Chemistry and catalysis advances in organometallic chemistry and catalysis
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- Figure 47.7
- 47.2.3 Ferrocenyl Aniline and Acetanilide
- Figure 47.9
- 47.2.4 Ferrocenophanes
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639 0.0
0.2 0.4
0.6 0.8
−0.5 0.0
0.5 1.0
1.5 (a)
(b) E (V vs SCE) 0.0
0.2 0.4
0.6 0.8
E (V vs SCE) −0.5
0.0 0.5
1.0 1.5
OH OH Fe OH OH Fe 8 9 I (μ A) I (μ A) Figure 47.6 Cyclic voltammograms of 8 (a) and 9 (b) 1 mM in acetonitrile/Bu 4 NBF
4 (0.1 M). Platinum electrode (0.5 mm diameter), scan rate 0.2 V/s. Cyclic voltammograms recorded in the absence (black solid line) and in the presence of 1 M equiv (black dashed line) and 10 M equiv (gray solid line) of imidazole. R O
Fe R OH OH Fe R OH O • Fe R OH OH Fe +
R O O Fe R O O Fe +
(A) (B)
(C) (D)
−e −
° 1
−e −
° 3
−e −
E ° 2 < 0.40 V Im ImH + Im ImH + •
Base-promoted oxidation sequence of catechols 8 (R = CH
3 ) and 9 (R = Ph). oxidation of the catechol. Note that the deprotonations may be concerted with the electron transfers but such discussion is beyond the scope of this chapter. The second wave (one-electron process) corresponded to the reversible oxidation of the ortho-quinone into its ferricenium analog (step (D)). Moreover, the (A) + (B) + (C) sequence was fast enough to be observed within the same scan in the presence of imidazole. In order to confirm this oxidation mechanism, preparative electrolyses of catechols 8 and 9 were performed in the presence of imidazole at 0.48 V/SCE, that is, the potential value
640 FERROCIFENS: AN ELECTROCHEMICAL OVERVIEW Fe OH
Fe OH OH Charge (C) 1.0
2.0 (a)
(b) 1.5
1.0 0.5
I ( μ A) I ( μ A) 0.0 0.0
0.2 0.4
0.6 0.8
−0.5 0.5
0.0 0 400 800 b c a b ′ c ′ a ′ Time (s)
Charge (C) 5 8 6 4 2 0 −2 4 3 2 1 0 0 500 1000 Time (s)
8 9 E (V vs SCE) 0.0
0.2 0.4
0.6 0.8
E (V vs SCE) Figure 47.8 Cyclic voltammograms of acetonitrile/Bu 4 NBF
4 (0.2 M) solutions (Pt electrode of 0.5 mm diameter, scan rate 0.1 V/s) at various electrolysis stages. (a) Compound 8 (1.2 mM) (curve a); compound 8 (1.2 mM) + imidazole (15 mM) (curve b); and compound 8 (1.2 mM) + imidazole (15 mM) + 1.95 F/mol electrolysis at 0.48 V/SCE (curve c). (b) compound 9 (6 mM) (curve a’); compound 9 (6 mM) + imidazole (75 mM) (curve b’); and compound 9 (6 mM) + imidazole (75 mM) + 1.8 F/mol electrolysis at 0.48 V/SCE (curve c’). Insets = evolution of the charge versus time during electrolysis. corresponding to the diffusion tail of the first bielectronic wave and to the foot of the second monoelectronic wave. The concentration of the species was monitored by cyclic voltammetry, as reported in Fig. 47.8. For both compounds, a complete electrolysis at 0.48 V/SCE in the presence of imidazole corresponded to a total charge circa 2 F/mol. Curves c and c , recorded after the electrolyses, no longer displayed the first two-electron oxidation wave (as seen in curves b and b recorded before the electrolyses) but only the more anodic reversible one-electron oxidation ascribed to the OQ. Finally, the bielectronic nature of the first wave was quantitatively confirmed at the timescale of preparative electrolyses. The electrochemical oxidation of catechols 8 and 9 was dramatically affected by the presence of imidazole. In the absence of this base, both catechols only oxidized according to a reversible one-electron process centered on the ferrocene group. In the presence of imidazole, the cyclic voltammograms displayed two distinct processes, the first one corresponding to the bielectronic oxidation of the catechol to the OQ, the second one being the ferrocene-centered one-electron reversible oxidation of the OQ formed at the first wave. The oxidation sequence, although leading to OQs instead of QM, displayed kinetic and thermodynamic features very similar to those encountered in the electrochemical oxidation of ferrociphenols to QMs. Since orthoquinones are also potent anticancer drugs (through the involvement of their easily generated cation radicals [29]) formation of OQ may be an important issue.
Interestingly, the cytotoxic activity of ferrocifen compounds is not restricted to phenolic substituents. For instance, the substitution of the hydroxyl group by another protic and oxidizable functionality such as aniline or acetanilide (compounds
MDA-MB-231 breast cancer cell lines [30]. Yet, the electrochemical behavior changes of both 10 and 11 observed in the presence of a base were less dramatic than those obtained with the phenolic ferrocifen derivatives. Accordingly, the cyclic voltammograms of 10 and 11 obtained in DMF and DMF/imidazole showed a weaker base dependence, that is, a lower increase of the first oxidation wave coupled to a smaller decrease of its reversibility, especially for the acetanilide derivative (Fig. 47.9). DECIPHERING THE ACTIVATION SEQUENCE OF FERROCIFENS 641 NH 2 Fe 10 11 Fe HN O 0 0 0.1 0.2
0.3 0.4
0.5 0.6
0.7 0.8
0.9 −0.2
−0.2 −0.1
0 0.1
0.2 0.3
0.4 0 0.2 0.4 0.6
0.8 (a)
(b) 0.2
0.4 0.6
E (V vs SCE) E (V vs SCE) 0.8
1 1.2
I ( μ A)
μ A) C: addition of >500 molar equiv of imidazole B: addition of 10 molar equiv of imidazole A ′: no imidazole added C ′: addition of 250 molar equiv of imidazole B ′: addition of 50 molar equiv of imidazole C B A A’ B’ C’ Figure 47.9 Cyclic voltammograms for 10 (a) and 11 (b), in DMF. Pt (0.5 mm diameter) working electrode, platinum mesh counter- electrode, SCE reference electrode, scan rate 0.1 V/s. For 10, the first wave corresponds to the ferrocene oxidation, while the second corresponds to the amine oxidation. −2 −1
1 2 3 4 5 −0.4 0 0.4
0.8 1.2
E (V vs SCE) I (μ A) O 1 R 1 O 2 R 2 NH 2 Fe 10 a b Figure 47.10 Cyclic voltammograms of 10 (1 mM) in MeOH + LiClO 4
diameter) at 100 mV/s in the absence (a), and the presence (b) of collidine (50 equiv). Similar results were obtained in methanol in the presence of 2,4,6-trimethylpyridine (collidine, pK a = 7.4) used as the base [31]. In fact, in DMF, the cyclic voltammogram of complex 10 exhibited a superimposition of the two successive oxidation waves corresponding to the respective oxidations of the ferrocene and the amino centers without any evidence of interactions. In the presence of added collidine, the Fc/Fc + system was slightly shifted toward more positive potential values, but remained reversible suggesting that the intramolecular electron transfer was too slow to be observed at the cyclic voltammetry timescale (Fig. 47.10). The second oxidation wave experienced an increase of its current peak associated to a partial loss of its reversibility showing that the dication presented some acidity. Importantly, it was shown that the oxidation wave corresponding to the oxidation of the amino group gradually decreased upon repeated scans, suggesting the formation of a coating on the electrode surface. Electrolysis performed at the potential
642 FERROCIFENS: AN ELECTROCHEMICAL OVERVIEW −8 −4
4 8 −0.4 −0.2 0 0.2 0.4 0.6
0.8 1
I (μ A) Ω 1 R 1 Figure 47.11 Cyclic voltammogram performed in MeOH + LiClO 4
diameter) obtained after the controlled-potential electrolysis (E = +0.70 V). Sweep rate is 500 mV/s. Fe NH
− e E O1 Fe + NH 2 N Fe NH • + N H + C Pt Au H N Fe Fe NH 2 • + Fe NH OH −e, −H +
Proposed mechanism for the covalent attachment of the amino-ferrocifen complex 10 via the oxidation of the ferrocenyl group.
value at which the amino moiety was oxidized (i.e., wave O 2 ) confirmed the covalent grafting of the ferrocenyl aniline onto the electrode surface. A characteristic cyclic voltammogram of the modified electrode is shown in Fig. 47.11. As already reported with other amino derivatives, the oxidation of the amino group produces a cation radical which, upon deprotonation, yields an aminyl radical that reacts with the electrode surface [32–34]. More importantly, the grafting of complex 10 could be also achieved by oxidation at the potential value of the first wave O 1 (at which the ferrocene group is oxidized). This demonstrated that, given a much longer reaction time than voltammetric ones, the amine function could be indirectly oxidized through an intramolecular electron transfer from the amino group to the ferrocenyl center along the conjugated π-system (Fig. 47.12) and confirmed the mechanism proposed for the oxidation of ferrociphenols. It is noteworthy that the grafting of compound 10 was achieved not only on glassy carbon but also on metallic surfaces such as gold and platinum. By analogy to the results obtained with the phenol ferrocifen derivatives, the cytotoxicity of compounds 10 and 11 may be ascribed to the intermediate formation of imino methides (Fig. 47.12). Actually, imino methides have been implicated in cytotoxic processes [35–40]. However, while acetylated quinone imines are important toxic compounds, namely, identified in the metabolism of Parkinson’s disease drug tolcapone [41] and the analgesic acetaminophen [42], acetylated imine methides DECIPHERING THE ACTIVATION SEQUENCE OF FERROCIFENS 643 −40
−20 0 20 40 60 80 100 120
140 0 0.1 0.2 0.3
0.4 0.5
0.6 0.7
I (nA)
E (V vs SCE) 0.15 M
60 mM 0 15 mM 13 −250
0 0.1
0.2 0.3
0.4 0.5
0.6 500
E (V vs SCE) I (nA)
0 1 M 0.1 M 20 mM
0 250
750 (a)
(b) 12 HO OH Fe OH OH Fe Figure 47.13 Cyclic voltammograms of 12 (1 mM, scan rate 100 mV/s, a) and 13 (0.3 mM, scan rate 50 mV/s, b) in the presence of varying concentrations of imidazole. are rare. Actually, the only evidence of an acetylated p-imine methide was a short-lived species (1 ms) generated from laser flash photolysis of 4-acetylaminostilbene [43]. These compounds are probably unstable owing to the effect of the electron-withdrawing acetyl group, and delocalization of the nitrogen atom p-electrons over the ring favors the quinoid form over the aromatic form [44]. From a mechanistic point of view, the overall oxidation sequence of ferrocifens is thermodynamically and kinetically controlled by the acidity of either the phenol or the amino group of the original species. Such an energetic hurdle has been overcome upon oxidation of ferrocene into ferricenium, which dramatically enhanced the acidity of these groups through intramolecular electron transfer, allowing deprotonation and concerted or consecutive electron transfer from the phenol or amine to the ferricenium. Actually, the “reactivity” of a given ferrocifen toward oxidation depends on the relative pK a values
of its functional group (hydroxyl or amino) and of the base used, as well as the pK a values of the formal hydroxy or amino radical cations that can be envisioned as limit forms of the electrogenerated ferricenium (e.g., Fc + –OH and Fc–(OH) ·+ ).
Ferrocenophanes The quest for more active (cytotoxic) ferrocifen compounds led to the design of new molecules based on the [3] ferrocenophane molecular structure. These new structures, which preserve the key ferrocenyl-phenol core, appeared more cytotoxic than their noncyclic analogs. This could be ascribed to the rigidity of the molecules, which can bind more strongly to a receptor. In this context, two ferrocenophanes (12 and 13) were prepared and electrochemically investigated [45]. In the absence of imidazole, compounds 12 and 13 exhibited a monoelectronic oxidation process at 0.46 (12) and 0.48 V (13), ascribed to the ferrocenyl oxidation (Fig. 47.13). Upon addition of excesses of imidazole, the intensities of the oxidation waves of both compounds increased, a fact that supports the occurrence of the “classical” oxidation sequence of ferrociphenols, depicted above for compounds 4 and 7. However, the voltammograms were affected only at high imidazole excesses, suggesting that oxidation sequence is harder to trigger for compounds 12 and 13 than for 4 and, a fortiori, 7. For compound 12, the intramolecular proton/electron transfer from the phenol to the ferricenium can be rationalized by the delocalized structure. For the unconjugated 13, one must consider that the electron transfer proceeds either “through space,” or via the formation of an intermediate α-methylene radical (such α-methylene ferricenium molecules possess acidic protons) [46], which can delocalize over the π-system and undergo an additional oxidation step to yield the QM. Despite a kinetically and thermodynamically less-favored intramolecular electron transfer, compound 13 exhibited an IC 50 of 0.96 μM, a value in the same range as the ferrociphenol 4. Surprisingly, compound 12 possessed an outstanding IC 50 value of 0.09 μM [45]. Actually, the biological activity of 13 and, even more, that of 12, could not be derived nor anticipated from the electrochemical behavior of these compounds. In short, if the biological activity of a ferrocifen molecule appears to require an oxidizable hydroxy or amino function on the phenyl ring,
644 FERROCIFENS: AN ELECTROCHEMICAL OVERVIEW the energetics and kinetics associated to its initial cation radical conversion to QMs or imines may not directly correlate with their cytotoxicity. 47.3 SUPRAMOLECULAR INTERACTIONS OF FERROCIFENS WITH CYCLODEXTRINS AND LIPID BILAYERS 47.3.1 Solubilization In order to anticipate the use of ferrocifens in clinical studies, several formulation strategies have been envisioned, for example, using nanoparticles, lipid nanocapsules, or CDs [15, 47–49]. In this context, an interesting entry to the general topic related to the vectorization of ferrocifen drugs consisted in the electrochemical monitoring of (i) the electroactive species formed along the oxidative metabolism of ferrocifens in the presence of CDs or lipid bilayers and (ii) the possible modifications of the oxidation sequence in the presence of supramolecular interactions between ferrocifens and their host. The questions that first arose focused on the inclusion or noninclusion of the ferrocifens and their ferricenium metabolites in the CD cavity, and the reactivity of the latter species toward bases if encapsulated in the CD. The cyclic voltammetric experiments performed in MeOH/H 2 O (1 : 1) clearly demonstrated the effective inclusion of ferrocifen 4 in the cavity of Me- β-CD, most likely via the apolar ferrocene moiety (Fig. 47.14). The potential shift observed in Fig. 47.14 when Me- β-CD was added is due to the stabilization of 4 by the CD, which then becomes harder to oxidize as the cation radical is a priori less stabilized. On the other hand, the decrease in the peak current of wave O 1 could not be ascribed only to a bulkier (then more slowly diffusing) 4-CD complex compared to 4, as the shape of the voltammetric wave also evolved. We discuss that point in the next paragraph. As expected, the inclusion of 4 in the CD cavity was favored as the solvent polarity increased, and also depended on the nature of the CD. Fig. 47.14B compares the cyclic voltammograms obtained for the same concentration of 4 in MeOH/H
2 O (1 : 1) in the absence of and presence of 10 M equiv of either Me- β-CD or native β-CD. This figure clearly shows that both the decrease in I O
and the shift in E O 1 are greater in the presence of Me- β-CD than of β-CD, featuring a stronger complexation effect in the former case. This can be ascribed to strongest hydrophobic interactions between the cyclopentadienyl and/or the aromatic rings and the methoxy groups of the partially methylated CD. As mentioned above, an interesting point is the trend of wave O 1 to adopt a sigmoidal shape, which features the involvement of a consecutive chemical– electrochemical (CE) mechanism. In short, if an electroactive species forms a stable −8 −4 0 4 8 12 −0.1
0 0.1
0.2 0.3
0.4 0.5
I (μ A) E (V vs SCE) E (V vs SCE) R 1 O 1 + Me- β-CD (a)
−1.5 −1 −0.5 0 0.5
1 1.5
2 −0.1
0 0.1
0.2 0.3
0.4 R1 O 1 (a)
(b) (c)
I (μ A) (b) OH Fe OH 4 Figure 47.14 (a) Cyclic voltammograms of 4 (1 mM) in MeOH/H 2 O (1 : 1) with TBABF 4 (0.1 M) as the supporting electrolyte, recorded at a glassy carbon electrode (3 mm diameter) at a scan rate of 200 mV/s, in the absence and presence of Me- β-CD (5 equiv). (b) Cyclic voltammograms of 4 (1 mM) in MeOH/H 2 O (1 : 1) with TBABF 4 (0.1 M) as the supporting electrolyte, recorded at a glassy carbon electrode (3 mm diameter) at a scan rate of 50 mV/s, (a) in the absence of CD or (b), (c) in the presence of 10 equiv of β-CD and
Me- β-CD, respectively. SUPRAMOLECULAR INTERACTIONS OF FERROCIFENS WITH CYCLODEXTRINS AND LIPID BILAYERS 645 I (μ A) E (V vs SCE) OH Fe OH 4 −3 −2 −1 0 1 2 3 4 −0.1 0 0.1 0.2 0.3
0.4 0.5
(a) (b)
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