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Superacid promoted synthetic transformations and the development of new solid supported Brønsted acids

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Superacid promoted synthetic transformations and the development of new solid supported Brønsted acids

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SUPERACID PROMOTED SYNTHETIC TRANSFORMATIONS AND THE
DEVELOPMENT OF NEW SOLID SUPPORTED BRØNSTED ACIDS

by

Kevin E. Glinton

A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)

August 2010

Copyright 2010 Kevin E. Glinton
ii
DEDICATION

For
Helen and Ozzie,
Edna and Chile
Thank You Always

iii
ACKNOWLEDGMENTS

It is said that no one ever really succeeds in a vacuum and I most certainly would
not have been able to complete this work without the help and support of many special
individuals. I have to first express my gratitude and appreciation to Prof. G. K. Surya
Prakash for giving me the tremendous opportunity to work in his group here at USC and
Prof. George A. Olah for being a constant source of inspiration and wisdom. They have
both been tremendously supportive and inspiring and I have learned so much because of
them. In addition, I would also like to thank Dr. Thomas Mathew, Dr. Chiradeep Panja
and Dr. Sujith Chacko for their help and direction these past five years and for helping
me become a better researcher and scientist. I would also like to express my appreciation
to Prof. Golam Rasul and Dr. Bo Yang for their hard work, and collaborative efforts on
several projects.
Working in Loker has also been an enjoyable experience thanks to the many kind
and giving people who work there including Dr. Robert Anizfeld, Ms. Jessie May, Mrs.
Carole Phillips, Mr. Ralph Pan and Mr. David Hunter along with Michele Dea, Heather
Connor and Katie McKissick from the Chemistry Department. I am also grateful to my
friends and coworkers, Dr. Habiba Vaghoo, Mr. Clement Do, Dr. Rehana Ismael, Dr.
Alain Goeppert and all of the other past and present members of the group for their
camaraderie, help and encouragement.
As well, I would wish to express my gratitude to the amazing teachers I have been
privileged to have throughout my academic career; the late Prof. Robert Bau, Dr. Kyung
Jung, Dr. Katherine Shing and Prof. Nicos Petasis of USC, Prof. Princilla Smart-Evans,
iv
Dr. Robert Wingfield and Dr. Lawrence Pratt of Fisk University and Mrs. Missick and
Mr. Green from all the way back at St. Augustine’s College. They will forever be special
to me for nurturing my love of science and always encouraging me to pursue whatever
dreams I had with hard work and dedication.
Finally, more than anything, I am thankful for the unconditional love and support
I received from those closest to me. My friends Katja, Kyle, Tamara and Laurence have
been amazing for all these years as has my family especially my brother, Kristofor and
sister, Karin. The most important people to me, however, have been my parents who have
never let me give up when things got too challenging and never fail to inspire and
empower. I would not be here without them.
v
TABLE OF CONTENTS

DEDICATION ii

ACKNOWLEDGMENTS iii

LIST OF TABLES viii

LIST OF FIGURES ix

LIST OF SCHEMES x

ABSTRACT xii

1 Chapter 1: Introduction 1
1.1 Chapter 1: Acids - An Overview 1
1.1.1 Superacids and Superelectrophilic Activation 3
1.1.2 Solid Acids as Alternative Catalysts 8
1.2 Chapter 1: Aim and Scope of Present Work 12
1.3 Chapter 1: References 14

2 Chapter 2: Friedel-Crafts Alkylations of Arenes with Mono and
Bis(trifluoromethyl)oxiranes in Superacid Medium 17
2.1 Chapter 2: Introduction 17
2.2 Chapter 2: Results and Discussion 20
2.2.1 Friedel-Crafts Alkylations of Arenes with
Fluorinated Oxiranes 20
2.2.2 Density Functional Theory (DFT) Studies of
Fluorinated Oxiranes 24
2.3 Chapter 2: Conclusion 27
2.4 Chapter 2: Experimental 28
2.4.1 General Remarks 28
2.4.2 Typical Procedure for Friedel-Crafts Reactions
With Fluorinated Epoxides 28
2.4.3 Spectral Data: 29
2.4.4 Representative Spectra: 34
2.5 Chapter 2: References 40

vi
3 Chapter 3: Nafion-H Catalyzed Isomerization of Trifluoromethylated
Benzylimines to Benzaldimines En Route to
α-Trifluoromethylated Amines 42
3.1 Chapter 3: Introduction 42
3.2 Chapter 3: Results and Discussion 44
3.3 Chapter 3: Conclusion 51
3.4 Chapter 3: Experimental 52
3.4.1 General Remarks 52
3.4.2 Typical Procedure for the Synthesis of Substituted Imines 52
3.4.3 Typical Procedure for the Hydrolysis of Substituted Imines 53
3.4.4 Spectral Data: 53
3.4.5 Representative Spectra: 57
3.5 Chapter 3: References 60

4 Chapter 4: Superacid Assisted Aromatic Sulfonation and
Alkylsulfonation Reactions towards the Sulfonation
of Proton Exchange Fuel Cell Membranes 62
4.1 Chapter 4: Introduction 62
4.2 Chapter 4: Results and Discussion 65
4.2.1 Superacid Assisted Synthesis of Symmetrically Substituted Diaryl
Sulfones 65
4.2.2 Superacid Assisted Synthesis of Thiochroman-dioxides 70
4.2.3 Sulfonation and Alkylsulfonation of Polymer Membranes 74
4.3 Chapter 4: Conclusion 80
4.4 Chapter 4: Experimental 81
4.4.1 General Remarks 81
4.4.2 General Procedure for the Synthesis of Substituted
Diaryl Sulfones 81
4.4.3 General Procedure for the Synthesis of Thiochroman-dioxides 82
4.4.4 General Procedure for the Sulfonation of Aromatic
Polymer Membranes 82
4.4.5 Representative Spectra 84
4.5 Chapter 4: References 88

5 Chapter 5: The Development of Solid Supported Bronsted Acids
towards new Aromatic Nitrating Agents:
PVP:HNO
3
, PVP:H
2
SO
4
and PVPNM 91
5.1 Chapter 5: Introduction 91
5.2 Chapter 5: Results and Discussion 93
5.3 Chapter 5: Conclusion 102
5.4 Chapter 5: Experimental 103
5.4.1 General Remarks 103
5.4.2 Typical Preparation of PVP:HNO
3
complex 103
vii
5.4.3 Typical Preparation of PVP:HNO
3
:H
2
SO
4
complex 103
5.4.4 General Procedure for the Nitration of Aromatic
Compounds With PVP:HNO
3
and PVP:H
2
SO
4
104
5.4.5 General Procedure for the Nitration of Aromatic
Compounds With PVP:HNO
3
:H
2
SO
4
104
5.5 Chapter 5: References 106

6 Chapter 6: The Expanded use of PVD:H
2
O
2
and PVP:H
2
O
2

in Oxidation Reactions 108
6.1 Chapter 6: Introduction 108
6.2 Chapter 6: Results and Discussion 112
6.2.1 Selective Oxidation of Sulfides to Sulfoxides 112
6.2.2 Oxidation of Ketones to gem-Diperoxides 118
6.3 Chapter 6: Conclusion 122
6.4 Chapter 6: Experimental 123
6.4.1 General Remarks 123
6.4.2 General Procedure for the Oxidation of Sulfides to Sulfoxides 123
6.4.3 General Procedure for the Oxidation of
Ketones to gem-Diperoxides 124
6.4.4 Representative Spectra: 125
6.5 Chapter 6: References 129

7 Chapter 7: Aminomethylated Poly(styrene)-Hydrofluoric Acid
Complex and its use in One-Carbon Ring
Homologation Reactions 133
7.1 Chapter 7: Introduction 133
7.2 Chapter 7: Results and Discussion 135
7.3 Chapter 7: Conclusion 141
7.4 Chapter 7: Experimental 142
7.4.1 General Remarks 142
7.4.2 General Procedure for the Synthesis of
Aminomethylated(Polystyrene): Poly(Hydrogen Fluoride) 142
7.4.3 General Procedure for the Fluorination of Substituted Alcohols 142
7.4.4 General Procedure for the Synthesis of Homoadamantane 143
7.5 Chapter 7: References 144

BIBLIOGRAPHY 146

viii
LIST OF TABLES

Table 2.1 – Friedel-Crafts Alkylations of 2-Trifluoromethyloxirane 22
Table 2.2 – Friedel-Crafts Alkylations of 2,2-Bis(Trifluoromethyl)oxirane 23
Table 2.3 – Computed Geometries of Neutral Epoxides 25
Table 2.4 – Computed Geometries of O-Protonated Epoxides 26
Table 3.1 – Imine Formation and Rearrangement with Benzylamines 47
Table 3.2 – Reaction with Various Trifluoromethylated Acetophenones 49
Table 3.3 – Hydrolysis of Various Trifluoromethylated Benzaldimines 50
Table 4.1 – Pyridine-SO
3
Aromatic Sulfonylation Reaction 69
Table 4.2 – Aromatic Alkyl-Sulfonylation Reaction 73
Table 4.3 – Polymer Acidity after Superacidic Sulfonation with Pyridine-SO
3
76
Table 4.4 – Polymer Acidity after Superacidic Alkyl-Sulfonation 79
Table 4.5 – Polymer Acidity after Superacidic Arylation of Alkenes 80
Table 5.1 – Nitration Reactions with PVP:HNO
3
and PVP:H
2
SO
4
100
Table 5.2 – Nitration Reactions with PVP:HNO
3
:H
2
SO
4
101
Table 6.1 – PVD:H
2
O
2
Oxidation of Sulfides 116
Table 6.2 – PVP:H
2
O
2
Oxidation of Sulfides 117
Table 6.3 – Acid Catalyzed Synthesis of gem-Dihydroperoxides 121
Table 7.1 – AMPS:HF Catalyzed Alkylation of Isobutane with Isobutylene 136
Table 7.2 – AMPS:HF Reactions with Alcohols 137
ix
LIST OF FIGURES

Figure 1.1 – Acidity Range of Selected Superacids ........................................................... 5
Figure 1.2 – Common Inorganic Solid Acids .................................................................. 10
Figure 1.3 – Common Organic Solid Acids ..................................................................... 11
Figure 2.1 – Optimized Geometries of Selected Neutral Epoxides ................................. 25
Figure 2.2 – Optimized Geometries of Selected O-Protonated Epoxides ........................ 27
Figure 3.1 – Structure of Nafion
®
.................................................................................... 45
Figure 4.1 – Alternative Polyaromatic Sulfonic Acid Membranes .................................. 63
Figure 4.2 – Common Sulfone Containing Compounds .................................................. 65
Figure 4.3 – Poly(vinylidinefluoride) - Polystyrene ........................................................ 74
Figure 4.4 – Performance of PVP-SO
3
Sulfonated Membrane ........................................ 77
Figure 5.1 – Acid-Functionalized Polymeric Reagents ................................................... 94
Figure 5.2 – Acid-Functionalized Poly(vinyl pyridines) ................................................. 95
Figure 5.3 – PVP:HNO
3
................................................................................................... 96
Figure 5.4 – Surface Morphology of PVP (a) and PVP:HNO
3
(b) .................................. 97
Figure 5.5 – PVP:H
2
SO
4
.................................................................................................. 97
Figure 5.6 – Surface Morphology of PVP (a) and PVP:H
2
SO
4
(b) .................................. 97
Figure 5.7 – PVP:HNO
3
:H
2
SO
4
....................................................................................... 98
Figure 5.8 – Surface Morphology of PVP (a) and PVP:HNO
3
:H
2
SO
4
(b)....................... 98
Figure 6.1 – Calculated Structures of N-Ethylpyrrolidone
and 4-Ethylpyridine H
2
O
2
Complexes .................................................... 111
Figure 6.2 – Artemisinin and Related Anti-Malarial Compounds ................................. 119
Figure 7.1 – Common HF:Amine Complexes ............................................................... 135

x
LIST OF SCHEMES

Scheme 1.1 – Protonitronium Cation and Reaction with Methane 6
Scheme 1.2 – Synthesis of Substituted Benzophenones 6
Scheme 1.3 – Synthesis of Substituted Tetrahydro-Isoquinolines
and Benzophenones 7
Scheme 2.1 – General Acid Catalyzed Ring-Opening of
Electron Poor Epoxides 18
Scheme 2.2 – Triflic Acid Catalyzed Alkylations Utilizing Glycidates 20
Scheme 3.1 – Biomimetic Reductive Amination 43
Scheme 3.2 – Synthesis of Trifluoromethylated Benzylimines 46
Scheme 4.1 – Electrophilic Aromatic Sulfonation 64
Scheme 4.2 – Mechanism of Pyridine-SO
3
Sulfonylation Reaction 68
Scheme 4.3 – Aluminium Chloride Catalyzed Alkylation of Butane Sultone 71
Scheme 4.4 – Mechanism of Propane Sultone Ring Alkyation and Closing 72
Scheme 4.5 – Sulfonation of Polymers by Superacidic
Activation of Pyridine-SO
3
76
Scheme 4.6 – Superacid Assisted Alkyl-Sulfonation of Polymers 78
Scheme 4.7 – Superacid Assisted Perfluoroalkyl-sulfonation of Polystyrene 79
Scheme 4.8 – Superacid Assisted Activation and Arylation of Alkenes 80
Scheme 5.1 – Hughes-Ingold Mechanism of Electrophilic Aromatic Nitration 92
Scheme 6.1 – ipso-Hydroxylation of Arylboronic Acids
and Solid H
2
O
2
Complexes 112
Scheme 6.2 – Oxidation of Sulfides with Urea:H
2
O
2
114
Scheme 6.3 – Oxidation of Sulfides with Thiourea and TBHP 114
Scheme 6.4 – Oxidation of Sulfides With PVD:H
2
O
2
115
Scheme 6.5 – Synthesis of gem-Dihydroperoxides under Acidic Conditions 120
xi
Scheme 7.1 – Synthesis of Aminomethylated(Polystyrene):HF Complex 136
Scheme 7.2 – Koch-Haas Carboxylation of 1-Methyladamantanol 139
Scheme 7.3 – Synthesis of Amino-Substituted Homoadamantanes 139
Scheme 7.4 – Transformations of 1-Adamantanemethanol 140
Scheme 7.5 – Generation of Homoadamantane 141

xii
ABSTRACT

The following dissertation describes the development of several new
transformations by the application of a wide range of superacid catalysts and reagent
systems for many potential synthetic reactions. The synthesis of some new and novel
solid Brønsted acids and their applications in a number of classical organic reactions are
also reported in detail. In Chapter 1, a brief overview and history of acids and superacids
are given including their different forms and classifications. The strengths of acids and
the acidity function are also briefly highlighted along with the importance and application
of superacids in organic reactions. Finally, the properties of solid acids and their recent
emergence as eco-friendly catalytic alternatives are outlined.
The discussion of new superacid-assisted reactions begins with Chapter 2 in
which the triflic acid catalyzed Friedel-Crafts alkylation of aromatics with mono and
bis(trifluoromethyl)oxiranes is detailed. Ring opening reactions of these substrates
afforded fluorinated β-phenylethanols in excellent yields. The regioselectivity of oxirane
ring opening and subsequent Friedel-Crafts alkylation were found to depend upon
electronic and steric contributions from the substituents in the oxirane ring which were
further explored through DFT studies. Chapter 3 expounds the Nafion-H
®
catalyzed
synthesis of trifluoromethyl imines from benzylamine derivatives and trifluoromethylated
ketones. The formation of fluorinated benzaldimines occurs primarily by a previously
unreported, acid-catalyzed 1, 3-hydrogen shift. Fluorinated benzaldimines may
subsequently be converted to pharmaceutically important α-trifluoromethylated amines.
xiii
Chapter 4 summarizes the triflic acid catalyzed sulfonation and alkyl-sulfonation
of proton exchange membranes and new synthetic pathways to substituted diarylsulfones
and thiochroman dioxides. These reactions are considered new examples of direct
Friedel-Crafts cycli-alkyl-sulfonation. Reactions between Polyvinylidene Fluoride –
Polystyrene (PVDF-PS) and various reagents, under superacidic conditions, lead to
polymeric sulfonic acids while reactions with monomeric aromatics under similar
conditions lead to diaryl sulfones or thiochroman dioxides.
Chapter 5 describes the synthesis of polymer-bound Brønsted acids and their use
as convenient alternatives to liquid acids. Nitric acid and sulfuric acids have been
combined, both individually and as a mixture, with poly(4-vinyl pyridine). The new solid
acid systems have been used to nitrate several substituted arenes and proved to be quite
effective nitrating agents. In, Chapter 6, the complexes formed between hydrogen
peroxide (H
2
O
2
) and poly(N-vinyl pyrrolidone) (PVD) or poly(4-vinyl pyridine) (PVP)
have been revealed as successful solid H
2
O
2
equivalents. The complexes are used in the
selective oxidation of sulfides to sulfoxides and in the synthesis of gem-diperoxides from
ketones. The complexes proved to be convenient, safe and tolerant of a variety of
substituents. Finally, Chapter 7 discusses the use of (aminomethyl)polystyrene as an
efficient reservoir for anhydrous HF as the polymer forms ionic solid HF complexes with
varying amounts of anhydrous HF. The complexes can be used as a catalyst for
isobutylene alkylation as well as a convenient fluoride source for the fluorination of
alcohols. Interestingly, treatment of 1-adamantanemethanol with the reagent results in its
unexpected ring expansion to homoadamantane involving carbocationic intermediates.

1
1 Chapter 1: Introduction

1.1 Chapter 1: Acids – An Overview
Acids are the most intriguing and beguiling species found in nature. Derived from
the Latin word for “sour,” acids were commonly encountered compounds in everyday
human life. Citric acid for instance, is found in fruits while acetic acid was, and still is,
formed during the fermentation process and lactic acid is produced in our own bodies
during glucose metabolism. And beyond biological applications, early alchemists were
even known to utilize mineral acid based aqua regia, an equal parts mixture of
concentrated hydrochloric and nitric acids, in the isolation of gold and platinum. For
centuries, however, scientists struggled over how to properly classify these compounds.
Lavoisier
1
for instance proposed that acids were primarily formed when elements reacted
with oxygen and were then dissolved in water though this failed to account for organic
acids and those not containing oxygen at all. Later, Arrhenius
1
proposed that acids
produce hydronium ions (H
3
O
+
) in water in contrast to bases that produce hydroxide ions
(OH
-
). Though this represented an important development in the field of physical organic
chemistry, such a definition still could not adequately account for the behavior of acids in
non-aqueous solvents.
Arrhenius’ theories on dissociation were, however, useful as the basis for one of
our current definitions of acids. As described by J. N. Brønsted and T. M. Lowry, acids
are, essentially, compounds capable of releasing a proton while bases are compounds
capable of accepting said proton.
2,3
Such a definition allowed for the diverse array of
2
acidic species from mineral acids to biologically important nucleic and phosphoric acids
while diminishing the importance of water. Around the same time, G. N. Lewis proposed
his version of acid-base theory
4
whereby, he concluded, acids are compounds capable of
accepting an electron pair while bases are compounds capable of donating an electron
pair. Lewis’ definition allowed for the inclusion of many other compounds like aluminum
chloride (AlCl
3
) and boron trifluoride (BF
3
), as acids and together, the two distinct yet
complementary theories (Brønsted-Lowry and Lewis) have formed the basis of our
understanding of acid-base chemistry today.
With suitable definitions at hand, the next challenge for chemists was to properly
quantify the acidity function or acid strength of various acids. For Lewis acids, “strength
measurements” have not been easy as no single method has thus far been shown feasible.
Some relative conclusions, for instance, can be made based on the coordinating ability of
Lewis acids using the concepts of “hard and soft” acids and bases.
5
Similar measurements
have been proposed by Christe and co-workers who have detailed a Lewis acidity scale
based on a molecule’s affinity for the fluoride ion (F
-
).
6
However, both theories, and the
ones proposed by many others, can give insight into the reactivity of Lewis acids, though
no absolute scale has thus far proven fully reliable and general.
On the other hand, quantitative acidity measurements of Brønsted acids (proton
donor acids) were found to be rather simpler than those of Lewis acids as it involves
proton transfer as a common denominator. For dilute, weakly acidic solutions, the
concentration of hydronium ions can be estimated and used to calculate the
corresponding pH and pK
a
values. However, as one approaches acids of greater strength,
higher concentrations and those in non-aqueous solutions, the Hammett acidity function
3
(H
0
) must be used instead.
7
Acidity function calculations rely primarily upon the so called
“hydrogen-ion activity” which approximately defines the extent to which the acid in
question will protonate a given base.
8
The calculations also take into account the solvent
used and has been shown to converge with pH values even at much lower concentrations
making Hammett’s function a powerful and indispensible tool.
9,10
By using both scales
the strengths of many different acids can now be compared, from weakly acidic carbon
acids to those known colloquially as superacids.

1.1.1 Superacids and Superelectrophilic Activation
The term “superacid” was first used by J. B. Conant and Norris F. Hall in 1927, to
describe several acids capable of forming salts with very weak bases in glacial acetic
acid.
11,12
Later, R. J. Gillespie and T. E. Peel proposed 100% sulfuric acid as the lower
limit of superacidity and, though entirely arbitrary at the time, it is this definition that has
endured to this day.
13
Indeed, some of the earliest and best-studied superacidic systems
were variations of sulfuric acid and oleum. However, even though they seemed to possess
near limitless potential, superacids remained very much underutilized until the 1960’s
when Olah and coworkers began to probe the role of newly discovered carbocationic
species and use them in organic reactions.
14
Since then, not only have dozens of new
superacids been developed, but the field of superacid catalyzed reactions has blossomed
to include numerous transformations.
In accordance with Gillespie’s definition (H
0
≤ -12), many superacids have been
discovered over the past few decades. Along with sulfuric acid and oleum, there are also
halogenated sulfonic acids like fluorosulfonic (FSO
3
H), chlorosulfonic (ClSO
3
H) and
4
trifluoromethanesulfonic acids (CF
3
SO
3
H). Later, Olah and coworkers proposed that
Lewis acids more acidic than aluminum chloride (AlCl
3
) be termed superacids as well.
15

Lewis superacids have thus grown to include such compounds as the fluorides of
antimony (SbF
5
), tantalum (TaF
5
) and arsenic (AsF
5
) along with boron trifluoride (BF
3
)
and many of the newly synthesized carborane molecules.
16,17,18
However, some of the
strongest acid systems known have been made by combining strong Lewis and Brønsted
acids, forming conjugate Brønsted acids.
Lewis acids like SbF
5
, TaF
5
and AsF
5
for instance, can be dissolved in hydrogen
fluoride (HF)
19
and similar systems have also been prepared by adding HF or sulfur
trioxide (SO
3
) to other Brønsted acids as well. More extreme H
0
values, however, have
been reached by combining SbF
5
or AsF
5
with FSO
3
H or HF. The aptly named “Magic
Acid” discovered by Olah for instance, is an extremely acidic mixture of FSO
3
H and
SbF
5
used in much of his pioneering work with carbocation generation. The mixture has
even been postulated to possess H
0
values of up to -27 depending upon the molar
concentration of each constituent though only values between -23 and -25 have been
directly observed. Magic Acid and similar solutions of SbF
5
in HF represent the upper
limit for so-called “classical” superacid systems with higher acidity functions rarely
encountered outside of theoretical calculations.
5
Figure 1.1 – Acidity Range of Selected Superacids
10 15 20 25 30
H
2
SO
4
SO
3
(50%)
FSO
4
H
SbF
5
(50%) (90%)
(Magic Acid)
CF
3
SO
3
H
SbF
5
(45%)
HF
BF
3
(7%)
HF
SbF
5
(10%) (50%)
* Solid bars indicate experimental results, broken bars indicate theoretical
calculations, numbers in parenthesis indicate percentage of additive
- H
0

One of the defining features of a superacid is its ability to protonate weakly basic
species and form cationic intermediates. These highly reactive intermediates can
sometimes carry multiple positive charges and be surprisingly persistent under suitable
conditions leading to their highly electrophilic species termed “superelectrophiles”.
20

Such species can give tremendous insight into the probable mechanistic pathway of a
given reaction, lend insight in various group or substituent effects and lead to the
formation of many new and valuable products.
Much of the work in this area stemmed from the fervent research efforts of Olah
and coworkers who showed that protosolvated species are more reactive than their
monocharged counterparts.
21
One of their earlier studies, for instance, involved the
superelectrophilic reaction of nitronium salts with methane to produce nitromethane.
22
In
aprotic media, such a reaction was never observed, however, the formation of a doubly
charged intermediate in the presence of superacids like FSO
3
H or HF:BF
3
leads to the
desired product (Scheme 1.1).
6
Scheme 1.1 – Protonitronium Cation and Reaction with Methane
N O O
FSO
3
H
N OH O H C
H
H
H
NO
2
H
CH
2
NO
2
H
CH
3
2+
+
H

Since this work, countless other applications have been found for
superelectrophiles. Friedel-Crafts reactions, for example, have been frequently carried out
due to the moderate nucleophilicity of arenes and the ability of superacids to generate
such reactive species without coordinating or interfering in the reaction. Activated and
deactivated aromatics have been shown to react with carbonyls, carboxylic acids and
alkenes in the presence of superacids and many new protocols have been created as a
result. Methyl benzoate in the presence of superacid, for instance, readily forms two
protosolvated isomers that may both react with an arene to form substituted
benzophenones.
23
The intermediates are so reactive that even deactivated systems like
nitrobenzene are capable of nucleophilic attack (Scheme 1.2).
Scheme 1.2 – Synthesis of Substituted Benzophenones
O
CH
3
O
O
CH
3
OH
O
CH
3
OH
2
O
C
6
H
5
NO
2
H
NO
2
CF
3
SO
3
H

Frequently, tandem-type reactions are also possible after the formation of the
initial superelectrophile. Arylation, for instance, can be followed by intramolecular ring
closing reaction or vice versa as reported by Klumpp and co-workers. In the presence of
triflic acid for example, alkynes bearing an amine functionality first undergo ring closure
and then arylation to yield substituted tetrahydro-isoquinolines (Scheme 1.3a) while the
7
reaction of cinnamic acids results in arylation first and then subsequent ring-closure
(Scheme 1.3b).
24,25
Experimental evidence from kinetic studies has generally shown that
the rates of such reactions are generally H
0
-dependent.
Scheme 1.3 – Synthesis of Substituted Tetrahydro-Isoquinolines and Benzophenones
N
H
TMS
C
6
H
6
, 25 °C
CF
3
SO
3
H
N
H
H
N
H
3
C
Ph
H
a.
OH
O
C
6
H
6
, 25 °C
CF
3
SO
3
H
OH
OH
2
Ph
O
b.

But beyond the field of synthetic organic chemistry, the use of superacids has
expanded to several other areas. Within the petrochemical industry they are used to
convert waste materials into biodiesel and convert saturated hydrocarbons to other
products by isomerization and cracking.
26
And, in materials chemistry, superacids can be
used to polymerize monomers and have even been used to make solutions of single-
walled nanotubes for macroscopic assembly.
27
However, with the growing focus on the
environmental impact of industrial processes, one area that has been somewhat singled
out as important for future development has been solid acids.

8
1.1.2 Solid Acids as Alternative Catalysts
Solid acids, as befitting their title, are simply solids that will readily donate a
proton to or accept an electron pair from a base. Solid acids include naturally occurring
and synthetic compounds like clays, zeolites, metal oxides and salts, along with mixed
metal oxides, cationic exchange resins and acids mounted on inert solid supports.
28

Though each type may feature unique structural or synthetic properties, solid acids can
generally be adequately categorized according to their morphology, Lewis or Brønsted
acidity, strength and the quantity of acid sites. Such considerations can not only help
explain the reactivity of a given solid acid, but may also dictate its synthetic capabilities
for a given reaction. Some solid acids like zeolites for instance, will impose strict size
limitations on reactants due to the nature and shape selectivity of its active sites while,
some “pure” Lewis acids may also possess some Brønsted acid character.
However, while the size of acid sites can be somewhat easily ascertained, the
amount and strength of a solid acid can often be difficult to estimate. The strength of a
solid acid can be determined by its ability to convert an adsorbed neutral base into its
conjugate acid and this adsorption usually takes two similar forms.
29
In the first instance,
the acid is titrated with an amine in the presence of an indicator to give the total number
of sites, distribution and some information about strength but very little about whether the
acid is Lewis or Brønsted. Alternatively, acid sites can be examined by the adsorption
and desorption of a gaseous base. This method can give valuable information about the
behavior of the acid at its actual working temperature though there can be some overlap
between physical and chemical adsorption.
9
Solid acids can also be evaluated on the basis of model reactions. In this method,
the rate of a given reaction can be used to estimate the acidity and selectivity of the acid
in question.
30
Model reactions can include almost any established method like cracking or
alkylations but powerful information has been gleaned from more specific reactions like
hydride transfers and isomerizations.
31
Though somewhat time-consuming and
expensive, modeling can help to reveal the strength, density and nature of the acid unlike
other methods, which may only hint at a few characteristics. Nevertheless, these various
methods used to evaluate solid acid strength have lead to the discovery of countless
acidic species; some of which have even been proposed to be strong enough to be called
solid superacids.
Inorganic solid acids are some of the most fundamental solid acids available and
can be inexpensive, easy to modify and relatively safe to store and use. In general, most
are capable of much the same superelectrophilic activation as their liquid counterparts
with the added benefit that such reactions can sometimes be better controlled and more
selective.
32,33,34,35
Most act primarily as Lewis acids and are derived from the oxides of a
few metals even though most metal oxides are commonly assumed to be either basic or
amphoteric in nature. Oxides of aluminum, zirconium, titanium and silicon in particular
can act as mild acids themselves. More commonly, however, such oxides are encountered
as supports or within the structures of zeolites and clays; many of which can be classified
as superacids based upon their catalytic abilities for various hydrocarbon reactions.
Zeolites, for instance, consist of three-dimensional networks of SiO
4
or AlO
4
frames
while clays consist of multi-layered arrangements of these compounds with magnesium
and other metal oxides and hydroxides present in the framework (Figure 1.2).
10
Figure 1.2 – Common Inorganic Solid Acids
O
Si
O
Al
O
Si
O
H
Acidic Zeolite
O
Zr
O
Zr
O
Zr
O
S
O O
Sulfated Zirconia
Si
O
Si
O
Si
O
Si
O O
O O
Al H
Cl Cl
Silicated Aluminum Chloride
Si O O
F
5
SbO
Si O Al O
O SbF
5
H
H
SbF
5
Treated SiO
2
- Al
2
O
3
Similarly, strongly acidic systems can be created by combining mildly acidic
metal oxides or hydroxides with sulfuric acid or ammonium sulfate (Figure 1.2).
Catalysts like TiO
2
– SO
4
2-
and ZrO
2
– SO
4
2-
are much stronger acids than their parent
metal oxides with approximate H
0
values of -14.5 and -16 respectively.
16,36,37,38
Metal
oxides may also act as supports for strong Lewis acids and help to somewhat moderate
their reactivity as in the cases of both AlCl
3
and SbF
5
.
39,40
In particular, by binding to
silica or other metal surfaces, Brønsted acid sites are often simultaneously created
(Figure 1.2), adding interesting flexibility to the reactivity of such species.
Solid polymeric organic acids on the other hand, are usually composed of acid
groups covalently attached to a polymer and are known to act almost exclusively as
Brønsted acids. Many of these acids were originally used as ion-exchange membranes
and, being very effective in that capacity, it was not until much later that their synthetic
use could be discovered and explored thoroughly.
41

Materials such as Amberlyst
®
and Amberlite
®
are ion-exchange resins based on
sulfonic acid substituted polystyrene, cross-linked with divinylbenzene (Figure 1.3).
42
As
11
with zeolitic catalysts, the reactivity of Amberlyst-type polymers usually depends upon a
reactant’s ability to diffuse through the polymer matrix though with sufficient swelling,
many different reactions are indeed possible.
43

Figure 1.3 – Common Organic Solid Acids
x
SO
3
H
Amberlyst-Type Ionomers
CF
2
CF
2
CF
2
CF
2
CF
2
CF
2
CF
2
OCF
2
CF
2
SO
3
H
m
n
z
Nafion-Type Ionomers

Similar catalysts have been based on perhalogenated acid polymers; the most
common of which are perfluorinated Nafion-H
®
and related species (Figure 1.3).
44

Modeling reactions have shown Nafion-H
®
to be superacidic in character with the acid
groups forming porous ionomeric channels through which reactants can pass with
molecules of water incorporated as well.
45
Though it continues to be one of the most
utilized polymer electrolytes (in fuel cells and electrolyzers) the synthetic utility of
Nafion-H
®
as a catalyst in organic transformations has been extensively investigated.
Like zeolites, Amberlyst membranes and all the other solid acids, Nafions are valued for
their stability, ease of use, recyclability and excellent selectivity.
41,46
Indeed, as a whole,
solid acid compounds represent an encouraging step towards more responsible and
efficient syntheses but as always, there are still substantial areas open for alternatives and
improvements.
12
1.2 Chapter 1: Aim and Scope of Present Work
Chemists have indeed come a very long way in their understanding and use of
acidic species. Drug syntheses, industrial processes and mechanistic studies can now all
be found to involve at least one acid catalyzed step and many organic transformations
have now been shown to be driven through superelectrophilic activation. But, as their
chemical profiles and complexities have grown, many aspects of acids remain open to
exploitation and improvement. The work presented here has, therefore, been carried out
in order to accomplish several key goals. The first is the application of superacids
towards the synthesis of novel fluorinated molecules.
Over the past few decades, the use of fluorine as a substituent in molecules has
seemingly exploded due to the unique properties it can impart in countless
pharmaceuticals, materials and small molecules.
47,48
However, because the natural
abundance of fluorochemicals, apart from certain minerals, remains low, synthesis of
fluorinated molecules became somewhat inevitable. In these synthetic strategies,
superacids thus play an important role. Fluorinated substrates often yield interesting and
reactive superelectrophilic intermediates that often behave differently from other similar
species. The present work aims to make use of these intermediates in the synthesis of
novel fluorinated alcohols and amines.
It is also well known that superelectrophilic activation can play a significant part
in Friedel-Crafts reactions. Another major aim, therefore, is the use of superacids in
Friedel-Crafts reactions towards the development of new sulfonation techniques. As one
of the cornerstones of organic chemistry, the aromatic sulfonation process plays a vital
role throughout industry, academia and the development of alternative energy sources.
13
Superacids can now be used to activate new sulfonic acid sources and yield alternative
pathways to compounds like linear and cyclic sulfones. Finally, the research efforts
outlined will detail the attempts made to create solid versions of traditional strong acids
like sulfuric and nitric acids. Though these species are some of the most ancient and
traditional reagents in organic chemistry, very little about their use, preparation and forms
have changed. However, with growing social and environmental consciousness, the
general public has begun to demand safer and more responsible industrial processes from
its scientists through sustainable development. More and more emphasis is being placed
on renewable and recyclable resources along with safer and less toxic materials. As later
detailed, we have now prepared several solid acids and reagents to help address these
needs. By developing solid versions of these species, it is hoped that effective, powerful
acids as well as reagents can be made lessening many of their difficult handling aspects
and opening up new facets of their characters to study and exploration.
14
1.3 Chapter 1: References

1. Pagni, R. M. Found. Chem. 2009, 11, 43.
2. Bronsted, J. N. Chem. Rev. 1928, 5, 232.
3. Lowry, T. M. Trans. Faraday Soc. 1930, 26, 45.
4. Lewis, G. N. J. Franklin Inst. 1938, 226, 293.
5. Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533.
6. Christe, K. O.; Dixon, D. A.; McLemore, D.; Wilson, W. W.; Sheehy, J. A.;
Boatz, J. A. J. Fluor. Chem. 2000, 101, 151.
7. Hammett, L. P.; Deyrup, A. J. J. Am. Chem. Soc. 1932, 54, 2721.
8. Paul, M. A.; Long, F. A. Chem. Rev. 1957, 57, 1.
9. Hammett, L. P.; Paul, M. A. J. Am. Chem. Soc. 1934, 56, 827.
10. Hammett, L. P.; Paul, M. A. J. Am. Chem. Soc. 1934, 56, 830.
11. Hall, N. F.; Conant, J. B. J. Am. Chem. Soc. 1927, 49, 3047.
12. Conant, J. B.; Hall, N. F. J. Am. Chem. Soc. 1927, 49, 3062.
13. Gillespie, R. J.; Peel, T. E. Adv. Phys. Org. Chem. 1971, 9, 1.
14. Olah, G. A. Agnew. Chem. Int. Ed. 1973, 12, 173.
15. Olah, G. A.; Prakash, G. K. S.; Sommer, J. Science, 1979, 206, 13.
16. Olah, G. A.; Prakash, G. K. S.; Molnár, Á.; Sommer, J. Superacid Chemistry;
John Wiley & Sons, Inc: Hoboken, 2009.
17. Juhasz, M.; Hoffman, S.; Stoyanov, E.; Kim, K.-C.; Reed, C. A. Angew. Chem.
Int. Ed. 2004, 43, 5352
18. Avelar, A.; Tham, F. S.; Reed, C. A. Angew. Chem. Int. Ed. 2009, 48, 3491.
19. Gillespie, R. J.; Liang, J. J. Am. Chem. Soc. 1988, 110, 18.
20. Olah, G. A.; Klumpp, D. A. Acc. Chem. Res. 2004, 37, 211.
21. Olah, G. A. J. Org. Chem. 2001, 66, 5943.

15

22. Olah, G. A.; Germain, A.; Lin, H. C.; Forsyth, D. A. J. Am. Chem. Soc. 1975, 97,
2928.
23. Hwang, J. P.; Prakash, G. K. S.; Olah, G. A. Tetrahedron, 2000, 56, 7199.
24. Klumpp, D. A.; Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.; Dang, H. J. Org.
Chem. 2004, 69, 8108.
25. Rendy, R.; Zhang, Y.; McElrea, A.; Gomez, A.; Klumpp, D. A. J. Org. Chem.
2004, 69, 2340.
26. Fu, B.; Gao, L.; Niu, L.; Wei, R.; Xiao, G. Energy & Fuels, 2009, 23, 569.
27. Davis, V. A.; Parra-Vasquez, A. N. G.; Green, M. J.; Rai, P. K.; Behabtu, N.;
Prieto, V.; Booker, R. D.; Schimdt, J.; Kesselman, E.; Zhou, W.; Fan, H.; Adams,
W. W.; Hauge, R. H.; Fischer, J. E.; Cohen, Y.; Talmon, Y.; Smalley, R. E.;
Pasquali, M. Nature Nanotechnology, 2009, 4, 830.
28. Tanabe, K.; Misono, M.; Ono, Y.; Hattori, H. New Solid Acids and Bases: Their
Catalytic Properties; Elsevier Science: New York, 1989.
29. Gorte, R. J. Cat. Lett. 1999, 62, 1.
30. Guisnet, M. R. Acc. Chem. Res. 1990, 23, 392.
31. Kramer, G. M.; McVicker, G. B. Acc. Chem. Res. 1986, 19, 78.
32. Arata, K. Green Chem. 2009, 11, 1719.
33. Koltunov, K. Y.; Walspurger, S.; Sommer, J. Chem. Commun. 2004, 1754.
34. Clark, J. H.; Macquarrie, D. J. Chem. Commun. 1998, 853.
35. Souna Sido, A. S.; Barbiche, J.; Sommer, J. Chem. Commun. 2010, 46, 2913.
36. Hino, M.; Arata, K.; Chem. Commun. 1979, 1148.
37. Corma, A. Chem. Rev. 1995, 95, 559.
38. Matsuhashi, H.; Miyazaki, H.; Kawamura, Y.; Nakamura, H.; Arata, K. Chem.
Mater. 2001, 13, 3038.
39. Wilson, K.; Clark, J. H. Pure Appl. Chem. 2000, 72, 1313.
40. Marczewski, M.; Dȩ bowiak, M.; Marczewska, H. Phys. Chem. Chem. Phys.
2001, 3, 1103.

16

41. Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis, 1986, 513.
42. Kunin, R.; Meitzner, E. F.; Oline, J. A.; Fisher, S. A.; Frisch, N. I&EC Product
Research and Development, 1962, 1, 140.
43. Chakrabarti, A.; Sharma, M. M. Reactive Polymers, 1993, 20, 1.
44. Ford, W. T. ed. Polymeric Reagents and Catalysts; ACS Symposium Series,
American Chemical Society: Washington, DC, 1986.
45. Mauritz, K. A.; Moore, R. B. Chem. Rev. 2004, 104, 4535.
46. Gelbard, G. Ind. Eng. Chem. Res. 2005, 44, 8468.
47. O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308.
48. Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37,
320.
17
2 Chapter 2: Friedel-Crafts Alkylations of Arenes with
Mono and Bis(trifluoromethyl)oxiranes in Superacid
Medium

2.1 Chapter 2: Introduction
Packing seemingly endless possibilities in only a three atom skeletal core,
epoxides are wonderfully simple, yet indispensible, intermediates in organic synthesis.
Through nucleophilic ring opening reactions, epoxides often yield valuable 1,2-
difunctionalized products of sometimes high regioselectivity and stereoselectivity.
1,2

Because of this, methods are continually being developed to utilize both epoxides and
nucleophiles in a myriad of reactions ranging from simple alkylations to more complex
cascade syntheses of natural products. These reactions are however dependent not so
much on the nucleophile involved, but on the structure and reactivity of the participating
epoxide itself. Much of the chemistry being developed in this area therefore, has centered
on ways to enhance and exploit both the ring strain and electron-deficient nature in
epoxides, hoping to make them more attractive targets for nucleophiles.
Under basic or neutral conditions, ring opening is thought to be governed
primarily by steric interactions between the incoming nucleophile and ring substituents
thereby making it possible to predict products rather simply.
2,3
Under acidic conditions
however, these same predictions are not as easily made. Brønsted or Lewis acid catalysts
are frequently added to epoxides to increase their electrophilicity by drawing electron
density away from one of the carbon centres. This leads to ionic ring opening of one of
the constituent C-O bonds of the molecule but the direction of cleavage depends largely
18
upon factors associated with substituents such as steric interference, conjugative
interactions and polar inductive effects.
3,4
Under the influence of these factors for
instance, some reactions will feature nucleophilic attack at the least substituted carbon
after the formation of a stable ionic intermediate while others may feature attack at the
more substituted carbon in spite of the steric strain encountered.
One interesting variant of these reactions on the other hand, arises when a strong
electron withdrawing group (EWG) lies in the α-position of an epoxide. The results of
acid catalysis in these cases are largely dependent upon electronic factors. Ring opening
resulting from O-protonation will lead to the formation of a carbenium ion in the β β β β-
position to avoid forming a positive charge adjacent to the dipole (Scheme 2.1). Such
outcomes have been well established in early examples of sulfuric acid catalyzed ring
openings and boron trifluoride catalyzed rearrangements of keto epoxides.
5,6
Likewise,
groups shown capable of directing such β-cleavage reactions cleanly include halogens,
esters, amides, phosphonate esters, sulfoxides and sulfones.
1,6,7,8,9

Scheme 2.1 – General Acid Catalyzed Ring-Opening of Electron Poor Epoxides
O
EWG
H
+
O
EWG
H
δ+
O
EWG
H
δ+
δ+
δ+
more stable
less stable
Nu
-
Nu
-
EWG
Nu
EWG
OH
OH
Nu
α α α α
β β β β

19
With all of the research efforts being dedicated to epoxides however, two areas
found to be somewhat overlooked were the use of epoxides in Friedel-Crafts type
reactions and new application of perfluorinated epoxides. As strong and regioselective
electrophiles, electron deficient epoxides should also make excellent substrates for
Friedel-Crafts alkylation reactions. However, few such reactions have been successfully
developed. Aromatics, as somewhat weak nucleophiles, react slowly with electrophiles in
the absence of catalysts or elevated temperatures; conditions usually too harsh to allow
for broad applicability. On the other hand, perfluorinated epoxides are an intriguing class
of substrates, though they too possess a few synthetic limitations. Though valuable as
building blocks in the synthesis of fluorinated polymers
10,11
and α- ketones,
12,13,14,15,16,17

fluorinated epoxides are particularly volatile and easily degraded within extreme
environments.
18
Along with this, the strong electron withdrawing effect of the fluorine
atoms within the molecules can inhibit oxygen protonation and lead to an overall slower
rate of reaction and decreased yield.
One way to expand our knowledge of the synthetic potential of epoxides and
overcome both sets of limitations would be through the use of superacid medium. High
acidity associated with superacids helps ensure that the epoxide does in fact become
protonated at ambient temperatures, ensuring its sufficient activation for electrophilic
aromatic substitution and avoid harmful side reactions, like isomerizations or oxidations,
associated with other acid catalysts. Olah et al., for example, have applied such an
approach to the preparation of α–hydroxy-β-arylpropionates from arenes and methyl (R)-
glycidates (Scheme 2.2).
19

20
Scheme 2.2 – Triflic Acid Catalyzed Alkylations Utilizing Glycidates
O
O
O
CF
3
SO
3
H
O
O
O
H
H
O
O
H
OH
Ar
OH
CO
2
Me
R

As electron withdrawing groups, glycidates are expected to undergo β-cleavage
ring openings exclusively. However, Friedel-Crafts reactions previously carried out were
found to still result in product mixtures. Along with this, the glycidates themselves are
known to be susceptible to acid-catalyzed decarboxylations with certain acids at elevated
temperatures.
20
In the presence of superacidic trifluoromethanesulfonic acid on the other
hand a stable, superelectrophilic intermediate is created whereby nucleophilic attack at
the β-position is strongly favoured and leads to only one cleavage product. Based upon
this approach, it was reasoned that superacids can also be used as effective catalysts and
media for the synthesis of trifluoromethylated arylethanols from selected perfluorinated
epoxides.

2.2 Chapter 2: Results and Discussion
2.2.1 Friedel-Crafts Alkylations of Arenes with Fluorinated Oxiranes
Due to the growing interest in fluorinated substrates both within the
pharmaceutical and industrial fields, many methods towards fluorinated alcohols have
emerged. Fluorinated alcohols have often been synthesized through the reduction of
substituted fluorinated ketones and efforts to induce enantioselectivity into these
reactions, have yielded fascinating new catalysts by Brown
21,22
and Mikami.
23
Olah and
co-workers have also demonstrated that substituted fluoro-alcohols can similarly be
21
prepared stereospecifically by alkylation of indoles with trifluoropyruvate esters in the
presence of cinchona alkaloids.
24
Early ring opening reactions of fluorinated epoxides on
the other hand, were extensively described by C. W. Roberts and co-workers utilizing a
variety of nucleophiles and conditions.
25,26
Later, Takahashi and his group largely
explored the Friedel-Crafts reactions of these epoxides and described at length the
regiomeric effects of fluorine substitution on reaction outcomes.
27
However, superacid
catalyzed methods involving these epoxides have not been well explored since that time.
As a continuation of the efforts towards Friedel-Crafts alkylation of methyl (R)-
glycidates, the superacid catalyzed reactions of arenes with 2-trifluoromethyloxirane as
an electrophile were studied. In the presence of triflic acid, a similar procedure was found
to lead to the formation of β-aryl ethanols (Table 2.1), in good yields when compared to
reactions with methyl glycidate. As previously mentioned, the sensitive nature of these
epoxides necessitated that reactions be conducted under relatively mild conditions in
order to avoid decomposition, multiple alkylations of activated arenes and
rearrangements. However, this does not seriously affect the rate of the reaction as the
strongly protonating reaction medium coupled with the strongly electron withdrawing α-
CF
3
group still results in reactions that can be completed within a matter of minutes.
Electron deficient aromatics though, failed to react under similar reaction conditions.
The typical Friedel-Crafts electrophilic substitution patterns were observed as is
evident from the formation of a mixture of products from more substituted arenes. The
formation of significant amounts of meta-substituted products may be due to
isomerization within the strong acid medium while steric effects seem most likely to have
influenced the abundance of para-substituted products.
11,12
22
As expected, no evidence of α-cleavage was found and the inductive effect of the
CF
3
group appears to also stabilize the α-carbinols, avoiding any dehydration under
strongly acidic conditions.
Table 2.1 – Friedel-Crafts Alkylations of 2-Trifluoromethyloxirane
R
1
R
2
+
CF
3
O
CF
3
SO
3
H
R
1
R
2
OH
CF
3
H
H
CH
2
Cl
2
0
o
C - RT

Entry Product (o:m:p) Yield (%)
CH
3
R
1
R
2
a.
b.
c.
d.
e.
f.
H H
CH
3 H
C
2
H
5
H
C
3
H
7
(n) H
CH
3
4-CH
3
3-CH
3
78
94
70
81
95
95
24:36:40
CF
3
OH
H
CF
3
OH
H
CF
3
OH
H
CF
3
OH
H
H
3
C
CH
3
CH
3
H
3
C
74:0:26
CF
3
OH
H
C
2
H
5
31:28:41
CF
3
OH
H
C
3
H
7
11:77:12
CH
3

Friedel-Crafts alkylations were carried out with the related 2,2-
bis(trifluoromethyl)oxirane also as the starting epoxide (Table 2.2). Along with further
exploring the effects of electron deficiency on the reactivity of epoxides, the addition of a
23
second trifluoromethyl group also allows us to access synthetically important
bis(trifluoromethyl) substituted alcohols, highly useful in semiconductor
photolithography.
28

Table 2.2 – Friedel-Crafts Alkylations of 2,2-Bis(Trifluoromethyl)oxirane
R
1
R
2
+
CF
3
O
CF
3
SO
3
H
R
1
R
2
OH
CF
3
CF
3
CF
3
CH
2
Cl
2
0
o
C - RT

Entry Product (o:m:p) Yield (%)
CH
3
CH
3
CH
3
R
1
R
2
a.
b.
c.
d.
e.
f.
H H
CH
3
H
C
2
H
5
H
C
3
H
7 H
CH
3
4-CH
3
CH
3
3-CH
3
81
92
80
78
95
75
29:29:42
21:16:63
33:20:47
5:80:15
CF
3
OH
CF
3
CF
3
OH
CF
3
CF
3
OH
CF
3
CF
3
OH
CF
3
CF
3
OH
CF
3
CF
3
OH
CF
3
H
3
C
C
3
H
7
C
2
H
5
H
3
C

The strong electron withdrawing effect of two geminal trifluoromethyl groups in
the molecule serves to make the α-carbon center highly electrophilic and susceptible to
aromatic substitution reactions faster than the corresponding mono-substituted oxirane.
24
The yields of products in this reaction were generally good and were found comparable to
those obtained with the mono-substituted epoxide. High regioselectivity is always
observed not only due to the electronic effects but steric factors as well.
29

2.2.2 Density Functional Theory (DFT) Studies of Fluorinated Oxiranes
To help rationalize the observed high regioselectivity and compare reactivities,
computational studies were performed over four neutral molecules, 2-(trifluoromethyl)-
oxirane (2a), 2,2-bis(trifluoromethyl)oxirane (2b), methyl glycidate (2c), 2-methyl
oxirane (2d), and their O-protonated structures (5a-d). Not only do such calculations help
reconcile experimental observations with theoretical predictions, in this case they are
helpful in highlighting just how complicated the interplay between steric, conjugative and
polar inductive effects can be in relation to reactivity and selectivity. The structures
(Tables 2.3, 2.4) were calculated using density functional theory (DFT) methods
30
based
on the GAUSSIAN-98 package of programs
31
and optimized geometries were obtained at
the B3LYP/6-31G** level (Figures 2.1, 2.2).
32

For neutral molecules 2a-c (Table 2.3), the β-carbon, C
1
(+2H), usually carries
more positive charge than the α-carbon, C
2
(+H). Since these molecules all contain
electron withdrawing groups, this observation supports the β-cleavage model postulated
in literature and is further confirmed by the only slight difference in atomic charges found
between C
1
(+2H) and C
2
(+H) for 2d. In accordance with this, the length of the C
1
-O
bonds for structures 2a and 2b were also found to be significantly longer than the C
2
-O
bonds also indicating that the latter would be more easily cleaved. These favorable
features in molecules 2a and 2b are consistent with the experimentally observed
25
regioselectivities though it is interesting to note that in the case of methyl glycidate (2c),
the C
2
-O bond was found to be slightly longer than the C
1
-O bond.
Table 2.3 – Computed Geometries of Neutral Epoxides
O
R
1
R
2
Entry R
1
: R
2
C
2
(+H)
2a.
2b.
2c.
2d.
CF
3
: H 1.420
CF
3
: CF
3
1.414
CO
2
CH
3
: H 1.428
CH
3
: H 1.435
1
2
2a-d
Atomic Charge Bond Length (Å)
-0.136 +0.315 -0.059 +0.185
-0.118
-0.124
-0.149
+0.359
+0.316
+0.271
-0.027
-0.051
-0.050
+0.027
+0.195
+0.270
C
1
C
1
(+2H) C
2
1.436
1.438
1.423
1.434
C
1
-O C
2
-O

Figure 2.1 – Optimized Geometries of Selected Neutral Epoxides

The possible structures of the transition states in the presence of acid were also
studied by DFT calculations on the O-protonated structures of each epoxide molecule.
Oxonium ions, 5a-d, exhibit many of the characteristics similar to those of their neutral
26
counterparts, though with protonation, most of these have been intensified (Table 2.4). In
all cases, for instance, the C
1
carbon becomes more electrophilic with the addition of acid
with the effect being even more pronounced in fluorinated molecules 5a and 5b. The
fluorinated epoxides also showed dramatically longer C
2
-O bonds when compared to the
C
1
-O bonds which also agreed with experimental results.
As predicted, 2-methyl oxirane still showed a strong tendency towards α-cleavage
when protonated even though its C
1
(+2H) appears to carry more positive charge than its
C
2
(+H). Surprising however, protonated glycidate appears to also favour α-cleavage even
though it too possesses an electron withdrawing group. Upon further examination
however, it becomes clear that this is due to the formation of an internal hydrogen bond
between the protonated oxygen and the carbonyl group (Figure 2.2). This effect may be
exactly what lessens the reactivity of 2c when compared to 2a and 2b and may also lead
to the formation of cleavage product mixtures.
Table 2.4 – Computed Geometries of O-Protonated Epoxides
O
R
1
R
2
5a.
5b.
5c.
5d.
1
2
H
5a-d
Entry R
1
: R
2
C
2
(+H)
CF
3
: H 1.515
CF
3
: CF
3
1.510
CO
2
CH
3
: H 1.533
CH
3
: H 1.592
Atomic Charge Bond Length (Å)
-0.088 +0.502 -0.012 +0.307
-0.073
-0.091
-0.102
+0.531
+0.485
+0.461
+0.073
-0.003
+0.108
+0.073
+0.314
+0.392
C
1
C
1
(+2H) C
2
1.532
1.534
1.514
1.513
C
1
-O C
2
-O

27
Figure 2.2 – Optimized Geometries of Selected O-Protonated Epoxides

2.3 Chapter 2: Conclusion
In conclusion, regioselective ring opening of oxiranes bearing highly electron
withdrawing CF
3
groups followed by Friedel-Crafts alkylation on various arenes has been
achieved using superacidic trifluoromethanesulfonic acid. The reaction can be used in the
preparation of a variety of α-trifluoromethylated β–phenylethanols which can be further
oxidized to corresponding desired trifluoromethyl ketones, potential inhibitors of
hydrolytic enzymes. Substituted arenes produce a mixture of o-, m- and p-substituted
products as usually observed in the case of Friedel-Crafts reaction. In addition, the
observed differences among reactivities of oxiranes carrying electron withdrawing groups
such as 2-(trifluoromethyl)oxirane, 2,2-bis(trifluoromethyl)oxirane and the observed
regioselectivities were examined and ratified through density functional theory
calculations.
28
2.4 Chapter 2: Experimental
2.4.1 General Remarks
Unless otherwise mentioned, all chemicals were purchased from commercial
sources.
1
H,
13
C, and
19
F NMR spectra were recorded on a 400 MHz Varian NMR
spectrometer.
1
H NMR chemical shifts were determined relative to TMS as the internal
standard at 0.0 ppm.
13
C NMR chemical shifts were determined relative to CDCl
3
at 77.0
ppm while
19
F NMR chemical shifts were determined relative to CFCl
3
as the internal
standard at 0.0 ppm. Column chromatography was carried out using Siliaflash G60 silica
gel (70-230 mesh) and HRMS data was obtained from a high resolution Micromass GCT
(GC-MS TOF) spectrometer at the Mass Spectrometry Facility, Department of
Chemistry, University of Arizona.
2.4.2 Typical Procedure for Friedel-Crafts Reactions With Fluorinated Epoxides
A solution of benzene (1.2 mL, 13.5 mmol) with triflic acid (1.05 mL, 11.3 mmol)
in 0.75 mL of CH
2
Cl
2
was first cooled to 0° C. A solution of 2-(trifluoromethyl)oxirane
(2a) (0.126 g, 1.13 mmol) in CH
2
Cl
2
(0.75 mL) was added dropwise using a syringe over
a period of 4 minutes with stirring. When the reaction mixture turned dark, the cooling
bath was removed and the reaction mixture was allowed to come to room temperature.
The mixture was then poured onto 10 g of crushed ice, made slightly basic with NaHCO
3

and extracted with Et
2
O.
The organic phase was washed with 30 mL each of brine and water, and then
dried over anhydrous MgSO
4
. The residue obtained after concentration under vacuum
was purified by flash column chromatography using a mixture of n-hexane and diethyl
29
ether (3:1). The α-trifluoromethyl-β-phenylethanol obtained was then confirmed
structurally by NMR and HRMS. In the case of isomeric mixtures where separation
proved difficult, spectral data of the mixtures were reported instead.
2.4.3 Spectral Data:
1,1,1-Trifluoro-3-phenylpropan-2-ol (Table 2.1a)
1
H NMR (400 MHz, CDCl
3
): δ 2.26 (bs, 1H) 2.71 (dd, 1H, J
1
= 10.22 Hz, J
2
= 14.19
Hz,), 2.94 (dd, 1H, J
1
= 2.90, J
2
= 14.19 Hz,), 3.98 (m, H), 7.20 (m, 5H);
13
C NMR (100
MHz, CDCl
3
): δ 36.10, 71.44 (sept, J = 30.67 Hz), 124.87 (q, J = 282.17 Hz), 127.24,
128.79, 129.46, 135.76;
19
F NMR (376.1 MHz, CDCl
3
): δ -80.06 (d, J = 7.63 Hz, 3F);
HRMS (EI) for C
10
H
10
F
3
O: Calcd 190.0605, Found 190.0610.
1,1,1-Trifluoro-3-tolylpropan-2-ol (Table 2.1b)
1
H NMR (400 MHz, CDCl
3
): δ 2.26 (s, 3H), 2.52 (m, 1H), 2.73 (m, 1H), 2.96 (m, 1H),
4.00 (m, 1H), 7.07 (m, 4H);
13
C NMR (100 MHz, CDCl
3
): δ 30.05, 35.59, 36.44, , 42.26,
71.76 (q, J = 30.87 Hz), 125.08 (q, J = 281.96 Hz), 126.39, 127.57, 127.94, 128.79,
129.13, 129.23, 129.27, 129.38, 129.58, 129.76, 136.02, 141.46;
19
F NMR (376.1 MHz,
CDCl
3
): δ -80.33 (d, J = 7.63 Hz), -80.09 (d, J = 6.10 Hz), -80.04 (d, J = 6.10 Hz);
HRMS (EI) for C
10
H
10
F
3
O: Calcd 204.0762 Found 204.0752.
3-Ethylphenyl-1,1,1-trifluoropropan-2-ol (Table 2.1c)
1
H NMR (400 MHz, CDCl
3
): δ 1.23 (m, 3H), 2.16 (bs, 1H), 2.71 (m, 2H), 2.83 (m, 1H),
3.03 (m, 1H), 4.15 (m appear as bs, 1H), 7.16 (m, 4H);
13
C NMR (100 MHz, CDCl
3
): δ
15.19, 15.57, 25.52, 28.48, 28.78, 32.56, 35.71, 36.13, 71.46 (q, J = 30.67 Hz), 124.90 (q,
J = 281.41 Hz), 126.14, 126.67, 126.81, 127.58, 128.32, 128.52, 128.78, 128.89, 129.04,
30
129.39, 130.35, 132.77, 143.31, 144.93;
19
F NMR (376.1 MHz, CDCl
3
): δ -80.30 (d, J =
6.10 Hz), -80.08 (d, J = 6.10 Hz), -80.06 (d, J = 6.10 Hz); HRMS (EI) for C
10
H
10
F
3
O:
Calcd 218.0918, Found 218.0909.
1,1,1-Trifluoro-3-(n-propylphenyl)propan-2-ol (Table 2.1d)
1
H NMR (400 MHz, CDCl
3
): δ 0.94 (m, 3H), 1.65 (m, 2H), 2.23 (bs, 1H), 2.59 (m, 2H),
2.76 (m, 1H), 3.02 (m, 1H), 4.06 (m, 1H), 7.14 (m, 4H);
13
C NMR (100 MHz, CDCl
3
): δ
13.85, 14.13, 24.28, 24.58, 24.62, 32.60, 34.72, 35.76, 35.73, 36.14, 37.67, 37.97, 71.65
(q, J = 26.07 Hz), 124.90 (q, J = 281.41 Hz), 125.61, 126.17, 126.67, 127.38, 127.42,
128.23, 128.49, 128.69, 128.91, 129.12, 129.29, 129.662, 129.76, 130.36, 132.76, 133.49,
135.49, 141.36, 141.76, 143.40;
19
F NMR (376.1 MHz, CDCl
3
): δ -80.32 (d, J = 6.10
Hz), -80.08 (d, J = 7.63 Hz), -80.06 (d, J = 6.10 Hz); HRMS (EI) for C
10
H
10
F
3
O: Calcd
232.1075, Found 232.1077.
3-(2,5-Dimethylphenyl)-1,1,1-trifluoropropan-2-ol (Table 2.1e)
1
H NMR (400 MHz, CDCl
3
): δ 2.25 (s, 3H), 2.29 (s, 3H), 2.78 (dd, J
1
= 10.18 Hz, J
2
=
14.34 Hz, 1H), 2.99 (dd, J
1
= 2.82 Hz, J
2
= 14.27 Hz, 1H), 4.00 (m, 1H), 6.97 (s, 1H),
6.98 (s, 1H), 7.05 (d, J
1
= 8.24 Hz, 1H);
13
C NMR (100 MHz, CDCl
3
): δ 18.99, 20.92,
33.33, 70.72 (q, J = 30.50 Hz), 125.08 (q, J = 282.17 Hz), 128.141, 130.67, 131.10,
133.66, 133.96, 135.85;
19
F NMR (376.1 MHz, CDCl
3
): δ 80.33 (d, J = 6.1Hz); HRMS
(EI) for C
11
H
13
F
3
O: Calcd 218.0918, Found 218.0918.
3-(Dimethylphenyl)-1,1,1-trifluoropropan-2-ol (Table 2.1f)
1
H NMR (400 MHz, CDCl
3
): δ 2.10 (bs, 1H), 2.24 (m, 6H), 2.75 (dd, J
1
= 10.38 Hz, J
2
=
14.34 Hz, 1H), 2.98 (dd, J
1
= 2.82 Hz, J
2
= 14.42 Hz, 1H), 3.97 (m, 1H), 6.83-7.00 (m,
31
3H);
13
C NMR (100 MHz, CDCl
3
): δ 19.35, 20.27, 20.93, 21.23, 32.89, 70.73 (q, J =
30.50 Hz), 125.07 (q, J = 282.29 Hz), 126.98, 127.07, 127.26, 128.59, 128.93, 130.29,
131.09, 131.54, 136.63, 137.07, 138.49;
19
F NMR (376.1 MHz, CDCl
3
): δ -80.61 (d, J =
7.63 Hz), -80.30 (d, J = 6.10 Hz), -80.13 (d, J = 6.10 Hz); HRMS (EI) for C
11
H
13
F
3
O:
Calcd 218.0918, Found 218.0920.
2-Benzyl-1,1,1,3,3,3-hexafluoropropan-2-ol (Table 2.2a)
1
H NMR (400 MHz, CDCl
3
): δ 2.82 (s, 1H), 3.26 (s, 2H), 7.26-7.36 (m, 5H);
13
C NMR
(100 MHz, CDCl
3
): δ –35.55, 75.84 (sept, J = 26.84 Hz), 123.07 (q, J = 287.54 Hz),
128.43, 129.013, 130.775, 131.157;
19
F NMR (376.1 MHz, CDCl
3
): δ -76.77 (s).
1,1,1,3,3,3-Hexafluoro-2-(methylbenzyl)propan-2-ol (Table 2.2b)
1
H (400 MHz, CDCl
3
): δ 2.35, 2.36, 2.37 (3H), 2.78, 2.79, 2.80 (1H), 3.24, 3.34 (4H),
7.20 (m, 4H);
13
C NMR (100 MHz, CDCl
3
): δ 19.79, 21.11, 21.34, 31.81, 35.11, 35.41,
75.64 (sept, J = 28.37 Hz), 123.20 (q, J = 286.77 Hz), 126.47, 127.42, 128.18, 128.67,
129.02, 129.32, 129.84, 130.51, 131.07, 131.43, 131.88, 132.26, 138.47, 139.00;
19
F
NMR (376.1 MHz, CDCl
3
): δ -77.14 (s), -76.82 (s), -76.78 (s); HRMS (EI) for
C
11
H
10
F
6
O: Calcd 272.0636, Found 272.0649.
2-(Ethylbenzyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Table 2.2c)
1
H NMR (400 MHz, CDCl
3
): δ 1.24 (t, J = 7.612 Hz, 3H), 2.66 (q, J = 7.619 Hz, 2H),
2.82, 2.85, 2.86 (m, 1H), 3.25, 3.26, 3.36 (s, 2H), 7.20 (m, 4H);
13
C NMR (100 MHz,
CDCl
3
): δ 15.28, 15.41, 15.56, 25.42, 28.49, 28.74, 31.06, 35.02, 35.40, 75.63 (sept, J =
28.37 Hz), 122.99 (q, J = 288.31 Hz), 126.24, 127.51, 128.03, 128.31, 128.54, 128.83,
32
129.00, 129.46, 130.40, 130.67, 131.04, 132.30, 144.61, 145.22;
19
F NMR (376.1 MHz,
CDCl
3
): δ -77.05 (s), -76.84 (s), -76.83 (s).
1,1,1,3,3,3-Hexafluoro-2-(n-propylbenzyl)propan-2-ol (Table 2.2d)
1
H NMR (400 MHz, CDCl
3
): δ 0.94 (t, J = 7.327 Hz, 3H), 1.64 (hept, J = 7.601 Hz, 2H),
2.58 (t, J = 7.256 Hz, 2H), 2.78, 2.81, 2.83 (1H), 3.23, 3.24, 3.35 (2H), 6.99-7.28 (m,
4H);
13
C NMR (100 MHz, CDCl
3
): δ 13.85, 14.13, 24.28, 24.56, 24.59, 24.62, 32.60,
34.72, 35.74, 36.14, 37.67, 37.97, 38.10, 71.33 (sept, J = 30.67 Hz), 124.89 (q, J =
281.41 Hz), 125.61, 126.17, 126.67, 127.38, 127.42, 128.23, 128.49, 128.69, 128.91,
129.12, 129.29, 129.662, 129.76, 130.36, 132.76, 133.49, 135.49, 141.36, 141.76,142.73,
143.40;
19
F NMR (376.1 MHz, CDCl
3
): δ -80.32 (d, J = 6.10 Hz), -80.08 (d, J = 7.63
Hz), -80.06 (d, J = 6.10 Hz).
2-(2,5-Dimethylbenzyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Table 2.2e).
1
H NMR (400 MHz, CDCl
3
): δ 2.30 (s, 3H), 2.82 (s, 1H), 3.29 (s, 2H), 7.03-7.10 (m,
3H);
13
C NMR (100 MHz, CDCl
3
): δ 19.26, 20.85, 31.76, 75.58 (sept, J = 29.14 Hz),
123.29 (q, J = 287.54 Hz), 128.72, 129.46, 131.36, 132.82, 135.71, 136.11;
19
F NMR
(376.1 MHz, CDCl
3
): δ -77.20 (s); HRMS (EI) for C
12
H
12
F
6
O: Calcd 286.0792, Found
286.0780.
2-(Dimethylbenzyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (Table 2.2f).
1
H NMR (400 MHz, CDCl
3
): δ 2.30, 2.31, 2.36 (s, 6H), 2.72, 2.74, 2.78 (s, 1H), 3.18,
3.29, 3.44 (s, 2H), 6.86-7.18 (m, 3H);
13
C NMR (100 MHz, CDCl
3
): δ 19.70, 20.99,
21.22, 31.50, 35.31, 75.64 (sept, J = 29.14 Hz), 123.34 (q, J = 288.31 Hz), 125.79,
33
127.27, 128.27, 128.94, 129.29, 130.26, 130.35, 132.20, 132.23, 138.56, 138.76, 138.94;
19
F NMR (376.1 MHz, CDCl
3
): δ -77.38 (s), -77.18 (s), -76.92 (s); HRMS (EI) for
C
12
H
12
F
6
O: Calcd 286.0792, Found 286.0786.

34
2.4.4 Representative Spectra:
1
H NMR spectrum of 1,1,1-Trifluoro-3-phenylpropan-2-ol (Table 2.1a)

ppm (t1)
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
5.00
1.00
1.07
1.05
0.94
OH
CF
3
35
2.4.4 Representative Spectra (continued):
13
C NMR spectrum of 1,1,1-Trifluoro-3-phenylpropan-2-ol (Table 2.1a)

ppm (t1)
0 50 100
OH
CF
3
36
2.4.4 Representative Spectra (continued):
19
F NMR spectrum of 1,1,1-Trifluoro-3-phenylpropan-2-ol (Table 2.1a)

ppm (t1)
-50 0
ppm (t1)
-80.250 -80.200 -80.150 -80.100 -80.050 -80.000
OH
CF
3
37
2.4.4 Representative Spectra (continued):
1
H NMR spectrum of 2-Benzyl-1,1,1,3,3,3-hexafluoropropan-2-ol (Table 2.2a)

ppm (t1)
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
5.00
2.07
0.98
OH
CF
3
F
3
C
38
2.4.4 Representative Spectra (continued):
13
C NMR spectrum of 2-Benzyl-1,1,1,3,3,3-hexafluoropropan-2-ol (Table 2.2a )

ppm (t1)
0 50 100
ppm (t1)
75.50 76.00 76.50 77.00 77.50
OH
CF
3
F
3
C
39
2.4.4 Representative Spectra (continued):
19
F NMR spectrum of 2-Benzyl-1,1,1,3,3,3-hexafluoropropan-2-ol (Table 2.2a)

ppm (t1)
-50 0
OH
CF
3
F
3
C
40
2.5 Chapter 2: References

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Weinheim, 2006.
2. Parker R. E.; Isaacs N. S. Chem. Rev. 1959, 59, 737.
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6. Hikino, H.; Suzuki, N.; Takemoto, T. Chem. Pharm. Bull. 1966, 14, 1441.
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8. Kesavan, V.; Bonnet-Delpon, D.; Bèguè, J. P. Tetrahedron Lett. 2000, 41, 2895.
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2000, 65, 6749.
10. Sangermano, M.; Bongiovanni, R.; Malucelli, G.; Priola, A.; Pollicino, A.; Recca
A. J. Applied Polymer Sci. 2003, 89, 1524.
11. Sakakibara, K.; Nakano K.; Nozaki, K. Chem. Commun. 2006, 3334.
12. Bèguè, J. P.; Bonnet-Delpon, D. Tetrahedron, 1991, 47, 3207.
13. Peet, N. P.; Burkhart, J. P.; Angelastro, M. R.; Giroux, E. L.; Mehdi, S.; Bey, P.;
Kolb, M.; Neises, B.; Schirlin, D. J. Med. Chem. 1990, 33, 394.
14. Parisi, M. F.; Abeles, R. H. Biochemistry, 1992, 31, 9429.
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E. W. J. Med. Chem. 1993, 36, 2431.
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41

19. Palomino, P. J. L.; Prakash, G. K. S.; Olah, G. A. Helv. Chim. Acta. 2005, 88,
1221.
20. Singh, S. P.; Kaga, J. J. Org. Chem. 1970, 35, 2203.
21. Ramachandran, P. V.; Teodorovic, A. V.; Gong, B.; Brown, H. C. Tetrahedron:
Asymmetry, 1994, 5, 1061.
22 . Ramachandran, P. V.; Teodorovic, A. V.; Gong, B.; Brown, H. C. Tetrahedron:
Asymmetry, 1994, 5, 1075.
23. Ishii, A.; Soloshonok, V. A.; Mikami, K. J. Org. Chem. 2000, 65, 1597.
24. Török, B.; Abid, M.; London, G.; Esquibel, J.; Török, M.; Mhadgut, S. C.; Yan,
P.; Prakash, G. K. S. Angew. Chem. Int. Ed. 2005, 44, 3086.
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27. Takahashi, O.; Fukuhashi, K.; Fukumasa, M.; Hirai, T. Tetrahedron Lett. 1990,
31, 7031.
28. Feiring, A. E.; Crawford, M. K.; Farnham, W. B.; French, R. H.; Leffew, K. W.;
Petrov, V. A.; Schadt III, F. L.; Tran, H. V.; Zumsteg, F. C. Macromolecules,
2006, 39, 1443.
29. Petrov, V.A. Synthesis, 2002, 15, 2225.
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31. Gausian 98 (Revision A.5), Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.;
Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery,
J. A.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J.M.; Daniels, R. E.;
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42
3 Chapter 3: Nafion-H Catalyzed Isomerization of
Trifluoromethylated Benzylimines to Benzaldimines En
Route to α-Trifluoromethylated Amines

3.1 Chapter 3: Introduction
As mentioned in Chapter 2, fluorinated bioactive molecules have garnered much
attention in recent years due to the unique properties imparted by fluorine substitution.
1,2,3

In particular, α-trifluoromethylated amino compounds have become useful and
indispensable building blocks in the synthesis and design of fungicides, pesticides,
insecticides, selective antibacterial agents, enzyme inhibitors and enzyme receptor
antagonists or agonists.
4,5,6,7,8
Much of the desirability associated with these precursors
derives from the fact that α-trifluoromethylated amines may act as efficient isosteres to
the carbonyl groups of amide bonds.
9,10,11
Trifluoromethyl substitution at this position
helps lower the basicity of the neighboring amino group and in turn, helps to enhance the
lipophilicity and metabolic stability of the parent compound.
12
As such powerful
precursors, it comes as no surprise therefore, that there have been a number of reported
synthetic routes to these compounds.
One of the most commonly exploited methods is the reductive amination of
trifluoromethylated carbonyl compounds usually through the use of chiral metal
catalysts.
13,14
Other well known methods however, include the nucleophilic alkylation of
trifluoromethyl imines
15,16
, various reductions or ring opening reactions of fluorinated
1,2-oxazolidines
17,18
and nucleophilic additions of TMSCF
3
to nitrones and
imines.
19,20,21,22,23
Within the last decade however, much of the synthetic work in this area
43
has been focused on the base catalyzed isomerization of trifluoromethylated imines as
studied by Soloshonok and coworkers.
24,25,26
This so called “biomimetic reductive
amination” approach exploits the electron withdrawing nature of the α-trifluoromethyl
group by favoring the irreversible formation of substituted benzaldimines instead of
benzylimines.
27,28,29

The reaction leads to the formation of a more stable imine and has even been
shown to occur thermally without the use of catalysts.
30
The Schiff bases that result from
such reactions can later be hydrolyzed under mildly acidic conditions to yield
trifluoromethylated amines.
9-10
However, while it is an important and elegant discovery,
this methodology still suffers significantly from several drawbacks, the most serious of
which is its multistep approach.
Scheme 3.1 – Biomimetic Reductive Amination
R R
f
O
Ar NH
2
R
f
R
N Ar
H
+
Base
R
f
R
N Ar
1,3-Proton
Shift
H
+
Hydrolysis
R
f
R
NH
2
Ar R
O
+
(R=Alkyl, Rf=Fluoroalkyl, Ar=Aromatic)

The synthesis of trifluoromethylated amines as starting materials is not, for
example, a trivial process as it often requires the use of strong acids under reflux.
Afterwards, the use of a strong base during the second step also means that the reaction
cannot be conducted in “one-pot” but must instead involve several neutralization and
44
purification steps. There then emerges from these observations, a need for cleaner and
more efficient routes to these valuable products. Our attempts to improve the practical
application of the biomimetic route to trifluoromethylated amines began by attempting to
improve the way in which trifluoromethylated imines are prepared.

3.2 Chapter 3: Results and Discussion
Most trifluoromethylated imines, as previously indicated, are synthesized through
reactions catalyzed by acids such as p-toluenesulfonic acid. Therefore we attempted to
improve this process by choosing Nafion-H
®
, a solid supported perfluoroalkane sulfonic
acid resin as our acid catalyst. In chemical reactions, Nafion-H
®
remains thermally stable
up to 210 °C, can be easily removed and recycled and proves to be chemically inert to
many side reactions.
31,32
Nafion
®
resins were first developed by Dupont and their
remarkable properties led to their vast application as electrolyte membranes for
electrochemical cells.
33

Nafion
®
is formed by the copolymerization of a perfluorinated vinyl ether
comonomer possessing a sulfonated terminus with tetrafluoroethylene (TFE). Within the
polymer’s superstructure, the sulfonate groups tend to form aggregates or clusters
through which cations can freely travel and it is this characteristic that gives the polymer
its powerful conductivity (Figure 3.1).
34
These ionomeric channels also play an
important part in the remarkable acidic characteristics of Nafion
®
. In its acid form, the
presence of so many electron withdrawing fluorine atoms within the polymer’s backbone
makes the acidity of Nafion-H
®
comparable to that of concentrated sulfuric acid and in
45
effect a solid superacid. At the same time, because the acid sites lie buried within the
superstructure, bulk acidification of the solvent can largely be avoided.
Figure 3.1 – Structure of Nafion
®

CF
2
CF
2
CF
2
CF
2
CF
2
CF
2
CF
2
OCF
2
CF
2
SO
3
-
m
n
z
a. Polymer Backbone

SO
3
- SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
-
SO
3
- SO
3
-
4nm
5nm
1nm
SO
3
- SO
3
-
SO
3
-
SO
3
-
b. Cluster Network-Model

Olah and coworkers have extensively studied the applications of Nafion-H
®
in a
wide range of reactions such as alkylations, acylations, nitrations sulfonations and
isomerizations.
31
The broad range of applicable reactions not only demonstrates how
convenient and versatile the polymer is synthetically, but its many environmental benefits
as well. Products of these reactions can simply be filtered from the polymer and isolated
without the excessive use of hazardous solvents while, because of its high stability, the
used polymer can be cleaned and regenerated for recycling. Thus, instead of using a
soluble organic acid catalyst such as p-toluenesulfonic acid or trifluoromethanesulfonic
acid, Nafion-H
®
could be an effective catalyst for many reactions including imine
synthesis that require both strong acidities and higher temperatures.
46
During the course of our experiments towards the synthesis of trifluoromethylated
imines using Nafion-H
®
, we found that reactions between aniline derivatives and
trifluoromethylated ketones do in fact produce imines in quantitative yields. Surprisingly
however, when the reaction was extended to benzylamines, the corresponding fluorinated
imines were obtained along with a small amount of trifluoromethylated benzaldimines;
products identical to the ones obtained by the biomimetic 1,3-shift mechanism. Upon
further investigation, it was revealed that a simple elevation in reaction temperature
resulted in enhancement in the yield of benzylidene-(2,2,2-trifluoro-1-phenyl-ethyl)-
amine (Scheme 3.2), being obtained. The reaction was carefully monitored at different
conditions and the most suitable for maximum conversion to rearranged product with the
least side reaction was found.
Scheme 3.2 – Synthesis of Trifluoromethylated Benzylimines
N CF
3
R
Nafion-H
Ar
164 °C
N
CF
3
Ar
H
R
H
+
major
minor
Nafion-H
185 °C
N CF
3
R
Ar
N
CF
3
Ar
H
R
H
+
major minor
H H
H H
R CF
3
O
ArCH
2
NH
2
ArCH
2
NH
2

When extending the range of the reaction, most benzylamines showed comparable
reaction rates and product distributions though significant substituent effects were
observed when aromatic substituents were altered. Benzylamines bearing electron-
donating groups for example generally led to a faster rate of initial imine formation but
47
had very little effect on the subsequent isomerization step (Table 3.1). As expected, more
electron rich amines were able to act as better or more potent nucleophiles than their
electron deficient counterparts. Conversely, it is known that the presence of electron
withdrawing groups in ketones dramatically increases their electrophilicity. Thus, despite
the presence of a trifluoromethyl group in the substrate, the addition of another fluorine
atom still helps to significantly enhance the electrophilicity of the ketones and ultimately
the reaction yields (Table 3.1 entries f-h).
Table 3.1 – Imine Formation and Rearrangement with Benzylamines
NH
2
O
CF
3
Nafion-H
Toluene
185 °C
+
R
1
R
2
N
H
H CF
3
R
1
R
2

R
1
R
2
H
4-Cl
2-Me
H
H
H
H
4-OMe H
3-F
Yield (%)
65
a
55
a
75
a
3-F
a.
b.
c.
d.
e.
f.
g.
h.
70
b
50
a
60
b
68
b
62
a
3-F
a
Isolated chemical yield
b
Yield calculate on the basis of GCMS and NMR data
4-F
H
4-Cl
4-F
Time (hr)
24
24
24
24
24
24
24
24
Entry

Though we generally found high boiling solvents best suited to this methodology,
the amount of solvent used in each reaction initially proved crucial. An excess of our
solvent of choice, toluene, led to a mixture of imine isomers while a minimal amount (1
mL of toluene per mole of substrates) predominantly led to formation of the
benzaldimine as the major product. The aggregate-cluster model of Nafion-H
®
(Figure
48
3.1b) ensures, as mentioned, that acid sites are only found within the substructure of the
catalyst’s pockets and not throughout the solution as with other acids. Our reaction
therefore requires a higher concentration of the reaction mixture so that dilution effects
can be minimized as more reactants are forced into the proximity of acid sites in the
catalyst. Beyond the issue of access to the acid sites, inconsistencies in Nafion-H
®

catalyzed reactions observed in some cases can be due to inconsistencies in the
distribution and arrangement of monomers during the polymerization process. In order to
address this and further improve and enhance our reactions, we examined high surface
area Nafion-H
®
SAC-13, a catalyst derived from Nafion-H with a varied morphology and
its synthetic potential in the present protocol has also been explored. First reported by
Harmer and coworkers in 1996, Nafion-H
®
SAC-13 is a silica supported form of the solid
Nafion-H
®
.
35,36,13
By immobilizing Nafion
®
on a silica matrix, Harmer and his group
found that the surface area of the catalyst could be improved almost tenfold.
13

This provides for greater accessibility to acidic sites and, in our experiments,
allowed for further yield improvements and even greater selectivity. We found in fact,
that using Nafion-H
®
SAC-13 led to the formation of trifluoromethylated benzaldimines
cleanly and, in some cases, as the sole product. This presented a significant advantage as
separation of the two imine isomers proved exceedingly difficult whenever mixtures were
obtained. Thus the reaction has been expanded to a variety of trifluoromethylated
acetophenones to give the trifluoromethylated benzaldimines in good yields (Table 3.2).
49
Table 3.2 – Reaction with Various Trifluoromethylated Acetophenones
Nafion-H SAC-13
Toluene, 185

° C
O
CF
3
+
R
CH
2
NH
2 N
H
H CF
3
R

Product Time (Hr) R Yield (%)
N
H
H CF
3
N
H
H CF
3
N
H
H CF
3
N
H
H CF
3
N
H
H CF
3
CH
3
CF
3
Br
Cl
N
H
H CF
3
S
N
H
H CF
3
OCH
3
N
H
H CF
3
F
4-CF
3
4-OCH
3
CF
3
S O
24
24
24
24
24
48
48
48
a.
b.
c.
d.
e.
g.
i.
h.
4-CH
3
4-Br
4-Cl
4-F
H
N
H
H CF
3
CF
3 24 f. 3-CF
3
82
94
71
66
80
73
50
83
92
Entry

50
Substituents effects in these reactions could, once again, be clearly observed as
electron deficient acetophenones generally reacted faster than electron rich ones.
However, even in instances where the use of longer reaction time was required, reactions
still went essentially to completion with good yields. Afterwards, the isolated products
may be further converted to the synthetically valuable, fluorinated benzylamines by
previously established mineral acid hydrolysis (Table 3.3). This particular transformation
was carried out on a selected number of trifluoromethylated benzaldimines and the
corresponding benzylamine hydrochloride salts were obtained in good yields.
Table 3.3 – Hydrolysis of Various Trifluoromethylated Benzaldimines
H
3
N
H CF
3
R
2
3N HCl
N
H
CF
3
H
R
Et
2
O, RT
+ H
O

H
3
N
H CF
3
H
3
N
H CF
3
H
3
N
H CF
3
CF
3
F
H
3
N
H CF
3
OCH
3
Product Yield (%)
H
3
N
H CF
3
Cl
H
3
N
H CF
3
a.
b.
c.
d.
e.
f.
R
4-CF
3
4-OCH
3
3-CF
3
4-Cl
4-F
H
CF
3
Entry
77
74
79
64
77
72

51
Interestingly, even though the 1,3-proton shift has been shown to occur under
simple thermal conditions, we were able to detect the presence of benzaldimine products
at temperatures well below 185 °C. As the reaction mixtures were heated from room
temperature, we were able to observe by
19
F NMR, the initial formation of one imine
isomer and its subsequent conversion to the rearranged isomer. After carefully
monitoring the formation of the ketimine and its rearrangement to the benzaldimine at
various stages of the reaction, it becomes evident that the rate-determining step in the
reaction is the initial imine formation. As observed from the enhancement of yield and
selectivity of the benzaldimine upon changing the solid acid morphology to more
accessible acidic sites, the reaction is in fact acid catalyzed. Thus elevated heating may
serve to merely ensure reaction completion in a more timely fashion.

3.3 Chapter 3: Conclusion
In conclusion, Nafion-H
®
and its silica supported form act as effective acid
catalysts in the one pot synthesis of trifluoromethylated benzaldimines from
trifluoromethylated ketones and benzylamines. The two-step reaction is clean, proceeds
with good yields and is general for a variety of ketones and benzylamines. The novel
products may also be easily converted to trifluoromethylated benzylamines, important
precursors for materials integral to pharmaceutical and industrial applications.

52
3.4 Chapter 3: Experimental
3.4.1 General Remarks
Substituted benzylamines and fluorinated ketones were purchased from
commercial sources and used as received. Nafion-K
®
was received as a generous gift
from DuPont and was converted to its acidic form following previously established
procedures.
31
Nafion-H
®
SAC 13 was purchased from commercial sources and finely
powdered before being using in reactions.
1
H,
13
C, and
19
F NMR spectra were all
recorded on a Varian NMR at 400 MHz.
1
H NMR chemical shifts were determined
relative to TMS as the internal standard (0.0 ppm).
13
C NMR chemical shifts were
determined relative to CDCl
3
at 77.0 ppm while
19
F NMR chemical shifts were
determined relative to CFCl
3
as the internal standard (0.0 ppm). Column chromatography
was carried out using Siliaflash G60 silica gel (70-230 mesh). HRMS data was obtained
from high resolution Micromass GCT (GC-MS TOF) spectrometer at the Mass
Spectrometry Facility, Department of Chemistry, University of Arizona.
3.4.2 Typical Procedure for the Synthesis of Substituted Imines
A solution of 2,2,2-trifluoroacetophenone (2 mmol, 0.348 g) in toluene (1 mL) is
first added to a pressure tube containing 0.10 g of Nafion-H
®
SAC 13. To this mixture, a
solution of benzylamine (3 mmol, 0.321 g) in toluene (1 mL) is slowly added with
stirring. The mixture is supplemented with another 1 mL of toluene, capped and finally
heated slowly to 185 °C. The reaction is then monitored by
19
F NMR and GC/MS. Upon
completion, the mixture is allowed to cool to room temperature, 50 mL of
dichloromethane was added and the mixture was filtered. The filtrate was then
53
concentrated under vacuum and purified by flash column chromatography using a
mixture of n-hexane and ethyl acetate (9:1). The solvent was removed in a rotary
evaporator and the product benzylidene-(2,2,2-trifluoro-1-phenyl-ethyl)-amine, was
obtained as a pale yellow oil (0.432 g, 82%).
3.4.3 Typical Procedure for the Hydrolysis of Substituted Imines
Benzylidene-(2,2,2-trifluoro-1-phenyl-ethyl)-amine (1 mmol, 0.272 g) is first
dissolved in 2 mL of diethyl ether and placed in a small vial. Hydrochloric acid (3N, 5
mL) is slowly added after which the vial is capped and stirred for 24 hours. Upon
completion (as determined by TLC) the reaction mixture is added to ice water (10 mL)
and then washed with diethyl ether (2 X 30 mL). The aqueous layer is then made slightly
basic by the addition of aqueous sodium hydroxide (3 N) after which the solution is
concentrated under vacuum to obtain the hydrochloride salt of 2,2,2-trifluoro-1-phenyl-
ethylamine.
3.4.4 Spectral Data:
Benzylidene-(2,2,2-trifluoro-1-phenyl-ethyl)-amine (Table 3.2a)
1
H NMR (400 MHz, CDCl3): δ 4.79 (q, 1H, J = 7.63 Hz), 7.349-7.47 (m, 6H), 7.56 (d,
2H, J = 7.50 Hz), 7.83 (dd, 2H, J
1
= 1.70 Hz, J
2
= 7.90 Hz), 8.37 (s, 1H);
13
C NMR (100
MHz, CDCl
3
): δ 75.07 (q, J = 28.23 Hz), 124.67 (q, J = 280.76 Hz), 128.57, 128.65,
128.79, 128.91, 128.98, 131.66, 134.98, 135.31, 165.81;
19
F NMR (376.1 MHz, CFCl
3
):
δ -74.35 (d, 3F, J = 7.63 Hz).
54
Benzylidene-[2,2,2-trifluoro-1-(4-fluoro-phenyl)-ethyl]-amine (Table 3.2b)
1
H NMR (400 MHz, CDCl
3
): δ 4.82 (q, 1H, J = 7.50 Hz), 7.12 (t, 2H, J = 8.70 Hz), 7.48
(m, 3H), 7.59 (dd, 2H, J = 5.60 Hz, J = 8.6 Hz), 7.88 (dd, 2H, J
1
= 1.50 Hz, J
2
= 8.00
Hz), 8.41 (s, 1H);
13
C NMR (100 MHz, CDCl
3
): δ 74.37 (q, J = 28.60 Hz), 115.55 (d, J =
21.6 Hz), 124.50 (q, J = 280.60 Hz), 128.70, 128.81, 130.46 (d, 1H, J = 8.2 Hz), 130.79,
131.79, 135.18, 163.00 (d, J = 247.70 Hz), 166.02;
19
F NMR (376.1 MHz, CFCl
3
): δ -
113.29 (d, 1F, J = 9.16 Hz), -74.63 (d, 3F, J = 7.63 Hz); HRMS (EI) for: C
15
H
11
F
4
N
Calcd. 281.0828, Found 281.0813.
Benzylidene-[1-(4-chloro-phenyl)-2,2,2-trifluoro-ethyl]-amine (Table 3.2c)
1
H NMR (400 MHz, CDCl
3
): δ 4.75 (q, 1H, J = 7.40 Hz), 7.41 (m, 7H), 7.82 (dd, 2H, J
1

= 1.60 Hz, J
2
= 8.00 Hz), 8.36 (s, 1H);
13
C NMR (100 MHz, CDCl
3
): δ 74.56 (q, J =
28.60 Hz), 124.51 (d, J = 281.20 Hz), 128.85, 128.94, 128.97, 130.22, 131.99, 133.55,
135.04, 135.25, 166.30;
19
F NMR (376.1 MHz, CFCl
3
): δ -74.51 (d, 3F, J = 7.63 Hz);
HRMS (EI) for: C
15
H
11
ClF
3
N Calcd. 297.0532, Found 297.0520.
Benzylidene-[1-(4-bromo-phenyl)-2,2,2-trifluoro-ethyl]-amine (Table 3.2d)
1
H NMR (400 MHz, CDCl
3
): δ 4.74 (q, 1H, J = 7.40 Hz), 7.46 (m, 7H), 7.82 (dd, 2H, J
1

= 1.60 Hz, J
2
= 8.10 Hz), 8.37 (s, 1H);
13
C NMR (100 MHz, CDCl
3
): δ 74.46 (q, J =
28.60 Hz), 123.11, 124.28 (q, J = 283.60 Hz), 128.70, 128.82, 130.38, 131.74, 131.84,
133.91, 135.08, 166.20;
19
F NMR (376.1 MHz, CFCl
3
): δ -74.51 (d, 3F, J = 7.63 Hz);
HRMS (EI) for: C
15
H
11
BrF
3
N Calcd. 341.0027, Found 341.0026.
55
Benzylidene-[2,2,2-trifluoro-1-(4-trifluoromethyl-phenyl)-ethyl]-amine (Table 3.2e)
1
H NMR (400 MHz, CDCl
3
): δ 4.84 (q, 1H, J = 7.40 Hz), 7.47 (m, 3H), 7.68 (dd, 4H, J
1

= 8.30 Hz, J
2
= 25.50 Hz), 7.84 (dd, 2H, J
1
= 1.50 Hz, J
2
= 8.00 Hz), 8.40 (s, 1H);
13
C
NMR (100 MHz, CDCl
3
): δ 74.71 (q, J = 28.80 Hz), 123.89 (q, J = 272.30 Hz), 124.14
(q, J = 261.40 Hz), 125.48, 125.52, 128.74, 128.87, 129.21, 131.11 (q, J = 32.50 Hz),
131.97, 134.99, 138.77, 166.52;
19
F NMR (376.1 MHz, CFCl
3
): δ -63.25 (s, 3F), -74.29
(d, 3F, J = 7.60 Hz).
Benzylidene-[2,2,2-trifluoro-1-(3-trifluoromethyl-phenyl)-ethyl]-amine (Table 3.2f)
1
H NMR (400 MHz, CDCl
3
): δ 4.83 (q, 1H, J = 7.40 Hz), 7.46 (m, 4H), 7.62 (d, 1H, J =
7.80 Hz), 7.78 (d, 1H, J = 7.70 Hz), 7.85 (m, 3H), 8.40 (s, 1H);
13
C NMR (100 MHz,
CDCl
3
): δ 74.96 (q, J = 28.70 Hz), 124.09 (q, J = 272.30 Hz), 124.38 (q, J = 269.20 Hz),
125.80 (m), 125.97 (q, J = 3.70 Hz), 128.91, 129.07, 129.27, 131.16 (q, J = 32.51 Hz),
132.34, 132.49, 135.17, 136.09, 166.76;
19
F NMR (376.1 MHz, CFCl
3
): δ -69.10 (s, 3F), -
74.45 (d, 3F, J = 7.40 Hz); HRMS (EI) for: C
16
H
11
F
6
N Calcd. 331.0796, Found
331.0790.
Benzylidene-(2,2,2-trifluoro-1-p-tolyl-ethyl)-amine (Table 3.2g)
1
H NMR (400 MHz, CDCl
3
): δ 2.32 (s, 3H), 4.74 (q, 1H, J = 7.60 Hz), 7.17 (d, 2H, J =
7.90 Hz), 7.39 (m, 5H), 7.80 (dd, 2H, J
1
= 1.60 Hz, J
2
= 7.90 Hz), 8.32 (s, 1H);
13
C NMR
(100 MHz, CDCl
3
): δ 21.26, 74.77 (q, J = 28.40 Hz), 124.92 (q, J = 280.80 Hz), 128.75,
128.87, 129.42, 131.71, 132.17, 135.50, 138.91, 165.76;
19
F NMR (376.1 MHz, CFCl
3
):
δ -74.38 (d, 3F, J = 7.63 Hz); HRMS (EI) for: C
16
H
14
F
3
N Calcd. 277.1078, Found
277.1082.
56
Benzylidene-[2,2,2-trifluoro-1-(4-methoxy-phenyl)-ethyl]-amine (Table 3.2h)
1
H NMR (400 MHz, CDCl
3
): δ 3.81 (s, 3H), 4.75 (q, 1H, J = 7.70 Hz), 6.92 (d, 2H, J =
8.90 Hz), 7.44 (m, 5H), 7.83 (dd, 2H, J
1
= 1.60 Hz, J
2
= 8.00 Hz), 8.37 (s, 1H);
13
C NMR
(100 MHz, CDCl
3
): δ 55.29, 74.45 (q, J = 28.50 Hz), 113.98, 124.75 (q, J = 280.80 Hz),
127.09, 128.66, 128.77, 129.91, 131.61, 135.39, 159.97, 165.54;
19
F NMR (376.1 MHz,
CFCl
3
): δ -74.68 (d, 3F, J = 7.63 Hz); HRMS (EI) for: C
16
H
14
F
3
NO Calcd. 293.1027,
Found 293.1034.
Benzylidene-(2,2,2-trifluoro-1-thiophen-2-yl-ethyl)-amine (Table 3.2i)
1
H NMR (400 MHz, CDCl
3
): δ 5.11 (q, 1H, J = 7.20 Hz), 7.04 (dd, 1H, J
1
=3.60 Hz, J
2
=
5.10 Hz), 7.19 (d, 1H, J = 3.60 Hz), 7.35 (dd, 1H, J
1
= 1.20 Hz, J
2
= 5.10 Hz), 7.45 (m,
3H), 7.83 (dd, 2H, J
1
= 1.50 Hz, J
2
= 8.10 Hz), 8.37 (s, 1H);
13
C NMR (100 MHz,
CDCl
3
): δ 70.59 (q, J = 30.00 Hz), 123.98 (q, J = 280.80 Hz), 126.66, 126.74, 126.93,
128.68, 128.89, 131.88, 134.98, 136.26, 166.34;
19
F NMR (376.1 MHz, CFCl
3
): δ -74.95
(d, 3F, J = 7.63 Hz); HRMS (EI) for: C
13
H
10
F
3
NS Calcd. 269.0486, Found 269.0480.
57
3.4.5 Representative Spectra:
1
H NMR spectrum of Benzylidene-(2,2,2-trifluoro-1-p-tolyl-ethyl)-amine (Table 3.2g)

ppm (t1)
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
1.00
2.00
5.02
2.16
1.00
3.08
N
H
H CF
3
CH
3
58
3.4.5 Representative Spectra (continued):
13
C NMR spectrum of Benzylidene-(2,2,2-trifluoro-1-p-tolyl-ethyl)-amine (Table 3.2g)

ppm (t1)
0 50 100 150
N
H
H CF
3
CH
3
59
3.4.5 Representative Spectra (continued):
19
F NMR spectrum of Benzylidene-(2,2,2-trifluoro-1-p-tolyl-ethyl)-amine (Table 3.2g)

ppm (t1)
-50 0
ppm (t1)
-74.60 -74.50 -74.40 -74.30
N
H
H CF
3
CH
3
60
3.5 Chapter 3: References

1. Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-VCH: Weinheim, 2004.
2. Chambers, R. D. Fluorine in Organic Chemistry; Blackwell: Oxford, 2004.
3. Smart, R. E.; Banks, B. E.; Tatlow, J. C. Organofluorine Chemistry: Principles
and Commercial Applications; Plenum: New York, 1994.
4. Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; Wiley: New
York, 1991.
5. Banks, R. E. Organofluorine Chemicals and their Industrial Applications; Ellis
Harwood: New York, 1979.
6. Peters, R. Carbon-Fluorine Compounds Chemistry, Biochemistry and Biological
Activities. A Ciba Foundation Symposium; Elsevier: Amsterdam, 1972.
7. Walsh, C. T. Ann. Rev. Biochem. 1984, 53, 493.
8. Dolbier Jr., W. R. J. Fluorine. Chem. 2005, 126, 157.
9. Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds.; Biomedical Frontiers of Fluorine
Chemistry; American Chemical Society: Washington, DC, 1996.
10. Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J. P.; Leger,
S.; Li, C. S.; Masse, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud,
J.; Tsou, N.; Zamboni, R,. Bioorg. Med. Chem. Lett. 2005, 15, 4741.
11. Li, C. S.; Deschenes, D.; Desmarais, S.; Falgueyret, J.-P.; Gauthier, J. Y.;
Kimmel, D. B.; Leger, S.; Masse, F.; McGrath, M. E.; McKay, D. J.; Percival, M.
D.; Riendeau, D.; Rodan, S. B.; Therien, M.; Truong, V.-L.; Wesolowski, G.;
Zamboni, R.; Black; W. C. Bioorg. Med. Chem. Lett. 2006, 16, 1985.
12. Bohm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.; Muller, K.; Obst-
Sander, U.; Stahl, M. ChemBioChem. 2004, 5, 637.
13. Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.Y.; Volante, R. P.
Org. Lett. 2005, 7, 355.
14. Torok, B.; Prakash, G. K. S. Adv. Synth. Catal. 2003, 345, 165.
15. Gong, Y.; Kato, K. Tetrahedron: Asymmetry, 2001, 12, 2121.
16. Gong, Y.; Kato, K.; Kimoto H. Bull. Chem. Soc. Jpn. 2002, 75, 2637.

61

17. Katagiri, T.; Takahashi, M.; Fujiwara, Y.; Ihara, H.; Uneyama, K. J. Org. Chem.
1999, 64, 7323.
18. Lebouvier, N.; Laroche, C.; Huguenot F.; Brigaud, T. Tetrahedron Lett. 2002, 43,
2827.
19. Blazejewski,J.-C.; Anselmi E.; Wilmshurst, M. P. Tetrahedron Lett. 1999, 40,
5475.
20. Yokoyama, Y.; Mochida, K., Tetrahedron Lett. 1997, 38, 3443.
21. Nelson, D.; Owens, J.; Hiraldo, D., J. Org. Chem. 2001, 66, 2572.
22. Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew, Chem. Int. Ed. 2001, 40, 589.
23. Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757.
24. Soloshonok, V. A.; Berbasov D. O. J. Fluorine Chem. 2004, 125, 1757.
25. Berbasov, D. O.; Ojemaye, I. D.; Soloshonok, V. A. J. Fluorine Chem. 2004, 125,
603.
26. Soloshonok, V. A.; Yasumoto, M. J. Fluorine Chem. 2007, 128, 170.
27. Ono, T.; Kukhar, V. P.; Soloshonok, V. A. J. Org. Chem. 1996, 61, 6563.
28. Soloshonok, V. A.; Kirilenko, A. G.; Kukhar, V. P.; Ono, T. Tetrahedron Lett.
1994, 35, 3119.
29. Soloshonok, V. A.; Kirilenko, A. C.; Galushko, S. V.; Kukhar, V. P. Tetrahedron
Lett. 1994, 35, 5063.
30. Yasumoto, M.; Ueki, H.; Soloshonok, V. A., J. Fluorine Chem. 2007, 128, 736.
31. Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis, 1986, 7, 513.
32. Mauritz, K. A.; Moore R. B. Chem. Rev. 2004, 104, 4535.
33 Conolly, D. J.; Gresham, W. F. U.S. Patent 3,282,875, 1966.
34. Hsu, W. Y.; Gierke, T. D. J. Membr. Sci. 1983, 13, 207.
35. Harmer, M. A.; Farneth, W. E.; Sun Q. J. Am. Chem. Soc., 1996, 118, 7708.
36. Harmer, M. A.; Sun, Q.; Vega, A. J.; Farneth, W. E.; Heidekum, A.; Hoelderich,
W. F. Green Chemistry, 2000, 7.
62
4 Chapter 4: Superacid Assisted Aromatic Sulfonation and
Alkylsulfonation Reactions towards the Sulfonation of
Proton Exchange Fuel Cell Membranes

4.1 Chapter 4: Introduction
In light of dwindling supplies and negative socio-economic and environmental
effects, governments all over the world have tried to encourage the development of
several cleaner, more efficient alternatives to fossil fuels.
1
As a result of these efforts,
solar, geothermal and wind energy programs have all seen tremendous growth, however,
the most promising new way to harness energy may be through the use of fuel cells. Fuel
cells are electrochemical devices consisting of an electrolyte in contact with two
electrodes that is capable of converting a consumable fuel into electrochemical energy.
Proton Exchange Membrane or Polymer Electrolyte Membrane (PEM) fuel cells utilize a
solid polymer electrolyte instead of a liquid or solution, which may allow the cell to
operate at lower temperatures and generate higher specific power and power density than
other fuel cell variations.
2

Most PEMs rely on acidic functionalities for proton exchange and the most
commonly utilized materials for these purposes continues to be the previously described
Nafion resins (see Chapter 1) developed by Dupont. Nafion has been renowned for its
stability, conductivity and strength. Yet, there has arisen recently an interest in
developing better or more broadly applicable membranes. Many of these promising new
materials are in fact, polyaromatic-sulfonic acids that can be both inexpensive and simple
to manufacture.
63
These include polymers incorporating poly(styrenesulfonic acid) (PSSA),
3,4

sulfonated polyphosphazenes (SPOP),
5
sulfonated poly(ether ether ketones) (SPEEK),
6,7

sulfonated benzimidazoyl based polymers (SPPBI),
8,9
sulfonated polybenzothiazoles
(SPBT)
10
and others
11,12
(Figure 4.1). However, the last step in synthesizing these films
is usually a direct sulfonation reaction and it is this step that initially drew our interest.
Figure 4.1 – Alternative Polyaromatic Sulfonic Acid Membranes
SO
3
H
n
N
N
H
N
N
SO
3
H
n
O O
SO
3
H
C
O
n
S
N
S N
S
O
HO
3
S
SO
3
H
O
n
SPBT
SPPBI
PSSA
SPEEK
N P
O
O
R
SO
3
H
SO
3
H
HO
3
S
n
SPOP

Aromatic sulfonation has been postulated, studied, and documented for decades
yet the reaction and its applications continue to evolve and inspire. Products of
sulfonation reactions and their derivatives have been used as protecting and leaving
groups, featured within molecules of medicinal importance and, of course, incorporated
into polymers and other industrial materials like dyes and detergents. The sulfonation of
aromatic compounds in particular, involves the addition of sulfur trioxide (SO
3
) to an
arene in a typical electrophilic aromatic substitution reaction (Scheme 4.1).
13,14

64
Scheme 4.1 – Electrophilic Aromatic Sulfonation
SO
3
+
H SO
3
H SO
3
HSO
3
-
+
SO
3
SO
3
H
+
+
SO
3
H

Sulfonation can generally be carried out with SO
3
itself or the host of other
sulfonating reagents that have been reported including sulfur trioxide addition
compounds, sulfuric acid at various concentrations, halosulfonic acids, sulfonate salts and
many others. Such reagents can, however, be difficult to control and handle during the
course of reactions and sulfonations have been known to be accompanied by numerous
side reactions like sulfonylations and desulfonations.
13,14
Therefore, we decided to
investigate superacid assisted sulfonation reactions involving several unconventional
sources of sulfur trioxide. However, along with the sulfonation reactions, these studies
unexpectedly lead to additional transformations such as sulfonylation reactions and the
synthesis of organosulfones.
65
4.2 Chapter 4: Results and Discussion
4.2.1 Superacid Assisted Synthesis of Symmetrically Substituted Diaryl Sulfones
Organosulfones have long been known as versatile and interesting organic
building blocks. Aryl sulfones in particular are important compounds in both classical
organic synthesis and the pharmaceutical industry due to their prominent structural role in
the backbones of several important drugs. Dapsone (diamino-diphenyl sulfone) for
instance, remains one of the most visible diarylsulfone based drugs though it was
originally developed as a treatment for leprosy.
15,16
Over time, the drug and related
compounds have been found active against many different microorganisms causing
diseases such as malaria,
17,18,19
leishmaniasis,
20
and more recently human
immunodeficiency virus (HIV).
21
Aryl sulfones have also been used extensively in
agricultural areas as pesticides and even in industrial processes as polymer precursors.
Such a diverse range of applications for aryl sulfones has therefore inspired the
development of many different routes to their synthesis over the years (Figure 4.2).
Figure 4.2 – Common Sulfone Containing Compounds
S
O
O
NH
2
H
2
N
Dapsone
N
N
CF
3
S
H
2
N
O
O
Celecoxib (Celebrex
TM
)
S Cl Cl
Cl
Cl
O
O
Tetradifon (pesticide)
S
N
S
Promizole (antibiotic)
O
O
H
2
N
NH
2
O
S
CF
3
N
N
HN
O O
O
O
O
Ponazuril (equine antibiotic)
F
S
O
O
Fluoresone
(anticonvulsant)

66
Diaryl sulfones were first observed as byproducts of electrophilic aromatic
sulfonation reactions carried out with SO
3
or oleum (H
2
SO
4
.SO
3
) for the preparation of
arylsulfonic acids.
13,14
Usually, this type of synthesis, however, only yields limited
amounts of sulfone. The harsh reaction conditions employed can frequently promote the
formation of a number of other unwanted products. Other more efficient methods such as
Friedel-Crafts type aromatic sulfonylation with sulfonyl halides,
22
oxidation of
corresponding aryl sulfides,
23
and reactions of sulfonyl halides with boronic acids
24,25,26
have been proposed. Recently, we reported the sulfonylation of aromatic compounds
using sulfonic acids in the presence of Nafion-H
27
while others have also reported similar
reactions utilizing triflic anhydride (Tf
2
O)
28,29
instead. Additionally, Dubac and
coworkers have also shown that arylsulfonyl halides may sulfonylate a variety of
aromatic substrates under microwave conditions using FeCl
3
and other Lewis acid
catalysts.
30
However, very few reactions are able to cleanly produce diaryl sulfones
directly from aromatics under relatively mild conditions.
Among the promising class of sulfonylating reagents, the various complexes of
sulfur trioxide are not well studied. Because of the electron deficient nature of the sulfur
atom at the center of SO
3
, the molecule acts as a strong electron acceptor (a strong Lewis
acid) and undergoes polymerization, forms hydrates and complexes with other Lewis
bases.
31
The resulting compounds vary broadly in their stability and reactivity depending
upon the strength of the base employed. Freshly distilled, monomeric SO
3
for example,
exothermically sulfonates aromatics almost instantaneously to produce sulfonic acids,
diarylsulfones, arylsulfonyl anhydrides and many other products. On the other hand, the
complex between SO
3
and dioxane, a moderately strong Lewis base, produces a complex
67
that sulfonates benzene cleanly at room temperature in 24 hours. The complex is however
unstable and usually must be prepared immediately before use as it decomposes over
time. A more attractive alternative is pyridine-SO
3
, one of the most stable complexes of
SO
3
. The complex has been shown useful in the sulfation of biologically important
alcohols, sulfamation of amines, amides and proteins and even the sulfonation of some
highly activated aromatics. However, pyridine-SO
3
fails to sulfonate less active aromatics
even upon prolonged heating at 150 ºC. Yet, because of its stability and commercial
availability, pyridine-SO
3
remains an attractive alternative to other sulfonating agents.
Though SO
3
is usually thought of as primary species in aromatic sulfonation reactions,
we reasoned that the electrophilicity of pyridine-SO
3
could be increased by using a
superacid to protonate one of the oxygen atoms of the complex.
However, in the presence of the superacid triflic acid (CF
3
SO
3
H) and benzene as a
substrate, the reaction produced diphenyl sulfone in almost quantitative yields instead of
phenylsulfonic acid. The reaction was also attempted with superacidic boron trifluoride
monohydrate (BF
3
.H
2
O) with similar results. We found such an outcome intriguing as
even stoichiometric ratios of complex and arene still lead to sulfones as the only product.
On the other hand, reactions carried out on polymeric aromatics still lead to acidic
polymers. We propose therefore that protonation of one oxygen atom of the sulfur
trioxide group might be followed by nucleophilic attack by one aromatic group and
subsequent cleavage of the N-S bond in the pyridine-SO
3
complex. The resultant
arenesulfonic acid is then protonated once more which leads to a second arylation leading
to sulfone with the loss of a molecule of water (Scheme 4.2).
68
Scheme 4.2 – Mechanism of Pyridine-SO
3
Sulfonylation Reaction
N
S
O
O
SO
3
R R
N
S O O
OH
R
H
+
ArH
R
S
O
O
OH
2
R
H
+
ArH

This sulfonylation reaction proved general for a variety of monomeric aromatic
species. Though the reaction takes place at elevated temperatures over the course of
several hours, we were still able to sulfonylate even deactivated aromatics such as
halobenzenes in moderate yields (Table 4.1). While all reactions may not have gone to
completion, the complex remained intact after reactions with no evidence of side
reactions or substituted sulfonic acids.
We reason that arylsulfonic acids produced during the first step undergo
subsequent arylation under superacidic conditions. We previously described sulfonylation
reactions between sulfonic acids and arenes as occurring slowly, over the course of
several hours in the presence of Nafion-H
®
. In this particular case, higher temperatures,
and the homogenous and hygroscopic nature of our catalyst may have dramatically
accelerated the rate at which a second nucleophilic attack occurs and the rate at which
water is eliminated. The fact that this phenomena were not clearly observed in polymers
can be due to a variety of factors including the greater distances between aromatic side
chains in a polymer matrix and even and the existence of both sulfone cross-linkages and
sulfonic acids.
69
Table 4.1 – Pyridine-SO
3
Aromatic Sulfonylation Reaction
N
S
O
O
CF
3
SO
3
H
100
o
C
SO
3
R
+
R
R

CH
3
CH
3
H
3
C
CH
3
CH
3
CH
3
H
3
C
F
Cl
Br
Aromatic
Product Yield (%)
S
O
O
S
O
O
CH
3
H
3
C
S
O
O
H
3
C
CH
3
CH
3
H
3
C
S
O
O
CH
3
CH
3
H
3
C
H
3
C
S
O
O
CH
3
H
3
C CH
3
H
3
C
S
O
O
F F
S
O
O
Cl Cl
S
O
O
Br Br
Ph
S
O
O
Ph Ph
75
83
77
78
88
59
52
33
63
tBu
S
O
O
tBu tBu
50
Entry
a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
Time (hr)
18
18
18
18
18
18
18
24
24
24
(p-p = 60%)

70
4.2.2 Superacid Assisted Synthesis of Thiochroman-dioxides
Much like sulfur-trioxide complexes, sultones are another intriguing class of
sulfur based synthons. As sulfur analogues of lactones, sultones can be easily prepared
from a number of simple synthetic methods but the most common of these are the
cyclization of sulfonic acids and their derivatives and the sulfonation of olefins. These
reactions give rise to sultones of varying ring sizes, side groups and, as a result of these
two factors, varying reactivities and stabilities.
32
Five and six-membered sultones in
particular have been exploited in ring-opening reactions with hydrides, alkoxides,
organometallics, halide anions and amines.
33
Ring opening reactions thus can yield
alkylsulfonic acids and salts of tremendous utility and diversity. In particular, 1,3-
propane sultone and its derivatives have been used as precursors for pharmaceuticals
34

and ionic liquids,
35,36
as protein modifiers,
37
electrolyte additives in lithium ion batteries
38

and as surfactants.
39,40
Our interests however, lie in the use of 1,3-propane sultone as a
surface modifier.
Many applications require the presence of an acid or charged species on surfaces
and there have been many publications put forth that seek to utilize 1,3-propane sultone
in such a fashion. The sultone has been used for instance in the synthesis of cation-
exchange membranes by sulfo-alkylation reactions of cellulose, cellulose acetate and
polyacrylnitrile.
41
1,3-Propane sultone has been used to sulfo-alkylate zeolite membranes
in direct methanol fuel cells in order to decrease permeability and cross-over rates.
42
In
both of these cases however, sultone ring opening is accomplished by hetero-atom based
nucleophiles and very few examples of Friedel-Crafts type sulfo-alkylation reactions
have been described for polymers. Friedel-Crafts reactions of sultones were first reported
71
by Truce and Hoerger during the 1950’s using aluminium chloride as a catalyst.
43
The
reactions produced only aryl-alkylsulfonic acids in good yields with no evidence of
subsequent ring closing sulfonylation observed (Scheme 4.3).
Scheme 4.3 – Aluminium Chloride Catalyzed Alkylation of Butane Sultone
+
O
S
S
O Na
O
O
R
R
1) AlCl
3
2) Na
2
CO
3
O O
[R = H or CH
3
]

In the following years, very few advances in the field have been reported
32
as
most researchers have focused on other methods like the oxidation of the corresponding
aromatic alkylsulfides or disulfides.
44,45,46
Though seemingly very practical, this approach
also can lead to side products due to over-oxidation and decomposition depending upon
the oxidant utilized. Therefore, in our ongoing attempts to find new methods of
sulfonating aromatic polymers, we decided to examine the use of 1,3-propane sultone in
Friedel-Crafts reactions as catalyzed by superacids. Such an approach could also provide
a metal free route to sulfo-alkylation that could be applied to aromatic polymer
membranes.
We began our studies by looking at the reaction of 1,3-propane sultone with
benzene in the presence of triflic acid (CF
3
SO
3
H). After workup and purification steps,
the product was identified not as 3-phenyl-propane-1-sulfonic acid but thiochroman 1,1-
dioxide, the product of Friedel-Crafts cycloalkylation-sulfonylation (alkylation followed
by cyclization through intramolecular sulfonylation). Similar results were also obtained
when the reaction was attempted using boron trifluoride monohydrate (BF
3
.H
2
O) albeit
with lower yields. Interestingly, we also found that the reaction went essentially to
72
completion at temperatures much lower than those cited by Truce and Hoerger
43
with
almost no evidence of acid products detected (Scheme 4.4).
Scheme 4.4 – Mechanism of Propane Sultone Ring Alkyation and Closing
S
O
O
O
H
+
ArH
S
H
O
O
O
R
H
+
S
O
O
OH
2
R S
O O
R

Similar to our previous studies with pyridine-SO
3
complexes, the reaction of 1,3-
propane sultone is expected to begin with the protonation of the bridging oxygen atom.
This weakens the sultone’s C-O bond and forms an electrophilic carbocation center,
which quickly undergoes attack by an arene nucleophile. The resultant sulfonic acid
undergoes intramolecular sulfonylation to produce energetically favored, six-membered
heterocycles, the corresponding thiochroman-1,1-dioxides. Overall, the reaction can be
considered as Friedel-Crafts cycli-alkylation-sulfonylation.
With some modifications however, Friedel-Crafts, alkylsulfonylation reactions of
1,3-propane sultone could be applied to a number of aromatic species to yield a range of
substituted thiochroman 1,1-dioxides (Table 4.2). Alkylsulfones in general have become
increasingly attractive to chemists in many areas because of their ease of preparation and
their ability to form carbanions at the α-position to the sulfone group. This allows for the
preparation of a broad range of sulfones while simultaneously introducing a large amount
of diversity in α-substituents. Thiochroman dioxides in particular, are an unexplored class
of sulfone derivatives due to the lack of many efficient routes for their synthesis. Our new
method thus presents an efficient and facile route to these interesting species thereby
opening them up for further exploration and exploitation.
73
Table 4.2 – Aromatic Alkyl-Sulfonylation Reaction
S
O
O
O
R
CF
3
SO
3
H
+
S
O O
R

CH
3
CH
3
H
3
C
CH
3
CH
3
CH
3
H
3
C
F
Cl
Br
Yield (%)
98
95
93
91
89
CH
3
H
3
C
H
3
C
CH
3
81
63
50
40
Aromatic Products (ratio o:m:p)
S
O O
S
O O
S
O O
S
O O
S
O O
S
O O
S
O O
S
O
O
CH
3
CH
3
H
3
C
H
3
C
H
3
C
CH
3
F
Cl
CH
3
CH
3
H
3
C
H
3
C
H
3
C
Entry
a.
c.
d.
e.
i.
b.
f.
g.
h.
Time (hr) Temp. (°C)
80 18
80 18
80 18
80 18
80 18
100 24
100 24
100 24
80 18
(32:30:38)
(17:0.5:82.5)
(34:17:49)
S
O
O
H
3
C
H
3
C
S
O O
Br
(35:22:43)
(40) (60)

74
4.2.3 Sulfonation and Alkylsulfonation of Polymer Membranes
Our group has previously reported the synthesis of poly(styrenesulfonic) acid
(PSSA) – poly(vinylidene fluoride) (PVDF) composites as low cross-over proton
exchange membranes for direct methanol fuel cells (DMFC).
47
The material is made by
initially hot-pressing or casting a PVDF membrane as an inert matrix and then
impregnating with styrene polymerized with cross-linked divinyl benzene followed by
sulfonation (Figure 4.2). Though PSSA-PVDF has proven itself an excellent alternative
to Nafion
®
, we have still sought ways to improve its production and properties. The one
area identified as particularly open to improvement was the sulfonation of the membrane
following co-polymerization.
Figure 4.3 – Poly(vinylidinefluoride) - Polystyrene
n
H
2
C
F
2
C
m
PVDF Matrix
Polystyrene

As previously mentioned, the sulfonation of polymer membranes has begun to
receive great attention with the growing prominence of PEM fuel cells. As a result of
this, there has been more emphasis on reactions that can be carried out safely,
economically and in an environmentally friendly manner. Quite often, chlorosulfonic acid
is chosen as the sulfonating agent due to its high reactivity. However, chlorosulfonic acid
and many other commonly utilized sulfonating agents
48,49
are highly toxic and corrosive
75
and can react violently. With many different and promising membranes types being
developed
50
already, there is still a need for sulfonation methods that are safer, cleaner
and easier to carry out. In our efforts towards alternative sulfonation methods, we
therefore focused on the use of less expensive, non-traditional and safer SO
3
sources that
could be attached to the PVDF/PS backbone in reactions catalyzed by superacids. We
have already described the use of both 1,3-propane sultone and pyridine-SO
3
as
sulfonylation reagents for aromatic compounds but more interesting, is their use as
sulfonating agents for aromatic polymers. We decided to investigate these reactions along
with superacid promoted, polymer alkylsulfonation reactions with 2-methyl-prop-2-ene-
1-sulfonic acid and 3,3,4,4-tetrafluoro-(1,2)-oxathietane 2,2-dioxide.
Reactions were generally carried out on polystyrene as a control before being
tested PVDF/PS which, because of its thickness (125–350 μm), was allowed to first swell
in chloroform in an attempt to increase its permeability and ensure more uniform
reaction. To this mixture was added a sulfonating agent along with superacid and the
entire solution was then stirred and heated for a specific amount of time. Afterwards, the
polymer was filtered, soaked in distilled water and then compared to Nafion
®
resins by
examining its equivalent weight, one of the parameters used to determine the proton
conductivity of polymers. A polymer’s equivalent weight, much like liquid acids,
indicates the mass of the material containing one mole of protons. More acidic
compounds will, therefore, tend to have a lower measure of equivalent weight and greater
proton conductivity than those that are less acidic.
We monitored our reactions therefore, by comparing them to commercially
available Nafion117 for instance, which has an equivalent weight of 1100. The course of
76
reactions could also often be estimated visually as most polymers tended to darken
appreciably but we generally found equivalent weight measurements a much more
accurate indicator of reaction completion. Pyridine-SO
3
, for instance, was found to
sulfonate aromatic polymers in the presence superacid (Scheme 4.5) with better
equivalent weights being obtained with Triflic acid instead of BF
3
.H
2
O. Both systems
proceeded noticeably slower than analogous reactions with either chlorosulfonic acid or
sulfur trioxide, and had to be heated to temperatures that we feared would lead to
sulfonylation (Table 4.3) as in our previous experiments.
Scheme 4.5 – Sulfonation of Polymers by Superacidic Activation of Pyridine-SO
3

N
SO
3
+
Polymer
H
+
N
S O O
OH
SO
3
H
n
n
n

Table 4.3 – Polymer Acidity after Superacidic Sulfonation with Pyridine-SO
3

Entry Time (Hr) Acid Temp. (°C) Eq. Weight Polymer
BF
3
.H
2
O
CF
3
SO
3
H
CF
3
SO
3
H
80
90
80
12
72
48
817
1200
3020
a.
b.
c.
Polystyrene
PVDF-PSSA
PVDF-PSSA

The reactions of pyridine-SO
3
with polymeric structures however, still seem to
produce films with large equivalent weights. This may be due to many factors including
the use of excess pyridine-SO
3
, the much more dilute reaction conditions used with
polymers or even the fact that reactions were carried out on a solid polymer instead of a
more mobile liquid phase. Because the results seemed promising, a larger sample of
77
pyridine-SO
3
sulfonated PVDF-PS was made and tested in a working Direct Methanol
Fuel Cell (DMFC). The membrane was allowed to run at 90 °C with a 0.5 M solution of
methanol at the anode and the results compared to a standard Nafion-117 membrane
(Figure 4.3).
Figure 4.4 – Performance of PVP-SO
3
Sulfonated Membrane
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 25 5 10 15 20
I (mA/cm
2
)
E (V)
90 °C
0.5 M MeOH
0.1 L/min O
2
PVP-SO
3
Nafion117

Though the PVP-SO
3
sulfonated membrane showed a good measure of acidity in
titration experiments, its performance under standard conditions was rather inconsistent.
While the membrane starts at a higher open circuit potential, this tends to drop off rather
quickly as the current density increases. This fact points to a dramatic increase in the
membrane’s internal resistance but it cannot be easily ascertained whether this is due to a
specific chemical or physical characteristic of the membrane. Because PVP-SO
3
is known
to form sulfones under similar conditions, some sulfone cross-linkages may indeed have
formed causing a significant performance drop. However, this cannot completely address
the problem at hand as sulfone based polymers have themselves been used as proton
exchange membranes with reasonable results.
9

78
As a more acceptable explanation, the decrease in the membrane’s efficiency may
be attributed to the nature of the method in which it was prepared. While PVDF-PS has
been sulfonated with various other strong acids, the prolonged heating of the membrane
in the presence of triflic acid may lead to at least some chemical degradation even after
sulfonation has occurred. This explanation appears to have some merit as membranes
were frequently found to become brittle and darkened after reaction.
Along with direct sulfonation reactions, we were also interested in alkyl-
sulfonation reactions as a means of adding sulfonic acid groups to polymers. Unlike
direct methods, the insertion of an alkyl chain between the aromatic and sulfonic acid can
help to eliminate desulfonation reactions and allow such membranes to be used at higher
temperatures than previously possible.
3
Incorporation of alkyl chains is expected to
increase the mechanical stability and flexibility of the membranes over the course of their
use. Alkyl-sulfonation reactions were thus carried out with 1,3-propane sultone in the
presence of superacids (Scheme 4.6). The resultant membranes were generally formed
faster than those with pyridine-SO
3
and showed comparable equivalent weights (Table
4.4). Once again, any sulfone cross-linkages that may have occurred appear not to have
affected the general outcome of the reaction even though the presence and extent of these
linkages have not been truly explored.
Scheme 4.6 – Superacid Assisted Alkyl-Sulfonation of Polymers
S
O
O
O
+
Polymer
H
+
S
H
O
O
O
(CH
2
)
3
SO
3
H
n
n
n

79
Table 4.4 – Polymer Acidity after Superacidic Alkyl-Sulfonation
Entry Time (Hr) Acid Temp. (°C) Eq. Weight Polymer
BF
3
.H
2
O
CF
3
SO
3
H
CF
3
SO
3
H
100
80
80
48
48
48
1776
1201
2300
a.
b.
c.
Polystyrene
PVDF-PSSA
PVDF-PSSA

We also examined the reactions between polymeric structures and 3,3,4,4-
tetrafluoro-1,2-oxathietane 2,2-dioxide or tetrafluoroethane β-sultone. It was initially
hoped that ring opening and alkylation of this particular sultone would result in aromatic
perfluorinated sulfonic acids however this was not to be the case. Though the reaction of
the sultone with polystyrene produced a material of excellent acidity, further experiments
were hampered by the generally unstable nature of this particular sultone and its low
boiling point.
Scheme 4.7 – Superacid Assisted Perfluoroalkyl-sulfonation of Polystyrene
+
Polymer
H
+
(CF
2
)
2
SO
3
H
O S
O
O
F
F F
F
HO S
O
O
F
F F
F
n
n
n

Entry Time (Hr) Acid Temp. (°C) Eq. Weight Polymer
CF
3
SO
3
H 100 72 388 a. Polystyrene

One of the final sulfonate sources examined was the sodium salt of 2-methyl-
prop-2-ene-1-sulfonic acid (Scheme 4.8). Unlike many of the previous substrates, this
particular alkenyl-sulfonic acid was first activated by protonation of the substituent
alkene functionality. This creates a stable tertiary carbocation for electrophilic alkylation
on aryl functionalities within the polymer membranes and lead to acids attached by fairly
80
lengthy alkyl chains. The salt tended to dissolve completely in BF
3
:H
2
O and only slightly
in triflic acid and organic solvents which may have affected the extent of those particular
alkylation reactions. Whereas reactions with BF
3
:H
2
O occur fairly slowly yet still yielded
membranes of better equivalent weight, reactions with triflic acid took place fairly
quickly but at a higher temperature and lead to less acidic membranes (Table 4.5).
Scheme 4.8 – Superacid Assisted Activation and Arylation of Alkenes
+
Polymer
H
+
SO
3
Na
H
3
C
SO
3
Na
CH
3
C(CH
3
)
2
CH
2
SO
3
Na
n
n
n

Table 4.5 – Polymer Acidity after Superacidic Arylation of Alkenes
Entry Time (Hr) Acid Temp. (°C) Eq. Weight Polymer
BF
3
.H
2
O
CF
3
SO
3
H 80
70
24
72
2488
1750
a.
b.
PVDF-PSSA
PVDF-PSSA

4.3 Chapter 4: Conclusion
The addition of sulfonic acid groups to Proton Exchange Membranes can be
achieved by superacid assisted alkyl-sulfonation or sulfonylation reactions with pyridine-
SO
3
, 1,3-propanesultone, 2-methyl-2-propene-sulfonic acid and tetrafluoroethane β-
sultone. Subsequent conductivity measurements show that such sulfonated materials may
be good candidates for fuel cell applications though there is still much room for
improvement in both methodologies and results. The methods described can also be
applied to simple aromatic systems to produce novel, symmetrically substituted
diarylsulfones and thiochroman-1,1-dioxides in good yields.
81
4.4 Chapter 4: Experimental
4.4.1 General Remarks
Unless otherwise mentioned, all chemicals were purchased from commercial
sources and used as received.
1
H,
13
C, and
19
F NMR spectra were recorded on a Varian
NMR at 400 MHz.
1
HNMR chemical shifts were determined relative to TMS, the internal
standard at δ 0.0 ppm.
13
C NMR chemical shifts were determined relative to CDCl
3
at δ
77.0 ppm while
19
F NMR chemical shifts were determined relative to CFCl
3
, the internal
standard at δ 0.0 ppm. Column chromatography was carried out using Siliaflash G60
silica gel (70-230 mesh).
4.4.2 General Procedure for the Synthesis of Substituted Diaryl Sulfones
Pyridine-SO
3
sulfonation reactions were generally carried out by adding triflic
acid to a mixture of the aromatic substrate and SO
3
complex in a pressure tube. In the
case of benzenesulfonic acid for example, a mixture of 2 mL of benzene and 2 mmol of
Pyridine-SO
3
(0.318 g) is stirred for 5 minutes. To this is added 1 mL of Triflic acid after
which the pressure tube was capped and allowed to stir at 100 ºC for 24 hours. The
mixture was then quenched by the addition of ice water (20 mL) and then extracted with
dichloromethane (3 x 50 mL). After the evaporation of CH
2
Cl
2
under vacuum, the
product was then, if necessary, purified by column chromatography using a mixture of
hexanes and ethyl acetate (2:1). The product was then examined by NMR and identified
as diphenylsulfone by comparing the spectral data with that of authentic samples.
82
4.4.3 General Procedure for the Synthesis of Thiochroman-dioxides
Syntheses of thiochroman-dioxides were generally carried out in fashion similar
to that for diaryl-sulfones. In the case of benzene, for example, a mixture of 1 mL of
benzene, 2 mmol of 1,3-propane sultone (0.244 g) and 1 mL of triflic acid, was stirred in
a pressure tube at 80 ºC for 18 hours. The mixture was then quenched by addition to ice
water (20 mL) and extracted with dichloromethane (3 x 50 ml). After concentration under
vacuum and column chromatography (if necessary), the product was identified as
thiochroman-1,1-dioxide.
4.4.4 General Procedure for the Sulfonation of Aromatic Polymer Membranes
For equivalent weight determinations, a small sample of PVDF/PS (0.5 g) was cut
into one centimeter squares and placed in a pressure tube. The strips were then allowed to
swell by adding in 4mL of chloroform and allowing the mixture to stir at room
temperature for one hour. Afterwards, 1 mL of the desired acid was added after which the
pressure tube was capped and heated to the desired temperature for a predetermined
amount of time. The strips were then filtered or decanted away from the spent acid and
solvent followed by stirring in distilled water for several hours.
To determine its equivalent weight, the sulfonated polymer was first dried under
vacuum with moderate heating to avoid decomposition at high temperatures. The sample
was then weighed and allowed to swell in de-ionized water at 70 ºC for 24 hours. The
material was later transferred to a 3 M KCl solution at 70 ºC for another 24 hours to
allow the protons of the sample to be fully exchanged with potassium ions.
83
The resulting liquid is finally titrated with 5 x 10
-3
M solution of Na
2
CO
3
and the
volume of solution needed to reach the neutral point is recorded in liters. The equivalent
weight can thus be calculated by dividing the weight of the dried polymer by (mL
Na
2
CO
3
× 0.005 × 2).
84
4.4.5 Representative Spectra:
1
H NMR spectrum of p-Xylene Sulfone (Table 4.1c)

ppm (t1)
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0
1.00
1.23
1.06
3.10
3.09
S
O
O
85
4.4.5 Representative Spectra (continued):
13
C NMR spectrum of p-Xylene Sulfone (Table 4.1c)

ppm (t1)
0 50 100
S
O
O
86
4.4.5 Representative Spectra (continued):
1
H NMR spectrum of 5-Chloro-thiochroman 1,1-dioxide (Table 4.2h)

ppm (t1)
0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
1.00
1.02
1.08
2.32
2.32
2.32
S
O O
Cl
87
4.4.5 Representative Spectra (continued):
13
C NMR spectrum of 5-Chloro-thiochroman 1,1-dioxide (Table 4.2h)

ppm (t1)
0 50 100 150
S
O O
Cl
88
4.5 Chapter 4: References

1. Hydrogen, Fuel Cells & Infrastructure Technologies Program. Multi-Year
Research, Development and Demonstration Plan: Planned Program Activities for
2005-2015; United States Dept. of Energy - Energy Efficiency and Renewable
Energy, US Government Printing Office: Washington, DC, 2009.
2. Viswanathan, B.; Scibioh, M. A. Fuel Cells: Principles and Applications; CRC
Press: Boca Raton, 2007.
3. Yu, J.; Yi, B.; Xing, D.; Liu, F.; Shao, Z.; Fu, Y.; Zhang, H. Phys. Chem. Chem.
Phys. 2003, 5, 611.
4. Bae, B.; Ha, H. Y.; Kim, D. J. Membr. Sci. 2006, 276, 51.
5. Wycisk, R.; Pintauro P. N. J. Membr. Sci. 1996, 119, 155.
6. Xing, P.; Robertson, G. P.; Guiver, M. D.; Mikhailenko, S. D.; Wang, K.;
Kaliaguine, S. J. Membr. Sci. 2004, 229, 95.
7. Kobayashi, T.; Rikukawa, M.; Sanui, K.; Ogata, N. Solid State Ionics, 1998, 106,
219.
8. Gieselman, M. B.; Reynolds, J. R.; Macromolecules, 1993, 26, 5633.
9. Jouanneau, J.; Mercier, R.; Gonon, L.; Gebel, G. Macromolecules, 2007, 40, 983.
10. Tan, N.; Xiao, G.; Yan, D. Chem. Mater. 2010, 22, 1022.
11. Gieselman, M. B.; Reynolds, J. R.; Macromolecules, 1990, 23, 3118.
12. Miyatake, K.; Shouji, E.; Yamamoto, K.; Tsuchida, E. Macromolecules, 1997, 30,
2941.
13. Cerfontain, H.; Mechanistic Aspects in Aromatic Sulfonation and Desulfonation;
Interscience: New York, 1968.
14. Gilbert, E. E.; Sulfonation and Related Reactions; Interscience: New York, 1965.
15. Millikan, L. E. Ed.; Drug Therapy in Dermatology; Marcel Dekker Inc.: New
York, 2000.
16. Shephard, C. C. Annu. Rev. Pharmacol. 1969, 9, 37
17. Alkadi, H. O. Chemotherapy, 2007, 53, 385.

89

18. Elslager, E. F.; Worth, D. F., Nature, 1965, 206, 630.
19. Rozman, R. S. Annu. Rev. Pharmacol. 1973, 13, 127.
20. Dogra, J.; Lal, B. B.; Misra, S. N. Int. J. Dermatol. 1986, 25, 498.
21. McMahon, J. B.; Gulakowski, R. J.; Weislow, O. S.; Schultz, R. J.; Narayanan, V.
L.; Clanton, D. J.; Pedemonte, R.; Wassmundt, F. W.; Buckheit Jr., R. W.;
Decker, W. D.; White, E. L.; Bader, J. P.; Boyd, M. R. Antimicrob. Agents
Chemother. 1993, 37, 754.
22. Graybill, B. M. J. Org. Chem. 1967, 32, 2931.
23. Gilman, H.; Broadbent, H. S. J. Am. Chem. Soc. 1947, 69, 2053.
24. Bandgar, B. P.; Bettigeri, S. V.; Phopase, J. Org. Lett. 2004, 6, 2105.
25. Kar, A.; Sayyed, I. A.; Lo, W. F.; Kaiser, H. M.; Beller, M.; Tse M. K. Org. Lett.
2007, 9, 3405.
26. Huang F.; Batey R. A. Tetrahedron, 2007, 63, 7667.
27. Olah, G. A.; Mathew, T.; Prakash, G. K. S. Chem. Commun. 2001, 1696.
28. Alizadeh, A.; Khodaei, M. M.; Nazari, E. Tetrahedron Lett. 2007, 48, 6805.
29. Yao, B.; Zhang, Y. Tetrahedron Lett. 2008, 49, 5385.
30. Marquie, J.; Laporterie, A.; Dubac, J. J. Org. Chem. 2001, 66, 421.
31. Gilbert, E. Chem. Rev. 1962, 62, 549.
32. Roberts, D. W.; Williams, D. L. Tetrahedron, 1987, 43, 1027.
33. Mustafa, A. Chem. Rev. 1954, 54, 195.
34. Bachand, B.; Atfani, M.; Samim, B.; Levesque, S.; Simard, D.; Kong, X.
Tetrahedron Lett. 2007, 48, 8587.
35. Xu, D. Q.;Wu, J.; Luo, S. P.; Zhang, J. X.; Wu, J. Y.; Du, X. H.; Xu, Z. Y. Green
Chem. 2009, 11, 1239.
36. Liu, X.; Zhou, J.; Guo, X.; Liu, M.; Ma, X.; Song, C.; Wang, C. Ind. Eng. Chem.
Res. 2008, 47, 5298.
37. Ruegg, U.; Rudinger, J. Int. J. Pept. Protein Res. 1974, 6, 447.

90

38. Park, G.; Nakamura, H.; Lee, Y.; Yoshio, M. J. Power Sources, 2009, 189, 602.
39. Fisher, R. F. Ind. Eng. Chem. 1964, 56, 41.
40. Chu, Z.; Feng, Y. Synlett, 2009, 16, 2655.
41. Van der Velden, P. M.; Rijpkema, B.; Smolders, C. A.; Bantjes, A. Eur. Polymer
J. 1977, 13, 37.
42. Wang, Y.; Yang, D.; Zheng, X.; Jiang, Z.; Li, J. J. Power Sources 2008, 183, 454.
43. Truce, W. E.; Hoerger, F. D. J. Am. Chem. Soc. 1954, 76, 5357.
44. Colonna, S.; Manfredi, A.; Spadoni, M.; Casella, L.; Gullotti, M. J. Chem. Soc.
Perkin Trans. I 1987, 71.
45. Gu, D.; Harpp, D. N. Tetrahedron Lett. 1993, 34, 67.
46. Freeman, F.; Angeletakis, C. N. J. Org. Chem. 1985, 50, 793.
47. Prakash, G. K. S.; Smart, M. C.; Wang, Q.-J.; Atti, A.; Pleyner, V.; Yang, B.;
McGrath, K.; Olah, G. A.; Narayanan, S. R.; Chun, W.; Valdez, T.; Surampudi, S.
J. Fluor. Chem. 2004, 125, 1217.
48. Cremlyn, R. J. Chlorosulfonic Acid: A Versatile Reagent; The Royal Society of
Chemistry; Cambridge, 2007.
49. Gilbert, E. E.; Veldhuis, B.; Carlson, E. J.; Giolito, S. L. Ind. Eng. Chem. 1953,
45, 2065.
50. Hickner, M. A.; Ghassemi, H.; Kim, Y. S.; Einsla, B. R.; McGrath, J. E. Chem.
Rev. 2004, 104, 4587.
91
5 Chapter 5: The Development of Solid Supported
Bronsted Acids towards new Aromatic Nitrating Agents:
PVP:HNO
3
, PVP:H
2
SO
4
and PVPNM

5.1 Chapter 5: Introduction
Since the initial reports by Mitscherlich in 1834,
1,2
the nitration of organic
compounds has maintained its position as one of the most useful and widely studied
reactions in organic chemistry. This addition/substitution of a nitro group at a carbon,
oxygen or nitrogen center yields products of immense importance to almost all facets of
the field. Industrially, the reaction is used to produce nitrobenzene and aniline,
explosives, precursors for dyes, pharmaceuticals, polymers and many other applications.
With such an array of uses, it is no wonder that nitration continues to be the subject of
countless publications and studies and among various methods, electrophilic aromatic
nitration has been tremendously helpful as well. For instance, both C. K. Ingold and
Robert Robinson used nitration to help elucidate mechanistic aspects of aromatic
reactivity.
3,4,5
Further, the reaction has proven useful in explaining substituent activating-
deactivating effects, directing effects and the flow of electrons in electrophilic
substitution reaction.
6,7,8

The generally accepted Ingold-Hughes mechanism for nitration involves the
generation of nitronium (NO
2
+
) cation followed by its subsequent electrophilic
substitution to an aromatic center (Scheme 5.1).
9
The nitronium cation is usually
generated in situ by the use of neat nitric acid or by adding a second, stronger acid to help
accelerate the reaction rate. The classic two-acid system has, for decades, been a mixture
92
of nitric acid and concentrated sulfuric acid (1:1 nitrating mixture) but several other acids
have been used in the place of sulfuric acid. These have included mixtures of nitric acid
with aluminium chloride, polyphosphoric acid, perchloric acid, methanesulfonic acid,
hydrogen fluoride and even superacids like boron trifluoride, trifluoroacetic acid, triflic
acid, fluorosulfonic acid and many others.
1,3

Scheme 5.1 – Hughes-Ingold Mechanism of Electrophilic Aromatic Nitration
NO
2
+
+
H NO
2
H NO
2
A
-
+
NO
2
HNO
3
+ HA
H
2
NO
3
+
H
2
NO
3
+
NO
2
+
+ H
2
O
+ HA
+
A
-

However, though highly effective at nitrating aromatic substrates, liquid based
systems, when carried out on a large scale, can be hard to separate and usually lead to
large waste streams that can be both dangerous and difficult to dispose of. There has
therefore, emerged a growing need for the development of better and more ecologically
sustainable nitrating agents. A growing area of research has involved the development of
nitrogen-containing salts as a cheaper, more accessible source of nitronium ions.
Nitrates of metals like sodium, potassium and silver, for instance, can be activated
in the presence of an acid to yield free nitronium ions or polarized complexes capable of
electrophilic aromatic nitration. Along with these, nitration reactions have also been
described using alkyl nitrates, nitryl halides, silyl nitrates and the various oxides of
93
nitrogen.
1,2
Also commonly employed, are the nitronium salts. Though known for
decades,
10
nitronium salts were not particularly practical as nitrating agents until Olah
and coworkers were able to significantly improve and simplify their synthesis and
use.
11,1213
On the other hand, some of the most attractive new nitrating mixtures are those
employing solid acid catalysts. Such methods generally allow for safer and more
controlled reactions with far less acid waste. In addition, many of the solid catalysts can
be easily separated from reaction mixtures and regenerated for repeated use.
Many diverse systems have been reported over the years such as montmorillonite
clays,
14,15
zeolites,
16,17
Nafion-H,
18
sulfated zirconia
19
and even silica supported sulfuric
acid
20
and nitric acid.
21
However, the use of polymer supported reagents in aromatic
nitrations has very rarely been explored and in our efforts towards solid supported
Brønsted acids, we prepared poly(4-vinyl pyridine) complexes of both concentrated nitric
acid (HNO
3
) and concentrated sulfuric acid (H
2
SO
4
). We have also prepared
PVP:Nitrating Mixture complex (PVP:NM) consisting of equal parts concentrated nitric
and sulfuric acids (HNO
3
:H
2
SO
4
) and have examined their potential to nitrate various
aromatic compounds.

5.2 Chapter 5: Results and Discussion
The use of polymer-bound or polymer-supported reagents in synthetic organic
chemistry has seen exponential growth since R. B. Merrifield’s pioneering work on solid
phase peptide synthesis
22
and the significant advances in the area of protein synthesis.
Polymeric reagents are usually solid and reasonably stable thus their primary advantage
over other reagents types are the ease with which they may be removed and recycled after
94
reactions.
23
Polymeric support can also help modulate the reactivity of reagents making it
possible to use them in excess, scale up and even automate reactions without significantly
deleterious effects. The benefits associated with polymer supported reagents are often
countered by several drawbacks like the difficulty sometimes associated with their
characterization, the thermal and chemical sensitivity of some polymers and sometimes
longer reactions that give poor yields. In general however, the development of polymeric
reagents is now seen as an important and influential contribution to both industrial and
academic research and the field has continued to grow and prosper.
Polymeric synthetic reagents take many varied forms, however, of particular
interest are those containing acidic functionalities. Reagents of this kind rely upon several
different methods for incorporating acidic species into polymers. Some of them (Figure
5.1), such as the familiar Nafion-H
24
or poly(vinylphosphonic acid) (5.1a),
25
consist of
polymerized acidic monomers while many others consist of acid-functionalized
polystyrenes (5.1b),
26
the related silica supported acids (5.1c)
27
and a growing class of
polymer-coordinated Lewis acids (5.1d-e).
28
For our polymer-supported acid system,
however, we chose as a polymer support, poly(4-vinyl pyridine).
Figure 5.1 – Acid-Functionalized Polymeric Reagents
P O
OH
HO
n O
O
Si
OR
SO
3
H
Tf
H
Tf
F
F F
F
n
Sc(OTf)
3
a.
b.
c.
d.
e.
(CF
2
CF
2
)nOCF
2
CF
2
SO
3
3
Yb

95
It has long been known that nitrogen bases form salts or hydrogen bonding
complexes upon neutralization with strong acids and such salts have been exploited in a
variety of ways.
29
Kuwabata, for example, described the use of poly(vinyl pyridine)
hydrochloride salt (Figure 5.2a) as an acid catalyst for the acetalization of carbonyls and
the esterification of carboxylic acids.
30
The group found the polymer complex less
hygroscopic than the monomer and more tolerant of sensitive functionalities than other
acidic resins. Later, a similar form of the hydrochloride reported by Krieger and
associates was found to be a highly efficient catalyst in the tetrahydropyranylation of
alcohols and phenols.
31
Menger and Chu had performed the same reaction with the p-
toluenesulfonate salts of poly(vinylpyridine) earlier (Figure 5.2b,c).
32
The same
complexes were also later found useful in the reverse hydrolysis of the ethers by Li and
Ganesan.
33

Figure 5.2 – Acid-Functionalized Poly(vinyl pyridines)
N
H
m
Cl
n
n
N
H
OSO
2
Tol-p
m
N
H
OSO
2
Tol-p
m
a. b. c.
N
H
m
[F(HF)
n
]
d.

Polymeric amine-acid complexes have been extensively studied by Olah and
coworkers during the last four decades. Amine-anhydrous hydrogen fluoride (HF)
complexes have been used in nucleophilic fluorination, bromination and alkylation
reactions.
34,35
In particular, PVP (poly(4-vinyl pyridine)) forms stable polyhydrogen
fluoride complexes (Olah’s Reagents) with varying amounts of hydrogen fluoride
(Figure 5.2d).
36,37,38
Amines can act a reservoir for HF and the volatility of HF is
96
significantly reduced by amine complexation. Therefore, the complexes can be
considered as “green” reagents and it is generally much easier to modulate their acidity
and catalytic activity than the free acid itself. Intrigued by these facts, we anticipated
poly(4-vinyl pyridine) to be an effective support for other strong acids and also the
resultant solid complexes could be used as strong acid catalysts for reactions including
aromatic nitration.
Poly(4-vinyl pyridinium) poly(nitric acid) (Figure 5.3) for instance, was prepared
from poly(4-vinyl pyridine) and 98% nitric acid. Commercially available 2% cross linked
poly(4-vinyl pyridine) was carefully added to nitric acid that had been cooled to -78 ºC
and mixed thoroughly. A 1:5 loading ratio of polymer to acid lead to the formation of a
fluffy, free-flowing, white solid although ratios from 1:4 to 1:8 can also be obtained. The
resulting complex is found to contain 75% nitric acid by weight and can be stored in a
closed Nalgene bottle for several months in the refrigerator. The complex was further
examined by scanning electron microscopy (Figure 5.4) and was found to remain
consistent in both particle size and shape when compared to the parent polymer. It is very
important to mention that for complex formation and preparation of solid complexes ideal
for organic reactions, the use of cross-linked polymers is required. Noncross-linked
polymers were found to always lead to a sticky, semi-solid mess.
Figure 5.3 – PVP:HNO
3

N
H
[NO
3
(HNO
3
)
n-1
]
m

97
Figure 5.4 – Surface Morphology of PVP (a) and PVP:HNO
3
(b)

a. b.
Poly(4-vinyl pyridinium) poly(sulfuric acid) (Figure 5.5), was also prepared from
poly(4-vinyl pyridine) and concentrated sulfuric acid in a similar manner. The acid in this
case formed a free-flowing peach colored solid with a loading ratio of 1 equivalent of
polymer to 5 equivalents of acid and ratios from 1:4 to 1:7.5 are also possible. The
complex containing 83% sulfuric acid by weight is stored in a closed Nalgene bottle in
the refrigerator. The complex was also similarly found to remain consistent in both
particle size and shape when compared to the parent polymer (Figure 5.6).
Figure 5.5 – PVP:H
2
SO
4

N
H [HSO
4
(H
2
SO
4
)
n-1
]
m

Figure 5.6 – Surface Morphology of PVP (a) and PVP:H
2
SO
4
(b)

a. b.
98
Finally, a poly(4-vinyl pyridinium) mixed acid nitrating agent has been prepared
from poly(4-vinyl pyridine), sulfuric acid and nitric acid. The two acids are first mixed
together at -78 ºC before adding 2% cross linked poly(4-vinyl pyridine). The resulting
mixture forms PVPNM (PVP:Nitrating mixture) with one equivalent of polymer reacted
with 5 equivalents of each acid. The complex contains 35% nitric acid, 54% sulfuric acid
and 11% poly(4-vinyl pyridine) by weight and is a free-flowing, white solid that fumes
slightly in air but remains microscopically uniform as clearly manifested in SEM studies
(Figure 5.8).
Figure 5.7 – PVP:HNO
3
:H
2
SO
4

N
H
x
N
H [HSO
4
(H
2
SO
4
)
n-1
]
y
[(HNO
3
)
n-1
NO
3
]

Figure 5.8 – Surface Morphology of PVP (a) and PVP:HNO
3
:H
2
SO
4
(b)

a. b.
To assess their capabilities as acid catalysts, the complexes were subsequently
used as nitrating reagents for the nitration of various aromatics. To begin with, we
conducted nitration reactions of aromatics and a combination of PVP:HNO
3
complex and
PVP:H
2
SO
4
complex. Equal portions of each acid were added one after the other to a
solution of the substrate and then stirred for a particular time and temperature (Table
99
5.1). We found that reactions generally took place at room temperature within two hours
for activated aromatic systems while even deactivated arenes could be nitrated at
moderate temperatures. Yields in all cases were generally good though nitration of
nitrobenzene was found to be rather difficult even with prolonged heating. It is interesting
to note that the exclusive mononitration of aromatic substrates was observed in all cases.
Also, all systems showed a general preference for para-substituted products with some
deactivated systems reaching up to a 4:1 ratio of para to ortho products.
The nitrating capacity of PVPNM, obtained from PVP and previously prepared
nitrating mixture, was found to be superior than using the two individual complexes by
separate addition (Table 5.2). While product yields from separate addition remained
below 90%, our new direct PVPNM complex was able to nitrate most substrates almost
quantitatively. Yields in this case were all above 75% with a persistent preference for the
para-substituted isomer and with exclusive mononitration. Therefore, neat PVPNM
complex seems to be slightly more reactive than the combined acid complexes though,
both systems seem to be less reactive than liquid solutions. However, other major
advantages such as recyclability, simplicity and higher sustainability override the less
reactive nature and make these complexes superior to liquid acid systems.

100
Table 5.1 – Nitration Reactions with PVP:HNO
3
and PVP:H
2
SO
4

R
R
NO
2
PVP:HNO
3
PVP:HNO
3
CH
2
Cl
2
Entry Product (o:m:p) Temp. (° C)
NO
2
NO
2
NO
2
NO
2
C
3
H
7
C
2
H
5
H
3
C
H
3
C
CH
3
NO
2
F
Cl
NO
2
RT
RT
RT
RT
RT
75
75
50
Br
NO
2
75
b.
c.
d.
e.
f.
g.
h.
a.
i.
Arene
H
3
C
C
2
H
5
C
3
H
7
H
3
C CH
3
NO
2
F
Cl
Br
NO
2
O
2
N
75 j.
O
2
N
Yield (%)
83
88
69
70
60
51
55
88
72
0
Time (hr)
2
2
2
2
2
2
2
2
2
24
NO
2
(39:3:58)
(40:5:55)
(35:3:62)
(22:0:78)
(21:0:79)
(17:0:83)

101
Table 5.2 – Nitration Reactions with PVP:HNO
3
:H
2
SO
4

R
PVPNM
R
NO
2
CH
2
Cl
2

Entry Product (o:m:p) Temp. (° C)
NO
2
NO
2
NO
2
NO
2
C
3
H
7
C
2
H
5
H
3
C
H
3
C
CH
3
NO
2
F
Cl
NO
2
RT
RT
RT
RT
RT
75
75
50
Br
NO
2
75
b.
c.
d.
e.
f.
g.
h.
a.
i.
Arene
H
3
C
C
2
H
5
C
3
H
7
H
3
C CH
3
NO
2
F
Cl
Br
NO
2
O
2
N
75 j. O
2
N
Yield (%) Time (hr)
2
2
2
2
2
2
2
2
2
24
NO
2
(39:3:58)
(40:5:55)
(35:3:62)
(22:0:78)
(21:0:79)
(17:0:83)
95
98
99
87
99
76
99
83
95
0

102
Even though both nitrating complex systems are highly effective reagents,
leaching of acid during the reaction reduces the activity of the catalyst system
significantly. The major goal of solid catalysts nevertheless, is to minimize workup and
the amount of waste generated which we are able to accomplish by simple filtration and
neutralization before characterization. In general, the ease with which the complexes can
be handled, recovered and regenerated and their efficiency as solid acid nitrating reagents
helps compensate for some of their shortcomings.

5.3 Chapter 5: Conclusion
In conclusion, we have investigated the extensive hydrogen-bonding of polymeric
poly (4-vinyl pyridine) (PVP) with nitric and sulfuric acid and have found the polymers
are capable of acting as an acid reservoir for proposed organic synthesis reactions. All
complexes form free flowing solids that are easy to handle and can be regenerated. We
have discovered that PVP readily forms stable complexes with separate as well as
equimolar mixtures of acids. The resultant nitrating mixture complexes are stable free-
flowing solid that successfully nitrate a number of aromatic species under mild conditions
and may find many important applications in the future.

103
5.4 Chapter 5: Experimental
5.4.1 General Remarks
Unless otherwise mentioned, all chemicals were purchased from commercial
sources and used as received.
1
H,
13
C, and
19
F NMR spectra were recorded on a Varian
NMR at 400 MHz.
1
H NMR chemical shifts were determined relative to
tetramethylsilane (TMS) as the internal standard at δ 0.0 ppm.
13
C NMR chemical shifts
were determined relative to CDCl
3
at δ 77.0 ppm while
19
F NMR chemical shifts were
determined relative to CFCl
3
as the internal standard at δ 0.0 ppm. Column
chromatography was carried out using Siliaflash G60 silica gel (70-230 mesh). Scanning
electron microscope images were obtained from a JEOL JSM6610 instrument at the
Center for Electron Microscopy and Microanalysis, University of Southern California.
5.4.2 Typical Preparation of PVP:HNO
3
complex
Fuming nitric acid (0.5 mol) was cooled to -78 °C in a 500 mL Nalgene bottle.
2% cross-linked poly(4-vinyl pyridine) (0.100 mol) is then slowly added with constant
swirling and cooling to ensure a controlled and uniform reaction. After a fluffy, white
solid is obtained, the bottle was allowed to come to room temperature, capped and then
stored in a refrigerator for further use. PVP:H
2
SO
4
can be prepared in a similar fashion to
yield a fluffy, cream colored solid.
5.4.3 Typical Preparation of PVP:HNO
3
:H
2
SO
4
complex
PVP supported nitrating mixture was made by first cooling 0.750 mol of fuming
nitric acid to -78 °C in a 500 mL Nalgene bottle. Next, 0.750 mol concentrated sulfuric
acid is slowly added to the nitric acid with slight stirring. 2% cross-linked poly(4-vinyl
104
pyridine) (0.100 mol) is then gradually added to the mixture with constant swirling until a
fluffy solid is obtained. The mixture is finally capped and stored at 0 ºC for several hours
before experimental use.
5.4.4 General Procedure for the Nitration of Aromatic Compounds With
PVP:HNO
3
and PVP:H
2
SO
4

In general, 1 mmol of a selected arene was dissolved in 5-10 mL of
dichloromethane and stirred. PVP:HNO
3
(0.5 g, 2 mmol) is then added and the solution
allowed to stir for 5 min. PVP:H
2
SO
4
(0.5 g, 2 mmol) is then gradually added after which
the reaction vessel was covered and stirred for a certain time. Reactions at room
temperature were carried out in a glass vial while those requiring heating were carried out
in a pressure tube. All reactions were monitored by thin layer chromatography. Upon
completion, the reaction mixture was diluted with dichloromethane (50 mL) and then
filtered. The filtrate was washed in turn with 50 mL of saturated NaHCO
3
solution, 50
mL of saturated NaCl solution and 50 mL of water before being dried over anhydrous
MgSO
4
. The solvent was then removed under reduced pressure and the product verified
by
1
H NMR. If necessary, products were purified by column chromatography after which
the ratio of ortho, meta and para isomers was determined by GC/MS.
5.4.5 General Procedure for the Nitration of Aromatic Compounds With
PVP:HNO
3
:H
2
SO
4

1 mmol of a selected arene was first dissolved in 5-10 mL of dichloromethane and
stirred. PVP:7.5HNO
3
:7.5H
2
SO
4
(0.8755 g, 5 mmol) was then added to the solution after
which the vessel is covered and allowed to stir for a certain amount of time. Reactions
were monitored by thin layer chromatography and carried out in a glass vials at room
105
temperature and in pressure tubes at elevated temperatures. Completed reactions were
then diluted with dichloromethane (50 mL) and filtered. The filtrate was washed with 50
mL of saturated NaHCO
3
solution, 50 mL of saturated NaCl solution and finally 50 mL
of water. The product was then dried over anhydrous MgSO
4
before being concentration
under vacuum. The product was then verified by
1
H NMR after which the percentage of
ortho, meta and para isomers was analyzed by GC/MS.

106
5.5 Chapter 5: References

1. Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods and Mechanism;
VHC Publishers: New York, 1989.
2. Schofield, K. Aromatic Nitration; Cambridge University Press, Cambridge, 1980.
3. Hoggett, J. G.; Moodie, R. B.; Penton, J. R.; Schofield. K. Nitration and Aromatic
Reactivity; Cambridge University Press: Cambridge, 1971.
4. Ingold, C. K. Structure and Mechanism in Organic Chemistry; Cornell University
Press: Ithaca, 1969.
5. Saltzman, M. D. Natural Products Reports, 1987, 4, 53.
6. Holmes, E. L.; Ingold, C. K. J. Chem. Soc., Trans. 1925, 127, 1800.
7. Allan, J.; Oxford, A. E.; Robinson, R.; Smith, J. C. J. Chem. Soc. 1926, 376.
8. Allan, J.; Robinson, R. J. Chem. Soc. 1926, 401.
9. Hughes, E. D.; Ingold, C. K.; Reed, R. I. J. Chem. Soc. 1950, 2400.
10. Goddard, D. R.; Hughes, E. D.; Ingold, C. K. J. Chem. Soc. 1950, 2559.
11. Kuhn, S. J.; Olah, G. A. J. Am. Chem. Soc. 1961, 83, 4564.
12. Salzbrunn, S.; Simon, J.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A. Synlett,
2000, 1485.
13. Prakash, G. K. S.; Panja, C.; Mathew, T.; Surampudi, V.; Petasis, N. A.; Olah, G.
A. Org. Lett. 2004, 6, 2205.
14. Laszlo, P.; Pennetreau, P. J. Org. Chem. 1987, 52, 2407.
15. Choudary, B. M.; Sarma, M. R.; Kumar, K. V. J. Mol. Cat. 1994, 87, 33.
16. Choudary, B. M.; Sateesh, M.; Kantam, M. L.; Rao, K. K.; Prasad, K. V. R.;
Raghavan, K. V.; Sarma, J. A. R. P. Chem. Commun. 2000, 25.
17. Smith, K.; Almeer, S.; Black, S. J. Chem. Commun. 2000, 1571.
18. Olah, G. A.; Malhotra, R.; Narang, S. C. J. Org. Chem. 1978, 43, 4628.
19. Parida, K. M.; Pattnayak, P. K. Cat. Lett. 1997, 47, 255.

107

20. Zolfigol, M. A.; Mirjalili, B. F.; Bamoniri, A.; Zarchi, M. A. K.; Zarei, A.;
Khazdooz, L.; Noei, J. Bull. Korean Chem. Soc. 2004, 25, 1414.
21. Tapia, R.; Torres, G.; Valderrama, J. A. Synth. Commun. 1986, 16, 681.
22. Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149.
23. Akelah, A.; Sherrington, D. C. Chem. Rev. 1981, 81, 557.
24. Olah, G. A.; Iyer, P. S.; Prakash, G. K. S. Synthesis, 1986, 7, 513.
25. Akbey, U.; Graf, P.; Chu, P. P.; Spiess, H. W. Aus. J. Chem. 2009, 62, 848.
26. Ishihara, K.; Hasegawa, A.; Yamamoto, H. Angew. Chem. Int. Ed. 2001, 40,
4077.
27. Corma, A.; Garcia, H. Adv. Synth. Catal. 2006, 348, 1391.
28. Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1998, 120, 2985.
29. Benaglia, M.; Puglisi, A.; Cozzi, F. Chem. Rev. 2003, 103, 3401.
30. Yochida, J.; Hashimoto, J.; Kawabata, N. Bull. Chem. Soc. Jpn. 1981, 54, 309.
31. Johnston, R. D.; Marston, C. R.; Krieger, P. E.; Goe, G. L. Synthesis, 1993, 393.
32. Menger, F. M.; Chu, C. H. J. Org. Chem. 1981, 46, 5044.
33. Li, Z.; Ganesan, A. Synth. Commun. 1998, 28, 17, 3209.
34. Olah, G. A.; Mathew, T.; Goeppert, A.; Torok, B.; Bucsi, I.; Li, X.-Y.; Wang, Q.;
Marinez, E. R.; Batamack, P.; Aniszfeld, R.; Prakash, G. K. S. J. Am. Chem. Soc.
2005, 127, 5964.
35. Olah, G. A.; Welch, J. T.; Vankar, Y. D.; Nojima, M.; Kerekes, I.; Olah, J. J. Org.
Chem. 1979, 44, 3872.
36. Gregorcic, A.; Zupan, M. J. Fluor. Chem. 1984, 24, 291.
37. Olah, G. A.; Li, X. Y.; Wang, Q.; Prakash, G. K. S. Synthesis, 1993, 693.
38. Olah, G. A.; Li, X. Y. Synlett, 1990, 267.
108
6 Chapter 6: The Expanded use of PVD:H
2
O
2
and
PVP:H
2
O
2
in Oxidation Reactions

6.1 Chapter 6: Introduction
Oxidation reactions play a vital part in both the natural and scientific world from
cellular respiration to the oxidation of hydrocarbons in fuel chemistry. Oxidants
themselves come in a great variety of forms but in synthetic applications, there has arisen
a growing push for oxidants that more accurately mimic the environmentally friendly
characteristics of natural ones. Apart from transition-metal based catalysts, some of the
most accessible of these reagents are usually organic peroxides and related peroxy
compounds. From very early on however, it was well recognized that many peroxy
compounds possess significant drawbacks that can make their use both limited and, at
times, dangerous.
One of the most popular reagents, m-chloroperoxybenzoic acid (mCPBA) for
instance, is known to be shock sensitive and poor in terms of its oxygen content. Other
peroxides such as t-butyl hydroperoxide can become unstable and explosive making them
difficult to both implement into a large scale process and dispose of after a reaction is
completed. In response to these concerns, many have begun to look back to the “classic”
use of simple hydrogen peroxide due to its high oxygen content, reliable reactivity and
the formation of only water as the byproduct of its reactions.
1
However, even hydrogen
peroxide poses risks due to its oxidative strength and reactivity.
2
The molecule also, for
instance, reacts violently with metals and reducing agents, can become explosive above
certain concentrations and acts as a strong bleaching agent. Hydrogen peroxide can also
109
be destabilized by extreme pH and form explosive mixtures with organics upon
prolonged exposure. On the other hand, H
2
O
2
can also form extended hydrogen-bonded
complexes with organic bases and many see these compounds as a safer way to store and
access the peroxides for oxidations. Indeed, such complexes can reduce the volatility of
the hydrogen peroxide and allow its storage and use in higher concentrations for extended
periods of time without seriously affecting reactivity.
Well before its molecular structure was agreed upon,
3
hydrogen peroxide was
known to form adducts with various bases. Urea:H
2
O
2
(CO[NH
2
]
2
) for instance, was the
first such adduct discovered and for almost a century has been the model for subsequent
peroxide complexes. Commercially available Urea:H
2
O
2
is a crystalline, white,
hygroscopic solid that is generally stable at room temperature. With such favorable
characteristics, it comes as no surprise that Urea:H
2
O
2
is known as a dependable, solid
alternative to hydrogen peroxide with established utility in a range of oxidative
applications.
4
Such reactions include epoxidations,
5
the oxidation of sulfides,
6
selenium
compounds,
7
benzylic carbons
8
and many other reactions.
9
Hydrogen peroxide also forms
a stable complex with 1,4-diazabicyclo[2.2.2]octane (DABCO),
10
though complexes with
other tertiary amines have been known to degrade easily and are less useful.
11

Interestingly, some of the more effective supports or carriers for hydrogen
peroxide are polymeric bases and heterocycles. In particular, poly(vinyl pyrolidone) has
been known to form stable, free flowing, solid complexes with various concentrations of
hydrogen peroxide. Since their discovery during the 1960’s,
12
PVD:H
2
O
2
complexes have
been used as peroxide surrogates in many different capacities. Many differing
formulations have been proposed
13,14,15
and most are used for surface sterilizations,
16,17,18

110
tissue preservations,
19
acne treatments,
20
tooth whiteners
21,22
and radical polymerization
initiations.
23
However, while its industrial and cosmetic applications have been well
documented, PVD:H
2
O
2
has only within the last few decades been shown useful in
everyday synthetic organic transformations. Unlike other complexes, hydrogen peroxide
within PVD:H
2
O
2
has been shown to preferentially bond with the carbonyl moiety of the
amido group.
24
Inevitably, this alternative bond site and the presence of a polymeric
backbone have both lead to interesting and new applications of these complexes.
PVD:H
2
O
2
for instance has been used by Pourali and associates in the production
of iodinated arene.
25
The complex was used in conjunction with KI or molecular iodine
and catalytic amounts of hydrated tungestophosphoric acid and produced a range of
products in good yields. The duo have also used the complex in the epoxidation of
ketones and α,β-enones in the presence of sodium hydroxide
26
and Mn porphyrins
27
as
catalysts. Recently however, Olah and co-workers have sought to expand upon the
synthetic role of hydrogen peroxide complexes. The group has reported on the use of
both PVD:H
2
O
2
and the newly formed poly(4-vinylpyridine) hydrogen peroxide complex
(PVP:H
2
O
2
).
28
PVP:H
2
O
2
, like other peroxide complexes, is formed by hydrogen bonds
through the amine substituent and forms a free-flowing, pale, yellow solid. Both
complexes were used in the synthesis of phenols and halophenols from arylboronic acids
under very mild conditions (Scheme 6.1). Calculations were also performed to help
elucidate the extended structure of the complexes and it was found that both PVP and
PVD form stable, extended hydrogen bonded structures with a linear arrangement of 3-5
molecules of hydrogen peroxide being preferred over a cyclic structure (Figure 6.1).
28

111
Figure 6.1 – Calculated Structures of N-Ethylpyrrolidone and 4-Ethylpyridine H
2
O
2

Complexes

N-Ethylpyrrolidone:H
2
O
2
Complex

4-Ethylpyridine:H
2
O
2
Complex

112
Scheme 6.1 – ipso-Hydroxylation of Arylboronic Acids and Solid H
2
O
2
Complexes
PVD:H
2
O
2
PVP:H
2
O
2
N
O
H
O
O
H
n
N
n
H
O
O
H
B(OH)
2
R
OH
R
Solid-H
2
O
2
Complex
CH
2
Cl
2
, RT

Interestingly, the group also found PVD:H
2
O
2
to perform significantly better than
PVP:H
2
O
2
in most applications though this may be simply a difference in catalyst loading
between the two. Nonetheless, as efficient, solid forms of hydrogen peroxide, both
complexes showed impressive promise as oxidative catalysts. In our efforts to continue
exploring the oxidative applications of hydrogen peroxide complexes, we now described
their use in the oxidation of sulfides to sulfoxides and the use of PVD:H
2
O
2
in the
oxidation of ketones to gem-dihydroperoxides.

6.2 Chapter 6: Results and Discussion
6.2.1 Selective Oxidation of Sulfides to Sulfoxides
The oxidation of sulfides to sulfoxides is one of the most deceptively simple, yet
particularly important transformations in organic chemistry. Sulfoxides are indispensible
as they appear in numerous natural products and drug molecules, act as chiral auxiliaries
and C-C bond forming reagents, and even participate as intermediates in some molecular
rearrangements and transformations. Because of this, numerous reagents and methods
have been developed in an effort to produce sulfoxides as selectively and inexpensively
113
as possible. Of these, the oxidation of sulfides has been proven as one of the most durable
and pervasive methods in synthetic organic chemistry.
29,30
Sulfoxides have been made
from sulfides using nitrates in combination with halogens,
31,32,33
hypervalent iodine or
periodic acids,
34,35
and of course peroxy-acids and peroxides in conjunction with multiple
transition metal catalysts.
36,37,38,39,40
However, with the growing emphasis on
environmentally benign processes, more and more chemists have sought out ways to
bring about this transformation with greater selectivity and as minimal by-products and
waste as possible. The use of the many inorganic oxidants for instance is seen as less than
optimal due to their tendency to over-oxidize sulfides and interfere with sensitive
functional groups while peroxy-acids can be hazardous and lead to excessive waste
streams.
Instead, the use of hydrogen peroxide (H
2
O
2
) as a sulfide oxidant is seen as a
more viable alternative due to its strong oxygen content, safety and low cost. Hydrogen
peroxide also acts as a milder oxidant than other reagents and only produces water as a
waste product. The molecule has been used to oxidize sulfides for decades both alone and
in the presence of another catalyst.
41,42
Such additives can help increase reactivity,
decrease reaction times and induce stereoselectivity though an increase in the amounts of
sulfone produced may also occur as well. Khodaei and coworkers have, for instance,
reported the use of triflic anhydride (Tf
2
O) in conjunction with H
2
O
2
where the peroxy-
acid generated in situ acts as the oxidative species.
43
In other cases, hydrogen-bonding
additives can play a part in the activation of peroxide. For example, Varma and Naicker
have shown that commercially available Urea:H
2
O
2
complexes are capable of such
oxidations under solvent-free conditions (Scheme 6.2).
4

114
Scheme 6.2 – Oxidation of Sulfides with Urea:H
2
O
2

H
N N
H
O
H H
H
O
O
H
R
2
S
R
1
R
2
S
R
1
Urea:H
2
O
2
R
2
S
R
1
O

In this instance, complexation is thought to mitigate the reactivity of H
2
O
2
and
help minimize the production of sulfones as side products. Similarly, Lattanzi and Russo
have shown that the electrophilicity of t-butyl hydroperoxide (TBHP) can be enhanced by
the presence of various thioureas (Scheme 6.3).
44
The resultant, hydrogen-bonded
complexes once again lead to sulfoxides in excellent yields and very little traces of
sulfones as side products.
Scheme 6.3 – Oxidation of Sulfides with Thiourea and TBHP
N N
S
H H
R
R
R
R
t-Bu
O
O
H
R
2
S
R
1
R
2
S
R
1
Thiourea
TBHP
R
2
S
R
1
O

Inspired by these successful examples, we decided to examine the use of
PVD:H
2
O
2
and PVP:H
2
O
2
as oxidants for arylsulfides. Initially, as with many oxidation
reagents, when using PVD:H
2
O
2
we obtained mixtures of both sulfoxides and sulfones as
products with the sulfone being more predominant at elevated temperatures and longer
heating times.
115
Scheme 6.4 – Oxidation of Sulfides With PVD:H
2
O
2

S
R
1
R
2
CH
3
CN
85° C, 18Hr
PVD:H
2
O
2 S
R
1
R
2
O
S
R
1
R
2
O O
20% 80%

However, unlike many other oxidants, PVD:H
2
O
2
proved highly amenable to
control and optimization making the reaction highly tunable. By monitoring the progress
of reactions with thin layer chromatography and modifying the reaction temperature,
selective formation of various sulfoxides derivatives could be achieved (Table 6.1). The
relatively simple modifications lead to excellent yields and diverse side groups like
alkenes, amines and alkyl chlorides were tolerated. More importantly, by using a solid
form of H
2
O
2
, we were able to eliminate the steps associated with workup as well as
products separation the amount of solvents has been significantly reduced.
We also examined the use of PVP:H
2
O
2
as an oxidant and found the results
similar to those obtained by use of PVD:H
2
O
2
. PVP:H
2
O
2
was found to selectively
oxidize arylsulfides to sulfoxides, however, reactions were generally much slower and
required much higher catalysts loading than expected (Table 6.2). Yields were generally
lower than those observed in PVD:H
2
O
2
reactions. Interestingly, a few substrates
possessing sensitive groups seemed to undergo complex side reactions leading to
mixtures. Nonetheless, PVP:H
2
O
2
still proved effective as an environmentally friendly
H
2
O
2
surrogate in oxidizing a range of sulfides.
116
Table 6.1 – PVD:H
2
O
2
Oxidation of Sulfides
S
R
1
R
2
CH
3
CN, 70 ° C
PVD:H
2
O
2
S
R
1
R
2
O

Substrate Entry Product Yield (%) Time (hr)
a.
b.
c.
d.
e.
f.
g.
h.
i.
j.
81
94
82
99
83
84
82
85
93
88
6
6
3
5
24
24
3
3
3
6
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
H
2
N
MeO
Cl
Cl
MeO
H
2
N
O
O
O
O
O
O
O
O
O
O
Br
Br
Cl
Cl

117
Table 6.2 – PVP:H
2
O
2
Oxidation of Sulfides
S
R
1
R
2
CH
3
CN, 70 ° C
PVP:H
2
O
2
S
R
1
R
2
O

S
a.
H
2
N
S
S
b.
c.
S
MeO
d.
S
Cl
e.
S
Br
f.
S
g.
S
h.
i.
j.
S
Substrate Entry Product
S
H
2
N
S
S
S
MeO
S
Cl
S
Br
S
S
S
O
O
O
O
O
O
O
O
O
S S
O
Yield (%)
72
86
82
71
74
70
81
60
23
95
Time (hr)
24
24
24
24
24
24
24
24
24
24

118
6.2.2 Oxidation of Ketones to gem-Diperoxides
With hundreds of millions of cases leading to over a million deaths every year,
malaria unfortunately continues to be one of the most widespread and potent threats to
lives and communities within the tropics.
45
Transmitted by mosquitoes, malaria stems
from infections of protozoan members of the Plasmodia genus and causes fever,
headaches and vomiting that can escalate into organ failure and neurological distress.
Because of these factors, many synthetic antimalarials have been developed over the
years but, as with many diseases, many of the protozoa have begun to develop some form
of resistance to some of these molecules like chloroquine and more alarmingly, quinine.
46

As a result, there has been a concerted effort to discover newer, more potent molecules
for the treatment of malaria.
One of the most promising of these is the naturally occurring artemisinin, isolated
by Chinese scientist in 1971 from Artemisia annua.
47
Artemisinin is toxic to malaria
parasites at micro and even nanomolecular concentrations and the prime factor behind its
activity has been shown to be its characteristic endoperoxide structure. Within the
microorganism, artemisinin generates destructive radicals that ultimately disrupt the cell
membrane and lead to cellulolysis.
48
However, while its antimalarial properties cannot be
denied, artemisinin is still only slightly soluble in oil and water and has a very short half-
life. This means that complex formulations must be administered repeatedly over several
days when most artemisinin is still isolated directly from natural sources.
Thus many synthetic derivatives of artemisinin were and are still being developed
for easy administration, longer lasting effects and greater lipophilicity while retaining the
all-important peroxide linkage in active form.
49,50
These include a range of molecules
119
from those closely mimicking the original artemisinin framework with simpler structures
that are easier to synthesize. As is evident from looking at their structures (Figure 6.2),
one of the best synthetic paths to many of these compounds could be through the use of
gem-diperoxides.
Figure 6.2 – Artemisinin and Related Anti-Malarial Compounds
O
O
H
H
O
O
O
O
O
H
H
O
O
OCH
3
F
3
C CF
3
O
O
O
O HO
H
O
O
OCH
3
O
O
O
F
F
H
O
O O
O O
O O
O
O
O
O
a. Artemisinin b. Artemether
c. Arteflene
d. Fenozan
e.
g.
f.
h.

Gem-diperoxides have been encountered as by-products of various oxidation
reactions for a very long time but were very rarely explored because of their perceived
instability.
51,52
Though many of the derivatives can indeed be explosive,
53
the continued
search for better pharmaceuticals and the abundance of peroxide containing targets have
made gem-dihydroperoxides more attractive and sought after targets for some synthetic
chemists. The molecules, for instance, have been used as starting materials or
intermediates for a number of pharmaceuticals including 1,2-dioxolanes
54
and 1,2,4,5-
tetroxanes
55,56
and as oxidative reagents themselves in epoxidation reactions.
57

120
In terms of their own synthesis, gem-dihydroperoxides have been made in only a
few primary ways. Dihydroperoxides can be synthesized through the ozonolysis of enol
ethers as described by McCullough and others although the reaction is not general as
ozone sensitive functionalities are not well tolerated.
58,59,60
Hydroperoxidation of
ketals
61,62
has also been shown in some cases to lead to gem-diperoxides though, one is
limited to ketals as a starting materials.
63
In contrast to these two paths, the mildest and
most general route to gem-diperoxides appears to be through the H
2
O
2
oxidation of
ketones in the presence of an acid catalyst.
Several different acids have been used in such a process including the original
acid of choice, formic acid
51,64
and, more recently, phosphomolybdinic
65,66
and
camphorsulfonic acids.
67
However, in terms of both strength and ease of use, the most
intriguing acid for such reactions could be sulfuric acid.
68,69,70
Terent’ev and co-workers
for example, have shown that acid activation of ketones can successfully lead to geminal
bishydroperoxides in good yields(Scheme 6.5). Interestingly, the reactions were carried
out in tetrahydrofuran as a solvent which the authors claim helps the solvation of the
products preventing further reaction.
Scheme 6.5 – Synthesis of gem-Dihydroperoxides under Acidic Conditions
O
H
+
OH
H
2
O
2
H
O
O
H
H
+
H
2
O
2
OH
2
H
O
O
H
HOO
OOH HOO
n
n
n
n

We sought therefore, to use hydrogen peroxide complexes in such a manner. By
combining PVD:H
2
O
2
and our previously described PVP:H
2
SO
4
(see Chapter 5), we
121
found that gem-dihydroperoxides could be formed from several cyclic and acyclic
ketones. Reactions were generally carried out by first stirring the substrate of choice and
our acid catalyst in tetrahydrofuran at 0 °C. PVD:H
2
O
2
was then added followed by
warming the entire mixture to room temperature and allowing it to stir for 24 hours
(Table 6.3).
Table 6.3 – Acid Catalyzed Synthesis of gem-Dihydroperoxides
R
1
R
2
O
2. PVD:H
2
O
2
R
1
R
2
HOO OOH
1. PVP:H
2
SO
4
THF, RT

O
O
O
O
O
O
OOH HOO
Entry Ketone Product Yield (%)
a.
b.
c.
d.
e.
f.
g.
HOO
HOO
HOO
HOO
HOO
HOO
HOO
HOO
HOO
OOH
57
77
80
72
h.
O
HOO OOH
70
O
OOH
OOH
65
51
42
Time
24
24
24
24
24
24
24
24

122
We found that the yields for the reaction are generally better for cyclic ketones
such as cyclohexanone derivatives though ring size also appeared to play an important
role. Benzylic ketones were found to be very resistant to reactions though such
difficulties have been noted by other groups as well. Results were also dependent upon
the amount of acid used. Though Terent’ev and co-workers have described ratios
between 8:0.3 and 4:0.3 for hydrogen peroxide to acid as optimal, we found most
reactions to progress best with a 2:1 ratio of peroxide to acid. This may be due entirely to
the nature of our solid oxidant system instead of liquids. Even though such systems have
been found to under H
2
O
2
leaching slightly in solvents, their reactivity is still somewhat
tempered by the strong bonds between polymer and oxidant molecules.

6.3 Chapter 6: Conclusion
Hydrogen peroxide has been found to form stable complexes with poly(4-vinyl
pyridine) and poly(N-vinyl pyrolidone). Such complexes have been used for several
transformations and have now been found useful in the oxidations of sulfides exclusively
to sulfoxides and ketones to bishydroperoxy compounds. The complexes are safe, easy to
use, and more environmentally friendly than other oxidants as they have the potential to
be recycled and reused after only producing water as a by-product.

123
6.4 Chapter 6: Experimental
6.4.1 General Remarks
Unless otherwise mentioned, all chemicals were purchased from commercial
sources and used as received. Poly(N-vinyl pyrolidone) hydrogen peroxide and poly(4-
vinyl pyridine) hydrogen peroxide were both prepared from previously described
procedures.
28
Products were identified by the analysis of
1
H,
13
C, and
19
F NMR spectra
recorded on a 400 MHz Varian NMR spectrometer.
1
HNMR chemical shifts were
determined relative to TMS as the internal standard at δ 0.0 ppm.
13
C NMR chemical
shifts were determined relative to CDCl
3
at δ 77.0 ppm while
19
F NMR chemical shifts
were determined relative to CFCl
3
as the internal standard at δ 0.0 ppm. Column
chromatography, when necessary, was carried out using Siliaflash G60 silica gel (70-230
mesh).
As with all peroxides, gem-dihydroperoxide products were handled with extreme
caution and stored between 0-5 °C. Although we found them stable, such compounds are
known to be shock sensitive and to decompose violently upon heating. As such, they
must be kept away from direct heat sources, transition metal salts, mechanical shocks and
strong light sources.
6.4.2 General Procedure for the Oxidation of Sulfides to Sulfoxides
In the case of benzylphenylsulfide, 2 mmol (0.400 g) of the substrate is first added
to a pressure tube and supplemented with 1 mL of acetonitrile. Following this, 0.5 g of
PVD:H
2
O
2
is then added to the mixture along with an additional 2 mL of acetonitrile. The
tube is then capped and heated, with stirring, to 70 °C. The reaction’s progress is
124
followed by thin layer chromatography (30% hexanes: 70% ethyl acetate) and, upon
completion, 30 mL of dichloromethane was added and filtered. The residue was then
dried over anhydrous sodium sulfate and concentrated under vacuum. The resultant
product was then purified by column chromatography to remove any residual starting
material using a 7:3 mixture of ethyl acetate and hexanes and finally confirmed as
benzylphenylsulfoxide by comparing the spectral data with those of the authentic sample.
6.4.3 General Procedure for the Oxidation of Ketones to gem-Diperoxides
For cyclohexanone, 2 mmol (0.196 g) was added to a vial (8 dr) and then
dissolved in 1 mL of THF. To this was added 0.2 g of PVP:H
2
SO
4
and another 1 mL of
THF after which the solution was placed in an ice bath and stirred. After approximately 5
minutes, 0.5 g of PVD:H
2
O
2
was added to the tube along with 1 mL of THF. The tube
was then capped and allowed to stir in the ice bath for a further 5 minutes. The mixture
was then allowed to come to room temperature and then monitored by TLC (3:7,
ethylacetate and hexanes). Upon completion, the reaction mixture was diluted with 60
mL of dichloromethane and filtered. The filtrate was then washed with 30 mL of
saturated sodium bicarbonate solution, 30 mL of brine solution followed by 30 mL of
distilled water. The organic layer was dried over anhydrous sodium sulfate, concentrated
under vacuum and the residue was then purified by column chromatography (3:7 mixture
of ethyl acetate and hexanes). The product was finally identified by NMR as 1,1-
dihydroperoxycyclopentane.
125
6.4.4 Representative Spectra:
1
H NMR spectrum of (2-Chloro-ethanesulfinyl)-benzene (Table 6.1i)

ppm (t1)
2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0
1.94
2.84
1.00
1.00
2.03
S
Cl
O
126
6.4.4 Representative Spectra (continued):
13
C NMR spectrum of (2-Chloro-ethanesulfinyl)-benzene (Table 6.1i)

ppm (f1)
0 50 100
S
Cl
O
127
6.4.4 Representative Spectra (continued):
1
H NMR spectrum of 4-Methyl-cyclohexane-1,1-diyl bis-hydroperoxide (Table 6.3c)

ppm (t1)
0.0 5.0 10.0
1.86
1.97
1.89
2.93
2.10
3.00
HOO
HOO
128
6.4.4 Representative Spectra (continued):
13
C NMR spectrum of 4-Methyl-cyclohexane-1,1-diyl bis-hydroperoxide (Table 6.3c)

ppm (t1)
0 50 100
HOO
HOO
129
6.5 Chapter 6: References

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133
7 Chapter 7: Aminomethylated Poly(styrene)-Hydrofluoric
Acid Complex and its use in One-Carbon Ring
Homologation Reactions

7.1 Chapter 7: Introduction
The search for “green” alternatives to traditional acid catalysts has become one of
the fastest growing areas in chemical research over the past several decades. An
important component of these efforts is the group of ionic complexes that have recently
emerged.
1,2,3
Both ionic solids and liquids, besides serving as catalysts or solvents, can
also serve as a means of immobilizing volatile or dangerous chemicals in a stable and
reusable form without wholly sacrificing their reactive capabilities. The preceding
chapters for instance, have outlined the formation of several complexes between acids
and polymer bases and the beneficial qualities these complexes exhibit such as decreased
volatility and more controlled reactivity. Such complexes have been known for quite
some time and indeed, much of the work behind these particular complexes was inspired
by the introduction of Olah’s reagent and the related acid-base complexes of hydrogen
fluoride (HF).
4
They can also even be considered as ionic liquids.
Hydrogen fluoride is a widely applicable compound with several uniquely
interesting properties. Though it tends to form comparatively less acidic aqueous
solutions than other haloacids, anhydrous HF is still well within the realm of the so called
“superacids” (H
0
= -15.1).
5,6
The anhydrous acid is extremely toxic and corrosive though
it has been used in the petrochemical, ceramic and glass industries as a catalyst and
etchant. In various organic and inorganic reactions anhydrous HF has also been used as a
134
superacid catalyst, fluorinating agent and even solvent. But beyond these more concrete
applications, the simplicity and extreme polarity of the HF molecule has also made it an
authoritative model for intermolecular hydrogen-bonding. There has been, for instance, a
large amount of theoretical work dedicated to studying these forces in hope of applying
the findings to more complex systems like protein interactions and dissolution models.
Most of these findings point out that neat HF tends to form strong, extended hydrogen-
bonded networks within the solid, vapor and liquid phases.
7,8,9
Such powerful hydrogen
bonding ability has naturally lead many scientists to examine other molecules that HF
may bond to and lead to the creation of a whole new class of HF complexes. The HF
molecule is capable of forming strong hydrogen bonds strongly with bases and the nature
and properties of these bonds have been studied in detail for many decades. Aniline
hydrofluoride for instance, was first reported in 1879 while diazonium hydrofluorides
were first reported later in 1903 but in reality, the HF molecule has been found to form
stable complexes with various Lewis bases ranging from amines and phosphines to
carbamic acids and ethers.
10

Beyond their intrinsic theoretical value, however, the acid-base complexes can
also serve as much safer synthetic alternatives to anhydrous HF. As mentioned, many of
the synthetic applications of HF complexes in fact, stem from Olah and coworkers’
pioneering work with Pyridine:HF (Olah’s reagent). In a series of publications during the
1970’s, the group outlined the preparation of the compound and its use in numerous
fluorination reactions.
4,11

135
Since then, many Amine:HF complexes have been developed (Figure 7.1) and
their numbers and uses have continued to grow to this day.
12,13,14,15,16,17
Such compounds
benefit from the extensive hydrogen bond networks present which help stabilize the acid
and lower its volatility while still creating a reliable source of nucleophilic fluorine.
Figure 7.1 – Common HF:Amine Complexes
N
H
[F(HF)
n
]
NH
[F(HF)
n
]
NH
3
[F(HF)
n
]
N
H
m
[F(HF)
n
]
N
H
[F(HF)
n
]
NH [F(HF)
n
]
Triethylamine:HF Pyridine:HF
N,N-Dimethylaniline:HF
Aniline:HF Quinoline:HF
Poly(vinylpyridine):HF

7.2 Chapter 7: Results and Discussion
One of the great advantages of using HF complexes is the ease with which they
may be used when compared to highly volatile anhydrous HF (boiling point = 19.7 °C)
though many of the complexes still require the use of special handling procedures and
non-glass reaction vessels. Most of these complexes are however liquids with PVP:HF as
one of the only solids. In exploring the complexes of HF, we found that hydrogen
fluoride can also form stable complexes with (aminomethyl) polystyrene (AMPS) as a
polymeric support. The simple addition of anhydrous HF to the polymer at lowered
temperatures lead to the formation of a dark red, free-flowing solid that fumes in air and
must be kept at lowered temperatures (Scheme 7.1).
136
Scheme 7.1 – Synthesis of Aminomethylated(Polystyrene):HF Complex
H
2
C
[F(HF)
n-1
]
m
H
2
C
nHF
-78 °C
m
NH
2
NH
3

Hydrogen fluoride is used in a variety of reactions and one of the most useful
among them is the alkylation of isobutylene to yield high octane alkylates. Olah and
coworkers have therefore, used many of the HF complexes in this industrially
indispensible reaction as so called “green” catalysts with excellent results (Table 7.1).
18

HF complexes, including AMPS:HF, produce a mixture of hydrocarbons in good yields
with the desired 2,2,4-trimethylpentane (isooctane) as the major product. It has been
found that though the complexes act as adequate catalysts, only those containing a fairly
high loading of HF proved useful.
Table 7.1 – AMPS:HF Catalyzed Alkylation of Isobutane with Isobutylene
CH
3
C H
3
C
CH
2
AMPS/HF
+
H
3
C
C
CH
3
H
2
C
H
3
C C
CH
3
CH
3
H +
2,2,4-Trimethylpentane
(Isooctane)
C
5
, C
6
, C
7
, C
8
and C
9

hydrocarbons
H
3
C C
CH
3
CH
3
H

Alkyl Products (%) HF H
2
SO
4 PVP:HF
C
5
C
6
C
7
C
8
2,2,4-TMP*
C
9+
1.1
1.8
2.9
88.3
54.2
5.9
1.6
4.3
5.4
38.9
15.9
49.8
0.2
4.0
4.6
67.3
41.5
23.9
2.5
3.4
5.2
70.1
43.5
18.8
*2,2,4-Trimethylpentane
(isooctane)
AMPS:HF

137
HF complexes are also commonly utilized as a source of nucleophilic
fluorine.
19,20,21
Thus AMPS:HF proves capable of fluorinating several simple alcohols
(Table 7.2). However, the results become more interesting when adamantanemethanol is
fluorinated. Though other adamantanols for instance undergo fluorination cleanly, the
reaction between adamantanemethanol and AMPS-HF produced not a fluorinated
adamantane but homoadamanatane formed by homologation. Di-deuterated
adamantanemethanol provided the corresponding di-deuterated derivative in high yields.
Table 7.2 – AMPS:HF Reactions with Alcohols
AMPS-HF
CH
2
Cl
2
-78 ° C - RT
R
1
R
2
OH
R
1
R
2
F

OH
OH F
OH F
OH F
Substrate Product Time (Hr)
18
6
6
18
Conv (%)*
96
90
95
>99
*Determined By GC/MS
18 ~90
D
2
C
OH
D
D
Entry
a.
b.
c.
d.
e.

138
The transformations of substituted adamantanes have always been the subject of
intense and keen inquiry. Not only can such reactions lead to new and interesting
products, but valuable information on rearrangement mechanisms can be gleaned and
applied to other, less complex systems. Isolated from petroleum, adamantane was
originally named for the Greek word for diamond. Much like the precious stone, the
unique properties and chemistry of adamantane have intrigued organic chemists since the
very beginning.
Made up of three fused chair cyclohexane rings, the molecule is unusually rigid,
strain-free and possesses one of the highest melting points of any hydrocarbon.
22
In
addition, adamantane substitution has been shown to preferentially occur at the
molecule’s bridgehead carbons and proceed through a particularly stable tertiary
carbocation. With such interesting characteristics, it is no surprise then that adamantane
and its derivatives have been shown to undergo numerous transformations with
homologation being one notable example.
It is well known that substituted methyladamantanes may form homoadamantane
(tricyclo[4.3.1.1]undecane) under certain conditions. In general, acids are first used to
form the 1-methyladamantyl cation from the parent alcohol, ester or halide after which
the molecule may rearrange to the 1-homoadamantyl derivative. Because
homoadamantane is about 10 kcal/mol more strained that adamantane, rearrangement
tends to occur rapidly but not irreversibly unless other factors are in place.
23

Homoadamantanes, in fact, have been known to revert back to an adamantane framework
with prolonged heating or under strongly acidic conditions.
24,25

139
Nonetheless, substituted homoadamantanes can be formed through a variety of
methods. The Koch-Haaf reaction of 1-methyladamantanol, for instance, will produce
homoadamantane-1-carboxylic acid almost exclusively (Scheme 7.2).
22

Scheme 7.2 – Koch-Haas Carboxylation of 1-Methyladamantanol
CH
2
OH
CO
2
H
HCO
2
H-H
2
SO
4

The molecule can also result from acid catalyzed ring opening and insertion
reactions of 1,2-methanoadamantane and sometimes from the oxidation of 2-
methyleneadamantane with thallium (III) perchlorate.
26,27
A more common pathway to
the synthesis of homadamantane-type structures is through the treatment of
adamantanones or adamantanols with azides or diazo-compounds.
28,29,30,31
Such reactions
are used to introduce a nitrogen atom into the ring system that can be easily
functionalized later to nitrones, isoxazolidines and pyrroles or even rearranged once again
to substituted amino-adamantanes. Eguchi and coworkers, for instance, first reacted 2-
adamantanol with sodium azide in the presence of an acid to yield the corresponding
imino-homoadamantane.
32
Subsequent reduction of the molecule leads to an amino-
substituted homoadamantane that can be further transformed into countless other species
(Scheme 7.3).
Scheme 7.3 – Synthesis of Amino-Substituted Homoadamantanes
OH
H
+
NaN
3
N
R
R
NaBH
3
CN
NH
R
140
However, even though it is well established that 1-methyladamantyl cations will
rearrange to homoadamantyl cations, this does little to explain the behavior observed
with AMPS:HF. In its reaction with 1-adamantanemethanol, AMPS:HF seems to behave
unlike other strong acids and quite contrary to its reputation as an HF surrogate.
Anhydrous HF, for example, reacts with 1-adamantanemethanol to produce only 1-
fluoromethyladamantane, the expected result of combining an alcohol with a source of
nucleophilic fluorine ions (Scheme 7.4). On the other hand, when combined with a
mixture of anhydrous HF and triflic acid, 1-adamantanemethanol is reduced to 1-
methyladamantane exclusively.
Scheme 7.4 – Transformations of 1-Adamantanemethanol
OH
-78 °C - RT
HF
-78 °C - RT
HF/CF
3
SO
3
H
-78 °C - RT
F
CH
3
AMPS:HF

It is clear that AMPS:HF does not always act as a fluoride source, but may act as
simply a strong acid under the present conditions. At such a low temperature, for
example, the methyladamantyl carbocation is generated quite readily which quickly
rearranges to the homoadamantyl carbocation and then to homoadamantane by hydride
abstraction instead of the fluorinated product (Scheme 7.5).
141
Scheme 7.5 – Generation of Homoadamantane
CH
2
HO
AMPS:HF
DCM, -78 °C
H
2
C
OH
2
CH
2
Hydride
Tranfer

Such reactions point to the specific features of AMPS:HF complex which are yet
to be investigated in detail. It is also interesting to note that even upon warming to room
temperature and workup, no noticeable amount of 1-methyladamantane was uncovered
demonstrating that very little molecular rearrangement occurred after the cation was
reduced. However, the actual cause of these effects, whether the acid strength of the
complex, the presence of a primary amine as the complexing agent or simply the
conditions employed, is unknown.

7.3 Chapter 7: Conclusion
Hydrogen fluoride has been found to form stable solid complexes with
(Aminomethyl)polystyrene. The complexes act as convenient HF reservoirs and
nucleophilic fluorinating agents and react with several alcohols to produce substituted
fluorides. The complexes have also been found to catalyze the one-carbon ring
homologation of 1-adamantanemethanol to homoadamantane involving hydride transfer.
In light of these new and interesting results, further studies are highly warranted in order
to explore more synthetic utilities of the complex in organic transformations.
142
7.4 Chapter 7: Experimental
7.4.1 General Remarks
Unless otherwise mentioned, all chemicals were purchased from commercial
sources and used as received. Product compounds were identified by
1
H,
13
C, and
19
F
NMR spectra recorded on a 400 MHz Varian NMR spectrometer.
1
HNMR chemical
shifts were determined relative to TMS as the internal standard at δ 0.0 ppm.
13
C NMR
chemical shifts were determined relative to CDCl
3
at δ 77.0 ppm while
19
F NMR
chemical shifts were determined relative to CFCl
3
as the internal standard at δ 0.0 ppm.
Column chromatography was carried out using Siliaflash G60 silica gel (70-230 mesh).
As always, HF and all HF complexes were handled with extreme caution and stored only
in Nalgene bottles between -20 – 10 °C.
7.4.2 General Procedure for the Synthesis of Aminomethylated(Polystyrene):
Poly(Hydrogen Fluoride)
Aminomethylated poly(styrene) (8.5 g) is first cooled to -78 ºC in a 500 mL
Nalgene bottle. Anhydrous HF (45 g) is then carefully added with constant stirring to
ensure even and complete complexation. The resulting dark red crystalline solid is kept
closed in a Teflon bottle and stored between 0 – 10 ºC for further use.
7.4.3 General Procedure for the Fluorination of Substituted Alcohols
Adamantan-1-ol (0.002 mmol, 0.304 g) is first dissolved in 10 mL of
dichloromethane in a 50 mL Nalgene bottle and then cooled, with stirring, to –78 °C.
AMPS:HF (0.5 g) is then slowly added to the mixture after which, the bottle is capped
and continually stirred at -78 °C for another hour. The solution is then allowed to warm
to room temperature and monitored by
19
F NMR. Upon completion, 10 g of ice is added
143
to the reaction mixture which is then extracted with 50 mL of dichloromethane. The
organic mixture is then washed with NaHCO
3
solution (50 mL) and then distilled water
(50 mL). After being concentrated under vacuum, the product is finally identified as 1-
fluoroadamantane.
7.4.4 General Procedure for the Synthesis of Homoadamantane
1-Adamantanemethanol (0.002 mmol, 0.333 g) is first dissolved in 10 mL of
dichloromethane in a 50 mL Nalgene bottle and then cooled, with stirring, to –78 °C.
AMPS:HF (0.5 g) is then slowly added to the mixture after which, the bottle is capped
and continually stirred at -78 °C for another hour. The solution is then allowed to warm
to room temperature and stirred for 5 hours. Upon completion, 10 g of ice is added to the
reaction mixture which is then extracted with 50 mL of dichloromethane. The organic
mixture is then washed with NaHCO
3
solution (50 mL) and then distilled water (50 mL).
After being concentrated under vacuum, the product is finally identified as
homoadamantane.
144
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Abstract (if available)

Abstract The following dissertation describes the development of several new transformations by the application of a wide range of superacid catalysts and reagent systems for many potential synthetic reactions. The synthesis of some new and novel solid Brønsted acids and their applications in a number of classical organic reactions are also reported in detail. In Chapter 1, a brief overview and history of acids and superacids are given including their different forms and classifications. The strengths of acids and the acidity function are also briefly highlighted along with the importance and application of superacids in organic reactions. Finally, the properties of solid acids and their recent emergence as eco-friendly catalytic alternatives are outlined.

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University of Southern California Dissertations and Theses

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Asset Metadata

Creator Glinton, Kevin E. (author)

Core Title Superacid promoted synthetic transformations and the development of new solid supported Brønsted acids

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 08/04/2010

Defense Date 06/23/2010

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag acids,OAI-PMH Harvest,superacids

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Prakash, G.K. Surya (committee chair), Olah, George A. (committee member), Shing, Katherine S. (committee member)

Creator Email glinton@usc.edu,k_glinton@hotmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-m3274

Unique identifier UC1208058

Identifier etd-Glinton-3860 (filename),usctheses-m40 (legacy collection record id),usctheses-c127-370912 (legacy record id),usctheses-m3274 (legacy record id)

Legacy Identifier etd-Glinton-3860.pdf

Dmrecord 370912

Document Type Dissertation

Rights Glinton, Kevin E.

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Repository Name Libraries, University of Southern California

Repository Location Los Angeles, California

Repository Email cisadmin@lib.usc.edu