# Introduction of a Phosphine Group onto the Ferrocene Moiety in Ferrociphenol Opens Access to New Heterobimetallic Complexes with Anticancer Activity

Magda Křelinová, Michèle Salmain, Petr Štěpnička, Ivana Císařová, Benoît

Bertrand, Jiří Schulz

► To cite this version:

Magda Křelinová, Michèle Salmain, Petr Štěpnička, Ivana Císařová, Benoît Bertrand, et al. Introduction of a Phosphine Group onto the Ferrocene Moiety in Ferrociphenol Opens Access to New Heterobimetallic Complexes with Anticancer Activity. ChemistryEurope, 2025, pp.e202500048. 10.1002/ceur.202500048. hal-05046099

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# Introduction of a Phosphine Group onto the Ferrocene Moiety in Ferrociphenol Opens Access to New Heterobimetallic Complexes with Anticancer Activity

Magda Křelinová, Michèle Salmain, Petr Štěpnička, Ivana Císařová, Benoît Bertrand,* and Jiří Schulz*

Ferrocene analogs of biologically active compounds often exert favorable properties, as demonstrated by ferrocifens derived from the selective estrogen receptor modulator tamoxifen. This contribution reports an original approach to modify the structure of one of the first ferrocifens, namely ferrociphenol, by means of a diphenylphosphinyl moiety appended to the unsubstituted cyclopentadienyl ring of the ferrocene unit. The phosphine-substituted ferrociphenol 1 is synthesized by two alternative routes and fully characterized including structure determination. Compound 1 is converted to the corresponding phosphonium salt 1·Mel and used to prepare a series of

bimetallic (arene)metal and chloridogold(I) complexes. The biological evaluation reveals a relatively lower antiproliferative activity of the newly synthesized compounds compared to the parent ferrociphenol and [AuCl(FcPPh₂-κP)] (Fc = ferrocenyl) toward both tumorigenic and nontumorigenic cells. All the compounds exhibit complicated redox behavior due to chemical steps that follow the initial, ferrocene-centered oxidation. Overall, the collected data indicate that the introduced phosphine substituent affects the redox and biological properties of the resulting compounds and, very likely, their mode of action.

## 1. Introduction

Replacing organic groups with organometallic fragments in molecules with biological activity is a viable route toward new biologically active compounds.[1–10] The organometallic moiety not only modulates the steric and physicochemical properties (e.g., solubility) of the parent compound but can also bring in new chemical reactivity and redox activity inherent to the metal centers, thereby changing the overall biological activity or even the mode of action of the new compounds. In this regard, the ferrocene unit[11,12] has proven particularly attractive as a surrogate of aryl groups due to its high chemical stability, well-explored synthetic chemistry, unique steric properties, and defined (and tunable) redox behavior. To date, numerous

ferrocene counterparts of biologically active compounds and drugs have been reported.[1–10] Among them, ferrocenyl analogs of the selective estrogen receptor modulator (SERM) tamoxifen (Scheme 1)[13–16] stand out due to their unique properties.

First described in 1996,[17,18] hydroxyferrocifen and ferrociphenol (A) (Scheme 1, top) were among the first organometallic SERMs. In contrast to tamoxifen, which is widely used for the adjuvant treatment of hormone-dependent breast cancer,[19] the ferrocene analogs exert antiproliferative activity on hormone-independent breast cancer cell lines for which tamoxifen is inactive. It is believed that the biological activity of these complexes is associated with the redox properties of the ferrocene moiety[1–10]: conversion of the inactive ferrocene form to ferrocenium species in cells presumably occurs via the Fenton reaction and produces reactive oxygen species.[20] For ferrociphenol, the proposed mechanism of action involves the intracellular formation of a reactive quinone methide resulting from two one-electron oxidations and two proton abstraction steps (vide infra).[21–23] This quinone methide may then react with biological nucleophiles such as glutathione owing to its strong electrophilic character. Although the aforementioned quinone methide also arises from hydroxytamoxifen,[24] the ferrocene moiety in ferrociphenol plays the role of a redox relay, which— in the form of a ferrocenium cation—facilitates the formation of the quinoid structure by accepting an electron from the arene moiety.[21]

In subsequent work, the ferrocifen and ferrociphenol structures have been modified to gain access to alternative potent anticancer agents. So far, the modifications have focused mainly on the benzene rings and substituents localized at the double bond carbon adjacent to the ferrocene moiety (Scheme 1,

M. Křelinová, P. Štěpnička, I. Císařová, J. Schulz

Department of Inorganic Chemistry

Faculty of Science

Charles University

Hlavova 2030, 128 00 Prague, Czech Republic

E-mail: schulz@natur.cuni.cz

M. Salmain, B. Bertrand

Sorbonne Université

CNRS

Institut Parisien de Chimie Moléculaire

4 place Jussieu, 75005 Paris, France

E-mail: benoit.bertrand@sorbonne-universite.fr

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Supporting information for this article is available on the WWW under https://doi.org/10.1002/ceur.202500048

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© 2025 The Author(s). ChemistryEurope published by Chemistry Europe and Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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<figure><img src="image_7.png" /><figcaption>**Scheme 1.** (top) The structures of the archetypical tamoxifen, its active metabolite 4-hydroxytamoxifen and ferrocifens and (bottom) main routes toward ferrociphenol modification and the structure of compound 1.</figcaption></figure>

bottom). [25–32] Also reported were ferrocifen analogs with a bridged ferrocene moiety, either ferrocenophane-type[33–38] or ferrocenovanellated,[39,40] and compounds where the entire ferrocenyl moiety

was exchanged for another, metallocene-like organometallic fragment.[26,41,42] However, only a few ferrociphenol derivatives bearing functional substituents at the ferrocene unit have been reported.[43] This led us to design a new ferrociphenol derivative 1 (Scheme 1, bottom) equipped with a diphenylphosphinyl substituent at the other cyclopentadienyl ring. We anticipated that the presence of the lipophilic and Lewis basic phosphine moiety may not only alter the properties of the parent ferrociphenol but also open ways to new dual-mode anticancer agents through coordination to transition metal fragments.[44–46]

Herein, we report the synthesis of compound 1 and complexes featuring this compound as P-monodentate ligand bonded to the isoelectronic (η⁶-arene)Ru(II) and (η⁵-C₅Me₅)M(III) (M = Rh and Ir) fragments and the chloridogold(I) moiety. We also report the electrochemical behavior of these compounds and the results of preliminary biological tests, aiming at the initial assessment of the antiproliferative properties of the prepared compounds against a panel of human breast adenocarcinoma, lung cancer, and nontumorigenic cell lines.

## 2. Results and Discussion

### 2.1. Synthesis of the Phosphine-Modified Ferrociphenol 1

The targeted phosphinylated ferrociphenol, compound 1, was prepared by two alternative synthetic routes. The procedure developed first (Scheme 2) was inspired by a literature method based on the reaction of thioketones with diazo compounds and subsequent desulfurization of isolated thiirane intermediates.[47]

<figure><img src="image_8.png" /><figcaption>**Scheme 2.** Synthesis of 1 involving a thiirane intermediate.</figcaption></figure>
<figure><img src="image_9.png" /></figure>

The procedure involved monolithiation of 1,1'-dibromoferrocene[48,49] with n-BuLi in tetrahydrofuran (THF) followed by electrophilic quenching of the lithiated intermediate with Weinreb amide[50-52] CH3CH2CON(Me)OMe that afforded ketone 2 after aqueous workup. In the following step, ketone 2 was thionated with Lawesson's reagent[53-55] in refluxing THF to produce compound 3. The rather unstable thioketone was in turn reacted with 4,4'-(diazomethylene)bis(methoxybenzene),[56] generated in situ by adding oxalyl chloride/dimethyl sulfoxide to a mixture of 4,4'-dimethoxybenzophenone hydrazone and triethylamine in THF at low temperature (Swern oxidation).[57-59] The resulting thiorane 4 was subsequently reacted with tris(dimethylamino)phosphine in THF to give bromoferrocenide derivative 5.[47] This compound was lithiated with tert-butyllithium in diethyl ether (N.B. no reaction was observed under the otherwise standard conditions using n-BuLi in THF[48]), and the lithiated intermediate was directly treated with chloro-diphenylphosphine to produce phosphine 6. Subsequently, the phosphine was reacted with excess BBr3 in dichloromethane, which not only removed the methoxy groups but also led to the formation of the phosphine-BBr3 adduct 1·BBr3. Deprotection of the phosphine moiety[60] was achieved by reacting 1·BBr3 with 1,4-diazabicyclo[2.2.2]octane (dabco)[61] in warm toluene; the resulting 1-[1,1-bis(4-hydroxyphenyl)]but-1-en-2-yl]-1'-(diphenylphosphino)ferrocene (1) was isolated as an air-stable, orange solid by column chromatography. The yield of 1 from 1,1'-dibromoferrocene was 16%.

An alternative route designed later (Scheme 3) also used 1,1'-dibromoferrocene as the starting material. Using a previously reported one-pot procedure,[62] the dibromide was converted to the P-protected intermediate 7, which was converted to ketone 8 via lithiation and reaction with the mentioned Weinreb amide. The ketone was reacted with an equimolar amount of 4,4'-dihydroxybenzophenone under the McMurry conditions (i.e., using TiCl4/Zn in THF)[63-67] to produce adduct 1·BH3. This step proved most problematic in the synthetic sequence: the reaction suffered from an inherently low selectivity, producing not only 1·BH3 but also both possible homocoupling products (24% of (E)- and (Z)-"bis-Ferrocifens" and 30% of 1,1,2,2-tetrakis(4-hydroxyphenyl) ethene; for details, see the Supporting Information). Still, the yield of 1·BH3 after chromatography reached an acceptable 47%. Subsequent deprotection with dabco proceeded smoothly and afforded the targeted compound 1 in 69% isolated yield; the yield of 1 relative to 1,1'-dibromoferrocene was 20%. Although the difference in the overall yields of the two routes is not dramatic,

the second approach utilizing McMurry coupling as the crucial, molecule-assembling step was more practical mainly because it was operationally simpler, more straightforward, and avoided additional protection/deprotection and the associated purification steps.

Compound 1 and all intermediates were fully characterized using a combination of multinuclear NMR, electrospray ionization mass spectrometry, and elemental analysis. In the ¹H NMR spectra, the compounds displayed the expected signals, including four characteristic, second-order multiplets due to the ferrocene protons. Only for compound 4 containing a stereogenic carbon atom, the ferrocene CH groups were diastereotopic and gave rise to eight distinct signals. The corresponding signals were also observed in the ¹³C{¹H} NMR spectra, which displayed additional resonances of the two nonequivalent aryl substituents and the diphenylphosphinyl group. The presence of the phosphine moiety was further manifested in the ¹³P{¹H} NMR spectra, namely by a sharp singlet at δP-17.1 for 1 (cf. δP-15.9 for (diphenylphosphino)ferrocene[68]) and broad multiplets centered at δP 16.0 and 4.2 for the borane adducts 1·BH3 and 1·BBr3.

Structure determination of 1·CHCl3 (Figure 1) reveals an unper turbed ferrocene moiety with slightly tilted cyclopentadienyl rings (dihedral angle: 4.2(1)°) in a sterically relaxed 1,3' conformation[69] as indicated by the torsion angle C1-Cg1-Cg-C6 of 134.3(1)° (Cg1 and Cg2 stand for the centroids of the cyclopentadienyl rings

<figure><img src="image_10.png" /><figcaption>**Figure 1.** View of the molecule in the structure of 1·CHCl3. Selected distances and angles (in Å and deg): Fe-C(1–10) range 2.038(2)–2.054(2), P1–C6 1.800(2), P1–C27 1.830(2), P1–C33 1.826(2), C6–P1–C27 103.21(7), C6–P1–C33 103.01(7), C27–P1–C33 103.81(7), C1–C11 1.481(2), C11–C12 1.355(2), C1–C11–C13 115.5(1), C15–C12–C21 114.7(1), C18–O1 1.367(2), C24–O2 1.387(2). The conventional displacement ellipsoids plot is available as Supporting Information.</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>**Scheme 3.** Synthesis of 1 using McMurry coupling as the molecule-assembling step.</figcaption></figure>
C(1-5) and C(6-10), respectively). The central double bond C1=C12 (1.355(2) Å) is twisted as indicated by the torsion angles C1-C11-C12-C15 (−167.9(2)°) and C13-C11-C12-C21 (−166.6(2)°) so that the “terminal” planes {C11, C1, C13} and {C12, C15, C21} subtend a dihedral angle of 12.9(2)° and is also tilted by 12.7(1)° with respect to the cyclopentadienyl plane C(1-5). Individual molecules in the crystal of 1·CHCl₃ assemble into infinite zig-zag chains oriented along the axis *c* (i.e., along the crystallographic 2₁ screw axis) via O1-H1O···O2 hydrogen bonds (O1···O2 = 2.730(2) Å) while the other OH group is involved in an interaction with the phosphorus lone pair[70] (O2-H2O···P1, O2···P1 = 3.114(1) Å; Figure S3 and S4, Supporting Information).

Compound **1** was further methylated at the phosphine moiety to produce phosphonium salt **1·Mel** (*Scheme* **4**). This derivative was expected to exert a different polarity and solubility, which might further affect the biological properties.[71–76] Successful methylation of **1** was indicated by the additional signals of the introduced methyl group and by a low-field shift of the ³¹P resonance (δₚ 26.9).

In addition, compound **1** was used to prepare a series of isoelectronic Ru(II), Rh(III), and Ir(III) complexes with auxiliary arene ligands,[77–80] [(arene)MCl₂(1-κP)] (**9–14** in *Scheme* **5**). Complexation reactions involving the respective dimeric precursors [(arene)MCl₂]₂ and **1** in stoichiometric amounts (M:1 = 1:1) proceeded cleanly. Consequently, the products could be isolated by simple evaporation, usually resulting in the form of hydrates as air-stable, deeply colored solids in excellent yields (>90%). For solubility reasons, the reaction using the Ru(II), Rh(III), and Ir(III) precursors had to be performed in a methanol-dichloromethane mixture (3:1).

The ¹H and ¹³C{¹H} NMR spectra of the prepared complexes displayed the characteristic signals due to the metal fragments in addition to those of coordinated **1**; they also confirmed the presence of water molecules in the structure. The ³¹P{¹H} NMR resonances were observed at δₚ 20–26 for the (η⁶-arene)Ru(II) complexes and at δₚ 24.6 and −5.9 for the Cp*·M complexes **13** and **14**, respectively. The signals were often broad, most likely due to structure dynamics, but their position corresponded to the data reported for similar compounds.[81–87]

The series of complexes was expanded by the chloridogold(I) complex **15** (*Scheme* 5),[88] obtained by substitution of the labile tetrahydrothiophene ligand (tht) in [AuCl(tht)] with the equivalent amount of **1**. The compound was isolated by precipitation and obtained as a yellow-brown solid in essentially quantitative yield. The ³¹P{¹H} NMR signal of **15** was detected at δₚ 29.4 (in CD₃CN),

<figure><img src="image_12.png" /><figcaption>**Scheme 4.** Synthesis of phosphonium salt **1·Mel**.</figcaption></figure>

<figure><img src="image_13.png" /><figcaption>**Scheme 5.** Synthesis of complexes **9–15** (tht = tetrahydrothiophene).</figcaption></figure>

which matches the value reported for [AuCl(FcPPh₂-κP)] (δₚ 27.6 in CDCl₃; FcPPh₂ = (diphenylphosphino)ferrocene).[89]

The compounds were characterized by spectroscopic methods, and the structures of the representative compounds **9·4CH₂Cl₂** and **15** were determined by single-crystal X-ray diffraction analysis. Complex **9** adopts the characteristic piano-stool structure, wherein the η⁶-benzene ring is oriented parallel to the plane of the remaining donor atoms (P1, Cl1, Cl2) (dihedral angle: 1.69(4)°) (*Figure* **2** and Figure S5 and S6, Supporting Information). The geometry around the Ru(II) ion is similar to that in [(η⁶-arene)RuCl₂(L-κP)] containing 1'-functionalized

<figure><img src="image_14.png" /><figcaption>**Figure 2.** View of the complex molecule in the structure of 9·4CH₂Cl₂. Selected distances and angles (in Å and deg): Ru1-P1 2.3448(4), Ru1-Cl1 2.4038(4), Ru1-Cl2 2.4176(4), Ru1-C(39-44) 2.177(1)-2.246(1), P1-Ru1-Cl1 84.13(1), P1-Ru1-Cl2 87.68(1), Cl1-Ru1-Cl2 87.54(1), Fe1-C(1-10) 2.040(1)-2.061(1), P1-C6 1.800(1), P1-C27 1.822(1), P1-C33 1.821(1), C11-C12 1.350(2), C1-C11 1.479(2), C11-C13 1.517(2), C12-C15 1.493(2), C12-C21 1.489(2), C1-C11-C13 1.151(9), C15-C12-C21 1.146(9).</figcaption></figure>
<figure><img src="image_15.png" /></figure>

ferrocene phosphines as the P-donors, such as [(η⁶-p-cymene)RuCl₂(Ph₂PfcY-κP)] (fc = ferrocene-1,1'-diyl, Y = CO₂H[⁹⁰] and amides derived thereof,[⁸³,⁸⁶] CH₂OMe,[⁹¹] and N=CHNMe₂[⁹²]) and similar compounds with η⁶-hexamethylbenzene and mesitylene ligands.[⁸⁴,⁸⁷] Compared to the structure of the uncoordinated ligand, the P-bound 1 shows smaller twisting at the C=C bond as indicated by the torsion angles C1-C11-C12-C15 (−173.2(1)°) and C13-C11-C12-C21 (−174.4(1)°), close to the ideal value 180° (N.B. the dihedral angle of the {C11, C1, C13} and {C12, C15, C21} planes of 6.3(2)° is also smaller). Cyclopentadienyls in the ferrocene unit were tilted by 4.40(7)°, and their substituents were more distant than in free 1 (C1-Cg1-Cg-C6 = 140.20(9)°); the planes of terminal C₆H₄OH rings are mutually tilted by 73.60(6)°.

Compound 15 crystallized as a twin with two structurally very similar molecules in the asymmetric unit, one of which showed a disorder at the $=C(C_6H_4OH)_2$ moiety, presumably due to the complexity of intermolecular interactions generated by the OH groups (see Supporting Information, Figures).[⁹³,⁹⁴] The structure of 15 (Figure 3) reveals linearly coordinated Au(I) centers with Au-donor distances within the expected ranges[⁶²,⁹⁵⁻⁹⁸]: Au-P 2.232(3) Å [2.229(3) Å], Au-Cl 2.283(3) Å [2.275(4) Å], and P-Au-Cl 175.4(1)° [177.4(1)°] for molecule 1 [molecule 2]. Bond distances and angles within the ferrocene ligands are also unexceptional. The ferrocene units are tilted by 3.4(7)° [2.5(8)°] and, presumably due to the low steric demands of the ligated metal centers, adopt an intermediate conformation with the substituents rotated closer than in complex 9 and even free 1 (C1-Cg1-Cg-C6 = −90.3(0)° [−89(1)°]). Individual molecules in the crystal assemble into a two-dimensional network via O–H···Cl hydrogen bonds (Figure S7 and S8, Supporting Information); no significant aurophilic contacts were detected.[⁹⁹⁻¹⁰¹]

## 2.2. Electrochemistry and DFT Calculations

The electrochemical behavior of the prepared compounds was examined using voltammetric techniques, predominantly

focusing on the anodic region. All measurements were performed using a platinum disc electrode and dichloromethane solutions containing 0.1 M Bu₄N[PF₆] as the supporting electrolyte.

It was previously shown that ferrociphenol A undergoes (in methanol) reversible oxidation attributed to the ferrocene/ferrocenium redox couple.[¹⁰²] In the presence of pyridine, however, the redox response changed: two irreversible oxidations were observed, and the peak current associated with the first oxidation increased, suggesting a multielectron nature of the first oxidation step. This was explained by an intramolecular electron transfer (from the phenol unit to the generated ferrocenium) and associated with proton removal by pyridine, leading to a quinoid structure, which is oxidized and deprotonated in the following step to ultimately produce reactive quinone methide Q (Scheme 6). The formed Q then undergoes another standard ferrocene-ferrocenium redox transition, reflected by the second irreversible redox wave.

Notably, the redox behavior of uncoordinated phosphinoferrocenes is often similarly affected. The ferrocenium ion generated by electron removal converts back to the ferrocene species via electron transfer from the phosphine moiety. The unstable phosphonium cation radical thus formed undergoes further chemical transformations (e.g., in the presence of oxygen or water, it forms the corresponding phosphine oxide), making the overall redox change quasi-reversible or irreversible.[¹⁰³⁻¹⁰⁶] No such complications are observed after coordination, alkylation, or oxidation of the phosphine moiety to phosphine oxide or sulfide.[¹⁰³]

The behavior of 1 could be interpreted as a combination of these redox responses. In dichloromethane, the compound underwent a reversible, diffusion-controlled redox transition (Figure 4; for further diagrams, Figure S9, Supporting Information). This redox change, tentatively attributed to one-electron oxidation of the ferrocene moiety, occurred at 0.03 V relative to the ferrocene reference.[¹⁰⁷,¹⁰⁸] This value

<figure><img src="image_16.png" /><figcaption>**Figure 3.** View of molecule 1 in the structure of 15. Selected distances and angles for molecule 1 [molecule 2] (in Å and deg): Fe1-C(1-10) 2.03(1)-2.08(1) [2.02(1)-2.08(1)], P1-C6 1.78(1) [1.79(1)], P1-C27 1.81(1) [1.82(1)], P1-C33 1.81(1) [1.83(1)], C11-C12 1.33(2) [1.33(2)], C1-C11 1.48(2) [1.52(2)], C11-C13 1.52(2) [1.49(2)], C12-C15 1.49(2) [dis], C12-C21 1.49(2) [dis], C1-C11-C13 114(1) [115(1)], C15-C12-C21 112.2(9) [dis]; dis = value affected by disorder at the C₆H₄OH rings.</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>**Scheme 6.** A simplified chart showing the electrochemical conversion of ferrociphenol (A) to quinone methide (Q). Note: B = base; the ferrocene moiety is replaced by a circle with an indicated redox state.</figcaption></figure>
<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /><figcaption>**Figure 4.** Cyclic (CV) and differential pulse (DPV) voltammograms of 1 recorded on a Pt disc electrode in dichloromethane containing Bu₄N[PF₆] as the supporting electrolyte (CV: scan rate 100 mV s⁻¹, DPV: modulation amplitude 10 mV, step 1 mV). An arrow indicates the scan direction, and the wave of an electrochemically generated product is marked with a blue asterisk. The second scan in CV is shown by a dashed line, and a partial cyclic voltammogram highlighting the reversible nature of the first redox transition is shown in red. The current in the DPV was scaled by factor 5.</figcaption></figure>

corresponds with the redox potentials reported for (diphenyl-phosphino)ferrocene (E°' = 0.10 V)[109] and 1-(diphenylphosphino)-2-alkenylferrocenes, where alkenyl = vinyl and (E)-styryl (E°' = 0.11 and 0.09 V, respectively) under similar conditions.[110] An additional, broad oxidation peak was detected at more positive potentials, apparently arising from a combination of two proximal irreversible waves (maximum at 0.56 V); the convolution of two closely spaced waves was corroborated by a differential pulse voltammetry experiment (Figure 4). In such a "wide" scan, the first redox process became expectedly irreversible and was followed by an additional broad wave attributable to a product of an EC process, likely a phosphine oxide[103] (marked with a blue asterisk in Figure 4), during the second and following scans.

The addition of imidazole rendered the first oxidation irreversible and easier (E<sub>pa</sub> = -0.07 V). It also led to the appearance of two separate irreversible oxidation steps at more positive potentials (peak potentials ≈0.30 and 0.55 V). Unfortunately, imidazole addition also enhanced the adsorption of the electrochemically generated species on the electrode surface, which resulted in a virtually complete electrode coverage after a single scan (Figure S10, Supporting Information).

The redox behavior of (arene)Ru(II) complexes 9–12 was even more difficult to analyze. These compounds displayed a reversible redox transition, followed by a complicated irreversible redox process reflected by a broad composite wave (Figure 5 and Figure S11–14, Supporting Information). The latter appeared to consist of several narrow-spaced redox steps as if the response due to ligand 1 was further combined with an additional, probably Ru(II)/Ru(III) redox process. Unfortunately, any detailed analysis was not possible because the redox steps following the initial oxidation resulted in an immediate and complete blocking of the electrode surface; practically no redox waves were observed during the following scans, and the electrode had to be polished

<figure><img src="image_20.png" /><figcaption>**Figure 5.** Cyclic voltammograms of complex 10 recorded on a Pt disc electrode in dichloromethane containing Bu₄N[PF₆] as the supporting electrolyte (scan rate 100 mV s⁻¹). An arrow indicates the scan direction, and the second scan is shown by a dashed line.</figcaption></figure>

after every run (see Figure 5; N.B.: compound 12 displayed a new irreversible oxidation peak in the second cycle). Although the redox potentials of the first reversible oxidation (Table 1) were quite similar, they still reflected the variable donor ability of the arene ligands. Compound 12 with the most electron-donating C₆Me₆ ring showed the lowest potential, whereas compound 9 with an unsubstituted benzene ring was oxidized by 80 mV more positively. The redox potentials determined for 1 and compounds 10 and 11 fell in between these values.

The redox response of the Rh(III) and Ir(III) pentamethylcyclopentadienyl complexes 13 and 14 was practically identical (Figure S15 and S16, Supporting Information). Conversely, the gold(I) complex 15 displayed a reversible oxidation at 0.25 V followed by an irreversible event at ≈0.8 V. Compared to other complexes, the initial oxidation wave of 15 was not only shifted toward more positive potentials but also remained reversible even after traversing the second irreversible redox step (Figure 6 and Figure S17, Supporting Information).

The results of the electrochemical measurements were compared with DFT calculations focused on the nature of the frontier molecular orbitals and changes in electron density upon electron removal. The frontier molecular orbitals in the molecule of 1 were delocalized across the ferrocene unit and the C≡C(C₆H₄OH)₂ fragment, suggesting conjugation between these molecular parts.

<table><caption>**Table 1.** Potentials of the first oxidation of 1 and 9–15.</caption><thead><tr><th>Compound</th><th>E°' [V]</th><th>Compound</th><th>E°' [V]<sup>a)</sup></th></tr></thead><tbody><tr><td>9</td><td>0.05</td><td>1</td><td>0.03</td></tr><tr><td>10</td><td>0.00</td><td>13</td><td>0.01</td></tr><tr><td>11</td><td>0.02</td><td>14</td><td>0.01</td></tr><tr><td>12</td><td>-0.03</td><td>15</td><td>0.25</td></tr></tbody></table>

<footnote><sup>a)</sup>The values were determined as an average of the anodic and cathodic peak potentials, E°' = 1/2(E<sub>pa</sub> + E<sub>pc</sub>), and are expressed relative to the ferrocene/ferrocenium couple.</footnote>
<figure><img src="image_21.png" /></figure>

The frontier molecular orbitals of the ruthenium complex 9 (see Figure S19, Supporting Information) showed significant contributions from the arene-ruthenium moiety. The HOMO involved the π-orbitals of the ferrocifenol backbone, combined with iron 3d orbitals (≈7%) and contributed from ruthenium and the chloride ligands (≈12% from Ru 4d, and ≈15% from Cl 3p orbitals). The HOMO-1 and HOMO-2 were even more ruthenium-centered, with contributions of 20 and 27% from Ru 4d orbitals and 29 and 44% from Cl 3p orbitals, respectively, while iron orbitals added only modestly (7 and 12% from Fe 3d orbitals, respectively). The LUMO of 9 was primarily localized on the arene-ruthenium moiety as well, involving contributions from ruthenium (24%, Ru 4d), chloride ligands (13% of 3p(Cl)), and the arene π-orbitals (27% of 2p(C)).

The gold(I) complex **15** exhibited a similar pattern as the uncoordinated ligand. Thus, the HOMO was delocalized over the ferrocifenol backbone, though the contribution from iron orbitals was reduced (10%, 3d orbitals of Fe; Figure S20, Supporting Information). The lower-lying orbitals, HOMO-1 and HOMO-2, were still primarily iron-centered (86 and 79% from Fe 3d orbitals, respectively). In contrast, the LUMO was largely localized on the diphenylphosphine group, with contributions of 81% from 2p orbitals of carbon and ≈5% from 3p orbitals of phosphorus. Similarly to **1**, the change in electron density associated with one electron removal of **9** and **15** was limited to the ferrocene iron (Figure S21–S23, Supporting Information), thereby supporting the assignment of the primary oxidation as a ferrocene-to-ferrocenium transition.

## 2.3. Biological Tests

The antiproliferative properties of the prepared compounds were initially evaluated against the triple-negative human breast adenocarcinoma cell line MDA-MB-231 using the standard MTT assay which relies on its conversion to purple formazan crystals by mitochondrial succinate dehydrogenases of living cells.[116] (Diphenylphosphino)ferrocene and ferrociphenol A were included in the panel of tested compounds for comparison. Cell viability was determined after incubation of the cells with the tested

<figure><img src="image_22.png" /><figcaption>**Figure 6.** Cyclic voltammograms of complex 15 recorded on a Pt disc electrode in dichloromethane containing Bu₄N[PF₆] as the supporting electrolyte (scan rate 100 mV s⁻¹. An arrow indicates the scan direction, and the second scan is shown by a dashed line.</figcaption></figure>

In particular, the highest occupied molecular orbital (HOMO) primarily consisted of the π-electrons of the double bond (≈26% of 2p(C) orbitals) and extended to both phenyl rings (≈34% in total, 2p(C) orbitals) and the ferrocenyl group (≈17%, mainly Fe 3d orbitals). The lowest unoccupied molecular orbital (LUMO) had a similar spatial distribution but corresponded rather to an antibonding π-orbitals of the double bond (see Figure S18, Supporting Information).

Notably, the two nearest occupied orbitals HOMO-1 and HOMO-2, lying ≈0.5 eV below the HOMO level, were predominantly iron-centered (85 and 64% contribution from Fe 3d orbitals, respectively). Correspondingly, the change in the electron density from 1 to 1⁺, ρ(1⁺) – ρ(1), mapped at the equilibrium geometry of the parent species **1** (Figure 7),[111–115] was confined to the ferrocene iron, corroborating the assignment of the primary oxidation as ferrocene-based, while the conjugated nature of the HOMO corresponded with the proposed mechanism of follow-up processes associated with the primary electron removal.

<figure><img src="image_23.png" /><figcaption>**Figure 7.** (left) The HOMO of compound **1** (isosurfaces at ±0.05 a.u. level) and (right) the contours of difference electron densities ρ(1⁺)–ρ(1) (±0.02 a.u.) mapped at the equilibrium geometry of the native species **1**.</figcaption></figure>
<figure><img src="image_24.png" /></figure>

compounds at 1 and 10 µM concentrations for 72 h. The results presented graphically in **Figure 8** enabled the identification of the most active compounds, viz., **compound 1**, the corresponding phosphonium salt **1-Mel**, the Au(I) complex **15**, and ferrociphenol **A**. These compounds decreased cell viability by 77–95% at 10 µM concentration. The antiproliferative activity of Ru(II), Rh(III), and Ir(III) complexes **9–14** was lower at both tested concentrations. These results are in line with previous reports showing higher activity of phosphine-AuCl complexes relative to (arene)RuCl₂ complexes.[117,118] Interestingly, (diphenylphosphino)ferrocene (FcPPh₂) appeared nontoxic at both concentrations, highlighting the decisive role of the ferrociphenol moiety in determining the biological activity of **1**.

The antiproliferative activity of the most potent compounds, **1**, **1-Mel** and **15** and ferrociphenol **A**, as well as [AuCl(FcPPh₂-κP)] and cisplatin as the references, was subsequently evaluated in more detail using the mentioned triple-negative breast cancer line MDA-MB-231, human lung cancer cells A549, and nontumorigenic epithelial cells MCF-10A. The results are presented in **Table 2**. When compared to ferrociphenol **A**, compound **1** appeared 2.5- to 9-fold less cytotoxic depending on the cell line, thereby showing the detrimental effect of the diphenylphosphinyl group on the antiproliferative properties of ferrociphenol itself. This could tentatively be attributed to a negative impact of the phosphine group on the generation of the active quinone methide (consistent with the electrochemical results). The cell screening also revealed a variable impact of the methylation of the phosphine group in **1** depending on the considered cell line. While the methylation of the phosphine group enhanced the cytotoxicity against the two breast cell lines (cancerous and noncancerous), it led to a reduction of the activity against the lung cancer cell line. Interestingly, coordination of the AuCl fragment induced similar effects with enhancement of the activity against the two breast cell lines and reduction of the activity against the lung cancer cells. Moreover, the free

<table><caption>**Table 2.** IC₅₀ values determined after 72 h of incubation for 1, 1-Mel, 15, ferrociphenol (A), [AuCl(FcPPh₂-κP)] and cisplatin on the MDA-MB-231, A549 and MCF-10A cells.</caption><thead><tr><th rowspan="2">Compound</th><th colspan="3">IC<sub>50</sub> [µM]<sup>a)</sup></th></tr><tr><th>MDA-MB-231</th><th>A549</th><th>MCF-10A</th></tr></thead><tbody><tr><td>1</td><td>6.4 ± 1.1</td><td>8.2 ± 0.9</td><td>10.5 ± 1.0</td></tr><tr><td>1-Mel</td><td>4.7 ± 0.6</td><td>11.7 ± 0.8</td><td>6.7 ± 0.7</td></tr><tr><td>15</td><td>5.3 ± 0.8</td><td>11.3 ± 1.8</td><td>3.5 ± 1.0</td></tr><tr><td>A</td><td>2.5 ± 0.2</td><td>0.90 ± 0.18</td><td>3.0 ± 0.2</td></tr><tr><td>[AuCl(FcPPh<sub>2</sub>-κP)]</td><td>1.4 ± 0.4</td><td>3.4 ± 0.1</td><td>0.22 ± 0.02</td></tr><tr><td>Cisplatin<sup>b)</sup></td><td>20.4 ± 3.4</td><td>1.7 ± 0.5</td><td>3.2 ± 0.8</td></tr></tbody></table>

phosphine FcPPh₂ was noncytotoxic, whereas its Au(I) complex, [AuCl(FcPPh₂-κP)] showed high cytotoxicity, in particular against the noncancerous cells. The introduction of a ferrociphenol moiety led to a general reduction of the cytotoxicity of the corresponding Au(I) complex **15**, but this reduction was larger in the case of the noncancerous cell line than against the two cancer cell lines. Compounds **1, 1-Mel, 15, A** and [AuCl(FcPPh₂-κP)] appeared more cytotoxic than cisplatin against the triple-negative breast cancer cells (showing 3–14-fold activity enhancement). At the same time, only ferrociphenol **A** presented higher activity than cisplatin against the lung cancer cells.

### 3. Conclusion

In summary, we have reported a new and efficient approach toward the modification of the parent ferrociphenol structure by exploiting the unique properties of the ferrocene moiety that enables one to combine functional moieties by introducing them on the two cyclopentadienyl rings available in the structure. Although the two functional parts are not fully independent due to the conjugated nature of the ferrocene scaffold, their mutual influence (e.g., steric) is reduced by the flexibility of the central ferrocene scaffold. The reactive and coordinating diphenylphosphino moiety selected in the present case opens at least two ways to further structure modifications: (1) by altering the phosphine group itself (e.g., by conversion to P(V) derivatives or alkylation) and (2) by its coordination to a transition metal fragment. Both approaches were demonstrated in this contribution. It is also noteworthy that the key compound **1** was obtained by two alternative synthetic routes, differing in the way the central olefin moiety was created.

Preliminary cytotoxicity screening of compound **1** demonstrated its antiproliferative activity in the low micromolar range. When compared with the two reference compounds (FcPPh₂ and **A**), compound **1** appeared more active than the former compound lacking the “tamoxiphenol” part but less toxic than parent ferrociphenol (**A**), which highlighted the biological effects of both functional “parts” combined in the structure of compound **1**. The deleterious effect of the diphenylphosphino group could be partially counterbalanced by methylation. Coordination

<figure><img src="image_25.png" /><figcaption>**Figure 8.** Percentage of living MDA-MB231 cells after 72 h incubation with the newly prepared compounds, (diphenylphosphino)ferrocene (FcPPh₂) and ferrociphenol (A) at 10 µM (green bars) and 1 µM (red bars) concentration. The values are presented as an average of the results from three or four independent runs with the error bars representing standard uncertainties.</figcaption></figure>

<footnote><sup>a)</sup>The values are presented as an average of three independent experiments ± standard uncertainty. <sup>b)</sup>See reference.[119]</footnote>
<figure><img src="image_26.png" /></figure>

of (arene)RuCl₂, Cp*RhCl₂, and Cp*IrCl₂ fragments led to a strong reduction of the antiproliferative properties of compound 1, whereas the coordination of an AuCl fragment had the same biological impact as the methylation of the phosphine moiety, making gold complexes attractive targets for future research. Exploration of a larger family of Au(I/III) complexes with ligand 1 and a detailed investigation into the mode of their biological action are currently underway in our laboratories.

## Acknowledgements

This work was supported by the Charles University Research Centre program (project no. UNCE/24/SCI/010), by Sorbonne Université and Centre National de la Recherche Scientifique. Computational resources were provided by the e-INFRA CZ project (ID: 90254), supported by the Ministry of Education, Youth and Sports of the Czech Republic.

## Conflict of Interest

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

**Keywords:** anticancer activities · ferrocene compounds · ferrociphenol · metal complexes · phosphines

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Manuscript received: February 28, 2025

Revised manuscript received: April 2, 2025

Version of record online: