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. Nguyen Kim Phi Phung Independent examiner 2: Assoc. Pham Thanh Huyen Examiner 1: Assoc. Nguyen Thi Dung Examiner 2: Assoc.
Vu Anh Tuan Examiner 3: Assoc. Pham Thanh Quan ADVISORS: 1. Phan Thanh Son Nam 2. Truong Vu Thanh 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 i 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 3- acetylcoumarin đạt độ chuyển hóa 86% ở 100 oC sau 3 giờ, sử dụng chất lỏng ion [BMIM]Br làm dung môi. Phản ứng 2: Ngưng tụ giữa 1,2-phenylenediamine và acetone để tổng hợp 1,5- 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.
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)-2-chloroethane hydrochloride và 2- methylindole để tạo 1-(2-(N-morpholino)ethyl)-2-methylindole đạt hiệu suất khoảng 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 ii 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 iii 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. 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. 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. 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.
Paal-Knorr reaction for synthesis of pyrroles was performed [BMIM]PF6 ionic liquid with 100% conversion after 40 minutes at 30 oC. 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 iv 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 v 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.
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. 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 vi TABLE OF CONTENTS DECLARATION OF ORIGINALITY.vi TABLE OF CONTENTS.
vii LIST OF FIGURES .xi LIST OF SCHEMES. xiii LIST OF TABLES .xvi LIST OF ABBREVIATION.1 Introduction to ionic liquids .2 Imidazolium ionic liquids .3 Synthesis of Ionic Liquids .4 Properties of ILs .2 Ionic liquids as solvents .2 Reaction of bromobenzene with butyl acrylate in molten tetraalkylammonium and tetraalkylphosphonium bromide salts (Suzuki reaction) .4 Transition metal catalysis .5 Alkene hydrogenation reactions .3 Reactions Literature review .2 Carbon-Nitrogen coupling .4 AIMS AND OBJECTIVES .1 Materials and instrumentation.2 Synthesis of ionic liquids .1 Preparation of 1-alkyl-3-methylimidazolium bromide .2 Preparation of 1-alkyl-3-methylimidazolium hexafluorophosphate [AMIM]PF6] ILs .1 Synthesis of coumarin derivatives .2 Synthesis of 1,5-benzodiazepine derivatives .3 Synthesis of 1-(4-nitrophenyl)piperidine derivatives .4 Synthesis of 1-[2-(N-morpholino)ethyl]-2-methylindole derivatives .5 Synthesis of pyrrole derivatives .6 Halogen exchange reaction. RESULTS AND DISCUSSION .1 The synthesis of ionic liquids .1 The synthesis of [AMIM]Br.1 [AMIM]Br ILs characterization .2 The synthesis of [AMIM]PF6 .3 [AMIM]PF6 ILs characterization .2 Synthesis of coumarin derivatives (Reaction 1) .1 Effect of the alkyl chain length in the cation of ionic liquid on reaction conversion .2 Effect of various anion species of ionic liquid on the reaction conversion .3 Effect of different solvents on the reaction conversion .4 Reusability of [BMIM]Br ionic liquid .3 Synthesis of 1,5-benzodiazepine derivatives (Reaction 2) .1 Effect of temperature on the reaction conversion .2 Effect of [HMIM]Br concentration on the reaction conversion .3 Effect of acetone: 1,2-phenylenediamine molar ratio on the reaction conversion .4 Effect of different ionic liquid-based catalysts on the reaction conversion .5 Effect of different catalysts on the reaction conversion .6 Reusability of [HMIM]Br ionic liquid for the reaction .1 Effect of temperature on the reaction conversions.2 Effect of the alkyl chain length in the cation of ionic liquid on the reaction conversion .3 Effect of piperidine: 4-bromonitrobenzene molar ratio on the reaction conversion .4 Effect of solvents on the reaction conversion .5 Effect of the halogen in 4-nitrophenyl halide on the reaction conversion 81 3.6 Reusability of Ionic liquid [BMIM]Br .5 The synthesis of 1-(2-(N-morpholino)ethyl)-2-methylindole derivatives (Reaction 4) .1 Effect of the reaction time .2 Effect of 1-(N-morpholino)-2-chloroethane hydrochloride : 2- methylindole molar ratio .3 Effect of KOH: 2-methylindole molar ratio .4 Effect of different bases .5 Effect of the reaction temperature .6 Effect of [BMIM]PF6 : 2-methylindole molar ratio .7 Effect of different ionic liquid solvents .8 Solvent [BMIM]PF6 recycling studies .6 Synthesis of pyrrole derivatives (Reaction 5) .1 The effect of reagent molar ratio .2 The effect of the amount of ionic liquid .3 Effect of the alkyl chain length in the cation of ionic liquid on the reaction conversion .4 The effect of organic solvents .5 The effect of amines .6 The reusability of [BMIM]PF6 ionic liquid .7 Halogen exchange reaction (Reaction 6) .1 Effect of time reaction on reaction yield .2 Effect of 4'-iodoacetophenone/copper(I) bromide molar ratios on the reaction yield .3 Effect of temperature on the reaction yield .4 Effect of solvents on the reaction yield .5 Effect of different catalysts on the reaction yield .6 Effect of aryl halide substituents on the reaction yield .7 Reusability of [BMIM]Br ionic liquid .111 CONCLUSIONS AND FUTURE WORK .119 LIST OF PUBLICATIONS .136 Page x 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 .
