the chemistry of 1,1,2,2,9,9,10,10-octafluoro[2.2...
TRANSCRIPT
THE CHEMISTRY OF 1,1,2,2,9,9,10,10-OCTAFLUORO[2.2] PARACYCLOPHANES
By
YIAN ZHAI
A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY
UNIVERSITY OF FLORIDA
2005
Copyright 2005
by
Yian Zhai
The work presented in this dissertation is dedicated to my wife Lazhen.
ACKNOWLEDGMENTS
I would like to thank my advisor and the chair of my committee, Dr. William R.
Dolbier, Jr., for affording me the opportunity to study in his laboratory. The time spent
under his direction has been invaluable, and I am indebted to him for his patience,
guidance, and encouragement.
With as much owed respect and thanks, the friendship and mentoring of Dr. Merle A.
Battiste will not be forgotten as well as his insight and inspiration on my research.
Without Dr. Ion Ghiviriga’s help in NMR characterizations, I would have had serious
problems in identifying compounds; I also thank Dr. Merle A. Battiste, Dr. Ion Ghiviriga,
Dr. Weihong Tan, and Dr. John Sabin for being on my committee and for their time and
effort. I acknowledge Dr. Khalil Abboud for the x-ray analysis with great appreciation.
Personally, I would also like to thank my wife La-Zhen Xiang. Without her love and
support, I would not be in this position today. I also thank my family: mother Feng-Xian
Zhang, father Jian-Ting Zhai, my sister Xiao-Chun Zhai, Xiao-Yan Zhai, my mother-in-
law Qin-Ju Tang, and father-in-law Li-Wang Xiang. Their support and love are
acknowledged, and I thank them for that.
Over the years I have been taught by some truly inspirational teachers, I extend my
thanks to Dr. Wei-Jue Ding for her mentoring and for opening the door into the realm of
organic chemistry. I wish to thank past and present members of the Dolbier group for
their friendship and help. I also want to take a moment to specifically thank Dr. Jian-Xin
Duan for his friendship and help in everything. I would also like to give specific thanks to
iv
Dr. David Powell, and the MS group as well as the CHN group for their technical support
with my MS characterization elemental analysis. Dr. Kirk S. Schanze’s group provided
the UV and fluorescence instruments for some of my compounds. Dr. Yao Liu helped me
in the fluorescence spectra characterization.
Finally, I appreciate everything that the Chemistry Department has done during my
time here.
v
TABLE OF CONTENTS page
ACKNOWLEDGMENTS ..................................................................................................iv
LIST OF TABLES............................................................................................................viii
LIST OF FIGURES .............................................................................................................x
ABSTRACT..................................................................................................................... xiv
CHAPTER 1 INTRODUCTION......................................................................................................1
1.1 A Brief History of Cyclophane Chemistry .....................................................1 1.1.1 [2.2] Paracyclophane........................................................................3 1.1.2 Other Cyclophanes...........................................................................5
1.2 The Physical and Chemical Properties of Cyclophanes ...............................10 1.3 1, 1, 2, 2, 9, 9, 10, 10-Octafluoro[2.2]paracyclophane (AF4) .....................14 1.4 Aryne Chemistry...........................................................................................17
2 4,5-DEHYDRO- AND 4,5,15,16-BIS-
DEHYDROOCTAFLUORO[2.2]PARACYCLOPHANES: FACILE GENERATION AND EXTRAORDINARY DIELS-ALDER REACTIVITY .......24
2.1 Introduction...................................................................................................24 2.2 Results and Discussions................................................................................26
2.2.1 Synthesis of Aryne Precursors .......................................................26 2.2.2 Reactions of 4, 5-Dehydrooctafluoro[2.2]paracyclophane, 1........272.2.3 Reactions of 4,5,15,16-Bis-
(Dehydro)octafluoro[2.2]paracyclophane, 17...............35 2.2.4 NMR Discussion.100.......................................................................36 2.2.5 X-ray Discussion............................................................................38
2.3 Conclusion ....................................................................................................40 2.4 Experimental .................................................................................................41
3 CADOGAN METHOD AND REACTION MECHANISM ...................................55
3.1 Introduction...................................................................................................55 3.2 Results and Discussion .................................................................................56
3.2.1 The Cadogan Method.....................................................................56 3.2.2 Ene Reactions.................................................................................57
vi
3.2.3 2-Methoxynaphthalene Reaction ...................................................60 3.2.4 Tetracyclone Reaction ...................................................................61 3.2.5 Norbornadiene Reactions...............................................................62 3.2.6 Reaction with 1,3,5-Cycloheptatriene............................................63
3.3 Mechanistic Study of AF4-yne .....................................................................69 3.3.1 Base and Solvent Study .................................................................70 3.3.2 The Different Selectivity of the Two Methods ..............................71 3.3.3 The Selectivity of AF4-yne Toward Diels-Alder and
Ene reaction...................................................................74 3.3.4 t-Butoxide Ion Adduct ...................................................................76 3.3.5 Mechanism.....................................................................................77 3.3.6 Isotopic Labeling Experiments ......................................................82 3.3.7 Reactions in the Presence of Electron Trap Reagents ...................83
3.4 Conclusion ....................................................................................................85 3.5 Experimental .................................................................................................87
4 EFFICIENT SYNTHESES OF NOVEL NAPHTHALENO- AND
ANTHRACENO-OCTAFLUORO[2.2]PARACYCLOPHANES...........................99
4.1 Introduction...................................................................................................99 4.2 Results and Discussion ...............................................................................103 4.3 UV and Fluorescence Spectrum..................................................................109 4.4 Conclusion ..................................................................................................116 4.5 Experimental ...............................................................................................117
5 NOVEL CAGE COMPOUND...............................................................................121
5.1 Introduction.................................................................................................121 5.2 Result and Discussions ...............................................................................124
5.2.1 Synthesis of Cage Compound......................................................124 5.2.2 Cage with Triplet Oxygen............................................................130 5.2.3 Cage with Chlorine ......................................................................131 5.2.4 Cage with Singlet Oxygen ...........................................................132 5.2.5 Cage with Bromine ......................................................................134
5.3 Conclusion ..................................................................................................135 5.4 Experimental ...............................................................................................135
X-RAY DATA.................................................................................................................142
LIST OF REFERENCES.................................................................................................158
BIOGRAPHICAL SKETCH ...........................................................................................174
vii
LIST OF TABLES
Table page
1-1 Structural features of AF4 and [2.2]paracyclophane11 ...............................................15
2-1. Diels-Alder reactions from treatment of 4-iodooctafluoro[2.2] paracyclophane, 1, with potassium t-butoxide. ........................................................30
2-2. Diels-Alder reactions from treatment of 4, 15-diodo-octafluoro [2.2]paracyclophane, 18, with potassium t-butoxide, in refluxing solvent.................................................36
3-1 [2+2+2] to [2+2] products ratio of norbornadiene with AF4-yne ..............................63
3-2 Base and solvent effects in AF4-yne reaction with anthracene..................................70
3-3 Base solubility in butyl ether solvent .........................................................................71
3-4 Competition reactions of naphthalene to benzene......................................................72
3-5 Selectivity in Diels-Alder reaction under Cram conditions........................................73
3-6 Competition reactions of benzene to 1-octene ...........................................................74
3-7 Competition reaction of anthracene with 1-octene in butyl ether for 5 hours at 110℃ under Cram condition...............................................................................74
3-8 Reaction of AF4-yne with olefins in butyl ether ........................................................75
3-9 The AF4-yne selectivity of DA over Ene reaction under Cadogan conditions (3 h at 110℃ in butyl ether) .....................................................................................75
3-10 Summary of t-butoxide adduct under Cram’s conditions.........................................77
3-11 Ionization potential of alkenes126..............................................................................78
3-12 IAF4 reduced to AF4 in refluxing butyl ethera.........................................................83
3-13 Additive effect on the reduction of AF4-yne with 1-octene under Cram conditions at 110℃ for 3 h ........................................................................................................84
3-14 Additive effect on the reaction of AF4-yne with anthracene under Cram conditions at 110℃ for 3 h ........................................................................................................85
viii
4-1 Fluorescence spectra data of fluorinated [2.2]paracyclophanes...............................116
5-1 Base screening results...............................................................................................126
5-2 Solvent effect in the reaction of pseudo-ortho-diIAF4 with anthracene under microwave conditions ..................................................................................127
ix
LIST OF FIGURES
Figure page
1-1 [2.2](1,3)Cyclophane.....................................................................................................1
1-2 [2.2](1,4)Cyclophane.....................................................................................................1
1-3 Chemical shift (1H NMR) and charge transfer complex of [2.2] paracyclophane ........3
1-4 Geometry of [2, 2] paracyclophane11 ............................................................................4
1-5 Different bridge connection of [2.2]cyclophane............................................................4
1-6 Chemical vapor deposition (CVD) polymerization.......................................................5
1-7 π Effect on aromatic protons .........................................................................................6
1-8 Distances of two aromatic protons to the other benzene deck ......................................7
1-9 Synthesis of [2.2][1,4]naphthalenoparacyclophane.......................................................7
1-10 Synthesis of [2.2](1,4)naphthalenophane ....................................................................8
1-11 [2.2]Anthracenophane and [2.2](2,5)heterophanes .....................................................8
1-12 [2.2](1,4)Athracenophane............................................................................................9
1-13 Highly condensed phanes ..........................................................................................10
1-14 Photo reaction of [2.2]naphthalenopahane ................................................................12
1-15 Photo and thermal reversibility of [2.2](1,4)anthracenophane..................................13
1-16 Octafluoro[2.2]paracyclophane (AF4 ) .....................................................................15
1-17 Nitration and dinitration of AF4................................................................................16
1-18 Generation of benzofuran aryne ................................................................................17
1-19 C14 Labelling experiment...........................................................................................18
1-20 Methods of benzyne generation.................................................................................18
1-21 Aryne with furan........................................................................................................19
x
1-22 Co-cyclisation of arynes with alkynes to phenanthrene derivatives..........................20
1-23 Palladium catalyzed reactions of allyl chlorides with benzyne.................................20
1-24 Palladium catalyzed reaction between allytributylstannane, allyl chloride, and benzyne.....................................................................................................................21
1-25 Paracyclophane aryne ................................................................................................22
1-26 [2.2]Paracyclophane bis-aryne ..................................................................................22
2-1 Bis-paracyclophane aryne with furan reaction ............................................................25
2-2 Mono- and bis-AF4-yne ..............................................................................................26
2-4 Diels-Alder reaction of AF4-yne.................................................................................29
2-5 Products of 1,4-dimethylnaphthalene and 2,3-dimethylnaphthalene ..........................31
2-6 Products of 2-methoxylnaphthalene with AF4-yne.....................................................32
2-7 Products of furan and 2,5-diphenylfuran with AF4-yne..............................................33
2-8 Product of [2.2]paracyclophane with AF4-yne (bold shifts on this structure indicate protons pointed toward the viewer) ............................................................34
2-9 Products of bicyclo[2.2.1]hepta-2,5-diene with AF4-yne ...........................................35
2-10 The bis-Diels-Alder reaction of AF4-yne..................................................................37
2-11 ORTEP drawing of anthracene adduct 5 and endo furan adduct 12a........................39
2-12 ORTEP drawing of [2.2]paracyclophane adduct 14 and bis naphthalene adduct 20 ..................................................................................................................39
3-1 Decomposition of benzene-diazonium slat..................................................................55
3-2 1-Octene with AF4-yne reaction .................................................................................57
3-3 Chemical shifts of cyclopentene and cyclohexene products .......................................58
3-4 Chemical shifts of products from the reaction of α-methylstyrene with AF4-yne......60
3-5 Retro Diels-Alder reaction of 2-methoxynaphthalene adduct to phenyl anthraceno[2.2] paracyclophane.........................................................................................................61
3-6 Chemical shifts of tetracyclone with AF4-yne product...............................................61
3-7 Chemical shifts of cycloheptatriene products 8 and 9 .................................................65
xi
3-8 Primary AF4-yne ene product with AF4-yne reaction to products 8a&8b .................68
3-9 SRN1 reduction of IAF4 to AF4 ...................................................................................80
3-10 Reduction mechanism of IAF to AF4 in the presence of olefin................................81
3-11 Olefin with KOtBu complex......................................................................................82
4-1 Anthracenophane 1 and naphthalenophane 2 ............................................................100
4-2 [2.2](1,4)(9,10)anthracenophane 3, [2.2] paracyclo(9,10) anthracenophane 4 and [2.2](1,4)naphthaleno(9,10)anthracenophane ........................................................100
4-3 Polyfluoroaryl [2.2]cyclophanes 6 and 7...................................................................101
4-4 Diles-Alder reaction of mono and bis-AF4-yne ........................................................102
4-5 Bridge fluorinated [2.2]cyclophane 12, 13, 14 and 15 ..............................................103
4-6 Reaction of adduct with 3,6-dipyridinyl-1,2,4,5-tetrazine 16 ...................................104
4-7 Fragment of [2.2]cyclophane 12................................................................................105
4-8 Chemical shifts of [2.2]cyclophane 12, 13, 14 and 15 ..............................................106
4-9 Dimerization of phenyl anthracenophane 21.............................................................108
4-10 ORTEP drawing of compound 21 ...........................................................................108
4-11 UV spectra of bridge fluorinated [2.2]cyclophanes 12-15 ......................................110
4-12 Fluorescence spectra of bridge fluorinated [2.2]cyclophane...................................111
4-13 UV spectra in dichloromethane of compound 21 and 22 compared to compound 12 and 13. .............................................................................................113
4-14 Fluorescence spectra in dichloromethane of compound 21 and 22.........................114
4-15 Fluoresence of Diels-Alder products in dichloromethane.......................................115
5-1 Pyramidalized alkene.................................................................................................122
5-2 Some pyramidalized alkenes .....................................................................................123
5-3 Tribenzo-4,7-dihydroacepentalene derivative ...........................................................123
5-4 4,5,15,16-bis(dehydrooctafluoro[2.2]paracyclophane 4 and 4,5,12,13-bis(dehydrooctafluoro[2.2]paracyclophane 5.........................................................124
xii
5-5 The reaction of the pseudo-ortho-4,12-diiodooctafluoro[2.2]paracyclophane with anthracene...............................................................................................................124
5-6 NMR assignments of pseudo-ortho-diiodoAF4 with anthracene products under Cram conditions .....................................................................................................125
5-7 ORTEP drawing of the cage compound (right) and epoxide (left) ...........................129
5-8 Tricycle[3.3.2.03,7]-dec-3(7)-ene 10 and dodecahedradiene 11 ................................130
5-9 Cage compound reaction with oxygen ......................................................................130
5-10 Syn-sesquinorbornene..............................................................................................131
5-11 Bubbling oxygen through the solution of cage compound......................................132
5-12 Trapping the intermediate of the reaction of singlet oxygen with pyramidalized alkene .....................................................................................................................133
5-13 Compound 14 and cage with singlet oxygen product 15.........................................134
5-14 Reaction of cage with bromine................................................................................135
xiii
Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy
THE CHEMISTRY OF 1,1,2,2,9,9,10,10-OCTAFLUORO[2.2] PARACYCLOPHANES
By
Yi-An Zhai
May 2005
Chair: William R. Dolbier, Jr. Major Department: Chemistry
The chemistry of [2.2]cyclophanes has a number of unique and interesting
theoretical and practical aspects that have attracted the interests of organic chemists for
more than 50 years. It has been demonstrated in earlier work from our lab that the
chemistry of 1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane differs significantly form
that of its non fluorinated analogs.
The initial research in the current project involved the discovery of two good
methods for the generation of 4,5-dehydro and 4,5,15,16- bis(dehydro)-1,1,2,2,9,9,10,10-
octafluoro[2.2]paracyclophane-yne (AF4-yne and bis-AF4-yne) chemistry. The AF4-yne
generated from the reaction of potassium t-butoxide with iodo AF4 derivatives gave very
high yields for Diels-Alder (DA) reactions, including the very poor DA substrate,
benzene. Bis-AF4-yne also gave high yields for DA reactions. A new synthetic method of
synthesizing new bridge fluorinated polynuclear paracyclophanes has been developed by
xiv
using these DA adducts as intermediates. The physical and chemical properties of those
new paracyclophanes were investigated.
When AF4 aryne is generated from the nitrosyl acetamide AF4 derivative, it has a
very different reactivity towards alkene substrates compared to that generated from IAF4
via the KOtBu method. Experiments including isotopic labelling reactions were carried
out to gain an understanding of the differences observed for the two methods.
A novel cage compound was discovered by the reaction of pseudo-ortho-diiodo-
AF4 with KOtBu and anthracene. The physical and chemical properties of this cage
compound were investigated.
Finally, a study of the reduction of AF4-yne to AF4 was carried out, and it was
found that electron acceptor reagents have an effect on the reduction rate of IAF4 to AF4.
This process might involve electron transfer (ET) to produce radical anion as reaction
intermediate.
The selectivity of AF4-yne toward DA reaction under different reaction conditions
was established, and it was found that the DA reaction of anthracene with AF4-yne is
2.7*104 times faster than the same reaction with benzene.
xv
CHAPTER 1 INTRODUCTION
1.1 A Brief History of Cyclophane Chemistry
Cyclophane chemistry has been studied for more than one century and has been
broadened dramatically. Cyclophane chemistry has both theoretical and practical use and
plays an important role in the study of electronic interactions and system strain. It
demonstrates that two or more closely placed π electron clouds have both steric and
electronic interactions. Transannular interactions also play an important role in the
stabilization of the cations and anions generated from cyclophanes.
The first cyclophane was synthesized by Pellegrin1 in 1899 through Wurtz coupling
of 1,3-bis(bromomethyl)benzene (Figure 1-1).
CH2Br
Na2
CH2Br
Figure 1-1 [2.2](1,3)Cyclophane
Brown and Farthing synthesized [2.2] paracyclophane in 1949 by pyrolysis of p-
xylene (Figure 1-2), and published a low resolution X-ray structure analysis.2, 3 German
chemists Lüttringhaus4 and Huisgen5 first reported the synthesis of alphatic bridged
cyclophanes.
Figure 1-2 [2.2](1,4)Cyclophane
1
2
These studies illustrated that the aromatic rings in cylcophanes are not planar but
distorted out of planarity by bending. The x-ray study unequivocally revealed that a
benzene ring can be distorted into boat-, chair-, and twist-forms by clamping or bridging
them in cyclophanes. These aberrations led to unusual spectroscopic properties and
chemical reactivities.
The interaction in the [2.2]paracyclophane between the two benzene rings leads to a
novel extended π-electron system. The Highest Occupied Molecular Orbital (HOMO) is
higher than that of the corresponding alkyl benzene; the Lowest Unoccupied Molecular
Orbital (LUMO) is lower than that in the open chain molecule. Thus, the energy gap
between the HOMO/LUMO is much lower than the open chain compounds. The same
type of interaction, albeit weaker, exists in the [3.3]cyclophane but is absent in the more
widely separated [4.4]cyclophane, where the individual benzenes behave as separated π-
electron systems.
Cyclophane chemistry gives an opportunity to increase the distortion gradually and
successively, which changes the chemical and spectroscopic properties of the aromatic
units. Some interesting functionized units can be placed very close to the aromatic ring.
For example, one can compare the transannular electronic effects and steric strain of
multi-layered cyclophanes or heterocyclophanes with these in the parent hydrocarbon
compounds.6 Cyclophane chemistry also has found applications. Cyclophane may serve
as a building unit for nests, hollow cavities, ‘multi-floor’ structures, helices, macro-
polycyclics, macro-hollow tubes, novel ligand systems, etc. Cyclophane chemistry also
has importance in supermolecular chemistry, molecular recognition, and may be used as a
building block for organic catalysts (novel ligand) and crown ethers.6-8
3
How far can aromatic rings be distorted? What are the physical and chemical
properties of these cyclophanes? These questions have been pursued for decades. The
chemistry of uniquely strained [2.2]paracyclophane and other cyclophanes has been the
subject of research since Cram’s first description of [2.2]paracyclophanes.9 Since then,
numerous publications have emerged. Many different cyclophanes such as meta, para and
heterocyclophanes have been synthesized and studied.
1.1.1 [2.2] Paracyclophane
The [2.2] paracyclophane is a special example and reflects the essence of
cyclophane chemistry. Its two aromatic rings are placed face to face and have a chair-
like configuration instead of planar (deformation of the benzene ring), due to the π-
electron interaction between the two aromatic rings. Chemists are also interested in the
transannular electronic effects on the chemical reactivities of the ring and bridge. Their
reactivity is induced by the other ring and also causes a charge transfer interaction
(Figure 1-3) between the two aromatic rings.8, 10
6.373.051
23
45
67 89
1011
12 13
141516
H1
Figure 1-3 Chemical shift (1H NMR) and charge transfer complex of [2.2]paracyclophane
In [2.2] paracyclophane, the aromatic proton signal appears at 6.37 ppm, shifted
about 0.5 ppm upfield from that of p-xylene.9 This is due to a shielding effect from the
ring current of the benzene ring on the opposite deck.
According to Cram,10 the stereochemical course of several polar addition and
substitution reactions at the bridge position of [2,2] paracyclophane system is best
4
explained on the basis of a species similar to 1. The cation positive charge can be
distributed over both aromatic rings to compensate for the bond angle strain.
Figure 1-4 shows the approximate structure based on the x-ray crystal structure.11
The intermolecular separation (d) between the central carbon atoms of the two benzene
rings is shortened to 3.09 Å (the normal Van der Waals separation between parallel
benzene rings is set at 3.40 Å as a minimum). The two benzene rings are in boat
configuration. This is attributed to a considerable transannular π-π overlap. The bridge
bond length is unusually large, 1.630 Å at 291 K (X-ray structure analysis was taken at
93 K) to compensate for the transannular steric and electronic repulsion.
Figure 1-4 Geometry of [2, 2] paracyclophane11
The bond angle and bond length deformations, as well as the face to face
compression of two benzene rings, lead to high ring strain in cyclophanes. Boyd
measured the heat of combustion of cyclophanes 2, 3, 4 (Figure 1-5), and determined
their strain as 12, 31, 23 kcal/mol, respectively.6, 12-14
2 3 4
Figure 1-5 Different bridge connection of [2.2]cyclophane
5
Chemical vapor deposition (CVD) polymerization of [2.2]paracyclophane (Figure
1-6),15 at 550℃ and 0.5mm pressure can form a thin, tough, polymer film called
“parylene” on the objects with true confirmality of the coating to all surfaces including
deep penetration into small spaces. This film has been found to be useful at temperatures
up to 130oC.16
nheat, CVD
2nH2C
H2C* *
2n
H2C
H2C
Figure 1-6 Chemical vapor deposition (CVD) polymerization
1.1.2 Other Cyclophanes
Nonbenzenoid aromatic compounds, such as azulene, tropolone, etc, are also
important in aromatic chemistry. These compounds have interesting deformation
structures caused by bridging. The charge transfer effects and π–electron cloud
interactions can be examined by bringing two nonbenzenoid rings together. Cyclophanes
which contain tropylium ions have been synthesized to test the charge-transfer
interactions.17, 18 When the tropylium rings are placed in a face-to-face position (9)
(Figure 1-7), the tropylium protons move to higher fields in the NMR spectrum(⊿δ≈1.22
ppm) than those unbridged tropylium ions (δ=9.28 ppm). This high-field shift is
attributed to the diamagnetic ring current effect of the benzene ring and the enhanced
electron density due to a charge-transfer effect. The singlet protons of a benzene ring in
stair-like compounds 7and 8 are at much higher fields than those in compounds 5, 6 and
6
9(⊿δ≈ 1.2 ppm). The benzene ring protons in 5 and 6 are nonequivalent because of their
fixed geometry (NMR time scale). The ring-flip of 8 does not occur until 120oC, whereas
the equilibration in two conformers of 6 happens at a higher temperature.
H
HH
H
H
7.76
7.19
6.00
8.49
H
H 7.69
5.98
H
H
H
H
7.43
H H
H7.63
8.76
H H
H
H
5.51
4.76
7.717.31
8.93
H
H
H
H4.55
8.84
7.20
H MeH
H H
8.067.70
6.94 5.70
9
5 6 7
8
Figure 1-7 π Effect on aromatic protons
[2]Azuleno[2]phanes 10 and 12 (Figure 1-8) are 10π systems.19, 20 The C(9)-C(10)
bond (azulene numbering) is elongated, and the azulene ring and benzene ring in
compound 10 are distorted up to 9o and 13.8o, respectively. The distance between the
single proton and the benzene rings in the intermediates for 10, 11, and 12 are estimated
to be 1.20, 1.50, and 1.75 Å, respectively depending on the different barriers to ring
inversion, which stem from the extent of steric crowding in the intermediate between the
single proton and the neighboring benzene ring.
7
10
11
12
Figure 1-8 Distances of two aromatic protons to the other benzene deck
The cylcophanes with naphthalene rings and anthracene rings are of special interest,
because naphthalene and anthracene have a more extensive aromatic core. It would be
interesting to study the nature and extent of deformation of the naphthalene ring and
anthracene ring, the strain energy, and static and dynamic stereochemistry, as well as
charge transfer effects between neighboring aromatic units.
Naphthalenophane 13 was first synthesized in low yield from [2, 2] paracyclo-
phane by the annulation method in 1963 (Figure 1-9).9 Then, Wasserman and Keehn
reported the synthesis by coupling the p-xylene in situ from the pyrolysis of quaternary
ammonium salt with silver oxide in 41% yield,21, 22 which is an anti- and syn- mixture
NMe3 NMe3Br Br
+
Xylenereflux, 10h
S
S
hv(EtO)3P
13
Figure 1-9 Synthesis of [2.2][1,4]naphthalenoparacyclophane
8
that can be separated by crystallization. The optimum procedure to produce 13 would be
using the photochemical sulfur extrusion method with triethyl phosphate as a solvent.23
A considerable number of investigations have been made into the chemistry of
[2.2](1,4) naphthalenophanes. The syn- and anti- isomer 14 and 15 were first synthesized
by elimination-cycloaddition of 4-methyltrimethylammonium hydroxide in 3% yield
(Figure 1-10) each.24 The anti- configuration was confirmed by an alternate nine-step
synthesis, in which only anti- isomer was generated. Wasserman and Keehn modified the
procedure and got 40% anti- isomer and 4% syn- isomer.21 A highly efficient route to
compound 15 was designed by Brown and Sondheimer,25 which involved the solvolysis
of the corresponding ditosylate 16.
14 15
CH2OTs
CH2OTs16
Figure 1-10 Synthesis of [2.2](1,4)naphthalenophane
Anthracenophanes are virtually 1,4- or 9,10-disubstituted anthracenes, which have
lower ionization potential than naphthalene or benzene. Golden first reported [2.2] (9,10)-
anthracenophane (17) (Figure 1-11) in 1961.26 The synthesis and electronic absorption
and emission spectra of five member ring incorporated anthracenophanes (18) were
reported in 1977.27, 28
X
X=O, S
17 18
Figure 1-11 [2.2]Anthracenophane and [2.2](2,5)heterophanes
9
CO2Et
CH3
CH2Br
CH3
CH2NMe3
CH3
OH
1) LiAlH4
2) PBr3
1) NMe3
2) Ion exchangeresin
19
Figure 1-12 [2.2](1,4)Athracenophane
In order to study the effect of transannular π-electron interactions in excimer
fluorescence, photodimerization, and ESR phenomena, Misumi et al.29, 30 have
synthesized many cyclophanes which incorporate anthracenes. The first compound in this
series was synthesized from dimerization of 1,4-anthraquinodimethane, in turn derived by
a Hofmann elimination of a quaternary ammonium hydroxide (Figure 1-12). The anti-
isomer (19) was obtained in 14% yield.
Other cyclophanes, such as hetero- and meta-cyclophanes were also synthesized.31
Replacing benzene rings with pyridine rings results in [2.2](2,6)pyridinophane 20 (Figure
1-13).32 One of the pyrenophanes, [2.2](1,3) pyrenophane 21, was reported by Misumi at
al.,33 as well as a few “mixed,” “asymmetrical” pyrenophanes. Porphyrine 22, which is
very important in biological transformations, also has cyclophane characteristics and is
considered a special cyclophane serial.29 Calixarenes 23 belong to the [1n]cyclphane
10
group; their basket-like shape was adapted to host-guest or receptor-substrate
chemistry.31
N
N
20 21
N
NH N
HN
OH
HOHOOH
R
R
R
R22 23
Figure 1-13 Highly condensed phanes
1.2 The Physical and Chemical Properties of Cyclophanes
Unusual structural features help chemists understand molecules and pursue their
structural distortion limit. The works in this field provide useful information in
developing, confirming, and refining the theoretical underpinnings of science.
Cyclophane chemistry has provided insight into the ways in which molecules distribute
strain, the effects of strain on molecular reactivity, transannular effects on chemical
stability and spectroscopic properties, and as well as the criteria for aromatic stabilization.
The X-ray analysis of [2.2](1,4)paracyclophane reveals that the two benzene
moieties are separated by a distance of 299 pm, which is much smaller than the usual π-
system van der Waals contact distance of 340 pm between the two parallel aromatic rings
in crystals.34 As shown (Figure 1-4), the bridged carbons are only 278 pm apart, and the
11
center carbons are 309 pm, which means that the two aromatic rings are bent out of plane
by an angle of 12.6o.
It is obvious that two π clouds pressed hard against each other should lead to
additional steric repulsion between the two rings. One would intuitively assume that this
steric repulsion would be relieved by lowering the number of interacting π-electrons. In
contrast, the bending does not unambiguously increase or decrease the π electron
ionization energies.35 The benzene system would be deformed and decrease its
aromaticity due to lack of planarity, thus, ionization should be facilitated. On the other
hand, bending a π-system would localize its bond, i.e., forms a more polyenic type of
structure which would increase the ionization energy.
Model calculations using localized orbitals have shown that out of plane
deformations of ethylene have a negligible influence on its π-1 ionization energy, as long
as they do not exceed certain limits, typically about 20o for bending and/or twisting
modes.36, 37 The deformation results in decreasing ionization energy if it is not
compensated by the necessary admixture of low-lying 2s atomic orbitals to accommodate
the bulge, which would increase the ionization energy.
The study of π-electron energies in a series of cyclophanes by photoelectronic (PE)
spectra indicates that ionization energies of π-electrons are affected by the substituent
group in the benzene deck.35 The mean ionization energy for the two HOMOs of methyl
substituted benzenes decreased by 0.5 eV. The cyclophanes had a smaller decrease in
ionization energy. The ionization energy of superphane is not close to 6 eV as expected,
but rather 7.5 eV. The monobromine substitution in the benzene ring has negligible
influence on the PE spectra, while the amino group shifted the PE band towards the lower
12
field. Bridge octafluoro paracyclophane (AF4) is an extreme example. The fluorine
substitution induced the ionization energy shifts up field from 1.0 to 1.3 eV for the
corresponding orbitals. The analysis of PE spectra leads to the recognition of a novel
consequence of the “fluoro-effect”.
Cyclophanes involving higher aromatic systems have a lower ionization potential,
especially cyclophanes with incorporated anthracene. The syn- and anti-isomers of [2,
2](1,4)naphthalenophanes21, 38, 39 (Figure 1-14) can be interconverted by light. Irradiation
of syn-isomer 25 in degassed benzene leads primarily to the anti-isomer 24, while
continued irradiation of the 24 solution gives other products. Irradiation with light above
intermediate
2 + 2
2 + 2
4 + 4
hv 254 nm
-190oC
>190oC
24
25
26
26a 27
28
29
20oC
hv 350 nm
hv -hv
Figure 1-14 Photo reaction of [2.2]naphthalenopahane
13
290 nm gives intermolecular rearrangement product 28, which rearomatizes to 24 at room
temperature with a half life time of 76 s at 20oC. 28 is a kinetic product, because
extended irradiation for 10 days at room temperature leads to the thermodynamically
more stable product, dibenzoquinene 29, in 25-50% yield. This compound is confirmed
by x-ray, and presumably arises through two sequential [2π + 2π] additions (26a first then
26).
Normal naphthalene does not react with oxygen, but anti-[2.2]paracyclonaph-
thalene reacts with singlet oxygen to form transannular peroxide.22 This is due to the
deformation of the naphthalene ring by the strain.
hv 374 nm220oCor hv 254 nm
240oC
30
31 32
Figure 1-15 Photo and thermal reversibility of [2.2](1,4)anthracenophane
[2.2]Anthracenenophanes (Figure 1-15) are fascinating compounds. Both the anti-
and syn- isomers (31 and 32) are synthesized from the dimerization of 1,4-anthraquino-
dimethane.30, 40 The syn-isomer 32 can be rearranged thermally to the anti structure 31.
When light is used, the isomer 32 undergoes a rapid photo induced cyclization reaction to
form cage compound 30, which is both thermally and photochemically reversible.
14
The transannular effect on the spectroscopy of cyclophanes has been utilized in the
chemical luminescence polymer. π-Conjugated polymers having cyclophane derivatives
as the key unit have been synthesized by Chujo et al.41 These polymers were soluble in
common organic solvents, and self standing thin films exhibit strong blue photophoto-
luminescence in solution and strong bluish-green photoluminescence in solid state.
1.3 1, 1, 2, 2, 9, 9, 10, 10-Octafluoro[2.2]paracyclophane (AF4)
Fluorine has the largest electronegativity, while its Van der Waals radius is just
10% larger than that of hydrogen. The replacement of hydrogen by fluorine does not
cause much steric problem, but changes the bond dipolemoment dramatically. The C-F
bond, which is the strongest among the carbon-halogen bonds, is the shortest next to the
C-H bond but it is much stronger in energy. Accordingly, various types of
perfluorocarbons are both thermally and chemically stable compounds in sharp contrast
to perchlorocarbons. The electron cloud in the C-F bond is slightly polarized towards the
fluorine atom, thus electron repulsion between unshared electron pairs of fluorine atoms
is substantial. The characteristic features correspond to the stability of perfluorocarbons
against biological, chemical and physical stimuli.42 Perfluorocarbons have some salient
physical properties, such as low boiling point, insolubility in water and hydrocarbons,
and low surface tension.
Bridge fluorinated cyclophane (AF4), as mentioned above, has some unique
properties including its thermal and chemical stability. The synthesis of AF4 was a
challenge in organic chemistry for almost half of a century. The first chemical synthesis
of AF4 was published by Cram et al. in 1951,14 in which a highly diluted system was
used, and the reaction could not be scaled up. There are abundant derivatives of [2.2]
paracyclophane and other cyclophanes, but the derivatives of AF4 are scarce. One reason
15
for this is because of the lack of a large scale synthetic method for AF4. AF4 was
commercially unavailable until Dolbier’s group solved this problem in 2000.43-47 The
interest in synthesizing AF4 is mainly driven by the industrial application of this
compound as a monomer for chemical vapor deposition (CVD) (Figure 1-6)
polymerization of AF4, known in industry as “parylene-HT”. The C-F bond is not readily
oxidized, and compounds with multiple C-F bonds exhibit greatly improved oxidative
and thermal stability. The parylene-HT polymer has a much lower dielectric constant
(2.25) and a higher thermal stability (0.3% weight loss/h at 450℃) as well as a lower
moisture absorption,48 compared to the parent non fluorinated “parylene” polymer.
“Parylene-HT” film is expected to be an excellent insulator in Information Technology
(IT) industry.
FF
F F
FF
FF
Figure 1-16 Octafluoro[2.2]paracyclophane (AF4 )
Table 1-1 Structural features of AF4 and [2.2]paracyclophane11 AF4 [2,2]
Paracyclcophane α(deg) 11.8 12.6 β(deg) 12.6 11.2 c (Å) 2.80 2.78 d (Å) 3.09 3.09 e (Å) 1.380 1.394 f (Å) 1.577 1.569
The structure of AF4 11 is very similar to that of [2.2] paracyclophane.2 Some key
structural data are listed in Table 1-1 (also see Figure 1-16).
16
After successfully solving the problem of the synthesis of AF4, Dolbier’s group
published several electrophilic substitution reactions of AF4. Nitration and dinitration of
AF4 (Figure 1-17) gave nitrated AF4 derivatives, which were reduced to amino-
compounds. Other functionalities can be introduced into the AF4 molecule by the
Sandmeyer reaction or coupling reaction, which opened the way to AF4 derivatives22 and
fluorinated cyclophanes.49-52
FFF
F F F
F
FFF
F
F F F
F
F
NO2
98%
Fuming HNO3
FFF
F
FFF
F
FFF
F
FFF
F
O2N
NO2
pseudo-para:pseudo-meta:pseudo-ortho = 1:1:1
NO2BF4
Supholane80oC
33 34
Figure 1-17 Nitration and dinitration of AF4
Because fluorine is the strongest electron-withdrawing element, the bridge fully
fluorinated compound 1,1,2,2,9,9,10,10-octafluoro [2.2](1,4)paracyclophane (AF4) has
different physical and chemical properties than the non-fluorinated parent compound.
The effect of the neighboring aromatic ring electron cloud towards the reactivity of the
other ring is also an intriguing issue. For example, unsubstituted [2.2] paracyclophane has
a single 1H-NMR absorption for the aromatic proton at δ= 6.3 ppm, while this peak in
AF4 is shifted to δ= 7.3 ppm. When unsubstituted paracyclophane is treated with
bromine and iron, mono- or di-brominated [2.2] paracyclophane is the product,
17
depending on the mole ratio of bromine.24 There is no product under the same or harsher
conditions in case of bridge fluorinated AF4.51 When [2.2]paracyclophane was treated
with fuming nitric acid in glacial acetic acid, a mixture of dinitro[2.2]paracyclophane was
produced immediately.53 In contrast, the corresponding dinitro-AF4 can only be realized
by using a very strong nitration reagent, nitronium tertafluoroborate, in polar solvent
sulfolane and heated to 80℃ overnight.50 Fluorine substitutes deactivate the electrophilic
substitution reactions of AF4 dramatically. On the other hand, the same electron
withdrawing effect would make the aromatic protons more acidic in AF4 than that in the
non-fluorinated parent compound, and making it easier to deprotonate from the
fluorinated AF4.
1.4 Aryne Chemistry
The existence of aryne was first reported by Stoermer and Kahlert in the Chemical
Institute of University of Rostock over one century ago. 3-Bromobenzofuran was treated
with base in ethanol, and 2-ethoxybenzofuran was the product, 2,3-dehydrobenzo-furan
35 (Figure 1-18) was postulated as the reactive intermediate.54 Wittig and coworkers
proved the existence of ortho-benzyne later in 1942.55
O35
O
BrBase, ethanol
OOCH2CH3
Figure 1-18 Generation of benzofuran aryne
It was a milestone in benzyne chemistry that Roberts et al. found solid evidence of
benzyne 36 in 1953.56 1-C13 Labeled benzene chloride was treated with potassium amide,
18
and a 1:1 ratio products 1- and 2- aniline were isolated (Figure 1-19). Since then, aryne
chemistry has been extensively studied and used in organic synthesis.
CCl
C C CNH2
NH2KNH2
-KCl, NH3NH3
+
36
Figure 1-19 C14 Labelling experiment
The triple bond in the intermediate is significantly weaker than the unstrained triple
bond. Intermediate 36 is better described as a strained alkyne rather than a biradical
because of its large energy gap between the singlet and triplet states of the biradical
(37.5±0.3 kcalmol-1).57 The formation enthalphy of the strained alkyne was 106.6± 3.0
kcalmol-1 by Wenthold and Squires.57, 58 The corresponding bond length found
experimentally was 124±2 ppm which is close to triple bond length 120.3 ppm and its IR
stretching absorption was 1846cm-1.59 Therefore, benzyne has alkyne-like reactivity. For
example, the Diels-Alder reaction, [2+2] reactions, etc. The methods of benzyne
generation as summarized in Figure 1-20.
X
H
X
Y
X
X
M
NN
NNH2
NN
NN
CO2-
N2+
CO2H
NH2
36
Figure 1-20 Methods of benzyne generation
Benzene halide compounds were treated with a strong base such as an amide,60 to
remove the ortho-proton and generate benzyne via an anion. Dihalogen substituted
benzenes 61 were treated with lithium or magnesium to give the corresponding ortho-
19
metal halogen benzene, followed by E1b like elimination to form the desired benzyne.
Decomposition of benzenediazonium-2-carboxylate 62 is considered the best method of
benzyne generation and generally used in organic synthesis. Deprotonation of 1-amino-
benzotriazole derivatives by oxydation followed by extrusion of nitrogen to generate
benzyne.63, 64
The fluoride ion displacement of the trimethylsilyl group by utilizing the large Si-F
bond energy gives a convenient route to benzyne under mild conditions (Figure 1-21). 65
SiMe3
OTfO
OBu4NF
61%
Figure 1-21 Aryne with furan
The use of aryne in organic synthesis was well reviewed by Pellissier.66 The
reaction of arynes with lithioacetonitriles derivatives was important in the synthesis of the
basic skeleton of ergot and alkaloids.67, 68 Aminoisoquinolines were synthesized through
aryne with two equivalents of 2-pyrridinylacetonitrile.69 Heteroarynes can be generated in
a similar manner and used in the synthesis of heterocyclic compounds.70
When transition metals are present, metal-aryne complexes can be formed. The
synthetic applications of metal-aryne complexes are limited due to the lack of a general
and mild method for aryne generation. Recently, Castedo and Yamamoto have reported
some examples of successful generation of metal-aryne complexes under mild conditions.
Palladium catalyzed co-cyclisation of aryne with alkyne produced the phenanthrene
derivatives exclusively in 63% yield (Figure 1-22).71 Pena et al. also described the
synthesis of phenanthrenes and naphthalenes by co-cyclization of arynes with alkynes.72,
73 In their later work, electron deficient alkynes, such as hexafluoro-2-butyne and
20
dimethyl acetylenedicarboxylate (DMAD) gave phenanthrene derivatives in the presence
of Pd(Ph3P)4, while with Pd2(dba)3, naphthalene derivatives were separated in high yield.
Finally, the intermolecular cycloaddition of arynes with DMAD can be made highly
chemoselective and be easily switched between the formation of phenanthrenes and
naphthalenes by appropriate catalyst selection. In addition, by the appropriate choice of
catalyst, the reaction can be selectively directed either towards the co-cyclisation of one
aryne molecule with two molecules of alkyne or to the reaction of two molecules of aryne
with one alkyne molecule.74, 75
TMS
OTfR1 R2
R1
R2Pd(OAc)2
P(o-tol)3, CsF+
Figure 1-22 Co-cyclisation of arynes with alkynes to phenanthrene derivatives
TMS
OTfR
Pd (5%)+
Cl
CsF
RR
R=H: 70% (100:0)
R=Me: 70% (70:30)
R=ph: 71% (73:23)
+
Figure 1-23 Palladium catalyzed reactions of allyl chlorides with benzyne
Yamamoto successfully used aryne as a highly reactive carbopalladation partner
with allyl chloride to give phenanthrene derivatives in high yields (Figure 1-23).76 In the
same way, benzyne also successfully co-cyclized with alkyne-alkene.
Aryne reacted with bis-π-allyl palladium complexes in an amphiphilic fashion to
produce 1,2-diallyl benzene in high yields.77 The reaction of an aryne precursor with
21
allytributylstannane and allyl chloride in acetonitrile in the presence of 2.5 mol%
Pd2(dba)3 at 40℃ produces the corresponding diallyl benzene in 76% yield (Figure 1-24).
The reaction mechanism is the insertion of Pd(0) to allyl chloride to form the π-allyl
palladium complex 37, which is converted to bis-π-allyl palladium complexes 38 via the
reaction with allyltributylstannane. The addition of two allyl groups of 38 to the benzyne
triple bond leads to the final products.
TMS
OTf
Pd2(dba)3 2.5%+Cl
CH3CN, CsF
SnBu3+
76%
-Pd--Pd--Pd-
37 38
Figure 1-24 Palladium catalyzed reaction between allytributylstannane, allyl chloride, and benzyne
The first 4,5-dehydro[2.2]paracyclophane aryne (Figure 1-25), reported by Cram in
1969, was generated from 4-bromo[2.2]paracyclophane 39 and gave three products.24
The total yield of cyclophane aryne intermediates is less than 30%. The dibromide
derivatives (40 and 41) show the same reactivity as monobromide to produce
intermediate 42. Bis-aryne cannot be generated from dibromide derivatives.
BrBr Br Br
Br Br
39 40 41 42
22
Br (CH3)3COK
(CH3)2SO
OC(CH3)3
OH OH
SCH3
4%
14% 10%
+
+
Figure 1-25 Paracyclophane aryne
Bis-dehydro[2.2]paracyclophane7 was generated from 4,5,15,16-tetrabromo[2.2]-
paracyclophane (Figure 1-26) by Cram.
Br
Br
Br
Br
OO
n-BuLi, Et2O
-78 oCO
84%
Figure 1-26 [2.2]Paracyclophane bis-aryne
The perfluorinated o-benzyne had been isolated in cryogenic matrices by photolysis
of the corresponding phthalic anhydride,78, 79 and the CASSCF calculation showed that
the singlet-triplet energy gap of tetrafluoro-o-benzyne was larger than that of non-
fluorinated benzyne by several kilocalories per mole.79 Radziszewski et al.80 identified
the C≡C bond stetching vibration of tetrafluoro-o-benzyne at 1878cm-1, while the length
of that is similar to C≡C bond. The chemistry of fluorinated benzyne differs
significantly from that of none fluorinated one, the former is much more electrophilic and
reactive. For example, tetrafluoro-o-benzyne reacted readily with thiophene.81, 82
23
Other benzynes, such as meta-, para-benzynes and heteroarynes, were also studied
extensively and summarized in an excellent review article by Wenk et al.83
Benzyne chemistry has been studied for over one century and is still a very active
research field. Exploring different aryne generation methods will bring new features into
aryne chemistry and help us understand more about its chemical reactivity. Bridge
fluorinated paracyclophane has just become commercially available recently, and
studying the AF4 derivatives would be cheaper than it was before. AF4 derivatives will
also bring new feature into cyclophane chemistry and reveal more electronic effects in
cyclophane chemistry. These derivatives may also service as new synthon for other
fluorinated cyclophanes.
CHAPTER 2 4,5-DEHYDRO- AND 4,5,15,16-BIS-
DEHYDROOCTAFLUORO[2.2]PARACYCLOPHANES: FACILE GENERATION AND EXTRAORDINARY DIELS-ALDER REACTIVITY
2.1 Introduction
Benzyne was first discovered over a century ago by Stoermer and Kahlert,54 while
the landmark in benzyne chemistry is the isotopic labeling studies on the KNH2 mediated
reaction of chlorobenzene, which left little doubt on the existence of benzyne as a highly
reactive intermediate.56 The most striking feature of these dehydroaromatic intermediates
is their dienophilic reactivity with other aromatic systems as diene partners. Depending
on mode of generation and the nature of the aryne component, however, the yields in
these Diels-Alder type reactions can often be modest or poor.60 For example, 75% is the
best yield reported for benzyne addition to anthracene, considered one of the most
reactive aromatic substrates in Diels-Alder reactions with arynes.84, 85 In that case, the
benzyne was generated from benzenediazonium carboxylate, which is generally
considered to be among the best methods for carrying out Diels-Alder chemistry
involving benzyne.86 Benzene is a much poorer Diels-Alder substrate, and it yielded only
9% Diels-Alder adduct in a similar reaction with benzyne,87, 88 although its reactions with
tetrafluorobenzyne and tetrachlorobenzyne (among the more reactive arynes) yielded 33
and 62% of adduct, respectively.89, 90
Examples of 4,5-dehydro-[2.2]paracyclophanes in the literature are rare. The parent
4,5-Dehydro[2.2]paracyclophane appears to have been mentioned but once, in 1969 when
Longone and Chipman reported its generation by potassium t-butoxide promoted
24
25
dehydrobromination of 4-bromo-[2.2]paracyclophane in t-butylbenzene in the presence
of excess anthracene, with only a 15% yield of Diels Alder adduct being obtained.24, 91
Their yield is similar to that obtained in Cadogan’s original report of the use of this
method to generate benzyne from bromoaromatics, in which he obtained high yields of t-
butyl aryl ethers, but, when generated in the presence of anthracene only produced 21%
yield of tripticene.92
Although the Longone and Cram papers are the only mentions of dehydro[2.2]
paracyclophanes in the literature, there also exists another report by Cram in 1969 of a
bis-dehydro[2.2]paracyclophane,7 where sequential aryne-furan Diels-Alder reactions of
the nominal 4,5,15,16-bis-dehydro[2.2]-paracyclophane was carried out via the double
dehalogenation of 4,5,15,16-tetrabromo[2.2]paracyclophane (Figure 2-1).
Br
BrBr
Br n-BuLi, Et2O
-78 oC
O
OO
84%
Figure 2-1 Bis-paracyclophane aryne with furan reaction
Because of competitive trapping by the nucleophilic t-butoxide, the use of
Cadogan’s t-butoxide method to generate arynes has almost never been used to initiate
Diels-Alder chemistry. Following the successfully solving the AF4 synthetic issue, we
applied these conditions for dehydroiodination 4-iodo-1,1,2,2,9,9,10,10-octafluoro[2.2]
paracyclophane 2 to mono-AF4-yne 1, 49, 52 and the sequential double dehydroiodination
of 4,15-diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane 18 to bis-AF4-yne 1750
(Figure 2-2) which led to efficient Diels-Alder trapping of the intermediate arynes with
virtually no observed competitive interception of the intermediates by the t-butoxide ion.
26
F
F
F
F
F
F
F
F
1
F
F
F
F
F
F
F
F
17
Figure 2-2 Mono- and bis-AF4-yne
2.2 Results and Discussions
2.2.1 Synthesis of Aryne Precursors
The 4-iodo- and 4,15-diiodooctafluoro[2.2]paracyclophane precursors were
prepared from 1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane (AF4) by improved
procedures based on those previously published (Figure 2-3).51, 52 Noteworthy is the
double-nitration procedure, in which essentially equal amounts of the pseudo-ortho (4,12-
dinitro-), pseudo-meta (4,15-dinitro-), and pseudo-para (4,16-dinitrooctafluoro[2.2]
paracyclophane) products (23a, b, and c, respectively) are formed. The pseudo-meta and
pseudo-para isomers are readily separated from the pseudo-ortho isomer by column
chromatography, and it is this mixture of 4,15- and 4,16-dinitro isomers (23a and 23b,
respectively) that is used in subsequent steps to eventually synthesize a mixture of 4,15-
and 4,16-diiodooctafluoro-[2.2]paracyclophanes (18a and 18b, respectively). Since both
of these isomers lead to the same bis-aryne (17), this mixture was used as the "precursor"
of 4,5,15,16-bis-dehydrooctafluoro[2.2]paracyclophane. The reduction of nitro
compound by palladium (10%) on carbon with hydrogen at room temperature gives
quantitatively yield. Product was filtered through a short pad of silicon Gel to get rid of
palladium and carbon, while no further purification is necessary. Chromatography
purification was required for other reduction methods and the yield was much lower.
27
F F
FF
FF
F
F
F F
FF
FF
F
F
FF
FF
FF
F
F
NO2
FF
FF
FF
F
FNH2
90% HNO3
I
Pd/C, Methanol, H2
a) 0oC, NaNO2, H2SO4 HOAc
b), KI/H2O, RT, 8h
2
FF
FF
FF
F
F
F F
FF
FF
F
F
X
X
5 equiv, sulfolane 80oC
25, X=NO225a, pseudo meta25b, pseudo para25c, pseudo ortho, 23%
49%
25a&b 26a&b (X=NH2)
26a&b pseudo meta, 18apseudo para, 18b (X=I) 68%
Pd/C, Methanol
a) 0oC, NaNO2, H2SO4 HOAc, H2O
b) KI/H2O, RT, 8h
NO2+BF4
-
H2
Figure 2-3 Synthesis of precursor
2.2.2 Reactions of 4, 5-Dehydrooctafluoro[2.2]paracyclophane, 1
When monoiodide 2 was treated with potassium t-butoxide in refluxing benzene, in
refluxing t-butylbenzene in the presence of stoichiometric amounts of naphthalene or
anthracene, the corresponding Diels-Alder adducts were obtained (Table 2-1), yields are
from 60% to 88% (Figure 2-4). The yields obtained with benzene and naphthalene are the
largest yet reported for aryne reactions with these substrates.
The structural integrity of compounds 3-5, as well as the stereochemistry of
compound 4, were demonstrated by NMR as illustrated below for the representative
adduct 5. In the proton spectrum of 5, the signals at 6.96, 7.32 and 7.27 ppm are the
28
second order multiplets that are characteristic for an ortho-phenylene group. The proton
at 7.65 has an extra coupling, most likely a through-space coupling with fluorine. Of the
three remaining aromatic CH’s the two with protons at 7.20 and 5.84 are on the same
aromatic ring as revealed by their mutual 1H-13C long-range couplings. The final
aromatic proton, at 6.72, displays a nOe with the proton at 7.20, leaving the signal at 5.84
to be assigned as those facing the moiety originating from anthracene, and indeed the
signal at 5.84 displays nOe’s with the protons at 7.27 and 7.65, and no nOe’s with those
at 7.32 and 6.96. In a similar fashion, in compound 4, the proton at 5.78 ppm, displays
nOe’s with those at 7.27 and 7.59, and no nOe with the alkene proton at 6.93, proof for
the endo stereochemistry. The upfield chemical shift of 5.78, which is comparable with
the 5.84 signal in compound 5 and significantly smaller than the 7.16 signal of the parent
cyclophane, is diagnostic for its position above the plane of an aromatic ring. The
chemical shift of the corresponding proton in compound 3, 6.91 ppm, demonstrates that
significantly less shielding is to be expected for a proton having a similar position above
a double bond.
Interestingly, no products deriving from nucleophilic capture of the presumed aryne
intermediates by the excess t-butoxide base were detected in any of these reactions, even
when the reaction was carried out in refluxing t-butylbenzene with no substrate added. In
this case a surprisingly high (78%) yield of the DA adduct (6) with t-butylbenzene was
obtained. This is in contrast to Longone and Chipman’s results,91 as well as those of
Cram and co-workers,24 where t-butoxide adducts were found to be a major side product
in each of their respective studies where this method of aryne generation was used.
29
FF
FF
FF
FF
I
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
2 3
4
5
128.8134.1
118.8
119.9127.3 146.8
45.7
137.6
141.8
126.3
7.26
7.056.91
6.78
6.60
5.48
129.0
7.59
7.27
5.75
6.93
6.70
7.22
5.78
128.8127.6134.0
118.7
119.8128.5 145.2
47.6
141.1
143.3
125.3
125.8
127.3
128.9127.9134.0
118.7
120.1
128.2
128.7144.4
50.3
144.4
142.7
124.5
126.1
125.7
126.5
7.65
7.27
6.01
7.32
6.96
6.725.84
7.20
2
2
(86%)
(86%)
(84%)
naphthalene
t-BuOKt-butylbenzene, reflux
benzene
t-BuOK, reflux
anthracene
t-BuOKt-butylbenzene, reflux
FF
FF
FF
FF
6
128.9128.6
133.9128.9
129.0120.0
120.0
126.3
147.346.8
137.4 138.3
130.3
130.3
134.3
126.9
34.7
27.6
147.5126.6 45.5
7.28
7.246.97
6.90
7.067.02
6.19
6.62
5.43
5.39
0.93
6.62
2 t-BuOKt-butylbenzene, reflux
(78%)
Figure 2-4 Diels-Alder reaction of AF4-yne
30
Table 2-1. Diels-Alder reactions from treatment of 4-iodooctafluoro[2.2]paracyclophane, 1, with potassium t-butoxide.
Substrate Solvent T(℃) Time
(min)
Product
( %)
benzene benzene reflux (80) 20 3 (86)
naphthalene butyl ether reflux (142) 20 4 (88)
anthracene t-butylbenzene reflux (169) 15 5 (84)
t-butylbenzene t-butylbenzene reflux (169) 40 6 (78)
1,4-
dimethylnaphthalene
butyl ether reflux (142) 30 7(60)
(4.55:1/endo:exo)
2,3-
dimethylnaphthalene
butyl ether reflux (142) 30 8(67)
2-
methoxylnaphthalene
butyl ether reflux (142) 30 9:10:11(18:4:27)
furan t-butylbenzene reflux (142) 20 12a & b (80)
2,5-diphenylfuran butyl ether Reflux
(142)
30 13(84)
[2.2]paracyclophane t-butylbenzene reflux (169) 20 14 (86)
bicyclo[2.2.1]hepta-
2,5-diene
butyl ether reflux (142) 30 15 & 16 (67)
The stereoselectivity exhibited by 1 in its virtually exclusive formation of the endo-
isomer (4) from naphthalene addition is remarkable, particularly since both molecular
mechanics and AM1 calculations predict only a very slight thermodynamic preference for
this isomer (0.75 and 0.02 kcal/mol, respectively).49 The endo transition state may be
favored because of a stabilizing ‘herringbone’ H-π interaction93 of the 5.78 ppm protons
that interact with the π cloud of the endo benzene ring. This hypothesis were further
supported by AF4-yne reactions with 1,4-Dimethylnaphthalene and 2,3-dimethyl-
naphthalene. In 1,4-Dimethylnaphthalene reaction (Figure 2-5), product 7a&b were
31
obtained in 60% yield, in which aryne added exclusively to the ring without methyl
substitutes due to the steric effects. It is interesting that the product ratio of endo- and
exo- is about 100:37 with the more bulky aromatic ring inside. When 2,3-dimethyl-
naphthalene was the substrate, as expected, adduct 8 was produced in 67% yield, which
has a better electronic match with the electron deficient dieneophile, AF4-yne.
FF
FF
FF
FF
6.51127.5
128.5120.4 145,4
7.07128.6
119.1
134.4
5.65127.9
18.12.49
141.4
6.86127.4
131.3
6.79141.5
43.95.92
FF
FF
FF
FF
7.13129.0
134.2
119.0
145.7
6.55127.4
120.1
6.91129.4
44.25.87 137.5
7.06
6.54126.5
143.518.12.23
137.6
130.1
7a 7b
FF
FF
FF
FF
7.12128.9
7.47124.76.61
127.1
127.9120.0 144.9
16.51.64
5.2253.5
143.1
133.9 7.18125.7
141.2
118.7
5.65127.6
8
Figure 2-5 Products of 1,4-dimethylnaphthalene and 2,3-dimethylnaphthalene
The reaction of AF4-yne with 2-methoxynaphthalene gave three products 9, 10, and
11(Figure 2-6) which comply with the electronic requirement: the addition occurred
mostly on the electron rich aromatic ring (totally 45% yields). The enol ether 9 was
32
hydrolyzed to give ketone product 11(27%). Only 4% adducts 10 occurred on the other
aromatic ring.
F2C
CF2
CF2
CF2
CF2
F2C
119
10
OCH3
F2C
CF2
CF2
F2C
O
F2C
CF2
O
Figure 2-6 Products of 2-methoxylnaphthalene with AF4-yne
Furan has generally been considered to be a good Diels-Alder diene substrate in
trapping reactions with arynes. Indeed, when iodide 2 was treated with potassium t-
butoxide in refluxing t-butylbenzene in the presence of 1.1 equivalents of furan, an
almost 50:50 mixture of the endo- and exo-adducts 12 a&b of furan to aryne 1 was
obtained in 80% yield. The two isomers were distinguished by NMR (vide infra), but a
corroborative X-ray crystal structure of the endo-adduct was also obtained. Interestingly,
in case of 2,5-diphenylfuran reaction with AF4-yne, the exo- and endo- ratio of two
products 13a:13b is 76:24 with exo-product predominant (Figure 2-7).
33
FF
FF
FF
FF
12a
134.2
119.3
127.7
147.5
140.6
127.9
81.45.88
7.41128.8
7.29
6.51118.7
FF
FF
FF
FF
12b
129.2
118.9
134.8 129.7
119.4150.4 144.1127.3
81.0
7.22
7.33
6.99
6.65127.1
5.91
O
128.56.76
O
FF
FF
FF
FF OFF
FF
FF
FF
O
13a 13b
7.20128.3
135.0130.27.33
6.64127.2
118.6
119.1127.7 152.6 94.7
135.0148.37.25
127.27.85
128.37.56na
7.50
Figure 2-7 Products of furan and 2,5-diphenylfuran with AF4-yne
There have been few previous reports in the literature of aryne additions to a [2.2]
paracyclophane. Perhaps the best example is Heaney’s study of tetrafluorobenzyne,
where he got a yield of 44% of its addition to [2.2]paracyclophane in 1969.94 Such a
reaction also posed no problem for aryne 1, which, under the usual conditions, underwent
Diels-Alder addition to the hydrocarbon [2.2]paracyclophane in 84% yield (Figure 2-8).
Although fully characterized by NMR (vide infra), an X-ray crystal structure of adduct 14
was also obtained. The regiochemistry of addition observed in the formation of adduct 14
was consistent with that reported earlier for the tetrafluorobenzyne/[2.2]paracyclophane
adduct.
34
FF
FF
FF
FF
2.882.5634.9
2.823.1233.7
139.5
128.16.95
6.93133.0
139.9
33.32.572.98
34.22.382.20
133.07.07
6.96128.1
137.95.63
142.0
4.5451.5
147.5
51.14.48
5.94134.4
146.9
147.0126.4
119.9
6.47125.8
6.47125.8
126.0
7.18128.6
7.22128.9 134.3
118.7
118.8
120.0129.16.78133.8
6.73127.8
14
Figure 2-8 Product of [2.2]paracyclophane with AF4-yne (bold shifts on this structure indicate protons pointed toward the viewer)
Bicyclo[2.2.1]hepta-2,5-diene (norbornadiene) may act as diene or dienophile
depending on the reaction conditions and substrates. Stereochemistry of norbornadiene in
the DA reaction has been extensively studied,95-97 and there have been a few studies of
benzyne additions to norbornadiene. Both [2+2] and [2+2+2] addition products were
obtained for the reactions of tetrafluoro- and tetrachloro-benzyne with norbornadiene,
with ratios of 6:1 and 3:1, being observed respectively.98 The ratio of [2+2] and [2+2+2]
products did not change with the pressure of the reaction of tetrachlorobenzyne, which
was generated from butyllithium with hexachlorobenzene, with norbornadiene.99 The
reaction of AF4-yne with bicyclo[2.2.1]hepta-2,5-diene was examined to determine its
preferred selectivity. Four products (Figure 2-9), exo- and endo-[2+2+2]- addition
products 15 a&b, endo- and exo-[2+2]- addition products 16 a&b were obtained in a total
yield of 67.6% in butyl ether. The ratios of products 15a:15b:16a:16b is 62:27:3:8, with
[2+2+2] products being predominant. When reaction was carried out in neat
norbornadiene, the ratios of products changed to 74:12:10:4. This observed preference for
[2+2+2] products contrast with the regioselectivity of other arynes with norbornadiene. In
35
addition, all the major products are formed from the endo-addition to norbornadiene. The
endo selectivity for both types of products should be noted.
FF
FF
FF
FF
7.27130.0
FF
FF
FF
FF7.14128.3
FF
FF
FF
FFFF
FF
FF
FF
6.80128.3
127.9119.9 149.9
3.0556.5
1.8133.7
23.81.88
21.31.12
47.03.37
119.1135.17.40128.8
134.5 118.8
6.65127.8
128.2
119.6
145.3
49.03.40
56.41.88
31.01.66
2.0425.2
1.7819.9
7.02128.8
118.9134.9
6.98128.9
7.56128.6 1.92
1.8142.8
40.33.17
136.96.28
50.43.05
142.7126.7
6.62131.1
118.6
118.4134.87.23129.8
7.31124.6
6.92128.9
128.5118.4 147.9
46.62.88
0.7341.41.21
42.72.86
137.16.31
15a 15b
16a 16b
Figure 2-9 Products of bicyclo[2.2.1]hepta-2,5-diene with AF4-yne
No adducts were able to be observed with other alkenes under these conditions,
neither [2+2] or Ene reaction being seen. Reactions with 1-octene, cyclohexene, t-
butylethylene and 1,3,5-cycloheptatriene were all attempted with neither [2+2] or ene
reaction being observed. instead, the AF4-I was observed to convert largely to AF4.
Mechanistic ramification of this adduct will be discussed further in next chapter.
2.2.3 Reactions of 4,5,15,16-Bis-(Dehydro)octafluoro[2.2]paracyclophane, 17
Incredibly, the yields of bis-adducts obtained from the sequential bis-dehydro-
iodination of diiodide 18a and 18b under analogous conditions were comparable to those
36
for the mono-adducts! Adducts 19-22 (Figure 2-10) were thus obtained in 83, 86, 80 and
84 % yields, respectively. Reaction conditions and results were listed in Table 2-2. All
adducts were fully characterized by 1H, 19F, and 13C NMR, and an X-ray crystal structure
was obtained for bis-naphthalene adduct, 20. Again, the highly shielded aromatic protons
of the AF4 benzene ring that face the endo benzene rings of adducts 20 and 21(δ=5.24
and 5.38 ppm, respectively) are noted with interest.
Table 2-2. Diels-Alder reactions from treatment of 4, 15-diodo-octafluoro [2.2]paracyclophane, 18, with potassium t-butoxide, in refluxing solvent.
Substrate Solvent Temperature
(oC)
Time
(minutes)
Product
(%)
benzene benzene reflux (80) 150 19 (83)
naphthalene butyl ether reflux (142) 30 20 (86)
anthracene t-butylbenzene reflux (169) 30 21 (80)
[2.2]paracyclophane t-butylbenzene reflux (169) 30 22 (84)
2.2.4 NMR Discussion.100
The structural integrity of most compounds and the stereochemistry of compounds
4, 6, and 12 a&b were demonstrated by NMR. The numerous nOes’ on such rigid
structures were diagnostic for stereochemical assignment. Of the three pairs of vicinal
protons originating from compound 2 (e.g., 6.47 and 6.47, 7.18 and 7.22, and 6.73 and
6.78 ppm for adduct 14), the one on the formerly benzyne ring (6.47 and 6.47 ppm) can
be identified by its couplings to the carbons at ca. 147 ppm, carbons that in turn couple to
protons originating from the arene (4.54, 4.48, 5.63, and 5.94 ppm) . NOes with this pair
(6.47 and 6.47 ppm) identified the pair (7.18 and 7.22 ppm) syn to it. Long-range
couplings between the protons and the carbons in the para-phenylene ring of 14 allowed
37
the assignment of the pair anti to the protons originating in the benzyne ring of 1 (6.73
and 6.78 ppm, meta to 7.22 and 7.18 ppm, correspondingly).
FF
FF
FF
FF
I
FF
FF
FF
FF
benzene
t-BuOK, reflux
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
FF
22a 22b
19
20 21
2.772.49
3.083.05
6.92
6.93
2.562.96
2.392.20
4.44
4.497.02
6.935.61
5.886.046.01
5.965.98
7.19125.3126.47.59
143.1
5.9650.4
144.4124.47.30126.06.94
119.9
128.1
144.6
5.38124.4
7.20125.6
124.97.53
5.6947.4140.96.89
145.3
127.5
120.05.24124.3 143.8
7.05138.0
5.4845.6
141.56.78
120.2
126.8
146.8
6.29124.6
I
m, or p-diiodo AF4
Figure 2-10 The bis-Diels-Alder reaction of AF4-yne
In compound 14, 6.78 displayed a nOe with 5.94 and 4.48 ppm, which in turn displayed
nOe’s with 7.07 and 6.96 ppm. Other NOEs afforded positive stereochemical assignment
of the aliphatic protons, e.g., 2.88 ppm displayed nOe’s with 5.94, 6.78, and 7.07 ppm.
Compounds 22 a&b were analyzed as a mixture. The fragments originating from
[2.2]paracyclophane displayed very similar proton chemical shifts in both 14a and 14b.
38
The protons originating from the fluorinated aryne 1 display two ABs of roughly the
same intensity (6.04, 5.96 and 6.01, 5.98 ppm) indicative that 22a and 22b are formed in
equal amounts. Low solubility precluded obtaining ghmbc spectra. The structural
integrity of these compounds was confirmed by nOe’s similar to those observed for
compound 14.
For the furan adducts 12 a&b, the major isomer was assigned as 12a on the basis of
the nOes’ between the protons at 6.76 ppm (identified as anti to the protons originating
from the aryne ring of 1 as mentioned above) and the protons at 7.29 ppm, originating in
the furan.
Isomer 6 would be expected on steric grounds, and the exo-structure was
unambiguously confirmed on the basis of nOe’s that were observed between the
cyclophane protons that are pointed toward the former tert-butylbenzene (6.97 and 6.90
ppm) and the vinylic protons at 7.02 and 7.06 ppm.
In a similar fashion, in compound 4, the proton at 5.78 ppm displays nOe’s with
those at 7.27 and 7.59 ppm and no nOe with the alkene proton at 6.93 ppm, proof for the
endo stereochemistry.
2.2.5 X-ray Discussion.
Some of adducts were analyzed by X-ray diffraction (Appendix). Crystal structures
of anthracene adduct and bis-naphthalene adduct were demonstrated below. The crystal
structure of the anthracene adduct 5 (Figure 2-11 and also Appendix Figure 2) indicates
that, although there are several ways for the AF4 moiety to be distorted upon derivation,
the main impact is that the torsion angles around the bridging C7-C8 and C15-C16
moieties (for example, the C6-C7-C8-C9 torsion angle, as seen in Figure 2-11) open to
39
values of 26.5 and 27.0 , respectively. This is accomplished by twisting the phenyl rings
by an angle of 11.6 around an axis perpendicular to them.
Figure 2-11 ORTEP drawing of anthracene adduct 5 and endo furan adduct 12a
According to the X-ray structure of endo furan adduct, 12a (Figure 2-11 and also
Appendix Figure 3), the distortion parameters of its AF4 moiety involve bridging torsion
angles of 12.6 and 21.9 , with a twist angle of 7.7 , whereas for [2.2]paracyclophane
adduct 14 (Figure 2-12 and also Appendix Figure 1), the bridging torsion angles are 14.1
and 22.1 , two phenyl rings of AF4 moiety have a twist angle of 14.9o connected to
[2.2]paracyclophane and 8.1o on the other one.
Figure 2-12 ORTEP drawing of [2.2]paracyclophane adduct 14 and bis naphthalene adduct 20
40
The X-ray analysis of bis-naphthalene adduct 20 (Figure 2-12 and also Appendix
Figure 4) indicates that there are two molecules of 20 in its asymmetric unit. For
molecule A, the bridging torsion angles are 28.0 and 30.1 , with a twist angle of 12.4 ,
whereas for molecule B the bridging torsion angles are 27.7 and 28.9 , with its twist
angle being 23.1 .
In summary, there is a trend observed in these X-ray structures when considering
how the AF4 moiety is distorted in order to relieve the strain of adding a large substituent
to the benzene rings. Small variations in the dihedral angles between the benzene rings of
each of the four crystal structures of from 1.2 to 4.9 are observed. More significantly,
and presumably in order to minimize nonbonded interactions, the benzene rings twist
around an axis perpendicular to the benzene rings, with more twist being observed for
larger substituents. Such twist is coupled with an opening of the bridging torsion angles
of the CF2-CF2 units.
2.3 Conclusion
On the basis of the results that have been presented, it can be concluded that the
reactive arynes, 1 and 17, have been generated and are responsible for the chemistry
observed and discussed. The relative ease of their generation (refluxing benzene) can be
ascribed to an increase in acidity of the proton vicinal to the halogen, induced by the
highly electronegative fluorinated bridges. The fluorinated bridges of 1 and 17 should
also make them highly electrophilic and therefore more reactive arynes (compared to the
nonfluorinated dehydro[2.2]paracyclophane). However, such high electrophilicity should
also lead to enhanced reactivity with nucleophiles such as t-butoxide ion, which is not
observed. At this time, the only potential explanation we have for the chemoselectivity
41
exhibited by arynes 1 and 17 is the possible electrostatic repulsion of the t-butoxide
nucleophile by the fluorinated bridges of the two arynes. The base used in aryne reactions
above is not soluble in above system, which means that reactions occur heterogeneously.
Heterogeneous characteristics may also explain the absence of t-butoxide ion addition
product, which is a major product in Cadogan’s early report. Other aspect of the reaction
mechanism will be discussed further in the next chapter.
2.4 Experimental
General Methods. 1H (500 MHz), 13C (126 MHz), and 19F (282 MHz) NMR
spectra were recorded using CDCl3 as the solvent, and chemical shifts ( values) were
measured relative to the signals for CHCl3, CDCl3, and CFCl3, respectively. 1H and 13C
chemical shift data are directly indicated on the structures of the adducts in the Results
and Discussion section above, whereas 19F NMR data are provided in the Experimental
Section below. X-ray crystal analyses were performed by the Center for X-ray
Crystallography and HRMS and CH micro elemental analyses by the Spectroscopic
Services Group at the University of Florida. Column chromatography was performed
using chromatographic silica gel, 200-425 mesh, as purchased from Fisher, unless
otherwise mentioned.
4-Nitro-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane. Into 200 mL of 90%
nitric acid was added 10.0 g (2.8 mmol) of AF4 in one batch. The mixture was stirred
overnight, after which it became a clear solution. This solution was then added to 500 g
of ice in an Erlenmeyer flask, and a white precipitate formed. The mixture was filtered to
give 10.0 g (90%) of the yellow-white mononitro product, 23.52
42
Isomeric Dinitro-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes. Explicitly
following the published procedure,51 22.1 g (166 mmol) of nitronium tetrafluoroborate
undergoes reaction with 10.2 g (29 mmol) of AF4 in sulfolane (100 mL) in an overnight
reaction at 80℃ to form a white solid product when poured into ice. Column
chromatography (hexane/ethyl acetate, 10:1) gave 6.3 g (49%) of an almost 1:1 mixture
of the 4,15- and 4,16-dinitrooctafluoro[2.2]paracyclophanes, 25a and 25b, respectively,
along with 3.0 g (23%) of the 4,12-dinitro isomer.
4-Amino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane, 24. A anhydrous
methanol (100ml) solution of 23 (3.0 g, 7.6 mmol) was added ammonium formate (7.2g,
114mmol) and Pd/C (0.24g, 0.23mmol) under nitrogen at room temperature.101 The
mixture was purged with hydrogen three times, and then a hydrogen balloon was attached
to it. After stirring the reaction mixture overnight, solution was filtered over a short pad
of silica Gel. The solvent was evaporated to give 2.55 g amine 24 in yield of 91%.
Mixture of 4,15- and 4,16-Diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes, 26a and 26b. Likewise, 0.51 g (1.15 mmol) of the mixture of 25a,b was
converted to 0.39 g (89%) of a mixture of pseudo-meta and pseudo-para diamines, 26a
and 26b, respectively.
4-Iodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophane, 2.52 A solution of amine
16 (1.9 g, 5.2 mmol) in acetic acid (4 mL) was cooled to 0℃ in an ice/brine bath. Ice (1.5
g) and 1.5 mL of H2SO4 were added with stirring, and ensuring that the temperature was
still below 0℃, Na NO2 (2.0 g, 29 mmol) was added in one batch. After the reaction was
stirred for 2 h at 0℃, it was poured, with vigorous stirring, into 10 mL of an aqueous
43
solution of KI (5.2 g, 30.8 mmol) at room temperature. After stirring overnight, the
mixture was filtered and the solid purified by column chromatography (alumina,
hexane/EtOAc, 50:1) to give 1.7 g (67%) of the 4-iodo product, 2.
Mixture of 4,15- and 4,16-Diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclo-
phanes, 18a and 18b.51 A solution of the mixture of 4,15- and 4,16-diaminooctafluoro
[2.2]paracyclophanes, 26a and 26b, respectively, (2.0 g, 5.2 mmol) in acetic acid (4 mL)
was cooled to 0℃ in an ice/brine bath; ice (1.5 mL) and concentrated sulfuric acid (1.5
mL) were added with stirring. With the temperature maintained below 0℃, sodium nitrite
(2.0 g, 29.0 mmol) was added as quickly as possible to the solution. The reaction was
stirred at this temperature for 2 h, and then the mixture was added to an aqueous solution
(10 mL) of potassium iodide (5.2 g, 30.8 mmol) at room temperature with vigorous
stirring. This mixture was kept stirring at room temperature overnight and then filtered
with the solid being purified by column chromatography (hexane/ethyl acetate, 50:1) to
give 2.2 g (68%) of a mixture of 18a and 18b.
Generation of 4,5-Dehydrooctafluoro[2.2]paracyclophane, 1, and its Reaction
with [2.2]Paracyclophane. Into a three-necked round-bottomed 50 mL flask were added
iodide 2 (0.478 g, 1 mmol) and potassium t-butoxide (0.56 g, 5 mmol) along with 10 mL
of dry t-butylbenzene under a nitrogen flow. Then, [2.2]paracyclophane (0.22 g, 1.1
mmol) was added and the mixture heated to 170℃ and refluxed for 20 min. The oil bath
was then removed and the reaction product mixture examined by 19F NMR. The reaction
was worked up by filtering the mixture through a short pad of silica Gel, washed with
3X10 ml dichloromethane. Solvent was evaporated away, and products were further
44
purified through silicon Gel column to give 86% yield of 8: mp 140-142℃; 1H NMR
(500MHz) (CDCl3/TMS): δ 7.22(d, J=8.7Hz, 2H), 7.18(d, J=8.4Hz, 1H), 7.07, 6.96(ABX,
J=8.2, and 1.5Hz, 2H), 6.95, 6.93(ABX, J=8.1, 1.5Hz, 2H), 6.78, 6.73(AB, J=8.6Hz, 2H),
6.47(s, 2H), 5.94(d, J=6.2Hz, 1H), 5.63(d, J=6.6Hz, 1H), 4.54(ABX, J=6.3, 2.8Hz, 1H),
4.48(ABX, J=6.2, 1.8Hz, 1H), 3.12(ABX, J=12, 7.1, 2.6Hz, 1H), 2.98(ABX, J=13.2, 8.0,
4.0Hz, 1H), 2.88(m, 1H), 2.82 (DT, J=13.1, 7.9Hz, 1H), 2.58, 2.55(AB, J=7.9Hz, 2H),
2.38(ABM, J=15.1, 8.1, 4.1, 2.0Hz, 1H), 2.20(ABX, J=15.2, 8.1, 0.6Hz, 1H); 19F
NMR(282MHz, CDCl3/CFCl3), four equal intensity AB quartets at -111.4 (J = 244.2 Hz)
and -111.7 (J = 243.9 Hz), -115.0 (J = 243.9 Hz) and -115.7 (J = 244.2 Hz), -116.7 (J =
239.7 Hz) and -117.7 (J = 241.1 Hz), -119.4 (J = 240.8 Hz) and -119.9 (J = 239.7 Hz);
HRMS calcd for C32H22F8 558.1594, found 558.1594.
Reaction of Aryne 1 with Anthracene. The procedure is the same as above, except
that 0.18 g (1.1 mmol) of anthracene was used and the reaction was refluxed for 15 min.
Two isomers, in a ratio of 93:7 (from 19F NMR) were obtained in a total yield of 84%.
The major isomer was isolated via silica gel chromatography (hexane/EtOAc, 100:1).
Major isomer (5): mp 296-298℃; 1H NMR (300MHz, CDCl3/TMS) δ Isomer 1 7.65(m,
2H), 7.32(m, 2H), 7.27(m, 2H), 7.20(s, 2H), 6.96(m, 2H), 6.72(s, 2H), 6.01(s, 2H), 5.84(s,
2H); 13C NMR(126MHz, CDCl3) δ 144.4, 142.7, 134.0, 128.9, 128.7, 128.2, 127.9, 126.1,
125.7, 124.5, 120.0, 118.7, 50.3; MS(EI): 528(M+, 76), 352, 301, 176, 69; 19F NMR
(282MHz, CDCl3/CFCl3), two equal intensity AB quartets at -111.4 (d, J = 243.9 Hz)
and -115.1 (d, J = 243.9 Hz), -116.53 (J = 240.8 Hz) and -119.4 (d, J = 240.8 Hz); Anal.
Calcd for C30H16F8: C, 68.18, H, 3.05. Found: C, 67.73; H, 2.86. Minor isomer: Isomer 2
7.76(s, 2H), 7.78(m, 2H), 7.52(m, 2H), 7.30(m, 2H), 7.18(s, 2H), 6.94(m, 2H), 5.80(m,
45
2H), 5.64(s); 19F NMR(282MHz, CDCl3/CFCl3), two equal intensity AB quartets at -
111.1 (d, J = 243.9 Hz) and -115.4 (d, J = 243.9 Hz), -116.3 (d, J = 237.7 Hz) and -119.5
(d, J = 240.8 Hz).
Reaction of Aryne 1 with Benzene. The procedure is the same as above, except
that the reaction was carried out in refluxing benzene at 80 ℃ for 150 min. The product
was purified by silica gel chromatography (hexane/EtOAc, 100:1) with a 86% yield of 3:
mp 144-146℃; 1H NMR (500MHz, CDCl3) δ 7.26(s, 2H), 7.05(AB, J=3.3, 4.2Hz, 2H),
6.91(d, J=1.1Hz, 2H), 6.78(dd, J= 3.0, 4.5Hz, 2H), 6.60(s, 2H), 5.48(m, 2H); 19F
NMR(282MHz, CDCl3/CFCl3), two equal intensity AB quartets, -111.9 (d, J = 247.0 Hz)
and -115.7 (d, J = 244.0 Hz), -117.79 (d, J = 240.8 Hz) and -119.54 (d, J = 240.8 Hz);
MS (EI) 428 (M+), 368, 252, 192, 176 and 57; 13C NMR(126MHz, CDCl3) δ 146.8, 141.8,
137.6, 134.1, 128.9, 128.8, 127.3, 126.3, 45.7; HRMS calcd for C22H12F8 428.0811,
found 428.0811. Anal. Calcd for C22H12F8: C, 61.69; H, 2.83. Found: C, 61.52; H, 2.69.
Reaction of Aryne 1 with t-Butylbenzene. The procedure was identical to those
above, except that the reaction was carried out using refluxing tert-butylbenzene (bp 169
℃) as both a solvent and a reactant. The product was purified by silica gel
chromatography (hexane/EtOAc, 100:1) with the yield of 6 being 78%: mp 131-133℃;
1H NMR (500MHz, CDCl3/TMS) δ 7.28(d, J=8.4Hz, 1H), 7.24(d, J=8.4Hz, 1H), 7.06(m,
1H), 7.02(m, 1H), 6.97(d, J=8.7HzHz, 1H), 6.90(d, J=8.7Hz, 1H), 6.62(s, 2H), 6.19(d,
J=6.2Hz, 1H), 5.49(d, J=5.6Hz, 1H), 5.39(m, 1H), 0.91(s, 9H); 19F NMR (282MHz,
CDCl3/CFCl3), four equal intensity AB quartets at -111.4 (J = 243.9 Hz) and -112.5 (J =
243.9 Hz), -115.3 (J = 243.9 Hz) and -115.9 (J = 243.9 Hz), -117.2 (J = 240.8 Hz) and -
46
119.8 (J = 240.8 Hz), -118.4 (J = 241.1 Hz) and -119.4 (J = 240.8 Hz); 13C NMR
(126MHz, CDCl3) 147.5, 147.3, 138.3, 137.4, 134.3, 133.9, 130.3, 129.0, 128.9, 128.6,
126.9, 126.6, 126.3, 126.2, 120.0, 46.8, 45.5, 34.7, 27.6; Anal. Calcd for C26H20F8: C,
64.46; H, 4.17. Found: C, 64.22; H, 4.22.
Reaction of Aryne 1 with Naphthalene. The procedure was carried out as above
except that di-n-butyl ether (bp 142℃) was used as the solvent and naphthalene as the
substrate (0.14 g, 1.1 mmol). Refluxing for 30 min provided a mixture of products (ratio
>10:1), which after chromatography in the usual manner gave major product endo-adduct
4 in a yield of 88%: mp 204-206℃; 1H NMR (300MHz, CDCl3/TMS) δ 7.59(m, 2H),
7.27(m, 2H), 7.22(s, 2H), 6.93(m, 2H), 6.70(s, 2H), 5.78(s, 2H), 5.75(s, 2H); 13C NMR
(126MHz, CDCl3) 145.2,143.3, 141.2, 133.9, 130.0, 128.8, 127.58, 127.0, 125.8, 125.3,
47.5; 19F NMR(282MHz, CDCl3/CFCl3), two equal intensity AB quartets, -111.2, -115.5
(JAB = 243.9 Hz), and -116.4, -119.5 (JAB = 247.0 Hz); HRMS calc 478.0967, found
478.0968. Anal. Calc for C26H14F8: C, 65.28; H, 2.95. Found: C, 65.05; H, 2.89. Minor
product (presumably exo-adduct): 19F NMR, two equal intensity AB quartets, -112.0, -
115.3 (JAB = 246.8 Hz) and d -117.8, -119.6 (JAB = 236.9 Hz).
Reaction of Aryne 1 with Furan. This reaction was carried out as above in
refluxing tert-butylbenzene for 20 min with furan as the substrate. A mixture of the endo
and the exo-adducts, 12a,b, (ratio = 1:0.6), was obtained in 80% yield. Chromatography
in the usual manner provided partial separation of the isomers, such that small amounts of
individual, pure isomers could be obtained, along with larger amounts of mutually
contaminated fractions. endo-Isomer, 12a: mp 162-163.5℃; 1H NMR (300MHz,
47
CDCl3/TMS) isomer1 δ 7.33(s, 2H), 7.22(s, 2H), 6.99(d, J=0.9Hz, 2H), 6.65(s, 2H),
5.91(d, J=3.9Hz, 2H); 13C NMR (126MHz, CDCl3)δ 150.4, 144.1, 134.8, 129.7, 129.2,
127.6, 127.3, 119.4, 118.9, 81.0; 19F NMR(282MHz, CDCl3/CFCl3), two equal intensity
AB quartets, -112.6, -119.2 (JAB = 243.9 Hz), -116.1, -117.9 (JAB = 240.8 Hz); HRMS
calcd for C20H10F8 418.0604, found 418.0604. exo-Isomer, 12b: 1H NMR (300MHz,
CDCl3/TMS) δ 7.41(s, 2H), 7.29(s, 2H), 6.76(s, 2H), 6.51(s, 2H), 5.88(m, 2H); 13C NMR
(126MHz, CDCl3) δ 147.5, 140.6, 134.2, 128.8, 128.5, 127.9, 127.7, 119.3, 118.7; 19F
NMR(282MHz, CDCl3/CFCl3), two equal intensity AB quartets, -111.9, -114.3 (JAB =
243.9 Hz), -116.2, -118.0 (JAB = 238.0 Hz).
Reaction of Aryne 1 with Bicyclo[2.2.1]hepta-2,5-diene: The procedure was
carried out as above except that di-n-butyl ether (bp 142℃) was used as the solvent and
bicyclo[2.2.1]hepta-2,5-diene (0.043g, 50ul, 0.46mmol) was used as the substrate (0.14 g,
1.1 mmol). A mixture of products (ratio15a:15b:16a:16b=62:27:3:8) was obtained after
refluxing for 30 min. A product mixture (75 mg) was obtained in a total 67% yield after
chromatography in the usual manner, which includes four different isomers: exo- and
endo-1,4-addition products 15a&b, endo- and exo-1,2- addition products 16a&b with a
ratio of 62:27:3:8. Spectrum of 15a: 1H NMR (500MHz, CDCl3/TMS) δ 7.27(s, 2H),
7.14(S, 2H), 6.80(s, 2H), 3.37(s, 2H), 3.05(s, 1H), 1.88(m, 1H), 1.81(m, 2H), 1.12(m,
2H); 13C NMR(126MHz, CDCl3) δ 149.9, 135.1, 130.0, 128.3, 127.9, 119.9, 119.1, 56.5,
47.0, 33.7, 23.8, 21.3; 15b: 1H NMR (500MHz, CDCl3/TMS) δ 7.40(s, 2H), 7.02(s, 2H),
6.65(s, 2H), 3.40(s, 2H), 2.04(m, 1H), 1.88(m, 1H), 1.78(m, 1H), 1.66(s, 2H); 13C
NMR(126MHz, CDCl3) δ 145.3, 134.5, 128.8, 128.8, 128.2, 127.8, 119.6, 118.8, 56.4,
48
49.0, 31.0, 25.2, 19.9; 19F NMR (282MHz, CDCl3/CFCl3) δ -110.5 (d, J=240.83Hz), -
111.9 (d, J=240.83Hz), -112.79(d, J=241.11Hz), -114.09(d, J=247.03Hz), -114.98(d,
J=237.73Hz), -115.04(d, J=240.83Hz), -115.15 (d, J=237.73Hz), -116.16 (d, J=238.0), -
116.28 (d, J=241.11Hz), -116.99 (d, J=234.62Hz), -117.14 (d, J=240.83Hz), -117.18 (d,
J=237.73Hz), -118.14 (d, J=237.73Hz), -117.35 (d, J=243.93Hz), -119.16 (d, J=238.0Hz),
-119.69 (d, J=241.11Hz); 16a: 1H NMR (500MHz, CDCl3/TMS) δ 7.56(s, 2H), 6.98(s,
2H), 6.62(s, 2H), 6.28(m, 2H), 3.17(s, 2H), 1.92(s, 1H), 1.81(m, 1H); 13C NMR(126MHz,
CDCl3) δ 142.7, 136.9, 134.9, 131.1, 126.7, 128.6, 128.9, 126.7, 118.9, 118.6, 50.4, 42.8,
40.3; 16b: 1H NMR (500MHz, CDCl3/TMS) δ 7.31(s, 2H), 7.23(s, 2H), 6.92(s, 2H),
6.31(m, 2H), 2.88(m, 2H), 2.86(m, 2H), 1.21(s, 1H), 0.73(m, 1H); 13C NMR(126MHz,
CDCl3) δ 147.9, 137.1, 134.8, 129.8, 128.9, 128.5, 124.6, 118.4, 118.4, 46.6, 42.7, 41.4;
19F NMR (282MHz, CDCl3/CFCl3) δ -111.42 (d, J=244.21Hz), -112.48 (d, J=243.93Hz),
-115.31(d, J=244.21Hz), -115.92 (d, J=244.21Hz), -117.17 (d, J=240.55Hz), -118.35 (d,
J=240.55Hz), -119.40 (d, J=240.26Hz), -119.81 (d, J=240.55Hz); MS(EI) m/z
442(M+)(3), 191(100), 176(63), 126(13). HRMS Calc. for C23H14F8 442.0967, Found
442.0974 (EI).
When pure bicyclo[2.2.1]hepta-2,5-diene is used as solvent and reactant, the ratio of
15a:15b:16a:16b is 74:12:10:4. Isomer 15a is separated from the others by
chromatography and has a melting point of 233-235℃.
Reaction of Aryne 1 with 1,4-Dimethylnaphthalene: The procedure was carried
out as above except that 1,4-dimethylnaphthalene (0.10 g, 0.6mmol) was used as the
substrate. A mixture of products (ratio 3.43:1) was obtained after refluxing for 30 min,
49
which after chromatography in the usual manner gave major product endo-5,8-adduct 7
in a yield of 60%. Endo- product: 1H NMR (500MHz, CDCl3/TMS) δ 7.07(s, 2H), 6.86(s,
2H), 6.79(m, 2H), 6.51(s, 2H), 5.92(s, 2H), 5.65(s, 2H), 2.49(s, 6H); 13C NMR(126MHz,
CDCl3) δ 145.4, 141.6, 141.4, 134.4, 131.3, 128.6, 128.6, 127.9, 127.5, 127.4, 120.4,
119.1, 43.9, 18.1; 19F NMR (282MHz, CDCl3/CFCl3) δ -108.94, -114.22 (AB,
J=243.93Hz, 4F), -114.76, -118.48 (AB, J=238.01, 4F); Exo- product: 1H NMR (500MHz,
CDCl3/TMS) δ 7.13(s, 2H), 7.06(s, 2H), 6.91(s, 2H), 6.55(s, 2H), 6.54(s, 2H), 5.87(m,
2H), 2.23(s, 6H); 13C NMR(126MHz, CDCl3) δ 145.7, 143.6, 137.6, 137.5, 134.2, 130.1,
129.4, 129.0, 127.4, 126.5, 120.1, 119.0, 44.2, 18.1; 19F NMR (282MHz, CDCl3/CFCl3) δ
-111.86, -115.20 (AB, J=243.93Hz, 4F), -117.74, -119.21 (AB, J=240.83Hz, 4F); MS(EI)
m/z 506(M+)(99), 330(100), 176(8); HRMS Calc. for C28H18F8 506.1280, Found
506.1293 (EI). The stereochemistry was proven by the nOe’s between 2.49 and 5.65 in
the major and between 7.06 and 6.91 in the minor.
Reaction of Aryne 1 with 2,3-Dimethylnaphthalene: the procedure was carried
out as above except that 2,3-dimethylnaphthalene (0.10 g, 0.6mmol) was used as the
substrate. A sole endo product was obtained after refluxing for 30 min, which after
chromatography in the usual manner gave major product endo-adduct 8 (85 mg) in a
yield of 67%. Solid starts to decompose at 168℃. 1H NMR (300MHz, CDCl3/TMS) δ
7.53 (m, 2H), 7.24(m, 2H), 7.17(d, J=1.2Hz, 2H), 6.67(s, 2H), 5.71(s, 2H), 5.27(d,
J=1.8Hz, 2H), 1.71(s, 6H); 19F NMR (282MHz, CDCl3/CFCl3) δ -111.19, -114.90 (AB,
J=243.93 Hz, 4F), -116.44, -119.42 (AB, J=237.73Hz, 4F); 13C NMR(75MHz, CDCl3) δ
144.9, 143.1, 141.2, 133.9, 128.9, 127.9, 127.6, 127.1, 125.7, 124.7, 120.0, 118.7, 53.5,
50
16.5; MS(EI) m/z 506(M+)(77), 330(100), 176(14); HRMS Calc. for C28H18F8 506.1280,
found 506.1288 (EI).
Reaction of Aryne 1 with 2-Methoxynaphthalene: the procedure was carried out
as above except that 2-dimethoxylnaphthalene (0.11 g, 0.7mmol) was used as the
substrate (0.14 g, 1.1 mmol). A product mixture of was obtained after refluxing for 30
min, which after chromatography in the usual manner gave three products.
Isomer 9, 18%: 1H NMR (300MHz, CDCl3/TMS) δ 7.44(dd, J=8.1, 2.1Hz, 1H),
7.20(S, 2H), 7.17(t, J=2.5Hz, 1H), 6.90(m, 2H), 6.73(dd, J=8.1, 2.4Hz, 1H), 6.66(s, 2H),
5.83(dd, J=9.3, 12.6Hz, 2H), 5.64(d, 4.8Hz, 2H), 3.86(s, 3H) 19F NMR (CDCl3/CFCl3) δ
-111.20, -115.45(AB, J=243.9Hz, 2F), -111.27, -115.48(AB, J=245.4Hz, 2F), -116.23, -
119.48(AB, J=237.7Hz), -116.35, -119.63(AB, J=242.5Hz, 2F) 13C NMR (75MHz,
CDCl3) δ157.98, 145.38, 145.28, 144.99, 141.75, 140.83, 135.31, 133.94, 128.74, 128.42,
128.10, 127.64, 127.44, 127.10, 126.17, 125.61, 125.44, 124.20, 123.19, 119.93, 118.65,
112.54, 109.64, 102.16, 55.92, 47.50, 46.53. MS(EI) m/z C27H16F8O 508(M+)(77),
332(71), 276(35), 176(100); HRMS Calc. for C27H16F8O 508.1073, Found 508.1075 (EI).
Isomer 10, 4%: 1H NMR (500MHz, CDCl3/TMS) δ 7.18(t, J=5.8Hz, 2H), 7.12(d,
J=8.1Hz, 1H), 7.09(d, J=7.2Hz, 1H), 7.02(d, J=8.1Hz, 1H), 6.91(s, 2H), 6.76(d, J=2.4Hz,
1H), 6.60(s, 2H), 6.34(dd, J=8.0, 2.5Hz, 1H), 5.58(dt, J=6.6, 1.18Hz, 1H), 5.57(dt, J=6.01,
1.86Hz, 1H), 3.69(s, 3H); 19F NMR (282MHz, CDCl3/CFCl3) δ -111.98 (d, J=243.93Hz,
1F), -112.05 (d, J=243.93Hz, 1F), -115.37(d, J=243.93Hz, 1F) , -115.22(d, J=243.93Hz,
1F), -116.8 (d, J=241.11Hz, 1F), -116.91(d, J=238.01Hz, 1F), -119.26(d, J=237.73Hz,
1F), -119.44(d, J=237.73Hz, 1F); 13C NMR (126MHz, CDCl3) δ 157.2, 146.9, 146.0,
145.4, 138.1, 137.4, 137.1, 127.8, 127.8, 127.5, 127.5, 134.1, 134.1, 129.3, 129.3, 128.9,
51
128.9, 124.4, 111.2, 109.4, 55.8, 47.9, 46.9; MS(EI) m/z 508(M+)(100), 332(90), 176(18);
HRMS Calc for C27H16F8O 508.1073, Found 508.1068 (EI).
Isomer 11, 27%: 1H NMR (300MHz, CDCl3/TMS) δ 7.65 (tt, J=6.9, 1.8Hz, 2H),
7.48(m, 2H), 7.17(s, 2H), 7.02(s, 2H), 5.75(dd, J=24.6, 8.7Hz, 2H), 5.40(s, 1H), 5.20(t,
J=2.7Hz, 1H), 2.02, 2.29(AB, J=18.3, 2.7Hz, 2H). 19F NMR (282MHz, CDCl3/CFCl3) δ -
111.67 (d, J=247.03Hz, 1F), -112.16 (d, J=247.03Hz, 1F), -114.68 (d, J=246.75Hz, 1F), -
115.45(d, J=243.93Hz, 1F), -117.05 (d, J=238.0Hz, 1F), -117.22 (d, J=241.11Hz, 1F), -
119.32(d, J=240.83Hz, 1F), -119.40(d, J=240.83Hz, 1F); 13C NMR(75MHz, CDCl3) δ
202.04, 142.0, 140.0, 135.7, 134.5, 134.3, 134.0, 133.6, 130.3, 130.0, 129.7, 129.0, 128.7,
128.2, 128.0, 127.9, 127.5, 125.79, 125.77, 123.7, 122.1, 119.7, 118.5, 59.2, 41.8, 37.9;
MS(NBA-C3) m/z 495 [M+H]+(13), 452(17), 276(24); HRMS Calc for C26H13F8O (M+H)
495.0995, Found 495.1970 (NBA-C3).
Reaction of Aryne 1 with 2,5-Diphenylbenzofuran: the procedure was carried out
as above except that 2,5-diphenylbenzofuran (0.11 g, 0.5mmol) was used as the substrate.
A product mixture (ratio exo: endo=84:16) was obtained after refluxing for 30 min, which
after chromatography in the usual manner gave major product exo-adduct 13a and endo-
adduct 13b in a yield of 71% and 14% respectively. Exo-product gets soft at 220-222℃
and decompose at temperature above 240℃, while endo-adduct decompose at 192℃.
Exo-Isomer: 1H NMR (500MHz, CDCl3/TMS) δ 7.85(m, 4H), 7.56(t, J=7.7Hz, 4H),
7.50(t, J=7.6Hz, 2H), 7.33(s, 2H), 7.25(s, 2H), 7.20(, s, 2H), 6.64(s, 2H); 13C
NMR(126MHz, CDCl3) δ 152.6, 148.3, 135.0, 135.0, 130.2, 128.3, 128.3, 128.3, 127.7,
127.2, 127.2, 127.2, 119.1, 118.6, 94.7; 19F NMR (282MHz, CDCl3/CFCl3) -113.18(d,
J=250.13Hz, 2F), -114.19(d, J=249.85Hz, 2F), -116.73(d, J=243.93Hz, 2F), -120.70(d,
52
J=243.93Hz, 2F); endo-Isomer: δ 1H NMR (500MHz, CDCl3/TMS) δ 7.84(s, 4H),
7.54(m, 4H), 7.48(s, 2H), 7.43(m, 2H), 6.98(s, 2H), 6.60(s, 2H); 13C NMR(126MHz,
CDCl3) δ153.0, 142.7, 136.2, 133.7, 129.5, 128.8, 128.7, 128.4, 128.2, 128.0, 118.5,
118.2; 19F NMR (282MHz, CDCl3/CFCl3) δ -106.25(d, J=238.01Hz, 2F), -109.26(d,
J=237.73Hz, 2F), -114.60(d, J=234.91Hz, 2F), -118.96(d, J=234.62Hz, 2F); MS(EI) m/z
570(M+)(6), 176(3), 105(100); HRMS Calc for C32H18F8O 570.1230, Found 570.1239
(EI).
Reaction of Bis-aryne 17 with Benzene: the analogous procedure was carried out
by using 0.60 g (1 mmol) of the isomeric diiodides, 18a and 18b, and 1.12 g (10 mmol)
of potassium t-butoxide. This mixture was refluxing in 10 mL of benzene for 2.5 h and
product was purified by silica gel chromatography (hexane/EtOAc, 100:1) to give 0.42 g
(83%) of the bis-adduct 19. Mp> 315℃; 1H NMR (CDCl3/TMS) δ 6.98(m, 4H), 6.73(m,
4H), 6.22(s, 4H), 5.41(m, 4H); 13C NMR (CDCl3/TMS) δ 146.8, 141.5, 138.0, 126.8,
124.6, 120.2, 45.6; 19F NMR(282MHz, CDCl3/CFCl3), one AB quartet, -110.9, -115.5
(JAB = 243.9 Hz); HRMS Calc for C22H16F8 504.1124, found 504.1120.
Reaction of Bis-aryne 17 with Naphthalene: The reaction was carried out as in
the preceding example, except that the solvent was 10 mL of di-n-di-n-butyl ether, and
0.28 g (2.2 mmol) of naphthalene was added as the substrate. The mixture was refluxed at
142℃ for 30minutes. The residue was purified by silica gel chromatography
(hexane/EtOAc, 100:1) to give 0.52 g (86%) of white solid, bis-adduct 20. Mp 253℃
(dec.); 1H NMR (300MHz, CDCl3/TMS) δ 7.53(m, 4H), 7.20(m, 4H), 6.89(m, 4H),
5.69(m, 4H), 5.24(s, 4H); 13C NMR (126MHz, CDCl3) 145.3, 143.8, 140.9, 127.5, 125.6,
53
124.9, 124.3, 120.0, 47.4; 19F NMR (282MHz, CDCl3/CFCl3), one AB quartet, -108.9, -
115.0 (JAB = 243.9 Hz); HRMS Calc 604.1437, found 604.1437. Anal. Calc for C36H20F8:
C, 71.52; H, 3.33. Found: C, 71.10; H, 3.28.
Reaction of Bis-aryne 17 with Anthracene: The procedure was the same as in the
preceding examples, except that the reaction was carried out for 30 min at 169℃ in 10
mL of refluxing t-butyl benzene, using 0.39 g (2.2 mmol) of anthracene as a substrate.
The product was purified by silica gel chromatography (hexane/EtOAc, 100:1) with 0.56
g (80%) of the bis-adduct, 21, being obtained: mp > 310℃; 1H NMR (300MHz,
CDCl3/TMS) δ 7.59(m, 2H), 7.29(m, 2H), 7.19(m, 2H), 6.38(m, 2H), 5.96(s, 2H), 5.37(s,
2H); 19F NMR (282MHz, CDCl3/CFCl3), one AB quartet, -109.1, -114.7 (JAB = 243.9
Hz); HRMS calcd for C44H24F8 704.1744, found 704.1748.
Reaction of Bis-aryne 17 with [2.2]Paracyclophane: The procedure was carried
out in refluxing t-butylbenzene, as in the previous example, and 0.46 g (2.2 mmol) of
[2,2]paracyclophane was used as a substrate. The crude product was purified by silica gel
chromatography (hexane/EtOAc, 100:1), a 50:50 mixture of the diastereoisomeric bis-
adducts 22a and 22b, 0.64 g (84%) white solid was obtained: mp 315℃ (dec.); 1H NMR
(300MHz, CDCl3/TMS) δ 7.03(d, J=7.8, 2H), 6.94(d, J=8.4Hz), 6.93(s, 4H), 6.05(d,
J=8.4, 2H), 5.97(d, J=8.4Hz, 2H), 5.89(d, J=6.3Hz, 2H), 5.62(d, J=6.0Hz, 2H), 4.51(m,
2H), 4.44(m, 2H), 3.09(m, 2H), 2.99(m, 2H), 2.78(m, 4H), 2.54(m, 4H), 2.38(m, 2H),
2.23(m, 2H); 13C NMR (126MHz, CDCl3) δ 147.07, 142.51, 139.84, 139.62, 137.61,
134.63, 133.03, 128.05, 126.41, 126.08, 125.76, 125.37, 125.04, 124.37, 123.11, 51.59,
51.10, 34.66, 34.24, 33.64, 33.36; 19F NMR (282MHz, CDCl3/CFCl3) (isomer 1) two
54
equal intensity AB quartets, -109.6, -115.0 (JAB = 243.9 Hz), -110.9, -115.6 (JAB =
240.8 Hz); (isomer 2) two equal intensity AB quartets, -109.7, -115.2 (JAB = 231.8 Hz),
-110.6, -115.4 (JAB = 231.5 Hz); HRMS calcd for C48H36F8 764.2689, found 764.2689.
CHAPTER 3 CADOGAN METHOD AND REACTION MECHANISM
3.1 Introduction
N-nitrosoacetanilide was also reported by Cadogan in 1972 to generate benzyne via
decomposition of the intermediate benzene-diazonium salt.102 103 The mechanism that he
proposed is illustrated in Figure 3-1, and in this chapter we will describe the application
of Cadogan’s method to the generation of AF4-yne.
NO
N ON N O
ON N O
O
N NO N2 Ac2O++
Figure 3-1 Decomposition of benzene-diazonium slat
Aryne chemistry is very important in the synthesis of natural products and has been
well reviewed.66 Three main classes of reactions have been observed: a) Diels-Alder (DA)
addition with 1,3-dienes; b) ene-reaction with alkene possessing a suitable allylic proton;
c) 2+2 cycloaddition.
55
56
The generation of an aryne by treatment of an aryl halide with potassium t-butoxide
is first reported by Cram, and in this chapter we will describe this procedure as the” Cram
method”. In his original study, aryne reactions were carried out in dimethyl sulfoxide,
and the t-butoxide ion adduct was the major product. We have already discussed the 4, 5-
dehydro- and 4, 5, 15, 16-bis(dehydro)- octafluoro [2,2] paracyclophane aryne reactions
generated by potassium t-butoxide with the corresponding iodo- derivatives in Chapter
2.49, 50 High yields of DA products were obtained using the Cram method. When the
Cadogan method is applied to the same system, it will be seen that the two methods gave
essentially the same results with regard to DA reactions. However, in the reaction of
aryne with alkenes, the outcomes are totally different. The latter method gives ene
products whereas the former method gives no ene reactions, but instead a reduced,
octafluoro[2.2]paracyclophane (AF4) product.
3.2 Results and Discussion
3.2.1 The Cadogan Method
Cadogan first reported decomposition of benzene diazonium salt to generate
benzyne in situ in 1972.102 Biphenyl was obtained in up to 80% yields in benzene
solution (radical reaction), but giving 31% of ene products in a reaction with methyl
methacrylate.103 When this method is applied to the AF4 system, it gave results virtually
identical to these obtained via the Cram method, when carried out in the presence of a
diene trap, such as benzene, naphthalene or anthracene. For the Cadogan method, 90%,
93% and 95% yields of DA products were obtained for DA reactions with benzene,
naphthalene and anthracene, respectly, as compared to 86%, 88%, 84% when using the
Cram method. The ratios of product isomers varied a little bit. The ratio of anthracene
57
adducts changed from 97:3 to 95:5, whereas the naphthalene product mixture contains
15-17% exo-adduct versus 8-10% when using the Cram method.
3.2.2 Ene Reactions
When 4-iodo-octafluoro[2.2]paracyclophane (IAF4) was allowed to react with
potassium t-butoxide and 1-octene in butyl ether or in pure 1-octene as solvent, only the
reduced AF4 was observed. In contrast, AF4-yne generated from the decomposing of 4-
(N-nitroso)-acetamide-octafluoro[2.2]paracyclophane (the Cadogan method) gave ene
product 1 in 83% yield with only minor (5%) amount of reduced product AF4 (Figure 3-
2). The critical step in the generation of aryne in the Cadogan method is the loss of the
proton ortho to the diazonium group. The strong electron withdrawing fluorinated bridge
groups make the proton more acidic and thus easier to lose, making the rate of aryne
generation faster than the radical generation in the AF4 system.
F2C
CF2HN
O
CF2
F2C
F2C
CF2
CF2
F2C
Cl
O
ONO
1-Octene
+
butyl ether
F2C
CF2
N
O
CF2
F2CNO
1
Figure 3-2 1-Octene with AF4-yne reaction
When cyclohexene and cylopentene were allowed to react with AF4-yne generated
by the Cadogan method, ene products were obtained in 55% and 53% yields, respectively.
The reaction of AF4 -yne with cyclopentene afforded a 5.6:1 mixture of diastereomers
58
2a/2b (Figure 3-3), identified by NMR of the product mixture. The structural integrity of
compound 2a was demonstrated by the H1-H1 and H1-C13 (one-bond and long-range)
couplings seen in the DQCOSY, GHMQC and GHMBC spectra, correspondingly.
Couplings of the three aliphatic carbons with both of the alkene protons revealed the
cyclopentene moiety. The couplings of 4.23 with 127.8 and 146.5 and of 5.23 with 146.5
CF2
CF2
F2C
CF2
119.8
118.9
7.16130.3
129.47.02118.9
118.0
7.16130.3
7.08129.4
6.88127.3
7.08129.4
127.86.92
135.4146.5
135.4
135.4
135.0
47.0
5.23135.0
5.65131.1
32.92.522.52
30.32.152.52
H4.23
2a
CF2
CF2
F2C
CF2
119.8
118.9
7.17130.3
129.47.04118.9
118.0
7.16130.3
7.08129.4
6.88127.3
7.08129.4
127.86.83
135.4148.1
135.4
135.4
135.0
47.6
1.152.2434.8 2.24
2.2431.9
130.36.07
136.15.86
H4.15
2b
CF2
CF2
F2C
F2C
120.0
119.0
129.47.12
129.47.03
119.0
119.0
7.12129.4
7.04129.4
6.93129.4
7.12132.6
127.66.96
135.4148.1
134.6
134.6
135.4
38.1
3.71
1.101.8233.7
1.211.4319.9
1.941.9425.2
132.16.07
126.75.82
3a
CF2
CF2
F2C
CF2120.0
119.0
129.47.09
129.47.00
119.0119.0
7.16129.4
7.06129.4
6.90129.4
7.09132.6
127.66.98
135.4
146.4
134.6
134.6
135.4
3.71
38.6
5.09131.6
5.53127.6
1.982.0124.7
1.941.7522.2
1.842.1827.6
3b
HH
Figure 3-3 Chemical shifts of cyclopentene and cyclohexene products
demonstrated the connection of the cyclopentene moiety to the AF4 frame. Similar
couplings were seen between the protons and the carbons of the minor diastereomer. The
assignment of the protons and carbons of the AF4 moiety in the major product was based
59
on the H1-H1 and H1-C13 (one-bond and long-range) couplings and the nOe’s seen
between the protons of one ring and the protons of another. No such assignments were
possible for the minor product, due to the overlap with the signals of the major.
The relative stereochemistry of the two compounds was assigned based on the
nOe’s between the protons of the cyclopentene moiety and the protons on the phenyl
rings. In the major, it is the aliphatic protons at 2.15 and 2.52 which display nOe’s with
the protons at 6.92 and 7.16. The proton trans- to 4.23, at 2.15, displays an extra nOe
with 7.02. Conversely, the proton at 5.86 in the minor displays nOe’s with the protons at
6.83, 7.17 and 7.04 (the weakest) which were assigned as in Figure 3-3, based on the
nOe’s intensity and chemical shifts. A weaker nOe was seen between 4.23 and 6.92. All
these nOe’s are consistent with the stereochemistry proposed by MM calculations, which
indicate that in the lowest energy conformation the proton of the cyclopentene (4.23 and
4.15) is in the plane of the benzene ring and facing the closest CF2 group. The other
conformation with the proton in the plane of the benzene ring is ca. 10 kJ/mol higher in
energy.
Similarly, cyclohexene products 3a and 3b were assigned as in Figure 3-3, but the
ratio of two isomers was 1:1.
Surprisingly, when AF4-yne was generated using the Cram method, no ene
products were observed in the presence of 1-octene, or cyclohexene with the reduced
product, AF4, being the only observable product. Even pure 1-octene just gave reduction
to AF4 under the Cram conditions.
The AF4-yne generated under Cadogan conditions reacted with α-methylstyrene to
give the DA adduct 5 (24%) and ene product 4 (37%) (Figure 3-4). Another minor
60
product alcohol, 6 (4% yield) may arise from the oxidation of ene product during its
purification.
CF2
F2C
F2C
CF2
116.24.67 5.35
126.37.29
128.17.28
127.57.28
132.17.32
3.544.08
39.0
145.9
140.6
140.7
132.7
135.4
118.8
6.91130.4
118.9 7.09132.1
7.13130.2
7.02129.6 134.6
7.22126.5
129.46.87
134.8
118.8
119.7
F F
F FF F
F F
7.78120.5
136.2 2.7720.5
132.1
7.99123.5
128.37.64
7.55125.9
8.17133.1
129.8129.9
130.0
118.8
7.39129.8
7.24127.8
7.34128.8
6.47127.2
127.16.13
118.8
119.77.23129.9
129.8
118.1
CF2
F2C
F2C
CF2
HO7.27134.4
128.47.32122.8
7.4927.91.84
68.2
138.53.41
38.32.55
135.67.35
134.6
131.2
120.0
119.8
7.71130.5
130.76.85
134.8
7.43128.9
7.25127.0 133.6
118.9
118.7
6.82131.1
6.97131.7
130.4
45
6 Figure 3-4 Chemical shifts of products from the reaction of α-methylstyrene with AF4-
yne
3.2.3 2-Methoxynaphthalene Reaction
2-Methoxynaphthalene reacts with IAF4 and KOtBu in butyl ether to produce
products (Chapter 2), the ketone product deriving from hydrolysis of the enol ether
during the reaction or purification. In contrast, when 2-methoxynaphthalene reacts with
AF4-yne generated via the Cadogan method, the major product obtained from the
mixture is anthraceno[2.2]paracyclophane (43%), which had been alternatively
synthesized by the reaction of 3,6-dipyridinyl-1,2,4,5-tetrazine with the AF4-yne
61
naphthalene adduct (chapter 4). DA reactions on both substituted and unsubstituted ring
were also observed under Cadogan’s conditions (total yields are 12%). It must be
assumed that the phenyl anthraceno[2.2]paracyclophane is derived from a retro DA
reaction by losing the methoxyetheno group as showed in Figure 3-5.
CF2
F2C
F2C
CF2
OCH3CF2
CF2
F2C
F2C
retro DA
Figure 3-5 Retro Diels-Alder reaction of 2-methoxynaphthalene adduct to phenyl anthraceno[2.2] paracyclophane
3.2.4 Tetracyclone Reaction
Tetraphenylcyclopentadienone (tetracyclone) is an excellent diene trap in Diels-
Alder reactions.102 1,2,3,4-Tetraphenylnaphthalene (70%) was obtained by Cadogan
when using tetracyclone to trap benzyne in his original report. In the case of AF4-yne,
83% yield of adduct was obtained (Figure 3-6).
CF2
F2C
F2C
CF2
PhPh
7.45128.0
133.5117.7
7.30131.7132.9
117.8138.6138.6
143.5 139.7
129.96.03 127.1
6.64
6.89125.9
7.15126.6
7.35132.4
131.16.80
142.6
7.07132.3
6.95126.46.93
127.4 7.09126.5
7.15127.1
Figure 3-6 Chemical shifts of tetracyclone with AF4-yne product
62
The assignment of the protons on the phenyl rings of this adduct was accomplished
based on the H1-H1 couplings seen in the DQCOSY spectrum. Both phenyl rings
displayed non-equivalence of the ortho and meta positions, indicative of restricted
rotation. A quick variable temperature run showed that the pairs 6.80 – 7.07 coalesced at
50 – 60 °C, while the protons on the other ring displayed no broadening at 60 °C. The
assignment of the carbons on the phenyl ring, as well as of those adjacent to the ipso
positions was done on the basis of the H1-C13 couplings, one-bond and long-range, seen
in the GHMQC and GHMBC spectra, correspondingly. The NOESY spectrum at room
temperature displayed a nOe between 7.45 and 7.30, which identified the protons on the
same side of the paracyclophane. The assignment of the rest of the carbons followed from
the H1-C13 couplings. The only other non-trivial nOe in the NOESY spectrum was 6.93-
7.35. A ROESY spectrum was then run at -20 °C, temperature at which all protons
displayed sharp signals. The nOe between 7.30 and 6.80 (chemical shifts at room
temperature) allowed the assignment of the faster rotating phenyl ring to position 1 on the
naphthalene, and of the proton at 6.80 to the side exo to the cyclophane moiety. The nOe
between 7.35 and 6.93 agrees with a MM calculation in Perch, in which the phenyls in
positions 2 and 3 are on the side of the naphthalene ring towards the cyclophane, while
the phenyls in positions 1 and 4 are on the opposite side. NOe’s of 7.07 with both 7.35
and 6.03, in conditions in which 6.80 does not display any nOe with protons on the other
phenyl ring, agree with this model.
3.2.5 Norbornadiene Reactions
As described in Chapter 2, the AF4-yne generated from IAF4 under Cram
conditions, gave major [2+2+2] adducts instead of the major [2+2] products that were
observed by Heaney98 and Noble99 in their studies of the reactions of halogenated
63
benzyne with norbornadiene. Tabushi, et al. also reported the predominant [2+2]
cycloaddition products in the reactions of norbornadiene and quadricyclane with benzyne,
ratio of 73/27 and 67/33, respectively, compared to [2+2+2] products.104 In the case of
AF4-yne as generated from 4-(N-nitroso)- AF4 acetamide (Cadogan method),103 the
major products formed with norbornadiene were the [2+2+2] products as listed in Table
3-1, but the preference was not so strong as under Cram conditions.
Table 3-1 [2+2+2] to [2+2] products ratio of norbornadiene with AF4-yne method solvent Temperature(℃)a Ratio(15a:15b:16a:16b)b
Cram Butyl ether 142(160) 62:27:3:8
Cram norbornadiene 90(110) 74:12:10:4
Cadogan Butyl ether 90(110) 39:21:21:19
a. Temperature in the parenthesis is the oil bath value. b. see Chapter 2
3.2.6 Reaction with 1,3,5-Cycloheptatriene
The reaction of cycloheptatriene with benzyne provided another illustrative
example of novel benzyne chemistry. Initially, Tabushi et al.104 claimed that
cycloheptatriene underwent a [2+6] cycloaddition along with ene reaction (approximately
1:1 ratio) in its reaction with benzyne. It turned out that the product was a [2+2] instead
of a [2+6] cycloadduct, as reported by Lombardo105, 106 and Crews107shortly thereafter,
with an overall yield in the reaction was about 25%. [2+4] Cycloadducts were not
observed in these investigations. Tropone reacted with benzyne to give a predominant
[2+4] cycloadduct under the same conditions.106 The rationale is that tropone has a planar
structure while that of cycloheptatriene is not planar.
Surprisingly, AF4-yne generated from Cadogan’s method didn’t yield any [2+2]
cycloadduct. All observed products were derived from an initial ene reaction (yields of
64
61%). The primary ene product then reacted with another AF4-yne, apparently via the
norcaradiene tautomer to give bis-AF4 adducts endo- 8a and exo-8b (1:1) in 38% yields
as showed in Figure 3-7. In contrast, the AF4-yne as generated from Cram’s method gave
only reduced AF4 (31%) plus the t-butoxide ion adduct (51%) in the reaction with
cycloheptatriene. Neither [2+2], [2+4] nor ene reactions were observed.
Proton and carbon chemical shifts of the products are illustrated below. The
sequence of protons in the contiguous coupling network of [4.1.0]-bicyclohepta-3-ene
moiety was revealed by the DQCOSY experiment. The carbons to which these protons
are bound were identified in the GHMQC spectrum. Proton-carbon couplings of ca. 165-
175 Hz confirmed the methines of the cyclopropyl ring. The three carbons on the AF4
frames to which the [4.1.0]-bicyclohepta-3-ene moiety is attached (at ca. 140-145 ppm)
have been identified by their cross-peaks in the GHMBC spectra to protons two or three
bonds away. The carbons adjacent to them couple with the protons three bonds away, e.g.,
in the case of 8a, 2.54 couples with 126.5 and 131.4, 129.2 couples with 4.89, and 128.5
couples with 4.74. Three of these carbons, at 129.2, 128.5 and 131.4 are split as a triplet
of ca. 30-35 Hz by the two fluorines two bonds away. The remaining protons and carbons
on the para-phenylene moieties to which the [4.1.0]-bicyclohepta-3-ene moiety is
attached were assigned on the basis of the couplings between protons and carbons three
bonds away. The DQCOSY spectrum confirmed the large coupling between protons
which are ortho and the small couplings between protons which are meta.
The configuration of compounds 8a and 8b was established by nOe’s. In both 8a
and 8b, the cyclopropyl protons adjacent to the AF4 display an nOe to the alkene protons
65
FF
FF
FF
FF
F F
F F
FF
FF
F F
F F
FF
FF
F F
FF
FF
FF
2.541.67
1.97
4.74
6.17
6.23
4.89
6.706.67
7.36
7.36
6.896.94 6.53
6.95
7.13
7.19
7.06
7.08
7.40
7.04
6.846.11
6.94
7.317.01
7.10
2.451.30
0.94
4.74
6.49
6.554.94
6.826.81
7.19
7.17
6.856.84
26.4
24.4
25.0140.9
125.8
36.6
36.9128.5
129.1144.1
143.8
131.0
27.126.4
24.4
37.4
37.1
132.1
132.5
143.6
129.2
118.6
126.8126.5
128.5
118.6
143.9
126.5
141.4
131.4
125.4
117.4
125.0126.9
128.3128.3
127.3126.6
126.1
128.4
125.5
128.6
127.6
129.0
130.8
127.6129.2
125.4
128.3128.6
125.2
127.6
125.0
117.6
117.6
118.6
118.9
133.1
132.8
130.8
130.9
118.2
117.7
133.1
133.9
117.6
117.4
117.4
117.4
117.4
117.6
118.2
134.2
133.9
133.1
133.1
132.8
133.9
8b
8a
F F
F F
FF
FF
F F
F F
FF
FF
6.997.16
7.04
7.16
7.217.11
126.8131.2
117.9
126.8126.7 130.9 118.4
128.2127.5
128.2126.7
117.6
117.6
133.3
134.0
142.9 39.1
116.2 125.5
129.4
130.0
123.2120.2
7.183.06
5.506.45
6.70
6.62
6.044.58
7.11
7.277.09
6.98
117.57.09
142.6 139.3
126.96.26 120.1
5.47
26.6 2.372.42
122.15.49
125.06.24
133.46.53
9a 9b Figure 3-7 Chemical shifts of cycloheptatriene products 8 and 9
(2.54 with 6.17 and 6.23; 2.45 with 6.49 and 6.55) while the other cyclopropyl protons do
66
not, therefore the configuration of the [4.1.0]-bicyclohepta-3-ene moiety is endo in
bothcompounds. In 8a, the cyclopropyl protons at 1.67 and 1.97 display an nOe with two
aromatic protons at 6.89 and 6.94, while in 8b the alkene protons at 6.49 and 6.55 display
nOe’s with the aromatic protons at 6.84 and 6.85, indicating that the addition of the
[4.1.0]-bicyclohepta-1,3-diene yielded the endo product for 8a and the exo product for 8b.
The relative size of these nOe’s allowed the assignment of the aromatic protons, i.e., the
nOe of 1.67 with 6.89 was larger than the nOe of 1.67 with 6.94.
The use of nOe’s in the assignment of the configuration of the AF4 unit bound to
the cyclopropyl was based on the fact that the cyclopropyl proton α to the AF4 (2.54 in
8a) is approximately in the plane of the para-phenylene and is facing the nearest CF2.
This is the geometry found by a conformational search using MM2 in Hyperchem, and
confirmed by the nOe’s displayed by the products of the reaction of the AF4 arene with
cyclopentene and with cyclohexene [page 59]. In compound 8a, 1.97 displays nOe’s with
two aromatic protons at 7.08 and 7.40, while 1.67 does not, therefore the other para-
phenylene ring of the AF4 moiety bound to the cyclopropyl ring is on the same side of
this ring as 1.97. Of 7.40 and 7.08, only the former displays an nOe with 2.54, therefore
they are syn. Similar nOes’ were used in the case of 8b, to assign the protons at 7.31 and
7.04.
Simple ene products 9a and 9b (2:1) as depicted in Figure 3-6 were also obtained
in 23% yield, the latter deriving from 9a via subsequent 1,5-H shift. The GHMBC
spectrum displayed couplings for 9a between the protons at 5.50 and 4.58 and the carbon
at 142.9, and for 9b between the protons at 6.26 and 6.53 and the carbon at 142.6, which
identified the carbon on the AF4 moiety to which the cycloheptatriene moiety is
67
connected. Couplings between the protons and carbons of the methines at 39.1, 3.06 and
at 126.8, 7.18 identified the methine ortho to 142.9 in 9a. A similar coupling between the
proton at 7.09 and the carbon at 139.3 identified the proton ortho to 142.6 in 9b. Long-
range couplings between the protons and carbons in a meta relationship were used to
assign the chemical shifts on the AF4 moiety for 9a. In the case of the minor product 9b,
these assignments could not be made because of severe overlap with the stronger peaks of
9a.
The assignment of the protons on the cycloheptatriene moiety in 9a assumed a
geometry in which the proton at 3.06 is in the plane of the para-phenylene and is facing
the nearest CF2. This is the geometry found by a conformational search using MM2 in
Hyperchem, and confirmed by the nOe’s displayed by the products of the reaction of the
AF4 arene with cyclopentene and with cyclohexene [page 59]. Two nOe’s, between 3.06
and 7.21 and between 5.50 and 7.11 allowed the assignment of the protons on the face of
the other para-penylene moiety of the AF4, as 7.21 being syn to 3.06. 4.58 display a nOe
with 7.18 only. The conformation of the cycloheptatriene ring in 9a is with the double
bond having 6.62 and 6.70 folded toward 3.06, as demonstrated by nOe’s between 3.06
and these other two protons.
In the case of 9b, both 6.26 and 6.53 display nOe’s with 7.27 and 7.09, as
expected for little preference for one orientation or the other of the cycloheptatriene
moiety. The most shielded proton at 7.27 was assigned as syn to the cycloheptatriene.
The side endo to the AF4 displayed deshielding compared to the side exo in all of the
compounds studied; therefore one can assume that the preferred conformation has the
CH2 of cycloheptatriene on the exo side of the AF4.
68
Normally, cycloheptatriene undergoes DA reactions with most dienophiles via its
valence tautomer, bicyclo[4.1.0]hepta-2,4-diene (norcaradiene) which is present in very
small quantities in equilibrium with cycloheptatriene.108, 109 With an extremely reactive
reagent such as benzyne, the benzyne is apparently so reactive that it reacts preferentially
with the major tautomer and there is simply too little norcaradiene present to lead to
significant product.
Why should the very reactive AF4-yne give rise to norcaradiene derived products
(8a& 8b) when benzyne itself did not? It may be that the primary ene product, 7-AF4-
substituted cycloheptatriene, has a much greater amount of its respective norcaradiene
tautomer present in equilibrium, thus allowing AF4-yne to react with this tautomer in the
preferred manner. Ciganek et al. found that substitutents containing π systems would help
the stabilization of the norcaradiene valence isomer.110 AF4 system is quite electron
deficient due to the two bridge fluorine substitutents, and importantly, AF4 moiety is
quite bulky which will force the equilibrium to the side of norcaradiene tautomer.109
AF4
H AF4H
AF4-yneDA products 8a & 8b
Figure 3-8 Primary AF4-yne ene product with AF4-yne reaction to products 8a&8b
Equilibrium of cycloheptatriene with norcaradiene has been extensively studied in
1960’s and 1970’s. No norcaradiene valence tautomer could be detected by variable-
temperature 1H NMR even down to -150℃.111, 112 Only ca. 3% norcaradiene could be
observed for 7-carboxyl acid substituted derivative at the above temperature.113 With two
π acceptor substitutents at 7 position, for example, CN, the norcaradiene is the more
stable form by ca. 6 kcal,110, 114 whereas that of unsubstituted cycloheptatriene is the more
69
stable form by ca. 11 kcal.115, 116 Adam et al.109 studied the cycloaddition of 7-substituted
cycloheptatriene with singlet oxygen and 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD),
which is a very dienophilic reagent. He found that the product ratio with singlet oxygen
follow the order CHO ∽ CO2Me ∽ CN > ph > H > MeO, the norcaradiene [2+4] adduct
increase from the left to right, being exclusively norcaradiene adduct for MeO and
exclusively cyclohetpatriene adduct for CHO, CO2Me and CN. For H mainly the former
and for ph mainly the later are formed. In contrast, only the norcaradiene [2+4] adduct
was produced for PTAD for all substituents. Π electron acceptor such as CN, CO2Me and
CHO, stabilize the cyclopropane ring by decreasing the antibonding C1-C6 electron
density, while the effect is reversed for π donor MeO. His rationale for the abnormal
product for PTAD is that the cycloaddition activation energy for cycloheptatriene is much
high than that of norcaradiene, 17-20 kcal/mol, lie well beyond the equilibrium activation
energy, 2-12kcal/mol. Comparing with the singlet oxygen, PTAD is much more slower
and more selective with in its dienophilic reaction with cycloheptatriene.
Similarly, AF4-yne is quite bulky and reactive intermediate, the cycloaddition
activation energy must be very high for cycloheptatriene due to the steric issue, while that
for norcaradiene is much lower and faster reaction. On the other hand, AF4 moiety is
electron deficient π acceptor, the equilibrium of 7-AF4-cycloheptatriene would favor the
7-AF4-norcaradiene, which in turn would increase the reaction rate of norcaradiene with
AF4-yne.
3.3 Mechanistic Study of AF4-yne
The parent benzyne and eventually all 1,2-arynes have singlet ground state, with o-
benzyne itself having a singlet-triplet energy gap of 37.5 kcalmol-1.57, 117 Since arynes are
70
simple strained alkynes, the Woodward-Hoffmann rules do not permit a concerted
superafacial (S) 2S+2S thermal cycloaddition. On the other hand, [2+4] cycloadditions
should be concerted, stereospecific reactions. Dienes generally undergo [2+4]
cycloadditions with arynes, but when the diene system is sufficiently distorted from
planarity, step wise [2+2] cycloaddition with benzyne becomes energetically feasible.107
3.3.1 Base and Solvent Study
Arynes are also very reactive towards nucleophilic addition.66, 118-120 There is a
question therefore regarding why there is no t-butoxide ion adduct formed in the AF4-yne
reactions, in contrast to that Cram originally reported with his benzyne study.24 Base and
solvent effects in this AF4-yne system were investigated (Table 3-2). A striking
observation is that no DA reaction with anthracene is observed when sodium t-butoxide
is used instead of potassium t-butoxide. After refluxing in butyl ether for two hours, most
starting material remains. Sodium amide, which is a strong and commonly used base for
aryne generation,70, 121-123 also gives no anthracene adduct in butyl ether (of course, it
may be destroyed by butyl ether). Reduced product AF4 plus 5% DA products with some
starting material were observed when refluxing in t-butylbenzene for two hours in the
reaction of IAF4 with NaOtBu. In the polar solvent DMF, sodium amide simply reduces
IAF4 to AF4 in over 90% yield.
Table 3-2 Base and solvent effects in AF4-yne reaction with anthracene Solvent Base Temperature
(℃)
Time
(min)
Diels-Alder adduct %
(from the 19F spectrum)
t-butylbenzene KOBut 169 30 83
Butyl ether KOBut 142 30 82
Butyl ether NaOBut 142 120 SM
t-butylbenzene NaOBut 169 60 IAF4:AF4:DA
71
9.24:1:1.27
Butyl ether NaNH2 142 120 Starting Material
t-butylbenzene NaNH2 169 270 IAF4:AF4:DA
2.70:1.21:1
Butyl ether NaHMDS Room 18h Starting material
DMF NaNH2 Room 18h AF4 (90%)
DMF: dimethylformamide; HMDS: 1,1,1,3,3,3-hexamethyldisilazane; DA: Diels-Alder adduct.
Why is the same base with different cations so different in the aryne generation?
Sodium t-butoxide works better than sodium amide and potassium t-butoxide in the
formation of t-butyl hypoiodite in cyclohexane by Wirth.124 The solubility played an
important role in that reaction system. Thus, the solubility of sodium and potassium t-
butoxide in butyl ether was examined (Table 3-3).
Table 3-3 Base solubility in butyl ether solvent Base Refluxing time solubility
NaO tBu (0.1132g) 5 min in 14 ml Clear solution
KOtBu (0.1123g) 30 min in 64 ml Most solid remains
It is obvious that sodium t-butoxide has much better solubility in butyl ether than
potassium t-butoxide does. A heterogeneous reaction system makes the base stronger!
The dehydrogenation probably occurs on the surface of the strong base. The lack of
reaction with sodium amide might be due to its limited surface area (pellets). In the
reaction of IAF4 with sodium amide in t-butylbenzene, only 20% DA product was
observed, whereas 100% of the starting material is recovered in butyl ether (Table 3-3).
3.3.2 The Different Selectivity of the Two Methods
Why does the same aryne generated by different methods have such a huge
difference in reactivity towards the same substrates? AF4-yne generated via the Cadogan
method gave ene products in the presence of alkene, whereas only reduced AF4 was
72
observed from the AF4-yne generated by the Cram method for the same type of reaction.
The selectivity of arynes towards different substrates was examined first.
Anthracene is such an excellent diene trap that the difference of speed of aryne
generation may not be discerned between two methods. Therefore, naphthalene and
benzene were first used as the diene trap in the competition experiments between
Cadogan and Cram methods. Two methods’ selectivity towards benzene and naphthalene
are listed in Table 3-4. Both methods show that naphthalene reacts much faster as the
benzyne trap, which is consistent with earlier reports.87, 88 The selectivities of naphthalene
to benzene in Cadogan and Cram method are 512:1 and 285:1, respectively.
Anthracene is the one of the most reactive diene trap in benzyne chemistry, but its
actual selectivity versus benzene and naphthalene was not available. The competition
between anthracene and naphthalene in DA reaction was carried out under Cram
conditions, and the result was summarized in Table 3-5. In order to compare the result
between Cram and Cadogan methods, some reactions were carried out in butyl ether at
110℃, which are the typical conditions for Cadogan method.
Table 3-4 Competition reactions of naphthalene to benzene method substrate Time
(min) Product
ratio selectivity
Cram Ben:Naph=1:1 30 Naph adduct 100% Cram Ben:Naph=112:1 180 Naph:Ben
74:26 Naph:Ben=307:1
Cram Ben:naph=169:1 180 Naph:Ben 63:37
Naph:Ben=287:1
Cram Ben:naph=449:1 180 Naph:Ben 37:63
Naph:Ben=260:1
Cadogan Ben:naph=63:1 Over night
Naph:Ben 84:16
Naph:Ben=332:1
Cadogan Ben:naph=215:1 Over night
Naph:Ben 76:24
Naph:Ben=688:1
Cadogan Ben:naph=493:1 Over night
Naph:Ben 54:46
Naph:Ben=516:1
73
Cram 1,4-dimethylnaph 20 Endo:exo 80:20
Adduct on non substituted ring
Cadogan 1,4-dimethylnaph Over night
Endo:exo 65:35
Adduct on non substituted ring
Cram 2,3-dimethylnaph 30 Endo Adduct on substituted ring
Cadogan 2,3-diemthylnaph Over night
endo Adduct on substituted ring
Cram 2-methoxynaph 30 3 adducts endo major
Adduct on substituted ring
Cadogan 2-methoxynaph Over night
different product
Adduct on substituted ring
Reactions were run at 110℃ in butyl ether. Naph=naphthalene; Ben=benzene; DA=Diels-Adler. Table 3-5 Selectivity in Diels-Alder reaction under Cram conditions
substrates Temp (℃) DA adduct ratio selectivity
Anth:Naph=1:10 142(reflux) Anth:Naph=73:27 Anth:Naph=26:1
Anth:Naph=1:10 110 Anth:Naph=75:25 Anth:Naph=30:1
Naph:Ben=1:50 110 Naph:Ben=80:20 Naph:Ben=200:1
When temperature is lower, AF4-yne has better selectivity to anthracene over
naphthalene, 30/1 at 110℃ compared to 26/1 at 142℃. While the selectivity to
naphthalene over benzene is 200/1 under Cram conditions compared to 512/1 under
Cadogan conditions, which shows that AF4-yne generated under Cadogan conditions has
better selectivity. We can deduce that selectivity to anthracene over benzene is 6000/1
under Cram conditions.
Benzene is stable and the worst diene trap in benzyne DA reactions,87 which is also
obvious from the competition results above. The competition reaction of benzene with 1-
octene (Table 3-6) gave only ene product under Cadogan conditions. When the same
reaction was carried out under Cram conditions, reduced AF4 was the sole product with a
large excess of 1-octene. t-Butoxide ion addition product was the major product along
74
with reduced AF4 (former: AF4=1.5:1) if only 1.2 equivalents of 1-octene is used.
Normally, t-butoxide adduct is not observed under Cram conditions.
Table 3-6 Competition reactions of benzene to 1-octene method substrate Time(min) results
Cram Ben:1-octene=1:1 5 hrs AF4:DA:other=32:2:46
Cram Ben:1-octene=1:4 5hrs AF4:DA:other=76:4:20
Cram Ben:1-octene=1:45 5 hrs AF4
Cadogan Ben:1-octene=1:1 Over night Ene product
Reactions were run at 110℃ in butyl ether. Ben=benzene; DA=Diels-Adler; other=t-butoxide ion adduct.
3.3.3 The Selectivity of AF4-yne Toward Diels-Alder and Ene reaction
Benzene is apparently not fast enough to capture all the AF4-yne when it is formed
under Cram condition, thus, the above results could not provide the right information on
the degree of aryne formation. Thus, anthracene was used as the diene trap in competition
reactions with 1-octene. We assume that all the arynes were trapped by anthracene as
soon as arynes were formed. The result is showed in Table 3-7.
Table 3-7 Competition reaction of anthracene with 1-octene in butyl ether for 5 hours at 110℃ under Cram condition
Ratio(anthracene/1-octene) Results (DA products/AF4) 1:1 100 1:10 82:18 1:40 55:45 1:100 30:70
The data shows explicitly that aryne was formed even with 100 equivalents excess
of 1-octene. So why was no ene reaction observed under Cram condition? The reduction
rate of IAF4 to AF4 increases as the concentration of 1-octene increases. But this is not
the case in norbornadiene reactions. The reactions of other alkenes with AF4-yne under
Cram condition were summarized in Table 3-8. The amount of reduced AF4 increases as
75
the amount of olefins increases, which means that olefin does have some effect in the
reduction of AF4-yne.
Table 3-8 Reaction of AF4-yne with olefins in butyl ether Method Substrate (equiv.) Conditions Results
Cadogan 1-octene(2) 110℃ 83% ene products
Cram 1-octene(2) 110℃ 3h 26%AF4 + 74% othera
Cram 1-octene(10) 110℃ 3h 64%AF4 + 36% othera
Cram Cycloheptatriene(4) 120℃ 5h 31%AF4 + 50% othera
Cram Pure 1-octene Reflux 3h >90% AF4
Cadogan Cyclohexene(2) 110℃ 55% ene products
Cram 1-hexene(2) 110℃ 3h 22%AF4 + 76% othera
Cram 1-hexene(40) 110℃ 6h >90%AF4
Cram t-butylethylene (2) 110℃ 5h 42% AF4 + 57% otherb
Cram t-butylethylene(100)
anthracene(1) 110℃ 5h IAF4:AF4:DA
64:11:25
a: t-butoxide adduct; b: 2+2 cycloadduct Is AF4-yne formed under Cadogan conditions? Ene product was the only
observable one when benzene and 1-octene were presented in a 1:1 ratio (Table 3-6). Is
there any special selectivity toward ene reaction under Cadogan condition? Competition
of ene with DA reaction was investigated and summarized in Table 3-9.
Table 3-9 The AF4-yne selectivity of DA over Ene reaction under Cadogan conditions (3 h at 110℃ in butyl ether)
substrates Products ratio (DA:Ene) Selectivity (DA/ene)
Benzene:1-octene 1:1 Ene --
Benzene:1-octene 40:1 19:81 1/139
Anthracene:1-octene 1:10 96:4 197/1
76
Naphthalene:1-octene 1:1 69:31 2/1
The DA reaction of anthracene with AF4-yne is 197 times faster than ene reaction
of AF4-yne with 1-octene, while that is just 2 times faster with naphthalene as diene trap
in competition with ene reaction. It is very clear that benzene is much poorer diene trap
than anthracene and naphthalene. Anthracene is 2.7*104 faster in DA reaction than
benzene, which is consistent with the very poor yields for the DA reaction of benzene
with some benzynes.
Looking back at Table 3-4 and Table 3-5, we found that anthracene was more
reactive than naphthalene and benzene by 30 times and 6000 times respectively under
Cram conditions. The same relative reactivities are 98 and 2.7*104 toward naphthalene
and benzene respectively under Cadogan conditions. The reason for the significant
difference is not clear. To keep in mind that the former reactivity measurement was based
on competition of DA reactions, whereas the latter one was based on the DA vs ene
reactions.
3.3.4 t-Butoxide Ion Adduct
One of the control experiments of IAF with KOtBu and anthracene was carried out
in butyl ether, with 100 equivalents of t-butylethylene added to the reaction mixture.
After stirring at 110℃ for 6 hours, 11% reduced AF4 and 25% anthracene adduct were
obtained with 64% starting material remaining. The slower rate may due to the lower
boiling point of t-butylethylene (bp 41℃). When the alkene concentration was low, t-
butoxide ion adduct was observed predominantly and this product decreases as the olefin
concentration increases. Table 3-10 summarizes the results where the t-butoxide ion
77
adduct was observed. Cycloheptatriene with AF4-yne under Cram’s conditions give 50%
t-butoxide ion adduct with 31% AF4, acting as a normal alkene in this case.
Table 3-10 Summary of t-butoxide adduct under Cram’s conditions reaction Yield of t-butoxide adduct (5)
Benzene+1-octene (1:1) 46
Benzene+1-octene (4:4) 20
1-octene (2) 74
1-octene(10) 36
1-hexene(2) 76
Cycloheptatriene(4) 50
50% of t-Butoxide ion adduct was obtained with 31% AF4 in the reaction of
cycloheptatriene with AF4-yne generated under Cram conditions, whereas 61% ene
reaction product was observed under Cadogan conditions. 1-Hexene works the same way
as 1-octene does to give 76% t-butoxide ion adduct if 2 equivalents 1-hexene is used.
3.3.5 Mechanism
What is the difference between these olefins? Norbornadiene, a reactive olefin, gave
mainly [2+2+2] cycloadducts under Cram’s conditions, whereas other alkenes do not
give adducts. Was AF4-yne reduced by alkenes through electron transfer mechanism?
The ionization potential of some alkenes is listed in Table 3-11. Electrons in the
norbornadiene double bonds are delocalized due to the strain induced overlap. The bond
order for the carbon-carbon bonds calculated by Brunger et al is 1.90 for the double
bonds and 0.924 for the single bonds in norbornadiene, respectively.125 The ionization
potential of norbornadiene is 8.69 -8.73 eV, which is nearly 1 eV lower that of 1-octene.
78
The energy level of electrons becomes higher as the substitutents on the double bond
increase. It is interesting that the ionization potential of benzyne is 9.75 eV, much higher
than most olefins. IAF4 is reduced by 1-octene but not by norbornadiene (chapter 2), thus,
the reduction of AF4-yne by electron transfer from the olefin can be excluded from
consideration.
Iodide is a good leaving group and the fluorinated bridges provide the strong
electron-withdrawing groups in the AF4 molecule. Therefore it should be possible to
reduce IAF4 to AF4 directly. It has been found that alkyl halides undergo substitution
reactions by the electron transfer, or SRN1 mechanism.127, 128 In the study of
perfluoroalkyl iodides, which can not undergo SN1 or SN2 substitution with nucleophiles,
Chen at al found that perfluoroalkyl iodide can be substituted by a SRN1 type reaction
very easily.129, 130 Perfluoroalkyl halides can also be reduced by a SRN1 mechanism.131
Iodide ion was released in 68% yield after 30 min in the reaction of iodobenzene with
potassium pinacolone enolate in the dark, while bromo-derivative was much less reactive
under the same conditions.132 Costentin at al reported thermal type SRN1 reaction with 4-
nitrocumyl chloride and 2-nitropropanate ion, which underwent either concerted or
stepwise dissociation of C-Cl bond depending on the properties of the nucleophile.133
Table 3-11 Ionization potential of alkenes126 alkene ionization potential* (eV)
norbornadiene 8.69-8.73 (PE)
propene 9.70-10.2(PE), 9.73(PI)
1-butene 9.62-9.77(PE), 9.59(PI)
cyclohexene 9.11-9.12(PE), 8.94(PI)
79
t-butylethylene 9.45(PE)
1-octene 9.60(PE), 9.427(PI)
cis-2-octene 9.10(PE), 8.913(PI)
benzene 9.2-9.25(PE), 9.20-9.27(EI)
fluorobenzene 9.11-9.37(PE), 9.75(PI)
α,α,α-trifluorobenzene 9.68(PE)
benzyne(1,3-cyclohexadien-5-yne) 9.75(EI)
*PE, photoelectron spectroscopy; PI, photoionization; EI, electron impact. Potassium t-butoxide could act as electron donor and could potentially reduce IAF4
via a SRN1 mechanism (Figure 3-9). After the first electron transfer from the base, the
AF4 radical could be obtained through dissociation of IAF4 radical anion. The radical
could either accept another electron to become an anion and be protonated to form AF4
from there, or it could react with t-butoxide ion to get another radical anion (SRN1
reaction). The latter radical anion could then transfer an electron to another IAF4 and
produce t-butoxide ion adduct and close the free radical chain circle. The t-butoxide ion
adduct was observed in the reactions where the olefin concentration was not high (Table
3-9). When the concentration of alkenes was high (>10eqiv.), the reduction from the AF4
radical directly must be predominant process.
80
FFF
FF F
F
F
electron transfer(CH3)3CO
FFF
F F FF
F
ET
FFF
FF F
F
F
OC(CH3)3
FFF
FF F
F
F
RH
(CH3)3COK (5)
FFF
FF F
F
F
I
FFF
FF F
F
F
H
butyl ether110oC, 3h
I
+ I
(CH3)3CO
IAF4
FFF
FF F
F
F
OC(CH3)3
Figure 3-9 SRN1 reduction of IAF4 to AF4
From Table 3-7, the AF4-yne was formed during the reaction process even with 100
equivalents of 1-octene. Thus, AF4-yne must be generated with or without any diene trap
inside. If there was no substrate, reduced AF4 was observed with over 90% yields in the
reaction of IAF4 with KOtBu in butyl ether (Table 3-7). Therefore, a reduction
mechanism was proposed depending on the information above (Figure 3-10). After the
first electron transfer, radical anion was formed, which would grab proton from the
surrounding to generate the AF4 radical. The AF4 radical could be further reduced by
another electron transfer or attacked by t-butoxide ion to produce another radical anion
and close the mechanism circle. Since no t-butoxide ion adduct was observed in the
81
absence of olefin, the AF4 radical was reduced by second electron transfer to produce
AF4.
FFF
FF F
F
F
electron transfer
(CH3)3CO
FFF
FF F
F
F FFF
FF F
F
F
H ET
FFF
FF F
F
F
OC(CH3)3
H
FFF
FF F
F
F
H
RH
RH
(CH3)3COK (5)
FFF
FF F
F
F
I
1-octene
FFF
F F FF
F
H
butyl ether110oC, 3h
+
(CH3)3CO
FFF
FF F
F
F
OC(CH3)3
H
electron
Figure 3-10 Reduction mechanism of IAF to AF4 in the presence of olefin
Olefin in the reaction mixture may act as phase transfer reagent toward t-butoxide
ion to increase the solubility of t-butoxide ion in butyl ether by forming a complex
(Figure 3-11) which would make the t-butoxide ion attack on the AF4 radical more
feasible to generate the t-butoxide ion adduct. When the concentration of olefin became
much higher, solution became electron rich and olefin accelerated the electron transfer
process.
82
n
KO
Figure 3-11 Olefin with KOtBu complex
3.3.6 Isotopic Labeling Experiments
Isotopic labeling experiments were carried out to examine the mechanism. The
reaction of IAF4 with KOtBu was much slower in the presence of equal amount of t-butyl
alcohol (Table 3-12). Alcohol increased the solubility of KOtBu and made the base
weaker. The NMR spectrum found deuterium incorporation in the reduced product of
IAF4 with KOBut/DOtBu without a diene trap. The MS also showed fragment of
176(100), 177(53), 352(14), and 353(14), which meant about half of the reduced AF4
(38%) was deuterated. Deuterium exchange was also observed in this reaction.
Recovered starting material IAF4 (22%) showed a peak at 479(5), 478(3), the isotopic
ratio was much higher than that in pure IAF4 with MS peaks of 479(6) and 478(60). As
expected, 44% DA products were observed in the presence of 1 equivalent of anthracene
in the above reaction. AF4 was obtained in 52% and 40% yields in the reactions of AF4-
yne with acetonitrile and N,N-dimthylformamide (DMF) as solvents, respectively.
Dideuterated AF4 was observed in the reaction of IAF4 with KOtBu in CD3CN in a ratio
1:1 with respect to the mono-deuterated AF4. The MS spectrum showed peaks at 354(19),
353(31), 353(12), 352(9) and fragments 178(54), 177(54), 177(35), 176(100) respectively,
which meant that half of the AF4 obtained the second proton from the surrounding or
moist during the workup. The formation of dideuterium substituted AF4 may indicate
83
that the AF4-yne was formed and then reduced during the reaction course. The peaks of
353(12) and 177(35) came from the natural 13C isotope of carbon.
Table 3-12 IAF4 reduced to AF4 in refluxing butyl ethera
Reaction Time
(min)
Result (AF4)
IAF4 + KOBut (5)b 30 >90%
IAF4 + anthracene+ KOBut (5) + HOBut (5) 300 31% + 44% DA + other
productsc
IAF4 + KOBut (5) + HOBut (5) 300 47% + other productsc
IAF4 + KOBut (5) + DOBut (5) 300 50.6% +other productsc
IAF4 + KOBut (5) + acetonitrile 30 AF4 (33%)+ ring opening
IAF4 + KOBut (5) + DMF 30 AF4 (40%) + unknown
a Default solvent unless mentioned separately; b In the parenthesis is the equivalent used; c the other products are ether adduct to AF4-yne. DA: Diels-Alder adduct.
The reaction of IAF4 with KOtBu in 1,1,1’,1’-tetradeuterobutyl ether was also
investigated and was much slower than the same reaction in the non deuterated ether.
After refluxing overnight, most starting material remained. This may due to the 1,1,1’,1’-
tetradeuterobutyl ether is not pure enough or some alcohol is inside, which would make
reaction much slower.
3.3.7 Reactions in the Presence of Electron Trap Reagents
p-Dinitrobenzene (p-DNB) was used as electron trap reagents for verifying the SRN1
mechanism,132, 134 and p-DNB suppressed the electron transfer process in the radical
nucleophilic substitution of perfluoroalkyl iodide.130 The additive experiments were
carried out to test our proposal, and results are listed in Table 3-13.
84
Table 3-13 Additive effect on the reduction of AF4-yne with 1-octene under Cram conditions at 110℃ for 3 h
Additive Results (ratio)
AF4:IAF4:t-butoxide adduct
p-DNB (2) 45:55:0
p-DNB (0.2) 31:0:69
Nitrobenzene (4) 38:62:0
Nitrobenzene (2) 54:25:21
Nitrobenzene (1) 62:14:24
Nitrobenzene (0.5) 59:0:41
However, no ene product is observed by adding either p-DNB or nitrobenzene.
Nevertheless, these two additives did have effect on the reaction of IAF4; the reaction
rate is much slower with 1 equivalent of nitrobenzene, 14% IAF4 remains after stirring at
110℃ for 3 h in butyl ether. The amount of starting material increased as the amount of
nitrobenzene or p-DNB increased. 45% Reduced AF4 was detected by 19F NMR from the
crude reaction mixture along with 55% of starting material after 3 h at 110℃ with 2
equivalents of p-DNB, while that was 25% with 2 equivalents of nitrobenzene. The t-
butoxide ion product decreased as the amount of additive increased. There was no
difference compared to the reaction of IAF4 with 1-octene under Cram conditions
without any additive (Table 3-6) if only 0.2 equivalent of p-DNB or 0.5 equivalents of
nitrobenzene was added. In Scamehorn’s study of halobenzene reactions,132 p-DNB gave
substantial electron trapping effect, while the nitrobenzene only had limited inhibition at
the beginning, and then was followed by an increasing reaction rate. It seems that
nitrobenzene is not as effective as p-DNB is, but they both work the same way in this
85
system. Excess of p-DNB or nitrobenzene might change the entire reaction course due to
nitro- group strong electron withdrawing capability, while it was consumed quickly by
the t-butoxide ion and had limited impact with limited amount.
Table 3-14 Additive effect on the reaction of AF4-yne with anthracene under Cram conditions at 110℃ for 3 h
Additive Result (AF4:IAF4:DA adduct)
Nitrobenzene (1) 5:0:95
Nitrobenzene (4) 11:5:84
Nitrobenzene (4) + 1-ocetne (2) 10:30:60
p-DNB (2) +1-octene (2) 38:17:45
Similarly, the addictive effects on the DA reaction were carried out with anthracene
as substrate (Table 3-14). Large amount of nitrobenzene (4 equiv.) would increase the
amount of reduced AF4 to 11% along with 5% starting material from 5% AF4 and no
starting material in the presence of 1 equivalent of nitrobenzene. The addition of 1-octene
did have effect on the formation of AF4-yne. 30% of starting material remained in the
same reaction with of 2 equiv. of 1-octene inside and the DA adduct decreased to 60%
from 80% in the absence of 1-octene. While replacing the nitrobenzene with p-DNB, the
amount of AF4 simply increased to 38%, which meant that p-DNB had more effect on
the reduction of IAF4 or AF4-yne to AF4.
3.4 Conclusion
A different method of generating AF4-yne in situ from N-(nitroso)-AF4 acetamide
was discussed (Cadogan method), which gave the same results as Cram method in DA
reactions, but a totally different outcome in the reactions with alkenes. Unusual ene
reaction preference was observed in the reaction of AF4-yne generated by Cadogan
86
method in the presence of benzene. The relative reactivity of different diene traps toward
AF4-yne in DA reactions was established for the first time. Anthracene is 2.7*104 times
more reactive than benzene referring to the AF4-yne ene reaction with 1-octene under
Cadogan conditions, which, in turn, was faster than the DA reaction of AF4-yne with
benzene by 139 times.
The reaction of aryne with norbornadiene gave [2+2+2] products as the major one
under Cram’s conditions, while almost equal amount of [2+2] and [2+2+2] products were
obtained under Cadogan conditions. No [2+2] product was obtained in the reactions of
AF4-yne with cycloheptatriene under Cadogan conditions, contrary to expectations based
on the literature. All these results gave indication of the unique properties of the AF4-yne
that was generated from N-(nitroso)-AF4 acetamide under Cadogan conditions.
The anthracene versus 1-octene competition study under Cram conditions explicitly
demonstrated that AF4-yne was formed even in the presence of 100 equiv. of 1-octene.
This was further proved by the isotopic experiment of IAF4 with KOtBu in DOtBu and
deuterated acetonitrile, where deuterated IAF4 and dideuterated AF4 were obtained,
respectively.
A reduction mechanism was proposed for the reduction of AF4-yne generated under
Cram conditions. 1-Octene also had effect on the formation rate of AF4-yne. Alkenes
increased the solubility of t-butoxide ion in butyl ether when theirs concentration was low,
whereas olefin helped the electron transfer process and reduced the AF4 radical to AF4
directly when the concentration of olefin became much higher (>10 equiv.). It was
possible that both mechanisms (direct reduction of IAF4 to AF4 or via AF4-yne) worked
together depending on the amount of 1-octene present, i.e., the reduction from AF4-yne
87
playing the major role in the absence of 1-octene, whereas AF4 reduction from IAF4 by
SRN1 increased as the concentration of 1-octene increased.
The nitrobenzene or p-DNB, which is well known electron trap for SRN1 reactions,
slowed down the reaction of IAF4 with KOtBu and increased the reduction rate of IAF4
to AF4 or via AF4-yne, which could be considered as evidence of the reduction of IAF4
or AF4-yne to AF4 by an electron transfer mechanism. Ene reactions were not fast
enough to trap the AF4-yne generated under Cram conditions, which are harsh, with
reduction by base ion by electron transfer process to AF4 directly.
3.5 Experimental
General Methods. 1H (500 MHz), 13C (126 MHz), and 19F (282 MHz) NMR
spectra were recorded using CDCl3 as the solvent, and chemical shifts ( values) were
measured relative to the signals for CHCl3, CDCl3, and CFCl3, respectively. 1H and 13C
chemical shift data are directly indicated on the structures of the adducts in the Results
and Discussion section above, whereas 19F NMR data are provided in the Experimental
Section below. X-ray crystal analyses were performed by the Center for X-ray
Crystallography and HRMS and CH micro elemental analyses by the Spectroscopic
Services Group at the University of Florida. Column chromatography was performed
using chromatographic silica gel, 200-425 mesh, as purchased from Fisher, unless
otherwise mentioned.
All the competition reactions were carried out in the same way as the model
reactions. The equivalents of reactants are displayed in the tables. One typical experiment
of benzene with 1-octene is listed below.
Benzene and 1-octene with 4-(N-nitroso)-acetamide AF4: in a three-necked
round 50ml bottle were charged with AF4 acetamide (0.12 g, 0.25mmol), 10 ml n-butyl
88
ether and 1-octene (47µl, 0.30mmol). This mixture was heated to 110℃ and the p-
chlorobenzoyl nitrite (0.12 g, 0.63mmol) in butyl ether (3ml) was added during 30
minutes with stirring. This mixture was maintained at this temperature over night and
then was cooled. Solvent was evaporated under vacuum, and the residue was purified by
silica gel chromatography. Reduced AF4 was separated (26mg, 32%) first, and then, t-
butoxide ion adduct (45mg, 46%) was separated as a mixture with benzene adduct (1.7%
from the 19F NMR). 1H NMR (300MHz, CDCl3/TMS) δ 7.66(d, J=8.1Hz, 1H), 7.12(m,
3H), 6.96(d, J=8.1Hz, 1H), 6.86(d, J=8.7Hz, 1H), 6.35(s, 1H), 1.23(s, 9H); 19F NMR
(282MHZ, CDCl3/CFCl3) δ -110.52(d, J=243.1Hz, 1F), -114.08(d, J=236.0Hz, 1F), -
114.88(d, J=235.8Hz, 1F), -115.05(d, J=235.8Hz, 1F), -116.07(d, J=236.9Hz, 1F), -
117.1(d, J=238.0Hz, 1F), -118.09(d, J=238.3Hz, 1F), -119.08(d, J=237.2Hz, 1F).
4--acetamide AF4: 4-aminoAF4 (5 g, 13.6mmol) was dissolved in 100 ml acetic
anhydride and the mixture was refluxed for 6 h. Then, reaction mixture was cooled to
room temperature and solvent was evaporated under vacuum. The black residue was
purified by silica gel column chromatography, then recrystallization from ethanol to give
a white solid (5.12 g 92%), mp 183-185℃. 1H NMR (300MHz, CDCl3/TMS) δ 8.38(s,
1H), 7.92(d, J=6.6Hz, 1H), 7.54(d, J=8.4Hz, 1H), 7.42(m, 2H), 7.32(d, J=8.4Hz, 1H),
7.2(d, J=8.4Hz, 1H), 7.11(d, J=8.4Hz, 1H), 2.55(s, 3H); 19F NMR (282MHz,
CDCl3/CFCl3) δ -107.83(dq, J=249.8, 9.0Hz, 1F), -112.85(dd, J=240.8, 9.0Hz, 1F), -
114.18(d, J=250.1Hz, 1F), -114.71(d, J=241.1Hz, 1F), -117.13(d, J=237.7Hz, 1F), -
117.18(d, J=237.7Hz, 1F), -118.46(d, J=240.8Hz, 1F), -118.51(d, J=234.6Hz, 1F).
p-Chlorobenzoyl nitrite: following the literature method,102 to a sodium
bicarbonate solution (9.0g, 0.11mol) in water was added 4-chlorobenzoic acid (17 g, 0.12
89
mol). The solution was filtered hot and to the filtrate silver nitrate (19g, 0.11mol) in water
was added during stirring. The precipitate silver p-chlorobenzoate was filtered and
washed with ethanol (twice) and dried over P2O5 under vacuum for one day.
To a stirred suspension of silver p-chlorobenzoate (20 g, 75 mmol) in 180ml dry
CCl4 at -10℃ was added nitrosonium chloride (8g, 125mmol) during 30 minutes. The
mixture was stirred for a further 20 minutes at -10℃ and 1 h at room temperature. The
mixture was filtered rapidly after that and residue was washed with CCl4 twice. The
filtrates were combined and evaporated under vacuum. The residue was distilled under
vacuum (84-85℃/2.5mmHg) to give 12.1 g yellow-reddish solid (86%). Product was
made into 0.86M solution in benzene or butyl ether for future use.
1-octene reacts with 4-(N-niroso)-acetamide AF4: a three-necked round 50 ml
bottle was charged with AF4 acetamide (0.24 g, 0.5mmol), 10 ml n-butyl ether and 1-
octene (80µl, 1.0mmol). This mixture was heated to 110℃ and the p-chlorobenzoyl
nitrite (0.16 g, 0.85mmol) in butyl ether was added during 30 minutes. This reaction
mixture was maintained at this temperature over night. Then the mixture was cooled and
solvent was evaporated under vacuum. The residue was purified on a silicon gel column
and eluted with hexanes/ethyl acetate (100:1) to give oily product 1 (83%). 1H NMR
(300MHz, CDCl3/TMS) δ7.33(m, 1H), 7.2(m, 2H), 7.1 (m, 2H), 7.0(d, J=8.1Hz, 1H),
6.86(s, 1H), 5.51(m, 1H), 5.33(m, 1H), 3.55(m, 1H), 3.3(m, 1H), 2.05(m, 2H), 1.3(m,
6H), 0.9(m, 3H); 19F NMR (282MHz, CDCl3/CFCl3) δ -110.7(d, J=242.5Hz), -111.2(d,
J=244.2Hz), -113.6 (d, J=243.9Hz), -114.8 (d, J=241.1Hz), -115.8(d, J=237.7Hz), -117.5
(d, J=237.7Hz), -118.8 (d, J=238.0), -119.0 (d, J=240.8Hz); 13C NMR (75MHz, CDCl3)
δ142.5, 135.3, 134.7, 134.5, 133.3, 131.7, 130.4, 129.6, 129.3, 127.0, 126.5, 126.2, 125.2,
90
123.5, 122.5, 119.6, 119.0, 115.5, 36.8, 32.7, 31.6, 29.4, 22.7, 14.3; MS(EI) m/z
462(M+)(15), 391(16), 365(17), 189(45), 215(19), 176(100), HRMS Calc. for C24H22F8
462.1594, Found 462.1593 (EI); Elemental analysis Calc. for C24H22F8: C: 62.34, H:
4.795; Found C: 62.42, H: 5.01.
IAF4 with 1-Octene: the procedure was the same as AF4-yne DA reactions under
Cram conditions if butyl ether was the solvent. There was no other product except the
reduced AF4, and there was no trace amount of ene reaction product from crude 19F
NMR. The reaction was refluxed at 123℃ for 30 minutes if 1-octene was the solvent,
which gave the same result as above.
Anthracene, naphthalene and benzene with 4-(N-nitroso)-acetamide AF4: the
reaction of naphthalene was carried out in butyl ether (10ml) at 110 ℃, while anthracene
and benzene were reacted in refluxing benzene (10ml). Yields checked with α,α,α-
trifluoromethylbenzene as standard were of 95%, 93% and 90% respectively. The isomer
ratio of anthracene adduct varied from 97:3 to 95:5, while that of naphthalene adduct
changed from 8-10% exo-adduct to 15-17% exo-adduct.
Norbornadiene with 4-(N-nitroso)-acetamide AF4: the reaction procedure was
the same as above except that norbornadiene (54mg, 63µl, 0.59mmol, 2equiv) was the
substrate. Products were a mixture of four compounds with the ratio of [2+2+2]-endo:
[2+2+2]-exo: [2+2]-endo:[2+2]-exo/39:21:21:19 in a combined yield of 67%.
Cyclopentene with 4-(N-nitroso)-acetamide AF4: the procedure was the same as
above except that n-butyl ether was the solvent and cyclopentene (2 equivalents, 0.22ml)
was the reactant. The yield was 53% with two stereoisomers 2a and 2b ratio of 5.6:1. 1H
NMR (500MHz, CDCl3/TMS) Isomer1 δ 7.16(d, J=8.5Hz, 2H), 7.08(d, J=8.5Hz, 2H),
91
7.02(s, 1H), 6.92(s, 1H), 6.88(d, J=8.5Hz, 1H), 5.65 (m, 1H), 5.23(m, 1H), 4.23(m, 1H),
2.52(m, 3H), 2.15(m, 1H); 13C NMR(126MHz, CDCl3) δ 146.5, 135.4, 135.4, 135.4,
135.0, 135.0, 131.1, 130.3, 130.3, 129.4, 129.4, 129.4,127.3, 127.8, 118.9, 118.9, 119.8,
118.9, 47.0, 32.9, 30.3; Isomer2 δ 7.17(m, 1H), 7.16(m,1H), 7.08(m, 2H), 7.04(m, 1H),
6.88(m, 1H), 6.83(s, 1H), 6.07(m, 1H), 5.86(m, 1H), 4.15(m, 1H), 2.24(m, 3H), 1.15(m,
1H); 13C NMR (75MHz, CDCl3) δ 148.1, 136.1, 135.4, 135.4, 135.4, 135.0, 130.3, 130.3,
130.3, 129.4, 129.4, 129.4, 127.3, 127.8, 118.9, 118.9, 119.8, 118.9, 47.8, 34.8, 31.9; 19F
NMR (282MHz, CDCl3/CFCl3) isomer1 δ -109.9, -112.7(AB, J=241Hz), Iosmer2 δ -
107.9, -112.9(AB, J=244Hz); MS(EI) m/z 418(M+)(33), 242(100), 176(28); HRMS Calc.
for C21H14F8 418.0967, Found 418.0942 (EI); Elemental analysis Calc. for C21H14F8: C:
60.29, H: 3.37; Found: C:60.08, H: 3.38.
Cyclohexene with 4-(N-nitroso)-acetamide AF4: to a mixture of AF4 acetamide
(0.30g, 0.73mmol), and cyclohexene (0.15ml, 1.5mmol) in 20 ml butyl ether was added
p-chlorobenzonitrite butyl ether solution (4.8ml 0.3M) slowly at 110℃. This mixture was
stirred overnight at this temperature. Solvent was evaporated under vacuum and the
residue was purified through silica gel chromatography. White solid 0.175 g was obtained
in 55% yield, which was analyzed as a mixture of ennationmers (3a and 3b) in 1:1 ratio.
19F NMR (282MHz, CDCl3/CFCl3) δ -109.08(d, J=243.93Hz), 109.82(d, J=243.93Hz), -
111.72(d, J=243.93Hz), -112.85(d, J=243.93Hz), -115.28(d, J=241.11Hz), -116.57(d,
J=241.11Hz), -116.86(d, J=240.83Hz), -117.13(d, J=237.73Hz), -117.47(d, J=240.83Hz),
-117.58(d, J=240.83Hz), -119.0(d, J=238.01Hz), -119.25(d, J=237.73Hz), -119.33(d,
J=240.83Hz), -119.54(d, J=240.83Hz); Isomer 1 1HNMR (500MHz, CDCl3/TMS) δ 1.10,
1.82(m, 2H), 1.21, 1.43(m, 2H), 1.94(m, 2H), 3.71(m, 1H), 5.82(dq, J=10.4, 2.5Hz, 1H),
92
6.07(dtd, J=10.1, 3.7, 2.1Hz, 1H), 6.93(s, 1H), 6.96(s, 1H), 7.03(s, 1H), 7.04(s, 1H),
7.12(s, 3H); 13C NMR (126MHz, CDCl3) δ 19.9, 25.2, 33.7, 38.1, 119.0, 119.0, 119.0,
120.0, 126.7, 127.6, 129.4, 129.4, 129.4, 129.4, 129.4, 132.1, 135.4, 135.4, 132.6, 134.6,
134.6, 148.1, Isomer 2 1HNMR (500MHz, CDCl3/TMS) δ 1.75, 1.94(m, 2H), 1.84,
2.18(m, 2H), 1.98, 2.01(m, 2H), 3.71(m, 1H), 5.09(dq, J=9.9, 2.0Hz, 1H), 5.53(dq,
J=10.0, 3.3Hz, 1H), 6.90(s, 1H), 6.98(s, 1H), 7.00(s, 1H), 7.06(s, 1H), 7.09(s, 2H), 7.16(s,
1H); 13C NMR (126MHz, CDCl3) δ 22.2, 24.7, 27.6, 38.6, 119.0, 119.0, 119.0, 120.0,
127.6, 127.6, 129.4, 129.4, 129.4, 129.4, 129.4, 131.6, 132.6, 134.6, 134.6, 135.4, 135.4,
146.4; MS (EI) m/z 432(M+)(33), 255(100), 176(78); HRMS Calc for C22H16F8
432.1124, Found 432.1104 (EI).
α-Methylstyrene with 4-(N-nitroso)-acetamide AF4: to a mixture of AF4
acetamide (0.30g, 0.73mmol), and α-methylstyrene (0.48ml, 3.6mmol) in 20 ml butyl
ether was added p-chlorobenzonitrite butyl ether solution (4.8ml 0.3M) slowly at 110℃.
This mixture was stirred overnight at this temperature. Solvent was evaporated under
vacuum and the residue was purified through silica gel chromatography. White solid
0.252 g was obtained in 65% yield, which includes three products, ene reaction product
(4) 37%, Diels-Alder product (5)24% and hydrolyzed ene product (6) 4%.
Ene product 4: 1HNMR (500MHz, CDCl3/TMS) δ 3.54(dd, J=17.0, 2.6Hz, 1H),
4.08(d, J=16.6Hz, 1H), 4.67(q, J=1.3Hz, 1H), 5.35(q, J=0.8Hz, 1H), 6.87(d, J=8.6Hz,
1H), 6.91(d, J=8.6Hz, 1H), 7.02(d, J=8.8Hz, 1H), 7.09(d, J=9.2Hz, 1H), 7.13(d, J=8.8Hz,
1H), 7.22-7.32(m, 7H); 19F NMR (282MHz, CDCl3/CFCl3) δ -111.76(d, J=243.93Hz, 1F),
-113.67(d, J=243.93Hz, 1F), -114.99(d, J=240.83Hz, 1F), -115.94(d, J=240.83Hz, 1F), -
117.63(d, J=237.73Hz, 1F), -117.68(d, J=237.73Hz, 1F), -119.23(d, J=241.11Hz, 1F), -
93
119.38(d, J=240.83Hz, 1F); 13C NMR (126MHz, CDCl3) δ 145.9, 140.7, 140.6,
135.4,134.6, 130.2, 134.8, 132.1, 132.7, 132.1, 130.4, 129.6, 129.4, 128.1, 128.1,127.5,
126.3, 126.5, 126.3, 119.7, 118.8, 118.9, 118.8, 116.2, 39.0; MS (EI) m/z 468(M+)(35),
292(16), 291(57), 241(100), 176(58); HRMS Calc for C25H16F8 468.1124, Found
468.1115 (EI).
Diels-Alder product 5: 1HNMR (500MHz, CDCl3/TMS) δ 2.77(s, 3H), 6.13(d,
J=8.6Hz, 1H), 6.47(dq, J=8.7, 1.8Hz, 1H), 7.23-7.24(m, 2H), 7.34(dq, J=8.4, 1.7Hz, 1H),
7.39(d, J=8.4Hz, 1H), 7.55(t, J=7.6Hz, 1H), 7.64(ddd, J=8.3, 7.4, 1.4Hz, 1H), 7.78(d,
J=3.3Hz, 1H), 7.99(d, J=8.3Hz, 1H), 8.17(t, J=8.7Hz, 1H); 19F NMR (282MHz,
CDCl3/CFCl3) δ -103.5(d, J=253.24Hz, 1F), -215.56(d, J=251.54Hz, 1F), -111.38(dt,
J=247.03, 12.13Hz, 1F), -112.93(d, J=247.03Hz, 1F), -113.59(d, J=240.83Hz, 1F), -
117.14(dd, J=238.01, 12.13Hz, 1F), -118.86(dd, J=237.73, 6.2Hz, 1F), -121.44(d,
J=240.83Hz, 1F); 13C NMR (126MHz, CDCl3) δ 136.2, 134.3,133.6, 133.1, 132.1, 131.8,
130.0, 129.8, 129.9, 129.9, 129.8,129.8, 128.8,128.3, 127.8, 127.2, 127.1, 120.5, 123.5,
125.9, 119.7, 118.8, 118.8, 118.1, 20.5; MS (EI) m/z 466(M+)(77), 291(12), 290(66),
289(100), 275(93), 176(28); HRMS Calc for C25H14F8 466.0968 Found 466.0959; UV
(CH2Cl2): λmax (log ε) = 395.0 (3.27), 379.0 (3.20), 318.3(3.79), 292.0(4.31).
Hydroxyl product 6: 1HNMR (500MHz, CDCl3/TMS) δ 1.84(s, 3H), 2.55(d,
J=17.5Hz, 1H), 3.41(dd, J=18.1, 4.6Hz, 1H), 6.82(d, J=8.7Hz, 1H), 6.85(d, J=8.5Hz, 1H),
6.97(d, J=8.6Hz, 1H), 7.25(d, J=8.8Hz, 1H), 7.27(m, 1H), 7.32(m, 2H), 7.35(d, J=8.0Hz,
1H), 7.43(d, J=8.6Hz, 1H), 7.49(m, 2H), 7.71(d, J=8.4Hz, 1H); 19F NMR (282MHz,
CDCl3/CFCl3) δ -106.49(dd, J=247.03, 9.3Hz, 1F), --110.48(d, J=259.16Hz, 1F), -
110.51(d, J=243.93Hz, 1F), -110.65(d, J=249.85Hz, 1F), -112.69(dd, J=241.11, 9.02Hz,
94
1F), -115.66(d, J=237.73Hz, 1F), -119.46(d, J=238.01Hz, 1F), -121.64(d, J=240.83Hz,
1F); 13C NMR (126MHz, CDCl3) δ 138.5, 135.6, 134.6,134.8, 134.4,133.6, 131.2,131.1,
131.7, 130.7, 130.5, 130.4, 128.9, 128.4, 128.4, 127.0, 122.8, 122.8, 120.0,119.8, 118.9,
118.7, 68.2, 38.3, 27.9; MS (EI) m/z HRMS Calc for C25H18F8O 486.1230,
Tetracyclone with 4-(N-nitroso)-acetamide AF4: to a n-butyl ether solution of
1,1,2,2,9,9,10,10-octafluoroparacyclophane 4-acetamide (0.32g, 0.78mmol) and 2,3,4,5-
tetraphenylcyclopentadiene (0.33g, 0.85mmol) in a three necked round bottom flask was
added p-chlorobenzoyl nitrite (2.5 ml, 0.47M) in n-butyl ether in 10 minute at 110℃. The
mixture was stirred at this temperature overnight. The solvent was eveaperated under
vacuum, and product was separated by silica gel chromatography using the
hexane:dichloromethane (10:1) as eluent. The yield was 83% with internal methyl
benzoate standard. 1HNMR (500MHz, CDCl3/TMS) δ 7.45(s, 2H), 7.35(d, J=8.0Hz, 2H),
7.30(s, 2H), 7.15(t, J=7.7Hz, 4H), 7.09(t, J=7.4Hz, 2H), 7.07(s, 2H), 6.95(t, J=7.0Hz, 2H),
6.93(s, 2H), 6.89(t, J=7.5Hz, 2H), 6.80(d, J=7.2Hz, 2H), 6.64(t, J=7.6Hz, 2H), 6.03(d,
J=7.7Hz, 2H); 13C NMR (126MHz, CDCl3) δ 143.5, 142.6, 139.7, 138.6, 138.6, 133.5,
132.9, 132.4, 131.7, 132.3, 131.1, 129.9, 128.0, 127.4, 127.1, 127.1, 126.6, 126.4, 126.5,
125.9, 117.8, 117.7; 19F NMR (282MHz, CDCl3/CFCl3) δ -107.73 (d, J=252.95Hz, 2F), -
109.86(d, J=250.13Hz, 2F), -116.25(d, J=240.83Hz, 2F), -120.80(d, J=240.83Hz, 2F);
MS (EI) m/z 706(M+)(14), 526(26), 352(6), 176(100); HRMS Calc for C44H26F8,
706.1907; Found 706.1933 (EI).
Cycloheptatriene with 4-(N-nitroso)-acetamide AF4: the procedure was the same
as above except that cycloheptatriene (81mg, 91µl, 0.88mmol, 2equiv) was used as the
substrate. The mixture was worked up by usual way and two products were obtained.
95
8a: 1HNMR (500MHz, CDCl3/TMS) δ 7.40(s, 1H), 7.36(s, 2H), 7.19(s, 1H), 7.13(s,
1H), 7.08(s, 1H), 7.06(s, 1H), 6.95(s, 1H), 6.94(d, J=7.6Hz, 1H), 6.89(s, 1H), 6.70(d,
J=8.4Hz, 1H), 6.67(d, J=9.3Hz, 1H), 6.53(s, 1H), 6.23(t, J=7.1Hz, 1H), 6.17(t, J=6.9Hz,
1H), 4.89(t, J=5.4Hz, 1H), 4.74(s, 1H), 2.54(s, 1H), 1.97(dt, J=8.6, 4.3Hz, 1H), 1.67(dt,
J=8.0, 4.0Hz, 1H); 13C NMR (126MHz, CDCl3) δ 143.9, 143.6, 141.4, 134.2, 133.9,
133.1, 133.1, 132.8, 132.5, 132.1, 131.4, 130.8, 129.2, 128.6, 128.6, 128.5, 128.3, 127.6,
127.6, 127.3, 126.8, 126.6, 126.5, 126.5, 125.4, 125.2, 118.6, 118.6, 118.2, 117.4, 117.4,
117.4, 117.6, 117.4, 37.4, 37.1, 27.1, 26.4, 24.4; 19F NMR (282MHz, CDCl3/CFCl3) δ
8b: 1HNMR (500MHz, CDCl3/TMS) δ 7.31(d, J=8.8Hz, 1H), 7.19(s, 1H), 7.17(s,
1H), 7.10(s, 1H), 7.04(s, 1H), 7.01(s, 1H), 6.94(d, J=7.6Hz, 1H), 6.85(d, J=8.9Hz, 1H),
6.84(d, J=9.3Hz, 1H), 6.84(s, 1H), 6.82(s, 1H), 6.81(s, 1H), 6.55(t, J=7.1Hz, 1H), 6.49(td,
J=6.8, 1.5Hz, 1H), 6.11(s, 1H), 4.94(t, J=5.0Hz, 1H), 4.74(m, 1H), 2.45(s, 1H), 1.30(dt,
J=8.7, 4.2Hz, 1H), 0.94(dt, J=8.3, 4.2Hz, 1H); 13C NMR (126MHz, CDCl3) δ 143.9,
144.1, 140.9, 133.9, 133.9, 133.1, 133.1, 131.0, 132.8, 130.9, 129.0, 129.2, 129.1, 128.5,
128.4, 128.3, 128.3, 127.6, 126.9, 126.1, 125.8, 125.5, 125.4, 125.0, 125.0, 118.9, 118.6,
118.2, 117.4, 117.7, 117.6, 117.6, 117.6, 36.9, 36.6, 26.4, 24.4, 25.0; MS (EI) m/z
792(M+)(14), 442(2), 352(8), 177(19), 176(100); HRMS (EI), Calc for C39H20F16
792.1309, found 792.1331.
9a: 1HNMR (500MHz, CDCl3/TMS) δ 7.18(s, 1H), 7.16(d, J=8.8Hz, 2H), 7.04(d,
J=8.4Hz, 1H), 6.99(d, J=7.8Hz, 1H), 6.70(dd, J=10.6, 5.7Hz, 1H), 6.62(dd, J=10.6, 5.9Hz,
1H), 6.45(dd, J=9.5, 6.1Hz, 1H), 6.04(dd, J=9.2, 6.1Hz, 1H), 5.50(dd, J=9.3, 5.8Hz, 1H),
4.58(dd, J=8.6, 6.2Hz, 1H), 3.06(t, J=5.9Hz, 1H); 13C NMR (126MHz, CDCl3) δ 142.9,
130.9, 134.0, 133.3, 131.2, 130.0, 129.4, 128.2, 128.2, 127.5, 126.7, 126.7, 126.8, 126.8,
96
125.5, 123.2, 120.2, 118.4, 117.9, 117.6, 117.6, 116.2, 39.1; 19F NMR (282MHz,
CDCl3/CFCl3) δ -110.75(d, J=225.0Hz, 1F), -111.62(d, J=224.8Hz, 1F), -111.80(d,
J=229.5Hz, 1H). -111.91(d, J=244.2Hz, 1F), -112.18(d, J=244.2Hz, 1F), -112.66(d,
J=229.8Hz, 1F), -114.31(d, J=244.5Hz, 1F), -114.39(d, J=239.4Hz, 1F), -115.0(d,
J=244.2Hz, 1F), -115.91(d, J=95.6Hz, 1F), -116.0(d, J=112.5Hz, 1F), -115.99(d,
J=177.7Hz, 1F),
9b: 1HNMR (500MHz, CDCl3/TMS) δ 7.27(d, J=9.8Hz, 1H), 7.11(d, J=9.8Hz, 2H),
7.09(s, 2H), 6.98(s, 2H), 6.53(d, J=5.8Hz, 1H), 6.26(dd, J=9.0, 2.2Hz, 1H), 6.24(s, 1H),
5.49(m, 1H), 5.47(m, 1H), 2.42(m, 1H), 2.37(m, 1H); 13C NMR (126MHz, CDCl3) δ
142.6, 139.3, 133.4, 134.0, 133.3, 131.2, 130.9, 128.2, 128.2, 127.5, 126.9,126.7,
126.7,126.8, 126.8, 125.0, 122.1, 120.1, 117.6, 117.9, 117.6, 118.4, 26.6. MS (EI) m/z
442(M+)(29), 352(9), 265(70), 177(17), 176(100); HRMS Calc for C23H14F8 442.0968,
found 442.0977.
1,1-Dideuterobutanol: Following the published procedure,135 to lithium aluminum
deuteride (15g, 0.357mol) solution in ethyl ether (300ml) in a one-liter three-necked flask
equipped with refluxing condenser, dropping funnel and magnetic stirrer, and protected
nitrogen flow, was added dropwise a ethyl ether (150ml) solution of butyric acid (27.5 ml,
0.30mol) at a rate such as to produce gentle reflux. Thirty minutes after the addition has
been completed and with continued stirring and cooling of the flask, water was added
cautiously to decompose excess hydride. Then 150 ml of 10% H2SO4 was added (the
flask may have to be cooled in ice water) and a clear solution results. The product was
separated from the water solution and the water solution was extracted with 100 ml ethyl
ether three times. Organic layers were combined together and purified by fractional
97
distillation through a 24 inch column to give 21.4 g clear liquid (115-116℃). 1HNMR
(300MHz, CDCl3/TMS) δ 2.72(s, 1H), 1.49(t, J=7.8Hz, 2H), 1.34(m, 2H), 0.88(t,
J=7.2Hz, 3H).
1,1-Dideuterobutyl bromide: As in the literature procedure,136 to a solution of 2,3-
dichloro-5,6-dicyanobenzoquinone (DDQ) (39.68g, 0.175mol) in dry methylene chloride
(200ml) was added triphenylphophine (45.86g, 0.175mol) cautiously, then tetrabutyl
ammonium bromide (56.35g, 0.175mol), at room temperature. 1,1-dideuterobutanol
(11.07g, 0.145mol) was then added to the mixture. The yellow color of the mixture
immediately changed to deep red. The liquid phase was vacuumed out by pump and fresh
methylene chloride 100 ml was added to the mixture to extract product twice. The liquid
phase was combined together and fractional distilled to give 7.5 g product (38%) (80-90
℃). 1HNMR (300MHz, CDCl3/TMS) δ 1.82(t, J=7.5Hz, 2H), 1.46(m, 2H), 0.92(t,
J=7.5Hz, 3H).
1,1,1’,1’-Tetradeuterobutyl ether: to a suspension of sodium hydride (4.7g, 60%,
0.118mol) in tetrahydrofuran (THF) (50ml) was added slowly 1,1-dideuterobutanol
(4.09g, 54mmol) in 10ml THF at room temperature. The mixture was heated to reflux
and kept refluxing for 20 h. Then, the mixture was cooled to room temperature, 1,1-
dideuterobutyl bromide (7.5g, 54mmol) in 10 ml THF was added slowly to the mixture.
The reaction mixture was kept refluxing for 23 h and then cooled to room temperature
again. Water (20 ml) was added slowly to the mixture to destroy excess sodium hydride.
After that, 100ml water was added and mixture was extracted with ethyl ether (50ml)
four times. Organic phase was combined together and distilled through a 24 inch column
to collect from 80-120℃ then redistill to give 6.3 g product (115-116℃, 66%). 1HNMR
98
(300MHz, CDCl3/TMS) δ 1.53(t, J=6.9Hz, 4H), 1.35(m, 4H), 0.92(t, J=6.0Hz, 3H); 13C
NMR (75MHz, CDCl3) δ 69.96(m), 31.84, 19.51, 14.16; MS (EI) m/z 134(M+)(12),
91(100), 76(35), 74(35), 60(83); HRMS Calc for C8H14D4O 134.1608, Found 134.1603.
Reaction of IAF4 with KOtBu in 1,1,1’,1’-tetradeuterobutyl ether: to a IAF4
(60mg, 0.12mmol) in 2ml 1,1,1’,1’-tetradeuterobutyl ether solution was added KOtBu
(70mg, 0.62mmol) and refluxed for 20 h. The reaction mixture was worked up by the
usual method and products were purified by preparative TLC plates. First product was the
ether adduct plus reduced AF4 and second one was IAF with reduced AF4.
Reaction of IAF4 with KOtBu/DOtBu: to a IAF4 (0.16g, 0.33mmol) in 10 ml
butyl ether solution was added KOtBu (0.18g, 1.65mmol) and DOtBu (0.16ml,
1.65mmol). The mixture was kept for refluxing for 5 h and worked up as usual way. AF4
was separated by silica gel chromatography and then preparative TLC. AF4 (35mg, 30%)
was obtained along with ether adducts. MS (EI) m/z: 353 (7), 352(6), 177(28), 177(10),
176(100).
Reaction of IAF4 with KOtBu/CD3CN: to a IAF4 (0.12g, 0.25mmol) solution in
CD3CN (4ml) was added KOtBu (0.17g, 1.5mmol). The mixture turned black
immediately and was kept refluxing for half hour. The mixture was cooled and worked
up by the usual way. Products were separated by silica gel chromatography. AF4 (46mg,
52%) was obtained along with ring opening product (8mg, 8%). MS (EI) m/z: 354(19),
353(31), 353(12), 352(9), 178(54), 177(54), 177(35), 176(100).
CHAPTER 4 EFFICIENT SYNTHESES OF NOVEL NAPHTHALENO- AND ANTHRACENO-
OCTAFLUORO[2.2]PARACYCLOPHANES
4.1 Introduction
Since the isolation of the parent compound by Brown et al. in 19492 and its first
directed synthesis by Cram et al. in 1951,14 interest in molecules containing the unique
structural features of [2.2]paracyclophanes has never waned and has generated a literature
filled with unusual structural features and chemistry.31 The characteristic proximity of the
face-to-face aromatic rings, coupled with the rigid skeleton and high strain energy of the
[2.2]paracyclophane system, leads to unique transannular interactions that affect both the
chemistry and the spectroscopy of these systems.100, 137 One of most interesting aspects of
the chemistry of [2.2]paracyclophanes is their ability to be ‘cracked’ thermally, via a 1,6-
cleavage process, forming a highly reactive p-xylylene species. This characteristic serves
as the basis for the important commercial application of [2.2]paracyclophanes as
precursors of parylene-type polymers formed via a vapor deposition process.138
Anthracenophane (1) and naphthalenophane (2) (Figure 4-1) are synthesized by
Toyada29, 30 and Wasserman9, 21, 25 respectively. The yields are poor, with 41% as the best
yield. Both syn- forms of anthracenophane and naphthalenophane are converted to anti-
forms by heating above 240℃.
99
100
anti-1 syn-1
anti-2 syn-2
Figure 4-1 Anthracenophane 1 and naphthalenophane 2
[2.2](1,4)(9,10)Anthracenophane (3), as well as [2, 2] paracyclo(9,10)
anthracenophane (4) and [2,2] (1,4)naphthaleno(9,10)anthracenophane (5) (Figure 4-2),
are synthesized from a cross hofmann elimination of quaternary ammonium
hydroxides.139 They show significant transannular π-electron interaction compared to
their open chain analogues.
3 4 5
Figure 4-2 [2.2](1,4)(9,10)anthracenophane 3, [2.2] paracyclo(9,10) anthracenophane 4
and [2.2](1,4)naphthaleno(9,10)anthracenophane 5
While non-fluorinated cyclophanes have been synthesized and studied,12 the
fluorinated ones are scarce. Tetrafluoro [2,2] paracyclophane (6) has only 1% yield via
the Wurtz coupling reaction.31 Polyfluoroaryl [2,2] cyclophanes (6) and (7) (Figure 4-3)
101
are synthesized by Filler et al.140, 141 Compound (6) shows transanunular π-π donor-
acceptor interaction, where the tetrafluorophenylene acts as an electron withdrawing “π-
acid.”142 This effect makes compound 6 inert to electrophilic attack.
F F
F F
F F
F F F FF F
6 7
Figure 4-3 Polyfluoroaryl [2.2]cyclophanes 6 and 7
The totally bridge fluorinated [2.2]paracyclophane, 1,1,2,2,9,9,10,10-octafluoro-
[2.2]paracyclophane (AF4, Figure [1-3]), has only become accessible during the last
decade since the relatively simple syntheses of Dolbier were published.43-45
The presence of the bridge fluorines makes AF4 the thermal precursor of an
extremely thermally stable parylene polymer with numerous novel properties, and their
presence also bestows novel chemical behavior to the [2.2]paracyclophane itself.48 As
such, AF4 is highly deactivated towards electrophilic aromatic substitution, although
synthetic procedures have been developed to allow the preparation of virtually any mono-
or multi-substituted derivative desired.51, 52 Recently it has been shown that the iodo
derivatives, mono- or bis-, serve as unexpectedly efficient precursors of aryne or bis-
aryne derivatives of AF4, which undergo high yield Diels-Alder reactions with benzene,
naphthalene, and other aromatics (Figure 4-4).50
102
FF
F F
FF
FF
FF
F F
FF
FF
FF
F F
FF
FF
KOtBu, Butyl ether reflux
I
8
9
FF
F F
FF
FF
FF
F F
FF
FF
FF
FF
FF
FF
KOtBu, Butyl ether reflux
I
10
11
I
Figure 4-4 Diles-Alder reaction of mono and bis-AF4-yne
Looking at the Diels-Alder (DA) products of mono and bis-AF4-yne, bridge
fluorinated [2.2]cyclophane may be generated by getting rid of one or two molecules of
ethylene from the adducts. In this chapter we will show how the mono- and bis-adducts
with benzene and naphthalene, 8-11 (Figure 4-4), can be used to prepare the four novel
103
naphthaleno and anthraceno derivatives of AF4, 12-15 (Figure 4-5), respectively, in an
efficient, one-pot process.
F2CCF2
F2CCF2
F2CCF2
F2CCF2
F2CCF2
F2CCF2
F2CCF2
F2CCF2
12 13
14 15
Figure 4-5 Bridge fluorinated [2.2]cyclophane 12, 13, 14 and 15
4.2 Results and Discussion
[2.2]Paracyclophanes containing condensed polycyclic aromatic subunits have been
prepared with one or two naphthalenes9, 21, 25, 143-146 and anthracenes,29, 139, 147 and their
novel structural topology gives rise to unusual spectroscopic properties that clearly derive
from their characteristic face to face aromatic systems.21, 137, 148, 149 The syntheses of these
compounds were generally via multi-step processes that resulted in overall low yields.
In contrast, the analogous bridge fluorinated, AF4-derived naphthaleno- and
anthraceno-[2.2]phanes can be readily synthesized via one-pot procedures involving the
reaction of 3,6-dipyridinyl-1,2,4,5-tetrazine (16) with the mono- and bis-Diels-Alder
adducts 8-11. As exemplified in the reaction of adduct 8 with 16 (Figure 4-6), the
conversion to 12 involves a three-step process beginning with a DA reaction of 8 with 16
to form the presumed intermediate adduct 17. This adduct then loses N2 to form
104
intermediate 18, which undergoes a rapid double aromatizing retro-Diels-Alder reaction
to form the bridge fluorinated [2.2](1,4)naphthalenoparacyclophane, 12
(mononaphthophane), in an isolated yield of 89%.
FF
F F
FF
FF
NN N
N
Pyr
Pyr
FF
F F
FF
FF
Pyr
N
Pyr NN N
H
H
NN
Pyr
Pyr
H
H
NN
Pyr
Pyr
pentyl ether
reflux, 187oC
N2
fast
8
16 17
18
12
+
-
Figure 4-6 Reaction of adduct with 3,6-dipyridinyl-1,2,4,5-tetrazine 16
Likewise, the [2.2](1,4)anthracenoparacyclophane, 13 (mono-anthophane), the anti-
[2.2](1,4)napth-alenophane, 14 (bis-naphthophane), and the anti-[2.2](1,4)
anthracenophane, 15 (bis-anthophane), were obtained in 87%, 85% and 85% yields,
respectively. All were fully characterized by 1H, 13C, and 19F NMR spectroscopy, and by
mass spectrometry.
The mass spectra was characterized by small signals due to parent ions (of exact
mass consistent with structure) and large signals of ions derived from the respective p-
xylylenes obtained from the expected 1,6-fragmentation of the parent species. Thus the
base peak in the (EI) mass spectrum of 12 was at mass 226 and derived from the p-
xylylene 19 radical cation (Figure 4-7 ). A 47% signal at mass 176 was derived from the
105
other p-xylylene fragment 20 (Figure 4-7]), whereas the signal for the parent ion at mass
402 was present only in the relative amount of 24%. Mass spectra of the other three
products were also consistent with expectations based on predominant 1,6-fragmentation
in the mass spectrometer.
CF2
CF2
CF2
CF2
M+ 226 (100) M+ 176 (47)
19 20
Figure 4-7 Fragment of [2.2]cyclophane 12
The chemical shifts of the 13C and 1H NMR spectra of products 12-15 are given
pictorially in Figure 4-8. In general they show the same trends as were observed in the
hydrocarbon series, although the presence of the bridge fluorines cause virtually all of the
protons to appear at lower fields than their counterparts in the hydrocarbon series.
Complete 1H and 13C chemical shift assignments for compounds 12-14 were made based
on the one bond and long range 1H-13C couplings, seen in their GHMBC spectra. In the
anthracene moiety, the peri of the two protons that display an A2B2 pattern couples with
a protonated carbon on the other ring. For the naphthalene moiety, this proton couples
with the carbon ipso to the CF2 group, which is a triplet. Couplings to this carbon, and to
the CF2 carbon that is a triplet of triplets identifies the proton of the naphthalene
(anthracene) moiety that is ortho to the CF2 group. Similar couplings were observed for
the para-phenylene moiety in mono-naphthophane 12 and mono-anthophane 13. The
shielded one of the two protons on this moiety displayed a nOe with the proton peri to the
CF2 group on the naphthalene (anthracene) moiety. In all of the compounds, this latter
106
proton also displayed a ca 2-3 Hz coupling with one of the fluorines, presumably a
through-space coupling with the closest fluorine.
FF
F F
FF
FF
FF
F FFF
FF
FF
F FFF
FF
FF
F FFF
FF
FF
F FFF
FF
12 13
14 15
AF4
7.16129.8
6.84129.3
133.4
6.24122.7
7.45127.8 132.1
131.7
118.7
119.9125.48.08
128.97.61
133.36.90128.8
5.90123.2
118.7
120.0
7.37127.7
129.2
131.4
124.78.63 128.9
8.03128.07.61
132.3
6.41124.5
129.5119.5
131.6
124.98.13
128.37.60
6.07
8.738.07 7.60
Figure 4-8 Chemical shifts of [2.2]cyclophane 12, 13, 14 and 15
The proton on naphthalene and ortho to the CF2 group is more shielded in bis-
naphthophane 14 than in mono-naphthophane 12 (6.41 vs. 7.45); therefore the orientation
of the two naphthalene groups in bis-naphthophane 14 is anti. On the basis of similar
facts, it was concluded that bis-anthophane 15 is also anti.
107
Bis-anthophane 15 had poor solubility in all of the deuterated solvents that we tried.
Even in tetrachloroethane-d2, at 70 °C, a 24 hours GHMBC spectrum did not afford any
cross-peaks. The assignments of the proton chemical shifts for bis-anthophane 15 were
based on the chemical shift trends that were common to the other three compounds.
Mono-anthophane 13 was not stable in solution; dimer 16 was formed in 33% yield
when an NMR sample was allowed to stand for one week in deuterated chloroform
solution at room temperature. This dimer was also observed in the reaction crude mixture
(10%) when mono-anthophane 13 was synthesized. However, trying to dimerize the pure
monomer under varied conditions proved difficult even under reflux conditions in pentyl
ether, which was the condition where dimer was observed in the synthesis of mono-
anthophane 13. Subjecting the chloroform solution of monomer, mono-anthophane 13, to
sunlight led to a complicated reaction mixture, which included the dimer. Interestingly,
dimerization could be cleanly observed when a sample of the chloroform solution of
mono-anthophane 13 was subjected to fluorescent light. A 32% yield of dimer was
obtained after one week at room temperature. Dimer was also seen to decompose to
monomer under different wavelength light conditions. When the dimer solution in CDCl3
was irradiated with UV light (>356nm) at room temperature in an NMR tube, monomer
was detected in 86% yield by proton NMR after 15 h. The dimer structure was confirmed
by both NMR analysis and crystalline x-ray diffraction analysis (Figure 4-10 and
Appendix Figure 8).
108
FF
F FFF
FF
F FF
F
FF F F F
F
FF
FF
FF
6.36128.4
116.8
133.7
6.02126.1
131.6
7.60128.4
7.40129.8
6.74132.4
7.55127.9
131.2
7.40127.6
129.87.33
128.17.18
131.9122.76.31
128.8121.9
50.8
118.04.2143.2
128.55.70
134.3
118.1
115.0
CDCl3room tempdimerize
21
Figure 4-9 Dimerization of phenyl anthracenophane 21.
Figure 4-10 ORTEP drawing of compound 21
The x-ray diffraction analysis indicates that there are two molecules of 21 in its
asymmetric unit. Aromaticity in the anthracene moiety was broken and linked to each
other by head to tail fashion; for molecule A, the center cyclobutyl ring had a twist angle
of 31.8o and a torsion angle C1-C2-C3-C4 of 22.4o to relieve the steric strain of the two
bulky anthracene moieties. The two fluorine bridges C1-C9-C10-C11 and C14-C17-C18-
C7 had torsion angles 40.1o and 26.9o respectively, in molecule A. The anthracene moiety
in bonds C5-C1-C2-C8 and C27-C3-C4-C30 had torsion angles 29.5o and 33.2o,
109
respectively.In molecule B, the cyclobutyl ring had a twist angle of 23.5o with torsion
angles of 35.1o and 20.6o in the two fluorine bridges.
4.3 UV and Fluorescence Spectrum
The transannular interactions between systems with π-electron distributions remain
a subject of considerable interest. The majority of recent research has focused on the
phenomenon termed formation of “excimers”.150, 151 The criterion for implication of an
excimer is the structureless fluorescence band which is red shifted from the normal
fluorescence band.
Figure 4-11 illustrates the UV absorption spectra of all 12-15 samples. They are
unremarkable and closely resemble those of their hydrocarbon counterparts.9, 21, 28, 139 All
the bands of bis-naphthophane 14 and bis-anthophane 15 have red shifted from these of
their non fluorinated counterparts, which are themselves all red shifted compared to the
1,4-dimethyl naphthalene and 1,4-dimethyl anthracene. In bis-naphthophane 14, the main
band of the absorption spectrum shifted from 310 nm in a non fluorinated anti-
[2.2]naphthalenoparacyclophane to 319 nm in a fluorinated one. Two new small bands
emerged in the absorption spectrum of bis-anthophane 15 at 303 nm and 315 nm
respectively. The main band in bis-anthophane 15 red shifted to 412 nm from 400 nm in
the anthraceno[2.2]paracyclophane and extended beyond 450 nm. These red shifts in
anthophane 13 and 15 are due to the extended π electron conjugation and decreasing
energy gap of their π-π* transitions compared to these of naphthophane 12 and 14.
The emission spectra of all four compounds are given in Figure 4-12. The spectra
are normalized to the same intensity to compare their band shift. Because of the solubility
issue for bis-anthophane 15, all the spectra all are carried out in dichloromethane solution.
110
Wavelength /nm
250 300 350 400 450 500
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
12131415
εlog
Figure 4-11 UV spectra of bridge fluorinated [2.2]cyclophanes 12-15
An excimer state has been shown to be the intermediate in the photodimerization
reaction of anthracene,152 in which an excited molecule is associated with a second
molecule in the ground state. Ferguson et al. found that this excimer type emission could
not be observed in the case of a stable anthracene dimer where only normal emission
spectrum was observed,153 which was supported by theoretical calculation.154
In the study of excimer fluorescence of non-fluorinated anthracenophane, Hayashi
et al.155 found that no emission spectra due to the excimer states of
[2.2](9,10)anthracenophane and anti-[2.2](1,4)anthracenophane could be observed at
room temperature as well as at 77K. However, the excimer fluorescence was observed in
syn-isomer of the latter one.155 Similar result was obtained in syn- and anti- isomer of
111
[2.2](1,4)naphthalenophane, i.e., excimer emission was found in the syn-isomer but not in
the anti-isomer.156
All the emission data are compared in Table 4-1. Cyclophanes 14 and 15 are fixed
anti- isomers and show broad emission as well as that of mono-anthophane 13. The
emission of mono-naphthophane 12 is quite narrow compared to the others. The
absorption and emission spectrum of mono-anthophane 13 have a red shift compared to
that of mono-naphthophane 12and bis-naphthophane 14.
Wavelength /nm
350 400 450 500 550 600 650
Inte
nsity
-0.2
0.0
0.2
0.4
0.6
0.8
1.0
1.2
12131415
Figure 4-12 Fluorescence spectra of bridge fluorinated [2.2]cyclophane after normalization. Concentrations in dichloromethane: 12, 4.77 × 10-5 M; 13, 2.83 × 10-5 M; 14, 1.20 × 10-5 M; 15, 5.79 × 10-6 M; silts, 2mm with LG350 filter
The absorption of bis-naphthophane 14 is very similar to the case of the non-
fluorinated one.156 The origin of this red shift may derive from the extended π
112
conjugation in 13 and hence different ring distortion. Compared with mono-anthophane
13, both the absorption and emission spectra of bis-anthophane 15 have red shift, which
is quite similar to the case of the non-fluorinated parent compound with a vibrational
structure in the excite states.155, 157 Similarly, the other three paracyclophanes also show
vibrational emission due to the rigid distorted structure, which led to a greater distance
between the two moieties. 155, 156
In the reaction of AF4-yne with α-methyl styrene, 24% of the DA product 22
(phenanthopahne) was obtained, and which has a methyl phenanthrene moiety on the
paracyclophane instead of anthracene moiety compared to mono-anthophane 13. The
change in UV and fluorescence spectra is shown in Figure 4-13 and Figure 4-14,
respectively. Spectra of mono-anthophane dimer are also studied with interest.
The UV spectrum of dimer 21 is quite similar to that of mono-naphthophane 12
after loss of one aromatic ring in anthracene moiety. Dimer 21 has a big broad absorption
form 254 nm to 275 nm, which is centered at 270 nm. The next band is quite similar to
that of mono-anthophane 13, while the longest band in mono-anthophane 13 and
phenanthophane 22 shrank to a sharp one at 358 nm in dimer 21. There is no absorption
after 360 nm compared to the monomer 13 and phenanthophane 22, which may arise
from the π-π* absorption. Basically, the absorption of phenanthophane 22 is the same as
that of mono-anthophane 13, except the red shift of the first band in phenanthophane 22
compared to mono-anthophane 13. It may be due to the donating effect of methyl group
on the phenanthrene moiety.
113
FF
F F
FF
FF
22
W avelength /nm
250 300 350 400 450 500
2.5
3.0
3.5
4.0
4.5
5.013221221
εlog
Figure 4-13 UV spectra in dichloromethane of compound 21 and 22 compared to
compound 12 and 13.
The emission spectra of mono-anthophane 13, dimer 21, and phenanthophane 22
have a red shift compared to that of mono-naphthophane 12, which has a naphthalenyl
instead of an anthracenyl moiety in the cyclophane.
It would be interesting to compare the emission spectra of AF4-yne DA products
with these bridge fluorinated paracyclophanes. Fluorescence spectra of compounds 23-25
were measured and shown in Figure 4-15. The non-fluorinated parent compound
[2.2](1,4)paracyclophane (AH4) was compared with interest.
114
W avelength /nm
350 400 450 500 550 600 650
Inte
nsity
0 .0
5.0e+5
1.0e+6
1.5e+6
2.0e+6
2.5e+6
3.0e+6
3.5e+612132221
Figure 4-14 Fluorescence spectra in dichloromethane of compound 21 and 22 compared
to compound 12 and 13; 16, 1.2*10-5M; 17, 2.15*10-5M; slits 2mm with LG350 filter.
Emission of AF4 has a 5 nm red shift compared to that of AH4. It is interesting that
compound 23 has a stronger fluorescence emission than phenanthophane 22 does, which
has an additional phenyl group on one of the cyclophane moieties. This may be due to the
‘Herringbone’ H-π effect in the endo isomer,93 where the π cloud was fixed to the H
atoms close to it. The steric hindrance of the endo isomer may also prevent the phenyl
ring from deformation in the excited states of 22. Thus, the emission is even weaker than
compound 23 which has two additional ethylene groups. All the compounds 22-25 emit
at almost the same wavelength, which is not an excimer emission as mentioned above.
115
FF
F F
FF
FF
FF
F F
FF
FF
HH
H H
HH
HH
23 24 25AH4
FF
F F
FF
FF
Wavelength /nm
400 500 600
Inte
nsity
0
1e+6
2e+6
3e+6
4e+6
5e+6
6e+6
252423AF4AH4
Figure 4-15 Fluoresence of Diels-Alder products in dichloromethane; AH4, 5.77*10-4M;
AF4, 3.07*10-4M; 17, 1.67*10-4M; 18, 1.68*10-4M; 19, 1.67*10-4M; slits 2mm with LG350 filter.
All the emission of bridge fluorinated compounds are excited at the λ with
maximum absorption and listed in Table 5-1. The extended conjugation in mono-
naphthophane 12 has limited effect on the orbital energy, whereas strained molecules,
such as 22, 23 and 24, have better effect on the excited singlet states and ground states.
116
Table 4-1 Fluorescence spectra data of fluorinated [2.2]paracyclophanes Compounds Concentration (10-5 M) Excitation (nm) Emission (nm)
12 4.38 310 370
13 2.83 270 455
14 2.48 316 394
15 0.579 275 464
21 1.2 290 460
22 2.15 290 438
23 16.7 290 382
24 16.8 290 385
25 16.7 290 380
AF4 30.7 280 371
AH4 57.7 285 366
4.4 Conclusion
In conclusion, four novel bridge fluorinated [2.2]paracyclophanes containing
naphthalene and anthracene condensed polycyclic aromatic subunits have been prepared
in an efficient one step procedure starting from the readily accessible adducts obtained
from the DA reactions of mono- or bis-arynes of AF4 with benzene and naphthalene. The
UV and fluorescence spectra of these cyclophanes were reported. Red shifts of absorption
spectra were observed, but no excimer emission was observed in any of the fluorinated
[2.2]paracyclophanes. A novel dimerization reaction was observed with mono-
anthopahen 13 under the influence of long wavelength irradiation at room temperature
and an x-ray diffraction analysis was also obtained. It is anticipated that these novel
117
compounds will serve as precursors of still more structurally novel [2.2]paracyclophane
derivatives.
4.5 Experimental
1H NMR (500 MHz), 13C NMR (125 MHz), and 19F NMR (282 MHz) spectra
were recorded using CDCl3 as the solvent, and chemical shifts (δ values) were measured
relative to the signals for CHCl3, CDCl3, and CFCl3 respectively. Column
chromatography was performed using chromatographic silica gel, 200-425 mesh, as
purchased from Fisher.
All photophysical studies were carried out with solution in 1cm x 1cm quartz
cuvettes using dichloromethane solution. For absorption measurements, sample
concentration were adjusted to produce Amax <1.0. Absorption spectra were recorded on
a Varian Cary 100 dual-beam spectrophotometer. Corrected steady-state emission
measurements were performed on a SPEX F-112 fluorimeter. The parameters are set as
following: Slits 2.0, filter LG350, integrator 1.0s.
1,1,2,2,11,11,12,12-Octafluoro[2.2]-(1,4)naphthalenoparacyclophane (12); Typical
Procedure
Adduct 8 (188 mg, 0.44 mmol) was dissolved in pentyl ether (10 mL) and brought
to reflux, after which 3,6-dipyridinyltetrazine (129 mg, 0.48 mmol) was added. The
solution was maintained at reflux for 2 h after which the solvent was evaporated under
vacuum, and the crude product purified via silica gel column chromatography (hexanes-
EtOAc, 1:100), to obtain 5 (158 mg, 89%) as a white solid; mp 176-177 °C.
1H NMR: δ = 8.08 (m, 2 H), 7.61 (m, 2 H), 7.45 (s, 2 H), 6.84 (s, 2 H), 6.24 (s, 2 H).
13C NMR δ = 133.4, 132.1, 131.7, 129.3, 128.9, 127.8, 125.4, 122.7, 119.9, 118.7. 19F
118
NMR: δ = -109.21, -114.43 (AB, J = 241.1 Hz, 4 F), -113.34, -114.75 (AB, J = 237.7 Hz,
4 F).MS (EI): m/z = 402 (24) [M+], 226 (100), 176 (47). HRMS (EI): m/z calcd for
C20H10F8: 402.0654; found: 402.0650. UV (CH2Cl2): λmax (log ε) = 313.0 (3.44),
294.4 (3.33), 259.0 (3.95) nm. Anal. Calcd for C20H10F8: C, 59.71; H, 2.51. Found: C,
59.51; H, 2.27.
1,1,2,2,13,13,14,14-Octafluoro[2.2]-(1,4)anthracenoparacyclophane (13); Typical
Procedure
Adduct 9 (105 mg, 0.2 mmol) was dissolved in pentyl ether (20 mL) and brought to
reflux, after which 3,6-dipyridinyltetrazine (64 mg, 0.23 mmol) was added. The solution
was maintained at reflux for 2 h during which it turned pale brown. After the solvent was
evaporated under vacuum, the crude product was purified via silica gel column
chromatography (hexanes-EtOAc, 1:100), to give 6 (85 mg, 87%) as a yellow solid; mp
230-231 °C.
1H NMR: δ = 8.63 (d, J = 1.8 Hz, 2 H), 8.03 (m, 2 H), 7.61 (m, 2 H), 7.37 (s, 2 H),
6.90 (s, 2 H), 5.90 (s, 2 H).13C NMR: δ = 133.3, 132.3, 131.4, 129.2, 128.9, 128.8, 128.0,
127.7, 124.7, 123.2, 120.0, 118.7.19F NMR: δ = -108.86, -110.59(AB, J = 242.8 Hz, 4 F),
-113.33, -114.27 (AB, J = 238.0 Hz, 4 F).MS (EI): m/z 452 (21) (M+), 276 (100), 176
(28).HRMS (EI): m/z calcd for C24H12F8: 452.0811; found: 452.0814.UV (CH2Cl2):
λmax (log ε) = 411.3 (3.26), 386.0 (3.43), 275.0 (4.44) nm.
Dimer 21: 1H NMR: δ 7.60(d, J=8.1Hz, 2H), 7.55(d, J=8.9Hz, 2H), 7.40(ddd, J=8.0,
6.9, 1.2Hz, 4H), 7.33(ddd, J=8.0, 6.8, 1.1Hz, 2H), 7.18(d, J=7.7Hz, 2H), 6.74(dd, J=3.1,
1.5Hz, 2H), 6.36(d, J=8.5Hz, 2H), 6.31(s, 2H), 6.02(d, J=8.4Hz, 2H), 5.70(d, J=8.3Hz,
2H), 4.21(d, J=7.0Hz, 2H); .13C NMR: 134.3, 133.7, 132.4, 131.9, 131.2, 129.8, 129.5,
119
127.9, 127.6, 129.8, 128.1, 122.7, 128.8, 128.4, 131.6, 128.4, 126.1, 118.0, 118.1, 116.8,
115.0, 50.8, 45.0, 43.2; MS (EI): m/z 452(21), 276(100), 176(49); HRMS (ESI-FT-ICR)
Calc for C48H24F16 + Na 927.1515, found 927.1504; UV (CH2Cl2): λmax (log ε)
=358.1 (3.22), 339.8 (3.64), 323.8 (3.97), 270.6 (4.55) nm.
anti-1,1,2,2,11,11,12,12-Octafluoro[2.2](1,4)napthalenophane (14); Typical
Procedure
Adduct 10 (66 mg, 0.13 mmol) was dissolved in pentyl ether (10 mL) and brought
to reflux, after which 3,6-dipyridinyltetrazine (72 mg, 0.27 mmol) was added. The
solution was maintained at reflux for 2 h until it turned pale brown. The solvent was then
evaporated under vacuum and the crude product purified by recrystallization from
CH2Cl2 and hexanes to give product 14 (50.2 mg, 85%) as a white solid; mp 250 °C
(dec).
1H NMR: δ = 8.13 (m, 4 H), 7.60 (m, 4 H), 6.41 (s, 4 H). 13C NMR: δ = 131.6,
129.5, 128.3, 124.9, 124.5, 119.5. 19F NMR: δ = -107.19, -108.93 (AB, J = 241.11 Hz, 8
F).MS (EI): m/z = 452 (10) [M+], 226 (100). HRMS (EI): m/z calcd for C24H12F8:
452.0811; found: 452.0813. UV (CH2Cl2): λmax (log ε) = 319.0 (3.59), 258.0 (3.93) nm.
anti-1,1,2,2,13,13,14,14-Octafluoro[2.2]-(1,4)anthracenophane (15); Typical
Procedure
Adduct 11 (49 mg, 0.08 mmol) was dissolved in pentyl ether (10 mL) and the
solution brought to reflux, after which 3,6-dipyridinyl-tetrazine (45 mg, 0.17 mmol) was
added. The mixture was maintained at reflux for 2 h until it turned pale brown. The
solvent was then evaporated under vacuum and the crude product purified by
recrystallization from toluene to give product 15 (50.2 mg, 85%) as a yellow powder.
120
This compound was sparingly soluble in most solvents and its melting point was above
290 °C.
1H NMR; δ = 8.73 (d, JF,H = 3.1 Hz, 4 H), 8.07 (m, 4 H), 7.60 (m, 4 H), 6.07 (s, 4
H). 19F NMR: δ = -106.28, -108.82 (AB, J = 234.91 Hz, 8 F). MS (EI): m/z = 552 (13)
[M+], 276 (100). HRMS (EI): m/z calcd for C32H16F8: 552.1124; found: 552.1127. UV
(CH2Cl2): λmax (log ε) = 412 (3.62), 315 (3.73), 303 (3.73), 272 (5.09) nm.
CHAPTER 5 NOVEL CAGE COMPOUND
5.1 Introduction
Pyramidalized alkenes are molecules that contain a carbon-carbon double bond
where one or both of the sp2 hybridized carbons do not lie in the same plane as the four
atoms attached to it.158 Weinshenker and Greens159 reported the first synthesis of a
pyramidalized alkene in 1968, and since then, the synthesis and study of these types of
compounds have become a field of active research. These compounds are interesting
targets for both synthetic and theoretical organic chemistry because of their intriguing
physical properties and fascinating reactivity.160-162
Pyramidalized alkenes are similar to cis-bending alkynes (benzynes), which are
highly reactive. By the calculation, cis-bending acetylene would have 25% greater force
constant than that of alkene pyramidalization. Thus, pyramidalized alkenes only have
80% of the strain localized in their double bond compared to the triple bond of
benzyne.158 The LUMO energy is substantially lower in a pyramidalized alkene, but the
pyramidalization has little effect on the energy of the HOMO. Thus, the energy gap
between the HOMO and LUMO is decreased. In addition, according to frontier orbital
theory, the large lowering of LUMO energy should enhance its reactivity toward
nucleophiles more than toward electrophiles. Also, the π—π* transition exhibits a red
shift.
Pyramidalization of a double bond does not just result in classical torsional strain,
which favors bond staggering at adjacent carbons. The Olefin Strain Energy (OSE) of a
121
122
pyramidalized alkene is derived from two sources.163 One source is the OSE present in
the unstrained skeleton of the bicyclic reference olefin; the second source is the
pyramidalization of the double bond in the skeleton. The Olefin Pyramidalization Strain
Energy (OPSE) is the difference between the OSE of a pyramidalized alkene and that of
the appropriate bicyclic reference compound, i.e. the OPSE is part of the OSE. For
example, the 6-31G* TCSCF calculated OPSE occupies up to 32% of the total OSE (58.9
kcal/mol) in cubene in reference to bicyclo[2.2.0]hex-1(4)-ene.163
θ
Figure 5-1 Pyramidalized alkene
The double bond in the pyramidalized alkene (Figure 5-1) is weakened due to the
decreased overlap between the two π-electron clouds. In some sense, the
pyramidalization angle correlates with the reactivity of the pyramidalized alkene.
Compound 1 (Figure 5-2) has a pyramidalization angle of 24-26o, and reacts readily with
triplet oxygens.158 Compound 3 has an angle of 32.4o, and must be protected by two
spiro-cyclopentyl groups.164 The greatest reported pyramidalization angle was calculated
to be 84.1o in cubene 2.158 Kuck and Meijiere reported the tribenzo-4,7-
dihydroacepentalene derivatives (Figure 5-3), in which the biggest angle between the C1-
C10 plane was determined to be 47.2o by x-ray.165
123
1 2 3
Figure 5-2 Some pyramidalized alkenes
R
R12
3 45
678
9
10
Figure 5-3 Tribenzo-4,7-dihydroacepentalene derivative
Pyramidalized alkenes are highly reactive and are not easily to generated or handled.
Pyramidalized alkenes are usually trapped by Diels-Alder (DA) reactions, and the
structures of the starting pyramidalized alkenes are deduced from the adducts.
Computation is a common method used in the study of highly pyramidalized alkenes.
Most spectroscopic data of pyramidalized alkenes has been obtained by using matrix
isolation technology.166 There is not much data with x-ray diffraction analysis.
In the second chapter, the treatment of pseudo-para (4,15) or meta-(4,16)
diiodooctatfluoro-[2.2]paracyclophane with strong base potassium t-butoxide in the
presence of diene trap was discussed, and high yields of DA adducts derived from
4,5,15,16-bis(dehydro)octafluoro[2.2]paracyclophane 4 (bis-AF4-yne) were obtained
(Figure 5-4). When pseudo-ortho- (4,13) diiodooctatfluoro-[2.2]paracyclophane was
treated under the same conditions, the corresponding 4,5,12,13-bis(dehydro)octafluoro
124
[2.2]paracyclophane 5, with two arynes on the same side of [2.2]paracyclophane was
generated and a highly pyramidalized olefin was generated in the presence of an
anthracene diene trap.
F
F
FF
F
F
FF
F
F
FF
F
F
FF
4 5
Figure 5-4 4,5,15,16-bis(dehydrooctafluoro[2.2]paracyclophane 4 and 4,5,12,13-bis(dehydrooctafluoro[2.2]paracyclophane 5
5.2 Result and Discussions
5.2.1 Synthesis of Cage Compound
One third (23%) of the pseudo-ortho-dinitro-AF4 was obtained from the dinitration
of AF4 (see chapter 2), which was reduced to the pseudo-ortho-diaminoAF4 and then
converted to pseudo-ortho-diiodoAF4 6. The same type of DA reaction was tried under
Cram conditions with an anthracene trap.
IF2C CF2
CF2F2C
I
Potassium t-Butyloxide
Anthracene
F2C
CF2
CF2
F2C
17%
CF2
CF2F2C
CF2
CF2
CF2F2C
CF2
4% 34%
+ +
87
Dibutyl ether, reflux
6
Figure 5-5 The reaction of the pseudo-ortho-4,12-diiodooctafluoro[2.2]paracyclophane
with anthracene
125
Fortunately, the desired novel cage type of compound 7 was obtained along with
the mono-anthracene DA product (34%) after careful chromatographic separation (Figure
5-5). This reaction is not consistent, and the ratio of mono-anthracene adduct to cage
product varies from 2:1 to 5:1, and sometimes very little cage product is obtained.
F2C
CF2
CF2
F2C
6.73125.0
127.07.20
6.67124.6
120.9
149.4
130.8
120.8
124.47.41
139.8
5.3751.5
48.35.48
150.3
6.84135.3
164.4
CF2
CF2F2C
CF2
CF2
CF2F2C
CF2
O
6.98129.7
119.47.11128.5
119.4
126.5 142.951.55.83
146.6125.46.77
123.87.12
143.6125.57.54
126.37.16
5.61135.8
46.95.35126.3
145.2
141.6
121.77.38
131.5
7.55127.5
126.07.30
6.82123.5
7.18131.9
135.0
118.1
5.10126.6
128.7154.5
82.10.8728.1
118.6
120.3
6.63127.8
6.77128.5
127.2
119.3
149.3
149.3128.3
51.06.02
145.6
7.17124.5
126.86.80
6.80124.8
7.15124.0
145.6
143.6
142.0
5.8250.2
124.87.53
126.67.13
125.67.13
7.48126.6
7
8 9
Figure 5-6 NMR assignments of pseudo-ortho-diiodoAF4 with anthracene products under Cram conditions
Along with the mono-anthracene adduct and the novel cage compound 7, bis-
anthracene adduct 8 was obtained in 4% yield. Compound 8 is quite bulky, which comes
from the first DA reaction at the 9,10 position followed by a 1,4-addition with another
anthracene molecule. When the reaction is carried out under microwave conditions, 10%
126
of compound 9 was obtained. No compound 9 was detected, which was observed with the
conventional heating method. Product 9 is an interesting t-butoxide adduct, which had
been observed in the previous AF4-yne with 1-octene reaction under Cram conditions.
After the first DA reaction with anthracene, the second aryne was captured by a t-
butoxide ion. All the NMR assignments are shown in Figure 5-6.
The steric hindrance of the phenyl group from the first DA addition product
combined with the bulky base may cause the low yield of the cage compound. Some
other bases were tried in order to improve the yield of the cage compound. The results are
summarized in Table 5-1. Mono-iodoAF4 was used in these experiments as a model
compound instead of ortho-diiodoAF4 because of the difficulty of starting material
synthesis. On the basis of these results, it seems that potassium t-butoxide and butyl ether
are the best choice. Interestingly, sodium t-butoxide did not work at all in this system,
with only aminor change in cation. It is concluded that the heterogeneous KOtBu system
makes the base stronger as discussed in Chapter 3.
Table 5-1 Base screening results
base solvent Temperature(℃) Results
Sodium tert-butoxide(6) Butyl ether 142 No reaction
Sodium amide (2) Butyl ether Room No reaction*
Sodium amide (6) Butyl ether 142 No reaction*
Sodium ethoxide (5) Butyl ether 142 No reaction
Sodium amide (6) DMF Room Reduced AF4
Sodium
bis(trimethylsilyl)amide(5)
Butyl ether Room Reduced AF4
* These reaction conditions will probably lead to the destruction of amides by reacting with the butyl ether.
127
Microwave conditions show some dramatic effects in organic synthesis compared
to conventional heating methodology.167-169 The ability to rapidly heat and thermally
quench by microwave resulted in dramatic increases in the rates and yields of a variety of
chemical transformations in organic chemistry.170-172
It is still unknown why microwaves have such an effect on reaction. The commonly
accepted rationale is that microwaves heat mixtures with even and high efficiency. We
decided to utilize microwaves to facilitate the formation of the second aryne and force the
reaction towards our desired direction. Indeed, the result from the microwave reactor is
repeatable, and the average yield of cage compound is much higher than the conventional
heating method. We conjecture that microwave heating also increases the starting
material collision rates and facilitates attack of the second base.
Does high temperature help the formation of the cage product? Trying to improve
the yield of the cage compound by increasing the reaction temperature and microwave
power proved abortive (Table 5-2).
Table 5-2 Solvent effect in the reaction of pseudo-ortho-diIAF4 with anthracene under microwave conditions
Solvent Temperature (℃)
Time(min) Result(from the 19F spectrum)
Tert-butylbenzene 169 10 cage compound with mixed aryne adducts
Decane 175 20 No cage product Butyl ether 142 10 17%Cage
compound Pentyl ether 189 10 No cage product N-methyl
pyrrolidinone 180 10 No 19F
2-methoxyethyl ether 180 10 No 19F Bis[2-(2-methoxy-ethoxy)ethyl] ether
200 10 No 19F
128
Several solvents with different boiling points were used and butyl ether was found
to be the best one. Increasing reaction temperatures had little effect on the yield of the
cage compound. The non-polar solvent, decane, gave no desired product but only the
mono-anthracene adduct. t-Butylbenzene gave even more complicated results compared
to butyl ether. N-methyl pyrrolidinone, 2-methoxyl ethyl ether, and Bis[2-(2-methoxy-
ethoxy)ethyl] ether systems simply destroyed the AF4 compound. Microwave power also
had limited impact in the formation of cage product due to steric problems.
Besides NMR characterization, a single crystal x-ray diffraction picture
demonstrates the structure of the cage compound (Figure 5-7 and Appendix Figure 6).
Intuitively, one would expect that less overlap of a π cloud would result in a longer bond
length. Surprisingly, like other strained olefins,165 the bond length of the pyramidalized
double bond C20-C29 is 1.341(3) Å, a little bit longer than the bond between C17-C18,
1.320(4) Å. Double bonds in the benzene ring C22-C27, C22-C23, C23-C24, and C24-
C25 are 1.393(3), 1.388(3), 1.392(4), and 1.372(4) Å respectively. The C22-C27 bond is
much longer than the opposite double bond C24-C25 by 0.02 Å. The bond angles C19-
C20-C21, and C30-C29-C28 are 121.40(18)o and 121.86(18)o respectively The average
pyramidalization angle (180o-θ) is 58.5o, which is the highest value that has ever been
observed by x-ray diffraction. The twist angle between the two faces of the four branches
of the double bond C19-C30-C20-C29 and C20-C29-C21-C28 is just 34.2o, which is
much smaller than the pyramidalization angle. The torsion angle of the two bridges C1-
C7-C8-C9 and C4-C15-C16-C12 on the AF4 moiety are almost intact with only 0.73o and
1.40o, respectively, which indicates no additional steric strain in the AF4 moiety. The two
phenyl rings in the AF4 moiety are twisted 13.0o and 13.2o toward its perpendicular axis,
129
respectively. It is noteworthy that in the MS, 526(M+)(EI) is observed with an intensity of
47 percent, the m/e 1052 (EI), dimer of cage compound, is also observed 1/37 compared
to its monomer intensity.
Figure 5-7 ORTEP drawing of the cage compound (right) and epoxide (left)
As mentioned above, the energy gap between the LUMO and HOMO orbitals of
pyramidalized double bond decreases with increasing pyramidalization angle. The center
double bond should be quite reactive under harsh reaction conditions. However, the cage
compound is stable during harsh reaction conditions followed by silica gel
chromatography. It is also stable towards molecular oxygen when it is dry, which is quite
remarkable in the pyramidalized olefin family. The double bond in tricycle[3.3.2.03,7]-
dec-3(7)-ene 10 (Figure 5-8)166is highly reactive towards electrophiles and nucleophiles
or [2+2] dimerization. Alkene 10 could only be characterized spectroscopically in an
argon matrix, and it dimerizes above 40K. On the other hand, dodecahedradiene 11 can
be handed as a crystalline compound at room temperature.173 The four allylic hydrogens
provide sufficient steric protection for the pyramidalization double bond against
dimerization. Similarly, the electronic cloud of the benzene ring in 7 and the neighboring
double bond around the center double bond may be responsible for the extraordinary
stability of its highly pyramidalized double bond.
130
10 11
Figure 5-8 Tricycle[3.3.2.03,7]-dec-3(7)-ene 10 and dodecahedradiene 11
In similar reactions with benzene and naphthalene as a diene trap for the ortho-bis-
AF4-yne under both conventional method and microwave conditions, no desired products
were observed except the mono-adducts plus other unknown compounds.
5.2.2 Cage with Triplet Oxygen
Nevertheless, the cage product is readily oxidized by triplet oxygen, with half of the
cage compounds being oxidized to epoxide 12 in the NMR tube after staying at room
temperature for three days (Figure 5-9). Cage compound 7 was also oxidized easily to
epoxide 12 during its purification on preparative TLC plates. The carbon signal of the
C20-C29 double bond shifted from 164.4ppm in the starting material to 66.4ppm in the
epoxide. The 19F-NMR spectra of the epoxide shifted downfield by 1.65ppm from the
cage compound with the same pattern. Fluorine atoms on the substituted side of the
molecule coupled with neighboring hydrogens, with the coupling constant being
15.2/12.4 and 15.2/12.1 for epoxide and the cage compound, respectively.
F2C
CF2
CF2
F2C
CDCl3, 3O2
room temperatureF2C
CF2
CF2
F2C
O
12
Figure 5-9 Cage compound reaction with oxygen
131
Increasing the number of double bonds in the sesquinorbornene also increased
reactivity toward triplet oxygen.158 The benzo derivative of compound 1 gave a mixture
of epoxide and diketone on exposure to triplet oxygen under conditions where compound
14 (Figure 5-10) failed to react.174 The neighboring double bond and benzene moieties
may also have such an effect on the pyramidalized double bond of 7.
14
Figure 5-10 Syn-sesquinorbornene
The crystal X-ray diffraction analysis of the epoxide is illustrated in Figure 5-7
(also Appendix Figure 7). The angles of C17-C30-C29 and C22-C21-C20 are 120.44(12)
and 121.06(13), respectively, which are very close to the pyramidilization angle of the
central double bond of cage compound 7. In contrast, the dihedral angle between the two
corresponding faces widened to 40.7o (139.3o), a little larger than that in the cage
compound 7. The torsion angle of the two bridges C4-C7-8-C9 and C12-C15-C16-C1 on
the AF4 moiety stayed the same, 0.44o and 2.80o, respectively, while the twist angle of
two phenyl rings changed to 12.7o and 13.1o, respectively.
5.2.3 Cage with Chlorine
When oxygen is bubbled into the deuterated chloroform solution slowly at room
temperature, another compound appeared in the 19F NMR. The ratio of this compound to
epoxide varied from 1.3:1 to 2.6:1. This variation might due to the different concentration
of substrate and different oxygen bubbling speed.174 The yield of the epoxide was 21%
132
whereas that of the new compound was 52%. This compound turned out to be the
chlorine adduct 13 (Figure 5-11). The pyramidalized double bond signal at 164.4 ppm in
the cage compound disappeared in the 13C NMR, and a new signal at 78.3 ppm appeared,
which is similar, but different from the epoxide signal at 66.4 ppm.
F2C CF2
F2C CF2
F2C CF2
F2C CF2
ClCl
CDCl3room temperature
saturated 3O2
13
F2C CF2
F2C CF2+
1252% 21%
O
Figure 5-11 Bubbling oxygen through the solution of cage compound
Pure chloroform is known to be decomposed by air, especially when at high oxygen
levels.175, 176 The mechanism is shown below.
4CHCl3 + 4O2= 4COCl2 + 2H2O + Cl2
2COCl2 + 2H2O= 2 CO2 + 4HCl
We believe that this chlorine product was trapped by the highly reactive double
bond under the reaction conditions, which led to the final product. This reaction is
analogous to the cage compound reaction with bromine. The dihedral angle between
C26-C29-C25-C30 and C24-C17-C25-C30 is 54.0o, which is much bigger than that of the
cage compound and the epoxide. The strain is thus further released in the dichloride
adduct.
5.2.4 Cage with Singlet Oxygen
In a study of the reaction of singlet oxygen with olefin, 177 a dioxetane was obtained
in 81% yield along with 19% of epoxide product. The reaction was hypothesized to
133
proceed through a perepoxide intermediate (Figure 5-12), which could be trapped
successfully with pinacolone to give epoxide and t-butyl acetate.
Paquette et al reported an interesting reaction of pyramidalized alkene 14 with
singlet oxygen.174 The rigid framework excluded the possibility of 2S+2A cycloaddition
with singlet oxygen. However, when the reaction was carried out in benzene with rose
Bengal as a sensitizer, a mixture of epoxide and diketone in a 1:3 ratio was obtained.
OO
hv, O2
sensitizerpinacolone
Ad Ad
O O
O
O
O
O+
81%
19% Figure 5-12 Trapping the intermediate of the reaction of singlet oxygen with
pyramidalized alkene
Our cage compound was subjected to singlet oxygen (Figure 5-13) generated via
the published method.178, 179 A CDCl3 solution of cage compound (3 mg)in a NMR tube
was added rose Bengal (5 mg) and immersed into a flowing cooling water bath to keep
the vessel at room temperature. Oxygen was bubbled into the solution through a long
metal needle while the solution was irradiated through a 0.05M K2Cr2O7 solution filter.
The reaction was complete after 5 hours of irradiation with a 250W Sylavi mercury lamp.
Epoxide 12 and diketone 15 were obtained in 66% and 33% (2:1 ratio), respectively, by
NMR characterization. Assignments of 1H and 13C are shown in Figure 5-12. The carbon
signal at 193.7 explicitly indicates the existence of carbonyl group. The chemical shifts of
134
protons in the AF4 moiety shifted to 7.26/7.25 ppm from that of 6.73/6.67 ppm in cage
compound 7, and the chemical shifts of olefin protons moved up field by 0.99 ppm from
that of 6.84 ppm in cage compound.
F2C CF2
F2C CF2
F2C CF2
F2C CF2
O
O
CDCl3room temperature
O2, Rose Bengal
15
F2C CF2
F2C CF2
+
1266% 33%
O
hv
F2C CF2
F2C CF2
O
O
193.7
127.55.85
136.3120.7
7.26130.3
135.4
130.27.25
120.7
135.6136.3
56.25.68
131.2129.37.58
128.77.29
54.55.09
15
Figure 5-13 Compound 14 and cage with singlet oxygen product 15
5.2.5 Cage with Bromine
When bromine was added to the cage compound solution in carbon tetrachloride at
0℃, the red brown color of bromine disappeared immediately, and a dibromide adduct
16 was obtained quantitatively. The C20-C29 carbon signal shifted from 164.4 ppm in
the pyramidalized double bond to 74.9 ppm in the bromine adduct, which is different
from that of 66.4 ppm in expoxide and 78.3 ppm in dichloride.
135
F2C CF2
F2C CF2CCl40oC
F2C CF2
F2C CF2
16100%
Br2, 1 equiv.
Br
Br
Figure 5-14 Reaction of cage with bromine
5.3 Conclusion
An unusual reaction of pseudo-ortho-4,12 –diiodooctafluoro[2.2]paracyclophane
with base potassium t-butoxide and anthracene led to the novel highly reactive
pyrimidalized alkene, which is stable in moist and oxygen at room temperature. This cage
compound reacts slowly with triplet oxygen to give epoxide, while the diketone can be
obtained with singlet oxygen.
5.4 Experimental
General Methods. 1H (500 MHz), 13C (126 MHz), and 19F (282 MHz) NMR
spectra were recorded using CDCl3 as the solvent, and chemical shifts ( values) were
measured relative to the signals for CHCl3, CDCl3, and CFCl3, respectively. 1H and 13C
chemical shift data are directly indicated on the structures of the adducts in the Results
and Discussion section above, whereas 19F NMR data are provided in the Experimental
Section below. X-ray crystal analyses were performed by the Center for X-ray
Crystallography and HRMS and CH micro elemental analyses by the Spectroscopic
Services Group at the University of Florida. Column chromatography was performed
using chromatographic silica gel, 200-425 mesh, as purchased from Fisher, unless
136
otherwise mentioned. Discover microwave from CEM Company with an output
frequency of 2450 MHz is used in all microwave reactions.
Photooxygenation was performed with a 250W Sylavi mercury lamp. The output of
the lamp was filtered with 0.05M K2Cr2O7 solution to remove light below 460 nm. The
photolysis was carried out in NMR tubes with outside water flow to keep the temperature
around 25℃. Oxygen was bubbled through the solution being photooxygenated via a
metal needle.
4,12-Dinitro-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes. See chapter 2
experimental.
4,12-Diamino-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes. See chapter 2
experimental.
4,12-Diiodo-1,1,2,2,9,9,10,10-octafluoro[2.2]paracyclophanes,51 A solution of
4,12-diaminooctafluoro[2.2]paracyclo-phanes (5.0 g, 13 mmol) in acetic acid (10 mL)
was cooled to 0 ℃ in an ice/brine bath; ice (5 mL) and concentrated sulfuric acid (5 mL)
were added with stirring. With the temperature maintained below 0 ℃, sodium nitrite
(5.0 g, 72.0 mmol) was added as quickly as possible to the solution in one batch. The
reaction was stirred at this temperature for 2 h, and then the mixture was poured into an
aqueous solution (10 mL) of potassium iodide (13 g, 77 mmol) at room temperature with
vigorous stirring. This mixture was kept stirring at room temperature overnight and then
filtered. The solid was purified by column chromatography (hexane/ethyl acetate, 50:1)
to give 4.98 g (63%) product.
137
Generation of 4,5,12,13-Bis(dehydro)octafluoro[2.2]paracyclophane, 1, and its
Reaction with [2.2]Paracyclophane. Into a three necked round flask were charged with
pseudo-ortho-diiodo AF4 (0.12 g, 0.2mmol), anthracene (78mg, 2.2mmol), and
potassium t-butoxide (0.23g, 2.0mmol) followed by 10ml butyl ether. The mixture was
then refluxed for 30 minutes. 19F NMR showed no starting material. The mixture was
allowed to cool down and filtered through a short pad of silicon gel, and washed with
3x10 ml dichloromethane. Solvent was evaporated under vacuum, and the products were
further purified through silicon gel column. Product No1 is the same product as AF4-yne
with anthracene reaction (34%); product No2 is cage compound 7 with a 17% yield; The
next product is pseudo-ortho-bisanthracene adduct 8 (4%), and product 9 (10%) was
obtained from the microwave reaction as described below.
Microwave reaction procedure: into a 50ml one neck-round flask was charged with
pseudo-ortho-diiodo AF4 (0.12 g, 0.2mmol), anthracene (78mg, 2.2mmol), and
potassium t-butoxide (0.23g, 2.0mmol) followed by 10ml butyl ether. The mixture was
degassed with vacuum pump three times. A nitrogen balloon was attached to the reaction
vessel, which was put into the microwave reactor with care. The parameters were set as
following: heating model, standard; solvent, dimethyl sulfoxide; no pressure; power,
180W; temperature, 150℃; runtime, 20minutes; hold time, 20minutes; stirrer, on; cooling,
on.
The spectra of cage compound 7 are: 1H NMR (300MHz, CDCl3/TMS) δ: 7.41(d,
J= 5.7Hz, 1H), 7.38(d, J=5.4Hz, 1H) 7.20(dd, J= 5.4, 3Hz 2H), 6.82(dd, J=4.5, 3Hz, 2H),
6.71(s, 2H), 6.66(s, 2H), 5.71(s, 2H), 5.48(dd, J=4.2, 3.6Hz, 2H); 13C NMR (126MHz,
CDCl3) δ 164.4, 150.3, 149.4, 139.8, 135.3, 130.8, 130.8, 127.0, 125.0, 124.6, 124.4,
138
120.9, 120.8, 51.5, 48.3; 19F NMR (282MHz, CDCl3/CFCl3) δ -104.20(d, J=243.9 Hz,
2F), -104.55(d, J=243.9 Hz, 2F), -107.59(dd, J=242.2, 12.1Hz, 2F), -108.0(dd, J=242.2,
15.2Hz, 2F). IR (cm-1) 3076, 3034, 2966, 2868, 1954, 1916, 1810, 1706, 1658, 1601,
1474, 1454, 1378, 1268, 1150, 1117; MS (EI) m/z 1052(2M+), 526(47)[M+], 352(10),
300(100), 276(11), 250(95); HRMS Calc for C30H14F8 526.0968, found 526.0967(EI);
UV (CH2Cl2) λmax 328, 309, 246nm.
The spectra of 8 are: 1H NMR (500MHz, CDCl3/TMS) δ: 7.55(dd, J=4.1, 3.4Hz,
2H), 7.54(t, J=3.2Hz, 2H), 7.38(s, 2H), 7.30(m, 2H), 7.16(m, 2H), 7.12(m, J=, 2H),
7.11(s, 2H), 6.98(s, 2H), 6.77(m, J=, 2H), 5.83(d, J=2.6Hz, 2H), 5.61(m, 2H), 5.35(m,
2H); 19F NMR (282MHz, CDCl3/CFCl3) δ: -111.18, -116.35(AB, J=250.13 Hz, 4F), -
113.72, -117.05 (AB, J=250.13 Hz, 4F); 13C NMR (126MHz, CDCl3) δ: 146.6, 145.2,
143.6, 142.9, 141.6, 135.8, 131.5, 129.7, 128.5, 127.5, 126.5, 126.3, 126.3, 126.0, 125.5,
125.4, 123.8, 121.7, 119.4, 119.4, 51.5, 46.9. MS (EI) m/z: 705 (30), 704(74)[M+],
352(49), 180(23), 178(52), 149(30), 77(100), HRMS: Calc for C44H24F8:704.1750, Found:
704.1765 (EI)
Spectra of compound 9 are: 1H NMR (500MHz, CDCl3/TMS) δ 7.53(m, 1H),
7.48(dt, J=5.0, 2.5Hz, 1H), 7.17(m, 2H), 7.13(m, 2H), 6.82(d, J=7.9Hz, 1H), 6.80(ddd,
J=6.2, 3.7, 1.2Hz, 1H), 6.77(d, J=9.4Hz, 1H), 6.63(dd, J=8.1Hz, 1H), 6.01(d, J=2.0Hz,
1H), 5.82(s, 1H), 5.10(s, 1H), 0.87(s, 9H); 19F NMR (282MHz, CDCl3/CFCl3) δ: -106.95,
-116.18(AB, J=240.83Hz, 2F), -109.25, -111.99 (AB, J=241.11Hz, 2F), -115.19, -
116.10(AB, J=214.96Hz, 2F), -117.95, -119.03(AB, J=240.83Hz, 2F); 13C NMR
(126MHz, CDCl3) δ: 154.5, 145.6, 145.0, 144.3, 144.3, 143.6, 142.0, 135.0, 131.9, 128.7,
128.5, 128.3, 127.8, 127.2, 126.8, 126.8, 126.6, 126.0, 125.6, 124.8, 124.8, 124.5, 124.0,
139
123.5, 120.3, 119.3, 118.6, 118.1, 82.1, 51.0, 50.2, 28.1; MS(EI) m/z 600(M+)(0.67),
585(3), 544(100), 353(21), 352(84); HRMS Calc. for C34H24F8O 600.1699, Found
600.1713 (EI).
Reaction of cage compound with triplet oxygen: cage compound (6mg,
0.01mmol) in 5mm NMR tube with 0.5 ml CDCl3 was placed at room temperature for
three days, NMR showed that half cage compound was oxidized to epoxide. No other
product was detected. 1H NMR (500MHz, CDCl3/TMS) δ: 7.23(m, 2H), 7.17(m, 2H),
6.91(s, 2H), 6.89(s, 2H), 6.34(m, 2H), 5.41(s, 2H), 5.14(t, J=3.9 Hz, 2H); 19F NMR
(282MHz, CDCl3/CFCl3) δ: -105.85, -109.88(AB, J=240.83Hz, 4F), -106.34, -110.38
(AB, J=243.93Hz, 4F), the coupling with proton adjacent is 15.2, and 12.4Hz; 13C NMR
(126MHz, CDCl3) δ: 147.8, 147.7, 137.9, 132.5, 132.4, 132.3, 127.5, 127.3, 127.2, 124.9,
120.9, 120.8, 66.4, 45.0, 41.4; MS(EI) m/z 542(M+)(22), 514(100), 288(47), 226(20);
HRMS Calc. for C32H14F8O 542.0917, Found 542.0916 (EI); UV (CH2Cl2) λmax 330,
290, 280.
Reaction of cage compound with bromine: cage compound (3.4mg, 0.006mmol)
in 10ml round flask with 5 ml CCl4 was placed in an ice bath. Bromine (1 mg, 0.33µl,
0.0063mmol) was added through 1µl syringe at a time and the red-brown color
disappeared immediately after the addition. The mixture was stirred at this temperature
for another 5 minutes, and then solvent was evaporated under vacuum. Pure bromine
adduct 16 (100%) was obtained without further purification. 1H NMR (500MHz,
CDCl3/TMS) δ 7.23(m, 2H), 7.10(m, 2H), 6.89(s, 2H), 6.87(s, 2H), 6.66(m, 2H), 5.46(s,
2H), 5.33(m, 2H); 13C NMR (126MHz, CDCl3) δ 142.5, 141.8, 140.6, 138.1, 132.6, 132.5,
128.2, 127.9, 127.4, 127.2, 120.4, 74.9, 55.1, 50.9; 19F NMR (282MHz, CDCl3/CFCl3) δ
140
-107.36, -112.21(AB, J=240.83Hz, 4F), -107.46, -112.46(AB, J=243.93Hz, 4F), the
splitting of fluorine by proton are 12.13 and 10.72 respectively. MS(EI) m/z 687(19),
685(36), 683(16), 526(21), 352(10), 276(23), 226(19), 149(100); HRMS Calc. for
C30H14Br2F8 683.9334, Found 683.9341 (EI); UV (CH2Cl2) λmax 330, 291, 282.
Reaction of cage compound with saturated triplet oxygen: oxygen was bubbled
into 0.5 ml CDCl3 solution of cage compound (5.6mg, 0.01mmol) in 5mm NMR tube at
room temperature over night. Yields were determined by internal standard α,α,α-
trifluoromethyl toluene by 19F NMR. The mixture was separated by preparative TLC
plates after the starting material was completely consumed. Epoxide and chlorine adducts
were obtained in 21% and 52% yield respectively. 1H NMR (500MHz, CDCl3/TMS) δ
7.23(m, 2H), 7.09(m, 2H), 6.89(s, 2H), 6.88(s, 2H), 6.65(, m, 2H), 5.30(s, 2H), 5.16(m,
2H); 13C NMR (126MHz, CDCl3) δ 142.7, 142.1, 139.5, 137.0, 132.6, 128.1, 127.9,
127.5, 120.t5, 120.4, 78.3, 54.4, 50.3; 19F NMR (282MHz, CDCl3/CFCl3) δ-107.43, -
112.21(AB, J=243.93Hz, 4F), -107.53, -112.47(AB, J=241.1Hz, 4F), the splitting of
fluorine by proton is 12.13, 15.23Hz respectively. MS(EI) m/z 598(25), 597(11),
596(M+)(37), 370(100), 276(33), 226(28), 149(44); HRMS Calc. for C30H14Cl2F8
596.0345, Found 596.0353 (EI).
Photooxygenation of cage: a 0.5 ml CDCl3 solution of cage compound (3 mg,
0.006mmol) containing rose Bengal (5 mg) was immersed into a flow-cooling water bath
to keep vessel at room temperature. Oxygen was bubbled into the solution through a long
metal needle while the solution is irradiated by a 250W Sylavi mercury lamp through a
0.05M K2Cr2O7 solution filter. Reaction is complete after 5 h with 66% of epoxide and
33% of diketone obtained. The products were separated by preparative silica gel TLC
141
plates. Diketone 15: 1H NMR (500MHz, CDCl3/TMS) δ 7.58(m, 2H), 7.29(m, 2H),
7,26(s, 2H), 7.25(s, 2H), 5.85(d, J=4.5Hz, 2H), 5.68(s, 2H), 5.09(d, J=3.6Hz, 2H); 19F
NMR (282MHz, CDCl3/CFCl3) δ -106.16(d, J=250.1Hz, 2F), -106.18(d, J=249.0Hz, 2F),
-109.73(d, J=240.8Hz, 2F), -110.26(d, J=241.7Hz, 2F). The coupling constant CFH is
19.4Hz; 13C NMR (126MHz, CDCl3) δ 193.7, 136.3, 136.3, 135.6, 135.4, 131.2, 130.2,
130.3, 129.3, 128.7, 127.5, 120.7, 120.7, 56.2, 54.5; MS (EI) m/z 558 (M+)(3), 276(100),
226(63); HRMS Calc for C30H14O2F8 558.0866, Found 558.0892 (EI).
APPENDIX X-RAY DATA
Figure 1: X-ray of octafluoro[2.2]parcyclophane aryne with [2.2]paractclophane
adduct
142
143
Table 1. Crystal data and structure refinement for yz02.
Identification code yz02 Empirical formula C32 H22 F8 Formula weight 558.50 Temperature 193(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 7.4353(4) Å α= 104.106(1)°. b = 11.4074(5) Å β= 97.453(1)°. c = 15.4130(7) Å γ = 104.071(1)°. Volume 1204.8(1) Å3 Z 2 Density (calculated) 1.540 Mg/m3 Absorption coefficient 0.132 mm-1 F(000) 572 Crystal size 0.32 x 0.19 x 0.12 mm3 Theta range for data collection 1.39 to 27.49°. Index ranges -9≤h≤9, -14≤k≤14, -20≤l≤19 Reflections collected 10991 Independent reflections 5421 [R(int) = 0.0275] Completeness to theta = 27.49° 98.0 % Absorption correction Integration Max. and min. transmission 0.9872 and 0.9563 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5421 / 0 / 361 Goodness-of-fit on F2 1.026 Final R indices [I>2sigma(I)] R1 = 0.0467, wR2 = 0.1173 [4305] R indices (all data) R1 = 0.0600, wR2 = 0.1264 Largest diff. peak and hole 0.308 and -0.246 e.Å-3
R1 = ∑(||Fo| - |Fc||) / ∑|Fo| wR2 = [∑[w(Fo2 - Fc2)2] / ∑[w(Fo2)2]]1/2
S = [∑[w(Fo2 - Fc2)2] / (n-p)]1/2
w= 1/[σ2(Fo2)+(0.0540*p)2+0.61*p], p = [max(Fo2,0)+ 2* Fc2]/3
144
Figure 2 : X-ray of octafluoro[2.2]parcyclophane aryne with anthracene adduct
145
Table 2. Crystal data and structure refinement for yz03. Identification code yz03t Empirical formula C28 H16 F8 Formula weight 504.41 Temperature 193(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 8.9041(5) Å α= 101.308(1)°. b = 9.3253(5) Å β= 91.161(1)°. c = 14.3897(8) Å γ = 107.872(1)°. Volume 1110.9(1) Å3 Z 2 Density (calculated) 1.508 Mg/m3 Absorption coefficient 0.134 mm-1 F(000) 512 Crystal size 0.23 x 0.11 x 0.10 mm3 Theta range for data collection 1.45 to 27.50°. Index ranges -11≤h≤11, -12≤k≤12, -18≤l≤18 Reflections collected 10130 Independent reflections 5004 [R(int) = 0.0331] Completeness to theta = 27.50° 97.9 % Absorption correction Integration Max. and min. transmission 0.9915 and 0.9717 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 5004 / 0 / 343 Goodness-of-fit on F2 1.066 Final R indices [I>2sigma(I)] R1 = 0.0413, wR2 = 0.1035 [3846] R indices (all data) R1 = 0.0598, wR2 = 0.1162 Largest diff. peak and hole 0.299 and -0.237 e.Å-3 R1 = ∑(||Fo| - |Fc||) / ∑|Fo| wR2 = [∑[w(Fo2 - Fc2)2] / ∑[w(Fo2)2]]1/2
S = [∑[w(Fo2 - Fc2)2] / (n-p)]1/2
w= 1/[σ2(Fo2)+(0.0464*p)2+0.55*p], p = [max(Fo2,0)+ 2* Fc2]/3
146
Figure 3 : X-ray of octafluoro[2.2]parcyclophane aryne with furan adduct:exo
isomer
147
Table 3. Crystal data and structure refinement for yz04. Identification code yz04 Empirical formula C20 H10 F8 O Formula weight 418.28 Temperature 193(2) K Wavelength 0.71073 Å Crystal system Trigonal Space group P3(2)21 Unit cell dimensions a = 9.2358(4) Å α= 90°. b = 9.2358(4) Å β= 90°. c = 33.198(2) Å γ = 120°. Volume 2452.4(2) Å3 Z 6 Density (calculated) 1.699 Mg/m3 Absorption coefficient 0.167 mm-1 F(000) 1260 Crystal size 0.19 x 0.11 x 0.08 mm3 Theta range for data collection 1.84 to 27.50°. Index ranges -11≤h≤12, -11≤k≤12, -42≤l≤42 Reflections collected 21640 Independent reflections 3743 [R(int) = 0.0437] Completeness to theta = 27.50° 100.0 % Absorption correction Integration Max. and min. transmission 0.9874 and 0.9725 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 3743 / 0 / 265 Goodness-of-fit on F2 1.080 Final R indices [I>2sigma(I)] R1 = 0.0424, wR2 = 0.0929 [3036] R indices (all data) R1 = 0.0583, wR2 = 0.1029 Absolute structure parameter 0.3(7) Extinction coefficient 0.0082(8) Largest diff. peak and hole 0.345 and -0.372 e.Å-3 R1 = ∑(||Fo| - |Fc||) / ∑|Fo| wR2 = [∑[w(Fo2 - Fc2)2] / ∑[w(Fo2)2]]1/2
S = [∑[w(Fo2 - Fc2)2] / (n-p)]1/2
w= 1/[σ2(Fo2)+(0.0350*p)2+1.31*p], p = [max(Fo2,0)+ 2* Fc2]/3
148
Figure 4: X-ray of octafluoro[2.2]parcyclophane bisaryne with naphtahlene adduct
149
Table 4. Crystal data and structure refinement for yz09. Identification code yz09 Empirical formula C36 H20 F8 Formula weight 604.52 Temperature 193(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 12.4437(7) Å α= 87.693(2)°. b = 13.2605(7) Å β= 78.725(2)°. c = 17.485(2) Å γ = 64.870(2)°. Volume 2558.8(2) Å3 Z 4 Density (calculated) 1.569 Mg/m3 Absorption coefficient 0.131 mm-1 F(000) 1232 Crystal size 0.24 x 0.19 x 0.11 mm3 Theta range for data collection 1.19 to 27.50°. Index ranges -8≤h≤16, -16≤k≤17, -21≤l≤22 Reflections collected 17002 Independent reflections 11267 [R(int) = 0.0266] Completeness to theta = 27.50° 95.9 % Absorption correction Analytical Max. and min. transmission 0.9888 and 0.9607 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 11267 / 0 / 793 Goodness-of-fit on F2 1.017 Final R indices [I>2sigma(I)] R1 = 0.0394, wR2 = 0.0963 [8161] R indices (all data) R1 = 0.0617, wR2 = 0.1062 Largest diff. peak and hole 0.304 and -0.223 e.Å-3 R1 = ∑(||Fo| - |Fc||) / ∑|Fo| wR2 = [∑[w(Fo2 - Fc2)2] / ∑[w(Fo2)2]]1/2
S = [∑[w(Fo2 - Fc2)2] / (n-p)]1/2
w= 1/[σ2(Fo2)+(0.522*p)2+0.4421*p], p = [max(Fo2,0)+ 2* Fc2]/3
150
Figure 5: X-ray of octafluoro[2.2]parcyclophane ortho-bis-aryne with anthracene
adduct
151
Table 5. Crystal data and structure refinement for yz17. Identification code yz17 Empirical formula C30 H14 F8 Formula weight 526.42 Temperature 173(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 9.3031(5) Å α= 90°. b = 14.1979(8) Å β= 104.872(2)°. c = 16.3548(9) Å γ = 90°. Volume 2087.9(2) Å3 Z 4 Density (calculated) 1.675 Mg/m3 Absorption coefficient 0.147 mm-1 F(000) 1064 Crystal size 0.27 x 0.19 x 0.17 mm3 Theta range for data collection 1.93 to 27.50°. Index ranges -10<=h<=12, -18<=k<=18, -20<=l<=21 Reflections collected 13606 Independent reflections 4738 [R(int) = 0.0405] Completeness to theta = 27.50° 98.8 % Absorption correction Integration Max. and min. transmission 0.9781 and 0.9633 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4738 / 0 / 419 Goodness-of-fit on F2 1.177 Final R indices [I>2sigma(I)] R1 = 0.0599, wR2 = 0.1303 [4088] R indices (all data) R1 = 0.0700, wR2 = 0.1355 Largest diff. peak and hole 0.351 and -0.268 e.Å-3
R1 = ∑(||Fo| - |Fc||) / ∑|Fo| wR2 = [∑[w(Fo2 - Fc2)2] / ∑[w(Fo2)2]]1/2
S = [∑[w(Fo2 - Fc2)2] / (n-p)]1/2
w= 1/[σ2(Fo2)+(0.0540*p)2+0.61*p], p = [max(Fo2,0)+ 2* Fc2]/3
152
Figure 6: X-ray of octafluoro[2.2]parcyclophane ortho-bis-aryne with anthracene
adduct epoxide
153
Table 6. Crystal data and structure refinement for yz20. Identification code yz20 Empirical formula C30 H14 F8 O Formula weight 542.41 Temperature 173(2) K Wavelength 0.71073 Å Crystal system Monoclinic Space group P2(1)/n Unit cell dimensions a = 9.2818(7) Å α= 90°. b = 14.745(2) Å β= 105.490(2)°. c = 15.9431(11) Å γ = 90°. Volume 2102.8(3) Å3 Z 4 Density (calculated) 1.713 Mg/m3 Absorption coefficient 0.152 mm-1 F(000) 1096 Crystal size 0.32 x 0.20 x 0.19 mm3 Theta range for data collection 1.91 to 28.03°. Index ranges -12≤h≤12, -19≤k≤19, -21≤l≤20 Reflections collected 18286 Independent reflections 4929 [R(int) = 0.0332] Completeness to theta = 28.03° 97.0 % Absorption correction Integration Max. and min. transmission 0.9750 and 0.9590 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 4929 / 0 / 352 Goodness-of-fit on F2 1.060 Final R indices [I>2sigma(I)] R1 = 0.0430, wR2 = 0.1149 [4138] R indices (all data) R1 = 0.0517, wR2 = 0.1206 Largest diff. peak and hole 0.320 and -0.285 e.Å-3 R1 = ∑(||Fo| - |Fc||) / ∑|Fo| wR2 = [∑[w(Fo2 - Fc2)2] / ∑[w(Fo2)2]]1/2
S = [∑[w(Fo2 - Fc2)2] / (n-p)]1/2
w= 1/[σ2(Fo2)+(m*p)2+n*p], p = [max(Fo2,0)+ 2* Fc2]/3, m & n are constants.
154
Figure 7: X-ray of octafluoro[2.2]parcyclophane ortho-bis-aryne with anthracene
adduct dichloride
155
Table 7. Crystal data and structure refinement for yz25. Identification code yz25 Empirical formula C30 H16 Cl2 F8 Formula weight 1797.98 Temperature 173(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P1 Unit cell dimensions a = 9.2819(5) Å α= 83.289(1)°. b = 9.7160(6) Å β= 80.492(1)°. c = 21.2585(12) Å γ = 64.244(1)°. Volume 1700.78(17) Å3 Z 3 Density (calculated) 1.755 Mg/m3 Absorption coefficient 0.374 mm-1 F(000) 906 Crystal size 0.20 x 0.14 x 0.08 mm3 Theta range for data collection 0.97 to 27.50°. Index ranges -11≤h≤12, -12≤k≤12, -27≤l≤27 Reflections collected 15109 Independent reflections 13236 [R(int) = 0.0284] Completeness to theta = 27.50° 96.4 % Absorption correction Integration Max. and min. transmission 0.9723 and 0.9254 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 13236 / 3 / 1081 Goodness-of-fit on F2 0.913 Final R indices [I>2sigma(I)] R1 = 0.0602, wR2 = 0.1575 [11283] R indices (all data) R1 = 0.0688, wR2 = 0.1664 Absolute structure parameter -0.01(5) Largest diff. peak and hole 1.295 and -0.682 e.Å-3 R1 = ∑(||Fo| - |Fc||) / ∑|Fo| wR2 = [∑[w(Fo2 - Fc2)2] / ∑[w(Fo2)2]]1/2
S = [∑[w(Fo2 - Fc2)2] / (n-p)]1/2
w= 1/[σ2(Fo2)+(m*p)2+n*p], p = [max(Fo2,0)+ 2* Fc2]/3, m & n are constants.
156
Figure 8 X-ray of dimer of anthraceno[2.2]parcyclophane 12
157
Table 8. Crystal data and structure refinement for yz27. Identification code yz27 Empirical formula C97.50 H51 Cl3 F32 Formula weight 1936.73 Temperature 173(2) K Wavelength 0.71073 Å Crystal system Triclinic Space group P-1 Unit cell dimensions a = 10.4307(6) Å α= 77.937(2)°. b = 19.5561(11) Å β= 84.115(2)°. c = 19.6381(11) Å γ = 87.310(2)°. Volume 3895.4(4) Å3 Z 2 Density (calculated) 1.651 Mg/m3 Absorption coefficient 0.248 mm-1 F(000) 1950 Crystal size 0.21 x 0.10 x 0.09 mm3 Theta range for data collection 1.07 to 27.50°. Index ranges -13≤h≤12, -21≤k≤25, -25≤l≤25 Reflections collected 25923 Independent reflections 17167 [R(int) = 0.0362] Completeness to theta = 27.50° 95.8 % Absorption correction Integration Max. and min. transmission 0.9805 and 0.9508 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 17167 / 0 / 1180 Goodness-of-fit on F2 0.787 Final R indices [I>2sigma(I)] R1 = 0.0415, wR2 = 0.0900 [8451] R indices (all data) R1 = 0.0919, wR2 = 0.0969 Largest diff. peak and hole 0.354 and -0.475 e.Å-3 R1 = ∑(||Fo| - |Fc||) / ∑|Fo| wR2 = [∑[w(Fo2 - Fc2)2] / ∑[w(Fo2)2]]1/2
S = [∑[w(Fo2 - Fc2)2] / (n-p)]1/2
w= 1/[σ2(Fo2)+(m*p)2+n*p], p = [max(Fo2,0)+ 2* Fc2]/3, m & n are constants.
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BIOGRAPHICAL SKETCH
Zhai Yi-An was born in Xupu, Hunan Province, P. R. China. He received his B.S. in
chemistry and M. S. in organic chemistry from Xiangtan University in July 1993 and
Shanghai University in March 1996, respectively. After four years working in Shanghai
Institute of Organic Chemistry in China, he came to the University of Florida as a
research scholar in Dolbier’s group. He became a graduate student of organic chemistry
in Spring 2002 and joined Prof. William R. Dolbier, Jr.’s lab. Yian Zhai will receive his
Ph.D. in May 2005.
174