SYNTHESIS OF l-CHLOROHEXAN-2-ONE

CAUTION: All operations in this preparation must be carried out in an efficient fume cupboard owing to the toxicity of benzene. 

• Equip a 1 -litre three-necked flask with a sealed Hershberg stirrer (preferably of tantalum wire), a reflux condenser and a 250-ml dropping funnel (1). 

• All apparatus must be thoroughly dry. 

• Place 8.1 g (0.33 mol) of dry magnesium turnings in the flask, add 60 ml of anhydrous ether through the dropping funnel and charge the latter with a solution of 46 g (35.5 ml, 0.33 mol) of butyl bromide in 1 10 ml of dry ether. 

• Start the stirrer and prepare the Grignard reagent in the usual manner. 

• When the formation of the Grignard reagent is complete, cool the flask in an ice bath with stirring, remove the dropping funnel and, when cold, add 32.7 g (0.178 mol) of anhydrous cadmium chloride in portions from a small conical flask during 5-10 minutes. 

• Replace the dropping funnel, remove the ice bath, stir for 5 minutes and then heat the mixture under reflux with stirring for 45 minutes; at this point a test for the presence of Grignard reagent is made (2); continue stirring and refluxing until the test is negative. 

• Replace the reflux condenser by a bend adapter connected to a condenser set for distillation, distil off the ether as stirring is continued; continue the distillation, with stirring, on a water bath until it becomes very slow and dark viscous residue remains. 

• At this point add 120 ml of anhydrous benzene (CAUTION) from the dropping funnel, and continue the distillation until a further 35 ml of liquid has passed over. 

• Then add 120 ml of dry benzene and replace the reflux condenser; reflux the mixture with vigorous stirring in order to break up the cake inside the flask. 

• Remove the heating bath, cool the mixture to about 5°C in an ice bath and add a solution of 38 g (25.5 ml, 0.33 mol) of chloroacetyl chloride (b.p. 105 °C) in 70 ml of anhydrous pure benzene from the dropping funnel during 2-3 minutes. 

• After completion of the addition, stir the reaction mixture and hold the temperature at 1 5-20 °C for 3 hours and then at 20-25 °C for a further 1.5 hours. 

• Add excess of crushed ice (c. 200 g) and dilute sulphuric acid. 

• Separate the benzene and aqueous layers; extract the aqueous phase with two 30 ml portions of benzene. 

• Wash the combined benzene layers successively with 70 ml of water, 70 ml of saturated sodium hydrogen carbonate solution, 70 ml of water and 35 ml of saturated sodium chloride solution. 

• Filter the benzene solution through a little anhydrous sodium sulphate (this separates most of the suspended water), remove the benzene by flash distillation at atmospheric pressure and distil the residue under reduced pressure through a short fractionating column. 

• Collect the l-chlorohexane-2-one at 71-72°C/15mmHg; the yield is 24 g (54%).

Notes to keep in mind:

1.  It is best to conduct the preparation in a nitrogen atmosphere; the apparatus may be used.

2.  A slight excess of Grignard reagent should be present at this stage. Test for the presence of the reagent as follows. Remove 0.5 ml of the clear liquid with a dropper pipette and add 0.5 ml of a 1 per cent solution of Michler's ketone [4,4'-bis(dimethyl-amino)benzophenone] in benzene, followed by 1 ml of water and 3-4 drops of 0.01 M iodine in glacial acetic acid; shake. A greenish-blue colour results if a Grignard reagent is present. In the absence of iodine, the colour fades. A dye of the diphenylmethane type is produced.

Cognate preparations: Tetradecane-5,10-dione (via lithium dialkylcuprates)¹²⁷ª

• Into a dry 50-ml, two-necked round-bottomed flask, equipped with a rubber septum and a three-way stopcock bearing a wired-on balloon, is placed a magnetic stirrer bar and copper(i) iodide (571 mg, 3.00 mmol). 

• The balloon is filled with nitrogen. 

• The three-way stopcock is used to evacuate and then fill the flask with nitrogen. 

• The purging procedure is repeated two more times, and the flask is gently flamed during the last evacuation. 

• Anhydrous diethyl ether (8 ml) is added and the system is cooled to — 40 °C (1). n-Butyllithium in pentane (4.5 ml of a 1.32 m solution, 6.0 mmol) is injected. 

• After about 5 minutes at — 40 °C, the temperature is lowered to — 78 °C. A precooled ethereal solution (1 ml) of 6-oxodecanoyl chloride (213 mg, 1.04 mmol) (2) is injected. 

• After 15 minutes at — 78 °C, absolute methanol (352 mg, 11.0 mmol) is injected and the reaction mixture is allowed to reach room temperature. 

• It is poured with stirring into an equal volume of saturated aqueous ammonium chloride; ether extraction followed by rotary evaporation gives 193 mg (83%) of tetradecane-5,10-dione, m.p. 59-62 °C, with consistent i.r. and n.m.r. spectroscopic properties. Recrystallisation from pentane gives white needles (162 mg, 70%), m.p. 65-66 °C.

Notes to keep in mind:

1.  A temperature of 0°C is used in the case of reactions involving methyllithium, i.e. for the preparation of alkyl methyl ketones.

2. This acid chloride is prepared from oxalyl chloride and 6-oxodecanoic acid¹²⁷ᵈ. The reaction procedure is applicable to a range of unsubstituted and substituted aliphatic and aromatic acid chlorides.

General procedure for the preparation of ketones from A,A-dimethylcarbox-amides and alkyllithiums¹²⁷ᶜ 

• A suspension of lithium ribbon (1.6g-atom), cut into small pieces, in anhydrous ether (800 ml) is prepared in a flask fitted with a reflux condenser, nitrogen inlet tube, thermometer, a pressure-equalising addition funnel and a stirrer. 

• The suspension is cooled to — 10 °C, and, while the system is being swept with nitrogen, a solution of the required alkyl bromide (0.83 mol) in ether (200 ml) is added over a period of 2 hours. 

• The mixture is stirred for 1 hour longer at — 10 °C. Then the temperature is lowered to — 20 °C and a solution of the required JV,JV-dimethylcarboxamide in anhydrous ether (200 ml) is added dropwise over a period of 1.5 hours. 

• The temperature is then allowed to rise gradually to 25 °C over a period of 3 hours with continued stirring under a nitrogen atmosphere. 

• At the end of this time, he solution is cooled to — 10 °C and cold, saturated ammonium chloride solution (500 ml) is slowly added. 

• The mixture is stirred for 30 minutes, the ether layer is separated, washed with 1 m hydrochloric acid, water and dried. Evaporation of the solvent under reduced pressure leaves a colourless liquid residue which is distilled through a 25-cm Vigreux column.