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.

SYNTHESIS OF 2-(4-METHYLPHENYL)-PROP-2-EN-l-OL AND 6-METHYL-2-(4-METHYLPHENYL)HEPTA-l,5-DIENE

1,2-Epoxy-2-(4-methylphenyI)propane:

• To a solution of dimethyloxosulphonium methylide [prepared from sodium hydride (1.5g, 50% dispersion), finely powdered trimethyloxosulphonium iodide (6.6g) and dimethyl sulphoxide (30 ml) under a nitrogen atmosphere] is added with stirring, a solution of p-methylacetophenone (3.4g) in dimethyl sulphoxide (10 ml). 

• The reaction mixture is left overnight at room temperature and then heated to 50 °C for 1 hour. 

• After cooling and adding water (60 ml), the mixture is extracted with ether, the combined ethereal extracts washed with water and then dried over anhydrous sodium sulphate. 

• Evaporation of the solvent followed by chromatography over neutral alumina using light petroleum (b.p. 40-60 °C) as eluant, affords the epoxide (3.3g, 90%).

2-(4-methyIphenyI)prop-2-en-l-oI:

• To a solution of diisopropylamine (3g) in ether is added with stirring butyllithium (15 ml, 2.1 m in ether) under a nitrogen atmosphere. 

• After 30 minutes, the solution of the foregoing epoxide (3g) in ether (40 ml) is added slowly with stirring and the mixture left overnight at room temperature. 

• The mixture is refiuxed for 4 hours and the disappearance of epoxide is monitored by t.l.c. 

• The solution, after cooling, is partitioned between ether and water, the organic phase washed successively with water and brine and then dried over anhydrous sodium sulphate. 

• Solvent evaporation followed by chromatography over neutral alumina affords 2-(4-methyl-phenyl)prop-2-en-l-ol (2.6g, 85%), pure by t.l.c. analysis; b.p. 105-107 °C/5-7mmHg; i.r. (film) 3380, 1050 (OH), 3070, 1650, 890 (>C=CH₂), and 820 cm⁻¹ (para-substituted benzene).

Conversion into 6-methyI-2-(4-methylphenyI)hepta-l,5-diene:2-(4-methyl-phenyl)prop-2-enyl vinyl ether

• A mixture of the foregoing allylic alcohol (2.5g), ethyl vinyl ether (75 ml) and freshly crystallised mercury(n) acetate (600 mg) is refiuxed continuously for 12 hours on a water bath. 

• The reaction mixture is chilled in ice and mixed with 10 per cent aqueous sodium carbonate solution (25g) and stirred well for 30 minutes at °C. 

• The organic layer is separated, washed with water and dried over anhydrous potassium carbonate. 

• Evaporation of the solvent and chromatography of the residue on neutral alumina (50g) furnished, on elution with light petroleum (b.p. 40-60 °C), the allyl vinyl ether which is further purified by distillation under reduced pressure, b.p. 90-92 °C/5-7mmHg; yield 2.0g (80%); 1630, 1610 (C=C), 1200 (vinyl ether), 900 (>C=H 2 ) and 820 cm⁻¹ (para-substituted benzene).

Claisen-Cope rearrangement of the allyl vinyl ether:

• The ether (1.1g) is heated for 30 minutes at 180-185 °C under nitrogen in a fully immersed half-filled sealed Pyrex glass tube (CAUTION). 

• After cooling, the product is distilled under reduced pressure to furnish 4-(4-methylphenyl)pent-4-enal (850 mg, 87%), b.p. 100-102 °C/5-7mmHg; i.r. (film) 2700, 1710 (CHO), 3070, 1650, 890 (>C=CH₂), and 825 cm⁻¹ (para-substituted benzene).

Wittig reaction:

• To the phosphorane [prepared from isopropyltriphenyl-phosphonium iodide (2.6g) in dimethyl sulphoxide (6 ml) and sodium hydride (300 mg, 50% dispersion) under a nitrogen atmosphere], is added the foregoing aldehyde (700 mg) in tetrahydrofuran (1ml). 

• The contents are stirred for 2 hours and then left overnight at room temperature and warmed to 50 °C for 2 hours. 

• The cooled reaction mixture is poured on to crushed ice and extracted with light petroleum (b.p. 40-60 °C). 

• The organic extract is dried over anhydrous sodium sulphate, the solvent removed and the residue chromatographed over neutral alumina (20g) when elution with light petroleum (b.p. 40-60 °C) gives 6-methyl-2-(4-methylphenyl)hepta-1, 5-diene (450 mg, 66%). 

• This is further purified by distillation under reduced pressure, b.p. 110-113 °C/5-7mmHg; p.m.r. (CCl₄ , TMS) 𝜹 1.52 (s, 6H, C=C(Me)₂), 2.34 (s, 3H, Ar.Me), 5.05 (t, 1H, — CH=C— ), 5.24 (broad s, 2H,>C=CH₂), and 7.23 (4H, aromatic protons).

SYNTHESIS OF O-ETHYL S-ETHYL DITHIOCARBONATE

CAUTION: These preparations must be conducted in an efficient fume cupboard.

Potassium O-ethyI dithiocarbonate:

• Into a 500-ml round-bottomed flask, fitted with a reflux condenser, place 42g (0.75 mol) of potassium hydroxide pellets and 120g (152 ml) of absolute ethanol. 

• Heat under reflux for 1 hour. 

• Allow to cool and decant the liquid from the residual solid into another dry 500-ml flask; add 57g (45 ml, 0.75 mol) of carbon disulphide (1) slowly and with constant shaking. 

• Filter the resulting almost solid mass, after cooling in ice, on a sintered glass funnel at the pump, and wash it with three 25 ml portions of ether. 

• Dry the potassium O-ethyl dithiocarbonate in a vacuum desiccator over silica gel. The yield is 74g. If desired, it may be recrystallised from absolute ethanol but this is usually unnecessary.

O-EthyI S-ethyl dithiocarbonate:

• Place 32g (0.2 mol) of potassium O-ethyl dithiocarbonate and 50 ml of absolute ethanol in a 500-ml round-bottomed flask provided with a double surface condenser. 

• Add 32g (1 6.5 ml, 0.205 mol) of ethyl iodide. 

• No reaction appears to take place in the cold. 

• Heat on a water bath for 3 hours: a reaction sets in within 15 minutes and the yellow reaction mixture becomes white owing to the separation of potassium iodide. 

• Add about 150 ml of water, separate the lower layer and wash it with water. 

• Dry it with anhydrous calcium chloride or anhydrous calcium sulphate and distil collecting O-ethyl S-ethyl dithiocarbonate at 196-198 °C. The yield is 23g (77%).

Notes to keep in mind:

1. Carbon disulphide is toxic and has a dangerously low flash point.

Cognate preparation: O-Ethyl S-butyl dithiocarbonate

• Use 32g (0.2 mol) of potassium O-ethyl dithiocarbonate, 37g (23 ml, 0.2 mol) of butyl iodide and 50 ml of absolute ethanol. 

• Reflux on a water bath for 3 hours. 

• Pour into 150 ml of water, saturate with salt (in order to facilitate the separation of the upper layer), remove the upper xanthate layer, wash it once with 25 ml of saturated salt solution and dry with anhydrous calcium chloride or anhydrous calcium sulphate. 

• Distil under reduced pressure and collect the pale yellow O-ethyl S-butyl dithiocarbonate at 90-91 °C/4mmHg. The yield is 34g (95%).

O-[1,2,2-Trimethylpropyl] S-methyl dithiocarbonate:

• In a 2-litre three-necked flask equipped with a stirrer, reflux condenser and dropping funnel, prepare potassium t-pentoxide by dissolving 48.5g (60 ml, 0.55 mol) of 2-methyl-butan-2-ol (t-pentyl alcohol) in 750 ml of dry toluene and adding in portions 21.5g (0.55 mol) of potassium metal (1) and refluxing gently until reaction is complete. 

• Then add 51g (63 ml, 0.5 mol) of 3,3-dimethylbutan-2-ol to the hot solution slowly and with stirring. 

• Cool and add slowly 57g (0.75 mol) of carbon disulphide. 

• When the reaction has subsided, cool the resulting orange xanthate suspension to room temperature, add 78g (34 ml, 0.55 mol) of methyl iodide and heat on a water bath for 4-5 hours. 

• Filter, remove toulene and the residual alcohols on a rotary evaporator (fume cupboard) and distil the product under reduced pressure collecting the xanthate ester at 85-87 °C/6mmHg (2). The yield is 63g (70%).

Notes to keep in mind:

1. Great care must be taken in the handling of potassium and of methyl iodide.

2. Use a 500-ml flask fitted with a short fractionating column; the distillation is accompanied by considerable frothing.

SYNTHESIS OF ISOBUTYL 2,4-DINITROPHENYL SULPHONE

• Dissolve 340 mg of Isobutyl 2,4-dinitrophenyl sulphide in 10 ml of acetic acid, warm to about 50 °C and add dropwise 8 ml of 3 per cent aqueous potassium permanganate solution. 

• Maintain the solution at about 50 °C for 20 minutes, and then pass through the solution a stream of sulphur dioxide to decompose excess potassium permanganate. 

• Add crushed ice to the yellow solution to precipitate the crude sulphone. 

• Filter the precipitate, dry and recrystallise from rectified spirit to give the yellow crystalline product, m.p. 105-106 °C; the yield is 190 mg (50%).

SYNTHESIS OF DIBENZYL SULPHOXIDE

• Stir 2.35g (0.01l mol) of sodium metaperiodate in 45 ml of a 1:1 mixture of water and methanol held at 0°C. 

• Add portionwise 2.14g (0.01 mol) of dibenzyl sulphide and continue to stir the mixture at °C for several hours, preferably overnight. 

• Extract the reaction mixture (which contains precipitated sodium iodate) with three 20 ml portions of chloroform. 

• Dry the combined chloroform extracts over magnesium sulphate and remove the solvent on a rotary evaporator. 

• Recrystallise the product from ethanol. The yield of dibenzyl sulphoxide is 2.2g (96%), m.p. 135°C.

SYNTHESIS OF ISOBUTYL 2,4-DINITROPHENYL SULPHIDE

• Dissolve 1g (0.005 mol) of 1-chloro-2,4-dinitrobenzene in 5 ml of rectified spirit with warming and add a solution of 0.5 ml (0.005 mol) of 2-methyl-propane-1-thiol in 5 ml of rectified spirit containing 2 ml of 10 per cent aqueous sodium hydroxide. 

• Heat under reflux for 10 minutes and decant the hot solution from any insoluble material into a clean conical flask. 

• Allow the solution to cool, filter and recrystallise the sulphide twice from methanol. 

• The product is obtained as yellow flakes, m.p. 75-76 °C; the yield is 440 mg (35%).

SYNTHESIS OF DIPROPYL SULPHIDE

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

• Place 56g (0.5 mol) of finely powdered, fused sodium sulphide and 100 ml of rectified spirit in a 500-ml round-bottomed flask equipped with a reflux condenser. 

• To the boiling mixture add 46g (34 ml, 0.374 mol) of propyl bromide slowly and reflux for 6 hours. 

• Distil off the ethanol on a water bath, and add a large excess of water to the distillate. 

• Separate the upper layer of crude sulphide, wash it with three 40-ml portions of 5 per cent sodium hydroxide solution, then with water until the washings are neutral, and dry over anhydrous calcium chloride or anhydrous calcium sulphate. 

• Distil, and collect the dipropyl sulphide at 141-143 °C. The yield is 20g (91%). If the sulphide is required perfectly pure, it should be redistilled from a little sodium.

Cognate preparation: Dibenzyl sulphide

• Heat a solution of 63g (0.5 mol) of benzyl chloride in 160 ml of rectified spirit on a steam bath and stir while adding a solution of 29g (0.25 mol) of fused sodium sulphide in about 50-60 ml of water. 

• Continue stirring and heating for 3 days, remove the ethanol on a rotary evaporator and pour the residue on to 350g of crushed ice. 

• Separate the oil and triturate with a little 70 per cent ethanol to crystallise the product. Recrystallise from the same solvent; the yield of dibenzyl sulphide is 26g (83%), m.p. 49 °C.

SYNTHEIS OF S-BENZYL-L-CYSTEINE [L-2-Amino-3-(benzylthio)-propanoic acid]

• Collect about 750 ml of liquid ammonia in a 1-litre three-necked flask, surrounded by a lagging bath of cork chips and fitted with a sealed stirrer unit, a soda-lime guard-tube and a stopper. 

• Weigh out 24g (0.1 mol) of L-cystine, and about 10g (0.48 mol) of sodium cut into small pieces under dry light petroleum. 

• Start the stirrer, add about 2g of the sodium followed by L-cystine in small portions until the blue colour has disappeared. 

• Repeat this addition sequence until all of the cystine has been added and a permanent blue colour remains. 

• Discharge the blue colour by gradually adding powdered ammonium chloride, and then add dropwise 25.3g (23 ml, 0.2 mol) of benzyl chloride. 

• Remove the stirrer and lagging bath and allow the ammonia to evaporate overnight. 

• Dissolve the residue in 100 ml of cold water and add concentrated hydrochloric acid until the resulting mass is acid to Congo red. 

• Heat the mixture gradually to boiling to dissolve the precipitated product and allow to cool. 

• Filter off the long needles of S-benzyl-L-cysteine which separate, wash with a little cold water and allow to dry in the air. The yield is 38g (90%), m.p. 214 °C (decomp.).

SYNTHESIS OF S-BENZYLISOTHIOURONIUM CHLORIDE

• Dissolve 76g (1 mol) of thiourea in 200 ml of warm water in a 1-litre round-bottomed flask. 

• Dilute the solution with 135 ml of rectified spirit and add 126.5g (1 mol) of benzyl chloride. 

• Heat the mixture under reflux on a water bath until the benzyl chloride dissolves (about 15 minutes) and for a further 30 minutes taking care that the mixture is well shaken from time to time. 

• Cool the mixture in ice: there is a tendency to supersaturation so that it is advisable to stir (or shake) the cold solution vigorously, when the substance crystallises suddenly. 

• Filter off the solid at the pump. 

• Evaporate the filtrate to about half bulk in order to recover a further small quantity of product. 

• Dry the compound upon filter paper in the air. The yield of S-benzylisothiouronium chloride, m.p. 174 °C, is 200g (99%). 

• Recrystallise the salt from 400 ml of 0.2 m hydrochloric acid; filter off the solid which separates on cooling. The yield of recrystallised salt, m.p. 175 °C, is 185g (91%); some of the dimorphic form, m.p. 150 °C, may also separate.