Luận văn thạc sĩ Kỹ thuật hóa học: Maetal-Organic Frameworks Cu-OBA as Efficient Heterogeneous Catalysts for Synthesis of a-Ketoesters and amidine

LIST OF SCHEMES Scheme 1.1: The N-Sulfonyl Amidine synthesis method using copper [25].. 9 Scheme 1.4: The synthesis of N-sulfonyl Amidine using Cu as catalyst for oxidative reaction [27]

- -

NGUYỄN TRỌNG ANH

“METAL-ORGANIC FRAMEWORKS Cu-OBA AS EFFICIENT HETEROGENEOUS CATALYST FOR SYNTHESIS OF α-KETOESTERS AND AMIDINE”

Chemical Engineering Major:

Major ID: 60 52 03 01

MASTER OF SCIENCE THESIS

Ho Chi Minh City, March 05th - 2016

Cán bộ hướng dẫn khoa học : TS Trương Vũ Thanh

4 Ủy viên: TS Nguyễn Quang Long 5 Thư ký: TS Lê Xuân Tiến

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)

NHIỆM VỤ LUẬN VĂN THẠC SĨ

Chuyên ngành: Kỹ thuật hóa học MS: 60 52 03 01

I TÊN ĐỀ TÀI: “Tổng hợp vật liệu khung hữu cơ kim loại Cu-OBA làm xúc tác dị thể cho phản ứng tổng hợp α-ketoesters và amidine”

II.NHIỆM VỤ VÀ NỘI DUNG:

- Tổng hợp và kiểm tra cấu trúc vật liệu khung hữu cơ – kim loại Cu-OBA - Khảo sát hoạt tính xúc tác của vật liệu cu-oba với phản ứng tổng hợp α-Ketoesters

và Amidine - Khảo sát khả năng thu hồi và tái sử dụng xúc tác sau phản ứng

III.NGÀY GIAO NHIỆM VỤ: 19/01/2015IV.NGÀY HOÀN THÀNH NHIỆM VỤ: 01/03/2016

V CÁN BỘ HƯỚNG DẪN: TS Trương Vũ Thanh

Tp Hồ Chí Minh, ngày 05 tháng 03 năm 2016

TRƯỞNG KHOA KTHH

(Họ tên và chữ kí)

This work would not have been completed without help and support of many individuals I would like to thank everyone who has helped me along the way

In the first place I would like to express my appreciation to Doctor Truong Vu Thanh for his supervision, guidance and financial support through this thesis

Many especial thanks go in particular to Ms Nguyen Thi Hoai Huong, Mr Nguyen Binh Nguyen, Ms Dang Thi Hang for their help, guidance and full contribution to the experimental works of this thesis

My sincere thanks also go to my classmates, my friends and my fellow labmates for always being my talented and loyal friends

Last but not the least, I would like to thank my family: my parents for giving birth to me at the first place and supporting me spiritually throughout my life

Vật liệu khung hữu cơ-kim loại Cu-OBA đã được tổng hợp bằng phương pháp nhiệt dung môi và kiểm tra đặc trưng cấu trúc, tính chất hóa lý Bằng các phương pháp phân tích như: nhiễu xạ tia X dạng bột (PXRD), kính hiển vi điện tử quét (SEM), kính hiển vi điện tử truyền qua (TEM), phân tích nhiệt trọng lượng (TGA), phổ hồng ngoại (FT-IR) Vật liệu Cu-OBA này đã lần lượt được khảo sát hoạt tính xúc tác trên

phản ứng tổng hợp α-Ketoestes phản ứng tổng hợp Amidine Xúc tác Cu-OBA cho

hiệu suất tinh chế cao có thể thu hồi và tái sử dụng nhiều lần mà hoạt tính gần như thay đổi không đáng kể

ABSTRACT

Metal-organic framework Cu-OBA was synthesized by solvothermal method and characterized the structure, physical properties by using modern analysis: Powder X-ray Diffraction (PXRD), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Thermo Gravimetric Analysis (TGA), Fourier Transform Infrared The catalytic activity of metal-organic framework Cu-OBA was

surveyed on the synthesis of α-Ketoestes and the synthesis of Amidine Cu-OBA gave

the good yield on the reaction and could be recycled and reused while the catalytic activity changed insignificant

LỜI CAM ĐOAN

Tôi xin cam đoan đây là công trình nghiên cứu của tôi dưới sự hướng dẫn và hỗ trợ từ Thầy TS Trương Vũ Thanh Các nội dung nghiên cứu và số liệu kết quả trong đề tài này là trung thực và chưa từng được người khác công bố trong bất cứ công trình nào trước đây Những số liệu trong các bảng biểu, đồ thị phục vụ cho việc phân tích, nhận xét, đánh giá được chính tác giả tiến hành thực nghiệm và ghi nhận Nếu phát hiện có bất kì sự gian lận hay không trung thực nào, tôi xin hoàn toàn chịu trách nhiệm trước Hội đồng

Tp Hồ Chí Minh, ngày 05 tháng 03 năm 2016

Học viên thực hiện

Nguyễn Trọng Anh

1.2.1 Structure and synthesis of Cu-OBA 4

1.2.2 Determination of the characteristics structure, physical and chemical analysis and application of Cu-OBA catalytic 6

1.3 Amidine compounds and synthesis of N-Sulfonyl Amidine 7

1.4 α-Ketoesters and synthesis methods 10

2 EXPERIMENTAL 13

2.1 Materials and instruments 13

2.2 Synthesis of Cu-OBA 14

2.3 Synthesis procedure of α-ketoesters 15

2.4 Synthesis procedure of Amidine 17

3 RESULTS AND DISCUSSION 19

3.2.1 Effect of pyridine concentration on the reaction 22

3.2.2 Effect of base on the reaction 23

3.2.3 Effect of temperature on the reaction 24

3.2.4 Effect of time to the reaction 25

3.2.5 Effect of solvent on the reaction 26

3.2.6 Effect of solvent volume on the reaction 27

3.2.7 Effect of catalyst loading on the reaction 28

3.2.8 Effect of reactants ratio 29

3.2.9 Effect of homogeneous catalyst and heterogeneous catalyst 30

3.2.10 The leaching test 32

3.2.11 Catalyst recycling and reusing 32

3.2.12 Other conditions 34

3.3 Catalytic studies of Cu-OBA on Oxydative couplings of ketones and alcohols 35

3.3.1 Effect of reactant’s ratio on the reaction 35

3.3.2 Effect of temperature on the reaction 37

3.3.3 Effect of catalyst loading on the reaction 38

3.3.4 Effect of different bases on the reaction 39

3.3.5 Effect of base concentration on the reaction 39

3.3.6 Effect of solvent on the reaction 40

3.3.7 Effect of solvent volume on the reaction 41

3.3.8 Effect of different Copper salts and Cu-MOFs on the reaction 42

3.3.9 Effect of time on the reaction 43

4 CONCLUSION 45

5 SUGGESTION 45

LIST OF ABBREVIATIONS

DMF: N,N’-Dimethylformamide

DMA: N,N’-dimethyacetamide

NMP: 1-Methy-2-pyrrolidinone DMSO: Dimethyl sulfoxide THF: Tertrahydrofuran DABCO: 1,4-Diazabicyclo[2.2.2]octane FT-IR: Fourier Transform Infrared GC: Gas Chromatographic ICP: Inductively Coupled Plasma IRMOF: Iso-reticular metal organic framework MOFs: Metal-Organic Frameworks

MS: Mass Spectrometry NMR: Nuclear Magnetic Resonance PXRD: Powder X-ray Diffraction SEM: Scanning Electron Microscopy TEM: Transmission Electron Microscopy TGA: Thermo Gravimetric Analysis TMP: 2,2’,6,6’-tetramethylpiperidine TEMPO: 2,2’,6,6’-tetramethyl-1-piperidinyloxy

LIST OF FIGURES

Figure 1.1: The structure of UiO-67 showing a single octahedral cage (large sphere) The face of each octahedral is shared with 8 smaller tetrahedral cages (small spheres)

[4] 1

Figure 1.2: The structure of some MOFs with different metal ion and linker [6] 2

Figure 1.3: The surface area of some typical MOFs [8] 3

Figure 1.4: The ligand H2OBA (4,4’-oxybis benzoic acid) 4

Figure 1.5: The link and coordination of cluster Cu(II) in Cu-OBA [17] 5

Figure 1.6: Helical structure to form pores on Cu-OBA [17] 5

Figure 1.7: The X-ray Powder Diffraction pattern (a) and Thermo Gravimetric Analysis (b) of Cu-OBA [17] 6

Figure 1.8: The isothermal gas adsorption N2 (77K) and CO2 (195K) (a) and H2 adsorption (b) of Cu-OBA [17] 6

Figure 1.9: Structure of some drugs containing Amidine [21] 7

Figure 1.10: α-Ketoesters in structure of Androsteron (a) and Testosteron (b) 10

Figure 3.1.1: The XRD pattern of Cu-OBA 19

Figure 3.1.2: FT-IR spectra of H2OBA and Cu-OBA 20

Figure 3.1.3: SEM (a), TEM (b) micrograph of Cu-OBA 20

Figure 3.1.4: TGA analysis of Cu-OBA 21

Figure 3.2.1: Effect of pyridine concentration on the synthesis of Amidine 23

Figure 3.2.2: Effect of bases on the synthesis of Amidine 24

Figure 3.2.3: Effect of temperature on the synthesis of Amidine 25

Figure 3.2.4: Effect of time on the synthesis of Amidine 26

Figure 3.2.5: Effect of solvent on synthesis of Amidine 27

Figure 3.2.6: Effect of solvent volume on the synthesis of Amidine 28

Figure 3.2.7: Effect of catalyst loading on the synthesis of Amidine 29

Figure 3.2.8: The effect of reactants ratio on the synthesis of Amidine 30

Figure 3.2.9: Effect of different copper salts on the synthesis of Amidine 31

Figure 3.2.10: Effect of heterogeneous catalyst on the synthesis of Amidine 31

Figure 3.2.11: The leaching test of the synthesis of Amidine 32

Figure 3.2.12: Catalyst recycling studies of the synthesis of Amidine 33

Figure 3.2.13: XRD of Cu-OBA fresh and reuse 34

Figure 3.2.14: Other condition on synthesis of Amidine 35

Figure 3.3.1: Effect of reactant’s ratio on the synthesis of α-Ketoesters 36

Figure 3.3.2: Effect of temperature on the synthesis of α-Ketoesters 37

Figure 3.3.3: Effect of catalyst loading on the synthesis of α-Ketoesters 38

Figure 3.3.4: Effect of bases on the synthesis of α-Ketoesters 39

Figure 3.3.5: Effect of base concentration on the synthesis of α-Ketoesters 40

Figure 3.3.6: Effect of solvent on the synthesis of α-Ketoesters 41Figure 3.3.7: Effect of solvent volume on the synthesis of α-Ketoesters 42Figure 3.3.8: Effect of different Copper salts and Cu-MOFs on the synthesis of α-Ketoesters 42 Figure 3.3.9: The kinetic of the synthesis of α-Ketoesters 43

LIST OF SCHEMES

Scheme 1.1: The N-Sulfonyl Amidine synthesis method using copper [25] 8

Scheme 1.2 : The synthesis of N-Sulfonyl Amidine from p-toluenesulfonyl azide and tertiary amine used CuCl as catalyst [24] 9

Scheme 1.3: The synthesis of N- Sulfonyl Formanmidine in the presence of an oxidant TBHP [26] 9

Scheme 1.4: The synthesis of N-sulfonyl Amidine using Cu as catalyst for oxidative reaction [27] 10

Scheme 1.5: The synthesis of N-sulfonyl Amidine using Copper as heterogeneous catalyst for oxidative reaction 10

Scheme 1.6: Methods of synthesizing α-ketoester 11

Scheme 1.7: Synthesis of α-ketoester using Cu-catalyzed [49] 11

Scheme 1.8: The synthesis of α-keto esters from β-ketonitriles using phenyliodine(III) diacetate [50] 12

Scheme 1.9: The synthesis of α-ketoesters with acetophenone and cyclohexanol using heterogeneous catalyst 12

Scheme 2.1: The synthesis of Cu-OBA 14

Scheme 2.2: Synthesis procedure of Cyclohexyl 2-oxo-2-phenylacetate 16

Scheme 2.3: Synthesis procedure of N-sulfonyl Amidine 18

Schem 3.2.1 The synthesis of N-sulfonyl Amidine using Copper as heterogeneous catalyst for oxidative reaction 22

Schem 3.3.1: The synthesis of Cyclohexyl-2-oxo-2-phenylacetate using Cu-OBA as heterogeneous catalyst 35

1 OVERVIEW OF RESEARCH 1.1 Metal-Organic Frameworks

1.1.1 Introduction

Metal-Organic Frameworks (MOFs) are porous compounds containing the coordination networks between metal ions (or coordinated cluster) and organic ligands to form one-, two-, three-dimensional structure Unlike other porous solid materials such as zeolite and activated carbon, MOFs have flexibility by simply changing the ratio of metal, ligand organic synthesis, temperature and polarization of the solvent [1, 2]

The organic linkers have at least two functional groups for covalent metal to form a three-dimensional framework structure Several popular suitable functional groups for covalent linkage with metal ion are carboxylate, phosphonate, sulfonate, phenolate, and nitrogen derivatives such as pyridine and imidazole, etc … [3]

Figure 1.1: The structure of UiO-67 showing a single octahedral cage (large sphere) The face of each octahedral is shared with 8 smaller tetrahedral cages

(small spheres) [4] 1.1.2 Structure characteristic

MOFs are composed of two major components: a metal ion or cluster of metal ions and an organic molecule called a linker Thus, the materials are often referred to as hybrid organic-inorganic materials However this terminology has recently been

explicitly discouraged [4] The organic units are typically mono-, di-, tri-, or tetravalentligands [5]

The choice of metal and linker dictates the structure and properties of the MOF For example, the metal's coordination preference influences the size and shape of pores by dictating how many ligands can bind to the metal and in which orientation [6]

Figure 1.2: The structure of some MOFs with different metal ion and linker [6] 1.1.3 Physical characteristic

1.1.3.1 High porosity and large surface area

MOFs are different from others traditional porous materials that structured in the form of molecular septum thickness Therefore, MOFs have greater surface area and pore volume higher than traditional porous materials Highly porous of MOFs allow them in many applications in the field of storage and gas adsorption [7]

The major challenges of the researchers are how to design and synthesize porous materials with high surface area Such as the highest surface area of disordered carbon structure is 2030 m2/g, zeolite structure is 904 m2/g while a particularly

345 816

1547 1781 2096 2160 2516

28334500

010002000300040005000

The limitations of the MOFs stability can easily improve by changing the organic linkers or arrangement of elements in space, it can’t be done in other materials

1.1.3.3 Characteristics of the metal ion

It is noticeable that the density of metal in MOFs used in catalysis is much larger than in the zeolite or silica This makes the cost of catalyst is reduced, while the catalysis is more effective And an important point is that while in zeolite or silica materials, the metal is mounted on the solid carriers or retained by loose coordinating links, which makes metal easily leaching into the reaction solution, making it difficult for the recovery of catalyst In contrast, metals in MOFs are fixed in location of network nodes and are surrounded by coordinating links in three-dimensional space, it is difficult to be leaching out of the lattice This allows for the recovery and reuse of catalyst easily after each reaction [10] For example, ZIF-8, a kind of MOFs

material is surveyed activity in Knoevenagel reaction, can recover 5 times that the structure remains unchanged, and the response performance after 5 times was above 85% [11]

In addition to the synthesis and research structure of MOFs, the world's scientists are particularly interested in exploring the application of MOFs such as gas storage, adsorption, gas separation, catalytic, drug carried, magnetic, luminescence, sensors, etc [12]

1.2 Introduction to Cu-OBA

1.2.1 Structure and synthesis of Cu-OBA

In recent years, the use of 4,4’-oxybis (benzoic acid) as ligand to synthesize MOFs has been reported This ligand can link with several metal ions or clusters: Zn2+, Co2+, Mg2+, In+ [13-16] to perform different kinds of MOFs These MOFs have highly porous property that should be applied in the field of gas storage, drug delivery and catalysis … [14, 15]

In 2011, Bu Xiang-He and co-worker published a report finding a new material is Cu-OBA[17] Cu-OBA is an asymmetric unit including two clusters of Cu(II), one is cluster Cu(I), and the other is Cu(II) link together by different OBA linkers One cluster Cu(I) coordinates with DMF and the other Cu(II) coordinates with H2O Each Cu(II) ion bonds with four Oxygens of carboxylate to perform tertiary shape with square bottom The top of structure link with DMF or H2O, bottom links with Oxygen of carboxylate [17] (Figure 5)

Figure 1.4: The ligand H2OBA (4,4’-oxybis benzoic acid)

Figure 1.5: The link and coordination of cluster Cu(II) in Cu-OBA [17]

Each pair of Cu2+ ion links with four Oxygens of carboxylate to perform a bridge or a second building unit (SBU), [Cu2(CO2)4)]1 The second unit create a node, Nodes link together by ligand OBA, become 3D structure [17] Despite the incorporating structure, metal organic frameworks still have open channels with the porosity is about 40% The length of Cu-O is 1,928 – 2,180 Å

Cu-OBA synthesized by dissolving H2OBA (0,2 mmol), Cu(NO3)2.3H2O (0,4 mmol) in DMF/H2O with ratio 2:1 (according to volume ratio) The mixture is divided in to vials and placed in oven at 1000C for 48 hours The crystal of MOFs is cooled at room temperature, washed with DMF then activated in low-pressure condition The Cu-OBA crystals obtained have light blue colour

Figure 1.6: Helical structure to form pores on Cu-OBA [17]

1.2.2 Determination of the characteristics structure, physical and chemical analysis and application of Cu-OBA catalytic

TGA and XRD are used to test the stability, the purity of metal organic framework XRD is the method to determine the structure Moreover, XRD is also the best method to determine the crystalline phase and the phase ratio after synthesis MOFs Other features of the XRD provides information on the unit cell size, degree of crystal, crystal size, the type of atoms and their positions in the crystal [18]

Figure 1.7: The X-ray Powder Diffraction pattern (a) and Thermo Gravimetric

Analysis (b) of Cu-OBA [17]

Figure 1.7 (b) shows the weight lost of Cu-OBA from room temperature and to 3000C, because of the removing of guest molecules Metal organic framework materials remains stable at temperatures of 3600C Base on the result, the Cu-OBA has great thermal stability up to 3600C [17]

Figure 1.8: The isothermal gas adsorption N2 (77K) and CO2 (195K) (a) and H2

adsorption (b) of Cu-OBA [17]

Specific surface area and pore diameter of MOFs materials can be determined by gas adsorption capacity Under 1 atm pressure, the N2 (77K) adsorption of Cu-OBA is 116 m3/g, CO2 (195K) is 116m3/g (Figure 1.8a) [17]

In N2 adsorption, BET specific surface area is 562 m2/g, Langmuir surface area is 747 m2/g, average pore diameter is 6,2 Å In H2 adsorption at temperatures of 77 K and 87 K with pressure 800 mmHg, the H2 adsorption capacity is 0,89 wt% (99.5 m3/g at a standard temperature and pressure); 0,57 wt% (64 cm3/g at standard conditions for temperature and pressure) [17] (Figure 1.8b)

With these outstanding properties, Cu-OBA is highly suitable for catalyzing organic fusion qualify the requirements of green chemistry and be able to re-use several times There have been some studies on catalytic ability of OBA [14] But just a few of them describe the catalytic capabilities of Cu-OBA in organic synthesis

1.3 Amidine compounds and synthesis of N-Sulfonyl Amidine

1.3.1 Introduction to Amidine compounds and its derivatives

Amidine is widely applied in organic synthesis as reactants in for preparation of many substances with high bio-activity [19, 20] Some drugs containing amidine are Bucainide and Mixidine (Figure 1.9) [21] Bucainide is used in quick hypoglycemic quickly and anti-arrhythmia treatment while Mixidine has direct effect on the sinus

Figure 1.9: Structure of some drugs containing Amidine [21]

Among Amidine derivatives, the N-Sulfonyl Amidine is one of the most important compound in organic chemistry This is an intermediate that can be converted into substances with unique structure and high activity [21], an indispensable component of different drugs [19, 22, 23], and an organic transition

metal bridge [24] In industrial antisense, the effective arrangement of sulfonamide instead of phenytriazoles in position 5 of 2’-deoxyuridine could perform stable DNA to create RNA hybrid [19] To meet the needs of drug production, as well as organic synthesis, the synthesis N-Sulfonyl Amidine is essential

1.3.2 N-Sulfonyl Amidine synthesis methods

Due to the importance of N-Sulfonyl Amidine compounds, over the years there have been many methods to synthesize N-Sulfonyl Amidine published

In 2008, in South Korea, Chang and co-worker published a report about Sulfonyl Amidine synthesis method using copper as catalyst The reaction was carried out in dichloromethane, phenylacetylene, p-toluenesulfonyl azide, CuI (10% mol), NH4Cl, trimethylamine at 250C, on 1 hour, reached 90% of yield (Scheme 1.1) [25]

N-Scheme 1.1: The N-Sulfonyl Amidine synthesis method using copper [25]

The advantage of this method is using ammonium salts as reactants (cheap) to increase yield, Besides, adjust the amount of ammonium salt could be adjusted to produce 2H-1,2,4-benzothiadiazine-1,1–dioxides that has high bio-activity However, this reaction used p-toluenesulfonyl azide that is a poison, explosive compound, while homogenous catalyst inhibited the ability to recall and reuse

Similarly in 2009, Xiao Nian Li's group has published articles on the synthesis of N-Sulfonyl Amidine from p-toluenesulfonyl azide and tertiary amine using CuCl as catalyst The reaction was carried out in carbon tetrachlorua with a significant reduction in CuCl amount (0,2 – 0,3% mol), in 10 hours at room temperature, performed 71% yield (Scheme 1.2)[24] A Wide range of different amines has been investigated However, limitations of this method is the use of p-toluenesulfonyl azide which are toxic, explosive, with low reactivity

Scheme 1.2 : The synthesis of N-Sulfonyl Amidine from p-toluenesulfonyl azide

and tertiary amine used CuCl as catalyst [24]

In 2011, Xiaobing Wank and co-worker reported the synthesis of N- Sulfonyl Formanmidine using catalyst in the presence of oxidant TBHP The reaction used NaI as catalyst, oxidant, tolunenesulfonamide in DMF at 900C, 3 hours 90% of yield was obitained (Scheme 1.3) [26] This method has advantages of high performance, not using azide and transition metal catalysts On the other hand, using a large amount of catalyst (20% mol) and an oxidant, homogenous catalyst were this reaction limitations

Scheme 1.3: The synthesis of N- Sulfonyl Formanmidine in the presence of an

oxidant TBHP [26]

In 2014, Shannon S Stahl and co-worker published the synthesis of N-sulfonyl Amidine through mediators Ynamine using Cu as catalyst for oxidative reaction The reaction used phenylacetylene, diisopropyl amine, toluenesulfonamide in Toluene as solvent The reaction performed in Oxygen medium catalyst was Cu(OTf)2 (5% mol) at 700C, in 15 hours, reached 96% yield (Scheme 1.4)[27] The advantages of this reaction were high-performance, non-use of p-toluenesulfonyl azide compounds limiting toxic, explosive A wide range of secondary amines instead of using sulfonamide could be replaced, with the same performance However, using aromatic amines did not generate Amidine Similarly, Toluenesulfonamide could be replaced by sulfonamide with no reduction performance The drawback of this method was using homogenous catalyst that can not recovered and reused, product contained metals This reaction was not investigated with tertiary amines and other aromatic amines

Scheme 1.4: The synthesis of N-sulfonyl Amidine using Cu as catalyst for oxidative

reaction [27]

Applying above reaction, the synthesis of N-sulfonyl Amidine would be improve using less toxic reagents which are toluensulfonyl and diethyl amine More than that, heterogeneous catalyst Cu-OBA could overcome the limitation of homo-systems (Scheme 1.5)

Scheme 1.5: The synthesis of N-sulfonyl Amidine using Copper as heterogeneous

catalyst for oxidative reaction

1.4 α-Ketoesters and synthesis methods

α-Ketoesters are ubiquitous units in many bio active compounds [28-30] Furthermore, As well as useful precursors in organic synthesis [31]

Figure 1.10: α-Ketoesters in structure of Androsteron (a) and Testosteron (b)

Therefore, various effort has been made to construct α-ketoesters Some traditional methods are esterification of α-ketoacyl halides and α-ketoacids (1, Scheme 1.6) [32, 33], oxidation of α hydroxy ester (2, Scheme 1.6) [34, 35], double carbopalladative esterification (3, Scheme 1.6) [36], and other relevant methods (4, Scheme 1.6) [37] So far, these procedures have been developed, such as esterification

of α-ketoacyl derivatives [38-40], carbonylation using palladium-catalyst [34, 41] and dehydrogenation of α-hydroxyl ester [36, 42, 43] However, these methods usually suffered from harsh conditions, low atom economy, and the usage of a noble metal catalyst

Scheme 1.6: Methods of synthesizing α-ketoester

Due to the cheapness and low toxicity of copper catalysts and the natural, abundant, and environmentally friendly characteristic of oxygen, copper catalyzed the aerobic oxidation [44, 45] and oxygenation [46-48] represented as attractive strategy for α-ketoesters synthesis

For instance, Ning Jiao and co-workers reported two approaches to ketoesters synthesis via copper catalyzed aerobic oxidative esterification of alcohols with 1,3- diones or α-carbonyl aldehydes However, the low atom efficiency and the need of extra steps to prepare starting materials might limit their applications Recently, using Cu-catalysis, Chun Zhang and co-workers developed a novel approach to construct α-ketoesters through C–C bond cleavage [49]

α-Scheme 1.7: Synthesis of α-ketoester using Cu-catalyzed [49]

In 2015, the first report about the application of hypervalent iodine(III) reagents in the synthesis of α-keto esters was published by Yuanyuan Xie and co-worker This methods use β-ketonitriles and phenyliodine(III) diacetate as reagents, giving good yield in the present of base[50]

Scheme 1.8: The synthesis of α-keto esters from β-ketonitriles using

phenyliodine(III) diacetate [50]

However, some drawbacks may limit its application: (1) an excess amount of alcohol substrate is required for the transformation; (2) since the fragmentation of the intermediate could couple with alcohol to afford the byproduct, the atom economy is not high; (3) pure molecular oxygen is required to ensure high efficiency Despite the numerous efforts toward the synthesis of α-ketoesters, development of mild, efficient, and environmentally friendly methods is still desirable

In addition, the use of heterogeneous Cu-OBA will give the new challenges with many advantages in green chemistry aspects such as purification,, reusability …

Scheme 1.9: The synthesis of α-ketoesters with acetophenone and cyclohexanol

using heterogeneous catalyst

2 EXPERIMENTAL2.1 Materials and instruments

All reagents and starting materials were obtained commercially from Sigma–Aldrich, Guangzhou, and Merck were used as received without any further purification unless otherwise noted

X-ray powder diffraction (XRD) patterns were recorded using a Cu Kα radiation source on a D8 Advance Bruker powder diffractometer Fourier transform infrared (FT-IR) spectra were obtained on a Nicolet 6700 instrument, with samples being dispersed on potassium bromide pallets Scanning electron microscopy studies were conducted on a JSM 740 scanning electron microscope (SEM) Transmission electron microscopy studies were performed using a JEOL JEM 1400 transmission electron micro-scope (TEM) at 100 kV The Cu-OBA samples were dispersed on holey carbon grids for TEM observation A Netzsch Thermoanalyzer STA 409 was used for thermogravimetric analysis (TGA) with a heating rate of 10 oC/min under a nitrogen atmosphere Nitrogen physisorption measurements were conducted using an ASAP 2020 system Samples were pretreated by heating under vacuum at 140 oC for 3h

Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010-Plus equipped with a flame ionization detector (FID) and a SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 µm)

In the synthesis of Amidine: the temperature program for GC analysis heated samples at 100 ◦C and held for 1 min, then heated them from 100oC to 280oC at 40oC/min; held them at 280oC for 8,5 min Diphenyl ether was used as an internal standard to calculate reaction conversion

In the synthesis of α-ketoesters: the temperature program for GC analysis heated samples at 120 ◦C and held for 0.5 min, then heated them from 120oC to 130oC at 40oC/min; held them at 130oC for 1 min Finally, the samples were heated up to 280oC at 40oC/min and were hold for 4.5 min Diphenyl ether was used as an internal standard to calculate reaction conversion

GC–MS analyses were performed by using a Hewlett Packard GC-MS 5972 with an RTX-5MS column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.5 nm) The temperature program for GC–MS analysis heated samples from 60 to 280 oC at 10 oC/min and held them at 280 oC for 2 min Inlet temperature was set constant at 280 oC

1H, and 13C NMR spectra were recorded in CDCl3 using TMS as an internal standard on a Bruker spectrophotometer at 500 and 125 MHz respectively

2.2 Synthesis of Cu-OBA

Scheme 2.1: The synthesis of Cu-OBA

Cu-OBA

Stir, 30min, R.TCharge in vials 100 0C, 2 days Cu(NO3)2·3H2O, H2OBA

DMF, H2O

DMF (3 x 15mL)

MeOH (3 x 15mL)

160 0C , 6 hours Mix

React

Purify

Exchange solvent

Activate

Cu-OBA was initially synthesized by solvothermal method H2OBA (H2OBA = 4,4’-oxybis benzoic acid (6,4 mmol; 1,6512g), and Cu(NO3)2·3H2O (12,8 mmol; 3,0976 g) were dissolved in the mixture of DMF/ H2O (64 mL, v/v: 2:1) The mixture was sealed in a small capped vial and heated at 1000C in an oven for 48 h, followed by slow cooling to room temperature in 12 h After cooling, the solid product was removed by decanting with mother liquor, washed with DMF (3×10 ml) and exchanged solvent with Methanol (3×10 ml) at room temperature The product was dried at 1600C for 6h under vacuum, pure light blue crystals were collected weight 1,3503g ~ 30% yield base on H2OBA [51]

Crystal after activation were analyzed using modern analytical methods: XRD, SEM, TEM, TGA, IR …

2.3 Synthesis procedure of α-ketoesters

Mixture of acetophenone (0,4 mmol; 0,048 g), cyclohexanol (1,2 mmol; 0,1200g), TMP (2,2’,6,6’-tetramethylpiperidine) (20 % mol, 0,0113g) and diphenyl ether (0,4 mmol; 0,0680g) as internal standard and solvent 1,2-dichlorobenzene (2mL) was stirred in a schlenk tube (50 mL) Then, catalyst Cu-OBA (5% mol) was added, catalysts molar ratio is calculated based on the ratio of the number of moles Cu/acetophenone The mixture was stirred at 1400C for 24h under O2 (balloon) After 24 hours, the efficiency of the reaction is monitored by GC Samples of the reaction mixture was extracted with 1 mL of 5% HCl and ethyl acetate 3mL, then dried over Na2SO4 anhydrous

After completing, the mixture was extracted by ethyl acetate/ HCl 5%, to pursue organic product Then the product was isolated by column chromatography (Petroleum ether/ethyl acetate = 15:1) The product structure was confirmed by 1H NMR and 13C NMR in CDCl3

Cyclohexyl 2-oxo-2-phenylacetate: 1H NMR (CDCl3, 500 MHz): δ = 7.96 (m, 2H), 7.65 (tt, J1 = 7.4 Hz, J2 = 1.2 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H), 5.14-5.05 (m, 1H), 2.03-1.98 (m, 2H), 1.82-1.75 (m, 2H), 1.67-1.54 (m, 3H), 1.49-1.24 (m, 3H); 13C NMR (CDCl3, 100 MHz): δ = 186.8, 163.6, 134.7, 132.5, 129.9, 128.8, 75.4, 31.4, 25.1, 23.6 ppm

8.02-Scheme 2.2: Synthesis procedure of Cyclohexyl 2-oxo-2-phenylacetate

0,0480g acetophenone + 0,1200g cyclohexanol +

2 mL dichlorobenzene

0,0064g Cu-OBA + 0,0113g TMP

Conversion

%

Na2SO4 Ethyl acetate HCl 5%

chromatography

2.4 Synthesis procedure of Amidine

Mixture of phenylacetylene (0,1 mmol; 0.0104 g), diphenyl ether (0.1 mmol; 0,0170g) as internal standard and the solvent toluene (1 mL) was stirred in a vial (8 mL) Then, catalysts Cu-OBA (10% mol), benzensunfonamide (0.2 mmol; 0,3020g), diethylamine (0.2 mmol; 0,0146g) was added Catalysts molar ratio is calculated based on the ratio of the number of moles Cu/phenylacetylene The mixture was heated constant at a temperature of 800C for 16 hours After 16 hours, the efficiency of the reaction was monitored by GC samples of the reaction mixture was extracted with 1 mL of 5% KOH and ethyl acetate 3mL, then dried by Na2SO4 anhydrous

To examine the recoverability of the catalysts, Cu-OBA after decanting from the reaction was washed with DMF (10 mL x 3), then activated at 1500C for 6 hours Catalyst then wwould be be reused as initial conditions

To demonstrate the heterogenous property of catalyst, catalysts was removed after 2 hours reaction by filter The reaction mixture is transferred to a different vial heated at 800C temperature, in 16h Samples were extracted interrupted by time, analyzed by and gas chromatographic to monitor performance changes

After completing, the mixture was extracted by ethyl acetate/ KOH 5%, washed with saturated NaCl solution, pursue organic product Then the product was isolated by column chromatography (Hexane/ethyl acetate = 2:1) The product was determined by 1H NMR and 13C NMR in CDCl3

N1,N1 – dietyl-N2(benzensulfonyl)-2-phenyacetamidine: white solid: 1H NMR (500 MHz, CDCl3, ppm):1HNMR (500 MHz, CDCl3) d7,902 (s, 1H); d7,886 (d, J = 1.5 Hz, 1H), 7,451-7,372 (m, 3H), 7,264 – 7,113 (m, 5H); 4,396 (s, 2H); 3,507 (q, J = 7 Hz, 2H); 3,215 (q, J = 7 Hz, 2H); 1,155 (t, J = 7 Hz, 3H); 0,954 (t, J = 7 Hz, 3H)

Scheme 2.3: Synthesis procedure of N-sulfonyl Amidine

0,0104 g phenylacetylene + 0,017 g diphenyl ether

+ 1mL toluene

0,0032g Cu-OBA + 0,320g benzensufonamide

+ 0,0146g dietylamine

Conversion

%

Na2SO4 Ethyl acetate KOH 5%

Column chromatography

3 RESULTS AND DISCUSSION 3.1 Characterization of Cu-OBA

3.1.1 XRD pattern

According to the experimental section, Cu-OBA was synthesized by solvothermal method between Cu(NO3).3H2O salt and ligand 4,4’ oxybis (benzoic acid) H2OBA Product after collected was blue crystaline Solvent were removed by activating in shlenk-line system at 1500C, in 6 hours After 6 hours obtained crystal mass was 1.3503 g Performance was 30% base on H2OBA

Structure of Cu-OBA crystal is determined by X-ray diffraction XRD analysis results show Cu-OBA material obtained highly structure crystalline by a diffraction nose appeared at the locator 2 = 60 with high intensity The results were consistent with previously published works [17]

Figure 3.1.1: The XRD pattern of Cu-OBA

2 Theta scale

3.1.2 FT-IR

Figure 3.1.2: FT-IR spectra of H2OBA and Cu-OBA

FT-IR spectra of materials Cu-OBA (Figure 12) shows the peak at 1597.11 cm-1, that was characteristic for C = O link of carboxylate group In 4-4’ oxybis (benzoic acid) ligand, this peak appear at 167,41 cm-1 Characterization for ether group was the peak at 1257 cm-1 Wide peak at 3487,41 cm-1 represented for O-H showed that the material was hygroscopic

3.1.3 SEM, TEM

Figure 3.1.3: SEM (a), TEM (b) micrograph of Cu-OBA

5001000

15002000

25003000

35004000

Wave number (cm-1)

Ligand OBACu(OBA)_fresh

Scanning electron microscope results of crystal OBA showed that OBA MOF crystals were shaped blade (a) TEM results showed that Cu-OBA MOF had porous structure (b)

Cu-3.1.4 TGA results

Figure 3.1.4: TGA analysis of Cu-OBA

TGA pattern showed that the material Cu-OBA started to loss weight from 3400C There are about 8.386% wt lost from 3400C to 3990C, corresponding to the loss of DMF and H2O remaining in the material Next was a decrease in weight about 30.66% from 3990C to 6200C, the structure of materials Cu-OBA started decomposing at a temperature of 6200C because of the destruction of organic bridge was destroyed, in Cu-OBA Ending the analysis, weight remained at 63.56% wt of samples that could be metal oxides and carbon components

3.2 Catalytic studies of Cu-OBA on reaction between phenylacetylene, diethylamine, benzenesufonamide

In 2014, Jiho Kim, Shannon S Stahl reported the synthesis of N-Sulfonyl Amindine using Cu as homogeneous catalyst for the reaction of phenylacetylene, isopropylamine and toluenesufonamide This thesis will examine the activity of heterogeneous catalytic Cu-OBA on the reaction of phenylacetylene, dietylamine, benzensunfonamide to produce N- Sulfonyl Amindine (Scheme 3.2.1)

Schem 3.2.1 The synthesis of N-sulfonyl Amidine using Copper as heterogeneous

catalyst for oxidative reaction

In this section, the factors affecting to reaction yield will be explored such as reaction time, temperature, catalyst concentration, the ratio of reactants In addition, other factors affecting such as solvents, pyridine concentration, bases, antioxidants also surveyed Otherwise, the properties of heterogeneous catalyst Cu-OBA could be checked via leaching test, recovery and reuse experiments Also, the catalytic activity was also compared with other types of homogenous catalyst and other MOFs

3.2.1 Effect of pyridine concentration on the reaction

The amount of pyridine is a factor significantly affecting the performance of the reaction So the amount of pyridine was selected as the first survey element According to research by Jiho Kim, Shannon S Stahl in 2014 [27], the reaction was carried out in the absence of pyridine, with catalyst Cu(OTF)2, the reaction efficiency was 93% But when performing oxidative reaction between phenylacetylene, diethylamine and benzensunfonamide with catalytic Cu-OBA without pyridine, the reaction efficiency is only 34% According to another study by Shannon S Stahl and co-worker in 2008 using some kinds of base as Na2CO3 (2equiv), pyridine (2equiv) performance of reaction gained 89% and 62%, respectively So in this study the reaction between phenylacetylene, diethylamine and benzensunfonamide to create N- Sulfonul Amindine compounds surveyed equivalent of pyridine that was 0, 1equiv, 2

equiv, 3 equiv, 4 equiv The reaction used ratio of reactants phenylacetylene: diethylamine: benzensunfonamide was 1:2:2 (0,1mmol: 0,2 mmol: 0,2 mmol), Cu-OBA as catalyst (10% mol), diethyl ether as internal standard (0,1 mmol) in toluene (1 mL) The reaction was carried out at 800C, in 16h and under O2

Figure 3.2.1: Effect of pyridine concentration on the synthesis of Amidine

The survey results showed that without pyridine, the performance was 34%, while increasing the amount of pyridine to 1equiv, 2 equiv, performance has also increased respectively to 35% and 62% However, if continue to increase the pyridine to 3 equiv and 4 equiv, efficiency of reaction reduced to 49%, 53% The results showed that 2 equiv of pyridine was the best This result was entirely consistent with previous studies in 2008 of Shannon S Stahl and co-worker [27]

3.2.2 Effect of base on the reaction

After examining the effects of amount of base, different kinds of base were also surveyed These base contained organic base as pyridine, sodium terbutoxide, potasium terbutoxide, DABCO, and inorganic base: Na2CO3, K2CO3, K3PO4, KHCO3, NaHCO3, CsCO3 The reaction was carried out with reactants ratio phenylacetylene: diethylamine: benzensunfonamide was 1:2:2 (0,1 mmol: 0,2 mmol: 0,2 mmol), Cu-OBA as catalyst (10% mol), diethyl ether as internal standard (0,1 mmol) in toluene (1 mL), at 800C, in 16h and under O2

62

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Figure 3.2.2: Effect of bases on the synthesis of Amidine

The study results showed that, with the type of inorganic bases such as K2CO3, K3PO4, KHCO3, CsCO3 was not effective for the reaction (0 -11%) However, when using Na2CO3, NaHCO3, the reaction efficiency increased to 45%, 51% This was as same as previous survey including that NaHCO3 base used for fusion Ynamide (intermediates in the synthesis of N-Sulfonyl Amidine) with high performance [52] With organic bases such as pyridine, DABCO, 4,4'-dipyridine, the high response performance of 62%, 58%, 49% were optained, respectively In which pyridine (2 equiv) was still the optimal condition

3.2.3 Effect of temperature on the reaction

Using of pyridine (2 equiv) in order to investigate the influence of temperature Temperature is selected in ranges from 70 to 1000C base on previous studies [27, 53], For instance, the reaction temperature surveyed at RT, 700C, 800C, 900C, 1000C The reaction was carried out with reactants ratio phenylacetylene: diethylamine: benzensunfonamide was 1:2:2 (0,1 mmol: 0,2 mmol: 0,2 mmol), Cu-OBA as catalyst (10% mol), diethyl ether as internal standard (0,1 mmol) in toluene (1 mL), reaction performed at 800C, in 16h and under O2

Figure 3.2.3: Effect of temperature on the synthesis of Amidine

According to previous studies, the temperature greatly affected to reaction rates Indeed, the survey results showed that at room temperature, desired product was not formed But when the temperature increased to 700C, the reaction efficiency was 59% and at 800C, the efficiency was 62% When continuing raising the temperature 900C, 1000C, it did not improve the reaction yield, was 53% and 49%, respectively Because phenylacetylene, diethylamine, benzensunfonamide were volatile, so the temperature increased, would lead to the performance decrease Therefore, the optimum temperature was 800C

3.2.4 Effect of time to the reaction

The time element is also an important factor affecting the performance of the reaction In this study, the period of time between 0 to 18 hours will be examined The reaction was carried out with phenylacetylene: diethylamine: benzensunfonamide, ratio was 1:2:2 (0,1 mmol: 0,2 mmol: 0,2 mmol), Cu-OBA as catalyst (10% mol), diethyl ether as internal standard (0,1 mmol) in toluene (1 mL), reaction performed at 800C, under O2

Figure 3.2.4: Effect of time on the synthesis of Amidine

The study results showed that after 16 hours, the reaction efficiency is 62% But after a longer time (18 hours), the performance remains unchanged Therefore, 16 hours was the optimal time to conduct following surveys

3.2.5 Effect of solvent on the reaction

For oxidative reactions using transition metals as catalysts, solvents play an important role in dissolving the reactants and facilitate the reaction Solvent such as: DMF, DMA (N,N-dimethyacetamide), NMP (1-Methy-2-pyrrolidinone), DMSO (dimethyl sulfoxide), benzonitrile, n-butanol, toluene, dioxane, p-xylene, mesitylene, THF (tertrahydrofuran), chlorobenzen, dichlorobenzen were examined using 1 mL of each of these solvents The reaction was carried out with reactants ratio phenylacetylene: diethylamine: benzensunfonamide was 1:2:2 (0,1 mmol: 0,2 mmol: 0,2 mmol), Cu-OBA as catalyst (10% mol), diethyl ether as internal standard (0,1 mmol) in different solvents (1 mL), reaction performed at 800C in 16h, under O2

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