SYNTHESIS OF DIPHENYLMETHANE

CAUTION: This preparation should be conducted in an efficient fume cupboard.

• Fit a 500-ml three-necked round-bottomed flask with a sealed mechanical stirrer, attach a gas absorption device to one of the side-necks and stopper the third neck. 

• Place 38g (35 ml, 0.3 mol) of redistilled benzyl chloride and 150 ml of dry benzene (CAUTION) in the flask. 

• Weigh out 2g (0.015 mol) of anhydrous aluminium chloride into a dry capped specimen tube with the minimum exposure to the atmosphere. 

• Cool the flask in a bath of crushed ice and add about one-fifth of the aluminium chloride. 

• Stir the mixture; a vigorous reaction will set in within a few minutes and hydrogen chloride is evolved. 

• When the reaction has subsided, add a further portion of the aluminium chloride and repeat the process until all has been introduced. 

• The mixture should be kept well shaken and immersed in the ice bath during the addition. 

• After 15 minutes cautiously add lOOg of crushed ice, followed by 100 ml of water in order to decompose the aluminium complex. 

• Shake the mixture well, transfer to a separatory funnel and run off the lower aqueous layer. 

• Wash the upper layer successively with dilute hydrochloric acid and water and dry it with anhydrous calcium chloride. 

• Remove the benzene with the aid of the apparatus. 

• Distil the remaining liquid through an air condenser either with a free flame or from an air bath. 

• Collect the diphenylmethane at 250-275 °C (the pure substance boils at 262 °C) (1). 

• The distillate should solidify on cooling in ice and scratching with a glass rod, or by seeding with a crystal of the pure material. 

• If it does not crystallise, redistil from a small flask and collect the fraction, b.p. 255-267°C; this generally crystallises on cooling and has m.p. 24-25°C. The yield is 25g (50%).

Notes to Keep in Mind:

1. Alternatively the distillation may be conducted under diminished pressure; the fraction, b.p. 125-1 30 °C/10mmHg, is collected.

Cognate preparation: Triphenylmethane

• The apparatus is similar to that described above, but incorporating a reflux condenser to the outlet of which is fitted the gas absorption device. 

• Place a mixture of 200g (230 ml, 2.57 mol) of dry benzene (CAUTION) and 40g (26 ml, 0.33 mol) of dry chloroform in the flask, and add 35g (0.26 mol) of anhydrous aluminium chloride in portions of about 6g and at intervals of 5 minutes with constant stirring. 

• The reaction sets in upon the addition of the aluminium chloride and the liquid boils with the evolution of hydrogen chloride. Complete the reaction by refluxing for 30 minutes on a water bath. 

• When cold, pour the contents of the flask very cautiously on to 250g of crushed ice and 10 ml of concentrated hydrochloric acid. 

• Separate the upper benzene layer, dry it with anhydrous calcium chloride or with magnesium sulphate and remove the benzene by flash distillation. 

• Attach a Claisen still-head connected to a short air condenser and distil the remaining oil under reduced pressure; collect the fraction, b.p. 190-215 °C/10mmHg. 

• This is crude triphenylmethane which solidifies on cooling. 

• Recrystallise it from about four times its weight of ethanol; triphenylmethane separates in needles and melts at 92 °C. The yield is 30g (37%).

SYNTHESIS OF t-BUTYLBENZENE (2-Methyl-2-pheny\propane)

CAUTION: This preparation should be conducted in an efficient fume cupboard.

• Place 50g (0.33 mol) of anhydrous aluminium chloride (1) Into a 1-litre three-necked flask and 200 ml (2.25 mol) of dry benzene (CAUTION); cool in a bath of crushed ice. 

• Stir the mixture and add 50g (59 ml, 0.54 mol) of t-butyl chloride from the dropping funnel during 4-5 hours; the first addition should be 3-4 ml in order to prevent the benzene from freezing. 

• Maintain the mixture at a temperature of 0-5 °C by the addition of salt to the ice, if necessary. 

• When all the t-butyl chloride has been run in, continue the stirring for 1 hour longer. 

• Remove the separatory funnel and add 200g of finely crushed ice in small portions with stirring; finally add 100 ml of cold water to complete the decomposition of the intermediate addition compound. 

• Arrange the flask for steam distillation and steam distil the resulting reaction mixture. 

• Transfer the steam distillate to a separatory funnel, remove the upper hydrocarbon layer, extract the water layer with two 50 ml portions of ether and combine the extracts with the upper layer. 

• Dry with magnesium sulphate, distil off the ether on a water bath and fractionally distil the residue twice, using a well-lagged column. 

• Collect the t-butylbenzene at 165-170 °C. The yield is 45g (62%). Pure t-butylbenzene boils at 168.5 °C. 

• Note the characteristic absorptions for the aromatic system at c. 3050 cm⁻¹ , at 1600, 1590 and 1500 cm⁻¹ and at c. 700 and 765 cm⁻¹ for a monosubstituted nucleus. The t-butyl group shows characteristic carbon-hydrogen stretching absorptions at c. 2950 cm⁻¹.

Notes to Keep in Mind:

1. In an alternative procedure 25g of anhydrous iron(m) chloride replace the aluminium chloride, the mixture is cooled to 10 °C and the 50g of t-butyl chloride are added. The mixture is slowly warmed to 25 °C and maintained at this temperature until no more hydrogen chloride is evolved. The reaction mixture is then washed with dilute hydrochloric acid and with water, dried and fractionally distilled. The yield of t-butyl benzene, b.p. 167-170 °C, is 60g.

SYNTHESIS OF ETHYLBENZENE

Method A. Huang-Minion modification of the Wolff-Kishner reduction

• Place 36.0 g (0.3 mol) of redistilled acetophenone, b.p. 201 °C, 300 ml of diethylene glycol, 30 ml of 90 per cent hydrazine hydrate and 40g of potassium hydroxide pellets in a 500-ml two-necked round-bottomed flask fitted with a reflux condenser; insert a thermometer supported in a screw-capped adapter in the side-neck so that the bulb dips into the reaction mixture. 

• Warm the mixture on a boiling water bath until most of the potassium hydroxide has dissolved and then heat under reflux for 1 hour either by means of a free flame or by using a heating mantle. 

• Remove the reflux condenser and fit a still-head and condenser for downward distillation. 

• Distil until the temperature of the liquid rises to 175 °C (1). 

• Separate the upper hydrocarbon layer from the distillate and extract the aqueous layer twice with 20 ml portions of ether. Dry the combined upper layer and ethereal extracts with magnesium sulphate, remove the ether on a water bath and distil the residue. 

• Collect ethylbenzene at 135-136 °C; the yield is 20g (62.5%). The i.r. spectrum shows absorptions at c. 3050 and 2950 cm⁻¹ for the stretching of the aromatic and alkyl carbon-hydrogen bonds respectively. 

• Monosubstitution is confirmed from the absorption at c. 690 and 745 cm⁻¹ arising from five adjacent hydrogens. The p.m.r. spectrum (CDCl₃, TMS) shows signals at 𝛿 1.19 (q, 3H, Me), 2.53 (t, 2H, CH 2 ) and 7.07 (s, 5H, C— H). The ¹³C-n.m.r. spectrum (CDCl₃ , TMS) shows signals at 𝛿 15.8, 29.1, 125.8, 127.9, 128.4 and 144.1.

Notes to keep in mind:

1. The reduction takes place at a comparatively low temperature and is fairly rapid for acetophenone. With higher ketones, the upper layer of the distillate should be returned to the contents of the flask and the heating under reflux continued for 3-5 hours. The reaction mixture and the aqueous distillate are then combined, extracted with ether and the ether extract treated as described above.

Method B

• The toluene-p-sulphonylhydrazone of acetophenone (0.721g, 2.5mmol) (1), m.p. 140-141.5 °C, is placed in a flame-dried, nitrogen-filled flask containing 5 ml of chloroform. 

• Catecholborane (0.52 ml, 5.0mmol) is added and the reduction allowed to proceed for 2 hours at room temperature (2). 

• Methanol (1 ml) is added to destroy the excess of hydride followed by the addition of tetrabutylammonium acetate (0.7g, 2.5mmol). 

• The reaction mixture is stirred for 4 hours when g.l.c. analysis indicates a 94 per cent yield of ethylbenzene. The product is isolated by distillation, yield 0.21g (79%), b.p. 132-136 °C.

Notes to keep in mind:

1. The general procedure for the preparation of toluene-p-sulphonylhydrazones.

2. The reaction may be monitored by removing aliquot portions with a syringe, mixing with deuterochloroform in an n.m.r. tube, and recording the spectra.

SYNTHESIS OF HEXYLBENZENE (1-Phenylhexane)

• Clemmensen reduction. Prepare 200 g of amalgamated zinc in a 2-litre three-necked flask. 

• Fit the flask with a reflux condenser, a sealed stirrer and a gas entry tube reaching to within 1 cm of the bottom; connect the last-named through an intermediate empty wash bottle to a Kipp's apparatus supplying hydrogen chloride gas. 

• Place a mixture of 500 ml of concentrated hydrochloric acid and 100ml of water in the flask and introduce 100g (0.57 mol) of l-phenylhexan-3-one. 

• Stir the mixture and pass a slow stream of hydrogen chloride gas while warming the flask on a suitable wire gauze by means of a small flame. 

• If the reaction becomes unduly vigorous, stop the supply of hydrogen chloride until it subsides somewhat. 

• Most of the zinc dissolves after 6 hours, by which time the reaction is almost complete; allow to stand overnight. 

• Arrange the apparatus for steam distillation and pass steam into the flask, heated by means of a small flame, until the distillate is clear. 

• Separate the upper hydrocarbon layer, wash it with 5 per cent sodium hydroxide solution, then with water and dry over magnesium sulphate. 

• Distil from a 100 ml flask and at 218-230 °C collect the crude hexyl benzene, which contains some unsaturated compounds. 

• These can be removed by repeated shaking with 5 per cent of the volume of concentrated sulphuric acid until the latter is colourless or, at most, very pale yellow. 

• The hydrocarbon is then washed with 5 per cent sodium carbonate solution, then with water and dried over magnesium sulphate. 

• It is then distilled twice from sodium when pure hexylbenzene, b.p. 220-225 °C is obtained. The yield is 40g (43%).

SYNTHESIS OF PENTYLBENZENE (1-Phenylpentane)

• In a 1500-ml three-necked flask equipped with a dropping funnel, a sealed stirrer unit and a double surface condenser to which is attached a guard-tube filled with a mixture of calcium chloride and soda-lime, prepare an ethereal solution of benzylmagnesium chloride from 24.3 g (1 mol) of clean, dry magnesium turnings (under 100 ml of anhydrous ether) and a solution of 126.5g (115 ml, 1 mol) of freshly distilled benzyl chloride in 500 ml of anhydrous ether. 

• Use a crystal of iodine as a catalyst. 

• Finally, cool the flask by immersion in a bath of ice-water. 

• Place a solution of 456g (2 mol) of butyl toluene-p-sulphonate in about twice the volume of anhydrous ether in the dropping funnel, and add it slowly to the vigorously stirred benzylmagnesium chloride solution, at such a rate that the ether just boils; a white solid soon forms. 

• The addition is complete after about 2 hours. 

• Pour the reaction product slowly into a mechanically stirred mixture of 1 kg of finely crushed ice, 1 litre of water and 125 ml of concentrated hydrochloric acid contained in a 4- or 5-litre beaker; the precipitated magnesium toluene-p-sulphonate will ultimately pass into the solution. 

• Separate the ether layer, extract the aqueous layer with 250 ml of ether and wash the combined ether solutions with about 100 ml of water. 

• Dry the ether solution with about 10g of anhydrous potassium carbonate. 

• Distil off the ether on a rotary evaporator, add to the mixture 5-7g of sodium cut into small pieces and heat under reflux for about 2 hours in order to remove any benzyl alcohol which may have formed by atmospheric oxidation of benzylmagnesium chloride. 

• Decant the solution and distil it from an air bath through a well-lagged and efficient fractionating column; collect the fraction, b.p. 190-210 °C. 

• Redistil and collect the pentylbenzene at 198-203 °C. The yield is 90 g (61%). 

• Record the i.r. spectrum and the p.m.r. spectrum and assign the absorptions using the spectra quoted above for butulbenzene a guide. Interpret the m.s. which shows principal fragment ions at m/z 148, 105, 91, 77 and 65.

SYNTHESIS OF BUTYLBENZENE (2-Phenylbutane)

• Equip a 500-ml three-necked flask as detailed for p-toluic acid and pass a slow stream of nitrogen through the apparatus. 

• Charge the flask with 150 ml of sodium dried, sulphur-free toluene and 13.8g (0.6mol) of sodium wire. 

• Place 34g (31ml, 0.3 mol) of chlorobenzene in the dropping funnel and add it dropwise through the condenser during 1 hour, with vigorous stirring, while maintaining the temperature inside the flask at 30-35 °C. 

• The start of the reaction is indicated by the appearance of black specks on the sodium surface. (If the reaction is slow to start, it may be instantly initiated by a few drops of butanol.) Complete the formation of phenylsodium by stirring for 2-3 hours at 30 °C.

• Attach a calcium chloride tube to the top of the reflux condenser and reflux the mixture for 40 minutes. 

• The reflux temperature, initially 107 °C, gradually falls to 103 °C as benzene is formed by the exchange reaction. 

• Remove the heating bath and add 27.6 g (20.5 ml, 0.224 mol) of redistilled propyl bromide during 20-25 minutes at 103-105 °C; the reaction is strongly exothermic. 

• Allow the reaction mixture to cool to room temperature: maintain the stirring and the slow stream of nitrogen. 

• Add water slowly to destroy the excess of sodium. 

• Separate the toluene layer, dry it (magnesium sulphate) and distil it through a short, jacketed column filled with glass helices (19 cm packed length, 14 mm diameter;). 

• After removal of the toluene (up to 111 °C) and a small intermediate fraction (11 1-179 °C), pure butylbenzene passes over at 179.5-181 °C/752 mmHg (23g, 77%). 

• A brown residue (4g) remains in the flask. 

• The i.r. spectrum shows absorptions at c. 3050 and 2950 cm⁻¹ for the aromatic and alkyl carbon-hydrogen stretching vibrations respectively, at 1600, 1590 and 1500 cm⁻¹ for the ring breathing vibrations (the 1450 cm¹ absorption is obscured by the alkyl carbon-hydrogen deformation vibrations), at c. 700 and 750 cm⁻¹ characteristic of monosubstitution, and well-defined summation bands at 1600-2000 cm⁻¹. 

• The p.m.r. spectrum (CCl₄, TMS), shows signals at 𝛿 0.92 (t, 3H, Me), 1.10-1.80 (m, 4H, — CH₂CH₂—), 2.58 (t, 2H, ArCH₂) and 7.09 (s, 5H, C— H). The m.s. shows significant fragment ions at m/z 134 (M), 105 (M - C₂H₅), 91 (M - C₃H₇, base peak), and 65 (91 - C₂H₂).

SYNTHESIS OF RESOLUTION OF ᴅⳑ-ALANINE

Benzoyl ᴅ alanine:

• Dissolve 100g (1.1 mol) of ᴅ-alanine in 400 ml of water containing 44.5g (1.1 mol) of sodium hydroxide and cool the solution in an ice bath. 

• Add 175g (1.2 mol) of benzoyl chloride and a solution of 49g (1.2 mol) of sodium hydroxide in 200 ml of water to the stirred, cooled, amino acid solution, alternately and in portions during 2 hours; continue to stir for a further 2-hour period. 

• Boil the reaction mixture with 10g of decolourising charcoal, filter, cool the clear yellow filtrate to °C and acidify carefully to Congo red with concentrated hydrochloric acid. 

• Triturate a portion of the oil which separates with water to induce crystallisation and then seed the bulk of the acidified solution with crystals and leave in an ice bath to complete the crystallisation process. 

• Filter off the product, wash the filter cake with 500 ml of ice-cold water and recrystallise from about 3.5 litres of boiling water. The yield of benzoyl-ᴅⳑ-alanine, m.p. 162-164 °C, is 194.5g (90%).

Benzoyl-l-alanine anilide:

• Use freshly boiled, cooled, distilled water throughout this stage. 

• Prepare an 0.1 m citrate buffer solution by dissolving 48g of anhydrous citric acid and 16.5g of sodium hydroxide in 2.5 litres of water. 

• Stir together 50g of technical powdered papain (1) and 4g of potassium cyanide in 500 ml of the buffer solution, adjust the pH to 5 (narrow range pH paper) with glacial acetic acid, and stir for a further 75 minutes. 

• Filter this enzyme extract through a Celite filter bed. 

• Dissolve 193g (1 mol) of benzoyl-ᴅ-alanine by warming it in 300 ml of the citrate buffer to which has been added 120 ml of 2.5 molar sodium hydroxide, 360 ml of 3 m sodium acetate solution and 93g (91 ml, 1 mol) of redistilled aniline; adjust the pH of this solution to 5 with sodium hydroxide solution. 

• Cool the solution to 45 °C, add the filtered enzyme extract and transfer the mixture to several conical flasks of suitable size such that each is filled to the neck and tightly stoppered with a rubber bung to exclude air. 

• Leave the flasks in an incubator held at 37 °C, shaking them occasionally during the early stages.

• Product begins to separate within 5 minutes and the contents of the flasks becomes almost immobile within 2 hours. 

• After 24 hours filter the mixture and return the filtrate to the incubator for a further 24 hours and remove the additional crop of solid which separates. 

• Wash the combined solids with 250 ml of water and recrystallise from 1 litre of 50 per cent aqueous ethanol with the aid of decolourising charcoal. The yield of benzoyl-l-alanine anilide is 122g (91%), m.p. 175-176 °C, [𝜶]ᴅ²⁰ -7.8° (c5 in MeᐧCO₂H).

l-Alanine:

• Heat a mixture of 50g (0.187 mol) of benzoyl-l-alanine anilide and 250 ml of 6 m hydrochloric acid under reflux for 5 hours. 

• Leave the mixture at room temperature overnight, remove the precipitated benzoic acid by filtration and evaporate the filtrate to dryness under reduced pressure (rotary evaporator). 

• Dissolve the brown oily residue in 100 ml of water and boil it with decolourising charcoal. 

• Filter and pass the filtrate through 450g of a weakly basic anion exchange resin, e.g. Amberlite IR4B (which has been washed free from soluble colour with dilute hydrochloric acid and regenerated with dilute aqueous ammonia) in the form of a column 60 cm long. 

• Collect the effluent (in all about 2 litres) until it gives no colour when boiled with ninhydrin. 

• Evaporate the effluent to dryness under reduced pressure (rotary evaporator) and boil the yellow solid residue with 20 ml of water and a little decolourising charcoal. 

• Add ethanol to the hot filtered solution until crystallisation begins and cool in ice to complete the separation of the L-alanine. The yield is 13.9g (76%), [𝜶]ᴅ²⁰ , + 12.0° (c4 in 1M HCl).

Notes to keep in mind:

1.  An inexpensive crude commercial product (dried papaya latex) was used; the activity was not determined. Purified highly active enzyme preparations may, however, be obtained 259 (e.g. Koch-Light, Sigma, etc.).

SYNTHESIS OF RESOLUTION OF (±)-𝜶-METHYLBENZYLAMINE [(±)-1-Phenylethylamine]

(—)-𝜶-MethylbenzyIamine:

• Add 450 ml of methanol to 31.5g (0.21 mol) of (+)-tartaric acid in a 1-litre conical flask and heat the mixture almost to boiling on a water bath. 

• Then add cautiously with swirling 24.2g (0.20 mol) of (+)-𝜶-methylbenzylamine; too rapid an addition may cause the mixture to boil over. 

• Allow the mixture to cool to room temperature and then to stand for 24 hours to allow slow separation of the (-)-amine-(+)-hydrogen tartrate as prismatic crystals (1). 

• Filter off the product (17.9g); concentrate the filtrate to 225 ml under reduced pressure on a rotary evaporator and allow it to stand at room temperature for 24 hours to obtain a second crop. The total yield of the (-)-amine-(+)-hydrogen tartrate is about 21g (77%).

• Shake the total product with 90 ml of water in a 250-ml separating funnel and basify the mixture by cautiously adding 50 per cent aqueous sodium hydroxide. 

• Extract out the liberated amine with three 40 ml portions of ether, dry the extract over anhydrous sodium sulphate, filter and concentrate to about 25 ml using a rotary evaporator. 

• Remove the remainder of the ether in a distillation apparatus and fractionally distil the residue at atmospheric pressure (2), collecting the (-)-𝜶-methylbenzylamine as a fraction of b.p. 184-186 °C; the yield is about 5g (53%). 

• Measure the optical rotation of the neat liquid and calculate the specific rotation. 

• Pure (-)-𝜶-methylbenzylamine has d₄²² 0.950, [𝜶]ᴅ²² -40.3° (neat); [𝜶]ᴅ²º -31.5° (c 3.2 in EtOH).

(+)-𝜶-Methy!benzyIamine:

• This enantiomer may be recovered using the following procedure. 

• Evaporate the methanolic filtrate from the isolation of the (-)-amine salt to dryness using a rotary evaporator. 

• Convert the residual salt to the free amine by treatment with sodium hydroxide solution followed by ether extraction as described above. 

• Do not distil the recovered amine but remove the last traces of ether completely by warming under reduced pressure. 

• Weigh the resulting product (x g), measure its optical rotation and calculate the specific rotation. 

• The ratio of this value to that of pure ( + )-amine is the optical purity of the sample; the weight of ( + )-amine in the sample in excess of that present in the racemic modification is given by:

• For each gram of excess (+)-amine present add firstly 10.0 ml of rectified spirit, bring to the boil and then add, for each gram, a hot solution of 0.44g of 98 per cent sulphuric acid (1.03 times the theoretical amount) in 21.5 ml of rectified spirit. 

• Allow the solution to cool slowly to room temperature, filter off the crystalline (+)-amine sulphate and wash it with cold rectified spirit.

• The yield is about 1g of sulphate per gram of (+)-amine (71%). 

• Liberate the free (+)-amine from the sulphate as described for the (-)-amine from the tartrate, but use 4 ml of water and 0.5 ml of 50 per cent aqueous sodium hydroxide for each gram of sulphate. The yield of (+)-amine, b.p. 184—186°C, is 60 per cent of theory; its optical purity is 95 per cent.

Notes to keep in mind:

1. If fine needles separate, the mixture should be warmed until they redissolve, and the solution allowed to cool. The solution should be seeded with the prismatic crystals if these are available.

2. The free amine rapidly absorbs carbon dioxide. It is therefore essential to protect the distillation apparatus from the atmosphere with a guard-tube filled with soda-lime. As the product tends to foam excessively during distillation, the apparatus used should be larger than is customary for the volume of liquid to be distilled.

SYNTHESIS OF RESOLUTION OF (±)-OCTAN-2-OL*

• Heat a mixture of 65g (0.5 mol) of dry octan-2-ol (b.p. 178-180°C), 74g (0. 5 mol) of pure phthalic anhydride (1) and 40g of dry pyridine (CAUTION) on a water bath for 1 hour, and allow to cool. 

• Dissolve the resulting viscous mass in an equal volume of acetone. 

• Add slowly, preferably with stirring, 55 ml of concentrated hydrochloric acid diluted with an approximately equal volume of crushed ice: if an oil separates before all the hydrochloric acid has been added, introduce more acetone to render the mixture homogeneous. 

• Add ice-water until the oil is completely precipitated; this usually sets to a hard mass within 1-2 hours. 

• If the resulting mass is semi-solid or pasty (2), transfer it to a large flask and pass steam through it until the octan-2-one is removed, i.e. until the steam distillate is clear; pour the contents of the flask while still warm into a beaker. 

• The (±)-2-octyl hydrogen phthalate solidifies on cooling. 

• Filter the octyl hydrogen phthalate at the pump, wash it with water, grind it thoroughly in a mortar with water, filter again and dry in the air. 

• The crude material is quite satisfactory for the subsequent resolution (3). 

• Introduce 197g (0.5 mol) of anhydrous brucine (CAUTION: poisonous) or 215g of the air-dried dihydrate (4) into a warm solution of 139g of (±)-2-octyl hydrogen phthalate in 300 ml of acetone and warm the mixture under reflux on a water bath until the solution is clear. 

• Upon cooling, the brucine salt [(+)-A, (—)-B] separates as a crystalline solid. 

• Filter this off on a sintered glass funnel, press it well to remove mother-liquor and wash it in the funnel with 123 ml of acetone. 

• Set the combined filtrate and washings (W) aside. 

• Cover the crystals with acetone and add, slowly and with stirring, a slight excess (to Congo red) of dilute hydrochloric acid (1:1 by volume; about 60 ml); if the solution becomes turbid before the introduction of the acid is complete, add more acetone to produce a clear liquid. 

• Add ice-water until the precipitation of the active 2-octyl hydrogen phthalate [crude (+)-A] is complete; filter (5), wash with cold water and dry in the air. 

• The yield is about half that of the (±)-ester originally taken (6). 

• Concentrate the combined filtrate and washings (W) to about half the original volume, and pour it into slightly more than the calculated amount of dilute hydrochloric acid (use a mixture of 30 ml of concentrated hydrochloric acid and 30 ml of ice-water); then add about 300 ml of water. 

• Collect the active 2-octyl hydrogen phthalate (crude(—)-A) as above (5). 

• The weight of the air-dried ester is about half that of the (±)-ester originally used (7). 

• Crystallise the two lots of crude active 2-octyl hydrogen phthalates separately twice from 90 per cent acetic acid; use 2g of acetic acid to each gram of solid. 

• The recrystallised esters, if optically pure (8), will melt sharply at 75 °C; if the melting points are below 75 °C, further recrystallisation is necessary. 

• The yields of optically pure products, m.p. 75 °C, are 48g and 49g respectively. To obtain optically pure (+)- and (—)-octan-2-ol, steam distil the respective esters with 30 per cent sodium hydroxide solution; use the proportions 1 mol of ester to 2 mols of sodium hydroxide. 

• Separate the alcohols from the steam distillate, dry over anhydrous potassium carbonate and distil under diminished pressure. 

• Both samples boil at 86 °C/20 mmHg (9) and have the following rotations:

• The yields from the 2-octyl hydrogen phthalates are almost quantitative.

Notes to keep in mind:

1. If the presence of phthalic acid is suspected, it may be readily removed by mixing with cold chloroform; phthalic anhydride dissolves readily, but the acid is insoluble.

2. This is due to octan-2-one in the original octan-2-ol; it is most easily separated by steam distillation as described.

3. The inactive 2-octyl hydrogen phthalate may be recrystallised from light petroleum, b.p. 60-80 °C, or from glacial acetic acid, and then melts at 55 °C. If the octan-2-ol is pure, the yield of pure material is almost quantitative.

4. Commercial brucine is usually the tetrahydrate C₂₃H₂₆O₄N₂, 4H₂O; upon air drying, this loses two molecules of water of crystallisation and passes into the dihydrate.

5. The filtrates from the decomposition of the brucine salts with dilute hydrochloride acid should be carefully preserved. The brucine is recovered by the addition of an excess of dilute ammonia solution (1:4); if the solution becomes turbid before all the ammonia solution is added, introduce a little ethanol until the solution becomes clear. After several hours in an open beaker, filter off the brucine, wash it well with cold water and dry it in the air.

6. The rotation in absolute ethanol is about [𝜶]ᴅ +44°, [𝜶]₅₄₆₁ +47°.

7. The rotation in absolute ethanol is about [𝜶]ᴅ -44°,  [𝜶]₅₄₆₁ -47°.

8. The optically pure esters have rotations in ethanol of [𝜶]ᴅ —48.4°, [𝜶]₅₄₆₁ —58.5°, and [𝜶]ᴅ +48.4°, [𝜶]₅₄₆₁ +58.5° respectively. A preliminary check of the optical purity is, however, more simply made by a m.p. determination; the rotation is determined, if desired, when the m.p. is 75 °C.

9. The boiling point under atmospheric pressure is 179 °C.

SYNTHESIS OF FUMARIC ACID AND MALEIC ANHYDRIDE

Conversion of maleic acid into fumaric acid:

• Dissolve 10g of maleic acid in 10 ml of warm water, add 20 ml of concentrated hydrochloric acid and boil gently under reflux for 30 minutes. 

• Crystals of fumaric acid soon crystallise out from the hot solution. 

• Allow to cool, filter off the fumaric acid and recrystallise it from hot 1m hydrochloric acid. The m.p. in a sealed capillary tube is 286-287 °C.

Conversion of maleic acid into maleic anhydride:

CAUTION:All operations must be conducted in an efficient fume cupboard, owing to the highly toxic nature of the solvent. 

• Mix l00g of maleic acid with 1,1,2,2-tetrachloroethane (100 ml) in a distillation flask fitted with a Claisen still-head, a thermometer and a condenser set for downward distillation. 

• Heat the mixture on an air bath; when the temperature reaches 150°C, 75 ml of 1,1,2,2-tetrachloroethane and between 15 and 15.5 ml of water are present in the receiver. 

• Continue the distillation using an air condenser and change the receiver flask when the temperature reaches 190 °C. 

• Collect the maleic anhydride at 195-197 °C. 

• Recrystallise the crude anhydride from chloroform. The yield of pure maleic anhydride, m.p. 54 °C, is 70g (83%).

SYNTHESIS OF BUT-2-YNOIC ACID

3-MethylpyrazoI-5-one:

• Place 65g (0.5 mol) of ethyl acetoacetate in a conical flask and stir magnetically during the slow dropwise addition of a solution of 25g (0.5 mol) of hydrazine hydrate (98-100%) in 40 ml of absolute ethanol. 

• The temperature rises during this addition which should be regulated so that a temperature of about 60 °C is maintained; a crystalline deposit separates. 

• After further stirring for 1 hour at room temperature, cool the reaction mixture in an ice bath to complete the crystallisation, and filter. 

• Wash the product with ice-cold ethanol; it is then pure enough for use in the next stage. The yield is 43g (90%), m.p. 222 °C (phase change at 195 °C; microscope m.p. apparatus).

4,4-Dibromo-3-methyIpyrazoI-5-one:

• Dissolve 20.0g (0.2 mol) of 3-methyl-pyrazol-5-one in 80 ml of glacial acetic acid and stir magnetically during the slow dropwise addition of a solution of 32g (0.2 mol) of bromine in 20 ml of glacial acetic acid (1). 

• On completion of this addition, add 50 ml of water and continue the dropwise addition of a further 32g (0.2 mol) of bromine dissolved in 20 ml of glacial acetic acid. 

• On completion of this second addition of bromine solution allow the mixture to stand at room temperature overnight.

• Add water to precipitate the dibromopyrazolone, filter and wash the solid product under suction with distilled water until the washings are neutral. 

• The air-dried product, sufficiently pure for use in the next statge, has m.p. 130—132 °C, the yield is 41g (79%).

But-2-ynoic acid:

• Prepare a solution of 20g of sodium hydroxide in 500 ml of water and stir magnetically in an ice bath until the temperature reaches 0-5°C. 

• Add portion wise over 10 minutes 34g (0.132 mol) of 4,4-dibromo-3-methylpyrazol-5-one. 

• The bromoketone dissolves to give an orange-red solution which evolves nitrogen gas; the temperature of the solution during the addition shows only a slight tendency to rise. 

• Stir the reaction mixture for 1 hour at 0-5 °C and then at room temperature for 1 hour. 

• Cool the solution again and acidify it with concentrated hydrochloric acid. 

• Continuously extract the acidified solution with ether overnight, dry the ethereal extract with magnesium sulphate and remove the solvent on a rotary evaporator. 

• Place the flask containing the orange oil in a vacuum desiccator and allow to stand until it solidifies. 

• Extract the orange crystalline deposit with successive portions of boiling light petroleum (b.p. 60-80 °C) and concentrate the combined extracts to about 50 ml. 

• Filter the slightly off-white product, m.p. 74-75 °C; recrystallise by dissolving in the minimum volume of light petroleum (b.p. 80-100 °C), adding an equal volume of light petroleum (b.p. 40-60 °C) and allowing to cool. 

• The pure but-2-ynoic acid has m.p. 75-76 °C, the yield is 5.9g (54%). The i.r. spectrum shows absorption at 2950 (broad, —OH), 2240(sharp, disubstituted—C=C—), 1690 cm⁻¹ (broad, — 0=0 in carboxylic acid).

Notes  to keep in mind:

1. Removal of a portion of the reaction mixture when 1 mol of bromine has been added and addition to it of water results in the precipitation of the monobromo compound, m.p. 180-182 °C.

SYNTHESIS OF 3-HEXYLACRYLIC ACID (Non-2-enoic acid)

• Dissolve 57g (0.55 mol) of malonic acid in 92.5 ml of dry pyridine contained in a 500-ml round-bottomed flask, cool the solution in ice and add 57g (70 ml, 0.5 mol) of freshly distilled heptanal with stirring or vigorous shaking. 

• After a part of the aldehyde has been added, the mixture yields a semi-solid slurry of crystals. 

• Insert a calcium chloride tube into the mouth of the flask and allow the mixture to stand at room temperature for 60 hours with periodic shaking. 

• Finally, warm the mixture on a water bath until the evolution of carbon dioxide ceases (about 8 hours) and then pour into an equal volume of water. 

• Separate the oily layer and shake it with 150 ml of 25 per cent hydrochloric acid to remove pyridine. 

• Dissolve the product in benzene, wash with water, dry with anhydrous sodium sulphate and distil under reduced pressure. Collect the nonenoic acid at 130-132 °C/2mmHg. The yield is 62g (79%).

Cognate preparations: Crotonic acid [(E)-But-2-enoic acid] 

• Mix together in a 250-ml flask carrying a reflux condenser and a calcium chloride drying tube 25g (32 ml, 0.57 mol) of freshly distilled acetaldehyde with a solution of 59.5g (0.57 mol) of dry, powdered malonic acid in 67g (68.5 ml, 0.85 mol) of dry pyridine to which 0.5 ml of piperidine has been added. 

• Leave in an ice chest or refrigerator for 24 hours. 

• Warm the mixture on a steam bath until the evolution of carbon dioxide ceases. 

• Cool in ice, add 60 ml of 1:1 sulphuric acid (by volume) and leave in the ice bath for 3-4 hours. 

• Collect the crude crotonic acid (c. 27g) which has separated by suction filtration. 

• Extract the mother-liquor with three 25 ml portions of ether, dry the ethereal extract, and evaporate the ether; the residual crude acid weighs 6g. 

• Recrystallise from light petroleum, b.p. 60-80 °C; the yield of crude crotonic acid, m.p. 72 °C, is 20g (41%).

Sorbic acid (Hexa-2,4-dienoic acid):

• Place 40g (46.5 ml, 0.57 mol) of croton-aldehyde (b.p. 101-103 °C), 60g (0.575 mol) of malonic acid and 60g (61 ml, 0.76 mol) of dry pyridine (b.p. 113-115 °C) in a 500-ml round-bottomed flask, attach a reflux condenser and heat on a water bath for 3 hours. 

• At the end of this period the vigorous evolution of carbon dioxide will have ceased. 

• Cool the mixture in ice and cautiously acidify it by the addition of a solution of 21.3 ml of concentrated sulphuric acid in 50 ml of water with shaking. 

• Most of the sorbic acid separates out immediately; a more complete separation is obtained by cooling the solution in ice for 3-4 hours. 

• Filter the acid at the pump and wash it with a little ice-cold water. 

• Recrystallise from about 125 ml of boiling water; the maximum recovery of purified acid is achieved by leaving the solution in an ice chest or a refrigerator overnight and then filtering.The yield of sorbic acid, m.p. 134°C, is 20g (31%).

SYNTHESIS OF ETHYL CYCLOHEXYLIDENEACETATE

CAUTION: Hydrogen gas is evolved in the first part of this experiment, hence the apparatus should be sited in an efficient fume-cupboard.

• Triethyl phosphonoacetate (11.2g, 0.05 mol) is added dropwise at 20 °C to a slurry of 50 per cent sodium hydride (2.4g, 0.05 mol) in 100 ml of dry 1,2-dimethoxyethane. 

• After the addition, the reaction mixture is stirred for 1 hour at room temperature until gas evolution has ceased. 

• Cyclohexanone (4.9g, 0.05 mol) is added dropwise at such a rate that the temperature is maintained below 30 °C. 

• After the addition, the solution is stirred for 15 minutes at room temperature during which time a viscous semi-solid appears. 

• The mixture is taken up in a large excess of water, and the aqueous solution extracted with ether. 

• The ether layer, after being dried over magnesium sulphate and evaporated, gives a liquid residue, b.p. 88-90 °C/10mmHg, 5.8g (70%), nᴅ²⁵ 1.4704. The i.r. spectrum shows a strong absorption band at 1660 cm⁻¹.

Cognate preparation: Ethyl (E)-but-2-enoate 2SS (PTC procedure)

• A solution of triethyl phosphonoacetate (35 mmol) and acetaldehyde (35 mmol) in dichloromethane (5 ml) is added dropwise to a stirred two-phase system consisting of dichloromethane (35 ml), aqueous sodium hydroxide (20 ml, 50%) and tetrabutylammonium iodide (0.7g) (1). 

• The strongly exothermic reaction is complete in 15 minutes. 

• The organic layer is separated, washed with water (5 ml), and dried with magnesium sulphate. 

• Evaporation of the solvent and distillation of the residue affords the product, b.p. 51-52 °C/25mmHg, in 54 per cent yield.

Notes to keep in mind:

1. To avoid undesirable reactions of the aldol-type, both substrates should be added simultaneously to the reaction mixture.

SYNTHESIS OF ERYTHRO- AND THREO-2-(1' -HYDROXYBENZYL) CYCLOHEXANONES

1-TrimethyIsiIyIoxycycIohexene:

• To a well-stirred suspension of lithium sulphide (1.5g, 30mmol) (1) in dry acetonitrile (25 ml) in a 100-ml round- bottomed flask, fitted with a water condenser and a nitrogen inlet, is added chlorotrimethylsilane (6.3 ml, 50 mmol). 

• To this mixture are added cyclohexanone (1.96g, 20 mmol) and triethylamine (3 ml, 20 mmol) in succession, and the solution is allowed to stir at room temperature (25 °C). 

• The progress of the reaction is monitored by removing aliquots periodically and analysing them after work-up by t.l.c. (silica gel plates with hexane as an eluant). 

• Soon after the completion of the reaction (c. 16 hours), the mixture is taken up in ether (50 ml) and washed thoroughly with ice-cold aqueous 5 per cent hydrochloric acid solution (4 x 50 ml) to remove all basic and water-soluble materials. 

• The ethereal extract is washed with ice-cold aqueous 5 per cent sodium hydrogen carbonate solution (50 ml), water (50 ml), and brine (25 ml). 

• It is dried over anhydrous sodium sulphate and subjected to distillation under reduced pressure to obtain the crude enol silyl ether. 

• The product is further purified by distillation (b.p. 70-71 °C/12mmHg) to obtain spectrally (p.m.r. and i.r.) pure 1-trimethylsilyloxyclohexene (95%).

Erythro- and Threo-2-(1'-Hydroxybenzyl)cycIohexanones:

• A dichloro-methane (10 ml) solution of 1-trimethylsilyloxycyclohexene (0.426g, 2.5mmol) is added dropwise into a mixture of benzaldehyde (0.292g, 2.75 mmol) and titanium(IV) chloride (0.55g, 2.75 mmol) (2) in dry dichloro-methane (20 ml) under an argon atmosphere at — 78 °C, and the reaction mixture is stirred for 1 hour. 

• After hydrolysis (with water) at that temperature, the resulting organic layer is extracted with ether, and the extract is washed with water and dried over anhydrous sodium sulphate. 

• The extract is evaporated under reduced pressure, and the residue is purified by column chromatography (silica gel). 

• Elution with dichoromethane affords 115mg (23%) of erythro-2-(1'-hydroxybenzyl)-cyclohexanone, m.p. 103 °C (recrystallised from propan-2-ol, m.p. 103.5-104.5 °C); i.r. 3530 (OH), 1700 (C=0) cm⁻¹ ; p.m.r. (CDCl₃ , TMS) 1.1-2.7 (broad, 9H, aliphatic CH), 3.05 (s, 1H, OH, exchangeable with D₂O), 5.40 (d, 1H, J = 2.5 Hz, O— CH), and 7.27 (s, 5H, aryl CH).

• From the last fraction, 346 mg (69%) of threo-2-(1'-hydroxybenzyl)cyclohexanone are obtained, m.p. 74 °C (recrystallised from hexane-ether, m.p. 75 °C); i.r. 3495 (OH), 1695 (C=0) cm⁻¹; p.m.r. (CCl₄, TMS) 1.1-2.9 (broad, 9H, aliphatic CH), 3.77 (s, 1H, OH, exchangeable with D₂O), 4.83 (d, 1H, J = 9.0 Hz, O— CH), 7.29 (s, 5H, aryl CH).

Notes to keep in mind:

1.  Lithium sulphide is obtained from Alfa Ventron. Acetonitrile is purified and stored over molecular sieves.

2. Titanium(iv) chloride is distilled under an argon atmosphere before use.

SYNTHESIS OF MESITYL OXIDE (4-Methylpent-3-en-2-one)

4-MethyI-4-hydroxypentan-2-one (diacetone alcohol):

• Fit a 1-litre round-bottomed flask with a large Soxhlet extractor and attach an efficient double surface condenser to the latter. 

• Place 595g (750 ml, 10.25 mol) of commercial acetone, preferably dried over anhydrous potassium carbonate, and a few fragments of porous porcelain in the flask. 

• Select as large a Soxhlet thimble as the extractor will accommodate and three-quarters fill it with barium hydroxide (1). 

• Fill the remaining space in the thimble with glass wool. 

• Insert the charged thimble into the extractor. Heat the flask on a water bath or steam bath so that the acetone refluxes back into the extractor rather rapidly. 

• Continue the heating until the acetone no longer refluxes when the flask is almost completely immersed in the boiling water bath (72-120 hours). 

• The refluxing may be interrupted at any time for as long as desired without influencing the preparation. 

• Equip the flask with a fractionating column attached to an efficient double surface condenser set for downward distillation. 

• Immerse the flask in an oil bath and raise the temperature gradually to 125 °C; maintain this temperature as long as acetone distils over. 

• The recovery of acetone is complete when the temperature at the top of the column is about 70 °C. 

• Distil the residue(2) under diminished pressure (3); a little acetone passes over first, followed by the diacetone alcohol at 71-74 °C/ 23mmHg (or 62-64°C/13mmHg). The yield is 450g (75%).

Mesityl oxide:

• Fit a 750-ml round-bottomed flask with a fractionating column attached to a condenser set for downward distillation. 

• Place 400g (3.44 mol) of diacetone alcohol (the crude product is quite satisfactory), 0.1g of iodine and a few fragments of porous porcelain in the flask. 

• Distil slowly with a small free flame (best in an air bath) and collect the following fractions: (a) 56-80 °C (acetone and a little mesityl oxide); (b) 80-126 °C (two layers, water and mesityl oxide); and (c) 126-131 °C, which is almost pure mesityl oxide. 

• Separate the water from fraction (b), dry with anhydrous potassium carbonate or anhydrous sodium sulphate and fractionate from a small flask. 

• A further quantity of mesityl oxide is thus obtained. The total yield is about 320g (95%).

Notes to keep in mind: 

1. If crystallised barium hydroxide [Ba(OH)₂ ,8H₂O] is employed, this becomes dehydrated after one run; the anhydrous compound is just as satisfactory and may be used repeatedly.

2. The residual liquid contains about 95 per cent of diacetone alcohol and is satisfactory for the preparation of mesityl oxide.

3. Diacetone alcohol partially decomposes when distilled under normal pressure.

SYNTHESIS OF 2-ETHYLHEX-2-ENAL

• Place 100 ml of 1 m sodium hydroxide solution in a 500-ml three-necked flask fitted with a sealed stirrer unit and an efficient reflux condenser. 

• Heat the solution to 80 °C and attach to the flask a dropping funnel containing 216g (264 ml, 3.0 mol) of redistilled butyraldehyde. 

• With vigorous stirring, add the butyraldehyde as rapidly as the efficiency of the reflux condenser will allow and then boil the reaction mixture under reflux for 1 hour. 

• Cool, separate the organic layer and distil it without further treatment under reduced pressure through a fractionating column (e.g. of the Vigreux type). 

• Collect the pure 2-ethylhex-2-enal as a fraction of b.p. 66-67 °C/ 25 mmHg; the yield is 160g (85%).

Cognate preparation: 2-Methylpent-2-enal

• Add 174g (215ml, 3.0mol) of propionaldehyde with vigorous stirring to 100 ml of 1 m sodium hydroxide solution, but without initial heating, during 15 minutes. 

• Cool rapidly in an ice bath, isolate the organic product with the aid of a little ether and fractionally distil. The yield is 70 per cent; b.p. 38-39 °C/25 mmHg, 136-137 °C/ 760 mmHg.

SYNTHESIS OF 2-OXOUNDEC-3-ENE

• Potassium carbonate (8.3g, 60mmol) in water (10 ml) is added to a vigorously stirred mixture of octanal (3.84g, 30mmol) and diethyl 2-oxopropane-phosphonate (7.0g, 36mmol) at room temperature. 

• The mixture is stirred for 18 hours at room temperature, water (15 ml) is then added, and the organic phase is extracted with hexane (3 x 25 ml). 

• The extract is dried with magnesium sulphate (1g), evaporated, and the residue distilled to give 2-oxoundec-3-ene; 4,4g (87%), b.p. 80-83 °C/0.7 mmHg.