Phenylacetic acids, reactions

The ketones are readily prepared, for example, acetophenone from benzene, acetyl chloride (or acetic anhydride) and aluminium chloride by the Friedel and Crafts reaction ethyl benzyl ketones by passing a mixture of phenylacetic acid and propionic acid over thoria at 450° and n-propyl- p-phenylethylketone by circulating a mixture of hydrocinnamic acid and n-butyric acid over thoria (for further details, see under Aromatic Ketones, Sections IV,136, IV,137 and IV,141). 

Phenylacetic acid. Use 5 0 g. of magnesium, 25 g, (23 ml.) of redistilled benzyl chloride (Section IV,22) and 75 ml. of sodium-dried ether. Allow the reaction mixture to warm to 15° and then decompose it with dilute hydrochloric or sulphuric acid. Filter off the crude acid and recrystallize it from water. The yield of pure phenylacetic acid, m.p. 76-77°, is 11 g. 

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 mechanism of the reaction la not known with certainty. It is known from studies utilising as tracer that no change in the carbon skeleton occurs during the reaction, and also that unsaturated hydrocarbons can undergo reactions very similar to those of ketones thus both styiene and phenyl-acetylene can react with sulphur and morpholine to produce phenylaceto-thiomorphoUde, hydrolysis of which yields phenylacetic acid ... 

This is a way to do this procedure without having to use one of those crazy tube furnaces stuffed with thorium oxide or manganous oxide catalyst [21]. The key here is to use an excess of acetic anhydride. Using even more than the amount specified will insure that the reaction proceeds in the right direction and the bad side reaction formation of dibenzylketone will be minimalized (don t ask). 18g piperonylic acid or 13.6g phenylacetic acid, 50mL acetic anhydride and 50mU pyridine are refluxed for 6 hours and the solvent removed by vacuum distillation. The remaining residue is taken up in benzene or ether, washed with 10% NaOH solution (discard the water layer), and vacuum distilled to get 8g P2P (56%). 

The phenylacetic acid derivative 469 is produced by the carbonylation of the aromatic aldehyde 468 having electron-donating groups[jl26]. The reaction proceeds at 110 C under 50-100 atm of CO with the catalytic system Pd-Ph3P-HCl. The reaction is explained by the successive dicarbonylation of the benzylic chlorides 470 and 471 formed in situ by the addition of HCl to aldehyde to form the malonate 472, followed by decarboxylation. As supporting evidence, mandelic acid is converted into phenylacetic acid under the same reaction conditions[327]. 

Phenyl-7-aminocoumarin is obtained by a Knoevenagel reaction of substituted saUcylaldehydes with phenylacetic acid or ben2yl cyanide. Further synthesis of the individual end products is carried out by usual procedures. 

Reactions of the Side Chain. Benzyl chloride is hydrolyzed slowly by boiling water and more rapidly at elevated temperature and pressure in the presence of alkaHes (11). Reaction with aqueous sodium cyanide, preferably in the presence of a quaternary ammonium chloride, produces phenylacetonitrile [140-29-4] in high yield (12). The presence of a lower molecular-weight alcohol gives faster rates and higher yields. In the presence of suitable catalysts benzyl chloride reacts with carbon monoxide to produce phenylacetic acid [103-82-2] (13—15). With different catalyst systems in the presence of calcium hydroxide, double carbonylation to phenylpymvic acid [156-06-9] occurs (16). Benzyl esters are formed by heating benzyl chloride with the sodium salts of acids benzyl ethers by reaction with sodium alkoxides. The ease of ether formation is improved by the use of phase-transfer catalysts (17) (see Catalysis, phase-thansfer). 

Diphenylbutadiene has been obtained from phenylacetic acid and cinnamaldehyde with lead oxide, by the dehydrogenation of l,4-diphenyl-2-butene with butyllithium, and by the coupling reaction of benzenediazonium chloride and cinnamyl-ideneacetic acid." The present method gives better yields than those previously reported, is adaptable to the preparation of a variety of substituted bistyryls, and is relatively easy to carry out. 

Condensation of an appropriately substituted phenylacetic acid with phthalic anhydride in the presence of sodium acetate leads to aldol-like reaction of the methylene group on the acid with the carbonyl on the anhydride. Dehydration followed by decarboxylation of the intermediate affords the methylenephthal-ides (12). Treatment of the phthalides with base affords directly the indandiones, probably via an intermediate formally derived from the keto-acid anion (13). The first agent of this class to be introduced was phenindandione (14) this was followed by anisindandione (1S) and chlorindandione (16). ... 

Phthalic anhydride is reacted with phenylacetic acid to form 3-benzylidenephthalide which is then hydrogenated to 2-phenethylbenzoic acid. Conversion to the acid chloride followed by intramolecular dehydrochlorination yields the ketone, 5H-dibenzo[a,d] cyclohepten-5-one. The ketone undergoes a Grignard reaction with 3-(dimethylamino)propyl chloride to give 5-(7-dimethylaminopropylidene)-5H-dibenzo[a,d] cycloheptene. 

A completely different dipolar cycloaddition model has been proposed39 in order to rationalize the stereochemical outcome of the addition of doubly deprotonated carboxylic acids to aldehydes, which is known as the Ivanov reaction. In the irreversible reaction of phenylacetic acid with 2,2-dimethylpropanal, metal chelation is completely unfavorable. Thus simple diastereoselectivity in favor of u f/-adducts is extremely low when chelating cations, e.g., Zn2 + or Mg- +, are used. Amazingly, the most naked dianions provide the highest anti/syn ratios as indicated by the results obtained with the potassium salt in the presence of a crown ether. 

Yamase and Goto406 determined first- and second-order rate coefficients for the aluminium chloride-catalysed reaction of halide derivatives of benzoic acid (lO5 = F, 1.73 Cl, 4.49 Br, 4.35 I, 0.81) and phenylacetic acid (105fc2 = F, 12 Cl, 21 Br, 9 I, 6) with benzene. The maxima in the rates for the acid chloride are best accommodated by the assumption that a highly (but not completely) polarised complex takes part in the transition state. Polarisation of such a complex would be aided by electron supply, and consistently, the acetyl halides are about a hundred times as reactive as the benzoyl compounds (see p. 180, also Tables 105 and 108). 

In the anodic decarboxylation of phenylacetic acid benzaldehyde is the major product (80%) at low current density (< 3.2mA/cm ). Its formation is supposed to occur by reaction of the intermediate benzyl radical with oxygen, which is possibly simultaneously generated at the anode [31]. 

As an example the deactivation of immobilised Pen G acylase, which catalyses the reaction of Pen G to 6-Aminopenicillanic acid and Phenylacetic acid, was studied. This enzyme was covalently bound on an ion-exchanger and cross-linked by glutaric aldehyde. To maintain a high reaction velocity, a neutral pH value (removal of Phenylacetic acid) and therefore the supply of NaOH and stirring for distribution of the base are required. 

The dehydration reaction of aldoxime to form nitriles using the resting cells of Rhodococcus sp. YH3-3 was optimized. We found that the enzyme was induced by aldoxime and catalyzed the stoichiometric synthesis of nitriles from aldoximes at pH 7.0 and 30°C. Phenylacetonitrile once synthesized from phenylacetaldoxime was hydrolyzed to phenylacetic acid, since the strain has nitrile degradation enzymes such as nitrile hydratase and amidase. We have been successful in synthesizing phenylacetonitrile and other nitriles stoichiometrically by a selective inactivation of nitrile hydratase by heating the cells at 40°C for 1 h. Various nitriles were synthesized under optimized conditions from aldoximes in good yields. 

Similarly, Pd/tppts was used by Hoechst (Kohlpainter and Beller, 1997) as the catalyst in the synthesis of phenylacetic acid by biphasic carbonylation of benzyl chloride (Fig. 2.29). The new process replaces a classical synthesis by reaction of benzyl chloride with sodium cyanide, followed by hydrolysis of the resulting benzyl cyanide. Although the new process produces one equivalent of sodium chloride, this is substantially less salt production than in the original process. Moreover, sodium cyanide is about seven times as expensive per kg as carbon monoxide. 

Highly reactive mixed anhydrides can also promote acylation. Phenylacetic acid reacts with alkenes to give 2-tetralones in TFAA-H3P04.55 This reaction involves an intramolecular Friedel-Crafts alkylation subsequent to the acylation. 

The Hammett equation is the best-known and most widely studied of the various linear free energy relations for correlating reaction rate and equilibrium constant data. It was first proposed to correlate the rate constants and equilibrium constants for the side chain reactions of para and meta substituted benzene derivatives. Hammett (37-39) noted that for a large number of reactions of these compounds plots of log k (or log K) for one reaction versus log k (or log K) for a second reaction of the corresponding member of a series of such derivatives was reasonably linear. Figure 7.5 is a plot of this type involving the ionization constants for phenylacetic acid derivatives and for benzoic acid derivatives. The point labeled p-Cl has for its ordinate log Ka for p-chlorophenylacetic acid and for its abscissa log Ka for p-chloroben-zoic acid. The points approximate a straight line, which can be expressed as... 

The hydrochloride of 3-amino-4-hydrazinopyridine 65 was prepared by reaction of the 4-chloro-3-nitropyridine derivative with ethoxycarbonyl-hydrazine in phenol to give the hydrochloride of ethyl 3-(3-nitro-4-pyridyl)carbazate 64 (R2 = OEt), which on successive heating in concentrated hydrochloric acid and hydrogenation over Pd/C gave 65. Its reaction with phenylacetic acid or with phenoxyacetic acid gave the hydrochloride... 

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