Expt #5. Part 2. Preparation of DEET from m-Toluic Acid

Relevant textbook readings - Mohrig Chapter 7.2-7.3. Klein Chapter 21.6-21.8, 21.12.

Literature References

(1) Reaction procedures adapted from http://chemconnections.org/organic/chem227/deet-procedure-09.html (accessed Jan 21, 2013).

(2) (a) Jensen, B. L.; Fort, R. C. Jr. J. Chem. Educ. 2001, 78, 538-540. (b) Gryff-Keller, A.; Szczeciński, P. Org. Mag. Res. 1978, 11, 258–261.

Overview - The 3-methylbenzoic acid prepared in part 1 of expt 5 will be chlorinated using thionyl chloride and the product formed (m-toluoyl chloride) will be reacted with diethylamine hydrochloride and sodium hydroxide to form the common insect repellant, N,N-diethyltoluamide (DEET). The product will be characterized by proton NMR and IR.

Background

Amides are easily prepared by treating a carboxylic acid with thionyl chloride to form an acyl chloride (eq 1), which can then be reacted with an amine to form the desired amide (eq 2). The reaction of the acyl chloride with the amine (eq 2) is usually very rapid and exothermic so that, in many cases, the rate must be controlled by cooling or other means.

In the absence of an added base, it is necessary to use 2.0 equiv of amine for eq 2 because the reaction produces HCl, which reacts rapidly with the amine to form an ammonium salt (eq 3). Although the reaction is often carried out in this manner (using excess amine) it can be wasteful (especially if the amine is valuable) and the ammonium salt formed presents a product purification problem depending on how difficult it is to separate from the product. These disadvantages can be avoided if a base such as pyridine or sodium hydroxide is included as an additional reactant.

The Schotten-Baumann reaction is the variation of this reaction that uses aqueous sodium hydroxide as the base (eq 4). Water-soluble acyl chlorides are unsuitable reactants for this procedure because they will hydrolyze rapidly in water to form carboxylic acids (thus undoing eq 1). However, most aromatic acyl chlorides are practically insoluble in water and, therefore, hydrolyze much more slowly. The use of NaOH also makes it possible to use an amine hydrochloride rather than the free amine (e.g. Et₂NH₂⁺ Cl⁻ instead of Et₂NH) because the salt reacts with base to form the amine in situ. Many amines are corrosive and malodorous so the use of an amine salt is often advantageous.

A disadvantage of the Schotten-Baumann reaction is that very efficient mixing is necessary to provide adequate contact between the water-insoluble acyl chloride and the amine. To overcome this we will use a detergent known as sodium lauryl sulfate. Detergent action helps disperse the acyl chloride into smaller particle sizes that increase the reaction rate.

Procedures

Preparation of m-Toluoyl Chloride

Use dry glassware and wear gloves for these procedures! Thionyl chloride decomposes violently on contact with water to produce poisonous gases (HCl and SO₂). Avoid skin contact with it, keep away from water, and do not breathe its vapors.

Place 5 mmol m-toluic acid and 6 mmol thionyl chloride in a 4-mL conical vial (14/10 standard taper) equipped with a magnetic spin vane. Attach a condenser and gently refluxwith stirring for 30 minutes or until the evolution of gases stops. Check for HCl evolution using litmus paper inserted into the top of the reflux condenser. Cool the reaction mixture to ~10 ^oC on an ice bath. Stopper the vial and leave the m-toluoyl chloride in the hood until you are ready to use it in the next step. (Do not determine the yield of this product!)

Reaction of m-Toluoyl Chloride with Diethylamine Hydrochloride

Add 6.0 mL of 3.0 M NaOH(aq) to a 25 mL r.b. flask. Add a stir bar and cool the mixture on an ice bath. Carefully add 5 mmol of diethylamine hydrochloride. Add 0.1 g sodium lauryl sulfate. Attach a reflux condenser to the flask. Use a pipet to slowly add (through the top of the condenser) the cold m-toluoyl chloride from part A to the stirring NaOH/ Et₂NH₂⁺ Cl⁻ solution . When the addition is complete, heat on a hot water bath for 15 min.

Work-up

Cool the reaction mixture to room temperature. Transfer it to a test tube and extract it with three 3-mL portions of dichloromethane. Wash the combined DCM extracts with 5mL each of 1 M HCl, then 5% NaOH, and finally water. Dry over sodium sulfate and then evaporate the solvent using the rotary evaporator. Determine the yield.

Characterization. Obtain the proton NMR spectrum and, if you have enough material, also the IR spectrum.