COOLING OF REACTION MIXTURES

It is often necessary to obtain temperatures below that of the laboratory. Finely crushed ice is used for maintaining the temperature at 0-5 °C it is usually best to use a slush of crushed ice with sufficient water to provide contact with the vessel to be cooled and to stir frequently. It is of course essential to insert a thermometer into the reaction mixture to ensure that the desired temperature is attained. For temperatues below 0°C, the commonest freezing mixture is an intimate mixture of common salt and crushed ice a mixture of one part of common salt and three parts of ice will produce a temperature of about —5 to 

The use of cooling baths employing other solvents with solid carbon dioxide enables other temperatures to be attained. An extensive list has been published21 from which the following have been selected ethylene glycol/Cardice, 

The attainment of temperatures lower than —100 °C requires the use of baths employing liquid nitrogen,23 either alone, or admixed with other solvents. The hazards of using liquid nitrogen are pointed out in Section 2.3.2, p. 38, and the use of such cooling baths is not advised except in the hands of experienced workers. 

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Then cool the reaction-mixture, filter it at the pump, leaving a black residue of selenium, and wash out the flask twice with 2x5 ml. of acetic acid, passing the washings also through the filter. Dilute the united filtrates with water, and make the solution alkaline with 10% aqueous sodium hydroxide, which precipitates the camphorquinone. Cool, filter off the yellow camphorquinone at the pump, wash with water and drain thoroughly. 

An alternative method for isolating the n-butyl ether utilises the fact that n-butyl alcohol is soluble in saturated calcium chloride solution whilst n-butyl ether is slightly soluble. Cool the reaction mixture in ice and transfer to a separatory fimnel. Wash cautiously with 100 ml. of 2-5-3N sodium hydroxide solution the washings should be alkaline to litmus. Then wash with 30 ml. of water, followed by 30 ml. of saturated calcium chloride solution. Dry with 2-3 g. of anhydrous calcium chloride, filter and distil. Collect the di-n-butyl ether at 139-142°. The yield is 20 g. 

Cool the reaction mixture to room temperature and add gradually a solution of 75 g. of sodium hydroxide in 125 ml. of water if the mixture boils during the addition of the alkah, cool again. The hydroxide of tin which is flrst precipitated should all dissolve and the solution should be strongly alkahne the anihne separates as an oil. Equip the flask for steam distillation as in Fig. II, 40, 1, and pass steam into the warm... 

Reflux gently in a test-tube under a short air condenser 1 g. of the base with 2 5 mols or 3 0 g. (3 0 ml.) if the molecular weight is unknown of redistilled acetic anhydride for 10-15 minutes. Cool the reaction mixture and pour it into 20 ml. of cold water (CAUl ION). Boil to decompose the excess of acetic anhydride. When cold, filter the residual insoluble acetyl derivative and wash it with a little cold water. Recrystal-/ise from water or from dilute alcohol. 

To the cold acid chloride add 175 ml. of pure carbon disulphide, cool in ice, add 30 g, of powdered anhydrous aluminium chloride in one lot, and immediately attach a reflux condenser. When the evolution of hydrogen chloride ceases (about 5 minutes), slowly warm the mixture to the boiling point on a water bath. Reflux for 10 minutes with frequent shaking the reaction is then complete. Cool the reaction mixture to 0°, and decompose the aluminium complex by the cautious addition, with shaking, of 100 g. of crushed ice. Then add 25 ml. of concentrated hydrochloric acid, transfer to a 2 htre round-bottomed flask and steam distil, preferably in the apparatus, depicted in Fig. II, 41, 3 since the a-tetralone is only moderately volatile in steam. The carbon disulphide passes over first, then there is a definite break in the distillation, after whieh the a-tetralone distils completely in about 2 htres of distillate. 

Method 2. Place 48 g. (41 -5 ml.) of freshly-distilled furfural, 52 g. of dry malonic acid (1), and 24 ml. of dry pyridine (2) in a 500 ml. round-bottomed flask, fitted with a reflux condenser. Heat the flask on a boiling water bath for 2 hours, cool the reaction mixture and dilute with 50 ml. of water. Dissolve the acid by the addition of concentrated ammonia solution, filter the solution and wash the filter paper with a... 

Introduce a solution of 15 g. of the diazo ketone in 100 ml. of dioxan dropwise and with stirring into a mixture of 2 g. of silver oxide (1), 3 g. of sodium thiosulphate and 5 g. of anhydrous sodium carbonate in 200 ml. of water at 50-60°. When the addition is complete, continue the stirring for 1 hour and raise the temperature of the mixture gradually to 90-100°. Cool the reaction mixture, dilute with water and acidify with dilute nitric acid. Filter off the a-naphthylacetic acid which separates and recrys-talhse it from water. The yield is 12 g., m.p. 130°. 

Benzoylpropionitrile. To a mixture of 21 4 g. of p dimethylamino propiophenone hydrochloride, 13 0 g. of potassium cyanide in a 500 ml. flask, add 260 ml. of boiling water heat the heterogeneous mixture under reflux for 30 minutes. Part of the dimethylamine, which is eliminated in the reaction, distils collect this in dilute hydrochloric acid. Cool the reaction mixture in ice the oil sohdifies and crystals form from the aqueous layer. Collect the solid (crude p benzoylpropiouitrile, 10-5 g.) by suction filtration and recrystallise it from benzene - light petroleum (b.p. 40-60°) it separates as almost colourless blades, m.p. 76°. 

Dinitroaniline from 3 5-dinItrobenzoic acid. Place a solution of 50 g. of 3 5-dinitrobenzoic acid (Section IV, 168) in 90 ml. of 10 per cent, oleum and 20 ml. of concentrated sulphuric acid in a 1-litre three necked flask equipped with a reflux condenser, mechanical stirrer, adropping funnel, and thermometer (FUME CUPBOARD ). Add 100 ml. of clJoroform and raise the temperature to 45°. Stir rapidly and add 17 -5g. of sodium azide in small portions whilst maintaining the temperature at 35-45°. The reaction is accompanied hy foaming, which usually commences after about 3 g. of sodium azide has been introduced. After all the sodium azide has been added raise the temperature so that the chloroform refluxes vigorously and maintain this temperature for 3 hours. Then cool the reaction mixture, pour it cautiously on to 500 g. of crushed ice, and dilute with 3 litres of water. After 1 hour, separate the yellow solid by filtration at the pump, wash well with water and dry at 100°. The yield of 3 5-dinitroaniline, m.p. 162-163°, is 39 g. The m.p. is unaffected by recrystallisation from dilute alcohol. 

Dissolve 14 g. of p-phenetidine (2) in 240 ml. of water to which 20 ml. of 5N hydrochloric acid (or 9 ml. of the concentrated acid) have been added stir the solution with about 5 g. of decolourising carbon for 5 minutes, warm, and filter the solution with suction. Transfer the cold filtered solution of p-phenetidine hydrochloride to a 700 ml. conical flask, add 13 g. (12 ml.) of acetic anhydride and swirl the contents to dissolve the anhydride. Immediately add a solution of 16 g. of crystallised sodium acetate in 50 ml. of water and stir (or swirl) the contents of the flask vigorously. Cool the reaction mixture in an ice bath, filter with suction and wash with cold water. RecrystaUise from hot water (with the addition of a little decolourising carbon, if necessary), filter and dry. The yield of pure phenacetin, m.p. 137°, is 12 g. 

Reduction of a nitro compound to a primary amine. In a 50 ml. round-bottomed or conical flask fitted with a reflux condenser, place 1 g. of the nitro compound and 2 g. of granulated tin. Measure out 10 ml. of concentrated hydrochloric acid and add it in three equal portions to the mixtiue shake thoroughly after each addition. When the vigorous reaction subsides, heat under reflux on a water bath until the nitro compound has completely reacted (20-30 minutes). Shake the reaction mixture from time to time if the nitro compound appears to be very insoluble, add 5 ml. of alcohol. Cool the reaction mixture, and add 20-40 per cent, sodium hydroxide solution imtil the precipitate of tin hydroxide dissolves. Extract the resulting amine from the cooled solution with ether, and remove the ether by distillation. Examine the residue with regard to its solubility in 5 per cent, hydrochloric acid and its reaction with acetyl chloride or benzene-sulphonyl chloride. 

Because this reaction is highly exothermic, the equiUbrium flame temperature for the adiabatic reaction with stoichiometric proportions of hydrogen and chlorine can reach temperatures up to 2490°C where the equiUbrium mixture contains 4.2% free chlorine by volume. This free hydrogen and chlorine is completely converted by rapidly cooling the reaction mixture to 200°C. Thus, by properly controlling the feed gas mixture, a burner gas containing over 99% HCl can be produced. The gas formed in the combustion chamber then flows through an absorber/cooler to produce 30—32% acid. The HCl produced by this process is known as burner acid. 

Ethyl 4,5-Dlbenzamldopent-4-enoate (2) Ethyl 3-lmidazol-4(5)-ylpropanoale 1 (9.2 g, 54 mmol) In ElOAc (140 mL) was treated with benzoyl chloride (15 7 g, 112 mmol) In ElOAc (40 mL) and 1M NaHCOa (380 mL) added simultaneously In 1 h under Ice-cooling. The reaction mixture was stirred for 1 h, then a further portion of benzoyl chloride (IS 7 g, 112 mmol) in ElOAc) and iM NaHCOa (280 mL) was added m the same manner, followed by an additional portion o( 1M NaHCOa (200 mL) The reaction mixture was stirred for 24 h, then the organic layer was separated, concentrated, and the residue dissolved in THF (300 mL) The THF solution was stirred with 10% NaHCOa (600 mL) for 24 h to decompose any N-lormyl intermediate and to remove benzoic acxl Extraction with EtOAc, drying (Na2S04), solvent evaporation and recrystallization of the residue from EtOAc hexane afforded 16 24 g of 2 (84%), mp 128-129°C... 

D. s-Aaetyl-2(3B)-oxaaolone. The crude mixture of 3-acety1 4- and 5-chloro-2-oxazolidinone from Step C is placed in a 2-L, three-necked flask equipped with a thermometer, sealed mechanical stirrer, and gas discharge tube. The material is heated to 120°C with stirring, and the temperature is then slowly increased to 150 C and held there until the evolution of gas ceases (Note 10). The cooled, black reaction mixture is distilled at 20 nm. The fractions boiling up to 150°C are collected and redistilled through a 50-cm X 3-cm Vigreux column fitted with a variable take-off head. There is obtained 140-172 g (55-68%) of product, bp 108-112°C (24 mm), which solidifies, rap 35-37°C (Note 11). 

After cooling, the reaction mixture is diluted with ether, the organic phase washed with ice-cold water and dried over anhydrous sodium sulfate. Evaporation of the solvent and crystallization of the residue from ether-hexane gives 6,6,8j5-d3-5a-androstan-3j5-ol-7-one (11) in 84% yield mp 141-142,5° isotopic composition 6% d2,93% da and 1 %... 

A solution of 5a-pregn-9-en-12-one (36, 29 mg) in methanol-OD (5 ml) is saturated with 20% sodium deuterioxide in deuterium oxide and heated under reflux for 3 days. After cooling, the reaction mixture is diluted with ether... 

A solution of estradiol (38, 15 mg) in methanol-OD (4 ml) and one drop of 10% deuteriosulfuric acid in deuterium oxide is heated under reflux for 5 days. After cooling the reaction mixture is diluted with ether, washed with dilute sodium bicarbonate solution and water, then dried over anhydrous sodium sulfate. Evaporation of the ether gives crystalline 2,4-d2-estradiol (39, 15 mg, 99%), mp 173-175° (ether-hexane), exhibiting 82% isotopic purity and only one aromatic hydrogen by NMR. (For an experimental procedure describing the exchange of aromatic protons under Clemmensen conditions, see section III-D.)... 

A detailed procedure for the use of MCPBA recently appeared in Reagents for Organic Synthesis by Fieser and Fieser. The commercially available MCPBA (Aldrich) is 85% pure the contaminant, m-chlorobenzoic acid, can be removed by washing with a phosphate buffer of pH 7.5. The epoxidation is usually performed as follows a solution of 3 -acetoxy-5a-androst-16-ene (2.06 g, 6.53 mmoles) in 25 ml of chloroform (or methylene dichloride) is chilled to 0° in a flask fitted with a condenser and drierite tube and treated with a solution of commercial MCPBA (1.74 g, 20% excess) in 25 ml chloroform precooled to the same temperature. The mixture is stirred and allowed to warm to room temperature. After 23 hr (or until TLC shows reaction is complete) the solution is diluted with 100 ml chloroform and washed in sequence with 100 ml of 10% sodium sulfite or sodium iodide followed by sodium thiosulfate, 200 ml of 1 M sodium bicarbonate and 200 ml water. The chloroform extract is dried (MgS04) and evaporated in vacuo to a volume of ca. 10 ml. Addition of methanol (10 ml) followed by cooling of the mixture to —10° yields 0.8 gof 16a,17a-epoxide mp 109.5-110°. Additional product can be obtained by concentration of the mother liquor (total yield 80-90%). 

A-Homo-estra- Q>),2,Aa-triene-4, l-dione (45) from the l-ketal mono-dibromocarbene adduct (43b). A solution of monoadduct 17-ketal (43b 0.46 g) and dry pyridine (20 ml) is heated at reflux for 2 hr. After cooling the reaction mixture, the pyridine hydrobromide (0.1 g) is removed by filtration and the filtrate is concentrated under reduced pressure. The resultant gum is dissolved in ether and washed successively with water, ice-cold 4 N hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, water, saturated salt solution and dried over anhydrous magnesium sulfate. Evaporation of the solvent at reduced pressure gives 3-bromo-4-methoxy-A-homo-estra-2,4,5(10)-trien-17-one (44 0.22 g) mp 158-162° after crystallization from ether. 

The addition of primary amines to fluoroolefins under anhydrous conditions yields imines The hexafluoropropene dimer, perfluoro-2-methyl-2-pcntcne, and ten butylamine react to yield a mixture of two compounds m a 9 4 ratio [4] (equation 3) rather than just the major keteiiimme-imine, as previously reported [5] It IS claimed that this result is possible by means of isomerization to the terminally unsaturated difluoromethylene isomer prior to nucleophilic attack Secondary amines add to fluoroolefins under anhydrous conditions to give fluonnated ternary amines m good yields If the fluoroolefin is added to the amine without cooling the reaction mixture, or if an excess of the secondary armne is used, there is a tendency toward dehvdrofluonnation of the ternary amine The products... 

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