Indirect Electrochemical Synthesis of p-Hydroxyphenylacetic Acid

p-Hydroxyphenylacetic acids are used in the synthesis of pharmaceutical drugs such as atenolol, betaxolol, or bufexamac. In this work, the indirect ...
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Ind. Eng. Chem. Res. 2000, 39, 1-6

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APPLIED CHEMISTRY Indirect Electrochemical Synthesis of p-Hydroxyphenylacetic Acid† Marina Ingle´ s, Pedro Bonete, Eduardo Expo´ sito, Jose´ Gonza´ lez-Garcı´a, and Vicente Montiel* Departamento de Quı´mica-Fı´sica, Grupo de Electroquı´mica Aplicada, Facultad de Ciencias, Universidad de Alicante, Ap. correos 99, E-03080 Alicante, Spain

p-Hydroxyphenylacetic acids are used in the synthesis of pharmaceutical drugs such as atenolol, betaxolol, or bufexamac. In this work, the indirect electrosynthesis of p-hydroxyphenylacetic acid is carried out using the redox system Cr(II)/Cr(III) as a mediator. Effluents that are not contaminated by chromium salts are obtained because the reductant, Cr(II), can be electrochemically regenerated. Voltammetric and galvanostatic studies were performed to find the best reaction conditions for the reduction of Cr(III) to Cr(II). An “ex-cell” procedure has been used for this process. Current efficiency, for Cr(II) synthesis, higher than 90% was reached using a bismuth-doped carbon-felt electrode. In the chemical reduction of the p-hydroxymandelic acid by electrochemically generated Cr(II), the presence of a cosolvent, reaction temperature, and molar Cr(II)/p-hydroxymandelic acid relationship was investigated. High material conversion and nearly quantitative yield was obtained at 90 °C using 2-propanol as the cosolvent. 1. Introduction p-Hydroxyphenylacetic acids are used in the synthesis of pharmaceutical drugs such as atenolol, betaxolol, or bufexamac. Atenolol is used to treat cardiovascular diseases such as arterial hypertension, angina pectoris, cardiac arrhythmia, and acute myocardial infarction. Atenolol is a compound that blocks the heart’s β receptors to prevent excitatory compounds acting on heart cells.1 There exists a certain number of methods for the synthesis of p-hydroxyphenylacetic acid (phpaa) by reduction of p-hydroxyphenylmandelic acid (phma), for example, using Cr(II)2 obtained by reduction of Cr(III) with Zn/HgCl2, with tin salts in hydrochloric acid,3 with phosphorous acid in the presence of a catalytic amount of iodine,4 with red phosphorus in hydroiodic acid,5 by catalytic hydrogenation over Pd/C,6 and finally with bisulfite/formic acid or dithionite.7 All these processes present disadvantages because of contamination of effluents or the high cost of reagents and catalysts or because an autoclave is required. Despite the advantages offered by electrochemistry in the organic synthesis field,8,9 only a process for the obtention of phpaa by electrochemical reduction of phma has been described in the literature. It is a direct process with compartment separation that uses an aqueous sulfuric acid solution as the anolyte and an organic solvent with triethylammonium citrate as the supporting electrolyte in the catholyte.10 In past decades a great number of indirect electrochemical syntheses using mediator systems procedures for the reduction as well * To whom correspondence should be addressed. Phone: (+34)965903628.Fax: (+34)965903537.E-mail: [email protected]. † A preliminary account of this work was presented at the 50th ISE Meeting, Pavia, Italy, Sept 5-10, 1999.

as oxidation reactions has appeared.11-17 However, this useful tool has not been used in the reduction of phma. In this paper the research of the direct and indirect reduction reaction of phma to obtain phpaa is described. The direct reduction reaction has been studied using an aqueous medium at acidic, neutral, and basic pH and the electrocatalytic effect of some electrodes has been studied too. In the indirect electrosynthesis of phpaa, Cr(II) has been used as a mediator following an ex-cell method (Figure 1). The “ex-cell” mode applied to this process consists of the electrogeneration of a Cr(II) solution, from Cr(III), which it is used for the reduction of phma. After work up, phpaa and a Cr(III) solution are obtained. The Cr(III) solution can be reused for the electrogeneration of the initial Cr(II) solution. This process can be run in a closed loop; thus, there are no problems with effluents contaminated by chromium salts. In summary, the present work consists of two parts. The feasibility of the direct electrochemical reduction of the phma was assessed on the first part. The second part points out the indirect reduction of the phma by electrochemically generated Cr(II). Voltammetric and galvanostatic studies were performed to find the best reaction conditions for Cr(II) generation. 2. Experimental Section 2.1. Chemicals. All reagents were of the best grade (Merck, Aldrich, Fluka, Sigma, and Panreac) and were used as received. Sodium p-hydroxymandelate was used from Prodesfarma SA. Deionized or ultrapure water (Millipore MiliQ + Organex) was used in the preparation of all solutions. 2.2. Instrumentation. Voltammetric curves were recorded on a Voltalab-32 radiometer with a DEA-I potentiostat and IMT-101 electrochemical interface or

10.1021/ie990524b CCC: $19.00 © 2000 American Chemical Society Published on Web 01/04/2000

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Figure 1. Electrochemical indirect reduction of the phma using the Cr(II)/Cr(III) redox system.

on a programmable signal generator EG & G Model 175, Amel Model 553 potentiostat, and a XY Philips Model PM8133 chart recorder. All potential values are given versus the standard calomel electrode (SCE) reference. Cathodic currents are negative in the current densitypotential (j-E) curves shown. Cr(III) reduction was carried out at constant a current supplied by an AMEL 2055 power supply. 2.3. Electrodes. The working electrodes used in the voltammetric study were a 0.13-cm2 nickel rod (Goodfellow, 99.98%), a 0.07-cm2 graphite rod (CV25 Sofacel, Le Carbone Lorraine), and a 0.07-cm2 polyoriented platinum bead (Goodfellow, 99.95%). The platinum working and counter electrodes were thermally treated as usual and cooled in air protected by a droplet of ultrapure water.18 Ni and graphite electrodes were treated as previously described.19 2.4. Electrochemical Reduction of the phma. The voltammetric study was carried out in a classical glass cell using a platinum counter electrode. The direct electrochemical reduction of phma in aqueous solution was studied by recording current density-potential curves. Attempts to reduce phma electrochemically were made using graphite, nickel, and polycrystalline platinum electrodes in acid (0.5 M H2SO4), basic (0.2 M NaOH), and neutral-buffered (0.1 M NaH2PO4/NaOH) media. The indirect electrochemical reduction of phma in aqueous solution on a graphite electrode was studied by cyclic voltammetry using Cr(III)/Cr(II) as a mediator in acidic media (HCl or H2SO4). The influence of the acid nature, acid and mediator concentration, and the presence of a catalyst on the electrochemical reduction of Cr(III) has been investigated. 2.5. Electrochemical Generation of the Mediator. The experimental setup shown in Figure 2 was used to carry out the generation of Cr(II) by reduction of Cr(III). It comprises two jacketed glass solution reservoirs (350 mL), an electrochemical homemade filter-press reactor (UA63.10), two circulation pumps (Nikkiso Eiko Co. Ltd Model CP08-PPRV-24) with polypropylene bodies, and gas measurement systems. All interconnecting tubing was made of flexible PVC having an internal diameter of approximately 12 mm. Catholyte solution was bubbled with nitrogen to remove all the oxygen dissolved. The UA63.10 filter-press reactor is shown in Figure 3. In this design the electrodes were attached to its corresponding EPDM (ethylene-poly(propylene)-diene monomer) plate; polypropylene frames were used for the solution inlet and outlet and for internal flow distributors. Silicone gum and EPDM gaskets were used. The interelectrode gap was ≈12 mm. The 63-cm2 projected area electrodes used were a lead dioxide on platinized expanded titanium sheet anode20 and a carbon felt (RVC

Figure 2. Experimental setup for the electrochemical generation of the Cr(III)/Cr(II) redox system: (1) Tank of anolyte solution; (2) tank of catholyte solution; (3) electrolytic cell, UA63.10; (4) recirculating pumps; (5) gas measurement systems; (6) nitrogen inlet.

Figure 3. Electrolytic UA63.10 filter-press cell: (1) Backplate; (2) elastomer; (3) anode; (4) EPDM gasket; (5) SCE reference electrode; (6) distributor; (7) membrane; (8) silicone gasket; (9) carbon felt; (10) graphite collector.

4002 Le Carbone Lorraine) cathode with a graphite collector. A Nafion 450 cationic membrane separated the anolyte and catholyte compartments. 2.6. phpaa Synthesis. The reduction of phma was carried out in a jacketed-150 mL reactor fitted with a Liebig condenser by adding sodium p-hydroxymandelate and 2-propanol to the electrochemically generated Cr-

Ind. Eng. Chem. Res., Vol. 39, No. 1, 2000 3

(II) solution. The influence of reaction temperature and phma/Cr(II) molar ratio was studied. Samples taken were analyzed by HPLC on a HewlettPackard 1050 series with a HP 1040M diode array detector with the following conditions: nucleosil column (OTO-B7499); wavelength, 254 nm; eluant, water/ methanol 7/3 volume; rate, 1 mL/min. In a typical experiment, the reduction of phma was carried out by adding sodium p-hydroxymandelate (4.75 g, 50 mmol) and PriOH (35 mL) to the electrochemically generated Cr(II) solution (50 mL) at 80 °C and the reaction mixture was stirred magnetically for 4.5 h under positive nitrogen pressure. Then, 2-propanol was removed at reduced pressure (15 Torr) and the reaction mixture was then extracted with diethyl ether (3 × 50 mL), saving the aqueous layer which contains the Cr(III) salts for its later regeneration. The ethereal phases were unified, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by column chromatography. Identification of the products was performed by comparative retention times measurements, IR, GC-MS, and 1H and 13C NMR. 3. Results and Discussion 3.1. Electrochemical Reduction of the phma. Voltammetric Study. Attempts to reduce phma electrochemically were made using graphite, nickel, and polycrystalline platinum electrodes at acid (0.05 M phma in 0.5 M H2SO4), basic (0.05 M phma in 0.2 M NaOH), and neutral-buffered (0.05 M phma in 0.1 M NaH2PO4/NaOH) media. No current peaks attributable to phma reduction were obtained in the voltammetric curves recorded (not shown), although it may occur together with intensive hydrogen evolution. If the direct electrochemical reduction occurs, it will not be efficient on these electrodes in the media studied. Regardless of the voltametric results, electrolyses were done on these conditions but no reduction of phma was obtained. 3.2. Indirect Electrochemical Reduction of phma. Voltammetric Study. The purpose of this study was to determine the indirect electrochemical reduction method as well as to define the experimental conditions for generating the mediator Cr(II) solution. Indirect electrochemical reactions can be performed in two ways, in an “in-cell” or “ex-cell” process, depending on the kinetics of the process, stability of the substrate or products, inactivation of the electrodes, and so forth.11 The study of the electrochemical reduction of Cr(III) was carried out on a graphite electrode in an acid medium where the mediator is chemically stable. First, the influence of the acid nature on the electrocatalysis and reversibility of the Cr(III)/Cr(II) redox system was studied. Figures 4 and 5 show the voltammetric curves obtained for hydrochloric and sulfuric acid, respectively. Cr(III) can be reduced at -0.8 V in a hydrochloric acid or sulfuric acid medium but no good current efficiency values can be expected because the hydrogen evolution process occurs simultaneously. Lower reversibility for Cr(III)/Cr(II) in a sulfuric acid medium is obtained (Figure 5b) and the oxidation of Cr(II) occurs at -0.22 V whereas -0.38 V was obtained in hydrochloric acid (Figure 4b). Previous works from our laboratory21 showed the electrocatalytic effect of the bismuth-doped graphite electrode on the Cr(III) reduction in hydrochloric acid. The addition of Bi2O3 (2 × 10-3 M) into the 0.1 M CrCl3 in 1 M HCl solution produced the electrodeposition of

Figure 4. Voltammetric curves for the Cr(III)/Cr(II) redox system in 1 M hydrochloric acid over graphite or bismuth-doped graphite electrodes: (a) 1 M HCl; (b) 0.1 M Cr(III) and 1 M HCl; (c) 2 × 10-3 M Bi(III), 0.1 M Cr(III), and 1 M HCl. Scan rate, 50 mV/s.

Figure 5. Voltammetric curves for the Cr(III)/Cr(II) redox system in 1 M sulfuric acid over graphite and bismuth-doped graphite electrodes: (a) 1 M H2SO4; (b) 0.1 M Cr(III) and 1 M H2SO4; (c) 2 × 10-3M Bi(III), 0.1 M Cr(III), and 1 M H2SO4. Scan rate, 50 mV/ s.

bismuth at -0.26 V on the cathodic polarization of the electrode (Figure 4c). On the bismuth-doped graphite electrode Cr(III) reduction occurs at -0.69 V, 0.2 V higher than hydrogen evolution. During the positive sweep the Cr(II) oxidation current peak appears at -0.57 V and a current peak at -0.18 V, with a typical stripping shape, for the Bi oxidation was obtained. In a sulfuric acid medium (Figure 5), a lower amount of Bi is electrodeposited on the cathodic polarization at -0.16 red V. Thus, lower reversibility [∆(Eox p - Ep ) ) 0.37 V] and the current density are achieved using the same conditions for the Cr(III)/Cr(II) couple. Figure 6 shows the voltammograms obtained for 0.5 M phma, 2 × 10-3 M Bi2O3 in 1 M HCl or 1 M H2SO4. In a hydrochloric acid medium the presence of phma does not have remarkable influence on the Bi(III)/Bi0 redox system. Their current peaks appear nearly at the

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Figure 6. Voltammetric curves for the Cr(III)/Cr(II) redox system in 1 M hydrochloric acid (a) and 1 M sulfuric acid (b) over a bismuth-doped graphite electrode in the presence of 0.5 M phma. Scan rate, 50 mV/s.

same potential with the same current densities (Figure 6a). There are not big variations obtained on the Cr(III)/Cr(II) redox system either. Charge measurements of the reduction and oxidation peaks (1.40 mC, -0.8 V and 1.47 mC, 0.52 V for reduction and oxidation peaks, respectively, Figure 6a reveals no reaction between Cr(II) and phma. Slow kinetics is expected for this reaction at room temperature. Therefore, an “in-cell” indirect method will not be appropriate for this process and the “ex-cell” method should be used. In a sulfuric acid medium (Figure 6b) in the presence of phma the reduction of Cr(III) occurs at more negative potentials, with the hydrogen evolution, and the reversibility of the redox system decreases seriously. According to these features, the “in-cell” method cannot be used in a sulfuric acid medium either. At this point, the “excell” method appears as the only suitable method for the indirect electrochemical reduction of the phma, using Cr(II) as a mediator. It consists of two steps that can be optimized independent of each other, the electrogeneration of the mediator and the chemical reaction with the substrate. Therefore, according to the obtained results, hydrochloric acid as a supporting electrolyte seems more suitable for the electrogeneration of Cr(II) than sulfuric acid. Figure 7 shows the voltammograms obtained from 0.1 M CrCl3 and 2 × 10-3 M Bi2O3 in different concentrations of hydrochloric acid solutions. A lower quantity of bismuth is electrodeposited in 0.4 M HCl solution and poorer reversibility of the Cr(III)/Cr(II) system is obtained. Peaks at -0.81 V and 8.8 mA/cm2 for the reduction and -0.46 V and 5.7 mA/cm2 for the oxidation process were observed (Figure 7a). For 1 and 3 M HCl solutions (Figure 7b,c, respectively), both current density and reversibility are very similar for the Cr(III)/ Cr(II) redox system; nevertheless, the Bi(III)/Bi0 pair appears at more negative potentials for the 3 M HCl solution. A maximum current density peak of 16.8 and 15.7 mA/cm2 at -0.69 V was obtained for the reduction of Cr(III) in 1 and 3 M HCl solutions, respectively. In the oxidation sweep, the maximum current density peaks of 8.4 mA/cm2 at -0.57 V for the 1 M HCl solution

Figure 7. Voltammetric curves for the Cr(III)/Cr(II) redox system in different hydrochloric acid solutions over a bismuth-doped graphite electrode: 2 × 10-3 M Bi(III), 0.1 M Cr(III), and (a) 0.4 M HCl, (b) 1 M HCl, and (c) 3 M HCl. Scan rate, 50 mV/s.

Figure 8. Voltammetric curves for the Cr(III)/Cr(II) redox system in 3 M hydrochloric acid over bismuth-doped graphite electrodes: 2 × 10-3 M Bi(III), 3 M HCl, and (a) 0.1 M Cr (III) and (b) 0.5 M Cr(III). Scan rate, 50 mV/s.

and 9.8 mA/cm2 at -0.55 V for the 3 M HCl solution were obtained. Therefore, high HCl concentrations produce a high reversibility and high current density of the Cr(III)/Cr(II) redox system. Because the high current densities are needed for industrial purposes, the influence of the Cr(III) concentration in the reversibility and current peaks was studied. Figure 8 shows the voltammograms obtained for 3 M HCl, 2 ×10-3 M Bi2O3, and 0.1or 0.5 M CrCl3 solutions (Figure 8a,b, respectively). The highest Cr(III) concentration used the lower reversibility and the higher current densities were obtained. 3.3. Electrochemical Generation of the Cr(II) Solution. The electrochemical preparation of the Cr(II) solution was performed galvanostatically at room temperature using the setup showed in Figure 2. The catholyte (250 mL) was a 1 M CrCl3 and 2 × 10-3 M

Ind. Eng. Chem. Res., Vol. 39, No. 1, 2000 5 Table 1. Reaction Temperature Influence of the Reduction of phma with Cr(II) Using the Stoichiometric Relationship

Table 2. Reaction Temperature Influence of the Reduction of phma with Cr(II) Using a 1:3 Molar Relationship

entry

T (°C)a

p-hydroxymandelic acid (%)b,c

Θphpaa (%)c,d

entry

T (°C)a

p-hydroxymandelic acid (%)b,c

Θphpaa (%)c,d

1 2 3 4 5 6

40 50 60 70 80 90

100 100 57 41 50 11

0 0 11 24 40 80

1 2 3 4 5

40 50 60 70 90

100 100 77 48 12

0 0 56 73 92

a

Bathtemperature. b Unreactedp-hydroxymandelicacid. c HPLC. d 100 × (mol of phma converted to phpaa)/total mol of phma consumed.

Bi2O3 in a 3 M HCl solution whereas the anolyte (150 mL) contained a 1 M sulfuric acid solution. The only competitive electrochemical reaction is the reduction of H+; thus, the hydrogen evolved was measured during the electrolysis and it was used for calculation of the Cr(II) concentration and the percentage current efficiency [ΦCr(II)%] value defined by

ΦCr(II)% ) [(QT - QH)/QT] × 100 where QT is the total charge passed and QH is the charge used in hydrogen evolution. In all the experiments the theoretical charge [1 F/mol of Cr(III)] was passed. To optimize the current efficiency and the reaction time, several current programs were studied. These two parameters have a significant influence on the cost and production of the electrochemical process. It should be desirable to have high production with low electrical cost. High constant currents give short reaction times and then the production could be increased; however, when high constant currents are used, current efficiencies lower than 100% should be expected. When electrolysis was carried out at constant current of 50 mA/cm2, a 60% current efficiency was obtained in the generation of Cr(II) whereas 90% was reached when 50 mA/cm2 was used until the current circulating was 40% of the theoretical charge and then 25 mA/cm2 was used. Higher current efficiencies can be reached using lower current densities but it would mean long reaction times. 3.4. Reaction of Cr(II) with phma. From voltammetric data it was concluded that the kinetics of phma reduction with Cr(II) is not very fast, so it is not interesting to carry it out when the mediator is being generated in the electrochemical reactor. Using the indirect “ex-cell” procedure chemical and electrochemical steps can be optimized independent of each other. Cosolvents are required to increase the solubility of the reactants and products in the reaction medium; in this way, isopropyl alcohol has been used, giving good results. Isopropyl alcohol is largely soluble in water and chemically stable in the reaction medium. The best results were found in a 6:4 Cr(II) electrogenerated solution/isopropyl alcohol ratio. A wide study of reaction temperature could be done because the aqueous isopropyl alcohol solutions have a boiling point close to 95 °C. Table 1 shows the results obtained for the reduction of phma using a 1:2 phma/Cr(II) molar relationship at different temperatures. A 4.5-h reaction time was used in all reactions. No reaction occurs between phma and Cr(II) at temperatures lower than 50 °C and only a moderate

a Bathtemperature. b Unreactedp-hydroxymandelicacid. c HPLC. 100 × (mol of phma converted to phpaa)/total mol of phma consumed.

d

material conversion as well as a percentage chemical yield were obtained at 60 °C. At higher temperatures the unreacted starting material decreases quickly, although from 70 to 80 °C the amount of unreacted phma increases slightly. No efforts were made to explain that fact because of the good results obtained for the 90 °C reaction. When higher temperatures were used, chemical yields were enhanced too. Afterward, the influence of the reaction temperature was studied using an excess of reductant. A 6:4 Cr(II) solution/isopropyl alcohol volume ratio was used and the molar relationship between phma and Cr(II) was 1:3. The results are shown in Table 2. No conversion was observed either at temperatures lower than 50 °C. Low quantities of unreacted phma remained when the temperature was increased. No insoluble chromium compounds were observed in both cases, 1:2 and 1:3 molar relationships. Comparing the data obtained of material conversion and percentage material yield at the same temperature using a different stoichiometric relationship, there are no remarkable differences in the unreacted phma at both temperatures, whereas the chemical yield is considerably increased when an excess of reductant was employed. This behavior is clearer at low temperatures where the reacted phma is minimal. The chemical yield obtained at different temperatures indicates the existence of secondary products. This point was confirmed from the HPLC analysis where four peaks were detected. Two of them were attributed to phma and phpaa because they have the same retention times as authentic samples. The byproducts were isolated and identified corresponding to the isopropyl ester of both the starting and final products. Finally, these compounds were quantitatively analyzed in the reactions carried out at 90 °C, where the best yields were found to make a mass balance. Taking into account the isopropyl esters formed, if we consider the unreacted starting material such as phma and its isopropyl ester, for the reaction performed at 90 °C using an excess of reductant, only 15% of the starting material remained unreacted and a nearly quantitative chemical yield was obtained. 4. Conclusions The simplest method for obtaining phpaa from phma, a direct electrochemical reduction, unfortunately has not been accomplished by using the studied nickel, graphite, or platinum electrodes in an aqueous medium. Nevertheless, the present investigation demonstrates the feasibility of phpaa synthesis from phma using an excell process where two steps, an electrochemical and a chemical reaction, are combined. In the electrochemical

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step Cr(II) is obtained by reducing Cr(III). Moreover, the conditions for electrogenerating Cr(II) solutions are general and can be used for other processes. The big advantage of the electrochemical generation of Cr(II) compared with ordinary chemical procedures using Zn/ Hg is the effective contribution to pollution control. Because of the direct electron transfer, it avoids the problem of separation and waste treatment of the poisonous end products of the chemical reductant (Zn and Hg ions). In the chemical step of the ex-cell process phma has been reduced by the electrochemically generated Cr(II). We have tried to combine the two steps in only one process (in-cell method), but the slow reaction rate of the substrate reduction made that useless. Current efficiency, for Cr(II) synthesis, higher than 90% was reached using a bismuth-doped carbon-felt electrode and a current density of 50 mA/cm2 until 40% of the theoretical charge was circulated and then 25 mA/ cm2 until 100% was circulated. The second part of the process points at the chemical reduction of the p-hydroxymandelic acid by the electrochemically generated Cr(II). A great effect of the temperature on the reduction reaction rate was observed. For temperatures lower than 90 °C the kinetics of the reaction is very slow; in fact, at 50 °C no phpaa was detected for a 4.5-h reaction time, even when more than the stoichiometric Cr(II) was used. When a 1:3 molar relationship between phma and Cr(II) was used, a higher reduction reaction rate was obtained. So high temperatures and more than the stoichiometric Cr(II) should be used to increase the reaction rate. High material conversion and nearly quantitative yield was obtained at 90 °C and a 1:3 phma/Cr(II) molar relationship using 2-propanol as the cosolvent. Finally, the phma reduction is an example of a doublemediator process where two catalysts are used to obtain phpaa. First, bismuth has an electrocatalytic effect on the Cr(III) reduction, and second , Cr(II) is used on the reduction of phma. The next stage of the research should be focused not only on checking the synthesis conditions, obtained in this viability stage, in pilot plant scale reactors but also on modeling both the electrochemical and chemical processes with the goal of trying a hypothetical implantation of the industrial process. Literature Cited (1) Burger, A. J.; Kamalesh, M.; Kumar, S.; Nesto, R. Effect of Beta Adrenergic Receptor Blockade on Cardiac Autonomic Tone in Patients with Chronic Stable Angina. Pacing. Clin. Electrophysiol. 1996, 19, 411. (2) Edwards, Ph. N. Process for the Manufacture of p-Hydroxyphenyl Acetic Acid. U.S. Patent 4,198,526, 1978.

(3) Mitchell, A.; Bailey, T. p-Hydroxyphenylacetic Acid. Br. Patent 2,078,718, 1982. (4) Vallejos, J. C.; Christidis, Y. Process for the Preparation of Alkanoic Acids. Eur. Patent 0,221,815, 1986. (5) Spielmann, W.; Schaeffer, G. Process for the Manufacture of p-Hydroxyphenyl Acetic Acid. U.S. Patent 4,590,295, 1985. (6) Edwards, Ph. N. p-Hydroxymandelic Acid. Ger. Patent 2,820,854, 1982. (7) Vallejos, J. C.; Legrand, O.; Christidis, Y. A New System for the Reduction of 4-Hydroxymandelic Acids. Bull. Soc. Chim. Fr. 1997, 134, 101. (8) Organic Electrochemistry: An Introduction and a Guide; Lund, H., Baizer, M. M., Eds.; Marcel Dekker: New York, 1991. (9) Technique of Electroorganic Synthesis, Part III; Weinberg, N. L., Tilak, B. V., Eds.; Wiley-Interscience: New York, 1982. (10) Tsunehiko, M.; Yoshihisa, T.; Hiroyasu, H. Manufacture of 4-Substituted Phenyl Acetic Acid. JP Patent 58,117,886, 1983. (11) Steckhan, E. Organic Syntheses with Electrochemically Regenerable Redox Systems. In Topics in Current Chemistry, Electrochemistry I Vol. 142; Steckhan, E., Ed.; Springer-Verlag: Berlin, Heidelberg, 1987. (12) Wagenknecht, J. H.; Coleman, J. P.; Hallcher, R. C.; McMackins, D. E.; Rogers, T. E.; Wagner, W. G. Electrogeneration of Mn(III) in an Undivided Cell. J. Appl. Electrochem. 1983, 13, 535. (13) Kuhn, A. T.; Birkett, M. Current Efficiency Losses in Indirect Electrochemical Processing. J. Appl. Electrochem. 1979, 9, 777. (14) Fleischmann, M.; Pletcher, D.; Rafinski, A. Kinetics of the Silver (I)/Silver (II) Couple at a Platinum Electrode in Perchloric and Nitric Acids. J. Appl. Electrochem. 1971, 1, 1. (15) Comninellis, Ch.; Plattner, E.; Javet, Ph. Preparation of 1-Nitroanthraquinone. J. Appl. Electrochem. 1979, 9, 753. (16) Lapicque, F.; Stork, A. Use of a Phase Transfer Agent in a Mediated Electrochemical Process. Application to the Oxidation of 4-Nitrotoluene. Electrochim. Acta 1985, 30, 1247. (17) Wendt, H.; Schneider, H. Reaction Kinetics and Reaction Techniques for Mediated Oxidation of Methylarenes to Aromatic Ketones. J. Appl. Electrochem. 1986, 16, 134. (18) Clavilier, J.; Armand, D.; Sun, S. G.; Petit, M. Electrochemical Adsorption Behavior of Platinum Stepped Surfaces in Sulfuric Acid Solutions. J. Electroanal. Chem. 1986, 205, 267. (19) Gonza´lez-Garcı´a, J.; Iniesta, J.; Aldaz, A.; Montiel, V. Effects of Ultrasound on the Electrodeposition of Lead Dioxide on Glassy Carbon Electrodes. New J. Chem. 1998, 22, 343. (20) Gonza´lez-Garcı´a, J.; Montiel, V.; Sa´nchez-Cano, G.; Aldza, A. Nuevos Electrodos de Dio´xido de Plomo, Procedimiento para su Preparacio´n y sus Aplicaciones. Sp. Patent P9,401,259, 1994. (21) Lo´pez-Atalaya, M. M. Estudio Electroquı´mico de Diferentes Electrodos para el Sistema Cr(III)/Cr(II). Desarrollo de un Prototipo de Acumulador Redox Fe/Cr de 4V. Ph.D. Dissertation, Universidad de Alicante, Alicante, Spain, 1991.

Received for review July 16, 1999 Revised manuscript received October 20, 1999 Accepted November 22, 1999 IE990524B