Study of the Electrochemical Behavior of N-Substituted-4-Piperidones Curcumin Analogs: A Combined Experimental and Theoretical Approach

The electrochemical behavior of N-methyl- and N-benzyl-4-piperidone curcumin analogs were studied experimentally and theoretically. The studied compounds present different substituents at the para position in the phenyl rings (-H, -Br, -Cl, -CF3, and -OCH3). We assessed their electrochemical behavior by differential pulse and cyclic voltammetry, while we employed density functional theory (DFT) M06 and M06-2x functionals along with 6-311+G(d,p) basis set calculations to study them theoretically. The results showed that compounds suffer a two-electron irreversible oxidation in the range of 0.72 to 0.86 V, with surface concentrations ranging from 1.72 × 10−7 to 5.01 × 10−7 mol/cm2. The results also suggested that the process is diffusion-controlled for all compounds. M06 DFT calculations showed a better performance than M06-2x to obtain oxidation potentials. We found a good correlation between the experimental and theoretical oxidation potential for N-benzyl-4-piperidones (R2 = 0.9846), while the correlation was poor for N-methyl-4-piperidones (R2 = 0.3786), suggesting that the latter suffer a more complex oxidation process. Calculations of the BDEs for labile C-H bonds in the compounds suggested that neither of the two series of compounds has a different tendency for a proton-coupled electron transfer (PCET) oxidation process. It is proposed that irreversible behavior is due to possible dimerization of the compounds by Shono-type oxidation.


Introduction
Curcumin (diferuloylmethane), a yellow compound isolated from the turmeric plant (Curcuma longa), is one of the most extensively studied naturally occurring polyphenols. The pharmacological properties of curcumin, related to a large variety of diseases, have attracted great interest [1][2][3][4][5][6][7]. Despite these interesting pharmacological properties, it suffers from several drawbacks for practical applications, due to its poor bioavailability, which is a consequence of low chemical stability and low water solubility [8][9][10]. The latter has prompted the search for curcumin analogs that keep or improve their bioactivity, while, at the same time, overcoming their drawbacks. Several structural modifications have been afforded to enhance the bioavailability of curcumin [11][12][13]. It has been proposed that compounds possessing a β-diketone moiety, as in the case of curcumin, are a substrate of liver aldo-keto reductases, which probably contribute to their rapid in vivo metabolism [12,14,15]. To avoid this drawback, multiple synthetic alternatives have been assayed, among which replacing the β-diketone moiety with a heterocyclic ring has shown 2 of 14 to be effective [12,16]. Among the alternatives, synthetic analogs of curcumin possessing a 4-piperidone scaffold have shown high bioactivity, e.g., as anti-inflammatory and anticancer agents [17][18][19][20][21].
One of the aspects of curcumin that have presented some controversy is its electrochemical behavior [22][23][24][25]. During recent years, the electrochemical behavior of some of the derived curcuminoid families also have been studied, e.g., the electrochemistry of pyrazole derivatives of curcumin [26], the electrochemistry and antioxidant capacity of curcumin derivatives obtained by esterification of its phenol groups [27], and the electronic and conductance properties of a couple of thiophene curcuminoids using electrochemical techniques, ultraviolet spectroscopy, and DFT calculations [27]. However, until now, the electrochemical behavior of N-substituted-4-piperidone curcumin analogs has not been reported, which seems relevant to study due to their interesting pharmacological properties, which have been suggested to be associated with the electron transfer process [13]. Besides our previous work on the reactivity of these compounds, only theoretical work dealing with the potential technological application for the non-linear optics of this type of curcuminoid can be found [16,28].
Based on the above, in this work we propose to study the electrochemical behavior of N-substituted-4-piperidone curcuminoid analogs ( Table 1). The effect of different substituents on the aromatic rings and the variation in the N-substituent of the piperidone ring (methyl and benzyl) could help in the understanding of the electrochemical behavior and help in the design of curcumin piperidone derivatives with biological activity, besides determining the oxidation potentials that could be useful in obtaining derivatives by electrochemical synthesis [29][30][31]. We employ differential pulse and cyclic voltammetry to experimentally study the electrochemistry of compounds, and DFT calculations to obtain theoretical redox potentials, which are then compared with those obtained experimentally, assessing the effects of the substituents at the phenyl substituent. a substrate of liver aldo-keto reductases, which probably contribute to their rapid in vivo metabolism [12,14,15]. To avoid this drawback, multiple synthetic alternatives have been assayed, among which replacing the β-diketone moiety with a heterocyclic ring has shown to be effective [12,16]. Among the alternatives, synthetic analogs of curcumin possessing a 4-piperidone scaffold have shown high bioactivity, e.g., as anti-inflammatory and anticancer agents [17][18][19][20][21].
One of the aspects of curcumin that have presented some controversy is its electrochemical behavior [22][23][24][25]. During recent years, the electrochemical behavior of some of the derived curcuminoid families also have been studied, e.g., the electrochemistry of pyrazole derivatives of curcumin [26], the electrochemistry and antioxidant capacity of curcumin derivatives obtained by esterification of its phenol groups [27], and the electronic and conductance properties of a couple of thiophene curcuminoids using electrochemical techniques, ultraviolet spectroscopy, and DFT calculations [27]. However, until now, the electrochemical behavior of N-substituted-4piperidone curcumin analogs has not been reported, which seems relevant to study due to their interesting pharmacological properties, which have been suggested to be associated with the electron transfer process [13]. Besides our previous work on the reactivity of these compounds, only theoretical work dealing with the potential technological application for the non-linear optics of this type of curcuminoid can be found [16,28].
Based on the above, in this work we propose to study the electrochemical behavior of N-substituted-4-piperidone curcuminoid analogs ( Table 1). The effect of different substituents on the aromatic rings and the variation in the N-substituent of the piperidone ring (methyl and benzyl) could help in the understanding of the electrochemical behavior and help in the design of curcumin piperidone derivatives with biological activity, besides determining the oxidation potentials that could be useful in obtaining derivatives by electrochemical synthesis [29][30][31]. We employ differential pulse and cyclic voltammetry to experimentally study the electrochemistry of compounds, and DFT calculations to obtain theoretical redox potentials, which are then compared with those obtained experimentally, assessing the effects of the substituents at the phenyl substituent.
CH2Ph OCH3 Table 2. Synthesis of the obtained compounds.

Synthesis
Compounds were obtained by the base-catalyzed aldolic condensation of N-methyl or N-benzyl-4-piperidones with the corresponding aldehyde (Table 2). Moderate to high yields were achieved, ranging from 48% for compound C9 to 88% for compound C5. Compounds C1 to C8 and C10 have been previously described (see references indicated in Table 2), while compound C9 is described here for the first time.

Differential Pulse Voltammetry (DPV) Results
DPV results reveal that derivatives exhibited one well-defined anodic peak at potentials higher than +0.7 V versus Ag/AgCl (non-aqueous) ( Figure 1 and Table 3). Oxidation peak potential values for the derivatives with electron-withdrawing groups were shifted towards more positive values, whereas derivatives with electron-releasing groups were shifted towards negative values. Similarly, when we compare the oxidation peak potential of N-methyl-substituted derivatives (C1 to C5) with N-benzyl-substituted derivatives (C6 to C10), the latter shifted the oxidation potential towards more positive values.

Differential Pulse Voltammetry (DPV) Results
DPV results reveal that derivatives exhibited one well-defined anodic peak at potentials higher than +0.7 V versus Ag/AgCl (non-aqueous) ( Figure 1 and Table 3). Oxidation peak potential values for the derivatives with electron-withdrawing groups were shifted towards more positive values, whereas derivatives with electron-releasing groups were shifted towards negative values. Similarly, when we compare the oxidation peak potential of N-methyl-substituted derivatives (C1 to C5) with N-benzyl-substituted derivatives (C6 to C10), the latter shifted the oxidation potential towards more positive values.
Compounds were obtained by the base-catalyzed aldolic condensation of N-methyl or N-benzyl-4-piperidones with the corresponding aldehyde ( Table 2). Moderate to high yields were achieved, ranging from 48% for compound C9 to 88% for compound C5. Compounds C1 to C8 and C10 have been previously described (see references indicated in Table 2), while compound C9 is described here for the first time.

Differential Pulse Voltammetry (DPV) Results
DPV results reveal that derivatives exhibited one well-defined anodic peak at potentials higher than +0.7 V versus Ag/AgCl (non-aqueous) ( Figure 1 and Table 3). Oxidation peak potential values for the derivatives with electron-withdrawing groups were shifted towards more positive values, whereas derivatives with electron-releasing groups were shifted towards negative values. Similarly, when we compare the oxidation peak potential of N-methyl-substituted derivatives (C1 to C5) with N-benzyl-substituted derivatives (C6 to C10), the latter shifted the oxidation potential towards more positive values.

Number of Electrons (n) Calculation
Our results showed that by increasing the scan rate, the peak potential is shifted to more positive potentials. Laviron's equation was used to estimate n as follows [32]: where E is the potential; E 0 is the formal standard potential; ks is the standard heterogeneous reaction rate constant; n is the transfer electron number; α refers to the charge-transfer coefficient; υ is scan rate; R is the gas constant; T is the temperature; and F is the Faraday constant. When plotting the graph between Ep versus lnυ, the slope gives the value of RT/αnF (α = 0.5); from this, we can calculate the number of electrons involved in the process (Table 4). In this way, n was found to be 2, implying that two electrons were transferred in the electrochemical redox reaction. Table 3. Oxidation potentials of the compounds.

Surface Concentration
The surface concentrations of piperidone derivatives (Γ) were calculated employing the following equation: where I is the peak current; n = 2 (number of electrons involved in the electrochemical process); F is the Faraday constant 96,485 C mol −1 ; A is the surface area, 0.0707cm 2 (the diameter of the working electrode, the glassy carbon electrode, is 0.3 cm, and from this, the surface area of the electrode was calculated); υ represents the scan rate; R is the gas constant, 8.314 JK −1 mol −1 ; and T = 293 K. If we plot the graph of Ip versus the scan rate, which conforms to the following equation: Ip (µA) = 0.721υ + 10.223 (R 2 = 0.9153), in this equation the slope, gives the value of n 2 F 2 AΓ/4RT, from which we can calculate Γ. The results are presented in Table 4.
In the electrochemical process, there is an important difference between the concentration of a species at the surface of the electrode and its concentration at some distance from it, generally known as bulk concentration. The surface concentration depends on the rate at which the reactants are brought to the electrode surface by either diffusion or flow processes, which determines the rate of the electrochemical reaction.

Cyclic Voltammetry Characterization
Scan rate has a great influence on the redox process of the electrode surface. Therefore, cyclic voltammograms of 2 mM of the derivatives were recorded in the scan rate range from 10 to 500 mVS −1 and the peak current increased with increased scan rate for all compounds (Figures 2a and 3a). The linear relationships of the square root of the scan rate and the scan rate on the peak current are shown in Figures 2c and 3c. diffusion or flow processes, which determines the rate of the electrochemical reaction.

Cyclic Voltammetry Characterization
Scan rate has a great influence on the redox process of the electrode surface. Therefore, cyclic voltammograms of 2 mM of the derivatives were recorded in the scan rate range from 10 to 500 mVS −1 and the peak current increased with increased scan rate for all compounds (Figures 2a and 3a). The linear relationships of the square root of the scan rate and the scan rate on the peak current are shown in Figures 2c and 3c.  The dependence between I p and ν shows a good linear correlation; the relationship can be presented by the following equation: Ip (µA) = 0721ν (V/s) + 10.223 (R 2 = 0.9153) (Figure 2b). However, I p on ν 1/2 has better linear correlation, whose relationship can be presented by the following equation: Ip (µA) = 1.9526 (V 1/2 /s 1/2 ) − 0.149 (R 2 = 0.9808) (Figure 2c). A similar analysis was performed for the compound 7, which shows Ip (µA) = 0.1354ν (V/s) + 21.558 (R 2 = 0.9597) (Figure 3b), and for i p on ν 1/2 , Ip (µA) = 3.6023 (V 1/2 /s 1/2 ) + 2.8508 (R 2 = 0.9926) (Figure 3c). These observations strongly suggest that redox reactions of both derivatives are diffusion-controlled. Similar analyses were performed for all derivatives, and similar behavior was found in all cases. Figures 2d and 3d shows the relationship between the logarithm of redox peak current and the logarithm of scan rate, which conformed to the following equation: log Ip (A) = 0.5065 Log ν (V/s) + 0.2688 (R 2 = 0.9919). As is known, the slope close to 0.5 is ascribed to a diffusion-controlled process, whereas the slope close to 1.0 is ascribed to an adsorption-controlled process.  The dependence between Ip and ν shows a good linear correlation; the relationsh can be presented by the following equation: Ip (μA) = 0721ν (V/s) + 10.223 (R 2 = 0.915 ( Figure 2b). However, Ip on ν 1/2 has better linear correlation, whose relationship can presented by the following equation: Ip (μA) = 1.9526 (V 1/2 /s 1/2 ) − 0.149 (R 2 = 0.9808) (Figu 2c). A similar analysis was performed for the compound 7, which shows Ip (μA) = 0.135 (V/s) + 21.558 (R 2 = 0.9597) (Figure 3b), and for ip on ν 1/2 , Ip (μA) = 3.6023 (V 1/2 /s 1/2 ) + 2.85 (R 2 = 0.9926) (Figure 3c). These observations strongly suggest that redox reactions of bo derivatives are diffusion-controlled. Similar analyses were performed for all derivativ and similar behavior was found in all cases. Figures 2d and 3d shows the relationship between the logarithm of redox pe current and the logarithm of scan rate, which conformed to the following equation: log (A) = 0.5065 Log ν (V/s) + 0.2688 (R 2 = 0.9919). As is known, the slope close to 0.5 is ascrib to a diffusion-controlled process, whereas the slope close to 1.0 is ascribed to adsorption-controlled process.

Quantum Chemical Calculation
The oxidation potentials at DFT M06 and M06-2x level using 6-311+G(d,p) basis were obtained for the ten derivatives. M06-2X functionals have been extensively used calculate redox potentials [33][34][35][36][37]; however, in the specific case of oxidation potenti previous work has shown that functionals with high levels of Hartree-Fock (HF) exchan percentage tend to significantly overestimate the potential [38]. Therefore, we tested M0 2X (54% HF) and M06 functionals to obtain the potentials. The number of electro transferred in the reactions, according to Laviron's equation in Section 3.2, was tw (a)

Quantum Chemical Calculation
The oxidation potentials at DFT M06 and M06-2x level using 6-311+G(d,p) basis set were obtained for the ten derivatives. M06-2X functionals have been extensively used to calculate redox potentials [33][34][35][36][37]; however, in the specific case of oxidation potential, previous work has shown that functionals with high levels of Hartree-Fock (HF) exchange percentage tend to significantly overestimate the potential [38]. Therefore, we tested M06-2X (54% HF) and M06 functionals to obtain the potentials. The number of electrons transferred in the reactions, according to Laviron's equation in Section 3.2, was two. Accordingly, we considered the two possible electronic states for oxidized species (singlet and triplet dications) for the calculations. Tables 5 and 6 show the values for experimental and theoretical oxidation potentials calculated with M06-2X and M06 functionals, respectively. In all cases, the mean absolute error (MAE) for M06 was lower than for M06-2X, which agrees with what has been previously reported [38]. MAE values are still overestimated with the M06 functional, but they are in the range of previous work of calculated oxidation potentials [39]. Based on the above, we use data obtained with the M06 functional to discuss the results.
Taking both series (N-methyl and N-benzyl) together, experimental and theoretical potentials did not correlate well, neither when considering the oxidized species as a triplet, nor as a singlet (R 2 = 0.0796 for singlet, R 2 = 0.1667 for triplet). However, when both series were treated separately, it was found that the series with the N-benzyl group at the piperidone ring presented a good correlation between experimental and theoretical oxidation potential. Figure 4 presents the correlation between experimental and theoretical oxidation potential for the N-methyl (A) and N-benzyl (B) series considering the oxidized species 7 of 14 as a singlet, and for the N-methyl (C) and N-benzyl (D) series considering the oxidized species as a triplet.  Table 6. Experimental and theoretical oxidation potential (M06) for all compounds, considering the oxidized species in the singlet state.

M06 (S) M06 (T) Exp Error [V] (S) Error [V] (T)
N-methyl C1 For the series with N-benzyl (compounds C6 to C10), good correlations were found considering both kinds of oxidized species, triplet or singlet (R 2 = 0.8886 and R 2 = 0.9846, respectively). Meanwhile, the series with the N-methyl group did not show a good correlation between experimental and theoretical oxidation potentials, neither when considering the oxidized species as triplet nor as singlet (R 2 = 0.4918 and R 2 = 0.3786, respectively).
Considering that the N-benzyl derivative series presented a good correlation between experimental and theoretical oxidation potentials, unlike that evidenced for the N-methyl series, it can be suggested that oxidation of this last series of compounds did not occur by a simple mechanism. The above indicates that variation of the substituent at nitrogen is a key factor that determines the redox behavior of these derivatives. In addition, based on the structural analysis mentioned above, it is reasonable to consider that the trend for both series will remain independent of the addition of more compounds for each series.
Triplet oxidized species for all compounds present a similar geometry, regardless of the substituent on the N-position or phenyl rings. However, for singlet oxidized species, the behavior varies between the N-methyl and N-benzyl series ( Figure 5). For the N-methyl series, the oxidized species of compounds C2, C3, and C5 (with p-Br, p-Cl, and p-OCH3 in the phenyl rings) present a notable geometry distortion of the piperidone ring, which does not occur for C1 and C4 (unsubstituted and with p-CF3 in the phenyl rings). On the other hand, all oxidized species of the N-benzyl series present a notable geometrical distortion of the piperidone ring, regardless of the substituent on the phenyl rings. For the series with N-benzyl (compounds C6 to C10), good correlations were found considering both kinds of oxidized species, triplet or singlet (R 2 = 0.8886 and R 2 = 0.9846, respectively). Meanwhile, the series with the N-methyl group did not show a good correlation between experimental and theoretical oxidation potentials, neither when considering the oxidized species as triplet nor as singlet (R 2 = 0.4918 and R 2 = 0.3786, respectively).
Considering that the N-benzyl derivative series presented a good correlation between experimental and theoretical oxidation potentials, unlike that evidenced for the N-methyl series, it can be suggested that oxidation of this last series of compounds did not occur by a simple mechanism. The above indicates that variation of the substituent at nitrogen is a key factor that determines the redox behavior of these derivatives. In addition, based on the structural analysis mentioned above, it is reasonable to consider that the trend for both series will remain independent of the addition of more compounds for each series.
Triplet oxidized species for all compounds present a similar geometry, regardless of the substituent on the N-position or phenyl rings. However, for singlet oxidized species, the behavior varies between the N-methyl and N-benzyl series ( Figure 5). For the Nmethyl series, the oxidized species of compounds C2, C3, and C5 (with p-Br, p-Cl, and p-OCH3 in the phenyl rings) present a notable geometry distortion of the piperidone ring, which does not occur for C1 and C4 (unsubstituted and with p-CF3 in the phenyl rings). On the other hand, all oxidized species of the N-benzyl series present a notable geometrical distortion of the piperidone ring, regardless of the substituent on the phenyl rings. The geometry of the singlet and triplet oxidized species for all compounds are in Tables S1 and S2 of the Supplementary Materials.
To obtain insights into the behavior observed for these two series of compounds, we studied the energy of frontier molecular orbitals. In previous works, theoretical calculations of some of these compounds had been carried out to study their reactivity and the behavior of their radical anions [16], as well as optical properties [28]. In our previous work [16], we obtained, at the B3LYP/6-31G(d) level, the energies of the frontier molecular orbitals of some compounds studied here (C1, C2, C3, C6, C7, and C8). Table 7 shows the values for HOMO and LUMO energies (EHOMO and ELUMO, respectively) and the HOMO-LUMO energy gap (GAPH-L). These values, calculated at M06/6-311+G(d,p), showed slight differences from those calculated previously for some of the compounds at the B3LYP/6-31G(d) level. The EHOMO values calculated at M06/6-311+G(d,p) tend to be The geometry of the singlet and triplet oxidized species for all compounds are in Tables S1 and S2 of the Supplementary Materials.
To obtain insights into the behavior observed for these two series of compounds, we studied the energy of frontier molecular orbitals. In previous works, theoretical calculations of some of these compounds had been carried out to study their reactivity and the behavior of their radical anions [16], as well as optical properties [28]. In our previous work [16], we obtained, at the B3LYP/6-31G(d) level, the energies of the frontier molecular orbitals of some compounds studied here (C1, C2, C3, C6, C7, and C8). Table 7 shows the values for HOMO and LUMO energies (E HOMO and E LUMO , respectively) and the HOMO-LUMO energy gap (GAP H-L ). These values, calculated at M06/6-311+G(d,p), showed slight differences from those calculated previously for some of the compounds at the B3LYP/6-31G(d) level. The E HOMO values calculated at M06/6-311+G(d,p) tend to be lower, while the E LUMO values tend to be higher, which leads to the GAP H-L being lower for M06/6-311+G(d,p). However, the tendency for the three compounds in common for each series is the same. Unsubstituted derivatives in the aromatic ring show the highest E HOMO and E LUMO , followed by p-Br and p-Cl (both for N-methyl and N-benzyl series). In addition, it can be observed that the value of GAP H-L did not show significant differences among compounds from the N-methyl and N-benzyl series. We examined the correlation among E HOMO and experimental E ox pairs, considering that electrons on this orbital are those that are removed in the oxidation process. Figure 6 shows the correlation for both the N-methyl and N-benzyl series. We found that the E HOMO of N-benzyl derivatives correlates well with experimental E ox , with an R 2 = 0.9524. On the other hand, N-methyl derivatives did not present a good correlation, obtaining an R 2 = 0.6342. These results also support the assumption that the oxidation of the N-methyl derivatives, unlike the N-benzyl ones, suffers a complex oxidation process that does not only involve the direct subtraction of two electrons from the HOMO. We examined the correlation among EHOMO and experimental Eox pairs, considering that electrons on this orbital are those that are removed in the oxidation process. Figure 6 shows the correlation for both the N-methyl and N-benzyl series. We found that the EHOMO of N-benzyl derivatives correlates well with experimental Eox, with an R 2 = 0.9524. On the other hand, N-methyl derivatives did not present a good correlation, obtaining an R 2 = 0.6342. These results also support the assumption that the oxidation of the N-methyl derivatives, unlike the N-benzyl ones, suffers a complex oxidation process that does not only involve the direct subtraction of two electrons from the HOMO. To evaluate alternative possible mechanisms, which can imply the heterolytic cleavage of a carbon-hydrogen (C-H) bond, we study the bond dissociation enthalpies (BDEs) of the C-H bonds potentially breakable in compounds 1 and 6 (BDE1 and BDE2 in Table 8). A significant difference between the lower BDE would be indicative of a possible differential mechanism between the compounds of both series.  To evaluate alternative possible mechanisms, which can imply the heterolytic cleavage of a carbon-hydrogen (C-H) bond, we study the bond dissociation enthalpies (BDEs) of the C-H bonds potentially breakable in compounds 1 and 6 (BDE1 and BDE2 in Table 8). A significant difference between the lower BDE would be indicative of a possible differential mechanism between the compounds of both series. To evaluate alternative possible mechanisms, which can imply the heterolytic cleavage of a carbon-hydrogen (C-H) bond, we study the bond dissociation enthalpies (BDEs) of the C-H bonds potentially breakable in compounds 1 and 6 (BDE1 and BDE2 in Table 8). A significant difference between the lower BDE would be indicative of a possible differential mechanism between the compounds of both series. Results show that for both compounds, the BDE2 was the lowest, and there are no significant differences in the values (61.50 kcal/mol for 1 vs. 60.15 kcal/mol for 6). The latter suggests that neither of the two series of compounds (N-methyl and N-benzyl derivatives) has a significant preference for the proton-coupled electron transfer (PCET) mechanism; therefore, this cannot explain the differences between both series.
A plausible explanation for the irreversible oxidation of the compounds is to consider a chemical reaction coupled to the electrochemical process. For heterocyclic tertiary amines, an electrochemical oxidation reaction (Shono oxidation) has been described that gives products with a substituent in the carbon vicinal to the nitrogen [30,40,41]. The process consists of a two-electron oxidation coupled to a proton transfer to generate an iminium cation intermediate which reacts with nucleophiles to achieve a great variety of products depending on the conditions [42][43][44]. In our case, it is possible that the attacking Results show that for both compounds, the BDE2 was the lowest, and there are no significant differences in the values (61.50 kcal/mol for 1 vs. 60.15 kcal/mol for 6). The latter suggests that neither of the two series of compounds (N-methyl and N-benzyl derivatives) has a significant preference for the proton-coupled electron transfer (PCET) mechanism; therefore, this cannot explain the differences between both series.
A plausible explanation for the irreversible oxidation of the compounds is to consider a chemical reaction coupled to the electrochemical process. For heterocyclic tertiary amines, an electrochemical oxidation reaction (Shono oxidation) has been described that gives products with a substituent in the carbon vicinal to the nitrogen [30,40,41]. The process consists of a two-electron oxidation coupled to a proton transfer to generate an iminium cation intermediate which reacts with nucleophiles to achieve a great variety of products depending on the conditions [42][43][44]. In our case, it is possible that the attacking nucleophile corresponds to the same molecule generating a dimer. This hypothesis needs to be evaluated in future works that delve into mechanistic aspects of the oxidation of these compounds.

Synthesis
The synthesis of 4-piperidinone derivatives was performed in agreement with reported methods with slight modification (Table 1). To a solution of 1-methyl-or 1-benzyl-4piperidone (0.30 g, 1.0 equivalent) in ethanol:water 1:1 (2 mL), KOH (0.3 g) was added and sonicated for 5 min. Then, the appropriate aldehyde (2.0 equivalents) was added, and the mixture was sonicated for 15 min at room temperature. The separated solid was filtered and washed with ethanol-water (20 mL) to obtain a yellow solid. Finally, product C1 was crystallized from ethanol, compound C5 was crystallized from methanol, and the other compounds were crystallized from a mixture of chloroform:methanol. Synthesis of the new compound (3E,5E)-1-benzyl-3,5-bis(4-(trifluoromethyl)benzylidene)piperidin-4-one (C9) was carried out as follows: to a solution of 1-benzyl) 4-piperidone (0.30 g, 1.59 mmol) in ethanol:water 1:1 (2 mL), KOH (0.3 g) was added and sonicated for 5 min. Then, 4trifluoromethylbenzaldehyde (0.55 g, 3.18 mmol) was added and the mixture was sonicated for 15 min at room temperature. The separated solid was filtered and washed with ethanolwater (20 mL) to obtain a yellow solid (0.83 g, 52% yield). Finally, the product was purified by column chromatography using hexane:ethyl acetate 4:1. 1

Electrochemical Experiments
Electrolytic medium: acetonitrile containing 0.1 M tetrabutylammonium perchlorate (TBAP) was used as the electrolytic medium and the working concentrations of each compound were 2 mM.
Differential pulse voltammetry (DPV), cyclic voltammetry (CV), square wave voltammetry, and electrochemical impedance spectroscopy (EIS) were carried out with a CH Instrument (CHI 750) electrochemical workstation. All electrochemical experiments were carried out with 2.0 mM of each piperidone derivative. A stationary glassy carbon electrode (GCE, CH Instrument with an area of 0.0707 cm 2 ) was used as the working electrode. The surface of the electrode was polished to a mirror finish with 0.1 µm alumina powder before each experiment, and the surface was cleaned with ethanol under an ultrasonication for 30 s. A platinum spiral wire was used as an auxiliary electrode and the potentials were measured against a non-aqueous Ag/Ag + reference electrode CH Instrument 112. All experiments were performed in ambient conditions.

Computational Details
All calculations were carried out using Gaussian 09 [45] program package, revision a.01; Gaussian, Inc.: Wallingford, CT, USA). Geometries were calculated without symmetry constraints at the DFT M06 and M06-2X level with the 6-311+G (d,p) basis set. The conductor-like polarizable continuum (C-PCM), which has shown good performance to redox potential calculations [8], was used to include the solvent effect (acetonitrile). No imaginary vibrational frequencies were found at the optimized geometries, indicating that they are the true minima of the potential energy surface.
In previous work [46], we applied a thermodynamic cycle to obtain the Gibbs free energy of the reaction in solution (G • (t)) for calculation of the redox potentials of quinones, and we used the same approach here. Reduction potentials concerning the Ag/AgCl reference electrode were obtained by the following equation: where the value 4.72 V corresponds to the redox potential of the Ag/AgCl couple. Bond dissociation enthalpies were calculated following a previous methodology [8,47].

Conclusions
In this work, the electrochemical behavior of N-substituted-4-piperidone curcumin analogs was studied experimentally and theoretically. Oxidation potentials ranged from 0.72 to 0.89 V, with N-methyl-4-piperidones values approximately 0.1 V lower than those of N-benzyl-4-piperidones. We found that the electrochemical oxidation of these compounds implies a two-electron transfer process. Cyclic voltammetry studies showed that compounds suffer irreversible oxidation and suggested that it is a diffusion-controlled process. DFT quantum chemical calculations with M06 and M06-2x functionals showed that the formed works better to calculate the oxidation potentials of these compounds. The results also suggested that the electronic state for oxidized species is a singlet. A good correlation between experimental and calculated oxidation potentials for N-benzyl-4-piperidones (r = 0.9846) showed that calculations were representative of the oxidation process. On the other hand, the calculated oxidation potentials for N-methyl-4-piperidones exhibited a poor correlation with the experimental values. The latter indicates that calculations do not represent the process well and suggests that the oxidation of N-methyl-4-piperidones is a more complex process. Calculations of the BDEs for labile C-H bonds in the compounds did not show significant differences, suggesting that neither of the two series of compounds has a significant preference for proton-coupled electron transfer (PCET). It was proposed that irreversible behavior of the compounds is due to a potential dimerization by a Shono-type oxidation reaction, which is a common electrochemical reaction in tertiary heterocyclic