edited by
ARDEN P. ZIPP
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 pu-
rification of Nfl-diethvl-m-toluamide. deet
( 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
chloride (3) with thionyl chloride. Treat-
ment of (3) with excess diethylamine pro-
duces 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).
A278 Journal of Chemical Education
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 rela-
tive to 2) and gives a cleaner reaction with-
out the formation of Son or dark-colored
impurities. Flash chromatography is espe-
cially well-suited to the microscale purifica-
tion 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 chrama-
tography (TLC) may he used to choose the
correct solvent for the column separation
and to analyze the collected fractions if de-
sired.
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 diethy-
lamine (eq 2).
Experimental
Synthesis of m-ToW Chloride (3) from
m-TOIUICAdd (2)
Oven-dry a micro-reflux condenser, a
CaCl2 drying tube, a microClaisen head,
SUNY-Conland
Coniand. NY 13045
and a 3-mL conical vial containing a spin
vane. Let cool to room temperature in a des-
iccator. 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 re-
flux 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 ac-
cording to the procedure below.
Conversion of m-Toluyl Chloride (3)
into N,N-Dlethylm-toluarnide ( 1 )
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 pi-
pet. 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 diethyla-
mine hydrochloride forms immediately. Af-
ter all of the diethylamine has been added,
test for basicity with a micropipet and lit-
mus paper, and, if necessary, add more
diethylamine dropwise until the solution is
basic. Let the vial warm to room tempera-
ture 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 ex-
traction. 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 Pas-
teur 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.
Purification of N,N-Diethylm-toluamide
(1) by flash Chromtogr~phy
Prepare 250 mL of solvent, 2:3 (by vol-
ume) ethyl aeetate:petroleum ether (b.p.
30-60 "C). These solvents should he dis-
tilled 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 plac-
~~ ..
ine,. 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 pres-
ence of deet in the fractions by TLC. Thin-
layer 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.
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 cor-
rr~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
m-toluvl chloride (3) and. oresumnhlv. m-
diethylamine, and anew spot corresponding
to deet ( I ) appears a t Rr = 0.30. After flash
chromatography the deet is detected no ear-
lier 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 ex-
petted for each nonequivalent methylene
group at room temperature and a
broad m u l t i ~ l e tare observed. As the tem-
perature is raised and free rotation begins to
occur about the C N bond, the two methyl-
ene 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 lab-
oratorv in a series of three 3-h labs. The
micro&ale techniques employed are de-
scribed 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 pro-
ject can easily he incorporated into the mi-
croscale organic laboratory.
Acknowledgment
J. W. LeFevre thanks the students in
Chem. 334L for their hard work on thjs pro-
Volume 67
iect. T.indn LeFevre for helo in orranizinc
York, College a t Oswego for its support of
the Chemistry Department.
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. w 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.
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,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.
' 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, Mllwau-
kee, 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 dicyclohexylcarboai-
imide at room temperature In tetrshydmfuran.
These conditions are known t o produce anyhy-
drides.
Number 11 November 1990 A279