Synthesis of N,N-diethyltoluamide /DEET
http://chemconnections.org/organic/chem227/deet-procedure-09.html
Background and Methodology:
Amides are usually prepared by treating a carboxylic acid derivative with ammonia or with a
primary or secondary amine Acid anhydrides or esters are sometimes used as the acid derivative,
but acyl chlorides are the most useful for preparing the widest variety of amides. Because of the
high reactivity of acyl chlorides, the reactions are usually rapid and exothermic, so much so that,
in many cases, the rate must be controlled by cooling or by using an appropriate solvent. When
the reaction is carried out in an inert solvent such as diethyl ether or toluene, it is necessary to
use at least a 100% excess of the nitrogen compound, because the reaction produces HCl which
reacts with one equivalent of amine (or ammonia) to form the amine salt. This salt may also be
difficult to separate from the product. One way to avoid these disadvantages is to add a base such
as pyridine, triethylamine, or sodium hydroxide to react with the evolved HCl.
The synthetic method that uses aqueous sodium hydroxide (or potassium hydroxide) as the base
is known as the Schotten-Baumann reaction. It has been used to prepare esters and other acyl
derivatives as well as amides. Some acyl chlorides, particularly low-molecular-weight aliphatic
ones, hydrolyze rapidly in water to form carboxylic acids and thus are unsuitable reactants for
this procedure. However, aromatic and long chain aliphatic acyl chlorides are nearly insoluble in
water and therefore hydrolyze much more slowly; the small amount of acyl chloride lost by
hydrolysis can be compensated for by using an excess of this reactant. The presence of aqueous
alkali in the reaction mixture also makes it possible to use an amine hydrochloride rather than the
free amine, as the salt reacts with base to liberate the amine in situ. Since many amines are
volatile, corrosive, and quite unpleasant to handle, the use of an easy to handle amine salt is an
advantage.
The acyl chlorides used for preparing amides are generally themselves prepared from the
corresponding carboxylic acids. Several reagents are commonly used for this reaction; each has
certain advantages and disadvantages. Thionyl chloride (SOCl2) has the great advantage that all
of the inorganic reaction products (HCl and SO2) are gases and can be easily removed from the
acyl chloride, which is often used for further reactions without isolation.
In this experiment, you will first prepare m-toluoyl chloride by treating m-toluic acid with excess
thionyl chloride. And, then without isolating the acid chloride, run a Schotten-Baumann reaction
with diethylamine (from the amine hydrochloride salt) to prepare N,N-diethyl-m-toluamide
(DEET). Because corrosive acidic gases are released during the reactions, a sodium hydroxide
gas trap will be used to keep them out of the lab environment. [NOTE: In the Schotten-Baumann
reaction, efficient mixing is necessary to provide adequate contact between the water-insoluble
acyl chloride and the amine. Use of the sodium lauryl sulfate, which acts like a detergent, which
helps disperse the acyl chloride into smaller particle sizes that increase the reaction rate.]
PROCEDURE:
A. Preparation of m-Toluoyl Chloride
NOTE: All glassware must be thoroughly dried for this procedure. Carry out the reactions
under a hood; equip the reflux condenser with a gas trap containing dilute NaOH.
Thionyl chloride and m-toluoyl chloride are both corrosive and lachrymators. They can cause
severe damage to the eyes, skin, and the respiratory system. Thionyl chloride decomposes
violently on contact with water to produce poisonous gases (HCl and SO2). Wear gloves, and
work under a hood; avoid contact with thionyl chloride and the reaction mixture, keep them
away from water, and do not breathe their vapors.
Under the hood, combine ~30 mmol of m-toluic acid with ~2.6 mL (~36 mmol) of thionyl
chloride in a round bottom flask. Reflux the mixture gently for at least 20 minutes, until the
evolution of gases stops. Cool the reaction mixture to ~10 oC or below in an ice bath. Leave the
m-toluoyl chloride under the hood in the stoppered reaction flask (supported in a small beaker)
until you are ready to use it in the next step.
B. Preparation of N,N-Diethyl-m-toluamide
Diethylamine hydrochloride irritates the skin, eyes, and respiratory tract. Avoid contact and
inhalation. In the reaction mixture, it forms diethylamine, which is corrosive and has toxic
vapors. Diethyl ether is extremely flammable and may be harmful if inhaled. Do not breathe its
vapors, and keep it away from flames and hot surfaces.
Reaction with Magnetic Stirring. Assemble an apparatus for addition and reflux, using a 100mL round bottom flask equipped with a magnetic stir bar. Carry out the reaction out under a
hood. Add ~35 mL of 3.0 M aqueous sodium hydroxide, and cool the flask in an ice bath. While
stirring the NaOH solution, add ~25 mmol of diethylamine hydrochloride in small portions,
followed by 0.1 g of sodium lauryl sulfate. Under the hood, transfer the cold m-toluoyl chloride
from part A to the dry addition funnel; stopper the funnel immediately, and replace it on the
reassembled reaction apparatus. Handle all materials under the hood. Keeping an ice bath
handy for moderating the reaction if necessary, slowly add the acid chloride to the reaction
mixture while stirring vigorously. When the addition is complete, heat and stir the reaction
mixture over a boiling water bath for about 15 minutes. At this point, the acid chloride should be
gone, and the reaction mixture should be basic to litmus.
Separation. Cool the reaction mixture to room temperature or below, and extract it with three
20-mL portions of ethyl ether. Wash the combined ether extracts with 30 mL of saturated
aqueous sodium chloride, dry the ether layer with magnesium sulfate, and by use of the rotary
evaporator, evaporate the solvent.
Post lab QUESTIONS
1. Write an equation that describes the reaction of thionyl chloride with water.
2. Write the reaction that would take place if the acid chloride of m-toluic acid were mixed with
water.
3. Why is the final reaction mixture extracted with 5% sodium hydroxide?
4. If N,N-diethyl-m-toluamide distills at 165 oC at 20 mm, what should its boiling point be at 760
mm?
5. Write a mechanism for each step in the preparation of N,N-diethyl-m-toluamide.