The Synthesis of 2-Methyl-4-Heptanone An Ant Alarm Pheromone Elma A. d e Jong and Ben L. Feringal University of Groningen, Nijenborgh 16, NL-9747 AG Groningen, The Netherlands
In order to stimulate students' interest in syntheticorganic laboratow courses, it is fruitful to combine basic svnthetic methodoio& with the presentation of target mole~culesof biolopical oripin. We oresent a two-step route to such a mole&le (2) ;sing common preparation;, i.e., the Grignard reaction and the oxidation of secondary alcohols.
pling reaction (7). In addition the less reactive alkyl chloride instead of the more reactive alkyl bromide penerallv shows a lower reactivity in side reaction; (8).common side &actions are: Grignard coupling, reduction of the starting carbonyl compound to the alcohol by the Grignard reagent, and reaction of the Grignard reagent with a proton a to the carbonyl functionalitv (enolizationl. The nroduct. 2-methvl-4-heo.~ g n o l ( I ) , can be identifiedby its refractive indexand IR *Ad 'H NMR spectrum. T h e OH signal position in the NMR spectrum may be established by adding a few drops of DsO to the sample and shaking vigorously. A recorded spectrum shows the disappearance of the OH signal. The ketone, 2-methyl-4-heptanone (2) is produced by sodium hypochlorite oxidation of the alcohol2. This simple method yields ketones from secondary alcohols in high yield (9,lO). We used a sodium hypochlorite solution that is commercially available as a cleaning agent. As obtained, i t was determined bv titration (11) to be 2.1 molar (12.7% available ehlirine by weight). he ketone is identified b y its refractive index, 'HNMR and IR spectrum. T h e synthesis of 1and 2 combines a number of important techniques in preparation, isolation, and identification, with a target molecule of natural origin. In addition it focuses students' attention on the imoortant field of insect oheromones.
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An alarm oheromone of two a n t s~ecies.T a d n o m a niggerimum (1,-2) and Tapinoma simrothi (3). ig2-methyl-4s common in the Mediterheotanone (2). Both mt s ~ e c i eare ranean area. he alarm pheromones are secreted by anal glands, located a t the tip of the ant's abdomen. T h e synthesis of 2-methyl-4-heptanone (2) proceeds in two steps from The Grignard synbutanal and 1-chloro-2-methyl-propane. thesis of 2-methyl-4-heptanol (1) was first performed by Levene and Marker (4), using 1-bromo-2-methyl-propane. The Grimard reaction followed bv the oxidation makes the experiment described here a valuible alternative to the synthesis of 4-methyl-3-heptanone, the alarm pheromone of the harvester ant, reported earlier in this Journal (5). T h e synthesis of 4-methyl-3-heptanone has some severe drawbacks, as we and others (6)experienced. T h e intermediate Droduct 4-methvl-3-heotanol, synthesized in the Grign&d reaction is coitamina&d with the ketone, 4-methyl-3heptanone (13%) and the Grignard coupling product, 4,5dimethyloctane (15-25%). The three produds cannot be separated easily by distillation. The synthesis of 2-methyl-4-heptanone (2) presented here does not suffer the drawbacks mentioned above. It is simple and proceeds in high yield. 2-Methyl-4-heptanol(1) is prepared by the Grignard reaction between l-chloro-2m e t h v l ~ r o ~ a nand e butanal. First the Grienard reazent - is " prepared from 1-cbloro-2-metbylpropaneand magnesium. T h e use of a orimarv. alkvl . halide (1-chloro-2-methvl~ropane) instead of a secondary alkyl halide (2-bromo-p&&ne is used in the svnthesis of 4-methyl-3-heptanol, mentioned above) reducesthe relative importance ofthe Grignard cou-
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Alternatively 2-mafhyl-eheptanol (1) may be oxidized by adding 2.00 g (0.015) mol of the alcohol dropwise to a sodium dichromatel dilute sulfudc acid SOiutiOn, which contains 3.2 g (0.01 mol) sodium dichromate, 2 mL concentrated sulfuric acid, and 20 mL water. Stirring at room temperature for 1.5 hand workup by adding ether and washing the etharal solution with 1Naqueous NaOH yieldsthe ketone (2) in 86%.
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Experimental 2-Methyl-eheptanol( 1) A 250-mL,three-neckedflask,apressure-equalized dropping funnel, a glass stopper, a CaClz tuhe, a double surface reflux condenser and an egg-shaped magnetic stirring bar, are dried for 1 night in an oven at 80 OC before use. The reaction is performed in a hood, in a nitrogen atmosphere. Ether is distilled from PnOs hefare use. 1Chloro-2-methylpropaneis dried over Ns2SO& for 1 night. Commercially available hutanal contains considerableamounts of water. For the purpose of the reaction 50 mL hutanal is first dried over Na2SOn and then fractionally distilled. The butanal/water azeotrope (12) boils at 68 'C. The fraction boiling from 75 OC to 76 O C is used in the reaction. The magnesium is activated just before the start of the reaction, by agitating it together with a few crystals of iodind in a mortar. A 250-mL, three-necked flask is fitted with a condenser with CaClz tuhe, a pressure-equalized dropping funnel with Nz inlet, an egg-shaped magnetic stirring har and a glass stopper. The flask is flushed thoroughly with Nz and then filled with Nz. The dropping funnel is charged with a solution of 4.81 g (5.45 mL; 52.0 mmol) 1chloro-2-methyl-propanein30 mLdryether. Subsequently 1.9g (78 mmol) of activated magnesium is added to the flask along with a few crystals of iodine. By means of a heating gun the iodine is sublimed onto the magnesium turnings. The 1-chliro-2-methylpropanesolution is added dropwise at such a rate that a gentle reflux is maintained. The start of the reaction is indicated hv.a lieht effervescence on the mapnesium oarticles. The reaction mixture assumes s mad brown c&. ~ h e n ' a lof l the magnesium in the flask is coverid Gy liquid, thestirrer is started. After completeaddition (approximately 20 min),refluxis maintained by means of an electric heatingmantle for an additional 20 min. The solution is cooled down to room temperature and a solution of 2.40 g (2.94 mL; 33.3 mmol) hutanal in 10 mL anhydrous ether is added dropwise with stirring to the GriVolume 68
Number 1 January 1991
71
