The Use of Methyl 2-(Fluorosulfonyl)-2,2-Difluoroacetate as the Difluorocarbene Source to Generate an In-Situ Source of ...

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Title:
The Use of Methyl 2-(Fluorosulfonyl)-2,2-Difluoroacetate as the Difluorocarbene Source to Generate an In-Situ Source of Difluoromethylene Triphenylphosphonium Ylide
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1 online resource (82 p.)
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english
Creator:
Thomoson, Charles S
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University of Florida
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Gainesville, Fla.
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Thesis/Dissertation Information

Degree:
Master's ( M.S.)
Degree Grantor:
University of Florida
Degree Disciplines:
Chemistry
Committee Chair:
DOLBIER,WILLIAM R,JR
Committee Co-Chair:
APONICK,AARON
Committee Members:
CASTELLANO,RONALD K

Subjects

Subjects / Keywords:
difluoromethylene -- dilfuoroalkenes -- mfda -- triphenylphosphonium -- wittigtype -- ylide
Chemistry -- Dissertations, Academic -- UF
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Chemistry thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract:
Under moderate conditions in the presence of a demethylating reagent, such as iodide, methyl 2,2,-difluoro-2-(fluorosulfonyl)acetate (MFDA) releases difluorocarbene, which, in the presence of triphenylphosphine, forms difluoromethylene triphenylphosphonium ylide. When the process is carried out also in the presence of aldehydes or activated ketones, the ensuing in situ Wittig-type reaction of the ylide with the carbonyl reactants produces 1,1-difluoroalkenes in good yield. Density Functional Theory calculations were used to provide new estimates of the energies and structures of singlet and triplet states of CH2:, CHF:, and CF2: carbenes, as well as those of their respective triphenylphosphonium ylides
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In the series University of Florida Digital Collections.
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Statement of Responsibility:
by Charles S Thomoson.
Thesis:
Thesis (M.S.)--University of Florida, 2013.
Local:
Adviser: DOLBIER,WILLIAM R,JR.
Local:
Co-adviser: APONICK,AARON.

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UFE0046329:00001


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1 THE USE OF METHYL 2 (FLUOROSULFONYL) 2,2 DIFLUOROACETATE AS THE DIFLUOROCARBENE SOURCE TO GENERATE AN IN SITU SOURCE OF DIFLUOROMETHYLENE TRIPHENYLPHOSPHONIUM YLIDE By CHARLES S. THOMOSON A THESIS PRESENTED T O THE GRADUATE SCHOOL OF THE UNIVER SITY OF FLORIDA IN PARTIAL F ULFILLMENT OF REQUIR EMENTS FOR THE DEGRE E OF MASTER OF SCIENCE UNIVERSITY OF FLORID A 2013

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2 2013 Charles Seth Thomoson

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3 To my family and friends for supporti ng me

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4 ACKNOWLEDGEMENTS I would like to thank my advisor, Dr. William R. Dolbier Jr., for providing me the opportunity to perform my graduate research in his lab. He has given me great advice, knowledge, direction, and support throughout my graduate res earch. I would also like to thank my committee members, Dr. Ronald K. Castellano, Dr. Aaron Aponick, Dr. Ben Smith and Dr. Kenneth Sloan, for their support and help as well. my r esearch here at the University of Florida. In particular, I would like to thank Dr. Fei Wang for his experience and guidance with reactions as well as being a great mentor. I would like to thank Dr. Zhaoyun Zheng for his knowledge and Henry Martinez for hi s help with calculations. I would also like to thank Masamune Okamoto, Dr. Xiao jun Tang, and Dr. Kanishev Oleksandr for help with research and being good labmates. Outside of the University of Florida, I would like to thank my family for their support and encouragement during my research. Finally, I would like to thank all of my friends for their support, notably Donovan Thompson for his support and encouragement.

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5 TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ................................ ................................ ............................... 4 LIST OF TABLES ................................ ................................ ................................ ............ 7 LIST OF FIGURES ................................ ................................ ................................ .......... 8 ABSTRACT ................................ ................................ ................................ ................... 10 1 BACKGROUND ................................ ................................ ................................ ...... 11 1.1 Introduction ................................ ................................ ................................ ....... 11 1.1.1 Fluorine ................................ ................................ ................................ 11 1.1.1.1 Properties of Fluorine and the C F Bond ................................ 11 1.1.1.2. Pharmaceuticals, materials, and agrochemicals ..................... 15 1.1.2 Classical Olefination Reactions Containing Phosphonium Ylides ......... 17 1.1.2.1 The Wittig reaction ................................ ................................ ... 17 1.1.2.2. Horner Wadsworth Emmons olefination ................................ 19 1.2 Events Leading to This Research ................................ ................................ ..... 20 1.2.1 Methyl 2,2 Difluoro 2 (Fluorosulfonyl) Acetate (MDFA) ......................... 20 1.2.2 1,1 Difluoroalkenes ................................ ................................ ............... 22 1.2.2.1 Uses of 1,1 difluoroalkenes ................................ ..................... 22 1.2.2.2 Synthesis of 1, 1, difluoroalkenes ................................ ............ 23 2 RESULTS ................................ ................................ ................................ ............... 26 2.1 Initial Experiments To Prepare 1,1 Difluo roalkenes. ................................ ......... 26 2.2 Demethylating Reagent ................................ ................................ .................... 26 2.2.1 Experiments on the Effect of Phase Transfer Catalysts as Demethylating Reagent ................................ ................................ ....... 27 2.2.2 Experiments on the Effect of Potassium/Sodium Salts as Demethylating Reagents ................................ ................................ ..... 28 2.2.3 Other Experiments with Demethylation ................................ ................. 28 2.3 Optimization of Experiments with Selected Demethylating Reagents ............... 29 2.3.1 Tetrabutylphosphonium Bromide (TBPB) ................................ .............. 30 2.3.1.1 TBPB with alternating solvents, concentration and temperature ................................ ................................ ............ 30 2.3.1.2 Effect of equiv. MFDA and TBPB ................................ ............ 31 2.3.1.3 Expanded substrate scope with TBPB ................................ ..... 32 2.3.2 Potassium Iodide (KI) ................................ ................................ ............ 32 2.3.2.1 Potassium iodide with alternating solvents, concentration and temperature ................................ ................................ ..... 32 2.3.2.2 Potassium iodide with alternating equiv. of MFDA and KI ....... 33 2.3.3 Other Optimization Attempts ................................ ................................ 34 2.4 Optimized React ion Conditions and Expanded Substrate Scope ..................... 34

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6 2.4.1 Alkyl Aldehydes ................................ ................................ ..................... 36 2.4.2 4 Nitrobenzaldehyde ................................ ................................ ............. 37 2.4.3 Aromatic and Aliphatic Ketones ................................ ............................. 37 3 DISCUSSION ................................ ................................ ................................ ......... 39 3.1 Mechanism and Calculations ................................ ................................ ............ 39 3.2 Ground State Calculations of the Single and Triplet State for CH 2 CHF and CF 2 Carbenes ................................ ................................ ................................ 40 3.3 Ca lculated Ground State Structures of the CH 2 PPh 3 CHF PPh 3 and CF 2 PPh 3 Ylides ................................ ................................ ................................ .... 41 4 CONCLUSION ................................ ................................ ................................ ........ 46 5 EXPERIMENTAL ................................ ................................ ................................ .... 47 5.1 General Informati on ................................ ................................ .......................... 47 5.2 General Procedure or 1,1 Difluoroalkenes Reactions. ................................ ...... 47 5.2.1. 4 Bromo (2,2 difluoroethenyl)benzene ................................ ................ 47 5.2.2 (2, 2 Difluoroethenyl)benzene (2a) ................................ ......................... 48 5.2.3 4 Methyl (2,2 difluoroethenyl)benzene (2b) ................................ ......... 48 5.2.4 4 Methoxy (2,2 difluoroethenyl)benzene (2c) ................................ ........ 48 5.2.5 4 Thiomethyl (2,2 difluoroethenyl)benzene (2d) ................................ .... 48 5.2.6 2 Bromo (2,2 difluoroethenyl)benzene (2e) ................................ .......... 49 5.2.8 4 Trifluoromethyl (2,2 difluoroethenyl)benzene (2g) ............................. 49 5.2.9 4 Benzyloxy (2,2 difluoroethenyl)benzene (2i) ................................ ...... 49 5.2.10 2,3,4,5,6 Pentafluoro (2,2 difluoroethenyl)benzene (2j) ...................... 49 5.2.11 1 (2,2 Difluoroethenyl) thiophene (2k) ................................ ................. 49 5.2.12 1 (2,2 Difluoroethenyl)furan (2l) ................................ .......................... 50 5.2.13 1,1 Difluoro 1 heptene (2m) ................................ ............................... 50 5.2.14 1,1 Difluoro 1 octene (2n) ................................ ................................ ... 50 5.2.15 4 Nitro (2,2 difluoroethenyl)benzene (3a) ................................ ........... 50 5.3 Computational Method ................................ ................................ ...................... 50 AP P ENDIX A NMR Spectra of Corresponding Compounds ................................ .......................... 52 LIST OF REFERENCES ................................ ................................ ............................... 78 BIOGRAPHICAL SKETCH ................................ ................................ ............................ 82

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7 LIST OF TABLES Table Page 1 1 Electronegativities of Elements according to Pauli ng scale. ............................... 12 1 2 Van der Waals radii and average C X bond lengths of common elements ......... 12 1 3 Bond lengths and bond angles ................................ ................................ ........... 13 1 4 Acidity of carboxylic acids ,, ................................ ................................ ................. 13 2 1 PTC as Demethylating reagent ................................ ................................ ........... 27 2 2 Sodium and potassium salts as demethylating reagents ................................ .... 28 2 3 Other attempt at demethylation of MFDA ................................ ........................... 29 2 4 Effect of solvent an d concentration with TBAB ................................ ................... 30 2 5 Effects of temperature and concentration with TBAB ................................ ......... 31 2 6 Effect of concentration of MFDA and tem perature ................................ .............. 32 2 7 Effects of solvent and temperature with potassium iodide ................................ .. 33 2 8 Effects of concentration of MFDA and potassium iod ide ................................ .... 34 2 9 Effect of solvents and temperature with sodium iodide ................................ ....... 34 2 1 0 Optimization of substrate hexanal ................................ ................................ ...... 36 2 1 1 Optimization of substrate heptanal ................................ ................................ ..... 36 2 1 2 Optimization of substrate octanal ................................ ................................ ....... 37 3 1 Geometrical data and energy gaps for various methyl carbenes at the M06 2X/6 311+G(2df,2p) level. a,b ................................ ................................ ............... 41 3 2 Geometrical data for various phosphonium ylides at the M06 2X/6 311+G(2df,2p) level a ................................ ................................ ........................... 42 3 3 Relative 298 K free energies (kcal/mol) for CH 2 CHF and CF 2 triphenylphosphonium ylides a ................................ ................................ ............ 44

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8 LIST OF FIGURES Figure Page 1 1 Elimination of fluorine and nucleophilic substitution ................................ ............ 14 1 2 Conformation of 1,2 difluoromethane ................................ ................................ 15 1 3 PE vs. PTFE ................................ ................................ ................................ ....... 16 1 4 Common pharmaceuticals an d herbicides ................................ .......................... 17 1 5 Typical Wittig Reaction ................................ ................................ ....................... 18 1 6 Typical Wittig mechanism ................................ ................................ ................... 18 1 7 Previous work with MFDA ................................ ................................ .................. 21 1 8 MFDA preparation ................................ ................................ .............................. 21 1 9 Synthetic uses for 1,1 difluoroalkenes ................................ ................................ 23 1 10 Fuqua procedure ................................ ................................ ................................ 24 1 11 Burton procedure ................................ ................................ ................................ 25 2 1 Initial Rrsults using Ph3P as both nucleophile and ylide component .................. 26 2 2 Yields of 1,1 difluoroalkenes from respective subtrates ................................ ...... 35 2 3 Reac tion with 4 Nitro Benzaldehyde ................................ ................................ ... 37 2 4 Reaction using tri(dimethylamino) phosphine under optimized conditions ......... 38 3 1 Depictions of the calculated structures of (a) CH 2 =PPh 3 (b) CHF=PPh 3 and (c) CF 2 =PPh 3 ................................ ................................ ................................ ...... 42 3 2 Calculated reaction for formation of ylides from carbene and Ph 3 P .................... 43 A 1 19 F NMR of (2,2 Difluoroethenyl)benzene (2a) ................................ ................... 52 A 2 19 F NMR of (2,2 Difluoroethenyl)benzene (2a) ................................ ................... 53 A 3 1 H NMR of (2,2 Difluoroethenyl)benzene (2b) ................................ .................... 54 A 4 19 F NMR of 4 Methyl (2,2 Difluoroethenyl)benzene (2b) ................................ ... 55 A 5 1 H NMR of 4 Methyl (2,2 Difluoroethenyl)benzene (2c) ................................ .... 56 A 6 19 F NMR of 4 Methoxy (2,2 Difluoroethenyl)benzene (2c) ................................ 57

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9 A 7 1 H NM R of 4 Thiomethoxy (2,2 Difluoroethenyl)benzene (2d) .......................... 58 A 8 19 F NMR of 4 Thiomethoxy (2,2 Difluoroethenyl)benzene (2d) ......................... 59 A 9 1 H NMR of 2 Bromo (2,2 Difluoroethenyl)benzene (2e) ................................ .... 60 A 10 19 F NMR of 2 Bromo (2,2 Difluoroethenyl)benzene (2e) ................................ ... 61 A 11 1 H NMR of 4 Fluoro (2,2 Difluoroethenyl)benzene (2f) ................................ ..... 62 A 12 19 F NMR of 4 Fluoro (2,2 Difluoroethenyl)benzene (2f) ................................ ..... 63 A 13 19 F NMR of 4 Trifluoromethyl (2,2 difluoroethenyl)benzene (2g) ........................ 64 A 14 19 F NMR of 4 Trifluoromethyl (2,2 difluoroethenyl)benzene (2g) ........................ 65 A 15 1 H NMR of 4 Bromo (2,2 Difluoroethenyl)benzene (2h) ................................ .... 66 A 16 19 F NMR of 4 Bromo (2,2 Difluoroethenyl)benzene (2h) ................................ ... 67 A 17 1 H NMR of 4 Benzyloxy (2,2 Difluoroethenyl)benzene (2i) ................................ 68 A 18 19 F NMR of 4 Benzyloxy (2,2 Difluoroethenyl)benzene (2i) ............................... 69 A 19 19 F NMR of 2,3,4,5,6 Pentafluoro (2,2 difluoroethenyl)benzene (2j) .................. 70 A 20 1 H NMR of 1 (2,2 Difluoroethenyl) thiophene (2k) ................................ .............. 71 A 21 19 F NMR of 1 (2,2 Difluoroethenyl) thiophene (2k) ................................ ............. 72 A 22 13 C NMR of 1 (2,2 Difluoroethenyl) thiophene (2k) ................................ ............. 73 A 23 19 F NMR of 1 (2,2 Difluoroethenyl) furan (2l) ................................ ...................... 74 A 24 19 F NMR of 1,1 Difluoro 1 heptene (2m) ................................ ............................ 7 5 A 25 19 F NMR of 1 ,1 Difluoro 1 octene (2n) ................................ ................................ 76 A 26 19 F NMR of 4 Nitro (2,2,2 trifluoroethyl)benzene (3b) ................................ ......... 77

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10 Abstract of Thesis Presented to the Graduate School of the Univ ersity of Florida in Partial Fulfillment of Requirements for the Degree of Master of Science THE USE OF METHYL 2 (FLUOROSULFONYL) 2,2 DIFLUOROACETATE AS THE DIFLUOROCARBENE SOURCE TO GENERATE AN IN SITU SOURCE OF DIFLUOROMETHYLENE TRIPHEN YLPHOSPHONIUM YLIDE By Charles S. Thomoson December 2013 Chair: William R. Dolbier, Jr. Major: Chemistry Under moderate conditions in the presence of a demethylating reagent, such as iodide, methyl 2,2, difluoro 2 (fluorosulfonyl)acetate (MFDA) releas es difluorocarbene, which, in the presence of triphenylphosphine, forms difluoromethylene triphenylphosphonium ylide. When the process is carried out also in the presence of aldehydes or activated ketones, the ensuing in situ Wittig type reaction of the yl ide with the carbonyl reactants produces 1,1 difluoroalkenes in good yield. Density Functional Theory calculations were used to provide new estimates of the energies and structures of singlet and triplet states of CH 2 :, CHF:, and CF 2 : carbenes, as well as those of their respective triphenylphosphonium ylides.

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11 CHAPTER 1 BACKGROUND 1.1 Introduction 1.1.1 Fluorine 1.1.1.1 Properties of Fluorine and the C F B ond Elemental fluorine was first isolated by Henri Moissan in 1886. He would later be recognized for h is effort by being awarded the Nobel Prize in 1906. Since this discovery, incorporation of fluorine into organic molecules has become increasingly important to organic and medicinal chemist because of the ability of fluorine to enhance the physical propert ies of fluorinated compounds. Fluorine is the most electronegative element. This characteristic associated with smallest atomic radii of all period 2 elements. 1 Fluo removal of electrons to form F + extremely difficult. On the other hand, the acceptance of an electron to form F is much easier. The electronegativity of fluorine is 4.0 (Pauling, Table 1 1) 1 and 4.44 (Mulliken) 2 The Van der Waal radii for fluorine is 1.47 Angstroms (Table 1 2), which is smaller than both carbon and oxygen. The effect of radii size on bond length is also shown in Table 1 2, with the C F bond length (1.35 ) being shorter than the C O and C C bonds both. 1 The C F bond is also more polarized than other bonds. By subtracting the electronegativity of carbon(2.5) from fluorine(4.0), one can calculate the polarity of the C F bond. The polarity of the C F bond is about 1.5, which is more polarized than the C Cl bond ( 0.61). 2

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12 Table 1 1 Electronegativities of Elements according to Pauling scale. 1 Table 1 2. Van der Waals radii and average C X bond lengths of common elements 1 These attributes make the C F bond the strongest bond in organic chemistry. The formation to the C F bond places most of the electron density on fluorine. 1 2 Thus bond strength can be associated with the attraction between F and C which is known as the inductive effect. Therefore, as the number of fluorine atoms about a carbon center increases, the carbon becomes increasing positive and the C F bond is shortened (Table 1 3) 1 On steric grounds, medicinal chemists often u se fluorine to replace hydrogen. 1 The replacement of hydrogen with fluoride can alter a compounds bond angles and pka value. 1 3 4 5 As fluorine pulls electron density toward it, the repulsion between C H bonds is relaxed and the bond angle widens. 1 These t rends can be seen as we go from fluoromethane to tetrafluoromethane (Table1 3) 1 When

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13 hydrogen is replaced by fluorine on an alkanoic acid, the pKa is lowered and acidity increased (Table 1 4) 3 4 5 As the fluorine is moved closer to the carboxylic acid th e acidity of the molecule will steadily increase Table 1 3 Bond lengths and bond angles 1 Table 1 4 Acidity of carboxylic acids 3 4 5 Fluorine addition can also alter the electronegativit y of a functional group. 2 By removing a single hydrogen atom from a methyl group and replacing it with a fluorine atom, the electronegativity of the group is increased. For example, the electronegativity of a methyl substituent is 2.3, which is similar to elemental carbon. On the other hand, a trifluoromethyl substituent has an electronegativity around 3.4. This closely resembles that of oxygen. These effects can also be seen with other electronegative elements but are more substantial with fluorine. 2 The s trength of the C F bond makes it a poor leaving group. 1 2 Therefore, it cannot undergo S N 2 type chemistry. Fluorine can be displaced in E1 CB elimination reactions. For example, when 2

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14 fluorine, inductive withdrawal by fluorine stabilizes the resulting anion produced. The fluoride ion is then eliminated to neutralize the intermediate. The mo st common case of C F bond cleavage is in nucleophilic aromatic substitution reactions. Fluorine, like most halogens is electron withdrawing. When fluorine is attached to a benzene ring, the benzene ring is considered electron poor. This characteristic mak es the aromatic ring susceptible to nucleophilic attack. Fluorine then stabilizes the negative charge on the ring before it is eliminated Figure 1 1). 1 Figure 1 1 Elimination of fluorine and n ucleophilic s ubstitu tion 1 Th e electron withdrawing nature of fluorine can also lead to unexpected conformations. The most common example is that of 1,2 difluoroethane (Figure 1 2). In this example the gauche conformation is preferred to the anti by 1.8 kcal/mol. 2 6 In the anti confor mation, fluorine atoms are aligned such that an excellent acceptor (C F) is placed anti to an excellent donor (C F). On the other hand, when the fluorine atoms are placed gauche, two good acceptors (C F) are anti to C H. Although, C H is not a strong

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15 donor it is better the C F. Orbital interactions stabilize what would be an overall strained structure. 2 6 Figure 1 2. Conformation of 1,2 difluoromethane 1.1.1.2. Pharmaceuticals, materials, and a grochemicals In the developed world, we encounter compounds containing fluorine every day. Naturally occurring fluorinated molecules are scarce; therefore most fluorinated molecules are developed synthetically. Over the last few decades, the interest in these molecules has grown due t o the effect that fluorine can have on their physical, chemical, and biological properties. 1 7 Chlorofluorocarbons (CFC) were the first fluorinated chemical used in the modern world. 7 They were used as refrigerants, but were replaced by hydrofluorocarbons (HFC) because of potential environmental impacts. Chlorofluorocarbons found a new synthetic use in the production of tetrafluoroethylene, which would be responsible for the development of polytetrafluoroethylene (PTFE). This polymer was of great value bec ause it was more chemical and thermal resistant than the hydrocarbon version polyethylene (Figure1 3). Unlike the hydrogens in polyethylene, fluorine (in PTFE) has three electrons pairs in its outer valence shell. nucleophilic attack, therefore providing the increased chemical and thermal resistance. Since this development, fluorinated materials are now used in waterproof clothing, non

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16 stick cookware, and artificial veins. Other materials such as perfluoropolyethers are used as lubricants on spacecraft because they remain fluid over a wide temperature range ( 90C to 250C). 7 Figure 1 3. PE vs. PTFE Organofluorines have also found uses in the medi cinal field. Currently, perfluorobutane, a perfluorocarbon (PFC), is used as an ultrasound contrast imaging agent for visualizing heart and liver disease. 7 Other PFCs have been used to fill deflated lungs in premature babies. The synthesis of the first flu orinated steroid showed that a single fluorinated substituent could increase the biological activity of the parent steroid. This discovery led to the development of many fluorinated pharmaceuticals such as Prozac and Cipro (Figure1 4). The ability for Pr ozac to cross the blood brain barrier is owed to the presence of the trifluormethyl group. Prozac and Cipro were two of the top 20 bestselling drugs as of 2009. 7 The agrochemical industries regularly use some well known brand name fluorinated chemicals as herbicides, pesticides, and even fertilizer (Figure 1 4). 7 They are all manufactured and produced in large quantities. The use of fluorinated compounds is still currently being studied, but over half of the current products in field trials are fluorinat ed. 7 Therefore, fluorinated products will play an increased role in the future.

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17 Figure 1 4. Common pharmaceuticals and herbicides 1.1.2 Classical Olefination R eactions C ontaining P hosphonium Y lides 1.1.2.1 The Wittig r eact ion The Wittig reaction is a classical reaction used to prepare alkenes from aldehydes and ketones using an ylide prepared from a phosphonium salt (Scheme 2). The reaction was first discovered in 1954 by Georg Wittig. 8 He would later win the Nobel Prize in Chemistry for his work in 1979. The Wittig reaction produces high yields of di and tri substituted alkenes. On the other hand, preparation of tetra substituted alkenes produce lower yields because of steric bulk. The phosphonium ylide (Wittig reagent) i s prepared by reacting tri substituted phosphines with an alkyl halide. This reaction produces a phoshonium salt. Once this salt is treated with base (i.e NaH, NaOMe, BuLi etc.), the Wittig reagent results. Researchers usually observe a color change in the reaction once the ylide is produced. Ylides are resonance stabilized, and can exist in a zwitterionic form with positive and negative charges on adjacent atoms. Wittig reagents are prepared in situ and not isolated because of their relative instability in air. There are two types of ylides, stabilized and non stabilized. Non stabilized ylides

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18 are reacted under inert conditions. These ylides have an election donating group adjacent to the negatively charged carbon. They are less stable, react faster and pro duce (Z) alkenes. The stabilized ylide has an electron withdrawing group adjacent to the negatively charge carbon. This ylide is stabilized by conjugation and leads to the (E) alkene. 9 Figure 1 5. Typical Wittig Reaction The general mechanism for the Wittig reaction is initiated by nucleophilic addition of the negatively charged carbon of the ylide on the carbonyl carbon. This initial step produces a betaine that can cyclize to give an oxaphosphetane intermediate. This in termediate will decompose to give an alkene and a phosphine oxide. The driving force behind the Wittig reaction is the formation of the more stable double bond between the phosphorus and oxygen in phosphine oxide (Figure 1 6). 8 9 Figure 1 6. Typical Wittig mechanism

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19 The mechanisms for the unstabilized and stabilized ylide can be analyzed from a stereochemical perspective. The unstabilized ylide reacts with the carbonyl compound but they approach each other at right angles to form a puckered four membered oxaphosphetane ring. This syn oxaphosphetane places large substituents away from each other and is less stable than the anti form. The instability of the intermediate does not allow time for the more stable conformation to form. Therefore, the kinetically controlled Z alkene is formed. In the case of stabilized ylides, the opposite is true. This reaction can form both syn and anti intermediates. The stabilization of the intermediate gives adequate time for the syn formation to interconvert to form the anti conformation. Thus, the E alkene predominates and the final product is thermodynamically controlled. 9 1.1.2.2. Horner Wadsworth Emmons o lefination Another classical reaction that features a phosphonium ylide is the Horner Wadsworth Emmons Olefination. In 1958, Horner and coworkers proposed a modified version of the Wittig reaction using phosphonate stabilized carbanions. 10 11 This discovery was then expanded upon by Wadsworth and Emmons in the early 1960s. 12 Phoshonate stab lized carbanions have some advantages over phosphonium ylides used in the Wittig reaction. For example, phoshonate stablized carbanions are more nucleophilic and basic. They are susceptible to alkylation unlike phosphonium ylides. The dialkyl phosphate sal t, a byproduct of the Horner Wadsworth Emmons process, is easier to remove compared to the triphenylphosphine oxide associated with the Wittig. 13 The overall mechanism for the Horner Wadworth Emmons olefination is similar to that of the Wittig. The first step is deprotonation to form the phosphate carbanion. The rate limiting step is the addition of the carbanion into the corresponding aldehyde or ketone. The elimination is driven by the formation of the phosphorus oxygen bond and

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20 an electron withdrawing g roup (EWG) alpha to the phosphonate. If the EWG is not present, the resulting is an alpha hydroxyphosphonate. This reaction yields E alkenes and Z alkenes, but the overall reaction favors the E alkene, which is determined by the equilibrium of the intermed iates. 13 1.2 Events Leading to This Research 1.2.1 Methyl 2,2 D ifluoro 2 ( F luorosulfonyl) A cetate (MDFA) MDFA has previously been primarily known as an excellent precursor of trifluoromethyl copper (Figure 1 7). 14 The initial step of this reaction involves formation of the copper salt with elimination of methyl halide. The salt then decomposes to release difluorocarbene and a fluoride ion, which are in equilibrium with trifluoromethyl anion. Dimethyl formaldehyde (DMF) is used as a solvent since it stabiliz es the anion. In the presence of CuI, the equilibrium shifts to form [ CF 3 CuI ], thus, forming the stable CuCF 3. Trifluoromethyl copper then undergoes a reaction with aryl or alkyl halides to produce trifluoromethyl aryl and alkyl substrates. Recently we reported that MDFA could be used as an effective source of difluorocarbene to synthesize difluorocyclopropanes from alkenes (Figure 1 7). In the latter reaction, difluorocarbene formation was initiated by demethylation of MDFA by an iodide ion, with trime thylsilyl chloride (TMSCl) being used to trap fluoride ion. Since difluorocarbene is relatively unreactive with alkenes, this reaction required high temperatures to obtain the product in higher yields. 15

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21 Figure 1 7. Previo us work with MFDA Although commercially available, MFDA can be easily prepared by reacting 3,3,4,4 tetrafluoro[1,2]oxathiethane 2,2 dioxide with sodium methoxide in diethyl ether at 0C (Figure 1 8). 21 If can also be prepared from difluoro (fluorosulfonyl) acetic acid. This acid is added to silver oxide to from the silver salt in diethyl ether. The silver salt, silver difluoro(fluorosulfonyl) acetate, is then reacted with methyl iodide to produce MFDA. 22 Another convenient way to form MFDA is by adding metha nol dropwise to trimethysilyl Fluorosulfonyl difluoroacetae (TFDA) at 0C, allowing the mixture to warm to room temperature, and then refluxing overnight. MFDA is also commercially available. 23 Figure 1 8. MFDA preparation ]

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22 1.2.2 1,1 Difluoroalkenes 1.2.2.1 Uses of 1,1 d ifluoroalkenes 1,1 Difluoroalkenes have generated interest as potential enzyme inhibitors, 24 27 but more commonly they have been utilized as fluorinated building blocks (Figure 1 9). Monofluoroalkenes can ea sily be prepared from difluoroalkenes using a benzene solution of sodium bis(2 methoxyethoxy)aluminum hydride (SBAH). This reaction gives excellent yields of the desired product with no over reduction detected. 28 Difluoroalkenes can also undergo the additi on of fluoride in the presence of a proton source to give 2,2,2 trifluoroethyl groups. Burton and coworkers showed that in the presence of potassium fluoride, a fluoride anion would attack the terminal carbon of the olefin. The subsequent anion could then be protonated by water in DMF. 31 This procedure was later modified by substituting tetrabutylammonium fluoride for KF in THF at room temperature. 30 Nucleophillic attack is not limited to the fluorine anion; other nucleophiles can also be implemented such a s lithium alkyl reagents. These reactions were performed using exo difluorinated vinyloxiranes as the substrates. The addition of the alkyl to the double bond followed an S N adjacent epoxide. 32 Difluoroalkenes are p recursors of ring fluorinated heterocycles via intramolecular cyclization reactions. 33 35 1,1 Difluoroalkenes are also precursors of esters and carboxylic acids (Figure 1 9). 16

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23 Figure 1 9. Synthetic uses for 1,1 difluoroa lkenes 1.2.2.2 Synthesis of 1, 1, d ifluoroalkenes The versatility of the chemistry with difluoroalkenes has led to various approaches for their preparation, many of them involving a Wittig reaction involving the presumed, but thus far undetected, difluoro methylene triphenylphosphonium ylide. Fuqua and coworkers were the first to propose the intermediacy of difluoromethylene triphenylphosphonium ylide and to study the reaction of this presumed intermediate with aldehydes to form 1,1 difluoroalkenes. 17,18 I n 1964, they reported a process involving a refluxing solution of sodium chlorodifluoroacetate in diglyme at 160 o C in the presence of Ph 3 P and aldehyde substrate. High yields were obtained, as shown in Scheme 7 below. Aliphatic aldehydes were also decent substrates with heptanal yielding 52% of 1,1 dif luoro 1 octene.

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24 Figure 1 10. Fuqua procedure Although the mechanism proposed by Fuqua involved initial formation of difluorocarbene by thermal decomposition of chlorodifluo roacetate, followed by trapping of the carbene by triphenylphosphine to form the ylide, Burton has suggested that alternative mechanisms, not involving the intermediacy of CF 2 :, are more likely. 19 Their suggestion was based upon the fact that the thermal d ecomposition of the sodium chlorodifluoroacetate in diglyme was much faster in the presence of Ph 3 P, thus requiring involvement of Ph 3 P in the rate determining step of the mechanism, as well as to the fact that no cyclopropanation was observed to occur whe n 2,3 dimethyl 2 butene was added to the reaction mixture. Herkes and Burton were successful in using essentially the same process with activated ketone substrates, such as trifluoroacetophenone (68% yield). 19 Burton subsequently introduced another approa ch for preparing this ylide intermediate, via reaction of CF 2 Br 2 with triphenylphosphine at room temperature (Figure 1 11), which gave higher yields in reactions with activated ketones, but lower with aldehydes. 36,37 Again, this process did not require the intermediacy of difluorocarbene. In subsequent papers, they found that using (Me 2 N) 3 P instead of Ph 3 P led to high yields in reactions with non activated ketones. 38,39 Another example of a difluorocarbene/Ph 3 P procedure, using (CF 3 ) 2 Hg as the CF 2 : source p roved effective with non activated ketones. 20

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25 Figure 1 11. Burton procedure 1,1 Difluoroalkenes can also be synthesized from aldehydes and ketones via Horner Wadsworth Emmons/Horner Wittig type 40,42 and Julia 42 or Julia Kocienski protocols, 43 which require the preparation of fluorinated phosphonate, sulfinate or sulfone precursors, the use of strong bases and low temperatures. The latter reaction is exceptional in that it provides excellent yields from non activated keton e substrates. These past successes led us to investigate new uses for MFDA. In particular, we wanted to use MFDA to produce 1,1 difluoroalkenes and have comparable yields to previous mentioned procedures.

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26 CHAPTER 2 RESULTS 2.1 Initi al Experiments To Pre pare 1,1 D ifluoroalkenes. Initially, it was hoped that Ph 3 P might be used both to demethylate MDFA and combine with the generated CF 2 : to form the ylide. Thus initial experiments involved simply adding Ph 3 P to MDFA in THF at 100 o C in the presence of benza ldehyde (Figure 2 1). Although about 5% of desired difluorostyrene was formed, the major product of this reaction, quite unexpectedly, was difluorotriphenylphosporane, 45,46 characterized unambiguously by its 19 F NMR signal, a doublet at 41.1 ( 1 J PF = 664 Hz). This result indicated that the S N 2 nucleophilic demethylation reaction with Ph 3 P was not effectively competing with the alternative mechanism that led to Ph 3 PF 2 (most probably initiated by Ph 3 P attack on the carbonyl oxygen of MDFA). 47 Figure 2 1 Initial Rrsults using Ph3P as both nucleophile and ylid e component 2.2 Demethylating R eagent After initial attempts, efforts were made to find an appropriate demethylating reagent to initiate this reaction. Various iodide and bromide sources were investigated that hopefully would complete with the non product ive reaction instigated by Ph 3 P alone. These experiments would mirror the initial experiment, except 2 equivalence of a demethylating reagent would be added to the reaction (Figure 2 1).

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27 2.2.1 Experiments on the Effect of Phase T ransfer Catalysts as Demeth ylating R eagent Phase transfer catalysts (PTCs) were first chosen as suitable bromide and iodine sources because they display great solubility in most organic solvents and are commercially available. We investigated two types of PTCs which include phosphon ium and ammonium salts. When comparing the phosphonium salts, tetrabutylphosphonium bromide (TBPB, Entry 1,Table 2 1) gave a higher yield than tetrabutylphosphonium iodide (TBPI, Entry 5, Table 2 1). These results were unexpected because previous research suggests iodide sources to be the best reagents to initiate these reactions. Alternatively, ammonium salts gave the opposite result. Tetrabutylammonium bromide (TBAB, Entry 2, Table 2 1) gave a lower yield than tetrabutylammonium iodide (TBAI, Entry 3, Tab le 2 1). Next, it was proposed that methyltriphenylphosphonium iodide could be formed in situ from the reaction of triphenylphosphine and methyiodide produced from iodide attacking the methyl group on MFDA. Therefore, methyltriphenylphosphonium iodide was synthesized and used for the demethylating reagent. This reaction produced a 35% yield of 1,1 difluorostyrene (Entry 4, Table 2 1). Table 2 1. PTC as Demethylating reagent

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28 2.2.2 Experiments on the Effect of Potassium/Sodi um Salts as D emet hylating R eagents After success with PTCs, other iodide and bromide sources such as sodium iodide, potassium iodide, and potassium thiocyanide were all examined as potential demethylating reagents. These salts are relatively inexpensive an d commercially available. The same protocol was followed as previous experiments. Under these conditions, these salts did not display great solubility in organic solvents compared to the PTCs. Nevertheless, potassium iodide still gave a moderate yield of d esired product (Table 2 2, Entry 1). Sodium iodide was the least soluble. This factor contributed to the lower yield (Table 2 2, Entry 3). Although potassium thiocyanide displayed moderate solubility, it gave the poorest results of these salts (Table 2 2, Entry 2). The thiocyanide anion prefer to attack the carbonyl directly, compared to the demethylation pathway. Table 2 2. Sodium and potassium salts as demethylating reagents 2.2.3 Other Experiments with D emethylation Since PTCs and potassium/sodium salts were efficient demethylating reagents, it seemed plausible that catalytic amounts of these reagents could be used to initiate

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29 these reactions. After initiation, free fluorine anion would be trapped by TMSX (X= I or Cl) and release X (I or Cl ) that would push the reaction to completion. Reaction conditions were similar to the previous except 10% demethylating reagent and 2 equiv. on TMSX were added to the mixture. If only TMSX was used, no reaction occurred (Entry 1 & 2, Table 2 3). When catalytic amounts of tetrabutylammonium iodide with either TMSI or TMSCl, yields decreased ( Entry 3 & 4, Table 2 3). Therefore, these reactions were not pursued further. In another attempt, zinc (II) iodide was used in the place of th e demethylating reagents, but no desired product was obtained (Entry 5 ) Table 2 3. Other attempt at demethylation of MFDA 2.3 Optimization of Experiments with Selected Demethylating R eagents In examining various sou rces of these nucleophiles, tetrabutyl phosphonium bromide (TBPB) and potassium iodide (KI) were found to give the best results, and they were chosen to be used in experiments designed to optimize conditions of the reaction.

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30 2.3.1 Tetrabutylphosphonium B ro mide (TBPB) 2.3.1.1 TBPB with alternating solvents, concentration and temperature Since this reaction worked well in 10 mL of the polar aprotic solvent THF (Entry 1, Table 2 4), other solvents with similar characteristics were selected to optimize the reac tion. Acetonitrile and 1, 4 dioxane were both tested under similar conditions as previously mentioned (Entry 2 & 3, Table 2 4). The yields decreased in acetonitrile and no reaction occurred in 1, 4 dioxane. Next the concentration of the solution was examin ed. We hypothesized that with less solvent and thus a more concentrated solution, that yields would increase. Since THF gave the best results, reactions were run with 5 mL and 2 mL of this solvent (Entry 4 & 5, Table 2 4). Initial yields decreased slightly to 37% in 5 mL but signi ficantly in 2 mL (11%). Next, temperatures were lowered previous results, but for 5 mL reaction, increased yields of 50% were observed (Entry 1 and 2, Table 2 5). Lowering the temperature was not beneficial to the overall yields of this reaction. This could be due to poor decomposition of MFDA by TBAB at lower temperatures. Table 2 4. Effect of solvent and concentration with TBAB

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31 Table 2 5. Eff ects of temperature and concentration with TBAB 2.3.1.2 Effect of e quiv. MFDA and TBPB To determine if the amount of MFDA and TBPB added affected the overall yield, experiments were designed to test these factors. First a of both MFDA and TBPB were added, but yields decreased to 26%. The same 6). If TBPB was increased to 2.5 equiv. and MFDA left at 2 equiv., the reactio n again gave lower yields (Entry 2, Table 2 6). The same was observed when MFDA was decreased but TBPB was constant (Entry 4, Table 2 6). This suggested that the overall reaction ns remaining the same as the initial experiment.

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32 Table 2 6. Effect of concentration of MFDA and temperature 2.3.1.3 Expanded substrate scope with TBPB Due to success with benzaldehyde, we examined aliphatic aldehyde s and ketones. Under optimal conditions and hexanal as a substrate, the overall reaction gave a yield of 30%. On the other hand, ketones such as tert butylketone and 3 pentanone were unreactive under these conditions. 2.3.2 Potassium Iodide (KI) Since pota ssium iodide gave highest yields of the potassium/sodium salts, efforts were made to optimize these conditions. 2.3.2.1 Potassium i odide with alternating solvents, concentration and temperature After witnessing the affect solvent, concentration, and tempe rature had on previous reactions, we decide to vary these conditions to optimize this reaction. Since yields improved when solvent amount was decreased from 10 mL to 5 mL, all experiments were run using the latter. Under initial conditions, the highest yie lds tetrahydrofuran. The overall yield increased in both cases, the former (45%) and the latter (40%) (Table 2 tions

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33 were repeated. Acetonitrile gave the best results, but tetrahydrofuran also showed improvement (Entry 2 & 5, Table 2 yields. Toluene was explored as a solvent, but yields obtained were low. Table 2 7 Eff ects of solvent and temperature with potassium iodide 2.3.2.2 Potassium i odide with alternating e quiv. of MFDA and KI In the first set of experiments, KI would be varied using acetonitrile as the solvent variables would remain the same. Increasing the amount of KI had a negative impact on the yield overall (Table 2 8). If the amount of KI was decreased, the amount of MFDA at the end of the reaction increased. The second set of experiments would consist of keeping KI constant, but varying the amount of MFDA(Table 2 8). When MFDA was lowered to 1.75 equiv. the overall yield increased to 75%. However, using less MFDA than this led to a decreased yield.

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34 Table 2 8. Effects of concentration of MFDA and potassiu m iodide 2.3.3 Other O ptimization A ttempts Due to the lower cost of sodium iodide (NaI) compared to KI, efforts were made to optimize conditions with this demethylating reagent. In an attempt to increase solubility of NaI in organic solvents, experiments were performed in tetrahydrofuran, acentonitrile, and 1,4 dioxane. Solubility increased, but the reaction did not perform well acetonitrile (Ta ble 2 9, Entry 1). Further optimization did not improve results. Table 2 9. Effect of solvents and temperature with sodium iodide 2.4 Optimized R eaction C onditions and E xpanded S ubstrate S cope Once best conditions were de termined, a variety of aldehydes and activated ketones were examined to determine the scope of the reaction. The results of these

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35 reactions are found in Table 2 10. These results indicate that MDFA gives the desired product in high yield for substituted be nzaldehydes, activated ketones, and electron rich heterocyclic aldehydes. Results were less satisfactory for aliphatic aldehydes or highly electron deficient benzaldehydes, or the highly electron deficient 2 or 3 pyridinecarboxaldehyde under standard cond itions 4 (Dimethylamino) benzaldehyde also failed as a substrate. Small amounts of the above mentioned difluoromethyl phosphonium co product always accompanied formation of the desired 1,1 difluoroalkenes. Figure 2 2 Yields of 1,1 difluoroalkenes from r espective subtrates

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36 2 .4.1 Alkyl Aldehydes Alkyl aldehydes gave poor results under optimized conditions. The best results are summarized in Table 2 10. Hexanal, heptanal and octanal were chosen to explore these reactions f urther because of their higher boiling point compared to shorter chained aldehydes. Overall, the reactions with hexanal, heptanal, and octanal were not dependent on solvent choice. Acetonitrile was the best solvent for these three aldehydes. On the other h and, an increase in temperature and MFDA did increase the yield of both hexanal and heptanal. These results are summarized in Table 2 11, Table 2 12, and Table 2 13. Table 2 1 0 Optimization of substrate hexanal Table 2 1 1 Optimization of substrate heptanal 2 m 2 n

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37 Table 2 1 2 Optimization of substrate octanal 2.4.2 4 Nitrobenzaldehyde In the reaction with 4 nitrobenzaldehyde, desired product ( 3a ) was obtained in low yield. We considered that this might be due to poor solubility of the starting material in CH 3 CN. An attempt to increase the yield by changing solvents resulted in the formation of 4 nitro (2,2,2 trifluoro ethyl)benzene ( 3b ) (Figure 2 2). Compound 3b presumably derives from nucleophilic attack by fluoride ion at the terminal CF 2 group of the initial product formed, 3a Such a reaction has precedent and indeed has been demonstrated to be a reasonable method for synthesizing 2,2,2 trifluoroethyl aromati cs from difluorostyrenes 29,30 Figure 2 3 Reaction with 4 Nitro Benzaldehyde 2.4.3 Aromatic and Aliphatic Ketones Under optimized conditions when triphenylphosphine was used to form the difluoromethyl ylide, no product could be observed by 19 FNMR with aromatic or aliphatic

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38 ketones. Previous work suggested the use of tri(dimethyamino)phosphine, which is better suited for Wittig reactions with aliphatic ketones and aromatic ketones. Two substrates, cyclohexanone and 4 chloroacet ophenone were used for these experiments. In both cases, only trace amount of product were observed by 19 FNMR. The main product appeared to be difluoro, tri(dimethylamino)phoshonium salt [(NMe 3 )PF] + F This could be due to the high reactivity of (NMe 3 )P. T his result indicated that the S N 2 nucleophilic demethylation reaction of KI was not effectively competing with the alternative mechanism that led to (NMe 3 )PF 2 (most probably initiated by (NMe 3 )P attack on the carbonyl oxygen of MDFA). 30 Figure 2 4 Reaction using tri(dimethylamino) phosphine under optimized conditions

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39 CHAPTER 3 DISCUSSION 3.1 Mechanism and C alculations Although the involvement of difluoromethylene triphenylphosphonium ylide, Ph 3 P=CF 2 as the key intermed iate in the Wittig type reactions reported by Fuqua, Burton and many others, as discussed above, has never been questioned, the nature and stability of this intermediate, in particular the strength of binding between the Ph 3 P and CF 2 : entities has definite ly been an issue addressed in a number of papers. Our specific results appear to be unambiguously derived from the generation of difluorocarbene, followed by its combination with Ph 3 P to form the ylide Ph 3 P=CF 2 with subsequent Wittig reaction of this yli de with aldehydes and ketones by the usual mechanism to form 1,1 difluoroalkenes. Therefore, we considered that it would be worthwhile to carry out a computational reexamination of the binding and structure of this ylide. Difluorocarbene has, itself, been subject of several computational studies 49 51 with the large energy difference between its singlet (S) and triplet (T) states (with the singlet being the ground state) creating particular interest in this carbene. When compared with the CH 2 carbene, repla cement of hydrogen with fluorine has been shown to contribute significantly to the stabilization of the singlet versus the triplet state. combined with triphenylphosphine, form their respective triphenylphosphonium ylides. All three of these ylides have been used as Wittig reagents, but, in contrast to methylene triphenylphosphonium ylide, 52 neither the CHF or the nCF 2 ylides are sufficiently stable to be isolated. 19,53

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40 In 1986, using ab initio molecular orbital theory (SCF level), 54 Dixon and Smart examined the interaction between the CF 2 (S) and PH 3 At this level of theory, it was found that the bond length between the CF 2 carbon and the phosphorous was 3.54 , which is essent ially two separate species with little interaction. In addition, the binding energy between the CF 2 and the PH 3 was calculated to be only 1.2 kcal/mol, which was 2 =PPh 3 ylide. 54 However, ca lculations by Allen and co workers in 1988 at the HF/3 21G* level reported that the C P bond length of the same molecule was 1.635 55 which could be interpreted as a double bond considering that their calculations for the C P bond length of CH 2 PH 3 was 1 .646 . Unfortunately, the authors did not mention or discuss the discrepancy between their results and those of Dixon and Smart. Because of the apparent weak interaction between the CF 2 (S) and PH 3 reported by Dixon and Smart, we considered that the use of density functionals, and more important those that include medium range attractive interactions such as M06 2X, 56 58 might provide greater insight in calculating the structures and energies of these types of molecules. 3.2 Ground State Calculations of the Single and Triplet State for CH 2 CHF and CF 2 Carbenes Ground state calculations of the singlet and triplet state for the CH 2 CHF and CF 2 carbenes were carried out and the results were compared with available experimental data. Both structures and S T e nergy gaps (Table 3 1) were found to be in good agreement with available experimental and previous computational results. 49 51

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41 Table 3 1 Geometrical data and energy gaps for various methyl carbenes at the M06 2X/6 311+G(2df,2p) level. a,b C H () C F ( ) X C Y (Degrees) DE (T S) (kcal/mol) CH2(S) 1.106 (1.107) -102.0 (102.4) 11.26 ( 9.37) CH2(T) 1.076 (1.075) -134.3 (133.9) CHF(S) 1.118 (1.138) 1.299 (1.305) 102.3 (103.5) 9.59 (8.0 14.60) CHF(T) 1.083 (1.088) 1.307 (1.304) 121.9 (121.2) CF2( S) -1.293 (1.304) 104.5 (104.8) 54.25 (56.60) CF2(T) -1.307 (1.298) 118.9 (118.1) a In parenthesis are experimental values or difference dedicated configuration interaction results, available from [32] and references therein; b X= H,F ; Y = H,F. As expected, all singlet carbenes have greater bond lengths and smaller X C Y angles than the triplet carbenes, consistent w ith the presumed sp 2 and sp hybridization, respectively. Although energy gaps have been calculated more precisely with different density functionals and basis sets, 51 our calculated energy gaps between the triplet and singlet carbenes using the M06 2X func tion are close to earlier reported values. Our structural calculations are also consistent with the experimental data reported for CH 2 42,43 3.3 Ca lculated Ground State S tructures of the CH 2 PPh 3 CHF PPh 3 and CF 2 PPh 3 Y lides With our calculated ground sta te structures and energies of the singlet carbenes in excellent agreement with both previous theory and experiment, the ground state structures of the CH 2 PPh 3 CHF PPh 3 and CF 2 PPh 3 ylides were then calculated. These structures are depicted in Figure 3 1, with the data being provided in Table 3 2.

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42 (a) (b) (c) Figure 3 1. Depictions of the calculated structures of (a) CH 2 =PPh 3 (b) CHF=PPh 3 and (c) CF 2 =PPh 3 Table 3 2. Geometrical data for various phosphonium ylides at the M06 2X/6 311+G(2df,2p) level a Distance ( ) Angle (Deg rees) P C C H C F P Ph(2, 3) P Ph1 X C Y P C H P C F CH 2 PPh 3 1.674 (1.662) 1.082 (0.932) -1.821 (1.816) 1.847 (1.839) 116.0 (121.9) 116.2 (118.8) -CHF PPh 3 1.707 1.085 1.391 1.814 1.842 111.8 115.6 115.3 CF 2 PPh 3 1.815 -1.378 1.808 1.82 105.1 -109.2 a Experimental values in parenthesis when available [33] In comparing the structures of all three ylides, one can see that the methylene carbon of CH 2 PPh 3 has the greatest sp 2 character, with this carbon taking on

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43 increasing sp 3 character as each H is replaced by F. These changes are reflected in the longer C P bonds and the greater pyramidalization as one proceeds from the CH 2 to the CHF to the CF 2 ylide. Although our calculat ed bond length for the C P bond in CF 2 =PPh 3 (1.815 ) is much shorter than the 3.54 calculated by Dixon and Smart for CF 2 PH 3 it is significantly longer than the 1.635 calculated by Allen. The X C Y angle is observed to decrease as the number of fluor ine increases, a trend consistent with the change from sp 2 to sp 3 hybridization at the methylene carbon. In order to quantify the stability of the CF 2 PPh 3 ylide, the enthalpy and the free energy of the reaction between the singlet carbene and triphenylpho sphine to produce the ylide was calculated (Figure 3 2). Both gas phase and solvent were considered and the data is shown in Table 3 3. Figure 3 2. Calculated reaction for formation of ylides from carbene and Ph 3 P

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44 T able 3 3 Relative 298 K free energies (kcal/mol) for CH 2 CHF and CF 2 triphenylphosphonium ylides a a Energies in kcal / mol. b Solv = Acetonitrile c. Dipole in Debye In the gas phase, fo rmation of both the CH 2 and the CHF ylide are highly exothermic and exergonic, whereas for the CF 2 ylide the reaction is exothermic, but endergonic. However, since the dipole moment of the CF 2 PPh 3 ylide is much larger than those of the CH 2 and CHF ylides, this suggests that the CF 2 ylide might be more favored than the others in polar solvents. When acetonitrile was included as solvent in the calculation, formation of the CH 2 and CHF ylides remained highly exothermic and exergonic, but the values were not m uch different from those for the gas phase. On the other hand, in the polar solvent, formation of the CF 2 ylide proved to be not only exothermic, but also exergonic to the extent of 4.1 kcal/mol. These results suggest that formation of the CF 2 PPh 3 ylide would be favored in polar solvents, and it should thus be possible for it to participate in Wittig reactions. In order to have a better understanding of the stability and behavior of the CF 2 PPh 3 ylide, the transition state for the C P bond formation/diss ociation was calculated (Figure 3 2, Table 3 3), and the reaction was seen to have a relatively flat potential energy surface at 298K, with a calculated activation free energy in acetonitrile of 5.17 kcal/mol, relative to the singlet CF 2 carbene and PPh 3 a t infinite separation. Thus the dissociation of the ylide to its carbene and phosphine components would only have to CH 2 PPh 3 CHF PPh 3 CF 2 PPh 3 CF 2 PPh 3 TS H (Gas) 79.02 43.57 6.80 3.21 G (Gas) 67.15 30.85 5.42 8.38 H (Solv) b 79.12 46.55 14.42 4.53 G (Solv) b 69.15 35.73 4.10 5.17 Dipole 2.96 4.42 5.78

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45 overcome a 9.27 kcal/mol barrier. This is consistent with the kind of reversibility of ylide formation that was observed by Burton 53

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46 CHAPTER 4 C ONCLUSION In conclusion, it has been found that under moderate conditions, in the presence of a demethylating reagent such as iodide, methyl 2,2, difluoro 2 (fluorosulfonyl)acetate releases difluorocarbene, which in the presence of triphenylphosphine forms difluoromethylene triphenylphosphonium ylide. When the process is carried out in the presence of aldehydes or activated ketones, an in situ Wittig type reaction of the ylide with the carbonyl reactants produces 1,1 difluoroalkenes in good yield. Calculations indicated that the ylide intermediate was only weakly bound, but was sufficiently stable to propose its involvement in the kind of usual Wittig reaction expected of phosphonium ylides.

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47 CHAPTER 5 EXPERIMEN TAL 5.1 General Information NMR spectra were obtained in CDCl 3 using TMS and CFCl 3 as the internal standards for 1 H/ 13 C NMR and 19 F NMR spectra, respectively. The identities of known compounds 2h, 2j, 2l 2n, and 3 were initially determined on the basis of their characteristic fluorine NMR spectra, but were also confirmed by examination of their proton spectra. New compounds 2d, 2i, and 2k were fully characterized on the basis of their 1 H, 13 C, and 19 F NMR spectra, and by their exact masses as determined by HRMS. 5.2 General P rocedure or 1,1 Di fluoroalkenes R eactions. 5.2.1. 4 Bromo (2,2 difluoroethenyl)benzene A 250 mL, three necked round bottomed flask was equipped with a stir bar. Th e vessel was then fitted with a condenser topped by a T tube with slow flow of N 2 and then sealed with septa. The vessel was flamed dried and then allowed to cool to room temperature. Under the inert, nitrogen atmosphere, acetonitrile (75 mL) was added to the vessel, and the temperature was increased to 70 C. Then triphenylphosphine (34.5 g, 135 mmol, 3 equiv), potassium iodide (15.0 g, 90 mmol, 2 equiv), and 4 bromobenzaldehyde (9.80 g, 45 mmol, 1 equiv) were added and let stir for 30 min. Methyl 2,2 dif luoro 2 (fluorosulfonyl)acetate (MDFA) (19.7 g, 78.75 mmol,1.75 equiv) was then added slowly over a period 1 hr. The resulting mixture was stirred for three hours, a nitrogen atmosphere being maintained until the end of the reaction Then the reaction was quenched with water and extracted with ethyl acetate. Trifluorotoluene (15 mmol) was added as internal standard and the yield of the crude reaction was measured by 19 F NMR (72%). The ethyl acetate was then removed by rotary

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48 evaporation to produce a black, semi solid slurry. Product was isolated from the slurry and separated from residual triphenylphosphine by extraction 5 times with hexane (100 mL) The combined hexane extracts were combined and concentrated. Additional impurities were removed via column chr omatography using a 95:5 mixture of hexanes: methylene chloride to obtain pure product: (6.9g (70%), clear liquid); 1 J = 9.1 Hz 2H), 7.21 (d, J = 8.1 Hz, 2H), 5.25 (dd, J = 25 Hz, J = 3.1 Hz, 1H); 19 F NMR, J = 30.1 Hz, J = J = 29.1 Hz, J = 3.8 Hz, 1F). The above data is in accord with those reported in the literature. 44 5.2.2 (2,2 Difluoroethenyl)benzene (2a) 1 H NMR 5.40 (dd, 3 J FH = 26.6 & 4.1 Hz, 1H), 7.55 (m, 5H); 19 F NMR J = 3 3.6 Hz, 27.4 J = 31.7 Hz, 1F). 19,61,62 5.2.3 4 Methyl (2,2 difluoroethenyl)benzene (2b) 1 H NMR d 5.25 ( 3 J FH = 26.4 & 4.2 Hz, 1 H), 7.16 (d, 3 J HH = 8.4 Hz, 2H), 7.24 (d, 3 J HH = 8.4 Hz, 2H); 19 F NMR J = 38.1 Hz, 28.2 Hz, 1 J = 37.5 Hz, 1F) 61 63 5.2.4 4 Methoxy (2,2 difluoroethenyl)benzene (2c) 1 H NMR d 3.83 (s, 3H), 5.24 (dd, 3 J FH = 26.3 & 4.5 Hz, 1H), 6.91 (d, 3 J HH = 8.6 Hz, 2H), 7.29 (d, 3 J HH = 8.6 Hz, 2H); 19 J = 42.3Hz, J = 26.8 Hz, 1F), 89.2 (d, J = 41.3 Hz,1F) 61 63 5.2.5 4 Thiomethyl (2,2 difluoroethenyl)benzene (2d) 1 H NMR, 2.48 (s, 3H), 5.23 (dd, 3 J FH = 25.5 & 3.6 Hz, 1H), 7.23 (m, 4H); 19 85.3 (dd, J = 34.9Hz, J J = 35.3 Hz,1F); s, DART TOF MS): calcd C 9 H 9 F 2 S (M) + 187.0393, found 187.0399.

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49 5.2.6 2 Bromo (2,2 difluoroethenyl)benzene (2e) 1 H NMR 5.24 (dd, 3 J FH = 26.1 & 3.9 Hz, 1H), 7.04 (m, 2H), 7.29 (m, 2H); 19 J = 25.9Hz, J J = 28 Hz, J = 2 1F) 64 5.2.7 4 Fluoro (2,2 difluoroethenyl)ben zene (2f) 1 H NMR 5.24 (dd, 3 J FH = 26.1 & 3.6 Hz, 1H), 7.02 (m, 2H), 7.25 (m, 2H); 19 J = 36.6Hz, J J = 33.8 Hz, J =3.7,1F). 18,62 5.2.8 4 Trifluoromethyl (2,2 difluoroethenyl)benzene (2g) 19 77.9 (m,1F), 76.8 (qq, J=1 0.4Hz, J=24.3Hz, J=33.3Hz, J= 46.5Hz, 1F) 59.7 (dd, J = 10.4 Hz, J = 24.3 Hz, 3F) 64 5.2.9 4 Benzyloxy (2,2 difluoroethenyl)benzene (2i) 1 H NMR, 5.21 (dd, 3 J FH = 26.1 & 3.6 Hz, 1H), 6.07 (s, 3H), 6.95 (m, 2H), 7.33 7.44 (m, 5H); 19 2 J FF = 42.6Hz, 3 J HF 2 J FF = 40.6 Hz,1F); TOF MS): calcd C 15 H 13 F 2 O (M) + 247.0934, found 247.0933. 5.2.10 2,3,4,5,6 Pentafluoro (2,2 difluoroethenyl)benzene (2j) 77.3 (m, 1F), 81.1 (s, 1F), 141.3 (t, J ) 17.8 Hz, 2F), 157.4 (t, J ) 21Hz, 1F), 164.6 (m, 2F). 30 5.2.11 1 (2,2 Difluoroethenyl) thiophene (2k) 1 J = 1 Hz 1H), 7.24(d, J = 1 Hz, 1H), 7.0 (d, J = 3 Hz, 1H), 5.55 (dd, 3 J HF = 24 Hz, 3 J HF = 2.1 Hz, 1H). 19 (dd, 2 J FF = 32.4 Hz, J = 1 Hz, 1F), 2 J FF = 32.4 Hz, J = 1.7 Hz, 1F). 13

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50 TOF MS): calcd C 6 H 5 F 2 S (M + H )+ 147.0080, found 147.0082. 5.2.12 1 (2,2 Difluoroethen yl)furan (2l) 19 3 J HF = 31.8 Hz, 2 J FF 2 J FF = 29.3 Hz,1F) 18 5.2.13 1,1 Difluoro 1 heptene (2m) 19 85.1 (dd, J = 35.3Hz, J J =32.2Hz,1F) 61 5.2.14 1,1 Difluoro 1 octene (2n) 19 91.8 (d J J =28.2 Hz, J =26.7Hz 1F) 62 5.2.15 4 Nitro (2,2 difluoroethenyl)benzene (3a) 19 80.1 (dd, J =26.2Hz, J (d) J = 18 Hz, 1F) 18,62 5.2.4 4 Nitro (2,2,2 trifluoro ethyl)benzene (3b) 19 F NMR: 66.5 (t, J = 10.7 Hz, 3F) 18,66 5.3 Computational Method All quantum chemical calculations were performed using Gaussian 09 Rev. A.02 65 at the M06 2X/6 311+G(2df,2p) level of theory 56 58 including frequency calculation to identify the structures as e ither ground state or transition state. All calculated transition states presented one and only one negative frequency. The influence of acetonitrile as a solvent was evaluated using the SMD continuum solvation model 68 Free energies in solution were calc ulated by summing the gas phase thermal contributions with the single point SMD/M06 2X energies. Correction from the

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51 gas to the solution phase was made by adding 1.9 kcal/mol (RT Ln([Sln]/[Gas])) to the free energy of each molecule.

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5 2 A PPE NDIX A NMR S pectra of C orresponding C ompounds Figure A 1 19 F NMR of (2,2 Difluoroethenyl)benzene (2a)

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53 Figure A 2 19 F NMR of (2,2 Difluoroethenyl)benzene (2a)

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54 Figure A 3 1 H NMR of (2,2 Difluoroethe nyl)benzene (2b)

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55 Figure A 4 19 F NMR of 4 Methyl (2,2 Difluoroethenyl)benzene (2b)

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56 Figure A 5 1 H NMR of 4 Methyl (2,2 Difluoroethenyl)benzene (2c)

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57 Figure A 6. 19 F NMR of 4 Methoxy (2,2 Difluoroethenyl)benzene (2c)

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58 Figure A 7. 1 H NMR of 4 Thiomethoxy (2,2 Difluoroethenyl)benzene (2d)

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59 Figure A 8. 19 F NMR of 4 Thiomethoxy (2,2 Difluoroethenyl)benzene (2d)

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60 Figure A 9. 1 H NMR of 2 Bromo (2,2 Difluoroethenyl)benzene (2e)

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61 Figure A 10. 19 F NMR of 2 Bromo (2,2 Difluoroethen yl)benzene (2e)

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62 Figure A 11 1 H NMR of 4 Fluoro (2,2 Difluoroethenyl)benzene (2f)

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63 Figure A 12. 19 F NMR of 4 Fluoro (2,2 Difluoroethenyl)benzene (2f)

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64 Figure A 13 19 F NMR of 4 Trifluoromethyl (2,2 difluoroethenyl)benzene (2g)

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65 Figure A 14. 19 F NMR of 4 Trifluoromethyl (2,2 difluoroethenyl)benzene (2g)

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66 Figure A 15. 1 H NMR of 4 Bromo (2,2 Difluoroethenyl)benzene (2h)

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67 Figure A 16. 19 F NMR of 4 Bromo (2,2 Difluoroethenyl)benzene (2h)

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68 Figure A 17. 1 H NMR of 4 Benzyloxy (2,2 Di fluoroethenyl)benzene (2i)

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69 Figure A 18. 19 F NMR of 4 Benzyloxy (2,2 Difluoroethenyl)benzene (2i)

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70 Figure A 19. 19 F NMR of 2,3,4,5,6 Pentafluoro (2,2 difluoroethenyl)be nzene (2j)

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71 Figure A 20. 1 H NMR of 1 (2,2 Difluoroethenyl) thiophene (2k)

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72 Figure A 21. 19 F NMR of 1 (2,2 Difluoroethenyl) thiophene (2k)

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73 Figure A 22. 13 C NMR of 1 (2,2 Difluoroethenyl) thiophene (2k)

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74 Figure A 23. 19 F NMR of 1 (2,2 Difluoroethenyl) furan (2l)

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75 Figure A 24. 19 F NMR of 1,1 Difluoro 1 heptene (2m)

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76 Figure A 25. 19 F NMR of 1,1 Difluoro 1 octene (2n)

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77 Figure A 26. 19 F NMR of 4 Nitro (2,2,2 trifluoroethyl)benzene (3b)

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78 LIST OF REFERENCES 1) D. Hagan, J. Chem. Soc Rev. 37 (2008) 308 319 2) Anslyn, E. V., & Dougherty, D. A. (2006). Modern physical organic chemistry. Sausalito, CA: University Science 3) Dolbier, W. R.,Jr. Guide to Fluorine NMR for Organic Chemists; John Wiley & Sons: New Jersy, 2009 4) Chambers, R. D., Fluorine in Organic Chemistry; John Wiley & Sons: New York, 1973 5) Lide, D.R., CRC Handbook of Chemistry & Physics, 84th edition; CRC Press: Boca Raton, 2003 6) Kitazume, T.; Yamazaki, T., Experimental Methods in Organic Fluorine Chemistry; 1 ed.; Kon dansha: Tokyo Japan,1998 7) Sandford, G. Phil. Trans. R. Soc. Lond. A (2000) 358, 455 471 ( Industrial aspects of F) 8) Wittig, G.; Geissler, Liebigs. Ann. (1953) 44, 580 9) Vedeis, F.; Peterson, M.J., Top. Stereochem. (1994) 21, 1 157 10) Homer, L.; Hoff man, H. M. R.;. Wipper H.G.,Chem. Ber. (1958) 91, 61 63 11) Homer, L.; Hoffman, H. M. R. ; Wipper H.G., Chem. Ber. (1959) 92, 2499 2505 12) Wadsworth, W.S.; Emmons, W.D., J. Org. Chem. (1961) 83,1733 1738 13) Wadsworth, W.S. J. Org. React. (1977) 25, 73 253 14) Fei,X. S.; Tian, W.S.; Chen Q.Y. J. Chem. Soc. Perkin Trans. 1 (1998) 1139 1142 15) Eusterwiemann, S.; Martinez H.; Dolbier Jr., W.R., J. Org. Chem. 77 (2012) 5461 5464 16) Hayashi, S. I.; Nakai, T.; Ishikawa, N.; Chem. Lett. (1980) 651 654. 17) Fuqua, S. A.; Duncan, W. G.; Silverstein, R. M., Tetrahedron Lett. (1964) 1461 1463. 18) Fuqua, S. A.; Duncan, W. G.; Silverstein, R. M.; J. Org. Chem. 30 (1965) 1027 1029. 19) Herkes, F. E.; Burton, D. J.; J. Org. Chem. 32 (1967) 1311 1318.

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82 BIOGRAPHICAL SKETCH Charles Seth Thomoson was born i n Tifton, Georgia. He graduated with honors from Tift. County High School in 2006. After graduation, he attended Abraham Baldwin Agricultural College for one year before he decided to move to Statesboro, Georgia in 2007. He then attended Georgia Southern U niversity in f all 2007, where he pursued a degree in the field of chemistry. He performed undergraduate research at the University of New Hampshire under the advisement of Dr. Ch arles Zercher. He graduated in f all 2010 from Georgia Southern University with a B.S in Chemistry. He accepted a job at Imperial Sugar Company in f all 2010 preforming duties to maintain quality control and quality assurance of products. He enrolled int o the University of Florida in f all 2011 as a graduate student in organic chemistr y under the direction of Dr. William R. Dolbier Jr., where he studied organic chemistry involving fluorine.