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Syntheses and Studies of Perfluoroalkyl Substituted Compounds

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Title:
Syntheses and Studies of Perfluoroalkyl Substituted Compounds
Creator:
POOPUT, CHAYA ( Author, Primary )
Copyright Date:
2008

Subjects

Subjects / Keywords:
Aldehydes ( jstor )
Disulfides ( jstor )
Imines ( jstor )
Iodides ( jstor )
Ketones ( jstor )
Kinetics ( jstor )
Nuclear magnetic resonance ( jstor )
Phenyls ( jstor )
Room temperature ( jstor )
Sulfides ( jstor )

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Source Institution:
University of Florida
Holding Location:
University of Florida
Rights Management:
Copyright Chaya Pooput. Permission granted to University of Florida to digitize and display this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Embargo Date:
7/30/2007
Resource Identifier:
74493193 ( OCLC )

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Full Text












SYNTHESES AND STUDIES OF PERFLUOROALKYL SUBSTITUTED
COMPOUNDS
















By

CHAYA POOPUT


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


2005



























This dissertation is dedicated to my parents, Chatchawan and Payom Pooput.















ACKNOWLEDGMENTS

I express my deep gratitude to my advisor (Dr. William R. Dolbier, Jr.).

Throughout the years I have spent in his laboratory, I was able to acquire invaluable

knowledge to help me achieve my goals. Without his ideas, guidance and support, I

would not have been able to complete my research. I thank Dr. Samia Ait-Mohand for

helping me get started in research in my first year. I thank Dr Dolbier's group members

for their help. I thank David Duncan for helping me in experiments on TDAE analogue

project. I thank the Chemistry Department of the University of Florida for accepting me

in the graduate program. I thank all my friends, especially Valerie, Igor, Rachel, Rafal,

Janet, Jim, Gary, Rong and Hongfang for their support and friendship. I would like to

thank again Valerie for always being here for me, for cheering me up when I was down

and for sharing with me most of the wonderful moments I have in Gainesville. I also

thank Valerie's parents (Vale and Iris) for welcoming me in their home in Puerto Rico

and for giving me warmth and love that make me feel like I was a part of their family. I

thank Valerie's big family in Puerto Rico, Sonia, Mia, Nilda, Nelson and Nydia for their

love. I also thank my aunt Wanee for her support and love when I was in France. I thank

my sister for being who she is and for her love. Finally I am eternally grateful to my

parents. Because of their sacrifices, I was able to achieve this high level of education.

Their constant support and love gave me strength.
















TABLE OF CONTENTS

page

A C K N O W L E D G M E N T S ......... ...................................................................................... iii

LIST OF TABLES ........ ... .................................. ........ .. .................. viii

LIST OF FIGURES ............................... ... ...... ... ................. .x

LIST OF SCHEMES .......... .................................. ....... ....... xiii

ABSTRACT ........ .............. ............. ...... ...................... xvi

CHAPTER

1 IN TR O D U C TIO N ........................ .... ........................ ........ ..... ................

1.1 G general Inform ation .......................................................... ............... 1
1.2 P reviou s W ork ................... .... .......................... .. ......... ............ ..
1.2.1 Starting Point .......................................... ...... .... ........ .... .3
1.2.2 Preliminary Results in the Group.......................................4
1.2.3 New and Efficient Method for Synthesis of Trifluoromethyl
S u lfid e s .............................. ......................... ................ 5
1.2.4 New and Efficient Method for Synthesis of Trifluoromethyl
Selenides ............................................................. ............... 10

2 SYNTHESIS OF PERFLUOROALKYL THIO AND SELENOETHERS ..........12

2 .1 Introdu action .............................................. ........... ................ 12
2.2 Synthesis of Pentafluoroethyl Thioethers ............................................14
2.3 Synthesis of Pentafluoroethyl Selenoethers.............................................16
2.4 Synthesis of Perfluorobutyl Thioethers ...................................................17
2.5 Synthesis of Perfluorobutyl Selenoethers ............................................... 19
2.6 Conclusion ......................................... ................... .... ...... 19
2 .7 E xperim ental ................... .................. ...... ..... .......... .. .. ..... .....20
2.7.1 General Synthesis ofPentafluoroethyl Thio and Selenoethers :
Synthesis of Phenyl Pentafluoroethyl Sulfide.............................20
2.7.2 General Synthesis ofNonafluorobutyl Thio and Selenoethers :
Synthesis of Phenyl Nonafluorobutyl Sulfide.............................22










3 PERFLUOROALKYLATION OF IMINE TOSYLATES...............................25

3 .1 Intro du action ....... .. .... .. .. ...... ..................... ....................2 5
3.2 Synthesis of Tosyl Im ines........................................... ......................... 28
3.3 Pentafluoroethylation of Tosyl Imines...........................................29
3.4 Perfluorobutylation of Tosyl Im ines.................................. ... ..................31
3 .5 C o n c lu sio n ........................................................................................... 3 3
3.6 E xperim mental ............................ .. .... .............. ............... ............ 33
3.6.1 Syntheses of Tosyl Imines ............................ ...............33
3.6.2 General Procedure for Pentafluoroethylation of Tosyl Imines :
Synthesis of Methyl-N-(3,3,3,2,2-pentafluoro- 1 -phenyl-propyl)-
benzenesulfonamide (3.1a) ........................ .....................36
3.6.3 General Procedure for Perfluorobutylation of Tosyl Imines:
Synthesis of 4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-
methyl-phenyl)-propyl]-benzenesulfonamide (3.2b)...................40

4 PERFLUOROAKYLATION OF ALDEHYDES AND KETONES....................44

4 .1 In tro du ctio n ............... ................ ... ............... ............... 4 4
4.2 Pentafluoroethylation of Aldehydes and Ketones................ .......... 45
4.3 Perfluorobutylation of Aldehydes and Ketones ................. ............... 47
4 .4 C o n c lu sio n ........................................................................................... 4 8
4 .5 E xperim ental ................................................. ..... .............. ............... 48
4.5.1 General Procedure of Pentafluoroethylation of Aldehydes and
Ketones: Synthesis of 1-Phenyl-2,2,3,3,3-pentafluoropropan-1-
o l (4 .2 ) ............................................... ............... ... ............... 4 8
4.5.2 General Procedure for Perfluorobutylation of Aldehydes and
Ketones: Synthesis of 1-Phenyl-2,2,3,3,4,4,5,5,5-
nonafluoropentan-l-ol............... ................. .. ............. 50

5 SYNTHESES AND STUDIES OF
TETRAKIS(DIMETHYLAMINO)ETHYLENE ANALOGUES .........................52

5 .1 In tro d u ctio n .......................... .. .............. ............................. 5 2
5.2 Syntheses of TDAE Analogues ..................... .....................54
5.2.1 Synthesis of 1,3,1',3'-Tetraalkyl-2,2'-bis(imidazolidene) ............54
5.2.2 Synthesis of 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene).54
5.3 Attempts of Trifluoromethylation using the TDAE Analogues ................56
5.3.1 Attempts of Trifluoromethylation using 1,3,1',3'-Tetraalkyl-
2,2'-bis(imidazolidene) instead of TDAE.................................. 56
5.3.2 Nucleophilic Trifluoromethylation of Phenyl disulfide using
1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene) ..................59
5 .4 C o n c lu sio n ........................................................................................... 6 0
5.5 E xperim mental ......................... ..... .......... ... .... .... ........ ..... ......... .....60
5.5.1 Synthesis of 1,3,1',3'-Tetraethyl-2,2'-bis(imidazolidene) (5.1) ....60









5.5.4 Synthesis of 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene)
( 5 .4 ) ............................ ................................ ................ 6 1

6 DIMERIC DERIVATIVES OF OCTAFLUORO[2,2]PARACYCLOPHANE
(AF4) : A NEW SOURCE OF PERFLUOROALKYL RADICALS....................63

6.1 Introduction .......... .... ...... ..................................... .......... 63
6.1.1 General Information...................... ... ......................... 63
6.1.2 Synthesis of AF4...........................................64
6.2 K inetic Studies of CF3-AF4-dim ers................................... ... ..................66
6.2.1 Synthesis of CF3-AF4-dimer....................................... 66
6.2.2 Thermal Decomposition of the CF3-AF4-dimer........................68
6.2.3 Kinetic Study of Homolysis of CF3-AF4-Dimers........................70
6.3 Kinetic Studies of C2F5-AF4-dim ers ............................... ............... .74
6.3.1 Synthesis of C2F5-A F4-dim ers ................. .......... .....................74
6.3.2 Kinetic Studies of the Homolysis of C2F5-AF4-dimers.................76
6 .4 C o n c lu sio n ........................................................................................... 8 0
6 .5 E x p erim en tal ...................................................... ............ .................... 8 0
6.5.1 Synthesis of CF3-AF4-D im er ........... ..................... .................. 80
6.5.2 Kinetic Studies of CF3-AF4-Dimer ............................................ 81
6.5.2.1 G general procedure................................... ... ..................81
6.5.2.2 Kinetic data and graphs for CF3-AF4-Dimer
at 14 0 .1 oC ....................................................... 8 2
6.5.2.3 Kinetic data and graphs for CF3-AF4-Dimer at
1 5 1 .0 C ......................................................... 8 4
6.5.2.4 Kinetic data and graphs for CF3-AF4-Dimer at
1 6 0 .7 C ......................................................... 8 6
6.5.2.5 Kinetic data and graphs for CF3-AF4-Dimer at
1 7 0 .3 oC ......................................................... 8 8
6.5.2.6 Kinetic data and graphs for CF3-AF4-Dimer at
179 .7 C ...................................... ...... .. ....... 90
6.5.3 Synthesis of C2F -AF4-Dim er ....................................... .......... 92
6.5.4 X-ray Structure of C2F5-AF4-Dimers ................. ................. 93
6.5.5 Kinetic Studies of C2F5-AF4-Dimers...........................................96
6.5.5.1 G general procedure ..........................................................96
6.5.5.2 Kinetic data and graphs of C2F5-AF4-Dimers at
1 1 8 .8 C ...................................................... .. 9 7
6.5.5.3 Kinetic data and graphs of C2F5-AF4-Dimers at
12 5 .7 C ...................................................... .. 9 9
6.5.5.4 Kinetic data and graphs of C2F5-AF4-Dimers at
1 3 0 .5 oC ..................................................... .. 1 0 1
6.5.5.5 Kinetic data and graphs of C2F5-AF4-Dimers at
1 3 9 .6 C ..................................................... .. 1 0 3
6.5.5.6 Kinetic data and graphs of C2F5-AF4-Dimers at
14 5 .3 C ..................................................... .. 1 0 5
6.5.5.7 Kinetic data and graphs of C2F5-AF4-Dimers at
1 5 1 .3 C ..................................................... 1 0 7









6.5.5.8 Kinetic data and graphs of C2F5-AF4-Dimers at
1 5 6 .4 C ..................................................... .. 1 0 9
6.5.5.9 Kinetic data and graphs of C2F5-AF4-Dimers at
161.0 C ............................... .... ................. 111
6.5.5.10 Kinetic data and graphs of C2F5-AF4-Dimers at
165.9 C .................................... ....... ................ 113

GENERAL CON CLU SION ................................................................ ............... 115

LIST OF REFEREN CE S ..................................................................... ............... 116

B IO G R A PH ICA L SK ETCH ........... ..................................................... .....................122
















LIST OF TABLES


Table page

1-1 Trifluorom ethylation of disulfides ........................................ ......................... 7

1-2 Trifluoromethylation of disulfides using a higher amount of CF3I..........................

1-3 Synthesis of trifluoromethyl selenoethers .......................................... ..........11

2-1 Synthesis of pentafluoroethyl thioethers ............................................................... 15

2-2 Synthesis of pentafluoroethyl selenoethers ............................... ..................16

2-3 Synthesis of perfluorobutyl thioethers ...............................................................17

2-4 Synthesis of perfluorobutyl selenides .............................. .... .... ...................... 19

3-1 Synthesis of tosyl im ines............................................................................ .... ... 28

3-2 Nucleophilic pentafluoroethylation of tosyl imines..............................................30

3-3 Nucleophilic perfluorobutylation of tosyl imines .............. .... ...............32

4-1 Compared yields between pentafluoroethylation and trifluoromethylation of
aldehydes and ketones ......... ..... .. ..... .......................... .. ............. 46

4-2 Perfluorobutylation of aldehydes and ketones ............................... ................47

6-1 Rate constants of the 2 diasteromers of CF3-AF4-dimers.................... ........ 71

6-2 Half-life times of the homolysis of CF3-AF4-dimers.................... ..................72

6 -3 A rrh en iu s p lot d ata ........................................................................ ..................... 74

6-4 Activation parameters for CF3-AF4-dimers........................................ ...............74

6-5 Rate constants of the 2 diasteromers of C2F5-AF4-dimers ............. ...............77

6-6 Half-life times of the homolysis of C2F5-AF4-dimers ................ ........ ...........77

6-7 Arrhenius plot data for C2F5-AF4-dim ers ..................................... .................78









6.8 Activation parameters for C2F5-AF4-dimers.....................................78

6-9 Kinetic data of d,l-CF3-AF4-Dimer at 140.1 C..................................................... 82

6-10 Kinetic data of meso-CF3-AF4-Dimer at 140.1 C ...............................................82

6-11 Kinetic data of CF3-AF4-Dimers at 151.0 C............................ ............... 84

6-12 Kinetic data of CF3-AF4-Dimers at 160.7 C.............................................. 86

6-13 Kinetic data of CF3-AF4-Dimers at 170.3 C.............................................. 88

6-14 Kinetic data of CF3-AF4-Dimers at 179.7 C.............................................. 90

6-15 Crystal data and structure refinem ent.................................... ....................... 95

6-16 Selected bond lengths [A] and angles [] .......................... ............ .............. 96

6-17 Kinetic data of C2F5-AF4-Dimers at 118.8 C ................................. ... ................ 97

6-18 Kinetic data of C2F5-AF4-Dimers at 125.7 C .......................... .................99

6-19 Kinetic graph of C2F5-AF4-Dimers at 130.5 C............... ....................101

6-20 Kinetic data of C2F5-AF4-Dimers at 139.6 C ............................... ............103

6-21 Kinetic data of C2F5-AF4-Dimers at 145.3 C ............................... ............105

6-22 Kinetic data of C2F5-AF4-Dimers at 151.3 C ............................... ............107

6-23 Kinetic data of C2F5-AF4-Dimers at 156.4 C ............................... ............109

6-24 Kinetic data of C2F5-AF4-Dimers at 161.0 C ................. ... .................111

6-25 Kinetic data of C2F5-AF4-Dimers at 165.9 C ................. ... ................. 113

















LIST OF FIGURES

Figure page

1-1 Prozac ...................................................................

1-2 C eleb rex ....................................................... 1

1-3 Fipronil ..................... ................ ........................... .............................. 1

2-1 2A28: insecticide .................................................................................... ...... ..... ........ 12

2-2 2B29: insecticide ......................... ......... .. .. ........... ......... 12

2-3 2C 30: pesticide ........................ ...................... .. .. .... ........ ........ 12

3 1 3 A ..................................................................................2 5

3 -2 3 B .........................................................................2 5

3 -3 3 C .........................................................................2 7

3 -4 3 D ................... ...................2...................7..........

3-5 A resonance form of N-(N-methyl-3-indolylmethylene)-p-
m ethylbenzenesulfonam ide .............................................................. ..............31

4 -1 4 A 56 F u n g icid e ................................................................................................. 4 4

4-2 4B57 : insecticide ................................................................44

5-1. Structure of a chiral TD AE analogue ....................................................... 53

5-2 Non chiral TDAE analogue ......... .. ....................... 53

5-3 benzim idazole TDAE analogue ......................................................... 54

5-4 Cyclic voltammogram for 1,3,1',3'-Tetraethyl-2,2'-bis(imidazolidene), C =
3mM in DMF + 0.1 mM Et4NBF4 at 20 'C, scan rate: 0.2V/s..............59...............5

6-1 [2,2]-paracyclophane ................................................................. ..... ........64




x









6 -2 A F 4 .................................................................................. 6 4

6-3 Trifluoromethyl-AF4 derivative....................... .... ............................ 65

6-4 19F NMR distinction examining the d,l and the meso forms of CF3-AF4-dimers ...67

6-5 Arrhenius plot for the 2 diasteromers of CF3-AF4-dimers ....................................73

6-6 19F NMR distinction examining the d,l and the meso forms of C2F5-AF4-dimers ..75

6-7 Perspective view (ORTEP) of meso-C2F5-AF4-dimer ............... ...............76

6-8 Arrhenius plot for the 2 diasteromers of C2F5-AF4-dimers ...................................79

6-9 Kinetic Graph of d,l-CF3-AF4-Dimer at 140.1 C .............................. ...............83

6-10 Kinetic Graph of meso-CF3-AF4-Dimer at 140.1 C.........................................83

6-11 Kinetic Graph of d,l-CF3-AF4-Dimer at 151.0 C ................................................85

6-12 Kinetic Graph of meso-CF3-AF4-Dimer at 151.0 C .........................................85

6-13 Kinetic Graph of d,l-CF3-AF4-Dimer at 160.7 C .............................. ...............87

6-14 Kinetic Graph of meso-CF3-AF4-Dimer at 160.7 C .........................................87

6-15 Kinetic graph of d,l-CF3-AF4-Dimers at 170.3 C.............................. ...............89

6-16 Kinetic graph of meso-CF3-AF4-Dimers at 170.3 C ................... ................... 89

6-17 Kinetic graph of d,l-CF3-AF4-Dimers at 179.7 C.............................. ...............91

6-18 Kinetic graph of meso-CF3-AF4-Dimers at 179.7 C ................... ................... 91

6-19 X-ray structure of meso-C2F5-AF4-dimer..........................................................94

6-20 Kinetic graph of d,l-C2F5-AF4-Dimers at 118.8 oC .............................................98

6-21 Kinetic graph of meso-C2F5-AF4-Dimers at 118.8 C..................... ..........98

6-22 Kinetic graph of d,l-C2F5-AF4-Dimers at 125.7 C ......... .............................100

6-23 Kinetic graph of meso-C2F5-AF4-Dimers at 125.7 C.......................................100

6-24 Kinetic graph of d,l-C2F5-AF4-Dimers at 130.5 C ......... ............................102

6-25 Kinetic graph of meso-C2F5-AF4-Dimers at 130.5 C.......................................102

6-26 Kinetic graph of d,l-C2F5-AF4-Dimers at 139.6 C ......... .............................104









6-27 Kinetic graph of meso-C2F5-AF4-Dimers at 139.6 C .............. ..............104

6-28 Kinetic graph of d,l-C2F5-AF4-Dimers at 145.3 C ............................................106

6-29 Kinetic data of meso-C2F5-AF4-Dimers at 145.3 C .................. ...............106

6-30 Kinetic data of d,l-C2F5-AF4-Dimers at 151.3 C.................................. ...............108

6-31 Kinetic data of meso-C2F5-AF4-Dimers at 151.3 oC .................. ...............108

6-32 Kinetic graph of d,l-C2F5-AF4-Dimers at 156.4 C ............ .......... ............110

6-33 Kinetic graph of meso-C2F5-AF4-Dimers at 156.4 C .............. .............. 110

6-34 Kinetic graph of d,l-C2F5-AF4-Dimers at 161.0 C ....................................112

6-35 Kinetic graph of meso-C2F5-AF4-Dimers at 161.0 C ............................. 112

6-36 Kinetic graph of d,l-C2F5-AF4-Dimers at 165.9 C ............ .......... ............114

6-37 Kinetic graph of meso-C2F5-AF4-Dimers at 165.9 C .............. .............. 114
















LIST OF SCHEMES


Scheme p

1-1 Trifluoromethylation of benzaldehyde using fluoroform.................. ............ 2

1-2 Trifluoromethylation of benzaldehyde using trifluoromethyl zinc iodide .............2

1-3 Examples of trifluoromethylation reactions using Me3SiCF3................ ......... 3

1-4 Difluoromethylation reactions of aromatic aldehydes with TDAE .......................3

1-5 Difluoromethylation reactions of ethyl pyruvates with TDAE.............................4

1-6 Trifluoromethylation reaction of aldehydes and ketones.....................................4

1-7 Trifluoromethylation reaction of acyl chlorides ................................................... 4

1-8 Trifluoromethylation reaction of vicinal diol cyclic sulfate...................................5

1-9 Synthesis oftrifluoromethyl phenyl sulfide via SRN1 type reaction ......................5

1-10 Synthesis of trifluoromethyl phenyl sulfide using various sources of CF3 ............6

1-11 Synthesis of trifluoromethyl thioethers ............................................ ...............6

1-12 Efficient synthesis of trifluoromethyl sulfides .................... ......................... 7

1-13 M echanism of trifluoromethylation of disulfides............................... ... .................7

1-14 Another possible mechanism of formation of trifluoromethyl sulfide...................10

1-15 Synthesis of trifluoromethyl selenoethers ........................................... ..........10

2-1 Different methods for synthesis of perfluoroalkyl sulfides and selenides ..............13

2-2 Synthesis of trifluoromethyl sulfides with CF3I / TDAE methodology................... 13

2-3 Tandem CF3I process in the synthesis of trifluoromethyl sulfides ..........................14

2-4 Pentafluoroethylation of disulfides ................... ...................................... 15

2-5 Pentafluoroethylation of diselenides ................. ......... ...........................16









2-6 Synthesis of perfluorobutyl thioethers ............................................ ...............17

2-7 Synthesis of perfluorobutyl selenides .................. ................... ......................19

3-1 Trifluoromethylation of imines using Ruppert's reagent............... ...................26

3-2 Trifluoromethylation ofimines using CF3I / TDAE ......................... ............27

3-1 Synthesis of tosyl im ines........... ................. ............ ............... ............... 28

3-2 Nucleophilic pentafluoroethylation of tosyl imines..............................................29

3-3 Nucleophilic perfluorobutylation of tosyl imines .............. .... ...............31

4-1 Pentafluoroethylation of aldehydes and ketones.................................................45

4-2 Nucleophilic perfluorobutylation of aldehydes and ketones................................47

5-1 C F 3I / T D A E com plex ...................................................................... .................. 52

5-2 Synthesis 1,3,1',3'-tetraalkyl-2,2'-bis(imidazolidene) ............ ......... .........54

5-3 Multi-step synthesis of benzimidazol TDAE analogue.......................... .........55

5-4 Nucleophilic trifluoromethylation of benzaldehyde using 1,3,1',3'-tetraalkyl-
2,2'-bis(im idazolidene) ...................... .. .... ................................ ...........56

5-5 Synthesis of phenyl trifluoromethyl sulfide by using imidazolidene TDAE
a n a lo g u e .......................................................................... 5 7

5-6 Possible decomposition pathways for imidazolidene TDAE analogue................57

5-7 Reactivities of imidazolidene carbene towards benzaldehyde............................58

5-8 Attempt of synthesis of phenyl trifluoromethyl sulfide by using 1,3,1',3'-
Tetramethyl-2,2'-bis(benzimidazolylidene) .................................. .................59

6-1 Synthesis of A F4 ...... ......... ........................... .... .... .......... .......... .. .......... ...... .. 64

6-2 M echanism of form ation of AF4............................ ....................... ............... 65

6-3 Synthesis of CF3-A F4-dim er ........ .......................... .....................66

6-4 Form action of CF3-AF4-dimer.... ... ................................................................66

6-6 Two possible pathways for decomposition of CF3-AF4-dimer ............................68

6-7 Resulting products from radical trapping in different possible mechanism
p ath w ay ............................................................................. 6 9









6-8 Kinetic study of homolysis of CF3-AF4-Dimers..............................................70

6-9 Synthesis of C2F -AF4-dimers ........................................................................... 75















Abstract of Dissertation Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Doctor of Philosophy

SYNTHESES AND STUDIES OF PERFLUOROALKYL SUBSTITUTED
COMPOUNDS

By

Chaya Pooput

August 2005

Chair: William R. Dolbier, Jr.
Major Department: Chemistry

Numerous compounds containing perfluoroalkyl groups are found to be

biologically active and are largely used in pharmaceutical and agrochemical areas.

Although several methods have been developed to incorporate trifluoromethyl group into

molecules, few are for longer perfluoroalkyl chains.

Nucleophilic trifluoromethylation has been largely developed in our laboratory by

using CF3I and Tetrakis(dimethylamino)ethylene (TDAE). This methodology was

extended to longer perfluoroalkyl iodides. Pentafluoroethyl iodide and nonafluorobutyl

iodide were used instead of trifluoromethyl iodide.

Reactions with disulfides and diselenides provided efficiently perfluoroalkyl thio-

and selenoethers, where, in most cases, both halves of the disulfides or diselenides were

converted quantitatively to thio or selenoethers.

Numerous pentafluoroethyl and nonafluorobutyl substituted amines could be

obtained in high yields by extending the methodology with tosyl imines.









Reactions with aldehydes and ketones provided good yields of pentafluoroethyl

substituted alcohols. But reactions using nonafluorobutyl iodide afforded low yields.

The extension of CF3I / TDAE methodology to longer perfluoroalkyl iodides will

allow us to access to a much larger number of biologically active compounds.

Several TDAE analogues were also synthesized but their reactivity towards CF3I is

completely different from TDAE and couldn't be used as TDAE substituents.

The syntheses and kinetic studies of perfluoroalkyl substituted AF4 dimers

provided valuable information on the use of these compounds as a stable source of

perfluoroalkyl radicals.















CHAPTER 1
INTRODUCTION

1.1 General Information

Pharmaceutical and agrochemical industries have a growing interest in compounds

containing perfluoroalkyl groups. Many new drugs contain trifluoromethyl groups:

examples are shown in Figures 1-1 and 1-2:

0 NHCH3
O N CF3

F3 H2N-S N



Figurel-1. Prozac Figurel-2. Celebrex



0
NC S-CF3


CCNH






CF3

Figurel-3. Fipronil

Among the several methods of incorporating the trifluoromethyl group into a

compound, one of the most useful is to generate in situ the unstable trifluoromethyl anion

to undergo nucleophilic trifluoromethylation on electrophilic substrates.









Various methods have been used to generate the trifluoromethyl anion: i) The

groups of Roques1 and Normant2 effectively performed nucleophilic trifluoromethylation

by using fluoroform (CF3H) in the presence of base; and ii) Kitazume3 used

trifluoromethylzinc iodide, prepared from trifluoromethyl iodide and zinc powder with

ultrasonic irradiation, as a trifluoromethylation reagent (Scheme 1-2).

O OH
CF3
+H 1) DMF, -50 C H
CF3H +
CFH 2)tBuOK, lh
3) AcOH, 0 C 20 C

Yield = 67%

Scheme 1-1. Trifluoromethylation of benzaldehyde using fluoroform

Curently the most commonly used source of the nucleophilic trifluoromethyl anion

is (trifluoromethyl)trimethylsilane (TMSCF3). In the past few years the groups of Prakash

and Shreeve have developed the method of generating in situ CF3 by reaction of

(trifluoromethyl)trimethylsilane (CF3TMS) with TBAF,4 CsF.5 Fuchikami6 reported that

trifluoromethylation reactions of carbonyl compounds can also be catalyzed by Lewis

bases, such as triethylamine, pyridine or triphenyl phosphine.

0 OH
CF3
H DMF H
+ CF3I + Zn
ultrasound


Yield = 72%

Scheme 1-2. Trifluoromethylation of benzaldehyde using trifluoromethyl zinc iodide

Extensive research had been performed on the use of this reagent with different

substrates, such as ketones, esters and disulfides.









+ OH

S+ Me3SiCF3 --- 0 H3O R R2
Rz R2 CsF
CF3

O 0

+ Me3SiCF3 HO
Rz OMe Bu4N+ RF CF3


R-S-S-R + Me3SiCF3 + Bu4N+ F THF R-S-CF3
0 C

Scheme 1-3. Examples of trifluoromethylation reactions using Me3SiCF35'7' 8

Even though (trifluoromethyl)trimethylsilane is a powerful trifluoromethylation

agent, it is very expensive. Our group wanted to find a less expensive and more direct

way to generate the nucleophilic CF3 anion.

1.2 Previous Work

1.2.1 Starting Point

Since 1998, with the collaboration of Dr. Maurice Medebielle, we have

demonstrated that tetrakis(dimethylamino)ethylene (TDAE) can be used as an efficient

reductant to generate nucleophilic difluoromethyl anions from chloro- and

bromodifluoromethyl compounds.9' 10

OH

RCF2X + ArCHO TDAE Ar H
DMF CF2R
CF2R
-20 0 to RT

Scheme 1-4. Difluoromethylation reactions of aromatic aldehydes with TDAE

OH
RCF2X + CH3COCO2Et TDAE H3C CO2Et
DMF
-20 o to RT CF2R










Scheme 1-5. Difluoromethylation reactions of ethyl pyruvates with TDAE

Pawelke earlier demonstrated that TDAE could be used with trifluoromethyl iodide

to prepare CF3TMS from TMSC1.1 With these results, we decided to use TDAE to

reduce trifluoromethyl iodide into trifluoromethyl anion.

1.2.2 Preliminary Results in the Group

With the aldehydes and ketones, the CF3I / TDAE system provided very good

yields, which were comparable to those obtained in analogous reactions using CF3TMS.12

0 OH
+ CF3I + TDAE hv, 12hrs O R+ R
R R2 -20 0 to RT 2
CF3
DMF
1 eq 2.2 eq 2.2 eq 53-95 %

Scheme 1-6. Trifluoromethylation reaction of aldehydes and ketones

Aryl acyl chlorides also underwent clean relations.13


0
SI1


F3C CF30


S 'Cl CF3I / TDAE I "
x -, DME X
-200 C to RT
48-98 %
RT, 2 hrs

Scheme 1-7. Trifluoromethylation reaction of acyl chlorides

Unfortunately the CF3I / TDAE system was not successful in reactions with

epoxides. But in 1988 Gao and Sharpless demonstrated that vicinal diol cyclic sulfates

could be used as epoxide equivalents, with a higher reactivity.14


O 0 + + 20% H2S04 HO CF3 F3C O
S+ CF3I + TDAE 3C ./
THF +
20 C t ROT 55%


)H

1%


5 hrs


1 eq 2.2 eq 2.2 eq


HO I
40%


X









Scheme 1-8. Trifluoromethylation reaction of vicinal diol cyclic sulfate

The reaction is highly regioselective because only 1% of the other isomer is

formed. Since the cyclic sulfate is highly reactive, competition between the iodide anion

and the trifluoromethyl anion occurred, which did not happen with other substrates.15

1.2.3 New and Efficient Method for Synthesis of Trifluoromethyl Sulfides

Aryl trifluoromethyl sulfides continue to attract much interest within

pharmaceutical companies, as witnessed by the significant number of process patent

applications recently submitted that are devoted to their preparation17. This interest

derives from the recognized potential of the SCF3 group to have a positive influence on

biological activity.

Diverse methods have been reported for the synthesis of aryl trifluoromethyl

sulfides18, but two seem to emerge as preferred methods.

The first is the SRN1 reaction of aryl thiolates with trifluoromethyl iodide or

bromide. Yagulpolskii was the first to report the reaction in 1977, using trifluoromethyl

iodide and UV irradiation19:

Ph-SH + CF3I NaOCH3, UV Ph-S-CF3 89%
CH3CN, 0 5 C

Scheme 1-9. Synthesis of trifluoromethyl phenyl sulfide via SRN1 type reaction

Wakselman and Tordeux used trifluoromethyl bromide in high pressure

(2 atm),20 21 and with other variations,22 23 this method is generally efficient when using

aryl thiolates but gives a much lower yield when using alkanethiolates.24

The other popular method involves the reaction of trifluoromethyl anion (generated

in situ by various methods) with aryl and alkyl disulfides:










PhS-SPh + CF3SiMe3 Bu4N F Ph-S-CF3 + Ph-S
THF, OC 3
32% s

PhS-SPh + CF3CO2K sulfolane, A Ph-S-CF3 + Ph-S

56% 25

84% 26

OH Ph tBuOK
PhS-SPh + F3C N N-' Ph-S-CF3 + Ph-S
H 27
87% 27

Scheme 1-10. Synthesis of trifluoromethyl phenyl sulfide using various sources of CF3

Although good yields can be obtained, the method suffers from the fact that half of

the disulfide is wasted in the process (formation of thiolates for the other half).

In our investigation16, the CF3I / TDAE system turned out to be a better method for

synthesis of trifluoromethyl sulfides than with Ruppert reagents (Table 1-1). Both aryl

and aliphatic disulfides provided near 100 % yield. The reaction is very fast only 2

hours of stirring at room temperature was sufficient to give a quantitative yield, as shown

in the entries 4 and 5.

R-S-S-R + TDAE + CF3I DMF R-S-CF3
0 OC to RT
RT several hr
1 eq. 2.2 eq 2.2 eq

Scheme 1-11. Synthesis oftrifluoromethyl thioethers









Table 1-1. Trifluoromethylation of disulfides
entry R Stirring time at RT M yi
entry R NMR yield
(hrs)
1 Phenyl 12 80

2 butyl 12 >98

3 ethyl 12 >98

4 butyl 4 >98

5 butyl 2 >98


R-S-S-R + TDAE + CF3I DMF R-S-CF3
0 oC to RT
180 200%
RT several hr
based of equivalents
1 eq. 2.2 eq 4.2 eq of disulfides


Scheme 1-12. Efficient synthesis of trifluoromethyl sulfides

It has been demonstrated that the mechanism of the reaction is as shown in the

Scheme 1-13.
0 20
TDAE + CF3I CF3 + I + TDAE2

R-S-S-R + CF3 -G R-S-CF3 + R-S

R-S0 + CF3I R-S-CF3 + I

Scheme 1-13. Mechanism of trifluoromethylation of disulfides

It occurred to us that CF3I could also be used as a substrate for reaction, via the

SRN1 mechanism, with the thiolate coproduct; thus, potentially enabling both halves of the

disulfide to be used in a one pot reaction, where CF3I would be used in two different

reactions, both of which lead to the same desired product. First TDAE reduces CF3I to

nucleophilic "CF3 ", which reacts with the disulfide to form trifluoromethyl sulfide and









thiolate. The resulting thiolate reacts with the excess of CF3I, in a SRN1 type mechanism

to create the second molecule of sulfide.

When more than 4.2 equivalents of CF31 are USed while the quantity of TDAE stays

at 2.2 equivalents, trifluoromethyl sulfides can be obtained at nearly 200% yield, based

on the number of equivalents of disulfides, as shown in the Table 1-2.

Table 1-2 Trifluoromethylation of disulfides using a higher amount of CF31


N
s benzothiazolyl group

*based of number of equivalents of disulfides

The entries 1 to 3 show that with 5 equivalents of CF3I, yields of nearly 200%

could be obtained whether with aryl disulfide or alkyl disulfide. The following entries are

attempts to optimize the procedure: 3.2 equivalents of CF3I did not seem to be sufficient,


Stirring time at RT
entry R Equiv. of CF3I Stirring time at NMR yield*
(hrs)

1 Phenyl 5 12 186

2 butyl 5 12 170

3 4-pyridyl 5 12 z 200

4 butyl 5 4 170

5 butyl 4.2 4 175

6 butyl 3.2 4 130

7 butyl 4.2 2 170

8 ethyl 4.2 2 180

9 2-pyridyl 4.2 2 180

10 t-butyl 4.2 12 0

11 2-nitrophenyl 4.2 2 185

12 benzothiazolyl 4.2 2 190

13 4-aminophenyl 4.2 12 20









since the yield was only 130% (entry 6) whereas more than 4.2 equivalents gave nearly

quantitative yields. Moreover 2 hours of stirring at room temperature was sufficient.

Although with t-butyl disulfide, we were unable to perform the trifluoromethylation

(entry 10), the result is nevertheless interesting because this shows a high influence of the

steric effect for the reaction. Moreover the lack of reactivity of t-butyl disulfide has been

noted previously, when CF3TMS was used as trifluoromethyl anion source.8 The entry 13

revealed another limitation of this methodology: CF3 anion being extremely unstable

reacts preferable first towards acidic protons, such as the ones present in the amino group

hence the very low yield for the reaction with 4-aminophenyl disulfide (Table 1-2, entry

13). All the groups containing acidic protons need then to be protected first before

undergoing trifluoromethylation with CF3I / TDAE method. In the case of 4-aminophenyl

disulfide, 4-nitrophenyl disulfide can be used and the nitro group can be reduced later to

obtain the amino group; the amino group can also be protected twice with BOC to avoid

the harsh conditions of reduction of nitro group.

It might be argued that these results could derive from reduction by TDAE of

disulfide to 2 equivalents of thiolate anion. The thiolate could react then with CF3I

proceeding entirely via SRN1 type reaction. If that were the case, the 2.2 equivalents of

CF3I along with 2.2 equivalents of TDAE should have been sufficient to obtain the high

yields observed in the Table 1-2. However, in the case where 2.2 equivalents of CF3I

were used (Table 1-1), yields never exceeded 100%. This probably means that CF3I is

reduced faster than the disulfides.










TDAE + R-S-S-R -- 2 R-S + TDAE2O

2R-S + 2CF31 2 R-S-CF3 + 2 1

Scheme 1-14. Another possible mechanism of formation of trifluoromethyl sulfide

Nevertheless, a control reaction was carried out to provide more definitive evidence

for the proposed dual mechanism synthetic process. CF3I (5 equiv.) and TDAE (2 equiv.)

were added first together at -200C so that TDAE would be totally oxidized by the

reaction with CF3I. The solution was then allowed to warm to -50C, at which time, n-

butyl disulfide was introduced. At this point there should be little if any TDAE remaining

to react with the disulfide. Despite this, the observed yield from this reaction was 160%,

which compares well with the 170% obtained when using the normal procedure (Table 1-

2, entry 5). This can be concluded that the reaction likely proceeds via the two-stage

process described earlier. These interesting results mean that the disulfides provide two

molecules of trifluoromethyl sulfides, which was never observed before in the other

methods.

1.2.4 New and Efficient Method for Synthesis of Trifluoromethyl Selenides

Since diselenides have similar reactivities than that of disulfides, reactions of

nucleophilic trifluoromethylation were also performed on diphenyl diselenide6.

R-Se-Se-R + TDAE + CF3I DMF R-Se-CF3
0 C to RT
-200%
RT overnight based of number of
1 eq. 2.2 eq 4.2 equivalents of diselenides


Scheme 1-15. Synthesis of trifluoromethyl selenoethers









Tablel-3. Synthesis of trifluoromethyl selenoethers
Entry R NMR Yield (%)*

1 phenyl 198

2 4-Chlorophenyl = 200

3 methyl 180
*based of number of equivalents of diselenides

The methodology is efficient for both aliphatic and aromatic diselenides.

The CF3I / TDAE methodology are very efficient for many electrophilic subtrates,

we are interested now to extend this methodology to longer perfluorinated chains by

using other perfluoroalkyl iodides. We would be able to access to a higher amount

biologically active compounds.













CHAPTER 2
SYNTHESIS OF PERFLUOROALKYL THIO AND SELENOETHERS

2.1 Introduction

Parallel to trifluorothioethers, trifluoroselenoethers, longer perfluoroalkyl chains are also

developed to be used as biologically active compounds. Few examples are given below.

Cl CF3 N112
SNH2

H3C ( N
S Cl
SCF2CF3 Br SCF2CF3

Figure 2-1. 2A28: insecticide Figure 2-2. 2B29: insecticide


SC4F9 CN


NN xNN

Cl Cl



CF3

Figure 2-3. 2C30: pesticide

Despite the increasing interest in perfluoroalkyl sulfides, few methods have been

developed to synthesize them. The two main methods consists in first through SRN1

reaction of aryl thiolates with perfloroalkyl iodide31 or bromide.32 The second method

involves perfluoroalkyl anion, generated from thermal decarboxylation of potassium









perfluoroalkyl carboxylate,33 with aryl disulfides with the inconvenience of possible

carbanion rearrangement or decomposition and one half of the disulfide is wasted.

Another notable method for synthesis of perfluoroalkyl selenides consists in reaction

between perfluoroalkyl radicals and diselenides.34 So far there is no efficient method for

synthesis of perfluoroalkyl aliphatic sulfides.


PhSH + C4F9I NaH p PhS-C4F9

66% 31

PhSK + CF3CF2Br PhS-CF2CF3

33% 32

PhS-SPh + CF3CF2CO2K A PhS-CF2CF3 + PhSK

70 %33

PhSe-SePh + 2 C4F9I HOCH a 2 PhSe-C4F9

57%34


Scheme 2-1. Different methods for synthesis of perfluoroalkyl sulfides and selenides

Our laboratories have developed a new and efficient method for synthesis of

trifluoromethyl sulfides and selenides, using CF3I / TDAE system.16 This methodology

has now been extended to longer perfluoroalkyl iodides.


R-S-S-R + TDAE + CF3I DMF 0 R-S-CF3
0 C to RT
180 200%
RT several hr 180200%
based of equivalents
1 eq. 2.2 eq 4.2 eq of disulfides

Scheme 2-2. Synthesis of trifluoromethyl sulfides with CF3I / TDAE methodology









2.2 Synthesis of Pentafluoroethyl Thioethers

The same way that TDAE reduces trifluoromethyl iodide into trifluoromethyl

anion, pentafluoroethyl iodide was also expected to be reduced by TDAE into

pentafluoroethyl anion. The tandem process, involving nucleophilic attack of

trifluoromethyl anion to disulfide followed by SRN1 by the resulting thiolate on the excess

of CF3I (Scheme 2-3), was also expected.


TDAE + CF3I CF3 + I + TDAE2

R-S-S-R + CF9 R-S-CF3 + R-S0

R-S + CF3I R-S-CF3 + I

Scheme 2-3. Tandem CF3I process in the synthesis of trifluoromethyl sulfides16

The first experiment was carried out using 1 equivalent of phenyl disulfide, 4.2

equivalents of C2F5I and 2.2 equivalents of TDAE added at -20 oC. The color of the

solution turned quickly deep red as TDAE was introduced. This may show the formation

of the complex between TDAE and C2F5I, like in the case between TDAE and CF3I. The

reaction mixture was allowed to warm up slowly. But unlike CF3I where the complex

with TDAE starts decomposing at 0 OC, the complex with C2F5I started decomposing

around -10 C, as white salt could be seen forming. Apparently the complex between

C2F5I and TDAE is less stable than that with CF3I. But the fact that TDAE was able to

form a complex with C2F5I was a good sign meaning that the reaction may proceed in the

same way as with CF3I / TDAE. The mixture was stirred overnight. 19F NMR was taken

to calculate the yield. The reaction yielded 198 % based on the number of equivalents of

disulfides (Table 2-1, entry 1).









R-S-S-R + TDAE + CF3CF2I DMF R-S-CF2CF3
-10 oC to RT
RT several hr
1 eq. 2.2 eq 4.2 eq

Scheme 2-4. Pentafluoroethylation of disulfides

Reactions with different disulfides (aromatic and aliphatic) were then performed.

The results are shown in Table 2-1.

Table 2-1. Synthesis of pentafluoroethyl thioethers
Entry R time at RT (hrs) NMR yield*

1 Phenyl32 12 >198

2 phenyl 2 >198

3 ethyl 2 135

4 ethyl 4 170

5 ethyl 12 175

6 butyl 12 180

7 2-pyridyl35 2 >198

8 4-pyridyl 2 190
*Based on the number of equivalents of disulfides

The entries 2, 7 and 8 proved that, as in the case of CF3I, 2 hours are sufficient to

obtain quantitative yield for aryl disulfides. But in entries 3 to 5, two, even four hours

didn't seem to be sufficient to obtain good yields in the case of aliphatic disulfides. The

mixture required to stirring overnight to be able to obtain 175 %. Even though, the yields

are very similar to the ones with CF3I, aliphatic disulfides require a much longer time.

This may be explained by the fact that it is more diificult for aliphatic thiolates to

undergo SRN1 reaction. Somehow the presence of TDAE seems to enhance the reactivity









of aliphatic thiolates on SRN1 reaction, since we could always obtain good yields from

aliphatic disulfides with CF3I / TDAE system. In the case of C2FI5 the complex formed

with TDAE is less stable than with CF3I and this may one of the reasons why the reaction

is slower for aliphatic disulfides. It may also come from the fact that C2FsI is less reactive

as a substrate in the SRN1 process.

In spite of longer reaction time for aliphatic disulfides, the yields obtained are

similar to the ones from CF3I. The two halves of the disulfides are used efficiently to

form two molecules of pentafluorethyl thioethers.

2.3 Synthesis of Pentafluoroethyl Selenoethers

Since diselenides have similar reactivities as disulfides. The reactions of

nucleophilic pentafluoroethylation were also performed on diselenides.


R-Se-Se-R + TDAE + CF3CF21 DMF R-Se-CF2CF3
-10 oC to RT
RT overnight
1 eq. 2.2 eq

Scheme 2-5. Pentafluoroethylation of diselenides

Table 2-2. Synthesis of pentafluoroethyl selenoethers
Entry R Eq. of C2F5I NMR yield* (%)

1 Phenyl34 2.2 100

2 phenyl 4.2 z 200

3 4-chlorophenyl 4.2 z 200
*Based on the number of equivalents of diselenides

As expected, from 1 equivalent of diselenides, 2.2 equivalents of C2FI5 gave

quantitatively 1 equivalent of pentafluoroethyl selenides (Table 2-2, entry 1) and 4.2

equivalents provided efficiently 2 equivalents of selenides.









2.4 Synthesis of Perfluorobutyl Thioethers

Since the nucleophilic perfluoroalkylation using TDAE was successfully extended

to C2F5I, longer perfluoroalkyl iodides were then considered for experiments, we decided

to performed reactions with nonafluorobutyl iodided


R-S-S-R + TDAE + C4F9I DMF R-S-C4F9
-20 oC to RT
RT overnight
1 eq. 2.2 eq

Scheme 2-6. Synthesis of perfluorobutyl thioethers

The reactions were performed in the same fashion as the usual reactions of

trifluoromethylation of disulfides, with the difference that C4F9I is a liquid instead of a

gas like CF3I or C2F5I, the total reflux condenser was not needed any longer. The

complex C4F9I / TDAE seems to be much less unstable than the ones from CF3I / TDAE,

since the usual TDAE salt was formed just above -20 C, very shortly after the addition of

TDAE.

Table 2-3. Synthesis of perfluorobutyl thioethers
Entry R Eq. of C4F91 NMR yield* (%)

1 Phenyl36 2.2 70

2 ethyl 2.2 40

3 butyl 2.2 40

4 2-pyridyl37 2.2 -100

5 4-pyridyl 2.2 z200

6 phenyl 4.4 140

7 butyl 4.4 40

8 2-pyridyl 4.4 195
*Based on the number of equivalents of disulfides









Aryl disulfides gave satisfactory to good yields (Table 2-3, entries 1 and 4) when

2.2 equivalents of C4F91 were used. But aliphatic disulfides resulted in only modest

yields, 40%, (Table 2-3, entries 2 and 3). This may be explained by the low stability of

the C4F9I / TDAE complex or the low reactivity of C4F9 anion towards aliphatic

disulfides. The case of 4-pyridyl disulfide (Table 2-3, entry 5) proved to be very

interesting. With only 2.2 equivalents of C4F9I, we were able to obtain 2 equivalents of

perfluorobutyl 4-pyridyl sulfide, where usually 4.2 equivalents were needed to obtain the

same results in other cases. This means that the tandem process16 (where the

perfluoroalkyl anion, formed by reduction of perfluoroalkyl iodide by TDAE, attacks

disulfide to form the first thioether and then the resulting thiolate reacts with the excess

of perfluoroalkyl iodide through SRN1 reaction to form the second thioether (Scheme 2-

3)) is not applicable anymore in this case. TDAE didn't reduce C4F9I into C4F9 anion but

instead reduced entirely 4-pyridyl disulfide, forming 2 equivalents of thiolate which react

with C4F9I through SRN1 mechanism. It seems that C4F9I is not as reactive towards TDAE

as CF3I or C2FsI and since the disulfide was also present in the reaction mixture when

TDAE was added and aryl disulfides can be easily reduced, TDAE preferably reduced 4-

pyridyl disulfide over C4F9I. This problem was not encountered in the case of CF3I and

C2FsI because their reactivity towards TDAE was high enough that TDAE reduced them

first.

When 4.4 equivalents of C4F91 were used on phenyl or 2-pyridyl disulfide, 140 %

and 195 % ofthioethers were obtained respectively (Table 2-3, entries 6 and 8). But 40 %

yield was only obtained for butyl disulfide, the same yield as when 2.2 equivalents of









C4F9I were used. It seems that aliphatic thiolates anions couldn't undergo reaction at all

through an SRN1 reaction with C4F91.

2.5 Synthesis of Perfluorobutyl Selenoethers

The syntheses of perfluorobutyl selenides were also performed.

R-S-S-R + TDAE + C4F9I DMF R-S-C4F9
-20 oC to RT
RT overnight
1 eq. 2.2 eq

Scheme 2-7. Synthesis of perfluorobutyl selenides

Table 2-4. Synthesis of )erfluorobutyl selenides
Entry R Eq. of C4F91 NMR yield* (%)

1 Phenyl34 2.2 z 200

2 methyl 2.2 z 200
*Based on the number of equivalents of diselenides

As with 4-pyridyl disulfide, both aryl and aliphatic diselenides only underwent

through SRN1 process, resulting in nearly 200 % yields when 2.2 equivalents of C4F91

were used (Table 2-4). Contrary to disulfides, aliphatic deselenides could react

quatitatively with C4F9I via SRN1 process.

2.6 Conclusion

The nucleophilic perfluoroalkylation methodology developed with CF3I / TDAE

system was successfully extended to C2F5I: similar results were obtained and the two

halves of disulfides and deselenides were efficiently used. The methodology seemed to

reach its limits with C4F9I. Whereas some aryl disulfides still gave good yields, aliphatic

disulfides resulted in poor yields. But the most important point is the fact that for some

disulfides and for all the diselenides, TDAE was unable to react with C4F9I and









preferably reduced disulfides or diselenides instead, forcing the reactions to undergo

exclusively through SRN1 mechanism of thiolate anion. From a synthetic point of view,

this didn't present a problem. On the contrary, a smaller amount of TDAE and

perfluorobutyl iodide was used to give 200% yields. But in the mechanistic point of view,

the tandem process, where the perfluoroalkyl iodide switches roles from being a reactant

to being a substrate in one pot reaction, couldn't be applied anymore and the role of

TDAE was only to reduce the disulfides. Moreover reducing disulfides to form thiolates

seems to be much less convenient than deprotonating a more easily available thiols by a

base, as the usual methods for perfluoralkyl thioether synthesis via SRN1 reactions.

However this C4F9I / TDAE, even when TDAE served only as reductant of

disulfides, still presents an advantage to other methods where the yields were not higher

than 60 %31,34

2.7 Experimental

Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus

300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with

external tetramethylsilane (TMS, 6 = 0.00 ppm) as a reference. Fluorine (19F) and proton

(1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFC13, 6 =

0.00 ppm) as a reference for 19F NMR and TMS (6 = 0.00 ppm) for H NMR. Deuterated

chloroform (CDC13) was used as NMR solvent.

2.7.1 General Synthesis of Pentafluoroethyl Thio and Selenoethers : Synthesis of
Phenyl Pentafluoroethyl Sulfide

In 25 mL, 3-neck-round bottom flask, equipped with a dewar type condenser and

N2, diphenyl disulfide (0.8 g, 3.68 mmol) was disolved in 10 mL of anhydrous DMF. The

solution was cooled at -20 oC. Pentafluoroethyl iodide (3.8 g, 15.45 mmol) was then









introduced to the solution. TDAE (2 mL, 8.1 mmol) was added around -15 C. The

reaction mixture became quickly dark red. The reaction was allowed to warm up slowly

to room temperature. And as the bath temperature reached -10 C white solid was formed.

The reaction mixture was stirred at room temperature for 2 hours (or overnight in the case

of alkyl disulfides). The orange solution was filtered and the solid was washed with

diethyl ether. The orange solution was filtered and the solid was washed with diethyl

ether (20 mL). 20 mL of water was added to the ether solution. The two phases were

separated and the aqueous phase was extracted with 20 mL of ether 2 more times. The

combined ether layers were washed with brine and dried over MgSO4. The solvent was

removed and the crude product was purified by silica gel chromatography (CH2C2 /

hexanes = 1:9) to give phenyl pentafluoroethyl sulfide in the yield of 198%

19F NMR(300 MHz, CDC13) 6 -83.00 (t, JFF = 3.1 Hz, 3F, CF3); -92.32 (q, JFF = 3.1

Hz ,2F, CF2) ppm

Ethyl Pentafluoroethyl Sulfide

1H NMR(300 MHz, CDC13) 6 2.70 (q, J = 7.2 Hz, 2H, CH2); 1.32 (t, J = 7.2 Hz,

3H, CH3)

19F NMR(300 MHz, CDC13) 6 -83.00 (t, JFF = 3.2 Hz ,3F, CF3); -92.32 (q, JFF = 3.2

Hz, 2F, CF2) ppm

Butyl Pentafluoroethyl Sulfide

H NMR(300 MHz, CDC13) 6 2.69 (t, J = 7.3 Hz, 2H, CH2); 1.66 (quintet, J = 7.6

Hz, 2H, CH2); 1.42 (sextuplet, J = 7.6 Hz, 2H, CH2); 0.93 (t, J = 7.3 Hz, 3H, CH3)

19F NMR(300 MHz, CDC13) 6 -82.95 (t, JFF = 3.2 Hz ,3F, CF3); -92.55 (q, JFF = 3.2

Hz, 2F, CF2) ppm









2-Pyridyl Pentafluoroethyl Sulfide35

1H NMR(300 MHz, CDC13) 6 8.47 (m, 1H, ArH); 7.62 (m, 2H, ArH); 7.11 (m, 1H,

ArH)

19F NMR(300 MHz, CDC13) 6 -83.17 (t, JFF = 2.01 Hz ,3F, CF3); -91.03 (q, JFF

2.01 Hz ,2F, CF2) ppm

4-Pyridyl Pentafluoroethyl Sulfide

1H NMR(300 MHz, CDC13) 6 8.51 (dd, J1 = 4.8 Hz, J2 = 2.0 Hz, 2H, ArH); 7.37

(dd, Ji = 4.7 Hz, J2 = 1.75 Hz, 2H, ArH)

19F NMR(300 MHz, CDC13) 6 -82.95 (t, JFF = 2.14 Hz, 3F, CF3); -90.78 (q, JFF

2.14 Hz, 2F, CF2) ppm

Phenyl Pentafluoroethyl Selenide34

19F NMR(300 MHz, CDC13) 6 -84.74 (t, JFF = 3.2 Hz, 3F); -92.14 (q, JFF = 3.2 Hz,

2F, CF2) ppm

2.7.2 General Synthesis of Nonafluorobutyl Thio and Selenoethers : Synthesis of
Phenyl Nonafluorobutyl Sulfide

In a 25 mL round bottom flask, equipped with a rubber septum and N2, diphenyl

disulfide (0.8 g, 3.68 mmol) was disolved in 10 mL of anhydrous DMF. The solution was

cooled at -30 oC. Nonafluorobutyl iodide (1.4 mL, 15.45 mmol) was then introduced to

the solution. TDAE (2 mL, 8.1 mmol) was added around -20 C. The reaction mixture

became quickly dark red. White solid was formed shortly after the addition of TDAE.

The mixture was allowed to warm up slowly to the room temperature was stirred

overnight. The orange solution was filtered and the solid was washed with diethyl ether

(20 mL). 20 mL of water was added to the ether solution. The two phases were separated

and the aqueous phase was extracted with 20 mL of ether 2 more times. The combined









ether layers were washed with brine and dried over MgSO4. The solvent was removed

under vacum and the crude product was purified by silica gel chromatography (CH2C2 /

hexanes = 1:9) to give phenyl nonafluorobutyl sulfide in the yield of 140%

19F NMR(300 MHz, CDC13) 6 -81.28 (t, JFF = 10.2 Hz, 3F, CF3); -87.43 (m, 2F,

SCF2); -120.46 (m, 2F, CF2); -125.90 (m, 2F, CF2) ppm

Ethyl Nonafluorobutyl Sulfide

1H NMR(300 MHz, CDC13) 6 2.70 (q, J = 7.2 Hz, 2H, CH2); 1.32 (t, J = 7.2 Hz,

3H, CH3)

19F NMR(300 MHz, CDC13) 6 -81.30 (t, JFF = 8.9 Hz, 3F, CF3); -87.80 (m, 2F,

SCF2); -121.05 (m, 2F, CF2); -125.60 (m, 2F, CF2) ppm

Butyl Nonafluorobutyl Sulfide

H NMR(300 MHz, CDC13) 6 2.69 (t, J = 7.3 Hz, 2H, CH2); 1.66 (quintet, J = 7.6

Hz, 2H, CH2); 1.42 (sextuplet, J = 7.6 Hz, 2H, CH2); 0.93 (t, J = 7.3 Hz, 3H, CH3)

19F NMR(300 MHz, CDC13) 6 -81.35 (t, JFF = 8.5 Hz, 3F, CF3); -87.68 (m, 2F,

SCF2); -120.97 (m, 2F, CF2); -125.48 (m, 2F, CF2) ppm

2-Pyridyl Nonafluorobutyl Sulfide37

1H NMR(300 MHz, CDC13) 6 8.47 (m, 1H, ArH); 7.62 (m, 2H, ArH); 7.11 (m, 1H,

ArH)

19F NMR(300 MHz, CDC13)6 -81.13 (t, JFF = 10.7 Hz, 3F, CF3); -86.13 (m, 2F,

SCF2); -120.35 (m, 2F, CF2); -125.70 (m, 2F, CF2) ppm

4-Pyridyl Nonafluorobutyl Sulfide

1H NMR(300 MHz, CDC13) 6 8.51 (dd, J1 = 4.8 Hz, J2 = 2.0 Hz, 2H, ArH); 7.37

(dd, Ji = 4.7 Hz, J2 = 1.75 Hz, 2H, ArH)






24

19F NMR(300 MHz, CDC13) 6 -81.20 (t, JFF = 10.5 Hz, 3F, CF3); -86.00 (m, 2F,

SCF2); -120.25 (m, 2F, CF2); -125.60 (m, 2F, CF2) ppm

Phenyl Nonafluorobutyl Selenide34

19F NMR(300 MHz, CDC13) 6 -81.47 (t, JFF = 10.7 Hz, 3F, CF3); -87.34 (m, 2F,

SCF2); -119.14 (m, 2F, CF2); -126.05 (m, 2F, CF2) ppm














CHAPTER 3
PERFLUOROALKYLATION OF IMINE TOSYLATES

3.1 Introduction

Our laboratories have developed methodologies for nucleophilic

trifluoromethylation of numerous substrates, such as aldehydes12, cyclic sulfates5,

benzoyl chlorides13 or disulfides16, using CF3I / TDAE system. Trifluoromethylamines

are very interesting compounds because they can serve as synthetic intermediates to

biologically active molecules, as shown in Figures 3-1 and 3-2, where 3A can be used as

pesticide38 and 3B as pain-reliever39

F3C NH

S CF3 I I
I N, I N Z


S H

Figure 3-1. 3A Figure 3-2. 3B

Previously trifluoromethylamines were only synthesized from precursors (i.e.

ketones) already containing trifluoromethyl group.40-48 Prakash and coworkers have used

Ruppert's reagent (CF3TMS) with imine derivatives to prepare trifluoromethylamines49

and, in particular, chiral trifluoromethylamines.50'51 Indeed, the use of CF3TMS proved to

be very effective for nucleophilic trifluoromethylation of N-tosyl aldimines and N-(2-

methyl-2- propane-sulfinyl)imines (Scheme 3-1), with the latter reactions exhibiting

excellent diastereoselectivity.









Simple alkyl- or aryl-substituted imines are relatively unreactive toward

nucleophilic trifluoromethylation, although Blazejewski and co-workers were able to

obtain modest to good yields for aryl systems by facilitating the reaction of CF3TMS

using TMS-imidazole.52 As Prakash showed, the reactivity of imines toward nucleophilic

trifluoromethylation can be significantly enhanced by using N-tosylimines, with thep-

toluenesulfonyl group being removed from the adduct by its treatment with phenol and

48% HBr to give the respective primary amine products.49

F3C
TBAT
__N-Ts + CF3TMS TBAT N Ts
Ph THF, 0 5 C / H
Ph Ph
90%


O F3C O
-N-S + CF3TMS a N-S
Ph tBu Ph tBu
P \tBu THF, -55 C Ph/ \ \
80%
d.r > 97%

Scheme 3-1. Trifluoromethylation of imines using Ruppert's reagent

Using the same CF3I / TDAE methodology than developed for trifluoromethylation

of aldehydes12, similar results53 to Prakash's methods could be obtained (Scheme 3-2).

Unfortunately, the analogous reactions with imines bearing aliphatic substituents on the

imine carbon did not produce the desired adducts. Such attempts included the N-

tosylimines of acetophenone, p-chloroacetophenone, cyclohexanone, and hexanal. In

contrast, aliphatic aldehydes had been reported to provide adducts using Prakash's

CF3TMS methodology.49









F3C
Ts CF3I / TDAE (2.2 equiv.) N Ts

Ar DMF, -30 0 C H
Ar Ar
62 86%



0 F3C. 0
N- S CF3I / TDAE (2.2 equiv.) N

Ph Tol DMF, -30-0 C Ph Tol
66%
d.r = 87:13

Scheme 3-2. Trifluoromethylation of imines using CF3I / TDAE

Parallel to trifluoromethylamines, higher perfluoroalkylamines gather also much

interest from pharmaceutical and agrochemical industries. For example, 3C can be used

as a treatment against osteoporosis54 and 3D as a treatment of Alzheimer's disease5





OCH3 N-/


NHN
0 H 0

NC A N
NC H tBu CF2CF3 H CF2CF3


Figure 3-3. 3C Figure 3-4. 3D

Since in Chapter 2, we have shown that the CF3I / TDAE methodology could be extend

to longer perfluoroalkyl iodides, such as pentafluoroethyl iodide or nonafluorobutyl

iodide, we decided then to try to synthesize other perfluoroalkyl amines










3.2 Synthesis of Tosyl Imines


R1 R1
O_ + H2N T __T BF3.OEt2 or Ts-OH _=
O + H2N Ts N--Ts
toluene, reflux
R2 R2

Scheme 3-1. Synthesis oftosyl imines

The imines were easily prepared from aromatic aldehydes and tosyl amine, as shown in

Table 3-1. Unfortunately because of the electron withdrawing character of the tosyl

group, tosyl amine was not reactive towards ketones or alphatic aldehydes (entries 3.14-

3.16)

Table 3-1 Syvnthesis oftosvl imines


entry R1 R2 Yield (%)


3.1 H 80




3.2 H 85
Me"



3.3 H 85
Cl



3.4 H 88
F



3.5 H 80
F3C


. .. .











3.6 / H 30




3.7 / H 65
0




3.8 H 95
^-~N
CH3


3.9 CH3 0




3.10 CF3 0




3.11 C7H15 H 0


3.3 Pentafluoroethylation of Tosyl Imines


Ar

A=rN-Ts + CF3CF2I

H


+ TDAE DMF
-20 OC to RT


Scheme 3-2. Nucleophilic pentafluoroethylation of tosyl imines









Table 3-2. Nucleophilic pentafluoroethylation of tosyl imines
Yield with
Entry Ar Yield (%) CF3153 (



3.1a 50 86




3.2a 70 84
Me"



3.3a 70 78
Cl



3.4a 72 81
F



3.5a 6 68
F3C



3.6a ( 55
S



3.7a 60





3.8a 0 -
CHN
_________CH3 __________ ______









In general, the reactions provided similar results than with CF3I / TDAE system,

with slightly lower yields. For the case of 1-methylindol-3-imine tosylate (entry 3.10a)

the absence of reactivity may be explained by one of the resonance forms shown in

Figure 3-1: with the carbon being on the position 3, the indole group becomes a good

electron donating group, reducing hugely the electrophilic character of the carbon on the

imine, thus the lack of reactivity towards C2F5 nucleophile.

Ts Ts



0 NN

\ "N



Figure 3-5. A resonance form of N-(N-methyl-3-indolylmethylene)-p-
methylbenzenesulfonamide

3.4 Perfluorobutylation of Tosyl Imines

Since good yields could be obtained with C2FsI, experiments with C4F91 were performed

to extend further the methodology


Ar C4F9

N-Ts + C4F91 + TDAE DMF Ar N-

H -20 OC to RT

1 2.2 2.2


Scheme 3-3. Nucleophilic perfluorobutylation oftosyl imines

In general the yields are lower than with C2FsI, but when the aryl group contains

electron withdrawing elements, the yields are good and comparable to the ones from

C2FsI (Table 3-3, entries 3.3b 3.5b). Furyl and thiophenyl tosyl imines are not very









reactive but the yields are decent. Like as C2FsI, 1-methyl 3-indolyl tosyl imine is not

reactive at all toward perfluoroalkylation. (Table 3-3, entry 3.8b)

Table 3-3. Nucleophilic perfluorobutylation of tosyl imines

Entry Ar Yield (%)



3.2b 50
Me"



3.3b 70
ClI



3.4b 70
F


3.5b 75
F3C


3.6b / \ 45
S


3.7b / O 40




3.8b 0
^-~N
CH3

Surprisingly the system C4F9I / TDAE provided rather good yields. Unlike with

disulfides where C4F9I didn't seem to be reactive enough (Chapter 2), the system C4F9I /

TDAE provided sometimes yields similar to the ones from C2F5I / TDAE.









3.5 Conclusion

The nucleophilic trifluoromethylation methodology of tosyl imines using

trifluoromethyl iodide and TDAE could be extended successfully with pentafluoroethyl

iodide and nonafluorobutyl iodide. Different substrates were used and provided fair to

very good yields.

3.6 Experimental

Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus

300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with

external tetramethylsilane (TMS, 6 = 0.00 ppm) as a reference. Fluorine (19F) and proton

(1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFC13, 6 =

0.00 ppm) as a reference for 19F NMR and TMS (6 = 0.00 ppm) for H NMR. Deuterated

chloroform (CDC13) was used as NMR solvent.

3.6.1 Syntheses of Tosyl Imines

Synthesis ofN-(benzylidene)-p-methylbenzenesulfonamide (3.1)

In a 100 mL one-neck round bottom flask, 4-toluenesulfonamide (2.57g, 15 mmol)

and benzaldehyde (1.52 mL, 15mmol) was mixed in 40 mL of toluene. BF3-EtO2 (0.15

mL) was added under N2. The flask was equipped with a Dean-Stark apparatus. The

reaction mixture was refluxed for 14 hours, then cooled to room temperature and poured

into 2M NaOH (10mL). The organic phase was washed with brine and water until neutral

pH, dried over anhydrous magnesium sulfate and the solvent was removed by vacuum.

The oily residue was recrystallized from ethyl acetate to give a white solid; yield: 3.11 g

(80 %)









1HNMR (CDC13) 6 9.03 (s, 1H, CH=N-Ts); 7.91 (m, 4H, ArH); 7.62 (m, 1H,

ArH); 7.48 (m, 2H, ArH); 7.34 (m, 2H, ArH); 2.44 (s, 3H, CH3) ppm.

Synthesis of N-(4-methylbenzylidene)-p-methylbenzenesulfonamide (3.2)

The procedure and the workup are the same as the synthesis of N-(benzylidene)-p-

methylbenzenesulfonamide, using 4-methylbenzaldehyde toyield 85 % of white solid

1H NMR (CDC13) 6 8.99 (s, 1H, CH=N-Ts); 7.88 (d, J = 8.1 Hz, 2H, ArH); 7.82 (d,

J = 8.1 Hz, 2H, ArH); 7.34 (d, J = 8.1 Hz, 2H, ArH); 7.29 (d, J = 8.1 2H, ArH); 2.43 (s,

6H, CH3) ppm.

Synthesis of N-(4-chlorobenzylidene)-p-methylbenzenesulfonamide (3.3)

In a 100 mL one-neck round bottom flask, 4-toluenesulfonamide (2.57g, 15 mmol)

and 4-chlorobenzaldehyde (2.10g, 15mmol) was mixed in 40 mL of toluene. BF3-EtO2

(0.15 mL) was added under N2. The flask was equipped with a Dean-Stark apparatus. The

reaction mixture was refluxed for 14 hours, and then cooled to room temperature. White

crystals precipitated upon cooling. The solid was filtered, then washed with water and

dried under vacuum. Yield = 2.74 g (85 %)

H NMR (CDC13) 6 8.99 (s, 1H); 7.89 (d, J = 6.3 Hz, 2H); 7.86 (d, J = 6.3 Hz, 2H);

7.47 (d, J = 8.4 Hz, 2H); 7.35 (d, J = 8.4 Hz, 2H); 2.44 (s, 3H) ppm.

Synthesis of N-(4-fluorobenzylidene)-p-methylbenzenesulfonamide (3.4)

The procedure and the workup are the same as the synthesis of N-(benzylidene)-p-

methylbenzenesulfonamide, using 4-fluorobenzaldehyde to yield 88% of white solid.

H NMR (CDC13) 6 9.00 (s, 1H, CH=N-Ts); 7.96 (m, 2H, ArH); 7.89 (d, J = 8.4

Hz, 2H, ArH); 7.35 (d, J = 8.7 Hz, 2H, ArH); 7.19 (m, 2H, ArH); 2.44 (s, 3H, CH3) ppm.

19F NMR (CDC13) 6 -101.59 (t, J = 8.7 Hz, 1F) ppm.









Synthesis of N-(4-trifluoromethylbenzylidene)-p-methylbenzenesulfonamide (3.5)

Following the above procedure for 3.3, by using 4-trifluoromethylbenzaldehyde

(2mL, 15mmol), provided 3.92 g (80% yield) of white solid.

1H NMR (CDC13) 6 9.08 (s, 1H, CH=N-Ts); 8.04 (d, J = 8.1 Hz, 2H, ArH); 7.90 (d,

J = 8.4 Hz, 2H, ArH); 7.75 (d, J = 8.1 Hz, 2H, ArH); 7.34 (d, J = 8.4 Hz, 2H, ArH); 2.45

(s, 3H, CH3) ppm.

19F NMR (CDC13) 6 -63.83 (s, 3F, CF3) ppm.

Synthesis of N-(2-thiophenylmethylene)-p-methylbenzenesulfonamide (3.6)

In a 100 mL one-neck round bottom flask, 4-toluenesulfonamide (2.57g, 15 mmol)

and 2-thiophenecarboxaldehyde (1.4 mL, 15mmol) was mixed in 40 mL of toluene. A

catalytic amount of p-toluenesulfonic acid monohydrate was added. The flask was

equipped with a Dean-Stark apparatus. The reaction mixture was refluxed for 14 hours.

The solution turned quickly dark green and black tar was formed. After 14 hours,

charcoal was added to the hot solution and the mixture was stirred at 100 oC for 1 hour

and filtered while it was still hot. The solvent was removed under vacuum.

Recrystallization from benzene gave 1.07g (30%) of N-(2-thiophenylmethylene)-p-

methylbenzenesulfonamide as a silvery gray solid

1H NMR (CDC13) 6 9.11 (s, 1H, CH=N-Ts); 7.87 (d, J = 8.7 Hz, 2H, ArH); 7.77 (d,

J = 4.2 Hz, 2H, ArH); 7.34 (d, J = 8.7 Hz, 2H, ArH); 7.21 (m, 1H, ArH); 2.44 (s, 3H,

CH3) ppm.









Synthesis of N-(2-furanylmethylene)-p-methylbenzenesulfonamide (3.7)

The same procedure and workup as for N-(2-thiophenylmethylene)-p-

methylbenzenesulfonamide, using 2-furfural (1.24mL, 15 mmol), gave 2.43 g (65%) of

light brown solid.

1HNMR (CDC13) 6 8.81 (s, 1H, CH=N-Ts); 7.87 (d, J = 8.4 Hz, 2H, ArH); 7.74

(m, H, ArH); 7.34 (m, 3H, ArH); 6.64 (dd, J = 5.1 and 3.3 Hz, 1H, ArH); 2.43 (s, 3H,

CH3) ppm.

Synthesis of N-(N-methyl-3-indolylmethylene)-p-methylbenzenesulfonamide (3.8)

In a 100 mL one-neck round bottom flask, 4-toluenesulfonamide (2.57g, 15 mmol)

and N-methyl-3-indolcarbaxaldehyde (2.39 g, 15mmol) was mixed in 40 mL of toluene.

A catalytic amount of p-toluenesulfonic acid monohydrate was added. The flask was

equipped with a Dean-Stark apparatus. The reaction mixture was refluxed for 14 hours.

The solution became rapidly deep purple. After reflux, the reaction mixture was cooled to

room temperature and the solvent was removed in vacuo. The crude solid was

recrystallized in benzene to give 4.27 g (95% yield) of N-(N-methyl-3-indolylmethylene)-

p-methylbenzenesulfonamide as a purple solid.

1H NMR (CDC13) 6 9.09 (s, 1H, CH=N-Ts); 8.30 (d, J = 6.9 Hz, 1H, ArH); 7.89 (d,

J = 8.1 Hz, 2H, ArH); 7.74 (s, 1H, ArH); 7.33 (3, 5H, ArH); 3.88 (s, 3H, N-CH3); 2.40 (s,

3H, CH3) ppm.

3.6.2 General Procedure for Pentafluoroethylation of Tosyl Imines : Synthesis of
Methyl-N-(3,3,3,2,2-pentafluoro-1-phenyl-propyl)-benzenesulfonamide (3.1a)

In 25 mL, 3-neck-round bottom flask, equipped with a total reflux condenser and

N2, N-(benzylidene)-p-methylbenzenesulfonamide (0.259 g, 1 mmol) was disolved in 6

mL of anhydrous DMF. The solution was cooled at -30 oC. Pentafluoroethyl iodide (0.6









g, 2.4 mmol) was then introduced to the solution. TDAE (0.51 mL, 2.2 mmol) was added

around -20 C. The reaction mixture became quickly orange red. The reaction was

allowed to warm up slowly to room temperature. And as the bath temperature reached -

10 C white solid was formed. The reaction mixture was stirred at room temperature

overnight. About 15 mL of 10% H2S04 aqueous solution was added slowly to quench the

reaction. As the acid solution was added, the reaction mixture first became clear as the

TDAE salt was dissolved in water. But the mixture became cloudy again as the product

precipitated out. The solution was stirred for a while as more and more product

precipitated. The solid was collected via filtration and dissolved in 30 mL of ether. The

ether solution was washed 3 times with water to eliminate remaining DMF. The ether

phase was dried over anhydrous MgSO4 and the solvent was removed by vacuum. The

pale yellow crude product was recrystallized in toluene to afford 0.189 g of a white solid.

(50%)

1HNMR (CDC13) 6; 7.52 (d, J = 8.4 Hz, 2H, ArH); 7.24 (m, 3H, ArH); 7.10 (m,

4H, ArH); 5.48 (d, J = 9.9 Hz, 1H, NH); 4.97 (m, 1H, CH-N); 2.33 (s, 3H, CH3) ppm.

19F NMR (CDC13) 6 -81.42 (s, 3F, CF2-CF3); -120.67 (dd, J1 = 291.9 Hz, J2 = 12.9

Hz, 1F, CF-CF3); -122.86 (dd, Ji = 291.6 Hz, J2 = 12.6 Hz, 1F, CF-CF3) ppm.

Anal. Calcd for C16H14F8NO2S: C, 50.670; H, 2.694; N, 3.694. Found: C, 50.390;

H, 3.591; N, 3.590.









4-Methyl-N- [3,3,3,2,2-pentafluoro-(4-methyl-phenyl)-propyl]-benzenesulfonamide

(3.2a) White solid (70 % yield)

1H NMR (CDC13) 6; 7.52 (d, J = 8.1 Hz, 2H, ArH); 7.09 (d, J = 8.1 Hz, 2H, ArH);

7.02 (d, J = 8.4 Hz, 2H, ArH); 6.98 (d, J = 8.7 Hz, 2H, ArH); 5.50 (d, J = 9.9 Hz, 1H,

NH); 4.92 (m, 1H, CH-N); 2.34 (s, 3H, CH3); 2.29 (m, 3H, CH3) ppm.

19F NMR (CDC13) 6 -81.42 (s, 3H, CF2-CF3); -120.72 (dd, J1 = 291.6 Hz, J2 = 12.6

Hz, IF, CF-CF3); -122.78 (dd, Ji = 291.6 Hz, J2 = 12.6 Hz, IF, CF-CF3) ppm.

Anal. Calcd for C17H16F5NO2S: C, 51.908; H, 4.071; N, 3.562. Found: C, 51.716;

H, 4.015; N, 3.503.

4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-chloro-phenyl)-propyl]-benzenesulfonamide

(3.3a) White solid (70 % yield)

1HNMR (CDC13) 6; 7.51 (d, J = 8.4 Hz, 2H, ArH); 7.21 (d, J = 8.4 Hz, 2H, ArH);

7.13 (d, J = 8.4 Hz, 2H, ArH); 7.05 (d, J = 8.4 Hz, 2H, ArH); 5.24 (d, J = 9.3 Hz, 1H,

NH); 4.98 (m, 1H, CH-N); 2.38 (s, 3H, CH3) ppm.

19F NMR (CDC13) 6 -81.39 (s, 3H, CF2-CF3); -120.35 (dd, J1 = 293.7 Hz, J2 = 13.5

Hz, 1F, CF-CF3); -123.33 (dd, Ji = 293.7 Hz, J2 = 13.5 Hz, 1F, CF-CF3) ppm.

Anal. Calcd for C16H13C1F5N02S: C, 46.398; H, 3.141; N, 3.383. Found: C, 46.255;

H, 3.122; N, 3.355.

4-Methyl-N- [3,3,3,2,2-pentafluoro-(4-fluoro-phenyl)-propyl] -benzenesulfonamide

(3.4a) White solid (72 % yield)

1H NMR (CDC13) 6; 7.52 (d, J = 8.4 Hz, 2H, ArH); 7.12 (m, 4H, ArH); 6.92 (t, J =

8.4 Hz, 2H, ArH); 5.37 (d, J = 9.3 Hz, 1H, NH); 4.98 (m, 1H, CH-N); 2.36 (s, 3H, CH3)


ppm.









19F NMR (CDC13) 6 -81.39 (s, 3H, CF2-CF3); -111.84 (m, IF, ArF) -120.60 (dd, J1

= 291.3 Hz, J2 = 11.1 Hz, IF, CF-CF3); -123.19 (dd, J1 = 293.7 Hz, J2 = 13.5 Hz, IF, CF-

CF3) ppm.

Anal. Calcd for C16H13F6NO2S: C, 48.363; H, 3.274; N, 3.526. Found: C, 48.259;

H, 3.266; N, 3.333

4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-trifluoromethyl-phenyl)-propyl]-

benzenesulfonamide (3.5a) White solid (68 % yield)

1H NMR (CDC13) 6 7.47 (d, J = 6.1 Hz, 2H, ArH); 7.45 (d, J = 6.1 Hz, 2H, ArH);

7.23 (d, J = 8.1 Hz, 2H, ArH); 7.06 (d, J = 8.1 Hz, 2H, ArH); 5.65 (d, J = 9.9 Hz, 1H,

NH); 5.05 (m, 1H, CH-CF2); 2.31 (s, 3H, CH3) ppm.

19F NMR (CDC13) 6 -63.54 (s, 3F, CF3); -81.41 (s, 3H, CF2-CF3); -119.54 (dd, J1 =

292.5 Hz, J2 = 14.4 Hz, IF, CF-CF3); -123.91 (dd, J1 = 292.5 Hz, J2 = 14.4 Hz, IF, CF-

CF3) ppm.

Anal. Calcd for C17H13F8NO2S: C, 45.638; H, 2.908; N, 3.132. Found: C, 45.340;

H, 2.833; N, 3.011.

4-Methyl-N- [3,3,3,2,2-pentafluoro-(2-thiophenyl)-propyl]-benzenesulfonamide (3.6a)

White solid (55 % yield)

1HNMR (CDC13) 6 7.58 (d, J = 8.4 Hz, 2H, ArH); 7.25 (m, 1H); 7.17 (d, J = 8.4

Hz, 2H, ArH); 6.88 (m, 2H); 5.34 (m, 1H, CH-N); 5.018 (m, 1H, NH) 2.38 (s, 3H, CH3)

ppm.

19F NMR (CDC13) 6 -82.29 (s, 3H, CF2-CF3); -120.71 (dd, J1 = 289.2 Hz, J2 11.1

Hz, IF, CF-CF3); -123.36 (dd, J1 = 289.2 Hz, J2 = 11.1 Hz, IF, CF-CF3) ppm.









Anal. Calcd for C14H12F5N02S2: C, 43.636; H, 3.117; N, 3.636. Found: C, 43.578;

H, 3.099; N, 3.620.

4-Methyl-N-[3,3,3,2,2-pentafluoro-(2-furanyl)-propyl]-benzenesulfonamide (3.7a)

Light brown solid (60 % yield)

1HNMR (CDC13) 6 7.60 (d, J = 8.4 Hz, 2H, ArH); 7.19 (m, 3H); 6.21 (m, 2H,

ring); 5.33 (d, J = 10.2 Hz, 1H, NH); 5.11 (m, 1H, CH-CF2); 2.38 (s, 3H, CH3) ppm.

19F NMR (CDC13) 6 -82.02 (s, 3H, CF2-CF3); -120.72 (dd, J1 = 291.3 Hz, J2 = 13.2

Hz, 1F, CF-CF3); -122.33 (dd, J1 = 289.2 Hz, J2 = 13.1 Hz, 1F, CF-CF3) ppm.

Anal. Calcd for C14H12F5NO3S: C, 45.528; H, 3.252; N, 3.790. Found: C, 45.246;

H, 3.255; N, 3.747.

3.6.3 General Procedure for Perfluorobutylation of Tosyl Imines: Synthesis of 4-
Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-methyl-phenyl)-propyl]-
benzenesulfonamide (3.2b)

In a 25 mL round bottom flask, connected with N2, N-(4-methylbenzylidene)-p-

methylbenzenesulfonamide (0.273 g, 1 mmol) was disolved in 6 mL of anhydrous DMF.

The solution was cooled at -30 oC. Nonafluorobutyl iodide (0.38 mL, 2.2 mmol) was then

introduced to the solution. TDAE (0.51 mL, 2.2 mmol) was added around -20 C. The

reaction mixture became quickly orange red and white solid was formed shortly after the

addition of TDAE. The reaction was allowed to warm up slowly to room temperature.

The reaction mixture was stirred at room temperature overnight. About 15 mL of 10%

H2SO4 aqueous solution was added slowly to quench the reaction. As the acid solution

was added, the reaction mixture first became clear as the TDAE salt was dissolved in

water. But the mixture became cloudy again as dark brown oil could be seen forming.

The solution was stirred for several hours as more brown vicous oil was formed. 30 mL









of ether were added to dissolve the oil. The two phases were separated and the ether

solution was washed 3 times with water to eliminate remaining DMF. The ether phase

was dried over anhydrous MgSO4 and the solvent was removed by vacuum. The pale

yellow crude product was recrystallized in toluene to afford 0.189 g of a white solid.

(50%)

1HNMR (CDC13) 6; 7.51 (d, J = 8.4 Hz, 2H, ArH); 7.09 (d, J = 8.1 Hz, 2H, ArH);

7.00 (m, 4H, ArH); 5.33 (d, J = 9.9 Hz, 1H, NH); 5.04 (m, 1H, CH-N); 2.34 (s, 3H, CH3);

2.29 (s, 3H, CH3) ppm.

19F NMR (CDC13)6 -81.43 (t, J = 9.9, 3F, CF2-CF3); -116.98 (dm, J1 = 301.5 Hz,,

1F, CF-CH); -118.88 (dm, J1 = 301.5 Hz, 1F, CF-CH); -121.47 (m, 2F, CF2); 126.53 (m,

2F, CF2) ppm.

Anal. Calcd for C19H16F9NO2S: C, 46.212; H, 3.243; N, 2.837. Found: C, 46.239;

H, 3.185; N, 2.821

4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-chloro-phenyl)-propyl]-

benzenesulfonamide (3.3b) White solid (70 % yield)

1HNMR (CDC13) 6; 7.50 (d, J = 8.4 Hz, 2H, ArH); 7.18 (d, J = 8.7 Hz, 2H, ArH);

7.11 (d, J = 7.8 Hz, 2H, ArH); 7.04 (d, J = 8.4 Hz, 2H, ArH) 5.60 (d, J = 9.9 Hz, 1H,

NH); 5.07 (m, 1H, CH-N); 2.37 (s, 3H, CH3) ppm.

19F NMR (CDC13)6 -81.41 (t, J = 11.1, 3F, CF2-CF3); -116.52 (dm, J1 = 304.8 Hz,

1F, CF-CH); -119.38 (d3, J = 304.8 Hz, 1F, CF-CH); -121.37 (m, 2F, CF2); 126.55 (m,

2F, CF2) ppm.

Anal. Calcd for C18H13C1F9NO2S: C, 42.038; H, 2.530; N, 2.724. Found: C, 41.904;

H, 2.457; N, 2.685.









4-Methyl-N- [5,5,5,4,4,3,3,2,2-nonafluoro-(4-trifloromethyl-phenyl)-propyl]-

benzenesulfonamide (3.5b) White solid (75 % yield)

1H NMR (CDC13) 6; 7.47 (d, J = 8.1 Hz, 2H, ArH); 7.42 (d, J = 8.4 Hz, 2H, ArH);

7.22 (d, J = 8.1 Hz, 2H, ArH); 7.04 (d, J = 8.4 Hz, 2H, ArH) 5.99 (d, J = 10.2 Hz, 1H,

NH); 5.16 (m, 1H, CH-N); 2.31 (s, 3H, CH3) ppm.

19F NMR (CDC13)6 -63.57 (s, 3F, Ar-CF3); -81.41 (t, J = 11.1 Hz, 3F, CF2-CF3); -

115.84 (dm, J = 304.5 Hz, IF, CF-CH); -119.77 (dm, J = 304.5 Hz, IF, CF-CH); -121.33

(m, 2F, CF2); 126.52 (m, 2F, CF2) ppm.

Anal. Calcd for C19H13F12N02S: C, 41.654; H, 2.375; N, 2.558. Found: C, 41.751;

H, 2.297; N, 2.553

4-Methyl-N- [5,5,5,4,4,3,3,2,2-nonafluoro-(2-thiophenyl -phenyl)-propyl]-

benzenesulfonamide (3.6b) White solid (45 % yield)

1H NMR (CDC13) 6; 7.57 (d, J = 8.1 Hz, 2H, ArH); 7.23 (m, 1H, ring); 7.14 (d, J =

8.1 Hz, 2H, ArH); 6.90 (m, 1H, ring); 6.83 (m, 1H, ring); 5.42 (m, 2H, CH-N and NH);

2.36 (s, 3H, CH3) ppm.

19F NMR (CDC13) 6 -81.39 (t, J = 11.1 Hz, 3F, CF2-CF3); -116.69 (dm, J = 297.9

Hz, 1F, CF-CH); -119.22 (dm, J = 297.9 Hz, 1F, CF-CH); -121.47 (m, 2F, CF2); 126.52

(m, 2F, CF2) ppm.

Anal. Calcd for C16H12F9NO2S2: C, 39.555; H, 2.472; N, 2.884. Found: C, 39.567;

H, 2.421; N, 2.778









4-Methyl-N- [5,5,5,4,4,3,3,2,2-nonafluoro-(2-furanyl-phenyl)-propyl]-

benzenesulfonamide (3.7b) Brown solid (40 % yield)

1HNMR (CDC13) 6; 7.59 (d, J = 8.4 Hz, 2H, ArH); 7.26 (m, 1H, ring); 7.19 (d, J =

8.4 Hz, 2H, ArH); 6.21 (m, 2H, ring); 5.42 (m, 2H, CH-N and NH); 2.38 (s, 3H, CH3)

ppm.

19F NMR (CDC13) 6 -81.40 (t, J = 11.1 Hz, 3F, CF2-CF3); -116.69 (dm, J = 297.9

Hz, 1F, CF-CH); -119.22 (dm, J = 297.9 Hz, 1F, CF-CH); -121.47 (m, 2F, CF2); 126.52

(m, 2F, CF2) ppm.

Anal. Calcd for C16H12F9NO3S: C, 40.908; H, 2.557; N, 2.983. Found: C, 40.733;

H, 2.446; N, 2.907
















CHAPTER 4
PERFLUOROAKYLATION OF ALDEHYDES AND KETONES

4.1 Introduction

Along with a-trifluoromethyl alcohols, longer a-perfluoroalkyl alcohols are

generating growing interests from industries, as one can notice the fast increase of the

number of patented molecules containing a-perfluoroalkyl alcohol function in the past

few years. These molecules can be used as fungicide56 (Figure 4-1) or insecticide.57


o



OH F
F3 C- CF 2

Figure 4-1. 4A56 : Fungicide

Cl CF 3

NC \ I


Cl
F3C- (CF2) 3-CH NH2

OH

Figure 4-2. 4B57 : insecticide

Our laboratories have developed successfully nucleophilic trifluoromethylation of

aldehydes and ketones by using CF3I / TDAE system12. Since the methodology could be

extended for pentafluoroethyl iodide and nonafluorobutyl iodide for disulfides (Chapter

2) and tosyl imines (Chapter 3), the research was then performed on aldehydes and

ketones.









4.2 Pentafluoroethylation of Aldehydes and Ketones

The procedure for the pentafluoroethylation of aldehydes and ketones is very

similar than the trifluoromethylation of aldehydes12. Since earlier studies on the C2F5I /

TDAE system have shown that the resulting complex is stable below -10 C (Chapter 2),

the reaction could be performed at -15 or -10 OC.

O OH
11 + CF3CF2I + TDAE DMF Ri R2
R, R2 -15 oC to RT
CF2CF3
hv, 1 hr
1 eq 2.2 eq 2.2 eq RT, 12 hrs

Scheme 4-1. Pentafluoroethylation of aldehydes and ketones

By comparison to the yields obtained in trifluoromethylation, the products from

pentafluoroethylation were obtained in very similar yields. The yields are generally lower

except for fluorenone (entry 4.5) where the yield was 95 % compared to 73 % for

trifluoromethylated product. The aromatic aldehydes provided high yields (entries 4.1-

4.3). The yields from ketones products are decent, but this may be explained by a lower

reactivity than aldehydes towards nucleophilic reaction for ketones. As expected, ketones

or aldehydes bearing a hydrogen on c-carbon resulted in low to very low yields (entries

4.6 and 4.7). Butyraldehyde, that had already low yield for trifluoromethylation, provided

only 5 % yield, which is not really interesting. These low yields can be explained by the

fact that TDAE is also a strong base and would readily deprotonate acid hydrogens in the

substrates, creating enolates, in the case of aldehydes and ketones.









Table 4-1. Compared yields between pentafluoroethylation and trifluoromethylation of
aldehydes and ketones
Yield with
Entry Substrate Yield (%) CF3112 (%)

O

4.1 90 Quant.





4.2 75 80





4.3 0 80 83





4.4 Q 95 73

0

0
4.5 & 0 55 68



0
4.6 50 50





4.7 / o 5 15









4.3 Perfluorobutylation of Aldehydes and Ketones

Since nucleophilic pentafluoroethylation of aldehydes and ketones with C2FsI /

TDAE system could provide good yields and comparable to trifluoromethylation with

CF3I / TDAE system, the methodology was extended with C4F91.

0 OH
S + C4F9I + TDAE DMF RI R2
R, R2 -20 oC to RT
C4F9
hv, 1 hr
1 eq 2.2 eq 2.2 eq RT, 12 hrs

Scheme 4-2. Nucleophilic perfluorobutylation of aldehydes and ketones

The yields obtained are very low: 35 % for benzaldehyde and 20 % for

cyclohexanone. Similar low reactivity of C4F9I / TDAE system was already observed in

the case of disulfides (Chapter 2). The fact that the C4F9I / TDAE complex is not very

stable and tends to decompose shortly after the addition of TDAE to the reaction mixture

may explain this low reactivity. Moreover the Sun Lamp that provided the light

irradiation produces a lot heat, this additional heat may be the cause of lower yields.

Table 4-2. Perfluorobutylation of aldehydes and ketones

Entry Substrate % yield







0
4.9 2059

4.9 d 2059









4.4 Conclusion

In the same manner than with disulfides and tosyl imines the C2FsI / TDAE system

provided very similar yields than CF3I / TDAE system. However C4F9I / TDAE system

proved to be not reactive enough towards aldehydes and ketones and provided really low

yields. The CF3I / TDAE methodology could be successfully extended to C2F5I. But

C4F91 seems to be the limit of this methodology in nucleophilic perfluoroalkylation of

aldehydes because the yields are so low that it is not interesting to develop further the

reaction.

4.5 Experimental

Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus

300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with

external tetramethylsilane (TMS, 6 = 0.00 ppm) as a reference. Fluorine (19F) and proton

(1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFC13, 6 =

0.00 ppm) as a reference for 19F NMR and TMS (6 = 0.00 ppm) for H NMR. Deuterated

chloroform (CDC13) was used as NMR solvent.

4.5.1 General Procedure of Pentafluoroethylation of Aldehydes and Ketones:
Synthesis of 1-Phenyl-2,2,3,3,3-pentafluoropropan-l-ol (4.2)

In 25 mL, 3-neck-round bottom flask, equipped with a reflux condenser and N2,

benzaldehyde (0.37 mL, 3.68 mmol) was disolved in 10 mL of anhydrous DMF. The

solution was cooled at -20 oC and C2F5I (2.0 g, 8.1 mmol) was introduce into the solution.

Then TDAE (2 mL, 8.1 mmol) was added into the reaction mixture. The color of the

reaction mixture became dark red as TDAE was added. The mixture was allowed to

warm up slowly to room temperature. The reaction was irradiated by a Sun lamp for 1

hour. White solid was formed as the temperature of the bath reached -10 C. The reaction









mixture was stirred at room temperature overnight. The orange solution was filtered and

the solid was washed with diethyl ether. The DMF solution was hydrolyzed with water

and was extracted with ether (3 times). The combined ether layers were washed with

brine and dried over MgSO4. The solvent was removed and the crude product was

purified by column chromatography to afford colorless liquid60 at 90 % yield

1HNMR (CDC13, 300MHz) 6 7.45 -7.70 (m, 5H, ArH); 5.06 (m, 1H, CHCF2); 2.87

(s, 1H, OH) ppm.

19F NMR (CDC13, 300 MHz) 6 -81.90 (m, 3F, CF3), -122.80 (m, 1F, CF3CFF), -

129.50 (m, 1F, CF3CFF) ppm.

1-Naphthyl-2,2,3,3,3-pentafluoropropan-l-ol (4.2)

1H NMR (CDC13, 300MHz) 6 8.05 (d, J = 8.4 Hz, 1H, ArH); 8.0 7.82 m, 3H,

ArH); 7.65- 7.32 (m, 3H, ArH); 5.89 (m, 1H, CHCF2); 2.85 (s, 1H, OH) ppm

19F NMR (CDC13, 300 MHz) = -81.54 (m, 3F, CF3), -118.15 (dd, J1 = 290.4 Hz, J2

= 20.7 Hz, 1F, CF2), -130.24 (dd, J1 = 290.4 Hz, J2 = 20.7 Hz, 1F, CF2) ppm

1,1,1,2,2-Pentafluoro-5-(2methoxy-phenyl)-pent-4-en-3-ol (4.3)

1HNMR (CDC13, 300MHz) 6 7.45 (dd, J1 = 7.7 Hz, J2 = 1.8 Hz, 1H, ArH); 7.31

(m, 1H, ArH); 7.25 (d, J = 16.2 Hz, 1H, ArH); 6.95 (m, 1H, ArH); 6.87 (dd, Ji = 7.5 Hz,

J2 = 0.9 Hz, 1H) 6.27 (dd, J1 = 16.2, Hz, J2 = 7.1 Hz, 1H); 4.66 (m, 1H, CHCF2); 3.87 (s,

3H, OCH3); 2.26 (s, 1H, OH)

19F NMR (CDC13, 300 MHz) = -81.40 (m, 3F, CF3), -122.25 (AB, dd, Ji = 291 Hz,

J2 = 9.9 Hz, 1F, CFF CF3); -129.12 (dd, Ji = 291 Hz, J2 = 9.9 Hz, 1F, CFFCF3) ppm









9-Pentafluoroethyl fluoren-9-ol (4.4)

1H NMR (CDC13, 300MHz) 6 7.67 (m, 4H, ArH); 7.48 (m, 2H, ArH); 7.36 (m, 2H,

ArH); 3.01 (s, 1H, OH)

19F NMR (CDC13, 300 MHz) = -78.62 (s, 3F, CF3), -121.29 (s, 2F, CF2) ppm

1,1-Diphenyl-2,2,3,3,3-pentafluoropropan-l-ol (4.5)61

19F NMR (CDC13, 300 MHz) = -84.65 (s, 3F, CF3), -115.97 (s, 2F, CF2) ppm

Pentafluoroethyl cyclohexan-1-ol (4.6)62

19F NMR (CDC13, 300 MHz) = -78.17 (s, 3F, CF3), -126.25 (s, 2F, CF2) ppm

1,1,1,2,2-Pentafluorobutan-3-ol (4.7)63

19F NMR (CDC13, 300 MHz) = -81.57 (m, 3F, CF3), -122.75 (m, 1F, CF3CFF), -

131.40 (m, 1F, CF3CFF) ppm

4.5.2 General Procedure for Perfluorobutylation of Aldehydes and Ketones:
Synthesis of 1-Phenyl-2,2,3,3,4,4,5,5,5-nonafluoropentan-l-ol

In a 25 mL round bottom flask, connected N2, benzaldehyde (0.37 mL, 3.68 mmol)

was disolved in 10 mL of anhydrous DMF. The solution was cooled at -30 oC and C4F9I

(0.75 mL, 8.1 mmol) was introduce into the solution via a syringe. Then TDAE (2 mL,

8.1 mmol) was added into the reaction mixture at -20 oC. The color of the reaction

mixture became dark red as TDAE was added. The reaction was irradiated by a Sun

lamp.The mixture was allowed to warm up slowly to room temperature. White solid was

formed shortly after the addition of TDAE. The reaction mixture was stirred at room

temperature overnight with the presence ofiradiation. The orange solution was filtered

and the solid was washed with diethyl ether. 20 mL of water were added to the filtrate the

two layers were separated and the aqueous phase was extracted with ether (3 times). The






51


combined ether layers were washed with brine and dried over MgSO4. The solvent was

removed by vacuum and the crude product was purified by column chromatography.













CHAPTER 5
SYNTHESES AND STUDIES OF TETRAKIS(DIMETHYLAMINO)ETHYLENE
ANALOGUES

5.1 Introduction

Our laboratories have successfully developed methodologies for nucleophilic

perfluoroalkylation of numerous subtrates.12,13,14,15,50 These methodologies consist in

reducing perfluoroalkyl iodides with tetrakis(dimethylamino)ethylene (TDAE), creating

perfluoroalkyl anions which can undergo nucleophilic reactions on different eletrophilic

substrates. The mechanism of the reactions is still not totally understood. But it is known

that as TDAE was introduced into the reaction mixture containing perfluoroalkyl iodide

and the substrate, TDAE formed a temperature-dependently stable complex with

perfluoroalkyl iodide. As the reaction temperature rose above these critical temperatures

(0 C for CF3I, -10 C for C2FsI and -20 C for C4F9I), the complex decomposed freeing

perfluoroalkyl anion, which only then reacted with the substrate (Scheme 5-1).


Substrate -20 oC Substrate
0 product
CF3I complex

TDAE TDAE2+ CF3 I-

Scheme 5-1. CF3I / TDAE complex

At this point, we have little knowledge about the complex and its decomposition. It

is not sure whether the product resulted from an attack from a free perfluoroalkyl anion

or from an intermediate form where TDAE is still involved. In the latter case, the

presence of chirality in the complex would induce chirality in the final product. This









would be particularly interesting in the case of reactions with aldehydes and ketones

where an asymmetric carbon is created from the addition of perfluoroalkyl group to the

carbonyl carbon. Since there is no preferential side of attack, the resulting ca-

perfluoroalkyl alcohol is a racemic mixture. The aim is then to synthesize analogue

molecules to TDAE, conserving the tetrakis-amino ethylene part and possessing a

structure that would be able to bear asymmetric carbons. The structure would be a cyclic

analogue to TDAE containing asymmetric carbons, as shown in Figure 5-1.


R R
R' R'


N N
R R

Figure 5-1. Structure of a chiral TDAE analogue

But the non chiral cyclic TDAE analogue -1,3,1',3'-tetraalkyl-2,2'-

bis(imidazolidene)- (Figure 5-2), would be first synthesized and studied to see if

comparable results than TDAE could be obtained.


R R
/ \
N N


N N
R /
R R


Figure 5-2. Non chiral TDAE analogue









5.2 Syntheses of TDAE Analogues

5.2.1 Synthesis of 1,3,1',3'-Tetraalkyl-2,2'-bis(imidazolidene)

Two analogues were synthesized where R were methyl group and ethyl group. The

one-pot synthesis involved reaction between N, N'-diethylethylene diamine or N,N'-

dimethylethylene diamine and N,N'-dimethylformamide dimethyl acetate64. The two

reagents were dissolved in benzene and were heated at 110 oC for 4 hours then the

product was collected via distillation under reduced pressure. The resulting products are a

pale yellow liquid for 1,3,1',3'-tetraethyl-2,2'-bis(imidazolidene) and a pale yellow solid

for 1,3,1',3'-tetramethyl-2,2'-bis(imidazolidene) with 40% yield for both products.

R R R
/ / \
NH -0 / bN N
/ benzene ___
NH --O reflux 4 hrs
NH -0 N N
R R R

1 equiv. 1.2 equiv. 40%
R= Me (5.1)
or Et

Scheme 5-2. Synthesis of 1,3,1',3'-tetraalkyl-2,2'-bis(imidazolidene)

5.2.2 Synthesis of 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene)

The other analogue we were interested in synthesizing was.


/


Figure 5-3. benzimidazole TDAE analogue








The synthesis of 1,3,1',3'-tetramethyl-2,2'-bis(benzimidazolylidene)consisted in 3

steps. The first step is the synthesis ofbenzimidazole65 by reacting 1,2-diaminobenzene

with formic acid. The reaction yielded 87%.

The second step was the methylation of the amino groups with iodomethane to

form 1,3-dimethyl-benzimidazolium iodide66 in 85% yield. The final step involved

deprotonation of the hydrogen on imine carbon, producing a carbene which recombined

to itself to form 1,3,1',3'-tetramethyl-2,2'-bis(benzimidazolylidene)67 resulting in a

brown solid in 50%.

H
NH 2 A+ H20
+ HCO2H + H20
NH, N
(5.2)

H
N /
S+ 2MeI >
"N "No p1

(5.3)



2 NaHl
>N i THF HN /N

(5.4)

Scheme 5-3. Multi-step synthesis of benzimidazole TDAE analogue









5.3 Attempts of Trifluoromethylation using the TDAE Analogues

5.3.1 Attempts of Trifluoromethylation using 1,3,1',3'-Tetraalkyl-2,2'-
bis(imidazolidene) instead of TDAE

The first attempts of nucleophilic trifluoromethylation using the imidazolidene

TDAE analogue were performed in the same conditions than with TDAE: Anhydrous

DMF was used as solvent and the analogue was added to the solution ofbenzaldehyde

and CF3I at -20 C. The reaction mixture color didn't become deep red as it was always

the case for TDAE. Instead the solution became darker yellow than the color of the

analogue. But the mixture seemed to discolored back to pale yellow few moments later.

The usual salt formation at 0 OC for CF3I / TDAE couldn't be seen by using the

analogue. The solution stayed clear throughout the reaction process. 19F NMR revealed

the presence of the trifluoromethylated adduct but in a yield lower than 10 %. Numerous

reactions of optimization have been performed but no more than 15 % of the product

could be obtained. The "optimized" procedure would introduce the imidazolidene TDAE

analogue at -40 OC, instead of -20 C, and the temperature was kept at -40 OC for more

than 40 minutes before allowing the reaction mixture to warm up slowly to room

temperature and stirred overnight. The reaction was irradiated for 12 hours.


R R CF3
N N
+ CF3I + DMF OH
N N -40 C to RT
R R
1 2.2 2.2 15%

Scheme 5-4. Nucleophilic trifluoromethylation of benzaldehyde using 1,3,1',3'-
tetraalkyl-2,2'-bis(imidazolidene)






57


R R
/ \
N N
PhS-SPh + CF3I + N N \ N DMF PhS-CF3
N N -40 Cto RT 11 %*
\ /
R R based on equiv.
1 4.2 2.2 of disulfides

Scheme 5-5. Synthesis of phenyl trifluoromethyl sulfide by using imidazolidene TDAE
analogue

An attempt of trifluoromethylation of phenyl disulfide was also performed. Only

110 % of phenyl trifluoromethyl thioether could be obtained, instead of nearly 200 % in

the case of TDAE. But the thioether may be resulted from the SRN1 reaction of phenyl

thiolate, formed by reduction of disulfide by TDAE analogue, with CF3I, since the

analogue cannot efficiently create trifluoromethyl anion.


R R R R
N N- + CF, SET N N +
rI)C N N N NN
R R
R = alkyl


I H20 (work-


R R
N, N !
--- \> + :!+ ;CFj +1
N N
R R

up) 11/202


SF3C N



R I R
R R

N N
>: + F3C

R R


R R
I I
N OH
R>LCF3 0=
N N
R R


Scheme 5-6. Possible decomposition pathways for imidazolidene TDAE analogue










The explanation of this lack of reactivity of the TDAE analogue towards CF3I may

be the fact that the cyclic TDAE analogues may give, after one-electron transfer to CF3I,

the corresponding colored radical cation. It seems that the radical cation is quite unstable

since the color disappeared. By decomposing the radical cation would probably give the

corresponding carbene and a new "smaller" radical cation.68 According to recent

studies69, the carbene should not dimerize to form back to the TDAE analogue but may

react with 02 to form a cyclic urea or with benzaldehyde to form an intermediate that

may give a bezoin condensation or the corresponding 2-benzoylimidazoline as final

products.70 (Figure 5-7)


SR R R










R
E c c vy h sPhCHh s rN

N N
N H N Ph
SR R R oe R


R R
NH
N CCHP



Scheme 5-7. Reactivities ofimidazolidene carbene towards benzaldehyde

The cyclic voltammetry experiment was also performed on 1,3,1',3'-tetraethyl-

2,2'-bis(imidazolidene). But the resulting graph didn't show any reversible oxidation

waves corresponding to the formation of stable radical cations (Figure 5-4), whereas

TDAE cyclic voltammetry graph shows reversibility.71




















-- ... --- "" ---- S --esel
3.ooE-06 2.00E-06 1.0E-O 0o. F00 -1.00E -2.oE- 06 -300E-06 -4.00E-B1 -S.00E-06




-2000


-3000



Figure 5-4. Cyclic voltammogram for 1,3,1',3'-Tetraethyl-2,2'-bis(imidazolidene), C =
3mM in DMF + 0.1 mM Et4NBF4 at 20 "C, scan rate: 0.2V/s

5.3.2 Nucleophilic Trifluoromethylation of Phenyl disulfide using 1,3,1',3'-
Tetramethyl-2,2'-bis(benzimidazolylidene)

The attempt of trifluoromethylation of phenyl disulfide with 1,3,1',3'-Tetramethyl-

2,2'-bis(benzimidazolylidene) only provided traces of phenyl trifluoromethyl sulfide. The

analogue may be either too stable or may decompose directly to carbenes since the

compound was synthesized via dimerization oftwo carbenes.

/ \

PhS-SPh + CF3I + N DF PhS-CF3
N N -40 C toRT trace
\ / trace

1 4.2 2.2

Scheme 5-8. Attempt of synthesis of phenyl trifluoromethyl sulfide by using 1,3,1',3'-
tetramethyl-2,2'-bis(benzimidazolylidene)









5.4 Conclusion

The idea of using chiral TDAE analogues to induce chirality in the final products

would have been an interesting project since industries are looking for chiral fluorinated

compounds as biologically active molecules. But the incapacity of these analogues to

generate CF3 anion from CF3I didn't allow us to develop further the idea.

5.5 Experimental

Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus

300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with

external tetramethylsilane (TMS, 6 = 0.00 ppm) as a reference. Fluorine (19F) and proton

(1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFC13, 6 =

0.00 ppm) as a reference for 19F NMR and TMS (6 = 0.00 ppm) for H NMR. Deuterated

chloroform (CDC13) was used as NMR solvent.

5.5.1 Synthesis of 1,3,1',3'-Tetraethyl-2,2'-bis(imidazolidene) (5.1)

N,N-dimethylformamide dimethylacetate (20 mL, 151 mmol) and N,N-

diethylethylene diamine (18.3 mL, 130 mmol) was dissolved in 80 mL of dry benzene.

The solution was refluxed at 110 OC for 3 hours. The azeotrope methanol/benzene was

then distilled out. The remaining solution was cooled to the room temperature and the

solvent was removed by vacuum. The product was distilled out under vacuum (bp = 86-

88 C/3 mmHg). Even though the melting point of 1,3,1',3'-tetraethyl-2,2'-

bis(imidazolidene) is around 48 C, it remained a yellow liquid66. Yield = 50 %

5.5.2 Synthesis of Benzimidazole (5.2)

In a 250 mL round bottom flasko-phenylenediamine (27g, 0.25 mol) is treated with

15 mL of formic acid (17.3 g, 0.38 mol). The mixture was heated and refluxed at 100 C









2 hours. After cooling, 10 % NaOH solution was added until the pH became just basic.

The crude brown product was collected by filtration and was rinsed with ice-cold water.

The crude benzimidazole was then dissolved in 400 mL of boiling water. About 1 g of

celite was added and the mixture was stirred while boiling for 15 minutes before hot

gravity filtration. The filtrate was allowed to cool slowly to room temperature and then

was placed in an ice bath for 20 minutes. The product was filtered and washed with ice-

cold water. The product was dried in the oven overnight to afford 25.69 g (87 % yield) of

pale yellow powder65

MP = 171 173 C

1H NMR(CDC13, 300 MHz) 6 8.10 (s, 1H, N-CH=N); 7.68 (m, 2H, ArH); 7.31 (m,

2H, ArH)

5.5.3 Synthesis of 1,3-Dimethyl-benzimidazolium iodide (5.3)

In a 100 mL round bottom flask, 1.4 g of sodium was added in small portions in 25

mL of absolute ethanol. After all sodium was dissolved, 7.1 g (60 mmol) of

benzimidazole was added to the solution, followed by 25g of iodomethane (180 mmol)

and 20 mL of benzene. The reaction mixture was refluxed for 15 hours. After the reflux,

the solvents were removed by vacuum. And the crude was recrystallized with ethanol to

yield 14.09 g (85 %) of 1,3-dimethyl-benzimidazolium iodide as a pale pinkish solid66.

1H NMR(CDC13, 300 MHz) 6 11.07 (s, 1H, N-CH=N); 7.72 (m, 4H, ArH); 4.28 (s,

3H, CH3); 4.27 (s, 3H, CH3)

5.5.4 Synthesis of 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene) (5.4)

In a 250 mL round bottom flask, 1,3-dimethyl-benzimidazolium iodide (10.09 g,

34.8 mmol) was dissolved in 100 mL of freshly distilled THF and sodium hydride (1.25






62


g, 52.2 mmol) was added slowly to the solution. The mixture was stirred for 3 hours at

the room temperature then 2 hours at 50 C. The solvent was removed by vacuum. 50 mL

of toluene was added to the dark brown residue. The mixture was heated to boil and was

hot-gravity filtered. The yellow filtrate was concentrated, n-hexane was added and the

solution was cooled at -30 oC for overnight. The recrystallized light brown solid was

filtered and dry to give 5.0 g of 1,3,1',3'-tetramethyl-2,2'-bis(benzimidazolylidene)67 (50

% yield)














CHAPTER 6
DIMERIC DERIVATIVES OF OCTAFLUORO[2,2]PARACYCLOPHANE (AF4) : A
NEW SOURCE OF PERFLUOROALKYL RADICALS

6.1 Introduction

6.1.1 General Information

Since their first designed synthesis in 1951,72 [2.2]paracyclophanes have been

considered valuable compounds for testing theories of bonding, ring strain, and 'r-

electron interactions.73-75 A number of methods have been devised for the relatively

convenient synthesis of the parent hydrocarbon, all of which require the use of high

dilution methodology.76-78 In addition, it has been recognized since the mid-1960s that

[2.2]paracyclophanes are useful chemical vapor deposition (CVD) precursors of thin film

polymers, known in the industry as "parylenes".79 Such parylenes are ideally suited for

use as conformal coatings in a wide variety of applications, such as in the electronics,

semiconductor, automotive, and medical industries. Parylene coatings are inert and

transparent and have excellent barrier properties. Parylene N, which is generated from the

parent hydrocarbon 1, has been found to be useful at temperatures up to 130 OC.

1,1,2,2,9,9,10,10-Octafluoro[2.2]paracyclophane,80 the bridge-fluorinated version of 1

(and known in the industry as AF4), is the CVD precursor of Parylene-HT polymer,

poly(u,a,a',a'-tetrafluoro-p-xylylene). The Parylene-HT polymer combines a low

dielectric constant (2.25)79 with high thermal stability (<1 wt % loss/2 h at 450 C), low

moisture absorption (<0.1%), and other advantageous properties.81'82 With such

properties and because its in vacuo deposition process ensures conformality to










microcircuit features and superior submicron gap-filling capability, Parylene-HT

continues to show considerable promise as an interlayer dielectric for on-chip high-speed

semiconductor device interconnection.

H2C- CH2 F2C- CF2




H2C- CH2 F2C- CF2

Figure 6-1. [2,2]-paracyclophane Figure 6-2. AF4

6.1.2 Synthesis of AF4

CF2CI F2C CF2

4 eq Zn
DMA, 100 C

CF2CI 3h F2C CF2
60%

Scheme 6-1. Synthesis of AF4

AF4 is produced in 60% yield in a reaction of Zn with 0.35 M

p-bis(chlorodifluoromethyl)-benzene in DMA at 100 OC.The mechanism of formation of

AF4 is shown in Scheme 6-2. p-bis(chlorodifluoromethyl)-benzene is reduced first by

zinc metal to p-xylylene intermediate 2, which reacts with itself to form dimer diradical

3. The two radicals reconnect to each other to form AF4.

The unique chemical characteristics of 1,1,2,2,9,9,10,10-octafluoro[2.2]-

paracyclophane (AF4) have been amply demonstrated by a number of recent publications

related to its synthesis,83-85 its chemical reactivity,86'87 and its role as the CVD precursor

of the highly thermally stable, low-dielectric thin film polymer known as parylene-HT.88

90










CF2Cl CF2
reduction CF2
P bimolecular F F

C-C bond formation F F
CF2CI CF2 F2CF F
F2C
1 2 3-extended



rotation
*
F2C polymerization
| F

A F 4 F
F 3-syn
F

F2C



Scheme 6-2. Mechanism of formation of AF4

Because ring-substituted derivatives of AF4 have the potential to produce parylene

films with enhanced properties, efforts have been directed at the synthesis of compounds

such as trifluoromethyl derivative (Figure 6-1).

F2C- CF2
CF3




F2C- CF2

Figure 6-3. Trifluoromethyl-AF4 derivative

Although 1 has been prepared by a traditional four-step synthetic sequence

beginning with nitration of AF4,76 a more direct method based on Sawada's free-radical

trifluoromethylation methodology appeared potentially attractive.91 However, when

trifluoroacetyl peroxide was allowed to decompose in the presence of AF4 in refluxing

CH2C12, although the trifluoromethyl radical indeed added to one of the aromatic rings of

AF4, no rearomatization to 1 was observed. Instead, the intermediate cyclohexadienyl










radical 2 proved to be uncommonly stable, so stable that it survived sufficiently long to

dimerize to a 57:43 mixture of the novel and structurally unprecedented diasteromeric

products, d,1- and meso-3, in a total yield of 60%

6.2 Kinetic Studies of CF3-AF4-dimers

6.2.1 Synthesis of CF3-AF4-dimer


F2C- CF2 F2C CF2 F2C CF2
1) 1 eq H202 (50%), 3eq (CF3CO)20

CH2CI2 -78 OC to RT. F3C CF3
F2C- CF2 2) reflux overnight F2C CF2 F2C CF2

60%
d,l : meso = 57:43


Scheme 6-3. Synthesis of CF3-AF4-dimer

The dimer is formed via radical addition of CF3' radical to AF4, forming a

trifluoromethylated AF4 radical that readily dimerizes into d,l and meso forms.

F2C CF2 F2C CF2

2 CF3 .
2 ,_ 2
F3C
F2C CF2 F2C CF2






F2C CF2 F2C CF2



F3C CF3
F2C CF2 F2C CF2


Scheme 6-4. Formation of CF3-AF4-dimer











The CF3' radical was formed by thermal decomposition of trifluoroacetyl peroxide,

which was prepared in situ by reacting trifluoroacetic anhydride with hydrogen peroxide.

(Scheme 6-5) Trifluoroacetic anhydride converts to trifluoro-peroxy acetic acid which

reacts with another molecule of trifluoroacetic anhydride to form trifluoroacetyl peroxide.

The resulting peroxide decomposes thermally into 2 molecules of carbon dioxide and 2

molecules of the CF3' radical.

(CF3CO)20 + H202 CF3CO3H + CF3CO2H


CF3CO3H + (CF3CO)20 CF3C(O)-O-O-C(O)CF3 + CF3CO2H


CF3C(O)-O-O-C(O)CF3 2 CF3 + 2 CO2


Scheme 6-5. Mechanism of formation of CF3' radical


F2C CF2
H
F2C CF2


F2C CF2
TTC ^^


< CF2

D,L







-64.5 -65.0 -6S.S


F2C ^CF2


F3C CF3
HH
F2C / CF2

F2C M CF2


MESO


- I
-i5.0 -56.5


-17.0 ppm


Figure 6-4. 19F NMR distinction examining the d,l and the meso forms of CF3-AF4-
dimers


^*V-f/^rLn


n


F2C










The two disateromers, d,l and meso forms, are distinguishable by 19F NMR, as

shown in Figure 6-4, the multiple peaks corresponding to the CF3 group having slightly

different chemical shifts. They could also be separated by column chromatography.

6.2.2 Thermal Decomposition of the CF3-AF4-dimer

The dimers are stable indefinitely at room temperature. But as they are heated, they

decompose to regenerate back AF4 and release 2 equivalents of CF3' radical. Two

different pathways for the mechanism of decomposition can be presented (Scheme 6-6).

The decomposition can be stepwise where the dimer is first broken into two molecules of

trifluoromethylated AF4 radical (A) and then CF3' radicals were eliminated, forming back

AF4 (path A) or the process is concerted and AF4 and CF3' are formed in one single step

(path B).

F2C CF F2C CF F2C CF2

path A

F3C CF3 F3C
F2C CF2 F2C CF2 F2C CF2
A







F2C CF2


2 + 2CF3'

F2C CF2

Scheme 6-6. Two possible pathways for decomposition of CF3-AF4-dimer

An experiment was performed to determine the mechanism of decomposition: the

dimer was dissolved in acetonitrile with an excess of 1,4-cyclohexadiene, in a sealed









NMR tube. 1,4-cyclohexadiene served as radical trap as it readily quenches radicals

present in the reaction by giving 2 hydrogen radical to form benzene. The reaction

moisture was heated above 160 C for several hours. If the mechanism is the path B, the

presence of 1,4-cyclohexadiene will not disturb anything and only AF4 will be formed

but if it's the path A, 1,4-cyclohexadiene will trap trifluoromethylated AF4 radical A and

A' will be found instead of AF4 (Scheme 6-7).

F2C CF2 F2C CF2 F2C CF2

\. N/ \ ^path A \

F3C CF3 F3C
F2C CF2 F2C CF2 F2C CF2
A

0 pathB 0




F2C CF2 F2C CF2
H
2 + 2 CF3H 21
F3C
F2C CF2 F2C CF2
A'

Scheme 6-7. Resulting products from radical trapping in different possible mechanism
pathway

19F NMR revealed a huge amount of AF4 in the reaction mixture but a small

quantity of A' could also be found. The presence of A', even in a small amount, proved

that the mechanism of the decomposition proceeds in a stepwise manner (path A). The

presence of the large quantity of AF4 can be explained by the fact that the formation of

AF4 from the radical A is much faster than the trapping by 1,4-cyclohexadiene.








6.2.3 Kinetic Study of Homolysis of CF3-AF4-Dimers
The study of the mechanism of the decomposition of the CF3-AF4-dimer showed

that the rate determining step is the first step of the mechanism where the dimer broke

down into two CF3-AF4 radical A. A kinetic study was the performed on the homolysis

of the two diasteromers to determine rate constants and half lives at different

temperatures and the activation energy of the reaction.
F2C CF2 F2C CF2 F2C CF2


F3C CF3 k F3
F2C CF2 F2C CF2 F2C CF2



0
1 a
F2C CF2

2 1
F3C
F2C CF2

Scheme 6-8. Kinetic study of homolysis of CF3-AF4-Dimers
The rate being first order, the slope of the plot of Ln of concentrations versus times

would give the rate constant of the temperature of experimentation, following the

equation below:

Ln([C]) = -k t

The experiments consisted of dissolving one diasteromer in dry acetonitrile with

an excess of 1,4-cyclohexadiene and a known amount of a,a,a-trifluorotoluene as

internal standard in a sealed NMR tube. The tube was heated in an oil bath at fixed









temperature. The tube was taken out of the oil bath regularly to measure the quantity of

the dimer by 19F NMR and the time was measured. From all the data, a graph of Ln of

concentration of dimer versus time was plotted and the slope of the linear regression gave

the rate constant k. The values of k at different temperatures are shown in Table 6-1.

Table 6-1. Rate constants of the 2 diasteromers of CF3-AF4-dimers

Temperatures (C) k (d,l) (s-1) k (meso) (s-1)

140.1 7.37 x 10-6 8.62 x 10-6

151.0 2.24 x 105 2.81 x 105

160.7 7.14 x 105 8.50 x 105

170.3 1.57 x 10-4 3.21 x 10-4

179.7 4.55 x 10-4 4.94 x 10-4



The rate constants of the meso form were always greater than that of the d,l form

but they are of the same order and pretty close. The difference in rate constants between

the two diasteromers seemed to decrease as the temperatures increase.

From these rate constants values, the half-life times could be calculated according

to the following equation:

k
TZ1/2 ---
Ln 2

The values are shown in Table 6-2. These half-life values confirmed the high

stability of the compounds at room temperature: the half-lives of both dimers are above

22 hours at 140 OC. But they decrease very rapidly as the temperatures increase, from

more than 22 hours to 25 min in less than 40 C.






72


Table 6-2. Half-life times of the homolysis of CF3-AF4-dimers

Temperatures (C) T (d,l) T (meso)

140.1 26hrs 7 min 22hrs 20min

151.0 8hrs 36min 6hrs 51min

160.7 2hrs 42min 2hrs 16min

170.3 74 min 36min

179.7 25.4 min 23.4 min



By using the Arrhenius equation, the activation energy of the homolysis could be

-Ea
obtained: k = A exp( ) K being the rate constant, Ea the activation energy and T the
RT

temperature in Kelvin.In the logarithmic form the equation beccomes:

Ea
Ln(k)= + Ln(A)
RT

By plotting Ln(k) versus 1/T, the slope of the graph would give access to the

activation energy.



















dl
A meso
- Linear (meso)
- Linear (dl)


y = -20.059x + 36.901
R2 = 0.9876


-7.5



-8



-8.5



-9



a -9.5



-10



-10.5



-11



-11.5



-12
2.20


y = -19.352x + 34.997
R2 = 0.9977


2.25 2.30 2.35
1/T x 1000


2.40


Figure 6-5. Arrhenius plot for the 2 diasteromers of CF3-AF4-dimers


% A


4*
A %









Table 6-3. Arrhenius plot data

1/T x 1000 Ln(k[d,l]) Ln(k[meso])

2.42 -11.82 -11.66

2.36 -10.71 -10.48

2.31 -9.55 -9.37

2.26 -8.76 -8.04

2.21 -7.70 -7.61



Table 6-4. Activation parameters for CF3-AF4-dimers

Ea (kcal/mol) Log A

d,l-Form 38.43 15.20

meso-Form 39.83 16.02



6.3 Kinetic Studies of C2F5-AF4-dimers

We were interested in study behaviors of AF4 dimers with a longer

perfluoroalkylated chains. Kinetic studies of pentafluoroethyl-AF4-dimers were then

performed.

6.3.1 Synthesis of C2F5-AF4-dimers

In the same manner as the synthesis of CF3-AF4-dimers, C2F5-AF4-dimers were

formed from C2F5 radical addition to AF4, the C2F5 radical being formed from thermal

decomposition of pentafluoropropionyl peroxide, formed in situ by reaction of

perfluoropropionic anhydride with hydrogen peroxide. Since pentafluoropropionyl

peroxide is much less stable than trifluoroacetyl peroxide, stirring overnight at room

temperature was sufficient to decompose the peroxide.











FC- CF2 FC CF, FC CF,
1 eq HzOz (50%),3eq (CF3CF2CO),O0

CH2C12 -78 OC to R.T. F3CFC CF2CF
F2C- CF2 FC- CF2 F2C CF2

50%
d,l: meso = 55:45


Scheme 6-9. Synthesis of C2F5-AF4-dimers

The dimer products are composed of two diasteromers, the d,l and meso forms, in a


ratio of 55 and 45 respectively. They can be distinguished from each other by 19F NMR


spectrum by examining the peaks of CF3 groups of the CF2CF3 chain, as shown in the


Figure 6-6


F2C -<'F IF-CF2 /^ =F


FFC CCF2
F2C~ CF2
H CF2CF3
CF2CF3 F3CF2C CF2C]
H H
F2C CF2 F2C -CF

F2C F2 F2C CF


D,L MESO









a3a -4 z "-4 34.1 -4* -M.4 -SE-0 pp


Figure 6-6. 19F NMR distinction examining the d,l and the meso forms of C2F5-AF4-
dimers

The structure of the meso form was determined by X-ray analysis and a perspective


view is shown in Figure 6-7.

































Figure 6-7. Perspective view (ORTEP) of meso-C2F5-AF4-dimer


6.3.2 Kinetic Studies of the Homolysis of C2F5-AF4-dimers

The kinetic studies on C2F5-AF4-dimer were performed using the same procedure

as applied to the CF3-AF4-dimers. The rates constants are summarized in Table 6-5.

Whereas for CF3-AF4-dimers, where the rate constants of the meso form

werealways greater than that of the d,l form, for C2F5-AF4-dimers (with the exception of

118.8 C, where k(meso) is higher than k(d,l)) the rates constants of d,l and meso forms

are almost identical, with the tendency for d,l rate constants to be slightly greater.









Table 6-5. Rate constants of the 2 diasteromers of C2F5-AF4-dimers

Temperatures (C) k (d,l) (s-1) k (meso) (s1)

118.8 1.16 x 10-6 1.80 x 10-6

130.5 5.02 x 10-6 4.63 x 10-6

139.6 9.53 x 10-6 1.00 x 105

145.3 2.31 x 105 2.14 x 105

151.3 4.16 x 105 4.10 x 105

156.4 5.86 x 105 5.83 x 10-5

161.0 1.09 x 10-4 1.10 x 10-4



The half-lives times at different temperatures are shown in Table 6-6. For C2F5-

AF4-dimers, the half-life times decrease very rapidly, from more than 100 hours to

around 70 minutes with only a 40 C change in temperatures. The decrease was much

greater than was observed for the CF3-AF4-dimers.

Table 6-6. Half-life times of the homolysis of C2F5-AF4-dimers

Temperatures (oC) z (d,l) z (meso)

118.8 166hrs 31min 107hrs 9min

130.5 38hrs 19min 41hrs 35min

139.6 20hrs 12min 19hrs 13min

145.3 8hrs 1 min 9hrs

151.3 4hrs 38min 4hrs 42min

156.4 3hrs 17min 3hrs 18min

161.0 77min 80min









An Arrhenius graph was plotted to obtain to the activation energies of the

homolysis reaction.

Table 6-7. Arrhenius plot data for C2F5-AF4-dimers

1/T x 1000 LnK (d,l) LnK (meso)

2.55 -13.67 -13.23

2.42 -11.56 -11.51

2.36 -10.09 -10.10

2.33 -9.74 -9.75

2.39 -10.67 -10.75

2.48 -12.20 -12.28

2.30 -9.13 -9.12



Table 6.8. Activation parameters for C2F5-AF4-dimers

Ea (kcal/mol) Log A

d,l-Form 35.65 13.90

meso-Form 33.01 12.60



The activation energies for C2F5-AF4-dimers are somewhat lower than that of the CF3-

AF4-dimers (38.43 kcal/mol for d,l and 39.83 kcal/mol for meso).















arrhenius plot


-9.0


-9.5


-10.0 -

y = -16.6237x + 29.0156,
-10.5 R2 = 0.9894 1


-11.0 -
d,
2 meso
-11.5 -
Linear (meso)
Linear (d,I)
-12.0 -


-12.5


-13.0-


-13.5 y=-17.9533x + 32.1679
R2 = 0.9941
-14.0
2.25 2.30 2.35 2.40 2.45 2.50 2.55
1/T *1000


Figure 6-8. Arrhenius plot of the 2 diasteromers of C2Fs-AF4-dimers









6.4 Conclusion

The AF4-dimers proved to be very interesting compounds. Their stability at room

temperature and their ability to release perfluoroalkyl radicals at high temperatures make

them an ideal source of perfluoroalkyl radicals where they can be used as initiators for

polymerization reactions of fluorinated monomers92 in which a high purity is required

since other initiators, such as AIBN, would introduce other functional groups to the

polymer chains

6.5 Experimental

Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus

300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with

external tetramethylsilane (TMS, 6 = 0.00 ppm) as a reference. Fluorine (19F) and proton

(1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFC13, 6 =

0.00 ppm) as a reference for 19F NMR and TMS (6 = 0.00 ppm) for H NMR. Deuterated

chloroform (CDC13) was used as NMR solvent.

6.5.1 Synthesis of CF3-AF4-Dimer

In 100 mL, 1-neck round bottom flask, 3g of AF4 (9 mmol) was dissolved in 25

mL of freshly distilled dichloromethane. Trifluoroacetic anhydride (4.2 mL, 30 mmol)

were added. The solution was cooled at -78 C and 50% H202 (3.4 mL, 10 mmol) was

introduced slowly via a syringe. The reaction mixture was kept at -78 C for one hour and

was allowed to warm to the room temperature. The reaction was stirred at room

temperature overnight and was then refluxed for at least 12 hours. White solid could be

seen in the flask. After reflux, the mixture was cooled to room temperature and the









solution was filtered. The crude was then purified86 and the two diasteromers were

separated via column chromatography (hexanes/ CH2C2 : 9/1)

6.5.2 Kinetic Studies of CF3-AF4-Dimer

6.5.2.1 General procedure

In a 5 inch NMR tube, 2 mg of one of the diasteromers of CF3-AF4-Dimer, 200 ptL

of 1,4-cyclohexadiene and 0.6 ptL of ca,a,a-trifluorotoluene were dissolved in 500 ptL of

deuterated acetonitrile (CD3CN). A rubber septum was place on the tube and the solution

was frozen at -78 C in dry ice / 2-propanol bath. The tube was degassed under vacuum

for several minutes. The NMR tube was flamed sealed. The tube was immersed in a

constant temperature bath for an appropriate time, then removed, cooled and analyzed by

19F NMR, with the concentration of the dimer being measured versus a,a,a-

trifluorotoluene, used as internal standard. The rates were determined for each isomer at

different temperatures.









6.5.2.2 Kinetic data and graphs for CF3-AF4-Dimer at 140.1 C

The following tables and figures show kinetic data and graphs for CF3-AF4-Dimer

at 140.1 oC.

Table 6-9. Kinetic data of d,l-CF3-AF4-Dimer at 140.1 C
d,l form

Time (min) C.103 (mol/L) LnC

8 3.75 -5.59

279 3.11 -5.77

545 2.82 -5.87

744 2.59 -5.96

1206 2.11 -6.16

1533.5 1.83 -6.31

1926.5 1.50 -6.50

2360 1.24 -6.69

2691 1.12 -6.79

2923 1.01 -6.89

Table 6-10. Kinetic data ofmeso-CF3-AF4-Dimer at 140.1 C
meso form

Time (min) C.103 (mol/L) LnC

0 2.09 -6.17

254 1.84 -6.30

453 1.67 -6.40

915 1.31 -6.64

1242.5 1.12 -6.80

1635.5 0.89 -7.02

2069 0.70 -7.26

2400 0.62 -7.39

2632 0.54 -7.52










83





-5.5
400 800 1200 1600 2000 2400 2800 3200


5.7




-5.9




-6.1 y = -0.00044225x 5.62532632

R= 0.99751858


S-6.3




-6.5




-6.7




-6.9




-7.1
t (min)


Figure 6-9. Kinetic Graph of d,1-CF3-AF4-Dimer at 140.1 C



-6.0
) 500 1000 1500 2000 2500 3000


-6.2



-6.4 y = -0.00051719x 6.16656971
R2 = 0.99951338


-6.6



-6.8



-7.0



-7.2



-7.4



-7.6



-7.8
t (min)


Figure 6-10. Kinetic Graph of meso-CF3-AF4-Dimer at 140.1 C




Full Text

PAGE 1

SYNTHESES AND STUDIES OF PERFLUOROALKYL SUBSTITUTED COMPOUNDS By CHAYA POOPUT A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2005

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This dissertation is dedicated to my parents, Chatchawan and Payom Pooput.

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iii ACKNOWLEDGMENTS I express my deep gratitude to my advisor (Dr. William R. Dolbier, Jr.). Throughout the years I have spent in his labo ratory, I was able to acquire invaluable knowledge to help me achieve my goals. W ithout his ideas, guidance and support, I would not have been able to complete my research. I thank Dr. Samia At-Mohand for helping me get started in research in my first year. I thank Dr DolbierÂ’s group members for their help. I thank David Duncan for he lping me in experiments on TDAE analogue project. I thank the Chemistr y Department of the University of Florida for accepting me in the graduate program. I thank all my frie nds, especially Valerie, Igor, Rachel, Rafal, Janet, Jim, Gary, Rong and Hongfang for th eir support and friendship. I would like to thank again Valerie for always being here for me, for cheering me up when I was down and for sharing with me most of the wonderf ul moments I have in Gainesville. I also thank ValerieÂ’s parents (Vale and Iris) for we lcoming me in their home in Puerto Rico and for giving me warmth and love that make me feel like I was a part of their family. I thank ValerieÂ’s big family in Puerto Rico, S onia, Mia, Nilda, Nels on and Nydia for their love. I also thank my aunt Wanee for her suppo rt and love when I was in France. I thank my sister for being who she is and for her l ove. Finally I am eternally grateful to my parents. Because of their sacrifices, I was ab le to achieve this high level of education. Their constant support and love gave me strength.

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iv TABLE OF CONTENTS page ACKNOWLEDGMENTS.................................................................................................iii LIST OF TABLES...........................................................................................................viii LIST OF FIGURES.............................................................................................................x LIST OF SCHEMES........................................................................................................xiii ABSTRACT.....................................................................................................................xv i CHAPTER 1 INTRODUCTION...................................................................................................1 1.1 General Information.....................................................................................1 1.2 Previous Work.............................................................................................3 1.2.1 Starting Point...................................................................................3 1.2.2 Preliminary Results in the Group.....................................................4 1.2.3 New and Efficient Method for Synthesis of Trifluoromethyl Sulfides............................................................................................5 1.2.4 New and Efficient Method for Synthesis of Trifluoromethyl Selenides........................................................................................10 2 SYNTHESIS OF PERFLUOROALKYL THIO AND SELENOETHERS..........12 2.1 Introduction................................................................................................12 2.2 Synthesis of Pentafluoroethyl Thioethers..................................................14 2.3 Synthesis of Pentafluor oethyl Selenoethers...............................................16 2.4 Synthesis of Perfluorobutyl Thioethers.....................................................17 2.5 Synthesis of Perfluorobutyl Selenoethers..................................................19 2.6 Conclusion.................................................................................................19 2.7 Experimental..............................................................................................20 2.7.1 General Synthesis of Pentafluor oethyl Thio and Selenoethers : Synthesis of Phenyl Pentafluoroethyl Sulfide................................20 2.7.2 General Synthesis of Nonafluor obutyl Thio and Selenoethers : Synthesis of Phenyl Nonafluorobutyl Sulfide................................22

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v 3 PERFLUOROALKYLATION OF IMINE TOSYLATES....................................25 3.1 Introduction................................................................................................25 3.2 Synthesis of Tosyl Imines..........................................................................28 3.3 Pentafluoroethylation of Tosyl Imines.......................................................29 3.4 Perfluorobutylation of Tosyl Imines..........................................................31 3.5 Conclusion.................................................................................................33 3.6 Experimental..............................................................................................33 3.6.1 Syntheses of Tosyl Imines.............................................................33 3.6.2 General Procedure for Pentafluor oethylation of Tosyl Imines : Synthesis of MethylN -(3,3,3,2,2-pentafluoro-1-phenyl-propyl)benzenesulfonamide (3.1a)............................................................36 3.6.3 General Procedure for Perfluorobutylation of Tosyl Imines: Synthesis of 4-MethylN -[5,5,5,4,4,3,3,2,2-nonafluoro-(4methyl-phenyl)-propyl]-benzenesulfonamide (3.2b).....................40 4 PERFLUOROAKYLATION OF ALDEHYDES AND KETONES.....................44 4.1 Introduction................................................................................................44 4.2 Pentafluoroethylation of Aldehydes and Ketones......................................45 4.3 Perfluorobutylation of Aldehydes and Ketones.........................................47 4.4 Conclusion.................................................................................................48 4.5 Experimental..............................................................................................48 4.5.1 General Procedure of Pentafl uoroethylation of Aldehydes and Ketones: Synthesis of 1-Ph enyl-2,2,3,3,3-pentafluoropropan-1ol (4.2)............................................................................................48 4.5.2 General Procedure for Perfl uorobutylation of Aldehydes and Ketones: Synthesis of 1-Phenyl-2,2,3,3,4,4,5,5,5nonafluoropentan-1-ol....................................................................50 5 SYNTHESES AND STUDIES OF TETRAKIS(DIMETHYLAMINO)ETHYLENE ANALOGUES.........................52 5.1 Introduction................................................................................................52 5.2 Syntheses of TDAE Analogues.................................................................54 5.2.1 Synthesis of 1,3,1Â’,3Â’-Tetraalkyl-2,2Â’-bis(imidazolidene)............54 5.2.2 Synthesis of 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene).54 5.3 Attempts of Trifluoromethyla tion using the TDAE Analogues................56 5.3.1 Attempts of Trifluoromethyl ation using 1,3,1Â’,3Â’-Tetraalkyl2,2Â’-bis(imidazolidene) instead of TDAE......................................56 5.3.2 Nucleophilic Trifluoromethylati on of Phenyl disulfide using 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene).....................59 5.4 Conclusion.................................................................................................60 5.5 Experimental..............................................................................................60 5.5.1 Synthesis of 1,3,1Â’,3Â’-Tetraethyl-2,2Â’-bis(imidazolidene) (5.1)....60

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vi 5.5.4 Synthesis of 1,3,1',3'-Tetramethyl-2,2'-bis(benzimidazolylidene) (5.4)................................................................................................61 6 DIMERIC DERIVATIVES OF OCTAFLUORO[2,2]PARACYCLOPHANE (AF4) : A NEW SOURCE OF PERFLUOROALKYL RADICALS....................63 6.1 Introduction................................................................................................63 6.1.1 General Information.......................................................................63 6.1.2 Synthesis of AF4............................................................................64 6.2 Kinetic Studies of CF3-AF4-dimers...........................................................66 6.2.1 Synthesis of CF3-AF4-dimer..........................................................66 6.2.2 Thermal Decomposition of the CF3-AF4-dimer...........................68 6.2.3 Kinetic Study of Homolysis of CF3-AF4-Dimers..........................70 6.3 Kinetic Studies of C2F5-AF4-dimers.........................................................74 6.3.1 Synthesis of C2F5-AF4-dimers.......................................................74 6.3.2 Kinetic Studies of the Homolysis of C2F5-AF4-dimers.................76 6.4 Conclusion.................................................................................................80 6.5 Experimental..............................................................................................80 6.5.1 Synthesis of CF3-AF4-Dimer.........................................................80 6.5.2 Kinetic Studies of CF3-AF4-Dimer...............................................81 6.5.2.1 General procedure...........................................................81 6.5.2.2 Kinetic data and graphs for CF3-AF4-Dimer at 140.1 C.......................................................................82 6.5.2.3 Kinetic data and graphs for CF3-AF4-Dimer at 151.0 C...........................................................................84 6.5.2.4 Kinetic data and graphs for CF3-AF4-Dimer at 160.7 C...........................................................................86 6.5.2.5 Kinetic data and graphs for CF3-AF4-Dimer at 170.3 C...........................................................................88 6.5.2.6 Kinetic data and graphs for CF3-AF4-Dimer at 179.7 C...........................................................................90 6.5.3 Synthesis of C2F5-AF4-Dimer.......................................................92 6.5.4 X-ray Structure of C2F5-AF4-Dimers............................................93 6.5.5 Kinetic Studies of C2F5-AF4-Dimers.............................................96 6.5.5.1 General procedure...........................................................96 6.5.5.2 Kinetic data and graphs of C2F5-AF4-Dimers at 118.8 C...........................................................................97 6.5.5.3 Kinetic data and graphs of C2F5-AF4-Dimers at 125.7 C...........................................................................99 6.5.5.4 Kinetic data and graphs of C2F5-AF4-Dimers at 130.5 C.........................................................................101 6.5.5.5 Kinetic data and graphs of C2F5-AF4-Dimers at 139.6 C.........................................................................103 6.5.5.6 Kinetic data and graphs of C2F5-AF4-Dimers at 145.3 C.........................................................................105 6.5.5.7 Kinetic data and graphs of C2F5-AF4-Dimers at 151.3 C.........................................................................107

PAGE 7

vii 6.5.5.8 Kinetic data and graphs of C2F5-AF4-Dimers at 156.4 C.........................................................................109 6.5.5.9 Kinetic data and graphs of C2F5-AF4-Dimers at 161.0 C.........................................................................111 6.5.5.10 Kinetic data and graphs of C2F5-AF4-Dimers at 165.9 C.........................................................................113 GENERAL CONCLUSION............................................................................................115 LIST OF REFERENCES.................................................................................................116 BIOGRAPHICAL SKETCH...........................................................................................122

PAGE 8

viii LIST OF TABLES Table page 1-1 Trifluoromethylation of disulfides.............................................................................7 1-2 Trifluoromethylation of disulf ides using a higher amount of CF3I............................8 1-3 Synthesis of trifluoromethyl selenoethers................................................................11 2-1 Synthesis of pentaf luoroethyl thioethers..................................................................15 2-2 Synthesis of pentafl uoroethyl selenoethers..............................................................16 2-3 Synthesis of perfluorobutyl thioethers.....................................................................17 2-4 Synthesis of perfluorobutyl selenides......................................................................19 3-1 Synthesis of tosyl imines..........................................................................................28 3-2 Nucleophilic pentafluoroe thylation of tosyl imines.................................................30 3-3 Nucleophilic perfluorobutylation of tosyl imines....................................................32 4-1 Compared yields between pentafluor oethylation and trif luoromethylation of aldehydes and ketones..............................................................................................46 4-2 Perfluorobutylation of aldehydes and ketones.........................................................47 6-1 Rate constants of the 2 diasteromers of CF3-AF4-dimers........................................71 6-2 Half-life times of the homolysis of CF3-AF4-dimers..............................................72 6-3 Arrhenius plot data...................................................................................................74 6-4 Activation parameters for CF3-AF4-dimers.............................................................74 6-5 Rate constants of the 2 diasteromers of C2F5-AF4-dimers......................................77 6-6 Half-life times of the homolysis of C2F5-AF4-dimers.............................................77 6-7 Arrhenius plot data for C2F5-AF4-dimers................................................................78

PAGE 9

ix 6.8 Activation parameters for C2F5-AF4-dimers............................................................78 6-9 Kinetic data of d,l-CF3-AF4-Dimer at 140.1 C.......................................................82 6-10 Kinetic data of meso-CF3-AF4-Dimer at 140.1 C..................................................82 6-11 Kinetic data of CF3-AF4-Dimers at 151.0 C...........................................................84 6-12 Kinetic data of CF3-AF4-Dimers at 160.7 C...........................................................86 6-13 Kinetic data of CF3-AF4-Dimers at 170.3 C...........................................................88 6-14 Kinetic data of CF3-AF4-Dimers at 179.7 C...........................................................90 6-15 Crystal data and structure refinement.......................................................................95 6-16 Selected bond lengths [] and angles [].................................................................96 6-17 Kinetic data of C2F5-AF4-Dimers at 118.8 C.........................................................97 6-18 Kinetic data of C2F5-AF4-Dimers at 125.7 C.........................................................99 6-19 Kinetic graph of C2F5-AF4-Dimers at 130.5 C.....................................................101 6-20 Kinetic data of C2F5-AF4-Dimers at 139.6 C.......................................................103 6-21 Kinetic data of C2F5-AF4-Dimers at 145.3 C.......................................................105 6-22 Kinetic data of C2F5-AF4-Dimers at 151.3 C.......................................................107 6-23 Kinetic data of C2F5-AF4-Dimers at 156.4 C.......................................................109 6-24 Kinetic data of C2F5-AF4-Dimers at 161.0 C.......................................................111 6-25 Kinetic data of C2F5-AF4-Dimers at 165.9 C.......................................................113

PAGE 10

x LIST OF FIGURES Figure page 1-1 Prozac.................................................................................................................... ..1 1-2 Celebrex.................................................................................................................. 1 1-3 Fipronil.................................................................................................................. ..1 2-1 2A28: insecticide.......................................................................................................12 2-2 2B29: insecticide.......................................................................................................12 2-3 2C30: pesticide..........................................................................................................12 3-1 3A......................................................................................................................... ....25 3-2 3B......................................................................................................................... ....25 3-3 3C......................................................................................................................... ....27 3-4 3D......................................................................................................................... ....27 3-5 A resonance form of N -( Nmethyl-3-indolylmethylene)p methylbenzenesulfonamide......................................................................................31 4-1 4A56 : Fungicide.......................................................................................................44 4-2 4B57 : insecticide......................................................................................................44 5-1. Structure of a chiral TDAE analogue.........................................................................53 5-2 Non chiral TDAE analogue......................................................................................53 5-3 benzimidazole TDAE analogue...............................................................................54 5-4 Cyclic voltammogram for 1,3,1Â’,3Â’-Tet raethyl-2,2Â’-bis(imi dazolidene), C = 3mM in DMF + 0.1 mM Et4NBF4 at 20 C, scan rate: 0.2V/s.................................59 6-1 [2,2]-paracyclophane................................................................................................64

PAGE 11

xi 6-2 AF4........................................................................................................................ ...64 6-3 Trifluoromethyl-AF4 derivative...............................................................................65 6-4 19F NMR distinction examining the d,l and the meso forms of CF3-AF4-dimers...67 6-5 Arrhenius plot for the 2 diasteromers of CF3-AF4-dimers......................................73 6-6 19F NMR distinction examining the d,l and the meso forms of C2F5-AF4-dimers..75 6-7 Perspective view (ORTEP) of meso-C2F5-AF4-dimer.............................................76 6-8 Arrhenius plot for the 2 diasteromers of C2F5-AF4-dimers.....................................79 6-9 Kinetic Graph of d,l-CF3-AF4-Dimer at 140.1 C...................................................83 6-10 Kinetic Graph of meso-CF3-AF4-Dimer at 140.1 C...............................................83 6-11 Kinetic Graph of d,l-CF3-AF4-Dimer at 151.0 C...................................................85 6-12 Kinetic Graph of meso-CF3-AF4-Dimer at 151.0 C...............................................85 6-13 Kinetic Graph of d,l-CF3-AF4-Dimer at 160.7 C...................................................87 6-14 Kinetic Graph of meso-CF3-AF4-Dimer at 160.7 C...............................................87 6-15 Kinetic graph of d,l-CF3-AF4-Dimers at 170.3 C...................................................89 6-16 Kinetic graph of meso-CF3-AF4-Dimers at 170.3 C..............................................89 6-17 Kinetic graph of d,l-CF3-AF4-Dimers at 179.7 C...................................................91 6-18 Kinetic graph of meso-CF3-AF4-Dimers at 179.7 C..............................................91 6-19 X-ray structure of meso-C2F5-AF4-dimer................................................................94 6-20 Kinetic graph of d,l-C2F5-AF4-Dimers at 118.8 C.................................................98 6-21 Kinetic graph of meso-C2F5-AF4-Dimers at 118.8 C.............................................98 6-22 Kinetic graph of d,l-C2F5-AF4-Dimers at 125.7 C...............................................100 6-23 Kinetic graph of meso-C2F5-AF4-Dimers at 125.7 C...........................................100 6-24 Kinetic graph of d,l-C2F5-AF4-Dimers at 130.5 C...............................................102 6-25 Kinetic graph of meso-C2F5-AF4-Dimers at 130.5 C...........................................102 6-26 Kinetic graph of d,l-C2F5-AF4-Dimers at 139.6 C...............................................104

PAGE 12

xii 6-27 Kinetic graph of meso-C2F5-AF4-Dimers at 139.6 C...........................................104 6-28 Kinetic graph of d,l-C2F5-AF4-Dimers at 145.3 C...............................................106 6-29 Kinetic data of meso-C2F5-AF4-Dimers at 145.3 C.............................................106 6-30 Kinetic data of d,l-C2F5-AF4-Dimers at 151.3 C..................................................108 6-31 Kinetic data of meso-C2F5-AF4-Dimers at 151.3 C.............................................108 6-32 Kinetic graph of d,l-C2F5-AF4-Dimers at 156.4 C...............................................110 6-33 Kinetic graph of meso-C2F5-AF4-Dimers at 156.4 C...........................................110 6-34 Kinetic graph of d,l-C2F5-AF4-Dimers at 161.0 C...............................................112 6-35 Kinetic graph of meso-C2F5-AF4-Dimers at 161.0 C...........................................112 6-36 Kinetic graph of d,l-C2F5-AF4-Dimers at 165.9 C...............................................114 6-37 Kinetic graph of meso-C2F5-AF4-Dimers at 165.9 C...........................................114

PAGE 13

xiii LIST OF SCHEMES Scheme page 1-1 Trifluoromethylation of be nzaldehyde using fluoroform...........................................2 1-2 Trifluoromethylation of benzaldehyd e using trifluoromethyl zinc iodide.................2 1-3 Examples of trifluorom ethylation reactions using Me3SiCF3....................................3 1-4 Difluoromethylation reactions of aromatic aldehydes with TDAE...........................3 1-5 Difluoromethylation reactions of ethyl pyruvates with TDAE..................................4 1-6 Trifluoromethylation reacti on of aldehydes and ketones...........................................4 1-7 Trifluoromethylation re action of acyl chlorides.........................................................4 1-8 Trifluoromethylation reaction of vicinal diol cyclic sulfate.......................................5 1-9 Synthesis of trifluoromethyl phenyl sulfide via SRN1 type reaction..........................5 1-10 Synthesis of trifluoromethyl phenyl sulfide using various sources of CF3..............6 1-11 Synthesis of trifluoromethyl thioethers......................................................................6 1-12 Efficient synthesis of trifluoromethyl sulfides...........................................................7 1-13 Mechanism of trifluorom ethylation of disulfides.......................................................7 1-14 Another possible mechanism of form ation of trifluoromethyl sulfide.....................10 1-15 Synthesis of trifluoromethyl selenoethers................................................................10 2-1 Different methods for synthesis of pe rfluoroalkyl sulfides and selenides...............13 2-2 Synthesis of trifluoromethyl sulfides with CF3I / TDAE methodology...................13 2-3 Tandem CF3I process in the synthesis of trifluoromethyl sulfides..........................14 2-4 Pentafluoroethylation of disulfides..........................................................................15 2-5 Pentafluoroethyla tion of diselenides........................................................................16

PAGE 14

xiv 2-6 Synthesis of perfluorobutyl thioethers.....................................................................17 2-7 Synthesis of perfluorobutyl selenides......................................................................19 3-1 Trifluoromethylation of imin es using RuppertÂ’s reagent.........................................26 3-2 Trifluoromethylation of imines using CF3I / TDAE...............................................27 3-1 Synthesis of tosyl imines..........................................................................................28 3-2 Nucleophilic pentafluoroe thylation of tosyl imines.................................................29 3-3 Nucleophilic perfluorobutylation of tosyl imines....................................................31 4-1 Pentafluoroethylation of aldehydes and ketones......................................................45 4-2 Nucleophilic perfluorobutyla tion of aldehydes and ketones....................................47 5-1 CF3I / TDAE complex..............................................................................................52 5-2 Synthesis 1,3,1Â’,3Â’-tetraal kyl-2,2Â’-bis(imidazolidene)............................................54 5-3 Multi-step synthesis of benzimidazol TDAE analogue............................................55 5-4 Nucleophilic trifluoromethylation of benzaldehyde using 1,3,1Â’,3Â’-tetraalkyl2,2Â’-bis(imidazolidene)............................................................................................56 5-5 Synthesis of phenyl trifluoromethyl sulfide by using imidazolidene TDAE analogue...................................................................................................................57 5-6 Possible decomposition pathways for imidazolidene TDAE analogue....................57 5-7 Reactivities of imidazolidene carbene towards benzaldehyde................................58 5-8 Attempt of synthesis of phenyl trifluoromethyl sulfide by using 1,3,1',3'Tetramethyl-2,2'-bis(benzimidazolylidene).............................................................59 6-1 Synthesis of AF4......................................................................................................64 6-2 Mechanism of formation of AF4..............................................................................65 6-3 Synthesis of CF3-AF4-dimer....................................................................................66 6-4 Formation of CF3-AF4-dimer...................................................................................66 6-6 Two possible pathways for decomposition of CF3-AF4-dimer...............................68 6-7 Resulting products from radical trap ping in different possible mechanism pathway....................................................................................................................69

PAGE 15

xv 6-8 Kinetic study of homolysis of CF3-AF4-Dimers.....................................................70 6-9 Synthesis of C2F5-AF4-dimers.................................................................................75

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xvi Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy SYNTHESES AND STUDIES OF PERFLUOROALKYL SUBSTITUTED COMPOUNDS By Chaya Pooput August 2005 Chair: William R. Dolbier, Jr. Major Department: Chemistry Numerous compounds containing perfl uoroalkyl groups are found to be biologically active and are largely used in pharmaceutical and agrochemical areas. Although several methods have been developed to incorporate trifluoromethyl group into molecules, few are for longer perfluoroalkyl chains. Nucleophilic trifluoromethylation has been largely developed in our laboratory by using CF3I and Tetrakis(dimethylamino)ethy lene (TDAE). This methodology was extended to longer perfluoroalk yl iodides. Pentafluoroethyl iodide and nonafluorobutyl iodide were used instead of trifluoromethyl iodide. Reactions with disulfides and diselenides provided efficiently perfluoroalkyl thioand selenoethers, where, in most cases, both ha lves of the disulfides or diselenides were converted quantitatively to thio or selenoethers. Numerous pentafluoroethyl and nonafl uorobutyl substituted amines could be obtained in high yields by extending the methodology with tosyl imines.

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xvii Reactions with aldehydes and ketones provi ded good yields of pentafluoroethyl substituted alcohols. But reactions using nonafluorobutyl iodide a fforded low yields. The extension of CF3I / TDAE methodology to longer pe rfluoroalkyl iodides will allow us to access to a much larger number of biologica lly active compounds. Several TDAE analogues were also synt hesized but their reactivity towards CF3I is completely different from TDAE and c ouldnÂ’t be used as TDAE substituents. The syntheses and kinetic studies of pe rfluoroalkyl subst ituted AF4 dimers provided valuable information on the use of these compounds as a stable source of perfluoroalkyl radicals.

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1 CHAPTER 1 INTRODUCTION 1.1 General Information Pharmaceutical and agrochemical industrie s have a growing interest in compounds containing perfluoroalkyl groups. Many ne w drugs contain trifluoromethyl groups: examples are shown in Figures 1-1 and 1-2: O F3C NHCH3 N S N CF3O O H2N Figure1-1. Pro zac Figure1-2. Celebrex N N CF3S NC Cl Cl NH2O CF3 Figure1-3. Fipronil Among the several methods of incorporat ing the trifluoromethyl group into a compound, one of the most useful is to generate in situ the unstable trifluoromethyl anion to undergo nucleophilic trifluoromethyl ation on electrophilic substrates.

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2 Various methods have been used to gene rate the trifluoromethyl anion: i) The groups of Roques1 and Normant2 effectively performed nucle ophilic trifluoromethylation by using fluoroform (CF3H) in the presence of base; and ii) Kitazume3 used trifluoromethylzinc iodide, pr epared from trifluoromethyl iodide and zinc powder with ultrasonic irradiation, as a trifluoromethylation reagent (Scheme 1-2). H O CF3H+1) DMF, -50 oC 2) tBuOK, 1h 3) AcOH, 0 oC 20 oC H OH CF3Yield=67% Scheme 1-1. Trifluoromethylation of ben zaldehyde using fluoroform Curently the most commonly used source of the nucleophilic trifluoromethyl anion is (trifluoromethyl)trimethylsilane (TMSCF3). In the past few years the groups of Prakash and Shreeve have developed the method of generating in situ CF3 by reaction of (trifluoromethyl)trimethylsilane (CF3TMS) with TBAF,4 CsF.5 Fuchikami6 reported that trifluoromethylation reactions of carbonyl compounds can also be catalyzed by Lewis bases, such as triethylamine, pyridine or triphenyl phosphine. H OultrasoundH OH CF3Yield = 72% CF3IZn ++ DMF Scheme 1-2. Trifluoromethylation of benzal dehyde using trifluoromethyl zinc iodide Extensive research had been performed on the use of this reagent with different substrates, such as ketones, esters and disulfides.

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3 R1R2O Me3SiCF3R1R2OH CF3CsF H3O++ R1OMe O Me3SiCF3Bu4N+ F-H3O++ R1CF3O R-S-S-R Me3SiCF3THF 0oC ++ R-S-CF3Bu4N+ FScheme 1-3. Examples of trif luoromethylation reactions using Me3SiCF3 5, 7, 8 Even though (trifluoromethyl )trimethylsilane is a pow erful trifluoromethylation agent, it is very expensive. Our group want ed to find a less expensive and more direct way to generate the nucleophilic CF3 anion. 1.2 Previous Work 1.2.1 Starting Point Since 1998, with the colla boration of Dr. Maurice Mdebielle, we have demonstrated that tetrakis(dimethylamino)et hylene (TDAE) can be used as an efficient reductant to generate nucleophilic difl uoromethyl anions from chloroand bromodifluoromethyl compounds.9, 10 RCF2X ArCHO DMF OH Ar CF2R H -200to R T TDAE Scheme 1-4. Difluoromet hylation reactions of arom atic aldehydes with TDAE RCF2XCH3COCO2Et DMF OH H3C CF2R CO2Et -200to R T TDAE

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4 Scheme 1-5. Difluoromet hylation reactions of et hyl pyruvates with TDAE Pawelke earlier demonstrated that TDAE coul d be used with trifluoromethyl iodide to prepare CF3TMS from TMSCl.11 With these results, we decided to use TDAE to reduce trifluoromethyl iodide into trifluoromethyl anion. 1.2.2 Preliminary Results in the Group With the aldehydes and ketones, the CF3I / TDAE system provided very good yields, which were comparable to thos e obtained in analogous reactions using CF3TMS.12 R1R2O CF3I DMF OH R1CF3R2TDAE -20 0 to RT h 12 hrs 1 eq2.2 eq2.2 eq Scheme 1-6. Trifluoromethylati on reaction of aldehydes and ketones Aryl acyl chlorides also underwent clean recations.13 Cl O X O O F3C CF3XX CF3I / TDAE DME -20O C to RT RT, 2 hrs Scheme 1-7. Trifluoromethyla tion reaction of acyl chlorides Unfortunately the CF3I / TDAE system was not su ccessful in reactions with epoxides. But in 1988 Gao and Sharpless demonstr ated that vicinal di ol cyclic sulfates could be used as epoxide equiva lents, with a hi gher reactivity.14 O S O O O CF3I THF CF3HO I HO OH F3C TDAE -20o C to RT 20% H2SO455% < 1% 40%5 hrs+ 1 eq 2.2 eq 2.2 eq 53-95 % 48-98 %

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5 Scheme 1-8. Trifluorom ethylation reaction of vici nal diol cyclic sulfate The reaction is highly regios elective because only 1% of the other isomer is formed. Since the cyclic sulfate is highly reactive, competition between the iodide anion and the trifluoromethyl anion occurred, wh ich did not happen with other substrates.15 1.2.3 New and Efficient Method for Synt hesis of Trifluoromethyl Sulfides Aryl trifluoromethyl sulfides continue to attract much interest within pharmaceutical companies, as witnessed by the significant number of process patent applications recently submitted that are devoted to their preparation17. This interest derives from the recogni zed potential of the SCF3 group to have a positive influence on biological activity. Diverse methods have been reported for the synthesis of aryl trifluoromethyl sulfides18, but two seem to emerge as preferred methods. The first is the SRN1 reaction of aryl thiolates wi th trifluoromethyl iodide or bromide. Yagulpolskii was the first to repor t the reaction in 1977, using trifluoromethyl iodide and UV irradiation19: Ph-SHCF3I CH3CN, 0 5 oC + Ph-S-CF3NaOCH3,UV 89% Scheme 1-9. Synthesis of trif luoromethyl phenyl sulfide via SRN1 type reaction Wakselman and Tordeux used trifluor omethyl bromide in high pressure (2 atm),20, 21 and with other variations,22, 23 this method is generally efficient when using aryl thiolates but gives a much lowe r yield when using alkanethiolates.24 The other popular method involves the reacti on of trifluoromethyl anion (generated in situ by various methods) with aryl and alkyl disulfides:

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6 PhS-SPhCF3SiMe3THF, 0 oC +Ph-S-CF332% 8Ph-S -+ Bu4N+ FPhS-SPhCF3CO2K +Ph-S-CF3sulfolane, 56% 2584% 26Ph-S -+ PhS-SPh + Ph-S-CF387% 27Ph-S -+tBuOK NN OH F3C H Ph Scheme 1-10. Synthesis of trifluoromethyl phenyl sulfide using various sources of CF3 Although good yields can be obtained, the method suffers from the fact that half of the disulfide is wasted in the process (formation of thiolates for the other half). In our investigation16, the CF3I / TDAE system turned out to be a better method for synthesis of trifluoromethyl sulfides than w ith Ruppert reagents (Table 1-1). Both aryl and aliphatic disulfides provided near 100 % yield. The reaction is very fast only 2 hours of stirring at room temperature was suffi cient to give a quantit ative yield, as shown in the entries 4 and 5. R-S-S-RTDAECF3I DMF 0 oC to RT R-S-CF3+ + RT several hr 1 eq.2.2 eq2.2 eq Scheme 1-11. Synthesis of trifluoromethyl thioethers

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7 Table 1-1. Trifluoromet hylation of disulfides entry R Stirring time at RT (hrs) NMR yield 1 Phenyl 12 80 2 butyl 12 >98 3 ethyl 12 >98 4 butyl 4 >98 5 butyl 2 >98 R-S-S-RTDAECF3I DMF 0 oC to RT R-S-CF3+ + RT several hr 1 eq.2.2 eq4.2 eq 180 200%based of equivalents of disulfides Scheme 1-12. Efficient synthesi s of trifluoromethyl sulfides It has been demonstrated that the mechan ism of the reaction is as shown in the Scheme 1-13. TDAECF3I CF3R-S-S-R R-S CF3I CF3R-S-CF3R-S-CF3I I R-S + TDAE 2++ ++ + + Scheme 1-13. Mechanism of trif luoromethylation of disulfides It occurred to us that CF3I could also be used as a substrate for reaction, via the SRN1 mechanism, with the thiola te coproduct; thus, potentially enabling both halves of the disulfide to be used in a one pot reaction, where CF3I would be used in two different reactions, both of which l ead to the same desired product. First TDAE reduces CF3I to nucleophilic “CF3”, which reacts with the disulfide to form trifluoromethyl sulfide and

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8 thiolate. The resulting thiolate reacts with the excess of CF3I, in a SRN1 type mechanism to create the second molecule of sulfide. When more than 4.2 equivalents of CF3I are used while the quantity of TDAE stays at 2.2 equivalents, trifluoromethyl sulfides can be obtained at nearly 200% yield, based on the number of equivalents of disulfides, as shown in the Table 1-2. Table 1-2. Trifluoromethyl ation of disulfides us ing a higher amount of CF3I entry R Equiv. of CF3I Stirring time at RT (hrs) NMR yield* 1 Phenyl 5 12 186 2 butyl 5 12 170 3 4-pyridyl 5 12 200 4 butyl 5 4 170 5 butyl 4.2 4 175 6 butyl 3.2 4 130 7 butyl 4.2 2 170 8 ethyl 4.2 2 180 9 2-pyridyl 4.2 2 180 10 t-butyl 4.2 12 0 11 2-nitrophenyl 4.2 2 185 12 benzothiazolyl4.2 2 190 13 4-aminophenyl4.2 12 20 S N benzothiazolyl group *based of number of equivalents of disulfides The entries 1 to 3 show that with 5 equivalents of CF3I, yields of nearly 200% could be obtained whether with aryl disulfide or alkyl disulfide. Th e following entries are attempts to optimize the pro cedure: 3.2 equivalents of CF3I did not seem to be sufficient,

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9 since the yield was only 130% (e ntry 6) whereas more than 4.2 equivalents gave nearly quantitative yields. Moreover 2 hours of stir ring at room temperature was sufficient. Although with t-butyl disulfide, we were unable to perform the trifluoromethylation (entry 10), the result is nevertheless interesting because this shows a high influence of the steric effect for the reaction. Moreover the lack of reactivity of t-butyl disulfide has been noted previously, when CF3TMS was used as trifluoromethyl anion source.8 The entry 13 revealed another limitation of this methodology: CF3 anion being extremely unstable reacts preferable first towards acidic protons such as the ones present in the amino group hence the very low yield for the reaction w ith 4-aminophenyl disulfide (Table 1-2, entry 13). All the groups containing acidic protons need then to be protected first before undergoing trifluoromethylation with CF3I / TDAE method. In the case of 4-aminophenyl disulfide, 4-nitrophenyl disulfide can be used and the nitro group can be reduced later to obtain the amino group; the amino group can also be protected twice with BOC to avoid the harsh conditions of reduction of nitro group. It might be argued that these results could derive from reduction by TDAE of disulfide to 2 equivalents of thiolate anion. The thiolate could react then with CF3I proceeding entirely via SRN1 type reaction. If that were the case, the 2.2 equivalents of CF3I along with 2.2 equivalents of TDAE should have been sufficient to obtain the high yields observed in the Table 1-2. However, in the case where 2.2 equivalents of CF3I were used (Table 1-1), yields never ex ceeded 100%. This probably means that CF3I is reduced faster than the disulfides.

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10 TDAE R-S-S-R 2 R-S 2 CF3I 2 R-S 2 R-S-CF32 I +TDAE 2+ ++ Scheme 1-14. Another possible mechanism of formation of trif luoromethyl sulfide Nevertheless, a control reaction was carried out to provide more definitive evidence for the proposed dual mechanism synthetic process. CF3I (5 equiv.) and TDAE (2 equiv.) were added first together at –20C so th at TDAE would be totally oxidized by the reaction with CF3I. The solution was then allowed to warm to -5C, at which time, nbutyl disulfide was introduced. At this point there should be little if any TDAE remaining to react with the disu lfide. Despite this, th e observed yield from this reaction was 160%, which compares well with the 170% obtained when using the norma l procedure (Table 12, entry 5). This can be concluded that th e reaction likely proceeds via the two-stage process described earlier. Thes e interesting results mean that the disulfides provide two molecules of trifluoromethyl sulfides, whic h was never observed before in the other methods. 1.2.4 New and Efficient Method for Synthe sis of Trifluoromethyl Selenides Since diselenides have similar reactivities than that of disulfides, reactions of nucleophilic trifluoromethylation were al so performed on diphenyl diselenide16. R-Se-Se-RTDAECF3I DMF 0 oC to RT R-Se-CF3RT overnight 1 eq.2.2 eq + + 4.2 ~200%based of number of equivalents of diselenides Scheme 1-15. Synthesis of trifluoromethyl selenoethers

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11 Table1-3. Synthesis of tr ifluoromethyl selenoethers Entry R NMR Yield (%)* 1 phenyl 198 2 4-Chlorophenyl 200 3 methyl 180 *based of number of equivalents of diselenides The methodology is efficient for both aliphatic and aromatic diselenides. The CF3I / TDAE methodology are very effici ent for many electr ophilic subtrates, we are interested now to extend this methodology to longe r perfluorinated chains by using other perfluoroa lkyl iodides. We would be able to access to a higher amount biologically active compounds.

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12 CHAPTER 2 SYNTHESIS OF PERFLUOROALKYL THIO AND SELENOETHERS 2.1 Introduction Parallel to trifluorothioethers, trifluoroselenoethers, longer perfluoroalkyl chains are also developed to be used as biologically activ e compounds. Few examples are given below. ClCF3Cl N S H3C SCF2CF3 NH2H N Br BrSCF2CF3O Figure 2-1. 2A28: insecticide Figure 2-2. 2B29: insecticide Cl CF3Cl N N CN SC4F9N H N Figure 2-3. 2C30: pesticide Despite the increasing interest in perfluor oalkyl sulfides, few methods have been developed to synthesize them. The two ma in methods consists in first through SRN1 reaction of aryl thiolates with perfloroalkyl iodide31 or bromide.32 The second method involves perfluoroalkyl ani on, generated from thermal decarboxylation of potassium

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13 perfluoroalkyl carboxylate,33 with aryl disulfides with the inconvenience of possible carbanion rearrangement or decomposition and one half of the disulfide is wasted. Another notable method for synthesis of perf luoroalkyl selenides consists in reaction between perfluoroalkyl ra dicals and diselenides.34 So far there is no efficient method for synthesis of perfluoroalk yl aliphatic sulfides. PhS-SPh + CF3CF2CO2K PhS-CF2CF3 + PhSK 70 %33PhSe-SePh + 2 C4F9I HOCH2SO2Na 2 PhSe-C4F957%34PhSH + C4F9I NaH PhS-C4F966% 31PhSK + CF3CF2BrPhS-CF2CF333% 32 Scheme 2-1. Different methods for synthesis of perfluoroa lkyl sulfides and selenides Our laboratories have developed a new and efficient method for synthesis of trifluoromethyl sulfides and selenides, using CF3I / TDAE system.16 This methodology has now been extended to l onger perfluoroalkyl iodides. R-S-S-RTDAECF3I DMF 0 oC to RT R-S-CF3+ + RT several hr 1 eq.2.2 eq4.2 eq 180 200%based of equivalents of disulfides Scheme 2-2. Synthesis of tr ifluoromethyl sulfides with CF3I / TDAE methodology

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142.2 Synthesis of Pentafluoroethyl Thioethers The same way that TDAE reduces trifl uoromethyl iodide in to trifluoromethyl anion, pentafluoroethyl iodi de was also expected to be reduced by TDAE into pentafluoroethyl anion. The tandem pro cess, involving nucleophilic attack of trifluoromethyl anion to disulfide followed by SRN1 by the resulting thiolate on the excess of CF3I (Scheme 2-3), was also expected. TDAECF3I CF3R-S-S-R R-S CF3I CF3R-S-CF3R-S-CF3I I R-S + TDAE 2++ ++ + + Scheme 2-3. Tandem CF3I process in the synthesis of trifluoromethyl sulfides16 The first experiment was carried out usi ng 1 equivalent of phenyl disulfide, 4.2 equivalents of C2F5I and 2.2 equivalents of TDAE added at -20 C. The color of the solution turned quickly deep red as TDAE was introduced. This may show the formation of the complex between TDAE and C2F5I, like in the case between TDAE and CF3I. The reaction mixture was allowed to warm up slowly. But unlike CF3I where the complex with TDAE starts decomposing at 0 C, the complex with C2F5I started decomposing around -10 C, as white salt could be seen forming. Apparently the complex between C2F5I and TDAE is less stable than that with CF3I. But the fact that TDAE was able to form a complex with C2F5I was a good sign meaning that the reaction may proceed in the same way as with CF3I / TDAE. The mixture was stirred overnight. 19F NMR was taken to calculate the yield. The reaction yielded 198 % based on the number of equivalents of disulfides (Table 2-1, entry 1).

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15 R-S-S-RTDAECF3CF2I DMF -10 oC to RT R-S-CF2CF3++ RT several hr 1 eq.2.2 eq4.2 eq Scheme 2-4. Pentafluoroe thylation of disulfides Reactions with different disulfides (aro matic and aliphatic) were then performed. The results are shown in Table 2-1. Table 2-1. Synthesis of pe ntafluoroethyl thioethers Entry R time at RT (hrs) NMR yield* 1 Phenyl32 12 >198 2 phenyl 2 >198 3 ethyl 2 135 4 ethyl 4 170 5 ethyl 12 175 6 butyl 12 180 7 2-pyridyl35 2 >198 8 4-pyridyl 2 190 *Based on the number of equivalents of disulfides The entries 2, 7 and 8 proved th at, as in the case of CF3I, 2 hours are sufficient to obtain quantitative yield for aryl disulfides. But in entries 3 to 5, two, even four hours didnÂ’t seem to be sufficient to obtain good yields in the case of aliphatic disulfides. The mixture required to stirring overnight to be able to obtain 175 %. Even though, the yields are very similar to the ones with CF3I, aliphatic disulfides require a much longer time. This may be explained by the fact that it is more diificult for aliphatic thiolates to undergo SRN1 reaction. Somehow the presence of TDAE seems to enhance the reactivity

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16 of aliphatic thiolates on SRN1 reaction, since we could alwa ys obtain good yields from aliphatic disulfides with CF3I / TDAE system. In the case of C2F5I the complex formed with TDAE is less stable than with CF3I and this may one of th e reasons why the reaction is slower for aliphatic disulfides. It may also come from the fact that C2F5I is less reactive as a substrate in the SRN1 process. In spite of longer re action time for aliphatic disulf ides, the yields obtained are similar to the ones from CF3I. The two halves of the disulfides are used efficiently to form two molecules of pe ntafluorethyl thioethers. 2.3 Synthesis of Pentafluoroethyl Selenoethers Since diselenides have similar reactiv ities as disulfides. The reactions of nucleophilic pentafluoroethylation were also performed on diselenides. R-Se-Se-RTDAECF3CF2I DMF -10 oC to RT R-Se-CF2CF3RT overnight 1 eq.2.2 eq + + Scheme 2-5. Pentafluoroe thylation of diselenides Table 2-2. Synthesis of pe ntafluoroethyl selenoethers Entry R Eq. of C2F5I NMR yield* (%) 1 Phenyl34 2.2 100 2 phenyl 4.2 200 3 4-chlorophenyl 4.2 200 *Based on the number of equivalents of diselenides As expected, from 1 equivalent of diselenides, 2.2 equivalents of C2F5I gave quantitatively 1 equivalent of pentafluoroeth yl selenides (Table 22, entry 1) and 4.2 equivalents provided efficiently 2 equivalents of selenides.

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17 2.4 Synthesis of Perfluorobutyl Thioethers Since the nucleophilic perfluoroalkylati on using TDAE was successfully extended to C2F5I, longer perfluoroalkyl i odides were then considered for experiments, we decided to performed reactions w ith nonafluorobutyl iodided R-S-S-RTDAEC4F9I DMF -20 oC to RT R-S-C4F9+ + RT overnight 1 eq.2.2 eq Scheme 2-6. Synthesis of perfluorobutyl thioethers The reactions were performed in the sa me fashion as the usual reactions of trifluoromethylation of disulfides, with the difference that C4F9I is a liquid instead of a gas like CF3I or C2F5I, the total reflux condenser was not needed any longer. The complex C4F9I / TDAE seems to be much less unstable than the ones from CF3I / TDAE, since the usual TDAE salt was formed just abov e -20 C, very shortly after the addition of TDAE. Table 2-3. Synthesis of perfluorobutyl thioethers Entry R Eq. of C4F9I NMR yield* (%) 1 Phenyl36 2.2 70 2 ethyl 2.2 40 3 butyl 2.2 40 4 2-pyridyl37 2.2 100 5 4-pyridyl 2.2 200 6 phenyl 4.4 140 7 butyl 4.4 40 8 2-pyridyl 4.4 195 *Based on the number of equivalents of disulfides

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18 Aryl disulfides gave satisfactory to good yi elds (Table 2-3, entries 1 and 4) when 2.2 equivalents of C4F9I were used. But aliphatic disulfides resulted in only modest yields, 40%, (Table 2-3, entries 2 and 3). Th is may be explained by the low stability of the C4F9I / TDAE complex or th e low reactivity of C4F9 anion towards aliphatic disulfides. The case of 4-pyridyl disulfide (Table 2-3, entry 5) proved to be very interesting. With only 2.2 equivalents of C4F9I, we were able to obtain 2 equivalents of perfluorobutyl 4-pyridyl sulfide, where usually 4.2 equivalent s were needed to obtain the same results in other cases. This means that the tandem process16 (where the perfluoroalkyl anion, formed by reduction of perfluoroalkyl iodide by TDAE, attacks disulfide to form the first thioether and then the resulting thiolate reacts with the excess of perfluoroalkyl iodide through SRN1 reaction to form the second thioether (Scheme 23)) is not applicable anymore in this case. TDAE didnÂ’t reduce C4F9I into C4F9anion but instead reduced entirely 4-pyrid yl disulfide, forming 2 equivalents of thiolate which react with C4F9I through SRN1 mechanism. It seems that C4F9I is not as reactive towards TDAE as CF3I or C2F5I and since the disulfide was also pr esent in the reaction mixture when TDAE was added and aryl disu lfides can be easily reduced, TDAE preferably reduced 4pyridyl disulfide over C4F9I. This problem was not encountered in the case of CF3I and C2F5I because their reactivity towards TDAE was high enough that TDAE reduced them first. When 4.4 equivalents of C4F9I were used on phenyl or 2-pyridyl disulfide, 140 % and 195 % of thioethers were obtained respectiv ely (Table 2-3, entries 6 and 8). But 40 % yield was only obtained for butyl disulfide, the same yield as when 2.2 equivalents of

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19 C4F9I were used. It seems that aliphatic thio lates anions couldnÂ’t undergo reaction at all through an SRN1 reaction with C4F9I. 2.5 Synthesis of Perfluorobutyl Selenoethers The syntheses of perfluorobutyl se lenides were also performed. R-S-S-RTDAEC4F9I DMF -20 oC to RT R-S-C4F9+ + RT overnight 1 eq.2.2 eq Scheme 2-7. Synthesis of perfluorobutyl selenides Table 2-4. Synthesis of perfluorobutyl selenides Entry R Eq. of C4F9I NMR yield* (%) 1 Phenyl34 2.2 200 2 methyl 2.2 200 *Based on the number of equivalents of diselenides As with 4-pyridyl disulfide, both aryl and aliphatic diselenides only underwent through SRN1 process, resulting in nearly 200 % yields when 2.2 equivalents of C4F9I were used (Table 2-4). Cont rary to disulfides, alipha tic deselenides could react quatitatively with C4F9I via SRN1 process. 2.6 Conclusion The nucleophilic perfluoroalkylat ion methodology developed with CF3I / TDAE system was successfully extended to C2F5I: similar results were obtained and the two halves of disulfides and deselenides were efficiently used. The methodology seemed to reach its limits with C4F9I. Whereas some aryl disulfides still gave good yields, aliphatic disulfides resulted in poor yields. But the most important point is the fact that for some disulfides and for all th e diselenides, TDAE was unable to react with C4F9I and

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20 preferably reduced disulfides or diselenide s instead, forcing the reactions to undergo exclusively through SRN1 mechanism of thiolate anion. From a synthetic point of view, this didnÂ’t present a problem. On the contrary, a smaller amount of TDAE and perfluorobutyl iodide was used to give 200% yi elds. But in the mechanistic point of view, the tandem process, where the perfluoroalkyl iodide switches roles from being a reactant to being a substrate in one pot reaction, couldnÂ’t be appl ied anymore and the role of TDAE was only to reduce the disulfides. Moreover reducing disulfides to form thiolates seems to be much less convenient than deprot onating a more easily available thiols by a base, as the usual methods for perf luoralkyl thioether synthesis via SRN1 reactions. However this C4F9I / TDAE, even when TDAE se rved only as reductant of disulfides, still presents an advantage to ot her methods where the yields were not higher than 60 %31,34 2.7 Experimental Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus 300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with external tetramethylsilane (TMS, = 0.00 ppm) as a reference. Fluorine (19F) and proton (1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFCl3, = 0.00 ppm) as a reference for 19F NMR and TMS ( = 0.00 ppm) for 1H NMR. Deuterated chloroform (CDCl3) was used as NMR solvent. 2.7.1 General Synthesis of Pentafluoroethyl Thio and Selenoethers : Synthesis of Phenyl Pentafluoroethyl Sulfide In 25 mL, 3-neck-round bottom flask, equi pped with a dewar type condenser and N2, diphenyl disulfide (0.8 g, 3.68 mmol) was disolved in 10 mL of anhydrous DMF. The solution was cooled at -20 C. Pentafluoroe thyl iodide (3.8 g, 15.45 mmol) was then

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21 introduced to the solution. TDAE (2 mL, 8.1 mmol) was added around -15 C. The reaction mixture became quickly dark red. The reaction was allowed to warm up slowly to room temperature. And as the bath temper ature reached -10 C white solid was formed. The reaction mixture was stirred at room temp erature for 2 hours (or overnight in the case of alkyl disulfides). The orange solution was filtered and the solid was washed with diethyl ether. The orange solution was filtered and the solid was washed with diethyl ether (20 mL). 20 mL of water was added to the ether solution. The two phases were separated and the aqueous phase was extracte d with 20 mL of ether 2 more times. The combined ether layers were wash ed with brine and dried over MgSO4. The solvent was removed and the crude product was purif ied by silica gel chromatography (CH2Cl2 / hexanes = 1:9) to give phenyl pentafl uoroethyl sulfide in the yield of 198% 19F NMR(300 MHz, CDCl3) -83.00 (t, JFF = 3.1 Hz 3F, CF3); -92.32 (q, JFF = 3.1 Hz ,2F, CF2) ppm Ethyl Pentafluoroethyl Sulfide 1H NMR(300 MHz, CDCl3) 2.70 (q, J = 7.2 Hz, 2H, CH2); 1.32 (t, J = 7.2 Hz, 3H, CH3) 19F NMR(300 MHz, CDCl3) -83.00 (t, JFF = 3.2 Hz ,3F, CF3); -92.32 (q, JFF = 3.2 Hz, 2F, CF2) ppm Butyl Pentafluoroethyl Sulfide 1H NMR(300 MHz, CDCl3) 2.69 (t, J = 7.3 Hz, 2H, CH2); 1.66 (quintet, J = 7.6 Hz, 2H, CH2); 1.42 (sextuplet, J = 7.6 Hz, 2H, CH2); 0.93 (t, J = 7.3 Hz, 3H, CH3) 19F NMR(300 MHz, CDCl3) -82.95 (t, JFF = 3.2 Hz ,3F, CF3); -92.55 (q, JFF = 3.2 Hz, 2F, CF2) ppm

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22 2-Pyridyl Pentafluoroethyl Sulfide35 1H NMR(300 MHz, CDCl3) 8.47 (m, 1H, ArH); 7.62 (m, 2H, ArH); 7.11 (m, 1H, ArH) 19F NMR(300 MHz, CDCl3) -83.17 (t, JFF = 2.01 Hz ,3F, CF3); -91.03 (q, JFF = 2.01 Hz ,2F, CF2) ppm 4-Pyridyl Pentafluoroethyl Sulfide 1H NMR(300 MHz, CDCl3) 8.51 (dd, J1 = 4.8 Hz, J2 = 2.0 Hz, 2H, ArH); 7.37 (dd, J1 = 4.7 Hz, J2 = 1.75 Hz, 2H, ArH) 19F NMR(300 MHz, CDCl3) -82.95 (t, JFF = 2.14 Hz 3F, CF3); -90.78 (q, JFF = 2.14 Hz, 2F, CF2) ppm Phenyl Pentafluoroethyl Selenide34 19F NMR(300 MHz, CDCl3) -84.74 (t, JFF = 3.2 Hz, 3F); -92.14 (q, JFF = 3.2 Hz, 2F, CF2) ppm 2.7.2 General Synthesis of Nonafluorobutyl Th io and Selenoethers : Synthesis of Phenyl Nonafluorobutyl Sulfide In a 25 mL round bottom flask, equipped with a rubber septum and N2, diphenyl disulfide (0.8 g, 3.68 mmol) was disolved in 10 mL of anhydrous DMF. The solution was cooled at -30 C. Nonafluorobut yl iodide (1.4 mL, 15.45 mmol) was then introduced to the solution. TDAE (2 mL, 8.1 mmol) wa s added around -20 C. The reaction mixture became quickly dark red. White solid was fo rmed shortly after the addition of TDAE. The mixture was allowed to warm up slowly to the room temperature was stirred overnight. The orange solution was filtered a nd the solid was washed with diethyl ether (20 mL). 20 mL of water was added to the et her solution. The two phases were separated and the aqueous phase was extracted with 20 mL of ether 2 more times. The combined

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23 ether layers were washed w ith brine and dried over MgSO4. The solvent was removed under vacum and the crude product was pur ified by silica gel chromatography (CH2Cl2 / hexanes = 1:9) to give phenyl nonafluo robutyl sulfide in the yield of 140% 19F NMR(300 MHz, CDCl3) -81.28 (t, JFF = 10.2 Hz 3F, CF3); -87.43 (m, 2F, SCF2); -120.46 (m, 2F, CF2); -125.90 (m, 2F, CF2) ppm Ethyl Nonafluorobutyl Sulfide 1H NMR(300 MHz, CDCl3) 2.70 (q, J = 7.2 Hz, 2H, CH2); 1.32 (t, J = 7.2 Hz, 3H, CH3) 19F NMR(300 MHz, CDCl3) -81.30 (t, JFF = 8.9 Hz 3F, CF3); -87.80 (m, 2F, SCF2); -121.05 (m, 2F, CF2); -125.60 (m, 2F, CF2) ppm Butyl Nonafluorobutyl Sulfide 1H NMR(300 MHz, CDCl3) 2.69 (t, J = 7.3 Hz, 2H, CH2); 1.66 (quintet, J = 7.6 Hz, 2H, CH2); 1.42 (sextuplet, J = 7.6 Hz, 2H, CH2); 0.93 (t, J = 7.3 Hz, 3H, CH3) 19F NMR(300 MHz, CDCl3) -81.35 (t, JFF = 8.5 Hz 3F, CF3); -87.68 (m, 2F, SCF2); -120.97 (m, 2F, CF2); -125.48 (m, 2F, CF2) ppm 2-Pyridyl Nonafluorobutyl Sulfide37 1H NMR(300 MHz, CDCl3) 8.47 (m, 1H, ArH); 7.62 (m, 2H, ArH); 7.11 (m, 1H, ArH) 19F NMR(300 MHz, CDCl3) -81.13 (t, JFF = 10.7 Hz 3F, CF3); -86.13 (m, 2F, SCF2); -120.35 (m, 2F, CF2); -125.70 (m, 2F, CF2) ppm 4-Pyridyl Nonafluorobutyl Sulfide 1H NMR(300 MHz, CDCl3) 8.51 (dd, J1 = 4.8 Hz, J2 = 2.0 Hz, 2H, ArH); 7.37 (dd, J1 = 4.7 Hz, J2 = 1.75 Hz, 2H, ArH)

PAGE 41

2419F NMR(300 MHz, CDCl3) -81.20 (t, JFF = 10.5 Hz 3F, CF3); -86.00 (m, 2F, SCF2); -120.25 (m, 2F, CF2); -125.60 (m, 2F, CF2) ppm Phenyl Nonafluorobutyl Selenide34 19F NMR(300 MHz, CDCl3) -81.47 (t, JFF = 10.7 Hz 3F, CF3); -87.34 (m, 2F, SCF2); -119.14 (m, 2F, CF2); -126.05 (m, 2F, CF2) ppm

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25 CHAPTER 3 PERFLUOROALKYLATION OF IMINE TOSYLATES 3.1 Introduction Our laboratories have develope d methodologies for nucleophilic trifluoromethylation of numerous substrates, such as aldehydes12, cyclic sulfates15, benzoyl chlorides13 or disulfides16, using CF3I / TDAE system. Trifluoromethylamines are very interesting compounds because they can serve as synthetic intermediates to biologically active molecules, as shown in Figur es 3-1 and 3-2, where 3A can be used as pesticide38 and 3B as pain-reliever39. N S S O O CF3 N N N N H F3C NH F3C Figure 3-1. 3A Figure 3-2. 3B Previously trifluoromethylamines were only synthesized from precursors (i.e. ketones) already contai ning trifluoromethyl group.40-48 Prakash and coworkers have used RuppertÂ’s reagent (CF3TMS) with imine derivatives to prepare trifluoromethylamines49 and, in particular, chiral trifluoromethylamines.50,51 Indeed, the use of CF3TMS proved to be very effective for nucleophi lic trifluoromethylation of N-tosyl aldimines and N-(2methyl-2propane-sulfinyl)imines (Scheme 3-1), with the latter reactions exhibiting excellent diastereoselectivity.

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26 Simple alkylor aryl-substituted imin es are relatively unreactive toward nucleophilic trifluoromethylation, although Blaze jewski and co-workers were able to obtain modest to good yields for aryl sy stems by facilitating the reaction of CF3TMS using TMS-imidazole.52 As Prakash showed, the reactivit y of imines toward nucleophilic trifluoromethylation can be si gnificantly enhanced by using N-tosylimines, with the ptoluenesulfonyl group being removed from th e adduct by its treatment with phenol and 48% HBr to give the respec tive primary amine products.49 N Ph Ts CF3TMS N H Ts + TBAT THF, 0 5 oC 90% F3C Ph N Ph S CF3TMS N H S + TBAT THF, -55 oC 80% tBu O tBu O F3C Ph d.r >97% Scheme 3-1. Trifluoromethylation of imines using RuppertÂ’s reagent Using the same CF3I / TDAE methodology than deve loped for trifluoromethylation of aldehydes12, similar results53 to PrakashÂ’s methods could be obtained (Scheme 3-2). Unfortunately, the analogous reactions with im ines bearing aliphati c substituents on the imine carbon did not produce the desired a dducts. Such attempts included the Ntosylimines of acetophenone, p-chloroacetophenone, cyclohe xanone, and hexanal. In contrast, aliphatic aldehydes had been re ported to provide adducts using PrakashÂ’s CF3TMS methodology.49

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27 N Ar Ts N H Ts F3C Ar DMF, -30 0 oC 62-86% CF3I / TDAE (2.2 equiv.) N Ph S N H S DMF, -30 0 oC 66% Tol O Tol O F3C Ph d.r = 87:13 CF3I / TDAE (2.2 equiv.) Scheme 3-2. Trifluoromet hylation of imines using CF3I / TDAE Parallel to trifluoromethylamines, higher perfluoroalkylamines gather also much interest from pharmaceutical and agrochemical industries. For example, 3C can be used as a treatment against osteoporosis54 and 3D as a treatment of AlzheimerÂ’s disease55. N H N N H OCH3CF2CF3tBu NC O N O HN O O N H O CF2CF3 Figure 3-3. 3C Figure 3-4. 3D Since in Chapter 2, we have shown that the CF3I / TDAE methodology could be extend to longer perfluoroalkyl iodide s, such as pentafluoroeth yl iodide or nonafluorobutyl iodide, we decided then to try to sy nthesize other perfluoroalkyl amines

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28 3.2 Synthesis of Tosyl Imines O R2 R 1H2NTs BF3.OEt2 or Ts-OH toluene, reflux N R2 R 1Ts + Scheme 3-1. Synthesis of tosyl imines The imines were easily prepared from aroma tic aldehydes and tosyl amine, as shown in Table 3-1. Unfortunately because of the el ectron withdrawing char acter of the tosyl group, tosyl amine was not reactive towards ke tones or alphatic aldehydes (entries 3.143.16) Table 3-1. Synthesis of tosyl imines entry R1 R2 Yield (%) 3.1 H 80 3.2 Me H 85 3.3 Cl H 85 3.4 F H 88 3.5 F3C H 80

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29 3.6 S H 30 3.7 O H 65 3.8 N CH3 H 95 3.9 CH3 0 3.10 CF3 0 3.11 C7H15 H 0 3.3 Pentafluoroethylation of Tosyl Imines N H Ar Ts CF3CF2I TDAE DMF -20 oC to RT CF2CF3ArN H H Ts ++ 12.2 2.2 Scheme 3-2. Nucleophilic pentaf luoroethylation of tosyl imines

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30 Table 3-2. Nucleophilic pentafl uoroethylation of tosyl imines Entry Ar Yield (%) Yield with CF3I53 (%) 3.1a 50 86 3.2a Me 70 84 3.3a Cl 70 78 3.4a F 72 81 3.5a F3C 68 3.6a S 55 3.7a O 60 3.8a N CH3 0

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31 In general, the reactions provide d similar results than with CF3I / TDAE system, with slightly lower yields. Fo r the case of 1-methylindol-3-i mine tosylate (entry 3.10a) the absence of reactivity may be explaine d by one of the resonance forms shown in Figure 3-1: with the carbon being on the position 3, the indole group becomes a good electron donating group, reducing hugely the electrophilic character of the carbon on the imine, thus the lack of reactivity towards C2F5 nucleophile. N N Ts N N Ts Figure 3-5. A resonance form of N-(N-methyl-3-indolylmethylene)-pmethylbenzenesulfonamide 3.4 Perfluorobutylation of Tosyl Imines Since good yields could be obtained with C2F5I, experiments with C4F9I were performed to extend further the methodology N H Ar Ts C4F9I TDAE DMF -20 oC to RT C4F9ArN H H Ts ++ 12.2 2.2 Scheme 3-3. Nucleophilic perfluorobutylation of tosyl imines In general the yields are lower than with C2F5I, but when the aryl group contains electron withdrawing elements, the yields are good and comparable to the ones from C2F5I (Table 3-3, entries 3.3b 3.5b). Furyl and thiophenyl tosyl imines are not very

PAGE 49

32 reactive but the yields are decent. Like as C2F5I, 1-methyl 3-indolyl tosyl imine is not reactive at all toward perfluoroalkyl ation. (Table 3-3, entry 3.8b) Table 3-3. Nucleophilic perfl uorobutylation of tosyl imines Entry Ar Yield (%) 3.2b Me 50 3.3b Cl 70 3.4b F 70 3.5b F3C 75 3.6b S 45 3.7b O 40 3.8b N CH3 0 Surprisingly the system C4F9I / TDAE provided rather good yields. Unlike with disulfides where C4F9I didnÂ’t seem to be reactive enough (Chapter 2), the system C4F9I / TDAE provided sometimes yields similar to the ones from C2F5I / TDAE.

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333.5 Conclusion The nucleophilic trifluor omethylation methodology of tosyl imines using trifluoromethyl iodide and T DAE could be extended successf ully with pentafluoroethyl iodide and nonafluorobutyl iodide Different substrates were used and provided fair to very good yields. 3.6 Experimental Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus 300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with external tetramethylsilane (TMS, = 0.00 ppm) as a reference. Fluorine (19F) and proton (1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFCl3, = 0.00 ppm) as a reference for 19F NMR and TMS ( = 0.00 ppm) for 1H NMR. Deuterated chloroform (CDCl3) was used as NMR solvent. 3.6.1 Syntheses of Tosyl Imines Synthesis of N-(benzylidene)-p-methylbenzenesulfonamide (3.1) In a 100 mL one-neck round bottom flask, 4toluenesulfonamide (2.57g, 15 mmol) and benzaldehyde (1.52 mL 15mmol) was mixed in 40 mL of toluene. BF3EtO2 (0.15 mL) was added under N2. The flask was equipped with a Dean-Stark apparatus. The reaction mixture was refluxed for 14 hours, then cooled to room temperature and poured into 2M NaOH (10mL). The organic phase was washed with brine and water until neutral pH, dried over anhydrous magnesium sulfat e and the solvent was removed by vacuum. The oily residue was recrystallized from ethyl acetate to give a wh ite solid; yield: 3.11 g (80 %)

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341H NMR (CDCl3 9.03 (s, 1H, CH=N-Ts); 7.91 (m, 4H, ArH); 7.62 (m, 1H, ArH); 7.48 (m, 2H, ArH); 7.34 (m, 2H, ArH); 2.44 (s, 3H, CH3) ppm. Synthesis of N-(4-methylbenzylidene)-p-methylbenzenesulfonamide (3.2) The procedure and the workup are the same as the synthesis of N-(benzylidene)-pmethylbenzenesulfonamide, using 4-methyl benzaldehyde toyield 85 % of white solid 1H NMR (CDCl3 8.99 (s, 1H, CH=N-Ts); 7.88 (d, J = 8.1 Hz, 2H, ArH); 7.82 (d, J = 8.1 Hz, 2H, ArH); 7.34 (d, J = 8.1 Hz, 2H, ArH); 7.29 (d, J = 8.1 2H, ArH); 2.43 (s, 6H, CH3) ppm. Synthesis of N-(4-chlorobenzylidene)-p-methylbenzenesulfonamide (3.3) In a 100 mL one-neck round bottom flask, 4toluenesulfonamide (2.57g, 15 mmol) and 4-chlorobenzaldehyde (2.10g, 15mmol) was mixed in 40 mL of toluene. BF3EtO2 (0.15 mL) was added under N2. The flask was equipped with a Dean-Stark apparatus. The reaction mixture was refluxed for 14 hours, and then cooled to room temperature. White crystals precipitated upon cooling. The solid was filtered, then washed with water and dried under vacuum. Yield = 2.74 g (85 %) 1H NMR (CDCl3) 8.99 (s, 1H); 7.89 (d, J = 6.3 Hz, 2H); 7.86 (d, J = 6.3 Hz, 2H); 7.47 (d, J = 8.4 Hz, 2H); 7.35 (d, J = 8.4 Hz, 2H); 2.44 (s, 3H) ppm. Synthesis of N-(4-fluorobenzylidene)-p-methylbenzenesulfonamide (3.4) The procedure and the workup are the same as the synthesis of N-(benzylidene)-pmethylbenzenesulfonamide, using 4-fluorobenz aldehyde to yield 88% of white solid. 1H NMR (CDCl3 9.00 (s, 1H, CH=N-Ts); 7.96 (m, 2H, ArH); 7.89 (d, J = 8.4 Hz, 2H, ArH); 7.35 (d, J = 8.7 Hz, 2H, ArH); 7.19 (m, 2H, ArH); 2.44 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -101.59 (t, J = 8.7 Hz, 1F) ppm.

PAGE 52

35Synthesis of N-(4-trifluoromethylbenzylidene)-p-methylbenzenesulfonamide (3.5) Following the above procedure for 3.3, by using 4-trifluoromethylbenzaldehyde (2mL, 15mmol), provided 3.92 g (8 0% yield) of white solid. 1H NMR (CDCl3) 9.08 (s, 1H, CH=N-Ts); 8.04 (d, J = 8.1 Hz, 2H, ArH); 7.90 (d, J = 8.4 Hz, 2H, ArH); 7.75 (d, J = 8.1 Hz, 2H, ArH); 7.34 (d, J = 8.4 Hz, 2H, ArH); 2.45 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -63.83 (s, 3F, CF3) ppm. Synthesis of N-(2-thiophenylmethylene)-p-methylbenzenesulfonamide (3.6) In a 100 mL one-neck round bottom flask, 4toluenesulfonamide (2.57g, 15 mmol) and 2-thiophenecarboxaldehyde (1.4 mL, 15mmo l) was mixed in 40 mL of toluene. A catalytic amount of p-toluenesulfonic aci d monohydrate was added. The flask was equipped with a Dean-Stark apparatus. Th e reaction mixture was refluxed for 14 hours. The solution turned quickly dark green and black tar was formed. After 14 hours, charcoal was added to the hot solution and the mixture was stirred at 100 C for 1 hour and filtered while it was still hot. The solvent was removed under vacuum. Recrystallization from be nzene gave 1.07g (30%) of N-(2-thiophenylmethylene)-pmethylbenzenesulfonamide as a silvery gray solid 1H NMR (CDCl3 9.11 (s, 1H, CH=N-Ts); 7.87 (d, J = 8.7 Hz, 2H, ArH); 7.77 (d, J = 4.2 Hz, 2H, ArH); 7.34 (d, J = 8.7 Hz, 2H, ArH); 7.21 (m, 1H, ArH); 2.44 (s, 3H, CH3) ppm.

PAGE 53

36Synthesis of N-(2-furanylmethylene)-p-methylbenzenesulfonamide (3.7) The same procedure and workup as for N-(2-thiophenylmethylene)-pmethylbenzenesulfonamide, using 2-furfural (1.24mL, 15 mmol), gave 2.43 g (65%) of light brown solid. 1H NMR (CDCl3 8.81 (s, 1H, CH=N-Ts); 7.87 (d, J = 8.4 Hz, 2H, ArH); 7.74 (m,1H, ArH); 7.34 (m, 3H, ArH); 6.64 (dd, J = 5.1 and 3.3 Hz, 1H, ArH); 2.43 (s, 3H, CH3) ppm. Synthesis of N-(N-methyl-3-indolylmethylene)-p-methylbenzenesulfonamide (3.8) In a 100 mL one-neck round bottom flask, 4toluenesulfonamide (2.57g, 15 mmol) and N-methyl-3-indolcarbaxaldehyde (2.39 g, 15 mmol) was mixed in 40 mL of toluene. A catalytic amount of p-toluenesulfonic acid monohydrate was added. The flask was equipped with a Dean-Stark apparatus. Th e reaction mixture was refluxed for 14 hours. The solution became rapidly deep purple. After reflux, the reaction mixture was cooled to room temperature and the solvent was re moved in vacuo. The crude solid was recrystallized in benzene to gi ve 4.27 g (95% yield) of N-(N-methyl-3-indolylmethylene)-p-methylbenzenesulfonamide as a purple solid. 1H NMR (CDCl3 9.09 (s, 1H, CH=N-Ts); 8.30 (d, J = 6.9 Hz, 1H, ArH); 7.89 (d, J = 8.1 Hz, 2H, ArH); 7.74 (s, 1H, ArH); 7.33 (3, 5H, ArH); 3.88 (s, 3H, N-CH3); 2.40 (s, 3H, CH3) ppm. 3.6.2 General Procedure for Pentafluoroethylat ion of Tosyl Imines : Synthesis of Methyl-N-(3,3,3,2,2-pentafluoro-1-phenyl-propyl)-benzenesulfonamide (3.1a) In 25 mL, 3-neck-round bottom flask, equi pped with a total reflux condenser and N2, N-(benzylidene)-p-methylbenzenesulfonamide (0.259 g, 1 mmol) was disolved in 6 mL of anhydrous DMF. The solution was cooled at -30 C. Pentafluor oethyl iodide (0.6

PAGE 54

37 g, 2.4 mmol) was then introduced to the so lution. TDAE (0.51 mL, 2.2 mmol) was added around -20 C. The reaction mixture became quickly orange red. The reaction was allowed to warm up slowly to room temperat ure. And as the bath temperature reached 10 C white solid was formed. The reaction mixture was stirred at room temperature overnight. About 15 mL of 10% H2SO4 aqueous solution was added slowly to quench the reaction. As the acid solution was added, th e reaction mixture first became clear as the TDAE salt was dissolved in water. But the mixture became cloudy again as the product precipitated out. The solution was stirred for a while as more and more product precipitated. The solid was coll ected via filtration and dissolv ed in 30 mL of ether. The ether solution was washed 3 times with water to eliminate remaining DMF. The ether phase was dried over anhydrous MgSO4 and the solvent was removed by vacuum. The pale yellow crude product was re crystallized in toluene to af ford 0.189 g of a white solid. (50%) 1H NMR (CDCl3; 7.52 (d, J = 8.4 Hz, 2H, ArH); 7.24 (m, 3H, ArH); 7.10 (m, 4H, ArH); 5.48 (d, J = 9.9 Hz, 1H, NH); 4.97 (m, 1H, CH-N); 2.33 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -81.42 (s, 3F, CF2-CF3); -120.67 (dd, J1 = 291.9 Hz, J2 = 12.9 Hz, 1F, CF-CF3); -122.86 (dd, J1 = 291.6 Hz, J2 = 12.6 Hz, 1F, CF-CF3) ppm. Anal. Calcd for C16H14F8NO2S: C, 50.670; H, 2.694; N, 3.694. Found: C, 50.390; H, 3.591; N, 3.590.

PAGE 55

384-Methyl-N-[3,3,3,2,2-pentafluoro-(4-methyl-ph enyl)-propyl]-benzenesulfonamide (3.2a) White solid (70 % yield) 1H NMR (CDCl3; 7.52 (d, J = 8.1 Hz, 2H, ArH); 7.09 (d, J = 8.1 Hz, 2H, ArH); 7.02 (d, J = 8.4 Hz, 2H, ArH); 6.98 (d, J = 8.7 Hz, 2H, ArH); 5.50 (d, J = 9.9 Hz, 1H, NH); 4.92 (m, 1H, CH-N); 2.34 (s, 3H, CH3); 2.29 (m, 3H, CH3) ppm. 19F NMR (CDCl3) -81.42 (s, 3H, CF2-CF3); -120.72 (dd, J1 = 291.6 Hz, J2 = 12.6 Hz, 1F, CF-CF3); -122.78 (dd, J1 = 291.6 Hz, J2 = 12.6 Hz, 1F, CF-CF3) ppm. Anal. Calcd for C17H16F5NO2S: C, 51.908; H, 4.071; N, 3.562. Found: C, 51.716; H, 4.015; N, 3.503. 4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-chloro-p henyl)-propyl]-benzenesulfonamide (3.3a) White solid (70 % yield) 1H NMR (CDCl3; 7.51 (d, J = 8.4 Hz, 2H, ArH); 7.21 (d, J = 8.4 Hz, 2H, ArH); 7.13 (d, J = 8.4 Hz, 2H, ArH); 7.05 (d, J = 8.4 Hz, 2H, ArH); 5.24 (d, J = 9.3 Hz, 1H, NH); 4.98 (m, 1H, CH-N); 2.38 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -81.39 (s, 3H, CF2-CF3); -120.35 (dd, J1 = 293.7 Hz, J2 = 13.5 Hz, 1F, CF-CF3); -123.33 (dd, J1 = 293.7 Hz, J2 = 13.5 Hz, 1F, CF-CF3) ppm. Anal. Calcd for C16H13ClF5NO2S: C, 46.398; H, 3.141; N, 3.383. Found: C, 46.255; H, 3.122; N, 3.355. 4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-fluorophenyl)-propyl]-benzenesulfonamide (3.4a) White solid (72 % yield) 1H NMR (CDCl3; 7.52 (d, J = 8.4 Hz, 2H, ArH); 7.12 (m, 4H, ArH); 6.92 (t, J = 8.4 Hz, 2H, ArH); 5.37 (d, J = 9.3 Hz, 1H NH); 4.98 (m, 1H, CH-N); 2.36 (s, 3H, CH3) ppm.

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3919F NMR (CDCl3) -81.39 (s, 3H, CF2-CF3); -111.84 (m, 1F, ArF) -120.60 (dd, J1 = 291.3 Hz, J2 = 11.1 Hz, 1F, CF-CF3); -123.19 (dd, J1 = 293.7 Hz, J2 = 13.5 Hz, 1F, CFCF3) ppm. Anal. Calcd for C16H13F6NO2S: C, 48.363; H, 3.274; N, 3.526. Found: C, 48.259; H, 3.266; N, 3.333 4-Methyl-N-[3,3,3,2,2-pentafluoro-(4-trifluoromethyl-phenyl)-propyl]benzenesulfonamide (3.5a) White solid (68 % yield) 1H NMR (CDCl3 7.47 (d, J = 6.1 Hz, 2H, ArH); 7.45 (d, J = 6.1 Hz, 2H, ArH); 7.23 (d, J = 8.1 Hz, 2H, ArH); 7.06 (d, J = 8.1 Hz, 2H, ArH); 5.65 (d, J = 9.9 Hz, 1H, NH); 5.05 (m, 1H, CH-CF2); 2.31 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -63.54 (s, 3F, CF3); -81.41 (s, 3H, CF2-CF3); -119.54 (dd, J1 = 292.5 Hz, J2 = 14.4 Hz, 1F, CF-CF3); -123.91 (dd, J1 = 292.5 Hz, J2 = 14.4 Hz, 1F, CFCF3) ppm. Anal. Calcd for C17H13F8NO2S: C, 45.638; H, 2.908; N, 3.132. Found: C, 45.340; H, 2.833; N, 3.011. 4-Methyl-N-[3,3,3,2,2-pentafluoro-(2-thiophenyl )-propyl]-benzenesulfonamide (3.6a) White solid (55 % yield) 1H NMR (CDCl3 7.58 (d, J = 8.4 Hz, 2H, ArH); 7.25 (m, 1H); 7.17 (d, J = 8.4 Hz, 2H, ArH); 6.88 (m, 2H); 5.34 (m, 1H, CH-N); 5.018 (m, 1H, NH) 2.38 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -82.29 (s, 3H, CF2-CF3); -120.71 (dd, J1 = 289.2 Hz, J2 = 11.1 Hz, 1F, CF-CF3); -123.36 (dd, J1 = 289.2 Hz, J2 = 11.1 Hz, 1F, CF-CF3) ppm.

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40 Anal. Calcd for C14H12F5NO2S2: C, 43.636; H, 3.117; N, 3.636. Found: C, 43.578; H, 3.099; N, 3.620. 4-Methyl-N-[3,3,3,2,2-pentafluoro-(2-furanyl)-p ropyl]-benzenesulfonamide (3.7a) Light brown solid (60 % yield) 1H NMR (CDCl3 7.60 (d, J = 8.4 Hz, 2H, ArH); 7.19 (m, 3H); 6.21 (m, 2H, ring); 5.33 (d, J = 10.2 Hz, 1H, NH); 5.11 (m, 1H, CH-CF2); 2.38 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -82.02 (s, 3H, CF2-CF3); -120.72 (dd, J1 = 291.3 Hz, J2 = 13.2 Hz, 1F, CF-CF3); -122.33 (dd, J1 = 289.2 Hz, J2 = 13.1 Hz, 1F, CF-CF3) ppm. Anal. Calcd for C14H12F5NO3S: C, 45.528; H, 3.252; N, 3.790. Found: C, 45.246; H, 3.255; N, 3.747. 3.6.3 General Procedure for Perfluorobutylation of Tosyl Imines: Synthesis of 4Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-methyl-phenyl)-propyl]benzenesulfonamide (3.2b) In a 25 mL round bottom flask, connected with N2, N-(4-methylbenzylidene)-pmethylbenzenesulfonamide (0.273 g, 1 mmol) was disolved in 6 mL of anhydrous DMF. The solution was cooled at -30 C. Nonafluorobutyl iodide (0.38 mL, 2.2 mmol) was then introduced to the solution. TDAE (0.51 mL 2.2 mmol) was added around -20 C. The reaction mixture became quickly orange red a nd white solid was formed shortly after the addition of TDAE. The reaction was allowed to warm up slowly to room temperature. The reaction mixture was stirred at room temperature overnight. About 15 mL of 10% H2SO4 aqueous solution was added slowly to que nch the reaction. As the acid solution was added, the reaction mixture first became clear as the TDAE salt was dissolved in water. But the mixture became cloudy again as dark brown oil could be seen forming. The solution was stirred for several hours as more brown vicous oil was formed. 30 mL

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41 of ether were added to dissolve the oil. Th e two phases were separated and the ether solution was washed 3 times with water to eliminate remaining DMF. The ether phase was dried over anhydrous MgSO4 and the solvent was removed by vacuum. The pale yellow crude product was recrystallized in toluene to afford 0.189 g of a white solid. (50%) 1H NMR (CDCl3; 7.51 (d, J = 8.4 Hz, 2H, ArH); 7.09 (d, J = 8.1 Hz, 2H, ArH); 7.00 (m, 4H, ArH); 5.33 (d, J = 9.9 Hz, 1H, NH); 5.04 (m, 1H, CH-N); 2.34 (s, 3H, CH3); 2.29 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -81.43 (t, J = 9.9, 3F, CF2-CF3); -116.98 (dm, J1 = 301.5 Hz, 1F, CF-CH); -118.88 (dm, J1 = 301.5 Hz, 1F, CF-CH); -121.47 (m, 2F, CF2); 126.53 (m, 2F, CF2) ppm. Anal. Calcd for C19H16F9NO2S: C, 46.212; H, 3.243; N, 2.837. Found: C, 46.239; H, 3.185; N, 2.821 4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4-chloro-phenyl)-propyl]benzenesulfonamide (3.3b) White solid (70 % yield) 1H NMR (CDCl3; 7.50 (d, J = 8.4 Hz, 2H, ArH); 7.18 (d, J = 8.7 Hz, 2H, ArH); 7.11 (d, J = 7.8 Hz, 2H, ArH); 7.04 (d, J = 8.4 Hz, 2H, ArH) 5.60 (d, J = 9.9 Hz, 1H, NH); 5.07 (m, 1H, CH-N); 2.37 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -81.41 (t, J = 11.1, 3F, CF2-CF3); -116.52 (dm, J1 = 304.8 Hz, 1F, CF-CH); -119.38 (d3, J1 = 304.8 Hz, 1F, CF-CH); -121.37 (m, 2F, CF2); 126.55 (m, 2F, CF2) ppm. Anal. Calcd for C18H13ClF9NO2S: C, 42.038; H, 2.530; N, 2.724. Found: C, 41.904; H, 2.457; N, 2.685.

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424-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(4 -trifloromethyl-phenyl)-propyl]benzenesulfonamide (3.5b) White solid (75 % yield) 1H NMR (CDCl3; 7.47 (d, J = 8.1 Hz, 2H, ArH); 7.42 (d, J = 8.4 Hz, 2H, ArH); 7.22 (d, J = 8.1 Hz, 2H, ArH); 7.04 (d, J = 8.4 Hz, 2H, ArH) 5.99 (d, J = 10.2 Hz, 1H, NH); 5.16 (m, 1H, CH-N); 2.31 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -63.57 (s, 3F, Ar-CF3); -81.41 (t, J = 11.1 Hz, 3F, CF2-CF3); 115.84 (dm, J = 304.5 Hz, 1F, CF-CH); -119.77 (dm, J = 304.5 Hz, 1F, CF-CH); -121.33 (m, 2F, CF2); 126.52 (m, 2F, CF2) ppm. Anal. Calcd for C19H13F12NO2S: C, 41.654; H, 2.375; N, 2.558. Found: C, 41.751; H, 2.297; N, 2.553 4-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(2-thiophenyl -phenyl)-propyl]benzenesulfonamide (3.6b) White solid (45 % yield) 1H NMR (CDCl3; 7.57 (d, J = 8.1 Hz, 2H, ArH); 7.23 (m, 1H, ring); 7.14 (d, J = 8.1 Hz, 2H, ArH); 6.90 (m, 1H, ring); 6.83 (m 1H, ring); 5.42 (m, 2H, CH-N and NH); 2.36 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -81.39 (t, J = 11.1 Hz, 3F, CF2-CF3); -116.69 (dm, J = 297.9 Hz, 1F, CF-CH); -119.22 (dm, J = 297.9 Hz, 1F, CF-CH); -121.47 (m, 2F, CF2); 126.52 (m, 2F, CF2) ppm. Anal. Calcd for C16H12F9NO2S2: C, 39.555; H, 2.472; N, 2.884. Found: C, 39.567; H, 2.421; N, 2.778

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434-Methyl-N-[5,5,5,4,4,3,3,2,2-nonafluoro-(2-furanyl-phenyl)-propyl]benzenesulfonamide (3.7b) Brown solid (40 % yield) 1H NMR (CDCl3; 7.59 (d, J = 8.4 Hz, 2H, ArH); 7.26 (m, 1H, ring); 7.19 (d, J = 8.4 Hz, 2H, ArH); 6.21 (m, 2H, ring); 5. 42 (m, 2H, CH-N and NH); 2.38 (s, 3H, CH3) ppm. 19F NMR (CDCl3) -81.40 (t, J = 11.1 Hz, 3F, CF2-CF3); -116.69 (dm, J = 297.9 Hz, 1F, CF-CH); -119.22 (dm, J = 297.9 Hz, 1F, CF-CH); -121.47 (m, 2F, CF2); 126.52 (m, 2F, CF2) ppm. Anal. Calcd for C16H12F9NO3S: C, 40.908; H, 2.557; N, 2.983. Found: C, 40.733; H, 2.446; N, 2.907

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44 CHAPTER 4 PERFLUOROAKYLATION OF ALDEHYDES AND KETONES 4.1 Introduction Along with trifluoromethyl alcohols, longer perfluoroalkyl alcohols are generating growing interests from industries, as one can notice the fast increase of the number of patented molecules containing perfluoroalkyl alcohol function in the past few years. These molecules can be used as fungicide56 (Figure 4-1) or insecticide.57 CF 2 Me F 3 C F S O O N N OH Figure 4-1. 4A56 : Fungicide (CF 2 ) 3 NC CF 3 F 3 C Cl Cl NH 2 N N CH OH Figure 4-2. 4B57 : insecticide Our laboratories have developed successfu lly nucleophilic trif luoromethylation of aldehydes and ketones by using CF3I / TDAE system12. Since the methodology could be extended for pentafluoroethyl iodide and nonafluorobut yl iodide for disulfides (Chapter 2) and tosyl imines (Chapter 3), the re search was then performed on aldehydes and ketones.

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454.2 Pentafluoroethylation of Aldehydes and Ketones The procedure for the pentafluoroethylat ion of aldehydes and ketones is very similar than the trifluor omethylation of aldehydes12. Since earlier studies on the C2F5I / TDAE system have shown that the resulting co mlplex is stable below -10 C (Chapter 2), the reaction could be perfo rmed at -15 or -10 C. R1R2O CF3CF2I DMF OH R1CF2CF3R2TDAE -15 oC to RT h 1 hr 1 eq2.2 eq2.2 eq RT, 12 hrs Scheme 4-1. Pentafluoroethyl ation of aldehydes and ketones By comparison to the yields obtained in trifluoromethylation, the products from pentafluoroethylation were obtai ned in very similar yields. Th e yields are generally lower except for fluorenone (entry 4.5) where the yield was 95 % compared to 73 % for trifluoromethylated product. The aromatic aldehydes provided high yields (entries 4.14.3). The yields from ketones products are d ecent, but this may be explained by a lower reactivity than aldehydes toward s nucleophilic reaction for ket ones. As expected, ketones or aldehydes bearing a hydrogen on -carbon resulted in low to ve ry low yields (entries 4.6 and 4.7). Butyraldehyde, that had already low yield for trifluoromethylation, provided only 5 % yield, which is not really interesti ng. These low yields can be explained by the fact that TDAE is also a st rong base and would readily depr otonate acid hydrogens in the substrates, creating enolates, in th e case of aldehydes and ketones.

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46 Table 4-1. Compared yields between pentafluoroethylati on and trifluoromethylation of aldehydes and ketones Entry Substrate Yield (%) Yield with CF3I12 (%) 4.1 O 90 Quant. 4.2 O 75 80 4.3 O OMe 80 83 4.4 O 95 73 4.5 O 55 68 4.6 O 50 50 4.7 O 5 15

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474.3 Perfluorobutylation of Aldehydes and Ketones Since nucleophilic pentafluoroethylati on of aldehydes and ketones with C2F5I / TDAE system could provide good yields and comparable to trifluoromethylation with CF3I / TDAE system, the methodology was extended with C4F9I. R1R2O C4F9I DMF OH R1C4F9R2 TDAE -20 oC to RT h 1 hr 1 eq2.2 eq2.2 eq RT, 12 hrs Scheme 4-2. Nucleophilic perfluor obutylation of al dehydes and ketones The yields obtained are very low: 35 % for benzaldehyde and 20 % for cyclohexanone. Similar low reactivity of C4F9I / TDAE system was already observed in the case of disulfides (Chapt er 2). The fact that the C4F9I / TDAE complex is not very stable and tends to decompose shortly after the addition of TDAE to the reaction mixture may explain this low reactivity. Moreover the Sun Lamp that provided the light irradiation produces a lot heat, this additional heat may be the cause of lower yields. Table 4-2. Perfluorobutylat ion of aldehydes and ketones Entry Substrate % yield 4.8 O 3558 4.9 O 2059

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484.4 Conclusion In the same manner than with disulfides and tosyl imines the C2F5I / TDAE system provided very similar yields than CF3I / TDAE system. However C4F9I / TDAE system proved to be not reactive enough towards alde hydes and ketones and provided really low yields. The CF3I / TDAE methodology could be successfully extended to C2F5I. But C4F9I seems to be the limit of this methodol ogy in nucleophilic perf luoroalkylation of aldehydes because the yields are so low that it is not interesting to develop further the reaction. 4.5 Experimental Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus 300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with external tetramethylsilane (TMS, = 0.00 ppm) as a reference. Fluorine (19F) and proton (1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFCl3, = 0.00 ppm) as a reference for 19F NMR and TMS ( = 0.00 ppm) for 1H NMR. Deuterated chloroform (CDCl3) was used as NMR solvent. 4.5.1 General Procedure of Pentafluoroeth ylation of Aldehydes and Ketones: Synthesis of 1-Phenyl-2,2,3,3,3-pentafluoropropan-1-ol (4.2) In 25 mL, 3-neck-round bottom flask, equi pped with a reflux condenser and N2, benzaldehyde (0.37 mL, 3.68 mmol) was diso lved in 10 mL of anhydrous DMF. The solution was cooled at -20 C and C2F5I (2.0 g, 8.1 mmol) was in troduce into the solution. Then TDAE (2 mL, 8.1 mmol) was added into the reaction mixture. The color of the reaction mixture became dark red as TDAE was added. The mixture was allowed to warm up slowly to room temperature. The reaction was irradiated by a Sun lamp for 1 hour. White solid was formed as the temperat ure of the bath reach ed –10 C. The reaction

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49 mixture was stirred at room temperature overnight. The orange solution was filtered and the solid was washed with diethyl ether. The DMF solution was hydrolyzed with water and was extracted with ether (3 times). The combined ether layers were washed with brine and dried over MgSO4. The solvent was removed and the crude product was purified by column chromatography to afford colorless liquid60 at 90 % yield 1H NMR (CDCl3, 300MHz) 7.45 -7.70 (m, 5H, ArH); 5.06 (m, 1H, CHCF2); 2.87 (s, 1H, OH) ppm. 19F NMR (CDCl3, 300 MHz) -81.90 (m, 3F, CF3), -122.80 (m, 1F, CF3CFF), 129.50 (m, 1F, CF3CFF) ppm. 1-Naphthyl-2,2,3,3,3-pentafluoropropan-1-ol (4.2) 1H NMR (CDCl3, 300MHz) 8.05 (d, J = 8.4 Hz, 1H, ArH); 8.0 – 7.82 m, 3H, ArH); 7.657.32 (m, 3H, ArH); 5.89 (m, 1H, CHCF2); 2.85 (s, 1H, OH) ppm 19F NMR (CDCl3, 300 MHz) = -81.54 (m, 3F, CF3), -118.15 (dd, J1 = 290.4 Hz, J2 = 20.7 Hz, 1F, CF2), -130.24 (dd, J1 = 290.4 Hz, J2 = 20.7 Hz, 1F, CF2) ppm 1,1,1,2,2-Pentafluoro-5-(2methoxy -phenyl)-pent-4-en-3-ol (4.3) 1H NMR (CDCl3, 300MHz) 7.45 (dd, J1 = 7.7 Hz, J2 = 1.8 Hz, 1H, ArH); 7.31 (m, 1H, ArH); 7.25 (d, J = 16.2 Hz, 1H, ArH); 6.95 (m, 1H, ArH); 6.87 (dd, J1 = 7.5 Hz, J2 = 0.9 Hz, 1H) 6.27 (dd, J1 = 16.2, Hz, J2 = 7.1 Hz, 1H); 4.66 (m, 1H, CHCF2); 3.87 (s, 3H, OCH3); 2.26 (s, 1H, OH) 19F NMR (CDCl3, 300 MHz) = -81.40 (m, 3F, CF3), -122.25 (AB, dd, J1 = 291 Hz, J2 = 9.9 Hz, 1F, CFF CF3); -129.12 (dd, J1 = 291 Hz, J2 = 9.9 Hz, 1F, CFFCF3) ppm

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509-Pentafluoroethyl fluoren-9-ol (4.4) 1H NMR (CDCl3, 300MHz) 7.67 (m, 4H, ArH); 7.48 (m, 2H, ArH); 7.36 (m, 2H, ArH); 3.01 (s, 1H, OH) 19F NMR (CDCl3, 300 MHz) = -78.62 (s, 3F, CF3), -121.29 (s, 2F, CF2) ppm 1,1-Diphenyl-2,2,3,3,3-pentafluoropropan-1-ol (4.5)61 19F NMR (CDCl3, 300 MHz) = -84.65 (s, 3F, CF3), -115.97 (s, 2F, CF2) ppm Pentafluoroethyl cyclohexan-1-ol (4.6)62 19F NMR (CDCl3, 300 MHz) = -78.17 (s, 3F, CF3), -126.25 (s, 2F, CF2) ppm 1,1,1,2,2-Pentafluorobutan-3-ol (4.7)63 19F NMR (CDCl3, 300 MHz) = -81.57 (m, 3F, CF3), -122.75 (m, 1F, CF3CFF), 131.40 (m, 1F, CF3CFF) ppm 4.5.2 General Procedure for Perfluorobutyl ation of Aldehydes and Ketones: Synthesis of 1-Phenyl-2,2,3,3,4,4,5,5,5-nonafluoropentan-1-ol In a 25 mL round bottom flask, connected N2, benzaldehyde (0.37 mL, 3.68 mmol) was disolved in 10 mL of anhydrous DMF. The solution was cooled at -30 C and C4F9I (0.75 mL, 8.1 mmol) was introduce into the solution via a syringe. Then TDAE (2 mL, 8.1 mmol) was added into the reaction mixt ure at -20 C. The color of the reaction mixture became dark red as TDAE was added. The reaction was irradiated by a Sun lamp.The mixture was allowed to warm up slow ly to room temperature. White solid was formed shortly after the addition of TDAE. The reaction mixture was stirred at room temperature overnight with the presence of iradiation. The orange solution was filtered and the solid was washed with diethyl ether. 20 mL of water were added to the filtrate the two layers were separated and the aqueous pha se was extracted with ether (3 times). The

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51 combined ether layers were wash ed with brine and dried over MgSO4. The solvent was removed by vacuum and the crude product wa s purified by column chromatography.

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52 CHAPTER 5 SYNTHESES AND STUDIES OF TETRAKIS(DIMETHYLAMINO)ETHYLENE ANALOGUES 5.1 Introduction Our laboratories have successfully de veloped methodologies for nucleophilic perfluoroalkylation of numerous subtrates.12,13,14,15,50 These methodologies consist in reducing perfluoroalkyl iodides with tetrakis(dimethyl amino)ethylene (TDAE), creating perfluoroalkyl anions which can undergo nucleophilic reaction s on different eletrophilic substrates. The mechanism of the reactions is still not totally understood. But it is known that as TDAE was introduced into the reac tion mixture containing perfluoroalkyl iodide and the substrate, TDAE formed a temperature-dependently stable complex with perfluoroalkyl iodide. As the reaction temperature rose above these critical temperatures (0 C for CF3I, -10 C for C2F5I and -20 C for C4F9I), the complex decomposed freeing perfluoroalkyl anion, whic h only then reacted with th e substrate (Scheme 5-1). Substrate CF3I TDAE TDAE2+ CF3 I-complex Substrate product 0 oC -20 oC Scheme 5-1. CF3I / TDAE complex At this point, we have little knowledge about the complex and its decomposition. It is not sure whether the product resulted from an attack from a free perfluoroalkyl anion or from an intermediate form where TDAE is still involved. In the latter case, the presence of chirality in the complex would induce chirality in the final product. This

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53 would be particularly interesting in the case of reactions with aldehydes and ketones where an asymmetric carbon is created from the addition of perfluoroalkyl group to the carbonyl carbon. Since there is no preferen tial side of attack, the resulting perfluoroalkyl alcohol is a racemic mixture. The aim is then to synthesize analogue molecules to TDAE, conserving the tetrak is-amino ethylene part and possessing a structure that would be able to bear asymmetric carbons. Th e structure would be a cyclic analogue to TDAE containing asymmetric carbons, as shown in Figure 5-1. N N N N R R R R R' R'* Figure 5-1. Structure of a chiral TDAE analogue But the non chiral cyclic TDAE an alogue -1,3,1Â’,3Â’-tetraalkyl-2,2Â’bis(imidazolidene)(Figure 5-2), would be first synthesized and studied to see if comparable results than TDAE could be obtained. N N N N R R R R Figure 5-2. Non chiral TDAE analogue

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545.2 Syntheses of TDAE Analogues 5.2.1 Synthesis of 1,3,1Â’,3Â’-Tetraal kyl-2,2Â’-bis(imidazolidene) Two analogues were synthesized where R were methyl group a nd ethyl group. The one-pot synthesis invo lved reaction between N, NÂ’-diethylethylene diamine or N,NÂ’dimethylethylene diamine and N,NÂ’-dimethylformamide dimethyl acetate64. The two reagents were dissolved in benzene and we re heated at 110 C for 4 hours then the product was collected via distil lation under reduced pressure. The resulting products are a pale yellow liquid for 1,3,1Â’,3Â’-tetraethyl-2,2 Â’-bis(imidazolidene) and a pale yellow solid for 1,3,1Â’,3Â’-tetramethyl-2,2Â’-bis(imidazo lidene) with 40% yield for both products. NH NH R R N O O N N N N R R R R benzene reflux 4 hrs + 1 equiv.1.2 equiv.40% R = Me (5.1) orEt Scheme 5-2. Synthesis of 1,3,1Â’ ,3Â’-tetraalkyl-2,2Â’-bis(imidazolidene) 5.2.2 Synthesis of 1,3,1',3'-Tetramethyl -2,2'-bis(benzimidazolylidene) The other analogue we were interested in synthesizing was. N N N N Figure 5-3. benzimidazole TDAE analogue

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55 The synthesis of 1,3,1',3'-tetramethyl-2,2 '-bis(benzimidazolylidene)consisted in 3 steps. The first step is the synthesis of benzimidazole65 by reacting 1,2-diaminobenzene with formic acid. The reaction yielded 87%. The second step was the methylation of the amino groups with iodomethane to form 1,3-dimethyl-benzimidazolium iodide66 in 85% yield. The final step involved deprotonation of the hydrogen on imine carbon, producing a carbene which recombined to itself to form 1,3,1',3'-tetramethyl-2,2'-bis(benzimidazolylidene)67 resulting in a brown solid in 50%. HCO2H N H N+NH2NH2H2O+(5.2) N H N N N I 2 MeI + (5.3) N N I NaH THF 2 N N N N (5.4) Scheme 5-3. Multi-step synthesis of benzimidazole TDAE analogue

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565.3 Attempts of Trifluoromethyla tion using the TDAE Analogues 5.3.1 Attempts of Trifluoromethylati on using 1,3,1’,3’-Tetraalkyl-2,2’bis(imidazolidene) instead of TDAE The first attempts of nucleophilic trif luoromethylation using the imidazolidene TDAE analogue were performed in the sa me conditions than with TDAE: Anhydrous DMF was used as solvent and the analogue was added to the solution of benzaldehyde and CF3I at -20 C. The reaction mixture color di dn’t become deep red as it was always the case for TDAE. Instead the solution becam e darker yellow than the color of the analogue. But the mixture seemed to discolored back to pale yello w few moments later. The usual salt formation at 0 C for CF3I / TDAE couldn’t be seen by using the analogue. The solution stayed clear throughout the reaction process. 19F NMR revealed the presence of the tr ifluoromethylated adduct but in a yi eld lower than 10 %. Numerous reactions of optimization have been perf ormed but no more than 15 % of the product could be obtained. The “optimized” proce dure would introduce the imidazolidene TDAE analogue at -40 C, instead of -20 C, and th e temperature was kept at -40 C for more than 40 minutes before allowing the reaction mixture to warm up slowly to room temperature and stirred overnight. Th e reaction was irradiated for 12 hours. N N N N R R R R OH CF3CF3I O + + DMF h -40 oC to RT 15% 1 2.22.2 Scheme 5-4. Nucleophilic trifluoromethyl ation of benzaldehyde using 1,3,1’,3’tetraalkyl-2,2’-bis(imidazolidene)

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57 PhS-SPh N N N N R R R R CF3I + DMF -40 oC to RT PhS-CF3110 % 14.22.2 + based on equiv. of disulfides Scheme 5-5. Synthesis of phenyl trifluor omethyl sulfide by using imidazolidene TDAE analogue An attempt of trifluoromethylation of phe nyl disulfide was also performed. Only 110 % of phenyl trifluoromethyl thioether could be obtained, instead of nearly 200 % in the case of TDAE. But the thioether may be resulted from the SRN1 reaction of phenyl thiolate, formed by reduction of disulfide by TDAE analogue, with CF3I, since the analogue cannot efficiently cr eate trifluoromethyl anion. Scheme 5-6. Possible decomposition pathways for imidazolidene TDAE analogue

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58 The explanation of this lack of reac tivity of the TDAE analogue towards CF3I may be the fact that the cyclic TDAE analogues may give, after one-electron transfer to CF3I, the corresponding colored radical cation. It s eems that the radical cation is quite unstable since the color disappeared. By decomposing the radical cation would probably give the corresponding carbene and a ne w “smaller” radical cation.68 According to recent studies69, the carbene should not dimerize to fo rm back to the TDAE analogue but may react with O2 to form a cyclic urea or with benzaldehyde to form an intermediate that may give a bezoin condensation or the corresponding 2-benzoylimidazoline as final products.70 (Figure 5-7) Scheme 5-7. Reactivities of imid azolidene carbene towards benzaldehyde The cyclic voltammetry experiment was also performed on 1,3,1’,3’-tetraethyl2,2’-bis(imidazolidene). But the resulting gr aph didn’t show any reversible oxidation waves corresponding to the formation of stab le radical cations (Figure 5-4), whereas TDAE cyclic voltammetry graph shows reversibility.71

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59 Figure 5-4. Cyclic voltammogram for 1,3,1Â’ ,3Â’-Tetraethyl-2,2Â’-bis(imidazolidene), C = 3mM in DMF + 0.1 mM Et4NBF4 at 20 C, scan rate: 0.2V/s 5.3.2 Nucleophilic Trifluoromethylation of Phenyl disulfide using 1,3,1',3'Tetramethyl-2,2'-bis(benzimidazolylidene) The attempt of trifluoromethylation of phe nyl disulfide with 1,3,1',3'-Tetramethyl2,2'-bis(benzimidazolylidene) only provided trac es of phenyl trifluoromethyl sulfide. The analogue may be either too stable or may decompose directly to carbenes since the compound was synthesized via di merization oftwo carbenes. PhS-SPh N N N N CF3I + DMF -40 oC to RT PhS-CF31 4.2 2.2 + trace Scheme 5-8. Attempt of synthesis of phenyl trifluoromethyl sulfide by using 1,3,1',3'tetramethyl-2,2'-bis(benzimidazolylidene)

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605.4 Conclusion The idea of using chiral TDAE analogues to induce chirality in the final products would have been an interesti ng project since industries are looking for chiral fluorinated compounds as biologically active molecules. But the incapacity of these analogues to generate CF3 anion from CF3I didnÂ’t allow us to develop further the idea. 5.5 Experimental Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus 300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with external tetramethylsilane (TMS, = 0.00 ppm) as a reference. Fluorine (19F) and proton (1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFCl3, = 0.00 ppm) as a reference for 19F NMR and TMS ( = 0.00 ppm) for 1H NMR. Deuterated chloroform (CDCl3) was used as NMR solvent. 5.5.1 Synthesis of 1,3,1Â’,3Â’-Tetraethyl-2,2Â’-bis(imidazolidene) (5.1) N,N-dimethylformamide dimethyl acetate (20 mL, 151 mmol) and N,Ndiethylethylene diamine (18.3 mL, 130 mmol) was dissolved in 80 mL of dry benzene. The solution was refluxed at 110 C for 3 hours. The azeotrope methanol/benzene was then distilled out. The remaining solution wa s cooled to the room temperature and the solvent was removed by vacuum. The product was distilled out under vacuum (bp = 8688 C/3 mmHg). Even though the melti ng point of 1,3,1Â’ ,3Â’-tetraethyl-2,2Â’bis(imidazolidene) is around 48 C, it remained a yellow liquid66. Yield = 50 % 5.5.2 Synthesis of Benzimidazole (5.2) In a 250 mL round bottom flasko-phenylenediami ne (27g, 0.25 mol) is treated with 15 mL of formic acid (17.3 g, 0.38 mol). The mixture was heated and refluxed at 100 C

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61 2 hours. After cooling, 10 % NaOH solution wa s added until the pH became just basic. The crude brown product was collected by filtrat ion and was rinsed with ice-cold water. The crude benzimidazole was then dissolved in 400 mL of boiling water. About 1 g of celite was added and the mixture was stirre d while boiling for 15 minutes before hot gravity filtration. The filtrate was allowed to cool slowly to room temperature and then was placed in an ice bath for 20 minutes. The product was filtered and washed with icecold water. The product was dried in the oven overnight to afford 25.69 g (87 % yield) of pale yellow powder65. MP = 171 – 173 C 1H NMR(CDCl3, 300 MHz) 8.10 (s, 1H, N-CH=N); 7.68 (m, 2H, ArH); 7.31 (m, 2H, ArH) 5.5.3 Synthesis of 1,3-Dimethyl-benzimidazolium iodide (5.3) In a 100 mL round bottom flask, 1.4 g of sodium was added in small portions in 25 mL of absolute ethanol. After all sodi um was dissolved, 7.1 g (60 mmol) of benzimidazole was added to the solution, followed by 25g of iodomethane (180 mmol) and 20 mL of benzene. The reaction mixture was refluxed for 15 hours. After the reflux, the solvents were removed by vacuum. And the crude was recrystallized with ethanol to yield 14.09 g (85 %) of 1,3dimethyl-benzimidazolium iodide as a pale pinkish solid66. 1H NMR(CDCl3, 300 MHz) 11.07 (s, 1H, N-CH=N); 7.72 (m, 4H, ArH); 4.28 (s, 3H, CH3); 4.27 (s, 3H, CH3) 5.5.4 Synthesis of 1,3,1',3'-Tetramethyl-2,2' -bis(benzimidazolylidene) (5.4) In a 250 mL round bottom flask, 1,3-dimethyl-benzimidazolium iodide (10.09 g, 34.8 mmol) was dissolved in 100 mL of fres hly distilled THF and sodium hydride (1.25

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62 g, 52.2 mmol) was added slowly to the solu tion. The mixture was stirred for 3 hours at the room temperature then 2 hours at 50 C The solvent was removed by vacuum. 50 mL of toluene was added to the dark brown resi due. The mixture was heated to boil and was hot-gravity filtered. The yellow filtrate wa s concentrated, n-hexane was added and the solution was cooled at -30 C for overnight The recrystallized light brown solid was filtered and dry to give 5.0 g of 1,3,1',3'-tetramethyl-2,2'-bis(benzimidazolylidene)67 (50 % yield)

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63 CHAPTER 6 DIMERIC DERIVATIVES OF OCTAFLUO RO[2,2]PARACYCLOPHANE (AF4) : A NEW SOURCE OF PERFLUOROALKYL RADICALS 6.1 Introduction 6.1.1 General Information Since their first designed synthesis in 1951,72 [2.2]paracyclophanes have been considered valuable compounds for testi ng theories of bonding, ring strain, and electron interactions.73-75 A number of methods have b een devised for the relatively convenient synthesis of the parent hydrocar bon, all of which requi re the use of high dilution methodology.76-78 In addition, it has been rec ognized since the mid-1960s that [2.2]paracyclophanes are useful chemical vapor deposition (CVD) precursors of thin film polymers, known in the industry as “parylenes”.79 Such parylenes are ideally suited for use as conformal coatings in a wide variety of applications, such as in the electronics, semiconductor, automotive, and medical indus tries. Parylene coatings are inert and transparent and have excellent barrier properties. Parylene N, which is generated from the parent hydrocarbon 1, has been found to be useful at temperatures up to 130 C. 1,1,2,2,9,9,10,10-Octafluoro[2.2]paracyclophane,80 the bridge-fluorinated version of 1 (and known in the industry as AF4), is th e CVD precursor of Parylene-HT polymer, poly(-tetrafluoro-p-xylylene). The Parylene-HT polymer combines a low dielectric constant (2.25)79 with high thermal stability (<1 wt % loss/2 h at 450 C), low moisture absorption (<0.1%), a nd other advantageous properties.81,82 With such properties and because its in vacuo depos ition process ensures conformality to

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64 microcircuit features and superior subm icron gap-filling capability, Parylene-HT continues to show considerable promise as an interlayer dielectric for on-chip high-speed semiconductor device interconnection. H2C H2C CH2CH2 F2C F2C CF2CF2 Figure 6-1. [2,2]-paracyclopha ne Figure 6-2. AF4 6.1.2 Synthesis of AF4 CF2Cl CF2Cl 4 eq Zn F2C F2C CF2CF2DMA, 100 oC 3h 60% Scheme 6-1. Synthesis of AF4 AF4 is produced in 60% yield in a reaction of Zn with 0.35 M p-bis(chlorodifluoromethyl)-benzene in DMA at 100 C.The mechanism of formation of AF4 is shown in Scheme 6-2. p-bis(chlorodifluoro methyl)-benzene is reduced first by zinc metal to p-xylylene intermediate 2, which reacts with itself to form dimer diradical 3. The two radicals reconnect to each other to form AF4. The unique chemical characteristics of 1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane (AF4) have been amply demons trated by a number of recent publications related to its synthesis,83-85 its chemical reactivity,86,87 and its role as the CVD precursor of the highly thermally stable, low-dielectr ic thin film polymer known as parylene-HT.8890

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65 CF2Cl CF2Cl CF2CF2F F F2C F2C F F AF4CF2F2C F F F F polymerization reduction bimolecular C-C bond formation 1 23-extended 3-syn rotation Scheme 6-2. Mechanism of formation of AF4 Because ring-substituted derivatives of AF 4 have the potential to produce parylene films with enhanced properties, efforts have been directed at the synthesis of compounds such as trifluoromethyl derivative (Figure 6-1). F2C F2C CF2CF2CF3 Figure 6-3. Trifluor omethyl-AF4 derivative Although 1 has been prepared by a traditi onal four-step synthetic sequence beginning with nitration of AF4,76 a more direct method base d on SawadaÂ’s free-radical trifluoromethylation methodology ap peared potentia lly attractive.91 However, when trifluoroacetyl peroxide was allowed to decompose in the presence of AF4 in refluxing CH2Cl2, although the trifluoromethyl radical indeed added to one of the aromatic rings of AF4, no rearomatization to 1 was observed. Instead, the intermediate cyclohexadienyl

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66 radical 2 proved to be uncommonly stable, so stable that it survived sufficiently long to dimerize to a 57:43 mixture of the novel a nd structurally unprecedented diasteromeric products, d,land meso-3, in a total yield of 60% 6.2 Kinetic Studies of CF3-AF4-dimers 6.2.1 Synthesis of CF3-AF4-dimer F2C F2C CF2CF2 1 eq H2O2 (50%) 3eq (CF3CO)2O CH2Cl2F2C F2C CF2CF2CF3F2C F2C CF2CF2F3C 1) -78 OC to R.T. 2) reflux overnight 60% d,l : meso = 57:43 Scheme 6-3. Synthesis of CF3-AF4-dimer The dimer is formed via radical addition of CF3 • radical to AF4, forming a trifluoromethylated AF4 radical that read ily dimerizes into d,l and meso forms. F2C F2C CF2CF2F2C F2C CF2CF2F3C.2 CF3.F2C F2C CF2CF2CF3F2C F2C CF2CF2F3C22 Scheme 6-4. Formation of CF3-AF4-dimer

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67 The CF3 • radical was formed by thermal decomp osition of trifluoroacetyl peroxide, which was prepared in situ by reacting trif luoroacetic anhydride with hydrogen peroxide. (Scheme 6-5) Trifluoroacetic anhydride conve rts to trifluoro-pe roxy acetic acid which reacts with another molecule of trifluoroacetic anhydride to form trifluoroacetyl peroxide. The resulting peroxide decomposes thermally into 2 molecules of carbone dioxide and 2 molecules of the CF3 • radical. (CF3CO)2O + H2O2CF3CO3H+ CF3CO2H CF3CO3H + (CF3CO)2OCF3C(O)-O-O-C(O)CF3 + CF3CO2H CF3C(O)-O-O-C(O)CF32 CF3. + 2 CO2 Scheme 6-5. Mechanism of formation of CF3 • radical Figure 6-4. 19F NMR distinction examining the d,l and the meso forms of CF3-AF4dimers F2C F2C CF2CF2H F3C H F2C F2C CF2CF2CF3H H MESO F2C F2C CF2CF2F2C F2C CF2CF2CF3H H CF3H H D,L

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68 The two disateromers, d,l and meso forms, are distinguishable by 19F NMR, as shown in Figure 6-4, the multiplet peaks corresponding to the CF3 group having slightly different chemical shifts. They could also be separated by column chromatography. 6.2.2 Thermal Decomposition of the CF3-AF4-dimer The dimers are stable indefinitely at room temperature. But as they are heated, they decompose to regenerate back AF 4 and release 2 equivalents of CF3 • radical. Two different pathways for the mechanism of d ecomposition can be presented (Scheme 6-6). The decomposition can be stepwise where the di mer is first broken into two molecules of trifluoromethylated AF4 radical (A) and then CF3 • radicals were eliminated, forming back AF4 (path A) or the process is concerted and AF4 and CF3 • are formed in one single step (path B). F2C F2C CF2CF2F2C F2C CF2CF2F3CCF3F2C F2C CF2CF2F3C F2C F2C CF2CF22 CF3..2 2 +path Ap a t h BA Scheme 6-6. Two possible pathways for decomposition of CF3-AF4-dimer An experiment was performed to determine the mechanism of decomposition: the dimer was dissolved in acetonitrile with an excess of 1,4-cyclohexadiene, in a sealed

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69 NMR tube. 1,4-cyclohexadiene served as ra dical trap as it read ily quenches radicals present in the reaction by giving 2 hydrogen radical to form benzene. The reaction misture was heated above 160 C for several hour s. If the mechanism is the path B, the presence of 1,4-cyclohexadiene will not disturb anything and only AF4 will be formed but if itÂ’s the path A, 1,4-cyclohexadiene wi ll trap trifluoromethyl ated AF4 radical A and AÂ’ will be found instead of AF4 (Scheme 6-7). F2C F2C CF2CF2F2C F2C CF2CF2F3CCF3F2C F2C CF2CF2F3C F2C F2C CF2CF22 CF3H.2 2 +path AApath BF2C F2C CF2CF2F3C 2A'H Scheme 6-7. Resulting products from radical trapping in different possible mechanism pathway 19F NMR revealed a huge amount of AF4 in the reaction mixture but a small quantity of AÂ’ could also be found. The pres ence of AÂ’, even in a small amount, proved that the mechanism of the decomposition pr oceeds in a stepwise manner (path A). The presence of the large quantity of AF4 can be explained by the fact that the formation of AF4 from the radical A is much faster than the trapping by 1,4-cyclohexadiene.

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706.2.3 Kinetic Study of Homolysis of CF3-AF4-Dimers The study of the mechanism of the decomposition of the CF3-AF4-dimer showed that the rate determining step is the first step of the mechanism where the dimer broke down into two CF3-AF4 radical A. A kinetic study wa s the performed on the homolysis of the two diasteromers to determine rate constants and half lives at different temperatures and the activation energy of the reaction. F2C F2C CF2CF2F2C F2C CF2CF2F3CCF3 F2C F2C CF2CF2F3C F2C F2C CF2CF2F3C k.2 2 Scheme 6-8. Kinetic st udy of homolysis of CF3-AF4-Dimers The rate being first order, the slope of the plot of Ln of concentrations versus times would give the rate constant of the temp erature of experimentation, following the equation below: Ln([C]) = -k t The experiments consisted of dissolving one diasteromer in dry acetonitrile with an excess of 1,4-cyclohexadiene and a known amount of trifluorotoluene as internal standard in a sealed NMR tube. The tube was heated in an oil bath at fixed

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71 temperature. The tube was taken out of the o il bath regularly to measure the quantity of the dimer by 19F NMR and the time was measured. From all the data, a graph of Ln of concentration of dimer versus time was plotte d and the slope of the linear regression gave the rate constant k. The values of k at di fferent temperatures ar e shown in Table 6-1. Table 6-1. Rate constants of the 2 diasteromers of CF3-AF4-dimers Temperatures (C) k (d,l) (s-1) k (meso) (s-1) 140.1 7.37 x 10-6 8.62 x 10-6 151.0 2.24 x 10-5 2.81 x 10-5 160.7 7.14 x 10-5 8.50 x 10-5 170.3 1.57 x 10-4 3.21 x 10-4 179.7 4.55 x 10-4 4.94 x 10-4 The rate constants of the meso form were always greater than that of the d,l form but they are of the same order and pretty cl ose. The difference in rate constants between the two diasteromers seemed to decrease as the temperatures increase. From these rate constants values, the half -life times could be calculated according to the following equation: 22 / 1Ln k The values are shown in Table 6-2. Th ese half-life values confirmed the high stability of the compounds at room temperatur e: the half-lives of both dimers are above 22 hours at 140 C. But they decrease very rapi dly as the temperatur es increase, from more than 22 hours to 25 min in less than 40 C.

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72 Table 6-2. Half-life tim es of the homolysis of CF3-AF4-dimers Temperatures (C) (d,l) (meso) 140.1 26hrs 7 min 22hrs 20min 151.0 8hrs 36min 6hrs 51min 160.7 2hrs 42min 2hrs 16min 170.3 74 min 36min 179.7 25.4 min 23.4 min By using the Arrhenius equation, the activ ation energy of the homolysis could be obtained: ) exp( RT Ea A k K being the rate constant, Ea the activation energy and T the temperature in Kelvin.In the logari thmic form the equation beccomes: ) ( ) ( A Ln RT Ea k Ln By plotting Ln(k) versus 1/T, the slop e of the graph would give access to the activation energy.

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73 Figure 6-5. Arrhenius plot for the 2 diasteromers of CF3-AF4-dimers y = -20.059x + 36.901 R2 = 0.9876 y = -19.352x + 34.997 R2 = 0.9977 -12 -11.5 -11 -10.5 -10 -9.5 -9 -8.5 -8 -7.5 -7 2.202.252.302.352.40 1/T x 1000Ln K dl meso Linear (meso) Linear (dl)

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74 Table 6-3. Arrhenius plot data 1/T x 1000 Ln(k[d,l]) Ln(k[meso]) 2.42 -11.82 -11.66 2.36 -10.71 -10.48 2.31 -9.55 -9.37 2.26 -8.76 -8.04 2.21 -7.70 -7.61 Table 6-4. Activation parameters for CF3-AF4-dimers Ea (kcal/mol) Log A d,l-Form 38.43 15.20 meso-Form 39.83 16.02 6.3 Kinetic Studies of C2F5-AF4-dimers We were interested in study behaviors of AF4 dimers with a longer perfluoroalkylated chains. Ki netic studies of pentafluoroe thyl-AF4-dimers were then performed. 6.3.1 Synthesis of C2F5-AF4-dimers In the same manner as the synthesis of CF3-AF4-dimers, C2F5-AF4-dimers were formed from C2F5 • radical addition to AF4, the C2F5 • radical being formed from thermal decomposition of pentafluoropropionyl pero xide, formed in situ by reaction of perfluoropropionic anhydride with hydroge n peroxide. Since pe ntafluoropropionyl peroxide is much less stable than trifluor oacetyl peroxide, stirri ng overnight at room temperature was sufficient to decompose the peroxide.

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75F2C F2C CF2CF2 1 eq H2O2 (50%) 3eq (CF3CF2CO)2O CH2Cl2F2C F2C CF2CF2CF2CF3F2C F2C CF2CF2F3CF2C -78 OC to R.T. 50% d,l : meso = 55:45 Scheme 6-9. Synthesis of C2F5-AF4-dimers The dimer products are composed of two dias teromers, the d,l and meso forms, in a ratio of 55 and 45 respectively. They can be distinguished from each other by 19F NMR spectrum by examining the peaks of CF3 groups of the CF2CF3 chain, as shown in the Figure 6-6 Figure 6-6. 19F NMR distinction examining the d,l and the meso forms of C2F5-AF4dimers The structure of the meso form was determ ined by X-ray analysis and a perspective view is shown in Figure 6-7. F2C F2C CF2CF2F2C F2C CF2CF2CF2CF3H H CF2CF3H HD,L F2C F2C CF2CF2H F3CF2C H F2C F2C CF2CF2CF2CF3H HMESO

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76 Figure 6-7. Perspective view (ORTEP) of meso-C2F5-AF4-dimer 6.3.2 Kinetic Studies of the Homolysis of C2F5-AF4-dimers The kinetic studies on C2F5-AF4-dimer were performed using the same procedure as applied to the CF3-AF4-dimers. The rates constants are summarized in Table 6-5. Whereas for CF3-AF4-dimers, where the rate constants of the meso form werealways greater than that of the d,l form, for C2F5-AF4-dimers (with the exception of 118.8 C, where k(meso) is higher than k(d,l) ) the rates constants of d,l and meso forms are almost identical, with the tendency for d,l rate constants to be slightly greater.

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77 Table 6-5. Rate constants of the 2 diasteromers of C2F5-AF4-dimers Temperatures (C) k (d,l) (s-1) k (meso) (s-1) 118.8 1.16 x 10-6 1.80 x 10-6 130.5 5.02 x 10-6 4.63 x 10-6 139.6 9.53 x 10-6 1.00 x 10-5 145.3 2.31 x 10-5 2.14 x 10-5 151.3 4.16 x 10-5 4.10 x 10-5 156.4 5.86 x 10-5 5.83 x 10-5 161.0 1.09 x 10-4 1.10 x 10-4 The half-lives times at different temperatures are shown in Table 6-6. For C2F5AF4-dimers, the half-life times decrease ve ry rapidly, from more than 100 hours to around 70 minutes with only a 40 C change in temperatures. The decrease was much greater than was observed for the CF3-AF4-dimers. Table 6-6. Half-life times of the homolysis of C2F5-AF4-dimers Temperatures (C) (d,l) (meso) 118.8 166hrs 31min 107hrs 9min 130.5 38hrs 19min 41hrs 35min 139.6 20hrs 12min 19hrs 13min 145.3 8hrs 11min 9hrs 151.3 4hrs 38min 4hrs 42min 156.4 3hrs 17min 3hrs 18min 161.0 77min 80min

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78 An Arrhenius graph was plotted to obta in to the activation energies of the homolysis reaction. Table 6-7. Arrhenius plot data for C2F5-AF4-dimers 1/T x 1000 LnK (d,l) LnK (meso) 2.55 -13.67 -13.23 2.42 -11.56 -11.51 2.36 -10.09 -10.10 2.33 -9.74 -9.75 2.39 -10.67 -10.75 2.48 -12.20 -12.28 2.30 -9.13 -9.12 Table 6.8. Activation parameters for C2F5-AF4-dimers Ea (kcal/mol) Log A d,l-Form 35.65 13.90 meso-Form 33.01 12.60 The activation energies for C2F5-AF4-dimers are somewhat lower than that of the CF3AF4-dimers (38.43 kcal/mol for d, l and 39.83 kcal/mol for meso).

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79 Figure 6-8. Arrhenius plot of the 2 diasteromers of C2F5-AF4-dimers arrhenius plot y = -16.6237x + 29.0156 R2 = 0.9894 y = -17.9533x + 32.1679 R2 = 0.9941 -14.0 -13.5 -13.0 -12.5 -12.0 -11.5 -11.0 -10.5 -10.0 -9.5 -9.0 2.252.302.352.402.452.502.55 1/T *1000ln (k) d,l meso Linear (meso) Linear (d,l)

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80 6.4 Conclusion The AF4-dimers proved to be very intere sting compounds. Their stability at room temperature and their ability to release perfl uoroalkyl radicals at high temperatures make them an ideal source of perfluoroalkyl radical s where they can be used as initiators for polymerization reactions of fluorinated monomers92 in which a high purity is required since other initiators, such as AIBN, woul d introduce other func tional groups to the polymer chains 6.5 Experimental Nuclear Magnetic Resonance (NMR) spectra were recorded on a Varian Unity plus 300 MHz Spectrometer system. The proton (1H) NMR were recorded at 300 MHz with external tetramethylsilane (TMS, = 0.00 ppm) as a reference. Fluorine (19F) and proton (1H) NMR were recorded at 300 MHz with external fluorotrichloromethane (CFCl3, = 0.00 ppm) as a reference for 19F NMR and TMS ( = 0.00 ppm) for 1H NMR. Deuterated chloroform (CDCl3) was used as NMR solvent. 6.5.1 Synthesis of CF3-AF4-Dimer In 100 mL, 1-neck round bottom flask, 3g of AF4 (9 mmol) was dissolved in 25 mL of freshly distilled dichloromethane. Trifluoroacetic anhydride (4.2 mL, 30 mmol) were added. The solution was cooled at -78 C and 50% H2O2 (3.4 mL, 10 mmol) was introduced slowly via a syringe The reaction mixture was kept at -78 C for one hour and was allowed to warm to the room temper ature. The reaction was stirred at room temperature overnight and was then refluxed fo r at least 12 hours. White solid could be seen in the flask. After reflux, the mixtur e was cooled to room temperature and the

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81 solution was filtered. The crude was then purified86 and the two diasteromers were separated via column chromatography (hexanes/ CH2Cl2 : 9/1) 6.5.2 Kinetic Studies of CF3-AF4-Dimer 6.5.2.1 General procedure In a 5 inch NMR tube, 2 mg of one of the diasteromers of CF3-AF4-Dimer, 200 L of 1,4-cyclohexadiene and 0.6 L of -trifluorotoluene we re dissolved in 500 L of deuterated acetonitrile (CD3CN). A rubber septum was place on the tube and the solution was frozen at -78 C in dry ice / 2-propa nol bath. The tube was degassed under vacuum for several minutes. The NMR tube was flam ed sealed. The tube was immersed in a constant temperature bath for an appropriate time, then removed, cooled and analyzed by 19F NMR, with the concentration of the dimer being measured versus trifluorotoluene, used as internal standard. The rates were determined for each isomer at different temperatures.

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826.5.2.2 Kinetic data and graphs for CF3-AF4-Dimer at 140.1 C The following tables and figures show kinetic data and graphs for CF3-AF4-Dimer at 140.1 C. Table 6-9. Kinetic data of d,l-CF3-AF4-Dimer at 140.1 C d,l form Time (min) C.103 (mol/L) LnC 8 3.75 -5.59 279 3.11 -5.77 545 2.82 -5.87 744 2.59 -5.96 1206 2.11 -6.16 1533.5 1.83 -6.31 1926.5 1.50 -6.50 2360 1.24 -6.69 2691 1.12 -6.79 2923 1.01 -6.89 Table 6-10. Kinetic data of meso-CF3-AF4-Dimer at 140.1 C meso form Time (min) C.103 (mol/L) LnC 0 2.09 -6.17 254 1.84 -6.30 453 1.67 -6.40 915 1.31 -6.64 1242.5 1.12 -6.80 1635.5 0.89 -7.02 2069 0.70 -7.26 2400 0.62 -7.39 2632 0.54 -7.52

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83 Figure 6-9. Kinetic Graph of d,l-CF3-AF4-Dimer at 140.1 C Figure 6-10. Kinetic Graph of meso-CF3-AF4-Dimer at 140.1 C y = -0.00051719x 6.16656971 R2 = 0.99951338 -7.8 -7.6 -7.4 -7.2 -7.0 -6.8 -6.6 -6.4 -6.2 -6.0 050010001500200025003000 t (min)ln C y = -0.00044225x 5.62532632 R2 = 0.99751858 -7.1 -6.9 -6.7 -6.5 -6.3 -6.1 -5.9 -5.7 -5.5 0400800120016002000240028003200 t (min)Ln C

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846.5.2.3 Kinetic data and graphs for CF3-AF4-Dimer at 151.0 C The following table and figures show kinetic data and graphs for CF3-AF4-Dimer at 151.0 C. Table 6-11. Kine tic data of CF3-AF4-Dimers at 151.0 C d,l form Time (min) C.103 (mol/L) LnC 31 1.37 -6.59 65.5 1.26 -6.67 105.5 1.23 -6.70 178.5 1.10 -6.81 361.5 0.88 -7.03 925.5 0.41 -7.80 1115.5 0.313 -8.07 meso form Time (min) C.103 (mol/L) LnC 28.5 0.89 -7.03 69.5 0.85 -7.07 111.5 0.81 -7.12 219.5 0.68 -7.29 329.5 0.57 -7.47 893.5 0.21 -8.45 1083.5 0.15 -8.78

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85 Figure 6-11. Kinetic Graph of d,l-CF3-AF4-Dimer at 151.0 C Figure 6-12. Kinetic Graph of meso-CF3-AF4-Dimer at 151.0 C y = -0.00134211x 6.56228224 R2 = 0.99943388 -8.30 -8.10 -7.90 -7.70 -7.50 -7.30 -7.10 -6.90 -6.70 -6.50 020040060080010001200 t (min)ln C y = -0.00168423x 6.94225137 R2 = 0.99897753 -8.80 -8.70 -8.60 -8.50 -8.40 -8.30 -8.20 -8.10 -8.00 -7.90 -7.80 -7.70 -7.60 -7.50 -7.40 -7.30 -7.20 -7.10 -7.00 -6.90 020040060080010001200 t (min)ln C

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866.5.2.4 Kinetic data and graphs for CF3-AF4-Dimer at 160.7 C The following table and figures show kinetic data and graphs for CF3-AF4-Dimer at 160.7 C. Table 6-12. Kine tic data of CF3-AF4-Dimers at 160.7 C d,l form Time (min) C.103 (mol/L) LnC 19 2.59 -5.96 68 2.02 -6.20 97 1.84 -6.30 139 1.55 -6.47 196 1.19 -6.74 256 0.93 -6.98 meso form Time (min) C.103 (mol/L) LnC 0 1.92 -6.26 73 1.31 -6.64 122 0.99 -6.91 151 0.89 -7.02 193 0.73 -7.23 250 0.53 -7.55 310 0.39 -7.85

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87 Figure 6-13. Kinetic Graph of d,l-CF3-AF4-Dimer at 160.7 C Figure 6-14. Kinetic Graph of meso-CF3-AF4-Dimer at 160.7 C y = -0.00428300x 5.88704159 R2 = 0.99839077 -7.2 -7.0 -6.8 -6.6 -6.4 -6.2 -6.0 -5.8 050100150200250300 t (min)ln C y = -0.00510220x 6.26401120 R2 = 0.99904593 -8.0 -7.8 -7.6 -7.4 -7.2 -7.0 -6.8 -6.6 -6.4 -6.2 -6.0 050100150200250300350 t (min)ln C

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886.5.2.5 Kinetic data and graphs for CF3-AF4-Dimer at 170.3 C The following table and figures show kinetic data and graphs for CF3-AF4-Dimer at 170.3 C. Table 6-13. Kine tic data of CF3-AF4-Dimers at 170.3 C d,l form Time (min) C.103 (mol/L) LnC 15 2.17 -6.13 45 1.58 -6.45 61 1.38 -6.59 86 1.11 -6.81 116 0.84 -7.09 146 0.63 -7.37 190 0.41 -7.80 meso form Time (min) C.103 (mol/L) LnC 15 2.52 -5.98 45 1.28 -6.66 61 0.93 -6.98 77 0.69 -7.27 98 0.44 -7.72 113 0.35 -7.96 142 0.22 -8.43

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89 Figure 6-15. Kinetic graph of d,l-CF3-AF4-Dimers at 170.3 C Figure 6-16. Kinetic graph of meso-CF3-AF4-Dimers at 170.3 C y = -0.009413x 6.005657 R2 = 0.999477 -8.00 -7.80 -7.60 -7.40 -7.20 -7.00 -6.80 -6.60 -6.40 -6.20 -6.00 020406080100120140160180200 t (min)ln C y = -0.019281x 5.766482 R2 = 0.995762 -8.50 -8.30 -8.10 -7.90 -7.70 -7.50 -7.30 -7.10 -6.90 -6.70 -6.50 -6.30 -6.10 -5.90 020406080100120140160 t (min)ln C

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906.5.2.6 Kinetic data and graphs for CF3-AF4-Dimer at 179.7 C The following table and figures show kinetic data and graphs for CF3-AF4-Dimer at 179.7 C. Table 6-14. Kine tic data of CF3-AF4-Dimers at 179.7 C d,l form Time (s) C.103 (mol/L) LnC 109 3.62 -5.62 1012 2.35 -6.06 1920 1.61 -6.43 2829 1.11 -6.80 3740 0.67 -7.31 4348 0.53 -7.55 meso form Time (s) C.103 (mol/L) LnC 109 3.65 -5.61 712 2.77 -5.89 1620 1.79 -6.33 2225 1.31 -6.64 2838 0.95 -6.96 3446 0.71 -7.25

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91 Figure 6-17. Kinetic graph of d,l-CF3-AF4-Dimers at 179.7 C Figure 6-18. Kinetic graph of meso-CF3-AF4-Dimers at 179.7 C y = -0.00045479x 5.57046614 R2 = 0.99808643 -7.60 -7.40 -7.20 -7.00 -6.80 -6.60 -6.40 -6.20 -6.00 -5.80 -5.60 0500100015002000250030003500400045005000 t (s)ln C y = -0.00049442x 5.54362604 R2 = 0.99958986 -7.30 -7.10 -6.90 -6.70 -6.50 -6.30 -6.10 -5.90 -5.70 -5.50 05001000150020002500300035004000 t (s)ln C

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926.5.3 Synthesis of C2F5-AF4-Dimer The procedure for the synthesis of C2F5-AF4-Dimer was the same than for CF3AF4-Dimer, by using pentafluoropropionic anhy dride instead of trifluoroacetic anhydride and no reflux was needed. The reaction yielde d 40% as a 55:45 mixture of diasteromers, as determined by 19F NMR. The d,l and meso diasteromers were separated via column chromatography using hexanes/CH2Cl2 (9/1) as solvent. The x-ray analysis indicated that the minor isomer was the meso form. NMR for d,l-C2F5-AF4-dimer: 1H NMR (acetone-d6, 300 MHz): 7.83 (d, J = 8.1 Hz, 2H, ArH); 7.75 (m, 4H, ArH); 7.49 (d, J = 8.1 Hz, 2H, ArH); 6.34 (m, 2H); 6.13 (d, J = 7.2, 2H); 3.68 (m, 2H); 2.58 (m, 2H) 19F NMR (acetone-d6, 300 MHz): -83.59 (m, 6F, CF3); -108.90 (d, J = 260.4 Hz, 2F); -109.60 (d, J = 267.0 Hz, 2F); -110.14 (dd, J1 = 284.4 Hz, J2 = 59.4 Hz, 2F); -112.45 (d, J = -68.4 Hz, 2F); -113.83 (m, 6F); -116.27 (m, 6F) NMR for meso-C2F5-AF4-dimer: 1H NMR (acetone-d6, 300 MHz): 7.76 (m, 6H, ArH); 7.47 (d, J = 8.1 Hz, 2H, ArH); 6.20 (m, 4H); 3.81 (m, 2H); 2.69 (m, 2H) 19F NMR (acetone-d6, 300 MHz): -83.42 (m, 6F, CF3); -108.23 (d, J = 280.2 Hz, 2F); -109.11 (d, J = 282.6 Hz, 2F); -111.04 (dm, J = 262.8 Hz, 2F); -113.20 (m, 4F); 114.01 (dm, J = 269.4, 2F); -115.23 (d, J = 256.2, 2F) -115.96 (m, 6F)

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936.5.4 X-ray Structure of C2F5-AF4-Dimers X-ray experimental: Data were collected at 173 K on a Siemens SMART PLATFORM equipped with A CCD area dete ctor and a graphite monochromator utilizing MoK radiation ( = 0.71073 ). Cell parameters were refined using up to 8192 reflections. A full sphere of data (1381 frames) was collected using the -scan method (0.3 frame width). The first 50 frames we re remeasured at the end of data collection to monitor instrument and crysta l stability (maximum correction on I was < 1 %). Absorption corrections by integration were applied based on measured indexed crystal faces. The structure was solved by the Direct Methods in SHELXTL5, and refined using full-matrix least squares. The non-H atoms were treated anisotropically, whereas the hydrogen atoms were calculated in ideal pos itions and were riding on their respective carbon atoms. A total of 559 parameters were refined in the final cycle of refinement using 5920 reflections with I > 2 (I) to yield R1 and wR2 of 3.84% and 9.77%, respectively. Refinement was done using F2. Sheldrick, G. M. (1998). SHELXTL5 Bruker-AXS, Madison, Wisconsin, USA.

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94 Figure 6-19. X-ray structure of meso-C2F5-AF4-dimer

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95 Table 6-15. Crystal data and structure refinement Empirical formula C36 H16 F26 Formula weight 942.49 Temperature 193(2) K Wavelength 0.71073 Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 12.4560(6) = 90. b = 17.3580(9) = 111.396(2). c = 16.8135(9) = 90. Volume 3384.7(3) 3 Z 4 Density (calculated) 1.850 Mg/m 3 Absorption coefficient 0.208 mm -1 F(000) 1864 Crystal size 0.23 x 0.18 x 0.16 mm 3 Theta range for data collection 1.75 to 27.50. Index ranges -16 h 16, -22 k 22, -21 l 21 Reflections collected 29845 Independent reflections 7757 [R(int) = 0.0330] Completeness to theta = 27.50 99.8 % Absorption correction Analytical Max. and min. transmission 0.9690 and 0.9534 Refinement method Full-matrix least-squares on F 2 Data / restraints / parameters 7757 / 0 / 559 Goodness-of-fit on F 2 1.022 Final R indices [I>2sigma(I)] R1 = 0.0384, wR2 = 0.0977 [5920] R indices (all data) R1 = 0.0541, wR2 = 0.1086 Largest diff. peak and hole 0.369 and -0.322 e. -3 R1 = (||F o | |F c ||) / |F o | wR2 = [ w(F o 2 F c 2 ) 2 ] / w F o 2 2 ]] 1/2 S = [ w(F o 2 F c 2 ) 2 ] / (n-p)] 1/2 w= 1/[ 2 (F o 2 )+(0.049*p)2+1.8006*p], p = [max(F o 2 ,0)+ 2* F c 2 ]/3

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96 Table 6-16. Selected bond lengths [] and angles [] _____________________________________________________ C1-C1' 1.577(2) C4-C17 1.538(2) C17-C18 1.537(3) C4'-C17' 1.529(3) C17'-C18' 1.537(3) C2-C1-C6 108.75(13) C2-C1-C1' 110.64(13) C6-C1-C1' 114.76(13) C5-C4-C3 109.48(13) C5-C4-C17 114.04(14) C3-C4-C17 111.45(14) C18-C17-C4 114.84(15) C2'-C1'-C6' 108.89(13) C2'-C1'-C1 110.41(13) C6'-C1'-C1 113.87(13) C3'-C2'-C1' 123.66(15) 6.5.5 Kinetic Studies of C2F5-AF4-Dimers 6.5.5.1 General procedure The procedure for the kinetic experiments on C2F5-AF4-Dimers are the same than for CF3-AF4-dimers.

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976.5.5.2 Kinetic data and graphs of C2F5-AF4-Dimers at 118.8 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 118.8 C. Table 6-17. Kinetic data of C2F5-AF4-Dimers at 118.8 C D,l form Time (min) C.103 (mol/L) LnC 449 4.16 -5.48 932 4.04 -5.51 1125 3.98 -5.53 1561 3.86 -5.56 1889 3.77 -5.58 Meso form Time (s) C.103 (mol/L) LnC 449 3.41 -5.68 678 3.35 -5.70 932 3.27 -5.72 1125 3.17 -5.75 1889 2.93 -5.83

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98 Figure 6-20. Kinetic graph of d,l-C2F5-AF4-Dimers at 118.8 C Figure 6-21. Kinetic graph of meso-C2F5-AF4-Dimers at 118.8 C y = -6.9378E-05x 5.4493E+00 R2 = 9.9796E-01 -5.60 -5.58 -5.56 -5.54 -5.52 -5.50 -5.48 -5.46 -5.44 0200400600800100012001400160018002000 time (min)ln C y = -1.0782E-04x 5.6278E+00 R2 = 9.9408E-01 -5.85 -5.80 -5.75 -5.70 -5.65 -5.60 0200400600800100012001400160018002000 time (min)ln C

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996.5.5.3 Kinetic data and graphs of C2F5-AF4-Dimers at 125.7 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 125.7 C. Table 6-18. Kinetic data of C2F5-AF4-Dimers at 125.7 C D,l form Time (min) C.103 (mol/L) LnC 222 1.24 -6.70 772 1.00 -6.90 1649 0.74 -7.21 2032 0.66 -7.31 2972 0.449 -7.61 4206 0.33 -8.02 4632 0.30 -8.10 5532 0.23 -8.37 Meso form Time (min) C.103 (mol/L) LnC 222 0.43 -7.76 772 0.36 -7.93 1649 0.29 -8.16 2032 0.26 -8.26 2972 0.21 -8.48 4206 0.15 -8.83 5532 0.11 -9.11

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100 Figure 6-22. Kinetic graph of d,l-C2F5-AF4-Dimers at 125.7 C Figure 6-23. Kinetic graph of meso-C2F5-AF4-Dimers at 125.7 C y = -3.1439E-04x 6.6633E+00 R2 = 9.9816E-01 -8.50 -8.30 -8.10 -7.90 -7.70 -7.50 -7.30 -7.10 -6.90 -6.70 -6.50 0100020003000400050006000 t (min)lnC y = -2.5453E-04x 7.7280E+00 R2 = 9.9852E-01 -9.40 -9.20 -9.00 -8.80 -8.60 -8.40 -8.20 -8.00 -7.80 -7.60 0100020003000400050006000 t (min)lnC

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1016.5.5.4 Kinetic data and graphs of C2F5-AF4-Dimers at 130.5 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 130.5 C. Table 6-19. Kinetic graph of C2F5-AF4-Dimers at 130.5 C D,l form Time (min) C.103 (mol/L) LnC 554 1.05 -6.86 1132 0.83 -7.10 1724 0.70 -7.27 2670 0.53 -7.54 2930 0.50 -7.60 3908 0.38 -7.89 4276 0.33 -8.03 Meso form Time (min) C.103 (mol/L) LnC 554 1.73 -6.36 1132 1.41 -6.56 1724 1.20 -6.72 2670 0.93 -6.97 2930 0.86 -7.05 3908 0.68 -7.29 4276 0.59 -7.44

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102 Figure 6-24. Kinetic graph of d,l-C2F5-AF4-Dimers at 130.5 C Figure 6-25. Kinetic graph of meso-C2F5-AF4-Dimers at 130.5 C y = -3.0148E-04x 6.7271E+00 R2 = 9.9722E-01 -8.20 -8.00 -7.80 -7.60 -7.40 -7.20 -7.00 -6.80 050010001500200025003000350040004500 t (min)LnC y = -2.7780E-04x 6.2323E+00 R2 = 9.9751E-01 -7.60 -7.40 -7.20 -7.00 -6.80 -6.60 -6.40 -6.20 050010001500200025003000350040004500 t (min)LnC

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1036.5.5.5 Kinetic data and graphs of C2F5-AF4-Dimers at 139.6 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 139.6 C. Table 6-20. Kinetic data of C2F5-AF4-Dimers at 139.6 C D,l form Time (min) C.103 (mol/L) LnC 65 1.52 -6.49 145 1.46 -6.53 197 1.39 -6.58 286 1.34 -6.62 439 1.23 -6.70 823 0.98 -6.92 Meso form Time (min) C.103 (mol/L) LnC 65 3.49 -5.66 92 3.46 -5.67 197 3.16 -5.76 286 3.07 -5.78 439 2.80 -5.88 823 2.21 -6.12

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104 Figure 6-26. Kinetic graph of d,l-C2F5-AF4-Dimers at 139.6 C Figure 6-27. Kinetic graph of meso-C2F5-AF4-Dimers at 139.6 C y = -5.7181E-04x 6.4520E+00 R2 = 9.9832E-01 -6.95 -6.90 -6.85 -6.80 -6.75 -6.70 -6.65 -6.60 -6.55 -6.50 -6.45 0100200300400500600700800900 time (min)ln C y = -6.0131E-04x 5.6193E+00 R2 = 9.9652E-01 -6.20 -6.10 -6.00 -5.90 -5.80 -5.70 -5.60 0100200300400500600700800900 time (min)Ln C

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1056.5.5.6 Kinetic data and graphs of C2F5-AF4-Dimers at 145.3 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 145.3 C. Table 6-21. Kinetic data of C2F5-AF4-Dimers at 145.3 C D,l form Time (min) C.103 (mol/L) LnC 47.5 3.09 -5.78 97.3 2.93 -5.83 222.7 2.40 -6.03 348.0 2.08 -6.18 476.5 1.70 -6.38 608.4 1.43 -6.55 Meso form Time (min) C.103 (mol/L) LnC 47.5 1.36 -6.60 97.3 1.29 -6.65 222.7 1.08 -6.83 348.0 0.95 -6.96 476.5 0.78 -7.15 608.4 0.66 -7.32

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106 Figure 6-28. Kinetic graph of d,l-C2F5-AF4-Dimers at 145.3 C Figure 6-29. Kinetic data of meso-C2F5-AF4-Dimers at 145.3 C y = -0.001388131x 5.708866629 R2 = 0.998660941 -6.60 -6.50 -6.40 -6.30 -6.20 -6.10 -6.00 -5.90 -5.80 -5.70 0.0100.0200.0300.0400.0500.0600.0700.0 t (min)Ln C y = -0.001283123x 6.533644303 R2 = 0.998427577 -7.40 -7.30 -7.20 -7.10 -7.00 -6.90 -6.80 -6.70 -6.60 -6.50 0.0100.0200.0300.0400.0500.0600.0700.0 t (min)Ln C

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1076.5.5.7 Kinetic data and graphs of C2F5-AF4-Dimers at 151.3 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 151.3 C. Table 6-22. Kinetic data of C2F5-AF4-Dimers at 151.3 C D,l form Time (min) C.103 (mol/L) LnC 65.5 0.71 -7.25 107.0 0.63 -7.36 143.5 0.57 -7.47 175.5 0.53 -7.54 300.7 0.39 -7.85 361.0 0.34 -7.99 meso form Time (min) C.103 (mol/L) LnC 65.5 1.81 -6.31 107.0 1.65 -6.41 143.5 1.47 -6.52 175.5 1.39 -6.58 238.5 1.19 -6.74 300.7 1.02 -6.88 361.0 0.87 -7.05

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108 Figure 6-30. Kinetic data of d,l-C2F5-AF4-Dimers at 151.3 C Figure 6-31. Kinetic data of meso-C2F5-AF4-Dimers at 151.3 C y = -2.4964E-03x 7.0980E+00 R2 = 9.9899E-01 -8.10 -8.00 -7.90 -7.80 -7.70 -7.60 -7.50 -7.40 -7.30 -7.20 50100150200250300350400 t (min)ln C y = -2.4601E-03x 6.1523E+00 R2 = 9.9904E-01 -7.10 -7.00 -6.90 -6.80 -6.70 -6.60 -6.50 -6.40 -6.30 -6.20 50100150200250300350400 t (min)ln C

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1096.5.5.8 Kinetic data and graphs of C2F5-AF4-Dimers at 156.4 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 156.4 C. Table 6-23. Kinetic data of C2F5-AF4-Dimers at 156.4 C D,l form Time (min) C.103 (mol/L) LnC 0.0 3.29 -5.72 35.4 2.92 -5.84 94.3 2.36 -6.05 125.9 2.13 -6.15 176.9 1.83 -6.30 224.5 1.48 -6.52 262.8 1.30 -6.64 meso form Time (min) C.103 (mol/L) LnC 0.0 1.31 -6.64 35.4 1.18 -6.74 94.3 0.94 -6.97 125.9 0.85 -7.07 176.9 0.73 -7.22 224.5 0.59 -7.43 262.8 0.53 -7.55

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110 Figure 6-32. Kinetic graph of d,l-C2F5-AF4-Dimers at 156.4 C Figure 6-33. Kinetic graph of meso-C2F5-AF4-Dimers at 156.4 C y = -0.00351656x 5.71255775 R2 = 0.99816665 -6.80 -6.60 -6.40 -6.20 -6.00 -5.80 -5.60 0.050.0100.0150.0200.0250.0300.0 time (min)Ln C y = -0.00349577x 6.62845692 R2 = 0.99809669 -7.60 -7.40 -7.20 -7.00 -6.80 -6.60 -6.40 0.050.0100.0150.0200.0250.0300.0 time (min)ln C

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1116.5.5.9 Kinetic data and graphs of C2F5-AF4-Dimers at 161.0 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 161.0 C. Table 6-24. Kinetic data of C2F5-AF4-Dimers at 161.0 C D,l form Time (min) C.103 (mol/L) LnC 7.1 1.08 -6.83 32.5 0.89 -7.02 57.6 0.77 -7.17 77.0 0.66 -7.32 101.0 0.58 -7.45 125.5 0.50 -7.60 meso form Time (min) C.103 (mol/L) LnC 7.1 2.69 -5.92 32.5 2.25 -6.10 57.6 1.91 -6.26 77.0 1.67 -6.40 101.0 1.45 -6.54 125.5 1.23 -6.70

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112 Figure 6-34. Kinetic graph of d,l-C2F5-AF4-Dimers at 161.0 C Figure 6-35. Kinetic graph of meso-C2F5-AF4-Dimers at 161.0 C y = -6.5162E-03x 6.7972E+00 R2 = 9.9696E-01 -7.70 -7.60 -7.50 -7.40 -7.30 -7.20 -7.10 -7.00 -6.90 -6.80 -6.70 0.020.040.060.080.0100.0120.0140.0 t (min)Ln C y = -6.5753E-03x 5.8788E+00 R2 = 9.9925E-01 -6.80 -6.70 -6.60 -6.50 -6.40 -6.30 -6.20 -6.10 -6.00 -5.90 -5.80 0.020.040.060.080.0100.0120.0140.0 t (min)Ln C

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1136.5.5.10 Kinetic data and graphs of C2F5-AF4-Dimers at 165.9 C The following table and figures show kinetic data and graphs for C2F5-AF4-Dimers at 165.9 C. Table 6-25. Kinetic data of C2F5-AF4-Dimers at 165.9 C D,l form Time (min) C.103 (mol/L) LnC 7.4 1.49 -6.51 24.7 1.34 -6.62 51.4 1.01 -6.90 70.6 0.84 -7.08 96.1 0.64 -7.35 116.4 0.56 -7.49 153.5 0.42 -7.78 meso form Time (min) C.103 (mol/L) LnC 7.4 0.82 -7.11 24.7 0.74 -7.20 51.4 0.56 -7.49 70.6 0.48 -7.64 96.1 0.37 -7.90 116.4 0.33 -8.02 153.5 0.24 -8.35

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114 Figure 6-36. Kinetic graph of d,l-C2F5-AF4-Dimers at 165.9 C Figure 6-37. Kinetic graph of meso-C2F5-AF4-Dimers at 165.9 C y = -8.6562E-03x 7.0302E+00 R2 = 9.9681E-01 -8.60 -8.40 -8.20 -8.00 -7.80 -7.60 -7.40 -7.20 -7.00 0.020.040.060.080.0100.0120.0140.0160.0180.0 t (min)Ln C y = -9.0095E-03x 6.4363E+00 R2 = 9.9538E-01 -8.00 -7.80 -7.60 -7.40 -7.20 -7.00 -6.80 -6.60 -6.40 0.020.040.060.080.0100.0120.0140.0160.0180.0 t (min)Ln C

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115 GENERAL CONCLUSION The CF3I / TDAE methodology could be su ccessfully extended to longer perfluorinated alkyl iodides, su ch as pentafluoroethyl iodide or nonafluorobutyl iodide. In the case of disulfides, tosyl im ines, aldehydes or ketones as substrates, almost the same yields than CF3I / TDAE system could be obtained with C2F5I / TDAE system. These reactions represent efficient and easy ways to access to numerous biologically active compounds containing pentafluor oethyl groups. Whereas the C2F5I / TDAE system was very successful, mixed results were obtained with C4F9I / TDAE system. In most case the system provided low yields, thus less intere sting. These results showed the limit of the extension of the methodology. Longer perfluoroal kyl iodides may not be able to be used. Only in the tosyl imine case, the C4F9I / TDAE system could provide some good yields and the methodology might be able to be extended for longer chains. The TDAE analogue project would have b een very interesting if the analogues could have reacted the same way than T DAE. But unfortunately these analogues had totally different reactivities than TDAE. The AF4-dimers represent very interesting molecules, structurally and chemically. They are proved to be indefinitely stable at the room temperature but are able to free perfluoroalkyl radicals as they decompose at high temperatur es. This reaction can be used to initiate radical polymerizations.

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122 BIOGRAPHICAL SKETCH Chaya Pooput was born on September 22nd, 1977, in Bangkok, Thailand. In 1989, at the age of 12, he moved to Paris, France, to study, living with his aunt, Wanee Pooput. He graduated from high school, Lyce Michel et, receiving his Baccalaurat des Sciences in 1995 with honors. From 1995 to 1997, he spen t 2 years in Classes Prparatoires in Lyce Michelet, in order to prepare to the National Competitive Exams for entering a Grande cole, a National Higher School fo r Engineers. In 1997, he was accepted in l’cole Nationale Suprieure de Chimie de Montpellier (The Na tional Higher School of Chemistry of Montpellier), in Montpellier, south of France. During the 3 years he spent in L’cole de Chimie de Montpellier, he worked as trainee in several research laboratories. One of them was in Dr. William Do lbier’s laboratory at the Universitity of Florida, (Gainesville, Florida, USA) for 3 m onths in 1999, as a part of REU program and another was an industrial resear ch project at Solvay Resear ch and Development (Bussels, Belgium), for 7 months in 2000. After obtaining “le Diplme des Ingenieurs” (Diploma of Engineers, equivalent to a master’s degree) in 2000, Chaya was accepted in the graduate school of the University of Florida in the Department of Chemistry, and performed his research in Dr Dolbier’s laboratory. He obtained a master of Science degree in May 2004