Partial Synthesis of a Novel Tetra-amido Macrocyclic Ligand for Potential Use as a Green Oxidation Catalyst

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Title: Partial Synthesis of a Novel Tetra-amido Macrocyclic Ligand for Potential Use as a Green Oxidation Catalyst
Physical Description: Book
Language: English
Creator: Flowerday, Adam
Publisher: New College of Florida
Place of Publication: Sarasota, Fla.
Creation Date: 2013
Publication Date: 2013


Subjects / Keywords: TAML
Green Oxidation Catalyst
Green Chemistry
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theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation


Abstract: In recent years, advancements in environmentalism, such as the development of electric-powered cars and the increased practices of recycling, have been made in an effort to reduce the negative side-effects of technology uses. Research in alternative sources of energy, as well as cleaner methods of production for every day goods, has significantly advanced over the past fifty years. One of the scientific areas that has contributed greatly to this advancement is green chemistry, which focuses on developing chemicals and syntheses of chemicals that are more environmentally benign. Within this area of chemistry, an area of interest is the development of green oxidation catalysts, which can be utilized for a wide variety of functions. One of the current projects in synthesizing green oxidation catalysts is the tetra-amido macrocyclic ligands (TAML) project being conducted by Prof. Terrence J. Collins' research group at Carnegie Mellon University. The ligands that are being developed have the potential for many applications in water purification, such as the removal of endocrine-disrupting chemicals and de-coloration of effluent streams. This thesis discusses in detail the need for environmental chemistry and the partial synthesis of one of the TAML project's catalyst designs. Various attempts were made to synthesize a full macrocycle, but complications during the synthesis process prevented completion of this molecule.
Statement of Responsibility: by Adam Flowerday
Thesis: Thesis (B.A.) -- New College of Florida, 2013
Bibliography: Includes bibliographical references.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Local: Faculty Sponsor: Scudder, Paul

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Source Institution: New College of Florida
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Material Information

Title: Partial Synthesis of a Novel Tetra-amido Macrocyclic Ligand for Potential Use as a Green Oxidation Catalyst
Physical Description: Book
Language: English
Creator: Flowerday, Adam
Publisher: New College of Florida
Place of Publication: Sarasota, Fla.
Creation Date: 2013
Publication Date: 2013


Subjects / Keywords: TAML
Green Oxidation Catalyst
Green Chemistry
Genre: bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation


Abstract: In recent years, advancements in environmentalism, such as the development of electric-powered cars and the increased practices of recycling, have been made in an effort to reduce the negative side-effects of technology uses. Research in alternative sources of energy, as well as cleaner methods of production for every day goods, has significantly advanced over the past fifty years. One of the scientific areas that has contributed greatly to this advancement is green chemistry, which focuses on developing chemicals and syntheses of chemicals that are more environmentally benign. Within this area of chemistry, an area of interest is the development of green oxidation catalysts, which can be utilized for a wide variety of functions. One of the current projects in synthesizing green oxidation catalysts is the tetra-amido macrocyclic ligands (TAML) project being conducted by Prof. Terrence J. Collins' research group at Carnegie Mellon University. The ligands that are being developed have the potential for many applications in water purification, such as the removal of endocrine-disrupting chemicals and de-coloration of effluent streams. This thesis discusses in detail the need for environmental chemistry and the partial synthesis of one of the TAML project's catalyst designs. Various attempts were made to synthesize a full macrocycle, but complications during the synthesis process prevented completion of this molecule.
Statement of Responsibility: by Adam Flowerday
Thesis: Thesis (B.A.) -- New College of Florida, 2013
Bibliography: Includes bibliographical references.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Local: Faculty Sponsor: Scudder, Paul

Record Information

Source Institution: New College of Florida
Holding Location: New College of Florida
Rights Management: Applicable rights reserved.
Classification: local - S.T. 2013 F6
System ID: NCFE004762:00001

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Partial Synthesis of a Novel Tetra amido Macrocyclic Ligand for Potential Use as a Green Oxidation Catalyst By Adam Flowerday A Thesis In partial fulfillment of the requirement for the degree of Bachelor of Arts in Natural Sciences Under the spon sorship of Dr. Paul Scudder Sarasota, Florida May, 2013


ii Acknowledgements I would first like to thank Dr. Paul Scudder for his sponsorship of this have been completed. me to think outside of the norm for this project, and in doing so prompted me to conduct novel reactions, some of which were actually successful. perience to the extent I could have, the help he offered was invaluable and greatly appreciated. I would also like to thank Dr. Suzanne Sherman and Dr. Venus Dookwah Roberts for providing me with experienced insight to my reactions as I was conducting the m. Their help gave me the direction needed with the novel reactions that were conducted over the course of this thesis, often when the reactions seemed as if they had hit a dead end. Katie Nugent is also someone I would like to thank, as she was in lab oratory with me throughout the majority of my lab work. Countless hours were spent in the laboratory in the attempts of synthesizing the target compound of this thesis, and there is no way those hours could have been as


iii bearable as they were without her c ompany, consistent support, and good attitude. If anyone understands the difficulties gone through over the course Lastly I would like to thank everyone that was not directly in volved in the writing or lab work conducted over the course of this thesis. No amount of words can describe the growth I have gone through as a person over my academic career at New College of Florida, and naming all of the people responsible for that wou ld be a difficult if not impossible task. My special thanks goes to my mom, Laurie, my dad, Jim, my brothers, Drew and Micah, and my other family: Kathleen Brindley, Ali Vargas, Jennie Caskey, Nicole Noujaim, Zachary Low, Lydia Dumais, Katie Newton, Heath er Barnes, Mackenzie Pawliger, Ca rlos Arias, Grayson Chester, Judy Lobo and Je rri Lynn Knight


iv Contents 1. Introduction 1 1.1. A Brief History o 1.1.1. 1.1.2. 1.1.3. 1.1.4. Before the Age 1 1.1.5. The I 1.1.6. Late 19 th Cen 1.2. The Environmental Movem e nt and the Chemistry Behind It 17 1.2.1. Advan 1.2.2. Mo 1.3. Green Chemistry: The Aim to Fix Yesterday, Today, and Tomorr 1.3.1. How Gre en Che 26 1.3.2. 30 1.3.3. 1.4. The TAML Proj ect 35


v 1.4.1. .. 35 1.4.2. 1.4.3. 44 2. Results and Discussio 51 2.1. Modifications to the 52 2.1.1. 5 2 2.1.2. Prospective Benefits of the Modified Ligand Design 5 3 2.1.3. 4 2.2. 2.2.1. 2.2.2. Dichlorobis 1,2 2.2.3. O Phenylenediamine a 2.3. Bis(2 8 2.3.1. 9 3. Genera 6 2 3.1. Synthesis of tert butyl (2 aminophenyl) carbamate 6 3 3.2. 6 5 3.3. Synthesis of Dichlorobis(1,2 phenylenediamine) Nickel(II) 6 7 3.3.1. Maxcy et al. 6 7


vi 3.3.2. 9 3.4. Synthesis of Methyl Propargyl Malonyl Diethyl Ester 7 0 3.5. Synthesis of Methyl Propargyl Malonic Acid 2 4. Concludsion 7 4 A PPENDIX A .. .. 7 5 References 82


vii List of Figures 1.1 Reaction Mechanism of O zone (O 3 ) w ith the CFC Freon 11 (CFCl 3 1.2 A S tructural T imeline of the TAML P P rogress ... 3 9 1.3 General Reaction Mechanism o f Dioxygen Activating 1.4 TAML Molecule That Has Been Designated the Most Efficient 5 1.5 Reaction P athway U sed by Terrence J. Collins 47 1. 6 A Predicted trans Conformati D iamino oxanilide .. 4 9 2.1 4 3.1 Synthesis of T ert butyl (2 aminophenyl) C arbamate 62 3.2 Synthesis of bis(2 nitrophenyl) M alonamide ......... 64 3.3 S ynthesis of D ichlorobis(1,2 phenylenediamine) nickel(II) 6 6 3. 4 Synthesis of M ethyl P ro pargyl D iethyl E ... 69 3. 5 Synthesis of M ethyl P roparg yl M 7 1


viii ABSTRACT Technological advancement has been an intricate part o f the development of human civilizations since nomadic people first established permanent settlements. Technology has not only helped to accommodate for the increased demand in resources as the population has increased, but has also helped in improving th e quality of life of many civilizations for c advancement, however, many environmental problems have stemmed from the use and overuse of technology. Only recently have developments b een made that focus not only on the demands of the present, but also on reducing potentially negative consequences in the future. In recent years, advancements in environmentalism such as the development of electric powered cars and the increased practice s of recycling, have been made in an ef fort to reduce the negative side effects of technology uses. Research in alternative sources of energy, as well as cleaner methods of production for every day goods, has significantly advanced over the pa st fifty yea rs. One of the scienti fic areas that has contributed greatly to this advancement is green chemistry, which focuses on developing chemicals and syntheses of chemicals that are more environmentally benign. Within this area of chemistry, an area of interest is


ix the development of green oxidation catalysts, which can be utilized for a wide variety of functions. One of the current projects in synthesizing green oxidation catalysts is the tetra amido macrocyclic ligands ( TAML ) project being conducted by Prof. Te The ligands that are being developed have the potential for many applications in water purification, such as the removal of endocrine disrupting chemicals and de coloration of effluent strea ms. This thesis discusses in detail the need for environmental chemistry and the partial attempts were made to synthesize a full macrocycle, but complications during the synthesis process p revented completion of this molecule. Paul H. Scudder


C hapter 1 I ntroduction 1.1. A Brief History of Man and the Environment It is a well known fact that the existence of mankind has had an impact on the environment, just like the existence of eve ry animal, plant, rock, body of water, and everything else on earth has in some way It can be said, however, that humans have had the greatest environmental impact in their utilization of not only technology but also of external sources of labor power This exploitation of labor power, first from animals of burden and later from machines, can be referred to as amplification of effort, and is debatably the main reason humans have advanced so much further than any other species on earth This development, though, has had negativ e consequences that humans have only recently begun to deliberately address ; these consequences have extended to the point that really unaffected by human activity as ] air pollution, intensification


2 in t he acidity of precipitation, radioactive fallout, and the penetration of ultraviolet radiation due to the depletion of the ozone layer in the high atmosphere [1]. The developmen t of the technologies and cultures of civilizations over the course of histor y shows how modern humans came to have such a widespread impact on the environment, and these same developments can in turn eventually lead to a resolution for that impact 1.1.1 The Beginning All of the accomplishments made by the human race up to the present day can be traced back as having the common facto r of amplification of effort It can be sa id that without the initial utilization of animals of burden, such as oxen cows, and horses, greatly hindered and therefore never would have reached the level of advancement that it has today In fact Guns, Germs, and Steel specifically addresses the fact that the early civilizations that were ab le to advance the furthest were those to which the mos t farming efficient beasts of burden were native [2] These early civilizations then migrat ed, bringing with them technologies that would eventually shape the modern world


3 The formation of civilizations happened over thousands of years in both gradual shifts and revolutionary transitions As nomadic early humans evolved, traveled, and developed cultures, advances in technology continued at an exponential rate and a mong the most important of these revolutionary t ransition s was the development of agricu lture Approximately 11,000 years ago nomadic humans began the process of domesticating plants and animals while establi shing more permanent settlements, which in turn led to the foundations of modern civilizations While this revolution, known as the Ne u nquestionably one of the most important events in [ 3 ] lifestyle are to this day an issue of controversy Many scholars believe, however, that agriculture was the result of early plant domestication coupled with the aftermath of a worldwide climate shift [2] Though the definite origin of the practice of agriculture may never be incontestably proven, the earliest signs of town formation have lead many researcher s to an explanation for this revolutionary practice Archeological formed around 11,500 years ago, right around the end of a 1000 year long ice age This village was discovered in t he Fertile Crescent, an area located in what now consists of parts of Egypt and the Middle East, near the city of


4 Jericho. Many archeologists and other specialists theorize that the reason for the formation of this village would have been the lack of reso urces elsewhere mainly edible plants, available to p eople due to a harsh climate change right after the end of the ice age [2] The need to conserve as many resources as possible would have forced people to remain in areas that had reliable sources of fo od, like the plants which were able to endure the harsh weather changes With evidence of an early form of a granary in th e ancient village near Jericho the idea that plants were harvested and stored for future use is a very likely theory and the growt h and regrowth of crops would have attracted animals that could be captured and used for more than their meat T hese animals, known as beasts of burden were b red and eventually domesticate d enabling the people of Jericho to exploit the power of a nimals s uch as the cow, the oxen, and the horse, to harvest and plant crops more efficiently [ 2 ]. A steady supply of food led to an overall longer life expectancy, which eventually caused a steady increase in the population The settling down of nomadic humans m arked a distinct transition in many aspects of life for our species The steady supply of nutrition allowed for an increase in population which in turn le d to a larger work fo rce, which, along with the incorporation of surplus storage, produced food in pl entiful


5 enough quantities that not every member of a town or city was needed in order to mainta in a consistent and sufficient food supply The surplus of food available to developing civilizations coupled with the increase in population allowed for the de velopment of task specialization outside of those directly related to survival, which brought about crafts such as metallurgy and pottery New skills that required high levels of heat consequently required burning large amounts of wood, resulting in an in creased level of air pollution in developing cultures in which the people practiced these skills With the creation of cities, drinking water became available via irrigation systems and wells The systems of waste dispos al also involved waterways, includ ing sewage and offal (i e meat from animals not consumed) Waste that was not disposed of via water systems was simply garbage and excrement on to the unpaved streets which were period ically covered with clay, eventually raising the street levels to the extent that stairs [ 4 ] This waste would build up and attract opportunistic organisms, and the accumulated waste would then be washed by rain into rive rs and groundwater The effects of these careless water and waste management practices became more noticeable over time, showing a


6 clear example of the consequences for mankind when the environment is not properly cared for 1.1.2 Moving Forward In one light the rise of agriculture brought about resources that allowed for the rapid increase in human population This increase in population, though, was coupled with the adverse effect of a noticeable decrease in standard of health When comparing pre and po st Neolithic revolution skeletons of human beings archeologists note that N eolithic villagers were less healthy than hunters and herders, but city dwellers showed further decline; studies of their skeletal remains show that they were shorter in stature, lived briefer lives, suffered more from bad teeth and bones, and were subject to [1] Though population and population density increased within these cities, quality of life visibly decreased, and created a pattern which amplified the impact humans had on the environment over generations As evidence shows, the development of civilization s involved a great number of techno logical, cultural, and economic advances Cities developed and grew, both in size and number, and began to rel y on not only the


7 environment in which they were located, but on those of other cities as well This inspire d even more production of commodities, as well as more trade routes for easier travel between cities, and existing problematic practices only incre ased [empires] had the ability to organize numbers of people in vast projects that transformed the landscape, such as irrigation schemes, road [ 1 ]. While these practices were damaging, mankind did no t remain completely oblivious to the impact it was having on the environment In fact, during what is known as the Axial Age many ways of viewing the environment and the world as a whole began to reform s been a direct product of their ability to obtain and maintain resources As civilizations were built, destroyed, conquered, and expanded, t he demand for resources, including food, weapons, and textiles, became such that, i n Greek writings, many acts of human interference with the environment, such as agriculture and animal domestication, were depicted as positive actions on the environment Seeing planned efforts make the landscape more beautiful a nd serviceable for human purposes [1] which only encouraged further environmental impact both for function and for aesthetics With thorough exploitation of the environment


8 being societally condoned and with the s teady population increase, the condi tion of the environment worsened over time 1.1.3 The Middle Ages By the beginning of the Middle Ages around 500 a d human population had increased worldwide to approximately 2 0 0 million with the technologically advanced populations of Europe an d Asia comprising over eighty percent of this number This large population, along with the development of useful inventions in agriculture magnified environmental problems such as demand for resources and the amount and types of land that could be plowe d for agriculture and architecture The demand for more goods prompted innovation in b oth technology and processes used to obtain said goods; two notable advancements were the heavy plough and the development of the three field crop rotation [5] which en abled and required, respect i vely t he clearing of even more land By t he end of the M iddle A ges the world population had increased to around 500 million, and with such a sharp increase in only one thousand years, the resources of Europe and Asia would so on be depleted to a dangerously low level During the medieval period deforestation had become one the most prominent environmental problems in Europe; wood was used for everything


9 from fuel to house building People would clear wooded areas not only for their resources but for the land as well, utilizing the land for settlement and grazing are as for farm animals People in Europe during the middle ages began to view forests as a waste of land convinced that the manipulatio n of nature was not only benef icial but also encouraged by the near ubiquitous Christian religion This toward forested areas lead to virtually uninhibited clearing of woodlands, increasing p roblems attributed to deforestation, such as flooding and the eradication o f various plant and animal species [6] Deforestation would eventually lead Europe in to a state of depleted resources, forcing the citizens of Europe into famine numerous times throughout this era The ability to grow and distribute food at a rate matchi ng that of the increase in demand was hindered greatly by several factors including deforestation The main hindrance, however, was that resources were not being replenished as fast as they were being used By the 1300s, overall population had nearly doubled since the beginning of the middle ages, from around 26 million to 50 million people, and [7] It was during the fourteenth century that both the Great Famin e of 1315 1322 and the Black Plague affected Europe; the impact of the Black Plague was


10 actually worsened by the fact that many people were starving and therefore weakened and more vulnerable to infection by the time the p lague hit In taking out such a large percent of Plague brought attention to several problems that the people of Europe needed to take responsibility in solving three percent by the Black Pl ague, and survivors of it were left with a devastating aftermath The plague most ly affected the poor population, which deteriorated the labor force significantly consequently causing an economic downturn This downturn forced empires and local township s to enforce capes could not be lined with fur; the wicks of funeral candles had to be [7] The sharp decrease in demand for resources, both through the sharp popul ation reduction and through economic depressi on, was before the Plague, totaling around 46 million people


11 1.1.4 Before the Age of Industry Shortly after the medieval period of European history between the late fifteenth century and the mid eighteenth century, marked another significant step in the environmental impact that humans were making: the beginnin g of European empires sought to seize control of the undeveloped land North paralleled that of Eu rope and therefore made it ideal for cultivating crops native to Europe Ecosystems were completely restructured with the introduction of foreign crops and animals along with viruses and germs that the people native to the Americas had no immunities t o Technology was also much more advanced in Europe than in the Americas, and weapons wielded by European conquerors greatly outmatched the primitive weaponry used by native Americans [2] In conquering the New World, a vast array of resources became ava ilable for use and exploitation by the European invaders The E arly Modern Period of Europe is an era most represented by what is known as the Renaissance During the Renaissance many changes took place in the theory and practice of technological advance ment: scientific knowledge previously lost to the church was recovered, and


12 scientific m easuring tools such as the microscope, barometer, and thermometer were invented During the Renaissance is also when Johannes G u tenb rg invented the printing press, re volutionizing the efficiency in which humans could shar e information [8] It was also during the renaissance that d eforestation from the Middle Ages had left the people of the renaissance with plenty of timber for fuel and ship building as well as a deva stated environment [6] Major contributing factors in environmental awareness came from the short and long term effects of settlers onto new lands The short term effects were seen by the rapid and excessive utilization of resources, sometimes to the po int of multiple The long term effects, however, came in the form of other types of domina tion : exotic species invasion With new climates that mimicked those of Europe, plant s animal s and microbe s that were carried to the Americas on European ships caused ju st as much if not more of an environmental disturbance than did the settlers themselves In fact, it is thought that the smallpox virus was a key factor in the Span numbers and terrain familiarity [2] This was only one in a long list of diseases spread by the overseas travel of the Europeans, including chicken pox, mumps, malaria, and pneumonia During the early modern period, as the


13 Americas f dealt with new, unforeseen environmental problems 1. 1 5 The Industrial Revolution The Industrial Revolution was the time period approximately between 1750 and 1850 in which technological advancement and popularization brought about an unpreceden ted economic growth During this time bulk production and automation were made easier and for the first time in history neither man nor animal power was always necessary in order to make a large number of products Bulk manufacturing, however, brought a number of ecological problems with the number of resources and the fuel used up by these industrial practices One of the key inventions that defined the Industrial Revolution w as the steam engine, a device that was patented during the Early Modern per iod The reason that the steam engine did not become such a driving force until almost one hundred years after it s first use in mining and textile industries was because the early models required large amounts of coal and were only practical near natural water sources. While commercially available by 1712, the steam engine gained most of its popularity after James Watt was able to make improvements on it that allowed for more efficient


14 fuel consumption and also allowed for placement of factories away from flowing water sources such as rivers [9] With the practical steam engine commercially available, the use of coal as its fuel source escalated to unprecedented levels The use of coal as a common fuel source, as opposed to wood, meant an increase in fuel efficiency The burning of coal release s sulfur into the atmosphere and produces carbon dioxide and fly ash ; i n developing cities during the Industrial Revolution where coal was replacing wood as a fuel source the by products of burning coal bec ame detrimental to the health of the people in these cities Along with the health effects that the transition from wood to coal was causi ng, the environment surrounding these coal burning factories became covered in soot This soot created a darkened ha bitat in which light colored animals were at a disadvantage, resulting in industrial melanism, or the darkening of skin, plumage, and/or pelage of the animals found in these environments [10] Majorly impacting more industrialized cities, and just as cons equential as the air pollution caused by the increased use of fossil fuels was the sewage pollution caused by the sudden surge in population Even though by the 1800s sewer systems with collection sewers and pumping stations had been impl emented in more d eveloped cities, like London, these


15 sewage systems still discharged into nearby rivers without any pollution removal, solid or otherwise [3] As sewers bec ame more popular with the progression of the Industrial Age build up of the sewage in rivers became a health risk Chemistry during the Industrial Revolution flourished with the discovery of several mass production techniques that yielded high products Two major contributions that were precursors to many other large scale production techniques were the synthesis of sulfuric acid by the lead chamber process in 1746 and the production of sodium carbonate by the Leblanc process in 1791 [11] The Industrial Age also marked a distinct period in which more definite procedures of syntheses were available increasing the number and kinds of advancements that took place in the chemical industry, and in turn widening the spectrum of pharmacological benefits and consequently improving the quality of life in humans 1. 1 6 Late 19 th Century to the Presen t Day With the highest rate of technological advance ments having occurred in the last couple hundred years, people of this era began approaching environmental problems from a more educated standpoint Many advances such as the development of the periodic table of elements by Dmitri


16 Mendeleev and the foundation of chemical thermodynamics by Josiah Willard Gibbs happened during the 19 th century [12] helping to increase the understanding of chemical properties and principles Long term effects, however, of common chemical uses such as pesticides for crops and the burning of fuels were not yet understood, and therefore these practices were largely unregulated up until the second half of the 20 th century As a utomation became more conventional and while wast e emissions remained unregulated, air pollution increased due to the r eliance on fossil fuels for factories automobiles and other forms of transportation, and electricity distribution O ver the course of history, technological advancements have been ma de to not only aid in growing need for survival but also to satiate the desire to thrive The invention o f the internal combustion engine and subsequently the gasoline engine, ha s been one of the most influential contributions to modern s ociety, enabling humans to p erform a multitude of tasks, s uch as long distance trade, without the requirement of much physical labor, if any at all Throughout the past 150 years in what i s known as the Technological Era, engines have been used to move trains, cars, airplanes, and tractors It can therefore be said that the gasoline engine


17 is one of the most widely used invention s in developed countries, and has thus become a major contributor to pollution around the world T echnology has developed at its fastest rate during the Technological Era, and the scientific understanding of the processes and consequences of said technology has in turn expanded Advances have been made over this era in understanding processes like the reactions that occur betw een chlorofluorocarbons and ozone As mankind moved into the 20 th and 21 st centuries thorough understanding of our own technology has allowed us to revise old, harmful processes and come up with new, more efficient, more environmentally friendly alternat ives Innovative ideas with ecological impact in mind continue to arise today, but, without the environmental movement of the mid 20 th century, would very likely not have had such enthusiastic support 1.2 The Environmental Movement and the Chemistr y Behind It Chemistry like many other sciences has seen some of its most rapid advancement in the past 2 50 years with m odern discoveries in chemistry including nylon, polycarbonate, refrigerants, anti cancer medication and


18 plastics [13] Some advancem ents that have been made, however, have had unforeseen, often negative effects on not only the environment like ozone depletion but on the people that have been exposed to the chemicals used to produce these new products Fortunately during this rapid advancement, practices in chemistry are improving as our knowledge and understanding of the driving forces behind chemical reactions expands In understanding the chemistry behind our technologies, progress can be made to counteract the harmful substances that still exist in the environment 1. 2 1 Advances in Modern Chemistry Many modern advances in chemistry have greatly benefitted our society, including the invention of plastics as a convenient lightweight material pesticides that work preventativel y, and refrigeration technologies that improved food storage and trade world wide. Many people, though, have not viewed the advancement of chemistry as positive technology for reasons such as the fact that p lastics are chemically so stable that their abil ity to biodegrade is yet undocumented, and therefore present a problem as being an unnatural presence in the environment long after they are disposed of [12] With so many uses for plastic, such as bottles, bags, and can holders, animals are in danger of finding these products and dying as a result of


19 ingestion or entrapment This, however, is only one of many destructive chemical impacts Chemical pesticides became increasingly popular as agricultur al practices increased The most notable of these art ificial pesticides was the use of DDT, a now banned pesticide, which still persists in the environment fifty years after the d iscontinuation of its use as a pesticide DDT D ichloro D iphenyl T richloroethane ) cause d detrimental effects to the e supply and underground water This began a process in which small animals in the water would eat plants that had absorbed the DDT and then when larger animals, such as small fish, ate those animals the DDT would Eventually, after years of DDT use, the birds, which ate the fish which had accumu lated DDT in their systems, began to lay eggs with softer shells which would break therefore banned in 1972 i n the United States though it still persists today in our environment as a probable human carcinogen and a detriment to the ner vous and reproductive system [14] Another chemical group discovered and subsequently banned in the past hundred years or so was that of chlorofluorocarbons (CFCs) which were


20 use s as refrigerants, aerosols, and insulating foams CFC gases are inherently non toxi c to humans colorless, odorless, nonflammable, and stable when emitted and this is one of the reasons they became s o popular in so many products; [15] CFC s, however, de compose under ultravio let (UV) light in the stratosphere : chlorine is releas ed as its free radical which then attacks a molecule of ozone (O 3 ) The ozone molecule then degrades, creating oxygen gas (O 2 ) and the hypochlorite free radical Two of these free radicals then react to form chlorine pero xide, eventually releasing two chlorine radicals and forming oxygen gas (Figure 1.1) This catalytic degradation of ozone into oxygen gas has, over time, depleted the ozone layer in the stratosphere, reducing the amount of absorption of UV light With more UV light reaching the surface of the E arth the risk of melanoma has increased since the use of CFCs and although laws to phase out CFCs in the United States have been in effect since 1978, their effects are still recognized as a problem today


21 F igure 1.1: Reaction mechanism of ozone (O 3 ) with the CFC Freon 11 (CFCl 3 ) [1 5 ] A third example pollution in the water supply Over the last century, pollutants, pesticides and hormones have become real concerns as studies continue to show not only the increasing levels of these artificial chemicals found in everyday drinking water, but also the long term effects these chemicals have had on generations of people that have been subject to them A certain group of these pollu tants, called endocrine disrupting chemicals, (or EDCs) has raised concern in their attribution to a multitude of developmental disorders which can be traced back to the endocrine system In a scientific statement released by the Endocrine Society, variou s studies showed disruptors have effects on male and female reproduction, breast development


22 and cancer, prostate cancer, neuroendocrinology, thyroid, metabolism and [ 16 ] With even more evidence being collected against the effects of EDCs and other chemicals found in the current water supply, a method of eliminating these contaminants becomes ever more necessary 1. 2 2 Modern Environmentalism While there have been many negative consequences in the development of chemicals and chemical procedures, awareness of these consequences has led to many positive steps taken to fix the problems we have caused over the course of our existence For the United States of America, one of the more monumenta l movements in bettering the environment was the creation of Earth Day and the EPA Earth Day was an idea conceived by Senator Gaylord Nelson in the summer of 1969 after an oil spill off of the coast of Santa Barbara This inspired Senator Nelson to orga nize enough people to send out a message across the country that the environment needed to be recognized as a problem worth fixing In April of the following year, thousands in New Yor k or Philadelphia or with events big and small at [ 1 7 ]


23 During Senator awareness, President Richard Nixon was establishing governmental policies tha t would eventually lead to the formation of the Environmental Protection Agency (EPA) During his term in office, President Nixon established what was known as the Environmental Quality Council, which discussed the need for structural reform not only in c onserving wildlife but also in protecting other aspects of the environment such as the air and water This reform le d to what are now known as Environmental Impact Statements, or project reports submitted by all federal agencies that account for likely e nvironmental consequences of said projects President Nixon also unprecedented 37 [that included] asking d a clean up of federal [ 1 7 ] An autonomous government agency was created in 1970 to oversee these reformations, marking the formation of the United States Environmental Protection Agency era of major environmental reform with the implementation of over 20 new conservation laws including the Clean Air


24 standards as well as national standards for significant new pollution [ 1 8 ] This act would require the reduction of hydrocarbon and carbon monoxide emissions to ten percent of their original l evels by 1975 In 1977, the fully amended Clean Water Act gave the EPA authority to initiate the regulation of water p ollution in an effort to reduce waste in water and to set standards in what was and was not allowed to be disposed of in effluent streams and other natural water sources While cities today still face large environmental problems including air polluti on and waste disposal problems, much of the Unit ed States and the world have begun to see a slow but steady shift i n both attitude and achievements of environmental preservation and restoration The i mplementation of environmental laws and, consequently, more environmental awareness has led to such advancements as commercially available e lectric cars and more efficient utilization of solar energy In fact, in the United States alone, EPA projects span country wide, from educating schools on problems like mercury to retrofitting green infrastructure into the storm water systems to reduce pollution [19] Novel ideas and projects like the ones being carried out by the EPA will not only help reduce future pollution emissions and degradation of the environment, but


25 will hopefully also be able to resolve or even reverse problems that have existed for centuries or even millennia 1.3 Green Chemistry: The Aim to Fix Yesterday, Today, and Tomorrow Green chemistry as an idea was not coine Paul Anastas of the EPA Based on the idea of sustainable development, which is [ 20 ] green chemistry aims to develop new methods, as well as synthesize new chemicals, that will minimize the impact the chemical industry has on the environment There are a variety of ways that this can be done, including atom economy which analyzes the sto ichiometry of a reaction not only for reactant use and product yield, but also incorporates waste by products to measure the efficiency of a reaction Green chemistry is a concept that is beneficial not only from an environmental standpoint, but from an ec onomic standpoint as well, and therefore is practiced from high school s and college s to large industrial factories at a steadily increasing rate


26 1. 3 1 How Green Chemistry is Helping Green chemistry is a practice that focuses on a multitude of issues in the chemical industry today One of the main foci of green chemistry is to environmental ly and economic ally im prove on obsolete reactions The aim of g reen chemistry is to have high product yield, complete starting material conversion and as low toxicity as possible In order to achieve these goals, g reen chemistry follows twelve principles which were established by Paul T. Anastas and John C. Warner and are quoted as follows: Prevention It is better to prevent waste than to treat or clean up waste after it has been created Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product Less Hazardous Chemical Synthesis Wherever practicable, synthetic methods shou ld be designed to use and generate substances that possess little or no toxicity to people or the environment Designing Safer Chemicals Chemical products should be designed to affect their desired function while minimizing their toxicity Safer Solvents a nd Auxiliaries The use of auxiliary substances (e g solvents or separation agents) should be made unnecessary whenever possible and innocuous when used Design for Energy Efficiency


27 Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized If possible, synthetic methods should be conducted at ambient temperature and pressure Use of Renewable Feedstocks R aw material or feedstock should be renewable rather than depleting whenever te chnically and economically practicable Reduce Derivatives Unnecessary derivatization (use of blocking groups, protectio n/ de protection, and temporary modification of physical c hemical processes) should be minimized or avoided if possible, because such ste ps require additional reagents and can generate waste Catalysis Catalytic reagents (as selective as possible) are superior to stoichiometric reagents Design for Degradation Chemical products should be designed so that at the end of their function they br eak down into innocuous degradation products and do not persist in the environment Real time Analysis for Pollution Prevention Analytical methodologies need to be further developed to allow for real time, in process monitoring and control prior to the for mation of hazardous substances Inherently Safer Chemistry for Accident Prevention Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including r eleases, explosions, and fire s [ 20 ] In order to find methods that best follow these twelve principles, chemists must systematically attempt a variety of reactions to determine whether or not they are the best means of synthesizing a chemical


28 The techniques that can be classified a are ever expanding One of the more common of these techniques is known as micro scale reactions; these reactions are run on millimolar scales, usually in research facilities and educational laboratories Micro scale reacti ons have both positive and negative qualities about them: they require a minimal amount of starting material, reducing the material required and the waste output of each reaction Micro scale reactions, however, are more easily effected by the surrounding environment and miniscule amounts of water or other impurities in the air can significantly reduce the yield In order to predict the efficiency of any re coined by Barry M. Trost can be defined as the efficiency of a che mical process in yielding product, while taking all reactants, solvents, and products into account The concept of atom economy means to replace the now economy calculations are based on at om utilization as represented by the [ 2 1 ] ; while yield calculations focus only on the stoichiometry of the product(s), atom economy takes the entire reaction into account Atom economy is measu red in percentage, and can be written in the form of the following equation:


29 While atom economy is an important factor in the process of finding the most cost effective, l east damaging methods of chemical syntheses, there are a large range of factors that must be taken into consideration before a conclusion is made The modern practice of green chemistry takes into account the efficiency of reactions as well as the risk in volved in conducting these reactions As history shows, the lack of foresight in the practical application of any environmental action usually leads to much more difficult obstacles that cannot be so easily overcome Many industries have, because of this adopted what is known as a process flow sheet (PFS) A PFS is a diagram that depicts the various stages a product goes through before it is commercially available, giving necessary information like cost of supplies, energy required, and waste produced. Each stage typically has several preliminary options, and through a PFS different departments can collaborate to establish the most economic, least hazardous method of production. Using a PFS, a multitude of questions can be addressed by experts in diffe rent fields of a waste, mass balance, product contaminants, material cost outline, complexity of processing and associated costs, requirement for any special equipment, energy requirements, and toxicity/handling [ 22 ]


30 Typically for any given synthesis, several PFSs are compared, using the theoretical product yield as the point of reference for efficiency of the process. 1.3.2 Toxicity and Waste Another key function of green chemistry is the reduct ion of toxicity and waste, and the proper treatment of these issues faced by chemists Chemical toxicity is an important factor to take into consideration before proceeding with any reaction, because the safety of the individual handling the chemicals in question must be taken into account While any chemical can be considered toxic in the right quantity trends in compounds have led to the ability to identify whether or not certain chemicals should be handled with special care In the PFS method describ ed abov e, toxicity plays a role in calculating the measureable function of risk In the handling of toxic materials, risk is defined as a function of the hazard faced by the given chemical and the exposure faced by the individual to that chemical [ 2 2 ] T he aim of green chemistry is to reduce this factor of risk as much as possible and to allow the handling of very hazardous materials only after all other options have been examined


31 G reen chemistry along with addressing the handling of toxic reactants, a lso deals with the handling and disposal of waste chemicals Waste is an unfortunate inevitability that is tackled daily by chemists everywhere ; since no reaction can be one hundred percent atom economic, waste material will nearly always need to be dispo sed of The methods of disposing of waste materials have advanced over the last century, with modern techniques including separation of organic, inorganic, and solid wastes, and neutralization of acids and bases before disposal. M any of the outdated prac tices, however, are still in use today, such as disposal into effluent streams and direct gas emission into the air, though these practices are now regulated by the EPA. The first way of handling waste products in reactions is to make the by products as non harmful as possible reen chemistry changes the intrinsic nature of the [hazardous] substances ... so as to reduce or eliminate the hazard posed by the substances [ 20 ] For this, PFSs can be used to reduce the harmfulness of the wastes that form from industrial reactions Another method of waste treatment is the physical separation of wastes into similar phases This can be done through a variety of techniques, including filtration and centrifugation, and makes the organization of waste products eas ier A third method of waste treatment, used in waste streams with a high


32 concentration of metal ions, is electrochemical waste treatment This process can separate metal ions in the water and return them to their neutral state, a process which allows th e reuse of these metals and therefore adheres to the green method These methods, along with new processes that are constantly being developed and improved up on, are being u s ed separately or in combination to help reduce the impact made by the chemical in dustry, along with every other industry that generates waste products 1.3.3 Thinking Ahead The goal of green chemistry to conduct p roper waste disposal is only one of its improvements on outdated methods and another practice employed by practicing green chemists is to have the majority of reactions involve reusable materials and/or catalysts of some sort in order to reduce overall waste to the bare minimum While this environmental impact cannot be measured to its full extent, a method known as th e Life Cycle Assessment (LCA) of a molecule can be used to pre dict the long term impacts of all of the by products formed in a given reaction A LCA can be performed using four steps: planning, analysis, impact assessment, and interpretation Planning gi ves the routes being analyzed and their overall products Analysis is the data collection that reveals things like atom economy The


33 impact assessment is arguably the most important part of a LCA, because it attributes various forms of impacts to each by product and quantifies it, allowing for the last step In terpretation is the determining of which steps in which steps should be revised [ 2 2 ] While these processes have been able to greatly reduce the impact made by chemical processes, choosing the most effective, least hazardous syntheses is not always a simple decision. After everything is taken into account concerning a given chemical process, a choice must be made on the most beneficial, or least harmful, route of synthesis Many times this choice may not be as apparent as one would think: the issue of quantity and quality of the by products is typically one that prevents simple decisions in synthesis If in the comparison of two different process flow sheets for the synthesis of a molecule, one method produces more of a by product that is less toxic, while another produces less by product that is more toxic, the ultimate decision on which method to use is unclear In concern ing other variables of constructing a PFS and LCA important factors include catalysts, solvents (or lack thereof), and energy consumed versus utilizable created energy [ 22 ] By expanding on the number of factors that chemists are able to manipulate, gree n chemists hope


34 to achieve the most efficient met hods of synthesis with the minimum amount of produced waste One of the most efficient methods to date of obtaining a high atom economy is the use of catalysts In discussing the main topic of this thesi s, catalysts will be examined in more depth, but in terms of green chemistry and atom efficiency, catalysts are known to increase reaction rate by up to factors ranging in the millions transformation that is desired without being consumed as part of the reaction [ 20 ] ; because catalysts a re neither changed nor consumed, they do not diminish the overall atom economy of a reaction of catalysis as a means of improv ing the efficiency of reactions is preceded by biological reactions which chemists even today analyze as a means of bettering current reactions in both an economic and ecological regard The refinement of chemical synthes is methodology comprises only part of the goals of green chemists today Another major achievement sought in the field of green chemistry is the synthesis of chemicals that can reduce or even reverse the impact made by man on the world so far In the cas e of CFC gases, for example, hydrofluorocarbons were used as replacements once the effects of these CFCs were known and they were


35 banned from production Similarly DDT substitutes that were less harmful to the environment were implemented once DDT was ban ned As our understanding of chemical reactions continues to expand, green chemistry recognizing that all of the advances and innovations towards this goal will contain some discrete r [20] P rogress in green chemistry continues to be made, both by reducing the inherit risk of lab procedures and by synthesizing new chemicals that are intended to resolve environmental problems that humans face today 1.4 The TAML Project 1. 4. 1 The Downfalls of Current Water Purification Since the Clean Water Act was established, improvements on wastewater treatment have continuously been made to accommodate for increased levels of pollution and also for new types of pollution that are rele ased into waterways. It is required, in accordance to the Clean Water Act, that wastewater treatment plants meet a minimum of secondary treatment on all incoming waste water. In 2004, for example


36 municipal facilities produced a nd discharged effluent at higher levels of treatment than the minimum federal st andards for secondary treatment [ 23 ]. The two main methods of purification used in wastewater treatment plants are physical/c hemical (this category can also be separated into two categories), and b iological, with a vast assortment of technologies fitting in these two categories. Most modern purification techniques, however, have limited ranges of the amount and types of chemicals that they are able to remove from waterways. The first type of process, physical/chemical, is defined by the EPA as [23] Chemical and physical processes are typically grouped together becaus e chemical processes involve chemically altering the pollutants to increase the ability to remove them, while p hysical processes use filters to collect solids or remove solids by gravity settling One such technology that incorporates both of these proces ses is a coagulation/floccation/sedimentation method, which destabilizes suspended solids using a coagulant, then seeds the polluted water with microsand to initiate flocculation, or flake formation of suspended particles. The particles are then removed v ia filter and the wastewater is collected for further treatment or reuse.


37 Biological treatment processes are the second cat egory of wastewater management techniques, and use microorganisms to degrade contaminants from wastewater. These treatment methods have become more efficient and cost effective over the past two decades and are the preferred method of water treatment, though the microorganisms used in these processes have to be removed via physical treatment. These methods are most effective in remo val of ammonia and conversion of nitrogen in amine compounds into inert nitrogen gas [ 23 ] While both physical/chemical and biological methods are effective in removing much of the waste particles found in effluent stre ams, further technological advances are being made to target even more polluting chemicals found in wastewater streams. 1. 4.2 The TAML Project The iron TAML (short for tetra amido macrocyclic ligand) project that is the focus of this thesis is one that was initiated over three decades ag o by Terrence J Collins of Carnegie Mellon University The initial purpose of this ligand was to incorporate catalytic peroxide activators into water purification, using oxidation chemistry as a means of selectively degrading complex organic molecules in to more easily removable compounds. In early designs, as published by Collins and his fellow researchers, the design for


38 the ligand was intended to be coordinated with cobalt to attain a stable c obalt (IV) complex as part of oxidation chemistry research The new iron ligand design has further developed over the course of the project to incorporate a set of rules for designing these catalysts [ 24 ] Over two decades of work, the oxidation catalyst design has been altered in both synthesis technique s and st ructure to develop the cleanest synthesis for the most efficient catalyst (Figure 1.2) It should be noted that, until 1987, the term TAML did not apply to the oxidation catalyst design being synthesized ; i t was found that mido N l igands, as opposed to acyclic tetradentate amido N containing ligands, can be made sufficiently resistant to be useful not only to oxidative degradation, but also to hydrolysis [25]


39 Figure 1.2: ess [25] In order to understand the i ron TAML project and the multitude of applications it has potential for, the process of degradation performed by the molecule should be better understood The current model for the TAML project can be closely describe d as a cytochrome P 450 active site mimic (Figure 1.3) Cytochrome P 450 is a group of enzyme s in the body t hat catalyze oxidation reactions first by binding the ferric form of the enzyme to the substrate ( B ) One electron is then transferred from the NA PDH P450 reductase to the ferric P450 iron to give the ferrous enzyme substrate complex ( C ) The reduced complex then binds to O 2 at the iron to form a ferr ic enzyme O 2 substrate complex ( D ). The reductase then donates a


40 second electron to form a compl ex represented as Fe +3 O 2 2 [ 26 ] ( E E ) The complex is then cleaved at the oxygen oxygen bond to give water and an activated oxygen (F) which then reacts with the substrate, two product is then released, regenerating the native ferric p450 that is available to begin [ 26 ] This catalytic oxidation provides a potentially ecologically benign way of removing the multitude of chemicals found today in water supplies Fi gure 1.3: Reaction Mechanism of C ytochrome P 450 [ 27 ]


41 P 450 active site is essential in its proposed function of degrading eco persistent molecules Eco persistent molecules are typica lly large and/or aromatic compounds, and because of this stability in structure, they are difficult to decompose While other oxidation catalysts have been able to break these molecules down, they have their own respective issues, such as incomplete degra dation or residual toxin release by the catalysts themselves What makes the TAML compound so unique is its ability to completely degrade a vast number of organic and chloro organic compounds into much more environmentally benign compounds In the exampl e of pentachlorophenol, a common toxic chemical used in wood treatment, the TAML hydrogen peroxide complex degrades the molecules into chlori d e ions, carbon dioxide, and oxalic acid [ 28 ] These resulting products are much less harmful to the environment t han pentachlorophenol, and the reaction is one of many examples of the proposed utilizations of the TAML compound The i ron proposed application extends further than degradation of commonplace pollutants in the water supply; one of its main intended purposes is its use in the pulp and paper industry Originally, chemical pulps used in making paper were bleached using sodium hypochlorite (household bleach), but are now usually bleached using


42 chlorine dioxide because it will make strong paper age Both of these processes use chlorine, however, produces unacceptable quantities of chlorinated pollutants, including polychlorinated [ 25 ] Chlorin ated compounds are nevertheless still u sed in many countries due to their low cost This has prompted the effort of making totally chlorine free (TCF) methods of bleaching that can also be economical Although TAML catalysts were initially designed to develop ligands that might lead to improved metall oredox active oxidants (in the oxidation reaction, an oxidation state reduction occurs at the metal center). TAML catalysts also have been tested to remove color from the effluent streams of pulp mills This is an important factor in considering TAML cat alysts as an e penetration into rivers and lakes, thereby disturbing the ecological system [ 25 ] In the tests that were run using (early versions of) TAML catalysts, duced typically by 50% on introduction of a TAML activator [ 25 ] with small amounts of both the catalyst and hydrogen peroxide The catalysts can also be applied to multiple chlorophenols, and have been tested on both pentachlorop henol (PCP) and 2,


43 4, 6 trichlorophenol (2, 4, 6 TCP) in water to show that, after treatment, no detectable products were identified as toxic While the TAML project has reached a point where practical application can be attained for certain periods of time, the current model does have a few issues that need to be resolved before synthesis on a mass scale can commence higher catalytic pH ; using the most recent model of the TAML design, kinetics ana lyses showed that is found at pH9 [ 29 ] The basicity of the TAML molecule prevents it from performing at its maximum potential in neutral water It should be noted that the reason for this catalytic activity involves the deproto nated complex of the TAML molecule At lower pH there is a higher ratio of ferric iron to ferrous iron; as the pH increases, more electron donor s are available and more complex es are reduced to their ferrous form, prompting the catalytic reaction While this issue prevents TAML catalysts from performing most efficiently at neutral pH, catalysts must also be able to perform for long enough periods of time to be considered significantly eff i cient and again the current TAML model falls short of this charact eristic TAML molecules like most catalysts, undergo degradation over a certain amount of time TAML catalysts, however, also undergo self


44 degradation which further decreases their efficiency While the current model is so far the most stable, this lac k of selectivity allows the molecule to retain a li f e of [only] [ 29 ] In its current form, commercial use of the TAML molecule would require such large amounts of it that the iron left over from degradation of the molecules would rapidly beco me yet another source of waste in the very streams they would be used in While the most recent structure design in the TAML project (Figure 1.4) has certain shortcomings it is by far the most effective design yet in the development of the project As has been done with each step in this process, the current design has been analyzed to determine the reasons for the drawbacks in the design and a few modifications in the target molecule have been made The next chapter discusses the identified weak poin ts and potential solutions to them While these solutions are only speculative, they are based in preceden t and therefore have been hypothesized as the greenest and most efficient alterations to the molecule 1.4.3 Previous Attempts The purpose of t his thesis was to determine a synthesis route that would effectively yield a tetraamido macrocyclic ligand that was structurally similar to the molecule designed by Terrence J. Collins in his 2009 article


45 More Powerful Iron TAML Peroxidase Enz yme Mimic s (shown in figure 1.4 ) [29] Figure 1.4: TAML molecule (e) that has been designated the most efficient to date [ 2 9 ] Two other theses, however, have attempted to synthesize the mimic of this molecule, in which the quaternary carbon (C17) is altered to a tertiary carbon or even a secondary carbon, removing one or both of the methyl groups, respectively. The first of these theses dedicated to this synthesis was written by Daniel Kaplan, who attempted using 2 nitroaniline as a precursor for the macrocy cle. Eric Andreansky who attempted the project more recently, conducted his syntheses using 1,2 phenylene diamine as a precursor and also synthesized methyl propargyl malonyl dichloride in an attempt to form the macrocycle [ 3 2] Both of these projects, howe ver, fell


46 short of their synthetic goals, and both authors were able to speculate as to why their respective synthesis routes failed. In the literature procedure provide d by Collins et al. [29] the use of 4 nitro o phenylene diamine as a precursor is fir st subj ect to boc protection of the C2 amine group. The protected compound is then reacted with dimethylmalonyl dichloride, then deprotected. The unclosed macrocycle then reacts with oxalyl chloride, forming the uncoordinated closed macrocycle (Figure 1. 5) [ 30 ] Altering this route, Daniel Kaplan used 2 nitroaniline as opposed to boc protected 4 nitro o phenylene diamine. He also reacted 2 nitroaniline with oxalyl chloride before reacting it with the malonyl dichloride Referencing r esearch by Rothnie and Black [30] Kaplan attempted to reduce the nitro groups in the second step, then add the malonyl fragment to close the macrocycle. The bis(2 nitroaniline) oxanilide, however, was found to be insoluble in all but boiling DMSO. The lac k of solubility prevented Kaplan from further conducting experiments, and the synthesis of the macrocycle was never achieved


47 Figure 1.5: Reaction pathway used by Terrence J. Collins [ 3 1 ] In the thesis concerning this project following Danie Andreansky attempted to use di tert butyl dicarbonate to create a tert


48 butoxycarbonyl (Boc) protecting group on one of the amine groups of o phenylenediamine. After this successful synthesis, oxalyl chloride was then reacted with the o ph enylenediamine N tertbutoxycarbonyl in a 1:2 ratio, respectively, to give 2,2' (dicarbamate, tert butyl ester)oxanilide. After de diaminooxanilide molecule was to undergo a reaction with methyl propargyl malonyl dic hloride, a molecule synthesized specifically for the thesis, to form the uncoordinated macrocycle, 15 methyl 15 propargyl 5, 8, 13, 17 tetrahydro 5, 8 13, 17 tetraaza dibenzo[a, g] cyclotridecene 6, 7, 14, 16 tetraone. Analyses of multiple attempts at thi s last step however, showed significant impurities suggesting reaction incompletion and even polymerization [3 2 ] Tetraamido that incompletion of the macrocyclization attempted in his thesis could have diaminooxanilide. If the molecule retains a trans conformation, as shown in figure 1.6 then macrocyclization would be hindered by the position of the amine groups, requiring a conformational change to adhere to the shape of the macrocycle. This trans conformation would theoretically allow for the cancellation of dipole moments in the molecule, and would also potentially allow for hydrogen


49 bondi ng between the carbonyl oxygen atoms and the amine hydrogen atoms. The hydrogen bonding and dipole cancellation would be theoretically stable, and would decrease the likelihood of the molecule obtaining a cis conformation [32 ] This hypothesis, explainin g the difficulty of synthesizing diaminooxanilide, prom pted, in this thesis, a synthe tic route mirroring that of the literature procedure provided by Terrence J. Collins. Figure 1. 6 : A predicted trans aminooxanilide [ 32 ] The order in which previous reactions were conducted was an attempt to perform said reactions in the most efficient way possible; methyl propargyl malonyl dichloride is not a commercially available molecule and is derived from propar gyl bromide and diethyl methyl malonate. By using diaminooxanilide while simultaneously conducting the synthesis of methyl propargyl malonyl dichloride, the overall synthesis of the macrocycle would


50 not have to be linear and therefore would be more efficient. Without the achievement of the macrocycle, however, an alternative route was necessary. The project to design a stable Tetraamido Macrocyclic Ligand has been worked on for ove r thirty years and was initiated in the attempt to remove pollutants from the effluent streams specifically used by textile industries. Terrence J. Collins and his associates have been modifying the original design based on kinetics analyses taken of each model, with noticeable variations made each time the design was improved. The most recent (and effective) design of the i ron TAML (Figure 1.4, e), with slight alterations, was the target ligand attempted in this thesis.


51 Chapter 2 Results and Discussi on According to the literature procedures published by Terrence Collins, o phenylenediamine N tertbutoxycarbonyl is reacted with dimethyl malonyl dichloride first, followed by the deprotection of the amine groups, and finally oxalyl chloride is used to close the macrocycle. While it is not reported that the uncoordinated macrocycle synthesis yielded 55% product (final procedure) [ 29 ] It can be rationalized that the extra carbon th at malonate groups have (as opposed to oxalyl groups) allows for more stereoflexibility, increasing the likelihood of reaction success for the closing of the macrocycle. Attempts at these reactions, however, using o phenylene diamine and malonyl dichlorid e, as opposed to the structural analogs used in product(s) were not present. Alternative reactions were therefore researched in an attempt to find a novel synthetic route for the macro cycle.


52 2.1 Modifications to the TAML Structure 2.1.1 Alterations In this thesis, both designs of the 2009 TAML molecule, with and without the nitro groups, have been attempted in synthesis Collins reports that the di nitro variation of the com pound was found to be the catalyst with the lowest rate of degradation however i n using 4 nitro o phenylenediamine as a precursor, the process of drying the compound for practical use as a reactant req uired a large amount of ethanol in proportion to the 4 nitro o phenylediamine being dried ; subsequently t he waste produced in the drying process reduce d the atom economy of the overall proce dure O phenylenediamine was therefore preferred in the synthesis process following that of Collins et al One of the alterations made in the target design of this thesis was that the C1 7 carbon (figure 1.4) (quaternary bonded to the dimethyl group) would have either one or no methyl groups attached This would leave the C1 7 site open for deprotonation and it was theor ized that the tertiary (or secondary) carbon would possibly allow for the addition of a triazole functional group the projected final alteration to the up to date model


53 2.1.2 Prospective Benefits of the Modified Ligand Design As shown in figure 2.1 the triazole ring w ould be attached to the which, hopefully, w ould atoms with the iron This square pyramidal structure w oul d, in theory, allow for more selectivity in the catalytic reactions, hopefully reducing degradation between catalysts The last prospective benefit to the altered structure of the current TAML design again involves t he triazole group, attaching to it a so lid suppor t system It is hypothesized that this will improve the kinetics of the catalytic ability of the molecule by reducing the amount of interactions between catalysts, reducing the degradation that occurs with the current model


54 Figure 2.1: The pr oposed macrocyclic ligand 2.1.3 Identifying the Functional Groups In synthesizing a novel ligand, it is beneficial to identify potential reactants by separating the compound into groups As can be seen in figure 2.1 the triazole group (marked as G ro up A) forms one functional group, then there is an identifiable malonate group ( G roup B) the symmetrical phenylenediamine groups (Group C) and an oxalyl group (Group D) While these are simply designated functional groups, and certainly not the only rea ction sites, they are the focus of this thesis and therefore alternate routes


55 will not be discussed in detail Based off of the literature procedures published by Terry Collins, the first reaction necessary is the protection of o phenylenediamine, followe d by addition of the malonate fragment, and finally a reaction with oxalyl chloride to close the macrocycle (Figure 1.5) 2.2 Attempted Pathways In the conclusion of his thesis, Eric Andrea nsky states that the best synthesis route to take is to first protect o phenylene diamine using di tert butyl dicarbonate (boc protection) reacting the boc protected compound with the malonyl group in a 2:1 ratio, respectively, and then finally closing the macrocycle with oxalyl chloride [32] This was the intended pathway of this thesis though instead of following the route provided by Collins research group [ 29], alternate pathways were researched and tested in an attempt to find the route with the best atom economy. 2.2.1 Methyl Propargyl Malonyl Dichloride [29, 32] One notable difference in the syntheses performed in this the sis is that, because the malonyl group is intended to react with the phenylene diamine groups reactions to close the macrocycle could not begin until the synthesis


56 of methyl propargyl malonyl dichloride was completed, and because the dichloride was report ed by Eric Andreansky as being unstable for extended periods of time, it was quickly realized that approaching the macrocycle via this method would result in various complications One of the most prominent complications of this method would be that, shou ld all of the methyl propargyl malonyl dichloride be used up in failed reactions, attempting another reaction would require the time needed to resynthesize the dichloride and would reduce the overall efficiency of the reaction pathway This decrease in ef ficiency prompted a revision of the synthesis, u sing malonyl dichloride (as well as diethyl methyl malonate and diethyl malonate) as a precursor instead, which would, theoretically, leave the C2 carbon susceptible to deprotonation once the macrocycle was c omplete This would prospectively allow the attachment of a solid support as proposed earlier 2.2.2 Dichlorobis 1, 2 Phenylenediamine Nickel Another of the methods attempted in synthesizing this ligand was a coordination of o phenylenediamine to nickel (II) chloride in a 2:1 ratio, respectively The reason behind this method stems from the symmetry of o phenylenediamine and the desire to eliminate as many by products as


57 necessary It was hypothesized that in synthesizing d ichlorob is 1, 2 phenylenediamine nickel, the coordination of the two phenylenediamines would prevent unwanted by products in the next reaction with malonyl dichloride L iterature procedures having synthesiz ed the nickel coordinated bis phenylenediamine, however, reported reactions lasting seven days [ 3 3 ] and when these syntheses were attempted, it was found that sufficient analysis of the product was unavailable The inefficiency of the reaction coupled with the lack of determination of its completion led to the use of alternative routes 2.2.3 O Phenylenediamine and Malonyl Dichloride Figure 2.2: Proposed scheme from Karabcek et. al. [34] Bis (2 aminophenyl) malonamide were conducted using the literature procedure published by Karabcek et al reacting malonyl dichloride with o phenylenediamine in a 1:2 ratio (respectively) and using dichloromethane as the solvent This procedure was X


58 chosen because, in theory, it would eliminate the need for protecti ng groups and therefore increase the overall atom economy of the reaction (pending the yield) The article used, however, does not report removal or evidence of hydrogen chloride, the byproduct of deprotonation of the amine group by the chloride ion produced by malonyl dichlori de [ 3 4 ] Thus, although crude NMR spectra revealed evidence of product formation in several reactions, t he work up of the reaction proved ineffective in isolating analysis grade product in every attempt This literature procedure was hence regarded as ha ving insufficient information for the complete synthesis and isolation of bis (2 aminophenyl) malonamide 2.3 Bis(2 Nitrophenyl) Malonamide bis(2 nitrophenyl) malonamide was considered as a possible precursor for the complete d macrocycle I t was theorized that the nitro group in 2 nitroaniline could act as a protecting group in the synthesis of N, bis(2 nitrophenyl) malonamide, and the nitro groups could later be reduced to form the amino derivative The use of malonyl dichloride as opposed to oxalyl chloride was proposed to eliminate or at least reduce the insolubility problems that Kaplan faced


59 2.3.1 Using Diethyl Malonate [35] bis(2 nitrophenyl) malonamide using diethyl malonate as a react ant was a procedure found during the research of the malonamide compound The article, Synthesis and Characterization of Alkaline Earth Metal Complexes of Schiff Bases is by Xiao et al and is written completely in simplified Han Chinese The lack of tr anslation, along with limited access to the article resulted in having only guidelines to reference when conducting the procedure in the laboratory The reactants used were 2 nitroaniline and diethyl malonate, the solvent used was xylene, and the reactio n was heated to reflux for two hours, then to 195 o C until the reaction reached completion No mass or mole amounts for reactant or solvent were available, so the reaction was conducted using 25 mmol of diethyl malonate and 50 mmol of 2 nitroaniline Sinc e the boiling point of xylene ranges from 138 o C (p xylene) to 144 o C (o xylene), it was apparent that the solvent needed to be removed after being heated to reflux in order to reach 195 o C, roughly the boiling point of diethyl malonate [3 5 ] The procedure based on the article by Xiao et al was found to yield product after several attempts The mass yield, however, proved to be much less than what was reported in the guidelines used Furthermore, complete


60 isolation of the product required several hot et hanol washes, and consequently produced large quantities of waste While NMR and IR analyses of the product confirm reaction completion, the low yield of product and high energy consumption and waste amount made this reaction undesirable in terms of atom economy Furthermore, only one out of the several reactions attempted yielded significant amount of product, and this reaction was therefore regarded as being too inefficient to be used in the synthesis of the novel macrocycle design. After the single su bis(2 nitrophenyl) malonamide, attempts at reduction of the nitro groups were conducted on less than 5mmol scales Nitro reduction reactions are common in organic chemistry, and therefore several different methods of the synt bis(2 aminophenyl) malonamide were conducted Due to the small amount of starting material available to conduct these reactions, howev er, the number of attempts possible for each reaction was limited to one, and since there were no availa ble article s for the exact synthesis being conducted, each reaction had to be modified to compensate for the di nitro compound This lack of availability of starting material and lack of sufficient literature resulted in failure for each reduction attempt




62 Chapter 3 General Experimental All of the following reactions used chemicals purchased from either Acros or Sigma Aldrich. All chemicals were used as received unless otherwise noted. Solvents were dried in the fol lowing manner: dichloromethane and trie thylamine were dried over calcium hydride, subsequently distilled, and stored over 5 molecular sieves; tetrahydrofuran was dried over sodium/ benzophenone ketyl, distilled, and used immediately. A Bruker AC 250 NMR spectrometer was used for all NMR studie s. Analytical TLC was done on fl uorescent aluminum backed silica gel TLC plates. Visualization of TLC plates was done by iodine. A polyethylene glycol (PEG) bath or heating mantle was used for heating all reactions unless otherwise indicated. Common abbre viations used: DCM (dichloromethane, methylene chloride); DI (deionized water ); DMF (dimethyl formamide); DMSO (dimethyl sulfoxide); Et 3 N (triethylamine); EtOH (ethanol); NaOEt (sodium ethoxide); pyr (pyridine); rb ( round bottom ); rt (room temperature); TH F (tetrahydrofuran); wt (weight).


63 3. 1 Synthesis of tert butyl (2 aminophenyl) carbamate Figure 3.1: Synthesis of tert butyl (2 aminophenyl) carbamate [29] 1 5 mL dry triethyl amine was added to approximately 10 mL of dry THF in a 50 mL round bottom fl ask with stirring under nitrogen gas 0 911 g (8 32 mmol) of o phenylene diamine was then added to the flask, followed by 1 98 g (9 05 mmol) di tert butyl dicarbonate The reaction was left to stir overnight and the solvent was then removed under reduced pressure The remaining crude product was sonicated under hexanes for approximately half an hour and then vacuum filtered to obtain 1 212 g (5 8 mmol, 69 9% yield) tert butyl (2 aminophenyl) carbamate 1 H NMR (d 6 DMSO) 8 3 ppm (s, 1H, NHC=O), 7 2 ppm (d 1H, Ar H), 6 8 ppm (t, 1H, Ar H), 6 65 ppm (t, 1H, Ar H), 6 5 ppm (d, 1H, Ar H), 4 8 ppm (s, 2H, Ar NH 2 ), 1 5 ppm (s, 9H, C(CH 3 ) 3 )


64 Notes: Di tert butyl dicarbonate has a melting point of approximately 22 C Gently heating the container in a warm wat er bath will therefore melt the solid and the compound can be added via syringe The crude product (after solvent removal) was found to exist in several different forms The following step of sonication under hexanes is therefore crucial in isolating th e final product


65 3.2 Synthesis of N, N nitrophenyl) Malonamide Figure 3. 2 : bis(2 nitrophenyl) malonamide [35] In a 3 neck, 500 mL Rb Flask, 6 94 g (50 mmol) 2 nitroaniline was added to 100 mL xylenes with stirring 3 8 mL (25 m mol) diethyl malonate was added to the reaction, and the reaction was heated to reflux using a collection flask to ensure the removal of the solvent The reaction was left to stir at reflux overnight, and after 20 hours was taken off heat Once cooled, a ny remaining solvent was removed under reduced pressure and the solid was then put under high vacuum for 1 hour The reaction was again heated, this time to 175 o C, and left overnight once more The solid was then suspended in approximately 50mL ethanol and heated to reflux Vacuum filtering of the mixture yielded a yellow solid and red filtrate Crude NMR of the solid showed evidence of product, and the yellow solid was again


66 suspended in ethanol (20 mL) and heated to reflux Vacuum filtration of this mixture yielded 3 12 g of crude product


67 3.3 Synthesis of D ichlorobis(1,2 phenylenediamine) N ickel(II) Figure 3. 3 : Synthesis of dichlorobis(1,2 phenylenediamine) nickel(II) 3.3.1 Maxcy et al. [33] 138 mg (1.06 mmol) nickel (II) chloride w as dissolved in 30 mL 4.02 mM hydrochloric acid to form approximately 1.06 mmol of the nickel (II) chloride hexahydrate complex. 229 mg (2.12 mmol) o phenylenediamine was then mixed into the solution and let stir at room temperature for five days. Stirri ng was then stopped and the solution was stored in the refrigerator to recrystallize for nine days. The reaction showed no signs of recrystallizing, so the solution was left uncovered in the hood to allow for gentle evaporation of the water. The solution was then gently evaporated under reduced pressure to yield wet crystals. The crystals were then dissolved in 40 mL of ethanol and evaporated under reduced pressure. This


68 step was repeated to obtain 305 mg (83.3% yield) of product (possibly dichlorobis(1 ,2 phenylenediamine) nickel(II)) Notes: This procedure is taken from literature mentioned in the annotated bibliography (Maxcy et al. ) and is performed at half the scale used in this procedure. The amount of solution, however, remained the same, which accounts for the difficulty in recrystallizing the product. The literature procedure calls for 1, 2 phenylenediamine di hydrochlor i d e a compound which was not available in this laboratory. Hence, approximately 2mmol of hydrochloric acid was added to th e distilled water to compensate for this. Analysis of this compound could not be conducted in the laboratory, brown, match that of the color observed by the literature procedure.


69 3.3.2 Novel Reaction 127 mg NiCl 2 (0. 98 mmol) was added to 30 mL EtOH in a 100 mL rb flask with stirring and was heated to approximately 50 O C. 206 mg (1.91 mmol) 1,2 phenylenediamine was then added, along with 1.12 mL distilled water. The reaction was left to run overnight, and was taken off heating and stirring. The precipitate was collected by vacuum filtration and washed with hexane. 250 mg (est. 72.3% yield) collected. Notes: A small amount of water is necessary in this reaction in order to form the nickel (II) chloride hexahydrate complex which dissolves in ethanol more readily than its anhydrous counterpart. The precipitate formed in this reaction, the presumed product, is a light blue powder. Analyses of this compound using equipment in the laboratory are inconclusive


70 3. 4 Syn thesis of Methyl Propargyl Malonyl Diethyl Ester Figure 3. 4 : Synthesis of methyl propargyl malonyl diethyl ester [32] 0.887 g (40.3 mmol) sodium metal was cut under hexane, dried, and allowed to dissolve in 50 mL ethanol in a 250 mL round bottom flask. Afte r the sodium was completely consumed, 5.4 mL (47.16 mmol) diethyl methyl malonate was added and allowed to react for one hour at room tempe rature 7 mL (62.8 mmol) propargyl bromide (80% wt. in toluene ) was then added drop wise to the reaction, with white precipitate noted within five minutes of its addition. The reaction was then left to run overnight, and was then quenched with 25 mL distilled water. The ethanol was then evaporated under reduced pressure, and extraction was performed using 3 x 25 mL di chloromethane. The combined organic phases were then dried over anhydrous sodium sulfate filtered, and the solvent was evaporated under reduced pressure to obtain 6.68 g (66.7% yield) of methyl propargyl malonyl diethyl ester as a yellow orange oil. 1 H NMR (CDCl 3 ): 4.2 ppm (q, 4H, O CH 2 CH 3 ); 2.7 ppm (d, 2H, CH 2 C CH); 2.1 ppm (t, 1H, CH 2 C CH ); 1.4


71 ppm (s, 3H, CH 3 ); 1.1 ppm (t, 6H, OCH 2 CH 3 ). 13 C NMR (d 6 DMSO): 170 ppm (C = C H); 74 ppm ( C CH); 60 ppm (O C H 2 CH 3 ); 52 ppm ( C CH 3 ); 24 ppm ( C H 2 C CH); 19 ppm (C C H 3 ); 14 ppm (OCH 2 C H 3 ). Notes: Fresh absolute ethanol is required for the success of this reaction, as trace amounts of water will consume sodium metal, preventing the necessary amount of sodium eth oxide from being formed.


72 3. 5 Synthesis of Methyl Propargyl Malonic Acid Figure 3.5 : Synthesis of methyl propargyl malonic acid [32] 3.63 g (90.8 mmol) solid sodium hydroxide was dissolved in 5 mL distilled water with stirring in a 25 mL round bottom flask. After the solid was completely dissolved, 1.08 g (5 mmol) methyl propargyl malonyl diethyl ester was added, forming a bilayer re action mixture and, after a few minutes of stirring, a small amount of precipitat e The reaction was then placed on a water/ ic e bath, followed by the addition of concentrated hydrochloric acid mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pr essure to obtain 380 mg (49% yield) of methyl propargyl malonic acid, a light yellow orange solid. 1 H NMR (d 6 DMSO): 9.3 ppm (b, 2H, CO OH ); 2.8 ppm (s, 1H, CH 2 C H ); 2.6 ppm (s, 2H, CH 2 3 ). 13 C NMR (d 6 DMSO):


73 171 ppm (C=O); 81 ppm C H); 73 ppm ( C CH 3 ); 27 ppm ( C H 2 3 ). Notes: Rigorous stirring is required in order to properly mix the immiscible starting material with the sodium hydroxide solution. This can be done with a magnetic stirring bar due


74 Chapter 4 Conclusion and Further Work Seve ral different types of reactions were condu ct ed in an effort to synthes ize a novel tetra amido macrocyclic ligan d in the most atom economic way possible. After multiple attempts using several different literature procedures no significant progress in closing the macr ocycle or reducing the atom economy was made. It was therefore concluded that, until a better procedure is found, the route conducted by the research group at Carnegie Mellon should be pursued in order to ultimately synthesize the novel macrocycle. After ma crocycle closure, coordinating the ligand with iron will be the final step be fore solid support attachment.


75 Appendix A Spectra


76 Figure A1: HNMR Spectra of Boc protected O phenylene D iamine


77 Figure A 2: C NMR Spectra of Boc protected O pheny lene Diamine


78 Figure A 3: H NMR Spectra of Methyl Propargyl Malonyl Dieth yl Ester


79 Figure A4 : CNMR Spectra of Methyl Propargyl Malonyl Diethyl Ester


80 Figure A5: HNMR Spectra of Methyl Propargyl Malonic Acid


81 Figure A6: CNMR Spectra of Methyl Propargyl Malonic Acid


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