# Chemically Mediated Artificial Electron Transport Chain

Yu-Dong Yang, Qian Zhang, Lhoussain Khrouz, Calvin Chau, Jian Yang, Yuying Wang, Christophe Bucher, Graeme Henkelman, Han-Yuan Gong, Jonathan Sessler

► To cite this version:

Yu-Dong Yang, Qian Zhang, Lhoussain Khrouz, Calvin Chau, Jian Yang, et al., Chemically Mediated Artificial Electron Transport Chain. ACS Central Science, 2024, 10 (6), pp.1148-1155. 10.1021/acs-centsci.4c00165. [https://doi.org/10.1021/acs-centsci.4c00165](https://doi.org/10.1021/acs-centsci.4c00165)

HAL Id: hal-04788506

https://hal.science/hal-04788506v1

Submitted on 10 Dec 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Chemically Mediated Artificial Electron Transport Chain

Yu-Dong Yang<fnref n="1" />, Qian Zhang<fnref n="1" />, Lhoussain Khrouz<fnref n="2" />, Calvin V. Chau<fnref n="1" />, Jian Yang<fnref n="1" />, Yuying Wang<fnref n="1" />, Christophe Bucher<fnref n="2" />**, Graeme Henkelman<fnref n="1" />**, Han-Yuan Gong<fnref n="3" />**, Jonathan L. Sessler<fnref n="1" />*

## Introduction

Small molecules, such as nicotinamide adenine dinucleotide (NADH), flavin adenine dinucleotide (FADH₂), ubiquinone, cytochrome c, chlorophyll, and pheophytin, play critical roles in biological electron transport chains (ETCs). (1–8) Efforts to modulate these molecules and their function have led inter alia to the development of porphyrin analogues as photosensitizers for photodynamic therapy, (9–11) strategies for enhancing reactive oxygen species (ROS) concentrations, (12–14) the use of metformin, a Complex I inhibitor, to reduce tumorigenesis and treat other conditions, (15–18) as well as the construction of artificial photosynthesis systems (19–21) and dye-sensitized solar cells. (22–24)

Proton-coupled electron transfer (PCET) plays a critical role in a multitude of redox reactions, spanning from biological electron transport chains to numerous artificial catalyst and energy transfer systems. (25–29) Numerous examples of electron transfer between two redox active entities are now known. (30–38) Moreover, three-component electron transfers have been observed in some catalysis-focused reaction systems, (39–41) particularly in organic photocatalysis. (42–44) However, thermally driven electron transport chains mediated by small molecules and modulated through environmental changes (e.g., concentration) are far less explored, and the development of such systems constitutes an unmet challenge. This lack of development may reflect the difficulty associated with controlling complex, freestanding chemical systems and the corresponding stepwise orchestration of electron flow.

While macrocycles have been widely employed in the development of electron transfer systems and related materials, only a limited number of examples involving macrocycle-based PCET are known. (45–47) Notably, to our knowledge, there is no reported demonstration of PCET occurring between two macrocycles. Here, we report a novel PCET system between two macrocycles, cyclo[8]pyrrole 1 and meso-aryl hexaphyrin (1.0.1.0.1.0) (naphthorosarin 2), upon the addition of TFA, as well as demonstrate a chemical mediated artificial electron transfer chain consisting of 1, 2, I₂, and trifluoroacetic acid (TFA) (Scheme 1). We show that the reaction stoichiometry, along with the presence or absence of TFA, may be used to control the electron transfer events within this multicomponent system. Specifically, oxidation of the formal 30 π-electron (30 π) neutral aromatic form of 1 with I₂ leads to the formation of the corresponding radical species 1⁺ (29 π), along with I₃⁻. On the other hand, PCET between 1 and 2 is seen with the participation of TFA. Depending on the molar ratio of 1, 2, and the added TFA, different reduced forms of 2, namely a radical H₃2*<fnref n="2" />⁺ (25 π) and an aromatic cation H₃2⁺ (26 π), are produced from the initial triprotonated antiaromatic species H₃2³⁺ (24 π) (counteranion = CF₃CO₂⁻) (Scheme 1A). Adding I₂ to a mixed solution of 1 and 2 in dichloromethane, leads to the selective formation of a one-electron oxidized form of 1 (1*⁺) and I₃⁻ without affecting 2. Upon addition of TFA to the solution, I₃⁻ acts as an electron carrier and produces

<footnote n="1">¹Department of Chemistry, The University of Texas at Austin, 105 East 24th Street, Stop A5300, Austin, TX 78712-1224, USA.</footnote>

<footnote n="2">²Université de Lyon, ENS de Lyon, CNRS UMR 5182, Laboratoire de Chimie, Lyon 69364, France.</footnote>

<footnote n="3">³College of Chemistry, Beijing Normal University, No. 19, XinJieKouWai St, HaiDian District, Beijing 100875, P. R. China.</footnote>
$H_32^{•*2+}$ while undergoing concomitant oxidation back to $I_2$. The radical dication $H_32^{•*2+}$ disproportionates to $H_2^+$ (24 π) and $H_32^+$ (26 π) at low concentrations (≤1.0 µM), a conversion that involves further electron transfer steps (Scheme 1B). The ability to control PCET between two macrocycles and associated thermally driven ETC processes through multiple redox steps and two different electron carriers ($I_3^-$ and $H_32^{•*2+}$), as demonstrated here, is expected to lead to an increased understanding of complex biological redox-based signaling, as well as small molecule therapeutic design and advances in energy conversion and storage.

<figure><img src="image_2.png" /><figcaption>Scheme 1. Schematic Representations of Non-Covalent Multi-Component Electron Transport Composed of 1, $I_2$, and 2. (A) PCET from 1 to give $H_32^+$ and $H_32^{•*2+}$. (B) ETC Involving 1, $I_2$, and 2.</figcaption></figure>

## Results and Discussion

### Electron Transfer from 1 to $I_2$

Cyclo[8]pyrrole 1 is an expanded porphyrin that is relatively easy to oxidize. (48) Cyclic voltammetry (CV) studies revealed a very low value for the first one-electron oxidation of 1*/1 process ($E_{1/2}$ = -0.12 V versus Fc+/Fc) along with good reversibility. This led us to explore whether $I_2$, which has a more positive reduction potential $I_2/I_3^-$ ($E_{pc}$ = +0.05 V versus Fc+/Fc) determined under the same conditions, could be used to oxidize 1. (Note: See Table S5 for a listing of redox potentials relevant to the present study). Adding 5 molar equiv (eq) of $I_2$ into a solution of 1 (0.1 mM in dichloromethane) caused the orange color of the initial solution to change to brown-green immediately (Figure 1B). Further UV-vis-NIR spectral titrations revealed a decrease in the characteristic absorption maximum of 1 ($\lambda_{max}$ = 1150 nm), as well as the simultaneous appearance of shoulders at 744 and 832 nm and a broad peak at 1750 nm. These latter features were readily assigned to 1*+ based on independent preparations (see Figures S5–8, S39). A peak at $\lambda_{max}$ = 296 nm ascribed to $I_3^-$ was also seen after addition (Figure 1C). The equilibrium constants corresponding to the reaction between 1 and $I_2$ were calculated to be $K_{a1}$ = (2.5 ± 0.2) × 10⁵ M⁻¹, $K_{a2}$ = (1.0 ± 0.1) × 10⁵ M⁻¹, and $K_{a3}$ = (3.5 ± 0.3) × 10⁶ M⁻¹ for a 2:3 binding interaction for complex 1*•I₃⁻ as inferred from a UV-vis-NIR spectroscopic Job plots and associated titration studies (Figure S3–4). Subsequent ¹H NMR spectral studies in dichloromethane-d₂ revealed the disappearance of the ethyl group signals for 1 upon the addition of 5 molar eq of $I_2$ (Figure S9). An electron paramagnetic resonance (EPR) spectral analysis of a 1:5 mixture of 1 and $I_2$ in dichloromethane confirmed the presence of a strong signal at g = 2.0059 as expected for the formation of an organic radical species (Figure 1D). Collectively, these findings were taken as evidence that electron transfer from 1 to $I_2$ occurs to produce the one-electron oxidized radical form 1*+.
<figure><img src="image_3.png" /><figcaption>**Figure 1.** Solution and solid-state studies of the electron transfer from **1** to $I_2$. (A) Schematic representation of the proposed electron transfer from **1** to $I_2$. (B) Photographs of dichloromethane solutions of **1** (0.1 mM), a mixture of **1** (0.1 mM) and 5.0 eq of $I_2$, and $I_2$ (0.5 mM) alone. (C) UV-vis-NIR spectral changes seen when a solution of **1** (10 µM) in dichloromethane is titrated with $I_2$. (D) EPR spectrum of **1** (0.1 mM) recorded in the presence of 5.0 eq of $I_2$ in dichloromethane. (E) Side view of the iodic complex of $1^+$ seen in the solid-state structure of single crystals of [(1*)₂·(I₂₅)²⁻·I₂]. Hydrogen atoms have been omitted for the sake of clarity.</figcaption></figure>

An X-ray diffraction analysis of the iodic complex of 1⁺ provided additional evidence for the proposed electron transfer between 1 and $I_2$. Single crystals of [(1*)₂·(I₂₅)²⁻·I₂] containing a polymeric iodine cluster were obtained by exposing a 1.0 mM dichloromethane solution of 1 containing 10 molar eq of $I_2$ to n-hexane vapor for 2 days at 298 K. The resulting structure is shown in Figure 1E. Conversion of 1 to radical 1⁺ led to a loss in bond length uniformity (Figure S30) as reflected in the difference between the shortest and longest interpyrrole C–C bond (Δd) within the macrocyclic core (Δd = 0.03 Å vs 0.10 Å for 1 and 1⁺, respectively). In addition, a greater deviation from the mean plane (defined by all core atoms) is seen in 1⁺ (0.51 Å) as compared to 1 (0.38 Å). (48) The overall complex consists of two molecules of 1⁺ bound to an I₂₅²⁻ cluster (a collection of 25 atoms that share two total negative charges) and one molecule of $I_2$, a structure that is stabilized by presumed halogen-π and anion-π interactions. The closest iodine-to-pyrrole distances are on the order of 3.6–3.9 Å (Figure S31).

## PCET from 1 to 2

Naphthorosarin **2** exhibits distinctive redox reactivity upon protonation (cf. Table S5 in the Supporting Information). For instance, the (24 π) antiaromatic species (**2**) can be converted to the triply protonated state **H₃2**³⁺ or, separately, reduced to give **H₃2**·²⁺ (25 π) or **H₃2**⁺ (26 π) upon treatment with certain acids F₃CSO₃H, HCl, or HI, respectively. (47) In dichloromethane and in the presence of 20 molar eq of TFA, the two one-electron reduction potentials of **H₃2**³⁺ and **H₃2**·²⁺ at +0.41 and +0.02 (E₁/₂, versus F⁺/Fc), respectively, is more positive than the one-electron oxidation potential of 1⁺/1 (E₁/₂ = -0.10 V, versus F⁺/Fc) (Table S5). We thus postulated that **1** would be able to reduce the triply protonated form of naphthorosarin **2** (H₃2**3⁺**) to the corresponding 25 or 26 π form.
To test this hypothesis, UV-vis-NIR spectral studies were carried out. Mixing **2** with one or two molar eq of **1** in dichloromethane did not result in obvious color or spectral changes. However, addition of 40 molar equiv of TFA to these solutions led to an immediate color change from the initial light brown to pink and green, respectively. In addition to features corresponding to 1•⁺ resulting from oxidation of **1**, new absorption peaks at 562 and 620 nm were observed (Figure 2B). These signals correspond to the 25 π (H₃2•²⁺) and 26 π (H₃2⁺) species as reported previously. (47) Adding ≥20, or even 40, molar equiv of TFA into solutions of **2** or **1** alone produced only minor changes in the absorption spectral features, a finding that leads us to suggest that the observed changes reflect PCET between **1**, **2**, and TFA rather than simple protonation effects (Figure S11–13).

<figure><img src="image_4.png" /><figcaption>**Figure 2.** Solution studies of electron transfer from **1** to **2**. (A) Schematic representation of electron transfers from **1** to give H₃2⁺ and H₃2•²⁺. (B) UV-vis-NIR spectra and photographs of various samples: I) **1** (5.0 µM), II) **2** (5.0 µM), III) a mixture of **2** (5.0 µM) and 2.0 eq **1**, IV) a mixture of **2** (5.0 µM), 2.0 eq **1**, and 40 eq of TFA, and V) a mixture of **2** (5.0 µM), 1.0 eq **1**, and 40 eq of TFA in dichloromethane.</figcaption></figure>

Further UV-vis-NIR spectral titrations were performed by adding TFA portion-wise into a 1:1 solution of **1** and **2** (Figure S15). In this titration, H₃2⁺ was observed as the primary product after the addition of 5.0 molar eq of TFA, with H₃2•²⁺ being formed upon the addition of further TFA. This finding is consistent with H₃2⁺ being oxidized back to H₃2•²⁺ by H₃2³⁺ in the presence of an excess of TFA and a deficit of **1**. In an effort to simplify the underlying interactions, a second set of titrations was performed (Figure S16a-c); this was done by adding TFA into a 2:1 solution of **1** and **2**. Under these conditions, a redox reaction between H₃2⁺ and **2** is precluded due to the presence of **1** in excess. Indeed, upon completion of the titration, H₃2⁺ was observed as the primary product. Collectively, these observations are taken as evidence of equilibrium-driven interconversions between the three limiting redox states of **2**, namely the 24 π, 25 π, and 26 π species, and the oxidized and reduced forms of **1** as shown in equations (Equats.) 1 and 2. The corresponding equilibrium constants were calculated as K₁ = (1.5 ± 0.2) × 10¹⁸ M⁻², and K₂ = (7.6 ± 0.5) × 10⁵ M, respectively (Figure S16 d-g). This allowed the approximate populations of **2**, H₃2•²⁺, and H₃2⁺ to be determined; gratifyingly, the resulting values were found concordant with those calculated based on the change in the absorption intensities of the respective species (Figure S16).

$$ [1] + [2] + 3[\text{CF}_3\text{CO}_2\text{H}] \xrightarrow{K_1} [1^{\bullet+} \cdot \text{CF}_3\text{CO}_2^{-}] + [\text{H}_3\text{2}^{\bullet+2+} \cdot (\text{CF}_3\text{CO}_2^{-})_2] \quad (1) $$

$$ [1] + [\text{H}_3\text{2}^{\bullet+2+} \cdot (\text{CF}_3\text{CO}_2^{-})_2] \xrightarrow{K_2} [1^{\bullet+} \cdot \text{CF}_3\text{CO}_2^{-}] + [\text{H}_3\text{2}^{\bullet+} \cdot \text{CF}_3\text{CO}_2^{-}] \quad (2) $$
¹H NMR spectral studies of **2** (0.5 mM in dichloromethane-*d*₂) containing 1.0 or 2.0 molar eq of **1** revealed no discernible signals when recorded in the presence 20 molar eq of **TFA** (Figures S17 and 18). An EPR spectral analysis of this solution revealed a strong signal at g = 2.000 ascribed to the radical species **1**⁺ and **H₃2**⁺²⁺ (Figure S19). Exposure of the mixed solution consisting of **2** (0.5 mM in dichloromethane), **1** (1.0 or 2.0 equiv), and TFA (20 equiv) to ethyl acetate vapor for 2 days yielded single crystals of [**1**⁺•**CF₃CO₂**⁻] in the case of both solutions. Structural analysis of the resulting complex [**1**⁺•**CF₃CO₂**⁻], revealed that the conformation of **1**⁺ was similar to that of [(**1**⁺)₂•(**I₂**)²⁻•**I₂**]. One molecule of **CF₃CO₂**⁻ was found bound outside of the cavity, through apparent N–H–O hydrogen bonds and CF–π interactions (Figure 3A). Exposure of the above solutions to *n*-hexane vapor for 2 days led to the formation of small dark crystals, which following recrystallization from CHCl₃, gave single crystals of [**H₃2**⁺²⁺•(**CF₃CO₂**⁻)₂•CHCl₃]. The deviation from the mean plane (defined by all core atoms) is 0.27 Å in **H₃2**⁺²⁺, which is comparable to what is seen in **2** (0.23 Å) (Figure 3B).

<figure><img src="image_5.png" /><figcaption>**Figure 3.** Solid-state studies of electron transfer from **1** to **2**. (A) and (B) Top (**a**₁, **b**₁) and side views (**a**₂, **b**₂) of the complexes **1**⁺•**CF₃CO₂**⁻ and **H₃2**⁺²⁺•(**CF₃CO₂**⁻)₂ seen in single crystals of [**1**⁺•**CF₃CO₂**⁻] and [**H₃2**⁺²⁺•(**CF₃CO₂**⁻)₂•CHCl₃], respectively. Solvents molecules and some hydrogen atoms have been omitted for clarity.</figcaption></figure>

Considered in concert, these results collectively provide support for the conclusion that electron transfer from **1** to **2** is coordinated with the protonation of **2** by TFA. Both electron transfer and protonation occur when all three compounds are involved. This cooperative-like function differs from classical PCET where both the electron and proton are transferred to or from the same compound.

## Electron Transport Chain Composed of 1, I₂, and 2

In an acidic environment (20 mM TFA in dichloromethane), the reduction potential of I₂/I₃⁻ (*E*<sub>pc</sub> = +0.05 V versus Fc⁺/Fc) obtained from cyclic voltammetry studies, is more positive than the oxidation potential of **1**⁺/1 (*E*<sub>1/2</sub> = -0.10 V versus Fc⁺/Fc). Likewise, the oxidation potential of I₂/I₃⁻ (*E*<sub>pa</sub> = +0.25 V versus
Fc⁺/Fc) is more negative than the reduction potential of H₃2*³⁺/H₃2*²⁺ (E₁/₂ = +0.41 V versus Fc⁺/Fc) but more positive than the reduction potential of H₃2*²⁺/H₃2⁺ (E₁/₂ = +0.02 V versus Fc⁺/Fc) (Table S5 in the Supporting Information). These values, in conjunction with the above predictive studies, led us to test whether **1**, **I₂**, and **2** in concert would serve as a noncovalent electron transport chain subject to chemical modulation by TFA. With this consideration in mind, a mixed solution of **1** (5.0 µM), **2** (1.0 equiv), and **I₂** (5.0 equiv) in dichloromethane was prepared and analyzed using UV-vis-NIR spectroscopy. The results showed that **1** was oxidized to **1**⁺ with the characteristic absorption peak at 296 nm for I₃⁻ appearing concurrently. However, under these conditions no changes in the absorption features for naphthorosarin **2** were seen (Figure 4B). These observations are interpreted in terms of the electron transfer between **1** and I₂.

<figure><img src="image_6.png" /><figcaption>**Figure 4.** Solution studies of electron transfer reactions involving **1**, **I₂**, and **2**. (A) Schematic representation of the proposed electron transport chain. (B) UV-vis-NIR spectra for mixed solutions of **2** (5.0 µM) and 1.0 eq 1 recorded upon the stepwise addition of 5.0 eq of I₂ and 20 eq of TFA in dichloromethane. (C) UV-vis-NIR spectral titrations of TFA into a mixture of **2** (5.0 µM), 1.0 eq **1**, and 5.0 eq I₂. (D) Plot of the concentration and percentage of **2**, H₃2*²⁺, and H₃2⁺ vs TFA based on the data presented in C. (E) UV-vis-NIR spectra for mixed solutions of **2** (1.0 µM) and 2.0 eq 1 recorded upon the stepwise addition of 10 eq of I₂ and 40 eq of TFA. (F) Time-dependent UV-vis-NIR spectra of a mixed solution of **2** (1.0 µM), 2.0 molar eq of **1**, 10 molar eq of I₂, and 40 molar eq of TFA. (G) Plot of concentration and percentage of **2**, H₃2*²⁺, and H₃2⁺ vs time based on the data in part F.</figcaption></figure>

Upon adding TFA to the above mixture, a discernible color change (from light brown to pink) and a significant increase in the intensity of peak at 562 nm characteristic of the reduced 25 π form H₃2*²⁺ was seen. A decrease in the intensity of the 296 nm band corresponding to I₃⁻ was also observed, but
no changes in the absorption features for 1•+ were noted (Figure 4B). The spectra and concentration changes for 2, H32•2+, and H32+ seen upon treatment with TFA are shown in Figure 4C, 4D. As 2 did not display any apparent absorption change in the presence of I2 (5.0 equiv), either in the presence or absence of TFA (Figure S21), we interpret these results in terms of conversion of 2 to H32•2+ mediated by oxidation of I3- by H323+. An increase in the concentration of H32•2+ is also observed when TFA is added to a mixture of 2 (5.0 µM), I2 (3.5 equiv), and I3- (1.0 eq, as its tetrabutylammonium (TBA+) salt) (Figure S22). We thus suggest that under these conditions the I3- produced as a byproduct of the oxidation of 1 acts as an electron carrier and transports electrons to 2 upon protonation, as shown in Figure 4A.

With regard to the second step in the proposed electron transfer chain, we note that I3- on its own is unable to reduce H32•2+ to H32+ as inferred from their respective redox potentials. However, as shown in Figures 4C and 4D, when subjected to titration with 1.0–4.0 molar eq of TFA, a small amount of the 26 π species H32+, characterized by an absorption maximum at 612 nm, is also observed. The level of this species does not increase as the concentration of H32•2+ is raised (>1.0 µM) (Figure 4D). We thus suggest that the observed H32+ comes from the disproportionation of H32•2+ at low concentrations. The disproportionation mentioned here necessarily involves a further electron transfer process. Concentration dependent UV-vis-NIR spectroscopic studies of crystalline H32•2+•(CF3CO2- )2 dissolved in dichloromethane revealed that upon dilution, the percentage of H32•2+ decreased, whereas that of H32+ increased. Essentially all of the H32•2+ disproportionates to produce a 1:1 mixture of H32+ and the protonated 24 π species, H2+, when the concentration of all species is ≤1.0 µM, as deduced from UV-vis-NIR spectroscopic analyses (Figure S23) and DFT calculations (Tables S6, S7).

In a separate experiment, 2 (1.0 µM), 1 (2.0 equiv), and I₂ (10 equiv) were mixed in dichloromethane. Under these conditions only 1•+ and I₃⁻ are generated; however, the subsequent addition of 40 molar eq of TFA produces the reduced 26 π species, H₃₂⁺, within 60 min as reflected in the production of its characteristic absorption feature at 612 nm (Figure 4E). Time-dependent UV-vis-NIR spectroscopic studies revealed that 2 was reduced to H₃₂•²⁺ first and then further to H₃₂⁺ via the disproportionation of H₃₂•²⁺ (Figure 4F, 4G). Increasing the concentration of 2 by 10- to 100-fold promotes aggregation and stabilization of H₃₂•²⁺. This prevents its disproportionation and is presumably promoted by the weak π-π intersubunit interactions seen in the solid-state structure of H₃₂•²⁺•(CF₃CO₂⁻)₂, with the result that little if any H₃₂⁺ is produced (Figures S27 and S28). In contrast, under low concentration conditions (e.g., 1.0 µM), the electron carrier I₃⁻ transports an electron to H₃₂•²⁺, which undergoes disproportionation to give H₂⁺ and H₃₂⁺. DFT calculations (vide infra) support this conclusion (Tables S6, S7). [Note: I₃⁻ is unable to reduce H₃₂•²⁺ to H₃₂⁺.] The net result is an electron transport chain with three steps involving multiple redox active species, as illustrated in Figure 4A.

Exposing a dichloromethane solution of 1, I₂ (5.0 equiv), 2 (0.5 or 1.0 equiv), and 20 molar eq of TFA to ethyl acetate vapor for 2 days produced single crystals of [1•••CF₃CO₂⁻] and [(H₃2•2+)₂⇌(SO₄²⁻)•2I₃⁻ •2.5I₂•6.25H₂O] as a separable mixture. A core dimer (H₃2•2+)₂⇌(SO₄²⁻) was found in the resulting structure [(H₃2•2+)₂ Specification of the sulfate anion is sandwiched between the two H₃2•2+ subunits and held in place via presumed N–H–O hydrogen bonds and possible π–π interactions. The two H₃2•2+ subunits are identical and quasi-planar as reflected in a mean plane deviation of 0.58 Å (Figure 5).
<figure><img src="image_7.png" /><figcaption>Figure 5. Single crystal structure of $(H_32^{*2+})_2 \rightleftharpoons SO_4^{2-} \cdot 2I_3^-$. (A) Top and (B) side views of $(H_32^{*2+})_2 \rightleftharpoons SO_4^{2-} \cdot 2I_3^-$ seen in single crystals of $[(H_32^{*2+})_2 \rightleftharpoons (SO_4^{2-}) \cdot 2I_3^- \cdot 2.5I_2 \cdot 6.25H_2O]$. Some solvent molecules and hydrogen atoms have been omitted for the sake of clarity.</figcaption></figure>

## DFT Calculations

Further support for the suggestion that **1**, **I₂**, and **2** interact to form an electron transport chain came from theoretical calculations. Based on the single crystal structures reported in this study and previous reports, (47,48) the lowest energies in dichloromethane for **1**, **I₂**, **2**, TFA, and their ion species were calculated via DFT methods using the Gaussian 09 program. (49) The resulting reaction energies ($ΔE$) are given in Figure 6 and Table S6, S7. It was found that the reaction energies of the relevant species decreased along the proposed electron transfer sequence, leading us to infer that the experimentally observed electron transport events are driven by thermodynamics.

<figure><img src="image_8.png" /><figcaption>Figure 6. Optimized relative-energy profiles for complexes produced from **1**, **I₂**, and **2** generated along the proposed electron transport chain. Their optimized geometries and relative energies were obtained by DFT calculations using the 6-311+G(d,p)-D3 and def2-TZVPD basis sets (Note: The $CF_3CO_2^-$ counteranions have been omitted for clarity).</figcaption></figure>
## Conclusions

Presented here is an unusual example of a PCET system and an artificial electron transport chain that consists of multiple redox active chemical components, including cyclo[8]pyrrole (1), naphthorosarin (2), and $I_2$. The electron transfer events within these ensembles can be regulated by treatment with small molecules, such as TFA, or via concentration control. Depending on the molar ratio of 1, 2, and added TFA, different reduced forms of 2, namely $H_32^{*2+}$ and $H_32^+$ are produced via the PCET process. Transport of electrons from 1 to give $I_3^-$ could be induced by the treatment with $I_2$. At high concentrations (≥5.0 µM) the $I_3^-$ produced in this way transfers electrons to the protonated form of 2 to produce $H_32^{*2+}$. At low concentrations (e.g., 1.0 µM), $H_32^{*2+}$ undergoes further disproportionation-mediated electron transport to give $H_2^+$ and $H_32^+$. The level of specificity we show here and the demonstration of a bona fide electron transport chain are not readily replicated when three redox active components are mixed. Rather, direct electron transfer from the best electron donor to the best electron acceptor occurs directly in marked contrast to what is observed in, e.g., the respiratory electron transport chain. Nevertheless, in preliminary work, we have found that $I_2$ can be replaced by (tris-(4-bromophenyl)ammoniumyl hexachloroantimonate, [(p-BrC<sub>6</sub>H<sub>4</sub>)<sub>3</sub>N<sup>*+</sup>]<sup>•</sup>[SbCl<sub>6</sub>]<sup>-</sup>), which acts as an effective mediator to promote electron transfer from cyclo[8]pyrrole (1) to naphthorosarin (2) (Figure S40). This finding lends support to the suggestion that the present findings may be readily generalizable, provided the systems in question are the product of appropriate design. More broadly, we believe that our results can serve as a useful framework for the design and development of novel artificial electron transport systems with potential applications in various fields such as energy storage and conversion, catalysis, and electronics.

## Acknowledgments

The work was supported by the US National Science Foundation (CHE1807152) through May of 2020, as well as by the Robert A. Welch Foundation (F-0018 and F-1841). H.Y.G. is grateful to the National Natural Science Foundation of China (92156009 and 21971022), the Fundamental Research Funds for the Central Universities, the Beijing Municipal Commission of Education, and Beijing Normal University for financial support. C.B. is grateful to the ENS and the ANR for financial support (ANR-21-CE06-0020-01). The authors thank Prof. Harry Gray for kindly reviewing the manuscript prior to submission.

## References

1. Kracke, F.; Vassilev, I.; KrAmer, J. O. Microbial electron transport and energy conservation-the foundation for optimizing bioelectrochemical systems. *Front. Microbiol.* **2015**, *6*, 575, DOI: 10.3389/fmicb.2015.00575

2. Baccelli, I.; Gareau, Y.; Lehnertz, B.; Gingras, S.; Spinella, J.-F.; Corneau, S.; Mayotte, N.; Girard, S.; Frechette, M.; Blouin-Chagnon, V. Mubritinib targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia. *Cancer Cell* **2019**, *36*, 84–99, DOI: 10.1016/j.ccell.2019.06.003

3. Kampjut, D.; Sazanov, L. A. The coupling mechanism of mammalian respiratory complex I. *Science* **2020**, *370*, eabc4209, DOI: 10.1126/science.abc4209

4. Lencina, A. M.; Franza, T.; Sullivan, M. J.; Ulett, G. C.; Ipe, D. S.; Gaudu, P.; Gennis, R. B.; Schurig-Briccio, L. A. Type 2 NADH dehydrogenase is the only point of entry for electrons into the
streptococcus agalactiae respiratory chain and is a potential drug target. *mBio* **2018**, *9*, e01034-18, DOI: 10.1128/mBio.01034-18

5. Van Vranken, J. G.; Nowinski, S. M.; Clowers, K. J.; Jeong, M.-Y.; Ouyang, Y.; Berg, J. A.; Gygi, J. P.; Gygi, S. P.; Winge, D. R.; Rutter, J. ACP acylation is an acetyl-CoA-dependent modification required for electron transport chain assembly. *Mol. Cell* **2018**, *71*, 567-580, DOI: 10.1016/j.molcel.2018.06.039

6. Weinberg, F.; Hamanaka, R.; Wheaton, W. W.; Weinberg, S.; Joseph, J.; Lopez, M.; Kalyanaraman, B.; Mutlu, G. M.; Budinger, G. R. S.; Chandel, N. S. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. *Proc. Natl. Acad. Sci. U. S. A.* **2010**, *107*, 8788-8793, DOI: 10.1073/pnas.1003428107

7. Spinelli, J. B.; Rosen, P. C.; Sprenger, H.-G.; Puszynska, A. M.; Mann, J. L.; Roessler, J. M.; Cangelosi, A. L.; Henne, A.; Condon, K. J.; Zhang, T.; Kunchok, T.; Lewis, C. A.; Chandel, N. S.; Sabatini, D. M. Fumarate is a terminal electron acceptor in the mammalian electron transport chain. *Science* **2021**, *374*, 1227-1237, DOI: 10.1126/science.abi7495

8. Titov, D. V.; Cracan, V.; Goodman, R. P.; Peng, J.; Grabarek, Z.; Mootha, V. K. Complementation of mitochondrial electron transport chain by manipulation of the NAD+/NADH ratio. *Science* **2016**, *352*, 231-235, DOI: 10.1126/science.aad4017

9. Hu, H.; Wang, H.; Yang, Y.; Xu, J.-F.; Zhang, X. A bacteria responsive porphyrin for adaptable photodynamic/photothermal therapy. *Angew. Chem., Int. Ed.* **2022**, *61*, e202200799, DOI: 10.1002/anie.202200799

10. Jin, G.-Q.; Chau, C. V.; Arambula, J. F.; Gao, S.; Sessler, J. L.; Zhang, J.-L. Lanthanide porphyrinoids as molecular theranostics. *Chem. Soc. Rev.* **2022**, *51*, 6177-6209, DOI: 10.1039/D2CS00275B

11. Pham, T. C.; Nguyen, V. N.; Choi, Y.; Lee, S.; Yoon, J. Recent strategies to develop innovative photosensitizers for enhanced photodynamic therapy. *Chem. Rev.* **2021**, *121*, 13454-13619, DOI: 10.1021/acs.chemrev.1c00381

12. Luo, T.; Nash, G. T.; Xu, Z.; Jiang, X.; Liu, J.; Lin, W. Nanoscale metal-organic framework confines zinc-phthalocyanine photosensitizers for enhanced photodynamic therapy. *J. Am. Chem. Soc.* **2021**, *143*, 13519-13524, DOI: 10.1021/jacs.1c07379

13. Roca, F. J.; Whitworth, L. J.; Prag, H. A.; Murphy, M. P.; Ramakrishnan, L. Tumor necrosis factor induces pathogenic mitochondrial ROS in tuberculosis through reverse electron transport. *Science* **2022**, *376*, eabh2841, DOI: 10.1126/science.abh2841

14. Wu, W.; Mao, D.; Xu, S.; Kenry, H. F.; Li, X.; Kong, D.; Liu, B. Polymerization-enhanced photosensitization. *Chem.* **2018**, *4*, 1937-1951, DOI: 10.1016/j.chempr.2018.06.003

15. Han, H.; Hou, Y.; Chen, X.; Zhang, P.; Kang, M.; Jin, Q.; Ji, J.; Gao, M. Metformin-induced stromal depletion to enhance the penetration of gemcitabine-loaded magnetic nanoparticles for pancreatic cancer targeted therapy. *J. Am. Chem. Soc.* **2020**, *142*, 4944-4954, DOI: 10.1021/jacs.0c00650

16. Yang, X.; Cheng, Y.; Zhou, J.; Zhang, L.; Li, X.; Wang, Z.; Yin, S.; Zhai, L.; Huang, T.; Wu, X.; Shen, B.; Dong, Y.; Zhao, L.; Chi, Y.; Jia, Y.; Wang, J.; He, Y.; Dong, X.; Xiao, H.; Wang, J. Targeting cancer metabolism plasticity with JX06 nanoparticles via inhibiting PDK1 combined with metformin for
endometrial cancer patients with diabetes. *Adv. Sci.* **2022**, *9*, 2104472, DOI: 10.1002/advs.202104472

17. Landry, D. A.; Yakubovich, E.; Cook, D. P.; Fasih, S.; Upham, J.; Vanderhyden, B. C. Metformin prevents age-associated ovarian fibrosis by modulating the immune landscape in female mice. *Sci. Adv.* **2022**, *8*, eabq1475, DOI: 10.1126/sciadv.abq1475

18. Bridges, H. R.; Blaza, J. N.; Yin, Z.; Chung, I.; Pollak, M. N.; Hirst, J. Structural basis of mammalian respiratory complex I inhibition by medicinal biguanides. *Science* **2023**, *379*, 351–357, DOI: 10.1126/science.ade3332

19. Lv, J.; Xie, J.; Mohamed, A. G. A.; Zhang, X.; Feng, Y.; Jiao, L.; Zhou, E.; Yuan, D.; Wang, Y. Solar utilization beyond photosynthesis. *Nat. Rev. Chem.* **2023**, *7*, 91–105, DOI: 10.1038/s41570-022-00448-9

20. Reyes Cruz, E. A.; Nishiori, D.; Wadsworth, B. L.; Nguyen, N. P.; Hensleigh, L. K.; Khusnutdinova, D.; Beiler, A. M.; Moore, G. F. Molecular-modified photocathodes for applications in artificial photosynthesis and solar-to-fuel technologies. *Chem. Rev.* **2022**, *122*, 16051–16109, DOI: 10.1021/acs.chemrev.2c00200

21. Wang, Z.; Hu, Y.; Zhang, S.; Sun, Y. Artificial photosynthesis systems for solar energy conversion and storage: platforms and their realities. *Chem. Soc. Rev.* **2022**, *51*, 6704–6737, DOI: 10.1039/D1CS01008E

22. Daeneke, T.; Kwon, T.-H.; Holmes, A. B.; Duffy, N. W.; Bach, U.; Spiccia, L. High-efficiency dye-sensitized solar cells with ferrocene-based electrolytes. *Nat. Chem.* **2011**, *3*, 211–215, DOI: 10.1038/nchem.966

23. Hashmi, S. G.; Ozkan, M.; Halme, J.; Zakeeruddin, S. M.; Paltakari, J.; Gratzel, M.; Lund, P. D. Dye-sensitized solar cells with inkjet-printed dyes. *Energy Environ. Sci.* **2016**, *9*, 2453–2462, DOI: 10.1039/C6EE00826G

24. Muñoz-García, A. B.; Benesperi, I.; Boschloo, G.; Concepcion, J. J.; Delcamp, J. H.; Gibson, E. A.; Meyer, G. J.; Pavone, M.; Pettersson, H.; Hagfeldt, A.; Freitag, M. Dye-sensitized solar cells strike back. *Chem. Soc. Rev.* **2021**, *50*, 12450–12550, DOI: 10.1039/D0CS01336F

25. Jackson, M. N.; Pegis, M. L.; Surendranath, Y. Graphite-conjugated acids reveal a molecular framework for proton-coupled electron transfer at electrode surfaces. *ACS Cent. Sci.* **2019**, *5*, 831–841, DOI: 10.1021/acscentsci.9b00114

26. Kaila, V. R. I. Long-range proton-coupled electron transfer in biological energy conversion: towards mechanistic understanding of respiratory complex I. *J. R. Soc. Interface* **2018**, *15*, 20170916, DOI: 10.1098/rsif.2017.0916

27. Weinberg, D. R.; Gagliardi, C. J.; Hull, J. F.; Murphy, C. F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess, D. H.; McCafferty, D. G.; Meyer, T. J. Proton-coupled electron transfer. *Chem. Rev.* **2012**, *112*, 4016–4093, DOI: 10.1021/cr200177j

28. Reece, S. Y.; Nocera, D. G. Proton-coupled electron transfer in biology: results from synergistic studies in natural and model systems. *Annu. Rev. Biochem.* **2009**, *78*, 673–699, DOI: 10.1146/annurev.biochem.78.080207.092132

29. Nocera, D. G. Proton-coupled electron transfer: The engine of energy conversion and storage. *J. Am. Chem. Soc.* **2022**, *144*, 1069–1081, DOI: 10.1021/jacs.1c10444
30. Dasari, R. R.; Wang, X.; Wiscons, R. A.; Haneef, H. F.; Ashokan, A.; Zhang, Y.; Fonari, M. S.; Barlow, S.; Coropceanu, V.; Timofeeva, T. V.; Jurchescu, O. D.; Brédas, J.-L.; Matzger, A. J.; Marder, S. R. Charge transport properties of F₆TNAP Based charge transfer cocrystals. *Adv. Funct. Mater.* **2019**, *29*, 1904858, DOI: 10.1002/adfm.201904858

31. Gao, G.; Chen, M.; Roberts, J.; Feng, M.; Xiao, C.; Zhang, G.; Parkin, S.; Risko, C.; Zhang, L. Rational functionalization of a C₇₀ buckybowl to enable a C₇₀: buckybowl cocrystal for organic semiconductor applications. *J. Am. Chem. Soc.* **2020**, *142*, 2460–2470, DOI: 10.1021/jacs.9b12192

32. Kim, T.; Feng, Y.; O'Connor, J. P.; Stoddart, J. F.; Young, R. M.; Wasielewski, M. R. Coherent vibronic wavepackets show structure-directed charge flow in host-guest donor-acceptor complexes. *J. Am. Chem. Soc.* **2023**, *145*, 8389–8400, DOI: 10.1021/jacs.2c13576

33. Nakamura, M.; Horiuchi, S.; Kagawa, F.; Ogawa, N.; Kurumaji, T.; Tokura, Y.; Kawasaki, M. Shift current photovoltaic effect in a ferroelectric charge-transfer complex. *Nat. Commun.* **2017**, *8*, 281, DOI: 10.1038/s41467-017-00250-y

34. Saha, S. Anion-induced electron transfer. *Acc. Chem. Res.* **2018**, *51*, 2225–2236, DOI: 10.1021/acs.accounts.8b00197

35. Stoltzfus, D. M.; Donaghey, J. E.; Armin, A.; Shaw, P. E.; Burn, P. L.; Meredith, P. Charge generation pathways in organic solar cells: assessing the contribution from the electron acceptor. *Chem. Rev.* **2016**, *116*, 12920–12955, DOI: 10.1021/acs.chemrev.6b00126

36. Wang, Y.; Wu, H.; Jones, L. O.; Mosquera, M. A.; Stern, C. L.; Schatz, G. C.; Stoddart, J. F. Color-tunable upconversion-emission switch based on cocrystal-to-cocrystal transformation. *J. Am. Chem. Soc.* **2023**, *145*, 1855–1865, DOI: 10.1021/jacs.2c11425

37. Wu, H.; Wang, Y.; Song, B.; Wang, H.-J.; Zhou, J.; Sun, Y.; Jones, L. O.; Liu, W.; Zhang, L.; Zhang, X.; Cai, K.; Chen, X.-Y.; Stern, C. L.; Wei, J.; Farha, O. K.; Anna, J. M.; Schatz, G. C.; Liu, Y.; Fraser Stoddart, J. A. contorted nanographene shelter. *Nat. Commun.* **2021**, *12*, 5191, DOI: 10.1038/s41467-021-25255-6

38. Park, J. S.; Karnas, E.; Ohkubo, K.; Chen, P.; Kadish, K. M.; Fukuzumi, S.; Bielawski, C. W.; Hudnall, T. W.; Lynch, V. M.; Sessler, J. L. Ion-mediated electron transfer in a supramolecular donor-acceptor ensemble. *Science* **2010**, *329*, 1324–1327, DOI: 10.1126/science.1192044

39. Furstner, A. Iron catalysis in organic synthesis: A critical assessment of what it takes to make this base metal a multitasking champion. *ACS Cent. Sci.* **2016**, *2*, 778–789, DOI: 10.1021/acscentsci.6b00272

40. Crossley, S. W.; Obradors, C.; Martinez, R. M.; Shenvi, R. A. Mn-, Fe-, and Co-catalyzed radical hydrofunctionalizations of Olefins. *Chem. Rev.* **2016**, *116*, 8912–9000, DOI: 10.1021/acs.chemrev.6b00334

41. Yi, H.; Zhang, G.; Wang, H.; Huang, Z.; Wang, J.; Singh, A. K.; Lei, A. Recent advances in radical C-H activation/radical cross-coupling. *Chem. Rev.* **2017**, *117*, 9016–9085, DOI: 10.1021/acs.chemrev.6b00620

42. Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. *Chem. Rev.* **2016**, *116*, 10075–10166, DOI: 10.1021/acs.chemrev.6b00057
43. Matsui, J. K.; Lang, S. B.; Heitz, D. R.; Molander, G. A. Photoredox-mediated routes to radicals: the value of catalytic radical generation in synthetic methods development. *ACS Catal.* **2017**, *7*, 2563–2575, DOI: 10.1021/acscatal.7b00094

44. Li, H.; Cheng, C.; McGonigal, P. R.; Fahrenbach, A. C.; Frasconi, M.; Liu, W.-G.; Zhu, Z.; Zhao, Y.; Ke, C.; Stoddart, J. F. Relative unidirectional translation in an artificial molecular assembly fueled by light. *J. Am. Chem. Soc.* **2013**, *135*, 18609–18620, DOI: 10.1021/ja4094204

45. Hutchison, P.; Kaminsky, C. J.; Surendranath, Y.; Hammes-Schiffer, S. Concerted proton-coupled electron transfer to a graphite adsorbed metalloporphyrin occurs by band to bond electron redistribution. *ACS Cent. Sci.* **2023**, *9*, 927–936, DOI: 10.1021/acscentsci.3c00186

46. Sun, R.; Liu, M.; Zheng, S. L.; Dogutan, D. K.; Costentin, C.; Nocera, D. G. Proton-coupled electron transfer of macrocyclic ring hydrogenation: The chlorinphlorin. *Proc. Natl. Acad. Sci. U. S. A.* **2022**, *119*, e2122063119, DOI: 10.1073/pnas.2122063119

47. Ishida, M.; Kim, S.-J.; Preihs, C.; Ohkubo, K.; Lim, J. M.; Lee, B. S.; Park, J. S.; Lynch, V. M.; Sessler, J. L. Protonation-coupled redox reactions in planar antiaromatic meso-pentafluorophenyl-substituted *o*-phenylene-bridged annulated rosarins. *Nat. Chem.* **2013**, *5*, 15–20, DOI: 10.1038/nchem.1501

48. Bucher, C.; Devillers, C. H.; Moutet, J.-C.; Pécaut, J.; Sessler, J. L. Electrochemical synthesis of cyclo[8]pyrrole. *Chem. Commun.* **2006**, 3891–3893, DOI: 10.1039/B606998C

49. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A. et al. Gaussian 09, Revision A.1. *Gaussian*, Wallingford, CT, 2009.