ĐẠI HỌC QUỐC GIA THÀNH PHỐ HỒ CHÍ MÌNH
TRƯỜNG ĐẠI HỌC BÁCH KHOA

ƠNG ĐỨC TỒN

INTRODUCTION OF TRIFLUOROMETHYL GROUP INTO
BORONIC ACID AND ITS DERIVATIVES USING MOF CU(INA)2

CHUYÊN NGÀNH:

KỸ THUẬT HÓA HỌC

MÃ SỐ:

60 52 03 01

LUẬN VĂN THẠC SĨ

TP. HỒ CHÍ MINH, tháng 6 năm 2017


ĐẠI HỌC QUỐC GIA THÀNH PHỐ HỒ CHÍ MINH
TRƯỜNG ĐẠI HỌC BÁCH KHOA

INTRODUCTION OF TRIFLUOROMETHYL GROUP INTO
BORONIC ACID AND ITS DERIVATIVES USING MOF CU(INA)2

CHUYÊN NGÀNH: KỸ THUẬT HÓA HỌC
MÃ SỐ CHUYÊN NGÀNH: 60 52 03 01

LUẬN VĂN THẠC SĨ

Cán bộ hướng dẫn Khoa học:

TS. Trương Vũ Thanh

Học viên: Ông Đức Tồn
MSHV: 1570005

TP. HỒ CHÍ MINH, tháng 7 năm 2017


CƠNG TRÌNH ĐƯỢC HỒN THÀNH TẠI
TRƯỜNG ĐẠI HỌC BÁCH KHOA – ĐHQG – HCM

Cán bộ hướng dẫn khoa học: TS. TRƯƠNG VŨ THANH
………………………….
Cán bộ chấm nhận xét 1:

PGS.TS. NGUYỄN THỊ PHƯƠNG PHONG
……………………………………………………

Cán bộ chấm nhận xét 2:

PGS.TS. NGUYỄN ĐÌNH THÀNH
……………………………………………………

Luận văn thạc sĩ được bảo vệ tại Trường Đại học Bách Khoa, ĐHQG Tp. HCM
ngày 01 tháng 08 năm 2017.
Thành phần Hội đồng đánh giá luận văn thạc sĩ bao gồm:
1.
2.

3.
4.
5.

Chủ tịch: PGS. TS. Phạm Thành Quân
Phản biện 1: PGS. TS. Nguyễn Thị Phương Phong.
Phản biện 2: PGS. TS. Nguyễn Đình Thành
Ủy viên: TS. Tống Thành Danh
Thư ký: Phan Thị Hoàng Anh.

Xác nhận của Chủ tịch Hội đồng đánh giá LV và Trưởng Khoa quản lý chuyên
ngành sau khi luận văn đã được sửa chữa (nếu có)

CHỦ TỊCH HỘI ĐỒNG

PGS. TS. Phạm Thành Quân

TRƯỞNG KHOA KTHH


ĐẠI HỌC QUỐC GIA TP.HCM
TRƯỜNG ĐẠI HỌC BÁCH KHOA
------------

CỘNG HÒA XÃ HỘI CHỦ NGHĨA VIỆT NAM
Độc lập – Tự do – Hạnh phúc
------------

NHIỆM VỤ LUẬN VĂN THẠC SĨ
Họ tên học viên:

Ngày, tháng, năm sinh:
Chun ngành:
I.

II.

Ơng Đức Tồn
28/01/1992
Kỹ thuật hóa học

MSHV: 1570005
Nơi sinh: Tp.HCM
Mã số: 60520301

TÊN ĐỀ TÀI LUẬN VĂN:
Introduction of trifluoromethyl group into boronic acid and its derivatives using
MOF Cu(INA)2.
NHIỆM VỤ VÀ NỘI DUNG:
 Tổng hợp MOF Cu(INA)2.
 Phân tích cấu trúc MOF Cu(INA)2 bằng các phương pháp XRD, SEM, TGA,
FT-IR.
 Khảo sát phản ứng tổng hợp hợp chất hữu cơ chứa nhóm CF3 từ axit boronic và
các dẫn xuất của axit boronic.
 Xác định sẩn phẩm thu được bằng các phương pháp phân tích NMR và GC-MS.

III.

NGÀY GIAO NHIỆM VỤ:

07/2016


IV.

NGÀY HOÀN THÀNH NHIỆM VỤ:

06/2017

V.

CÁN BỘ HƯỚNG DẪN: TS. Trương Vũ Thanh

CÁN BỘ HƯỚNG DẪN

Tp. HCM, ngày tháng năm 2017
CHỦ NHIỆM BỘ MÔN ĐÀO TẠO

TRƯỞNG KHOA


ACKNOWLEDGEMENT
I am deeply grateful to my supervisor Dr. Truong Vu Thanh, for his
encouragement and guidance. He always helps me to have a favorable condition to do
my research and gives me great guidance to finish my thesis with his wonderful
patience, motivation, enthusiasm, and immense knowledge.
Besides, I wish to thank all of the teaching staffs of Organic Chemical
Engineering Department for their meaning encouragement and help. I am grateful to
my family who is always by my side to encourage me.
Ho Chi Minh, June 19, 2017
Ong Duc Toan



Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

2017

Contents
LIST OF FIGURE .............................................................................................................. 3
LIST OF SCHEME ............................................................................................................ 4
LIST OF TABLE ............................................................................................................... 5
ABSTRACT ....................................................................................................................... 6
CHAPTER I: LITERATURE REVIEW ............................................................................ 8
1.1 Trifluoromethylation ................................................................................................ 8
1.1.1.

Trifluoromethylation of boronic acid: ........................................................ 9

1.2 Metal-organic frameworks (MOFs) ....................................................................... 15
1.2.1 Cu(INA)2 ......................................................................................................... 16
1.3. Our approach ......................................................................................................... 17
CHAPTER II: EXPERIMENTAL ................................................................................... 19
2.1 Synthesis and characterization of the metal-organic frame work Cu(INA)2:...... 19
2.1.1. Materials and instrument: .............................................................................. 19
2.1.2. Synthesis of MOF Cu(INA)2: ........................................................................ 20
2.2. Catalytic study: ..................................................................................................... 21
2.2.1. Materials and instrumentation: ...................................................................... 21
2.2.3. GC yield determination: ................................................................................. 24
2.2.4. Isolated yield determination: .......................................................................... 26
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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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2.2.5. Catalyst recycling ........................................................................................... 27
CHAPTER 3 : RESULTS AND DISCUSSIONS ........................................................... 28
3.1 Cu-MOF synthesis ................................................................................................. 28
3.1.1. Characterization of Cu(INA)2: ....................................................................... 28
3.2 Trifluormethylation of boronic acids ..................................................................... 30
3.2.1. Effect of catalyst loading on the reaction yield ............................................. 32
3.2.2. Effect of different fluoride anion to the reaction yield .................................. 33
3.2.3. Effect of temperature on the reaction yield.................................................... 34
3.2.4. Effect of TMSCF3 ratio on the reaction yield ................................................ 34
3.2.5. Effect of 1,10-phenanthroline amount on the reaction yield ......................... 35
3.2.6. Effect of different solvent on the reaction yield ............................................ 36
3.2.7. Effect of different copper-based catalysts on the reaction yield .................... 38
3.2.8. Leaching test .................................................................................................. 39
3.2.9. The recyclability of Cu(INA)2 ....................................................................... 40
3.2.10 Substrate scope for trifluormethylation of boronic acid ............................... 41
CHAPTER 4: CONCLUSION......................................................................................... 45
REFERENCE ................................................................................................................... 46
APPENDICES ................................................................................................................. 53

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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LIST OF FIGURE
Figure 1. 1 Natural occurring fluoro-organic compounds ................................................ 8
Figure 1.2. Several active ingredients containing trifluormethyl group10. ...................... 10
Figure 1. 3 View of the crystal structure of Cu(INA)2 .................................................... 16
Figure 2.1. Synthesized procedure of MOF Cu(INA)2 ……………………………….20
Figure 2. 2 General procedure for the trifluormethylation of 4-methoxyphenyl boronic
acid ................................................................................................................................... 23
Figure 2. 3 Calibration curve of 4-trifluormethyl anisole ................................................ 26
Figure 3. 1 Powder X-ray diffraction patterns of the synthesized Cu(INA)2 (a) and the
calculated pattern (b)

…………………………………………………………….28

Figure 3. 2 FT–IR spectra of the Cu(INA)2. .................................................................... 29
Figure 3. 3 SEM micrograph of the Cu(INA)2. ............................................................... 30
Figure 3. 4 TGA curve of the Cu(INA)2 .......................................................................... 30
Figure 3. 5 Effect of catalyst loading on reaction yield ................................................... 32
Figure 3. 6 Effect of different fluoride anion to the reaction yield .................................. 33
Figure 3. 7 Effect of temperature on the reaction yield ................................................... 34
Figure 3. 8 Effect of TMSCF3 amount on reaction yield ................................................. 35
Figure 3. 9 Effect of 1,10-phenanthroline amount on the reaction yield ......................... 36
Figure 3. 10 Effect of different copper-based catalysts on the reaction yield ................. 39
Figure 3. 11 Leaching test ................................................................................................ 40
Figure 3. 12 Catalyst recycle studies. .............................................................................. 41
Figure 3.13 X-ray powder diffractograms of the fresh (a) and reused (b) [Cu(INA)2]
catalyst.............................................................................................................................. 41

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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LIST OF SCHEME
Scheme 1. 1. Copper-mediated perfluoroalkylation of aromatic compounds. .................. 9
Scheme 1. 2 Copper-mediated radical trifluoromethylation of boronic acids ................. 10
Scheme 1. 3 Ruthenium(II) and copper-catalyzed radical trifluoromethylation of boronic
acids.................................................................................................................................. 11
Scheme 1. 4. Copper-catalyzed electrophilic trifluoromethylation of boronic acids. ..... 12
Scheme 1. 5. Copper-catalyzed oxidative trifluormethylation of boronic acids. ............ 13
Scheme 1. 6. Copper-mediated oxidative trifluoromethylation of boronic acids ............ 13
Scheme 1. 7 Copper-promoted oxidative trifluoromethylation of alkyl boronic acids. .. 14
Scheme 1. 8. Fluoroform-derivated CuCF3 for trifluoromethylation of boronic acids ... 14
Scheme 1. 9 Cu(INA)2 as an efficient heterogeneous catalyst for the ligand-free Narylation of heteroarenes .................................................................................................. 17
Scheme 1. 10 Trifluoromethylation of boronic acids over Cu-MOF .............................. 18
Scheme 3.1 Copper-mediated trifluoromethylation of 4-phenoxyphenyl boronic acid
…………………………………………………………………………………...31
Scheme

3.2

Proposed

mechanism

trifluoromethylation of boronic acids

for


the

copper-mediated

oxidative

32

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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LIST OF TABLE
Table 1. 1 List of chemicals for MOF synthesis .............................................................. 19
Table 2. 1 List of chemicals for trifluormethylation of boronic acids 21
Table 2. 2 Dilution preparation for 4-trifluormethyl anisole .......................................... 25
Table 2. 3 Calibration curve preparation for 4-trifluormethyl anisole ............................ 25
Table 3. 1 Effect of different solvent on the reaction yield

………………………36

Table 3. 2 Reaction scope of coupling components ........................................................ 42

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2


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ABSTRACT
Herein, we describe the first heterogeneous and catalytic protocol for nucleophilic
trifluormethylation of aryl boronic acids. In particular, a crystalline porous metal
organic framework copper isonicotinate Cu(INA)2 [INA = 1,4-(NC5H4CO2)] exhibit
exceptional catalytic activity toward the trifluormethylation of boronic acids. The
Cu(INA)2 was synthesized and characterized via X-ray powder diffraction (XRD),
scanning electron microscopy (SEM), thermogravimetric analysis (TGA), and Fourier
transform infrared (FT-IR). The optimal condition involves the use of Cu(INA)2 catalyst
(30% mol), nucleophilic trifluormethyltrimethylsilane (TMSCF3) and CsF reagent in
1,2-dichloroethane (DCE) solvent at room temperature in 2 h. Oxygen was employed as
oxidant. Leaching tests confirmed the heterogeneity of Cu(INA)2 during reaction. In
addition, Cu(INA)2 was showed to be recovered and reused several times without a
significant degradation in catalytic catalyst activities, almost similar reaction yield was
still obtained at 6 th run.

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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Tóm Tắt Luận Văn
Trong phần luận văn này, chúng tơi trình bày về phản ứng trifluormethyl hóa các
hợp chất hữu cơ axit boronic, lần đầu tiên sử dụng xúc tác dị thể và tác nhân fluor hóa ái
nhân. Cụ thể, phản ứng được thúc đẩy bởi xúc tác MOF đồng isonicotinate Cu(INA)2
[INA = 1,4-(NC5H4CO2)] . Xúc tác Cu(INA)2 được tổng hợp và phân tích bằng phương

pháp phân tích nhiễu xạ tia X (XRD), phương pháp quét kính hiển vi điện tử (SEM),
phương pháp phân tích nhiệt trọng lượng (TGA), và phân tích quang phổ hồng ngoại
(FT-IR). Điều kiện phản ứng tối ưu thu được khi sử dụng 30% mol xúc tác MOF
Cu(INA)2 cùng với tác nhân fluor hóa ái nhân trifluormethyltrimethylsilane (TMSCF3),
và CsF trong dung môi khan 1,2-dichloroethane (DCE) tại nhiệt độ phịng trong thời
gian 2h. Khí oxi được sử dụng làm tác nhân oxi hóa. Đồng thời, vai trò của xúc tác dị
thể của MOF Cu(INA)2 được khẳng định bằng thí nghiệm kiểm tra leaching. Thêm vào
đó, xúc tác MOF Cu(INA)2 có thể được thu hồi và tái sử dụng nhiều lần mà hiệu suất
phản ứng không bị giảm đáng kể với lần thí nghiệm thứ 6.

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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CHAPTER I: LITERATURE REVIEW
1.1 Trifluoromethylation
Fluorination chemistry has been an attractive field for many scientists due to its
widespread applications in pharmaceuticals,1

agrochemicals,2 materials,3 and

radiotracers for positron emission tomography (PET).4 It has been reported that 20% of
pharmaceuticals and up to 30% of agrochemicals on the market are fluorine-containing
compounds,1a which indicates the vital role of these compounds in numerous areas. In
pharmaceutical research, introducing fluorine atom(s) into an organic compound can
change its physical, distribution, metabolism and excretion properties1a while remaining
the molecular size due to the similar atomic radius of fluorine to hydrogen atom. Despite

fluorine is the 13th most abundant element found in the earth’s crust, the amount of
natural fluorinated compounds known is very low (Figure 1.1).5 Therefore, there is a
large interest in methodology to introduce selectively fluorine and fluorine-containing
groups into organic compounds for improvements of biological activities.

Figure 1. 1 Natural occurring fluoro-organic compounds
The first metal-mediated direct perfluoroalkyllation was invented by McLoughlin
and Thrower in 1965. They successfully introduced perfluoroalkyl group into the
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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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predetermined position of aromatic compounds bearing a wide variety of substituent
(carboxy, nitro, amino, hydroxyl, etc.) with the presence of copper under 110-130 oC
(Scheme 1.1). It was also clearly demonstrated that the copper perfluoroalkyl Cu-Rf was
formed as a mediated species, which then reacted with aryl halide to produce the desired
product.6 However, it was not until 1986 that the copper perfluoroalkyl comple x was
first identified via spectroscopic studies.7

Scheme 1. 1. Copper-mediated perfluoroalkylation of aromatic compounds.
Since 1960’s, further developments have been continuously reported, regarding the
use of various transition-metal-based catalysts.8 Among that, copper-mediated
trifluoromethylation has been studied most extensively because of the high efficiency
and low cost of copper8.
1.1.1. Trifluoromethylation of boronic acid:
One of the most important classes of fluorinated substances consists of compounds
bearing a trifluormethyl group. The effects of trifluormethyl introduction into molecules

are similar to that of fluorine, including enhancing chemical and metabolism stability,
lipophilicity and binding selectivity of initial compounds.9 Hence, such these
compounds are used widely as active ingredients in drugs as well as agrochemicals,
some examples of them are shown in Figure 1.2.

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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Figure 1.2. Several active ingredients containing trifluormethyl group10.
Looking for new methods to introduce trifluormethyl group into organic
molecules is also an attractive field owing to their important applications in many
areas.10 Molecules bearing a trifluormethylation group represent one of the most
important classes of selectively fluorinated compound. 11
In 2012, Standford and co-workers reported the copper-mediated radical
trifluoromethylation of aryl boronic acids with the radical reagent sodium
trifluoromethanesulfinate NaSO2CF3, in conjunction with tert-butyl hydroperoxide,
proceeding under ambient conditions at room temperature (Scheme 1.2).12 Herein,
trifluoromethyl radical could be generated from the radical reagent to participate in the
reaction as a reactive species.13 One limitation of this method is the use of
stoichiometric amounts of copper salt.

Scheme 1. 2 Copper-mediated radical trifluoromethylation of boronic acids

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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The merger of photoredox catalyst ruthenium(II) and copper catalysis was also
described by Sanford et al.,14 which developed a mild protocol to carry out the crosscoupling reaction of boronic acids and CF3I in radical pathway (Scheme 1.3). Although
this work employed readily available reagents and provide simple experimental
procedure, the high cost of metal catalysis made it less favorable.

Scheme 1. 3 Ruthenium(II) and copper-catalyzed radical trifluoromethylation of boronic
acids
Trifluoromethylated arenes were also synthesized from boronic acids via
electrophilic pathway, utilizing electrophilic reagents which produce trifluoromethyl
cation as a reactive species to react with nucleophiles. In these cases, Togni’s reagent15
and Umemoto’s reagent16 were used (Scheme 1.4). Considerably, despite comprising of
the same substrate scope, the method employing Togni’s reagent (Scheme 4a) displayed
better yields when using a low loading of copper catalysts. The employment of
extremely expensive electrophilic reagents is the main disadvantage of these reports.

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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Scheme 1. 4. Copper-catalyzed electrophilic trifluoromethylation of boronic acids.
The development in this field over last few decades involved the use of
transition-metal catalyst via nucleophilic, electrophilic, and radical pathway.11 Among
these strategies, the Ruppert-Prakash reagent Me3SiCF3 has made nucleophilic approach

a method of choice due to its low-cost, stability, and easy to handling over related
trifluormethylated

reagents.

17

In

particular,

studies

in

the

formation

of

trifluormethylated (hetero) arenes by utilizing Me3SiCF3 have been intensively reported
using expensive palladium catalysts. 18
Recently, a copper-mediated oxidative trifluormethylation of alkynes and aryl
boronic acids was disclosed. Quing and Chu first focused their efforts towards oxidative
trifluormethylation of boronic acids

19

(Scheme 1.5a), wherein a nucleophilic reagent in


conjunction with an oxidant was used to carry out the transformation. In 2012, they
developed the procedure to reduce the amount of copper to a catalytic amount (10
mol%) (Scheme 1.5b). However, the slow addition of boronic acid as well as
nucleophilic reagent made this process less practical.

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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Scheme 1. 5. Copper-catalyzed oxidative trifluormethylation of boronic acids.
Following the idea, a more economical protocol was then studied by Buchwald’s
group, which employed Cu(OAc)2 as a copper source and dry O2 as the oxidant (Scheme
1.6).20 However, the utilizing of hazardous solvent isobutyronitrile and a stoichiometric
amount of copper has limited the application of this method.

Scheme 1. 6. Copper-mediated oxidative trifluoromethylation of boronic acids
Regarding to the trifluoromethylation of sp3-hybridized carbon centers, Fu and
co-wokers reported their work on copper-promoted oxidative trifluoromethylation of
primary and secondary alkyl boronic acids (Scheme 1.7).21 The use of expensive silver
catalyst made this method less practical.

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2


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Scheme 1. 7 Copper-promoted oxidative trifluoromethylation of alkyl boronic acids.
Later, an alternative low-cost reagent fluoroform-derived CuCF3 for oxidative
trifluormethylation was recommended by Grushin et al. in 2012.22 A wide range of
trifluormethylated aromatic compounds were obtained in up to 99% yield under mild
condition (Scheme 1.8). However, the need of a complex multiple-step process to
generate CuCF3 was one limitation of this method.

Scheme 1. 8. Fluoroform-derivated CuCF3 for trifluoromethylation of boronic acids
In general, all of these approaches have successfully conducted the
trifluormethylation of boronic acids to obtain the trifluormethylated compounds.
However, either stoichiometric amount of copper salts or slow addition of reagents by
syringe pump was required to achieve good yields. Furthermore, to the best of our
knowledge, reports using heterogeneous catalysts for trifluormethylation reactions have
not been described yet. Due to the presence of fluorine in 20% of pharmaceuticals and

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

30% of agrochemicals,

1a

2017

the development of more practical and efficient protocols


using recyclable catalytic systems is highly needed especially for industrial applications.
1.2 Metal-organic frameworks (MOFs)
Metal organic frameworks (MOFs) are a class of porous crystalline materials of
one-, two- or three-dimensional networks constructed from metal ions/clusters and
organic ligands23. With enormous surface areas and high pore volumes in uniformlysized pores, MOFs are favorable materials for various applications in energy storage24,
CO2 adsorption25, hydrocarbon adsorption/separation26, catalysis27, magnetism28,
sensor29, drug delivery30, luminescene31, and others. First published in 199032, these
novel materials have attracted lots of attention of various research groups, with the
remarkable increase in the number of papers published in this field during recent years33
and more than 20 000 different MOFs being reported and studied within the past
decade34.
In general, the MOFs are constructed by joining the metal-containing units, socalled SBUs (secondary building unit), with organic linkers through coordination
bonds34. Normally, SBUs are molecular clusters (rather than single atoms) of simple
geometrical shapes such as triangle, square, tetrahedra, and octahedra, etc.35. These
clusters are linked by organic polytopic linkers, which could be categorized as ditopic,
tritopic or above, into periodic structures36.
So far, the main routes to synthesize MOFs are hydrothermal or solvothermal
methods, wherein MOFs are prepared in small scales by electrical heating23. However,
this pathway requires long reaction time, up to several days, which limits large-scale
synthesis. Alternatively, to reduce the reaction time and obtain smaller as well as
uniform crystals, several strategies were studied such as microwave-assisted37,
sonochemical38, electrochemical39, mechanochemical methods40, etc. Despite huge
improvements in MOFs synthesis methods during recent years, further investigations are
required for scale-up synthesis23.
With their high surface area and ultrahigh porosity41, MOFs are employed in
numerous fields23. One of the most promising applications is utilizing MOFs as
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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2


heterogeneous catalysis, due to their

2017

high intrinsic metal content42 and uniform,

periodically aligned active sites33. Besides that, large pore size is one of the properties
that make MOFs more suitable as catalysts for liquid-phase reactions than classical
zeolites43. Due to these benefits, there is a vast potential for MOFs in application as
catalysts in organic reactions.
1.2.1 Cu(INA)2
Cu(INA)2 (INA = isonicotinate) is a single-net three-dimensional sprial openframework combined by the square pyramidal Cu(II) and IN (isonicotinate) ligand. The
structure of the material consists of copper atom coordinated by two pyridyl groups and
three carboxylate groups of five IN units.44 It can be synthesized from copper salts as a
source of copper and isonicotinic acid (HINA) as a ligand, according to a literature
procedure.45

Figure 1. 3 View of the crystal structure of Cu(INA)2
The discovery of Cu(INA)2 framework with Cu(II) square-pyramidal geometry
possessing exceptionally high chemical ability and hydrophobicity opens its application
especially in catalysis.

46

Moreover, structure elucidation indicated the weak interaction

between copper centers, which is structurally rare for metal organic framework. Lately,
Cu(INA)2 was successfully used as catalyst for the ligand-free N-arylation of
heterocycles,46 which demonstrated the efficiency of this MOF as


heterogeneous

catalyst for organic reactions.
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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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Scheme 1. 9 Cu(INA)2 as an efficient heterogeneous catalyst for the ligand-free Narylation of heteroarenes
Mechanistic studies in trifluormethylation disclosed that flexibility in copper
center favors the reductive elimination forming C-CF3 bond.11, 47 Herein, we report the
first heterogeneous protocol for trifluormethylation of aryl boronic acids under
Cu(INA)2 catalysis. It is worth mentioning that this is also the first catalytic route from
this transformation under copper-based system.
1.3. Our approach
Transition-metal mediated trifluoromethyl chemistry has improved significantly
to become a focus of numerous researches, especially in the last five years.48 However,
the use of homogeneous catalysts has limited their industrial applications, especially in
pharmaceutical industry. Difficulties in isolating process49 may lead to the poor purity of
products, which is the important consideration in bioactive compound synthesis.
In contrast, the recoverability and the demand of simple separation process makes
heterogeneous catalysis the better option for industrial applications. Metal-organic
frameworks (MOFs), one of the most favorable transition metal heterogeneous catalysts,
are promising candidates due to their high catalytic activity.50
Inspired by those reasons, this thesis aims to investigate the possibility of
employing heterogenous catalysts - in particular MOFs - in trifluoromethylation. So far,
no trifluoromethylation reactions have been reported using heterogeneous catalysis.

Therefore, a novel methodology to introduce trifluoromethyl groups into organic
compounds – immersing transition metal heterogeneous catalysis – is worth being
presented, leading to a more convenient and practical strategy for direct
trifluoromethylation. Following the idea, the objective of our approach is conducting

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Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

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trifluoromethylation reations of boronic acids using copper-based MOF since copper is
relatively cheap and usually acts efficiently.8
The work of Buchwald’s group exhibited a simple, mild, and high efficiency
procedure.20 The use of stoichiometric amounts of copper catalyst was the only
limitation of this method. Hence, this thesis aims to replace the homogeneous catalyst
with copper-based MOF with a lower amount to overcome this drawback

Scheme 1. 10 Trifluoromethylation of boronic acids over Cu-MOF

18


Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

2017

CHAPTER II: EXPERIMENTAL
2.1 Synthesis and characterization of the metal-organic frame


work Cu(INA)2:

2.1.1. Materials and instrument:
All reagents and starting materials were obtained commercially from SigmaAldrich, Merck, Xilong, and were used as received without any further purification.
Table 1. 1 List of chemicals for MOF synthesis
Chemical

Source

Cu(NO3)2.3H2O

Xilong

Isoniconic acid

Sigma Aldrich

N,N’-Dimethylformamide 99.5%

Xilong

N-Methyl-2-pyrrolidone 99.5%

Merk

Pyridine 99%

Xilong


Dichloromethane

Xilong

A Netzsh Thermoanalyzer STA 409 was used for thermogravimetric analysis
(TGA) with a heating rate of 10 oC/min under a nitrogen atmosphere. Powder X-ray
diffraction (PXRD) patterns were recorded using a Cu K radiation source on a D8
Advance Bruker powder diffractometer. Scanning electron microscopy studies were
conducted on a S4800 Scanning Electron Microscope (SEM). Fourier transform infrared
(FT-IR) spectra were obtained on a Nicolet 6700 instrument, with samples being
dispersed on potassium bromide pallets.

19


Introduction of trifluoromethyl group into boronic acid and its derivatives using MOF Cu(INA)2

2017

2.1.2. Synthesis of MOF Cu(INA)2:
1.93 g Cu(NO3)2.3H2O in 70
mL NMP

15 mL pyridine

Dissolving

Heating
DMF


DCM

0.492 g HINA in 170
mL DMF

o

100 C
72 hr

Washing

Solvent
exchanging

Activating

Cu(INA)2

o

140 C
3 hr
52%

Figure 2.1. Synthesized procedure of MOF Cu(INA)2
MOF Cu(INA)2 was synthesized following a literature procedure45. In a typical
experiment, solution of Cu(NO3)2.3H2O (1.93 g, 8 mmol) in N-Methyl-2-pyrrolidone
(NMP, 70 mL) was added to a beaker containing solution of HINA (isonicotinic acid)
(0.492 g, 4 mmol) in N,N’-dimethylformamide (DMF, 170 mL) under stirring condition

at room temperature. Pyridine (15 mL) was then added to the mixture. The resulting
solution was distributed to twenty 10 mL vials. The vials were then heated at 100 oC in
an isothermal oven for 72 h. After cooling the vial to room temperature, the solid
20