In the Laboratory
Synthesis of N,N-Diethyl-3-methylbenzamide (DEET): Two Ways to the Same Goal Jean Christophe Habeck, Lamine Diop, and Michael Dickman* Coll ege Universitaire de Saint-Boniface, Winnipeg, MB, Canada, R2H 0H7 *
[email protected] The laboratory synthesis of N,N-diethyl-3-methylbenzamide (DEET) is an effective way to combine organic chemistry teaching with a student's day-to-day life outside the classroom. Interest in DEET as a mosquito repellent has been heightened because of the rise of the West Nile virus across much of North America (1). To take advantage of the increased awareness of DEET, we took another look at its preparation, which commonly is carried out by reacting carboxylic acid with thionyl chloride (SOCl2) followed by aqueous condensation with an amine to give the amide (2) (Scheme 1, method 1). Our goal was to develop a different route to DEET to give our beginner chemistry students a deeper appreciation of the flexibility of organic chemistry synthesis. Our starting point was a very clean method developed by Knoess and Neeland (3) based on the classic procedure mentioned above. Their modifications of the initial reaction giving m-toluoyl chloride eliminated the need for vacuumdistillation at the end of the synthesis. Thus, the crude DEET they obtained was a pale oil needing no further purification. To complement their synthesis, we decided that another way of converting m-toluic acid to the acyl chloride followed by a nonaqueous addition of diethylamine was necessary. Such an alternative has been published by LeFevre (4), but it requires two or three laboratory periods to complete and on a technical level is more suited to upper-level undergraduates. We were looking for a quick, easy, and inexpensive method to be used in a first- or second-year laboratory. This led us to the following procedure using oxalyl chloride (5) (Scheme 1, method 2).
Scheme 1. Synthesis of DEET by Two Methods: (Top) Using Thionyl Chloride and an Aqueous Second Step and (Bottom) Using Oxalyl Chloride and an Organic Second Step
Scheme 2. Carboxylic Acid-Acid Chloride Exchange Reaction Catalyzed by DMF
Experimental Procedure Excess oxalyl chloride in hexane, with N,N-dimethylformamide (DMF) as a catalyst, efficiently converts carboxylic acids to acyl chlorides. The volatile side-products (CO, CO2, and HCl) escape through a drying tube, and all other nonvolatile, unwanted chemical species precipitate. After 30 min at room temperature, filtration to remove the solids and evaporation to remove excess oxalyl chloride yields the crude acyl chloride. Subsequent condensation with excess secondary amine at 0 °C for 1 min in hexane followed by another round of filtration and evaporation leaves the amide in the flask (6) (Scheme 1, method 2). We found that oxalyl chloride tolerated our experimental conditions. No special attempt was made to exclude water aside from using a CaCl2 drying tube and an oven-dried roundbottomed flask during the first step. 528
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Results and Discussion When we attempted this procedure, starting with m-toluic acid and finishing with diethylamine, DEET was obtained in high yield. Second-year students had no problem completing the synthesis within a three-hour laboratory period. Analysis was done by comparative TLC, and each student was asked to return later to acquire a NMR spectrum of their sample on our 60 MHz teaching instrument.
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Vol. 87 No. 5 May 2010 pubs.acs.org/jchemeduc r 2010 American Chemical Society and Division of Chemical Education, Inc. 10.1021/ed800169h Published on Web 03/10/2010
In the Laboratory Table 1. Comparison of the Two Synthetic Methods Area of Comparison
Method 1: Thionyl Chloride
Method 2: Oxalyl Chloride
Basic mechanism
Nucleophilic tetrahedral substitution
Nucleophilic tetrahedral substitution
Catalyst
Pyridine
DMF
Effect of the catalyst on the mechanism
Nucleophilic catalysis: the pyridine introduces an additional substitution.
Production of a new reactive species, N,N-dimethylchloromethyleneammonium chloride, which reacts with the carboxylic acid.
Equilibrium
Gas evolution pushes reaction to completion
Gas evolution pushes reaction to completion
The formal laboratory exercise involved having each student in a group of two students doing either method 1 of Knoess and Neeland or method 2, the one just described. We asked the students to compare the difficulty, time, yield, and purity of the syntheses. Most students found method 2 to be less work, but the yield was lower, usually around 80%, compared to close to 100% for method 1. Both methods gave pure DEET as measured by 1 H NMR (60 MHz, CDCl3, δ): 1.17 (t, 6H), 2.37 (s, 3H), 3.38 (broad multiplet, 4H), and 7.16 (m, 4H), which was identical to commercial product. The TLC analysis showed one spot when the synthetic product was mixed with commercial product. We also encouraged the students to analyze the mechanistic similarities and differences between the two ways of producing the intermediary acyl chloride. The thionyl route involves nucleophilic substitution by a chloride ion to eliminate a highly reactive acyl chlorosulfite that degrades to SO2 and HCl. Pyridine probably introduces an additional substitution step, which accelerates the overall reaction. The oxalyl route is an exchange reaction converting one carboxylic acid-acid chloride mixture to another and, therefore, an equilibrium that must be directed to one side. Oxalyl chloride is ideal for this method because oxalic acid is unstable and breaks down to CO, CO2, and HCl. Thus, a mixture of carboxylic acid and oxalyl chloride will give the new acid chloride. DMF serves as a powerful catalyst in this conversion by combining with oxalyl chloride to produce the iminium salt, N, N-dimethylchloromethyleneammonium chloride (7) (Scheme 2). This highly reactive species activates the carboxylic acid thus taking the reaction to completion in a few minutes. The type of analysis we hope to see from the students is presented in Table 1. Hazards Oxalyl chloride and diethylamine are toxic and volatile. They should be used only in a fume hood. Both evaporation steps should be made with a water aspirator installed in a fume hood. Hexane is flammable. DMF is toxic. m-Toluic acid is incompatible with strong oxidizing agents, and causes eye, skin, and respiratory tract irritation. Pyridine may be combustible at high
r 2010 American Chemical Society and Division of Chemical Education, Inc.
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temperature and causes eye, skin, and respiratory tract irritation. Thionyl chloride is corrosive and causes burns to any area of contact, and vapors cause severe irritation to skin, eyes, and respiratory tract. It reacts violently with water. Ether is extremely flammable and harmful if swallowed, inhaled, or absorbed through skin. Ethyl acetate is flammable and harmful if swallowed or inhaled. Conclusion Thus m-toluic acid is converted easily and quickly in two different ways to the product DEET. More importantly, students observe firsthand that a given compound can be transformed in a variety of ways to the same final product. It is our hope that this sort of lab exercise will impress upon the students that if ever an envisaged synthetic method turns out to be impossible, there almost always is another method to the same goal. Literature Cited 1. (a) Katritzky, A. R.; Wang, Z.; Slavov, S.; Tsikolia, M.; Dobchev, D.; Akhmedov, N., G.; Hall, C. D.; Bernier, U. R.; Clark, G. G.; Linthicum, K. J. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 7359– 7364. (b) Katz, T. M.; Miller, J. H.; Hebert, A. A. J. Am. Acad. Dermatol. 2008, 58, 865–871. (c) Roberts, J. R.; Reigart, J. R. Pediatr. Ann. 2004, 33, 443–453. (d) Sudakin, D. L.; Trevathan, W. R. J. Toxicol. Clin. Toxicol. 2003, 41, 831–839. 2. Solomons, T. W. G.; Fryhle, C. B. Organic Chemistry, 9th ed.; John Wiley & Sons, Inc.: New York, 2008; pp 794-807. 3. Knoess, H. P.; Neeland, E. G. J. Chem. Educ. 1998, 75, 1267–1268. 4. LeFevre, J. W. J. Chem. Educ. 1990, 67, A278–A279. 5. Ward, D. E.; Rhee, C. K. Tetrahedron Lett. 1991, 32, 7165–7166. 6. Smith, M. B.; March, J. Advanced Organic Chemistry, 5th ed.; John Wiley & Sons Inc.: New York, 2001; pp 506-507. 7. Fulisawa, T.; Sato, T. Org. Synth. 1988, 66, 121–124.
Supporting Information Available Detailed instructions for students and some additional tips for instructors. This material is available via the Internet at http://pubs.acs. org.
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