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Flow chemistry experiments in the undergraduate teaching laboratory: synthesis of diazo dyes and disulfides

Flow chemistry experiments in the undergraduate teaching laboratory: synthesis of diazo dyes and... By embedding flow technology in the early phases of academic education, students are exposed to both the theoretical and practical aspects of this modern and widely-used technology. Herein, two laboratory flow experiments are described which have been carried out by first year undergraduate students at Eindhoven University of Technology. The experiments are designed to be relatively risk-free and they exploit widely available equipment and cheap capillary flow reactors. The experiments allow students to develop a hands-on understanding of continuous processing and gives them insights in both organic chemistry and chemical engineering. Furthermore, they learn about the benefits of microreactors, continuous processing, multistep reaction sequences and multiphase chemistry. Undoubtedly, such skills are highly valued in both academia and the chemical industry. . . . . Keywords Flow chemistry First-year undergraduate Organic chemistry Chemical engineering Hands-on training Introduction is a high demand for skilled personnel with at least a notion of flow chemistry. It is therefore obvious that flow chemistry Continuous-flow chemistry has rapidly established itself as a courses should be implemented in the academic training of go-to technology to carry out difficult-to-handle reagents and future generations of chemists and chemical engineers reaction conditions [1, 2]. Notable examples where flow has [20–29]. made an undeniable impact are photochemistry [3–5], electro- However, flow chemistry courses in the chemistry curric- chemistry [6–8], multiphase reactions [9–12] and handling of ula are actually conspicuous by their absence. Historically, toxic, explosive or other hazardous reagents and intermediates undergraduate teaching laboratories have focused on the use [13–15, 16, 17]. Its value has been recognized by the industry of round-bottom flasks to carry out organic chemistry exper- as well and many companies are establishing small expert iments. Although, it is important for undergraduates to learn to groups specialized in flow chemistry [18, 19]. Hence, there work with this conventional and widely-used labware, it is all too often the only reactor type that students see in their entire Electronic supplementary material The online version of this article education. Herein, we demonstrate that a broader education (https://doi.org/10.1007/s41981-020-00118-1) contains supplementary with regard to reactor technologies should not require a com- material, which is available to authorized users. plete rethinking of the classical curriculum nor should it be expensive. * Timothy Noël Implementation of flow chemistry in both theoretical and t.noel@uva.nl; https://www.noelresearchgroup.com practical courses should be a focus of every chemistry major. Department of Chemical Engineering and Chemistry, Sustainable Indeed, some reactions are better carried out in a flow reactor. Process Engineering, Micro Flow Chemistry and Synthetic As an example, some of the typical synthetic organic chemis- Methodology, Eindhoven University of Technology, Het try experiments require long reaction times (several hours or Kranenveld 14, 5600, MB Eindhoven, The Netherlands days) which is not always advantageous in a busy teaching The Chemical Engineering and Chemistry Education Institute, schedule. Such reactions can often be accelerated in flow re- Eindhoven University of Technology, Het Kranenveld 14, 5600, MB actors via a strategy called process intensification [30, 31]. Eindhoven, The Netherlands This would allow students to carry out more experiments Present address: Flow Chemistry Group, van ‘t Hoff Institute for within the given time slot. Moreover, hazardous reactions Molecular Sciences (HIMS), Universiteit van Amsterdam (UvA), Science Park 904, 1098 XH, Amsterdam, The Netherlands can be carried out in flow without risk, e.g. by generating in 8 J Flow Chem (2021) 11:7–12 situ small quantities of a toxic substance which is subsequent- All starting materials were selected because of their low cost ly reacted away in a follow-up transformation. Such experi- and relative low toxicity. The concentration of the different ments provide students with fundamental insights into reac- solutions is low (C = 0.01 M) which is advantageous both in tion safety and the development of safe reaction environ- terms of reduced chemical consumption and enhanced safety. ments. Furthermore, students can get insight in the importance The setup is assembled by the students in pairs as shown of fundamental transport phenomena, like mass and heat schematically in Fig. 1b. The two reactors are made from transport. This is especially important for multiphase reaction perfluoroalkoxy alkane (PFA) capillaries (ID = 760 μm, vol- conditions (gas-liquid or liquid-liquid biphasic reactions) or ume 1 mL) according to a procedure described elsewhere for exothermic reactions, two notoriously challenging exam- (Fig. 1c)[38]. The reactors are connected to the syringe pump, ples to execute and to scale in both academia and industry to each other and to the outlet with standard microfluidic fit- [32]. tings. Once the setup is assembled, the different solutions are As many chemical engineering and chemistry students will made with the proper concentrations. To gain time, the solu- pursue a career in industry, where continuous processes are tions can also be made by the supervising tutors. The solutions often encountered, it is paramount that students are familiar are taken up in 4 plastic syringes (BD Discardit II®), which with the basic principles of continuous manufacturing and are subsequently mounted onto a syringe pump. In addition, flow chemistry. While organic chemistry often lingers with the concentrations of the reagents are calculated so that all batch processing, chemical engineering often sticks to resi- syringes are pushed at the same flow rate. By doing so, only dence time distribution experiments or the determination of a single syringe pump is required per experiment, reducing other reactor parameters. By combining organic synthesis further the cost associated with this experiment. Next, several with continuous-flow techniques, students from both chemis- samples are collected (1 mL/sample) for different residence try and chemical engineering tracks can learn from each times (t = 15, 30, 45, 60, 90, 120, 150 and 300 s). Prior to other’s disciplines, i.e. chemists acquire skills in continuous each sample, students need to wait four residence times in processing while engineers pick up the benefits for the syn- order to ensure steady state data collection. Samples are sub- thesis of organic molecules. This will create a mutual under- sequently diluted and the conversion is measured using a standing, fostering more fruitful collaborations in the future. benchtop UV-vis spectrometer (λ = 400 nm). Herein, we disclose our experience with two flow chemis- Next, the students are asked to analyze their results. First, try experiments which have been implemented in the opening they need to calculate the kinetic constant. The reaction is first teaching laboratory course at Eindhoven University of order in aniline, which allows us to use the following equa- Technology. One experiment involves the synthesis of haz- tion: ardous diazonium salts which can be subsequently reacted dC away to yield a diazo dye (Solvent Yellow 7). A second ex- − ¼ kC ð1Þ dt periment involves an organic-aqueous biphasic oxidation of thiols to disulfides and provides insight in segmented flow. with C, the concentration [M] and t, the reaction time [s]. Both experiments have been carried out by >400 students in Integration of this equation leads to. the past 4 years and have been well received. ln ¼ kt ð2Þ 1−X Experiment 1: Synthesis of solvent yellow 7 with in continuous flow C −C 0 t X ¼ ð3Þ The synthesis of Solvent Yellow 7 involves two distinct steps, including a diazotization to yield the corresponding diazoni- The value of the rate constant (k) can be readily obtained by um compound and a subsequent diazo coupling reaction with plotting the conversion in function of the residence time phenol to generate the targeted diazo dye (Fig. 1a). This ex- (Fig. 2a). Next, ln [1/(1-X)] is plotted in function of the resi- periment is an example of multistep flow reaction sequences dence time (Fig. 2b). The value for the rate constant can be [33–35] and shows convincingly how to handle hazardous −1 subsequently derived from its slope, i.e. k = 0.0045 s .While intermediates. The explosion-sensitive diazonium salts are slight variations are obtained by different sets of students, the generated in the first step and immediately reacted away in order of magnitude of the rate constant is the same for all. an electrophilic substitution reaction [36, 37]. Hence, at any Next, we ask the students to calculate the time needed to given time, the total inventory of the hazardous intermediate is obtain 99% conversion of the starting material. By using kept small alleviating the safety risks associated with this equation 2 with X = 0.99, it can be easily understood that transformation. The first reaction takes place under acidic con- t ≥ 1024 s. ditions, while the second reaction requires basic conditions. R J Flow Chem (2021) 11:7–12 9 Fig. 1 Continuous-flow synthesis of Solvent Yellow 7 via an in-situ generation of diazonium salts. a Reaction scheme. b Flow setup. c Picture of the flow setup Equation 2 can be reorganized to result into the following By plotting this equation using the obtained rate constant equation: (Fig. 2c), the conversion can be estimated for all residence times. By adding also the measured datapoints, both theory −kt X ¼ 1−e ð4Þ and experiment can be compared in a single plot (Fig. 2c)and Fig. 2 Experimental data for the continuous-flow synthesis of Solvent Yellow 7. a Conversion in function of residence time. The conversion was calculated by dividing the obtained UV-vis absorption (A ) at 400 nm by the absorption observed at full conversion (A ). b Linearization of the obtained data to retrieve the rate constant k. c Plot of equation 4 using the obtained reaction rate k and overlay with the obtained experimental values 10 J Flow Chem (2021) 11:7–12 Fig. 3 Continuous-flow biphasic synthesis of disulfides using hydrogen peroxide as oxidant. a Reaction scheme. b Schematic representation of the segmented flow regime. c Schematic representation of the flow setup gives confidence to the students that their calculations were yet operationally simple procedure which avoided the use of accurate. mass flow controllers to dose air or oxygen into the liquid In principle, the entire experiment requires about four hours stream [45]. A biphasic reaction protocol was developed with of research time per pair of students, this includes setting up 0.1 M octanethiol and 1 mol% I in ethyl acetate and a 10% the reactor assembly, carrying out the experiments and aqueous hydrogen peroxide solution (Fig. 3a). Both solutions performing the UV-vis measurements. Since this experiment are taken up in two syringes and mounted on a single syringe is done by first year students in the first month of their aca- pump (Fig. 3c). Upon merging of the two solutions, a seg- demic track, we have decided to spread the experiment over mented flow regime can readily be observed. The reaction is two half days. The first day is mainly used to construct the completed in about 5 min residence time. After discarding the setup and ensuring its proper performance, e.g. no leakage, first four reactor volumes to reach steady state, the students are chemicals mixed in right stoichiometry, calculating the re- asked to collect sufficient material to isolate the disulfide quired residence times and getting familiar with the analysis (20 mL solution, to isolate 1 mmol of the targeted disulfide). equipment. On the second day the data can be collected and This solution is subsequently washed with 0.2 M thiosulfate in a handled. A detailed procedure can be found in the Supporting separatory funnel. Note that this is an exothermic reaction which Information. consumes the excess of iodine and thus caution is required. Hence, the combined layers have to be gently shaken and pres- sure needs to be released from the separatory funnel. The organic phase is subsequently washed two more times with fresh 0.2 M Experiment 2: Dimerization of octanethiol thiosulfate solution. The organic phase is dried with magnesium in continuous flow sulfate and evaporated. The latter step can be preferably done in vacuo using a rotavapor or, since we have >100 students, evap- A second experiment was introduced in our undergraduate teach- oration can be done in a fume hood by heating the flask in a ing laboratory to showcase the advantages provided by water bath. The reaction should in principle afford the corre- microreactor technology for the execution of multiphase reaction sponding disulfide in quantitative yield (276 mg of a transparent conditions (Fig. 3). Upon merging two immiscible phases, a oil), but we observed sometimes yields >100% due to insuffi- segmented flow regime is established in the capillary cient removal of the solvent. All experimental operations can be microreactor where the two phases are brought into close contact carried out by the students in four hours. with each other [40]. Segmented flow provides fast mixing due so-called Taylor recirculation flow patterns, a well-defined inter- facial area and reduced axial dispersion, allowing the reactor to operate as an ideal plug-flow reactor (Fig. 3b). Assessment We selected the synthesis of disulfides via oxidative dimer- ization of thiols in flow, which has been developed previously This practical course is for some students their first experi- in our group using photocatalytic [41–43]or electrochemical mental experience. Consequently, every practical experiment activation [44]. For the practical course, we wanted a robust, is preceded by an in-depth discussion of the mechanisms of J Flow Chem (2021) 11:7–12 11 the reactions, the setup, the procedures and the required cal- capillary microreactors and only a single syringe pump per culations and plots. This allows teachers to make sure that all experiment. We believe that these experiments can be readily students have enough background to carry out the experi- implemented into both chemistry and chemical engineering ments and to understand the observations. curricula. The students are assessed for the experiments in two ways, Acknowledgments The execution of a practical course with >100 stu- viz. an evaluation of the practical performance and skills of the dents per annum is without a doubt a formidable team effort at the de- student and an objective assessment of the written report. The partment of Chemical Engineering and Chemistry at TU Eindhoven. We practical performance is evaluated as follows: would like to thank ir. P. F. A. M. (Peter) Janssens, who is the Director of Education at the department of Chemistry and Chemical Engineering, for his support during the implementation of flow chemistry in the curricu- 1. Students need to be able to follow the flow procedures lum. Also, we would like to thank all the student assistants in the past five accurately, including building up the flow setup, calculat- years who helped guiding and supervising this practical course. Finally, ing the flow rates correctly to reach certain residence we like to thank Ms. Christa Schilders for the administrative tasks during times and executing the recipes with accuracy. the practicum. 2. They have to abide the safety regulations at all times. 3. They have to be able to accurately note down the made Open Access This article is licensed under a Creative Commons observations and the obtained results in the laboratory Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as notebook. long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if The written report can be assessed more objectively on its changes were made. The images or other third party material in this article completeness, e.g. accurate description of the observations, are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the correct calculations and plots, adequate conclusion and per- article's Creative Commons licence and your intended use is not spective. We tolerate small mistakes (e.g. rate constant is off), permitted by statutory regulation or exceeds the permitted use, you will especially when the students assess their performance accu- need to obtain permission directly from the copyright holder. To view a rately in the conclusion. Generally, the written reports on the copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. flow experiments are of good to excellent quality. However, it is important to note that the flow experiments are the last ones in the practical course. Hence, the students have by that time already more experience in writing reports and have received References ample feedback on previous reports. 1. Plutschack MB, Pieber B, Gilmore K, Seeberger PH (2017) The Hitchhiker’s guide to flow chemistry. Chem Rev 117:11796–11893 2. Govaerts S, Nyuchev A, Noel T (2020) Pushing the boundaries of Hazards C–H bond functionalization chemistry using flow technology. J Flow Chem 10:13–71 While microreactors can handle safely small amounts of haz- 3. Sambiagio C, Noël T (2020) Flow photochemistry: Shine some light on those tubes! Trends in Chemistry 2:92–106 ardous chemicals, one should still be careful as the stock so- 4. Noël T (2017) A personal perspective on the future of flow photo- lutions and the collecting vessels contain still several mL of chemistry. J Flow Chem 7:87–93 solution. Links to appropriate safety hazards data for all 5. 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Su Y, Hessel V, Noël T (2015) A compact photomicroreactor de- biphasic system. J Chem Educ 95:1069–1072 sign for kinetic studies of gas-liquid photocatalytic transformations. 24. Simeonov SP, Afonso CAM (2013) Batch and flow synthesis of 5- AICHE J 61:2215–2227 hydroxymethylfurfural (HMF) from fructose as a bioplatform inter- 43. Bottecchia C, Erdmann N, Tijssen PMA, Milroy L-G, Brunsveld L, mediate: an experiment for the organic or analytical laboratory. J Hessel V, Noel T (2016) Batch and flow synthesis of disulfides by Chem Educ 90:1373–1375 visible-light-induced TiO2 Photocatalysis. ChemSusChem 9:1781– 25. Volpe K, Podlesny EE (2020) Modernization of a photochemical reaction for the undergraduate laboratory: continuous flow 44. Laudadio G, Straathof NJW, Lanting MD, Knoops B, Hessel V, Photopinacol coupling. J Chem Educ 97:586–591 Noel T (2017) An environmentally benign and selective electro- 26. 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J Chem Educ 91:112–115 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Flow Chemistry Springer Journals

Flow chemistry experiments in the undergraduate teaching laboratory: synthesis of diazo dyes and disulfides

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Springer Journals
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Copyright © The Author(s) 2020
ISSN
2062-249X
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2063-0212
DOI
10.1007/s41981-020-00118-1
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Abstract

By embedding flow technology in the early phases of academic education, students are exposed to both the theoretical and practical aspects of this modern and widely-used technology. Herein, two laboratory flow experiments are described which have been carried out by first year undergraduate students at Eindhoven University of Technology. The experiments are designed to be relatively risk-free and they exploit widely available equipment and cheap capillary flow reactors. The experiments allow students to develop a hands-on understanding of continuous processing and gives them insights in both organic chemistry and chemical engineering. Furthermore, they learn about the benefits of microreactors, continuous processing, multistep reaction sequences and multiphase chemistry. Undoubtedly, such skills are highly valued in both academia and the chemical industry. . . . . Keywords Flow chemistry First-year undergraduate Organic chemistry Chemical engineering Hands-on training Introduction is a high demand for skilled personnel with at least a notion of flow chemistry. It is therefore obvious that flow chemistry Continuous-flow chemistry has rapidly established itself as a courses should be implemented in the academic training of go-to technology to carry out difficult-to-handle reagents and future generations of chemists and chemical engineers reaction conditions [1, 2]. Notable examples where flow has [20–29]. made an undeniable impact are photochemistry [3–5], electro- However, flow chemistry courses in the chemistry curric- chemistry [6–8], multiphase reactions [9–12] and handling of ula are actually conspicuous by their absence. Historically, toxic, explosive or other hazardous reagents and intermediates undergraduate teaching laboratories have focused on the use [13–15, 16, 17]. Its value has been recognized by the industry of round-bottom flasks to carry out organic chemistry exper- as well and many companies are establishing small expert iments. Although, it is important for undergraduates to learn to groups specialized in flow chemistry [18, 19]. Hence, there work with this conventional and widely-used labware, it is all too often the only reactor type that students see in their entire Electronic supplementary material The online version of this article education. Herein, we demonstrate that a broader education (https://doi.org/10.1007/s41981-020-00118-1) contains supplementary with regard to reactor technologies should not require a com- material, which is available to authorized users. plete rethinking of the classical curriculum nor should it be expensive. * Timothy Noël Implementation of flow chemistry in both theoretical and t.noel@uva.nl; https://www.noelresearchgroup.com practical courses should be a focus of every chemistry major. Department of Chemical Engineering and Chemistry, Sustainable Indeed, some reactions are better carried out in a flow reactor. Process Engineering, Micro Flow Chemistry and Synthetic As an example, some of the typical synthetic organic chemis- Methodology, Eindhoven University of Technology, Het try experiments require long reaction times (several hours or Kranenveld 14, 5600, MB Eindhoven, The Netherlands days) which is not always advantageous in a busy teaching The Chemical Engineering and Chemistry Education Institute, schedule. Such reactions can often be accelerated in flow re- Eindhoven University of Technology, Het Kranenveld 14, 5600, MB actors via a strategy called process intensification [30, 31]. Eindhoven, The Netherlands This would allow students to carry out more experiments Present address: Flow Chemistry Group, van ‘t Hoff Institute for within the given time slot. Moreover, hazardous reactions Molecular Sciences (HIMS), Universiteit van Amsterdam (UvA), Science Park 904, 1098 XH, Amsterdam, The Netherlands can be carried out in flow without risk, e.g. by generating in 8 J Flow Chem (2021) 11:7–12 situ small quantities of a toxic substance which is subsequent- All starting materials were selected because of their low cost ly reacted away in a follow-up transformation. Such experi- and relative low toxicity. The concentration of the different ments provide students with fundamental insights into reac- solutions is low (C = 0.01 M) which is advantageous both in tion safety and the development of safe reaction environ- terms of reduced chemical consumption and enhanced safety. ments. Furthermore, students can get insight in the importance The setup is assembled by the students in pairs as shown of fundamental transport phenomena, like mass and heat schematically in Fig. 1b. The two reactors are made from transport. This is especially important for multiphase reaction perfluoroalkoxy alkane (PFA) capillaries (ID = 760 μm, vol- conditions (gas-liquid or liquid-liquid biphasic reactions) or ume 1 mL) according to a procedure described elsewhere for exothermic reactions, two notoriously challenging exam- (Fig. 1c)[38]. The reactors are connected to the syringe pump, ples to execute and to scale in both academia and industry to each other and to the outlet with standard microfluidic fit- [32]. tings. Once the setup is assembled, the different solutions are As many chemical engineering and chemistry students will made with the proper concentrations. To gain time, the solu- pursue a career in industry, where continuous processes are tions can also be made by the supervising tutors. The solutions often encountered, it is paramount that students are familiar are taken up in 4 plastic syringes (BD Discardit II®), which with the basic principles of continuous manufacturing and are subsequently mounted onto a syringe pump. In addition, flow chemistry. While organic chemistry often lingers with the concentrations of the reagents are calculated so that all batch processing, chemical engineering often sticks to resi- syringes are pushed at the same flow rate. By doing so, only dence time distribution experiments or the determination of a single syringe pump is required per experiment, reducing other reactor parameters. By combining organic synthesis further the cost associated with this experiment. Next, several with continuous-flow techniques, students from both chemis- samples are collected (1 mL/sample) for different residence try and chemical engineering tracks can learn from each times (t = 15, 30, 45, 60, 90, 120, 150 and 300 s). Prior to other’s disciplines, i.e. chemists acquire skills in continuous each sample, students need to wait four residence times in processing while engineers pick up the benefits for the syn- order to ensure steady state data collection. Samples are sub- thesis of organic molecules. This will create a mutual under- sequently diluted and the conversion is measured using a standing, fostering more fruitful collaborations in the future. benchtop UV-vis spectrometer (λ = 400 nm). Herein, we disclose our experience with two flow chemis- Next, the students are asked to analyze their results. First, try experiments which have been implemented in the opening they need to calculate the kinetic constant. The reaction is first teaching laboratory course at Eindhoven University of order in aniline, which allows us to use the following equa- Technology. One experiment involves the synthesis of haz- tion: ardous diazonium salts which can be subsequently reacted dC away to yield a diazo dye (Solvent Yellow 7). A second ex- − ¼ kC ð1Þ dt periment involves an organic-aqueous biphasic oxidation of thiols to disulfides and provides insight in segmented flow. with C, the concentration [M] and t, the reaction time [s]. Both experiments have been carried out by >400 students in Integration of this equation leads to. the past 4 years and have been well received. ln ¼ kt ð2Þ 1−X Experiment 1: Synthesis of solvent yellow 7 with in continuous flow C −C 0 t X ¼ ð3Þ The synthesis of Solvent Yellow 7 involves two distinct steps, including a diazotization to yield the corresponding diazoni- The value of the rate constant (k) can be readily obtained by um compound and a subsequent diazo coupling reaction with plotting the conversion in function of the residence time phenol to generate the targeted diazo dye (Fig. 1a). This ex- (Fig. 2a). Next, ln [1/(1-X)] is plotted in function of the resi- periment is an example of multistep flow reaction sequences dence time (Fig. 2b). The value for the rate constant can be [33–35] and shows convincingly how to handle hazardous −1 subsequently derived from its slope, i.e. k = 0.0045 s .While intermediates. The explosion-sensitive diazonium salts are slight variations are obtained by different sets of students, the generated in the first step and immediately reacted away in order of magnitude of the rate constant is the same for all. an electrophilic substitution reaction [36, 37]. Hence, at any Next, we ask the students to calculate the time needed to given time, the total inventory of the hazardous intermediate is obtain 99% conversion of the starting material. By using kept small alleviating the safety risks associated with this equation 2 with X = 0.99, it can be easily understood that transformation. The first reaction takes place under acidic con- t ≥ 1024 s. ditions, while the second reaction requires basic conditions. R J Flow Chem (2021) 11:7–12 9 Fig. 1 Continuous-flow synthesis of Solvent Yellow 7 via an in-situ generation of diazonium salts. a Reaction scheme. b Flow setup. c Picture of the flow setup Equation 2 can be reorganized to result into the following By plotting this equation using the obtained rate constant equation: (Fig. 2c), the conversion can be estimated for all residence times. By adding also the measured datapoints, both theory −kt X ¼ 1−e ð4Þ and experiment can be compared in a single plot (Fig. 2c)and Fig. 2 Experimental data for the continuous-flow synthesis of Solvent Yellow 7. a Conversion in function of residence time. The conversion was calculated by dividing the obtained UV-vis absorption (A ) at 400 nm by the absorption observed at full conversion (A ). b Linearization of the obtained data to retrieve the rate constant k. c Plot of equation 4 using the obtained reaction rate k and overlay with the obtained experimental values 10 J Flow Chem (2021) 11:7–12 Fig. 3 Continuous-flow biphasic synthesis of disulfides using hydrogen peroxide as oxidant. a Reaction scheme. b Schematic representation of the segmented flow regime. c Schematic representation of the flow setup gives confidence to the students that their calculations were yet operationally simple procedure which avoided the use of accurate. mass flow controllers to dose air or oxygen into the liquid In principle, the entire experiment requires about four hours stream [45]. A biphasic reaction protocol was developed with of research time per pair of students, this includes setting up 0.1 M octanethiol and 1 mol% I in ethyl acetate and a 10% the reactor assembly, carrying out the experiments and aqueous hydrogen peroxide solution (Fig. 3a). Both solutions performing the UV-vis measurements. Since this experiment are taken up in two syringes and mounted on a single syringe is done by first year students in the first month of their aca- pump (Fig. 3c). Upon merging of the two solutions, a seg- demic track, we have decided to spread the experiment over mented flow regime can readily be observed. The reaction is two half days. The first day is mainly used to construct the completed in about 5 min residence time. After discarding the setup and ensuring its proper performance, e.g. no leakage, first four reactor volumes to reach steady state, the students are chemicals mixed in right stoichiometry, calculating the re- asked to collect sufficient material to isolate the disulfide quired residence times and getting familiar with the analysis (20 mL solution, to isolate 1 mmol of the targeted disulfide). equipment. On the second day the data can be collected and This solution is subsequently washed with 0.2 M thiosulfate in a handled. A detailed procedure can be found in the Supporting separatory funnel. Note that this is an exothermic reaction which Information. consumes the excess of iodine and thus caution is required. Hence, the combined layers have to be gently shaken and pres- sure needs to be released from the separatory funnel. The organic phase is subsequently washed two more times with fresh 0.2 M Experiment 2: Dimerization of octanethiol thiosulfate solution. The organic phase is dried with magnesium in continuous flow sulfate and evaporated. The latter step can be preferably done in vacuo using a rotavapor or, since we have >100 students, evap- A second experiment was introduced in our undergraduate teach- oration can be done in a fume hood by heating the flask in a ing laboratory to showcase the advantages provided by water bath. The reaction should in principle afford the corre- microreactor technology for the execution of multiphase reaction sponding disulfide in quantitative yield (276 mg of a transparent conditions (Fig. 3). Upon merging two immiscible phases, a oil), but we observed sometimes yields >100% due to insuffi- segmented flow regime is established in the capillary cient removal of the solvent. All experimental operations can be microreactor where the two phases are brought into close contact carried out by the students in four hours. with each other [40]. Segmented flow provides fast mixing due so-called Taylor recirculation flow patterns, a well-defined inter- facial area and reduced axial dispersion, allowing the reactor to operate as an ideal plug-flow reactor (Fig. 3b). Assessment We selected the synthesis of disulfides via oxidative dimer- ization of thiols in flow, which has been developed previously This practical course is for some students their first experi- in our group using photocatalytic [41–43]or electrochemical mental experience. Consequently, every practical experiment activation [44]. For the practical course, we wanted a robust, is preceded by an in-depth discussion of the mechanisms of J Flow Chem (2021) 11:7–12 11 the reactions, the setup, the procedures and the required cal- capillary microreactors and only a single syringe pump per culations and plots. This allows teachers to make sure that all experiment. We believe that these experiments can be readily students have enough background to carry out the experi- implemented into both chemistry and chemical engineering ments and to understand the observations. curricula. The students are assessed for the experiments in two ways, Acknowledgments The execution of a practical course with >100 stu- viz. an evaluation of the practical performance and skills of the dents per annum is without a doubt a formidable team effort at the de- student and an objective assessment of the written report. The partment of Chemical Engineering and Chemistry at TU Eindhoven. We practical performance is evaluated as follows: would like to thank ir. P. F. A. M. (Peter) Janssens, who is the Director of Education at the department of Chemistry and Chemical Engineering, for his support during the implementation of flow chemistry in the curricu- 1. Students need to be able to follow the flow procedures lum. Also, we would like to thank all the student assistants in the past five accurately, including building up the flow setup, calculat- years who helped guiding and supervising this practical course. Finally, ing the flow rates correctly to reach certain residence we like to thank Ms. Christa Schilders for the administrative tasks during times and executing the recipes with accuracy. the practicum. 2. They have to abide the safety regulations at all times. 3. They have to be able to accurately note down the made Open Access This article is licensed under a Creative Commons observations and the obtained results in the laboratory Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as notebook. long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if The written report can be assessed more objectively on its changes were made. The images or other third party material in this article completeness, e.g. accurate description of the observations, are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the correct calculations and plots, adequate conclusion and per- article's Creative Commons licence and your intended use is not spective. We tolerate small mistakes (e.g. rate constant is off), permitted by statutory regulation or exceeds the permitted use, you will especially when the students assess their performance accu- need to obtain permission directly from the copyright holder. To view a rately in the conclusion. Generally, the written reports on the copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. flow experiments are of good to excellent quality. However, it is important to note that the flow experiments are the last ones in the practical course. 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Journal of Flow ChemistrySpringer Journals

Published: Oct 7, 2020

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