Reaction mixture neutralization

The Michaelis-Arbuzov reaction works well for the less complex aroyl and alkanoyl chlorides, where purification by distillation is possible. Moreover, there has been less success in the preparation of oc,P-unsaturated acylphosphonates, where multiple addition products are often observed. Recourse has been found in an attractive route that entails oxidation of dialkyl 1-hydroxyalkyl- or 1-hydroxyaryIphosphonates produced by nucleophilic addition of dialkyl phosphites to carbonyl compounds under basic conditions (Pudovik reaction). Alkali metal salts of dialkyl phosphites are currently used in the Pudovik reaction, and the more common procedure of generating the anion involves the addition of a small amount of alcoholic alkoxide ion to the reaction mixture. Neutral amines represent an alternative to the use of anionic bases. In recent years, the use of solid-phase materials as basic catalysts has been successfully developed (Scheme 7.7). One system involves the addition of basic alumina to the carbonyl compound and dialkyl phosphite the other involves the addition of KF or CsF to the mixture of carbonyl compound and dialkyl phosphite. - Such a process for generating dialkyl 1-hydroxyalkyIphosphonates is very flexible and accommodates a large variety of carbonyl compounds. 

When groups such as hydroxyl or amino that are sensitive to oxidation are present as well as an alkyl group, then oxidation of the latter is seldom a smooth reaction. Amino groups can be acetylated, so that, for example, p-(acetylamino)benzoic acid is obtained from A-acetyl-p-toluidine by permanganate 404 anthranilic acid can be derived similarly from A-acetyl-o-toluidine. In such cases it is best to keep the reaction mixture neutral by adding magnesium sulfate. 

Place 5 ml of oil in a Hirschsohn flask and add about 50 ml of 20 per cent sodium sulphite solution and a few drops of phenolphthalein solution. Heat the flask on a water-bath with continuous shaking, keeping the reaction mixture neutral by the continuous addition of 10 per cent acetic acid solution from a burette, until no further alkali is liberated. The process usually occupies from one-half to one hour. Drive the uncombined oil into the neck of the flask by the addition of more sulphite solution and measure the volume of non-aldehydic residue after some hours. 

In using sodium hydroxylamine disulfonate, the reagent is treated with a carbonyl compound, warmed, and cooled. Only at this point is the reaction mixture neutralized with an alkaline solution [6]. This method is suitable for the preparation of a range of carbonyl compounds. Negative results were obtained in the case of benzil and qui-none monoxime, either because the oximes are not sufficiently soluble in the reaction medium or because the oximes produced are not stable in the acidic reaction solution. 

The problem with the fiowsheet shown in Fig. 10.5 is that the ferric chloride catalyst is carried from the reactor with the product. This is separated by washing. If a reactor design can be found that prevents the ferric chloride leaving the reactor, the effluent problems created by the washing and neutralization are avoided. Because the ferric chloride is nonvolatile, one way to do this would be to allow the heat of reaction to raise the reaction mixture to the boiling point and remove the product as a vapor, leaving the ferric chloride in the reactor. Unfortunately, if the reaction mixture is allowed to boil, there are two problems ... 

After all the diethyl sulphate has been introduced, reflux the mixture gently for 2 hours with stirring. Transfer the diluted reaction mixture to a separatory funnel, run oflF the lower aqueous layer, wash successively with water, dilute sulphuric acid (twice), and with water until the washings are neutral to litmus. Dry over anhydrous calcium chloride or magnesium sulphate, and distil. Collect the phenyl ethyl ether (a colourless liquid) at 168-170°. The yield is 50 g. 

A solution of l,3-dimethyl-5-methoxyindole (4.5 g, 0.026 mol) in DMSO (27 ml) was maintained at as cone. HCl (23 ml, 0.77 mol) was added dropwise over 15 min. Stirring was continued for 3 h at room temperature and the reaction mixture was then poured into ice-watcr (100 ml). The mixture was neutralized vvith NaHCOj to pH 7 and extracted with EtOAc (100 ml x 2). The EtOAc was removed in vacuo and the residue purified by chromatography on silica using hexane-EtOAc (7 3) for elution. The yield was 4.35 g (88%). 

Step 5 Acidification of the reaction mixture This is performed m a separate synthetic operation to give the product m its neutral form for eventual isolation... 

In another process variant, only 88% of the nitrobenzene is reduced, and the reaction mixture then consists of two phases the precious metal catalyst (palladium on activated carbon) remains in the unreacted nitrobenzene phase. Therefore, phase separation is sufficient as work-up, and the nitrobenzene phase can be recycled direcdy to the next batch. The aqueous sulfuric acid phase contains 4-aminophenol and by-product aniline. After neutralization, the aniline is stripped, and the aminophenol is obtained by crystallization after the aqueous phase is purified with activated carbon (53). 

Polyphosphoric acid, P2O5, POCl, and PCl are suitable phosphorylatiag agents. Reaction of an alkyl sulfate with sodium pyrophosphate has also been reported for preparation of alkyl pyrophosphates (77). In general, phosphorylation leads to a mixture of reaction products that are sold without further separation. Thus, when lauryltri(ethyleneoxy)ethanol reacts with 0.3 mol of P2O5 at 50°C and is neutralized with 50% aqueous NaOH, the reaction mixture contains the foUowiag products ... 

The latter method typically requires less severe conditions than the former because of the labile nature of the organic anhydride (87,137). Both of these reactions can result in explosions and significant precautions should be taken prior to any attempted synthesis of a peracid (87). For soHd peracids the reaction mixture can be neutralized with sodium hydroxide and the resulting fUtercake washed with water. In the case of the sulfuric acid mediated reaction the peracid has sodium sulfate incorporated in the cake (135). The water of hydration present in the sodium sulfate is desirable to prevent detonation or deflagration of the soHd peracid when isolated in a dry state (87,138,139). 

Manufacturing Processing and Uses. In commercial production, aqueous urea solution is mixed with acetaldehyde in 1 1 molar ratios. An acid catalyst is introduced into the reaction mixture which is staged at various process temperatures. After neutralization with a base, the CDU is separated from the mother hquor by filtration or spray drying. 

Methoxy 6( 2 Chlorobenzoyl)-ben2o(c acid (2).2 3-Metboxy-2(3-cblorobenzoyl)-benzolc acid 1 (1.0 g, 3.4 mmoQ was heated In cone. H2S04 (6 mL) for 1 h at 6S°C. The cooled reaction mixture was poured into ice and neutralized. The cyclized product was filtered off (0 2 g) and the filtrate was acidHIed to give 2, rrp 205°C. 

B. Cyclization. The above oil is poured dropwise into a well-stirred mixture of 110 ml. of 90% phosphoric acid (sp. gr. 1.75) and 23.4 ml. of sulfuric acid (sp. gr. 1.83) which is kept at —10°. The temperature is allowed to rise to 0-10°, and the stirring is continued for 2 hours. The viscous reaction mixture is poured into 500 ml. of ice and w ater, and the acid is partially neutralized with 300 ml. of 40% sodium hydroxide solution with efficient cooling. The viscous cream-colored oil is extracted with three 150-ml. portions of ether the ether extract is washed well with water and sodium bicarbonate solution to remove the last traces of acid and then dried over anhydrous sodium sulfate. The... 

Two hundred grams of eleaned and dried crab shells (Note 1) ground to a fine powder is placed in a 2-1. beaker, and an excess of dilute (approximately 6 N) commercial hydrochloric acid is added slowly to the powdered material until no further action is evident. Much frothing occurs during the addition of the acid, and care must be exercised to avoid loss of material due to foaming over the sides of the beaker. After the reaction has subsided, the reaction mixture is allowed to stand from 4 to 6 hours to ensure complete removal of calcium carbonate. The residue is then filtered, washed with water until neutral to litmus, and dried in an oven at 50-60°. The weight of dried chitin is usually about 70 g., but with some lots of crab shells it may be as low as 40 g. 

B. a-Hydroxyphenazine (demethylalion). A solution of 4.2 g. (0.02 mole) of a-methoxyphenazine, from A above, in 125 ml. of 55% hydrobromic acid (Note 7) is placed in a 250-ml. round-bottomed flask fitted with a reflux condenser. The flask is immersed in an oil bath, and the solution is heated to 110-120° for 5 hours the evolved gases are absorbed with water in a trap. The reaction mixture is cooled to room temperature, diluted with about 125 ml. of water, almost neutralized with sodium hydro.xide (Note 8), and extracted six times with 30- to 40-ml. portions of ether. The combined ether extracts arc extracted with 25-ml. portions of 10% sodium hydroxide solution (Note 9) until no more purple sodium salt is remox ed from the ether. The aqueous extracts are combined, made acid to litmus with dilute acetic acid, and re-extracted four times with 50-ml. portions of ether. The combined ether extracts are dried over anhydrous sodium sulfate, and the ether is removed by distillation on a steam bath. The residue is recrystallized as follows It is dissolved in the least possible amount of hot alcohol, water... 

Concentrated sodium hydroxide solution (about 100 ml. of 35%) is used at the beginning of the neutralization, and dilute sodium hydroxide solution is added towards the end. The reaction mixture should be just faintly acid to litmus. 

In a 3-I. flask are placed a solution of 184 g. (4.6 moles) of sodium hydroxide in 300-400 cc. of water and sufficient ice to make the total volume about 1500 cc. Chlorine is passed into the solution, keeping the temperature below 0° by means of a salt-ice bath, until the solution is neutral to litmus (Note i). After the addition of a solution of 34 g. of sodium hydroxide in 50 cc. of water, the flask is supported by a clamp and equipped with a thermometer and an efficient stirrer. The solution is warmed to 55°, and 85 g. (0.5 mole) of methyl d-naphthyl ketone (Note 2) is added. The mixture is vigorously stirred and, after the exothermic reaction commences, the temperature is kept at 60-70° (Note 3) by frequent cooling in an ice bath until the temperature no longer tends to rise. This requires thirty to forty minutes. The solution is stirred for thirty minutes longer and then the excess hypochlorite is destroyed by adding a solution of 50 g. of sodium bisulfite in 200 cc. of water (Note 4). After cooling to room temperature, the reaction mixture is transferred to a 4-I. beaker and carefully acidified with 200 cc. 

In a 500-ml. round-bottomed flask equipped with a reflux condenser and a magnetic stirrer (Note 6) are placed 150 ml. of methanol, 150 ml. of 6N hydrochloric acid, and the total yield of 4,4 -bis(acetamido)azobenzene. The mixture is heated under reflux for 1.5 hours. The reaction mixture is cooled and the violet solid collected on a Buchner funnel (Note 7). The damp product is suspended in 500 ml. of water in a 1-1. beaker equipped with a stirrer, and the mixture is slowly neutralized by the addition of 2.5N sodium hydroxide. In the course of the neutralization, the salt dissolves and the free base separates. The 4,4 -diaminoazo-benzene is collected on a Buchner funnel, washed with water, and dried under reduced pressure. The yield of yellow product, m.p. 238-241° (dec.),is ll-12g. The over-all yield from/ -amino-acetanilide is 52-56%. 

Approximately 3 lb. of sodium bisulfite is required to reduce the iodine. Technical grade bisulfite may be used satisfactorily. Caution should be observed in adding the bisulfite, since evolution of sulfur dioxide can cause excessive foaming. This foaming occurs a short time after each addition and is most noticeable when the iodine is almost neutralized. Iodine and product clinging to the upper walls of the flask and in the condenser may be conveniently rinsed into the reaction mixture with a stream of water from a wash bottle. 

The addition of weak base (e.g. triethyl amine) to the reaction mixture gives a product having somewhat more of the 5j8-isomer than is observed in the neutral medium " but in strong base the 5j8-product is formed almost exclusively. This latter result is also obtained with other substituents on the molecule (however, cf. below) and even occurs on hydrogenation of dienones and trienones incorporating the A -3-keto entity. 

The reactions are generally run at room temperature or below. With steroids the product is usually isolated by addition of the reaction mixture to water followed by filtration or extraction. The inorganic product of the reaction, chromium III, is soluble in neutral or aqueous acid solutions and can be removed by washing. When steroidal amines are oxidized, the work-up is usually modified such that the steroid may be extracted from the insoluble basic chromium III salts. °... 

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