Deet

and "Jungle Juice 100".L In this paper a microscale synthesis and purification of deet is described. Previous authors (13) have synthesized deet on a ...
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The Microscale Synthesis and Purification of N,IY-Diethyl-m Toluamide [Deet) An Experiment for a Project-Oriented Organic Chemistry Laboratory

Joseph W. LeFevre State University 01 New Yak, College at Oswega Oswego. NY 13126

A popular experiment in undergraduate organic laboratories is the synthesis and pudeet rification of Nfl-diethvl-m-toluamide. ( I ) , whieh is the active ingredient in many commercial insect repellents such as "OFF" and "Jungle Juice 100".L In this paper a microscale synthesis and purification of deet is described. Previous authors (13) have synthesized deet on a multigram scale by converting m-toluic acid (2) to rn-toluyl

The procedure described here contains several changes in addition to reducing the scale of the synthesis. Specifically, his(trichloromethyl)carbonate, triphosgene (4), is used as the chlorinating agent and flash chromatography (5) is employed as a ~urificationmethod. Triphosgene (6) offers several advantages over thionyl chloride. Triphosgene is a solid, which is required in smaller amounts (only 113 equivalent relative to 2) and gives a cleaner reaction without the formation of Son or dark-colored impurities. Flash chromatography is especially well-suited to the microscale purification of deet since it provides students with experience in column chromatography, whieh is rapid because air pressure ia used to speed the separation. Thin-layer chramatography (TLC) may he used to choose the correct solvent for the column separation and to analyze the collected fractions if desired. The synthesis can be broken down into two steps; the conversion of rn-toluic acid (2) into m-toluyl chloride (3) (eq I). and the conversion of the acid chloride (3) todeet ( I ) by treatment with excess diethylamine (eq 2).

chloride (3) with thionyl chloride. Treatment of (3) with excess diethylamine produces deet, which can he purified by either vacuum distillation or column chromatogra. phy on alumina. Following the completion of our work a microscale synthesis of deet appeared (4).

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Journal of Chemical Education

and a 3-mL conical vial containing a spin vane. Let cool to room temperature in a desiccator. T o the vial add 136 mg (1.00 mmol) of pure m-toluie acid, 0.50 mL of methylene chloride (CHC$) and stir until the solid dissolves. T o this solution add 100 mg (0.34 mmal) of triphosgeneZand one drop of dry dimethylformamide (DMF). Fit the vial with the Claisen head. Cap the opening above the vial sndadd the condenser (fitted with the drying tuhe) to the other opening (4). Connect a piece of Tygon tubing from the drying tuhe to a small, inverted glass funnel placed just under the surface of a 10% NaOH solution in a beaker to neutralize the HCL generated during the preparation of 3. Heat the solution in a sand bath under reflux conditions for 1h. Buhhles of C 0 2 and HCI can be observed in the gas trap shortly after the reaction begins. The acid chloride (3) is not isolated but is reacted in situ according to the procedure below.

Conversion of m-Toluyl Chloride (3) into N,N-Dlethylm-toluarnide ( 1 )

Experimental

During the reflux period place 0.50 mL of CHzClzin a dry 1-mL conical vial and add 0.22 mL (2.15 mmal) of freshly distilled diethylamine via an automatic delivery pipet. Cool the solution to 0 OC in an ice bath. After the reflux period has ended, cool the clear, pale yellow reaction solution to 0 "C. Using a dry l-mL syringe inserted through the Claisen head, add dropwise at 0 'C over several minutes the diethylamine-CHgClz solution. The acid chloride is quite reactive and a copious white precipitate of diethylamine hydrochloride forms immediately. After all of the diethylamine has been added, test for basicity with a micropipet and litmus paper, and, if necessary, add more diethylamine dropwise until the solution is basic. Let the vial warm to room temperature to complete the reaction. Extract the solution with 1 mL of 10% NaOH to remove any unreacted rn-toluic acid. Extract the lower CHC12 layer with 1 mL of 3 N HC1 to remove the diethylamine hydrochloride followed by a l-mL water extraction. Dry the CH2C12layer with 150 mg of granular anhydrous sodium sulfate (NarSOn). Transfer the solution to a dry, tared 10-mL Erlenmeyer flask using a Pasteur filter pipet. Rinse the NanS01 with a fresh 0.30-mL portion of CHzCIz. Evaporate the CH2C12by leaving the flask unstoppered in the hood until the next laharatory period leaving crude deet as a pale yellow oil.

Synthesis of m-ToW Chloride (3) from m-TOIUICAdd (2)

(1) by flash Chromtogr~phy

Oven-dry a micro-reflux condenser, a CaCl2 drying tube, a microClaisen head,

Prepare 250 mL of solvent, 2:3 (by volume) ethyl aeetate:petroleum ether (b.p.

Purification of N,N-Diethylm-toluamide

30-60 "C). These solvents should he distilled prior t o use. Pack a chromatography column (30 em long, i.d. 7 mm) with -15 gof silica gel using the slurry technique. Silica Gel 60 (E. Merck #9385) particle size 0.040-0.063 mm (230-400 mesh) was used. Prepare asimple air flow controller by placine,. a number-two rubber s t o ~ o e rwith a hale runraining a glass Y joint i r m l v in t h e top 001t h e c o l u m n . C o n n e c t apiece oi'l'ygon tubing from one opening of the Y joint t o the air valve. Open the air valve slightly and use an index finger to adjust the pressure so that solvent flows through the column a t a rate of 1in.130 s (5). Collect 20 10-mL fractions in numbered test tubes. Check for the presence of deet in the fractions by TLC. Thinlayer chromatograms were run on 0.2-mm thickness Silica Gel 60 F254 plates with a plastic backing (E. Merck #5735). The spots were visualized hy a UV lamp a t 254 nm. Combine the deet-containing fractions and evaporate the solvent under reduced pressure leaving pure deet as a colorless oil. A proton NMR spectrum (in CDCls) end/or an IR spectrum (neat) can be run.

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Discusslon Valuable TLC experience can he gained by having students determine the correct composition of the flash chromatographic solvent, which should give an Rr value of 0.35 (5) far deet. Also. the Droeress of the reaction can be convenientl; monitored bv obaervmg t h e disappearance o f t h e spot corrr~pondingto m-tduic acid (2) a t R = 0.40 (solvent-ethyl acetate:petroleum ether, 1:2 by volume) and the appearance of two new mots s t Rr = 0.79snd 0.71 corresponding to ~~

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m-toluvl chloride (3) and. oresumnhlv. m-

iect. T.indn LeFevre for helo in orranizinc

diethylamine, and anew spot corresponding to deet ( I ) appears a t Rr = 0.30. After flash chromatography the deet is detected no earlier than fraction 6 and is usually ~ foff the column by fraction 15, Student yields of pu. rified deet ranged from 22 to 68% with an average of 51%. A proton NMR temperature dependence study in CDC& easily he performed to illustrate the hindered rotation around the C-N amide bond (7). The two quartets expetted for each nonequivalent methylene at room temperature and a broad m u l t i ~ l e tare observed. As the temperature is raised and free rotation begins to occur about the C N bond, the two methylene groups condense into a single sharp quartet a t 90 T. Oswego has been quite active in recent years in there types of project-oriented l a b s (6-12,. Thw project was performed h) pairs uf srlrdents in our ad\,anrerl rhemi;tru laboratorv in a series of three 3-h labs. The micro&ale techniques employed are described in detail by Mayo, e t al. (13). The experiment provides students with valuable experience in functional group conversion, acid-base chemistry, flash and thin-layer chromatography, and NMR interpretation. Because the materials are low-cost, the project can easily he incorporated into the microscale organic laboratory.

York, College a t Oswego for its support of the Chemistry Department.

group

Acknowledgment

J. W. LeFevre thanks the students in Chem. 334L for their hard work on thjs pro-

Volume 67

Literature Clted I.Pavia.D. L.iL~mpman.GM.:Kriz,G.S. Introduction to Orpnnic L o b o r a t o r y Techniques, 3rd ed.: Saundes: Phiiadelphia. 1988:pp 123-126. 2. ~ehmsn.J. opwotionai organic chemistry, 2nd ed.: AM and &con: ~oston.1988:pp 365-377. 3. W a w B.J-S. J. ChmEduc. 1974.51.631. 4. Pavia.D.L.;Lampmsn.G. M.:Kiiz.G.S.:En8el,R.G. Introduction to Orgonic Labomtory Techniyucs-A ~icrnscole~pproaeh:~sundor~: ~hiladelphis.1990. 5 . St3i.C. W.: Kahn, M.;Mitra,A. J. Org. Chsm. 1978.43, 2923. 6. &kerf, H.;Forster. B. Angaw. Chem. Inf. Ed. Engi. ,us7 98,4, 1196 -.,-. 7. Stowan. W. E : Siddi, T H. Chsm. Re". 1970, 70,517. 8. Silueira, A . Jr. J. Chem. Educ. 1978.55.57. 9. Silueira.A..Jr.:Satra,S.K.J.O~g.Chrm.1979,41.873. LO. Silveira.A.,dr.: Bretherick, H. D.; Negi8ht.E. J. Chem. Educ 1979,56,560. 11. Silueira.A..Jr.; Koehier, J.A.;Beadei,E.F., JI.:M~"roe.P.A. J. Chem.Educ. 1984.61.264. 12. Siluelra.A..Jr.;Oriando,S.C.J.Chem.Educ.1988.85, 630. 13. Mayo, D. W.; Pike, R. M.; Butcher, S. S. Microrroie OrsonieLaboratnry.2nd ed.; Wiley: New York, 1989.

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Jbngle Ju CB 100 is 9 5 % pure oeet and can os p ~ c h a s e IromRecreat d onal Eqwpment. 1°C.. P 0 Box 88125 Seance. WA 98138-0125 1 servesas an excellent TLC standard. Triphosgene can be purchased horn Aidrlch Chemical Company. Inc., PO. Box 2060, Mllwaukee, Wi 53201 (Catalogue number 33,075-2). The spot at R, = 0.71 has an Identical Rr value t o that which results from the treatment of m t o i u i c acid with 0.5 equlvslent.of dicyclohexylcarboaiimide at room temperature In tetrshydmfuran. These conditions are known t o produce anyhydrides.

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Number 11

November 1990

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