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Electroreduction of lichexanthone
Electrochimica Acta 54 (2009) 2290–2297
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Electroreduction of lichexanthone Adriana E. Carvalho, Glaucia B. Alcantara, Sebastião M. Oliveira, Ana C. Micheletti, Neli K. Honda, Gilberto Maia ∗,1 Departamento de Química, Universidade Federal de Mato Grosso do Sul, C.P. 549, Campo Grande, MS 79070-900, Brazil
a r t i c l e
i n f o
Article history: Received 14 July 2008 Received in revised form 3 October 2008 Accepted 24 October 2008 Available online 31 October 2008 Keywords: Lichexanthone Electroreduction Radical anion Dianion 2-Hydroxy-4-methoxy-6-methylphenyl 2-hydroxy-4-methoxyphenyl ketone
a b s t r a c t This paper reports the first study on the electrochemical reduction of lichexanthone (1H) (1-hydroxy-3,6dimethoxy-8-methylxanthen-9-one) on glassy carbon (GC) electrodes in DMSO, using cyclic voltammetry, rotating disc and ring electrodes, and long-term controlled-potential electrolysis. Parameters involving data from cyclic voltammetry and rotating disc electrodes, such as current functions, Epc1 vs. log , Epc2 vs. log , Epc/2,1 − Epc1 , −Ipc1ox /Ipc1red , Ipc2 /Ipc1 , E1/2 vs. log ω, and collection efficiency (rotating disc and ring electrode data), were used to elucidate the reduction mechanism of 1H that involves two one-electron transfers (two reduction peaks in the voltammograms), the first of which, with reversible characteristics, involves electroreduction of 1H, producing a radical anion 1H•− , whereas the second, with irreversible characteristics, involves electroreduction of 1H•− , producing a dianion 1H2− . Both transfers appear to involve an Er Cslow -type mechanism with a chemical step consisting of breakage of a bond followed by protonation of residual water, or parent compound, or solvent, etc., to yield 2hydroxy-4-methoxy-6-methylphenyl 2-hydroxy-4-methoxyphenyl ketone (1H3 ), directly, in the case of 1H2− involved. Compound 1H3 was elucidated by 1D- and 2D-NMR methods. D0 = 2.66 × 10−6 cm2 s−1 was found for the electrochemical reduction of 1H. © 2008 Elsevier Ltd. All rights reserved.
1. Introduction Xanthones or 9H-xanthen-9-ones (dibenzo-␥-pirones) are an important class of oxygenated heterocycles with a well-known role in Medicinal Chemistry. The biological activities of this class of compounds are associated with their tricyclic scaffold, but they may vary depending on the nature and/or position of substituents [1]. Recently, Pinto et al. [1] reviewed biological and pharmacological effects of synthetic and natural xanthone derivatives, with emphasis on some studies on structure–activity relationships. The antitumor activity of some xanthones and examples of “hit” compounds involved in cancer therapy — namely psorospermin, mangiferin, norathyriol, and mangostins, are highlighted by the authors [1]. Day and Biggers [2] found that in alkaline solutions xanthone exhibits one polarographic reduction wave. Kalinowski et al. [3] studied the polarographic behavior of fluorenone, xanthone, benzophenone, and 4-chlorobenzophenone, observing that aromatic ketones were reduced in two one-electron steps, the first of them behaving as a reversible one-electron (plus eventually one-proton)
∗ Corresponding author. Tel.: +55 67 33453551; fax: +55 67 33453552. E-mail address: [email protected] (G. Maia). 1 ISE member. 0013-4686/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.electacta.2008.10.035
transfer. The authors comment on the greater stability of the xanthone ketyl radical and report that all those molecules form dimmers (pinacols). Kalinowski and Grabowski [4] investigated the dimerization equilibrium and dismutation kinetics of fluorenone and xanthone ketyl radicals with electrochemical methods at various pH values. Whitman and Wiles [5] studied the polarographic reduction of xanthone and methoxyxanthone and suggested that in strong acid the reduction of xanthone and their monomethyl ethers is a reversible one-electron process. They suggested that the single-wave reduction of xanthones produces a free radical, which eventually undergoes dimerization. Fournier et al. [6] studied the electrochemical reduction of hindered aromatic ketones (e.g. indanone, chromanone, xanthone) in the presence of Mn(II) chloride, observing that a selective hydrodimerization into an ␣-glycol takes place, with total absence of polymerization. With dissymmetric ketones, dl diastereoisomers of diols are preferentially produced. Bannerjee and Chakraborty [7] recorded DC polarograms of xanthone at different pH values and suggested that in acidic solutions, where two one-electron waves occur, the mechanisms involved are CECE (chemical–electrochemical–chemical–electrochemical) in a lower pH range (2.01 and 3.1) and CEEC in an intermediate range (3.5, 4.7, and 5.6). Between pH 5.6 and 8.6, previous protonation was regarded as improbable and an EECC mechanism was assumed. The investigators proposed that a competitive dimerization of ion radicals formed through a one-electron uptake also occurs in this pH
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Table 1 1 H NMR (300 MHz) and 13 C NMR (75 MHz) data for compounds 1H (CDCl3 ) and 1H3 (CDCl3 ). Position
1H
1H3
1
H NMR ı (ppm); multiplicity; number of hydrogens
13
gHMBC
1
C NMR ı (ppm)
H NMR ı (ppm); multiplicity; number of hydrogens
13
C NMR ı (ppm)
gHMBC
1 2 3 4
13.39; s; OH 6.29; d; 1H – 6.32; d; 1H
163.70 96.8 165.9 92.1
C-1; C-2; C-3; C-9 C-1; C-3; C-4; C-9a; C-9 – C-2; C-3; C-9; C-4a; C-9a
13.54; s; OH 6.40; s; 1H – 6.31; d; 1H
162.2 94.8 161.0 92.5
6.67; d; 1H – 6.65; d; 1H
98.5 163.75 115.4
C-6; C-7; C-9; C-10a; C-8a – 8-CH3 ; C-6; C-9; C-8a ;
6.80; d; 1H – 6.65; d; 1H
98.7 164.1 116.2
– – – – – – 3.86; s; 3H 3.89; s; 3H 2.84; s; 3H
143.8 182.7 157.0 113.0 104.3 159.5 55.6 55.7 23.4
– – – – – – C-3 C-6 C-7; C-8; C-9; C-5a; C-8a; C-10a
– – 6.66; d; 1H – – 13.98; s; OH 3.98; s; 3H 3.92; s; 3H 2.84; s; 3H
143.8 182.6 98.0 113.0 104.3 163.72 56.6 55.8 23.4
C-1; C-2; C-9; C-9a C-1; C-9a – C-2; C-3; C-4a; C-9aa – – 8-CH3 ; C-6; C-9; C-8aa – – C-1; C-2; C-3 – – – C-3 C-6 C-6; C-7; C-8; C-9; C-5a; C-8a; C-10a
5 6 7 8 9 4a 8a 9a 10a 3-OCH3 6-OCH3 8-CH3
Position numbers are based on the biosynthetic route, to facilitate comparison of all compounds. The IUPAC nomenclature was not used. a Correlation for compound 1H3 overlapped to correlation for compound 1H.
range. Above pH 8.6 a second wave appeared, which, at increasing pH values, grew at the expense of the first, leading the authors to propose an EECC mechanism by which the intermediate anion radical can also combine with a cation and the stabilized complex ion thus formed is reduced to the final product at more negative potentials. Lichexanthone can be obtained synthetically [8] or isolated from natural products [9] and lichens [10]. Kathirgamanathar et al. [11] showed that lichexanthone has larvicidal activity against secondinstar larvae of the mosquito Aedes aegypti and that it enhances human sperm motility. Despite the availability of electroreduction studies on xanthone and molecules such as benzophenone, among others, no electroreduction investigations have, to our knowledge, been conducted on lichexanthone. The present study focuses on lichexanthone and proposes an electroreduction mechanism for this compound. This mechanism can be used as a model for the reduction of other xanthones, such as 1H, whose structure contains a nucleofugic moiety (ether), in addition to exhibiting biologic activity. The electrochemical procedures utilized were cyclic voltammetry, hydrodynamic voltammetry, and long-term controlled-potential electrolysis. The elucidation of product 1H3 was based on 1D and 2D-NMR methods. 2. Experimental Compound 1H was isolated from the lichen Parmotrema sp. according to Micheletti et al. [12]. Anthracene (Aldrich, reagent grade) and 2-methylanthraquinone (MAQ) (Acros Organics) were used to estimate the number of electrons transferred during the electroreduction of 1H. Tetramethylammonium hydroxide (TMAOH, Aldrich) utilized was prepared from a 25 wt% solution in water, dissolved in 5 mL of methanol, and dried in a glass apparatus (Schlenck tube) under reduced pressure and inert atmosphere (N2 ). After a few minutes of solvent evaporation, the dry salt was obtained. The supporting electrolyte used in the electrochemical measurements was tetrabutylammonium perchlorate (TBAP, Acros, electrochemical grade) and the solvent was DMSO (<0.05% water, Vetec). All other chemicals were of analytical grade and were used as received.
1 H, 13 C, and 2D-NMR experiments were recorded on a 7.05-T Bruker DPX300 instrument using a 5-mm dual direct-detection and a broadband inverse-detection probe, with Bruker TopSpin software package (version 1.3) for data processing (Table 1). The voltammograms, rotating disc and ring current responses, and electrolysis data were obtained using a Pine AFCBP1 bipotentiostat. The voltammetric and rotating disc and ring curves were obtained with a three-electrode system. The working electrodes were a GC disc and ring (0.25-cm2 and 0.19-cm2 areas, respectively; Pine Instrument Co.), of which only the disc was used during the voltammetric measurements. Before each measurement, the surfaces of the electrodes were polished with 0.05-m alumina, subjected to ultrasonication, and washed with KMnO4 (10%) + H2 SO4 (30%) and H2 O2 (15%) + H2 SO4 (50%) solutions. After that, the electrodes were copiously washed with water and dried with paper towel and N2 . The reference electrode was an aqueous saturated calomel electrode (SCE), separated from the solution by a jacket equipped with a sintered glass junction, in order to minimize water leakage. The counter-electrode was platinum gauze (Degusa). All solutions were degassed by nitrogen bubbling prior to the experiment and maintained under a nitrogen atmosphere during the measurement procedures. Long-term controlled-potential electrolyses (4 h) at a concentration of 3.5-mM 1H (50 mg dissolved in 50 mL of a 0.1-M solution of TBAP + DMSO) were performed at the potential reached after the first and second reduction peaks (−2.1 and −2.6 V vs. SCE, respectively). The working electrode was a GC plate (8-cm2 area; Johnson Matthey Co.). The counter-electrode was platinum gauze (Degusa) and the reference electrode was SCE, both isolated from the solution by a bridge equipped with a sintered glass junction. The solution was stirred with N2 during electrolysis. For isolation purposes, the organic compounds were extracted from the electrolyzed solutions by adding water and ethyl acetate. The organic extract was dried in a rotary evaporator under vacuum at r.t. and then solubilized in methanol, yielding a supernatant and a solid residue. Once separated from the supernatant, the solid residue was again washed with methanol two or three times. Both the supernatant and the solid residue were dried at r.t. NMR analysis showed the supernatant to contain 1H and 1H3 (in a lower proportion than 1H), whereas only 1H was present in the solid residue.
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Fig. 1. Cyclic voltammograms of the reduction in DMSO containing 0.1-M TBAP, at a GC electrode, of (a) DMSO containing 0.1-M TBAP and (b, c) 2.4-mM 1H. Scans start at 0 V vs. SCE in the negative potential direction. Scan rate: 200 mV s−1 .
Fig. 3. Plots of first (A) and second (B) cathodic peak current functions (Ipc −1/2 c−1 ) vs. the potential scan rate for the reduction of solutions containing: () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM 1H in DMSO with 0.1-M TBAP.
3. Results and discussion
Fig. 1 shows typical cyclic voltammograms recorded with the stationary GC electrode in a 2.4-mM solution of 1H in DMSO (0.1M TBAP). Two reduction and one oxidation peaks were observed at approximately −1.77 and −2.57, and −1.70 V ( = 200 mV s−1 ), respectively. The current peak for the second reduction had about the half-value of the first one – measured by stopping the potential scan at a value 50–60 mV more negative than −1.77 V and allowing the current to decay to a small value, then continuing the scan and measuring the current to second peak. By reversing the potential scan immediately after the peak potential of the first reduction peak the oxidation peak was observed to increase in current (curve b, Fig. 1), fact also observed with the increase in potential scan rate. This behavior may suggest, albeit only very roughly so far, a reversible heterogeneous charge transfer for the first reduction of 1H, producing 1H•− (a radical anion), followed by behavior-type irreversible heterogeneous charge transfer for the second reduction. We analyzed the dependence of the peak current (Ipc1 or Ipc2 ) against the square root of the potential scan rate (1/2 ) (Fig. 2A and B, respectively) and the initial substrate concentration (not
shown, but directly deduced from Fig. 2). The first dependence was linear between 50 and 4000 mV s−1 . The second dependence was linear between 0.66 and 4.8 mM in the range of potential scan rates (50–4000 mV s−1 ). These linear dependences indicate the occurrence of a diffusion-controlled process for the reduction of 1H [13]. One important dependence was Ipc2 /Ipc1 vs. , since it was found that this ratio can be considered as constant when the potential scan rate is increased. This behavior suggests that the second reduction involves the reduction of species formed after the first reduction (1H•− ). Important dependences were Ipc1 −1/2 c−1 (or Ipc2 −1/2 c−1 ) vs. (Fig. 3A and B, respectively). With the increase of the potential scan rate, the current functions were found to increase and reach constancy at different concentrations of 1H. This behavior suggests a mechanism Er Cslow (heterogeneous charge transfer – chemical reaction) [14] for both dependences. The cyclic voltammetry data were obtained with ohmic drop compensation, and they allowed us to observe that peak potentials tended to be displaced toward more negative potentials with the increase of potential scan rates (Fig. 4) revealing linear dependences, with average inclinations from −14.5 to −49 mV at different concentrations of 1H, for Epc1 vs. log (Fig. 4A), and another average inclination of −43 mV at different concentrations of 1H, for Epc2 vs. log (Fig. 4B). This behavior suggests an EC-type mechanism
Fig. 2. Dependences of the first (A) and second (B) cathodic peak currents on the square root of the potential scan rate in the reduction of solutions containing: () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM 1H in DMSO with 0.1-M TBAP.
Fig. 4. Dependences of the first (A) and second (B) cathodic peak potentials on log() for the reduction of solutions containing: () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM 1H in DMSO with 0.1-M TBAP.
3.1. Cyclic voltammetry experiments
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Fig. 5. Cyclic voltammograms of the reductions of 0.66 mM of (—) MAQ, (– – –) 1H, and (· · ·) anthracene in DMSO containing 0.1-M TBAP, at a GC electrode. Scans start at 0 V vs. SCE in the negative potential direction. Scan rate: 200 mV s−1 .
(∂Ep /∂log change from 0 to −30/n mV as a function of potential scan rate [14]) for both dependences. The value of Epc/2,1 − Epc1 was found to be around 70 mV (average) at low potential scan rate (50–800 mV s−1 ) and the ratio −Ipc1ox /Ipc1red increased to 0.65 at high potential scan rate (4000 mV s−1 ) at different concentrations of 1H. These last two behaviors suggest an ECslow -type mechanism [14]. The number of electrons transferred during the electrochemical reduction of 1H was determined by comparison with those of MAQ [15] and anthracene [16], which involve two successive oneelectron reductions. With MAQ, the first electron transfer (−0.86 V vs. SCE, 200 mV s−1 , 0.66 mM) is known to be reversible [15]. When we compared the first peak current for 1H with those for MAQ or anthracene (Fig. 5), we found approximately the same peak current for the first process (the same behavior was observed at a concentration of 2.4 mM), a feature that reveals the involvement of one electron during the first heterogeneous electron transfer in the reduction of 1H. To further describe the reduction mechanism of 1H we conducted cyclic voltammetry experiments with 1.24-mM 1H to which 12-mM TMAOH was added (an excess of strong base free of water), 1.24-mM 1H to which 6-mM HClO4 (an excess of strong enough acid) was added, and also of 1.24-mM 1H to which 0.03-M NaClO4 (Merck) was added (Fig. 6). A pronounced change was observed in the current responses for the reduction of 1H in the presence of TMAOH, given the absence of peaks. The presence of HClO4 modified the current response, as shown by the enlargement of the first reduction peak of 1H and the disappearance of second reduction and oxidation peaks. The presence of NaClO4 displaced the reduction peaks a few mV and the anodic peak corresponding to the first reduction peak of 1H after the potential scan was reversed at −2.6 V was sharply decreased. The deprotonation of the acidic hydrogen of 1H in presence of TMAOH producing 1− shows that 1− is electroinactive (absence of peaks) in the potential range used in this experiment. The response obtained in the presence of HClO4 shows that 1H present some dependence on a protonation step occurring in the potential range of the first reduction of 1H (even though the cathodic peak current did not change in comparison with 1H in the absence of HClO4 given the fact that the corresponding anodic peak disappeared in the range of potential scan rates studied, whether or not the potential scan was reversed after the first reduction peak) and the second reduction of 1H either was displaced toward a more negative potential or did not occur at all. In fact, these results obtained in the presence of HClO4 suggest a slow
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Fig. 6. Cyclic voltammograms of the reduction in DMSO containing 0.1-M TBAP, at a GC electrode, of (—) 1.24-mM 1H in the presence of 12-mM TMAOH and (– – –) 1.24mM 1H, (· · ·) 1.24-mM 1H in the presence of 0.03-M NaClO4 and (– · – ·) 1.24-mM 1H in the presence of 6-mM HClO4 . Scans start at 0 V vs. SCE in the negative direction. Scan rate: 200 mV s−1 .
protonation of 1H•− by HClO4 . The effect of ion pairing between Na+ and 1H•− is not accentuated due the small reduction potential displacement for the second reduction of 1H in presence of NaClO4 . Also, the decreased reversibility of the first reduction peak of 1H in presence of NaClO4 can be attributed to the increase of acidity of 1H for the stabilization of its anion with Na+ (Na+ /1− pair). 3.2. Rotating ring-disc electrode experiments We conducted experiments under forced-convection conditions by using rotating ring and disc electrodes. Fig. 7 shows the current responses for GC rotating disc and ring electrodes in the presence of 1H. One well-defined wave can be seen in the current responses at the rotating disc electrode (ID ), corresponding to the electrochemical reduction of 1H and involving around one electron, as confirmed by the current responses to 1H, MAQ, and anthracene
Fig. 7. Current responses at rotating disc and ring GC electrodes vs. potential at a GC rotating disc electrode during the reduction of 2.4-mM 1H in DMSO containing 0.1M TBAP. (The potential at the GC rotating ring electrode was maintained constant at 0 V vs. SCE throughout the scan (rate: 20 mV s−1 ) performed with the GC rotating disc electrode.) Scans start at 0 V vs. SCE in the negative potential direction. Rotation rates for the rotating electrodes: (a) 400 rpm, (b) 900 rpm, (c) 1600 rpm, (d) 2500 rpm, (e) 3600 rpm, and (f) 4500 rpm.
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Fig. 8. Current responses at rotating disc GC electrode vs. potential at a GC rotating disc electrode during the reduction of 0.66-mM (—) MAQ, (– – –) 1H, and (· · ·) anthracene in DMSO containing 0.1-M TBAP. Scans start at 0 V vs. SCE in the negative potential direction. Scan rate: 20 mV s−1 . Rotation rate for the rotating electrode: 1600 rpm.
at the rotating disc electrode (Fig. 8). The current responses at the rotating ring electrode (IR ) were well-defined at the potential range corresponding to the first reduction of 1H (Fig. 7). Collection efficiencies (−IR /ID ) at a −1.15-V potential for MAQ and −2.15-V for anthracene (Fig. 8) reached a value of 0.35 (0.37 being the theoretical collection efficiency for the GC electrode used in the present study). Collection efficiency at a −2.1-V potential for 1H was highest (0.267) at 4500 rpm and lowest (0.185) at 400 rpm. The experimental collection efficiency observed in this study, being close to the theoretical value for MAQ [15] and anthracene, supports the view of a global reversible charge-transfer behavior of these two molecules and less reversibility for 1H. 1H appears to be responsible for a certain kinetic contribution to the collection efficiency. Fig. 9 shows the linear behavior and zero crossing of the rotating disc limit currents (values for different concentrations of 1H) for the first wave at ω1/2 , supporting the view of a diffusion control occurring for this charge transfer. From the curve inclination in Fig. 9 [13] we obtained D0 = 2.66 × 10−6 cm2 s−1 for the electrochemical reduction of 1H, a value close to that estimated for 1-methoxyxanthone (D0 = 3.27 × 10−6 cm2 s−1 ) [5].
Fig. 9. Plot of limit cathodic currents at a GC rotating disc electrode vs. square root of rotation rates (ω1/2 ) for the reduction of () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM 1H in DMSO containing 0.1-M TBAP.
Fig. 10. Plot of first-wave limit cathodic current functions (Ilc1 ω−1/2 c−1 ) vs. the rotation rate for the reduction of solutions containing: () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM of 1H in DMSO with 0.1-M TBAP.
Fig. 10 shows the rotating disc limit current function (Ilc1 ω−1/2 c−1 ) vs. ω for different concentrations of 1H. The current functions can be considered constant with the increase of ω, suggesting a mechanism involving Er [13]. E1/2,1 (obtained from rotating disc results with ohmic drop compensation) vs. log ω (not shown) exhibited linear behavior with average inclinations from 0 to −15 mV for different concentrations of 1H, suggesting an Er Cslow type mechanism [14], as compared with the relations drawn from cyclic voltammetry data. We also conducted rotating ring-disc experiments for 1.24-mM 1H by adding 12-mM TMAOH, 1.24-mM 1H to which 6-mM HClO4 was added, as well as for 1.24-mM 1H to which 0.03-M NaClO4 was added. We observed that in the presence of TMAOH the rotating ringdisc waves disappeared in contrast with the response to 1H alone (Fig. 11) suggesting that 1− is electroinactive in the potential range used in this experiment. The presence of HClO4 modified the ringdisc current responses (Fig. 11), as shown by an displacement to more positive potential of disc currents in relation to the first reduction wave of 1H alone, appearance of a peak with larger current (not
Fig. 11. Current responses at rotating disc and ring GC electrodes vs. potential during the reduction in DMSO containing 0.1-M TBAP at a GC rotating disc electrode, at 1600 rpm of the rotating electrodes, of (a) 1.24-mM 1H in the presence of 12mM TMAOH, (b) 1.24-mM 1H in the presence of 6-mM HClO4 , (c) 1.24-mM 1H and (d) 1.24-mM 1H the presence of 0.03-M NaClO4 . (The potential at the GC rotating ring electrode was maintained constant at 0 V vs. SCE throughout the scan (rate: 20 mV s−1 ) performed with the GC rotating disc electrode.) Scans start at 0 V vs. SCE in the negative potential direction.
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Scheme 1. Proposed electroreduction route for 1H in DMSO (0.1-M NaClO4 ) related to the first reduction peak or wave.
twice) as compared with the limit current to reduction of 1H alone and absence of ring currents. The presence of NaClO4 displaced the reduction waves a few mV and the ring currents corresponding to the first reduction wave of 1H were decreased in relation to those of 1H alone. The response obtained in the presence of HClO4 suggests that 1H (Fig. 11) present some dependence on a protonation step occurring in the potential range of the first reduction wave of 1H (the cathodic wave current increased in comparison with 1H in the absence of HClO4 and the corresponding anodic wave current disappeared in the range of rotation rates investigated). The effect of ion pairing between Na+ and 1H•− is not accentuated due the small reduction potential displacement for the second reduction of 1H in presence of NaClO4 . Also, the decreased reversibility of the first reduction wave (decrease in ring currents) of 1H in presence of NaClO4 can be attributed to the increase of acidity of 1H for the stabilization of its anion with Na+ (Na+ /1− pair). 3.3. Long-term controlled-potential electrolysis Long-term controlled-potential electrolyses at −2.6 V vs. SCE (see Section 2) were performed in order to yield products from the reduction of 1H. The electrolyses conducted at −2.1 V vs. SCE led to the same main products obtained at −2.6 V vs. SCE, although in smaller amounts for the same electrolysis time (4 h). One important observation was that 4 h of electrolysis at −2.6 V vs. SCE corresponded to a charge consumption of around 1.0 e− /molecule. Also, 4 h of electrolysis at −2.1 V vs. SCE to 1H in presence or absence of acetic acid corresponded to a charge consumption of around 1.0 e− /molecule. The faradic efficiency was roughly 20%, considering two electrons/molecule to yield product 1H3 (see Scheme 1), since we were able to recover around 90% of the starting material. Electroreduction selectivity in producing compound 1H3 was around 100%. Compound 1H3 (Scheme 1) was elucidated by NMR analysis. A cyclic voltammetry experiment conducted after 4 h of longterm controlled-potential electrolysis at −2.6 V vs. SCE revealed nearly the same behavior and peak current (90% of the value
observed in a similar experiment carried out before electrolysis), characterizing partial production of 1H3 . 3.4. NMR analysis The structures of 1H and 1H3 were elucidated by NMR spectroscopy using a mixture of both compounds. Initially, hydrogen signals were observed in the 1D spectrum at 300 MHz. Elucidation was greatly aided by 1D 13 C spectra (75 MHz), along with the 2D-NMR techniques gHSQC (heteronuclear single-quantum coherence), gHMBC (heteronuclear multiple-bond correlation), and gNOESY (nuclear Overhauser enhancement spectroscopy) (see Table 1 for complete NMR assignments). For compound 1H, signals at ı 6.67 and ı 6.32 showed correlation in a gHMBC experiment with signals at ı 159.5 and ı 157.0, respectively. These correlations demonstrated the presence of an ether bond between carbons C-4a and C-10a, corroborating the structure of lichexanthone. In addition, only one signal corresponding to a hydroxyl group was observed at ı 13.39, due to its hydrogen bond interaction with carbonyl (C9), which was confirmed by correlations with the carbons at positions 1, 2, 9a, and 9 (Fig. 12). For compound 1H3 , although a relevant similarity has been observed between the NMR signals of compounds 1H and 1H3 , the presence of a new aromatic hydrogen at ı 6.66 (1H) and two hydroxyl groups at ı 13.54 and ı 13.98 was decisive for differentiation. The correlation found in the gHSQC experiment between the signals at ı 6.66 (1H) and ı 98.0, along with the correlations obtained in the gHMBC experiment between this hydrogen and the carbons at positions 1, 2, and 3, suggest the presence of an aromatic hydrogen bonded at position 4a (see enlarged detail in Fig. 12). Moreover, two hydroxyl groups at ı 13.54 (due to hydrogenbond interaction with carbonyl (C-9)) and ı 13.98 were detected (enlarged detail in Fig. 12). According to these observations, the ether bond present in compound 1H was broken in compound 1H3 , and a new hydroxyl group was formed at position 10a, corroborating the structure proposed. Additionally, for compound 1H3 , the gNOESY experiment showed correlation between hydrogens at positions 2 (ı 6.40) and
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Fig. 12. gHMBC correlations for a mixture of 1H and 1H3 , with enlarged detail of the range comprising a new aromatic hydrogen at ı 6.66 and two hydroxyl groups at ı 13.45 and ı 13.98.
3-OMe (ı 3.98), as well as between those at positions 5 (ı 6.80) and 6-OMe (ı 3.92). These correlations were relevant for elucidation of the aromatic hydrogen located near methoxyl groups, according to the NMR assignment proposed in Table 1. 3.5. Mechanistic proposition The voltammetric responses for the electroreduction of 1H suggest a mechanism involving two one-electron heterogeneous transfers (two peaks observed, one electron involved in each), as determined from the electrochemical reduction of 1H in comparison with MAQ and anthracene, in the potential range of −1.5 to −2.6 V vs. SCE. The linear dependences Ipc1 (or Ipc2 ) vs. 1/2 (or concentration of 1H) and Ilc1 vs. ω1/2 (or concentration of 1H) indicate the occurrence of a diffusion-controlled process in the reduction of 1H. The current functions Ipc1 −1/2 c−1 (or Ipc2 −1/2 c−1 ) vs. and Ilc1 ω−1/2 c−1 vs. ω suggests a mechanism Er Cslow . The linear dependences of Epc1 vs. log (−14.5 to −49 mV), Epc2 vs. log (−43 mV), and Epc/2,1 − Epc1 (70 mV) at low potential scan rates and El/2,1 vs. log ω (0 to −15 mV) suggest a mechanism of type ECslow . The increase in the −Ipc1ox /Ipc1red ratio with the increase of the potential scan rate suggests also an ECslow -type mechanism. The absence of voltammetric and rotating ring-disc responses (peaks or waves) for the electroreduction of 1H obtained in the presence of TMAOH corroborates the electroinactivity of 1− in the potential range studied. The voltammetric and rotating ring-disc responses obtained in presence of HClO4 show that 1H present some dependence on a protonation step occurring in the potential range of the first reduction of 1H. This is revealed by the enlargement of the first reduction peak of 1H and the disappearance of second reduction and oxidation peaks, and by an displacement to more positive potential of disc currents in relation to the first wave of 1H alone, appearing of a peak with larger current (not twice) as compared with the limit current to reduction of 1H alone and absence of ring currents. The results obtained in the presence of HClO4 suggest slow protonation of 1H•− (chemical reaction) by HClO4 , which can depends on a previous breakage of a bond. The effect of ion pairing between Na+ and 1H•− is small but perceptible in the displacement of peak or wave potentials (voltam-
metric and rotating disc results) when NaClO4 is added. Also, the effect of ion pairing is present in the increase of acidity of 1H (Na+ /1− pair), given the decreased reversibility of the first reduction peak (or wave) when NaClO4 is added. The structure of compound 1H3 , elucidated by 1D- and 2D-NMR experiments, involves two electrons/molecule. After the 4-h long-term controlled-potential electrolysis, nearly 100% (electroreduction selectivity) of compound 1H3 was recovered. This percentage of recovery was calculated considering 2.0 e− /molecule to yield product 1H3 . Faradic efficiency was roughly 20%, considering that around 90% of the starting material was recovered. After the 4 h of electrolysis at −2.1 V vs. SCE to 1H in presence or absence of acetic acid, or −2.6 V vs. SCE to 1H, corresponded to a charge consumption of around 1.0 e− /molecule. Using the observations described above we propose the scheme for the production of compound 1H3 . In the mechanism we propose for the reduction of 1H (Scheme 1) (first peak or wave) an electron is received and a radical anion 1H•− is produced. This radical anion receives a second electron (second peak) producing 1H2− , which absorbs two protons from residual water, or parent compound, or solvent, or impurities, etc., yielding 1H3 (Scheme 1). Also, the radical anion 1H•− can suffer the breakage of a bond (slow) followed by a protonation from residual water, or parent compound, or solvent, etc., and disproportionation, for instance with 1H•− , producing anion 1H2 − , which absorbs a proton from residual water, or parent compound, or solvent, etc., yielding 1H3 (Scheme 1). To our knowledge, compound 1H3 has not been previously reported in the literature. Compound 1H3 , a ketone formed from a xanthone (1H) — an uncommon occurrence in the literature — results from the breakage of an ether bond between two aromatic rings. Although the breakage of a bond involving allylic ether is a common occurrence [17], that of an ether bond between two aromatic rings, as previously detected by our team [18], is not. 4. Conclusions The electrochemical data and criteria for the reduction of 1H, in addition to the information obtained from 1D- and 2D-NMR experiments in the elucidation of compound 1H3 , suggest a mechanism by which compound 1H initially receives one electron through reversible heterogeneous electron transfer with production of a radical anion 1H•− . This step is followed by a slow chemical reaction (breakage of a bond, for example). The second reduction peak for 1H was attributed to the electroreduction of 1H•− , which undergoes one-electron transfer, with production of a dianion 1H2− , which is protonated by residual water, or parent compound, or solvent, etc., producing in turn compound 1H3 , which, to our knowledge, is a new substance: a ketone obtained from a xanthone — an unexpected occurrence. It is possible the radical anion 1H•− with breakage of a bond to be protonated by residual water, or parent compound, or solvent, etc., producing a radical 1H2 • . This radical 1H2 • can suffer a disproportionation with 1H•− producing an anion 1H2 − , which is protonated by residual water, or parent compound, or solvent, etc., producing in turn compound 1H3 . The diffusion coefficient (D0 ) for 1H was found to be 2.66 × 10−6 cm2 s−1 . Acknowledgments The authors thank PROPP-UFMS, FUNDECT-MS (Grant 23/ 200.119/2007), CAPES, and CNPq (Brazil) for their financial support. Thanks are also given to one of the referees who reviewed this paper, for the valuable contributions provided.
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[11] S. Kathirgamanathar, W.D. Ratnasooriya, P. Baekstrom, R.J. Andersen, V. Karunaratne, Pharm. Biol. 44 (2006) 217. [12] A.C. Micheletti, A. Beatriz, D.P. Lima, N.K. Honda, C.O. Pessoa, M.O. Moraes, L.V. Lotufo, H.I.F. Magalhães, N.C.P. Carvalho, Quim. Nova, in press. [13] A.J. Bard, L.R. Faulkner, Electrochemical Methods, Fundamentals and Applications, Wiley, New York, 2001. [14] R.S. Nicholson, I. Shain, Anal. Chem. 36 (1964) 706. [15] M.C.E. Bandeira, G. Maia, Electrochim. Acta 53 (2008) 4512. [16] S.T. Pedersen, T.B. Christensen, T. Thomasen, K. Daasbjerg, J. Electroanal. Chem. 454 (1998) 123. [17] F. Guibé, Tetrahedron 53 (1997) 13509. [18] A.E. Carvalho, A. Barison, N.K. Honda, A.G. Ferreira, G. Maia, J. Electroanal. Chem. 572 (2004) 1.
Contents lists available at ScienceDirect
Electrochimica Acta journal homepage: www.elsevier.com/locate/electacta
Electroreduction of lichexanthone Adriana E. Carvalho, Glaucia B. Alcantara, Sebastião M. Oliveira, Ana C. Micheletti, Neli K. Honda, Gilberto Maia ∗,1 Departamento de Química, Universidade Federal de Mato Grosso do Sul, C.P. 549, Campo Grande, MS 79070-900, Brazil
a r t i c l e
i n f o
Article history: Received 14 July 2008 Received in revised form 3 October 2008 Accepted 24 October 2008 Available online 31 October 2008 Keywords: Lichexanthone Electroreduction Radical anion Dianion 2-Hydroxy-4-methoxy-6-methylphenyl 2-hydroxy-4-methoxyphenyl ketone
a b s t r a c t This paper reports the first study on the electrochemical reduction of lichexanthone (1H) (1-hydroxy-3,6dimethoxy-8-methylxanthen-9-one) on glassy carbon (GC) electrodes in DMSO, using cyclic voltammetry, rotating disc and ring electrodes, and long-term controlled-potential electrolysis. Parameters involving data from cyclic voltammetry and rotating disc electrodes, such as current functions, Epc1 vs. log , Epc2 vs. log , Epc/2,1 − Epc1 , −Ipc1ox /Ipc1red , Ipc2 /Ipc1 , E1/2 vs. log ω, and collection efficiency (rotating disc and ring electrode data), were used to elucidate the reduction mechanism of 1H that involves two one-electron transfers (two reduction peaks in the voltammograms), the first of which, with reversible characteristics, involves electroreduction of 1H, producing a radical anion 1H•− , whereas the second, with irreversible characteristics, involves electroreduction of 1H•− , producing a dianion 1H2− . Both transfers appear to involve an Er Cslow -type mechanism with a chemical step consisting of breakage of a bond followed by protonation of residual water, or parent compound, or solvent, etc., to yield 2hydroxy-4-methoxy-6-methylphenyl 2-hydroxy-4-methoxyphenyl ketone (1H3 ), directly, in the case of 1H2− involved. Compound 1H3 was elucidated by 1D- and 2D-NMR methods. D0 = 2.66 × 10−6 cm2 s−1 was found for the electrochemical reduction of 1H. © 2008 Elsevier Ltd. All rights reserved.
1. Introduction Xanthones or 9H-xanthen-9-ones (dibenzo-␥-pirones) are an important class of oxygenated heterocycles with a well-known role in Medicinal Chemistry. The biological activities of this class of compounds are associated with their tricyclic scaffold, but they may vary depending on the nature and/or position of substituents [1]. Recently, Pinto et al. [1] reviewed biological and pharmacological effects of synthetic and natural xanthone derivatives, with emphasis on some studies on structure–activity relationships. The antitumor activity of some xanthones and examples of “hit” compounds involved in cancer therapy — namely psorospermin, mangiferin, norathyriol, and mangostins, are highlighted by the authors [1]. Day and Biggers [2] found that in alkaline solutions xanthone exhibits one polarographic reduction wave. Kalinowski et al. [3] studied the polarographic behavior of fluorenone, xanthone, benzophenone, and 4-chlorobenzophenone, observing that aromatic ketones were reduced in two one-electron steps, the first of them behaving as a reversible one-electron (plus eventually one-proton)
∗ Corresponding author. Tel.: +55 67 33453551; fax: +55 67 33453552. E-mail address: [email protected] (G. Maia). 1 ISE member. 0013-4686/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.electacta.2008.10.035
transfer. The authors comment on the greater stability of the xanthone ketyl radical and report that all those molecules form dimmers (pinacols). Kalinowski and Grabowski [4] investigated the dimerization equilibrium and dismutation kinetics of fluorenone and xanthone ketyl radicals with electrochemical methods at various pH values. Whitman and Wiles [5] studied the polarographic reduction of xanthone and methoxyxanthone and suggested that in strong acid the reduction of xanthone and their monomethyl ethers is a reversible one-electron process. They suggested that the single-wave reduction of xanthones produces a free radical, which eventually undergoes dimerization. Fournier et al. [6] studied the electrochemical reduction of hindered aromatic ketones (e.g. indanone, chromanone, xanthone) in the presence of Mn(II) chloride, observing that a selective hydrodimerization into an ␣-glycol takes place, with total absence of polymerization. With dissymmetric ketones, dl diastereoisomers of diols are preferentially produced. Bannerjee and Chakraborty [7] recorded DC polarograms of xanthone at different pH values and suggested that in acidic solutions, where two one-electron waves occur, the mechanisms involved are CECE (chemical–electrochemical–chemical–electrochemical) in a lower pH range (2.01 and 3.1) and CEEC in an intermediate range (3.5, 4.7, and 5.6). Between pH 5.6 and 8.6, previous protonation was regarded as improbable and an EECC mechanism was assumed. The investigators proposed that a competitive dimerization of ion radicals formed through a one-electron uptake also occurs in this pH
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Table 1 1 H NMR (300 MHz) and 13 C NMR (75 MHz) data for compounds 1H (CDCl3 ) and 1H3 (CDCl3 ). Position
1H
1H3
1
H NMR ı (ppm); multiplicity; number of hydrogens
13
gHMBC
1
C NMR ı (ppm)
H NMR ı (ppm); multiplicity; number of hydrogens
13
C NMR ı (ppm)
gHMBC
1 2 3 4
13.39; s; OH 6.29; d; 1H – 6.32; d; 1H
163.70 96.8 165.9 92.1
C-1; C-2; C-3; C-9 C-1; C-3; C-4; C-9a; C-9 – C-2; C-3; C-9; C-4a; C-9a
13.54; s; OH 6.40; s; 1H – 6.31; d; 1H
162.2 94.8 161.0 92.5
6.67; d; 1H – 6.65; d; 1H
98.5 163.75 115.4
C-6; C-7; C-9; C-10a; C-8a – 8-CH3 ; C-6; C-9; C-8a ;
6.80; d; 1H – 6.65; d; 1H
98.7 164.1 116.2
– – – – – – 3.86; s; 3H 3.89; s; 3H 2.84; s; 3H
143.8 182.7 157.0 113.0 104.3 159.5 55.6 55.7 23.4
– – – – – – C-3 C-6 C-7; C-8; C-9; C-5a; C-8a; C-10a
– – 6.66; d; 1H – – 13.98; s; OH 3.98; s; 3H 3.92; s; 3H 2.84; s; 3H
143.8 182.6 98.0 113.0 104.3 163.72 56.6 55.8 23.4
C-1; C-2; C-9; C-9a C-1; C-9a – C-2; C-3; C-4a; C-9aa – – 8-CH3 ; C-6; C-9; C-8aa – – C-1; C-2; C-3 – – – C-3 C-6 C-6; C-7; C-8; C-9; C-5a; C-8a; C-10a
5 6 7 8 9 4a 8a 9a 10a 3-OCH3 6-OCH3 8-CH3
Position numbers are based on the biosynthetic route, to facilitate comparison of all compounds. The IUPAC nomenclature was not used. a Correlation for compound 1H3 overlapped to correlation for compound 1H.
range. Above pH 8.6 a second wave appeared, which, at increasing pH values, grew at the expense of the first, leading the authors to propose an EECC mechanism by which the intermediate anion radical can also combine with a cation and the stabilized complex ion thus formed is reduced to the final product at more negative potentials. Lichexanthone can be obtained synthetically [8] or isolated from natural products [9] and lichens [10]. Kathirgamanathar et al. [11] showed that lichexanthone has larvicidal activity against secondinstar larvae of the mosquito Aedes aegypti and that it enhances human sperm motility. Despite the availability of electroreduction studies on xanthone and molecules such as benzophenone, among others, no electroreduction investigations have, to our knowledge, been conducted on lichexanthone. The present study focuses on lichexanthone and proposes an electroreduction mechanism for this compound. This mechanism can be used as a model for the reduction of other xanthones, such as 1H, whose structure contains a nucleofugic moiety (ether), in addition to exhibiting biologic activity. The electrochemical procedures utilized were cyclic voltammetry, hydrodynamic voltammetry, and long-term controlled-potential electrolysis. The elucidation of product 1H3 was based on 1D and 2D-NMR methods. 2. Experimental Compound 1H was isolated from the lichen Parmotrema sp. according to Micheletti et al. [12]. Anthracene (Aldrich, reagent grade) and 2-methylanthraquinone (MAQ) (Acros Organics) were used to estimate the number of electrons transferred during the electroreduction of 1H. Tetramethylammonium hydroxide (TMAOH, Aldrich) utilized was prepared from a 25 wt% solution in water, dissolved in 5 mL of methanol, and dried in a glass apparatus (Schlenck tube) under reduced pressure and inert atmosphere (N2 ). After a few minutes of solvent evaporation, the dry salt was obtained. The supporting electrolyte used in the electrochemical measurements was tetrabutylammonium perchlorate (TBAP, Acros, electrochemical grade) and the solvent was DMSO (<0.05% water, Vetec). All other chemicals were of analytical grade and were used as received.
1 H, 13 C, and 2D-NMR experiments were recorded on a 7.05-T Bruker DPX300 instrument using a 5-mm dual direct-detection and a broadband inverse-detection probe, with Bruker TopSpin software package (version 1.3) for data processing (Table 1). The voltammograms, rotating disc and ring current responses, and electrolysis data were obtained using a Pine AFCBP1 bipotentiostat. The voltammetric and rotating disc and ring curves were obtained with a three-electrode system. The working electrodes were a GC disc and ring (0.25-cm2 and 0.19-cm2 areas, respectively; Pine Instrument Co.), of which only the disc was used during the voltammetric measurements. Before each measurement, the surfaces of the electrodes were polished with 0.05-m alumina, subjected to ultrasonication, and washed with KMnO4 (10%) + H2 SO4 (30%) and H2 O2 (15%) + H2 SO4 (50%) solutions. After that, the electrodes were copiously washed with water and dried with paper towel and N2 . The reference electrode was an aqueous saturated calomel electrode (SCE), separated from the solution by a jacket equipped with a sintered glass junction, in order to minimize water leakage. The counter-electrode was platinum gauze (Degusa). All solutions were degassed by nitrogen bubbling prior to the experiment and maintained under a nitrogen atmosphere during the measurement procedures. Long-term controlled-potential electrolyses (4 h) at a concentration of 3.5-mM 1H (50 mg dissolved in 50 mL of a 0.1-M solution of TBAP + DMSO) were performed at the potential reached after the first and second reduction peaks (−2.1 and −2.6 V vs. SCE, respectively). The working electrode was a GC plate (8-cm2 area; Johnson Matthey Co.). The counter-electrode was platinum gauze (Degusa) and the reference electrode was SCE, both isolated from the solution by a bridge equipped with a sintered glass junction. The solution was stirred with N2 during electrolysis. For isolation purposes, the organic compounds were extracted from the electrolyzed solutions by adding water and ethyl acetate. The organic extract was dried in a rotary evaporator under vacuum at r.t. and then solubilized in methanol, yielding a supernatant and a solid residue. Once separated from the supernatant, the solid residue was again washed with methanol two or three times. Both the supernatant and the solid residue were dried at r.t. NMR analysis showed the supernatant to contain 1H and 1H3 (in a lower proportion than 1H), whereas only 1H was present in the solid residue.
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Fig. 1. Cyclic voltammograms of the reduction in DMSO containing 0.1-M TBAP, at a GC electrode, of (a) DMSO containing 0.1-M TBAP and (b, c) 2.4-mM 1H. Scans start at 0 V vs. SCE in the negative potential direction. Scan rate: 200 mV s−1 .
Fig. 3. Plots of first (A) and second (B) cathodic peak current functions (Ipc −1/2 c−1 ) vs. the potential scan rate for the reduction of solutions containing: () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM 1H in DMSO with 0.1-M TBAP.
3. Results and discussion
Fig. 1 shows typical cyclic voltammograms recorded with the stationary GC electrode in a 2.4-mM solution of 1H in DMSO (0.1M TBAP). Two reduction and one oxidation peaks were observed at approximately −1.77 and −2.57, and −1.70 V ( = 200 mV s−1 ), respectively. The current peak for the second reduction had about the half-value of the first one – measured by stopping the potential scan at a value 50–60 mV more negative than −1.77 V and allowing the current to decay to a small value, then continuing the scan and measuring the current to second peak. By reversing the potential scan immediately after the peak potential of the first reduction peak the oxidation peak was observed to increase in current (curve b, Fig. 1), fact also observed with the increase in potential scan rate. This behavior may suggest, albeit only very roughly so far, a reversible heterogeneous charge transfer for the first reduction of 1H, producing 1H•− (a radical anion), followed by behavior-type irreversible heterogeneous charge transfer for the second reduction. We analyzed the dependence of the peak current (Ipc1 or Ipc2 ) against the square root of the potential scan rate (1/2 ) (Fig. 2A and B, respectively) and the initial substrate concentration (not
shown, but directly deduced from Fig. 2). The first dependence was linear between 50 and 4000 mV s−1 . The second dependence was linear between 0.66 and 4.8 mM in the range of potential scan rates (50–4000 mV s−1 ). These linear dependences indicate the occurrence of a diffusion-controlled process for the reduction of 1H [13]. One important dependence was Ipc2 /Ipc1 vs. , since it was found that this ratio can be considered as constant when the potential scan rate is increased. This behavior suggests that the second reduction involves the reduction of species formed after the first reduction (1H•− ). Important dependences were Ipc1 −1/2 c−1 (or Ipc2 −1/2 c−1 ) vs. (Fig. 3A and B, respectively). With the increase of the potential scan rate, the current functions were found to increase and reach constancy at different concentrations of 1H. This behavior suggests a mechanism Er Cslow (heterogeneous charge transfer – chemical reaction) [14] for both dependences. The cyclic voltammetry data were obtained with ohmic drop compensation, and they allowed us to observe that peak potentials tended to be displaced toward more negative potentials with the increase of potential scan rates (Fig. 4) revealing linear dependences, with average inclinations from −14.5 to −49 mV at different concentrations of 1H, for Epc1 vs. log (Fig. 4A), and another average inclination of −43 mV at different concentrations of 1H, for Epc2 vs. log (Fig. 4B). This behavior suggests an EC-type mechanism
Fig. 2. Dependences of the first (A) and second (B) cathodic peak currents on the square root of the potential scan rate in the reduction of solutions containing: () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM 1H in DMSO with 0.1-M TBAP.
Fig. 4. Dependences of the first (A) and second (B) cathodic peak potentials on log() for the reduction of solutions containing: () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM 1H in DMSO with 0.1-M TBAP.
3.1. Cyclic voltammetry experiments
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Fig. 5. Cyclic voltammograms of the reductions of 0.66 mM of (—) MAQ, (– – –) 1H, and (· · ·) anthracene in DMSO containing 0.1-M TBAP, at a GC electrode. Scans start at 0 V vs. SCE in the negative potential direction. Scan rate: 200 mV s−1 .
(∂Ep /∂log change from 0 to −30/n mV as a function of potential scan rate [14]) for both dependences. The value of Epc/2,1 − Epc1 was found to be around 70 mV (average) at low potential scan rate (50–800 mV s−1 ) and the ratio −Ipc1ox /Ipc1red increased to 0.65 at high potential scan rate (4000 mV s−1 ) at different concentrations of 1H. These last two behaviors suggest an ECslow -type mechanism [14]. The number of electrons transferred during the electrochemical reduction of 1H was determined by comparison with those of MAQ [15] and anthracene [16], which involve two successive oneelectron reductions. With MAQ, the first electron transfer (−0.86 V vs. SCE, 200 mV s−1 , 0.66 mM) is known to be reversible [15]. When we compared the first peak current for 1H with those for MAQ or anthracene (Fig. 5), we found approximately the same peak current for the first process (the same behavior was observed at a concentration of 2.4 mM), a feature that reveals the involvement of one electron during the first heterogeneous electron transfer in the reduction of 1H. To further describe the reduction mechanism of 1H we conducted cyclic voltammetry experiments with 1.24-mM 1H to which 12-mM TMAOH was added (an excess of strong base free of water), 1.24-mM 1H to which 6-mM HClO4 (an excess of strong enough acid) was added, and also of 1.24-mM 1H to which 0.03-M NaClO4 (Merck) was added (Fig. 6). A pronounced change was observed in the current responses for the reduction of 1H in the presence of TMAOH, given the absence of peaks. The presence of HClO4 modified the current response, as shown by the enlargement of the first reduction peak of 1H and the disappearance of second reduction and oxidation peaks. The presence of NaClO4 displaced the reduction peaks a few mV and the anodic peak corresponding to the first reduction peak of 1H after the potential scan was reversed at −2.6 V was sharply decreased. The deprotonation of the acidic hydrogen of 1H in presence of TMAOH producing 1− shows that 1− is electroinactive (absence of peaks) in the potential range used in this experiment. The response obtained in the presence of HClO4 shows that 1H present some dependence on a protonation step occurring in the potential range of the first reduction of 1H (even though the cathodic peak current did not change in comparison with 1H in the absence of HClO4 given the fact that the corresponding anodic peak disappeared in the range of potential scan rates studied, whether or not the potential scan was reversed after the first reduction peak) and the second reduction of 1H either was displaced toward a more negative potential or did not occur at all. In fact, these results obtained in the presence of HClO4 suggest a slow
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Fig. 6. Cyclic voltammograms of the reduction in DMSO containing 0.1-M TBAP, at a GC electrode, of (—) 1.24-mM 1H in the presence of 12-mM TMAOH and (– – –) 1.24mM 1H, (· · ·) 1.24-mM 1H in the presence of 0.03-M NaClO4 and (– · – ·) 1.24-mM 1H in the presence of 6-mM HClO4 . Scans start at 0 V vs. SCE in the negative direction. Scan rate: 200 mV s−1 .
protonation of 1H•− by HClO4 . The effect of ion pairing between Na+ and 1H•− is not accentuated due the small reduction potential displacement for the second reduction of 1H in presence of NaClO4 . Also, the decreased reversibility of the first reduction peak of 1H in presence of NaClO4 can be attributed to the increase of acidity of 1H for the stabilization of its anion with Na+ (Na+ /1− pair). 3.2. Rotating ring-disc electrode experiments We conducted experiments under forced-convection conditions by using rotating ring and disc electrodes. Fig. 7 shows the current responses for GC rotating disc and ring electrodes in the presence of 1H. One well-defined wave can be seen in the current responses at the rotating disc electrode (ID ), corresponding to the electrochemical reduction of 1H and involving around one electron, as confirmed by the current responses to 1H, MAQ, and anthracene
Fig. 7. Current responses at rotating disc and ring GC electrodes vs. potential at a GC rotating disc electrode during the reduction of 2.4-mM 1H in DMSO containing 0.1M TBAP. (The potential at the GC rotating ring electrode was maintained constant at 0 V vs. SCE throughout the scan (rate: 20 mV s−1 ) performed with the GC rotating disc electrode.) Scans start at 0 V vs. SCE in the negative potential direction. Rotation rates for the rotating electrodes: (a) 400 rpm, (b) 900 rpm, (c) 1600 rpm, (d) 2500 rpm, (e) 3600 rpm, and (f) 4500 rpm.
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Fig. 8. Current responses at rotating disc GC electrode vs. potential at a GC rotating disc electrode during the reduction of 0.66-mM (—) MAQ, (– – –) 1H, and (· · ·) anthracene in DMSO containing 0.1-M TBAP. Scans start at 0 V vs. SCE in the negative potential direction. Scan rate: 20 mV s−1 . Rotation rate for the rotating electrode: 1600 rpm.
at the rotating disc electrode (Fig. 8). The current responses at the rotating ring electrode (IR ) were well-defined at the potential range corresponding to the first reduction of 1H (Fig. 7). Collection efficiencies (−IR /ID ) at a −1.15-V potential for MAQ and −2.15-V for anthracene (Fig. 8) reached a value of 0.35 (0.37 being the theoretical collection efficiency for the GC electrode used in the present study). Collection efficiency at a −2.1-V potential for 1H was highest (0.267) at 4500 rpm and lowest (0.185) at 400 rpm. The experimental collection efficiency observed in this study, being close to the theoretical value for MAQ [15] and anthracene, supports the view of a global reversible charge-transfer behavior of these two molecules and less reversibility for 1H. 1H appears to be responsible for a certain kinetic contribution to the collection efficiency. Fig. 9 shows the linear behavior and zero crossing of the rotating disc limit currents (values for different concentrations of 1H) for the first wave at ω1/2 , supporting the view of a diffusion control occurring for this charge transfer. From the curve inclination in Fig. 9 [13] we obtained D0 = 2.66 × 10−6 cm2 s−1 for the electrochemical reduction of 1H, a value close to that estimated for 1-methoxyxanthone (D0 = 3.27 × 10−6 cm2 s−1 ) [5].
Fig. 9. Plot of limit cathodic currents at a GC rotating disc electrode vs. square root of rotation rates (ω1/2 ) for the reduction of () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM 1H in DMSO containing 0.1-M TBAP.
Fig. 10. Plot of first-wave limit cathodic current functions (Ilc1 ω−1/2 c−1 ) vs. the rotation rate for the reduction of solutions containing: () 0.66 mM; (䊉) 1.23 mM; () 2.4 mM; () 4.8 mM of 1H in DMSO with 0.1-M TBAP.
Fig. 10 shows the rotating disc limit current function (Ilc1 ω−1/2 c−1 ) vs. ω for different concentrations of 1H. The current functions can be considered constant with the increase of ω, suggesting a mechanism involving Er [13]. E1/2,1 (obtained from rotating disc results with ohmic drop compensation) vs. log ω (not shown) exhibited linear behavior with average inclinations from 0 to −15 mV for different concentrations of 1H, suggesting an Er Cslow type mechanism [14], as compared with the relations drawn from cyclic voltammetry data. We also conducted rotating ring-disc experiments for 1.24-mM 1H by adding 12-mM TMAOH, 1.24-mM 1H to which 6-mM HClO4 was added, as well as for 1.24-mM 1H to which 0.03-M NaClO4 was added. We observed that in the presence of TMAOH the rotating ringdisc waves disappeared in contrast with the response to 1H alone (Fig. 11) suggesting that 1− is electroinactive in the potential range used in this experiment. The presence of HClO4 modified the ringdisc current responses (Fig. 11), as shown by an displacement to more positive potential of disc currents in relation to the first reduction wave of 1H alone, appearance of a peak with larger current (not
Fig. 11. Current responses at rotating disc and ring GC electrodes vs. potential during the reduction in DMSO containing 0.1-M TBAP at a GC rotating disc electrode, at 1600 rpm of the rotating electrodes, of (a) 1.24-mM 1H in the presence of 12mM TMAOH, (b) 1.24-mM 1H in the presence of 6-mM HClO4 , (c) 1.24-mM 1H and (d) 1.24-mM 1H the presence of 0.03-M NaClO4 . (The potential at the GC rotating ring electrode was maintained constant at 0 V vs. SCE throughout the scan (rate: 20 mV s−1 ) performed with the GC rotating disc electrode.) Scans start at 0 V vs. SCE in the negative potential direction.
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Scheme 1. Proposed electroreduction route for 1H in DMSO (0.1-M NaClO4 ) related to the first reduction peak or wave.
twice) as compared with the limit current to reduction of 1H alone and absence of ring currents. The presence of NaClO4 displaced the reduction waves a few mV and the ring currents corresponding to the first reduction wave of 1H were decreased in relation to those of 1H alone. The response obtained in the presence of HClO4 suggests that 1H (Fig. 11) present some dependence on a protonation step occurring in the potential range of the first reduction wave of 1H (the cathodic wave current increased in comparison with 1H in the absence of HClO4 and the corresponding anodic wave current disappeared in the range of rotation rates investigated). The effect of ion pairing between Na+ and 1H•− is not accentuated due the small reduction potential displacement for the second reduction of 1H in presence of NaClO4 . Also, the decreased reversibility of the first reduction wave (decrease in ring currents) of 1H in presence of NaClO4 can be attributed to the increase of acidity of 1H for the stabilization of its anion with Na+ (Na+ /1− pair). 3.3. Long-term controlled-potential electrolysis Long-term controlled-potential electrolyses at −2.6 V vs. SCE (see Section 2) were performed in order to yield products from the reduction of 1H. The electrolyses conducted at −2.1 V vs. SCE led to the same main products obtained at −2.6 V vs. SCE, although in smaller amounts for the same electrolysis time (4 h). One important observation was that 4 h of electrolysis at −2.6 V vs. SCE corresponded to a charge consumption of around 1.0 e− /molecule. Also, 4 h of electrolysis at −2.1 V vs. SCE to 1H in presence or absence of acetic acid corresponded to a charge consumption of around 1.0 e− /molecule. The faradic efficiency was roughly 20%, considering two electrons/molecule to yield product 1H3 (see Scheme 1), since we were able to recover around 90% of the starting material. Electroreduction selectivity in producing compound 1H3 was around 100%. Compound 1H3 (Scheme 1) was elucidated by NMR analysis. A cyclic voltammetry experiment conducted after 4 h of longterm controlled-potential electrolysis at −2.6 V vs. SCE revealed nearly the same behavior and peak current (90% of the value
observed in a similar experiment carried out before electrolysis), characterizing partial production of 1H3 . 3.4. NMR analysis The structures of 1H and 1H3 were elucidated by NMR spectroscopy using a mixture of both compounds. Initially, hydrogen signals were observed in the 1D spectrum at 300 MHz. Elucidation was greatly aided by 1D 13 C spectra (75 MHz), along with the 2D-NMR techniques gHSQC (heteronuclear single-quantum coherence), gHMBC (heteronuclear multiple-bond correlation), and gNOESY (nuclear Overhauser enhancement spectroscopy) (see Table 1 for complete NMR assignments). For compound 1H, signals at ı 6.67 and ı 6.32 showed correlation in a gHMBC experiment with signals at ı 159.5 and ı 157.0, respectively. These correlations demonstrated the presence of an ether bond between carbons C-4a and C-10a, corroborating the structure of lichexanthone. In addition, only one signal corresponding to a hydroxyl group was observed at ı 13.39, due to its hydrogen bond interaction with carbonyl (C9), which was confirmed by correlations with the carbons at positions 1, 2, 9a, and 9 (Fig. 12). For compound 1H3 , although a relevant similarity has been observed between the NMR signals of compounds 1H and 1H3 , the presence of a new aromatic hydrogen at ı 6.66 (1H) and two hydroxyl groups at ı 13.54 and ı 13.98 was decisive for differentiation. The correlation found in the gHSQC experiment between the signals at ı 6.66 (1H) and ı 98.0, along with the correlations obtained in the gHMBC experiment between this hydrogen and the carbons at positions 1, 2, and 3, suggest the presence of an aromatic hydrogen bonded at position 4a (see enlarged detail in Fig. 12). Moreover, two hydroxyl groups at ı 13.54 (due to hydrogenbond interaction with carbonyl (C-9)) and ı 13.98 were detected (enlarged detail in Fig. 12). According to these observations, the ether bond present in compound 1H was broken in compound 1H3 , and a new hydroxyl group was formed at position 10a, corroborating the structure proposed. Additionally, for compound 1H3 , the gNOESY experiment showed correlation between hydrogens at positions 2 (ı 6.40) and
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Fig. 12. gHMBC correlations for a mixture of 1H and 1H3 , with enlarged detail of the range comprising a new aromatic hydrogen at ı 6.66 and two hydroxyl groups at ı 13.45 and ı 13.98.
3-OMe (ı 3.98), as well as between those at positions 5 (ı 6.80) and 6-OMe (ı 3.92). These correlations were relevant for elucidation of the aromatic hydrogen located near methoxyl groups, according to the NMR assignment proposed in Table 1. 3.5. Mechanistic proposition The voltammetric responses for the electroreduction of 1H suggest a mechanism involving two one-electron heterogeneous transfers (two peaks observed, one electron involved in each), as determined from the electrochemical reduction of 1H in comparison with MAQ and anthracene, in the potential range of −1.5 to −2.6 V vs. SCE. The linear dependences Ipc1 (or Ipc2 ) vs. 1/2 (or concentration of 1H) and Ilc1 vs. ω1/2 (or concentration of 1H) indicate the occurrence of a diffusion-controlled process in the reduction of 1H. The current functions Ipc1 −1/2 c−1 (or Ipc2 −1/2 c−1 ) vs. and Ilc1 ω−1/2 c−1 vs. ω suggests a mechanism Er Cslow . The linear dependences of Epc1 vs. log (−14.5 to −49 mV), Epc2 vs. log (−43 mV), and Epc/2,1 − Epc1 (70 mV) at low potential scan rates and El/2,1 vs. log ω (0 to −15 mV) suggest a mechanism of type ECslow . The increase in the −Ipc1ox /Ipc1red ratio with the increase of the potential scan rate suggests also an ECslow -type mechanism. The absence of voltammetric and rotating ring-disc responses (peaks or waves) for the electroreduction of 1H obtained in the presence of TMAOH corroborates the electroinactivity of 1− in the potential range studied. The voltammetric and rotating ring-disc responses obtained in presence of HClO4 show that 1H present some dependence on a protonation step occurring in the potential range of the first reduction of 1H. This is revealed by the enlargement of the first reduction peak of 1H and the disappearance of second reduction and oxidation peaks, and by an displacement to more positive potential of disc currents in relation to the first wave of 1H alone, appearing of a peak with larger current (not twice) as compared with the limit current to reduction of 1H alone and absence of ring currents. The results obtained in the presence of HClO4 suggest slow protonation of 1H•− (chemical reaction) by HClO4 , which can depends on a previous breakage of a bond. The effect of ion pairing between Na+ and 1H•− is small but perceptible in the displacement of peak or wave potentials (voltam-
metric and rotating disc results) when NaClO4 is added. Also, the effect of ion pairing is present in the increase of acidity of 1H (Na+ /1− pair), given the decreased reversibility of the first reduction peak (or wave) when NaClO4 is added. The structure of compound 1H3 , elucidated by 1D- and 2D-NMR experiments, involves two electrons/molecule. After the 4-h long-term controlled-potential electrolysis, nearly 100% (electroreduction selectivity) of compound 1H3 was recovered. This percentage of recovery was calculated considering 2.0 e− /molecule to yield product 1H3 . Faradic efficiency was roughly 20%, considering that around 90% of the starting material was recovered. After the 4 h of electrolysis at −2.1 V vs. SCE to 1H in presence or absence of acetic acid, or −2.6 V vs. SCE to 1H, corresponded to a charge consumption of around 1.0 e− /molecule. Using the observations described above we propose the scheme for the production of compound 1H3 . In the mechanism we propose for the reduction of 1H (Scheme 1) (first peak or wave) an electron is received and a radical anion 1H•− is produced. This radical anion receives a second electron (second peak) producing 1H2− , which absorbs two protons from residual water, or parent compound, or solvent, or impurities, etc., yielding 1H3 (Scheme 1). Also, the radical anion 1H•− can suffer the breakage of a bond (slow) followed by a protonation from residual water, or parent compound, or solvent, etc., and disproportionation, for instance with 1H•− , producing anion 1H2 − , which absorbs a proton from residual water, or parent compound, or solvent, etc., yielding 1H3 (Scheme 1). To our knowledge, compound 1H3 has not been previously reported in the literature. Compound 1H3 , a ketone formed from a xanthone (1H) — an uncommon occurrence in the literature — results from the breakage of an ether bond between two aromatic rings. Although the breakage of a bond involving allylic ether is a common occurrence [17], that of an ether bond between two aromatic rings, as previously detected by our team [18], is not. 4. Conclusions The electrochemical data and criteria for the reduction of 1H, in addition to the information obtained from 1D- and 2D-NMR experiments in the elucidation of compound 1H3 , suggest a mechanism by which compound 1H initially receives one electron through reversible heterogeneous electron transfer with production of a radical anion 1H•− . This step is followed by a slow chemical reaction (breakage of a bond, for example). The second reduction peak for 1H was attributed to the electroreduction of 1H•− , which undergoes one-electron transfer, with production of a dianion 1H2− , which is protonated by residual water, or parent compound, or solvent, etc., producing in turn compound 1H3 , which, to our knowledge, is a new substance: a ketone obtained from a xanthone — an unexpected occurrence. It is possible the radical anion 1H•− with breakage of a bond to be protonated by residual water, or parent compound, or solvent, etc., producing a radical 1H2 • . This radical 1H2 • can suffer a disproportionation with 1H•− producing an anion 1H2 − , which is protonated by residual water, or parent compound, or solvent, etc., producing in turn compound 1H3 . The diffusion coefficient (D0 ) for 1H was found to be 2.66 × 10−6 cm2 s−1 . Acknowledgments The authors thank PROPP-UFMS, FUNDECT-MS (Grant 23/ 200.119/2007), CAPES, and CNPq (Brazil) for their financial support. Thanks are also given to one of the referees who reviewed this paper, for the valuable contributions provided.
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