CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

Introduction

Porphyrins are an aromatic, immensely conjugated, and colorful macrocyclic array with remarkable optical, electrochemical, and biological features. It is one of the most fascinating heterocyclic molecules which have various applications in catalysis, materials sciences, photochemistry and medicinal chemistry. Owing to the strong absorption in the visible region, these 18π-electron systems also demonstrate excellent photoluminescence properties. Therefore, porphyrin hybrids have been widely used as efficient sensitizers for PDT applications and dye-sensitized solar cells (DSSCs). Because the majority of porphyrin hybrids are synthesized by modifying β- and meso-positions of porphyrin, thus numerous chromophoric groups and biologically important scaffolds have been attached to porphyrins at these positions in recent years.

In the past, many synthetic procedures have been utilized to covalently connect a porphyrin with a chromophoric group. Among these, the copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction [1,2] of azides with terminal alkynes is a popular and well established process to link a porphyrin with other moieties via 1,2,3-triazole group [3] (Figure 1).

The term “click chemistry” was introduced for the first time by K. B. Sharpless in 1999 at the 217th ACS annual meeting [4]. Most recently, K. B. Sharpless shared the 2022 Nobel Prize in Chemistry with C. R. Bertozzi and M. Meldal for the development of click chemistry and bioorthogonal chemistry. Due to high product yields, quick reaction times, and excellent regioselectivity, the "click" cycloaddition reaction has enabled the synthesis of several compounds with a wide range of applications in a variety of sectors, including bioconjugation [5,6] drug development [7,8], glycoscience [9,10], porphyrin chemistry [11], nanoscience [12], and materials research [13,14].

Moreover, this review describes the use of the click methodology for the construction of various β- and meso-substituted 1,2,3-triazoloporphyrins by using azide or alkyne-substituted porphyrin as substrate (Figure 2). Every example mentioned in this review includes a brief synthetic procedure with reaction conditions, product yields, and photophysical and other properties of the end products.

Review

Overview of CuAAC click reactions on porphyrins

The CuAAC-inspired click reaction is particularly useful for the coupling of two different moieties comprising azide and alkyne groups in high yield and regioselectivity without using harsh reaction conditions. In recent years, this click protocol has been successfully employed in porphyrin chemistry to synthesize various triazoloporphyrins by attaching an azide or alkyne moiety to the periphery of the porphyrin. Since all of the triazole-linked porphyrins discussed in this review were prepared for different applications, most of the discussion focuses on the clicked synthetic parts under different reaction conditions that include different Cu catalysts, solvent systems, ligands, and temperatures. Most of the porphyrins used in the Cu(I)-catalyzed click reaction have been metalated prior to the reaction; otherwise, Cu metal can be inserted into the porphyrin cavity. As a result, the catalytic activity of Cu will decrease, it will be more difficult to remove, and more additional steps will be required to synthesize other corresponding metal derivatives. To this end, the review is divided into two major sections, the first of which describes the synthesis of β-triazole-bridged porphyrin conjugates and the second of which discusses the preparation of meso-triazole-linked porphyrin conjugates. Because the literature on meso-substituted triazole-bridging porphyrin synthesis is more than that of β-substituted triazoloporphyrin, therefore, the second section is further divided into five subsections to discuss the synthesis of meso-substituted mono-, di-, tri-, tetra-, and octatriazole-linked porphyrin conjugates.

Synthesis of β-triazole-bridged porphyrin conjugates

In recent years, many β-triazole-linked porphyrin conjugates have been synthesized using the “click chemistry” protocol. For the synthesis of these compounds, an azide moiety was introduced at the β-position of various porphyrins. In 2007, Shen et al. [15] exploited the concept of “click chemistry” for the construction of β-substituted-triazoloporphyrins 3a–c in 65–95% yield by the reaction of β-azidotetraphenylporphyrins 1 with various arylalkynes 2a–c via copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction in DMF at 50 °C in the presence of CuSO₄·5H₂O and ascorbic acid as shown in Scheme 1. It was noted that an alkyne with an electron-withdrawing group 2c was found to be more reactive than an electron-donating group 2b in the formation of triazoloporphyrins.

Similar to porphyrins, coumarin and its derivatives also possess diverse biological as well as optical properties. Moreover, the versatility of coumarin hybrids finds numerous applications including fluorescent brightening agents [16], optical sensors [17], organic light emitting diodes [18,19], light harvesting materials [20] and fluorescent probes in biological imaging [21]. Therefore, keeping the biological and optical properties of coumarin and porphyrin in mind, in 2015 we reported the synthesis and photophysical studies of β-triazole-bridged porphyrin-coumarin conjugates 11–15 [22] and β-triazolomethyl-linked porphyrin-coumarin dyads 16–20 [23] by using a click reaction approach. First, copper and zinc derivatives of the porphyrin-coumarin conjugates 11a–20a were synthesized in excellent yields by the click reaction between copper(II)-2-azido-5,10,15,20-tetraphenylporphyrin (4) or zinc(II)-2-azidomethyl-5,10,15,20-tetraphenylporphyrin (5) and various alkyne-substituted coumarins 6–10 in the presence of CuSO₄·5H₂O and ascorbic acid in DMF at 80 °C (Scheme 2). Further, the corresponding free-base porphyrins 11b–20b were obtained in good yields after demetallation of copper and zinc porphyrins under acidic conditions. Also, their zinc analogues 11c–15c were obtained by the treatment of free-base porphyrins with zinc acetate. The photophysical studies of these synthesized conjugates revealed that some of them show substantial intramolecular energy transfer between porphyrin and coumarin moieties.

Similar to coumarins, synthetic and naturally occurring xanthones also possess many biological [24] as well as fluorescent properties [25]. Therefore, considering these properties of xanthone, we used a click chemistry protocol to prepare β-triazole-linked porphyrin-xanthone conjugates 23–27 and xanthone-bridged β-triazolobisporphyrin conjugates 28, 29 [26] (Scheme 3). Initially, the click reaction was performed between copper azidoporphyrin 4 or zinc porphyrin 5 with various alkyne-substituted xanthones 21a–c and 22 for the construction of porphyrins 23a–29a. Furthermore, these metalated porphyrins underwent demetallation under acidic conditions to give the corresponding free-base porphyrins 23b–29b in good yields. In addition, their zinc analogues 23c–25c were also obtained in excellent yields by the reaction of free-base porphyrins with zinc acetate. The preliminary photophysical studies of the porphyrin-xanthone dyads show a bathochromic shift in the absorption and fluorescence spectra.

Synthesis of meso-triazole-bridged porphyrin conjugates

In recent years, many chromophoric moieties have been introduced at the meso-position of porphyrins by implying diverse synthetic procedures. Among these, the CuAAC click-mediated reactions are proving to be a popular choice for the construction of meso-substituted triazoloporphyrins. For this purpose, an azide or alkyne group was incorporated either on the meso-phenyl ring or on an alkyl chain of various porphyrin derivatives. This section covers the synthesis of porphyrin conjugates containing one, two, three, four, and eight 1,2,3-triazole units.

Mono-triazole-bridged porphyrin systems

This section will describe the synthesis of meso-triazole-linked porphyrins containing one triazole ring by using meso-substituted azide or alkyne bearing porphyrins. In 2007, Séverac et al. [27] reported the preparation of meso-phenyl-linked triazoloporphyrins 32a–c and triazole-bridged bisporphyrins 34 in good yields. The “click reaction” of azidoporphyrin 30 with the terminal alkynes 31a–c and 33 in a THF/water (3:1) mixture was investigated by using different catalytic systems. Among these, copper carbene (SIMes)CuBr proved to be a better catalyst than other copper catalysts, as it provided higher yields of the desired products (Scheme 4).

In 2010, Shetti and Ravikanth [28] nicely utilized the "click reaction" approach for the preparation of a series of triazole-bridged porphyrin-ferrocene dyads 37a–d in 48–52% yield by the reaction between two clickable subunits, azido-porphyrins 35a–d and alkyne-functionalized ferrocene 36 in the presence of CuI and DIPEA in THF/CH₃CN (Scheme 5).

Interestingly, among the various copper(I)-catalyzed click reaction conditions, the best yields were obtained when CuI/DIPEA (0.1:1) was used in a THF/CH₃CN mixture. In a photophysical investigation, a weak interaction was observed between two subunits at ground state in porphyrin-ferrocene dyads. Also, the fluorescence of porphyrin was significantly quenched in porphyrin-ferrocene conjugates due to photoinduced electron transfer from ferrocene to porphyrin subunits.

Bryden and Boyle [29] presented a mild and facile one-pot synthesis of meso-substituted zinc(II) azido-porphyrin 39a–c in excellent yield by using a diazo-transfer reagent and utilized it for the preparation of 1,2,3-triazole-linked porphyrin conjugates 40a,b using copper(I)-catalyzed click reactions (Scheme 6). The authors selected the hydrogen sulfate salt of imidazole-1-sulfonyl-azide for the formation of azide porphyrins 39a–c due to its greater shock stability and storage than its HCl salt. After the successful preparation of the zinc triazoloporphyrins 40a,b, their corresponding free-base analogues 41a,b were also obtained by the treatment with HCl in dioxane.

The conjugation of carbohydrate with porphyrin improves the solubility of porphyrin in aqueous medium and also improves the optical and medicinal properties of porphyrins [30]. Considering these properties of glycoporphyrins, Locos et al. [31] successfully used the Cu(I)-catalyzed click reaction to synthesize triazole-linked glycoporphyrins under microwave conditions. At first, the glycoporphyrins 43a,b were synthesized in good yields by the reaction between zinc(II) 5-(4-azidophenyl)-10,15,20-triphenylporphyrin (39a) and protected α-propargylglucose 42a or mannose 42b in the presence of CuCl in a toluene/H₂O (4:1) (Scheme 7). Further a fully deprotected mannosyl residue 42c was also introduced via "click reaction”, yielding the glycoporphyrin 43c. Moreover, this methodology can also be utilized to introduce various carbohydrate sequences suitable for tumor-binding-associated lectins on the porphyrin periphery.

Continuing our work on the functionalization of porphyrin at the meso-position [32,33], we used the CuAAC click protocol to synthesize meso-phenyltriazole-linked porphyrin-coumarin dyads 44–48 in good to excellent yields. Firstly, Zn(II) meso-phenyltriazole-linked porphyrin-coumarin conjugates 44a–48a were synthesized by using the “click reaction” between zinc(II) 5-(4-azidophenyl)-10,15,20-triphenylporphyrin (39a) and diverse alkyne-substituted coumarins 6–10 in DMF containing CuSO₄·5H₂O and ascorbic acid at 80 °C [34] (Scheme 8). Further, nickel derivatives 44b–48b were also obtained from their zinc analogues by demetallation with concentrated HCl and metalation with nickel acetate. The preliminary photophysical results revealed a significant intramolecular energy transfer between the porphyrin core and the coumarin moiety in the case of zinc porphyrin analogues.

In 2017, Yamana et at. [35] reported the synthesis of porphyrin-DNA conjugate 50 by a solid-phase “click reaction” between azidoporphyrin 39a and oligodeoxynucleotides 49 bearing an ethynyl group in the presence of CuSO₄·5H₂O and sodium ascorbate in DMSO (Scheme 9).

According to UV–vis and circular dichroism (CD) spectrum measurements, the authors state that the formation of the dimer of porphyrin 50 can be attributed to DNA hybridization and through-space electronic interactions. In this investigation, it was found that the DNA serves as a useful skeleton to regulate the relative location of the porphyrin molecules in order to produce the improved photocurrent response from the DNA modified electrodes.

In 2018, Coutsolelos et al. [36] established a “click chemistry” protocol to prepare meso-triazole-fused porphyrin conjugates 53 and 55 as sensitizers for dye-sensitized solar cells (DSSCs). These porphyrin conjugates were synthesized through the click reaction between azidoporphyrin 51 and alkynes 52 or 54. Further, porphyrin 57 bearing a CN and a COOH group was prepared by the treatment of porphyrin 55 with 2-cyanoacetic acid (56) in piperidine as shown in Scheme 10.

To prepare these conjugates, a porphyrin with a pentafluorophenyl ring (because of its strong electron-withdrawing ability) was chosen and used in the synthesis of azidoporphyrin 51 by replacing the para-fluoro atom with an azide group. Interestingly, the photovoltaic device performance of porphyrins 53 and 57 was increased by eight-fold and four-fold, respectively, as compared to reference compounds without a triazole ring.

Likewise, Nikolaou et al. [37] used zinc porphyrin 58 and copper-corrole 59 to synthesize first porphyrin-corrole dyad 60 through click protocol in a 42% yield by using CuI and DIPEA in THF at room temperature (Scheme 11). Their photophysical studies revealed that the fluorescence of zinc porphyrin 58 is strongly quenched due to the copper-corrole 59 in the dyad 60. Also, an efficient excited-state interaction was found between zinc-porphyrin and copper-corrole moieties upon photoexcitation. Moreover, the theoretical calculations suggested that the porphyrin moiety acted as a donor while the corrole unit acted as an acceptor in dimer 60.

Recently S. Y. Yap and co-workers [38] used “click chemistry” to link a water-soluble porphyrin with a histidine like group for the development of theranostic agents. Firstly, zinc triazole-porphyrins 63 and 66a were synthesized by the click reaction between water-soluble azidoporphyrin 61 and ᴅ-propargylglycine 62 or trifunctional-propargyllysine 65 in 83.6% and 77% yield, respectively, under microwave conditions as described in Scheme 12. After the successful synthesis of porphyrins 63 and 66b, their corresponding rhenium complexes 64a and 67a were prepared in good yields by using [Re(CO)₃Br₃][NEt₄]₂ at 65 °C in 2 hours. In addition to these, the radiolabeled products 64b and 67b were also constructed from the corresponding rhenium complexes by using [^99mTc(CO)₃(H₂O)₃]⁺ at pH 7.4 and 90 °C temperature.

Santos et al. [39] reported in 2008 the synthesis of CuAAC-ensembled 1,2,3-triazole-linked porphyrin-quinolone conjugates 70a–e by considering the biological significance of both the porphyrin and quinolone groups. The click reaction was performed between alkyne-substituted porphyrins 68a–e and 6-azidoquinolone 69 for the preparation of mono-, di-, tri-, and tetratriazoloporphyrin-quinolone conjugates 70a–e in 53–93% yields (Scheme 13).

In the following reports, Leroy-Lhez et al. [40] used a similar synthetic protocol to link porphyrin 71 to a fluorescein 72 through a 1,2,3-triazole linker to form the porphyrin-fluorescein conjugate 73 in 91% yield (Scheme 14).

Furthermore, the fluorescence study of conjugate 73 revealed an intramolecular energy transfer between fluorescein and porphyrin subunits and was more efficient in DMSO as compared to chloroform. Also, a clear evidence of a folded conformer was found by electrostatic and CH–π interactions, which was also, confirmed by density functional theory (DFT) calculations.

In another report, meso-triazole-bridged porphyrin-carborane conjugates 76a,b were synthesized in 80% yield by Ol’shevskaya et al. where a porphyrin unit 74a is covalently linked to 1-azidomethyl-o-carborane 75 [41] (Scheme 15). This boronation of the amide was performed via “click chemistry” in СН₂Сl₂/Н₂О solvent system using Cu(OAc)₂·2H₂O and sodium ascorbate as the catalyst at room temperature. In addition, the free-base porphyrin-carborane conjugate 76b was successfully obtained after the treatment of 76a with trifluoroacetic acid in СН₂Сl₂.

The research group of Ravikanth [42] prepared the triazole-bridged porphyrin-BODIPY conjugates 78 and 80 via CuAAC reaction in 45–50% yields. This click reaction was performed between 3-azido-BODIPY 77 and zinc porphyrin 35a or 21,23-dithiaporphyrin 79 in the presence of CuI/DIPEA in THF/CH₃CN (Scheme 16). UV–vis absorption and electrochemical studies revealed the presence and interaction of both the moieties in the conjugates. In addition to this, the fluorescence studies suggested that the energy transfer was not efficient in Zn(II) porphyrin-BODIPY and 21,23-dithiaporphyrin-BODIPY conjugates.

Dalip Kumar and his co-workers reported a CuAAC click reaction to prepare novel water soluble triazole-linked cationic porphyrin-carboline conjugate 85 [43] and porphyrin-psoralen conjugates 87 [44] as shown in Scheme 17. Firstly, zinc(II) porphyrin-carboline conjugate 84 and porphyrin-psoralen conjugate 86b were synthesized in good yields by the CuAAC reaction between porphyrin 81b and azide 82 or 83. Interestingly, the click reaction between free-base porphyrin 81a and azide 83 gives Cu(II)-porphyrin-psoralen conjugates 86a which do not give the demetallated product upon reaction with TFA. To this end, zinc porphyrins 84 and 86b were treated with HCl to remove the metal from its cavity and were then methylated with MeI in DMF to afford the cationic products 85 and 87 in good yields. The synthesized conjugates exhibited high photocytotoxicity towards A549 cancer cells as compared to a tumor-localizing and potent photosensitizing agent, TMPyP. Further, the authors discovered that the porphyrin-carboline conjugates 85 and porphyrin-psoralen conjugate 87 could be potential candidates for PDT applications.

Recently, Charisiadis et al. [45] explored this modular click chemistry protocol for the synthesis of a noble metal-free meso-triazole cobalt porphyrin diimine-dioxime conjugate 91 by covalently connecting a zinc porphyrin sensitizer with a H₂-evolving cobalt diimine dioxime catalyst. First, the Zn porphyrin 88b was coupled with the copper diiminedioxime complex 89 via the CuAAC click reaction to give porphyrin complex 90 in 74% yield (Scheme 18). Furthermore, a stable Co(III) complex was obtained by the metal exchange reaction of porphyrin 90 with excess CoCl₂·6H₂O in an acetone/THF (1:1) mixture. The results of the photophysical investigations demonstrated that these dyads exhibit adequate electronic interactions between the sensitizer and catalyst in the excited state. In this study, NiO films were sensitized with porphyrin 91 and used in a photoelectrochemical cell for H₂ generation. The NiO electrode is a transparent p-type conducting oxide and is used for hole injection from the HOMO of the excited dyes [46].

Very recently, Arellano et al. [47] synthesized the meso-triazole-bridged zinc porphyrin-N-doped graphene hybrid 96 through the CuAAC reaction. For the click reaction synthesis of hybrid 96, azide-functionalized N-doped graphene 94 and TMS-protected porphyrin 95 bearing an alkyne group were first prepared, as shown in Scheme 19. Subsequently, deprotected porphyrin bearing a terminal alkyne subunit was obtained after treatment of porphyrin 95 with TBAF. Finally, the CuAAC reaction was performed for the synthesis of triazole conjugates 96 by the reaction between acetylenic porphyrin with NG-N₃ 94 in the presence of CuSO₄·5H₂O and sodium ascorbate in N-methyl-2-pyrrolidone (NMP). The fluorescence investigation of hybrid 96 revealed that the fluorescence of zinc porphyrin was strongly quenched, and the electron-transfer quenching mechanism was validated by easy oxidation. Furthermore, femtosecond transient-absorption spectrum investigations offered proof of the charge-separation process. The ultrafast pump-probe technique was used to determine the photoinduced charge separation in zinc porphyrin 96 and the rate constant was found on the order of 10¹⁰ s⁻¹, clearly showing ultrafast electron-transfer between graphene and porphyrin units. Hence, these hybrids could be useful for light-induced applications.

Similar to porphyrins, fullerene C₆₀ also possesses superior acceptor properties, low reduction potential and low reorganization energy [48,49]. Thus, keeping the diverse properties of fullerene in mind, de Miguel et al. [50] successfully prepared and characterized the triazole-linked porphyrin-fullerene dyads 100a–d and 104a,b. Firstly, meso-triazole-linked porphyrin conjugates 99a–d and 103a,b were synthesized from porphyrins 97a,b and 101, as shown in Scheme 20. For the click reaction between porphyrin 101 and alkyne 102a,b, one equivalent of tris(benzotriazolylmethyl)amine (TBTA) was also added as an additive to increase the yield of triazoloporphyrins 103a,b. When TBTA, a tertiary amine with a 1,2,3-triazole ring, is added to a Cu-catalyzed click reaction, it forms a complex to stabilize the Cu(I) oxidation state and speeds up the reaction. Further, these 1,2,3-triazole conjugates (99a–d, 103a,b) were utilized for the preparation of porphyrin-fullerene dyads 100a–d and 104a,b in 30–70% yield by the reaction with C₆₀ and sarcosine in toluene under microwave conditions.

The photophysical and computational studies of these ZnP-Tri-C₆₀ conjugates revealed that the 1,2,3-triazole linker significantly influences the charge separation, charge recombination, and photoinduced electron transfer processes. Since, the through-bond distance is approximately the same for all the synthesized ZnP-Tri-C₆₀ conjugates, therefore, the variation in charge separation and charge recombination dynamics is primarily related to the electronic properties of the conjugates, such as electron affinity, orbital energies, and excited state energies.

In another report, Nikolaou et al. [51] described the synthesis of two novel porphyrin dyads 107b and 108b containing terminal carboxylic acid groups by using a CuAAC click reaction between azide and acetylene-substituted porphyrins in good yields as shown in Scheme 21. The photophysical and electrochemical studies along with DFT calculations showed that these dyads possess suitable frontier orbital energy levels for the use as sensitizers in DSSCs. Moreover, porphyrin conjugates 107b- and 108b-based solar cells were fabricated, resulting in power conversion efficiencies (PCEs) of 3.82 and 5.16%, respectively. In addition, the authors discovered that dyads 108b containing shorter triazole bridges have a stronger absorption profile and higher dye loading of the corresponding solar cell.

Recently, Chauhan and co-workers [52] demonstrated a click-chemistry-inspired synthesis of porphyrin-meso-triazole-ruthenium(II) conjugates, as shown in Scheme 22. First, the porphyrin conjugates 111a,b (inverse tri-py) and 115a,b (regular tri-py) were prepared in 85–90% yield from their corresponding meso-substituted (p-alkynyl- or p-azidophenyl)porphyrins (109 or 113) under click reaction conditions. Further, these zinc and free-base meso-triazole-bridged porphyrin conjugates were reacted with cis-Ru(bpy)₂Cl₂ in THF to afford the porphyrin-meso-triazole-ruthenium(II) conjugates 112a,b and 116a,b in 18–20% yield. Their photophysical and electrochemical studies revealed that the orbital energies depend on the ligands/linker, connecting pattern of linkers, and the presence of Zn metal ions in the porphyrin core. Ligand exchange studies also suggested that the regular Ru(II)-tri-py complex are more stable than their inverse analogues.

Ditriazole-bridged porphyrin system

This section describes the synthesis of porphyrin conjugates having two triazole units. In a report, Natali et al. [53] synthesized the novel dyad 119 (ZnP-NDI) and triad 121 (Fc-ZnP-NDI) via “click reaction” containing a zinc porphyrin (ZnP), a naphthalenediimide (NDI) and a ferrocene (Fc) moiety (Scheme 23). Firstly, dyad 119 was synthesized in 80% yield by the reaction between azido-Zn-porphyrin 117 and naphthalenediimide 118 containing an alkyne moiety via CuAAC reaction and was subjected to deprotection of the triisopropylsilyl group with tetra-n-butylammonium fluoride (Bu₄NF). Similarly triad 121 was prepared by the click reaction between dyads 119 and azido-ferrocene 120 in a 40% overall yield. The photophysical investigation revealed that dyad 119 exhibited relatively inefficient quenching of the ZnP singlet excited state, slow charge separation, and fast charge recombination processes on the visible excitation of ZnP and UV excitation of NDI chromophores. On the other hand, excitation of the NDI chromophore leads to the charge separation via both singlet and triplet quenching pathways.

The construction of water-soluble porphyrin nanospheres was reported by Zhang et al. in 2014 [54] by intramolecular host–guest interactions using porphyrin 126 containing two permethyl-β-cyclodextrin (PM-β-CD) and two dicarboxylatophenyl arms at meso-positions. The synthesis of porphyrin 126 was accomplished in four steps as shown in Scheme 24. First, porphyrin 123 was obtained by zinc metalation of the free-base porphyrin 122 using zinc acetate in a chloroform-methanol mixture. Further, the azide–alkyne click reaction between porphyrin 123 and 6-azido-6-deoxy-PM-β-CD 124 in the presence of CuSO₄ and sodium ascorbate in THF/H₂O furnished the bis-triazole-bridged porphyrin-cyclodextrin conjugate 125 in 65% yield. Finally, porphyrin 126 was obtained from porphyrin 125 after ester hydrolysis with KOH and demetallation with concentrated HCl. After the successful synthesis of porphyrin 126, it was used to form water-soluble porphyrin nanospheres by self-inclusion complex formation in water.

Tritriazole-bridged porphyrin system

This section contains the synthesis of porphyrin conjugates having three 1,2,3-triazole groups as linkers. In 2012, Beletskaya and co-workers [55] described the synthesis of the novel 1,3,5-benzene-centered and triazole-bridged porphyrin star trimer 129 (Scheme 25) in 30% yield via CuAAC click reaction. In the UV–vis absorption spectrum, the absorption bands of product trimer 129 and starting compound 127 were almost coincided with each other, which suggested a weak intramolecular inter-porphyrin communication. Further investigation also revealed that the interaction of the star compound 129 with DABCO and Bipy possibly led to the double star formed by the axial coordination of ligand with zinc centers.

The synthesis of supramolecular nanoassemblies from an amphiphilic 1,2,3-triazole-bridged porphyrin-permethyl-β-CD conjugates 131a,b was reported by Liu et al. [56] in 2015. First the porphyrin-cyclodextrin conjugates 131a,b were obtained in 90% and 70% yields, respectively, by the CuAAC click reaction between zinc(II) meso-tris(ethynylphenyl)porphyrin 130a,b and 6-deoxy-6-azido-PM-β-CD 124 using copper sulfate and sodium ascorbate in THF/H₂O (Scheme 26). Furthermore, the supramolecular nanoarchitectures as potential candidates for controlling drug delivery were prepared by complexing the porphyrins 131a,b with tetrasodium tetraphenylporphyrintetrasulfonate 132.

Recently, Pathak et al. [57] reported the synthesis of porphyrin-lantern-functionalized bright G-quadruplex nanostructures via a “tether and mask” approach in water (Scheme 27).

In this study, a large porphyrin dye 133 was first attached to short G-rich sequences and then clicked with azide 124 in the presence of copper bromide and tris((1-benzyl-4-triazolyl)methyl)amine (TBTA) in DMSO/H₂O to give a porphyrin-lantern (PL)-DNA sequence in 45% yield after cleavage and deprotection. These PL-DNA sequences were further used to construct strong and fluorescent G-wires that could be useful for photonics applications.

Tetratriazole-bridged porphyrin system

In this section, the click chemistry protocol for the synthesis of tetratriazole-bridged conjugates has been discussed. In the following report [58], Roberts et al. explored the click approach and designed the synthesis of hydrophobic and hydrophilic triazole-linked porphyrin-polymer conjugates (PPCs) (Scheme 28). The PPCs 137 and 139 were prepared by the reaction between tetraazido-Zn-porphyrin 135 or diazido-Zn-porphyrin 138 with polymers 136 bearing various hydrophilic and hydrophobic substituents using CuSO₄∙4H₂O and ascorbic acids under microwave irradiation conditions. The prepared nanoparticles from free-base PPCs showed colorimetric aqueous pH sensing, which suggests that the PPC nanoparticles could serve as chemical sensing applications.

In 2008, the Crossley’s group [59] reported the synthesis of a ‘capped’ porphyrin 142 forming a rigid 1,2,3-triazole linker between the porphyrin and the capping group using the CuAAC click reaction (Scheme 29). Capped porphyrin 142 was synthesized in similar yields under both aqueous (method A) and anhydrous (method B) conditions.

Method A produced capped porphyrin 142 in 19% yield by clicking zinc(II) tetraazidoporphyrin 140 and tetraalkyne 141 in the presence of CuSO₄∙5H₂O, ʟ-ascorbic acid, and triethylamine in H₂O/THF (1:10). In this procedure, the tertiary amine base was used to increase the rate of the CuAAC reaction. In contrast, method B reported the synthesis of porphyrin 142 with 14% yield using Cu(MeCN)₄PF₆ and triethylamine in anhydrous DMF. This ‘capped’ porphyrin was designed so that the rigid triazole linkers prevent the capping group from collapsing onto the porphyrin. Gilday et al. [60] also synthesized porphyrin 142 and studied its anion-binding properties and found that it has very strong anion-binding affinities for various anions.

In 2019, Ol’shevskaya [61] and co-workers synthesized meso-tetratriazole-bridged fluorinated porphyrin-maleimine conjugates 145a–c in 54–58% yields by using the CuAAC reaction between azidoporphyrins 143a,b and N-propargylmaleimide (144) in CH₂Cl₂. In addition, the free-base counterpart 145c was also prepared in quantifiable yield by removing zinc from porphyrin 145a using CF₃COOH in CHCl₃ (Scheme 30).

In a report, Aguilar-Ortíz and co-workers [62] used the CuAAC tool for the synthesis of novel dendritic molecules 148a,b containing a porphyrin and peripheral cholic acid moiety (Scheme 31). At first, the zinc derivative of porphyrin-tetracholic acid conjugate 148a was synthesized by the CuAAC click reaction between porphyrin 146 and 3α,7α,12α-trihydroxy-24-azido-5β-cholane (147) in the presence of CuBr(PPh₃)₃ in Et₃N/THF mixture in 73% yield.

Furthermore, this zinc conjugate was demetallated using H₃PO₄ in THF to form the free-base porphyrin 148b in 90% yield. The photophysical properties of this dendronized porphyrin molecule was investigated by absorption and fluorescence spectroscopy in different solvents, and the amphiphilic properties of the cholic acid units in porphyrin conjugates were also studied. The zinc-metalated porphyrin-cholic acid conjugate tends to form J-aggregates in various solvents with different polarities, whereas demetallated porphyrin-cholic acid conjugates show different patterns.

The research group of Cheng [63] designed a click inspired synthesis of novel discotic mesogen bearing a porphyrin unit, a triazole linkage, and a peripheral 3,4,5-trialkoxybenzyl unit (Scheme 32). Firstly, free-base porphyrin conjugates 151a–c were obtained by the CuAAC reaction between metal free tetraalkynylporphyrin 149 and benzyl azides 150a–c. Furthermore, the metal-porphyrin conjugates 152a–c and 153a,b were obtained in good yields from the corresponding free-base porphyrins 151a–c by the reaction with zinc acetate and copper acetate, respectively. The authors revealed that these compounds can self-assemble into hexagonal columnar phases in their pure states and can form organogels in 1,4-dioxane with an unusual flower-like sphere morphology.

Ol'shevskaya et al. [64] recently established a CuAAC-based synthesis of a novel series of meso-triazoloporphyrin-carborane conjugates, as shown in Scheme 33. First, the metalated triazole-linked porphyrin-carborane dyads 155 and 158a,b were synthesized in 75–79.2% yields by the click reaction between porphyrins 146 or 157a,b and azidomethyl-o-carborane 154. Further, porphyrin 155 was alkylated using excess trimethyloxonium tetrafluoroborate in CH₂Cl₂ to afford the free-base tetracationic triazolium salt 156 in quantitative yield. Also, a free-base dyad 158c was obtained in 95% yield by the demetallation of zinc porphyrin 158a with trifluoroacetic acid in a CHCl₃/MeOH mixture. These synthesized conjugates showed great affinity for major biological carriers like albumin and LDL. Furthermore, the Zn and Pd porphyrin complexes revealed a good capability to yield singlet oxygen (quantum yield >70%) and exhibited significant photoinduced cytotoxicity.

In another report, Prakash Rao et al. [65] highlighted the click protocol to accomplish the synthesis of hydrogenated cardanol-triazole-zinc-porphyrin conjugate 160 and triazole-zinc-porphyrin conjugate 162 by the reaction between zinc porphyrin 146 with cardanol azide 159 or 161, respectively (Scheme 34). Different solvents were used to conduct their UV–vis and fluorescence experiments and the results were compared to other related molecules. Based on the collected data, the porphyrin complex 160 was found to show J-type aggregation in both polar and nonpolar solvents. In polar solvents, aggregation was induced by van der Waals interactions between H-cardanol moieties, while π–π stacking interactions between porphyrin groups were observed in nonpolar solvents. In addition, UV–vis and fluorescence spectra also showed that the 1,2,3-triazole moiety can stabilize zinc porphyrin by forming an intermolecular coordination complex. Also, it was found that porphyrin complex 160 is easy to synthesize, is fat soluble and showed good fluorescence emission; thus, it could be used as a photodynamic therapy application.

In 2013, Liu and colleagues [66] used a click chemistry approach to synthesize meso-tetratriazole-bridged Zn(II) porphyrin-boron dipyrromethane conjugates 164 in 85% yield by reacting porphyrin 146 with BODIPY 163 containing an azide moiety (Scheme 35). Photophysical studies confirmed that a good spectral overlap was found between the energy donor (BODIPY) and the energy acceptor (porphyrin subunits). Also, complex 164 exhibited a highly efficient photoinduced energy transfer process with an energy transfer quantum yield of 0.98. These conjugates could be useful in light-harvesting applications because of their optical characteristics.

In 2008, Liu et al. [67] nicely demonstrated Cu(I)-catalyzed click chemistry for the synthesis of tetrakis(PM-β-CD)-modified zinc(II) porphyrin 166a and tetra(β-CD)-modified zinc(II) porphyrin 166b in 90% and 70% yield, respectively (Scheme 36). The synthesis of these porphyrins 166a,b was accomplished by the reaction between porphyrin 146 and 6-deoxy-6-azido-PM-β-CD 124 or 6-deoxy-6-azido-β-CD 165 in the presence of CuSO₄∙5H₂O and sodium ascorbate in H₂O/THF. Furthermore, these two structurally similar porphyrins 166a,b were used as hosts for the intermolecular formation of inclusion complexes with tetrasodium tetraphenylporphyrintetrasulfonate 132 in aqueous solution, leading to the constructions of two different nanoarchitectures with alternating porphyrin and cyclodextrin assembly.

Recently, Nasri and co-workers [68] constructed the triazole-bridged meso-arylporphyrins 171a–c and 172a–c by using the CuAAC reaction in good yields (Scheme 37). Initially, the triazolo-linked compounds 170a–c were prepared by reacting 3-methoxy-4-(prop-2-ynlyloxy)benzaldehyde (168) with azides 169a–c in the presence of CuI and DIPEA in toluene under microwave conditions. Further, three triazole-meso-porphyrins 171a–c were prepared using a slightly modified Adler–Longo procedure. Also, the corresponding zinc derivatives 172a–c of these free-base porphyrins were synthesized in excellent yields using Zn(OAc)₂ in a CHCl₃/MeOH mixture. Their UV–vis titration study revealed that these host systems exhibit strong anion-binding affinities. Furthermore, with the help of kinetic studies, the absorption efficiency of malachite green dye was investigated by using free-base porphyrins 171a–c and the corresponding zinc(II) compounds 172a–c as adsorbents. In addition to that, various factors affecting the degradation phenomenon have been studied.

Octatriazole-bridged porphyrin systems

This section describes the preparation of porphyrin conjugates containing eight triazole rings. In 2009, Jayawickramarajah and co-workers [69] synthesized a water-soluble porphyrin-fullerene (C₆₀) nanorod through the formation of an inclusion complex between an octa(permethylated-β-CD)-Zn-porphyrin 174 and a pristine C₆₀. For the construction of the nanorod, porphyrin 174 was first obtained in 65% yield by a Cu(I)-catalyzed click reaction between 5,10,15,20-tetrakis(3,5-dipropargyloxyphenyl)-Zn-porphyrin 173 and the azide 124 in the presence of CuSO₄ and sodium ascorbate in THF/H₂O (Scheme 38). UV–vis spectroscopy showed that the porphyrin 174 was readily soluble in water, and no porphyrin–porphyrin stacking interaction was observed.

In 2010, the same group also reported the construction of a well-defined porphyrin nanowire [70] in water using Zn(II) porphyrin-CD conjugate 174 and free-base porphyrin-adamantane conjugate 176b through a robust 1:1 β-CD/adamantane host–guest interaction. First, porphyrin 176b was prepared in 96% by the CuAAC click reaction between octaalkynyl-Zn-porphyrin 173 and 1-azidoadamantane 175, followed by demetallation with HCl (Scheme 38).

Since porphyrin 174 was water soluble and porphyrin 176b was insoluble in water; however, when porphyrin 176b was added to an aqueous solution of porphyrin 174 and stirred at room temperature for 24 h, solubilization occurred, resulting in a homogeneous solution. This is due to the formation of a supramolecular assembly in which the hydrophobic adamantane arms of 176b are sequestered by the β-CD arms of porphyrin 174, resulting in water solubility. These prepared porphyrin nanowires were subjected to surface microscopy and fluorescence energy transfer experiments, which elucidated their stability and resistance to disassembly.

Conclusion

Cu(I)-catalyzed “click chemistry” is a well-established protocol for the facile access of complexes from simple molecular architectures featuring 1,4-disubstituted triazole units with high yield and higher regioselectivity. The click-inspired synthesis and photophysical properties of diverse triazole-linked porphyrin conjugates are discussed in this review. This review includes a number of recent and important research articles in which various chromophoric groups are linked to the porphyrin periphery via an 1,2,3-triazole ring, either at β- or meso-positions. First, the review describes the synthesis of β-triazole-linked porphyrins and then meso-triazole-linked porphyrins containing one or more triazole rings. The CuAAC click reaction has been shown to bind a variety of chromophores bearing azide or alkyne groups to the porphyrin periphery, including coumarin, xanthone, DNA, ferrocene, corrole, fluorescein, carborane, BODIPY, graphene, carboline, fullerene, NDI, β-cyclodextrin, cholic acid, quinolone, etc. Some of these porphyrin complexes have shown significant electron and/or energy transfer between the porphyrin and the accompanying chromophore, and the 1,2,3-triazole bridge affects charge-separation and photoinduced electron transfer processes between connecting molecules. Various combinations of copper catalysts have been used for the CuAAC-based synthesis of these porphyrin conjugates, the majority of the reports using CuSO₄ with either ascorbic acid or sodium ascorbate, and Cu(OAc)₂ with sodium ascorbate under an organic solvent or a mixture of organic solvents and water. In addition, other Cu(I)-catalysts such as CuI, (SIMes)CuBr, Cu(MeCN)₄PF₆, and CuBr(PPh₃)₃ have been also used in some reactions. Furthermore, a few reports describe the use of ligands like DIPEA, TBTA, NMP, Et₃N, etc. along with copper catalysts to stabilize the Cu(I)-oxidation state and speed up the click reaction. It has been observed that the presence of a porphyrin ring has little influence on the click reaction and it is compatible with almost all kinds of porphyrin derivatives under different reaction conditions. When an azido or alkyne group is attached to an alkyl chain, the click reaction requires milder reaction conditions and gives higher yields of product than directly linked azido or alkynyl porphyrins. Many applications for porphyrin click products have been proposed, including chemical sensing, anion-binding affinity, photovoltaics devices, light-harvesting materials, and in the synthesis of water-soluble nanowires, nanorods, and nanospheres. In addition, these triazoloporphyrins have a wide range of medical applications, including photoinduced cytotoxicity against cancer cells, drug delivery, as phototherapeutic agents, and PDT applications. I believe this review will be useful and encourage researchers around the world to use CuAAC and its modifications in various fields of industrial and scientific research, which can be useful in materials to medical and other applications.