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 longchain 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 raection; 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.
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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, helps disperse the acyl chloride into smaller particle sizes that increase the reaction rate.]
After the product is isolated by extraction with ether, it can be purified by vacuum distillation or column chromatography. By comparing the infrared spectrum of the product with those of the starting materials, one can see evidence for the functional group conversions that have taken place. The proton NMR spectrum of the product consists of well-separated signals, which are easy to assign and useful to confirm the Deet structure.
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. Either
use the following procedure or the procedure below.
Measure ~35 mL of 3.0 M aqueous sodium hydroxide
into an Erlenmeyer flask, and cool the flask in an ice bath. Add, in small
portions and with swirling, ~25 mmol of diethylamine hydrochloride; then
mix in 0.1 g of sodium laurvl sulfate. Under the
hood, transfer the cold m-toluoyl chlonde from Part A to a dry addition
funnel supported on a ringstand, and stopper the funnel immediately. Handle
all materials under the hood. Add the m-toluoyl
chloride in small portions (about 1 mL each) to the reaction flask, swirling
the flask in the ice bath after each addition until the reaction subsides.
When the addition is complete, remove the flask from the ice bath, stopper
it, and shake and swirl it vigorously for several minutes. Then loosen
(but do not remove) the stopper, and heat the mixture on a steam bath for
about 15 minutes, with continued shaking. At this point, the
acid chloride should be gone and the reaction mixture should be basic to
litmus. (Go on to the Separation step.)
Reaction with Magnetic Stirring. Assemble an apparatus for addition and reflux, using a 100-mL round bottom flask equipped with a magnetic stirbar. 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 laurvl 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 evaporate the solvent .
Purification andAnalysis: Purify the N,N-diethyl-m-toluamide by either semimicro vacuum distillation or column chromatography as assigned by Dr. R.. Weigh the product, bottle the sample, label, record the IR spectrum and turn in. Interpret the proton and 13C NMR spectra, which will be provided by Dr. R.
The product can be purified by a reduced-pressure distillation or by column chromatography. If it is purified by column chromatography, alumina should be used as the adsorbent (~4-5 cm of dry alumina in a 25-mm-diameter column), and the elution solvent should be petroleum ether. The first compound to elute will be N,N-diethyl- m-toluamide. Evaporation of the petroleum ether should give the purified amide as a pure colorless or light tan liquid (bp 160-163 oC at 20 mm).
Report: Compare your spectrum with the IR spectra of the reactants. Point out important bands that have appeared, disappeared, or changed location in going from reactants to product, and tell how these bands provide evidence that the expected reaction has taken place.
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.
6. Consult the following readings. Briefly describe how DEET works
on a molecular level to repel mosquitoes. Include one drawing that best illustrates
its mode of action.
Deet I: Science(2008)
Deet II: Science(2008)
7. Advise Dr. R. if it would be wise for his two infant granddaughters to use DEET. Cite one or more reliable references to support your advice.