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Synthesis and Purification of

Ristovska, Anastazija*
Chemistry Department, Rice University,
Houston, Texas 77005, USA
Received date

Abstract. N,N-diethyl-m-toluamide is the most common

active ingredient of insect repellents. DEET was
synthesized from m-toluic acid, thionyl chloride, and
diethyl amine as starting material in a two-step reaction.
The product was purified using lab-made 10-cm silica
column as well as TLC-plate elution in two separate
purification methods. DEET The 1H NMR analysis showed
>99% purity of DEET obtained through both purification
methods. DEET is the most common active ingredient of
insect repellents.

Scheme 1. Synthesis of N,N-diethyl-m-toluamide (DEET)

Experimental Procedure. 4.85g m-toluic acid was added
to a 250-mL round-bottom flask together with 3mL thionyl
chloride. This mixture was refluxed for 20min under the
hood ad the reaction was determined to have gone to
completion after there was no more visible evolution of
HCl and SO2 gas. 35 mL 3M NaOH was measured in a
250-mL Erlenmeyer flask and the flask was cooled in an
ice-water bath for 5min. 3.75g diethylamine hydrochloride

was added in small increments to the Erlenmeyer flask

while swirling, followed by the addition of 0.1g sodium
lauryl sulfate to the same flask. The content of the
Erlenmeyer flask was transferred to a 50-mL separatory
funnel and was washed with 2-3 mL deionized water. The
content that was retained in the separatory funnel, after the
water used for rinsing has eluted, was added to the roundbottom flask that was moved to a cold stir-plate supported
by a cork where it was stirred simultaneous to the addition
of the diethylamine. The rate of addition of the funnel
content to the round-bottom flask was 6-8 mL/min. A hot
water bath was prepared at 95C. The round-bottom flask
was heated in the hot water bath for 15min. After the
basicity of the mixture was confirmed using litmus paper,
the solution was cooled to room temperature and was
transferred to another separatory funnel. N,N-diethyl-mtoluamide (DEET) was extracted using three rinses of 20
mL diethyl ether. The DEET retained in the organic, diethyl
ether, phase was collected in a 100-mL separatory funnel.
The extracts in the 100-mL funnel were washed with 30 mL
1M HCl, swirling and venting periodically, after which the
organic phase was washed with 30 mL brine. A very small
amount of sodium sulfate was added to the retained diethyl
ether phase. The DEET-containing solution was then
transferred to a 500-mL round-bottom flask and the ether
was evaporated using rotary evaporation.
Purification. A 10-cm pipet silica column was set up to
which 1/3 of a same-sized pipet DEET was added. 1/3 pipet
of hexanes was added after this step, and more hexane was
added upon need till the DEET had eluted. In the
meanwhile a TLC plate with a 50% ethyl acetate in hexanes
was used for analysis of the column-purified product. To
prepare the column, a piece of cotton was inserted into the
pipet and slurry of 1 gram of silica in 3 pipet-full volumes
of hexanes was loaded onto the cotton-stopped pipet. Once
most of the hexanes solvent has eluted from the column,
1/3 of a pipet of diluted DEET was added to the column.
The six fractions collected were analyzed using TLC, and
the first three fractions, which were also the fractions with
the Rf values close in value, were collected in a 100-mL
round-bottom flask. The solvent was eliminated via rotary
evaporation. The remaining diluted product that was not
passed through the column was purified using preparatory
TLC. A large TLC plate was spotted with lots of small
spots of product and was placed in a 50% ethyl acetate in
hexanes solvent system. The product that eluted with an Rf
=0.59 value was scrapped off the glass plate together with
the silica material the plate composed of. The scrapped off
material was transferred to a new pipet column designed in
the same way as the previous one and was eluted for 20min
using ethyl acetate. The eluted product together with the
solvent was collected in a 50-mL round-bottom flask, and
was UV tested for no UV activity. The solvent was
removed from the product using rotatory evaporation and
was stored for NMR. A single 1H NMR was taken for the
mixed samples of both purification procedures.

Discussion of Purification Methods. The 1H-NMR
showed >99% purity obtained through both purification
methods combined together, meaning that both methods
were equally efficient in eliminating impurities. However,
the silica column elution method is preferred because of the
shorter time required for procedure and smaller loss of
product (greater percent yield) compared to the second
purification method that combined TLC scrapping with
silica column elution.
N,N-diethyl-3-methylbenzamide. 1H-NMR (CDCl3, 400
MHz) : 1.09 (t, 3H), 1.23 (t, 3H), 2.35 (s, 3H), 3.24 (q,
2H), 3.53 (q, 2H), 7.3 7.1 (m, 4H).

Figure 1. 1H NMR of DEET


Supporting Information Available: For complete tables of

physical properties of the chemicals used, please visit
Acknowledgements. We are grateful to V. Farrukh for NMR
References. Additional information on the synthesis of DEET
can be found at <http://www.google.com/patents/US6441034>
U.S. Patent 6441034.