Using ionic liquid as solvent for coupling, and halogen exchange rections

More interestingly, the results showed that dialkylimidazolium ionic liquid could effectively act as green solvents for coupling reactions, and halogen exchange reaction with high conver

VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY

HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY

NGUYEN THI HONG ANH

USING IONIC LIQUID AS SOLVENT FOR COUPLING,

AND HALOGEN EXCHANGE REACTIONS

PHD THESIS

HO CHI MINH CITY 2018

VIETNAM NATIONAL UNIVERSITY – HO CHI MINH CITY

HO CHI MINH CITY UNIVERSITY OF TECHNOLOGY

NGUYEN THI HONG ANH

USING IONIC LIQUID AS SOLVENT FOR COUPLING,

AND HALOGEN EXCHANGE REACTIONS

Major: Organic Chemical Technology

Major code: 62527505

Independent examiner 1: Prof Dr Nguyen Kim Phi Phung

Independent examiner 2: Assoc Prof Dr Pham Thanh Huyen

Examiner 1: Assoc Prof Dr Nguyen Thi Dung

Examiner 2: Assoc Prof Dr Vu Anh Tuan

Examiner 3: Assoc Prof Dr Pham Thanh Quan

ADVISORS:

1 Prof Dr Phan Thanh Son Nam

2 Dr Truong Vu Thanh

Page i

DECLARATION OF ORIGINALITY

I hereby declare that this is my own research study The research suitable condition and conclusions in this thesis are true, and are not copied from any other resources The literature references have been quoted with clear citation as requested

Thesis Author

Sign

Nguyen Thi Hong Anh

Page ii

TÓM TẮT LUẬN ÁN

Trong nghiên cứu này, chất lỏng ion 1-alkyl-3-methyl imidazolium bromide được tổng hợp thành công dưới sự hỗ trợ của vi sóng với chế độ gián đoạn 10 giây một tạo ra các chất lỏng ion có màu vàng nhạt Sau đó, các chất lỏng ion này được đem đi thực hiện phản ứng trao đổi anion với hexafluorophosphoric acid để tạo các chất lỏng ion 1-alkyl-3-methyl imidazolium hexafluorophosphate Các đặc trưng cấu trúc của chất lỏng ion sau tổng hợp được xác định bằng phương pháp phổ cộng hưởng từ hạt nhân (1H, 13C NMR) và phổ khối lượng (MS) Các chất lỏng ion 1-alkyl-3-methyl imidazolium được khảo sát khả năng làm dung môi cho các phản ứng ghép đôi và phản ứng trao đổi halogen để tìm ra điều kiện thích hợp cho mỗi phản ứng và được đối chiếu với các dung môi hữu cơ thông thường khác

Kết quả nghiên cứu thu được là tìm được loại chất lỏng ion thích hợp cho từng phản ứng cũng như tất cả các điều kiện thích hợp cho từng loại phản ứng là không trùng hoàn toàn với các công trình khác cụ thể được mô tả dưới đây:

Phản ứng 1: Ngưng tụ của salicylaldehyde với methyl acetoacetate để tạo thành acetylcoumarin đạt độ chuyển hóa 86% ở 100 oC sau 3 giờ, sử dụng chất lỏng ion [BMIM]Br làm dung môi

3-Phản ứng 2: Ngưng tụ giữa 1,2-phenylenediamine và acetone để tổng hợp benzodiazepine được tiến hành ở nhiệt độ thường có sử dụng chất lỏng ion [HMIM]Br làm dung môi với độ chuyển hóa 100% sau 3 giờ ở 45 oC

1,5-Phản ứng 3: N-aryl hóa giữa piperidine và 4-bromonitrobenzene để tạo 1-

(4-nitrophenyl)piperidine độ chuyển hóa đạt 94% sau 3 giờ ở 90 oC, khi sử dụng [BMIM]Br làm dung môi

Phản ứng 4: Phản ứng giữa 1-(N-morpholino)-chloroethane hydrochloride và methylindole để tạo 1-(2-(N-morpholino)ethyl)-2-methylindole đạt hiệu suất khoảng

2-75% sau 7 giờ Phản ứng được thực hiện trong dung môi [BMIM]PF6 ở 30 oC

Phản ứng 5: Phản ứng Paal-Knorr tổng hợp pyrrole được thực hiện giữa 2,5-hexadione

và amin trong dung môi chất lỏng ion [BMIM]PF6 với độ chuyển hóa đạt 100% trong thời gian 40 phút ở nhiệt độ 30 oC

Page iii

Phản ứng 6: Phản trao đổi halogen giữa aryl iodides và đồng (I) bromide được thực hiện sử dụng [BMIM]Br làm dung môi để tạo thành aryl bromide tương ứng với hiệu suất phản ứng đạt trên 90% sau thời gian 8 giờ ở 140 oC

Ngoài ra, các chất lỏng ion 1-alkyl-3-methyl imidazolium được thu hồi và tái sử dụng nhiều lần cho các phản ứng mà hiệu quả giảm không đáng kể

Các sản phẩm chính thu được trong mỗi phản ứng được xác định cấu trúc qua

MS và NMR

Page iv

ABSTRACT

In this research, 1-alkyl-3-methyl imidazolium bromide ionic liquids were successfully synthesized under microwave conditions After that, 1-alkyl-3-methyl imidazolium hexafluorophosphate [AMIM]PF6 ionic liquid was prepared by anion exchange reaction of dialkylimidazolium bromide with hexafluorophosphoric acids The structural properties of prepared ionic liquids were characterized by using Nuclear Magnetic Resonance (1H, 13C NMR) and Mass Spectrometry (MS) analysis

More interestingly, the results showed that dialkylimidazolium ionic liquid could effectively act as green solvents for coupling reactions, and halogen exchange reaction with high conversion under low temperature and shorter reaction time in comparison with conventional solvents

Some typical results are described below:

Reaction 1 The condensation reaction of salicylaldehyde and methyl acetoacetate formed 3-acetylcoumarin with approximately 86% conversion after 3 hours at 100 °C with, [BMIM]Br ionic liquid as a solvent

Reaction 2 The condensation reaction between 1,2-phenylenediamine and acetone to synthesize 1,5-benzodiazepine could occur at 45 oC with 100% conversion after 3 hours in [HMIM]Br ionic liquid

Reaction 3 The N-aryl reaction between piperidine and 4-bromonitrobenzene to form

1-(4-nitrophenyl) piperidine can reach approximately 94% conversion after 3 hours with [BMIM]Br as a solvent at 90 oC

Reaction 4 1-(2-(N-morpholino)ethyl)-2-methylindole was synthesized by the reaction between 1-(N-morpholino)-2-chloroethane hydrochloride and 2-methylindole formed

with about 75% conversion after 7 hours in [BMIM]PF6 ionic liquid at 30 oC

Reaction 5 Paal-Knorr reaction for synthesis of pyrroles was performed [BMIM]PF6

ionic liquid with 100% conversion after 40 minutes at 30 oC

Reaction 6 Halogen exchange reaction between aryl iodides and copper (I) bromide to form aryl bromide derivatives could reach more than 90% conversion in [BMIM]Br ionic liquid as a solvent after 8 hours at 140 oC

Page v

Interestingly, the recycle of [BMIM]Br ionic liquid was performed The results showed that [BMIM]Br ionic liquid can be recovered and successfully recycled into subsequent reactions without significant loss of activity The main products were identified by GC-MS and NMR

Page vi

ACKNOWLEDGMENT

First and foremost I am deeply grateful to my advisor Prof Dr Nam Phan Thanh Son for his excellent guidance during the work It has been an honor to be his Ph.D student He has taught me, both consciously and unconsciously, how well experimental physics is done I am also thankful to Dr Truong Vu Thanh, who guided

me through my studies with kindness and huge encouragement, especially during a difficult period of studying to complete my thesis

I am indebted to the organic department members including: Dr Le Thi Hong Nhan, Dr Le Thanh Dung, Dr Tong Thanh Danh and PhD student Le Vu Ha, who had accompanied me throughout the process of implementing the thesis Additionally,

I will never forget the support, encouragement and great memories of my colleagues that we had been experienced during working time in the Manar laboratory-University

of Technology, Vietnam National University HCMC

I am especially thankful to my husband, Associate Professor Dr Nguyen Van Cuong for his love and support during my study He is always there for me whenever I need him I am also deeply thankful to my little angels, Nguyen Tuan Thanh and Nguyen Anh Thanh Ngoc for giving me smile and motivation to try myself best to do anything I am extremely grateful to my parents, my sisters and my brothers for their priceless consolation, encouragement and support through my academic work

Last, but not least, I wish to thank to my colleagues, my friends at Ho Chi Minh City University of Food Industry for their supports during the work

Nguyen Thi Hong Anh, 2018

Page vii

TABLE OF CONTENTS

DECLARATION OF ORIGINALITY i

TÓM TẮT LUẬN ÁN ii

ABSTRACT .iv

ACKNOWLEDGMENT vi

TABLE OF CONTENTS vii

LIST OF FIGURES xi

LIST OF SCHEMES xiii

LIST OF TABLES xvi

LIST OF ABBREVIATION xvii

INTRODUCTION xix

CHAPTER 1 LITERATURE REVIEW 1

1.1 IONIC LIQUIDs (ILs) 1

1.1.1 Introduction to ionic liquids 1

1.1.2 Imidazolium ionic liquids 5

1.1.3 Synthesis of Ionic Liquids 6

1.1.4 Properties of ILs 7

1.2 Ionic liquids as solvents 12

1.2.1 Heck reaction 15

1.2.2 Reaction of bromobenzene with butyl acrylate in molten tetraalkylammonium and tetraalkylphosphonium bromide salts (Suzuki reaction)

15

1.2.3 The esterification 16

1.2.4 Transition metal catalysis 17

1.2.5 Alkene hydrogenation reactions 17

1.2.6 Hydroformylation 18

1.2.7 Oxidation 19

1.3 Reactions Literature review 19

1.3.1 Condensative reaction 19

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1.3.2 Carbon-Nitrogen coupling 24

1.3.3 Halogen exchange 34

1.4 AIMS AND OBJECTIVES 39

CHAPTER 2 EXPERIMENTAL 40

2.1 Materials and instrumentation 40

2.2 Synthesis of ionic liquids 42

2.2.1 Preparation of 1-alkyl-3-methylimidazolium bromide 42

2.2.2 Preparation of 1-alkyl-3-methylimidazolium hexafluorophosphate [AMIM]PF6] ILs 44

2.3 Studied Reaction 46

2.3.1 Synthesis of coumarin derivatives 46

2.3.2 Synthesis of 1,5-benzodiazepine derivatives 47

2.3.3 Synthesis of 1-(4-nitrophenyl)piperidine derivatives 48

2.3.4 Synthesis of 1-[2-(N-morpholino)ethyl]-2-methylindole derivatives 49

2.3.5 Synthesis of pyrrole derivatives 50

2.3.6 Halogen exchange reaction 51

CHAPTER 3 RESULTS AND DISCUSSION 53

3.1 The synthesis of ionic liquids 53

3.1.1 The synthesis of [AMIM]Br 53

3.1.1 [AMIM]Br ILs characterization 55

3.1.2 The synthesis of [AMIM]PF6 58

3.1.3 [AMIM]PF6 ILs characterization 60

3.2 Synthesis of coumarin derivatives (Reaction 1) 62

3.2.1 Effect of the alkyl chain length in the cation of ionic liquid on reaction conversion 63

3.2.2 Effect of various anion species of ionic liquid on the reaction conversion

64

3.2.3 Effect of different solvents on the reaction conversion 65

3.2.4 Reusability of [BMIM]Br ionic liquid 67

3.3 Synthesis of 1,5-benzodiazepine derivatives (Reaction 2) 69

3.3.1 Effect of temperature on the reaction conversion 69

3.3.2 Effect of [HMIM]Br concentration on the reaction conversion 70

Page ix

3.3.3 Effect of acetone: 1,2-phenylenediamine molar ratio on the reaction

conversion 71

3.3.4 Effect of different ionic liquid-based catalysts on the reaction conversion

72

3.3.5 Effect of different catalysts on the reaction conversion 73

3.3.6 Reusability of [HMIM]Br ionic liquid for the reaction 74

3.4 Synthesis of 1-(4-nitrophenyl)piperidine derivatives: N-arylation reaction (Reaction 3) 76

3.4.1 Effect of temperature on the reaction conversions 77

3.4.2 Effect of the alkyl chain length in the cation of ionic liquid on the reaction conversion 78

3.4.3 Effect of piperidine: 4-bromonitrobenzene molar ratio on the reaction conversion 79

3.4.4 Effect of solvents on the reaction conversion 80

3.4.5 Effect of the halogen in 4-nitrophenyl halide on the reaction conversion 81 3.4.6 Reusability of Ionic liquid [BMIM]Br 82

3.5 The synthesis of 1-(2-(N-morpholino)ethyl)-2-methylindole derivatives (Reaction 4) 84

3.5.1 Effect of the reaction time 85

3.5.2 Effect of 1-(N-morpholino)-chloroethane hydrochloride : 2-methylindole molar ratio 86

3.5.3 Effect of KOH: 2-methylindole molar ratio 87

3.5.4 Effect of different bases 88

3.5.5 Effect of the reaction temperature 89

3.5.6 Effect of [BMIM]PF6 : 2-methylindole molar ratio 90

3.5.7 Effect of different ionic liquid solvents 91

3.5.8 Solvent [BMIM]PF6 recycling studies 92

3.6 Synthesis of pyrrole derivatives (Reaction 5) 95

3.6.1 The effect of reagent molar ratio 96

3.6.2 The effect of the amount of ionic liquid 96

3.6.3 Effect of the alkyl chain length in the cation of ionic liquid on the reaction conversion 98

3.6.4 The effect of organic solvents 99

Page x

3.6.5 The effect of amines 100

3.6.6 The reusability of [BMIM]PF6 ionic liquid 102

3.7 Halogen exchange reaction (Reaction 6) 105

3.7.1 Effect of time reaction on reaction yield 105

3.7.2 Effect of 4'-iodoacetophenone/copper(I) bromide molar ratios on the reaction yield 106

3.7.3 Effect of temperature on the reaction yield 107

3.7.4 Effect of solvents on the reaction yield 108

3.7.5 Effect of different catalysts on the reaction yield 109

3.7.6 Effect of aryl halide substituents on the reaction yield 110

3.7.7 Reusability of [BMIM]Br ionic liquid 111

CONCLUSIONS AND FUTURE WORK 115

REFERENCES 119

LIST OF PUBLICATIONS 135

APPENDICES 136

Page xi

LIST OF FIGURES

Figure 1-1 Chemical structures of cations in ionic liquids [22, 23] 3

Figure 1-2 Applications of ionic liquids [29] 4

Figure 1-3 Structure of 1-alkyl-3-methylimidazolium-based ionic liquids[4, 30] 5

Figure 1-4 Typical procedure for synthesis of 1-alkyl-3-methylimidazolium-based ionic liquids [33] 6

Figure 1-5 Normalised solvent polarity scale (ET(30) = 0.00 for Me4Si and ET(30) = 1.00 for H2O)—reproduced from [58] 15

Figure 1-6 Top pharmaceuticals containing chloride and fluoride functional groups [145] 34

Figure 2-1 The synthesis of 1-alkyl-3- methylimidazolium bromide 43

Figure 2-2 The synthetic procedure of 1-alkyl-3- methylimidazolium hexafluorophosphate ionic liquids 45

Figure 3-1 The yield of synthetic process of [AMIM]Br ILs 54

Figure 3-2 The structure of [BMIM]Br IL 56

Figure 3-3 The structure of [HMIM]Br IL 57

Figure 3-4 The structure of [OMIM]Br IL 57

Figure 3-5 The yield of synthetic process of [AMIM]PF6 ILs 59

Figure 3-6 The structure of [BMIM]PF6 IL 60

Figure 3-7 The structure of [HMIM]PF6 IL 61

Figure 3-8 The structure of [OMIM]PF6 IL 61

Figure 3-9 Effect of the alkyl chain length in the cation of ionic liquid on the reaction conversion 64

Figure 3-10 Effect of different anion species of ionic liquid on reaction conversion 65

Figure 3-11 Effect of different solvents on the reaction conversion 66

Figure 3-12 Reusability of [BMIM]Br ionic liquid 67

Figure 3-13 The structure of 3-acetylcoumarin 68

Figure 3-14 Effect of the temperature on the reaction conversion 69

Figure 3-15 Effect of [HMIM]Br concentration on the reaction conversion 70

Figure 3-16 Effect of acetone:1,2-phenylenediamine molar ratio on the reaction conversion 71

Figure 3-17 Effect of different ionic liquid on reaction conversion 72

Figure 3-18 Effect of different catalysts on reaction conversion 73

Figure 3-19 Reusability of [HMIM]Br ionic liquid as catalyst for reaction of 1,2-phenylenediamine with acetone to form 1,5-benzodiazepine 75

Figure 3-20 The structure of 1,5-benzodiazepine derivatives 76

Figure 3-21 Effect of temperature on the reaction conversion 78

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Figure 3-22 Effect of the length of the alkyl chain in 1-alkyl-3-methylimidazolium

bromide ionic liquid on reaction conversion 79

Figure 3-23 Effect of piperidine: 4-bromonitrobenzene molar ratio on the reaction conversion 80

Figure 3-24 Effect of solvents on the reaction conversion 81

Figure 3-25 Effect of the halogen in 4-nitrophenyl halide on the reaction conversion 82 Figure 3-26 Ionic liquid recycling study for the N-arylation reaction between piperidine and 4-bromonitrobenzene 83

Figure 3-27 The structure of 1-(4-nitrophenyl)piperidine 84

Figure 3-28 Effect of reaction time on the product yield 86

Figure 3-29 Effect of 1-(N-morpholino)-2-chloroethane hydrochloride: 2-methylindole molar ratio 87

Figure 3-30 Effect of KOH: 2-methylindole molar ratio 88

Figure 3-31 Effect of different bases to reaction yield of N-alkylation of indole 89

Figure 3-32 Effect of reaction temperature 90

Figure 3-33 Effect of [BMIM]PF6: 2-methylindole molar ratio 91

Figure 3-34 Effect of different ionic liquid solvents 92

Figure 3-35 Solvent recycling studies 92

Figure 3-36 The structure of 1-(2-(N-morpholino)ethyl)-2-methylindole 94

Figure 3-37 The effect of reagent molar ratio on the Paal Knorr reaction conversion 96 Figure 3-38 The influence of the used amount of ionic liquid 97

Figure 3-39 The influence of some kinds of ionic liquids on the reaction conversion 98 Figure 3-40 The effect of other organic solvents on the reaction conversion 100

Figure 3-41 Effect of temperature on the reaction conversions of 4-methoxyaniline as amine 101

Figure 3-42 The reusability of ionic liquid 103

Figure 3-43 The structures of pyrrole derivatives 104

Figure 3-44 Effect of the reaction time on yield of 4'-bromoacetophenone reaction 106 Figure 3-45 Effect of molar ratio between 4'-iodoacetophenone/CuBr on the reaction yield 107

Figure 3-46 Effect of temperature on reaction yield 108

Figure 3-47 Effect of solvents on reaction yield 109

Figure 3-48 Effect of catalysts on the reaction yield 110

Figure 3-49 Reusability of [BMIM]Br ionic liquid 112

Page xiii

LIST OF SCHEMES

Scheme 1-1 Pd-catalyzed Heck reaction in ionic liquid [60] 15Scheme 1-2 Pd-catalyzed Suzuki cross-coupling reaction in a [BMIM]BF4 ionic liquid [61] 16Scheme 1-3 Brønsted acidic ionic liquid 1-methylimidazolium tetrafluoroborate: a green catalyst and recyclable medium for esterification [62] 16Scheme 1-4 Biphasic hydrogenation of 1-pentene with the cationic “Osborn complex” [Rh(nbd)(PPh3)2][PF6] (nbd = norbornadiene) in ionic liquids with weakly coordinating anions [67] 18Scheme 1-5 The reaction of styrene with H2O2 in ionic liquids [70] 19Scheme 1-6 The reaction between β-ketoester phloroglucinol in ILS [85] 20Scheme 1-7 The reaction of phenol derivatives with ethyl acetoacetate under the catalyst Sm (NO3)3.6H2O [88] 21Scheme 1-8 The reaction between β-ketoesters and phenol derivatives under the catalytic Lewis ZrOCl2.8H2O/SiO2 [83] 21Scheme 1-9 The reaction between substituted salicylaldehyde and 4-hydroxy-6-

methyl-2H-pyran-2-one [89] 21

Scheme 1-10Reaction oxidative acylation/cyclization between alkynoates with aldehydes [90] 22Scheme 1-11Synthesis of coumarin derivatives from phenolic acetates and acrylates via C–H bond activation [91] 22Scheme 1-12Condensation of α-aroylketene dithioacetals and 2-hydroxyarylaldehydes [92] 22Scheme 1-13Synthesis of 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones [100] 23Scheme 1-14Synthesis of 2,3-dihydro-1-H-1,5-benzodiazepine from o-

phenylenediamine and acetophenone [101] 23Scheme 1-15Pd catalyst based on two biarylphosphine ligands for C−N cross-coupling reactions [116] 25Scheme 1-16Mechanism Buchwald-Hartwig reaction [116] 25Scheme 1-17Ullmann amination of aryl halides with aqueous methylamine [119] 26Scheme 1-18CuI/Oxalic diamide catalyzed coupling reaction of (hetero)aryl chlorides and amines[120] 26

Page xiv

Scheme 1-19Mechanism of Paal-Knorr reaction [125, 126] 27

Scheme 1-20Microwave assisted synthesis of pyrrole [127] 28

Scheme 1-21Paal-knorr catalyzed by zeolite [130] 29

Scheme 1-22Reaction between α-amino carbonyl compounds and aldehydes with I2 -catalyst [131] 30

Scheme 1-23Cyclization of α-propargyl-β-keto esters with Indium-catalyst [132] 31

Scheme 1-24Iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes [133] 31

Scheme 1-25Mechanism of nucleophilic substitution SN2 [134] 31

Scheme 1-26Nucleophilic substitution reaction of naphthalene derivatives and nucleophiles in ionic liquids [135] 32

Scheme 1-27Nucleophilic hydroxylation in water media promoted by a hexa-ethylene glycol-bridged dicationic ionic liquid [136] 32

Scheme 1-28N-Alkylation of heterocyclic compounds [140] 33

Scheme 1-29Coupling terminal acetylenes with N,N-dialkyl-o-iodoanilines in the presence of a Pd/Cu catalyst [141] 33

Scheme 1-30Metal-mediated halogen exchange of aryl halides 35

Scheme 1-31Halogenation with N-halosuccinimide and gold(III) catalyst [155] 36

Scheme 1-32Conversion of aryl triflates into aryl fluorides [156] 36

Scheme 1-33Conversion of aryl triflates into aryl chlorides and bromides [149] 36

Scheme 1-34Halogen exchange with phase-transfer catalyst 37

Scheme 1-35Fluorination by halide exchange with ruthenium(II) complex [153] 37

Scheme 1-36Halide exchange of aryl halides using nickel(II) salts [161] 38

Scheme 1-37Copper-mediated halogen exchange of aryl halides [162] 38

Scheme 2-1 The synthesis of 1-alkyl-3-methylimidazolium bromide 43

Scheme 2-2 The formation of 1-alkyl-3-methylimidazolium hexafluorophosphate by anion metathesis 44

Scheme 2-3 Synthesis of coumarin from salicylaldehyde and methyl acetoacetate 46

Scheme 2-4 The cyclocondensation reaction of 1,2-phenylenediamine with acetone to form 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine 47

Scheme 2-5 The N-arylation between 4-bromonitrobenzenes and heterocyclic amines in ionic liquids 48

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Scheme 2-6 The reaction between 1-(N-morpholino)-2-chloroethane hydrochloride

and 2-methylindole in the [BMIM]PF6 ionic liquid 49Scheme 2-7 The reaction between 2,5-hexadione and amine in the [BMIM]PF6 ionic liquid 50Scheme 2-8 Reaction between 4'-iodoacetophenoneand copper(I) bromide 51Scheme 3-1 Catalyst-free synthesis of coumarin derivatives from 5-substituted salicylaldehydes and active methylene compounds 62Scheme 3-2 The cyclocondensation reactions of 1,2-phenylenediamine with ketones

to form 1,5-benzodiazepine derivatives using solvent 1,3-dialkylimidazolium-based ionic liquid as catalyst 69Scheme 3-3 The N-arylation between 4-halonitrobenzenes and piperidine in ionic

liquids 76Scheme 3-4 Possible mechanism for the formation of 1-(4-nitrophenyl)piperidine derivative reaction 84Scheme 3-5 The reaction between 1-(N-morpholino)-2-chloroethane hydrochloride

and 2-methylindole in the [BMIM]PF6 ionic liquid 85Scheme 3-6 The Paal-Knorr cyclocondensation between 2,5-hexanedione and amines

in ionic liquids 95Scheme 3-7 The halogen exchange reactions 105Scheme 3-8 Possible mechanism for the halogen exchange reaction 114

Page xvi

LIST OF TABLES

Table 1-1 Comparison of properties of ionic liquids with organic solvents [20, 21] 2

Table 1-2 Melting points (°C) and thermochemical radii of the anions (Å) for Na+ and [EMIM]+ salts The ionic radii of the cations are 1.2 Å (Na+) and 2 x 2.7 Å ([EMIM]+, non-spherical) [38] 8

Table 1-3 Melting points for isomeric [BMIM]PF6 and [PMIM]PF6 ionic liquids, with various degree of branching in the alkyl substituent [38] 9

Table 1-4 Comparison of the viscosity of chloride-contaminated and low chloride content in ionic liquids at 20 oC [36] 9

Table 1-5 The ultrasound-assisted synthesis of substituted pyrroles in the presence of ZrCl4 under solvent-free condition [128] 28

Table 1-6 Comparison of the yield of various Pyrrole derivatives over different zeolites [130] 29

Table 1-7 Paal–Knorr reaction of acetonylacetone and aniline under different reaction conditions [130] 30

Table 1-8 Bond dissociation energies of aryl halides [151] 35

Table 3-1 The yield of [AMIM]Br synthesis 55

Table 3-2 The yield of synthetic process of [AMIM]PF6 58

Table 3-3 The suitable synthetic conditions for preparation of coumarins 68

Table 3-4 The reaction conversions of the optimized synthetic conditions for predation of 1,5-benzodiazepines 75

Table 3-5 The reaction conversions of the optimized synthetic conditions for N-arylation reaction 83

Table 3-6 The reaction yield of the suitable synthetic conditions for reaction 93

Table 3-7 Reaction of 2,5-hexanedione with amines 102

Table 3-8 The reaction conversions of the optimized synthetic conditions for reaction 103

Table 3-9 Yields of some halide derivativesa 111

Table 3-10 The reaction yield of the optimized synthetic conditions for reaction 112

Page xvii

LIST OF ABBREVIATION

[AMIM]Br : 1-alkyl-3-methylimidazolium bromide

[AMIM]PF6 : 1-alkyl-3-methylimidazolium hexafluorophosphate

[BMIM][BF4] : 1-n-butyl-3-methylimidazolium tetrafluoroborate

[C4C1IM]BF4 : 1-butyl-3-methylimidazolium tetrafluoroborate

[C4C1IM]PF6 : 1-butyl-3-methylimidazolium hexafluorophosphate

[C4MIM]X : 1-n-butyl-3-methylimidazolium salts

[PMIM]PF6 : 1-propyl-3-methylimidazolium hexafluorophosphate

IL-1 ([BMIM]Br) : 1-butyl-3-methylimidazolium bromide

IL-2 ([HMIM]Br) : 1-hexyl-3-methylimidazolium bromide

IL-3 ([OMIM]Br) : 1-octyl-3-methylimidazolium bromide

IL-4 ([BMIM]PF6) : 1-butyl-3-methylimidazolium hexafluorophosphate

IL-5 ([HMIM]PF6) : 1-hexyl-3-methylimidazolium hexafluorophosphate

IL-6 ([OMIM]PF6) : 1-octyl-3-methylimidazolium hexafluorophosphate

In(NTf2)3 : Indium(III) tris(trifluoromethanesulfonimide)

In(Otf)3 : Indium(III) trifluoromethanesulfonate

NSAIDs : Non-steroidal antiinflammtory drugs

Pd(dppf) : 1,1-Bis(diphenylphosphino)ferrocene]palladium(II) complex

Page xviii

Reaction 1 : Synthesis of coumarin derivatives reaction

Reaction 2 : Synthesis 1,5-benzodiazepine derivatives reaction

Reaction 3 : Synthesis of 1-(4-nitrophenyl)piperidine derivatives:

N-arylation reaction Reaction 4 : The synthesis of 1-(2-(N-morpholino)ethyl)-2-methylindole

derivatives reaction Reaction 5 : Synthesis of pyrrole derivatives reaction

Reaction 6 : Halogen exchange reaction

scCO2 : Supercritical carbon dioxide

SNAr : Nucleophilic aromatic substitution reaction

TSILs : Task-specific ionic liquids

ET(30)-Values : Empirical parameters of solvent polarity

IC50 : The half maximal inhibitory concentration

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INTRODUCTION

The field of ionic liquids (ILs) has been investigated by a great number of authors for the past some decades, and the increase in number of publications can be attributed to their unique properties such as the ease of product separation, the reduction of emission of toxic compounds, the facilitation of catalyst recovery and reuse [1] Especially, the synthesis of ILs with the support of microwave has attained not only faster reaction rate but also higher yield as well [1, 2]

Ionic liquids based on the imidazolium cation, have emerged as an attractive alternative to conventional solvents in organic synthesis due to their unique properties such as good solvating ability, tunable polarity, high thermal stability, negligible vapor pressure, and easy recyclability Up to now, numerous chemical reactions, such as polymerization, hydrogenation, regioselective alkylation, Friedel–Crafts reactions, Diels–Alder reactions, cross-coupling reactions and some enzymatic reactions can be carried out in imidazolium-based ionic liquids [3-8]

In this thesis, we wish to report the coupling reactions C-N with mild conditions and

high conversions such as N-arylation reaction, synthesis of imines, Paal-Knorr

reaction, cycloconsendation reaction for synthesis of coumarin, synthesis of benzodiazepine and the reaction of halogen exchange using 1,3-dialkylimidazolium-based as solvent More interesting, the ionic liquid could be recycled and reused several times without a significant degradation in performance

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1.1 IONIC LIQUIDs (ILs)

1.1.1 Introduction to ionic liquids

Ionic liquids (ILs) have been played extensive roles in the fields of synthesis, catalysis, extraction, electrochemistry, etc Welton reported that ILs are not new, and some of the ILs such as [EtNH3][NO3] was first described in

1914 [9, 10] Until the 1970s and 1980s, ionic liquids obtained through the mixing of alkyl-substituted imidazolium and pyridinium cations with halide/trihalogenoaluminate anions were initially developed for use as electrolytes in battery applications [11, 12] Additionally, the imidazolium halogenaluminate salts have important physical properties, such as viscosity, melting point, and acidity adjusted by changing the alkyl substituent and the imidazolium(pyridinium)/halide (halogenoaluminate) ratios [13] However, two major drawbacks for applications of ILs were moisture sensitivity and acidity/basicity In 1992, Wilkes and Zaworotko obtained ionic liquids with weakly neutral coordinating anions such as hexafluorophosphate (PF6-) and tetrafluoroborate (BF4-), opening up a renaissance of the rich chemistry of molten salts and the much wider range of their applications [14] Recently, the combination of the cation 1-ethyl-3-methylimidazolium and the smaller anion tetrachloroaluminate to form 1-ethyl-3-methylimidazolium tetrachloroaluminate and the related alkylhalogenoaluminate(III) ionic liquids had been widely studied

by the time 2001 As 2004, 1,3-dialkyl imidazolium salts were the most popular and investigated classes of room temperature ionic liquids [15, 16]

ILs are a subset of molten salts with melting points (Tm) below 373 oK

In Walden’s original paper on The European Article Numbering system, he described a class of materials as “water-free salts” which melt at relatively low temperatures, about up to 100 °C [17] With the continuous efforts of some chemists, ILs have not only become increasingly popular as an extraction media

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but also widely as “green solvents”, which are regarded as powerful alternatives

to the volatile organic compounds (VOCs) in the field of organic synthesis Furthermore, the task-specific ionic liquids (TSILs) where a functional group is covalently tethered to the cation or anion (or both) of the ionic liquid, are the latest generation of ionic liquids The incorporation of this functionality should imbue the ionic liquid with a capacity not only as a reaction media but also as a reagent or catalyst in some reactions or processes [18] The environmental interest has centered on the usage of ionic liquids as “greener” alternatives to volatile organic solvents The ionic liquids have been attractive as potential solvents due to they exhibit very low vapor pressures under ambient conditions and thus are non-volatile solvents [19] Due to the application as green solvents for many reactions, ionic liquids have also become effective catalysts, co-catalysts, ligand sources and other industrial applications with more advantages

in comparison with conventional solvents

Table 1-1 Comparison of properties of ionic liquids with organic solvents [20,

Catalytic ability Common and tunable Rare

Vapor pressure Negligible under normal

condition

Obeys the Clapeyron Equation Flammability Usually nonflammable Usually flammable

Clausius-Solvation Strongly solvating Weakly solvating

Tunability Unlimited range means

times greater than ILs

Normally inexpensive

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Properties Organic solvents Ionic liquids

Recyclability Economic imperative Green imperative

CF3CO2 , CF3SO3 , and CH3SO3  [22, 23]

Cation:

Figure 1-1 Chemical structures of cations in ionic liquids [22, 23]

Nowadays, ionic liquids are interdisciplinary tools for chemists, physicists, biologists, engineers, and simulators using them to tackle important scientific problems This has been spurred by green chemistry movement due to ionic liquid solvents can be integrated into existing systems [24]

Room temperature ionic liquids are generated by the use of bulk organic cations associated with inorganic or organic anions [25] Additionally, the fact that many ionic liquids can be synthesized by a suitable combination of anions and cations This unlimited range means ionic liquids being described as

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“designer solvents”[26] Their properties can be adjusted and controlled by suitable choice of cations and anion ILs exhibit many properties which make them potentially attractive media for homogeneous catalysis such as [27]:

 No vapor pressure which facilitates product separation by distillation

 Reasonable thermal stability

 Ability to dissolve a wide range of organic, inorganic and organometallic compounds

 The attractive solvents for catalytic hydrogenations, carbonylations, hydroformylations, and aerobic oxidations with H2, CO and O2

 Immiscibility in some organic solvents, e.g alkanes, and, hence, can be used in two-phase systems

 Polarity and hydrophilicity/lipophilicity can be readily adjusted by changing cation/anion and thus ILs have been referred as ‘designer solvents’ [28]

 Chloroaluminate ions-based ILs are usually strong Lewis, Franklin and Bronsted acids that can replace for hazardous acids such as HF in several acid-catalyzed reactions

 Almost ILs can be preserved for a long time without decomposition

Figure 1-2 Applications of ionic liquids [29]

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1.1.2 Imidazolium ionic liquids

Figure 1-3 Structure of 1-alkyl-3-methylimidazolium-based ionic liquids[4, 30]

The first ILs, such as organo-aluminate ILs, have a limited range of applications because they were unstable to air and water Furthermore, these ILs were not inert towards various organic compounds [16] After the first reports on

the synthesis and applications of air stable ILs such as

1-n-butyl-3-methlyimidazolium tetrafluoroborate ([BMIM]BF4) and

1-n-butyl-3-methlyimidazolium hexafluorophosphate ([BMIM]PF6), the number of air and water stable ILs have started to increase rapidly

Researchers have discovered that ILs are more than just green solvents They have found several applications such as replacing them with volatile organic solvents, making new materials, effective heat conducting , support for enzyme-catalyzed reactions, host for a variety of catalysts, purification of gases, homogenous and heterogeneous catalysis, biological reactions media and removal of metal ions [30] The number of researches on ILs and their specific

(Possible π-stacking)

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applications are increasing rapidly in the literature For example, the methylimidazolium cation has been the most widely studied until 2001 Nowadays, 1,3-dialkyl imidazolium salts are the most popularly used and investigated class of ILs The asymmetric 1,3-dialkylimidazolium salts are the most intensively investigated to start generating a low-melting salt of any particular anion [19, 31, 32]

1-ethyl-3-1.1.3 Synthesis of Ionic Liquids

1.1.3.1 Standard route to 1-alkyl-3-methylimidazolium-based ionic liquids

The most common reactions for synthesis of almost ionic liquids were via salt metathesis reactions However, attempts to a great challenge in the synthesis

of high purity ILs had led to the continuous development in new synthetic routes and purification procedures

Figure 1-4 shows the most widely procedure for preparation of ionic liquids, by taking 1-alkyl-3-methylimidazolium-based ionic liquids as an example Similarly, other types of cations, notably pyridinium systems could be prepared through this process

Figure 1-4 Typical procedure for synthesis of

1-alkyl-3-methylimidazolium-based ionic liquids [33]

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1.1.3.2 Microwave-assisted preparation of ILs

In comparison with the preparation of ILs using conventional heating (oil bath at 80 oC), the similar synthesis was carried out using microwave (MW) irradiation under solvent-free conditions Interestingly, the result reported that MW-assisted chemical process offered favorable features in contrast to the limitation in the conventional approach Particularly, the reaction required only a few minutes to afford reasonable yield while the conventional heat needed several hours to take place Another noticeable advantage of the microwave supported method was the use of only stoichiometric amount of reactants under solvent-free condition in comparison to a large excess of alkyl halides/organic solvents in the conventional heat [34] Additionally, the purity of products from MW-assisted method is higher than that of conventional one However, to overcome the drawbacks that the reaction occurred in the opened container, Khadilkar and Rebeiro investigated a new method using a closed pressure reactor [35]

1.1.4 Properties of ILs

It is critical to pay much attention to the purification of ILs in order to avoid the possible interactions between reactants and impurities and to prevent the nature of these solvents from altering [36] ILs possess a unique range of physico-chemical properties such as such as negligible vapor pressure, large liquidus range, high thermal stability, high ionic conductivity, large electrochemical window, and ability to solvate compounds of widely varying polarity However, several described properties are now subjected to controversy: e.g electrochemical window, long-term thermal stability, polarity and volatility under certain conditions [37] Bulk physical and chemical properties of ILs will

be discussed in the following part

1.1.4.1 Melting point

Melting point is a very important property of ILs because ILs have a large liquids range determined by their low melting points as well as high decomposition

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points, and the solubility of ILs in water or organic solvents is strongly correlated with their melting points Melting point of ILs is governed by van der Waals forces and electrostatic interaction force and the impact of the two forces play different roles on different kinds of ILs They have relatively low melting points, ideally below the ambient temperature due to bulky organic cations in ionic liquids It was illustrated in Table 1-2 that the reduction in melting points can be approached by enhancing the size of the anion, or that of the cation

Table 1-2 Melting points (°C) and thermochemical radii of the anions (Å) for

Na+ and [EMIM]+ salts The ionic radii of the cations are 1.2 Å (Na+) and 2 x 2.7

In addition, the symmetry of the ions remarkably influences on the melting points

of correspondent ILs To be more specific, raising the symmetry in the ions increases the ion–ion packing in the crystal cell leading to an increase in the melting point On the contrary, low-symmetric ions distort the Coulombic charge distribution causing the reducing of melting points It can be explained that the ionic liquids containing large asymmetric cations have low melting points Another factor makes the difference in melting point is the degree of branching Table 1-3 illustrates that the melting point increases with the increasing the degree of chain branching for alkyl chain in imidazolium [38]

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Table 1-3 Melting points for isomeric [BMIM]PF6 and [PMIM]PF6 ionic liquids,

with various degree of branching in the alkyl substituent [38]

ILs have higher viscosity than those of conventional organic solvents It

is similar to viscosity of oils and the viscosity of ILs depends on several factors such as van der Waals interactions and H bonding It was observed that the viscosity of ILs decreased with increasing the temperature, but remained unchanged with increasing shear rate [39-41] Moreover, small amounts of impurities in the ionic liquids have a dramatical impact on the viscosity For example, the presence of even low concentrations of chloride in the ionic liquids substantially increased the viscosity [36]

Table 1-4 Comparison of the viscosity of chloride-contaminated and low

chloride content in ionic liquids at 20 oC [36]

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imidazolium cation ring [42]

It was noted that in a series of non-haloaluminate ILs with the same cation, an alteration in the anion strongly affected the viscosity The increasing viscosity along with the change of anion is in the following order: [(CF3SO2)2N]– ≤ [BF4]– ≤ [CF3CO2]– ≤ [CF3SO3] – ≤ [(C2H5SO2)2N]– ≤ [C3F7CO2]– ≤ [CH3CO2]– ≤ [CH3SO3]– ≤ [C4F9SO3]– [25] In case of the same anion with different type of cations, the larger alkyl substituents on the imidazolium cation lead to higher viscous fluids For example, the increasing viscosity for the non-haloaluminate ionic liquids composed of substituted imidazolium cations and the bis-trifyl imide anion is in the order: [EMIM]+, [EEIM]+, [BEIM]+, [BMIM]+, [PMMIM]+, [EMMIM]+ Additionally, the highly asymmetric alkyl substitution of the cation also has been recognized as essential for reducing viscosities [43]

1.1.4.3 Solubility and solvation

According to the solvatochromatic studies, the polarities of ILs are similar to those of short-chain alcohols and other polar, aprotic solvents such as DMSO, DMF, etc The miscibility of ILs with water can be varied by changing the nature of the anion, temperature and the length of the alkyl chain on the imidazolium cation For example, the length of alkyl chain, [HMIM]PF6, shows a low solubility in water even at 25 oC but 1,3-dimethylimidazolium hexafluoro- phosphate is water soluble [39, 40] It is also noted that ILs are not water-soluble but appeared to adsorb water from the atmosphere through the H-bonding between water molecule and [PF6]-, [BF4]-, [SbF6]-, [ClO4]-, [CF3SO3]- and [Tf2N]- To be more specific, most of the water molecule should exist in symmetrical 1:2 type H-bonded complexes: anion∙∙∙HOH∙∙∙anion with the increasing strength of H-bonding between anion and water in the order of [PF6]-

< [SbF6]- < [BF4]- < [Tf2N]- < [ClO4]- < [NO3]- < [CF3CO2]- [44]

The two-phase systems or biphasic systems composed of two immiscible phases are clean alternatives for traditional organic–organic solvent extraction

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systems By acquiring the knowledge of the miscibility and immiscibility of ILs with other solvents compatible with the separation process in two-phase systems can be approached The most usually IL/aqueous biphasic systems in which the

IL is the less polar phase and organic/IL systems in which the IL is used as the polar phase In these two-phase systems, extraction both to and from the IL phase

is important [25] Also, it can be concluded from a set of general observations:

(i) Simple ionic compounds are generally poorly soluble in ILs

(ii) Ionic complexes are more soluble

(iii) Compounds are solubilized by complexation

(iv) The peripheral environments of the ligands are important in affecting the solubility, and can be modified to provide better solubility [25]

1.1.4.4 Thermal stability

Thermal stability is strongly dependent on the structure of ILs For certain ions, it also depended on the sample pan composition Most ILs are reported to have high thermal stability with a liquid range of up to more than 400 oC For example, 1-ethyl-3-methylimidazolium tetrafluoroborate is stable to about 300 oC and [(CF3SO2)2N] (m.p -3 oC) is stable up to even more than 400 oC It is concluded that the thermal decomposition stays unchanged with different cations but decrease with increasing of the anion hydrophilicity The thermal stability dependence on the anion is [PF6]- > [Tf2N]-

; [BF4]- > halide [20] Additionally, the thermal stability of ILs showed that high decomposition temperatures do not imply long-term thermal stability [21] For example, The mass loss can be observed with 1-alkyl-3-methylimidazolium hexafluorophosphate and 1-decyl-3-methyl-imidazolium triflate after 10 h, at decomposition temperature of 200 oC [44]

1.1.4.5 Polarity

Polarity of chemicals is commonly used to classify the solvents The terms used as polar, nonpolar and apolar are generally related to the values of dielectric constants, dipole moments, polarizabilities [30] The polarity of ILs can be

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measured with solvatochromic dyes, Reichardt’s dye, and Nile Red Since the polarity is the simplest indicator of solvent strength, researchers compared polarities of ILs and conventional solvents Carmichael and Seddon showed that 1-alkyl-3-methylimidazolium ILs with anions [PF6], [BF4], [(CF3SO2)2N], and [NO3] are in the same polarity region as 2-aminoethanol and low alcohols (methanol, ethanol and butanol) [45] As regard to ILs with short alkyl chain, variations in polarities were much affected by anions In contrast, the polarity of ILs with long alkyl chain was more affected by cations For example, polarities

of 1-butyl-3-methylimidazolium ILs decreased in order: [NO2]- > [NO3]- > [BF4]

-> [NTf2]- > [PF6]- Additionally, it was also noted that the presence of HO- or ROgroup in the alkyl chain could make the polarity varied in the wide range [44]

-1.1.4.6 Surface tension

Surface tension of ILs is considered as an important property due to the fact that ILs were widely used in catalyzed reactions under multiphase homogeneous conditions, these reactions are believed to occur at the interface between the IL and the overlying organic phase In general, these liquid/air surface tension values are somewhat higher than those of conventional solvents

As a result, the rate of these processes depends on the surface tension Several factors influenced the surface tension values are varied with temperature and the different alkyl chain length For example, the surface tension decreases with an increase in the alkyl chain length Generally, for a fixed cation, the compound with the larger anion has the higher surface tension [21] However, alkylimidazolium [PF6]- salts have higher surface tensions than the corresponding [Tf2N]- salts

1.2 Ionic liquids as solvents

A majority of common solvents have potential health hazards although they are extensively utilized For example, approximately half of 189 hazardous air pollutants regulated by Clean Air Act Amendment of U.S (1990) are VOCs including solvents such as dichloromethane [46] The VOCs are the workhorses

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of industrial chemistry in the pharmaceutical and petrochemical areas [47] The physical and chemical properties of ILs are varied by changing the alkyl chain length on the cation and the anion types For example, Huddleston et al [39] concluded that the density of ILs increases with a decrease in the alkyl chain length on the cation and an increase in the molecular weight of the anion The composition and the specific properties of these liquids depend on the type of cation and anion in the IL structure By combining various kinds of cation and anion structures, it is estimated that 1018 ILs can be designed [30, 44]

The unique properties of ILs and the ability to design their properties by choice of anion, cation and substituents create many more processing options, alternative to the ones of conventional solvents The most important advantage of the use of these ionic liquids as solvents was the facile separation of the products from the reaction by simple decanting (in most of the cases) and the recovered ionic catalyst solution

Moreover, in various cases, ionic liquids have been shown to promote reactions which are difficult or do not occur in conventional organic solvents For chemical reactions carried out in conventional solvents, the solvent must be isolated from the products by evaporation In addition, there are some chemicals that can decompose under high temperature of heating Therefore, ILs seem to be potentially good solvents for many chemical reactions in the cases where distillation is not practical, or water insoluble or thermally sensitive products are the components of a chemical reaction Although, ILs are not considered to be

distilled due to their low volatility, Earle et al [37] showed that many ionic

liquids, especially bistriflamide ILs, can be distilled at 200–300 oC and low pressure without decomposition

A solvent is generally characterized by macroscopic physical constants

“bulk properties” such as vapor pressure, boiling point, density, cohesive pressure, relative permittivity e.g “dielectric constants”, surface tension, refractive index The large number of studies have been devoted to the characterization of ILs “bulk”

As solvents, ILs posses several advantages over conventional organic solvents,

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which make them environmentally compatible [10, 48-55]:

ILs have the ability to dissolve many different organic, inorganic and organometallic materials

ILs are highly polar

ILs consist of loosely coordinating bulky ions

ILs do not evaporate since they have very low vapor pressures

ILs are thermally stable, approximately up to 300 oC

Most of ILs have a liquid window of up to 200 oC which enables wide kinetic control

ILs have high thermal conductivity and a large electrochemical window ILs are immiscible with many organic solvents

ILs are nonaqueous polar alternatives for phase transfer processes

The solvent properties of ILs can be tuned for a specific application by varying the anion cation combinations

The polarity is one of the most important properties for characterizing the solvent effect in chemical reactions [56] It is also the property which has probably been the most widely discussed in the case of ILs There is no single parameter and direct measurement that can characterize the IL polarity The difficulty in the case of ILs is to find a suitable soluble probe which measures the polarity parameters as independently as possible of the other influences of the solvent [57, 58] This is probably the scale that has been applied to the greatest number of ILs [57, 59]

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Figure 1-5 Normalised solvent polarity scale (ET(30) = 0.00 for Me4Si and

ET(30) = 1.00 for H2O)—reproduced from [58]

1.2.1 Heck reaction

The first example of Heck reaction in ionic liquid was reported by

Kaufmann et al in 1996 [60] Butyl trans-cinnamate was produced in high yield

by reaction of bromobenzene with butyl acrylate in molten tetraalkylammonium and tetraalkylphosphonium bromide salts No formation of palladium metal was observed and the product was obtained by distillation from the ionic liquid (Scheme 1-1)

Scheme 1-1 Pd-catalyzed Heck reaction in ionic liquid [60]

tetraalkylammonium and tetraalkylphosphonium bromide salts (Suzuki reaction)

Suzuki cross-coupling reactions using Pd(PPh3)4 as catalyst in

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[BMIM]BF4 have been reported by Mathews and co-workers [61] The best suitable conditions were achieved by pre-heating the aryl halide to 110 °C in the ionic liquid with the Pd-complex The arylboronic acid and Na2CO3 were later added to start the reaction Several advantages over the reaction as performed under the conventional Suzuki conditions were described This work has clearly shown that ionic liquid offers a significantly enhanced activity in formation of the homo-coupling aryl by-product Moreover, the ionic catalyst layer could be reused after extraction of the products with ether and removal of the by-products (NaHCO3 and NaXB(OH)2) with excess water No deactivation was observed with this procedure over three further reaction cycles

Scheme 1-2 Pd-catalyzed Suzuki cross-coupling reaction in a [BMIM]BF4

ionic liquid [61]

1.2.3 The esterification

As known, it is very difficult to recycle the liquid inorganic acid catalysts which need to be neutralized after the reaction Moreover, large amounts of volatile organic solvents and liquid inorganic acids cause the pollution when discharge to the environment Consequently, a Brønsted acidic ionic liquid, 1-methylimidazolium tetrafluoroborate ([HMIM]BF4) was used as a recyclable catalyst and solvent in the esterification of carboxylic acids with alcohols, for example [62] Recently, the heteropoly anion-based Brønsted acidic ionic liquids were successfully prepared for esterification of oleic acid for biodiesel application

Scheme 1-3 Brønsted acidic ionic liquid 1-methylimidazolium

tetrafluoroborate: a green catalyst and recyclable medium for esterification [62]

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1.2.4 Transition metal catalysis

The use of ILs as versatile solvent/catalysts could overcome disadvantages

of solid catalysts For instance, some acidic ILs are prepared by the reaction of

neutral nucleophiles n-butyl imidazole or triphenylphosphine with

1,4-butanesultone or 1,3-propanesultone, respectively The usage of these ILs provided a good product selectivity as well as reaction yields and the ease of catalyst/substrate separation Moreover, ILs can dissolve many organic and inorganic substrates and they also readily recycled [63] Additionally, ILs that exhibited both as solvent and as co-catalyst in transition metal catalysis were formed by treatment of a halide salt with a Lewis acid (such as chloroaluminate

or chlorostannate melts) This could be explained that the Lewis acidity or basicity, which was always present (at least latently), resulted in strong interactions with the catalyst complex It was noted that the Lewis acidity of an ionic liquid was used to convert the neutral catalyst precursor into the corresponding cationic active form For example, the activation of Cp2TiCl2 in

acidic chloroaluminate melts [64]:

It is well known that alkylaluminum(III) compounds react vigorously with protons to deliver the corresponding alkane The using of ionic liquids derived from ethylaluminium(III) dichloride could prevent the cationic side reaction Alkylaluminum(III) compounds can be used as alkylating agents which allowed

a greater number of potential catalysts to be used [19]

1.2.5 Alkene hydrogenation reactions

It appeared that transition metal-catalyzed hydrogenation reactions in ionic liquids were particularly promising based on several factors: (1) the large number of ionic hydrogenation catalysts were available [65] and (2) the solubility

of many alkenes and the availability of hydrogen in many ionic liquids appeared

to be sufficiently high to achieve good reaction rates It was noteworthy that the diffusion of hydrogen into ionic liquids was found to be relatively fast, the ease

of its transfer from the gas phase into the melt is of special importance [66]

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In 1996, Suarez and co-workers investigated the Rh-catalyzed

hydrogenation of cyclohexene in 1-n-butyl-3-methylimidazolium ([BMIM])

tetrafluoroborate [33] and Farve dissolved the cationic “Osborn complex” [Rh(nbd)(PPh3)2][PF6] (nbd = norbornadiene) in ionic liquids with weakly coordinating anions (e.g., [PF6]–, [BF4]–, and [SbF6]–) and used the obtained ionic catalyst solutions for the biphasic hydrogenation of 1-pentene [67] (Scheme 1-4) Although the reactants had the limited solubility in the catalyst phase, the rates of hydrogenation in [BMIM][SbF6] were five times faster than that of reaction in acetone

Scheme 1-4 Biphasic hydrogenation of 1-pentene with the cationic “Osborn

complex” [Rh(nbd)(PPh3)2][PF6] (nbd = norbornadiene) in ionic liquids with

weakly coordinating anions [67]

1.2.6 Hydroformylation

Although there were already a highly efficient aqueous or organic biphasic industrial process for the hydroformylation of olefins, these could only be used with short-chain (≤ 5C) olefins However, ionic liquids present the higher solubilities for the higher olefins, and offered the possibility of replacing the water layer and extending the usefulness of the biphasic technique

The hydroformylation of 1-hexene in a variety of ionic liquids with imidazolium and pyrrrolidinium cations and different anions was carried out by Favre and co-workers [67] Initially they introduced the rhodium as [Rh(CO)2(ACAC)] with four equivalents of the charged phosphine TPPMS (triphenylphosphine-3-monosulfonate) and measured the turnover frequency of the catalyst in the different ionic liquids For the [BF4]−, [PF6]−, [CF3SO3]−, and [CF3CO2]− ionic liquids they found that the turnover frequency (TOF) of the reaction was dependent upon the solubility of the 1-hexene in the ionic liquid,

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possibly suggesting a mass transfer limited process However, when they used three different [(CF3SO2)2N]− based ionic liquids the TOF did follow the solubility of the 1-hexene in these ionic liquids, but the TOF’s of the whole set were lower than expected when compared to the other ionic liquids [68]

Additionally, hydroformylation reaction was considered as a potential application in ionic liquid–scCO2 systems Because of the good solubilities of reagents and products in the scCO2 allowed for continuous flow reactors with a charged ligand-catalyst in the ionic liquid [69]

1.2.7 Oxidation

The application of nonvolatile ionic liquids as the solvent in catalytic oxidation reactions offered notable benefits Particularly, ILs did not cause the problem by the formation of explosive mixtures in the gas phase, which occurred

to volatile organic solvents

Considering the Wacker oxidation of styrene to acetophenone catalyzed

by PdCl2 in the presence of [C4MIM]BF4 and [C4MIM]PF6 [70], it was shown that even a very small amount of ionic liquid could improve the reaction rate significantly

Scheme 1-5 The reaction of styrene with H2O2 in ionic liquids [70]

1.3 Reactions Literature review

1.3.1 Condensative reaction

1.3.1.1 Coumarin synthesis

The development of novel methodologies for the synthesis of biologically active heterocyclic compounds has been attracted more and more attention by organic chemists [71, 72] Amongst heterocyclic compounds, coumarin derivatives are becoming popular due to their important pharmacological properties such as anti-inflammatory, antioxidant, antiallergic, antithrombotic,