# Mild and easy access to sappyrins by electrochemical synthesis

Rostislav Sponar, Claude P Gros, Charles H Devillers, Nicolas Desbois

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Rostislav Sponar, Claude P Gros, Charles H Devillers, Nicolas Desbois. Mild and easy access to sappyrins by electrochemical synthesis. Journal of Porphyrins and Phthalocyanines, 2025, 29 (3-4), pp.478-487. 10.1142/S1088424625500415 . hal-05524029

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# Mild and easy access to sappyrins by electrochemical synthesis

Rostislav Sponar<sup>a, b</sup>, Claude P. Gros<sup>b</sup>, Charles H. Devillers<sup>*b</sup>, Nicolas Desbois<sup>*b</sup>

Dedicated to Prof. Karl M. Kadish on the occasion of his 80th birthday

Received date (to be automatically inserted after your manuscript is submitted)

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**ABSTRACT:** Here we report the optimized synthesis of pentapyrroles. We succeeded in increasing the yield for pentapyrrole PPy **1a** by heating at 100 °C for 4.5 h. These conditions also allowed a greater increase in the yield for PPy **1c**. In contrast, with PPy **1d** and **1e** possessing EDGs the formation of pentapyrroles was not observed. These pentapyrroles then allowed us to access to sappyrins (e.g. cyclic analogs of pentapyrroles) by electrosynthesis. The optimized conditions for obtaining the fluorinated sappyrins **2a** and **2b** involve the addition of 10 mol% TBAI (tetra-n-butylammoniom iodide), 2 eq. of TFA in CHCl<sub>3</sub>. In comparison with classical organic synthesis, the amount of TFA was considerably reduced from 100 to 2 eq. and the oxidizing agent, *i.e.* iodine, was continuously electrogenerated from the catalytic amount of TBAI used as a redox mediator.

**KEYWORDS:** sappyrin, pentapyrrole, electrosynthesis, oxidative C-C cyclization

## INTRODUCTION

Sappyrins are part of the expanded porphyrin family. They were first discovered by Woodward in 1966 as one of the side products in the study of Vitamin B<sub>12</sub> synthesis. [1] They are currently poorly described in the literature because the

<footnote><sup>a</sup>Department of Organic Chemistry, University of Chemistry and Technology, Prague Technická 5, 166 28 Prague 6, Czech Republic</footnote>

<footnote><sup>b</sup>Univ. Bourgogne Europe, Institut de Chimie Moléculaire de l'Université Bourgogne Europe (ICMUB), UMR CNRS 6302, 9, Avenue Alain Savary. 21 000 Dijon, France</footnote>

<footnote>*Correspondence to: Charles H. Devillers, e-mail : charles.devillers@u-bourgogne.fr and Nicolas Desbois, e-mail : nicolas.desbois@u-bourgogne.fr</footnote>
methods for obtaining them are still delicate. However, several studies have highlighted their potential applications as photosensitizers in PDT, [2] [3] as potential agents for the treatment of leishmaniasis [4] or as anticancer agents. [5] [6]. The first synthesis of sappyrins was reported by Johnson's group in 1972. They were able to synthesize sappyrins bearing β-substituents using a MacDonald-type condensation reaction. [7] This pioneering method was then modified by Sessler and co-workers using substituted diformylbipyrrole and tripyrromethane diacid. [8] However, the main drawback of this preparation is the large number of steps required to obtain the intermediates, usually isolated in low yields. Thus, this approach was slightly modified to a [3 + 1 + 1] methodology using a tripyrromethane diacid derivative and pyrrole. This method improved the overall yield of the reaction by reducing the number of steps required to prepare the intermediates. In this approach, the formation of meso-substituted sappyrins via a protonated intermediate was also observed. [9] A simple approach has been also developed by the group of Latos-Grażyński. [10] It consists of the condensation of pyrrole and benzaldehyde catalyzed by trifluoroborate etherate. [10] This reaction produces the desired sappyrin, but also some by-products, N-confused porphyrin, and tetraarylporphyrin. Analysis of the spectroscopic data of this sappyrin also showed that the pyrrolic unit opposite to the bipyrrrole moiety was inverted. This was particularly proven by ¹H NMR, where the NH proton singlet was observed around δ = 12 ppm, while the β-CH proton peak was located in the upfield part around δ = -1.50 ppm. Interestingly, this sappyrin derivative with the inverted pyrrolic unit was able to undergo flipping of the pyrrole ring to normal form upon protonation. Again, this conformation change was confirmed by ¹H NMR analyses where the signals of the β-CH protons were shifted to the downfield part of the NMR spectrum. Further improvement of the synthesis was made by Chandrashekar's group, [11] which used different 5-phenyl dipyrromethanes treated with TFA, followed by oxidation with p-chloranil. These experiments gave higher yields, but the formation of the desired sappyrins depended on the type of acid catalyst and its concentration. [11] A new synthetic route to sappyrins has been described in recent years and has been developed in particular by us. [12-14] This approach is performed in only 2 steps. The first one involves the condensation of pyrrole with benzaldehyde derivative, to give corrole [15,16] as the main product of the reaction and pentapyrrole as a side product. The second step concerns the oxidative cyclization of pentapyrrole, which affords the desired sappyrin (Scheme 1). Two different conditions are reported for this second step. Indeed, this cyclization reaction occured either in glacial acetic acid, or in toluene in the presence of iodine and TFA. Using this novel approach, we were able to prepare several meso-aryl sappyrins in fewer steps than with older methods.

<figure><img src="image_2.png" /><figcaption>**Scheme 1.** Synthesis of sappyrins *via* pentapyrrole intermediates</figcaption></figure>

In this work, we were interested in developing a new and efficient method to access sappyrins by electrochemically-driven cyclization of pentapyrroles. Advantageously, electrochemistry allows a fine tuning of the oxidizing power by selecting the working electrode potential (or the current) and the spent charge can be precisely controlled. For these reasons, and due to the increasing importance of electrosynthesis in organic transformations, [17-20] the exploration of this approach offers great potential. Although electrosynthesis currently appears highly relevant as an alternative “green” approach
to obtain new organic molecules, only a few examples of preparation of macrocycles by electrosynthesis have been reported so far. Thus, the synthesis of cyclo[8]pyrrole was accomplished *via* C(2)–C(2)’ oxidative coupling of bipyrrole derivatives either chemically [21] or electrochemically [22]. The isolated compound was in its protonated form and the initial H₂SO₄ acid or HSO₄⁻ anion coming from the supporting electrolyte were crucial to enhance the cyclisation yield thanks to a template effect. Based on these pioneering results, the electrochemical strategy was successfully applied to the synthesis of other expanded porphyrins. For example, electrosynthesis was used in the preparation of thiophene-containing cyclo[9]pyrrole derivative. [23] This compound is fully symmetric and contains three thiophene and six pyrrole units. The final isolated product was shown to be protonated and it has to be noted that it could not be synthesized by standard chemical coupling. [23]

# EXPERIMENTAL

## Materials and Instrumentation

All used chemicals and solvents were of analytical grade. Silica gel 60 (40–63 µm, VWR Chemicals) was used for column chromatography. Absolute dichloromethane (CH₂Cl₂, 99.8%) from Fisher Chemicals, was used for measurement of the UV/Vis spectra without further purification. Acetonitrile (ACN) and toluene used for electrochemistry were dried over alumina cartridges using a solvent purification system PureSolv PS-MD-5 model from Innovative Technology and kept under an Ar atmosphere. Chloroform used for electrochemistry was dried over activated molecular sieves (4Å) during 48 h and kept under an Ar atmosphere. Tetraethylammonium tetrafluoroborate (TEABF₄) and tetra-*n*-butylammonium hexafluorophosphate (TBAPF₆) were prepared by adding carefully (slowly) stoichiometric amount of HBF₄ (48% in water) or HPF₆ (60% in water) into the corresponding cooled (ice bath) tetraethylammonium/tetra-*n*-butylammonium hydroxide solution (35 and 40% in water, respectively), under stirring. The resulting precipitates were filtered on a Büchner filter and the obtained solids were recrystallised in EtOH (for TBAPF₆, three consecutive recrystallisations were performed) or MeOH (for TEABF₄, one recrystallization was made). The resulting crystals were dried in an oven at 110°C for 48 h. ¹H NMR and ¹⁹F NMR spectra were recorded on Bruker AV400 or AV500 spectrometers (400 and 500 MHz) and CDCl₃ was used as a solvent. Chemical shifts (δ) are given in ppm and are relative to residual CHCl₃ (7.26 ppm). MALDI/TOF mass spectra were recorded on a Bruker Ultraflex Extreme MALDI Tandem TOF Mass Spectrometer. Cyclic voltammetry was carried out with Metrohm Autolab potentiostat/galvanostat (PGSTAT302N) with a homemade cell and a three-electrode system which consisted of a platinum working electrode (ø = 1.6 mm), a platinum wire counter electrode and a saturated calomel reference electrode (SCE). The SCE was separated from the bulk of the solution by a fritted-glass bridge of low porosity which contained the solvent/supporting electrolyte mixture. Before each voltammetric analysis, the Pt electrode was polished with a diamond suspension. In these conditions, when operating in CH₃CN (0.1 M TEABF₄), the formal potential for the ferrocene (+/0) couple was +0.40 V vs SCE. For the electrosynthesis, a three-compartment cell was used with a platinum spiral as working electrode (l = 50 cm, ∂ = 1 mm, S ≈ 15 cm²), a platinum foil as counter electrode and SCE. The counter electrode and SCE were both separated from the bulk of the solution by a fritted-glass bridge of low porosity which contained the solvent/supporting electrolyte mixture.

## Preparation of pentapyrroles 1a-e
**Protocol A (described):** Appropriate aldehyde (10 mmol) was dissolved in MeOH (400 mL). In the flask was then added H₂O (400 mL) with 35% HCl (8.5 mL). To this solution, pyrrole (20 mmol) was added dropwise and the reaction mixture was stirred at r.t. for 3 h. The mixture was then extracted with CHCl₃ (3x100 mL). The organic phase was washed with water (2x100 mL) and dried over Na₂SO₄. After filtration, the resulting solution was filled up to a total volume of 600 mL with CHCl₃ and p-chloranil (10 mmol) was added. This mixture was heated to reflux for 1 h. The solution was then cooled down to room temperature, washed with water (2x100 mL) and the solvent was evaporated under reduced pressure. Purification details for each compound are described below.

**Protocol B (optimized):** Appropriate aldehyde (10 mmol) was dissolved in MeOH (400 mL). Under N₂ atmosphere was added H₂O (400 mL) with 35% HCl (8.5 mL). To this solution, pyrrole (20 mmol) was added dropwise and the reaction mixture was heated to 100 °C (Heat-on Block) for 4.5 h. The mixture was then cooled down to room temperature and extracted with CHCl₃ (3x100 mL). The organic phase was washed with water (2x100 mL) and dried over Na₂SO₄. After filtration, the resulting solution was filled up to a total volume of 600 mL with CHCl₃ and p-chloranil (10 mmol) was added. The mixture was heated to reflux for 1 h. The reaction mixture was cooled down to room temperature, washed with water (2x100 mL) and the solvent was evaporated under reduced pressure. Purification details for each compound are described below.

**Pentapyrrole 1a.** PPy 1a was obtained by protocol B. The crude mixture was first purified on a short plug of silica with 100% DCM. Mixture of PPy 1a and tris(3,5-difluorophenyl)corrole was chromatographed on basic Al₂O₃ with DCM/n-heptane (1:2, v/v, Rf ≈ 0.8) then on silica gel with toluene/n-pentane (1:3, v/v, Rf ≈ 0.6). PPy 1a was obtained in 6.0% yield (120 mg). λmax (nm) (ε x10⁻³ L mol⁻¹ cm⁻¹, CH₂Cl₂): 373 (34), 448 (17), 504 (36), 815 (5.7), 880 (6.8). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 12.60 (s, 3H, NH), 6.99 (d, ³Jₐ⁻ = 7.3 Hz, 4H, Ar–H), 6.90–6.77 (m, 8H, Ar–H), 6.73 (s, 2H, H-pyrrolic), 6.58 (d, ³Jₐ⁻ = 4.6 Hz, 2H, H-pyrrolic), 6.51 (d, ³Jₐ⁻ = 2.4 Hz, 2H, H-pyrrolic), 6.44 (d, ³Jₐ⁻ = 4.6 Hz, 2H, H-pyrrolic), 6.13–6.08 (m, 2H, H-pyrrolic), 6.06 (dd, ³Jₐ⁻ = 3.9, 2.4 Hz, 2H, H-pyrrolic). ¹⁹F NMR (470 MHz, CDCl₃) δ (ppm): -109.91 (s, 4F), -110.78 (s, 4F). MS (MALDI-TOF): m/z found 826.02 [M+H]⁺, 826.22 calcd for C₄₈H₂₈F₈N₅.

**Pentapyrrole 1b.** PPy 1b was obtained by protocol A. The crude mixture was purified on a short plug of silica with 100% DCM. Fractions containing pentapyrrole were purified by chromatography on silica gel using toluene as solvent (Rf ≈ 0.39). PPy 1b was obtained in 2.1% yield (68.0 mg). λmax (nm) (ε x10⁻³ L mol⁻¹ cm⁻¹, CH₂Cl₂): 379 (17), 499 (4.31), 812 (3.1), 894 (3.8). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 12.77 (br s, 3H, NH), 7.41 (m, 4H, Ar–H), 7.20–7.08 (m, 8H, Ar–H), 7.01 (t, ³Jₐ⁻ = 8.5 Hz, 4H, Ar–H), 6.60 (s, 2H, H-pyrrolic), 6.53 (d, ³Jₐ⁻ = 4.5 Hz, 2H, H-pyrrolic), 6.51 (s, 2H, H-pyrrolic), 6.37 (d, ³Jₐ⁻ = 4.5 Hz, 2H, H-pyrrolic), 6.00 (d, ³Jₐ⁻ = 3.8 Hz, 2H, H-pyrrolic), 5.98–5.94 (m, 2H, H-pyrrolic). ¹⁹F NMR (470 MHz, CDCl₃) δ (ppm): -113.76, -113.90 (m, 2F), -114.47, -114.60 (m, 2F). MS (MALDI-TOF): m/z found 754.53 [M+H]⁺, 754.26 calcd for C₄₈H₃₂F₄N₅.

**Pentapyrrole 1c.** PPy 1c was obtained by protocol B. The crude mixture was chromatographed on a short plug of silica with 100% DCM. Second fraction with red colour was further purified by silica gel chromatography with 100% DCM and then by silica gel chromatography with DCM/MeOH (99:1, v/v, Rf ≈ 0.87). Obtained fraction with pentapyrrole was precipitated in the mixture of DCM/MeOH. PPy 1c was obtained in 8.0% yield (156.5 mg). λmax (nm) (ε x10⁻³ L mol⁻¹ cm⁻¹, toluene): 389 (43), 447 (28), 509 (46), 843 (8.1), 909 (7.2). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 12.59 (br s, 3H, NH), 7.74 (d, ³Jₐ⁻ = 8.5 Hz, 4H, Ar–H), 7.63 (d, ³Jₐ⁻ = 8.5 Hz, 4H, Ar–H), 7.57 (d, ³Jₐ⁻ = 8.0 Hz, 4H, Ar–H), 7.32 (d, ³Jₐ⁻ = 8.0 Hz, 4H, Ar–H), 6.72 (s, 2H, H-pyrrolic), 6.56–6.49 (m, 4H, H-pyrrolic), 6.39 (d, ³Jₐ⁻ = 4.5 Hz, 2H, H-pyrrolic), 6.09–6.05 (m, 4H, H-pyrrolic). MS (MALDI-TOF): m/z found 782.27 [M+H]⁺, 782.33 calcd for C₅₂H₃₁N₉.
**Pentapyrrole 1d.** PPy 1d was obtained by protocol A. The crude mixture was dissolved in DCM and filtrated on Al₂O₃. Filtrate was then chromatographed on silica gel with DCM/ethyl acetate (95:5, v/v, Rf ≈ 0.8), then on another silica gel with toluene/n-heptane/acetone (10:8:2, v/v/v, Rf ≈ 0.46). PPy 1d was obtained in 1.0% yield (10 mg). λmax (nm) (ε x10⁻³ L mol⁻¹ cm⁻¹, toluene): 388 (42), 498 (47), 848 (6.8), 896 (7.8). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 12.72 (s, 3H, NH), 7.38 (d, ³Jₕ-ₕ = 8.2 Hz, 4H, Ar–H), 7.16 (d, ³Jₕ-ₕ = 8.2 Hz, 4H, Ar–H), 6.96 (d, ³Jₕ-ₕ = 8.4 Hz, 4H, Ar–H), 6.88–6.78 (m, 4H, Ar–H), 6.63 (s, 2H, H-pyrrolic), 6.60 (d, ³Jₕ-ₕ = 4.5 Hz, 2H, H-pyrrolic), 6.47 (d, ³Jₕ-ₕ = 3.8 Hz, 2H, H-pyrrolic), 6.42 (d, ³Jₕ-ₕ = 4.5 Hz, 2H, H-pyrrolic), 6.03 (d, ³Jₕ-ₕ = 3.8 Hz, 2H, H-pyrrolic), 5.93 (dd, ³Jₕ-ₕ = 3.8, 2.4 Hz, 2H), 3.87 (s, 6H, CH₃), 3.84 (s, 6H, CH₃). MS (MALDI-TOF): m/z found 802.92 [M+H]⁺, 802.34 calcd for C₅₂H₄₄N₅O₄.

**Pentapyrrole 1e.** PPy 1e was obtained by protocol A. The crude mixture was purified on silica gel with DCM/n-heptane (4:6, v/v, Rf ≈ 0.6) and then on basic Al₂O₃ with DCM/n-heptane (1:1, v/v, Rf ≈ 0.8). PPy 1e was obtained in 2.0% yield (20 mg). UV/Vis λmax (nm) (ε x10⁻³ L mol⁻¹ cm⁻¹, CH₂Cl₂): 354 (14), 385 (15), 440 (13), 495 (14). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 12.80 (s, 3H, NH), 7.34 (d, ³Jₕ-ₕ = 7.8 Hz, 4H, Ar–H), 7.22 (d, ³Jₕ-ₕ = 7.8 Hz, 4H, Ar–H), 7.11 (s, 8H, Ar–H), 6.62 (s, 2H, H-pyrrolic), 6.57 (d, ³Jₕ-ₕ = 4.5 Hz, 2H, H-pyrrolic), 6.48 (s, 2H, H-pyrrolic), 6.41 (d, ³Jₕ-ₕ = 4.5 Hz, 2H, H-pyrrolic), 6.02 (d, ³Jₕ-ₕ = 3.7 Hz, 2H, H-pyrrolic), 5.95–5.90 (m, 2H, H-pyrrolic), 2.42 (s, 6H, CH₃), 2.38 (s, 6H, CH₃). MS (MALDI-TOF): m/z found 738.29 [M+H]⁺, 738.36 calcd for C₅₂H₄₄N₅.

## Synthesis of sappyrins 2a-b

General procedure. The supporting electrolyte (TBAPF₆) was degassed in the electrochemical cell under vacuum and kept under argon before use (3 cycles of vacumm/Ar). Then it was dissolved under argon in 25 mL of dry CHCl₃ to a concentration of 0.1 mol L⁻¹. Part of this solution was transferred to the cathodic compartment (5 mL), part to reference electrode compartment (5 mL) and the rest of the solution (15 mL) was transferred under argon, in the anodic compartment. The appropriate pentapyrrole was added to the anodic compartment to a concentration of 10⁻³ mol L⁻¹. Cyclic voltammograms of pure PPy were measured. Then TFA was added (2 eq.) and 10 mol% TBAI, and cyclic voltammograms of this mixture were measured. Electrosynthesis was conducted at Eapp = 0.70 V / SCE. After abstraction of 1.60 or 1.82 F for 1a or 1b, respectively, the reaction mixture was washed with hot H₂O (3 × 20 mL, 50 °C) to remove the supporting electrolyte. The organic phase was then evaporated. Purification of the crude product and changes in procedure are mentioned in the Results and Discussion part.

**Sappyrin 2a.** The crude mixture was chromatographed on silica gel with ethyl acetate/n-heptane (1:3, v/v, Rf ≈ 0.6). Sappyrin 2a was obtained in 62% yield (8.7 mg) from 14 mg of pentapyrrole 1a. λmax (nm) (ε x10⁻³ L mol⁻¹ cm⁻¹, CH₂Cl₂): 493 (115), 517 (72), 640 (5.6), 698 (11), 801 (4.1). ¹H NMR (400 MHz, CDCl₃) δ (ppm): 11.64 (s, 1H, NH inverted), 10.10 (d, ³Jₕ-ₕ = 4.7 Hz, 2H, H-pyrrolic), 9.16 (d, ³Jₕ-ₕ = 4.6 Hz, 2H, H-pyrrolic), 9.13 (d, ³Jₕ-ₕ = 4.6 Hz, 2H, H-pyrrolic), 8.99 (d, ³Jₕ-ₕ = 4.5 Hz, 2H, H-pyrrolic), 7.88 (d, ³Jₕ-ₕ = 23.2 Hz, 8H, Ar–H), 7.33 (t, ³Jₕ-ₕ = 9.0 Hz, 2H, Ar–H), 7.11 (t, ³Jₕ-ₕ = 8.6 Hz, 2H, Ar–H), -1.17 (s, 2H, H-pyrrolic inverted), -2.20 (br s, 2H, NH inner core). ¹⁹F NMR (470 MHz, CDCl₃) δ (ppm): -108.16 (s, 4F), -111.24 (s, 4F). MS (MALDI-TOF): m/z found 824.27 [M+H]⁺, 824.21 calcd for C₄₈H₂₆F₈N₅. HRMS (ESI+): m/z found 824.20440 [M+H]⁺, 824.20550 calcd for C₄₈H₂₆F₈N₅.

**Sappyrin 2b.** The crude mixture was chromatographed on silica gel with methanol/DCM (98.5:1.5, v/v, Rf ≈ 0.5). It was impossible to separate the starting pentapyrrole 1b from the sappyrin 2b. Sappyrin 2b was obtained in 53% yield (estimated by NMR measurement). λmax (nm) (ε x10⁻³ L mol⁻¹ cm⁻¹, CH₂Cl₂): 490 (63), 516 (39), 636 (6.8), 696 (9.3), 797 (4.3). ¹H NMR (500 MHz, CDCl₃) δ (ppm): 11.60 (br s, 1H, NH), 10.09 (d, ³Jₕ-ₕ = 4.6 Hz, 2H, H-pyrrolic), 9.13 (d, ³Jₕ-ₕ =
4.5 Hz, 2H, H-pyrrolic), 9.03 (d, $^3J_{H-H}$ = 4.4 Hz, 2H, H-pyrrolic), 8.94 (d, $^3J_{H-H}$ = 4.4 Hz, 2H, H-pyrrolic), 8.31 (m, 8H, Ar-H), 7.60-7.50 (m, 2H, Ar-H), 7.50-7.42 (m, 2H, Ar-H), 7.09 (m, 2H, Ar-H), -1.22 (s, 2H, H-pyrrolic inner core), -1.49 (br s, 2H, NH inner core). $^{19}$F NMR (470 MHz, CDCl$_3$) δ (ppm): -113.84 (s, 2F), -115.04 (s, 2F). MS (MALDI-TOF): m/z found 752.32 [M+H]$^+$, 752.24 calcd for C$_{48}$H$_{30}$F$_4$N$_5$.

## RESULTS AND DISCUSSION

### Optimization of pentapyrroles synthesis

To consider cyclization by electrosynthesis, the first step is to prepare pentapyrroles (PPy). We wanted to see if we could improve the synthesis of these macrocycles because they are often obtained with yields lower than 5%. [13] [14] Optimization was carried out starting from the reaction normally used for the synthesis of corroles (Scheme 1, Chart 1). Our intention was to improve the yield of PPy and the ratio between PPy and corrole. 3,5-Difluorobenzaldehyde was used as the starting material in the optimization of the preparation of PPy **1a**.

<figure><img src="image_3.png" /></figure>

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Chart 1.** Synthesized pentapyrroles and sappyrins.</figcaption></figure>

The first experiment was conducted under the same conditions as those already published. [14] MeOH/water in ratio 1:1 was used as a solvent mixture with the addition of conc. HCl. Starting materials were used in a ratio of 10 mmol of aldehyde and 20 mmol of pyrrole. After 3 h, p-chloranil was added. From this reaction, 93.1 mg of PPy **1a** was obtained (Table 1, Entry 1, 5.3% yield). This result is consistent with what is described in the literature (the ratio between PPy and corrole was approximately 30/70). [14] Other side-products were observed by MALDI-TOF mass spectrometry (hexapyrrole and other polypyrrolic polymers) but were not further isolated.

<table><caption>**Table 1.** Optimization of the synthesis of PPy **1a**</caption><thead><tr><td>Entry</td><td>Pyrrole/CHO</td><td>Temperature [°C]</td><td>[HCl] (mL)</td><td>PPy 1a [mg]</td><td>PPy/corrole</td><td>Reaction time (h)</td></tr></thead><tbody><tr><td>1</td><td>2/1</td><td>21</td><td>8.5</td><td>93.1 (5.3%)</td><td>30/70</td><td>3</td></tr><tr><td>2</td><td>2/1</td><td>100</td><td>8.5</td><td>120 (6.0%)</td><td>70/30</td><td>4.5</td></tr><tr><td>3</td><td>1.25/1</td><td>100</td><td>8.5</td><td>-</td><td>-</td><td>4.5</td></tr><tr><td>4</td><td>2/1</td><td>100</td><td>17</td><td>46.8 (2.3%)</td><td>52/48</td><td>4.5</td></tr><tr><td>5</td><td>2/1</td><td>100</td><td>4.25</td><td>51.2 (2.5%)</td><td>55/45</td><td>4.5</td></tr><tr><td>6</td><td>2/1</td><td>80</td><td>8.5</td><td>60.0 (2.9%)</td><td>58/42</td><td>4.5</td></tr></tbody></table>
In a first attempt to improve the reaction yield and optimize the PPy/corrole ratio, the temperature was changed and the reaction was heated to 100 °C (Heat-on block) (Entry 2). The conversion of the 3,5-difluorobenzaldehyde to PPy 1a was observed by ¹⁹F NMR, after 4.5 h of heating. The obtained yield was 6.0% (120 mg) for PPy 1a which is slightly better compared to the reaction without any heating. We also observed a better PPy/corrole ratio, which was 70/30. On the other hand, this methodology does not prevent the formation of other by-products (hexapyrroles, polypyrroles). We then changed the ratio between pyrrole and 3,5-difluorobenzaldehyde from 2/1 to 1.25/1 (pyrrole/aldehyde), which is the theoretical ratio between pyrrolic and aryl units in the desired PPy 1a (Entry 3). Other experimental conditions and work-ups remained the same. The formation of porphyrin instead of corrole or PPy was observed, so it was necessary to return to the initial 2/1 (pyrrole/aldehyde) ratio. Then, the effect of different amounts of conc. HCl was studied. In Entry 4 the amount of conc. HCl was increased to 17 mL. PPy 1a was obtained in 2.3% yield (46.8 mg) from this reaction and the ratio of PPy/corrole changed to 52/48. Throughout this reaction, the presence of porphyrin was again observed. The amount of HCl was decreased to 4.25 mL (Entry 5). PPy 1a was obtained in 2.5% yield (51.2 mg) from these modified conditions, which is very similar to the previous experiment. The ratio of PPy/corrole was also similar to the reaction of Entry 4. On the other hand, we did not observe any side-products other than the classical polypyrroles. The impact of the temperature was then studied. So far, the reaction heated to 100 °C gave the best yield and ratio of PPy 1a. In the next experiment, the temperature was decreased from 100 °C to 80 °C (Entry 6). The PPy 1a was obtained in a yield of 2.9% (60.0 mg) and the PPy/corrole ratio was increased to 58/42. The best conditions for the preparation of PPy 1a seemed to be those developed in Entry 2. Compared to the original protocol (Entry 1), these modifications consist of heating at 100 °C instead of r.t., for 4.5 h instead of 3 h. Generally, we observe precipitation at r.t. which mainly corresponds to the bilane, intermediate of corrole. We think that by heating to 100 °C, we increase the solubility of polymeric intermediates and hence the pentapyrrolic intermediates.

These optimized conditions (Table 1, Entry 2) were used for the preparation of PPy 1b-e. Under these optimized conditions, PPy 1b was prepared with a slightly lower yield (2.1%, 68.0 mg), compared to the previously reported yield of 3.0% [12] while PPy 1c was prepared with a two-fold higher yield (8.0%, 156.5 mg), compared to the previously reported yield of 3.8%. [13] On the other hand, in the case of compounds bearing electron-donating groups 1d and 1e, these conditions were not successful as the formation of porphyrin was systematically observed instead of the desired PPy. Thus, for the preparation of these electron-rich PPy, the original conditions remain the most efficient.

## Electrosynthesis of sappyrins from pentapyrroles

As mentioned above, one of the main goals of this work was to prepare sappyrin (Sapph) by electrosynthesis. Therefore, the electrosynthesis of Sapph 2a was studied starting from PPy 1a and experimental conditions were optimized. First of all, cyclic voltammograms of the starting material, PPy 1a, and the target molecule, Sapph 2a, were measured (Fig. 1). The redox behavior of these molecules depends on the solvent. For PPy 1a three oxidation systems ($E_{pa}$(O₁) = 0.60 V, $E_{pa}$(O₂) = 0.77 V, $E_{pa}$(O₃) = 0.94 V), that are not fully reversible and two reversible reductions ($E_{1/2}$ (R1) = -0.73 V ($ΔE_p$ = 80 mV) and $E_{1/2}$ (R2) = -0.97 V ($ΔE_p$ = 80 mV)) are observed in a mixture of toluene/ACN (11:8, v/v) (Fig. 1a). When the solvents were changed to pure chloroform, it was also necessary to change the supporting electrolyte to TBAPF₆, due to the low solubility of TEABF₄ in chloroform. In this case, only two oxidations ($E_{pa}$(O₁) = 0.70 V, $E_{pa}$(O₂) = 0.89 V) that are not fully reversible, and only one irreversible reduction ($E_{pc}$(R₁) = -1.08 V) are seen (Fig. 1b). The cyclic voltammogram of Sapph 2a was measured in toluene/ACN (11:8, v/v). In the positive potential range, one reversible and one pseudo-reversible oxidations are observed at ($E_{1/2}$ (O1) = 0.67 V ($ΔE_p$ = 80 mV) and $E_{pa}$(O₂) = 1.08 V, respectively). In the negative
potential range, four irreversible reductions are visible ($E_{pc}(R_1) = -0.89$ V, $E_{pc}(R_2) = -1.05$ V, $E_{pc}(R_3) = -1.29$ V, $E_{pc}(R_4) = -1.40$ V) (Fig. 1c). These initial measurements showed that PPy **1a** could be oxidized selectively, without over-oxidizing the possibly formed Sapph **2a**. In the following discussion, only the toluene/ACN (11:8, v/v) mixture ($0.1 \text{ mol L}^{-1} \text{ TEABF}_4$) will be considered.

<figure><img src="image_6.png" /><figcaption>**Figure 1.** Cyclic voltammograms of PPy **1a** and Sapph **2a**, $c = 10^{-3} \text{ mol L}^{-1}$, $v = 100 \text{ mV s}^{-1}$, WE: Pt, $\theta = 1.6$ mm, a) **1a** in toluene/ACN (11:8, v/v), $0.1 \text{ mol L}^{-1} \text{ TEABF}_4$, b) **1a** in chloroform, $0.1 \text{ mol L}^{-1} \text{ TBAPF}_6$, c) **2a** in toluene/ACN (11:8, v/v), $0.1 \text{ mol L}^{-1} \text{ TEABF}_4$.</figcaption></figure>

The first experiment was performed without any additive. The applied potential was $E_{app} = 0.61$ V and the theoretical charge required for the reaction corresponds to the abstraction of 4 F *per* mole of PPy. After abstraction of 0.9 F/mol of PPy, the peak corresponding to the first oxidation disappeared at the expense of a new one at $E_{pa} = 0.83$ V. MALDI-TOF mass spectrometry (MS) analysis of an aliquot of the resulting crude solution showed the formation of the corresponding protonated PPy **1a**. The reaction was continued with application of $E_{app} = 0.83$ V and abstraction of 3.1 F/mol of PPy. CV and MALDI-TOF MS analyses of the crude mixture were performed. Only PPy **1a** and side-product at *m/z* 839.19 were observed by mass spectrometry. This mass could correspond to structure **1aO** (Fig. 4), the product resulting from the nucleophilic attack of $H_2O$ on the oxidized PPy **1a**. In the next part, the reactivity of PPy **1a** in the presence of TFA was studied since this acid was used for the chemical preparation of the corresponding sapphyrin. Thus, it was suggested that protonation of PPy **1a** may favor the cyclisation reaction. The redox behavior of PPy **1a** with different amount of TFA was studied by CV (Fig. 2).
<figure><img src="image_7.png" /><figcaption>**Figure 2.** Cyclic voltammograms of PPy **1a** (a) and Sapph **2a** (b) with increasing amount of TFA, in toluene/ACN (11:8, v/v), c = 10⁻³ mol L⁻¹, 0.1 mol L⁻¹ TEABF₄, v = 100 mV s⁻¹, WE: Pt, ø = 1.6 mm (c) Cyclic voltammograms of PPy **1a** with increasing amounts of 2,6-lutidine in toluene/ACN (11:8, v/v), c = 10⁻³ mol L⁻¹, 0.1 mol L⁻¹ TEABF₄, v = 100 mV s⁻¹, WE: Pt, ø = 1.6 mm</figcaption></figure>

After addition of 1 eq. of TFA to the solution of **1a**, the initial first oxidation peak ($E_{pa}(O_1) = 0.60$ V) disappears and a new oxidation peak was observed at $E_{pa} = 0.71$ V.

When more TFA was added, this new oxidation peak was progressively shifted toward more positive potentials (Fig. 2a). The behavior of Sapph **2a** with different amounts of TFA was also measured. The main reason for this comparison between these 2 compounds was to know, if overoxidation of the desired product could occur. A similar redox behavior as for **1a** was also observed with **2a**, with a progressive shift of the first oxidation peak toward more positive potential as the amount of TFA is increasing (Fig. 2b). The oxidation potentials of the protonated compounds **1a** and **2a** are summarized in Table 2.

<table><caption>**Table 2.** Oxidation potentials of protonated PPy **1a** and Sapph **2a** in toluene/ACN (11:8, v/v), 0.1 mol L⁻¹ TEABF₄, v = 100 mV s⁻¹, WE: Pt, ø = 1.6 mm.</caption><thead><tr><th rowspan="2">TFA [eq.]</th><th colspan="1">Protonated PPy 1a</th><th colspan="2">Protonated Sapph 2a</th></tr><tr><th>E<sub>pa</sub>(O<sub>1</sub>) [V]</th><th>E<sub>pa</sub>(O<sub>1</sub>) [V]</th><th>E<sub>pa</sub>(O<sub>2</sub>) [V]</th></tr></thead><tbody><tr><td>5</td><td>0.75</td><td>1.15</td><td>-</td></tr><tr><td>10</td><td>0.81</td><td>1.18</td><td>1.39</td></tr><tr><td>50</td><td>0.89</td><td>1.21</td><td>1.40</td></tr><tr><td>100</td><td>0.92</td><td>1.22</td><td>1.38</td></tr></tbody></table>

Based on the previous measurements with TFA, several experiments were conducted (Table 3). In the first experiment, 5 eq. of TFA was used. After the abstraction of charges mentioned in Table 3, the reaction was stopped and worked-up. After purification, no desired Sapph **2a** was obtained according to MALDI-TOF MS measurements, compound **1aO** was present (Table 3, Entry 1). The next experiment was conducted with the addition of 10 eq. TFA (Entry 2). After the reaction and further purification, it was seen that sappyrin was not present. Again, the formation of compound **1aO** was observed, as well as, according to MALDI-TOF MS monitoring, dimer and trimer of PPy **1a**. Electrosynthesis was then performed with larger amounts of TFA (50 and 100 eq., Entry 3, 4). After the work-up of each reaction, the desired Sapph **2a** was not obtained and similar unwanted products as in the previous cases were observed.
<table><caption>**Table 3.** Electrosynthesis with addition of different amount of TFA in 10⁻³ mol·L⁻¹ PPy **1a**. in toluene/ACN (11:8, v/v), 0.1 mol·L⁻¹ TEABF₄.</caption><thead><tr><td>Entry</td><td>TFA [eq.]</td><td>E<sub>app</sub> [V]</td><td>Q [F/mol]</td><td>Product(s)</td></tr></thead><tbody><tr><td>1</td><td>5</td><td>0.80</td><td>2.7</td><td>1aO</td></tr><tr><td>2</td><td>10</td><td>0.95</td><td>4.0</td><td>1aO, dimer trimer</td></tr><tr><td>3</td><td>50</td><td>0.92</td><td>4.0</td><td>1aO, dimer trimer</td></tr><tr><td>4</td><td>100</td><td>0.96</td><td>3.5</td><td>1aO, dimer trimer</td></tr></tbody></table>

In the following experiments, 2,6-lutidine was tested as an additive since it could positively impact the yield. Indeed, this hindered base generally favors C-C coupling reactions since it can trap protons that are released subsequently during the C-C coupling step. [23] [24] After the addition of 1 eq. of 2,6-lutidine, only one oxidation peak was present (Fig. 2c) instead of three oxidation peaks observed without additives (Fig. 1). In the reduction part of the voltammogram no changes were observed. The addition of more equivalents of 2,6-lutidine did not show significant changes except that the potential of the oxidation peak shifted to less positive values, from E<sub>pa</sub>(O<sub>1</sub> for 1 eq.) = 0.55 V to E<sub>pa</sub>(O<sub>1</sub> for 10 eq.) = 0.50 V. Electrosynthesis was then performed with 10 eq. of 2,6-lutidine with E<sub>app</sub> = 0.55 V and abstraction of 3.0 F/mol of PPy **1a**. In these conditions, no Sapph **2a** was obtained. Compound **1aO** was observed as the main product, as in the experiments with the addition of TFA. Since Sapph **2a** was never observed during these electrosynthesis experiments, the experimental conditions were modified, bringing it closer to the chemical route ones (ca. 2 eq. of I<sub>2</sub> and 100 eq. of TFA). [12] Thus TBAI (tetra-*n*-butylammonium iodide) was selected since it can generate I<sub>2</sub> *in situ* by electrochemical oxidation according to the following mechanism:

$$3I^{-} - 2e^{-} \rightarrow I_{3}^{-} \qquad (O_{11})$$

$$I_{3}^{-} - e^{-} \rightarrow \frac{3}{2} I_{2} \qquad (O_{21})$$

$$\text{Globally: } 3I^{-} - 3e^{-} \rightarrow \frac{3}{2} I_{2} \qquad (O_{1})$$

The reaction (O<sub>11</sub>) corresponds to the oxidation of iodide to triiodide I<sub>3</sub><sup>-</sup>. Then I<sub>3</sub><sup>-</sup> is oxidized to iodine (O<sub>21</sub>). Thus, the global reaction (O<sub>1</sub>) involves one electron *per* iodide for the formation of iodine. Oxidation peaks corresponding to the above mentioned reactions (O<sub>11</sub>) and (O<sub>21</sub>) were indeed observed on the cyclic voltammograms, even in the presence of PPy **1a** and TFA (Fig. 3).
<figure><img src="image_8.png" /></figure>

<figure><img src="image_9.png" /><figcaption>**Figure 3.** Cyclic voltammograms of PPy **1a** with 100 eq. of TFA, c = 10⁻³ mol L⁻¹, v = 100 mV·s⁻¹, WE: Pt, ø = 1.6 mm, a) with 4 eq. TBAI in toluene/ACN (11:8, v/v), 0.1 mol L⁻¹ TEABF₄, b) with 1 eq. TBAI in chloroform, 0.1 mol·L⁻¹ TBAPF₆</figcaption></figure>

A first experiment was performed in the presence of 100 eq. of TFA and 4 eq. of TBAI, which corresponds to 2 eq. of I₂, amount that is commonly used for the organic synthesis of sappyrins. A mixture of toluene/ACN (11:8, v/v, 0.1 M TEABF₄) and an applied potential of Eₐpp = 0.76 V were used. This potential corresponds to the second oxidation peak, where I₂ was formed (peak (O₂I), Fig. 3a). Abstraction of 4 F/mol of PPy **1a** was used in these experiment (Table 4, Entry 1).

<table><caption>**Table 4.** Electrosynthesis in different solvents and with different additives (TFA and TBAI), 0.1 M TEABF₄ in toluene/ACN, 0.1 M TBAPF₆ in chloroform, *estimated from ¹H and ¹⁹F NMR spectra, **Initially, Eₐpp = 0.68 V and after generation of protonated PPy **1a** potential was increased to Eₐpp = 0.70 V.</caption><thead><tr><th>Entry</th><th>Solvent (v/v)</th><th>TFA [eq.]</th><th>TBAI</th><th>E<sub>app</sub> [V]</th><th>Q [F/mol]</th><th>Sapph 2a [%]</th></tr></thead><tbody><tr><td>1</td><td>Toluene/ACN (11:8)</td><td>100</td><td>4 eq.</td><td>0.76</td><td>4.0</td><td>25*</td></tr><tr><td>2</td><td>CHCl<sub>3</sub></td><td>100</td><td>4 eq.</td><td>0.70</td><td>3.7</td><td>44</td></tr><tr><td>3</td><td>CHCl<sub>3</sub></td><td>100</td><td>1 eq.</td><td>0.70</td><td>2.6</td><td>37</td></tr><tr><td>4</td><td>CHCl<sub>3</sub></td><td>100</td><td>10 mol%</td><td>0.70</td><td>3.6</td><td>71</td></tr><tr><td>5</td><td>CHCl<sub>3</sub></td><td>-</td><td>10 mol%</td><td>0.68**</td><td>3.2</td><td>-</td></tr><tr><td>6</td><td>CHCl<sub>3</sub></td><td>2</td><td>10 mol%</td><td>0.70</td><td>1.6</td><td>62</td></tr></tbody></table>

After purification of the product, PPy **1a** was obtained, but also Sapph **2a** (25% yield, estimated by ¹H NMR measurement, since it was not possible to separate it from the PPy **1a**. Compound **1aO** was again observed as a side-product. As some efficient chemical reactions have been performed in chloroform, [13] the solvent was changed to chloroform. As TEABF₄ is poorly soluble in this solvent, it was replaced by TBAPF₆. The rest of the conditions remained the same (Entry 2). After the purification of the reaction mixture, Sapph **2a** was obtained in 44% yield and no more PPy **1a** remained. There was not a large amount of side products contrary to what was observed in the previous experiments and only a little amount of compound with m/z = 857.20 was visible on the MALDI-TOF mass spectrum. This mass could
correspond to the structure **1aO<sub>2</sub>**, which could be formed by a double nucleophilic attack of H<sub>2</sub>O on the oxidized protonated PPy **1a** (Fig. 4).

<figure><img src="image_10.png" /><figcaption>**Figure 4.** Proposed side-products **1aO** (m/z 839.19) and **1aO<sub>2</sub>** (m/z 857.20).</figcaption></figure>

In the next experiments, different concentrations of TBAI were studied. TBAI molar amount was decreased from 4 eq. to 1 eq. With 1 eq. of TBAI (Entry 3) and an applied potential corresponding to the second oxidation peak (generation of I<sub>2</sub>) (Fig. 3), Sapph **2a** was isolated in 37% yield, after abstraction of 2.6 F/mol of PPy **1a**. Interestingly, no PPy **1a** and side-products, as compounds **1aO** or **1aO<sub>2</sub>**, were obtained under these conditions. With the goal to decrease organic waste as much as possible, the next experiment was conducted with a catalytic amount of TBAI (10 mol%, Entry 4), used in this case as a redox mediator. The desired Sapph **2a** was produced in 71% yield, without PPy **1a** or side-products. According to the previous experiment, where we were able to generate the protonated PPy **1a** by electrochemical oxidation (without TFA), the next experiment was conducted in the same conditions but without any addition of TFA (Entry 5). Due to the similar oxidation potential for the generation of I<sub>2</sub> and radical cation of PPy **1a**, the first applied potential was *E*<sub>app</sub> = 0.68 V. After generation of the protonated PPy **1a** (abstraction of 1.8 F/mol of PPy **1a**), the applied potential was increased to *E*<sub>app</sub> = 0.70 V. After abstraction of 3.2 F/mol of PPy **1a** and after purification, it was not possible to isolate pure Sapph **2a** since numerous side products were formed. In comparison with previous experiments, more side-products such as compounds **1aO** or **1aO<sub>2</sub>** were produced. As TFA seems to be an important additive for the success of the reaction, the last studied conditions involved a reduced amount of TFA (2 eq.) as well as 10 mol% of TBAI (Entry 6). After purification, Sapph **2a** was obtained in 62% yield, and no side-products were observed.

The electrochemical preparation of Sapph **2b** was then explored. Previously optimized conditions of Entry 6 were reproduced on PPy **1b**. After abstraction of 1.82 F/mol of PPy **1b**, the formation of Sapph **2b** was observed. The reaction was stopped after 32 h, which was the same duration as for the successful preparation of Sapph **2a**, but this time PPy **1b** was still present. It was not possible to separate PPy and Sapph, so a yield of 53% was estimated by <sup>19</sup>F NMR. Thus, the best conditions (Table 4, Entry 6) were applied on PPy with EDGs **1d** and PPy **1e**. In both experiments, consumption of pentapyrroles was observed. After measurement of the crude mixtures by <sup>1</sup>H NMR and MALDI-TOF mass spectrometry, no desired sappyrins were observed. This also corresponds to what we observed during our chemical cyclization tests. [14]

## CONCLUSION

Smooth and easy access to sappyrins macrocycles remains limited. In our attempt to achieve this goal, we report herein the optimized synthesis of pentapyrrole intermediates and their cyclization by electrochemical route. After several experiments under different conditions, we succeeded in increasing the yield for PPy **1a** by heating at 100 °C for 4.5 h.
These conditions also allowed a more significant increase in the yield of PPy 1c. In contrast, with PPy 1d and 1e possessing EDGs the formation of pentapyrroles was not observed and only the formation of porphyrin occurred. We then cyclized these pentapyrroles into sappyrins by electrochemical synthesis, for the first time. The optimization of the electrosynthesis was studied with Sapph 2a. The optimized conditions involve the addition of 10 mol% TBAI, 2 eq. of TFA, and CHCl3 as solvent. In comparison with organic synthesis, the amount of TFA was reduced from 100 to 2 eq., and the oxidizing agent, i.e. iodine, was continuously electrogenerated from a catalytic amount of TBAI (10 mol%), used as a redox mediator. These conditions were applied to the synthesis of Sapph 2b. In this experiment, the formation of the desired sappyrin was observed without any significant side products, but a longer reaction time to reach complete conversion was required. These optimized conditions were also applied to PPy 1d and 1e bearing electron-donating groups. Unfortunately, no desired electron-donating groups-substituted sappyrin was obtained by this methodology and only decomposition of the starting materials was observed. Based on these results, the electrochemical approach, which has proven successful, will be further investigated and the search for successful conditions will continue to be of great interest.

## Acknowledgements

This work was supported by the CNRS (UMR CNRS 6302) and by the Université Bourgogne Europe (UBE). The authors thank the "Plateforme d'Analyse Chimique et de Synthèse Moléculaire de l'Université de Bourgogne" (PACSMUB, http://www.wpcm.fr) for access to spectroscopy instrumentation. The authors also thank Dr Quentin Bonnin and Mrs Marie-José Penouilh (Université Bourgogne Europe, PACSMUB) for HRMS analysis. Mrs Sandrine Pacquelet is warmly acknowledged for synthetic contribution. The MAPYRO network (GDR CNRS n°2067, https://mapyro.chimie.unistra.fr) is acknowledged.

## ORCIDs

Claude. P. Gros: https://orcid.org/0000-0002-6966-947X

Charles H. Devillers: https://orcid.org/0000-0001-9078-7035

Nicolas Desbois: https://orcid.org/0000-0002-1156-4608

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