Corroles and Hexaphyrins: Synthesis and Application in Cancer Photodynamic Therapy

Abstract

Corroles and hexaphyrins are porphyrinoids with great potential for diverse applications. Like porphyrins, many of their applications are based on their unique capability to interact with light, i.e., based on their photophysical properties. Corroles have intense absorptions in the low-energy region of the uv-vis, while hexaphyrins have the capability to absorb light in the near-infrared (NIR) region, presenting photophysical features which are complementary to those of porphyrins. Despite the increasing interest in corroles and hexaphyrins in recent years, the full potential of both classes of compounds, regarding biological applications, has been hampered by their challenging synthesis. Herein, recent developments in the synthesis of corroles and hexaphyrins are reviewed, highlighting their potential application in photodynamic therapy.

1. Introduction

Corroles are tetrapyrrolic macrocycles containing 4 pyrrole units, 3 methine bridges and a direct pyrrole–pyrrole linkage (Figure 1). Therefore, corroles are contracted porphyrinoids with one methine (=CH–) bridge less than porphyrins, which leads to lower symmetry, higher fluorescence quantum yields, lower oxidation potentials and more intense absorption in the low-energy region of the visible spectrum. Despite being less studied than porphyrins over the years, probably due to their challenging synthesis, there was a significant change in this scenario after the synthetic breakthroughs by Gryko, Gross and Paolesse [1,2,3]. In fact, many efforts have been devoted to the synthesis of corroles in recent years [4,5,6,7]. Their free-bases and metal complexes have been explored in a wide range of applications [8,9], namely as promising drug candidates for prevention and treatment of diverse diseases, such as diabetes, neurodegenerative diseases and cancer [10,11,12,13,14], as antibacterial agents [15] as well as bio-imaging agents [16]. Corroles also found application in the photodynamic inactivation of microorganisms (PDI) [17], sonodynamic therapy [18] and photodynamic therapy (PDT) [19,20,21].

Expanded porphyrins [7,22,23,24] have gained remarkable attention due to their interesting and versatile features, such as diverse π-conjugation pathways owing to flexible structures [25], near- infrared (NIR) absorption/emission [26], facile interconversion between multiple redox states [27], and multi-metal coordination cavities for various divalent and trivalent metal ions (Figure 1) [22,28]. Beyond the study of these unique properties and their applications, the interest in expanded porphyrins has been focused on exploring the limits to which the classic Hückel definition of aromaticity may be applied. The goal has been to understand what factors endow a fully conjugated macrocycle with characteristics that can be considered aromatic or antiaromatic. Among the known expanded porphyrins that can combine from 5 to 12 pyrrole rings and diverse meso-bridges, hexaphyrins stand-out because these six-pyrrole macrocycles can adopt various conformations and electronic states such as Hückel aromatic, Hückel antiaromatic, Möbius aromatic, Möbius antiaromatic and stable radical states [29,30].

[26]Hexaphyrins(1.1.1.1.1.1) and [28]hexaphyrins(1.1.1.1.1.1), having six meso-bridges, are attractive molecules in view of aromaticity/antiaromaticity with a 26 and 28 π-electronic system, respectively, intense uv-vis absorption and a small HOMO-LUMO gap (Figure 1). [26]Hexaphyrins(1.1.1.1.1.1) can adopt a double-sided rectangular ring conformation with Hückel aromaticity while [28]hexaphyrins(1.1.1.1.1.1) adopt a single-sided twisted ring conformation with Möbius aromaticity. The unique uv-vis-NIR absorption/emission properties of these expanded π conjugated molecular systems offer useful optical nonlinear properties such as two-photon absorption (TPA) [31], which make them a promising class of two-photon absorption chromophores, with potential for a wide range of applications including microscopy, microfabrication, three-dimensional data-storage, optical power limiting, up-converted lasing, localized release of bio-active species, as well as application in photodynamic therapy [32].

2. Synthesis of New Corrole Derivatives

In recent decades, the synthesis of corroles and metallocorroles had attracted considerable attention from the scientific community and some reviews have been published [4,6,7,9,33,34]. Nevertheless, the relevance of corroles’ applications has driven the development of interesting approaches to construct macrocycles with new moieties, via classical and novel methodologies, collected herein.

2.1. Classical Synthetic Methodologies

One of the most explored routes to meso-substituted corroles relies on the synthesis of bilanes, obtained from the condensation of dipyrromethanes (DPs) with aldehydes, followed by oxidative macrocyclization. This strategy was applied to the synthesis of new corroles to be used in diverse applications.

Liu and coworkers described the synthesis of trans-A₂B corroles meso-substituted by phenothiazine (PTZ) and 2,3-di(2-pyridyl)quinoxaline (DPQ) groups. The HCl-catalyzed condensation of PTZ and DPQ formyl derivatives 2 and 4 with 5-pentafluorophenyldipyrromethane (1) followed by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-promoted macrocyclization gave the target corroles 3 and 5 in 31 and 34% yield, respectively (Scheme 1) [35]. Corroles 3 and 5 are novel donor-acceptor systems, in which the corrole scaffold is an acceptor and PTZ or DPQ moiety is an energy/electron donor. The absorption spectra of both dyads are a superposition of the absorption spectra of the monomers, indicating a weak electronic interaction between the corrole and either PTZ or DPQ groups, which was corroborated by the observed electrochemical properties. A detailed study of the excited state deactivation of both dyads shows that the singlet–singlet energy transfer from PTZ to the corrole unit is the main process in the case of dyad 3, while in the case of 5 a reductive electron transfer, from the ground state of DPQ to the excited state of the corrole, is the main process. Therefore, one dyad mimics the primary process and the other mimics the reaction center events in photosynthesis. The proton-triggered emission studies of dyad 5 and OFET studies indicate that they can be applied in the DNA photocleavage.

The synthesis of 10-(4-methyl-bipyridyl)-5,15-di(pentafluoropheny)corrole (7) was achieved through Gryko’s methodology, i.e., the condensation of dipyrromethane 1 with the bipyridyl-aldehyde 6 in a mixture of H₂O/MeOH using HCl as catalyst. Oxidation with DDQ afforded corrole 7 in 17% yield (Scheme 2) [36]. The uv-vis spectrum exhibits a strong Soret band at approximately 400 nm and the Q bands appear between 500 and 700 nm; a single emission band is observed in the fluorescence spectrum. The photophysical properties studied in dichloromethane (DCM) showed that corrole 7 fluorescence quantum yield is 0.04, the internal conversion quantum yield is 0.45 and the triplet quantum yield formation is about 0.54. The singlet oxygen quantum yield, a measure of the ability of the photosensitizer to generate cytotoxic singlet oxygen and an important parameter to evaluate the capability of the molecules to act as photosensitizers for PDT, was measured as 0.47, indicating a high efficiency in energy transfer from the corrole triplet state.

The trifluoroacetic acid (TFA)-catalyzed condensation of meso-pentafluorophenyl-dipyrromethane (1) with 8-hydroxyquilonine-2-carboxaldehyde (8) gave the low-symmetric A₂B-type corrole 9 in 16% yield. Free base corrole 9 was treated with an excess of GaCl₃ in refluxing pyridine to produce the Ga(III) corrole 10 in 40% yield (Scheme 3) [37]. According to the fluorescence studies, Ga(III) corrole 10 was a good “off-on-off” pH sensor in 1–14 pH range. The Ga(III) complex presents a fluorescence band with maximum at 603 nm, fluorescence quantum yield of 11.7% and a fluorescence lifetime of 2.42 ns in DCM solution. The intensity of fluorescence decreases gradually with the acidity of the solution and increases when the solution is more basic.

The condensation of 5-(4-nitrophenyl)dipyrromethane (11) with aromatic aldehydes, followed by oxidation with p-chloranil allowed the isolation of trans-A₂B corroles 12 in 29–38% yield (Scheme 4) [38]. The photophysical properties in toluene show characteristic absorption/emission spectra with Soret type bands between 420 and 450 nm, Q-type bands around 590–655 nm and the fluorescence bands in the range of 673–690 nm. The fluorinated corroles present fluorescence quantum yields higher than the carboxymethyl derivative, 0.76 for 12a, 0.80 for 12b and 0.77 for 12c. Corroles 12a–d showed an excellent affinity for the fluoride ions, allowing for an unusual selectivity for fluoride ions. The quenching of the fluorescence emission with the addition of fluorine ion indicates that these corroles can be used as fluorine ion sensors.

Liang and coworkers developed the synthesis of three low-symmetry A₂B type manganese(III) meso-triarylcorroles providing a push–pull electronic system (Scheme 5). The acid-catalyzed condensation of dipyrromethane 13 with the appropriate aldehyde followed by oxidation with p-chloranil gave corroles 14. The reaction of these macrocycles with manganese chloride in DMF afforded metallocorroles 15a–c in high yields (63–90%) [39]. The fluorescence studies reveal that Mn(III) corroles 15a–c strongly interact with the cell-free circulating tumor DNA in solution and the ability of this interaction increases with the electron-donating character of the 10-substituent of the triarylcorrole. This interaction with DNA can be used for tumor detection and targeting drug delivery in vivo.

Triaryl corroles with a meso-iodoaryl substituent were prepared and their photophysical properties were studied in order to evaluate their capabilities as photosensitizers for PDT. A₂B-type triaryl corroles 17 were synthesized through the TFA-catalyzed condensation of DP 1 with 2-hydroxybenzaldehyde and m-iodinated 2-hydroxybenzaldehydes, 16, followed by oxidation with DDQ (Scheme 6) [40]. The presence of iodine atoms did not significantly influence the absorption spectra and only a slight decrease in the absorption coefficient of the Soret band (ca. 420 nm) was observed with the increase in the number of iodine atoms. However, the fluorescence quantum yield and fluorescence lifetime are strongly influenced by the iodine atom. Corrole 17a, without iodine atoms, has a fluorescence quantum yield of 0.143 that decreases to 0.031 in the case of mono-iodo-corrole 17b and to 0.023 for the di-iodo-corrole 17c. The decrease in the fluorescence quantum yield is accompanied by the decrease in the fluorescence lifetime and a slight increase in the triplet quantum yields showcasing the heavy atom effect. Despite the increase in the efficiency of the triplet state formation, the singlet oxygen quantum yield (Φ_Δ) decreased, going from mono-iodo-corrole 17b (Φ_Δ = 0.9) to di-iodo-corrole 17c (Φ_Δ = 0.4).

During the synthesis of the bulky bis-pocket corrole 20a, Chang and coworkers identified another green compound as being the β-chlorinated corrole 20b, fully supported by characterization data, including X-ray crystallography analysis (Scheme 7) [41]. The β-chloro-corrole 20b was formed through the mono-chlorination of corrole 20a in which DDQ acted as both oxidant and chlorinating agent. The presence of a chlorine atom at the β-position of corrole 20b induced a slight red shift in the absorption and fluorescence emission spectra, together with a significant decrease in fluorescence intensity. Fluorescence lifetimes, as well as the fluorescence quantum yields, are shorter for β-chloro-corrole 20b (2.5 ns) than for corrole 20a (4.2 ns). However, the decrease in the fluorescence did not promote the increase in the capability to generate singlet oxygen, since non-chlorinated corrole 20a demonstrated a higher ability to generate singlet oxygen than the β-chlorinated corrole 20b.

The three component one-pot reaction of pyrrole, p-trifluoromethylbenzaldehyde and azulene (21), catalyzed by TFA, followed by oxidation with DDQ, allowed the isolation of novel meso-triarylazulicorrole 22 (Scheme 8) [42]. Despite the poor yield (<1%), carbacorrole 22 could be converted into the corresponding Cu(III) and Au(III) complexes. Single-crystal X-ray structures were obtained for the free-base and Cu(III) derivatives, uncovering detailed structural information on these novel macrocyles. The meso-triarylazulicorroles show absorption spectra with absorption features extending into the NIR region, opening the way to their application in bioimaging and photodynamic therapy.

2.2. New Synthetic Methodologies

The above-described syntheses of corroles were based on classical methodologies involving acid-catalyzed condensation of pyrroles or meso-substituted dipyrromethanes and aldehydes, followed by oxidation. Recently, Pinho e Melo et al. described an innovative synthesis of A₂B-type corroles, bearing an oxime functionality, by exploring the reactivity of dipyrromethanes toward nitrosoalkenes (Scheme 9) [43]. In situ dehydrohalogenation of the α,α-dihalo-oximes 23 generates transient α-chloro-nitrosoalkenes, which react with dipyrromethanes either via hetero-Diels−Alder reaction or conjugated addition to give the corresponding alkylated dipyrromethanes. The side chains of these DPs undergo another dehydrohalogenation to afford new nitrosoalkenes, allowing the synthesis of the target bilanes 24 (16–40%) upon reaction with a second molecule of the dipyrromethane. The oxidative macrocyclization with DDQ affords the corresponding corroles 25 in 40–84% yields. These are the first examples of meso-substituted corroles with an oxime functionality.

3. Functionalization at the Inner Core and Peripheral Positions of Corroles

In addition to the synthesis of new corrole derivatives, the functionalization of the basic core of corroles is another aspect that has been largely used for the modulation of their properties. This includes the introduction of different metals and ligands in the internal cavity of the corrole or the introduction of functionalities, side chains or heterocycles, on the corrole’s periphery.

Gross and coworkers explored the influence of the presence of trifluoromethyl groups in the structure of phosphorus corroles as photocatalysts [44]. The authors developed several strategies to functionalize the phosphorus(V) tri(pentafluorophenyl)corrole (26) in order to obtain a library of complexes with different numbers of CF₃ substitutions. Mixtures of monosubstituted corroles were obtained via direct electrophilic CF₃ incorporation using FSO₂CF₂CO₂Me and copper iodide. The mono-CF₃-substituted corrole 27 could also be obtained in 50% yield carrying out the trifluoromethylation with 5-(trifluoromethyl)dibenzothiophenium tetrafluoroborate and N-methylmorpholine (NMM) (Scheme 10). The reaction of corrole 27 with FSO₂CF₂CO₂Me/CuI afforded the bis-CF₃-substituted derivative 28 in 10% yield. On the other hand, the synthesis of corroles with more than two CF₃ groups required initial bromination leading to 2,3,8,17,18-pentabrominated derivatives, followed by treatment with the trifluoromethylating reagent (FSO₂CF₂CO₂Me/CuI). The DFT analysis, electrochemistry and photophysical measurements reveal that compounds with a higher number of β-CF₃ groups are the best photocatalysts for the bromination of phenol, toluene and benzene.

The same authors described the synthesis of tris- (30a) and tetra-CF₃ substituted (30b) gallium corrole complexes bearing four bromine atoms at beta-positions (Scheme 11) [45]. A red shift was observed in the uv-vis absorption and emission spectra going from the non-brominated corroles to the tetra-brominated derivatives. Moreover, an increased reduction potential was observed, resulting in an enhancement performance of corroles 30, especially corrole 30b, regarding the photocatalytic bromide-to-bromine conversion when compared with octabrominated gallium corroles.

Gross and Zhao also described the synthesis and photophysical properties of fluorinated phosphorus corrole complexes 32 and the corresponding β-iodo-substituted derivatives 34 [46]. The preparation of complexes 32 was achieved in quantitative yield by the axial hydroxyl ligand exchange of complexes 31 with fluorides, upon reaction with aqueous hydrofluoric acid (Scheme 12). The synthesis of corrole complexes 34 required the iodination of complexes 31 with N-iodosuccinimide (NIS) to give tetra-iodo corrole complexes 33, whose subsequent treatment with aqueous hydrofluoric acid afforded the target molecules in high yields (85–90%). The presence of the iodine atoms red-shifts the absorption by 16–19 nm, and the absorption of the Q band (589 nm) is more intense. Corrole complexes 32 exhibit emission bands between 525 and 700 nm, while the iodine complexes 34 have emission bands at ca. 796 nm indicating that these emit phosphorescence. The fluorescence quantum yields and lifetimes decrease drastically with the addition of iodine atoms. On the other hand, the singlet oxygen quantum yields of the iodine-containing complexes 34 (60–71%) were higher than those observed for the non-iodinated complexes 32 (46–49%). These experimental results are in agreement with DFT and TDDFT computational calculations [47,48] performed with non-substituted and iodine substituted phosphorus corrole complexes. The results demonstrated that iodine-substituted phosphorus corrole complexes, such as 34, are good candidates to act as photosensitizers in photodynamic therapy.

Catalytic water splitting via oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) are electrochemical processes that produce oxygen (O₂) and hydrogen (H₂), respectively, and constitute an interesting strategy for the conversion of renewable energy into chemical energy with applications in fuel cells and metal–air batteries. In this context, the bis-aminophenyl-substituted cobalt(III) corrole 36 was synthesized in order to evaluate its capability to act as an electrocatalyst for OER and HER (Scheme 13) [49]. Corrole 12a was synthesized in high yield (51%) via HCl-catalyzed condensation of dipyrromethene 11 with pentafluorobenzaldehyde and converted into bis-aminophenyl-corrole 35 through the SnCl₂/HCl reduction in the nitro groups. Reacting the free-base corrole 35 with Co(OAc)₂·4H₂O in refluxing pyridine, cobalt(III) corrole complex 36 was obtained in 81% yield. It was demonstrated that this aminophenyl-substituted cobalt(III) corrole acts as a bifunctional electrocatalyst for the oxygen and hydrogen evolution reactions. The strong electron-withdrawing pentafluorophenyl group present on the corrole ring was associated with the shift in the redox process towards the anodic direction and being responsible for the HER performance, whereas the increase in basicity due to the aminophenyl group was associated with the improvement in the OER activity.

The introduction of aryl and alkyl groups in the β-position of the meso-triarylcorrole complexes is a topic of interest, since it can lead to significant changes in their spectroscopic and electrochemical properties. Thus, Paolesse, Smith and coworkers applied the Stille reaction to introduce aryl and ethynyl groups at β-positions of silver corrole complex 37 [50]. Thus, the reaction of corrole 37 with tributylphenyl tin or tributylethynyl tin derivatives in presence of palladium tetrakis(triphenylphosphine) gave β-aryl silver corrole complex 38 in high yields, as well as 3,17-diethynyl-substituted and 3,17-di(arylethynyl)-substituted silver corrole complexes 39 (54–92%) (Scheme 14). The introduction of acetylenic moieties is particularly interesting since it opens the possibility to explore “click” reactions as a route to corrole-based materials/conjugates. β-Ethynyl/arylethynyl silver corrole complexes 39 exhibit red shifts (ca. 20 nm) of the B and Q bands in the absorption spectra when compared with the corresponding unsubstituted or halogenated silver corroles. DFT calculations can assign the clear impact, especially on the Q bands, of the conjugation of the β-ethynyl/arylethynyl units with the corrole π-system, made possible by the coplanar orientation of the acetylenic groups at the beta-positions with the corrole macrocycle. The shift in the B and Q bands towards lower energies was more pronounced for p-nitrophenylethynyl derivative 39a. This increase in the absorption within the therapeutic window (650–800 nm) points to the applicability of this compound in photodynamic therapy.

Truxene-corrole 41 and the truxene-bridged BODIPY-corrole dyad 42 were obtained from the reaction of corrole 40 with a truxene derivative or with the truxene-BODIPY derivative, as outlined in Scheme 15 [51]. Truxene-bridged BODIPY-corrole dyad 42 shows strong and broad absorption between 300 and 676 nm, i.e., the combination of the BODIPY and corrole chromophores allowed to improve the uv-vis absorption characteristics of the corrole core, with their use as photosensitizers in mind. The dyad showed fast singlet–singlet energy transfer from BODIPY to corrole, resulting in a triplet state with characteristics (energy and lifetime) that are more adequate to achieve an efficient energy transfer to oxygen, which results in a higher singlet oxygen photosensitizing ability (70% for 42) when compared with the corresponding corrole (58%). Moreover, when the dyad is used as triplet photosensitizer for triplet−triplet annihilation upconversion, with red excitation at 589 nm, the upconversion emission intensity is higher than the corrole itself and the upconversion quantum yield (2.57%) increases by ca. 2-fold. The combination of BODIPY and corrole results in a dyad with improved photophysical properties to be used as a photosensitizer for PDT.

Ghosh and coworkers described the synthesis of meso-pyrrole–appended isocorroles via oxidative coupling of corroles with pyrrole. The treatment of triarylcorroles 43 with an excess of pyrrole in the presence of DDQ gave 5-isocorroles 44 and 10-isocorroles 45 (Scheme 16) [52]. 5- Isocorroles 44 were isolated in higher yields (30–56%) than the isomeric 10-isocorroles 45 (2–5%). The pyrrole-appended isocorroles could be further complexed with Cu(II) in moderate yield by reacting with copper(II) acetate. Single-crystal X-ray structures were reported for two of these interesting macrocycles. The uv-vis spectra of free base isocorroles (44 and 45) and the corresponding Cu(II)-complexes (46 and 47) show absorption in the NIR region. The Cu(II) complexes exhibit more significant red-shifted spectra, relatively, to the free bases for both Soret and Q bands. The most significant shift was observed for the strong Q bands, which appear broad and double-humped at about 650–725 nm in the case of the free bases, whereas the Cu complexes also exhibit double-humped Q bands but sharper and red-shifted bands into the near-infrared (800–855 nm). These features make the free base isocorroles and their Cu complexes potential agents for biological applications, namely, as photodynamic agents.

Ghosh and coworkers also described the efficient synthesis, single-crystal X-ray structure analyses and photophysical properties of rhenium(V)-oxo triarylcorroles 48 (Scheme 17). Macrocycles 48 were isolated in high yields (61–84%) by oxidative metalation of meso-triarylcorroles 43 with dirhenium decacarbonyl in refluxing decalin (Scheme 17) [53]. The different metallo-triarylcorrole derivatives 48 exhibit very similar uv-vis spectra despite bearing different meso-aryl-substituents. Rhenium complexes 48 show moderate near-infrared phosphorescence (from λ_em = 770 to λ_em = 788 nm) with lifetimes between 56 and 74 μs and quantum yields ranging from 1.07 to 1.52%. The dyes were evaluated as potential optical oxygen sensors and as sensitizers in triplet–triplet-annihilation-based upconversion. It was demonstrated that ReO corroles are viable sensitizers for triplet–triplet-annihilation-based upconversion, covering the orange part of the electromagnetic spectrum (λ_abs = 590 nm and upconversion quantum yield = 0.16). These features and the excellent photostability of the rhenium(V)-oxo corroles 48 make them good candidates to be used as sensitizers in photodynamic therapy [54].

Cobalt(III) corroles 50, substituted at the 10-meso-phenyl position by an electron-withdrawing or electron-donating group, were prepared in high yields (62–70%) by metalation of the corresponding free base corroles 49 with cobalt acetate in the presence of triphenylphosphine (Scheme 18) [55]. These corroles act as electrocatalysts in hydrogen evolution reactions. Showing high stability under electrolysis conditions, complex 50a was more active than 50b and 50c. This suggests that the introduction of suitable peripheral substituents is a way to modulate the catalytic performance of Co(III) corroles.

Aiming to develop photocatalysts, the synthesis of antimony(III) corrole complexes 51 and (oxo)antimony(IV) corrole complexes 52 was described by the group of Kar [56]. The Sb(III) complexes 51 were obtained in good yields (85–86%) by the metalation of the corresponding free base corroles with antimony(III) chloride in pyridine. The oxidation with iodoxobenzene in dichloromethane gave the (oxo)antimony(IV) complexes 52 (Scheme 19). The uv-vis spectra of complexes 51 show split Soret bands at 440–462 nm, while complexes 52 exhibit a single Soret band at 408–413 nm, which indicates that complexes 51 are less symmetric than 52. Corrole complexes 51 and 52 show weak emission at 630–649 nm and a shoulder at 688–711 nm.

The A₃-type chromyl(V) triarylcorrole complexes 53 were prepared from the corresponding free base corroles in moderate yields by metalation with chromium oxide in refluxing toluene (Scheme 20) [57]. Even though having high similarity in electronic and structural properties, complexes 53 show some differences in redox potentials, which were associated with the inductive effect of the substituents at the 4 position of the aryl groups.

Axial ligand exchange is another way to modulate the properties of phosphorus corrole complexes. The treatment of corrole dihydroxophosphorus (V) complex 54 with the appropriate alcohol in presence of TFA, at room temperature during 10 min, afforded corrole complexes 55 in high yields (80–95%) (Scheme 21) [58]. This acid-catalyzed ligand exchange was followed by uv-vis and ³¹P-NMR spectroscopy analyses. The absorption and emission spectra of corrole complexes 54 and 55 were very similar. Fluorescence quantum yields for complexes 55 (28–30%) are slightly lower than the ones observed for complex 54 (32%). This decrease was accompanied with shorter fluorescence lifetimes. The study of six-coordinate phosphorus corroles included derivatives with axial ligands containing terminal halides, thiols and alkenyl groups, which are very interesting functionalities since they open the way for further functionalization in order to enhance photophysical properties and applicability.

A series of tetragonal phosphorus(V) cations (e.g., 57) have been prepared, characterized and their ability to act as Lewis acid catalysts in selected chemical transformations evaluated (Scheme 22) [59]. The cationic phosphoracorroles 57 were prepared in two steps, starting from the free base meso-triphenylcorrole. Treatment of corrole 43 with phenyl tetrachlorophosphorane or 3,5-bis(trifluoromethyl)phenyl tetrachlorophosphane in presence of trimethylamine, followed by addition of tetrabutylammonium triacetoxyborohydride, afforded the hexacoordinate corroles 56a and 56b, respectively. The second step was the treatment of corroles 56 with [Ph₃C][B(C₆F₅)₄] which led to tetragonal phosphorus(V) cations 57. These cationic phosphoracorroles demonstrated high tolerance toward hydroxylic functionalities and proved to be very efficient Lewis acid catalysts for carbonyl hydrosilylation, C_sp3–H bond functionalization and carbohydrate deoxygenation reactions.

The synthesis of iron(II) corrolate 59 has been described, as well as its reactivity towards molecular oxygen and organic electrophiles (Scheme 23) [60]. The reaction of corrole 58 with stoichiometric quantities of KC8 in tetrahydrofuran afforded the iron(II) corrolate 59, K(THF)2[Fe(TPC)]. This corrole complex of divalent iron could be isolated and crystallographically characterized. Corrole 59 reacts with carbon monoxide to generate the anion 60, with molecular oxygen, giving the Fe(III) corrole 61, and with methyl iodine, affording the Fe(IV)-methyl complex 62.

Liang and coworkers described the synthesis and the optical and redox properties of A₂B type Ir(III) triaryl corroles 64 containing meso-substituents with push–pull effect and A₃ type triphenyl corroles 65, differing in the axial pyridine ligands (Scheme 24) [61]. The metalation of the A₂B type corroles 63 leading to iridium(III) triaryl corroles 64 was carried out upon reaction with [Ir(cod)Cl]₂ in the presence of potassium carbonate in refluxing THF, followed by the addition of pyridine. The A₃ type Ir(III) triphenyl corroles 65 were prepared by a similar metalation procedure starting from the triphenyl corrole 43, using p-substituted pyridines in the last step. The Ir(III) corroles 64 and 65 demonstrated similar optical and redox properties, showing interesting electrocatalytic properties in oxygen reduction reactions. The nature of the meso-substituents of the A₂B type corroles and the nature of the axial pyridine ligands of the A₃ type Ir(III) triarylcorroles modulates their reactivity.

Photophysical studies of six-coordinated Ir(III) triarylcorroles showed that regardless of the aryl substituent (phenyl, p-methoxyphenyl, p-methylphenyl, p-fluorophenyl or p-trifluoromethylphenyl) and axial ligand (pyridine, trimethylamine, isoquinoline, p-dimethylaminopyridine or p-picolinic acid) these complex exhibit low phosphorescence at room temperature. Remarkably, Ir(III) complex of 5,10,15-tris(p-trifluorophenyl)corrole were found to be singlet oxygen sensitizers. The ability to produce singlet oxygen was found to be dependent on the axial coordination. The complex bearing p-dimethylaminopyridine as an axial ligand presents a singlet oxygen formation quantum yield of 0.38, while the complex with pyridine as an axial ligand shows a significant increase in singlet oxygen formation quantum yield to 0.71. Thus, iridium corroles show adequate characteristics to be used as PDT sensitizers [62].

Phosphorus (66-P), gallium (66-Ga) and tin (66-Sn) complexes were prepared in high yields (85–87%) by the reaction of tri(4-pyridyl)corrole 66 with POCl₃ or the appropriate metal source (Scheme 25) [63]. These corrole derivatives exhibit sharper and stronger Soret bands that the free base corrole 66, the major red-shift being observed for corroles 66-Sn and 66-Ga. High fluorescence quantum yields were found for complexes 66-P (0.41) and 66-Ga (0.31) while complex 66-Sn has a fluorescence quantum yield lower than that observed for free base corrole 66 (0.12). Complex 66-Sn has the lowest fluorescence lifetime (0.2 ns) and free base corrole 66 the highest (3.2 ns), whereas complexes 66-P and 66-Ga have similar fluorescence decays, 2.3 and 2.1 ns, respectively. Complex 66-Sn has the highest singlet oxygen quantum yield (0.71) which, together with its great photostability, makes it an interesting photosensitizer.

4. New Materials Containing Corroles

In recent years, new materials containing the corrole motif, such as nanoparticles, metal organic frameworks (MOFs), covalent organic framework (COF) and porous organic polymers (POPs), have attracted the interest of the scientific community.

Lu and coworkers described the synthesis of 10-(p-hydroxyphenyl)corrole copper complex 69 and its corresponding self-assembled nanostructure [64]. The free base corrole 68 was prepared in 22% yield by condensation of 5-phenyldipyrromethane (67) and p-hydroxybenzaldehyde in the presence of HCl, followed by oxidation with p-chloranil (Scheme 26). Metalation of the free base corrole 68 with copper(II) acetate gave the expected complex 69 in good yield (50%). The copper corrole 69 self-assembled into large-scale, needle-like nanostructures, with H-aggregate nature and relevant intermolecular π-π interactions. These nanostructures revealed high electric conductivity, acting as gas sensors with high selectivity for NO₂ gas.

Contrary to porphyrins, where aggregates have been deeply investigated, the aggregation of corroles has been less explored. Nevertheless, it has been demonstrated that in aqueous media and in biological conditions, hydrophobic corroles and metallocorroles form nanoparticles (NPs) due to aggregation processes. In fact, stable nanoparticles were prepared by rapid injection of DMSO or pyridine solutions of tris-pentafluorophenyl corrole complexes 70 (M = Ga, Al and Au) in aqueous media (Figure 2). The analysis of uv-vis, IR spectra and DFT calculations of these NPs showed only small changes in comparison to the corresponding monomer, which was attributed to very weak intermolecular interactions in these nanoparticles [65].

Gross and coworkers studied the correlation between the lipophilicity/hydrophilicity of corroles and their metal complexes and their capability to act as anticancer agents. The authors found high affinity of corroles with the very-low-density lipoprotein fraction (VLDL) of human serum and high photocytotoxicity [66]. It was observed that the cytotoxicities increased in the order Ga < Fe < Al < Mn < Sb < Au for the studied corroles [67]. They studied assemblies of NPs of corroles with native serum proteins, soluble in aqueous media, to act as controlled release drug delivery systems. The formulation of NPs using specific proteins enables the targeting cells in which the corresponding receptors are overexpressed, and therefore increases the selectivity of corroles for the targeted tissue. The cellular uptake in DU-145 prostate cancer cells, followed by optical imaging, reveals that transferrin/corrole 70 nanoparticles were internalized, with distribution into the endoplasmic reticulum and lysosomes, to a greater extent by the transferrin-receptor-rich DU-145 cells, than albumin/corrole 70 NPs. Moreover, the stability and enhanced uptake properties of transferrin/corrole 70 NPs indicate that these can be applied as imaging agents (Figure 2) [67].

Gallium corrole-coated zinc oxide (ZnO) nanoparticles were prepared by the addition of corrole 73 to an ethanol solution of zinc acetate (nanoparticle precursor). Knoevenagel reaction with cyanoacetic acid was used to introduce a monodentate anchoring group into acrolein-substituted gallium corrole complex 72, leading to the target corrole 73 in high yield (94%) (Scheme 27) [68]. The presence of the α-cyanocarboxylic group affects the photophysical properties of the corrole 73, namely, a red-shift was observed in the Soret and Q bands, the fluorescence emission was also redshifted (32 nm) and the fluorescence quantum yield decreased to 2.2%. The nanoparticles showed a diameter smaller than 100 nm and the presence of the corrole macrocycle in the hybrid material could be confirmed by fluorescence microscopy analysis. The proprieties of the hybrid nanostructured material incorporating gallium corrole dyes indicates a large range of potential applications, namely, their use in medical diagnostic or chemical sensors fields.

Tang and coworkers synthesized trans-A₂B meso-(4-chlorophenyl)-corrole 75 and the corresponding cobalt(III) complex 76 (Scheme 28) which was incorporated onto graphene oxide (GO) through π-π interactions. The gas sensing ability of corroles 75, 76 and the corrole-functionalized GO was evaluated. Cobalt(III) complex 76 exhibits better NO₂ gas sensitivity than the corresponding free-base corrole (75), due to the presence of the coordination metal. Likewise, the Co(III)corrole complex functionalized GO also demonstrated higher gas sensitivity [69].

A simple method for the regioselective thiocyanation of 5,10,15-triphenylcorrole (43) was developed by Kar’s group. The treatment of a solution of corrole 43 in carbon disulfide with an excess of ammonium thiocyanate (NH₄SCN) at reflux, gave the β-thiocyanate corrole 77 in 40% yield (Scheme 29) [70]. Gold nanoparticles coated with the β-thiocyanate corrole, Au-77, were prepared by the addition of sodium borohydride to a premixed mixture of corrole and tetrachloroauric acid (HAuCl₄). The formation of Au-77 was monitored by uv-vis spectroscopy, starting from a solution of corrole 77 in DMF, with no significant changes upon addition of NaBH₄ but both the Soret and Q bands of corrole underwent drastic changes in intensity upon the addition of the HAuCl₄ solution. The final absorption spectra of Au-77 show the presence of the characteristic Soret band from the corrole 77, a strong plasmon resonance band of gold nanoparticles (525 nm) and the presence of Q bands (655 nm), despite being significantly reduced. The intensity of emission bands is significantly reduced, going from corrole 77 to Au-77, the same trend observed for the fluorescence lifetime, from 3.69 to 1.19 ns, respectively. A plausible structure of gold-corrole nano-assemblies was proposed based on a face-off binding mode of corrole, which would be possible due to pyrrole–pyrrole linkage (lack of one meso-carbon). The Au-77 nanoparticle size is about 6.5 nm and they are stable under ambient conditions, which makes the corrole framework an excellent stabilizer for gold nanoparticles.

The synthesis of an organic–inorganic photocatalyst to promote the photodegration of the pollutant di-anionic azo-dye Acid Black 1 was described by Zhu and coworkers. This photocatalyst consists of corrole 78 linked to glycidoxypropyltrimethoxysilane (GPTMS)-modified TiO₂ nanoparticles (Scheme 30). The corrole-GPTMS/TiO₂ nanoparticles 79 demonstrated high photodegradation efficiency and reusability [71].

Metal–organic frameworks (MOFs) are porous crystalline materials composed of a three-dimensional (3D) network of metal, held in place by multidentate organic molecules. Zhang and coworkers developed robust corrole-based MOFs (e.g., 84) using 9-connected Zr₆ or Hf₆ and corrole as the organic linker (Scheme 31) [72]. The free base corrole 81 was prepared in 21% by the reaction of pyrrole with methyl p-formylbenzoate (80) in the presence of HCl, followed by oxidation with p-chloranil. The metalation with FeCl₂ and hydrolysis of the ester group afforded the corrole (e.g., 83) in good yield. Polycrystalline [corrole-MOF(Fe)Cl] 84 was isolated in 84% yield from the reaction of corrole 83 with ZrCl₄ in DMF at 120 °C in the presence of acetic acid. This procedure was also applied to synthesize other corrole-MOFs, namely, using HfCl₄ as metal source or the free base corrole as a linker. [Corrole-MOF(Fe)Cl] 84 was successfully used as a heterogeneous catalyst in hetero-Diels-Alder reactions of dienes with inactivated aldehydes.

Many of the porous solids, such as MOFs, are not stable enough for some applications, due to their being built through coordination bonds between the organic ligand and the metal donors. Thus, to overcome some instability, Porous Organic Polymers (POPs) emerged as a new class of porous materials, which are built by covalent bonding between organic building blocks [73]. The synthesis of POP-CorCo 88 and 90 can be made following two strategies, having di-iodophenyl corrole 86 as the starting point (Scheme 32) [74]. Corrole 86 was prepared in 26% yield by the acid-catalyzed condensation of meso-(p-iodophenyl)dipyrromethane (85) with benzaldehyde, followed by oxidation with p-chloranil. The first strategy (via 1) to prepare POP-CorCo 88 is the reaction between the free base di-iodophenyl corrole 86 and the tetrahedral-shaped 87 through the copper-free palladium-catalyzed Sonogashira cross-coupling, followed by cobalt complexation, leading the target POP in 78% overall yield. The second methodology (via 2) involves the preparation of cobalt corrole complex 89, protected by two amine ligands, followed by the coupling reaction to give the POP-CorCo 90 in 70% yield. The POP-CorCo 90 prepared by the two pathways exhibits similar high permanent porosity and the ability to selectively capture or sense carbon monoxide, even in the presence of other gases, such as CO₂, O₂ and N₂.

5. Corroles as PDT Agents in Cancer Treatment

The chemical, physical and photophysical properties of corroles make them valuable photosensitizers for PDT. Therefore, the development of photosensitizers based on the corrole macrocycle has attracted the attention of several research groups and some review articles on this topic have been published [9,19,20,75]. Herein, the compilation of the latest advances is presented.

Mack and coworkers described the synthesis and characterization of two Sn(IV) corroles with thien-2-yl (92) and phenyl (93) substituents at meso-positions and their photodynamic activity against breast cancer cells (MCF-7) [76]. The condensation of pyrrole with the appropriate aldehyde in presence of HCl followed by oxidation with p-chloranil gave corroles 91 and 43. Sn(IV) triarylcorroles 92 and 93 were obtained via metalation with SnCl₂ in refluxing DMF (Scheme 33). Sn(IV) tris-thyen-2-yl corrole 92 shows an absorption spectrum red shift compared with the phenyl analogue 93, which leads to a better absorption in the therapeutic window. Along with the absence of aggregation in solution, tin(IV) complexes 92 and 93 have high values of singlet oxygen quantum yields (0.87 and 0.54, respectively) and triplet state lifetimes of 31 and 50 μs, respectively. The cellular uptake of both corrole complexes in MCF-7 cancer cells reached a peak after 24 h of incubation, with the concentration of 92, two times higher than 93. The photocytotoxicity assays of Sn(IV) corroles 92 and 93 show values of IC₅₀ of 3.2 and 13.1 μM against MCF-7 cancer cells after irradiation and non-toxicity in the dark. The higher photocytotoxicity of corrole complex 92 was attributed to its high singlet oxygen quantum yield and lipophilicity.

Mono-hydroxyphenyl metallocorroles 95a–c have been prepared from the corresponding free base corroles 94a–c by complexation with iron(III), manganese(III) and copper(III) in high yields (Scheme 34) and their DNA-binding ability and photodynamic antitumor activity were evaluated [77]. The DNA binding studies indicate that metallocorroles 94a–c bind to CT-DNA by an external binding mode, with the ortho-hydroxyphenyl metallocorroles (95a) being the ones with less binding affinity. Cytotoxicity assays were performed using carcinoma A549 (lung), HepG2 (liver), MCF-7 (breast), DU145 (prostate) cell lines and one normal cell line, GES-1 (gastric epithelial). Under dark or light conditions, all the metallocorroles are non-toxic for the normal cells GES-1 and only Cu-95b was slightly cytotoxic against DU145 cells. On the other hand, manganese(III) and copper(III) corroles revealed weak cytotoxicity against A549, HepG2 and MCF-7 when compared with iron(III) corroles, in the absence or presence of light. In addition, Fe-95c shows a significant photocytotoxicity against A549 cells with IC₅₀ of 30 μM, being noncytotoxic in the dark. The studies demonstrated that Fe-95c induced the A549 cell apoptosis and necrosis, high cellular ROS level and disruption of the mitochondrial membrane potential.

Tri-hydroxy corrole 96 was prepared in high yield (79%) from corrole 94c by aromatic nucleophilic substitution using 2-aminoethanol as the nucleophile, followed by complexation with gallium(III) to produce the metallocorrole 97 in 85% yield (Scheme 35) [78]. Similarly to mono-hydroxy complexes 95, corroles 96 and 97 established outside binding with DNA. Corroles 96 and 97 showed moderate cytotoxicity in the dark, with corrole complex 97 being more cytotoxic than the free base 96, and both exhibited high photocytotoxicity against lung cancer cells A549, hepatoma cell HepG2 and breast cancer cell MCF-7 (IC₅₀ = 0.3 μM). The PDT treatment of HepG2 cells with 96 or 97 induces the potential destruction of the mitochondrial membrane and, consequently, tumor cell apoptosis.

Water-soluble sodium salts of sulfonated corrole 98 and its metal complexes of copper (99-Cu), iron (99-Fe) and manganese (99-Mn) were prepared and their photodynamic anti-cancer activity against human tumor cell lines, namely lung carcinoma (A549), hepatocellular cancer (HepG2) and cervical cancer (HeLa), was evaluated (Figure 3) [79]. Photocytotoxicity studies demonstrated that all the tested cell lines are sensitive to the presence of corrole 98, especially A549 cells (IC₅₀ = 5.0 μM), while no dark toxicity was observed with the studied corroles. Similar behavior was already found for corrole–cyclodextrin conjugates when compared with the corrole-free base 70 [80]. The studies to clarify the mechanism of PDT activity of corrole 98 evidenced a large production of reactive oxygen species (ROS), which could induce A549 cell apoptosis and activate the mitochondrial apoptosis, with the SIRT1 protein degradation being crucial for the process. The PDT activity of corrole 98 in vivo was also assessed and a significant decrease in tumor growth (A549 xenografted tumor), without obvious loss of mice body weight, was observed.

Re^VO 5,10,15-tris(meta-methoxycarbonylphenyl)corrole, Re^VO 5,10,15-tris(para-methoxycarbonylphenyl)corrole and their corresponding carboxylic acids were evaluated as sensitizers for PDT. This metallocorroles present a high singlet oxygen formation quantum yield (0.72) regardless of the ester or acid functionalities at the phenyl rings. The Re^VO carboxylic acids were found to exhibit high photocytotoxicity against rat bladder cancer cells (AY27) and human colon carcinoma cells (WiDr), achieving 50% cell death within 5–7 min of blue light exposure. Cell death rates for WiDr cell line in the absence of light are much lower (23% cell death after 24 h incubation with a 10 μM concentration of sensitizer) [81].

Recently, the synthesis of a two-dimensional corrole-based covalent organic framework (COF) was developed. The corrole-based COF-100 with desymmetrized structure was isolated in 86% yield from the [3 + 2] imine condensation reaction of the approximately T-shaped tris(p-aminophenyl)corrole (78) with the linear terephthaldehyde (Scheme 36) [82]. COF-100 demonstrated high chemical stability and permanent porosity, with a sphere-like morphology and a Brunauer–Emmett–Teller (BET) surface area of 745 m²/g. The uv-vis absorption spectrum shows an absorption intensity in the entire visible and NIR regions with a Soret band at 399 nm, which is redshifted by 7 nm relative to corrole 78. COF-100 exhibits a high capability to generate oxygen singlet (90% efficiency of 1,3-diphenylisobenzofuran (DPBF) degradation, whereas monomeric corrole showed sharply decreased activity for degrading DPBF with a low conversion of 56%), weaker fluorescence intensity and a shorter fluorescence lifetime of 0.082 ns compared with 78 (0.19 ns). Laser irradiation (0.18 W cm⁻²) of MCF-7 cells incubated with COF-100 (50 μg/mL), at 635 nm for 10 min, led to the death of 85% of the cancer cells. These results clearly demonstrated that COF-100 is a promising candidate to be used as a photosensitizer in photodynamic therapy.

In summary, the efforts to develop new corrole-based entities useful as a photosensitizer for photodynamic therapy have followed different strategies: (i) optimization of the photophysical parameters through halogenation at meso or beta positions of the corrole core, where the iodination at 3-position of the meso-phenyl ring and beta-pyrrolic positions stand out, leading to the increase in singlet oxygen quantum yield; (ii) modification of the inner core through complexation with metals, namely Fe, Sn, Ir and Re complexes, which proved to be more efficient singlet oxygen sensitizers than the free-base corroles, with the Ga complexes also being more photocytotoxic; (iii) solubility issues have been overcome through the introduction of polar groups (SO₃Na or COOH), by the formation of macrostructures such MOF or nanoparticles; (iv) the modification of uv-vis-NIR absorption characteristics was achieved by extending the π-conjugated system.

6. Hexaphyrins: Synthesis and Applications

Gossauer et al. described, in 1983, the first synthesis of hexaphyrins with six meso-bridges, β-substituted aromatic macrocycles with 26-electron conjugation, following a “3 + 3” approach, i.e., through the condensation of two tripyrromethanes [83]. Following this work, meso-substituted [28]hexaphyrins were synthetized using the classical methodologies for the synthesis of porphyrins, such as Lindsey and Rothemund synthetic approaches [84,85]. Although these methods are convenient and effective, when stabilized with electron-withdrawing groups at the meso-position, the simultaneous formation of every size of expanded porphyrins, at least up to dodecamer, inevitably causes serious separation difficulties. Therefore, more ring-size selective syntheses using dipyrromethanes and tripyrromethanes as the starting materials were developed [86,87].

More recently, Osuka and coworkers described the synthesis of hexaphyrins bearing two benzoyl groups at meso-positions and their complexes [88]. [28]Hexaphyrin 103 was synthesized as a stable compound in 12% overall yield by p-toluenesulfonic acid catalyzed cross-condensation of tripyrrane 101 with phenylglyoxal monohydrate (102), at 0 °C under N₂ atmosphere with protection from room light for 1.5 h, followed by oxidation with DDQ (Scheme 37). X-Ray diffraction analysis has revealed that 103 adopts a dumbbell-like conformation, held by effective intramolecular hydrogen bonding between the pyrrolic NH protons and benzoyl carbonyl groups. Oxidation of 103 with MnO₂ afforded [26]hexaphyrin 104, quantitatively. However, hexaphyrin 104 is easily reduced back to 103 under ambient conditions, indicating that [28]hexaphyrin is more stable than [26]hexaphyrin despite its distinct antiaromatic character. The complexation of 103 with Au(III) afforded two bis-Au(III) isomeric complexes 105a and 105b in 32% and 3%, respectively (Scheme 37). X-Ray crystal analysis showed that both complexes present rectangular conformations with hydrogen bonding between the benzoyl groups and the outer NH protons.

Complex 105b was quantitatively reduced to [26]hexaphyrin Au(II) complex 106 with NaBH₄ at room temperature, which could oxidize back to 105b without significant degradation by treatment with MnO₂. The benzoyl substituents and pyrrolic NH-protons of the bis-Au(III) complex of [28]hexaphyrin 106 were used as peripheral bidentate coordination sites to prepare the boron(II) complex 107. The complexation was achieved in 90% yield by heating a mixture of 106, BF₃-OEt₂ and DIPEA in dichloromethane at 40 °C for 24 h (Scheme 38) [88].

The absorption spectrum of the [28]hexaphyrin 103 in CH₂Cl₂ shows a Soret band at 516 nm and a Q band (without fine structure) between 700–900 nm. The absorption spectra of gold complexes 105a and 105b are similar, showing Soret-like bands around 670 nm and Q-like bands in the NIR region at ca. 822, 930 and 1195 nm, supporting their 26π aromaticity. The absorption spectrum of the reduced complex 106 shows broad absorption bands at 544, 603, and 738 nm and weak absorption in NIR region, reflecting its antiaromaticity. The absorption spectrum of 107 is red-shifted by ca. 100 nm and sharper than that of 106, probably due to structural rigidity and the presence of electron withdrawing BF₂-moieties.

5,20-Bis(ethoxycarbonyl)-[28]hexaphyrin 109 was synthesized using meso-pentafluorophenyl tripyrrane 101 and ethyl 2-oxoacetate (108) as starting materials and the previously described methodology to promote the cross-condensation, followed by oxidation with DDQ (Scheme 39) [89]. X-Ray crystallographic analysis revealed that 109 presents a dumbbell-like conformation held by effective intramolecular hydrogen bonding between the pyrrolic NH protons and carbonyl oxygen of ethoxycarbonyl group. The uv-vis spectrum of 109 displayed characteristic features of antiaromatic porphyrinoids with a broad Soret-like band at 514 nm, and relatively weak Q-like bands. [28]Hexaphyrin 109 can serve as a bis-NNNO ligand to form square planar bis-Ni(II) and bis-Cu(II) complexes. The reaction of 109 with 20 equiv. of nickel(II) acetylacetonate (Ni(acac)₂) in dry toluene at 100 °C for 48 h afforded a bis-Ni(II) complex 110 in 48% yield. X-Ray crystallographic analysis has confirmed that 110 has a square planar geometry formed through the coordination of the three nitrogen atoms inner and the carbonyl oxygen atom to the Ni(II) ion, and that this bis-complex kept the dumbbell-like conformation. The complexation with a large excess of CuCl₂ in the presence of NaOAc in CH₂Cl_2, at room temperature, for 24 h, yields the bis-Cu(II) complex 111 in 79% yield, which also takes on a dumbbell-like conformation and square planar geometry. The absorption spectrum of 110 in CH₂Cl₂ showed a broad Soret-like band at 508 and 621 nm, Q-like band at 830 nm and a weak absorption tail up to 1700 nm. The complexation with copper modified the absorption spectrum of 111, narrowing the Soret-like band at 520 and 635 nm, blue-shifting the Q-like bands to 814 nm and also the very weak absorption tail up to ca. 1500 nm. Oxidation of 5,20-bis(ethoxycarbonyl)-[28]hexaphyrin 109 with a large excess of PbO₂ in CH₂Cl₂ at room temperature for 3 min afforded [26]hexaphyrin 112 in 73% yield. This hexaphyrin was easily reduced back to 109 with NaBH₄ in a mixture of CH₂Cl₂/MeOH at room temperature for 10 min (Scheme 39). Interestingly, the hexaphyrin 112 was the sole product, in contrast with the formation of two isomeric [26]hexaphyrins in the oxidation of 5,20-dibenzoyl-[28]hexaphyrin with MnO₂ [88]. The uv-vis-NIR absorption spectrum of 112 showed a sharp Soret-like band at 562 nm and Q-like bands at 712, 770, 892, and 1022 nm, characteristic features of aromatic porphyrinoids.

Following studies on the complexation of aromatic electron-deficient meso-pentafluorophenyl [26]hexaphyrin and electron rich meso-pentafluorophenyl [28]hexaphyrin with Möbius aromaticity, Osuka and coworkers reported the synthesis of π-ruthenium complexes [90]. The treatment of mono- and bis-gold(III) complexes of [28]hexaphyrin 113a and 113b with five equivalents of [RuCl₂(p-cymene)] in the presence of NaOAc in a mixture of toluene/DMF at 100 °C for 65 h afforded π-ruthenium complexes 114a and 114b in 45% and 56% yield, respectively (Scheme 40). When the meso-pentafluorophenyl [26]hexaphyrin was submitted to the same reaction conditions, only decomposition products were obtained, suggesting that the formation of ruthenium π-complexes might need an electron-rich hexaphyrin. The absorption spectrum of 114b shows two intense bands at 490 and 656 nm and two less intense and more broad bands at 1066 and 1250 nm. The treatment with TFA yielded the trifluoroacetate 115, with the absorption spectrum of this salt presenting the same bands, and blue shifted to 455, 609, 1066 and 1097 nm.

Ru-metalation of [26]hexaphyrin bis-Pd(II) complex 116, a unique complex with a characteristic conjugated aromatic circuit and relatively acidic outer pyrrolic NH protons [27,91], was achieved through a reaction with [RuCl₂(p-cymene)] in the presence of NaOAc in a mixture of toluene/DMF (4:1) at 100 °C for 12 h [90]. The [26]hexaphyrin bis-Pd(II)-bis-Ru(II) complex 117, a triple-decker complex with both the [(p-cymene)Ru(II)] moieties located above and below the center of the hexaphyrin framework, was obtained in 57% yield (Scheme 41). The absorption spectrum of 117 in CH₂Cl₂ shows two Soret-like bands at 461 and 650 nm and a Q-like band at 829 nm.

Hexaallyloxy-appended hexaphyrin 119 prepared through nucleophilic aromatic substitution reaction of 5,10,15,20,25,30-hexakis(pentafluorophenyl)-[26]hexaphyrin (118) with allyl alcohol, [92] was subjected to olefin metathesis reaction using the improved Hoveyda–Grubbs catalyst. When the reaction was conducted at room temperature, only peripherally strapped [26]hexaphyrin monomer 120 was obtained in a 37% yield. Decreasing the amount of catalyst and increasing the reaction temperature to 40 °C led to the formation of 120 as a minor product (9% yield) and cyclophane-type [26]hexaphyrin dimer 121 in 21% yield (Scheme 42). The treatment of dimer 121 with NaBH₄ at room temperature for 10 min afforded [28]hexaphyrin dimer 122 in 30% yield, which could be transformed back into 121 by oxidation with MnO₂ (Scheme 42) [93]. The uv-vis-NIR absorption spectrum of aromatic [26]hexaphyrin 120 shows a typical sharp Soret-like band at 569 nm and Q-like bands at 718, 908, and 1031 nm. Dimer 121 shows split Soret-like bands at 543 and 577 nm, attributed to the exciton coupling of the two hexaphyrin cores in a stacked geometry, [94] and Q-like bands 724, 899, and 1031 nm. The absorption spectrum of 122 exhibits characteristics of anti-aromatic [28]hexaphyrins, smaller absorption bands at 490, 526, and 571 nm and a weak absorption at the near-infrared region.

Following the pioneer work of Osuka and coworkers on regioselective nucleophilic substitution reactions of meso-hexakis(pentafluorophenyl)-substituted [26]hexaphyrin with an alkoxides and isopropyl amine [95], Wiehe and coworkers achieved the synthesis of hexa-glycosylated [28]hexaphyrin 124 in high yield (Scheme 43) [96]. [28]Hexaphyrin 123, obtained in 96% yield through a reduction in [26]hexaphyrin 118 with NaBH₄ in methanol at room temperature for 20 min, was transformed into the hexa-glycosilated derivative in 78% yield by nucleophilic substitution of the para fluorine substituent of all six pentafluorophenyl units, using 1-thio-β-D-glucose sodium salt as nucleophile, in dry DMF overnight at room temperature. Attempts to promote the glycosylation of [26]hexaphyrin 118 delivered a complex mixture with traces of the expected product and evidence for the formation of the corresponding reduced form, [28]hexaphyrin 123.

To create well-defined NIR-II dyes, chemical modification of the hexapyrrolic core is an alternative viable approach. Recently, Sessler and coworkers reported the synthesis of a new hexaphyrin, pyrihexaphyrin (0.1.0.0.1.0) 125, (Figure 4) that, upon uranyl dication complexation, undergoes ring contraction, affording 22 π-electron aromatic contracted pyrihexaphyrin (0.0.0.0.1.0)-uranyl complex, 126, which displays Hückel type aromatic features. In fact, uv-vis spectroscopic analysis revealed marked differences in comparison to the precursor. A relatively weak Soret-like band was observed at 549 nm along with Q-type bands at 734 and 1003 nm [97]. A robust bis-rhodium(I) complex of π-extended planar, anti-aromatic meso-pentafluorophenyl-β,β-phenylene-bridged hexaphyrin [1.0.1.0.1.0], rosarin 127, was synthesized in 60% yield from the corresponding free-base (Figure 4). Both the ligand and the bis-Rh(I) complex show uv-vis spectra in CH₂Cl₂ with broad bands between 400–700 nm [98].

The synthesis of doubly N-confused dioxohexaphyrins 128a,b as well as their Zn and Cu complexes, was also reported (Figure 4). These are interesting small molecule-based photoacoustic agents that respond to NIR-II light excitation and constitute a promising platform for deep-tissue NIR-II photoacoustic imaging applications [99].

Hexaphyrin (2.1.2.1.2.1), also known as rubyrins, 129a and b and their rhodium, zinc and copper metal complexes, were obtained to explore the control of aromaticity and cis-/trans-isomeric structure of non-planar hexaphyrins (Figure 4). While the free-base and Zn complex exhibit uv-vis spectra similar to the ones observed for porphyrins, the copper complex has a significant red-shifted bands with Q-like bands at 859 and 947 nm. The rhodium complex displayed a sharp, intense Soret-like band, and a weak Q-like band in the NIR region [100,101].

The incorporation of chalcogenic elements into five-membered rings (i.e., furan and thiophene) significantly affects the dipole vector and charge displacement. This causes a reversal in the direction of the dipole moment between the furan/thiophene and pyrrole [102]. The change in the polarization results in electronic perturbations of the π conjugation. In this regard, chalcogen-substituted hexaphyrins have been synthesized [103,104,105,106,107,108], some of them having been explored as NIR photodynamic therapy agents [109], and others such as dithiabronzaphyrin 130 [108] show intense absorption and fluorescence in the NIR region, opening the way for their use in biological applications.

7. Conclusions

The efforts of several research groups to develop the synthesis of corroles and hexaphyrins followed three main strategies: (a) improvement in classical methodologies for the synthesis of the macrocycle; (b) development of methodologies for the functionalization of the peripheral positions and (c) improvement in complexation methods to modify the inner core. In addition to the above, a few novel methodologies have been developed and all, together, opened the way to corroles and hexaphyrins with new substitution patterns. The resulting modulation of the photophysical properties lays the foundation for the development of further applications.