (Table 4.1, entry 5). To a small extent, addition of pyruvic acid 53 to MoCl5/AgSbF6 catalysis shifted selectivity of pyrone formation toward isocoumalic acid. The minimal impact of pyruvic acid on MoCl5/AgSbF6 catalysis suggested that pyruvic acid might not be an intermediate leading to isocoumalic acid in this particular reaction. Another side product formed in MoCl5/AgSbF6 and AuCl/AgSbF6 in TCE was trans,trans- muconic acid 41. Complexation of metal catalyst and AMCA affords metal acetylide 58 (Scheme 10)12. Reppe reactions of acetylenes can lead to ene-yne 59. Mo and Au catalysts are known for 53 catalyzing homogenous and heterogeneous hydrogenation.15 Coordination of the alkyne to the metal-H2 complex 60 is followed by insertion into a metal-hydrogen bond to form hydrogenated product 61 which undergo protodemetallation to afford trans,trans-muconic acid 41 (Scheme 10). Instead of complexing with metal-H2, ene-yne 57 could complex with a metal-hydroxy complex to form 62. 1,3-hydration of ene-yne complex 62 leads to 63 which can undergo protodemetallation to form hydroxymuconic 54. Cyclization of 54 led to isocoumalic acid observed in Mo catalysis. This proposed mechanism could explain why addition of pyruvic acid had little to no impact on MoCl5/AgSbF6 catalysis. Scheme 4.11. Mechanism to muconic and hydroxymuconic acid in Mo catalysis 4. RuCl3 - catalyzed 1,3-hydration of AMCA – Synthesis of pyruvic acid Scheme 4.12. Hydration of AMCA catalyzed by RuCl3 54 As part of our collaboration with Prof. Karen Draths, we developed a strategy to synthesize lactic acids from methane and CO2-derived AMCA. While the reduction of pyruvic acid 53 to lactic acids catalyzed by lactate dehydrogenase (LDH) using NADH as co-factor is well-known, there are only two relevant examples to hydration of AMCA.10.11 Reaction of 0.25 M concentrations of AMCA with H2O (Fig 6) catalyzed by RuCl3 (1 mol%) was examined under a variety of solvent conditions (Table 4.2). Products formed (Scheme 4.11) included pyruvic acid 53a, hydrated pyruvic acid 53b, acetaldehyde 64a, hydrated acetaldehyde 64b, and acetic acid 65. Pyruvic acid 53a and its hydrate 53b are the products of the desired 1,3-addition of H2O to AMCA (Scheme 4.11). Competing, undesired 1,4-addition of water leads to malonic semialdehyde 49, which decarboxylates to form acetaldehyde 64a and acetaldehyde hydrate 64b (Fig. 6). Wacker-style oxidation of 64a and 64b leads to acetic acid 65 (Scheme 4.11). In H2O as solvent at 100 ºC (entry 1, Table 4.2), RuCl3-catalyzed the hydration of AMCA to produce a 64% combined yield of pyruvate 53a and its hydrate 53b. Significant yields of acetaldehyde 64a (5%), its hydrate 64b (5%) and acetic acid 65 (15%) were also formed (entry 1, Table 4.2). Only trace quantities of pyruvic acid 53a and its hydrate 53b were observed in THF at 65 ºC (entry 2, Table 4.2). Dioxane as solvent at 100 ºC (entry 3, Table 4.2) afforded a combined yield of 51% yield of pyruvic acid 53a and its hydrate 53b along with formation of acetic acid 63 (17%). Dioxane at 100 ºC with 10 equiv. of pivalic acid (PvOH) and 1 equiv of H2O relative to AMCA (entry 4, Table 4.2) afforded a 54% combined yield of pyruvic acid 53a and its hydrate 53b along with a 7% yield of acetic acid. The highest combined yields at 92% of pyruvic acid 53a and its hydrate 53b were observed when RuCl3-catalyzed hydration was run in HOAc as solvent with 1 equiv. of H2O relative to AMCA (entry 5, Table 4.2). 55 Table 4.2. RuCl3-catalyzed hydration of AMCA in various solvents Entrya Solvent Temp %Yieldb (mol/mol) 1 2c 3c 4d 5d H2O THF dioxane dioxane/ PvOH HOAc 100 ºC 65 ºC 100 ºC 100 ºC 100 ºC 34 1 31 48 75 30 1 20 6 17 5 0 0 0 0 5 0 0 0 0 15 0 17 7 - 0 90 0 0 0 a All hydrations contained 0.25 M AMCA and 1 mol% RuCl3 and were run under N2 for 12 h in solvents containing the indicated number of equivalents of H2O. b Yields determined by 1H NMR. c 10 equiv. of H2O. d 1 equiv. of H2O. Hydration of AMCA in HOAc and H2O catalyzed by RuCl3 likely begins (Scheme 4.13) with formation of a Ru-vinylidine complex (Paths A, B, C, D). Given the preferred attack of protic nucleophiles such as water and alcohols at the carbon atom attached to the metal of metal- vinylidene complexes to yield Fischer carbenes (Path B), malonic semialdehyde 49a-c would be expected to dominate as the hydration product over formation of pyruvic acid 53a-c (Scheme 4.13). An extensive literature covers Ru-catalyzed hydration of terminal alkynes. This literature predicts (Scheme 4.13) that Ru-catalyzed hydration of AMCA (a terminal alkyne) would yield the 1,4-hydrate (Path B), which is malonic acid semialdehyde 49a-c and not the 1,3-hydrate, which is pyruvic acid 53a-c (Path A). Preferred formation, let alone exclusive formation of pyruvic acid 53a-c, is an unexpected result. 56 Scheme 4.13. Mechanistic analysis of Ru-catalyzed hydration of AMCA Exclusive formation of pyruvic acid 53a-c can possibly be explained (Scheme 4.13) by invoking anchimeric (neighboring group) participation of the C-1 carboxylic acid (Path C, D). Such anchimeric assistance could lead to a three-membered α-lactone (Path C) or a four-membered β-lactone (Path D). Formation of an α-lactone is a 3-exo-trig cyclization (Path C) that is predicted to be a favored cyclization. Formation of a β-lactone is a 4-endo-dig cyclization (Path D) that is predicted by the Alabugin, Gilmore, Manoharan modification of Baldwin's rules to be a disfavored cyclization.13 Rules for predicting the course of cyclizations involving metal vinylidenes have not yet been formulated using a combination of extensive literature examples and computational analysis. Nonetheless, Baldwin's rules provide an initial hypothesis explaining exclusive formation of pyruvic acid 53a-c over malonic acid 49a-c resulting from RuCl3-catalyzed hydration of AMCA in HOAc and H2O (entry 5, Table 4.2). Catalysis of methane and CO2-derived AMCA opens a new route to terephthalic 1, isophthalic 2 and phthalic 3 acids without the necessity of (a) petroleum-derived xylenes as starting material and (b) sizeable carbon footprint of Amoco-Midcentury oxidation. TfOH catalysis 57 proceeds via 1,4-hydration of AMCA, allowing a one-step process to highest total combined yield of terephthalic and isophthalic acids. MoCl5/AgSbF6 and RuCl2(p-cymene)]2/AgSbF6 catalyzed both 1,3- and 1,4- hydration of AMCA are pivotal intermediates leading to isocoumalic 23 and coumalic 22 acids. Cycloaddition of coumalic 22 and isocoumalic 23 acids with AMCA, catalyzed by TiCl4, afford selective formation of terephthalic 1 and phthalic 3 acids. 1,3-hydration of AMCA catalyzed by RuCl3 also enable an efficient route to methane and CO2-derived pyruvic acid. Chemoenzymatic step converts pyruvic to lactic acids will establish a sustainable synthesis of poly(lactic acid) PLA. Scheme 4.14. The pyrone route leading to terephthalic, isophthalic and phthalic acids from methane and carbon dioxide (a) 1200-3200 ˚C plasma jet, 95%. (b) Cu(I) or Ag(I), ligand, Cs2CO3, 1 atm. (c) MoCl5, 0.8 mol%, AgSbF6, 4.0 mol%, dioxane, 100 ˚C, 12h or [RuCl2(p-cymene)]2, 5.0 mol%, AgSbF6, 20 mol%, HOAc, 80 ˚C, 12 h. (c) TiCl4, 5.0 mol%, toluene, 110 ˚C, 12 h. 58 REFERENCES 59 REFERENCES 1. Stoner, C. E., and Brill, T. B. Thermal decomposition of energetic materials. Inorg. Chem. 1989, 28, 4500-4506. 2. Manikandan, R.; Jeganmohan, M. Ruthenium-catalyzed dimerization of propiolates: a simple route to α-pyrones. Org. Lett. 2014, 16, 652-655. 3. Yeom, H. –S.; Koo, J.; Park, H. –S.; Wang, Y.; Liang, Y.; Yu, Z.-X.; Shin, S. Gold-catalyzed intermolecular reactions of propiolic acids with alkenes: [4+2] annulation and enyne cross metathesis. J. Am. Chem. Soc. 2012, 134, 208-211. 4. Hayes, J. C.; Guan, H. Collias, D. I. Production of terephthalic acid via reductive coupling of propiolic acid or propiolic acid derivatives. U.S Patent Appl. 20160264506. 5. Baidossi, W.; Goren, N.; Blum, J.; Schumann, H.; Hemling, H. Homogeneous and biphasic oligomerization of terminal alkynes by some water-soluble rhodium catalysts. J. Mol. Catal 1993, 85, 153-162. 6. Field, L. D.; Ward, A. J.; Turner, P. The dimerization and cyclotrimerization of acetylenes mediated by phosphine complexes of cobalt(I), rhodium(I), and iridium(I). Aust J Chem 1999, 52, 1085-1092. 7. Ashworth, I. W.; Bowden, M. C.; Dembofsky, B.; Levin, D.; Moss, W.; Robinson, E.; Szczur, N.; Virica, J. A new route for manufacture of 3-cyano-1-naphthalenecarboxylic acid. Organic Process Research & Development 2003, 7, 74-81. 8. Nantz, M. H.; Fuchs, P. L. Cycloaromatization reactions of methyl 4-carbomethoxy-5- methoxy-penta-2,4-dienoate. Syn. Comm. 1987, 17, 761-771. 9. (a) Lee, J. J.; Pollock III; G. R.; Mitchell, D. Kasuga, L.; Kraus, G. A. Upgrading malic acid to bio-based benzoates via a diels-alder-initiated sequence with the methyl coumalate platform. RSC Advances 2014, 4, 45657-45665. (b) Lee, J. J.; Kraus, G. A. One-pot formal synthesis of biorenewable terephthalic acid from methyl coumalate and methyl pyruvate. Green Chemistry 2014, 16, 2111-2116. (c) Kraus, G. A.; Lee, J. J. Of regioselective synthesis of terephthalates. U.S Patent Appl. 20140275608, Sept. 18, 2014. (d) Kraus, G. A.; Pollock III, G. R.; Beck, C. L.; Palmer, K. Winter, A. H. (e) Aromatics from pyrones: esters of terephthalic acid and isophthalic acid from methyl coumalate. RSC Advances 2013, 3, 12721- 21725. 10. Ogo, S.; Fukuzumi, S.-I. Method for synthesis of keto acid or amino acid by hydration of acetylene compound. U.S.8,153839, April 10, 2012. 60 11. Halpern, J.; James, B. R.; Kemp, A. L. W. Catalysis of the hydration of acetylenic compounds by ruthenium(III) chloride. J. Am. Chem. Soc. 1961, 83, 4097-4098. 12. (a) Bullock, R. M.; Voges, M. H. Homogenous catalysis with inexpensive metals: ionic hydrogenation of ketones with molybdenum and tungsten catalysts. J. Am. Chem. Soc. 2000, 122, 12594-12595. (b) Bond, G. C. Hydrogenation by gold catalysts: an unexpected discovery and a current assessment. Gold Bulletin 2016, 49, 53-61. 13. Alabugin, I. V.; Gilmore, K.; Manoharan, M. Rules for anionic and radical ring closure of alkyne. J. Am. Chem. Soc., 2011, 133, 12608-12623. 61 CHAPTER 5: EXPERIMENTAL 1. General Cycloadditions of acetylenemonocarboxylic acid 19 with isoprene 13, coumalic acid 22 or isocoumalic acid 23 were run in a 25 mL Titanium Parr series 4590-Bench Top Micro Reactor. 1H NMR spectra were recorded on a 500 MHz spectrometer. Chemical shifts for 1H NMR spectra are reported (in parts per million) relative to CDCl3 (δ = 7.26 ppm) or to DMSO-d6 (δ = 2.62 ppm). When D2O was used as the solvent, chemical shifts are reported (in parts per million) relative to sodium 3-(trimethylsilyl)propiomate-2,2,3,3-d4 (TSP, δ = 0.00 ppm). 13C NMR spectra were recorded at 125 MHz and the shifts for these spectra are reported (in parts per million) relative to CDCl3 (δ = 77.0 ppm). When D2O was used as the solvent, chemical shifts are reported (in parts per million) relative to sodium 3-(trimethylsilyl)propiomate-2,2,3,3-d4 (TSP, δ = 0.00 ppm). HPLC spectra were recorded on an Agilent HPLC 1100 chromatograph equipped with an autosampler. PtCl2, PtCl4, HgCl2, Hg2Cl2, and AuCl3 were purchased from Strem. All other catalysts used in catalyst screening for conversion of acetylenemonocarboxylic acid to coumalic, isocoumalic, terephthalic, isophthalic, and phthalic acids were purchased from Millipore-Sigma. Acetylenemonocarboxylic acid was purchased from Millipore-Sigma and distilled at 83 mmHg and 85 ˚C before used. Solvents were purified via distillation before used. 2. Product Analyses Reaction crude was dissolved in 50 mL of N,N-dimethylacetamide (DMA) in a 50 mL volumetric flask. Filtration (0.45 µm Whatman filter) was followed by analysis to determine crude yield of terephthalic 1, isophthalic 2, phthalic 3, coumalic 22, trimellitic 39, trimesic 40 acids using an Agilent Zorbax SB-C18 column (4.6 x 150 mm, 5 µm particle size) and isocratic elution with 12/88, (v/v); CH3CN/H2O (100 mM NH4 +HCO2 -, pH 2.5 ). Muconic acid 41 was analyzed using 62 Grace Alltima Amino column (4.6 x 250 mm, 5 µm particle size) and isocratic elution with 80/20 (v/v); CH3CN/H2O (100 mM NH4 +HCO2 -, pH 2.5). Requisite buffers were prepared with degassed, deionized, distilled water which had been filtered through a DURAPORE 0.45 µm HV filter (Millipore) Terephthalic, isophthalic, phthalic, coumalic, trimellitic and trimesic acids used for the HPLC standard calibration curve are commercially available from Sigma. Crude yield of isocoumalic acid 23 (δ 6.62, d, 1H) and unreacted acetylenemonocarboxylic acid 19 (δ 4.3, s, 1H) was analyzed by 1H-NMR using maleic acid as standard (δ 6.32, s, 2H) as standard. Crude yield of pyruvic acid 53a (δ 2.5, s, 3H) and pyruvate hydrate 53b (δ 1.7, s, 3H) was analyzed by 1H-NMR using TSP as standard. Response factors were determined by adding a known quantity of each compound in 0.7 mL of 10mM maleic acid in DMSO-d6 or 0.7 mL of 10 mM TSP in D2O stock solutions. The concentration of isocoumalic acid 23 was calculated by application of a calibration formula derived from standard taken using laboratory-synthesized isocoumalic acid 23: [mM]actual = 1.03 [mM]NMR The concentration of acetylenemonocarboxylic acid 19 was calculated by application of a calibration formula derived from distilled acetylenemonocarboxylic acid 19: The total concentration of pyruvic acid 53a and pyruvic hydrate 53b were calculated by application [mM]actual = 0.97 [mM]NMR of a calibration formula derived from distilled pyruvic acid 53: [mM]actual = 0.95 [mM]NMR 63 3. 4-Methyl-1,4-cyclohexadiene-1-carboxylic acid 16 from cycloaddition of AMCA 19 with isoprene 13 To a solution of propiolic acid 2 (1.0 g, 95%, 13 mmol) in a 25 mL Titanium Parr was added 4.0 mL of toluene and isoprene 3 (7.1 mL, 71 mmol) at rt. The reactor was flushed with N2 (3x) and then pressurized to 10.3 bar under N2. The reaction was heated at 60°C for 36 h. After completion of the reaction, the reactor was cooled to rt. The para product that crystallized as a white solid was vacuum filtrated and washed with 7 mL of toluene. After one recrystallization, 1.3 g of pure para-product was obtained in 67% yield, and 0.7 g of para/meta product mixture (1:4.4 para:meta ratio) was recovered in 29% yield from the mother liquid. 1H NMR (500 MHz, CDCl3) δ = 1.70 (s, 3H), 2.80 (m, 2H), 2.90 (m, 2H), 5.48 (s, 1H), 7.11 (s, 1H), 11.70 (br s, 1H). 13C NMR (125 MHz, CDCl3) δ = 22.8, 25.7, 32.0, 118.5, 127.1, 129.2, 139.2, 172.4. 4. Solvent-free conversion of AMCA 19 catalyzed by AuCl/AgSbF6 To a 5 mL one-neck round bottom flask under N2 was added AuCl (17 mg, 7.2 µmol) and AgSbF6 (25 mg, 7.2 µmol) followed by acetylenemonocarboxylic acid 19 (633 mg, 9.0 mmol). The stirred reaction mixture was heated at 100 ˚C for 5 min under N2. The crude reaction was cooled to rt, dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column. Products formed in the reaction included: 100 mg of terephthalic acid 1 (20 %), 19 mg of isophthalic acid (4%), 63 mg of coumalic acid 22, 6 mg of trimesic acid 40 (1%), and 4 mg of trimellitic acid 39 (1%). The amount of unreacted acetylenemonocarboxylic acid 19 was 83 mg (13%). Terephthalic acid 1: 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 4H). 13C NMR (125 MHz, DMSO-d6) δ = 129.7, 131.4, 133.3, 166.9. Isophthalic acid 2: 1H NMR (500 MHz, DMSO-d6) δ 7.64 (t, 1H), 8.16 (dd, 2H), 8.47 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ129.2, 130.4, 131.5, 133.8, 167.3. Coumalic acid 22: 1H NMR (500 64 MHz, DMSO-d6) δ 6.42 (dd, 1H), 7.86 (dd, 1H), 8.42 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 112.2, 114.9, 142.8, 159.1, 160.2, 166.3. Trimellitic acid 39: 1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, 1H), 8.12 (dd, 1H), 8.21 (d, 1H). Trimesic acid 40: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 3H), 13.42 (br s, 3H), 13C NMR (125 MHz, DMSO-d6) δ 132.74, 134.43, 166.7. 5. Conversion of AMCA 19 catalyzed by AuCl/AgSbF6 in TCE To a 5 mL one-neck round bottom flask under N2 was added AuCl (17 mg, 7.2 µmol) and AgSbF6 (25 mg, 7.2 µmol) followed by addition of TCE (1.7 mL). Acetylenemonocarboxylic acid 19 (633 mg, 9.0 mmol) was added to the reaction mixture. The stirred reaction mixture was heated at 100 ˚C for 12h under N2. The crude reaction was cooled to rt, dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column. Products formed in the reaction included: 20 mg of terephthalic acid 1 (4%), 9 mg of isophthalic acid 2 (2%), 50 mg of coumalic acid 22 (8%), 6 mg of trimesic acid 40 (1%), 5 mg of trimellitic acid 39 (1%), and 75 mg of muconic acid 41 (12%). The amount of unreacted acetylenemonocarboxylic acid 19 was 63 mg (10%). Terephthalic acid 1: 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 4H). 13C NMR (125 MHz, DMSO-d6) δ = 129.7, 131.4, 133.3, 166.9. Isophthalic acid 2: 1H NMR (500 MHz, DMSO-d6) δ 7.64 (t, 1H), 8.16 (dd, 2H), 8.47 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ129.2, 130.4, 131.5, 133.8, 167.3. Coumalic acid 22: 1H NMR (500 MHz, DMSO-d6) δ 6.42 (dd, 1H), 7.86 (dd, 1H), 8.42 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 112.2, 114.9, 142.8, 159.1, 160.2, 166.3. Trimellitic acid 39: 1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, 1H), 8.12 (dd, 1H), 8.21 (d, 1H). Trimesic acid 40: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 3H), 13.42 (br s, 3H), 13C NMR (125 MHz, DMSO-d6) δ 132.74, 134.43, 166.7. Muconic acid 11: 1H NMR (500 MHz, DMSO-d6) δ 6.30 (ddd, 2H), 7.27 (ddd, 2H). 13C NMR (125 MHz, DMSO-d6) δ 129.6, 141.5, 167.4. 65 6. Solvent-free conversion of AMCA 19 catalyzed by MoCl5/AgSbF6 To a 5 mL one-neck round bottom flask under N2 was added MoCl5 (20 mg, 7.2 µmol) and AgSbF6 (140 mg, 36 µmol) followed by acetylenemonocarboxylic acid 19 (633 mg, 9.0 mmol). The stirred reaction mixture was heated at 50 ˚C for 1h under N2. The crude reaction was cooled to rt, dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using Agilent Zorbax SB-C18 and Grace Alltima Amino columns. Products formed in the reaction included: 5 mg of terephthalic acid 1 (1%), 4 mg of isophthalic acid 2 (1%), 151 mg of coumalic acid 22 (24%), 76 mg of isocoumalic acid 23 (12%), 70 mg of trimellitic acid 39 (11%), 12 mg of trimesic acid 40 (2%), 73 mg of muconic acid 41 (11%). The unreacted acetylenemonocarboxylic acid 19 was 43 mg (7%). Terephthalic acid 1: 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 4H). 13C NMR (125 MHz, DMSO-d6) δ = 129.7, 131.4, 133.3, 166.9. Isophthalic acid 2: 1H NMR (500 MHz, DMSO-d6) δ 7.64 (t, 1H), 8.16 (dd, 2H), 8.47 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ129.2, 130.4, 131.5, 133.8, 167.3. Coumalic acid 22: 1H NMR (500 MHz, DMSO-d6) δ 6.42 (dd, 1H), 7.86 (dd, 1H), 8.42 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 112.2, 114.9, 142.8, 159.1, 160.2, 166.3. Isocoumalic acid 23: 1H NMR (500 MHz, DMSO-d6) δ 6.62 (d, 1H), 7.12 (d, 1H), 7.67 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 110.4, 120.3, 143.9, 149.9, 160.4, 160.9. Trimellitic acid 39: 1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, 1H), 8.12 (dd, 1H), 8.21 (d, 1H). Trimesic acid 40: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 3H), 13.42 (br s, 3H), 13C NMR (125 MHz, DMSO-d6) δ 132.74, 134.43, 166.7. Muconic acid 41: 1H NMR (500 MHz, DMSO-d6) δ 6.30 (ddd, 2H), 7.27 (ddd, 2H). 13C NMR (125 MHz, DMSO-d6) δ 129.6, 141.5, 167.4. 66 7. Conversion of AMCA 19 catalyzed by MoCl5/AgSbF6 in dioxane To a 10 mL one-neck round bottom flask under N2 was added MoCl5 (20 mg, 7.2 µmol) and AgSbF6 (140 mg, 36 µmol) followed by addition of dioxane (2.5 mL). The reaction turned dark green and white precipitate formed immediately. After 5 minutes, acetylenemonocarboxylic acid 19 (633 mg, 9.0 mmol) was added to the reaction mixture. The stirred reaction mixture was heated at 100 ˚C for 4h. The crude reaction was cooled to rt, dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18. Products formed in the reaction included: 191 mg of coumalic acid 22 (30%), 76 mg of isocoumalic acid 23 (20%), 63 mg of trimellitic acid 39 (10%), 11 mg of trimesic acid 40 (2%), 37 mg of muconic acid 41 (6%). The unreacted acetylenemonocarboxylic acid 19 was 56 mg (9%). 8. Conversion of AMCA 19 catalyzed by RuCl2(p-cymene)]2/AgSbF6 in dioxane/PvOH To a 25 mL one-neck round bottom flask under N2 was added [RuCl2(p-cymene)]2 (77 mg, 12.5 µmol) and AgSbF6 (170 mg, 50 µmol) followed by addition of dioxane (2.5 mL) and pivalic acid (1.02 g, 25 mmol). The reaction turned bright orange and white precipitate formed immediately. After 10 minutes, acetylenemonocarboxylic acid 19 (170 mg, 2.5 mmol) was added to the reaction mixture. The stirred reaction mixture heated at 80 ˚C for 12h. The crude reaction was cooled to rt, dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using Agilent Zorbax SB-C18 and Grace Alltima Amino columns. Products formed in the reaction included: 10 mg of coumalic acid 22 (6%), 42 mg of isocoumalic acid 23 (24%), 1.7 mg of trimellitic acid 39 (1%), and 2 mg of trimesic acid 40 (1%). Coumalic acid 22: 1H NMR (500 MHz, DMSO-d6) δ 6.42 (dd, 1H), 7.86 (dd, 1H), 8.42 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 112.2, 114.9, 142.8, 159.1, 160.2, 166.3. Isocoumalic acid 23: 1H NMR (500 MHz, DMSO-d6) δ 6.62 (d, 1H), 7.12 (d, 1H), 7.67 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 110.4, 120.3, 143.9, 149.9, 160.4, 160.9. 67 Trimellitic acid 39: 1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, 1H), 8.12 (dd, 1H), 8.21 (d, 1H). Trimesic acid 40: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 3H), 13.42 (br s, 3H), 13C NMR (125 MHz, DMSO-d6) δ 132.74, 134.43, 166.7. 9. Conversion of AMCA 19 catalyzed by RuCl2(p-cymene)]2/AgSbF6 in HOAc To a 25 mL one-neck round bottom flask under N2 was added [RuCl2(p-cymene)]2 (77 mg, 12.5 µmol) and AgSbF6 (170 mg, 50 µmol) followed by addition of HOAc (4.0 mL). The reaction turned bright orange and white precipitate formed immediately. After 10 minutes, acetylenemonocarboxylic acid 19 (170 mg, 2.5 mmol) was added to the reaction mixture. The stirred reaction mixture was heated at 80 ˚C for 12 h under N2. The crude reaction was cooled to rt, dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column. Products formed in the reaction included: 4 mg of terephthalic acid 1 (3%), 16 mg of isophthalic acid 2 (12%), 27 mg of coumalic acid 22 (16%), 41 mg of isocoumalic acid 23 (24%), 22 mg of trimellitic acid 39 (13%), 20 mg of trimesic acid 40 (12%). Terephthalic acid 1: 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 4H). 13C NMR (125 MHz, DMSO- d6) δ = 129.7, 131.4, 133.3, 166.9. Isophthalic acid 2: 1H NMR (500 MHz, DMSO-d6) δ 7.64 (t, 1H), 8.16 (dd, 2H), 8.47 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ129.2, 130.4, 131.5, 133.8, 167.3. Coumalic acid 22: 1H NMR (500 MHz, DMSO-d6) δ 6.42 (dd, 1H), 7.86 (dd, 1H), 8.42 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 112.2, 114.9, 142.8, 159.1, 160.2, 166.3. Isocoumalic acid 23: 1H NMR (500 MHz, DMSO-d6) δ 6.62 (d, 1H), 7.12 (d, 1H), 7.67 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 110.4, 120.3, 143.9, 149.9, 160.4, 160.9. Trimellitic acid 39: 1H NMR (500 MHz, DMSO-d6) δ 7.75 (d, 1H), 8.12 (dd, 1H), 8.21 (d, 1H). Trimesic acid 40: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 3H), 13.42 (br s, 3H), 13C NMR (125 MHz, DMSO-d6) δ 132.74, 134.43, 166.7. 68 10. Solvent-free conversion of AMCA 19 catalyzed by TfOH To a 25 mL one-neck round bottom flask under Ar was added acetylenemonocarboxylic acid 19 (1.1 g, 15.7 mmol). TfOH (208 µL, 350 mg, 0.24 mmol) was added dropwise over 3 min. The stirred reaction mixture heated at 100˚C for 4h until solidified. Temperature was increased to 110˚C for 12h. The crude reaction was cooled to rt, dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column. Products formed in the reaction included: 165 mg of terephthalic acid 1 (19%), 173 mg of isophthalic acid 2 (20%), 165 mg of coumalic acid 22 (15%), and 66 mg of trimesic acid 40 (62%). Unreacted acetylenemonocarboxylic acid 19 was 132 mg (12%). Terephthalic acid 1: 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 4H). 13C NMR (125 MHz, DMSO-d6) δ = 129.7, 131.4, 133.3, 166.9. Isophthalic acid 2: 1H NMR (500 MHz, DMSO-d6) δ 7.64 (t, 1H), 8.16 (dd, 2H), 8.47 (s, 1H). 13C NMR (125 MHz, DMSO-d6) δ129.2, 130.4, 131.5, 133.8, 167.3. Coumalic acid 22: 1H NMR (500 MHz, DMSO-d6) δ 6.42 (dd, 1H), 7.86 (dd, 1H), 8.42 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 112.2, 114.9, 142.8, 159.1, 160.2, 166.3. Trimesic acid 40: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (s, 3H), 13.42 (br s, 3H), 13C NMR (125 MHz, DMSO-d6) δ 132.74, 134.43, 166.7. 11. Isolation of terephthalic acid 1 and isophthalic 2 from the solvent-free conversion of AMCA 19 catalyzed by TfOH To a 50 mL one-neck round bottom flask under Ar was added acetylenemonocarboxylic acid 19 (2.2 g, 31.4 mmol). TfOH (416 µL, 700 mg, 0.48 mmol) was added dropwise over 10 min. The stirred reaction mixture heated at 100˚C for 4h until solidified. Temperature was increased to 110˚C for 16h. The crude reaction was cooled to rt and suspended in 50 mL of ice water in a 100 mL beaker, and a white solid precipitated from the solution. This white solid was collected by filtration and dried overnight in vacuo. Suspension of the solid in 30 mL EtOAc followed by a 69 filtration removed terephthalic acid 1 (890 mg, 17%). The filtrated was concentrated and dried to afford isophthalic acid 2 (1.09 g, 21%) and trimesic acid (350 mg, 7%). 12. Conversion of AMCA 19 to coumalic acid 22 catalyzed by TfOH in TCE To a 50 mL one neck round bottom flask under Ar was added acetylenemonocarboxylic acid 19 (2.2 g, 31.4 mmol), followed by addition of TCE (5.5 mL). TfOH (555 µL, 0.94 g, 6.3 mmol, 20 mol%) was added dropwise to the reaction mixture over 5 min. The stirred reaction mixture was heated at 80˚C for 28h. The crude product was filtered and washed with cold EtOAc to afford 1.3 g of coumalic acid 22 (61%). The filtrate was extracted with EtOAc (100 mL x3), and the combined organic layer was dried over Na2SO4. The organic layer was concentrated to yield 310 mg of coumalic acid 22 (14%). The combined coumalic acid 22 was recrystallized in dry MeOH to form off white crystal (1.3 g, 60%), mp(dec): 234-236˚C. 13. Conversion of AMCA 19 to diacrylic ether 50 catalyzed by TfOH in TCE To a 250 mL three-neck round bottom flask under Ar was added acetylenemonocarboxylic acid 4 (2.1 g, 30 mmol), followed by addition of TCE (131.2 mL). TfOH (5.3 mL, 9.0 g, 60 mmol) was added dropwise to the stirred reaction mixture over 20 min, followed by filtered DI H2O (5.4 µL, 1 mol%). The reaction was heated at 100˚C for 20h under N2. The crude product was isolated from the reaction mixture via extraction with cold EtOAc (4 x 250 mL). The combined organic layer was dried over Na2SO4 overnight. EtOAc was removed and the crude product was dried in vacuo, followed by recrystallization in hot hexanes to give diacrylic ether 50 in the form of white rod-shaped crystal (1.8 g, 85%), mp:85-88˚C. Anal. calc.: C: 45.56%, H: 3.83%. Found: C: 45.05%, H: 3.95%. 70 14. Uncatalyzed cycloaddition of isocoumalic acid 23 and AMCA 19 Toluene (6.0 mL), isocoumalic acid 23 (168 mg, 1.2 mmol), and acetylenemonocarboxylic acid 19 (544 μL, 8.4 mmol) were added to a 25 mL Ti Parr reactor. The reactor was flushed with N2 (3x) and then pressurized to 10 bar under N2. The reaction was heated at 110 ˚C for 12h. The crude reaction was cooled to rt slowly. The crude product mixture was collected via vacuum filtration and dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column in which the formation of phthalic acid 3 was 8 mg (4%) and the unreacted isocoumalic acid 23 was 159 mg (94%). Phthalic acid 3: 1H NMR (500 MHz, DMSO-d6) δ 7.59 (m, 2H), 7.66 (m, 2H). 13C NMR (125 MHz, DMSO-d6) δ 128.8, 131.4, 133.2, 169.0. Isophthalic acid 2: 1H NMR (500 MHz, DMSO-d6) δ 7.64 (t, 1H), 8.16 (dd, 2H), 8.47 (s, 1H), 13.1 (br s, 2H). 13C NMR (125 MHz, DMSO-d6) δ 129.2, 130.4, 131.5, 133.8, 167.3. 15. TiCl4-catalyzed cycloaddition of isocoumalic acid 23 and AMCA 19 Toluene (3.0 mL), isocoumalic acid 23 (168 mg, 1.2 mmol), TiCl4 (6.5 μL, 0.06 mmol), and acetylenemonocarboxylic acid 19 (544 μL, 8.4 mmol) were added to 25 mL Parr reactor. The reactor was flushed with N2 (3x) and then pressurized to 10 bar under N2. The reaction was heated at 110 ˚C for 12h. The crude reaction was cooled to rt slowly. The crude product mixture was collected via vacuum filtration and dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column, in which the formation of phthalic acid 3 was 149 mg (75%) and the formation of isophthalic acid 2 was 30 mg (15%). The unreacted isocoumalic acid 23 was 11 mg (6%). 71 16. Isolation of phthalic acid 3 and isophthalic acid 2 from the TiCl4-catalyzed cycloaddition of isocoumalic 23 and AMCA 19 Toluene (6.0 mL), isocoumalic acid 6 (336 mg, 2.4 mmol), TiCl4 (13 μL, 0.12 mmol), and acetylenemonocarboxylic acid 19 (1090 μL, 16.8 mmol) were added to 25 mL Parr reactor. The reactor was flushed with N2 (3x) and then pressurized to 10 bar under N2. The reaction was heated at 110 ˚C for 24h. The crude reaction was cooled to rt slowly. The crude product mixture was collected via vacuum filtration and dried overnight in vacuo at 50˚C to convert phthalic acid 3 to phthalic anhydride. The product mixture was added into 10 mL of diethyl ether in a 50 mL beaker, and a white solid precipitate from the solution. The solid was collected by filtration to afford 45 mg of isophthalic acid 2 (11%). The filtrate was concentrated to afford a white solid containing isocoumalic acid 6 (14 mg, 4%) and phthalic anhydride (255 mg, 72%). The solid was dissolved in 10 mL of hot water, recrystallized at rt, filtered and dried to afford phthalic acid 3 (278 mg, 70%). 17. Uncatalyzed cycloaddition of coumalic acid 22 and AMCA 19 Toluene (6.0 mL), coumalic acid 5 (140 mg, 1.0 mmol), and acetylenemonocarboxylic acid 19 (195 μL, 3.0 mmol) were added to a 25 mL Ti Parr reactor. The reactor was flushed with N2 (3x) and then pressurized to 10 bar under N2. The reaction was heated at 110 ˚C for 12 h. The crude product mixture was collected via vacuum filtration and dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column, in which the formation of terephthalic acid 1 was 33 mg (20%) and the formation of isophthalic acid 2 was 25 mg (15%). The unreacted coumalic acid 22 was 84 mg (60%). Terephthalic acid 1: 1H NMR (500 MHz, DMSO-d6) δ 8.04 (s, 4H), 13.3 (br s, 2H). 13C NMR (125 MHz, DMSO-d6) δ 129.7, 131.4, 133.3, 166.9. Isophthalic acid 2: 1H NMR (500 MHz, DMSO-d6) δ 7.64 (t, 1H), 8.16 72 (dd, 2H), 8.47 (s, 1H), 13.2 (br s, 2H). 13C NMR (125 MHz, DMSO-d6) δ 129.2, 130.4, 131.5, 133.8, 167.3. 18. TiCl4-catalyzed cycloaddition of coumalic acid 22 and AMCA 19 Toluene (6.0 mL), coumalic acid 5 (140, 1.0 mmol), TiCl4 (6.5 μL, 0.06 mmol), and acetylenemonocarboxylic acid 4 (195 μL, 3.0 mmol) were added to a 25 mL Ti Parr reactor. The reactor was flushed with N2 (3x) and then pressurized to 10 bar under N2. The reaction was heated at 110 ˚C for 12 h. The crude product mixture was collected via vacuum filtration and dissolved in 50 mL of DMA in a 50 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column, in which the formation of terephthalic acid 1 was 80 mg (48%) and the formation of isophthalic acid 2 was 33 mg (20%). The unreacted coumalic acid 22 was 23 mg (16%). 19. Synthesis of methyl 4-carbomethoxy-5-methoxy-penta-2E, 4Z-dienoate 45 45 was prepared using a modified procedure Nantz and Fuch.1 To a solution of coumalic acid 22 (500 mg, 3.5 mmol) in 9 mL of trimethylorthoformate and 3 mL of methanol was added conc. H2SO4 (0.6 mL, 11 mmol) at room temperature. The reaction mixture was refluxed for 18 h after which it was cooled to 0˚C and diluted with 10 mL of EtOAc. The solution was then extracted with sat. NaHCO3. The organic layer was then washed with brine and dried over Na2SO4. EtOAc was removed in vacuo to yield crude products which were separated by plug filtration (4:1, CHCl3: hexane) to yield 26 (0.5 g, 71% yield). mp 54-56˚C.1 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1H), 7.59 (d, J = 16.2 Hz, 1H), 6.64 (d, J = 16.2 Hz, 1H), 4.30 (s, 3H), 3.78 (s, 3H), 3.75 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.1, 166.6, 164.7, 134.4, 119.3, 106.8, 63.0, 51.5, 51.3. Anal. calcd for C9H12O5: C, 53.98%, H, 6.04%. Found: C, 54.48%, H, 6.24%. 73 20. Cycloaromatization of methyl 4-carbomethoxy-5-methoxy-penta-2E, 4Z-dienoate 45 and methyl acetylenemonocarboxylate to trimethyl trimesate 48 To a 5 mL one neck round bottom flask was added 45 (100 mg, 0.5 mmol) and methyl acetylenemonocarboxylate (47 mg, 0.56 mmol). TfOH (7.5 μL, 15 mol%) was added to the reaction mixture under Ar at rt. The stirred reaction mixture was heated under N2 at 100 ˚C for 2h. After cooled down to rt, the reaction mixture was dissolved in 5 mL of ACN in a 5 mL volumetric flask to be analyzed by GC-HP5 column, in which the formation of trimethyl trimesate was 50 mg (40%). 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 3.89 (s, 3H). 13C NMR (125 MHz, DMSO- d6) δ 164.62, 133.48, 131.0, 52.97. 21. Solvent-free conversion of diacrylic ether 50 to coumalic acid 22 catalyzed by TfOH To a 5 mL one neck round bottom flask was added diacrylic ether 30 (47 mg, 0.3 mmol). TfOH (5.5 μL, 20 mol%) was added to the reaction mixture under Ar. The stirred reaction mixture was heated under N2 at 100 ˚C for 2h. After cooled down to rt, the crude product was dissolved in 25 mL of DMA in a 25 mL volumetric flask, followed by HPLC analysis using the Agilent Zorbax SB-C18 column, in which the formation of terephthalic acid 1 was 3 mg (11%) and the formation of isophthalic acid 2 was 2 mg (8%). The unreacted coumalic acid 22 was 23 mg (55%). 22. Synthesis of isocoumalic acid 23 from diethyl oxalate and ethyl crotonate Chemically synthesized isocoumalic acid 23 was used to facilitate cycloaddition of isocoumalic acid 23 and acetylenemonocarboxylic acid 19. The synthesis is a two-step process from commercially available ethyl crotonate and diethyl oxalate. Procedures of these reactions are provided below. 2,3 74 22.a. Diethyl-2-hydroxy-2,4-hexadien-1,6-dioate The diester was prepared using a modified procedure of Lapworth2 and Dawson.3 Potassium (4.1 g, 0.11 mol) was slowly added to tert-butyl alcohol (40 mL) under Nitrogen. The reaction mixture was stirred for 1 h. Diethyl ether (25 mL) was added to the mixture and stirred for 15 min at 0 ˚C. A solution of diethyl oxalate (14.0 mL, 0.1 mol) in 10 mL of diethyl ether was added slowly at the same temperature and stirred for 1h. Ethyl crotonate (12.5 mL, 0.1 mol) in 10 mL of diethyl ether was added slowly to the reaction mixture at the same temperature. The reaction was kept at 0˚C for 6h to allow precipitation of the potassium salt of the diester. Crude product was collected by filtration and then dissolved in 400 mL of ice water. Glacial acetic acid (20 mL) was added and the resultant precipitate was collected by filtration and washed with cold water to give diester in the form of a yellow crystalline powder (16.3 g, 72%). 1H NMR (500 MHz, CDCl3) δ 1.24 (t, 3H), 1.34 (t, 3H), 4.20 (q, 2H), 4.32 (q, 2H), 5.96 (d, 1H), 6.26 (d, 1H), 6.43 (br s, 1H), 7.61 (dd, 1H). 13C NMR (125 MHz, CDCl3) δ 13.7, 60.1, 63.4, 108.4, 123.2, 136.7, 143.7, 164.5, 166.4 22.b. Isocoumalic acid 23 Diethyl 2-hydroxy-2,4-hexadien-1,6-dioate (1.1 g, 0.5 mmol) was dissolved in 10 mL of water, 8 mL of glacial acetic acid, and 2 mL of concentrated H2SO4. The reaction mixture was heated up to 95˚C for 3h. Reaction mixture was cooled down to rt, and solvents was removed to stimulate precipitation of product. Product was collected by filtration, and recrystallized in H2O (0.6g, 84%). 1H NMR (500 MHz, DMSO-d6) δ 6.62 (d, 1H), 7.12 (d, 1H), 7.67 (dd, 1H). 13C NMR (125 MHz, DMSO-d6) δ 110.4, 120.3, 143.9, 149.9, 160.4, 160.9. 75 23. General procedure for screening of metal catalysts for conversion of AMCA 19 to terephthalic 1, isophthalic 2, coumalic 22, and isocoumalic 23 acids Screening of catalysts for the conversion of acetylenemonocarboxylic acid 19 to terephthalic, isophthalic, coumalic and isocoumalic acids employed a 5 mL flask equipped with a magnetic stir bar that was charged with a metal catalyst MXn (26 µmol) and a AgX (n x 26 µmol) (X = OTf, OTFA, SbF6, PF6, BF4, OAc). A solvent (0.8 mL) was then added if necessary. Acetylenemonocarboxylic acid 19 (211 mg, 3 mmol) was added dropwise via syringe. A color change was often observed immediately after addition of acetylenemonocarboxylic acid 19 to the catalysts. The stirred reaction mixture was run for 12 h under N2 at an indicated temperature. The crude reaction mixture was then dissolved in 25 mL DMA in a 25 mL volumetric flask, followed by NMR and HPLC analysis. Catalysts, solvents, temperatures and data are included in Appendix A for each reaction. 24. General procedure for solvent screening for hydration of acetylenemonocarboxylic acid 19 catalyzed by RuCl3 Screening of solvents for the hydration of acetylenemonocarboxylic acid 19 employed a 50 mL flask equipped with a magnetic stir bar that was charged with RuCl3 (11 mg, 50 µmol). An organic solvent or H2O (20 mL) was added to the flask to form black suspension. When an organic solvent was employed for the reaction, H2O (90 µL, 5 mmol) was added to the reaction mixture. Acetylenemonocarboxylic acid 19 (350 mg, 5 mmol) was added to the reaction mixture. The stirred reaction mixture was run under N2 for 12 h at 100 ˚C. When THF was used, the reaction temperature was 65 ˚C. The reaction was cooled down to rt. A 0.5 mL aliquot of the reaction mixture was used to NMR analysis using 10 mM TSP in D2O as standard. Data for each reaction is included in Chapter 4, Table 4.2. 76 25. Isolation of pyruvic acid 53 from the hydration of AMCA 19 catalyzed by RuCl3 To a 50 mL two neck flask was added 11 mg of RuCl3.xH2O (22 mg, 1 mol%) and 40 mL of DI H2O. Acetylenemonocarboxylic acid 19 (620 µL, 10 mmol) was added to the reaction mixture at rt. The reaction was heated under N2 at 100 ˚C for 12 h. After cooled down to rt, pyruvic acid was isolated via extraction using MTBE (60 mL x 3). Removal of MTBE in vacuo yielded 484 mg (55%) of pyruvic acid 53. Pyruvic acid 53: 1H NMR (500 MHz, DMSO-d6) δ 2.5 (s, 3H), 13.75 (br s, 1H). 13C NMR (125 MHz, DMSO-d6) δ 27.0, 167.7, 194.0. 77 APPENDICES 78 APPENDIX A: CATALYST SCREENING DATA Screening of Catalysts for Conversion of AMCA to pyrone and aromatic products Scheme 5.1. Conversion of AMCA to pyrone and aromatic products 79 Table 5.1. Acid catalyzed conversion of AMCA to pyrone and aromatic products Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al Group IV 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg TiCp2Cl2 0.8 neat -- 21 12 h TiCp2Cl2 0.8 neat -- 50 12 h TiCp2Cl2 0.8 neat -- 75 12 h TiCp2Cl2 0.8 neat -- 100 12 h TiCp2Cl2 AgSbF6 TiCp2Cl2 AgSbF6 TiCp2Cl2 AgSbF6 TiCp2Cl2 AgSbF6 TiCp2Cl2 AgSbF6 TiCp2Cl2 AgSbF6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h DCE 25 100 12 h dioxane 25 100 12 h 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 5 2 0 0 0 0 0 0 0 0 0 0 0 1 1 2 2 0 8 14 16 28 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 2 3 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 56 57 25 26 15 17 10 12 88 89 35 44 20 38 15 39 15 46 15 15 1 2 3 4 5 6 7 8 9 10 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 80 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 11 12 13 14 15 16 17 18 19 20 21 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg ZrCp2Cl2 0.8 neat -- 21 12 h ZrCp2Cl2 0.8 neat -- 50 12 h ZrCp2Cl2 0.8 neat -- 75 12 h ZrCp2Cl2 0.8 neat -- 100 12 h ZrCp2Cl2 AgSbF6 ZrCp2Cl2 AgSbF6 ZrCp2Cl2 AgSbF6 ZrCp2Cl2 AgSbF6 ZrCp2Cl2 AgSbF6 ZrCp2Cl2 AgSbF6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h DCE 25 100 12 h dioxane 25 100 12 h HfCp2Cl2 0.8 neat -- 21 12 h 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 5 2 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 3 0 0 2 16 28 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 2 3 1 0 1 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 50 51 35 36 20 21 7 10 85 86 53 54 20 25 15 40 15 47 15 16 40 44 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 81 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al HfCp2Cl2 0.8 neat -- 50 12 h HfCp2Cl2 0.8 neat -- 75 12 h HfCp2Cl2 0.8 neat -- 100 12 h 22 23 24 25 26 27 28 29 30 31 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 4 4 4 0 0 0 1 0 0 0 0 0 1 3 0 0 0 0 0 0 0 0 0 0 0 0 0 1 3 0 3 6 3 18 0 0 0 0 0 0 0 0 0 0 0 0 0 2 3 0 1 2 3 1 1 1 1 1 1 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 32 40 20 31 15 20 30 34 24 33 13 20 5 28 49 50 30 31 21 22 HfCp2Cl2 AgSbF6 HfCp2Cl2 AgSbF6 HfCp2Cl2 AgSbF6 HfCp2Cl2 AgSbF6 CrCl2 AgSbF6 CrCl2 AgSbF6 CrCl2 AgSbF6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h Group VI neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h 0 0 0 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 82 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 32 33 34 35 36 37 38 39 40 41 42 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg CrCl2 AgSbF6 CrCl3 AgSbF6 CrCl3 AgSbF6 CrCl3 AgSbF6 CrCl3 AgSbF6 MoCl3 0.8 1.6 0.8 2.4 0.8 2.4 0.8 2.4 0.8 2.4 0.8 neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h MoCl3 0.8 neat -- 50 12 h MoCl3 0.8 neat -- 75 12 h MoCl3 MoCl3 AgSbF6 MoCl3 AgSbF6 0.8 0.8 2.4 0.8 2.4 neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 4 0 0 0 0 0 0 0 0 0 0 0 0 2 1 1 3 2 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 10 12 15 16 10 11 7 0 10 2 38 39 21 22 7 0 8 4 20 27 10 11 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 83 Table 5.1. (cont’d) Scale Catalysts Mol % 0.8 2.4 0.8 2.4 0.8 Solv. wt % T (˚C) Time neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h MoCl3 AgSbF6 MoCl3 AgSbF6 MoCl5 MoCl5 0.8 neat -- 50 12 h MoCl5 0.8 neat -- 75 12 h MoCl5 MoCl5 AgSbF6 MoCl5 AgSbF6 MoCl5 AgSbF6 MoCl5 AgSbF6 MoCl5 AgSbF6 0.8 0.8 4.0 0.8 4.0 0.8 4.0 0.8 4.0 0.8 4.0 neat -- 100 12 h neat -- 21 12 h neat -- 50 1 h neat -- 75 1 h neat -- 100 1 h neat -- 50 1 h 43 44 45 46 47 48 49 50 51 52 53 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 600 mg % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 0 0 2 2 2 8 5 1 1 0 0 0 2 1 1 1 5 1 2 3 0 0 1 2 0 1 2 8 1 0 0 0 0 0 0 0 0 0 0 0 6 7 0 0 0 2 16 21 19 16 0 0 0 0 0 1 0 7 8 8 22 13 1 1 0 1 1 2 0 1 1 2 2 Tot al 15 15 5 3 19 22 19 24 27 35 0 0 1 2 4 11 17 45 8 16 46 10 11 13 65 11 10 13 9 7 7 59 68 11 11 10 71 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 84 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 54 55 56 57 58 59 60 61 62 63 64 200 mg 200 mg 400 mg 400 mg 400 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg MoCl5 AgSbF6 MoCl5 AgSbF6 MoCl5 AgSbF6 MoCl5 AgSbF6 MoCl5 AgSbF6 0.8 4.0 0.8 4.0 0.8 4.0 0.8 4.0 0.8 4.0 DCE 25 100 12 h dioxane 25 100 12 h dioxane 25 100 12 h dioxane 5 100 12 h dioxane 50 100 12 h MoCp2Cl2 0.8 neat -- 100 12 h MoCp2Cl2 AgSbF6 MoCp2Cl2 AgSbF6 MoCp2Cl2 AgSbF6 MoCp2Cl2 AgSbF6 WCl4 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h 1 1 0 0 0 0 0 0 1 1 0 1 1 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 19 10 29 17 30 20 0 0 24 15 2 1 7 14 0 0 0 9 14 10 1 0 2 2 2 0 2 1 1 1 1 1 1 10 11 0 8 1 1 4 8 7 1 11 13 Tot al 66 75 9 9 6 6 3 7 15 10 79 20 23 7 8 63 27 1 25 29 10 16 38 22 13 69 12 5 51 0 34 37 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 85 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al WCl4 0.8 neat -- 50 12 h WCl4 0.8 neat -- 75 12 h 65 66 67 68 69 70 71 72 73 74 75 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg WCl4 WCl4 AgSbF6 WCl4 AgSbF6 WCl4 AgSbF6 WCl4 AgSbF6 WCp2Cl2 AgSbF6 WCp2Cl2 AgSbF6 WCp2Cl2 AgSbF6 WCp2Cl2 AgSbF6 0.8 0.8 3.2 0.8 3.2 0.8 3.2 0.8 3.2 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0 0 0 1 5 3 0 0 0 0 1 1 neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h 14 12 neat -- 21 12 h neat -- 50 12 h 0 4 neat -- 75 12 h 10 neat -- 100 12 h 5 0 0 2 5 0 0 0 0 0 0 0 0 0 0 0 2 2 3 2 14 8 16 2 7 13 7 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 1 2 1 1 1 1 1 1 1 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 15 19 10 14 7 12 19 24 4 26 18 31 7 51 26 29 15 28 10 36 5 24 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 86 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al WCl6 0.8 neat -- 21 12 h WCl6 0.8 neat -- 50 12 h WCl6 0.8 neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h WCl6 WCl6 AgSbF6 WCl6 AgSbF6 WCl6 AgSbF6 WCl6 AgSbF6 WCl6 AgSbF6 0.8 0.8 4.8 0.8 4.8 0.8 4.8 0.8 4.8 0.8 4.8 0 0 0 0 1 2 3 7 0 0 0 0 0 1 3 3 0 0 0 0 0 0 0 0 0 1 1 3 3 2 14 20 34 18 0 0 0 0 0 0 0 0 0 1 1 1 11 1 1 1 2 3 0 0 0 0 0 1 0 1 1 0 0 0 0 0 0 0 0 0 21 23 15 17 8 4 12 18 19 23 11 30 4 4 31 51 10 54 76 77 78 79 80 81 82 83 84 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 600 mg 85 200 mg neat -- 100 12 h 10 12 Group VII CoCl2 0.8 neat -- 100 12 h 1 0 0 1 0 1 0 0 14 17 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 87 Mol % 0.8 1.6 Solv. wt % T (˚C) Time neat -- 100 12 h 5 THF 50 65 24 h THF 50 65 24 h Group VIII neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 21 12 h % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 8 0 0 1 2 3 0 0 0 2 0 0 0 1 6 0 0 0 0 0 0 0 0 0 0 0 0 5 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 1 1 1 0 0 0 0 10 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 Tot al 21 11 2 5 0 0 10 13 19 24 11 23 27 27 15 15 0 0 Table 5.1. (cont’d) Scale Catalysts CoCl2 AgSbF6 (PPh3)3 CoCl (PPh3)3 CoCl AgSbF6 FeCl2 FeCl2 AgSbF6 FeCl2 AgSbF6 FeCl3 5.0 5.0 0.8 0.8 1.6 0.8 1.6 0.8 86 87 88 89 90 91 92 93 94 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg FeCl3 0.8 neat -- 50 12 h FeCl3 0.8 neat -- 75 12 h a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 88 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 95 96 97 98 99 100 101 102 103 104 105 200 mg 200 mg 200 mg 200 mg 200 mg 600 mg 200 mg 200 mg 200 mg 200 mg 200 mg FeCl3 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 2.4 0.8 2.4 neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h 0 0 0 0 1 0 0 0 1 0 4 0 0 0 0 1 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 6 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 20 20 14 14 13 13 10 12 16 16 12 13 7 7 8 10 15 15 3 18 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 89 Table 5.1. (cont’d) Scale Catalysts 106 107 108 109 110 111 112 113 114 200 mg 200 mg 200 mg 200 mg 100 mg 100 mg 100 mg 100 mg 100 mg FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 FeCl3 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AuCl AgSbF6 [RuCl2(p- cymene)]2 AuCl AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 Mol % 0.8 2.4 0.8 2.4 4.0 12.0 20.0 60.0 5.0 20.0 5.0 20.0 5.0 1.0 21.0 1.0 1.0 5.0 1.0 4.0 Solv. wt % T (˚C) Time neat -- 75 12 h neat -- 100 12 h neat -- 100 12 h neat -- 100 12 h HOAc 4 110 12 h % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 1 1 4 2 5 0 1 4 3 16 0 0 0 1 0 2 10 6 20 0 0 0 0 21 24 1 0 1 3 8 0 0 1 1 9 0 0 0 0 0 6 2 0 0 0 Tot al 10 14 16 30 83 HOAc 4 110 12 h 4 10 0 23 26 9 19 0 0 91 HOAc 4 110 12 h 2 0 0 11 10 8 4 0 0 35 HOAc 4 110 12 h 3 1 0 2 3 4 2 0 0 15 HOAc 4 110 12 h 5 0 0 1 2 1 1 0 0 10 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 90 Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al Table 5.1. (cont’d) Scale Catalysts 115 116 117 118 119 120 121 122 123 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 KPF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 Mol % 5.0 1.0 21.0 1.0 1.0 5.0 5.0 20.0 dioxane PvOH 5.0 20.0 dioxane PvOH 5.0 20.0 dioxane PvOH 5.0 20.0 dioxane PvOH 5.0 20.0 5.0 20.0 5.0 20.0 DCE PvOH DCE PvOH TCE PvOH HOAc 4 110 12 h 1 HOAc 4 110 12 h 1 4 110 12 h 0 4 110 12 h 1 4 110 12 h 1 12 1 4 80 4 h 0 4 110 12 h 1 4 80 4 h 0 0 5 0 0 0 1 4 0 0 0 2 7 21 5 3 9 3 3 21 2 6 3 2 6 5 8 30 9 0 30 7 0 4 26 1 1 1 15 9 34 5 0 0 0 0 0 0 0 0 40 5 24 0 29 0 60 0 81 8 40 0 70 0 8 6 2 0 0 14 30 4 110 12 h 1 10 1 16 7 24 3 0 0 62 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 91 Table 5.1. (cont’d) Scale Catalysts 124 125 126 127 128 129 130 131 132 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 Mol % 5.0 20.0 5.0 20.0 5.0 20.0 TCE PvOH 4 80 4 h 0 PvOH 4 110 12 h 1 dioxane 4 110 12 h 1 5.0 20.0 dioxane PvOH 5.0 20.0 HOAC dioxane 4 110 12 h 1 4 110 12 h 1 5.0 20.0 TFA 4 110 12 h 0 5.0 20.0 TFA dioxane 4 110 12 h 1 5.0 20.0 TCA 4 110 12 h 0 5.0 20.0 TCA dioxane 4 110 12 h 1 Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 0 5 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 12 4 4 1 4 8 4 0 0 2 21 4 6 13 0 2 8 0 1 12 0 2 12 0 2 4 0 1 1 2 5 5 7 3 1 3 0 15 36 0 0 0 0 0 0 0 0 0 15 0 13 0 34 0 25 0 17 0 17 0 15 0 10 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 92 Table 5.1. (cont’d) Scale Catalysts 133 134 135 136 137 138 139 140 141 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 [RuCl2(p- cymene)]2 AgSbF6 NiCl2 NiCl2 AgSbF6 NiCl2 AgSbF6 NiCl2 AgSbF6 PdCl2 200 mg 200 mg 400 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg Mol % 5.0 20.0 5.0 20.0 5.0 20.0 5.0 20.0 0.8 0.8 0.8 0.8 1.6 0.8 1.6 0.8 Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al HOAc 4 50 12 h 0 HOAc 4 110 12 h 0 0 0 0 0 5 0 1 8 13 6 1 4 0 0 0 7 0 31 HOAc 8 110 12 h 3 12 0 15 19 12 13 0 0 80 HOAc 4 80 12 h 4 2 0 8 24 7 9 0 0 61 Group X neat -- 100 12 h neat -- 100 12 h neat -- 21 12 h neat -- 100 12 h neat -- 100 12 h 1 1 1 4 1 0 3 0 2 0 0 0 0 0 0 1 1 1 1 1 0 0 0 0 0 1 1 1 1 3 0 0 0 0 0 0 0 0 0 0 1 4 30 36 20 23 0 8 10 15 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 93 Table 5.1. (cont’d) Scale Catalysts 142 143 144 145 146 147 148 149 150 151 152 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg Mol % 0.8 0.8 0.8 0.8 0.8 Solv. wt % T (˚C) Time neat -- 21 12 h neat -- 100 12 h neat -- 100 4 h PdCl2 AgSbF6 PdCl2 AgSbF6 PtCl2 PtCl2 0.8 neat -- 50 12 h PtCl2 PtCl2 AgSbF6 PtCl2 AgSbF6 PtCl2 AgSbF6 PtCl2 AgSbF6 PtCl2 AgSbF6 PtCl2 AgSbF6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 1.6 0.8 1.6 0.8 1.6 neat -- 100 4 h neat -- 100 1 h neat -- 100 1 h neat -- 50 12 h neat -- 100 1 h neat -- 100 1 h neat -- 50 12 h % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 2 2 0 0 0 0 0 0 0 0 0 2 0 0 0 1 2 0 1 2 1 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 1 3 3 5 4 13 4 0 0 1 0 1 0 0 0 0 0 0 1 4 2 0 2 1 1 1 1 1 1 0 0 1 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 30 36 1 8 10 15 60 60 13 19 2 2 0 0 0 0 9 6 7 7 15 5 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 94 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 7 7 0 0 10 19 0 0 0 0 0 0 2 0 9 8 10 17 11 18 6 5 153 154 155 156 157 158 159 160 161 162 163 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg PtCl2 AgSbF6 PtCl2 AgSbF6 PtCl4 PtCl4 AgSbF6 PtCl4 AgSbF6 PtCl4 AgSbF6 PtCl4 AgSbF6 PtCl4 AgSbF6 PtCl4 AgSbF6 CuCl CuCl AgSbF6 0.8 0.8 0.8 1.6 0.8 0.8 0.8 0.8 1.6 0.8 2.4 0.8 3.2 0.8 3.2 0.8 3.2 0.8 0.8 0.8 PvOH 10 100 12 h PvOH 10 100 12 h neat -- 50 12 h neat -- 50 12 h neat neat neat neat neat neat neat -- -- -- -- -- -- -- 50 12 h 50 12 h 50 12 h 100 1 h 50 12 h Group XI 100 12 h 100 12 h 1 1 1 0 0 1 1 1 1 1 1 3 2 0 1 1 1 5 0 5 0 1 0 0 0 0 0 0 0 0 0 0 0 2 4 2 6 5 6 9 8 11 1 1 0 0 0 0 0 0 0 0 0 0 0 1 1 6 1 1 1 1 1 1 1 1 0 0 1 0 0 1 1 1 0 1 1 0 0 0 0 0 0 0 0 0 0 0 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 95 Mol % 0.8 0.8 AgPF6 AgBF4 neat neat AgOTf 0.8 neat AgNTf2 0.8 neat AgSbF6 0.8 neat AgSbF6 0.8 neat -- -- -- -- -- -- 100 12 h 100 12 h 100 12 h 100 12 h 21 12 h 21 24 h AuCl 0.8 neat -- 21 48 h neat -- 100 12 h neat -- 21 12 h AuCl AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 164 165 166 167 168 169 170 171 172 173 174 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 2 runs 200 mg 0 0 0 0 1 2 0 4 1 0 0 0 0 1 1 0 1 1 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 0 1 1 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 0 1 1 1 1 1 1 1 1 0 1 1 0 0 0 0 0 0 0 0 0 Tot al 3 3 3 3 5 6 0 0 0 0 0 0 31 31 31 39 -- 5 Table 5.1. (cont’d) Scale Catalysts Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b neat -- 100 12 h 24 5 0 1 0 1 1 0 -- 32 neat -- 100 12 h 20 4 0 5 0 1 1 0 15 46 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 96 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al neat -- 75 12 h 7 3 0 16 0 1 1 0 10 38 neat -- 50 12 h 8 2 0 14 0 1 1 0 10 36 AuCl AgSbF6 0.8 0.8 AuCl AgSbF6 AuCl AgSbF6 0.8 0.8 0.4 0.4 AuCl AgSbF6 0.03 0.03 200 mg 6 runs 200 mg 5 runs 200 mg 175 176 177 178c 7 g 179 180 181 182 183 184 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg neat -- 100 12 h neat -- 100 12 h AuCl AgSbF6 0.08 neat -- 100 12 h AuCl 0.08 neat -- 50 12 h AuCl 8 neat -- 50 12 h AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 0.08 0.08 0.08 0.8 0.8 4.0 neat -- 100 12 h neat -- 100 12 h neat -- 100 12 h 1 3 1 0 2 1 1 1 1 2 0 0 1 0 3 1 0 0 0 0 0 0 0 0 1 1 1 1 2 1 2 3 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 1 5 15 26 14 18 17 20 5 12 10 14 0 0 8 7 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 97 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 185 186 187 188 189 190 191 192 193 194 195 200 mg 200 mg 200 mg 800 mg 600 mg 800 mg 200 mg 200 mg 200 mg 200 mg 200 mg AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 TiCl4 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 8.0 8.0 8.0 8.0 8.0 8.0 0.2 0.2 0.8 0.8 0.2 0.2 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 100 12 h neat -- 50 12 h neat -- 21 12 h neat -- 100 12 h neat -- 100 12 h neat -- 100 12 h neat -- 100 12 h PvOH 10 100 12 h PvOH 50 100 12 h anisole 50 100 12 h cyclope ntane 10 100 12 h 1 1 1 5 4 5 0 0 4 0 0 1 2 0 1 1 1 0 4 3 0 0 0 0 0 0 0 0 0 0 0 0 0 3 3 1 1 8 9 0 1 11 0 2 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 0 2 2 2 1 1 1 2 1 1 1 0 1 0 0 0 0 0 0 0 0 0 0 0 Tot al 8 9 4 10 16 32 2 7 20 0 0 0 0 0 0 0 0 0 0 0 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 98 15 20 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 15 15 0 0 196 197 198 199 200 201 202 203 204 205 206 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 cyclope ntane cyclope ntane 25 100 12 h 50 100 12 h DCM 25 21 12 h DCM 25 50 12 h DCM 25 75 12 h DCM 25 100 12 h dioxane 25 21 12 h dioxane 25 50 12 h dioxane 25 75 12 h dioxane 25 100 12 h toluene 25 21 12 h 1 1 0 1 3 0 0 0 0 1 0 1 1 0 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 6 9 0 1 2 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 2 2 0 1 1 0 0 0 0 1 0 5 2 0 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 27 27 20 25 15 23 10 10 0 0 0 0 7 0 0 0 5 7 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 99 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 5 5 2 19 0 0 0 0 0 0 0 0 5 2 0 0 0 0 207 208 209 210 211 212 213 214 215 216 217 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 400 mg 200 mg 200 mg 200 mg 200 mg AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgSbF6 AuCl AgOTf AuCl AgBF4 AuCl AgNTf2 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 toluene 25 50 12 h toluene 25 75 12 h toluene 25 100 12 h toluene 50 100 12 h DMA 25 100 12 h DMA 50 100 12 h TCE 25 100 12 h neat -- 100 12 h neat -- 100 12 h neat -- 100 12 h neat -- 21 12 h 0 0 0 6 0 0 4 1 3 3 0 0 1 0 6 0 0 2 1 2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 8 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 1 1 1 1 0 0 0 0 1 0 0 1 1 8 8 0 12 10 38 0 0 0 0 0 5 10 25 10 25 15 16 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 100 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 218 219 220 221 222 223 224 225 226 227 228 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg AuCl AgNTf2 AuCl AgNTf2 AuCl AgNTf2 AuCl AgOTFA AuCl AgOTFA AuCl AgOTFA AuCl AgOTFA AuCl AgOAc AuCl AgOAc AuCl AgOAc AuCl AgOAc 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h 0 0 0 0 0 0 0 0 0 0 0 0 2 4 0 3 2 0 3 3 3 2 0 0 0 0 0 0 0 0 0 0 0 2 2 2 1 1 1 1 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 12 15 0 0 4 6 15 16 0 0 0 7 5 0 0 4 3 1 12 8 3 3 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 101 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 229 230 231 232 233 234 235 236 237 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg AuCl HNTf2 AuCl HNTf2 (PPh3) AuCl AgBF4 (PPh3) AuCl AgSbF6 (PPh3) AuCl AgSbF6 (PPh3) AuCl AgSbF6 (PPh3) AuCl AgSbF6 (PPh3) AuCl AgSbF6 (PPh3) AuCl AgOTf 0.8 1.6 0.8 1.6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 50 12 h neat -- 100 12 h neat -- 100 12 h 1 1 1 neat -- 21 12 h 0 neat -- 100 12 h 0 toluene -- 21 24 h 0 toluene -- 50 12 h 0 neat -- 21 12 h 0 neat -- 100 12 h 1 2 1 1 0 0 0 0 1 6 0 0 0 0 0 0 0 0 0 1 1 1 0 0 1 4 2 4 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 0 1 1 1 0 0 1 0 0 0 0 0 15 21 10 15 4 0 0 8 2 2 0 14 17 0 0 0 2 5 7 9 4 17 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 102 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 238 239 240 241 242 243 244 245 246 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg (PPh3) AuCl AgOTf (PPh3) AuCl AgOTf P(OMe)3 AuCl AgSbF6 P(OMe)3 AuCl AgSbF6 P(OMe)3 AuCl AgSbF6 P(OMe)3 AuCl AgSbF6 P(OPh)3 AuCl AgSbF6 P(OPh)3 AuCl AgSbF6 P(OPh)3 AuCl AgSbF6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 toluene -- 21 12 h 0 toluene -- 50 12 h 0 neat -- 21 72 h 3 neat -- 50 12 h 2 neat -- 75 12 h 2 neat -- 100 12 h 0 neat -- 21 12 h 0 neat -- 50 12 h 0 neat -- 75 12 h 0 0 0 0 0 1 1 0 0 0 0 0 0 0 1 1 4 7 0 0 0 0 0 13 0 0 0 0 0 4 1 2 4 0 0 0 0 1 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 15 17 0 0 0 0 0 1 0 3 7 0 10 0 16 0 5 0 10 11 0 0 5 11 3 7 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 103 Table 5.1. (cont’d) Scale Catalysts 247 248 249 250 251 252 253 254 255 256 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg P(OPh)3 AuCl AgSbF6 JohnPhos AuCl JohnPhos AuCl JohnPhos AuCl JohnPhos AuCl JohnPhos AuCl AgSbF6 JohnPhos AuCl AgSbF6 JohnPhos AuCl AgSbF6 JohnPhos AuCl AgSbF6 JohnPhos AuCl AgOTf Mol % 0.8 0.8 0.8 0.8 Solv. wt % T (˚C) Time neat -- 100 12 h neat -- 21 12 h 0.8 neat -- 50 12 h 0.8 neat -- 75 12 h 0.8 neat -- 100 12 h 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 21 12 h neat -- 50 12 h 0 neat -- 75 12 h 0 neat -- 100 12 h 0 neat -- 21 12 h 0 % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 1 0 0 1 3 2 2 5 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 Tot al 4 1 0 0 1 3 2 2 5 2 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 104 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 257 258 259 260 261 262 263 264 265 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg JohnPhos AuCl AgOTf JohnPhos AuCl AgOTf JohnPhos AuCl AgOTf JohnPhos AuCl AgNTf2 JohnPhos AuCl AgNTf2 JohnPhos AuCl AgNTf2 JohnPhos AuCl AgNTf2 JohnPhos AuCl AgPF6 JohnPhos AuCl AgPF6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 50 12 h 0 neat -- 75 12 h 0 neat -- 100 12 h 0 neat -- 21 12 h 0 neat -- 50 12 h 0 neat -- 75 12 h 0 neat -- 100 12 h 2 neat -- 21 12 h 0 neat -- 50 12 h 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 2 2 2 2 2 2 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Tot al 1 4 2 4 3 2 4 3 2 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 105 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 266 267 268 269 270 271 272 273 274 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg JohnPhos AuCl AgPF6 JohnPhos AuCl AgPF6 JohnPhos AuCl AgBF4 JohnPhos AuCl AgBF4 JohnPhos AuCl AgBF4 JohnPhos AuCl AgBF4 JohnPhos AuCl AgSbF6 JohnPhos AuCl AgSbF6 JohnPhos AuCl AgSbF6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 75 12 h 0 neat -- 100 12 h 0 neat -- 21 12 h 0 neat -- 50 12 h 0 neat -- 75 12 h 0 neat -- 100 12 h 0 DCM 25 21 12 h 0 DCM 25 50 12 h 0 DCM 25 75 12 h 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 2 2 2 2 1 1 3 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 0 0 Tot al 2 1 3 2 2 2 9 1 4 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 106 Table 5.1. (cont’d) Scale Catalysts Mol % 0.8 0.8 Solv. wt % T (˚C) Time DCM 25 100 12 h JohnPhos AuCl AgSbF6 275 276 277 278 279 280 281 282 283 284 285 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg IPrAuCl 0.8 neat -- 21 12 h IPrAuCl 0.8 neat -- 50 12 h IPrAuCl 0.8 neat -- 75 12 h IPrAuCl 0.8 neat -- 100 12 h IPrAuCl AgSbF6 IPrAuCl AgSbF6 IPrAuCl AgSbF6 IPrAuCl AgSbF6 IPrAuCl AgOTf IPrAuCl AgOTf 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 0 0 0 0 0 0 0 0 0 0 0 0 0 6 2 2 1 1 2 2 4 5 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Tot al 7 2 3 1 1 3 2 7 8 1 1 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 107 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 286 287 288 289 290 291 292 293 294 295 296 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg IPrAuCl AgOTf IPrAuCl AgOTf IPrAuCl AgNTf2 IPrAuCl AgNTf2 IPrAuCl AgNTf2 IPrAuCl AgNTf2 IPrAuCl AgNTf2 IPrAuCl AgPF6 IPrAuCl AgPF6 IPrAuCl AgPF6 IPrAuCl AgBF4 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 2 2 3 3 3 2 2 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Tot al 3 2 2 4 4 4 2 2 2 2 1 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 108 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 297 298 299 300 301 302 303 304 305 306 307 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg IPrAuCl AgBF4 IPrAuCl AgBF4 IPrAuCl AgBF4 IPrAuCl AgSbF6 IPrAuCl AgSbF6 IPrAuCl AgSbF6 IPrAuCl AgSbF6 (PhF5)3 AuCl (PhF5)3 AuCl (PhF5)3 AuCl (PhF5)3 AuCl 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h DCM 25 21 12 h DCM 25 50 12 h DCM 25 75 12 h DCM 25 100 12 h neat -- 21 12 h 0.8 neat -- 50 12 h 0.8 neat -- 75 12 h 0.8 neat -- 100 12 h 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 2 2 2 1 1 2 2 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 6 5 3 0 Tot al 2 2 2 1 1 2 2 7 7 5 3 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 109 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 308 309 310 311 312 313 314 315 316 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg (PhF5)3 AuCl AgSbF6 (PhF5)3 AuCl AgSbF6 (PhF5)3 AuCl AgSbF6 (PhF5)3 AuCl AgSbF6 (PhF5)3 AuCl AgOTf (PhF5)3 AuCl AgOTf (PhF5)3 AuCl AgOTf (PhF5)3 AuCl AgOTf (PhF5)3 AuCl AgNTf2 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 21 12 h 2 neat -- 50 12 h 1 neat -- 75 12 h 1 neat -- 100 12 h 0 neat -- 21 12 h 0 neat -- 50 12 h 0 neat -- 75 12 h 0 neat -- 100 12 h 0 neat -- 21 12 h 1 0 0 1 2 0 0 0 1 0 0 0 0 0 0 0 0 0 0 2 3 3 3 1 1 1 4 1 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 8 14 0 0 0 4 5 5 9 10 5 0 0 6 1 5 0 13 16 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 110 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 8 2 6 0 0 0 0 0 0 317 318 319 320 321 322 323 324 325 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg (PhF5)3 AuCl AgNTf2 (PhF5)3 AuCl AgNTf2 (PhF5)3 AuCl AgNTf2 (PhF5)3 AuCl AgPF6 (PhF5)3 AuCl AgPF6 (PhF5)3 AuCl AgPF6 (PhF5)3 AuCl AgPF6 (PhF5)3 AuCl AgBF4 (PhF5)3 AuCl AgBF4 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 neat -- 50 12 h 1 neat -- 75 12 h 0 neat -- 100 12 h 0 neat -- 21 12 h 0 neat -- 50 12 h 0 neat -- 75 12 h 0 neat -- 100 12 h 0 neat -- 21 12 h 0 neat -- 50 12 h 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 5 2 5 1 2 2 1 1 1 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 15 17 0 0 0 0 0 6 3 0 7 0 9 6 1 8 1 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 111 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 5 5 0 0 0 0 0 10 11 0 0 0 0 0 0 0 0 0 0 9 0 1 3 3 13 23 14 21 13 18 (PhF5)3 AuCl AgBF4 (PhF5)3 AuCl AgBF4 (PhF5)3 AuCl AgSbF6 (PhF5)3 AuCl AgSbF6 (PhF5)3 AuCl AgSbF6 (PhF5)3 AuCl AgSbF6 AuBr3 AuBr3 AgSbF6 AuCl3 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 2.4 0.8 326 327 328 329 330 331 332 333 334 335 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg neat -- 75 12 h 0 neat -- 100 12 h 1 DCM 25 21 12 h 0 DCM 25 50 12 h 0 DCM 25 75 12 h 0 DCM 25 100 12 h neat -- 100 12 h 0 1 neat -- 100 12 h 12 neat -- 21 12 h 1 0 0 0 0 0 0 0 0 4 0 2 0 0 0 0 0 0 0 0 0 0 5 3 1 1 3 3 1 5 1 2 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 1 0 1 0 0 0 0 0 0 1 1 5 0 AuCl3 0.8 neat -- 50 12 h a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 112 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 14 5 6 2 336 337 338 339 340 341 342 343 344 345 346 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg AuCl3 0.8 neat -- 75 12 h AuCl3 AuCl3 AgSbF6 AuCl3 AgSbF6 AuCl3 AgSbF6 AuCl3 AgSbF6 AuCl3 AgSbF6 AuCl3 AgSbF6 AuCl3 AgSbF6 AuCl3 AgSbF6 AuCl3 AgSbF6 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 0.8 2.4 neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h 0 1 0 6 1 3 0 1 0 6 1 3 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 2 0 2 5 2 1 2 9 13 2 2 0 0 0 0 0 0 0 0 0 0 0 2 1 3 4 2 0 4 0 1 0 0 1 0 1 2 2 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 10 16 6 5 0 9 7 3 0 7 26 12 4 15 21 24 11 11 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 113 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 11 13 16 5 3 0 347 348 349 350 351 352 353 354 355 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg AuCl3 AgSbF6 AuCl3 AgSbF6 AuCl3 AgSbF6 C6H4N AuCl2O2 AgSbF6 C6H4N AuCl2O2 AgSbF6 C6H4N AuCl2O2 AgSbF6 0.8 2.4 0.8 2.4 0.8 2.4 0.8 1.6 0.8 1.6 0.8 1.6 neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 50 12 h 1 1 2 0 0 0 0 1 0 0 0 0 4 8 11 5 0 0 0 0 neat -- 75 12 h 14 2 0 13 0 neat -- 100 10 min 1 1 0 13 0 Group XII Zn(OTf)2 0.8 neat -- 100 12 h Hg2Cl2 0.4 neat -- 21 12 h Hg2Cl2 0.4 neat -- 50 12 h 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 3 1 1 0 0 0 0 1 1 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 14 23 7 38 2 20 30 31 90 90 80 80 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 114 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 356 357 358 359 360 361 362 363 364 365 366 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg Hg2Cl2 0.4 neat -- 75 12 h Hg2Cl2 Hg2Cl2 AgSbF6 Hg2Cl2 AgSbF6 Hg2Cl2 AgSbF6 Hg2Cl2 AgSbF6 HgCl2 0.4 0.4 0.8 0.4 0.8 0.4 0.8 0.4 0.8 0.8 neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h HgCl2 0.8 neat -- 50 12 h HgCl2 0.8 neat -- 75 12 h HgCl2 HgCl2 AgSbF6 0.8 0.8 0.8 neat -- 100 12 h neat -- 21 12 h 0 0 1 1 1 0 0 0 0 0 1 0 0 0 1 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5 10 4 3 0 0 0 0 4 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 50 50 20 22 15 22 0 0 0 13 8 5 70 70 26 26 10 10 7 19 15 21 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 115 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 13 8 2 4 15 7 7 0 0 0 1 7 3 3 367 368 369 370 371 372 373 374 375 376 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg HgCl2 AgSbF6 HgCl2 AgSbF6 HgCl2 AgSbF6 HgCl2 AgSbF6 HgCl2 AgSbF6 HgCl2 AgSbF6 HgCl2 AgSbF6 HSbF6 x6H20 HSbF6 x6H20 HSbF6 x6H20 0.8 0.8 0.8 0.8 0.8 0.8 0.8 1.6 0.8 1.6 0.8 1.6 0.8 1.6 neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h neat -- 21 12 h neat -- 50 12 h neat -- 75 12 h neat -- 100 12 h 1 1 0 0 0 0 0 Bronsted Acids 2 neat -- 100 7 h 10 neat -- 100 7 h 20 neat -- 100 7 h 0 1 1 1 2 1 0 1 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 10 4 0 2 6 3 3 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 40 43 34 37 25 29 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 116 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al MsOH 20 neat -- 100 7 h TsOH 20 neat -- 100 7 h 3 4 7%P2O5. MsOH 7%P2O5. MsOH xP2O5. H3PO4 xP2O5. H3PO4 TFA 10 neat -- 100 12 h 1 20 10 20 20 neat neat neat neat -- -- -- -- -- 100 12 h 100 12 h 100 12 h 100 12 h 100 12 h 3 0 1 0 0 377 378 379 380 381 382 383 384 385 386 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 200 mg 3 0 1 5 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 6 4 1 4 0 1 3 0 15 25 22 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 2 1 3 4 4 1 1 0 1 1 1 1 1 0 0 0 0 0 20 34 10 20 0 26 33 0 0 0 0 0 0 0 0 15 31 30 32 29 36 27 33 30 32 15 56 18 72 17 70 C4F9SO3H 10 neat C4F9SO3H 10 neat -- 100 12 h 11 12 C4F9SO3H 20 neat -- 100 12 h 13 12 387 1 g C4F9SO3H 20 neat -- 100 12 h 14 13 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 117 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 388d 1 g C4F9SO3H Kugelrohr 20 neat -- 100 - 140 12 h 20 21 389 1 g C4F9SO3H 20 TCE 25 100 20 h 3 2 4 3 390 391 392 393 394 395 396 397 200 mg 200 mg 600 mg 200 mg 600 mg 200 mg 200 mg 600 mg TfOH 2 neat -- 100 12 h TfOH 10 neat -- 100 7 h 10 10 TfOH 10 neat -- 100 7 h 10 10 TfOH 15 neat -- 100 7 h 12 12 TfOH 15 neat -- 100 7 h 13 14 TfOH TfOH 20 neat -- 100 2 h 11 10 40 neat -- 100 12 h 12 12 TfOH 20 neat -- 100 3 h 10 10 0 0 0 0 0 0 0 0 0 0 23 13 5 15 15 19 25 32 40 18 0 0 0 0 0 0 0 0 0 0 6 5 1 3 3 4 6 4 4 6 0 0 0 1 1 1 1 1 3 0 0 0 0 0 0 0 0 0 0 0 17 87 36 61 15 26 18 57 17 56 17 65 15 74 15 73 14 65 10 54 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 118 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 96 84 7 1 398d 600 mg TfOH Kugelrohr 399d 1 g TfOH Kugelrohr 20 neat -- 100 - 180 3 h 19 26 20 neat -- 180 20 h 21 20 400 1 g TfOH 15 neat -- 100 3.5 h 13 14 401d 1 g 402d 1 g TfOH sublime TfOH sublime 15 neat -- 240 4 h 10 5 15 neat -- 140 3 h 16 19 403d 2 g TfOH 15 neat -- 100 4.5 h 10 9 404d 2 g TfOH Kugelrohr 15 neat -- 405 2 g TfOH 15 neat -- 100 - 140 100 - 110 8.5 h 20 22 16 h 19 20 406 3g 407 3 g 15 TfOH MS 3A TfOH MS 3A 15 neat -- 100 9 h 16 18 neat -- 140 4 h 18 20 0 0 0 0 0 0 0 0 0 0 32 27 25 18 14 25 12 15 13 10 0 0 0 1 1 0 0 0 0 0 6 6 6 4 6 4 6 6 4 6 6 3 1 1 1 0 2 0 0 2 0 0 0 0 0 0 0 0 0 0 15 74 38 77 36 93 25 73 36 98 12 72 15 66 29 85 Kugelrohr a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 119 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 408 6 g TfOH 15 neat -- 100 7 h 18 14 409d 6 g TfOH Kugelrohr 15 neat -- 100 - 140 7 h 23 24 410 6 g TfOH 10 neat -- 100 7 h 12 12 411d 6 g TfOH Kugelrohr 10 neat -- 100 - 140 7 h 25 30 412 6 g TfOH 10 neat -- 100 7 h 13 14 413d 6 g TfOH Kugelrohr 10 neat -- 100 - 160 7 h 26 32 414 6 g TfOH 415d 6 g TfOH Kugelrohr 2 2 neat -- 100 24 h 6 7 neat -- 100 - 140 24 h 10 13 416 417 200 mg 200 mg TfOH 20 dioxane 25 100 12 h TfOH 20 HOAc 25 100 12 h 0 0 0 0 0 0 0 0 0 0 0 0 0 0 28 15 33 11 30 10 4 1 4 5 0 0 0 0 0 0 0 0 0 0 4 7 4 5 4 6 3 3 3 6 0 0 0 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 20 84 19 88 25 86 21 92 22 83 19 93 35 55 30 57 37 44 26 39 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 120 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time 418 419 420 200 mg 600 mg 600 mg TfOH 20 DCE 25 100 12 h TfOH 20 DCE 25 100 12 h TfOH 20 TCE 25 100 12 h 421 6 g TfOH 20 TCE 25 80 28 h % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 1 3 4 1 8 4 0 0 1 4 4 6 14 6 1 0 9 1 10 0 0 0 0 0 0 0 0 0 0 0 29 14 26 60 41 30 5 3 20 1 3 0 0 0 0 0 0 0 0 0 0 0 1 1 2 7 6 5 2 1 4 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 30 62 23 45 10 46 12 86 12 81 37 82 65 73 75 79 30 74 80 84 0 23 TfOH Kugelrohr TfOH Kugelrohr TfOH Kugelrohr TfOH Kugelrohr TfOH Kugelrohr 422d 6 g 423d 6 g 424d 6 g 425d 6 g 426d 3 g 427 428 400 mg 400 mg 20 TCE 25 100 18 h 20 TCE 10 100 18 h 20 TCE 20 TCE 5 2 100 18 h 100 18 h 20 DCB 25 100 18 h 11 FSO3H 1 neat -- 100 24 h FSO3H 10 neat -- 100 20 h 1 9 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 121 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b Tot al 429 2 g FSO3H 10 neat -- 100 20 h 11 12 0 0 0 0 0 0 0 0 0 0 0 6 18 5 2 5 11 21 28 3 1 1 0 0 0 0 0 0 0 0 0 0 0 2 3 1 1 2 2 1 2 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 16 53 24 64 70 79 60 67 0 42 11 55 20 57 21 73 76 85 0 0 4 1 430 2 g FSO3H 15 neat -- 100 20 h 431 2 g FSO3H 10 TCE 25 100 20 h 8 1 3 11 2 3 432 433 400 mg 400 mg HSbF6 HSbF6 434 2 g HSbF6 435 2 g HSbF6 436 2 g HSbF6 437 2 g HSbF6 438 439 200 mg 200 mg Zeolite B-H Zeolite Y-H 1 5 5 10 15 5 -- -- neat -- 100 24 h neat -- 100 20 h 12 11 neat -- 100 20 h 14 17 neat -- 100 20 h neat -- 100 20 h TCE 25 100 20 h 6 9 2 9 13 2 Heterogenous Catalysts neat 100 100 12 h neat 100 100 12 h 1 0 1 0 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 122 Table 5.1. (cont’d) Scale Catalysts Mol % Solv. wt % T (˚C) Time % Yield (mol/mol) 1a 2a 3a 22a 23b 40a 39a 41a 19b 440 441 442 200 mg 200 mg 200 mg HZSM-5 Nafion Dowex-50 -- -- -- neat 100 100 12 h neat 100 100 12 h neat 100 100 12 h 1 1 3 1 0 4 0 0 0 0 0 12 0 0 0 1 0 4 0 0 0 0 0 0 0 0 0 Tot al 3 1 23 a Determined by HPLC. b Determined by NMR. c Run in Ti vessel. d Rxn run at 100 ˚C, 1atm, 4.5h. Kugelrohr started at 80 ˚C, 83 mmHg, ended at indicated temp., 2 mmHg. All reactions run under 1 atm N2 unless indicated otherwise. 123 APPENDIX B: NMR Spectra 124 Figure 5.1. 1H - NMR spectrum of solated 4-methyl 1,4-cyclohexadiene carboxylic acid 20 125 Figure 5.2. 13C- NMR spectrum of solated 4-methyl 1,4-cyclohexadiene carboxylic acid 20 126 Figure 5.3.1H-NMR spectrum of isolated terephthalic acid 1 127 Figure 5.4. 13C-NMR spectrum of isolated terephthalic acid 1 128 Figure 5.5. 1H-NMR spectrum of coumalic acid 22 129 Figure 5.6. 13C-NMR spectrum of coumalic acid 22 130 Figure 5.7. 1H-NMR spectrum of trans-diacrylic ether 50 131 Figure 5.8. 13C-NMR spectrum of trans-diacrylic ether 50 132 Figure 5.9. 1H-NMR spectrum of isolated isophthalic acid 2 133 Figure 5.10. 13C-NMR spectrum of isolated isophthalic acid 2 134 Figure 5.11. 1H-NMR spectrum of isolated phthalic acid 3 135 Figure 5.12. 13C-NMR spectrum of isolated phthalic acid 3 136 Figure 5.13. 1H-NMR spectrum of methyl 4-carbomethoxy-5-methoxy-penta-2E,4Z-dienoate 45 137 Figure 5.14. 13C-NMR spectrum methyl 4-carbomethoxy-5-methoxy-penta-2E,4Z-dienoate 45 138 1H and 13C NMR spectra of isolated isocoumalic acid 23 (Exp. 22, p. 74)2 Figure 5.15. 1H spectrum of isolated isocoumalic acid 23 139 Figure 5.16. 13C-NMR spectrum of isolated isocoumalic acid 23 140 Figure 5.17. 1H-NMR spectrum of pyruvic acid 59 141 Figure 5.18. 13C-NMR spectrum of pyruvic acid 59 142 REFERENCES 143 REFERENCES Nantz, M. H.; Fuchs, P. L. Cycloaromatization reactions of methyl 4-carbomethoxy-5- 1. methoxy-penta-2,4-dienoate. Syn. Comm. 1987, 17, 761-771. 2. orientating groups. J. Chem. Soc. 1901, 79, 1265-1284. 3. for a non-natural substrate. J. Am. Chem. Soc. 2005, 127, 5862-5868. Lapworth, A. J. The form of change in organic compounds, and the function of the meta- Metanis, N.; Keinan, E.; Dawson, P. A designed synthetic analogue of 4-OT is specific 144