Two Approaches to the Synthesis of Dimethyl Fumarate That

Laboratory Experiment pubs.acs.org/jchemeduc

Two Approaches to the Synthesis of Dimethyl Fumarate That Demonstrate Fundamental Principles of Organic Chemistry Brian E. Love* and Lisa J. Bennett Department of Chemistry, East Carolina University, Greenville, North Carolina 27858, United States S Supporting Information *

ABSTRACT: Two experiments are described which lead to the preparation of dimethyl fumarate, a compound currently used in the treatment of multiple sclerosis. Preparation of a compound with “real-world” applications is believed to increase student interest in the experiment. One experiment involves the isomerization of dimethyl maleate to the target compound through reversible nucleophilic addition of an amine, assisted by a Lewis acid catalyst. This experiment facilitates a discussion of the requirements for nucleophilic addition to alkenes, Lewis acid catalysis of carbonyl-based reactions, as well as stereochemical effects on compound stability and physical properties, such as melting point. As the experiment involves heating a solution at reflux, the rationale for and the equipment involved in this technique can also be discussed. The second experiment involves a classic Fischer esterification. This not only reinforces a reaction students will have studied in their lecture class but also facilitates a discussion of how reversible reactions can be driven toward product formation through an application of LeChatelier’s principle. Additionally, the product crystallizes out of the reaction mixture in a rather dramatic fashion, making the experiment visually memorable. The fact that the same compound can be made by two entirely different reactions helps illustrate the point that even simple compounds can be prepared by a variety of synthetic routes. KEYWORDS: Second-Year Undergraduate, Organic Chemistry, Laboratory Instruction, Hands-On Learning/Manipulatives, Esters, Medicinal Chemistry, Synthesis

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INTRODUCTION Laboratory experiments in which some commonly known or useful compound is prepared are often especially appealing to students, as the “real-life application” of such syntheses is more readily apparent. Many such experiments have been described in the educational literature. For example, just within the past five years, a number of syntheses of natural products have been described. The target molecules have either had recognizable fragrances,1,2 been medicinally useful,3,4 or possessed other interesting properties.5 Syntheses of other compounds with medicinally relevant6−8 or other properties9,10 have also been described. In March 2013, Biogen Idec began to market a drug for the treatment of multiple sclerosis, a disease of the central nervous system that is often disabling. The drug is sold under the trade name Tecfidera, and early sales figures were impressive, with annual sales in 2014 reaching $2.9 billion.11 The active ingredient in Tecfidera is the simple diester dimethyl fumarate. Reported herein are two different syntheses of dimethyl fumarate that students have been conducting in second-year © 2017 American Chemical Society and Division of Chemical Education, Inc.

undergraduate organic chemistry laboratories. The two experiments not only provide the students with an opportunity to prepare a medicinally useful compound, but together they illustrate the fact that even simple compounds can often be synthesized in completely different ways.

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EXPERIMENTS

Isomerization Approach

The first experiment, titled “Alkene Isomerization,” involves heating a mixture of dimethyl maleate, morpholine, and zinc chloride at reflux in methanol as shown in Scheme 1. This allows isomerization of the cis diester (dimethyl maleate) to the more thermodynamically favorable trans diester (dimethyl fumarate). Experiments involving this isomerization have been described previously in education-related journals, utilizing either Received: October 25, 2016 Revised: July 19, 2017 Published: August 22, 2017 1543

DOI: 10.1021/acs.jchemed.6b00818 J. Chem. Educ. 2017, 94, 1543−1546

Journal of Chemical Education

Laboratory Experiment

Scheme 1. Isomerization of Dimethyl Maleate to Dimethyl Fumarate

Scheme 2. Esterification of Fumaric Acid to Dimethyl Fumarate

halogens12−14 or amines15,16 as the isomerization catalysts, with diethylamine being used in both amine-catalyzed reactions. In one case16 it was used as the solvent, and in the other,15 a variety of amine solutions, ranging from 165−33 mol % (relative to dimethyl maleate) were examined. In this experiment, approximately 20 mol % of morpholine is used in the presence of approximately 7 mol % of zinc chloride. After allowing the isomerization to occur, the product is separated from the reaction mixture by means of an ether extraction. The solvent is allowed to evaporate from the ethereal solution, and students then isolate the product by simply scraping it out of the container into which the original solution had been placed. The dimethyl fumarate is characterized by its melting point during the subsequent lab session. Pedagogic goals of the experiment include (1) a demonstration of the need for electron-withdrawing groups on the alkene in order for nucleophilic addition to the alkene carbon to occur and (2) a demonstration that when two isomers are in equilibrium, the equilibrium will favor the more stable isomer. To assess students’ understanding of these concepts, they are asked to respond to specific questions on the write-up sheet for the experiment. With regard to the need for an electron-deficient alkene, students are asked, “Do you think this method (using morpholine and zinc chloride) could be used as a high-yielding method to convert cis-2-butene into trans-2-butene? Why or why not?” With regard to the position of the equilibrium, they are asked, “Do you think this method (using morpholine and zinc chloride) could be used as a highyielding method to convert dimethyl fumarate into dimethyl maleate? Why or why not?” (see the Supporting Information for an example of the write-up sheet for this experiment). The prelab lecture for this experiment typically lasts from 45 min to 1 h, including the time allotted for taking the prelab quiz. Students then conduct the experimental individually, typically completing the experiment in 1−1.5 h.

Although dimethyl fumarate does not possess a distinctive fragrance, it offers the advantage of crystallizing in a fashion that most students find memorable, in addition to its medicinal significance. The product is collected by suction filtration and characterized by its melting point after traces of solvent have been allowed to evaporate. Pedagogic goals of the experiment include (1) a demonstration of the need for an excess of methanol in order to drive the equilibrium toward the product through an application of LeChatelier’s principle and (2) understanding the role of the acid catalyst in the reaction. Students’ understanding of the first concept can be assessed through questions on the write-up sheet such as, “According to reaction stoichiometry, only two equivalents of methanol should be necessary to convert fumaric acid into dimethyl fumarate, so why was an excess of methanol used?” and, “Would Fischer esterification be a useful method for converting fumaric acid into its mono methyl ester (HO2CCHCHCO2Me)? Briefly explain how this could be done, or why it would not work.” Alternatively, students’ understanding of this concept can be assessed through similar questions on the prelab quiz (see the Supporting Information). Students’ understanding of the role each reagent plays in the reaction is assessed by means of the prelab quiz. The prelab lecture for this experiment typically lasts around 45 min, including the time allotted for taking the prelab quiz. Students then conduct the experimental individually, typically completing the experiment in about 1.5 h.

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HAZARDS


Dimethyl maleate is harmful if swallowed, and both dimethyl maleate and dimethyl fumarate may cause an allergic reaction upon contact with the skin. Methanol is toxic by ingestion, inhalation, and absorption through the skin. Methanol can also permeate nitrile gloves, therefore gloves should be replaced if methanol contacts them. Additionally, methanol is flammable. The hazards described for methanol also apply to methanolic solutions used in the experiment. Zinc chloride is an irritant, harmful if swallowed, and very toxic to aquatic life. Morpholine may cause irritation upon either skin contact or inhalation of vapors. Diethyl ether is extremely flammable and is harmful if swallowed.

Esterification Approach

The second experiment involves a classic Fischer esterification, as shown in Scheme 2. Numerous experiments involving Fischer esterification have appeared previously in the chemicaleducation literature, with most target molecules having been selected on the basis of their fragrance. Both conventional17−21 and microwave heating22,23 have been utilized, and some experiments demonstrate combinatorial chemistry through the production of a variety of esters from several carboxylic acid and alcohol reactants.24−26


Both fumaric acid and p-toluenesulfonic acid are harmful if swallowed and are irritants. In addition, p-toluenesulfonic acid 1544




On the basis of the data included in the Supporting Information, the average melting-point range is 9.6 °C for products obtained in this experiment. This is deceptively large, however, because the data contain a number of exceptionally large melting-point ranges. The median value for these data is 5 °C, and the mode is 2 °C. The average percent yield for this experiment was 47%. Prelab quiz scores for four sections of lab were compared (approximately 20 students per lab), with quiz averages for each section ranging from a low of 49% to a high of 73%. The average for all four sections was 64%.

is corrosive. Hazards associated with dimethyl fumarate and methanol are identical to those described for the isomerization experiment.

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RESULTS AND DISCUSSION

General Discussion

Both experiments have been taught for over 10 years in secondyear undergraduate organic chemistry laboratories, which have typical enrollments of approximately 500 students each semester. Prelab lectures for the experiments typically last 40−50 min, including the time provided to take a prelab quiz. Although there is significant variation among students regarding the time needed to complete the actual experiments, most students require no more than 90 min to complete either experiment. Examples of student data obtained (yields and melting points) are included in the Supporting Information. In some cases yields of greater than 100% were reported (due in no doubt to impure samples), and some melting points that were higher than literature values were recorded. In most cases, melting points, even when the range is narrow, are below literature values. This is due at least in part to the use of nonmercury thermometers which have not been meticulously calibrated and have been found to read as much as 8 °C low at temperatures near the melting point of dimethyl fumarate.


Use of a Fischer esterification not only exposes students to a “classic” chemical transformation but also provides an opportunity to discuss the phenomenon of organic “name reactions.” As part of the prelab lecture, the mechanism of a Fischer esterification is described, which also allows a review of reversible reactions in general. Students are reminded of how the use of an excess of reagent (in this case, the alcohol) allows the equilibrium to be driven toward product formation through an application of LeChatelier’s principle. Under the reaction conditions employed, the esterification is complete after approximately 45 min of heating the solution at reflux, so the experiment can easily be completed in one 3 h lab session (including time for the prelab lecture and quiz). At the end of the reflux period, the product is completely soluble in the hot methanol, but as the solution cools, the product crystallizes out, often “filling” the container with transparent crystals of dimethyl fumarate. This not only provides product of high purity but also is visually appealing and often fascinating for the students to observe, since once the crystallization begins, the process is usually complete in under a minute. (See still photos and a short, low-resolution movie in the Supporting Information.) p-Toluenesulfonic acid is used to catalyze the reaction, and the practical advantages of this acid compared to gaseous HCl and concentrated sulfuric acid are often discussed as part of the prelab lecture. It is noted that p-toluenesulfonic acid is an easily measured solid, whereas sulfuric acid, being a liquid, is more susceptible to accidentally being spilled. The advantages it has over gaseous HCl are more readily appreciated. Since students are asked to calculate the percent yield for their product, it is sometimes necessary to point out that neither the methanol nor the p-toluenesulfonic acid are the limiting reagent for the reaction, since the former is used in large excess and the latter is a catalyst and hence is not consumed. On the basis of the data included in the Supporting Information, the average melting-point range is 8.3 °C for products obtained in this experiment. As with the alkeneisomerization experiment, the values used in determining this average include a number of exceptionally large melting-point ranges. The median value for these data is 3 °C, and the mode is 2 °C. The average percent yield for this experiment was only 27%. Prelab quiz scores for four sections of lab were compared (approximately 20 students per lab), with quiz averages for each section ranging from a low of 63% to a high of 76%. The average for all four sections was 71%.


The experiment promotes discussion of several useful topics. Concepts typically covered in the prelab lecture include: (1) the trend of the greater stability of trans alkenes relative to cis alkenes due to steric considerations (2) the lack of “free rotation” around typical carbon−carbon double bonds and thus the need to temporarily convert them into single bonds to allow for isomerization (3) electrophilic vs nucleophilic attack on alkenes, with the latter requiring the presence of an electron-withdrawing group conjugated with the alkene (4) Lewis acid catalysis of nucleophilic additions to carbonyl compounds The fact that dimethyl maleate is a liquid whereas dimethyl fumarate is a solid at room temperature also provides an entry into a discussion of the effect of molecular shape on physical properties. It is noted that dimethyl fumarate is more linear in overall shape than dimethyl maleate, and as a result, the molecules can pack together more tightly, resulting in stronger intermolecular forces holding the individual molecules together. The higher strength of the intermolecular forces (relative to dimethyl maleate) means that more energy is required to separate the molecules, which translates to a higher melting point. Although isomerizations of this type can be conducted with other amines without the need of Lewis acid catalysis,15,16 use of zinc chloride not only allows lesser amounts of the amine to be used, but also provides the opportunity to demonstrate and hence, discuss, Lewis acid catalysis of reactions of carbonyl compounds. Though not part of the experiment described herein, use of both morpholine and zinc chloride as catalysts also makes it possible to compare results obtained when both catalysts are used with those obtained when either one catalyst or the other is omitted. (See Supporting Information for other possible variations on the experiment as described.) 1545



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CONCLUSIONS/SUMMARY Although numerous experiments have been published that utilize isomerizations and/or esterifications, this combination of experiments not only involves preparation of a useful pharmaceutical agent (which helps emphasize the “real-world” applicability of the experiments) but also illustrates the fact that a variety of approaches may often be employed in the synthesis of a target molecule. Both of these experiments provide a context in which to discuss a number of significant chemical concepts. For example, the alkene-isomerization experiment not only facilitates a discussion of what methods can and cannot be used to isomerize alkenes but also brings to light issues such as nucleophilic attack on electron-deficient alkenes, Lewis acid catalysis of carbonyl-based reactions, and the effects of molecular shape on physical properties. The Fischer esterification experiment not only exposes students to a “classic” transformation in organic chemistry but also allows instructors to revisit some fundamental topics such as the reversibility of reactions and how equilibria can be shifted through application of LeChatelier’s principle. The experiment also provides students with an opportunity to observe crystallization of a product from a homogeneous solution. In this particular instance, the crystallization is typically fairly rapid (occurs within minutes of the solution cooling) and fills the beaker with crystals, making the event quite memorable.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available on the ACS Publications website at DOI: 10.1021/acs.jchemed.6b00818. The background information on the two experiments provided in a student “course pack”, including the experimental procedures and the “write-up sheets” students use to report results for the experiments, examples of student data obtained (yields and melting points), copies of the “instructor’s notes,” as well as questions used in prelab quizzes and other relevant information (PDF), (DOCX) Still photographs of the crystallization process (PDF) Short low-resolution movie showing the crystallization process (MOV)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] ORCID

Brian E. Love: 0000-0002-8649-1677 Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Brettler, S.; Van Zee, N.; Dragojlovic, V. Synthesis of Jasminaldehyde by a Crossed Aldol Condensation: An Experiment for Undergraduate Organic Chemistry Students. Chem. Educ. 2015, 20, 314−320. (2) Breton, G. W. The Synthesis of Isoamyl Acetate (Banana Oil) via an SN2 Reaction. Chem. Educ. 2011, 16, 6−8. (3) Nahra, F.; Riant, O. Recruiting the Students To Fight Cancer: Total Synthesis of Goniothalamin. J. Chem. Educ. 2015, 92, 179−182. (4) Touaibia, M.; Guay, M. Natural Product Total Synthesis in the Organic Laboratory: Total Synthesis of Caffeic Acid Phenethyl Ester 1546


Two Approaches to the Synthesis of Dimethyl Fumarate That

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