SYNTHESIS OF 12-HYDROXYDODECANOIC ACID LACTONE (Dodecanolide)

• Cyclododecanone (2.0g, 1 1 mmol) is added to m-chloroperbenzoic acid (4.2g, 21 mmol) in 25 ml of dry chloroform.

• The reaction mixture is heated at reflux for 48 hours after which time a starch-iodide test for peroxide is negative. 

• After the mixture is cooled in ice-water, the precipitated m-chlorobenzoic acid is removed by filtration and the chloroform is evaporated to dryness. 

• The residue is taken up in 60 ml of ether, washed three times with 20-ml portions of aqueous potassium carbonate, and once with brine. 

• After drying and removal of solvent there remains crude dodecanolide (1.9g, 9.6 mmol, 87%), which is used without further purification.

Conversion into 12-iodododecanoic acid:

• The above dodecanolide (1.9g, 9.6 mmol) is added to a mixture of 67 per cent hydriodic acid (5g, 24 mmol) and glacial acetic acid (3g). 

• The reaction mixture is held for 2 hours at 100 °C and after cooling is poured out into 50 ml of a cold 10 per cent aqueous solution of sodium thiosulphate. 

• The reaction mixture is extracted three times with 25-ml portions of chloroform. 

• The combined extracts are dried over magnesium sulphate, and the solvent is removed to leave crude 12-iodododecanoic acid, which after recrystallisation from ether-light petroleum (b.p. 40- 60 °C) is obtained in 93 per cent yield (2.95g), m.p. 61-62.5 °C.

Cognate preparations: Dodecanolide (use of permaleic acid)

• The precautions that must be adopted when using 30 per cent hydrogen peroxide.Safety screens and extra personal protection measures should also be employed.

• Dichloromethane (1.6 litres) and acetic anhydride (1.25 litres) are stirred in a 5-litre flask fitted with a double surface condenser and an overhead stirrer, a dropping funnel, and cooled externally (ice-water) while 30 per cent hydrogen peroxide (1 litre) is added. 

• After 1 hour maleic anhydride (1 kg) is added, the mixture is cooled and stirred for 1 hour, and then the cooling bath is removed, when the temperature rises during 1.5 hours and the mixture begins to reflux. 

• External cooling is resumed when needed to moderate the reaction. 

• When little more heat is evolved, cyclododecanone (250g) is added; this does not greatly increase the rate of heating, and when spontaneous refluxing ceases, a heating mantle is used to maintain the mixture at its boiling point for 15 hours. 

• The mixture is then cooled and the separated maleic acid is filtered off. 

• The filtrate is washed in turn with water (3 x 600 ml), an aqueous solution containing 10 per cent each of potassium hydroxide and sodium sulphite (2 x 300 ml), and then water (600 ml); tests for peroxide are now negative. 

• After being dried over anhydrous sodium sulphate the filtrate is evaporated to give the lactone (210.4g, 77%); when potassium carbonate, rather than potassium hydroxide, is used for washing, the crude lactone contains a pungent contaminant, possibly peracetic acid.

Conversion into 12-hydroxydodecanoic acid:

• The foregoing lactone is added to a solution of potassium hydroxide (150g) in methanol (800 ml) and the mixture is heated under reflux for 1 hour. 

• Most of the solvent is then removed on a rotary evaporator. Water (2 litres) is added and the solution is extracted with ether (2 x 400 ml). 

• The aqueous layer is acidified (concentrated hydrochloric acid) and the precipitated acid is collected, dried in vacuo, and recrystallised from acetone-light petroleum (b.p. 60-80 °C) to afford the acid (185.8g, 63% from cyclododecanone), m.p. 84 °C.

8-Hydroxynonanoic acid lactone

• The precautions to be adopted in the use of 90% hydrogen peroxide. Safety screens and extra personal protection must be employed.

• To a mixture of 90 per cent hydrogen peroxide (1 ml, 40mmol) and dichloro methane (5 ml) at 0°C is added dropwise trifluoroacetic acid (7 ml, 50mmol). 

• The resulting homogeneous solution could be stored at — 20 °C for several weeks. 

• To a solution of 2-methylcyclooctanone (1.12g, 8 mmol) (1) in dichloromethane (8 ml) and buffered with anhydrous disodium hydrogen phosphate (7.1g, 50 mmol), is added at °C dropwise pertrifluoroacetic acid solution (7 ml, 22 mmol). 

• The resulting mixture is stirred at room temperature for 5 hours, poured into water, washed with aqueous sodium hydrogen carbonate and dried over magnesium sulphate. 

• After removal of the solvents at reduced pressure, the oily residue is flash chromatographed using 4 per cent ethyl acetate in light petroleum to yield 890 mg (72%) of the lactone as a transparent sweet-smelling oil (3% of starting material is recovered); i.r. (thin film) 2940, 1730, 1450cm⁻¹ ; p.m.r. (CCl₄ , TMS) 𝜹1.23 (d, 3H, J = 7Hz), 1.1 - 2.0 (m, 10H), 2.15 (m, 2H), 5.00 (m, 1H); t.l.c (silica gel, 5% ethyl acetate in pentane) R𝑓 0.36.

Notes to keep in mind:

1.  2-Methylcyclooctanone may be prepared by the procedures noted in earlier sections. Thus cyclooctanone may be converted into 1-methylcyclooctanol by reaction with methylmagnesium bromide; dehydration then gives 1-methyl-cyclooct-1-ene; hydroboration gives trans-2-methylcyclooctanol; finally, oxidation with PCC yields 2-methylcyclooctanone.