A solution of sodium ethoxide is prepared by the cautious addition of 46 g. (2 gram atoms) of clean sodium to 600 cc. of anhydrous ethyl alcohol (Note 1) in a 2-l. three-necked flask equipped with a dropping funnel, a mercury-sealed stirrer, and a reflux condenser carrying a calcium chloride tube. The flask is then immersed in an ice-salt bath and the stirrer is started. When the temperature of the solution has reached 10° (Note 2) an ice-cold solution of 196 g. (2 moles) of cyclohexanone (Note 3) in 292 g. (2 moles) of ethyl oxalate (Note 4) is added from the dropping funnel over a period of about fifteen minutes. Vigorous stirring is required to prevent complete solidification of the reaction mixture (Note 5). When the addition is complete, the ice bath is retained for an hour, and then the mixture is stirred at room temperature for about six hours.

The reaction mixture is then decomposed by the careful addition of ice-cold dilute sulfuric acid prepared by adding 56 cc. of concentrated acid (sp. gr. 1.84) to 435 g. of ice. During this neutralization the temperature of the mixture is maintained at about 5–10° by means of an ice-salt bath. The solution, which should now be acid to Congo red paper, is diluted with cold water to a volume of about 4 l. The ethyl 2-ketocyclohexylglyoxalate separates as a heavy oil and is removed. The aqueous solution is extracted with four 500-cc. portions of benzene. The crude product is combined with the extracts, and the resulting solution is washed with two 200-cc. portions of water. The benzene solution is then allowed to stand in a separatory funnel for a few minutes until it is free from suspended water.

The benzene solution, without drying, is transferred in portions of about 500 cc. to a 1-l. Claisen flask connected to a water-cooled condenser. The flask is heated on the steam bath until the benzene no longer distils. The steam bath is then replaced by an oil bath and the system is gradually evacuated to a pressure of 10–12 mm. while the oil bath is held at about 90°. When all the benzene, unchanged ester, and ketone have distilled (Note 6) the temperature of the oil bath is increased. When the temperature of the distillate reaches 105°/10–12 mm. the receiver is changed. The bath temperature is immediately raised to 175° and all material distilling between 105° and 165° at 10–15 mm. is collected. This requires one-half to one hour. During this time the bath temperature is slowly increased to 200° to obtain the last portions. The yield is 250–265 g. (63–67 per cent of the theoretical amount). The distillate is transferred to a 500-cc. modified Claisen flask, and a trace of iron powder and some finely ground soft glass are added (Note 7). The mixture is distilled at 40 mm. with the bath temperature maintained at 165–175° (Note 8). Carbon monoxide is evolved and the distillate is collected between 125° and 140°. About one and a half to two hours is required for the pyrolysis. The yield of ethyl 2-ketohexahydrobenzoate is 200–210 g. (59–62 per cent of the theoretical amount based on cyclohexanone). This product, whose refractive index at 25° varies from 1.476 to 1.479, is sufficiently pure for use in the next step without redistillation.

In a 2-l. three-necked flask equipped with a dropping funnel, a reflux condenser, and a special stirrer (Note 9) is placed 100 g. (2.5 moles) of sodium hydroxide and 300 cc. of anhydrous methyl alcohol. The stirred mixture is heated for one hour in an oil bath held at 120° in order to effect solution of most of the sodium hydroxide. Stirring and heating are continued while 100 g. (0.59 mole) of ethyl 2-ketohexahydrobenzoate is added over a period of two hours. The resulting mixture is heated for one hour longer with the bath temperature at 120°. It is then diluted with 600 cc. of water and the condenser is arranged for distillation. The methyl alcohol is removed by distillation until a thermometer immersed in the boiling solution reads 98–100°. The residual aqueous solution is vigorously stirred, and exactly 210 cc. of concentrated hydrochloric acid (sp. gr. 1.18) is carefully added drop by drop from a dropping funnel (Note 10). The hot acid solution is treated with 2–4 g. of Darco and is filtered through a heated Büchner funnel. The filtrate is cooled in an ice bath. The pimelic acid is collected on a Büchner funnel and is crystallized from 100 cc. of boiling water for each 45 g. of acid. After drying in the air the acid melts at 103.5–104° and weighs 65–73 g. The mother liquors from the hydrolysis and recrystallization are combined and evaporated to dryness on a steam bath. The resulting solid is extracted with two 500-cc. portions of acetone. The acetone is distilled from a steam bath, and the residual crude pimelic acid is recrystallized from the minimum quantity of benzene, yielding an additional 10–12 g. of pure material. The total yield is 75–83 g. (80–88 per cent of the theoretical amount based on ethyl 2-ketohexahydrobenzoate; 47–54 per cent based on cyclohexanone).

Four hundred cubic centimeters of freshly distilled isoamyl alcohol (b.p. 128–132°) is heated to 90–100° on an oil bath in a 5-l. two-necked flask fitted with a dropping funnel and reflux condenser. Two hundred forty grams (10.4 gram atoms) of clean sodium is then added, and the temperature of the oil bath is raised rapidly until the alcohol is brought to vigorous boiling (Note 1). A solution of 100 g. (0.73 mole) of salicylic acid in 2 l. of isoamyl alcohol is allowed to flow into the flask at the rate of 100 cc. every four minutes, so that the entire amount is added over a period of eighty minutes. The dropping funnel is then rinsed with 100 cc. of isoamyl alcohol. The solution in the flask is clear at first, then becomes cloudy with the addition of the salicylic acid. The temperature of the oil bath is regulated so that the alcohol refluxes rapidly throughout the course of the experiment. The sodium goes completely into solution in seven to eight hours.

The flask is then allowed to cool to 100°, and 800 cc. of hot water is added with vigorous shaking (Note 2). The hot mixture is transferred to a 5-l. separatory funnel, the flask being rinsed with 200 cc. of hot water (Note 3). The mixture is shaken well and the layers separated. The isoamyl alcohol layer is extracted with four or five 200-cc. portions of nearly boiling water (Note 4). The combined aqueous extracts are then steam-distilled in order to remove any isoamyl alcohol from the aqueous solution of the sodium salt. About 500 cc. of distillate is collected (Note 5).

The flask is allowed to cool, and 920 cc. of hydrochloric acid (sp. gr. 1.19) is added. The unchanged salicylic acid is then steam-distilled from the mixture. The flask is strongly heated, so that its contents are concentrated and, towards the end of the distillation, sodium chloride begins to precipitate. The removal of salicylic acid is practically complete when about 10–12 l. of distillate has come over, although the distillate still gives a ferric chloride test for salicylic acid. The solution in the flask is allowed to cool overnight and is finally chilled in an ice bath.

The crystalline precipitate, which is a mixture of sodium chloride and pimelic acid, is then collected on a suction filter without washing. The product is dried in an evaporating dish on the water bath for several hours, with frequent stirring, whereby the brown mass is partially melted. The mass, after cooling, is transferred to a 500-cc. Soxhlet thimble. The Soxhlet apparatus is mounted over a hot plate and the solid extracted with about 650 cc. of benzene. Complete extraction is indicated when the liquid in the siphon is no longer turbid (Note 6). The extraction is complete when evaporation of a small quantity of the solution in the extractor leaves no residue (two to three hours). After the extraction is complete, the benzene solution is concentrated to about 300 cc. and the pimelic acid allowed to crystallize. The crystals are collected on a filter, washed with cold benzene, and dried in the air. The product melts at 104–105° and weighs 50–58 g. (43–50 per cent of the theoretical amount).