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

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: Prof Dr Phan Thanh Son Nam Dr 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 tổng hợp thành công hỗ trợ vi sóng với chế độ gián đoạn 10 giây tạo chất lỏng ion có màu vàng nhạt Sau đó, chất lỏng ion đem thực phản ứng trao đổi anion với hexafluorophosphoric acid để tạo chất lỏng ion 1-alkyl-3-methyl imidazolium hexafluorophosphate Các đặc trưng cấu trúc chất lỏng ion sau tổng hợp xác định phương pháp phổ cộng hưởng từ hạt nhân (1H, 13 C NMR) phổ khối lượng (MS) Các chất lỏng ion 1-alkyl-3-methyl imidazolium khảo sát khả làm dung môi cho phản ứng ghép đôi phản ứng trao đổi halogen để tìm điều kiện thích hợp cho phản ứng đối chiếu với dung môi hữu thông thường khác Kết nghiên cứu thu tìm loại chất lỏng ion thích hợp cho phản ứng tất điều kiện thích hợp cho loại phản ứng khơng trùng hồn tồn với cơng trình khác cụ thể mô tả đây: Phản ứng 1: Ngưng tụ salicylaldehyde với methyl acetoacetate để tạo thành 3acetylcoumarin đạt độ chuyển hóa 86% 100 oC sau giờ, sử dụng chất lỏng ion [BMIM]Br làm dung môi Phản ứng 2: Ngưng tụ 1,2-phenylenediamine acetone để tổng hợp 1,5benzodiazepine tiến hành nhiệt độ thường có sử dụng chất lỏng ion [HMIM]Br làm dung mơi với độ chuyển hóa 100% sau 45 oC Phản ứng 3: N-aryl hóa piperidine 4-bromonitrobenzene để tạo 1- (4nitrophenyl)piperidine độ chuyển hóa đạt 94% sau 90 oC, sử dụng [BMIM]Br làm dung môi Phản ứng 4: Phản ứng 1-(N-morpholino)-2-chloroethane hydrochloride 2methylindole để tạo 1-(2-(N-morpholino)ethyl)-2-methylindole đạt hiệu suất khoảng 75% sau Phản ứng thực dung môi [BMIM]PF6 30 oC Phản ứng 5: Phản ứng Paal-Knorr tổng hợp pyrrole thực 2,5-hexadione amin dung môi chất lỏng ion [BMIM]PF6 với độ chuyển hóa đạt 100% thời gian 40 phút nhiệt độ 30 oC Page ii Phản ứng 6: Phản trao đổi halogen aryl iodides đồng (I) bromide thực sử dụng [BMIM]Br làm dung môi để tạo thành aryl bromide tương ứng với hiệu suất phản ứng đạt 90% sau thời gian 140 oC Ngoài ra, chất lỏng ion 1-alkyl-3-methyl imidazolium thu hồi tái sử dụng nhiều lần cho phản ứng mà hiệu giảm không đáng kể Các sản phẩm thu phản ứng xác định cấu trúc qua MS 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 The condensation reaction of salicylaldehyde and methyl acetoacetate formed 3-acetylcoumarin with approximately 86% conversion after hours at 100 °C with, [BMIM]Br ionic liquid as a solvent Reaction The condensation reaction between 1,2-phenylenediamine and acetone to synthesize 1,5-benzodiazepine could occur at 45 oC with 100% conversion after hours in [HMIM]Br ionic liquid Reaction The N-aryl reaction between piperidine and 4-bromonitrobenzene to form 1-(4-nitrophenyl) piperidine can reach approximately 94% conversion after hours with [BMIM]Br as a solvent at 90 oC Reaction 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 hours in [BMIM]PF6 ionic liquid at 30 oC Reaction Paal-Knorr reaction for synthesis of pyrroles was performed [BMIM]PF6 ionic liquid with 100% conversion after 40 minutes at 30 oC Reaction 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 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.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 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 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 1.1 LITERATURE REVIEW .1 IONIC LIQUIDs (ILs) .1 1.1.1 Introduction to ionic liquids 1.1.2 Imidazolium ionic liquids 1.1.3 Synthesis of Ionic Liquids 1.1.4 Properties of ILs 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 Page vii 1.3.2 Carbon-Nitrogen coupling 24 1.3.3 Halogen exchange .34 1.4 AIMS AND OBJECTIVES .39 CHAPTER 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 3.1 RESULTS AND DISCUSSION 53 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 viii APPENDIX 40: MS OF REUSED [BMIM]Br diphenyl ether Aryl bromide Aryl iodide APPENDIX 41: GC OF HALOGEN EXCHANGE REACTION AFTER 8H diphenyl ether Aryl bromide Aryl iodide APPENDIX 42: GC OF THE RECOVERY AND REUSE OF ILS ON THE HALOGEN EXCHANGE REACTION APPENDIX 43: PREPARATION OF 1-ALKYL-3-METHYLIMIDAZOLIUM TETRAFLUOROBORATE [AMIM][BF4] ILS Scheme 3.1 The formation of 1-alkyl-3-methylimidazolium tetrafluoroborate by anion metathesis In a typical procedure for preparation of 1–butyl–3–methylimidazolium tetrafluoroborate, 70 mL HBF4 48 % (98.05 g, 0.536 mol) was added to a plastic conical flask containing 50 mL of cold distilled water This mixture was stirred and immersed in an ice bath for 30 minutes to be cooled down to 0-5 oC (mixture I) The mixture of 1–butyl– 3–methylimidazolium bromide (100 g, 0.456 mol) with 50 mL of cold distilled water was also stirred and immersed in another ice bath for 30 minutes (mixture II) Next, the mixture I was added dropwise to mixture II The resulting mixture was continuously stirred and cooled for 24 hours After that, the upper acidic aqueous layer was almost separated by decanting and the resulting mixture was washed by cold water until the almost excess acid was removed The acidity was tested by pH paper The excess water was removed by a vacuum rotary evaporation at 70 oC to obtain [BMIM]BF4 APPENDIX 44: TEMPERATURE PROGRAM OF GAS CHROMATOGRAPHIC (GC) 44.1 Synthesis of coumarin derivatives and Synthesis of 1,5-benzodiazepine derivative (Reaction + 2) Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010-Plus equipped with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) at Ho Chi Minh city university of technology The temperature program for GC analysis heated samples from 120 to 280 o C at 40 oC/min and held them at 280 oC for Inlet and detector temperatures were set constant at 280 oC Diphenyl ether was used as an internal standard to calculate reaction conversions 44.2 Synthesis of 1-(4-nitrophenyl)piperidine derivatives (Reaction 3): Gas chromatographic (GC) analyzes were performed using a Shimadzu GC 17-A equipped with a flame ionization detector (FID) and an DB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 µm) at Ho Chi Minh city university of technology The temperature program for GC analysis heated samples from 60 to 120 ◦C at 30◦C/min and held them at 120 ◦C for min; then heated them from 120 to 200 ◦C at 40 ◦C/min and held them at 200 oC for min; then heated them from 200 to 300 ◦C at 50 ◦C/min and held them at 300 ◦C for Inlet and detector temperatures were set constant at 300 ◦C 4-Bromoanisole was used as an internal standard to calculate reaction conversions 44.3 Synthesis of 1-[2-(N-morpholino)ethyl]-2-methylindole derivatives (Reaction 4) Gas chromatographic (GC) analyzes were performed using a Shimadzu GC 17-A equipped with a flame ionization detector (FID) and an DB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 µm) at Ho Chi Minh city university of technology The temperature program for GC analysis heated samples from 60 to 200 ◦C at 30 ◦C/min and held them at 200 oC for min; then heated them from 200 to 300 ◦C at 50 ◦C/min and held them at 300 ◦C for Inlet and detector temperatures were set constant at 300 ◦C with an internal standard 4- Bromoanisole 44.4 Synthesis of pyrrole derivatives (Reaction 5) Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010-Plus equipped with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) at Ho Chi Minh city university of technology The temperature program for GC analysis heated samples from 60 to 280 o C at 60 oC/minute and held at 280 oC for minutes Inlet temperature was set constant at 280 oC p-xylene was used as an internal standard to calculate reaction conversions 44.5 Halogen exchange reaction (Reaction 6) Gas chromatographic (GC) analyses were performed using a Shimadzu GC 2010Plus equipped with a flame ionization detector (FID) and an SPB-5 column (length = 30 m, inner diameter = 0.25 mm, and film thickness = 0.25 μm) at Ho Chi Minh city university of technology The temperature program for GC analysis heated samples from 60 to 280 o C at 60 oC/minute and held at 280 oC for minutes Inlet temperature was set constant at 280 oC Diphenyl ether was used as an internal standard to calculate reaction yields APPENDIX 45: EQUATION FOR CALCULATING CONVERSION AND YIELD REACTION 45.1 Calibration curve preparation for synthesis of halogen exchange In order to determine the performance of the reaction based on the suitable condition of the GC analysis we used interpolation method based on the calibration curve Calibration curve is based on the ratio between the number of mols of product/the number of mols of internal standard and the percentage area of product/area of internal standard Calibration curve 0.7 0.648 0.6 0.5 0.455 0.4 0.346 0.3 0.2 y = 0.6512x + 0.0023 R² = 0.9985 0.194 0.1 0.063 0 0.2 Point 0.4 0.6 The number of product mols/the number of mols of internal standard 0.101 0.301 0.505 0.694 1.001 0.8 1.2 The percentage area of product/area of internal standard 0.063 0.194 0.346 0.455 0.648 Figure 4.1 Calibration curve for 4'-Bromoacetophenone 45.2 Yield determination From the calibration curve, yield of 4'-bromoacetophenone can be calculated by the formula (1): GC yield(%) = mPr × 100% SPr 100% = ( × 0.6512 + 0.0023) × mIS × mPr ' SIS mPr ' (1) Where: mPr (mg): Mass of 4'-bromoacetophenone obtained mPr’(mg): Calculated mass of 4'-bromoacetophenone when yield = 100% SPr: Peak area of 4'-bromoacetophenone in sample SIS: Peak area of diphenyl ether in sample mIS (mg): Mass of diphenyl ether in sample 45.3 Isolated yield determination Isolated yield was calculated by the formulas (2) and (3) Isolated yield(%) = misolated × 100% mtheorical (2) mtheorical (mg) = nPr × MPr (3) Where: misolated (mg): mtheorical (mg): nPr (mmol): MPr (g/mol): Mass of isolated product Calculated mass of product when yield = 100% Mol of product Molecular weight of product 45.4 General equation for calculating reaction conversion S1 S (t )  (t x ) S S2  (%)  x100 S1 (t ) S2 Where: (4) η (%): S1, S2: Conversion (%) Peak area of subtrate and internal standard, respectively t0: Time of beginning tx: Time of withdrawing the sample APPENDIX 46: GC FOR CALCULATING YIELD ON HALOGEN EXCHANGE REACTION APPENDIX 47: ILS SOLVENTS WERE USED IN COMPARISON WITH CONVENTIONAL ORGANIC SOLVENTS ... 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... 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. .. hydrochloride and 2-methylindole formed with about 75% conversion after hours in [BMIM]PF6 ionic liquid at 30 oC Reaction Paal-Knorr reaction for synthesis of pyrroles was performed [BMIM]PF6 ionic liquid