Communication pubs.acs.org/jchemeduc
Preparing 4‑Ethoxyphenylurea Using Microwave Irradiation: Introducing Students to the Importance of Artificial Sweeteners and Microwave-Assisted Organic Synthesis (MAOS) Spence C. Pilcher* and Joshua Coats Department of Natural Science, Northeastern State University, 611 North Grand Avenue, Tahlequah, Oklahoma 74464, United States S Supporting Information *
ABSTRACT: In today’s world of instant coffee, instant meals, and instant messaging, undergraduate students prefer not to have to wait 30−60 min for an organic reaction to take place. Heating with microwaves is rapidly becoming more commonplace due to dramatically reduced reaction times and higher product yields. Students appreciate the short reaction times and like working with advanced technology by means of the commercial microwave reactors available today. Furthermore, undergraduate organic students like being able to relate an experiment to something that they see every day. For these reasons, the synthesis of pharmaceuticals, extracting caffeine from tea, and isolating trans-cinnamaldehyde from cinnamon sticks are popular experiments. One such experiment is the synthesis of the artificial sweetener dulcin (4ethoxyphenylurea), which can be prepared from the reaction of p-phenetidine and urea. Artificial sweetening agents are extremely important to the food industry because of the national concern with diet and weight control. The synthesis of this particular sweetener typically takes at least 30 min to reach completion. However, using microwave irradiation, the reaction reached completion in 5 min using a temperature of 125 °C. This procedure was implemented into the second semester undergraduate organic chemistry laboratory curriculum where students successfully prepared dulcin with reported yields ranging from 10% to 86% and an average yield of 39% after recrystallization. KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Amides, Laboratory Instruction, Nucleophilic Substitution, Green Chemistry
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INTRODUCTION
compound where the students can readily understand the use of the formed product (an artificial sweetener). The majority of students are familiar with the associated trade names for artificial sweetening agents such as sucralose, aspartame, and saccharin. These artificial sweeteners are important to the food industry because of the national concern with diet and weight control and are exceedingly important medicinally for persons struggling with diabetes who must limit their consumption of sugar. Students are less familiar with dulcin (4-ethoxyphenylurea) which is about 200 times sweeter than sucrose.4 It was discovered in 1884 by Joseph Berlinerblau shortly after the first synthetic sweetener, saccharin, was developed in 1878.5 Despite its discovery only six years after saccharin, dulcin was not as successful marketwise as saccharin even though it held an advantage over saccharin in not possessing a bitter aftertaste.5 Artificial sweeteners are not without their controversy due to adverse physiological effects that have been shown, or in other cases speculated. For example, following an FDA study in 1951 citing chronic toxicity from prolonged use, dulcin was removed from the market (almost 70 years after its discovery and early
At the end of the introductory organic chemistry laboratory course, an informal survey is given as to which experiments the students enjoyed and which laboratories they did not like. The general pattern that can be inferred from these surveys is that undergraduate organic lab students typically like experiments that use familiar substances or synthesize compounds that have a readily understood function. One of the most common questions after an organic synthesis in the organic laboratory is “What is a use for this compound?” Conversely, students listed experiments that had extended waiting periods involved among their least favorite laboratories. For many organic syntheses involving extended reaction times (over 30 min), microwaveassisted organic synthesis (MAOS) has become increasingly popular by shortening that reaction time, increasing the yield, and in many cases resulting in increased product purity.1 MAOS has allowed many reactions that were too long to fit into the time constraints of a typical undergraduate organic lab (3−4 h) to be performed and/or have allowed more time for characterization of the obtained compound.2,3 However, many of these procedures are for products detailing reactions that have been covered in the organic chemistry lecture, and the students may not see a direct function of the formed product. This procedure details the microwave-assisted synthesis of a © XXXX American Chemical Society and Division of Chemical Education, Inc.
Received: April 14, 2016 Revised: November 26, 2016
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DOI: 10.1021/acs.jchemed.6b00279 J. Chem. Educ. XXXX, XXX, XXX−XXX
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Communication
Scheme 1. MAOS of 4-Ethoxyphenylurea
Scheme 2. Generation of Isocyanic Acid
Scheme 3. Reaction of p-Phenetidine with Isocyanic Acid
toxicity tests).6 A study in the early 1970s linked saccharin with the development of bladder cancer in rats which resulted in a requirement that all food containing saccharin be labeled with a warning label indicating: “Use of this product may be hazardous to your health. This product contains saccharin which has been determined to cause cancer in laboratory animals.”7 However, in 2000, the warning labels were removed after studies showed that physiological differences between rats and humans indicated that tumor formation in rats was not predictive of tumor formation in humans, and saccharin was deemed safe for human consumption.7 Concerns about possible carcinogenic properties of aspartame were raised in the 1970s and again in 1996 by a 60 Minutes report suggesting that aspartame was linked to brain cancer.8 These results have been discredited by the FDA, and aspartame has been reviewed as safe for human consumption.9 There are different procedures that can be used to synthesize dulcin including a multistep synthesis from acetaminophen requiring two laboratory periods.10 By contrast, the method described here uses microwave irradiation, requires just one laboratory session, and parallels the traditional synthesis of dulcin involving the reaction of p-phenetidine (p-ethoxyaniline) with isocyanic acid (Scheme 1).11 The instability of isocyanic acid requires its in situ formation from ammonium cyanate which exists in equilibrium with urea under acidic conditions (Scheme 2).12 Nucleophilic addition of the amino group of pphenetidine to isocyanic acid followed by protonation affords the urea functional group observed in the product (Scheme 3).
In this laboratory experiment, students learn the importance and history of artificial sweeteners, along with the controversy associated with some of these sweeteners. This allows students to associate organic chemistry to a substance with which they are readily familiar making organic chemistry relevant to their everyday life. The students gain an understanding that MAOS can be used to speed reaction times oftentimes increasing the yield and purity of a product obtained from an organic reaction. Students learn that generating reagents in situ is sometimes necessary for organic reactions which is a topic that may have limited coverage in the introductory organic chemistry lecture sequence. Additionally, this particular reaction is not just an illustration of a reaction covered in lecture. The students have to use their knowledge about nucleophilic substitution on a carbonyl compound to figure out how the reaction works. Assessment of the learning outcomes involved the completion of pre- and postlaboratory questions included on their laboratory reports and performance on questions associated with the experiment embedded on their written final examination.
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EXPERIMENTAL DETAILS All reactions in a lab section were performed in a commercial microwave system designed for microwave-assisted organic syntheses at one time using the following procedure. To a microwave reaction vessel equipped with a magnetic stir bar were added urea, p-phenetidine, and water. The reaction vessel was then fitted with the load disk, capped, and shaken by hand. The cap was removed, and concentrated HCl and glacial acetic B
DOI: 10.1021/acs.jchemed.6b00279 J. Chem. Educ. XXXX, XXX, XXX−XXX
Journal of Chemical Education
Communication
The 1H NMR spectrum for p-phenetidine displays a peak for the amino group at 3.33 ppm whereas the product (dulcin) has the two amido groups shifted further downfield. The chemical shift from the NH2 in the product is similar to the chemical shift displayed by the NH2 group in urea (5.5 ppm), but the signal for the NH from dulcin that is between the carbonyl and aromatic ring is shifted further downfield past the aromatic peaks at 8.4 ppm. The appearance of this peak indicated that the students successfully made the product (spectra for a student-made product are included in the Supporting Information).
acid were added to the reaction vessel. The vessel was once again shaken before being placed in the microwave turntable. The reaction vessel was ramped to a temperature of 125 °C over a 3 min period and then held at this temperature for 5 min. Once the vessel had cooled to room temperature, cold water was added to the solidified mass to create a slurry of crystals. The crude product was recrystallized from boiling water using decolorizing charcoal to remove any colored impurities. The recrystallized product was weighed, and the melting point was determined. IR and NMR spectroscopies were used to further characterize the formed product. Detailed instructions are available in the Supporting Information.
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HAZARDS
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RESULTS AND DISCUSSION
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SUMMARY This experiment provides students the opportunity to work with advanced technology (a microwave-assisted organic synthesis) that is currently being used extensively in the chemical and pharmaceutical industry and exposes them to a topic (artificial sweeteners) in which they are readily familiar. The chemicals required for the synthesis are relatively inexpensive, and the procedure uses water as both the solvent and in the recrystallization of the formed product. The use of water in the procedure and the clean, fast, efficient synthesis that is carried out using the microwave would classify the performed reaction in the category of green chemistry. The microwave procedure was first developed and carried out by a third year undergraduate research student and introduced into the second semester introductory organic chemistry laboratory course at NSU for six years encompassing nine sections and 152 students working individually. The procedure was performed in a 3-h laboratory period and allowed enough time for characterization. Alternatively, if the procedure is adopted, the instructor may choose to distribute the NMR spectra since dulcin is sparingly soluble in CDCl3 and deuterated DMSO must be used. Students’ grades on their laboratory report indicated the success of the learning goals for the experiment. Of the 152 students, 84% received a grade of A or B (>80%) on the graded lab report that included pre- and postlab questions with only 5% of students receiving a grade of less than a C (
