Ice-salt baths

Dissolve 36 g. of p-toluidine in 85 ml. of concentrated hydrochloric acid and 85 ml. of water contained in a 750 ml. conical flask or beaker. Cool the mixture to 0° in an ice-salt bath with vigorous stirring or shaking and the addition of a httle crushed ice. The salt, p-toluidine hydrochloride, will separate as a finely-divided crystalline precipitate. Add during 10-15 minutes a solution of 24 g. of sodium nitrite in 50 ml. of water (1) shake or stir the solution well during the diazotisation, and keep the mixture at a temperature of 0-5° by the addition of a httle crushed ice from time to time. The hydrochloride wUl dissolve as the very soluble diazonium salt is formed when ah the nitrite solution has been introduced, the solution should contain a trace of free nitrous acid. Test with potassium iodide - starch paper (see Section IV,60). 

Dissolve 34 g. of o-nitroaniline in a warm mixture of 63 ml. of concentrated hydrochloric acid and 63 ml. of water contained in a 600 ml. beaker. Place the beaker in an ice - salt bath, and cool to 0-5° whilst stirring mechanically the o-nitroaniline hydrochloride will separate in a finely-divided crystalline form. Add a cold solution of 18 g. of sodium nitrite in 40 ml. of water slowly and with stirring to an end point with potassium iodide - starch paper do not allow the temperature to rise above 5-7 . Introduce, whilst stirring vigorously, a solution of 40 g. of sodium borofluoride in 80 ml. of water. Stir for a further 10 minutes, and filter the solid diazonium fluoborate with suction on a sintered glass funnel. Wash it immediately once with 25 ml. of cold 5 per cent, sodium borofluoride solution, then twice with 15 ml. portions of rectified (or methylated) spirit and several times with ether in each washing stir... 

This last solution should be prepared slowly as it is quite exothermic. Set all three aside in a freezer. Now prepare the mixing apparatus which will be a stainless steel "mixing bowl" suspended In the ice/salt bath made earlier. We use a stainless steel bowl here so that heat transfer will be maximal, while preventing any corrosive interaction. A glass bowl will not be sufficient for larger scale preparations as it will not conduct heat fast enough to prevent the reactants from going over IOC (at which point the Haloamide will decompose and you ll have to start over). Take the Sodium Hydroxide solution out of the freezer once it is cool, but not cold. 

Prepare a paste out of 65g Sodium Azide (lm NaN ) and 65mL of water in a beaker. Add 400mL of either Chloroform or Benzene to this paste (depending on what you have available, but be consistent later on) and stir well. Dump this mixture into a round bottom flask situated in an ice/salt bath, drop in a stirrer magnet, attach a Claisen adapter, addition funnel, and thermometer. Let this mixture cool to OC. 

The flask A is surrounded by an ice-salt bath and the stirrer is started. When the temperature of the acid has dropped to 10°, 132 g. (3 moles) of ethylene oxide is added over a period of about two and one-half hours (Note 3). The stirring is continued for one hour (Note 4) after all of the ethylene oxide has been added and the temperature is maintained below 10° during the reaction. 

A filtered solution of the crude product in 200 cc. of hot absolute alcohol is treated with 250 cc. of concentrated hydrochloric acid. Most of the hydrochloride precipitates at once and is filtered, washed with alcohol and dried. The filtrate is cooled in an ice-salt bath and again filtered, and the prccijiitatc is... 

A. Nilrosothymol.—To a solution of 100 g. (0.666 mole) of thymol in 500 cc. of 95 per cent ethyl alcohol is added 500 cc. of concentrated hydrochloric acid. This mixture is cooled to 0° in a 2-1. beaker set in an ice-salt bath, and to it is added 72 g. (i mole) of commercial sodium nitrite in portions of about 5 g. each. 

In a 5-1, 3-necked flask fitted with a mechanical stirrer (Note 1), a dropping funnel, and a thermometer for reading low temperatures is placed 790 ml. (7 moles) of 48% h drobromic acid. The fl.ask and contents are cooled to 10-20 in an ice-salt bath, and 150 g, (1.59 moles) of 2-aminopyridine (Note 2) is added over a period of about 10 minutes. While the temperature is kept at 0° or lower, 240 ml. (4.7 moles) of bromine is added dropwise (Note 3). A solution of 275 g. (4 moles) of sodium nitrite in 400 ml. of water is added dropwise over a period of 2 hours, the temperature being carefully maintained at 0° or lower (Note 4). After an additional 30 minutes of stirring, a solution of 600 g. (15 moles) of sodium hydroxide in 600 ml. of water is added at such a rate that the temperature does not rise above 20-25° (Note 5). The nearly colorless reaction mixture is extracted with... 

The ice-salt bath is renewed before the sodium nitrite is added and once during the addition. 

Norite, is heated to boiling by introduction of steam, filtered through a Norite filter pad by suction, and cooled in an ice-salt bath. The muconic acid is precipitated by the addition of a large excess (1500 ml.) (sp. gr. 1.18) of concentrated hydrochloric acid to the cold solution. The acid is added in a thin stream to the well-stirred solution. After 2 hours the muconic acid is filtered, washed first with two 400-ml. portions of cold water and then with 200 ml. of methyl alcohol, and dried at 85°. The yield of nearly colorless product melting at 296-298°, with decomposition, amounts to 165-195 g. (37-43%). 

Desyl chloride (a-cbloro-desoxybenzoin, m-chloro-co-phenyl acetophenone) [447-31-4] M 230.7, m 62-64 , 66-67 ,67.5 , 68 . For the purification of small quantities recrystallise from pet ether (b 40-60°), but use MeOH or EtOH for larger quantities. For the latter solvent, dissolve 12.5g of chloride in 45mL of boiling EtOH (95%), filter and the filtrate yields colourless crystals (7.5g) on cooling. A further crop (0.9g) can be obtained by cooling in an ice-salt bath. It turns brown on exposure to sunlight but it is... 

Ammonium nitrate [6484-52-2] M 80.0, m 210 (dec explosively), d 1.72. Crystd twice from distilled water (ImL/g) by adding EtOH, or from warm water (0.5mL/g) by cooling in an ice-salt bath. Dried in air, then under vacuum. After 3 recrystns of ACS grade it contained Li and B at 0.03 and 0.74 ppm resp. 

B. cis-1,2-Gyclohexanedimethanol Dimethanesulfonate. In a 5-1., three-necked, round-bottomed flask, immersed in an ice-salt bath and fitted with a mechanical stirrer and an addition funnel, is plaeed a solution of 111 g. (0.97 mole) of methanesulfonyl chloride in 1.21. of pyridine. While cooling and stirring, a solution of 46.4 g. (0.322 mole) of m-l,2-cyclohexanedimethanol in 250 ml. of pyridine is added dropwise at a rate such that the temperature does not exceed 0° (Note 5). Upon completion of the addition, the mixture is stirred at — 5° to 0° for an additional 2 hours. Two liters of cold 10% hydrochloric acid is introduced at a rate which maintains the reaction mixture below 20° (Note 5). The solid which separates is isolated by suction filtration, washed sequentially with 11. of dilute hydrochloric acid and 21. of water, and air-dried. There is isolated 93-95 g. (96-98%) of the dimethanesulfonate having m.p. 66-67.5°. Reorystallization from methanol gives needles melting at 75-76° (Note 6). 

B. (l-Azido-3,3-dimethoxy-l-propenyl)benzene. In a 2-1., one-necked, round-bottomed flask equipped with a magnetic stirrer and powder funnel are placed 156 g. (0.45 mole) of the iodoazide from Part A and 1500 ml. of anhydrous ether. The solution is stirred and cooled in an ice-salt bath (— 5° to 0°), and 62 g. (0.55 mole) of potassium <-butoxide (Note 6) is added. The powder funnel is then replaced by a calcium chloride drying tube and the mixture is stirred for 4 5 hours at 0°. At the end of this time 350 ml. of water is added while the mixture is still cold. The ethereal layer is then separated and washed with three 350-ml. portions of water and dried over magnesium sulfate. The solvent is removed with a rotary evaporator without heating, leaving 67-75 g. (68-76%) of (l-azido-3,3-dimethoxy-l-propenyl)-benzene as a dark oily liquid (Note 7). This material can be used without further purification for Part C (Note 8). 

With a good ice-salt bath, the time required for the addition is 1.5-2.0 hours. 

B. Putrescine dihydrochloride. A 2-1. wide-mouthed Erlen-meyer flask containing 200 ml. of concentrated hydrochloric acid and 400 g. of cracked ice is clamped in an ice-salt bath and provided with an efficient stirrer (inefficient stirring may lower the yield). The stirring is started, and 80 g. (0.46 mole) of adipyl hydrazide is added all at once, followed by 500 ml. of ether (Note 5). While the temperature is maintained below 10° (Note 6), a solution of 80 g. (1.15 moles) of sodium nitrite in 150 ml. of water is added over about 30 minutes through a dropping funnel whose stem reaches below the bottom of the ether layer, but not into the path of the stirrer. The operations in the next paragraph should be conducted without delay after the completion of the addition of the nitrite. 

B. 2,4,6-Tnbromohenzoic acid. A 5-1. three-necked flask, equipped with a mechanical stirrer and thermometer and surrounded by an ice-salt bath, is charged with a precooled mixture of 1.02 1. of concentrated sulfuric acid and 500 ml. of water. Cooling during the reaction period is assisted by the ice-salt bath, but is effected chiefly by periodic additions of large amounts... 

In a 600-ml. beaker fitted with a thermometer and mechanical stirrer are placed 150 ml. of concentrated hydrochloric acid and 55 g. (0.32 mole) of o-bromoaniline. After brief stirring, 100 g. of ice is added and the beaker is surrounded by an ice-salt bath. The solution is then diazotized by the dropwise addition with stirring of a solution of 24.3 g. (0.35 mole) of sodium nitrite in 100 ml. of water, the temperature being kept at 0-5°. 

A suspension of lithium aluminum deuteride (1.6 g) in dry tetrahydrofuran (60 ml) is added dropwise to a stirred and cooled (with ice-salt bath) solution of 5a-androst-l4-ene-3j3,17j3-diol (179, 1.6 g) and boron trifluoride-etherate (13.3 g) in dry tetrahydrofuran (60 ml). The addition is carried out in a dry nitrogen atmosphere, over a period of 30 min. After an additional 30 min of cooling the stirring is continued at room temperature for 2 hr. The cooling is resumed in a dry ice-acetone bath and the excess deuteriodiborane is destroyed by the cautious addition of propionic acid. The tetrahydrofuran is then evaporated and the residue is dissolved in propionic acid and heated under reflux in a nitrogen atmosphere for 8 hr. After cooling, water is added and the product extracted with ether. The ether... 

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