Porphycenes and Related Isomers - American Chemical Society

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Porphycenes and Related Isomers: Synthetic Aspects Gonzalo Anguera and David Sánchez-García* Grup d’Enginyeria de Materials, Institut Químic de Sarrià, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona, Spain ABSTRACT: Porphyrins, called the pigments of life, have been studied for decades. However, the first constitutional isomer of porphyrin, porphycene, was not synthesized until 1986. This milestone marked the beginning of a new era in the field of porphyrinoids and presented opportunities for the creation of an abundance of new pigments. The unique structural and electronic features of these compounds give rise to interesting physical and optical properties with applications in biomedicine and materials science. This review focuses on the synthetic methodologies available for the preparation of porphycenes (functionalized porphycenes, extended porphycenes, benzoporphycenes, naphthoporphycenes, and heteroanalogues) and the other known isomers, namely, corrphycene, hemiporphycene, and isoporphycene. Although the classical synthetic approaches are discussed, particular emphasis is placed on improvements to the known methodologies and recent advances in the field.

CONTENTS 1. Introduction 2. Porphycenes 2.1. Structural and Electronic Description 2.2. Preparation of Porphycenes 2.2.1. Classical Synthesis: 2,2′-Bipyrroles via Ullmann Coupling 2.2.2. Expeditious Syntheses: 2,2′-Bipyrroles via Oxidative Couplings 2.2.3. Diversity-Oriented Synthesis: Substituted 2,2′-Bipyrroles via Suzuki Couplings 2.2.4. Novel Approaches: Macrocyclization by Oxidative Ring Closure 2.3. Reactivity and Functionalization of Porphycenes 2.3.1. Hydrogenation 2.3.2. Reactivity of Porphycenes with Electrophiles: Halogenation, Sulfonylation, Formylation, and Nitration 2.3.3. Acetoxylation and Hydroxylation 2.3.4. Palladium Cross-Coupling Reactions 2.3.5. Functionalization of Positions 2, 7, 12, and 17 2.4. Extended and Expanded Porphycenes 2.4.1. Synthesis of Extended Porphycenes 2.4.2. Syntheses of Benzoporphycenes 2.5. Porphycene Heteroanalogues 3. Porphycene Isomers: Corrphycene, Hemiporphycene, and Isoporphycene 3.1. Corrphycene 3.2. Hemiporphycene 3.3. Isoporphycene 4. Conclusions and Outlook Author Information © XXXX American Chemical Society

Corresponding Author ORCID Notes Biographies References

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1. INTRODUCTION Aromaticity is a fundamental concept in organic chemistry.1,2 The study of aromaticity has not only provided insight into the nature of chemical bonding but also presented new reactivity and fostered the discovery of fascinating compound families.3−9 Exceptional examples of the latter are the chemistry of annulenes10 and the preparation of the constitutional isomers of porphyrin (Figure 1). For decades, annulenes11 have been regarded as privileged models for the study of aromaticity. One striking finding is the importance of the planarity and rigidity of the macrocycle to determine its reactivity. For example, Sondheimer’s [18]annulene 6 is better described as a polyene, whereas bridged congeners (i.e., 1,6-methano[10]annulene 7 or its 1,6-iminobridged counterpart) display benzenoid reactivity10 (Figure 2). The same benzenoid characteristics are present in porphyrins, which can also be regarded as aza-bridged [18]annulenes.10 Generalizing this idea, the set of all possible configurations of the [18]annulene gives rise to isomeric macrocycles that can accommodate imino bridges (NH or N-alkyl)12,13 in distinct positions along the unsaturated chain (Scheme 1). Using this rationale, Vogel14 envisioned the family of constitutional isomeric porphyrins.

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Special Issue: Expanded, Contracted, and Isomeric Porphyrins Received: June 2, 2016

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DOI: 10.1021/acs.chemrev.6b00345 Chem. Rev. XXXX, XXX, XXX−XXX

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porphycenes is described. The classical synthesis by Vogel is discussed in light of recent new advances. Furthermore, novel synthetic approaches are studied in detail with an emphasis on novel methodologies based on the preparation of 2,2′bipyrroles via oxidative coupling. In section 2.3, the basic chemistry of porphycene and its functionalization are illustrated with examples of the preparation of derivatives with applications in materials chemistry and biomedicine. Syntheses of three families of related macrocycles are presented: extended porphycenes and benzoporphycenes in section 2.4 and heteroanalogues in section 2.5. In section 3, different approaches to prepare corrphycene, hemiporphycene, and isoporphycene are discussed.

2. PORPHYCENES 2.1. Structural and Electronic Description

Figure 1. Structures of porphyrin and synthesized constitutional isomers.

Formally known as [18]porphyrin-(2.0.2.0), 20 porphycene7,15,21 (2a) was first prepared in 1986 by Vogel et al.15 The defining structural feature of this macrocycle is the presence of two 2,2′-bipyrrole units linked by two bridges with two sp2 carbons (Figure 3). The planar, conjugated (18 πelectrons) structure of porphycene confers aromatic characteristics to the macrocycle according to Hückel’s rule.

Figure 2. Structures of [18]annulene and 1,6-methano[10]annulene.

Scheme 1. Porphyrin and Porphycene Frameworks

Figure 3. Structure of porphycene.

Although the macrocyclic framework of porphycenes can be regarded as an aza-[18]annulene, porphycenes display benzenoid reactivity rather than typical annulene reactivity; annulenes are more prone to polymerization.2 This reactivity is explained by considering the rigidity imposed by the pyrrolic nitrogen atoms on the unsaturated macrocycle. Consistent with this behavior, porphycenes undergo smooth electrophilic substitution with a variety of reagents,22 such as halogens, SO3, and fuming HNO3. To enhance the solubility of the parent macrocycle, Vogel et al.23 prepared the first 2,7,12,17-tetrasubstituted derivative, the tetra-n-propyl-substituted porphycene 2b. The presence of these chains improves the crystallinity and solubility of the macrocycle in organic solvents. The substitutients of these porphycenes range from functionalized alkyl chains to aromatic moieties. Other families of substituted porphycenes include the so-called etioporphycenes,24 bearing substituents at positions 3, 6, 13, and 16, and the meso-substituted porphycenes25 with substitutions at positions 9, 10, 19, and 20 (Figure 3). As with porphyrins, most of porphycene’s properties and applications are a consequence of two structural features: the conjugated macrocyclic framework and the presence of an N4 central core (Figure 4). The particular electronic structure of porphycene26−28 gives rise to strong absorbance bands in the UV−vis spectrum: the B-bands (Soret) that usually split (350− 370 nm) and the so-called Q-bands in the red portion of the visible spectrum (620−760 nm).29,30 Because of the lower symmetry of porphycene (D2h) (2) relative to porphyrins (8) (D4h), porphycene Q-bands are more intense and display a

The first constitutional isomer of porphyrin to be prepared was porphycene.15 Owing to its synthetic accessibility, chemical stability, and remarkable optical properties, porphycene is one of the most-studied porphyrinoids. Subsequently, alkylsubstituted derivatives of corrphycene16 3 and hemiporphycene17 4 were obtained (Figure 1). In 1999, the syntheses of metal complexes and derivatives of isoporphycene18 5 were achieved. To date, 5 is the most recently reported isomer, containing all pyrrolic nitrogen atoms inside the macrocycle hole (the N4 core). Isomeric forms with nitrogen atoms at the peripheral positions of the macrocycle (so-called “N-confused” or “mutant” porphyrins) have been prepared and reviewed elsewhere.19 Thus, this review is devoted to synthetic methodologies for preparation of the four known porphyrin isomers. Section 2 covers porphycenes, beginning with a structural and electronic description in section 2.1. In section 2.2, the preparation of B


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Table 1. Porphycene Heteroanalogues Containing Furan and Thiophene

Figure 4. Comparison of the geometry between porphycenes and porphyrins.

notable bathochromic shift. This effect is ascribed to a loss of degeneracy in the LUNOs (lowest unoccupied natural orbitals) of the ligand. Moreover, porphycenes show moderate red fluorescence29 (Φf ≈ 0.1−0.38). These spectral properties, along with their ability to produce singlet oxygen (ΦΔ ≈ 0.2− 0.7), make porphycenes attractive candidates for biomedical applications such as photodynamic therapy31 (PDT). The electronic properties of porphycenes can be modulated by addition of unsaturated subunits to the 18 π-electron conjugation pathway, such as an even number of sp2 or sp carbon atoms, for instance, macrocycle32 9, or fused aromatic rings to the macrocyclic framework,10,33 as in 10 and 11. These structural variations to the porphycene core give rise to families of extended porphycenes and benzoporphycenes (Figure 5).

2.2. Preparation of Porphycenes

Synthetic strategies to obtain porphycenes are primarily inspired by the macrocycle symmetry.58 Accordingly, two synthetic pathways have been envisioned (Scheme 2): reductive coupling of 2,2′-bipyrrole dialdehydes (31) and oxidative cyclization of dipyrrolethanes (32). The first approach has been adopted as the standard synthesis, as proposed by Vogel et al.15 in their seminal paper in 1986. The alternative strategy was devised in 2008 by Srinivasan and co-workers.59 This group reported a novel synthesis of tetraaryl meso-substituted porphycenes that includes the formation of two 2,2′-linkages followed by aromatization. 2.2.1. Classical Synthesis: 2,2′-Bipyrroles via Ullmann Coupling. The synthesis of porphycene by Vogel et al.15 (2a) involves the reductive dimerization of 5,5′-diformyl-2,2′bipyrrole (31a) via McMurry coupling. The resulting 20 πelectron macrocycle must be oxidized to obtain the aromatic 18 π-electron porphycene. For most porphycenes, this oxidation is spontaneous in the presence of air. However, in some systems,60,61 an oxidative step must be added to the synthetic pathway (Scheme 3). Preparation of the parent porphycene 2a is straightforward (four steps from pyrrole);15,62 however, the synthesis of substituted derivatives requires more elaborate synthetic schemes.23 In general, these syntheses rely on the use of three key reactions: Ullmann reaction63 to provide the 2,2′bipyrrole moiety and Vilsmeier−Haack formylation64 and McMurry coupling65 to cause the cyclization that leads to a macrocycle, which is oxidized, often in situ, to furnish the corresponding aromatic porphycene (Scheme 4). The starting materials for the Ullmann coupling are 2iodopyrroles. These pyrroles can be produced from commercially available chemicals by robust methodologies.66,67 For preparation of 2,7,12,17-substituted porphycenes,23 the required starting pyrroles 36 are synthesized by the Knorr pyrrole reaction. This reaction uses simple β-keto esters and can be easily scaled up. The resulting pyrrole 36 bears a methyl group at the α-position that is readily oxidized to the corresponding carboxylic acid by use of Br2 and SO2Cl2 as reagents. Finally, the pyrrolecarboxylic acid 37 undergoes decarboxylative iodination66 with I2/KI to yield iodopyrrole 38.

Figure 5. Representative structures of an extended porphycene and benzoporphycenes.

The formal substitution of pyrrole rings in the macrocycle by other heterocycles leads to a new class of aromatic and nonaromatic porphycene analogues. The electronic characteristics and the balance between global (18 π-electrons) and local (inherent to the heterocycle, 6 π-electrons) aromaticity of the resulting macrocycles greatly depend on the nature of the incorporated heterocycle. To date, the list of heterocycles replacing pyrrole includes furan34−36 and thiophene36−39 (Table 1) and imidazole40,41 and thiazole42 (Table 2). Although the central N4 core of porphycenes is smaller than that of porphyrins, a wide variety of metal cations can be accommodated43 (i.e., 24−30). The complexation ability of the macrocycle depends on the geometry of the porphycene core, which is influenced by the presence of peripheral substituents due to their steric interactions.25,44 Recently, a novel modality of complexation has been reported45 consisting of a π-complex (30) produced by interaction between a pyrrole ring of the macrocycle and an [RuCp*] fragment (Cp* = pentamethylcyclopentadienyl). This is one example of the rich complexation chemistry of porphycene,43,46,47 which has created opportunities for a wide range of applications, such as molecular mimicry48−53 (28), materials science54−56 (24, 27, 29), and catalysis57 (Figure 6). C


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Table 2. Porphycene Heteroanalogues Containing Imidazole and Thiazole

Figure 6. Representative examples of metal complexes with porphycenes as ligands.

following a methodology by Matsumoto and co-workers69 that involves the reaction between an isocyanoacetate and an aromatic70 or aliphatic aldehyde in the presence of 1,8diazabicyclo[5.4.0]undec-7-ene (DBU). Subsequently, iodination is achieved by treatment of the corresponding pyrrole with iodine in a biphasic system [dichloromethane (DCM) or 1,2dichloroethane (DCE)/water]. Alternatively, Jux and coworkers71 have optimized the halogenation step with ICl. By this procedure, iodopyrroles 38f,g were produced in almost quantitative yield. Once pyrroles 38 are in hand, the synthetic sequence is identical to Vogel’s procedure. A similar approach was adopted by Kobayashi and coworkers72 in 2009 by preparing the required pyrrole from an

Scheme 2. Retrosynthetic Analysis of Porphycenes

In 2006, Sessler and Sánchez-Garcı ́a68 devised a shorter synthesis for preparation of 2-iodopyrroles 38 (Scheme 5). The procedure entails direct iodination of a properly functionalized α-free pyrrole. The starting α-free pyrrole 43 was synthesized D


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Scheme 3. General Synthesis of Porphycenes

Scheme 4. Synthesis of 2,7,12,17-Substituted Porphycenes 2b,c

substituted by the more concise and flexible Barton−Zard76 reaction. The mechanism of this transformation involves the condensation of an alkyl isocyanoacetate (i.e., ethyl isocyanoacetate) with a nitro compound under basic conditions (DBU is usually used as the base). Ethyl isocyanoacetate is commercially available; however, the required nitro compounds (i.e., 53) must be prepared by a reaction of nitro derivatives with aldehydes (Henry reaction) to provide the corresponding alcohols, which must be acetylated by treatment with Ac2O. Alternatively, conjugated nitro compounds56 (i.e., olefin 56) can be used for pyrrole preparation (Scheme 8). With the iodinated pyrroles in hand, the next step in the synthesis is their coupling via the Ullmann reaction to provide the corresponding 2,2′-bipyrrole.63 To ensure good yields in this transformation, it is necessary for the substrate to bear one

alkyne instead of an aldehyde. The synthesis of this pyrrole (43j) follows the protocol reported by Yamamoto and coworkers73 in 2005, which consists of a copper-catalyzed reaction between ethyl isocyanoacetate and electron-deficient alkynes. The presence of the ester moiety in the alkyne ensures reactivity, while the other terminus introduces the desired substituent to the macrocycle (Scheme 6). It has been shown that isocyanoacetates play a major role in the synthesis of pyrroles. Another application of these reagents is the synthesis of β,β′-disubstituted pyrroles 46, which are precursors for the preparation of etioporphycenes,24,56,74,75 such as macrocycle 51 (Scheme 7). These β,β′-substituted pyrroles (i.e., pyrrole ester 46) can be prepared by the Kleinspehn66,67 variant of the Knorr reaction. However, this method can usually be advantageously E


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Scheme 5. Simplified Preparation of Porphycenesa

a

Sessler and Sánchez-Garcia.́ 68

Scheme 6. Optimized Synthesis of Porphycenesa

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Kobayashi and co-workers.72

Scheme 7. Synthesis of Etioporphycene 51

or more electron-withdrawing groups, such as esters. Considering this requirement, Sessler and Hoehner77 described an efficient procedure to improve the coupling yield by derivatization of the pyrrole nitrogen atom with a tbutyloxycarbonyl (Boc) protecting group. The authors claim that yields of Ullmann couplings can be enhanced by 20−30% with this modification. The beneficial effect of the Boc group is

rationalized in terms of substrate activation and because it acts as a blocking group that prevents the competing Nheteroarylation reaction. After the corresponding 2,2′-bipyrrole has formed, the Boc groups can be readily removed by thermal treatment of the substrate at 180 °C under an inert atmosphere or vacuum. F


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Scheme 8. Synthesis of β,β′-Substituted Pyrrolesa

a

bipyrrole 41. When bipyrrole diesters 39 (Scheme 4) are the starting materials, the procedure of Vogel et al.23 to generate the α,α′-free bipyrrole consists of two different processes. The first process is saponification of tetraesters 39 by treatment with NaOH in an alcohol, followed by sublimation of the tetraacid 40. A simplified route78 that avoids the sublimation step is based on treatment of the tetraester with NaOH at high temperatures (170−190 °C) in ethylene glycol. This methodology furnishes the corresponding α,α′-free bipyrrole in a onepot, two-step procedure. The resulting bipyrrole is obtained by filtration after the addition of degassed water to the reaction mixture. Extensive washings with water yield a dark green crude product that is usually sufficiently pure to undergo the formylation step. The formylation reaction occurs in two distinct steps: electrophilic substitution of pyrrole by the Vilsmeier reagent, prepared by exposure of DMF to POCl3, and hydrolysis of the intermediate by treatment with a basic aqueous solution, usually NaOAc(aq) or NaOH(aq). A convenient solvent for the reaction is DMF or a halogenated solvent. After the hydrolysis reaction is complete, the dialdehyde is readily isolated by filtration. The yields of the formylation step are usually excellent (80−100%). The preparation of alkyl or aryl meso-substituted porphycenes25 requires bipyrroles bearing ketone moieties at the αpositions. In these cases, the corresponding α,α′-free bipyrroles are acylated by a variant of the Vilsmeier−Haack reaction that replaces DMF with a suitably substituted tertiary amide. For instance, in the synthesis of meso-substituted porphycene 66, Yamada and co-workers75 prepared bipyrrole 65 by acylation of α,α′-free bipyrrole 41j with MeCONMe2. The acylation furnished diketone 65 in 92% yield (Scheme 10). Another method for installation of the aldehyde functionality, presented by Nonell and co-workers,83 consists of conversion of the α-ester groups of bipyrroles to the corresponding tosyl (Ts) hydrazones followed by basic hydrolysis. This transformation is known as the MacFadyen−Stevens reaction. Although the procedure adds an extra step, the overall yield

Barton and Zard.76

The Ullmann reaction is usually23 performed at high temperatures78 (100−120 °C) in the presence of a pure form of copper (so-called “copper-bronze”). The solvent has a critical effect on the coupling, and dimethylformamide (DMF) is usually the solvent of choice. However, Vogel and Deponte79 have shown that aromatic solvents such as toluene improve the reaction yield. An alternative method for synthesis of 2,2′-bipyrroles that avoids use of the Ullmann coupling was developed in 2007 by Smith and co-workers.80,81 In this reaction, copper is replaced by a catalytic system consisting of Pd/C and zinc. The coupling occurs smoothly, starting from β,β′-substituted 2-iodopyrroles bearing formyl,80,82 ester,81 and nitrile80 groups in mixtures of toluene/water or acetone/water at room temperature in moderate yields. The main advantage of this protocol80 is the simplified synthesis of functionalized bipyrrole dialdehydes such as 64, which are ready to participate in McMurry coupling to afford etioporphycenes (Scheme 9). According to Vogel’s procedure, once the bipyrrole has been prepared, the following step is formylation at positions 5 and 5′. In the context of pyrrole chemistry, formylation is typically performed by the Vilsmeier−Haack reaction. Hence, the procedure requires preparation of the corresponding α,α′-free Scheme 9. Synthesis of 2,2′-Bipyrrole Dialdehydesa

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Smith and co-workers.80,81 G


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Scheme 10. Synthesis of Diketo-Substituted 2,2′-Bipyrrole 65

Scheme 11. Nontetradecarboxylative Synthesis of Porphycenesa

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Nonell and co-workers.83

Scheme 12. Synthesis of Trifluoromethyl-Containing Porphycenesa

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Hayashi and co-workers.61,84

of MnO2. Unfortunately, the overall yield of dialdehyde 31c obtained by this methodology was low (21% yield from diester 69c). In some syntheses, the functional groups present in the starting pyrrole determine the reactions to produce the dialdehyde. For example, in the preparation of porphycenes bearing trifluoromethyl groups 77, Hayashi and co-workers61,84 first installed the aldehyde moiety by oxidation of a methyl group at the α-position of pyrrole 71, which was then masked as an acetal (Scheme 12). Note that under the reaction conditions (Br2, SO2Cl2), the expected product is the carboxylic acid. However, the presence of the CF3 group might reduce the reactivity of halogenation at the α-methyl group to yield the

is excellent (82% from 69c to 31c; Scheme 11). Most importantly, the reaction avoids tetradecarboxylation of the bipyrrolic precursor and isolation of the unstable intermediates 41 (Scheme 4). To implement this strategy, ester groups at the β-position must be removed prior to conversion of the α-esters into hydrazones. To accomplish this goal, bipyrrole 68c is functionalized with benzyl (Bn) esters at the β-positions. Hence, the ester groups can be smoothly removed by hydrogenolysis and heating at 170 °C (Scheme 11). In the same report, the authors proposed transformation of the ester groups to aldehydes by reduction with hydrides. Thus, bipyrrole 69c was treated with LiAlH4 to furnish the corresponding dialcohol, which was oxidized in the presence H


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aldehyde. Alternatively, direct conversion of α-methyl groups into aldehydes can be achieved by use of cerium ammonium nitrate82 (CAN) (see Scheme 9). Once the required bipyrrolic aldehydes are in hand, the next step is formation of the macrocyclic framework by reductive coupling via the McMurry reaction65 (Scheme 13). This

2.2.2. Expeditious Syntheses: 2,2′-Bipyrroles via Oxidative Couplings. The synthesis proposed by Vogel et al.15 relies on Ullmann coupling to prepare 2,2′-bipyrroles. 2Iodopyrrole precursors for the coupling can be obtained by following simple procedures; however, more than two steps are often required. To simplify the synthetic pathway, methodologies based on oxidative couplings to prepare 2,2′-bipyrroles have emerged. Waluk and co-workers90,91 introduced a new approach that avoids Ullmann coupling in the synthesis of porphycene 2a (Scheme 14). The strategy is based on oxidative coupling of 2pyrrole carbanions upon the addition of CuCl. These anionic species were obtained by deprotonation of a tosyl-protected pyrrole, such as 83, with lithium 2,2,6,6-tetramethylpiperidide (LTMP). The harsh conditions to cause the coupling require protection of the pyrrole NH group (tosyl group, Ts), thus adding two steps to the synthesis. In the same report,90 the synthesis of 2,2′-bipyrroles was used to prepare the parent porphycene 2a (2−3% yield). The procedure exploits the lability of the t-butyl group, which imparts solubility to 31e under acidic conditions when bonded to an aromatic nucleus. From a mechanistic perspective, the process is a retro Friedel−Crafts alkylation (Scheme 14). Inspired in part by the simplicity of Waluk’s oxidative coupling to afford 2,2′-bipyrroles, Sánchez-Garcı ́a and coworkers92,93 devised a synthesis of β-substituted 2,2′-bipyrroles by exposure of 2-(trimethylstannyl)pyrroles 87 to Cu(NO3)2· 3H2O (Scheme 15). This methodology takes advantage of a modification of the synthesis of β-substituted pyrroles by van Leusen and co-workers.94 According to this procedure, 2(trimethylstannyl)pyrroles were prepared by treatment of tosylmethyl isocyanide (TosMIC) with 2 equiv of n-BuLi, followed by sequential exposure of the dilithiated intermediate to an excess of Me3SnCl and a variety of Michael acceptors 86. This synthesis provided β-substituted 2-(trimethylstannyl)pyrroles 87 in yields ranging from 40% to 90%. With pyrroles 87 in hand, the biheterocycle was produced by oxidative coupling in the presence of copper salts such as Cu(NO3)2· 3H2O. Both the preparation of 2-(trimethylstannyl)pyrroles and their oxidative coupling can be conducted in the same vessel, providing a one-pot preparation of aryl-substituted 2,2′bipyrroles from cinnamates. Generally, the low solubility of bipyrroles 88 in ethyl acetate enables their easy isolation without chromatographic purification. Finally, saponification and decarboxylation of bipyrroles 88 yielded aryl-substituted α,α′-free bipyrroles 41. An example of application of this chemistry can be found in the preparation of porphycene 2m, which was named Temocene93 by the authors because of its structural resemblance to the photosensitizer temoporfin (Foscan). The electron-rich nature of pyrroles permits their direct metal-mediated oxidative coupling to provide cyclic oligomers95,96 and polymers.97 This approach has been applied in the preparation of β-alkyl-substituted bipyrroles and requires the use of strong oxidizers such as FeCl3,98 Na2Cr2O7,99 and Pb(OAc)4100 or expensive palladium(II) salts.100−102 Unfortunately, the use of these reagents is not suitable for synthesis of functionalized bipyrroles. However, the development of hypervalent iodine chemistry103 has provided selective and efficient reagents to smoothly achieve the oxidative coupling of pyrroles. This transformation belongs to the broad family of “Scholl reactions”.98,104 Thus, in 2007, Kita and co-workers105 reported the oxidative dimerization of pyrroles with the aid of

Scheme 13. Simplified McMurry Coupling Mechanism

reaction is arguably the most complex step in the synthesis of porphycenes in terms of having a practical procedure. The reaction is performed in an ethereal solvent, typically tetrahydrofuran (THF), under strictly anhydrous conditions with reflux. Unfortunately, the starting dialdehydes are not usually highly soluble in this solvent, which explains the low yields found in the macrocyclization step. For instance, unsubstituted porphycene15 2a is obtained in 3% yield, whereas some etioporphycenes56 produced from highly soluble functionalized dialdehydes are synthesized in yields as high as 41%. The reaction involves the so-called low-valent titanium reagent85 (Scheme 13). This reagent is prepared by reduction of a titanium source, typically TiCl4. TiCl4 is difficult to handle because it is a dense liquid and is highly sensitive to humidity. An alternative to this reagent is the solid complex TiCl4· 2THF,86 which can be easily handled and stored. The nature of the reductant is diverse, and examples include LiAlH4, Zn, and the Zn/Cu couple, among others. In early reports on porphycenes, the modification by Mukaiyama et al.87 of the McMurry reaction (TiCl4/Zn) was the preferred method. Furthermore, some preparations recommended addition of additives such as pyridine88 to improve the yield of the couplings. However, these procedures have been abandoned in favor of the TiCl4−Zn/CuCl system.89 A systematic study devoted to optimization of McMurry conditions in the synthesis of porphycenes is lacking. The final step of the synthesis is oxidation of the macrocycle to furnish the aromatic porphycene. This step is sometimes neglected because most porphycenes are oxidized by simple stirring of a solution of the reduced precursor in contact with air. However, in some instances, the aromatic porphycene is obtained only after exposure of the reduced macrocycle to an oxidant, such as 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ).61 In this regard, the reluctance of some mesosubstituted porphycenes, such as 81 (Figure 7), to undergo oxidation is noteworthy. This behavior is rationalized in terms of slow conformational motion to reach the planar geometry required for ring aromatization due to the presence of meso substituents.60,75

Figure 7. Dihydroporphycene 81. I


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Scheme 14. Optimized Synthesis of Porphycene 2a

Scheme 15. Optimized Synthesis of Porphycenesa

a

Sánchez-Garcı ́a and co-workers.92,93

Scheme 16. Expeditious Synthesis of Meso-Substituted Porphycenes

In 2014, this new methodology was applied by Rana and Panda107 for preparation of octasubstituted porphycenes 94 and 97 (Scheme 17). In particular, β-octamethoxyporphycene (94) was prepared in two steps from pyrrole 92. This precursor was dimerized in the presence of PIFA and TMSBr at −45 °C. The resulting unstable 2,2′-bipyrrole was subjected to Vilsmeier−Haack formylation without any further purification to prevent its decomposition, affording dialdehyde 93 in 39% yield. Finally, McMurry coupling of 93 provided octamethoxyporphycene 94 in 14% yield.

phenyliodine bis(trifluoroacetate) (PIFA) in the presence of a Lewis acid. This methodology affords symmetrically β,β′disubstituted bipyrroles in good yields (61−78%). In contrast, only modest results were obtained with β-monosubstituted pyrroles. Using this chemistry, in 2012, Waluk and co-workers58 developed a synthetic route for meso-substituted porphycenes 91a that relies on preparation of 2,2′-bipyrrole (41a) in one step from pyrrole.106 The reaction furnishes 41a in 78% yield by treatment of pyrrole with PIFA in the presence of bromotrimethylsilane (TMSBr) (Scheme 16). J


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Scheme 17. Syntheses of β-Octamethoxyporphycene 94 and β-Octakis(methylthio)porphycene 97

Scheme 18. Preparation of β-Tetrachlorotetramethoxyporphycenes

unexpectedly failed to dimerize. Interestingly, the use of iron(III) chloride and trifluoroacetic acid (TFA) was found to be the proper choice for this coupling to produce the corresponding bipyrrole 105b, although in poor yield (15%) (Scheme 18). These findings reflect the difficulties in determining a general method for the coupling of pyrroles. 2.2.3. Diversity-Oriented Synthesis: Substituted 2,2′Bipyrroles via Suzuki Couplings. The electronic nature of the groups attached to the starting pyrrole influences the performance of the coupling reaction, in some instances impeding access to functionalized bipyrroles.110 To overcome this lack of robustness in preparation of 2,2′-bipyrroles, in 2006, Borrell and co-workers110 reported a general methodology to

One year later, with the goal of studying third-order nonlinear optical (NLO) properties of selected porphycenes, the same group 108 synthesized β-octakis(methylthio)porphycene 97. The synthetic pathway was adapted from the previous methodology. However, in this preparation, optimization of the oxidative coupling yield led the authors to use BF3·OEt2 as the Lewis acid instead of TMSBr (Scheme 17). Unfortunately, despite the good results in some syntheses, the use of PIFA is dependent on the nature of the substrate. In 2015, during synthesis of β-tetrachlorotetramethoxyporphycenes, Rana and Panda109 found that although coupling of pyrrole 104a under previously optimized conditions (PIFA, BF3·OEt2) provided bipyrrole 105a, the α-free pyrrole 104b K


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Scheme 19. Diversity-Oriented Synthesis of 4,4′-Diaryl-Substituted 2,2′-Bipyrroles

the use of 5,6-diaryldipyrroethenes 111 instead of 5,6diaryldipyrroethanes 109. The advantage of using these olefins is their availability, as they can be readily prepared via McMurry coupling of the corresponding ketones 110. These ketones were synthesized from pyrrole via Friedel−Crafts acylation in the presence of anhydrous AlCl3. Finally, macrocyclization to furnish meso-substituted porphycenes 91 was performed following the previous protocol. The primary advantage of this preparation over the previous method is that it enables the introduction of a wider range of meso substituents (Scheme 21).

prepare chemical libraries of 4,4′-aryl- and heteroarylsubstituted 2,2′-bipyrroles. The strategy is based on synthesis of a stable dibrominated bipyrrole 108, which was utilized as a scaffold ready for substitution with boronic acids via Suzuki coupling. Compound 108, protected with 2-(trimethylsilyl)ethoxy]methyl (SEM), is produced from thienobipyrrole 107 in a two-step synthesis (Scheme 19). In turn, synthesis of 107 entails the condensation of thiophene-2,5-dicarboxaldehyde and ethyl azidoacetate in the presence of sodium methoxide, followed by the Hemetsberger−Knittel reaction.111 This methodology affords bipyrrole 107 in an overall yield of 46% from the aldehyde. Finally, the 4,4′-disubstituted bipyrroles 69 can be used as starting materials for preparation of porphycenes, following the methodology developed by the same group83 (Scheme 11). 2.2.4. Novel Approaches: Macrocyclization by Oxidative Ring Closure. Along with preparation of 2,2′-bipyrroles, the other obstacle to porphycene preparation is the final McMurry coupling, which is difficult to scale up and usually provides the macrocycles in only moderate yields. Considering this problem along with the molecule symmetry, in 2008, Srinivasan and co-workers59 reported the first synthesis of a porphycene by formation of 2,2′-linkages. The synthesis consists of a coupling reaction of 5,6-diaryldipyrroethanes 109 with p-toluenesulfonic acid (p-TSA) as the acid catalyst, followed by oxidation with DDQ. The starting materials can be conveniently prepared from the corresponding benzoin or benzyl derivative (Scheme 20). This straightforward procedure

2.3. Reactivity and Functionalization of Porphycenes

As mentioned, porphycenes can be regarded as aza-[18]annulenes, which satisfy Hückel’s rule for aromatic compounds. Thus, although porphycenes display certain polyene characteristics, as can be inferred, for instance, from their reaction with hydrogen, their reactivity exhibits the main features of benzenoid systems. In particular, porphycenes are susceptible to electrophilic substitution reactions,22 which furnish halogenated, sulfonated, formylated, and nitrated porphycenes. Chemically, porphycenes are relatively stable compounds. However, under certain conditions, they easily undergo oxidative transformations. For instance, the β-positions of one pyrrole ring of the macrocycle can react with H2O2 to initially render a dihydroxylated porphycene and then eventually a mixture of the corresponding 2- and 3-oxoporphycenes.113 The most interesting synthesis of this type of reaction is the dehydroacyloxylation of the meso positions of the macrocycle. This transformation can be performed by use of reagents such as Pb(OAc)4 to provide acetoxy derivatives.114 These transformations, electrophilic substitutions, and oxidative reactions allow the peripheral functionalization of porphycenes, which is a key strategy to customize the chromophore for specific applications. For instance, the introduction of functional groups permits modulation of spectral properties of the macrocycle. Moreover, reactive groups attached to the macrocycles allow the preparation of conjugates. With the same aim, recently, iodinated porphycenes have been used to prepare dyads and triads via palladiumcatalyzed cross-couplings. Alternatively, the classical strategy for preparation of functionalized porphycenes is derivatization of properly functionalized 2,7,12,17-substituted macrocycles such as 2d or 2k. 2.3.1. Hydrogenation. Porphycenes can be selectively hydrogenated with careful selection of the reducing system (Scheme 22). For instance, when the parent macrocycle 2a is treated with sodium in an alcohol solvent, hydrogenation occurs at the meso positions (112). In contrast, exposure of the same porphycene to hydrogen in the presence of a palladium catalyst furnishes the chlorin-like 2,3-dihydroporphycene (113a) in 80−90% yield.115

Scheme 20. Synthesis of meso-Porphycenes 91a,ba

a

Srinivasan and co-workers.59

provides easy access to meso-substituted aromatic porphycenes in three steps from commercially available reagents. The macrocyclization yield is low, ranging from 3% to 5%. However, in contrast to the McMurry coupling, this reaction is theoretically easy to perform and to scale up. In 2014, the synthesis of 9,10,19,20-tetraarylporphycenes was refined by modifying the preparation of the precursors. The procedure, reported by Ravikanth and co-workers,112 suggests L


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Scheme 21. General Synthesis of meso-Porphycenes 91

Scheme 22. Reduction of Porphycenes

halogen22,117,118 or via halogenating reagents.22,117 In the case of bromination, the reaction can be achieved by use of either bromine22,117 or N-bromosuccinimide (NBS).22 The regioselectivity of this transformation depends on the substitution pattern of the substrate. For instance, the parent macrocycle (2a) is brominated exclusively at position 2 with NBS.22 In contrast, 2,7,12,17-substituted porphycenes undergo bromination at the remaining unsubstituted β-pyrrolic positions.117 Selective polybromination of n-(tetrapropyl)porphycene (2b) was achieved in 2008 by Hisaeda and co-workers.119 To this end, 2b was exposed to increasing stoichiometric amounts of bromine in CCl4 at room temperature. Careful control of the stoichiometry and reaction time led to isolation of pure mono-, di-, tri-, and tetrabrominated porphycenes 114−117 (Figure 8). The properties of brominated porphycenes as singlet oxygen sensitizers have been studied in detail by Hisaeda and co-

The outcome of the reduction reaction depends on the substitution pattern of the substrate. In 2012, Hisaeda and coworkers116 attempted the hydrogenation of tetrapropylsubstituted porphycene 2b in the presence of Pd/C. Contrary to experiments with porphycene (2a), the reduction was unsuccessful. The authors argue that this outcome was probably due to the steric bulk of the β-substituents. However, when the reducing agent was Zn powder in a HCl(aq)/CH2Cl2 mixture (113b), the hydrogenation was successful, occurring at one of the four pyrrole rings of the macrocycle (Scheme 22). Interestingly, under the same experimental conditions (Zn/ HCl), 5,10,15,20-tetraphenylporphyrin and 2,3,7,8,12,13,17,18octaethylporphyrin do not undergo hydrogenation, suggesting that the lower energy of the lowest unoccupied molecular orbital (LUMO) in porphycenes explains their facile reduction. 2.3.2. Reactivity of Porphycenes with Electrophiles: Halogenation, Sulfonylation, Formylation, and Nitration. Due to the aromatic characteristics of porphycene, the macrocycle is amenable to SEAr-type reactions such as halogenation, sulfonylation, Vilsmeier−Haack formylation, and nitration. From a practical perspective, the installation of these functionalities leads to direct derivatization of porphycenes or it introduces a method to convert these functionalities into more reactive groups; this is the case when nitro groups are transformed into amines. 2.3.2.1. Halogenation. Halogenation of porphycenes can be accomplished by treatment of the macrocycle with the

Figure 8. Bromination of porphycene 2b. M


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workers.119 Surprisingly, no reports describe the synthetic applications of these compounds. An interesting exception to this observation is the macrocyclic framework contraction of porphycene 117 to yield isocorrole 118 under basic conditions117 (Scheme 23).

pyrrolic positions122 (Figure 10). The sodium salts of monoand trisulfonated porphycenes 122 and 123 were easily isolated

Scheme 23. Preparation of Isocorrole 118

Figure 10. Structures of sulfonated porphycenes 122 and 123.

from this mixture by an efficient liquid−liquid extraction procedure in 3% and 40% yield, respectively. Unfortunately, disulfonated porphycenes were obtained as an inseparable mixture of isomers. As anticipated, introduction of the sulfonic functionality imparts water solubility to the macrocycles; in addition, the Qbands are red-shifted. These features make these derivatives attractive for biomedical applications. An alternative method to prepare sulfonated porphycenes is a two-step transformation involving treatment of the macrocycle with chlorosulfonic acid to render the corresponding sulfonyl chloride derivative, followed by hydrolysis in a water/pyridine mixture.123 Note that because of its reactivity toward amines, 3chlorosulfonyl porphycene 124 has emerged as a versatile intermediate for the synthesis of 3-substituted sulfonamides (Scheme 24). Exposure of porphycene 124 to appropriately substituted amines has allowed straightforward synthesis of functionalized porphycenes 125 and 127 in excellent yields. These compounds have been applied in immobilization of porphycenes on silica films124 and preparation of soluble sensitizers in ionic liquids,125 respectively. 2.3.2.3. Vilsmeier−Haack Formylation. The Vilsmeier− Haack formylation of porphycene can be performed by treatment of the nickel complex of the macrocycle with phosphorus oxychloride in DMF, followed by hydrolysis33,113 (Scheme 25). The formyl derivative 129 can participate in Wittig olefinations to afford the corresponding α,β-unsaturated esters. An example of an application is the synthesis of benzochloracenes126 11 (Figure 5). Analogously, exposure of the nickel complex of 2b to 3-dimethylaminoacrolein (DMAA) in the presence of POCl3 renders a mixture of vinylogous aldehydes 130 and 131 in 15% and 23% yield, respectively. Interestingly, in this case, the reaction is not regioselective, and both the meso- and β-substituted isomers are obtained. Knoevenagel reaction of these porphycenes with malonic acid affords access to their corresponding diacids. These latter compounds have been used for the preparation of dyesensitized solar cells.127 2.3.2.4. Nitration and Related Transformations. In contrast to the preceding reactions, nitration of porphycene does not affect the β-positions of the macrocycle but affords the mesosubstituted derivatives. Introduction of the nitro group can be performed by direct treatment with fuming nitric acid.22 Alternatively, the use of an AgNO3/acetic acid22 system offers a safer methodology and provides similar results. In 2011, Sánchez-Garcı ́a and co-workers128 studied this reaction in detail with the aim of optimizing the production of mononitrated porphycene 132c (Scheme 26). Under all conditions tested, it was observed that, along with the 9-nitro

Similarly, iodination of 2,7,12,17-substituted porphycenes can be performed by exposing the macrocycle to I2, yielding the corresponding 3-iodoporphycene22 119b (Figure 9). Introduc-

Figure 9. Iodinated porphycenes.

tion of more than one iodine atom has been achieved with the use of N-iodosuccinimide (NIS). To explore the phosphorescence properties of porphycenes, Waluk and co-workers58 prepared 3,13-diiodoporphycene 120e by reacting 2,7,12,17tetra-tert-butylporphycene with NIS. Interestingly, in the course of their investigations, the researchers noticed the presence of a mixed iodobromo derivative 121e in the crude reaction mixture, presumably because of contamination of the NIS reagent with NBS.58 In 2014, Yamada and co-workers120 optimized the iodination reaction with the aid of additives such as TFA and silica gel, which are well-known activators of this type of reaction. The best yield of monoiodoporphycene 119j (66%) was obtained with TFA as an activator and 1.1 equiv of NIS, whereas use of 2.5 equiv of NIS and silica gel as additive afforded 3,13diiodoporphycene 120j in 54% yield. Interestingly, the iodination is regioselective, as the 3,16-iodo isomer was present in less than 13% yield. Addition of excess NIS did not provide higher iodinated products (tri- and tetraiodinated porphycenes), probably because of the steric hindrance imposed by the iodine atoms attached to the macrocycle (Figure 9). 2.3.2.2. Sulfonylation. Introduction of the sulfonic acid functionality is a straightforward and attractive procedure to prepare water-soluble derivatives of porphyrinoids.121 When porphycene 2b was exposed to fuming sulfuric acid (oleum), the macrocycle underwent electrophilic substitution, yielding a complex mixture of porphycenes bearing sulfonic groups at the N


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Scheme 24. Applications of Porphycene with Substituted Sulfonamides

Scheme 25. Formylation of Porphycenes

Scheme 26. Nitration of Porphycene 2c

this reduction, such as hydrazine monohydrate22 and Raney nickel and SnCl2·2H2O.131 However, the most common method is the Zinin reduction.22 This reaction is performed in a biphasic DCM/NaOH(aq) system with a sodium dithionite reductant. Note that 9-aminoporphycenes are relatively unstable, especially in solution. Therefore, the crude porphycene is commonly used without further purification. These 9-aminoporphycenes are key intermediates for the formation of amides by reaction with acid chlorides. The intrinsic robustness of the amide bond is ideal for use as a linker

derivative, the reaction furnished a complex mixture of polynitrated porphycenes. In this work, the mixture of dinitrated porphycenes 133 and 134 was separated from the mononitrated and higher nitrated porphycenes by column chromatography. Careful fractional crystallization allowed the isolation of regioisomers 133 and 134. Compared with other available methods to functionalize porphycene, nitration is arguably the most versatile,22,29,114,129,130 primarily because 9-nitroporphycenes can be readily transformed into the corresponding 9-amino derivatives.22 Several reagents have been described to perform O


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Scheme 27. Reduction of 9-Nitroporphycenes 132 and Their Conversion into Amides

Scheme 28. Reactivity of 9-Isothiocyanate Porphycene 140

Scheme 29. Structure of 9-Hydroxyporphycene 145 and Ferrocene−Porphycene Dyads 146 and 147

in the synthesis of conjugates with cationic polymers132 (138), antibodies133 (139), or graphene134 (136) (Scheme 27). In the context of biomedicine, an alternative functionality suitable for conjugation is the isothiocyanate group. The selective reaction of isothiocyanates with primary amines permits the attachment of chromophores to biomolecules through a strong thiourea linkage. The application of this chemistry to porphyrinoids has been demonstrated in the preparation of porphyrin,135,136 chlorin,136 and bacteriochlorin136 bioconjugates. Considering this application, the introduction of the isothiocyanate group into the porphycene ring can be accomplished by treatment of 9-aminoporphycene 135c with 1,1′-thiocarbonyldi-2(1H)-pyridone137 (TCP). Following this procedure, the isothiocyanate derivative 140 was obtained in good yield. Moreover, as anticipated, these compounds reacted with alkyl and aryl primary amines to afford the corresponding thioureas 142. Although the 9-thioureas were expected to be stable compounds, Nonell and co-workers138 found that these compounds underwent spontaneous internal cyclization to afford thiazole-fused porphycenes 143 (Scheme 28). It is hypothesized that this cyclization is due to nucleophilic attack of the sulfur atom on the adjacent meso

carbon of the macrocycle. Strikingly, neither porphyrin nor phthalocyanine analogues exhibit this behavior. The authors suggested that this process is particularly favored in porphycenes due to their lower gap between the highest occupied molecular orbital (HOMO) and LUMO, compared with those of more symmetrical macrocycles, such as porphyrins. 2.3.3. Acetoxylation and Hydroxylation. Another reaction that occurs selectively at the meso positions of porphycenes is acetoxylation (dehydroacyloxylation).22 This transformation is performed with the aid of a Pb(IV) salt, usually PbO2, in the presence of a carboxylic acid or Pb(OAc)4. The combination of PbO2 and a carboxylic acid affords access to the preparation of esters of the corresponding acid, and the Pb(OAc)4 reagent installs the acetoxy group. In terms of synthesis, the latter transformation is versatile because treatment of the substituted macrocycle with sodium methoxide furnishes the corresponding 9-hydroxyporphycene 145 in good yields.139 Then the hydroxyl group can be easily transformed into ethers114,140 and esters114,130,140 such as ferrocene−porphycene dyads141 146 and 147 (Scheme 29). P


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As with nitration, acetoxylation is highly regioselective, giving the derivative at position 9 as a major product. Hisaeda and coworkers142 have examined this reaction using excess Pb(OAc)4 and prolonged reaction times. Under these conditions, all possible meso-acetoxylated compounds were obtained. Pure products were separated from the reaction mixture by column chromatography, with the exception of disubstituted porphycenes 149 and 150. Interestingly, isomer 148, containing two acetoxy groups at adjacent positions 9 and 10, was isolated in relatively good yield (8%) (Figure 11).

prepared a series of porphycene−diketopyrrolopyrrole conjugates using iodoporphycenes as starting materials. In the first step of the synthesis, monoiodoporphycene 119j and diiodoporphycene 120j were reacted with trimethyl[(tributylstannyl)ethynyl]silane under Stille conditions to give the corresponding coupling products in 89% and 88% yield, respectively. The trimethylsilyl groups (TMS) were removed by treatment with tetrabutylammonium fluoride (TBAF). Subsequently, ethynyl porphycenes 157 and 159 were coupled with the corresponding mono- and dibrominated diketopyrrolopyrroles via Sonogashira coupling to provide conjugates 158 and 160 in moderate yields. In an analogous manner, triad 161 was prepared by coupling of monoethynyl porphycene 119j with the corresponding dibrominated diketopyrrolopyrrole (DPP) derivative in 52% yield (Scheme 31). From the same monoiodoporphycene 119j as a precursor, porphycene dyads143 162 and 163 with acetylene spacers were synthesized. Preparation of 162 involves the Sonogashira coupling of monoiodoporphycene 119j with acetylene derivative 157 (Scheme 31) using bis(triphenylphosphine)palladium(II) as a catalyst in the presence of copper iodide and a base. Dyad 162 was obtained in 45% yield. To prepare 163, terminal acetylene 157 was dimerized via Glaser−Hay coupling in the presence of CuI and tetraethylethylenediamine (TMDA). This reaction furnished dimer 163 in 72% yield (Scheme 32). 2.3.5. Functionalization of Positions 2, 7, 12, and 17. With the aim of preparing functional dyes for biological applications, Vogel et al.129 prepared tetra(β-methoxyethyl)substituted144 porphycene 2d as a building block. The methoxy moiety was carefully chosen; this group enhances the solubility of the macrocycle in organic solvent and is inert under all reaction conditions in the classical synthesis. However, its exposure to stoichiometric amounts of a Lewis acid such as BBr3 readily provides the mono- (164), di-, and trihydroxyl derivatives (Scheme 33). An application of this chemistry is the preparation of conjugates. For instance, the porphycene−sugar derivative129 168 is obtained by treatment of alcohol 164 with AgCO3, followed by exposure to 2,3,4,6-tetra-O-acetyl-α-Dgalactopyranosyl bromide and deprotection with NaOMe. Another example is the synthesis of porphycene−DNA

Figure 11. Preparation of polyacetoxy porphycenes.

In 2013, the same group reported the first mixed functionalization of porphycenes.131 This methodology enables the preparation of porphycenes containing nitro and acetoxy groups. To this end, two different synthetic routes that differ only in the order of the reactions have been proposed. In the first strategy, acetoxylation was achieved on 9-nitroporphycene 132b. This treatment gave a 1:1 mixture of regioisomers, inseparable by recrystallization or flash chromatography. In contrast, when 9-acetoxyporphycene 144 was nitrated, only 9acetoxy-19-nitroporphycene 153 was isolated in 66% yield. Subsequent reduction of 9-acetoxy-19-nitroporphycene 153 with SnCl2·2H2O provided the aminated porphycene 154 in good yield (63%) (Scheme 30). 2.3.4. Palladium Cross-Coupling Reactions. Halogenated porphycenes were among the first porphycene derivatives to be prepared. However, although these compounds are potentially endowed with a rich chemistry, especially organometallic transformations, only a few reports have focused on this aspect. The first communication on the use of halogenated porphycenes participating in a Pd-mediated reaction was published in 2014. In this report, Yamada and co-workers120 Scheme 30. Bifunctionalization of Porphycenes

Q


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Scheme 31. Syntheses of DPP−Porphycene Dyads and Triads via Pd-Mediated Couplings

Scheme 32. Preparation of Porphycene Dimers 162 and 163

conjugate145 170 due to formation of a phosphodiester linker

ing activated porphycene 165, which can be converted into a variety of functionalized macrocycles129 (166 and 167). Another interesting synthetic application of porphycene 2d is its conversion into the brominated derivative 169. In the

with the alcohol group of 164. Furthermore, acylation of 164 with methanosulfonyl chloride (MsCl) renders the correspondR


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Scheme 33. Functionalization of Positions 2, 7, 12, and 17

Scheme 34. Synthesis of Tricationic Porphycenes

intermediate was treated with HBr in acetic acid and then

presence of B(OH)3, acidic cleavage of the methoxy group of the nickel(II) complex of 2d provided the corresponding brominated derivative 169 after demetalation. These derivatives undergo elimination in the presence of a strong base (DBU) to furnish vinyl-substituted porphycenes129,144 (see Scheme 44). Considering Vogel’s building block 2d and studies by Jux146 on porphyrin functionalization, in 2010, Sánchez-Garcı ́a, Nonell, and co-workers147 synthesized cationic porphycenes 172 and 173 (Scheme 34) starting from tetra(methoxymethylphenyl)porphycene 2k (Scheme 15). The objective of the project was the preparation of tricationic photosensitizers for antimicrobial PDT. The envisioned synthetic route involved the selective substitution of methoxy groups at the benzylic positions by bromine atoms. Thus, treatment of 2k with HBr afforded a mixture of brominated porphycenes. Porphycene 171 was isolated from the crude reaction mixture by silica-gel column chromatography, with a yield of 10%. Subsequently, this compound was dissolved in pyridine147 or a solution of NMe3148 in ethanol, and the mixture was heated at 80 °C. Tricationic porphycene 172 or 173 was recovered by centrifugation in 85% or 84% yield, respectively (Scheme 34). The same methodology of functionalization was applied in the preparation of an octacationic porphycene, 175, by Jux and co-workers.149 Analogous to the procedure delineated in Scheme 34, the corresponding octamethoxylated porphycene

reacted with tert-butylpyridine in toluene under reflux to afford porphycene 175 in 61% yield (two steps) (Figure 12).

Figure 12. Structure of octacationic porphycene 175. S


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2.4. Extended and Expanded Porphycenes

structure 176 (Figure 13), three different types of extended porphycenes can be conceived. The first group encompasses porphycenes containing extended linkages at the meso positions. The synthesis of these macrocycles requires the insertion of two sp2-hybridized carbons at the meso positions of the macrocycle. This insertion can be accomplished by McMurry coupling of the corresponding vinylogous aldehydes. This general strategy allows the preparation of macrocycles10 179 and 181 (Scheme 35).

Elongation of the electronic pathway of the macrocycle by incorporating unsaturated fragments, namely, olefins, alkynes, or aromatic rings, gives rise to a broad family of extended and expanded porphycenes. From a structural and synthetic perspective, this group of porphyrinoids can be divided into two families: extended porphycenes 176 and benzoporphycenes 177 (Figure 13).

Scheme 35. Synthesis of Extended Porphycenes 179 and 181

Figure 13. General structures of extended porphycenes and different types of benzoporphycenes.

Extended porphycenes result from the insertion of an even number of sp- or sp2-hybridized carbons or heterocyclic rings into the connecting positions of the pyrroles. Therefore, two different families of macrocycles can be envisioned: porphycenes with extended linkages at the meso positions or those with linkages at the interpyrrolic positions. The insertion of sp 2 -hybridized carbon atoms with concomitant cyclization gives rise to benzoporphycenes.150 Depending on how the benzene ring is fused to the macrocyclic framework, five types of benzoporphycenes can be devised (Figure 13). The first member of this family of porphycenes is type I. Preparation of these porphycenes was reported by Vogel10 in 1993. The key structural feature of these macrocycles is the linkage between the internal β-carbons of each bipyrrole with an ethylene bridge, giving rise to a benzene ring. A closely related family is type II, the naphthoporphycenes. Synthesis of these macrocycles was reported in 2010 by Sessler and co-workers;151 these molecules are generated by addition of a benzene ring to the fused benzo group of type I structures. When fusion of the benzo group occurs at the meso positions, type III macrocycles are produced.152 Type IV was first explored by Richert et al.144 in 1994. Later, the synthesis of symmetrical derivatives was presented by Kobayashi and coworkers. 72 In this family of structures, benzene 72 or naphthalene153 rings are fused with pyrroles at β-positions. Finally, type V is an interesting family of macrocycles that were prepared by Kisters113 from the Vogel group in 1995; they are referred to in the literature as benzochloroacenes (i.e., 11) (Figure 5).33,126 These molecules can be prepared by cationic cyclization of properly functionalized meso-substituted porphycenes. 2.4.1. Synthesis of Extended Porphycenes. The extension of the (4n + 2) π-electron conjugated pathway of porphycenes leads to chromophores that exhibit bathochromic shifts in their absorption spectra compared to the regular macrocycle.6,154 This differential feature endows these macrocycles with interesting properties for biomedical applications.155 2.4.1.1. Extended Porphycenes Containing Extended Linkages at the Meso Positions. According to the general

2.4.1.2. Extended Porphycenes Containing Extended Linkages at Interpyrrolic Positions. The second family of extended porphycenes requires the preparation of bis(pyrroles) linked by one (184) or two alkyne units (186). The general outline for synthesis of the precursors was reported by Vogel and co-workers156 in 1990 and refined by Kim and coworkers157 and Vicente and co-workers.158 More recently, in 2015, this methodology was adapted by Kim, Panda, and coworkers159 to prepare the β-octamethoxy-substituted 22π and 26π extended porphycenes 185f and 187f. The synthetic pathway starts with a Sonogashira coupling of iodopyrroles 63f and (trimethylsilyl)acetylene. After elimination of the silyl group, the acetylene-substituted pyrrole can be coupled with the iodopyrrole precursor by the same Pd-mediated reaction. When the longer congener is desired, pyrrole 183f can be dimerized by a Glaser−Hay coupling protocol (Scheme 36). Extended porphycenes 185 underwent hydrogenation with H2 gas in the presence of a palladium catalyst to yield the corresponding [22]porphyrin-(2,2,2,2) 9. The original method, reported by Vogel et al.,32 required the use of Lindlar’s catalyst. The yield of porphycene 9e was 35%. In 2015, Kim, Panda, and co-workers159 revisited the reaction and increased the yield by replacing Lindlar’s catalyst with Pd/C (84%). In the same report, the authors highlighted different rates of absorption of H2 by the substrates. Porphycene 185e is reduced in 20 h, whereas approximately 48 h is required for the octamethoxy analogue 185f. Alternatively, the same compounds can be prepared by reductive coupling of dialdehydes 188, although in very low yields159 (Scheme 37). A direct synthesis of the related N-methylated stretched porphycene 192 was envisioned by Rodriguez-Val160 from the Vogel group. In this approach, the macrocyclization was T


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Scheme 36. Optimized Synthetic Pathway for Preparation of Acetylene−Cumulene Porphycenesa

a

Kim, Panda, and co-workers.159

Scheme 37. Preparation of [22]Porphyrin-(2,2,2,2) and Its Tetramethylated Congener

Scheme 38. Retrosynthetic Analysis of 193

achieved by subjecting dialdehyde 190 to McMurry coupling conditions. The resulting macrocycle 191 was obtained in 12% yield (Scheme 37).

Insertion of one or two heterocyclic units (pyrrole, thiophene, or furan) into the macrocyclic framework gives rise to the third type of extended porphycene. This class of U


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macrocycles encompasses two different extended porphycenes named ozaphyrin161 and bronzaphyrin.86,162 The synthesis of these porphyrinoids affords access to terpyrroles and their analogues. The common precursor of this family of compounds is a bis(pyrrole) 1,4-diketone 194, which is transformed into oligopyrroles 193 as a result of the Paal−Knorr reaction (Scheme 38). The first member of this family of macrocycles, ozaphyrin (197a), was prepared in 1993 by Ibers and co-workers.161 The synthesis was based on McMurry coupling of an equimolar mixture of bipyrrole 31b and 2,5-bis(5-formyl-4-propyl-2pyrrolyl)furan (196a). Macrocycle 197a was obtained in 5% yield. According to 1H NMR and UV−vis spectroscopy, ozaphyrin 197a displays aromatic characteristics. The green color of its chloroform solutions inspired the name ozaphyrin, after the Emerald City of Oz. Similarly, the thiophenecontaining analogue 197b was prepared by the same authors in 1994163 (Scheme 39).

Scheme 40. Synthesis of Benzoporphycene 10

2.4.2.2. Benzoporphycenes Type II. The use of naphthobipyrroles 207 instead of benzobipyrroles 201 gives rise to a related family of porphyrinoids known as naphthoporphycenes (Scheme 41). This type of porphycene was first reported in 2010 by Sessler and co-workers.151 Preparation of the required bipyrrole 205 entails a three-step synthesis. The first step is formation of α-keto ester 203 by reaction of diethyl oxalate (202) with a Grignard reagent. This intermediate adds flexibility to the synthesis, allowing the introduction of a wide range of substituents (R) at the β-positions of bipyrrole 205. The role of these substituents R is manifold: they improve the solubility of the intermediates and the final macrocycle and, importantly, block the β-positions, directing formylation toward the α-carbons. Due to the bis(indole) characteristics of bipyrrole 206, the formylation would normally occur at the β-positions. Next, the reaction of ethyl α-oxocarboxylates with 2,3-naphthalene bis(hydrazine) gave the corresponding bis(hydrazones) 204 in very good yield. Thermal cyclization of the bis(hydrazones) 204 in refluxing ethanol under acidic conditions led to their conversion to the corresponding diethyl 3,8-dialkyl-1,10-dihydrobenzo[e]pyrrolo[3,2-g]indole-2,9-dicarboxylate derivatives 205. From a mechanistic perspective, this process can be defined as a double Fisher indole synthesis. Once these compounds were in hand, diester 205 was saponified and decarboxylated to yield α-free bipyrrole 206. Introduction of the formyl groups was achieved via the Vilsmeier−Haack reaction. Subsequently, McMurry coupling of dialdehyde 207 provided a yellow-green solution that was assumed to be the corresponding dihydroporphycene. As for benzoporphycene 10, treatment of the reduced species with DDQ produced a deep blue solution. This coloration was ascribed to the presence of porphycene 208 (Scheme 41). In 2011, Panda and co-workers166 reported the preparation of tetraalkyl-substituted dinaphthoporphycenes via an essentially equivalent synthetic pathway to study the nonlinear optical properties of these macrocycles. 2.4.2.3. Benzoporphycenes Type III. The first example of benzoporphycene type III was prepared unexpectedly152 by spontaneous electrocyclization of the extended porphycene 209. The putative intermediate was not isolated. However, upon heating in refluxing benzene for 2 days, porphycene 210b, bearing a benzo group fused to the meso carbons, was obtained. Although the synthetic procedure is straightforward, the overall yield is very low (only 0.7% based on 178) (Scheme 42). In 2015, to gain insight into the properties of this family of benzoporphycenes, Hayashi and co-workers167 reported a more efficient synthetic approach to facilitate their availability (Scheme 43). The envisioned methodology relies on the synthesis of key compound 214, which can be prepared in three steps. First, the commercially available Boc-protected pyrrole was dimerized under oxidative conditions to give bipyrrole 212 in 65% yield. Monoborylation of the α-position of bipyrrole 212 was performed by deprotonation with lithium tetrame-

Scheme 39. Synthesis of Ozaphyrins 197

Along with thioozaphyrin 197b, the crude reaction mixture of McMurry coupling between bipyrrole 31b and 196b contained the corresponding homocoupled products: porphycene 2b and a 26π aromatic hexaphyrin termed bronzaphyrin163 (198). In subsequent years, Johnson86 prepared analogues of bronzaphyrin, 199 and 200. Interestingly, the difuran (X = Y = O), furan−pyrrole (X = O, Y = NH), and dipyrrole (X = Y = NH) congeners have not been reported in the literature (Figure 14).

Figure 14. General structure of bronzaphyrins.

2.4.2. Syntheses of Benzoporphycenes. 2.4.2.1. Benzoporphycenes Type I. The synthesis of benzoporphycenes dates back to 1993 when Vogel10 synthesized benzoporphycene 10 (type I), which was prepared via McMurry coupling of benzopyrrole 201. The parent benzopyrrole precursor164 is accessible following a two-step procedure reported by Sannicolò and co-workers165 in 1987. Note that this cyclization renders a nonaromatic macrocycle; only after treatment with DDQ is the aromatic benzoporphycene produced (Scheme 40). V


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Scheme 41. Scheme for Synthesis of Naphthoporphycenes 208

Scheme 42. Synthesis of meso-Benzoporphycene 210b

monobenzoporphycene 222. The synthetic strategy exploits the availability of tetramethoxy-substituted porphycene 2d and, particularly, its nickel(II) complex. As has been shown, this complex can be readily converted into the monobrominated derivative 169 by selective bromination with a Lewis acid followed by demetalation (Scheme 33). The resulting monobromo derivative 169 was treated with DBU to yield the vinyl-substituted porphycene 220. Finally, introduction of the benzo group was achieved via a Diels−Alder cycloaddition of 220 and dimethyl acetylenedicarboxylate (DMAD) (221) (Scheme 44). In 2009, inspired by the symmetrical structure of benzoporphyrins and phthalocyanines, Kobayashi and coworkers72 reported a systematic methodology to prepare porphycenes 233, which contain four isoindole rings (Scheme 45). The synthetic scheme follows the principles of the classical synthesis of etioporphycenes. However, the isoindole units are uniquely masked as heterocyclic Diels−Alder adducts. In the last step, the masking group is released by high-temperature heating (retro-Diels−Alder reaction).

thylpiperidide (LTMP), followed by exposure to B(OEt)3 and hydrolysis. In the next step, a double Suzuki coupling afforded bis(bipyrrole) 214 in 82% yield. Formylation of this intermediate and removal of the Boc groups provided dialdehyde 216. McMurry coupling of aldehyde 216 furnished benzoporphycene 210a in 48% yield. Using the straightforward synthesis of bis(bipyrrole) 214, the same group envisaged a strategy for preparation of benzoporphycene 219. The synthetic pathway relies on the ring closure used by Dietrich152 from the Vogel group in the synthesis of 210b, but with bis(bipyrrole) 217 as starting material. According to this plan, thermal Boc removal from 214 rendered 217, which was transformed into dialdehyde 218 via a vinylogous Vilsmeier−Haack reaction. Finally, McMurry coupling of dialdehyde 218, followed by exposure to pchloranil, afforded dibenzoporphycene 219 in 20% yield (Scheme 43). 2.4.2.4. Benzoporphycenes Type IV. Installation of benzo groups at the β-position of pyrrole furnishes porphycenes that formally contain isoindole units. The first example of this type of macrocycle, presented in 1994 by Richert et al.,144 was W


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Scheme 43. Synthetic Pathways for meso-Benzoporphycene 210a and meso-Dibenzoporphycene 219

Scheme 44. Preparation of Monobenzoporphycene 222

exposure of the α,α′-free pyrrole 237 to PIFA in the presence of TMSBr in 47% yield. Compared to Kobayashi’s route, this new procedure shortens the preparation of bipyrrole 230 to three synthetic steps. Next, Vilsmeier−Haack acylation was used to install an aromatic ketone at the α,α′-free positions of bipyrrole 230. Finally, diketone 238 was reacted under McMurry conditions with dialdehyde 31b. Interestingly, 2,7,12,17-tetra-n-propylporphycene (2b) was the main product of the coupling (23%), whereas the symmetrical annulated porphycene was not present in the crude reaction. The only annulated porphycene was 239, obtained in a modest 0.5% yield. As expected, the retro-Diels−Alder reaction, performed by heating 239 at 205 °C in vacuo, afforded benzoporphycene 240 in high yield (Scheme 46). In 2011, Yamada and co-workers153 extended Kobayashi’s strategy for preparation of benzoporphycenes 233 (Scheme 45) to synthesis of naphthoporphycenes 250 (Scheme 47). The key compound of the synthetic plan was bipyrrole 246. This intermediate was synthesized via Ullmann coupling of the corresponding protected iodopyrrole 245, which was prepared by treatment of 243 with the iodinating reagent BTMA·ICl2, followed by exposure to Boc2O. The preparation of pyrrole 243 is another example of the versatility of the Barton−Zard reaction. In this case, pyrrole 243 was synthesized from sulfone

The starting pyrrole 225 was prepared168 via Barton−Zard reaction from the condensation of ethyl isocyanoacetate with Diels−Alder adduct 224 in 82% yield. Iodination169 of pyrrole ester 225 was achieved by treatment with benzyltrimethylammonium dichloroiodate (BTMA·ICl2). Unexpectedly, Ullmann coupling of 226 did not give bipyrrole 229 but instead primarily afforded the corresponding N−C coupling product. To prevent this coupling, the NH moiety of iodopyrrole 226 was blocked with a Boc group. When protected 227 was used as the starting material, bipyrrole 228 was obtained in 55% yield. After the Boc groups were removed, bipyrrole 229 was saponified169 and decarboxylated to produce α,α′-free bipyrrole 230. Vilsmeier− Haack acylation of bipyrrole 230 afforded 231a−c in 90−97% yield.72,75 Finally, porphycenes fused with four bicyclo[2.2.2]octadiene (BCOD) units 232 were obtained by reductive coupling of 231a−c. The last step of the synthesis was thermal treatment of the macrocycles to quantitatively produce benzoporphycenes 233a−c (Scheme 45). In 2015, Brenner and Jux170 used PIFA-mediated coupling of pyrroles105 to synthesize 2,2′-bipyrrole 230. To implement this new methodology, pyrrole 237, selected as the starting material, is available from propargylic bromide in three steps according to a method reported by Jeong et al.171 in 2012. The key molecule in the synthesis is bipyrrole 230, prepared by X


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Scheme 45. Synthesis of Benzoporphycenes 233

Scheme 46. Simplified Synthesis of Benzoporphycenesa

a

Brenner and Jux.170

242 in 91% yield.172 The required sulfone 242 was prepared in three steps from olefin 241. A convenient method173 to obtain

241 is composed of three steps starting from commercially available 1,4-benzoquinone in an overall yield of 35%. Y


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Scheme 47. Synthesis of Naphthoporphycene 250

report on porphycenes. In this report, Vogel et al.34 communicated the preparation of the first oxygen-containing porphycene analogue, the tetraoxaporphycene dication. Since then, many porphycene analogues have been prepared (Table 3).

Saponification, decarboxylation, and formylation via the Vilsmeier−Haack reaction of 246 gave dialdehyde 248 in excellent yield. McMurry coupling of dialdehyde 248 furnished macrocycle 249 in 10% yield. Finally, thermal treatment of 249 quantitatively afforded naphthoporphycene 250 by a retroDiels−Alder reaction. The synthetic accessibility of bipyrroles 230 and 247 has allowed the preparation of mixed systems that combine some of the substitution patterns possible in porphycenes. These new porphycenes expand the chemical space of porphycenes available for exploration75,153 (Figure 15).

Table 3. Synthesis of Porphycene Heteroanalogues Containing Furan and Thiophene

Figure 15. Miscellaneous mixed benzo- and naphthoporphycenes.

2.5. Porphycene Heteroanalogues

With some exceptions,38 almost all the analogues prepared are unsubstituted macrocycles. The general synthetic pathway follows the main principles of Vogel’s synthesis of porphycenes and is predicated on the McMurry coupling of the proper dialdehydes. The experimental details for each family of compounds have been reviewed.21

The conception of porphycenes as bridged [18]annulenes encouraged the preparation of porphycene analogues constructed by the substitution of nitrogen and carbon atoms with other heteroatoms.34−37,39 This novel family of compounds is termed porphycene heteroanalogues.6 The first example of this type of macrocycle was reported in 1988, not long after the first Z


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(257). The latter compound, which is not stable, was coupled directly with 5-bromothiophene-2-carboxaldehyde (258) with the aid of Pd(PPh3)4 to furnish dialdehyde 259 in 37% yield from bifuran 256. Finally, macrocycle 260 was synthesized by heating dialdehyde 259 in the presence of the low-valent titanium reagent (McMurry reaction) in 18% yield. Interestingly, the same group reported an attempted synthesis of benzo[i]21,24-dioxa-22,24-dithiaporphycene 261. Unfortunately, the failure of Suzuki coupling between o-diiodobenzene and 2-thiopheneboronic acid precluded preparation of the required starting material. The substitution of pyrroles in the porphycene framework by thiazole42,174 and imidazole40,41 rings leads to a different class of porphycene heteroanalogues containing heteroatoms at the periphery of the macrocycle (Table 4). The first members of this family of compounds, 20 and 21, were reported by Neidlein and co-workers in 2000.174 The structure of these macrocycles results from the formal substitution of two pyrrole rings with two thiazole units. The synthesis is based on McMurry coupling of the proper dialdehyde. The corresponding macrocycles were isolated in 2−18% yield, depending on the nature of the substitution. Oxidation with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) provided the aromatic porphycene analogue. A similar approach was used to prepare 22, which contains four triazole units.42 Despite its structural similarity to 20 and 21, the macrocycle resulting from the McMurry coupling could not be oxidized to give the aromatic porphycene. Interestingly, the trimeric species 20bt and 22t were isolated from the crude reaction mixture of reductive dimerization of 20b and 22, although in low yields. In 2003, the synthesis of tetraazaporphycenes or imidacenes 23 was reported independently by the groups of Allen, Sessler, and co-workers41 and Teixidó and co-workers.40 The name “imidacene” refers to the fact that all four pyrrole units of the porphycene have been replaced by imidazole rings. Although the two proposed syntheses are conceptually different, both preparations converge to provide the required substituted 1H,1H′-[2,2′-biimidazole]-5−5′-dicarbaldehydes, which are the starting materials for the macrocyclization. McMurry coupling of these aldehydes rendered the corresponding dihydrotetraazaporphycenes as yellow powders. The latter compounds were oxidized by treatment with iodine or DDQ to give the acidlabile green macrocycles 23.

Table 3 reveals that the coupling of unsymmetrical biaryls renders one of the possible isomers in higher yield than the other. This is the case, for instance, for 17 and 18. The authors rationalized this result in terms of steric interaction between the heteroatoms of the rings after the first coupling of the aldehydes (i.e., furan−furan coupling is favored over furan− thiophene coupling).35 To elucidate the factors that affect the outcome of mixed couplings, in 2015, Bebbington and co-workers36 studied the reductive cross-coupling of biheteroaryl dialdehydes, such as 253 and 254, with bipyrrolic dialdehydes. Interestingly, only homodimers were obtained. Computational calculations performed by the authors suggested that more electron-rich heterocycles were more difficult to reduce. This observation implies that bipyrroledicarbaldehydes are significantly more difficult to reduce and are less prone to participate in the coupling than are bifurandicarbaldehydes or bithiophenedicarbaldehydes. Consequently, biheteroaryls 253 and 254 can produce homocoupling products and the mixed thiophene− furan macrocycle 19 (Scheme 48). However, when a mixture of Scheme 48. Synthesis of Porphycene Analogue 19

253 or 254 with a bipyrrole dialdehyde such as 31j is subjected to McMurry coupling conditions, only products from homocoupling are obtained. According to these findings, the authors of the study conclude that although steric effects play a key role in the coupling, it is likely that the electron affinity of the precursors is an important factor in governing the selectivity of the crossed reactions. In parallel with the synthesis of other benzoporphycenes, a mixed heteroanalogue−benzoporphycene was prepared by Dai and Mak.35 The synthetic plan, delineated in Scheme 49, is one of the first examples of Pd chemistry applied to the preparation of porphyrinoids. Given the symmetry of the target molecule, the first step was the synthesis of bifuran 256 via a double Suzuki coupling in 37% yield. Subsequently, two boronic acid moieties were installed at the α-positions of the furan ring

Scheme 49. Synthetic Pathway for Synthesis of Benzoporphycene Analogue 260

AA


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Table 4. Synthesis of Porphycene Heteroanalogues Containing Imidazole and Thiazole

3. PORPHYCENE ISOMERS: CORRPHYCENE, HEMIPORPHYCENE, AND ISOPORPHYCENE In 1991, Waluk and Michl175 reported a complete theoretical study on the electronic structure of porphyrin, secophyrin (parent of texaphyrin), and all hypothetically possible isomers of porphyrin, including porphycene. Computational calculations indicated that of all the possible isomers of porphyrin (in principle, up to seven constitutional isomers with an N4 core can be formed), the most stable isomer was porphycene 2, followed by corrphycene 3, hemiporphycene 4, and isoporphycene 5. To date, other than porphycene, only derivatives and metal complexes43 of these three isomers have been synthesized and characterized18 (Figure 16).

not performed under THF reflux, which is typical for the syntheses of porphycenes, but at 0 °C. Furthermore, the resulting macrocycle did not undergo spontaneous aromatization but required exposure to an oxidizer such as iron(III) chloride to render the aromatic corrphycene, with an overall yield from the dialdehyde of 3%. The tetrapyrrole intermediate 263 was obtained in three steps. First, the α,α′-free bipyrrole 49 was coupled with 2 equiv of pyrrole ester 262 under acidic conditions. Subsequently, hydrogenation of the tetrapyrrolic intermediate to remove the benzyl moiety, followed by treatment with triethyl orthoformate and trifluoroacetic acid (TFA), afforded dialdehyde 263 (Clezy formylation). A distinct method was reported by Falk and Chen176 in 1996. Typically, in the synthesis of porphyrinoids, the 2,2′-bipyrrole moiety is used as a preformed building block. However, in this approach, the bipyrrolic moiety was produced at the end of the synthetic sequence by Ullmann coupling. The product isolated from this coupling was the copper complex 270. Corrphycene 271 was obtained by treatment of 270 with sulfuric acid in excellent yield. The synthesis of the open-chain precursor is inspired by the chemistry of natural bile pigments.177 Accordingly, dihalides 269 are obtained by acidic condensation of bis(pyrrolyl)ethane 267 and aldehydes 266. The preparation177 of bis(pyrrolyl)ethane 268 entails a two-step synthesis involving McMurry reductive dimerization of aldehyde 268 and reduction of the olefin (Scheme 51).

Figure 16. Relative stability of some porphycene isomers.

3.1. Corrphycene

3.2. Hemiporphycene

The first synthetic objective to be addressed was corrphycene. The name of the macrocycle is reminiscent of corrole and porphycene. For the synthesis of this compound, two different approaches have been envisaged. However, note that the main difference between the strategies is the order of the synthetic steps, as both synthetic schemes rely on the McMurry and Ullmann couplings as key reactions. The first synthesis of corrphycene was reported by Sessler, Vogel, and co-workers16 in 1994. The synthetic strategy is predicated on McMurry coupling of a properly functionalized tetrapyrrole 263 (Scheme 50). Interestingly, this coupling was

Synthesis of the following isomer, hemiporphycene, was reported by Callot et al.17 in 1995. The name of this isomer was proposed on the basis of its structure, which is a hybrid of porphyrin and porphycene. The authors found that acidic treatment (HCl(c)) of homoporphyrin 272 provided a mixture of, among other macrocycles, isomeric hemiporphycenes 273a and 274a in an overall yield of 10%. This result, although unexpected, is consistent with the susceptibility of the homoporphyrinic ring to oxidations and rearrangements (Scheme 52). AB


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Scheme 50. Synthesis of Corrphycenea

a

Sessler, Vogel, and co-workers.16

Scheme 51. Synthesis of Corrphycene 271a

a

Falk and Chen.176

Scheme 52. Synthesis of Hemiporphycenes 273b and 274ba

a

Callot et al.17

methane 277. Interestingly, upon neutralization of the reaction mixture, a dimeric species 280 was formed, likely through an air-mediated oxidative coupling. Despite this unexpected coupling, under reductive McMurry conditions, dialdehyde 280 furnished the desired macrocycle after exposure of the crude reaction mixture to an oxidant [iodine or iron(III)

A rational approach to the synthesis of hemiporphycenes was presented two years later by Vogel, Sessler, and co-workers.178 The synthetic plan was based on the open-chain precursor 279. Again, the chosen reaction to effect the ring closure was McMurry coupling. The required α,ω-dialdehyde was prepared by MacDonald condensation of bipyrrole 278 and dipyrrylAC


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Scheme 53. Rational Synthesis of Hemiporphycene 282

chloride] (Scheme 53). The parent unsubstituted macrocycle has been recently obtained by Waluk and co-workers179 by a similar strategy. Alternatively, hemiporphycenes can be prepared by the expansion of corroles. In 2005, Paolesse and co-workers180 prepared macrocycle 284 via treatment of corrole 283 with carbon tetraiodide. The mechanism was investigated, and the authors proposed a cyclopropane intermediate to explain the ring expansion. Similarly, in 2014, Kadish, Paolesse and coworkers181 described another example of hemiporphycene formation through the expansion of corrole 285 (Scheme 54).

Scheme 54. Synthesis of Hemiporphycenes via Corrole Expansion

3.3. Isoporphycene

Compared with syntheses of the other isomers, the preparation of isoporphycene is unique, as ring closure is achieved via a metal-induced cyclization (Scheme 55). In 1997, Vogel et al.18 first reported the preparation of the palladium(II) complex of isoporphycene. This complex was obtained by cyclization of the tetrapyrrolic aldehyde 289 in the presence of palladium(II) chloride. The open-chain precursor was synthesized through Vilsmeier−Haack reaction of bis(bipyrrole) 288 with DMAA. The acylation reaction was not very efficient, affording only a 33% yield of the desired compound along with minor impurities. In contrast, 288 was readily available in 90% yield from treatment of bipyrrole 287 with triethyl orthoformate in the presence of TFA. Cyclization of 289 was difficult; the reaction was first attempted under MacDonald conditions. However, although many experimental conditions were tested, the acid-catalyzed condensation led only to undefined products. To overcome this obstacle, the authors adapted an early report on the use of Cu2+

ions to perform the cyclization of appropriately functionalized biladiene-ac salts to furnish porphyrins.182 This procedure produced a cyclization; unfortunately, the product was not the expected isoporphycene but instead the copper complex of 9AD


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Scheme 55. Preparation of Pd(II) Complexes of Isoporphycene

Scheme 56. Pathway for Synthesis of Isoporphycene 297

4. CONCLUSIONS AND OUTLOOK

formyloctaethylisocorrole. Next, inspired by the chemistry of Pd-mediated cyclizations,183 the copper salts were replaced with palladium(II) chloride. Thus, the exposure of aldehyde 289 to PdCl2 afforded a mixture of geometric isomers 290 and 291 (3%) along with the (Z)-isoporphycene aldehyde 292 in 7% yield. Compounds 290 and 291 constitute a photochromic pair but cannot be interconverted thermally. Hence, the ratio of isomers in the mixture is variable (Z:E ranges from 40:60 to 50:50). In the same report,18 the template cyclization of dialdehyde 293 in the presence of a divalent metal184,185 such as Pd or Ni was presented. This reaction allows access to the corresponding metal complex of 15-formyl-(Z)-octaethylisoporphycene (Scheme 56). Two years later, capitalizing on the availability of this aldehyde, the same group communicated the smooth decarbonylation of 294 via exposure to tris(triphenylphosphine)rhodium(I) chloride (Wilkinson’s catalyst) in 60% yield. Finally, acidic treatment of complex 295 with sulfuric acid liberated the metal, affording the E isomer of ligand 297 in 23% yield.

The synthesis of porphycene in 1986 by Vogel’s group is a clear example of the value of fundamental research leading to unexpected discoveries. Since then, the field has progressed from aromaticity and annulenes to new fascinating porphyrinoids, such as porphyrin isomers. In turn, these findings have spurred research on porphycene-related compounds ranging from heteroanalogues or exotic structures, such as benzoporphycenes. In light of this structural diversity, it is conceivable that with the aid of contemporary synthetic methods, particularly metal-mediated reactions, novel expanded porphycenes with unique properties will be synthesized. However, efficient methods are still required that enable the derivatization of the macrocycle to prepare complex conjugated systems for applications in materials science and biomedicine. Thus, this field has a bright future, as the quest for new porphycenes depends only on efficient synthetic methods and the creativity of researchers. AE


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(14) Vogel, E. Porphyrinoid macrocycles: A cornucopia of novel chromophores. Pure Appl. Chem. 1996, 68, 1355−1360. (15) Vogel, E.; Köcher, M.; Schmickler, H.; Lex, J. Porphycene, a new type of porphine isomer. Angew. Chem., Int. Ed. Engl. 1986, 25, 257− 259. (16) Sessler, J. L.; Brucker, E. A.; Weghorn, S. J.; Kisters, M.; Schaefer, M.; Lex, J.; Vogel, E. Corrphycene: a new porphyrin isomer. Angew. Chem., Int. Ed. Engl. 1994, 33, 2308−2312. (17) Callot, H. J.; Rohrer, A.; Tschamber, T.; Metz, B. A novel porphyrin isomer: hemiporphycene. Formation and single-crystal Xray diffraction structure determination of a hemiporphycene nickel complex. New J. Chem. 1995, 19, 155−159. (18) Vogel, E.; Bröring, M.; Erben, C.; Demuth, R.; Lex, J.; Nendel, M.; Houk, K. N. Palladium complexes of the new porphyrin isomers (Z)- and (E)-isoporphycene-PdII-induced cyclization of tetrapyrrolealdehydes. Angew. Chem., Int. Ed. Engl. 1997, 36, 353−357. (19) Toganoh, M.; Furuta, H. Blooming of confused porphyrinoidsfusion, expansion, contraction, and more confusion. Chem. Commun. 2012, 48, 937−954. (20) Gosmann, M.; Franck, B. Synthesis of a Fourfold Enlarged Porphyrin with an Extremely Large, Diamagnetic Ring-Current Effect. Angew. Chem., Int. Ed. Engl. 1986, 25, 1100−1101. (21) Sánchez-García, D.; Sessler, J. L. Porphycenes: synthesis and derivatives. Chem. Soc. Rev. 2008, 37, 215−232. (22) Vogel, E.; Koch, P. A.; Rahbar, A.; Cross, A. D., Derivatives of porphycene of direct utility in photodynamic therapy or as intermediates for synthesis of photoactivatable dyes suitable for photodynamic therapy. International Patent WO 1992012636 A1, 1992. (23) Vogel, E.; Balci, M.; Pramod, K.; Koch, P.; Lex, J.; Ermer, O. 2,7,12,17-Tetrapropylporphycene - pendant of octaethylporphyrin in the porphycene series. Angew. Chem., Int. Ed. Engl. 1987, 26, 928−931. (24) Vogel, E.; Koch, P.; Hou, X. L.; Lex, J.; Lausmann, M.; Kisters, M.; Aukauloo, M. A.; Richard, P.; Guilard, R. New porphycene ligands: octaethyl- and etioporphycene (OEPc and EtioPc): four and five-fold coordinated zinc complexes from OEPc. Angew. Chem., Int. Ed. Engl. 1993, 32, 1600−1604. (25) Vogel, E.; Köcher, M.; Lex, J.; Ermer, O. Steric modulation of the porphycene system by alkyl substituents: 9,10,19,20-tetraalkylporphycenes. Isr. J. Chem. 1989, 29, 257−266. (26) Waluk, J. ChemInform Abstract: Structure, spectroscopy, photophysics, and tautomerism of free-base porphycenes and other porphyrin isomers. ChemInform 2013, 44 (31); DOI: 10.1002/ chin.201331280. (27) Waluk, J. Porphycenes: spectroscopy, photophysics, and tautomerism. In CRC Handbook of Organic Photochemistry and Photobiology, 3rd ed, Vol. 1; Griesbeck, A. G., Oelgemöller, M., Ghetti, F., Eds.; CRC Press: Boca Raton, FL, 2012. (28) Waluk, J.; Müller, M.; Swiderek, P.; Köcher, M.; Vogel, E.; Hohlneicher, G.; Michl, J. Electronic states of porphycenes. J. Am. Chem. Soc. 1991, 113, 5511−5527. (29) Braslavsky, S. E.; Müller, M.; Mártire, D. O.; Pörting, S.; Bertolotti, S. G.; Chakravorti, S.; Koç-Weier, G.; Knipp, B.; Schaffner, K. Photophysical properties of porphycene derivatives (18 π porphyrinoids). J. Photochem. Photobiol., B 1997, 40, 191−198. (30) Berezin, D. B.; Talanova, A. E.; Shukhto, O. V.; Guseinov, S. S.; Krest’yaninov, M. A.; Petrova, D. V.; Semeikin, A. S. Synthesis and physico-chemical properties of 2,7,12,17-tetraphenylporphycene and its metal complexes. Russ. J. Gen. Chem. 2015, 85, 1876−1884. (31) Stockert, J.; Cañete, M.; Juarranz, A.; Villanueva, A.; Horobin, R.; Borrell, J.; Teixido, J.; Nonell, S. Porphycenes: Facts and Prospects in Photodynamic Therapy of Cancer. Curr. Med. Chem. 2007, 14, 997−1026. (32) Vogel, E.; Jux, N.; Rodriguez-Val, E.; Lex, J.; Schmickler, H. Porphyrin homologs. [22]Porphyrin(2.2.2.2), an extended porphycene. Angew. Chem., Int. Ed. Engl. 1990, 29, 1387−1390. (33) Masuno, M. N.; Robinson, B. C.; Phadke, A. S. A new porphycene-derived ring structure: octaethylbenzochloracene. J. Porphyrins Phthalocyanines 2001, 5, 177−180.

AUTHOR INFORMATION Corresponding Author

*E-mail [email protected]. ORCID

David Sánchez-García: 0000-0002-3936-9329 Notes

The authors declare no competing financial interest. Biographies Gonzalo Anguera received his degree in chemistry from the Institut Quı ́mic de Sarrià (Universitat Ramon Llull) in 2010. He joined the Sánchez-Garcı ́a group, obtaining his Ph.D. in 2015 for work on the chemistry of oligopyrroles and expanded porphyrins. He is currently a postdoctoral researcher in the group of Professor Jonathan L. Sessler at The University of Texas at Austin. His current research interests are focused on the synthesis of pyrrolic macrocycles. David Sánchez-Garcı ́a was born in Barcelona, Catalonia, Spain. He studied chemistry at the Institut Quı ́mic de Sarrià (Universitat Ramon Llull) in Barcelona and received his Ph.D. in 2003 for research on the chemistry of tetraazaporphycenes. He conducted postdoctoral research (2004−2006) with Professor Jonathan L. Sessler (University of Texas at Austin), developing new strategies for the synthesis of pyrrolic macrocycles. In 2006, he performed postdoctoral work in foldamer chemistry in the laboratory of Dr. Ivan Huc (Institut Européen de Chimie et Biologie, France). In 2008, he joined the faculty of the Institut Quı ́mic de Sarrià, where he is currently an associate professor. His research interests are focused on functional chromophores based on pyrrole and nanoparticles for theranostics. In addition to chemistry, he enjoys playing the violin.

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