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New synthetic methods for organonitrogen compounds

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New synthetic methods for organonitrogen compounds

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Content NEW SYNTHETIC METHODS FOR ORGANONITROGEN COMPOUNDS by Laxman Gurung A Dissertation presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) December 2015 Copyright 2015 Laxman Gurung ii DEDICATION To My Family & Teachers iii ACKNOWLEDGEMENTS I would like to express my gratitude to my advisor Professor G. K. Surya Prakash for providing me a great opportunity to pursue my graduate education in his laboratory. I am fortunate to have worked under his guidance first as an undergraduate summer research student and later as a graduate student. Throughout my stay at USC, he has provided an excellent support and guidance and has been a constant source of inspiration and encouragement. I am immensely grateful to him for providing freedom in research which allowed me to pursue research in different areas of chemistry. I am very thankful to Professor George A. Olah for sharing his profound knowledge of chemistry and his philosophical insights, observations and commentaries on science, religion, society, politics, history, law and so on, which will always remind me to step back and look at the big picture. I am also thankful for the inspiration and encouragement he provided during my stay at USC. I am honored to have him on my qualifying exam and dissertation committees. I would like to thank Dr. Thomas Mathew for his endless encouragement and immense help in all aspects of my research here at USC. Whenever I needed any help in the lab, he was never hesitant to put on his lab coat and get his hands dirty. I greatly admire his enthusiasm, work ethic and commitment to research. I would also like to thank Professor Katherine Shing for agreeing to serve on my qualifying exam and dissertation committees despite her busy schedule. I am thankful to Professor Nicos A. Petasis and Professor Thieo E. Hogen-Esch for serving on my qualifying exam committee. I would like to extend my appreciation to Dr. Robert Anizfeld for his support throughout the program. iv I am grateful to Dr. Sujith Chacko for mentoring me during my stay in the Olah-Prakash lab as an undergraduate summer research student in 2007 and also for introducing me to the synthetic organic chemistry research. Philipp Schmid (Ludwig Maximilian University, Munich) and Dr. Fang Wang are thanked for their help in the “nitrosation” project. I must also thank Dr. Alain Goeppert who helped me with the “carbon dioxide adsorption” project. I collaborated with Professor Eric R. Marinez (California State University Long Beach) on “electrophilic amination” project and would like to thank him as well for his help. Several undergraduate and high school students worked with me in various projects and I enjoyed working with them. I would like to thank Tisa Thomas (USC), Tito Thomas (USC), Kavitha George (La Canada High School), Nimisha Ganesh (Diamond Bar High School) and Shikhar Gupta (Irvine High School). I am grateful to the past and the current members of the Olah-Prakash group for their friendship and also helping me in one way or another way over the years. They include Dr. Golam Rasul, Dr. Patrice Batamack, Dr. Miklos Czaun, Dr. Atilla Papp, Dr. Akihisa Saitoh, Dr. Somesh K. Ganesh, Dr. Aditya Kulkarni, Dr. Habiba Vaghoo, Dr. Clement Do, Dr. Rehana Ismail, Dr. Fabrizio Pertusati, Dr. John- Paul Jones, Dr. Hema Krishnan, Dr. Arjun Narayanan, Sankar, Jothee, Huong, Kavita, Hang, Marc, Dean and Archith. I must thank the staff members at the Loker Hydrocarbon Research Institute and the Chemistry Department, including Carole, Ralph, Gloria, Magnolia, Phillip and Darrell. I would like to appreciate Michelle Dea for always being helpful with administrative aspects of my graduate program. Jessy May was always ready to help with the administrative work here at Loker and I would like to thank her as well. v I would like to take this opportunity to thank my alma mater Berea College for providing a scholarship for my undergraduate studies. Without the generosity and the unique mission of Berea College, I would not be here today. I am very grateful to my parents who despite having never been to school instilled in me the value of education and inspired me to pursue higher education. Finally, I would like to thank my wife Sabina for her patience and understanding during my increasingly long stays in the lab in the past several months. vi TABLE OF CONTENTS DEDICATION ii ACKNOWLEDGEMENTS iii LIST OF SCHEMES ix LIST OF FIGURES xi LIST OF TABLES xiii ABSTRACT xv 1 Chapter 1: An Introduction to Organonitrogen Compounds 17 1.1 Chapter 1: Introduction to Nitrogen and Nitrogen Fixation 17 1.2 Chapter 1: Nitrogen Containing Organic Compounds: Organonitrogen Compounds 19 1.3 Chapter 1: Synthesis of Nitrogen Containing Organic Compounds 21 1.4 Chapter 1: Aim and Scope of Current Work 26 1.5 Chapter 1: References 29 2 Chapter 2: Direct Synthesis of Diverse β-Fluoroethylamines by a Multi- component Protocol 31 2.1 Chapter 2: Introduction 31 2.2 Chapter 2: Results and Discussion 34 2.3 Chapter 2: Conclusions 47 2.4 Chapter 2: Experimental 2.4.1 General 2.4.2 Experimental Procedures 2.4.3 Spectral Data and Representative Spectra 48 2.5 Chapter 2: References 77 vii 3 Chapter 3: A Multi-component Protocol for Fluorinated α- amino Acids and β-amino Esters 82 3.1 Chapter 3: Introduction 82 3.2 Chapter 3: Results and Discussion 86 3.3 Chapter 3: Conclusions 94 3.4 Chapter 2: Experimental 3.4.1 General 3.4.2 Experimental Procedures 3.4.3 Spectral Data and Representative Spectra 94 3.5 Chapter 3: References 104 4 Chapter 4: Electrophilic Amination of Aromatics with Sodium Azide in BF 3 - H 2 O 106 4.1 Chapter 4: Introduction 106 4.2 Chapter 4: Results and Discussion 111 4.3 Chapter 4: Conclusions 117 4.4 Chapter 4: Experimental 4.4.1 General 4.4.2 Experimental Procedures 4.4.3 Spectral Data and Representative Spectra 117 4.5 Chapter 4: References 125 5 Chapter 5: Ipso-Nitrosation of Arylboronic Acids with Chlorotrimethylsilane and Sodium Nitrite 128 5.1 Chapter 5: Introduction 128 5.2 Chapter 5: Results and Discussion 131 5.3 Chapter 5: Conclusions 136 5.4 Chapter 5: Experimental 5.4.1 General 5.4.2 Experimental Procedures 5.4.3 Spectral Data 136 viii 5.5 Chapter 5: References 140 6 Chapter 6: Chlorotrimethylsilane as a mild reagent in the reduction of Nitrosoarenes to Azoxyarenes 144 6.1 Chapter 6: Introduction 144 6.2 Chapter 6: Results and Discussion 147 6.3 Chapter 6: Conclusions 159 6.4 Chapter 6: Experimental 6.4.1 General 6.4.2 Experimental Procedures 6.4.3 Spectral Data and Representative Spectra 160 6.5 Chapter 6: References 166 7 Chapter 7: Polyamines Supported on Fibrous Silica Nanospheres: New Regenerable Adsorbents for CO 2 Recycling 173 7.1 Chapter 7: Introduction 173 7.2 Chapter 7: Results and Discussion 178 7.3 Chapter 7: Conclusions 189 7.4 Chapter 7: Experimental 7.4.1 General 7.4.2 Experimental Procedures 190 7.5 Chapter 7: References 194 BIBLIOGRAPHY 196 ix LIST OF SCHEMES Scheme 1.1 Nitrogen fixation methods 18 Scheme 1.2 Strecker reaction 22 Scheme 1.3 Biginelli reaction 23 Scheme 1.4 Bucherer–Bergs reaction 23 Scheme 1.5 Passerini reaction 24 Scheme 1.6 Ugi reaction 24 Scheme 1.7 Hantzsch dihydropyridine synthesis 25 Scheme 1.8 Mannich reaction 25 Scheme 1.9 Petasis reaction 26 Scheme 2.1 Preparation of β-fluoro(phenylsulfonyl)ethylamines from α- fluoro(phenylsulfonyl)methanes, formaldehyde and amines 32 Scheme 2.2 Formation of β-fluoro(phenylsulfonyl)ethylamines from iminium salts and its precursor gem-aminoether 35 Scheme 2.3 Formation of fluoroethanol 7 via a competing pathway during the synthesis of β-fluoroethylamines 3 and 4 36 Scheme 3.1 Some examples of synthetic schemes currently in use for the preparation of fluorinated - and β-amino acids 84 Scheme 3.2 New approach for the synthesis of fluorinated β-amino esters (Eq. 1) and fluorinated α-amino acids (Eq. 2) 86 Scheme 3.3 Formation of the undesirable β-fluoroethanol (10) via a competing pathway during the synthesis of fluorinated β-amino ester 4a 87 Scheme 3.4 Reaction of N, N-dimethylamine and glyoxylic acid with α- fluoro-bis(phenylsulfonyl)-methane (FBSM, 1b) or α-fluoro-α- nitro(phenylsulfonyl)methane (FNSM, 1c) 91 Scheme 4.1 Selected reactions catalyzed by BF 3 -H 2 O 108 Scheme 4.2 Electrophilic Amination of Aromatics 111 x Scheme 4.3 (i) Formation of Hydrazoic Acid; (ii) Formation of Aminodiazonium Ion 116 Scheme 4.4 Mechanism for the Electrophilic Amination of Aromatics 116 Scheme 5.1 Chemical transformations of nitroso compounds 129 Scheme 5.2 Synthetic routes towards nitrosoarenes 129 Scheme 5.3 ipso-nitration of arylboronic acids with MNO 3 and TMSCl 130 Scheme 5.4 Proposed mechanism of ipso-nitrosation of phenylboronic acid with NaNO 2 and TMSCl 130 Scheme 5.5 The equilibrium between boronic acid and boroxine 134 Scheme 5.6 Elucidation of the oxidation of nitrosoarenes 134 Scheme 6.1 Reduction of Nitrosobenzene to Azoxybenzene by Chlorotrimethylsilane 148 Scheme 6.2 Reduction of Nitrosobenzene to Azobenzene via in situ generated Azoxybenzene 151 Scheme 6.3 Mechanism of Reduction of Nitrosobenzene to Azoxybenzene by TMSCl 153 Scheme 6.4 Dimerization of Nitrosobenzene 154 Scheme 6.5 Nucleophilic addition of Nitrosobenzene to Pyruvic Acid 155 Scheme 6.6 Mechanism of Reduction of Nitrosobenzene to Azoxybenzene by TMSCl 155 Scheme 6.7 Mechanism of Deoxygenation of Sulfoxides to Sulfides by Iodotrimethylsilane 156 Scheme 7.1 CO 2 as a major source for methanol and derived products 176 Scheme 7.2 Fibrous nanosilica formation from (EtO) 4 Si with the help of cetylpyridinium bromide (CPB) 179 Scheme 7.3 The CO 2 -amine interaction in each repeating unit of polyethylenimine 181 xi LIST OF FIGURES Figure 1.1 Some receptors within the body 20 Figure 1.2 Some Organonitrogen drugs 21 Figure 2.1 Selected reactions of α-fluorobis(phenylsulfonyl)methane (FBSM) 34 Figure 2.2 X-ray crystal structure of the three component reaction product 4e from FBSM, formalin and ethyl methyl amine 44 Figure 3.1 Comparison of 19 F NMR spectra of ethyl 2-fluoro-2- (phenylsulfonyl)acetate (1a) and ethyl 3-(tert-butylamino)-2- fluoro-2-(phenylsulfonyl)-propanoate (4a) 88 Figure 6.1 Reduction of Nitrosobenzene to Azoxybenzene by Chlorotrimethylsilane 148 Figure 7.1 Concentration of atmospheric CO 2 1958-2014 174 Figure 7.2 Proposed Carbon Neutral Cycle of the Methanol Economy Concept 174 Figure 7.3 Anthropogenic Carbon Cycle 177 Figure 7.4 SEM images of fibrous silica nanospheres of LHI-S1 180 Figure 7.5 HRTEM images of fibrous silica nanospheres of LHI-S1 180 Figure 7.6 SEM images of fibrous nanosilica supported LHI-S1-PEI (MW 800) 180 Figure 7.7 TGA plot obtained for the adsorption/desorption of CO 2 on LHI-S1:PEI (MW 750000) (1:1) at 25, 55 and 85 o C (left to right) followed by 10 short adsorption/desorption cycles at 85 o C 183 Figure 7.8 TGA plot obtained for the adsorption/desorption of CO 2 on LHI-S1:PEHA (1:3) at 25, 55 and 85 o C (left to right) followed by 10 short adsorption/desorption cycles at 85 o C 183 Figure 7.9 Caffeine and Urotropine as additives to control pore volumes 185 xii Figure 7.10 TGA plot obtained for the adsorption/desorption of CO 2 on KCAF1-PEHA1 at 25, 55 and 85 o C (left to right) followed by 10 short adsorption/desorption cycles at 85 o C 188 Figure 7.11 TGA apparatus 192 Figure 7.12 Schemtatic of adsorption/desorption cycles of CO 2 on silica- polyamine sorbents at various temperatures 193 xiii LIST OF TABLES Table 1.1 Top five drugs in the US based on the sales value for the year 2014-2015 20 Table 2.1 Synthesis of β-fluoronitro(phenylsulfonyl)ethylamines by three component reaction of α-fluoro-α- nitro(phenylsulfonyl)methane, amine and formalin without the addition of a base 38-39 Table 2.2 Synthesis of β-fluorobis(phenylsulfonyl)ethylamines by three component reactions of α-fluorobis(phenylsulfonyl)methane which requires a base 41 Table 2.3 Synthesis of β-fluorobis(phenylsulfonyl)ethylamines by three component reaction of α-fluorobis(phenylsulfonyl)methane, amine and formalin without the addition of a base 43 Table 2.4 Synthesis of β-fluoroethylamines by reductive di- desulfonylation of β-fluorobis(phenylsulfonyl)-N,N- dialkylethylamines 45 Table 2.5 Reaction of α-fluoro-α-nitro(phenylsulfonyl)methane with formalin and chiral amines 47 Table 3.1 Dependence of yield of the desired fluorinated β-amino ester 4a on various combinations of solvents and bases for the multi- component synthesis reaction of EFPA with tert-butylamine and formaldehyde 89 Table 3.2 Synthesis of fluorinated β-amino esters by the three component reaction of ethyl 2-fluoro-2-(phenylsulfonyl)acetate 1a using various primary amines and formaldehyde 90 Table 3.3 Reactions of FBSM with N, N-diethylamine and glyoxylic acid in different solvents 92 Table 3.4 Fluorinated α-amino acids via three component reactions of α- fluoro-bis(phenylsulfonyl)-methane (FBSM, 1b) or α-fluoro-α- nitro(phenylsulfonyl)methane (FNSM, 1c), primary amines/secondary amines and glyoxylic acid 93 Table 4.1 A survey of reaction conditions for the amination of Toluene with NaN 3 and BF 3 -H 2 O 112 Table 4.2 Primary Amination of Arenes with NaN 3 and BF 3 -H 2 O 113 xiv Table 5.1 Optimization of Reaction Conditions 132 Table 5.2 ipso-Nitrosation of arylboronic acids 133 Table 6.1 Bond Energies of X 2 and Si-X; Bond Lengths of Si-X 145 Table 6.2 Reduction of in situ generated Azoxybenzene to Azobenzene with various reducing agents 150 Table 6.3 GCMS monitoring of the reduction of Nitrosobenzene to Azobenene with Zn/aq. NH 4 Cl 151 Table 6.4 Reduction of Nitrosoarenes to Azoxyarenes by Chlorotrimethylsilane 152 Table 7.1 CO 2 adsorption capacities (mg of CO 2 adsorbed per g of adsorbent) of adsorbents based on fibrous nanosilica supported polyamines 184 Table 7.2 Pore volume, surface area and pore diameter of prepared silica materials 186 Table 7.3 CO 2 adsorption capacities of sorbents based on PEHA impregnated silica solid supports prepared with caffeine as an additive 188 xv ABSTRACT This dissertation describes the development of new methodologies for the synthesis of organonitrogen compounds, which include -fluoroethylamines, mono-fluorinated - amino acids and -amino esters, primary anilines, nitrosoarenes, and azoxy and azobenzenes. It also expounds on the utilization of polyamines and imines in preparation of solid adsorbents for efficient capture and release of carbon dioxide. Chapter 1 provides a brief overview of Nitrogen atom, its incorporation into living organisms, the important role of organonitrogen compounds as well as some multi-component reactions for their synthesis. The aim and scope of this dissertation is also included in Chapter 1. Chapter 2 describes the development of a direct multi-component protocol for the synthesis of highly diverse derivatives of β-fluoro(phenylsulfonyl)ethylamine by a Mannich-type reaction from their molecular sub-units, α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM), or α- fluorobis(phenylsulfonyl)methane (FBSM), formalin, and various primary and secondary amines. The products are obtained in high yields and selectivity even without the use of base in many cases. In Chapter 3, the multi-component protocol is extended to furnish fluorinated - amino acids and -amino esters. The methodology employs simple molecular units, an organofluorine unit, an amine and a carbonyl unit to generate the fluorinated organonitrogen compounds. Boron trifluoride monohydrate is an excellent Brønsted acid catalyst system for a wide range of reactions. It is a non-oxidizing acid catalyst prepared easily by bubbling BF 3 into water. Chapter 4 deals with the application of boron trifluoride monohydrate/sodium azide combination as an efficient reagent system for electrophilic amination of aromatics. The present method xvi avoids the use of expensive superacids such as trifluoromethane sulfonic acid and provides a facile access to aromatic amines directly from aromatics. Nitroso compounds are versatile reagents in synthetic organic chemistry. A feasible protocol for the ipso-nitrosation of aryl boronic acids using chlorotrimethylsilane/sodium nitrite combination as a unique nitrosation reagent system is described in Chapter 5. Chlorotrimethylsilane is a readily available reagent widely used in organic chemistry. As a reducing agent it is used mainly in combination with other reducing agents. Chapter 6 describes the use of chlorotrimethylsilane as the sole reagent in the reduction of nitrosobenzene to azoxybenzene. Attempts to extend the substrate scope of the reaction are also described in this chapter. The protocol is based on the high reactivity of nitrosoarenes and the extraordinary affinity of silicon towards oxygen. Synthetic design of innovative materials with high adsorption capacity is essential for capturing, storing and recycling carbon dioxide (CO 2 ) efficiently. CO 2 recycling is a crucial step towards the “Methanol Economy” which is based on methanol as a viable renewable energy storage medium and also as a chemical feedstock. Chapter 7 delineates the development of new fibrous nanosilica-supported polyamine materials for CO 2 adsorption. It also describes the use caffeine to effect higher pore volumes and average pore diameters of the mesoporous silica nanospheres, which displayed high CO 2 adsorption values when impregnated with polyamines. 17 Chapter 1: An Introduction to Organonitrogen Compounds 1.1 Chapter 1: Introduction to Nitrogen and Nitrogen Fixation Nitrogen is the seventh most abundant element in the Milky Way and our Solar System and is the primary constituent of Earth’s atmosphere, occupying 78.1% of the atmospheric volume. Discovered as a chemical element by Daniel Rutherford in 1772, 1 it is a colorless and odorless gas. With an atomic number of 7, Nitrogen atom has the electronic configuration, 1s 2 2s 2 2p 3 and the three 2p electrons are distributed evenly in the 2p x , 2p y and 2p z orbitals. In its elemental form, nitrogen exists as a diatomic gas constituting two nitrogen atoms triply bonded to each other. With the bond energy of 1206 kJ/mol, the nitrogen-nitrogen triple bond is one of the strongest bonds. The strength of the nitrogen-nitrogen triple bond makes the N 2 molecule very unreactive. It reacts only with some transition metal complexes, carbides and nitrogen fixing bacteria. Therefore, it is not surprising that elemental nitrogen (nitrogen molecule) makes over three fourths of the Earth’s atmosphere. The high stability of the nitrogen molecule is also the reason for the unstable and often explosive nature of many nitrogen containing compounds. In a process called Nitrogen Fixation, the highly stable nitrogen molecule is broken apart into its atoms, which then combine with other atoms to form nitrogen containing compounds. 1 In nature, it occurs during lightning, which provides the enormous energy required to break the highly strong nitrogen-nitrogen triple bond of the nitrogen molecule and combine with oxygen in the air to form nitrogen oxides (Scheme 1. Eq.1). The conversion of atmospheric nitrogen to ammonia is also performed at room temperature by bacteria, archaea and some specialized fungi with the help of enzymes called nitrogenases (Scheme 1. Eq.2). Once ammonia is available, 18 plants then utilize it for the synthesis of amino acids and heterocyclic N-compounds. For animals, the nitrogen they need is supplied from the plants or other animals in their diet. Proteins, which are biopolymers composed of amino acid monomers linked together by peptide (amide) bonds, are the macromolecular units of plants and animals. Amino acids have three components: amine (-NH 2 ) and carboxylic acid (-COOH) functional groups and a side-chain specific to each amino acid. Therefore, it is difficult to imagine a living system that does not contain nitrogen. Scheme 1.1 Nitrogen fixation methods Apart from the natural nitrogen fixation processes, atmospheric nitrogen can be converted to ammonia by reacting it with hydrogen under high temperatures (450-550 o C) and pressures (200-300 atm) (Scheme 1. Eq. 3). 1,2 This artificial nitrogen fixation process, called Haber-Bosch process, was discovered by Fritz Haber in 1908 and further developed for industrial level application by Carl Bosch, which is commercially practiced on a large scale. 19 1.2 Chapter 1: Nitrogen Containing Organic Compounds: Organonitrogen Compounds In a neutral nitrogen atom, the valence orbital 2s is occupied by a lone pair of electrons and only the singly occupied three valance orbitals 2p x , 2p y and 2p z are available for bonding. Therefore, a neutral nitrogen atom can form only three bonds. When it forms three covalent bonds with each of three chemically equivalent hydrogen atoms, a stable ammonia molecule, NH 3 , is formed in which the lone pair of electrons still belongs to the central nitrogen atom. Nitrogen containing organic compounds can be thought of as derivatives of ammonia in which, one or more hydrogen atoms have been replaced by carbon-containing groups. 2 For example, the replacement of one, two or three hydrogen atoms of ammonia by an alky or aryl group produces primary, secondary and tertiary amines, respectively. They can also be thought of as nitrogen substituted hydrocarbons, formed as a result of replacement of at least one carbon or hydrogen atom by a nitrogen atom. A wide variety of nitrogen containing organic compounds exists in nature. The diversity of nitrogen containing compounds is reflected in the large variety of functional groups containing nitrogen atoms. Owing to their immense diversity, nitrogen containing compounds have found numerous applications in fields spanning pharmaceuticals, agrochemicals, explosives, cosmetics and toiletries, dyes etc. Nitrogen containing compounds perform many important biochemical roles in living systems. There are many receptors within the body that bind to amines. Of these, the most important and the most well known receptors are serotonin, dopamine, noradrenaline, acetylcholine and γ-aminobutyric acid (GABA). Given that these receptors all possess an amine 20 functional group (Figure 1.1), it is not surprising that many psychotropic drugs also often contain amine or other nitrogen containing functional groups. Indeed, the presence of nitrogen containing moieties, particularly amines, not only assists drugs to be transported to the target site in the body but also helps to lock the drugs onto the desired receptors. 1 Therefore; nearly every major pharmacological drug class has a nitrogen atom. For example, three of the top five drugs based on the sales value for the year 2014-2015 (Table 1.1) 20 in the US had multiple nitrogen atoms in their structural backbone (Figure 1.2). Figure 1.1 Some receptors within the body. Table 1.1 Top five drugs in the US based on the sales value for the year 2014-2015 20 Rank Drug/Brand name Sales Value 1 Adalimumab/Humira $8,290,106,091 2 Aripiprazole/Abilify $7,995,192,015 3 Sofosbuvir/Sovladi $6,957,331,432 4 Rosuvastatin/Crestor $5,958,997,432 5 Etanercept/Enbrel $5,953,627,734 21 Figure 1.2 Some Organonitrogen drugs. 1.3 Chapter 1: Synthesis of Nitrogen Containing Organic Compounds Depending on the type of nitrogen containing functionality they possess, there are numerous reactions for their synthesis. For the purpose of generating a diverse library of nitrogen atom containing compounds, multi-component reactions involving incorporation of a nitrogen atom or a nitrogen containing moiety in the final adduct are of great importance. Such multi- component reactions provide a direct and economically attractive access to a wide variety of compounds. The first documented multi-component reaction was reported in 1850 3,4 and it involved mixing commonly available ammonia, acetaldehyde, and hydrogen cyanide for a certain period of time to afford the adduct amino nitrile, which upon hydrolysis gave alanine. This reaction is now known as Strecker reaction, named after its discoverer Adolph Strecker. 22 Scheme 1.2 Strecker reaction Since then, Strecker reaction has been shown to work equally well with ammonium salts to give unsubstituted amino acids, and with primary and secondary amines to give substituted amino acids. When ketones are used instead of aldehydes, the resulting product is α,α- disubstituted amino acids. 5 More than 110 years after the discovery of the Strecker reaction, a chiral auxiliary-assisted Strecker reaction was reported by Harada in 1963. 6 The classic Strecker reaction was modified by replacing ammonia with enantiopure (S)-R-phenylethylamine to give the corresponding R-amino nitrile, which after further transformations gave chiral alanine in an overall yield of 17% and with 90% ee. The cyclocondensation of 1,3 dicarbonyl compounds with aldehydes and urea derivatives to form dihydropyrimidinone derivatives is known as Biginelli reaction after the Italian Chemist, who first reported it in 1893. 7 Dihydropyrimidinones, the products of the reaction, possess a wide range of biological activities such as antiviral, antitumor, antibacterial, and anti- inflammatory properties as well as calcium channel modulating activity. 8 Therefore, a great variety of Brønsted acids, Lewis acids and protic acids have been well-established to efficiently promote the Biginelli reaction. 9 Recently, successful catalysis of the reaction by a Bronsted base (t-BuOK) has also been achieved. 10 23 Scheme 1.3 Biginelli reaction Glycolylurea is an oxidized derivative of imidazolidine. Its synthesis is achieved via the Bucherer–Bergs reaction involving the reaction of ammonium carbonate and potassium cyanide with either aldehydes or ketones. 11 Scheme 1.4 Bucherer–Bergs reaction Amide bonds are ubiquitous in nature. Amino acid monomers in protein are held together by amide bonds. Due to their hydrogen bonding ability, they provide structural rigidity as evidenced by the resilience of materials such as Nylon and Kevlar, both of which are polyamides. Multi-component protocols developed by Passerini and Ugi are useful ways of generating organonitrogen compounds with amide bonds. In Passerini reaction, this is achieved by a one pot reaction of isocyanide, an aldehyde (or ketone), and a carboxylic acid to form an α- acyloxy amide. 12, 13 24 Scheme 1.5 Passerini reaction The Ugi reaction is even more versatile in that it brings together four reactants, namely, a ketone or an aldehyde, an amine, an isocyanide and a carboxylic acid to form a single adduct with two amide moieties. 14 The greater number of reactants allows for the synthesis of a great many variety of bis-amides. Scheme 1.6 Ugi reaction Another multi-component reaction for organonitrogen compounds, which brings together four components in a single reaction vessel, is the Hantzsch dihydropyridine synthesis. 15 This reaction allows for the preparation of dihydropyridine derivatives by condensation of an aldehyde with two equivalents of ethyl acetoacetate in the presence of a suitable nitrogen donor such as ammonia, ammonium acetate or an appropriate amine. The initial product dihydropyridine can be decarboxylated to produce the corresponding pyridines. 25 Scheme 1.7 Hantzsch dihydropyridine synthesis In the classic Mannich reaction, β-amino-carbonyl compounds are formed through amino alkylation of formaldehyde and ammonia (or a primary or secondary amine). 16 Several modern variants of the reaction have been developed in which instead of using amines and formaldehyde, imines and iminium salts are used. By using proline derivatives as organocatalysts, asymmetric Mannich reactions have also been developed. 17 Scheme 1.8 Mannich reaction The Petasis reaction, 18 in which an amine, aldehyde and vinyl- or aryl-boronic acid react together to form substituted amines, can be considered as a type of Mannich reaction. The reaction can be used to generate α-amino acid by substituting aldehyde with α-keto acids, such as glyoxylic and pyruvic acids. 19 26 Scheme 1.9 Petasis reaction 1.4 Chapter 1: Aim and Scope of Current Work Owing to their importance, the development of new and improved methods for the synthesis of nitrogen containing compounds remains an active area of research. The work described in this dissertation contributes to the area of organonitrogen chemistry by developing new methods, which allow for the synthesis of organonitrogen compounds. Of these organonitrogen compounds, some are well known compounds whereas others were hitherto unknown. The importance of incorporation of nitrogen atom(s) in the structure of drugs has already been mentioned in the previous section. Another atom that plays important role in the efficacy of drugs is fluorine. The presence of fluorine in organic compounds brings forth significant changes in their biological properties. Fluorine in drug molecules has a profound impact in their physicochemical, pharmacokinetic and pharmacological properties. The important role of fluorine in medicinal chemistry and drug design is established by the fact that about one-third of the top-performing drugs currently on the market contain fluorine atoms in their structure. 21 Indeed, of the top five best selling drugs in Table 1.1, both Sofosbuvir and Rosuvastatin contain a fluorine atom in addition to the usual nitrogen atoms (Figure 1.2). Chapters 2 and 3 describe 27 the synthesis of compounds which contain both fluorine and nitrogen. Specifically, chapter 2 deals with transformation of primary and secondary amines into -fluorinated amines by forming a C-N bond followed by a C-F bond formation in a single reaction vessel via a multi- component reaction mechanism. The extension of this protocol to synthesize fluorinated a-amino acids and  -amino esters is described in Chapter 3 of the dissertation. Chapter 4 explores the development of a new method for the synthesis of well known primary aromatic amines. Instead of using expensive and hazardous superacids, the method makes use of BF 3 -H 2 O, an inexpensive Bronsted acid to obtain primary aromatic amines by using sodium azide as an inexpensive source of nitrogen atom. In chapter 5, another important class of organonitrogen compounds nitrosoarenes are synthesized by using sodium nitrite as a source of nitrogen atom in the presence of chlorotrimethylsilane. Chapter 6 described further use of this commonly available versatile reagent chlorotrimethylsilane as the sole reducing agent for the reduction of nitrosobenzene to azoxybenzene which in turn, is in situ reduced to azobenzene by zinc metal powder under acidic conditions. Finally, in Chapter 7, polyamines and imines are impregnated on solid supports of silica nanospheres and the solid adsorbents thus prepared are studied for their efficacy as solid adsorbents for capturing and releasing carbon dioxide. In addition, caffeine, a high nitrogen containing organonitrogen compound, has been used to effect higher pore volumes and average pore diameters of the mesoporous silica nanospheres. Polyamine impregnated silica nanospheres with high pore volume and high average pore diameter were found to show high carbon dioxide adsorption values. 28 In summary, this dissertation describes new and efficient methods for the synthesis of organonitrogen compounds. The facile methods furnish both hitherto unknown as well as well known organonitrogen compounds. The dissertation also describes utilization of polyamines and imines in preparation of solid adsorbents for capturing and releasing carbon dioxide effectively even from air. In addition, the utility of caffeine in controlling the pore volume and average pore diameter of silica nanospheres is also described in the dissertation. 29 1.5 Chapter 1: References 1. Lawrence, S. A. Amines: Synthesis, Properties and Applications; Cambridge University Press: Cambridge, 2004. 2. Ginsburg, D. Concerning Amines: Their Properties, Preparation and Reactions; Pergamon Press: New York, 1967. 3. Strecker, A. Ann. Chem. Pharm. 1850, 75, 27. 4. Mundy, B. P.; Ellerd, M. G.; Favaloro, Jr, F. G. Name Reactions and Reagents in Organic Synthesis, 2nd Edition; John Wiley & Sons, 2005. 5. Masumoto, S.; Usuda, H.; Suzuki, M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2003, 125, 5634–5635. 6. Harada, K. Nature 1963, 200, 1201. 7. Biginelli, P. Gazz. Chim. Ital.1893, 23, 360-416. 8. (a) Kappe, C. O. Molecules 1998, 3, 1; (b) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043. 9. Rodriguez-Dominguez, J. C.; Bernardi, D.; Kirsch, G. Tetrahedron Lett. 2007, 48, 5777 and references cited therein. 10. Shen, Z. L.; Xu, X. P.; Ji, S. J. J. Org. Chem. 2010, 75, 1162– 1167. 11. (a) Bucherer, H. T.; Fischbeck, H. T. J. Prakt. Chem. 1934, 140, 69; (b) Ware, E. Chem. Rev. 1950, 46, 403. 12. Passerini, M.; Simone, L. Gazz. Chim. Ital. 1921, 51, 126–29. 30 13. Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. Engl. 2000, 39, 3168–3210. 14. Ugi, I. Angew. Chem. Int. Ed. Engl. 1962, 1, 8-21. 15. Hantzsch, A. Chemische Berichte, 1881, 14, 1637–1638. 16. Arend, M.; Westermann, B.; Risch, N. Angew. Chem. 1998, 110, 1096- 1122; Angew. Chem. Int. Ed. 1998, 37, 1044-1070. 17. Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. 18. Petasis, N. A.; Akritopoulou, I. Tetrahedron Lett. 1993, 34, 583–586. 19. Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445–446. 20. Brown, T. “100 Best-Selling, Most Prescribed Branded Drugs Through March.” Medscape. 06 May, 2015. 19 Oct. 2015. <http://www.medscape.com/viewarticle/844317> 21. Wang, J; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432. 31 Chapter 2: Direct Synthesis of Diverse β-Fluoroethylamines by a Multicomponent Protocol 2.1 Chapter 2: Introduction Multi-component reactions (MCRs) offer high structural diversity and incorporate molecular units of all components in a single step 1 and are therefore, synthetically highly efficient and economic. A well-known example of an MCR is the Mannich reaction in which the educts formaldehyde, amine and ketone or aldehyde are converted directly into the adduct bearing the molecular fragments of all components. It has been established as a powerful tool for C-C and C-N bond forming reactions. 2 In recent years, Mannich-type reactions of fluorinated substrates have actively been explored 3 because of the interesting properties imparted by the incorporation of a fluorine atom into a molecule. The presence of fluorine in organic compounds brings forth significant changes in their biological properties. Specifically, fluorine in drug molecules has a profound impact in their physicochemical, pharmacokinetic and pharmacological properties. 4 For example, monofluoroacetic acid has been found to be a powerful inhibitor for the Krebs cycle. 5 Compounds with a monofluoromethyl moiety are of great importance with regards to isostere-based drug design. 6 The classical intermolecular Mannich reaction, however, has a number of serious disadvantages. 2 Often, the drastic reaction conditions and the long reaction times lead to unwanted side reactions and products. When the amine component is a primary amine or an ammonia, the reaction can continue until all the H atoms on the nitrogen are replaced. One way to avoid this has been the use of preformed electrophiles such as imines and iminium salts or nucleophiles such as enolates, enol ethers, and enamines. The preformed Mannich electrophilic reagents increase the concentration of the electrophile with significant reduction of reaction 32 temperatures and times. Consequently, many undesired side reactions, which often cause problems in the Mannich reaction, are avoided, even with sensitive substrates. 2 Therefore, it is not surprising that direct Mannich reactions of fluorinated molecules involving three components are scarce. 3i In most Mannich type reactions of fluorinated substrates, preformed imines are used as Mannich reagents in combination with other nucleophiles. 3a-h While the effectiveness of preformed electrophiles has been demonstrated extensively, 2 a fast and selective reaction using simple and basic molecular units in a Mannich type reaction is highly desirable. Herein, we report a new protocol (Scheme 2.1) for the synthesis of fluoroethylated amines via a Mannich type three component reaction of formalin, amine (primary and secondary) and an activated fluoromethane, namely α-fluoro-α-nitro(phenyl- sulfonyl)methane (FNSM, 1a) or α-fluorobis(phenylsulfonyl)-methane (FBSM, 1b). To the best of our knowledge, this is the first report of a three component protocol involving α- fluorocarbanion for the preparation of diverse N-alkyl and N, N-dialkylfluoroethylamines from their molecular sub-units. By introducing a suitable fluoromethyl pronucleophiles, the method avoids the use of corrosive or expensive fluorinating reagents such DAST, Morpho-DAST, SF 4 , HF-amine complex etc, for selective fluorination. The reaction is simple, efficient and provides high yields of the products. Scheme 2. 1 Preparation of β-fluoro(phenylsulfonyl)ethylamines from α- fluoro(phenylsulfonyl)methanes, formaldehyde and amines. 33 Application of α-fluorobis(phenylsulfonyl)methane (FBSM) as a monofluoromethide equivalent was independently reported by Hu and Shibata for nucleophilic fluoroalkylation of epoxides 7a and asymmetric allylic fluorobis(phenylsulfonyl)methylation of allyl acetates respectively. 7b Highly electron-withdrawing groups such as phenylsulfonyl, fluoro, nitro, cyano, acetyl etc. activate the sp 3 -hybridized C-H bond by significantly enhancing its acidity, making it an efficient fluoromethyl transfer agent. [8a] Since its discovery, FBSM has been used by our group and others efficiently for fluoromethide transfer in a variety of reactions 8 (Figure 2.1). Because the preparation of FBSM by electrophilic fluorination of bisphenylsulfonylmethane with Selectfluor is less atom economic ,8a our group recently discovered an efficient method for the high yield, multigram synthesis of FBSM from inexpensive and readily available potassium fluoride as the sole fluorinating source. 8b, c On the other hand, the highly electrophilic nature of iminium salts makes them very reactive and attractive species in organic synthesis. Iminium salts are the most commonly used Mannich electrophilic reagents in the synthesis of a variety of molecules containing the C-N bond. 2, 9a-j 34 Figure 2.1 Selected reactions of α-fluorobis(phenylsulfonyl)methane (FBSM). 2.2 Chapter 2: Results and Discussion We began by testing the reactivity of dimethylmethylideneammonium chloride with α- fluorobis(phenylsulfonyl)methane (FBSM, 1b), which has a highly acidic C-H bond (pK a ~ 12 in DMSO). 10 In contrast to our expectation, FBSM showed no reactivity towards dimethyl- methylideneammonium chloride in the absence of a base, even after stirring for 12 hours at room temperature. However, with the addition of an equivalent amount of triethylamine, the reaction proceeded smoothly with 100% conversion (as shown by TLC and 19 F NMR) to give the desired product 2-fluoro-N, N-dimethyl-2,2-bis(phenylsulfonyl)ethanamine 4a. Under similar conditions, 35 the iminium salt, dimethylmethylideneammonium chloride reacted with FNSM (which is more acidic than FBSM because of the nitro group, pK a ~ 7 in DMSO) 10 also to give the desired product 2-fluoro-N,N-dimethyl-2-nitro-2-(phenylsulfonyl)ethan-amine 3a as the sole product. Higher reactivity displayed by FNSM, prompted us to continue our study with FNSM, which resulted in quantitative conversion to 3a as expected. Owing to their high electrophilicity, iminium salts are normally hygroscopic and prone to fast hydrolysis. Particularly, salts with simple anions such as Cl - are less stable and more sensitive towards hydrolysis. 2 On the other hand, gem-aminoethers, which are the immediate precursors of the iminium salts, 11 have themselves been successfully utilized as effective electrophiles in various organic reactions. 12 Therefore, we wished to find out the reactivity of gem-aminoether towards FBSM or FNSM to avoid the difficulties in using the iminium salts. To our delight, when the compound 5 (R 1 = R 2 = propyl) was reacted with FNSM under similar conditions as used above, the reaction proceeded smoothly to give the corresponding product N- (β-fluoro-β-nitroethyl)amine 3c in high yield (Scheme 2.2). Scheme 2.2 Formation of β-fluoro(phenylsulfonyl)ethylamines from iminium salts and its precursor gem-aminoether. 36 We presumed that if the methylene carbon α to both N and O in gem-aminoether 5 is sufficiently electrophilic to react with FNSM, then the aminal 6, which can be generated from formaldehyde and N,N-dipropylamine should also be able to react with FNSM. Therefore, the reaction of FNSM with in situ generated aminal would allow us to obtain α-fluoro-α- nitro(phenylsulfonyl)methyl derivatives following a simple three component Mannich type reaction. Intrigued by this approach, we carried out a series of reactions. N,N-dipropylamine, paraformaldehyde and potassium carbonate were stirred together to generate hemiaminal 6 in situ, followed by the addition of FNSM to the reaction mixture. The reaction was complete within 15 min of the addition of FNSM and the desired product 3c was isolated in 65% yield. The yield of 3c was diminished due to the formation of the side product 2-fluoro-2-nitro-2- (phenylsulfonyl)ethanol 7a isolated in 28% yield. It is obvious that 7a was formed from the direct addition of FNSM to formaldehyde, which was confirmed by conducting a separate reaction of FNSM with formaldehyde (formalin or paraformaldehyde) in dichloromethane when 7a was separated in 93% yield. Under similar conditions, 7b, the adduct of FBSM and formaldehyde was isolated in 90% yield (Scheme 2.3). Scheme 2.3 Formation of fluoroethanol 7 via a competing pathway during the synthesis of β-fluoroethylamines 3 and 4. 37 N, N-dipropylamine itself is a good base, therefore, we decided to carry out this reaction without the addition of another base. However, to increase the yield of the product, the competing pathway - the formation of 7a should be suppressed (Scheme 2.3). To achieve this, the availability of formaldehyde in the reaction mixture for the amine to form aminal and to drive the reaction of FNSM in the desired direction during its addition must be promoted. This was achieved by using formalin (37% aqueous solution) instead of the solid polymer paraformaldehyde. Indeed, the use of formalin was found to increase the selectivity as well as the yield of the product. The efficacy of the reaction could be further improved by initially stirring amine and formalin to allow the formation of aminal in ample concentration before the addition of FNSM (Table 2.1). 38 Table 2.1 Synthesis of β-fluoronitro(phenylsulfonyl)ethylamines by three component reaction of α-fluoro-α-nitro(phenylsulfonyl)methane, amine and formalin without the addition of a base. [a] Isolated yields. [b] Reaction was carried out at 90 o C. 39 Table 2.1 Continued. [a] Isolated yields. [b] Reaction was carried out at 90 o C. 40 Although the reaction was complete within 15 min after the addition of FNSM in the case of N,N-dipropylamine, the required reaction time depended on the type of amine (e.g., primary or secondary amine) used in the reaction. In general, optimized conditions were found to be 1 equivalent of FNSM for 1.7 equivalents of secondary amine, and 1.5 equivalent of formaldehyde with a reaction time of 2 h before adding FNSM and 1h after adding FNSM (Table 2.1). Secondary amines generally took longer time than primary amines for the completion of the reaction. In terms of the selectivity of β-fluoro(phenylsulfonyl)ethylamines 3 (or 4) over β- fluoro(phenylsulfonyl)ethylalcohol 7a (or 7b) reactions with secondary amines were less selective than those with primary amines. This is reflected in the slightly higher yields of the products for reactions involving primary amines. In addition to aliphatic amines, aromatic amines also underwent the reaction smoothly giving the products in high yields (Table 2.1, entries 14, 15). FBSM is an attractive reagent for monofluoroalkylation due to susceptibility of the products to reductive desulfonylation to the corresponding monofluoroalkylated products in many cases. Reductive di-desulfonylation of FBSM to use it as monofluoromethide equivalent has been successfully carried out in similar systems using Mg and MeOH by our group and others. 8b, k; 13 Expecting similar results for α-fluorobis(phenylsulfonyl)methane (FBSM), the three component strategy has also been extended to FBSM. 41 Table 2.2 Synthesis of β-fluorobis(phenylsulfonyl)ethylamines by three component reactions of α-fluorobis(phenylsulfonyl)methane which requires a base. [a] Isolated yields. [b] Reaction was carried out at 90 o C. [c] Reaction time was 3 h. 42 Longer reaction times were required for the complete and selective conversion of FBSM to the desired product. As in the case of reactions with FNSM, reactions with primary amines were faster and selective than those with secondary amines. Although secondary amines did react with FBSM and formalin (formaldehyde) in the absence of a base, use of a base such as NaH along with heating promoted the selective and complete conversion of FBSM to the desired products (Table 2.2). As in the case of FNSM, aromatic amines also participated in three component reaction with FBSM and formalin to give the expected products, albeit in low yields (Table 2.2, entries 9, 10). Neither base nor heating was required for the complete conversion of many primary amines to their respective products (Table 2.3, entries 1-7). 43 Table 2.3 Synthesis of β-fluorobis(phenylsulfonyl)ethylamines by three component reaction of α-fluorobis(phenylsulfonyl)methane, amine and formalin without the addition of a base. [a] Isolated yields. [b] Solvent was EtOH. [c]When the reaction mixture was heated to 90 o C after the addition of FBSM, the reaction was complete after 1 h. 44 Dialkylation has been reported to occur during alkylation of primary amines. Therefore, alkylation of primary amines is usually carried out by prior protection and de-protection after alkylation. 14 In our reactions with primary amines no such dialkylation was observed. The validity of the three component reaction was further confirmed by single-crystal X-ray crystallographic analysis of the product 4e (Figure 2.2). Figure 2.2 X-ray crystal structure of the three component reaction product 4e from FBSM, formalin and ethyl methyl amine. 15 Fluorinated ethylamines can be prepared by many methods, 15 such as direct alkylation of amines, 16a-c reaction of lithium amides with 2-fluoroethyl bromide 14 and alkylation of suitably protected aniline by 2-fluoroethyl 4-methylbenzenesulfonate. 16d Fluoride exchange with anhydrous KF on N,N-bis(2-tosylethyl)anilines can also yield N,N-bis(2-fluoroethy1)anilines. 17a Reductive amination of α-fluoroacetophenone using ammonia in EtOH in the presence of titanium isopropoxide followed by NaBH 4 reduction gives 1-aryl-2-fluoroethylamines. 17b Recent reports of stereoselective nucleophilic monofluoromethylation of (R)-(tert-butanesulfinyl)-imines by Hu et al. 18 and enantioselective monofluoromethylation of in situ generated prochiral imines by Shibata et.al. 3h are also efficient methods. However, in both cases, preformed imines or imines formed in situ from protected α-amidosulfone and strong bases in equimolar amounts or more were always required. To our knowledge, the present method is the only direct method 45 utilizing the simple molecular units, namely, amine, formaldehyde (formalin) and FBSM for the formation of fluorinated ethylamines and therefore inreases the scope for making the reaction more diverse. Further, a few β-fluorobis(phenylsulfonyl)ethylamines 4 were subjected to reductive di-desulfonylation using Mg in MeOH at 0 o C under Argon to obtain monofluoroethylamines 8 (Table 2.4). Table 2.4 Synthesis of β-fluoroethylamines by reductive di-desulfonylation of β- fluorobis(phenylsulfonyl)-N,N-dialkylethylamines [a] [a] Isolated yields. 46 Mechanistically, both the iminium salt as well as the aminal can be possible reactive intermediates as manifested from the reactivity of both with FNSM. However, under the present conditions, aminal can be considered as the viable one because the formation of significant amounts of the iminium salt is less likely (due to the absence of acid) and its stability is rather low (due to the presence of water). Having developed a facile methodology for the synthesis of β-fluoroethylamines, we were interested in extending the methodology for the synthesis of diastereomerically pure β- fluoroethylamines by the use of chiral amines as chiral auxillaries to induce chirality in the product of the multi-component reaction. However, even though the reactions proceeded with complete conversion into the products (Except for Table 2.5, Entry 5), there was no diastereomeric selectivity as evidenced by the 1:1 ratio of the diastereomers which was determined by 19 F NMR (Table 2.5). 47 Table 2.5 Reaction of α-fluoro-α-nitro(phenylsulfonyl)methane with formalin and chiral amines. [a] Diastereomeric ratio (dr) was determined by 19 F NMR analysis 2.3 Chapter 2: Conclusions In conclusion, we have developed the direct Mannich-type reaction for the facile synthesis of β-fluoro(phenylsulfonyl)ethyl-amines by using fluorinated carbon pronucleophiles, FNSM and FBSM. The reaction is performed under mild conditions and is highly feasible for both primary and secondary amines and no base is required in many cases. More importantly, the reaction adheres to the classical Mannich reaction conditions, bringing in all three components formaldehyde, amine and the activated fluoromethane together in one step to form fluorinated ethylamine in high yields. These β-fluoro(phenylsulfonyl)ethylamines are expected to be potential candidates for further studies on their biological effects and therapeutic activities. 48 2.4 Chapter 2: Experimental 2.4.1 General Unless otherwise mentioned, all the chemicals were purchased from commercial sources. Sodium hydride (95%, Sigma-Aldrich) was used as received. Mg powder (20-100 Mesh, 99.8%) was purchased from Alfa Aesar. Formalin solution containing 37% formaldehyde in water purchased from Sigma-Aldrich was used in the reactions. Selectfluor and Potassium fluoride (99+%) were purchased from SynQuest Labs and Alfa Aesar, respectively. α- fluorobis(phenylsulfonyl)methane and α-fluoro-α-nitro(phenylsulfonyl)-methane were prepared following literature procedures. [8a,b,c] Silica gel chromatography was performed to isolate the products using 60-200 mesh silica gel (from silicycle) and using hexane-dichloromethane or hexane-ethyl acetate solvent system as eluent. 1 H, 13 C, and 19 F spectra were recorded on 400 MHz Varian Inova NMR spectrometer. 1 H NMR chemical shifts were determined relative to tetramethylsilane (TMS) as the internal standard (δ 0.00 ppm). 13 C NMR shifts were determined relative to internal TMS at δ 0.00 ppm or to the CDCl 3 δ 77.0 ppm. 19 F NMR chemical shifts were determined relative to internal standard CFCl 3 at δ 0.00 ppm. C 6 F 6 was used as internal reference for 19 F NMR wherever required. Mass spectra were recorded on a high resolution mass spectrometer, in the EI, FAB or ESI mode. 2.4.2 Experimental Procedures Typical procedure for the synthesis of β-fluoronitro(phenylsulfonyl)ethylamines N-Ethylmethyl-amine (50 mg, 0.85 mmol, 2 equiv) and formalin (51 mg, 0.64 mmol, 1.5 equiv) were stirred in dichloromethane (2 mL) in a glass pressure tube at room temperature for 3 h. α-Fluoro-α-nitro (phenylsulfonyl)methane (93 mg, 0.43 mmol, 1 equiv) was added followed 49 by 1 mL dichloromethane. The reaction mixture was stirred at room temperature and the completion of the reaction was monitored by 19 F NMR. After completion (1 h), the reaction mixture was washed with saturated NH 4 Cl solution (aqueous) and water followed by extraction with dichloromethane (3 x 15 mL). The combined organic layers were collected and dried with Na 2 SO 4 . Removal of the solvent under reduced pressure and high vacuum gave the pure product 3f (112.8 mg, 91%). Typical procedure for the synthesis of β-fluorobis(phenylsulfonyl)ethylamines (a) Reaction not requiring a base: In a 10-20 mL vial, formalin solution (38 mg, 0.48 mmol, 1.5 equiv) was added followed by n-butylamine (45 mg, 0.62 mmol, 2 equiv) and the reaction vial was sealed. To this vial 2 mL of dichloromethane was added and the reaction mixture was stirred at room temperature for 3-4 h under argon. After 3-4 h, a solution of FBSM (100 mg 0.31 mmol, 1 equiv) in 2 mL of dichloromethane was added to the reaction mixture and the resulting reaction mixture was stirred at room temperature for overnight. Reaction mixture was diluted with dichloromethane and washed with water (2 x 15 mL), followed by brine (1 x 15 mL). Organic layer was dried over sodium sulfate before removal of the solvent in vacuo to get crude product. Column Chromatography using ethyl acetate: hexane (4:6) gave 105 mg of pure product 4j (85% yield). (b) Reaction requiring a base: In a 10-20 mL vial, formalin solution (38 mg, 0.48 mmol, 1.5 equiv) was added followed by dipropylamine (74 mg, 0.62 mmol, 2 equiv) and the reaction vial was sealed. To this vial 2 mL of dichloromethane was added and the reaction mixture was stirred at room temperature for 3-4 hours under argon. In a separate vial, sodium hydride (7.7 mg, 0.31 mmol, 1 equiv) was dissolved in 2 mL of dichloromethane. The suspension obtained was added to a solution of FBSM (0.31 mmol, 1 equiv, 100 mg) in 2 mL of dichloromethane and stirred for 50 5 min. The new suspension obtained (a mixture of FBSM and sodium hydride) was added to the reaction mixture drop wise and the resulting reaction mixture was stirred at 90 o C for overnight. Reaction mixture was diluted with dichloromethane and washed with water (2 x 15 mL), followed by brine (1 x 15 mL). Organic layer was dried over sodium sulfate before removal of the solvent in vacuo to get crude product. Column Chromatography using ethyl acetate: hexane (4:6) gave 126 mg of pure product 4b (95% yield). Typical procedure for the synthesis of 2-fluoroethanols Formalin (25 mg, 0.32 mmol, 1.5 equiv) was added to a solution of α- fluorobis(phenylsulfonyl)methane (68 mg, 0.22 mmol, 1 equiv) or α-fluoro-α- nitro(phenylsulfonyl)methane (47 mg, 0.22 mmol, 1 equiv) in dichloromethane (2 mL) and stirred with K 2 CO 3 (30 mg, 0.22 mmol) at room temperature for 12 h. The reaction mixture was washed with water followed by extraction with dichloromethane (3 x 15 mL). The combined organic layers were collected and dried with Na 2 SO 4 . Removal of the solvent under reduced pressure and high vacuum gave the pure product 7a or 7b in 93% and 90% yield, respectively. Typical procedure for the synthesis β-fluoroethylamines by reductive di-desulfonylation of β-fluorobis(phenylsulfonyl)ethylamines Mg powder (20-100 Mesh, 190 mg, 7.8 mmol, 60 equiv) was heated in a Schlenk flask under vacuum at 80 o C for 1 h. After cooling the flask to 0 o C, methanol (anhydrous, 5 mL) was added to the flask under argon atmosphere, followed by the addition of a solution of 2-fluoro-N- methyl-N-(naphthalen-1-ylmethyl)-2,2-bis(phenylsulfonyl)ethanamine 4s (65 mg, 0.131 mmol, 1 equiv in 1 mL CH 2 Cl 2 ). The reaction mixture was stirred at 0 o C under argon and the completion of the reaction was monitored by 19 F NMR (complete after 4 h). The reaction mixture was 51 washed with saturated NH 4 Cl solution (aqueous) and water followed by extraction with dichloromethane (3 x 15 mL). The combined organic layers were collected, dried with Na 2 SO 4 and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (3:7 Ethyl acetate: Hexane, R f : 0.65), to provide the pure product 2-Fluoro-N- methyl-N-(naphthalen-1-ylmethyl)ethanamine 8s (21.7 mg, 76% yield). 2.4.3 Spectral Data and Representative Spectra 2-Fluoro-N, N-dimethyl-2-nitro-2-(phenylsulfonyl)ethanamine (3a) Yellow oil, 92% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = δ 7.90 -7.95 (m, 2H), 7.60 -7.67 (m, 2H), 7.77 -7.83 (m, 1H), 3.88 (dd, J = 32.1 Hz, 15.2 Hz, 1H), 3.34 (dd, J = 15.2 Hz, 9.9 Hz, 1H), 2.34 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ = δ 136.18, 131.88, 130.70, 129.61, 123.53 (d, 1 J C- F = 283.8 Hz), 57.59 (d, 2 J C-F = 15.8 Hz), 46.85. 19 F NMR (376 MHz, CDCl 3 ): δ = -129.62 (dd, J=32.1 Hz, 9.7 Hz). HRMS (ESI): m/z calcd. for C 10 H 14 FN 2 O 4 S [(M+H) + ] 277.06528, found 277.06543. N, N-diethyl-2-fluoro-2-nitro-2-(phenylsulfonyl)ethanamine (3b) Yellow oil, 95% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = δ 7.88 -7.95 (m, 2H), 7.76 -7.83 (m, 1H), 7.59 -7.66 (m, 2H), 3.97 (dd, J= 32.1 Hz, 15.6 Hz, 1H), 3.50 (dd, J=15.6 Hz, 9.2 Hz, 1H), 52 2.62 (q, J = 7.5 Hz, 4H), 0.93 (t, J = 7.1 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ = 136.12, 132.01, 130.65, 129.62, 123.94 (d, 1 J C-F = 282.72 Hz), 53.33 (d, 2 J C-F = 15.6 Hz), 48.17, 11.60. 19 F NMR (376 MHz, CDCl 3 ): δ = -129.30 (dd, J = 32.0 Hz, 9.1 Hz). HRMS (ESI): m/z calcd. for C 12 H 18 FN 2 O 4 S [(M+H) + ] 305.0966, found 305.0968. N-(2-fluoro-2-nitro-2-(phenylsulfonyl)ethyl)-N-propylpropan-1-amine (3c) Yellow oil, 95% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.89 – 7.93 (m, 2H), 7.75-7.83 (m, 1H), 7.59-7.66 (m, 2H), 4.02 (dd, J = 32.5 Hz, 15.6 Hz, 1H), 3.50 (dd, J = 15.6 Hz, 8.4 Hz, 1H), 2.48 (t, 7.5 Hz, 4H), 1.23-1.44 (m, 4H), 0.79 (t, J = 7.3 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ = 136.09, 131.9, 130.58, 129.60, 123.60 (d, 1 J C-F = 282.6 Hz), 57.03, 54.51 (d, 2 J C-F = 15.4 Hz), 19.93, 11.3. 19 F NMR (376 MHz, CDCl 3 ): δ = -129.33 (dd, J = 32.5 Hz, 8.3 Hz). HRMS (ESI): m/z calcd. for C 14 H 22 FN 2 O 4 S [(M+H) + ] 333.1279, found 333.1280. N-benzyl-2-fluoro-N-methyl-2-nitro-2-(phenylsulfonyl)ethanamine (3d) Yellow oil, 93% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.91-7.93 (m, 2H), 7.78-7.82 (m, 1H), 7.60-7.64 (m, 2H), 7.25-7.30 (m, 3H), 7.15-7.17 (m, 2H), 4.07 (dd, J = 32.4 Hz, 15.4 Hz, 1H), 3.66 (q, J = 32.3 Hz, 2H), 3.52 (dd, J=15.4 Hz, 8.7 Hz, 1H), 2.27 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ = 137.38, 136.27, 131.86, 130.68, 129.71, 128.82, 128.38, 127.51, 123.60 (d, 1 J C-F = 53 283.4 Hz), 63.18 (d, J = 1.3 Hz), 56.05 (d, 2 J C-F = 15.7 Hz), 43.12. 19 F NMR (376 MHz, CDCl 3 ): δ = -129.41 (dd, J = 32.3 Hz, 8.6 Hz). HRMS (ESI): m/z calcd. for C 16 H 18 FN 2 O 4 S [(M+H) + ] 353.09658, found 353.09653. 1-(2-Fluoro-2-nitro-2-phenylsulfonyl)ethyl)pyrrolidine (3e) Yellow oil, 94% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.91 – 7.96 (m, 2H), 7.76 – 7.83 (m, 1H), 7.59 – 7.66 (m, 2H), 4.07 (dd, J = 32.3 Hz, 15.0 Hz, 1H), 3.48 (dd, J=15.0 Hz, 11.4 Hz, 1H), 2.81 – 2.67 (m, 2H), 2.65 – 2.51 (m, 2H), 1.78 – 1.63 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ): δ = 136.08, 132.17, 130.73, 129.53, 123.40 (d, 1 J C-F = 283.1 Hz), 55.23, 55.06 (d, 2 J C-F = 16.6 Hz), 24.05. 19 F NMR (376 MHz, CDCl 3 ): δ = -128.08 (dd, J = 32.2 Hz, 11.3 Hz). HRMS (ESI): m/z calcd. for C 12 H 16 FN 2 O 4 S [(M+H) + ] 303.08093, found 303.08087. N-ethyl-2-fluoro-N-methyl-2-nitro-2-(phenylsulfonyl)ethanamine (3f) Yellow oil, 91% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.87-7.96 (m, 2H), 7.75-7.84 (m, 1H), 7.59-7.68 (m, 2H), 3.93 (dd, J = 32.1 Hz, 15.4 Hz, 1H), 3.40 (dd, J = 15.4 Hz, 9.6 Hz, 1H), 2.68 – 2.47 (m, 2H), 2.32 (s, 3H), 0.96 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ = 136.12, 131.93, 130.65, 129.58, 123.66 (d, 1 J C-F = 282.72 Hz), 55.70 (d, 2 J C-F = 15.7 Hz), 52.80, 42.90, 54 11.72. 19 F NMR (376 MHz, CDCl 3 ): δ = -129.31 (dd, J = 32.0 Hz, 9.5 Hz). HRMS (ESI): m/z calcd. for C 11 H 16 FN 2 O 4 S [(M+H) + ] 291.0809, found 291.0813. N-(2-fluoro-2-nitro-2-(phenylsulfonyl)ethyl)-N-methylpropan-2-amine (3g) Yellow oil, 97% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.89-7.95 (m, 2H), 7.76 -7.83 (m, 1H), 7.60-7.66 (m, 2H), 3.95 (dd, J = 32.3 Hz, 15.4 Hz, 1H), 3.38 (dd, J = 15.4 Hz, 9.2 Hz, 1H), 2.83 (hept, J = 6.7 Hz, 1H), 2.26 (s, 3H), 0.95 (d, J = 6.6 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ = 136.11, 132.0, 130.63, 129.61, 123.92 (d, 1 J C-F = 283.0 Hz), 55.64, 53.59 (d, 2 J C-F = 15.7 Hz), 37.88, 18.04, 17.70. 19 F NMR (376 MHz, CDCl 3 ): δ = -128.74 (dd, J = 32.3 Hz, 9.1 Hz). HRMS (ESI): m/z calcd. for C 12 H 18 FN 2 O 4 S [(M+H) + ] 305.09658, found 305.09603. N-(2-fluoro-2-nitro-2-(phenylsulfonyl)ethyl)-N-isopropylpropan-2-amine (3h) Yellow oil, 95% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.90 -7.95 (m, 2H), 7.75-7.82 (m,1H), 7.59- 7.66 (m, 2H), 4.03 (dd, J = 31.6 Hz, 16.0 Hz, 1H), 3.64 (dd, J = 16.0 Hz, 7.6 Hz, 1H), 2.97 (hept, J = 6.7 Hz, 2H), 0.95 (d, J = 6.6 Hz, 6H),0.92 (d, J= 6.7 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ = 136.04, 132.13, 130.60, 129.61, 123.73 (d, 1 J C-F =281.5 Hz), 49.72, 47.57 (d, 2 J C-F =16.1 Hz), 21.51, 20.40. 19 F NMR (376 MHz, CDCl 3 ): δ = -126.91 (dd, J = 31.6 Hz, 7.3 Hz). HRMS (ESI): m/z calcd. for C 14 H 22 FN 2 O 4 S [(M+H) + ] 333.12788, found 333.12792. 55 N-benzyl-2-fluoro-2-nitro-2-(phenylsulfonyl)ethanamine (3i) Yellow solid, mp 71-74 o C, 92% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.86 – 7.95 (m, 2H), 7.75 – 7.82 (m, 1H), 7.56 – 7.66 (m, 2H), 7.22 – 7.34 (m, 3H), 7.20 – 7.22 (m, 2H), 3.99 (dd, J =30.5 Hz, 14.9 Hz, 1H), 3.82 (q, J = 3.57 Hz , 2H), 3.70 (dd, J = 14.9 Hz, 9.5 Hz, 1H), 1.60 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ = 138.55, 136.28, 131.69, 130.72, 129.67, 128.61, 127.99, 127.55, 123.11 (d, 1 J C-F = 281.4 Hz), 53.60, 48.09 (d, 2 J C-F = 17.1 Hz). 19 F NMR (376 MHz, CDCl 3 ): δ = -129.87 (dd, J = 30.5 Hz, 9.5 Hz). HRMS (ESI): m/z calcd. for C 15 H 16 FN 2 O 4 S [(M+H) + ] 339.08093, found 339.08100. N-(2-fluoro-2-nitro-2-(phenylsulfonyl)ethyl)butan-1-amine (3j) Yellow oil, 94% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.89 – 7.97 (m, 2H), 7.76 – 7.85 (m, 1H), 7.59 – 7.68 (m, 2H), 4.01 (dd, J = 30.9 Hz, 14.9 Hz, 1H), 3.70 (dd, J = 14.9 Hz, 9.5 Hz, 1H), 2.65 (qt, J = 11.7 Hz, 7.0 Hz, 2H), 2.42 (s, 1H), 1.19 – 1.51 (m, 4H), 0.83 – 0.95 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ = 136.22, 131.79, 130.72, 129.65, 123.16 (d, 1 J C-F = 279.4 Hz), 52.54, 48.89 (d, 2 J C-F = 17.0 Hz), 32.01, 19.96, 13.81. 19 F NMR (376 MHz, CDCl 3 ): δ = -130.24 (dd, J = 30.9 Hz, 9.5 Hz). HRMS (ESI): m/z calcd. for C 12 H 18 FN 2 O 4 S [(M+H) + ] 305.09658, found 305.09631. 56 N -(2-fluoro-2-nitro-2-(phenylsulfonyl)ethyl)propan-2-amine (3k) Yellow oil, 95% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.90 – 7.95 (m, 2H), 7.77 – 7.84 (m, 1H), 7.60 – 7.67 (m, 2H), 3.99 (dd, J = 30.9 Hz, 14.8 Hz, 1H), 3.68 (dd, J = 14.8 Hz, 9.5 Hz, 1H), 2.82 (hept, J = 6.3 Hz, 1H), 1.02 (d, J = 6.3 Hz, 3H), 0.99 (d, J = 6.3 Hz, 3H), 0.86 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ = 136.17, 131.85, 130.68 (d, J = 0.8 Hz), 129.60, 123.16 (d, 1 J C-F = 280.4 Hz), 49.08, 46.43(d, 2 J C-F = 17.1 Hz), 22.92, 22.58. 19 F NMR (376 MHz, CDCl 3 ) δ = - 130.44 (dd, J= 30.9 Hz, 9.3 Hz). HRMS (ESI): m/z calcd. for C 11 H 16 FN 2 O 4 S [(M+H) + ] 291.0809, found 291.0809. N -(2-fluoro-2-nitro-2-(phenylsulfonyl)ethyl)cyclopentanamine (3l) Yellow oil, 96% yield. 1 H NMR (400 MHz, CDCl 3 ) δ = 7.89 – 7.96 (m, 2H), 7.76 – 7.84 (m, 1H), 7.59 – 7.67 (m, 2H), 3.97 (dd, J = 30.9 Hz, 14.8 Hz, 1H), 3.67 (dd, J = 14.8 Hz, 9.5 Hz, 1H), 3.10 (p, J=6.2 Hz, 1H), 1.68 – 1.84 (m, 2H), 1.57 – 1.68 (m, 2H), 1.57 – 1.43 (m, 2H), 1.31 – 1.20 (m, 2H), 1.13 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ) δ = 136.19, 131.89, 130.72, 129.62, 123.11 (d, 1 J C-F = 280.8 Hz), 59.78, 47.54 (d, 2 J C-F = 17.1 Hz), 33.16, 32.68, 23.6, 23.56. 19 F NMR (376 MHz, CDCl 3 ) δ = -130.26 (dd, J = 30.9 Hz, 9.5 Hz). HRMS (ESI): m/z calcd. for C 13 H 18 FN 2 O 4 S [(M+H) + ] 317.09658, found 317.09667. 57 N -(2-fluoro-2-nitro-2-(phenylsulfonyl)ethyl)hexan-1-amine (3m) Yellow oil, 93% yield. 1 H NMR (400 MHz, CDCl 3 ) δ = 7.75 – 7.87 (m, 1H), 7.88 – 7.98 (m, 2H), 7.55 – 7.71 (m, 2H), 4.00 (dd, J = 30.8 Hz, 14.9 Hz, 1H), 3.69 (dd, J = 14.9 Hz, 9.6 Hz, 1H), 2.62 (m, 2H), 2.43 (m, 1H), 1.12 – 1.53 (m, 8H), 0.87 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ) δ = 136.21, 131.80, 130.71, 129.63, 123.14 (d, 1 J C-F = 281.4 Hz), 49.98, 48.90 (d, 2 J C-F = 17.1 Hz), 31.54, 29.87, 26.48, 22.54, 14.00. 19 F NMR (376 MHz, CDCl 3 ) δ = -129.73 (dt, J = 40.2 Hz, 14.7 Hz). HRMS (ESI): m/z calcd. for C 14 H 22 FN 2 O 4 S [(M+H) + ] 333.12788, found 333.12763. N -benzyl-2-fluoro-2-nitro-2-(phenylsulfonyl)ethanamine (3n) Yellow oil, 94% yield. 1 H NMR (400 MHz, CDCl 3 ) δ = 7.88 – 8.03 (m, 2H), 7.72 – 7.87 (m, 1H), 7.55 – 7.72 (m, 2H), 7.19 (dd, J = 8.5, 7.4 Hz, 2H), 6.81 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 8.3 Hz, 2H), 3.83 (t, J= 7.05 Hz, 1H), 4.70 (ddd, J = 28.0 Hz, 15.9 Hz, 8.5 Hz, 1H), 4.32 (ddd, J = 15.6 Hz, 9.0 Hz, 6.1 Hz, 1H). 13 C NMR (100 MHz CDCl 3 ) δ = 144.49, 135.48, 130.30, 129.73, 128.75, 128.39, 121.18 (d, 1 J C-F =283.4 Hz), 118.78, 112.54, 44.21 (d, 2 J C-F =17.8 Hz). 19 F NMR 58 (376 MHz, CDCl 3 ) δ -129.36 (dd, J = 27.9 Hz, 9.1 Hz). HRMS (ESI): m/z calcd. for C 14 H 14 FN 2 O 4 S [(M+H) + ] 325.06528, found 325.06528. N -benzyl-2-fluoro-2-nitro-2-(phenylsulfonyl)ethanamine (3o) S F O O NO 2 NH OMe Yellow oil, 93% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.77 – 7.93 (m, 2H), 7.73 (ddt, J = 8.7 Hz, 7.2 Hz, 1.3 Hz, 1H), 7.44 – 7.64 (m, 2H), 6.60 – 6.74 (m, 2H), 6.46 – 6.61 (m, 2H), 4.56 (dd, J = 28.3 Hz, 15.8 Hz, 1H), 4.17 (dd, J = 15.7 Hz, 9.1 Hz, 1H), 3.66 (s, 3H), 3.51 (s,1H). 13 C NMR (100 MHz, CDCl 3 ): δ = 152.60, 138.35, 135.43, 130.39, 129.71, 128.73, 121.27 (d, 1 J C-F = 282.4 Hz), 113.78, 114.37, 54.61, 45.45 (d, 2 J C-F = 17.8 Hz). 19 F NMR (376 MHz, CDCl 3 ): δ = -129.48 (dd, J = 28.2 Hz, 9.1 Hz). HRMS (ESI): m/z calcd. for C 15 H 16 FN 2 O 5 S [(M+H) + ] 355.07585, found 355.07597. 2-Fluoro-N, N-dimethyl-2,2-bis(phenylsulfonyl)ethanamine (4a) S S F N O O O O Viscous oil, 67% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.90 (m, 4H), 7.61 (m, 2H), 7.46 (m, 4H), 3.33 (d, J = 24.8 Hz, 2H), 1.96 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ):  = 136.7, 134.7, 131.0, 128.3, 116.6 (d, 1 J C-F = 272 Hz), 56.7 (d, 2 J C-F = 16 Hz), 46.1 (d, J = 3 Hz). 19 F NMR (376 59 MHz, CDCl 3 ):  = -147.7 (t, J = 25 Hz, 1F). HRMS (EI): m/z calcd. for C 16 H 19 FNO 4 S 2 [(M+H) + ] 372.0734, found 372.0733. N-(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)-N-propylpropan-1-amine (4b) S S F N O O O O Viscous oil, 95% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.67 (m, 2H), 7.92 (m, 4H), 7.52 (m, 4H), 3.66 2.30 (m, 4H), 1.10 (m, 4H), 0.68 (m, 6H), (d, J = 22.8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ):  = 136.9, 134.6, 130.7, 128.4, 116.8 (d, 1 J C-F = 271 Hz), 55.8, 53.5 (d, 2 J C-F = 15.3 Hz), 18.1, 11.5, 19 F NMR (376 MHz, CDCl 3 ):  = -148.0 (t, J = 22.7 Hz, 1F). HRMS (EI): m/z calcd. For C 20 H 26 FNO 4 S 2 [(M+H) + ] 428.1360, found 428.1364. N-benzyl-2-fluoro-N-methyl-2,2-bis(phenylsulfonyl)ethanamine (4c) S S F N O O O O White solid, m. p. 143-144 o C, 87% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.97 (m, 4H), 7.70 (m, 2H), 7.53 (m, 4H), 7.22 (m, 3H), 6.97 (m, 2H), 3.61 (d, J = 22.1 Hz, 2H), 3.48 (s, 2H), 1.98 60 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ):  = 136.8, 136.4, 134.8, 130.9, 129.2, 128.6, 128.0, 127.2, 116.3 (d, 1 J C-F = 271 Hz), 62.8 (d, J = 2 Hz), 55.2 (d, 2 J C-F = 15.3 Hz), 42.4 (d, J = 2 Hz). 19 F NMR (376 MHz, CDCl 3 ):  = -148.3 (t, J = 22 Hz, 1F). HRMS (EI): m/z calcd. for C 22 H 23 FNO 4 S 2 [(M+H) + ] 448.1047, found 448.1050. 1-(2-Fluoro-2,2-bis(phenylsulfonyl)ethyl)pyrrolidine (4d) S S F N O O O O Viscous yellow oil, 91% yield. 1 H NMR (400 MHz, CDCl 3 ): 7.96 (m, 4H), 7.68 (m, 2H), 7.52 (m, 4H), 3.64 (d, J = 26 Hz, 2H), 2.33 (m, 4H),  = 1.43 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ):  = 136.8, 134.7, 130.9, 128.3, 116.4 (d, 1 J C-F = 272 Hz), 115.5, 54.7, 53.7 (d, 2 J C-F = 16 Hz), 23.7. 19 F NMR (376 MHz, CDCl 3 ):  = -147.0 (t, J = 26 Hz, 1F). HRMS (EI): m/z calcd. for C 18 H 21 FNO 4 S 2 [(M+H) + ] 398.0890, found 398.0888. N-ethyl-2-fluoro-N-methyl-2,2-bis(phenylsulfonyl)ethanamine (4e) S S F N O O O O White solid, m. p. 137-138 o C, 89% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.87 (m, 4H), 7.61 (m, 2H), 7.46 (m, 4H), 3.46 (d, J = 24.6 Hz, 2H), 2.27 (q, J = 7 Hz, 2H), 1.89 (s, 3H), 0.67 (t, J = 61 7 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ):  = 136.7, 134.7, 130.9, 128.4, 118.1 (d, 1 J C-F = 268.8 Hz), 54.9 (d, 2 J C-F = 15.6 Hz), 52.3, 41.6, 10.5. 19 F NMR (376 MHz, CDCl 3 ):  = -147.3 (t, J = 24.5 Hz, 1F). HRMS (EI): m/z calcd. for C 17 H 20 FNO 4 S 2 [(M+H) + ] 386.0890, found 386.0885. N-(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)-N-methylpropan-2-amine (4f) S S F N O O O O Viscous colorless oil, 86% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 0.77 (d, J = 7 Hz, 6H), 1.88 (s, 3H), 2.73 (sep, J = 7 Hz, 1H), 3.53 (d, J = 24 Hz, 2H), 7.52 (m, 4H), 7.68 (m, 2H), 7.94 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ):  = 16.9, 35.6, 53.4 (d, 2 J C-F = 16 Hz), 54.8, 116.9 (d, 1 J C-F = 272 Hz), 128.4, 130.8, 134.7, 136.8. 19 F NMR (376 MHz, CDCl 3 ):  = -146.7 (t, J = 24.3 Hz, 1F). HRMS (EI): m/z calcd. for C 18 H 23 FNO 4 S 2 [(M+H) + ] 400.1047, found 400.1046. N-benzyl-2-fluoro-2,2-bis(phenylsulfonyl)ethanamine (4g) S S F HN O O O O 62 Viscous yellow oil, 65% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.70 (m, 2H), 7.90 (m, 4H). 7.52 (m, 4H), 7.27 (m, 3H), 7.18 (m, 2H), 3.70 (s, 2H), 3.41 (d, J = 14 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ):  = 138.6. 135.2, 130.8, 128.9, 128.4, 128.0, 127.4, 127.0, 112.3 (d, 1 J C-F = 268 Hz), 53.6, 48.0 (d, 2 J C-F = 20 Hz). 19 F NMR (376 MHz, CDCl 3 ):  = -144.4 (t, J = 13 Hz, 1F). HRMS (EI): m/z calcd. for C 21 H 21 FNO 4 S 2 [(M+H) + ] 434.0890, found 434.0897. N -(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)aniline (4h) S F O O SO2Ph NH Viscous yellow oil, 41% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.87 – 8.00 (m, 4H), 7.72 – 7.76 (m, 2H), 7.49 – 7.61 (m, 4H), 6.71 (t, J = 7.24 Hz,1H), 7.05 – 7.09 (m, 2H), 6.32 (d, J = 8.2 Hz, 2H), 4.16 (d, J = 12.20 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ = 146.30, 135.45, 134.69, 130.87 (d, J= 1.1 Hz), 129.17, 129.14, 118.62, 112.81, 112.76 (d, 1 J C-F = 269.89 Hz), 43.57 (d, 2 J C-F = 20.0 Hz). 19 F NMR (376 MHz, CDCl 3 ): δ = -147.00 (t, J = 12.9 Hz). HRMS (ESI): m/z calcd. for C 20 H 19 FNO 4 S 2 [(M+H) + ] 420.07340, found 420.07376. N -(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)-4-methoxyaniline (4i) S F O O SO2Ph NH OMe Brown solid, mp 112-115 o C, 46% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.93 (d, J = 8.41 Hz, 4H), 7.72 (t, J = 7.5, 2H), 7.54 (t, J = 8.13 Hz, 4H), 6.66 (d, J = 8.78 Hz, 2H), 3.71 (s, 3H), 6.30 63 (d, J = 8.9 Hz, 2H), 4.08 (dd, J = 13.2, 7.0, 2H), 3.94 (t, J = 7.0, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ = 152.74, 140.32, 135.40, 134.80, 130.86 (d, J = 1.0), 129.10, 114.67, 114.24, 113.01 (d, 1 J C-F = 1269.49 Hz), 55.66, 44.61(d, 2 J C-F = 20.0 Hz). 19 F NMR (376 MHz, CDCl 3 ): δ = - 147.00 (t, J = 13.0 Hz). HRMS (ESI): m/z calcd. for C 21 H 21 FNO 5 S 2 [(M+H) + ] 450.08397, found 450.08432. N-(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)butan-1-amine (4j) S S F HN O O O O Viscous colorless oil, 85% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.95 (d, J = 7.5 Hz, 4H), 7.70 (t, J = 8.4 Hz, 2H), 7.54 (t, J = 7.6 Hz, 4H), 3.46 (d, J = 14.7 Hz, 2H), 2.44 (t, J = 6.7 Hz, 2H), 1.26 (m, 4H), 0.85 (t, J = 7.2 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ):  = 135.4, 135.0, 130.8, 128.7, 13.8, 114.0 (d, 1 J C-F = 267.7 Hz), 49.7, 48.8 (d, 2 J C-F = 19.5 Hz), 31.7, 20.0. 19 F NMR (376 MHz, CDCl 3 ):  = -144.96 (t, J = 14.7 Hz, 1F). HRMS (EI): m/z calcd. for C 18 H 23 FNO 4 S 2 [(M+H) + ] 400.1047, found 400.1054. N-(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)propan-2-amine (4k) S S F HN O O O O 64 Viscous yellow oil, 78% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.96 (d, J = 8.1 Hz, 4H), 7.70 (t, J = 7.1 Hz, 2H), 7.54 (t, J = 8.01 Hz, 4H), 3.48 (d, J = 15 Hz, 2H), 2.61 (septet, J = 6.27 Hz, 1H), 0.89 (d, J = 6.27 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ):  = 135.5, 135.1, 130.8, 128.7, 114.0 (d, 1 J C-F = 267.7 Hz), 48.9, 46.4 (d, 2 J C-F = 19.5 Hz), 22.3. 19 F NMR (376 MHz, CDCl 3 ):  = -145.44 (t, J = 15 Hz, 1F). HRMS (EI): m/z calcd. for C 17 H 21 FNO 4 S 2 [(M+H) + ] 386.0890, found 386.0892. N-(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)cyclopentanamine (4l) S S F HN O O O O Viscous yellow oil, 97% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.94 (d, J = 7.48 Hz, 4H), 7.70 (t, J = 7.46 Hz, 2H), 7.53 (t, J = 7.57 Hz, 4H), 1.15 (m, 2H), 1.44 (m, 2H), 3.44 (d, J = 15.1 Hz, 2H), 2.86 (pentet, J = 6.05 Hz, 1H), 1.60 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ):  = 135.4. 135.0, 130.7, 128.6, 114.0 (d, 1 J C-F = 267.5 Hz), 59.9, 47.4 (d, 2 J C-F = 19.4 Hz), 32.4, 23.6. 19 F NMR (376 MHz, CDCl 3 ):  = -145.17 (t, J = 15.1 Hz, 1F). HRMS (EI): m/z calcd. for C 19 H 23 FNO 4 S 2 [(M+H) + ] 412.1047, found 412.1043. N-(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)heptan-2-amine (4m) 65 Viscous colorless oil, 88% yield. 1 H NMR (400 MHz, CDCl 3 ):  = 7.95 (m, 4H), 7.70 (m, 2H), 7.54 (m, 4H), 3.50 (m, 2H), 2.47 (m, 1H), 1.26 (m, 9H), 0.87 (t, J = 6.7 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ):  = 135.6, 135.1, 130.9, 128.7, 114.1 (d, 1 J C-F = 267.5 Hz), 53.4, 46.4 (d, 2 J C-F = 19.4 Hz), 36.6, 31.8, 25.3, 22.5, 19.7, 14.0. 19 F NMR (376 MHz, CDCl 3 ):  = -145.4 (t, J = 14.5 Hz, 1F). HRMS (EI): m/z calcd. for C 21 H 29 FNO 4 S 2 [(M+H) + ] 442.1516, found 442.1521. N -ethyl-2-fluoro-N-methyl-2-nitro-2-(phenylsulfonyl)ethanamine (4n) Viscous Colorless oil, 86% yield. 1 H NMR (400 MHz, CDCl 3 ): δ 7.92 – 8.02 (m, 4H), 7.67 – 7.76 (m, 2H), 7.51 – 7.61 (m, 4H), 0.81 (d, J = 6.5 Hz, 3H), 3.50 (m, 2H), 2.30 (m, J = 6.4 Hz, 1H), 1.60 – 1.78 (m, 2H), 1.48 – 1.60 (m, 2H), 1.33 – 1.48 (s, broad, 1H), 1.05 – 1.27 (m, 5H), 0.84 – 0.96 (m, 2H). 13 C NMR (100 MHz, CDCl 3 ): δ = 135.58 (d, J=15.0 Hz), 135.06 (d, J=3.9 Hz), 130.87 (dd, J=3.6 Hz, 1.3 Hz), 128.79 (d, J = 1.1 Hz), 114.06 (d, 1 J C-F = 267.3 Hz), 58.32, 46.84 (d, 2 J C-F = 19.6 Hz), 42.59, 29.55, 27.67, 26.60, 26.50, 26.35, 16.13. 19 F NMR (376 MHz, CDCl 3 ): δ = -145.19 (t, J = 14.2 Hz).HRMS (ESI): m/z calcd. for C 22 H 29 FNO 4 S 2 [(M+H) + ] 454.1517, found 454.1521. 66 N -(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)adamantan-1-amine (4o) S F O O SO 2 Ph NH White solid, mp 130-132 o C, 94% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.97 (d, J = 8.20 Hz, 4H), 7.71 (t, J = 7.35 Hz, 2H), 7.55 (t, J = 7.8 Hz, 4H), 3.55 (d, J = 15.8 Hz, 2H), 2.01 (s, 3H), 1.70 (s, 1H), 1.51 – 1.64 (m, 6H), 1.44 (d, J=2.8 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ = 135.92, 134.99, 131.03, 128.69, 114.66 (d, 1 J C-F = 267.7 Hz), 50.69, 42.14, 41.00 (d, 2 J C-F = 19.4 Hz), 36.49, 29.40. 19 F NMR (376 MHz, CDCl 3 ): δ = -145.36 (t, J= 15.8 Hz). HRMS (ESI): m/z calcd. for C 24 H 29 FNO 4 S 2 [(M+H) + ] 478.1517, found 478.1517. N -decyl-N-(2-fluoro-2,2-bis(phenylsulfonyl)ethyl)decan-1-amine (4p) Viscous yellow oil, 87% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.92-7.94 (m, 4H), 7.60 – 7.73 (m, 2H), 7.41 – 7.59 (m, 4H), 3.65 (d, J = 23.2 Hz, 2H), 2.32 (m, 4H), 1.26 (m, 16H), 0.89 (m, 6H). 13 C NMR (100 MHz, CDCl 3 ): δ = 136.95, 134.63, 130.80 (d, J=1.6 Hz), 128.44, 116.95 (d, 2 J C-F = 271.0 Hz), 53.85, 53.55 (d, 1 J C-F = 15.1 Hz), 31.89, 29.57, 29.54, 29.49, 29.31, 27.27, 24.84, 22.67, 14.10. 19 F NMR (376 MHz, CDCl 3 ): δ = -148.10 (t, J = 23.1 Hz). HRMS (ESI): m/z calcd. for C 34 H 55 FNO 4 S 2 [(M+H) + ] 624.3551, found 624.3555. 67 2-Fluoro-N-phenethyl-2,2-bis(phenylsulfonyl)ethanamine (4q) Yellow oil, 89% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.90 (d, J = 8.4 Hz, 4H), 7.67- 7.70 (m, 2H), 7.49 – 7.53 (m, 4H), 7.26- 7.30 (m, 2H), 7.18- 7.24 (m, 1H), 7.10- 7.12 (m, 2H), 3.47 (d, J = 14.7 Hz, 2H), 2.71 (m, 2H), 2.63 (m, 2H), 1.55 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ = 139.42, 135.43, 135.27, 130.87 (d, 3 J C-F = 1.1 Hz), 128.94, 128.74, 128.53, 126.33, 113.89 (d, 1 J C-F = 267.6 Hz), 51.39, 48.75 (d, 2 J C-F = 19.7 Hz), 36.14. 19 F NMR (376 MHz, CDCl 3 ): δ = - 144.92 (t, J = 14.7 Hz). HRMS (ESI): m/z calcd. for C 22 H 22 FNO 4 S 2 [(M+H) + ] 448.10470, found 448.10415. 2-fluoro-N-(1-phenylethyl)-2,2-bis(phenylsulfonyl)ethanamine (4r) Yellow oil, 93% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 1.25 (d, J=6.6 Hz, 3H), 1.97 (s, 1H), 3.28 (dt, J = 44.0 Hz, 14.8 Hz, 2H), 3.61 (q, J = 6.6 Hz, 1H), 7.09- 7.12 (m, 2H), 7.17- 7.26 (m, 3H), 7.45 – 7.51 (m, 4H), 7.64- 7.69 (m, 2H), 7.85- 7.92 (m, 4H). 13 C NMR (100 MHz, CDCl 3 ): δ = 24.03, 46.91 (d, 2 J C-F = 19.6 Hz), 58.31, 113.77 (d, 1 J C-F = 267.5 Hz), 126.48, 127.18, 128.55, 128.87, 128.94, 130.47 – 131.11 (m), 135.03 – 135.39 (m), 143.89. 19 F NMR (376 MHz, CDCl 3 ): δ = -145.39 (t, J = 14.1 Hz). HRMS (ESI): m/z calcd. for C 22 H 22 FNO 4 S 2 [(M+H) + ] 448.10470, found 448.10502. 68 2-fluoro-N-methyl-N-(naphthalen-1-ylmethyl)-2,2-bis(phenylsulfonyl)ethanamine (4s) Yellow solid, mp 115-118 o C, 68% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 8.17 (d, J = 7.6 Hz, 1H), 7.92- 7.94 (d, J=8.5 Hz, 4H), 7.83- 7.85 (m, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.63- 7.67 (m, 2H), 7.48- 7.53 (m, 2H), 7.43- 7.47 (m, 4H), 7.31- 7.35(m, 1H), 7.14 (d, J = 6.8 Hz, 1H), 3.97 (s, 2H), 3.78 (d, J = 21.0 Hz, 2H), 1.93 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ = 136.04, 134.97, 133.67, 133.11, 132.13, 130.97 (d, J = 1.2), 128.69, 128.43, 128.09, 127.58, 126.02, 125.64, 125.04, 124.28, 115.90 (d, 1 J C-F = 271.7 Hz), 60.70, 56.36 (d, 2 J C-F = 15.6 Hz), 42.76. 19 F NMR (376 MHz, CDCl 3 ): δ = -147.39 (t, J = 20.9 Hz). HRMS (ESI): m/z calcd. for C 26 H 24 FNO 4 S 2 [(M+H) + ] 498.11927, found 498.12012. 2-Fluoro-2-nitro-2-(phenylsulfonyl)ethanol (7a) Yellow oil, 93% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.86 – 8.00 (m, 2H), 7.75 – 7.88 (m, 1H), 7.56 – 7.72 (m, 2H), 4.77 (dd, J = 24.8 Hz, 13.7 Hz, 1H), 4.52 (dd, J = 13.7 Hz, 10.4 Hz, 1H), 2.48 (s, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ = 135.59, 130.37, 129.77, 128.79, 120.18 (d, 1 J C-F = 282.7 Hz), 60.05 (d, 2 J C-F = 19.4 Hz). 19 F NMR (376 MHz, CDCl 3 ): δ = -132.36 (dd, J = 25.0 Hz, 10.5 Hz). HRMS (ESI): m/z calcd. for C 8 H9FNO 5 S [(M+H) + ] 250.01800, found 250.01784. 69 2-Fluoro-2,2-bis(phenylsulfonyl)ethanol (7b) White solid, mp 120-121 o C, 90% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.85 – 8.14 (m, 4H), 7.68 – 7.86 (m, 2H), 7.49 7 – 7.67 (m, 4H), 4.27 (dd, J = 10.6 Hz, 7.2 Hz, 2H), 2.91 (t, J = 7.2 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 ): δ = 135.63, 134.56, 130.93, 129.16, 111.15 (d, 1 J C-F =268.8 Hz), 60.60 (d, 2 J C-F = 22.6 Hz). 19 F NMR (376 MHz, CDCl 3 ): δ = -148.32 (t, J = 10.6 Hz). HRMS (ESI): m/z calcd. for C 14 H 14 FO 5 S 2 [(M+H) + ] 345.02612, found 345.02662. N -(2-fluoroethyl)heptan-2-amine (8m) Colorless oil, 35% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.58 (m, 1H), 4.46 (m, 1H), 2.85 (m, 2H), 2.62 (m, 1H), 2.44 (s, 1H), 1.27 (m, 8H), 1.03 (d, J = 6.10 Hz, 3H), 0.86 (m, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ = 83.82 (d, 1 J C-F = 164.9 Hz), 52.91, 47.10 (d, 2 J C-F = 19.9 Hz), 37.00, 32.02, 25.61, 22.62, 20.20, 14.03. 19 F NMR (376 MHz, CDCl 3 ): δ = -224.24 (tt, J = 47.5 Hz, 28.1 Hz). HRMS (ESI): m/z calcd. for C 9 H 21 FN [(M+H) + ] 162.1653, found 162.1653. 1-Cyclohexyl- N -(2-fluoroethyl)ethanamine (8n) 70 Colorless oil, 72 % yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.60 (m, 1H), 4.48 (m, 1H), 2.88 (m, 2H), 2.47 (q, J = 6.1 Hz, 1H), 1.66-1.77 (m, 9H), 1.11 – 1.25 (m, 4H), 1.00 (d, J = 6.5 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ = 83.87 (d, 1 J C-F = 164.7 Hz), 57.58, 47.40 (d, 2 J C-F = 19.8 Hz), 42.82, 29.84, 27.83, 26.71, 26.60, 26.45, 16.65. 19 F NMR (376 MHz, CDCl 3 ): δ = -224.17 (tt, J = 47.5 Hz, 28.2 Hz). HRMS (ESI): m/z calcd. for C 10 H 21 FN [(M+H) + ] 173.1573, found 173.1580. N -(2-fluoroethyl)adamantan-1-amine (8o) White solid, mp 135-137 o C, 55% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 4.59 (t, J = 5.0 Hz, 1H), 4.47 (t, J = 5.0 Hz, 1H), 2.93 (t, J = 5.0 Hz, 1H), 2.86 (t, J = 5.0 Hz, 1H), 2.08 (broad, 3H), 1.58 – 1.70 (m, 13H). 13 C NMR (100 MHz, CDCl 3 ): δ = 83.65 (d, 1 J C-F = 165.2 Hz), 49.15, 41.70, 39.67 (d, 2 J C-F = 19.9 Hz), 35.67, 28.53. 19 F NMR (376 MHz, CDCl 3 ): δ = -224.02 (tt, J = 47.4 Hz, 27.2 Hz). HRMS (ESI): m/z calcd. for C 12 H 21 FN [(M+H) + ] 198.1653, found 198.1653. 2-Fluoro- N -(1-phenylethyl)ethanamine (8r) Colorless oil, 81% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 7.32 – 7.35 (m, 2H), 7.30 – 7.32 (m, 2H), 7.21 – 7.25 (m, 1H), 4.50 - 4.59 (m, 1H), 4.38 – 4.47 (m, 1H), 3.80 (q, J = 6.6 Hz, 1H), 2.62 – 2.85 (m, 2H), 1.37 (d, J = 6.6 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ = 145.11, 128.49, 127.03, 126.58, 83.71 (d, 1 J C-F = 164.5 Hz), 58.06, 47.57 (d, 2 J C-F = 19.4 Hz), 24.42. 19 F NMR 71 (376 MHz, CDCl 3 ): δ = -234.12 – -218.52 (m). HRMS (ESI): m/z calcd. for C 10 H 14 FN [(M+H) + ] 168.11830, found 168.11842. 2-Fluoro-N-methyl- N -(naphthalen-1-ylmethyl)ethanamine (8s) Colorless oil, 76% yield. 1 H NMR (400 MHz, CDCl 3 ): δ = 8.29 (d, J = 8.2 Hz, 1H), 7.85 (d, J = 7.9 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.45-7.54 (m, 2H), 7.39-7.45 (m, 2H), 4.59 (dt, J = 47.6 Hz, 5.0 Hz, 2H), 3.99 (s, 2H), 2.83 (dt, J = 27.2 Hz, 4.9 Hz, 2H), 2.34 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ): δ = 134.32, 133.84, 132.41, 128.42, 128.10, 127.51, 125.94, 125.64, 125.09, 124.52, 82.57 (d, 1 J C-F = 167.4 Hz), 60.88, 57.12 (d, 2 J C-F = 20.0 Hz), 42.86. 19 F NMR (376 MHz, CDCl 3 ): δ = -223.39 – -212.23 (m). HRMS (ESI): m/z calcd. for C 14 H 16 FN [(M+H) + ] 218.13395, found 218.13395. 72 N -(2-Fluoro-2,2-bis(phenylsulfonyl)ethyl)aniline (4h) 73 2-Fluoro-N-methyl- N -(naphthalen-1-ylmethyl)ethanamine (8s) 74 * *acetone 75 2.4.4 Crystal Structure of C 17 H 20 NFO 4 S 2 Diffraction data were collected at 150 K on a SMART APEX CCD diffractometer with graphite fine-focused monochromatic Mo-Kα radiation (λ = 0.71073 Ǻ). The cell parameters for (C 17 H 20 NFO 4 S 2 ) were obtained from the least-squares refinement of the spots (from 60 collected frames) using the SMART program of a colorless crystal sample measuring 1.0 x 0.22 x 0.05 mm3 in size. A hemisphere of data were collected up to a resolution of 0.75 Ǻ, the intensity data were processed using the Saint Plus program. All calculations for the structure determination were carried out using the SHELXTL package (version 6.14).47 Initial atomic position were located by direct methods using XS, and the structure was refined by the least square methods using SHELX with 3478 independent reflections and within the range of theta 2.27 to 27.45o (completeness 94.2%). Absorption corrections were applied by SADABS.48 Calculated hydrogen position were input and refined in a riding manner along with the corresponding carbons. A summary of the refinement details and the resulting factors are given in Table 2.5. Table 2.5. Crystal data and structure refinement for C 17 H 20 NFO 4 S 2 . Identification code mo_pvj91_0m Empirical formula C 17 H 20 F N O 4 S 2 Formula weight 385.46 Temperature 100(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 11.93500(10) Å  = 90°. b = 12.17890(10) Å  = 93.8680(10)°. c = 12.23810(10) Å  = 90°. Volume 1774.82(3) Å 3 Z 4 Density (calculated) 1.443 Mg/m 3 76 Absorption coefficient 0.332 mm -1 F(000) 808 Crystal size 0.466 x 0.391 x 0.282 mm 3 Theta range for data collection 1.71 to 30.60°. Index ranges -17<=h<=17, -17<=k<=17, -17<=l<=17 Reflections collected 113383 Independent reflections 5466 [R(int) = 0.0323] Completeness to theta = 26.00° 100.0 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7461 and 0.6807 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 5466 / 0 / 228 Goodness-of-fit on F 2 1.052 Final R indices [I>2sigma(I)] R1 = 0.0263, wR2 = 0.0701 R indices (all data) R1 = 0.0300, wR2 = 0.0734 Largest diff. peak and hole 0.392 and -0.339 e.Å -3 77 2.5 Chapter 2: References 1. Reviews on MCR: a) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123-131; b) Ugi, I. Pure and Appl. Chem. 2001, 73, 187-191; c) Domling, A.; Ugi, I. Angew. Chem. Int. 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Tetrahedron Lett. 1996, 37, 575-578; h) Panday, S. K.; Griffart-Brunet, D.; Langlois. N. Tetrahedron Lett. 1994, 35, 6673-6676; i) Ezquerra, J.; Pedregal, C.; Mico, I.; Najera, C. Tetrahedron: Asymmetry 1994, 5, 921- 926; j) Fleming, I.; Kilburn, J. D. J. Chem. Soc. Perkin Trans.1 1992, 24, 3295-3302. 10. Bordwell, F. G.; Puy, M. V. D.; Vanier, N. R. J. Org. Chem. 1976, 41, 1883-1885. The values of non-fluorinated carbon acids bis(phenylsulfonyl)methane and nitro(phenylsulfonyl)methane are 12.2 and 7.1 respectively. Therefore, fluorinated derivatives are expected to be stronger carbon acids and have lower values. 11. Rochin, C.; Babot, O.; Dunogues, J.; Duboudin, F. Synthesis 1986, 3, 228-229. 12. a) Hancock, M. T.; Minto, R. E.; Pinhas, A. R. Tetrahedron Lett. 2003, 44, 8357-8360; b) Quintard, J. P.; Elissondo, B.; Jousseaume, B. Synthesis 1984, 6, 495-498; c) Heaney, H.; Papageorgiou, G.; Wilkins, R. F. J. Chem. Soc., Chem. 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W. J. Med. Chem. 1967, 10, 481-484; b) Thvedt, T. H. K.; Fuglseth, E.; Sundby, E.; Hoff, B. H. Tetrahedron 2010, 66, 6733-6743; 18. Li, Y.; Ni, C.; Liu, J.; Zhang, L.; Zheng, J.; Zhu, L.; Hu, J. Org. Lett. 2006, 8, 1693- 1696. 82 Chapter 3: A Multi-component Protocol for Fluorinated α- amino Acids and β-amino Esters 3.1 Chapter 3: Introduction Amino acids are important building blocks of proteins and key intermediates in the metabolism of both plants and animals. Ever since the discovery and isolation of amino acids, humans have attempted to mimic nature’s synthesis of amino acids. Adolph Strecker has been credited with the earliest attempt at systematic scientific studies on the synthesis of amino acids from either aldehydes or ketones. 1 Alexander Oparin and J.B.S. Haldane proposed the concept of a primordial “soup” containing organic molecules that were synthesized from chemical reactions involving inorganic precursors during the evolution of early earth. 2 Stanley Miller tested this hypothesis by performing the now famous Miller-Urey experiment in which a mixture of methane, ammonia, water and hydrogen was continuously circulated past an electric spark. 3 Miller proposed that by using electric discharge as a substitute for the ultraviolet light, which bathed the early earth, he could generate reactive free radicals to form organic compounds. His solution was indeed found to contain a mixture of organic compounds, including amino acids. In recent years, the scientific community has been greatly interested in the investigation of the many interesting properties of amino acids through the use of fluorinated amino acids. 4 The fluorine atom offers a number of advantages including its small steric size, high electronegativity, high carbon-fluorine bond strength, and large 19 F- 1 H coupling constants that result in several novel and interesting physical, chemical and biological properties for fluorinated molecules. 4a Fluorinated amino acids have found widespread bioorganic applications in biological tracers, mechanistic probes, enzyme inhibitors and medical applications including in the control 83 of blood pressure, allergies and tumor growth. 4a,b From a characterization stand point, fluorinated biomolecules can be studied with high sensitivity using 19 F-NMR spectroscopy and offer better bioactivities than their non-fluorinated counterparts. 4b Specifically, fluorinated α-amino acids have been found to irreversibly inhibit pyridoxal phosphate-dependent enzymes. 4a, 5 For example, β-fluoroalanine 6 and (S)- -fluoromethylhistidine 7 inhibit the corresponding bacterial alanine racemases and histidine decarboxylase. Fluorinated α-amino acids have an important role in the development of drugs such as anti-tumor agents. 8 Similarly, fluorinated β-amino acids have also attracted a great deal of attention due to their potential biological applications and therapeutic value. In addition, some fluorinated β-amino acids have been characterized as potent competitive serine protease inhibitors 9 as well as useful synthetic precursors to β-lactam antibiotics, 10 fluoroalkene dipeptide isosteres, 11 quinolines with antibacterial activity 12 and [ 18 F]- radiolabeled markers. 4c, 13 Currently, most methods for the synthesis of fluorinated amino acids utilize imines, which are separately constructed by combining amines with aldehydes or ketones (Scheme 3.1). 21 The major flaw with these approaches is that simple imines, particularly aliphatic imines, are prone to hydrolysis 22 and therefore require protecting groups, resulting ultimately in low- yield synthesis due to the increased number of steps for creating fluorinated amino acids. In addition to imines, metal-based catalysts are often used for the synthesis of fluorinated amino acids. (Scheme 3.1). 21 However, metal-catalyzed reactions may not be economical due to the high cost of precious metals and ligands, and the need for proper disposal of toxic metals after the reaction. 23 84 Scheme 3.1 Some examples of synthetic schemes currently in use for the preparation of fluorinated - and β-amino acids. In contrast, multi-component reactions are highly efficient and economical as they offer a high degree of structural diversity while incorporating molecular units of all components within a single step. 24 Although in most Mannich-type reactions imines are used as electrophiles, 25 our ability to use simple molecular units in the reaction while yet keeping the reaction fast and selective eliminates the need for preformed imines. Previous multi-component reactions were unsuccessful in synthesizing fluorinated amino acids directly. Strecker reactions using fluorinated ketones required further hydrolysis of the aminonitriles 26a while reactions using fluorinated keto esters require protected imines. 26b On the other hand, the extremely high reactivity, toxicity and inconvenience of using either hydrogen fluoride (HF) or fluorine (F 2 ) preclude their direct use as selective fluorinating 85 agents. 14 Therefore many organofluorine compounds are prepared by transferring fluoroalkyl and fluoroaryl groups using activated fluoroalkane and arenes. Among the various fluorination methods, nucleophilic fluoroalkylation is considered one of the superior methods for the introduction of fluoroalkyl moieties into organic molecules. 15,16 α- fluorobis(phenylsulfonyl)methane (FBSM, 1b) (Scheme 3.2) was reported as a good monofluoromethyl transfer agent for fluoroalkylation in 2006 and has been widely used since. 18,19 The highly electron-withdrawing phenylsulfonyl group activates the C-H bond by significantly enhancing its acidity to facilitate the formation of a carbanion by deprotonation in the presence of a base. The fluorine-bearing carbanion has low thermal stability due to its high tendency to undergo α-elimination of the fluoride ion to form a carbene. However, the phenylsulfonyl group also stabilizes the fluorinated carbanion via electron delocalization, thereby reducing the electron repulsion between the electron pairs on the carbanionic carbon and those on the fluorine atoms. Additionally, the sulfonyl group can subsequently be removed easily through reductive desulfonylation after the desired molecular transformations have been achieved. 18-20 Here, we report a new protocol for the synthesis of fluorinated α- amino acids and β- amino esters by using a nucleophilic fluoroalkylation approach for fluorine incorporation via a Mannich-type three component reaction of glyoxylic acid or formaldehyde, an amine and an activated fluoromethane (Scheme 3.2). Using formalin and ethyl 2-fluoro-2- (phenylsulfonyl)acetate (EFPA, 1a), we were able to synthesize the corresponding fluorinated β- amino esters whereas by using glyoxylic acid and an activated fluoromethane, either α-fluoro- bis(phenylsulfonyl)-methane (FBSM, 1b) or α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM, 1c) we were able to synthesize the corresponding fluorinated α-amino acids. Previously, we had 86 demonstrated the synthesis of β-fluoroethylamines via a similar Mannich-type reaction. 17 However, to our knowledge, this is the first report of a three component protocol involving an α- fluorocarbanion for the direct synthesis of both fluorinated α- amino acids and β-amino esters from their molecular sub-units. Scheme 3.2 New approach for the synthesis of fluorinated β-amino esters (Eq. 1) and fluorinated α-amino acids (Eq. 2) 3.2 Chapter 3: Results and Discussion As shown in Scheme 3.3 below, when ethyl 2-fluoro-2-(phenylsulfonyl)acetate (EFPA, 1a) was stirred together with paraformaldehyde and tert-butylamine in dichloromethane (CH 2 Cl 2 ) in the presence of lithium carbonate (Li 2 CO 3 ), we were able to obtain the expected three component product ethyl 3-(tert-butylamino)-2-fluoro-2-(phenylsulfonyl)propanoate (4a), the fluorinated β-amino ester with 25% yield. Another product, later determined to be ethyl 2- fluoro-3-hydroxy-2-(phenylsulfonyl)-propanoate (10, the product from 1a and formalin) was isolated with 36% yield. It became clear that in order to increase the yield of the desired product (4a), the competing pathway - the formation of 10 should be suppressed. We were able 87 successfully achieve its suppression by initially stirring amine and formalin to allow the formation of aminal 9 in sufficient concentration before the addition of the nucleophile EFPA. The use of formalin (37% aqueous solution of formaldehyde) instead of the solid polymer paraformaldehyde was also found to improve reaction efficacy. Scheme 3.3 Formation of the undesirable β-fluoroethanol (10) via a competing pathway during the synthesis of fluorinated β-amino ester 4a. After stirring the reaction mixture at 80 o C for 1 h, analysis of the reaction mixture showed that the product 4a was formed with a significantly increased (56%) yield. Further improvement was achieved by initially stirring the amine and formalin for 0.5 h in acetonitrile (CH 3 CN) at room temperature followed by the addition of EFPA and Li 2 CO 3 and heating at 80 o C for 1h (with a reactant ratio EFPA/formaldehyde/Li 2 CO 3/ amine = 1:1.5:1.5: 2) leading to our best conversion (91%) for the product. 4a (Table 3.1, Entry 4). Figure 3.1 depicts the comparison of 19 F NMR spectra of ethyl 2-fluoro-2-(phenylsulfonyl)acetate (1a) and ethyl 3-(tert- butylamino)-2-fluoro-2-(phenylsulfonyl)-propanoate (4a), showing the conversion of the original doublet at -180.9 ppm to a multiplet at -162.4 ppm. 88 Figure 3.1 Comparison of 19 F NMR spectra of ethyl 2-fluoro-2-(phenylsulfonyl)acetate (1a) and ethyl 3-(tert-butylamino)-2-fluoro-2-(phenylsulfonyl)-propanoate (4a). High conversions to the product were also obtained using dimethylformamide (DMF) and CH 2 Cl 2 (Table 3.1, Entries 3, 9) as solvents. CH 3 CN, DMF and CH 2 Cl 2 all are polar aprotic solvents with high dielectric constants of 37.5, 38 and 9.1, respectively. The high dielectric constant of the solvent contributes positively to the reaction through improved solvation of the intermediate aminal 9 as compared to that for other solvents with low dielectric constants. As to the influence of the bases on product yield, while both Li 2 CO 3 and Cs 2 CO 3 enhanced product yields within the appropriate solvents, for reactions using stronger bases such as sodium hydride (NaH) and sodium ethoxide (NaOEt) none of the compounds 4a, 10 or 1a was detected in the reaction mixture. Instead, for the NaH and NaOEt reactions a triplet at -211 ppm was observed in the 19 F NMR spectrum and this compound is yet to be identified. 89 Table 3.1 Dependence of the yield of the desired fluorinated β-amino ester 4a on various combinations of solvents and bases for the multi-component synthesis reaction of EFPA with tert-butylamine and formaldehyde [a] Entry Base 4a Li 2 CO 3 25 1 [b] CH 2 Cl 2 Solvent Li 2 CO 3 EtOH Et 2 O Toluene 37 46 78 56 91 46 2 3 4 5 6 7 CH 2 Cl 2 DMF CH 3 CN Li 2 CO 3 Li 2 CO 3 Li 2 CO 3 Li 2 CO 3 Li 2 CO 3 10 36 5 3 22 0 5 5 39 41 49 0 43 4 48 1a (Unreacted) [c] [a] Reactions were carried out using EFPA (1 equiv), Amine (2 equiv), and base (1.5 equiv) in solvent at room temperature. (1.5 hr) and at 80 0 C (1 h). [b] All the reactants were mixed at once. [c] Determined by 19 F NMR Spectroscopy. Touene CH 2 Cl 2 Toluene 89 0 62 8 9 12 Cs 2 CO 3 Cs 2 CO 3 NaH 5 0 0 6 0 37 CH 2 Cl 2 CH 2 Cl 2 5 0 10 11 NaOEt CsOH 0 0 95 0 H N C H 2 F PhO 2 S H 2 N CH 3 CH 3 CH 3 C 2 H 5 O O 4a CH 3 CH 3 CH 3 PhO 2 S OC 2 H 5 O F CH 2 OH 10 CH 2 O + + + PhO 2 S OC 2 H 5 O F 1a Yield (%) [c] Having optimized the reaction conditions for high product yield, we subsequently examined the influence of the type of amine substrate on the multi-component reaction. As shown in Table 3.2, the reactions generated good product conversions for the various amines that 90 were tested. With aromatic amines, however, only the starting material EFPA was recovered under our reaction conditions. Table 3.2 Synthesis of fluorinated β-amino esters by the three component reaction of ethyl 2- fluoro-2-(phenylsulfonyl)acetate 1a using various primary amines and formaldehyde [a] Next, we turned our attention to the synthesis of fluorinated α-amino acid derivatives. We attempted to synthesize fluorinated α-amino acid by simply using α -fluoro-α- nitro(phenylsulfonyl)methane (FNSM ) or α-fluorobis(phenylsulfonyl)methane (FBSM) instead of EFPA and formaldehyde instead of glyoxylic acid. 91 Our research began by stirring N, N-diethylamine (2 equivalent) and glyoxylic acid (1.5 equivalent) in CH 2 Cl 2 at room temperature for 1 hour and then adding α-fluoro-α- nitro(phenylsulfonyl)methane (FNSM, 1 equivalent) to the solution (Scheme 3.4). After allowing it to stir at room temperature for 12 hours, the 19 F NMR analysis of the reaction mixture showed the disappearance of a doublet at -142.2 (d, J = 48.4 Hz) which corresponds to FNSM, and the appearance of a doublet at -136.6 (d, J = 29.3 Hz) along with other very small peaks. After a simple workup, the product was extracted in dichloromethane, dried with sodium sulfate and the solvent was removed to give a light yellow oily liquid which was sufficiently pure, as evidenced by its 1 H and 13 C NMR spectra. Its 13 C NMR spectrum had doublet carbon peaks at 122.1 (d, J= 289.3 Hz), 72.3 (d, J= 22.8 Hz), 169.2 (d, J= 2.9 Hz). The coupling constant values of 289.3, 22.8 and 2.9 Hz are consistent with the splitting pattern displayed by a carbon atom present at , β and γ positions, respectively from a fluorine atom. The integration of the 1 H NMR peaks was also consistent with the structure of the product 6b expected from the Mannich type combination of the educts FNSM, N, N-diethylamine and glyoxylic acid. Scheme 3.4 Reaction of N, N-dimethylamine and glyoxylic acid with α-fluoro- bis(phenylsulfonyl)-methane (FBSM, 1b) or α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM, 1c). 92 Next, we tested the ability of α-fluoro-bis(phenylsulfonyl)-methane (FBSM, 1b) to undergo similar reaction with N, N-diethylamine and glyoxylic acid to form the corresponding fluorinated α-amino acid derivative. As before, by varying the reaction in different solvents, we found that the α-amino acid synthesis reaction had the highest yield in ethanol (Table 3.3, Entry 2) with a reactant ratio FBSM/glyoxylic acid/amine = 1:1.5:2. Ethanol is a polar protic solvent with a high dielectric constant of 24.55. As in the case of the synthesis of fluorinated β-amino esters, the high dielectric constant has a similar positive effect on the α-amino acid yield via the improved solvation of the reaction intermediates. Such high dielectric constant solvents may help in the stabilization of reaction intermediates through increased hydrogen bonding. Table 3.3 Reactions of FBSM with N, N-diethylamine and glyoxylic acid in different solvents [a] We synthesized fluorinated α-amino acids 5a and 5b using the above techniques (Table 4, Entries 1, 2). When α-fluoro-α-nitro(phenyl-sulfonyl)methane (FNSM) was used instead of 93 FBSM, the reaction had a high (80%) product yield (Table 4, Entry 3). Unlike in the case of EFPA-based reactions for the synthesis of fluorinated β-amino esters, the multi-component reactions using FNSM and FBSM did not require the addition of a base, possibly due to the higher acidity of FNSM and FBSM (pK a ~ 6 and ~11 in DMSO) compared to that of EFPA (pK a ~ 12.5 in DMSO). Table 3.4 Fluorinated α-amino acids via three component reactions of α-fluoro- bis(phenylsulfonyl)-methane (FBSM, 1b) or α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM, 1c), primary amines/secondary amines and glyoxylic acid [a] 94 3.3 Chapter 3: Conclusions In conclusion, we have succeeded in developing, for the first time, a multi-component protocol for the facile synthesis of fluorinated β-amino esters by using fluorinated carbon pronucleophile ethyl 2-fluoro-2-(phenylsulfonyl)acetate (EFPA, 1a), formaldehyde and amines. The reaction of α-fluoro-bis(phenylsulfonyl)-methane (FBSM, 1b) or α-fluoro-α-nitro(phenyl- sulfonyl)methane (FNSM, 1c) with glyoxylic acid and amines gave α- amino acid derivatives. The reactions are performed under relatively mild conditions and have been shown to be feasible for both primary and secondary amines with no base being required for generating fluorinated α- amino acids. So far, the reaction is limited to aliphatic amines. However, in order to fully explore the breadth and applicability of this novel synthetic methodology, additional amine substrates should be tested under further optimized reaction conditions. 3.4 Chapter 3: Experimental 3.4.1 General 1 H, 13 C, and 19 F NMR spectra were recorded on Varian NMR spectrometers at 400 MHz. Structures of the known substrates 1a-c were confirmed by comparison of the spectral data with those of standard samples. 26 1 H NMR chemical shifts were determined relative to tetramethylsilane at δ 0.0 ppm as an internal standard. 13 C NMR chemical shifts were determined relative to the internal tetramethylsilane at δ 0.0 ppm or 13 C signal of CDCl 3 at δ 77.16 ppm. 19 F NMR chemical shifts were determined relative to CFCl 3 at δ 0.0 ppm as internal standard. High Resolution Mass Spectrometry (HRMS) analysis of samples was performed at the University of Arizona in ESI and CI modes. 95 Anhydrous Lithium carbonate, paraformaldehyde and formalin were purchased from Mallinckrodt. Ethyl 2-fluoro-2-(phenylsulfonyl)acetate (EFPA, 1a), α- fluorobis(phenylsulfonyl)methane (FBSM, 1b) and α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM, 1c) were prepared by the electrophilic fluorination of the corresponding 2- phenylsulfonyl) methanes with Selectfluor in the presence of NaH in THF/DMF following a previously reported procedure. 27 3.4.2 Experimental Procedures General procedure for the synthesis of fluorinated β-amino esters: Formaldehyde (0.24 mmol, 1.5 equivalent), and amine (0.32 mmol, 2 equivalent) were stirred in CH 3 CN (2 mL) in a pressure tube at room temperature for 0.5 hr. Ethyl 2-fluoro-2-(phenylsulfonyl)acetate (EFPA, 1a) (25.56 % by weight in toluene) (0.16 mmol, 1 equivalent) was added to the reaction mixture followed by the addition of Li 2 CO 3 or Cs 2 CO 3 (0.24 mmol, 1.5 equivalent) and more CH 3 CN (1 mL). The mixture was stirred at room temperature for 1 h and then at 80 o C for 1 h. Completion of the reaction was confirmed by 19 F NMR/TLC analysis of the reaction mixture. The reaction mixture was extracted with CH 2 Cl 2 (2 mL) and washed with water. The organic phase was dried with anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated under reduced pressure in a rotary evaporator and the residue was purified using column chromatography. The molecular structure of the product was identified by NMR analysis ( 1 H, 13 C, and 19 F) and HRMS. General procedure for the synthesis of fluorinated α-amino acids: Glyoxylic acid (0.24 mmol, 1.5 equivalent), and amine (0.32 mmol, 2 equivalent) were stirred in CH 2 Cl 2 (2 mL) in a pressure tube at room temperature for 1 h. Fluorine-substituted active methylene compound FBSM (1b) or FNSM (1c) (0.16 mmol, 1 equivalent) was dissolved in CH 2 Cl 2 (2 mL) and the 96 solution was added drop wise to the reaction mixture at room temperature. The reaction mixture was stirred for 12 h. After confirming the completion of the reaction by 19 F NMR/TLC analysis, the reaction mixture was extracted with CH 2 Cl 2 (2 mL) and washed with water. The organic phase was dried with anhydrous Na 2 SO 4 and filtered. The filtrate was evaporated under reduced pressure in a rotary evaporator to furnish the desired of sufficient spectroscopic purity. The molecular structure of the product was identified by NMR analysis ( 1 H, 13 C, and 19 F). 3.4.3 Spectral Data and Representative Spectra Ethyl 3-(tert-butylamino)-2-fluoro-2 (phenylsulfonyl)propanoate (4a) 1 H NMR (400 MHz, CDCl3) δ= 1.05 (s, 9H), 1.23 (t, J = 7.1 Hz, 3H), 1.58 (s, 1H), 3.35 (t, J = 12.8 Hz, 1H), 3.60 (dd, J = 34.6 Hz, 13.2 Hz, 1H), 4.20 (q, J = 7.1Hz, 2H), 7.59 (t, J = 7.7, 2H), 7.69 – 7.76 (m, 1H), 7.93 (d, J = 7.5, 2H). 13 C NMR (100 MHz, CDCl 3 ) δ= 13.91, 28.84, 43.01 (d, J = 18.6 Hz), 50.61, 63.0, 107.33 (d, J = 231.6 Hz), 129.13, 130.17, 134.93, 134.97, 163.01, 163.26 (d, J = 25.6 Hz). 19 F NMR (376 MHz, CDCl 3 ): δ = -162.41 (dd, J = 34.60 Hz, 13.50 Hz). HRMS (ESI): m/z calcd. for C 15 H 23 FNO 4 S [(M+H) + ] 332. 13263, found 332.13208. Ethyl 3-adamantan-1-ylamino)-2-fluoro-2-(phenylsulfonyl)propanoate (4b) 19 F NMR (376 MHz, CDCl 3 ): δ = -162.54 (dd, J = 35.33 Hz, 12.33 Hz). HRMS (ESI): m/z calcd. for C 21 H 28 FNO 4 S [(M+H) + ] 332. 13263, found 332.13208. 97 Ethyl 3-(cyclopentylamino)-2-fluoro-2-(phenylsulfonyl)propanoate (4c) 19 F NMR (376 MHz, CDCl 3 ): δ = -161.94 (dd, J = 35.33 Hz, 12.33 Hz). HRMS (ESI): m/z calcd. for C 16 H 23 FNO 4 S [(M+H) + ] 344.13263, found 344.13195. Ethyl 2-fluoro-3-(phenethylamino)-2-(phenylsulfonyl)propanoate(4d) 19 F NMR (376 MHz, CDCl 3 ): δ = -161.50 (dd, J = 35.33 Hz, 12.33 Hz). Ethyl 2-fluoro-3-hydroxy-2-(phenylsulfonyl)propanoate(10) 19 F NMR (376 MHz, CDCl 3 ): δ = -163.96 (dd, J = 25.70 Hz, 15.16 Hz). HRMS (ESI): m/z calcd. for C 11 H 13 FNaO 5 S [(M+Na) + ] 299.03599, found 299.03660 98 2-(diethylamino)-3-fluoro-3,3-bis(phenylsulfonyl)propanoic acid (5a) 1 H NMR (400 MHz, CDCl3) δ= 9.54(broad, 1H), 8.09 (m, 4H), 7.98 (m, 2H), 7.90 (m, 4H), 4.44 (d, 6.24 Hz, 1H), 3.01 (q, J = 7.02 Hz, 4H), 1.35 (t, J = 7.02 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ):  = 170.19 (d, 3 J C-F = 2.21 Hz), 137.05, 134.89, 131.42, 129.43, 113.78 (d, 1 J C-F = 270.94 Hz), 70.46 (d, 2 J C-F = 17.67 Hz), 42.63, 11.86. 19 F NMR (376 MHz, CDCl 3 ): δ = -136.84 (d, J = 5.94 Hz). 2-(diethylamino)-3-fluoro-3-nitro-3-(phenylsulfonyl)propanoic acid (6a) 1 H NMR (400 MHz, CDCl3) δ= 9.01 (broad, 1H), 8.09 (m, 2H), 7.75 (m, 1H), 7.59 (m, 2H), 5.08 (d, 29.28 Hz, 1H), 2.89 (q, J = 7.03 Hz, 4H), 1.20 (t, J = 7.03 Hz, 6H). 13 C NMR (100 MHz, CDCl 3 ):  = 169.17 (d, 3 J C-F = 2.95 Hz), 135.61, 133.76, 131.71, 128.89, 122.13 (d, 1 J C-F = 289.34 Hz), 72.35 (d, 2 J C-F = 22.82 Hz), 42.48, 11.12. 19 F NMR (376 MHz, CDCl 3 ): δ = - 136.58 (d, J = 29.28 Hz). 2-(cyclopentylamino)-3-fluoro-3,3-bis(phenylsulfonyl)propanoic acid (5b) 19 F NMR (376 MHz, CDCl 3 ): δ = -136.32 (d, J = 6.3 Hz). 99 19 F NMR of 2-(diethylamino)-3-fluoro-3-nitro-3-(phenylsulfonyl)propanoic acid 100 1 H NMR of 2-(diethylamino)-3-fluoro-3-nitro-3-(phenylsulfonyl)propanoic acid 101 13 C NMR of 2-(diethylamino)-3-fluoro-3-nitro-3-(phenylsulfonyl)propanoic acid 102 19 F NMR of ethyl 3-(tert-butylamino)-2-fluoro-2 (phenylsulfonyl)propanoate (4a) 1 H NMR of ethyl 3-(tert-butylamino)-2-fluoro-2 (phenylsulfonyl)propanoate (4a) 103 13 C NMR of ethyl 3-(tert-butylamino)-2-fluoro-2 (phenylsulfonyl)propanoate (4a) s 104 3.5 Chapter 3: References 1. 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Chem. 2008, 4, 17. 106 Chapter 4: Electrophilic Amination of Aromatics with Sodium Azide in BF 3 -H 2 O 4.1 Chapter 4: Introduction Boron trifluoride was first prepared by Gay-Lussac and Thenard 1 in 1809 and since then, chemists have explored the remarkable propensity of this Lewis acid to form coordination compounds with a variety of Lewis n-donor bases such as water and alcohols in giving rise to strong conjugate Brønsted acid systems. 2 Unlike the other boron trihalides, boron trifluoride resists hydrolysis to boric acid and combines readily with water, resulting in highly acidic Brønsted acid solutions, the strength of which depends on the amount of water present. 3 Meerwein and collaborators 4 found that boron trifluoride forms stable monohydrate and dihydrate complexes which they prepared, characterized, and showed to be highly ionized in the liquid state. 5 Boron trifluoride dihydrate, BF 3 -2H 2 O, exists in the liquid state predominately as the ionic form, [H 3 O] + [BF 3 OH] - , and has a Hammett acidity of H o = -6.85, which is of the same order of acidity as that of 100% nitric acid. 3-4 On the other hand, the monohydrate complex BF 3 - H 2 O exists in the liquid state as [H] + [BF 3 OH] - 5 and with a Hammett acidity of H o = -11.4, it is significantly more acidic than the dihydrate complex, its acidity being similar in strength to that of anhydrous sulfuric acid. 3-4 Farcasiu and Ghenciu 3c investigated the Hammett acidity of boron trifluoride water complexes and found that boron trifluoride monohydrate is a superacid with H 0 <-14. Boron trifluoride monohydrate is a colorless fuming liquid with a density of 1.8 g/mL and melting point of 6.2 °C. 107 With a Hammett acidity value (H o ) of -14.1, triflic acid (trifluoromethanesulfonic acid, CF 3 SO 3 H) is a superacid according to the widely accepted definition of superacids by Gillespie 6 that acids having an H 0 ≤ −12 are considered superacids. Triflic acid has, in general, been the superacid of choice in studying superacid catalyzed reactions that proceed by superelectrophilic activation. However, a major drawback of triflic acid is its expense, which limits the opportunity to conduct many of these novel transformations on a larger scale. On the other hand, BF 3 -H 2 O can be conveniently and inexpensively prepared in the laboratory by simply bubbling boron trifluoride gas in water with cooling and can be stored at -20 o C in Nalgene® bottles for more than a year without appreciable loss of activity. Its H 0 value of ~ -11.4 qualifies it as a superacid as well. Like triflic acid 7 , boron trifluoride monohydrate is non-oxidizing in nature, which can be critically important when dealing with reactions that are sensitive to oxidation. Consequently, boron trifluoride monohydrate has been described in the literature as an efficient and inexpensive acid catalyst in comparison to expensive superacids such as triflic acid in a variety of organic transformations. It has been used in the oligomerization of 1-alkenes, 8 alkylation of aromatics with alkenes, 9 the Koch-Haaf carbonylation of alkenes or alcohols to carboxylic acids, 10 the Ritter reaction of alkenes to formamides, 11 deuteration of activated aromatics and polycyclic aromatics using BF 3 -D 2 O, 12 and the ionic hydrogenation of polycyclic aromatics, 13 aromatic organosulfur compounds 14 and disubstituted naphthalenes 15 in the presence of triethylsilane and also in the presence of catalytically active hydrogen. 16 Owing to our interest in developing acid catalyzed methodology, Olah and co-workers have reported the utility of boron trifluoride monohydrate in the thioacetalization of ketones and aldehydes with 1,2-ethanedithiol, 17a one-flask preparation of sulfides from carbonyl compounds with thiols and triethylsilane, 17b the nitration of aromatics with either potassium nitrate or nitric 108 acid, 17c the 2,2,2-trifluoro-1-(ethylthiol)ethylation of aromatics with trifluoroacetaldehyde hydrate and ethanethiol, 17d the preparation of nitrite free alkyl nitrates from alcohols, 17e the preparation of symmetric bisulfides via reductive thiolation of dicarbonyl with thiols or of carbonyl compounds with dithiols, 18a electrophilic halogenations of arenes with N- halosuccinimides, 18b the Fries rearrangment, 18c and hydroxyalkylation of arenes with pyridinecarboxaldehydes and quinolinecarboxaldehydes to form diaryl- methylpyridines and diarylmethylquinolines, 18d hydroxyalkylation of arenes with benzaldehyde, and dialdehydes to form triarylmethanes, triarylmethane aldehydes and anthracenes, 18e synthesis of 1,1,1-trifluoro- and 1,1-difluoro-2,2-diarylethanes from arenes and fluorinated hemiacetals, 18f and condensation of aryldiamines with ketones to form perimidine and 1,5-benzodiazepine derivatives. 18g Scheme 4.1 shows selected BF 3 -H 2 O catalyzed reactions that our group has investigated over the years. Scheme 4. 1 Selected reactions catalyzed by BF 3 -H 2 O. 109 On the other hand, aromatic amines are synthetically valuable intermediates. Aniline, the simplest of the aromatic amines, was discovered in 1826 by Otto Unverdorben. In 1856, William Henry Perkin discovered the first aniline dye Mauveine. Since their initial use as precursors to dyes, aromatic amines have found widespread use in pharamaceuticals, agrochemicals, polymers etc. 19 Commercially, primary aromatic amines are prepared via nitration of aromatics followed by hydrogenation of nitroarenes over metal based catalysts. 20 They can also be prepared by nucleophilic aromatic substitution of haloarenes with amines. 21 Coupling aryl triflates with primary amides in the presence of a palladium catalyst also furnishes primary aromatic amines. 22 Recently, several methods have been reported wherein primary aromatic amines are obtained via electrophilic amination of aryl boronic acids. 23 The simplest of the synthetic methods for the synthesis of primary aromatic amines, however, would be direct amination of aromatic compounds. Many of the single-step production of primary aromatic amines via the direct amination of aromatics have focused on the use of gaseous ammonia as the aminating agent. However, the strength of the N–H bond in ammonia (107 kcal mol−1) makes the “N–H activation” challenging. 24 Therefore, noble-metal and transition-metal catalysts and rigorous reaction conditions (high temperature and high pressure) are required to activate the N-H bond of gaseous ammonia. 25 Moreover, the aniline yield in these reports is low even at high temperature and high pressure, for example, less than 10% conversion at 623 K and 30 MPa. 25a, 26 Hydroxylammonium chloride is another aminating agent that has been used for the direct electrophilic amination of aromatics in the presence of Friedel-Crafts catalysts. 27 Other reagents such as hydroxylamine and its salts, 28a alkylhydroxylamines, 28b hydroxylamine-O-sulfonic acid, 28c,d and hydrazoic acid. 28e have also been used for amination of aromatics. 110 Schmidt was the first obtain aniline from benzene by sodium azide in concentrated sulfuric acid, albeit in low yield. 29a Hoop and Tedder found that solutions of sodim azide in concentrated sulfuric acid were able to aminate a wide variety of aromatic nuclei, but the yields of amines were very low. 29b They concluded that except with mesitylene, which gave a mixture of mesidine, diaminomesitylene and 3-amino-2,4,6-trimethylbenzenesulfonic acid, solutions of hydrazoic acid in sulfuric acid have little value as aminating agents. Kovacic and co-workers compared the reaction of hydrazoic acid with toluene in presence of sulfuric acid and aluminum chloride and found that aluminum chloride gave higher yield of toluidines. 28e Olah and co- workers were able to show by NMR spectroscopy 29c that protonation of hydrazoic acid and methyl or ethyl azides with superacids FSO 3 H/SbF 5 , HF/SbF 5 , or HF/BF 3 results in the formation of stable aminodiazonium ions. The aminodiazonium ion was also prepared in situ from NaN 3 /A1C1 3 /HC1 or (CH 3 ) 3 SiN 3 /A1C1 3 /HC1 [(CH 3 ),SiN 3 /HF/BF 3 ]. For the purpose of direct amination of aromatics, aminodiazonium ion was prepared by reacting sodium azide (or trimethylsilyl azide) with anhydrous aluminum chloride and subsequently with dry hydrogen chloride gas to form the aminodiazonium tetrachloroaluminate. Olah and co-workers subsequently reported 29d trimethylsilyl azide/triflic acid as a highly improved reagent system that allowed simple and efficient direct amination of aromatics. Primary aromatic amines can also be obtained from the reaction of hydrazoic acid with aromatics in presence of both trifluoromethanesulfonic acid (TFSA) and trifluoroacetic acid (TFA). 29e However, the use of an excess amount aromatic compounds and low reaction regioselectivity are the drawbacks of these methods. Moreover, the yields are based on the aminating agent and not on the aromatic substrates to be aminated. Borodkin and co-workers 29f have reported direct one step amination of aromatics by using NaN 3 /Triflic Acid/Aromatics in molar ratio of 1:3:1. However, the 111 reaction was successful only in the case of very active substrates mesitylene and methyl substituted aromatics. Also, the reactions were carried out under ultrasonic irradiation for 8-11h followed by incubation for 4 days. Based on our previous work on utilization of boron trifluoride monohydrate as a readily available and significantly cheaper alternative to triflic acid, we hypothesized that boron trifluoride monohydrate could be used for the protonation of sodium azide to generate aminodiazonium ion in situ which could then be used for the electrophilic amination of aromatics. Scheme 4.2 Electrophilic Amination of Aromatics. 4.2 Chapter 4: Results and Discussion At first, we prepared boron trifluoride monohydrate by bubbling boron trifluoride gas into distilled water in a Nalgene® bottle placed in a dry ice-acetone bath while swirling and shaking the bottle to mix the contents. When the weight of the complex began to remain constant at a weight corresponding to a ratio of 1:1 for the BF 3 -H 2 O complex, the process was stopped. Next we investigated the potential of the thus obtained thick, viscous and colorless liquid BF 3 - H 2 O complex to aminate aromatics. 112 Table 4.1 A survey of reaction conditions for the amination of Toluene with NaN 3 and BF 3 -H 2 O Initially, we stirred NaN 3 in a large excess of toluene (~2200 equiv.) in the presence of boron trifluoride monohydrate (10 equiv.) at 55 o C for an hour and were able to obtain the desired product toluidines in 28% yield (Table 4.1, Entry a). A longer reaction time improved the yield, but the effect was not much pronounced (Table 4.1, Entry b, c). Even when a much smaller amount of toluene was used, the desired product was obtained in a comparable yield under the same conditions (Table 4.1, Entry d). Therefore, in the next experiment (Table 4.1, Entry e) we used an equimolar amount of toluene. However, we also increased the boron trifluoride monohydrate by three folds so that it could act as a protic medium for the dissolution of the 113 inorganic salt NaN 3 , in addition to providing acidity required for the protonation of the azide anion. This time we were able to obtain the desired product toluidines in 75% yield (Table 4.1, Entry 5). The relative ratio of the ortho, meta and para isomers of toluidine was 61:6:33 as shown by 1 H NMR and GCMS analysis (Table 4.2, Entry b). Table 4.2 Primary Amination of Arenes with NaN 3 and BF 3 -H 2 O 114 Various aromatic substrates were reacted with NaN 3 under similar reaction conditions. As shown in the summary of results in Table 4.2, alkyl benzenes reacted with NaN 3 to give the corresponding primary aromatic amines in good yield. Highly activated arene methoxybenzene also reacted in good yield (Table 4.2, Entry f) with an ortho, meta and para isomer distribution ratio of 36:7:57. The amination of unsubstituted arene benzene gave aniline in a moderate yield (Table 4.2, Entry a). By contrast, highly deactivated arenes reacted only sluggishly. While fluorobenzene reacted to give the corresponding fluoroanilines, albeit in low yield( Table 4.2, Entry g), only trace amounts of nitroanilines were observed in the case of nitrobenzene even after prolonged heating (Table 4.2, Entry h). Therefore, as in other electrophilic amination procedures reported earlier, 29c,d,f this amination procedure is not suitable for substrates that are strongly deactivated by electron withdrawing groups. Nevertheless, our present protocol for primary aromatic amines via the direct amination of aromatics provides several advantages. In our present work, we have used sodium azide, which is much more atom economic than the previously reported aminating agents hydroxylammonium choride, 27 hydroxylamine salts, 28a hydroxylamine-O-sulfonic acid, 28c,d and trimethylsilyl azide. 29c,d Unlike these previous reports, which used an excess of aromatics, in our present research we have used the aminating agent and the aromatics in an equimolar amount, while achieving decent yields of the products. Therefore, from the perspective of atom economy, our present work offers a viable alternative to the previously reported direct amination of aromatics. Boron trifluoride monohydrate can be prepared in the laboratory by a simple procedure from boron trifluoride and water. As an easy to prepare efficient non-oxidizing Brønsted acid catalyst with sufficient acidity required for the reaction, boron trifluoride monohydrate offers a readily available and significantly inexpensive alternative to triflic acid, 115 which was previously used in the direct amination of aromatics. 29d,f It also provides a metal free alternative to previously used metal based solid acid AlCl 3 . 28d In our reactions, boron trifluoride monohydrate also acts as an effective protic solvent for the sodium azide, an inorganic salt. Thus, by avoiding the use of organic solvents the use of boron trifluoride monohydrate reduces waste- generation and makes the reaction environmentally friendlier. The direct amination of aromatics with NaN 3 in the presence of boron trifluoride monohydrate can be presumed to undergo through a mechanism similar to the one proposed by Olah and co-workers in earlier studies. 29c Hydrazoic acid m is formed in situ by the reaction of sodium azide with boron trfiluoride monohydrate (Scheme 4.3, i). Under superacidic stable ion conditions, hydrazoic acid is protonated at the nitrogen atom already bonded to a hydrogen atom to form aminodiazonium ion, the isomers n, o and p of which are shown in Scheme 4.3, ii. The aminodiazonium hydroxyl boron trifluoride r acts as a synthon for the nitrenium ion “NH 2 , + ” which undergoes electrophilic addition to the aromatic substrate with the elimination of nitrogen and boron trifluoride gases along with water (Scheme 4.4, i). It is also possible that nitrenium ion formed by the elimination of nitrogen gas from aminodiazonium ion (Scheme 4.4, ii) is the reactive species, as earlier presumed by Borodkin and co-workers. 29f 116 Scheme 4.3 (i) Formation of Hydrazoic Acid; (ii) Formation of Aminodiazonium Ion. Scheme 4. 4 Mechanism for the Electrophilic Amination of Aromatics. 117 4.3 Chapter 4: Conclusions We have described an effective protocol for the synthesis of primary aromatic amines directly from aromatics by using sodium azide in the presence of boron trifluoride monohydrate. Boron trifluoride monohydrate acts as an effective protic solvent for the sodium azide and also provides sufficient acidity for the protonation of azide ion to eventually generate aminodiazonium ion which acts as the nitrenium ion “NH 2 + ” that undergoes electrophilic addition to the aromatics, to give primary aromatic amines. Unlike previous reports of electrophilic amination of aromatics which used an excess of aromatics, our reactions use both the aminating agent and the aromatic substrate are used in equimolar amounts. Our study also demonstrates that for the purpose of electrophilic amination, an easy to make inexpensive boron trifluoride monohydrate can be used as an effective substitute for expensive superacids such as triflic acid. 4.4 Chapter 4: Experimental 4.4.1 General General: Unless otherwise mentioned, all chemicals were purchased from commercial sources and used as received. 1 H, and 19 F NMR spectra were recorded on a Varian NMR at 400 MHz. 1 H NMR chemical shifts were determined relative to tetramethylsilane (TMS) as the internal standard at δ 0.0 ppm. 19 F NMR chemical shifts were determined relative to CFCl 3 as the internal standard at δ 0.0 ppm. Gas chromatograms were recorded on Bruker 450-GC and mass spectra were recorded on Bruker 300-MS in the ESI mode. The products were characterized by comparing their spectral data with those reported in the literature. The ortho, meta and para isomeric ratios of the products were determined based on 1 H NMR, 19 F NMR and GCMS. 118 4.4.2 Experimental Procedures General Procedure for the Preparation of BF 3 -H 2 O(1:1) Complex: Caution: BF 3 forms toxic aerosol clouds. Therefore, the whole procedure was carried out in a well ventilated hood. In a Nalgene® bottle (500 mL wide mouthed polypropylene bottle from VWR), distilled water (36 g, 2 mol) was taken and fitted with a cap equipped with an inlet reaching the bottom. BF 3 was passed carefully into the bottle at -78 o C 1 while swirling and shaking the bottle to mix the contents, followed by measuring the weight of the complex. The process was continued until the weight of the complex started to remain constant at 134 g, which corresponds to a ratio of 1:1 for the BF 3 -H 2 O complex. Since the formation of BF 3 -H 2 O was highly exothermic, Nalgene® bottle was placed in a dry-ice acetone bath intermittently when BF 3 was bubbled into water. When the complex solidified and bubbling of BF 3 became difficult, the bottle was taken out of the bath intermittently and was placed back in the dry-ice acetone bath after the melting took place. The bottle cap was occasionally opened to release the pressure of excess BF 3 . General Procedure for the Amination of Arenes with NaN 3 and BF 3 -H 2 O: After allowing the solidified BF 3 -H 2 O stored at -20 o C to thaw into liquid at room temperature, in a well ventilated fume hood the fuming liquid BF 3 -H 2 O (300 mmol, 25.74 g) was poured and weighed into a 25 mL conical flask and quickly added to NaN 3 (10 mmol, 0.65 g) in a 125 mL glass pressure tube. Then a volume of selected arene (10 mmol) was added via a syringe, the pressure tube was sealed and the reaction mixture was stirred at 55 o C for a specified time indicated in Table 4.2, which had been determined by carrying out the same experiment at a smaller scale. The solution was then cooled to room temperature and poured onto ice. The solution was neutralized and then 119 made basic by adding NaOH pellets slowly until a pH of about 13 was reached, as indicated by pH paper. The arylamines were then extracted with diethyl ether (3X) and dried over sodium sulfate. Product arylamines were isolated after evaporating the solvent and were analyzed by GCMS and NMR analysis. 4.4.3 Spectral Data and Representative Spectra 1. Substrate: Benzene Aniline 30, 31 : 1 H NMR (400 MHz, Chloroform-d) δ = 3.58 (br, s, 2H), 6.66 (d, J=8.5 Hz, 2H), 6.75 (t, J=7.4 Hz, 1H), 7.15 (t, J=7.4 Hz, 2H). 2. Substrate: Toluene 2-Methylbenzeneamine 31, 32 : 1 H NMR (400 MHz, Chloroform-d) δ = 2.13 (s, 3H), 3.53(br, s, 2H), 6.61 – 6.66 (m, 1H), 6.66 – 6.74 (m, 1H), 6.97 – 7.08 (m, 1H). 3-Methylbenzeneamine 31 : 1 H NMR (400 MHz, Chloroform-d) δ = 2.25 (s, 3H), 3.53(br, s, 2H), 6.47 (m, 1H), 7.03 (m, 1H). Multiplets at 6.49 and 6.56 ppm (1 H each) are not visible due to either being too small (3-Methylbenzeneamine is only 6% of the three isomers) or overlapping with peaks from the other isomers. 4-Methylbenzeneamine 31 : 1 H NMR (400 MHz, Chloroform-d) δ = 2.23 (s, 3H), 3.53(br, s, 2H), 6.55 – 6.60 (m, 2H), 6.90 – 6.97 (m, 2H). 3. Substrate: Ethylbenzene 2-Ethylbenzenamine 31 : 1 H NMR (400 MHz, Chloroform-d) δ = 1.24 (t, J=7.6 Hz, 3H), 2.5 (q, J=7.5 Hz, 2H), 3.55 (br, s, 2H), 6.66 (dd, J=7.8 Hz, 1.2 Hz, 1H), 6.75 (td, J=7.4 Hz, 1.2 Hz, 1H), 7.00 – 7.03 (m, 1H), 7.04 – 7.08 (m, 1H). 120 4-Ethylbenzenamine 31 : 1 H NMR (400 MHz, Chloroform-d) δ = 1.18 (t, J=7.6 Hz, 3H), 2.53 (q, J=7.5 Hz, 2H), 3.55 (br, s, 2H), 6.61 (d, J=8.4 Hz, 2H), 6.95 – 7.01 (d, J=8.4 Hz, 2H). 4. Substrate: p-xylene 2,5-Dimethylaniline 31 : 1 H NMR (400 MHz, Chloroform-d) δ = 2.12 (s, 3H), 2.24 (s, 3H), 3.52(br, s, 2H), 6.50 (s, 1H), 6.52 (d, J=7.6 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H). 5. Substrate: m-xylene 2,3-Dimethylaniline 31, 33 : 1 H NMR (400 MHz, Chloroform-d) δ = 2.06 (s, 3H), 2.26 (s, 3H), 3.47 (br, s, 2H), 6.54 (d, J=7.9 Hz, 1H), 6.62 (d, J=7.5 Hz, 1H), 6.89 (m, 1H). 3,4-Dimethylaniline 30,31 : 1 H NMR (400 MHz, Chloroform-d) δ = 2.14 (s, 3H), 2.17 (s, 3H), 3.47 (br, s, 2H), 6.44 (dd, J=7.9 Hz, 2.4, 1H), 6.49 (d, J=2.3 Hz, 1H), 6.91 (m, 1H). 6. Substrate: Methoxybenzene 2-Methoxyaniline 31, 32 : 1 H NMR (400 MHz, Chloroform-d) δ = 3.40-3.49 (br, s, 2H), 3.82 (s, 3H), 6.76-6.82 (m, 4H; not visible due to overlapping with peaks from aromatic Hs from p- Methoxybenzene). 3- Methoxyaniline 31, 32: 1 H NMR (400 MHz, Chloroform-d) δ = 3.40-3.49 (br, s, 2H), 3.74 (s, 3H), 6.29-7.17 (m, 4H; not visible due to overlapping with peaks from aromatic Hs from p- Methoxybenzene). 4- Methoxyaniline 31, 35: 1 H NMR (400 MHz, Chloroform-d) δ = 3.40-3.49 (br, s, 2H), 3.72 (s, 3H), 6.62 (d, J=8.8 Hz, 2H), 6.73 (d, J=8.8 Hz, 2H). 121 7. Substrate: Fluorobenzene 2-Fluoroaniline 34, 35 : 19 F NMR (376 MHz, Chloroform-d) δ = -138.71 – -132.60 (m). 1 H NMR (400 MHz, Chloroform-d) δ = 3.71 (br, s, 2H), 6.64 – 6.71 (m, 2H), 6.89 – 6.95 (m, 2H). 3- Fluoroaniline 34 : 19 F NMR (376 MHz, Chloroform-d) δ = -113.20 (ddd, J=10.7 Hz, 8.7 Hz, 6.8 Hz). 4- Fluoroaniline 34, 35 : 19 F NMR (376 MHz, Chloroform-d) δ = -126.88 (dt, J=8.5 Hz, 4.2 Hz). 1 H NMR (400 MHz, Chloroform-d) δ = 3.53 (br, s, 2H), 6.59 (m, 2H), 6.84 (m, 2H). 122 1 H NMR of Fluoroanilne (o:m:p =21:6:73) 123 19 F NMR of Fluoroanilne (o:m:p =21:6:73) 124 GC/MS of 2-Fluoroaniline (selected peak) in a mixture of its isomers (o:m:p =21:6:73) 125 4.5 Chapter 4: References 1. Gay-Lussac, J. L.; Thenard, L. J. Ann. Chim. 1809, 69, 204-220. 2. Topchiev, A. V.; Zavgorodnii, S. V.; Paushkin, Y. M. Boron Trifluoride and its Compounds as Catalysts in Organic Chemistry, Pergamon: New York, 1959. 3. a) Rochester, C. 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As depicted in Scheme 5.1, 1 such dual reactivity allows nitroso compounds to participate in many chemical transformations, 2 such as ene reactions, 1 nitroso aldol reactions, 3 coupling reactions with alkynes 4 and amines 5 and Grignard reactions. 6 Nitroso compounds have also been exploited in various cycloaddition reactions 7 and redox reactions. 8,9 In addition to these synthetic utilities, nitrosobenzenes have also been utilized as radical scavengers, 10 antioxidants in lubricating oil, 11 metal coordinating agents 12 and antiviral compounds. 13 Although nitroso compounds have been widely utilized, facile synthetic approach towards these compounds is still limited. To date, a number of methods have been developed for aromatic nitrosoarene synthesis, including oxidation of aniline derivatives (Scheme 5.2, Eq. 1), reduction of nitroarenes (Scheme 5.2, Eq. 2), and electrophilic nitrosation of aryl metallic compounds (Scheme 5.2, Eq. 3). 14,15 Direct nitrosation of arenes can also be achieved using nitrosonium salts (NO + X − ) 16 through a Wheland intermediate (Ar(H)NO + ) (Scheme 5.2, Eq. 4). 17 In addition to nitrosonium salts, other nitrosating agents, such as alkyl nitrites, 18 have also been utilized. Despite the fact that many nitrosoarenes have been obtained via the above mentioned methods, these methods remain disadvantaged in some aspects, such as substrate scope, regioselectivity or the availability of relevant reagents. Recently, Molander and co-worker disclosed the facile ipso-nitrosation of aryl and heteroaryltrifluoroborates as well as arylboronic acid and esters using nitrosonium tetrafluoroborate (NO + BF 4 - ), which demonstrates remarkable selectivity and substrate scope (Scheme 5.2, Eq. 5). 19 129 Scheme 5.1 Chemical transformations of nitroso compounds. Scheme 5.2 Synthetic routes towards nitrosoarenes. 130 Scheme 5.3 ipso-nitration of arylboronic acids with MNO 3 and TMSCl. Scheme 5.4 Proposed mechanism of ipso-nitrosation of phenylboronic acid with NaNO 2 and TMSCl. Our research group previously reported the ipso-nitration of arylboronic acids using chlorotrimethylsilane (TMSCl) and nitrate salts, 20 (Scheme 5.3) via the in situ generation of the nitrating species TMSONO 2 . On the basis of this report, we envisioned expected that aromatic nitrosation of arylboronic acids could be achieved using TMSCl and nitrite salts via a similar pathway (Scheme 5.4). It is worth noting that trimethylsilyl nitrite (TMS-O-NO), the proposed 131 key reaction intermediate has been previously proposed and utilized. 21a Yamamoto et al. recently showed that in situ generated R 3 SiONO could serve as an effective nitrosating reagent to oxidize silyl enol ethers. 21b Here we describe the ipso-nitrosation of arylboronic acids with readily available nitrosating reagents sodium nitrite and TMSCl (Scheme 5.4). 5.2 Chapter 5: Results and Discussion Our investigation began with 4-methoxyphenylboronic acid (4-MeOPhB(OH) 2 ) which was expected to possess enhanced reactivity due to the electron-donating MeO-group. The reaction was performed by adding 4-MeOPhB(OH) 2 (1.0 equiv, 93% boroxine content, determined by 1 H NMR) 22 to a stirred mixture of NaNO 2 (2.2 equiv) and TMSCl (2.2 equiv) in anhydrous dichloromethane under argon at room temperature. GC–MS analysis of the reaction mixture did not show any detectable progress even after stirring for 72 h (Table 5.1, entry 1). This unsuccessful result was probably due to the low ionic dissociation constant of sodium nitrite in dichloromethane. Further investigation was thus carried out under similar reaction conditions with the addition of 0.5 equiv of water (Table 5.1, entry 2). GC–MS and TLC analysis of the reaction mixture indicated the formation of 4-methoxynitrosobenzene and the complete consumption of 4-MeOPhB(OH) 2 after 3 hours, confirming the crucial role of water. Additional optimization revealed that the reaction could also be promoted with moisture in air, thereby considerably streamlining the operation (Table 5.1, entry 3). With these reaction conditions in hand, further exploration was focused on solvent effects. Similar to the nitration reactions using TMSCl and NaNO 3 , 20 chlorinated solvents were generally suitable for the present reaction (Table 5.1, entries 2–5), whereas highly polar/coordinating solvents generally led to inferior results (Table 5.1, entries 6–8). 132 Table 5.1 Optimization of Reaction Conditions a a. Isolated yield; b. Determined by GC-MS analysis without calibration. We examined the scope of the protocol with our optimized reaction conditions. As shown in Table 5.2, although 2,4,6-trifluorophenylboronic acid and 4-phenylphenylboronic acid were inert under the reaction conditions, most arylboronic acids participated in the reaction. We found that 4-alkoxy- and 4-phenoxyphenylboronic acids underwent the reaction smoothly to afford the corresponding nitrosoarenes in both high yields and good chemoselectivities (Table 5.2, entries 9–12). Noticeably, although arylboronic acids bearing electron-withdrawing substituents also participated in the reaction, nitroarenes were obtained as the major products (Table 5.2, entries 1, 4–6, 8, and 14). In general, the amount of nitro products was found to decrease with the increase of the electron donating ability of the substituents (through resonance effects). Despite the fact that 2-alkoxy substituted phenylboronic acids are also considered to be ‘electron-rich’, relatively lower yields and poor chemoselectivities were obtained with these substrates (Table 5.2, Entries 13 and 14), implying that the inductive effect of oxygen may also play a pivotal role in reaction yield. 133 Table 5.2 ipso-Nitrosation of arylboronic acids a a. Reaction conditions: arylboronic acid (0.5 mmol), TMSCl (1.1 mmol) and sodium nitrite (1.1 mmol) in CH 2 Cl 2 , stirred under air at room temperature; the conversion was determined by GC–MS. b. Conversions and yields were determined by GC and were not calibrated. c. The numbers in parentheses are isolated yields. 134 Scheme 5.5 The equilibrium between boronic acid and boroxine. Scheme 5.6 Elucidation of the oxidation of nitrosoarenes. 135 In order to elucidate the mechanistic aspects of the reaction, a series of control experiments were carried out. It is well known that the condensation of three boronic acids to give their corresponding boroxines occurs readily at room temperature (Scheme 5.5). 22 Therefore, we determined the composition of two samples of phenylboronic acid (A and B). According to 1 H NMR spectroscopy, 23 Samples A and B contained respectively, 95 mol % and 68 mol % triphenylboroxine (PhBO) 3 . While the ipso-substitution reaction with (PhBO) 3 (Sample A) proceeded smoothly under open air conditions, the reaction was found to be retarded under argon-protected anhydrous conditions ( Scheme 5.4, Eq. 2). By adding 0.5 equiv of water to the reaction mixture with Sample A (containing 95 mol % (PhBO) 3 ), nitrobenzene was obtained as the major product, thereby suggesting the essential role of water (Scheme 5.4, Eq. 3). In contrast, using Sample B as the starting material, nitrosobenzene and nitrobenzene were afforded in a ratio of 15%:85% in the absence of water and oxygen (Scheme 5.4, Eq. 4). The delineated observation could be ascribed to the in situ trimerization of PhB(OH) 2 , which could release a small amount of water to facilitate the reaction. It is worth mentioning that the necessity of water was also noticed by Molander and co-worker in the reaction between aryltrifluoroborates and sodium nitrite. 19 However, water in Molander’s reaction was proposed to allow the formation of tricoordinate boron species from aryltrifluoroborates, which in turn facilitates the nitrosation. Since nitrobenzene was obtained as a major product even under argon atmosphere, dioxygen (O 2 ) could be excluded as a potential oxidant responsible for the formation of nitrobenzene (Scheme 5.4, Eqs. 2–4). This hypothesis was made further evident by the fact that nitrosobenzene was not oxidized in the presence of TMSCl or NaNO 2 alone under open-air conditions (Scheme 5.4, Eqs. 5–7). On the other hand, although nitrosobenzene was found to 136 convert to nitrobenzene with a mixture of TMSCl and NaNO 2 in the presence of air (open-air), such a conversion was not observed under inert atmosphere (Scheme 5.4, Eqs. 8 and 9). This result showed that the oxidation of nitrosobenzene originated from a combination of TMSCl, NaNO 2 and water which could presumably lead to the formation of HNO 2 . As HNO 2 can readily undergo disproportionation to render HNO 3 and NO, 24 the in situ oxidation of nitrosobenzene can be ascribed to the presence of these two species. 25 Noticeably, the in situ oxidation of nitrosoarenes was also observed in the reaction between aryltrifluoroborates and NO + BF4 - , indicating the intrinsic lability of nitrosoarenes under direct nitrosation reaction conditions. 5.3 Chapter 5: Conclusions In conclusion, we have demonstrated that the combination of chlorotrimethylsilane-nitrite salt could be used as a viable system for the ipso-nitrosation of electron-rich arylboronic acids. Arylboronic acids bearing electron-withdrawing groups, although undergo ipso- functionalization, generally lead to nitration products instead of desired nitroso compounds. This observation is similar to many other direct nitrosation reactions, in which nitrosoarenes are in situ oxidized. 5.4 Chapter 5: Experimental 5.4.1 General Unless otherwise mentioned, all the chemicals were purchased from commercial sources and used without further purification. Silica gel chromatography was performed to isolate the products using Biotage SNAP Cartridges KP-Sil 10 g or 25 g with hexane-dichloromethane, dichloromethane or dichloromethane-ethyl acetate solvent systems as eluent. 1 H and 13 C spectra 137 were recorded on 400 MHz Varian NMR spectrometer. 1 H NMR chemical shifts were determined relative to residual solvent peak of CDCl 3 (at 7.26 ppm). 13 C NMR shifts were determined relative to the solvent peak of CDCl 3 (at 77.16 ppm). Mass spectra were recorded on spectrometer in the ESI mode. The yields determined by GC–MS analysis were not calibrated with internal standard. 5.4.2 Experimental Procedures General procedure for the ipso-nitrosation of arylboronic acids with NaNO 2 and TMSCl: To CH 2 Cl 2 (5 mL) in a 15 mL pressure tube were added NaNO 2 (76 mg, 1.1 mmol) and TMSCl (120 mg, 1.1 mmol) with stirring. Arylboronic acid (0.5 mmol) was added after 5 min. The tube was purged with argon after the color change (15–60 min) and continued to stir. The reaction was monitored by TLC (CH 2 Cl 2 /ethyl acetate = 6:4) and GC. After TLC showed the complete consumption of the arylboronic acid, the mixture was filtered. The filtrate was dried over Na 2 SO 4 and the volatile materials were evaporated under reduced pressure. The crude product was purified by column chromatography using CH 2 Cl 2 as eluent. 5.4.3 Spectral Data 1-Methoxy-4-nitrosobenzene: Green–blue oil, 72% yield. The product was contaminated with 5 mol% 1-methoxy-4- nitrobenzene as indicated by 1 H NMR. 138 1 H NMR (400 MHz, CDCl 3 , 25 °C): δ 7.92 (d, br, 3 J = 7.9 Hz, 2H), 7.03 (d, 3 J = 9.1 Hz, 2H), 3.95 (s, 3H). 13 C NMR (100 MHz, CDCl 3 , 25 °C): δ 165.0, 164.0, 124.5 (br), 113.9, 56.0. 1-Ethoxy-4-nitrosobenzene: Green–blue oil, 48% yield. The product was contaminated with 3 mol % 1-ethoxy-4- nitrobenzene as indicated by 1 H NMR. 1 H NMR (400 MHz, CDCl 3 , 25 °C): δ 7.89 (d, br, 3 J = 6.8 Hz, 2H), 6.99 (d, 3 J = 9.2 Hz, 2H), 4.17 (q, 3 J = 7.0 Hz, 2H), 1.46 (t, 3 J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 , 25 °C): δ 165.1, 164.0, 124.5 (br s), 114.2, 64.5, 14.6. 1-Isopropoxy-4-nitrosobenzene: Green–blue oil, 58% yield. The product was contaminated with 9 mol % 1-isopropoxy-4- nitrobenzene as indicated by 1 H NMR. 1 H NMR (400 MHz, CDCl 3 , 25 °C): δ 7.89 (br s, 2H), 6.98 (d, 3 J = 7.9 Hz, 2H), 4.73 (hept, 3 J = 6.4 Hz, 6H), 1.41 (d, 3 J = 6.4 Hz, 1H). 13 C NMR (100 MHz, CDCl 3 , 25 °C): δ 164.4, 163.9, 124.5 (br s), 115.0, 71.0, 21.9. 139 1-Phenoxy-4-nitrosobenzene: Green–blue oil, 52% yield. The product was found to be contaminated with 15 mol % 1- phenoxy-4-nitrobenzene as indicated by 1 H NMR (400 MHz, CDCl 3 , 25 °C): δ 7.90 (d, br, 3 J = 7.9 Hz, 2H), 7.45 (d, 3 J = 7.6 Hz, 2H), 7.27 (d, 3 J = 7.4 Hz, 1H), 7.12 (d, 3 J = 8.7 Hz, 2H), 7.08 (d, 3 J = 7.8 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 , 25 °C): δ 164.3, 163.8, 154.5, 130.3, 125.5, 125.0 (br s), 120.8, 116.7. 140 5.5 Chapter 5: References 1. Recent review: Adam, W.; Krebs, O. Chem. Rev. 2003, 103, 4131–4146. 2. (a) Zuman, P.; Shah, B. Chem. Rev. 1994, 94, 1621–1641; (b) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 3514–3525. 3. Recent reviews: (a) Guillena, G.; Ramon, D. J. Tetrahedron: Asymmetry 2006, 17, 1465– 1492; (b) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 28, 3514– 3525; (c) Merino, P.; Tejero, T. Angew. Chem. 2004, 116, 3055–3058; Angew. Chem. Int. Ed. 2004, 43, 2995–2997. 4. (a) Tibiletti, F.; Simonetti, M.; Nicholas, K. M.; Palmisano, G.; Parravicini, M.; Imbesi, F.; Tollari, S.; Penoni, A. Tetrahedron 2010, 66, 1280–1288; (b) Murru, S.; Gallo, A. A.; Srivastava, R. S. Eur. J. Org. Chem. 2011, 11, 2035–2038. 5. (a) Priewisch, B.; Rück-Braun, K. J. Org. Chem. 2005, 70, 2350–2352; (b) Goelitz,P.; Meijere, A. Angew. Chem. Int. Ed. 1977, 16, 854–855. 6. (a) Kopp, F.; Sapountzis, I.; Knochel, P. Synlett 2003, 885–887; (b) Goldman, J. Tetrahedron 1973, 29, 3833–3843; (c) Forrester, A. R.; Hepburn, S. P. J. Chem. Soc. C 1971, 20, 3322–3328; (d) Aston, J. G.; Menard, D. F. J. Am. Chem. Soc. 1935,57, 1920– 1924. 7. [4+2] Reactions: (a) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595– 607; (b) Waldmann, H. Synthesis 1994, 6, 535–551 [3+3] Reactions: (c) Pagar, V. V.; Jadhav, A. M.; Liu, R.-S. J. Am. Chem. Soc. 2011, 133, 20728–20731; [2+2] Reactions: (d) Staudinger, H.; Jelagin, S. Ber. Dtsch. Chem. Ges. 1911, 44, 365–374; (e) Wang, T.; 141 Huang, X.-L.; Ye, S. Org. Biomol. Chem. 2010, 8, 5007– 5011; (f) Chatterjee, I.; Jana, C. K.; Steinmetz, M.; Grimme, S.; Studer, A. Adv. Synth. Catal. 2010, 352, 945–948; (g) Dochnahl, M.; Ye, G. C. Angew. Chem., Int. Ed. 2009, 48, 2391–2393; (h) Bodnar, B. S.; Miller, M. J. Angew. Chem., Int. Ed. 2011, 50, 5630–5647. 8. Oxidation reaction to nitro compounds: (a) Bonner, T. G.; Hancock, R. A.J. Chem. Soc. B 1970, 3, 519–524; (b) Ibne-Rasa, K. M.; Lauro, C. G.; Edwards, J. O. J. Am. Chem. Soc. 1963, 85, 1165–1167. 9. Reduction to amines: (a) Dutta, D. K.; Konwar, D.; Sandhu, J. S. J. Chem. Res., Synop. 1994, 10, 388–389; (b) Feuer, H.; Braunstein, D. M. J. Org. Chem. 1969, 34, 2024–2026. 10. (a) Torssell, K. Tetrahedron 1970, 26, 2759–2773. and references cited therein; (b) Forrester, A. R.; Henderson, J.; Reid, K. Tetrahedron Lett. 1983, 24, 5547–5550; (c) Kaur, H. Free Radical Res. 1996, 24, 409–420. and references cited therein. 11. (a) Bordoloi, A.; Halligudi, S. B. Adv. Synth. Catal. 2007, 349, 2085–2088; (b) Sakaue, S.; Sakata, Y.; Nishiyama, Y.; Ishii, Y. Chem. Lett. 1992, 2, 289–292; (c) Burckard, P.; Fleury, J. P.; Weiss, F. Bull. Soc. Chim. Fr. 1965, 10, 2730–2733. 12. Cameron, M.; Gowenlock, B. G.; Vasapollo, G. Chem. Soc. Rev. 1990, 19, 355–379. 13. Rice, W. G.; Schaeffer, C. A.; Graham, L.; Bu, M.; McDougal, J. S.; Orloff, S. L.; Villinger, F.; Young, M.; Oroszlan, S.; Fesen, M. R.; Pommier, Y.; Mendeleyev, J.; Kun, E. Nature 1993, 361, 473–475. 14. (a) Sandler, S. R.; Karo, W. Organic Functional Group Preparations, 2nd ed.; Academic Press: Orlando, 1986; Vol. 2, Chapter 16.; (b) Williams, D. H. Nitrosation; Cambridge 142 University Press: Cambridge, 1988; Chapters 2 and 3.; (c) Touster, O. Org. React. 1953, 7, 327; (d) Boyer, J. H. Methods of Formation of the Nitroso Group and Its Reaction. In The Chemistry of the Nitro and Nitroso Groups, Part 1; Feuer, H., Ed.; Interscience: New York, 1969; Chapter 5, pp 891–1016.; (e) Katritzky, A. R.; Meth-Cohn, O.; Rees, C. W. Comprehensive Functional Group Transformations; Pergamon Press: London, 1995. 15. Lee, J.; Chen, L.; West, H. A.; Richter-Addo, G. B. Chem. Rev. 2002, 102, 1019– 1065. 16. Bosch, E.; Kochi, J. K. J. Org. Chem. 1994, 59, 5573–5586. 17. Hubig, S. M.; Kochi, J. K. J. Am. Chem. Soc. 2000, 122, 8279–8288. 18. Zyk, N. V.; Nesterov, E. E.; Khlobystov, A. N.; Zefirov, N. S. Russ. Chem. Bull. 1999, 48, 506–509. 19. Molander, G. A.; Cavalcanti, L. N. J. Org. Chem. 2012, 77, 4402–4413. 20. Prakash, G. K. S.; Panja, C.; Mathew, T.; Surampudi, V.; Petasis, N. A.; Olah, G. A. Org. Lett. 2004, 6, 2205–2207. 21. (a) Lee, J. G.; Kwak, K. H.; Hwang, J. P. Tetrahedron Lett. 1990, 31, 6677–6680; (b) Baidya, M.; Yamamoto, H. J. Am. Chem. Soc. 2011, 133, 13880–13882. 22. (a) Tokunaga, Y.; Ueno, H.; Shimomura, Y.; Seo, T. Heterocycles 2002, 57, 787–790; (b) Tokunaga, Y.; Ueno, H.; Shimomura, Y. Heterocycles 2007, 74, 219–223. 23. It has been shown that the composition of aryl boronic acids and triarylboroxines can be determined via 1 H NMR spectroscopy Tokunaga, Y.; Ueno, H.; Shimomura, Y.; Seo, T. Heterocycles 2002, 57, 787–790. 143 24. Decomposition of HNO 2 : (a) Bonner, F. T.; Donald, C. E.; Martin, M. N. J. Chem. Soc., Dalton Trans. Inorg. Chem. 1989, 527–532; (b) Hodgson, H. H.; Nicholson, D. E. J. Chem. Soc. 1941, 470–475. 25. Oxidation of nitrosobenzene with NO 2 or NO: Astolfi, P.; Carloni, P.; Damiani, E.; Creci, L.; Marini, M.; Rizzoli, C.; Stipa, P. Eur. J. Org. Chem. 2008, 3279–3285. Oxidation of nitrosobenzene with nitric acid, see references 324–327 in Ref. 2a. 144 Chapter 6: Chlorotrimethylsilane as a mild reagent in the reduction of Nitrosoarenes to Azoxyarenes 6.1 Chapter 6: Introduction Chlorotrimethylsilane (TMSCl) is a commonly available versatile reagent widely used in organic chemistry. It is used in protection of alcohols, 1 phenols, 2 carboxyls 3 and terminal alkynes. 4 It is also used in the mild deprotection of Boc protecting group. 5 As a Lewis acid it has been used to activate imines 6 and nitrones. 7 TMSCl is a suitable chlorine source in a variety of chlorination reactions. 8 TMSCl is also a suitable dehydrating agent for scavenging water generated in various reactions. 9 Other uses of TMSCl include formation of TMS enol ethers of aldehydes and ketones, 10 formation of silyl-substituted vinylallenes from enynes, 11 conversion of ketones to vinylsilanes 12 and ring opening of epoxides to O-protected vicinal chlorohydrins. 13 In addition to these reactions, TMSCl can also act as a reducing agent. Usually, TMSCl is used in combination with another reducing agent. For example, TMSCl has been used in combination with NaBH 4 or LiBH 4 to alter its reducing ability and has been applied in the reduction of a number of different functional groups. 14 In many reactions the addition of TMSCl makes it possible to carry out reductions with LiBH 4 or NaBH 4 , which are either very slow or do not occur in its absence. 14a NaBH 3 CN/TMSCl is another reducing agent combination that has been studied. With this reagent system, aldehydes, ketones, and acetals attached to benzo[b]furans or activated aromatic rings are completely deoxygenated to produce the corresponding alkyl arenes. 15 In many other reactions, TMSCl is used as an additive to various reducing systems to improve the reactivity and/or increase the selectivity. In reductions using metals such as Mg, 16 Zn, 17 Sm, 18 Ti, 19 Na, 20 In 21 the addition of TMSCl not only increases the 145 reactivity but also increases the selectivity. Other reducing systems in which the addition of TMSCl enhances the reactivity and the selectivity are Mn/PbCl 2 , 22 La/I 2 /CuI, 23 CHI 3 /Mn/CrCl2, 24 9 CrCl 2 /H 2 O. 25 However, TMSCl by itself has not been used in any reduction reaction. This is in contrast to iodotrimethylsilane (TMSI) and bromotrimethylsilane (TMSBr) both of which have been used in reductions without any external additive. 25 In the reactions using TMSI, for example, in the reduction of styrenes and benzylic alcohols to alkanes, it is presumed that the reduction occurs via the formation of HI. 26 In the reduction of sulfoxides to sulfides, the use of TMSCl/NaI produces sulfides in higher yield than TMSI alone and the reason for this is considered to be due to catalysis of the reaction by excess iodide ion. 25b The excellent reducing power of iodide is also cited as the driving force in the deoxygenation of nitro and nitrosalkanes with TMSI. 27 In general, with TMSX, the ease of reaction depends not only on the nucleophilicity of the anion X - , but also on the ease of its oxidation to X 2 . 25b The bond energies of X 2 are shown in Table 6.1. Therefore, since I - and Br - are more nucleophilic than Cl - , TMSI and TMSBr are able to participate in reduction whereas TMSCl needs to be used in combination with other reducing systems. This explanation is in addition to the bond length and bond energy consideration for the Si-X bond cleavage. For Si-Cl, the bond energy is more and the bond length is less than those of Si-Br and Si-I (Table 6.1), and hence the difficulty in cleaving the Si-Cl bond. Table 6.1 Bond Energies of X 2 and Si-X; Bond Lengths of Si-X. X-X Bond Energy (Kcal/mol) Si-X Bond Energy (Kcal/mol) Bond Length (pm) F-F 37 Si-F 135 160 Cl-Cl 58 Si-Cl 91 202 Br-Br 46 Si-Br 74 215 I-I 36 Si-I 56 243 146 The difficulty in cleaving the Si-Cl bond can also be explained in terms of Hard-Soft Acid-Base theory. In TMSI, silicon is a hard acid and iodide is a soft base. 28 This reagent, therefore, reacts readily with organic compounds containing oxygen (a hard base) forming a strong silicon-oxygen bond. The iodide then acts as a strong nucleophile in a subsequent displacement step, thus resulting in cleavage of carbon-oxygen bond (for example, in the case of carbonyls). However, Cl - is considered as borderline hard base, and therefore it may not readily react with oxygen (a hard base) to initiate the reduction process. For the purpose of reduction by TMSCl alone, nitrosoarenes are ideal candidates. They possess high reactivity and are prone to oxidation with ease. The high reactivity and ease of oxidation make nitrosoarenes difficult targets in traditional solution-based synthetic chemistry. This has led some scientists to develop mechanochemical Oxone oxidation of anilines to nitrosoarenes combining solvent-free synthesis with solvent-free separations. 29 However, the high reactivity of nitrosoarenes has also made them useful reagents in many reactions. In nitroso compounds, the polarization of the N-O double bond resembles that of the C-O double bond in carbonyl groups. Therefore, the N atom in nitroso group can act as an electrophile. As a result, the vast majority of reactions of nitroso functional group are those in which it acts as an electrophile in condensations with nucelophiles. These nucleophiles could be oxygen nucleophiles 30 , sulfur nucleophiles, 31 carbon nucelophiles 32 and nitrogen nucelophiles. 33 In the presence of acid catalysts, nitrosobenzene can act as an oxy electrophile. In the O-nitroso aldol reactions, oxygen is introduced at the α-position of carbonyl compounds by using nitrosobenzene as an oxy electrophile. 34 The high reactivity of nitrosobenzenes have also led to their use as precursors in the synthesis of photoactive non-symmetrical azobenzenes 35 and as active sites in MOFs (Metal Organic Frameworks) capable of covalently trapping small molecules. 36 147 Reaction of nitrosoarenes with TMSCl also allows for the opportunity to utilize the extraordinary affinity silicon toward oxygen. The unusual affinity of silicon towards oxygen has been widely used in a variety of reactions. For example, the cleavage of esters, 38 ethers 39 and carbamates 40 as well as the conversion of alcohols to iodides 41 using iodotrimethylsilane are based on exploiting the high bond strength of Si-O bond (110 Kcal/mol). The deoxygenation of sulfoxides to sulfides 42 with TMSI is also based on the high affinity of silicon towards oxygen. Therefore, while the intrinsic reactivity of TMSCl cannot be changed, one may be able to use it to reduce a substrate possessing certain characteristics that may compensate for the low reactivity of TMSCl and thus allow for reduction. Herein, we report the results of our studies on utilizing nitrosoarenes as substrates that can be reduced to azoxyarenes by TMSCl alone without the need to use co-reductants or other additives. 6.2 Chapter 6: Results and Discussion We began our studies by adding a freshly distilled TMSCl (1 mmol) to a solution of nitrosobenzene (0.5 mmol) in dichloromethane (4 mL) at room temperature. In about 15 minutes, the color of the reaction mixture changed from green to brown. After one hour, GC/MS analysis showed that nitrosobenzene had reacted completely and azoxybenzene was the major product with the formation of some unidentified products. After a brief survey of reaction conditions, we found that the reaction was complete in 15 minutes at room temperature and that when equimolar amounts of nitrosobenzene and TMSCl are used, only very small amounts of side products are formed (Figure 6.1). Accordingly, azoxybenzene was isolated in 86 % yield (Scheme 6.1). 148 Figure 6. 1 Reduction of Nitrosobenzene to Azoxybenzene by Chlorotrimethylsilane. Scheme 6. 1 Reduction of Nitrosobenzene to Azoxybenzene by Chlorotrimethylsilane. 149 Having developed an expedient method for the synthesis of azoxybenzne from nitrosobenzene, in the next step we attempted to further reduce it to azobenzene. Azobenzenes are important class of compounds. They are widely used in the chemical industry as dyes and pigments, 43 food additives, indicators , 44 radical reaction initiators 45 and therapeutic agents. 46 They have also found application in electronics 47 and drug delivery. 48 One of the methods for the synthesis azobenzenes is the reduction of azoxyarenes. For example, hydrazine hydrate in the presence of aluminium in methanol under reflux or microwave irradiation effectively reduces azoxyarenes to azobenzenes. 49 Azobenzenes are also obtained by the treatment of azoxyarene with AlI 3 50 or In(III)Cl 3 , 51 Zn(OTf) 2 or Cu(OTf) 2 52 and AlCl 3 •6H 2 O/KI. 53 Another method involves the use of yeast–NaOH in ethanol and H 2 O 54 for the reduction of azoxyarenes to azoarenes. Other reducing agents include tertiary phosphines, 55 iodine activated Tris- (dimethylamino) phosphine and tertiary phosphites. 56 Our attempts to reduce the in situ generated azoxybenzene to azobenzene with reducing agents In(III)Cl 3 , 51 and AlCl 3 •6H 2 O/KI 53 were unsuccessful (Table 6.2, Entry 1, 2). NH 4 CO 2 H/Pd-C/MeOH, 57 Fe/HoAC 58 and Zn/aq. NH 4 Cl 59 have been previously used for deoxygenation of heteroaromatic N-oxides. Both NH 4 CO 2 H/Pd-C/MeOH and Fe/HOAC failed to furnish the desired product (Table 6.2, Entry 3, 4). With Fe/HOAc, there was an excessive reduction of azoxybenzene to aniline. With Zn/aq. NH 4 Cl, however, the reaction mixture had 36% azobenzene after 4 hours at room temperature (Table 6.2, Entry 5). We also found that when THF was the sole solvent during the in situ generation of azoxybenzene, the reaction was much cleaner. 150 Table 6. 2 Reduction of in situ generated Azoxybenzene to Azobenzene with various reducing agents. In the next step, we carefully monitored by GC/MS the progress of the reaction after addition the addition of Zn/aq. NH 4 Cl to the azoxybenzene generated in situ in THF from nitorobenzene and TMSCl (Table 6.3). Most of the conversion of azoxybenzene to azobenzene takes place within 5 minutes of the addition of Zn and aq. NH 4 Cl. A small amount of aniline and chlorinated azobenzene also observed in the reaction mixture. Afterwards the progress of the reaction is sluggish, with 11% unreacted azoxybenzene in the reaction mixture even after an hour. The amount of aniline and chlorinated azobenzene increased, by only by a small percentage. After a prolonged stirring, only trace amount of azoxybenzene was left in the reaction mixture while the amount of azobenzene decreased to 74% as it was further reduced to 151 aniline, which made up 20% of the reaction mixture. Based on these findings, we repeated the reaction, this time stopping it after 15 minutes of adding Zn/aq. NH 4 Cl (Scheme 6.2). After working up the reaction, the desired product azobenzene was isolated in 76% yield (See the experimental section). Table 6. 3 GCMS monitoring of the reduction of Nitrosobenzene to Azobenene with Zn/aq. NH 4 Cl. Scheme 6. 2 Reduction of Nitrosobenzene to Azobenzene via in situ generated Azoxybenzene 152 Next, we attempted to reduce some commercially available nitrosoarenes to their corresponding azoxy compounds by the treating them with equimolar TMSCl (Table 6. 4). Unfortunately, except in the case of 1-methyl-2-nitrosobenzene, the desired product was not observed even after prolonged reaction times. It is likely that the hydroxyl and amino substituents of the nitrosoarenes (Table 6.4, Entries 2-4) interfere with the reactivity of TMSCl through Si-O and Si-N interactions, although we did not observe any silyl ethers. Even after 5 days, the reaction mixture of 1-methyl-2-nitrosobenzene and TMSCl had only 28% of the azoxy compound, while the rest was unreacted starting material. The low reactivity is probably due to steric hindrance by the methyl group at the ortho position. Table 6. 4 Reduction of Nitrosoarenes to Azoxyarenes by Chlorotrimethylsilane. 153 The possible reaction mechanism for the reduction of nitrosoarenes to azoxyarenes can be illustrated by using nitrosobenzene as a model. The nitroso functionality of aromatic nitroso compounds displays a high reactivity. The polarization of the N=O bond resembles that of the C=O bond and it behaves as a weak C=O. As a result, the N atom of N=O group is susceptible to additions of nucleophiles and the O atom becomes a good nucelophile. 60 Scheme 6.3 Mechanism of Reduction of Nitrosobenzene to Azoxybenzene by TMSCl. Although N is a better nucleophile than O, in this case due to the higher bond energy of Si-O (Si-O 110 Kcal/mol) than Si-N (Si-N 89 Kcal/mol), O is more likely to be a better nucleophile than N to attack the electropositive Si of TMSCl. The high affinity of Si towards O has already been mentioned. Therefore, the initial step for the reaction could be a nucleophilic attack by the O atom of the nitroso group on the electropositive Si of the silane as depicted in Scheme 6.3 (a) to give the intermediate 2. The intermediate 2 can then react with nitrosobenzene to give the intermediate 3 (Scheme 6.3, b). The possibility of nucelophilic attack by the N atom of nitrosobenzene is supported by the fact that in some cases nitrosoarenes can also serve as nucleophiles because of the free 154 electron pair on nitrogen. As a nucleophile, nitrosobenzene can add to carbon-oxygen, carbon- nitrogen, or activated carbon-carbon double bonds. 60 For example, the potential nucelophilic character of nitroso group is illustrated by the strong tendency of nitrosoarenes to form dimers. 61 This dimerization occurs from the interaction of the nonbonding electron pair on the nitroso N with another nitroso group (Scheme 6.4) Scheme 6.4 Dimerization of Nitrosobenzene. In the presence of an acid, nitrosobenzene adds to the carbonyl group of formaldehyde, acetaldehyde, trifluoroacetaldehyde, glyoxylic acid, and pyruvic acid to give the corresponding N-phenylhydroxamic acid. 62-64 As illustrated in Scheme 6.5 for pyruvic acid, the first step is a nucleophilic attack of the nitroso group on the carbonyl group, followed by a protonation of the intermediate, which undergoes decarbonylation or elimination of a carboxylic acid proton. Once 3 is obtained, it can undergo further reaction as follows: Nucleophilic attack at the electropositive N atom of 3 by chloride ion leads to the formation of an intermediate 4 (Scheme 6.6). The O in between Si and N may then attack the electropositive Si of TMSCl to give an intermediate 5. Irreversible formation of hexamethyldisiloxane (TMSOTMS) triggered by the 155 abstraction of Cl + from 5 would give 6 which is a resonance structure of the product azoxybenzene 7. Scheme 6.5 Nucleophilic addition of Nitrosobenzene to Pyruvic Acid. Scheme 6.6. Mechanism of Reduction of Nitrosobenzene to Azoxybenzene by TMSCl. The potential reaction mechanism described above is somewhat analogous to the reaction mechanism of the reduction of sulfoxides to sulfides by in situ generated TMSI reported by Olah et al. 65 Facilitated by the high bond energy of Si-O bond (110 Kcal/mol), the electropositive Si atom in TMSI undergoes a nucelophilic attack by the O atom of sulfoxide to form an intermediate 8 with the cleavage of the weak Si-I bond (Scheme 6.7). Driven again by the 156 potential to form the high bond energy Si-O bond, the electropositive Si atom of another molecule of TMSI undergoes a nucleophilic attack by the O atom of the intermediate 8, again cleaving the weak Si-I bond to form an intermediate 9. Abstraction of I + from the intermediate 9 by iodide generates I 2 and releases hexamethyldisiloxane with the formation of the sulfide. Scheme 6.7 Mechanism of Deoxygenation of Sulfoxides to Sulfides by Iodotrimethylsilane 65 The synthesis of azoxyarenes is an important research objective. Azoxyarenes are widely used in the area of organic non-linear optics in modern technology due to their liquid crystalline properties. 66 Azoxyarenes have been utilized as therapeutic medicines, dyes, analytical reagents and photosemiconductors. 67 In particular, azoxyarenes bearing alkyl- or alkoxy-substituents in the p,p′-position exhibit interesting properties as liquid crystals. 68, 69 Azoxyarenes can also be 157 reduced to amines or 2-phenyl indazoles. 70 Carbonylation of azoxyarenes by carbon monoxide in the presence of 5% PdCl 2 /NaX and ferric chloride additives gives carbamates. 71 Cylohexylamine and dicyclohexylamine are obtained on the reduction of azoxybenzene with formic acid and palladium on carbon. 72 Several methods already exist for the synthesis of azoxyarenes. The common starting materials are anilines, nitroarenes and nitrosoarenes. However, as described further, the existing methologies for the synthesis of azoxyarenes are not without their drawbacks. The transformation of arylamines to azoxyarenes appears to be the most cost effective method for the sysnthesis fo azoxyarenes and there are methods for such transformation. However, these methods suffer from the need to use explosive oxidant H 2 O 2 or expensive catalysts. For example, arylamines are transformed into azoxyarenes over titanosilicate ETS-10 in the presence of H 2 O 2 or tert-butyl hydroperoxide as the oxidant. 73 The titanium silicate molecular sieve TS-1 catalyzes the oxidation of aniline selectively to azoxybenzene with aqueous H 2 O 2 as oxidant. 741 However, although a selectivity of the order of 97% to azoxybenzene could be achieved, only 25 mol% conversion of aniline was achieved. Another common method for the synthesis of azoxyarenes is the reduction of nitroarenes to azoxyarenes. A variety of reducing reagents such as alkaline metal borohydrides, 75 sodium arenetellurolate, 76 phosphine, 77 InBr 3 -Et 3 SiH, 78 and metals such as samarium, 79 thallium, 80 and ultrasonically activated nickel 81 can be used to carry out the conversion of nitroarenes into the corresponding azoxyarenes. However, most of these methods suffer from drawbacks such as high costs, lengthy reactions, poor yields, or inconvenient workup procedures. Hence, there is a 158 need for a facile, economical, and effective synthetic procedure for the preparation of azoxyarenes. Azoxyarenes can also be obtained from nitrosoarenes. The condensation of nitrosobenzene with N-phenylhydroxylamine is known to form azoxybenzene. 82 The partial reduction of PhNO with PhCHO and Et 3 N in the presence of thiazolium salt predominantly gives azoxybenzene with the concurrent oxidation of PhCHO to PhCO 2 Me. 83 Reaction of metal carbonyls with nitrosoarenes and photolysis has been found to be an effective method for the reduction of nitrosoarenes to azoxyarenes. However, over reduction to amines or azo compounds is known to occur. 84 A method recently reported involves the reductive coupling of nitrosoarenes to azoxyarenes by using rhodium catalyst [Rh(trop 2 NH)(PPh 3 )]OTf in ethanol and THF in the presence of K 2 CO 3 . 85 Azoxybenzene derivatives were formed in high yields (69-99%) after a rection time of 2-4 h. Compared to these existing methods for the synthesis of azoxyarenes, the methodlogy we have developed is very simple since only nitrosoarene and TMSCl are required to obtain azoxyarenes. The halosilane used in the reaction is TMSCl, which is relatively inexpensive and widely available than TMSBr and TMSI both of which are extremely sensitive to light, air and moisture. 86 They also fume in air due to hydrolysis to HI and HBr and become discolored upon prolonged storage owing to the generation of I 2 and Br 2 . The methodology is somewhat limited by the fact that only limited number of nitrosoarenes are commercially available. Several methods exist for the synthesis of nitrosoarenes, including oxidation of aniline derivatives, reduction of nitroarenes, and electrophilic nitrosation of aryl metallic compounds. 87, 88 Direct nitrosation of arenes can also be achieved using nitrosonium salts (NO + X - ). 89 However, for the purpose of convenient synthesis 159 in the laboratory, the recently reported emethod of the nitrosation of aryl and heteroaryltrifluoroborates by using nitrosonium tetrafluoroborate, 90 may be used. Another limitation, as the preliminary results show, is that hydroxyl and amino substituents appear to interfere with the reactivity of the TMSCl with the nitroso functionality. However, further investigation of reaction conditions is needed to conclude if this is indeed the case. 6.3 Chapter 6: Conclusion Chlorotrimethylsilane is an important organosilicon reagent. It is the most common halotrimethylsilane and compared to TMSBr and TMSI, it is inexpensive and more stable and hence convenient to use. In reductions, it is mainly used in combination with other reducing reagents due to its relative lack of reactivity. Here, we have demonstrated that suitably reactive substrates such as nitrosoarenes can be reduced to azoxyarenes without the requirement of a co- oxidant or other additives. The reaction is further driven by the strong tendency of silicon to form a strong Si-O bond with oxygen. Further, by using inexpensive reagents Zn and aq. NH 4 Cl, the in situ generated azoxybenzene has been converted to azobenenzene, which gives us a direct route to azobenzene from nitrosobenzene. With further investigation of substrate scope, this methodology has the potential to offer several advantages over currently available methodologies for azoxy- and azoarene synthesis many of which necessitate the use of oxidizing reagents such as hydrogen peroxide and expensive catalysts. 160 6.4 Chapter 6: Experimental 6.4.1 General General Remarks: Unless otherwise mentioned, all chemicals were purchased from commercial sources and used as received. 1 H, and 13 C NMR spectra were recorded on a Varian NMR at 400 MHz. 1 H NMR chemical shifts were determined relative to tetramethylsilane (TMS) as the internal standard at δ 0.0 ppm. 13 C NMR shifts were determined relative to internal TMS at δ 0.00 ppm or to the CDCl 3 at δ 77.0 ppm. Gas chromatograms were recorded on Bruker 450-GC and mass spectra were recorded on Bruker 300-MS in the ESI mode. The products were characterized by comparing their spectral data with those reported in the literature. 6.4.2 Experimental Procedures General Procedure for the Synthesis of Azoxybenzene: Nitrosobenzene (1 mmol) was added to a solution of Chlorotrimethylsilane (1 mmol) in THF (3 mL) and allowed to stir at room temperature. After 1 hour, the mixture was diluted with water (5 mL) and extracted with diethyl ether (3 x 8 mL). The organic layer was dried with anhydrous Na 2 SO 4 . The solvent was removed under reduced pressure and the residue was purified by column chromatography (ethyl acetate/hexanes: 1/9) to give azoxybenzene (86% yield). General Procedure for the Synthesis of Azobenzene: Nitrosobenzene (1 mmol) was added to a solution of Chlorotrimethylsilane (1 mmol) in in THF (3 mL) and allowed to stir for 1 hour at room temperature. Zinc powder (4 mmol) was added followed by the addition of saturated aqueous NH 4 Cl (2 mL) and the reaction mixture was allowed to stir at room temperature. After 1 hour, the mixture was filtered, diluted with water (5 mL) and extracted with diethyl ether (3 x 8 mL). The organic layer was dried with anhydrous Na 2 SO 4 . The solvent was evaporated and the 161 residue was purified by column chromatography (ethyl acetate/hexanes: 4/6) to give azobenzene (76% yield). 6.4.3 Spectral Data and Representative Spectra Azoxybenzene 91 1 H NMR (400 MHz, Chloroform-d) δ = 8.33- 8.30 (m, 2 H), 8.18- 8.16 (m, 2 H), 7.57- 7.38 (m, 6 H). 13 C NMR (400 MHz, Chloroform-d) δ = 148.33, 143.99, 131.61, 129.63, 128.82, 128.71, 125.53, 122.36. MS (ESI) m/z: 199.2 [(M+H) + ]. Azobenzene 92 1 H NMR (400 MHz, Chloroform-d) δ = 7.94- 7.92 (M, 4 H), 7.55- 7.45 (m, 6H). 13 C NMR (400 MHz, Chloroform-d) δ = 152.62, 130.98, 129.08, 122.83. 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Instruments on Hawaii's Mauna Loa observatory first recorded a peak level of 400.5 parts per million (ppm) in May 2013. Later, in March 2014 alone the CO 2 level in the atmosphere had crossed 401 ppm three times and hit a record 401.6 ppm on March 12. 1 The increasing levels of carbon dioxide (Figure 7.1) and other greenhouse gases have resulted from the increased consumption of non-renewable energy resources, mainly fossil fuels, due to the lack of sufficient alternative inexpensive energy sources. In the U.S., CO 2 accounted for about 84% of all greenhouse gas emissions from human activities (anthropogenic) and it is widely accepted as the major contributor to climate change. 2 Another major detrimental effect of CO 2 is ocean acidification, a major challenge for the survival of marine organisms. Efforts to mitigate the CO 2 emission problem stand as the top priority among all scientific engagements at the international level through a number of high-profile collaborative programs such as the Intergovernmental Panel on Climate Change (IPCC) of the United Nations. A growing, viable economy concept, the methanol economy, addresses this challenge of climate change and CO 2 emissions effectively. 174 Figure 7.1 Concentration of atmospheric CO 2 1958-2014 1 Figure 7.2 Proposed Carbon Neutral Cycle of the Methanol Economy Concept 3 The “Methanol Economy” concept (Figure 7.2) 3 proposes a carbon neutral cycle in which CO 2 can be captured from the environment, stored, chemically utilized for our energy needs and then recycled for further use. After CO 2 is captured, any available energy source (alternative 175 energies such as solar, wind, geothermal and atomic energy) can be used for the chemical conversion of CO 2 . CO 2 can be effectively reduced to methanol and dimethyl ether which are excellent transportation and industrial fuels for internal combustion engines (ICE), energy generating turbines and household uses. These energy storage media can replace gasoline, diesel fuel, liquefied petroleum gas (LPG) and natural gas (NG). Furthermore, methanol and DME are the building blocks in the petrochemical industry for the preparation of synthetic olefins, aliphatic, aromatic hydrocarbons and other derived products and materials through the well known Methanol to Olefins (MTO) process (Scheme 7.1). Presently, these products and materials are obtained from sources such as oil and natural gas, resulting in the aforementioned CO 2 emissions and climate change. Essentially, the “Methanol Economy” proposes that carbon dioxide can be chemically transformed from a detrimental greenhouse gas causing global warming into a valuable, renewable and inexhaustible carbon source of the future. This allows an environmentally neutral use of carbon fuels and derived hydrocarbon products. The “Methanol Economy” offers a feasible roadmap to liberate humankind from its dependence on diminishing oil and natural gas resources, while simultaneously utilizing and storing all sources of both renewable and atomic energies. At the same time, by chemically recycling CO 2 , one of the major man-made causes of climate change- global warming - will be significantly mitigated while rendering carbon-containing fuels and materials regenerative Therefore, the capturing of CO 2 and the subsequent proper utilization of the captured CO 2 by suitable physical and chemical modifications especially to renewable energy storage medium has become one of the most challenging ventures of our time. Effective CO 2 capture and storage (CCS) as well as effective utilization especially for growing needs of energy and fuels are 176 considered viable solution for this problem. However, on the required enormous scale, none of the existing technologies has been proven efficient and our project addresses this need by focusing on the carbon capture and storage step of the carbon neutral cycle proposed in the “Methanol Economy” concept. CO 2 CH 4 Biomass CH 3 OH H 2 C CH 2 H 2 C CH and or Synthetic hydrocarbons and derived products CH 3 CH 3 OCH 3 Scheme 7.1 CO 2 as a major source for methanol and derived products A wide range of separation techniques involving both physical and chemical processes are known for the removal and capture of CO 2 from flue gas streams. The captured CO 2 can be sequestered in geological formations or under the sea and can be recycled and used as raw material for the synthesis of fuels and useful synthetic materials. This can be considered as the human version of natural photosynthesis now often referred to as anthropogenic carbon cycle (Figure 7.3). 5 177 Figure 7.3 Anthropogenic Carbon Cycle 7 Our efforts to improve CO 2 separation and capture technologies led us to an intensive search for the development of stable and highly efficient recyclable CO 2 absorbents. Due to the lack of a foreseeable change in the consumption of energy sources and the types of sources used, a more specific and viable goal of green chemistry is to improve carbon dioxide separation and capture techniques. 4 A specific and more widely used technique is absorbing CO 2 using aqueous amines. However, these methods face certain disadvantages such as potential corrosion, degradation and high energy and high absorbent regeneration costs. In order to reduce the high cost associated with the existing technologies, significant improvement in these processes or development of new highly economic procedures is necessary. Many solid adsorbent systems have been recently developed, among which nanostructured silica supported organoamine system developed in our laboratory shows high efficacy. 4,5,6,7,8 One of the important properties, which improves the CO 2 capture efficiency significantly is the high surface area of the hybrid silica-amine adsorbent system. 178 Recently, synthesis of silica nanospheres with fibrous morphology has been reported. We decided to prepare fibrous nanosilica supported amine systems expecting good CO 2 capture and release under ambient or moderate conditions. The preparation of the fibrous nanosilica material using a microwave assisted hydrothermal technique was reported by Polshettiwar et. al. 9 However, we found that it can be prepared under normal thermal conditions as well. Herein, we report the development of a new efficient and recyclable solid adsorbent system based on nanosilica supported polymeric amine with fibrous morphology. Results from CO 2 adsorption studies show that the new material is highly promising and temperature controlled adsorption and release of CO 2 can be achieved under ambient pressure. 5.2 Chapter 5: Results and Discussion High surface area silica nanospheres (LHI-S1) were prepared using our modified procedure based on a previous report. 9 Tetraethylorthosilicate was hydrolyzed by urea, followed by assembly of hydrolyzed, negatively charged SiO 4 - species in the space available between the self-assembled template molecules (Scheme 7.2) of the surfactant, cetylpyridinium bromide (CPB) for aggregation along free radial directions as well as the tangential direction. This was followed by the condensation of self-assembled silicate leading to crystallization of the silica material within the isolated micelles to yield fibrous silica nanospheres. 179 Cetylpyridinium bromide micells (CPB, surfactant) (EtO) 4 Si Calcination LHI-S1 CPB SiO 4 H 2 N NH 2 O Scheme 7.2 Fibrous nanosilica formation from (EtO) 4 Si with the help of cetylpyridinium bromide (CPB) 9 Scanning electron microscopy (SEM) images (Figure 7.4) indicate that the silica material consists of colloidal spheres. Close inspection of these images reveals that the material possesses dendrimeric fibers arranged in three dimensions to form spheres, which can allow easy access to the available high surface area (425-478 m 2 g -1 ). Further structural characterization of synthesized silica nanospheres was performed by high-resolution transmission electron microscopy (HRTEM), revealing well-defined and ordered fibers coming out from the center of the particles with uniform radial distribution (Figure 7.5). Despite the use of a modified procedure, these observations are consistent with the results reported earlier. 9 The Brunauer–Emmett–Teller (BET) surface area of our silica material LHI-S1 (478 m 2 g -1 ) was also high (Table 7.2, Entry 1) , though not as high as the one reported in the literature (641 m 2 g -1 ). Pore volume and average pore diameter were measured to be 1.42 cm 3 g -1 and 3.31 nm, respectively. Both the surface area and the pore volume decreased while the pore diameter increased slightly on doubling the reaction time to 8 hours (Table 7.2, Entry 2). 180 Figure 7.4 SEM images of fibrous silica nanospheres of LHI-S1. Figure 7.5 HRTEM images of fibrous silica nanospheres of LHI-S1. Figure 7.6 SEM images of fibrous nanosilica supported LHI-S1-PEI (MW 800). 181 Studies in our laboratory, showed that polyethylenimine on silica support with small particle size (fumed silica) displayed a high CO 2 capture efficiency. Reaction of CO 2 with amines is well known. Scheme 7.3 shows the interaction of amino groups in the monomeric unit of polyethtylenimine with CO 2 . There are three different amino groups (primary, secondary and tertiary) in the branched polymer. The primary and secondary amino groups in the unit react with CO 2 to form the corresponding carbamate, which in the presence of water forms the bicarbonate. This process is reversible. Therefore, amines on nanoslilica support with fibrous morphology are expected to perform with high CO 2 capture efficacy. N NH 2 N H n + CO 2 N NHCO 2 N H 2 n Carbamate H 2 O N NH 3 N H n HCO 3 Bicarbonate Polyethylenimine Scheme 7.3 The CO 2 -amine interaction in each repeating unit of polyethylenimine. We have impregnated fibrous nanosilica with low and high molecular weight, linear as well as branched polyethylenimine and conducted CO 2 adsorption studies by TGA. The results are summarized in Table 7.1. Initially, a sorbent LHI-S1:PEI (MW 800) composed of LHI-S1 and PEI (MW 800) in 1:1 ratio was prepared. SEM images of fibrous nanosilica supported LHI-S1-PEI (MW 800) shows the changed morphology with imine coating (Figure 182 7.6). Afterwards, CO 2 adsorption and desorption measurements were carried out with it. At 25 °C, the adsorption was 76.8 mg (1.73 mmol) of CO 2 per gram of the sorbent (Table 7.1, Entry 1). At 55 °C, the adsorption increased to 120.3 mg (2.73 mmol). The adsorption further increased to 152.9 mg (3.47 mmol) at 85°C. However, the sorbent was not very stable as shown by its decreasing capacity to adsorb CO 2 after a few adsorption/desorption cycles (indicated by the slope of the adsorption capacities in each of the ten cycles). In order to decrease the leaching of the low molecular weight polyimine (MW 800), which decreases the CO 2 adsorption capacity of sorbents at the end of each adsorption/desorption cycle, higher molecular weight imine (MW 750000) was used in the preparation of the sorbent LHI-S1:PEI (MW 750000) (1:1) (Table 7.1, Entry 5). As observed from the TGA plot (Figure 7.7), the sorbent LHI-S1:PEI (MW 750000) (1:1) showed improved ability to maintain its CO 2 adsorption capacity. It showed an adsorption capacity of 143.3 mg of CO 2 per gram of the at 55 o C and is very robust, with the loss of <1% (0.78%) adsorption capacity at the end of 10th adsorption/ desorption cycle at 85 o C. It is the most stable one among the sorbents used in the present study. The activity of amines such as pentaethylenehexamine (PEHA), supported by fibrous nanosilica has also been studied. Fibrous nanosilica-PEHA system showed excellent level of adsorption (Table 7.1, Entries 9, 12, 14). LHI-S1:PEHA (1:3) displayed the highest adsorption capacity of 215.6 mg of CO 2 per gram of the sorbent at 85 o C (Table 7.1, Entry 12). However, its adsorption capacity decreased with the number of adsorption/desorption cycles from leaching of the amine due to low molecular weight of PEHA. Figure 7.8 displays the adsorption/desorption cycles of LHI-S1:PEHA (1:3) which gave the highest adsorption capacity of the sorbents studied thus far. 183 Figure 7.7 TGA plot obtained for the adsorption/desorption of CO 2 on LHI-S1:PEI (MW 750000) (1:1) at 25, 55 and 85 o C (left to right) followed by 10 short adsorption/desorption cycles at 85 o C. Figure 7.8 TGA plot obtained for the adsorption/desorption of CO 2 on LHI-S1:PEHA (1:3) at 25, 55 and 85 o C (left to right) followed by 10 short adsorption/desorption cycles at 85 o C. 184 Table 7.1 CO 2 adsorption capacities (mg of CO 2 adsorbed per g of adsorbent) of adsorbents based on fibrous nanosilica supported polyamines. Silica/Amine mg of CO 2 adsorbed per g of adsorbent Entry Adsorbent Ratio 25°C 55°C 85°C 1 LHI-S1: PEI (MW 800) 1 : 1 75.9 120.3 152.9 2 LHI-S1: PEI (MW 25,000) 1 : 1 60.7 122.0 138.9 3 LHI-S1: PEI (MW 25,000) 1 : 2 6.5 23.4 54.9 4 LHI-S1: PEI (MW 750,000) 1 : 1 137.0 143.3 122.6 5 LHI-S1: PEI (MW 750,000) 1 : 2 32.9 75.0 125.8 6 a LHI-S1: PEI (MW 750,000) 1: 1 52.1 97.4 130.0 7 b LHI-S1: PEI (MW 25,000) 1 : 1 65.8 115.0 119.5 8 LHI-S1: PEI (MW 10,000) 1 : 1 62.2 106.1 124.4 9 LHI-S1: PEHA 1 : 1 133.9 172.5 176.1 10 LHI-S1: PEHA 1 : 2 89.9 150.6 202.0 11 LHI-S1: PEHA 2 : 1 92.9 105.8 107.9 12 LHI-S1: PEHA 1 : 3 112.7 159.9 215.7 13 LHI-S1: PEHA : PEI (MW 750,000) 1 : 1 : 1 91.9 139.5 159.5 14 LHI-S1: PEI 750K (1 : 1) & LHI-S1: PEHA (1 : 2) 1 : 1 94.4 148.4 177.9 a. LHI-S1 and PEI (MW 750000) were mixed at 60 o C; b. PEI (MW 25,000) was linear For the purpose of CO 2 adsorption, an ideal support should be able to accommodate a greater amount of PEI because the more the PEI, the greater the potential interaction with CO 2 . 10 To accommodate more PEI, the pore volume of the support should be large. In addition, the active amino groups of the PEI should also be accessible by CO 2 for which large pore diameters and windows openings are also needed. Therefore, pore volume is an important factor in the CO 2 adsorption performance of PEI impregnated solid supports. Pore size of mesoporous materials can be controlled by employing different types of surfactants. 11 Changing the reaction temperature or adding organic co-solvents as swelling agents 11, 12, 13, 14 changes the hydrophobic volumes of the templates and allows greater control over pore size of mesoporous materials. For example, in their pioneering study, 15 Stucky and co-workers systematically varied the amounts 185 of the organic swelling agent mesitylene or 1,3,5-trimethylbenzene (TMB) added to the a triblock copolymer template Pluronic P-123 solution during the preparation of mesostructured cellular foams (MCFs) and found that cell sizes increased linearly with the cube root of the TMB concentration. The cell diameter could also be adjusted by adding the appropriate amount of TMB. Figure 7.9 Caffeine and Urotropine as additives to control pore volumes. Caffeine (Figure 7.9) is a naturally occurring compound found in the seeds, leaves, and fruits of many plants. It is consumed in the form of beverages such as tea and coffee rather than in its pure form, which is a bitter and white crystalline powder. As the global coffee consumption increases, so does the consumption of decaffeinated coffee which is currently estimated to be about 10% of the global coffee market. 16 Nowadays, most of the caffeine in the world is produced as a byproduct of the production of decaffeinated coffee. In one of the major decaffeination process, caffeine is separated through supercritical carbon dioxide extraction in which the supercritical CO 2 acts as a selective solvent to dissolve the caffeine from the coffee beans, leaving other components responsible for the flavor of the coffee. Although this process occurs under supercritical conditions (pressure >72.9 atm, 186 temperature >31.1 o C), we were interested to investigate if caffeine plays any role in CO 2 adsorption under the conditions employed in our investigations. Accordingly, during the addition of cetylpyridinium solution to tetraethylorthosilicate solution, caffeine powder (1.62 molar equivalent of the surfactant) was also added in small amounts and the preparation of the silica nanospheres was carried out without any additional change in the procedure except for the increase in reaction time from 4 hours to 24 hours. After calcination of the as- synthesized material under identical conditions, a fluffy fine white powder (name: KCAF1) was obtained. Compared to LHI-S1, which had been prepared without the addition of caffeine, its surface area was lower but the pore volume and the average pore diameter were significantly higher (Table 7.2, Entry 3). The pore volume decreased from 2.08 to 1.7 cm 3 g -1 and the surface area decreased from 367.86 to 248.52 m 2 g -1 when the procedure was repeated to synthesize the material again (Table 7.2, Entry 4). Nevertheless, the pore volume and pore diameter were significantly higher than those of the silica nanospheres prepared under identical conditions without the addition of caffeine (Table 7.2, Entry 6). Table 7.2 Pore volume, surface area and pore diameter of prepared silica materials. Entry Name Molar Ratio Time Pore Volume Surface Area Pore Diameter CPB Caffeine (h) (cm 3 g -1 ) (m 2 g -1 ) (nm) 1 LHI-S1 1.00 0.00 4 1.42 477.90 3.31 2 LHI-S2 1.00 0.00 8 0.91 425.27 3.51 3 KCAF1 1.00 1.62 24 2.08 367.86 14.99 4 KCAF2 1.00 1.62 24 1.68 248.52 22.48 5 KCAF3 1.00 0.81 24 2.67 200.00 16.80 6 LHI-S3 1.00 0.00 24 0.72 299.62 3.50 7 a KURO1 1.00 0.00 24 0.96 317.21 3.51 a. Urotropine was used as an additive 187 Next, we prepared adsorbents by impregnating the solid support KCAF1 by PEHA in different proportions as shown in Table 7.3. These adsorbents were then tested for their CO 2 adsorption capacity at 25, 55 and 85 o C. As shown in Table 7.3, the adsorbent KCAF1-PEHA1, with 1 equivalent of PEHA impregnated onto the support, showed the highest adsorption capacity of 183.79, 228.55 and 246.20 mg of CO 2 adsorbed per g of the adsorbent at 25, 55 and 85 o C, respectively. The sorbent also displayed fast adsorption/desorption kinetics at 25 and 55 o C. For example, at 25 o C, the sorbent reached its maximum adsorption capacity within about ten minutes of the flow of pure CO 2 (Figure 7.10). However, at 85 o C, both the adsorption/desorption cycles are slow. Despite higher amine loading, KCAF1-PEHA2 and KCAF1-PEHA3 adsorbed less CO 2 than KCAF1-PEHA1, probably due to clogging of the pores, which may occur with higher amine loading. With a PEHA loading of four equivalents of the silica support KCAF1, the resulting adsorbent was a sticky semi-solid and it was not tested for its CO 2 adsorption capacity. Comparing the adsorption capacity of KCAF1-PEHA1 (Table 7.3, Entry 1) with that of LHI-S1:PEHA (1: 1) (Table 7.1, Entry 9), it is clear that higher pore volume and pore diameter of the solid support KCAF1 had a significant positive effect on the adsorption capacity of KCAF1-PEHA1. Despite having a lower surface area than LHI-S1, due to its higher pore volume and higher average pore diameter, KCAF1 proved to be a superior support for PEHA for the purpose of preparing hybrid silica-polyamine adsorbent system. This demonstrates the important role the pore volume and the average pore diameter of the solid silica support play in the efficacy of such hybrid silica-polyamine adsorbent systems. 188 Table 7.3 CO 2 adsorption capacities of sorbents based on PEHA impregnated silica solid supports prepared with caffeine as an additive. CO 2 Absorption Capacity (mg of CO 2 adsorbed per g of adsorbent) Entry Adsorbent KCAF1/PEHA Ratio 25 o C 55 o C 85 o C 1 KCAF1-PEHA1 1:01 183.8 228.6 246.2 2 KCAF1-PEHA2 1:02 138.6 168.5 224.6 3 KCAF1-PEHA3 1:03 173.2 197.5 180.0 Figure 7.10 TGA plot obtained for the adsorption/desorption of CO 2 on KCAF1-PEHA1 at 25, 55 and 85 o C (left to right) followed by 10 short adsorption/desorption cycles at 85 o C. Realizing the important role played by pore volume of solid supports in the CO 2 adsorption capacity of amine impregnated solid supports, we attempted to investigate if decreasing the amount of caffeine added would have any effect on the pore volume. When the 189 CPB/caffeine ratio was decreased from 1/1.62 to 1/0.82, the pore volume increased from 2.08 cm 3 g -1 to 2.67 cm 3 g -1 (Table 7.3, Entry 5) and the average pore diameter increased from 15 nm to 16.8 nm. In contrast, the surface area decreased from 367.86 m 2 g -1 to 200.00 m 2 g -1 . Encouraged by our results of using caffeine as an additive in the synthesis of silica material with high pore volume and pore diameter, we also investigated if a high nitrogen containing molecule such as hexamethylenetetramine (Figure 7.9), also known as urotropine, could also play a role similar to caffeine. Substituting caffeine for hexamethylenetetramine, we synthesized silica material KURO1 under identical conditions. However, compared to the silica nanospheres LHI-S3 prepared without any additive (Table 7.2, Entry 6), its average pore diameter remained almost identical and there was only a very small increase in the pore volume (Table 7.2, Entry 7). 7.3 Chapter 7: Conclusions After preparing silica nanospheres with fibrous morphology and high surface area, we investigated their ability and efficacy as solid supports for amines and polyimines for CO 2 adsorption. The highest adsorption capacity of 215.6 mg of CO 2 adsorbed per g of the adsorbent was observed at 85 o C for the nanosilica impregnated with three equivalents for PEHA (adsorbent LHI-S1:PEHA (1:3)). The sorbent LHI-S1:PEI (MW 750000) (1:1) had an adsorption capacity of 143.3 mg mg of CO 2 adsorbed per g of the adsorbent at 55 o C and was very robust, with the loss of <1% (0.78%) adsorption capacity at the end of 10th adsorption/ desorption cycle at 85 o C . Another important finding of our study is that when caffeine is added as an additive, the pore volume and the pore diameter of the resulting material are enhanced significantly. With CPB/caffeine ratio of 1/1.62, the silica material had a pore volume of 2.08 cm 3 g -1 and the 190 resulting adsorbent with PEHA proved to have an excellent CO 2 adsorption capacity of 183.8, 228.6 and 246.2 mg of CO 2 adsorbed per g of the adsorbent at 25, 55 and 85 o C, respectively. Although the silica material with a pore volume of 2.67 cm 3 g -1 is yet to be investigated for its efficacy as a solid support for CO 2 adsorption, based on the findings of this study and those reported in the literature, it is expected to have an even higher CO 2 adsorption capacity than the one obtained so far in this study. 7.4 Chapter 7: Experimental 7.4.1 General Polyethylenimines (PEI) of molecular weights 800, 10000, 25000, 25000, 750000 (all branched), pentaethylenehexamine (PEHA), tetraethylorthosilicate, cetylpyridinium bromide, and urea were purchased from Sigma-Aldrich. PEI of molecular weight 25000 (linear) was purchased from Polysciences, Inc. Solvents such as pentane, methanol and cyclohexane were also obtained from Sigma-Aldrich. Calcination was performed in a Lindberg Bluebox Furnace at 550 o C. SEM (JSM-7001F-LV) and HRTEM (JEOL 2100F) analyses were conducted at the Center for Electron Microscopy and Microanalysis, University of Southern California. 7.4.2 Experimental Procedures Preparation of Fibrous Silica Nanospheres: High surface area silica nanospheres (LHI-S1) were prepared using our modified procedure based on a previous report. 9 Tetraethyl orthosilicate (TEOS, 12 mmol) was dissolved in 30 mL of cyclohexane and 1.5 mL of pentanol. A solution of cetylpyridinium bromide (CPB, 2.6 mmol) and urea (1 mmol) in 30 mL of water was slowly added. The mixture was first stirred at room temperature for 30 minutes and then in an oil bath for 4 hours at 120 o C instead of 191 previously reported microwave procedure. After cooling to room temperature, silica was isolated by simply spreading as a thin layer on a flat tray and allowing to dry overnight. Though previous protocols involved centrifugation with acetone and solvent removal by rotary evaporator for the isolation of silica, we found it convenient to isolate it by simply pouring the reaction mixture onto a petri-dish or a tray and then allowing it to dry overnight inside a fume hood. Finally, the collected silica was calcined (heated) for 6 hours at 550 o C (temperature ramp 17.5 o C/min). The surface morphology of the snow white powder obtained after calcination was examined by scanning electron microscopy (SEM) and further characterization by high resolution transmission electron microscopy (HRTEM). Preparation of Silica material with Caffeine as an additive: Apart from the addition of caffeine powder in small amounts during the addition of a solution of cetylpyridinium bromide and urea to the solution of tetraethyl orthosilicate in cyclohexane, the procedure is same as in the preparation of fibrous silica nanospheres. Preparation of the Sorbents: The following is an illustrative example of the preparation of a supported amine sorbent composed of 50 wt% polyethylenimine and 50 wt% silica. Polyethylenimine (LMW 800, branched, 0.4 g) was dissolved in 25 mL of methanol. This solution was then added stepwise under stirring to 0.4 g of our silica nanospheres (LHI-S1) suspended in 100 mL methanol to ensure a good dispersion of the polyethylenimine on the LHI- S1 support. The solution was then mixed for an additional three hours. After that, the solvent was removed from the mixture by heating at 50 o C under vacuum on a rotavapor followed by vacuum treatment overnight (< 1 mm Hg). The supported amine sorbent LHI-S1:PEI (MW 800) 192 was obtained as a white solid. CO 2 Capture and Release Studies The CO 2 adsorption and desorption measurements were performed on a Shimadzu TGA- 50 thermogravimetric analyzer. In general, 5 mg of solid adsorbent was loaded in a platinum pan and placed into the TGA instrument (Figure 7.11). The sample was initially heated to 110 °C under a pure N 2 atmosphere (flow rate = 60 mL/min) and this temperature was maintained for 30 minutes to desorb moisture and CO 2 from the surface (Figure 7.12). The temperature was then lowered to 25 °C and the adsorbent was exposed to pure CO 2 (flow rate = 60 mL/min). CO 2 was then desorbed under N 2 at 85°C. The adsorption and desorption times were 180 and 90 minutes, respectively. The adsorption/ desorption cycle was repeated at 55 °C and 85 °C. Then, at 85°C, ten short adsorption/ desorption cycles with adsorption and desorption times of 15 and 25 minutes, respectively, were performed to study the stability of the sorbent. Figure 7.11 TGA apparatus 8 193 Figure 7.12 Schemtatic of adsorption/desorption cycles of CO 2 on silica-polyamine sorbents at various temperatures. 194 7.5 Chapter 7: References 1. 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Abstract (if available)

Abstract This dissertation describes the development of new methodologies for the synthesis of organonitrogen compounds, which include β-fluoroethylamines, mono-fluorinated α-amino acids and β-amino esters, primary anilines, nitrosoarenes, and azoxy and azobenzenes. It also expounds on the utilization of polyamines and imines in preparation of solid adsorbents for efficient capture and release of carbon dioxide. ❧ Chapter 1 provides a brief overview of Nitrogen atom, its incorporation into living organisms, the important role of organonitrogen compounds as well as some multi-component reactions for their synthesis. The aim and scope of this dissertation is also included in Chapter 1. ❧ Chapter 2 describes the development of a direct multi-component protocol for the synthesis of highly diverse derivatives of β-fluoro(phenylsulfonyl)ethylamine by a Mannich-type reaction from their molecular sub-units, α-fluoro-α-nitro(phenylsulfonyl)methane (FNSM), or α-fluorobis(phenylsulfonyl)methane (FBSM), formalin, and various primary and secondary amines. The products are obtained in high yields and selectivity even without the use of base in many cases. ❧ In Chapter 3, the multi-component protocol is extended to furnish fluorinated α- amino acids and β-amino esters. The methodology employs simple molecular units, an organofluorine unit, an amine and a carbonyl unit to generate the fluorinated organonitrogen compounds. ❧ Boron trifluoride monohydrate is an excellent Brønsted acid catalyst system for a wide range of reactions. It is a non-oxidizing acid catalyst prepared easily by bubbling BF₃ into water. Chapter 4 deals with the application of boron trifluoride monohydrate/sodium azide combination as an efficient reagent system for electrophilic amination of aromatics. The present method avoids the use of expensive superacids such as trifluoromethane sulfonic acid and provides a facile access to aromatic amines directly from aromatics. ❧ Nitroso compounds are versatile reagents in synthetic organic chemistry. A feasible protocol for the ipso-nitrosation of aryl boronic acids using chlorotrimethylsilane/sodium nitrite combination as a unique nitrosation reagent system is described in Chapter 5. ❧ Chlorotrimethylsilane is a readily available reagent widely used in organic chemistry. As a reducing agent it is used mainly in combination with other reducing agents. Chapter 6 describes the use of chlorotrimethylsilane as the sole reagent in the reduction of nitrosobenzene to azoxybenzene. Attempts to extend the substrate scope of the reaction are also described in this chapter. The protocol is based on the high reactivity of nitrosoarenes and the extraordinary affinity of silicon towards oxygen. ❧ Synthetic design of innovative materials with high adsorption capacity is essential for capturing, storing and recycling carbon dioxide (CO₂) efficiently. CO₂ recycling is a crucial step towards the “Methanol Economy” which is based on methanol as a viable renewable energy storage medium and also as a chemical feedstock. Chapter 7 delineates the development of new fibrous nanosilica-supported polyamine materials for CO₂ adsorption. It also describes the use caffeine to effect higher pore volumes and average pore diameters of the mesoporous silica nanospheres, which displayed high CO₂ adsorption values when impregnated with polyamines.

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Creator Gurung, Laxman (author)

Core Title New synthetic methods for organonitrogen compounds

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 05/16/2017

Defense Date 10/21/2015

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag boron trifluoride monohydrate,chlorotrimethylsilane,electrophilic amination,ipso-nitrosation,multi-component reactions,OAI-PMH Harvest,organonitrogen compounds,β-fluoroethylamines

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Language English

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Advisor Prakash, G. K. Surya (committee chair), Olah, George A. (committee member), Shing, Katherine (committee member)

Creator Email gurungla@gmail.com,lgurung@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-200443

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Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA