Influence of the nature of the substrate and of operative parameters in the electrocarboxylation of halogenated acetophenones and benzophenones

Electrochimica Acta 50 (2005) 3231–3242

Influence of the nature of the substrate and of operative parameters in the electrocarboxylation of halogenated acetophenones and benzophenones Onofrio Scialdone, Alessandro Galia1 , Chiara La Rocca, Giuseppe Filardo∗,1 Dipartimento di Ingegneria Chimica dei Processi e dei Materiali, Universit`a di Palermo, Viale delle Scienze, 90128 Palermo, Italy Received 3 September 2004; received in revised form 4 November 2004; accepted 29 November 2004 Available online 19 January 2005

Abstract The electrocarboxylation of halogenated acetophenones and benzophenones to the corresponding hydroxycarboxylic acids has been carried out in undivided cell equipped with aluminium sacrificial anode and using 1-methyl-2-pyrrolidinone (NMP) as the solvent. The radical anion generated by the electro-reduction of the aromatic ketone is involved in several competitive reactions which lead to the formation of the target hydroxycarboxylic acid, the corresponding alcohol and pinacol and the de-halogenated parent ketone. If sufficiently negative working potentials are imposed, the latter is reduced to the corresponding carboxylate, pinacol and alcohol. Very different results in terms of selectivity and faradic efficiency in the target hydroxycarboxylic acids were obtained when the substrate was changed. Higher selectivities were obtained with chlorobenzophenones with respect to the homo-substituted chloroacetophenones as a result of a less relevant formation of dehalogenated compounds, alcohols and pinacols. The cleavage of the carbon–halogen bond was, moreover, more favoured by changing from meta to para to ortho isomer and from fluoro to chloro to bromo derivatives. The performances of the process have been found to be strongly dependent on the adopted values of temperature, substrate concentration and working potential. © 2004 Elsevier Ltd. All rights reserved. Keywords: Electrocarboxylation; Halobenzophenones; Haloacetophenones; Reductive dehalogenation; Radical anions

1. Introduction Carbon dioxide can be proposed as a central building block in organic synthesis. Its low cost and its facile reaction with carbanions explain why many efforts have been made in order to obtain speciality chemicals by carbon dioxide insertion in organic molecules. Carbanions can be easily generated by the electrochemical reduction of organic halides [1] or aromatic ketones. Hence, the electrocarboxylation of these compounds is potentially an easy way to prepare carboxylated products, some of them of industrial interest, particularly for the production of anti-inflammatory drugs. Moreover, the electrochemical route presents the advantage of not using phosgene and cyanides. This explains why many efforts have been made in the last fifty years in ∗ 1

Corresponding author. Tel.: +39 091 6567257; fax: +39 091 6567280. E-mail address: [email protected] (G. Filardo). ISE member.

0013-4686/$ – see front matter © 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.electacta.2004.11.059

order to investigate mechanistic and preparative aspects of the electrocarboxylation of ketones to the corresponding 2-hydroxy-2-aryl propionic acids (see Eq. (1)) both in divided [2] or undivided [3–6] cells. In particular, very promising results were obtained in undivided cells equipped with sacrificial anodes.

In recent years, different studies have shown that it is possible to produce with high yields the 2-hydroxy2-(6-methoxy-2-naphthyl) propionic acid, the precursor of Naproxen® , by the electrocarboxylation, in bench and pilot scale in undivided cell equipped with aluminium sacrificial anodes, of the 6-methoxy-2-acetonaphtone [7–9]. Good results were achieved also in the electrocarboxylation of 2-ethanoylnaphtalene to the correspondent hydroxy acid [10]. The above-mentioned electrochemical methodology appeared very interesting from an applicative point of

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Scheme 1.

view on the basis of the versatility and wide applicability of the method, the large choice of electrocarboxylation reactions of commercial interest in the fine chemistry field and the possibility of employing the same reaction system for several analogous reactions [11]. Otherwise, although in principle widely applicable, the process has been tested up to now only on a restricted number of ketones. To this purpose, a systematic research aimed to give a complete definition of the influence of the nature of the substrate on the process is currently under development by the authors. In a previous study, we have shown that the performances of the electrocarboxylation of substituted alkyl phenyl ketones, acetonaphtone and benzophenones strongly depends on the nature of the substrate [12]; lower yields in the carboxylate are obtained with substituted alkyl phenyl ketones, high yields with the corresponding benzophenones and intermediate results with 6-methoxy-2-acetonaphtone. For the above-mentioned substrates, in the adopted experimental conditions, the most relevant products of the synthesis were the hydroxy acids and the correspondents alcohols and pinacols. As an extension of this work, we report here the electrocarboxylation of halogenated acetophenones and benzophenones. For these substrates, the possibility of the expulsion of the halide ion from the radical anion generated by the reduction of the substrate, leading to the de-halogenated parent ketones, may complicate the reaction pathway. In the last decades, it was, in fact, shown by many researchers that the electroreduction of halo substituted acetophenones and benzophenones often involves the loss of an halide anion with the formation of de-halogenated compounds. In 1970, Fry et al. [13] observed that the electrolyses of 3-bromoacetophenone and 4-bromo-␥-chlorobutyrophenone, respectively, afford acetophenone and ␥-chlorobutyrrophenone virtually quantitatively. It has been shown that the ketyl radical anion generated by the reduction of halogenated ketones is involved in a unimolecolar cleavage reaction with the formation of the aryl radical [14–16]. The radical, can on its turn, abstracts an hydrogen atom from the solvent or be reduced, homogeneously or heterogeneously, to a carbanion, which is then rapidly protonated. Ikeda and Manda [17] have shown that it is possible to carboxylate halogenated benzophenones, in the presence of

saturation concentration of carbon dioxide, with high yields in products by using a mercury cathode in a glass frit divided cell equipped with a platinum anode. Those authors reported that the C Cl bond cleavage, which is commonly observed in the electrochemical reduction of 4-chlorobenzophenone in N,N-dimethylformamide (DMF), did not occur in the abovementioned system. In contrast, 4-bromobenzophenone gave benzylic acid in 30% yield, which resulted as a consequence of the reductive cleavage of the C Br bond. In spite of the quite high reported yields in carboxylic derivatives, the use of the highly toxic mercury cathode made the system impractical for its development into a commercially useful process. Recently Isse et al. [18] investigated the electrochemical reduction of some mono and bi-halogenated benzophenones in the absence and in the presence of carbon dioxide in undivided cells equipped with sacrificial anodes. In the presence of carbon dioxide the main product was, always, the target hydroxyacid. The results reported here refer to a systematic investigation on the influence of the nature of the substrate on the performances of the electrocarboxylation process of aceto and benzophenones performed in undivided cell equipped with aluminium sacrificial anode. To this purpose, the electroreduction of numerous ketones in the absence and in the presence of carbon dioxide was studied in detail. The compounds investigated are shown in Scheme 1. It should be emphasized as high selectivity and faradic efficiency are relevant figures of merit in order to achieve a sustainable electrochemical process competitive with the conventional ones. Hence, we have, furthermore, investigated the influence of various synthetic parameters on the performances of the process with the aim of optimising the selectivity and the faradic efficiency in the target hydroxycarboxylic acid.

2. Experimental 2.1. Electroanalytical procedure The electroanalytical experiments were carried out in N,N-dimethylformamide (DMF) or N-methyl-2-pyrrolidone (NMP) with 0.1 M tetrabutylammonium bromide (Bu4 NBr)

O. Scialdone et al. / Electrochimica Acta 50 (2005) 3231–3242

as the supporting electrolyte, a platinum disc as the working electrode (area, 3.14 mm2 ), a platinum spiral as the counter electrode and SCE or Ag/AgI/I− 0.1 M in DMF as the reference electrode. Potential scan were performed by an AMEL System 5000 potentiostat and oscilloscope Nicolet 3091 for data acquisition. 2.2. Electrosynthesis Potentiostatic electrolyses were performed in undivided tank glass cells with coaxial cylindrical geometry equipped with a gas inlet, an Ag/AgI/I− 0.1 M DMF reference electrode, a 99.99% aluminium sacrificial anode and a graphite cathode. The volume of the electrolytic solution was of 50 mL. The cathode was constituted by a cylinder of compact graphite (1.5 cm diameter) and the counter electrode was cut from a 4 cm inner diameter 99.99% aluminium tube with a wall thickness of 2 mm (interelectrode gap of 1.25 cm) that were assembled in the cell with coaxial geometry. The volume of the electrolytic solution was of 50 mL, which in the adopted cell corresponds to a wetted cathode surface of 10 cm2 . Aluminium electrodes were treated with 20% (w/w) aqueous hydrochloric acid, then carefully washed with distilled water and acetone and finally dried with nitrogen. The graphite electrodes were washed with distilled water and acetone, then mechanically polished with sand paper and treated by heating to a red colour prior to use. The counter electrode reaction was the anodic dissolution of the aluminium electrode. The electrolytic solution was stirred by a cylindrical teflon coated magnetic stir bar and by the continuous bubbling of feeded carbon dioxide. Considering the small volume (about 50 cm3 ) of the reaction mixture, and turbulence promoter effect of the electrodes and of the carbon dioxide diffuser it is reasonable to assume a mixing condition which is intermediate between natural convection and perfect mixing of the liquid phase. The apparatus used to supply electric power in preparative scale experiments was an AMEL Model 533 potentiostat equipped with an AMEL Model 731 coulometer. Identification of products was performed using high performance liquid chromatography (HPLC) by comparison with commercial standards or by GC–MS analyses. An HPLC instrument (Perkin Elmer 410 LC) equipped with a UV detector and Supelco LC8 and LC18 columns was employed. The eluent was a mixture of MeCN and water, acidified with CH3 COOH. GC–MS analyses were carried out by using a Perkin Elmer Turbomass and Autosystem XL chromatograph, equipped with a SGE capillary column. Products concentrations were evaluated by HPLC. Although the main carboxylation products were easily identified and quantified by this approach, in a few cases it was not possible the identification of some by-products, especially alcohols and acids derived from dehalogenated ketones. In such cases, the analyses were repeated after separation of the products according to a procedure already described elsewhere [18].

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The acidic components were identified as methylated derivatives. 2.3. Reagents N,N-Dimethylformamide (DMF) and N-methyl-2pyrrolidone (NMP) anhydroscan from Labscan (maximum water content, 100 ppm) were used as solvents without further treatment. The ammonium salt Bu4 NBr was crystallized twice from ethyl acetate. Ketones were purchased from Aldrich and used as received; carbon dioxide was Air Liquide 4.8. 3. Results and discussion 3.1. Electroanalytical results 3.1.1. Experiments performed in the absence of CO2 The electroanalytical behaviour of halo aceto and benzophenones in aprotic solvents has been widely described previously in the literature [14–21,23–32]. The investigated halogenated acetophenones (see Scheme 1), with the exception of the fluorine substituted 1e, exhibit, at low sweep rates in the absence of carbon dioxide, an analogous cyclovoltammetric behaviour characterized by two successive peaks, respectively, irreversible and partially reversible. The second peak is located at the same potential as the peak of unsubstituted acetophenone, and exhibits the same degree of reversibility, thus suggesting that acetophenone is the major product obtained from the reduction of these halogenated ketones. 1b, 1d and 1f all showed the same behaviour also at the highest adopted scan rate (50 V/s). In the case of 1c, when the scan rate was increased, the first peak became partially reversible, while the second decreased (Fig. 1). In the case of

Fig. 1. Cyclic voltammetry of 1c (3 mM) in NMP 0.1 M Bu4 NBr at a platinum electrode at scan rates: (a) 1 V s−1 and (b) 0.1 V s−1 ; reference: Ag/AgI/I− ; T = 20 ◦ C.

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fluorine 1e compound, only one-electron partially reversible peak was observed already at low scan rates, thus showing that for this substrate the cleavage of the carbon–halogen bond of the radical anion does not occur in an appreciable way in agreement with the higher energy of the fluorine–carbon bonds. The case of chloro benzophenones was investigated in detail in a previous work [18]; while in the case of 2c, no evidence of dehalogenation process occurs, for both 2b and 2d the reduction of the halobenzopenone is likely to lead to the benzophenone. It has been observed that the ketyl anion generated by the reduction of aromatic ketones can be involved in dimerisation and protonation reactions [2,7,12,29]. In order to evaluate the variation of reversibility with the substrate concentration, the cyclic voltammetries of ketones which give rise to a partially reversible first peak (1c, 1e, 2b and 2c) were repeated at different ketone concentrations. For 1e, the ratio of anodic to cathodic peak current intensity was found to decrease when the substrate concentration was enhanced. In the case of 1c, where two peaks were observed, the ratio of anodic to cathodic current of both peaks was a decreasing function of the substrate concentration. These results are in agreement with the hypothesis that a second order dimerisation reaction occurs, as previously supposed by Jensen and Daasbjerg [29] for 3-chloroacetophenone. Furthermore, some cyclic voltammetries, performed after addition of water in the system, has shown a decrease in the ratio of anodic to cathodic peak current, according with the presence of a protonation reaction of the radical anion. In the case of halobenzophenones, no influence of the substrate concentration on the ratio of anodic to cathodic peak current intensity was found. Hence, it should be supposed in first approximation that these ketones are not involved in a relevant way in dimerization processes [22] for their high steric hindrance. 3.1.2. Considerations on the cathodic reduction mechanism of haloacetophenones and halobenzophenones According to the literature [14–16,18] for all the investigated substrates with the exception of 1e and 2c, the experimental results are consistent with the reaction mechanism depicted in Scheme 2. Reduction of halogenated aceto and benzophenones gives rise to the expulsion of the halide ion from the initially formed radical anion (Eq. (2)). It has been demonstrated, for the 4-bromobenzophenone [16], that the leading path for the reaction of the aryl radical is the abstraction of a hydrogen atom from the solvent (ECC process) (Eq. (5)). The occurrence of competitive reduction of the radical generated in reaction 2 to a carbanion by electron transfer from the radical anion initially generated (DISP process) or from the electrode (ECE), followed by rapid protonation cannot be excluded and should depend on the experimental conditions and on the substrate involved [23]. The path for the reaction of the radical S formed in reaction 5, has been widely discussed in literature [18,13].

According with the previously reported electroanalytical results, the ketyl radical anion could be involved also in dimerization (Eq. (3)) and protonation processes (Eq. (4)) with the formation, respectively, of the corresponding pinacol (Eq. (8)) and alcohol (Eq. (6)). The pinacol formation can arise also from the coupling between the radical anion formed in (4) which can both dimerize (Eq. (7)) or reduce to the corresponding anion which can be protonated to the alcohol during the synthesis or in the work-up (Eq. (6)). Alcohol formation may involve, also, an hydrogen abstraction from the solvent, which can then be reduced to the corresponding anion. The coupling reaction 3 is probably negligible for halogenated benzophenones. In the case of 1e and 2c, the mechanism of the first reduction is, otherwise, probably constituted simply by a one-electron transfer leading to a partially stable anion radical which could be involved in reactions 3 and 4. 3.1.3. Kinetic constants of the expulsion of the halide ion It was not an objective of the present work to achieve an accurate estimation of the kinetic constants k2 of the cleavage of the ketyl radical anions. Otherwise, to have some indications on the rate of the cleavage, the rate constants were estimated by fitting of the experimental cyclic voltammograms obtained at different scan rates to simulated curves. Several researches were, previously, devoted to compute the cleavage rate constant for different ketones prevalently in acetonitrile (ACN) and DMF and more rarely in NMP. It was observed that the cleavage rate constants are scarcely influenced by the solvents [18,28,29,31] and in particular that k2 assume only slightly greater values in NMP with respect to DMF [29,18]. According with literature data and with our results (Table 1), the cleavage rate constant of the radical Table 1 Dehalogenation rate constant (k2 ) of haloacetophenones and halobenzophenones as derived from cyclic voltammetry in NMP at 20 ◦ C Group

Ketone

k2 (s−1 ) This study

Literature

1

1e 2c

<0.1 <0.1

0a –0.04b

2

1c 2b

6 6–15

1.9c –3.5d –15e –5f 19b –27g –30h –40i –10a –42j

3

1b 1d 1f

>102 >102 >102

3 × 103e 3 × 105e >8 × 106e

2d

n.d.

a b c d e f g h i j

2.54b –3.30g × 102 20 ◦ C.

Nadjo and Saveant [14] in DMF at Isse et al. [18] in DMF at 25 ◦ C. Jensen and Daasbjerg [29] in DMF at 20 ◦ C. Jensen and Daasbjerg [29] in NMP at 20 ◦ C. Wipf and Wigtmann [30] in ACN. Gores et al. [32] in DMF at 20 ◦ C. Isse et al. [18] in NMP at 25 ◦ C. Javorski and Leszczynski [28] in DMF. Javorski and Leszczynski [28] in NMP. Aalstad and Parker [31] in DMF at 23 ◦ C.

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Scheme 2.

anion assumes negligible values in the cases of 1e and 2c (group 1), about 6–40 s−1 for 1c and 2b (group 2), about 103 for 1b and higher than 105 s−1 for 1d and 1f (group 3). 3.1.4. Experiments performed in the presence of carbon dioxide When the voltammograms were recorded in NMP saturated with carbon dioxide, different behaviors were observed for the different groups of substrates previously defined. For the substrates of group 1 in Table 1, the first reduction peak shifts towards positive potentials and become two-electronic and irreversible at all sweep rates according with the presence of a carboxylation process [33]. For the substrates of group 2, the first reduction peak shifts towards positive potentials and become two-electronic and irreversible while the peak of the dehalogenated ketone disappears according with a fast and bielectronic carboxylation reaction of the radical anion

initially formed preventing the cleavage of the ketyl radical anion (see Fig. 2). For substrates of group 3, in the presence of saturation concentration of carbon dioxide, the current densities of both the two first peaks increased and the second one became irreversible (Fig. 3), according with the occurrence of the carboxylation of both halogenated and dehalogenated compounds. Hence, for this class of compounds, carboxylation is presumably less rapid than fragmentation of the radical anion. Hence, for substrates belonging to groups 2 and 3, the voltammetric results seem consistent with a competition pathway between the carboxylation of the radical anion initially formed and the expulsion of the halide ion. The occurrence of protonation and dimerization reactions can not, furthermore, be excluded. To support these results, we must observe that the electrolyses of 1b and 2b, carried out at 20 ◦ C in NMP saturated with carbon dioxide at atmo-

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Fig. 2. Cyclic voltammetry of 3 mM 2b at T = 20 ◦ C in NMP 0.1 M in Bu4 NBr at a platinum electrode at v = 0.1 V s−1 in the (a) absence and (b) presence of saturated carbon dioxide.

spheric pressure, lead in both cases to the formation of the target hydroxycarboxylic acid, of the dehalogenated hydroxycarboxylic acid, the dehalogenated ketone and corresponding alcohol. In the case of the acetophenone derivative 1b also pinacols were detected. 3.2. Experimental investigations in preparative scale electrolysis 3.2.1. Influence of the nature of the substrate A set of exhaustive potenstiostatic electrolyses were performed in undivided cell equipped with aluminum sacrificial

Fig. 3. Cyclic voltammetry of 5.9 mM 1b at T = 20 ◦ C in NMP 0.1 M in Bu4 NBr at a platinum electrode at v = 0.1 V s−1 in the (a) absence and (b) presence of carbon dioxide at saturation concentration with P = 1 atm (0.14 M).

anode in the presence of saturation concentration of carbon dioxide at 1 atm and temperature of 20 ◦ C with an initial concentration of substrate of 0.18 M, in order to investigate the influence of the nature of the substrate on the performances of the process. The working potential, selected by inspection of cyclic voltammograms, corresponds to the value at the foot of the substrate or of the dehalogenated ketone cyclovoltammetric peak if present. NMP, 0.1 M Bu4 NBr was chosen as solvent supporting electrolyte (SSE) system. The influence of the solvent was previously [18] discussed in the electrocarboxylation of halogenated benzophenones. In spite of the lower solubility of CO2 in NMP, which can be however easily compensated, if necessary, by a slight increase of CO2 partial pressure, this solvent was chosen for the electrolysis because it has a better safety profile with respect to DMF and ACN [35]. The current density was initially of about 15 mA/cm2 and gradually decreased during the electrolysis up to about 5% of the initial value when the conversion was higher than 90%. No passivation phenomena were observed during the electrolyses in contrast to what described in the electrocarboxylation of different organic halides [1]. As shown in Table 2, very different results in terms of yields and selectivities in halogenated and dehalogenated hydroxycarboxylic acids were obtained by changing the substrate. According with electroanalytical data and with the estimated values of the kinetic constants k2 (see Eq. (2)), different yields in the products arising from the de-halogenation process were observed for the substrates belonging to the different groups previously defined. The reduction of ketones belonging to group 1, whose voltammograms did not show the occurrence of the expulsion reaction, does not give rise to detectable amounts of products arising from the cleavage of the C Cl bond. The total selectivity in products arising from the dehalogenation (dehalogenated ketone and corresponding hydroxycarboxylic acid, alcohol and pinacol) was estimated to be around 10–15% for substrates of group 2 (k2 = 6–50 s−1 ) and more than 40% for ketones of group 3 (k2 > 103 s−1 ). These results confirm the well-known relevance of the competition between carboxylation and dehalogenation reactions for this class of compounds. Otherwise, it must be underlined that the selectivity in the target product depends also on the relative rates of other competitive reactions such as dimerisation (Eq. (3)) and protonation (Eq. (4)). In fact, it is possible to observe in Fig. 4 that electrolyses performed with substrates belonging to the same group, which lead to comparable yields in products arising from the C Cl cleavage, gives in some cases different yields in the target acid. In particular, in the case of halogenated benzophenones, the cumulative selectivity in the target acid, in benzophenone and its corresponding acid was close or higher than 90% as shown in Table 2. Furthermore very low yields (<2%) in the dehalogenated alcohol were computed. In the case of 2b, it was also detected the presence of halogenated alcohol.

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Table 2 Influence of the nature of the ketone on the selectivity in carboxylated products Ketone

Halogenated carboxylate faradic yielda (%)

Halogenated carboxylate selectivity (%)

Dehalogenated carboxylate selectivity (%)

Working potential vs. Ag/AgI/I−

1a 1d 1c 1b 1f 1e 2a 2d 2c 2b

– – 50–52 9–11 5–7 46–47 – 65–67 94–95 80–82

– – 56–58 16–18 13–15 50–52 – 67–69 95–96 82–84

33–35 34–36 4–6 12–14 19–21 – 76–80 14–16 – 8–10

−1.7 −1.7 −1.7 −1.7 −1.7 −1.6 −1.6 −1.6 −1.6 −1.6

Faradic efficiency in chloro-2-hydroxy-2-phenylpropionic acid evaluated according to Eq. (1). Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− 0.1 M in DMF. SSE: NMP; Bu4 NBr, 0.1 M. Initial substrate concentration: 0.2 M. Electrolytic solution saturated with CO2 at pressure of 1 atm. a

For the acetophenone derivatives, the total selectivity in the target acid and in dehalogenated ketone and its corresponding acid was always lower than 64%. For these substrates, it seems reasonable to assume that the other main coproducts are the pinacols and alcohols. This hyphotesis can be substantiated on the basis of the above-mentioned electroanalytical results and from the evidence that in the case of 1a it was possible to determine a cumulative yield in carboxylate, pinacol and alcohol higher than 80%. 3.2.2. Comparison between the electrocarboxylation of acetophenone and benzophenone derivatives As shown in Table 2, in the case of chloro acetophenones (1b–1d), lower selectivity in the target hydroxy acid were evaluated at the end of the electrolysis with respect to that obtained with the corresponding benzophenones (2b–2d) as a result of much relevant formation of dehalogenated compounds and alcohols and pinacols. In fact, as shown in Table 1, lower values of the cleavage kinetic constant were deter-

Fig. 4. Influence of the dehalogenation rate constant (k2 ) on the selectivity in the halogenated hydroxycarboxylic acid (
) and in the dehalogenated hydroxycarboxylic acid ( ). Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− : 0.1 M in DMF. SSE: NMP; Bu4 NBr, 0.1 M. Initial substrate concentration: 0.18 M. Electrolytic solution saturated with CO2 at pressure of 1 atm. The working potential were −1.7 V and −1.6 V vs. Ag/AgI/I− for, respectively, acetophenones and benzophenones derivatives.

mined for the diaryl ketones with the same position of the halogen in the ring. Moreover, as shown in Fig. 4, when we compare halo benzophenone and acetophenone with comparable k2 (2c and 1e, 2b and 1c) much higher yields in the target hydroxycarboxylic acid are obtained for the benzophenones, according with the fact that pinacol and alcohol formation are more favoured in the case of the acetophenone derivatives. In order to investigate the competition between dehalogenation and carboxylation processes, the concentrations of the substrate, the dehalogenated ketone, and of corresponding acids were monitored during the electrolysis of 1b and 2b. In both cases, a potential more negative with respect to the reduction potential of the dehalogenated ketone was involved. As shown in Fig. 5, for 1b at the beginning of the synthesis, an appreciable yield and selectivity in the dehalogenated ketone 1a were observed. With the progress of the experiments, after 1000 ◦ C of charge passed (corresponding to about 1.2 F/mol), the concentration of 1a starts to decrease and reaches negligi-

Fig. 5. ne , number of electrons exchanged/(initial number of molecules of substrate). Evolution of the yields in acetophenone (1a), halogenated and dehalogenated hydroxycarboxylic acids in the electrocarboxylation of 4chloroacetophenone (1b). Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− : 0.1 M in DMF. SSE: NMP; 0.1 M Bu4 NBr. Initial substrate concentration: 0.18 M. Electrolytic solution saturated with CO2 at pressure of 1 atm. Working potential: −1.7 V.

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ble values at the end of the electrolysis while the concentration of its acid increases. In order to explain this behaviour, it seems reasonable to suppose that in the first part of the synthesis, when high concentrations of 1b and low concentrations of 1a are present in the cell, the formation rate of 1a, presumably equal to the rate of the cleavage of the C Cl bond, is faster than its reduction rate and conversely in the second part of the electrolyses, when lower concentrations of 1b and higher concentrations of 1a are present, the reduction of 1a prevails on its formation. According with a high selectivity in dehalogenated products, the charge passed at the end of the electrolysis was equivalent to about four electrons per molecule of substrate. As shown in Fig. 6, a very different behaviour was observed for 2b. In this case, according with the fact that the cleavage kinetic constant assumes lower values for the 2b than for the correspondent 1b, the synthesis performed in the presence of the halobenzophenone derivative resulted in very small amounts of dehalogenated ketone and corresponding hydroxycarboxylic acid during all the synthesis. As a consequence, the charge passed at the end of the electrolysis was equivalent to only two electrons per molecule of reacted substrate. In order to explain the different results obtained with benzophenone and acetophenone derivatives, it is possible to observe that according to Isse and Gennaro [34], the carboxylation reaction of diaryl ketones should be faster than that of the acetophenone derivatives. Furthermore, in the case of the acetophenones, the substituents linked to the carbonyl group are less withdrawing than in the case of benzophenones. Hence, the radical anions generated by the reduction of the substrate should have higher spin density on the carbon atom of the carbonyl group and higher density of the negative charge on the oxygen atom and on the halogen atom for substituted acetophenones than for the corresponding benzophenones, thus favouring the reactions of protonation, dimerization and de-halogenation.

Fig. 6. ne , number of electrons exchanged/(initial number of molecules of substrate). Evolution of the yields in benzophenones (2a), halogenated and dehalogenated hydroxycarboxylic acids in the electrocarboxylation of 4chlorobenzophenone (2b). Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− : 0.1 M in DMF. SSE: NMP; 0.1 M Bu4 NBr. Initial substrate concentration: 0.2 M. Electrolytic solution saturated with CO2 at pressure of 1 atm. Working potential: −1.6 V.

3.2.3. Influence of the halogen position on the ring For both benzophenones and acetophenones yields in target hydroxycarboxylic acid increased (Table 2) when the cleavage constant decreased (Table 1) from 2- to 4- and to 3-chloro isomer. In particular, in the electrolysis of 1d, which is characterised by very high value of k2 (around 105 s−1 ), no carboxylation of the substrate was detected. The main products of the synthesis are the same obtained in the direct electrocarboxylation of acetophenone: the 2-hydroxy-2-phenylpropionic acid and the corresponding alcohol and pinacol; furthermore the selectivity in the 2-hydroxy-2-phenylpropionic acid was comparable to that obtain in the direct electrocarboxylation of 1a, thus showing that the reaction evolves, via the cleavage of the C Cl bond, almost quantitatively towards the formation of 1a which after reduction is involved in carboxylation, protonation and dimerization processes. According with a bielectronic process for the formation of 1a and with a twoelectron process both for the carboxylation and the alchool formation, around four electrons were necessary to convert one molecule of the substrate. It is interesting to observe that in the case of the 1c, 1e and 2c compounds, where the expulsion of the halogen ion is negligible, higher selectivity in the target halo hydroxycarboxylic acids are obtained with respect to the case of the unsubstituted ketones. These results seem in apparent contradiction with those obtained by Isse and Gennaro [34] who reported lower values of carboxylation kinetic constants for 3-chloroacetophenone and 3-chlorobenzophenone with respect to that of the parent unsubstituted compounds. Otherwise, it can be demonstrated that in the presence of very fast carboxylation reactions, the selectivity should depend mainly on the relative values of the kinetic constants of competitive reactions [12]. Hence, we have to focus mainly on the different reactivity of the radical anions generated by the reduction of these ketones towards dimerisation and protonation processes. In the case of the unsubstituted derivatives, the moieties linked to the carbonyl function are less withdrawing group than in the case of the halogen derivatives. Hence, in the case of acetophenone and benzophenone, the radical anion generated by the reduction of the substrate should have higher spin density on the carbon atom and higher density of the negative charge on the oxygen atom with respect to the case of correspondent chloro derivatives, thus strongly favouring the reactions of protonation and dimerization. 3.2.4. Influence of the nature of the halogen As shown in Table 2, increasing selectivity in the target hydroxycarboxylic acid and conversely decreasing selectivity in the dehalogenated products were obtained changing from F to Cl to Br derivative. In spite of the strong difference between the reported values of the cleavage kinetic constant of 4-bromo (k1 ∼ = 106 s−1 ) and 4-chloroacetophenone 3 −1 ∼ (k1 = 10 s ), only slight differences in the product distribution were detected in the electrocarboxylation of these two substrates. It can be observed that in the case of the 3-chloro

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isomer, despite the partial occurrence of the reaction of cleavage, slightly higher yields in the target hydroxycarboxylic acid are obtained with respect to the case of 4-fluoro isomer.

relevant, 1c and 2b of group 2, where both carboxylation and dehalogenation occur, and 1b and 1d for group 3 where mainly dehalogenation occur.

3.3. Influence of the synthetic parameters on the performances of the process

3.3.1. Influence of the working potential In the case of 1a (group 1), no appreciable differences in the selectivity and in the faradic yields in the main products were obtained by performing two electrolyses with 0.3 V of differences (−2.0 and −1.7 V versus Ag/AgI/I− ). A similar result was obtained in the case of 6-methoxy-2acetonaphtone [9]. For both 1c and 1b, two electrolyses were performed at working potential, respectively, more positive and more negative with respect to the reduction potential of acetophenone. As shown in Table 3, no appreciable differences in the yields in the target hydroxycarboxylic acids were found at the end of the syntheses by changing the working potential for both substrates. On the other hand, in the case of 1b (group 3, see Fig. 7 and Table 3), a less negative potential was effective to minimise the electroreduction of the generated 1a and the subsequent reactions, thus leading to higher conversions of the substrate for the same amount of charge passed and consequently

As above mentioned, high selectivity and faradic efficiency are important requisites in order to achieve a sustainable electrochemical process competitive with conventional synthetic route. Otherwise, all the investigated halogenated acetophenones give rise in standard experimental conditions (substrate concentration: 0.2 M; T: 20 ◦ C; solution saturated with CO2 at P = 1 atm) to faradic efficiencies and yields in the target hydroxycarboxylic acid, respectively, below 50% and 60%. Hence, we have focused our attention on the influence of various synthetic parameters on the process with the aim of optimising the selectivity and the faradic efficiency in the target product. In the literature [14,31], it was shown that in the case of the halo benzophenones, lower temperatures are effective to decrease the value of the kinetic constant k2 . Lower temperature and high partial pressure are also effective to increase the carbon dioxide solubility [36]. Thus, lower temperatures and higher pressures should favour the carboxylation with respect to the expulsion of the halide ion. In a previous paper, we have investigated in detail for methoxy aceto and benzophenones the competition between the carboxylation and the processes which leads to the formation of the alcohol and the pinacol. Lower bulk ketone concentrations, high carbon dioxide and low proton donor bulk concentrations favoured the carboxylation with respect to competitive processes. In order to increase the faradic efficiency in the target hydroxycarboxylic acid it should be also useful to avoid the reduction of the formed acetophenone by operating at potentials more positive with respect to its reduction value. Hence, we focused our research on the influence of the above-mentioned parameters on the process, by performing a set of potentiostatic electrolyses at different conditions of temperature, substrate and water concentration, and fixed working potential. As substrates the following ketones were chosen: 1a, 1e and 2c as representative of group 1, where dehalogenation is ir-

Fig. 7. ne , number of electrons exchanged/(initial number of molecules of substrate). Evolution of the concentrations of 4-chloroacetophenone and acetophenone, during the electrocarboxylation of 4-chloroacetophenone. Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− : 0.1 M in DMF. System solvent supporting electrolyte (SSE): NMP; 0.1 M Bu4 NBr. Initial substrate concentration: 0.18 M. Electrolytic solution saturated with CO2 at pressure of 1 atm; T = 25 ◦ C.

Table 3 Influence of the cathode fixed potential Starting material

Cathode fixed potential (V)

1a

−2.0 −1.7

1c

−1.7 −1.35

50–52 50–52

56–58 56–58

<1 <1

–

−1.7 −1.35

9–11 15–17

17–19 17–19

<1 22–24

12–14 2–3

1b a

Halogenated carboxylate faradic yielda (%)

Halogenated carboxylate selectivityb (%)

Dehalogenated ketone selectivity (%)

Dehalogenated carboxylate selectivity (%) 32–36 33–35 4–6

Faradic efficiency in halo-2-hydroxy-2-phenylpropionic acid evaluated according to Eq. (1). Selectivity in halo-2-hydroxy-2-phenylpropionic acid evaluated according to Eq. (1). Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− : 0.1 M in DMF. SSE: NMP; Bu4 NBr, 0.1 M. Initial substrate concentration: 0.2 M. CO2 saturated, atm. pressure; T = 20 ◦ C. b

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Fig. 8. Cyclic voltammetry of 5.9 mM 1b in NMP 0.1 M in Bu4 NBr at a platinum electrode at v = 0.1 V s−1 in the (a) absence and (b) presence of carbon dioxide at 4 ◦ C (A) and 20 ◦ C (B).

to higher faradic efficiency in the halogenated hydroxycarboxylic acid. In particular, about, respectively, two and four electrons per molecule reacted were necessary, respectively, for the syntheses performed at more positive and more negative potential. No significant effect on conversion and faradic efficiency was detected in the case of 1c (group 2) according with the fact that for this substrate the de-halogenation process was almost negligible. 3.3.2. Effect of the temperature A cyclic voltammetry was performed with 1b at 4 ◦ C in the absence and in the presence of carbon dioxide in order to have some preliminary information on the influence of the temperature on the competition between carboxylation and cleavage processes. As shown in Fig. 8, an analogous behaviour was observed at 4 ◦ C and 20 ◦ C in the absence of carbon dioxide, thus showing that also at 4 ◦ C, the cleavage of carbon–halogen bond occurs with fast kinetics. Otherwise, in the presence of carbon dioxide, the ratio of first to second current peaks increases at lower temperature. Hence, lower temperatures are likely to favour carboxylation process with respect to the cleavage. To investigate quantitatively the effect of the temperature on the electrocarboxylation of halogenated ketones, a set of electrolyses was performed at different temperatures and working potential with 1a and the three chloroacetophenones as substrates. In the case of 1a, only a slight increase of the selectivity in the carboxylate was observed at lower temperature (Table 4). More interestingly, in the case of 1b (group 3, k2 ∼ 3 × 103 ), the temperature value dramatically affected the selectivity of the process. A decrease in the selectivity in acetophenone and in its carboxylate and conversely a strong increase in the selectivity and faradic efficiency in the target

hydroxycarboxylic acid were observed at lower temperature, independently from the adopted potential. Obviously, the working potential strongly affects the faradic efficiency at the higher temperature when dehalogenation process is relevant but does not influence the process at −20 ◦ C, where no cleavage occurs, thus confirming that the role of the working potential is only to discriminate the possibility of the reduction of the de-halogenated ketone. A strong impact of the temperature on the performances of the process was obtained, also, for the 1c (group 2). On the other hand, even at 4 ◦ C, it was not possible to carboxylate the 1d (group 3, k2 ∼ 3 × 105 ). 3.3.3. Effect of substrate and water concentration To investigate the influence of the initial substrate concentration on the performances of the synthesis, the electrocarboxylation of 1b was performed in CO2 saturated (1 atm) NMP at constant potential of −1.35 V versus Ag/AgI/I− at 20 ◦ C and 4 ◦ C with different initial concentration of the halide. As a rule conversion higher than 95% were obtained with the exception of the electrolysis performed at 50 mM, when it was difficult to convert the last 10 wt.% of the substrate present in the system. As shown in Table 5, increasing selectivity in the target hydroxycarboxylic acid were obtained in the syntheses performed in the presence of lower initial ketone concentration both at 20 and 4 ◦ C. The sensitivity of selectivity in the halo carboxylic compound to the initial ketone concentration becomes negligible when very low initial amounts of substrate are used (Table 5, entries 5 and 6). Higher substrate concentrations give rise, furthermore, to a strong increase in the selectivity in acetophenone.

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Table 4 Influence of temperature in the electrocarboxylation of acetophenone and chloroacetophenones T (◦ C)

Substrate

Cathode potential (V)

1a

−1.7 −1.7

20 4

1b

−1.7

20 4 −20

9–11 24–26 36–38

17–19 34–36 37–39

<1 1–2 <1

12–14 3–4 <1

−1.35

20 4

15–17 31–33

17–19 34–36

10–12 4–5

2–3 <1

1d

−1.7

20 4

– –

– –

<1 <1

34–36 40–44

1c

−1.7

20 4

50–52 60–62

56–58 65–67

<1 <1

4–6 2–4

Carboxylate faradic yielda (%)

Carboxylate selectivityb (%)

Acetophenone selectivity (%)

2-Hydroxy-2-phenylpropionic acid selectivity (%) 34–36 38–40

a

Faradic efficiency in halo-2-hydroxy-2-phenylpropionic acid evaluated according to Eq. (1). Selectivity in halo-2-hydroxy-2-phenylpropionic acid evaluated according to Eq. (1). Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− : 0.1 M in DMF. SSE: NMP; Bu4 NBr, 0.1 M. Initial substrate concentration: 0.2 M. Electrolytic solution saturated with CO2 at pressure of 1 atm. b

Hence, it seems reasonable to assume that higher substrate concentrations are effective to favour process competitive to the carboxylation such as dimerization and dehalogenation processes. To verify if this influence is general for halogenated ketones, a set of electrolyses was performed with 1c, 1d and 2b at different initial substrate concentrations in the presence of carbon dioxide. For both 1c and 2b, lower substrate concentrations (see Table 6) were effective to increase the yield in the hydroxycarboxylic acid and conversely to decrease the selectivity in the dehalogenated product, even if a less drastic influence arises for 2b. In the case of 1d, no carboxylation of the substrate was detected under all the tested conditions. Higher selectivity in 2-hydroxy-2phenylpropionic acid and lower selectivity in the corresponding pinacol were, otherwise, observed at lower substrate concentrations. It should be underlined that these results are apparently surprising. It is quite normal, in fact, that high substrate concentration favors dimerisation processes with respect to the carboxylation of the radical anion generated by the ketone electroreduction. Otherwise, both carboxylation, dehalogenation and protonation of the radical anion, are first Table 5 Influence of the initial ketone concentration on the electrocarboxylation of 1b Entry

Initial ketone concentration (M)

Temperature (◦ C)

Selectivity in halogenated carboxylatea (%)

1 2 3 4 5 6

0.2 0.05 0.4 0.2 0.1 0.05

20 20 4 4 4 4

17–19 38–40 14–18 34–36 45–47 49–51

a Evaluated according to Eq. (1). Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− : 0.1 M in DMF. SSE: NMP; Bu4 NBr, 0.1 M. Electrolytic solution saturated with CO2 at pressure of 1 atm; E = −1.35 V.

order reactions with respect to the radical anion generated by the substrate reduction. Hence, it is not obvious why a variation in the substrate concentration should influence the competition between these processes. In order to explain these results, a focused investigation is under development by the authors [12,37]. The influence of water on the electrocarboxylation of halobenzophenones has been previously reported by Isse et al. [18]. According with these authors, upon increasing the initial concentration of water, the selectivity of the process shifts towards the formation of alcohol even if the carboxylate remains the main product. To examine the effect of water on the electrocarboxylation process, the experiments were repeated with 2b and 1b in the presence of 0.2 M of water (Table 7). In the case of 2b, a decrease of the selectivity in the target product compensated by an increase in alcohol was observed according with the above-mentioned results. Otherwise, a not significant influence of water content on selectivity in target product was observed in the case of 1b where the cleavage of the carbon–halogen bond is more relevant. Table 6 Influence of starting substrate concentration in the electrocarboxylation of 1c, 1d and 2b Substrate

[Substrate] (mM)

Carboxylate selectivitya (%)

2b

200 50

82–84 88–90

1d

200 50

– –

1c

200 50

65–67 79–81

a Evaluated according to Eq. (1). Potentiostatic electrolyses performed in undivided tank cells with cylindrical electrode arrangement. Reference electrode, Ag/AgI/I− : 0.1 M in DMF, cathode compact graphite, anode aluminum, working potential Ec = −1.35 V. SSE: 50 mL NMP, 0.1 M Bu4 NBr. Electrolytic solution saturated with CO2 at pressure of P = 1 atm, T = 4 ◦ C.

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Table 7 Influence of water concentration in the electrocarboxylation of 2a, 2b and 1b Substrate

[Water] (M)

Carboxylate selectivitya (%)

2b

– 0.2

82–84 75–77

1b

– 0.2

16–18 14–16

a Evaluated according to Eq. (1). Potentiostatic electrolyses. Reference electrode, Ag/AgI/I− : 0.1 M in DMF. System solvent supporting electrolyte (SSE): NMP, Bu4 NBr, 0.1 M. Initial substrate concentration: 0.2 M. Electrolytic solution saturated with CO2 at pressure of 1 atm; T = 20 ◦ C; Ec = −1.35 V: SSE.

4. Conclusion The reduction of halogenated acetophenones and benzophenones in the presence of carbon dioxide gives rise to different amounts of the corresponding hydroxycarboxylic acid, pinacol, alcohol and de-halogenation products. The performances of the process strongly depends on the nature of the substrate. The nature and position of the halogen strongly affects the competition between the carboxylation and the expulsion of the halide ion from the radical anion initially formed. The cleavage was more favoured by changing from meta to para to ortho isomer and from fluoro to chloro to bromo derivatives. For 2-chloroacetophenone, the cleavage of the carbon–halogen bond is so favoured that it was not possible to obtain the hydroxycarboxylic acid. For benzophenone derivatives, the carboxylation is more favoured than for the correspondent acetophenones as a result of less relevant formation of dehalogenated compounds, alcohols and pinacols. Operative conditions dramatically affect the selectivity and the faradic efficiency of the process. Lower temperature, lower substrate concentrations and less negative potentials were effective to increase dramatically the faradic yields in the hydroxycarboxylic acid.

Acknowledgements The MIUR and the University of Palermo are gratefully acknowledged for their financial support.

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