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1 THE ROLE OF FLUORINE IN ENERGETIC MATERIALS, AND ITS IMPACT ON LONG RANGE COUPLING CONSTANTS AND S N 2 E2 REACTIONS By HENRY MARTINEZ A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2011
2 2011 Henry Martinez
3 To my family
4 ACKNOWLEDGMENTS I would e specially like to thank my supervisor Dr. William R. Dolbier for not only g iving me the opportunity to work with him but also for supporting my ideas. He is a tru e example of what a great scientist should be hard worker, honest and a great professor. I hope one day to be half of what he is. I also want to thank all of the commi ttee members for their suggestions, time and kindness. I want to thank my mom for always being there for me, for believing in me, and for not giving me everything I wanted, but instead, teaching me how to get things myself. Thanks for being the greatest mo m ever and car ing so much about me. I will work really hard to make you proud every day Thank you mom for bringing in to my life my brother Felipe and my sister Veronica ; they are one of the reasons why I want to wake up every day ; they are the fuel my h eart uses to continue running without stop ping I also want to thank my Godparents, Nancy and Efrain, for believing in me and supporting me unconditionally T here is not a way for me to describe how thankful I am for both of you. To Alexander, my brother, thank you for always being there for me ; you are the best friend everyone wishes to have. To my grandmother, Stella, thank you for teaching that everything is possible and I just have to work hard for it. Thank you grandma for protecting me the way you did until the last day of you r life. To my entire family, my A unt Rosa, my U ncle Carlos, all my cousins, Erick, Vanessa, Fernanda, Dalhia, Adriana, Juan Carlos and Johanna, and to m y Goddaughter Sofia, thank you all for being part of my life.
5 To my except ional wife, Paula, thank you for car ing so much about me, for always giving me your best, your understanding, your trust and unconditional love. I am the luckiest guy on earth for having you. To all my friends, especially Lianhao Zhang, thank you all for t he great times, discussions and help. I hope I live enough to return all their kindness and care. Finally, last but not least, I want to thank God for bringing to my life every person I just mentioned and for giving me everything I needed to complete this journey W ithout H im I would not have reach ed this stage of my life.
6 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ .. 4 LIST OF TABLES ................................ ................................ ................................ ............. 8 LIST OF FIGURES ................................ ................................ ................................ ........ 10 LIST OF SCHEMES ................................ ................................ ................................ ....... 13 ABSTRACT ................................ ................................ ................................ .................... 15 CHAPTER 1 INTRODUCTION ................................ ................................ ................................ ..... 17 An Overview of Fluorine in Organic Chemistry ................................ ........................ 17 Fluorine as Pentafluorosulfanyl G roup ................................ ................................ .... 22 Fluorine and Pentafluorosulfanyl Group in Energetic Materials ............................... 25 Fluorine in [2.2]Paracyclophanes ................................ ................................ ............ 28 Fluorine NMR ................................ ................................ ................................ .......... 33 Fluorine in S N 2 and E2 Reactions ................................ ................................ ........... 36 2 DESIGN OF PENTAFLUOROSULFANYL ENERGETIC MATERIALS ................... 38 Introductory Remarks ................................ ................................ .............................. 38 Furazan Energetic Materials ................................ ................................ ............. 38 Pentafluorosulfanyl (SF 5 ) as Part of Energetic Materials ................................ .. 41 Results ................................ ................................ ................................ .................... 43 Aminofurazan Starting Materials ................................ ................................ ....... 43 Synthesis of SF 5 Furazan Based Energetic Materials ................................ ...... 44 The SF 5 acetyl building block ................................ ................................ ..... 44 Pentafluorosulfanylmethyl dicarbonyl building block ................................ .. 48 Miscellaneous reactions ................................ ................................ ............. 49 The pentafluorosulfanyl isocyn ate building block ................................ ........ 51 N Nitration and oxidation reactions ................................ ............................. 53 Discussion ................................ ................................ ................................ ............... 55 Addition of SF 5 Building Blocks ................................ ................................ ......... 55 Nitration and Oxidation Reactions ................................ ................................ ..... 65 Properties of the Synthesized SF 5 Furazan Bas ed Energetic Materials. ................................ ................................ ................................ ....... 67 Experimental Methods ................................ ................................ ............................. 72 Instrumentation ................................ ................................ ................................ 72 General Method for the Syntheses of Pentafluorosulfanyl Furazans ................ 73 General Method for the Syntheses of Pentafluorosulfanylurea Furazans ................................ ................................ ................................ ........ 75
7 3 CONFORMATIONAL AND 19F 19F COUPLING PATTERNS ANALYSIS IN MONO SUBSTITUTED PERFLUORO [2,2] PARACYCLOPHANES BY COMPUTATIONAL CALCULATIONS ................................ ............................... 78 Introductory Remarks ................................ ................................ .............................. 78 Results and Discussion ................................ ................................ ........................... 83 Ground State Calculations ................................ ................................ ................ 83 4 J (F m F n ) Coupling Constants ................................ ................................ ............ 84 5 J (F m F n ) Coupling Constants ................................ ................................ ............ 86 Preferred Conformations : Upper Deck Towards or Away ................................ 93 4 IMPACT OF FLUORINE SUBSTITUENTS ON THE RATES OF NUCLEOPHILIC ALIPHATIC SUBSTITUTION AND ELIMINATION .................... 97 Introductory Remarks ................................ ................................ .............................. 97 Results and Discussion ................................ ................................ ........................... 99 Kinetics ................................ ................................ ................................ ........... 101 Hydrocarbon Substrates ................................ ................................ ................. 102 Leaving group abilities, bromide versus iodide and tosylate ..................... 104 Effect of the nucleophile, methoxide versus azide ................................ .... 105 Solvent effect, methanol versus DMSO ................................ .................... 106 Fluorinated Substrates ................................ ................................ .................... 107 Fluorinated substrates ................................ ................................ ........... 107 Fluorinated substrates ................................ ................................ ........... 108 Fluoro substrate ................................ ................................ .................... 109 Difluoro substrate ................................ ................................ ............... 110 Fluorinated benzylic bromides ................................ ................................ .. 111 Computational Results ................................ ................................ .................... 113 Experimental Section ................................ ................................ ............................. 120 General Procedure for the Kinetic Experiments ................................ .............. 121 Computational Methods ................................ ................................ ......................... 122 5 CONCLUSIONS ................................ ................................ ................................ .... 123 Fluorine as Pentafluorosulfanyl Group in Furazan Energetic Materials ................. 123 Fluorine and Its Impact on Long Range Coupling Constants ................................ 125 Fluorine and Its Impact on S N 2 and E2 Reactions ................................ ................. 125 APPENDIX A SF 5 ENERGETIC MATERIALS ................................ ................................ ............. 127 B FLUORINE ON S N 2 AND E2 REACTIONS ................................ ........................... 132 LIST OF REFERENCES ................................ ................................ .............................. 134 BIOGRAPHICAL SKETCH ................................ ................................ .......................... 141
8 LIST OF TABLES Table page 1 1 Performance data of three common energetic materials. ................................ .... 27 2 1 p K a values of some aminofurazan derivatives. ................................ ................... 56 2 2 p K a vs C NH 2 bond distance. ................................ ................................ .............. 59 2 3 Calculated p K a values using the plot from Table 2 2. ................................ ......... 60 2 4 Thermogram data of the synthesized energetic materials. ................................ .. 70 2 5 Calculated performance data of the synthesized energetic materia ls. ................ 71 3 1 Relative energies for the conformational isomers of 51 and 52 .......................... 83 3 2 Calculated 4 J (F m F n ) c oupling constants and F F distance for compound 51 (R=OMe). a c ................................ ................................ .................. 84 3 3 Calculated 4 J (F m F n ) coupling constants and F F distance for compound 52 (R=NEt 2 ). a c ................................ ................................ ................... 85 3 4 Calculated 5 J (F m F n ) coupling constants and F F distance for compound 51 (R=OMe). a c ................................ ................................ .................. 87 3 5 Calculated 5 J (F m F n ) coupling constants and F F distance for compound 52 (R= NEt 2 ). a c ................................ ................................ .................. 89 3 6 Expansion of relevant CMOs in terms of NBOs in compound 51 Only NBOs involving F5, F9S, F10S and F12 are displayed. ................................ ...... 92 4 1 2 nd order rate constants for n alkyl iodide, bromide and and for benzyl bromide. ................................ ................................ ................................ ............ 104 4 2 Relative leaving group abilities in S N 2 reactions at 50 o C ................................ ... 105 4 3 Relative nucleophilicities of azide versus methoxide in S N 2 reactions. ............. 105 4 4 Relativ e rate constants for reactions in DMSO versus methanol ...................... 106 4 5 2 nd order rate constants for perfluoro n butylethyl bromide. .............................. 108 4 6 2 nd order rate constants for perfluoro n propylmethyl bromide .......................... 109 4 7 2 nd order rate constants for 1 bromo 1 fluorononane. ................................ ....... 110 4 8 2 nd order rate constants for 1 bromo 1,1 difluorohexane. ................................ 111 4 9 2 nd order rate constants for bromodifluoromethylbenzene. ............................... 112
9 4 10 Relative rates for S N 2 reactions of PhCH 2 Br versus PhCF 2 Br. .......................... 112 4 11 Relevant geometrical data and calculated energy barriers at the transition state for the S N 2 reaction between alkyl iodide substrates and hydroxide. ................................ ................................ ................................ ... 115 4 12 Relevant geometrical data and calculated energy barriers at the transition state for the E2 reaction between alkyl iodide substrates and hydroxide as base. ................................ ................................ ............................ 118 B 1 Complete data for the 2 nd order rate constants for n alkyl iodide, bromide and tosylate and for benzyl bromide ................................ .................... 132 B 2 Complete data for the 2 nd order rate constants for perfluoro n butylethyl bromide. ................................ ................................ ............................ 133
10 LIST OF FIGURES Figure page 1 1 Possible conformations for 1,2 difluoromethane. ................................ ................ 18 1 2 Examples of organo fluorine compounds in different areas of application ................................ ................................ ................................ .......... 18 1 3 Examples of reactions with the electrophilic fluorine reagent, Selectfluor. ................................ ................................ ................................ .......... 19 1 4 Synthesis and reacti ons of tetrabutylammonium fluoride anhydrous. 5 ................ 20 1 5 Fluorinations mediated by Palladium. 8,9 ................................ .............................. 21 1 6 Synthesis a nd reactions of deoxoflorinated reagent, Fluolead. ........................... 22 1 7 AB4 system in the pentafluorosulfanyl group. ................................ ..................... 23 1 8 Ex amples of SF 5 Organic compounds with different applications. ..................... 24 1 9 Radical addition of SF 5 Cl to double bonds using Et 3 B at 30 o C. ......................... 25 1 10 Examples of synthesis of SF 5 organic compounds. ................................ ............ 25 1 11 Higher density on SF 5 compounds. ................................ ................................ ..... 28 1 12 Polynitro SF 5 energetic material. ................................ ................................ ......... 28 1 13 Structure of [2.2]paracyclophane. ................................ ................................ ....... 29 1 14 Applications of [2.2]paracyclophane derivatives. ................................ ................. 30 1 15 Racemization of [2.2]paracyclophane derivatives. ................................ .............. 30 1 16 [2.2]Paracylo phane and the most common fluorinated [2.2]PCPs. ..................... 31 1 17 Most common methodologies for the synthesis of [2.2]paracyclophanes. ................................ ................................ ......................... 32 1 18 Examples of chemical reactions of fluorinated [2.2]paracyclophanes. ................ 33 1 19 Examples of through space spin spin coupling. ................................ .................. 35 1 20 Through space coupling identified by Ernst. ................................ ........................ 36 1 21 S RN 1 mechanism with perfluoroalkyl iodides. ................................ ...................... 37
11 2 1 Examples of SF 5 containing energetic materials. ................................ ................ 42 2 2 Additional synthesized aminofurazans starting materials. ................................ ... 43 2 3 Retrosynthetic approach for the synthesis of 3 amino 4 (pentafluorosulfanylmethyl) furazan ................................ ................................ ... 48 2 4 SF 5 acetyl building blocks. ................................ ................................ .................. 55 2 5 Methyl furazan derivatives synthetized by Fruttero. ................................ ............ 57 2 6 New energetic materials synthesized in this project. ................................ ........... 68 2 7 DSC/TGA thermogram of compound 28 ................................ ............................. 69 3 1 Towards and away upper deck orientations ................................ ........................ 78 3 2 Monosubstituted F8, where R= OMe ( 51 ), NEt 2 ( 52 ). ................................ .......... 84 3 3 ................................ ................................ .................. 85 3 4 Calculated most stable conformations for compounds 51 (left) and 52 (right). ................................ ................................ ................................ .................. 86 3 5 Unusual through space coupling transmitted by the electronic Ph d system. ................................ ................................ ................................ ................ 87 3 5 Representation of the unusual 5 J FF SSCCs. ................................ ........................ 88 3 7 Repulsive interaction between the CH 3 and the closest CF 2 on the F8 bridge. ................................ ................................ ................................ ................. 94 4 1 Example of a kinetic study followed by 1 H NMR. ................................ .............. 102 4 2 Two perspectives of the calculated transition state of the S N 2 reaction of hydroxide with CH 3 CH 2 CHFI. ................................ ................................ ........ 117 A 1 TGA DSC com pound 27 ................................ ................................ ................... 127 A 2 TGA DSC compound 28 ................................ ................................ ................... 127 A 3 TGA DSC compound 50 ................................ ................................ ................... 128 A 4 TGA DSC compound 29 ................................ ................................ ................... 128 A 5 TGA DSC compound 30 ................................ ................................ ................... 1 29 A 6 TGA DSC compound 31 ................................ ................................ ................... 129
12 A 7 TGA DSC compound 32 ................................ ................................ ................... 130 A 8 TGA DSC compound 48 ................................ ................................ ................... 130 A 9 TGA DSC compound 49 ................................ ................................ ................... 131
13 LIST OF SCHEMES Scheme page 2 1 Synthesis of common furazan building blocks. ................................ .................... 39 2 2 Amino Furazan tetrazole synthesis and its derivatives. ................................ ...... 40 2 3 Synthesis of Methyl 2 pentafluorosulfanyla cetate 24 ................................ ......... 44 2 4 Attempted reactions between DAF 1 and methyl SF 5 acetate 23 ...................... 44 2 5 Synthesis of pentafluorosu lfanylacetyl chloride. ................................ .................. 45 2 6 Synthesis of pentafluorosulfanylacetamide furazans. ................................ ......... 45 2 7 Synthesis of the benzot riazole derivative of SF 5 acetic acid. .............................. 45 2 8 Synthesis of 28 from the benzotriazole derivative of SF 5 acetic acid. ................. 46 2 9 Synthesis of DASF5 DAF from SF 5 acetic acid using EDC. ................................ 46 2 10 Reaction between different aminofurazans and SF 5 acetic acid in the presence of EDC. ................................ ................................ ................................ 47 2 11 Synthesis and addition of SF 5 Cl to methyl 2 methoxyacrylate 36. ...................... 48 2 12 Reactions attempted using compound 37. ................................ .......................... 49 2 13 4 (1H tetrazol 5 yl) 3 amine N (2,4,6 trinitrophenyl)furazan 41 .......................... 49 2 14 2,2 Dinitropropane 1,3 diol 42 as the starting mat erial in the reaction with SF 5 acetyl building blocks. ................................ ................................ ........... 50 2 15 Bromination of carboxylic acids. ................................ ................................ ...... 50 2 16 Succes sful functionalization of the carbon in the SF 5 acetic acid. ................... 51 2 17 Attempts of fluorination at the CH 2 in the SF 5 acetyl group. ................................ 51 2 18 Synthesis of a bis SF 5 carbamate energetic material. ................................ ......... 52 2 19 Reactions of SF 5 NCO with DAF and ANF. ................................ .......................... 52 2 20 Attempts at N nitration of DASF5 DAF 28 ................................ .......................... 53 2 21 Oxidation reactions of aminofurazans when SF 5 acetamide group present ................................ ................................ ................................ ................ 54
14 2 22 Oxidation reactions of aminofuranzan 41, when SF 5 urea group present. ................................ ................................ ................................ ............... 54 2 23 Attempts to add the 2,4,5 trinitrophenyl group to compounds 27 and 4 8. ................................ ................................ ................................ ....................... 55 2 24 Hydrolysis of compound 31 ................................ ................................ ................ 58 2 25 Intermediate between the SF 5 acetic acid and EDC. ................................ .......... 61 2 26 Reaction between ANF 4 and SF 5 NCO. ................................ .............................. 64 2 27 Decomposition of the SF 5 containing energetic material after N nitration. ................................ ................................ ................................ .............. 65 2 28 Change in the ratio between 30 and 30B after oxidation attempt. ....................... 66 4 1 S N 2 reaction of bromodifluoromethylb enzene. ................................ .................... 97 4 2 Literature examples of S N 2 reactions of azide with fluorinated substrates. ................................ ................................ ................................ ........... 98 4 3 Early Hine an d McBee kinetic studies ................................ ................................ 98 4 4 Preparation of 1 bromo 1 fluorononane 58 ................................ ...................... 100 4 5 Relative amounts of substitutio n versus elimination in reactions of n alkyl iodide, bromide and tosylate with methoxide. ................................ ........... 103 4 6 Reactions of perfluoro n butylethyl bromide with methoxide and azide ............ 107 4 7 Reactions of azide with perfluoro n propylmethyl bromide ................................ 108 4 8 Reactions of 1 bromo 1 fluorononane with methoxide and a zide. .................... 109 4 9 Reactions of 1 bromo 1,1 difluorohexane with methoxide and azide. ............... 110 4 10 Reactions of bromodiflu oromethylbenzene with methoxide and azide. ............. 111 4 11 Model structures used in the quantum chemical calculations. ........................... 114
15 Abstract of Dissertation Prese nted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy THE ROLE OF FLUORINE IN ENERGETIC MATERIALS, AND ITS IMPACT ON LONG RANGE COUPLING CONSTANTS AND S N 2 E2 REACTIONS By Henry Martinez December 2011 Chair: William R. Dolbier, Jr Major: Chemistry The role of fluorine has been investigated in three different areas: 1) energetic materials, 2) long range coupling constants and 3) bimolecular substitution and elimination reactions. High fluorine content can enhance the properties of energetic materials. It was demonstrated that t he presence of an SF 5 substituent within energetic compounds serves to increase their density while diminishing their shock sensi tivity, which when combined with other favorable properties of aminofurazans produces a new class of high density high performance energetic materials. T hermogravimetric analyses (DSC/TGA) as well as qualitative sensitivity tests indicated an improvement in the energetic prop erties of these new materials. The high fluorine content, combined with low hydrogen content upon detonation, which could allow such high energy, SF 5 conta ining furazan derivatives to be useful in combating chemical and biological weapons. Through space coupling of fluorines comprises an interesting aspect of 19 F NMR spectrum. T he 19 F NMR spectrum of new monosubstituted
16 perfluoro[2.2]paracyclophanes display unusual 19 F 19 F coupling patterns ( 4 J and 5 J) that suggest a skewed geometry in which the upper deck moves towards or away from the substituent. Quantum chemical calculations were performed at the HF/6 311+G(d,p)//B3LYP/EPR III level of theory using Gaussi an 03 and they shed light on the unusual structures and coup ling of F8 and its derivatives. 4 J FF coupling constants were found to be transmitted through the space by direct contact between the electron cloud of the interacting nuclei, while 5 J FF coupling constants were also found to be transmitted through the space, but with help of an intermediate moiety that relays the spin polarization from one fluorine to the other. Finally, a measure of the quantitative effect of proximate fluorine substituents on the rates of S N 2 and E2 reactions has been obtained through a study of reactions on fluorinated n alkyl bromides with a weak base, strong nucleophile azide ion and strong base/nucleophile methoxide ion in the protic solvent methanol and the aprotic solvent, D MSO. The order of reactivity for S N 2 reactions of azide in methanol at 50 o C was found to be: n alkyl Br > n alkyl CHFBr > n perfluoroalkyl CH 2 CH 2 Br >> n perfluoroalkyl CH 2 Br > n alkyl CF 2 Br. The order of reactivity for E2 reactions was found to be: n per fluoroalkyl CH 2 CH 2 Br >> n alkyl CF 2 Br > n alkyl CHFBr > n alkyl Br. Quantum chemical calculations support and help to understand these orders of reactivity.
17 CHAPTER 1 INTRODU CTION An Overview of Fluorine in Organic Chemistry Over the last few decades, fl uorine chemistry has become a well recognized and important field. Nowadays it is not only possible to find books in the general organo fluorine area, but also in more specialized areas such as medicinal fluorine chemistry, bio organic fluorine chemistry, fluorine in agrochemicals, and fluorine nuclear magnetic r esonance, among others. The carbon fluorine bond is the shortest single bond involving carbon (D) (~ 1.47 ) other than C H and the bond dissociation energy (BDE) is the largest (the CH 3 X BDE is 99, 8 5, 71, 83, 86 and 110 kcal/mol for H, Cl, Br, C O and F respectively). The inclusion of fluorine within organic molecules enhances the physical, chemical, and biological properties of the resulting organo fluorine compounds. The small size and high electr onegativity of fluorine not only make the C F bond the strongest bond to carbon but also create more polarized and hydrophobic molecules than those with a C H or another C halogen bond, properties that are important in the m edicinal chemistry field. 1,2 Fl uorine, like any other halogen, behaves as an electron withdrawing group, but it is also capable of electron donation by use of its electron lone pairs. The electron withdrawing ability of fluorine occasionally leads to unexpected conformations. For exampl e, the fluorines in 1,2 difluoroethane were expected to be in an anti periplanar conformation in order to minimize the repulsive interactions between the lone pairs of the fluorines in the gauche conformation (Figure 1 1). Instead the latter conformation i s
18 appro ximately 1 kcal/mol more stable t han the former. Although the repulsive interactions in the gauche conformer must exist, the stabilization by the Figure 1 1. Possible conformations for 1,2 difluoromethane. hyperconjugative interactions between th (CH) (CF) orbitals is greater than the destabilization from the electron electron repulsive interaction between (CH) (CF) orbitals also plays an important role in the In contrast, p fluorines due to the electron donation of the lone pairs. 1 The properties of o rgano fluorine compound s lead to many differ ent applications (Figure 1 2). O ne of the most interesting applications of fluorine is found in the medicinal chemistry field, since the introduction of fluorine frequently enhances the biological activity of a substrate. One reason fo r this derives from the increment on the dipole moment and lipophilicity of the molecule upon introduction of the fluorine. Figure 1 2. Examples of organo fluorine compounds in different areas of application
19 Polymer chemistry is another area where fluo rine plays an important role. Fluoro polymers are greatly benefited by the available electron lone pairs in the fluorine, which produce interesting surface properties that find applicability as water and hydrocarbon repellant. These properties combine with the generally high thermal and chemical stability of the organo fluorine compounds produce remarkable fluoro polymers such the widely known polytetrafluoroethylene Teflon. 2 Despite all the special properties that fluorine can bring to a molecule, the in troduction of fluorine into an organic compound it is not only a challenging task, but occasionally can be dangerous as well. Fortunately, the rapid growth of the field of organo fluorine chemistry generally allows the avoidance of reactive and toxic compo unds such as F 2 HF or SF 4 for most syntheses. For instance, the addition of fluorine to aromatic rings, double bonds, carbanions and other similar fun ctionalities can be done using commercially available electrophilic fluorinating agents such as N fluorom ethansulfonimide (NFOBS) or 1 chloromethyl 4 fluoro 1,4 diazoniabicyclo [2.2.2] octane bis tetrafluoroborate ( S electfluor), among other electrophilic fluorinated reagents (Figure 1 3). 3 Figure 1 3. Examples of reactions with the electrophilic fluorine r eagent, S electfluor.
20 Similarly, nucleophilic fluorine is also accessible through different commercially available reagents such as KF, CsF, tetrabutylammonium fluoride (TBAF) or relatively safe solutions (some ionic liquids) such as pyridine HF, triethylam ine HF, and THF HF. Anhydrous conditions are always an aspect of importance when nucleophilic fluorine is needed since its nucleophilicity is diminished by the presence of water. Highly anhydrous highly nucleophilic fluoride can be obtained at 35 o C by the reaction between hexafluorobenzene and tetrabutylammonium cyanide, which lets reactions to run at room temperature with short re action times in contrast to the usually harsh conditions required when using other sources of fluorine (Figure 1 4). 4,5 Any tra ce of water present in the solvent would react with the cyano groups at the hexafluorocyanide to form other derivatives, making the system highly anhydrous. It is important to mention that fluorine under extremely anhydrous conditions (naked fluorine) can also behave as an excellent base. Figure 1 4. Synthesis and reactions of tetrabutylammonium fluoride anhydrous. 5
21 The most important fluorinations mediated by transition metals generally involve palladium, silver and copper; however, many of these organo metallic reactions have proved to be very challenging and are still under study since only very few of these methods use a catalytic amount of the transition metal and are usually limited by the presence of other functional groups (Figure 1 5) 6 9 Figure 1 5. Fluorinations mediated by Palladium. 8,9 Transformation of alcohols, ketone/aldehydes and carboxylic acids to mono di and trifluoromethyl groups, respectively, has become a common method for the generation of fluoro organic compounds. The synthesi s of such materials can be accomplished by deoxofluorinating reagent s such as diethylaminosulfur trifluoride (DAST) and the recently developed 4 tert butyl 2,6 dimethylphenylsulfur trifluoride (FLUOLEAD) (Figure 1 6). 10 Although the synthesis of organo fl uorine compounds can be a challenging task, new and improved reagents allow the non fluorine chemist to incorporate fluorine into
22 their molecules using a large number of safe methodologies, as shown previously. Several other methodologies for the inclusion of fluorine into organic molecules, such as difluorocarbenes, trifluoromethyl anions, perfluororadicals, among others, can be found extensively in the literature and other specialized fluorine synthetic books. The difficulties of those reactions increase with the complexity of the molecule, but most general methodologies are widely described in the literature. Figure 1 6. Synthesis and reactions of deoxoflorinated reagent, Fluolead. Fluorine as Pentafluorosulfanyl Group The pentafluorosulfanyl group has received a lot of recent attention due to its 3 The pentafluorosulfanyl group has two types of fluorine (axial and equatorial, AB4 system) due to the octahedral config uration of the sulfur (Figure 1 7). The S F bond length (~1.54) is almost the same for both the axial and the equatorial fluorines, but generally the axial is slightly shorter than the equatorial and the angle between the two types of fluorines is about 9 0 o (~89.5 o ). The average C S bond length is 1.73 when
23 the carbon has no other fluorine attached. However, if one or more fluorines are attached, the C S bond length can be as high as 1.91. 11 Figure 1 7. AB4 system in the pentafluorosulfanyl group. The pentafluorosulfanyl group (SF 5 ) has a larger size than the CF 3 group (closer to a tert b utyl group), but due to the larger amount of fluorines, the SF 5 group is more lipophilic, with the hydrophobic value ( ) for the SF 5 being 1. 51 vs. 1.09 for the CF 3 5 3 )=0.54) brings a larger dipole moment to the organic molecules. 12 When compared with the CF 3 group or non fluorinated compounds, the pentafl uorosulfanyl group generally introduces a higher chemical and thermal stability to the organic material. 13 All these properties make the pentafluorosulfanyl potentially useful in agrochemicals, pharmaceuticals, liquid crystals, polymers and energetic mater ials, among others (Figure 1 8). 12,14 18 The differences in the physical properties of the trifluoromethyl and the pentafluorosulfanyl group result in an improvement in the properties of the material. For the pentafluorosulfanyl group, the liquid crystal in Figure 1 8 has an increment in the dielectric anisotropy from 13.0 (CF 3 ) to 14.3 (SF 5 ). Similar improvement is seen in the energetic material (Figure 1 8), where the pressure of detonation has an increme nt of 1.67 GPa. 15,18 Despite all the benefits that the pentafluorosulfanyl group can bring to organic molecules since its first appearance in the literature by Case and co workers 19 the
24 introduction of this group has generally been difficult, and the devel opment of new synthetic methods is an active research area. Figure 1 8. Examples of SF 5 Organic compounds with different applications. The synthesis of pentafluorosulfanyl compounds has been accomplished by various approaches. The reaction between thio ls or disulfides with CoF 3 AgF 2 or elemental fluorine (F 2 ) generates the pentafluorosulfanyl group. Relatively milder co nditions include the reaction of thiols or disulfides with chlorine and KF; however, the several by products and generally harsh condit ions of these reactions make them impractical. 11 One of the most common methods for the introduction of the pentafluorosulfanyl group is through the commercially available pentafluorosulfanyl chloride (SF 5 Cl), which can be prepared from SF 4 Cl 2 and CsF i n an autoclave. The reactions of SF 5 Cl are limited to free radical chemistry, and its addition to double and triple bonds was initially carried out in an autoclave. In 2002, Dolbier reported the radical addition of SF 5 Cl in solution at low temperature usi ng Et 3 B as a radical initiator and high yields were obtained (Figure 1 9) This new methodology is more accessible to regular organic chemists, is regiospecific, works with both double
25 Figure 1 9. Radical addition of SF 5 Cl to double bonds using Et 3 B at 30 o C. and triple bonds, reduces the amount of SF 5 Cl needed to complete the reaction, allows smaller scale reactions, and decreases the number of by products 20 The only limitation unsaturated carbonyl compounds, where the radical polymerization controls the reaction. This methodology presently remains the most important to generate aliphatic SF 5 building blo cks and final molecules (Figure 1 10). 21 23 Figure 1 10. Examples of synthesis of SF 5 organic compounds. Fluorine and P entafluorosulf anyl G roup in Energetic Materials After the Second World War, research in energetic materials increas ed substantially. Th e synthesis, and the chemical and physical properties of such compounds have become better known and understood since then. The continued
26 increase of chemical and biological weapons (CW/BW) requires the development of new mechanisms of defense 24 By defini tion, an energetic material is a compound or a mixture of compounds that, after an initiation process, undergo very rapid self propagating decomposition, producing gases at tremendous pressure and with the evolution of a lot of heat. The temperature can re ach up to 6000 K and the pressure up to 40 GP. 25 The performance of an energetic material is mainly evaluated by the type of products formed the energy released, the pressure and speed of detonation, and the thermal and chemical stability of the material. The carbon oxygen balance (OB) as well as the density are directly related to the performance. According to the semi empirical equation s developed by Kamlet and Jacobs, the square of the density is directly proportional to the performance of the compound (Equations. 1 1 to 1 3). 26 P (CJ) 2 (1 1) 1/2 (1 2) 1/2 Q 1/2 (1 3) P is the detonation pressure (GPa), D is the speed of detonation (m/s), A and B are constants, N is the number of moles of gaseous products of detonation per gram of explosive, M the avera ge molecular weight of the gases, Q is the heat of detonation in performance will be. Although the increase of oxygen balance results in a more sensitive material, i on of all carbons and hydrogens. M 27 Currently, most new energetic materials are compared to three of the most important known energetic materials: Cyclotrimethylenetrinitramine (RDX),
27 cyclotetramethylene tetranitramine (HMX) and trinitrotoluene (TNT). The performances of these three materials are listed in Table 1 1. 24 The development of new energetic materials with better performance than RDX, HMX or TNT constitutes an important area of current active research. Table 1 1. Performance data of three common energetic materials. 3 ) P (Gpa) D (m/s) RDX 1.81 33.8 8750 HMX 1.91 39.3 9100 TNT 1.65 20 .0 6900 In order to achieve better performance than RDX or HMX, some new, more advanced energetic materials (CHNO/F) have incorporated fluorine into the system. Fluorinated organic compounds are denser and are intrinsically more chemically and thermally stable than non fluorinated analogs. In several cases, the introduction of fluorine into energetic materials also enhances its performance. 24,26,27 During the last few decades, there has been an increased interest regarding the incorporation of the SF 5 group into energetic materials. 14,27 31 It has been previously mentioned that the inclusion of SF 5 generally increases the thermal and chemical stability of organic molecules 13 and in addition to this, it has been demonstrated that the presence of SF 5 also can increase the density, 28 and thus t he performance of the energetic material (Figure 1 11). The high fluorine content along with the presence of hydrogen leads to the formation of hydrogen fluoride (HF) upon detonation, generating a large amount of energy. The S F Bond Dissociation Energy (B DE) is 79 kcal /mol, while the BDE of H F is 136 kcal /mol. 14,28,30,31
28 Figure 1 11. Higher density on SF 5 compounds. The possibility of a higher density, larger energy release, and better thermal and chemical stability without increasing the sensitivity m ake the SF 5 group attractive in the synthesis of high energy materials (HEM). Figure 1 12 shows a polynitro SF 5 energetic material, which upon detonation produces HF as the only product containing fluorine, while the presence of sulfur (S) leads into the f ormation of COS, inhibiting the formation of COF 2 which is considered a loss of fluorine. 31 Figure 1 12. Polynitro SF 5 energetic material. Fluorine in [2.2]Paracyclophanes [2.2]Paracyclophane ([2.2]PCP) has two benzene rings face to face that are linke d by two ethylene groups in the para position. The proximity of the rings prevents the
29 rings from rotating freely and produces a repulsive interaction that generates not only unique geometrical structures, but also an interesting chemistry. Due to the repu lsive interactions the carbon carbon bond length in the ethylene bridges is extended from 1.54 (ethane) to 1.63 and generates an alteration in the planarity of the benzene rings giving them a ben t geometry that looks like a boat (Figure 1 13). Figure 1 13. Structure of [2.2]paracyclophane [2.2]Paracyclophane finds one of its most important applications as a monomer of parylene polymers. This type of polymer is transparent, has a high thermal and chemical resistance and has excellent barriers propertie s. All of these properties make this polymer useful for coatings in different fields such as electronic, automotive and medical industry. 32,33 Derivatives of [2.2]PCP have found also applications as ligands in asymmetric synthesis, 34 36 biologically active compounds, 37 optoelectronics, 38 40 among others (Figure 1 14). The interest on [2.2]p aracyclophanes has increased considerably in the last 20 years due to their unusual chemistry. [2.2]PCP s present transannular effects, thermal racemizations, faster poly electrophilic aromatic substit utions than simple aryl systems giving different type s of isomers, and several other attractive properties that make their chemistry an active research area. 41,42
30 Figure 1 14. Applications of [2.2]paracyclophane derivatives The thermal racemization after the generation of the first optically active derivatives of [2.2]paracyclophane was discussed in detail since three possibilities were considered for the racemization: 1) both of the carbon carbon bonds at the ethylene brid ges could break to generate a p quinodimethane and then dimerized back, 2) only one of the carbon carbon bonds at the ethylene bridges breaks homolytically to generate a biradical giving free rotation to the ring and 3) one carbon carbon bond from the benz ene ring and the ethylene bridge could break to generate a biradical and then free rotation to the ring as well. E xhaustive work done by Reich in 1968 demonstrate d that at 200 o C the correct mechanism for racemization of [2.2]p aracyclophanes is pathway 2 (F igure 1 15). 43 Figure 1 15. Racemization of [2.2]paracyclophane derivatives. Introduction of fluorine into [2.2]p aracyclophanes enhances some of its properties, and generates more interesting chemistry. 1,1,2,2,9,9,10,10 Octafluoro [2.2]paracyclophane (AF 4), which is the perfluorination of the ethylene bridges, is one of the most useful parylene polymers. The presence of fluorines
31 increases the thermal stability and decreases the moisture absorption when compared with its non fluorinated analog s These pro perties along with its low dielectric constant make parylene AF4 an excellent isolating material. 33 Although the presence of fluorinated methylene groups in the para positions decrease the rates towards electrophilic aromatic substitutions, several derivat ives have been reported in good yields. 41 Figure 1 16. [2.2]P aracylophane and the most common fluorinated [2.2]PCPs. Recently, the chemistry of perfluoro[2.2]p aracyclophane (F8) has been studied by Dolbier. The type of chemistry that is observed for this type of perfluorinated material is, in many ways, similar to that of perfluorobenzene and perfluoropyridine. 44,45 Surprisingly, the chemis try of the 4,5,7,8,12,13,15,16 octafluoro[2.2]p ben zene rings for fluorines, has hardly been studied. A search on Scifinder for this structure only generates 8 different references with 4 of them between 1965 1989 and the other 4 between 2003 2005, where most of them are dedicated to its synthesis, but not to the study of its chemistry. All the syntheses of [2.2]paracyclophane s are similar in their last step, which is the elimination of two groups at each methyl substituent to form a p quinodimethane. 32,33,44 Most of the methods that are described before 19 98 encounter the problems when the
32 reactions were scaled up for industrial production, eit her because the polymerizations lower the yield of the PCP or because of the high cost of the method. Dolbier et al. in 1998 discovered a method that allows the indus trial produc tion of AF4 in 60% yield using z inc, and proves to be a general method for the synthesis of other paracyclophanes such as F8. 32,44 Most common methodologies for the synthesis of PCPs are shown in Figure 1 17. Figure 1 17. Most common methodol ogies for the synthesis of [2.2]paracyclophane s. The chemistry of [2.2]paracyclophane and octafluoro [2.2]paracyclophane has been well studied. Derivatives of these two compounds are generally prepared through electr ophilic aromatic substitution and f urther products are usually made after the first substitution (Figure 1 1 8 ).
33 In contrast the type of chemistry that can be performed on perfluoro [2.2]paracyclophane is through nucleophilic aromatic substitution, and it has only recently been studied by Dolbier et al. (Figure 1 18). 45 49 Figure 1 18. Examples of chemical reactions of fluorinated [2.2]paracyclophane s Fluorine NMR Fluorine is probab ly the third most studied nucleus for nuclear magnetic resonance after hydrogen and carbon. Fluorine with a spin of and a 100% natural abundance has a similar sensitivity to that of h ydrogen. Fluorotrichloromethane (CFCl 3 ) is the most widely use internal reference and has an assigned chemical shift of zero. Most common organo fluorine molecules (aromatic fluorine, fluorines at sp, sp 2 or sp 3 carbons) are generally upfield to the internal reference (negative side), but the range in which fluorine can appear in the spectra goes from +70 to 220 ppm, with only a few exceptions. The fact that most organo fluorine reacti ons are run in non fluorinated solvents leads to an easier analysis of the reaction by 19 F NMR without need of work up. Similar to hydrogen, but to a greater extent, fluorine chemical shifts are sensitive to electronic ch anges around the fluorine nucleus For instance, Taft has shown
34 extensively that the fluorine chemical shift of substituted fluorobenzenes depends highly on the electron donor or withdrawing ability of the substituent and the difference between the chemical shifts of fluorobenzene and the s ubstituted fluorobenzene has been correlated with good agreem ent to the Hammett substituent c onstant ( Equation s 1 4 to 1 7) 50,51 (1 4) (1 5) (1 6) (1 7) Where is the chemical shift difference between fluorobenzene and the meta o r I R p m are the inductive, resonance, para and meta Hammett values respectively. Hydrogens and fluorines in the proximity of other fluorines will display splitting of its signals due to the coupling between the fluorines and the other nuclei. The spin spin or the intensity of the signals. 52 One of the most important differences between hydrogen and fluorine spin spin coupling is the ability of fluorine to have a strong through space coupling. This type of coupling can be transmitted through a series of diffe rent mechanisms, but all of them will involve an overlap of the orbitals where the fluorine lone pairs are located. As it might be expected, this through space coupling depend s on the distance and the angle with which the two nuclei interact (Figure 1 19). 52
35 Similar to proton and carbon, 2D NMR techniques using the fluorine nucleus such as NOESY, COSY, TOCSY, are great tools to determine most, if not all, of the long ra n ge coupling that fluorine usually exhibits This allows the full interpretation of the NMR spectrum without explaining the mechanism of those long ra n ge couplings. Figure 1 19. Examples of through space spin spin coupling. Seve ral publications have reported long range 19 F 19 F spin spin coupling s with a definitive conclusion that those c ouplings are highly dependent on distance between the interactive nuclei. Nevertheless, there seems to be a lack of complete understanding of the mechanism of some through space couplings. A simple rule indicates that if two fluorines are coupling through space the distances between the two interacting fluorines must be less than twice the Van der Waals radii of fluorine (2 x 1.47 = 2.94). This means that if two fluorines are within this distance the transmission is purely through the orbital interactio ns of the lone pairs of each fluorine. On the other hand, if the coupling fluorines are not within this distance, pathway. Although Ernst has done a great job identifying long range 19 F 19 F spin spin coupling constants of some fluorinated [2.2]paracyclophane s using different 2D NMR techniques, the mechanism of transmission for those in which the distances between the interacting fluorines is more than twice the Van der Waal s radii of fluorine was not discussed (Figure 1 20). 53
36 Figure 1 20. Through space coupling identified by Ernst. Fluorine in S N 2 and E2 R eactions As can be witnessed by examining any undergraduate textbook, the bimolecular nucleophilic substitution reacti on, S N 2, has been studied exhaustively with the result that influences on reactivity such as solvent polarity, leaving group ability, nucleophilicity and steric effects are considered pretty well understood. Each of these effects contributes individually, and sometimes cooperatively, in such a way as to either increase or decreas e the reaction barrier. It is well recognized that nucleophilic aliphatic substitution reactions of primary alkyl substrates proceed via the S N 2 mechanism. It is likewise recognized although perhaps not so universally, that primary perfluoroalkyl substrates will not participate in substitution reactions via the S N 2 mechanism, but rather are capable of undergoing nucleophilic substitution via the S RN 1 mechanism when the nucleophile c an undergo single electron transfer (SET) to initiate the free radical chain process (Figure 1 21). 54 fluorines in substrates with the structure RCH 2 CF 2 X is understood to severely inhibit, if not prevent, nucleophilic substitution. To our knowledge there are no examples of successful S N 2 nucleophilic substitutio n react ions of such compounds.
37 Figure 1 21. S RN 1 mechanism with perfluoroalkyl iodides. to the site of nucleophilic substitution will inhibit such substitution, and the clo ser they are, the more impact that they have. In contrast, the elimination reactions are accelerated by the presence of fluorine. This effect is due to the increment in the acidity of the hydrogens in the proximity of the fluorines: the closer they are, t he faster the elimination.
38 CHAPTER 2 DESIGN OF PENTAFLUOR OSULFANYL ENERGETIC MATERIALS Introductory Remarks Energetic materials can be considered massive controllable energy storage. The design of new materials with higher energy content, better performa nce, lower cost, less sensitivity to impact and with less danger to synthesize and process keeps this research area active. The synthesis of new materials has been focused on rings with high nitrogen content such as tetrazines, furazans, triazoles and tetr azoles due to the relatively positive heat of formation of these compounds. 25 Recently, the introduction of fluorine to th e se and other compounds has resulted in a boost in the performance of the energetic materials, mainly due to the increase in the densi ty and thermal and chemical stability. Following this trend, our research focused on the synthesis of a new type of SF 5 f urazan type energetic materials. Furazan Energetic Materials 1,2,5 oxadiazoles (commonly known as furazans) have been included in seve ral publications as great building block s for the generation of insensitive High Performance Energetic Materials (HEM). 27,55 65 The aromaticity present in the ring increases the thermal stability, while the planarity increases the density. That combined wi th the positive heat of formation (HOF) make furazans an excellent building block for the generation of HEM. 55 Since the first synthesis of 3,4 diaminofurazan 1 (DAF) by Coburn in 1968, 66 a vast number of furazan derivatives with good densities and energet ic properties have been prepared. The synthesis of aminofurazans generally starts with the synthesis of aminoglyoximes, followed by dehydration under basic conditions. Scheme 2 1 shows
39 the synthetic pathway applied in this work for the synthesis of some co mmon aminofurazan building blocks. 55,60 63 Scheme 2 1. Synthesis of common furazan building blocks. Although the furazan ring possesses an electron withdrawing ability that makes the amino group(s) in aminofurazans a challenge to derivatize, 67,68 the use of these materials as part of HEM remains of much interest. The majority of the chemistry that can be performed with aminofurazans is done through nucleophilic attack by the amino group, condensation reactions, oxidative reactions, or ring opening of the furazan ring. The l ast type of these reactions ends up destroying the energetic properties of the material. 67 Studies on the thermal decomposition of amino furazan derivatives at different temperatures have shown that the major percentages of products are between CO, CO 2 H 2 O, HCN, N 2 (when the azo or hydrazine moieties are present) and NO 2 (when present as a nitro group in the molecule). A minor percentage of the products is distributed between HCNO, NH 3 HNO 3 and N 2 O. The same studies indicate that most
40 a mino furazan s present a higher thermal stability than the most common energetic materials such as HMX or RDX. 65,69,70 Alternatively, the high nitrogen content and positive HOF of tetrazole also makes this group a good starting mate rial for the synthesis of HEM. Although tetrazole has a positive HOF, it exhibits good thermal stability. 71 73 Theoretical and experimental studies have shown that the thermal decomposition of 5 aminotetrazole goes through two different retro [3+2] mechanisms with relatively close activation energies. The first mechanism and most favorable generates NH 2 CN and HN 3 while the second one produces CH 3 N 3 and N 2 However, when the amino group of the aminotetrazole has been functionalized, the second mechanism is the most favorable. 71 75 Scheme 2 2. Amino Furazan tetrazole synthesis and its derivatives The combining of tetrazole and furazan rings have been previously reported, 76 but it was only in 2009 that Shreeve, et al. 77 reported furazan tetrazolate based salts as
41 highly insensitive energetic materials. The high calculated heats of formation and the good densities predicted a good energetic performance. This result, combined with the previously mentioned properties of furazans, makes this group attractive for the preparation of new h igh density energetic materials. Scheme 2 2 presents the synthetic pathway applied in this work for the synthesis of amino furazan tetrazole and the salts derivatives prepared by Shreeve. 76,77 Pentafluorosulfanyl (SF 5 ) as Part of Energetic Materials During the last few decades, there has been an increased interest regarding the incorporation of the SF 5 group into energetic materials. 14,27 31 It has been demonstrated that the inclusion of the SF 5 group can increase the density, 28 and thus the performance of the energetic material. It is important to remember from Chapter 1 that according to the semi empirical equation s propose by Kamlet and Jacobs (Equations 1 1 to 1 3), an increase in the density will boost the performance of the energetic material. The for mation of C F, H F or Al F bonds, which have a higher bond dissociation energy (BDE) than the S F bond in the pentafluorosulfanyl group, allows the release of large amounts of energy upon detonation. This combine d with the possibility of higher density, hi gher thermal and chemical stability and low sensitivity make s the pentafluorosulfanyl group very attractive for the synthesis of high performance energetic materials. 13,14,28,30,31 A large number of SF 5 containing energetic materials have been synthesized where the predicted performance is close to those for HMX, RDX and TNT, but with the benefit of lesser or no impact sensitivity (Figure 2 1). 14,18
42 Figure 2 1 shows five SF 5 containing energetic materials having densities around 1.85 g/cm 3 and with predic ted pressure and speed of detonation around 17.8 20.5 GPa and 6900 7100 m/s respectively. Figure 2 1. Examples of SF 5 containing energetic materials. Despite all the benefits provided by the SF 5 moiety, the amount of SF 5 containing energetic material s is still limited due to the few ultimate sources of the aliphatic SF 5 group: SF 5 Br and SF 5 Cl. The chemistry of these two starting materials is limited to free radical chemistry. For this reason, the synthesis of SF 5 building blocks that would allow the an incentive and challenge to many research groups. Figure 1 12 shows a polynitro SF 5 energetic material, which upon detonation produces HF as the only product containing fl uorine. The presence of sulfur (S) as SF 5 inhibited the formation of COF 2 which is considered a loss of fluorine. 31 Then it is considered potentially advantageous to combine the properties of aminofurazans, with those of the SF 5 group, in order to obtain high performance energetic materials. It is
43 expected that with high fluorine content and low hydrogen content, such materials might 2 The goal of this project can be summarized by three points: 1) the synthesis a nd evaluation of different SF 5 building blocks towards nucleophilic attack by aminofurazans. 2) The synthesis of high density SF 5 furazan based energetic materials Evaluation of the thermal and chemical stability of new energetic materials containing the SF 5 group as well as the possible energetic performance by Cheetah calculations. Results Aminofurazan Starting Materials Figure 2 2. Additional synthesized aminof urazans starting materials. In addition to compounds 1 4 5 and 11 a series of aminofurazans were synthesized according to various literature reports (Figure 2 2). 62,76,78 82 Compounds 20 and 21 were provide by the Defense Threat Reduction Agency (DTRA)
44 S ynthesis of SF 5 Furazan Based Energetic Materials The SF 5 acetyl building block 5 group into aminofurazans, methyl 2 pentafluorosulfanylacetate 24 was chosen as our initial SF 5 c ontaining building block (Scheme 2 3). 21 Scheme 2 3. Synthesis of Methyl 2 pentafluorosulfanylacetate 24 3,4 diaminofurazan 1 (DAF) was used as our initial starting furazan substrate, to establish conditions for preparation of the SF 5 acetamidofurazan d erivatives. Different reaction conditions were attempted using DAF and methyl SF 5 acetate 24 but these were unsuccessful in obtaining the desired product (Scheme 2 4). Scheme 2 4. Attempted reactions between DAF 1 and methyl SF 5 acetate 23 The lack of nucleophilicity from the DAF thus requires a more reactive SF 5 acetyl building block. Starting from the methyl ester 24 the SF 5 acetic acid 25 was obtained in 88% yield after optimization, which was then converted to the pentafluorosulfanylacetyl
45 chlorid e 26 in 42% yield in a similar methodology to that reported by Sitzmann (Scheme 2 5). 83 Scheme 2 5. Synthesis of pentafluorosulfanylacetyl chloride. The SF 5 acetyl chloride should be more reactive towards the nucleophilic attack of the aminofurazan, and the reaction between DAF and the SF 5 acetyl chloride is presented in Scheme 2 6. Scheme 2 6. Synthesis of pentafluorosulfanylacetamide furazans. The syntheses of MASF5 DAF 27 and DASF5 DAF 28 were achieved in decent yields after optimization; however, th e low yield in the synthesis of the SF 5 acetyl chloride 26 encouraged the use of an alternate SF 5 acetyl building block. The reaction between amines and N acetylbenzotriazole (and derivatives), has been widely use for the synthesis of amides, 84 providing better yields and cleaner reactions than those in the reaction between amines and acyl chlorides. Scheme 2 7. Synthesis of the benzotriazole derivative of SF 5 acetic acid.
46 The reaction between the SF 5 acetic acid with thionyl chloride and benzotriazole provided compound 29 with an excellent yield (Scheme 2 7). Indeed the reaction between DAF and compound 29 proved to be more efficient than the reaction with the ester, but it unfortunately was not better than that obtain ed when using the acyl chloride (Sc heme 2 8). Scheme 2 8. Synthesis of 28 from the benzotriazole derivative of SF 5 acetic acid. In trying to avoid the low yield synthesis of the SF 5 acetyl chloride 26 the SF 5 acetic acid 25 was allowed to react with DAF in the presence of a carbodiimide. This type of reaction is well known and typically produces very good results. Various carbodiimides were tried, and the best results were obtained with 1 ethyl 3 (3 dimethyl aminopropyl) carbodiimide (EDC) (Scheme 2 9). Scheme 2 9. Synthesis of DASF5 D AF from SF 5 acetic acid using EDC.
47 The reaction with DAF and SF 5 acetic acid using EDC was a more efficient and cleaner reaction, when compared to the reaction with SF 5 acetyl chloride. This method was then used for a series of reactions using various amin ofurazans. Scheme 2 10. Reaction between different aminofurazans and SF 5 acetic acid in the presence of EDC. Scheme 2 10 shows all of the reactions that were successful when using the EDC chemistry. All other aminofurazan starting materials failed to yie ld any product. Compound 32 was prepared with the help of Mr. Zheng, a graduate student in our group. In some cases we returned to the reaction between the aminofurazan and the SF 5 acetyl chloride, when the acid and EDC did not yield any product; however, no product could be obtained from those reactions either. The lack of either nucleophilicity or solubility of the aminofurazan substrates led to products in low yield or no product at all The two different amino groups in compound 21 result in the formati on of two isomers in a 95:5 ratio, where 95 correspond to the amino closest to the N=O moiety
48 Compounds 29 and 30 were used in a later reaction to introduce a second SF 5 amide moiety. Compound 29 showed 2% of product (bis amide) by 19 F NMR, but it never reacted to a point where it was possible to isolate the product, while compound 30 never showed the formation of the bis amide at all. Pentafluorosulfanylmethyl dicarbonyl building block The addition of SF 5 unsaturated carbonyl compounds under t he Et 3 B carbon, as well as the carbon. It was thought that the addition of an carbon might overcome both problems. Thus a different approach was attempted in order to obtain SF 5 furazan based energetic materials (Figure 2 3). Figure 2 3. Retrosynthetic approach for the synthesis of 3 amino 4 (pentafluorosulfanylmethyl) furazan Methyl 2 methoxyacrylate 36 was synthesized ac cording to a previous reported method. 85 The reaction between methyl 2 methoxyacrylate 36 and the SF 5 Cl using our Et 3 B method was shown to be not only possible, but also efficient (Scheme 2 11). Scheme 2 11. Synthesis and addition of SF 5 Cl to methyl 2 me thoxyacrylate 36.
49 M ethyl 3 pentafluorosulfanyl 2 chloro 2 methoxypropanoate 37 is the masked dicarbonyl material and could itself potentially be used directly to obtain SF 5 fur azan based energetic materials; However, various attempts to utilize compound 37 to prepare the desired new furazan wer e unfortunately not successful (Scheme 2 12). Scheme 2 12. Reactions attempted using compound 37. Conversion of 3 7 to the analogous thiocarbonyl compound, potentially a more reactive substrate, was attempted unsucce ssfully under various reaction conditions. In most cases decomposition of the starting material occurred. Miscellaneous reactions Scheme 2 13. 4 (1H tetrazol 5 yl) 3 amine N (2,4,6 trinitrophenyl)furazan 41 During the course of this project both 3 amin o 4 (tetrazo 5 yl) furazan 11 and picryl chloride 40 were synthesized according to the literature. It was called to our attention that the reaction between these two energetic compounds had not been
50 reported yet. The product, 4 (1 H tetrazol 5 yl) 3 amine N (2,4,6 trinitrophenyl)furazan 41 was synthetized and could have con siderable energetic properties (Scheme 2 13). 2,2 Dinitropropane 1,3 diol 42 has been also used in the synthesis of energetic materials. 29 The reaction between 42 and SF 5 acetic acid or a cetyl chloride was attempted, bu t no product could be obtained (Scheme 2 14). Scheme 2 14. 2,2 Dinitropropane 1,3 diol 42 as the starting material in the reaction with SF 5 acetyl building blocks. Substitution of hydrogen by fluorine in the SF 5 acetyl gr oup had always been included within the goals of our project, in order to reduce the amount of hydrogen present in the final energetic material. However, p revious attempts in the Dolbier group to functionalize the carbon of the methyl 2 pentafluorosulfa nylacetate 24 by alkaline enolate chemistry resulted in decomposition of the staring material. However, it was possible to prove the deprotonation of the carbon by hydrogen deuterium exchange. On the other hand, Zhang and coworkers in 1998 reported the bromination of carboxylic acids us ing NBS under acidic conditions (Scheme 2 15). 86 Scheme 2 15. Bromination of carboxylic acids.
51 Using conditions similar to those reported by Zhang, the bromination of pentafluorosulfanylacetic acid was not successf ul. However, the exchange of H 2 SO 4 by HSO 3 Cl gave the mo no bromo addition in 40% yield (Scheme 2 16). This is the first example in the literature of the functionalization of this type of materials. However, further attempts to improve the yield were unsu ccessful Scheme 2 16. Successful functionalization of the carbon in the SF 5 acetic acid. Realizing the possibility of an enol isomer in the methyl SF 5 acetate 18 the reaction s with fluorine and Selectfluor were tried. However, interestingly, no produ ct could be obtained, and the starting material was recovered (Scheme 2 17). Scheme 2 17. Attempts of fluorination at the CH 2 in the SF 5 acetyl group. The pentafluorosulfanyl isocynate building block The high reactivity of SF 5 NCO towards several nucleop hiles has been already carefully studied, 87,88 including its addition to polynitroalcohols to yield the respective carbamates. 29,89 Scheme 2 18 shows the synthesis of a bis SF 5 carbamate previously prepared by Sitzmann, 89 which compound will be used as a baseline material in this project. The SF 5 NCO was provided by Dr. Joseph Mannion of National Naval Laboratories at Indian Head.
5 2 Scheme 2 18. Synthesis of a bis SF 5 carbamate energetic material. The high reactivity of SF 5 NCO towards nucleophiles makes it a great building block. However, it is this same high reactivity that limits the possible solvents in which it can be used. A solvent screen carried out with SF 5 NCO indicated that it reacts with Scheme 2 19. Reactions of SF 5 NCO with DAF and ANF. weak n ucleophiles such as the enol of acetone (quick reaction), THF (slow) and acetonitrile (slow). In its reaction with the latter two solvents, the products are unknown, but formation of some type of product was clearly seen in each case by 19 F NMR. The isocy anate is unreactive with solvents such as dichloromethane and 1,2 dichloroethane. Water, of course, also reacts readily with SF 5 NCO, and therefore should be avoided at all times.
53 Due to the solvent limitation, only two compounds could be obtained from the reaction of SF 5 NCO with furazan derivatives (Scheme 2 19). All other aminofurazans were insoluble in either DCM or DCE, even at higher temperatures, and thus could not be used as substrates. N Nitration and oxidation reactions Although the previously synth esized SF 5 furazan based materials already likely have energetic material properties, an increase in C/O balance might improve their energetic performance. However, all attempts of N nitration failed. Three mild nitration conditions were used: 1) H 2 SO 4 (9 8%) HNO 3 (70%) 2) NH 4 NO 3 CF 3 CO 2 OH (TFAA) HNO 3 (70%) cat. and 3) NO 2 BF 4 CH 3 CN or THF. In all of these cases, the starting material was recovered. Thus, four stronger nitration conditions were used: 1) HNO 3 (>99%) fleshly made. 2) NO 2 NO 3 HNO 3 (>99%) 3) TFAA HNO 3 (>99%). 4) NO 2 BF 4 NaH or Py THF. Under these conditions, the starting materials ended up either partially or completely destroyed (Scheme 2 20) Scheme 2 20. Attempts at N nitration of DASF5 DAF 28 Another approach to adding additio nal oxygen to the synthesized SF 5 furazan materials could be through the oxidation of the amino groups to nitro groups, w hen an amino group is present The oxidation of MASF5 DAF 27 was successful under three different methods: 1) H 2 O 2 (50%) H 2 SO 4 (98%) Na 2 WO 4 in 50% yield. 2) HOF CH 3 CN in 65% yield. 3) H 2 O 2 (50%) H 2 SO 4 (98%) in 30% yield. In the last method the
54 azoxy ( N=N(O) ) moiety was the expected result, but the nitro group was obtained instead. The first method of oxidation was applied by Mr. Zheng on compound 27 with 35% yield, and further optimization yielded 50%. In the particular case of compound 30 no oxidation was obtained, but a change in the ratios of the two isomers was obtained (Scheme 2 21). Scheme 2 21. Oxidation reactions of am inofurazans when SF 5 acetamide group present The oxidation of SF 5 Urea amino furazan 48 was attempted using the same three methods previously mentioned for compounds MASF5 DAF 27 plus a fourth method using Ph 3 PCH 2 Ph + H 2 SO 5 CH 3 CN. In all cases the produc t was the amino nitro furazan 4 (Scheme 2 22) Scheme 2 22. Oxidation reactions of aminofuranzan 41, when SF 5 urea group present.
55 The final approach toward improving the performance of these SF 5 furazan based energetic materials was through the addition of the 2,4,5 trinitrophenyl group (Scheme 2 23). Scheme 2 23. Attempts to add the 2,4,5 trinitrophenyl group to compounds 27 and 48. Discussion Addition of SF 5 Building Blocks In order to achieve the synthesis of novel SF 5 furazan based energetic materia ls, the first step was the synthesis of a reliable SF 5 acetyl building block that would react with amino furazans efficiently. Figure 2 4 presents the four SF 5 acetyl building blocks that were prepared within this project. Figure 2 4. SF 5 acetyl buildin g blocks. T he synthesis of methyl 2 pentafluorosulfanylacetate 24 21 pentafluorosulfanylacetyl chloride 26 90 and pentafluorosulfanylacetic acid 25 90,91 have been previously reported. The pentafluorosulfanyacetyl chloride has been synthesized by the addit ion of SF 5 Cl to ketene; however, the possibility of a large scale production is
56 limited by the use of ketene and an autoclave. The SF 5 acetic acid 25 was synthesized in high yields from the acetyl chloride 26 and by the oxidation of the SF 5 acetaldehyde, 9 1 but only 20% yield is obtained under this method. Then, part of this project was to synthesize each of these materials by a more efficient method. Scheme 2 3 showed the synthesis of methyl 2 pentafluorosulfanylacetate 24 which can be done in very good y i eld according to given method. Scheme 2 5 shows the hydrolysis of 24 to p roduce the acid in good yield. The acid is then used to prepare the SF 5 acetyl chloride using a method similar to that previously reported by Sitzmann. 83 Lastly, Scheme 2 7 presents the synthesis of the benzotriazole derivative of the SF 5 acetic acid in excellent yield, using a similar methodology to that reported by Katritzky. 84 We believed that any of these SF 5 acetyl building blocks should be sufficiently reactive regarding a nucle ophilic attack by an aromatic amine However, the lack of nucleophilicity of the aminofurazan derivatives turned out to be a major problem within this project. The p K a values (NH 3 + ) of some aminofurazan derivatives have been previously reported and the val ues are presented in Table 2 1. 68 Table 2 1. p K a values of some aminofurazan derivatives. R pKa NH 2 1.94 CH 3 2.15 OCH 3 2.51 N 3 2.88 NO 2 4.46 The p K a values in Table 2 1 indicate the high electron withdrawing ability of the furazan ring, whic h diminishes the nucleophilicity of the amino group. A second
57 approach to support the high electron withdrawing ability of the furazan ring was done by Fruttero et al. in 1998 on 3 methyl furazan. 51 In this publication two methods were utlized to obtain th I R ) values: 1) The meta and para benzoic acid derivatives were prepared and the pKa values were measured; and 2) using correlation and Equation s 1 4 to 1 7 proposed by Taft, the meta and para fluorobenzene derivative s were prepared and the fluorine chemical shifts were measured in highly diluted methanol d 4 (Figure 2 5). Figure 2 5. Methyl furazan derivatives synthetized by Fruttero. Although both methods have been criticized, they are still widely used and accept ed. Using these two methods the authors concluded that the furazan ring has a strong attractor character similar to that observed for the halogens. The authors included the methyl group in the furazan in order to increase the stability of the compound and claimed that this should not effect their measurements. However, we performed the ground state calculation on the fluorobenzene derivatives and they indicate that due to the vicinal methyl group, the benzene ring in Figure 2 5 is twisted about 40 degrees o ut from the plane of the furazan ring, which suggest that there is not fluorines chemical shifts measurements will not be entirely accurate. The quantum chemical calcula tion was done at B3LYP/6 31+G(d,p) level of theory using Gaussian 03 Rev E01 software package. 92
58 Based on these findings, the reactivity of the SF 5 acetyl group must then be great in order to allow the possibility of a nucleophilic attack. This must be the reason why most of the amide forming reactions with DAF have required acyl chlorides as acylating agents. 93 Although the reactivity of the acyl chloride 26 with DAF is good enough to obtain the desired products, the reaction with SF 5 acetic acid in the pr esence of EDC proved to be not only more efficient, but also cleaner, which made it a more reliable method. Using this methodology we were able to prepare a new series of SF 5 furazan energetic materials (Schemes 2 9 and 2 10). All synthesized materials ex hibited good thermal and chemical stability, with the exception of 3 N pentaflurosulfanylacetamide 4 (1 H tetrazol 5 yl) furazan 3 1 This product is chemically stable in the solid state, but easily decomposes in solution T he presence of water (hydrolysis) or any other weak nucleophile leads to attack of the carbonyl group (Scheme 2 24) and destruction of 3 1 Scheme 2 24. Hydrolysis of compound 3 1 This can be explained the enhancement of the electron withdrawing ability of the furazan by the presence of t he high electron withdrawing tetrazole, which makes the carbonyl group of 3 1 more electron deficient. All other aminofurazans were unreactive to either the SF 5 acetyl chloride 26 or the SF 5 acetic acid 25 EDC method.
59 There is no significant information r elated to the reactivity of aminofurazans other than the few reported p K a values of some derivatives (Table 2 1) and the Hammett resonance and inductive values. In order to have a better understanding of the lack of reactivity of other aminofurazan derivat ives used in this project as starting materials, the ground states of some of these materials were calculated at B3LYP/6 31+G(d,p) level using Gaussian 03 Rev. E.01 92 and the calculated C NH 2 bond lengths were correlated with the p K a values reported by Tse linskii (Table 2 2). 68 Table 2 2. p K a vs C NH 2 bond distance. R pKa C NH 2 () NH 2 1.94 1.38516 CH 3 2.15 1.38093 OCH 3 2.51 1.37397 N 3 2.88 1.36974 NO 2 4.46 1.34938 y=71.674.9x 101.116.7 R 2 =0.9914. The equation derived from the plot of was found to be y=71.67x 101.11 with a correlation coefficient of R 2 =0.9914. This correlation coefficient indicates that there is strong correlation between these two parameters Using the equation from the plot in Table 2 2 and the calculated C NH 2 bo nd distances from the ground states of some aminofurazans used in this project, the p K a values (NH 3 + ) were estimated in order to understand and establish an order of reactivity (Table 2 3). Combining the experimental results with the calculated p K a values, it is possible to see that for any furazan NH 3 + that has a p K a greater or equal to 3.72 will give a product. This is the case of the 3 amino 4 (tetrazo 5 yl furazan), which can yield the
60 desired product, but w hich is not stable in solution (Scheme 2 24). The high electron withdrawing ability of the tetrazole in addition to the same effect from the furazan ring pushes the amino group to the limit of its reactivity with respect to nucleophilic attack. Table 2 3 Calculated p K a values using the plot from Ta ble 2 2. R C NH 2 () pKa 1 1.38516 1.94 a 4 1.34938 4.46 a 5 b 1.35792 c 3.77 c 1.35014 d 4.33 d 12 1.35046 4.31 13 b 1.37266 2.71 4 (NH 2 ) 1.39755 0.93 5 (NH) 20 1.3625 3.44 9 21 b 1.36186 c 3.49 7 c 1.36957 d 2.94 7 d 11 1.35872 3.72 5 a. Exp. Value Ref. 68 b. Unsymmetrical amino groups, two values are calculated. c. NH 2 group far from the =N O moiety. d. NH 2 group closer from the =N O moiety The azoxy aminofurazan 5 did not yield any product, and it has calculated p K a values of 3.77 a nd 4.33 for its unsymmetrical amino groups. There is a possibility that the desired product is formed, but that it is unstable under the reaction conditions. Interestingly, the dihydro azo diaminofurazan 13 has calculated p K a values greater than 3.72 ( 2.71 and 0.93), but it did not give products with either the SF 5 acetyl chloride or the SF 5 acetic acid EDC method. Considering the calculated C N distances (Table 2 3), it is our belief that the NH from the hydrazine moiety is more reactive than the N H 2 group and it reacts with the SF 5 acetyl building block, but the product is unstable due to the adjacent NH group. The reaction of aminofurazans with SF 5 acetic acid in the presence of EDC proved to be the most efficient and cleaner method for preparatio n of the desired compounds. The only weakness of this methodology is that the intermediate formed from the SF 5
61 acetic acid and the EDC, which is rapidly formed after mixing these two reagents, is unstable. This intermediate requires rapid attack by a decen t nucleophile (Scheme 2 25); otherwise it will decompose, destroying the SF 5 material in the process. Scheme 2 25. Intermediate between the SF 5 acetic acid and EDC. The weakness of the SF 5 acetic acid EDC method takes on more importance when the lack o f nucleophilicity of the amino furazans is considered. In order to overcome this problem, the addition of the SF 5 acetic acid was done slowly (drop wise) to the reaction mixture, which contains the aminofurazan and the EDC. In this manner the concentration of the aminofurazan is always high while the intermediate is forming in the reaction mixture. The synthesis of methyl 2 chloro 3 pentafluorosulfanyl 2 methoxypropanoate 37 unsaturated carbonyl starting material was very efficient under the triethylborane method (Scheme 2 11) As mentioned previously, the addition of SF 5 Cl to unsaturated compounds with Et 3 B could not be achieved due to the electron deficiency carbon and the possible radical polymerization at 82% yield of SF 5 Cl addition. It was thought that this material, as masked version of the dicar bonyl compound, could be used as a building block for the synthesis of SF 5 furazan based energetic materials. However, the reactivity of the carbonyl (ester) was low and no further functionalization was possible (Scheme 2 12)
62 The addition of SF 5 Cl to fluo rinated double bonds is impossible due to the electron deficiency of the carbon where the SF 5 is added. In order to reduce the amount of hydrogens and increase the amount of fluorines, changing the hydrogens at the methylene position of the SF 5 methyl este r 24 was attempted (Scheme 2 17) It is believed that due to the presence of the carbonyl and the SF 5 group there might be an enol equilibrium in this molecule in solution giving a chanc e of fluorination at the methylene position by using electrophilic fl uorine. Unfortunately this reaction did not yield any fluorination product. The use of different bases to increase the chances of an enolate destroyed the starting material; this last result was expected based on previous experiments done by other group me mbers. Trying to achieve this goal, a stronger reaction conditions was tried. F 2 ( 10% ) in N 2 was bubbled through a solution of acetonitrile containing the SF 5 compound. Interestingly, no fluorinated product was obtained, but neither did the product decompo se. This could mean that the expected ketone enol equilibrium does not exist for this molecule. The use of 2,2 dinitro propane 1,3 diol 42 as a building block for energetic materials has been previously reported using SF 5 NCO, as well as other polynitroa lc ohols, to produce biscarbamates (Scheme 2 18). 29,89 Based on these reports we attempted the reaction the reaction between 2,2 dinitro propane 1,3 diol 42 and SF 5 acetic acid EDC or SF 5 acetyl chloride under different reaction conditions without any suc cess (Scheme 2 14). The dinitro diol exhibited very low nucleophilicity, and decomposed when heated. It also decomposed quickly under basic conditions, making it difficult to add the SF 5 acetyl group.
63 During the process of making new SF 5 energetic material s, it was noted that the synthesis of 4 (1 H tetrazol 5 yl) 3 amine N (2,4,6 trinitrophenyl)furazan 41 had not been reported. We attempted the synthesis of this material and obtained a 65% yield (Scheme 2 13). Due to the high energy that the three rings pre sent on this compound, it was expected that this material should have good energetic properties. The use of SF 5 NCO as a derivatizing reagent was in some ways disappointing. The high reactivity of this material towards the addition of amines or alcohols was thought to make the perfect building block to react with the poorly nucleophilic aminofurazans. However, it was this same high reactivity that limited the solvents that could be used, after which the solubility of the aminofurazans became the problem. Onl y two solvents were feasible: dichloromethane and 1,2 dichloroethane. Other, similar solvents may also work, but the solvent properties would also be similar. Although the reactions could be done without the presence of a solvent, the high melting points o f some aminofurazans, along with the limited amount of SF 5 NCO we had, made this method impractical. The available amount of SF 5 NCO forced us to run reactions at milligram scale, so that it would be possible to carry out as many reactions as possible. The r eaction between DAF 1 and SF 5 NCO pro ved to be straightforward. 3,4 D iaminofurazan has a very low solubility in dichloromethane (0.5 mg/10 mL slv), but sufficient to allow the reaction proceed at room temperature. In 4 hours the reaction was almost complete (>90% by 19 F NMR), and in 16 hours it was done, 99% yield in a 1:1 DAF:SF 5 NCO reaction.
64 Interestingly, the product 4 amino 3 (3 pentafluorosulfanylurea 1 yl)furazan 48 is insoluble in the dichloromethane and even at higher temperature and more than 2 equi valents of SF 5 NCO, the reaction only produces the mono addition product 48 This compound was observed to be stable as a solid. However it decomposes in the presence of poor nucleophiles such as acetonitrile or water (moisture), as well as under acidic co nditions. This is due to the high electron deficiency of the carbonyl group induced by both the SF 5 and furazan moieties. In a similar manner, the reaction between ANF 4 and SF 5 NCO was successful, but only 20% conversion to product could be obtained. It is important to remember that according to Table 2 1, ANF is the worst nucleophile of the whole aminofurazan series. Unlike the other aminofurazans, ANF is highly soluble in DCM. This is why it was concluded that, in this case, it was a problem of reactivity and not of solubility. Several SF 5 NCO equivalents were added (up to 4 equiv.), and long reaction times (up to 15 days) were tried, but the result was the same as when using 1.5 equiv. of SF 5 NCO and 24 hours of reaction. A maximum of 20% of product could be obtained. Heating the reaction led to a decrease in the amount of product obtained. Scheme 2 26. Reaction between ANF 4 and SF 5 NCO. The product 4 nitro 3 (3 pentafluorosulfanylurea 1 yl)furazan 49 proved to be much more unstable to moisture and weak nucleophiles than 48 Based on the very low nucleophilicity ANF, we believe that there is an equilibrium established under these
65 reaction conditions, such that, even in the presence of 4 equiv. of SF 5 NCO, the reaction wil l not go significantly further (Sch eme 2 26). Nitration and Oxidation Reactions It was attempted to improve the performance of our compounds by N nitration of the amide moiety. However, all such reactions failed. When nitration was tried under mild conditions, the starting material was rec overed, probably because the lone pair of the nitrogen at the amide function is a relatively poor reducing agent. However, when strong nitration conditions were used, the SF 5 starting material was destroyed. It has been reported by Sheremetev in 2005, tha t N nitration of 3 acetamide 4 methyl furazan produces 3 nitramino 4 methylfurazan, which is also b e what must be happening in our case (Scheme 2 27). 60 Scheme 2 27. Decomposition of the SF 5 containing energetic material after N nitration. It is importan t to mention that no SF 5 product of any kind was seen by 19 F NMR after the reaction, which indicates that the SF 5 starting material/product decomposed. The high electron withdrawing effect from the furazan ring, the nitro group and the pentafluorosulfanyl group increase the electron deficiency of the carbonyl group, making the SF 5 acetyl group an excellent leaving group in the presence of weak nucleophiles such as water or acetonitrile.
66 The second approach by which we tried to improve the C/O balance was th e oxidation of the amino groups (wh en available) to nitro groups (Schemes 2 21 and 2 22). Three different methods were used to oxidize the amino group in DASF5 DAF 27 to a nitro group. Surprisingly, the H 2 O 2 (30%) with H 2 SO 4 which was anticipated to give the azoxy derivative, gave the nitro compound, with no presence of the expected product. This might be due to the electron withdrawing ability of the SF 5 acetamide group. Similar methods were tried with compounds 29 and 30 but oxidation was not observed f or them. Instead, in the case of 30 the ratio of products was changed (Scheme 2 28). Scheme 2 28. Change in the ratio between 30 and 30B after oxidation attempt. The same methods were applied to the 3 amino 4 SF 5 u rea furazan 48 but in all cases ANF 4 was obtained. As previously mentioned the urea moiety is sensitive to weak nucleophiles due to the electron withdrawing effect of both the furazan ring and the SF 5 group. The presence of a nitro group ortho to the urea enhances the leaving group ability of the SF 5 urea moiety (Scheme 2 22). It is important to emphasize that the SF 5 group in the acetamide moiety showed stability under strong oxidizing conditions such as H 2 O 2 (50%) or HOF/CH 3 CN, which allowed us to obtain compound 50 in good yield (Scheme 2 21).
67 The third and final attempt to improve the performance of our energetic materials involved the reaction between the available a mino groups and picryl chloride (Scheme 2 23). However, we were unable to obtain any condensation product. Under neutral c onditions the starting material was recovered and under basic reaction conditions the material was destroyed. Although the picryl chloride is a very reactive material towards nucleophilic attack, the presence of the SF 5 acetamide or SF 5 urea functionality is withdrawing enough to decrease the nucleophilicity of the amino group. On the other hand, the decomposition of the starting material under basic conditions was not a surprise since both the SF 5 acetamide or SF 5 urea contains highly acidic hydrogens that upon deprotonation might lead to the destruction of the SF 5 group. Properties of the Synthesized SF 5 Furazan Based Energetic Materials. Figure 2 6 presents all the new energetic materials that we were able to synthesize within this project. Three differen t methods were used to characterize these materials: shock sensitivity, thermal stability, and performance using Cheetah calculations. The impact sensitivity was evaluated qualitatively by placing 5 10 mg of sample in a flat polished area, and hitting the sample with a flat head hammer. With the exception of compound 41 all of the synthesized materials exhibited no sensitivity to impact under the conditions of this test. Sample 41 showed partial decomposition. By comparison, when nitroguanidine was tested in the identical manner, detonation occurred. Although there is a more technical procedure to evaluate the impact sensitivity, this particular test exemplifies the intrinsic ability of the SF 5 group to reduce the impact sensitivity of HEM. In order to ev aluate the thermal stability of the new materials, thermogravimetrical analysis (TGA) and Differential Scanning Calorimetry (DSC) were utilized for all
68 compounds in Figure 2 6 using a TA instrument SDT Q600, TGA/DSC combo instrument, which uses a ventilate d system (open pan). An example of a DSC/TGA thermogram is shown is Figure 2 7 and more detailed information is presented in Table 2 4. Figure 2 6. New energetic materials synthesized in this project. Figure 2 7 shows in green the loss of weight vs. the temperature. Compound 28 has a 5% weight loss at 243.73 o C which indicates high thermal stability. At 293 o C it has
69 lost almost 80% of its weight and remains the same even at temperature up to 1000 o C. This indicates that there is a remaining mass that did n ot convert into gas. This is probably due to the lack of oxygen in the molecule. This problem is usually addressed in the final explosive material by mixing the desired compound with some oxidizers, which blue line shows the heat flow with an exotherm (energy release) at the maximum point of 282.43 o C with an energy release of 247.2 J/g, indicating that this and the other derivatives are pr omising as energetic materials. Figure 2 7. DSC/TGA thermogram of compound 28 Compound 47 was taken as a baseline material. This compound has been previously synthesized, 89 and it exhibited good thermal stability. When compared to 47 a ll of our new energetic materials exhibited from g ood (>100 o C) to excellent (>200 o C)
70 thermal stability. Between compounds 27 and 28 there is a 65 o C difference in the starting decomposition temperature, where the bis acetamide 28 is more stable than the mono acetamide 27, indicating that the addition of t he SF 5 acetyl group increases the thermal stability of the energetic materials. Another example of this behavior is seen in compound 31 such that even though its starting decomposition temperature is the second lowest value (100.45 o C), its starting materi al, the 3 amino 4 (tetrazol 5 yl)furazan, starts to decompose at 45.76 o C. However, this is not always the c ase since DAF starts to decompose at 200 o C and after the addition of one SF 5 acetyl group it lowers to 169.01 o C. Table 2 4. Thermogram data of the sy nthesized energetic materials. Compound TGA Temp. of Decomp. ( o C) DSC ( o C, __, J/g) 27 169.01 245.95 149.79, endo, 76.38 225.32, endo, 67.15 28 234.73 293.09 28 2 .43, exo, 247.20 50 172.06 233.88 [161.98, 232.31], endo, 412.10 29 134.10 4 10.88 286.85, exo, 1023 30 214.81 382.10 [268.60, 325.27], exo, 1758 31 100.45 191.88 175.55, exo, 215.7 32 155.45 300.00 198.23, exo, 340.9 48 149.61 200.05 [159.28, 196.09], endo, 241.2 49 0 99.66 161.50 [114.46, 146.71], endo, 2481.0 41 141.00 201.46 172.58, endo, 55.52 267.78 300.00 294.32, exo, 708.4 732.75 971.64 895.99, endo, 2529 47 158.22 204.29 160.56, endo, 128.4 Compound 41 exhibits three stages of decomposition. This is characteristic of compounds that conta in the tetrazole group. The retro 1,3 dipolar cycloaddition at the tetrazole group releases nitrogen at the first stage followed by a subsequent unknown decomposition process.
71 Our baseline material exhibited an endotherm at 160.56 o C, even though it was exp ected to exhibit an exotherm instead. The open pan system used for this thermogram might not capture the energy liberated when gases are released rapidly. Four other materials also exhibited endotherms, whereas the other six energetic materials exhibited exotherms. The exotherms ranged up as high as 1758 J/g. After considering its impact sensitivity and thermal stability, the most important way to evaluate these materials is through the density, pressure and speed of detonation. The densities and heats of formation (HOF) were calculated by using the group additive method, while the pressure and speed of detonation, P and D respectively, were calculated using Cheetah software v6 at the Lawrence Livermore National Laboratory (Table 2 5). Table 2 5. Calcula ted performance data of the synthesized energetic materials. Compound Density (g/cm 3 ) HOF ( kcal /mol) P (Gpa) D(m/s) 27 2.01 239.05 20.22 6741 28 2.05 533.70 --50 2.02 251.56 29.48 7234 29 2.01 109.65 26.12 7368 30 2.03 109.17 28.62 7430 31 1.81 169.13 17.85 7002 32 1.96 174.52 --48 2.11 196.85 27.16 8049 49 2.10 209.36 30.67 6862 41 1.54 147.35 18.25 6788 47 1.99 623.00 23.73 6263 It is essential to remember that the density is one of the most important properties according t o the semiempirical equations suggested by Kamlet and Jacobs. 26 Only two compounds, 28 and 32, did not converge in the calculations when using the Cheetah software. The way SF 5 affects energetic materials upon detonation is still not fully
72 understood, and it is unknown why these two molecules did not converge during the calculations and they are still under study. From Table 2 5 it is possible to see that all of the synthesized materials have from good to excellent densities. When compared with the baselin e material, all but three have a greater density, and one of these three does not contain the furazan group ( 32 ), while another one does not contain an SF 5 group ( 41 ). This is consistent with the fact that a combination of these two groups has good potenti al to enhance the properties of energetic materials. Even though compound 41 has a positive HOF, it does not have the SF 5 group, which results then in a low density and relatively poor performance. Pressure and speed of detonation for most of our materi als are better than TNT, but be low RDX and HMX. When compared to our baseline material, most compounds have better performance, indicating once more that SF 5 and furazan groups combine to give good energetic properties. When our materials are compared to the SF 5 containing energetic materials synthesized by Shreeve et al. 14,18 ( Figure 2 1 ), where the average pressure and speed of detonation reported by Shreeve were 17.8 20.5 GPa and 6900 7100 m/s respectively, our materials performed much better, particularly in the pressure formation, but lower densities than our compounds. Experimental Methods Instrumentation All 1 H NMR (300 MHz), 19 F NMR (282 MHz) and 13 C NMR (75 MHz) spectra were recorded in CDCl 3 m, acetone d 6 or DMSO d 6 on VXR 300 spectrophotometer. Chemical shifts were referenced with TMS, CDCl 3 and CFCl 3 (0 for 1 H, 77.23 for 13 C and 0 for 19 F). Compounds were examined by high resolution mass spectrometry
73 (HRMS), Finnegan 4500 gas chromatograph/mass spectrometer using chemical ionization (CI). Thermal analyses were taken in a TA instrument SDT Q600, TGA/DSC combo instrument. See appendi x A to see relevant NMR spectra and DSC/TGA thermograms. General Method for the Syntheses of Pentafluorosulfanylacetamide Furazans To a solution of aminofurazan (7.2 mmol, 1.5 equiv.) and 1 ethyl 3 (3 dimethylaminopropyl) carbodiimide (EDC) (9.6 mmol, 2.0 equiv.) in anhydrous THF (30 mL), was added dropwise with stirring in a pressure e qualizi ng dropping funnel over 10 min. pentafluorosulfanylacetic acid (4.8 mmol, 1 equiv.) in anhydrous THF (15 mL) After the addition of the acid, 4 dimathylaminepyridine (DMAP) (0.48 mmol, 0.1 equiv.) was added, and the stirring continue for 16 h. The reaction mixture was then treated with 50 mL of water and extracted with ethyl acetate (3 x 30 mL). The organic solution was then dried over Na 2 SO 4 filtrated, and the solvent remove under reduce pressure. The resulting solid (or oil) was purified by column chromat ography (silica gel, 4:1 CH 2 Cl 2 : Ethyl acetate). 3 A mino 4 N (2 pentafluorosulfanylacetamide) 1,2,5 oxadiazole ( 27 ) :White solid, 90% yield; mp (DSC) = 133.5 o C. 1 H NMR (DMSO d6), 4.79 (q, J=9.0 Hz, 2H, CH 2 ), 6.00 (b, 2H, NH 2 ), 11.32 (b, 1H, NH); 19 F NMR (DMSO d6), A 83.60 (m, 1F), B 71.30 (d, J AB =149 Hz, 4F); 13 C NMR (DMSO d6), 72.2 (m, CH 2 ), 144.0 (s, C NH), 156.2 (s, C NH 2 ), 160.0 (m, CO); HRMS (M H, calc): 266.9981, found: 266.9992. 3,4 bis (2 pentafluorosulfanylacetamide) 1,2,5 oxadiazole ( 28 ): White solid 70% yield; mp (DSC,decomp.) = 234.7 o C; 1 H NMR (DMSO d6), 4.82 (q, J=9.0 Hz, 4H CH 2 ), 11.42 (b, 2H, NH); 19 F NMR (DMSO d6), A 83.57 (m, 1F), B 71.49 (d,
74 J AB =149 Hz, 4F); 13 C NMR (DMSO d6), 71.8 (m, CH 2 ), 146.4 (s, C NH), 160.0 (m, CO); HRMS (M+H, calc): 436.9794, found: 436.9796. 4 amine 4'' N (2 pentafluorosulfanylacetamide) [3,3':4',3''] Ter [1,2,5] oxadiazole ( 29 ): Light yellow solid, 45% yield; mp (DSC) = 133.3 o C; 1 H NMR (DMSO d6), 4.72 (q, J=9.0 Hz, 2H CH 2 ), 6.66 (b, 2H, NH 2 ) 12.44 (b, 1H, NH); 19 F NMR (DMSO d6), A 83.53 (m, 1F), B 71.53 (d, J AB =149 Hz, 4F); HRMS (M+H, calc): 405.0153, found: 405.0161. 4 amine 4'' N (2 pentafluorosulfanylacetamide) 2' oxy [3,3':4',3''] Ter [1,2,5] oxadiazole ( 30 ): Light yellow solid, 3 5% yield; mp (DSC) = 125.2 o C; 1 H NMR (DMSO d6), 4.73 (q, J=9.0 Hz, 2H CH 2 ), 6.67 (b, 2H, NH 2 ), 12.43 (b, 1H, NH); 19 F NMR (DMSO d6), A 83.51 (m, 1F), B 71.46 (d, J AB =147 Hz, 4F); HRMS (M H, calc): 418.9951, found: 418.9966. 3 N (2 pentafluorosulfany lacetamide) 4 (1H Tetrazo 5 yl) 1,2,5 oxadiazole ( 31 ): Light yellow solid 35% yield m.p (DSC,decomp.) = 100.5 o C; 1 H NMR (DMSO d6), 4.62 (q, J=9.0 Hz, 2H CH 2 ), 11.03 (b, 1H, NH); 19 F NMR (DMSO d6), A 82.32 (m, 1F), B 71.16 (d, J AB =149 Hz, 4F). HRMS ( M H, calc): 319.9995, found: 320.0001. 5 N (2 pentafluorosulfanylacetamide) 1H tetrazole ( 32 ): White S olid, 80% yield; mp (DSC,decomp.) = 155.5 o C; 1 H NMR (DMSO d6), 4.89 (q, J=9.0 Hz, 2H CH 2 ), 12.75 (b, 1H, NH); 19 F NMR (DMSO d6), A 84.00 (m, 1F), B 71.51 (d, J AB =149 Hz, 4F); 13 C NMR (DMSO d6), 72.0 (m, CH 2 ), 149.5 (s, =C NH), 159.8 (m, CO); HRMS (M H, calc): 251.9984, found: 251.9982. Synthesis of 3 N (2 pentafluorosulfanylacetamide) 4 nitro 1,2,5 oxadiazole ( 50 ): To a solution of 50% H 2 O 2 (1.6 g ) and concentr ated sulfuric acid (1.1 g) at 0 o C,
75 160 mg of Na 2 WO 4 .H 2 O and 30 mg of 3 amino 4 (pentafluorosulfanylmethyl)furazan (27) were added in one portion. The mixture was stirred until the staring material disappears on the TLC (~16 h, 4:1 CH 2 Cl 2 : Eth yl acetate). The mixture was then treated with 5 mL of water and extracted with ethyl acetate. The solvent was remove under reduce pressure and the resulting oil purified by column chromatography (silica gel, 4:1 CH 2 Cl 2 : Ethyl acetate), light yellow solid 50% yield m.p (DSC,decomp.) = 172.06 o C. 1 H NMR (DMSO d6, ppm), 5.11 (q, J=9.0 Hz, 2H CH 2 ), 11.87 (b, 1H, NH); 19 F NMR (DMSO d6, ppm), A 83.90 (m, 1F), B 71.97 (d, J AB =149 Hz, 4F); 13 C NMR (DMSO d6, ppm), 71.6 (m, CH 2 ), 144.7 (s, C NH), 158.2 (s, C NO 2 ), 160.0 (m, CO). HRMS (M+H, calc): 298.9873, found: 266.9902. General Method for the Syntheses of Pentafluorosulfanylurea Furazans To 30 ml of anhydrous DCM in a Glass Heavy Wall Pressure Vessel, closed with a septa at 40 o C, 7.8 mmol of pentafluorosul fanyl isocyanate was bubbled. Then, the septa was remove and quickly 7.8 mmol of aminofurazan were added, the septa is now replace by the sealed cap. The cold bath was removed and the reaction mixture was stirred for 24 h. After that the Vessel was open an d the solvent evaporated under reduced pressure. 3 amino 4 N (3 pentafluorosulfanylurea) 1,2,5 oxadiazole ( 48 ): White solid, 99% yield; mp (DSC,decomp.) = 149.61 o C; 1 H NMR (Acetone d6), 10.55 (b, 1H, NH SF 5 ), 8.83 (b, 1H, NH CO), 5.57 (b, 2H, NH 2 ); 19 F NMR (Acetone d6), A 77.44 (m, 1F), B 72.40 (d, J AB =149 Hz, 4F); 13 C NMR (Acetone d6), 145.0 (S, C NH 2 ), 148.7 (s, C NH), 153.0 (m, CO); HRMS (M H, calc): 267.9933, found: 267.9941.
76 3 N (3 pentafluorosulfanylurea) 4 nitro 1,2,5 oxadiazole ( 49 ): Yello w Solid, 20% NMR yield; mp (DSC,decomp.) = 99.7 o C; 1 H NMR (Acetone d6), 11.18 (b, 1H, NH SF 5 ), 9.19 (b, 1H, NH CO); 19 F NMR (Acetone d6), A 76.78 (m, 1F), B 72.13 (d, J AB =155 Hz, 4F); HRMS (M H, calc): 297.9575, found: 297.9678. Synthesis of 3 amine N (2,4,6 trinitrophenyl) 4 (1H tetrazol 5 yl) furazan ( 41 ): To a solution of 3 amino 4 (1H tetrazol 5 yl) furazan (153 mg, 1mmol) and K 2 CO 3 (2 mmol, 2 equiv.) in acetonitrile (10 ml), was added picryl chloride in one portion (371 mg, 1.5mmol, 1.5 equiv.). The reaction mixture was stirred overnight, and the precipitate was filtrated and washed with acetonitrile. The solid was recrystallized form Acetonitrile: Yellow s olid, 65% yield; mp (DSC,decomp.) = 141.2 o C. 1 H NMR (acetone d6), 8.56 (s, 2H, =CH), 6.53 (b, 1H, NH); HRMS (calc): 387.0157, found: 387.0155. Synthesis of 1 (1 H benzotriazolyl) 2 pentaflurosulfanylethanone ( 29 ) To a solution of SF 5 acetic acid (50 mg, 0.27mmol) in CH 2 Cl 2 (1 mL) was added dropwise a mixture of SOCl 2 (22 L, 0.29 mmol, 1.1 equi v.) and 1H benzotriazole (96 mg, 3 equiv.) in CH 2 Cl 2 (1.5 mL) and stirred for 4 h at r.t. the white precipitate was filtered off and the organic solution evaporated under reduce pressure. The resulting oil was purified by flash colum chromatography (silica gel, CH 2 Cl 2 ), recollecting 73.31 mg of product (95% yield): 1 H NMR (CDCl 3 ), 5.43 (q, J=7.2 Hz, 2H), 8.30 (d, J=8.2 Hz, 1H), 8.12 (d, J=8 8.2 Hz, 1H), 7.75 (t, J= 8.4 Hz, 1H), 7.60 (t, J= 8.4 Hz, 1H); 19 F NMR (CDCl 3 ), A 77.0 (m, 1F), B 71.6 (d, J AB =15 1 Hz, 4F). HRMS (calc M H + ): 288.0230 found: 288.0243 Synthesis of methyl 2 chloro 3 pentafluorosulfanyl 2 methoxypropanoate ( 3 7 ) : To a three necked flask equipped with a dry ice reflux condenser 5 g (43 mmol) of
77 2 methoxypropenoate 36 and 215 mL of hex a ne were added and cooled to 40 o C. 10.5 g (64.6 mmol, 1.5 eq) of SF 5 Cl were added slowly and the solution stirred for 5 min before the addition of 6.46 ml (6.46 mmol, 0.15 eq) of Et 3 B 1M in hexane. The sol ution was stirred for 2h at 30 o C and then allows warming to r.t. The mixture was hydrolyzed with aqueous NaHCO 3 (10%), and the organic layer dried over MgSO 4 The solvent was remove under reduce pressure, resulting in 11.96 g (82% yield) of product: colorless liquid ; 1 H NMR (CDCl 3 ), 3.79 (s, 3H, OCH 3 ) 3.90 (s, 3H, CO 2 CH 3 ), 4.29 (m, 1H, CHSF 5 ), 4.59 (m, 1H, CHSF 5 ); 19 F NMR (CDCl 3 ), A 80.4 (m, 1F), B 67.9 (d, J AB =145 Hz, 4F). HRMS (calc M H + ): 278.9881 found: 278.9882
78 CHAPTER 3 CONFORMATIONAL AND 1 9F 19F COUPLING PATTERN S ANALYSIS IN MONO SUBSTITU TED PERFLUORO [2,2] PARACYCLOPHANES BY C OMPUTATIONAL CALCULATIONS Introductory Remarks The chemistry of perfluoro[2.2]paracylophane (F8) was introduced in Chapter 1 During the course of studying the reactivity of F8 by Dolbier et al. 45 new mono substitut ed F8 derivatives were synthesized. The new compounds display unusual 19 F 19 F coupling patterns ( 4 J and 5 J) that suggest a skewed geometry in which the upper deck moves towards or away from the substituent (Figure 3 1) Neither the different configurations (towards or away) nor the unusual 19 F 19 F coupling patterns could be explained with traditional theory 1 Figure 3 1. Towards and away upper deck orientations Quantum chemical calculations were performed at the HF/6 311+G(d,p)/ /B3LYP/EPR III level of t heory using Gaussian 03 92 and they shed light on the unusual structures and coupling of F8 and its derivatives. However, before I get into the results and discussion of this project, some important background must be mentioned. Calculated spin spin coupl ing constants include the four isotropic Ramsey terms, Fermi contact (FC), spin dipolar (SD), paramagnetic spin orbit (PSO), and diamagnetic spin orbit (DSO) contributions. It is the sum of these four contributions that gives value 1 Reproduce in part with the permission from Magn. Reson. Chem 2011 49 (3), 93 105. License Number: 2730251383944
79 to the final coupling co nstant. Although final value is the one that can be seen experimentally, the four contributions can be calculated to help understand the mechanism of the coupling and also hints at the electronic structure of the molecule. 94,95 A spinning nucleus could sim ply be considered as a moving charged particle. Any particle that is moving with a charge simultaneously generates an electric current and a magnetic field. The magnetic field of a nucleus will induce both of the following local effects: 1) Electron spin p olarization and 2) orbital ring currents. Since the molecule is using Coulombic interactions, the mechanism by which the coupling will be transmitted is an extension of the loc al effects. The FC and the SD terms are part of mechanism 1 and the PSO and DSO terms are part of mechanism 2. The FC mechanism takes place in both interacting nuclei when the electron spin is at the site of the nuclear spin. This requires that the electro n has a non zero probability of being at the same position as the interacting nucleus (tunnel effect). The SD has a similar interaction but the electron is not at the coupling nuclei position; this phenomena is similar to the interaction of two small magne ts averaged in space and time. The PSO and DSO mechanisms are the interactions between the electronic spin and its motion around the generated nuclei orbital current. This interaction could be either paramagnetic or diamagnetic. 94 98 Short range couplings in teractions present in the bonds, which have contributions from all four isotropic Ramsey terms, with a major contribution from the FC term, followed by the PSO and ) could be transmitted through bonds, which requires hyperconjugative interactions, or through space (TS), which could be
80 95, 98 Long range couplings transmitted through bonds in saturated systems have of the type LP igher values and are of the type LP these cases the FC term is the main contributor to the coupling and the value of the coupling constant depends on the efficiency with which the hyperconjugation is transmitted. 95,98 The throu involves the superposition of the electronic clouds of the interacting nucle i, sometimes with the help of an intermediate moiety that connect s both coupling nucleus. As it might be expected, the TS mechanism d epends mainly on the distance and angle by which both atoms are interacting to each other. In the particular case of fluorine fluorine coupling interactions, lone pa irs. 96 98 On the other hand, TS coupling due to hyperconjugation depends on the range couplings could also be expressed in terms of the molecular orbitals. Specifically, th e canonical molecular orbitals (CMOs) are expanded in terms of the natural bond orbitals (NBOs), which helps to explain the Fermi Contact Coupling Pathways by analyzing the CMOs (FCCP CMOs). 95 The FCCP CMO analysis shows that there is at least one common a tom between the occupied and virtual molecular orbitals that will
81 transmit the spin polarization and generate the coupling. The efficiency of the coupling is then limited to the energy gap for the transition between the occupied and virtual orbitals that p articipate in the coupling. The following expanded theoretical explanation of the long range transmission mechanism has been contributed by Dr. Contreras and Dr. Tormena, both of them whom collaborated with us in the theoretical aspects of this research pr oject. It may be recalled that CMOs satisfy the Pauli exclusion principle and, therefore, the Fermi hole spans the whole spatial region of each CMO. Since it is known that the FC term is transmitted like the Fermi hole, 99,100 the spin information correspo nding to the FC term also spans that spatial region. Therefore, the studied coupling constants are expressed in terms of CMOs, where n stands for the number of formal bonds separating the coupling fluorine nuclei (Equation 3 1). To identify relevant CMOs for a given coupling its expression in terms of the polarization propagator approach, PP, at the RPA (Random Phase Approximation) is employed (Equation 3 2). (3 1) Where, i and j stand for occupied CMOs, while a and b stand for vacant CMOs, and each s um term in Equation 3 1 can be written as in Equation 3 2. 101 (3 2) Where ( ) are the so elements of the FC operator, i.e. the occupied i ( j ) and vacant a ( b ) CMOs evaluate
82 (3 3) Equation 3 3 show s the elements of the triplet PP matrix, and they can be 4). and (3 4) Each sum term in Equa tion 3 1 is dubbed an FCCP, and depends on both the ( ), i.e., a given FCCP is non negligible whenever both types of terms are simultaneously significant. Therefore here is described very briefly under which conditions those types of terms are significant. The diagonal matrix elements, i.e. those satisfying i = j and a = b are larger than non diagonal terms. They depend explicitly and strongly on the energy gap between the vacant a and the occupied i a,i a i a,I increases and vice versa. However, it is important to point out that, for a given coupling constant, many diagonal elements of the PP matrix are also negligibly small. terms are important whenev er there is a substantial overlap between i = j and a = b orbitals at the positions of both coupling nuclei. For a significant diagonal PP matrix element one occupied and one vacant CMO determine an efficient FCCP; those orbitals can be spotted when observ ing their respecti ve NBO expansions. bonds or lone orbit als containing the
83 coupling nuclei. It is also recalled that only the diagonal matrix elements depend solely upon the virtual a,i a i ). With this in mind it is easy to identify the CMOs that could constitute efficien t FCCPs for a given coupling constant. Results and Discussion Ground State C alculations The 19 F NMR spectra of the new mono substituted perfluoro[2.2]paracyclophane s (F8) displayed unusual 19 F 19 F coupling patterns ( 4 J and 5 J) that suggested a skewed geome try in which the upper deck can move either towards or away from the substituent (Figure 3 1). In order to understand this unusual behavior the first step of the characterization process was to calculate the ground state for two different substituted compo unds that display different NMR patterns, for example R=OMe ( 51 ) and R=NEt 2 ( 52 ) (Figure 3 1). Table 3 1. Relative energies ( kcal /mol) for the conformational isomers of 51 and 52 OMe( kcal /mol) NEt 2 (kcal /mol) Toward 0 +4.99 Away +2.13 0 The ground s tate calculation for each compound was carried out for the two possible conformations at the HF/6 311+G(d,p) level of theory using Gaussian 03 Rev. E01. 92 It was found that the towards conformation was the more stable for the OMe substituent, while the awa y was the more stable for the NEt 2 substituent. These results are consistent with the assumptions that were made in rationalizing the experimental n J FF SSCCs. The more stable conformation of each compound was used to calculate the corresponding F F couplin g constants. In all cases the SSCC calculation s include d
84 the four isotropic Ramsey terms, Fermi contact (FC), spin dipolar (SD), paramagnetic spin orbit (PSO), and diamagnetic spin orbit (DSO) contributions calculated at the B3LYP/EPR III level using Gauss ian 03. The numbering used in the following analysis is presented in Figure 3 2. Figure 3 2. Monosubstituted F8, where R= OMe ( 51 ) NEt 2 ( 52 ) 4 J (F m F n ) Coupling Constants All SSCCs displayed in Table 3 2 derive from a coupling pathway that could be clas through space via the FC term of the 4 J FF and it depends strongly on the F F distance. Table 3 2. Calculated 4 J (F m F n ) coupling constants and F F distance for compound 51 (R= OMe). a c F m F n J FC J SD J PSO J DSO J total J exp d( F n F m ) F10A F16 26.35 0.75 8.83 1.77 20.04 32 2.71 F9S F5 27.16 0.86 9.27 1.82 20.57 33 2.70 F9A F7 79.03 3.53 8.42 2.04 76.18 66 2.54 F10S F12 79.21 3.56 7.93 2.05 76.89 66 2.54 a. All Values are in Hz. b. Distances in c. See Figure 3 2 for numbering of the atoms. The calculated values compare well with the experimental ones Interestingly, from Table 3 2 it is possible to see that both the smaller and larger S SCCs are diagonal to each other (s ee the bonds selected in bold in Figure 3 2 ) Although all 4 J FF SSCC
85 have the same type of connections, two of them have a much higher coupling than the other two. In the same Table it is observed that, while the FC terms in 4 J F9A,F7 and in 4 J F10S,F12 are abo ut three times larger than in 4 J F9S,F5 and in 4 J F10A,F16 the PSO term does not change along the same series. These observations suggest that the much larger FC terms in 4 J F9A,F7 and 4 J F10S,F12 SSCCs originate mainly due to an increase in the FC term trans mitted through space. To support this assumption, the respective optimized F F distances are also shown in Table 3 2. Figure 3 The distances reported in Table 3 2 are shorter than twice the F Van der Waals radius, (2 x 1.47) which means that the FC term can be transmitted TS due to the overlap of fluorine lone pair orbitals It is known that the overlap of proximate lone pairs is an efficient pathway for transmitting the FC interaction, regardless of whether or not it is a n attractive or repulsive interaction. The dependence of the FC term on the F F distances is clearly seen in the Table as the larger coupling values correspond to the smaller F F distance, while the smaller coupling values correspond to the larger F F dist ance. These results are in good agreement with similar data discussed, among other authors, for example by Arnold and co workers. 102 Table 3 3. Calculated 4 J (F m F n ) coupling constants and F F distance for compound 52 (R=NEt 2 ). a c F m F n J FC J SD J PSO J DSO J t otal J exp d( F n F m ) F10A F16 77.23 3.383 8.64 2.04 74.46 67 2.54 F9S F5 77.43 3.87 8.02 2.04 75.32 75 2.52 F9A F7 27.12 0.81 8.99 1.84 20.78 33 2.70 F10S F12 28.21 0.85 9.43 1.91 21.54 35 2.68 a. All Values are in Hz. b. Distances in c. See Figu re 3 2 for numbering of the atoms.
86 Similar behavior is observed for analogous SSCCs in 52 (Table 3 3), with the exception that the larger SSCCs of 51 become the smaller ones of 52 and vice versa. This data supports not only the assumption made above about the relationship FC term vs. distance, but also the initial hypothesis of the different upper deck position for the two substituent s (Figure 3 4). Figure 3 4. Calculated most stable conformations for compounds 51 (left) and 52 (right). 5 J (F m F n ) Coupli ng Constants In Table 3 4 the calculated and experimental values for 4 different 5 J FF SSCCs in compound 51 are displayed. The most surprising result is the striking difference between 5 J F10A,F7 and 5 J F9S,F12 SSCCs which could not be experimentally observe d and their respective calculations are also close to 0 Hz, while 5 J F9A,F16 = 15 Hz and 5 J F10S,F5 = 17 Hz SSCCs were measured. The transmission mechanisms of the 5 J FF couplings cannot be rationalized on the same grounds as those operating for 4 J FF Althou gh the largest 5 J FF couplings are also dominated by the FC term like 4 J FF couplings, it is obvious that transmission mechanisms of the FC term for 4 J FF are notably different than those for the FC term of
87 5 J (F m F n ) since for all four couplings the distances between the coupling nuclei are always larger than twice the van der Waals radius and, therefore, any direct 5 J (FC) through space coupling should be ruled out. Table 3 4. Calculated 5 J (F m F n ) coupling constants and F F distance for compound 51 (R=OMe). a c F m F n J FC J SD J PSO J DSO J total J exp d( F n F m ) F9A F16 14.99 2.1 3.8 1.77 15.06 15 2.99 F10S F5 15.06 2.21 3.83 1.79 15.23 17 2.99 F9S F12 0.22 0.85 0.66 0.01 0.42 0 4.37 F10A F7 0.20 0.86 0.63 0.01 0.44 0 4.36 a. All Values are in Hz. b. Distances in c. See Figure 3 2 for numbering of the atoms. In order to rationalize the behavior of 5 J (F m F n ) (FC), it must be recalled that it is known that the FC term can be transmitted by an intermediate moiety, 103,104 like that suggested by Mallory, 105 where a coupling 6 J F F = 6.4 Hz is transmitted through a phenyl ring (Figure 3 5). Figure 3 5. Unusual through space coupling transmitted by the electronic Ph d system. This TS coupling between fluorines a and b is due to overlapping interactions between the lon e pair of each fluorine and the system of the phenyl group ( d ) with an anti symmetric linear orbital combination (F Ph F). It should be noted that the phenyl group (d) is perpendicular to the anthracene plane. It is also important to note that the appear ance of the fragment defining 5 J FF SSCCs shown in Table 3 4 can be represented by the fragment shown in Figure 3 6, where A, E and G represent fluorine atoms; here, 5 J FF is represented by J AG It seems
88 that the D E bond is playing the role of the Ph d pheny l group in Figure 3 5. Therefore, this additional coupling pathway is of the through space type, transmitted through the electric cloud corresponding to the fluorine atom occupying the E position. Figure 3 5. Representation of the unusual 5 J FF SSCCs. For instance, for 5 J (F9A F16) and 5 J (F10S F5) couplings the role of the intermediate is played by F10A and 9S, respectively. For example, the 5 J (F9A F16) coupling pathway might operate like this: the overlap between the F10A and F16 lone pairs yields 4 J (F10A F16)(FC) = 26 Hz, which is transmitted through space due to the pairs with the F16 FC spin information and then F 10A transmits the spin information to F9A by a second overlap. A similar pa th would apply for 5 J (F10S F5). In order to have an efficient coupling for the 5 J FF the entire F<==>F<==>F mechanism should be connected at once. Now the question becomes why this mechanism is efficient for 5 J (F9A F16) and 5 J (F10S F5) and not for 5 J (F10A F7) and 5 J (F9S F12)? To answer this, it is important to consider two different aspects: 1) for one side of the molecule, one 5 J FF is effective while the other is not; however, in both of them the 3 J FF aliphatic vicinal coupling is common and the efficienc y of the coupling is not coming from this connection, which take us to the second aspect, 2) the aromatic aliphatic 4 J FF connection. Interestingly, for the higher 4 J FF SSCCs previously discussed, the 5 J FF is ineffective, and for the smaller 4 J FF SSCCs, the 5 J FF is effective. These last
89 two statements mean that the effectiveness in the 5 J FF SSCC is not due to the distances between all interacting fluorines. It is believed at this point that there must be an orbital overlapping between all interacting fluori nes that transmit the spin polarization mechanism in such a manner that it is effective in one way and not the other. Thus, as with any orbital overlapping, there is not only distance dependence, but also an angular dependence. The calculated aromatic ali phatic F F dihedral angle for the effective 5 J FF SSCCs is around 40 o while the ineffective 5 J FF SSCCs the angles are all around 1 o Similar behavior is observed for analogous 5 J FF SSCCs in 52 (R=NEt 2 ), but with the opposite trend (Table 3 5). Table 3 5. C alculated 5 J (F m F n ) coupling constants and F F distance for compound 52 (R= NEt 2 ). a c F m F n J FC J SD J PSO J DSO J total J exp d( F n F m ) F9A F16 0.21 0.75 0.55 0.01 0.42 0 4.29 F10S F5 0.22 0.76 0.52 0.01 0.47 0 4.29 F9S F12 16.12 2.11 3.87 1.79 16.15 11 3. 08 F10A F7 16.27 2.34 3.91 1.81 16.51 11 3.05 a. All Values are in Hz. b. Distances in c. See Figure 3 2 for numbering of the atoms. In order to give further support to the previous hypothesis of having an intermediate moiety relaying the spin polari zation from one fluorine to the other, three more calculations were done. in one of the effective and one of the ineffective 5 J FF SSCCs (separate calculations). The chlorine atom has a larger Van der Waals radii, which makes the interacting distances between the F<==>Cl<==>F couplings shorter; but, since the distance seems to not be as important as the angle in this coupling pathway, the coupling constants should not be affec ted significantly. The calculations were performed only with
90 compound 51 using the ground state geometry previously calculated and only for the coupling constant in which the chloride atom might be part of. This is because the SSCC calculation requires si gnificant amounts of memory and time. The new calculated coupling constants were only about 0.5 Hz higher than the ones without the chlorine, which supports the assumption that the distance is not as important as the dihedral angle might be. The second cal culation was the change of the dihedral angle between the aromatic aliphatic fluorines. The calculation was performed only with compound 51 using the ground state geometry previously calculated, except for the change of 15 o in the dihedral angle of one ef fective coupling constant (from 40.77 o to 25.77 o ). The change in the dihedral angle for the ineffective coupling changes the vicinal aliphatic F F distance to a significantly larger value ( 3 J FF ) and the results would not be as precise since this particular 3 J FF coupling is distance dependent. The new calculated coupling constant changed from 15.06 Hz to 8.13 Hz, which supports the previously made assumption of angular dependence. The third, final, and probably most accurate calculation was done using the Fe rmi Contact Coupling Pathway Canonical Molecular Orbitals approach (FCCP CMOs) that was explained previously. This method verified that the 5 J FF SSCCs goes through an intermediate moiety. All of the calculations in this part were done using compound 51 a s the model. The analysis of these calculations was done by Dr. Contreras (University of Buenos Aires, Buenos Aires, Argentina) and Dr. Tormena ( University of Campinas, Sao Paulo, Brazil).
91 The occupied CMOs with an energy lower than 0.679055 a.u. or high er than + 1 a.u. are not tak en a,i a i ) energy gap and therefore their contributions to coupling constants relevant to this qualitative analysis should be too small to yield insight on the main fa ctors determining the observed experimental trends. CMO expansions in terms of NBOs as given by the 106 they are displayed using conventions used in the outputs of that program. Briefly they are, a) CMOs are numbered from lower to higher energy, indicating if they are occupied or vacant CMOs; CMO energies are given in atomic units, b) the first number, followed by an asterisk, when squared corresponds to each NBO contribution with a threshold of 5 %; c) the s econd number, in square brackets, corresponds to the NBO numbering, d) next, the NBO type is shown followed by the atom or atoms involved in it (numbered as in the Gaussian 03 program output), i.e. core, lone pair; bonding, antibonding, or Rydberg orbitals respectively. In Table 3 6 only the relevant NBOs whose atoms participate explicitly in 5 J (F10S F5), 5 J (F9S F12), 4 J (F9 A F 16 ) and 4 J (F10 A F 7 ) coupling constants is shown for each CMO. Occupied CMOs are presented from highest to lowest orbital energies, while vacant CMOs are presented from lowest to highest energies to visualize easily the corresponding energy gaps. There are only five CMO(vir) containing NBOs that include more than one of the atoms involved in coupling constants mentioned above. It is ob served that four of them include the F5 and F12 atoms, but neither F10S nor F9S atoms. These correspond to the transmission of the pseudo gem 9 J (F12 F5) but not to the 5 J syn (F9S F12) coupling. Therefore, the only virtual CMO that could be significant for
92 t ransmitting any of the 5 J syn (F10S F5), 5 J syn (F9S F12), 4 J syn (F9S F5) and 4 J syn (F10S F12) couplings is the CMO(vir) 130. The respective virtual transitions should be the following three, (I) CMO(occ)109 CMO(vir)130, (II) CMO(occ)108 CMO(vir)130 and (III) CM O(occ)98 CMO(vir)130. Table 3 6. Expansion of relevant CMOs in terms of NBOs in compound 51 Only NBOs involving F5, F9S, F10S and F12 are displayed. Occupied CMOs Vacant CMOs CMO 109 (occ) 0.419280 a.u CMO 129 (vir) 0.370*: LP ( 2) F5(lp) 0.277*: BD*( 1) C12 F12* 0.283*: LP ( 2) F9S(lp) 0.256*: BD*( 1) C5 F5* 0.240*: LP ( 3) F10S(lp) CMO 108 (occ) 0.424528 a.u. CMO 130 (vir) : 0.247*[ 94]: LP ( 2) F12(lp) 0.257*: BD*( 1) C10 F10S* 0.234*: LP ( 2) F5(lp) 0.242*: BD*( 1) C5 F5* 0.233*: LP ( 3) F10S(lp) MO 131 (vir) CMO 106 (occ) 0.430080 a.u. 0.300*: BD*( 1) C12 F12* 0.268*: LP ( 2) F9S(lp) 0.244*: BD*( 1) C5 F5* 0.230*: LP ( 2) F5(lp) MO 136 (vir) CMO 103 (occ) 0.440928 a.u. 0.235*: BD*( 1) C5 F5* 0.381*[ 94]: LP ( 2) F12(lp) 0.225*: BD*( 1) C12 F 12* 0.273*: LP ( 2) F10S(lp) MO 140 0.268*: LP ( 3) F10S(lp) 0.365*: BD*( 1) C5 F5* CMO 100 (occ) 0.456086 a.u. 0.257*: BD*( 1) C12 F12* 0.373*: LP ( 2) F5(lp) 0.366*: LP ( 2) F10S(lp) 0.325*[ 94]: LP ( 2) F12(lp) CMO 0.471647 a.u. 0.326*: LP ( 2) F5(lp) 0.253*: LP ( 3) F10S(lp) 0.249*[ 94]: LP ( 2) F12(lp) 0.225*: LP ( 3) F9S(lp) Obviously, the virtual transition (I) corresponds to the coupl ing pathway mentioned in the working hypothesis: CMO(occ)109 contains these lone pair orbitals: LP 2 (F5), LP 3 (F10S) and LP 2 transmitting the FC term of 5 J syn (F10S F5) coupling. It is highlig hted the CMO(vir)130
93 F9S) antibonding orbital since 4 J (F9S F5) coupling is transmitted by the overlap of LP(2) of F9S and LP(2) of F5. Virtual transition (II) contributes also to the 5 J (F10S F5) coupling transmission but its ener gy gap is about 0.005 a.u. larger than in (I), The same can be said abo ut the virtual transition (III). I n this case the respective energy gap is about 0.062 a.u. larger than in (I), showing a notably smaller efficiency for transmitting the 5 J (F10S F5) cou pling. There are not equivalent virtual transitions to transmit the FC term of 5 J (F9S F12) since there is no virtual CMO containing the equivalent to CMO(vir)130, i.e. a CMO(vir) of the upper deck for compound 4 leads to an important distortion of the F12 C 12 C11 C10 F10S moiety, which inhibits the existence of a virtual CMO containing simultaneously those two NBO antibonding orbitals, rendering a very inefficient coupling pathway for 5 J (F9S F12). This distortion renders also a much shorter F12 --F10S distan ce, increasing notably the overlap between their electronic clouds, increasing the through space transmission of 4 J (F10S F12). It is highlighted that all three CMOs(occ)108, 103 and 98 contribute to the through space via overlapping lone pairs the 4 J syn (F 10S F12) coupling, but they are not affected by the respective CMO orbital energies since they are transmitted by exchange interactions taking place in the lone pair overlap region. Similarly, 4 J (F9S F5) is transmitted by CMOs(occ) 109, 106, 100 and 98, i. e. such couplings do not require of antibonding orbitals for the transmission of their FC terms. Preferred Conformations : Upper Deck Towards or Away At this point it has been demonstrated experimentally and computationally that in fact the methoxy substi tuent has a different upper deck configuration (towards) than the
94 N,N diethylamine substituent (away); however, the preference between one and the other has not been rationalized. All the compounds that have been synthesized have shown to prefer the toward conformation as long as the substituent is not large. For those with a large substituent, such as N,N dimethylamino, N,N diethylamino and (CH 2 ) 4 N the away conformation is the preferred one. A potential energy scan around the aromatic C and the N bond in the N,N dimethylamino F8 compound indicated a highly repulsive interaction between the methyl group and the closest CF 2 in the bridge (Figure 3 7). This repulsive interaction causes the dimethylamino group to be out of the plane of the ring. The methyl gro ups push away the upper ring to minimize other repulsive interactions with the upper ring. Experimentally it was found that one methyl group from the Me 2 N and one methylene group from Et 2 N has splitting due to coupling with the fluorines of upper aromatic ring. Figure 3 7. Repulsive interaction between the CH 3 and the closes t CF 2 on the F8 bridge. During the time of this computational study, different members of the group prepared other mono substituted F8 derivatives that were included in this study, as they were needed. In particular, three new compounds help to fully understand the conformational preference: 1) NH 2 F8, 2) NHEt F8 and 3) H F8. The amino and the ethylamino F8, both showed experimentally and computationally to have a toward conformation. The ground state calculations indicate
95 that both nitrogens are conjugated with the ring. The ethylamino group has the ethyl group pointing away from the CF 2 in the bridge avoiding any repulsive interaction and allowing the lone pair of the nitrogen to be conjugated with the ring. Lastly, we were all expecting the H F8 compound to have a toward type conformation since the substituent is really small (smaller than methoxy or amino); however, both the NMR and the ground state calculation indicated that the aw ay is the preferred conformation. The computational calculation showed that the away conformer is 2.3 kcal/mol lower in energy than the toward. Taking into account that all the nucleophiles were heteroatoms, except for the hydride, then all the toward con formers have a substituent with a lone pair available. Previous reports have shown intermolecular attractive non covalent interactions intermolecular interaction is stronger whe n the ring is electron deficient, such a perfluorinated benzene ring. 107,108 The donating lone pair that is part of this non covalent interface could also come from a halogen, as previously reported. 109 Then it is believed that one lone pair of the heteroa tom substituent has a LP ring, in addition to the other three coming from the fluorine lone pairs: One from the ortho fluorine to the substituent (with the upper ring), and two from the pseudo meta and pseudo para fluorines with the lower ring (LP(F) The away conformation in all heteroatom substituent cases would also have 4 LP interactions coming all from fluorines, which suggests that the one coming from the heteroatom might be stronger. When the substituent is a hydrogen the toward
96 conformation would have only 3 LP have 4, and in all cases the donating lone pairs come from the fluorines. Interestingly, further support for the LP confo rmation is seen in the ground state geometries. It was noticed that the lone pair of the nitrogen in the amino F8 compound is pointing down in the away conformation, while it is pointing up in the towards conformation. Also, in all cases, the distances bet ween the heteroatom (lower ring) and the closest carbon in the upper ring are less than the sum of the Van der Waals radii of both atoms. Both of these points support the possibility of non covalent interaction between the lone pair and the pi system of th e upper ring. The final confirmation of this hypothesis was done calculating the ground state of the protonated version of the amino F8 for both towards and away ([NH 3 F8] + ). In this case it was thought that by protonating the nitrogen, the bulkiness of t he substituent is not affected, but the lone pair would not be available to do LP results of the calculations indicated that the away conformer is 5 kcal/mol more stable than the toward conformer, supporting the possibility of the LP nteraction with the upper ring.
97 CHAPTER 4 IMPACT OF FLUORINE S UBSTITUENTS ON THE R ATES OF NUCLEOPHILIC ALIPHATIC SUBSTITUTI ON AND ELIMINATION Introductory Remarks The mechanism in which primary perfluoroalkyl substrates will undergo aliphatic substitu tion was introduced in Chapter 1. These types of substrates cannot experience bimolecular aliphatic substitution (S N 2) but instead are capable of undergoing nucleophilic substitution via the S RN 1 mechanism (Figure 1 21). 54 emistry is that fluorine close to the site of nucleophilic substitution will inhibit such substitution; however, elimination reactions are accelerated by the presence of fluorine. Although it is known that the presence of fluorine affects the reaction rat es of both the S N 2 and the E2, limited information of a comprehensive and quantitative analysis can be found in the literature. Haas was able to observe apparent S N 2 substitution reactions with benzylic, arylCF 2 Br compounds (Scheme 4 1); however, the kine tic rate was not measured for this reaction 110 Scheme 4 1. S N 2 reaction of bromodifluoromethylbenzene. It has been also reported that carrying out nucleophilic substitutions on fluorinated substrates such as CF 3 CH 2 X or R F CH 2 X requires rather harsh conditions, even with relatively good nucleophiles, such as azide, and good leaving groups, such as OMs (Scheme 4 2). 111
98 Scheme 4 2. Literature examples of S N 2 reactions of azide with fluorinated substrates. group they are considered to have S N n alkyl halides, whereas fluorinated substrates also have sig nificantly enhanced E2 reactivities. Such considerations are important to recognize when one is designing syntheses of fluorous compounds using n R F CH 2 CH 2 X substrates. Scheme 4 3. Early Hine and McBee kinetic studies There are two early papers that prov ide some quantitative insight into the effects of fluorine substitution at the and positions of an alkyl halide on the rates of nucleophilic substitution, but to our knowledge there are no kinetic data available regarding the effect of fluorine on eliminations. Hine examined the reaction of phenyl thiolate with fluorinated e thyl iodide, 112 whereas McBee studied the reactions of iodide ion with and fluorinated alkyl bromides (Scheme 4 3). 113
99 Hine also provided the only data that is available on the effect of fluorine substitution with his study of the S N 2 reactivity of bromofluoromethane, which proved to be ~350 times less reactive than methylbromide in its reaction with iodide ion in acetone at 20 o C. 114 The purpose of the present work is to provide comprehensive, hopefully definitive kinetic data for substitution and el imination reactions of and fluorinated n alkyl systems under a variety of solvent, nucleophilic and basic conditions, in order to provide synthetic organic chemists with sufficient understanding of the chemistry of such systems to allow them to plan successful synthese s when using partially fluorinated aliphatic substrates. Comparative kinetic and reaction outcome data will be provided for the following partially fluorinated substrates: n RBr, n R f CH 2 CH 2 Br, n R f CH 2 Br n R CHFBr, n R CF 2 Br, and PhCF 2 Br in their reacti ons with two nucleophiles that have very different character, the strong base nucleophile, methoxide, and the weak base, strong nucleophile, azide; the kinetics of their reactions being examined in the protic solvent, methanol and the polar, aprotic solven t, DMSO. Computational results will also be presented in order to provide a more complete understanding of the unusual kinetic effects of fluorine substituents. Results and Discussion The specific substrates that were included in this kinetic study are n h eptyl bromide ( 53 ), n octyl iodide ( 54 ) and n octyl tosylate ( 55 ), 1 H 1 H perfluoro n butyl bromide ( 56 ), 1 H ,1 H ,2 H ,2 H perfluoro n hexyl bromide ( 5 7 ), 1 bromo 1 fluorononane ( 58 ), 1 bromo 1,1 difluorohexane ( 59 ), benzyl bromide ( 60 ), and
100 bromodifluoromethyl benzene ( 61 ). Substrates 53 54 56 5 7 and 60 were commercially available. Tosylate 55 was obtained from the alcohol in the usual manner. 115 1 Bromo 1 fluorononane ( 58 ) was obtained essentially by the method of Garcia Martinez (Scheme 4 4). 116 Interesti ngly, during the course of this study we attempted to synthetized 1 Iodo 1 fluorononane 1,1 diiodohexane was unreactive towards nucleophilic substitution by fluoride ion, when treated with CsF under various conditions and temperatures, or with commercial t etrabutyl ammonium fluoride. 1 Bromo 1,1 difluorohexane ( 59 ) was prepared as reported in our earlier study of its radical chemistry. 117 Scheme 4 4. Preparation of 1 bromo 1 fluorononane 58 All of the kinetic experiments were run under second order reac tion conditions, using two equivalents of nucleophile, and the rates were measured using either proton or fluorine NMR to follow the depletion of starting substrate and formation of substitution and elimination products. In all cases, the reactions, as st udied, appeared to be quantitative, since no other products could be detected by proton or fluorine NMR. In order to be able to compare most of the reactions at the common temperature of 50 o C, it was necessary to extrapolate the rate constants for very fa st or very slow reactions of some of the substrates to this temperature through the use of the Eyring equation. Rates of such reactions at two temperatures were used for this purpose.
101 Kinetics The second order character of bimolecular reactions such as S N 2 and E2 has long been recognized, since the rates of such reactions depend on the concentrations of both react ants ( A + B C ), the rate is first order for each one (Equation 4 1). In tegration of the rate expression results in a linear relation ship between l n(A o B/B o A) and time t (Equation 4 2 ) A o and B o are the initial concentrations of both reactants, while A and B are the concentrations at time t (4 1) (4 2) (4 3) Since experimentally it is usually easier to follow the reaction by the dec rease in the concentration (x) of one of the reactants, Equation.4 2 can be expressed in terms of x and the initial concentrations, A o and B o (Equation 4 3 ) Given that the reaction is first order for each reactant, the amount of x is the same in both case s. The plot between [1/( A o B o )Ln((B o (A o x))/( A o (B o x)) vs t gives the rate constant directly from the slope. This rate expression has been widely used for measuring the rate constants of second order reactions. 118 Some of the reactions presented in t his work undergo competitive substitution and elimination reactions. Since each reaction requires a 1:1 ratio between the substrate and the nucleophile/ base, the rate constant ( k obs ) derived from Equation 4 3 will be the sum of each of the individual rate constants, k SN2 and k E2 The ratio between the two products can then be used to obtain the individual rate constant s
102 Because proton or fluorine NMR was being used to measure the changes in concentration of substrate, it was necessary that the particular s tarting material and product NMR signals be sufficiently resolved to allow accurate individual integrations. Figure 4 1 shows an example of how the reaction was followed by 1 H NMR. This method led to some limitations with respect to reactions that could be studied. For this reason, rates for the reactions of alkyl iodide with azide and reactions of alkyl tosylate in DMSO could not be measured. Figure 4 1. Example of a kinetic study followed by 1 H NMR. Spectra 1 (bottom) is the reaction at t=0, while 2,3 a nd 4 are the spectra at consecutive times. Hydrocarbon Substrates Kinetic data that directly compare leaving group abilities and nucleophilicities for S N 2 reactions of alkyl halides and tosylates in protic and aprotic solvents can, of course, be found in t he old literature, but we believe that it is worthwhile to discuss these factors as they have revealed themselves in this study. The observed overall results for reactions of methoxide with n alkyl halides and tosylates are given in Scheme 4 5. As expecte d, elimination was found to compete with
103 substitution for reactions of n octyl iodide and n heptyl bromide with methoxide ion ( p K a = 15.5), but interestingly no elimination was observed when tosylate was the leaving group, either in methanol or DMSO. Sc heme 4 5. Relative amounts of substitution versus elimination in reactions of n alkyl iodide, bromide and tosylate with methoxide. Thus, based upon our admittedly limited data, tosylate, rather than halide, would seem to be the preferred leaving group for carrying out Williamson synthesis of ethers. synthesis. 119 Although reports of effective use of tosylates can be found, 120,121 including one paper involving solvent free alkylati ons that clearly showed that alkyl tosylates gave much less elimination in reactions with potassium tert butoxide than alkyl halides. 122 No trace of elimination products could be observed when using the much less basic azide ion ( p K a = 4.67). The kinetic d ata that were obtained for these reactions of non fluorinated n alkyl systems are given in Table 4 1 at 50 o C. Some of the rate constants presented in Table 4 1 are the values obtained after extrapolation of two different temperatures. See appendix B for a complete set of experiments.
104 Table 4 1. 2 nd order rate constants for n alkyl iodide, bromide and and for benzyl bromide. Expt. No Substrate Solvent Nucleophile T, o C 10 5 k 2 S N 2 10 5 k 2 E2 1 n C 8 H 17 I a CH 3 OH CH 3 O 50 6.19 0.24 0.469 0.016 4 b n C 8 H 17 I DMSO CH 3 O 50 276 41 76.8 13 5 n C 7 H 15 Br CH 3 OH CH 3 O 50 3.95 0.24 0.566 0.032 8 b n C 7 H 15 Br DMSO CH 3 O 50 116 15 40.4 1.1 9 n C 7 H 15 Br CH 3 OH N 3 50 6.89 0.064 no c 12 b n C 7 H 15 Br DMSO N 3 50 159 0 300 no 15 b n C 7 H 15 Br DMSO I 50 563 140 no 16 d n C 8 H 17 OTs CH 3 OH CH 3 O 50 12.7 0.70 no 17 d n C 8 H 17 OTs CH 3 OH N 3 50 23.8 1.0 no 18 Ph CH 2 Br CH 3 OH CH 3 O 15 13.5 0.59 e 20 b Ph CH 2 Br CH 3 OH CH 3 O 50 188 19 21 Ph CH 2 Br DMSO CH 3 O 15 10 20 74 22 Ph CH 2 Br CH 3 OH N 3 15 46.6 0.64 24 b Ph CH 2 Br CH 3 OH N 3 50 606 20 25 f Ph CH 2 Br DMSO N 3 15 7480 250 a The kinetics of reactions of n C 7 H 15 I with azide could not be studied because of overlap of relevant peaks in the proton NMR ; b These 2 nd order rate constants were approximated for comparison purposes using the Eyring equation; the given error was obtained by propagating that of the two data points; c no = not observed; d Reactions of n C 8 H 17 OTs in DMSO could not be studied kin etically because of overlap of relevant peaks in the proton NMR; e (dash) means product not possible; f approximate, single point rate constant (56.8% of substrate consumed after 30 sec) Leaving group abilities, bromide versus iodide and tosylate The relative leaving group abilities of bromide, iodide and tosylate are compared in Table 4 2. As expected, iodide is a somewhat better leaving group than bromide in reactions with methoxide. Such results are consistent with a reported study of the reaction of hydroxide with methyl iodide versus methyl bromide, where the iodide reacted slightly faster (ratio = 1.1). 123 In studies of S N 1 reactions, the difference between iodide and bromide as leaving groups is considerably greater, an example being the solvol ysis of phenylethyl iodide versus bromide in 80% ethanol at 75 o C where the rate ratio was 6.5. 124 Tosylate was a better leaving group than bromide in the methoxide/methanol reaction. To our knowledge there is no literature comparison of tosylate with brom ide in an S N 2 reaction. However, in the reaction of hydroxide with methyl bromide and mesylate in water, the mesylate was 3.6 faster. 123 In the phenylethyl solvolysis study mentioned just above, mesylate was found to be only
105 slightly poorer than tosylate (ratio = 1.2), 124 so the methanol results in Table 2.1 are more or less consistent with the literature. Table 4 2. Relative leaving group abilities in S N 2 reactions at 50 o C Substrate k rel (CH 3 O / CH 3 OH) k rel (CH 3 O /DMSO) k rel (N 3 /CH 3 OH) k rel (N 3 /DMSO ) n C 7 H 15 Br 1.0 1.0 1.0 1.0 n C 8 H 17 I 1.6 2.4 n C 8 H 17 OTs 3.2 3.5 Effect of the nucleophile, methoxide versus azide Azide is a better nucleophile than methoxide in both protic and aprotic solvents, but the difference is much greater in the aprot ic solvent (DMSO) (Table 4 3). As expected, elimination competed with substitution when methoxide was the nucleophile (Scheme 4 5), but no elimination product was observed when azide was the nucleophile. Table 4 3. Relative nucleophilicities of azide ver sus methoxide in S N 2 reactions. Substrate k rel (CH 3 OH) k rel (DMSO) n C 7 H 15 Br (50 o C) 1.7 13.7 n C 8 H 17 OTs (50 o C) 1.9 PhCH 2 Br (15 o C) 3.5 7.3 Rate of N 3 / rate constant of MeO s ignificantly greater amount of elimination observed in DMSO. Iodide was examined as a nucleophile in order to provide a comparison of our results with those of McBee. 113 It was a better nucleophile in DMSO than methoxide ( k rel = 4.9), but not as good as a zide ( k rel = 0.35). Azide was not sufficiently soluble in acetone for rates to be measured, and acetone versus ours in DMSO, acetone appears to be a slightly better solvent for S N 2 reactions of iodide ion.
106 Solvent effect, methanol versus DMSO Lastly, it is to be noted that the S N 2 reactions of both nucleophiles were much faster in DMSO than they were in methanol (Table 4 4), but rates for azide were affected more greatly than those of methoxide. Thus, as expected from previous literature reports, 125,126 the polar aprotic solvent DMSO facilitates S N 2 reactions better than does the polar protic solvent, methanol. Fuchs and Cole reported a rate ratio of 81 for the reaction of az ide with n hexyl tosylate at 40 o C for DMSO versus methanol. 125 The ratio that we observed for the analogous reaction of azide with n octyl tosylate at 50 o C was 54. Table 4 4. Relative rate constants for reactions in DMSO versus methanol Substrate Nucleophi le Temp, o C k rel n C 8 H 17 I CH 3 O 50 45 n C 7 H 15 Br CH 3 O 50 29 n C 7 H 15 Br N 3 50 231 PhCH 2 Br CH 3 O 15 76 PhCH 2 Br N 3 15 161 Rate of DMSO / rate constant of MeOH Also observed was a significant difference on the substitution/elimination competition for the two solvents, with eliminat ion being significantly more competitive in DMSO (7 13% elimination being observed in methanol as compared with 22 27% in DMSO). The rate of elimination for the reactions of methoxide with n heptyl bromide and n octyl iodide at 50 o C were 71 and 164 times faster, respectively, in DMSO than in CH 3 OH. One last insight can be gleaned from the data in Table 4 4, by comparing the rates of benzyl bromide with those of n heptyl bromide. Benzyl bromide is considerably more reactive than the primary alkyl bromide, 48 times faster in the reaction with methoxide in methanol and 88 times faster with azide the nucleophile in methanol, both at 50 o C. This
107 can be compared with a value of 78 given by Streitwieser for the reaction of iodide in ethanol. 127 Although similar comparative rate data can be found scattered throughout the early literature of nucleophilic substitution and elimination, the above data on S N 2 and E2 reactions of primary alkyl halides, to our knowledge, are not replicated in the literature, and they pro vide convenient access to quantitative information related to leaving group ability, nucleophilicity and solvent effects that can be useful for both teaching and research. Fluorinated S ubstrates Fluorinated substrates fluorine substituted substrate, n C 6 F 13 CH 2 CH 2 Br, exhibited completely different reactivity with the two nucleophiles, methoxide and azide, as seen in Scheme 4 6. In its reactions with the strong base nucleophile, methoxide, the R f CH 2 CH 2 Br substrate underwe nt exclusive elimination both in methanol and in DMSO, whereas when using weak base, strong nucleophile, azide, as the nucleophile, only substitution was observed. The rate data for this series of compounds are given in Table 4 5. Scheme 4 6. Reactions o f perfluoro n butylethyl bromide with methoxide and azide This series of reactions allows us to make a direct comparison of substitution and elimination rates of n alkyl versus perfluoro n alkylethyl bromides. The rate constants for elimination were much larger for methoxide reacting with perfluoro n butylethyl
108 bromide than for its reaction with n heptyl bromide ( k rel = 1115 in methanol at 50 o C, and 2466 in DMSO at 18 o C). Comparing the rates of substitution for n heptyl bromide with those of n C 4 F 9 CH 2 CH 2 Br at 50 o C, in methanol the hydrocarbon bromide underwent substitution 8.4 times faster than the perfluoroalkylethyl bromide, whereas in DMSO the acetone at 35 o C. 113 Th us, S N 2 chemistry can be observed relatively cleanly for perfluoroalkyethyl bromides when using a good nucleophile that is a weak base, although the presence of the perfluoroalkyl group has a significant damping effect upon the rates of substitution. On th e other hand, if the good nucleophile is also a strong base as in the case of methoxide, the rates of elimination are increased to such an extent that there appears to be little chance of observing any significant amount of substitution. Table 4 5. 2 nd or der rate constants for perfluoro n butylethyl bromide. Expt. No. Substrate Solvent Nuc T, o C 10 5 k 2 S N 2 10 5 k 2 E2 5 n C 7 H 15 Br CH 3 OH CH 3 O 50 3.95 0.24 0.566 0.032 28 c n C 4 F 9 CH 2 CH 2 Br CH 3 OH CH 3 O 50 no a 631 61 6 n C 7 H 15 Br DMSO CH 3 O 18 9.56 0.20 3 .48 0.075 29 n C 4 F 9 CH 2 CH 2 Br DMSO CH 3 O 18 no 8,580 b 9 n C 7 H 15 Br CH 3 OH N 3 50 6.89 0.064 no a 30 n C 4 F 9 CH 2 CH 2 Br CH 3 OH N 3 50 0.823 0.056 no 12 c n C 7 H 15 Br DMSO N 3 50 1590 no 33 c n C 4 F 9 CH 2 CH 2 Br DMSO N 3 50 227 71 no a no = not observed; b ca lculated on the basis that 61% of starting materi al had reacted after 30 seconds of reaction; c These 2 nd order rate constants w ere approximated for comparison purposes using the Eyring equation; the given error was obtained by propagating that of the two data points. Fluorinated substrates Scheme 4 7. Reactions of azide with perfluoro n propylmethyl bromide Substitution was the only process observed for reactions of azide with perfluoro n propylmethyl bromide in either methanol or DMSO (Scheme 4 7). However, the
109 an alogous reactions with methoxide did not lead to any observable products of substitution. No single product appeared to be formed in the methoxide reactions, elimination proce sses. There is precedent for elimination of fluoride in a related system. 128 The comparative rate data for the azide reactions can be found in Table 4 6. Table 4 6. 2 nd order rate constants for perfluoro n propylmethyl bromide Expt. No. Substrate Solven t Nuc T, o C 10 5 k 2 9 n C 7 H 15 Br CH 3 OH N 3 50 6.89 0.064 34 n C 3 F 7 CH 2 Br CH 3 OH N 3 50 6.90 0.25 x 10 4 12 a n C 7 H 15 Br DMSO N 3 50 1590 300 35 n C 3 F 7 CH 2 Br DMSO N 3 50 4.23 0.32 x 10 2 a Th is 2 nd order rate constant was approximated for comparison p urposes using the Eyring equation; the given error was obtained by propagating that of the two data points. The rates for S N 2 substitution of perfluoro n propylmethylbromide by azide were tremendously inhibited by the proximity of the perfluoroalkyl grou p, undergoing reaction at 50 o C almost 10,000 times slower in methanol and more than 37,000 times slower in DMSO. Fluoro substrate Scheme 4 8. Reactions of 1 bromo 1 fluorononane with methoxide and azide. As indicated by the data given in Table 4 7, a single fluorine substituent at the position inhibits substitution while accelerating elimination, although both effects are
110 modest. These effects combine to give rise to exclusive elimination when MeO is used as nucleophile/base, and to exclusive substitution when N 3 is used (Scheme 4 8). Table 4 7. 2 nd order rate constants for 1 bromo 1 fluorononane. Expt. No. Su bstrate Solvent Nuc T, o C 10 5 k 2 S N 2 10 5 k 2 E2 5 n C 7 H 15 Br CH 3 OH CH 3 O 50 3.95 0.24 0.566 0.032 36 n C 8 H 17 CHFBr CH 3 OH CH 3 O 50 no a 1.10 0.02 8 b n C 7 H 15 Br DMSO CH 3 O 50 116 15 40.4 1.1 37 n C 8 H 17 CHFBr DMSO CH 3 O 50 no 50.5 2.6 9 n C 7 H 15 Br CH 3 OH N 3 50 6.89 0.064 no 38 n C 8 H 17 CHFBr CH 3 OH N 3 50 1.42 0.04 no 12 b n C 7 H 15 Br DMSO N 3 50 1590 300 no 41 b n C 8 H 17 CHFBr DMSO N 3 50 226 5.3 no a no = not observed; b These 2 nd order rate constants were approximated for comparison purposes using the Eyring equation; the given error was obtained by propagating that of the two data points. Substitution of 1 bromo 1 fluorononane by azide ion, on the other hand, was modestly slower than of 1 bromoheptane, the non fluorine substituted compound undergoing reaction 4.9 times faster in methanol and 7.0 times faster in DMSO than its fluoro analog. The azide substitution reaction of the 1 bromo 1 fluoroalkane is 159 times faster in DMSO than it is in methanol. No product deriving from replacement of fluoride was observed for either the elimination or the substitution reactions. D ifluoro substrate Scheme 4 9. Reactions of 1 bromo 1,1 difluorohexane with methoxide and azide. No substitution involving displacement of bromide from the CF 2 Br group of 1 bromo 1,1 difluorohexane by either methoxide or azide ion was observed in either
111 solvent, and for the first time, when the reaction was carried out in DMSO, azide was observed to give rise to exclusive elimination (Scheme 4 9). Whereas substitution was strongly inhibited, elimination was enhanced. The rate elimination of n pentyl CF 2 Br was enhanced relative to that of n alkyl bromide, loss of HBr occurring 4.4 times faster in methanol and 59 times faster in DMSO at 50 o C. With no substitution being observed for the reaction of azide in methanol after 20 days at 50 o C, it was possi ble to calculate a maximum rate for the S N 2 process if one assumed that one could detect a minimum of 0.5% of product in Expt. No. 47. Therefore the S N 2 reaction at a CF 2 Br site is calculated to be at least 13,000 times slower than that at a CH 2 Br site of a primary alkyl bromide. Table 4 8 2 nd order rate constants for 1 bromo 1,1 difluorohexane. Expt. No. Substrate Solvent Nuc T, o C 10 5 k 2 S N 2 10 5 k 2 E2 5 n C 7 H 15 Br CH 3 OH CH 3 O 50.0 3.95 0.24 0.566 0.032 42 n C 5 H 11 CF 2 Br CH 3 OH CH 3 O 50.0 no a 2.50 0.016 8 b n C 7 H 15 Br DMSO CH 3 O 50.0 116 40.4 43 n C 5 H 11 CF 2 Br DMSO CH 3 O 15.5 no 225 6.7 44 n C 5 H 11 CF 2 Br DMSO CH 3 O 20.5 no 328 11 45 b n C 5 H 11 CF 2 Br DMSO CH 3 O 50.0 no 2380 660 9 n C 7 H 15 Br CH 3 OH N 3 50.0 6.89 0.064 no 46 c n C 5 H 11 CF 2 Br CH 3 OH N 3 50 .0 <5.2 x 10 4 no 12 b n C 7 H 15 Br DMSO N 3 50.0 1590 300 no 47 n C 5 H 11 CF 2 Br DMSO N 3 50.0 no 1.55 0.037 a no = not observed; b These 2 nd order rate constants were approximated for comparison purposes using the Eyring equation; the given error was obt ained by propagating that of the two data points; c No reaction was observed after 20 days at 50 o C; the maximum rate was approximated by assuming that 0.5% of product could have been detected. Fluorinated benzylic bromides Scheme 4 10. Reactions of brom odifluoromethylbenzene with methoxide and azide.
112 difluoroalkyl compound was not possible, even with the weak base strong nucleophile N 3 Only elimination was seen for this material. This demonstrates, so far, how big the effect of close by fluorines is in an S N 2 reaction. Nuc leophilic substitution at the CF 2 Br site of PhCF 2 Br has been reported, 110 and thus a study of this system where elimination cannot compete should be able to provide a more exact measure of the difference in S N 2 reactivity of a CF 2 Br versus a CH 2 Br site. In fact, both methoxide and azide were found to be effective nucleophiles in their reactions with PhCF 2 Br (Scheme 4 10). Table 4 9. 2 nd order rate constants for bromodifluoromethylbenzene. Expt. No. Substrate Solvent Nuc T, o C 10 5 k 2 S N 2 20 a PhCH 2 Br CH 3 OH C H 3 O 50 188 46 48 PhCF 2 Br CH 3 OH CH 3 O 50 4.29 30 x 10 3 21 PhCH 2 Br DMSO CH 3 O 15 1020 74 49 PhCF 2 Br DMSO CH 3 O 60 1.25 0.045 50 PhCF 2 Br DMSO CH 3 O 50 0.549 0.024 51 a PhCF 2 Br DMSO CH 3 O 15 1.96 0.58 x 10 2 24 a PhCH 2 Br CH 3 OH N 3 50 606 2 0 52 PhCF 2 Br CH 3 OH N 3 50 8.88 0.32 x 10 3 25 b PhCH 2 Br DMSO N 3 15 7480 250 53 PhCF 2 Br DMSO N 3 60 2.34 0.11 54 PhCF 2 Br DMSO N 3 50 1.06 0.058 55 a PhCF 2 Br DMSO N 3 15 4.35 1.8 x 10 2 a These 2 nd order rate constants were approximated for c omparison purposes using the Eyring equation; the given error was obtained by propagating that of the two data points; b approximate, single point rate constant (56.8% of substrate consumed after 30 sec) Table 4 10. Relative rates for S N 2 reactions of PhC H 2 Br versus PhCF 2 Br. Nucleophile Solvent Temp., o C k rel (CH 2 Br/CF 2 Br) CH 3 O CH 3 OH 50 43,800 CH 3 O DMSO 15 52,000 N 3 CH 3 OH 50 68,200 N 3 DMSO 15 172,000 From the data in Table 4 10, as well as in Table 4 8, one can see that the presence of two fluorines provides a formidable inhibition of S N 2 chemistry, such that
113 E2 chemi stry will exclusively dominate, except in those cases, such as in the benzyl system, where E2 is not possible. Computational R esults In the experimental part of this paper, we have quantified the effect that near by fluorines have on raising the S N 2 activa tion barrier, as well as their effect of lowering the E2 energy A recent computational paper by Liu et al. examined the effect of substituents on the S N 2 energy barrier 129 Examining 54 different structures using CH 3 Cl as a reference and fluoride as a nuc leophile, Liu broke down the observed effects into three contributions ( Equation 4 4 ), comprising the steric, the quantum, and electrostatic contribution. d by the Weizsack er kinetic energy, the quantum effect corresponds mainly to the exchange correlation contribution, whereas the electrostatic effect is defined by a combination of a) nuclear electron attraction, b) classical electron electron Coulomb repulsion and c) nucl ear nuclear repulsion energies. (4 4) exchange of one hydrogen on the CH 3 Cl by almost any other group leads to an increase in the energy barrier due to an increase in steric i nteractions, but that this is compensated by a decrease due to the quantum effect, with the result that the observed net overall increase in barrier is due largely to the impact of increasing electrostatic effect Liu finds that fluorine substituents do not fit this generalization. He does find that the substitution of hydrogens by one or more fluorines increases the energy barrier, but
114 the steric effect was found to decrease significantly for each hydrogen/fluorine replacement, with this decrease being com pensated now by an equivalent increase in barrier from the quantum effect. Again, the net result was that the overall increase in energy barrier derived largely from the incremental increases in the electrostatic effect as one replaced hydrogen with fluori ne, the largest contribution to this increase being the classical electron electron Coulomb repulsive interaction. In our computational study of the impact of fluorine on S N 2 and E2 transition state energies, we examined a series of model reactions involvi ng hydroxide acting either as a nucleophile or a base (Scheme 4 11). Scheme 4 11. Model structures used in the quantum chemical calculations The quantum chemical calculations were performed at MP2/6 31+G(d,p) LANL2DZ level of theory using DMSO as a sol vent, with the transition states being characterized by one and only one negative frequency and the Intrinsic Reaction Coordinate connecting both the starting material and the product. All the calculations
115 were performed using Gaussian 03 Software packag e 92 Table 4 11 presents the and some relevant geometrical data for the S N 2 transition state (TS) for the alky l iodide substrates with hydroxide as nucleophile Table 4 11. Relevant geometrical data and calcul ated energy barriers at the transition state for the S N 2 reaction between alkyl iodide substrates and hydroxide Substrate O C () a C I () b n C 3 H 7 I 2.22 2.54 40.5 0 19.24 CF 3 C 2 H 4 I 2.17 2.52 43.03 19.65 C 2 F 5 CH 2 I 2.13 2.50 39.24 25.92 C 2 H 5 CHFI 2.24 2.58 54.4 0 19.74 C 2 H 5 CF 2 I 2.31 2.70 62.2 0 29.17 \ a Oxygen Carbon center bond length; b Carbon center Iodide bond length; c Calculated energy barrier in kcal/mol Looking at the last column of Table 4 11, it is seen that all of the substi tution reactions are exothermic, as expected. Whereas the enthalpies of the and non fluorinated substrates do not differ greatly, those of the fluorinated substrates are stabilization derives from increased fluorine substitution on a carbon. 130 Similarly, it would be expected that the presence of an electronegative oxygen substituent on the same carbon as a fluorine or two fluorine substituents will provide significant st abilization to the molecule due to a hyperconjugative interaction of the type O(LP) F). Experimentally we found that the magnitude of the activation barrier for the S N 2 reaction using azide as a nucleophile had the following trend: n C 7 H 15 Br < n C 4 F 9 CH 2 CH 2 Br ~ n C 8 H 17 CHFBr << n C 3 F 7 CH 2 Br < n C 5 H 11 CF 2 Br. The calculated activation ba rriers shown in Table 4 11 for hydroxide acting as a nucleophile follow the
116 same trend, which is consistent with the experimental observation that the presence of fluorines near the reactive si t e increases the energy barrier. The increment al changes in the values found in the calculations can be unde rstood in two ways. First, t he partial positive charge that is generated at the carbon center of an S N 2 transition state should be inductively destab ilized by the an increase of the energy barrier. In the case fluorines this partial positive charge might be partially stabilized (by electron which brings u s to the second factor Taking into electrosta tic repulsive interactions between the incoming nucleophile and the electron clouds of the near by fluorines should increase the activation energy, with this effect being largest for the gem difluoro substrates As seen in Table 4 11, this repulsive effect due to the fluorines appears to give rise to larger distances between the nucleophile and the carbon center at the TS for the fluorinated molecules than for the n on fluorinated standard: C 2 H 5 CF 2 I > C 2 H 5 CHFI > n C 3 H 7 I. At the same time the length of the carbon i odi ne leaving group bond is also larger than th at for the non fluorinated substrate, which is consistent with the loss of the Iodide being assisted fluorines stabilizing the partial posit ive charge at the carbon center. The net increase in ba rrier indicates that the repulsive effect outweighs the stabilizing effect, slightly for the mono fluoro and greatly for the substrates with two fluorine substituents. Evidence for the stabilization of the partial positive charge by fluorines in the transition state is seen by comparison of the bond length s between the f luorine and the carbon center in the transition state s of the fluoro substrates. They are shorter than
117 those in the respective ground state s i.e. C F() changes from 1.42 to 1.36 for the reaction of C 2 H 5 CHFI and from 1.38 to 1.32 for the reaction of C 2 H 5 CF 2 I. Further insight can be obtained by looking at the geometry of the transition state for the reaction of C 2 H 5 CHFI, where the OH nucleophile is seen to approach the carbon center from an angle hydrogen than to the fluorine (Figure 4 2) This could be interpreted as the nucleophile avoiding the repulsive interaction fluorine. Figure 4 2. Two perspectives of the calculated transition state of the S N 2 reaction of hydro xide with CH 3 CH 2 CHFI Such avoidance would not be possible for the difluoro compound with the result that it would have a much higher activation barrier, whereas the monofluoro compound would only be slightly less reactive than the fluorine free com pound. Du ring the experimental study, it was found that methoxide acted exclusively as a base in reactions with all of the f luoro compounds where E2 was possible. Such results undoubtedly derive from a combination of two effects First, t he barriers for the potentially competitive S N 2 reaction s are increased when fluorine is present and secondly, the acidities of those hydrogens that are vicinal to fluorines are increased, such that the activation barrier s for the ir E2 process es are lower ed. This combination of
118 slowing down the S N 2 and enhancing the E2 reactions can explain the experimental results Table 4 12. Relev ant geometrical data and calculated energy barriers at the transition state for the E2 reaction between alkyl iodide substrates and hydroxide as base. Substrate O H () a H C () b C C () c C I () d C 3 H 7 I 1.33 1.31 1.43 2.43 36.41 19.87 CF 3 C 2 H 4 I 1.27 1.35 1.48 2.24 32.19 3.86 C 2 H 5 CHFI (E) 1.30 1.32 1.43 2.39 33.33 11.56 C 2 H 5 CHFI (Z) 1.31 1.32 1.43 2.39 33.63 11.67 C 2 H 5 CF 2 I 1.28 1.34 1.43 2.32 28.35 7.93 a Oxygen Hydrogen bond length (new OH bond); b Hydrogen Carbon bond length (Br eaking bond); c Carbon Carbon bond length (new double bond); d Carbon Iodide bond length (Breaking bond); e Calculated energy barrier in kcal/mol The quantum chemical calculations as represented in Table 4 12, support these conclusions Experimentally, difluoroalkyl bromide ha s such a high energy barrier for the S N 2 reaction, that even azide would prefer to behave a s a base albeit at a slow rate. The highest for substitution was 29.17 kcal/mol, which was for the 1,1 difluoro compound. Even with such a relatively high barrier, it seems reasonable that this reaction would have occurred were it not for the relative ease of the elimination reaction. Comparing values from Tables 4 11 and 4 12 one can see that for each of the reactions of fluorinated compounds where elimination is possible, the energy barrier for the E2 process is much lower than that for S N 2. The calculated trend for the activation barrier in the E2 reaction decrease s as follows: C 3 H 7 I > C 2 H 5 CHFI > C 2 H 5 CF 2 I > CF 3 C 2 H 4 I, which is consistent with the observed experimental trend. From the data in T able 4 12 it is possible to glean other interesting insight Although both CF 3 C 2 H 4 I and C 2 H 5 CF 2 I have multiple fluorines in the position with respect to the abstracted hydrogen the barrier to elimination o f the CF 2 I compound is double that of CF 3 C 2 H 4 I. We believe that this is due to the fact that in the
119 transition state for the elimination of CF 3 C 2 H 4 I one of the fluorine s from the CF 3 group have a dihedral angle of almost 180 o with respect to the hydrogen that is being removed. Thus, in addition to the inductive stabilization that the CF 3 group provides, there is hyperconjugative stabilization of this transition state, with interaction of the orbital of the anti C F bond In contrast, looking at the transition state for elimination from C 2 H 5 CF 2 I, both fluorines are skewed at a dihedral angle of about 60 o from the breaking C H bond, which means tha t these fluorines can only provide inductive stabilization of the developing negative charge on this carbon. All of the elimination transition states were characterized computationally as E2 processes H owever, one can values have the l ongest C H bond length s and least C C double bond character base d on bond length of the forming double bond and the shortest C I bond length These results suggest a highly unsymmetrical bimolecular elimination consistent with E 1 cb character The el imination of HI from the mono fluoro C 2 H 5 CHFI can result in formation of either cis ( Z ) and t rans ( E ) products. The calculated energy barriers for these reactions were found to be very similar, and this c orrelates with the almost 1:1 ratio observed experi mentally. Finally, the enthalpy of reactions presented on Table 10 2 help to support the proposed hyperconjugative interaction of the type O(LP) F) s ince there is not an OMe group attached in any of products, the enthalpy of the reaction does not chan ge as much as in Table 4 11. The data presented in Table 4 12 clearly supports that the Elimination vs Substitution is dominated by the transition state since all substituted
120 products are more stable than the eliminated ones. The Z product is slightly more stable than the E product for the C 2 H 5 CHFI compound, which is known due to the slightly Experimental Section Synthesis of 1 bromo 1 fluorononane (58) : In the following order 170 mL of anhydrous CH 2 Cl 2 5.1 mL (28.1 mmol, 1 equiv., 95%) of n onanal and 3.9 mL (33.7 mmol, 1.2 equiv.) of 2,6 lutidine were placed into a 250 mL round bottom ed flask. The mixture was then cooled down to 5 5 mL (56.2 mmol, 2 equiv.) of triflic anhydride in 20 m L of anhydrous CH 2 Cl 2 were added dropwise to t he reaction mixture over a period of 45 min. The reaction was stirred for 7h at 0 was then placed in the refrigerator (0 17 hours. The relatively dilute nonanal solution, the presence of the base and the slow addition of triflic anh ydride were important in order to obtain good yield in this reaction; otherwise a polymer is obtained as a major product. The solvent was removed and the dark remaining mixture was extracted with pentane (4 x 100 mL). The polyme r is insoluble in pentane. The o rganic layer was washed with aqueous HCl 1.2 M (2 x 100 mL), followed by concentrated aqueous NaHCO 3 (2 x 100 mL) and then brine (1 x 100 mL). The solution was dried over MgSO 4 filtered, and the solvent removed to give a dark yellow oil, 9.5 g, 80% y ield of the geminal bis triflate ( by NMR ) This material was used without further purification for the following step. Once the solvent is removed, the product should be kept in the refrigerator, since it not stable neat at room temperature The bis trifl ate ( 9.5 g 22.5 mmol, 1 equiv.) along with 150 mL of anhydrous CH 2 Cl 2 were placed in a 250 mL round bottom ed flask. The mixture was then cooled to 0 and 22.5 mL of TBAF 1M solution in THF (22.5 mmol, 1 e quiv.) were added and
121 stirred f or 12 h at 0 g (45 mmol, 2 equiv.) of tetrabutylammonium bromide were added and stirred at room temperature for 16 hours more The solvent was th en removed and the remaining oil y material was filtered through silica gel using pentane as a solvent. The solvent was removed and a second column in pentane was run to obtain 68% of product. The result is a mixture of 88% 1 bromo 1 fluorononane ( 58 ) and 1 2% 1,1 difluorononane which was used for the kinetic experiments as is. 1 H NMR ( CDCl 3 ) 6.36 6.53 (dt, 2 J HF = 50.7 Hz 3 J HH = 5.3 Hz 1H, C H F ), 2.00 2.45 (m 2H, CH 2 ), 1.20 1.75 (m 14H, CH 2 ), 0.89 (t 3H, CH 3 ); 19 F NMR (CDCl 3 ) 130.65 (ddd, 2 J HF = 50.3 Hz, 3 J HH = 20.5 Hz, 3 J HH = 18.2 Hz 1F ); 13 C NMR (CDCl 3 ) 95.9 (d, 1 J CF =252.5 H z C HF), 40.9 (d, 2 J CF =18.7 Hz CH 2 ( C HF)), 32.02 (CH 2 ), 29.56 (CH 2 ), 29.33 (CH 2 ), 28.91 (CH 2 ), 25.30 (CH 2 ), 22.86 (CH 2 ), 14.29 (CH 3 ); HRMS: Calc. 223.0503 ((M H) + ). Found 223.0489 ((M H) + ). 1 Octyl Tosylate (55) was prepared according to the literature 11 5 spectra were consistent with those in the literature 131 General P rocedu re for the Kinetic E xperiments Stock solutions of NaN 3 Na OMe and NaI ( 0.6 M in MeOH d 4 and DMSO d 6 ) were prepared prior to the kinetics experimen ts. For kinetic experiments bel ow room temperature, 0.75 mL of the required 0.6M stock solution, and 5 10 mg of internal standard (t oluene for 1 H NMR and t rifluorotoluene for 19 F NMR) were placed into an NMR tube and the tube cooled to the desire d temperature inside the NMR instrume nt. Then, 0.22 mmols of substrate previously dissolved in 0.25 mL of deuterated solvent were added to the NMR tube. The reaction was then followed by measurement of the decrease of one particular NMR signal with respect to the internal standard up to 30%
122 o f the reaction. For kinetic experiments above room temperature, 0.22 mmol of substrate in 0.25 mL of deuterated solvent were placed into an NMR tube, and then 0.75 mL of the corresponding 0.6M stock solution and 5 10 mg of internal s tandard were added. Th e NMR tube was warmed to the desired temperature and the reaction followed by NMR up to 30% of the reaction. Computational M ethods The quantum chemical calculations were performed with a hybrid basis set at MP2/6 31+G(d,p) LANL2DZ level of theory The eff ective core potential (ECP) of iodide was included in the calculations in order to minimize the time in the optimization. DMSO was used as a solvent in all calculations using the Polarizable Continuum Model (PCM). T he transition states were characterized b y one and only one negative frequency and the Intrinsic Reaction Coordinate (IRC) connecting both the starting material and the product. All the calculations were performed using Gaussian 03 Rev. E01 Software package 92
123 CHAPTER 5 CONCLUSIONS The role of fluorine in three areas has been evaluated. All three fields are consistent with the fact that fluorine brings very interesting chemistry and behavior to the molecules it is part of. We had the opportunity to work with fluorine synthetically, theoretica lly and kinetically and the conclusions have been divided into each individual area. Fluorine as Pentafluorosulfanyl Group in Furazan Energetic Materials The role of fluorine as p entafluorosulfanyl group in furazan energetic material was evaluated. Ten ne w energetic materials have been synthesized and characterized by the usual spectroscopic methods. An SF 5 acetyl building block was chosen, and the best reaction conditions to incorporate this group into aminofurazans were established. Eight of these materi als are SF 5 furazan based one being tetrazole based and t he last one does not contain an SF 5 group. The chemical and physical properties of the SF 5 and furazan groups, such as high density and good thermal and chemical stability, have been combined with g ood results. Good thermal stabilities and high densities are the two most important properties possessed by the SF 5 furazan based energetic materials. Their general level of performance was better than that of the baseline compound and of other previously synthesized SF 5 containing energetic materials. D uring the course of this project small scale reactions were utilized and there were no issues or accidents encountered while working with the final products. They proved to be stable under the laboratory co nditions that were used. The SF 5 group proved to be very stable under strong oxidizing conditions, but the electron withdrawing
124 ability of the furazan group makes the SF 5 acetyl or SF 5 urea functionalities good ability to isolate such derivatives. The lack of nucleophilicity of the aminofurazans was the most serious problem that we encountered within this project. The electron withdrawing ability of the furazan ring made the functionalization of the amino group s very challenging, and at times impossible. Solubility issues also presented a serious synthetic obstacle when trying to make many of the furazan derivatives. Based on the ir high density, good thermal and chemical stability, and the performance results o f these compounds as calculated by Cheetah, we believe that this new class of high density energetic materials creates much potential for future benefit to the field of high energy, high density materials. For these reasons we think is important to contin ue research on this new class of materials. Although the SF 5 acetyl building blocks are reactive enough for the functionalization of the aminofurazans, it is important to redesign the aminofurazans in such a way that the amino group (or alcohol) is separat e d by at least one carbon from the furazan group. This should help with both types of problems that we encountered, the nucleophilicity of the amino group and the stability of the new derivatives (amides, ureas, esters or carbamates). Finally, the high flu orine content, along with the low hydrogen content of these new compounds, as well as the presence of sulfur, allow these materials the possibility of in order to dete rmine quantitatively which gases are actually released when the materials are detonated.
125 Fluorine and Its Impact on Long Range Coupling Constants The results presented in this work show the important structural information that can be obtained by performin g a detailed analysis of long range J FF coupling constants in mono substituted perfluoro[2.2]paracyclophanes. In particular, OMe and Et 2 N substituents were taken as a model compounds to study, from a theoretical point of view, the influence of a skewed geo metry on the 4 J FF and 5 J FF couplings It was found that the 4 J FF Spin Spin Coupling Constants (SSCCs) are due to the through space transmission of the FC term by the contact of the orbital clouds of the interacting fluorines and they are strictly distanc e dependent. On the other hand, the 5 J FF SSCCs are also transmitted through the space but with the help of an intermediate moiety. To this end, the FCCP CMO approach was applied to rationalize the unusual trends observed for the FC term of such couplings The angle by which the orbitals interact seemed to be in this case the most important fact or in determining the coupling transmission. When the substituent on F8 was H, it was found that the preferential conformation f the substituent is not the only interaction determining the conformation of the type of monosubstituted perfluoroparacyclophanes studied in this work. Apparently, an important role determining such conformation is played by an attractive interaction betw een the available lone pairs on the heteroatoms and fluorines on Fluorine and Its Impact on S N 2 and E2 Reactions An experimental measure of the quantitative effect of proximate fluorine substituents on the rates of S N 2 and E 2 reactions has been ob tained. The study was comprised mainly of reactions of fluorinated n alkyl bromides with weak base, strong
126 nucleophile azide ion and strongly basic nucleophile methoxide ion in the protic solvent methanol and the aprotic solvent, DMSO. The order of reacti vity for S N 2 reactions of azide in methanol at 50 o C was n alkyl Br > n alkyl CHFBr > n perfluoroalkyl CH 2 CH 2 Br >> n perfluoroalkyl CH 2 Br > n alkyl CF 2 Br, with approximate relative rates of reaction being: 1, 0.20, 0.12, 1 x 10 4 7.7 x 10 5 The order of r eactivity for E 2 reactions was n perfluoroalkyl CH 2 CH 2 Br >> n alkyl CF 2 Br > n alkyl CHFBr > n alkyl Br, with the approximate relative rates for reaction of methoxide in methanol at 50 o C being: 1100, 4.4, 1.9, 1. It appears that the detrimental effect of fl uorine substituents on S N 2 reactions derive from two main effects: their electron withdrawing inductive effect, which destabilizes the partial positive charge that develops at the carbon center undergoing substitution, and the electrostatic repulsive influ ence of (particularly substituted) fluorine lone pairs on the approaching nucleophile. The rate enhancing effect of fluorine substituents on E 2 reactions appears to be largely due to their C H acidifying influence, which derives from two factors: their a forementioned inductive effect, and when geometry allows, their powerful hyperconjugative stabilization of developing negative charge.
127 APPENDIX A SF 5 ENERGETIC MATERIALS Figure A 1. TGA DSC compound 27 Figure A 2. TGA DSC compound 28
128 Figure A 3. TGA DSC compound 50 Figure A 4. TGA DSC compound 29
129 Figure A 5. TGA DSC compound 30 Figure A 6. TGA DSC compound 31
130 Figure A 7. TGA DSC compound 32 Figure A 8. TGA DSC compound 48
131 Figure A 9. TGA DSC compound 49 Figure A 10. TGA DSC compound 41
132 APPENDIX B FLUORINE ON S N 2 AND E2 REACTIONS Table B 1. Complete data for the 2 nd order rate constants for n alkyl iodide, bromide and tosylate and for benzyl bromide Expt. No Substrate Solvent Nucleophile T, o C 10 5 k 2 S N 2 10 5 k 2 E2 1 n C 8 H 17 I a CH 3 OH C H 3 O 50 6.19 0.24 0.469 0.016 2 n C 8 H 17 I DMSO CH 3 O 23 35.7 1.4 9.53 0.42 3 n C 8 H 17 I DMSO CH 3 O 33 79.3 3.7 21.5 1.1 4 b n C 8 H 17 I DMSO CH 3 O 50 276 41 76.8 13 5 n C 7 H 15 Br CH 3 OH CH 3 O 50 3.95 0.24 0.566 0.032 6 n C 7 H 15 Br DMSO CH 3 O 18 9.56 0.20 3.48 0.075 7 n C 7 H 15 Br DMSO CH 3 O 23 14.6 0.064 5.29 0.009 8 b n C 7 H 15 Br DMSO CH 3 O 50 116 15 40.4 1.1 9 n C 7 H 15 Br CH 3 OH N 3 50 6.89 0.064 no c 10 n C 7 H 15 Br DMSO N 3 18 101 3.4 no 11 n C 7 H 15 Br DMSO N 3 23 162 3.5 no 12 b n C 7 H 15 Br DMSO N 3 50 1590 300 no 13 n C 7 H 15 Br DMSO I 25 61.8 2.6 no 14 n C 7 H 15 Br DMSO I 30 99.0 3.7 no 15 b n C 7 H 15 Br DMSO I 50 563 140 no 16 d n C 8 H 17 OTs CH 3 OH CH 3 O 50 12.7 0.70 no 17 d n C 8 H 17 OTs CH 3 OH N 3 50 23.8 1.0 no 18 Ph C H 2 Br CH 3 OH CH 3 O 15 13.5 0.59 e 19 Ph CH 2 Br CH 3 OH CH 3 O 25 30.5 1.8 20 b Ph CH 2 Br CH 3 OH CH 3 O 50 188 19 21 Ph CH 2 Br DMSO CH 3 O 15 1020 74 22 Ph CH 2 Br CH 3 OH N 3 15 46.6 0.64 23 Ph CH 2 Br CH 3 OH N 3 25 103 1.4 24 b Ph CH 2 Br CH 3 OH N 3 50 606 20 25 f Ph CH 2 Br DMSO N 3 15 7480 250 a The kinetics of reactions of n C 7 H 15 I with azide could not be studied because of overlap of relevant peaks in the proton NMR; b These 2 nd order rate constants were approximated for compar ison purp oses using the Eyring E quation; the given error was obtained by propagating that of the two data points; c no = not observed; d Reactions of n C 8 H 17 OTs in DMSO could not be studied kinetically because of overlap of relevant peaks in the proton NMR; e (d ash) means product not possible; f approximate, single point rate constant (56.8% of substrate consumed after 30 sec)
133 Table B 2. Complete data for the 2 nd order rate constants for perfluoro n butylethyl bromide. Expt. No. Substrate Solvent Nuc T, o C 10 5 k 2 S N 2 10 5 k 2 E2 5 n C 7 H 15 Br CH 3 OH CH 3 O 50 3.95 0.24 0.566 0.032 26 n C 4 F 9 CH 2 CH 2 Br CH 3 OH CH 3 O 10 no a 45.3 1.0 27 n C 4 F 9 CH 2 CH 2 Br CH 3 OH CH 3 O 20 no 93.5 2.2 28 c n C 4 F 9 CH 2 CH 2 Br CH 3 OH CH 3 O 50 no 631 61 6 n C 7 H 15 Br DMSO CH 3 O 18 9.56 0.20 3 .48 0.075 29 n C 4 F 9 CH 2 CH 2 Br DMSO CH 3 O 18 no 8,580 b 9 n C 7 H 15 Br CH 3 OH N 3 50 6.89 0.064 no a 30 n C 4 F 9 CH 2 CH 2 Br CH 3 OH N 3 50 0.823 0.056 no 12 c n C 7 H 15 Br DMSO N 3 50 1590 no 31 n C 4 F 9 CH 2 CH 2 Br DMSO N 3 18 8.530 .31 no 32 n C 4 F 9 CH 2 CH 2 Br DMSO N 3 23 14.9 0.64 no 33 c n C 4 F 9 CH 2 CH 2 Br DMSO N 3 50 227 71 no a no = not observed; b calculated on the basis that 61% of starting material had reacted after 30 seconds of reaction; c These 2 nd order rate constants were approximated for comparison purpo ses using the Eyring Equation ; the given error was obtained by propagating that of the two data points.
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141 BIOGRAPHICAL SKETCH Henry Martinez was born in Cali, Colombia. He received his B.S. in chemistry from Universidad del Valle in 2006 with an outstanding undergraduate research award. He came to study his Ph.D. in chemistry at the University of Florida under the supervision of Professor William R. Dolbier, Jr. in 2007, and will receive his Ph.D. in December 2011. Henry married his lovely wife P aula, in Church in December of 2009.