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 DIETHYL ADIPATE

• Place 146 g (1 mol) of adipic acid, 360 ml (285 g, 6.2 mol) of absolute ethanol, 180 ml of toluene and 1.5 g of concentrated sulphuric acid in a 1 -litre round-bottomed flask, attach a short fractionating column connected to a down-ward condenser and heat in an oil bath at 115°C. 

• When the acid has dissolved, an azeotropic mixture of alcohol, toluene and water commences to distil at 75 °C; the temperature of the oil bath may then be lowered to 100-110°C. 

• Collect the distillate in a flask containing 150g of anhydrous potassium carbonate. 

• Continue the distillation until the temperature at the top of the column rises to 78 °C. 

• Shake the distillate thoroughly with the potassium carbonate, filter through a Buchner funnel or fluted filter paper and return the filtrate to the flask. 

• Heat the flask again until the temperature rises to 78-80 °C (1). 

• Transfer the warm residue to a flask of suitable size and distil under reduced pressure. 

• Alcohol and toluene pass over first, the temperature rises abruptly and the diethyl adipate distils at 138°C/20mmHg (2). The yield is 195 g (96%).

Notes to keep in mind:

1. The distillate contains ethanol, toluene and water, and may be dried with anhydrous potassium carbonate and used again for esterification after the addition of the necessary quantity of alcohol.

2. The b.p. may rise several degrees towards the end of the distillation owing to super-heating.

SYNTHESIS OF 3-O-BENZYL-1,2:5,6-DI-O-CYCLOHEXYLIDENE-𝛼-D-GLUCOFURANOSE

• In a 1 -litre three-necked round-bottomed flask fitted with an efficient stirrer and a reflux condenser, place 170g (0.5 mol) of 1,2:5,6-di-o-cyclohexylidene-𝛼-D-glucofuranose, 8.1 g (0.025 mol) of tetrabutylammonium hydrogen sulphate, 400ml of (E)-l,2-dichloroethylene, 76 g (0.6 mol) of benzyl chloride and a solution of 120 g (3 mol) of sodium hydroxide in 120 g of water. 

• Stir the reaction mixture vigorously and heat under reflux. 

• Thin-layer chromatography analysis (silica gel plates and ethyl acetate as developing solvent) shows the reaction to be complete within 2 hours. 

• Cool the mixture and pour into 1 litre of water, separate the organic layer, wash, dry and evaporate.

• Distil the viscous yellow residue in a molecular still (Section 2.28) using a vapour diffusion pump. 

• There is obtained a small forerun followed by the main fraction of 3-o-benzyl-l,2:5,6-di-o-cyclohexylidene-𝛼-D-glucofuranose, which distils at a temperature of 210-220 °C/ 10 mmHg. The yield is 172g (79%), [𝛼]ᴅ²⁰ -13.0° (c5 in CHCl₃).

SYNTHESIS OF 1,4-DIIODOBUTANE

• In a 500-ml three-necked flask, equipped with a thermometer, a sealed stirrer unit and a reflux condenser, place 32.5 g of phosphorus pentoxide and add 1 15.5 g (67.5 ml) of 85 per cent  orthophosphoric acid (1). 

• When the stirred mixture has cooled to room temperature, introduce 166g (1 mol) of potassium iodide and 22.5 g (0.25 mol) of redistilled butane- 1,4-diol (b.p. 228-230°C or 133-135 °C/18 mmHg). 

• Heat the mixture with stirring at 100-120 °C for 4 hours. 

• Cool the stirred mixture to room temperature and add 75 ml of water and 125 ml of ether. 

• Separate the ethereal layer, decolourise it by shaking with 25 ml of 10 per cent sodium thiosulphate solution, wash with 100 ml of cold saturated sodium chloride solution, and dry with magnesium sulphate. 

• Remove the ether by flash distillation on a steam bath and distil the residue from a flask with fractionating side-arm under diminished pressure. 

• Collect the 1,4-diiodobutane at 110°C/6mmHg, the yield is 65g(84%).

• Alternatively, add 18 g (20 ml, 0.25 mol) of redistilled tetrahydrofuran (b.p. 65-66 °C) to a mixture of 32.5 g of phosphorus pentoxide, 1 15.5 g (67.5 ml) of 85 per cent orthophosphoric acid and 1 66 g of potassium iodide, heat for 3-4 hours, cool and isolate the 1,4-diiodobutane as above. The yield of product, b.p. 1 10 °C/6 mmHg, is 70 g (90%).

Notes to keep in mind:

1. The orthophosphoric acid must be adjusted to a concentration of 95 per cent H3PO4. Alternatively, the commercial 100 per cent orthophosphoric acid may be diluted with water to this concentration. The 95 per cent acid is claimed to be the most efficient for the preparation of iodides from alcohols and glycols, and for effecting cleavage of tetrahydrofuran and tetrahydropyran. Anhydrous orthophosphoric acid does not give such good results because of the limited solubility of hydrogen iodide in the reagent.

Cognate preparations: 1,5-Diiodopentane (from pentane-l,5-diol)

• Proceed as for 1,4-diiodobutane but use 26 g (26.5 ml, 0.25 mol) of redistilled pentane-1,5-diol (b.p. 238-239 °C) in place of the butane- 1,4-diol. The yield of 1,5-di-iodopentane, b.p. 142-143 °C/16mmHg, is 65 g (80%).

1,5-Diiodopentane (from tetrahydropyran):

• Use 21.5 g (24.4 ml, 0.25 mol) of redistilled tetrahydropyran (b.p. 86.5-87.5 °C) in place of the tetrahydrofuran, otherwise proceed as for 1,4-diiodobutane. The yield of 1,5-diiodo-pentane, b.p. 142-143 °C/16mmHg, is 71 g (88%).

1,6-Diiodohexane:

• Proceed exactly as detailed for 1,4-diiodobutane but replace the butane- 1,4-diol by 29.5 g (0.25 mol) hexane-l,6-diol, m.p. 41-42 °C. The yield of 1,6-diiodohexane, b.p. 150°C/10mmHg, m.p. 10 °C, is 70g (83%).

Butyl iodide:

• Use 37 g (46 ml, 0.5 mol) of butan-1-ol together with the quantities of the other reactants used above; a 2-hour reaction time is sufficient. The yield of butyl iodide, b.p. 129-130 °C, is 64 g (70%).

Iodocyclohexane:

• Proceed as for butyl iodide using 50 g (0.5 mol) of redistilled cyclohexanol (b.p. 160-161 °C). Distil the iodocyclohexane under reduced pressure, b.p. 67-69 °C/9mmHg; the yield is 90 g (86%).