Acidity continued phenylacetic acid

Hydrolysis of benzyl cyanide to phenylacetamide. In a 1500 ml. three-necked flask, provided with a thermometer, reflux condenser and efficient mechanical stirrer, place 100 g. (98 ml.) of benzyl]cyanide and 400 ml. of concentrated hydrochloric acid. Immerse the flask in a water bath at 40°. and stir the mixture vigorously the benzyl cyanide passes into solution within 20-40 minutes and the temperature of the reaction mixture rises to about 50°, Continue the stirring for an additional 20-30 minutes after the mixture is homogeneous. Replace the warm water in the bath by tap water at 15°, replace the thermometer by a dropping funnel charged with 400 ml. of cold distilled water, and add the latter with stirring crystals commence to separate after about 50-75 ml. have been introduced. When all the water has been run in, cool the mixture externally with ice water for 30 minutes (1), and collect the crude phenylacetamide by filtration at the pump. Remove traces of phenylacetic acid by stirring the wet sohd for about 30 minutes with two 50 ml. portions of cold water dry the crystals at 50-80°. The yield of phenylacetamide, m.p. 154-155°, is 95 g. RecrystaUisation from benzene or rectified spirit raises the m.p. to 156°. 

The suspension of phenylacetamide may be further hydrolysed to phenylacetic acid by refluxing with stirring until the solid dissolves. The mixture becomes turbid after 30 minutes and the product begins to separate as an oil refluxing is continued for 6 hours, the mixture is cooled first with tap water and then by an ice-water bath for about 4 hours. The crude phenylacetic acid is filtered at the pump, washed with two 50 ml. portions of cold water, and dried in a desiccator. The resulting crude acid melts at 69- 70° it may be purified by recrystallisation from light p>etroleum (b.p. 40-60°) or, better, by vacuum distillation. 

Example 1 ot-AzidobenzylpenicWin via the Mixed Anhydride — A solution of o-azido-phenylacetic acid (8.9 grams, 0.05 mol) of triethylamine (5.1 grams, 0.05 mol) in 50 ml of dry dimethylformamide was stirred and chilled below -5°C. At this temperature ethyl chloroformate (4.7 ml) was added in portions so that the temperature was never above -5°C. After the mixture had been stirred for 20 minutes, dry acetone (100 ml), chilled to -5°C, was added in one portion, immediately followed by an ice-cold solution of 6-aminopenicillanic acid (10.8 grams, 0.05 mol) and triethylamine (5.1 grams, 0.05 mol) in 100 ml of water, and the stirring was continued for VA hours at 0°C. 

Benzyl cyanide (40 g. = 0 33 mole) is heated in a round-bottomed flask (capacity 0-5 1.), with a mixture of 50 c.c. of concentrated sulphuric acid and 30 c.c. of water. The flask is provided with an upright air condenser, and is placed in a conical (Babo) air bath. The heating is continued until the appearance of small bubbles of vapour indicates that a reaction, which rapidly becomes violent, has set in the liquid boils up, and white fumes are emitted. It is allowed to cool and then two volumes of water are added. After some time the phenylacetic acid which has crystallised out is filtered off with suction. If a sample of the material does not form a clear solution with sodium carbonate in water (presence of phenylacetamide), the whole of the crude material is shaken with sodium carbonate solution and the mixture is filtered. From the clear filtrate phenylacetic acid is reprecipitated with sulphuric acid, and can be recrystallised directly from a rather large volume of hot water or, after drying, from petrol ether. Because of its low melting point (76°) it often separates at first as an oil, but it can also be conveniently purified by distillation in vacuo from a sausage flask.2... 

Substituted benzyl chlorides were carbonylated using a Pd/tppts catalyst in aqueous/organic two phase systems under basic reaction conditions to afford the sodium salts of the corresponding phenylacetic acids. After acidification the phenylacetic acid dissolved in the organic phase and could be readily separated from the Pd/tppts catalyst contained in the aqueous phase (Figure 12) 466-468 TOFs up to 21 h 1 (turnover number, TON=165) and phenylacetic acid yields up to 94% were obtained at 70°C, 1 bar CO, tppts/Pd=10, NaOH/substrate=3/2 in an aqueous/toluene (1/1) two phase system in a batchwise procedure.466 The TOFs were improved to a maximum of 135 h 1 (TON=1560) in a continuous operation mode. Palladium catalysts modified with binas (Table 2 25) exhibited low catalytic activity (TONs up to 140) in the carbonylation of benzyl chloride 466 In strongly acidic media (pH=l) the Pd/25 catalyst was active and remained stable during the reaction which contrasts with Pd/tppts where palladium black was observed. However, the catalyst was completely deactivated after three cycles.466... 

The carbonylation of bromobenzene with palladium/tppts complexes was reported by Monteil and Kalck (81). Some of the aforementioned disadvantages were alleviated in a new process for carbonylation of substituted benzyl chlorides (82). The reaction was carried out in a two-phase system in the presence of CO at atmospheric pressure yields of phenylacetic acids of 80-94% were reported. The palladium catalyst contains tppts or BINAS-Na, 10, to allow water solubility. The maximum turnover frequency was found to be 135 h 1, and the lifetime of the catalyst increased as a result of continuous addition of reactants. 

Immobilized forms of penicillin amidases and acylases have replaced whole-cell biocatalysts for the production of 6-APA and 7-ACA as they can be reused many times, in some cases for over 1000 cycles. Another major advantage is the purity of the enzyme, lacking the /3-lactamase contaminants often present in whole cells. The productivity of these biocatalysts exceeds 2000 kg prod-uct/kg catalyst. A typical process for the production of 6-APA employs immobilized penicillin G acylase covalently attached to a macroporous resin. The process can be run in either batch or continuous modes. The pH of the reaction must be maintained at a value between 7.5 and 8 and requires continuous adjustment to compensate for the drop caused by the phenylacetic acid generated during the course of the reaction. Recycle reactors have been used, as they allow both pH control and the use of packed bed reactors containing the immobilized catalyst. The enzymatic process is cheaper, although not... 

In its 2007 report on the implementation of article 12 of the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988, the International Narcotics Control Board informs Governments of the notification that the Board has sent to the Secretary-General, to formally initiate the procedures to transfer phenylacetic acid from Table II to Table I of the Convention. The Board believes that the transfer is necessary because existing controls over phenylacetic acid are insufficient to prevent the diversion of the substance from continuing. 

It is reported that the two-phase carbonylation methodology has been used on a pilot plant scale by Montedison [31 ] for the conversion of benzyl chloride to phenylacetic acid for use in perfume constituents and pesticides (eq. (8)). The carbonylation is run in a biphasic medium employing diphenyl ether and aqueous 40 % sodium hydroxide as solvents. The catalyst system consists of a cobalt carbonyl complex and a benzyltrialkylammonium surfactant. The reaction takes place at low temperature and CO pressure, while benzyl chloride is added continuously to the reaction mixture. 

In the present enzymatic process, 5 ton 6-APA is obtained using immobilized penicillin acylase (5-10 kg) as the biocatalyst in 100 ton of an aqueous solution containing 10 ton Penicillin G at ambient conditions. During the enzymatic hydrolysis the pH is kept constant by the continuous addition of ammonia (500 kg). In addition, the phenylacetic acid formed upon the hydrolysis of 6-APA can be recycled for use in the Penicillin G fermentation process. 

The best way to produce phenylacetone on a large scale and continuous basis is by a catalyst bed inside a tube furnace. This has several advantages over the other methods described in this book. Cheap and very common acetic acid is used to react with phenylacetic acid instead of the expensive and more exotic acetic anhydride and pyridine. Use of the tube furnace frees up the glassware for use in other operations. The furnace requires very little attention while it is in operation, which allows the underground chemist to spend his time turning the phenylacetone into methamphetamine. There is no reason why this process cannot be used in small-scale production. It is just that its advantages really come out when large amounts of phenylacetone must be produced. 

The time for a breakthrough was ripe. It occurred in the isolation of 6-aminopenicillanic acid, 6-APA, by Batchelor et al. (1959). The compound was isolated from P. chrysogenum fermentations deprived of the normally supplied precursors such as phenylacetic acid. The availability of this penicillin nucleus in meaningful quantities now made possible the synthesis of an unlimited number of penicillins by acylating the P-6-amino group with an infinite number of acids, a process that has continued unabated. 

Arylacetic Acids and Esters. - The anti-inflammatory properties of these compounds continues to stimulate new work in this area existing approaches have been summarisd in a review. 3 Another version of the well established [1.2]-aryl migration route to phenylacetic acids consists simply of treatment of the... 

The most important modification of the Perkin reaction was developed by Oglialoro using the sodium salt of acetic acid (e.g., phenylacetic acid, phenoxyacetic acid ) in condensation with acetic anhydride and an aldehyde (e.g., benzaldehyde, paraldehyde ). This type of reaction is referred to as the Perkin-Oglialoro reaction,Perkin-Oglialoro condensation, or Oglialoro modification. Other modifications include the use of different bases as the catalysts, (e.g., NaB(OMe)4-LiCl, CaH2, CsOAc, and CsF ), the use of microwave irradiation and cesium acetate or fluoride in combination with a small amount of pyridine as catalyst and the continuous distillation of acetic acid to enhance the conversion rate. ... 

A mixture of phenylacetic acid, a slight excess of hydrazine hydrate, activated alumina (Alcoa F-1), and 1-butanol heated with vigorous stirring in an oil bath at 140-150°, benzene added gradually to maintain a heavy reflux at 94-95° with water separation in a Dean-Stark apparatus, and the product isolated after 5 hrs. -> phenylacetyl hydrazide. Y 99%. — Alumina shows a remarkable catalytic activity promoting exclusively the formation of monoacylhydrazide. The catalyst permits lowering of the reaction temp, to a point where byproducts are no longer formed. The water produced must be continuously removed. F. e. s. T. Rabini and G. Vita, J. Org. Chem. 30, 2486 (1965). 

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