Flow Chemistry in Undergraduate Organic Chemistry Education

Laboratory Experiment pubs.acs.org/jchemeduc

Flow Chemistry in Undergraduate Organic Chemistry Education Burkhard König,† Peter Kreitmeier,† Petra Hilgers,† and Thomas Wirth*,‡ †

Institut für Organische Chemie, Universität Regensburg, Universitätsstrasse 31, D-93040 Regensburg, Germany School of Chemistry, Cardiff University, Main Building, Park Place, Cardiff, CF10 3AT, United Kingdom

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S Supporting Information *

ABSTRACT: On the basis of already existing (batch-mode) experiments, novel experiments in flow reactors have been developed that are continuous (flow-mode), as analogous to many industrial processes. The new flow-mode experiments have been implemented as experiments in laboratory classes by designing new experimental protocols and incorporating them into existing courses. The flow-type reactions can be controlled easily and students can rapidly apply various reaction conditions and directly monitor the effect on the outcome of the reaction using either off-line or on-line analysis, which is not possible using current (batch-mode) equipment. This gives students a novel type of control over their experiments as they are “space-resolved”. The experiments using flow reactor technology consume much less solvents and chemicals. Students recognize the large impact on sustainability when performing reactions in flow reactors. KEYWORDS: Upper-Division Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Amides, Grignard Reagents, Laboratory Equipment/Apparatus, NMR Spectroscopy, Synthesis, Thin Layer Chromatography

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FLOW REACTORS IN THE CURRICULUM Flow reactor technology has an impact on sustainability. Due to the small dimensions of such flow reactors, only tiny amounts of solvents and chemicals are necessary to perform experiments. This leads to savings in teaching costs due to reduced chemical and solvent use. After the development of laboratory procedures for flow reactor experiments, the equipment can be reused in future years. Use of flow reactors enhances learning and teaching in many ways. Most students only learn theoretically that there are continuous flow processes in laboratories and in industries. Although such procedures are common in chemical industries, they are usually not taught in undergraduate chemistry laboratory classes. The use of continuous flow processes has been extended to undergraduate experiments in the teaching laboratory to demonstrate the principles of flow chemistry in a reliable, affordable, safe, and robust way. Six experiments (Table 1) have been developed and tested to demonstrate the principles of flow chemistry. The learning outcomes for the students performing these experiments consist of the under-

rganic chemistry laboratory is usually taught using batchtype reactions. In batch experiments, a defined amount of compound is reacted in a flask to the desired product. After the reaction, a work up is performed, followed by isolation and analysis of the product. A typical reaction setup (stirrer, flask, and condenser) is shown in Figure 1a. The approach of performing flow-type experiments within the undergraduate organic chemistry laboratory is emphasizing another important aspect of chemical synthesis. The concept of “reaction time” becomes a new dimension as the reactions performed under flow-type conditions are spatially resolved and the progress of the reaction can sometimes be followed directly in a flow reactor. As reactions performed in flow reactors are applicable in chemical synthesis, students will benefit by performing such experiments themselves and by learning about the basic concepts of this technology. Although a number of reports, reviews,1 and books2 on reactions of organic compounds using flow reactor equipment are present in the literature, only a few experiments for undergraduate education have been published.3−5 These publications concentrate on the analysis of reaction products using mass spectrometry4 or photospectroscopical methods.5 © XXXX American Chemical Society and Division of Chemical Education, Inc.

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dx.doi.org/10.1021/ed3006083 | J. Chem. Educ. XXXX, XXX, XXX−XXX

Journal of Chemical Education

Laboratory Experiment

Figure 1. Batch and flow reactor setup.

Table 1. Simple and Reliable Flow Reactor Experiments for the Teaching Laboratory Exp No.

Starting Material(s)

Product

Type of Reaction

1 2 3 4 5 6

4-Methoxyaniline; Benzoyl chloride 4-Nitrophenyl acetate Benzil; 1,3-Diphenylacetone Phenylmagnesium bromide; Fluorenone 4-Nitrophenol Anisole

N-(4-Methoxyphenyl)benzamide 4-Nitrophenol Tetraphenylcyclopentadienone 9-Phenyl-9H-fluoren-9-ol 4-Nitrophenyl acetate 4-Bromoanisole

Amide formation Hydrolysis Condensation Grignard reaction Esterification Bromination

standing of main principles of flow chemistry and their advantages and disadvantages compared to batch chemistry. The experiments span typical reaction mechanisms covered in the basic organic teaching laboratories, such as nucleophilic substitution, esterification−hydrolysis, or bromination. Reactions have been selected where the appearance of a colored product or the disappearance of a colored starting material permits following the course of a reaction very easily. In a general reaction setup, two reactants in syringes A and B (Figure 1b) are mixed in the mixing device and then reacted in a flow reactor. The progress of the reaction can be analyzed visually using glass flow reactors6 as shown in Figure 1c where a colored product is formed. The glass flow reactor can be replaced by less expensive flexible tubing with the disadvantage that the reaction can then not be monitored visually. Other methods of analysis are also possible. The flow reactors can also be heated or cooled to allow different reaction conditions. The reactions in the flow reactor will be typically driven by syringe pumps, which are equipment easily understood and handled by students. The nature of these experiments is in line with the theoretical knowledge of a second- or third-year undergraduate student. Each experiment can be performed in a typical 4 h lab class. These reactions have been safely and easily performed for several years by over 200 third-year undergraduate students in groups of 2−4 students.

of a batch with a flow reaction.7 In this experiment, a sparingly soluble compound, tetraphenylcyclopentadienone, is produced. The use of n-pentanol as a solvent together with a high dilution reduces the risk of crystallization during the experiment. Some students experience that low flow rates facilitate the crystallization in the flow reactor, which can lead to blockages. In the case of an unexpected blockage within the flow system, the syringe pump stalls to avoid any overpressure. Blocked flow reactors can be cleaned with acetone. Experiment 4, the reaction of a Grignard reagent with a ketone, is slightly more demanding as it requires the operation under dry conditions. At the beginning of this experiment, the flow reactor apparatus is flushed with dry solvent (THF). This allows the experiments to run without blockage of the reactor. Bromination of anisol (experiment 6) requires the use of a 2 M solution of bromine as a hazardous reagent. Safety notes are included in the experimental description in the Supporting Information. This experiment also demonstrates the safe use of hazardous reagents in a flow reactor environment. The product for each reaction was isolated and characterized by either thin-layer chromatography, NMR, or melting point. Detailed procedures for each experiment are given in the Supporting Information.

EXPERIMENTS Experiment 1 is a straightforward amide formation using an aniline derivative and benzoyl chloride. Experiments 2 and 5 are complementary as the ester (4-nitrophenyl acetate) formed in experiment 5 can be efficiently cleaved again in experiment 2. Experiment 3, the synthesis of tetraphenylcyclopentadienone, has two parts as it consists of a batch and a flow experiment of the same reaction allowing a student to compare directly results

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HAZARDS Links to safety and hazards data for all chemicals used and for all products prepared are included in the Supporting Information.

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RESULTS The students who have performed the experiments described above learned about the principles of flow chemistry by setting up the experiments. Only completely soluble compounds should be used and any solids must be avoided. Concentrations were adjusted accordingly so that also sparingly soluble B

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compounds are not crystallizing in the flow equipment. In experiment 3, flow and batch experiments were compared. Most students experienced an increased yield in the flow chemistry experiment (up to 45% yield) over the batch experiment (typically 20−30% yield); however, spillages and blocked equipment occurred more often and led to reduced yields. The students clearly saw the various challenges in flow chemistry, but also appreciated the ease of the process once the reaction was running. The results of each experiment were written up in the form of a report; in addition, the students had to answer a set of questions related to batch and flow chemistry.

Rahman, M. T.; Sato, M.; Ryu, I. Adventures in inner space: Microflow systems for practical organic synthesis. Synlett 2008, 151−163. (f) Yoshida, J.; Nagaki, A.; Yamada, T. Flash chemistry: Fast chemical synthesis by using microreactors. Chem.Eur. J. 2008, 14, 7450− 7459. (g) Watts, P.; Wiles, C. Micro reactors: A new tool for the synthetic chemist. Org. Biomol. Chem. 2007, 5, 727−732. (h) AhmedOmer, B.; Brandt, J. C.; Wirth, T. Advanced organic synthesis using microreactor technology. Org. Biomol. Chem. 2007, 5, 733−740. (i) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Greener approaches to organic synthesis using microreactor technology. Chem. Rev. 2007, 107, 2300−2318. (2) (a) Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.; Wiley-VCH: Weinheim, 2013. (b) Wiles, C.; Watts, P. Micro Reaction Technology in Organic Synthesis; CRC Press: Boca Raton, FL, 2011. (c) Micro Process Engineering; Hessel, V., Renken, A., Schouten, J. C., Yoshida, J., Eds.; Wiley-Blackwell: Oxford, 2009. (d) Yoshida, J. Flash Chemistry; Wiley: Chichester, 2008. (3) Tundo, P.; Rosamilia, A. E.; Aricò, F. Methylation of 2-naphthol using dimethyl carbonate under continuous-flow gas-phase conditions. J. Chem. Educ. 2010, 89, 1233−1235. (4) Young, M. A. Real-time monitoring of heterogeneous catalysis with mass spectrometry. J. Chem. Educ. 2009, 86, 1082−1084. (5) (a) Petrozzi, S. An open-ended experiment: Development from batch to automated flow injection analysis for phenolics determination. J. Chem. Educ. 2009, 86, 1311−1314. (b) Bisson, P. J.; Whitten, J. E. Studying fast reactions: Construction and use of a low-cost continuous-flow instrument. J. Chem. Educ. 2006, 83, 1860−1863. (6) The glass mixers and flow reactors used in the experiments described here were obtained from Little Things Factory, Ilmenau, Germany (http://www.ltf-gmbh.com/index.html) (accessed May 2013). (7) Williamson, K. L. Macroscale and Microscale Organic Experiments; Houghton Mifflin: Boston, MA, 1999.

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SUMMARY In performing these experiments, students learned about advantages and disadvantages of continuous flow-type reactions performed in flow reactors over conventional ways (batch-type) of performing experiments. This introduced an important area of synthetic chemistry into the teaching curriculum and also made a strong link to industrial applications, where many reaction processes on larger scale are carried out under continuous (flow-type) reaction conditions. The teaching of undergraduate students was improved substantially by introducing a current and interesting technique of research, which should prepare them much better for their future careers. Aspects of sustainability with largely reduced amounts of chemicals and solvents (due to the small dimensions of the flow reactors) are important as well. This also reduced the costs of the laboratory. The reduction of waste and the efficient use of resources was another important aspect for students to understand. In conclusion, six simple experiments have been outlined that demonstrate the versatile use of flow chemistry in organic synthesis. This will facilitate the implementation of flow chemistry using easily accessible equipment in organic chemistry teaching laboratories.

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ASSOCIATED CONTENT

S Supporting Information *

Detailed student instructions and instructor notes for the experiments. This material is available via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank DBU (Deutsche Bundesstiftung Umwelt) for support, financial support from Cardiff University (T.W.) is also gratefully acknowledged.

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REFERENCES

(1) (a) McMullen, J. P.; Jensen, K. F. Integrated microreactors for reaction automation: New approaches to reaction development. Annu. Rev. Anal. Chem. 2010, 3, 19−42. (b) Webb, D.; Jamison, T. F. Continuous flow multi-step organic synthesis. Chem. Sci. 2010, 1, 675−680. (c) Hartman, R. L.; Jensen, K. F. Microchemical systems for continuous-flow synthesis. Lab Chip 2009, 9, 2495−2507. (d) Wiles, C.; Watts, P. Continuous flow reactors, a tool for the modern synthetic chemist. Eur. J. Org. Chem. 2008, 1655−1671. (e) Fukuyama, T.; C

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