University of Southern California Dissertations and Theses

Reforming of green-house gases: a step towards the sustainable methanol economy; and, One-step deoxygenative fluorination and trifluoromethylthiolation of carboxylic acids

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Reforming of green-house gases: a step towards the sustainable methanol economy; and, One-step deoxygenative fluorination and trifluoromethylthiolation of carboxylic acids

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Content REFORMING OF GREEN-HOUSE GASES: A STEP TOWARDS THE SUSTAINABLE
METHANOL ECONOMY
and

ONE-STEP DEOXYGENATIVE FLUORINATION AND
TRIFLUOROMETHYLTHIOLATION OF CARBOXYLIC
ACIDS

By

Huong Dang

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

December 2021

Copyright 2021 Huong Dang
ii
DEDICATION

To my family
and
friends
iii
ACKNOWLEDGEMENTS

My Ph.D. wouldn’t have been possible without the support, encouragement, teaching,
training, and contribution of so many people. I would like to express my gratitude to all of them.
First of all, I would like to thank my doctoral advisor, Prof. G. K. Surya Prakash, for giving me a
chance to be a member of his lab, the freedom to learn, experience, fail, and grow up, the
opportunities to explore my curiosities, do research in diverse environments, as well as for his
financial support. It would be incomplete if not mentioned his willingness whenever I need his
help in research and in life.
Also, I’d like to thank my qualifying and dissertation committee members, Professors, Sri
Narayan, Matthew Pratt, Katherine Shing, Barry Thompson, and Dr. Ralf Haiges for their time,
feedback and support.
I thank Dr. Miklos Czaun for his time in training me when I first joined the lab. I’d like to
express my appreciation to Dr. Alain Goeppert for his help in training me, giving feedback, and
support throughout my Ph.D. Especially, I thank Drs Sankargarnesh Krishnamoorthy and
Jotheeswari Konthandaraman for their relentless support, not only in the lab but also in life, and
valuable friendship during the past six years. I thank Dr. Socrates Munoz for his guidance in the
last two chapters of my thesis. Also, I thank Dr. Robert Anizfeld for his support in providing
facilities and taking care of safety issues. Special thank to Ms. Jessie May for her support in
chemical orders and reimbursement and always listening and giving advice to my problems.
I would like to give special thanks to all Prakash group members, past and current, Dr.
Thomas Mathew, Dr. Patrice Batamack, Dr. Bo Yang, Dr. Hang Zhang, Dr. Dean Glass, Dr. Kavita
Belligund, Dr. Sayan Kar, Dr. Amanda Baxter, Archith Nirmachandar, Fang Fu, Sahar Roshandel,
iv
Vinayak Krisnanmurti, Vicente Galvan, Raktim Sen, Colby Barrette, and Xannath Ispizua-
Rodriguez for their support and maintaining friendly environment in the lab. I also want to thank
my fellows outside the lab, Dr. Damir Popov, Dr. Shuyang Shi, and Dr. Buddhinie Jayathilake for
their help, support, and friendship. I want to acknowledge all administrative staff of LHI and the
Department of Chemistry, Carole Phillips, David Hunter, Michele Dae, and Magnolia Benitez for
their help. Technical staffs at LHI, Department of Chemistry and CNI are appreciated for their
training, help and instrument maintenance, Ralph Pan and Allan Kershaw for NMR, Dr.Franklin
Devlin for XRD, Dr. Andrew Clough for XPS, Dr. Matthew Mecklenburg, Dr. Lang Shen, and
Thomas Orvis for TEM.
Besides, I want to give my appreciation to chị Thanh, chị Huyen, anh Phong, and all of my
Vietnamese friends at USC and LA area for their help and support throughout the last six years.
Finally, I would like to thank my parents, bố Yen and mẹ Lan, and my bother Long for their
patience and support during the hard times.

Knowledge is love and light and vision.

Helen Keller
v
TABLE OF CONTENTS
DEDICATION ............................................................................................................................. ii
ACKNOWLEDGEMENTS ....................................................................................................... iii
LIST OF TABLES .................................................................................................................... viii
LIST OF FIGURES .................................................................................................................... ix
LIST OF SCHEMES .................................................................................................................. xi
ABBREVIATIONS .................................................................................................................... xii
ABSTRACT ............................................................................................................................... xiii
PART I: REFORMING OF GREEN-HOUSE GASES: A STEP TOWARDS THE
SUSTAINABLE METHANOL ECONOMY ............................................................................. 1
CHAPTER 1. Methane Reforming Technologies: Challenges and Potential to the
Sustainable Methanol Economy ................................................................................................... 2
1.1 Green-house gas emissions and climate change ........................................................................ 2
1.2 Carbon neutral cycle and the sustainable methanol economy ................................................... 4
1.3 Methane reforming technologies: challenges and potential for industrial-scale production ..... 6
1.3.1 Steam reforming ............................................................................................................... 6
1.3.2 Dry reforming ................................................................................................................... 7
1.3.3 Bi-reforming ..................................................................................................................... 8
1.3.4 Partial oxidation ................................................................................................................ 9
1.3.5 Autothermal reforming ..................................................................................................... 9
1.4 Recent technology development and reactor design .................................................................. 9
1.4.1 Membrane enhanced reformer ........................................................................................ 10
1.4.2 Plasma assisted reformer ................................................................................................ 11
1.4.3 Solar thermal reforming .................................................................................................. 11
1.5 Recent catalysis developments for a stable and practical process ........................................... 12
1.5.1 Catalyst supports ............................................................................................................. 12
1.5.2 Metal loading and particle size ....................................................................................... 13
1.5.3 Catalyst promoters .......................................................................................................... 14
1.5.4 Catalyst preparation methods .......................................................................................... 14
1.6 Thesis scope ............................................................................................................................. 15
1.7 References ................................................................................................................................ 16
CHAPTER 2. Investigation of In-Situ Activation and Reactivation Conditions of Bi-
Reforming of Methane over Stable NiO/MgO Catalysts ..................................................... 22
vi
2.1 Introduction: Bi-reforming and the importance of stable and regenerable catalysts ............... 22
2.2 Experimental Section ............................................................................................................... 25
2.2.1 Material and instrument used .......................................................................................... 25
2.2.2 Catalyst synthesis ............................................................................................................ 26
2.2.3 Catalyst test – Reactor setup ........................................................................................... 26
2.2.4 Catalyst characterization methods .................................................................................. 30
2.3 Results and Discussion ............................................................................................................ 30
2.3.1 In-situ activation of NiO/MgO catalysts under different conditions .............................. 30
2.3.1a Effect of temperatures ............................................................................................. 30
2.3.1b Effect of pressures .................................................................................................. 33
2.3.1c Effect of NiO loadings ............................................................................................ 36
2.3.1d Effect of different ratios of CH4:H2O:CO2...........................................................................................37
2.3.1 e Comparing with H2 activation ................................................................................. 38
2.3.2 In-situ reactivation of NiO/MgO catalysts: the right condition matters ......................... 38
2.3.3 In-situ reactivation of NiO/MgO catalysts ...................................................................... 40
2.3.4 Catalyst characterizations and understanding of reaction conditions ............................. 41
2.3.4a XRD ........................................................................................................................ 41
2.3.4b TEM ........................................................................................................................ 42
2.4 Conclusions .............................................................................................................................. 43
2.5 References ................................................................................................................................ 43
CHAPTER 3. Stability Enhancement of Ni-M/MgO Catalysts for Dry Reforming of
Methane (M = In) ........................................................................................................................ 51
3.1 Introduction .............................................................................................................................. 51
3.2 Experimental Section ............................................................................................................... 52
3.2.1 Catalyst synthesis and materials ..................................................................................... 52
3.2.2 Catalyst test – Reactor setup ........................................................................................... 52
3.2.3 Catalyst characterization methods .................................................................................. 54
3.3 Results and Discussion ............................................................................................................ 54
3.3.1 Effect of temperatures ..................................................................................................... 56
3.3.2 Effect of catalysis compositions ..................................................................................... 56
3.3.3 Effect of pressures .......................................................................................................... 57
3.3.4 Catalyst Characterizations and understanding of reaction conditions ............................ 58
3.4 Conclusions .............................................................................................................................. 61
3.5 References ................................................................................................................................ 61
PART II: ONE-STEP DECARBOXYLATIVE FLUORINATION AND
THIOMETHYLTRIFLUORINATION OF CARBOXYLIC ACIDS .................................... 64
CHAPTER 4. Fluorination and Thiomethyltrifluorination: Applications, Challenges, and
Recent Developments .................................................................................................................. 65
4.1 Introduction .............................................................................................................................. 65
4.1.1 Medical application ......................................................................................................... 66
4.1.2 Agricultural application .................................................................................................. 67
4.1.3 Polymer/Material Sciences ............................................................................................. 67
vii
4.1.4 Pharmaceutical ingredients ............................................................................................. 69
4.2 Fluorinating reagents and C-F bond formations ...................................................................... 70
4.3 Previous literature review of trifluoromethylthiolation ........................................................... 73
4.4 References ................................................................................................................................ 75
CHAPTER 5. Direct Access To Acyl Fluorides From Carboxylic Acis Using A
Phosphine/Fluoride Deoxyfluorination Reagent System .......................................................... 79
5.1 Introduction .............................................................................................................................. 79
5.1.1 The utility of acyl fluoride .............................................................................................. 79
5.1.2 The previous methods of acyl fluoride synthesis and the proposal of the work ............. 80
5.2 Results and Discussions ........................................................................................................... 82
5.2.1 Optimization of reaction conditions ............................................................................... 82
5.2.2 Expand the scopes ........................................................................................................... 84
5.2.3 Identification of phosphonium intermediates by NMR spectroscopic studies ............... 87
5.3 Materials and procedures ......................................................................................................... 96
5.3.1 General procedure ........................................................................................................... 96
5.3.2 eneral procedure for the preparation of acyl fluorides and NMR yield determination 96
5.3.3 General procedure for the preparation/purification of acyl fluorides using PPh3 (Method
A) 97
5.3.4 General procedure for the preparation/purification of acyl fluorides using polymer-bound
PPh3 (Method B) ............................................................................................................................ 98
5.3.5 Procedure for the tandem deoxofluorination/amide-bond formation sequence .............. 99
5.3.6 Scale-up procedure for the synthesis of 4-Methoxybenzoyl fluoride ........................... 104
5.4 Conclusions ............................................................................................................................ 104
5.5 References .............................................................................................................................. 105
5.6 Characterization and NMR spectroscopic data of products ................................................... 108
CHAPTER 6. Trifluoromethylthiolation of Decarboxylic Acid using an Air- and Moisture-
Stable Copper Reagent ............................................................................................................. 124
6.1 Introduction ............................................................................................................................ 124
6.2 Results and Discussions ......................................................................................................... 125
6.2.1 Condition Optimization ................................................................................................ 125
6.2.2 Reaction scope .............................................................................................................. 127
6.2.3 Proposed Mechanism .................................................................................................... 130
6.3 Experimental setup ................................................................................................................ 131
6.3.1 Synthesis of (bpy)CuSCF3 ........................................................................................................................................ 132
6.3.2 General procedure for trifluoromethylthiolation of carboxylic acids and NMR yield
determination ............................................................................................................................... 132
6.4 Conclusions ............................................................................................................................ 133
6.5 References .............................................................................................................................. 134
viii
LIST OF TABLES

Table 2.1. Compare CO2 and CH4 conversions of reactions with different pressures during
activation time................................................................................................................................ 35
Table 2.2. Compare coke formation of reactions with different pressures during activation time..
....................................................................................................................................................... 36
Table 2.3. Effect of different ratios of CH4:H2O:CO2 ..................................................................................................37
Table 2.4. Comparing between bi-reforming condition and H2 condition for activation ............. 38
Table 2.5. Reactivation time, water flow, and carbon formation .................................................. 41
Table 4.1. Electronegativity of some elements and functional groups ......................................... 65
Table 4.2. Hansch parameter (πR) (lipophilicity measurement) of some substituents ................. 66
Table 4.3. Effect of Increasing Fluorine Content in Polymers ...................................................... 68
Table 4.4. Typical properties of some commercial fluorinated polymers ..................................... 69
Table 4.5 Structures of three fluorine-containing drugs in top five best-selling drugs in 2008 .......
....................................................................................................................................................... 70
Table 5.1. Optimization of the reaction conditions ....................................................................... 83
Table 6.1. Optimization of the reaction conditions ..................................................................... 127
ix
LIST OF FIGURES
Figure 1.1. The level of CO2 in the atmosphere for the past 800,000 years ................................... 2
Figure 1.2. Influence of all major human-produced greenhouse gases (1979-2018) ...................... 3
Figure 1.3. Carbon neutral cycle: Capture and Recycling (CCR)................................................... 5
Figure 1.4. Transformation of syngas to other useful commodity chemicals ................................. 6
Figure 1.5. Bi-reforming of methane .............................................................................................. 8
Figure 1.6. Operation conditions for ATR, POX, and SR ............................................................ 10
Figure 1.7. Catalyst activity on different supports ........................................................................ 13
Figure 2.1. Methanol and its derived products.............................................................................. 23
Figure 2.2. Bi-reforming of methane ............................................................................................ 24
Figure 2.3. High-pressure reactor system, purchased from Parr Instrument Company ................ 28
Figure 2.4. Sketch of the reactor system. MFC (mass flow controller), PT (pressure transducer,
T/C (thermal couple), PIC (pressure indicator controller), PG (pressure gauge), GC (gas
chromatography) ............................................................................................................................ 29
Figure 2.5. Arrangement of the catalyst and supporting materials inside the tabular alumina tube
....................................................................................................................................................... 30
Figure 2.6. The effect of calcination temperatures on CH4 and CO2 conversions ........................ 32
Figure 2.7. The effect of calcination temperature on the ratio of H2/CO ...................................... 33
Figure 2.8. The effect of calcination temperatures on carbon formation ...................................... 33
Figure 2.9. CH4 and CO2 conversions at different pressures during activation and reaction time...
....................................................................................................................................................... 34
Figure 2.10. Coke formation at different pressures during activation and reaction time .............. 35
Figure 2.11. Activity of catalyst under activation condition of CH4:H2O:CO2 = 3:4.5:1 ............. 38
Figure 2.12. Deactivation of catalyst under excess steam activation condition (CH4:H2O = 1:1.5)
....................................................................................................................................................... 39
Figure 2.13. Fast activation of catalyst under 1:1 ratio of CH4:CO2 condition ............................ 40
Figure 2.14. Original catalyst and spent catalysts under excess steam condition (CH4:H2O = 1:3)
and bi-reforming condition ............................................................................................................ 40
Figure 2.15. XRD spectra of 15-NiO-MgO at different calcination temperatures in a) 2θ 10-90
o
,
b) 2θ 122-132
0................................................................................................................................
42
Figure 2.16. TEM imaging of spent catalyst 15 wt% NiO-MgO .................................................. 43
Figure 3.1. Reactor system set-up ................................................................................................. 53
Figure 3.2. High pressure reactor for reforming of methane, purchased from Parr Instrument
Company ........................................................................................................................................ 54
Figure 3.3. CH4 conversion of different Ni-In/MgO catalysts at various temperature conditions ...
....................................................................................................................................................... 55
Figure 3.4. CO2 conversion of different Ni-In/MgO catalysts at various temperature conditions ...
....................................................................................................................................................... 55
Figure 3.5. Carbon formation over different Ni-In/MgO catalysts at various temperature
conditions ....................................................................................................................................... 56
Figure 3.6. Activities of different Ni-In/MgO catalysts at 100 psi pressure and 627
o
C a) CH4 and
CO2 conversions, b) carbon formation .......................................................................................... 57
Figure 3.7. XRD spectra of fresh reduced (a) and spent reduced (b) catalysts,Ni-MgO and 0.2In-
Ni-MgO after dry reforming at atmospheric pressure and 627
o
C ................................................. 59
x
Figure 3.8. TEM imaging of spent reduced Ni-MgO (left) and fresh reduced Ni-MgO (right)
catalysts, after dry reforming at atmospheric pressure and 627
o
C ................................................. 60
Figure 4.1. Fludrocortisone ........................................................................................................... 66
Figure 4.2. Some examples of commercialized peptisides in 2011-2017 ..................................... 67
Figure 4.3. Breakdown of fluorinated commercial agrochemicals into isectidies/acaricides,
fungicides, and herbicides/safeners ............................................................................................... 67
Figure 4.4. Structures of three fluorine-containing drugs in top five best-selling drugs in 2008.....
....................................................................................................................................................... 69
Figure 4.5. Common fluorinating reagents ................................................................................... 71
Figure 4.6. Electrophilic fluorination reported by Stavber and co-workers ................................. 72
Figure 4.7. Some examples of pharmaceutical and agrochemical products containing SCF3 group
....................................................................................................................................................... 73
Figure 4.8. Common SCF3 agents ................................................................................................ 74
Figure 4.9. Radical trifluoromethylthiolation method by Gloris et. al .......................................... 75
Figure 4.10. Aromatic trifluoromethylthiolation by Buchwald et. al ........................................... 75
Figure 5.1.
31
P NMR spectrum after addition NBS to vial containing PPh3.................................................88
Figure 5.2.
31
P NMR spectrum after addition of NBS to mixture of 1a and PPh3....................................89
Figure 5.3A.
31
P NMR spectrum after addition of 3HF-Et3N to vial containing
acyloxyphosphonium ion I ............................................................................................................. 90
Figure 5.3B.
19
F NMR spectrum after addition of 3HF-Et3N to vial containing
acyloxyphosphonium ion I ............................................................................................................. 91
Figure 5.4A.
19
F NMR spectrum after formation of species II ..................................................... 92
Figure 5.4.B.
31
P NMR spectrum after formation of species II .................................................... 93
Figure 5.5A.
19
F NMR spectrum after addition of benzoic acid (1a)............................................ 94
Figure 5.5B.
31
P NMR spectrum after addition of benzoic acid (1a) ............................................ 94
xi
LIST OF SCHEMES

Scheme 5.1. Synthetic utility of acyl fluorides .............................................................................. 80
Scheme 5.2. Prior art for acyl fluoride synthesis and current work .............................................. 81
Scheme 5.3. Working Hypothesis and Related Transformations .................................................. 82
Scheme 5.4. Direct deoxyfluorination of carboxylic acids ........................................................... 85
Scheme 5.5. Tandem deoxyfluorination/amidation sequence ....................................................... 87
Scheme 5.6. Mechanistic Hypothesis ............................................................................................ 95
Scheme 5.7. General Procedure for the preparation of acyl fluorides ........................................... 96
Scheme 6.1. Prior art of trifluoromethyl thioester synthesis and the current work ..................... 125
Scheme 6.2. Direct trifluoromethylthiolation of carboxylic acids .............................................. 128
Scheme 6.3. Proposed mechanism .............................................................................................. 131
Scheme 6.4. General procedure for trifluoromethylthiolation of carboxylic acids .................... 132
xii
ABBREVIATIONS

ATR AutoThermal Reforming
GHSV Gas Hourly Space Velocity
BET Brunauer-Emmet-Teller
DRM Dry Reforming of Methane
SRM Steam Reforming of Methane
BRM Bi-Reforming of Methane (combined CO2 and H2O reforming of methane)
TEM Transmission Electron Microscopy
XRD X-ray Diffraction
TGA Thermal Gravimetry Analysis
TCD Thermal Conductivity Detector
GC Gas Chromatography
wt% Weight Percent
xiii
ABSTRACT

There are two main research parts of my thesis work. Part I (Chapters 1-3) focused on the
development in the utilization of green-house gases via bi-reforming and dry reforming processes
of methane. Part II (Chapters 4-6) focused on the methodologies for deoxygenative fluorination
and trifluoromethylthiolation of carboxylic acids via acyloxyphosphonium ion intermediate.
Part I.

Global warming with the increasing emission of greenhouse gases, CO2 and methane CH4, has
imposed an immediate challenge to humankind and the environment nowadays. The concept of
Methanol Economy advocated by the late Nobel Laureate George A. Olah and his colleagues, Dr.
G. K. Surya Prakash and Dr. Alain Goeppert could provide a sustainable solution in which
methanol acts as a main fuel and chemical feedstock derived from CO2 capture, storage, and
conversion. In this process, green-house gases can be used as raw materials for the large-scale
production of syngas/metgas (syngas in which H2:CO = 2:1), which later can be transformed into
other fuels and commodity chemicals like methanol, hydrocarbons, and other alcohols/aldehydes.
The CO2 reforming processes conducted at atmospheric pressure are not suitable for the upstream
as well as downstream processes that are operated at high pressure as seen in the petrochemical
platforms. Despite many research efforts over the last decades, there are still challenges between
the laboratory experiment and the practical application. The biggest challenge is the deactivation
of the catalysts under high-pressure operating conditions. This requires the careful design of
reaction operation conditions and active catalysis. The scope of my thesis in chapters 1 and 2 is
aimed at showing some insights and improvements in the operational conditions and catalysis
design for a long-term continuity of reformer reactor operations. Chapter 1 succinctly reviews a
variety of reformer technologies.
xiv
Chapter 2 explores the right conditions for in-situ activation and reactivation of bi-reforming over
Ni-MgO catalysts without external supplements. This finding can help in the ease of operation and
cost savings.
Chapter 3 describes the efficacy of three different Ni-based catalysts for dry reforming of
methane. The doped metals (In) have demonstrated the ability in decreasing the coke formation in
dry reforming. The degree of coke formation also varies with different doped metals, least carbon
formation with In. This may be due to the low melting point of Indium; hence under high-
temperature dry reforming condition, Indium forms molten layers around the active Ni particles
reducing the degree of aggregation of Ni particles, which is the main reason for coke formation.

Part II.

Fluorine with its unique properties, high electronegativity, can modulate and enhance lipophilicity,
bioavailability of the fluorine containing molecules and materials. Hence, the introduction of
fluorine and fluoroalkyl groups into the organic molecules/materials has increasingly attracted
attention for various applications in medicinal, agrochemical, pharmaceutical and
polymer/material sciences fields. There are many reports of the methods to synthesize acyl fluoride
and trifluoromethylthiobenoates. However, the previous literature reports only have used toxic,
and environmental damaging harsh conditions.
Chapter 5 demonstrates a convenient methodology that employs common and available reagents,
PPh3, NBS, and triethyl amine hydrogen fluoride Et3N.3HF or KHF2/trifluoroacetic acid with
carboxylic acids, under mild condition, room temperature, for the formation of acyl fluoride. The
method was applicable to a wide-range substrate scope and functional groups. It also provided a
xv
potential scale-up procedure for 4-methoxybenzoyl fluoride which was in turn a potential
fluorinating reagent.
Continuing from Chapter 5, Chapter 6 shows another successful methodology which employed
acyloxyphosphonium ion as an intermediate to transform carboxylic acids to the corresponding
trifluoromethylthiolated products. The method also offered the applicability to various substrate
scopes and functional groups. Many pharmaceutical active ingredients also underwent
deoxygenative trifluoromethylthiolation by this method successfully.
1
PART I: REFORMING OF GREEN-HOUSE GASES: A STEP TOWARDS THE
RENEWABLE METHANOL ECONOMY
2

CHAPTER 1

Methane Reforming Technologies: Challenges and Potential to the Sustainable Methanol
Economy

1.1 Greenhouse gas emissions and climate change

Global warming has become a serious problem to humankind since the last two decades.
The level of CO2 concentration in the atmosphere has reached 412 ppm (NOAA Climate, 03-
2020), which is much higher than the level of 300 ppm, the highest level recorded for throughout
800,000 years record history by NOAA Climate, since the beginning of the industrial revolution
in the 19
th
century (Figure 1.1)
1
. Besides CO2, the other greenhouse gases like methane, water
vapor, nitrous oxide, CFC-12 and CFC-11 also contributed to the severe of global warming issue.
With the rapid rate of industrial and economic growth as well as the world’s human population
which is predicted to reach 11.2 billion by 2100 from 7.8 billion this year, 2020
2
, the emission
level of greenhouse gases into the atmosphere continues increasing rapidly and relentlessly.
According to the data published by NOAA Climate in 2018, the contribution of these greenhouse
gases to heating imbalance increased 43% when compared to the one in 1990 (Figure 1.2)
1
.
Figure 1.1 The level of CO2 in the atmosphere for the past 800,000 years
1
.
3

Figure 1.2 Influence of all major human-produced greenhouse gases (1979-2018)
1
.

The increasing of the greenhouse gas level in the atmosphere is the direct reason accounting
for the global warming, increase in the average temperature on the Earth and the abnormal weather
patterns around the world. The climate has become more unpredictable with many severe
conditions, hotter summer, colder winter, more frequently storms like El Nino. These sudden
changes in the weather led to several catastrophes around the world, forest fires in Australia and
Amazon
3
, which have killed at least hundreds of millions of animals, plus the loss of human,
properties and living habitats. Moreover, the increased temperature has led to the ice melting in
North and South Poles, sea level rising, and many lands submerging under the sea level and
becoming salty, thus unhabitable. According to NOAA prediction, until 2100, the sea level would
rise at least 8 inches (0.2 meters) above 1992 level
4
. Also, some CO2 will be absorbed into the
oceans. That makes the oceans become more acidic with the increasing of CO2 level and not be a
hospitable living place for marine organisms anymore
4,5
. Hence, global warming is the real and
immediate problem to all of us that needs immediate attention and long-term solutions.
4

Population will keep on growing in the next century and human activities, including
industrial production, transportation, and others, will never stop expanding. Thus, the emission of
greenhouse gases will continue growing and the Earth temperature will not stop leveling up. The
Earth itself cannot naturally control the excess CO2 concentration in the atmosphere in more timely
manner, more exactly the CO2 is not easily recycled and will persist for a long time – 300 to 1,000
years
5
. Therefore, there’s a need of a solution to this man-made anthropogenic problem. Capture
and storage of greenhouse gases (CCS – carbon capture and sequestration) has been suggested to
be one of the solutions to the problem.

1.2 Carbon neutral cycle and the sustainable methanol economy

Although there have been many technologies developed and improved to capture
greenhouse gases, storage of these gases imposed another problem. Due to the volatility of these
gases, storage of these gases requires large capacity containers that can hold high pressure. Other
suggestions include sequestration to storage of gases under oceans or underground into geological
formations. CO2 can also be used for enhanced oil recovery (EOR)
41
. However, these are not
sustainable in the long run since drilling and pumping gases underground can lead to fracture of
the land resulting in seismic activities and earthquakes; while pumping gases, especially CO2, into
the ocean, the acidity of the ocean will increase and be not suitable for aquatic organisms and coral
reefs. Therefore, for the long-term and large-scale prospect, utilization/recycle of greenhouse gases
(CCR – carbon capture and recycling) is more practical and beneficial. This pathway would lead
to a carbon neutral cycle as shown in Figure 1.3
41
.
5

Figure 1.3 Carbon neutral cycle: Capture and Recycling (CCR)
41
.

Both CO2 and methane, two greenhouse gases that play significant role in global warming,
can be used as raw materials to be transformed into synthesis gas (syngas), containing mostly
carbon monoxide, CO and hydrogen, H2, which can be transformed later to methanol, higher
carbon alcohols, aldehydes and hydrocarbons (Figure 1.4)
6
. Methanol is one of the most versatile
and simple chemical liquid fuels which can be obtained by direct CO2 hydrogenation, syngas
transformation (Eq. 1.1 and Eq. 1.2) or by electrochemical, or other means
27,41
. The produced
renewable methanol can later be processed into other commodity chemicals like dimethyl ether,
and hydrocarbons (ethylene, propylene, gasoline, diesel, etc.). The CO2 arises from the use of
methanol and its derivatives can captured and recycled back, which effectively closes the carbon
loop (Figure 1.3)
41
.
Eq. 1.1 CO2 + 3H2  CH3OH + H2O ΔH298K = -11.9 kcal/mol
6

Eq 1.2 CO + 2H2  CH3OH ΔH298K = -21.7 kcal/mol

Moreover, methanol is already one of the most important organic feedstocks in the
chemical industry with the current worldwide production of 70 million tons per year
54
.
Recognizing the significance of methanol in the economic and environmental contexts, the late
Nobel Laureate George A. Olah and his colleagues, Dr. G. K. Surya Prakash and Dr. Alain
Goeppert advocated the concept of a renewable and sustainable future economy based on the
Methanol in their book “Beyond Oil and Gas: The Methanol Economy”, published for the first
time in 2006. The book got published in its third edition in 2018
54
. The book is also translated into
Chinese, Japanese, Swedish, Hungarian and Russian.
Figure 1.4 Transformation of syngas to other useful commodity chemicals.

1.3 Methane reforming technologies: challenges and potential for industrial-scale
production
1.3.1 Steam reforming:

The steam reforming reaction was first introduced into industry in 1930 and had been
mainly applied in the United States due to the availability of natural gas as a feedstock. Steam
7

reforming of methane (Eq. 1.3)
41
was accounted for 95% production of hydrogen in the United
States in 2012
27,54
. Conventionally, steam reforming is operated by using Nickel catalyst supported
by metal oxide such as aluminum oxide, Al2O3 or magnesium oxide, MgO
18,41,43
; however, these
catalysts are prone to the deactivation due to coke formation, mainly by two side reactions,
methane decomposition (Eq 1.4) and Boudard reaction (Eq 1.5)
41
.
Eq 1.3
CH4 + H2O  CO + 3H2 ΔH298K = 49.1 kcal/mol
Eq 1.4 CH4  C + 2H2 ΔH298K = 18.1 kcal/mol
Eq 1.5
2CO  C + CO2 ΔH298K = -40.8 kcal/mol

However, the ratio of H2:CO in the steam reforming syngas mixture is 3:1 in which there
is an extra mole of hydrogen for the methanol synthesis (which requires only 2:1 ratio of H2:CO).
In order to improve the catalyst activity over long run and enhance the conversion of the highly
endothermic reforming reaction, the steam reforming is often operated at really high temperatures
700-1000
o
C (927 K-1227 K)
18
, which is not energy efficient for the subsequent processes at much
lower temperature, for example, methanol synthesis at 250-300
o
C
15,27,41,54
.

1.3.2 Dry reforming:

Dry reforming (no steam) of methane (Eq 1.6)
41
and other hydrocarbons was applied
commercially, (Calcor process) to produce high purity carbon monoxide CO
7-14
. The fact that dry
reforming efficiently utilizes CO2 and CH4, two most abundant greenhouse gases, in molecular
ratio 1:1 makes it attractive to mitigate global warming. However, the big drawback of this process
is that it suffers severely from coking, which results in short lifetime of the catalyst operation and
may damage the reactors
16,17,19-25
. The carbon formation can be in a variety forms, such as graphite,
carbon nanotubes, or whiskers. Furthermore, the ratio of H2/CO formation is low, only 1:1, which
8

is not suitable for methanol synthesis and needs to be supplied with additional mole of hydrogen
from other sources.
Eq 1.6 CH4 + CO2  2CO + 2H2 ΔH298K = 59.1 kcal/mol

1.3.3 Bi-Reforming:

Bi-reforming of methane is the combination of steam reforming and dry reforming in the
2 to 1 stoichiometric ratio (Figure 1.5)
41
in order to form “metgas”, syngas with 2:1 ratio of H2:CO
for later methanol synthesis. The process was advocated by Olah and Prakash
54
. Additionally, one
advantage of this process is that steam can alleviate the formation of carbon via gasification (Eq
1.7)
41
. Moreover, aliphatic hydrocarbons can also be utilized as feedstocks in this process (Eq 1.8)
which allows the utilization of wet shale gas
6,26,28
.

Figure 1.5 Bi-reforming of methane
41
.

Eq 1.7 C(s) + H2O  CO + H2 ΔH298K = 31.3 kcal/mol

Eq 1.8 3CnH2n+1 + (3n-1)H2O + CO2  (3n+1)CO + (6n +2)H2
9

1.3.4 Partial oxidation:

In partial oxidation of hydrocarbons, the raw materials, methane, biogas, or heavy oil
fractions, are gasified in the presence of oxygen without catalysis (Eq 1.9 and Eq. 1.10), and
possibly with steam at temperature 1300-1500
o
C and pressures of 3-8 MPa
28,41
.
Eq. 1.9 CH4 + 1/2O2 → CO + 2H2 ΔH298K = -8.5 kcal/mol

Eq 1.10 CH4 + 2O2 → CO2 + 2H2O ΔH298K = -210.2 kcal/mol

A part of the gas is burned, which provides heat for the endothermic processes like steam
reforming. Despite the self-supply of heat and less expensive operation of the reactor, the
technology overall is more expensive than the steam reforming due to the cost of the subsequent
conversion. Catalysts can be added to lower the operating temperature 700-1000
o
C
41,51,53
.
However, due to high temperature of operation (> 800
o
C), difficulty in thermal management, and
safety concerns, the practicality of the partial oxidation reforming is rather limited
41
.

1.3.5 Autothermal reforming:

In autothermal reforming (ATR), steam reforming (endothermic) is combined with
catalytic partial oxidation (exothermic) reaction. Hence, it is advantageous to run not requiring
external heat and being less expensive than steam reforming. Depending on the specific target of
hydrogen yield, the reformer could be selected for suitable operating conditions (Figure 1.6)
55
.
10

Figure 1.6 Operation conditions for ATR, POX, and SR
55
.

Moreover, under reforming conditions, there is concurrent occurrence of reverse water gas shift
(RWGS) reaction (Eq 1.11) which results in the ratio of H2/CO less than unity
47
.
Eq 1.11 CO2 + H2  CO + H2O ΔH298K = 9.8 kcal/mol

1.4 Recent technology developments and reactor design

1.4.1 Membrane enhanced reformer

Two types of membrane reactors have been investigated frequently, the Pd and Ni
membrane reactors
55,56
. The Pd-membrane reactor showed significant reduction in carbon
formation
55,56
. The efficiency of this type of reactor is due to the reduction in the reactor volume
and high surface-area-to-volume ratio. The drawback of this reactor is the intermetallic diffusion,
which lowers H2 permeation and its high cost
55,56
. In contrast, the Ni membrane reactor with a
narrow layer off non-active Ni particles plating on Al2O3 showed high selectivity to hydrogen
separation
55,56
. It is also highly temperature stable and has high degree of surface interaction of Ni
films and hydrogen. This enhances the conversion of CH4, the H2/CO ratio and limits RWGS
reaction, consequently inhibiting Boudouard reaction and mitigating coke deposition. This type
reactor is much cheaper than the Pd membrane reactor
55,56
.
11

1.4.2 Plasma-assisted reformer

In plasma reforming, in addition to free electron formation, radicals of H, OH, and O are
also formed, which creates conditions for both reductive and oxidative reactions. Plasma reforming
technologies have been applied for POX, ATR, and SR
55
.
Plasma devices, plasmatrons, can generate very high temperature (>2000
o
C) with high degree of
control using electricity
54,55
. The heat generated is independent of reaction chemistry and high
energy density associated with the plasma itself can reduce the size of the reformer and accelerate
thermodynamically favorable reactions without a catalyst or external heat
54
. There are several
advantages of plasma reformer over the conventional reformer, compactness and low weight, high
conversion efficiencies, reduced cost (simple metallic or carbon electrodes), fast response time,
operation with even heavy hydrocarbons and high sulfur diesel (no catalyst needed, therefore, no
sulfur poisoning). The disadvantages are the dependence on electrical energy and requirement of
high-pressure operation conditions which can increases electrode corrosion, resulting in decrease
of its lifetime.
55

1.4.3 Solar thermal reforming

In a solar thermal reformer, the heat is provided to the reaction by solar irradiation
54,55
. No
catalyst is needed, so there is no problem of catalyst deactivation and thus negligible coke
formation. The fine carbon particles in the system would enhance the radiative heat transfer during
the reaction process
54,55
. Furthermore, sunlight is a renewable source of energy, which could save
costs and has good environmental outcome. However, this technology is not very practical due to
such high temperature 2000 K needed to maintain inside the reactor
55
.
12

1.5 Recent catalysis developments for a stable and practical process

Several metals have been tested for different types of reforming of methane
16-20,22-52
. Noble
metals (such as Pd, Rh, Ru, Pt, etc.) show high activity and less prone to carbon formation.
However, the expensive price of these metals makes them less attractive in terms of large-scale
industrial application. Nickel with much cheaper price and similar activity arises as a potential
candidate for the large-scale application purpose. However, one drawback of using Ni is that it can
undergo severe coking problem
14,24,26,33,40,46,53
. Hence, alleviation of this issue in catalytic design
is critical. Extensive efforts in catalytic design of a promising Ni-based catalysts have been
probed
47,49-52
.

Methane decomposition occurs at 557
o
C and above, while Boudouard reaction occurs
below 700
o
C. Hence, the maximum carbon deposition is reported at the temperature range of 557-
700
o
C, based on thermodynamics analysis
14,53
.
It’s known that nickel undergoes severe aggregation upon heating under high temperature.
These large-size Ni particles are the main reason for coke formation to occur
9,37,53
. Therefore,
catalyst design plays an important role in reducing carbon deposition and reforming activity.

1.5.1 Catalyst supports

Support is the mesoporous material that helps to disperse active catalytic species. Supports
can be metal oxides like MgO, Al2O3, ZrO2 or nonmetal oxides like SiO2
8,11-22
. Moreover, the
nature and properties of the support and the interaction between support and active species can
affect the activity of the catalyst. High surface area and mesoporous structure of the support help
disperse the active metal greatly which could the lower the chance of aggregation to form larger
13

size particles. Moreover, it is known that for reforming reaction, the basicity of the support affects
greatly the coke formation process. It is also known that the Lewis basicity of the support
significantly increases the adsorption of the acidic CO2, which leads to the favor the formation of
CO and lower the possibility of carbon formation. Figure 1.7 summarizes the catalytic activity of
some metals on different supports
23,35,47,51,52
.

Figure 1.7 Catalyst activity on different supports
23,35,47,51,52
.

1.5.2 Metal loading and particle size

Several studies have shown positive correlation between the metal particle size and the
carbon formation
37,51-53
. Smaller particles favor the initial methane activation while large size
clusters lead to long term methane decomposition, producing carbon-filaments. One study showed
14

that smaller than 6 nm active metal particles resist excellently to the coke deposition on catalyst
surface
51
.
The amount of metal loading directly affects the size of the metal particles as well as the
activity of the catalysts
37,51-53
. With low metal loading, the active metals are dispersed better on
the support, thus retain their smaller size. However, the number of active sites is also lower, thus
resulting in lower reactivity. On the other hand, increasing metal loading could increase the
aggregation process, larger particle size and increase in carbon accumulation, as seen by the study
of Wang et. al
8
. Four different metal loadings of (Ni-Co) on ZrO2 were studied for DR, 3, 6, 12,
and 18%. With the loading of more than 12%, significant amount of carbon formation on catalyst
surface was observed.

1.5.3 Catalyst promoters

Promoters, the nonactive materials, could enhance the performance of the catalysts via
surface structure effects
26,31-33,38,45,46
. They can improve the dispersion of active metals on the
support, increase the basicity of the supports, or promote gasification of carbon accumulated on
the catalysts. Several promoters have been reported in the literature. Ag alters the carbon type
accumulated from whisker, which is known not undergoing gasification, to amorphous carbon,
which can be gasified easily
57
.

1.5.4 Catalyst preparation methods

Various preparation methods were examined carefully
12,30,43,49-51
. Among conventional
methods, precipitated and co-precipitated catalysts show less stability and activity than
impregnated and sol-gel catalysts, due to lower concentration of active site and higher partial
15

oxidation of the active Ni species by CO2 and H2O during the high temperature reaction
35,47,51,52
.
Moreover, any trace of alkaline metal ions could decorate nickel surface, thus decreasing the
catalytic activity. Hence, precipitation is not preferred in the catalyst preparation for reforming of
methane
43,51,52
.

For impregnation method, pore blockage was observed. NiO particles with crystal sizes of
9-11 nm were observed outside structure of SBA-15 support
23
. The impregnation method has three
advantages over the precipitation method, (1) no need of filtering and washing steps, (2) Catalyst
fabrication small metal loadings, (3) some control over the metal dispersion on the support
23,47
.
In sol-gel method, aerogel catalysts are more thermally stable than xerogel (dry gel)
catalysts
47
. The aerogel ones show a higher surface area, lower bulk density, smaller metal particle
size, higher metal dispersion and stronger metal interaction than the catalysts prepared by xerogel
method. Tested aerogel catalysts showed better activity and stability than impregnated
catalysts
47,49
.
Differing from the conventional methods, atomic layer dispersion (ALD) offers an
excellent improvement in catalysts performances. ALD prepared catalysts show excellent
conversion and coke resistance compared to other methods. The metal particle size is smaller than
3 nm with high dispersion and strong metal-support interactions
43,47-52
.

1.6 Thesis scope

The focus of this work is dedicated to the development of a stable, coke-resistant catalyst
for dry reforming at low temperatures and a practical process for long-term operation of bi-
reforming at high pressure without disruption. Low-temperature dry reforming (around 627
0
C)
could be suitable for coupling with other processes which then results in energy efficiency benefits
16

by heat transfer. Testing was also performed at higher temperatures (727-827
0
C) and higher
pressure (7 bar) for wider application, in order to gain further knowledge about the catalysts and
for comparison with the previous catalysts developed.
Coke formation is unavoidable during bi-reforming at higher pressures (up to 10 bar). This
is the main reason for the deactivation of the catalyst and disrupting the operation process. The in-
situ methods of activation and reactivation were investigated to improve the ease and continuity
of operation. The process continuously and successfully run for up to 200 hours without decrease
in activity.

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and Metal-Support Interactions.” Topics in Catalysis, 2018, 61, 9, 855–874.
(50) Shang, Zeyu; Li, Shiguang; Li, Ling; Liu, Guozhu; Liang, Xinhua. “Highly Active and
Stable Alumina Supported Nickel Nanoparticle Catalysts for Dry Reforming of
Methane.” Applied Catalysis B: Environmental, 2017, 201, 302–309.
21

(51) Wang, Ye; Yao, Lu; Wang, Shenghong; Mao, Dehua; Hu, Changwei. “Low-Temperature
Catalytic CO2 Dry Reforming of Methane on Ni-Based Catalysts: A Review.” Fuel
Processing Technology, 2017, 169, 199–206.

(52) Jang, Won-jun; Shim, Jae-oh; Kim, Hak-min; Yoo, Seong-yeun; Roh, Hyun-seog. “A
Review on Dry Reforming of Methane in Aspect of Catalytic Properties.” Catalysis,
2018, 324, 15–26.

(53) Aramouni, Nicolas Abdel Karim; Zeaiter, Joseph; Kwapinski, Witold; Ahmad,
Mohammad N. “Thermodynamic Analysis of Methane Dry Reforming: Effect of the
Catalyst Particle Size on Carbon Formation.” Energy Conversion and Management,
2017, 150, 614–622.

(54) Olah, George A.; Goeppert, Alain; Prakash, G. K. Surya. “Beyond Oil and Gas: The
Methanol Economy”, Wiley, 2018.

(55) Kalamaras, Christos M.; Efstathiou, Angelos M. “Hydrogen Production Technologies:
Current State and Future Developments”. Conference Paper in Energy, 2013, 1-9.

(56) Iulianelli, Adolfo; Liguori, Simona; Wilcox, Jennifer; Basile, Angelo. “Advances on
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Catalysis B: Environment, 2015, 165, 43-56.
22

CHAPTER 2

Investigation of In-Situ Activation and Reactivation Conditions of Bi-Reforming of
Methane over Stable NiO/MgO Catalysts

2.1 Introduction: Bi-reforming and the importance of stable and regenerable catalysts

The continuous growth of population and economies have led to the increasing demand of
energy uses, especially fossil fuels, which contributed to 90% of energy use nowadays
1
. However,
the problem of CO2 emission, global warming, and unequal access to non-renewable fossil fuel
resources demand the need to search for other renewable and sustainable energy sources. One of
these alternatives is methanol.
The concept of the “Methanol Economy” strongly advocated by Olah, Prakash and his
colleagues consists of a new social-economic model, where methanol plays a vital role to serve as
the main source for energy and synthetic materials
1,2
. Methanol is already an available energy
carrier and starting material for synthesis of many other commodity chemicals and materials
(Figure 2.1)
3,37,38
. It has advantages over others such as easier to store and transport than hydrogen,
and cleaner burning than fossil fuels. Moreover, it can also be used in fuel cell, and is
biodegradable.
The current annual production of methanol is around 70 Mtons
2,3
. It is mainly produced
from the syngas process, mostly steam reforming of natural gas and coal gasification. However,
the process is very energy consuming due to highly endothermic nature of the reaction. The other
source for methanol production is to use of biogas, but the process is still energy demanding since
the gas must be upgraded by purification processes to achieve the right ratio 2:1 of H2:CO. The
23

other problem of these processes is the deactivation of catalysts which causes difficulty in
continuous process operation.

Figure 2.1 Methanol and its derived products
3
.

Hence, the major challenge is the development of a novel, convenient, safe, renewable and
sustainable way to produce methanol from syngas in an industrially large scale. Bi-reforming of
methane, which is the combination of steam reforming and dry reforming
21,26,50,54,55,58,61
in an
appropriate syngas ratio, could offer a sustainable way to achieve the goal of 2:1 ratio H2:CO
(Figure 2.2)
1,16,42,66
. The produced syngas can be transferred directly to the other reactor for
methanol production without the need of purification or adjustment of syngas ratio, which could
result in cost savings and ease in reactor design. Moreover, the ratio of H2:CO is easily adjusted
24

by changing the ratio of input gases, CH4, H2O and CO2 as demonstrated by Olah et. al.
1,4,5
, which
makes the process promising for other chemical synthesis with different H2:CO ratio.

Figure 2.2 Bi-reforming of methane
1
.

Nickel-based catalysts has shown great promise due to their similar activity to the noble
metal catalysts based on Ru, Pt, Pd, etc. but much cheaper in price
10,11,29,34,40,43-47,49,51,52
. This makes
nickel a suitable catalytic metal for industrial application on a large scale. However, the big
drawback of nickel catalyst is its propensity to deactivation due to the carbon accumulation on the
catalyst. It is well known that the right oxide support can help to alleviate this problem. Among
several oxide support tested by Olah and co-workers
1,4
, it was reported that magnesium oxide MgO
is the best candidate for the role. Therefore, the same support was used in this study.
In addition, the process development, i.e. ease in operation, simpler reactor design, and
long-time continuous reaction operation is always of great benefit. It’s well known that the active
catalytic species for methane reforming is nickel free metal, not nickel oxide NiO
8,9,12
. However,
due to the ease of oxidation of Ni, it always naturally occurs in oxide form, especially after the
catalytic synthesis process
6,15
. Therefore, in order to activate the catalysts, reducing NiO to Ni
metal, there is a need for pure hydrogen gas to completely reduce the catalysts under high
temperature, typically 700-900
o
C, depending on the nature of the catalysts, the amount of NiO,
types of supports, and interaction between metal oxide, metal and support
7,12,15,17,18,20,59-62,65
.
25

Previous literatures have shown some examples of “self-activation” or in-situ activation
14,56,63
, i.e
no use of pure hydrogen, of different Ni-based catalysts. Choudhary and co-workers used
combined steam and dry reforming condition (CH4:H2O:CO2 = 1.0:0.55:0.55) to activate Ni-
supported CaO at 800
o
C
14
. More recently, Azadi and co-workers used condition of CH4:H2O 1:3
to activate 10 wt% NiO-YSZ at 700
o
C
63
. in both of these examples, the activation occurred at the
atmospheric pressure. However, there hasn’t been any systematic studies on the in-situ activation
of Ni-MgO catalysts under bi-reforming conditions at high pressure.
Under bi-reforming conditions, the formation of carbon on the catalysts NiO/MgO is
unavoidable as shown by Olah et. al.
4,5
, even though it is the best candidate among different
supports. Therefore, finding a way to reactivate the catalysts is a promising solution. As carbon on
catalysts can be removed by gasification, the excess steam supply during the reactivation time has
offered an excellent solution to the coking and catalysis reactivation problems.
In this study, we have demonstrated the systematic study for the in-situ activation and reactivation
of NiO-MgO catalysts under bi-reforming conditions at different pressures, up to 10 bar, without
the extra supply of pure hydrogen without any disruption in reactor operation. The nature of the
catalysts and carbon formation were also examined in order to understand the feasibility of the
process.

2.2 Experimental Section

2.2.1 Materials and instrument used

All materials were purchased from commercial suppliers without further purification. The
magnesium oxide 99.5% Mg, 35 mesh powder, was purchased from Strem Chemicals; nickel (II)
nitrate hexahydrate 99.999% trace metal basis from Alfa Aesar, and methanol from VWR.
26

Methane (UHP), CO2 (instrument grade), N2 (purified grade), and hydrogen (UHP) were obtained
from Airgas and Gilmore Gas. The supporting tabular alumina (different mesh sizes) and alumina
balls ¼ inch diameter were provided by Almatis.
The gas mixture was analyzed by an online Varian 450 series GC using a TCD detector.

The GC was equipped with a gas handling valve system.

2.2.2 Catalyst synthesis

The catalysts x wt% NiO/MgO were synthesized by wet impregnation method
3
. Basically,
5g of magnesium oxide, MgO was mixed together with an appropriate amount of nickel nitrate
hexahydrate and 10 mL methanol. The suspension was then stirred at 500 rpm at room temperature
for 20 hours. The solvent was evaporated and the solid was dried at 120
o
C in an oven overnight.
The catalyst was calcined at 550
o
C, 800
o
C, or 900
o
C, repectively, for 5 hours with the heating
rate of 5
o
C/min in a furnace. The solid collected was then ground in mortar and pestle into a
homogenous fine power. The catalysts were labeled x-NiO-MgO-y where x = 5, 15, or 25 which
corresponds to 5, 15, or 25 weight percent NiO in the catalysts and y = 550, 800, or 900, which
corresponds to the calcination temperature 500, 800, or 900
o
C.

2.2.3 Catalyst test – Reactor setup

The reactor for the bi-reforming experiments was designed by the Parr Instrument
Company and furthered modified for the specific use (Figure 2.3). The system can be operated
parallelly up to three reactions using three distinct tabular reactors. The reaction conditions
(pressure, temperature, and flow rate) can be modulated independently (Figure 2.4).
27

The catalyst and supporting materials were arranged inside a tabular alumina tube (Figure
2.5) which was placed inside the tabular stainless-steel reactor (inner diameter 1.25 cm). The
catalyst (100 mg) was mixed with 900 mg tabular alumina 60 – 200 mesh and placed inside the
tabular alumina tube (inner diameter 0.8 cm) in the order in Figure 2.3. A “blanket” nitrogen flow
20 mL/min was introduced into the space between the stainless-steel reactor and the tabular
alumina tube to avoid reactor corrosion.
For normal activation of catalysts by hydrogen gas, the catalyst was heated under hydrogen
and nitrogen mixture (ratio 1:1, flow rate 40 mL/min) to 850
o
C over 1.5 h, then kept at this
temperature for 3 h. After that, the gas was switched to nitrogen until the desired reaction pressure
and temperature (100 psi and 823
o
C) were achieved. At this time, the reaction gas mixture CO2
and CH4 and reference gas N2 (the total flow rate of 75 mL/min, the flow rate of CO2:CH4:N2 was
12.5:37.5:25 mL/min) were introduced into the reactors. Water was introduced with a flow rate of
0.018 mL/min, at the same time, into the reactor by a high-pressure pump and vaporized to steam
at the upper part of the reactor, where the temperature was high enough, before being mixed with
the other feed gases. The gas mixture coming out of the reactor was cooled by the cooling system
and connected to online GC (with a TCD detector) analysis. The reaction test was run for 100 h
continuously. After the test was finished, the catalyst was collected to perform characterization.
For the in-situ activation of catalyst, the heating under hydrogen step was omitted, the
desired temperature and/or pressure activation conditions were set up in the beginning. The
catalysts were heated under nitrogen with a flow rate of 40 mL/min until the reactor reached the
desired setup condition. Then, the mixture of CH4:CO2:H2O:N2 or CH4:H2O:N2 with an
appropriate ratio was input into the reactors until the H2 production no longer increased. This step
usually took part in 5 to 6 h. The next steps were like the hydrogen activation condition.
28

The conversions of CO2 and CH4 were calculated by the following formula:

% 𝑐𝑜𝑛𝑣𝑒𝑟 𝑠 𝑖𝑜𝑛 =
𝑋 in
− 𝑋 out

𝑋 in

× 100%

Where Xin is the input feed gas flow rate

Xout is the output feed gas flow rate

For the in-situ reaction of the catalysts, after the reactions were run for 100 h, the
reactivation period was started for 3 to 5 h by adding additional amount of H2O while the other
reaction conditions were kept the same, then the experiment was continued for another 100 h at
the standard conditions like before (100 psi, 823
o
C and the stoichiometric ratio of CO2:H2O:CH4).

Figure 2.3 High-pressure reactor system, purchased from Parr Instrument Company. Photo
credit from Parr Instrument Company.
29

Figure 2.4 Sketch of the reactor system. MFC (mass flow controller), PT (pressure transducer),
T/C (thermal couple), PIC (pressure indicator controller), PG (pressure gauge), GC (gas
chromatography).
30

Figure 2.5 Arrangement of the catalyst and supporting materials inside the tabular alumina tube.

2.2.4 Catalyst characterization methods

The catalysts, before and after experiments, were characterized by XRD, TEM (JEOL
2100F), and TGA. Power X-ray diffraction measurements were performed on Rigaku Ultima IV
Diffractometer with a Cu Kα (0.154056 nm) radiation source and a scan rate of 6
o
/min from a 2θ
value of 10
o
to 90
o
. Transmission electron microscopy TEM images were obtained on a JEOL
31

2100F with an acceleration voltage of 200 keV. Thermogravimetric analysis TGA was performed
on a TGA-50 Thermogravimetric analyzer (Shimadzu).

2.3 Results and Discussion

2.3.1 In-situ activation of NiO/MgO catalysts under different combined H2O and CO2
reforming conditions
2.3.1a Effect of calcination temperatures

The study was investigated at our standard conditions of 823
o
C and 100 psi, and the
stoichiometric ratio of CO2:H2O:CH4 (1:2:3 with a total flow of 75 mL/min) for the activation.
Three catalysts were used in this study 15-NiO-MgO-550, 15-NiO-MgO-800 and 15-NiO-MgO-
900.
As demonstrated in the previous study by our lab, the 15-NiO-MgO catalyst was able to be
self-activated in the bi-reforming condition and stable at the testing condition for 100 h. Similar
phenomena were also observed for the other two catalysts tested. These two catalysts were also
easily activated under the bi-reforming condition and showed stability and constant activity
continuously over 100 h. However, their activation rates were different with NiO-MgO-550
achieved its maximum activation after only 4 h while it took 6 h for NiO-MgO-800 and NiO-MgO-
900 as observed by the percent of hydrogen formation increasing in the output gas mixture as
analyzed by an online GC every 15 mins. The effect of calcination temperatures on kinetic rate
and reducibility of NiO supported on MgO under H2 gas was investigated by Parmaliana et. al.
36

NiO and MgO due to their similarity in ionic radius and both having NaCl lattice structure, can
form a “perfect” solid solution as it was observed by XRD spectra (Figure 2.15). As calcination
temperatures increased, at calcination temperature below 700
o
C, there are some forms of NiO
32

forming a surface solid solution with MgO. When the calcination temperature is higher than 700
o
C, these surface NiO dissolves into bulk NiO-MgO solid solution, which has a stronger interaction
with the core structure of MgO and is more difficult for their surface segregation and reduction
6
,
as shown by the stronger intensity in XRD peaks (Figure 2.15).
Also, their reactivities were different in terms of CH4 and CO2 conversions and the
formation ratio of H2/CO
33
. It is noticed that when the calcination temperatures increased from
550 to 800 and 900
o
C, the CO2 conversion increased while the CH4 conversion (Figure 2.6), the
H2/CO ratio (Figure 2.7) and the coke formation decreased (Figure 2.8). The CO2 conversion of
the 550-NiO-MgO catalyst was 67% while the conversions of the 800- and 900- ones were 67.9%
and 70.1%, respectively. The CH4 conversion most likely stayed the same with slight decrease
from 63.9% to 63.7% and 62.9% as the calcination temperatures of the catalyst increased from 550
to 800 and 900
o
C, respectively. The coke formation significantly reduced from 4.02 wt% to 1.36-
1.92 wt% as the calcination temperatures increased. A similar trend was observed with the H2/CO
ratio, a significant decrease, from 1.85 to 1.65-1.62.

Figure 2.6 The effect of calcination temperatures on CH4 and CO2 conversions.
33

Figure 2.7 The effect of calcination temperature on the ratio of H2/CO.

Figure 2.8 The effect of calcination temperatures on carbon formation.

2.3.1b Effect of pressures

Effect of pressure on the self-activation of the catalyst

To study the effect of pressure on the self-activation ability of the catalyst, a series of
different pressures of the activation condition was investigated (50-75-100-125-150 psi) with 15-
NiO-MgO-550. The temperature of the activation step and reaction was fixed at 823
o
C and the
ratio of gas mixture CO2:H2O:CH4 was used stoichiometrically. The reaction pressures were kept
the same as the activation pressure condition for each individual experiment. The 15-NiO-MgO-
34

550 was successfully activated by bi-reforming condition at 823
o
C and different pressures,
ranging from 50 psi to 150 psi. The reactions followed the thermodynamics law (Le Chatlier’s): at
higher pressure, the reverse reaction of bi-reforming happened more, which led to the lower in the
conversions of CO2 and CH4 (Figure 2.9). At 50 psi, the CO2 conversion reached 76.9 % while at
150 psi, it was lowered by 12.3% to 64.6%. Similarly, the CH4 conversion was also lowered by
13%, from 71.5% to 58.5% as the pressure increased from 50 psi to 150 psi. Coke formation also
followed the thermodynamics law. It was negligible at 50 and 75 psi (0.15 and 0.39 wt%
respectively). Continuous increase in the reaction pressures, the coke formation increased
dramatically in a linear relationship with pressure (Figure 2.10), from 3.01 wt% at 100 psi to 7.86
wt% at 150 psi.
Figure 2.9 CH4 and CO2 conversions at different pressures during activation and reaction time.
35

Figure 2.10 Coke formation at different pressures during activation and reaction time.

Pressure variance during activation and reaction

To fully understand the effect of pressure on the activation process, a series of different
pressures during activation time was employed while the pressure during reaction time was fixed
at 100 psi. It’s easily observed that the average conversions of CO2 and CH4 in three experiments
of different activation pressures 50, 100, and 150 psi were similar to each other and similar to the
ones of the experiment running at 100 psi for both activation and reaction time (Table 2.1). Only
the coke formations were slightly different (Table 2.2). It can be explained due to the different
pressures during 5 h activation.
Table 2.1 Compare CO2 and CH4 conversions of reactions with different pressures during
activation time.
Pressure during activation time (psi) CO2 conversion (%) CH4 conversion (%)
75 70.3 61.8
100 72.2 63.3
125 68.2 62.8
150 68.6 62.4
36

Table 2.2 Compare coke formation of reactions with different pressures during activation time.
Pressure during activation time (psi) Coke formation (wt%)
75 3.0
100 3.0
125 3.6
150 3.8

2.3.1c Effect of NiO loadings

A series of 5, 15 and 25 wt% NiO-MgO-550 was tested under the stoichiometric bi-
reforming in-situ activation condition. The temperature and pressure were fixed at 823
o
C and 100
psi for both activation and reaction processes. It was observed that the higher NiO loading was,
the easier and faster the activation occurred. For 5 wt% of NiO, the activation by bi-reforming
condition did not occur. However, with the increase in the content of NiO loading, the 15 wt% and
25 wt% ones, the activation almost immediately occurred within the first 15 mins (one cycle of
on-line GC analysis) since the time the gas mixture was added, recognized by the formation of H2
and CO. The activation was fully achieved faster in the case of 25 wt% NiO catalyst. Because of
their redox properties, CO2 and H2O can’t be activated on either MgO or NiO surfaces.
3,8,9,15
Due
to the formation of a solid solution between NiO and MgO, the reducibility of supported NiO is
not as easy as of unsupported one.
24,41
CH4 can’t be activated on MgO surfaces but be activated on
pure NiO at around 660
o
C.
9,15,17,22,23,25,28,57
CH4 is initially activated by the oxygen of the surface
NiO, followed by the slower activation by the bulk oxygen lattice bound to the Ni ions. As the
NiO loading increases, the oxygen coordination number with Mg decreases, while the one with Ni
increases, resulting in the instability of oxygen bound to Ni, and lowering activation energy of CH4
on oxygen lattice.
8,41
Hence, for the bi-reforming to occur, the NiO/MgO is initially activated by
CH4 over NiO surfaces which transforms Ni
2+
to isolated Ni
0
sites; then CO2 and H2O are activated
on Ni
0
sites.
37

With the 5 wt% NiO-MgO, almost no H2 formation was observed during the bi-reforming
activation condition. In contrast, the activation of 15 wt% and 25 wt% catalysts occurred quickly
and the 25 wt% one reached the full activation faster, 4 h when compared to 5.5 h of 15 wt%. This
is due to enhanced NiO availability on the surface of MgO support.
7,18,19,22,24,25,28,30,31,32,35

The more NiO loading is, the bigger NiO particles are. Therefore, the coke formation is
higher in the case of 25 wt% catalyst, 5.9% compared to 3.0% in the case of 15 wt% NiO catalyst.
On the other hand, the CH4 and CO2 conversions decreased to 61.7 and 63.8 respectively, which
were 1.6 and 8.4 % lower than the ones of 15-NiO-MgO (63.3% and 72.2%). Since 25-NiO-MgO
has higher NiO loading than 15-NiO-MgO, there’s more tendency that NiO particles aggregate.
The Ni particles with the bigger sizes are less active than the smaller ones.
1,12,17,27

2.3.1d Effect of different ratios of CH4:H2O:CO2

Altering the ratios of CH4:H2O:CO2 were also tested for the activating ability of the catalyst
(Table 2.3). However, during 100 h reaction time, the conversions of CH4 and CO2 and H2/CO
ratio were stable and similar to each other in all three cases. The coke formations varied somewhat,
higher steam addition resulted in lower carbon accumulation as the carbon was gasified by the
extra steam.
Table 2.3 Effect of different ratios of CH4:H2O:CO2
CH :H O:CO
4 2 2
%CH conversion
4
%CO conversion
2
wt% coke
H /CO
2
3:2:1 63.9 67.0 4.5 1.85
3:2.5:1 63.3 67.7 4.01 1.81
3:3:1 63.1 67.9 3.23 1.85

However, increasing the amount of steam, the catalyst became completely inactive as it
was not activated under the ratio CH4:H2O:CO2, 3:4.5:1. The low activity of CH4 and CO2
conversions were observed during 20 h as seen in Figure 2.11.
38

Figure 2.11 Activity of catalyst under activation condition of CH4:H2O:CO2 = 3:4.5:1.

2.3.1 e Comparing with H2 activation

A comparison of catalysts’ activities under self-activation and conventional H2 activation
was also carefully examined. A similarity in activities and coke formation was observed during bi-
reforming self-activation and H2 activation conditions at the same pressure. For example, at 50 psi,
the CH4 conversions under two conditions, self-activation and H2 activation, were 71.5% and 74%,
while CO2 conversions were 76.9% and 80.1%, and coke formations were 0.15 wt% and 0.49%.
Table 2.4 Comparison between bi-reforming and H2 conditions for activation.

2.3.2 In-situ activation of NiO/MgO catalysts under steam reforming conditions: the right
condition matters
The catalyst started being activated immediately under steam reforming condition
CH4:H2O = 1:1 (Figure 2.13), as observed by GC showing the peak of H2 of the gas outlet which
appeared right after the activation time was started. The activation process was complete within 5
Pressure
(psi)
CH4 Conversion (%) CO2 Conversion (%) Coke formation (wt%)
Seft-
activation
H2
activation
Seft-
activation
H2
activation
Seft-
activation
H2
activation
50 71.5 74.0 76.9 80.1 0.15 0.49
75 63.7 67.4 73.7 70.0 0.39 0.75
100 63.3 65.1 72.2 73.1 3.01 2.81
150 58.5 58.7 64.6 65.1 7.86 7.89

39

h and the activity was stable after that. However, as the steam input increased to the ratio of 1:1.5
CH4:H2), the catalyst was not activated as observed by the low activity during testing time (Figure
2.12). The spent catalyst in this case turned into light green color, as opposed to the light gray color
of the original NiO-MgO catalyst or the black color of the activated catalysts after bi-reforming
reaction (Figure 2.14). Even though the ratio of CH4:H2O was later reduced to 1:1, the catalyst
was still inactive for 3 h. This result was not observed in the case of 10 wt% NiO/YSZ by Azadi
et. al.
36
The catalyst was able to be activated under CH4:H2O ratio up to 1:3 after only 80 mins.
This phenomenon could be explained by the strong adsorption of H2O on the surface of basic
support MgO to form -OH surface layer and stronger interaction between NiO and MgO than NiO
and YSZ
13,20,24,25,53
.

Figure 2.12 Deactivation of catalyst under excess steam activation condition (CH4:H2O = 1:1.5)
40

Figure 2.13 Fast activation of catalyst under 1:1 ratio of CH4:CO2 condition.

Figure 2.14 Original catalyst and spent catalysts under excess steam (CH4:H2O = 1:3) and bi-
reforming conditions.

2.3.3 In-situ reactivation of NiO/MgO catalysts

The coke formation under stoichiometric ratio of bi-reforming condition at 100 psi and 823
o
C for 100 h was about 3 wt%. As observed, the carbon formations (in the same bi-reforming
operation condition, pressure and temperature) were less in the cases of reactivation conditions,
over more than 200 h operation in which 200 h was bi-reforming reaction and 15 or 20 h for
reactivation of the catalyst using excess steam supply. Especially in the case of 20 h reactivation
under CH4:H2O:CO2 = 3:3:1 (0.027 mL/min H2O), the carbon formation after reaction operation,
41

of total of 220 h, the carbon formation was negligible (< 0.09 wt%). With the higher steam supply,
the carbon formation at the end was less (Table 2.5).
Table 2.5 Reactivation time, water flow, and carbon formation.
Reactivation
time (h)
Water flow
(mL/min)
Carbon
(wt%)
Water flow
(mL/min)
Carbon
(wt%)
15 0.022 1.933 0.027 0.936
20 0.022 1.026 0.027 < 0.09

2.3.4 Catalyst Characterizations and understanding of the reaction conditions
2.3.4a XRD
Figure 2.15 shows the XRD spectra of 15-NiO-MgO catalysts calcined at different
temperatures and used MgO commercial powder over a 2θ range of 10-90
o
and 120-135
o
. The
XRD patterns of NiO-MgO are matched with the ones of MgO in the range of 10–90
o
, which
demonstrated the strong interaction between NiO and MgO and the formation of their solid
solution. It’s known that higher the calcination temperature, the higher degree of solid solution
formation as observed higher relative intensity of diffraction peaks of the catalysts calcined at 900
o
C and 800
o
C compared to the one calcined at 550
o
C (Figure 2.15a)
According to previous literature ref, it is more difficult to distinguish the diffraction peaks
of NiO, MgO, and NiO-MgO at 2θ > 100
o
. It’s known that the diffraction peaks of MgO could
slightly shift to higher angles when Ni
2+
diffuse into MgO lattice, while the diffraction peaks of
NiO could slightly shift to lower angles with the diffusion of Mg
2+
into NiO lattice
6,48
. This
explains why the diffraction peaks of NiO-MgO lie between the two diffraction peaks of MgO
(420) at 127.3
o
and NiO (420) at 129.16
o
as seen in Figure 2.15b. The further the shift is, the
higher degree of diffusion and solid solution formation. These data confirm the highest degree of
solid solution formation of the catalyst calcined at 900
o
C.
a)
42

b)

Figure 2.15 XRD spectra of 15-NiO-MgO at different calcination temperatures in a) 2θ 10-90
o
,
b) 2θ 122-132
o
.
2.3.4b TEM

The TEM imaging (Figure 2.16) showed that the carbon formation on the catalysts during
bi-reforming could be carbon whisker, which is formed by the dissociation of CH4 or CO on the
metal surface. The yielding C atoms dissolve within the metal particles. These carbon whiskers
43

have high mechanical strength and may destroy the catalyst particles when they hit the pore walls
of the particles
35,39,64
.
Figure 2.16 TEM imaging of spent catalyst 15 wt% NiO-MgO.

2.4 Conclusions

The study has demonstrated the successful application of in-situ activation and reactivation
of different Ni-based catalysts on MgO, which offers an ease in operation and simpler reactor
design. The activity of the catalysts, CH4 and CO2 conversions, is governed by the laws of
thermodynamics and the nature of the catalysts. Surprisingly, the catalyst of 15 wt% NiO-MgO
got completely deactivated under excess steam condition (CH4:H2O 1:1.5) and formed stable form
Ni
2+
-(OH)x even though the steam was lowered to ratio of 1:1 CH4:H2O later and the catalyst was
continuously heated at 823
o
C.

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44

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47

(34) Li, Maoshuai; van Veen, André C. “Coupled Reforming of Methane to Syngas (2H2-CO)
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51

CHAPTER 3

STABILITY ENHANCEMENT OF Ni-M/MgO CATALYSTS FOR DRY REFORMING
OF METHANE (M = In)

3.1 Introduction

Global warming and the depletion of fossil fuels lead to the need of finding the way to
utilize greenhouse gases and produce fuel on a large scale sustainably. Dry reforming, the process
consuming two most common greenhouse gases CO2 and CH4, has been in great of interest for the
last two decades to form mixture of CO and H2. This gas mixture can be used further in many
processes to produce other commodity chemicals, fuels and materials as described in the previous
chapters.
Despite many efforts in scientific research, this process is still not practical for an industrial
scale application because the commercially feasible supported Nickel catalysts are prone to
deactivation, which is caused by carbon (coke) formation on the catalysts when the reaction
conditions are not thermodynamically favorable, high pressure and temperatures lower than 870
o
C or temperatures higher than 1040
o
C
1,4,8-12,18
. The carbon formation is due to two sources:
methane decomposition and CO dissociation (Eq. 3.1 and 3.2)
Eq 3.1 CH4  C + 2H2

Eq 3.2 2CO  C + CO2

Doping the second metal has showed effectively reducing coke deposition on catalyst
surface. Several metals have been tested, for example, Fe, Pt, Mo, Ce, etc.
1,5-15,20-22
. Recently,
McFarland and co-workers
17
have used easily melting second metals (like In, Bi, Ga) for methane
decomposition to hydrogen, which has showed no formation of carbon. This gave the idea of using
52

In as doping metal for the catalyst. During this study was conducted in 2018, the study by Nemeth
et. al. has been published in which they used Ni-In/SiO2 as the catalysts for dry reforming of
methane without any observable coke formation
23
.

3.2 Experimental Section

3.2.1 Catalyst synthesis and materials

Nickel nitrate hexahydrate Ni(NO3)2.6H2O and In(NO3)3.xH2O wer purchased from Alfa
Aesar and magnesium oxide 35 mesh was purchased from Sigma Aldrich.
The catalysts 15 wt% NiO - x wt% M on MgO support (M = In) were synthesized by co-
wet impregnation method. Basically, 5g of magnesium oxide MgO was mixed together with an
appropriate amount of nickel nitrate hexahydrate and In metal nitrate in 10 mL deionized water.
The suspension then was stirred at 500 rpm at room temperature for 20 hours. The solvent was
evaporated and the solid was dried at 120
o
C in an oven overnight. The catalyst was calcined at
550
o
C for 5 hours with the heating rate of 5
o
C/min in a furnace. The solid collected was then
ground by mortar and pestle into a homogenous fine power. For M = In, the catalysts were labeled
x-Ni-M-MgO where x = 0.2, 1, 3 which corresponds to weight percent of M2O3 in the catalysts.

3.2.2 Catalyst test – Reactor setup

For atmospheric pressure testing, the reactor system setup used is displayed in Figure 3.1.
The catalyst (100 mg) was mixed with 900 mg tabular alumina 60 – 200 mesh and placed inside
the tabular alumina tube (inner diameter 0.9 cm). For activation of catalysts by hydrogen gas, the
catalyst was heated under hydrogen and nitrogen mixture (ratio 1:1, flow rate 40 mL/min) to 850
o
C in 1.5 h, then kept at this temperature for 2 h. After that, the gas was switched to nitrogen until
53

the desired reaction temperature (627
o
C, 727
o
C, and 827
o
C) were achieved. Subsequently, the
reaction gas mixture CO2 and CH4 and reference gas N2 (the total flow rate of 90 mL/min, the flow
rate of CO2:CH4:N2 was 32.5:32.5:25 mL/min) were introduced into the reactors.

Figure 3.1 Reactor system set-up.

For high pressure testing, the reactions were carried in the Parr reactor system (Figure 3.2).
The catalyst inside the reactor was organized in a similar way as indicated in Chaper 3. Basically,
100 mg catalyst was mixed with 900 mg tabular alumina support 250-500 μm and placed inside
the reactor supported by different sizes of tabular alumina and alumina balls. The activation
condition was kept the same as that of the reaction at atmospheric pressure. After the activation
time, the desired pressures and temperatures were set. The gas mixture flow was also kept at the
same ratio for the reaction at the atmospheric pressure.
54

Figure 3.2 High pressure reactor for reforming of methane, purchased from Parr Instrument
Company.

The gas mixture product after reaction was analyzed by on-line automated GC with FID
detector for every 15 min cycle.
3.2.3 Catalyst characterization methods

The catalysts, before and after experiments, were characterized by XRD, and TGA. Power
X-ray diffraction measurements were performed on Rigaku Ultima IV Diffractometer with a Cu
Kα (0.154056 nm) radiation source and a scan rate of 6
o
/min from a 2θ value of 10
o
to 90
o
.
Transmission electron microscopy TEM images were obtained on a JEOL 2100F with an
acceleration voltage of 200 keV. Thermogravimetric analysis TGA was performed on a TGA-50
Thermogravimetric analyzer (Shimadzu).

3.3 Results and Discussion

The activities of Ni-In-MgO were tested at different temperatures (627, 727, and 827
o
C)
and atmospheric pressure. The results were summarized in Figure 3.3, 3.4, and 3.5.
55

Figure 3.3 CH4 conversion of different Ni-In/MgO catalysts at various temperature conditions.

Figure 3.4 CO2 conversion of different Ni-In/MgO catalysts at various temperature conditions.
56

Figure 3.5 Carbon formation over different Ni-In/MgO catalysts at various temperature
conditions.

3.3.1 Effect of temperatures

As the general trend observed, the conversions of CH4 and CO2 increased with increasing
temperature. The conversions in the case of Ni-MgO were generally the highest compared to those
of other Ni-In-MgO.
At 627
0
C, the CH4 and CO2 conversions of Ni-MgO were 24.5% and 41.2% respectively.
As the temperature increases by 627
o
C to 727
o
C, the conversions of CH4 and CO2 increased
dramatically to 65.3% and 59.6%. The conversions were almost completed at 827
o
C, reaching
95.6% and 96.7%. The carbon formation decreased significantly, from 0.2 mmol/h at 627
o
C to
0.029 mmol/h (7 times decrease) at 727
o
C and almost negligible at 827
o
C.

Similar trends of conversions were also observed for other catalysts Ni-In-MgO. Specially, even
at 627
o
C, negligible carbon formation was found in the case of Ni-In-MgO.
3.3.2 Effect of catalyst compositions

The least amount of Indium doping system was similar to the undoped catalyst Ni-MgO
catalyst system in terms of CH4 and CO2 conversions at lower temperature, 627
o
C. At high
temperature, especially, the overall thermodynamics plays a major role as the conversions were
57

similar. However, even with minimal amount of Indium doping as in case of 0.2 wt% In, the carbon
formation was still negligible.
As the amount of indium doping increased, the conversions generally decreased, by 20-
20% compared to non-doping catalyst Ni-MgO, except at 1100 K, the decrease was smaller, about
5-15%. As seen in case of 1-Ni-In-MgO, the CH4 and CO2 conversions at 900 K were 9.1% and
22.2% and of 3-Ni-In-MgO were 6.5% and 14.3%.
3.3.3 Effect of pressures

At higher pressure, 100 psi or 6.8 atm, the conversions reduced slightly. For Ni-MgO at
627
o
C, the CH4 and CO2 conversions were 21.2% and 34.5% as compared to 24.5% and 41.2% at
atmospheric pressure. On the other hand, the activities of 0.2-Ni-In-MgO and 1-Ni-In-MgO
decreased significantly. For 0.2-Ni-In-MgO, the CO2 conversion reduced to 24% from 40%, and
for 1-Ni-In-MgO, it decreases dramatically to 10% from 20%. At this high pressure, only in the
case of 1-Ni-In-MgO, the carbon formation was still negligible, while coking deposition severely
affected in the case of Ni-MgO and 0.2-Ni-In-MgO with 0.55 mmol/h and 0.48 mmol/h carbon
formation, respectively.
45
40
35
30
25
20
15
10
5
0
Ni-MgO 0.2-In-Ni-MgO 1-In-Ni-MgO
CH4 Conversion CO2 Conversion
Conversion (%)
58

Figure 3.6 Activities of different Ni-In/MgO catalysts at 100 psi pressure and 627
o
C a) CH4 and
CO2 conversions, b) carbon formation.

3.3.4 Catalyst Characterizations and understanding of the reaction conditions
XRD:
Strong interaction between Ni and In with MgO support was observed by XRD (Figure 3.9a).
There is only one tiny observed diffraction peak of monometallic Ni around 41
o
, while there is no
observance of monometallic Indium. As seen by XRD spectra, only carbon formation was detected
in the case of spent Ni-MgO, the diffraction peak around 25
o
. Comparing the fresh and spent
catalyst, it was noticed that the relative intensity of monometallic diffraction peak decreased which
suggested that the metallic sites could be partially oxidized during the reaction
2,3,16,18,19
.
59

a)

b)

Figure 3.7 XRD spectra of fresh reduced (a) and spent reduced (b) catalysts Ni-MgO and 0.2-In-
Ni-MgO after dry reforming at atmospheric pressure and 900 K.
60

Ni particle
Ni particle
TEM:

Figure 3.8 TEM imaging of spent reduced Ni-MgO (left) and fresh reduced Ni-MgO (right)
catalysts, after dry reforming at atmospheric pressure and 900 K.

TEM imaging showed that the carbon formation during dry reforming over Ni-MgO is
essentially carbon filaments, which can cover the catalyst surface, thus hindering the reaction.
Since the reaction was tested at 627
0
C, which is lower than sintering temperature of nickel, around
727
0
C, the sintering was not severe in this case.
Two recent studies by Nemeth and co-workers
23,25
have investigated the mechanism on
Ni-In surface at 600
0
C to understand the reason why there is no carbon formation over Ni-In
catalysts. It was suggested that Indium changed the surface structure of the adsorption sites that
hinders the methane decomposition reaction producing carbon. Furthermore, electronic effect of
indium on nickel leads to stronger hydrogen chemisorption compared to nickel alone
23
. At 600
0
C,
CO dissociation on the Ni-In surface was remarkably hindered. The low melting point of In, which
may be molten at 600
0
C, may move to Ni/support interface. The metallic indium may prevent
nickel carbide and surface carbon formation sites due to high hydrogen coverage and hindering
CO dissociation
25
.
61

3.4 Conclusions

Indium doping Ni-based catalyst has played significant role in reducing the carbon
formation during dry reforming of methane, even at higher pressure 6.8 atm. At atmospheric
pressure, even low amount 0.2 wt% of Indium was successful in hindering coke deposition on
catalysts. This may be explained by the electronic effect and the strong interaction of In and Ni,
which hinders the absorption sites of CH4 decomposition and CO dissociation.

3.5 References

(1) Bare, Simon R.; Vila, F. D.; Charochak, Meghan E.; Prabhakar, Sesh; Bradley, William
J.; Jaye, Cherno; Fischer, Daniel A.; Hayashi, S. T.; Bradley, Steven A.; Rehr, J. J.
“Characterization of Coke on a Pt-Re/γ-Al2O3 Re-Forming Catalyst: Experimental and
Theoretical Study”. ACS Catal., 2017, 7, 2, 1452-1461.

(2) Rogers, Jessica L.; Mangarella, Michael C.; Amico, Andrew D. D.; Gallagher, James R.;
Dutzer, Michael R.; Stavitski, Eli; Miller, T.; Sievers, Carsten. “Differences in the Nature
of Active Sites for Methane Dry Reforming and Methane Steam Reforming over Nickel
Aluminate Catalysts”. ACS Catal., 2016, 6, 9, 5873-5886.

(3) Yuan, Kaidi; Zhong, Jian-qiang; Zhou, Xiong; Xu, Leilei; Bergman, Susanna L.; Wu,
Kai; Xu, Guo Qin; Bernasek, Steven L.; Li, He Xing; Chen, Wei. “Dynamic Oxygen on
Surface: Catalytic Intermediate and Coking Barrier in the Modeled CO2 Reforming of
CH4 on Ni (111)”. ACS Catal., 2016, 6, 7, 4330-4339.

(4) Jabbour, K.; Hassan, N. El; Davidson, A.; Casale, S.; Massiani, P. “Factors Affecting the
Long-Term Stability of Mesoporous Nickel-Based Catalysts in Combined Steam and Dry
Reforming of Methane.” Catalysis Science & Technology, 2016, 6, 4616–4631.

(5) Zhu, Minghui; Wachs, Israel E. “Iron-Based Catalysts for the High-Temperature Water
− Gas Shift (HT-WGS) Reaction: A Review”. ACS Catal., 2016, 6, 2, 722-732.

(6) He, Dedong; Luo, Yongming; Tao, Yongwen; Strezov, Vladimir; Nelson, Peter.
“Promoter Effects on Nickel-Supported Magnesium Oxide Catalysts for the Carbon
Dioxide Reforming of Methane”. Energy Fuels, 2017, 31, 3, 2353-2359.

(7) Lustemberg, Pablo G.; Ram, Pedro J.; Liu, Zongyuan; Grinter, David G.; Carrasco,
Javier; Senanayake, Sanjaya D.; Rodriguez, Jose A.; Vero, M. “Room-Temperature
62

Activation of Methane and Dry Reforming with CO2 on Ni-CeO2(111) Surfaces: Effect
of Ce
3+
Sites and Metal − Support Interactions on C − H Bond Cleavage”. ACS Catal.,
2016, 6, 12, 8184-8191.

(8) Zhang, Tingting; Liu, Zhongxian; Zhu, Yi-an; Liu, Zhicheng; Sui, Zhijun; Zhu, Kake.
“Dry Reforming of Methane on Ni-Fe-MgO Catalysts: Influence of Fe on Carbon-
Resistant Property and Kinetics.” Applied Catalysis B: Environmental, 2019, 264,
118497.

(9) Tomishige, Keiichi; Li, Dalin; Tamura, Masazumi; Nakagawa, Yoshinao. “Nickel-Iron
alloy catalysts for reforming of hydrocarbons: preparation, structure, and catalytic
properties”. Catalysis Science & Technology, 2017, 7, 3952–3979.

(10) Zhang, Shenghong; Muratsugu, Satoshi; Ishiguro, Nozomu; Tada, Mizuki. “Ceria-Doped
Ni/SBA-16 Catalysts for Dry Reforming of Methane”. ACS Catal., 2013, 3, 8, 1855-
1864.

(11) Kim, Sung Min; Abdala, Paula Macarena; Margossian, Tigran; Hosseini, Davood;
Foppa, Lucas; Armutlulu, Andac; Van Beek, Wouter; Comas-vives, Aleix; Cope,
Christophe; Muller, Christoph. “Cooperativity and Dynamics Increase the Performance
of NiFe Dry Reforming Catalysts”. J. Am. Chem. Soc., 2017, 139, 5, 1937-1949.

(12) Liu, Yan; Wu, Ye; Akhtamberdinova, Zarina; Chen, Xiaoping; Jiang, Guodong. “Dry
Reforming of Shale Gas and Carbon Dioxide with Ni-Ce-Al2O3 Catalyst: Syngas
Production Enhanced over Ni-CeOx Formation” ChemCatChem, 2018, 10, 4689–4698.

(13) Akri, Mohcin; Zhao, Shu; Li, Xiaoyu; Zang, Ketao; Lee, Adam F.; Isaacs, Mark A.; Xi,
Wei; Ganarajula, Yuvaraj; Luo, Jun; Ren, Yujing; Cui, Yi-Tao; Li, Lei; Su, Yang; Pan,
Xiaoli; Wen, Wu; Pan, Yang; Wilson, Karen; Li, Lin; Qiao, Botao; Ishii, Hirofumi; Liao,
Yen-Fa; Wang, Aiqin; Wang, Xiaodong; Zhang, Tao. “Atomically Dispersed Nickel as
Coke-Resistant Active Sites for Methane Dry Reforming.” Nature Communications,
2019, 5181.

(14) Enrique, Carlos; Kiennemann, Alain; Moreno, Sonia; Molina, Rafael. “Dry Reforming
of Methane Using Ni–Ce Catalysts Supported on a Modified Mineral Clay”. Applied
Catalysis A: General, 2009, 364, 1-2, 65–74.

(15) Bian, Zhoufeng; Das, Sonali; Wai, Ming Hui; Hongmanorom, Plaifa; Kawi, Sibudjing.
“A Review on Bimetallic Nickel-Based Catalysts for CO2 Reforming of Methane”.
ChemPhysChem, 2017, 18, 22, 3117–3134.

(16) Xie, Xiao; Otremba, Torsten; Littlewood, Patrick; Schomäcker, Reinhard; Thomas,
Arne. “One-Pot Synthesis of Supported, Nanocrystalline Nickel Manganese Oxide for
Dry Reforming of Methane.” ACS Catalysis, 2013, 3, 2, 224–229.
63

(17) Upham, D. Chester; Agarwal, Vishal; Khechfe, Alexander; Snodgrass, Zachary R.;
Gordon, Michael J.; Metiu, Horia; McFarland, Eric W. “Catalytic Molten Metals for the
Direct Conversion of Methane to Hydrogen and Separable Carbon.” Science, 2017, 358,
6365, 917–921.

(18) Zuo, Zhijun; Liu, Shizhong; Wang, Zichun; Liu, Cheng; Huang, Wei; Huang, Jun; Liu,
Ping. “Dry Reforming of Methane on Single-Site Ni/MgO Catalysts: Importance of Site
Confinement.” ACS Catal., 2018, 89, 9821–9835.

(19) Gili, Albert; Schlicker, Lukas; Bekheet, Maged F.; Go, Oliver; Penner, Simon; Gru,
Matthias; Gotsch, Thomas; Littlewood, Patrick; Marks, Tobin J.; Stair, Peter C.;
Schomacker, Reinhard; Doran, Andrew; Selve, Soren; Simon, Ulla; Gurlo, Aleksander.
“Surface Carbon as a Reactive Intermediate in Dry Reforming of Methane to Syngas on
a 5% Ni/MnO Catalyst”. ACS Catal., 2018, 8, 9, 8739-8750.

(20) Singha, R. K.; Shukla, A.; Sandupatla, A.; Deo, G. “Synthesis and Catalytic Activity of
a Pd Doped Ni–MgO Catalyst for Dry Reforming of Methane.” J. Mater. Chem. A, 2017,
5, 15688–99.

(21) Arora, Shalini; Prasad, R. “An Overview on Dry Reforming of Methane: Strategies to
Reduce Carbonaceous Deactivation of Catalysts.” RSC Advances, 2016, 6, 110, 108668–
108688.

(22) Kawi, Sibudjing; Kathiraser, Yasotha; Ni, Jun; Oemar, Usman; Li, Ziwei. “Progress in
Synthesis of Highly Active and Stable Nickel- Based Catalysts for Carbon Dioxide
Reforming of Methane” ChemSusChem, 2015, 8, 3556–3575.

(23) Németh, Miklós; Sáfrán, György; Horváth, Anita; Somodi, Ferenc. “Hindered Methane
Decomposition on a Coke-Resistant Ni-In/SiO2 Dry Reforming Catalyst.” Catalysis
Communications, 2018, 118, 56–59.

(24) Sehested, Jens; Gelten, Johannes A. P.; Helveg, Stig. “Sintering of Nickel Catalysts:
Effects of Time, Atmosphere, Temperature, Nickel-Carrier Interactions, and Dopants”.
Applied Catalysis A: General, 2006, 309, 2, 237–246.

(25) Miklos, Nemeth; Somodi, Ferenc; Horvath, Anita. “Interaction between CO and a
Coke-Resistant NiIn/SiO2 Methane Dry Reforming Catalyst: A DRIFTS and CO Pulse
Study”. J. Phys. Chem. C, 2019, 123, 45, 27509-27518.
64

PART II. ONE-STEP DEOXYGENATIVE FLUORINATION AND
TRIFLUOROMETHYLTHIOLATION OF CARBOXYLIC
ACIDS
65

CHAPTER 4

FLUORINATION AND THIOMETHYLTRIFLUORINATION: APPLICATIONS,
CHALLENGES AND RECENT DEVELOPMENTS

4.1 Introduction

As known by its position on the periodic table, fluorine possesses some extraordinary
properties, especially electronegativity (Table 4.1) and oxidation potential
1,2
.
Table 4.1. Electronegativity of some elements and functional groups
1
.
X H F O Cl N
CF3 CH3
Electronegativity
(Pauling scale)
2.1 4.0 3.5 3.2 3.0 3.5 2.3

Therefore, it is difficult to prepare fluorine element by chemical reaction
1,2
, and the
industrial production of fluorine gas is still carried out electrochemical synthesis method originally
discovered by Moissan
2
. Dues to its toxicity and violently reactivity, the development of fluorine
chemistry was extremely sluggish and required a lot of careful operation and courage of experts.
Not until 1930s-1950s with the accidently discovery of Teflon and the first fluorine-containing
pharmaceutical product
5
, fludrocortisone (Figure 4.1), the study of fluorine chemistry has been
accelerated
4-8
. Recognized by the special chemical, physical and biological properties induced by
fluorine, organofluorine compounds have gained increasing attention in the medicinal,
pharmaceutical, agricultural and material sciences
4-8
.
66

Figure 4.1. Fludrocortisone

Due to fluorine’s unique electronegativity, size, lipophilicity, and electrostatic interactions,
the introduction of fluorine, even just single atom, can dramatically change the
chemical/stereochemical properties, acidity/basicity of organic molecules. Thus, it leads to strong
change in binding affinity, pharmacokinetic properties, stability (the dissociation energy of C-F
bond 116 kcal/mol is much higher than that of C-H bond 98 kcal/mol, C-N bond 73 kcal/mol, C-
Cl 81 kcal/mol, C-Br 68 kcal/mol, or C-I 57 kcal/mol) and bioactivity/toxicity of a drug candidate
7
.
Lipophilicity (Table 4.2)
3
brought by fluorinated substituents plays an important role in enhancing
transmembrane permeation which increases the bioavailability of the compounds.
Table 4.2. Hansch parameter (πR - lipophilicity measurement) of some substituents
3
.
Substituent πR Substituent πR
F 0.14 OCH3 -0.02
Cl 0.71 OCF3 1.04
NO2 -0.27 SCH3 0.61
CH3 0.56 SCF3 1.44
CF3 0.88 SO2CH3 -1.63
OH -0.67 SO2CF3 0.55

4.1.1 Medical application

Due to the favorable half-life of
18
F isotope (109.8 min) when compared to
11
C (20.4 min)
and
124
I (4.2 days), fluorine is widely used in Positron Emission Tomography (PET) as functional
imaging technique in diagnostic medicine. Furthermore,
19
F nuclear magnetic imaging (MRI) is
applied to study the anatomy and physiological process of the body
5,10
.
67

4.1.2 Agricultural application

The number of fluorinated compounds used in agriculture has increased significantly over
the last 40 years. In 2011 – 2017, the number of commercial pesticides containing fluorine atoms
increased significantly, ~52% (Figure 4.2)
6-7
. Until 2003, there were about 28% chemicals used
in crop protection containing fluorine atoms, in which 54% of the products are herbicides/safeners,
27% are insecticides/acaricides and 19% are fungicides (Figure 4.3)
7
.

Figure 4.2. Some examples of commercialized peptisides in 2011-2017
6-7
.

Figure 4.3. Breakdown of fluorinated commercial agrochemicals into isectidies/acaricides,
fungicides, and herbicides/safeners
7
.

4.1.3 Polymer/Material Sciences

Since the discovery of polytetrafluoroethylene (PTFE) or called Teflon in 1938 with unique
outstanding favorable properties, fluorinated polymers emerge as such materials with promising
68

potential in many applications
2,4
. Due to intrinsic properties of fluorine in the structures of the
products, fully fluorinated and partially fluorinated polymers have showed unique properties, high
thermal stability, weather stability, low coefficient of friction, chemical stability/inert or
unreactivity, and lower surface energy compared to their non-fluorinated counterparts. Increasing
the fluorine content of olefinic polymers can affect their properties as shown in Table 4.3
2
. For
example, slight fluorination of polyolefin neutral surface makes the film polar and adherable.
Further increasing fluorination results in total neutral and passive film surface.
Table 4.3. Effect of Increasing Fluorine Content in Polymers.
2

Property Impact
Chemical resistance Increase
Melting point Increase
Coefficient of friction Decrease
Thermal stability Increase
Dielectric constant Decrease
Dissipation factor Decrease
Volume and surface resistivity Increase
Mechanical properties Decrease
Flame resistance Increase
Weathering resistance Increase

Some of the most common fluorinated polymers are polytetrafluoroethylene (PTFE),
polychlorotrifluoroethylene (PCTFE), polyvinylidene fluoride (PVDF), and polyvinyl fluoride
(PVF). Their properties are summarized in Table 4.4
2
.
69

Table 4.4. Typical properties of some commercial fluorinated polymers
2
.

4.1.4 Pharmaceutical ingredients

Since the first pharmaceutical drug containing fluorine in 1953, the research, development
and commercialization of fluorine-containing active pharmaceutical ingredients have increased
rapidly. In 1970, there were only 2% of commercial fluorine containing drugs; the current market
has grown up to about 25%
7
. Remarkably, three out of five best-selling drugs (Figure 4.4) in the
United States in 2008 contain fluorine, with fluorine-containing Lipitor at the first place with 5.9
billion US dollars of sale (Table 4.5)
5,8
.

Figure 4.4. Structures of three fluorine-containing drugs in top five best-selling drugs in 2008
5,8
.
70

Table 4.5. Three fluorine-containing drugs in top five best-selling drugs in USA, 2008
8
.
Position by sales relative to
all pharmaceuticals
Trade name US sales in 2008 ($ x 10
9
)
1 Lipitor 5.9
4 Advair Diskus 3.6
5 Prevacid 3.3

4.2 Fluorinating agents and C-F bond forming reactions

Due to its vigorous reactivity (safety and toxicity issues), the use of fluorine gas F2 as direct
fluorination agent has been limited in the industrial production only. Moreover, the low
nucleophilicity of fluoride and the relatively low availability of “F
+
” sources very few C-F bond
formation reactions exist when compared to other carbon-halogen bond formation reactions
25
. The
discovery of numerous fluorinating reagents (Figure 4.5) over the past decades has helped to
overcome these challenges
12-16,18,21-23,25
. Hydrogen fluoride HF, inorganic salts like KF and
pyridine-(HF)n complex (Olah’s reagent)
16,25
are the most common used agents for direct
nucleophilic fluorination. More recently, a series of direct nucleophilic fluorinating reagents has
been developed by introducing weakly coordinating quaternary ammonium cations as counterions
to enhance the nucleophilicity of fluoride. Some examples of these reagents are Me4NF
(anhydrous) by Christe, nBu4NF (TBAF anhydrous) by DiMagno, and nBu4NF(tBuOH)4 by
Kim
16,24,25
. Thanks to these reagents, a wide range of fluorinated compounds can be prepared,
including alkenyl fluoride, allylic fluoride, benzylic fluoride, alkyl fluoride, fluorohydrin, and
many
18
F-radiotracers for PET
10
.
71

72

Figure 4.5. Common fluorinating reagents
16,25
.

Facilitated by sulfur tetrafluoride and its derivatives, such as N,N-diethylaminosulfur
trifluoride (DAST), FluoleadTM, and XtalFluor-M®, the methods using deoxofluorinating agents
can allow the C-F bond formation from oxygenated substrates such as aliphatic alcohols, carbonyl
compounds, and carboxylic acid derivatives
11-14,16,17
. Although the existence of free “F
+”
” speices
remains unknow in the condense phase, some reagents have been employed in electrophilic
fluorination reactions such as Selectfluor and NFSI (Figure 4.6)
16,17
.

Figure 4.6. Electrophilic fluorination reported by Stavber and co-workers
16
.
73

Two systems of direct electrophilic fluorination of β-dicarbonyl compounds, which
employed Selectfluor in water or NFSI without solvent have been developed by Stavber and co-
workers
16
. The monofluorinated products were obtained in moderate to good yields.

4.3 Previous literature review of trifluoromethylthiolation

Thanks to its high lipophilicity (high Hansch’s hydrophobic parameter π = 1.44) and strong
electron withdrawing properties (Hammett constant σm = 0.40 and σp = 0.50)
8
, the
trifluolomethylthio group SCF3 has gained increasing attention in pharmaceutical, agrochemical
and material chemistry to modulate and tune liphophilicty, bioactivity and metabolic stability
(Figure 4.7)
9,15,26-33
.

Figure 4.7. Some examples of pharmaceutical and agrochemical products containing SCF3
group
9,30
.
The indirect methodologies of SCF3 introduction, which used halogen-fluorine exchange
reaction and the trifluoromethylthiolation of sulfur-containing compounds such as disulfides,
74

thiols and thiolates involved harsh conditions, formation of byproducts and limited substrate scope
to the functionalization of activated and inactivated C(sp
3
)-H bonds
27-30
. Therefore, the direct
introduction of SCF3 group is more desirable. However, due to the dearth of
trifluoromethylthiolation agents, the direct methods which employed the use of SCF3 radical
sources or electrophilic trifluoromethylthiolation reagents has been underdeveloped for decades.
Since the first report of Harris in 1961, using the highly toxic trifluoromethylsulfenyl chloride
CF3SCl for the free radical trifluoromethylthiolation of olefins, numerous of
trifluoromethylthiolation reagents have been developed (Figure 4.8)
30
.

Figure 4.8. Common SCF3 agents
30
.

Facilitated by these reagents, the significant progress has been made in the field, including
metal-catalyzed and non-catalytic methodologies. The radical trifluoromethylthiolation protocols
75

have employed sodium trifluoromethanesulfinate-tBuOOH by Langlois and
trifluoromethanesylfonyl chloride-photocatalyst by MacMillan
29-31
. Recently, Glorius et. al.
developed radical trifluoromethylthiolation method using Phth-SCF3-photocatalyst system
(Figure 4.9)
29
.

Figure 4.9. Radical trifluoromethylthiolation method by Glorius et. al
29
.

Metal-catalyzed aromatic trifluoromethylthiolation was pioneered by Chen et. al. in 1989,
using copper catalysis
27,31
. Later, this was also successfully achieved by Buchwald et. al. by using
Pd catalysis (Figure 4.10)
34
.
Figure 4.10. Aromatic trifluoromethylthiolation by Buchwald et. al
33
.

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78

(28) Luo, Puying; Ding, Qiuping; Ping, Yuanyuan; Hu, Jianan. “Regioselective ortho-
trifluoromethylthiolation of 2-arylbenzo[d]thiazole via tadem substrate-assisted C-H
iodination and trifluoromethylthiolation”. Org. Biomol. Chem., 2016, 14, 10, 2924–9.

(29) Mukherjee, Satobhisha; Patra, Tuhin; Glorius, Frank. “Cooperative Catalysis: A Strategy
to Synthesize Trifluoromethyl- Thioesters from Aldehydes”. ACS Catal., 2018, 8, 7,
5842-5846.

(30) Li, Man; Zhou, Biying; Xue, Xiao-song; Cheng, Jin-pei. “Establishing the
Trifluoromethylthio Radical Donating Abilities of Electrophilic SCF3 - Transfer
Reagents”. J. Org. Chem., 2017, 82, 16, 8697-8702.

(31) Lin, Ya-mei; Jiang, Lv.-Qi; Yi, Wen-bin. “Trifluoromethanesulfonyl-Based Reagents for
Direct Trifluoromethylthiolation through Deoxygenative Reduction”. Asian J. Org.
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(32) Dagousset, Guillaume; Simon, Cedric; Anselmi, Elsa; Tuccio, Beatrice; Billard, Thierry;
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(33) Teverovsky, Georgiy; Surry, David S.; Buchwald, Stephen L. “Pd-catalyzed Synthesis
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7314.
79

CHAPTER 5
*

DIRECT ACCESS TO ACYL FLUORIDES FROM CARBOXYLIC ACIS USING A
PHOSPHINE/FLUORIDE DEOXYFLUORINATION REAGENT SYSTEM

5.1 Introduction

5.1.1 The utility of acyl fluoride

Owing to their unique physicochemical and biological properties, organofluorine
compounds play a major role in life and materials sciences.
1
Accordingly, incorporation of fluorine
through synthetic protocols that enjoy practicality, operational simplicity, wide functional group
compatibility and ease of access of reagents, is a highly desirable goal. Acyl fluorides are versatile
intermediates in organic synthesis, owing to their superior stability and distinct reactivity, when
compared to other acyl halides. In this context, acyl fluorides have been successfully employed in
many challenging amidation and esterification reactions,
2
(i.e. with electron-deficient or sterically
encumbered nucleophiles), and they are ideal intermediates for both solution and solid-phase
peptide synthesis
3
. Furthermore, acyl fluorides stand as convenient precursors of anhydrous
fluoride ion and have been employed in SNAr fluorination chemistry with great success.
4
On the
other hand, transition-metal catalyzed, non-decarbonylative and decarbonylative transformations
of acyl fluorides, have also been developed.
5
In this fashion, their utilization as electrophiles, has

* Adapted from: Socrates B. Munoz
*
, Huong Dang
*
, Xanath Ispizua-Rodriguez
*
, Thomas
Mathew, G. K. Surya Prakash. Direct Access to Acyl Fluorides from Carboxylic Acids Using a
Phosphine/Fluoride Deoxyfluorination Reagent System. Organic Letters, 2019, 21, 6, 1659-1663.
80

enabled access to ketones,
5a-c
aldehydes,
5d-e
hydrocarbons,
5d
trifluoromethyl arenes,
5f
and more
recently biaryls
5g
(Scheme 5.1 paths A-F).
Scheme 5.1. Synthetic utility of acyl fluorides.

5.1.2 The previous methods of acyl fluoride synthesis and the proposal of the work

Hitherto, the known approaches for the preparation of acyl fluorides directly from
carboxylic acids are scarce. Pioneering work on this area was reported by Olah in the 70’s using
cyanuric fluoride
6
or SeF4/pyridine complex.
7
Alternative -fluoroamine reagents (Ishikawa’s and
Petrov’s reagent, TFFH) were employed in a few cases.
8
Other deoxyfluorination protocols heavily
rely on the use of sulfur-based reagents such as DAST,
9
Deoxo-Fluor
®
,
10
XtalFluor-E
®
,
11
etc.
(Scheme 5.2).
However, practical application of many of these reagents remains limited due to toxicity,
environmental pollution, thermal instability and/or drastic reaction conditions. Olah’s reagent (HF-
Pyridine) in combination with DCC
12
has also been used with low functional group compatibility.
Recently, a Sulfur (VI) Fluoride Exchange (SuFEx) reaction employing benzene-1,3-disulfonyl
fluoride was disclosed as part of an amidation protocol.
13
Very recently, Schoenebeck and
coworkers
14
delineated an additive-free protocol, employing Me4NSCF3 as an alternative sulfur-
based reagent. However, this reagent is not commercially available and must be prepared from S8,
TMSCF3 and expensive anhydrous Me4NF. Considering that acyl fluorides are inexpensive
81

sources of anhydrous fluoride, including expensive Me4NF
4
(Scheme 5.1, path c), utilization of
Me4NF-derived Me4NSCF3 in the synthesis of RCOF derivatives requires further justification.
Thus, practical, safe and operationally simple methods that enable access to a wide variety of acyl
fluorides are still sought-after. Herein, a convenient and inexpensive protocol for direct
deoxyfluorination of carboxylic acids was developed. Herein, a method that employs readily
available commodity chemicals was developed to offer practical utility and operational simplicity
to provide the corresponding acyl fluorides.
Scheme 5.2. Prior art for acyl fluoride synthesis and current work.

As it was recognized the rich chemistry of phosphorous reagents
16
and (acyl)oxyphosphonium
ions I
17
in peptide coupling, as well as in the Mitsunobu
18
and Appel
19
reactions, these
intermediates could be easily transformed into acyl fluorides. However, due to the preferred
formation of strong P-F bond in contrast to other P-X bonds (X = Cl, Br, I), such transformation
(Scheme 5.3, Eq 1) and the related Appel-type fluorination (Scheme 5.3, Eq 2) using
halophosphonium ions has not been reported thus far. Therefore, in this chapter, a seemingly
82

straightforward transformation, using acyloxyphosphonium ion as an intermediate will be
investigated (Scheme 5.3).
Scheme 5.3. Working Hypothesis and Related Transformations

Under Brønsted acidic conditions, intermediate I could be further protonated to enable the
desired C–F bond formation.

5.2 Results and Discussions

5.2.1 Optimization of reaction conditions

Benzoic acid 1a was selected as a model substrate and a variety of fluoride sources in
combination with PPh3/NBS were screened for a direct deoxyfluorination reaction (Table 5.1).
After activation of 1a by NBS/PPh3 (3 equiv each) in DCM and using an excess of Et3N-
3HF, the desired product, benzoyl fluoride 2a was obtained in quantitative yield after 2 h, (Table
5.51, entry 1). Utilization of Me4NF (3 equiv), afforded 2a in only 27% yield, while generating
large amounts of Ph3PF2 (
19
F NMR = δ -39.5) (Table 5.1, entry 2). Subsequent attempts have
shown that by conducting the reaction with 2:2.1:2 molar ratio of PPh 3:NBS:Et3N-3HF could
afford 2a in quantitative yield. Other fluoride sources such as KF, CsF and KHF2 in DCM were
83

unsuccessful, probably due to solubility issues (Table 5.1, entries 5-7). Using MeCN as solvent
led only to marginal improvements and large amounts of Ph3PF2 were detected in these cases also
(Table 5.1, entries 8-12). Interestingly, it was found that under acidic conditions (TFA, 2 equiv),
KF and KHF2 could afford the desired product, while completely inhibiting the formation of
Ph3PF2 (Table 5.1, entries 13-15). In this fashion, after 24 h, KHF2 also provided 2a in quantitative
yield (Table 5.1, entry 15).
20
However, due to its fast reaction rate and ease of addition, Et3N-3HF
was used in subsequent studies.
Table 5.1. Optimization of the reaction conditions
a

Entry Solvent PPh3 (equiv)
NBS (equiv) Fluoride (equiv) Yield (%)
b

1 DCM 3 3 Et3N-3HF (6)
99
2 DCM 3 3 Me4NF (3)
27
3 DCM 3 3 Et3N-3HF (3)
99
4 DCM 2 2.1 Et3N-3HF (2)
99
5 DCM 2 2.1 KF (2) 0
6 DCM 2 2.1 CsF (2) 0
7 DCM 2 2.1 KHF2 (2)
0
8
c
MeCN 2 2.1 KF (2) 28
9 MeCN 2 2.1 CsF (2) 0
10
c
MeCN 2 2.1 KHF2 (2)
trace
11
f
MeCN 2 2.1 KF (2) 17
12
f
MeCN 2 2.1 KHF2 (2)
7
13
c,d
MeCN 2 2.1 KF (2) 47
14
c,d
MeCN 2 2.1 KHF2 (2)
60
15
d,e
MeCN 2 2.1 KHF2 (2)
98
84

a
To a suspension of benzoic acid 1a (0.25 mmol, 1 equiv) and PPh 3 in DCM, solid N-Bromosuccinimide (NBS) was added at 0
o
C. After stirring for 15 min at room temperature, fluoride source was added and stirring was continued for 2 h;
b
As determined
by
19
F NMR spectroscopy;
c
17 h reaction time;
d
Trifluoroacetic acid (TFA, 2 equiv) was added along with fluoride;
e
Reaction
time: 24 h.
f
Reaction was performed at 50
0
C.

5.2.2 Expand the scopes

Application of this system to the deoxyfluorination of various carboxylic acids illustrates
its synthetic scope (Scheme 5.4). Benzoic acids bearing electron-neutral, electron-donating (-OMe,
-Et, -NMe2), as well as electron-withdrawing functionalities (-I, -Br, -F, -Ac) are converted to the
corresponding acyl fluorides in good to excellent yields (2a-2i). The present protocol is compatible
with unsaturated functionalities also, as evidenced by the successful preparation of vinyl
substituted acyl fluoride 2d in 73% isolated yield; no HF addition across the double bond was
observed. Halo-substituted benzoic acids (-Br and -F) also afforded the corresponding products in
good yields (2g and 2i, respectively).
21a
Substitution at the ortho-position of benzoic acid 1f, was
found amenable to the present transformation, providing the corresponding product 2f in 83%
isolated yield.
Another attractive feature of this method is scalability: preparation of 4-methoxybenzoyl
fluoride 2c, a reagent employed as anhydrous fluoride source for SNAr fluorinations,
4
was
performed on a 10 mmol scale and obtained in 70% isolated yield without further purification by
column chromatography.
21a
Thus, Et3N-3HF, an acidic and atom-economic fluoride source, could
be efficiently utilized for the preparation of an anhydrous fluoride surrogate.
Next, the applicability of our method to aliphatic carboxylic acids was tested. In this case,
phenylacetic-, phenylbutyric- and 1-adamantyl- carboxylic acids were all amenable to the reaction
conditions and afforded the corresponding products in good isolated yields (2j-2l). In addition,
cinnamic acids 1n and 1o afforded the corresponding acyl fluorides in good yields as determined
85

by
19
F NMR spectroscopy (80% and 89%, respectively).
22
Notably, the present protocol exhibited
excellent chemoselectivity towards -COOH moiety, as demonstrated by the preparation of 4-
hydroxylbenzoyl fluoride 2p in 50% isolated yield.

Scheme 5.4 Direct deoxyfluorination of carboxylic acids
a

86

a
Method A conditions: 1 (0.5 mmol, 1 equiv), PPh3 (2 equiv), DCM (5 mL), N-bromosuccinimide
(NBS, 2.1 equiv), 0
o
C-rt 15min. Then Et3N-3HF (2 equiv) rt, 2h;
b
Method B: using polymer-
bound phosphine reagent in place of PPh3; Isolated yields, average of two runs. Yields in
parenthesis determined by
19
F NMR spectroscopy, using internal standard.
To further illustrate the synthetic scope of this method, a series of active pharmaceutical
ingredients (API’s) bearing the -COOH functionality were subjected to the reaction conditions.
Gratifyingly, complex structures bearing double bonds, sulfonamide, indole, keto, nitrile and
thiazole functionalities all afforded the corresponding acyl fluoride analogues in high isolated
yields (Scheme 5.4, bottom section).
Heteroaromatic substrates such as picolinic, nicotinic and isonicotinic acids were all
successfully employed in a tandem deoxyfluorination/amidation sequence using sterically-
demanding 1-adamantanamine (Ad-NH2) (Scheme 5.5, top). All three isomeric pyridine-
carboxylic acids underwent the desired transformation, affording the corresponding pyridine-
carboxamides (3a-3c) in up to 91% yield, after adding a mixture of Ad-NH2 and Et3N to the formed
acyl fluorides.
21b
This procedure, eliminates the need for isolation of the acyl fluorides, and
represents a significant advantage over previous synthetic routes. For example, 3a has been
previously prepared in 32% from the corresponding acyl chloride,
23a
or in 89% yield from the
corresponding ethyl ester in the presence of La(OTf)3 as catalyst.
23b
Moreover, employing optimal
conditions
17c
for amide synthesis via acyloxyphosphonium intermediates, 3a was obtained in only
26% yield.
21b
This result demonstrates the synthetic utility of this tandem
deoxyfluorination/amidation protocol using sterically-encumbered amines.
87

Scheme 5.5 Tandem deoxyfluorination/amidation sequence.

Isolated yields shown; average of two runs.
a
Yield of acyl fluoride 3’ as determined by
19
F NMR.

In pursuit of easier purification of products, substituting PPh3 with the commercially
available, polymer-bound phosphine reagent. Gratifyingly, comparable yield of the 4-acetyl
benzoyl fluoride 2h was obtained (95% by
19
F NMR), with easy purification of the product in 72%
isolated yield. Similarly, amino acid fluoride bearing the acid-stable Fmoc- protecting group,
Fmoc-Phe-F 2q was prepared in 50% isolated yield (97% by
19
F NMR). In this fashion,
purification of products is easily achieved by simply filtering off the resin, followed by a simple
work-up procedure.
21b-c
(Scheme 5.7, Method B).

5.2.3 Identification of phosphonium intermediates by NMR spectroscopic studies

To gain insight into the mechanism of the present transformation, the following control
experiments were conducted.
Control experiment 1

88

On the bench-top, triphenylphosphine, PPh3 (0.5 mmol, 131.2 mg) of a was charged into
an oven-dried crimp-top vial equipped with a magnetic stir bar. This vial was sealed with a septum,
evacuated and backfilled with nitrogen 3 times. After this, anhydrous dichloromethane, DCM (2.5
mL) was added under a stream of nitrogen. This mixture was then cooled to 0
o
C using an ice-bath.
Subsequently, N-bromosuccinimide, NBS (2.1 equiv, 0.525 mmol, 94 mg) dissolved in anhydrous
DCM (2.5 mL) was added via syringe at 0
o
C. After stirring for 2 min an immediate color change
was observed and an aliquot (1 mL) was taken for NMR analysis. The
31
P NMR spectrum showed
two new signals at δ 27.5 and δ 31.5, which were assigned to OPPh 3 and bromophosphonium ion
A, respectively. In this case, it’s surmised that triphenyl phosphine oxide is formed due to
hydrolysis of A by adventitious H2O present in the system. (Figure 5.1).
Figure 5.1.
31
P NMR spectrum after addition NBS to vial containing PPh3.

Control experiment 2

89

In a separate experiment, benzoic acid 1a (0.25 mmol, 30.5 mg) and triphenylphosphine,
PPh3 (0.5 mmol, 131.2 mg) were charged into a crimp-top vial equipped with a magnetic stir bar.
This vial was sealed with a septum, evacuated and backfilled with nitrogen 3 times. After this,
anhydrous dichloromethane, DCM (2.5 mL) was added under a stream of nitrogen. This mixture
was then cooled to 0
o
C using an ice-bath. Subsequently, N-bromosuccinimide, NBS (2.1 equiv,
0.525 mmol, 94 mg) dissolved in anhydrous DCM (2.5 mL) was added via syringe at 0
o
C. After
stirring for 2 min an immediate color change was observed and an aliquot (1 mL) was taken for
NMR analysis. The
31
P NMR spectrum showed three signals at δ 28.2, δ 31.5 and δ 45.2 which
were assigned to triphenylphosphine oxide, residual bromophosphonium ion A and
acyloxyphosphonium ion I, respectively (Figure 5.2).

Figure 5.2.
31
P NMR spectrum after addition of NBS to mixture of 1a and PPh3.

After this time, 3HF-Et3N (2 equiv, 0.5 mmol, 82 L) was added via syringe to the vial
containing I. This mixture was stirred for 5 min, before taking a aliquot (1 mL) for NMR analysis.
The
31
P NMR spectrum showed a single peak at δ 29.2, corresponding to triphenylphosphine oxide
90

(Figure 5.3A), while the
19
F NMR spectrum showed three signals at δ 17.4, δ -39.6 (d, 660.8 Hz,
P-F coupling) and δ -172.3, assigned as benzoyl fluoride 2a, Ph3PF2 and residual HF (Figure
5.3B).

Figure 5.3A.
31
P NMR spectrum after addition of 3HF-Et3N to vial containing
acyloxyphosphonium ion I.
91

Figure 5.3B.
19
F NMR spectrum after addition of 3HF-Et3N to vial containing
acyloxyphosphonium ion I.

Control Experiment 3

On the bench top, triphenylphosphine, PPh3 (1 equiv, 0.5 mmol, 131.2 mg) was charged
into a vial equipped with a magnetic stir bar. To this vial 3HF-Et3N (0.5 mmol, 82 L) was added
via micropipette followed by anhydrous dichloromethane, DCM (2.5 mL) This mixture was then
cooled to 0
o
C using an ice-bath. Subsequently, N-bromosuccinimide, NBS (0.525 mmol, 94 mg)
was added as a solid at 0
o
C. This mixture was stirred and allowed to slowly warm up to room
temperature over 15 min. After this time internal standard, p-toluenesulfonyl fluoride (87 mg, 0.5
mmol, 1 equiv) dissolved in anhydrous DCM (1 mL) was added and the mixture was stirred for 2
min. After this time, an aliquot (1 mL) was taken and
19
F NMR (Figure 5.4A) and
31
P NMR
92

(Figure 5.4B) spectroscopic analysis. Triphenyldifluorophosphorane II formed in 85% yield, as
determined by
19
F NMR. The
31
P NMR spectrum showed two signals at δ 31.7 (s) and at -57.5 (t,
J = 659.0 Hz), which were assigned to triphenylphosphine oxide and Ph3PF2 II, respectively.

Figure 5.4A.
19
F NMR spectrum after formation of species II

93

Figure 5.4.B.
31
P NMR spectrum after formation of species II

Control Experiment 4

To Ph3PF2, II generated exactly as in control experiment 3, benzoic acid 1a (0.25 mmol,

30.5 mg) was added and this mixture was stirred further for 2 h at room temperature. After this
time, internal standard, p-toluenesulfonyl fluoride (87 mg, 0.5 mmol) dissolved in anhydrous DCM
(1 mL) was added and the mixture was stirred for 2 min. After this time, an aliquot (1 mL) was
taken for
19
F NMR (Figure 5.5A) and
31
P NMR (Figure 5B) spectroscopic analysis.
19
F NMR
spectrum showed no signal of the acyl fluoride or the intermediate II. The
31
P NMR spectrum only
shows one signal at δ 31.9 representing triphenylphosphine oxide. This experiment showed that
Ph3PF2, II is not the species responsible for the observed deoxyfluorination, further lending
94

support to the proposed mechanistic hypothesis via acyloxyphosphonium ion I. Ph3PF2 II
generated in this way, could be hydrolyzed to OPPh3 by adventitious water present in the system.
Ph3PF2 is known to be a highly moisture sensitive species.
v
Furthermore, independently prepared
Ph3PF2 was found to be a chemically incompetent species to promote the transformation under the
reaction conditions (DCM, rt).
21c
These observations are in full agreement with previous literature
reports.
17
Based on these observations, the following mechanistic pathway is proposed (Scheme
5.6).

Figure 5.5A.
19
F NMR spectrum after addition of benzoic acid (1a)
95

Figure 5.5B.
31
P NMR spectrum after addition of benzoic acid (1a)

Scheme 5.6 Mechanistic Hypothesis

Oxidation of PPh3 by NBS generates a bromophosphonium ion A, which reacts with
RCOOH derivatives 1, affording acyloxyphosphonium intermediate I. Under acidic conditions, I
could be protonated, followed by fluoride attack at the C-(acyl) moiety, giving rise to RCOF
products and Ph3PO. In the case of basic fluoride sources, fluoride attack at the P-center of I,
affording Ph3PF2, seems to be a dominant pathway.
96

5.3 Materials and procedures

5.3.1 General procedure

Unless otherwise mentioned, all the chemicals were purchased from commercial sources
and used without further purification. N-bromosuccinimide (NBS) was recrystallized from water
and dried over P2O5 under high vacuum. Anhydrous dichloromethane (DCM) was purchased from
EMD (drysolv) and used as received. Polymer-bound PPh3 (extent of labeling: 3 mmol/g) was
purchased from Sigma-Aldrich (Catalog No. 93093) and used as received. In the cases indicated,
flash column chromatography was performed to isolate products with suitable eluent as determined
by TLC.
1
H,
13
C, and
19
F spectra were recorded on 400 MHz or 500 MHz Varian NMR
spectrometers.
1
H NMR chemical shifts were determined relative to CDCl3 as the internal standard
at δ 7.26 ppm.
13
C NMR shifts were determined relative to CDCl3 at δ 77.16 ppm.
19
F NMR
chemical shifts were determined relative to CFCl3 at δ 0.00 ppm. Mass spectra were recorded on
a high-resolution mass spectrometer, EI or ESI mode.
**Caution! Et3N-3HF must be handled only by trained personnel, using appropriate personal
protection equipment in a well-ventilated hood. Contact with the skin must be avoided.
5.3.2 General procedure for the preparation of acyl fluorides and NMR yield determination
Scheme 5.7 General Procedure for the preparation of acyl fluorides.

On the bench-top, benzoic acid (0.25 mmol, 30.5 mg) and triphenylphosphine, PPh 3 (0.5
mmol, 131.2 mg) were charged into an oven-dried screw-cap vial equipped with a magnetic stir
97

bar. After this, anhydrous dichloromethane, DCM (2.5 mL) was added, the vial was capped, and
this mixture was then cooled to 0
o
C using an ice-bath. Subsequently, N-bromosuccinimide, NBS
(2.1 equiv, 0.525 mmol, 94 mg) was added as a solid in one portion, the vial was re-capped, and
the mixture was kept in the ice-bath for two minutes. After this time, the ice-bath was removed,
and this solution was further stirred for 15 min. Once this time concluded, the vial was opened and
3HF-Et3N (2 equiv, 0.5 mmol, 82 L) was added via micropipette. This mixture was stirred further
for 2 h at room temperature. After this time internal standard, p-toluenesulfonyl fluoride (45 mg,
0.26 mmol, 104% of theoretical yield) dissolved in anhydrous DCM (1 mL) was added, the mixture
was stirred for 2 min, then analyzed by
19
F NMR spectroscopy. The yield was determined by
comparing the relative integration of internal standard (p-tolylsulfonyl fluoride,
19
F NMR  65.8)
with the acyl fluoride.

5.3.3 General procedure for the preparation/purification of acyl fluorides using PPh3
(Method A)
Unless otherwise stated, the following representative procedure was used for the synthesis
and purification of acyl fluoride products 2. On the bench-top, carboxylic acid derivative 1 (1
equiv, 0.5 mmol) and triphenylphosphine, PPh3 (2 equiv, 1 mmol, 262.3 mg) and anhydrous DCM
(5 mL) were charged into an oven-dried screw-cap vial equipped with a magnetic stir bar. The vial
was capped, and this mixture was then cooled to 0
o
C using an ice-bath. Subsequently, N-
bromosuccinimide, NBS (2.1 equiv, 1.05 mmol, 187 mg) was added as a solid in one portion, the
vial was re-capped, and the mixture was kept in the ice-bath for two minutes. After this time, the
ice-bath was removed, and this solution was further stirred for 15 min. After this time, the vial was
opened and 3HF-Et3N (2 equiv, 1 mmol, 163 L) was added via micropipette. This mixture was
98

stirred further for 2 h at room temperature. After this time, the vial was opened, and the reaction
mixture was diluted with hexanes (20 mL), and the mixture was stirred for 10 min. During this
time, large amounts of succinimide and triphenylphosphine oxide precipitate, which are then
removed by passing the mixture through a short pad of silica (2 cm thick x 3 cm diameter).
Subsequently, the silica pad was further washed with hexanes or an appropriate mixture of solvent.
The filtrate was then concentrated under reduced pressure to afford pure product without the need
of further purification.

5.3.4 General procedure for the preparation/purification of acyl fluorides using polymer-
bound PPh3 (Method B)
For products 2h and 2q, this method using polymer-bound triphenylphosphine was
implemented. On the bench-top, carboxylic acid derivative 1 (1 equiv, 0.5 mmol) and
commercially-available polymer-bound triphenylphosphine, PS-PPh3 (extent of P-labeling = 3
mmol/g, 2 equiv, 1 mmol, 333 mg) and anhydrous DCM (5 mL) were charged into an oven-dried
screw-cap vial equipped with a magnetic stir bar. The vial was capped, and this mixture was then
cooled to 0
o
C using an ice-bath. Subsequently, N-bromosuccinimide, NBS (2.1 equiv, 1.05 mmol,
187 mg) was added as a solid in one portion, the vial was re-capped, and the mixture was kept in
the ice-bath for two minutes. After this time, the ice-bath was removed, and this solution was
further stirred for 20 min. After this time, 3HF-Et3N (2 equiv, 1 mmol, 163 L) was added via
micropipette and the mixture was stirred further for 2 h at room temperature. After this time, the
resin was removed by vacuum filtration and washed with DCM (2 mL) and hexanes (20 mL).
Further addition of hexanes (10 mL) to this filtrate and stirring for 10 min, resulted in precipitation
of succinimide, which was removed by filtration through a plug of celite, washing with hexanes
99

(5 mL). Concentration of the filtrate under reduced pressure afforded the corresponding acyl
fluoride without the need of further purification. If traces of succinimide are present in the product,
they could be easily removed by washing a DCM or CHCl3 solution with ice-cold water (5 mL x
2).
**Note: Slow hydrolysis to the carboxylic acid may occur if glassware/solvents are not properly
dried. It’s recommended using oven-dried glassware for all manipulations. If trace amounts of
starting materials are formed due to hydrolysis during work-up, they could be easily removed by
dissolving the mixture in CHCl3 and passing it through a short plug of silica.

5.3.5 Procedure for the tandem deoxofluorination/amide-bond formation sequence (Scheme
5.5)
N-(Adamantan-1-yl)picolinamide (3a)

3a’
19
F NMR δ 16.8

On the bench-top, picolinic acid (1 equiv, 0.5 mmol, 61.5 mg) and triphenylphosphine,
PPh3 (2 equiv, 1 mmol, 262.3 mg) and anhydrous DCM (5 mL) were charged into an oven-dried
screw-cap vial equipped with a magnetic stir bar. The vial was capped, and this mixture was then
cooled to 0
o
C using an ice-bath. Subsequently, N-bromosuccinimide, NBS (2.1 equiv, 1.05 mmol,
187 mg) was added as a solid in one portion, the vial was re-capped, and the mixture was kept in
the ice-bath for two minutes. After this time, the ice-bath was removed, and this solution was
further stirred for 15 min. After this time, 3HF-Et3N (2 equiv, 1 mmol, 163 L) was added via
micropipette and the mixture was stirred further for 2 h at room temperature. After this time, the
100

3b’
vial was opened, and a pre-mixed solution of adamantan-1-amine (1.2 equiv, 0.6 mmol, 91 mg)
and Et3N (10 equiv, 5 mmol, 697 L) in anhydrous DCM (1 mL) was added at room temperature
and the mixture was further stirred for 3h. After this time, the mixture was diluted with DCM and
passed through a plug of celite. The filtrate was poured into H2O (50 mL) and extracted with DCM
(20 mL, 3 times). The aqueous layer was acidified (1N HCl) and extracted again with DCM (10
mL, 2 times). The organic layers were combined, washed with NaHCO3 (aq. saturated), brine,
dried over MgSO4 and concentrated. The residue was purified by flash column chromatography
using EtOAc in hexanes (gradient from 0% to 16%). NMR Yield Determination: In a separate
experiment picolinoyl fluoride 3a’ was prepared in 95% as determined by
19
F NMR spectroscopy
with p-TolylSO2F (0.26 mmol) as internal standard, following general method A using picolinic
acid (1 equiv, 0.25 mmol, 30.7 mg), triphenylphosphine, PPh3 (2 equiv, 1 mmol, 131.2 mg), NBS
(2.1 equiv, 1.05 mmol, 94 mg), anhydrous DCM (2.5 mL) and 3HF-Et3N (2 equiv, 1 mmol, 82
L). However, its isolation was unsuccessful due to instability.

N-(Adamantan-1-yl)nicotinamide (3b) (Scheme 5.5)

19
F NMR δ 20.9

On the bench-top, nicotinic acid (1 equiv, 0.5 mmol, 61.5 mg) and triphenylphosphine,
PPh3 (2 equiv, 1 mmol, 262.3 mg) and anhydrous DCM (5 mL) were charged into an oven-dried
screw-cap vial equipped with a magnetic stir bar. The vial was capped, and this mixture was then
cooled to 0
o
C using an ice-bath. Subsequently, N-bromosuccinimide, NBS (2.1 equiv, 1.05 mmol,
187 mg) was added as a solid in one portion, the vial was re-capped, and the mixture was kept in
101

the ice-bath for two minutes. After this time, the ice-bath was removed, and this solution was
further stirred for 15 min. After this time, 3HF-Et3N (2 equiv, 1 mmol, 163 L) was added via
micropipette and the mixture was stirred further for 2 h at room temperature. After this time, the
vial was opened, and a pre-mixed solution of adamantan-1-amine (1.2 equiv, 0.6 mmol, 91 mg)
and Et3N (10 equiv, 5 mmol, 697 L) in anhydrous DCM (1 mL) was added at room temperature
and the mixture was further stirred for 3h. After this time, the mixture was diluted with DCM and
passed through a plug of celite. The filtrate was poured into H2O (50 mL) and extracted with DCM
(20 mL, 3 times). The aqueous layer was acidified (1N HCl) and extracted again with DCM (10
mL, 2 times). The organic layers were combined, washed with NaHCO3 (aq. saturated), brine,
dried over MgSO4 and concentrated. The residue was purified by flash column chromatography
using EtOAc in hexanes (gradient from 0% to 16%). *NMR Yield Determination: In a separate
experiment nicotinoyl fluoride 3b ’ was prepared in 97% as determined by
19
F NMR spectroscopy,
with p-TolylSO2F (0.26 mmol) as internal standard, following General Method A using nicotinic
acid (1 equiv, 0.25 mmol, 30.7 mg), triphenylphosphine, PPh3 (2 equiv, 1 mmol, 131.2 mg), NBS
(2.1 equiv, 1.05 mmol, 94 mg), anhydrous DCM (2.5 mL) and 3HF-Et3N (2 equiv, 1 mmol, 82

L). However, its isolation was unsuccessful due to instability.

N-(Adamantan-1-yl)isonicotinamide (3c) (Scheme 5.5)

3c’
19
F NMR δ 21.4

On the bench-top, isonicotinic acid (1 equiv, 0.5 mmol, 61.5 mg) and triphenylphosphine,
PPh3 (2 equiv, 1 mmol, 262.3 mg) and anhydrous DCM (5 mL) were charged into an oven-dried
102

screw-cap vial equipped with a magnetic stir bar. The vial was capped, and this mixture was then
cooled to 0
o
C using an ice-bath. Subsequently, N-bromosuccinimide, NBS (2.1 equiv, 1.05 mmol,
187 mg) was added as a solid in one portion, the vial was re-capped, and the mixture was kept in
the ice-bath for two minutes. After this time, the ice-bath was removed, and this solution was
further stirred for 15 min. After this time, 3HF-Et3N (2 equiv, 1 mmol, 163 L) was added via
micropipette and the mixture was stirred further for 2 h at room temperature. After this time, the
vial was opened, and a pre-mixed solution of adamantan-1-amine (1.2 equiv, 0.6 mmol, 91 mg)
and Et3N (10 equiv, 5 mmol, 697 L) in anhydrous DCM (1 mL) was added at room temperature
and the mixture was further stirred for 3h. After this time, the mixture was diluted with DCM and
passed through a plug of celite. The filtrate was poured into H2O (50 mL) and extracted with DCM
(20 mL, 3 times). The aqueous layer was acidified (1N HCl) and extracted again with DCM (10
mL, 2 times). The organic layers were combined, washed with NaHCO3 (aq. saturated), brine,
dried over MgSO4 and concentrated. The residue was purified by flash column chromatography
using EtOAc in hexanes (gradient from 0% to 16%). *NMR Yield Determination: In a separate
experiment isonicotinoyl fluoride 3c ’ was prepared in 94% as determined by
19
F NMR
spectroscopy, with p-TolylSO2F (0.26 mmol) as internal standard, following General Method A
using isonicotinic acid (1 equiv, 0.25 mmol, 30.7 mg), triphenylphosphine, PPh3 (2 equiv, 1 mmol,
131.2 mg), NBS (2.1 equiv, 1.05 mmol, 94 mg), anhydrous DCM (2.5 mL) and 3HF-Et3N (2 equiv,
1 mmol, 82 L).

Preparation of N-(Adamantan-1-yl)picolinamide (3a) via acyloxyphosphonium ion (Scheme
5.5)
103

For comparison, the title compound was also prepared using the previously reported
optimized reaction conditions
1
for amide synthesis via acyloxyphosphonium ions. On the bench-
top, picolinic acid (1 equiv, 0.5 mmol, 61.5 mg) and triphenylphosphine, PPh3 (1 equiv, 0.5 mmol,
131.2 mg) and anhydrous DCM (2.5 mL) were charged into an oven-dried screw-cap vial equipped
with a magnetic stir bar. The vial was capped, and this mixture was then cooled to 0
o
C using an
ice-bath. Subsequently, N-bromosuccinimide, NBS (1.1 equiv, 0.55 mmol, 98 mg) was added as a
solid in one portion, the vial was re-capped, and the mixture was kept in the ice-bath for two
minutes. After this time, the ice-bath was removed, and this solution was further stirred for 15 min.
Subsequently, a pre-mixed solution of adamantan-1-amine (1.2 equiv, 0.6 mmol, 91 mg) and
anhydrous pyridine (1.3 equiv, 0.65 mmol, 52 L) in anhydrous THF (1 mL) was added dropwise
at -25
o
C. After addition was complete, the mixture was left stirring while slowly warmed to room
temperature and further stirred for 3 h. After this time, the mixture was diluted with DCM (10 mL)
and washed with H2O (10 mL). The organic phase was separated, dried over MgSO4 and
concentrated under reduced pressure. The residue was purified by column chromatography. NMR
spectroscopic data was identical to the product obtained by our method, using in situ formed acyl
fluoride as acylating agent. This result demonstrates the superiority of acyl fluorides for amidation
reactions using sterically encumbered amines.

104

5.3.6 Scale-up procedure for the synthesis of 4-Methoxybenzoyl fluoride

For a 10 mmol (1.521 g) scale reaction, the title compound was obtained following the general
Method A, using p-anisic acid (10 mmol, 1.521 g), PPh3 (20 mmol, 5.25 g), NBS (21 mmol, 3.74
g) and 3HF-Et3N (20 mmol, 3.3 mL). The product was purified by filtration through a short plug
of silica, washing with a mixture of hexanes/EtOAC (20 mL, 20:1, v:v, 2 times).

5..4 Conclusions

In conclusion, a practical and convenient protocol for a direct deoxyfluorination of
carboxylic acids, using a phosphorous-based reagent system, in combination with Et3N-3HF as
fluoride ion source was developed. This protocol employs inexpensive commodity chemicals and
enables facile access to a wide array of substituted acyl fluorides possessing various functional
groups. The greater significance of this method is further emphasized by its scalability
(demonstrated by the fast and successful preparation of 2c, a common source of anhydrous
fluoride) and applicability to heteroaromatic substrates (demonstrated in a tandem
deoxyfluorination/amidation sequence). Utilization of polymer-supported triphenylphosphine
makes product separation easier and the process more convenient. Application of this approach to
deoxyfluorination of alcohols is currently underway in our laboratories and will be reported
elsewhere.
105

5.5 References

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19
F
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and
18
F
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methoxyethyl)aminosulfur Trifluoride: A New Broad-Spectrum Deoxofluorinating Agent
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107

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2
)-H Fluorination
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Trifluoromethylation of enamides using TMSCF3: access to trifluoromethylated
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Castro, B. R. “Replacement of Alcoholic Hydroxyl Groups by Halogens and Other
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108

Mitsunobu, O. “The Use of Diethyl Azodicarboxylate and Triphenylphosphine in
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(19) Appel, R. “Tertiary Phosphane/Tetrachloromethane, a Versatile Reagent for Chlorination,
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(20) (a) Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J. Superacid Chemistry, 2nd ed.;
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takes place and no desired product was observed. (c) Use of lesser amounts of
PPh3/NBS/Et3N-3HF also affords the expected products, albeit in longer reaction times (>
20h).

(21) (a) Polymer-bound phosphine was used only for easy purification; in all these cases, PPh3
also affords the corresponding products. (b) 2i exhibits instability toward silica gel,
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volatility. (d) For deoxyfluorination of alcohols using Ph3PF2 under drastic conditions see:
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Direct Amidation of Esters”. Org. Lett. 2014, 16, 2018.

5.6 Characterization and NMR spectroscopic data of products
Benzoyl fluoride (2a)

The title compound was obtained following the general Method A, using benzoic acid 1a (0.5
mmol, 61 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163
L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing the
silica plug with hexanes (20 ml). Obtained as a clear oil in 65% isolated yield (40.5 mg)
1
H NMR
(400 MHz, CDCl3) δ 8.06 (dd, J = 8.6, 1.2 Hz, 2H), 7.68 (ddt, J = 7.9, 7.1, 1.3 Hz, 1H), 7.53 –
109

7.46 (m, 2H).
19
F NMR (376 MHz, CDCl3) δ 17.6 (s, 1F). These data match the previously
reported structure.

4-Ethylbenzoyl fluoride (2b)

The title compound was obtained following the general Method A, using 4-ethylbenzoic acid 1b
(0.5 mmol, 37.5 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1
mmol, 163 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter),
washing the silica plug with a mixture of hexanes/EtOAc (15 ml; 5:1, v:v). Obtained as a clear oil
in 71% isolated yield (54 mg).
1
H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.2 Hz, 2H), 7.35 (d, J
= 7.7 Hz, 2H), 2.75 (q, J = 7.6 Hz, 2H), 1.28 (t, J = 7.6 Hz, 3H).
13
C NMR (126 MHz, CDCl3) δ
157.7 (d, J = 342.8 Hz), 152.8, 131.8 (d, J = 4.2 Hz), 128.8, 122.5 (d, J = 60.9 Hz), 29.3, 15.2.
19
F
NMR (376 MHz, CDCl3) δ 17.0 (s, 1F). HRMS-EI
+
(M
+
) Calcd. for C9H9OF = 152.0637, found
= 152.0636. FT/IR (max (neat) cm-1): 2961 2361, 2339, 1682, 1320, 1294, 913, 745, 661, 506.

4-Methoxybenzoyl fluoride (2c)

The title compound was obtained following the general Method A, using p-anisic acid 1c (0.5
mmol, 76 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163
L). Purified by filtration through a short plug of silica, washing the silica plug with a mixture of
hexanes/EtOAc (15 ml; 20:1, v:v). Obtained as a clear oil in 80% isolated yield (62 mg). For a 10
110

mmol (1.521 g) scale reaction, the product was purified by filtration through a short plug of silica
(2 cm thick x 3 cm diameter), washing with a mixture of hexanes/EtOAC (20 mL, 20:1, v:v, 2
times); the isolated yield was 70% (1.08 g).
1
H NMR (400 MHz, CDCl3)
1
H NMR (400 MHz,
CDCl3) δ 7.99 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.90 (s, 3H).
19
F NMR (376 MHz,
CDCl3) δ 15.4 (s, 1F). These data match the previously reported structure .

4-Vinylbenzoyl fluoride (2d)

The title compound was obtained following the general Method A, using 4-vinylbenzoic acid 1d
(0.5 mmol, 74.1 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1
mmol, 163 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter),
washing the silica plug with hexanes (15 ml). Obtained as a yellow oil in 73% isolated yield (55
mg).
1
H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 7.3 Hz, 2H), 6.78 (dd, J
= 17.6, 10.9 Hz, 1H), 5.95 (dd, J = 17.6, 7.0 Hz, 1H), 5.50 (t, J = 10.2 Hz, 1H).
13
C NMR (101

MHz, CDCl3) δ 157.4 (d, J = 343.0 Hz), 144.5, 135.7, 131.9 (t, J = 4.0 Hz), 126.8 (d, J = 12.1 Hz),
124.0 (d, J = 61.3 Hz), 119.0 – 117.4 (m).
19
F NMR (376 MHz, CDCl3) δ 17.3 (s, 1F). HRMS-
EI
+
(M
+
) Calcd. for C9H7OF = 150.04810, found = 150.04819. FT/IR (max (neat) cm-1): 2924,
2852, 1801, 1764, 1604, 1403, 1252, 1177, 1034, 1004, 923, 856, 770, 724, 702.

4-(Dimethylamino)benzoyl fluoride (2e)

111

The title compound was prepared following the general Method A, using 4-
(dimethylamino)benzoic acid 1e (0.5 mmol, 82.6 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol,
187 mg) and 3HF-Et3N (1 mmol, 163 L). Purified by filtration through a short plug of silica (2
cm thick x 3 cm diameter), washing the silica plug with a mixture of hexanes/DCM (15 ml; 1:1,
v:v). Obtained as a white solid in 73% isolated yield (61 mg).
1
H NMR (400 MHz, CDCl3) δ 7.86
(d, J = 9.1 Hz, 2H), 6.66 (d, J = 9.1 Hz, 2H), 3.09 (s, 6H).
19
F NMR (376 MHz, CDCl3) δ 11.8 (s,
1F). These spectra match the previously reported structure.

2-Iodobenzoyl fluoride (2f)

The title compound was prepared following the general Method A, using 2-iodobenzoic acid 1f
(0.5 mmol, 124 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol,
163 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing
the silica plug with a hexanes (15 ml). Obtained as a white solid, 83% isolated yield (104 mg).
1
H
NMR (400 MHz, CDCl3) δ 8.14 – 8.10 (m, 1H), 8.02 (dd, J = 7.9, 1.7 Hz, 1H), 7.50 (tdd, J = 7.4,
1.2, 0.4 Hz, 1H), 7.30 (ddd, J = 8.0, 7.4, 1.7 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ 28.7 (s, 1F).

These spectra match the previously reported structure .

4-Bromobenzoyl fluoride (2g)

112

The title compound was prepared following the general Method A, using 4-bromobenzoic acid 1g
(0.5 mmol, 100.5 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1
mmol, 163 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter),
washing the silica plug with hexanes (20 mL). Obtained as a white solid in 67% isolated yield (68
mg). Melting point: 93-94 ºC.
1
H NMR (400 MHz, CDCl3) δ 7.95 – 7.85 (m, 2H), 7.70 – 7.66
(m, 2H).
13
C NMR (101 MHz, CDCl3) δ 156.9 (d, J = 343.7 Hz), 132.8 (td, J = 5.8, 3.6 Hz), 132.7,
131.1, 124.0 (d, J = 62.5 Hz).
19
F NMR (376 MHz, CDCl3) δ 17.9 (s, 1F). HRMS-EI
+
(M
+
) Calcd.
for C7H4OFBr = 201.9430, found = 201.9427. FT/IR (max (neat) cm-1): 2292, 2361, 1802, 1398,
1247, 1024, 1001, 914, 839, 744, 673.

4-Acetylbenzoyl fluoride (2h)

The title compound was prepared in 99% yield as determined by
19
F NMR following the general
Method A, using 4-acetylbenzoic acid 1h (0.5 mmol, 84 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05
mmol, 187 mg) and 3HF-Et3N (1 mmol, 163 L). However, purification is best achieved by
employing Method B. In this manner, the title compound was prepared using 4-acetylbenzoic acid
1h (0.25 mmol, 42 mg), polymer-bound PPh3 (3 mmol/g, 166.5 mg), NBS (0.525 mmol, 94 mg)
and 3HF-Et3N (1 mmol, 82 L). Purified by removing the resin by vacuum filtration, washed with
DCM (2 mL) and hexanes (20 mL). Further addition of hexanes (10 mL) to this filtrate and stirring
for 10 min, resulted in precipitation of succinimide, which was removed by filtration through a
plug of celite, washing further with hexanes (5 mL). Concentration of the filtrate under reduced
pressure gave 2h as a white solid in 72% isolated yield (30 mg). Melting point: 201-202 ºC
1
H
113

NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.1 Hz, 2H), 8.08 (d, J = 8.2 Hz, 2H), 2.67 (s, 3H).
19
F
NMR (376 MHz, CDCl3) δ 19.7 (s, 1F).
13
C NMR (101 MHz, CDCl3) δ 197.1, 156.6 (d, J = 345.6
Hz), 142.1, 131.8 (d, J = 3.8 Hz), 128.8, 128.7 (d, J = 61.8 Hz), 27.1 (d, J = 9.8 Hz). HRMS-ES
+

(M+H
+
) Calcd. for C9H8O2F = 167.0508, found = 167.0508. FT/IR (max (neat) cm-1): 2919.70,
2851.24, 2366.23, 1809.87, 1690.30, 1401.51, 1359.57, 1238.08, 1032.21, 1006.66, 754.995.

3- Fluorobenzoyl fluoride (2i)

The title compound was prepared following the general Method A, using 3-fluorobenzoic acid 1i
(0.25 mmol, 35 mg), PPh3 (0.5 mmol, 131.2 mg), NBS (0.525 mmol, 94 mg) and 3HF-Et3N (0.5
mmol, 82 L). The isolation of the compound was not successful due to instability to silica gel.
Only yield as determined by
19
F NMR is provided using p-tolyl-SO2F (0.26 mmol, 45 mg) as
internal standard (
19
F NMR: δ 65.7):
19
F NMR (376 MHz, CDCl3) δ 18.6 (s, 1F) -111.5 (m, 1F).
These spectra match the previously reported structure.

Phenylacetyl fluoride (2j)

The title compound was prepared following the general Method A, using phenylacetic acid 1j (0.5
mmol, 68 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163
L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing the
silica plug with hexanes (20 mL). Obtained as a clear oil in 85% yield (58 mg).
1
H NMR (399
114

MHz, CDCl3) δ 7.41 – 7.33 (m, 3H), 7.32 – 7.27 (m, 2H), 3.82 (d, J = 2.5 Hz, 2H).
19
F NMR (376

MHz, CDCl3) δ 44.4 (t, J = 2.4 Hz, 1F). These spectra match the previously reported structure.

4- Phenylbutanoyl fluoride (2k)

The title compound was obtained following the general Method A, using phenyl butyric acid 1k
(0.5 mmol, 82.1 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1
mmol, 163 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter),
washing the silica plug with hexanes (20 ml). The filtrate was then concentrated under reduced
pressure (not lower than 150 torr at 40ºC) to afford a clear oil in 70% isolated yield (58 mg).
1
H
NMR (400 MHz, CDCl3) δ 7.34 – 7.29 (m, 2H), 7.24 – 7.16 (m, 3H), 2.72 (t, J = 7.5 Hz, 2H), 2.52
(t, J = 7.3 Hz, 2H), 2.03 (p, J = 7.4 Hz, 2H).
13
C NMR (126 MHz, CDCl3) δ 163.5 (d, J = 360.4
Hz), 140.5, 128.7, 128.6, 126.5, 34.6, 31.4 (d, J = 50.6 Hz), 25.6 (d, J = 2.0 Hz).
19
F NMR (376
MHz, CDCl3) δ 45.3 (s, 1F). HRMS-EI
+
(M
+
) Calcd. for C10H11OF = 166.0794, found = 166.0795.
FT/IR (max (neat) cm-1): 3030, 1836, 1707, 1490, 1457, 1217, 1094, 1024, 771, 698.

Adamantane-1-carbonyl fluoride (2l)

The title compound was obtained following the general Method A, using 1-adamantanecarboxylic
acid 1l (0.5 mmol, 91mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1
mmol, 163 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter),
washing the silica plug with hexanes (20 ml). Concentration of the filtrate under reduced pressure
115

gave 2l as a white low-melting solid in 81% isolated yield (74 mg).
1
H NMR (400 MHz, CDCl3)
δ 2.10 – 2.03 (m, 3H), 2.00 – 1.94 (m, 6H), 1.81 – 1.66 (m, 6H).
19
F NMR (376 MHz, CDCl3) δ
23.4 (s, 1F). These spectra match the previously reported structure.

2-Naphthoyl fluoride (2m)

The title compound was obtained following the general procedure A, using 2-naphthoic acid 1m
(0.25 mmol, 43 mg), PPh3 (0.5 mmol, 131.2 mg), NBS (0.525 mmol, 93.4 mg) and 3HF-Et3N (0.5
mmol, 82 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter)
washing with Hexanes (15 mL). White solid, 80% isolated yield (35.5 mg)
1
H NMR (400 MHz,
CDCl3) δ 8.64 (s, 1H), 8.03 – 7.98 (m, 2H), 7.95 (d, J = 11.0 Hz, 1H), 7.93 – 7.88 (m, 1H), 7.69
(ddd, J = 8.2, 6.8, 1.4 Hz, 1H), 7.62 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H).
19
F NMR (376 MHz, CDCl3)

δ 17.6 (s, 1F). These spectra match the previously reported structure.

Cinnamoyl fluoride (2n)

The title compound was obtained following the general Method A, using cinnamic acid 1n (0.5
mmol, 74 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163
L). Purified by filtration through a fritted funnel, washing the silica plug (2 cm thick x 3 cm
diameter) with pentane (30 ml x2). The filtrate was then concentrated under reduced pressure (not
lower than 150 torr at 40ºC) to afford clear oil in 35% isolated yield (26 mg).
1
H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 16.0 Hz, 1H), 7.59 – 7.55 (m, 2H), 7.49 – 7.41 (m, 3H), 6.38 (dd, J = 16.0,
116

7.3 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ 25.1 (d, J = 7.3 Hz, 1F). These spectra match the
previously reported structure.

(E)-3-(4-Chlorophenyl)acryloyl fluoride (2o)

The title compound was obtained following the general Method A, using chlorocinnamic acid 1o
(0.5 mmol, 91.3 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1
mmol, 163 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter),
washing the silica plug with hexanes (20 ml). White solid, 55% isolated yield (50.1 mg). Melting
point: 80-83
o
C.
1
H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 16.0 Hz, 1H), 7.53 – 7.47 (m, 2H),
7.44 – 7.37 (m, 2H), 6.34 (dd, J = 16.0, 7.1 Hz, 1H).
13
C NMR (126 MHz, CDCl3) δ 156.9 (d, J =
338.7 Hz), 150.0 (d, J = 6.0 Hz), 138.1, 131.7, 130.0, 129.7, 112.8 (d, J = 67.8 Hz).
19
F NMR (376
MHz, CDCl3) δ 25.5 (d, J = 7.1 Hz, 1F). HRMS-EI
+
(M
+
) Calcd. for C9H6OFCl = 184.0091, found
= 184.0093. FT/IR (max (neat) cm-1): 2963, 2923, 1786, 1630, 1592, 1491, 1408, 1306, 1178,

1086, 1012, 985, 816.

4-Hydroxybenzoyl fluoride (2p)

The title compound was obtained following the general Method A, using 4-hydroxybenzoic acid

1p (0.5 mmol, 69 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1
117

mmol, 163 L). Purified by column chromatography using DCM (100%) as eluent. Obtained as a
white solid in 52% isolated yield (36.4 mg).
1
H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz,
2H), 6.94 (d, J = 7.5 Hz, 2H), 5.73 (s, 1H).
19
F NMR (376 MHz, CDCl3) δ 15.7 (s, 1F). These
spectra match the previously reported structure.

Fmoc-L-Phe-F (2q)

The title compound was prepared following the general Method B, using commercially available
Fmoc-Phe-OH 1q (0.5 mmol, 194 mg), polymer-bound PPh3 (3 mmol/g, 1 mmol 333 mg), NBS
(1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163 L). Purified by removing the resin by vacuum
filtration, washed with DCM (2 mL) and hexanes (20 mL). Further addition of hexanes (10 mL)
to this filtrate and stirring for 10 min, resulted in precipitation of succinimide, which was removed
by filtration through a plug of celite, washing with hexanes (5 mL). Concentration of the filtrate
under reduced pressure gave 2q as a white solid in 50% isolated yield (97.3mg).
1
H NMR (400
MHz, CDCl3) δ 7.77 (d, J = 7.6 Hz, 2H), 7.54 (dd, J = 7.6, 3.4 Hz, 2H), 7.44 – 7.39 (m, 2H), 7.36
– 7.29 (m, 5H), 7.14 (d, J = 7.0 Hz, 2H), 5.07 (d, J = 8.4 Hz, 1H), 4.87 – 4.80 (m, 1H), 4.44 (qd, J

= 10.7, 6.9 Hz, 2H), 4.21 (t, J = 6.7 Hz, 1H), 3.21 – 3.16 (m, 2H).
19
F NMR (376 MHz, CDCl3) δ

30.3 (d, J = 2.8 Hz). The spectral data matches the previously

4-(1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)vinyl)benzoyl fluoride
(Bexarotene fluoride) (2r)
118

The title compound was obtained following the general Method A, using bexarotene 1r (0.5 mmol,

174.24 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163

L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing the
silica plug with a mixture of DCM/hexanes 1:1 (15 ml). White solid, 80% isolated yield (139.4
mg). Melting point: 90-94
o
C.
1
H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.7 Hz, 2H), 7.45 (d, J
= 7.7 Hz, 2H), 7.15 (s, 1H), 7.12 (s, 1H), 5.89 (d, J = 1.2 Hz, 1H), 5.43 (d, J = 1.2 Hz, 1H), 1.97

(s, 3H), 1.73 (s, 4H), 1.34 (s, 6H), 1.31 (s, 6H).
13
C NMR (101 MHz, CDCl3) δ 157.4 (d, J = 342.9

Hz), 148.9, 148.2, 144.8, 142.7, 137.6, 132.8, 131.7 (d, J = 3.7 Hz), 128.3, 128.2, 127.3, 123.7 (d,

J = 61.2 Hz), 118.3, 35.3, 35.3, 34.2, 34.0, 32.1, 32.0, 20.1.
19
F NMR (376 MHz, CDCl3) δ 17.4
(s, 1F). HRMS-EI
+
(M
+
) Calcd. for C 24H27OF = 350.2046, found = 350.2059. FT/IR ( max (neat) cm-
1): 2956, 2917, 2857, 1795, 1603, 1455, 1359, 1244, 1181, 1034, 1005, 922, 861, 774, 710

4-(N,N-dipropylsulfamoyl)benzoyl fluoride (Probenecid fluoride) (2s)

The title compound was obtained following the general Method A, using probenecid 1s (0.5 mmol,

142.7 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163

L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing the
silica plug with a mixture of DCM/hexanes 1:1 (10 ml). White solid, 73% isolated yield (105 mg).
Melting point: 65-71
o
C.
1
H NMR (400 MHz, CDCl3) δ 8.22 – 8.11 (m, 2H), 8.00 – 7.89 (m,
2H), 3.11 (t, J = 7.5 Hz, 4H), 1.55 (h, J = 7.5 Hz, 4H), 0.87 (t, J = 7.5 Hz, 6H).
13
C NMR (101
119

MHz, CDCl3) δ 156.2 (d, J = 345.7 Hz), 146.9, 132.2 (d, J = 3.7 Hz), 128.3 (d, J = 62.5 Hz), 127.7

(d, J = 0.8 Hz), 50.1, 22.1, 11.3.
19
F NMR (376 MHz, CDCl3) δ 19.7 (s, 1F). HRMS-EI
+
(M
+
)

Calcd. for C13H18NO3FS = 287.099, found = 287.0995. FT/IR (max (neat) cm-1): 3095, 2971,
2936, 2874, 1804, 1594, 1464, 1343, 1238, 1159, 1088, 1033, 994, 859, 733, 684.

2-(3-cyano-4-isobutoxyphenyl)-4-methylthiazole-5-carbonyl fluoride (Febuxostat fluoride)
(2t)

The title compound was obtained following the general Method A, using febuxostat 1t (0.5 mmol,

158.2 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163

L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing the
silica plug with a mixture of DCM/hexanes 1:1 (10 ml). White solid, 69% isolated yield (110 mg).
Melting point: 145-150
o
C.
1
H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 2.4, 0.9 Hz, 1H), 8.08
(dd, J = 8.8, 2.2 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H) 3.89 (d, J = 6.5 Hz, 2H), 2.75 (s, 3H), 2.18 (dt,

J = 13.3, 6.6 Hz, 1H), 1.07 (d, J = 6.8 Hz, 6H).
13
C NMR (101 MHz, CDCl3) δ 170.87, 166.79 (d,

J = 6.7 Hz), 163.31, 152.12 (d, J = 329.4 Hz), 133.10, 132.64, 125.38, 115.98 (d, J = 70.0 Hz),

115.33, 112.96, 103.42, 76.01, 28.33, 19.22, 17.97 (d, J = 2.1 Hz).
19
F NMR (376 MHz, CDCl3)
δ 37.1 (s, 1F). HRMS-EI
+
(M
+
) Calcd. for C16H15N2O2FS = 318.0838, found = 318.0847. FT/IR
(max (neat) cm-1): 3015, 3013, 2955, 1974, 1621, 1602, 1533, 1479, 1383, 1370, 1346, 1217,
1214, 987, 771, 769.
120

2-(4-isobutylphenyl)propionyl fluoride (Ibuprofen fluoride) (2u)

The title compound was obtained following the general Method A, using ibuprofen 1u (0.5 mmol,

103.15 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163

L). Diluted with pentane and purified by filtration through a short plug of silica (2 cm thick x 3
cm diameter), washing the silica plug with a mixture of DCM/hexanes 1:1 (10 ml). Concentrated
under reduced pressure at 36ºC, 200 torr (volatile). Light yellow oil, 91% isolated yield (95 mg).
1
H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 3.86 (q, J = 7.2
Hz, 1H), 2.50 (d, J = 7.1 Hz, 2H), 1.96 – 1.82 (m, 1H), 1.60 (dd, J = 7.2, 0.9 Hz, 3H), 0.93 (d, J =
6.6 Hz, 6H).
13
C NMR (101 MHz, CDCl3) δ 164.7 (d, J = 367.3 Hz), 141.9, 134.9 (d, J = 0.7 Hz),

130.0, 127.5, 45.2, 44.1 (d, J = 49.3 Hz), 30.4, 22.6, 18.3 (d, J = 1.4 Hz).
19
F NMR (376 MHz,
CDCl3) δ 38.7 (s, 1F). HRMS-EI
+
(M
+
) Calcd. for C13H17OF = 208.1263, found = 208.1254.
FT/IR (max (neat) cm-1): 3023, 2954, 2922, 1832, 1510, 1457, 1215, 1122, 1050, 923, 889, 769,
748, 667.

2-(6-methoxynaphthalen-2-yl)propionyl fluoride (Naproxen fluoride) (2v)

The title compound was obtained following the general Method A, using naproxen 1v (0.5 mmol,

115.15 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163

L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing the
121

silica plug with a mixture of DCM/hexanes 1:1 (20 ml). White solid, 69% isolated yield (80 mg).
Melting point: 75-79
o
C.
1
H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 21.1 Hz, 1H), 7.74 (d, J =
3.6 Hz, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 7.17 (dd, J = 8.9, 2.6 Hz, 1H),
7.13 (d, J = 2.6 Hz, 1H), 4.00 (q, J = 7.1 Hz, 1H), 3.93 (s, 3H), 1.67 (dd, J = 7.2, 0.9 Hz, 3H).
13
C

NMR (101 MHz, CDCl3) δ 164.6 (d, J = 367.3 Hz), 158.2, 134.3, 132.5 (d, J = 0.8 Hz), 129.5,

129.0, 127.9, 126.6, 125.9, 119.6, 105.8, 55.5, 44.4 (d, J = 49.5 Hz), 18.3.
19
F NMR (376 MHz,
CDCl3) δ 39.1 (s, 1F). HRMS-EI
+
(M
+
) Calcd. for C14H13O2F = 232.0900, found = 232.0909.
FT/IR (max (neat) cm-1): 3019, 2987, 2941, 2849, 1822, 1602, 1388, 1265, 1226, 1127. 1059,
1024, 852, 823, 674.

2-[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetyl fluoride (Indomethacin

fluoride) (2w)
7

The title compound was obtained following the general Method A, using indomethacin 1w (0.5
mmol, 178.90 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol,
163 L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing
the silica plug with a mixture of EtOAc/hexanes 1:1 (10 ml). White solid, 61% isolated yield (108
mg).
1
H NMR (400 MHz, CDCl3) δ 7.72 – 7.59 (m, 2H), 7.52 – 7.39 (m, 2H), 6.88 (d, J = 2.5 Hz,
1H), 6.84 (d, J = 9.1 Hz, 1H), 6.70 (dd, J = 9.0, 2.5, 1H), 3.87 (d, J = 2.6 Hz, 2H), 3.84 (s, 3H),

2.41 (s, 3H).
13
C NMR (101 MHz, CDCl3) δ 168.4, 160.7 (d, J = 363.9 Hz), 156.4, 139.8, 137.0,

133.7, 131.5, 130.9, 130.0, 129.4, 115.3, 112.3, 109.4 (d, J = 2.2 Hz), 100.9, 56.0, 28.5 (d, J = 58.0
122

Hz), 13.4.
19
F NMR (376 MHz, CDCl3) δ 43.9 (s, 1F). FT/IR (max (neat) cm-1): 3060, 2923,
1830, 1680, 1595, 1464, 1350, 1322, 1233, 1211, 1152, 1065, 1034, 1015, 908, 851, 754. The
spectral data matches the previously reported product

2-(3-benzoylphenyl)propionyl fluoride (Ketoprofen fluoride) (2x)

The title compound was obtained following the general Method A, using ketoprofen 1x (0.5 mmol,

127.15 mg), PPh3 (1 mmol, 262.3 mg), NBS (1.05 mmol, 187 mg) and 3HF-Et3N (1 mmol, 163

L). Purified by filtration through a short plug of silica (2 cm thick x 3 cm diameter), washing the
silica plug with a mixture of DCM/hexanes 1:1 (20 ml). Concentrated under reduced pressure at
36ºC, 200 torr (volatile). Light yellow oil, 78% isolated yield (100 mg).
1
H NMR (399 MHz,
CDCl3) δ 7.82 – 7.78 (m, 2H), 7.76 (t, J = 1.9 Hz, 1H), 7.74 (dt, J = 7.2, 1.6 Hz, 1H), 7.64 – 7.59
(m, 1H), 7.56 – 7.47 (m, 4H), 3.96 (q, J = 7.2 Hz, 1H), 1.64 (dd, J = 7.2, 0.9 Hz, 3H).
13
C NMR

(101 MHz, CDCl3) δ 196.3, 164.0 (d, J = 367.2 Hz), 138.6, 138.0, 137.4, 132.9, 131.6, 130.3,

130.1, 129.4, 129.2, 128.6, 44.3 (d, J = 49.8 Hz), 18.2.
19
F NMR (376 MHz, CDCl3) δ 38.7 (s,

1F). HRMS-EI
+
(M
+
) Calcd. for C16H13O2F = 256.0900, found = 256.0910. FT/IR (max (neat)

cm-1): 3259, 3058, 2978, 2934, 2877, 1834, 1736, 1704, 1656, 1596, 1579, 1447, 1315, 1281,

719, 700.

N-(Adamantan-1-yl)picolinamide (3a) was obtained as a white solid in 91% yield (117 mg).
1
H
NMR (400 MHz, CDCl3) δ 8.91 – 8.90 (m, 1H), 8.71 – 8.69 (m, 1H), 8.09 – 8.01 (m, 1H), 7.39 –
7.34 (m, 1H), 5.78 (br. s, 1H), 2.14 (br. s, 6H), 1.73 (br. s, 6H), 1.58 (br. s, 3H).
19
F NMR (376

MHz, CDCl3) δ 16.8 (s, 1F). The spectral data matches the previously reported product.
123

N-(Adamantan-1-yl)nicotinamide (3b) was obtained as a white solid in 83% yield (106.4 mg).

1
H NMR (400 MHz, CDCl3) δ 8.50 (t, J = 5.0, 1.0 Hz, 1H), 8.16 (d, J = 7.8 Hz, 1H), 7.88 (br. s,

1H), 7.82 (td, J = 7.7, 1.7 Hz, 1H), 7.38 (ddd, J = 7.7, 4.7, 1.3 Hz, 1H), 2.15 (br. s, 6H), 2.12 (br.
s, 3H), 1.73 (t, J = 15.0 Hz, 6H).
19
F NMR (376 MHz, CDCl3) δ 20.9 (s, 1F). The spectral data
matches the previously reported product.

N-(Adamantan-1-yl)isonicotinamide (3c) was obtained as a white solid in 73% yield (94 mg).

1
H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 5.8 Hz, 2H), 7.53 (d, J = 5.7 Hz, 2H), 5.78 (br. s, 1H),

2.10 (br. s, 6H), 1.71 (br. s, 6H), 1.57 (s, 3H).
19
F NMR (376 MHz, CDCl3) δ 21.4 (s, 1F). The

spectral data matches the previously reported product.
124

CHAPTER 6

TRIFLUOROMETHYLTHIOLATION OF CARBOXYLIC ACIDS USING AN AIR-
AND MOISTURE-STABLE COPPER REAGENT

6.1 Introduction

As emphasized in the previous chapter, synthesis of organofluorine compounds is an active
research interest in the field of pharmaceutical sciences, agricultural chemicals, and functional
materials due to their unique physical, chemical, and biological properties
1
. Among fluorine
moieties, trifluoromethylthio-containing compounds are particularly interesting because of the
electron-withdrawn and high lipophilic nature of the -SCF3 group.
2
Despite considerable interest,
there were few numbers of reported methods which efficiently enables the synthesis of
trifluoromethyl thioesters. These thioesters can be prepared directly from aryl halides which are
relatively unstable. The pioneering work developed by Man and co-workers
3
employed highly
toxic compound Hg(SCF3). In 2004, a work reported by Yagupolskii and co-workers
4
used highly
sensitive and unstable tetramethylammonium trifluoromethylthiolate Me4NSCF3 reacting directly
with aryl halides. More recently, in 2016, Weng and co-workers developed a method using an air-
and moisture- stable copper reagent (bpy)CuSCF3 and aryl halides
5
. On the other hand, carboxylic
acids are relatively more stable, non-toxic and abundant. However, there has been no reports of
trifluoromethyl thioester synthesis using carboxylic acids as precursors until recently, a work by
He and co-workers,
6
who reported a procedure using N- (trifluoromethylthio)phthalimide, at the
same time when this chapter was being prepared.
125

Continuing from the work in the previous chapter
7,8
, a method which enables the direct
synthesis of triluoromethyl thioesters from carboxylic acids was developed, using the air- and
moisture-stable reagent (bpy)CuSCF3 (Scheme 6.1). This protocol offers a direct and convenient
method that can be applicable to a wide range of aromatic and aliphatic carboxylic acids with
tolerance to a wide variety of functional groups and also pharmaceutical drugs.
Scheme 6.1. Prior art of trifluoromethyl thioester synthesis and the current work.

6.2 Results and Discussion

6.2.1 Condition Optimization

2-naphthoic acid 1a was selected as a model substrate to investigate the optimal condition
for direct trifluoromethylthiolation, forming the corresponding trifluoromethyl thioester 2a.
Different -SCF3 sources were also tested in this process (Table 6.1).
126

Starting with Me4NSCF3 (1.2 equiv) reagent, there was no observed product yield (Table
6.1, entry 1). Even when doubling the equivalents of PPh3 and NBS or changing the solvent to
more polar one MeCN, the product did not form (Table 6.1, entry 2 & 3). This is consistent with
the result in a recent publication by He’s group.
6
Hence, Me4NSCF3 is not the right reagent for our
reaction. Another -SCF3 reagent successfully transformed acid chlorides to trifluoromethyl
thioesters
5
, (bpy)CuSCF3 was used and the expected product 2a was observed in 37% yield (Table
6.1, entry 4) in MeCN solvent. In order to improve the yield of thioester, a series of different
solvents was investigated (Table 6.1, entry 5-7). It was found that the reaction condition
exclusively worked well in THF with 60% yield, much higher than in DCM (30% yield) and in
dioxane (21% yield). Increasing the equivalents of PPh3, NBS, or (bpy)CuSCF3 did not improve
the yield (Table 6.1, entry 8-14). Hence, the optimal condition was employed with 1 equiv PPh3,
1.1 equiv NBS, and 1.2 equiv (bpy)CuSCF3 in 2.5 mL THF. This condition was applied to further
investigate the scope of substrates.
127

Table 6.1. Optimization of the reaction conditions.

Entry Solvent PPh3 (equiv)
NBS (equiv) -SCF3 (equiv)
Yield (%)
a

1 DCM 1 1.1 Me4NSCF3 (1.2)
0
2 DCM 2 2.2 Me4NSCF3 (1.2)
0
3 MeCN 2 2.2 Me4NSCF3 (1.2)
0
4 MeCN 1 1.1 (bpy)CuSCF3 (1.2)
37
5 DCM 1 1.1 (bpy)CuSCF3 (1.2)
30
6 Dioxane 1 1.1 (bpy)CuSCF3 (1.2)
21
7 THF 1 1.1 (bpy)CuSCF3 (1.2)
60
8 THF 1.1 1.2 (bpy)CuSCF3 (1.2)
60
9 THF 1.1 1.2 (bpy)CuSCF3 (1.5)
62
10 THF 1 1.1 (bpy)CuSCF3 (2.0)
60
11 THF 1.2 1.3 (bpy)CuSCF3 (1.2)
48
12 THF 1.2 1.3 (bpy)CuSCF3 (1.5)
51
13 Dioxane 1 1.1 (bpy)CuSCF3 (1.5)
41
14 Dioxane 1 1.1 (bpy)CuSCF3 (2.0)
45
a
As determined by
19
F NMR spectroscopy with PhOCF3 as internal standard.

6.2.2 Reaction scope

The system was applied for trifluoromethylthiolation of various carboxylic acids (Scheme
6.2). A number of derivatives of benzoic acids bearing electron-neutral, electron-donating (-OMe,
-CH=CH2, -OH), as well as electron-withdrawing functionalities (-I, -Br, -F, -Ac, -CHO) were
converted into corresponding trifluoromethyl thioesters in moderate to good yields (2b-2j). It
should be noted that the aryl halides (-I, -Br, -F) were also tolerated under the reaction conditions.
Heteroaryl carboxylic acids were also compatible to give the corresponding trifluoromethyl
thioesters 2m-2n in slightly lower yields (66 and 39%) in comparison to the one obtained using
benzoic acids.
128

Furthermore, the compatibility of the method to aliphatic carboxylic acids was also
investigated. Phenylacetic-, phenylbutyric- and 1-adamantyl- carboxylic acids were all reactive
under the reaction conditions and provide the corresponding thioesters 2k, 2o, and 2l in satisfying
yields. Notably, the reaction condition was also applicable to protected amino acids and gave
moderate yields of 43-52% of the products (2p and 2q).
Scheme 6.2 Direct trifluoromethylthiolation of carboxylic acids.
a

129

130

a
Yields determined by
19
F NMR spectroscopy, using internal standard.

6.2.3 Proposed mechanism

Based on previous studies
6,7
, a tentative mechanism was proposed (Scheme 4). Similar to
the mechanism proposed in Chapter 6, firstly, PPh3 oxidized by NBS generates a
bromophosphonium ion A, which reacts with RCOOH derivatives 1, forming
acyloxyphosphonium intermediate I.
7
When (bpy)CuSCF3 was added into the above mixture
131

solution, the electrophilic SCF3 group reacts and generates intermediate II. Then, CF3S
-
anion
intermolecularly attacks the acyl carbon of III and gives the thioester product.
Scheme 6.3 Proposed mechanism.

6.3 Experimental Setup

Unless it’s stated, all materials were purchased from commercial providers and used
without further purification. Copper (II) fluoride 99% was purchased from Sigma Aldrich, sulfur
S8 was purchased from Alfa Aesar, trifluoromethyltrimethylsilane TMSCF3 was obtained from
TCI. All solvents were obtained from VWR. N-bromosuccinimide (NBS) was recrystallized from
water and dried over P2O5 under a high vacuum.
1
H,
13
C, and
19
F spectra were obtained using 400
132

MHz or 500 MHz Varian NMR spectrometers.
1
H NMR chemical shifts were determined relative
to CDCl3 as the internal standard at δ 7.26 ppm.
13
C NMR shifts were determined relative to CDCl3
at δ 77.16 ppm.
19
F NMR chemical shifts were determined relative to CFCl3 at δ 0.00 ppm.

6.3.1 Synthesis of (bpy)CuSCF3

The synthesis of (bpy)CuSCF3 was processed following the previous report by Weng et
al
9
. In a glovebox, CuF2 (1.428 g, 14 mmol) and S8 (0.448 g, 14 mmol) were added to an oven-
dried resealable Schlenk flask with a sidearm fitted with a PTFE. Then, under the inert condition,
60 mL CH3CN was added into the flask. Finally, TMSCF3 (6.2 mL, 42 mmol) was added into the
flask. The reaction mixture was stirred under reflux at 80
o
C for 10 h. After the reaction mixture
was cooled to room temperature, it was filtered through celite. The resulting dark brown solid was
collected and washed with Et2O three times (3 x 30 mL). Then the solid was redissolved in 12 mL
of CH3CN, and 2,2’-bipyridine (2.18 g, 14 mmol) in 30 mL Et2O was added into the solution. This
solution mixture was kept at -25
o
C for 24 h. The forming red crystals were collected and washed
with Et2O twice (2 x 10 mL) and dried to give the product (bpy)CuSCF3.

6.3.2 General procedure for trifluoromethylthiolation of carboxylic acids and NMR yield
determination
Scheme 6.4 General procedure for trifluoromethylthiolation of carboxylic acids.

133

In a glovebox, (bpy)CuSCF3 (1.2 equiv, 96 mg) was added into a microwave vial with a
magnetic stir bar and sealed. On the other side, on the bench-top, 2-naphthoic acid (0.25 mmol, 43
mg) and triphenylphosphine, PPh3 (0.25 mmol, 66 mg, 1 equiv) were charged into an oven-dried
screw-cap vial equipped with a magnetic stir bar. After this, anhydrous tetrahydrofuran, THF (2.5
mL) was added, the vial was capped, and this mixture was then cooled to 0
o
C using an ice-bath.
Subsequently, N-bromosuccinimide, NBS (1.1 equiv, 0.275 mmol, 49 mg) was added as a solid in
one portion, the vial was re-capped, and the mixture was kept in the ice-bath for two minutes. After
this time, the ice-bath was removed, and this solution was further stirred for 15 min. Once this
time concluded, the vial was opened, and all the mixture solution 2.5 mL was transferred into the
sealed microwave vial containing (bpy)CuSCF3 in one pot. This mixture was stirred further for 2
h at room temperature. After this time, an internal standard, (trifluoromethoxy)benzene PhOCF3
(0.15 mmol, 20 L, equivalent to 60% yield) was added, the mixture was stirred for 2 min, then
analyzed by
19
F NMR spectroscopy. The yield was determined by comparing the relative
integration of internal standard PhOCF3 (
19
F NMR  -57.8 ppm) with the -SCF3.

6.4 Conclusions

In conclusion, the developed protocol provided a rapid and direct one-step
trifluoromethylthiolation of a variety of carboxylic acids at room temperature, using commercially
available reagents PPh3 and NBS, and an electrophilic SCF3 reagent. It was applicable for both
aromatic and aliphatic carboxylic acids and tolerance in many functional groups. This method can
be applied to many active drugs which shows a potentially practical use in the pharmaceutical
industry.
134

6.5 References

(1) (a) Hiyama, T. Organofluorine Compounds: Chemistry and Applications. Berlin,
Heidelberg, Springer-Verlag, 2000. (b) Bégué, J.-P.; Bonnet-Delpon, D. Bioorganic and
Medicinal Chemistry of Fluorine. Wiley-VCH: Weinheim, 2008. (c) Catalán, S.; Munoz,
S. B.; Fustero, S. “Unique Reactivity of Fluorinated Molecules with Transition Metals”
Chimia International Journal for Chemistry, vol. 68, no. 6, 2014, pp. 382-409(28).

(2) (a) Leroux, Frederic; Jeschke, Peter; Schlosser, Manfred. “α-Fluorinated Ethers,
Thioethers, and Amines: Anomerically Biased Species” Chemical Reviews, vol. 105, no.
3, 2005, pp. 827-856. (b) Boiko, Vladimir N. “Aromatic and heterocyclic perfluoroalkyl
sulfides. Methods of Preparation.” Beilstein. Journal of Organic Chemistry, vol. 6, 2010,
pp. 880-921. (c) Leo, Albert; Hansch, Corwin; Elkins, David. “Partition coefficients and
their uses” Chemical Reviews, vol. 7, no. 6, 1971, pp. 525-616.

(3) Man, E.H.; Coffman, D.D.; Muetterties, E.L. “Synthesis and Properties of Bis-
(trifluoromethylthio)-mercury”. J. Am. Chem. Soc., 1959, 81, 14, 3575-3577.

(4) Kremlev, Mikhail M; Tyrra, Wieland; Naumann, Dieter; Yagupolskii, Yurii L. “S-
Trifluoromethyl esters of thiocarboxylic acids, RC(O)SCF3.” Tetrahedron Letters, vol.
45, no. 32, 2004, pp. 6101-6104.

(5) Zhang, M.; Chen, J.; Chen, Z.; Weng, Z. “Copper-mediated effective synthesis of S-
trifluoromethyl esters by trifluoromethylthiolation of acid chlorides” Tetrahedron, 2016,
72, 24, 3525-3530.

(6) Mao, Runze; Bera, Srikrishna; Cheseaux, Alexis; Hu, Xile. “Deoxygenative
trifluoromethylthiolation of carboxylic acids.” Chemical Science, vol. 10, no. 41, 2019,
pp. 9555-9559.

(7) Munoz, Socrates B.; Dang, Huong; Ispizua-Rodriguez, Xanath; Mathew, Thomas;
Prakash, G. K. Surya. “Direct Access to Acyl Fluorides from Carboxylic Acids Using a
Phosphine/Fluoride Deoxyfluorination Reagent System.” Organic Letters, vol. 21, no. 6,
2019, pp. 1659-1663.

(8) (a) Cadogan, J. Organophosphorus Reagents in Organic Synthesis. London, Academic
Press, 1979. (b) Allen, D. W. “Phosphines and related P-C-bonded compounds.”
Organophosphorus Chemistry, vol. 40, 2011, pp. 1-51. (c) Mitsunobu, Oyo.; Yamada,
Masaaki. “Preparation of Esters of Carboxylic and Phosphoric Acid via Quaternary
Phosphonium Salts” Bulletin of the Chemical Society of Japan, vol. 40, no. 10, 1967, pp.
2380-2382. (d) Mitsunobu, Oyo. “The Use of Aiethyl Azodicarboxylate and
Triphenylphosphine in Synthesis and Transformation of Natural Products.” Synthesis,
vol. 1, 1981, pp. 1-28. (e) Appel, Roft. “Tertiary Phosphane/Tetrachloromethane, a
135

Versatile Reagent for Chlorination, Dehydration, and P-N Linkage.” Angewandte Chemie
International Edition, vol. 14, 1975, pp. 801-811.

(9) Weng, Zhiqiang; He, Weiming; Chen, Chaohuang; Lee, Richmond; Tan, Davin; Lai,
Zhiping; Kong, Dedao; Yuan, Yaofeng; Huang, Kuo-Wei. “An Air-Stable Copper
Reagent for Nucleophilic Trifluoromethylthiolation of Aryl Halides.” Angewandte
Chemie International Edition, vol. 52, no. 5, 2013, pp. 1548-1552.

Abstract (if available)

Abstract There are two main research parts of my thesis work. Part I (Chapters 1-3) focused on the development in the utilization of green-house gases via bi-reforming and dry reforming processes of methane. Part II (Chapters 4-6) focused on the methodologies for deoxygenative fluorination and trifluoromethylthiolation of carboxylic acids via acyloxyphosphonium ion intermediate. ❧ Part I. ❧ Global warming with the increasing emission of greenhouse gases, CO₂ and methane CH₄, has imposed an immediate challenge to humankind and the environment nowadays. The concept of Methanol Economy advocated by the late Nobel Laureate George A. Olah and his colleagues, Dr. G. K. Surya Prakash and Dr. Alain Goeppert could provide a sustainable solution in which methanol acts as a main fuel and chemical feedstock derived from CO₂ capture, storage, and conversion. In this process, green-house gases can be used as raw materials for the large-scale production of syngas/metgas (syngas in which H₂:CO = 2:1), which later can be transformed into other fuels and commodity chemicals like methanol, hydrocarbons, and other alcohols/aldehydes. The CO₂ reforming processes conducted at atmospheric pressure are not suitable for the upstream as well as downstream processes that are operated at high pressure as seen in the petrochemical platforms. Despite many research efforts over the last decades, there are still challenges between the laboratory experiment and the practical application. The biggest challenge is the deactivation of the catalysts under high-pressure operating conditions. This requires the careful design of reaction operation conditions and active catalysis. The scope of my thesis in chapters 1 and 2 is aimed at showing some insights and improvements in the operational conditions and catalysis design for a long-term continuity of reformer reactor operations. Chapter 1 succinctly reviews a variety of reformer technologies. ❧ Chapter 2 explores the right conditions for in-situ activation and reactivation of bi-reforming over Ni-MgO catalysts without external supplements. This finding can help in the ease of operation and cost savings. ❧ Chapter 3 describes the efficacy of three different Ni-based catalysts for dry reforming of methane. The doped metals (In) have demonstrated the ability in decreasing the coke formation in dry reforming. The degree of coke formation also varies with different doped metals, least carbon formation with In. This may be due to the low melting point of Indium; hence under high-temperature dry reforming condition, Indium forms molten layers around the active Ni particles reducing the degree of aggregation of Ni particles, which is the main reason for coke formation. ❧ Part II. ❧ Fluorine with its unique properties, high electronegativity, can modulate and enhance lipophilicity, bioavailability of the fluorine containing molecules and materials. Hence, the introduction of fluorine and fluoroalkyl groups into the organic molecules/materials has increasingly attracted attention for various applications in medicinal, agrochemical, pharmaceutical and polymer/material sciences fields. There are many reports of the methods to synthesize acyl fluoride and trifluoromethyl thiobenzoates. However, the previous literature reports only have used toxic, and environmental damaging harsh conditions. ❧ Chapter 5 demonstrates a convenient methodology that employs common and available reagents, PPh₃, NBS, and triethylamine hydrogen fluoride Et₃N.3HF or KHF₂/trifluoroacetic acid with carboxylic acids, under mild condition, room temperature, for the formation of acyl fluoride. The method was applicable to a wide-range substrate scope and functional groups. It also provided a potential scale-up procedure for 4-methoxybenzoyl fluoride which was in turn a potential fluorinating reagent. ❧ Continuing from Chapter 5, Chapter 6 shows another successful methodology which employed acyloxyphosphonium ion as an intermediate to transform carboxylic acids to the corresponding trifluoromethylthiolated products. The method also offered the applicability to various substrate scopes and functional groups. Many pharmaceutical active ingredients also underwent deoxygenative trifluoromethylthiolation by this method successfully.

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Creator Dang, Huong (author)

Core Title Reforming of green-house gases: a step towards the sustainable methanol economy; and, One-step deoxygenative fluorination and trifluoromethylthiolation of carboxylic acids

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Degree Conferral Date 2021-12

Publication Date 10/03/2022

Defense Date 03/11/2020

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

Tag deoxygenative fluorination,deoxygenative trifluoromethylthiolation,methanol economy,OAI-PMH Harvest,reforming

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Advisor Prakash, G. K. Surya (committee chair), Narayan, Sri R. (committee member), Shing, Katherine (committee member)

Creator Email huongdan@usc.edu,huongdangusc@gmail.com

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