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Synthesis of Perfluoro[2.2]Paracyclophane and its Nucleophilic Substitutions

Permanent Link: http://ufdc.ufl.edu/UFE0041102/00001

Material Information

Title: Synthesis of Perfluoro2.2Paracyclophane and its Nucleophilic Substitutions
Physical Description: 1 online resource (141 p.)
Language: english
Creator: Zhang, Lianhao
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: nucleophilic, paracyclophane, transannular
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Perfluoro2.2paracyclophane and perfluoro2.2.2paracyclophane have been successfully synthesized in 42% and 1.2% yield respectively from their precursor, 1,4-bis (chlorodifluoromethyl)-2,3,5,6-tetrafluorobenzene by its reaction with activated zinc dust when heated in anhydrous acetonitrile at 100 oC. Two preparations of the precursor, first from 1,4-dicyano-2,3,5,6-tetrachlorobenzene and an improved method beginning from 1,2,4,5-tetrachlorobenzene, are also described and discussed as are key comparisons to our related synthesis of AF4. Perfluoro2.2paracyclophane was then used as starting materials in reactions with a large variety of nucleophiles. The aromatic fluorines of perfluoro2.2paracyclophane are extremely reactive with respect to nucleophilic substitution reactions. Chapter 3 emphasizes products of monosubstitution with hydroxide, alkoxide, tert-butyl lithium, thiolates, amines and dimethyl malonate in the presence of sodium hydride. Reactions of bidentate nucleophiles with perfluoro2.2paracyclophane provide cyclic products. All reactions appear to proceed via SNAr mechanisms. Reactivity issues are discussed including the effects of substituents on the further reactivity and regiochemistry of multisubstitution. The UV-vis absorption spectra of products show a progression toward longer wavelength absorption as the substitutents become increasingly electron donating. Bis-nucleophilic substitutions of F8 with sodium thiolates show replacement of the fluorine atom para to the first substitutent on the same benzene ring. In comparison, treatment of F8 with sodium 4-fluorophenolate or secondary amines gives a mixture of bis-substituted F8 derivatives. Reaction of F8 with 4 equivalents of sodium thiolates furnishes tetrakis-substituted F8 derivatives which contain two regioisomers. Each benzene ring has two substituents para to each other. The ratio of the two isomers is dependent on the group that is attached to sulfur. Treatment of F8 with 4 equivalents of sodium 4-fluorophenolate gives only one isomer. The reaction of F8 with 8 equivalents of pyrrolidines provides two tri-substituted F8 isomers. Treatment of F8 with two equivalents of 1,2-benzene-dithiol in the presence of sodium hydride furnishes bis-cycloadducts on the same benzene ring as a major product. Transannular effects of these products are measured by UV-vis spectra.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Lianhao Zhang.
Thesis: Thesis (Ph.D.)--University of Florida, 2009.
Local: Adviser: Dolbier, William R.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-12-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0041102:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041102/00001

Material Information

Title: Synthesis of Perfluoro2.2Paracyclophane and its Nucleophilic Substitutions
Physical Description: 1 online resource (141 p.)
Language: english
Creator: Zhang, Lianhao
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: nucleophilic, paracyclophane, transannular
Chemistry -- Dissertations, Academic -- UF
Genre: Chemistry thesis, Ph.D.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: Perfluoro2.2paracyclophane and perfluoro2.2.2paracyclophane have been successfully synthesized in 42% and 1.2% yield respectively from their precursor, 1,4-bis (chlorodifluoromethyl)-2,3,5,6-tetrafluorobenzene by its reaction with activated zinc dust when heated in anhydrous acetonitrile at 100 oC. Two preparations of the precursor, first from 1,4-dicyano-2,3,5,6-tetrachlorobenzene and an improved method beginning from 1,2,4,5-tetrachlorobenzene, are also described and discussed as are key comparisons to our related synthesis of AF4. Perfluoro2.2paracyclophane was then used as starting materials in reactions with a large variety of nucleophiles. The aromatic fluorines of perfluoro2.2paracyclophane are extremely reactive with respect to nucleophilic substitution reactions. Chapter 3 emphasizes products of monosubstitution with hydroxide, alkoxide, tert-butyl lithium, thiolates, amines and dimethyl malonate in the presence of sodium hydride. Reactions of bidentate nucleophiles with perfluoro2.2paracyclophane provide cyclic products. All reactions appear to proceed via SNAr mechanisms. Reactivity issues are discussed including the effects of substituents on the further reactivity and regiochemistry of multisubstitution. The UV-vis absorption spectra of products show a progression toward longer wavelength absorption as the substitutents become increasingly electron donating. Bis-nucleophilic substitutions of F8 with sodium thiolates show replacement of the fluorine atom para to the first substitutent on the same benzene ring. In comparison, treatment of F8 with sodium 4-fluorophenolate or secondary amines gives a mixture of bis-substituted F8 derivatives. Reaction of F8 with 4 equivalents of sodium thiolates furnishes tetrakis-substituted F8 derivatives which contain two regioisomers. Each benzene ring has two substituents para to each other. The ratio of the two isomers is dependent on the group that is attached to sulfur. Treatment of F8 with 4 equivalents of sodium 4-fluorophenolate gives only one isomer. The reaction of F8 with 8 equivalents of pyrrolidines provides two tri-substituted F8 isomers. Treatment of F8 with two equivalents of 1,2-benzene-dithiol in the presence of sodium hydride furnishes bis-cycloadducts on the same benzene ring as a major product. Transannular effects of these products are measured by UV-vis spectra.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Lianhao Zhang.
Thesis: Thesis (Ph.D.)--University of Florida, 2009.
Local: Adviser: Dolbier, William R.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-12-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0041102:00001


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1 SYNTHESIS OF PERFLUORO[2.2]PARACYCLOPHANE AND ITS NUCL EOPHILIC SUBSTITUTIONS By LIANHAO ZHANG 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 2009

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2 2009 Lianhao Z hang

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3 To my wife, Jinfeng Peng, my son, Pengcheng, and my daughter, Nina, with love

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4 ACKNOWLEDGMENTS I am deeply indebted to my supervisor, Professor William R Dolb ier, Jr., for his invaluable guidance, encouragement, and trust over years. It has been a rewarding experience and great honor to work with him. I would also like to take this opportunity to express my sincere gratitude to Drs. Weihong Tan, Sukwon Hong, Li sa McElwee White and Kenneth Sloan for their help, suggestions and time they have spent as my supervisory committee members. I am extremely grateful to Dr. Ion Ghiviriga for his critical help to elucidate the 19F NMR data to determine the regiochemistry of the multiplesubstituted compounds. I would like to give my special thanks to Henry Martinez for his helpful discussion and support for computer technologies My thanks also go to all Dolbier group members and my friends outside who are too many to ment ion individually, for their support and friendship. I deeply appreciate my parents for their unconditional love, support and enc ouragement, without which I cannot become a doctor. Finally, I am extremely grateful to my wife, Jinfeng Peng for everything s he has done for me.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................. 4 LIST OF TABLES ............................................................................................................ 7 LIST OF FIGUR ES .......................................................................................................... 9 ABSTRACT ................................................................................................................... 13 CHAPTER 1 AN OVERVIEW: SYNTHETIC METHODS OF [2.2]PARACYCLOPHANE, FLUORINATED[2.2]PARACYCLOPHANES AND THEIR APPLICATIONS ............ 15 1.1 Introduction ....................................................................................................... 15 1.2 Synthesis of [2.2]Paracyclophane and Fluoronated [2.2]paracyclophane ......... 17 1.2.1 Synthetic Methods for [2.2]Paracyclophane ............................................ 17 1.2.2 Synthetic Methods for Octafluoro[2.2]paracyclophane ............................ 18 1.2.3 Synthesis of 1,1,9,9Tetrafluoro[2.2]paracyclophane and 1,1,10,10Tet r afluoro[2.2]paracyclophane ..................................................................... 21 1.2.4 Synthesis of 4,5,7,8Tetrafluoro and 4,5,7,8,12,13, 15,16Octafluoro[2.2] paracyclophane ..................................................................... 22 1.3 Applications of [2.2]Paracyclophane, Octafluoro[2.2]Paracycyclophane and Their derivatives. ................................................................................................. 23 1.3.1 Application of [2.2]Paracyclophane ......................................................... 23 1.3.2 Application of Octafluoro[2.2]paracyclophane ......................................... 24 1.3.3 Application of [2.2]Paracyclophane Derivatives ....................................... 25 1.4 Reactivities and Reactions of [2.2]Paracyclophane .......................................... 31 1.4.1 Properties of [2.2]Paracyclophane .......................................................... 32 1.4.1.1 Structure and strain ........................................................................ 32 1.4.1.2 Steric inhibition of ring rotation ....................................................... 33 1.4.1.3 Reactions that reflect the strain in the [2.2]paracyclophanes ......... 35 1.4.2 Reactions of [2.2]Paracyclophane ........................................................... 36 1.4.2.1 Reactions at the ethylene bridges of [2.2]paracyclophane ............. 36 1.4.2.2 Reactions at the benzene rings ...................................................... 37 1.4.2.2. 3 Electrophilic substitution .................................................................... 38 1.4.2.2.3.1 Acetylation with acetyl chloride/aluminum chloride .................. 38 1.4.2.2.3.2 Nitration of [2.2] paracyclophane .............................................. 39 1.4.2.2.3.3 Bromination of [2.2]paracyclophane ......................................... 40 1.4.2.2.3.4 Dichlorination of [2.2]paracyclophane ...................................... 41 1.4.2.2.3.5 Transannular directive influences in electrophilic substitution of monosubstituted [2.2]paracyclophane ................................................ 41 1.5 Reactions of Octafluoro[2.2]paracyclophane and Its Derivatives ...................... 43 1.5.1 Reactions of Octafluoro[2.2]paracyclophane .......................................... 43

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6 1.5.2 Thermal Isomeriz ations of AF4 Derivatives ............................................. 45 1.5.3 Reactions of AF4 Derivatives .................................................................. 46 1.5.3.1 Aryne chemistry of octafluoro[2.2]paracyclophane ........................ 46 1.5.3.2 Novel ringcleaving reaction of 4nitro octafluoro [2.2]paracyclophane with nucleophiles ................................................... 48 1.5.3.2 Nucleophilic substitution of 4iodooctafluoro [2.2]PCP .................. 48 2 SYNTHESIS OF PERFLUORO[2.2]PARACYCLOPHANE AND PERFLUORO[2.2.2]PARACYCLOPHANE ............................................................. 50 2.1 Abst ract ............................................................................................................. 50 2.2 Introduction ....................................................................................................... 50 2.3 Experimental Section ........................................................................................ 56 3 REACTI ONS OF NUCLEOPHILES WITH PERFLUORO[2.2]PARACYCLOPHANE ................................................................ 62 3.1 Introduction ....................................................................................................... 62 3.2 Results .............................................................................................................. 63 3.3 Discussion ........................................................................................................ 71 3.4 Synthetic Conclusion ........................................................................................ 75 3.5 Characterization ................................................................................................ 75 3.6 Experimental Section ........................................................................................ 83 4 MULTIPLE NUCLEOPHILIC SUBSTITUTIONS OF PERFLUORO[2.2]PARACYCLOPHANE ................................................................ 95 4.1 Introduction ....................................................................................................... 95 4.2 Results and Discussion ..................................................................................... 97 4.3 Charaterization ............................................................................................... 106 4.4 Experimental Section ...................................................................................... 119 APPENDIX: X RAY DATA .......................................................................................... 131 LIST OF REFERENCES ............................................................................................. 135 BIOGRAPHICAL SKETCH .......................................................................................... 141

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7 LIST OF TABLES Table page 1 1 Pattern of electrophilic substitution of m onosubstituted [2.2]paracyclophanes ... 42 3 1 Reaction of nucleophiles w ith F8 in THF at RT ................................................... 66 3 2 Reaction of bidentate nucleophiles with F8 in THF at RT ................................... 70 3 3 Chemical shifts (ppm) and coupling constants (Hz) in the 19F spectrum of compound 112d. ................................................................................................. 77 3 4 NMR data for the ali phatic fluorines in compound 112d in benzened6 ............. 80 3 5 NMR data for the aromatic fluorines in compound 112d in benzened6. ............ 80 3 6 NMR data for the aliphatic fluorines in compound 112a in acetoned6 ............... 81 3 7 NMR data for the aromatic fluorines in compound 112a in acetoned6 .............. 81 3 8 NMR data for the aliphatic fluorines in compound 112b in benzened6 ............. 81 3 9 NMR data for the aromatic fluorines in compound 112b in benzened6. ............ 81 3 10 NMR data for the aliphatic fluorines in compound 112g in benzened6 ............. 82 3 11 NMR data for the aromatic fluorines in compound 112g in benzened6 ............. 82 3 12 NMR data for the aliphatic fluorines in compound 116b in benzened6 ............. 82 3 13 NMR data for the aromatic fluorines in compound 116b in benzened6 ............. 82 4 1 Reacti on of sodium thiolates (2 equiv ) with F8 in THF at RT .............................. 98 4 2 Reaction of sodium thi o lates (4 equiv ) with F8 in THF at RT ............................ 100 4 3 NMR data for the aliphatic fluorines in compound 121a in benzened6. ........... 109 4 4 NMR data for the aromatic fluorines in compound 121a in benzened6 ........... 109 4 5 NMR data for the aliphatic fluorines in compound 121b in benzened6 ........... 110 4 6 NMR data for the aromatic fluorines in compound 121b in benzened6. .......... 110 4 7 NMR data for the aliphatic fluorines in compound 121c in benzened6. ........... 110 4 8 NMR data for the aromatic fluorines in compound 121c in benzened6. .......... 111

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8 4 9 NMR data for the aliphatic fluorines in compound 121e in benzened6. ........... 112 4 10 NMR data for the aromatic fluorines in compound 121e in benzened6. .......... 112 4 11 NMR data for the aliphatic fluorines i n compound 125 (pseudopara) in benzened6 ....................................................................................................... 113 4 12 NMR data for the aromatic fluorines in compound 125 (pseudopara) in benzened6 ....................................................................................................... 113 4 13 NMR data for the aliphatic fluorines in compound 126 (pseudootho) in benzened6 ....................................................................................................... 113 4 14 NMR data for the aromatic fluorines in compound 126 (pseudoortho) in benzened6 ....................................................................................................... 113 4 15 NMR data for the aliphatic fluorines in compound 116b (ortho) in benzened6. .................................................................................................................... 113 4 16 NMR data for the aromatic fluorines in compound 116b (ortho) in benzened6. .................................................................................................................... 114 4 17 NMR data for the aliphatic fluorines in compound 114a in benzened6. ........... 114 4 18 NMR data for the aromatic fluorines in compound 114a in benzened6. .......... 114 4 19 NMR data for the aliphatic fluorines in compound 128 in benzened6 : acetoned6, 2:1. ................................................................................................ 116 4 20 NMR data for the aromatic fluorines in compound 128 in benzened6; acetoned6, 2:1. ................................................................................................ 116 4 21 NMR data for the aliphatic fluorines in compound 127 in benzened6 .............. 117 4 22 NMR data for the aromatic fluorines in compound 127 in benzened6 ............ 1 17

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9 LIST OF FIGURES Figure page 1 1 Structure of [2.2]paracyclophane ........................................................................ 16 1 2 Synthesis of [2.2]PCP by pyrolysis of p xylene ................................................... 17 1 3 Synthesis of [2.2]PCP by intramolecular Wurtz reaction .................................... 18 1 4 Preparation of [2.2]PCP by pyrolysis of ammonium salt ( 5 ) ............................... 18 1 5 Synthesis of AF4 by pyrolysis of bisalkylsulfonyl ( 6 ) or dihalop xylene ( 7 ) ........ 19 1 6 Preparation of AF4 using Ti0 as reducing reagent .............................................. 19 1 7 Preparation of AF4 using tinsilane as reducing reagent ..................................... 20 1 8 Synthesis of AF4 precursor ( 11) and AF4 using zinc as reducing reagent ......... 21 1 9 Synthesis of 1,1,9,9tetrafluoro[2.2]PCP and 1,1,10,10tet r afluoro[2.2]PCP ...... 21 1 10 Synthesis of 4,5,7,8,12,13,15,16octafluoro[2.2]PCP ......................................... 22 1 11 S ynthesis of 4,5,7,8tetrafluoro[2.2]PCP ............................................................ 22 1 12 [2.2]PCP and the conversion to ParyleneN polymer ......................................... 23 1 13 Gorham process for conversion of [2.2]PCP to Parylene polymers .................... 24 1 14 AF4 and their conversion to ParyleneHT polymers ........................................... 25 1 15 Formation of electron donor acceptor compounds using 4,13diamino[2.2]PCP as electron donor ................................................................................ 28 1 16 Rationalization of two molecules of the acceptor attack at the same nitrogen to give compounds 29, 31 and 33 instead of forming compound 34 ................... 28 1 17 [2.2]PCP derivatives as electroactive component ............................................... 29 1 18 [2.2]PCP substitution patterns and ligands ......................................................... 29 1 19 [2.2]PCP based ligands ...................................................................................... 30 1 20 Bridge substi tuted [2.2]PCP ligands ................................................................... 31 1 21 Structure of [2.2]PCP at 93 oK ............................................................................ 33

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10 1 22 Structures 49a and 49b are enantiomeric and possibly int erconvertible through state A ................................................................................................... 33 1 23 [2.2]PCP conversion to living polymers .............................................................. 35 1 24 Racemization of optically active ester 56 ............................................................ 36 1 25 Radical cleavage of [2.2]PCP ............................................................................. 36 1 26 Ionic reaction of [2.2]PCP ................................................................................... 36 1 27 Reaction of [2.2]PCP with superdienophile 61 ................................................. 37 1 28 Hydrogenation of [2.2]PCP ................................................................................. 38 1 29 Birch reduction of [2.2]PCP ................................................................................ 38 1 30 Acetylation of [2.2]PCP with acetyl chloride ....................................................... 39 1 31 Proposed mechanism for the formation of by products 70 and 71 ..................... 39 1 32 Dinitration of [2.2]PCP with HNO3/CH3COOH .................................................... 40 1 33 Dibromination of [2.2]PCP with Br2/Fe ................................................................ 40 1 34 Tetrabromination of [2.2]PCP with Br2/Fe ........................................................... 41 1 35 Dichlorination of [2.2]PCP with Cl2 in the presence of iodine .............................. 41 1 36 Transannular directive influences second electrophilic substitution of 4bromo[2.2]PCP .................................................................................................. 43 1 37 Synthesis of monosubstituted AF4 derivatives ................................................... 44 1 38 Synthesis of bis substituted AF4 derivatives ...................................................... 45 1 39 Thermal isomerization of pseudoorthobis(trifluoro acetamido) AF4 ................. 46 1 40 Highly pyramidalized cage alkene formed via the double Diels Alder cycloaddition of syn 4,5,13,14bis(dehydro)octafluoro[2.2]PCP to anthracene .. 47 1 41 Reaction of 4iodoAF4 with various dienes in the presence of t BuOK ............. 47 1 42 Ring opening reaction of 4nitro octafluoro[2.2]PCP .......................................... 48 1 43 Nucleophilic substitution of 4iodooctafluoro [2.2]PCP ...................................... 48 2 1 [2.2]Paracyclophane and its conversion to Parylene polymers .......................... 50

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11 2 2 Preparation of AF4 by reduction of dichloride ( 11) with zinc ............................... 51 2 3 First synthesis of F8 precursor 100 (Method A) .................................................. 53 2 4 Improved synthesis of F8 precursor 100 (Method B) .......................................... 54 2 5 Application of AF4 procedure to preparation of F8 ............................................. 54 2 6 Chemical characterization of bis zinc reagent 107 ............................................. 55 2 7 Synthesis of F8 and trimer perfluoro[2.2.2]paracycloph ane ............................... 56 3 1 Reactivity of hexafluorobenzene and pentafluoropyridine with nucleophiles ...... 63 3 2 Reactions of F8 with nucleophiles ...................................................................... 64 3 3 UV spectra of monosubstituted F8 compounds .................................................. 67 3 4 UV spectra of monosubstituted F8 compounds .................................................. 68 3 5 Com parison of UV spectra of F8 phenol and phenolate species ........................ 68 3 6 Reaction of F8 with bidentate nucleophiles ........................................................ 69 3 7 UV spectra of F8 adducts with benzene1,2diols and 1,2bis thiol .................... 70 3 8 UV spectra of F8bisamine adducts .................................................................... 70 3 9 Cyclic voltammogram (CV) of F8 ........................................................................ 72 3 10 Differential Pulse Voltammogram (DPV) of F8 ................................................... 72 3 11 19F spectrum of compound 1 experimental (top) and simulated (bottom). ......... 77 3 12 Step by step assignment of the 19F signals in compound 112d. ........................ 78 4 1 Bromination of 4acetyl[2.2]PCP ....................................................................... 96 4 2 Reaction of F8 with 2 equiv of sodium thiophenolate ......................................... 98 4 3 UV spectra of bis thio F8 derivatives .................................................................. 99 4 4 Reaction of F8 with 4 equiv. of sodium phenylthiolates .................................... 100 4 5 Reaction of F8 with 1,2benzenedithiol in the presence of NaH at RT ............. 101 4 6 UV spectra of tetrakis substituted F8 derivatives .............................................. 101 4 7 Reac tion of F8 with 2 equiv of sodium 4fluorophenolate ................................. 102

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12 4 8 Reaction of F8 with hydroquinone/resorcinol in the presence of NaH .............. 103 4 9 Reaction of F8 with aliphatic amines ................................................................ 104 4 10 UV spectra of bis substituted F8 derivatives .................................................... 104 4 11 UV spectra of bis substituted F8 derivatives .................................................... 105 4 12 Formation of trisubstituted products by the reaction of F8 with pyrrolidines ..... 105 4 13 UV spectra of tri substituted F8 ........................................................................ 106 4 14 Fluorines identifiable by their position to the substituent. ................................. 107 4 4 1 1 5 5 Isomers of disubstituted F8. ............................................................................. 108 4 16 R R e e g g i i o o i i s s o o m m e e r r s s o o f f t t r r i i s s u u b b s s t t i i t t u u t t e e d d F F 8 8 ..................................................................... 115 4 17 Structure of compound 128 .............................................................................. 116 4 18 S tructure of compound 127 .............................................................................. 117 4 19 Regioisomers of tetrakis substituted F8 ........................................................... 118 4 20 Assigning the two isomers is made using chemical shifts increments .............. 119 4 21 Coupling constants in minor isomer confirm the assignment ............................ 119 A 1 X ray structure of perfluoro[2.2]paracyclophane ............................................... 131 A 2 X ray structure of perfluoro[2.2.2]paracyclophane ............................................ 133

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13 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Pa rtial Fulfillment of the Requirements for the Degree of Doctor of Philosophy SYNTHESIS OF PERFLUORO[2.2]PARACYCLOPHANE AND ITS NUCEOPHILIC SUBSTITUTIONS By Lianhao Zhang December 2009 Chairman: William R. Dolbier, Jr. Major Department: Chemistry Perfluor o[2.2]paracyclophane and perfluoro[2.2.2]paracyclophane have been successfully synthesized in 42% and 1.2% yield respectively from the ir precursor, 1,4bis (chloro difluoromethyl) 2,3,5,6 tetrafluorobenzene by its reaction with activated zinc dust when heated in anhydrous acetonitrile at 100 oC. Two preparations of the precursor, first from 1,4 dicyano2,3,5,6tetrachlorobenzene and an improved method beginning from 1,2,4,5 tetrachlorobenzene, are also described and discussed as are key comparisons to our related synthesis of AF4. Perfluoro[2.2]paracyclophane was then used as starting materials in reactions with a large variety of nucleophiles. The aromatic fluorines of perfluoro[2.2]paracyclophane are extremely reactive with respect to nucleophilic substit ution reactions. C hapter 3 emphasizes products of monosubstitution with hydroxide, alkoxide, tertbutyl lithium, thiolates, amines and dimethyl malonate in the presence of sodium hydride. R eactions of bidentate nucleophiles with perfluoro[2.2]paracyclophane provide cyclic products. All reactions appear to proceed via SNAr mechanisms. R eactivity issues are discussed including the effects of substituents on the further reactivity and regiochemistry of multi substitution.

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14 The UV vis absorption spectra of produc ts show a progression toward longer wavelength absorption as the substitutent s become increasingly electron donating. Bis nucleophilic substitutions of F8 with sodium thiolates show replacement of the fluorine atom para to the first subs titute nt on the sam e benzene ring. In comparison, treatment of F8 with sodium 4 fluorophenolate or secondary amines gives a mixture of bis substituted F8 derivatives. Reaction of F8 with 4 equivalents of sodium thiolates furnishes tetrakis substituted F8 derivatives which co ntain two regioisomers. Each benzene ring has two substituents para to each other. The ratio of the two isomers is depend ent on the group that is attached to sulfur Treatment of F8 with 4 equivalents of sodium 4 fluorophenolate gives only one isomer. The reaction of F8 with 8 equivalents of pyrrolidines provides two tri substituted F8 isomers. Treatment of F8 with two equivalents of 1,2ben zenedithiol in the presence of sodium hydride furnishes bis cyclo adducts on the same benzene ring as a major product Transannular effects of these products are measured by U V vis spectra.

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15 CHAPTER 1 AN OVERVIEW: SYNTHET IC METHODS OF [2.2]P ARACYCLOPHANE, FLUORINATED[2.2]PARA CYCLOPHANES AND THEI R APPLICATIONS 1.1 Introduction [2.2] P aracyclophane ([2.2]PCP) chemistry has grown considerably since the parent [2.2]PCP was first prepared in 1949.1 Besides commercial application as monomers for parylenetype polymers,2 these molecules have spawned an unusual and unique chemistry.3 The two eclipsing aryl rings, or decks are held rigidly in place at the para positions by ethylene bridges. The proximity of the decks prohibits rotation of the rings without cleavage of one of the bridge C C bonds, which normally does not occur below 180oC. The separation of the two aromatic rings is less than the sum of the van der Waals radii for carbon (3.40 ) ranging from 2.78 for the bridging carbons (C6C11 ) to a maximum of 3.09 between C4C13.3 The rigid structure results i n the bridge C2 and C9C10) being held almost perpendicular to the aryl rings allowing C bond (1.63 vs 1.54 in ethane) (Figure 11). There is a strong repulsion between the two decks resulting in distortion of the aryl rings to give them a shallow boat like geometry It also engenders a Both its distinct electronic structure and the distortion of t he rings increases the basicity /nucleophilicity of the benzene group of [2.2]PCP; it undergoes electrophilic substitution complexes; for instance, the first order rate constant for the reaction of [2.2]PCP with Cr(CO)6 is ca. 25% greater than for p xylene.4

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16 Figure 11 Structure of [2.2]paracyclophane The chemistry of [2.2]PCP can generally be understood if one considers its unique structure. To a degree, its reactivity is that of a classic aromatic compound, keeping in mind that substituents on one deck can have a profound influence on the reactivity of the other deck. However, this simple srutucture (Figure 11) does not always hold up to close scrutiny; due to its distorted st ructure, steric effects and the interactions, [2.2]paracyclophane derivatives are often resistant to conventional transformations.5 The combination of all these facets often makes understanding the chemistry of [2.2]PCPs such an interesting chall enge. This overview will describe four aspects of [2.2]paracyclophane chemistry : 1. Synthetic methods of [2.2]paracyclophane and fluorinated[2.2]paracyclophanes. 2. Application s of [2.2]paracyclophane, octafluoro[2.2]paracyclophane and their derivatives. 3. Reactivity and reactions of [2.2]paracyclophane. 4. Reactions of octafluoro[2.2]paracyclophane and its derivatives.

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17 1.2 Synthesis of [2.2] Paracyclophane and Fluoronated [2.2] paracyclophane 1.2.1 Synthetic M ethods for [2.2] Paracyclophane [2.2]PCP was f irst synthesized by C. J. Brown and A. C. Farthing.1 p Xylene was pyroly zed at low pressure using the technique described by Szwarc,6 and extraction of the polymer with chloroform yielded low molecular weight compounds. This extract contained traces of an acetoneinsoluble fraction, having m.p 285 oC, which after recrystallization from pyridine and glacial aceti c acid yielded [2.2]PCP (Figure 12 ). Figure 1 2 Synthesis of [2.2]PCP by pyrolysis of p xylene A s econd synthetic method for [2.2]PCP was developed by D. J. Cram and H. Steinberg7 via an intramolecular Wurtz reaction with dibromide ( 4 ) to give only 2.1% yield. This reaction had two major disadvantages: 1. The yield was too low. 2. The reaction required tedious work with dibromide being added over 60 h period to sodium with stirring at 7000 r.p.m. (Figure 13 ). However, the observation of this reaction changed the mind of chemists, who had considered that the ring strain evidently present in the molecule could only be overcome by the extreme conditi ons of the pyrolysis reaction. These initial inferences were proved incorrect, when the [2.2]PCP was subsequently prepared by the intramolecular Wurtz reaction with dibromide. This reaction initiated further development of [2.2]PCP chemistry.

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18 Figure 13 Synthesis of [2.2]PCP by intramolecular Wurtz reaction The commercial production method for [2.2]PCP was eventually developed by T. Otsubo, H. Horita and S. Misumi.8 N,N,NTrimethyl1 p tolylmethanamm o nium chloride was pyroly zed in xylene at 140 oC to f orm [2.2]PCP in 33% yield, when phenothiazine was used as an inhibitor to avoid radical polymerization of the quinodimethane ( 2 ) intermediate (Figure 14 ). Figure 14 Preparation of [2.2]PCP by pyrolysis of ammonium salt ( 5 ) 1.2.2 Synthetic M ethods for O ctafluoro[2.2] paracyclophane The first synthetic method for preparation of octafluoro[2.2]paracy clophane (AF4) was the tedious Chow procedure9 ( Figure 15 Bis(alkylsulfonyl) tetrafluoro p xylene ( 6 ) was pyrolyzed at 600800 oC with steam as diluent, After the pyrolysate was condensed in toluene, isolation and purification of octafluoro[2.2]paracyclophane ( 9 ) was accomplished by evaporation, recrystallization, and sublimation. Variation of the alkyl groups in 6 from ethyl to butyl exhibited no significant difference in yields or in pyrolysis conditions. Steam dihalotetrafluoro p xylene ( 7 ) under similar conditions also yielded 9 Optimum yields (28.8%) were obtained when the pyrolysis chamber was packed with copper mesh. This method

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19 provided enough material to obtain preliminary physical and chemical data on the dimer and its Parylene polymer to recognize the potential of the latter material. Figure 15 Synthesis of AF4 by pyrolysis of bisalkylsulfonyl ( 6 ) or dihalop xylene ( 7 ) Since then, Dolbier et al reported a reduction process utilizing Ti0, using high dilution technology to generate and dimerize the p xylylene monomer. This process allowed preparation of gram quantities of AF4 for the first time.10,11 However, the process also proved virtually impossible to scale up significantly, with oligomerization of the p xylylene monomer dominating dimerization as quantities were increased ( Figure 1 6 ). Figure 16 Preparation of AF4 using Ti0 as reducing reagent Subsequently, a process involving the use of (trimethylsilyl)tributyltin with CsF instead of Ti0 resulted in a higher yield (40%) and sc ale up was feasible in the

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20 preparation of AF412,13. Indeed, kilogram quantities of AF4 were prepared for the first time using this procedure in 72L glass equipment. However, commercial use of this method was inhibited by the high costs of the required dibromide ( 10) and use of the tinsilane as a reducing agent including the potentially hazardous nature of the latter reagent ( Figure 17 ). Figure 17 Preparation of AF4 using tinsilane as reducing reagent The current commercial production procedure14,15 fo r preparation of AF4 was discovered by Dolbier et al in 1998. A mixture of 1,4bis (chlorodifluoromethyl)benzene ( 11) and 4 equivalents of zinc dust in dimethylacetamide was heated to 100 oC for 4 h to produce AF4 in 60% yield. The precursor, 1,4bis (chlo rodifluoromethyl)benzene ( 11) was prepared by the reaction of commercially available hexachlorop xylene with anhydrous HF at a low pressure in 80% yield. This procedure proved superior in every regard to the earlier methods. It used an inexpensive and readily accessible precursor 1,4bis (chlorodifluoromethyl)benzene ( 11), an inexpensive commercially available reducing reagent, zinc powder, and the AF4forming reaction could be carried out by a nonhigh dilution procedure that proved to be highly scaleable ( Figure 18 ). This invention was a milestone in the history of preparation of AF4.

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21 Figure 18 Synthesis of AF4 precursor ( 11) and AF4 using zinc as reducing reagent 1.2.3 Synthesis of 1,1,9,9T etrafluoro[2.2]paracyclophane and 1,1,10,10T et rafluor o [2.2]paracyclophane Bromination of [2.2]PCP with NBS in dry carbon tetrachloride16 gave a mixture of 1 ,1,9,9 tetrabromo[2.2]PCP ( 12) and 1,1,10,10tet r abromo[2.2]PCP ( 13) in a 2:3 ratio with a yield of 34%. The mixture of 12 and 13 was treated with AgBF4 in anhydrous dichloromethane to provide a mixture of 1,1,9,9tetrafluoro[2.2]PCP (14) and 1,1,10,10tetafluoro[2.2]PCP ( 15),17 followed by sublimation, column chromatography and fractional recrystallization to provide 14 and 15 in combined 50% yield ( Fig ure 19 ). Figure 19 Synthesis of 1,1,9,9tetrafluoro[2.2]PCP and 1,1,10,10tet r afluoro[2.2]PCP

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22 1.2.4 Synthesis of 4,5,7,8T etrafluoro and 4,5,7,8,12,13,15,16Octa fluoro[2.2] paracyclophane 4,5,7,8,12,13,15,16Octafluoro[2.2]PCP ( 16) was most efficient ly prepared by 1,6 H ofmann elimination from the quaternary ammonium hydroxide compound derived from 4 methyltetrafluorobenzyl bromide via the unstable tetrafluorop xylylene ( Figure 110). With vigorous mixing in dilute solutions, 16 was obtained in 42% yield.18 Figure 110 Synthesis of 4,5,7,8,12,13,15,16octafluoro[2.2]PCP 5,6,8,9Tetrafluoro2,11dithio[3.3]PCP ( 17) was obtained in high yields by condensation of either of two pairs of molecules. Extrusion of the two sulfur atoms in 17 afforded 18 i n 24% yield18 (Figure 111). Figure 111 S ynthesis of 4,5,7,8tetrafluoro[2.2]PCP

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23 1.3 Applications of [2.2] P aracyclophane, Octafluoro [2.2] P aracycyclophane and T heir derivatives. 1.3.1 Application of [2.2] Paracyclophane [2.2]PCPs are useful chemical vapor deposition (CVD) precursor of thin film polymers, known in the industry as Parylenes ( Figure 112).2 Such Parylenes are ideally suited for use as conformal coatings in a wide range of applications, such as in the automotive, medical, electronics, and se miconductor industries. Parylene coatings are chemically inert, transparent and have excellent barrier properties.19 Parylene N, which is generated from the parent hydrocarbon ( 3 ) has been found to be useful for several hours at temperatures up to 130 oC. Compared to other polymers, ParyleneN coatings are well known for 1. gas phase deposition and polymerization, 2. pinholefree deposition at room temperature, 3. adherence to metals, composites, plastics and elastomers, 4. infinitely controllable thicknes s, 5. effective gap fill. Figure 112 [2.2]PCP and the conversion to ParyleneN polymer Why do chemists need to make the dimer first? It is a difficult job and very expensive. Can p xylylene ( 2 ) be prepared from other precursors? The answer is yes. But by starting the coating process with dimer, one can generate the necessary p xylylene ( 2 ) in the most unambiguous manner, without any gaseous by products at all. The gaseous by products produced by most other routes to p xylylene ( 2 ) range from the corrosive gas (HCl, SO2) to carbon dioxide and hydrocarbons, and they are produced in integral molar ratios relative to the p xylylene ( 2 ).

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24 What equipment can be used for the process shown in Figure 112? Gorham2 designed the operation equipment for this process displayed in Figure 113. [2.2]PCP is vaporarized at 150 oC under vacuum (1 torr.) in the 1st chamber. The dimer is pyrolyzed to p xylylene (monomer) at 680 oC (0.5 torr.) in the 2nd chamber. The monomer is polymerized into ParyleneN coatings at 25 oC (0. 1 torr.) in the 3rd chamber. The process flow of p xylylene monomer into the deposition chamber is on the order of 100 sccm (standard cubic centimeters per minute), depending to a major extent on payload surface area. This particular flow is equivalent to a little over 0.6 g/min. of ParyleneN. Figure 113 Gorham process for conversion of [2.2]PCP to Parylene polymers 1.3.2 Application of O ctafluoro[2.2] paracyclophane Octafluoro[2.2]PCP ( 9 ) which was know n in the industry as ParyleneHT was heated t o more than 600 oC to pyrolyze it to the monomer 8 which polymerized at low

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25 temperature to form Parylenetetrafluoro p xylylene) ( Figure 1 14). In addition to keeping the properties of ParyleneN coatings, The ParyleneHT polymer combines a low dielectric constant ( ParyleneHT polymer (C8H4F4)n of 2.25 prediction with a density of 1.584g/ mL versus ParyleneN (C8H8)n of 2.76 with a density of 1.110 g/mL), with high thermal stability (<1% loss/ 2 h at 450oC), low moisture absorption (<0.1%) and other advantageous properties. With such p roperties, and because its in vacuo deposition process ensures conformality to microcircuit features and superior submicron gapfilling capability, ParyleneHT could have considerable application as an interlayer dielectric for onchip high speed se miconductor device interconnections. It is predicted that the more fluorinehydrogen replacements we make, the lower the dielectric constant will be. The perfluorinated version of Parylene, which we call Parylene F8 (the polymer of perfluorinated p xylyle ne C8F8) is the logical end of this path, and is predicted to have an isotropic dielectric constant of 2.11 and a density of 1.93 g/mL). To our knowledge, no synthetic method of preparation of perfluoro[2.2]paracyclophane (F8) existed, therefore, synthesis of F8 was a desirable research goal. Figure 114 AF4 and their conversion to ParyleneHT polymers 1.3.3 Application of [2.2] Paracyclophane D erivatives Traditionally, [2.2]PCP derivatives have been studied because of their unusual geometry, their steric, transannular and ring strain effects. They have been studied as

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26 probes for investigation of theories on bondi 35, 1923 Modern applications have seen [2.2]PCP used in biomedical research with various derivatives being employed as bioisoteres for a variety of heterocyclic systems.24 For instance, Compound 19 displayed interesting binding profiles as a D3 antagonists, which might be a starting point for the development of highly beneficial CNS active drugs, especially for the treatment of schizophrenia. Because of the planar chirality of the cyclophane skelton, stereoch emical differentiation was observed when the ( R ) enan tiomer ( R ) 19 showed significantly higher D3 affinity. Moreover, the high steric demand of the paracyclophanes of type 19 is well tolerated by the binding site of the dopamine D3 receptor, indicating substantial plasticity of the receptor excluded volumes. Thus, the paracyclophane derived D3 antagonists should serve as valuable molecular probes for the investigation of GPCR ligand interactions. It is quite remarkable that the relatively bulky [2.2]PCP moiety can be employed as a pharmaceutical element. Recent research has seen its properties exploited in two main areas: Its electronic properties have been utilized in the design of electron donor acceptor compounds25 and a variety of molecular electronic materials such as linear and nonlinear optoelectronics and conductive polymers.26 [2.2]PCPs are serving as excellent

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27 donating systems for electron donor acceptor compounds comparable to classical aromatic compounds, and it has been proven that this behavior is mainly due to the pres ence of transannular electronic interactions between the two benzene rings in the cyclophane molecule. El Shaieb et al used 4,13diamino[2.2]PCP ( 20) as electron donor to investigate its donating properties towards electron acceptors such as 7,7,8,8tetra cyanoquinodimethane (TCNQ, 21), 2 dicyanomethyleneindan1,3dione (CNIND, 22), 2,3 dichloro1,4naphthoquinone (DCHNQ, 23), 2,3 dicyano1,4naphthoquinone (DCNQ, 24), and 2,3dichloro 5,6dicyano1,4benzoquinone (DDQ, 25) to give corresponding electron donor acceptor compounds 26 33 respectively. The results of the reactions between 20 and these acceptors are shown in Figure 115. The attack of the two molecules of the acceptor at the same nitrogen to give compounds 29, 31 and 33 rather than forming com pound 34 may be rationalized in terms of the stability of the resonance structures 3638 (Figure 1 16). It is evident that in structure 35, the two positively charged nitrogen atoms are located in a pseudogeminal position so they are so close to each other to make this alternative adduct u nstable because of electronic repulsion. On the other hand, in structures 37 and 38, the lone pair of electrons on the disubstituted nitrogen atom enters into conjugation with the twoquinone moieties. Valentini et al r eported the synthesis and photoelectrical properties of two [2.2]PCP derivatives 39 and 40 (Figure 1 17), bearing conjugated alkyne units in the linear side chain. These compounds were incorporated as an electroactive component with a conductive polymer, f or example, poly (3butylthiophene). The blend showed a photoelectrical response higher than that of the neat polymer. The application of an electric bias during the preparation of the blend led to an increase in the photocurrent

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28 Figure 115 Formation of electron donor acceptor compounds using 4,13diamino[2.2]PCP as electron donor Figure 116 Rationalization of two molecules of the acceptor attack at the same nitrogen to give compounds 29, 31 and 33 instead of forming compound 34

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29 Figure 117 [2 .2]PCP derivatives as electroactive component Chiral [2.2]PCP derivatives have found considerable use in stereoselective synthesis. The use of [2.2]PCP derivatives as chiral auxiliaries, reagents and ligands has been summarized in two excellent reviews by Gibson27 and Rozenberg.28 The majority of [2.2]PCP ligands or reagents are based on one of four different substitution patterns ( 41 44, Figure 118), there are examples of derivatives that have been functionalized on the ethylene bridge ( 45) but these are rare. Figure 118 [2.2]PCP substitution patterns and ligands Prior to the advent of PhanePhos, 4,12bis (diphenylphosphino) [2.2]PCP 46 a pseudoortho disubstituted derivative, as chiral ligand in 1997,2931 reports on the use of

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30 [2.2]PCP in stereosel ective synthesis were scarce. It is the great success of PhanePhos in enantioselective hydrogenations that has fuelled research into the utility of [2.2]PCP as a scaffold for the preparation of chiral ligands. Unlike other common planar chiral scaffolds, such as metallocenes or metal arene complexes that require two (or more) substituents on one ring to become chiral, [2.2]PCP only requires one substituent to break the symmetry of the molecule. A number of monosubstituted[2.2]PCP derivatives have been screened in enantioselective catalysis, but the majority show moderate to low enantioslectivities, presumably due to excessive conformational freedom. The most studied substitution pattern is the ortho disubstituted [2.2]PCP ( 42) due to the ease of their preparation from monosubstituted derivatives. Amongst the most successful orthodisubstituted[2.2]PCP ligands are the 4hydoxy [2.2]paracyclophane aldimine 47a and ketimines 47b, c ligands of Brase32(Figure 119). These ligands are amongst the most successful kn own for the 1,2addition of alkyl, alkenyl and alkynylzinc reagents to aromatic and aliphatic aldehydes and imines. They can be considered bench marks not only for the success of [2.2]PCP based ligands but in the addition of functionalized zinc reagents in general. Figure 119 [2.2] PCPbased ligands

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31 The synthesis of pseudogeminal or 4,13disubstituted[2.2]PCP derivatives ( 44) from monosubstituted starting materials is also relatively simple, the transannular effect facilitates regioselective bromination. As a result, a large number of such ligands have been reported with varying degrees of success in enantioselective catalysis.3334 Functionalization of the bridging ethylene groups is extremely rare ( 45). To our knowledge only Hou et al have investigated the activity of such compounds as ligands.35 Significantly, sulfide 48 (Figure 120) was found to form a more reactive and more selective catalyst than the orthodisubstituted analogue in palladium catalyzed allylic alkylation reactions (94% vs 5063% ee). It is believed that the bridgesubstituted ligand 48 possesses a greater degree of flexibility than the ortho disubstituted derivative and is therefore able to adopt a more favorable conformation on complexation. It should be noted that compound 45 was an unexpected by product in the synthesis of the ortho substituted derivative. Figure 120 Bridge substituted [2.2] PCP ligands 1.4 Reactivities and R eactions of [2.2] Paracyclophane The inter ring distance in the [2.2]PCP is significantly smaller than the distance between the layers of graphite, and repulsions be electron density on the two rings results in a distortion of the benzene rings from planarity towards ei ther chair or boat conformations. They therefore provide excellent models for the study of

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32 molecular strain and its relationship to reactivity. The conformational simplicity and unique geometry of these molecules provide a means of investigating the transannular interactions between the aromatic rings, and yield information concerning the transmission of electronic effects from substituents on one ring to the second. When compared to classical arenes, the most distinctive chemical property of the [2.2]PCP s is the ease with which they undergo addition reactions such as Diels Alder cycloadditions, hydrogenations and ionic additions.36 However, t he typical regenerative behavior of aromatic molecules is not entirely suppressed, and substitution reactions such as bromination, Friedel Crafts acylation and nitration are well established. Besides these reactions at the aromatic groups, reactions at the ethylene bridges such as cleavage, isomerization, and functionalization also occur. 1.4.1 Properties of [2.2] Paracyclophane 1.4.1.1 Structure and strain The early X ray structure of [2.2]PCP1 indicated a rigid, face to face molecule with three mirror pla nes a nd bent benzene rings. A later and highly refined structure reveals that, even at 93 oK, the substance equilibrates between two structures in which the ethylene bridges are slightly deecilpsed.37 In this molecular motion, the benzene rings rotate about axis perpendicular to and passing through the center of each face. The angle swept by this rotation is about 6 o. A cross section and face view of the molecule are found in Figure 121

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33 Figure 121 Structure of [2.2]PCP at 93 oK The crystal structure demonstrates the presence of considerable strain and compression energy in the [2.2]PCP. The strain energy of [2.2]PCP is 31 kcal/ mole.38 1.4.1.2 Steric inhibition of ring rotation An engaging aspect of [2.2]PCP chemistry is the symmetry properties of the parent hydrocarbons and its derivatives. The smaller cycle is distributed more equally in the three dimensions than most other molecules. Most ball like molecules are rigid by virtue of their bonding interactions. The [2.2]PCP is rigid because of its nonbonding interactions. The rigidity and small nonbonded atomic distances in the [2.2]PCP lead to the possibility of stable conformational isomers, and the energy barriers to ring rotation of both benzene nuclei and carbon bridges have been studied. Structu res 49a and 49b are enantiomeric and possibly interconvertible through state A ( Figure 122). Carboxylic acid 5039, 5140, 5241 were resolved. Compound 5341 Figure 122 Structures 49a and 49b are enantiomeric and possibly interconvertible through state A

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34 was not resolvable, indicating facile benzene ring rotation at room temperature. When heated to 160 oC 52 racemized slowly with an estimated activation energy42 of 33 kcal/mole, but acid 51 failed to racemize at temperature up to 240 oC 40. The methyl es ter of 50 did racemize at 200 oC but only by an ethylenebridgecleaving mechanism42. From the temperaturedependent nmr spectra of diacetyl[4.4]PCP ( 54) the barrier to ring rotation was estimated as ~15 kcal/mole at 15 oC Rotation of the benzene ring a round the arylalkyl bond (structure A, Figure 122) detectable by racemi zation in the paracyclophane systems, requires the two hydrogens to pass the other aromatic ring, and, in the case of bent benzene rings conversion from one boat form to the other. This interconversion occurs easily in the unstrained [4.4]PCP with 16 atoms in the large ring and does not occur at reasonable temperatures in [3.3]PCP with 14 atoms in the large ring. Stuart Briegleb molecular models of compounds 50 53 uniquely allow both t he assembly and the correct prediction of room temperatures behavior with respect to ring rotation.

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35 1.4.1.3 Reactions that reflect the strain in the [2.2] paracyclophanes The 31kcal strain energy of [2.2]PCP, coupled with its almost rigid structure, give s rise to reactions of the bridge carbons that exhibit features peculiar to the system. Ring cleavage by a thermal process can relieve the strain in the molecule. The nature of the cleavage and fates of the intermediates have been investigated. Pyrolysis at 600 oC of [2.2]PCP and some of its derivatives produces two fragments2 which are sufficiently stable under low pressure (<1 Torr) that recombination is delayed until the vapor comes in contact with a surface at 30 oC where it forms a polymer. Whether the intermediates are diradical 55 or p xylylene 2 they combine in quantitative yield to form a living polymer which retains a concentration of free radical of 510 104 mole/mole of tetraene ( Figure 123). Figure 123 [2.2]PCP conversion to living polym ers Another example is the racemization without decomposition of optically active ester 56 when heated to 200 oC.42 An examination of molecular models of 56 provides the convincing conclusion that ring rotation cannot occur in this system without ring r upture. The data42 show that cleavage of only one benzyl benzyl bond occurred at this temperature, followed by aryl rotation and benzyl benzyl bond formation ( Figure 124).

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36 Figure 124 Racemization of optically active ester 56 1.4.2 Reactions of [2.2] P aracyclophane 1.4.2.1 Reactions at the ethylene bridges of [2.2]paracyclophane 1.4.2.1.1 Radical cleavage [2.2]PCP ( 3 ), pyrolysis at temperature above 200 oC in the presence of hydrogen donors like p diisopropylbenzene or thiophenol leads to 4,4'dimethylbibenzyl 57 (74% yield) ( Figure 125). Figure 125 Radical cleavage of [2.2]PCP 1.4.2.1.2 Ionic reaction Treatment of [2.2]PCP (3 ) with AlCl3/HCl in methylene chloride at 0 oC provides [2.2]metaparacyclophane 60 in 44% yield. The driving force for this reaction, which complexes 58 and 59 is most likely provided by the reduction of the strain energy ( E s of 3 : 134 kJ/mol; E s of 60: 100 kJ/mol) ( Figure 126). Figure 126 Ionic reaction of [2.2]PCP

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37 1.4.2.2 Reactions at t he benzene rings 1.4.2.2.1 DielsAlder reaction In contrast to the readiness of conjugated di and trienes to participate in [2 + 4] electron systems are normally extremely sluggish in Diels Alder additions one reason for the use of benzene, toluene, the various xylenes, and halobenzenes as solvents in these reactions. Despite the low arenes can react as dienes if the reaction is performed at high temperatures or in presence of Lewis acid catysts; reactive dienophiles also add.43 Nevertheless, the superdienophile 4N phenyl1,2,4triazoline3,5 dione ( 61) does not add to benzene or any of the polymethylbenzenes at room temperature after several weeks.44 However, [2.2]PCP (as a formal dimer of p xylene) reacts with 61 to afford the 1:2cycloadduct ( 62) after ca. six days at room temperature in 99% yield ( Figure 127). Figure 127 Reaction of [2.2]PCP with superdienophile 61 1.4.2.2.2 Hydrogenation Catalytic hydrogenation of [2.2]PCP under mild conditions produces a diene that either has structure 63 or 64, whereas slightly more rigorous reaction conditions yield perhydro[2.2]PCP 6545 ( Figure 128).

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38 Figure 128 Hydrogenation of [2.2]PCP Birch reduction of [2.2]PCP should t ake place readily because a substantial reduction in st r ain is expected for the transformation of nonplanar aromatic nuclei into boat configurated 1,4cyclohexadiene units. Under the conditions given in Scheme 21, [2.2]PCP 3 besides providing small amounts of the dihydrocompound 66, mainly affords the tetrahydro derivative 67 as well as 68 ( Figure 129). Figure 129 Birch reduction of [2.2]PCP The known strong dependence of the product composition in Birch reduction on small variations in the reaction conditions is also observed for 3 Whereas addition of a solution of 3 in tetrahydrofuran to a refluxing solution/ suspension of sodium in liquid ammonia, followed by addition of ethanol yields 4,4'dimethylbibenzyl 57 in 94% yield. Slow addition of 3 in THF/ethanol to a solution of sodium in refluxing ammonia leads quantitatively to 68. 1.4.2.2.3 Electrophilic substitution 1.4.2.2.3.1 Acetylation with acetyl chloride/aluminum chloride Acetylation of [2.2]PCP with acetyl chloride in the presence of aluminum chloride provides 4acetyl[2.2]PCP as major product together with two isomeric methyl ketones

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39 (C36H36O2). Careful chromatography on silica gel and fractional crystallization of the acetylated reaction mixture give 69 (75%), 70 (9%, mp 257oC ) and 71 (9%, mp 98101 oC ). Both 70 and 71 possess the same molecular formula C36H36O2 ( Figure 130). Compounds 70 and 71 are formed under Friedel Craft acylation. One acetyl group substituted in the [2.2]PCP nucleus deactivates both rings toward electrophilic at tack. Thus it seems reasonable to expect that the nucleus was first alkylated and then acylated in a second stage. The strain in the [2.2]PCP is probably responsible for the ease with which it undergoes ring opening with AlCl3. An attractive general mechanistic scheme is formulated ( Figure 131). Figure 130 Acetylation of [2.2]PCP with acetyl chloride Figure 131 Proposed mechanism for the formation of by products 70 and 71 1.4.2.2.3.2 Nitration of [2.2]paracyclophane Nitration of 3 with fuming nitri c acid in glacial acetic acid for 15 min provides mainly 4 nitro[2.2]paracyclophane.45 When the reaction time was extended, a large

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40 number of products were generated, which were pseudogem ( 72, yield: 0.7%) pseudometa ( 73, yield: 2%), pseudoortho( 74, yield: 2%) and pseudopara ( 75, yield: 1.4%) dinitro[2.2]PCPs ( Figure 132). Figure 132 Dinitration of [2.2]PCP with HNO3/CH3COOH 1.4.2.2.3.3 Bromination of [2.2]paracyclophane Iron catalyzed bromination of 3 with 2 equivalents of bromine in carbon tetrac hloride gave four isomeric dibromides in the yields indicated in Figure 133. The compounds were separated by a combination of chromatographic and crystallization techniques. Figure 133 Dibromination of [2.2]PCP with Br2/Fe

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41 Use of excess bromine in the presence of an iron catalyst gave two products (total isolated yield: 57%) after chromatography. The faster mov ing component (yield: 29%) was 4,7,12,15tetrabromo[2.2]PCP ( 80). The second slower moving tetrabromo isomer was 4,5,15,16tetrabromo[2.2]PCP ( 8 1 ) and isolated in 28% yield ( Figure 134). Figure 134 Tetrabromination of [2.2]PCP with Br2/Fe 1.4.2.2.3.4 Dichlorination of [2.2]paracyclophane The iodinecatalyzed dichlorination of [2.2]PCP did not proceed as discretely as the bromination. Subs tantial amounts of monochloro and trichloro products were generated when 2 mol of chlorine had been consumed. Only the insoluble pseudoparadichloro[2.2]paracyclophane ( 82) was isolated (10% yield, Figure 135). Figure 135 Dichlorination of [2.2]PCP wi th Cl2 in the presence of iodine 1.4.2.2.3.5 Transannular directive influences in electrophilic substitution of monosubstituted [2.2]paracyclophane Chemical and spectral evidence indicate the presence of strong transannular electronic interactions in [2.2]PCP and its derivatives.46 When second substituent is introduced into monosubstituted [2.2]PCP, the first substituent sh ould have a directive influence on the same benzene ring and a transannular directive impact on another

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42 benzene ring. Table 1 147 recor ds the results of an investigation of such directive influences. Table 11 Pattern of electrophilic s ubstitution of m onosubstituted [2.2] paracyclophanes % % pseudo Entry X Reagent para ortho para meta gem 1 COOCH 3 Br 2 Fe 89 2 COCH 3 Br 2 Fe 56 3 COOH Br 2 Fe 63 4 NO 2 Br 2 Fe 2 6 8 70 5 CN Br 2 Fe 16 25 26 6 Br Br 2 Fe 5 16 26 6 7 OH C 6 H 5 N 2 Cl 98 The data of T able 11 indicate that electophilic substitution of paracyclophane with strong electrondonating groups orients para in the ring bearing the substituent, as in diazonium coupling of 4hydoxy[2.2]PCP (entry 7), for weaker electrondonating group, besides parabis substituted[2.2]PCP, pseudopara, pseudoortho and pseudometa bis[2.2]PCP were produced, bromination of 4 bromo [2.2]PCP gives 5% para, 16% pseudoortho, 26% pseudopara and 6% pseudometa bisbromo[2.2]PCP (entry 6). The presence of one electronwithdrawing substituent in one ring deactivated both rings toward further electophilic attack. For the acetyl, ca rbomethoxy, carboxy, and nitro derivatives of [2.2]PCP, bromination occurs exclusively or predominantly in the position pseudogem to these groups to give the thermodynamically least stable isomer. The oxygens of these groups are ideally positioned to acce pt a proton from the pseudogem position. The lower specificity of the nitro compound probably reflects its lower basicity (entry 1 4) The cyano group apparently cannot function as an internal base because of its linear structure, and no pseudogem produc t pattern was observed in

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43 entry 5. The random product pattern in entry 5 rules out specific conjugative or inductive effects on positions of substitution. The mechanism favored by the data is illustrated with 4 bromo[2.2]PCP as substrate (entries 6). In t he over all scheme, the electrophile attacks the face of the unsubstituted ring, a proton is transferred from ring to ring, and the proton departs from the face of the originally substituted ring. Thus, electrophiles enter and leave from the system by the least hindered paths ( Figure 13 6 ) Figure 13 6 Transannular directive influences second electrophilic substitution of 4bromo[2.2]PCP 1.5 Reactions of O ctafluoro[2.2] p aracyclophane and I ts D erivatives 1.5.1 Reactions of Octafluoro [2.2] paracyclophane O ctafluoro[2.2]PCP (AF4) is a deactivated aromatic system because of fluoroalkyl group. Thus, the Friedel Craft type aromatic bromination, acylation and alkylation chemistry do not work.49 However, nitration of AF4 is successful, and nitration of AF4 with nitronium tetrafluoroborate in sulfolane at room temperature afforded mononitroAF4 ( 84) in 86% isolated yield49 with no dinitro derivatives observed. Reduction of 4nitro AF4 provides 4aminoAF4 in 82% yield ( 85). Examin ing the diazotization and Sandmeyer type chemistry of 85, a number of other derivatives including halo, hydroxyland phenylAF4 derivatives can be produced in yields ranging from poor to good ( Figure 138).

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44 Figure 13 7 Synthesis of monosubstituted AF4 derivatives When nitration was car ried out under the more forcing conditions of 5 equivalents of nitronium tetrafluoroborate and a temperature of 80 oC, the products generated were a mixture of pseudometa ( 86a), pseudopara ( 86b), and pseudoortho( 86c) dinitro AF4 derivatives in 81% combined isolated yield50, with the ratio of 1:1:1. pseudoortho Isomer could be separated from pseudometa and pseudopara isomers by column chromatography, but pseudometa and pseudopara isomers could not be separated by column chromatography, however, the pseudometa and pseudopara isomer mixture could be enriched in one isomer or the other by fractional crystallization, or sublimation. Reduction of the three isomeric dinitroAF4 compounds provides corresponding the diaminoAF4 compounds in 8284 % yield ( 87ac ). The double diazotization of these diaminosystems, followed by Sandmeyer type chemistry furnishes the three isomeric dibromo( 88ac ), diio dides ( 89ac ) and diphenylAF4 ( 90ac ) in good isolated yield (6078%) (Figure 139) Trifluoromethylation of the of the pseudometa and pseudopara diodes 89a,b with methyl 2 (fluorosulfonyl) difluoroacetate in the presence of catalytic amount of PdCl2 provides high yields of corresponding bis (trifluoromethyl)AF4 products ( 91a b ).

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45 Figure 13 8 Synthesis of bis substituted AF4 derivatives 1.5.2 Thermal Isomerizations of AF4 Derivatives It is known that [2.2]PCP derivatives can be racemized at 200 oC. Since replacement of hydrogen by fluorine in saturated systems usually increases thermal and chemical stabil ity,51 together with the lower stability of difluorobenzyl radicals relative to

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46 benzyl radicals,52 AF4 derivatives would be predicted to require a much higher temperature to undergo such isomerization. Indeed, pseudoorthobis(trifluoro acetamido) AF4 ( 92a ) proved to be perfectly stable and unchanged when heated neat at 300 oC for 8 h, but w hen it was heated to 390 oC for 2 h, NMR analysis indicated that it had been converted to a 5:1 ratio of 92a and pseudopara isomer ( 92b ). The above mixture was fur ther heated at 360 oC for 24 h, and the ratio of 92a:92b was found to have changed to 1:7 (Figure 139). Figure 139 Thermal isomerrization of pseudoorthobis( trifluoro acetamido) AF4 Therefore, the AF4 derivative has considerably more kinetic thermal s tability than the hydrocarbon [2.2]PCP system. This not only demonstrates the stabilizing effect of exchanging fluorine for hydrogen, but could have serious implications regarding the use of these AF4 derivatives as chiral ligands, catalysts and auxiliarie s, since they display fa r superior resistance to thermal isomerization than hydrocarbon analogues. 1.5.3 Reactions of AF4 Derivatives 1.5.3.1 Aryne chemistry of octafluoro[2.2] paracyclophane Dehydroiodination of 4iodooctafluoro[2.2]PCP by treatment with t Bu OK in the presence of benzene, naphthalene and anthracene affords each of the corresponding Diels Alder cycloadducts derived from the presumed aryne intermediates in high yield

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47 ( Figure 142).53 When 4,15diiodo octafluoro[2.2]PCP is used as starting m aterial instead of 4iodooctafluoro[2.2]PCP, Diels Alder bis cycloadducts are obtained in excellent yield.53 A double Diels Alder reaction of the formal syn bis(dehydro) octafluoro[2.2]PCP with anthracene leads to formation of a novel cage compound that contains a highly pyramidal double bond (Figure 14 0 ).54 W hen 4 a cetamidooctafluoro[2.2]PCP is treated with p chlorobenzoyl nitrite in the presence of various dienes, similar results55 are obtained as shown in Figure 14 1 Figure 14 0 Highly pyramidali zed cage alkene formed via the double Diels Alder cycloaddition of syn 4,5,13,14bis(dehydro)octafluoro[2.2]PCP to anthracene Figure 14 1 Reaction of 4iodoAF4 with various dienes in the presence of t BuOK

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48 1.5.3.2 Novel ringcleaving reaction of 4 ni tro octafluoro [2.2] paracyclophane with nucleophiles When 4n itro octafluoro[2.2]PCP is treated with nucleophiles such as alkoxides and cyanide, a novel ring opening reaction is observed via a SNAr mechanism. T he nucleophile apparently attacks the bridgehead aryl carbon vicinal to the nitro group, followed by subsequent arylCF2 bond cleavage to form 9 7 a b type products in moderate to good yields (5278%) ( Figure 14 2 ).56 Figure 14 2 Ring opening reaction of 4nitr o octafluoro[2.2]PCP 1.5.3.2 Nucleophil ic substitution of 4iodooctafluoro [2.2] PCP Reactions of 4iodoAF4 with thiophenol and dimethyl malonate in the presence of sodium hydride under irradiation of sunlamp provide corresponding products 98, 99 in high yields. In the absence of irradiation with sunlamp, the reaction cannot proceed even at 120 oC ( Figure 14 3 ) .57 Thus these reactions appear to proceed via SRN1 mechanisms Figure 14 3 Nucleophilic substitution of 4iodooctafluoro [2.2]PCP

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49 In conclusion, studies of [2.2]PCP has probed theori es on bonding, ring strain and their use in commercial application as monomers for Parylenetype polymers. The electronic properties of [2.2]PCP were employed in the design of charge transfer complexes and variety of molecular electronic material s such as linear and nonlinear optoelectronics and conductive polymers. The planar properties of [2.2]PCP were used in the preparation of chiral ligands and biomedical research. A successful synthetic method for preparation of AF4 was discovered in 1996. Besides the industrial application of this compound as a monomer for the ParyleneHT polymer, studies of the chemistry of AF4 began in 1999 because of the commercial availability of AF4. It is hoped that commercial applications for AF4 derivatives will be found much like their hydrocarbon analogues.

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50 CHAPTER 2 SYNTHESIS OF PERFLUO RO[2.2]PARACYCLOPHANE AND PERFLUORO[2.2.2]PARA CYCLOPHANE 2.1 A bstract A method for preparing perfluoro[2.2]paracyclophane has been sought ever since the partially fluorinated octaf luoro[2.2]paracyclophane (AF4) was first synthesized. This compound has now been prepared in 42% yield from the precursor, 1,4bis(chloro difluoromethyl) 2,3,5,6 tetrafluorobenzene by its reaction with zinc dust when heated in anhydrous acetonitrile at 100 oC. Two preparations of the precursor, first from 1,4dicyano2,3,5,6tetrachlorobenzene and an improved method beginning from 1,2,4,5tetrachlorobenzene, are also described as are key comparisons to our related synthesis of AF4. 2.2 Introduction [2.2] P aracyclophanes are useful chemical vapor deposition (CVD) precursors of a family of thin film polymers known as Parylenes.58 Parylene polymers are conformal coatings that are ideally suited for a wide variety of applications within the automotive, medical electronics and semiconductor industries. Parylene coatings are transparent, chemically inert, and they have excellent barrier properties. The process of conversion of [2.2]paracyclophane into a Parylene polymer is exemplified in Figure 21 for the parent hydrocarbon system. The hydrocarbon version Figure 2 1 [2.2]Paracyclophane and its conversion to Parylene polymers

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51 of polymer, Parylene N, has good thermal stability, remaining useful (for several hours) at temperatures up to 130 oC. However, for tho se applications that require a coating of greater thermal stability, the bridgefluorinated ParyleneHT, which exhibits only 0.3% weight loss per hour at 450 oC, is preferred. The precursor for Parylene HT is 1,1,2,2,9,9,10,10octafluoro[2.2]paracyclophane, commonly known as AF4, and which for the last 15 years has been the subject of considerable synthetic interest. Since Dr. Dolbier initially published its preparation method in 1993,11 which allowed gram quantities of AF4 to be prepared, four subsequent papers have provided procedures that would allow larger, even commercial quantities to be prepared.13,15,59,60 The best of our procedures, where 1,4bis(chlorodifluoromethyl)benzene was allowed to react with zinc in dimethylacetamide under nonhighdilution conditions, is shown in Figure 22.15 This process is currently used to manufacture AF4 for use in the Parylene industry. Figure 2 2 Preparation of AF4 by reduction of dichloride ( 11) with zinc Perfluoro[2.2]paracyclophane, herein referred to as F8, has been the subject of much interest as a potential Parylene precursor ever since AF4 was found to be so useful. It was predicted that the polymer derived from F8 would retain the high thermal stability of the AF4 derived polymer while having a lower diel ectric constant, better dielectric strength, a very low coefficient of friction, plus transparency in the regions of spectra ( IR spectra, in particular) that involve C H bonds. Nevertheless, until this report

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52 no synthesis of F8 has been reported.61,62 The method described below the first synthetic method for F8. The approach to the synthesis of F8 that ultimately proved successful emulated the method shown above for AF4. However, significant changes in the key steps were required because of the presence of the ring fluorines. A completely different synthesis of the logical [2.2]paracyclophane precursor 1,4bis(chlorodifluoromethyl) 2,3,5,6 tetrafluorobenzene ( 100) proved necessary because the ring fluorines effectively inhibited both the chlorination and br om ination steps of our published procedure for synthesis of the AF4 precursor.63 Instead, we utilized alternative synthetic schemes to prepare precursor 100. Our initial approach utilized commercially available 2,3,5,6tetrachloro1,4dicyanobenzene ( 101) as the starting material (Figure 23). Tetrafluoro compound 102 was prepared in 89% yield by facile Cl F exchange using KF in anhydrous DMF in the presence of 2% phase transfer agent tetrabutyl ammonium bromide.64 The cyano groups were then reduced using DIBAL H in toluene to form dialdehyde 103 in 69% yield.64,65 Dialdehyde 103 could be efficiently converted (87%) to the bis(difluoromethyl) compound 104 via reaction with SF4 in the presence of HF. Chlorination of compound 104 provided the desired precurso r 100 in 56% yield. Although this procedure allowed the synthesis of the required precursor 100, the required use of DIBALH and SF4 insured that this overall process would be too expensive to utilize for making larger quantities of F8. The chlorination s tep took 56 h

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53 Figure 23 First synthesis of F8 precu r sor 100 ( M ethod A) and the yield was only 56%. My contribution was developing a three step approach to the synthesis of 100, based on the preparation by Castaner and Riera of 1,4bis(dichloromethyl) 2,3,5,6 tetrachlorobenzene ( 106) by AlCl3catalyzed condensation of chloroform with 1,2,4,5tetrachlorobenzene ( 105).66 Thus, as shown in Figure 24,1,4bis(difluoromethyl) 2,3,5,6tetrafluorobenzene ( 104) could be prepared with overall yield of 65% from the inexpensive 1,2,4,5tetrachlorobenzene. The yield of chlorination of compound 104 was improved to 81% from 56% and the reaction time was reduced to 17 h simply by increasing reaction temperature from 60 oC to reflux (84 oC). In order to further reduce the price of 1,4bis(chlorodifluoromethyl) 2,3,5,6 tetrafluorobenzene ( 100), 1,2,4,5 tetrafluorobenzene was used as starting material instead of 1,2,4,5tetrachlorobenzene for AlCl3 catalyzed condensation with chloroform, but the reaction did not work. Another attempt was applied the same procedure for the ClF exchang e step by the use of KF or technical grade CsF replacing reagent grade CsF, but this reaction did not succeed either.

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54 Figure 24 Improved synthesis of F8 precursor 100 ( M ethod B) Conversion of dichloride precursor 100 to the paracyclophane F8 provided its own challenges, since the exact procedure used to synthesize AF4 when applied to 100 gave no perfluoro[2.2]paracyclophane product. Indeed, when precursor 100 was allowed to react with zinc in various polar aprotic solvents, a reaction proceeded very smoothly to consume 100 (Figure 25). Figure 25 Application of AF4 procedure to preparation of F8 A fluorine NMR spectrum of the reaction mixture indicated that 100 had been converted cleanl y to a single product that exhibited two singlet signals, at 101.5 and 146.4 ppm signals that were not inconsistent with the product actually being the desired perfluoro[2.2]paracyclophane. However, any attempt to work up the reaction gave no isolable fluorine containing product. It finally was concluded that these new

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55 signals were due to formation of the over reduced bis zinc reagent 107. This conclusion was based on two reactions of the intermediate, both of which were consistent with it being bis zin c reagent 107 ( Figure 2 6). Addition of bromine to the reaction mixture containing 107 led to formation of bis bromodifluoromethyl product 108. Whereas addition of acetic acid produced bis difluoromethyl compound 104.67 Also the observed fluorine chemical shift of 107 is consistent with its structure.68,69 Figure 26 Chemical characterization of bis zinc reagent 107 In view of these results, it was thought that using zinc in a less polar solvent might inhibit the over reduction that led to the bis Zn reagent 107. Indeed when acetonitrile was used as the reaction medium, a new product appeared in relatively low yield (20%) which also had two signals in the fluorine NMR, this time at 102.8 and 132.4 ppm (Figure 28). Upon isolation and characterization, this product proved to be the desired perfluoro[2.2]paracyclophane, F8, as characterized by 13C, 19F NMR, HRMS, elemental analysis and X ray structure analysis ( X ray structure of F8 see Appendix in Figure 1). The following optimization led to a pure product and higher yield. First, the reaction temperature was reduced from 120 oC to 100 oC (oil bath temperature) by

PAGE 56

56 activating the zinc with 2% hydrochloric acid. The reaction is believed to be more favorable for dimerization rather than polymerization at l ow temperature. Secondly, precursor 100 must be very pure; if precursor 100 contains even trace amount s of compound 104, smooth reaction is inhibited. As result of these optimization, this reaction yield was able to be increased to 42% of high purity product. In addition to giving F8, this reaction also produced the bridgeunsaturated product ( 110) and trimer perfluoro[2.2.2]paracyclophane ( 111) (X ray structure of 111 see Appendix in Figure 2) Figure 27 Synthesis of F8 and trimer perfluoro[2.2.2]parac yclop h ane Thus, for the first time, the perfluoro[2.2]paracyclophane is available for deposition experiments to determine the impact of perfluorination on properties of the respective Parylene polymer. Scale up experiments have now allowed us to produce m ore than 200 g of pure F8 for Specialty Coating System, Inc. for preparation and testing films. 2.3 Experimental Section 1,4Dicyano 2,3,5,6tetrafluorobenzene ( 101)64: 1 ,4 Dicyano 2,3,5,6tetra chlorobenzene (purity 95%) (40 g, 0.15 mol), KF (43.7 g, 5 equiv), and tetrabutuylammonium bromide (TBAB) (0.99 g, 2 mol%) were added to a flask containing dry DMF (250 mL), and the mixture was stirred overnight at 120 oC under N2. The reaction mixture was poured into ice water (2 L). The resulting precipitate was filtered and

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57 washed with water. The crude product was recrystallized from acetone to give 1,4dicyano2,3,5,6tetrafluorobenzene (25.5 g, 89%) as yellowish crystals. m p 197199 oC; 19 1 28.5 (s).64 2,3,5,6T etrafluorobenzene1,4dicarbaldehyde ( 103)64,65,70: To a solution of 1,4dicyano2,3,5,6tetrachlorobenzene ( 102 ) (20.0 g, 0.1 mol) and toluene (300 mL) at 0 oC was added 1 M diisopropylaluminum hydride (DIBALH) toluene solution dropwise under nitrogen. The reaction mixture was stirred at 0 oC for 1 h and then slowly warmed to room temperature and stirred overnight. The reaction was quenched by addition of 2 N hyd rochloric acid (300 mL) until pH< 2, and the mixture was stirred for 30 min. The resulting precipitate was filtered and washed with dichloromethane. The organic layer was separated from the filtrate and the aqueous layer was extracted with dichloromethane (50 mL 6). The combined organic layers were washed with saturated sodium bicarbonate and brine, dried over MgSO4, filtered and concentrated to give crude product (16 g), which was recrystallized from dichloromethane to obtain 2,3,5,6tetrafluorobenzene1,4 dicarbaldehyde ( 103) (14.2 g, 69%). m p 197199 oC; 1H NMR 1 0.33 (s);64 19F NMR 144.2 (s);64 MS 207 (M+H, 100). 1,4Bis(difluoromethyl) 2,3,5,6tetrafluorobenzene ( 104) ( Method A) 67: 2,3,5,6Tetrafluorobenzene1,4dicarbaldehyde ( 103 ) (27.3 g, 0.132 mol) and dichloromethane (50 mL) were added into a 250 mL autoclave, which was then cooled with a dry ice acetone bath. HF (8.0 g) and SF4 (135 g) was added, and the reaction mixture was stirred at 180 oC for 48 h. The reaction mixture was washed out with dichloromethane (200 mL) and kept overnight to release HF and other gaseous products. The reaction mixture was filtered and the filtrate was washed with brine (60 mL 3), dried over

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58 MgSO4, evaporated to dryness, and recrystallized from dichloromethane to afford product 104 (28.9 g, 87%): mp 6870oC (lit.67 mp 4550 oC); 1 6.97 (t, JFH = 53 Hz); 13C JFC = 242 Hz), 115.97 (br. S), 144.79 (d, JFC = 262 Hz), 19F NMR 115.2 (d, JFH = 52 Hz), 142.2 (s). Anal. Calcd for C8H2F8: C, 38.42; H, 0.81. Found: C, 38.07; H, 0.68. 1,4Bis(dichloromethyl) 2,3,5,6 tetrachlorobenzene (106)66: A mixture of 1,2,4,5tetrachlorobenzene (22.6 g, 0.1 mol) and aluminum chloride (30 g, 0.225 mol) in anhydrous chloroform (300 mL) was refluxed for 22 h. The reaction mixture was cooled to room temperature, diluted with chl oroform (200 mL) and poured into a mixture of hydrochloric acid (30 mL) and ice water (300 mL). The organic layer was separated, dried over magnesium sulfate, and concentrated to give crude product (45 g), which was recrystallized from hexanes (225 mL) to give 106 (31.6 g) as yellow solid. The mother liquor was concentrated to a volume of 45 mL, after which a second crop of product (4.1 g) was obtained. The total yield was 91.1%. mp 134136 oC (lit.66 mp 127129 oC); 1. s), 7.63 (br s) (eq ual intensity, due to atropismers deriving from restricted rotation of the dichloromethyl group);71 13 ca rbons not observed). 1,4Bis(difluoromethyl ) 2,3,5,6tetrafluorobenzene (104) (Method B) : A mixture of octachlorop xylene (120g, 314.1 mmol), cesium fluoride (476 g, 3.14 mol) and tetrabutylammonium bromide (4.2 g, 12.7 mmol) in anhydrous DMSO (520 mL) was heated to 120 oC for 6 h. The reaction mixture was then cooled down to room temperature and poured into ice water (1100 m L), then extracted with diethyl ether (2 500 mL). The combined organic layers were washed with water (1000 mL), dried over

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59 magnesium sulfate, concentrated to remove solvent. The residue was distilled at 72 oC with reduced pressure (20 mm Hg) to give crude product (60 g), which was recrystallized from hexanes (60 mL) to furnish octafluorop xylene (55.8 g, yield: 71.1%, m p: 7072 oC) as white crystals. 1H NMR 6.97 (t, JFH = 53 Hz); 13C 108.22 (t, JFC = 242 Hz), 115.97 (br. S), 144.79 (d, JFC = 262 Hz), 19F NMR 115.2 (d, JFH = 52 Hz), 142.2 (s). Anal. Calcd for C8H2F8: C, 38.42; H, 0.81. Found: C, 38.07; H, 0.68. 1, 4Bis (chlorodifluoromethyl) 2,3,4,5 tetrafluorobenzene (100) : T o a solution of octafluorop xylene (18.7 g, 74.8 mmol) in carbon tetrac hloride ( 250 mL) was bulbed chlorine under sunlamp for 17 h. The reaction mixture was slowly evaporated to remove carbon tetrachloride. The residue was distilled under reduced pressure (8587 oC/20 mmHg) to give 1, 4bis (chlorodifluoromethyl) 2,3,4,5tet rafluorobenzene (19.4 g, yield: 81.3%) as a colorless oil. 13C NMR 121.10 (t, JFC = 2 95 Hz), 143.61 (d, JFC = 26 8 Hz), 19F NMR 47.6 (m 4F ), 137.9 ( m, 4F ). HRMS calcd for C8F8Cl2 317.9249, found 317.9239; GC EI MS ( C8F8Cl2, 319, C8F8Cl, 283, C8F8, 248). 1.4Bis(bromodifluoromethyl) 2,3,5,6tetrafluorobenzene (108) : A mixture of 1, 4bis (chloro difluoromethyl) 2,3,4,5 tetrafluorobenzene ( 100) (1 g, 3.13 mmol) and zinc (0.82 g, 12.5 mmol) in anhydrous DMF (5 mL) was heated to 100 oC for 0.5 h. The reaction mixture was cooled to room temperature, and a 19F NMR spectrum of the mixture revealed two equal intensity singlets at 100.3 and 145.0 ppm. These two peaks were attributed to the presence of bis zinc intermediate 107: 19F NMR 100.3 and 145.0 ( equal intensity ). Bromine (0.65 g, 8 mmol) was then added to the reaction mixture and this mixture was stirred at room temperature for 4 h, quenched with ice water (30 g), extracted with diethyl ether (2 10 mL). The combined ethereal layers

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60 were dried over magnesium sulfate, and concentrated to give crude product, which was purified by column chromatography (silica gel, hexanes) to provide 1.4bis(bromo difluoromethyl) 2,3,5,6 tetrafluorobenzene (0.11 g, yield: 8.6% ) as sticky color less oil. 13C 110.4 (t, JFC = 308 Hz), 143. 1 (d, JFC = 2 84 Hz) (other carbon not seen); 19F NMR 43.8 (m 4F), 137.9 ( m, 4F ). HRMS (all three isotopic combinations) calcd for C8F8[79]Br2 405.8239, found 405.8214; calcd for C8F8[79]Br[81Br 407.8219, found 407.8228; calcd for C8F8[81]Br2 409.8198, found 409.8234. Perfluoro[2.2]paracyclophane (109) : A mixture of 1,4 bis (chloro difluoromethyl) 2,3,5,6tetrafluorobenzene (10 g, 31.3 mmol) and zinc (8.2 g, 125.2 mmol) in anhydrous acetonitrile (100 mL) was heated to 100 oC (oil bath temperature) under nitrogen atmosphere. The reaction mixture was refluxed gently for 38 h. The reaction mixture was then cooled to room temperature, filtered and washed with acetone (3 30 mL). The combined filtrates were concentrated to dry ness The residue was purified by column chromatography (silica gel, hexanes) to give crude product (3.8 g) as white powder. The crude product was recrystallized from chloroform (40 mL) to furnish 2.9 g of pure product as white needles. The mother liquor w as concentrated to dry ness The residue was recrystallized from chloroform (10 mL) to give second crop of pure product (0.37 g) as white needles. The yield is 42.1% based on isolated pure product. m p 195196 oC; 13C 118.0 ( t t, JFC = 283.29 Hz), 147.4 (d d JFC = 267.22 Hz) bridgehead carbon not seen; 19F NMR 102.8 (s 8F), 132.4 ( s, 8F ). HRMS calcd for C16F16 495.9739, found 495.9719; Anal. Calcd for C16F16: C, 38.73; H, 0.00; N, 0.00. Found: C, 39.07; H, 0.00; N, 0.04.

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61 Perfluoro[2.2.2]paracyclophane ( 111) : The accumulated mother liquor enriched with perfluoro [2.2.2]paracyclophane ( 111 ) and bridgeunsaturated compound ( 110), was concentrated to dry ness (12 g), and was purified by column chromatography (silica g el, hexanes). The first fraction was compound 110 (1.2 g, yield: 0. 6 %) as a white powder. The third fraction (3.6 g) contains compound 111, which was not pure. R ecrystallization it from acetonitrile (40 mL) ga ve perfluoro[2.2.2]paracyclophane (2.4 g, yie ld: 1.2%) as white crystals. m p 245246 oC ; 19F NMR 104.28 (s 12F), 134.17 ( s, 12F). HRMS calcd for C24F24 743.9617, found 743.9609; Anal. Calcd for C24F24: C, 38.73; H, 0.00; N, 0.00. Found: C, 38.54; H, 0.00; N, 0.263. Compound 110: m p 135137 oC ; 19F NMR 103.72 (m 4F), 122.67 (s, 2F), 129.47 (d, J = 10.4 Hz, 4F), 134.11 ( d, J = 12.7 Hz, 4F). HRMS calcd for C16F14 457.9776, found 457.9758; Anal. Calcd for C16F14: C, 41.95; H, 0.00; N, 0.00. Found: C, 42.00; H, 0.00; N, 0.02.

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62 CHAPTER 3 REACTIONS OF NUCLEOPHILES WITH PERFLUORO[2.2 ]PARACYCLOPHANE 3.1 Introduction Fluorine substituents on alkenes or aromatic rings are known to significantly enhance the electron deficiency of these unsaturated systems and as a result increase their reactivity towards nucleophiles.7274 Trifluoromethyl substituents, although not as effective as a nitrile group, are even more effective activating groups for such nucleophilic attack.7476 Such activation derives, of course, from the ability of these groups to stabi lize the carbanion Meisenheimer intermediates that would be formed, for example, during a nucleophilic aromatic substitution reaction proceeding via an SNAr mechanism. Such a process, proceeding by a carbanion intermediate is the most common by which nu cleophilic aromatic substitution reactions occur, such mechanism being facilitated by substituents that will increase the electron deficiency of the system. Because of the presence of multiple fluorine substituents, hexafluorobenzene and pentafluoropyridin e exhibit high reactivity towards nucleophiles (Figure 31), 73,74, 77,78 as do trifluoromethylsubstituted analogues, such as perfluorotoluene.74,75,79 In a kinetic study of the reactivity of perfluoropolymethylbenzenes towards nucleophiles, it was obser ved that in its reaction with -OCH3/HOCH3 at 25 oC, perfluorotoluene is 7000 times as reactive as hexafluorobenzene. Adding a second ( para) trifluoromethyl group (as in perfluorop xylene) leads to a somewhat lower reactivity, but it is still 2900 times m ore reactive than hexafluorobenzene.

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63 Fi gure 31 Reactivity of hexafluorobenzene and pentafluoropyridine with nucleophiles Perfluoro[2.2]paracyclophane (F8) has recently been synthesized80 and because its aromatic rings resemble those of perfluorop xy lene, it should be expected to exhibit high reactivity towards nucleophiles, although the reactivity may be somewhat diminished because of the nonplanarity of F8s benzene rings. 3.2 Results Indeed, F8 proved to be very reactive with a large variety of nucleophiles. In this chapter reactions that led mainly to monosubstitution will be emphasized, with discussion s centered on definition of factors that favor monosubstitution. Subsequent chapter will deal with multisubstitution reactions of F8, the regiochemistry of multi substitution, and characterization of the multi substituted products, including detailed multidimensional NMR analysis of these products. When F8 was allowed to react at room temperature with up to eight equivalents of NaOH in aqueous THF a single, monohydroxy product 112a was formed in 99% yield (Figure 32). A similar reaction of 2.2 equivalents of NaOMe in THF yielded the monosubstituted product 112b in 49% yield along with 14% of a dimethoxy product, the pseudopara isomer 113. Providing further contrast, a reaction of F8 with one equivalent of sodium thiophenolate yielded no monosubstituted product at all. Instead,

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64 the parabis (phenylthio) product 114a was obtained in 30% yield along with small amounts of tetrakis and hexak is (phenylthio) products. Figure 32 Reactions of F8 with nucleophiles All three of the above nucleophiles were highly reactive in their respective substitution reactions with F8, with the reactions being complete after two days at room temperature for hydroxide and methoxide. The reaction with phenyl thiolate required only one day. The differences exhibited by these nucleophiles with respect to multiple substitution can be explained based on the variable effects of the different substituents (O-, OMe and SPh) of the monoadducts on their reactions with a second equivalent of nucleophile. Substitution of fluorine by hydroxide to form phenol derivative 112a will, of course, under the reaction conditions actually form the deprotonated phenolate anion,

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65 and the Osubstituent will act as a powerful donor to the aromatic system that will strongly inhibit further reaction of a nucleophile with the ring bearing the O-. Not only that, but the impact of the Omust also be significantly transmitted to the other benzene ring of the paracyclophane, since a second strong hydroxide nucleophile is also not observed to add to that ring either. As a weaker donor, the methoxy substituent of 112b appears to inhibit its reaction with a second equivalent of methoxide, but its influence is not sufficiently strong to prevent substitution of the other, unsubstituted benzene ring of 112b. In contrast, the results obtained from the reaction of F8 with thiophenolate anion clearly indicate that the SPh substituent of the putative monoadduct must activate that ring towards addition of a second nucleophile. Such results are consistent with the previously observed formation of only p bis (phenylthio) 2,3,5,6 tetrafluorobenzene from the reaction of either one or two equivalents of phenylthiolate anion with hexafluorobenzene.81 Dimethyl malonate anion behaves much like hydroxide in its reaction with F8, forming only a monoadduct even when the nucleophile is present in great excess. The reason for this is much the same, since the monoadduct would become immediately deprotonated to form the highly unreactive carbanion. Other nucleophiles, generally oxygen and nitrogen nucleophiles that serve to deactivate the ring to which they become attached, have also been utilized in reaction with F8, with the results from all of these reactions being summarized in Table 31. Some negative results were obtained during the trials between F8 and various nucleophiles I f methyl lithium, n butyl lithium, phenyl lithium and N N diethylcyclohex 1 enamine were used as nucleophiles, no desired products were obtained. When F8

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66 react ed with nitromethane or 2nitro propane in the presence of 2 equivalents of NaH in anhydrous THF at room temperature or reflux, only the starting material F8 was recovered. No reac tion was observed between F8 and aniline, phenyl hydrazine, or the Reforma t sky reagent 1( ethoxyvinyloxy)zinc (II) bromide probably due to these reagents being too weak base. There is also no reaction when ethynyltrimethylsilane was used as nucleophile i n the presence of CsF Table 31 Reaction of nucleophiles with F8 in THF at RT Nucleophile Equivalents Reaction Time hr Product No. and Yield (%) Color HO 8 44 112a (99) Yellow MeO 2 48 112b (49) White 4 F C 6 H 4 O 1 18 112c (77) White CH(CO 2 Me) 2 4 4 8 112d (73) White tert Butyllithium 1.1 18 112e (54) White Et 2 NH 4.4 20 112f (91) Yellow (CH 2 ) 4 NH 2.2 24 112g (84) Yellow PhCH 2 NHCH 3 2.2 24 112h (68) Yellow (CH 3 ) 2 NH (aq) 2.2 1 112i (70) Yellow All of the above reactions were carried out preparatively for times of between 18 and 48 h, but it was later determined that the reactions of F8 with most of the nucleophiles were complete in less than an hour. Indeed, while conducting relative reactivity experiments it was determined that the reactions of methoxide with F8, hexafluorobenzene and pentafluoropyridine in THF were all complete within 15 minutes. Under conditions of direct competition, in the presence of equal amounts of F8 and pentafluoropyridine, methoxide reacted exclusively with pentafluoropyridine. Likewise, F8 reacted exclusively in competition with hexafluorobenzene. Thus in reactions with nucleophiles, pentafluoropyridine is much more reactive than F8, which is itself much more reactive than hexafluorobenzene.

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67 Interestingly, even when 4.4 equivalents of diethylamine were used, the only formed product was 111f no bis substitut ed product was detected due to steric hindrance. As with aqueous dimethylamine, the only product was 112i no 112a was detected by 19F NMR because nitrogen is more react ive than hydroxide group as nucleophiles. All of the reaction mixtures were observed to develop a yellow color during reaction. Among the monosubstituted products, the ether, malonate and t butyl products were colorless, whereas the hydroxy, sulfide and amine products were various shades of yellow. The UV spectra of these products show a progression towards longer wavelength absorption as the substituent becomes increasingly electron donating (Figures 33 and 34 and 35) Figure 33 UV spectra of monosu bstituted F8 compounds

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68 Figure 34 UV spectra of monosubstituted F8 compounds Figure 35 Comparison of UV spectra of F8 phenol and phenolate species Bidentate nucleophiles were also examined to determine whether the intramolecular mode of reaction for the second nucleophile might provide sufficient kinetic advantage to observe cyclic products (Figure 36 and Table 32). Reaction of ethylene glycol in the presence of excess NaH led simply to formation of the

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69 monoadduct 112j Attempts to stimulate cycli zation by raising the temperature of the reaction led only to decomposition. In contrast, catechol (odihydroxybenzene) gave the cyclic diether, 115a, resulting from consecutive nucleophilic substitution of F8 by the orthophenolate anions even when 2 equivalents of catechol in the presence of 4.4 equivalents of NaH w ere used, only monoadduct was formed. Compound 115b and 115c were obt ained respectively when 4nitro catechol and 1,2benzenedithiol were used as nucleophiles. UV spectra of these compounds were displayed in Figure 37. L ikewise, reactions of the primary and secondary bis amines, 1,2diaminoethane and 1,2di(ethylamino)ethane, also resulted in formation of the respective cyclic disubstituted products 116a and 11 6b. These two compounds were bot h red in color, with their uv bands extending past 500 nm (Figure 38). Figure 36 Reaction of F8 with bidentate nucleophiles

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70 Table 32 Reaction of bidentate nucleophiles with F8 in THF at RT Bidentate Nucleophile Equivalents Reaction Time hr Produ ct No. and Yield (%) Color HOCH 2 CH 2 OH 1.1 (excess NaH) 48 112j (50) White NH2CH2CH2NHCH2Ph 2.2 24 112k (58) Yellow 1,2 dihydroxybenzene 1.1 (excess NaH) 48 115a (78) Lt. yellow 1,2 dihydroxy 4 nitrobenzene 1.1 (excess NaH) 48 115b (56) Lt. yellow 1,2 benz ene dithiol 1.1 (excess NaH) 18 115c (86) Brown NH 2 CH 2 CH 2 NH 2 2.2 18 116a (70) Red EtNHCH 2 CH 2 NHEt 2.2 18 116b (62) Red Figure 37 UV spectra of F8 adducts with benzene1,2diols and 1,2bis thiol Figure 38 UV spectra of F8 bisamine adducts

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71 3.3 Discussion Although all of the reactions of F8 with nucleophiles can be understood within the context of the conventional SNAr addition elimination mechanism involving formation of a Meisenheimer (carbanion) intermediate, because of the extreme electron deficiency of the F8 substrate and the obvious electrontransfer ability of many of the nucleophiles in Table 31, it was considered prudent to also consider the possibility that the reactions might proceed via an electrontransfer, free radical chain SRN1 mechanism. In pursuit of evidence regarding this issue, the reduction potential of F8 was determined via cyclic voltammetry, and ESR studies were carried out to determine whether the F8 radical anion might be detected, either electrochemically or during the course of any of the reactions of F8 with the various nucleophiles. Electrochemistry Electrochemical characterization of F8 was performed by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) in acetonitrile with 0. 1 M tetrabutylammonium hexafluorophosphate (Bu4NPF6) as a supporting electrolyte. The cyclic voltammogram of F8 shows an irreversible reduction wave with a peak at 1.24 V (vs. SCE) (Figure 39). The voltammogram of F8 shows anodic current in the revers e scan, peaked at 0.80 V (vs. SCE), corresponding to the oxidation of reduced species. In addition, no change in the voltammogram was observed when scanning cycles were repeated 10 times, which suggests the chemically reversible nature of the redox proces s. The results suggest probable delocalization of the charge through the stacked system of F8 stabilizing the intermediate radical anion species.

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72 Figure 3 9 Cyclic voltammogram (CV) of F8 Figure 3 10 Differential Pulse Voltammogram (DPV) of F8 Because of the electrochemically irreversible nature of the redox process, the DPV tec hnique was utilized to determine the reduction potential of F8. The DPV voltammogram shows a reduction peak at 1.12 V (vs SCE) (Figure 3 10). Although the presence of a possible second reduction wave was observed, the results were inconclusive due to over lapping solvent reduction waves. The reduction potential of F8 in acetonitrile ( 1.12V vs SCE) is virtually the same as those of nitrobenzene ( 1.14V) and p fluoronitrobenzene ( 1.13V),82 and more negative than that of 4nitro AF4 (the

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73 nitro derivative of the bridgefluorinated [2.2]paracyclophane, AF4) ( 0.86V), but more positive than that of hexafluorobenzene ( 2.2V).83 Halonitroaromatics generally do not undergo substitution by the free radical chain SRN1 mechanism, mainly because the intermediat e nitrostabilized aromatic radical anions appear to be too stable to allow dissociation of halide to form the propagating aryl radical in a kinetically competitive manner.84,85 Moreover, fluoride has proved to be by far the worst halide leaving group for an SRN1 reaction.86,87 Thus, it seems unlikely that F8, which has a similarly stabilized radical anion and with only fluoride leaving groups, would participate in a productive SRN1 reaction. An attempt to directly observe the F8 radical anion by EPR under condi tions of electrochemical generation failed, although the F8 was destroyed by the potential; nor could this radical anion be detected in situ, during the reaction of F8 with PhS-Na+ i n THF. Electron transfer obviously was occurring during the electrochemi cal experiment; thus the lack of an observable EPR spectrum indicates that the intermediate radical anion (and any other radical species that are formed subsequently) must have been destroyed too rapidly to be observed. All that one can conclude by the la ck of an EPR signal during the chemical reactions is that if the reaction proceeds via an SET (single electron transfer) process, any radical anion/radical intermediates must be too short lived to be observed in the experiment. The fate of the F8 radical anion was determined by subjecting F8 to exhaustive electrochemical reduction in acetonitrile, wherein the products that were observed exhibited only alkyl hydrogen incorporation. No aromatic hydrogen was observed in the NMR spectrum of the isolated product mixture. This means that if and when F8s

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74 radical anion is formed, it prefers kinetically to lose fluoride from its bridges, rather than from its aromatic rings. Again, this result appears to preclude involvement of an SRN1 mechanism in the reac tion of F8 with nucleophiles. Additional mechanistic experiments The intervention of any free radical chain mechanism was additionally tested by an experiment in which the reaction of pyrrolidine with F8 was carried out in the presence of one equivalent of free radical trap, TEMPO. The reaction was not inhibited and proceeded to in a normal manner. This result again speaks clearly against involvement of a free radical chain process. Lastly, the involvement of a FRC process in the reaction of F8 with m ethoxide can be specifically ruled out by earlier work by Bunnett88 and Saveant,89 which indicated that methoxides preferred reaction with aryl radicals is hydrogen atom abstraction to form the CH2Oradical anion. No such reductive reaction was observed in any of our reactions. All of these results lead one to conclude that the reactions of F8 with nucleophiles cannot be proceeding via the free radical chain SRN1 mechanism, and that the most probable mechanism for these reactions is the SNAr mechanism proceeding via its usual delocalized (Meisenheimer) carbanion intermediate. One cannot completely rule out electron transfer or at least formation of a charge transfer complex as the initial step of the nucleophilic substitution mechanism, since nonradical chain SET processes, where an intermediate charge transfer complex of radical anion and radical collapse within the solvent cage to form the Meisenheimer complex have been proposed previously.90

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75 3. 4 Synthetic Conclusion The aromatic rings of perfluoro[2.2]paracyclophane are exceptionally receptive to nucleophilic substitution, and all of the observations related to F8s reactivity and regiochemistry of reactions wi th the various nucleophiles that have been presented and discussed in this chapter can be readily rationalized within the framework of the SNAr mechanism. 3. 5 Characterization 102.8, 132.4 ppm )80 for its eight equivalent bridge fluorines and eight equivalent aromatic fluorines in the 19F NMR spectrum due to its symmetric nature. When a single substituent is introduced into one of the rings, the symmetry is destroyed, and all fifteen fl uorines become nonequivalent. F8 derivatives display a multitude of 19F -19F couplings, ranging from ca 250 Hz for the geminal coupling to couplings smaller than 3 Hz, which are visible only when the line is not broaden by other small couplings. Couplings over 3 Hz, were identified in the DQF COSY spectrum, were confirmed and measured in selective decoupling experiments, that were refined through simulation in gNMR The experimental and simulated spectrum for compound 112d are given in Figure 3 11. Chemic al shifts and coupling constants are given in Table 3 3 The largest couplings only were used for the assignment of the fluorine signals. It has previously been demonstrated that in fluoroAF4s a bridge fluorine couples with a large coupling constant (2030 Hz) with the aromatic fluorine ortho and syn and with a somehow smaller constant (2010 Hz) with the aromatic fluorine which is pseudogem to the fluorine ortho and syn .91 The other large couplings us ed for the assignment were

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76 the ortho coupling of the aromatic fluorines, ca 20 Hz, significantly larger than the meta or para couplings, ca 6 10 Hz. The steps of the assignment procedure are presented in Figure 3 12 : a ) the pairs of geminal fluorines were identified by a large coupling, ca 250 Hz. b ) cou plings larger than 50 Hz identified the aromatic fluorines ( a9, a14, a15) ortho and syn to some of the bridge fluorines ( a8, a7 and a6, correspondingly). c ) couplings of 1040 Hz of these later bridge fluorines identified the aromatic fluorines ( a13, a10 a nd a11) pseudogem to the their ortho and syn partners. d ) other couplings larger than 20 Hz of these later aromatic fluorines ( a13, a10 and a11) identified the bridge protons ortho and syn to them ( a3, a2 and a4, correspondingly), which established the identity and relative orientation of the fluorines in a tetrafluoroethylene unit. In most cases, this assignment can be confirmed by couplings of 810 Hz between the bridge fluorines which are vicinal and syn The couplings with aromatic fluorines of the bri dge fluorines in the tetrafluoroethylene unit a2, a3, a7, a8 displays a diagonal pattern, i.e. the bridge fluorines displaying couplings over 50 Hz with the ortho and syn and couplings over 10 Hz with the fluorines pseudogem to the ones ortho and syn a re vicinal and anti This diagonal pattern can be applied to assign a12 as ortho and syn to a1, since a12 displays couplings with comparable constants with both a1 and a5. The position of a12 can also be established later on, based on the ortho coupling of the aromatic fluorines. e ) just one ortho coupling of the aromatic fluorines is necessary at this point to join the two half molecules determined in step d The other two ortho couplings confirm the whole assignments and determine/confirm the position of the aromatic fluorines which display comparable couplings with two bridge ones, like a12.

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77 -98.0 -98.5 -99.0 -99.5 -100.0 a1 a2 a3 a4 -103.5 -104.0 -104.5 -105.0 -105.5 -106.0 -106.5 a5 a6 a7 a8 -110.0 a9 -121.5 -122.0 a10 -129.0 -129.5 a11, a12 -132.0 a13 -134.5 -135.0 a14 a15 -100.0 -105.0 -110.0 -115.0 -120.0 -125.0 -130.0 -135.0 Figure 311 19F spectrum of compound 1 experimental (top) and simulated (bottom) Table 33 Chemical shifts (ppm) and coupling constants (Hz) in the 19F spectrum of compound 1 12d J an a1 J an a2 J an a3 J an a4 J an a5 J an a6 J an a7 J an a8 J an a9 Jana10 Jana11 Jana12 Jana13 Jana14 a1 98.31 a2 98.91 0.0 a3 99.88 0.0 0.0 a4 99.98 0.0 0.0 0.0 a5 103.83 12.0 0.0 0.0 249. 8 a6 105.07 250. 7 0.0 0.0 8.0 0.0 a7 105.33 0.0 12.0 252. 2 0.0 0.0 0.0 a8 106.15 0.0 252. 0 10.0 0.0 0.0 0.0 0.0 a9 109.93 0.0 2.0 2.0 0.0 0.0 0.0 0.0 74.2 a10 121.72 0.0 29.8 0.0 0.0 3.5 0.0 11.5 0.0 0.0 a11 129.14 0.0 0.0 0.0 25.6 0.0 28.1 0.0 0.0 9.0 22.0 a12 129.24 24.3 0.0 0.0 0.0 21.0 0.0 0.0 0.0 0.0 0.0 0.0 a13 131.79 0.0 0.0 33.2 0.0 0.0 4.0 0.0 13.0 3.0 0.0 0.0 20.0 a14 134.61 0.0 0.0 0.0 0.0 0.0 0.0 67.4 0.0 0.0 14.7 0.0 6.0 6.0 a15 135.06 2.0 0.0 0.0 0.0 0.0 69.7 0.0 0.0 0.0 0.0 10.0 8.0 8.0 20.0

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78 Figure 3 12 Step by step assignment of the 19F signals in compound 1 12d The complete assignments are given on the structure in Figure 3 12f. Alternately, the positions of the fluor ines in the representation of Fig. 312e are given in Figure 3 12g. The 19F spectrum of 112d (Figure 3 11) displays a pattern for the bridge fluorines which was seen in all of the compounds 112a112k, namely there are four more shielded and four more deshi elded fluorines, and each of the fluorines in the deshielded region has a geminal partner in the shielded region. The most shielded bridge fluorines ( a5a8) are the ones which display the largest coupling constants with the aromatic fluorine over four bonds and syn 4Jbridgearom These fluorines are on one side of the

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79 upper deck of the PCP (e.g. F1A and F10A in 1 12d) and on the opposite side of the lower deck (F9S in 1 12d), suggesting a skewed geometry in which the upper deck moves towards or away from the substituent. In a move towards the substituent, F1S, F2A, F9A and F10S are drawn closer to both the aromatic fluorine four bonds away and syn and to the aromatic fluorine on the remote deck five bonds away and syn The throughspace couplings between the bridge fluorine and these aromatic fluorines are expected to become larger. This is the case of compounds 112a and 112b. In compounds 1 12d and 112g, F9S, F10A and F1A display larger couplings both over four bounds with the aromatic fluorines syn and ov er five bonds with the aromatic fluorines on the opposite deck and syn in agreement with a move of the upper deck away from the substituent. This is to be expected, considering the larger size of the substituents in 1 12d and 112d, compared to 112a and 112b Smaller couplings, between 2 and 5 Hz, have been noticed in the DQFCOSY spectra, and have then been optimized through simulation. The longrange coupling constants between aromatic and bridge fluorines support also the skewed geometry, if one assumes t hat the angular dependence of the 19F -19F couplings parallels the one of the 1H -1H couplings. The bridge fluorine which is further away from the plane of the aromatic ring displays a small (ca. 5 Hz) coupling with the aromatic fluorine four bonds away and anti. This is similar to the cisoid allylic coupling, which reaches a maximum when the C H bond of the allyl proton is perpendicular to the plane of the double bond.92. The bridge fluorine which is closer to the plane of the aromatic ring and displays a co upling over 50 Hz with the aromatic fluorine ortho and syn also displays a coupling over five bonds with the aromatic fluorine meta and anti Similar couplings

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80 between the benzylic proton in the plane of the aromatic ring and the proton meta and anti have been reported.93 We have reported for the 4fluoroAF4 a coupling of F4 and F9A, which agrees with a skewed geometry in which the upper deck is displaced towards the fluorine substituent, geometry indicated by the larger couplings F4F1S and F4F2S.92 Mor e literature on the parallel displacement of the aromatic rings in Journal of Organic Chemistry 2007, 2469.94 Other couplings, in the range of 412 Hz, have been detected between vicinal and syn bridge fluorines. They are similar to the couplings seen in m onoand di fluoro AF4s, and are expected to be larger than the couplings between bridge fluorines vicinal and anti, based on the Karplus relationship, which was demonstrated to hold for fluorines too. Table 3 4 NMR data for the aliphatic fluorines in compound 1 12d in benzened6 Position (ppm) T1 (s) 2J (Hz) 3J (Hz) 4 Jsyn (Hz) 5 Jsyn (Hz) other n J (Hz) 1S 98.31 0.58 251 12 (F1S F2S) 8 (F1A F2A) 24 <3 (F15) 1A 105.07 0.69 67 28 <3 (F12) 2S 103.83 0.80 250 21 <3 (F7) 2A 99.98 0.64 26 0 9S 106.15 0.75 252 12 (F9A F10A) 10 (F9S F10S) 74 13 <3 (F8) 9A 98.91 0.70 30 0 <3 (F5) 10S 99.88 0.73 252 33 <3 <3 (F16) 10A 105.33 0.83 67 12 <3 (F13) Table 3 5 NMR data for the aromatic fluorines in compound 1 12d in benzened6 Position (ppm ) T1 (s) 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 5 109.93 0.30 0 9 3 7 121.72 0.22 22 0 14 8 129.16 0.25 a 9 10 12 131.79 0.27 20 6 8 10 13 129.19 0.25 a 6 8 15 135.06 0.20 20 6 8 10 16 134.61 0.22 6 8 14 a values measured as an average for two different fluorines, because of signal overlap.

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81 Table 3 6 NMR data for the aliphatic fluorines in compound 112a in acetoned6 Position (ppm) C6D62J (Hz) 3J (Hz) 4 J syn (Hz) 5 J syn (Hz) other n J (Hz) 1S 101.16 102.27 249 11 (F1A F2A) 63 3 (F16) 1A 98.33 99.06 28 0 3 (F13) 2S 97.96 98.92 244 0 3 (F8) 2A 103.56 103.56 77 19 3 (F5) 9S 99.47 100.14 249 11 (F9A F10A) 8 (F9S F10S) 30 0 3 (F7) 9A 104.85 104.79 69 14 10S 105.03 105.04 252 67 17 3 (F15) 10A 99.92 100.29 31 0 3 (F12) Table 3 7 NMR data for the aromatic fluorines in compound 112 a in acetoned6 Position (ppm) C6D6 3 J ortho (Hz) 4 J meta (Hz ) 5Jpara (Hz) 7 J pseudogem (Hz) 5 130.26 131.90 10 10 15 7 156.64 148.56 20 10 10 8 141.28 138.67 9 10 12 136.74 136.48 20 8 5 15 13 134.49 134.91 10 8 15 133.14 132.12 20 10 5 10 16 135.90 133.96 8 8 10 Table 3 8 NMR dat a for the aliphatic fluorines in compound 112b in benzened6 Position (ppm) T1 (s) 2J (Hz) 3J (Hz) 4 J syn (Hz) 5 J syn (Hz) other n J (Hz) 1S 104.39 1.58 b 249 5 (F1S F2S) 12 (F1A F2A) 62 5 (F16) 1A 99.14 1.45 30 0 <3 (F13) 2S 101.09 1.52 249 0 5 (F8) 2A 104.40 1.58b 76 15 4 (F5) 9S 100.15 1.49 a 251 10 (9S 10S) 11 (F10A F9A) 33 0 <3 (F7) 9A 105.06 1.66 c 66 15 10S 105.16 1.66 c 252 66 17 <3 (F15) 10A 100.08 1.49 a 32 0 <3 (F12) a, b, c values measured as an average for two different fluorines, because of signal overlap. Table 3 9 NMR data for the aromatic fluorines in compound 112b in benzened6 Position (ppm) T1 (s) 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 5 126.68 0.87 6 7 12 7 136.94 0.73 20 6 9 8 135.84 0.72 7 7 12 136.33 0.73 21 7 10 12

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82 Table 3 9. Continued 13 133.42 0.69 7 12 15 132.00 0.75 20 7 10 7 16 132.66 0.77 7 12 9 Table 3 10 NMR data for the aliphatic fluorines in compound 112g in benzened6 Position (ppm) T1 (s) a 2J (Hz) 3J (Hz) 4 J syn (Hz) 5 J syn (Hz) other n J (Hz) 1S 98.69 1.41 252 4 (F1S F2A) 8 (F1S F2S) 22 4 (F15) 1A 105.21 1.49 69 36 4 (F12) 2S 102.98 1.71 251 37 5 (F7) 2A 97.84 1.45 20 5 9S 105.21 1.51 251 10 (F9A F10A) 10 (F9S F10S) 73 10 3 (F7) 4 (F8) 9A 99.61 1.65 43 5 5 (F5) 10S 100.92 1.69 251 41 5 5 (F16) 10A 105.40 1.80 59 10 2 (F13) a In benzened6 : a cetoned6, 1:1. Table 3 11 NMR data for the aromatic fluorines in compound 112g in benzened6 Position (ppm) T1 (s) a 3 J ortho (Hz) 4 J meta (Hz) 5Jpara (Hz) 7Jpseudogem (Hz) 5 129.24 1.03 6 10 10 7 144.26 1.12 22 6 10 8 130.60 0.97 10 10 12 133.54 0.91 20 0 10 10 13 131.92 0.94 5 10 15 135.14 0.76 20 5 10 10 16 134.80 0.83 0 10 10 a In benzened6 : acetoned6, 1:1. Table 3 12 NMR data for the aliphatic fluorines in compound 116b in benzened6 Position (ppm) T1 (s) 2 J (Hz) 3 J (Hz) 1S 98.10 0.87 251 9 (F1S F2S) 3 (F1A F2A) 1A 105.65 0.94 2S 104.31 0.92 248 2A 94.81 0. 79 Table 3 1 3 NMR data for the aromatic fluorines in compound 116b in benzened6 Position (ppm) T1 (s) 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 8 139.26 0.61 20 10 10 22 5 (F2S) 13 133.35 0. 52 20 6 10 10 12 4 (F1A) 15 136.17 0.44 20 6 10 10 68 0

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83 3.6 Experimental S ection All chemicals were purchased from SigmaAldrich and used directly without further purification. All reactions were done under a nitrogen atmosphere. Column chromatography was carried out on silica gel. All melting points are uncorrected. 1H and 19F NMR were recorded in CDCl3 at 300 MHz and 282MHz, respectively (unless designated otherwise). Because of the perfluoro nature of the compounds synthesized in this chapter wh ich results in multiple one, two and threebond FC couplings for each signal with little difference in chemical shift, the respective 13C spectra do not provide useful observable structural information. Perfluoro[2.2]paracyclophan4 ol ( 112a) : To a sol ution of sodium hydroxide (128 mg, 3.2 mmol) in water (0.5 mL) was added tetrahydrofuran (THF) (8 mL) and perfluoro[2.2]paracyclophane (F8) (198.4 mg, 0.4 mmol). The reaction mixture was homogenous and stirred at room temperature (RT) for 44 h, and then it was concentrated to dryness. The residue was purified by column chromatography (ethyl acetate) to give 112a (196 mg, 99.2%) as a yellow solid: m p 192193 oC ; 1H NMR (acetoned6) 3.75 (br. S, 1H); 19F NMR (acetoned6) 98.15 (d, J = 255.0 Hz, 1F), 99.36 (ddm, J1 = 255.2 Hz, J2 = 25.1 Hz, 1F), 100.79 (dd, J1 = 247.0 Hz, J2 = 27.1 Hz, 1F), 101.27 (ddd, J1 = 251.0 Hz, J2 = 26.8 Hz, J3 = 10.4 Hz, 1F), 102.24 ( J1 = 249.0 Hz, J2 = 62.3 Hz, 1F), 105.20 (dddd, J1 = 244.8 Hz, J2 = 72.7 Hz, J3 = 16.6 Hz, J4 = 10.4 Hz, 1F), 106.54 (dddd, J1 = 247.0 Hz, J2 = 68.5 Hz, J3 = 16.6 Hz, J4 = 10.2 Hz, 1F), 106.82 (dddd, J1 = 251.0 Hz, J2 = 68.5 Hz, J3 = 18.6 Hz, J4 = 6.5 Hz, 1F), 131.96 (m, 1F), 134.80 (d, J = 22.1 Hz, 1F), 136.44 (m, 1F), 137.98 (d, J = 8.7 H z, 1F), 138.82 (d, J = 72.7 Hz, 1F), 144.13 (d, J = 78.9 Hz, 1F), 162.58 (br. S, 1F); HRMS (CI), Calcd for C16H1F15O, 493.9788; found, 493.9774.

PAGE 84

84 4 Methoxyperfluoro[2.2]paracyclophane (112b) and 4,16dimethoxy perfluoro[2.2]paracyclophane (113) : A solu tion of sodium methoxide (43.2 mg, 0.8 mmol) and F8 (198.4 mg, 0.4 mmol) in anhydrous THF (12 mL) was stirred at RT for 48 h, and the mixture then concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give 112b (100 mg, 49%) as a white solid and 113 (30 mg, 14%) as a white solid. 112b: mp 121122 oC; 1H NMR, 3.25 (d, J = 1.2 Hz, 3H); 19F NMR, 99.48 (ddd, J1 = 249.4 Hz, J2 = 29.7 Hz, J3 = 12.2 Hz, 1F), 100.04 (ddd, J1 = 251.1 Hz, J2 = 32.0 Hz, J3 = 12.0 Hz, 1F ), 101.45 (ddd, J1 = 256.4 Hz, J2 = 32.0 Hz, J3 = 11.7 Hz, 1F), 101.39 (dd, J1 = 248.2 Hz, J2 = 4.8 Hz, 1F), 104.68 (dd, J1 = 248.7 Hz, J2 = 59.4 Hz, 1F), 104.69 (dd, J1 = 248.5 Hz, J2 = 59.4 Hz, 1F), 105.36 (dddd, J1 = 251.3 Hz, J2 = 74.6 Hz, J3 = 14.8 Hz, J4 = 11.3 Hz, 1F), 105.46 (dddd, J1 = 252.3 Hz, J2 = 65.8 Hz, J3 = 15.4 Hz, J4 = 10.4 Hz, 1F), 126.98 (ddd, J1 = 19.5 Hz, J2 = 16.5 Hz, J3 = 3.6 Hz, 1F), 132.30 (ddd, J1 = 29.9 Hz, J2 = 15.8 Hz, J3 = 2.8 Hz, 1F), 132.96 (dddd, J1 = 18.5 Hz J2 = 21.7 Hz, J3 = 15.4 Hz, J4 = 4.1Hz, 1F), 133.68 (m, 1F), 136.13, (m, 1F), 136.59 (m, 1F), 137.2 (m, 1F); Anal. Calcd for C17H3F15O: C 40.18, H 0.60; Found: C 40.47, H 0.49. 113: 1H NMR, 3.85 (d, J = 1.2 Hz, 6H); 19F NMR, 99.08 (ddd, J1 = 2 44.8 Hz, J2 = 31.0 Hz, J3 = 14.7 Hz, 2F), 100.89 (d, J = 251.0 Hz, 2F ), 105.27 (ddd, J1 = 246.8 Hz, J2 = 64.3 Hz, J3 = 6.2 Hz, 2F), 105.49 (m, 2F), 127.06 (m, 2F), 135.87 (dd, J1 = 66.6 Hz, J2 = 20.6 Hz, 2F); Anal. Calcd for C18H6F15O2: C 41.56, H 1. 16; Found: C 41.77, H 1.00. 4,7bisPhenylthioperfluoro[2.2]paracyclophane (114) : A mixture of sodium benzenethioxide (29.4 mg, 0.2 mmol) and perfluoro[2.2]paracyclophane ( 99.2 mg, 0.2 mmol) in anhydrous tetrahydrofuran (4 mL) was stirred at room temper ature for 48 h.

PAGE 85

85 The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to obtain 4,7bis phenylthioperfluoro[2.2]paracyclophane (40 mg, yield: 29.6% based on sodium thio pheno late ) as a y ellow solid. m p 122124 oC; 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl3) 100.24 (dd, J1 = 245.4 Hz, J2 = 11.5 Hz, 2F), 100.72 (dd, J1 = 250.5 Hz, J2 = 42.6 Hz, 2F), 100.98 (d, J = 63.0 Hz, 2F), 102.22 (ddd, J1 = 245.2 Hz, J2 = 66.3 Hz, J3 = 6.4 Hz, 2F), 103.33 (dddd, J1 = 251. 7 Hz, J2 = 54.9 Hz, J3 = 15 Hz, J4 = 6.4 Hz, 2F), 128.49 (dd, J1 = 42.7 Hz, J2 = 10.5 Hz, 2F), 134.26 (dddd, J1 = 54.4 Hz, J2 = 19.8 Hz, J3 = 6.4 Hz, J4 = 4.0 Hz, 2F). Anal. Calcd for C28H10F14S2 C 49.71, H 1.49. Found: C 49.84, H 1.64. Note: F8 : PhSN a = 1:1. 4 (4 Fluorophenoxy) perfluoro[2.2]paracyclophane (112c) : A mixture of 4fluorophenol (28 mg, 0.25 mmol) in anhydrous THF (10 mL) was added 60% sodium hydride (11 mg, 0.275 mmol). The resulting reaction mixture was stirred for 30 minutes, after wh ich F8 (124 mg, 0.25 mmol) was added. The mixture was stirred at RT overnight, and then it was concentrated to dryness. The residue was purified by column chromatography (hexanes) to give 112c (110 mg, 76.9%) as white solid: mp 9899 oC ; 1 2H), 6.81 (m, 2H); 1999.46 (ddd, J1 = 249.0 Hz, J2 = 29.1 Hz, J3 = 10.4 Hz, 1F), 100.39 (ddd, J1 = 253.2 Hz, J2 = 31.0 Hz, J3 = 10.2 Hz, 1F), 100.59 (ddd, J1 = 251.0 Hz, J2 = 29.1 Hz, J3 = 10.4 Hz, 1F), 100,98 (d, J = 251.0Hz, 1F), 104.54 (dd, J1 = 244.8 Hz, J2 = 62.3 Hz, 1F), 104.87 (ddt, J1 = 249.0 Hz, J2 = 72.5 Hz, J3 = 14.7 Hz, 1F), 105.40 (ddt, J1 = 251.0 Hz, J2 = 62.3 Hz, J3 = 14.4 Hz, 2F), 118.98 (m, 1F), 122.02 (m, 1F), 131.74 (m, 2F), 132.32 (dd, J1 = 55.8 Hz, J2 = 10.4

PAGE 86

86 Hz, 1F), 133.19 (dt, J1 = 64.3 Hz, J2 = 16.6 Hz, 1F), 134.59 (m, 1F), 135.27 (m, 1F); Anal. Calcd for C22H4F16O C 44.92, H 0.69. Found: C 45.24, H 0.72. 4 ( Bis( carbomethoxyl ) methyl) perfluoro[2.2]paracyclophane (1d) : To a solution of dimethyl malonate (161.7 mg, 1.2 mmol) in anhydrous THF (10 mL) was added 60% sodium hydride (48 mg, 1.2 mmol) and the mixture stirred at RT for 10 minutes. Then F8 (148.8 mg, 0.3 mmol) was added and the reaction mixture stirred at RT for 2 days, after which it was concentrated to dryness. The residue was purified by column chromatography (chloroform) to give 112d (80 mg, 73% based on 60% conversion ) as a white solid: mp 148149 oC ; 1 (s, 3H); 1998.72 (ddd, J1 = 251.0 Hz, J2 = 24.8 Hz, J3 = 12.4 Hz, 1F), 99.31 (ddd, J1 = 251.0 Hz, J2 = 20.8 Hz, J3 = 8.2 Hz, 1F ), 100.01 (ddd, J1 = 249.0 Hz, J2 = 24.8 Hz, J3 = 8.2 Hz, 1F), 100.14 (ddd, J1 = 248.7 Hz, J2 = 33.0 Hz, J3 = 8.2 Hz, 1F), 104.60 (dt, J1 = 251.0 Hz, J2 = 16.6 Hz, 1F), 105.41 (dddd, J1 = 251.0 Hz, J2 = 68.5 Hz, J3 = 35.2 Hz, J4 = 8.4 Hz, 1F), 105.73 (ddt, J1 = 257.2 Hz, J2 = 68.5 Hz, J3 = 12.4 Hz, 1F), 106.61 (ddt, J1 = 252.9 Hz, J2 = 74.5 Hz, J3 = 12.4 Hz, 109.52 (dd, J1 = 72.5 Hz, J2 = 10.4 Hz, 1F), 122.07 (m, 1F), 129.04 (m, 2F), 131.83 (m, 1F), 134.13 (m, 1F), 134.54 (m, 1F); Anal. Calcd for C21H7F15O4 C 41.47, H 1.16. Found: C 41.76, H 1.06. 4 tert Butyl perf luoro[2.2]paracyclophane (112e) : To a mixture of tert butyl lithium (0.32 mL, 1.7 M, 0.55 mmol) in anhydrous THF (10 mL) was added F8 (248 mg, 0.5 mmol). The reaction mixture was stirred at RT overnight, after which it was concentrated to dryness. The resi due was purified by column chromatography (hexanes) to give 112e (140 mg, 54.4%) as a white solid: mp 104105 oC ; 1H NMR,

PAGE 87

87 1.35 (m, 9H); 19 97.12 (d, J = 246.8 Hz, 1F), 99.55 (ddd, J1 = 251.0 Hz, J2 = 29.0 Hz, J3 = 10.4 Hz, 1F), 100.42 (ddd, J1 = 253.0 Hz, J2 = 24.8 Hz, J3 = 10.2 Hz, 1F), 100.53 (ddd, J1 = 248.7 Hz, J2 = 24.8 Hz, J3 = 8.2 Hz, 1F), 103.05 (dd, J1 = 248.7 Hz, J2 = 60.1 Hz, 1F), 104.19 (dddd, J1 = 251.3 Hz, J2 = 76.6 Hz, J3 = 16.9 Hz, J4 = 8.2 Hz, 1F), 105.59 (dddd, J1 = 253 Hz, J2 = 66.5 Hz, J3 = 24.8 Hz, J4 = 11.5 Hz, 2F), 117.49 (m, 1F), 131.06 (ddd, J1 = 60.3 Hz, J2 = 16.6 Hz, J3 = 6.5 Hz, 1F), 132.89 (m, 2F), 136.21 (m, 2F), 137.09 (m, 1F); Anal. Calcd for C20H9F15 C 44.96, H 1.70. Found: C 44.62, H 1.59. 4 (N,N Diethylamino)perfluoro[2.2]paracyclophane (112f) : To a solution of diethylamine (80 mg, 1.1 mmol) in anhydrous THF (8 mL) was added F8 (124 mg, 0.25 mmol). The reaction mixture was stirred at RT for 20 h and then concentrated to dryness. The residue was purified by column chromatography (hexanes) to give 112f (125 mg, 91.2%) as a yellow solid: mp 121122 oC ; 1H NMR, 3.47 (m, 2H ), 3.24 (m, 2H), 1.12 (t, J = 6.9 Hz, 6H); 19F NMR, 97.78 (dd, J1 = 249.0 Hz, J2 = 20.6 Hz, 1F), 98.66 (ddd, J1 = 251.0 Hz, J2 = 26.8 Hz, J3 = 10.2 Hz, 1F), 99.48 (ddd, J1 = 236.6 Hz, J2 = 39.5 Hz, J3 = 10.4 Hz, 1F), 100.37 (ddd, J1 = 238.6 Hz, J2 = 35.3 Hz, J3 = 10.4 Hz, 1F), 104.60107.20 (m, 4F), 127.75 (d, J = 74.7 Hz, 1F), 128.91 (m, 1F), 130.81 (q, J = 24.8 Hz, 1F), 132.53 (t, J = 24.8 Hz, 1F), 135.17 (m, 2F), 138.69 (m, 1F); Anal. Calcd for C20H10F15N C 43.73, H 1.84, N 2.55. Found: C 43.82, H 1.59, N 2.49. 4 (Pyrrolidin 1 yl)perfluoro[2.2]paracyclophane (112 g) : To a solution of pyrrolidine (39 mg, 0.55 mmol) in anhydrous THF (8 mL) was added F8 (124 mg, 0.25 mmol). The resulting mixture was stirred at RT for 24 h, and then concentrat ed to dryness. The residue was purified by column chromatography (hexanes) to give 112g

PAGE 88

88 (115 mg, 83.9%) as a yellow solid: mp 120122 oC ; 1 2H), 2.00 (m, 2H), 1.87 (m, 2H); 19 98.48 (dd, J1 = 251.0 Hz, J2 = 18.6 Hz, 1F), 99.17 (dd, J1 = 249.0 Hz, J2 = 20.6 Hz, 1F), 100.09 (ddt, J1 = 251.0 Hz, J2 = 37.5 Hz, J3 = 4.2 Hz, 1F), 101.25 (dd, J1 = 257.2 Hz, J2 = 39.2 Hz, 1F), 103.59 (ddt, J1 = 246.8 Hz, J2 = 37.5 Hz, J3 = 4.0 Hz, 1F), 105.00106.70 (m, 3F), 129.40 (d, J = 72.5 Hz, 1F), 130.63 (m, 1F), 131.33 (q, J = 27.1 Hz, 1F), 133.01 (m, 1F), 134.83 (m, 2F), 144.30 (m, 1F); Anal. Calcd for C20H8F15N: C 43.89, H 1.47, N 2.56; Found: C 43.53, H 1.24, N 2.42. 4 (N Benzyl N methylamino)perfluoro[2.2]paracyclophane (112h) : To a solution of N benzyl N methylamine (66 mg, 0.55 mmol) in anhydrous THF (8 mL) was added F8 (124 mg, 0.25 mmol). The resulting mixture was stirred at RT for 24 h and then concentrated to dryness. The residue was purified by column chromatography (hexanes) to give 112h (101 mg, 67.8%) as a yellow solid: mp 105107 oC ; 1 7.31 (m, 3H), 7.18 (d, J = 6.9 Hz, 2H), 4.42 (s, 2H), 2.92 (d, J = 2.7 Hz, 3H); 19 97.80101.00 (m, 4F), 104.80107.20 (m, 4F), 127.49 (d, J = 76.9 Hz, 1F), 128.62 (m, 1F), 130.45 (q, J = 22.8 Hz, 1F), 132.32 (m, 1F), 134.91 (m, 2F), 138.42 (m, 1F); Anal. Calcd for C24H10F15N C 48.26, H 1.69, N 2.34. Found: C 47.88, H 1.45, N 2.12. 4 ( N,NDimethylamino)perfluoro[2.2]paracyclophane (112i): To a solution of dimethylamine (62 mg, 40% aqueous solution, 0.55 mmol) in anhydrous THF (8 mL) was added F8 (124 mg, 0.25 mmol). The reaction mixture was stirred at RT for 1 h and then concentrated to dryness. The residue was purified by column chromatography (hexanes) to give 112i (91.2 mg, 70%) as a yellow solid: mp 150152 oC ; 1H NMR,

PAGE 89

89 3.04 (s, 6H); 19F NMR, 98.28 (dd, J1 = 251.0 Hz, J2 = 18.6 Hz, 1F), 99.07 (ddd, J1 = 224.2 Hz, J2 = 37,2 Hz, J3 = 10.2 Hz, 1F), 99.92 (dd, J1 = 213.8 Hz, J2 = 10.4 Hz, 1F), 100.67 (ddd, J1 = 211.8 Hz, J2 = 35.3 Hz, J3 = 10.4 Hz, 1F), 104.80107.20 (m, 4F), 128.93 (d, J = 78.7 Hz, 1F), 129.19 (m, 1F), 131.03 (q, J = 22.8 Hz, 1F), 132.53 (t, J = 31.3 Hz, 1F), 135.13 (m, 2F), 140.43 (m, 1F); HRMS (APPI), Calcd for C18H6F15N: 522.0333 (M+H+), Found: 522.0356; Anal. Calcd for C18H6F15N: C 41.4 8, H 1.16, N 2.69; Found: C 43.82, H 1.59, N 2.49. 4 (2 Hydroxyethoxy)perfluoro[2.2]paracyclophane (112j): A mixture of ethylene glycol (31 mg, 0.5 mmol) in anhydrous THF (10 mL) was added 60% sodium hydride (44 mg, 1.1 mmol). The resulting reaction mixtur e was stirred for 30 minutes, after which F8 (248 mg, 0.5 mmol) was added. The mixture was stirred at RT overnight, and then it was concentrated to dryness. The residue was purified by column chromatography (hexanes : methylene chloride = 1:1) to give 112j (130 mg, 50%) as a white solid: mp 106107 oC ; 1H NMR, 4.17 (m, 1H), 4.07 (m, 1H), 3.93 (m, 2H), 1.99 (t, J = 6.3 Hz, 1H); 19F NMR, 99.48 (ddd, J1 = 251.0 Hz, J2 = 29.1 Hz, J3 = 12.4 Hz, 1F), 100.39 (dd, J1 = 249.0 Hz, J2 = 29.0 Hz, 2F ), 101.22 (d, J = 248.7 Hz, 1F), 104.10106.40 (m, 4F), 125.39 (m, 1F), 131.59 (s, 1F), 132.12 (s, 1F), 133.83 (dd, J1 = 62.3 Hz, J2 = 10.4 Hz, 1F), 135.70 (m, 2F), 136.47 (d, J = 66.3 Hz, 1F); Anal. Calcd for C15H5F15O2 C 40.17, H 0.94. Found: C 39.95, H 0.73. 4 (2 Benzylaminoethylamino)perfluoro[2.2]perfluorocy clophane (112k) : To a solution of N benzyl ethylenediamine (82 mg, 0.55 mmol) in anhydrous THF (8 mL) was added F8 (124 mg, 0.25 mmol). The resulting mixture was stirred at RT for 24 h,

PAGE 90

90 and then it was concentrated to dryness. The residue was purified by co lumn chromatography (hexanes) to give 112k (90 mg, 57.5%) as a yellow solid: mp 113114 oC ; 1 1H), 2.92 (m, 2H), 1.59 (br. S, 1H); 19 94.63 (d, J = 254.9 Hz, 1F), 97.8 0 (dd, J1 = 252.9 Hz, J2 = 55.8 Hz, 1F), 98.75 (dd, J1 = 259.2 Hz, J2 = 32.9 Hz, 1F), 99.80102.20 (m, 3F), 104.39 (ddt, J1 = 249.0 Hz, J2 = 64.3 Hz, J3 = 12.4 Hz, 1F), 105.32 (m, 1F), 132.06 (m, 1F), 132.94 (m, 1F), 133.40 (m, 1F), 136.68 (m, 3F), 150.41 (m, 1F); HRMS (APPI), Calcd for C25H13F15N2: 627.0912 (M+H+); Found: 627.0906; Anal. Calcd for C25H13F15N2: C 47.94, H 2.09, N 4.47; Found: C 47.98, H 2.19, N 4.37. Catechol adduct of F8 (115a ) : To a solution of catechol (110 mg, 1 mmol) in anhydrous THF (10 mL) was added 60% sodium hydride (88 mg, 2.2 mmol). The resulting reaction mixture was stirred at room temperature for 10 minutes, after which F8 (248 mg, 0.5 mmol) was added. The mixture was stirred at RT overnight, and then it was concentr ated to dryness. The residue was purified by column chromatography (hexanes) to give the 115a (220 mg, 77.5%) as a light yellow solid: mp 162163 oC ; 1H J1 = 6.6 Hz, J2 = 3.6 Hz, 2H), 6.93 (dd, J1 = 6.6 Hz, J2 = 3.6 Hz, 2H); 1999.62 (d, J = 249.0 Hz, 2F), 100.21 (ddd, J1 = 253.2 Hz, J2 = 24.8 Hz, J3 = 6.2 Hz, 2F ), 103.84 (ddq, J1 = 248.7 Hz, J2 = 74.7 Hz, J3 = 10.4 Hz, 2F) 104.57 (dd, J1 = 252.9 Hz, J2 = 62.3 Hz, 2F), 131.29 (m, 2F), 136.58 (d, J = 62.0 Hz, 2F), 139.24 (d, J = 70.5 Hz, 2F); Anal. Calcd for C22H4F14O2 C 46.66, H 0.71. Found: C 46.35, H 0.51. 4 Nitrocatechol adduct of F8 (115b) : To a solution of 4nit rocatechol (44 mg, 0.275 mmol) in anhydrous THF (10 mL) was added 60% sodium hydride (22 mg, 0.55

PAGE 91

91 mmol). The resulting reaction mixture was stirred at RT for 10 minutes after which F8 (124 mg, 0.25 mmol) was added. The mixture was stirred at RT overnight and then was concentrated to dryness. The residue was purified by column chromatography (hexanes:dichloromethane = 7:3) to give 115b (85 mg, 55.7%) as a slight yellow solid: mp 201202 oC ; 1J1 = 8.7 Hz, J2 = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 7.11 (d, J = 8.7 Hz, 1H); 19100.05 (dd, J1 = 251.0 Hz, J2 = 22.8 Hz, 2F), 100.77 (dd, J1 = 253.2 Hz, J2 = 22.8 Hz, 2F ), 103.21 (ddt, J1 = 251.0 Hz, J2 = 68.5 Hz, J3 = 12.4 Hz, 2F), 104.10 (ddt, J1 = 252.9 Hz, J2 = 6.2 Hz, J3 = 53.9 Hz, 2F), 130.68 (m, 2F), 135.84 (m, 4F); Anal. Calcd for C22H3F14NO4: C 43.23, H 0.49, N 2.29; Found: C 43.57, H 0.41, N 2.31. 1,2Benzenedithiol adduct of F8 (115c) : To a solution of 1,2benzenedithiol (90.6 mg, 0.61 mmol) in anhydrous THF (10 mL) was added 60% sodium hydride (48.9 mg, 1.22 mmol). The resulting reaction mixture was stirred at RT for 10 minutes after which F8 (276 mg, 0.55 mmol) was added. The mixture was stirred at RT overnight and then concentrated to dryness. The residue was purified by column chromatography (hexanes) to obtain the 115c (250 mg, 75.1%) as a yellow solid along with a tetrakis substituted compound (50 mg, 12.8%) as a brownish solid. 115c: mp 170172 oC ; 1H J1 = 6.0 Hz, J2 = 3.3 Hz, 2H), 7.45 (dd, J1 = 6.0 Hz, J2 = 3.3 Hz, 2H); 1994.99(d, J = 244.8, 2F), 98.21 (ddt, J1 = 246.8 Hz, J2 = 54.1 Hz, J3 = 6.2 Hz, 2F), 100.37 (dd, J1 = 253.2 Hz, J2 = 41.5 Hz, 2F ), 104.11 (dd, J1 = 248.7 Hz, J2 = 60.3 Hz, 2F), 124.59 (m, 2F), 131.49 (d, J = 41.4 Hz, 2F), 134.15 (d, J = 53.9 Hz, 2F); Anal. Calcd for C22H4F14S2: C 44.16, H 0.67; Found: C 44.49, H 0.63.

PAGE 92

92 E thylenediamine adduct with F8 (116a) : A mixture of F8 (124 mg, 0.25 mmol) and ethylenediamine (33 mg, 0.55 mmol) was stirred at RT for 16 h, after which the mixture was concentrated to dryness. The residue was purified by column chromatography (CH2Cl2) to obtain the 116a (90 mg, 69.5%) as a red solid: mp 210211 oC ; 119F NMR, 97.06 (dd, J1 = 252.9 Hz, J2 = 10.4 Hz, 2F ), 99.69 (m, 4F), 100.95 (ddd, J1 = 257.2 Hz, J2 = 76.7 Hz, J3 = 8.5 Hz, 2F), 132.87 (m, 2F), 137.73 (m, 2F), 151.85 (d, J = 68.2 Hz, 2F); Anal. Calcd for C18H6F14N2 C 41.88, H 1.17, N 5.43. Found: C 42.12, H 0.89, N 5.36. N, N Diethyl ethylenediamine adduct with F8 ( 116b) : A mixture of F8 (124 m g, 0.25 mmol) and N N diethylethylenediamine (61 mg, 0.55 mmol) was stirred at RT for 16 h, after which the mixture was concentrated to dryness. The residue was purified by column chromatography (hexanes) to give the 116b (120 mg, 62.1%) as a red solid: mp 158 oC (dec) ; 1J = 7.2 Hz, 3H), 1.19 (t, J = 7.2 Hz, 3H); 1995.44 (dd, J1 = 249.0 Hz, J2 = 16.1 Hz, 2F ), 98.67 (dm, J = 250.9 Hz, 2F), 104.84 (dq, J1 = 249.0 Hz, J2 = 10.2 Hz, 2F), 106.32 (ddd, J1 = 253.2 Hz, J2 = 68.5 Hz J3 = 22.6 Hz, 2F), 132.92 (m, 2F), 136.53 (d, J = 66.5 Hz, 2F), 140.07 (m, 2F); Anal. Calcd for C22H10F14N2 C 46.17, H 2.47, N 4.89. Found: C 46.24, H 2.18, N 4.73. Electrochemistry The cyclic voltammetry ( CV) experiments were performed on a Bioan alytical Systems CW50 electrochemical analyzer at a sweep rate of 100 mV/s using a platinum disc working electrode, a platinum wire auxiliary electrode, and a silver wire pseudo reference electrode. At the end of each scan, ferrocene was added as

PAGE 93

93 internal standard and potentials are referenced to the potential of ferrocene/ferrocenium redox couple. The differential pulse voltammetry experiments were performed with the same setup at scan rate of 20 mV/s, pulse amplitude of 50 mV, and pulse period of 200 msec Sample and pulse width were 17 msec and 50 msec respectively. Solutions of samples were prepared in acetonitrile. The supporting electrolyte was 0.10 M tetrabutylammonium hexafluorophosphate (TBAPF6). The experimental potentials obtained vs ferrocene/ferrocenium redox couple were corrected to the SCE standard (correction factor of +0.328 C) Bulk Electrolysis of F8: Bulk electrolysis of F8 was performed on a Bioanalytical systems CV27cyclic voltammograph, using a platinum gauze working electrode, a coil ed platinum wire auxiliary electrode, and a silver wire pseudoreference electrode. Ferrocene was used as an internal standard for the reference electrode potential. F8 (200 mg, 0.4 mmol) was dissolved in 20 mL of acetonitrile containing 0.10 M tetrbutylammonium hexafluorophosphate (TBAPF6) as supporting electrolyte. The solution was purged with nitrogen gas for 15 min. The potential of the working electrode was kept at 1.1 V (vs. SCE) for 4 h with continuous stirring. The solution turned darker brown as the electrolysis proceeded. The current was ca. 10 mA for the duration of the experiment. The resulting solution was concentrated to dryness, then purified by column chromatography (silica gel, hexanes) to obtain two fractions. The first fraction was recover ed F8 (120 mg), whereas the second fraction was a mixture of reduced products. Both proton and fluorine NMR spectra indicated an absence of aromatic C H bonds and the probable presence of a CH2 group resulting from reduction of two geminal fluorines on one of the bridges of F8 to form a CH2CF2 bridge.

PAGE 94

94 Reaction in the presence of TEMPO : To a solution of pyridine (20.5 mg, 0.29 mmol) and 2,2,6,6tetramethylpiperidine1 oxyl (TEMPO, 45 mg, 0.29 mmol) in anhydrous THF was added F8 (65.4 mg, 0.13 mmol). The res ulting reaction mixture was stirred for 1 h and then concentrated to dryness and purified by column chromatography (silica gel, hexanes) to provide 4(pyrrolidin 1 yl) perfluoro[2.2]paracyclophane ( 112g) (100% conversion, 84% isolated yield as a yellow s olid ) Competition experiments: To a mixture of pentafluoropyridine (50 mg, 0.295 mmol) and F8 (124 mg, 0.25 mmol) in anhydrous THF (6 mL) was added sodium methoxide (8 mg, 0.148 mmol). After stirring for 10 min at rt, a fluorine NMR of the mixture indicat ed that the methoxide anion had only reacted with the pentafluoropyrridine. The F8 was unreacted. A similar experiment designed to compare the reactivities of F8 and hexafluorobenzene resulted in reaction of methoxide only with the F8.

PAGE 95

95 CHAPTER 4 MULTIPL E NUCLEOPHILIC SUBST ITUTIONS OF PERFLUORO[2.2]PARACYCLOPHANE 4.1 Introduction Studies on [2.2]paracyclophane ([2.2]PCP ) demonstrate the presence of strong transannular effects in electrophilic substitutions.95,96 The presence of one electronwithdrawing su bstituent in one ring deactivated both rings toward further electrophilic attack.97,98 As an example, nitration of AF4 with nitronium tetrafluoroborate in sulfolane at room temperature afforded mononitroAF4 in 86% isolated yield49 with no dinitro derivati ves observed. When nitration was carried out under the more forcing conditions of 5 equivalents of nitronium tetrafluoroborate and a temperature of 80 oC, the products generated were a mixture of pseudometa pseudopara and pseudoortho dinitro AF4 deriv atives in 81% combined isolated yield50, with the ratio of 1:1:1. Electrophilic substitution of [2.2]PCP with one electrondonating group orient s ortho and para in the ring bearing the substitutent. According to C.J. Crams transannular directive influenc es study, regioselectivity for bis electrophilic substitution is determined by proton transfer to an acceptor site on the originally substituted ring. The geometry of [2.2]PCP is ideally suited for such proton transfer99 and the aromatic nuclei are expect ed to be at least of comparable base strength to the solvent and other bases such as bromide ion or aluminum tetrachloride ion The proximity of the rings hinders approach by these external bases and should favor intramolecular processes. Some cases exact ly follow this mechanism For instance, bromination of 4acetyl[2.2]PCP occurs exclusively in pseudogem position to acetyl to give the thermodynamically least stable isomer in 56% yield.100 The reason for

PAGE 96

96 the only formation of pseudogem isomer is the ox ygen of acetyl group ideally positioned to accept a proton from the pseudogem position (Figure 41). Figure 41 Bromination of 4acetyl[2.2]PCP However, the orientations of some electrophilic substitution are hard to understand. For example, brominati on of 4nitro [2.2]PCP provides 70% pseudogem isomer as major product, whereas nitration of 4nitro [2.2]PCP produces 0.7% pseudogem isomer as the minor product. Although electrophilic substitutions of [2.2]PCP have been studied extensively, including s urprising directing effects in multiple electrophilic substitution and unusual spectroscopic phenomena. N ucleophilic substitution has not been found to any extent N ucleophilic substitution of iodoAF4 with sodium thio pheno late and malonates in the presenc e of NaH provided the corresponding product s in high yield via SRN1 mechanism When 4n itro octafluoro[2.2]PCP was treated with nucleophiles such as alkoxides and cyanide, a novel ring opening reaction was observed via a SNAr mechanism. T he nucleophile apparently attacks the bridgehead aryl carbon vicinal to

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97 the nitro group, followed by subsequent aryl CF2 bond cleavage to form ring opening products in moderate to good yields.56 In the last chapter, reactions of perfluoro[2.2]paracyclophane (F8) that led mai nly to monosubstitution w ere emphasized and factors that favor mono substitution with a large variety of nuclophiles were discussed. This chapter will deal with multi substitution reactions of F8, the regiochemistry of multi substitution, and characteriz ation of the multi substituted products, including detailed multidimensional NMR analysis of these products. 4.2 R esults and D iscussion Reaction of perfluoro[2.2]paracyclophane (F8) with sodium thio phenolate (2 equiv.) in anhydrous tetrahydrofuran provided parabis (phenylthio) product 1 14a in moderate yield together with tetrakis ( phenylthio) product 117a and 118a (15%) ( Figure 42 ). Even when reaction of F8 with one equivalent of sodium thiophenolate yielded no monosubstituted product at all. The resul ts obtained from the reaction of F8 with thiophenolate anion clearly indicate that the SPh substituent of the putative monoadduct must activate that ring towards addition of a second nucleophile. Such results are consistent with the previously observed formation of only p bis (phenylthio) 2,3,5,6tetrafluorobenzene from the reaction of either one or two equivalents of thio phenolate anion with hexafluorobenzene.81 When sodium tertbutyl sulfide, sodium methanethiolate, and sodium 2,3,5,6tetrafluorobenzenethiolate were used as nucleophilic reagents in reaction with F8 similar results were obtained. The results were shown in T able 4 1 The uv spectra of these products were displayed in Figure 43.

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98 Figure 42 Reaction of F8 with 2 equiv. of sodium thio phenolate Table 41 Reaction of sodium thiolates (2 equiv ) with F8 in THF at RT Nucleophiles Equivalents Reaction time h Product No. Yield(%) C olor PhSNa 2 48 114a (44.2) Yellow tert BuSNa 2 24 114b (49.5) Yellow 2,3,5,6 tetrafluoro PhSNa 2 20 114c (47.0) Yellow MeSNa 2 20 114d (49.3) Yellow

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99 Figure 43 UV spectra of bis thio F8 derivatives Tr eament of F8 with 4 equivalents of sodium thiophen olate furnished two tetra kis phenylthioF8 regioisomers 117a and 118a Each benzene ring had two substitutents para to each other. Compound 117a was the major product, whereas 118a was the minor product (Figure 44 ). The t wo isomers could not be separated by column chromatography. The formation of 117a and 118a was via the intermediate 114a which the electrons of two substituents were transmitted to the pseudogem positions to result in these positions being less reactive. The other two substituents thus mainly enter ed the pseudo ortho positions. The ratio of 117: 118 had big variations depending on the donating or withdrawing of group which attached to sulfur. For phenyl and 2,3,5,6 tetrafluorophenyl group, due to their capable of delocalization of lone pair of sulfur to reduce donating ability of sulfur as an electron donor, the ratio of 117: 118 is from 1.5 to 1.3. As with tert butyl and methyl, because of their electron donating ability to increase donating ability of sulfur as an electron donor, the ratio of 117: 118 is range from 7.9 to

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100 6.5. The results were shown in Table 42. T he reaction of F8 with 4 equivalents of sodium p fluorophenolate (as a stronger donor) only isolated 4,7,12,15tetrakis p fluorophenoxy F8 ( 119)(Figure 44 ). Figure 44 Reaction of F8 with 4 equiv. of sodium phenylthiolates Table 42 Reaction of sodium thiolates (4 equiv ) with F8 in THF at RT Nucleophiles Equivalents Reaction time hr Product No. ra tio Yield(%) C olor PhSNa 4 48 117a: 118a = 1.5:1 (93.4) Brown tert BuSNa 4 48 117b: 118b = 6.5:1 (45.7 ) Brown 2,3,5,6 tetrafluoro PhSNa 4 24 117c: 118c = 1.3:1 (37.6) Brown MeSNa 4 20 117d: 118d = 7.9:1 (80.3 ) Brown 4 F PhONa 4 18 119 (43) White Sinc e the sulfur can activate the para position on the same benzene ring, it was predicted that the major product would be bis cycloadducts on the same benzene ring if F8 reacted with 2 eguivalents of 1,2benzene dithiol in the presence of sodium hydride. Indeed, the reaction of F8 with 1,2dithiol benzene in the presence of sodium hydride

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101 provided bis cycloadducts ( 1 20a ) on the same benzene ring and bis cycloadducts ( 1 20b ) on different benzene ring in 86% combined yield with a ratio of 49:1 for 1 20a : 1 20b ( Figure 45 ) UV spectra of these tetrakis substituted F8 derivatives are displayed in Figure 46 Compound 120 is red in color, with the UV bands extending past 450 nm Figure 45 Reaction of F8 with 1,2benzenedithiol in the presence of NaH at RT Figure 4 6 UV spectra of tetrakis substituted F8 derivatives

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102 Reaction of F8 with 2 equiv. of sodium p fluorophenolate produced five regioisomers ( para: 43%; meta : 10%; pseudopara: 21%; pseudoortho: 15%; pseudometa : 11%) ( 121) in combined 71% yield because 4F PhO was a weaker electron donor that could not have strong influence upon introduction of second substituent Interestingly, the ratio of 2 substituents in the same ring : 2 substituents in the different ring was almost 1:1 (Figure 47 ). Figure 47 Re act ion of F8 with 2 equiv of sodium 4fluorophenolate Reaction of F8 with catechol (1,2benzenediol) formed the catechol adduct of F8. However, simple 1,3benzenediol and 1,4benzenediol adducts of F8 did not form w hen 1,3benzenediol and 1,4benzenedi ol were used as nucleophiles to react with F8 in the presence of NaH. Instead, the reaction of F8 with 1,3benznediol in the presence of sodium hydride provided 4,7bis (3 hydroxy phenoxy) F8 ( 123) as a white solid, whereas 1,4benzenediol produced 4,16bis (4 hydroxy phenoxy) F8 ( 122) as a major product. The color of both react ion mixtures was blue (Figure 48 ). The reason for the formation of product 12 2 versus 123 is probably that the Oin para position made

PAGE 103

103 phenoxy a strong electrondonating group which deactivated the ring bearing substituent, while Ogroup in meta position could not be as strong electrondonating as the para hydroxy group. Figure 48 Reaction of F8 with hydroquinone/resorcinol in the presence of NaH When 4.4 equivalents of benzyl amine was used as nucleophile and base to neutralize the formed hydrogen fluoride, the formed bis substituted products were 4,15 and 4,16bis benzylaminoF8 derivatives ( 124) in combined 69% yield as a yellow solid, which could not be separated by column c hromatography. Since the amino group was very strong electron donating group that led the substituted ring to be electron rich and less reactive, no bis substituted product on the same benzene ring was formed. The reaction of F8 with 4.4 equivalents of pyr rolidine produced four regioisomers, pseudopara ( 125, 33%); pseudoortho (40%) as well as other two isomers ( 126) in 80% combined yield. 4,16bis p yrrolidin 1 yl F8 ( pseudopara isomer) was separated from other three isomers by co lumn chromatography (Figure 49 ). The UV spectra of these

PAGE 104

104 bis substituted products show a progression towards longer wavelength absorption as the substituent becomes increasingly electron donating (Figures 4 1 0 and 4 11) Figure 49 Reaction of F8 with aliphatic amines Figure 4 10 UV spectra of bis substituted F8 derivatives

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105 Figure 411 UV spectra of bis substituted F8 derivatives Reaction of F8 with 8.8 equivalents of pyrrolidine produced 4,7, 12( 127) and 4,7,13tri p yrrolidin 1 yl F8 ( 128) equally amount in combined 75.5% which can be separated by column chromatography completely (Figure 412). The UV spectra are shown in Figure 413. Figure 4 12 Formation of trisubstituted products by the reaction of F8 with pyrrolidines

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106 Figure 413 UV spectra of tri substituted F8 4.3 Charac terization The patterns of coupling constants of monosubstituted F8 derivatives can be used for the identification of the disubstituted F8s. First, the fluorines in the half of the molec ule depicted in Figure 41 4 are assigned relative to the su bstituent. Of the bridge fluorines, the one which doesnt display a coupling larger than 20 Hz with any aromatic fluorine is F2s. Its geminal partner is F2a. The fluorines in the other geminal pair are assigned based on the couplings F1s F2s and F1aF2a. The aromatic fluorines are assigned based on the largest coupling with the bridge fluorines. The correctitude of the assignment of the fluorines in the half molecule can be confirmed by the five bond couplings of the bridge fluorines with the fluorines syn on the remote ring, and also by the pattern of chemical shifts of the bridge fluorines. In a monosubstituted molecule, with F15 displaying a 6070 Hz coupling with the aromatic fluorine ortho and syn F1s and F2a are deshielded relative to F1a and F2s. In a

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107 disubstituted molecule, in which F13 has a coupling of 6070 Hz with the aliphatic fluorine ortho and syn (F1s) F1a and F2s are the deshielded ones. Figure 4 1 4 Fluorines identifiable by their position to the substituent. Disubstituted F8 have seven isomers, depicted in Fig ure 415. Applying the numbering of the half molecule from Figure 41 4 to these isomers is straightforward for the ortho, para pseudoortho and pseudopara isomers, and somehow confusing or inappropriate for the other three. These later isomers on the other hand are the easiest to identify. The bridge fluorines in the meta isomer have no geminal coupling. The pseudometa and pseudogem isomers have no couplings between fluorines from different geminal pairs. In the pseudometa isom er, fluorines in a geminal pair couple both with a 250 Hz and with a ca. 10 Hz coupling, while in the pseudogem isomer only the large coupling is present. When the coupling F1s F8 is noticeable, in the pseudometa isomer both fluorines in the bridge pair closest to the substituent couple with the same aromatic fluorine. The four isomers for which there is coupling between the fluorines from different geminal pairs can be then identified by the ortho coupling of the aromatic fluorines. Although an aromatic fluorine generally couples with the meta the para and the pseudogem fluorines, the ortho coupling stands out with a coupling constant, ca 20 Hz which is roughly double the value for the other couplings. The ort ho isomer displays no

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108 F F i i g g u u r r e e 4 4 1 1 5 5 Isomers of disubstituted F8 such coupling. The ortho isomer also will not show a coupling between two of the aromatic fluorines, F8 and F13. In the para isomer, F13 and F15 display an ortho coupling. The pseudoortho isomer displays an ortho coupling between F8 and F15, while the pseudopara has such a coupling between F8 and F13. This method we established for the assignment of the regiochemistry of di substituted F8s was applied to the examples which follow. The couplings between aliphatic fluorines were identified in a 19F -19F DQF COSY spectrum in which the spectral window was restricted to the smaller region of the bridge fluorines. The couplings of the aromatic fluorines were measured from 19F spectra with selective decoupling. Both the chemical shifts and the couplings were then refined in Peter Budzelaars gNMR program.

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1 09 Table 43 NMR data for the aliphatic fluorines in compound 121a ( para) in benzened6 Position a (ppm) T1 (s) 2 J (Hz) 3 J (Hz) 1S 101.73 c 250 6 (F1S F2S) 8 (F1A F2A) 1A 101.77 c 2S 102.78 0.88 b 250 2A 101.90 c a the fluorine in the substituent: 118.85 ppm, tt, 8.2, 4.1 Hz. b In benzened6 : acetoned6, 2:1. c Not measured, due to overlap with other signals. Table 44 NMR data for the aromatic fluorines in compound 121a ( para ) in benzened6 Position (ppm) T1 (s) b 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 8 123.98 0.42 10 58 0 13 131.57 0.38 20 6 35 0 15 134.02 0.39 20 6 10 35 0 b In benzened6 : acetoned6, 2:1. The aliphatic f luorines in compound 121a display two pairs with geminal coupling, and there is vicinal coupling between fluorines from different pairs. It is difficult to use the vicinal couplings to identify the syn fluorines in the tetrafluoroethylene bridge, because the signals of F1a and F1s are practically overlapped. In fact, these signals overlap signals from other isomers; TOCSY1D experiments with selection of each of the aromatic fluorines confirmed the position of the bridge fluorines. F13 and F15 have been ass igned based on the five bond and syn coupling of F15 and F2a. The 20 Hz coupling of F13 and F15 demonstrate that this is the para isomer. Again, the aromatic fluorine ortho to the substituent is the most deshielded. In fact, in all of these five isomers, these ortho fluorines are more deshielded, and fall in a region well separated from the rest of the signals. If one relies of the chemical shift to identify F8, then the assignment of the regiochemistry of compound 121a is straightforward: F2s, the only aliphatic fluorine which does not have a large coupling with an aromatic one, is geminal to a fluorine which has a large coupling with F8. Therefore, 121a is the para isomer.

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110 Table 45 NMR data for the aliphatic fluorines in compound 121b ( meta ) in benzened6 Position a (ppm) T1 (s) b 2 J (Hz) 3 J (Hz) 1 101.01 0.81 10 (F1F2) 8 (F9F10) 2 102.10 c 9 102.37 c 10 102.43 c a the fluorine in the substituent: 119.05 ppm, tt, 8.2, 4.1 Hz. b In benzened6 : acetoned6, 2:1. c Not measured, due to overlap wit h other signals. Table 46 NMR data for the aromatic fluorines in compound 121b ( meta ) in benzened6 Position (ppm) T1 (s) b 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 5 123.08 0.38 10 22 5 12 -134.27 0.39 20 10 10 22 5 13 131.24 0.34 20 10 24 5 b In benzened6 : acetoned6, 2:1. The aliphatic fluorines in compound 121b lack the large geminal coupling, therefore this is the meta isomer. All of the couplings given in Tables 4 5 and 4 6 were determined by simulation of 14 spin system in gNMR. The vicinal couplings of the syn aliphatic fluorines are in the usual range, 810 Hz. The couplings of the aliphatic fluorines with the aromatic fluorines over four bonds and syn are all of comparabl e values, 2224 Hz, which suggest that the differences in these couplings are due to the distortion of the PCP skeleton, not possible in the meta isomer. Table 4 7 NMR data for the aliphatic fluorines in compound 121c ( pseudopara) in benzened6 Position a (ppm) T1 (s) b 2 J (Hz) 3 J (Hz) 1S 104.68 0.82 248 6 (F1S F2S) 11 (F1A F2A) 1A 98.14 0.75 2S 99.84 0.89 249 2A 104.95 0.78 a the fluorine in the substituent: 119.07 ppm, tt, 8.2, 4.1 Hz. b In benzened6 : acetoned6, 2:1.

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111 Table 4 8 NM R da ta for the aromatic fluorines in compound 121c ( pseudopara) in benzened6 Position (ppm) T1 (s) b 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 8 136.14 0.39 20 10 10 77 0 5 (F2S) 13 131.24 0.37 20 4 64 0 4 (F1A) 15 122.25 0.41 4 10 10 26 17 5 (F2A) b In benzened6 : acetoned6, 2:1. Compound 121c has four different aliphatic fluorines in the tetrafluoroethylene bridge, which were positioned relativ e to each other based on the geminal and the syn vicinal couplings. The aromatic fluorines were positioned relative to the aliphatic ones based on the large coupling over four bonds and syn The coupling over five bonds and syn of F15 and F2a, as well as the pseudogeminal coupling of F8 and F15, c onfirmed the assignments in the half molecule. A 20 Hz coupling of F8 and F13 demonstrated that compound 121c is the pseudopara isomer. This is in agreement with F15 being the most deshielded aromatic fluorine. The couplings of the aromatic fluorines wi th the bridge ones follow the pattern of the monosubstituted F8s: the aromatic fluorines which have a large (6070 Hz) 4Jsyn have a small (<5 Hz) 5Jsyn and also couple with the geminal partner of the bridge fluorine four bonds away and syn These fluorines, F8 and F13, are ortho, as seen for the monosubstituted derivatives. The other aromatic fluorine, F15, displays a coupling with F2A similar to the one seen in monosubstituted derivatives for the aromatic fluorines which display couplings of 230 Hz with the bridge fluorines syn and four or five bonds away.

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112 Table 4 9 NMR data for the aliphatic fluorines in compound 121e ( pseudometa ) in benzened6 Position a (ppm) T1 (s) b 2 J (Hz) 3 J (Hz) 1S 98.80 0.80 247 10 (F9aF9S) 7 (F1A F1S) 1A 104.02 0.76 9S 99.28 0.77 251 9A 105.57 0.82 a the fluorine in the substituent: 118.67 ppm, tt, 8.2, 4.1 Hz. b In benzened6 : acetoned6, 2:1. Table 410 NMR data for the aromatic fluorines in compound 121e ( pseudometa ) in benzened6 Position (ppm) T1 (s) b 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 Jpseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 5 122.62 0.39 7 10 10 27 20 5 (F1a) 7 134.44 0.36 20 7 10 70 0 8 (F9S) 8 132.80 0.33 20 10 72 0 5 (F1S) b In benzened6 : acetoned6, 2:1. 121e has two pairs of aliphatic fluorines which do not display vicinal couplings between fluorines from different geminal pairs, therefore it is either the pseudog em or the pseudo meta isomer. The coupling of F5 with both F9A and F9S indicates that compound 121e is the pseudometa isomer. This is in agreement with F8 being more deshielded than F7. Smaller couplings have been noticed between the geminal bridge fluo rines, which also is to be expected for the pseudometa isomer, and not for the pseudogem Also, F5 and F7 couple with more than one coupling constant. The couplings of the aromatic fluorines with the bridge ones follow the pattern seen in the monosubstit uted F8s and in the pseudopara isomer. Like in the later, the aromatic fluorine ortho to the substituent displays couplings of 2030 Hz with the bridge fluorines syn and four or five bonds away.

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113 Table 411 NMR data for the aliphatic fluorines in compound 125 ( pseudopara ) in benzened6 Position (ppm) T1 (s) 2 J (Hz) 3 J (Hz) 1S 98.83 250 9 (F1S F2S) 1A 105.62 2S 104.99 248 2A 105.62 Table 4 1 2 NMR data for the aromatic fluorines in compound 125 ( pseudopara ) in benzened6 Position (pp m) T1 (s) 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 8 131.77 23 6 8 8 17 31 13 143.50 23 6 22 35 15 -129.89 8 8 85 0 5 (F1A) Table 4 13 NMR data for the aliphatic fluorines in compound 126 ( pseudootho ) in benzened6 Position a (ppm) T1 (s) 2 J (Hz) 3 J (Hz) 1S 100.66 0.83 254 5 (F2A F1S) 1A 103.11 0.83 2S 100.88 0.86 250 2A 98.84 0.90 Table 414 NMR data for the aromatic fluorines in compound 126 ( pseudoortho) in benzened6 Position (ppm) T1 (s) 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 8 131.72 0.44 23 10 6 38 32 13 129.73 0.57 10 10 45 33 15 -145.91 0.50 23 10 6 62 11 7 (F1S) Table 415 NMR data for the aliphatic fluorines in compound 116b ( or tho) in benzened6 Position (ppm) T1 (s) 2 J (Hz) 3 J (Hz) 1S 98.10 0.87 251 9 (F1S F2S) 3 (F1A F2A) 1A 105.65 0.94 2S 104.31 0.92 248 2A 94.81 0.79

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114 Table 416 NMR data for the aromatic fluorines in compound 116b ( ortho) in benzened6 Position (ppm) T1 (s) 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 8 139.26 0.61 20 10 10 22 5 (F2S) 13 133.35 0.52 20 6 10 10 12 4 (F1A) 15 136.17 0.44 20 6 10 10 68 0 Table 417 NMR data for the aliphatic fluorines in compound 1 14a ( para) in benzened6 Position (ppm) T1 (s) 2 J (Hz) 3 J (Hz) 1S 1 00.83 a 252 6 (F1S F2S) 10 (F1A F2A) 1A 10 3.27 a 2S 100.35 a 2 47 2A 102.19 a a Not measured, due to overlap with other signals. Table 418 NMR data for the aromatic fluorines in compound 1 14a ( para) in benzened6 Position (ppm) T1 (s) b 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 8 100.96 0.42 10 66 0 13 128.49 0.38 20 8.1 43 0 15 134. 26 0.39 20 8.1 10 54 0 b In benzened6 : acetoned6, 2:1 MS fragmentation data confirm the presence of a disubstituted aromatic ring (MW = 428) The chemical shift of two fluorines ortho to s ubstituents increased from ca. 120 to 100 ppm due to deshield of sulfur ( 114a) There are seven regiomers of tris ubstituted F8, presented in Figure 416. In all of them the bridge fluorines are not equivalent. The geminal pairs have been identified by their large coupling in the DQFCOSY spectrum. Vicinal fluorines in the same tetrafluoroethylene unit display small couplings. Their relative position, and the position of the substituents, was established on the basis of the couplings with aromatic

PAGE 115

115 fluorines The two half molecules were later joined based on the ortho couplings of the aromatic protons. F F i i g g u u r r e e 4 4 1 1 6 6 R R e e g g i i o o i i s s o o m m e e r r s s o o f f t t r r i i s s u u b b s s t t i i t t u u t t e e d d F F 8 8 The elucidation of the structure of 128 is presented in Figure 4 1 7 as an example. The fluorine signals were l abeled a1a13, according to their position in the spectrum, from lower to higher field. The geminal pairs ar e: a1a7, a2a4, a3a8, and a5a6. Large couplings, typically around 60 Hz, identified the aromatic fluorines four bonds away and syn to the bridge ones: a9 to a4, a10 to a7, a11 to a6, a12 to a8, and a13 to a5. The couplings a7 a12 (10 Hz) and a8 a10 (19 Hz) placed a7 syn to a8 and a3 syn to a 1 In the other tetrafluoroethylene unit, a2 is syn to a5 and a4 to a6 as demonstrated by the couplings a4 a11 (19 Hz), a2 a13 (21 Hz) and a6 a9 (17 Hz). The aromatic fluorines displayed only one large ortho coupli ng, between a12 and a13, which indicates that 128 is the 4,7,12 isomer.

PAGE 116

116 Figure 41 7 Structure of compound 128 Table 419 NMR data for the aliphatic fluorines in compound 128 in benzened6 : acetoned6, 2:1 Position (ppm) T1 (s) 2 J (Hz) 3 J (Hz) 1S 10 2.78 0.73 251 <5 (F1S F2S) <5 (F1A F2S) <5 (1S F2A) 1A 100.90 0.79 2S 97.45 0.77 247 2A 100.57 0.79 9S 103.36 0.71 252 8 (F9A F10A) <5 (F9S F10S) <5 (F9S F10A) <5 (F9A F10S) 9A 97.12 0.64 10S 98.37 0.60 252 10A 105.14 0.68 Table 420 NMR data for the aromatic fluorines in compound 128 in benzened6; acetoned6, 2:1 Position (ppm) T1 (s) 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 5 124.68 0.48 8 61 20 7 8 123.38 0.42 8 8 72 17 <5 (F2S) 12 13 131.38 0.49 0 8 63 19 <5 (F1A) 15 148.56 0.50 28 0 8 44 21 <5 (F1A) 16 131.96 0.40 8 62 10 Compound 127 displays very large couplings over four bonds and syn F8F2a and F12F10s, 98 and 88 Hz, respectively. Some five bonds and syn couplings

PAGE 117

117 between aromatic and bridge fluorines are also v ery large, 2030 Hz, which made the assignment of positions 9 and 10 ambiguous. Both assignments, however, generate the same isomer. Discrimination between the two possibilities was made based on the coupling of F12 and F16, an expected meta coupling in one assignment, which in the other would be a coupling between F10a and F16. The structure of 127 is depicted in Figure 418. Figure 418 Structure of compound 127 Table 421 NMR data for the aliphatic fluorines in compound 127 in benzened6 Position (p pm) T1 (s) 2 J (Hz) 3 J (Hz) 1S 97.90 0.66 250 8 (F1A F2S) 6 (F1S F2S) 1A 95.40 0.62 2S 92.36 0.54 253 2A 99.89 0.58 9S 98.94 0.64 248 5 (F9S F10A) 7 (F9A F10A) 9A 105.57 0.78 10S 106.25 0.65 250 10A 96.65 0.64 Table 4 22 NMR dat a for the aromatic fluorines in compound 127 in benzened6 Position (ppm) T1 (s) 3Jortho (Hz) 4Jmeta (Hz) 5Jpara (Hz) 7 J pseudogem (Hz) 4Jsyn (Hz) 5Jsyn (Hz) other nJ (Hz) 5 125.84 0.44 8 8 24 32 7 8 123.79 0.35 8 0 98 51 12 136.62 0.47 10 6 8 88 0 13 15 134.20 0.37 29 6 0 15 8 16 148.23 0.52 10 21 36

PAGE 118

118 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 S S S S F1 2 Figure 41 9 Regioisomers of tetrakis substituted F8 There are fourteen regiomers of t etrakis substituted F8, presented in Figure 41 9 S even of them display more than one aromatic signal, three isomers miss the geminal coupling, and 2 do not have an aromatic fluorine ortho to the substituent (and this would produce a more shielded F19). An attempt to assign the two isomers is made using chemical shifts increments (Figure 420).

PAGE 119

119 S S F1 4 F1 6 S S F1 4 S S S S F1 2 S S S S F1 2 -102.15 -100.35 -100.83 -103.27 -128.49 -100.96 -134.26 -102.90 -132.51 -102.15 -100.35 2.07 -0.37 4.02 -100.96 -1.75 -100.96-1.75= -102.71 -102.15-0.37= -102.53 -100.35+2.07= -98.28 -100.96+4.02= -96.94 -102.15+2.07= -100.08 -100.35-0.37= -100.72 Figure 420 Assigning the two isomers is made using chemical shifts increments Coupling constants in minor isomer confirm the assignment (Figure 42 1 ) Figure 42 1 Coupling constants in minor isomer confirm the assignment 4.4 Experimental Section All chemicals were purchased f rom Sigma Aldrich and used directly without further purification. All reactions were done under a nitrogen atmosphere. Column

PAGE 120

120 chromatography was carried out on silica gel. All melting points are uncorrected. 1H and 19F NMR were recorded in CDCl3 at 300 MH z and 282 MHz, respectively (unless designated otherwise). Because of the perfluoro nature of the compounds synthesized in this chapter, which results in mult iple one, two and threebond FC couplings for each signal with little difference in chemical s hift, the respective 13C spectra do not provide useful observable structural information. 4,7bisPhenylthioperfluoro[2.2]paracyclophane (114a) : A mixture of sodium thiophenolate (29.4 mg, 0.2 mmol) and perfluoro[2.2]paracyclophane ( 49.6 mg, 0.1 mmol) in anhydrous tetrahydrofuran (4 mL) was stirred at room temperature for 48 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give 4,7bis phenylthioperfluoro[2.2]paracyclophane ( 30 mg, yield: 44.2%) as a yellow solid. m p 122124 oC; 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl3100.24 (dd, J1 = 245.4 Hz, J2 = 11.5 Hz, 2F), 100.72 (dd, J1 = 250.5 Hz, J2 = 42.6 Hz, 2F), 100.98 (d, J = 63.0 Hz, 2F), 102.22 (ddd, J1 = 245.2 Hz, J2 = 66.3 Hz, J3 = 6.4 Hz, 2F), 103.33 (dddd, J1 = 251.7 Hz, J2 = 54.9 Hz, J3 = 15 Hz, J4 = 6.4 Hz, 2F), 128.49 (dd, J1 = 42.7 Hz, J2 = 10.5 Hz, 2F), 134.26 (dddd, J1 = 54.4 Hz, J2 = 19.8 Hz, J3 = 6.4 Hz, J4 = 4.0 Hz, 2F). Anal. Calcd for C28H10F14S2 C 49.71, H 1.49. Found: C 49.97, H 1.69. Note: F8 : PhSNa = 1:2. 4,7bistert Butylthio perfluoro[2.2]paracyclophane (114b): A mixture of sodium 2methyl2 propanethiolate (67.3 mg, 0.6 mmol) and F8 ( 148.8 mg, 0.3 mmol) in anhydrous tetrahydrofuran (12 mL) was stirred at room temperature for 24 h. The reaction m ixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give 4,7bis tert butylthioperfluoro[2.2]para

PAGE 121

121 cyclophane (94.5mg, yield: 49.5%) as a yellow solid. m p 127128 oC; 1H NMR (300 MHz, CDCl3 (s, 18H). 19F NMR (282 MHz, CDCl397.99 (d, J = 240.8 Hz, 2F), 98.36 (d, J = 66.3 Hz, 2F), 100.02 (ddt, J1 = 236.3 Hz, J2 = 76.9 Hz, J3 = 8.2 Hz, 2F), 100.69 (dd, J1 = 250.9 Hz, J2 = 43.4 Hz, 2F), 103.01 (ddt, J1 = 248.7 Hz, J2 = 49.9 Hz, J3 = 10.4 Hz, 2F), 128.53 (dd, J1 = 41.5 Hz, J2 = 29.0 Hz, 2F), 134.00 (m, 2F). Anal. Calcd for C24H18F14S2 C 45.29, H 2.85. Found: C 45.61, H 2.86. bis( 2,3,5,6Tetrafluorophenylthio) perfluoro[2.2]paracyclophane (114c): To a solution of 2,3,5,6tetrafluorothi ophenol (100.3 mg, 0.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added 60% sodium hydride (24 mg, 0.6 mmol). The resulting reaction mixture was stirred for 30 minutes. To the above mixture was added perfluoro[2.2]paracyclophane (148.8 mg, 0.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give 4,7bis ( 2,3,5,6tetrafluorophenylthio) perfluoro[2.2]paracyclophane (110 mg, yield: 47%) as yellow solid. m p 184186 oC; 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl3100.62 (dd, J1 = 252.7 Hz, J2 = 40.9 Hz, 2F), 101.02 (d, J = 243.1 Hz, 2F), 101.82 (m, 2F), 102.74 (dd, J1 = 245.3 Hz, J2 = 57.8 Hz, 2F), 103.59 (dddd, J1 = 250.1 Hz, J2 = 55.3 Hz, J3 = 14.4 Hz, J4 = 7.1 Hz 2F), 128.24 (m, 2F), 134.52 (d, J = 47.9 Hz, 2F), 134.48 (t, J = 9.6 Hz, 4F), 136.85 (m, 4F). Anal. Calcd for C28H2F22S2 C 40.99, H 0.25. Found: C 40.76, H 0.34. 4,7bisMethylthio perfluoro[2.2]paracyclophane (114d): A mixture of sodium methanethiol ate (35 mg, 0.5 mmol) and F8 ( 124 mg, 0.25 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at room temperature for 20 h. The reaction mixture

PAGE 122

122 was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to g ive 4,7bis methylthioperfluoro[2.2]paracyclophane (68 mg, yield: 49.3%) as a yellow solid. m p 114116 oC; 1H NMR (300 MHz, CDCl3 J = 2.1 Hz, 6H). 19F NMR (282 MHz, CDCl399.62 (d, J = 244.8 Hz, 2F), 100.08 (dd, J1 = 250.9 Hz, J2 = 41.7 Hz 2F), 101.24 (ddt, J1 = 244.8 Hz, J2 = 64.3 Hz, J3 = 8.2 Hz, 2F), 103.03 (dddd, J1 = 250.9 Hz, J2 = 51.9 Hz, J3 = 14.7 Hz, J4 = 6.2 Hz, 2F), 104.64 (dd, J1 = 62.0 Hz, J2 = 6.5 Hz, 2F), 129.42 (m, 2F), 134.65 (dd, J1 = 45.7 Hz, J2 = 18.6 Hz, 2F). Ana l. Calcd for C18H6F14S2 C 39.14, H 1.09. Found: C 39.30, H 0.93. 4,7,12,15tetrakisPhenylthioperfluoro[2.2]paracyclophane ( 117a, major ) and 4,7,13,16tetrakisphenylthioperfluoro[2.2]paracyclophane ( 118a, minor) : A mixture of sodium thiophenolate (58.8 m g, 0.2 mmol) and F8 ( 49.6 mg, 0.1 mmol) in anhydrous tetrahydrofuran (4 mL) was stirred at room temperature for 48 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give a mixt ure of 4,7,12,15tetrakis phenylthioperfluoro[2.2]paracyclophane ( 117a, major) and 4,7,13,16tetrakis phenylthioperfluoro[2.2]paracyclophane ( 118a, minor) (80 mg, yield: 93.4%) as a yellow solid. m p 145146 oC; 1H NMR (300 MHz, CDCl3 7.20 (m, 20H). 19F NMR (282 MHz, CDCl3) 117a: 97.4(dd, J1 = 53.9 Hz, J2 = 12.4 Hz, 4F), 100.23 (dd, J1 = 244.2 Hz, J2 = 39.2 Hz, 4F), 100.80 (dt, J1 = 244.8 Hz, J2 = 14.8 Hz, 4F); 117b: 98.29 (d, J = 243.3 Hz, 4F), 101.85 (ddd, J1 = 243.0 Hz, J2 = 68.8 Hz, J3 = 15.8 Hz, 4F), 103.01 (dd, J1 = 63.8 Hz, J2 = 13.2 Hz, 4F). Anal. Calcd for C40H20F12S4.CH2Cl2 52.29, H 2.35. Found: C 52.08, H 2.61.

PAGE 123

123 4,7,12,15tetrakistert Butylthioperfluoro[2.2]paracyclophane ( 117b, major) and 4,7,13,16tetrakis tert butylthio perfluoro[2.2]paracyclophane ( 118b, minor) : A mixture of sodium 2methyl2 propanethiolate (149.5 mg, 1.2 mmol) and perfluoro[2.2]paracyclophane ( 148.8 mg, 0.3 mmol) in anhydrous tetrahydrofuran (12 mL) was stirred at room temperature fo r 48 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give 4,7,12,15tetrakis tert butylthio perfluoro[2.2]paracyclophane ( 117b, major) and 4,7,13,16tetrakis tert butylthioperf luoro[2.2]paracyclophane ( 118b minor) (106.5 mg, yield: 45.7%) as a yellow solid. m p 149150 oC; 117b: 1H NMR (300 MHz, CDCl3 1.16 (s, 36H). 19F NMR (282 MHz, CDCl394.93 (dd, J1 = 54.1 Hz, J2 = 10.2 Hz, 4F), 97.22 (dd, J1 = 238.6 Hz, J2 = 58.1 Hz, 4F) 98.41 (dt, J1 = 236.6 Hz, J2 = 14.8 Hz, 4F); 118b: 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl3 96.19 (dd, J1 = 228.1 Hz, J2 = 10.4 Hz, 4F), 99.10101.00 (m, 8F). Anal. Calcd for C32H36F12S4 49.47, H 4.67. Found: C 49.77, H 4.76. 4,7,12,15tetrakis( 2,3,5,6Tetrafluorophenylthio) perfluoro[2.2]paracyclophane ( 117c, major) and 4,7,13,16tetraki s (2,3,5,6tetrafluorophenyl thio) perfluoro[2.2] paracyclophane ( 118c, minor) : To a solution of 2,3,5,6tetrafluorothiophenol (200.6 mg, 1.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added 60% sodium hydride (48 mg, 1.2 mmol). The resulting reaction mixture was stirred for 30 minutes. To the above mixture was added perfluoro[2.2]paracyclophane (148.8 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes:dichloromethane = 4:1) to give 4,7,12,15t etrakis -

PAGE 124

124 ( 2,3,5,6tetrafluorophenylthio) perfluoro[2.2]paracyclophane ( 117c, major) and 4,7,13,16tetrakis ( 2,3,5,6 tetrafluorophenylthio) perfluoro[2.2]paracyclophane ( 118c, minor) (120 mg, total yield: 37.6%) as a yellow solid. m p 200 oC decomposition; 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl3) 117c: 98.17 (t, J = 27.1 Hz, 4F), 101.71 (dd, J1 = 248.7 Hz, J2 = 37.2 Hz, 4F), 102.86 (dd, J1 = 248.7 Hz, J2 = 22.8 Hz, 4F); 134.33 (dt, J1 = 132.8 Hz, J2 = 10.4 Hz, 8F), 136.9 (m, 8F); 118c: 98.38 ( d, J = 244.8 Hz, 4F), 102.33 (ddd, J1 = 244.8 Hz, J2 = 66.3 Hz, J3 = 14.7 Hz, 4F), 103.40 (d, J = 76.7 Hz, 4F), 134.33 (dt, J1 = 132.8 Hz, J2 = 10.4 Hz, 8F), 136.9 (m, 8F). Anal. Calcd for C40H4F28S4 C 41.97, H 0.35. Found: C 42.03, H 0.24. 4,7,12,15tetrakisMethylthio perfluoro[2.2]paracyclophane ( 117d, major) and 4,7,13,16tetrakismethylthio perfluoro[2.2]paracyclophane ( 118d, minor) : A mixture of sodium methanethiolate (70 mg, 1.0 mmol) and F8 ( 124 mg, 0.25 mmol) in anhydrous tetrahydrofuran (10 mL) was stirred at room temperature for 20 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give 4,7,12,15tetrakis methylthioperfluoro[2.2]paracyclophane ( 117d, major) and 4,7,13,16tetrakis methylthioperfluoro[2.2]paracyclophane ( 118d, minor) (122 mg, yield: 80.3%) as a yellow solid. m p 180182 oC; 1H NMR (300 MHz, CDCl3) 117d: J = 1.2 Hz, 12H); 118d: J = 1.2 Hz, 12H). 19F NMR (282 MHz, CDCl3) 117d: 98.92 (dd, J1 = 244.5 Hz, J2 = 53.8 Hz, 4F), 101.03 (dd, J1 = 242.5 Hz, J2 = 20.6 Hz, 4F) 101.76 (d, J = 53.8 Hz, 2F), 101.83 (d, J = 49.6 Hz, 2F); 118d: 97.09 (d, J = 242.8 Hz, 4F), 100.80 (m, 4F), 107.24 (m, 4F). HRMS (CI) Calcd for C20H12F12S4 607.9630 (M+), found 607.9626. 4,7,12,15tetrakis(4 Fluorophenoxy) perfluoro[2.2]paracyclophane (119) :

PAGE 125

125 To a solution of 4fluorophenol (112 mg, 1 mmol) in anhydrous tetrahydrofuran (10 mL) was added 60% sodium hydride (44 mg, 1.1 mmol). The resulting reaction mixture was stirred for 30 minutes. To the above mixture was added perfluoro[2.2]paracyclophane (124 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes:dichloromethane = 4:1) to give 4,7,12,15tetrakis (4 fluorophenoxy) perfluoro[2.2]paracyclophane (86 mg, yield: 43%) as a white solid. m p 248250 oC; 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl3101.65 (dd, J1 = 249.0 Hz, J2 = 49.9 Hz, 4F), 102.98 (d, J = 248.7 Hz, 4F), 119.80 (m, 4F), 123.26 (d, J = 49.9 Hz, 4F). Anal. Calcd for C40H16F16O4 C 55.57, H 1.87. Found: C 55.18, H 1.81. b is 1,2B enzenedithiol adduct of F8 (120a, 120b): To a solution of 1,2benzenedithiol (69.2 mg, 0.467 mmol) in anhydrous tetrahydrofuran (10 mL) was added 60% sodium hydride (41.1 mg, 1.02 mmol). The resulting reaction mixture was stirred at room temperatur e for 10 minutes. To the above mixture was added F8 (98.9 mg, 0.20 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexan es) to give 120a (120 mg, yield: 86.3%) together with 120b (ratio is 49:1) as a brownish solid. m p 296298 oC; 1H NMR (300 MHz, CDCl3 7.62 (m, 4H), 7.41 (m, 4H). 19F NMR (282 MHz, CDCl3) 120a: 88.07 (s, 4F), 100.54 (m, 4F), 133.48 (t, J = 4.2 Hz, 4F); 120b: 96.05 (dm, J = 236.6 Hz, 4F), 98.1 (dd, J1 = 244.8 Hz, J2 = 56.1 Hz, 4F), 123.49 (dm, J = 66.3 Hz, 4F). Anal. Calcd for C28H8F12S4 C 48.00, H 1.15. Found: C 48.38, H 1.44.

PAGE 126

126 bis(4 Fluorophenoxy) perfluoro[2.2]paracyclophane (121) : To a solution of 4fluorophenol (112.1 mg, 1 mmol) in anhydrous tetrahydrofuran (10 mL) was added 60% sodium hydride (44 mg, 1.1 mmol). The resulting reaction mixture was stirred for 15 minutes. To the above mixture was added F8 (248 mg, 0.5 mmol). The r eaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give bis (4 fluorophenoxy) perfluoro[2.2]paracyclophane ( 121, 230 mg, yiel d: 71%) as a white solid. m p 9899 oC; 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl3103.11 (m, 8F), 119.30 (m, 2F), 122.38 (m, 1F), 124.12 (d, J = 49.9 Hz, 1F), 133.79 (m, 4F). HRMS (CI) Calcd for C28H8F16O2 680.0269 (M+), found 680.0337. 4,16bis(4 Hydroxyphenox y) perfluoro[2.2]paracyclophane (122): To a solution of 1,4benzenediol (110 mg, 1 mmol) in anhydrous tetrahydrofuran (10 mL) was added 60% sodium hydride (88 mg, 2.2 mmol). The resulting reaction mixture was stirred for 15 minutes. To the above mixture was added F8 (248 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness. The residue was diluted with water, extracted with diethyl ether (3 20 mL). The combined layers was dried over magnesium sulfate, filtered to remove magnesium sulfate and the filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel, dichloromethane) to give 4,16 bis (4 hydr oxyphenoxy)perfluoro [2.2]paracyclophane ( 122 60 mg, yield: 20.5%) as a white solid. m p 256257 oC; 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl399.71 (ddd, J1 = 246.8 Hz, J2 = 27.1 Hz, J3 = 8.2 Hz, 2F),

PAGE 127

127 101.29 (d, J = 248.7 Hz, 2F), 105.85 (ddd, J1 = 246.8 Hz, J2 = 66.3 Hz, J3 = 6.2 Hz, 2F), 106.37 (ddm, J1 = 247.0Hz, J2 = 78.9 Hz, 2F), 124.19 (m, 2F), 135.10 (dd, J1 = 64.3 Hz, J2 = 20.9 Hz, 2F), 139.37 (m, 2F). HRMS (CI) Calcd for C28H10F14O4 676.0356 (M+), found 676.0340. 4,7b is (3 H ydroxyphenoxy) perfluoro[2.2]paracyclophane (123): To a solution of 1,3benzenediol (110 mg, 1 mmol) in anhydrous tetrahydrofuran (10 mL) was added 60% sodium hydride (88 mg, 2.2 mmol). The resulting reaction mixture was stirred for 15 minutes. To the above mixture was added F8 (248 mg, 0.5 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness. The residue was diluted with water, extracted with diethyl ether (3 20 mL). The combined layers were dried over magnesium sulfate, filtered to remove magnesium sulfate and the filtrate was conc entrated to dryness. The residue was purified by column chromatography (silica gel, dichloromethane) to provide crude product, which was recrystallized from chloroform (3 mL) to give 4,7 bis (3 hydroxyphenoxy) perfluoro[2.2]paracyclophane ( 123, 100 mg, yiel d: 34.1%) as a white solid. m p 182183 oC; 1H NMR (300 MHz, CDCl3J =8.1 Hz, 2H), 6.65 (m, 2H), 6.56 (m, 4H). 19F NMR (282 MHz, CDCl3 103.15 (dd, J1 = 249.0 Hz, J2 = 45.4 Hz, 2F), 103.05 (d, J = 22.8 Hz, 2F), 103.13 (d, J = 24.8 Hz, 2F) 104.21 (dd, J1 = 246.8 Hz, J2 = 12.4 Hz, 2F), 126.79 (d, J = 43.4 Hz, 2F), 133.39 (m, 2F), 136.23 (m, 2F). HRMS (CI) Calcd for C28H10F14O4 (M+) 676.0356, found 676.0386. 4,16bisBenzylaminoperfluoro[2.2]paracyclophane (124a) and 4,15b is benzylamino perfluoro[2.2]paracyclophane (124b): To a solution of benzylamine (235 mg, 2.2 mmol) in anhydrous tetrahydrofuran (10 mL) was added F8 (124 mg, 0.25

PAGE 128

128 mmol). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture w as concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to give a mixture of 4,16bis benzylamino perfluoro[2.2]paracyclophane ( 124a) and 4,15bis benzylaminoperfluoro[2.2]paracyclophane ( 124b) (115 mg, yield: 68.7%) as a yellow solid. m p 134 oC decomposition; 1H NMR (300 MHz, CDCl3J = 1.2 Hz, 4H). 19F NMR (282 MHz, CDCl3) 124a: 93.85 (dd, J1 = 250.3 Hz, J2 = 51.3 Hz, 2F), 94.47 (dd, J1 = 254.6 Hz, J2 = 20.3 Hz, 2F), 101.65 (dd, J1 = 250.1 Hz, J2 = 40.6 Hz, 2F), 103.91 ( dddd, J1 = 250.4 Hz, J2 = 63.1 Hz, J3 = 16.9 Hz, J4 = 7.4 Hz, 2F), 102.37 (d, J = 39.4 Hz, 2F), 136.42 (ddd, J1 = 51.0 Hz, J2 = 22.8 Hz, J3 = 8.5 Hz, 2F), 149.46 (d, J = 63.8 Hz, 2F). 124b: 95.37 (d, J = 253.7 Hz, 2F), 97.60 (dd, J1 = 252.2 Hz, J2 = 59.7 Hz, 2F), 99.69 (dd, J1 = 252.5 Hz, J2 = 38.2 Hz, J3 = 5.2 Hz, 2F), 100.60 (ddddd, J1 = 254.5 Hz, J2 = 78.0 Hz, J3 = 20.5 Hz, J4 = 6.2 Hz, J5 = 2.1 Hz, 2F), 131.62 (s, 2F), 137.86 (d, J =78.4 Hz, 2F), 148.33 (dddd, J1 = 59.9 Hz, J2 = 22.9 H z, J3 = 9.2 Hz, J4 = 4.6 Hz, 2F). Anal. Calcd for C30H16F14N2 C 53.74, H 2.41, N 4.18. Found: C 53.81, H 2.54, N 3.89. 4,16bis(Pyrrolidin 1 yl) perfluoro[2.2]paracyclophane (125) and a mixture of 4,12bis ( pyrrolidin1 yl ) perfluoro[2.2]paracyclophane ( 60% as well as 40% other two isomers, 126) : To a solution of pyrrolidine (78 mg, 1.1 mmol) in anhydrous tetrahydrofuran (8 mL) was added F8 (124 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentr ated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to provide 4,16bis ( pyrrolidin 1 yl ) perfluoro[2.2]paracyclophane ( 125, 40 mg) and a mixture of

PAGE 129

129 4,12bis ( pyrrolidin 1 yl ) perfluoro[2.2]paracyclophane (60% as well as 40% other two isomers 126 ) (total yield: 80.0%) as a yellow solid. 125: m p 245 oC decomposition; 1H NMR (300 MHz, CDCl319F NMR (282 MHz, CDCl397.72 (m, 2F), 98.49 (dd, J1 = 246.8 Hz, J2 = 16.6 Hz, 2F), 105.99 (ddd, J1 = 249.0 Hz, J2 = 35.3 Hz, J3 = 10.4 Hz, 2F), 106.48 (ddd, J1 = 249.0 Hz, J2 = 85.2 Hz, J3 = 31 Hz, 2F), 130.36 (d, J = 87.1 Hz, 2F), 131.96 (m, 2F), 143.25 (m, 2F). Anal. Calcd for C24H16F14N2 C 48.17, H 2.70, N 4.68. Found: C 48.28, H 2.88, N 4.53. 126: m p 154 oC decomposition; 1H NMR (300 MHz, CDCl3 (m, 4H), 1.96 (m, 4H), 1.78 (m, 4H). 19F NMR (282 MHz, CDCl394.82106.08 (m, 8F), 129.60132.20 (m, 2F), 132.20133.80 (m, 2F), 146.20147.30 (m, 2F). Anal. Calcd for C24H16F14N2 C 48.17, H 2.70, N 4.68. Found: C 48.21, H 2.62, N 4.55. 4,7,12tri ( Pyrrolidin 1 yl ) perfluoro[2.2]paracyclophane (127) and 4,7,13tri ( pyrrolidin 1 yl ) perfluoro[2.2]paracyclophane (128) : To a solution of pyrrolidine (156 mg, 2.2 mmol) in anhydrous tetrahydrofuran (8 mL) was added F8 (124 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 96 h. The reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel, hexanes) to provide compound 127 (first fraction, 62 mg) and compound 128 (second fraction, 61 mg) (total yield: 75.5%) as a brownish solid. 127: m p 203 oC decomposition; 1H NMR (300 MHz, CDCl3 1.82 (m, 12H). 19F NMR (282 MHz, CDCl397.85 (dd, J1 = 246.8 Hz, J2 = 18.6 Hz, 1F), 98.35 (d, J = 251.0 Hz, 1F), 99.34 (dd, J1 = 257.2 Hz, J2 = 20.9 Hz, 1F), 101.44 (ddd, J1 = 251.0 Hz, J2 = 41.5 Hz, J3 = 14.4 Hz, 1F), 101.71 (ddd, J1 = 249.0 Hz, J2 = 74.7 Hz, J3 = 22.6 Hz, 1F), 103.86 (dd, J1 = 251.0 Hz, J2 = 62.3 Hz, 1F), 1 04.55 (dd, J1

PAGE 130

130 = 251.0 Hz, J2 = 58.1 Hz, 1F), 105.98 (dd, J1 = 252.9 Hz, J2 = 60.1 Hz, 1F), 124.22 (d, J = 72.8 Hz, 1F), 125.97 (dd, J1 = 58.1 Hz, J2 = 16.6 Hz, 1F), 131.82 (dd, J1 = 68.2 Hz, J2 = 26.8 Hz, 1F), 132.22 (d, J = 57.8 Hz, 1F), 147.72 (m, 1F). Anal. Calcd for C28H24F13N3 C 51.78, H 3.72, N 6.47. Found: C 51.44, H 3.50, N 6.12. 128: m p 219220 oC ; 1H NMR (300 MHz, CDCl3 12H). 19F NMR (282 MHz, CDCl3 92.97 (d, J = 251.0 Hz, 1F), 96.1 4 (dt, J1 = 248.2 Hz, J2 = 8.2 Hz, 1F), 97.53 (dd, J1 = 251.0 Hz, J2 = 20.6 Hz, 1F), 98.38 (d, J = 249.0 Hz, 1F), 99.95 (dd, J1 = 249.0 Hz, J2 = 25.1 Hz, 1F), 100.94 (ddd, J1 = 249.0 Hz, J2 = 95.3 Hz, J3 = 51.9 Hz, 1F), 106.91 (ddd, J1 = 249.0 Hz, J2 = 35.3 Hz, J3 = 6.2 Hz, 1F), 107.16 (ddd, J1 = 251.0 Hz, J2 = 84.9 Hz, J3 = 33.3 Hz, 1F), 124.73 (d, J = 97.6 Hz, 1F), 126.83 (m, 1F), 134.76 (m, 1F), 137.37 (d, J = 87.1 Hz, 1F), 148.73 (m, 1F). Anal. Calcd for C28H24F13N3 C 51.78, H 3.72, N 6.47. Found: C 51.47, H 3.51, N 6.29.

PAGE 131

131 APPENDIX X RAY DATA Figure A 1 X ray structure of perfluoro[2.2]paracyclophane

PAGE 132

132 Crystal Data and Structure Refinement for Perfluoro[2.2]paracyclophane Identification code px01 Empirical formula C16 F16 Form ula weight 496.16 Temperature 173(2) K Wavelength 0.71073 Crystal system Monoclinic Space group P2(1)/c Unit cell dimensions a = 13.9870(6) = 90. b = 8.8637(4) = 100.184(2). c = 11.7764(5) = 90. Volume 1437.00(11) 3 Z 4 Density (calculated) 2.293 Mg/m 3 Absorption coefficient 0.281 mm 1 F(000) 960 Crystal size 0.18 x 0.14 x 0.09 mm 3 Theta range for data collection 1.48 to 27.49. Index ranges 18 11 11 Reflections collected 8928 Independent reflections 3277 [R(int) = 0.0462] Completeness to theta = 27.49 99.0 % Absorption correction Integration Max. and min. transmission 0.9819 and 0.9548 Refinement method Full matrix least squares on F 2 Data / restraints / parameters 3277 / 0 / 289 Goodness of fit on F 2 1.061 Final R indices [I>2sigma(I)] R1 = 0.0350, wR2 = 0.0905 [2654] R indices (all data) R1 = 0.0464, wR2 = 0.0972 Largest diff. peak and hole 0.407 and 0.323 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 )+(m*p)2+n*p], p = [max(F o 2 ,0)+ 2* F c 2 ]/3, m & n are constants.

PAGE 133

133 Figure A 2 X ray structure of perfluoro[2.2.2]paracyclophane

PAGE 134

134 Crystal Data and Structure Refinement for Perfluoro[2.2.2]paracyclophane Identification code lhz2 Empirical formula C24 F24 Formula weight 744.24 Temperature 173(2) K Wavelength 0.71073 Crystal system Triclinic Space group P 1 Unit cell dimensions a = 10.056(3) = 70.809(4). b = 10.297(3) = 80.175(4). c = 13.570(4) = 61.718(4). Volume 1168.4(6) 3 Z 2 Density (calculated) 2.115 Mg/m 3 Absorption coefficient 0.259 mm 1 F(000) 720 Crystal size 0.23 x 0.08 x 0.05 mm 3 Theta range for data collection 1.59 t o 22.75. Index ranges 10 11 14 Reflections collected 5488 Independent reflections 3082 [R(int) = 0.0469] Completeness to theta = 22.75 97.9 % Absorption correction None Max. and min. transmission 0.9884 and 0.9433 Refinement method Fullmatrix least squares on F 2 Data / restraints / parameters 3082 / 0 / 433 Goodness of fit on F 2 1.004 Final R indices [I>2sigma(I)] R1 = 0.0337, wR2 = 0.0878 [2478] R indices (all data) R1 = 0.0442, wR2 = 0.0940 Largest diff. peak and hole 0.346 and 0.281 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 )+(m*p)2+n*p], p = [max(F o 2 ,0)+ 2* F c 2 ]/3, m & n are constants.

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135 LIST OF REFERENCES 1 Brown, C. J.; Farthing, A.C. Nature 1949, 164, 915 2 Gorham, W F. J. Polym. Sci. Part A1 1966, 4 3027 3 Reviews: (a) Vogtle, F. Cyclophane Chemistry; Wiley; New York, 1993. (b)Boekelheide, V. Top. Curr. Chem. 1983, 113, 87. (c) Hopf, H.; Marquard, C. Strain and Its Implications In Organic Chemistry; Kulwer; Dordrech t, 1989 4 Dyson, P. J.; Humphrey, D. G.; McGrady, J. E.; Mingos, D. M. P.; Wilson, D. J. J. Chem. Soc., Dalton Trans ., 1995, 4039 5 Brase, S.; Dahmen, S.; Hofener, S.; Lauterwasser, F.; Kreis, M.; Ziegert, R. E. Synlett 2004, 2647 6 Szwarc, M. J. Chem. Phys ., 1 948, 16, 128 7 Cram, D. J.; Steinberg, H. J. Am. Chem. Soc 1951, 5691 8 Otsubo, T.; Horita, H.; Misumi, S. Synthetic Communications, 1976, 6 591 9 Chow, S. W.; Pilano, L. A.; Wheelwright, W. L. J. Org. Chem 1970, 35, 20 10. Dolbier, W. R. Jr.; Asghar, M. A.; Pan, H. Q. US Patent 5210341, 1993 11. Dolbier, W. R. Jr.; Asghar, M. A.; Pan, H. Q.; Celewicz, L. J. Org. Chem. 1993, 58, 1827 12. Dolbier, W. R. Jr.; Rong, X. X. US Patent 5536892, 1995 13. Dolbier, W. R. Jr.; Rong, X. X.; Xu, Y.; Beach, W. F. J. Org. Chem 1997 62, 7500 14. Dolbier, W. R. Jr.; Duan, J. X.; Roche, A. J. US Patent 5841005, 1998 15. Dolbier, W. R. Jr.; Duan, J. X.; Roche, A. J. Org. Lett. 2000, 2 1867 16. Dewhirst, K. C.; Cram, D. J. J. Am. Chem. Soc. 1958 80, 3115> 17. Davila, A.; Escobedo, J. O.; Read, M. W.; Froncze k, F. R.; Strongin, R. M. Tetrahedron Lett 2001, 42, 3555 18. Filler, R.; Cantrell, G. L.; Wolanin, D, Naqvi, S. M. J. Fluorine Chem 1986, 30, 399 19. Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691 20. Furo, T.; Mori, T.; Wada, T.; Inoue, Y. J. Am. Che m. Soc. 2005, 127, 8242

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140 98. Cram, C. J.; Day, A.C. J. Org. Chem. 196 6 3 1 1227 99. Gantzel, P. K.; Trueblood, K. N. Acta Crsyt 1965, 18, 958 100. Reich, H. J.; Cram, D. J. J. Am. Che m. Soc 1968, 90, 1365

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141 BIOGRAPHICAL SKETCH Lianhao Zhang was from Shandong, Peoples Republic of China. He received his B.S. degree from Shandong University in July 1987, and the M.S. degree in organic chemistry from Northwest U niversity in July 1990. From July 1990 to January 1997, he worked in the Xian Modern Chemistry Research I nstitute as a research chemist. From January 1997 to June 2000, He worked in the University of Florida as a visiting scholar with Professors William R. Dolbier, Jr. and Alan R. Katritzky. From June 2000 to August 2006, he worked in Alchem Laborities Corporation as a research chemist. He started his Ph.D. program in the department of chemistry, University of Florida in August 2006 under the supervision of Professor William R. D olbier, Jr. He married with his wife, Jinfeng Peng. They have two children Pengcheng and Nina.