SYNTHESIS OF BUTYL FORMATE

• Into a 250- or 500-ml round-bottomed flask provided with a reflux condenser place 46g (38 ml, 1 mol) of formic acid (98/100%) and 37g (46 ml, 0.5 mol) of butan-1-ol. 

• Reflux for 24 hours. 

• Wash the cold mixture with small volumes of saturated sodium chloride solution, then with saturated sodium hydrogen carbonate solution in the presence of a little solid sodium hydrogen carbonate until effervescence ceases, and finally with saturated sodium chloride solution. 

• Dry with anhydrous sodium sulphate, and distil through a short fractionating column. 

• Collect the butyl formate at 106-107 °C. Yield: 38g (74%).

Cognate preparations: Ethyl formate

• Reflux a mixture of 61g (50 ml, 1.33 mol) of formic acid (98/100%) and 31g (39.5 ml, 0.67 mol) of absolute ethanol for 24 hours. 

• Attach a fractionating column to the flask, distil and collect the liquid passing over below 62 °C. 

• Wash the distillate with saturated sodium hydrogen carbonate solution and saturate with salt before removing the ester layer. 

• Dry with anhydrous sodium sulphate, filter and distil The ethyl formate passes over at 53-54 °C. The yield is 36g (72%).

Propyl formate

• Use 46g (38 ml, 1 mol) of formic acid (98/100%) and 30g (37.5 ml, 0.5 mol) of propan-1-ol and reflux for 24 hours. 

• Proceed as for ethyl formate, but collect the crude propyl formate up to 86 °C; b.p. 80.5-82 °C. Yield: 28g (65%); p.m.r. spectrum (CCl₄, TMS) 𝜹 0.99 (t,3H), 1.67 (m,2H), 4.08 (t,2H), 7.94 (s,1H).

SYNTHESIS OF BUTYL ACETATE

• Mix together 37g (46 ml, 0.5 mol) of butan-1-ol and 60g (60 ml, 1 mol) of glacial acetic acid in a 250 or 500-ml round-bottomed flask, and add cautiously 1 ml of concentrated sulphuric acid (use a small measuring cylinder or a calibrated dropper pipette). 

• Attach a reflux condenser and reflux the mixture for 3-6 hours (1). 

• Pour the mixture into about 250 ml of water in a separatory funnel, remove the upper layer of crude ester and wash it again with about 100 ml of water, followed by about 25 ml of saturated sodium hydrogen carbonate solution and 50 ml of water. 

• Dry the crude ester with 5-6g of anhydrous sodium sulphate. 

• Filter through a small funnel containing a fluted filter paper and distil on a wire gauze or from an air bath. 

• Collect the pure butyl acetate at 124-125 °C. The yield is 40 g (69%). The p.m.r spectrum (CCl₄ , TMS) show absorptions at 𝜹 0.93 (distorted t, 3H, Me⦁CH₂), 1.09-1.72 (m, 4H, ⦁CH₂⦁ CH₂), 1.95 (s, 3H, Me⦁CO) and 3.99 (t, 2H, CH₂⦁O).

Notes to keep in mind:

1.  A slightly better yield of ester can be obtained by increasing the quantity of acetic acid to 90-120g and refluxing for 12-18 hours.

Cognate preparations: sulphuric acid catalyst. Ethyl butanoate

• Use a mixture of 88g (92 ml, 1 mol) of butanoic acid, 23g (29 ml, 0.5 mol) of ethanol and 9g (5 ml) of concentrated sulphuric acid. 

• Reflux for 14 hours. 

• Pour into excess of water, wash several times with water, followed by saturated sodium hydrogen carbonate solution until all the acid is removed, and finally with water. 

• Dry with anhydrous sodium sulphate, and distil. 

• The ethyl butanoate passes over at 119.5-120.5 °C. Yield: 40g (69%). An improved yield can be obtained by distilling the reaction mixture through an efficient fractionating column until the temperature rises to 125 °C, and purifying the crude ester as detailed above under methyl acetate.

Diethyl sebacate

• Reflux a mixture of 101g (0.5 mol) of sebacic acid, 196g (248 ml, 4.25 mol) of absolute ethanol and 20 ml of concentrated sulphuric acid for 12 hours. 

• Distil off about half of the alcohol on a water bath, dilute the residue with 500-750 ml of water, remove the upper layer of crude ester and extract the aqueous layer with ether. 

• Wash the combined ethereal extract and crude ester with water, then with saturated sodium hydrogen carbonate solution until effervescence ceases, and finally with water. 

• Dry with magnesium sulphate or anhydrous sodium sulphate, remove the ether on a water bath and distil the residue under reduced pressure (b.p. 155-157 °C/6 mmHg). Yield: 110g (85%).

Methyl crotonate

• Use 43g (0.5 mol) redistilled crotonic acid (b.p. 180-182°C, m.p. 72-73 °C), 75g (95ml, 2.33mol) of absolute methanol, 3ml of concentrated sulphuric acid and reflux for 12 hours. 

• Isolate as for butyl acetate; the yield is 34g (68%), b.p. 118-120 °C. Record the p.m.r. spectrum and by careful measurement of J values assign the absorptions.

Benzyl acetate

• Mix 31g (29.5 ml, 0.287 mol) of benzyl alcohol and 45g (43 ml, 0.75 mol) of glacial acetic acid in a 500-ml round-bottomed flask; introduce 1 ml of concentrated sulphuric acid and a few fragments of 'porous pot'. 

• Attach a reflux condenser to the flask and boil the mixture gently for 9 hours. 

• Pour the reaction mixture into about 200 ml of water contained in a separatory funnel, add 10 ml of carbon tetrachloride (to eliminate emulsion formation owing to the slight difference in density of the ester and water, compare methyl benzoate) and shake. 

• Separate the lower layer (solution of benzyl acetate in carbon tetrachloride) and discard the upper aqueous layer. 

• Return the lower layer to the funnel, and wash it successively with water, concentrated sodium hydrogen carbonate solution (until effervescence ceases) and water. 

• Dry over 5g of magnesium sulphate, and distil from an air bath. 

• Collect the benzyl acetate (a colourless liquid) at 213-215 °C. The yield is 16g (37%).

Cognate preparations: hydrochloric acid catalyst. Cyclohexyl acetate

• Pass dry hydrogen chloride into 75g (0.75 mol) of pure cyclohexanol until 1.5g are absorbed, mix with 135g (2.25 mol) of glacial acetic acid in a 500-ml round-bottomed flask, attach a reflux condenser and reflux for 14 hours. 

• Pour into excess of water, wash the upper layer successively with water, saturated sodium hydrogen carbonate solution until effer-vescence ceases, and water. 

• Dry with anhydrous calcium chloride. 

• Distil through a well-lagged fractionating column (e.g. an all-glass Dufton column). 

• A small fraction of low boiling point (containing cyclohexene) passes over first, followed by cyclohexyl acetate (57g, 54%) at 168-170 °C. Upon redistillation, the boiling point is 170-172 °C, mainly 171-172 °C.

Cyclohexyl formate

• Use 103g (84.5 ml, 2.24 mol) of formic acid (98/100%) and 75g (0.75 mol) of cyclohexanol in which 1.5 g of dry hydrogen chloride gas are dissolved. 

• Reflux for 14 hours. Work up as above and distil through a well-lagged column; 5.5g of cyclohexene and 57 g (59%) of cyclohexyl formate, b.p. 156-158.5 °C (mainly 157-158.5 °C), are obtained. 

• On redistillation the sample boils at 158-160°C (mainly 159-160°C).

s-Butyl acetate

• Pass dry hydrogen chloride gas into 37g (46 ml, 0.5 mol) of butan-2-ol until 1.5g is absorbed. 

• Mix the solution with 60g (1 mol) of glacial acetic acid, and reflux for 10 hours. Isolate the ester as for butyl acetate (b.p. 110-112°C). Yield: 35g (60%).

Ethyl p-aminobenzoate

• Saturate 80 ml (63.2 g, 1.37 mol) of absolute ethanol with dry hydrogen chloride, add 12g (0.088 mol) of p-aminobenzoic acid and heat the mixture under reflux for 2 hours. 

• Upon cooling, the reaction mixture sets to a solid mass of the hydrochloride of ethyl p-aminobenzoate. It is better, however, to pour the hot solution into excess of water (no hydro-chloride separates) and add sodium carbonate to the clear solution until it is neutral to litmus. 

• Filter off the precipitated ester at the pump and dry in the air. The yield of ethyl p-aminobenzoate, m.p. 91 °C, is 10g (69%). Recrystallisation from rectified spirit does not affect the m.p.

SYNTHESIS OF SUCCINIC ANHYDRIDE

• In a 500-ml round-bottomed flask, provided with a reflux condenser protected by a calcium chloride drying tube, place 59g (0.5 mol) of succinic acid and 102g (94.5 ml, 1 mol) of redistilled acetic anhydride. 

• Reflux the mixture gently on a water bath with occasional shaking until a clear solution is obtained (c. 1 hour), and then for a further hour to ensure the completeness of the reaction. 

• Remove the complete assembly from the water bath, allow it to cool (observe the formation of crystals) and finally cool in ice. 

• Collect the succinic anhydride on a Buchner funnel or a sintered glass funnel, wash it with two 40 ml portions of anhydrous ether and dry in a vacuum desiccator.The yield is 45 g (90%), m.p. 1 19-120 °C.

SYNTHESIS OF HEXANOIC ANHYDRIDE

• Place 116g (126 ml, 1 mol) of dry hexanoic acid in a 250-ml Drechsel bottle and cool in ice. 

• Pass in 21-23 g of keten(1).

• Carefully distil the reaction mixture through a highly efficient fractionating column (e.g. a well-lagged Widmer column) (2), using an oil bath for heating. 

• A fraction of low boiling point, containing acetone, keten, acetic acid and a little acetic anhydride, is thus removed at atmospheric pressure. 

• Raise the temperature of the bath to 220 °C over a period of 1 hour and maintain it at this temperature for 3 hours from the time distillation commences: this time is necessary to ensure that the conversion of the mixed anhydride to hexanoic anhydride and acetic acid is complete and that the acetic acid is completely removed. 

• Discontinue the distillation, allow to cool somewhat and distil the residue in the flask under reduced pressure (3-10 mmHg). 

• Discard the small fraction (20g) of low boiling point and collect the hexanoic anhydride at 118-121 °C/6mmHg(or 109-1 12 °C/3 mmHg). The yield is 90g (84%). Record the i.r. spectrum and compare it with that of acetic anhydride.

Notes to keep in mind:

1. Excess of keten over the calculated quantity does not increase the yield; it leads to more acetic anhydride being collected in the low boiling point fraction.

2. The best results are obtained with a fractionating column surrounded by an electrically heated jacket but this is not essential for hexanoic anhydride. For the preparation of propanoic or butanoic anhydride, a highly efficient fractionating column must be used in order to obtain satisfactory results.

SYNTHESIS OF HEPTANOIC ANHYDRIDE

CAUTION: All operations should be conducted in an efficient fume cupboard owing to the toxicity of pyridine and benzene.

• In a 250-ml, round-bottomed three-necked flask, provided with a dropping funnel, stirrer and thermometer, place 15.8g (16.1ml, 0.2 mol) of dry pyridine and 25 ml of dry benzene. 

• Stir and add rapidly 14.8g (15.5 ml, 0.1 mol) of heptanoyl chloride; the temperature rises slightly and a pyridinium complex separates. 

• Introduce 13.0g (14.1ml, 0.1 mol) of heptanoic acid with stirring, over a period of 5 minutes; the temperature rises to 60-65 °C and pyridine hydrochloride is formed. 

• Continue the stirring for 10 minutes and collect the hygroscopic pyridine hydrochloride as rapidly as possible on a chilled Buchner or sintered glass funnel, and wash it with two 25-ml portions of dry benzene. 

• Remove the benzene from the filtrate under reduced pressure on a water bath, and distil the residue through a short fractionating column. 

• Collect the heptanoic anhydride at 170-173 °C/15mmHg; the yield is 20g (83%).

SYNTHESIS OF BUTYRYL CHLORIDE (Butanoyl chloride)

• Fit a 100-ml two-necked flask with a dropping funnel and a reflux condenser connected at the top to a gas absorption trap. 

• Place 36g (21.5 ml, 0.3 mol) of redistilled thionyl chloride in the flask and 22g (23 ml, 0.25 mol) of butyric acid in the separatory funnel. 

• Heat the flask gently on a water bath, and add the butyric acid during the course of 30-40 minutes (1). 

• When all the acid has been introduced, heat on a water bath for 30 minutes. 

• Rearrange the apparatus and distil: collect the crude acid chloride boiling between 70 and 110°C. 

• Finally, redistil from a flask provided with a short fractionating column and collect the butyryl chloride at 100-101 °C. The yield is 23g (86%).

Notes to keep in mind:

1.  Wrap a piece of absorbent cotton wool around the stem of the reflux condenser above the joint of the reaction flask to prevent condensed moisture seeping into the flask.

Cognate preparations: Hexanoyl chloride

• Place 58 g (62 ml, 0.5 mol) of hexanoic acid in the flask, heat on a water bath and add 72 g (43 ml, 0.6 mol) of redistilled thionyl chloride during 45 minutes; shake the flask from time to time to ensure mixing. 

• Reflux for 30 minutes and isolate the hexanoyl chloride by distillation, b.p. 150-155 °C. The yield is 56 g (83%).

Valeryl chloride (pentanoyl chloride)

• Use 51 g (0.5 mol) of valeric acid and 72 g (0.6 mol) of redistilled thionyl chloride. Proceed as for hexanoyl chloride; the yield of valeryl chloride is 42g (70%), b.p. 124-127 °C.

Isobutyryl chloride (2-methylpropanoyl chloride)

• Use 140 g (1.6 mol) of isobutyric acid and 236 g (2 mol) of redistilled thionyl chloride. Proceed as for hexanoyl chloride; the yield is 121 g (71%), b.p. 90-93 °C, after distillation through a Vigreux column (36 cm).

Isovaleryl chloride (3-methylbutanoyl chloride)

• Use 34 g (0.4 mol) of isovaleric acid and 47 g (0.5 mol) of thionyl chloride. Proceed as for hexanoyl chloride; the yield of isovaleryl chloride is 36 g (76%), b.p. 114-115°C, after distillation through a Vigreux column.

Cyclohexanecarbonyl chloride

• Use 91 g (0.7 mol) of cyclohexanecarboxylic acid and 166g (1.4 mol) of thionyl chloride. Proceed as for hexanoyl chloride but heat under reflux for 2 hours. The yield of cyclohexanecarbonyl chloride is 100 g (78%), b.p. 76-78°C/12mmHg, after distillation through a Vigreux column.

SYNTHESIS OF (S)-( + )-2-METHYLHEXANOIC ACID

Trans-(4S,5S)-2-ethyI-4-hydroxymethyI-5-phenyl-2-oxazoIine

• A mixture of 126.5g (0.76mol) of (lS,2S)-( + )-2-amino-1-phenylpropane-1,3-diol (1) and 160g (0.91 mol) of triethyl orthopropanoate in 550 ml of 1,2-dichloroethane is heated under reflux for 7 hours. 

• The solvent is removed leaving an oil (159g) which crystallises on standing. 

• This is treated with 70 ml of ether and cooled in a dry-ipe-acetone bath and the partially purified product collected by filtration. 

• The crystalline material is dissolved in ether (c. 600 ml), treated with charcoal, filtered, concentrated to about 300 ml and cooled to — 78 °C. 

• The recrystallised material is filtered and washed with a small amount (15-20 ml) of precooled (-78 °C) ether. The yield of product is 106.9 g (69%), m.p. 68-69°C, [𝛼]²²₅₈₉-135.1° (c 10.4 in CHCl₃).

(4S,5S)-2-Ethyl-4-methoxymethyI-5-phenyI-2-oxazoline (2)

• The foregoing compound (18.0g, 88mmol) in 150 ml of dry tetrahydrofuran is added dropwise at room temperature to a stirred heterogeneous suspension (under nitrogen), of sodium hydride [105.3 mmol; oil removed by washing with 50 ml of dry benzene (CAUTION)] at a rate to maintain a mild evolution of hydrogen. 

• When addition is complete the mixture is heated at 50-60 °C for 1.5 hours and cooled to ambient temperature; a solution of methyl iodide (16.2g, 114 mmol, CAUTION) in tetrahydrofuran (10 ml) is added dropwise. 

• The reaction mixture is stirred for 2 hours and slowly poured into 300 ml of ice-water, and then extracted with two 200-ml portions of ether. 

• The combined ether extracts are dried over anhydrous sodium sulphate and concentrated to give an oil which is distilled in vacuo to furnish the product in 87 per cent yield, b.p. 91-93 °C/0.25mmHg.

(S)-( + )-2-MethyIhexanoic acid

• A solution of the foregoing compound (15.4g, 70 mmol) in tetrahydrofuran (160 ml) under nitrogen is cooled to — 78 °C in a dry-ice-acetone bath. 

• To this is added a solution of 70 mmol of lithium diisopropylamide (from 9.8 ml of diisopropylamine and 33 ml of 2.2 m butyllithium in 75 ml of tetrahydrofuran) over a 20-minute period. 

• The resulting solution is stirred for 40 minutes at — 78 °C, and then the cooling bath is changed to methanol-liquid nitrogen and the reaction mixture allowed to cool to -98 °C for 30 minutes (3). 

• A solution of butyl iodide (14.7 g, 80 mmol) in tetrahydrofuran (20 ml) is added over 1 5-20 minutes at — 98 °C and the resulting almost colourless solution is stirred at this temperature for 2 hours, then slowly allowed to reach room temperature. 

• The reaction mixture is poured into 300 ml of saturated brine and extracted with two 150 ml portions of ether, dried over magnesium sulphate and concentrated to give 17.7 g (92%) of 2-(l-methylpentyl)-4-methoxymethyl-5-phenyl-2-oxazoline. 

• A small portion is distilled (bulb to bulb) to give an analytically pure product [𝛼]²⁴₅₈₉-35.2° (c 10.1 in CHCl₃); i.r. (thin film) 1670cm⁻¹ ; p.m.r. (CDCl₃, TMS) 𝜹7.33 (s, 5H), 5.33 (d, J = 7Hz, 1H), 4.33-3.93 (q, 1H), 3.80-3.33 (m, 2H), 3.43 (s,3H), 2.87-2.33 (m, 1H), and 2.00-0.67 (m, 12H).

• The crude oxazoline (17.2 g) is dissolved in 250 ml of 2 m sulphuric acid and heated to reflux for 3.5 hours, at which time the solution becomes homogeneous. 

• When the heating of the solution is initiated a crystalline solid appears which slowly dissolves as the reflux progresses. 

• After the heating is discontinued, the solution is cooled to room temperature and extracted with two 75-ml portions of ether. 

• The combined ether extracts are washed with three 100-ml portions of 5 per cent aqueous potassium carbonate solution and the aqueous extracts neutralised to pH 1 with 12 m hydrochloric acid. 

• The resulting turbid mixture is extracted with three 75-ml portions of ether and the extract dried over magnesium sulphate. 

• Concentration of the ether solution leaves an oil which is distilled (bulb to bulb) to give 5.80 g (66%) of (S)-( + )-2-methylhexanoic acid. Gas-liquid chromatography analysis (10% UCW-98) indicates only a single compound; [𝛼]²⁴₅₈₉ +14.5° (neat) (ee 78%, (4)].

Notes to keep in mind:

1.  This amino alcohol may be recrystallised by dissolving 1 part in 1 part of methanol and adding 2 parts of ethyl acetate and cooling. The pure material has m.p. 112-113 °C,[𝛼]²⁴₅₈₉ 26.6° (c 10.0 in MeOH).

2.  The apparatus set-up for this, and the following reaction, should take into account the moisture sensitivity of the reagents and the reaction intermediates. The reagents should be added by syringe through a rubber septum, the reaction media should be held under an atmosphere of nitrogen via a suitable nitrogen bubbler device, and the solutions should be stirred magnetically.

3.  Continued use of the cooling bath held at —78 °C leads to only a small diminution of optical purity in the final product.

4.  The specific rotation of optically pure acid is [𝛼]ᴅ²⁵ —18.7° (neat).

SYNTHESIS OF 2-PROPYGLUTARIC ACID

• Add 8.0g (10.0ml, 0.15 mol) of redistilled acrylonitrile to a stirred solution of diethyl propylmalonate (30.2 g, 0.15 mol) and of 30 per cent methanolic potassium hydroxide (4.0g) in t-butyl alcohol (100g). 

• Keep the reaction mixture at 30-35 °C during the addition and stir for a further 3 hours. 

• Neutralise the solution with 2 M-hydrochloric acid, dilute with water and extract with ether. 

• Dry the ethereal extract with anhydrous sodium sulphate and distil off the ether: the residue [diethyl (2-cyanoethyl)-propylmalonate; 1 1 g] solidifies on cooling in ice, and melts at 31-32 °C after recrystallisation from ice-cold ethanol. 

• Boil the cyanoethyl ester (10g) under reflux with 40 ml of 48 per cent hydrobromic acid solution for 8 hours, and evaporate the solution almost to dryness under reduced pressure. 

• Add sufficient water to dissolve the ammonium bromide, extract several times with ether, dry the ethereal extract and distil off the solvent. 

• The residual oil (4.5 g, 66%) soon solidifies: upon recrystallisation from water, pure 2-propylglutaric acid, m.p. 70 °C, is obtained.

Notes to keep in mind:

1.  Acrylonitrile forms an azeotropic mixture with water, b.p. 70.5 °C (12.5% water). The commercial product may contain the polymer; it should be redistilled before use and the fraction, b.p. 76.5-78 °C, collected separately as a colourless liquid.

SYNTHESIS OF 2,2-DIMETHYLSUCCINIC ACID

CAUTION: This preparation must be carried out in an efficient fume cupboard.

• Into a 500-ml round-bottomed flask, provided with a double surface condenser, place 50 g (63 ml, 0.86 mol) of pure, dry acetone, 50 g (47 ml, 0.44 mol) of ethyl cyanoacetate and 0.5 g of piperidine. 

• Allow to stand for 60 hours and heat on a water bath for 2 hours. 

• Treat the cold reaction mixture with 100 ml of ether, wash with dilute hydrochloric acid, then with water, and dry over anhydrous sodium sulphate. 

• Distil under diminished pressure and collect the ethyl isopropylidenecyanoacetate (ethyl 2-cyano-3,3-dimethylacrylate) at 114-1 16 °C/14mmHg (1). The yield is 39 g (58%). 

• Dissolve 20 g (0.13 mol) of the cyano ester in 100 ml of rectified spirit and add a solution of 19.2 g (0.295 mol) of pure potassium cyanide (CAUTION) in 40 ml of water. 

• Allow to stand for 48 hours, then distil off the alcohol on a water bath. 

• Add a large excess of concentrated hydrochloric acid and heat under reflux for 3 hours. (CAUTION: hydrogen cyanide evolved.) 

• Dilute with water, saturate the solution with ammonium sulphate and extract with four 75 ml portions of ether. 

• Dry the combined ethereal extracts with anhydrous sodium sulphate, and distil off the ether. 

• Recrystallise the residual acid from excess concentrated hydrochloric acid, and dry in the air. The yield of pure 2,2-dimethylsuccinic acid, m.p. 141-142 °C, is 12 g (63%). The p.m.r. spectrum is recorded in trifluoracetic acid and reveals signals at 5 1.48 (s, 6H, Me 2 ) and 2.92 (s, 2H, CH 2 ); the hydroxyl proton is not observed.

Notes to keep in mind:

1.  Higher (including cycloaliphatic) ketones may be condensed with ethyl cyanoacetate under the following conditions. Mix 0.50 mol of ethyl cyanoacetate, 0.55-0.70 mol of the ketone, 0.02 mol of piperidine and 50ml of dry benzene (CAUTION) and heat under reflux for 12-24 hours in an apparatus incorporating an automatic water separator. Piperidine may be replaced by a catalyst composed of 7.7 g (0.1 mol) of ammonium acetate and 24 g (0.4 mol) of glacial acetic acid. Wash the cold reaction mixture with three 25-ml portions of 10 per cent sodium chloride solution, and remove the benzene on a water bath under reduced pressure. Transfer the residue to a 1 -litre bottle containing a solution of 65 g of sodium metabi-sulphite in 250ml of water and shake mechanically for 2-6 hours. Dilute the turbid solution, which contains the sodium metabisulphite addition compound, with 400 ml of water, and extract the ethyl cyanoacetate with three 50 ml portions of benzene. Cool the bisulphite solution in ice, and add dropwise, with mechanical stirring, an ice-cold solution of 28 g of sodium hydroxide in 110 ml of water, Extract the regenerated unsaturated ester at once with four 25 ml portions of benzene, wash the extracts with 50 ml of 1 per cent hydrochloric acid and dry with anhydrous sodium sulphate. Filter and distil through a fractionating column under reduced pressure; the benzene may be conveniently removed by distilling at atmospheric pressure until the temperature rises to 90°C. Diethyl ketone yields ethyl 2-cyano-3,3-diethylacrylate, b.p. 123-125 °C/ 12mmHg or 96-97 °C/3 mmHg; dipropyl ketone gives ethyl 2-cyano-3,3-dipropyl-acrylate, b.p. 136-137 °C/11 mmHg or 1 16-1 17 °C/4 mmHg. The yield is 60-70 per cent.

The appropriate succinic acid can be prepared by condensation of the unsaturated cyano ester with alcoholic potassium cyanide and subsequent treatment with hydrochloric acid.

SYNTHESIS OF GLUTARIC ACID (Pentanedioic acid)

Tetraethyl propane-1,1,3,3-tetracarboxylate 

• Cool a mixture of 320 g (302 ml, 2 mol) of redistilled diethyl malonate and 80 g ( 1 mol) of 40 per cent formaldehyde solution ('formalin') contained in a 1 -litre round-bottomed flask to 5 °C by immersion in ice, and add 5 g (7 ml) of diethylamine. 

• Keep the mixture at room temperature for 15 hours and then heat under a reflux condenser on a boiling water bath for 6 hours. 

• Separate the aqueous layer, dry the organic layer with anhydrous sodium sulphate and distil under reduced pressure. 

• Collect the tetracarboxylate ester at 200-215 °C/20mmHg. The yield is 250g (75%).

Glutaric acid

• Heat a mixture of 125g (0.376 mol) of the preceding ester and 250 ml of 1:1-hydrochloric acid under reflux with stirring in a 1-litre two-necked flask equipped with a mechanical stirrer and reflux condenser. 

• Continue the heating until the mixture becomes homogeneous (6-8 hours). 

• Evaporate the contents of the flask to dryness on a steam bath (rotary evaporator) and distil the residual glutaric acid under reduced pressure. 

• Collect the fraction boiling at 185-195°C/10mmHg; it crystallises on cooling. 

• Moisten with a little water (to convert any glutaric anhydride present into the acid), heat gently and dry at 30 °C. 

• Recrystallise from chloroform (or benzene): the resulting practically pure glutaric acid, m.p. 96-97 °C, weighs 40 g (81%).

SYNTHESIS OF PROPYLMALONIC ACID

 

• Dissolve 156 g (2.78 mol) of potassium hydroxide in 156 ml of water in a 1.5-litre round-bottomed flask and add 500 ml of rectified spirit to produce a homogeneous solution. 

• Introduce 220g (1.09 mol) of diethyl propylmalonate slowly and with shaking. 

• Attach a double surface reflux condenser and reflux the mixture for 3 hours; hydrolysis is then complete, i.e. a test portion dissolves completely in excess of water. 

• Distil off as much ethanol as possible on a water bath, and dissolve the residue in a comparatively small volume of water. 

• Cool the solution in a large beaker surrounded by ice; add dilute sulphuric acid slowly from a suitably supported dropping funnel, whilst stirring vigorously with a mechanical stirrer, until the solution is acid to Congo red paper. 

• Extract the solution with three 150 ml portions of ether, dry the ethereal extract with anhydrous sodium sulphate and distil off the ether on a water bath. 

• Spread the syrupy residue in thin layers upon large clock glasses (1); after 2-3 days, filter off the crystals at the pump, using light petroleum, b.p. 40-60 °C, to facilitate the transfer from the clock glasses to the sintered glass filter funnel. 

• Spread the crystals on a porous tile to remove traces of oily impurities; the crude propylmalonic acid has m.p. 95-96 °C. 

• Spread the filtrate and washings on large clock glasses as before and filter off the solid which crystallises after 1 day. 

• Repeat the process until no further crystals are obtained. 

• Recrystallise all the crystals from hot toluene. The yield of pure propylmalonic acid, m.p. 96 °C, is HOg (69%).

Notes to keep in mind:

1.  An alternative procedure is to leave the syrupy residue in a vacuum desiccator over anhydrous calcium chloride and silica gel, and to filter off the successive crops of crystals as they separate. These are washed with light petroleum, b.p. 40-60 °C, spread on a porous tile and recrystallised.

Cognate preparations: Butylmalonic acid

• This acid may be similarly prepared from diethyl butylmalonate and melts at 102 °C after recrystallisation from benzene.

s-Butylmalonic acid

• From diethyl s-butylmalonate; the acid melts at 76 °C after recrystallisation from benzene.

SYNTHESIS OF HEXANOIC ACID

Diethyl butylmalonate

• Prepare a solution of sodium ethoxide from 34.5g (1.5 mol) of clean sodium and 1 litre of super-dry ethanol(1) in a 2-litre three-necked flask following the experimental conditions given for ethyl propylacetoacetate. 

• When the sodium ethoxide solution, which is vigorously stirred, has cooled to about 50 °C, add 247.5 g (234.5 ml, 1.55 mol) of redistilled diethyl malonate slowly through the separatory funnel; to the resulting clear solution introduce gradually (60-90 minutes) 205.5g (161.5 ml, 1.5 mol) of redistilled butyl bromide.

• Reaction occurs almost immediately and much heat is evolved; if the reaction becomes violent, cool the flask by directing a stream of cold water over it. 

• Reflux the reaction mixture on a water bath until it is neutral to moist litmus (about 2 hours). 

• Remove as much of the ethanol as possible by distillation under reduced pressure (rotary evaporator) on a water bath. 

• Cool the contents of the flask to about 20 °C, add 600 ml of water and shake well. 

• Separate the upper layer of crude ester, dry it with anhydrous sodium sulphate and distil under reduced pressure. 

• A low boiling point fraction passes over first, followed by diethyl butylmalonate at 130-135 °C/20mmHg. The yield is 285g (88%). 

• The distillation may also be conducted under normal pressure; the b.p. of the ester is 235-240 °C.

Hexanoic acid 

• Into a 2-litre three-necked flask, fitted with a separatory funnel, a mechanical stirrer and a reflux condenser, place a hot solution of 200 g of potassium hydroxide in 200 ml of water. 

• Stir the solution and add slowly 200 g (0.925 mol) of diethyl butylmalonate. 

• A vigorous reaction occurs and the solution refluxes. 

• When all the ester has been added, boil the solution gently for 2-3 hours, i.e. until hydrolysis is complete: a test portion should dissolve completely in water. 

• Dilute with 200 ml of water and distil off 200 ml of liquid in order to ensure the complete removal of the alcohol formed in the hydrolysis (2). 

• To the cold residue in the flask add a cold solution of 320g (174 ml) of concentrated sulphuric acid in 450 ml of water: add the acid slowly with stirring in order to prevent excessive foaming. 

• The solution becomes hot. 

• Reflux the mixture for 3-4 hours and allow to cool. 

• Separate the upper layer of the organic acid and extract the aqueous portion with four 150 ml portions of ether (3). 

• Combine the acid layer with the ether extracts, wash it with 25 ml of water and dry with anhydrous sodium sulphate. 

• Distil off the ether (rotary evaporator), transfer the residue to a flask fitted with a short fractionating column (the latter should be well lagged and, preferably, electrically heated) and distil the product from an air bath. 

• Collect the hexanoic acid at 200-206 °C. The yield is 80 g (75%). 

• Record the i.r. spectrum and compare it. If desired, the distillation may be conducted under reduced pressure. 

• The boiling points under various pressures are 99°C/10mmHg and 111°C/20 mmHg; a 3 °C fraction should be collected.

Notes to keep in mind:

1.  With commercial absolute ethanol, the yield is reduced to about 225 g.

2.  It is essential to remove the alcohol completely, otherwise some ethyl hexanoate, b.p. 168°C, is formed which will contaminate the final product.

3.  Better results are obtained if a continuous extraction apparatus (e.g. Fig. 2.92) is employed.

Cognate preparations: Diethyl propylmalonate

• Use 34.5 g (1.5 mol) of sodium and 345 g (440 ml) of super-dry ethanol, 240g (227.5 ml, 1.5 mol) of diethyl malonate and 185 g (136.5 ml, 1.5 mol) of propyl bromide. The yield of diethyl propylmalonate, b.p. 21 8-225 °C, mainly 219.5-221.5 °C, is 220g (72.5%).

Pentanoic acid (valeric acid)

• Convert the diethyl propylmalonate into valeric acid, b.p. 183-185 °C, following the procedure described for hexanoic acid. The yield is 75 per cent of theory.

3-Phenylpropanoic acid (hydrocinnamic acid)

• Use 1 1.5 g (0.5 mol) of sodium and 250 ml of dry ethanol, 80 g (75 ml, 0.49 mol) of diethyl malonate and 64g (58 ml, 0.51 mol) of redistilled benzyl chloride. 

• Follow the alkylation procedure described above and isolate the crude diethyl benzylmalonate. 

• Hydrolyse the latter with a solution of 75g of potassium hydroxide in 75 ml of water and isolate the resulting crude 3-phenylpropanoic acid as described previously, using 1 80 ml of 5 m sulphuric acid in the acidification stage. 

• Purify the product by distillation under reduced pressure, collecting the fraction of b.p. 164-172 °C/25 mmHg which solidifies at room temperature. 

• Recrystallise from light petroleum, b.p. 40-60 °C (or from water containing a little hydrochloric acid), to obtain 20 g (27%) of 3-phenylpropanoic acid of m.p. 47- 48 °C.

Nonanoic acid (pelargonic acid)

• Equip a 1 -litre three-necked flask with a reflux condenser, a sealed stirrer unit and a thermometer. 

• Place 23 g (1 mol) of sodium, cut in small pieces, in the flask, and add 500 ml of anhydrous butan-1-ol (1) in two or three portions: for the preparation of a solution of sodium ethoxide. 

• When the sodium has reacted completely, allow the solution to cool to 70-80 °C and add 160 g (152 ml, 1 mol) of redistilled diethyl malonate rapidly and with stirring. 

• Heat the solution to 80-90 °C, replace the thermometer with a dropping funnel and add 182.5 g (160ml, 1.02 mol) of 1-bromoheptane slowly at first until precipitation of sodium bromide commences, and subsequently at such a rate that the butanol refluxes gently. 

• Reflux the mixture until it is neutral to moist litmus (about 1 hour). 

• Transfer the entire reaction mixture, including the precipitated sodium bromide and the small volume of water used to rinse the reaction flask, to a 3-litre flask. 

• Add a solution of 140 g of potassium hydroxide in an equal quantity of water slowly and with shaking. 

• Attach a reflux condenser to the flask, introduce a few fragments of porous porcelain and heat the mixture cautiously, with occasional shaking, until refluxing commences. 

• Heat to gentle refluxing until hydrolysis is complete (about 5 hours, i.e. until a test portion is completely miscible with excess of water). 

• Immediately equip the flask for steam distillation and steam distil the mixture until no more butanol passes over. 

• Treat the residue cautiously with 270 ml of concentrated hydrochloric acid while shaking gently, and reflux the mixture for 1 hour; if sodium chloride separates as a solid cake, take care during the heating that the flask does not crack. 

• When cold, transfer the mixture to a separatory funnel and remove the oil to a 750-ml round-bottomed flask.

• Heat it under an air-cooled reflux condenser in an oil bath at 180°C until the evolution of carbon dioxide ceases (about 2 hours). 

• Decant the oil into a Claisen flask with fractionating side-arm (the latter should be well lagged) and distil under reduced pressure. 

• Collect the pelargonic acid at 1 40-1 42 °C/1 2 mmHg. The yield is 1 1 5 g (73%). 

Notes to keep in mind: 

1.  This is conveniently prepared by drying commercial butan-1-ol with anhydrous potassium carbonate or anhydrous calcium sulphate, distilling through a column and collecting the fraction, b.p. 117-118 °C.

SYNTHESIS OF MYRISTIC ACID (Tetradecanoic acid)

Method A

• Dissolve 23.2g (0. 184 mol) of redistilled hexanoic acid, b.p. 204.5-205.5 °C/7 60 mmHg, and 21.6g (0.1 mol) of methyl hydrogen sebacate in 200 ml of absolute methanol to which 0.13g of sodium has been added. 

• Electrolyse at 2.0 amps, while maintaining the temperature  between 30 and 40 °C, until the pH is about 8.0 (c. 6 hours). 

• Neutralise the contents of the electrolysis cell with a little acetic acid and distil off the methanol on a water bath. 

• Dissolve the residue in 200 ml of ether, wash with three 50 ml portions of saturated sodium hydrogen carbonate solution, once with water, dry with magnesium sulphate, and distil through an efficient fractionating column. 

• Collect the decane at 60°C/10mmHg (3.0g), the methyl myristate at 158-160 °C/10mmHg (12.5 g, 52%) and dimethyl octadecanedioate at 215-230 °C/7mmHg (1.5g).

• Reflux a mixture of 7.3g of methyl myristate with a solution of 4.8g of sodium hydroxide in 200 ml of 90 per cent methanol for 2 hours, distil off the methanol on a water bath, dissolve the residue in 400 ml of hot water, add 15 ml of concentrated hydrochloric acid to the solution at 50 °C in order to precipitate the organic acid, and cool. 

• Collect the acid by suction filtration, wash it with a little water and dry in a vacuum desiccator. The yield of myristic acid (tetradecanoic acid), m.p. 57-58 °C, is 5.9g (87%).

Method B

• Dissolve 55.2g (0.32 mol) of pure decanoic acid, m.p. 31-32 °C, and 25.6 g (0. 1 6 mol) of methyl hydrogen adipate in 200 ml of absolute methanol to which 0.25 g of sodium has been added. 

• Electrolyse at 2.0 amps at 25-35 °C until the pH of the electrolyte is 8.2 (c. 9 hours). 

• Neutralise the contents of the electrolytic cell with acetic acid, distil off the methanol on a water bath, dissolve the residue in about 200 ml of ether, wash with three 50 ml portions of saturated sodium hydrogen carbonate solution and remove the ether on a water bath. 

• Treat the residue with a solution of 8.0 g of sodium hydroxide in 200 ml of 80 per cent methanol, reflux for 2 hours and distil off the methanol on a water bath. 

• Add about 600 ml of water to the residue to dissolve the mixture of sodium salts: extract the hydrocarbon with four 50 ml portions of ether, and dry the combined ethereal extracts with magnesium sulphate. 

• After removal of the ether, 23.1g of almost pure octadecane, m.p. 23-24 °C, remains. 

• Acidify the aqueous solution with concentrated hydrochloric acid (c. 25 ml), cool to °C, filter off the mixture of acids, wash well with cold water and dry in a vacuum desiccator. The yield of the mixture of sebacic and myristic acids, m.p. 52-67 °C, is 26 g. 

• Separate the mixture by extraction with six 50 ml portions of almost boiling light petroleum, b.p. 40-60 °C. The residue (5.2 g), m.p. 132°C, is sebacic acid. 

• Evaporation of the solvent gives 20g (55%) of myristic acid, m.p. 52-53 °C; the m.p. is raised slightly upon recrystallisation from methanol.

Cognate preparations: Sebacic acid (decanedioic acid)

• Dissolve 40g (0.25 mol) of methyl hydrogen adipate in 100 ml of absolute methanol to which 0.1g of sodium has been added. 

• Pass a current of about 2.0 amps until the pH of the solution is about 8 (c.5 hours); test with narrow-range indicator paper. 

• Transfer the contents of the electrolysis cell to a 500-ml round-bottomed flask, render neutral with a little acetic acid and distil off the methanol on a water bath. 

• Dissolve the residue in 150 ml of ether, wash with three 50 ml portions of saturated sodium hydrogen carbonate solution, then with water, dry over magnesium sulphate and distil under reduced pressure. 

• Collect the dimethyl sebacate at 155°C/8mmHg; it melts at 26 °C and the yield is 14.6-16.0 g (51-56%). 

• Reflux 14.6g (0.064 mol) of the ester with a solution of 10 g of sodium hydroxide in 125 ml of 80 per cent methanol for 2 hours on a water bath. 

• Add 200 ml of water to dissolve the solid which separates, extract with two 30 ml portions of ether and warm the aqueous solution on a water bath to remove dissolved ether. 

• Acidify the ice-cold aqueous solution to litmus by the addition of concentrated hydrochloric acid. 

• Collect the precipitated acid by suction filtration, wash it with a little cold water and dry at 100 °C. The yield of sebacic acid, m.p. 133 °C, is 11.5g (89%).

Octadecanedioic acid

• Dissolve 31.5g (0.145 mol) of methyl hydrogen sebacate in 140 ml of absolute methanol to which 0.4g of sodium has been added. 

• Electrolyse at 2.0 amps until the pH of the electrolyte is 7.8-8.0 (3.5-4 hours). 

• Work up as described for sebacic acid. 

• Upon distillation, an unsaturated ester passes over at 111-113°C/20mmHg (4.6g), followed by dimethyl octadecanedioate at 212-219°C/4mmHg (mainly at 214-215 °C/4mmHg), m.p. 56°C(16.5g, 66%). 

• Reflux 6.8g of the dimethyl ester with a solution of 3.2g of sodium hydroxide in 150 ml of 80 per cent methanol for 2 hours on a water bath. 

• When cold, filter off the solid and wash it with a little cold methanol. 

• Dissolve the solid in 350 ml of warm water, add concentrated hydrochloric acid to the solution at 60 °C until acidic to litmus, filter off the precipitated acid, wash with a little water and dry at 100 °C. The resulting octadecanedioic acid, m.p. 122 °C, weighs 5.3g (84%). 

• Recrystallisation from absolute methanol raises the m.p.to 124.5 °C.

SYNTHESIS OF DODECANEDIOIC ACID

SebacoyI chloride:

• Convert 20 g (0. 1 mol) of sebacic acid into the corresponding acid chloride by heating it on a water bath in a flask fitted with a reflux condenser (protected with a calcium chloride tube) with 20 ml of thionyl chloride; the apparatus should be assembled in a fume cupboard. 

• Purify the product by distillation under reduced pressure (use appropriate traps to protect the pump from the fumes of hydrogen chloride and sulphur dioxide). 

• Collect the sebacoyl chloride as a fraction of b.p. 140-143 °C/2mmHg; the yield is 18 g (77%).

1,8-Bis-diazoacetyloctane

• Dissolve 7.4 g (0.033 mol) of the resulting sebacoyl chloride in anhydrous ether and add the solution slowly to an ethereal solution containing about 6.8 g of diazomethane, i.e. two portions of the ethereal solution. 

• Allow the mixture to stand overnight and remove any excess reagent together with some of the ether by distillation from a warm-water bath. 

• To ensure that no undue hazard results from the possible presence of undecomposed excess diazomethane use a distillation assembly as described for the distillation of diazomethane-ethereal solutions. 

• When the distillate is colourless, change the receivers, and complete the removal of solvent by distillation under reduced pressure (water pump). 

• After recrystallisation from benzene the resulting 1,8-bis-diazoacetyloctane has m.p. 91 °C; the yield is 6.4 g (83%).

Dodecanedioic acid

• Add, with stirring, a solution of 5 g (0.02 mol) of the bis-diazoketone in 100 ml of warm dioxane to a suspension of 6.0 g of freshly precipitated silver oxide (2) in 250 ml of water containing 8 g of sodium thiosulphate maintained at 75 °C. 

• A brisk evolution of nitrogen occurs; after 1.5 hours at 75 °C, filter the liquid from the black silver residue. 

• Acidify the almost colourless filtrate with nitric acid and extract the gelatinous precipitate with ether. 

• Evaporate the dried ethereal extract: the residue of crude dodecanedioic acid weighs 3.3 g (72%), and has m.p. 116-1 17 °C. 

• Recrystallisation from 20 per cent aqueous acetic acid raises the m.p. to 127-1 28 °C.

• Alternatively, treat 3.9 g (0.01 56 mol) of the bis-diazoketone in 50 ml of warm dioxane with 15 ml of 20 per cent aqueous ammonia and 3 ml of a 10 per cent aqueous silver nitrate solution under reflux in a 250- or 500-ml flask on a water bath. 

• Nitrogen is evolved for a few minutes, followed by a violent reaction and the production of a dark brown opaque mixture. 

• Continue heating for 30 minutes on the water bath and filter hot; the diamide of dodecane-dioic acid is deposited on cooling. 

• Filter the product and air dry; the yield is 3.1g (87%), m.p. 182-1 84 °C, raised to 184-185 °C after recrystallisation from 20 per cent aqueous acetic acid. Hydrolyse the diamide by refluxing for 2-5 hours with a four molar excess of 3m potassium hydroxide solution. 

• Acidify and recrystallise the precipitated acid from 20 per cent acetic acid. The yield of dodecanedioic acid, m.p. 127-128 °C, is almost quantitative.

Notes to keep in mind:

1.  Precautions in the use of diazomethane are fully described in Section 4.2.25, p. 430, and should be carefully noted; the operations should be carried out in a fume cupboard.

2.  Prepare the silver oxide by adding dilute sodium hydroxide solution gradually to a stirred 10 per cent aqueous silver nitrate solution - until precipitation is just complete. Wash the product thoroughly with distilled water.

SYNTHESIS OF 2-METHYLBUTANOIC ACID

• Fit a 1 -litre three-necked flask with a mechanical stirrer, a double surface condenser and a separatory funnel and provide both the condenser and funnel with calcium chloride guard-tubes. 

• Prepare an ethereal solution of but-2-ylmagnesium chloride from 12.5g (0.51 mol) of dry magnesium turnings, 46 g (52.5 ml, 0.5 mol) of dry 2-chlorobutane (1) and 400 ml of anhydrous ether, cognate preparation. 

• When the spontaneous reaction has subsided reflux the reaction mixture for a further 1 hour. 

• Cool the flask in a mixture of ice and salt to — 12°C and add a further 100 ml of anhydrous ether. 

• Weigh out (rough balance) 125g of Cardice (2) on a piece of stiff paper: wrap the Cardice in a stout cloth, and, by means of a pestle, break it into small lumps. 

• Empty the Cardice into a dry 1500-ml beaker and at once pour in the Grignard reagent in a slow steady stream; any unreacted magnesium will adhere to the sides of the flask. 

• A vigorous reaction occurs. Stir the mass well, and allow it to stand untilall the Cardice has evaporated. 

• Then add slowly a mixture of 300 g of crushed ice and 75 ml of concentrated hydrochloric acid. 

• Stir until the gelatinous compound is decomposed and there is a clean separation into two layers. 

• Pour the mixture into a separatory funnel; rinse the beaker with 50 ml of ether and transfer this to the funnel. 

• Separate the upper layer and extract the aqueous layer with three 40 ml portions of ether. 

• Cool the combined ether extracts by the addition of ice, and add cautiously 100 ml of 25 per cent sodium hydroxide solution; run off and keep the aqueous layer and repeat the extraction with a further 50 ml of alkali solution of the same strength. 

• The organic acid is thus converted into the sodium salt and passes into the aqueous layer; test the extracts with phenolphthalein to make certain that all the acid has been removed. 

• Distil the alkaline extract until its volume is reduced by about 10 per cent; this removes ether and other volatile impurities. 

• Allow to cool, and cautiously acidify with concentrated hydrochloric acid; it is advisable to stir the mixture during the acidification process. Separate the upper layer of acid. 

• Distil the water layer from a 1-litre flask until no more oily drops pass over; saturate the distillate with salt, remove the acid layer and combine it with the main product. 

• Dry the combined acid fractions with anhydrous calcium sulphate, and distil. 

• Collect the 2-methylbutanoic acid at 173-174 °C. The yield is 40g (79%).

Notes to keep in mind:

1.  2-Chlorobutane is employed in preference to the bromide because it is cheaper and the yield of acid is slightly higher.

2. Cardice should be handled with gloves or with a dry towel; if Cardice is held for a long time in the hand it may cause frost bite. The crushed Cardice should be used immediately otherwise it may absorb water which would react with some of the Grignard reagent.