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Selective fluoroalkylation methods and synthesis of water-soluble organic molecules for organic redox flow batteries

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Selective fluoroalkylation methods and synthesis of water-soluble organic molecules for organic redox flow batteries

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Content
SELECTIVE FLUOROALKYLATION METHODS AND SYNTHESIS OF WATER-
SOLUBLE ORGANIC MOLECULES FOR ORGANIC REDOX FLOW BATTERIES

By

Sankarganesh Krishnamoorthy

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)

Copyright August 2017 Sankarganesh Krishnamoorthy

ii

Dedicated
To My
Family, Mentors and Friends

iii
ACKNOWLEDGEMENTS
The work opportunity in the Olah-Prakash lab has been an excellent enterprise. I
have always said and thought that it is a wonderful place with exceptionally equipped
facilities to train and practice organic chemistry. The people that I had the opportunity to
work with have further improved the value of my experience. So I take these pages to
acknowledge my mentors and co-workers.
Prof. Prakash has been an excellent mentor, always available to discuss chemistry.
The opportunities that he provided to speak in the national, departmental, and in the
group meetings have been valuable in practicing my presentation skills. I highly value his
constant encouragement and receptive attitude for new chemistry. I enjoyed all the tissue-
paper discussions that we had over the Loker kitchen counter. His constant advice on my
writing has been very helpful to improve my scientific writing. I am grateful for his
mentorship through out my Ph.D. program.
It was a honor and a privilege to work with Prof. Olah. He means a great
inspiration. Though I had learned of his work on carbocations during my undergraduate
and masters years, I have never thought that I would get an opportunity to work with him.
I earnestly thank him for serving in my Ph.D. dissertation committee and his feedback on
the methods we developed.
I am grateful to Prof. Narayan for being a great teacher and a mentor. What begun
as a side-project with his lab, eventually has taken a significant portion of my
dissertation. I have been treated as a honorary member of the Narayan’s group for which
I would like to express my genuine gratitude. I was happy to learn electrochemistry from
one of the leaders in the field. I enjoyed all the meetings, talking about how to address the
next big challenge in the organic flow battery project. I sincerely thank him for serving in
my dissertation committee.
I would like to thank my external dissertation committee member Prof. Katherine
Shing and my screening and qualifying exam committee member Prof. Matthew Pratt for
their helpful discussions and feedback.
I would like to thank the fluorine chemistry team Dr. Somesh K. Ganesh, Dr.
Aditya Kulkarni, Dr. Jotheeswari Kothandaraman, Huong Dang, Sayan Kar, Fang Fu,
Simon Schnell and Jacqueline Saldana for their active collaboration and discussions.
iv
I would also like to thank senior members of the organic redox flow battery team,
Dr. Bo Yang and Dr. Lena Hoober-Burkhardt, for their active collaboration, for teaching
electrochemistry and instruments. I would like to thank and wish them good luck with
future endeavors on the organic flow battery to the next generation, Advaith Murali and
Archith Nirmalchandar.
I would like to acknowledge the past and the present members of the Olah-
Prakash lab for maintaining excellent work atmosphere, helping with new instruments
and techniques and participating in active discussions, Dr. Thomas Mathew, Dr. Alain
Goeppert, Dr. Miklos Czaun, Dr. Patrice Batamack, Dr. Attila Papp, Dr. Fang Wang, Dr.
Hema Krishnan, Dr. Arjun Narayanan, Dr. Anton Shakhmin, Dr. Zhe Zhang, Dr. Laxman
Gurung, Dr. Socrates Munoz, Dr. Xu Liu, Dr. Marc iluliucci, Dean, Kavita, Alex,
Vinayak, Sahar and Vicente.
Dr. Rasul Golam and Dr. John-Paul Jones assistance in introducing me to the
small molecule optimization and Gaussian view user interface is well appreciated.
Prof. Ralf Haiges is acknowledged for his help with crystal structure analysis and
introducing me to the vacuum manifold and fluorine gas use.
Thankful to the members of the Petasis lab, Dr. Kalyan Nagulapalli, who is a
good friend and was a great help with analytical and purification techniques, Dr. Rong,
Dr. Nikita, Dr. Steve and Caitlin, who were helpful in procuring needed chemicals that
we sometimes lacked in the Olah-Prakash lab.
I would like to thank admin staffs of Loker, Jessie May, Carole Phillips, and
David Hunter, and of the department, Michele Dea and Magnolia Benitez for guiding me
through all the paper work through out my Ph.D. program and helping me obtain my
reimbursement and awards checks on time. Allan Kershaw and Ralph Pan are thanked for
their help with NMR instruments.
I am grateful to my parents, Mr. M. Krishnamoorthy and Mrs. Amsa
Krishnamoorthy for their love, constant encouragement, and support through out my life.
I would like to thank my brother and family, Suresh, Sundari, Sanjay, and Kalai for their
love and encouragement. I am thankful to my friends Magi, Sudhakar, Senthil, Anbu,
Ramesh, Mayro, Ashwin and Janet for their constant encouragement. Finally, I would
v
like to thank Jotheeswari for showering limitless love, support and understanding through
out the graduate program as the best friend, a co-worker, a critique and as the wife.

vi
Table of contents

DEDICATION ii
ACKNOWLEDGEMENTS iii
ABSTRACT ix

[1] Chapter 1. Introduction to Silicon Based Reagents for Difluoromethylation
and Difluoromethylenation Reactions 1
1.1 Introduction 2
1.2 Trifluoromethyltrimethylsilane 3
1.3 (Difluoromethyl)trimethylsilane 10
1.4 Chlorodifluoromethyl)trimethylsilane 16
1.5 (Bromodifluoromethyl)trimethylsilane 17
1.6 (Iododifluoromethyl)trimethylsilane 22
1.7 [Difluoro(phenyl-thio)methyl]trimethylsilane 22
1.8 (Phenylsulfonyl)difluoromethylsilane 23
1.9 Diethyl (difluoro(trimethylsilyl)methyl)phosphonate 24
1.10 Ethyl difluoro(trimethylsilyl)acetate 25
1.11 Difluoro(trimethylsilyl)acetamides 29
1.12 Difluoro(trimethylsilyl)acetonitrile 30
1.13 Others 30
1.14 Focus of my study 31
1.15 References 31

[2] Chapter 2. N-Difluoromethylation of Imidazoles and Benzimidazoles Using the
Ruppert-Prakash Reagent under Neutral Conditions 44
2.1 Introduction 45
2.2 Results and discussion 47
2.3 Summary 55
2.4 Experimental section 55
2.5 References 77
vii
[3] Chapter 3. Direct S-Difluoromethylation of Thiols Using the Ruppert-Prakash
Reagent 81
3.1 Introduction 82
3.2 Results and discussion 83
3.2.1 Aromatic thiols 83
3.2.2 Aliphatic thiols 88
3.2.3 One-pot tolyllthiodifluoromethyl transfer to benzaldehyde 88
3.2.4 Mechanism 89
3.3 Summary and conclusions 90
3.4 Experimental section 90
3.5 References 102
[4] Chapter 4. Direct Difluoromethylenation of Carbonyl Compounds using
TMSCF
3
105
4.1 Introduction 106
4.2 Results and discussions 109
4.3 Summary and conclusion 117
4.4 Experimental Section 118
4.5 References 142
[5] Chapter 5. Investigation of Nucleophilic Difluoromethylation of Carbonyl
Compounds Using the Ruppert-Prakash Reagent 146
5.1 Introduction 147
5.2 Results and discussions 149
5.3 Summary and conclusions 155
5.4 Experimental Section 156
5.5 References 159
[6] Chapter 6. Fluorodecarboxylation: Synthesis of Aryl Trifluoromethyl Ethers
(ArOCF
3
) and Thioethers (ArSCF
3
) 161
6.1 Introduction 162
6.2 Results and discussions 164
6.2.1 Fluorodecarboxylation of ArOCF
2
CO
2
H 164
6.2.2 Fluorodecaroxboxylation of ArSCF
2
CO
2
H 168
viii
6.2.3 Mechanism 170
6.3 Conclusions 171
6.4 Experimental Section 171
6.5 References 187
[7] Chapter 7. Water-soluble Organic Molecules for an All-Organic Redox Flow
Battery 190
7.1 Introduction 191
7.1.1 Redox Flow Battery (RFB) for Grid-Scale Energy Storage 192
7.1.2 Quinones for ORBAT 194
7.1.3 Focus of My Work 196
7.2 Results and discussion 198
7.2.1 Determination of transformations of
4,5-dihydroxybenzene-1,3-disulfonic acid 198
7.2.2 Alternative positive materials for acid based ORBAT 202
7.2.3 Unimolecular approach 213
7.2.4 Negative material based on acetyl benzene 216
7.2.5 Positive material for basic conditions 218
7.3 Conclusions 219
7.4 Experimental Section 220
7.5 References 233

ix
ABSTRACT
The dissertation comprises two main parts. First, fluoroalkylation methods are
presented, where development of selective fluoroalkylation methods using inexpensive
silicon reagent, Me
3
SiCF
3
along with the fluorodecarboxylation method to synthesize
ArXCF
3
(X = O, S) are discussed. Later, design and synthesis of small molecules for all-
organic redox flow battery (Chapter 7) is presented.
Chapter 1 describes the advancement in the area of selective difluoromethylation
and difluoromethylenation using silicon regents.
In Chapter 2, Direct N-difluoromethylation of imidazoles and benzimidazoles is
showcased using TMS-CF
3
(the Ruppert–Prakash reagent) under neutral conditions.
Difluoromethylated products were obtained in good-to-excellent yields. Inexpensive,
commercially available starting materials, neutral conditions, and shorter reaction times
are advantages of this methodology. Reactions are accessible through conventional as
well as microwave irradiation conditions.
In Chapter 3, Direct S-difluoromethylation of aryl and aliphatic thiols using the
Ruppert–Prakash reagent is demonstrated. The reaction produces
trimethylsilyldifluoromethyl sulfides, which upon cleavage with fluoride produces the
difluoromethyl sulfides. The key reaction features are the use of relatively inexpensive
and commercially available starting materials, shorter reaction times, ambient
temperatures, easy reaction procedure, and selective S-difluoromethylation in the
presence of -OH, -NH
2
and -CO
2
H functional groups. Furthermore, one-pot
tolylthiodifluoromethyl transfer to PhCHO is also demonstrated.
Chapter 4 describes a deoxygenative difluoromethylenation of carbonyl
compounds using readily available, inexpensive trifluoromethyltrimethylsilane, LiI, and
PPh
3
. The presence of the Li
+
ion prevents the unproductive exhaustion of
trifluoromethyltrimethylsilane (TMSCF
3
) by keeping the soluble free fluoride
concentration in the reaction medium under control. The strategy of combining solvents
to increase the reactivity and thereby reduce the reaction temperature and time is also
discussed.
x
Chapter 5 reports the development of a nucleophilic difluoromethylation of
aromatic aldehydes, acetophenone and benzophenone using the Ruppert-Prakash reagent
in the presence of triphenyl and tributyl phosphines.
Chapter 6 discusses fluorodecarboxylation of aryloxydifluoroacetic acids
(ArOCF
2
CO
2
H) and arylmercaptodifluoroacetic acids (ArSCF
2
CO
2
H) towards ArXCF
3

(X= O, S) using silver (I) salts in the presence of Selectfluor in a biphasic system with the
trifluoroacetic acid additive.
Chapter 7 introduces the all-organic redox flow battery for the grid scale electrical
energy storage applications. It also describes the challenges associated with the small
organic molecules used in the flow battery system. Some these challenges have been
addressed using new molecular design and synthesis. These new molecules have been
demonstrated in full electrochemical cells to demonstrate stable cell performance.
Further, this chapter also details the criteria that need to be considered during new
molecule design and synthesis for further improvement.

1

Chapter 1
Introduction to Silicon Based Reagents for
Difluoromethylation and Difluoromethylenation Reactions

2
1.1 Introduction
Approved drugs
1
and agrochemicals
2
with fluorine have been growing in number and the
pharmaceutical and agrochemical industries have embraced fluorine and related groups in their
product development programs.
3
The material industry is no exception.
4
For instance,
perfluorinated and partially fluorinated building blocks have been utilized to synthesize unique
fluoropolymers with applications seeded in every aspects of our life.
5
The methodology
development to selectively introduce fluorine is being studied more than ever before. Fluorine
has been introduced into organic molecules as fluorine or as fluoroalkyl moieties.
6
The
fluoroalkyl groups may be introduced using a building block approach or direct introduction of
the fluoroalkyl groups. Direct introduction of fluoroalkyl moieties has been extensively pursued
to introduce, CF
3
, CF
2
H, CFH
2
, OCF
3
, SCF
3
, CF
2
CF
3
and -CF
2
- groups.
The success of silicon-based reagents has been remarkable in the area of
trifluoromethylation, which can be attributed to the ease of handling and milder activation and
reaction conditions. Interest has grown in the area of pharmaceuticals for the selective
introduction of CF
2
H and -CF
2
- moieties as they are considered as bioisosteres of -OH and -O-
groups, respectively. However, development in this area has been gaining momentum only in the
last decade. Therefore, there is a plenty of room for research for new transformations and
reagents in this field. There has been some progress in the direct difluoromethylation (-CF
2
H)
3
and difluoromethylenation (-CF
2
-) using silicon-based reagents (Me
3
SiCF
2
X; X = F, Cl, Br, I, -
SO
2
Ph, CO
2
Et, CN, H, P(O)(OEt)
2
, CONR
2
). In this chapter, the recent developments of reagents
and related transformations in these areas are summarized. Furthermore, for the completeness of
the introduction, the methods developed during my Ph.D. are also briefly included in the
discussion with appropriate chapter numbers.
1.2 Trifluoromethyltrimethylsilane (1)
The area of nucleophilic trifluoromethylation has changed forever after the introduction
of trifluoromethyltrimethylsilane (Me
3
SiCF
3
), 1 (Ruppert-Prakash reagent).
7
Several methods
have been reported for the preparation of 1 using various fluoroalkyl sources
7a,8
including
fluoroform,
9
and is commercially available to purchase for less than one USD per gram.
10
The
versatility of 1 to generate the trifluoromethyl anion under moderate conditions has been well
exploited.
11
Furthermore, the direct use of Me
3
SiCF
3
to synthesize -CF
2
X (X = TMS, H)
containing useful building blocks has been gaining momentum and the recent developments are
discussed in this following subsection.
Formation of difluoromethylene from the trifluoromethyl group has been known from
their metal complexes such as tin, iron, mercury and germanium since the early 1960s.
12
Though
synthetic applications have been demonstrated using some of these reagents, instability and
toxicity associated with the reagents have made them less attractive. In this regard, the ease of
4
preparation and handling, air and moisture stability and the inexpensive nature of Me
3
SiCF
3
have
allowed the researchers to employ it broadly for many organic transformations.

Scheme 1 Reaction pathway of Me
3
SiCF
3
.
Me
3
SiCF
3
undergoes a facile cleavage of the Si-CF
3
bond in the presence of nucleophiles
leading to generation of trifluoromethyl anion, which has been characterized recently. Though
the fluoride elimination from the CF
3
anion is thermodynamically not favored (endothermic by
25 kcal/more), the kinetic instability of CF
3
anion under most conditions leads to α-elimination
of fluoride to provide the singlet ground state CF
2
carbene (Scheme 1).
13
The stability of the
singlet state (ca. 56 kcal/mol) over the triplet state is attributed to the back donation of electrons
from the fluorine lone pairs into the p-orbitals of the carbon.
14

Interestingly, in 2009, Dilman and co-workers in their attempt to synthesize TfOSiMe
3

from 1 and trifluoromethanesulfonic acid discovered the formation of difluoromethyltriflate as
the major product. Other perfluoroalkylsulfonic acids underwent similar reactions to provide the
corresponding CF
2
HOR
f
. They found Lewis acids such as TiCl
4
accelerated the rate of these
transformations. Such an unusual transformation was proposed to proceed via a concerted route
with the elimination of HF and Me
3
SiOTf yielding the difluoromethylene, which upon reaction
with TfOH leads to the TfOCF
2
H. However, such a transformation was discovered to be specific
Me
3
SiCF
3
Nu
[CF
3
]
-
F
-
+
: CF
2
1
5
only to superacids. Therefore, the first published difluoromethylene transfer to construct useful
building blocks from 1 was reported only after two decades of its preparation. In 2011, the
Prakash and Hu groups demonstrated practical difluorocyclopropanation of alkenes in the
presence of catalytic amount of either NaI or TBAT (Scheme 2).
15
The difluorocyclopropenation
of alkynes was achieved at 110 °C with excess NaI. This report allowed the preparation of
several gem-difluorocyclopropanes and gem-difluorocyclopropenes. Later, Charatte et al.
showcased these processes in a flow system.
16
These protocols mostly used electron rich alkenes
and alkynes as starting materials.

Scheme 2 Difluorcyclopropanation and difluorocyclopropenation using 1.
Bruin and Dzik reported that n-butyl vinylester could be cyclopropanated to yield 40% of
the expected product in the presence of a phorphyrin Co complex (Scheme 3).
17

Scheme 3 Transition metal catalytic approach.
R
R'
R''
R'''
NaI (20 mol%), 65
o
C, 2h, THF
TBAT(5 mol%), -50
o
C to rt, 5 h, THF
or
R
R'
R''
R'''
F
2
C
R
R'
NaI, 110
o
C, 2h, THF
F
2
C
R
R'
+ 1
+ 1
16 examples
79-94% yield
12 examples
68-99% yield
A
B
N
N
N
N
Co
Ph
Ph
Ph
Ph
O
On-Bu
+
1
20 mol% NaI, THF, rt
5 mol%
O
On-Bu
F
2
C
40%
6
Following the cyclopropanation, Prakash and coworkers found that the difluoromethylene
can also be generated in polar solvents such as DMA or NMP in the presence of CaI
2
to achieve
a σ-bond insertion of Sn-H bonds, which provided R
3
SnCF
2
H compounds (Scheme 4).
18
The n-
Bu
3
SnCF
2
H was employed as a difluoromethyl coupling partner with aryl and vinyl halides (Br,
I). This reaction was found to proceed with sub-stoichiometric amount of CuI in Lewis basic
solvents. Such solvents were found to be crucial for the success of the transformation as they
were proposed to stabilize the CuCF
2
H species.

Scheme 4 Difluoromethylene insertion of Sn-H σ-bonds.
Although in these protocols (vide supra), the difluoromethylene has been successfully transferred
to prepare useful building blocks and reagents, utilization of the Ruppert-Prakash reagent to
transfer the difluoromethylene to acidic proton containing substrates has not been shown until
the difluoromethylene generation from 1 using LiI in ethereal solvents such as diglyme or
R
3
SnH + 1
CaI
2
, DMA
45-50
o
C, 2h
R
3
SnCF
2
H
R = n-Bu (80%), Me(54%), Cy (57%), Ph (54%)
X
I
R
or
Ar
X'
n-Bu
3
SnCF
2
H, DMA, KF
CuI, KF, 100-120
o
C, 24h
X = CH, N; X' = I, Br
X
CF
2
H
R
or
Ar
CF
2
H
CF
2
H
p-CHO, 61%
o-CHO, 70%
p-Ac, 74%
o-Ac, 71%
o-CN, 65%
p-Br, 51%
N CF
2
H
60%
N CF
2
H
Br
75%
R
R
CF
2
H
Br Br
CF
2
H
68%
72%
Ph
Ph Ph
CF
2
H
32%
A
B
7
triglyme at elevated temperatures. (For detailed discussion see Chapter 2). Using such
approaches N-difluoromethyl imidazoles and benzimidazoles were synthesized under neutral
conditions (Scheme 5).
19
Interestingly, N-difluoromethylated caffeine and isocaffein were also
synthesized. This was the first example where the difluoromethylene generated from 1 in the
presence of acidic protons such as N-H underwent a reaction to provide the N-CF
2
H products.
The authors argue that the Li
+
prevents run-away reactions by controlling the free fluoride in the
reaction mixture. This method led to the preparation of N-difluorocaffeine and N-
difluoroisocafeine from theophylline in 67% total yield.

Scheme 5 N-Difluoromethylation of nitrogen heterocycles.
Mikami and co-workers reported that lithium enolates generated using 1:1
LiHMDS/MeLi underwent an α-siladifluoromethylation in the presence of 1 at -78 °C.
20
Later,
the Prakash group reported that the both aromatic and aliphatic thiols underwent
trimethylsiladifluoromethylation in the presence of LiH/LiBF
4
. The products were easily
hydrolyzed using aqueous fluoride to provide the difluoromethyl thioethers (Covered in Chapter
mw, 1.5-2 h or (41-90 %)
Conventional heating 3 h (35-97 %)
N
N
R R'
CF
2
H
N
H
N
R R'
LiI (0.9 eq), Triglyme, 170
o
C
or
N
N
N
N
N
N
N
N
CF
2
H CF
2
H
Me
O
Me
O
Me
O
Me
O
40% 27%
N
N
CF
2
H
O
2
N
N
N
N
CF
2
H
12 examples
22% 75%
N-difluorocaffeine N-difluoroisocaffeine
8
3). This served as a further evidence to support that the Li
+
does control the fluoride ion
reactivity in these reactions.
21
However, the protocol failed to provide the expected product with
electron deficient thiols such as 4-nitrothiophenol. Based on these observations, the authors
proposed a 1-2 migratory substitution of the thiolate and a Li
+
assisted fluoride elimination to
yield the ArSCF
2
TMS product. Very recently, the siladifluoromethylation of boryllithium was
achieved at -78 °C from 1.
22

1,1-Difluoroolefins are valuable synthetic intermediates and new methods are being
developed to access them. A common approach is to use carbonyl compounds as starting
materials to carry out Wittig-type olefination. However, these methods face several challenges
such as higher operating temperatures, low reactivity with diarylketones, and poor reaction yield
with enolizable carbonyl compounds. Hu and colleagues employed diaryldiazocompounds along
with 1 in the presence of a catalytic amount of CuI and CsF to access a variety of the
corresponding gem-difluoroolefins (Scheme 6).
23
Later they discovered that the direct coupling
of electrophilic difluoromethylene generated from 1 in the presence of NaI, with nucleophilic
diazocompounds occurs under transition metal free conditions (Scheme 6), rendering access to
several other gem-difluoroalkenes from diazoacetates and diaryldiazomethanes.
24

9

Scheme 6 gem-Diflouoroolefins from diazo compounds.
Recently, Prakash and coworker demonstrated the direct synthesis of various gem-
difluoroalkenes from aromatic and enolizable aldehydes and ketones using 1 (Scheme 7), which
is covered in detail in Chapter 4.
25
In these protocols, a mixed solvent approach was employed
to affect the temperature at which the diflurocarbene was generated. For example, aromatic
aldehydes were reacted at 120 °C in 8% DMF/dioxane, where as the sensitive and enolizable
aldehydes and ketones were reacted at 45 °C in 30% DMF/toluene. Under both conditions, the
aryl ketones performed poorly. However, typically no trifluoromethylation was observed at the
elevated temperatue conditions, and only traces of trifluoromethylation products were seen at
lower temperatures. Under similar conditions, in the presence of LiBF
4
, TMS protection of the
phosphonium intermediate was observed, which was subsequently hydrolyzed to achieve
nucleophilic difluoromethylation of aromatic the aromatic aldehydes using 1 (for detailed
discussing see Chapter 5).
26

1
Ar
N
2
Ar'
Cat. CuI/CsF
Ar
CF
2
Ar'
Ar
N
2
X
NaI
(X = CO
2
Et, Ar)
Ar
CF
2
X
CO
2
Et
CF
2
R
MeO 82%
Br 64%
CF
3
50%
A
B
CF
2
X X
Br 84%
Cl 75%
F 95%
75%
69%
67%
B
X
A
R A
24 examples
48-86% yields
40 examples
14-97% yields
10

Scheme 7 gem-Difluoromethylenation of carbonyl compounds using 1.
1.3 (Difluoromethyl)trimethylsilane (Me
3
SiCF
2
H)
Tyutyunov and co-workers were aspiring to prepare NaBH
3
CF
3
by treating the Ruppert-
Prakash reagent with sodium borohydride in THF and to their surprise, 1 underwent a
monodefluorinative reduction to yield 2 (Scheme 8).
27
A higher yield of the product was
achieved, when the reaction was carried out in diglyme. The authors warn that though the use of
equimolar amount of NaBH
4
results in higher yield (80%), fire incidents were observed during
distillation. However, owing to the simplicity of the reduction protocol over other reported
methods for the preparation of 2,
28
the procedure has been widely employed to access
difluoromethyltrimethylsilane. Furthermore, 2 can also be commercially sourced.

CF
2
CF
2
N
Me
CF
2
CF
2
F
2
C
H
H
H
H
Si
CF
3
Me
Me
Me
+
82%
CF
2
83%
CF
2
R
MeO = 61%
Ph = 76%
Cl = 90%
Br = 88%
I = 76%
NC = 78%
O
2
N = 55%
F
3
C = 79%
R yield
R' R
O
R' R
CF
2
Conditions A = PPh
3
, LII, 8% DMF/dioxane, 120
o
C, 24h
34 examples
9-90% yields
Conditions A & B
Conditions B = PPh
3
, LII, 30% DMF/dioxane, 45
o
C, 40h
Br
CF
2
82%
43% 45%
CF
2
tBu
52%
CF
2
Me
2
N
60% 46% (with n-Bu
3
P)
56%
1 Me
3
SiCF
2
H
NaBH
4
, dioxane
rt, 2h
2, 70%
11
Scheme 8 Reduction of 1.
1.3.1 Nucleophilic addition
With one less fluorine atom, Me
3
SiCF
2
H is less Lewis acidic and less reactive to
nucleophiles compared to the Ruppert-Prakash reagent. In 1995, Fuchikami et al. reported that 2
required higher reaction temperatures (≈100 °C) in order to transfer the difluoromethy group to
aldehydes and ketones using a KF/DMF combination.
29
The yields from aromatic aldehydes,
enalizable aldehydes and enolizable ketones were observed to be excellent, moderate and low,
respectively. Further investigation on nucleophilic difluoromethylation from 2 was ignored until
Hu and co-workers reported that the KF/DMF allowed the reaction to take place efficiently at
ambient temperature in the presence of 18-crown-6 to complexed with the K
+
counter cation.
30

Similar results were obtained when CsF and TBAT were used as initiators (Scheme 9, A).
Aromatic aldehydes provided excellent yields of products ranging from 67-96%, whereas with
the enolizable aldehydes, the yields were lower than 50%. In the case of less reactive substrates,
such as diarylketones, resulted in an irreversible difluoromethylation of the solvent, DMF, was
observed under these conditions. Therefore, they investigated O-initiators such as KOt-Bu in
THF for less reactive ketones and N-tert-butylsulfinyl imines with success at -78 °C (Scheme 9,
B). In the case of sulfinylamines, the observed diastereoselectivity was high. However,
enolizable ketones failed to react due to competing enolization and condensation reactions.
12
Michurin et al. employed HMPA (hexamethylphosphoramide) or DMPU (N,N’-
dimethylpropyleneurea) in THF to minimize the enolization and improve the solubility of CsF in
THF, which proved effective in the nucleophilic difluoromethylation of enolizable ketones albeit
in moderate yields.
31
The Si-CF
2
H bond of 2 has also been shown to be cleaved by superbases,
leading to the development of organocatalytic difluoromethylation of primarily aromatic and
heteroaromatic aldehydes, whereas the enolizable aldehyde and less reactive diarylketone
resulted in moderate yields.
32
Mikami and co-workers employed a t-BuOK/EtOK mixture in
THF at room temperature to difluoromethylate diethyloxalate towards the preparation of
difluoromethyl pyruvate, which they utilized as a building block for the preparation of chiral
tertiary difluoromethyl group containing alcohols.
33

Scheme 9 Nucleophilic difluoromethylation using 2.
Furthermore, the CsF in DMF was also employed for the preparation of β-amino α-
(difluoromethyl)alcohols.
34
Very recently, Hu and co-workers found that using CsF/18-crown-6
RCHO
R = aryl and alkyl
+ 2
1) CsF, DMF, rt, 9h
2) TBAF, rt, 1h
R
CF
2
H
OH
Ar Ar
O
S
O
N R
H
2, t-BuOK, THF
-78
o
C to rt
Ar Ar
OH
CF
2
H
S
O
N
H
R
CF
2
H
12 examples
50-96% yield
3 examples
80-96% yield
8 examples
68-95% yield
A
B
dr (ca.) = 9:1
R =
Br N Ph
O
t-Bu-
87% 68% 88%
90% 90%
dr = 92:8 90:10) 80:20 91:9 92:8
13
in dimethoxyethane allowed difluoromethylation of enozliable ketones with 2 at room
temperature (Scheme 10). Interestingly, the reactivity towards enolizable ketones has been
shown to significantly affected by the counter cation of the initiating base (Cs
+
>K
+
>Na
+
). In their
elegant work, they were able to characterize the bis(difluoromethyl)trimethyl silicate, a
pentavalent carbon bonded silicon species by NMR spectroscopy.
35

Scheme 10 Nucleophilic difluoromethylation in presence of 18-Crown-6.
1.3.2 Nucelophilic substitution
Analogous to the Ruppert-Prakash reagent, difluoromethyl group from 2 can be
transferred to the sulfur atom of the disulfides to synthesize difluoromethyl thioethers.
36

1.3.3 Nucleophilic difluoromethylation of electron deficient heterocycles.
Larionov and co-workers observed a site selective transfer of difluoromethyl group on to
quinoline-N-oxides with limited efficacy using excess t-BuOK and 2 at -20 °C in THF.
37
Shibata
and co-workers reported nucleophilic difluoromethylation of isooxazoles that contain electron-
withdrawing groups (Scheme 11).
38

O
R
R'
R = Me, Et, Pr; R'= NO
2
, CO
2
Me, Br, NMe
2
; X = N
HO
R
R'
CF
2
H
+ 2
1) CsF/18-crown-6, DME, rt
2) TBAF, rt, 1h 3) HCl, rt, 1h
28 examples
37-98% yield
Examples also include
N
Bn
HO
CF
2
H
N
OH
CF
2
H
Ph CF
2
H
OH
82%
55%
Ph Ph
HO
CF
2
H
65% 50%
14

Scheme 11 Nucleophilic difluoromethylaiton of heterocycles.
1.3.4 Metal mediated cross coupling

Scheme 12 Metal mediated/catalyzed cross coupling approach.
The Hartwig group following their success of copper mediated trifluoromethylation of
aryl iodides, developed copper mediated difluoromethylation of aryl and vinyl iodides using 2
(Scheme 12). In this report, electron rich and neutral aryl iodides reacted smoothly in the
presence of CuI and CsF in NMP at 120 °C with 2 to provide variety of difluoromethylated
O
N
EWG
R'
R''
O
N
R''
R' = aryl, styryl; R'' = Me, Ph; EWG = NO
2
, SO
2
CF
3
, SO
2
Ph
1) 2, Me
4
NF, DMF, rt, 4h
HF
2
C
R'
EWG
2) HCl, rt, 30 min
14 examples
28-53% yield
Ar-X ArCF
2
H
[Cu] or [Pd]
2, initiators
X = I, Br, N
2
+
Hartwig [ref. 39]
tBu
CF
2
H
N
CF
2
H
COtBu
CF
2
H
NEt
2
CF
2
H
OCOtBu
60% 53% 76% 69%
Quing [ref. 40]
CF
2
H
EWG
EtO
2
C 80%
O
2
N 78%
NC 82%
iPrO
2
S 80%
EWG
N N
CF
2
H CF
2
H
70% 93%
Shen [ref. 42]
Et
2
NOC
CF
2
H
N
CF
2
H BnO
N
S
CF
2
H
OMe
65% 77% 58%
Sanford [ref. 43]
N
CF
2
H
CF
2
H
PhO
78%
66%
MeO
OMe
MeO
CF
2
H
68%
Goossen [ref. 41]
CF
2
H
R
R
NC 67%
O
2
N 83%
Me
2
N 84%
AcNH 76%
MeO
2
C 72%
PhCO 71%
N
Et
HF
2
C
HN
CF
2
H
78%
35%
15
arenes, containing functional groups such as amines, amides, alkoxy and -Br.
39
However, when
the electron deficient aryl iodides were reacted under these conditions, they underwent proto-
dehalogenation, limiting the scope of the protocol. Complementing the Hartwig’s method, the
Qing group accomplished difluoromethylation of electron-deficient aryl and heteroaryl iodides
by employing phenenthroline ligand and t-BuOK as an initiator at ambient temperature in
DMF.
40
The copper mediated chemistry developed was also utilized for the difluoromethylation
of diazonium salts, containing electron withdrawing and electron donating substituents, which
delivered difloromethylarenes in good to excellent yields at room temperature in DMF.
41
In these
transformations, CsF was employed to activate the Me
3
SiCF
2
H. Yang et al. achieved
difluoromethylation of aryl iodides as well as aryl bromides by employing dual catalysts based
on Pd and Ag, where they used t-BuONa base to activate 2 at 80 °C in dioxane or toluene.
42

Catalytic protocol has been demonstrated using copper NHC complexes, where the 2 is activated
at 120 °C in a 3:1 dioxane/toluene mixture using CsF.
43
Several other protocols to access
difluoromethylarenes using various other reagents have also been pursued.
44

1.3.5 Oxidative coupling of terminal alkynes
Qing and co-workers demonstrated that the terminal alkynes can be oxidatively coupled
with the –CF
2
H group derived from 2 using an equimolar amount of copper iodide and slight
excess of 9,10-phenanthraquinone as an oxidant in the presence of excess base, t-BuOK.
45
The
16
protocol proceeded at 0° – rt, tolerating electron-withdrawing groups as well as electron-
donating groups on the substrates. In their
19
F NMR experiments, the authors observed two
signals at −110.8 ppm (d, J= 45.3 Hz) and −116.9 ppm (d, J= 44.2 Hz), which they assigned to
CuCF
2
H and [Cu(CF
2
H)
2
]
-
species, respectively.
46
It is worth noting that the fully structurally
elucidated NHCCuCF
2
H appears at -119 ppm (d, J= 44.2 Hz).
43
Based on these observations, the
authors proposed the following mechanism (Scheme 13).

Scheme 13 Oxidative coupling with terminal alkynes.
Post-functionalizable difluoromethyl transfer reagents
Silicon based functional groups containing difluoromethylene transfer reagents are highly
attractive. Such groups can be easily modified further to build on other structural motifs that
contain the difluoromethylene group. In this regard, several reagents have been prepared and
their reactions are being explored. The topic is briefly reviewed by Dilman et al.
47
This section
describes the latest development with the TMSCF
2
X (X = Cl, Br, I, SPh, SO
2
Ph, P(O)OEt
2
, CN,
CONR
2
) type reagents.
1.4 (Chlorodifluoromethyl)trimethylsilane (Me
3
SiCF
2
Cl, 3)
2 t-BuOK +
CuI
CuCF
2
H Cu(CF
2
H)
2
-
R CuCF
2
H
Oxidant
R CF
2
H
R KOt-Bu
17
Originally the title compound was synthesized in a 20% yield by transfer of a CF
2
Cl
group to TMSCl from ozone depleting CF
2
BrCl.
48
Later, higher yield was achieved when
aluminum was employed as a reducing agent in place of P(NEt
2
)
3
.
49
Furthermore, other methods
have also been developed using non-ozone depleting starting materials.
50

Similar to the Ruppert-Prakash reagent, 3 undergoes nucleophilic addition to
electrophiles such as aldehydes and ketones in the presence of TBAF to provide
chlordifluoromethyl containing alcohols. It was found that TBAF performed better than KF or
CsF and the reactivity can be further improved by employing polar solvents such as NMP.
49

Dilman and co-workers reported nucleophilic chlorodifluoromethyl addition to iminium ions in
DCM using Lewis bases such as HMPA as additives along with stoichiometric excess of n-
Bu
4
NCl.
51
At elevated temperature (110 °C), Me
3
SiCF
2
Cl generates singlet difluoromethylene in
the presence of catalytic amount of n-Bu
4
NCl, which undergoes [2+1] cycloaddition with alkene
and alkynes.
52
gem-Difluoroolefins from aromatic aldehydes, 3-phenypropanal and activated
ketones were prepared using 3 in the presence of triphenylphosphine at temperatures between
70-80 °C in THF.
50

1.5 (Bromodifluoromethyl)trimethylsilane (Me
3
SiCF
2
Br, 4)
Methods based on silicon reagents are replacing the ozone depleting CF
2
Br
2
for the
convenience and higher yields.
48,49
For example, 1 can be directly treated with BBr
3
to obtain
18
52% of the title compound, whereas the Me
3
SiCF
2
H can be brominated using radical bromine
sources such as NBS to obtain 4 in 75-80% yield.
53,54

Scheme 14 First example of direct nucleophilic bromodifluoromethylation.
Though 4 was reported in 1990, unlike the Ruppert-Prakash reagent and Me
3
SiCF
2
Cl, the direct
nucleophilic transfer of CF
2
Br using initiators such as fluoride from the corresponding silicon
reagent to electrophiles such as aldehydes was reported to be unsuccessful, except for one select
example (Scheme 14).
55
Such a behavior is attributed to the ability of the CF
2
Br anion to readily
α-eliminate bromide to form the singlet difluoromethylene under the reaction conditions.
56

However, Dilman and co-workers showed that using excess bromide in the reaction mixture
allowed the transient BrCF
2
anion to be available for nucleophilic bromodifluoromethylation of
aromatic and nonenolizable aldehydes.
57
The excess bromide is proposed to combine with
difluoromethylene to push the equilibrium towards the BrCF
2
anion, which was confirmed by
treating the Ruppert-Prakash reagent with excess LiBr in the presence of benzaldehyde providing
the bromodifluoromethylated alcohol. In a similar approach, NaI and LiBr were used along with
4 to synthesize iododifluoromethylated alcohols from mainly nonenolizable aldehydes (Scheme
15, A).
58
The nucleophilic transfer of -CF
2
Br group has also been achieved with RSeCl to
N
N
O
O
O
TBAF
N
N
O
O
OSiMe
3
CF
2
Br
4 +
19
synthesize RSeCF
2
Br, which was employed as an electrophilic -SeCF
2
Br group transfer
reagent.
59
Recently, 4 was successfully employed in the presence of triphenylphosphine to
synthesize difluoromethylated alcohols and β-difluoromethylated nitro compounds from ketones
(Scheme 15, B) and nitroalkenes (Schme 15, C), respectively.
60

Scheme 15 Nucleophilic difluoromethylation of aldehydes.
The fast degradation process of the BrCF
2
anion formed from 4 allows efficient generation of
singlet difluoromethylene under mild base free conditions, which has been well exploited by the
Hu and Dilman groups to develop various difluoromethylene mediated processes. For instance,
Hu and co-workers utilized Me
3
SiCF
2
Br to generate singlet difluoromethylene under base free
conditions to access difluorocyclopropanes and difluorocyclopropenes using a catalytic amount
Me
3
SiCF
2
Br
Br
-
BrCF
2
:CF
2
+ Br
-
O
R
+
Li
+
-Me
3
SiBr
R CF
2
Br
OSiMe
3
Me
3
SiBr
4
A 11 examples; 77-96% yields
Ar R
O
NO
2
R'
4, PPh
3
. DMPU
CH
3
CN
Ar
TMSO
R
F
F
PPh
3
Br
aq. KOH
rt, 2h
Ar
OH
CF
2
H
R
OH
CF
2
H
X'
CF
2
H
OH
R
R yields
Br 84%
O
2
N 80%
NC 98%
MeO 80%
X' = O (90%); S (82%)
B 11 examples; 54-98% yields
C 15 examples; 72-96% yields
4, PPh
3
, DMPU
CH
3
CN, rt
R''
N
R'
R''
OTMS
O Ph
3
PF
2
C
1) TMSCl
2) Pyridine,
H
2
O, 80
o
C
NO
2
R'
R''
CF
2
H
eg.
NO
2
CF
2
H
R
R yields
H 91%
MeO 86%
Cl 92%
F 96%
NC 82%
20
of n-Bu
4
NBr in toluene at 100 °C, whereas under basic conditions, the heteroatom (O, N, S and
P) nucleophiles were readily difluoromethylated in a biphasic reaction medium (DCM/20% aq.
KOH or 10% aq. K
2
CO
3
) at 0 °C.
53
Analogous to 1, 4 has also been utilized as a
difluoromethylene source to synthesize gem-difluoroalkenes from diazo acetates as well as
diazirines.
24
The requirement of milder conditions for bromodifluoromethylation of iminium ions
was fulfilled by employing a Lewis base (HMPA) as an additive.
51

The singlet CF
2
generated from 4 has been added across silylenol ethers to obtain the
siloxydifluorocyclopropanes,
61,62,63
which are useful building blocks via their ring opening
processes. For instance, when the products were exposed to aqueous HBr/AcOH or NXS (X= Br,
I) the corresponding difluorohomologated ketones
61
or β-halo difluorohomologated ketones
62

were obtained, respectively. The carbene chemistry of 4 was also utilized to prepare
difluoromethylene containing dithiocarbamates
64
(Scheme 16) as well as S-difluoromethyl
dithiocarbamates.
65

Scheme 16 S-Difluoromethyl dithiocarbamate synthesis.
R
O
R'
+ 4 +
N
SK
S
R
HO
R'
F
S
F
S
N
0
o
C
CH
3
CN
21
The efficient procedure for generating the difluoromethylene from 4 has been utilized to
couple with diazocompounds to synthesize gem-difluoroalkenes,
24,66
to prepare difluoromethyl
ethers from aliphatic alcohols under mild conditions.
67

A difluoromethylene dianion synthon, Me
3
SiCF
2
ZnBr, has been prepared in the presence
of a cobalt catalyst from Me
3
SiCF
2
Br and i-PrZnI and its utility has been efficiently showcased
by performing copper-mediated allylation, followed by the fluoride catalyzed cleavage of Si-CF
2

to carry out nucleophilic addition to aldehydes (Scheme 17).
68
The copper-mediated Michael
type addition of Me
3
SiCF
2
ZnBr to arylidenes of Meldrum’s acids has also been achieved.
69

Scheme 17 Difluoromethylene dianion synthon from 4.
Difluoromethylene generated from 4 using NaOAc underwent insertion into several organozinc
reagents to form difluorohomologated zinc products, which underwent allylation
70
and
nitrosation
71
in the presence of a CuI/phenethroline catalyst and a n-BuONO/TMSCl mixture,
respectively to provide the corresponding products (Scheme 18).

Scheme 18 Difluoromethylene zinc compounds and related reactions.
i-PrZnI
1% CoBr
2
.dppe
Me
3
SiCF
2
ZnI
CuCN
Cl
Me
3
SiCF
2
RCHO
CsF
F
OSiMe
3
R
F
4
RZnBr
4, NaOAc
RCF
2
ZnBr
RCF
2
NO (32-75%)
R
F
F
n-BuONO
TMSCl
CH
3
CN, -20
o
C
CuI/Phen (10%)
allyl halides
R'
R''''
R'''
R''
DMF (2 equiv), -25
o
C
10 examples
15 examples
(66-90%)
22
1.6 (Iododifluoromethyl)trimethylsilane (Me
3
SiCF
2
I, 5)
Dilman et al. prepared the title compound by a cobalt-catalyzed zincation of Me
3
SiCF
2
Br
and quenching the corresponding Me
3
SiCF
2
ZnBr with iodine to obtain Me
3
SiCF
2
I in 70% yield,
which was used for nucleophilic iododifluoromethylation of aromatic aldehydes (Scheme 19).
57

Scheme 19 Nucleophilic iododifluoromethylation
1.7 [Difluoro(phenyl-thio)methyl]trimethylsilane (Me
3
SiCF
2
SPh, 6)

Scheme 20 General reaction pathways of 6.
The title compound was easily prepared by reducing bromodifluoromethylphenyl sulfide,
which was obtained by treating sodium thiophenalate with CF
2
Br
2
, using Mg in the presence of
Me
3
SiCl.
72
Similar to other perfluoroalkylsilicon reagents, Me
3
SiCF
2
SPh transferred the -
CF
2
SPh moiety to carbonyl compounds in the presence of a catalytic amount of fluoride (Scheme
20).
73
The sulfur based radical and oxidation chemistry allows post-transfer modifications of the
products making 6 a valuable reagent for the preparation of difluoromethylene containing
compounds. Pohmakotr and co-workers have been extensively studying the reactions of
Me
3
SiCF
2
SPh with a variety of electrophiles and their subsequent chemistry to prepare useful
Me
3
SiCF
2
I
I
ICF
2
:CF
2
+ I
-
O
Ar
+
Li
+
-Me
3
SiI
Ar CF
2
I
OSiMe
3
Me
3
SiBr
4
5 examples
75-98% yields
Me
3
SiCF
2
SPh
F
-
[PhSCF
2
]
-
E
+
PhSCF
2
E CF
2
E radical
6
23
products; and their work along with development in this area until 2014 has been reviewed in an
account recently.
74
More recently, the authors have reported the nucleophilic transfer of -CF
2
SPh
to nitrones for the preparation of CF
2
containing polyhydroxypyrrolizidines and -indolizidines
75

and to the Diels-Alder adducts of maleic anhydride with cyclopentadiene and cyclohexadiene,
which were further modified to offer novel difluoromethylene containing polycyclic cage
structures.
76
A radical cascade sequence leads to the formation of difluoromethylene containing
linear triquinanes.
77
Prakash et al. have observed that the Me
3
SiCF
2
SAr formed directly from
lithium thiophenolate and the Ruppert-Prakash reagent in the presence of LiBF
4
is able to
transfer –CF
2
SAr to electrophiles such as benzaldehyde in the same pot (Scheme 21).
21

Scheme 21 One-pot approach for –CF
2
SAr transfer.
1.8 (Phenylsulfonyl)difluoromethylsilane (Me
3
SiCF
2
SO
2
Ph, 7)
Me
3
SiCF
2
SO
2
Ph was first obtained by the oxidation of Me
3
SiCF
2
SPh with m-
chloroperbenzoic acid,
28c
later by treating the bromodifluoromethylphenyl sulfone with n-BuLi
and Me
3
SiCl.
78
The Lewis base mediated cleavage of Si-CF
2
allows transfer of CF
2
SO
2
Ph to
electrophilies such as carbonyl compounds,
78,79
in situ formed iminium ions,
80
alkyl halides,
81

hypervalent iodine (III) compounds,
82
boranes,
83
and RSe-Cl compounds (Scheme 22).
59
A
SH
1) 4 Å MS, DMF, LiH,
1, LiBF
4
, RT, 15 min
2) PhCHO, 12 h, RT
S
Me
F
F
Ph
OTMS
62 %
Me
24
CuCF
2
SOPh compound was readily prepared and coupled with alkynyl halides.
84
A new
electrophilic reagent to transfer SCF
2
SO
2
Ph has been recently prepared from the title
compound.
85
The Mg-mediated reductive desulfonylation of the derivatives readily offers the
difluoromethyl group containing substrates.
8

Scheme 22 General reaction pathways of 7.
1.9 Diethyl (difluoro(trimethylsilyl)methyl)phosphonate (Me
3
SiCF
2
P(O)OEt
2
, 8)
Burton synthesized 8 from bromodifluoromethyphosphonate mediated by Cd in the
presence of Me
3
SiBr in 25% yield.
86
Further improvement in the yield of 8 has been achieved
using the debromination of bromodifluoromethylphosphonate using Mg
80
or n-BuLi,
87
or the
deprotonation
88
of difluoromethylphosphonate in the presence of Me
3
SiCl.

Scheme 23 General reaction pathways of 8.
Similar to other Me
3
SiR
f
compounds, 8 is easily activated to transfer the difluoromethyl anion to
electrophiles in the presence of Lewis bases such as fluoride (Scheme 23). Obayashi and co-
workers reported that the base free transfer of CF
2
P(O)OEt
2
from 8 proceeded efficiently
compared to the lithium anion generated using LDA from HCF
2
P(O)OEt
2
.
89
Subsequently, -
F
-
Ph
S
O
CF
2
-
O
Ph
S
O
C
F
2
O
E
E
+ Mg
H
+
ECF
2
H 7
P
EtO
EtO
CF
2
O
F
- E
1
+
P
EtO
EtO
CF
2
E
1
O
E
2
CF
2
E
1
E
2
if E
1
carbonyl electrophile
initiator/H
2
O
8
25
CF
2
P(O)(OEt)
2
anion transfer to carbonyl compounds,
90
in situ generated iminium ions,
80b,91

pinacolborane,
83
trimethoxyborate
92
and N-tert-butanesulfinyl imines has been achieved.
93
The
nuclephilic transfer chemistry has been widely utilized by O’Hagan and others for the
preparation of difluoromethylene containing phosphate analogs and biologically relevant
molecule syntheses.
94

Qing and co-workers have reported copper mediated coupling of 8 with terminal
alkynes
95
and arylboronic acids.
96
Hypervalent iodine substrates have been successfully
employed to synthesize aryl, heteroaryl, vinyl and alkynyl difluoromethyl phosphonates by
Poisson and colleagues.
97
They also demonstrated a Sandmyer type method for aryl phosphonate
synthesis.
98
One select example of direct C-H difluormethylphosphorylation of p-xylene has
been shown with a silver system.
99

1.10 Ethyl difluoro(trimethylsilyl)acetate (Me
3
SiCF
2
CO
2
Et, 9)
The -CF
2
CO
2
Et group is considered a useful and a versatile difluoromethylene-containing
moiety, as it can be transformed into other useful fluorine containing groups by the carboxylic
acid and ester chemistry.
A reductive dehalogenative silylation approach has been a primary method to synthesize
the title compound from commercially available starting materials (Scheme 24),
100
compared to
the deprotonation approach.
101
Furthermore, the CF
2
CO
2
Et moiety has been shown to be an
26
effective precursor to install CF
2
X (X= F, Cl, Br, I, H) groups, based on post-decarboxylative
approaches.

Scheme 24 General methods for the preparation for 9.
Biran and co-workers showed, after their multigram electrochemical preparation, that 9
smoothly reacted with aldehydes and ketones in the presence of 5mol% KF,
100b
whereas ester
and acyl chloride required stoichiometric amounts. Mukaiyama and co-workers found that
LiOAc catalytically activated Me
3
SiR
f
(R
f
= CF
3
, CF
2
CF
3
& CF
2
CO
2
Et) in their reactions with
N-tosylimines,
102
while the activation of 9 with KF required more than stoichiometric amounts
(Scheme 25).
103

Scheme 25 Nucleophilic addition to imines.
An oxidatively generated iminium ion of tetrahydroisoquinoline smoothly underwent
nucleophilic addition with 9 in the presence of KF to provide ethoxycarbonyldifloromethylated
tetrahydroisoquinoline (Scheme 26).
91

XCF
2
CO
2
Et
Reduction
Me
3
SiX' (X' = Cl, Br)
Me
3
SiCF
2
CO
2
Et
(X = F, Cl, Br) 9
N
Ph
Ph
9
1) KF (1.1 equiv), HMPA
2) H
3
O
+ NH
Ph CF
2
CO
2
Et
25%
N
Ph
Ts
1) 10 mol% LiOAc, DMF, rt
2) H
3
O
+
+
NH
Ph
Ts
CF
2
CO
2
Et
85%
Ph
27

Scheme 26 Nucleophilic addition to in situ formed iminium ions.
Amii and co-workers demonstrated copper-mediated cross-coupling reactions of
Me
3
SiCF
2
CO
2
Et with aryl iodides containing electron-withdrawing, and electron rich substrates.

100c,104
The resulting esters were hydrolyzed and metal fluoride (KF or CsF) assisted proto-
decarboxylation was performed at 170 °C to obtain several aryldifluoromethyl compounds
containing electron-withdrawing groups. However, substrates with halo and phenyl moieties
required higher temperature (200 °C) for decarboxylation, whereas electron-rich substrates failed
to decarboxylate even at 200°C. Under the silver mediated reaction conditions, the 4-substituted
aromatic triazenes underwent a direct C-H ethoxycarbonyldifluoromethylation primarily at the
ortho position, however, a mixture of mono and disubstitution products was also observed
(Scheme 27). This was attributed to the use of excess 9 and the non-homogenous nature of the
reaction medium.
105
In an interesting communication, silver mediated hydrodifluoromethylation
of unactivated alkenes has been reported. The reaction mixture contained an oxidant as well as a
reductant. It is proposed that the hypervalent iodine compound mediates formation of the
ethoxycarbonyldifluoromethyl radical to add across the alkene, the resulting radical based on
N
Ph
DDQ, CsF
THF, rt, 24h
9 + N
Ph
CF
2
CO
2
Et
N
Ph
Mechanism
EtO CF
2
O
+
F -Me
3
SiF
DDQ
-DDQH
75%
28
alkene is further oxidized to a carbocation, which accepts an hydride from Hantzsch ester to
yield the product (Scheme 28).
106
The reaction condition tolerated amides, esters, heterocycles
and keto groups. Under similar conditions, by placing the activated alkenes on the aromatic ring
(eg. N-phenylmethacrylamide), several ethoxycarbonyldifluoromethyl containing oxindoles were
synthesized.
107
Mechanistically, the alkene based radical intermediate formed by the attack of
CF
2
CO
2
Et radical closes the ring to form an aryl radical, which further undergoes oxidation to
form an arenium ion and a deprotonation to rearomatize to the aryl system. Furthermore, the
silver mediated chemistry has also been employed for the direct C-H
ethoxycarbonyldifluoromethylation of arenes
99
and preparation of an electrophilic -SCF
2
CO
2
Et
transfer reagent.
108

Scheme 27 Direct C-H ethoxycarbonyldifluoromethylation of triazenes.

R
N
N
N
R
N
N
N
R
f
R
N
N
N
R
f
R
f
+
AgF, 100
o
C
16h, C
6
F
14
R = Halo, CO
2
Et, CN
9 +
yields 41-68%
R
f
= CF
2
CO
2
Et
R
2
R
1
+
Ag(I), PhI(OAc)
2
NaOAc, NMP, rt
R
2
R
1
CF
2
CO
2
Et
Me
3
SiCF
2
CO
2
Et
N
R''
O
R'''
R'
N
R''
O
R'
R'''
CF
2
CO
2
Et
N
CO
2
Et EtO
2
C
A
B
29
Scheme 28 CF
2
CO
2
Et radical mediated transformations.
The fluoroalkylated silicon reagents are masked fluoroalkyl anion equivalents and therefore they
form “ate” complexes with borates and boranes. Similar to other fluorinated silicon reagents,
Me
3
SiCF
2
CO
2
Et can transfer the anionic CF
2
CO
2
Et moiety to bromomethyl pinacol esters,
which is accompanied by a migratory nucleophilic substitution of the bromide (scheme 29).
83

Scheme 29 “Ate” complexes with bromomethyl pinacol ester.
1.11 Difluoro(trimethylsilyl)acetamides (Me
3
SiCF
2
CONR
2,
10)
Hartwig and co-workers prepared several α-silyldifluoroacetamides and employed as coupling
partners in their palladium catalyzed coupling reaction with aryl and heteroaryl bromides
(Scheme 30).
109
The products obtained can be converted to various difluromethylene containing
products. Hu et al. showed an example of copper mediated coupling of TMSCF
2
CONEt
2
with
iodobenzene.
110
Examples of direct silver mediated radical CF
2
CONR
2
addition to p-xylene was
reported.
99
With 15% silver salt, similar to Me
3
SiCF
2
CO
2
Et (Scheme 28, B), the radical
CF
2
CO
2
NR
2
participated in a cascade transformation with activated double bonds (eg, N-
phenylmethacrylamide) to obtain difluoromethylated oxindoles.
111

O
B
O
Br
+ Me
3
SiCF
2
X
O
B
O
Br
XF
2
C
O
B
O
KF
DMF, rt
CF
2
X
30

Scheme 30 Arydifluoracetamide synthesis and their further transformations.
The α-silyldifluoroacetamides in the presence of CsF have been shown to nucleophilically add to
the in situ generated iminium ions.
91

1.12 Difluoro(trimethylsilyl)acetonitrile (Me
3
SiCF
2
CN, 11)
Dilman and co-workers synthesized the Me
3
SiCF
2
CN in 80% yield from Me
3
SiCF
2
Br and
Me
3
SiCN in the presence of a catalytic amount of BnNEt
3
Cl at 110 °C in benzonitrile.
54
They
went on to showcase its nucleophilic reactivity with aromatic, heteroaromatic, aliphatic
aldehydes and imines in the presence of lithium acetate base (Scheme 31). Furthermore, the
reagent was utilized under acidic medium to cyano difluoromethylate enamines and unactivated
imines in the presence of KHF
2
/TFA.
112

Scheme 31 β-Cyanodifluoromethyl alcohols and amine synthesis.
1.13 Others
The chemistry of Me
3
SiCF
2
Ph, Me
3
SiCF
2
OPh
113
and Me
3
SiCF
2
CH
3
114
is also found in
the literature, albeit with a limited number of applications.
ArCF
2
CO
2
NR
2
ArCF
2
CH
2
OH
ArCF
2
CO
2
Me
ArCF
2
CO
2
H
ArCF
2
CO
2
n-Bu
ArCF
2
CHO
ArCF
2
CH
2
NR
2
ArBr
+ Me
3
SiCF
2
CONR
2
[Pd/Ligand] KF
X
R
X = O, NTs
LiOAc
X
R CF
2
CN
H
Me
3
SiCF
2
CN
31
1.14 Focus of my work
Developing new difluoromethylene and difluoromethylation methods using inexpensive
and readily available Me
3
SiCF
3
(Ruppert-Prakash reagent). The results are discussed in the
following order.
Chapter 2 describes the selective difluoromethylation of N-heterocyclic compounds such as
imidazoles and benzimidazoles under neutral condition. Chapter 3 discusses direct
difluoromethylation of thiols. Details of direct deoxygenative difluoromethylenation of carbonyl
compounds are discussed in Chapter 4, whereas the Chapter 5 presents the on recent results of
the nucleophilic difluoromethylation of carbonyl compounds such as aromatic aldehydes and
ketones to synthesize difluoromethyl alcohols.
In Chapter 6, silver catalyzed fluorodecarboxylation of ArOCF
2
CO
2
H and ArSCF
2
CO
2
H for the
synthesis of ArOCF
3
and ArSCF
3
, respectively, is presented.
Chapter 7 introduces organic flow battery for the grid scale energy storage, and describes the
challenges associated with materials used in the state of the art all-organic flow battery to
achieve stable battery performance, and synthesis of new stable molecules to address some of the
of these challenges.
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Org. Chem. 2015, 3787.
99) Li, J.; Wan, W.; Ma, G.; Chen, Y.; Hu, Q.; Kang, K.; Jiang, H.; Hao, J. European J. Org.
Chem. 2016, 4916.
42

100) a) Uneyama, K.; Mizutani, G.; Maeda, K.; Kato, T. J. Org. Chem. 1999, 64, 6717. b)
Clavel, P.; Biran, C.; Bordeau, M.; Roques, N.; Trevin, S. Tetrahedron Lett. 2000, 41, 8763. c)
Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett. 2011, 13, 5560. Also see ref. 67.
101) Iseki, K.; Kuroki, K.; Asata, T., Jpn Kokai Tokkyo Koho JP 10101614 A (April 21, 1998).
102) Kawano, Y.; Kaneko, N.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 2006, 79, 1133.
103) Bordeau, M.; Frébault, F.; Gobet, M.; Picard, J. European J. Org. Chem. 2006, 4147.
104) Hafner, A.; Bräse, S. Adv. Synth. Catal. 2013, 355, 996.
105) Hafner, A.; Bihlmeier, A.; Nieger, M.; Klopper, W.; Brase, S. J. Org. Chem. 2013, 78,
7938.
106) Ma, G.; Wan, W.; Li, J.; Hu, Q.; Jiang, H.; Zhu, S.; Wang, J.; Hao, J. Chem. Commun.
2014, 50, 9749.
107) Wang, X.; Wan, W.; Chen, Y.; Li, J.; Jiang, H.; Wang, Y.; Deng, H.; Hao, J. European J.
Org. Chem. 2016, 3773.
108) Shen, F.; Zhang, P.; Lu, L.; Shen, Q. Org. Lett. 2017, 19, 1032.
109) Ge, S.; Arlow, S. I.; Mormino, M. G.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 14401.
110) Zhu, J.; Ni, C.; Gao, B.; Hu, J. J. Fluor. Chem. 2015, 171, 139.
43

111) Wang, C.; Chen, Q.; Guo, Q.; Liu, H.; Xu, Z.; Liu, Y.; Wang, M.; Wang, R. J. Org. Chem.
2016, 81, 5782.
112) a) Kosobokov, M. D.; Struchkova, M. I.; Arkhipov, D. E.; Korlyukov, A. A.; Dilman, A. D.
J. Fluor. Chem. 2013, 154, 73. b) Kosobokov, M. D.; Struchkova, M. I.; Dilman, A. D. Russ.
Chemical Bull. Int. Ed. 2014, 63, 549.
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Hu, J. Chem. an Asian J. 2016, 11, 1789.

44

Chapter 2
N-Difluoromethylation of Imidazoles and
Benzimidazoles Using the Ruppert-Prakash Reagent
under Neutral Conditions

45
2.1 Introduction
Among the fluoroalkyl groups, the difluoromethyl group is of key interest as it resembles
conventional hydrogen bond donors (N-H, O-H). However, it exhibits enhanced
lipophilicity.
1
Moreover, it can serve as a non-conventional hydrogen bond donor (F
2
C-
H). Difluoromethylation has attracted significant attention
2
in the pharmaceutical industry
as the CF
2
H moiety, when introduced, appreciably affects the pharmacokinetic
properties, namely membrane permeability, bioavailability, binding affinity, metabolic
stability and lipophilicity of drug candidates.
3
Consequently, the CF
2
H moiety is notably
considered in isostere-based drug design.
4
For example, the commercial pharmaceuticals,
Eflornithine,
5
Pantaprazole,
6
and Garenoxacin,
7
and the marketed agrochemicals,
Sulfentrazone
8
and Carfentrazone-ethyl,
9
and related potential drug candidates
10
containe
-CF
2
H functionality.

Figure 1 Selected examples for a difluoromethyl containing drug and an agrochemical.
Imidazoles and benzimidazoles are key structural units, prevalent in biological
systems, and have wide applications in medicine,
11
material sciences
12
and catalysis.
13

Furthermore, fluorinated alkyl and arylated imidazoles and related structures are studied
for the preparation of novel imidazolium salts, which can be used as ionic liquids,
14
and
as precursors for the preparation of N-heterocyclic carbenes, which are useful
organocatalysts and ligands for transition metal catalyzed reactions.
15
In this context,
H
2
N
COOH
CF
2
H
NH
2
Eflornithine (DFMO)
Cure for African sleeping sickness
N
N
N
HF
2
C
O
Sulfentrazone (Herbicide)
Me Cl
Cl
NHSO
2
Me
46
selective introduction of the difluoromethyl group onto the imidazole and benzimidazole
nitrogen is of great interest.

Figure 2 Reagents for difluoromethylaiton of imidazoles.
There are several methods in the literature to obtain 1-difluoromethylimidazoles
and benzimidazoles using different reagents (Figure 2). Ozone depleting
chlorodifluoromethane is one of the frequently used reagents.
16
The others are sodium
trifluoroacetate,
17
methyl chlorodifluoroacetate,
18
chlorodifluoromethyl phenyl sulfone,
19

N-tosyl-S-difluoromethyl-S-phenyl-sulfoximine,
20
and the more recent sodium
chlorodifluoroacetate
21
and TMSCF
2
Br.
22,23
Hu et al, in their work, demonstrated the
versatility of TMSCF
2
Br in the difluoromethylation of heteroatom nucleophiles.
However, when they used TMSCF
3
in place of TMSCF
2
Br, they found no product
formation. Although effective and versatile, the lack of commercial availability of
TMSCF
2
Br and the strongly basic conditions put limitations on the method. Moreover, in
their procedure TMSCF
2
Br is derived either from TMSCF
3
using BBr
3
or TMSCF
2
H
with NBS. Recently, Dolbier et al continuouly bubbled fluoroform in alkaline mixture of
water/acetonitrile to prepared N-difluoromethylated heterocycles.
24

Previously the Prakash and Hu groups reported the generation of difluorocarbene from
the Ruppert-Prakash reagent
25
(TMSCF
3
) and successfully added it across alkenes,
HCF
2
Cl
CF
3
CO
2
Na
ClCF
2
CO
2
Me Ph
S
CF
2
Cl
O
O
Ph
S
CF
2
H
TsN
O
ClCF
2
CO
2
Na
Me
3
SiCF
2
Br
CF
3
H
Previously used reagents
47
alkynes
26a
and Sn-H bonds
25b
under neutral conditions using metal halides and non-
metallic fluorides (CaI
2
, NaI, TBAT, TMAF) as initiators.

Scheme 1 Difluorocarbene from the Ruppert-Prakash reagent.
2.2 Results and discussion
In this chapter, we discuss the one step difluoromethylation of imidazoles and
benzimidazoles in triglyme using TMSCF
3
and LiI as the initiator under neutral
conditions. 1H-Benzimidazole was chosen as a model substrate for the reaction screening
(Table 1). Screening for optimized conditions using previously reported carbene
generation and addition methods led to low conversions. For example, with CaI
2
in DMA
gave 20% (Table 1, entry 1), whereas NaI (THF) produced 30% conversion. Use of
fluoride initiators such as TBAT and KF in DMA or LiHMDS in THF resulted in 50%
conversion (Table 1, entries 3-5) with most of the TMSCF
3
consumed. However, our
attempts to optimize the conditions met with little success. Interestingly, lithium iodide in
THF produced 45% conversion after 24 hours at 90 °C (Table 1, entry 7) but still
unreacted TMSCF
3
was left behind.
CH
2
R
R
CH
2
R
R
F
F
Me
3
SiCF
3
, THF
cat. TBAT, -50
o
C
R
H
Me
3
SiCF
3
NaI, 120
o
C
R
F
F
R
3
SnH
Me
3
SiCF
3
CaI
2
, 50
o
C
R
3
SnCF
2
H
or
NaI, 65
o
C
1)
Me
3
SiCF
3
X
-
F
-
+
:CF
2
X = F
-
, I
-
2)
3)
48

Scheme 2 Proposed mechanism.
It was postulated that the generation of insoluble LiF during the course of the reaction
would help to push the carbene generation reaction forward, thereby resulting in an
increased yield of the difluoromethylated product (Scheme 2). At the same time, the
fluoride generated during carbene formation would be trapped by Li(I) preventing a
runaway reaction with the silyl group. Higher boiling ethereal solvents like triglyme
enabled the reactions to be performed safely at higher temperatures. Reactions carried out
with KF, NaF resulted in complete consumption of TMSCF
3
with no product formation
probably due to rapid decomposition of TMSCF
3
to CF
3
H, carbene oligomers and other
undesired side products. Control reactions carried out in triglyme a) without LiI (metal
salt initiator) and b) with LiF both resulted in no product formation. However, an equal
amount of unreacted TMSCF
3
was left behind. These results prompted us to postulate
that Li(I) plays a key role in controlling the availability of fluoride in the reaction
mixture, which otherwise will undergo runaway reaction with TMSCF
3
. Hence, LiI was
chosen to optimize the reaction conditions.

LiI TMSCF
3
TMSI CF
3
Li + + +
CF
3
: CF
2
+
F
: CF
2
+
N
N
CF
2
H
TMSI +
F TMSF + I
Li
LiF
NH
N
49
Table 1 Solvent and initiator screening.

Reactions were carried out in 0.25 mmol scale with 3 equiv. of TMSCF
3
.
a
The conversion
was determined by
19
F NMR spectroscopy using trifluorotoluene as internal standard.
Entry 6 and 7 are brought to RT from -78 °C. Entry 11 was further optimized (see
experimental section for details).

We optimized the reactions with 1H-benzimidazole (Table 2, entry 1), LiI and triglyme
under microwave conditions and the amount of TMSCF
3
and LiI were varied to achieve
an optimum conversion. It was observed that higher amounts of TMSCF
3
or LiI and
longer reaction times resulted in lower yields. This is probably due to decomposition of
the difluoromethylated product to CF
2
HI. The optimized conditions and the substrate
scope are shown in Table 2. The reactions can also be carried out under conventional
heating conditions albeit with longer reaction times (~3h).
Imidazoles and benzimidazoles showed similar reactivity with electron-donating and
electron-withdrawing substituents, whereas triazole and 4-azabenzimidazole produced the
desired products in lower yields. Substituted imidazole and benzimidazoles produced
both of the regioisomers (Table 2, entries 3-5, 10). In case of 4-nitroimidazole, only one
Entry Solvent MX (equiv) Temp (°C) t (h)
a
Conv(%)
1 DMA CaI
2
(0.15) 100 0.67 20
2 DMA K
2
CO
3
(1.0) 80 12 23
3 DMA TBAT (0.1) RT 2 54
4 DMA KF (0.5) RT 2 56
5 THF LiHMDS (1.2) -78 21 50
6 HMPA KF (0.5) 40 14 14
7 THF LiI (0.5) 90 24 45
8 THF t-BuOLi (1.2) -78 7 8
9 THF LiI (1.5) 140 72 63
10 Triglyme LiI (1.2) 140 8 70
11 Triglyme LiI (1.2) 170 (MW) 1 72
50
isomer was observed because of stereo-electronic constraints. Diphenylamine,
acetanilide, N-methylbenzenesulfonamide and indole failed to give products under these
conditions.
Table 2 Substrate Scope.*

*Yields from Condition 1: Microwave heating, 170 °C, 1.5 h (determined by
19
F NMR);
isolated yeilde in paranthesis; yield from Condition 2 (determined by
19
F NMR):
Conventional heating, 170 °C, 3 h.
a
Heated for 120 min.
b
Formed two isomers in 1:1 ratio
(based on
19
F NMR).
c
Eluted together as a mixture.
d
Product not isolated.
e
Isomers
formed MW (34:7); thermal (29:6), only the major isomer was isolated (10b).
f
Conversions were determined by
19
F NMR spectroscopy using trifluorotoluene as an
internal standard.
g
Isolated yield in paranthesis.

We decided to showcase the application of this methodology by introducing the -CF
2
H
group to synthesize biologically active compound analogs. Caffeine has been known to
N
N
CF
2
H
R
1
R
NH
N
R
1
R
TMSCF
3
, Triglyme, LiI
170
o
C, Conditions 1 or 2
N
N
CF
2
H
R
3
NH
N
R
3
R
2
R
2
N
N
CF
2
H
N
N
CF
2
H
N
N
CF
2
H
N
N
CF
2
H
N
N
F
3
C
CF
2
H
N
N
F
3
C
CF
2
H
N
N
CF
2
H
N
N
CF
2
H
O
2
N
N
N
CF
2
H
Ph
N
N
CF
2
H
MeO
1a, 90 (80), 82 a
2a, 86 (81), 70
b,c
3a& b,

77 (73), 77

b
4a, 75 (50), 85
a,b
5a, 77 (71), 78
6a, 89 (81), 96 7a, 88 (75), 97
d
8a, 76 (--), 41
N
N
CF
2
H
MeO
N
N
N
CF
2
H
9a, 44 (22), 46
N
N
N
N
N
N
CF
2
H
CF
2
H
10a&b, 41 (17), 35
3b
4b 5b
10a 10b
3a
4a 5a
51
influence cell cycle function, bringing about programmed cell death and also affecting
important regulatory proteins, for instance, the tumor suppressor protein.
27

Difluoromethylation of theophylline (Scheme 3) gave the the difluoromethylated analog
of caffeine (11b) and isocaffeine (11a) in 3:2 ratio.
28,29

Scheme 3 N-difluoromethylation of theophylline.

MW: 170 °C, 1.5 hours; Conventional heating: 170 °C, 3 hours; Gram scale: 170 °C 2
hours.
a
Conversions were determined by
19
F NMR spectrascopy using trifluorotoluene
internal standard.
b
Isolated yield (see Supporting Information for further details).

Single crystal X-ray diffraction (Figure 3) showed the presence of weak hydrogen
bonding interactions in both the isomers.
30
In 11a, the fluorine atoms are disposed
towards the C8 carbon, which was also evident from throughspace coupling of the C8
protons with C6 fluorines in the
1
H and
19
F NMR, whereas the fluorine atoms in 11b is
positioned away from the oxygen atom (O2) (Figure 4).
31
Interestingly, the conformer
with CF
2
-H pointing towards (O2) (Figure 4, c) is more stable (by 4.4 kcal/more) than
conformer where CF
2
-H is poiting in the opposite direction (180 °) (Figure 4, a) and
when the –CFH-F is pointed towards O2 (Figure 4, b), it is destablized by 8.8 kcal/mole
than conformer c.
52

Figure 3 Crystal structure difluoroisocaffeine (11a) and through space coupling.

Figure 4 Single crystal X-ray structure of 11b and computational calculation of various
conformations.
Difluoroisocaffeine
• Shows through space coupling (1.6 Hz)
between CH
3
and CF
2
H in
1
H and
19
F NMR
3.70 3.75 3.80
f1 (ppm)
3.74
3.75
3.75
-90.35 -90.30 -90.25 -90.20 -90.15
f1 (ppm)
• 
1
H NMR (DMSO-d6) • 
19
F NMR (DMSO-d6)
Distances (Å) Angles (Degrees)
F2-H8B 2.340 F2-H8B-C8 128.97
F1-H8A 2.478 F1-H8A-C8 114.60
F1-C8 3.053
F2-C8 3.053
• Exhibits weak H-bonding (CF
2
-H---O)
• The distances H6−O2 and C6−O2 and the
angle C6−H6−O2 are 2.418 Å, 3.146 Å,
and 129.04°, respectively.
• DFT-B3LYP (cc-pVDZ)
a
b
c
53
Another extension of this methodology is in synthesis of difluoromethylated analogs of
8-(1H-benzoimidazol-2-yl)-quinoline (8-BQ). Pt based 8-BQ complexes are known to
inhibit amyloid β-peptide in vivo studies.
32
During the synthesis, we obtained the desired
product (12a) in 32% yield along with an intersting fluoroscent by-product (12b) in 20%
yield (Scheme 3), which is probably formed by intramolecular nucleophilic substitution
of N-difluoromethyl carbanion on the quinoline ring. The structure of the compounds
were also confirmed by their single crystal X-ray strucutre (Figure 5).
N
N N
+
12b,
a
20% 12a,
a
32% 12
N
N NH
N N
CF
2
N
CF
2
H
TMSCF3, (2.35 equive), Triglyme
LiI (0.9 equive), MW, 170
o
C, 1.5 h

a
Isolated yield.
Scheme 4 Synthesis of N-difluoromethylated ligand for amyloid β-peptide inhibitor Pt
Complex.

2a
12b
Figure 5 Single crystal X-ray structures of 2a and12b (only a few selected protons are
shown for clarity).
The -CF
2
H group in 12a appeared as a broad singlet in
19
F NMR, which resolved into
two doublet of doublets at low temperatures (Figure 6). Surprisingly, the proton signal (t,
54
J = 59.5Hz) is not affected at any of these temperatures. Based on the experimental
coalescence temperature the rotational barrier was determined to be 8.5 kcal/mol
(ΔG
‡
233
). A comparable value was also obtained by DFT calculations, ΔG
‡
= 7 kcal/mol
(B3LYP/6-311+G**).

Figure 6 Crystal structure of 12a and rotational barrier determination by VT NMR.

N-Difluoromethylation of indole was also examined under similar conditions
(Table 3). However, the yield never improved beyond 55%.

Ligand for a β-amyloid inhibitor Pt-
Complex
• C17-H-N1 = 112.11 ; C---N = 3.20 Å
• CF
2
H appears as a broad singlet in
19
F NMR,
which resolves into two doublet of doublets
at low temperature.
• Surprisingly the proton signal (t, J = 59.5Hz)
is not affected at any of these
temperatures.
• Calculated ΔG
‡
= 7 kcal/mol (B3LYP/
6-311+G**
25 °C
0 °C
- 20 °C
- 40 °C
- 60 °C
- 80 °C
F
F
H
N
59.5Hz
223.8 Hz
55
Table 3 N-difluoromethylation of indole.*

Entry Solvent MX (equiv) T ( °C) Time yield
1 DMA KF (0.5) RT 6 hours 55%
2 DMA TBAT (0.5) RT 2 hours 55%
3 Triglyme LiI (2) 170, MW 90 min 0%
4 Triglyme KF (0.15) 80, MW 10 min 0%
5 Triglyme NaI (1.2) 170, MW 30 min 0%
*Reactions were carried out on 0.25 mmol scale in 2 mL solvent.
2.3 Summary
In summary, we have successfully demonstrated the difluoromethylation of imidazoles,
benzimidazoles and related molecules using TMSCF
3
and LiI under neutral conditions.
The difluoromethylated products were obtained in good-to-excellent yields under
relatively short reaction times.
2.4 Experimental Section
2.4.1 Materials and Instrumentation
1
H,
13
C,
19
F and NOESY 1D NMR spectra were recorded on Varian 500 MHz or
400 MHz NMR spectrometers.
1
H NMR chemical shifts were determined relative to the
signal of a residual protonated solvent, CDCl
3
(δ 7.24 ppm) or acetone-d
6
(2.05 ppm) or
DMSO-d
6
(2.5 ppm).
13
C NMR chemical shifts were determined relative to the
13
C signal
of solvent, CDCl
3
(δ 77.23 ppm) or DMSO-d
6
(39.52 ppm).
19
F NMR chemical shifts
were determined relative to CFCl
3
as an internal standard (δ 0.0 ppm). Mass spectral data
were recorded on a Bruker 300-MS TQ Mass Spectrometer at 70 eV for EI and 20 eV for
N
H
N
CF
2
H
Me
3
SiCF
3
(3 equiv)
Conditions
56
CI (CH
4
was used as the reagent gas) or an Agilent 6120 MS. HRMS data were obtained
from University of Arizona Mass Spectrometry Facility. Typically all reaction mixtures
were prepared in a N
2
glovebox. Unless otherwise mentioned all the reactants, reagents
and solvents were purchased from commercial sources.
2.4.2 Experimental procedures
Screening Conditions (extended list of Table 1)
In a typical procedure, benzimidazole (1 equiv, 0.25 mmol, 29.5 mg), initiator,
solvent (dry; 3 mL) and TMSCF
3
(3 equiv, 0.75 mmol) were added in a microwave vial
(2 mL; biotage) along with a stir vane and tightly sealed under N
2
(glovebox). The
conversion was determined by using
19
F NMR spectroscopy by trifluorotoluene as an
internal standard. Entry 6 and 7 are brought to RT from -78 °C. Entry 21 was further
optimized (see below for details). Entry 25-26 and 28-33 were carried out with 2.5 equiv.
TMSCF
3
. In entry 28-31, no TMSF was observed, however, all the reactions had same
amount of unreacted TMSCF
3
(≈ 0.46 equiv). Entry 32-33 showed TMSF but not
TMSCF
3
.
Screening Conditions (extended list of Table 1)*

Entry Solvent Initiators (equiv) Temp. (°C) Time (h) Conversion (%)
1 DMF CaI
2
(0.15) 100 0.67 20
3 Toluene NaI (0.5) 150 24 0
4 THF KI (0.5) 150 24 0
5 DMA CaI
2
(0.2) 170, MW 1 23
6 DMA K
2
CO
3
(1.0) 50 3 17
7 DMF K
2
CO
3
(1.0) 50 3 7
8 DMA Me
3
NO (1.0) 50 12 0
9 DMF Me
3
NO (1.0) 50 12 0
10 DMA K
2
CO
3
(1.0) 80 12 23
11 DMA TBAT (0.1) RT 2 54
12 DMA KF (0.5) RT 2 56
13 HMPA KF (0.5) 40 14 14
14 THF LiHMDS (1.2) -78 to RT 21 50
15 THF LiI (0.5) 90 24 45
57
16 THF t-BuOLi (1.2) -78 to RT 7 8
17 THF LiI (0.5) 100 168 43
18 THF LiI (0.5) 130 15 50
19 THF LiI (1.5) 140 72 63
20 Triglyme LiI (1.2) 140 8 70
21 Triglyme LiI (1.2) 170, MW 1 72
22 Triglyme CaI
2
(1.2) 170, MW 1 4
23 Triglyme NaI (1.2) 170, MW 1 29
24 Triglyme KI (1.2) 170, MW 1 0
25 Triglyme LiCl (1.0) 170 C 5 60
26 Triglyme LiBr (1.2) 170 C, MW 1 53
27 Triglyme NaCl (2.2) 170 C 1 0
28 Triglyme - 170 C, MW 1.5 0
29 Triglyme - 170 6 0
30 Triglyme LiF (0.9) 170 C, MW 1.5 0
31 Triglyme LiF (0.9) 170 6 0
32 Triglyme NaF (0.9) 170 C, MW 1.5 0
33 Triglyme NaF (0.9) 170 6 0
*Reactions were carried out in 0.25 mmol scale with 3 eq of TMSCF
3
. The conversion
was determined by
19
F NMR spectroscopy using trifluorotoluene as internal standard.
Entry 6 and 7 are brought to RT from -78 °C. Entry 11 was further optimized (see below
for details). Entry 25 and 26 were carried out with 2.5 eq TMSCF
3
.

Optimization of Entry 7, Table 4.

Entry
TMSCF
3

(equiv)
LiI (equiv)
Time (min) Conversion (%)
1 3.5 1.2 60 70
2 3.2 1.3 35 89
3 3 0.25 120 19
4 3
1.2
60 72
5 3 1.36 45 72
6 2.5 1.2 35 71
7 2.5 1.2 45 84
8 2.5 1.2 50 76
9 2.35 0.9 90 90
10 2.2 1 90 85
11 2.1 1.2 120 78
12 2 1 105 75
Reactions were carried out on 0.25 mmol scale under microwave condition at 170 °C.

Synthesis of N-difluoromethylated Benzimidazole and Imidazole (Table 2).
Condition 1: In a microwave vial (2 mL; Biotage), charged with a stir vane, were added
LiI (0.9 equiv; 0.22 mmol), required substrate (1 equiv; 0.25 mmol), triglyme (3 mL) and
TMSCF
3
(2.35 equiv; 0.59 mmol) under nitrogen atmosphere (a N
2
glove box) and
58
tightly sealed. This vial was heated at 170 °C for 90-120 min in a MW reactor (Biotage).
Usually the reaction mixture turns dark brown, which usually an indication of
culmination of the reaction. Generally, incomplete reaction was observed if the reaction
mixture was colorless or pale yellow. Conversions were determined by
19
F NMR using
trifluorotoluene internal standard.
Condition 2. In a microwave vial, charged with stir vane, were added LiI (0.9 equiv; 0.22
mmol), substrate (1.0 equiv; 0.25 mmol), triglyme (3 mL) and TMSCF
3
(2.35 equiv; 0.59
mmol) and tightly sealed under N
2
(N
2
Glovebox) and heated at 170 °C for 3 hours.
Typically, the culmination of the reaction was observed with the darkening of the
reaction mixture. The conversion was determined by
19
F NMR using trifluorotoluene
internal standard.
Purification of imidazoles and benzimidazoles (Table 2):
Method 1: (For entry, 6, 7 & 10, Table 2) EtOAc (5 mL) was added to the reaction
mixture, which was then washed with water (5 X 5 mL), dried over anhydrous Na
2
SO
4
,
and filtered. The resulting organic layer was dried in vacuo and purified by flash column
chromatography (Biotage) using EtOAc/Hexane gradient.
Method 2: (For entry, 1-5 & 9 in table 2 and Scheme 4) Reaction mixture was diluted
with methanol (4 mL) and eluted through SCX-2 cartridge (Biotage; 1 g; 6 mL) under
gravity. This cartridge was washed with methanol (7 mL) to remove triglyme. The
cartridge with the product was then eluted with 2M ammonia/methanol (7 mL) and
washed with methanol (5 mL). The resulting mixture was dried in vacuo and passed
through silica cartridge with ethyl acetate / hexane or pentane/diethyl ether gradient. The
59
pure fractions collected were combined and dried under reduced pressure to get the pure
product.
Method 3: (For Scheme 3) In case of water soluble substrates, triglyme was distilled
under vacuum (70 mTorr; 60 °C) to get a dark brown residue, which was then loaded on
a silica column and eluted with EtOAc/Hexane gradient (0-100%).
Note: Usually, for large scale reactions method 1 and 3 were adapted. In case of water
soluble substrates method 3 was preferred over method 1. For small scale, method 2 was
found to be handy.
Synthesis of difluorocaffeine (11b) and difluoroisocaffeine (11a) (Scheme 3)
• 0.25 mmol scale: Can be prepared using condition 1 or 2. As the resulting
products were stable and more water soluble, purification method 3 was used to
purify the products.
• Gram Scale (Conventional): A 150 mL pressure round bottom flask was
charged with a stir bar, lithium iodide (0.9 equiv, 9 mmol), theophylline (1.0
equiv, 10 mmol), triglyme (120 mL) and TMSCF
3
in a N
2
glovebox. The flask
was sealed tightly and stirred at 170 °C until the reaction turned dark brown (2
hours). Purification Method 3 was employed to isolate the isomers as pure solids.
The isolated isomers 11a and 11b were recrystallized in water (white) and
DCM/Pentane (yellow), respectively, to get crystals for single crystal X-Ray
structure study.
60

*MW: 170 °C, 1.5 hours; Conventional heating: 170 °C, 3 hours; Gram scale: 170 °C 2
hours.
a
Conversions were determined using trifluorotoluene.
b
Isolated yield.

Synthesis of 8-(1H-benzo[d]imidazol-2-yl)quinoline (8-DQ) (12).

Following the literature method,
[1]
Quinoline-8-carboxylic acid (174 mg, 1 mmol) and o-
phenylenediamine (108 mg, 1 mmol) in polyphosphoric acid (2 g) were heated at 175 °C
for 6 hours. The reaction mixture was cooled down to room temperature and poured on to
crushed ice and allowed to come to room temperature. The resulting yellow suspension
was brought to pH ≈ 8 using ammonium hydroxide. The resulting yellow solid was
filtered, dried and purified by column chromatography using EtOAc/Hexane (1:1).
Product structure was confirmed by LCMS and NMR—consistent with the literature
data.
[2]

Synthesis of 8-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)quinolone (12a)
(Scheme 4)

Difluoromethylation was performed using method A and purified by method 2.
12a and 12 eluted together. The resulting mixture was treated with hexane/diethyl ether to
get pure 12a as a white solid.
N
N
N
H
N
O
O
N
N
N
N
O
O
CF
2
H
58 % 34 %
+
N
N
N
N
O
O
CF
2
H
TMSCF
3
, LiI, Triglyme
a
MW
38 % 48 %
a
Conventional
b
Gram Scale (Conventional)
27 %
40 %
Conditions
11a 11b 11
N
H
N
N
NH
2
NH
2
N
COOH
PPA, 175
o
C
6 h
56%
+
N
N
N
+
12b, 20 % 12a, 32 % 12
N
N
N
H
N
N
C
F
2
N
CF
2
H
TMSCF
3
, LiI, Triglyme
170
0
C, MW, 1.5 h
61
2.4.3 Spectroscopic Data
1-(difluoromethyl)-1H-benzo[d]imidazole (1a):
20

White solid.
1
H NMR (500 MHz, CDCl
3
) δ 8.16 (s, 1H), 7.91 – 7.81 (m, 1H), 7.65 – 7.58
(m, 1H), 7.43 – 7.37 (m, 2H), 7.34 (t, J = 60.4 Hz, 1H).
13
C NMR (126 MHz, CDCl
3
) δ
143.89, 139.19, 130.66, 124.99, 124.36, 121.07, 111.23, 109.09 (t, J = 250.2 Hz).
19
F
NMR (470 MHz, CDCl
3
) δ -94.25 (d, J = 60.4 Hz, 2F). HRMS (MALDI, m/z):
169.057181 (M+H)
1-(difluoromethyl)-5,6-dimethyl-1H-benzo[d]imidazole (2a):

White Solid.
1
H NMR (500 MHz, CDCl
3
) δ 7.92 (s, 1H), 7.52 (s, 1H), 7.30 (s, 1H), 7.19
(t, J = 60.5 Hz, 1H), 2.33 (s, 3H), 2.31 (s, 3H).
13
C NMR (126 MHz, CDCl
3
) δ 142.66,
138.41, 134.31, 133.31, 129.14, 121.04, 111.35, 109.13 (t, J = 249.2 Hz), 20.67, 20.42.
19
F NMR (470 MHz, CDCl
3
) δ -94.03 (d, J = 60.5 Hz). HRMS (ESI, m/z) for
(C
10
H
10
F
2
N
2
): calculated 196.197059 (average neutral mass); found 197.088481
[(M+H)+]
1-(difluoromethyl)-5-methyl-1H-benzo[d]imidazole (3a) & 1-(difluoromethyl)-6-
methyl-1H-benzo[d]imidazole (3b):
3a 3b
N
N
CF
2
H
N
N
CF
2
H
N
N
CF
2
H
N
N
CF
2
H
62
Colourless Oil. 3a and 3b eluted together as a mixture. (
1
H,
19
F and
13
C below). HRMS
(EI, m/z): calculated for C
9
H
8
F
2
N
2
182.0656; found 182.0650 [(M+)+H].
1-(difluoromethyl)-5-methoxy-1H-benzo[d]imidazole (4a):

Colouless Oil.
1
H NMR (500 MHz, CDCl
3
). δ 7.49 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 2.4
Hz, 1H), 7.27 (t, J = 60.4 Hz), 7.03 (dd, J = 8.9, 2.4 Hz, 1H), 3.87 (s, 3H).
13
C NMR (126
MHz, CDCl
3
) δ 157.48, 145.14, 139.54, 124.98, 114.92, 111.66, 109.11 (t, J = 249.6 Hz),
103.19, 55.94.
19
F NMR (470 MHz, CDCl
3
) δ -93.97 (d, J = 60.4 Hz). Isomer confirmed
by NOESY 1D. HRMS (ESI, m/z) for (C
9
H
8
F
2
N
2
O): calculated 199.06775 [(M+H)+];
found 199.06771 [(M+H)+].
1-(difluoromethyl)-6-methoxy-1H-benzo[d]imidazole (4b):

White Solid.
1
H NMR (500 MHz, CDCl
3
) δ 8.00 (s, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.07
(d, J = 2.4 Hz, 1H), 7.00 (dd, J = 8.9, 2.4 Hz, 1H), 3.89 (s, 3H).
13
C NMR (126 MHz,
CDCl
3
) δ 158.03, 145.41, 138.48, 138.20, 121.60, 113.59, 109.17 (t, J = 248.6 Hz),
94.90, 56.06.
19
F NMR (470 MHz, CDCl
3
) δ -94.49 (d, J = 60.4 Hz). HRMS (ESI, m/z)
for (C
9
H
8
F
2
N
2
O): calculated 199.06775 [(M+H)+]; found 199.0677 [(M+H)+].
1-(difluoromethyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole (5a):

N
N
MeO
CF
2
H
N
N
CF
2
H
MeO
N
N
F
3
C
CF
2
H
63
Yellow solid.
1
H NMR (500 MHz, CDCl
3
) δ 8.25 (s, 1H), 8.17 (s, 1H), 7.83 – 7.60 (m,
2H), 7.38 (t, J = 60.3 Hz).
13
C NMR (126 MHz, CDCl
3
) δ 143.76, 140.87, 132.69, 127.16
(q, J = 32.8 Hz), 125.49 (q, J = 272.7 Hz), 121.99 (q, J = 3.5 Hz), 118.9 (q, J = 4.2 Hz),
111.92 (t, 1.7 Hz), 108.95 (t, J = 252.4 Hz).
19
F NMR (470 MHz, CDCl
3
) δ -61.72 (s,
3F), -94.36 (2F, d, J = 60.3 Hz). Isomer confirmed by NOESY 1D. HRMS: (ESI, m/z)
for (C
9
H
5
F
5
N
2
) calculated 237.04452 [(M+H)+]; found 237.04457 [(M+H)+].
1-(difluoromethyl)-6-(trifluoromethyl)-1H-benzo[d]imidazole (5b):

Yellow Oil.
1
H NMR (399 MHz, CDCl
3
) δ 8.25 (s, 1H), 8.03 – 7.88 (m, 2H), 7.72 – 7.59
(m, 1H), 7.38 (t, J = 59.9 Hz, 1H).
13
C NMR (100 MHz, CDCl
3
) δ 154.64 , 146.11 ,
141.26 , 130.03 , 127.24 (q, J = 32.6 Hz), 124.18 (q, J = 272.3 Hz), 121.59 , 121.28 (q, J
= 3.5 Hz), 108.79 (t, J = 251.3 Hz).
19
F NMR (376 MHz, CDCl
3
) δ -61.65 (s, 3 F), -94.26
(d, J = 60.1 Hz, 2F). Isomer confirmed by NOESY 1D. LCMS. 237.1 [(M+H)]+.
1-(difluoromethyl)-2-phenyl-1H-imidazole (6a):
18

Yellow Oil.
1
H NMR (500 MHz, CDCl
3
) δ 7.60 (m, 2H), 7.54 – 7.47 (m, 3H), 7.39 (s,
1H), 7.23 (s, 1H), 7.06 (t, J = 59.7 Hz, 1H).
13
C NMR (126 MHz, CDCl
3
) δ 147.51,
130.38, 130.21, 129.24, 129.06, 128.95, 118.75, 115.65, 108.77 (t, J = 249.9 Hz).
19
F
NMR (470 MHz, CDCl
3
) δ -91.02 (d, J = 59.7 Hz). HRMS (ESI, m/z) for (C
10
H
8
F
2
N
2
):
calculated 194.0656 (neutral mass); found 195.0728 [(M+H)+]
1-(difluoromethyl)-4-nitro-1H-imidazole (7a):
N
N
F
3
C
CF
2
H
N
N
CF
2
H
64

Off-white solid.
1
H NMR (500 MHz, CDCl
3
) δ 8.07 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 1.6
Hz, 1H), 7.23 (t, J = 60.5 Hz, 1H).
13
C NMR (126 MHz, CDCl
3
) δ 149.57, 133.46, 115.55
, 108.41 (t, J = 257.3 Hz).
19
F NMR (470 MHz, CDCl
3
) δ -93.38 (d, J = 60.5 Hz). Isomer
confirmed by NOESY 1D. MS (EI, m/z): 163.0 (M+); 78.0; 51.0. HRMS (EI, m/z) for
(C
4
H
3
F
2
N
2
): calculated 163.0193; found: 163.0190 [(M+H)+]
1-(difluoromethyl)-1H-imidazole (8a)
16b

19
F NMR (unlocked) (trifluortoluene reference: - 63.0 ppm): - 92.54 (d, J = 60.2 Hz) 1-
(difluoromethyl)-1H-benzo[d][1,2,3]triazole (9a)
[20,16b]

White solid.
1
H NMR (500 MHz, CDCl
3
) δ 8.15 (dd, J = 8.5, 0.9 Hz, 1H), 7.86 (t, J =
58.6 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 7.64 (ddd, J = 8.2, 7.0, 1.0 Hz, 1H), 7.51 (ddd, J =
8.1, 7.0, 1.0 Hz, 1H).
13
C NMR (126 MHz, CDCl
3
) δ 146.65, 130.12, 129.62, 125.73,
120.64, 111.43 (d, J = 251.6 Hz), 110.94 (t, J = 1.6 Hz).
19
F NMR (470 MHz, CDCl
3
) δ -
97.04 (d, J = 58.6 Hz). HRMS (ESI, m/z) for (C
7
H
5
F
2
N
3
): calculated 170.05236; found
170.05243 [(M+H)+].
1-(difluoromethyl)-1H-imidazo[4,5-b]pyridine (10a)
N
N
CF
2
H
O
2
N
N
N
CF
2
H
N
N
N
CF
2
H
65

White solid.
1
H NMR (500 MHz, CDCl
3
) δ 8.68 (dd, J = 4.8, 1.5 Hz, 1H), 8.39 (s, 1H),
8.00 (dd, J = 8.1, 1.5 Hz, 1H), 7.40 (t, J = 59.9 Hz, 1H), 7.37 (dd, J = 8.1, 4.8 Hz, 1H).
13
C NMR (126 MHz, CDCl
3
) δ 156.40, 146.95, 141.66, 123.26, 120.16 (m), 119.98,
109.26 (t, J = 247.8 Hz).
19
F NMR (470 MHz, CDCl
3
) δ -94.12 (d, J = 59.3 Hz). Isomer
confirmed by NOESY 1D. HRMS (EI, m/z) for C
7
H
5
F
2
N
3
; Calculated: 169.0452; found:
169.0447 [(M+H)+]
9-(difluoromethyl)-1,3-dimethyl-1H-purine-2,6(3H,9H)-dione )(11a)
28,21

Yellow solid.
1
H NMR (500 MHz, DMSO-d
6
) δ 8.17 (s, 1H), 8.11 (t, J = 59.0 Hz, 1H),
3.59 (t, J = 1.6 Hz, 3H), 3.24 (s, 3H).
13
C NMR (126 MHz, DMSO-d
6
) δ 156.61, 150.74,
138.29, 134.73 (t, J = 2.8 Hz), 117.56 , 108.76 (t, J = 252.9 Hz), 32.53 (t, J = 4.2 Hz),
28.29.
19
F NMR (470 MHz, DMSO-d
6
) δ -89.28 (dd,
2
J
F-H
= 58.7 Hz;
6
J
F-H
= 1.6 Hz).
Isomer was identified by NOESY 1D (See spectrum). HRMS (ESI, m/z) for
(C
8
H
8
F
2
N
4
O
4
): calculated 231.06881 [(M+H)+]; found 231.06878 [(M+H)+].
7-(difluoromethyl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (11b)
21,28

White solid.
1
H NMR (400 MHz, CDCl
3
) δ 8.06 (s, 1H), 7.82 (t, J = 60.2 Hz, 1H), 3.63
N
N
N
CF
2
H
N
N
O
O
N
N
CF
2
H
N
N
N
N
O
O
CF
2
H
66
(s, 3H), 3.43 (s, 3H).
13
C NMR (126 MHz, CDCl
3
) δ 154.71, 151.44, 149.13, 137.79,
107.38 (t, J = 257.8), 105.64, 30.29, 28.39.
19
F NMR (376 MHz, CDCl
3
) δ -93.58 (J =
60.2 Hz). Isomer was identified by NOESY 1D (See spectrum). HRMS (ESI, m/z) for
(C
8
H
8
F
2
N
4
O
4
): calculated 231.06881 [(M+H)+]; found 231.06882 [(M+H)+].
8-(1-(difluoromethyl)-1H-benzo[d]imidazol-2-yl)quinolone (12a)

White solid.
1
H NMR (399 MHz, CDCl
3
) δ 8.97 (dd, J = 4.2, 1.8 Hz, 1H), 8.29 (dd, J =
8.3, 1.8 Hz, 1H), 8.19 (dd, J = 7.2, 1.5 Hz, 1H), 8.08 (dd, J = 8.3, 1.5 Hz, 1H), 7.92 –
7.80 (m, 2H), 7.74 (dd, J = 8.2, 7.1 Hz, 1H), 7.52 (dd, J = 8.3, 4.2 Hz, 1H), 7.46 – 7.34
(m, 2H), 7.04 (t, J = 58.4 Hz, 1H).
13
C NMR (100 MHz, CDCl
3
) δ 151.63, 150.34,
146.00, 143.77, 136.72, 133.95, 132.17, 131.38, 128.50, 128.38, 126.78, 124.57, 124.02,
122.15, 120.56, 112.76 (t, J = 2.5 Hz), 110.76 (t, J = 247.5 Hz).
19
F NMR (376 MHz,
CDCl
3
) δ -96.97 (s (broad)). HRMS (ESI, m/z) for (C
17
H
11
F
2
N
3
): calculated 296.09935
[(M+H)+]; found 296.09938 [(M+H)+].
7,7-difluoro-7H-benzo[4',5']imidazo[1',2':1,5]pyrrolo[3,4-h]quinolone

Orangish yellow solid.
1
H NMR (500 MHz, CDCl
3
) δ 9.22 (dd, J = 4.2, 1.7 Hz, 1H), 8.23
(dd, J = 8.4, 1.8 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.91 (dt, J = 8.0, 0.9 Hz, 1H), 7.81 (dt,
J = 8.3, 0.9 Hz, 1H), 7.61 – 7.50 (m, 2H), 7.38 – 7.21 (m, 2H).
13
C NMR (126 MHz,
N
N
N
CF
2
H
N
N
C
F
2
N
67
CDCl
3
) δ 154.32, 153.89, 149.68, 142.33, 141.47 (t, J = 26.9 Hz), 136.65, 132.37,
131.07, 130.50, 127.42, 125.63, 123.97, 123.60, 122.37, 120.09, 117.72, 110.46 (t, J =
251.9 Hz).
19
F NMR (470 MHz, CDCl
3
) δ -95.60 (s, 2F). HRMS (ESI, m/z) for
(C
8
H
8
F
2
N
4
O
4
): calculated 294.08405 [(M+H)+]; found 294.08373 [(M+H)+]
1-(difluoromethyl)-1H-indole

Pale yellow liquid.
1
H NMR (399 MHz, Chloroform-d) δ 7.69 – 7.63 (m, 1H), 7.62 –
7.54 (m, 1H), 7.32 (ddd, J = 8.3, 7.2, 1.3 Hz, 1H), 7.29 (d, J = 3.6 Hz, 1H), 7.27 – 7.22
(m, 1H), 7.27 (t, J = 61.1 Hz, 1H) 6.66 (dd, J = 3.5, 0.8 Hz, 1H).
19
F NMR (376 MHz,
Chloroform-d) δ -91.59 (d, J = 61.1 Hz).
13
C NMR (100 MHz, Chloroform-d) δ 134.21,
129.75, 123.59, 123.28, 122.10, 121.58, 110.82, 108.91 (d, J = 246.0 Hz), 106.10.Data
corroborates with the literature report.
16b

N
CF
2
H
68
2.4.4 Representative spectra

1
H NMR (CDCl
3
)

With EtOAc/Hexanes

13
C NMR (CDCl
3
)

N
N
N
CF
2
H
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
f1 (ppm)
7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 8.9 9.0
f1 (ppm)
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
100 110 120 130 140 150 160 170 180 190
f1 (ppm)
69
19
F NMR (CDCl
3
)

NOESY 1D (CDCl
3
)

-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
-94.4 -94.2 -94.0 -93.8 -93.6 -93.4 -93.2 -93.0
f1 (ppm)
7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7
f1 (ppm)
70

1
H NMR (DMSO-d
6
)

13
C NMR (DMSO-d
6
)

N
N
O
O
N
N
CF
2
H
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5
f1 (ppm)
2.50
7.9 8.0 8.1 8.2 8.3
f1 (ppm)
3.54 3.55 3.56 3.57 3.58 3.59 3.60 3.61 3.62 3.63
f1 (ppm)
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
32.2 32.4 32.6 32.8
f1 (ppm)
134.5 135.0 135.5 136.0 136.5 137.0 137.5 138.0 138.5
f1 (ppm)
71
19
F NMR (DMSO-d
6
)

NOESY 1D (Acetone-d
6
)

-94.5 -94.0 -93.5 -93.0 -92.5 -92.0 -91.5 -91.0 -90.5 -90.0 -89.5 -89.0 -88.5 -88.0 -87.5 -87.0 -86.5 -86.0 -85.5 -85.0 -84.5 -84.0 -83.5 -83.0 -82.5
f1 (ppm)
-89.85 -89.80 -89.75 -89.70 -89.65 -89.60 -89.55 -89.50
f1 (ppm)
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13
f1 (ppm)
72

1
H (CDCl
3
)

13
C NMR (CDCl
3
)

N
N
N
N
O
O
CF
2
H
-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
f1 (ppm)
7.26 CDCl3
7.5 7.6 7.7 7.8 7.9 8.0 8.1 8.2
f1 (ppm)
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
101 102 103 104 105 106 107 108 109 110 111 112
f1 (ppm)
73
19
F NMR (CDCl
3
)

NOESY (1D)

-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
0.00
-94.1 -94.0 -93.9 -93.8 -93.7 -93.6 -93.5 -93.4 -93.3 -93.2
f1 (ppm)
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0
f1 (ppm)
74

1
H NMR (CDCl
3
)

*diethyl ether (3.48 (q) and 1.2 (t) ppm

13
C NMR (CDCl
3
)

N
N
N
CF
2
H
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0
f1 (ppm)
6.8 7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0
f1 (ppm)
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
110 115 120 125 130 135 140 145 150
f1 (ppm)
75
19
F NMR (CDCl
3
)

1
H NMR (CDCl
3
)

-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
0.00
-100 -95
f1 (ppm)
-96.97
N
N
C
F
2
N
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13
f1 (ppm)
7.0 7.2 7.4 7.6 7.8 8.0 8.2 8.4 8.6 8.8 9.0 9.2 9.4
f1 (ppm)
76
13
C NMR (CDCl
3
)

19
F NMR (CDCl
3
)

10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200
f1 (ppm)
114.5 115.0 115.5 116.0 116.5 117.0 117.5 118.0 118.5 119.0 119.5 120.0 120.5
f1 (ppm)
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
77
2.5 References

1) a) Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford, 2006. b) Marciano, D.;
Amir, D.; Berliner, A.; Sod-Moriah, G.; Yeffet, D.; Zafrani, Y.; Gershonov, E.; Saphier,
S. J. Med. Chem. 2017, 60, 797.
2) (a) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins,
M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494. (b) Fujiwara,
Y.; Dixon, J. A.; O’Hara, F.; Funder, E.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.;
Herlé, B.; Sach, N.; Collins, M. R. Ishihara, Y.; Baran, P. S. Nature. 2012, 492, 95. (c)
Liu, G.; Wang, X.; Xu, X.-H.; Lu, X.; Tokunaga, E.; Tsuzuki, S.; Shibata, N. Org. Lett.
2013, 15, 1044. (d) Fier, P.S.; Hartwig, J.F. Angew. Chem. Int. Ed. 2013, 52, 2092. (e)
Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524. (f) Prakash, G. K. S.;
Weber, C.; Chacko, S.; Olah, G. A. Org. Lett. 2007, 9, 1863.
3) (a) K. L. Kirk, Org. Process Res. Dev. 2008, 12, 305; (b) G. K. S. Prakash, S. Chacko,
Curr. Opin. Drug Discovery Dev. 2008, 11, 793.
4) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529.
5) Casero, R. A. Jr.; Woster, P. M. J. Med. Chem. 2009, 52, 4551.
6) Cheer, S. M.; Prakash, A.; Faulds, D.; Lamb, H. M. Drugs 2003, 63, 101.
7) Takagi, H.; Tanaka, K.; Tsuda, H.; Kobayashi, H. Int. J. Antimicrob. Agents 2008, 32,
468.
8) Dumas, D. J. US Patent 5990315, 1999.
9) Poss, K. M. PCT Int. Pat. WO 1990/002120, 1990.
10) Sato, N.; Ando, M.; Ishikawa, S.; Nagase, T.; Nagai, K.; Kanatani, A. PCT Int. Pat.
WO 2004/031175, 2004.
78

11) Bellina, F.; Rossi, R., Adv. Synth. Catal. 2010, 352, 1223.
12) Fang, Z.; Wang, S.; Zhao, L.; Xu, Z.; Ren, J.; Wang, X.; Yang, Q., Materials
Chemistry and Physics, 107, 2008, 305.
13) Rodionov, V. O.; Presolski, S. I.; Gardinier, S.; Lim, Y.-H.; Finn, M. G., J. Am.
Chem. Soc. 2007, 129, 12696.
14) Abate, A.; Petrozza, A.; Cavallo, G.; Lanzani, G.; Matteucci, F.; Bruce, D. W.;
Houbenov, N.; Metrangolo, P.; Resnati, G. J. Mat. Chem. A. 2013, 1, 6572.
15) (a) Rivera, G.; Elizalde, O.; Roa, G.; Montiel, I.; Bernès, S., J Org. Met. Chem. 2012,
699, 82. (b) Liu, T.; Zhao, X.; Shen, Q.; Lu, L. Tetrahedron. 2012, 68, 6535.
16) (a) Shen, T. Y.; Lucas, S.; Sarett, L. H. Tet. Lett. 1961, 2, 43. (b) Jończyk, A.;
Nawrot, E.; Kisielewski, M., J. J. Fluor. Chem. 2005, 126, 1587. (c) Levterov, V.;

Grygorenko, O. O.; Mykhailiuk, P. K.; Tolmachev, A. A. Synthesis. 2011. 8. 1243.
17) Poludnenko, V. G.; Didinskaya, O. B.; Pozharskii, A. F. Chem. Heterocycl. Compd.
1984, 20, 422.
18) Lyga, J. W.; Patera, R. M. J. Fluorine Chem. 1998, 92, 141.
19) (a) Zheng, J.; Li, Y.; Zhang, L.; Hu, J.; Meuzelaar, G. J.; Federsel, H.-J. Chem.
Commun. 2007, 5149. (b) Wang, F.; Zhang, L.; Zheng, J.; Hu, J. J. Fluor. Chem. 2011,
132, 521.
20) Zhang, W.; Wang, F.; Hu, J. Org. Lett. 2009, 11, 2109.
21) Mehta, V. P.; Greaney, M. F. Org. Lett. 2013, 15, 5036.
22 ) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem. Int. Ed. 2013. 52. ASAP.
DOI: 10.1002/anie.201306703
79

23) Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J.
Am. Chem. Soc. 1997, 119, 1572.
24) Thomoson, C. S.; Wang, L.; Dolbier, W. R. J. Fluor. Chem. 2014, 168, 34.
25) a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757. b) Prakash, G. K. S.;
Mandal, M. J. Fluor. Chem. 2001, 112, 123.
26) (a) Wang, F.; Luo, T.; Hu, J.; Wang, Y.; Krishnan, H. S.; Jog, P. V.; Ganesh, S. K.;
Prakash, G. K. S.; Olah, G. A. Angew. Chem. Int. Ed. 2011, 50, 7153; (b) Prakash, G. K.
S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood, K.; Swabeck, J. K.; Olah, G. A.
Angew. Chem. Int. Ed. 2012, 51, 12090.
27) Bode, A. M.; Dong, Z. Cancer Lett. 2007, 247, 26.
28) Hao, X.; Chen, W; Chen, M; Lan, S; Zhang, J; Li, W. Huazhong Shifan Daxue
Xuebao, Ziran Kexueban. 2007, 41, 546.
29) In reference 28, difluorocaffeine (11b) was claimed to have been made, however,
clear characterization details were not provided. In reference 21, the compounds 11a and
11b were reported to be a white solid and a yellow liquid, respectively. But in our work
we found that 11a and 11b as yellow and white solids, respectively, and were able to
characterize them by single crystal X-ray diffraction (Fig. 3 & 4).
30) (a) Lyga, J. W.; Henrie II, R. N.; Meier, G. A.; Creekmore, R. W.; Patera, R. M.
Magn. Reson. Chem. 1993, 31, 323. (b) Erickson, J. A.; McLoughlin, J. I. J. Org. Chem.
1995, 60, 1626.
31) Through space coupling details between C8 protons and C6 fluorines in 11a (Figure
3):
1
H 3.59 ppm (t,
6
J
F-H
= 1.6 Hz),
19
F -89.28 ppm (dd,
2
J
F-H
= 58.7 Hz;
6
J
F-H
= 1.6 Hz)
13
C NMR, C1 (t,
3
J = 2.8 Hz), C5 (s) and C8 (t,
5
J = 4.8 Hz). Single crystal X-ray
80

diffraction details (bond distances and bond angles): C8-F1 = 3.020 å; C8-F2 = 3.053 å;
F2-H8B = 2.340 å; F1-H8A = 2.478 å; C8-H8A-F1 = 114.60°; C8-H8B-F2 = 128.97°.
For 11b, the distance H6-O2, C6-O2 and the angle C6-H6-O2 are 2.418 å, 3.146 å and
129.04 °, respectively, which falls in the range of weak hydrogen bonding interaction
(Ref. 30).
32) Kenche, V.B.; Hung, L. W.; Perez, K.; Volitakes, I.; Ciccotosto, G.; Kwok, J.; Critch,
N.; Sherratt, N.; Cortes, M.; Lal, V.; Masters, C. L.; Murakami, K.; Cappai, R.; Adlard,
P. A.; Barnham, K. J. Angew. Chem. 2013, 125, 3458.
81

Chapter 3
Direct S-Difluoromethylation of Thiols Using the
Ruppert-Prakash Reagent

82
3.1 Introduction
Analogues to aryl and alphatic trifluoromethyl thioethers
1
, difluoromethyl
thioethers are promising synthons in medicinal chemistry and materials science. The
SCF
2
H group has attracted considerable attention recently as it promises a unique
lipophilic weak hydrogen bond donor property. Its popularity is also associated with the
more acidic nature of the SCF
2
-H proton compared to its carbon analogs.
2

A common approach to synthesize difluoromethyl thioethers is to use
difluorocarbene based reagents such as ClCF
2
CO
2
Na,
3
CF
2
HCl,
4
CF
3
H,
5

BrCF
2
PO(OEt)
2
,
6
and ArSONRCF
2
H
7
and Ph
3
P
+
CF
2
CO
2
-
,
8
An electrophilic reagent,
ArSONR
2
CF
2
H
+
, transferring -CF
2
H to nucleophiles

has also been used.
9
In contrast,
Goosen et al showed nucleophilic transfer of -CF
2
H to in situ formed electrophiles,
RSCN, generated from RBr/ROMs or ArN
2
+
,
10
In an alternative approach, a nucleophilic
-SCF
2
H group from (NHC)AgSCF
2
H is transferred to diazonium salts;
11
conversely,
Shen and co-workers electrophilically transferred –SCF
2
H from N-
difluoromethylthiothalimide to boronic acids, alkynes, amines, thiols and electron rich
aromatics
12
giving access to a wide variety of -SCF
2
H compounds. In the process of
discovery, drug or material, easy access to reagents in terms of the cost and handling and
simple procedures are highly desired.
Easy commercial and economical access, and ease of handling make the Ruppert-
Prakash reagent (TMSCF
3
) a popular nucleophilic trifluoromethylating agent
[ 13
].

Moreover, useful difluoromethyl
14
and difluoromethylene transfer reagents
15
have also
been prepared from TMSCF
3
and employed to make difluoromethylene (CF
2
) containing
compounds. Others and us have been exploring its direct use and reactivity as a
83
difluoromethylene transfer reagent as we can reduce the cost and efforts associated with
additional synthetic steps (Scheme 1).
16
So far only a handful of examples of direct
difluoromethylene (CF
2
) transfer from TMSCF
3
has been demonstrated to synthesize
difluorocyclopropane and cyclopropene,
16a
alkyl and aryl-difluoromethylstannnes,
15b
α-
siladifluoromethyl carbonyl compounds,
16b
gem-difluoroolefins
16c
and N-difluoromethyl
imidazoles and benzimidazoles.
16d
To the best of our knowledge, though the reagents
derived from TMSCF
3
such as TfOCF
2
H,
17
TMSCF
2
Br
18
and TMSCF
2
H;
10
have been
utilized for the S-difluoromethylation of thiols, TMSCF
3
has never been directly
employed until now.

Scheme 1 Difluorormethylene transfer from TMSCF
3
.
3.2 Results and discussion
3.2.1 Aromatic thiols
Following our base free difluoromethylation of imidazoles and benzimidazoles
with TMSCF
3
,
13b
we investigated difluoromethylation of thiols under similar reaction
conditions using naphthalene-2-thiol as a model substrate. For instance, LiI in triglyme or
diglyme produced less than 15% of the difluoromethylated product with complete
consumption of TMSCF
3
at 120 °C. In order to prevent the decomposition TMSCF
3
, we
opted relatively lower temperatures. TMSCF
3
can be activated with alkali and alkaline
earth metal halides in polar solvents such as DMF, DMA or NMP. With DMA as a
solvent, different MX salts were examined at 70 °C (Table 1). Interestingly, MgI
2

TMSCF
3'
Products'
Derived'reagents'
TMSCF
2
H,'TfOCF
2
H'
TMSCF
2
Br,'TMSCF
2
Cl'
Bu
3
SnCF
2
H'
Products'
84
produced siladifluoromethylated product (A) along with difluoromethylated product (B),
whereas LiCl offered only A in 40% conversion. Further reactions were explored with
LiCl at various temperatures. The maximum conversion obtained was 50%; attempts to
increase the conversion by leaving the reaction for longer time or heating at higher
temperature resulted in decomposition of product with the reaction mixture turning
orange. Attempts to stop the reaction before decomposition of the product were not
always successful.
Table 1 Screening conditions.*

Entry MX (1.2 equiv) A%
a
B%
a
Unreacted TMSCF
3
(equiv)
a

1 LiI 0 0 1.2
2 KI 0 0 2.2
3 NaI 0 0 2.1
4 CaI
2
9 0 1.2
5 MgI
2
24 9 1
6 LiBr 0 0 1.5
7 LiCl 40 0 1
*Conditions: Reactions were carried out on 0.25 mmol scale with DMA (2.5 mL)
and TMSCF
3
(3 equiv).
d
Determined by trifluorotoluene internal standard.

We propose that the lithium arylthiolate produced in situ by trifluoromethanide anion
from TMSCF
3
and LiCl is the active species that reacts with TMSCF
3
(Table 1, Entry 7).
However, the TMSCF
3
activation by LiCl for the generation of trifluoromethanide anion
requires temperature over 60 °C. But the resulting product decomposes overtime under
SH
TMSCF
3
DMA, MX, 70
o
C, 19h
SCF
2
TMS
+
SCF
2
H
A
B
85
the reaction conditions. Therefore, we decided to start from the lithium arylthiolate
directly.
Table 2 Optimization and screening using conditions lithium thiolate.*

Entry LiX Solvent Conversion (%)
a

1 LiCl DMA 50
2 LiCl DMF 53
3 LiCl THF 0
4 LiBr DMA 33
5 LiI DMA 33
6 LiPF
6
DMF 74
7 LiF DMF 0
8 - DMF 0
9 LiN(SO
2
CF
3
)
2
DMF 67
10 LiBF
4
DMF 78
11
b
LiBF
4
DMF 72
12
c
LiBF
4
DMF 84
13 LiOTf DMF 67
14 LiOAc DMF 44
*Conditions: Reactions were carried out on 0.25 mmol scale with 2.2 equiv of LiH, 3
equiv TMSCF
3
and 1.5 equiv LiX.
a
Determined by
19
F NMR using trifluorotoluene as an
internal standard.
b
15 or 50 mol% of LiBF
4
was used.
C
1.2 equiv of LiBF
4
was used.

For easy handling, LiH was selected as a base to deprotonate the thiols. When the
reaction was carried out with LiH in DMA at room temperature, the reaction proceeded
in less than a minute, giving the S-siladifluormethylated product in 50% conversion
SH
TMSCF
3
LiH, Solvent, LiX, RT
SCF
2
TMS
A
86
(Table 2, Entry 1). Similar results were obtained in DMF. Interestingly, when the reaction
was carried out without the LiCl additive, the reaction failed to produce any product
(Entry 8). Furthermore, we speculated that the Li
+
acts as fluoride trap, allowing the
siladifluoromethyl product and the TMSCF
3
to survive under the reaction conditions. We
also hypothesized that the more cationic nature of the lithium may assist in the fluoride
abstraction. As we expected, lithium salts of weakly coordinating anions increasingly
produced the product in the following order OTf = NTf
2
< PF
6
< BF
4
. When the amount
LiBF
4
was optimized, we observed that use of sub-stoichiometric amount (15 or 50
mol%) of LiBF
4
produced 72% conversion. Superior conversion (84%) was obtained
when slightly over an equivalent amount of LiBF
4
was employed.
An optimum conversion was obtained with LiH (1.2 equiv), TMSCF
3
(2.5 equiv),
5 min for deprotonation and 10 min for reaction time (Table 3). The resulting
siladifluoromethyl sulfides can be conveniently cleaved with either TBAF or aqueous
KF. Thiols with electron donating groups such as methyl and methoxy groups provided
excellent conversions. In general, the pKa of -SH is lower than -OH and -NH
2
, therefore
with the present conditions; we predicted that -SH could be selectively deprotonated and
difluoromethylated. Gratifyingly, -OH and -NH
2
substituents, typically considered
sensitive functional groups, produced 60% and 50% conversions, respectively. In the
halosubstituted thiols, 4-fluoro gave greater than 86% conversion, whereas -Cl and -Br
were over 60%. We hypothesized that by employing two equivalent of LiH, the ionized
carboxylic acid group can be made less electron-withdrawing and less sensitive. To our
delight, thiosalicylic acid produced 75% conversion. However, electron-withdrawing
87
substituents such as trifluoromethyl and nitro produced 25% and 0% products,
respectively.

Table 3 Optimized conditions and substrate scope.*

*Conditions: For convenient isolation, the substrate scope was explored on 0.5 mmol
scale with LiH (1.2 equiv), LiBF
4
(1.2 equiv) and TMSCF
3
(2.5 equiv) in dry DMF (2.5
ml).
a
KF or TBAF was used.
b
The yields in parentheses were determined by
19
F NMR
using trifluorotoluene as an internal standard.
c
Isolated yield.

SH
LiH, DMF (5 min)
TMSCF
3
(10 min)

a
F
-
10 min
R
SCF
2
TMS
R
SCF
2
H
R
1
SCF
2
H
SCF
2
H
SCF
2
H
SCF
2
H
SCF
2
H
SCF
2
H
SCF
2
H
SCF
2
H
Cl
Br
H
3
CO
H
3
C
HO
H
2
N
1a (83%)
b
1h, 54% (65%)
1j, 59% (68%)
1d, 82% (92%) 1b, 75%
c
(85%)
1e, 33% (60%)
1f, 24% (50%)
1m, 76%
c
(84 %)
SCF
2
H
1c, 82% (95%)
SCF
2
H
F
1g (86%)
SCF
2
H
SCF
2
H
O
2
N
1p, 0%
1l, 72% (78%)
SCF
2
H
1n, 49% (75%)
Br
SCF
2
H
1k, 46% (53%)
CO
2
H
SCF
2
H F
3
C
CF
3
1o, 25%
88
3.2.2 Aliphatic thiols
Similar reaction conditions were extended to aliphatic thiols with the 1-
dodecanethiol as a model substrate, the conversions were over 20%, which was
associated to higher reactivity of aliphatic thiols over aromatic thiols. Consequently,
lower reaction temperatures were examined. No reaction was observed at 0
o
C or lower
temperatures. When the reaction was allowed to come to room temperature from 0 °C,
the conversion improved to 56%. With the modified conditions, 1-butanethiol and
benzylthiol gave 71% and 51% conversions, respectively.
Table 4 Aliphatic difluoromethyl thioethers.*

*Conditions: Reactions were carried out on 0.5 mmol scale with LiH (1.2 equiv), LiBF
4

(1.2 equiv) and TMSCF
3
(2.5 equiv) in dry DMF (2.5 ml).
a
KF or TBAF was used.
b
The
yields in parentheses were determined by
19
F NMR using trifluorotoluene as an internal
standard.

3.2.3 One-pot tolyllthiodifluoromethyl transfer to benzaldehyde
RSCF
2
- transfer to organic molecules is an important area of research, as the
resulting products’ –SR group can be modified into several other useful functionalities.
The widely used PhSCF
2
TMS was first developed and employed by us
19
and
subsequently by others.
20
Moreover, recently ArSCF
2
H have also been used to transfer
ArSCF
2
- in the presence of bases.
21

R SH
1) LiH, DMF (5 min), RT
2) TMSCF
3
, 0
o
C to RT, ~ 2h
a
3) F
-
R SCF
2
H
SCF
2
H
SCF
2
H
2a (71%)
b
2c (56%)
SCF
2
H
2b 40% (51%)
89

Scheme 2 One-pot tolllmercaptodifluoromethylation of benzaldehyde.
Under the present conditions, we surmised that the resulting
siladifluoromethylated product could be made to react with electrophiles in the same pot.
To demonstrate that a one-pot transfer of the arylthiodifluoromethylene from the
intermediate, S-siladifluoromethyl thioether to electrophiles, tolylthiol was
siladifluoromethylated and the reaction mixture was subjected to vacuum to remove
excess TMSCF
3
and benzaldehyde was subsequently added and the reaction mixture was
stirred at room temperature for 12 hours to give 3a in 62% yield. We employed 4Å MS to
keep the reaction dry and to avoid formation of any ArSCF
2
H. The reaction also occurs in
the absence of molecular sieves, however, with 15% of ArSCF
2
H formation leading to
slight decrease in the yield of 3a. Similar approach can be extended to other carbonyl
compounds to make useful products in one-pot.
3.2.4 Mechanism

Scheme 3 Proposed mechanism.
Based on the experimental observations, a plausible mechanism can be proposed
(Scheme 3). Lithium thiolate is generated in the presence of lithium hydride, which
attacks silicon to produce a pentavalent intermediate; the pentavalent intermediate
SH
1) 4 Å MS, DMF, LiH, LiBF
4
, TMSCF
3
, RT, 15 min
2) PhCHO, 12 h, RT
S
F
F
Ph
OTMS
62 % (68% )
3a
SCF
2
H SCF
2
TMS
(8%) (9%)
+
+
R SH
LiH
Ph S Li
TMS-CF
3
Si H
3
C
S
CH
3
CH
3
Li
R
F
F
F
R S
Si
F
F
CH
3
CH
3
CH
3
- LiF
RSCF
2
H
F
-
H
+
90
eliminates a fluoride with help of Li
+
to give the product. When the reaction was
performed with TIPSCF
3
, where the Si center is sterically congested, no product
formation was observed and the TIPSCF
3
(Scheme 4) remained unreactive. Additionally,
use of sodium hydride as a base instead of LiH, led to decomposition of TMSCF
3
into
several unidentified signals along with CF
3
H and TMSF and no product was formed.
Moreover, no tetrafluoroethylene and related products was observed under the reaction
conditions.

Scheme 4 Reaction with TIPSCF
3
.
3.3 Summary and conclusions
Direct use of TMSCF
3
for difluoromethylation of aliphatic and aromatic thiols has
been presented. As the reaction produces siladifluoromethylated products in one-step,
without the need for use of CF
2
Br
2
or the consecutive use of Mg/TMSCl to generate the
reagent, one can directly use the present conditions to make diverse products from
various electrophiles. Similar, results can be achieved by preforming the lithium thiolates
using mild bases such as Li
2
CO
3
when the use of strong base such as LiH is detrimental
for the substrate. Given the unique acidity and nucleophilicity of thiolates, a
chemoselective S-difluoromethylation is easily adaptable to thiols with various functional
groups.
3.4 Experimental
3.4.1 General information
1
H,
13
C and
19
F NMR spectra were recorded on Varian 500 MHz or 400 MHz
NMR spectrometers.
1
H NMR chemical shifts were determined relative to the signal of a
SH
TIPSCF
3
(12 h)
no reaction
LiH, DMF, 5 min
91
residual protonated solvent, CDCl
3
(δ 7.24 ppm) or DMSO-d
6
(2.5 ppm).
13
C NMR
chemical shifts were determined relative to the
13
C signal of solvent, CDCl
3
(δ 77.23
ppm) or DMSO-d
6
(39.52 ppm).
19
F NMR chemical shifts were determined relative to
CFCl
3
as an internal standard (δ 0.0 ppm). HRMS data was obtained from University of
Illinois urbana-champaign’s mass spectrometry laboratory. Typically all reactions
mixtures were prepared and carried out under inert atmosphere in a Schlenk flask or a
sealed microwave vial. Unless otherwise mentioned, all the reactants, reagents and
solvents were purchased from commercial sources.
3.4.2 Synthesis of aryldifluoromethyl thioethers
To a mixture of LiBF
4
(1.2 equiv; 0.6 mmol, 56.2 mg), LiH (1.2 equiv; 0.6 mmol,
4.7 mg) and DMF (dry; 2.5 mL) was added, the required substrate (1 equiv; 0.5 mmol).
The mixture was stirred for 5 min under inert atmosphere in a microwave vial or a
Schlenk flask. To the vigorously stirring mixture, TMSCF
3
(180 µL) was quickly injected
and stirring continued for 10 more min. Aqueous KF (150 µL, 10M) or TBAF in THF
(2mL, 1M) was added and stirred for 10 min. Unreacted LiH was quenched with water (5
mL) (H
2
evolution; extra care must be taken for large scale reactions!) and extracted
in EtOAc or Et
2
O (2 x 5 mL) and these layers were combined and washed with water (3 x
10 mL) and brine (10 mL). The combined organic layers were then dried over anhydrous
MgSO
4
, filtered and dried in a rotary evaporator. The resulting residue was purified by
silica flash column chromatography using pentane or hexane/EtOAc gradient and the
pure fractions were combined and rotavaped to obtain the pure difluoromethyl thioethers.

92
3.4.3 Spectral data
(difluoromethyl)(p-tolyl)sulfane (1b)
Colorless oil (65.3 mg; 75% yield).
1
H NMR (399 MHz, CDCl
3
) δ 7.48 (d, J = 8.1
Hz, 2H), 7.21 (d, J = 7.8 Hz, 2H), 6.79 (t, J = 57.2 Hz, 1H), 2.38 (s, 3H).
19
F NMR (376
MHz, CDCl
3
) δ -92.18 (d, J = 57.1 Hz).
13
C NMR (100 MHz, CDCl
3
) δ 140.4, 135.7,
130.3, 122.5 (t, J = 3.0 Hz), 121.2 (t, J = 268.8 Hz), 21.4. The data corroborate with the
literature report [3, 5].
(difluoromethyl)(2,6-dimethylphenyl)sulfane (1c)
Colorless oil (77.1 mg; 82% yield).
1
H NMR (399 MHz, CDCl
3
) 7.25-7.21 (m,
1H), 7.17-7.15 (m, 2H), 6.67 (t, J = 57.0 Hz), 2.55 (s, 6H).
13
C NMR (100 MHz, CDCl
3
)
δ 145.1, 130.4, 128.7, 125.0, 121.7 (t, J = 275.9 Hz), 22.5.
19
F NMR (376 MHz, CDCl
3
) δ
-90.96 (d, J = 57.0 Hz). The data corroborate with the literature report [3].
(difluoromethyl)(4-methoxyphenyl)sulfane (1d)
Colorless oil (78 mg; 82% yield).
1
H NMR (399 MHz, CDCl
3
) δ 7.53 (d, J = 8.8
Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.74 (t, J = 57.1, 1H), 3.83 (s, 3H).
13
C NMR (126
MHz, CDCl
3
) δ 161.3, 137.7, 121.1 (t, J = 276.7 Hz), 116.2 (t, J = 3.1 Hz) 115.0, 55.5.
19
F NMR (376 MHz, CDCl
3
) δ -92.79 (d, J = 57.1 Hz. The data corroborate with the
literature report [3].
4-((difluoromethyl)thio)phenol (1e)
White solid (29.0 mg; 33%).
1
H NMR (500 MHz, CDCl
3
) δ 7.48 (d, J = 8.1 Hz,
1H), 6.84 (d, J = 7.9 Hz, 1H), 6.74 (t, J = 56.8 Hz, 1H), 5.27 (s, 1H).
13
C NMR (126
MHz, CDCl
3
) δ 157.5, 138.0, 126.4, 121.0 (t, J = 275.6 Hz), 116.5.
19
F NMR (470 MHz,
93
CDCl
3
) δ -92.82 (d, J = 57.2 Hz). ESI-HRMS: m/z calculated for C
7
H
6
F
2
OS [(M-H
+
)
-
]:
175.0029, Found: 175.0033 [(M-H
+
)
-
].
4-((difluoromethyl)thio)aniline (1f)
Colorless Oil (24%, 20.6 mg).
1
H NMR (399 MHz, CDCl
3
) δ 7.40 – 7.31 (m, 2H),
6.71 (t, J = 57.3 Hz, 1H), 6.69 – 6.63 (m, 2H), 3.87 (bs, 2H).
13
C NMR (100 MHz,
CDCl
3
) δ 148.5, 137.8, 121.4 (t, J = 274.0 Hz), 115.6, 112.9.
19
F NMR (376 MHz,
CDCl
3
) δ -93.03 (d, J = 57.4 Hz). ESI-HRMS: m/z calculated for C
7
H
7
F
2
NS: 176.0346
Found: 176.0354 [(M+H)
+
].
(4-chlorophenyl)(difluoromethyl)sulfane (1i)
Colorless Liquid. (53.6 mg, 55%).
1
H NMR (400 MHz, CDCl
3
) δ 7.53 (d, J = 8.3
Hz, 2H), 7.38 (d, J = 8.3 Hz, 2H), 6.82 (t, J = 56.7, 1H).
13
C NMR (126 MHz, CDCl
3
) δ
136.9, 136.7 , 129.8 , 124.4 (t, J = 3.1 Hz), 120.5 (t, J = 275.7 Hz).
19
F NMR (376 MHz,
CDCl
3
) δ -92.22 (d, J = 56.7 Hz). The data corroborate with the literature report [3].
(4-bromophenyl)(difluoromethyl)sulfane (1j)
Colorless Oil (70.5 mg, 59%).
1
H NMR (500 MHz, CDCl
3
) δ 7.53 – 7.49 (m, 2H),
7.48 – 7.42 (m, 2H), 6.81 (t, J = 56.6 Hz, 1H).
19
F NMR (470 MHz, CDCl
3
) δ -92.15 (d, J
= 56.6 Hz).
13
C NMR (126 MHz, CDCl
3
) δ 137.0, 132.7, 125.0 (t, J = 3.3 Hz), 124.9,
120.4 (t, J = 274.1 Hz). The data corroborate with the literature report [10].
(2-bromophenyl)(difluoromethyl)sulfane (1l)
Colorless Oil

(55 mg, 46%)
1
H NMR (500 MHz, CDCl
3
) δ 7.72-7.65 (m, 2H),
7.41 – 7.32 (m, 1H), 7.32 – 7.23 (m, 2H), 6.93 (t, J = 57.0, 1H).
19
F NMR (470 MHz,
CDCl
3
) δ -92.72 (d, J = 57.0 Hz).
13
C NMR (126 MHz, CDCl
3
) δ 136.57, 133.93, 131.14,
129.30, 128.54, 128.39, 120.63.

The data corroborate with the literature report [
22
].
94
(difluoromethyl)(naphthalen-1-yl)sulfane (1m)
Colorless liquid (75.7mg, 72%).
1
H NMR (500 MHz, CDCl
3
)
1
H NMR (500
MHz, Chloroform-d) δ 8.53 (d, J = 8.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 7.7
Hz, 2H), 7.69 – 7.42 (m, 3H), 6.83 (t, J = 57.1 Hz, 1H).
19
F NMR (470 MHz, CDCl
3
) δ -
91.30 (d, J = 57.2 Hz). (t, J = 273.6 Hz).
13
C NMR (126 MHz, CDCl
3
) δ 136.5, 135.4,
134.4, 131.4, 128.7, 127.6, 126.8, 125.9, 125.8, 123.6, 121.5 (t, J = 273.6 Hz). The data
corroborate with the reported literature [11].
(difluoromethyl)(naphthalen-2-yl)sulfane (1n)
Colorless oil (80.6 mg; 76% yield)
1
H NMR (399 MHz, CDCl
3
) δ 8.13 (s, 1H),
7.91 – 7.82 (m, 3H), 7.63 (d, J = 8.6, 1H), 7.60 – 7.53 (m, 2H), 6.92 (t, J = 56.9 Hz, 1H).
13
C NMR (100 MHz, CDCl
3
) δ 135.5, 133.6, 133.5, 131.5, 129.1, 128.0, 127.8, 127.5,
127.0, 123.3 (t, J = 3.0 Hz), 121.2 (t, J = 274.5 Hz).
19
F NMR (376 MHz, CDCl
3
) δ -
91.67 (d, J = 57.1 Hz). The data corroborate with the reported literature [11].
2-((difluoromethyl)thio)benzoic acid (1q)
Purified by acid base extraction. No column chromatography was performed.
White solid (49.8 mg, 49%).
1
H NMR (500 MHz, CDCl
3
) δ 8.09 (d, J = 7.9 Hz, 1H), 7.64
(d, J = 7.9 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.03 (t, J = 56.2 Hz,
1H).
19
F NMR (470 MHz, CDCl
3
) δ -93.51 (d, J = 56.2 Hz).
13
C NMR (126 MHz,
DMSO-d6) δ 167.4, 132.6, 131.3, 130.9, 130.8 (t, J = 3.7 Hz), 129.7, 127.4, 121.2 (d, J =
270.7 Hz). ESI-HRMS: m/z calculated for C
8
H
6
F
2
O
2
S (M-H
+
)
-
: 202.9978, found:
202.9975 (M-H
+
)
-
.
benzyl(difluoromethyl)sulfane (2b)
95
Colorless Liquid (40%, 34.8 mg).
1
H NMR (399 MHz,CDCl
3
) δ 7.52 – 7.11 (m,
5H), 6.73 (t, J = 56.6 Hz, 1H), 4.02 (s, 2H).
13
C NMR (100 MHz, CDCl
3
) δ 136.4, 129.0,
128.9, 127.8, 120.4 (t, J = 271.9 Hz), 31.9.
19
F NMR (376 MHz, CDCl
3
) δ -94.98 (d, J =
56.6 Hz). The data corroborate with the reported literature [10].
(2,2-difluoro-1-phenyl-2-(p-tolylthio)ethoxy)trimethylsilane (3a)
To a mixture of LiBF
4
(1.2 equiv; 0.6 mmol, 56.2 mg), LiH (1.2 equiv; 0.6 mmol,
4.7 mg), DMF (dry; 2.5 mL), 4A MS (250 mg, beads) and 4-methylbenzenethiol (1
equiv; 0.5 mmol) was added and the mixture stirred for 5 min under inert atmosphere in a
schlenk flask. TMSCF
3
(180 µL) was quickly injected and the mixture stirred vigorously
for 10 min. The reaction mixture was subjected to vacuum to remove unreacted TMSCF
3

that may be present and PhCHO (2 equiv) was added and stirred overnight. Unreacted
LiH was quenched with water (5 mL) (H
2
evolution; extra care must be taken for
large scale reactions!) and extracted in EtOAc (2 x 5 mL) and these layers were
combined and washed with water (3 x 10 mL) and brine (10 mL). The combined organic
layers were then dried over anhydrous MgSO
4
, filtered and dried under rotary evaporator.
The resulting residue was purified by silica flash column chromatography using
hexane/EtOAc gradient (0-10%) and the pure fractions were combined and rotary
evaporated to obtain the pure 3a as an off-white solid (62%, 109.2 mg).
1
H NMR (500
MHz, CDCl
3
) δ 7.51 – 7.40 (m, 4H), 7.40 – 7.30 (m, 3H), 7.19 – 7.08 (m, 2H), 4.98 (dd,
J = 10.9, 7.5 Hz, 1H), 2.58 – 2.11 (m, 3H), 0.12 (s, 9H).
13
C NMR (126 MHz, CDCl
3
) δ
139.72, 136.86, 136.41, 135.65, 133.42, 129.62, 128.82 (t, J = 284.0 Hz), 128.62, 127.95,
122.94, 21.23, -0.07.
19
F NMR (470 MHz, CDCl
3
) δ -80.59 (dd, J = 204.0, 7.5 Hz), -
96
83.83 (dd, J = 204.2, 11.0 Hz). EI-HRMS: m/z calculated for C
18
H
22
F
2
OSSi: 352.1129;
Found: 352.1128.
3.4.4 Representative spectra

1
H NMR (CDCl
3
)

13
C NMR (CDCl
3
)

SCF
2
H
HO
97
19
F NMR (CDCl
3
)

1
H NMR (CDCl
3
)

SCF
2
H
Br
98

13
C NMR (CDCl
3
)

19
F NMR (CDCl
3
)

99

1
H NMR (CDCl
3
)

13
C NMR (CDCl
3
)

SCF
2
H
100

19
F NMR (CDCl
3
)

1
H NMR (CDCl
3
)

OTMS
F
F
S
101
13
C NMR (CDCl
3
)

19
F NMR (CDCl
3
)

102
3.5 References

1) Landelle. G ; Panossian. A.; Leroux. F. R. Curr. Top. Med. Chem. 2014, 14, 941.
2) (a) Hu, M.; Wang, F.; Zhao, Y.; He, Z.; Zhang, W.; Hu, J. J. Fluor. Chem. 2012, 135,
45. (b) Punirun, T.; Soorukram, D.; Kuhakarn, C.; Reutrakul, V.; Pohmakotr, M. Eur. J.
Org. Chem. 2014, 2, 4162.
3) Mehta, V.P.; Greaney, M.F. Org. Lett. 2013, 15, 5036.
4) Langlois, B. R. J. Fluor. Chem. 1988, 41, 247.
5) Thomoson, C.S.; Dolbier, W.R. J. Org. Chem. 2013, 78, 8904.
6) Zafrani, Y.; Sod-Moriah, G.; Segall, Y.Tetrahedron. 2009, 65, 5278.
7) Zhang, W.; Wang, F.; Hu. J. Org. Lett. 2009, 11, 2109.
8) Deng, X.-Y.; Lin, J.-H.; Zheng, J.; Xiao, J.-C. Chem. Comm. 2015, 51, 8805.
9) Prakash, G.K.S.; Zhang, Z.; Wang, F.; Ni, C.; Olah. G. A. J. Fluor. Chem. 2011, 132,
792.
10) Bayarmagnai, B.; Matheis, C.; Jouvin, K.; Goossen. L.J. Angew. Chem. Int. Ed. 2015,
54, 5753.
11) The actual reagent is synthesized in two steps from TMSCF
2
H. Wu, J.; Gu, Y.; Leng,
X.; Shen, Q. Angew. Chem. Int. Ed. 2015, 54, 7648.
12) The actual reagent is synthesized in two steps from TMSCF
2
H. Zhu, D.; Gu, Y.; Lu,
L.; Shen, Q. J. Am. Chem. Soc. 2015, 137, 10547.
13) (a) Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195.
(b) Prakash, G.K.S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393–
395. (c) Prakash, G.K.S.; Yudin, A.K. Chem. Rev. 1997, 97, 757. (d) Liu, X.; Xu, C.;
Wang, M.; Liu, Q. Chem. Rev. 2014, 115, 683.
103

14) Tyutyunov, A. A.; Boyko, V. E.; Igoumnov, S. M. Fluorine notes, 2011, 74, 1.
(http://notes.fluorine1.ru/public/2011/1_2011/letters/letter2.html)
15) (a) Levin, V. V.; Dilman, A.D.; Belyakov, P. A.; Struchkova, M.I.; Tartakovsky, V.
A. J. Fluor. Chem. 2009, 130, 667. (b) For R
3
SnCF
2
H: Prakash, G.K.S.; Ganesh, S.K.;
Jones, J.-P.; Kulkarni, A.; Masood, K.; Swabeck, J.K.; Olah, G. A. Angew. Chem. Int. Ed.
2012, 51, 12090. (c) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem. Int. Ed. 2013, 52,
12390. (d) Wang, F.; Li, L.; Ni, C.; Hu, J. Beilstein J. Org. Chem. 2014, 10, 344.
16) (a) For difluorocyclopropane and propenes: Wang, F.; Luo, T.; Hu, J.; Wang, Y.;
Krishnan, H.S.; Jog, P. V.; Ganesh, S.K.; Prakash, G.K.S.; Olah, G.A. Angew. Chem. Int.
Ed. 2011, 50, 7153. (b) For α-siladifluoromethyl carbonyl compounds: Hashimoto, R.;
Iida, T.; Aikawa, K.; Ito, S.; Mikami, K. Chem. Eur. J. 2014, 20 2750. (c) For
difluoroolefins: Hu, M.; He, Z.; Gao, B.; Li, L.; Ni, C.; Hu. J. J. Am. Chem. Soc. 2013,
135, 17302. d) For N-difluoromethyl imidazoles: Prakash, G.K.S.; Krishnamoorthy, S.;
Ganesh, S.K.; Kulkarni, A.; Haiges, R.; Olah, G.A. Org. Lett. 2014, 16, 54.
17) Fier, P.S.; Hartwig, J.F. Angew. Chem. Int. Ed. 2013, 52, 2092.
18) Li, L.; Wang, F.; Ni, C.; Hu, J. Angew. Chem. Int. Ed. 2013, 52, 12390.
19) (a) Prakash, G.K.S.; Hu, J.; Olah, G.A. J. Org. Chem. 2003, 68, 4457. (b) Prakash,
G.K.S.; Hu, J.; Wang, Y.; Olah, G. A. J. Fluor. Chem. 2005, 126, 527.

20) Soorukram, D.; Kuhakarn, C.; Reutrakul, V.; Pohmakotr, M. Synlett. 2014, 25, 2558–
2573.
104

21) (a) Hu, M.; Wang, F.; Zhao, Y.; He, Z.; Zhang, W.; Hu, J. J. Fluor. Chem. 2012, 135,
45. (b) Punirun, T.; Soorukram, D.; Kuhakarn, C.; Reutrakul, V.; Pohmakotr, M. Eur. J.
Org. Chem. 2014, 2, 4162.
22) Prakash, G.K.S.; Weber, C.; Chacko, S.; Olah. G. A. Org. Lett. 2007, 9, 1863.

105

Chapter 4
Direct Difluoromethylenation of Carbonyl Compounds
using TMSCF
3

106
4.1 Introduction
The distinct electronic property and reactivity of 1,1-difluoroalkenes make them
invaluable synthetic intermediates towards fluorinated
1
as well as non-fluorinated
2

synthetic scaffolds (Figure 1). The C=CF
2
has been shown to serve as a unique
functionality in rational drug design
3
as a bioisoster of C=O group,
4
and therefore
synthesis of difluoro (C=CF2) analogues as bioactive C=O containing molecules has
garnered significant attention.
5

Figure 1 Electronics and reactivity of 1,1-difluoroalkenes and recent synthetic
applications.
6a-i

R
1
R
2
O
R
1
R
2
C
δ
− δ
+
F F
δ
+
δ
−
Nu
R
1
R
2
C
H H
Nu
-
X
X
O
R R
1
R
2
R R
N F
R
R
F
F
F
R
O
R
R
F
F
F
Ar
Ar
N
Bn
F
F
R
R
R R
F F
R R
R F
R
R
CF
2
F
CF
2
F
R
R
a
b
c
R
F
F
R
R
F
CN
R
d
e
f
g
h
h
i
R R
F
F
F(
18
F)
107
Table 1 Common starting materials used to synthesize 1,1-difluoroalkenes.

Table 2 SciFinder search results (April 2016).

Though there are several approaches that use various starting materials
7
including
alkyl halides and diazo compounds (Table 1), and reagents (Table 2)
8
to synthesize 1,1-
difluoroalkenes, the direct deoxygenative difluoromethylenation of carbonyl compounds
via Wittig type processes
9
has been deemed efficient as it employs readily available
reagents and starting materials (Table 1&2).
10
The reactive intermediate in these
reactions, difluoromethylene phosphonium ylide, can be generated with phosphine and
the singlet difluoromethylene. Though reagent derived from TMSCF
3
, namely,
R R'
X
X = Br, I
R R'
N
2
R R'
O
1) Moiture sensitive
2) Carcinogenic
1) Explosive hazard
2) Limited operating temperatue
3) Toxic and carcinogenic
4) Limitation in scalability
Common Starting Materials
Pros Cons
1) Availablity
1) Readily available
2) Stable
3) Not particularly toxic
1) High reactivity
2) Versatile intermediat
1)
2)
3)

Entry Reagent Vendor, purity
Price
($/mol)
No.
SciFinder hit
US
Vendors
1 Hg(CF
3
)
2
LabNetwork Compounds 143650 8 3
2 2-((difluoromethyl)sulfonyl)pyridine Sigma Aldrich, 97% 17385 22 13
3 TMSCF
2
Cl Aspira scientific, 97% 15072 15 10
4 TMSCF
2
Br SynQuest, 97% 3208 32 25
5 diethyl (difluoromethyl)phosphonate Simga Aldrich, 97% 2080 32 23
6 CF
2
Br
2
Sigma Aldrich, >95% 893 31 21
7
methyl 2,2-difluoro-2
(fluorosulfonyl)acetate
Matrix scientific, 97% 234 83 63
8 CF
2
ClCO
2
Na TCI America, >99% 168 89 68
9 TMSCF
3
Oakwood chemicals, 99% 128 113 85
10 Ph
3
P
+
CF
2
CO
2
-
LabNetwork Compounds Not listed 2 2

108
TMSCF
2
Cl has been reported for such a transformation, the direct use of TMSCF
3
has
been reported to be unsuccessful (Scheme 1).
11
Therefore, direct use of TMSCF
3
will
prove superior in terms of safety, synthetic convenience, and cost (Table 2). Further, its
preparation has been recently demonstrated from abundant, non-ozone depleting, by-
product of Teflon
®
manufacture, CF
3
H.
12

Scheme 1 Previously attempted direct difluoromethylenation with TMSCF
3
.
In general, employing TMSCF
3
poses challenges with substrates containing fairly
acidic protons or reactive electrophilic functional groups such as carbonyls
[13]
as the
reactive intermediates (CF
3
anion or the pentavalent silicon species) are prone to pick up
a proton (pKa of CF
3
H = 26)
[14]
or react with other electrophiles (Scheme 2). In addition,
for every mole equivalent of difluoromethylene formed, a mole equivalent of fluoride is
produced; and the presence of the silicophilic fluoride is known to accelerate the
formation of CF
3
anion from TMSCF
3
, which generally result in autocatalytic
[15]
or
runaway reactions producing copious amount CF
3
H and other undesired singlet
difluoromethylene based products. Such runaway reactions are exacerbated at the
elevated temperatures and therefore limit the higher reaction temperatures that might be
required to achieve some of the desirable chemical transformations. Therefore, curtailing
the amount of nascent fluoride produced in the process of difluoromethylene formation
will allow the non-fluoride based nucleophiles such as iodide to react with TMSCF
3
at
higher temperatures.
CHO
CF
2
+ PPh
3
(1.0 equiv)
(3.0 equiv)
TMSCF
3
(3.0 equiv)
THF, conditions 1 or 2
Conditions: 1) NaI (0.6 equiv), 70
o
C 2) NaI (6.0 equiv), 110
o
C
<5%
109

Scheme 2 Typical reaction pathways of TMSCF
3
.
4.2 Results and discussion
Table 3 Reaction conditions screening.
[a]

Entry Solvent T °C t (h) MX (equiv) Conv (%)
[b]

[c]
1 THF 70 10 NaI (0.6) 64
[c]
2 THF 110 10 NaI (6) 69
3 Diglyme 170 1 LiI (2.0) 74
4 Diglyme 170 3 LiI (2.0) 81
5 Diglyme 110 37 LiI (2.0) 47
[d]
6 Diglyme 70 24 LiI (2.0) 15
[d]
7 Diglyme 110 7 LiI (2.0) 10
[d]
8 Diglyme 170 1 LiI (2.0) 15
[e]
9 Diglyme 170 3 LiI (2.0) 8
[f]
10 Diglyme 170 3 LiI (2.0) 7
11 DMF RT 20 LiI (2.0) 10
12 5% DMF/THF 70 24 LiI (2.0) 35
13 5% DMF/THF 110 24 LiI (2.0) 77
14 5% DMF/Diglyme 170 0.5 LiI (2.0) 74
15 8% DMF/dioxane 120 24 LiI (2.0) 83
16 8% DMF/CH
3
CN 120 24 LiI (2.0) 78
17 16% DMF/Toluene 120 15 LiI (2.0) 83
[a] Reactions were carried out on 0.25 mmol scale with 2.5 mL of solvent. [b]
Conversions were determined by
19
F NMR using C
6
F
6
as an internal standard. [c] 3.0
equiv TMSCF
3
was used. [d] (Me
2
N)
3
P (2.0 equiv) replaced PPh
3
. [e] dibenzothiophene
(3.0 equiv) replaced PPh
3
. [f] (PhO)
3
P (3.0 equiv) replaced PPh
3
.

In the previous chapters (Chapter 2 & 3), we discussed that the Li
+
could be
employed in preventing such runaway reactions by controlling the amount of soluble free
nucleophilic fluoride present in the reaction solution,
[16]
which led us to re-examine the
TMSCF
3
+ Nu CF
3
a) R-H
F
+ CF
2
CF
3
-H
c) R-CHO
R CF
3
OTMS
b)
CHO
PPh
3
(3.0 equiv)
Conditions
CF
2
(2.5 equiv)
+ TMSCF
3
2a
110
conditions reported by Hu and co-workers (Scheme 1). Contrary to the reported results,
we observed >60% of 2a (Table 5, Entry 1 & 2). Further optimization of the conditions to
improve the yield with NaI proved challenging. To test the effect of Li
+
, NaI was
replaced with LiI. As the LiI requires higher temperatures to activate TMSCF
3
, our
previously developed conditions,
[16a]
LiI/diglyme/170 °C, were chosen with PPh
3
as an
additional reagent. The very first experiment carried out in the presence of LiI/PPh
3

produced 74% of 2a (Entry 3) and prolonging the reaction time increased the formation
of 2a to 81% (Entry 4). When the reaction temperature was lowered to 110 °C, decrease
in the reaction rate and yield were observed (Entry 5). To reduce the reaction temperature
and increase the reaction rate, two strategies were considered, 1) employing electron rich
phosphines such as (Me
2
N)
3
P to increase the nucleophilicity of ylide intermediate.
However, our investigation at various temperatures provided less than 15% of 2a (Entry
6-8), which could be attributed to the competing reaction of the electron-rich phosphine
with the aldehyde.
[17]
Further, use of dibenzothiophene (Entry 9) or (PhO)
3
P (Entry 10) in
place of the PPh
3
resulted in less than 8% of 2a. 2) The second strategy was to study the
effect of aprotic polar solvents such as DMF, as these solvents are commonly used for
nucleophilic substitution reactions involving alkali-metal halides and well known for the
activation of silicon centers.
[18]
Although, TMSCF
3
reacted at room temperature in DMF
with LiI, only 10% of the desired product 2a was obtained (Entry 11) along with 34% of
nucleophilic CF
3
addition product. Further reactions were investigated in solvent systems
comprised of DMF and various less polar solvents (THF, CH
3
CN, dioxane, diglyme,
benzene and toluene) in different ratios (Entry 12-17). 8% DMF in dioxane and 16%
DMF in toluene were found to be the optimum ratio for the reactions at 120 °C. Further
111
optimization of reagents was carried out in 8% DMF/dioxane to obtain the conditions
described in Table 4.
Table 4 Substrate scope of aromatic aldehydes and ketones (Condition A).
[a]

[a] Reactions were carried out on 0.25 mmol scale with 2.5 mL solvent. Isolated yield is
presented without parenthesis. Conversions in parenthesis were determined by
19
F NMR
using C
6
F
6
as an internal standard.

The scope of the optimized conditions on several aromatic aldehydes was
investigated (Table 4). The simple polycyclic aromatic aldehydes provided greater than
80% yield (2a-2d). Substrates with electron-donating substituents such as -OMe, -
OCH
2
Ph and -Ph yielded greater than 60% of the corresponding 1,1-difluoroalkenes (2e-
CF
2
2b, 82% (85%)
CF
2
CF
2
F
2
C
2c, (85%) 84 %
2d, 83% (83%)
2a, (85%)
R O
PPh
3
(1.5 equiv), LiI (1.0 equiv)
+
TMSCF
3
R CF
2
8% DMF/dioxane, 120
o
C, 24h
Br
MeO
CF
2
CF
2
CF
2
CF
2
CF
2
F
3
C
CF
2
2e, 61% (63%)
2k, (93%) 88%
CF
2
NC
2h, 22% (30%)
2m, (80%) 78%
O
2
N
2n, 55% (61%)
Ph
2g, 76% (79%)
CF
2
I
PhH
2
CO
CF
2
CF
2
Cl
CF
2
F
2l, 76% (82%)
2f, 62% (65%)
2i, (84%) 2j, 90% (94%)
2o, 79% (82%)
CF
2
Br
2v, (24%)
2r, (54%)
CF
2
CF
2
Cl
2s, (24%)
CF
2
2u, (9%)
N
Me
CF
2
N
Me
F
2
C
2p, (31%)
2q, Traces
(2.5 equiv)
R'
R'
CF
2
2t, Traces
Me
2
N
112
2g). Typically amino groups are sensitive functional groups for reaction with TMSCF
3
.
However, under the present conditions, the N,N-dimethylaminobenzaldehyde underwent
reaction to give 30% of 2h. Excellent yields of products, 2i-2l, were obtained with
halogen containing aldehydes. The substrates with electron-withdrawing groups such as -
CN, -NO
2
and –CF
3
groups also furnished good product yields (2m-2o). Among the
nitrogen containing heterocyclic aldehydes investigated, 31% of 2p was obtained with
indole-2-carboxaldehyde, whereas only traces of 2q was detected with indole-3-
carboxaldehyde and no product was observed with pyridine-3-carboxaldehyde. The α,β-
unsaturated carbonyls like cinnamaldehyde and 4’-chlorochalcone underwent reaction to
provide the difluoroalkenes 2r (54%) and 2s (24%); in these cases no CF
3
addition to
carbonyl groups or cyclopropanation of double bonds was seen. Under the present
conditions, fluorenone produced traces of 2t, whereas benzophenone yielded 9% of 2u.
When the enolizable 4-bromoacetophenone was investigated, only 24% of 2v was
observed.
We surmised that the enolization and consequent side reactions are pronounced at
elevated temperatures and therefore milder conditions might be needed for sensitive
functional groups containing aldehydes and ketones. Thus, the solvent combination
strategy to lower the reaction temperature was further explored. As we discussed earlier,
the singlet difluoromethylene can be generated with the right combination of solvent
system at various temperatures. Therefore, various ratios of DMF/THF and DMF/toluene
were investigated with 4-bromoacetophenone as a model substrate to carry out the
reaction around the boiling point of TMSCF
3
, to avoid TMSCF
3
staying in vapour phase
113
in the reaction vessel’s headspace, 30% DMF in toluene or 20% DMF in THF appeared
to have similar reactivity in terms of unreacted TMSCF
3
. However, 30% DMF in toluene
Table 5 Substrate scope of a variety of aldehydes and ketones (Condition B).
[a]

[a] Reactions were carried out on 0.25 mmol scale with 2.5 mL solvent. Isolated yield is
presented without parenthesis. Conversions in parenthesis were determined by
19
F NMR
using C
6
F
6
as an internal standard. [b] Light was excluded.

seemed to produce higher yield of the desired product. Hence, DMF/toluene combination
was chosen for further optimization. However, the reaction at room temperature
proceeded rather slowly. Therefore, reactions at various temperatures (45, 55, 65, & 75
°C) were investigated, and 45 °C found to be the optimum temperature with 84%
R O
PPh
3
(3.0 equiv), LiI (2.0 equiv)
+ TMSCF
3
R CF
2
30% DMF/Toluene, 45
o
C, 40h
R'
R'
Me
CF
2
Br
Me Me
Me
CF
2
2v, 82% (84%)
(2.5 equiv)
Et
CF
2
3a, 43% (48%)
3d, 52% (58%)
2r, 48% (54%)
CF
2
CF
2
2u, (21%)
CF
2
3b, (50%)
Me Me Me
Me
Me
CF
2
F
2
C
H
H
H
H
3e, 43% (53%)
3i,
[b]
56%, (58%)
CF
2
3h, 45% (54%)
n-Bu
CF
2
n-Bu
3f, (16%)
Me
CF
2
3g, (24%)
CF
2
3c, (18%)
N
Me
CF
2
2p, 45% (50%)
N
Me 2q, (65%)
CF
2
CF
2
Me
2
N
2h, (60%)
CF
2
MeO
2e, (71%)
NC
CF
2
2m, (25%)
114
conversion to 2v over 40 hours (Table 5). Further, reducing the amount of PPh
3
or LiI
decreased the reaction rate.
With milder optimized conditions, several enolizable and sensitive group containing
carbonyl compounds were studied (Table 5). Propiophenone reacted moderately well to
provide 3a (43%), whereas the cyclic aryl alkyl ketones, indanone and α-tetralone,
furnished 3b and 3c, in moderate and poor yields, respectively. Cyclic alkyl ketones such
as 4-tert-butylcyclohexanone and 5α-cholestan-3-one yielded greater than 50% products
(3d & 3e). However, the open chain ketone, 5-nonanone, performed poorly to give 16%
of 3f. Aliphatic enolizable aldehydes such as 2-phenylpropanal and 3-phenylpropanal
also reacted under these conditions, producing 3g (24%) and 3h (54%), respectively.
Non-enolizable cinnamaldehyde yielded 54% of 2r. The difluoromethylene analogue of
polyene containing retinal (3j) was obtained in 56% isolated yield. The poorly
performing aromatic aldehydes (Table 4) at 120 °C, namely, 4-
(dimethylamino)benzaldehyde, indole-2-carboxaldehyde and indole-3-carboxaldehyde
performed well under these conditions to provide 2h (60%), 2p (50%) and 2q (65%)
products, accordingly. However, no product was obtained in the case of pyridine-3-
carboxaldehyde. Only, 25% of 2m was obtained with 4-cyanobenzaldehyde.
Furthermore, no desired product was observed in the reactions with N-methyl and N-
phenyl succinimides and the simple aromatic carboxylic ester, ethyl benzoate. When
benzophenone was investigated under the present milder conditions (B), 21% of 2u was
formed. To avoid steric crowding, which may be an inhibiting factor in the formation of
oxaphosphatane intermediate; the tributylphosphine (cone angle (θ) = 132°) was
employed instead of PPh
3
(cone angle (θ) = 145°).
[19]
Consequently, 10% of the expected
115
product along with the 38% of the TMS protected intermediate 4 was observed in NMR
analyses (Scheme 3; also see SI).
20
One can speculate that the oxaphosphatane formation
is hindered and therefore the betaine picks up a TMS group leading to the formation of 4.
Our attempts to increase the conversion by increasing the temperature resulted in little
improvement in the yield. For instance, only 17% 2u was obtained at 75 °C. No product
was observed when dibenzothiophene, diphenylsulfide and tetrahydrothiopyran were
employed in place of (n-Bu)
3
P. Scalability and ease of the experiments were also
demonstrated on the bench top on a gram scale (20 mmol) using 4-bromoacetophenone to
obtain 76% isolated yield (3.46 g) of 2v (see the experimental section).

Scheme 3 Difluoromethylenation of benzophenone. Conversions in parentheses were
determined by
19
F NMR using C
6
F
6
as an internal standard.

Motivated by the fact that the adamantyl skeleton, referred in medicinal chemistry as
a lipophilic-bullet motif for its compact nature, found as a key structure in seven
approved drugs in the market,
[ 21 ]
difluoromethylenation of 2-adamantanone was
investigated. Under the conditions A (Table 4) and B (Table 5), the 2-admantanone failed
to react. Interestingly, when (n-Bu)
3
P was employed, 67% of 5 was obtained (Scheme 4).
However, the product was volatile, therefore benzene was employed as a co-solvent for
its easy separation.
O
P(n-Bu)
3
(3.0 equiv), LiI (2.0 equiv)
+
TMSCF
3
30% DMF/Toluene, 45
o
C, 40h
CF
2
+
CF
2
P(n-Bu)
3
OTMS
2u, (10%) 4, (38%)
(2.5 equiv)
(0.25 mmol)
X
-
(X = F
-
or I
-
)
116

Scheme 4 Difluoromethylenation of 2-adamantanone. Conversions in parentheses were
determined by
19
F NMR using C
6
F
6
as an internal standard.
[a]
isolated yield.
In the control experiments carried out under the conditions A and B with 2-
napthaldehyde and 4-bromoacetophenone, respectively, in the absence of DMF or LiI or
PPh
3
, no desired product was observed. Similarly, when the LiI was replaced with
triphenylphosphine oxide or LiF, the reactions failed to produce product. In all these
cases, majority of the TMSCF
3
remained unreacted. Though the LiF failed to react with
TMSCF
3
under the reaction conditions, TMSF was observed in all the reactions, which is
likely formed by the reaction of the in situ formed, more reactive TMSI or the
[Ph
3
POTMS]
+
intermediates. Consequently, the reactions should only require catalytic
amount of LiI. When catalytic amount of LiI (10 mol%) was employed under the
conditions A with 2-napthaldehyde, 68% of the desired alkene (2c) was obtained.
However, prolonging the reaction time did not improve the product formation.
Furthermore, the TMSI produced in the reaction mixture could be consumed by reacting
with the solvents.
22
Therefore, it is safe to say that the Li
+
lowers reactivity of fluoride
such that it only reacts with more Lewis acidic silicon center before it reacts with
TMSCF
3
. In the experiments carried out with 2-napthaldehyde in the presence of 1,1-
diphenylethylene, the difluoromethylenation of carbonyl prevailed over the
cyclopropanation of the alkene—traces of gem-difluorocyclopropane. On the other hand,
in the absence of 2-napthaldehyde and PPh
3
, >30% of such product was observed. Based
P(n-Bu)
3
(3.0 equiv), LiI (2.0 equiv)
+ TMSCF
3
30% DMF/Solvent, 45
o
C, 40h
O
CF
2
toluene (67%)
(2.5 equiv)
(2 mmol)
Solvent: toluene or benzene
5
benzene
[a]
46% (57%)
117
on the above observations and control experiments, the following mechanism has been
proposed (Scheme 5).

Scheme 5 Proposed mechanism.
4.3 Summary and conclusion
In conclusion, this work emphasizes the effect of Li
+
in the singlet
difluoromethylene generation and prevention of undesired decomposition of TMSCF
3
.
Furthermore, by finding the right conditions to activate TMSCF
3
in the presence of
phosphines at various temperatures (RT to 170 °C), we have achieved a practical and
versatile one-pot procedure for the synthesis of a series of functionalized gem-
difluoroalkenes, including difluoro analogs of biologically active compounds, from
aldehydes and ketones. The work also demonstrates that the mixed solvent system can be
critical to achieve controlled depletion of TMSCF
3
. We believe that the results presented
in this chapter will, in addition to providing access to interesting gem-difluoroalkenes,
propel the researchers to discover useful direct difluoromethylene transfer methods using
the readily available Ruppert-Prakash reagent.

Me
3
SiCF
3
LiI
PPh
3
Ph
3
PCF
2
+
R
O
R'
R
O
R'
CF
2
PPh
3
CF
2
+
R
CF
2
R'
Ph
3
PO +
118
4.4 Experimental Section.
4.4.1 Materials and Instrumentation

1
H,
13
C, and
19
F NMR spectra were recorded on Varian 600 MHz or 500 MHz or
400 MHz NMR spectrometers.
1
H NMR chemical shifts were determined relative to the
signal of a residual protonated solvent, CDCl
3
(δ 7.26 ppm).
13
C NMR chemical shifts
were determined relative to the
13
C signal of solvent, CDCl
3
(δ 77.16 ppm).
19
F NMR
chemical shifts were determined relative to CFCl
3
as an internal standard (δ 0.0 ppm).
Mass spectral data were recorded on a Bruker 300-MS TQ Mass Spectrometer at 70 eV
for EI. HRMS data was obtained from University of Illinois-Urbana Champagne Mass
Spectrometry Facility. Typically, all reactions mixtures were prepared under Argon
atmosphere (Ar glovebox). TMSCF
3
was distilled and stored over 4 Å MS. Dioxane and
THF were freshly distilled over sodium benzophenone ketyl before use. Unless otherwise
mentioned, all other reactants, reagents and solvents were purchased from commercial
sources.
4.4.2 Experimental procedures.
Procedure A (difluoromethylenation of aromatic aldehydes
A microwave vial (5mL, Biotage) was sealed under inert atmosphere (Ar
Glovebox) with stir bar, triphenylphosphine (1.5 equiv), lithium iodide (1.0) and solid
aldehydes (0.25 mmol) (liquid aldehydes are introduced using syringe outside the
glovebox). To this vial, freshly distilled dioxane (2.3 mL) and anhydrous DMF (0.2 mL)
were injected. Finally, TMSCF
3
(2.5 equiv) was added through a syringe. The resulting
mixture was heated at 120 °C for 24 hours. As the reaction proceeded, the reaction
mixture turned from pale orange to dark brown. The reaction vial was cooled down to
119
room temperature and internal standard (hexafluorobenzene) was added. For non-polar
substrates, methyl iodide (4-5 equiv) was added and stirred for 5 min to prevent
triphenylphosphine interference during the column chromatography separation (
31
P NMR
confirmed the absence of phosphine). The reaction mixture was quenched with water (5
mL) and extracted with (3 X 5 mL) diethyl ether. The combined ether layer was dried
over anhydrous MgSO
4
, filtered and dried on a rotary evaporator to obtain the crude
product. The crude product was dissolved in a small amount of dichloromethane (DCM),
and loaded on 1g silica cartridge, air-dried and eluted with pentane or hexane or
hexane/ethyl acetate gradient. The pure fractions were combined and the solvent was
evaporated to obtain the pure 1,1-difluoroolefins.
Procedure B (difluoromethylenation of enolizable carbonyl compounds)
A microwave vial (5mL, Biotage) was sealed under inert atmosphere (Ar
Glovebox) with a stir bar, triphenylphosphine (3.0 equiv), lithium iodide, (2.0) and solid
aldehydes (0.25 mmol) (Liquid aldehydes are injected outside the glovebox). To this vial,
anhydrous toluene (2.2 mL) and anhydrous DMF (0.3 mL) were injected. Finally,
TMSCF
3
(2.5 equiv) was added through a syringe. The resulting mixture was heated at 45
°C for 40 hours. As the reaction proceeded, the reaction mixture also turned from pale
orange to dark brown. The reaction vial was cooled down to room temperature and
internal standard (hexafluorobenzene) was added. For non-polar substrates, methyl
iodide (4-5 equiv) was added and stirred for 5 min to prevent triphenylphosphine
interference during the column chromatography separation (
31
P NMR confirmed the
absence of phosphine). The reaction mixture was quenched with water (5 mL) and
extracted with (3 X 5 mL) diethyl ether. The combined ether layer was dried over
120
anhydrous MgSO
4
, filtered and dried on a rotary evaporator to get the crude product. The
crude product was dissolved in a small amount of dichloromethane (DCM) and loaded on
a 1g silica cartridge, air dried and eluted with pentane or hexane or hexane/ethyl acetate
gradient. The pure fractions were combined and the solvent(s) was evaporated to obtain
the pure products.
Modified procedure for the gram scale reaction
An over dried Schlenk flask, charged with stir bar was cooled in a stream of
Argon. Triphenylphosphine (60 mmol; 15.737), 4-bromoacetophenone (20 mmol; 3.98g,)
and LiI (40 mmol; 5.354 g) were added under a stream of Argon. To this mixture, toluene
(70 mL; anhydrous) and DMF (30 mL; anhydrous) were added subsequently and stirred
to mix well before the addition of TMSCF
3
(50 mmol; 7.11g; 7.4 mL). This mixture was
moved to preheated oil bath at 45
o
C (fluctuation in the bath temperature slows down the
reaction) the bath temperature. After 52 hours the reaction mixture was diluted with water
and extracted in ether (2 x 40 mL) and the combined layer was washed with water (3 x 80
mL) and brine and dried over MgSO
4
, filtered and the solvent was removed under
vacuum. Majority of Ph
3
P and Ph
3
PO crystalized out, which was filtered and washed
with pentane/toluene. Residue (ca. 6.5g) was dissolved in a small amount of
dichloromethane and to prevent interferences of leftover Ph
3
P with product isolation, MeI
(4-5 mL) was added and the resulting solution was loaded on a silica column and eluted
with pentane, the pure fractions were combined and the solvent was removed in a rotary
evaporator to obtain 3.46 g (76%) of 2v as a colorless liquid.

121
4.4.3 Spectral data
(2,2-difluorovinyl)benzene (2a)

Benzaldehyde (26.5 mg) was used.
19
F NMR (unlocked; referenced to C
6
F
6
(-164.9
ppm)).
19
F NMR (376 MHz, Chloroform-d) δ -85.56 (dd, J = 34.7, 27.0 Hz), -87.34 (dd, J
= 34.9, 4.4 Hz). The data is in agreement with the literature data.
26b

1-(2,2-difluorovinyl)pyrene (2b)

Using pyrene-1-carbaldehyde (57.6 mg), 2b was isolated as a white solid (47.8 mg, 82%).
1
H NMR (500 MHz, Chloroform-d) δ 8.23 – 7.99 (m, 9H), 6.17 (dd, J = 24.8, 3.5 Hz,
1H).
19
F NMR (470 MHz, Chloroform-d) δ -83.3 (dd, J = 28.6, 3.6 Hz) -85.3 (dd, J =
25.4, 28.6 Hz).
13
C NMR (126 MHz, Chloroform-d) δ 156.9 (dd, J = 297.1, 289.0 Hz),
131.5, 130.9, 130.8, 128.8 (d, J = 3.8 Hz), 128.1, 127.7, 127.5, 126.4 (dd, J = 7.2, 1.7
Hz), 126.26, 125.61, 125.38, 125.02, 124.84, 124.18 (dd, J = 7.1, 5.2 Hz), 123.22, 79.52
(dd, J = 29.6, 15.2 Hz). HRMS (EI) for C
18
H
10
F
2
: calculated 264.0751; found 264.0751.
2-(2,2-difluorovinyl)naphthalene (2c)

Using 2-naphthaldehyde (39.0 mg), 2c was isolated as a white solid (40 mg, 84%).
1
H
NMR (500 MHz, Chloroform-d) δ 7.90 – 7.64 (m, 4H), 7.61 – 7.34 (m, 3H), 5.43 (dd, J =
CF
2
CF
2
CF
2
122
26.2, 3.9 Hz, 1H).
19
F NMR (470 MHz, Chloroform-d) δ -82.5 (dd, J = 30.8, 26.4 Hz), -
84.2 (dd, J = 27.3, 3.7 Hz).
13
C NMR (126 MHz, Chloroform-d) δ 156.6 (dd, J = 298.5,
288.5 Hz), 133.6, 132.4, 128.5, 128.0, 127.9, 127.8, 126.9 – 126.6 (m), 126.6, 126.2,
125.5 (dd, J = 6.6, 2.4 Hz), 82.6 (dd, J = 29.5, 13.3 Hz). EI-MS: m/z (relative intensity):
190.1 [M
+
] (100%). The data is in agreement with the literature data.
23,24

9-(2,2-difluorovinyl)anthracene (2d)

Using anthracene-9-carbaldehyde (51.6 mg), 2d was isolated as a pale yellow solid (50
mg, 83%).
1
H NMR (500 MHz, Chloroform-d) δ 8.47 (s, 1H), 8.16 (d, J = 8.6 Hz, 2H),
8.03 (d, J = 7.8 Hz, 2H), 7.61 – 7.46 (m, 4H), 5.99 (dt, J = 26.4, 1.2 Hz, 1H).
19
F NMR
(470 MHz, CDCl
3
) δ -82.3 (t, J = 27.2 Hz), -84.9 (d, J = 28.3 Hz).
13
C NMR (126 MHz,
Chloroform-d) δ 155.9 (dd, J = 293.8, 290.5 Hz), 131.5, 130.4 (d, J = 2.2 Hz), 128.9,
127.8, 126.3, 125.5, 125.4, 122.7 (dd, J = 7.1, 2.4 Hz), 76.6 (dd, J = 28.6, 20.0 Hz).
HRMS (EI) for C
16
H
10
F
2
: calculated 240.0751, found 240.07446.
1-(2,2-difluorovinyl)-4-methoxybenzene (2e)

Using 4-methoxybenzaldehyde (34 mg), 2e was isolated as a colorless liquid (26 mg,
61%).
1
H NMR (500 MHz, Chloroform-d) δ 7.25 (d, J = 8.9 Hz, 2H), 6.88 (dd, J = 8.7,
0.0 Hz, 2H), 5.21 (dd, J = 26.0, 3.8 Hz, 1H), 3.81 (s, 3H).
19
F NMR (470 MHz,
Chloroform-d) δ -85.2 (dd, J = 36.4, 26.5 Hz), -86.9 (dd, J = 36.7, 3.9 Hz).
13
C NMR
MeO
CF
2
F
2
C
123
(126 MHz, Chloroform-d) δ 158.7 (t, J = 2.3 Hz), 158.45 – 153.35 (m), 128.9 (dd, J =
6.2, 3.4 Hz), 122.8 (t, J = 6.2 Hz), 114.3 , 81.7 (dd, J = 29.2, 14.2 Hz), 55.4. EI-MS: m/z
(relative intensity) 170.1 [M
+
] (100). The data is in agreement with the literature data.
25

1-(benzyloxy)-4-(2,2-difluorovinyl)benzene (2f)

Using 4-(benzyloxy)benzaldehyde (53 mg), 2f was isolated as a white solid (38.2 mg,
61%).
1
H NMR (399 MHz, Chloroform-d) δ 7.45 – 7.29 (m, 5H), 7.24 (d, J = 8.8 Hz,
2H), 6.95 (d, J = 8.8 Hz, 2H), 5.21 (dd, J = 26.4, 3.9 Hz, 1H), 5.07 (s, 2H).
19
F NMR
(376 MHz, Chloroform-d) δ -85.0 (dd, J = 36.4, 26.4 Hz), -86.8 (dd, J = 36.4, 3.9 Hz).
EI-MS: m/z (relative intensity): 246.2 [M+] (10%), 91.2 (100%), 65.1 (26.4%), 51.2
(12.2%). The data is in agreement with the literature data.
26

4-(2,2-difluorovinyl)-1,1'-biphenyl (2g)

Using [1,1'-biphenyl]-4-carbaldehyde (45.6 mg), 2g was isolated as white solid (38.9 mg,
72%).
1
H NMR (600 MHz, Chloroform-d) δ 7.62 – 7.47 (m, 4H), 7.47 – 7.28 (m, 5H),
5.32 (dd, J = 26.4, 3.7 Hz, 1H).
19
F NMR (564 MHz, Chloroform-d) δ -82.4 (dd, J = 30.8,
26.4 Hz), -84.4 (dd, J = 30.6, 3.8 Hz).
13
C NMR (151 MHz, Chloroform-d) δ 156.5 (dd, J
= 288.4 Hz, 298.1 Hz), 140.7, 139.9 (d, J = 2.2 Hz), 129.7 – 129.4 (m), 128.9, 128.1 (dd,
J = 6.4, 3.5 Hz), 127.6, 127.5, 127.0 , 82.1 (dd, J = 29.2, 13.6 Hz). EI-MS: m/z (relative
intensity) 216.1 [M
+
] (100%), 165.2 (30%). The data is in agreement with the literature
data.
27

PhH
2
CO
CF
2
CF
2
Ph
124
4-(2,2-difluorovinyl)-N,N-dimethylaniline (2h)

Using 4-(dimethylamino)benzaldehyde (37.3 mg), 2h was isolated as a yellow liquid (10
mg, 22%).
1
H NMR (600 MHz, Chloroform-d) δ 7.21 (d, J = 8.8, 2H), 6.70 (d, J = 8.8,
2H), 5.17 (dd, J = 26.8, 4.1 Hz, 1H), 2.95 (s, 6H).
19
F NMR (564 MHz, Chloroform-d) δ -
86.4 (dd, J = 40.5, 26.8 Hz), -88.6 (dd, J = 40.6, 3.8 Hz).
13
C NMR (151 MHz,
Chloroform-d) δ 160.2 – 151.8 (m), 149.6, 128.6 (m), 118.3 , 112.7, 81.9 (dd, J = 28.4,
14.5 Hz), 40.6 . EI-MS: m/z (relative intensity) 183.2[M
+
] (100). The data is in
agreement with the literature data.
28,29
However, Riss et al
30
have incorrectly reported 12
carbon signals for this compound.
1-(2,2-difluorovinyl)-4-fluorobenzene (2i)

4-fluorobenzaldehyde (39.5 mg) was used.
19
F NMR (unlocked referenced to C
6
F
6
(-
164.9 ppm)) δ -85.85 (dd, J = 35.1, 27.2 Hz), -87.6 (dd, J = 35.5, 4.6 Hz), -116.37 (s).
The data is in agreement with the literature data.
30

1-chloro-4-(2,2-difluorovinyl)benzene (2j)

Using 4-chlorobenzaldehyde (35.1 mg), 2j was isolated as a colorless liquid (39.3 mg,
90%).
1
H NMR (399 MHz, Chloroform-d) δ 7.32 – 7.29 (m, 2H), 7.27 – 7.24 (m, 2H),
CF
2
F
CF
2
Cl
N
CF
2
125
5.25 (dd, J = 25.9, 3.6 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -82.1 (dd, J = 29.9,
25.9 Hz), -83.9 (dd, J = 29.8, 3.5 Hz).
13
C NMR (100 MHz, Chloroform-d) δ 156.5 (dd, J
= 298.4, 289.0 Hz), 132.9 (t, J = 2.6 Hz), 129.2 – 128.8 (m), 81.6 (dd, J = 29.9, 13.7 Hz).
EI-MS: m/z (relative intensity) 174.1 [M
+
](100%), 176.2 (26.7%), 139.1 (27.9%), 119.1
(43%), 50.2 (40.7%). The data is in agreement with the literature data.
28,29

1-bromo-4-(2,2-difluorovinyl)benzene (2k)

Using 4-bromobenzaldehyde (46.3), 2k was isolated as a colorless liquid (48 mg, 87%).
1
H NMR (399 MHz, Chloroform-d) δ 7.46 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H),
5.23 (dd, J = 25.8, 3.6 Hz, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 156.5 (dd, J =
298.6, 289.3 Hz), 132.0, 129.6 – 129.4 (m), 129.3 (dd, J = 6.6, 3.7 Hz), 121.0 (t, J = 2.8
Hz), 81.7 (dd, J = 29.8, 13.6 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -81.8 (dd, J =
29.2, 25.9 Hz), -83.6 (dd, J = 29.3, 3.5 Hz). EI-MS: m/z (relative intensity) 220 (100%),
218.1 [M
+
] (71.5), 139.2 (31.5%), 119.1 (88.5%), 99.2 (30%), 50.3 (33.5%). The data is
in agreement with the literature data.
31

1-(2,2-difluorovinyl)-4-iodobenzene (2l)

Using 4-iodobenzaldehyde (58 mg), 2l was isolated as a colorless liquid (50.6 mg, 76%).
1
H NMR (399 MHz, Chloroform-d) δ 7.66 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H),
5.21 (dd, J = 26.0, 3.6 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -81.4 (dd, J = 28.6,
25.9 Hz), -83.3 (dd, J = 28.6, 3.6 Hz).
13
C NMR (100 MHz, Chloroform-d) δ 156.4 (dd, J
Br
CF
2
CF
2
I
126
= 298.4, 288.4), 137.8, 130.1 – 129.7 (m), 129.3 (dd, J = 6.5, 3.5 Hz), 92.7 – 91.7 (m),
81.6 (dd, J = 29.7, 13.4 Hz). EI-MS: m/z (relative intensity) 266.1[M
+
] (100%), 139.2
(38.4%), 119.1 (59.5%), 63.2 (31.5%). The data is in agreement with the literature data.
32

4-(2,2-difluorovinyl)benzonitrile (2m)

Using 4-formylbenzonitrile (32.8 mg), 2m was isolated as a white solid (32 mg, 78%).
1
H
NMR (399 MHz, Chloroform-d) δ 7.62 (dd, J = 7.9, 1.2 Hz, 2H), 7.43 (d, 2H), 5.33 (dd,
J = 25.6, 3.4 Hz, 1H).
13
C NMR (100 MHz, Chloroform-d) δ 157.1 (dd, J = 293.3, 290.6
Hz) 135.7 – 135.3 (m), 132.6, 128.2 (dd, J = 6.9, 3.6 Hz), 118.8, 110.7 (t, J = 2.4 Hz),
82.3 – 81.6 (m).
19
F NMR (376 MHz, Chloroform-d) δ -78.3 (dd, J = 25.5, 20.6 Hz), -
80.0 (dd, J = 20.5, 3.5 Hz). EI-MS: m/z (relative intensity) 165[M
+
] (100). The data is in
agreement with the literature data.
33

1-(2,2-difluorovinyl)-4-nitrobenzene (2n)

Using 4-nitrobenzaldehyde (34.5 mg), 2n was isolated as a white solid (32 mg, 78%).
1
H
NMR (600 MHz, Chloroform-d) δ 8.20 (d, J = 8.9 Hz, 2H), 7.48 (d, J = 8.9 Hz, 2H), 5.40
(dd, J = 25.4, 3.3 Hz, 1H).
19
F NMR (564 MHz, Chloroform-d) δ -77.8 (dd, J = 25.5, 18.5
Hz), -79.2 (dd, J = 18.4, 3.4 Hz).
13
C NMR (151 MHz, Chloroform-d) δ 157.3 (dd, J =
301.7, 292.9 Hz), 146.6, 138.8 – 136.4 (m), 128.3 (dd, J = 6.9, 3.5 Hz), 124.2, 81.8 (dd, J
= 30.6, 12.8 Hz). EI-MS: m/z (relative intensity) 185.2[M
+
] (93), 169.4(26), 155.1(47),
CF
2
NC
CF
2
O
2
N
127
127.2(36), 119.2(100), 99.1(72), 77.1(83.6), 51.1 (49). The data is in agreement with the
literature data.
33

1-(2,2-difluorovinyl)-4-(trifluoromethyl)benzene (2o)

Using 4-(trifluoromethyl)benzaldehyde (43.5 mg), 2o was isolated as a colorless liquid
(41.1 mg, 79%).
1
H NMR (500 MHz, Chloroform-d) δ 7.70 – 7.55 (m, 2H), 7.43 (d, 8.0
Hz, 2H), 5.34 (dd, J = 25.7, 3.6 Hz, 1H).
19
F NMR (470 MHz, Chloroform-d) δ -63.2
(3F) , -80.2 (dd, J = 25.9, 23.5 Hz, 1F), -81.2 – -82.5 (m, 1F). EI-MS: m/z (relative
intensity) 208.0[M
+
] (100). The data is in agreement with the literature data.
34

1-bromo-4-(1,1-difluoroprop-1-en-2-yl)benzene (2v)

Using 1-(4-bromophenyl)ethan-1-one (49.8 mg), 2v was isolated as a colorless liquid
(47.8 mg, %).
1
H NMR (399 MHz, Chloroform-d) δ 7.48 (d, J = 8.6 Hz, 1H), 7.24 (d, J =
8.5 Hz, 0H), 1.95 (t, J = 3.4 Hz, 3H).
19
F NMR (376 MHz, Chloroform-d) δ -89.8 (dq, J =
41.7, 3.3 Hz), -90.3 (dq, J = 41.7, 3.6 Hz).
13
C NMR (100 MHz, Chloroform-d) δ 153.6
(dd, J = 291.0, 286.8 Hz), 133.9 (t, J = 4.3 Hz), 131.7, 129.2 (dd, J = 4.9, 3.4 Hz), 121.1
(t, J = 1.5 Hz), 87.0 (dd, J = 23.3, 14.1 Hz), 13.2 (t, J = 1.9 Hz). EI-MS: m/z (relative
intensity) 234.1 (89%), 232.1 (97.2%), 153.2 (28.7%), 133.2 (100%), 102.2 (35%) 77.1
(28.2%), 51.1 (47.3 %). The data is in agreement with the literature data.
28
(1,1-difluorobut-1-en-2-yl)benzene (3a)
F
3
C
CF
2
CF
2
Br
128

Using propiophenone (33.5 mg), 3a was isolated as a colorless liquid (18 mg, 43%).
1
H
NMR (500 MHz, Chloroform-d) δ 7.41 – 7.29 (m, 5H), 2.49 – 2.41 (m, 2H), 1.04 (t, J =
7.5 Hz, 3H).
19
F NMR (470 MHz, Chloroform-d) δ -92.9.
13
C NMR (126 MHz,
Chloroform-d) δ 153.4 (t, J = 289.0 Hz), 133.9, 128.5, 128.4 (t, J = 3.3 Hz), 127.3, 93.8
(dd, J = 18.5, 15.5 Hz), 21.3, 13.0. EI-MS: m/z (relative intensity) 168.2 [M
+
] (100%),
153.2 (85.6 %), 133.2 (91.5%), 127.1 (45.2%), 117.2 (46.9%), 103.2 (36.8), 78.2
(46.1%), 51.1 (78.4). The data is in agreement with the literature data.
35,36

1-(difluoromethylene)-2,3-dihydro-1H-indene (3b)

Using 1-indanone (33 mg), 3b (46 mg) was obtained with an unknown impurity (
19
F
NMR (376 MHz, Chloroform-d) δ -149.34 (d, J = 179.0 Hz), -154.07 (d, J = 179.0 Hz)).
1
H NMR (399 MHz, Chloroform-d) δ 7.47 – 7.41 (m, 1H), 7.31 – 7.27 (m, 1H), 7.25 –
7.15 (m, 2H), 3.09 – 3.02 (m, 2H), 2.83 – 2.74 (m, 2H).
19
F NMR (376 MHz,
Chloroform-d) δ = -89.2 (d, J = 51.1), -88.9 (d, J = 49.8).
13
C NMR (100 MHz,
Chloroform-d) δ 151.9 (dd, J = 291.0, 285.7 Hz), 144.9 (dd, J = 5.6, 1.6 Hz), 136.1 (d, J
= 5.6 Hz), 127.4 (t, J = 2.4 Hz), 127.0, 124.9 (d, J = 1.2 Hz), 123.3 (dd, J = 9.1, 2.4 Hz),
95.2 (dd, J = 25.7, 16.6 Hz), 30.6, 24.5 (t, J = 2.0 Hz). EI-MS: m/z (relative intensity)
CF
2
CF
2
129
165.4[M
+
] (100), 166.2 (83), 164.3 (55), 146.2 (44.1), 114.8 (52.9), 82.3 (50.4), 51.3
(32.1). The data is in agreement with the literature data.
37

1-(difluoromethylene)-1,2,3,4-tetrahydronaphthalene (3c)

Using α-tetralone (36.5 mg), 18% conversion (determined
19
F NMR using
hexafluororbenzene internal standard) of 3c was obtained.
19
F NMR (376 MHz,
Unlocked; referenced to C
6
F
6
) δ = -90.7 (d, J = 41.4 Hz), -90.4 (d, J = 41.4). The data is
in agreement with the literature data.
38

1-(tert-butyl)-4-(difluoromethylene)cyclohexane (3d)

Using 4-(tert-butyl)cyclohexan-1-one (38.6 mg), 3d was isolated as a colorless liquid
(24.5 mg, 52%).
1
H NMR (500 MHz, Chloroform-d) δ 2.49 (dd, J = 14.3, 2.9 Hz, 2H),
1.89 – 1.79 (m, 2H), 1.77 – 1.64 (m, 2H), 1.12 – 0.93 (m, 3H), 0.85 (s, 9H).
19
F NMR
(470 MHz, Chloroform-d) δ -99.99.
13
C NMR (126 MHz, Chloroform-d) δ 150.57 (t, J =
279.0, 278.5 Hz), 88.16 (t, J = 18.6 Hz), 47.95 , 32.63 , 27.68 , 27.37 (t, J = 2.0 Hz),
24.77 (t, J = 1.9 Hz). EI-MS: m/z (relative intensity) 188.3[M
+
] (14), 160.1 (19), 126.4
(31), 97.1 (30), 69.3 (39), 61.2 (75), 55.1 (100). EI-HRMS for C
11
H
18
F
2
: : calculated
188.1377; found 188.1373.
CF
2
CF
2
130
(5S,8R,9S,10S,13R,14S,17R)-3-(difluoromethylene)-10,13-dimethyl-17-((R)-6-
methylheptan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthrene (3e)

Using 5α-Cholestan-3-one (96.7 mg) and 3e was isolated as a white solid (45.2 mg, 43
%).
1
H NMR (399 MHz, Chloroform-d) δ 2.27 (d, J = 14.9 Hz, 2H), 2.03 (d, J = 14.7 Hz,
2H), 1.97 (dt, J = 12.6, 3.4 Hz, 2H), 1.93 – 1.42 (m, 7H), 1.42 – 0.93 (m, 18H), 0.90 (d, J
= 6.4 Hz, 3H), 0.86 (dd, J = 6.7, 1.8 Hz, 6H), 0.82 (d, J = 0.6 Hz, 3H), 0.65 (s, 3H).
19
F
NMR (376 MHz, Chloroform-d) δ -99.6 – -100.2 (m).
13
C NMR (100 MHz, Chloroform-
d) δ 150.8 (t, J = 280.0 Hz), 87.9 (t, J = 18.4 Hz), 56.6, 56.4, 54.3, 46.4, 42.7, 40.2, 39.7,
38.1, 36.3, 36.2, 35.9, 35.6, 32.0, 28.8, 28.4, 28.2, 26.8, 24.4, 23.9, 22.9, 22.7, 21.2, 20.1,
18.8, 12.2, 11.5. EI-HRMS: Calculated mas for C
28
H
46
F
2
: 420.3568; found: 420.3564.
5-(difluoromethylene)nonane (3f)

Using (35.6 mg) of nonan-5-one, 16% (3f) conversion was obtained (determined by 19F
NMR using hexafluororbenzene internal standard).
19
F NMR (376 MHz, Unlocked;
referenced to C
6
F
6
) δ = -98.6 (s). The data is in agreement with literature data.
39

(4,4-difluorobut-3-en-2-yl)benzene (3g)

n-Bu
CF
2
n-Bu
F
2
C
H
H
H
H
CF
2
131

Using 2-phenylpropanal (33.5 mg), 24% (3g) conversion (determined by
19
F NMR using
hexafluororbenzene internal standard) was obtained.
19
F NMR (376 MHz, Unlocked;
referenced to C
6
F
6
) δ -92.3 (d, J = 48.3 Hz), -93.1 (dd, J = 48.7, 25.5 Hz).
(4,4-difluorobut-3-en-1-yl)benzene (3h)

Using 3-phenylpropanal (33.5 mg), 3h was isolated as a colorless liquid (19 mg, 45%).
1
H NMR (399 MHz, Chloroform-d) δ 7.33 – 7.27 (m, 2H), 7.24 – 7.15 (m, 3H), 4.16
(dtd, J = 25.5, 7.8, 2.5 Hz, 1H), 2.69 (t, J = 7.6 Hz, 2H), 2.30 (qt, J = 7.5, 1.9 Hz, 2H).
19
F
NMR (376 MHz, Chloroform-d) δ -89.5 (dd, J = 47.3, 2.1 Hz), -91.6 (ddt, J = 47.3, 25.5,
2.0 Hz).
13
C NMR (100 MHz, Chloroform-d) δ 156.47 (dd, J = 287.2, 285.1 Hz), 141.1,
128.6 (d, J = 8.4 Hz), 127.2 – 125.3 (m), 35.8 (t, J = 2.4 Hz), 24.9 – 23.3 (m). EI-MS:
m/z (relative intensity) 168.1[M
+
] (23), 91.1(100), 65.1 (27). The data is in agreement
with literature data.
37,40

2-((1E,3E,5E,7E)-10,10-difluoro-3,7-dimethyldeca-1,3,5,7,9-pentaen-1-yl)-1,3,3-
trimethylcyclohex-1-ene (Retinal-CF
2
) (3i)

Using all-trans retinal (71.1 mg), under darkness, 3i was isolated as an orange liquid
(44.6 mg, 56 %).
1
H NMR (399 MHz, Chloroform-d) δ 6.60 (dd, J = 15.1, 11.2 Hz, 1H),
6.32 (d, J = 15.1 Hz, 1H), 6.22 – 6.07 (m, 3H), 5.97 (d, J = 11.7 Hz, 1H), 5.25 (ddd, J =
CF
2
CF
2
132
23.6, 11.7, 2.1 Hz, 1H), 2.02 (t, J = 6.4 Hz, 2H), 1.96 (d, J = 1.1 Hz, 3H), 1.86 (q, J = 1.2
Hz, 3H), 1.71 (d, J = 1.0 Hz, 3H), 1.67 – 1.56 (m, 2H), 1.51 – 1.42 (m, 2H), 1.03 (s, 6H).
19
F NMR (376 MHz, Chloroform-d) δ -85.7 (t, J = 22.6 Hz), -86.1 (d, J = 21.7 Hz).
13
C
NMR
13
C NMR (100 MHz, Chloroform-d) δ 157.0 (dd, J = 299.3, 292.6 Hz), 138.0,
137.8, 136.4 (dt, J = 11.7, 2.1 Hz), 135.6 (dd, J = 12.1, 3.9 Hz), 130.4, 129.5, 126.9,
125.0 (t, J = 3.0 Hz), 119.3 (t, J = 2.9 Hz), 80.2 (dd, J = 27.9, 16.5 Hz), 39.8, 34.4, 33.2,
21.9, 19.4, 12.9, 12.9. EI-HRMS for C
21
H
28
F
2
: calculated 318.2159; found 318.2156.
(E)-(4,4-difluorobuta-1,3-dien-1-yl)benzene (2r)

Using cinnamaldehyde (33 mg), 2r was isolated as a colorless liquid (20 mg, 48%).
1
H
NMR (399 MHz, Chloroform-d) δ 7.41 – 7.36 (m, 2H), 7.32 (ddd, J = 7.8, 6.8, 1.3 Hz,
2H), 7.26 – 7.21 (m, 1H), 6.66 (ddt, J = 15.9, 10.8, 1.2 Hz, 1H), 6.48 (d, J = 15.9 Hz,
1H), 5.14 (dddd, J = 24.0, 10.8, 1.5, 0.6 Hz, 1H).
19
F NMR (376 MHz, Chloroform-d) δ -
85.81 (dd, J = 26.6, 24.2 Hz), -87.53 (d, J = 26.5 Hz).
13
C NMR (101 MHz, Chloroform-
d) δ 157.0 (dd, J = 297.2, 291.5 Hz), 137.0, 131.2, 128.8, 127.8, 126.3, 117.9 83.01 (dd, J
= 27.7, 15.9 Hz). EI-MS: m/z (relative intensity) 166.2 (77), 146.1 (100), 115.1 (65), 63.1
(43), 51.1 (33). The data is in agreement with the literature data.
41

3-(2,2-difluorovinyl)-1-methyl-1H-indole (2p)

CF
2
N
Me
CF
2
133
Using 1-methyl-1H-indole-2-carbaldehyde (39.8 mg), 2p was isolated as a off white solid
(27.1 mg, 45%).
1
H NMR (399 MHz, Chloroform-d) δ 7.60 (dq, J = 8.0, 0.8 Hz, 1H),
7.32 (dt, J = 8.3, 1.0 Hz, 1H), 7.30 – 7.23 (m, 2H), 7.20 – 7.12 (m, 2H), 5.49 (ddd, J =
27.8, 2.3, 0.7 Hz, 1H), 3.80 (s, 3H).
19
F NMR (376 MHz, Chloroform-d) δ -84.19 (ddd, J
= 38.9, 27.8, 1.9 Hz), -90.59 (dd, J = 39.1, 2.3 Hz).
13
C NMR (100 MHz, Chloroform-d)
δ 156.03 (dd, J = 292.7, 285.6 Hz), 136.71, 127.72 – 126.22 (m), 122.25, 119.70, 118.77
(d, J = 1.4 Hz), 109.53, 73.71 (dd, J = 30.7, 19.1 Hz), 33.06. EI-HRMS for C
11
H
9
F
2
N:
Calculated 193.0703; found 193.0720.
2-(2,2-difluorovinyl)-1-methyl-1H-indole (2q)

Using 1-methyl-1H-indole-3-carbaldehyde (39.8 mg), 2q was isolated as a yellow oil (19
mg, 39 %).
19
F NMR (376 MHz, Acetonitrile-d
3
) δ -84.60 (dd, J = 44.0, 28.8 Hz), -91.36
(dd, J = 44.1, 2.7 Hz). GC-MS: 193.2 (100). (Seem to decompose during purification)
(2,2-difluoroethene-1,1-diyl)dibenzene (2u) (see Scheme 3, in the results and discussion
section)

The reaction mixture was analyzed with
19
F and
31
P NMR (see below).

Ph
CF
2
N
Me
F
2
C
134

19
F NMR (Unlocked), Referenced to C
6
F
6

31
P NMR (Unlocked) Referenced to n-Bu
3
PO

CF
2
P
+
(n-Bu)
3
OTMS
X
-
F
F
F
F
F
F
Ph
CF
2
Ph
CF
2
P
+
(n-Bu)
3
OTMS
X
-
135
(1r,3r,5r,7r)-2-(difluoromethylene)adamantane (volatile) (5)

A microwave vial (20 mL, Biotage) was sealed under inert atmosphere (Ar Glovebox)
with a stir bar, lithium iodide (2.0) and adamantanone (2 mmol). To this vial, anhydrous
benzene (14 mL) (or toluene), anhydrous DMF (6 mL), n-butylphosphine (3 equiv) and
TMSCF
3
(2.5 equiv) were injected. The resulting mixture was heated at 45 °C for 40
hours. In the course of the reaction, the reaction mixture turned pale yellow. The reaction
vial was cooled down to room temperature and internal standard (hexafluorobenzene)
was added. Benzene was slowly evaporated. The mixture was diluted with water and
extracted in pentane (2 x 10 mL) and the combined pentane layer was washed with water
(3 x 10 mL) and brine (10 mL) and dried on anhydrous MgSO
4
. Pentane was removed in
a rotary evaporator. To prevent excess phosphine eluting with the product, the residue
was treated with methyl iodide (1 mL) and the excess was rotary evaporated. The
resulting residue was dissolved in small amount of dichloromethane and loaded on a
silica frit (3g, Biotage) and eluted with pentane. The pure fractions were combined and
pentane was removed to get a pure product as a colorless liquid (170 mg, 46%).
1
H NMR
(500 MHz, Chloroform-d) δ 2.67 (s, 2H), 1.97 (s, 2H), 1.81 (dt, J = 30.3, 12.4 Hz, 10H).
19
F NMR (376 MHz, Chloroform-d) δ -102.3.
13
C NMR (126 MHz, Chloroform-d) δ
148.8 (t, J = 279.5 Hz), 95.8 (t, J = 17.8 Hz), 38.1 (t, J = 1.9 Hz), 37.0, 28.2 (t, J = 1.9
Hz), 28.1. EI-HRMS for C
11
H
14
F
2
: calculated 184.1064; found 184.1064.
4.4.4 Representative Spectra
CF
2
136

1
H NMR (CDCl
3
)

19
F NMR (CDCl
3
)

CF
2
137
13
C NMR (CDCl
3
)

1
H NMR (CDCl
3
)

Me Me Me
Me
Me
CF
2
138

19
F NMR (CDCl
3
)

13
C NMR (CDCl
3
)

139

1
H NMR (CDCl
3
)

S: Traces of pentane (0.88, 1.27 ppm).

19
F NMR (CDCl
3
)

CF
2
S
S
H
2
O
140

13
C NMR (CDCl
3
)

S: Traces of pentane (14.1, 22.7, 31.6 ppm); * unknown impurity

1
H NMR (CDCl
3
)

S * S S
F
2
C
H
H
H
H
141

19
F NMR (CDCl
3
)

13
C NMR (CDCl
3
)

142
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146

Chapter 5
Investigation of Nucleophilic Difluoromethylation of
Carbonyl Compounds Using the Ruppert-Prakash
Reagent

147
5.1 Introduction
Flouroalkylation has received significant interest in recent years among the
synthetic community owing to the importance of selectively fluorinated organic
compounds in drug discovery and development, pest control, agrochemicals and
catalysis.
1
The difluoromethyl group has been considered a distinct fluoroalkyl moiety as
it has been shown to be a lipophilic hydrogen bond donor. Consequently, it is considered
in the isostere based drug design approach
2
and is already found in marketed medicines
and agrochemicals (Figure 1).

Figure 1 An example of difluoromethyl containing pharmaceutical.
Nucleophilic fluoroalkylation of electrophiles is a direct approach for the
synthesis of fluorine containing compounds. Although nucleophilic perfluoroalkylation is
well documented in this respect,
3
the direct nucleophilc difluoromethylation has been
challenging. This can be attributed to lack of availability of versatile reagents that can
transfer the difluoromethyl anion under mild conditions.
4

Unlike the non-fluorinated analogs, the preparation of trifluoromethyllithium and
trifluoromethylmagnesium halides have been reported to be challenging and performed
poorly for the nucleophilic trifluoromethylation of aldehydes.
5
Similarly, it is assumed
that the preparation of the corresponding difluoromethyl compounds (LiCF
2
H and
HF
2
CMgX) would be significantly difficult baring their use in nucleophilic
diforomethylation. On the other hand, in general, the stability of transition metal based
difluoromethyl compounds was found to be better than trifluoromethyl lithium and
H
2
N
COOH
CF
2
H
NH
2
Eflornithin (DFMO)
Cure for African sleeping sickness
148
trifluoromethyl magnesium halides.
6
For instance, the following stability order, Zn> Cd >
Cu, was observed for the corresponding difluoromethyl compounds.
4
Although these
compounds were utilized for some synthetic applications, due to their less ionic nature of
the C-M bond, they proved to be ineffective for difluoromethylation of carbonyl
compounds such as aldehydes and ketones. On the contrary, the silicon regents have
shown significant success in this area. The first report by Fuchikami announced that the
nucleophilic difluoromethylation of aldehydes and ketones using
(difluoromethyl)trimethylsilane (Me
3
SiCF
2
H) required elevated temperature (100 °C) in
the presence of KF in DMF.
7
This indicated that the Si-CF
2
H bond is difficult to cleave
compared to the Si-CF
3
bond (eg. Me
3
SiCF
3
), demanding strongly basic conditions. This
notion was later proven by Hu et al using CsF or 18-crown-6 with KF for successful
difluoromethylation of aromatic aldehydes and non-enozlable ketones (Scheme 1, b) at
room temperature and sulfinylamines at -78 °C using KOt-Bu.
8
Between the years of
these two reports, alternative reagents of the anion
–
CF
2
Z (Z= SO
2
Ph,
9
P(O)OEt
2
,
10

CF
2
SPh,
11
SeCF
2
Ph,
12
CF
2
SiMe
3
13
) type with functional groups, which can be cleaved
after transfer to obtain the desired CF
2
H group or for further functionalization, have
thrived. However, a versatile in expensive reagent that requires mild conditions to
transfer difluoromethyl anion is still in high demand. In this chapter, the details of how
the common, readily available nucleophilic trifluoromethylating reagent, Me
3
SiCF
3
,
could be employed as a viable reagent for the direct difluoromethylation will be
discussed.

149

Scheme 1 Approaches for nucleophilic difluoromethylation of aldehydes and ketones.
5.2 Results and discussion
During our investigation of gem-difluoroolefination of carbonyl compounds (See
Chapter 4) using the Ruppert-Prakash reagent, the phophonium intermediate 2b was
observed as an intermediate based side product (Scheme 2). After the aqueous work up
of the reaction mixture, we noticed the presence of difluoromethylated product (2c).

Scheme 2 Observation of α-difluoromethylalcohol in the reaction of Me
3
SiCF
3
with
LiI/PPh
3
and 2-napthaldhyde.
Upon examining the literature, Hu et al in their attempt of difluoromethylenation
of carbonyl compounds using Me
3
SiCF
2
Br/PPh
3
observed such an intermediate by NMR
a, [
-
CF
2
H]
R
OH
R'
CF
2
H
R R'
O
b, [
-
CF
2
Z]
c, -Z
Z = SO
2
Ph, P(O)(OEt)
2
, SPh, etc
R R'
O
Me
3
SiCF
2
H
CsF or t-BuOK R R'
HO
CF
2
H
R R'
O
R R'
HO
CF
2
SO
2
Ph
PhSO
2
CF
2
H
LHMDS
Na(Hg) amalgam
Na
2
HPO
4
R R'
HO
CF
2
H
a)
b)
Main approaches
O
OTMS
CF
2
PPh
3
TMSCF
3
(2.75 equiv),
LiI(4 equiv), Ph
3
P (2 equiv)
CF
2
+
170
o
C, 1h
Aq. work up
2
2a, 16% 2b, 34%
OH
CF
2
H
2c
X
-
= I or F
150
spectroscopy (Scheme 3, a).
14
Later, Dilman and co-workers reported that these
intermediates hydrolyzed with a simple aqueous work up to provide difluoromethylated
alcohols (Scheme 3, b & c).
15

Scheme 3 Difluoromethylene phosphonium intermediate.
Based on these reports (Scheme 3) and our observations (Scheme 2), we debated
the possibility of using the Ruppert-Prakash reagent as a facile nucleophilic
difluoromethylating agent for carbonyl compounds. When the regents used for such
purposes were surveyed for their commercial accessibility and the cost, we found that the
TMSCF
3
would be the cheapest reagent available in the market (Table 1) and can be
procured for less than a USD per gram (Table 1, Entry 7).
Table 1 Regents survey (Accessed on 1/9/2017).
a

Entry Reagent
Vendors
price
$/mol Vendors, purity Global
US
1 PhSCF
2
TMS 14 11 205373 Matrixscientific, 95+
2 Ph
3
P
+
CF
2
CO
2
-
4 4 37744 LabNetwork, >99%
3 PhSO
2
CF
2
H 66 51 10935 Sigma Aldrich, >97%
4 TMSCF
2
Br 33 26 3209 SynQuest Laboratories, Inc, >95%
5 EtO
2
P(O)CF
2
H 33 24 2080 Sigma Aldrich, 97%
6 TMSCF
2
H 38 27 1980 Oakwoodchemical, 97%
7 TMSCF
3
98 72 86 Oakwoodchemical, 98%
TMSCF
2
Br, PPh
3
THF, 70
o
C, 10h
O
OTMS
C
F
2
PPh
3
Br
-
R
O
TMSCF
2
Br, PPh
3
DMPU/CH
3
CN
R CF
2
PPh
3
OTMS
Br
hydrolysis
CF
2
H
HO
R
R
O
Ph
3
PCF
2
CO
2
TMSCl, DMF
R CF
2
PPh
3
OTMS
Cl
R CF
2
H
OH
hydrolysis
a) [ref 14]
b) [ref. 15a]
c) [ref. 15b]
151
a
The prices are calculated based on the cheapest sources with the largest unit that is ready
to be shipped in a week are less.

Further, Me
3
SiCF
3
is a primary source for easy access of the commonly used nucleophilic
difluoromethylating reagents (Scheme 4), Me
3
SiCF
2
H and Me
3
SiCF
2
Br (vide supra)
Thus, we were convinced that developing nucleophilic difluoromethylation process using
Me
3
SiCF
3
would be a more desirable approach as it will minimize the cost and the
intermediate steps involved in the preparation of other reagents.

Scheme 4 Preparation of Me
3
SiCF
2
X (X = H, Br) from Me
3
SiCF
3
.
The optimization of the reaction was carried out with 2-napthaldehyde as a model
substrate for convenient handling, as it is a free flowing solid. First, to reduce the reaction
temperature from 170 °C, the mixed solvent approach (for detailed discussion see chapter
4) was employed. The 1:1 mixture of diglyme/DMF at room temperature provided 1:1
mixture of 2a and 2b at room temperature with total conversion of 42% and complete
consumption of the Ruppert-Prakash reagent. To reduce the reactivity of iodide and
prevent fast decomposition of TMSCF
3
, the amount of DMF was reduced to 20%, and
diglyme was replaced with THF for economical reasons. In this solvent system, the
reaction observed to be slower at room temperature, therefore the reaction mixture was
heated at 70 °C for 24 hours, which led to only 10% of the desired product (Table 1,
Entry 2). When other solvent systems were examined under similar conditions,
DMF/acetonitrile (Entry 4) was found to be better than DMF/benzene (Entry 2) or
DMF/THF (Entry 3). Although total higher conversion was obtained in 20%
DMF/acetonitrile, the ratio of 2a and 2b was observed to be 1:1. At this point, the
Me
3
SiCF
3
Me
3
SiCF
2
Br Me
3
SiCF
2
H
NaBH
4 BBr
3
NBS
or NaBr/H
2
O
2
H
2
SO
4
,

hν
Me
3
SiCF
2
Br
152
amounts of PPh
3
and LiI on the reaction results were closely examined. It was found that
less than an equivalent of PPh
3
reduced the total conversion, whereas the excess of PPh
3

had insignificant effect on the outcome of the reaction. However, when the amount of LiI
was increased, the amount of expected product 2b also increased (Entry 5 and 6). The
improvement was only moderate even after 6 equivalents of LiI. When DMPU was
examined as a replacement for the DMF (Entry 7-10), 15% DMPU performed similar to
DMF with more unreacted TMSCF
3
left in the reaction mixture. Thus, DMPU was
adapted for further investigation.
Table 2 Reaction conditions screening and optimization.

Entr
y
LiI
(equiv)
PPh
3

(equiv)
TMSCF
3
(equiv)
Solvent T °C t (h)
2a
(%)
2b
(%)
1 4 2 2.75 50% DMF/diglyme rt 12 20 22
2 4 1.5 2.5 20% DMF/THF 70 24 54 10
3 4 2 2.5 20% DMF/Benzene 85 24 2 0
4 4 2 2.5 20% DMF/CH
3
CN 85 24 44 37
5 5 2 2.5 20% DMF/CH
3
CN 85 24 28 40
6 6 2 2.5 20% DMF/CH
3
CN 85 24 33 44
7 4 2 2.5 5% DMPU/CH
3
CN 85 24 0 0
8 4 2 2.5 10% DMPU/CH
3
CN 85 24 0 0
9 4 2 2.5 15% DMPU/CH
3
CN 85 24 34 44
10 4 2 2.5 20% DMPU/CH
3
CN 85 18 42 26

Based on the above results and prior knowledge, we can speculate the following
possible reaction pathway for the reaction (Scheme 4). The Ruppert-Prakash reagent is
activated in the presence of iodide, providing the singlet ground state difluoromethylene
to combine with the PPh
3
forming the transient reactive difluoromethylene phosphonium
O
CF
2 CF
2
PPh
3
OTMS
X
-
+
TMSCF
3
,

LiI
Ph
3
P
Conditions 2 2a
2b
153
ylide, which undergoes Wittig type nucleophilic addition reaction with the aldehyde.
Under the conditions, there is a possibility of formation of two species, namely, the cyclic
oxaphosphatane and acyclic phosphabetaine, and the later has been proposed as a primary
species in the presence of alkali and alkaline metal salts such as Li or Magnesium. Since
we observed the alkenes, we proposed that these two species are likely to be in
equlibirium, and the alkene is formed via the cyclic intermediate, whereas the Li
+
ion
stabilized species reacted with available silylating species in the reaction mixture leading
to the expected product.

Scheme 5 Proposed reaction pathway.
Based on this reaction pathway, we proposed two strategies to affect the reaction
and achieve favorable reaction outcome, viz., 1) using electron rich phosphines with a
rational that the phosphonium ion will be less electrophilic to accept the incoming oxy
anion leading to primarily the open betaine intermediate and 2) using Li
+
salts of weakly
co-ordinating anions to make the Li
+
strongly Lewis acidic for the stabilization of the oxy
anion.
In the investigation with electron-rich phosphine such as tris(p-tolyl)phosphine
and tris(4-methoxyphenyl)phosphine, the former improved the yield of the expected
product, whereas the later completely suppressed the 2a formation and solely provided
the desired 2b. For the second strategy, LiOTf, LiNTf
2
and LiBF
4
were examined in the
presence of PPh
3
. The use of of LiBF
4
offered similar results to the case of using tris(4-
TMSCF
3
+ LiI :CF
2
PPh
3
+ Ph
3
P
F
F
+ ArCHO
O
P CF
2
Ph
Ph
Ph
Ar
Ar
OLi
C
F
2
PPh
3
I
-
Ar
CF
2
TMS+
Ar
OTMS
C
F
2
PPh
3
I
-
LiI
-LiF
-TMSI
154
methoxyphenyl)phosphine. However, for the economical reasons further optimizations
were carried out with LiBF
4
/PPh
3
to obtain the following optimized conditions (Table 3).
Subsequently, substrate scope of the optimized conditions was studied.
Table 3 Optimized conditions and substrate scope of aromatic aldehydes.
a

a
Reactions were carried out on 0.25 mmol with LiI (2 equiv), LiBF
4
(2.5 equiv) and
TMSCF
3
(2.7.5 equiv) in 15% DMPU/CH
3
CN (2 mL). Yields were determined by
19
F
NMR using trifluorotoluene as an internal standard.

Under these conditions, electron rich (Table 3, 3a-d), electron poor substrates (3f-
h) and halogen containing substrates performed well to provide good to excellent yields
of the desired product. The slightly lower yield of the electron poor substrates is due to
competing trifluoromethyl addition to the aldehyde groups.
When the enolizable 4-bromoacetophenone was examined under the optimized
condition, we obtained 1:1 mixture of the gem-difluoroalkene and the desired product.
Under the present conditions, enolization and subsequent condensation possibly reduces
the formation of the desired product. Further investigation is needed to obtain the desired
O
2) aq. KOH, rt
1) LiI, PPh
3
, LiBF
4
,TMSCF
3

DMPU/CH
3
CN, 85
o
C, 24h CF
2
H
OH
a, 81%
Br
MeO
F
3
C
NC
O
2
N
Ph
Et
Cl
OH
CF
2
H CF
2
H
OH
CF
2
H
OH
CF
2
H
OH
CF
2
H
OH
CF
2
H
OH
CF
2
H
OH
CF
2
H
OH
CF
2
H
OH
3b, 84% 3c, 93% 3d, 88%
3e, 87%
3f, 70%
3g, 40%
3h, 79% 3i, 91% 3j, 82%
Me
2
N
155
difluoromethylation products from enolizable products. The solvent combination
approach to reduce the reaction temperature is a possibility to minimize the enolization.

Scheme 6 Reaction with of an enolizable ketone.
The present reaction condition was also examined for the reaction with aryl
ketones, using benzophenone as a model substrate, giving the gem-difloroalkene as the
only product. Further, better outcome might be possible for such substrates with less
sterically encumbered, electron rich phosphines.

Scheme 7 Reaction with benzophenone.
5.3 Summary and conclusions
In conclusion, practicality of TMSCF
3
as an inexpensive nucleophilic
difluoromethylating agent has been showcased with aromatic aldehydes. The Li
+
in the
reaction medium has been proposed to assist the formation of protected phosphonium
products. A polar aprotic solvent, DMPU, has been used to modulate the reactivity of
TMSCF
3
and iodide. Consequently, a lower the reaction temperature is achieved for the
transformation. Further research is needed to accomplish the nucleophilic
difluoromethylation of adehydes, ketones, including enolizable ones, and imines.

O
Me
LiI, PPh
3
, LiBF
4
, TMSCF
3
OTMS
CF
2
P
+
Ph
3
Me
CF
2
Me
+
23%
24%
DMPU/CH
3
CN, 85
o
C, 24h
X
-
Br
Br
Br
O
Ph
LiI, PPh
3
, LiBF
4
, TMSCF
3
CF
2
Ph
33%
DMPU/CH
3
CN, 85
o
C, 24h
Ph
TMSO
F
2
C
PPh
3
X
-
0%
+
156
5.4 Experimental Section
5.4.1 Materials and Instrumentation

1
H,
13
C, and
19
F NMR spectra were recorded on Varian 600 MHz or 500 MHz or
400 MHz NMR spectrometers.
1
H NMR chemical shifts were determined relative to the
signal of a residual protonated solvent, CDCl
3
(δ 7.26 ppm).
13
C NMR chemical shifts
were determined relative to the
13
C signal of solvent, CDCl
3
(δ 77.16).
19
F NMR
chemical shifts were determined relative to CFCl
3
as an internal standard (δ 0.0). Mass
spectral data were recorded on a Bruker 300-MS TQ Mass Spectrometer at 70 eV for EI.
HRMS data was obtained from University of Illinois-Urbana Champagne Mass
Spectrometry Facility. Typically, all reactions mixtures were prepared under Argon
atmosphere (Ar glovebox). TMSCF
3
was distilled and stored over 4 Å MS. Dioxane and
THF were freshly distilled over sodium benzophenone ketyl before use. Unless otherwise
mentioned, all other reactants, reagents and solvents were purchased from commercial
sources.
5.4.2 General reaction procedure
A microwave vial (5mL, Biotage) was sealed under inert atmosphere (Ar
Glovebox) with stir a bar, triphenylphosphine (1.5 equiv), lithium iodide (1.0) and solid
aldehydes (0.25 mmol) (liquid aldehydes were introduced using syringe outside the
glovebox). To this vial, acetonitrile (1.7 mL) and DMPU (0.3 mL; ≥99% from Sigma-
Aldrich, H
2
O < 0.03%) were injected. Finally, TMSCF
3
(2.75 equiv) was added through
a syringe. The resulting mixture was stirred at 85 °C for 24 hours. The reaction vial was
cooled down to room temperature. To this mixture aq. KOH (2 M; 1 mL) was added and
stirred overnight. The mixture was acidified with 1 M HCl and extracted with diethyl
157
ether (2 x 5 mL) and the combined ether portion was washed with water (3 x 5 mL) and
brine (5 mL) and dried over MgSO
4
. The reaction mixture was quenched with water (5
mL) and extracted with (3 X 5 mL) diethyl ether. The combined ether layer was dried
over anhydrous MgSO
4
, filtered. To this clear solution was added hexaflorobenzene
internal standard to determine the desired product yield by
19
F NMR. The organic layer
was dried in a rotary evaporator to obtain the crude product, which was dissolved in a
small amount of DCM, loaded on a silica column and eluted with hexane/ethyl acetate
mixture. The pure fractions were combined and dried in a rotary evaporator to obtain the
desire product.
5.4.3 Representative spectral data
2,2-difluoro-1-(4-nitrophenyl)ethan-1-ol (3f)
Yellow solid,
1
H NMR (500 MHz, Chloroform-d
3
) δ 8.23 (d, J = 8.8 Hz, 2H),
7.62 (d, J = 8.8 Hz, 2H), 5.75 (td, J = 55.7, 4.6 Hz, 1H), 5.03-4.93 (m, 1H), 2.92 (d, J =
3.8 Hz, 1H).
19
F NMR (376 MHz, CDCl3) δ -127.43 (m). Data corroborates with the
literature report.
16

158
5.4.4 Representative spectra
1
H NMR (CDCl
3
)

19
F NMR (CDCl
3
)

-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
f1 (ppm)
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
159
5.5. References

1) a) Hiyama, T. Organofluorine Compounds: Chemistry and Applications; Springer:
New York, 2000. b) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine Chemistry:
Principles and Commercial Applications; Plenum Press: New York, 1994. c) Muller, K.;
Faeh, C.; Diederich, F. Science, 2007, 317, 1881. d) Hagmann, W. K. J. Med. Chem.
2008, 51, 4359. e) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305. f) Ojima, I.
Fluorine in Medicinal Chemistry and Chemical Biology; Wiley: Chichester, 2009. g)
Begue, J. P.; Bonnet-Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine;
Wiley-VCH: Weinheim, 2008. h) Uneyama, K. Organofluorine Chemistry; Blackwell:
Oxford, 2006. i) Uneyama, K. J. Fluorine Chem. 2008, 129, 550.
2) Marciano, D.; Amir, D.; Berliner, A.; Sod-Moriah, G.; Yeffet, D.; Zafrani, Y.;
Gershonov, E.; Saphier, S. J. Med. Chem. 2017, 60, 797.
3) a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97 (3), 757. b) Liu, X.; Xu, C.;
Wang, M.; Liu, Q. Chem. Rev. 2014, 115, 683.
4) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465.
5) a) Haszeldine, R. N. J. Chem. Soc. 1954, 1273. b) Kvicala, J.; Stambasky, J.; Skalicky,
M.; Paleta, O. J. Fluorine Chem. 2005, 126, 1390. c) Burton, D. J.; Yang, Z.-Y.
Tetrahedron, 1992, 48, 189.
6) Burton, D. J.; Hartgraves, G. A. J. Fluorine Chem., 2007, 128, 1198.
7) Hagiwara, T.; Fuchikami, T. Synlett 1995, 717.
8) Zhao, Y.; Huang, W.; Zheng, J.; Hu, J. Org. Lett. 2011, 13, 5342.
9) Prakash, G. K. S.; Hu, J. Acc. Chem. Res. 2007, 40, 921.
160

10) Alexandrova, A. V; Beier, P. J. Fluor. Chem. 2009, 130, 493.
11) Prakash, G. K. S.; Hu, J.; Wang, Y.; Olah, G. A. J. Fluor. Chem. 2005, 126 (4), 527.
12) Qin, Y.-Y.; Yang, Y.; Qiu, X.; Qing, F. Synthesis, 2006, No. 1475–1479.
13) Yudin, A. K.; Prakash, G. K. S.; Deffieux, D.; Bradley, M.; Bau, R.; Olah, G. A. J.
Am. Chem. Soc. 1997, 119, 1572.
14) Wang, F.; Li, L.; Ni, C.; Hu, J. Beilstein J. Org. Chem. 2014, 10, 344
15) a) Levin, V. V.; Trifonov, A. L.; Zemtsov, A. A.; Struchkova, M. I.; Arkhipov, D. E.;
Dilman, A. D. Org. Lett. 2014, 16, 6256. b) Trifonov, A. L.; Zemtsov, A. A.; Levin, V.
V; Struchkova, M. I.; Dilman, A. D. Org. Lett. 2016, 18, 3458.
16) Deng, Z.; Lin, J.; Cai, J.; Xiao, J. Org. Lett. 2016, 18, 3206.

161

Chapter 6
Fluorodecarboxylation: Synthesis of Aryl
Trifluoromethyl Ethers (ArOCF
3
) and Thioethers
(ArSCF
3
)

162
6.1 Introduction
Synthetic method development for the construction of -XCF
3
(X = O, S) groups is
an active area of research, as these moieties with high lipophilic index (Figure 1) promise
to positively impact the pharmacokinetic properties of biologically active molecules.
1

Particularly, development in the area of aryl trifluoromethyl ethers and thioethers has
been very limited, though examples of such scaffolds are already in the marketed drugs.
Groups SCF
3
> OCF
3
> CF
3
> CH
3
> OCH
3

Hyrophobicity (Π) 1.44 1.04 0.88 0.56 -0.02

Figure 1 SCF
3
and OCF
3
groups’ hydrophobicity and examples in the medical field.
Common synthetic approaches include (Scheme 1) 1) trifluoromethylation of
phenols and thiophenols
2
2) nucleophilic trifluoromethoxylation or
trifluoromethylthiolation of R-X compounds
3
and 3) fluoride exchange with ArXCY
3
(X
=O, S; Y= Cl, Br, I).
4

Scheme 1 Methods for the construction of XCF
3
(X = O, S) groups.

S NH
CF
3
N
S
H
2
N
O
CF
3
Riluzole
(Amyotrophic lateral sclerosis)
Tiflorex
(Anorectic drug)
[CF
3
]
+
R
X
CF
3
R
X
H
R-Z
-
YCF
3
R
Y
CF
3
X = S, O; X
3
= Cl
3
, F
2
Br
Ar
X
CY
3 Ar
X
C
F
F
F
1) CF
3
-X (X = O, S) bond formation: trifluoromethylation of thiols and alcohols
2) X-C (X = O, S) bond formation: Trifluoromethoxylation and trifluoromethylthiolation
3) Fluorination: C-F bond formation
163
The C-F bond forming method towards -XCF
3
is a promising approach for
18
F
labeling, which has become a powerful tool in PET imaging studies of biological
systems.
5
However, the short half-life (110 minute) of
18
F isotope demands that it is
introduced at late stage of the drug synthesis. Recently, Gouverneur et al. demonstrated
silver mediated
18
F
-
exchange of bromo/chloro difluoromethyl arylethers (ArOCF
2
X; X =
Cl or Br).
6
Following the protocol of Li and co-workers for the decarboxylative
fluorination of aliphatic carboxylic acids,
7
Gouverneur et al demonstrated
fluorodecarboxylation of ArCF
2
CO
2
H in the presence of
18
F-selectfluor and silver (I)
salts.
8
Sammis and co-workers demonstrated photo-induced fluorodecarboxylation for the
preparation of aryl mono and di-fluoromethyl ethers.
9
However, such light induced
decarboxylative fluorination of ArOCF
2
CO
2
H to ArOCF
3
has been reported to be
ineffective.
10
The synthetic pathway is believed to follow an arene excitation/oxidation
route. Alternatively, we hypothesized that aryloxydifluoromethylene radical generated by
a transition metal mediated oxidative decarboxylation (via carboxyl radical) could react
with radical fluorinating agents such as Selectfluor. As the silver catalysis in this area has
been shown to be effective, we began our investigation with catalytic amount of silver
salts for decarboxylative fluorination of aryloxy difluoroacetic acids. We presented our
preliminary results of fluorodecarboxylation of ArXCF
2
CO
2
H (X = O, S) in the 251
th

ACS national meeting.
11
During the preparation of our manuscript, Hartwig et al reported
decaboxylative fluorination approach using AgF
3
for the preparation of aryl
trifluoromethyl ethers,
12
Hu and co-worker presented their results using selectfluor and
Ag(1) under superacidic conditions,
13
and recently Sammis et al. used XeF
2
to
accomplish ArOCF
3
preparation.
14
In this chapter, efforts towards decarboxylative
164
fluorination of aryldifluoroacetic acid and aryl difluorthioacetic acids using Ag(I) using
selectfluor in a biphasic medium with trifluoroacetic acid additive is summarized.
6.2. Results and discussion
6.2.1 Fluorodecarboxylation of ArOCF
2
CO
2
H
6.2.1.1 Preparation of ArOCF
2
CO
2
H
The precursors, ArOCF
2
CO
2
H, can be easily prepared from inexpensive starting
materials, namely, phenols and chlorodifluoroacetic acid in high yields.
15
However,
preparation of electron-withdrawing substituted (4-NO
2
, 3,5-ditrifluoromethyl-) phenols
seemed to be rather challenging under these reaction conditions.
Table 1 Preparation of ArOCF
2
CO
2
H.
a

a
Isolated yields

6.2.1.2 Reaction screening for fluorodecarboxylation of ArOCF
2
CO
2
H
The decarboxylative fluorination was investigated with phenoxydifluoroacetic
acid (1a) as a model substrate (Table 2). Under the reported successful decarboxylative
fluorination conditions, AgX in acetone/water mixture at 55 °C, 1 hour, 1a produced
OCF
2
CO
2
H
OCF
2
CO
2
H
Br
OCF
2
CO
2
H
t-Bu
OCF
2
CO
2
H
Ph
OCF
2
CO
2
H
1a, 71%
1h, 84%
1k, 97%
1b, 75%
1l, 96%
1d, 89%
OCF
2
CO
2
H
MeO
1e, 96%
OH
R
OCF
2
CO
2
H
R
NaH, ClCF
2
CO
2
H
dioxane, reflux, 16-24h
OCF
2
CO
2
H
Cl
1g, 56%
t-Bu
OCF
2
CO
2
H
1c, 73%
F
OCF
2
CO
2
H
Br
OCF
2
CO
2
H
F
OCF
2
CO
2
H
1j, 58%
1i, 70%
1f, 52%
OCF
2
CO
2
H
165
desired product (2a) in 3% yield (Table 2, Entry 1) and protodecarboxylated
difloromethyl ether (5) in 36% yield. However, 48% of the starting material remained
unreacted.
Table 2 Screening of conditions and optimization.
a

Entry Catalyst Solvent Time (h) 2a (%) 3 (%)
1 AgNO
3
Acetone/H
2
O 1 3 36
2 AgNO
3
H
2
O 1 26 0
3 AgNO
3
Benzene/H
2
O 1 55 0
4 AgNO
3
DCM/H
2
O 1 31 traces
5 AgNO
3
Hexane/H
2
O 1 33 traces
6 AgNO
3
EtOAc/H
2
O 1 11 traces
b
7 AgNO
3
DCM/H
2
O 1 46 traces
8 AgOTf DCM/H
2
O 1 66 traces
9 AgOTf DCM/H
2
O/H
3
PO
4
1 90 traces
10 AgOTf DCM/H
2
O/TFA 1 65 traces
c
11 AgOTf DCM/H
2
O/H
3
PO
4
10 min 85 traces

a
The reactions were carried out on a 0.25 mmol scale with 2 equiv Selectfluor, 20 mol%
of catalyst. The yields were determined by using hexafluorobenzene as an internal
standard.
b
39:1 DCM/Water ratio.
c
Reaction was carried out at 85 °C under microwave
irradiation.

No reaction was observed in acetone and DMF, and greater than 95% of starting
material remained unreacted. However, when the reaction was performed in water, the
reaction proceeded to completion with an increase in trifluoromethyl phenyl ether to 26%
(Table 2, Entry 2) and no unreacted starting material was observed. Our extensive effort
Selectfluor, Catalyst
additive, Solvent, 55
o
C
+
1a
2a
5
OCF
2
CO
2
H
OCF
3 OCF
2
H
166
to improve the yield in water was fruitless. We speculated that the decomposition of
starting material could be controlled by a biphasic reaction system, wherein the organic
layer will serve as a shield for the starting material and the product from reactive species
in the aqueous phase. When benzene/water (1:1) was employed as the solvent, the
product conversion went up to 55%, only trace of difluoromethyl ether was observed
(Table 2, Entry 3). However, a new signal appeared at -65.2 ppm (18%) in the
19
F NMR,
which was confirmed from literature and by GC-MS to be PhOCF
2
Ph. Though the signal
around -65 ppm was minimal in chlorobenzene, trifluorotoluene and toluene, no
improvement in the desired product was obtained. Other biphasic systems such as DCM,
EtOAc and hexane with water produced conversion between 20-35% (Table 2, Entry 4-
6). For further investigation of the biphasic system, DCM/water seemed to be the best. A
close examination of the water/DCM ratio showed water is absolutely necessary for the
reaction to proceed. When a minimal amount of water (1:39) was used, the conversion
seems to improve from 30% to 46% (Table 2, Entry 7). The basic nature of the system
tends to decrease the conversion, which could be attributed to the reactivity of the anion
towards Selectfluor and increase in the amount of aryloxydifluoroacetate in the aqueous
system. When little over an equivalent of K
3
PO
4
was added to the reaction mixture with
AgNO
3
as a catalyst, the amount of the product significantly diminished (8%). With this
solvent system, other silver salts were investigated to find the following trend: AgOTf
(66%) (Table 2, Entry 8) > AgBF
4
(62%) > AgF (51%) > AgNO
3
(46%) > AgOAc (44%)
> Ag
2
CO
3
(38%). Therefore, further investigations were carried out with AgOTf.
Previously, in a similar system, Li et al found that when TFA or H
3
PO
4
used as additives,
the reaction yield seemed to improve.
16
Similarly, when H
3
PO
4
was used as an additive
167
for the present transformation, the conversions increased from 66% to 84%. The 9:1
DCM/water as a solvent and 4 equivalents of additive provided 90% of the desired
product in an hour at 55 °C (Table 2, Entry 9), whereas in the presence of TFA, 65%
product yield was observed (Table 2, Entry 10). When short reaction time (30 min) or
less than 20 mol% of AgOTf use lowered the product yield. Interestingly, the reaction
proceeded at RT in 12 hours to provide 75% conversion. For the PET imaging studies, a
short time for fluorination is desired as the
18
F half-life is 110 min, 85% conversion was
obtained at 85 °C in 10 min under microwave irradiation (Table 2, Entry 11).
6.2.1.3 Substrate scope of the optimized conditions
Table 3 Substrate scope.
a

a
Yields were determined by
19
F NMR using hexafluorobenzene as an internal standard.
The optimized condition was tested for the substrates in Table 1. tert-Butyl group
substituted acids performed poorly in the presence of phosphoric acid (2b and 2c, Table
3), which was attributed to their poor solubility. When phosphoric acid was replaced with
TFA, 53% and 61% conversion were obtained. Consequently, all the substrates were
OCF
3
OCF
3
Br
OCF
3
t-Bu
OCF
3
Ph
OCF
3
2a
2h
2k
2b,
2l
a) traces
OCF
3
MeO
a) & b) 0%
OCF
3
Cl
2g,
t-Bu
OCF
3
2c
F
OCF
3
Br
OCF
3
F
OCF
3
2j
2i
2f
R
OCF
2
CO
2
H
R
OCF
3
AgOTf (20 mol%), Selectfluor (2 equiv)
DCM/H
2
O (9:1), TFA or H
3
PO
4
(4 equiv)
55
o
C, 1 h
a) H
3
PO
4
b) TFA
a) 90%
b) 65%
a) 2%
b) 53 %
a) 4%
b) 61% b) traces 2d
2e
a) 16%
b) 19%
a) 51%
b) 60%
a) 37%
b) 43%
a) 15%
b) 23%
a) 54%
b) 38%
OCF
3
a & b) 0%
a) & b) 0%
168
studied in the presence of TFA as well as H
3
PO
4
. The 2,6-dimethyl phenoxy
difluoroacetic acid showed trace of the product (2d) in the
19
F NMR. Halogen
substituted substrates provided yields in the range of 19-60% (2f-j). In the case of
electron-donating methoxy group, trace of ring fluorination was seen in the
19
F NMR.
With the napthyl (2k) and 4-phenyl (2l) substrates, brown coloration of the reaction
mixture was observed and no product was detected in the
19
F NMR.
6.2.2 Fluorodecaroxboxylation of ArSCF
2
CO
2
H
6.2.2.1 Preparation of ArSCF
2
CO
2
H
The arylmecraptodifluoromethylacetic acids are easily accessible from the
corresponding thiols and chlorodifluoroacetic acid.The thiophenols under reflux in the
presence of NaH and ClCF
2
COH in dioxane easily delivered the ArSCF
2
CO
2
H
compounds (Table 4).
Table 4 Preparation of ArSCF
2
CO
2
H.
a

a
Isolated yields
6.2.2.2 Reaction screening and optimization: Aryltrifluoromethyl thioether (Table 5)
When the previously reported conditions were employed to for the
decarboxylation, we found that the reactions proceeded little slower (Table 5, Entry 1)
SCF
2
CO
2
H
Br
3d, 90%
SCF
2
CO
2
H
3a, 88%
R
SCF
2
CO
2
H
R
SCF
3
SCF
2
CO
2
H
Cl
3c, 92%
SCF
2
CO
2
H
MeO
SCF
2
CO
2
H
Me
Me
3b, 76%
SCF
2
CO
2
H
Br
SCF
2
CO
2
H
Br 3g, 86%
F
3
C CF
3
SCF
2
CO
2
H
3e, 84% 3f, 67%
NaH, dioxane
ClCF
2
CO
2
H, reflux, 4-5 h
3h, 60%
169
and increasing the reaction time to 1 hour and 30 min led to the completion of the
reaction (Table 5, entry 2). Since the TFA additive performed well under the previously
discussed conditions, the reaction was optimized with TFA. Increasing the temperature
seems to increase the rate of the reaction with significant product formation (Table 5,
Entry 12 & 13). For example, at 100 °C under microwave conditions, 73% product
formation was observed in 2 min.
Table 5 Conditions screening and optimization.
a

Entry
Catalyst (20
mol%))
[F]
+
Solvent
Time
(h)
T (°C)
4d
(%)
1 AgOTf Selectfluor (2.0 equiv) DCM/H
2
O 1 55 78
2 AgOTf Selectfluor (2.0 equiv) DCM/H
2
O 1.5 55 92
3 - Selectfluor (2.0 equiv) DCM/H
2
O 1.5 55 0
4 AgOTf Selectfluor (2.0 equiv) H
2
O 1.5 55 13
5 AgOTf Selectfluor (2.0 equiv) DCM 1.5 55 0
6 AgOTf NFSI (2.0 equiv) DCM 1.5 55 0
7 AgOTf NFSI (2.0 equiv) DCM/H
2
O 1.5 55 0
8 AgOTf N-Fluoropyridinium triflate DCM 1.5 55 0
9 AgOTf N-Fluoropyridinium triflate DCM/H
2
O 1.5 55 0
10 AgOTf Selectfluor (1.1 equiv) DCM/H
2
O 1.5 55 70
c
11 AgOTf Selectfluor (2.0 equiv) DCM/H
2
O 1.5 55 62
b
12 AgOTf Selectfluor (2.0 equiv) DCM/H
2
O 15 min 75 (mw) 76
b
13 AgOTf Selectfluor (2.0 equiv) DCM/H
2
O 2 min 100 (mw) 73
14 AgNO
3
Selectfluor (2.0 equiv) Acetone/H
2
O 1.5 55 11
a
The reactions were carried out on 0.25 mmol scale with 2 equiv Selectfluor, 20 mol% of
catalyst. The yields were determined by
19
F NMR using hexafluorobenzene as an internal
standard.
b
Reaction was carried out at 85 °C under microwave irradiation.
c
10 mol%
AgOTf was used.

6.2.2.3 Substrate scope of the optimized conditions

SCF
2
CO
2
H SCF
3
Br
Br
Conditions
4d
3d
170
Under the present conditions, electron-donating methyl groups performed well
(4b). However, the substrate with –OMe group produced lower yield of the product (4g).
19
F NMR of the reaction mixture showed evidence of direct ring fluorination and
oxidation of the sulfur atom. Halogen containing substrates (4c-f) produced excellent
yields. Electron-withdrawing bistrifluoromethyl containing substrate produced moderate
yield of the product (4h). The sulfur oxidation was also observed in the absence of the
silver salt.
Table 6 Substrate scope.
a

a
Yields in the parathesis were determined by
19
F NMR using hexafluorobenzene as an
internal standard.

6.2.3 Mechanism
Control experiments carried out without the silver salt or Selectfluor yielded no
product. Based on the observation of PhCF
2
OPh (Scheme 2) and the decrease in the
product yield when the reaction was carried out in the presence of air, we propose that the
reaction proceeds via PhOCF
2
radical produced by higher oxidation state silver species.
17

Compound 6 is more likely formed as a result of the PhOCF
2
radical reaction with the
SCF
3
Br
4d, 87% (92%)
SCF
3
4a, (85%)
R
SCF
2
CO
2
H
R
SCF
3
AgOTf (20 mol%), Selectfluor (2 equiv)
DCM/H
2
O (9:1), TFA (4 equiv)
55
o
C, 90 min
SCF
3
Cl
4c, 71%, (79%)
SCF
3
MeO
SCF
3
Me
Me
4b, (84 %)
SCF
3
Br
SCF
3
Br
4g, 28% (35%)
F
3
C
CF
3
SCF
3
4e, 40% (46%)
4f, (56%)
4h, (35%)
171
solvent. Similar reaction pathway is likely taking place in the case of
fluorodecarboxylation of arylmercaptodifluoro acetic acids.

Scheme 2 Formation of side products.
6.3 Conclusions
The work presented in this communication, though of limited substrate scope, is
one of the first examples of fluorodecarboxylation of aryloxydifluoroacetic acids and
arylmercaptodifluoroacetic acids to provide ary trifluoromethyl ethers and aryl
trifluoromethyl thioethers, respectively. We were able to demonstrate that the
ArXCF
2
CO
2
H (X = O, S) are useful substrates in realizing ArXCF
3
compounds by
oxidative fluorodecarboxylation approach. Therefore, we believe that ease of preparation
and commercial availability of substrates will encourage researchers to investigate other
metal mediated fluorodecarboxylation processes. Further, oxidative decarboxlative
fluorination using fluoride is the next key direction to take in this area as the techniques
are very well developed for the generation of
18
F anion using a cyclotron. Such a
development will be useful in late-stage fluorination and will be a powerful tool in PET
imaging studies.
6.4 Experimental Section
6.4.1 General information
1
H,
13
C and
19
F NMR spectra were recorded on Varian 500 MHz or 400 MHz NMR
spectrometers.
1
H NMR chemical shifts were determined relative to the signal of a
residual protonated solvent, CDCl
3
(δ 7.26) or DMSO-d
6
(δ 2.5).
13
C NMR chemical
Ph
F
2
C
O
Ph
PhOCF
2
CO
2
H
Selectfluor, AgNO
3
Benzene/water, 55
o
C, 1h
PhOCF
3
+
PhOCF
2
H
1a 2a 5
+
6
55%
traces 18 %
172
shifts were determined relative to the
13
C signal of solvent, CDCl
3
(δ 77.16) or DMSO-d
6

(δ 39.52).
19
F NMR chemical shifts were determined relative to CFCl
3
as an internal
standard (δ 0.0). HRMS data was obtained from the University of Illinois Urbana-
Champaign’s mass spectrometry laboratory. Typically, all mixtures were prepared and
the reactions were carried out under an inert atmosphere in sealed microwave vials.
Unless otherwise mentioned, all the reactants, reagents and solvents were purchased from
commercial sources.
Preparation of aryloxydifluoroacetic acid.
Under inert atmosphere (N
2
, Schlenk flask), to a suspension of sodium hydride (8.3 g,
346 mmol, 3.6 equiv) in freshly distilled dioxane (125 mL), phenols (144 mmol, 1.5
equiv) were introduced slowly (exothermic reaction and evolves H
2
gas). To this mixture,
the chlorodifluoroacetic acid (8.1 mL, 96.0 mmol, 1.0 equiv) was slowly added at 0 °C.
Then, the solution was immersed in a temperature controlled oil bath to achieve a gentle
reflux. The reaction progress was monitored by
19
F NMR. After 20-24 h, the acid was
completely consumed and the mixture was concentrated in a rotary evaporator. The
residue was dissolved in water (400 mL), and acidified with conc. HCl to reach pH = 1.
Subsequenlty, the mixture was basified with NaHCO
3
to reach pH = 8, and washed with
DCM to remove unreacted phenol. The solution then was acidified to pH = 1 and
extracted with DCM (4 x 200 mL). After drying the combined organic layer with MgSO
4
and filtration, the solvent was removed by rotary evaporation to obtain the compounds
listed in Table 2.
2,2–difluoro–2–phenoxyacetic acid (1a)
173
1
H NMR (DMSO-d
6
) δ 7.48–7.42 (m, 2H), 7.31 (t, J = 7.4 Hz, 1H), 7.24 (d, J = 7.7 Hz,
2H);
13
C–NMR (DMSO-d
6
) δ 160.6 (t, J = 39.4 Hz), 149.2, 130.0, 126.4, 121.2, 114.2 (t,
J = 271.9 Hz)
19
F NMR (DMSO-d
6
) δ –75.77; HRMS (ESI): calc. for C
8
H
5
O
3
F
2
[M-H]:
187.0207; found: 187.0208.
2–(4–(tert–butyl)phenoxy)–2,2-difluoroacetic acid (1b)
Melting point: 67–68 °C;
1
H NMR (DMSO-d
6
) δ 7.46 (d, J = 8.8 Hz, 2H), 7.15 (d, J =
8.7 Hz, 2H), 1.27 (s, 9H);
13
C NMR (DMSO-d
6
) δ 160.6 (t, J = 39.5 Hz), 148.8, 146.8,
126.7, 120.7, 114.2 (t, J = 271.4 Hz), 34.2, 31.1;
19
F NMR (DMSO-d
6
) δ –75.73; HRMS
(ESI): Calculated for C
12
H
13
O
3
F
2
[M-H]: 243.0833; found: 243.0835. The obtained
analytical data is consistent with the values found in the literature.
18

2-(3-(tert-butyl)phenoxy)-2,2-difluoroacetic acid (1c)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.39 – 7.28 (m, 2H), 7.16 (d, J = 2.7 Hz, 1H), 7.03
(ddd, J = 7.7, 2.7, 1.4 Hz, 1H), 1.27 (d, J = 1.1 Hz, 9H);
19
F NMR (376 MHz, DMSO-d
6
)
δ -75.66; HRMS (ESI): Calculated for C
12
H
13
O
3
F
2
[M-H]: 243.0833; found: 243.0833.
2–(2,6–dimethylphenoxy)–2,2-difluoroacetic acid (1d)
1
H NMR (DMSO-d
6
) δ 7.15–7.09 (m, 3H), 2.24 (s, 6H);
13
C NMR (DMSO-d
6
) δ 160.9 (t,
J= 39.7 Hz), 146.3, 132.0, 129.1, 126.6, 114.9 (t, J = 273.4 Hz), 16.6;
19
F NMR (DMSO-
d
6
) δ –74.14; HRMS (ESI): Calculated for C
10
H
9
O
3
F
2
[M-H]: 215.0520; found: 215.0519.
2,2–difluoro–2–(4–methoxyphenoxy)acetic acid (1e)
1
H NMR (DMSO-d
6
) δ 7.65 (d, J = 8.9 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 2.08 (s, 3H);
13
C NMR (DMSO-d
6
) δ 160.7 (t, J = 39.5 Hz), 157.4, 142.2, 122.8, 114.8, 114.2 (t, J
= 270.9 Hz), 55.5;
19
F NMR (DMSO-d
6
) δ –75.99; HRMS (ESI): Calculated for
C
9
H
7
F
2
O
4
[M-H]: 217.0312; found: 217.0318.
174
2,2-difluoro-2-(4-fluorophenoxy)acetic acid (1f)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.29 (s, 2H), 7.27 (s, 2H);
19
F NMR (376 MHz,
DMSO-d
6
) δ -76.30, -115.72 (p, J = 6.5 Hz);
13
C NMR (100 MHz, DMSO-d
6
) δ 160.7 (t,
J = 39.2 Hz), 160.6 (d, J = 242.9 Hz), 145.3 (d, J = 2.5 Hz), 123.6 (d, J = 8.8 Hz), 116.7
(d, J = 23.5 Hz), 114.3 (t, J = 272.5 Hz); HRMS (ESI): Calculated for C
8
H
4
F
3
O
3
[M-H]:
205.0113; found: 205.0111.
2-(4-chlorophenoxy)-2,2-difluoroacetic acid (1g)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.54 – 7.48 (m, 2H), 7.30 – 7.23 (m, 2H);
19
F NMR
(376 MHz, DMSO-d
6
) δ -76.21;
13
C NMR (126 MHz, DMSO-d
6
) δ 160.3 (t, J = 38.9
Hz), 147.9, 130.6, 129.9, 123.1, 114.1 (t, J = 273.1 Hz); HRMS (ESI): Calculated for
C
8
H
4
ClF
2
O
3
[M-H]: 220.9817; found: 220.9814.
2–(4–bromophenoxy)–2,2–difluoroacetic acid (1h)
Melting point: 53–55 °C;
1
H NMR (DMSO-d
6
) δ 7.65 (d, J = 8.5 Hz, 2H), 7.21 (d, J
= 8.4 Hz, 2H);
13
C NMR (DMSO-d
6
) δ 160.3 (t, J = 38.8 Hz), 148.5, 132.9, 123.4, 118.7,
114.1 (t, J = 272.7 Hz);
19
F NMR (DMSO-d
6
) δ –76.10; HRMS (ESI): Calculated for
C
8
H
4
O
3
BrF
2
[M-H]: 264.9312; found: 264.9310.
2-(3-bromophenoxy)-2,2-difluoroacetic acid (1i)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.54 (dtd, J = 8.0, 1.9, 0.9 Hz, 1H), 7.47 – 7.39 (m,
2H), 7.28 (ddq, J = 8.3, 2.2, 1.1 Hz, 1H);
19
F NMR (376 MHz, DMSO-d
6
) δ -76.13.
13
C
NMR (100 MHz, DMSO-d
6
) δ 160.5 (t, J = 38.9 Hz), 150.0 (d, J = 2.5 Hz), 131.7 (d, J =
7.7 Hz), 129.6, 124.3, 122.1, 120.5 (d, J = 4.8 Hz), 114.3 (t, J = 273.3 Hz); HRMS (ESI):
Calculated for C
8
H
4
BrF
2
O
3
[M-H]: 205.0113; found: 264.9308.
2,2-difluoro-2-(3-fluorophenoxy)acetic acid (1j)
175
1
H NMR (399 MHz, DMSO-d
6
) δ 7.50 (td, J = 8.2, 6.8 Hz, 1H), 7.24 – 7.05 (m, 3H);
19
F
NMR (376 MHz, DMSO-d
6
) δ -76.26 (s, 2F), -110.09 (q, J = 8.5 Hz, 1F);
13
C NMR (126
MHz, DMSO-d
6
) δ 162.2 (d, J = 245.8 Hz), 160.3 (t, J = 38.8 Hz), 150.0 (d, J = 11.1 Hz),
131.3 (d, J = 9.6 Hz), 117.1 (d, J = 3.0 Hz), 114.1 (t, J = 273.9, 273.5 Hz), 113.4 (d, J =
20.9 Hz), 108.9 (d, J = 24.9 Hz); HRMS (ESI): Calculated for C
8
H
4
F
3
O
3
[M-H]:
205.0113; found: 205.0112.
2,2–difluoro–2–(naphthalen–1–yloxy)acetic acid (1k)
1
H NMR (DMSO-d
6
) δ 8.09 (d, J= 8.1 Hz, 1H), 8.00 (d, J= 7.8 Hz, 1H), 7.89 (d, J=
8.2 Hz, 1H), 7.67–7.60 (m, 2H), 7.54 (t, J= 8.2 Hz, 1H), 7.4 (d, J= 7.6 Hz, 1H);
13
C NMR
(DMSO-d
6
) δ 160.7 (t, J = 39.1 Hz), 144.9, 134.3, 130.0, 127.9, 127.0, 126.3, 125.7,
121.2, 117.0, 114.6 (t, J = 272.8 Hz);
19
F NMR (DMSO-d
6
) δ –75.60; HRMS (ESI):
Calculated for C
12
H
7
O
3
F
2
[M-H]: 237.0363; found: 237.0359.
2–([1,1'–biphenyl]–4–yloxy)–2,2-difluoroacetic acid (1l)
1
H–NMR (DMSO-d
6
) δ 7.73 (d, J = 7.0 Hz, 2H), 7.66 (d, J = 6.8, 2H), 7.47–7.45 (m,
2H), 7.38–7.36 (m, 1H), 7.32 (d, J = 7.4 Hz, 2H);
13
C NMR (DMSO-d
6
) δ 161.5 (t, J =
39.2 Hz), 148.7, 139.0, 138.3, 129.0, 128.2, 126.7, 121.5, 114.3 (t, J = 272.2 Hz);
19
F
NMR (DMSO-d
6
) δ –75.73; HRMS (ESI): Calculated for C
14
H
9
O
3
F
2
[M-H]: 263.0520;
found: 263.0518.
Fluorodecarboxylation aryloxydifluoroacetic acids
A microwave vial (5 mL) was sealed under an inert atmosphere (Argon glovebox) with a
stir bar, Selectfluor (177.1 mg, 0.5 mmol, 2 equiv), silver trifluoromethanesulfonate
(12.8 mg, 0.05 mmol, 20 mol%) and aryloxydifluoroacetic acids (0.25 mmol, 1.0 equiv).
To this vial DCM (1.8 mL), trifluoroacetic acid (76.5 µL, 1.0 mmol, 4.0 equiv) and water
176
(0.2 mL) were injected. This mixture was heated for an hour at 55 °C. The resulting
mixture was cooled down to room temperature, diluted with dichloromethane (4 mL),
washed with water (3 X 5 mL), brine (5 mL), dried over anhydrous MgSO
4
and filtered.
The dried extract was concentrated on a rotary evaporator. The resulting crude product
was dissolved in a small quantity of dichloromethane and loaded on to a silica cartridge
(10g, Biotage), air dried and eluted with pentane. The pure fractions were combined and
the solvent was evaporated to obtain the pure products.
1-(tert-butyl)-4-(trifluoromethoxy)benzene (2b)
Yellow Oil.
1
H NMR (399 MHz, Chloroform-d) δ 7.41 – 7.35 (m, 2H), 7.19 – 7.10 (m,
2H), 1.32 (s, 9H);
19
F NMR (376 MHz, Chloroform-d) δ -58.4 (s, 3F).
6

1-(tert-butyl)-3-(trifluoromethoxy)benzene (2c)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.38 – 7.29 (m, 2H), 7.16 (s, 1H), 7.06 – 7.00 (m, 1H),
1.27 (s, 9H);
19
F NMR (376 MHz, Chloroform-d) δ -58.21.
19

1-chloro-4-(trifluoromethoxy)benzene (2g)
1
H NMR (399 MHz, Chloroform-d) δ 7.37 (d, J = 9.1 Hz, 2H), 7.18 – 7.13 (m, 2H);
19
F
NMR (376 MHz, Chloroform-d) δ -58.67.
20

1-bromo-4-(trifluoromethoxy)benzene (2h)
1
H NMR (399 MHz, Chloroform-d) δ 7.56 – 7.46 (m, 2H), 7.15 – 7.06 (m, 2H);
19
F NMR
(376 MHz, Chloroform-d) δ -58.13.
3

Preparation of arylmercaptodifluoroacetic acids
Similar procedure as of ArOCF
2
CO
2
H preparation was followed. However, with 5-20
hours of reflux time to obtain the ArSCF
2
CO
2
H compounds listed in the Table 4.
2,2-difluoro-2-(phenylthio)acetic acid (3a)
177
1
H NMR (399 MHz, Chloroform-d) δ 7.65 – 7.60 (m, 2H), 7.51 – 7.45 (m, 1H), 7.43 –
7.37 (m, 2H), 6.05 (s, 1H);
19
F NMR (376 MHz, Chloroform-d) δ -83.8. The data
corroborate with the literature report The data corroborate with the literature report.
21

2-((2,4-dimethylphenyl)thio)-2,2-difluoroacetic acid (3b)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.40 (s, 1H), 7.31 – 7.22 (m, 2H), 2.40 (s, 3H), 2.29 (s,
3H);
19
F NMR (376 MHz, DMSO-d
6
) δ -80.02;
13
C NMR (100 MHz, DMSO-d
6
) δ 162.5
(t, J = 30.3 Hz), 140.3, 138.3, 136.1, 131.8, 130.7, 123.6, 120.7 (d, J = 284.6 Hz), 20.4,
20.1; HRMS (ESI): Calculated for C
10
H
9
O
2
F
2
S: 231.0291; found: 231.0284.
2-((4-chlorophenyl)thio)-2,2-difluoroacetic acid (3c)
1
H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 8.5 Hz, 2H), 7.42 – 7.36 (m, 2H);
19
F
NMR (470 MHz, Chloroform-d) δ -83.52;
13
C NMR (126 MHz, Chloroform-d) δ 163.1,
138.1, 129.9, 122.9, 119.4 (t, J = 288.9 Hz); HRMS (ESI): Calculated for C
8
H
4
O
2
F
2
SCl
[M-H]: 236.9589; found: 236.9590.
2-((4-bromophenyl)thio)-2,2-difluoroacetic acid (3d)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.70 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H);
19
F
NMR (376 MHz, DMSO-d
6
) δ -83.10;
13
C NMR (100 MHz, DMSO-d
6
) δ 162.2 (d, J =
30.2 Hz), 138.0, 132.6, 124.7, 120.4 (t, J = 288.6 Hz); HRMS (ESI): Calculated for
C
8
H
4
O
2
F
2
SBr: 280.9083; found: 280.9081.
2-((2-bromophenyl)thio)-2,2-difluoroacetic acid (3e)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.86 – 7.76 (m, 1H), 7.52 – 7.42 (m, 1H);
19
F NMR
(376 MHz, DMSO-d
6
) δ -79.81; HRMS (ESI): Calculated for C
8
H
4
O
2
F
2
SBr: 280.9083;
found: 280.9077.
2-((3-bromophenyl)thio)-2,2-difluoroacetic acid (3f)
178
1
H NMR (399 MHz, DMSO-d
6
) δ 7.81 – 7.73 (m, 2H), 7.64 (dt, J = 7.8, 1.2 Hz, 1H),
7.45 (t, J = 7.9 Hz, 1H);
19
F NMR (376 MHz, DMSO-d
6
) δ -79.70;
13
C NMR (100 MHz,
DMSO-d
6
) δ 162.1 (t, J = 30 Hz), 137.9, 135.1, 133.6, 131.5, 126.9, 121.9, 120.4 (t, J =
288 Hz); HRMS (ESI): Calculated for C
8
H
4
O
2
F
2
SBr: 280.9083; found, 280.9083.
2,2-difluoro-2-((4-methoxyphenyl)thio)acetic acid (3g)
1
H NMR (399 MHz, DMSO-d
6
) δ 7.52 (d, J = 8.7 Hz, 2H), 7.22 – 6.72 (m, 2H), 3.80
(3H).
19
F NMR (376 MHz, DMSO-d
6
) δ -81.14.
13
C NMR (100 MHz, DMSO-d
6
) δ 162.5
(t, J = 30.5 Hz), 138.2, 120.3 (t, J = 285) 118.5, 115.1, 114.5, 55.4. HRMS (ESI):
Calculated for C
9
H
7
O
3
F
2
S: 233.0084; found: 233.0084.
2-((3,5-bis(trifluoromethyl)phenyl)thio)-2,2-difluoroacetic acid (3h)
1
H NMR (399 MHz, DMSO-d
6
) δ 8.28 (s, 1H), 8.25 (s, 3H);
19
F NMR (376 MHz,
DMSO-d
6
) δ -61.15 (s, 6F), -79.36 (s, 2F);
13
C NMR (100 MHz, DMSO-d
6
) δ 161.9 (t, J
= 29.6 Hz), 136.2 (d, J = 4.1 Hz), 131.3 (q, J = 33.5 Hz), 129.0, 124.5 (d, J = 4.0 Hz),
122.7 (q, J = 273.1 Hz), 120.3 (t, J = 288 Hz); HRMS (ESI). Calculated for C
10
H
3
O
2
F
8
S
[M-H]: 338.9726; found: 338.9721.
Preparation of aryltrifluoromethyl thioethers (ArSCF
3
)
A microwave vial (5 mL) was sealed under inert atmosphere (Ar Glovebox) with a stir
bar, Selectfluor (177.1 mg, 0.5 mmol, 2 equiv), silver trifluoromethanesulfonate
(12.8 mg, 0.05 mmol, 20 mol%) and arylmercaptodifluoroacetic acids (0.25 mmol,
1.0 equiv). To this vial, DCM (1.8 mL) and trifluoroacetic acid (76.5 µL, 1.0 mmol,
4.0 eq.) as well as water (0.2 mL) were added and the mixture was heated for 90 min at
55 °C. The resulting mixture was cooled down to room temperature, diluted with
dichloromethane (4 mL), washed with water (3 X 5 mL) and brine (5 mL), dried over
179
anhydrous MgSO
4
and filtered. The resulting extract was concentrated in a rotary
evaporator. The resulting crude product was dissolved in a small quantity of
dichloromethane and loaded on to a silica cartridge (10g, Biotage), air dried and eluted
with pentane. The pure fractions were combined and solvent evaporated to obtain the
pure products.
(2,4-dimethylphenyl)(trifluoromethyl)sulfane (4b)
1
H NMR (399 MHz, Chloroform-d) δ 7.48 (s, 1H), 7.23 – 7.17 (m, 2H), 2.49 (s, 3H),
2.34 (s, 3H);
19
F NMR (376 MHz, Chloroform-d) δ -42.93;
13
C NMR (100 MHz,
Chloroform-d) δ 140.9, 138.8, 136.8, 130.9, 130.0 (q, J = 319.1 Hz), 20.8, 20.8.
22

(4-chlorophenyl)(trifluoromethyl)sulfane (4c)
1
H NMR (500 MHz, Chloroform-d) δ 7.59 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5, 2H);
19
F
NMR (470 MHz, Chloroform-d) δ -43.35.
13
C NMR (126 MHz, Chloroform-d) δ 137.7,
137.6, 129.8, 129.3 (q, J = 309.7 Hz); GC-MS m/z (relative intensity): 212 (M) (64), 143
(100), 108 (100), 69 (43).
6

(4-bromophenyl)(trifluoromethyl)sulfane (4d)
1
H NMR (400 MHz, Chloroform-d) δ 7.61 – 7.47 (m, 4H);
19
F NMR (376 MHz, CDCl
3
)
δ -43.26; GC-MS m/z (relative intensity) 258 ([M+1]
+
) (48), 189.1 (40), 108.1 (100), 69
(57). The data corroborate with the literature report.
13

(2-bromophenyl)(trifluoromethyl)sulfane (4e)
1
H NMR (399 MHz, Chloroform-d) δ 2.59 – 2.54 (m, 1H), 2.54 – 2.49 (m, 1H), 2.20 –
2.08 (m, 2H);
19
F NMR (376 MHz, Chloroform-d) δ -42.52; GC-MS m/z (relative
intensity) 256.1 (M)(100), 187 (48), 108 (94), 69 (61). The data corroborate with the
literature report.
23

180
(3-bromophenyl)(trifluoromethyl)sulfane (4f)
1
H NMR (399 MHz, Chloroform-d) δ 7.85 – 7.79 (m, 1H), 7.66 – 7.58 (m, 2H), 7.31 (t, J
= 7.9 Hz, 1H);
19
F NMR (376 MHz, Chloroform-d) δ -42.88; GC-MS m/z (relative
intensity) 257.8 (M) (99), 188.7 (78), 107.9 (98.7), 69 (46).
24

(4-methoxyphenyl)(trifluoromethyl)sulfane (4g)
1
H NMR (399 MHz, Chloroform-d) δ 7.65 – 7.50 (m, 2H), 7.01 – 6.79 (m, 2H), 3.84 (s,
3H).
19
F NMR (376 MHz, Chloroform-d) δ -44.45. GC-MS m/z (relative intensity) 208.4
(7.6), 139 (100), 106.8 (40), 82 (36), 63 (50).
6

181
6.4.2 Representative spectra

1
H NMR (DMSO-d
6
)

19
F NMR (DMSO-d
6
)

OCF
2
CO
2
H
t-Bu
182
13
C NMR (DMSO-d
6
)

1
H NMR (CDCl
3
)

OCF
3
t-Bu
183

19
F NMR (CDCl
3
)

13
C NMR (CDCl
3
)

S: Pentane (14.1, 22.4 and 34.5 ppm)

s s
184

1
H NMR (CDCl
3
)

19
F NMR (CDCl
3
)

SCF
2
CO
2
H
Cl
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13
f1 (ppm)
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20
f1 (ppm)
-83.52
185
13
C NMR (CDCl
3
)

1
H NMR (CDCl
3
)

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200
f1 (ppm)
119.38
122.85
129.87
138.08
163.06
SCF
3
Cl
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5
f1 (ppm)
186
19
F NMR (CDCl
3
)

13
C NMR (CDCl
3
)

-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
187
6.5 References

1) a) Jeschke, P.; Schlosser, M. Chem. Rev. 2005, 105, 827. b) Leroux, F. R.; Manteau,
B.; Vors, J. P.; Pazenok, S. Beilstein J. Org. Chem. 2008, 4, 13. c) Landelle, G.;
Panossian, A.; Leroux, F.R. Curr. Top. Med. Chem. 2014, 14, 941. d) Xu, X. H.;
Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731.
2) a) Yagupolskii, L. M.; Kondratenko, N. V.; Timofeeva, G. N. J. Org. Chem. USSR
1984, 20, 103. b) Umemoto, T.; Adachi, K.; Ishihara, S. J. Org. Chem. 2007, 72, 6905. c)
Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem. 2007, 119, 768. d) Liu, J. B.; Chen,
C.; Chu, L.; Chen, Z.H.; Xu, X.H.; Qing, F.L. Angew. Chem. Int. Ed. 2015, 54, 11839.
3) Huang, C.; Liang, T.; Harada, S.; Lee, E.; Ritter, T. J. Am. Chem. Soc. 2011, 133,
13308.
4) a) Suda, M.; Hino, C. Tetrahedron Lett. 1981, 22,1997. b) Umemoto, T.; Ishihara, S. J.
Fluorine Chem. 1998, 92,181. c) Khotavivattana, T.; Verhoog, S.; Tredwell, M.; Pfeifer,
L.; Calderwood, S.; Wheelhouse, K.; Lee Collier, T.; Gouverneur, V. Angew. Chem. Int.
Ed. 2015, 54, 9991.
5) Preshlock, S.; Tredwell, M.; Gouverneur, V. Chem. Rev. 2016, 116, 719.
6 ) Khotavivattana, T.; Verhoog, S.; Tredwell, M.; Pfeifer, L.; Calderwood, S.;
Wheelhouse, K. Lee Collier, T.; Gouverneur, V. Angew. Chem. Int. Ed. 2015, 54, 9991.
7) Li, Z.; Wang, Z.; Zhu, L.; Tan, X.; Li, C. J. Am. Chem. Soc. 2014, 136, 16439.
8) Mizuta, S.; Stenhagen, I. S. R.; Duill, M. O.; Wolstenhulme, J.; Kirjavainen, A. K.;
Forsback, S. J.; Tredwell, M.; Sandford, G.; Moore, P. R.; Huiban, M.; Luthra, S. K.;
Passchier, J.; Solin, O.; Ox, O.; Centre, T. P. E. T.; Road, S.; Dh, D.; Healthcare, G. E.;
188

Centre, T. G.; Road, W. L.; K, A. H. P. U.; Building, E.; Park, R. B.; Sk, C. Org. Lett.
2013, 15, 2648.
9) Leung, J. C. T.; Chatalova-Sazepin, C.; West, J. G.; Rueda-Becerril, M.; Paquin, J. F.;
Sammis, G. M. Angew. Chem. Int. Ed. 2012, 51, 10804.
10) Leung, J. C. T. Radical fluorination methods for the synthesis of aryl mono-, di-, and
tri- fluoromethyl ethers. Ph.D. Dissertation. University of British Columbia, Vancouver,
Canada, 2013.
11) Krishnamoorthy, S.; Schnell, S.D.; Huong, D.; Prakash, G.K.S. Trifluoromethyl
ether and trifluoromethyl thioether synthesis by silver catalyzed decarboxylative
fluorination. Fluor-21. Presented at the 251
st
ACS National Meeting, San Diego,
California, USA.
12) Zhang, Q.; Brusoe, A. T.; Mascitti, V.; Hesp, K. D.; Blakemore, D. C.; Kohrt, J. T.;
Hartwig, J. F. Angew. Chem Int. Ed. Int. 2016, 9758.
13) Zhou, M.; Ni, C.; He, Z.; Hu, J. Org. Lett. 2016, 18, 3754.
14) Chatalova-sazepin, C.; Binayeva, M.; Epifanov, M.; Zhang, W.; Foth, P.; Amador,
C.; Jagdeo, M.; Boswell, B. R.; Sammis, G. M. Org. Lett. 2016, 4570.
15) Yagupol'skil, L.M.; Korin'ko, V.A. Zh. Obshch. Khim., 1969, 39, 1747.
16) Li, Z.; Wang, Z.; Zhu, L.; Tan, X.; Li, C. J. Am. Chem. Soc. 2014, 136, 16439.
17) Patel, N. R.; Flowers, R. A. J. Org. Chem. 2015, 80, 5834.
18) Han, Y.; Yang, S.; Wang, X.; Li, F. Arch. Pharm. Res. 2014, 37, 440.
19) Joshi-pangu, A.; Wang, C.; Biscoe, M. R. Journa Am. Chem. Soc. 2011, 133, 8478.
20) Ben-david, I.; Rechavi, D.; Mishani, E.; Rozen, S. J. Fluor. Chem. 1999, 97, 75.
21) Wu, J.; Li, H.; Cao, S. Beilstein J. Org. Chem. 2011, No. 7, 1070.
189

22) Zhang, P.; Li, M.; Xue, X.-S.; Xu, C.; Zhao, Q.; Liu, Y.; Wang, H.; Guo, Y.; Lu, L.;
Shen, Q. J. Org. Chem. 2016, 81, 7486.
23) Kalläne, S.I.; Braun, T. Angew. Chem. Int. Ed. 2014, 9311.
24) Pichat, L.; Tostain, J. J. Label. Compd. Radiopharm. 1978, 16, 245.

190

Chapter 7
Water-soluble Organic Molecules for an All-Organic
Redox Flow Battery

191
7.1. Introduction
The demand for electrical energy is increasing in a way that has never been seen
before. The world is estimated to produce 100 Terawatt hours/day
1
and is predicted to
consume energy primarily in the form of electricity at the end of next three decades.
2
The
following charts (Figure 1) project the global production of energy from various sources.
3

Figure 1 Projected energy production from various sources. (Adapted from U.S. Energy
Information Agency)
In the wake of anthropogenic climate change,
4,5
many countries aspire to achieve
carbon neutral
6
or carbon free energy supplies to fulfill their needs. Some of the pathways
include, 1) nuclear energy
7
and 2) utilizing renewable energy sources such as solar, wind,
hydropower, biomass, geothermal etc. Solar and wind are the largest energy sources
available for harvest
8
and are very appealing as they are environmentally benign,
especially compared to nuclear power plants during natural disasters.
9
However,
incorporating such intermittent energy sources into the electric grid poses challenges in
the supply/demand balance. Such challenges can be addressed by employing battery
systems capable of storing large-scale electrical energy. However, these batteries must
meet the challenge of storing thousands of gWh of energy per day. For example, in 2014
192
the state of California (US) consumed 7,620 trillion Btu, which translates into 255 GW
per hour or 6,120 GW per day.
10
Therefore, the required storage system is huge, even if
only part of this amount of energy is stored. Therefore, integration of storage into the
electric grid requires a cost-effective and environmentally-friendly energy storage
technology.
7.1.1 Redox Flow Battery (RFB) for Grid-Scale Energy Storage
Several electrical energy storage systems have been considered and reviewed
recently for grid scale energy storage applications (Table 1).
11

Table 1 Electrochemical energy-storage technology for stationary applications.
11

Among the several electrochemical storage technologies above, the flow battery is very
promising as it allows the power and energy to be decoupled, which allows easy scale up
for large-scale applications. Unlike the conventional battery systems, in the flow battery,
the redox active species are stored in external tanks as solutions (Figure 2), which are
capable of existing in both reduced or oxidized forms.
12
The power production unit, also
called a cell, is separated from the storage tanks. The solutions from the tanks are passed
through the cell using pumps. The cell typically contains three working components, 1)
positive electrode (cathode) 2) negative electrode (anode) and 3) selective ion conducting
polymer electrolyte membrane, separating the positive and negative electrolytes.
Technology
Typical
Capacity
(MWh)
Storage
Capacity Cost
($/kWh)
Life Time
(cycles/years)
Efficiency
(%)
Drawbacks
Supercapacitors 0.001-10 500-3000 500,000/20 >90% Explosion hazard, low energy density, high cost
Lead-Acid Batteries Mar-50 65-400 1000-4500/5-15 70-90 Low energy density, short lifetime, temperature sensitive
Li-ion Batteries 0.1-50 400-600 2000-5000/5-15 85-95 High cost, safety risks, short lifetime, self-discharge, temperature sensitive
Sodium-sulfur Batteries 0.25-50 300-500 4000-4500/6-15 70-90 High cost, high-temperature operation, safety risks
Flow Batteries (Vanadium) 0.5-40 150-2500 10000/5-15 60-85 Low energy density, high materials cost
193

Figure 2 Schematic of a typical redox flow cell.
In the all-organic redox flow batteries, the positive and the negative electrolytes are
typically organic compounds capable of undergoing reversible reduction and oxidation.
These compounds can either be dissolved in organic solvents, such as acetonitrile, or in
water (as an acidic or a basic or a neutral solutions). These batteries are known as organic
non-aqueous
13
and organic aqueous redox flow battery systems, respectively.
The battery voltage is defined by the reversible redox potential difference
between the two molecules employed. It should be noted that aqueous medium is
inherently bound to undergo oxygen evolution at a higher voltage at the positive
electrode and hydrogen evolution at a lower voltage at the negative electrode. The
organic molecules capable of undergoing redox reactions within this window (1.23V)
with a maximum possible potential difference would be ideal to use. Even though the
small voltage window is seen as a limitation, compared to flow batteries based in organic
solvents as they offer wider voltage window, it is believed that higher voltages than
1.23V may be achieved by inhibiting the kinetics of O
2
/H
2
evolutions. Compared to the
most developed vanadium RFB
14
and organic non-aqueous RFBs, the organic aqueous
flow battery’s (ORBAT) lower operational cost and environmentally benign nature of
Nega%ve material
storage tank
Posi%ve material
storage tank
Polymer electrolyte
membrane
Pump
Pump
Load/power
source
electrode
+ -
194
aqueous system are appealing for large-scale energy storage. Furthermore, as the redox
active molecules’ properties can be easily modified to obtain the suitable solubility as
well as the redox properties, the area is highly promising.
7.1.2 Quinones for ORBAT
The redox chemistry of quinones is well recognized and it has been widely used as
oxidants
15
as well as reductants in organic chemical production, and in biological
processes as charge carriers and anti-oxidants.
16
For example, the redox chemistry of
anthraquinone is used for the industrial scale production of hydrogen peroxide from
oxygen.
17

Scheme 1 Various oxidation states of benzoquinone.
Quinone can exist in three different oxidation states, namely: fully oxidized
quinone, fully reduced hydroquinone, and partially reduced semi-quinone (Scheme 1). In
theory, one can expect several intermediates species, such as radical cations and radical
anions, forming during the interconversion between these states.
18
Furthermore, the
intermediate formation depends on the conditions employed. For example, under acidic
pH, the electron coupled proton transfer from quinone to hydroquione becomes the
primary mode of reaction,
19
whereas under basic pH the interconversion proceeds via
radical species involving one electron transfer.
Though quinones have been characterized by electrochemical methods,

only
limited examples have been explored for the purposes of energy storage.
20
For example,
O
O OH
O
OH
OH
+e
-
, +H
+
-e
-
, -H
+
+e
-
, +H
+
-e
-
, -H
+
quinone semiquinone Hydroquinone
195
Wen and co-workers used 4,5-dihydroxybenzene-1,3-disulfonic acid as the positive side
of the cell against lead/lead sulfate.
21
Recently, the Aziz group has been exploring
anthraquinone-based compounds as negative side materials under acidic and basic
conditions against bromine/bromide
22
and ferro/ferricyanide
23
couples, respectively. For
the first time, in 2014, Narayan and co-workers reported a redox flow battery system that
uses solutions of

commercially available anthraquinone-2-sulfonic acid (2 or AQS) and
1,2-benzoquinone- 3,5-disulfonic acid (1 or BQDS) in 1 M H
2
SO
4
on the negative side
and the positive side of the redox flow battery, respectively.
24
As it uses organic
compounds on both sides of the battery, it was aptly named Organic Redox flow Battery
or ORBAT. In that ORBAT system, during charge and discharge, the following redox
reactions take place (Scheme 2).

Scheme 2 Redox reactions in the flow battery.
Based on the electrochemical observations, in 2009, Wen and co-worker reported
that the BQDS undergoes Michal addition under the cell cycling conditions to form 2,4,5-
trihydroxybenzene-1,3-disulfonic acid (1b) in 3M H
2
SO
4
, which was proposed to be the
actual compound that undergoes the redox process (Scheme 3).
21
Furthermore, they
claimed 1b did not undergo further transformations under their conditions.
OH
OH
HO
3
S SO
3
H
2e
-
+ + 2H
+
O
O
SO
3
H HO
3
S
E
0
= + 0.85 V
O
O
SO
3
H
2e
-
+ 2H
+
+
OH
OH
SO
3
H
E
0
= + 0.19V
1
1a
2 2a
196

Scheme 3 Chemical Transformations of BQDS in 3 M H
2
SO
4
.
However, unlike observations made by Wen and co-workers, Narayan and co-workers
observed that 1b appeared to underwent further transformations under similar conditions
(1 M H
2
SO
4
) during the electrochemical cycling.
24
Thus, such degradation leads to poor
performance of the ORBAT.
7.1.3 Focus of My Work
My contribution began with tracking various species formed on the positive side of the
ORBAT during cycling using NMR experiments and mass spectrometry. Consequently,
design and synthesis of alternatives to BQDS with the following criteria, namely, lower
cost, higher solubility and stability, minimal or no crossover, and higher redox potential
became part of my work and integral to the success of the ORBAT program.
Solubility of quinones
Simple quinones’ (eg., anthraquinone and benzoquinone) solubility is very limited in
water with few exceptions. Therefore, it is necessary that the molecules themselves are
highly polar or contain polar functional groups that render the molecule soluble in
aqueous medium. In order to determine if the molecule has reversible electrochemical
properties, it has to be dissolved in water for the proper measurements to be taken.
Furthermore, the flow battery can be operated in water at various pH, offering various
advantages and disadvantages for solubilizing the materials. However, the state of the art
redox flow battery systems use SO
3
H, R
4
N
+
and Ar-OH as solubilizing groups in acidic
OH
OH
-2H
+
, -2e
-
BQDS 1
1a
H
2
O
SO
3
H HO
3
S
O
O
SO
3
H HO
3
S
1b
OH
OH
SO
3
H HO
3
S
OH
Proposed to cycle
reversibly
197
(1 M H
2
SO
4
),
24
neutral
25
and basic media (1 M KOH),
26
respectively. It is important to
consider that the solubility effect coming from the hydroxyl groups of the hydroquinone
would not be there when they are oxidized, suggesting that the solubility of a quinone in
the oxidized form is expected to be lower than the reduced form. Though it is challenging
to calculate solubility of compounds with a high degree of accuracy, recently, ΔG°
solv
has
been calculated of several quinones.
27
In a recent review it is highlighted that for a cost-
effective redox flow battery based in aqueous media, the solubility should be in the range
of ≈1-2 M of the redox active species.
28
During the course of my study, various
functional groups are considered and incorporated into redox active small molecules,
which are otherwise poorly soluble, to improve their solubility in aqueous medium.
Crossover
Crossover may be defined as the tendency of a redox active species to move from one
side of the cell through the membrane to the opposite side of the cell. Such behavior
reduces the capacity and cycle life of the battery. Typically, in an acid-based organic
redox flow battery, a proton-conducting perfluorinated polymeric membrane is used (eg.,
Nafian 117), which is expected to only conduct protons and reject anionic species. It is
also recognized that high molecular weight compounds containing higher charges have
lower crossover.
29
Therefore, design and synthesis of such new redox active organic
compounds were explored, which can potentially minimize the rate of crossover and thus
improve the cell performance and longevity.
Redox potential
Depending on the side of the cell that the designed compound will be used for,
appropriate functional groups may be incorporated. For example, for a negative side
198
material to achieve more negative potential, electron-donating groups can be introduced.
On the other hand, for the positive side material, to achieve more positive redox potential,
electron-withdrawing groups may be installed. Recently, computational calculations have
been carried out to predict the redox potential of several quinone-based compounds.
27

Stability
High stability is crucial for the long term cycling of the system. Particularly, the positive
side materials are prone to hydration of carbonyl and hydroxylation of open aromatic
positions. Furthermore, it is important the molecule also has reasonable thermal stability
(60 -70 °C).
In this chapter, illustration of transformations of the positive side material
(BQDS), and identification and preparation of materials that are not susceptible to such
transformations are discussed. The preparation of these new materials was first primarily
adapted with consideration of the cost. However, as the new materials made presented
several problems during characterization and testing in ORBAT, our approach to the
discovery of new molecules sharpened as we gained more understanding of the issues.
This understanding has allowed us to define a set of optimized structural features for new
molecule discovery. The discussion and preparation will be presented in this chapter in
the order we prepared them. The results of testing ineffective or poorly performing
molecules are also discussed as they have significantly added to our knowledge base on
how to design the molecule with optimum desired properties.
7.2. Results and discussion
7.2.1 Determination of transformations of 4,5-dihydroxybenzene-1,3-disulfonic acid.
199
In a standard experiment, anthraquinone-2,6-disulfonic acid (3, AQDS) (600 mL,
1 M, 0.6 moles) and 4,5-dihydroxybenzene-1,3-disulfonic acid (1, BQDS) (100 mL, 2M,
0.2 moles) in 1 M H
2
SO
4
were circulated past the electrodes of the flow cell. The cell was
charged and discharged multiple times. The changes on the BQDS side were tracked by
1
H NMR (for related linear sweep voltammetry studies see ref. 39 and 30).

Figure 3
1
H NMR of BQDS samples taken after various numbers of cycles. Solutions
were diluted with D
2
O.
1
H NMR analysis of a sample from the AQDS side indicated no change in the molecular
composition during cycling and that it undergoes a reversible redox reaction similar to
AQS. On the other hand, significant changes were observed in the solution at the positive
electrode. Samples were withdrawn at the different intervals during the extended cell
cycling at 100 mA/cm
2
and analyzed by NMR (Figure 3). We observed that BQDS
underwent a slow chemical transformation in addition to the expected electro-oxidation
and electro-reduction during charge and discharge cycles. The two doublets at 7.34 ppm
200
(J = 2.2 Hz, 1H) and 7.10 ppm (J =2.2 Hz, 1H) in the proton NMR at the start of the
cycling corresponded to 4,5-dihydroxybenzene-1,3-disulfonic acid (BQDS), with protons
on the aromatic ring present in two distinct environments. After the first charge, the
1
H
NMR spectrum showed a new “aromatic” proton signal at 7.14 ppm (singlet) that was
attributed to 1,2,4-trihydroxybenzene-3,5-sulfonic acid. After extended cycling (120
cycles), the ratio of 1,2,4-trihydroxybenzene-3,5-sulfonic acid to BQDS had increased.
After 400 cycles, all the “aromatic” proton signals of BQDS and other reaction products
disappeared, indicating the occurrence of yet another transformation that produced
compounds with no peaks in the proton NMR spectrum, which was attributed to the
formation of 1,2,4,6- tetrahydroxybenzene-3,5-sulfonic acid (Scheme 4).

Scheme 4 Hydroxylation of BQDS during cycling via Michael addition of H
2
O.
Although the samples for NMR were obtained only after 120 cycles and 400
cycles, the electrochemical data indicated that changes were probably complete even in
the earlier stages of cycling. For instance, the capacity of cell stabilized only after about
five cycles of charge and discharge. The charge acceptance in the first cycle was about
three times that of the discharge capacity output following this charge. Therefore, the
coulombic efficiency in the first cycle was about 33%. However, in subsequent cycles the
coulombic efficiency gradually converged to 100%. In the initial cycles, the charging
OH
OH
-2H
+
, -2e
-
BQDS 1
1a
H
2
O
SO
3
H HO
3
S
O
O
SO
3
H HO
3
S
1b
OH
OH
SO
3
H HO
3
S
OH
1c
O
OH
SO
3
H HO
3
S
O
-2H
+
, -2e
-
H
2
O
1d
OH
OH
SO
3
H HO
3
S
OH
HO
201
curves showed a single voltage plateau that developed into two voltage plateaus,
suggesting the formation of at least two types of redox active species that underwent
transformations. The initial value of the charging voltage of the cell before the
transformations was 0.9 V (Figure 4b), and this value reduced to 0.7 V by the end of 100
cycles, suggesting that chemical transformations of the redox active species had occurred
during the cycling. The changes to the charge-discharge curves and the NMR spectra
during cycling were consistent with the stepwise transformation of 4,5-
dihydroxybenzene-1,3-disulfonic acid to 2,4,5-trihydroxybenzene-1,3-disulfonic acid and
ultimately to 1,2,4,6-tetrahydroxybenzene-3,5-disulfonic acid. These transformations
involve electrochemical oxidation of the hydroxyl group to the quinone, followed by the
addition of water to form reduced products (Scheme 4). The addition of nucleophiles
such as water to the α,β-unsaturated carbonyl compounds in a 1,4-fashion is called the
Michael reaction. In our study, the nucleophilic addition of water is accompanied by re-
aromatization and exchange of the proton. The Michael reaction necessitated additional
charge input for the re-oxidation of the product during charging. These observations were
also confirmed by linear sweep voltammetry studies of the BQDS side of the solution.
30

Following these transformations, the 1,2,4,6-tetrahydroxybenzene-3,5-disulfonic
acid became the positive electrode material that was repeatedly cycled against AQDS at
the negative electrode. These transformations of BQDS during the initial stages of
cycling presented some challenges with the overall cell operation. First, at least three
mole equivalents of AQDS were required compared to one mole equivalent of BQDS, in
order to completely convert all the BQDS to its final form. After BQDS had reached its
fully charged form, 66% of the AQDS remained unused during the subsequent cycles.
202
Secondly, the products formed after the Michael reactions are expected to reduce the cell
voltage, as additional hydroxyl substituents are added to BQDS. A reduction of about 150
mV in the charge voltage is noted after the first few cycles. This reduction is slightly
lower than the 100mV/hydroxyl group expected from the study of substituent effects.
31

1
H NMR was utilized to observe the amount of material penetrating through the
proton conducting membrane from one side to another. For example, NMR analysis of
the solutions even after 400 cycles confirmed that neither compound diffused through the
Nafion
®
membrane. These results were also consistent with the ex-situ studies― even
after 2 months of holding solutions of 0.2 M AQDS or BQDS dissolved in 1 M sulfuric
acid on one side of the membrane, and just 1 M sulfuric acid on the other side of the
membrane, no crossover was detected. The absence of crossover confirmed the low
permeability of the Nafion
®
membrane to the anionic form of the redox molecules.
Though at first, we were encouraged to prepare 1,2,4,6-tetrahydroxybenzene -3,5-
disulfonic acid by chemical methods and study its performance in the cell against AQDS,
during our preparation we realized it was an expensive route to take as the starting
material is not commercially accessible and the small scale isolation still required proton
exchange processes. Furthermore, with the addition of hydroxyl groups the compound
would have a lower reduction potential. Therefore, alternative molecules, which are
resistant to Michael addition and at the same time provide higher voltage compared to 1d,
were sought.
7.2.2 Alternative positive materials for acid based ORBAT
In order to prevent the Michael addition, substituted hydroquinones were
proposed as alternatives. However, none of the commercially available quinones were
203
suitable to fulfill the following criteria, namely: 1) sufficient solubility in water (1-2 M)
2) stability of oxidized and reduced forms under the aqueous media (1 M H
2
SO
4
) and 3)
reasonably positive redox potential to achieve >0.5V cell voltage against AQDS. A pool
of compounds was proposed considering the accessibility of starting material, and the
ease of preparation and scale up, in addition to the above criteria. Furthermore, the
aqueous medium (acidic/basic) of the electrochemical cell conditions limited the
substitutions that can survive on the positive side of the cell. For instance, halides,
methoxy, CN and CF
3
32,33
substitutions tend to hydrolyze under basic/acidic aqueous
conditions, particularly in the quinone form.
34
The nitro group was avoided in
consideration of its reactivity and general environmental concern.
35
Therefore, the
substitutions were limited to methyl, hydroxyl and carboxylic groups. Due to the
challenges associated with direct aromatic ring C-H methylation, hydroxylation and
carboxylation, sulfonation was adapted as the primary tool for the synthesis of new
positive materials. Furthermore, the sulfonic groups are key moieties as they render the
molecules water-soluble, while at the same time making the molecule undergo oxidation
at higher potentials under electrochemical redox process.
7.2.2.1 Synthesis of hydroxyl substituted benzenesulfonic acids

Scheme 5 Sulfonation of pyrogallol.
Pyrogallol (4) has wide applications in industry and is typically produced by
decarboxylation of gallic acid.
36 , 37
It is commercially available in multi-kilogram
OH
HO OH
SO
3
H HO
3
S
OH
OH HO
Conc. H
2
SO
4
RT, 24h
4a, 75%
4
204
quantities for lab scale processes. The inexpensive nature and resemblance of 4 to 1d led
us to investigate sulfonated pyrogallol, 4a.
The sulfonation of pyrogallol was carried out in concentrated sulfuric acid at
room temperature following a modified patent literature procedure (Scheme 5).
38
The
compound was easily isolated in the acid form without the need for proton exchange,
which made this process very appealing for commercialization and scale-up. However,
4a failed to undergo a reversible redox process in the cyclic voltammetry (CV) and
rotating disk electrode linear sweep voltammetry (RDE) studies. For further discussion
and investigation of CV of various quinones on various electrode surfaces, please see
Hoober-Burkhardt dissertation.
39

Scheme 6 Sulfonation of pyrogallol-4-carboxylic acid.
Monosulfonation of pyrogallol-4-carboxylic acid is a similar process to pyrogallol and
provides an expected product in 82% yield (Scheme 6). Similarly, the electrochemical
characterization revealed an irreversible redox process.
39

At this point, with the help of quantum mechanical structural optimization, we
speculated that the sulfonation of the quinones renders some of these molecules non-
planer, either in the oxidized or reduced states. Therefore, for complete determination of
the electrochemical nature of these molecules is strongly dependent on the electrode
structure. It may be necessary to develop a protocol that involves a series of CV
experiments on various electrode surfaces to specifically characterize molecules with
OH
HO
HO
Conc. H
2
SO
4
24 h, RT
CO
2
H
OH
HO
HO
CO
2
H
SO
3
H
5a, 82 %
5
205
similar functional groups or structural features. Furthermore, it is commonly agreed that
the intramolecular hydrogen bonding in these compounds significantly affects the
kinetics of the redox processes.
24

We hypothesized that replacing the hydroxyl groups with methyl groups will
make the redox potential higher.
31
For example, by completely substituting the aromatic
carbons of catechol with two methyl groups and two SO
3
H groups, the compound should
avoid Michael addition, while maintaining a high redox potential.
7.2.2.2 Methyl substituted benzoquinone sulfonic acids

Figure 4 Isomers of two -Me and two -SO
3
H groups containing o-quinone.

At first, o-quinones were chosen due to their higher redox potential compared to
the p-quinones. With two methyl and two sulfonic acid groups, four isomers are possible
(I-IV, Figure 4). I and III can be easily made by direct sulfonation of the dimethyl
catechol precursors, while II and IV are more difficult to synthesize as the sulfonation
adjacent to a sulfonic acid group is usually difficult due to steric and electronic reasons.
Therefore, mainly I and III were considered. However, none of their precursors are
commercially available for a reasonable price. The catechols needed to be synthesized
from their corresponding phenols, which are commercially available in kilogram
quantities. Between I and III, I was hypothesized to have better kinetics, as one of the
sulfonic acid groups is isolated from the hydroxyl groups and thus the slow kinetics
OH
OH
SO
3
H HO
3
S
OH
OH
SO
3
H
HO
3
S
OH
OH HO
3
S
SO
3
H
OH
OH HO
3
S
HO
3
S
I
II III IV
206
arising from the intramolecular hydrogenbonding interaction between SO
3
H and OH
groups is avoided.
24
Therefore, we decided to synthesize I.

Scheme 7 Retrosynthetic analysis for I.
The synthesis was conceived according to the above retrosynthetic analysis
(Scheme 7). Halogenation and hydroxylation was carried out following the previously
reported procedure (Scheme 8).
40
The halogenation proceeded smoothly and was easily
scaled up to obtain 125 g of the material in one batch. However, the reaction
concentration turned out to be an important variable to prevent side reactions in the
hydroxylation of 6b, and high dilution conditions for the reaction was a key hurdle in the
scale-up of the reaction. Alternatively, a direct oxidation and reduction method was also
explored, where a slight excess of IBX was used to oxidize the 2,4-dimethylphenol to its
corresponding o-quinone and then it was reduced using saturated solution of sodium
dithionite.
41
The efforts on iron (III) catalyzed direct hydroxylation using H
2
O
2
were,
however, unsuccessful. It would be highly desirable to have a metal catalyzed direct C-H
hydroxylation protocol using air or hydrogen peroxide as an oxidant. 6c underwent
sulfonation readily at room temperature in concentrated sulfuric acid to selectively
provide a monosulfonic acid (6d), which then was heated at 70 °C for 4 hours to provide
the expected disulfonic acid (I). The attempts to directly precipitate I in the acid form
using co-solvents, such as acetonitrile, were unsuccessful. Consequently, the compound
was isolated as the sodium salt, and later obtained in the proton form using a proton
exchange column. During the removal of water after proton exchange, the compound
OH OH
X
OH
OH
OH
OH
HO
3
S SO
3
H
Halogenation
Hydroxylation
Sulfonation
207
seems to decompose into several unidentified products, which may be attributed to the
higher temperature of the water bath used. Another portion was carefully rotary
evaporated under lower temperature, and used in a full cell electrochemical experiment.
Although reasonable cycling data was obtained for the first 10 cycles, the compound
degraded after that and the capacity of the cell deteriorated to 40% of the theoretical
capacity and continued to cycle at that capacity. The
1
H NMR analysis of the cycling
material revealed the presence of several degraded products; among them the
protodesulfonated monosulfonic acid compound was identified to be the major species.

Scheme 8 Preparation of 4,5-dihydroxy-2,6-dimethylbenzene-1,3-disulfonic acid.
The multistep synthesis and subsequent failure of the o-quinone prompted us to
pursue the p-quinone based compounds. Although the redox potential is expected to be
lower than the o-quinone, the starting material, 2,6-dimethylbenzene-1,4-diol, among
other possible dimethyl-p-quionone isomers, was readily available from commercial
sources, reducing the cost and time needed for their functionalization.
Sulfonation of 2,6-dimethylbenzene-1,4-diol was observed to provide a
monosulfonated product at room temperature in concentrated sulfuric acid (Scheme 9).
OH
OH
Br
OH
OH
HO
3
S SO
3
H
OH
OH
NBS, DMF
RT, 24h
CuSO
4
NaOH, Reflux
OH
OH
SO
3
H
conc. H
2
SO
4
70
o
C
4h
> 99% converison, 6c
rt, 24h
6b, 34% 6
6a, 91%
I, 66%
208
The efforts to achieve the second sulfonation in concentrated sulfuric acid at various
temperatures (rt-180 °C), in 60% SO
3
/H
2
SO
4
between room temperature to 40 °C, and in
with SO
3
.dioxane in DCM at room temperature failed to provide the disulfonated
compound in significant amounts. Consequently, we speculated that the rate of Michael
addition of the monosulfonted compound may be lower for steric reasons and it might
survive the electrochemical cycling conditions. Furthermore, it would only undergo one
Michael addition, which is still an improvement from the BQDS in terms of the extra
amount of negative side material required during the initial cycling. Therefore, the
monsulfonated compound synthesis was scaled up to obtain the desired product as a
potassium salt in 85% isolated yield. The compound was converted to its acid form using
a proton exchange column and subsequently studied using cyclic voltammetry and in an
electrochemical flow cell. As hypothesized, no Michael addition on the open C-H
position was observed during cycling of this compound. However, a new problem arose,
namely, protodesulfonation.
42
Protodesulfonation is exactly the opposite process of
sulfonation, where H
+
displaces the sulfonic acid group, rendering the molecule insoluble
in the aqueous media. The protodesulfonation is typically prevalent in lower pH aqueous
media and higher temperatures. The following issues were also observed: 1) the
compound still crossed over during cycling studies and 2) due to the difference in number
of sulfonic acid substituents compared to AQDS, transportation of water from the
positive side (side of 7a) to the negative AQDS side was observed (osmotic drag), which
increases the effective concentration of acid in the reservoir tank, which further increased
the rate of protodesulfonation.
39

209

Scheme 9 Sulfonation of 7.
In an effort to prepare a fully substituted hydroquinone from readily available
starting material, sulfonation of trimethylhydroquinone (available for purchase in multi-
kilogram quantities at 192 USD per kg, cheaper than 7) was explored. Under similar
sulfonation conditions, conc. H
2
SO
4
at room temperature over 24 hours (Scheme 10),
partial conversion was observed with a formation of a black substance. During the work
up of the reaction mixture, large quantities of the black solid crashed out, which did not
dissolve in acidic aqueous solutions. When the black solid was analyzed, the compound
was found to be the starting hydroquinone 8. Therefore, it is hypothesized that the
sulfonated material desulfonates during the dilution with water, and the exothermic
nature of the process accelerates the desulfonation process. The system is very electron
rich and therefore the rate of sulfonation/desuflonation is on a shallow potential energy
surface. To determine the rate of sulfonation, the compound was dissolved in conc.
H
2
SO
4
and transferred to frozen D
2
O, which quickly melted and transferred to an NMR
tube to record
1
H NMR spectrum, which showed already complete conversion to the
desired product. Thus, during the scale up of the reaction, careful quenching (using
sufficient ice) was initiated once the solid dissolved in conc. H
2
SO
4
achieving higher
yield of the sulfonated product (88%).
OH
OH
Conc. H
2
SO
4
24h, rt
OH
OH
SO
3
H
OH
OH
SO
3
K
7a', 85%
100% conv., 7a
K
2
CO
3
7, 50g scale
210

Scheme 10 Sulfonation of trimethylhydroquinone 8.
The sodium salt was subsequently converted to the proton form using a proton
exchange column and the material was characterized using cyclic voltammetry and
studied in an electrochemical flow cell. During the cycling studies, the molecule did not
undergo Michael addition of water but significant protodesulfonation was observed,
reducing the overall electrochemical cell performance. Furthermore, in an
electrochemical flow cell experiment, under basic media (1 M NaOH), the 8a’ was able
to be charged but failed to discharge. We speculate that upon oxidation of 8a’, the methyl
groups on the quinone form are susceptible to deprotonation (Scheme 11), leading to
formation of enolates 8c, which can undergo a condensation reaction with other quinones
(cross aldol) under the basic medium.
43
In an independent experiment, the methyl group
on 2-methylanthraquinone undergoes varying degrees of deuteration (by deuterium
NMR) in D
2
O/EtOH in the presence of KOH. Therefore, the compound was examined in
neutral and mildly acidic conditions (AcOH/NaOAc buffer and 0.1 M H
2
SO
4
) and found
to be stable and provided stable performance in an electrochemical flow cell.

Scheme 11 Enolization of 8b under strongly basic media.
OH
OH
SO
3
Na
OH
OH
1) Conc. H
2
SO
4
, 5-10 min
2) Na
2
CO
3
8
(commercial)
8a', 88%
ONa
ONa
SO
3
Na
O
O
SO
3
Na
H
H
H
OH
O
O
-
CH
2
SO
3
Na
enolate
condensation reactions
with quinones
-2Na, -2e
-
8a''
8b
8c
211
Since the materials synthesized thus far face problems such as protodesulfonation,
lower redox voltage, and a higher tendency to crossover, the need to obtain the
disulfonated, fully substituted benzoquinone became imperative. The additional sulfonic
acid group can play a key role in increasing the redox potential by as much as 100mV,
decreasing the rate of protodesulfonation, and lowering crossover as a dianionic species
with a larger molecular size and a higher molecular weight.
44

One of the conditions that was not explored for the sulfonation was the use of
chlorosulfonic acid. A key difference in the pathways of sulfonation with ClSO
3
H is that
it proceeds via formation of sulfates with phenolic compounds and subsequent migration
to the ortho position.
45
Therefore, it was speculated that the strongly acidic ClSO
3
H
might prove successful for the disulfonation reaction. As anticipated, the disulfonation of
the hydroquinone was observed in neat ClSO
3
H. When the reaction was closely
monitored, the reaction proceeded stepwise, monosulfonation followed by disulfonation,
identified by disappearance of two distinct methyl groups and an aromatic signal into one
singlet around 2.5 ppm in the
1
H NMR. Further experimentation with the conditions
showed that the reaction proceeded smoothly with ClSO
3
H in dichloromethane (Scheme
12), which allowed easy washing of organic impurities and excess ClSO
3
H from the
reaction mixture after the completion of the reaction. The product was isolated as a
potassium salt and later exchanged into the acid form using a proton exchange column.
Further improvement to the yield of 7b may be achieved by optimizing the purification
procedure.
212

Scheme 12 Disulfonation of 7 with ClSO
3
H.
To determine the stability of the compound under electrochemical cell cycling
conditions, 7b’ was mixed with an equivalent amount of sulfuric acid, and dissolved in 1
M sulfuric acid (0.5 M 7b in 1 M H
2
SO
4
) and heated at 60 °C for 24 h. The resulting
solution was analyzed by
1
H NMR in DMSO-d
6
. No degradation of 7b was observed.
When 7b was characterized using cyclic voltammetry and RDE (Figure 5, a), it provided
a more positive redox potential over 7a and 8a (H
+
form of 8a’). Therefore,
electrochemical cell cycling with AQDS could potentially offer a 1V cell voltage (Figure
5).

Figure 5 CV (blue) and RDE (red) studies of mixture containing AQDS and 7b.
7.2.2.3 Towards methyl group substituted bisphosphonic acid
Though the electron-withdrawing effect of a phosphonic acid group is less than a
sulfonic acid, a lack of studies on the redox active phosphonic acids for ORBAT
prompted us to study such molecules. Therefore, synthesis of
OH
OH
OH
OH
SO
3
K KO
3
S
1) ClSO
3
H, DCM
2) K
2
CO
3
7b', 35% 7, Commercial
Proton exchange
membrane
OH
OH
SO
3
H HO
3
S
100% conversion
7b
O
O
SO
3
H
HO
3
S
OH
OH
SO
3
H HO
3
S
213
dihydroxydimethylbenzenebisphophonic acid was proposed (Scheme 13). The
commercially available 2,5-dimethylbenzequinone (9) was reduced with hydrogen in the
presence of Pd/C in ethyl acetate. The corresponding hydroquinone (9a) was treated with
diethylphosphite in the presence of triethylamine to obtain the phosphate (9b), which in
the presence of LDA provided the corresponding phosphonate (9c) in a very low yield.
Furthermore, during the de-ethylation under 20% HCl reflux conditions,
protodephosphorylation was observed instead of de-ethylation. Since the protocol was
not successful, further studies were not pursued. However, the compound could
theoretically be prepared by adapting de-ethylation reaction performed with TMSI to
obtain the desired product, 9d.

Scheme 13 Synthetic efforts towards dimethylbenzenebisphosphonic acid.
7.2.3 Unimolecular approach
7.2.3.1 Synthesis of single quinone based molecule with four-electron (2 x 2e-/2H
+
)
redox chemistry
One of the key problems for the advancement of flow battery technology is the
crossover of the redox active materials across the membrane barrier, which reduces the
capacity and performance of the battery over time. With existing membrane technology,
O
O
O
O
OH
OH
Pd/C, RT
H
2
, EtOAc
9a, 83%
HP(O)(OEt)
2
, CCl
4
Et
3
N, RT, 12 h
OH
OH
P(O)(OEt)
2
(EtO)
2
(O)P
(EtO)
2
(O)P
P(O)(OEt)
2
9b, 95 %
9c, 5+ %
20% HCl
Reflux
OH
OH
H
2
O
3
P
PO
3
H
2
n-BuLi
i-Pr
2
NH
protodephosphorylation
observed
9
9b
9d
214
it is possible to prevent crossover by designing the redox active molecule with
sufficiently large size and/or increasing the number of charges on the molecule.
44

However, a single molecule that can undergo two 2e
-
, 2H
+
redox reaction at widely
different potentials would serve as superior compound as it will be fairly large in size and
it will be an active material no matter which side of the battery it is on. A similar
approach has been examined in organic solvents,
46
there was no literature precedent for
such molecules in aqueous media. Therefore, such a molecule would revolutionize the
organic redox flow battery field if the right combination of couple can be discovered and
synthesized. To test the proof of concept, a simple molecule was proposed and a
retrosynthesis of that molecule was put forth (Scheme 14).

Scheme 14 Retrosynthesis of a simple dicouple based on quinones.
7.2.3.2 Synthesis of a dicouple (Figure 6)
The commercially available 2-methylanthraquinone (10) was brominated
following a literature procedure to obtain the bromo compound (10a) in 82% yield,
47

which was hydrolyzed in dioxane/water (1:3) under reflux in the presence of n-Bu
4
NI
(10%) with 100% conversion. In order to couple the anthraquinone moiety with the
benzoquione, a Lewis acid, such as FeCl
3
in DCM at various temperatures (rt-100 °C),
was examined and found to be ineffective for the Friedel-Crafts reaction. Next, the
O
O
OH
OH
SO
3
H
O
O
OH
OH
Sulfonation
O
O
OH
OH
Friedel-Crafts
X
X = Br, OH
+
O
O
Bromination
215
reactions were examined in neat Bronsted acids, namely, trifluoromethylacetic acid,
trifluoromethanesulfonic acid, methanesulfonic acid, and phosphoric acid at various
temperatures (rt -100 °C). Phosphoric acid (98%) accomplished the desired reaction at
100 °C in 2 hours providing the desired product. With other acids, no reaction, or O-R
products were found. However, the reaction carried out with 50% phosphoric acid failed
to provide the desired product even at 130 °C after 2 hours. Therefore, the 98%
phosphoric acid was effectively used as the reaction medium to obtain the dicouple (10c)
in 65% isolated yield. The sulfonation of the dicouple in conc. H
2
SO
4
at room
temperature produced two isomers (10d’ and 10d’’); this mixture was directly studied in
cyclic voltammetry experiments without separation or isolation.

Figure 6 Synthesis and electrochemical characterization of the dicouples.
O
O
O
O
Br
O
O
OH
OH
NBS, mCPBA
CCl
4,
reflux
10, Commercial
O
O
OH
dioxane/H
2
O
98% H
3
PO
4
100
o
C
Hydroquinone
n-Bu
4
NI
reflux
10a, 82%
10b, 98%
10c, 65%
O
O
OH
OH
O
O
OH
OH
SO
3
H
SO
3
H
10d', 35%
10d'', 65%
+
Conc. H
2
SO
4
24h, rt
-2.5E-05
-2.0E-05
-1.5E-05
-1.0E-05
-5.0E-06
0.0E+00
5.0E-06
1.0E-05
1.5E-05
-0.7 -0.2 0.3 0.8
Current, Amperes
Voltage, Volts vs. MSE
-6.0E-05
-5.0E-05
-4.0E-05
-3.0E-05
-2.0E-05
-1.0E-05
0.0E+00
1.0E-05
2.0E-05
-0.7 -0.2 0.3 0.8
Current, Amperes
Voltage, Volts vs. MSE
a) CV
a) RDE
216
As shown in Figure 6, a and b, one molecule undergoes two different 2-
electron/2-proton redox processes at different redox potentials with ca. 0.7 V difference.
This unequivocally proves that such molecules are capable of serving as unimoelcular
organic compounds that can be used on both sides of the ORBAT in aqueous acid
medium. This molecule also triggered the symmetrical studies of an untangled mixed
electrolyte approach, wherein separate molecules such as AQDS and 7b are mixed and
used in both the side of the cell to study the performance of the mixtures. This approach
allowed us to achieve a stable performance. The small amount of capacity loss, primarily
arising from crossover, was about 0.1% per cycle over 25 cycles (Figure 7, a), which can
be mitigated by reversing the positive side to negative side and vice-versa after a certain
number of cycles to reverse the crossover. This is termed as the lead-switching protocol,
which can help to maintain a stable cell capacity over several cycles as the crossing over
material is shuttled back on forth. Furthermore, the smooth charge and discharge curves
(Figure 7, b) are indicative of absence of any chemical transformations during the
cycling.

0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0 5 10 15 20 25 30
Capacity (Ah)
cycle number
Cha Cap Discha Cap
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
-20 0 20 40 60 80 100
Cell Voltage (Volt)
Time (hour)
a) Capacity vs cycles b) voltage vs :me
hours
217
Figure 7 a) cell voltage vs time; b) capacity vs cycles.
7.2.4 Negative material based on acetyl benzene
1,4-diacetylbenezene has been shown to exhibit reversible redox behavior in
organic media (Scheme 15).
39
In our efforts to take advantage of this property in our
ORBAT studies, we proposed to investigate its redox properties in aqueous media.
However, the solubility of this compound is very limited in water. Therefore, the
compound was characterized in 80% DMF/water mixture and in 20% methanol/water
mixture.

Scheme 15 Redox chemistry of 1,4-diacetylbenzene.
7.2.4.1 Synthesis of N-methylimidazole derivative of 1,4-diacetylbenzene
In order to improve the solubility, functionalization of the diacetylbenzene was proposed.
As there are no commercially available compounds, we proposed to functionalize the
active α-methyls to the carbonyls with solubilizing groups, which will improve the
solubility of the compound but keep the redox potential essentially the same. As our
cycling studies involve the use of 1 M H
2
SO
4
, such compounds are expected to have
improved solubility.

Scheme 16 Retrosynthetic analysis of diacetyl derivatives.
Aldol condensation conditions were adapted from literature to accomplish condensation
(Scheme 17).
48
The resulting unsaturated products were reduced by hydrogenation with
O
O + 2H
+
, 2e
-
- 2H
+
, 2e
- OH
HO
O
O
O
O WSF
FSW
CHO
Aldol
Condensation
+
O
O WSF
FSW
WSF
Reduction
218
Pd/C.
49
Compared to the solubility of the parent diacetyl benzene, the derivatives were
highly soluble, for example a 1 M sample can be easily prepared in 1 M sulfuric acid.
Though these compounds appeared to produce a reversible cyclic voltammogram, when
imidazole derivative was scaled up and studied under full cell cycling conditions, we
were able to charge cell, but was unable to discharge. NMR analysis of the samples from
the reservoir showed irreversible reduction of the carbonyl groups to give the
corresponding alcohols (Scheme 17).

Scheme 17 Water soluble diacetylbenzene derivative.
7.2.4.2 Synthesis of the sulfonic acid derivative
The sulfonic acid derivative was prepared following the literature procedure (Scheme
18).
50
The products were characterized by cyclic voltammetry analysis to provide a
reversible cyclic voltammogram; however, the earlier results of similar compounds
(Scheme 17) discouraged further studies of these compounds in full electrochemical cell.

Scheme 18 Sulfonation of diacetylbenzene.
7.2.5 Positive Material for Basic Conditions
O
O
NaOMe
N
N
CHO +
O
O
N
N
N
N
O
O
N
N
N
N
MeOH, rt
10% Pd/C, H
2
DCM/MeOH (4:1)
N N
N N
OH
H
H
OH
11c'', 30%
O
N N
N N
OH
H
11c', 70%
+
in the
electrochemical
cell
11 55%, 11a
11b
100% conv.
O
O
Dioxane:SO
3
(1:1)
DCE, 4 h at 0
o
C
O
O
HO
3
S
SO
3
H
O
O
HO
3
S
25 % 76 %
+
219
As previously discussed, the methyl groups tend to undergo enolization in the
quionone form under basic medium. Therefore, a tetracarboxylic acid groups containing
compound was proposed as an alternative positive material for the basic conditions. A
literature procedure was adapted for the preparation (Scheme 19).
51
Among all the
quinone-based compounds prepared, this is the only compound that survived the basic
medium and provided a reversible CV.
39
However, the limited solubility of the compound
in 1 M NaOH discouraged further studies of the compound. When the CV was performed
in higher concentrations of NaOH to increase the solubility, multiple redox peaks
appeared at lower potentials, they were attributed to the various salts of sodium under the
conditions.

Scheme 19 Synthesis of Hydrquinonetetracarboxylic acid.
7.3 Conclusions
Significant progress for the positive material of the all-organic redox flow battery
electrolyte material has been accomplished with the synthesis of several quinone-based
molecules. Though most of them did not serve as the key molecule for ORBAT, they
certainly helped in understanding how such molecules perform under cycling conditions,
leading to better design of future molecules. Such understanding has also provided a set
of criteria to be considered, when one proposes a new molecule to be employed in the all-
organic aqueous redox flow battery. They are:
1) crossover
O O O
EtO OEt
Na/I
2
Et
2
O
OH
OH
CO
2
Et
CO
2
Et EtO
2
C
EtO
2
C
1) aq. KOH
2) aq. HCl
OH
OH
CO
2
H
CO
2
H HO
2
C
HO
2
C
2%
220
2) protodesulfonation / protodephophorylation
3) equal number of solutes to avoid water transport
4) sufficiently large size of the molecule to reduce crossover
5) higher charge on the molecule to take advantage of the anion rejection
6) isolating the acid form directly for better solubility and reduced cost
7) degassing and performing the cell experiments under inert gas atmosphere
8) stability of the molecules under slightly elevated temperatures (at least 40-60
°C)
9) a single molecule (unimolecule) with multiple (4 electron/proton shown) redox
sites and
10) compounds can be mixed instead of using a unimolecule.
Though the project finally took a concrete shape, it suffered heavily from severe
time constrains posed by the funding agency. Therefore, the present 7b vs AQDS system
was the best that our work could deliver. However, there is a plenty of room for
development in terms of optimizing the molecular design to increase the cell voltage and
stability, which nonetheless is limited by overall cost and economic considerations and
no means by the chemistry.
7.4 Experimental Section.
7.4.1 General information
1
H and
13
C NMR spectra were recorded on Varian 500 MHz or 400 MHz NMR
spectrometers.
1
H NMR chemical shifts were determined relative to the signal of a
residual protonated solvent, D
2
O (4.79 ppm).
13
C NMR chemical shifts were determined
relative to the
13
C signal of the solvent, DMSO-d
6
(39.52 ppm). HRMS analysis was
221
conducted at the University of Illinois Urbana-Champagne Mass Spectrometry Facility.
Regents and solvents were commercially purchased and used without purification, unless
otherwise mentioned.
7.4.2 Basic Electrochemical Characterization
Details of electrochemical characterization and full cell studies of synthesized
molecules can be found in Hoober-Burkhardt thesis.
39
Typically, all experiments for the
electrochemical characterization of the individual redox molecules were conducted in a
standard three-electrode cell consisting of a working electrode, a platinum-wire counter
electrode, and a mercury/mercurous sulfate reference electrode (E
o
= +0.65 V) for acidic
systems and a mercury/mercury oxide reference electrode (E
0
= +0.1 V) for alkaline
studies. For most experiments, the working electrode consisted of a rotating disk glassy
carbon electrode (Pine). However, for studies on different electrode surfaces, various
other electrodes were used, including an isomolded graphite rod (Graphtek LLC), a
carbon fiber microelectrode (Pine), carbon felt (SGL), Toray carbon paper, or an edge-
plane graphite rotating disk electrode. The quinones, in either the fully-reduced or fully-
oxidized form, were dissolved in 1 M sulfuric acid to a concentration of 1 mM. The
solutions were de-aerated and kept under a blanket of argon gas throughout the
experiments. Cyclic voltammetry experiments were conducted at a scan rate of 50 mV s
-
1
. Linear sweep voltammetry experiments were conducted with the glassy carbon rotating
disk electrode, at a scan rate of 5 mv s
-1
over a range of rotation rates from 500 rpm to
3000 rpm (Figure 1a). All experiments were conducted using a Versastat 300 Potentiostat
and rotating equipment from Pine Instruments.
7.4.3 Synthesis of 4,5,6-Trihydroxybenzene-1,3-disulfonic acid (1)
222
Pyrogallol (25 g) was added portion wise over 30 min to a stirring, degassed conc. H
2
SO
4

(50 mL) at 0 °C. The ice bath was removed after the addition. The reaction mixture
appeared as dark yellow with solid suspension. NMR analysis of aliquot after the addition
showed primarily presence of monosulfonated product. Over the time the reaction
mixture turned thick cream solid. The solid was left to stand for 24 hours at RT. NMR
analysis showed >99% conversion to the expected product. The cake was triturated with
butyronitrile to obtain white suspension, which was filtered and washed with cold
butyronitrile (2 x 10 mL) and pentane (2 X 10 mL) to obtain a white solid. The solid was
dried under high vacuum overnight to yield 1 (42.5g, 75%) as a white solid.
1
H NMR
(399 MHz, DMSO-d
6
) δ 7.14 (s, 1H).
13
C NMR (126 MHz, DMSO-d
6
) δ 144.4, 132.6,
122.2, 115.8.
38
Cyclic voltammetry was carried out on various electrode surfaces as
described in ref. 39.

7.4.3 Synthesis of 2,3,4-trihydroxy-5-sulfobenzoic acid (2)
Pyrogallol-4-benzoic (1g) acid was slowly added to conc. H
2
SO
4
(2 mL). The
mixture turned yellow and then solidified into an off-white cake. The solid was left at RT
for 24 h. The cake was taken up in acetonitrile (8 mL) to obtain a white suspension,
which was filtered, washed with acetonitrile and dried under high vacuum to obtain 2 as a
white solid (1.2 g, 82%).
1
H NMR (500 MHz, DMSO-d
6
) δ 7.51 (s, 1H).
13
C NMR (126
MHz, DMSO-d
6
) δ 172.1, 151.5, 147.9, 132.4, 123.5, 118.9, 104.1.
a) CV b) RDE
223

7.4.4 Synthesis of 2-Bromo-4,6-dimethylphenol (6a)
40

2,4-dimethylphenol (84 g) was mixed with DMF (150) and stirred at room temperature.
To this mixture, a solution of N-bromosuccinimide (122.6 g) in DMF (200 mL) was
added slowly (over 30 min). This mixture was stirred for 24 hours at room temperature.
The resulting mixture was diluted with water (2 L) and extracted with 5% benzene in
hexane. The resulting organic layer was washed with water, brine and dried over
anhydrous MgSO
4
. The solvent was removed by rotary evaporation to obtain a green
liquid. The liquid was subjected to vacuum distillation to obtain the expected product
(125.9g, 91%) as a pale yellow liquid.
1
H NMR (500 MHz, Chloroform-d) δ 7.10 (s, 1H),
6.87 (s, 1H), 5.37 (s, 1H), 2.26 (s, 3H), 2.23 (s, 3H).
13
C NMR (126 MHz, Chloroform-d)
δ 148.3, 131.3, 130.8, 129.5, 125.5, 109.9, 20.3, 16.7.
7.4.5 Synthesis of 3,5-Dimethylbenzene-1,2-diol (6b)
A solution of NaOH (120 g) in water (1.2 L) was degassed by bubbling argon (30 min).
To this solution, CuSO
4
(0.8g) was added and argon was continued bubbling for another
20 min. The mixture was transferred to a flask containing 2-bromo-4,6-dimethylphenol
(22.24 g). The resulting mixture was kept under reflux for 6 hours, cooled down to RT
and acidified with HCl. The mixture was extracted in diethyl ether and washed with
water, brine and dried over anhydrous MgSO
4
. Furthermore, under vacuum drying a
brown residue was obtained, which upon a short path distillation gave an off-white solid.
a) CV b) RDE
224
This solid was sublimed to obtain a yellowish crystalline solid (34%).
1
H NMR (399
MHz, DMSO-d
6
) δ 8.89 (s, 1H), 7.81 (s, 1H), 6.40 (s, 1H), 6.31 (s, 1H), 2.08 (s, 3H),
2.05 (s, 3H).
40

7.4.6 2,5-Dihydroxy-4,6-dimethylbenzene-1,3-disulfonic acid (I)
Conc. H
2
SO
4
(10 mL) was charged with a stirred bar and 3,5-dimethylbenzene-1,2-diol
(4.75 g, 34.4 mmol) was added portion wise and stirring continued for 24 hours at room
temperature. Sample withdrawn, selectively formed only isomer, namely 2,3-dihydroxy-
4,6-Dimethylbenzenesulfonic acid (6c).
1
H NMR (399 MHz, Deuterium Oxide) δ 6.51
(s, 1H), 2.29 (s, 3H), 2.02 (s, 3H).
13
C NMR (100 MHz, Deuterium Oxide) δ 141.4,
140.3, 132.4, 127.1, 126.0, 122.5, 15.9, 12.2. The reaction vessel was moved to a pre-
heated oil bath at 70 °C and heated for 4 hours.
1
H NMR analysis of the aliquot showed
disappearance of the aromatic signal. The mixture was poured onto ice and quenched
with solid sodium carbonate to a neutral pH. This solution was treated with acetone to
remove sodium sulfate and filtered. The resulting solution was rotary evaporated to
obtain a beige solid (50%).
1
H NMR (399 MHz, Deuterium Oxide) δ 2.06 (s, 3H), 1.78
(s, 3H). Elemental analysis: Estimated Hydrogen 2.36; found 2.36. For CV and RDE
experimental results see Hoober-Burkhardt thesis.
39

7.4.7 Potassium 3,6-dihydroxy-2,4-dimethylbenzenesulfonate
The 2,6-dimethylbenzene-1,4-diol (50 g) was added in small portions to vigorously
stirred concentrated sulfuric acid (100 mL) over a period of 15 minutes to form a pale
yellow solution that solidified in about 20 min. After leaving the resulting mixture
standing at room temperature for 24 h, it was added to a vessel with sufficient ice.
Sufficient ice is needed to avoid excessive heating during the exothermic dilution of
225
sulfuric acid; insufficient heat removal could lead to polymer formation. The resulting
aqueous solution was neutralized with a stoichiometric amount of solid potassium
carbonate. The resulting solid, at neutral pH, was filtered and washed with water.
Acetone was added to precipitate out the potassium sulfate, and the filtered solution was
concentrated by rotary evaporation and left overnight in a refrigerator for crystallization.
The resulting crystals were filtered and washed with cold 10% water/acetone and
acetone, and dried overnight under high vacuum. The crystallization procedure was
repeated to obtain 78.8 g (85% yield) of a beige crystalline solid.
1
H NMR (400 MHz,
D
2
O), 6.70 (s, 1H), 2.47 (s, 3H), 2.22 (s, 3H).
13
C NMR (126 MHz, DMSO-d
6
) 147.1
145.1, 128.2, 126.8, 124.1, 115.2, 16.9, 13.6. HRMS (ESI): calculated for C
8
H
9
O
5
S [M-
H]: 217.0171; found: 217.0171.
7.4.8 2,5-Dimethyl-1,4-phenylene tetraethylbis(phosphate) (9b)
To the mixture of 1,4-dihydroxy-2,5-dimethylbenzene (59.3 mmol) and diethylphosphite
(130 mmol) in 40 mL CCl
4
, triethylamine was slowly introduced at 0 °C for an hour and
the reaction mixture brought to room temperature and stirring continued overnight. The
reaction mixture was quenched with water and extracted in into EtOAc and the organic
layer was washed with water and dried over MgSO4 and dried under vacuum to obtain a
colorless liquid (95%, 24.5 g).
1
H NMR (399 MHz, Chloroform-d) δ 7.12 (s 1H), 4.29 –
4.09 (m, 8H), 2.24 (s, 6H), 1.34 (m, 12H).
13
C NMR (100 MHz, Chloroform-d) δ 145.8
(dd, J = 7.3, 1.9 Hz), 128.9 – 127.1 (m), 122.3 (d, J = 1.3 Hz), 64.7 (d, J = 6.4 Hz), 16.3,
16.2.
31
P NMR (162 MHz, Chloroform-d) δ -6.2.
7.4.9 Tetraethyl (2,5-dihydroxy-3,6-dimethyl-1,4-phenylene)bis(phosphonate) (9c)
226
To a solution of diisopropylamine (4.2 equiv) in THF (150 mL) at -78 °C, n-BuLi was
added and the mixture stirred at that temperature for 30 min. To this mixture, 2,5-
dimethyl-1,4-phenylene tetraethyl bis(phosphate) in THF (150 mL) was introduced via
cannula and allowed to come to ambient temperature (2 hours). This was quenched with
saturated ammonium chloride and ether, after removing the ether layer, aqueous layer
was further extracted with DCM. The combined organic layers were dried on MgSO4 and
dried under vacuum to obtain a thick liquid, which when mixed with DCM/pentane and
stored in the fridge, produced white crystals (1.19 g, 5%). No further crystals were
obtained upon further standing.
1
H NMR (399 MHz, Chloroform-d) δ 10.99 (s, 1H), 4.1
(q, 7.5), 2.34 (s, 6H), 1.36 (t, J = 7.5 Hz, 7H).
31
P NMR (162 MHz, Chloroform-d) δ
23.33 ppm. HRMS (ESI): Calculated for C
16
H
28
O
8
P
2
: 411.1338; found: 411.1333.
7.4.10 Potassium 2,5-dihydroxy-4,6-dimethylbenzene-1,3-disulfonate (7b’)
DCM (anhyd. 200 mL) and ClSO
3
H (40 mL, 6 equiv, 600 mmol) were mixed in a 500
mL Schlenk flask containing magnetic stir bar under N
2
in a glove bag. The flask was
connected to nitrogen line and the 2,6-dimethyl-1,4-dihydroxybenzene (100 mmol, 13.8
g) against the stream of N
2
(evolution of HCl). Once the effervescence stopped, the flask
was closed and stirred vigorously under nitrogen atmosphere. The reaction was
monitored by
1
H NMR. After 26 hours, the reaction mixture was allowed to stand,
separated into a DCM layer and a greenish thick oily layer. The DCM layer was carefully
decanted under N
2
atm. Greenish oily residue was stirred with anhydrous DCM (2 x 100
mL) and decanted. The greenish oily liquid was poured onto ice and washed with ice-
water. This mixture was heated at 40 °C for 2 hours on a water bath and then quenched
with solid K
2
CO
3
to reach a neutral pH. This mixture was treated with acetone (30-40%)
227
and cooled in ice to get a white precipitate, which was filtered and washed with 30%
acetone/water. To the resulting solution, 200 mL acetone was added and no precipitation
was observed. This solution was rotary evaporated to minimize the solvent and allowed
to stand in the fridge. No crystallization was observed. The solution was completely dried
by rotary evaporation to obtain a beige solid, which was azeotroped with EtOH and dried
under high vacuum.
1
H NMR of the mixture showed a signal around 2.22 ppm, which
was only removed by treating the solid with EtOH (3 x 150 mL) to obtain the potassium
slat in >97% purity by
1
H NMR. When the solid was calibrated with imidazole internal
standard, it appeared to be only 65% of the desired product. Therefore, the solid was
subjected to extraction with MeOH on a Soxhlet extractor and the solid was regularly
analyzed for the presence of the product. After extracting over 48 hours, only traces of
the product were found in the solid residue. The MeOH mixture was evaporated to obtain
a beige solid (13 g), which was dried under vacuum. Furthermore, analysis by IR of the
solid,
1
H NMR calibration with imidazole internal standard and acidity titration after
proton exchange confirmed absence of any significant quantity of K
2
SO4. Based on these
results, the weight difference is attributed to the hydration (≈10-15%) of the material.
Solubility of the potassium salt was found to be, H
2
O>MeOH>EtOH>CH
3
CN.
Furthermore, the crystallization technique using mixed solvent failed with acetone and
acetonitrile adding minimal amount of water, they formed two separate layers.
1
H NMR
(500 MHz, Deuterium Oxide) δ 2.54 (s, 1H).
13
C NMR (126 MHz, DMSO-d
6
) δ 145.8,
144.5, 129.0, 126.4, 14.4 (q, J = 15.7 Hz). IR (cm
-1
): 3148.7 (broad), 1688.8, 1409, 1183,
1154, 1038, 1006, 742, 656, 595. HRMS (ESI): Calculated for C
8
H
9
O
8
S
2
[M-H]:
296.9739; found: 296.9738.
228
7.4.11 Cell cycling experimental conditions
The flow cell was assembled with regular acid treated felt, E750 membrane and
new IDFF flow field.
24,52
The cell assembly was washed by circulating deionized water
over several hours. Then 1 M H
2
SO
4
was added and circulated for several hours. The cell
setup was purged with argon gas, including the pumps and the flow cell. When conc.
H
2
SO
4
was added to the solution of AQDS, the mixture became warm, so it was chilled
in water and allowed to come to room temperature. This mixture was mixed with 7b
(DHDMDS) in water to obtain 200 mL of 0.1 M in AQDS and DHDMDS and 1 M in
H
2
SO
4
. This mixture was split into two equal portions and added to the reservoir tanks,
two glass containers, against the stream of Argon. Then electrolytes were purged with
argon for 20 min. The cell resistance with electrolyte was measured to be 24 mohm. All
flow-cell experiments were carried out at 23 °C and an argon flow was maintained at all
times above these solutions to avoid reaction of the reduced form of the redox couples
with oxygen, which is critical to achieve stable cycling performance. The current-voltage
characteristics of the cells were measured at 100% state of charge. Charge/discharge
studies were carried out using a battery cycler (Maccor 4200 with 15 Amp capability).
Charge and discharge were conducted at a constant current of 8mA/cm
2
using voltage
cutoff of 1.0 V during charge and 0.005 V during discharge with 5 min rest period.
7.4.12 Sodium 2,5-dihydroxy-3,4,6-trimethylbenzenesulfonate (8a’)
Conc. H
2
SO
4
(50 mL) was poured into 125 Erlenmeyer flask containing 2,3,5-
trimethylbenzene-1,4-diol (25g) and mixed quickly. The solidified mixture was frozen at
-78 °C and ice water was added and scrapped with a glass rod and transferred to another
flask containing ice water bath. A small amount of black material formation was
229
observed (the yield of the product varies depending on its content). After all the ice had
melted, the mixture was filtered to remove any black residue to get a reddish solution,
which was neutralized with sodium carbonate to achieve to a neutral pH. Now the
solution was treated with acetone to precipitate out the sodium sulfate. The resulting
mixture was concentrated to obtain 88% (36.8g) of the desired product.
1
H NMR (399
MHz, Deuterium Oxide) δ 2.44 (s, 3H), 2.18 (s, 3H), 2.12 (s, 3H).
13
C NMR (100 MHz,
DMSO-d6) δ 145.5, 144.6, 127.1, 126.0, 121.2, 120.6, 13.8, 13.3, 12.3. HRMS (ESI):
Calculated for C
6
H
11
O
5
S: 231.0327; found: 231.0331.
7.4.13 Synthetic procedures for the dicouples
2-(Bromomethyl)anthracene-9,10-dione (10a)
2-Methylanthracene-9,10-dione (19.8 g) and NBS (Use a new or freshly crystalized batch
for better bromination) was treated with m-Chloroperbenzoic acid (ca. 230 mg) in CCl
4

(dry, 250 mL) under reflux for 10 hours. The reaction mixture was further diluted with
CCl
4
and filtered to remove succinimide and washed with more CCl
4
to obtain the crude
product. The excess unreacted NBS could be removed by washing the solution with
sodium bisulfite. The compound was purified by column chromatography to obtain the
pure product in 82% yield as an yellow solid (22g).
1
H NMR (399 MHz, Chloroform-d) δ
8.40 – 8.20 (m, 4H), 7.90 – 7.75 (m, 3H), 4.60 (s, 2H).
2-(Hydroxymethyl)anthracene-9,10-dione (10b)
2-(Bromomethyl)anthracene-9,10-dione (22 g) was subjected to reflux in dioxane/water
(3:1) mixture in the presence of n-Bu
4
NI (10% by wt.) until the reaction goes to
completion. The reaction mixture was rotary evaporated to remove dioxane and then
extracted with EtOAc and the combined layer was washed with water to obtain the pure
230
product in 98% (17g) yield as a yellow solid.
1
H NMR (399 MHz, Chloroform-d) δ 8.35
– 8.30 (m, 4H), 7.83 – 7.79 (m, 3H), 4.91 (s, 2H).
53

Synthesis of a dicouple, 2-(2,5-dihydroxybenzyl)anthracene-9,10-dione (10c).
A mixture of 2-(hydroxymethyl)anthracene-9,10-dione (1 equiv) and hydroquinone (5
equiv) in H
3
PO
4
(98%) was heated at 100 °C and the reaction was monitored by
1
H
NMR. After the completion of the reaction, the mixture was dumped in ice and the
resulting solid was filtered and dried under high vacuum. The solid triturated with EtOH
and filtered to obtain 65% of the desired product in >99% purity.
1
H NMR (399 MHz,
DMSO-d
6
) δ 8.81 (s, 1H), 8.63 (s, 1H), 8.20 (dt, J = 5.7, 3.3 Hz, 2H), 8.13 (d, J = 8.0 Hz,
1H), 8.04 (d, J = 1.8 Hz, 1H), 7.96 – 7.88 (m, 2H), 7.77 (dd, J = 8.0, 1.9 Hz, 1H), 6.64 (d,
J = 8.6 Hz, 1H), 6.56 (d, J = 2.9 Hz, 1H), 6.47 (dd, J = 8.6, 2.9 Hz, 1H), 4.00 (s, 2H).
13
C
NMR (126 MHz, DMSO-d6) δ 182.7, 182.3, 149.8, 148.9, 147.5, 134.8, 134.5, 134.4,
133.1, 133.1, 132.9, 131.0, 127.0, 126.7, 126.6, 126.5, 126.4, 117.0, 115.8, 114.0, 35.7.
7.4.14 (2E,2'E)-1,1'-(1,4-Phenylene)bis(3-(1-methyl-1H-imidazol-2-yl)prop-2-en-1-
one) (11a)
1,4-diacetylbenzene and NaOMe (2 equiv) were dissolved in MeOH (0.13M), 1-
methylimidazole carboxaldehyde (4 equiv) added and stirred at room temperature for 2
hours. After quenching with water and MeOH was removed under vacuum, the resulting
mixture was extracted in EtOAc, dried on MgSO4 and rotary evaporated to get the crude
product, which was purified by column chromatography using DCM/MeOH gradient.
Yellow solid (65%).
1
H NMR (500 MHz, Chloroform-d) δ 8.21 (d, J = 0.6 Hz, 1H), 8.04
(dd, J = 15.0, 0.6 Hz, 1H), 7.73 (d, J = 14.9 Hz, 0H), 7.25 – 7.02 (m, 1H), 3.84 (d, J = 0.5
231
Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 189.1, 143.9, 141.2, 131.0, 128.9, 128.4,
124.4, 123.1, 33.2.
7.4.15 1,1'-(1,4-Phenylene)bis(3-(1-methyl-1H-imidazol-2-yl)propan-1-one) (11b)
The compound was dissolved in a mixture of DCM/MeOH and reduced using 1 atm H
2
in
presence of Pd/C. After completion of the reaction, Pd/C was removed by filtering
through celite and the resulting solution was rotary evaporated to obtain the pure product
in 98% yield as a white solid.
1
H NMR (399 MHz, Chloroform-d) δ 8.10 (s, 4H), 6.92 (d,
J = 1.3 Hz, 2H), 6.81 (d, J = 1.3 Hz, 2H), 3.66 (s, 6H), 3.64 (t, J = 7.2 Hz, 4H), 3.08 (t, J
= 7.2 Hz, 4H).
13
C NMR (126 MHz, Chloroform-d) δ 198.6, 147.2, 139.9, 128.5, 127.1,
120.8, 36.7, 32.7, 20.6. HRMS (ESI): Calculated for C
20
H
23
N
4
O
2
[M+H]: 351.1821;
found: 351.1820.
7.4.16 Representative Spectra

1
H NMR (D
2
O)

OH
OH
SO
3
Na
-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0
f1 (ppm)
232
13
C NMR (DMSO-d
6
)

1
H NMR (D
2
O)

-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220
f1 (ppm)
OH
OH
SO
3
K KO
3
S
-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0
f1 (ppm)
233
13
C NMR (DMSO-d
6
)

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Abstract (if available)

Abstract The dissertation comprises two main parts. First, fluoroalkylation methods are presented, where development of selective fluoroalkylation methods using inexpensive silicon reagent, Me₃SiCF₃ along with the fluorodecarboxylation method to synthesize ArXCF₃ (X = O, S) are discussed. Later, design and synthesis of small molecules for all- organic redox flow battery (Chapter 7) is presented. ❧ Chapter 1 describes the advancement in the area of selective difluoromethylation and difluoromethylenation using silicon regents. ❧ In Chapter 2, Direct N-difluoromethylation of imidazoles and benzimidazoles is showcased using TMS-CF₃ (the Ruppert–Prakash reagent) under neutral conditions. Difluoromethylated products were obtained in good-to-excellent yields. Inexpensive, commercially available starting materials, neutral conditions, and shorter reaction times are advantages of this methodology. Reactions are accessible through conventional as well as microwave irradiation conditions. ❧ In Chapter 3, Direct S-difluoromethylation of aryl and aliphatic thiols using the Ruppert–Prakash reagent is demonstrated. The reaction produces trimethylsilyldifluoromethyl sulfides, which upon cleavage with fluoride produces the difluoromethyl sulfides. The key reaction features are the use of relatively inexpensive and commercially available starting materials, shorter reaction times, ambient temperatures, easy reaction procedure, and selective S-difluoromethylation in the presence of -OH, -NH₂ and -CO₂H functional groups. Furthermore, one-pot tolylthiodifluoromethyl transfer to PhCHO is also demonstrated. ❧ Chapter 4 describes a deoxygenative difluoromethylenation of carbonyl compounds using readily available, inexpensive trifluoromethyltrimethylsilane, LiI, and PPh₃. The presence of the Li⁺ ion prevents the unproductive exhaustion of trifluoromethyltrimethylsilane (TMSCF₃) by keeping the soluble free fluoride concentration in the reaction medium under control. The strategy of combining solvents to increase the reactivity and thereby reduce the reaction temperature and time is also discussed. ❧ Chapter 5 reports the development of a nucleophilic difluoromethylation of aromatic aldehydes, acetophenone and benzophenone using the Ruppert-Prakash reagent in the presence of triphenyl and tributyl phosphines. ❧ Chapter 6 discusses fluorodecarboxylation of aryloxydifluoroacetic acids (ArOCF₂CO₂H) and arylmercaptodifluoroacetic acids (ArSCF₂CO₂H) towards ArXCF₃ (X= O, S) using silver (I) salts in the presence of Selectfluor in a biphasic system with the trifluoroacetic acid additive. ❧ Chapter 7 introduces the all-organic redox flow battery for the grid scale electrical energy storage applications. It also describes the challenges associated with the small organic molecules used in the flow battery system. Some these challenges have been addressed using new molecular design and synthesis. These new molecules have been demonstrated in full electrochemical cells to demonstrate stable cell performance. Further, this chapter also details the criteria that need to be considered during new molecule design and synthesis for further improvement.

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Asset Metadata

Creator Krishnamoorthy, Sankarganesh (author)

Core Title Selective fluoroalkylation methods and synthesis of water-soluble organic molecules for organic redox flow batteries

School College of Letters, Arts and Sciences

Degree Doctor of Philosophy

Degree Program Chemistry

Publication Date 07/20/2019

Defense Date 05/19/2017

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

Tag difluoromethylation,difluoromethylenation,energy storage,fluoroalkylation,fluorodecarboxylation,OAI-PMH Harvest,organic redox flow battery,quinones,Ruppert-Prakash reagent,TMSCF₃

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

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

Creator Email sankargk@usc.edu,sankargkri@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-410566

Unique identifier UC11213758

Identifier etd-Krishnamoo-5555.pdf (filename),usctheses-c40-410566 (legacy record id)

Legacy Identifier etd-Krishnamoo-5555.pdf

Dmrecord 410566

Document Type Dissertation

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Rights Krishnamoorthy, Sankarganesh

Type texts

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

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA