Laboratory Experiment pubs.acs.org/jchemeduc
Microwave-Assisted Esterification: A Discovery-Based Microscale Laboratory Experiment Maureen K. Reilly, Ryan P. King, Alexander J. Wagner, and Susan M. King* Department of Chemistry, University of CaliforniaIrvine, Irvine, California 92967, United States S Supporting Information *
ABSTRACT: An undergraduate organic chemistry laboratory experiment has been developed that features a discovery-based microscale Fischer esterification utilizing a microwave reactor. Students individually synthesize a unique ester from known sets of alcohols and carboxylic acids. Each student identifies the best reaction conditions given their particular reagents (either excess alcohol or excess carboxylic acid) as well as the ideal workup procedure for their reaction. Products are analyzed using 1H NMR spectroscopy, IR spectroscopy, and scent. This modern adaptation of the classic Fischer esterification provides the opportunity for discussion of important chemistry concepts, including acid catalysis, Le Châtelier’s principle, and green chemistry.
KEYWORDS: Second-Year Undergraduate, Laboratory Instruction, Organic Chemistry, Hands-On Learning/Manipulatives, Inquiry-Based/Discovery Learning, Esters, Microscale Lab, Green Chemistry, NMR Spectroscopy, IR Spectroscopy
T
condensation, Robinson annulation, Wolff−Kishner reduction, Wittig reaction, Diels−Alder reaction, Williamson ether synthesis, and Fries rearrangement, as well as to carry out transesterification, N-formylation, base-catalyzed esterification, amine hydrolysis, solventless aldol condensation, and ester hydrolysis reactions.7 MAOS offers advantages such as reduced reaction time, increased yields, decreased solvent use, and reduced byproducts.8,9 Incorporating this state-of-the-art technique into undergraduate laboratories is important because microwave reactors have become standard equipment in many industrial and academic laboratories,7e and it allows students to gain a better understanding of how microwave energy heats chemical reactions.
he Fischer esterification is one of the most fundamental transformations in carboxylic acid chemistry, and it is a popular experiment in undergraduate organic chemistry laboratories.1 In the typical protocol for this reaction, a carboxylic acid and an alcohol are refluxed in the presence of an acid catalyst for approximately 1 h to generate the ester product. One of the marvels of this transformation is the drastic change in fragrance between the carboxylic acid reagent and the ester product. Low molecular weight carboxylic acids often have disagreeable odors while esters are more commonly associated with pleasant smells and are frequently used in flavorings and perfumes. Several recent publications on the Fischer esterification have capitalized on using ester fragrances to enhance learning. One example uses scent to conduct kinetic studies.1a Three other examples use the scent of wintergreen oil as a biochemical assay for a parallel combinatorial esterification experiment.1b,c,2 In this experiment, the standard Fischer esterification is turned into a discovery-based3 microwave-assisted reaction, featuring pedagogic goals of introducing students to the concept of green chemistry4,5 and using critical thinking to facilitate experimental design. A published microwave-assisted Fischer esterification procedure6 was adapted to allow for simultaneous processing of 14 different esters, with each student assigned to a different ester. Students choose the reaction conditions and workup procedure necessary for optimization of their individual ester. After the esters are isolated, students characterize their product by 1H NMR spectroscopy, IR spectroscopy, and scent. Microwave-assisted organic synthesis (MAOS) has been used in undergraduate laboratory experiments for the Knoevenagel © XXXX American Chemical Society and Division of Chemical Education, Inc.
■
EXPERIMENTAL OVERVIEW Each student chooses a different ester to synthesize from a list of 18 esters. Students are also given the option to synthesize an ester that is not on the list using any of the reagents supplied for the experiment. Students use retrosynthetic analysis to determine the appropriate carboxylic acid and alcohol. Then, students choose one of two procedures, procedure A (excess alcohol) or procedure B (excess carboxylic acid), for the experiment based on their particular alcohol and carboxylic acid. Detailed procedures are in the Supporting Information. Preparation: Procedure A
The carboxylic acid (10 mmol) is added to an excess of the alcohol (3.0 mL) in a 20 mL screw top microwave reaction vessel equipped with a stirbar. Sulfuric acid (0.25 mL) is
A
dx.doi.org/10.1021/ed400721p | J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
Figure 1. Ester products formed from the microwave conditions along with reported student yields and fragrances. Student yields varied ±20% of the given yields, up to 98%.
■
HAZARDS Students should wear disposable gloves and avoid chemical contact with skin, eyes, and clothing. All microwave reaction vessel preparation and reaction workup should be conducted in a fume hood. Low molecular weight carboxylic acids are especially malodorous, and therefore the reaction vessels are sealed when transported between the microwave reactor and the hood. Disposable gloves used to handle these carboxylic acids should be placed in a solid waste container to prevent fumes from entering the lab space. All of the carboxylic acids are irritants with prolonged exposure and can be corrosive in concentrated solutions. All of the alcohols are flammable and should be handled in the absence of any source of ignition. 1Pentanol is a lachrymator, causing irritation to the mucous membranes. Methanol is highly toxic if ingested or absorbed through the skin. Sulfuric acid is corrosive and may cause severe burns. Diethyl ether, hexanes, and acetone are flammable. nHexane, a major component of hexanes, is a neurotoxin. All of the ester products are irritants. The potential harmful effects of the carboxylic acids, alcohols, and synthesized esters have been minimized by using microscale quantities.
cautiously added dropwise with swirling. The reaction vessel is capped. Preparation: Procedure B
The alcohol (10 mmol) is added to an excess of the carboxylic acid (3.0 mL) in a 20 mL screw top microwave reaction vessel equipped with a stirbar. Sulfuric acid (0.25 mL) is cautiously added dropwise with swirling. The reaction vessel is capped. Microwave
Each reaction vessel is loaded into a microwave carousel. Vessels are arranged symmetrically when fewer than 24 vessels (full capacity) are used. The reaction vessels are heated for 3 min at 120 °C, with a 3 min ramp period to reach the desired reaction temperature, followed by a 20 min cool-down period to less than 55 °C. Workup
For procedure A, the reaction solution is diluted with diethyl ether and washed with water. For procedure B, the reaction solution is diluted with hexanes and washed with water. The organic layer is then washed with a saturated sodium bicarbonate solution, rinsed with brine, dried, and filtered. The solvent is removed by rotary evaporation to provide the crude product. An IR spectrum of the crude product is obtained and a sample is submitted to the laboratory teaching assistant for 1H NMR spectroscopy. Students interpret the IR spectrum and the 1 H NMR spectrum to confirm ester formation and evaluate purity. Students also smell the product (by wafting) to characterize the ester. Students then reflect on the importance of green chemistry in their postlaboratory report. A handout of important principles in green chemistry is included in the Supporting Information.
■
RESULTS AND DISCUSSION
Synthesis and Characterization
Because the Fischer esterification is an equilibrium process, procedures A and B used either excess alcohol or excess carboxylic acid to drive the equilibrium toward product formation using Le Châtelier’s principle. Students chose the best procedure for their reaction, giving careful consideration to factors such as ease of removal of either excess alcohol or excess carboxylic acid (boiling point, melting point, and solubility of all species, including the ester product), and the current cost of commercially available reagents, which students obtained online as part of their prelaboratory assignment. Students were reminded that methanol and ethanol can be removed using a B
dx.doi.org/10.1021/ed400721p | J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Laboratory Experiment
system. Variations in the absorbing capacity of different reagents and inhomogeneities in the microwave field distribution lead to different reaction temperatures in individual reaction vessels, and thus different product conversions over the same time.8,12 This can make obtaining reproducible yields difficult. In addition, in laboratory sections with fewer than eight students, lower microwave power settings were necessary to prevent overheating and decomposition. In practice, the highest overall yields were obtained when the probe was placed in a reaction vessel containing a medium microwave absorbing alcohol, such as 1-butanol. A more detailed procedure can be found in the Supporting Information.
rotary evaporator, but that higher molecular weight alcohols require a more time-consuming short-path distillation. Higher molecular weight esters were deliberately chosen to prevent students from losing the ester products on the rotary evaporator (the lowest boiling ester has a boiling point of 142 °C). Students were also told about the importance of green chemistry and how microwave reactions can minimize or eliminate the use of organic solvent during synthetic transformations. Procedure A workup was designed to maximize removal of excess alcohol. Any methanol or ethanol remaining in the organic phase after aqueous workup was easily removed by rotary evaporation. Procedure B workup was designed to maximize removal of the excess carboxylic acid. Use of hexanes as a solvent maximized transfer of the polar carboxylic acid into the aqueous phase, thus minimizing the number of subsequent sodium bicarbonate washes necessary to remove all of the carboxylic acid.10 After the appropriate workup procedure was used, esters showed high purity by spectroscopic characterization and no additional purification was necessary. Representative student 1H NMR spectra and IR spectra are included in the Supporting Information. This experiment took advantage of the availability of a variety of carboxylic acids and alcohols that can be combined to form an impressive range of esters. A sampling of the esters synthesized by students is shown in Figure 1. Not surprisingly, there was significant variation in student yields obtained for the various esters, and an even broader variability in the smells that students described for their esters. Ester R, for example, smelled like wintergreen to one student, mouthwash to another, and root beer to yet another. Ester I smelled like fruit cocktail to one student and like an energy drink to another. The grading rubric for this experiment focused on experimental procedure and product purity rather than yield or correct fragrance. Product purity was assessed by analysis of the 1H NMR spectra and IR spectra of the student’s ester. The appropriate experimental protocol provided the pure ester after workup. If noticeable amounts of carboxylic acid or alcohol were present by spectroscopic analysis, this resulted in a loss of points. This grading structure relieved students of the pressure to compete with their classmates for highest yield or “correct” fragrance, and provided them with the opportunity to take ownership of their unique ester.
Student Commentary
This experiment was conducted two times by a total of approximately 150 students over a period of two years in the third quarter of a three-quarter second-year undergraduate organic chemistry laboratory class populated by chemistry majors and honors students. The experiment was completed in 2−3.5 h. In the final quarter of lab, students are gradually moved toward increasing independence with challenging discovery-based guided-inquiry laboratories, culminating in a final three-week open-inquiry experiment.13,14 The ultimate pedagogic goal is to prepare students to go directly into undergraduate research after finishing the course. At the end of the quarter, students evaluated each experiment and provided feedback. Many of the students chose this as their favorite experiment, including comments such as: “The amount of time it took for the reaction to occur was amazingly fast thanks to the microwave” and “It was interesting how a carboxylic acid that could smell so bad can turn into a sweet scent.” Other students were fascinated by the fact that changing the carbon chain by one or two carbons could have such a dramatic effect on the fragrance of the ester. One student commented: “This experiment drilled Fischer esterification into my brainextremely helpful on both of my Ochem midterms.” Another wrote: “the retrosynthetic concepts were easy and fun to complete (similar to a real synthetic organic chemist)” and “It made us think and decide parts of the procedures for ourselvesit was a free, yet guided experiment.” Others liked the instant feedback that the correct smell gave them: “Based on the scent alone, you were able to determine whether the desired product had been isolated.”
■
Microwave Conditions
The application of microwave heating exposes students to modern technological advances in synthesis that allow them to adopt green chemistry principles, such as eliminating nonparticipating solvents from the reaction mixture. Microwave heating, when compared to traditional reflux heating, is more operationally simple and requires less time and energy.9 In our experience, minimal training is required to operate laboratory grade microwave reactors. Safety features, such as ventilation, temperature control, automatic stirring, and pressure relief, provide excellent control of the reaction conditions. Heating a pressurized reaction vessel allows higher temperatures without the need for a higher boiling solvent, which increases the reaction rate.7a,11 The microwave carousel allows simultaneous processing of up to 24 reaction vessels (parallel processing). In this experiment, up to 14 different esters were irradiated at the same time. Parallel processing can be problematic because only one vessel temperature can be monitored by the microwave
CONCLUSION By applying microwave heating, green chemistry principles, and combinatorial chemistry to the Fischer esterification reaction, an operationally simple laboratory experiment was designed for a second-semester undergraduate organic chemistry course. All reagents were commercially available, inexpensive, and common to teaching laboratory stockroom inventories. The experiment covered techniques essential to synthesis: acid/base extraction, washing and drying liquids, vacuum filtration, and solvent removal by rotary evaporation. The reaction was conducted neat and was run at the microscale level, which reduced waste, increased environmental awareness in students, and reduced operational costs. IR and NMR spectroscopy, two central spectroscopic techniques, were used to confirm the ester product and to evaluate its purity. Finally, interpretation of the fragrance of the ester provided a fun element of product analysis. C
dx.doi.org/10.1021/ed400721p | J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
■
Laboratory Experiment
or Microwave Conditions. J. Chem. Educ. 2007, 84, 1477−1479. (d) Musiol, R.; Tyman-Szram, B.; Polanski, J. Microwave-Assisted Heterocyclic Chemistry for Undergraduate Organic Laboratory. J. Chem. Educ. 2006, 83, 632−633. (e) Martin, E.; Kellen-Yuen, C. Microwave- Assisted Organic Synthesis in the Organic Teaching Lab: A Simple, Greener Wittig Reaction. J. Chem. Educ. 2007, 84, 2004− 2006. (f) Horta, J. E. Simple Microwave-Assisted Claisen and Dieckmann Condensation Experiments for the Undergraduate Organic Chemistry Laboratory. J. Chem. Educ. 2011, 88, 1014−1015. (g) Baar, M. R.; Falcone, D.; Gordon, C. Microwave-Enhanced Organic Syntheses for the Undergraduate Laboratory: Diels−Alder Cycloaddition, Wittig Reaction, and Williamson Ether Synthesis. J. Chem. Educ. 2010, 87, 84−86. (h) Miller, T. A.; Leadbeater, N. E. Microwave Assisted Synthesis of Biodiesel in an Undergraduate Organic Chemistry Laboratory Course. Chem. Educ. 2009, 14, 98− 104. (i) Montes, I.; Sanabria, D.; Garcia, M.; Castro, C.; Fajardo, J. A Greener Approach to Aspirin Synthesis Using Microwave Irradiation. J. Chem. Educ. 2006, 83, 628−631. (j) McKensie, L. C.; Huffman, L. M.; Hutchison, J. E.; Rogers, C. E.; Goodwin, T. E.; Spessard, G. O. Greener Solutions for the Organic Chemistry Teaching Lab: Exploring the Advantages of Alternative Reaction Media. J. Chem. Educ. 2009, 86, 488−493. (k) Damkaci, F.; Dallas, M.; Wagner, M. A MicrowaveAssisted Friedel−Crafts Acylation of Toluene with Anhydrides. J. Chem. Educ. 2013, 90, 390−392. (8) Kappe, C. O.; Dallinger, D.; Murphree, S. S. Starting with Microwave Chemistry. In Practical Microwave Synthesis for Organic Chemists: Strategies, Instruments, and Protocols; Wiley-VCH Verlag GmbH & Co.: Weinheim, Germany, 2009; pp 161−201. (9) Kappe, C. O. Controlled Microwave Heating in Modern Organic Synthesis. Angew. Chem., Int. Ed. 2004, 43, 6250−6284. (10) This “two procedures fits all” strategy broke down when ester O was synthesized. The large excess of phenylacetic acid solidified upon cooling, and it was not soluble enough in either hexane or water to dissolve. For this ester workup, diethyl ether was used, and additional sodium bicarbonate washes were necessary to remove excess carboxylic acid. (11) Zovinka, E. P.; Stock, A. E. Microwave Instruments: Green Machines for Green Chemistry? J. Chem. Educ. 2010, 87, 350−352. (12) Kappe, C. O.; Dallinger, D.; Murphree, S. S. Microwave Processing Techniques. In Practical Microwave Synthesis for Organic Chemists: Strategies, Instruments, and Protocols; Wiley-VCH Verlag GmbH & Co.: Weinheim, Germany, 2009; pp 87−160. (13) Horowitz, G. The State of Organic Teaching Laboratories. J. Chem. Educ. 2007, 84, 346−353. (14) Dunlap, N.; Martin, L. J. Discovery-based Labs for Organic Chemistry: Overview and Effectiveness. In Advances in Teaching Organic Chemistry; ACS Symposium Series; American Chemical Society: Washington, DC, 2012; pp 1−11.
ASSOCIATED CONTENT
* Supporting Information S
Instructor notes, the student experimental handout, representative student 1H NMR spectra, representative student IR spectra, and compiled 1H NMR data of the unpurified reactions after workup. The microwave method for 8−14 students and 4−8 students is included. This material is available via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS We thank the approximately 150 students in CHEM M52LC who participated in this experiment. We thank the teaching assistants, Margaret Greene, Carl Vogel, and Gidget Tay, for their enthusiasm and hard work. We also thank Michael Tran for his assistance in supervising the organic laboratories and providing materials for this experiment, as well as CEM Corporation for their tremendous customer service, for their help in trouble-shooting, and for providing microwave methods for smaller class sizes.
■
REFERENCES
(1) The following are examples of undergraduate laboratory experiments using the Fischer esterification: (a) Bromfield-Lee, D. C.; Oliver-Hoyo, M. T. An Esterification Kinetics Experiment That Relies on the Sense of Smell. J. Chem. Educ. 2009, 86, 82−84. (b) Birney, D. M.; Starnes, S. D. Parallel Combinatorial Esterification: A Simple Experiment for Use in the Second-Semester Organic Chemistry Laboratory. J. Chem. Educ. 1999, 76, 1560−1561. (c) Wade, P. A.; Rutkowsky, S. A.; King, D. B. A Simple Combinatorial Experiment Based on Fischer Esterification. An Experiment Suitable for the First-Semester Organic Chemistry Lab. J. Chem. Educ. 2006, 83, 927−928. (d) Touaibia, M.; Guay, M. Natural Product Total Synthesis in the Organic Laboratory: Total Synthesis of Caffeic Acid Phenethyl Ester (CAPE), A Potent 5-Lipoxygenase Inhibitor from Honeybee Hives. J. Chem. Educ. 2011, 88, 473−475. (e) Clausen, T. P. Combining a Standard Fischer Esterification Experiment with Stereochemical and Molecular-Modeling Concepts. J. Chem. Educ. 2011, 88, 1007−1009. (2) Whitlock, C. R.; Bishop, P. A. A Streamlined Combinatorial Esterification. Chem. Educ. 2003, 8, 352. (3) Domin, D. S. A Review of Laboratory Instruction Styles. J. Chem. Educ. 1999, 76, 543−547. (4) Anastas, P. T.; Kirchhoff, M. M. Origins, Current Status, and Future Challenges of Green Chemistry. Acc. Chem. Res. 2002, 35, 686−694. (5) Anastas, P. T.; Warner, J. Principles of Green Chemistry. In Green Chemistry: Theory and Practice; Oxford University Press: New York, 1998; pp 29−55. (6) Leadbeater, N.; McGowan, C. Experiment 2−Esterification. In Clean, Fast, Organic Chemistry: Microwave-Assisted Laboratory Experiments; CEM Publishing: Matthews, NC, 2006; pp 5−59. (7) Examples of undergraduate laboratory experiments utilizing microwave-assisted organic synthesis: (a) Katritzky, A. R.; Cai, C.; Collins, M. D.; Scriven, E. F. V.; Singh, S. K. Incorporation of Microwave Synthesis into the Undergraduate Organic Laboratory. J. Chem. Educ. 2006, 83, 634−636. (b) Murphree, S. S.; Kappe, C. O. Microwave-Assisted Carbonyl Chemistry for the Undergraduate Laboratory. J. Chem. Educ. 2009, 86, 227−229. (c) Cook, A. G. A Knoevenagel Initiated Annulation Reaction Using Room Temperature D
dx.doi.org/10.1021/ed400721p | J. Chem. Educ. XXXX, XXX, XXX−XXX
