Isophlorinoids: The Antiaromatic Congeners of Porphyrinoids

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Isophlorinoids: The Antiaromatic Congeners of Porphyrinoids B. Kiran Reddy, Ashokkumar Basavarajappa, Madan D. Ambhore, and Venkataramanarao G. Anand* Department of Chemistry, Indian Institute of Science Education and Research, Dr. Homi Bhabha Road, Pune − 411008, Maharashtra, India ABSTRACT: Ever since the discovery of the porphyrin ring in “pigments of life”, such as chlorophyll and hemoglobin, it has become a prime synthetic target for optoelectronic properties and in the design of metal complexes. During one such early expedition on the synthesis of porphyrin, Woodward proposed that condensing pyrrole with an aldehyde under acidic conditions yields the “precursor” porphyrinogen macrocycle. Its fourelectron oxidation leads to the “transitory” 20π isophlorin, which undergoes subsequent two-electron oxidation to form the 18π “porphyrin”. Due to its fleeting lifetime, it has been a synthetic challenge to stabilize the tetrapyrrolic isophlorin. This macrocycle symbolizes the antiaromatic character of a porphyrin-like macrocycle. In addition, the pyrrole NH also plays a key role in the proton-coupled, two-electron oxidation of isophlorin to the aromatic porphyrin. However, a major aspect of its unstable nature was attributed to its antiaromatic character, which is understood to destabilize the macrocycle upon conjugation. Antiaromaticity in general has not gained significant attention mainly due to the lack of stable 4nπ systems. In this regard, a stable isophlorin and its derivatives provide a glimmering hope to peek into the world of antiaromatic systems. This review will focus on the attempted synthesis of antiaromatic isophlorin ever since its conception. Based on recent synthetic advances, the chemistry of isophlorins can be expected to blossom into expanded derivatives of this antiaromatic macrocycle. Along with the synthetic details, the structural, electronic, and redox properties of isophlorin and its expanded derivatives will be elaborated.

CONTENTS

1. INTRODUCTION

1. Introduction 1.1. Genesis of Isophlorin 1.2. Aromaticity and Antiaromaticity 2. Syntheses 2.1. Synthetic Chemistry of Isophlorins 2.2. Isophlorin and Porphyrin Dications 2.3. Mononuclear Metal Complexes of Isophlorin 2.4. Dinuclear Metal Complexes of Isophlorin 2.5. Stable Isophlorins 2.6. Porphyrinoids with 20π Electrons 3. π Extended Isophlorinoids 3.1. Scope for Expanding the π Conjugation 3.2. Aromatic Expanded Isophlorins 3.3. Antiaromatic Expanded Isophlorins 3.4. Expanded Isophlorins with Ethylene Bridges 4. Isophlorin-like Macrocycles 4.1. Tetraepoxy Annulenes 4.2. Sulfur Bridged Annulenes 4.3. Oxidized Porphyrins 5. Summary and Outlook Author Information Corresponding Author ORCID Notes Biographies Acknowledgments References

© XXXX American Chemical Society

1.1. Genesis of Isophlorin

A A B C C C E G H K M M N P R S S T T U U U U V V V V

Nature employs porphyrin’s, 1 (Scheme 1), metal complexes for various enzymatic catalyses in biological systems. Now, it is a Scheme 1. Chemical Structures of 18π Porphyrin, 1, and 20π Isophlorin, 2

well-established chelator for most of the metals and a few nonmetals in the periodic table.1 By virtue of its macrocyclic π-conjugation, this naturally occurring pigment intensely absorbs visible light in the region between 400 and 600 nm.2 Combination of porphyrin’s metal ligating ability and the impressive electronic property has become an obvious choice for a host of applications.3 This has been a driving force for the synthesis of porphyrin and its analogues in the last few decades. Special Issue: Expanded, Contracted, and Isomeric Porphyrins Received: August 16, 2016

A

DOI: 10.1021/acs.chemrev.6b00544 Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 2. Proton Coupled Electron Transfer Induced Oxidation of Porphyrinogen, 3, into a Porphyrin through Isophlorin

belongs to the (4n+2)π class of molecules and hence is aromatic in nature. 20π isophlorin fits into antiaromatic 4nπ systems, which is supposed to be among the chief reasons for its unstable nature. In addition, the pyrrole nitrogen’s ability to be deprotonated with an accompanying one-step two-electrons transfer reaction aids the reduced stability of isophlorin 2. Structurally, the presence of four hydrogen atoms in the center of the macrocycle can develop sufficient repulsive forces to deviate the macrocycle from a completely planar conformation. Any transformation to reduce this strain should be facile, and hence, the oxidation of 2 to 1 is quite rapid at ambient temperature. Not surprisingly, the hypothetical tetrapyrrole, 2, remains a synthetic challenge to date.

Remarkably, this endeavor was crucial to the discovery of unnatural structural analogues in the form of N-confused porphyrin4,5 and isophlorin.6 N-Confused porphyrin and its derivatives are a class of tetrapyrrolic isomers of the porphyrin in which one or more pyrrole rings are disoriented, such that its β-carbon replaces the nitrogen in the center of the macrocycle.7,8 The modified core of the macrocycle is an ideal chelator for the synthesis of organo metallic complexes of porphyrin.9−11 Modifications on porphyrin are not restricted to the macrocyclic core alone, but have been employed extensively to extend its π-conjugation also.12,13 The expansion of π-conjugation is a common feature to porphyrin14−18 and N-confused porphyrins.19,20 Expanded porphyrins are a fascinating class of macrocycles that bear structural resemblance to a porphyrin. Generally they are identified as macrocycles with more than four pyrrole rings and usually have 17 or more atoms in their conjugated pathway.14 They have attracted significant curiosity for their structural and electronic properties, which are not native to the parent porphyrin. Unlike expanded porphyrins and the confused derivatives of porphyrins, isophlorin, 2, and its derivatives have lacked intense and continuous attention. It is a structural twin of porphyrin with antiaromatic properties. In this review, we describe the genesis and the evolving chemistry of isophlorin contributed by various research groups toward its synthesis, reactivity, and structural and electronic properties. Isophlorin is a not a naturally occurring macrocycle. Woodward conceptualized the π-framework of this macrocycle for the first time during the synthesis of chlorophyll.6 The idea of isophlorin was highlighted as a probable intermediate during the mechanistic pathway for the synthesis of porphyrin. Pyrrole and aldehyde assemble into an unconjugated tetrapyrrole porphyrinogen, 3 (Scheme 2), in acidic conditions.21 Further oxidation of 3 to the aromatic porphyrin is suspected to be a two-step process. At first, the porphyrinogen undergoes 4e− oxidation to the transient isophlorin, 2, which subsequently undergoes 2e− oxidation to yield the porphyrin, 1. 1 and 2 differ in their chemical composition by only two hydrogens, as clearly reflected in the core of the macrocycles. But there is a significant difference in the composition of the atoms along their conjugated pathway. Porphyrin can be considered as a heteroannulene due to the blending of two nitrogens in the sp2 framework of carbon atoms. Nitrogen doped carbon circuits sustain effective delocalization of π-electrons from the overlapping sp2 orbitals,22 as experimentally proved for porphyrin, 1. In contrast, only carbon atoms are accommodated in isophlorin’s π-circuit. Even though delocalization of π-electrons seems to be obvious for 2, the ensuing effect has not been experimentally observed until date due to its inherent instability under ambient conditions. A distinct difference due to the dissimilar composition alters the number of π-electrons along the conjugated pathway. Porphyrin accounts for 18π electrons, and isophlorin has 20π electrons. This difference in two π electrons has a marked difference as per Huckel’s rule of aromaticity. The 18π porphyrin

1.2. Aromaticity and Antiaromaticity

A further understanding of isophlorin and its electronic properties requires a brief mention about 4nπ electrons systems. Benzene, 4, with six π-electrons, represents the simplest example in support of Huckel’s (4n+2)π rule for aromatic compounds. Cyclobutadiene, 5, and cyclcooctatetraene, 6, are the simplest of the 4nπ electrons systems. As per Huckel’s rule, they are not aromatic and in principle should have an open shell configuration with a triplet ground state.23 However, the doubly degenerate orbitals may lose the degeneracy due to Jahn−Teller distortion, leading to closed shell 4nπ systems with a very small HOMO and LUMO energy gap compared to aromatic molecules.24 In support of this understanding, experimentally, both 5 and 6 are not found to be aromatic and highly vulnerable to addition reactions compared to benzene. As it turned out, cyclooctatetraene oscillates between two nonplanar conformations to avoid the perceived strain in the planar conformation of the ring.23 However, other cyclic π-conjugated systems were synthesized to experimentally verify the paratropic ring current effect in 4nπ molecules. Cyclododecatrienetriyene,25 bisdehydro[12]-, bisdehydro[16]-, bisdehydro[24]-annulenes,26,27 and cyclopropenyl anion28 represent the earliest examples of synthetic 4nπ molecules. A series of annulenes were synthesized later to understand the ring current effect in 4nπ systems. Sondheimer and co-workers attempted the synthesis of annulenes in a quest for a stable and planar 4nπ system.29 Annulenes represent a homologous series of fully conjugated monocyclic hydrocarbons identified with the general formula (C2H2)n. Cyclobutadiene (n = 2), benzene (n = 3), and cyclcooctatetraene (n = 4) are the starting members of this family followed by the higher analogues where “n” can be any positive integer. A variety of annulenes, both the 4nπ and (4n+2)π series, were successfully synthesized and characterized extensively through NMR spectroscopy (Scheme 3). The 18π annulene, 7,30 is an expanded congener of benzene and expected to display aromatic characteristics. Increasing the size of a cyclic system aids conformational flexibility, and hence, the molecule can have more than one stable conformer. Hence, the diatropic ring current effect on its protons was observed only at low temperature, owing to its fluxional behavior at higher temperatures. Only a singlet B


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Scheme 3. Representative Chemical Structures of Annulenes Bearing either 4nπ or (4n+2)π Electrons

Scheme 4. Thick Lines Highlight the Difference in the Annulene Framework between Porphyrin (1) and Isophlorin (2)

(δ 5.45 ppm) was observed at 110 °C, while a conspicuous absence of the resonances marked its room temperature proton NMR spectrum. Lowering the temperature to −60 °C resolved the high temperature singlet into two signals at δ 9.28 and −2.99 ppm. The induced diatropic ring current is responsible for the upfield chemical shift of the protons in the center of the annulene, while the peripheral protons resonate downfield. On a similar note, the characterization of 16π annulene, 8, displayed a significant difference between 4nπ and (4n+2)π systems.31 As observed for 7, 8 also exhibited a singlet (δ 6.73 ppm) at 35 °C. Anticipating the fluxional behavior, its proton NMR spec trum recorded at −120 °C displayed two signals at δ 10.43 and 5.4 ppm corresponding to inner and outer protons, respectively. The stark reversing of the shielding and deshielding effects on the protons of 4nπ systems is explained in terms of paratropic ring current effects. To signify this important difference, Breslow coined 4nπ systems as “antiaromatic”, in tune with conflicting ring current effects for 4nπ and (4n+2)π systems observed from NMR spectroscopy.32 Experimental estimation of the ring current effect has been predominantly based through NMR spectroscopy. It has been extremely useful to record strong ring current effects, while it can be ambiguous for molecules with weak ring current effects. Recently, quantum chemical calculations have immensely supported the experimentally observed ring current effects. Herges and co-workers have emphasized the concept of Anisotropy of the Induced Current Density (ACID) to quantify electronic delocalization as a general method for cyclic π-conjugated systems.33 Alternatively, Sundholm and others have estimated magnetically induced current densities from density functional theory. It provides the direction and strength of the current arising from the delocalization of π-electrons under and also the direction of the current. They have used this method for a variety of porphyrins and isophlorins to signify the aromatic and antiaromatic pathways in (4n+2)π and 4nπ systems, respectively.34−36 In parallel, Nucleus Independent Chemical Shift (NICS) has been widely used to estimate the strength of π-electron delocalization.37 Schleyer and co-workers proposed the concept of NICS for π conjugated cyclic systems, and it has been useful to analyze and interpret the ring current effects in porpyrinoids. As a convention, NICS estimates aromaticity and antiaromaticity as negative and positive values, respectively. In addition to the experimentally determined chemical shift values, NICS values, wherever required, will be highlighted in this review.

porphyrin and isophlorin as structural analogues of 18π and 20π annulenes, respectively. The pyrrole rings enhance the macrocyclic rigidity to overcome the fluxional property of the 18π annulene, 7. Since the conjugation path in isophlorin is only through the carbon atoms, it was envisaged that the heterocyclic rings could instill a stiff periphery for the macrocycle in a fashion similar to that for porphyrin. Also any heterocycle, structurally similar to pyrrole, should suffice to be a backbone for the 20π framework. Heterocycles such as furan/thiophene/selenophene are ideal substitutes for pyrrole. In addition to the structural rigidity, they could also inhibit the possible proton couple electron-transfer to oxidize isophlorin to the aromatic porphyrin. 2.2. Isophlorin and Porphyrin Dications

The unprecedented success of annulene chemistry inspired the synthesis of a unique cyclic conjugated systems to access unfamiliar 4nπ and (4n+2)π systems. Few of them were parallel, but oblivious, to the synthetic efforts toward a stable antiaromatic isophlorin. Frank and co-workers reported the 18π dication 9a,39 as its dibromide salt, which can be considered as the oxidized product of the corresponding tetra-N-methyl isophlorin (Scheme 5). Scheme 5. Oxidation of N-Tetramethyl Porphyrinogen to Its Corresponding Dication39

Substituting the hydrogen with a methyl group on the pyrrole nitrogens prevented the formation of a neutral porphyrin. Vogel and co-workers envisaged the antiaromatic 20π isophlorin, 10, with a modified core arising from a two-electron reduction of 18π aromatic macrocycle, 9. A 0.15 M solution of anthracene-sodium in THF was used as the reducing agent at −78 °C for the controlled two-electron reduction of the dication40 (Scheme 6). The resultant product was crystallized from an ethanol/hexane mixture to yield the 20π isophlorin 10 as brown needles, which revealed limited stability under ambient conditions. Its proton NMR spectrum displayed temperature dependent chemical shift values for the methyl protons in the center of the macrocycle. Ideally, a singlet for all the methyl protons would have suggested a rigid and high symmetry for the isophlorin. No signal was observed for the N-methyl protons under ambient conditions. A singlet appears upon increasing the temperature to 104 °C, while the same signal split into two singlets corresponding to equal number of protons at −72 °C. The resonance frequency for

2. SYNTHESES 2.1. Synthetic Chemistry of Isophlorins

Vogel and co-workers pioneered the synthetic pathways for a stable skeletal framework of a 20π macrocycle.38 The high tendency for 20π isophlorin, 2, to be oxidized to the aromatic porphyrin, 1, was a crucial blockade to the design of stable antiaromatic systems (Scheme 4). Inspired by the successful synthesis of annulenes, Vogel and co-workers represented C


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perchlorate and perchloric acid to yield the nonplanar tetraoxaporphyrinogen, 15, in less than 2% yields (Scheme 8).42 However, it degraded upon oxidation by nitric acid, while the dication was obtained by bromine/perchloric acid combination to yield 14. The distinct difference was evident by the transformation of colorless 15 to the violet 14 upon oxidation and the concomitant change in the absorption spectrum. (c) In an alternative and simple procedure, the acid catalyzed condensation of commercially available furfuryl alcohol, 16, yielded the unsubstituted tetraoxaporphyrinogen, 15, albeit in very low yields (Scheme 9).43

Scheme 6. Reversible Oxidation of N-Tetramethyl Isophlorin, 10, to Its Aromatic Dication, 940

the meso protons of the macrocycle was immune to the change in temperature. Unlike the 16π annulene, 8, isophlorin 10 exhibited partial fluxional behavior. This stems from the fact that the limited macrocyclic cavity of 10 sterically hinders the four −CH3 groups to adopt the expected planar conformation. Therefore, the macrocycle is forced into nonplanar conformations in which all the methyl groups are either above (or below) the mean macrocyclic plane or alternate pyrroles must be in syn, anti, syn, anti conformation. It was suspected that the orientation of the pyrrole rings was predecided by the precursor dication, 9, rather than the result of two-electron reduction. X-ray crystallographic analysis confirmed the alternate syn and anti orientations of the four pyrrole rings, leading to the collapse of the planar conformation. As planarity is crucial for effective ring current effects in either 4nπ or (4n+2)π systems, isophlorin 10 is a classic example for the structure induced loss of antiaromaticity. Unfortunately, the first synthetic success of 20π isophlorin was diminished by its non-antiaromatic characteristics. Alternate strategies to synthesize a stable isophlorin were developed by employing nonpyrrolic heterocyclic units. Furan’s comparable aromatic features and structural similarity with pyrrole were an attractive choice as a building block for the 20π macrocycle.41 Vogel and co-workers employed at least three different strategies for the synthesis of tetraoxaisophlorin, 11: (a) di-2-furaldehyde, 12, and 2,2′-difurylmethane, 13, were ideal precursors for a MacDonald condensation reaction (Scheme 7).

Scheme 9. Intermolecular Cyclization of Furfural into a Tetraoxaporphyrin Dication43

The subsequent oxidation of 15 with DDQ/nitric acid followed by perchloric acid yielded the perchlorate salt of the porphyrin dication, 14, in 86% yields. The structural characterization of the porphyrinogen 15 and the porphyrin dication 14 displayed the transformation from a nonplanar to planar conformation, proving the global aromaticity in the macrocycle. It was apparent that the 20π tetraoxaisophlorin, 11, was a fleeting intermediate, as suspected for the parent isophlorin 2, further dispelling the stability of antiaromatic systems. Even though oxidation of 11 to its corresponding dication is parallel to synthesis of porphyrin, the macroycle did not lose any of its hydrogens in the process of aromatization. Its propensity for oxidation to a dication by mineral acids is strikingly analogous to the chemical property of metals. Hence, Vogel likened isophlorin to a “pseudo metal”41 for its ability to undergo ring oxidation with mineral acids. Evolution of hydrogen seems to be an obvious byproduct, but sans significant detection until date. However, the reduction of the quinone (DDQ) to phenol in the presence of perchloric acid and the undetected isophlorin, 11, as the source of electrons justifies the two-electrons oxidation of the macrocycle (Scheme 10). Therefore, it opened the possibility of dication reduction to the neutral macrocycle.

Scheme 7. Synthesis of the Perchlorate Salt of Tetraoxaporphyrin Dication, 14, from Difuran Methane41

Scheme 10. Metal Type Character of Isophlorin 11 To Reduce the Quinone into Its Corresponding Phenol Oxidation of this reaction mixture by a combination of nitric acid and perchloric acid yielded the 18π tetraoxaporphyrin dication as a perchlorate salt, 14, in 8% yield. (b) In another effort, 2,2′-difurylmethane, 13, was reacted with formaldehyde in methanol/water in the presence of lithium Scheme 8. Irreversible Oxidation of Tetraoxaporphyrinogen into Its Corresponding 18π Aromatic Dication42

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of an annulene framework. Reductive coupling of 5,5′-bi-2,2′furaldehyde with low valent titanium yielded 20, the porphycene analogue of isophlorin, in 16% yields (Scheme 12).45 Surprisingly the 20π electrons macrocycle exhibited incredible stability under ambient conditions. A characteristic paratropic ring current effect was evident from the typical upfield chemical shifts for the protons of the furan rings close to δ 5.00 ppm and at δ 4.2 ppm for the ethylene bridged protons. X-ray crystallographic analysis revealed a planar macrocycle with a scant deviation from planarity. Indeed, 20 undergoes two-electron oxidation to yield the dicationic 18π 18. The oxidative transformation to the aromatic species was unambiguously confirmed from its proton NMR spectrum. The upfield chemical shifted protons of 20 were drastically shifted downfield by more than 6.6 ppm for the protons of the ethylene bridge in 18. Similarly large shifts were observed even for the protons of the furan rings, signifying a two-electron oxidation from the antiaromatic to the aromatic state of the macrocycle. It is apparent that the structural reorientation of a porphyrin skeleton to a porphycene encourages a stable 4nπ system. But the relative downfield chemical shifts for the protons of 20, in comparison to 11, reveal a significant reduction of the antiaromatic character. Presumably, unlike a single meso carbon bridge, the ethylene carbons in 20 do not induce significant perturbation on the π cloud of furan for effective delocalization over the macrocycle. Hayashi and co-workers synthesized a similar 20π porphycene with electron withdrawing trifluoromethyl groups which could undergo reversible oxidation to the 18π dication.46 Later, we describe the role of lengthy olefin bridges in between the two bifuran units in modulating the π cloud of furans for enhancing its (anti)aromatic character.

Unrelenting efforts from Vogel and co-workers did not go futile to isolate the whimsical antiaromatic 20π isophlorin. The isolated stable dication, 14, was reacted with potassium metal in THF under very stringent reaction conditions. Even though the reduction was successful, the dication consumed four electrons to yield the aromatic 22π tetraoxaporphyrin dianion,38 17 (Scheme 11). Scheme 11. Controlled Two-Electron Reduction of Aromatic Dication, 14, into 20π Tetraoxaisophlorin, 1138

Control over the reduction process was relatively difficult compared to the oxidation of dianion to the neutral macrocycle 11. An unconventional regulated two-electron oxidation of the dianion 17 was devised by passing molecular oxygen at very low temperatures, and the resultant product crystallized as airsensitive black crystals of isophlorin 11. Its proton NMR spectrum displayed two sharp singlets at δ 1.98 and −0.64 ppm for the furan and meso protons, respectively. The remarkable upfield chemical shifts for the protons of the heterocyclic rings and the meso carbon atoms justified the paratropic ring current effects of a 4nπ macrocycle. Even though they were successful at the preliminary X-ray crystallographic analysis to identify the planar configuration of the macrocycle, static and possibly dynamic disorder prevented the unambiguity over the molecular structure. Unlike the different variable temperature NMR spectra for the 16π annulene, the observation of unaffected sharp signals at −135 °C did not suggest any fluxional behavior for the macrocycle. Successful synthesis of tetraoxaisophlorin, 11, albeit for its instability under ambient conditions, stimulated confidence to access the elusive antiaromatic isophlorin. Structurally similar macrocycles synthesized with thiophene and selenophene did not support the isolation of a stable isophlorin. The same group had significant success in the synthesis and characterization of a tetraoxaporphycene dication, 18. Porphycene, 19, is one of the many possible structural isomers of 18π porphyrin, derived by transposing the pyrrole rings and meso carbon bridges.44 Vogel and co-workers first synthesized 19 by bridging the two bipyrrole units with two ethylene units. At best, it is a confluence of porphyrin and cyclophane within the gambit

2.3. Mononuclear Metal Complexes of Isophlorin

After the discovery of porphyrin dications, a long hiatus awaited further synthetic developments for stabilizing the antiaromatic isophlorin. Initial attempts to synthesize isophlorins were predominantly derived from β-substituted heterocyclic units or at most without any substituents. With the advent of significant advances in synthetic protocols, access to a variety of meso phenyl substituted porphyrins increased phenomenally. The effect of substituents did not impact the stability of metal complexes, but the reactivity of a metalloid’s β-substituted porphyrin complex was different from that of its meso phenyl porphyrin complex. For example, a silicon(IV) complex of an octaethyl porphyrin [Si(OEP)Cl2]47 was stable enough in acidic medium compared to the decomplexation followed by protonation of its meso tetraphenyl porphyrin complex [Si(TPP)Cl2], 21. In due course of time, 21 emerged as a convenient precursor in the design of the Si(IV) complex of isophlorin. The reaction between

Scheme 12. Synthesis of 18π Tetraoxaporphycene Dication, 18, Isolectronic to 1444,45

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a metal salt and ligand is a conventional synthetic protocol for metalloporphyrins. In principle, isophlorin’s four pyrrole rings can be expected to stabilize a metal ion in its +4 oxidation state and (or) above. The nonavailability of a stable isophlorin ligand is a stumbling block to explore the chemistry of its metal complexes. Nevertheless, Vaid and co-workers employed an alternative strategy to reduce [Si(IV)(TPP)Cl2], 21, to [Si(IV)(tetraphenylisophlorin)](THF)2, 22, which, in principle, reduced the porphyrin ring from −2 to −4.48 After reduction with 2 equiv of sodium amalgam over a period of 4 h, followed by filtration and drying under vacuum, 22 was isolated as an airsensitive dark orange solid in 46% yield (Scheme 13).

Scheme 14. Synthesis of a Tetracoordinate Ge(II) Porphyrin Complex, 23, from a Bis-lithium Porphyrin Complex49

Scheme 13. Reduction of a Si(IV) Porphyrin Complex, 21, into Si(IV) Isophlorin, 2248 dome-like structure. Such an observation is generally observed for metal ions, chelated by a porphyrin, in their lower oxidation states. The disordered molecules in the crystal lattice could not distinctly reveal the nature of the metal complex with respect to the oxidation state of the metal ion. Relying on spectroscopic techniques, the authors concluded that Ge indeed remained in the +2 oxidation state without reducing the porphyrin to isophlorin. This was marked by significant downfield shifts of the pyrrole protons in its NMR spectrum and a typical porphyrinic absorption spectrum. While the silicon complex, 22, could not be isolated without THF coordination, the Ge complex, 23, was stable enough without octahedral coordination, which is probably due to the presence of a lone pair of electrons on the central metal ion. But, it was at ease to coordinate two axial ligands upon dissolving in pyridine, to yield the hexacoordinate 24 (Scheme 15).

X-ray diffraction analysis displayed a ruffled structure of the porphyrin, similar to that observed for 10. The distortion from the flat topology was ascribed to the smaller size of Si(IV) in contrast to the cavity of the porphyrin. Silicon had four covalent bonds with as many nitrogens at the center of the macrocycle and coordinated through the oxygen of THF in both the axial positions of the octahedral geometry. The distance between nitrogen and silicon in 22 was shortened in comparison to the same in other porphyrin complexes of silicon, thereby confirming the +4 oxidation state for silicon. Unexpectedly, they were confronted with a complicated proton NMR spectrum to confirm the ring current effects of the macrocycle. A well-resolved spectrum was obtained upon replacing the THF by pyridine as the axial ligand. The chemical shift values for the β-protons of the pyrrole rings resonated as a singlet at δ 1.29 ppm, while the axial pyridine rings’ protons were deshielded at δ 20.35, 10.31, and 9.74 ppm due to their close proximity to the core of the macrocycle. This differences in the chemical shift values are in complete agreement with the paratropic ring current effects of a 4nπ system, implying a planar structure for the pyridine ligands in the solution state. The estimated NICS value of +39 ppm for the silicon complex 22 justified the antiaromatic character of the macrocycle. Efforts from the same group revealed that other elements of group(IV) were also good enough to be on par with silicon to sustain the 20π macrocyclic framework. The germanium complex of a porphyrin could also be reduced by two electrons to the corresponding isophlorin complex; albeit, the reaction path was not similar to its silicon counterpart. Sodium amalgam did not yield the desired result of reducing the porphyrin to isophlorin. In a simultaneous process, germanium doubled up as a metal ion and reducing agent (+II to +IV) for the macrocyclic framework.49 At first, a bis-lithium complex of porphyrin, Li2(TPP)(OEt2)2,50 was reacted with GeCl2 to yield a germanium complex of porphyrin, 23 (Scheme 14). Unlike the silicon complex, Ge yielded a tetracoordinate complex of the porphyrin with a close resemblance to square pyramidal geometry. Rather than a distorted macrocycle, the metalloid coordinated with four nitrogens at a distance (0.872 Å) little above the center of the macrocyclic cavity, leading to a

Scheme 15. Pyridine Coordination by Tetracoordinate Ge(II) Porphyrin Complex 23 To Yield the Octahedral Ge(IV) Isophlorin Complex 2449

They observed that the Ge complex binds the axial pyridine ligands over a period of 2 days, marked by a striking change in color from green to red. Its structure, elucidated from single crystal X-ray diffraction analysis, revealed a highly ruffled macrocyclic structure similar to that observed for 22. Accompanying the planar deformation was the unusual change in the bond lengths between Ge and the four nitrogen atoms. Compared to 23, the bond distance between Ge and all the nitrogen atoms reduced significantly in 24, contemplating the oxidation of Ge(II) to Ge(IV) upon the coordination of two pyridine axial ligands. This notion was confirmed by the observation of strong upfield resonances for the pyrrole protons in the NMR spectrum of 24, as expected from a 20π macrocycle. A chemical shift value of δ 0.6 ppm corresponding to pyrrole protons and an unusually low field resonance at δ 21.6 ppm for the pyridine protons signified the paratropic ring current effect of the antiaromatic macrocycle. These observations helped the authors to infer that pyridine aids the reduction of the aromatic 18π porphyrin to its corresponding antiaromatic 20π isophlorin through the F


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Scheme 16. Synthesis of Ethylene Complexed Isophlorin, 2751

stabilization of a Ge(IV) macrocyclic chelate. In further studies, the same authors convincingly proved that the electron-withdrawing substituents on the porphyrin ring hasten the reduction to the 20π isophlorin in the presence of pyridine. They came to this conclusion by the rapid conversion of the greenish Ge(II) complex of tetrakis[3,5-bis(trifluoromethyl)phenyl]porphyrin to its reddish Ge(IV) in pyridine. Surprisingly, a similar porphyrin complex with Sn(IV) is not feasible even though it belongs to the same group as Si and Ge. This has been reasoned with the role of the oxidation state of these elements. While the elements in the top of the group are stabilized by the +4 oxidation state, those at the bottom of the same group prefer the +2 state. Only Ge displays a unique ability to be stabilized in either the +4 or +2 state, as proved by the isolation of both the complexes. Perhaps, a higher oxidizing ability of the central metal ion under basic conditions appears to be a handy tool to realize complexes of isophlorins, which otherwise are not known to date to be synthesized through direct complexation of isophlorins with metal salts.

Scheme 17. Two-Electron Oxidation of Ethylene−Isophlorin Complex, 27, to Its Corresponding 18π Dication, 2851

Moreover, the estimated NICS value of δ −13.6 ppm for 28 was in support of the diatropic ring current effect for the aromatic macrocycle. The electronic absorption spectrum was much different from that of a metallopoprhyirn or a diprotonated porphyrin. The unusually intense absorptions replaced the typical Soret and Q-band features as a consequence of a probable π interaction between the 18π circuit and the ethylene π bond at the center of the macrocycle. The author noted that these absorption features are similar to those of the diboron complex of porphyrin. Penelope Brothers and co-workers52 reported a diboron complex of porphyrin, 29, which displayed an unusual chemistry as observed for the mononuclear porphyrin complex of Si and Ge. In their attempts to synthesize a boron complex of a porphyrin, dilithium porphyrin (Li2(TTP)) was reacted with boron trichloride to yield an air-sensitive diboron complex of a porphyrin, 29. Based on NMR analysis, the structure was elucidated to be [(BCl2)2TTP], with a transoid geometry such that the BCl2 moieties are one above and below the mean marocyclic plane (Scheme 18).

2.4. Dinuclear Metal Complexes of Isophlorin

Direct synthesis of isophlorin−metal complexes requires substantial efforts to match the privilege of porphyrin−metal complexes. Yet, indirect methods have evolved to realize dinuclear complexes with isophlorin, or with its structural isomer. Vaid reported what could be considered as a dicarbon complex of a isophlorin from a cobalt(II) complex of porphyrin.51 By invoking the oxidation of a Co(II) complex, 25, with diiodoacetylene, he was able to synthesize the diiodoethylene complex of porphyrin, 26 (Scheme 16). An important feature of this complex is the altered imine− amine configuration of a porphyrin ring in which they localize in one-half of the macrocycle. Further attempts at photolytic/ thermal conversion to its corresponding (CC)TPP, 27, went futile. However, SmI2 turned out as the ideal associate for this process in THF. Structural analysis of the ethylene complex revealed a ruffled structure with both the carbons in the center of the macrocycle. The covalent bond between the central carbon atoms and the nitrogens induced the macrocycle to adopt a 20π electronic circuit leading to an antiaromatic state. The NMR spectrum of this macrocycle displayed high field resonances (δ 2.38 and 2.67 ppm) for the pyrrole protons as a manifestation of paratropic ring current effects. In support of the antiaromatic features, an estimated NICS value of δ + 38.5 ppm further confirmed the reduction of the 18π aromatic cobalt complex, 25, to the antiaromatic 27. In comparison to the Si(IV) and Ge(IV) complexes of isophlorin, 27 is prone to two-electron oxidation in a fashion similar to Vogel’s isophlorins described earlier. Addition of silver triflate (AgOTf) quickly oxidized the antiaromatic 27 to its corresponding aromatic dication, 28 (Scheme 17). The author claim to this two-electron oxidation process was attested by NMR spectroscopy, which revealed low-field resonances (δ 9.44 and 9.47 ppm) for the pyrrole protons of the dication.

Scheme 18. Synthesis of a Diboron Complex of a Porphyrin, 2952

DFT calculations estimated the nonbonded distance between the two boron atoms to be within 2.05 Å, which is more than sufficient to accommodate a B−B single bond (∼0.85 Å). With this encouraging outcome, they reacted B2Cl4 with Li2(TPP) at −100 °C to yield the corresponding moisture sensitive diboron G


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bond in 33 was totally dependent on the oxidation state of the macrocycle. Adduct 34 is formed by the two electron oxidation of 30 leading to the 18π dication. The observation of diamagnetic ring currents effects for the pyrrole protons of the porphyrin ring (δ 9.52 ppm) was in tune with the estimated NICS(1) value of δ −16.1 ppm expected of aromatic macrocycles. On the other hand, the suspected borene complex of porphyrin, 33, displayed upfield chemical shift values of δ 1.05 and 0.51 ppm for the pyrrole protons, and the estimated NICS(1) value of +20.2 ppm explicitly revealed the characteristic feature of an antiaromatic system. As observed for the Si(IV) and Ge(IV) complexes of porphyrin, a strong paramagnetic shift for the protons of the pyrrole ring unequivocally corresponded to the 20π isophlorin, which supports the +2 oxidation state of boron. The computed structure for 33 yielded a planar conformation for the macrocycle and a distance of 1.73 Å between the boron centers. The absence of the expected decrease in the distance for the anticipated borene (BB) clearly marked the two-electron reduction of a porphyrin to the antiaromatic isophlorin.

complex [(BCl)2TTP], 30, with the retention of the B−B bond similar to the precursor and a halogen above and below the mean macrocyclic plane. NMR analysis revealed a singlet for the boron nuclei at δ −12 ppm and low field resonances for the protons on the pyrrole rings, as expected from the aromatic porphyrin. In the absence of single crystal X-ray diffraction data, a bond distance of 1.74 Å was estimated between the two boron atoms by DFT calculations. The presence of (BCl)2 moieties in 30 provided ample opportunities for creation of its derivatives, as established by the authors. Its reaction with the bidentate catechol yielded the corresponding catecholate complex, 31, in a fashion such that the boron atoms bonded with the oxygens on the same side of the macrocyclic plane. Up field chemical shift values for the catechol protons further established this conformation as anticipated from diamagnetic ring current effects. Nucleophilic substitution of the chlorides upon reaction with n-BuLi yielded the di-nbutyldiboranyl complex [(BnBu)2(TTP)], 32, without altering the geometry of the boron atoms. A similar product was obtained upon reacting 29 with 4 equiv of n-BuLi at −78 °C, suggesting simultaneous processes of substitution and reduction of the complex. Boron’s typical electron deficiency is always prone to electron rich groups or is an easy target for reduction. The ability of [(BCl2)2TTP] to accept electrons was demonstrated by its reduction to 30 by Na−K alloy. The same group envisaged further a two-electron reduction of 30 to a borene (BB) porphyrin complex, 33, expecting an unusual +1 oxidation state for boron. Addition of magnesium anthracenide induced a quick change in color from greenish-brown to reddish brown at −30 °C in THF (Scheme 19). Isolation of the product yielded an air and moisture sensitive black product. As an alternative, there did exist the possible reduction of the porphyrin to an isophlorin with a +3 oxidation state for boron and a single bond in-between the boron centers. To overcome the ambiguity between these two possibilities [(B−B) and (BB)], 30 was oxidized with 2 equiv of [NaB(ArF)4] to yield an air and moisture sensitive [B2(TTP)][B(ArF)4]2, 34, as a reference adduct with a single bond between the boron centers in the macrocycle. The presence of a single or double

2.5. Stable Isophlorins

Discussions in the above sections highlight the attempts at the synthesis of isophlorin, its complexes, and their apparent instability under ambient conditions. Based on many such efforts, few other synthetic approaches led to the successful synthesis of a stable isophlorin. Among these endeavors, Chen and co-workers53 serendipitously discovered the reduction of a mesotetraphenyl porphyrin Cu(II) complex to its corresponding demetalated isophlorin, 35 (Scheme 20). The strong electronegative trifluoromethyl groups on the β positions of the pyrrole were sufficient to enhance the macrocycle’s electron deficient nature. By treating the greenish DMSO solution of this copper complex, 36, with zinc powder at room temperature, they observed a quick change to a reddish brown solution in the absence of oxygen. X-ray diffraction analysis on the single crystals of the product revealed the structure of a demetalated macrocycle as 20π isophlorin, 35. The macrocycle adopted a saddle-like conformation induced by a relatively larger out of the plane distortion by trifluoromethyl

Scheme 19. Two-Electron Reduction of an 18π Diboron−-Porphyrin Complex, 30, to Its 20π Diboron Isophlorin Complex, 3352

H


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Scheme 20. Simultaneous Two-Electron Reduction and Demetallation of an 18π Cu(II) Porphyrin Complex, 36, into Its 20π Isophlorin, 3553,54

β-hydrogens of the furan rings, indicative of a higher symmetry for the molecule. The large upfield chemical shift value signified the paratropic ring current effects as expected of a 4nπ cyclic system. X-ray diffraction analysis of 38 revealed an absolute planar macrocycle with all the furans remaining coplanar with respect to the mean macrocyclic plane. In a modified synthetic protocol, furan was reacted with thiophene diol to obtain the dithia-dioxa-isophlorin, 39, apart from its higher analogue. Similar to the tetraoxa derivative, 39 also exhibited upfield chemical shift values at δ 3.37 and 3.33 ppm for the β protons of thiophene and furan. X-ray analysis revealed a planar conformation of this isophlorin with very minor geometrical alterations in the macroyclic core. Dissimilar structural features for isophlorins, 38 and 39, result from the unequal distance between the diagonally opposite oxygen atoms. It increases from 4.13 Å in 38 to 4.72 Å in 39 as the geometry transforms from a squarish tetraoxa isophlorin, 38, to a rectangular 39. The steric requirement of bulky sulfur is compensated by the decrease in cavity size upon replacing oxygen by sulfur. This is also illustrated by the relatively nonplanar conformation for the dication of tetrathia isophlorin. Unlike the oxidation of tetraoxa isophlorin, 11, to its corresponding dication, neither 38 nor 39 displayed any such tendency to be oxidized to the 18π aromatic species. Addition of DDQ, TFA, or iodine did not oxidize the macrocycles to their corresponding dication, substantiating its firm stability under ambient conditions. (However, it was observed that they can be oxidized with high equivalents of perchloric acid to yield the unstable 18π dication under ambient conditions). Shinmyozu and co-workers56 adopted a similar strategy to synthesize the meso-pentafluorophenyl tetrathia isophlorin, 40, from the acid catalyzed condensation of 2-(1-hydroxy-1-(pentafluoro)phenylmethyl)thiophene (Scheme 22). In contrast to the planar and antiaromatic features of 38 and 39, the tetrathia isophlorin, 40, was found to be nonplanar and non-antiaromatic in nature. A singlet at δ 6.19 ppm, in its proton NMR spectrum, is a significant large downfield shift, implying the loss of expected paratropic ring current effects. The structure elucidated from X-ray diffraction analysis revealed its nonplanar structure. Akin to tetrapyrrole isophlorin 35, analogous steric effects from the bulky sulfur atoms force a pair of diagonally thiophenes to tilt away from the mean macrocyclic plane. Consequently, it decreases the effective π conjugation and leads to structure induced loss of antiaromaticity. Apart from the effect of heteroatoms, the electronic effects of meso substituents are significant to the cause of stable isophlorins. This was demonstrated when the same group attempted to synthesize mesotetraphenyl tetrathia isophlorin. Addition of DDQ/HClO4 as the oxidizing agent to tetraphenyl tetrathia porphyrinogen, 41, yielded its corresponding dication with two [ClO4]− as its counter-anions, highlighting the influence of strong electron

substituted pyrrole rings in comparison to the unsubstituted pyrrole rings. Steric hindrance induced by four hydrogens in the macrocyclic cavity, compared to two hydrogens in porphyrin, could be an important reason for the nonplanar structure of isophlorin, 35. Spectroscopic evidence suggested reduced aromatic character as observed by the upfield chemical shift (δ 6.87 ppm) for protons of the unsubstituted pyrrole rings. Two signals at δ 8.4 and 9.87 ppm for the core NH protons were uncharacteristic of aromatic porphyrinic character. Both spectroscopic evidence and structural details mutually support the structure induced loss of both aromatic and antiaromatic features in the 20π macrocycle. They further confirmed the presence of four NH’s by deriving the tetra-N-methyl isophlorin, 37,54 with a similar nonplanar structure, which was relatively more stable than the parent macrocycle, 35. From these findings, it is apparent that electron deficient macrocycles play a key role to stabilize the 20π framework. However, the inherent steric hindrance in the macrocyclic cavity of the tetrapyrrolic isophlorin may avoid the much sought-after planar structure, as observed for porphyrin. Unfortunately, this macrocycle could not sustain the reversible oxidation to 18π porphyrin, as proposed earlier by Woodward. Replacing the nitrogens by other chalcogen atoms would be ideal to avoid the steric hindrance in the center of the cavity. However, the associated unstable nature of such a tetrafuran/ thiophene led to the facile two-electron oxidation into their corresponding aromatic dications. Resistance to two-electron oxidation of the 20π skeletal framework can be envisaged with appropriate electron withdrawing substituents on the macrocycle, as observed for the tetrapyrrole isophlorin, 37. By blending the observations from the synthetic strategies of Vogel and Chen, we attempted the synthesis of tetraoxaisophlorin with mesopentafluorophenyl substituents for their electron withdrawing properties. In a parallel to Vogel’s strategy, the pentafluorophenyl furfural was subjected to acid-catalyzed intermolecular condensation followed by oxidation to yield the meso-tetrakis(pentafluoro)phenyl tetraoxa isophlorin, 38 (Scheme 21).55 Scheme 21. Synthesis of 20π meso-Phenyl Tetraoxa and Dioxa−Dithia Isophlorins, 38 and 3955

The macrocycle was purified by column chromatography and did not reveal any sign of instability under ambient conditions. Its proton NMR spectrum revealed a singlet at δ 2.49 ppm for the I


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Scheme 22. Synthesis of 20π Tetrtathia Isophlorins 40 and 4156

porphyrin to isophlorin was observed for Si(IV), Ge(IV), and (I)B−B(I) complexes of porphyrin. Yet, the structure retained a near planar conformation in contrast to its complexes of group(IV) elements. Surprisingly, the computed NICS(0) value for the Pd complex was very close to zero, suggesting the loss of antiaromatic character of the macrocycle. In the continuous pursuit for a stable pyrrole derivative of antiaromatic isophlorin, we analyzed the role of core-modification of a porphyrin by sequential replacement of individual pyrrole rings. Core-modified porphyrins retain similar structural characteristics with altered electronic metal coordinating properties compared to the parent macrocycle, 1. Swapping one or two pyrrole rings with heterocycles such as furan or thiophene does not hinder the 18π electronic framework of the macrocycle. As described earlier, it is obvious that replacing all the four pyrroles by furan or thiophene alters the conjugated pathway from the 18π to 20π network, with negligible change in its ring size (Scheme 24). Surprisingly, the macrocycle with monopyrrole, 46, did not attract sufficient attention of synthetic chemists in spite of its striking antiaromatic structure. We employed a synthetic strategy to condense a modified dipyrromethane, 47, with meso-phenyl difuran carbinol, 48, under acidic conditions followed by oxidation with DDQ.60 Column chromatographic purification of the reaction mixture yielded the monopyrrole isophlorin, 46, as a yellowish-green solid (Scheme 25). At low temperature, its proton NMR spectrum displayed upfield chemical shift values in the region δ 3−1.8 ppm for the β protons of the heterocyclic rings, while the pyrrolic NH resonated deep downfield at δ 29.2 ppm. X-ray diffraction analysis revealed a planar structure for the macrocycle with a single NH at the center of the macrocycle. As the oxidation of the tetrapyrrolic isophlorin yields a porphyrin, it was a case of curious study to oxidize the amine type monopyrrole derivative to the prospective 19π radical, 49. In contrast, the ring underwent twoelectron oxidation either with [Et3O]+[SbCl6]− or with NOBF4 to yield the corresponding the dicationic porphyrin, 50. Proton NMR spectroscopy provided striking evidence for the aromatic feature of 50 in the form of an upfield shift at δ −4.6 ppm for the

withdrawing groups in 40 to prevent the oxidation of the antiaromatic isophlorin. Imahori and co-workers reported the synthesis of stable metal−isophlorin complexes, 42a−c, with a heteroporphyrin containing N, N, S, and P as the coordinating atoms of a modified porphyrin, 43 (Scheme 23).57−59 Scheme 23. Phosphole Containing Porphyrin and Its Reduction to Metal−Isophlorin Complexes57

Reaction of Pd(dba)2 with 43 was rapidly converted to the corresponding palladium complex of the macrocycle, 42a. Even though similar products, 42b−c, were identified when 43 was reacted with Pt(dba)2 and Ni(cod)2, it was observed that the Ni complex was very unstable and decomposed in the solution state. Since similar complexation did not occur with the disulfur analogue of 43, it was evident that phosphorus was crucial to metal coordination by the macrocycle. The proton NMR spectrum of 42a displayed slight upfield chemical shift values for the β protons of the macrocycle, while the P-phenyl protons were observed in low field with respect to the parent porphyrin, 43. However, these values do not imply crucial modifications to the ring current of the macrocycle. X-ray diffraction analysis of the palladium complex revealed the central Pd(II) coordinated to all four heteroatoms with a square planar geometry. Based on the Pd−N and Pd−S bond distances and the peripheral C−C bond alternation, the authors concluded the macrocycle to be a 20π isophlorin. Such metal complexation induced reduction of

Scheme 24. Modified π Conjugation and the Ring Current Effect upon Sequential Replacement of Pyrrole Rings by Furana

a

A similar feature is expected with thiophene/selenophene/N-methylpyrrole. J


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Scheme 25. Synthesis and Reversible Oxidation of Pyrrole Based Isophlorin, 4660

Scheme 26. Synthesis and Reversible Two-Electron Oxidation of Ni(II) meso-Azaporphyrin, 5161

hexachloroantimonate (magic blue) or AgPF6 yielded its corresponding 18π dication, [51]2+. Its molecular structure determined from X-ray diffraction analysis revealed two [SbCl6]− counteranions along with the macrocycle, without modifying the parent metal chelate framework. The proton NMR spectrum of [51]2+ displayed a downfield resonance at δ 8.72 and 8.33 ppm for its β protons of the pyrrole rings, validating its aromatic character. Interestingly, the dication could be reduced back to the 20π macrocycle upon its treatment with NaBH4 to highlight the reversible oxidation of 51. Mixing 51 with its dication, [(51)2+· 2(PF6)−], yielded the air-stable intermediate radical cation [(51)•+·(PF6)−]. Its paramagnetic property was established by EPR spectroscopy along with authentication from 31P NMR for the [PF6]− counteranion. Overall, they could establish a reversible two-electron oxidation between the 20π and 18π states of TADAP and were stable enough to be characterized in the solid state. Adding to the synthetic possibilities for isophlorin and its modified derivatives, Osuka and co-workers62 reported the synthesis of carbazole porphyrinoids. In this strategy, a predesigned acetylene bridged macrocycle was employed to transform them into either pyrrole or thiophene moieties within the π framework. Under Glaser coupling conditions, the 1,8-diethynylcarbazole, 53, was dimerized to yield the corresponding macrocycle, 54, with four acetylene units (Scheme 27). Higher homologues were also observed in this reaction. Upon refluxing a solution of 54 in mesitylene along with aniline and CuCl for 24 h, the dimmeric acetylene units were reorganized to N-phenyl pyrrole, leading to an isophlorin-like structure, 55. On the other hand, refluxing 54 with Na2S·9H2O in THF yielded the dithiophene isophlorin, 56. From the electronic spectrum of 55 and 56, the authors perceived that they lacked the effective π-conjugation expected of 20π isophlorin. But facile oxidation of 56 by MnO2 yielded the 18π porphyrin, 57, which could be reduced back by NaBH4 to the 20π isophlorin. The proton NMR spectrum displayed typical downfield shifts for the peripheral protons of 57 to substantiate the diatropic ring current effects of the aromatic macrocycle. The estimated NICS (0) values for 56 and 57 turned out to be +1.28 and −11.09 ppm, respectively, to affirm the non-antiaromatic feature of dithia isophlorin. Similar derivatives of furan and

pyrrolic NH. Similarly, the protons of the heterocyclic rings were observed in the region δ 10.6−9.6 ppm. A large Δδ value of more than 33 ppm for the NH proton between the 20π and 18π states is perhaps not encountered in the realm of core-modified porphyrins. The estimated NICS value of +27.6 and −13.8 ppm signifies the ring oxidation from 4nπ to (4n+2)π without the aid of pyrrole NH. Solid state analysis through X-ray diffraction revealed the dicationic porphyrin with two [SbCl6]− counteranions, one each above and below the planar macrocycle. Zn powder could reduce the aromatic dication back to the antiaromatic isophlorin, as monitored by electronic absorption spectroscopy. The 46/50 pair represents the first example of a redox reversible isophlorin−porphyrin pair as proposed by Woodward. 2.6. Porphyrinoids with 20π Electrons

Of late, there has been increased interest in the synthesis of isoelectronic structures of 20π isophlorin. They are constituted either as macrocyclic metal complexes or by accommodating unusual substituents within the porphyrin framework. Very recently, Matano and co-workers61 synthesized a Ni(II) complex of 20π 5,10,15,20-tetraaryl-5,15-diaza-5,15-dihydroporphyrin (TADAP), 51, which exhibited controlled reversible two-step, one-electron oxidation to the corresponding 18π dication, through the 19π radical cation intermediate (Scheme 26). The 20π TADAP was synthesized by the double reductive coupling of a Ni(II) dipyrrin complex, 52, with two nitrogen bridges diagonally opposite to each other. The global conjugation for the macrocycle is seemingly derived from the effective delocalization of the electron lone pairs from the bridging nitrogen atoms. Substantial support for this understanding was obtained from its proton NMR spectrum, which displayed the upfield signals at δ 4.61 and 3.30 ppm for the β-protons of the pyrrole rings. The relatively high field resonances in comparison to other 20π macrocycles (11, 22, 24, 38, 39, and 46) were suggestive of weak a paratropic ring current effect expected of the meso nitrogen atoms in the macrocycle. In tandem with feeble paratropic ring current effects, X-ray diffraction analysis revealed a square planar geometry for the Ni(II) incorporated inside a near planar macrocycle. Further oxidation of this metal complex either with 2 equiv of tris(4-bromophenyl)ammoniumyl K


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Scheme 27. Synthesis of the Carbazole Derivative of 20π Isophlorins, 55 and 5662

selenophene reported by Yoshioka63 and co-workers were also found to be exhibit non-antiaromatic characteristics. In yet another modification to the porphyrin core, Shen and co-workers64 synthesized a heteroporphyrin with one of the pyrroles fused to a thiophene ring. Thienopyrrole dialdehyde, 58, was condensed with tripyrrane diacid, 59, through an acid catalyzed “3 + 1” MacDonald method to yield the 20π porphyrin, 60 (Scheme 28).

radical anion as analyzed from ESR spectroscopy. Structurally, 60 varies from a typical isophlorin cyclic arrangement, as it has more than four meso carbons, which ideally leads to incomplete conjugation with four heterocyclic rings. The intervention of a fused thienopyrrole facilitates the completion of the π framework through an unsymmetrical path. Yet, it is surprising to see the loss antiaromatic character for 60 in spite of sustaining the flat topology. Furuta’s novel approach toward a confused approach on porphyrins led to the accidental discovery of doubly N-confused isophlorin, 61.65 During the exploration of porphyrins with inverted pyrrole rings, it was observed that confused derivatives of porphyrins undergo facile transformation to confused phlorins (Scheme 29). Interestingly, reduction of N-confused and N-fused porphyrin, 62, with benzenethiol clips the confused ring in addition to substitution of arylthio groups on both the α carbon atoms of both the confused pyrroles. The strain released from the breaking of the fused system inverts the confused pyrrole to attain a 20π skeleton. En route to this conformation, 61 does not emulate the sophisticated conjugation of the antiaromatic isophlorin, 2, due to connectivity through β carbons of the inverted pyrrole rings. Even though it exhibited good stability, it was oxidized to the doubly confused porphyrin, 63, over a period of 3 days under oxygen atmosphere. In its proton NMR spectrum, three resonances were observed (δ 8.14−9.15 ppm), corresponding to an inner NH, one outer NH of the pyrrole, and one inner β-CH proton of the inverted pyrrole in the center of the macrocycle. X-ray crystallographic analysis revealed a nonplanar geometry, in tune with the inference from its NMR spectrum. Supporting the loss of the antiaromatic property, the estimated NICS value of +3.39 ppm reflected a weak paratropic ring current effect for the deviation from a flat structure. The oxidized product, 63, is a unique feature of an aromatic porphyrin to contain four hydrogens in the center of the macrocycle. Consequently, steric hindrance of the crowded cavity forces the macrocycle to adopt a saddle structure. Surprisingly, its computed NICS value of δ −12.31 ppm signified a strong aromatic character for the porphyrin. But, the stability of the aromatic porphyrin, 63, diminishes in the presence of a reducing agent such as NaBH4 and reverts to the reduced nonantiaromatic isophlorin, 61. It can be observed that even minor deviations in the conjugated pathway can be detrimental to the antiaromatic feature of isophlorin. Prior to this report,

Scheme 28. Synthesis of a Heteroporphyrin, 60, Bearing a Theinopyrrole Unit with 20π Electrons64

From X-ray diffraction analysis, the macrocycle was found to adopt a near planar structure. The effect of ring current was examined from proton NMR spectroscopy through chemical shift values of the meso protons. As an unsymmetrical macrocycle, four different chemical shift values of δ 6.57, 6.20, 4.97, and 4.82 ppm were observed for the four meso hydrogens. Being accounted for 20π electrons, these resonances marked the absence of significant paratropic ring current effects, in comparison to the strong upfield shifts for the meso hydrogens of a isophlorin. The pyrrole N−H protons in the center of the cavity were found to resonate as three different signals in the region between δ 9 and 17 ppm. They also lead to three different tautomeric structures depending on the presence of N−H on any two of the three pyrroles. Computational studies predicted the most stable conformer with the two inner NH protons arranged in cis and trans alignments. The estimated low and positive NICS values suggested the non-antiaromatic feature of the macrocycle. Interestingly, 60 can be reduced by NaBH4 to the corresponding L


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Scheme 29. Synthesis of Doubly N-Confused Isophlorin, 61, by the Reduction of a Doubly Confused 18π Porphyrin, 6265

Scheme 30. Synthesis of Phosphorous Complex of N-Fused Porphyrin, 6566

Scheme 31. Synthesis of Thiaethyne-porphyrin, 66 and Its Dication, 6767

Scheme 32. Modified Conjugated Pathway (68b−d) upon Oxidizing the Pentapyrrolic Macrocycle and by Replacing Pyrrole by Other Heterocycles Such as Furan/Thiophene/Selenophene

Latos-Grazynski and co-workers66 reported the complexation of phosphorus with N-fused porphyrin, 64 (Scheme 30). They observed that the addition of PCl3 to 64 yielded its phosphorus complex, 65, without altering the fused framework of the macrocycle. However, structural elucidation revealed the oxidation of P(III) to P(V). The central phosphorus atom was complexed by three amine-type nitrogen atoms and was further oxidized by oxygen to yield the oxy-phosphorus complex. In an alternative procedure, the same complex was synthesized by the reacting N-confused porphyrin with PCl3. Modifications to the porphyrin ring are a common feature to synthesize antiaromatic macrocycles. Latos-Grazynski and co-workers67 reported the synthesis of a porphyrin-like macrocycle by replacing a pyrrole with an acetylene moiety, 66 (Scheme 31). This mutated porphyrin consisted of two pyrrole rings and a thiophene unit diagonally opposite to the acetylene. In spite of

two amine type nitrogens of the pyrrole ring, the macrocyclic ring was oxidized by two electrons to yield the corresponding dication, 67, without dehydrogenating the pyrrole NH. Its spectroscopic characteristics revealed typical antiaromatic properties of the macrocycle. These observations reveal the possibility of porphyrin-like macrocycles with 4nπ electrons, but not similar to a typical isophlorin skeleton. Altering to the skeletal framework of the parent isophlorin, 2, is a key factor to synthesize its modified analogues. However, the chemistry of isophlorin remains relatively unexplored in comparison to the fluid and rapid growth of porphyrin chemistry.

3. π EXTENDED ISOPHLORINOIDS 3.1. Scope for Expanding the π Conjugation

Expanding the π network of isophlorin is an ideal strategy to synthesize large and stable 4nπ macrocycles. Even though it M


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Scheme 33. Expanded Isophlorins Obtained by Acid Catalyzed Reaction between Pentafluorobenzaldehyde and Thiophene71

Scheme 34. Amphoteric Behavior Displayed by the One-Electron Oxidation and Reduction of 25π 69 to 24π [69]+ and 26π [69]− upon Addition of Appropriate Redox Reagents71

appears parallel to analogous porphyrinoids, π conjugated macrocycles derived by interlinking the heterocyclic units through bridging carbon atoms whose π circuits flow only through the carbon atoms may be considered as expanded isophlorins. These systems are expected to have different properties compared to the aromatic counterparts. This is apparent by the incomplete conjugation of macrocycles with an odd number of heterocyclic units having equal number of meso carbon bridges. If the parent isophlorin is expanded by inserting an additional pyrrole and a meso carbon, the macrocycle will be forced to retain a sp3 meso carbon which interrupts the continuous flow of the π circuit (Scheme 32). But pyrrole’s ability to alter between amine and imine nitrogen is an advantage for the pentapyrrolic systems 68a−d in completing their π circuit. Hence, many possibilities for a pentaphyrin are feasible depending on the number of nitrogens involved in the conjugated pathway. Even though the number of π electrons can vary from 24 to 20, pentaphyrin is predominantly stable with 22π electrons (68c),68 while the other forms of pentaphyrin are yet to be discovered. This π skeleton undergoes a major transformation upon substituting all the pyrrole rings by other heterocycles, such as furan/ thiophene/selenophene. Unlike the nitrogen, the chalcogens are not capable of sustaining a double bond with α carbons in the heterocyclic unit, and hence, the π circuit is forced to flow only through the carbon atoms. This predicament can find favor when expanded isophlorins with an even number of heterocyclic units

and bridging carbon atoms are able to form completely conjugated structures. In the following sections, we highlight the reports on the synthesis and structural characterization of expanded isophlorins. 3.2. Aromatic Expanded Isophlorins

Cavaleiro and co-workers reported the one-pot synthesis of hexapyrrolic systems upon refluxing pyrrole with pentafluoro benzaldehyde in acidic conditions.69 Later, Osuka and co-workers70 reported the remarkable acid catalyzed reaction of pyrrole with pentafluoro benzaldehyde, to isolate a variety of expanded porphyrins in a similar one-pot synthesis from these commercially available precursors. They were successful in the identification and characterization of expanded porphyrinoids bearing 5 to 12 pyrrole units. As mentioned earlier, all the macrocycles were completely conjugated owing to the pyrrole’s ability to alter its nitrogen between amine and imine form in favor of macrocyclic conjugation. Under similar reaction conditions, thiophene and pentafluoro benzaldehyde were catalyzed by BF3·OEt2 followed by oxidation with FeCl3 (Scheme 33).71 The MALDI TOF/TOF mass spectrum of this reaction mixture confirmed the formation of different macrocycles whose constitution varied from four to ten thiophene units. Among these, the pentathiophene, 69, was found to form in 35% yields. The isolated tetrathiophene, 40, was found to have similar characteristics as reported by Shinmyozu and co-workers. Other macrocycles with six to eight thiophene units were isolated in N


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relatively lower yields. In contrast to the expectation that expanded isophlorins with odd number of heterocyclic units cannot favor complete conjugation, it turned out that 69 was an absolutely conjugated 25π radical. The mass spectrum of this macrocycle further supported the formation of a neutral radical species. Its molecular structure as determined from X-ray diffraction analysis revealed a planar structure with the unpaired electron delocalized over the whole macrocycle. Its isolation from column chromatography was strongly suggestive of its high stability under ambient conditions. The availability of such a stable neutral radical is not very common.72−76 Its remarkable structural feature was the planarity stemming from the uniform orientation of all the thiophenes’ sulfur atoms toward the center of the macrocycle. Such a neat orientation has not been observed to date for meso-phenyl pentaphyrins. In a test of radical behavior, it revealed the single electron transfer (SET), and 69 was found to exhibit amphoteric behavior with suitable redox reagents (Scheme 34). It could be either oxidized into an antiaromatic 24π cation, [69]+, or reduced to an aromatic 26π anion, [69]−. In either case, the macrocycle retained its planar structure as observed from X-ray diffraction analysis. The ring current effect was distinct from their respective proton NMR spectrum, which clearly displayed a downfield singlet (δ 11.15 ppm) for the anion, [69]−, and an upfield singlet (δ −7.86 ppm) for the cation, [69]+, protons of the symmetrical macrocycle. They are in tune with the diatropic and paratropic ring current effects expected of the aromatic anion and the antiaromatic cation, respectively. In fact, the estimated NICS value of δ 37.5 ppm for [69]+ is one of the highest values reported among stable 4nπ systems. In the same reaction (Scheme 32), the isolated 30π expanded isophlorin, 70, with six thiophene rings, was found to be aromatic in nature. The macrocycle exhibited a planar rectangular topology, with inversion of two thiophene rings. Its upfield NMR chemical shift values at δ −0.46 ppm and downfield chemical shift values at δ 9.18 and 9.09 ppm revealed the effect of the diatropic ring current on the hydrogens at the center and on the periphery of the macrocycle, respectively. The same macrocycle was synthesized through a different strategy by reacting thiophene with thiophene diol under acidic conditions with subsequent oxidation (Scheme 35).77

30π macrocycles with different heteroatoms could be synthesized by employing the same synthetic strategy. Furan and selenophene were condensed with the thiophene diol to yield the respective 30π expanded isophlorins, 71 and 72. The replacement of three thiophenes by three furans in 70 induced alternate ring inversions, as observed from the two singlets at δ 7.99 and 1.87 ppm in the proton NMR spectrum of 71. Diselena expanded isophlorin, 72, retains a rectangular topology similar to that of 70; however, the diagonally opposite thiophene and selenophene rings were found to be inverted, leading to a reduced geometry of the macrocycle. In an alternate synthetic strategy, similar 30π expanded isophlorins were synthesized by the acid catalyzed condensation of 2,2′-(pentafluorophenylmethylene)dithiophene/ difuran with either thiophene diol or selenophene diol (Scheme 36). Macrocycles with four furan rings, 73 and 74, displayed symmetrical double furan ring inversion. Similar ring inversion by two thiophene rings was found to increase the symmetry of the macrocycle when there were four thiophene rings in the 30π expanded isophlorins, 70 and 72. Their proton NMR spectrum revealed the diatropic ring current effects expected of (4n+2)π systems with corresponding upfield and downfield shifts for the hydrogens in the center and the periphery of the macrocycle, respectively. Recently, Osuka and co-workers reported the 30π hexapyrrolic expanded isophlorin with diethylsulfanyl groups on the β positions of the pyrrole rings (Scheme 37).78 They synthesized the 30π hexaphyrin by condensing β substituted diethylsulfanyl pyrrole with dipyrromethane dicarbinol under acidic conditions followed by oxidation with DDQ. However, they could only identify the twisted 28π hexaphyrin, 75, which could be oxidized further to the 26π by MnO2. On the other hand, they successfully reduced 28π hexaphyrin to the corresponding 30π isophlorin, 76, wherein all the nirogens have a pyrrolic NH and hence the π circuit flows only through the carbon atoms. Its proton NMR spectrum displayed the downfield shift for the NH’s of the noninverted pyrrole rings (δ = 9.96 ppm) while the NH’s of the inverted pyrrole rings displayed an upfield chemical shift (δ = −1.37 ppm) in tune with the antiaromatic feature of the macrocycle. The solid state analysis by X-ray diffraction analysis confirmed the ring inversion of diagonally opposite pyrrole rings, similar to what is observed for rectangular hexathiophene expanded isophlorin. Importantly, they observed that the ethylsulfanyl groups were critical to the reduction of 28π hexaphyrin, 75, to the 30π expanded isophlorin 76. Yet, 76 was found to be unstable and succumbs to oxidation over a period of time in the presence of atmospheric oxygen, which further supports the unstable nature of highly reduced hexapyrrole hexaphyrin with 30π electrons. However, the stability of nonpyrrolic expanded isophlorins was further explored by replacing two thiophene units in 70 with benzene units (Scheme 38).79 These benzo isophlorinoids 77 and 78 can be synthesized either by condensing trithiophene with 1,4-benzene diol or by the condensation of 2,2′-(pentafluorophenylmethylene)dithiophene with 1,4-benzene diol. The characterization of 78 revealed the aromatic characteristics, which could be possible only when one of the benzene rings adopted a quinone-like structure. By altering the number of heterocyclic units, an isophlorin skeleton could be formatted into an aromatic macrocycle as well. Even though they are expected to be stable, pyrrole derivatives displayed strong susceptibility to oxidation.

Scheme 35. Synthesis of 30π Expanded Isophlorins by Acid Catalyzed Condensation of Thiophene Diol with Heterocycles such as Thiophene/Furan/Selenophene77

O


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Scheme 36. Synthesis of 30π Expanded Isophlorins by Acid Catalyzed Condensation of Dithienyl/Difuranyl Methane with Thiophene/Selenophene Diol77

When furan was reacted with pentafluoro benzaldehyde, under similar reaction conditions, only two products were identified from the reaction mixture (Scheme 39).80 Both the 30π hexa furan, 79, and the 40π octa furan, 80, have contrasting ring current effects. 79 could be easily identified as an aromatic macrocycle and adopted a structure similar to that of the 30π expanded isophlorin 71. Only two singlets at δ 7.85 and 2.5 ppm were observed in its proton NMR spectrum. Interestingly, its higher congener, 80, also exhibited a similar NMR spectrum with two singlets at δ 9.4 and 5.85 ppm. Its molecular structure, determined from X-ray diffraction studies, appeared to be an extended version of the 30π macrocycle, 71. It revealed symmetrical inversions of four furan rings, such that the oxygens of the alternate furan rings were pointed away from the center of the macrocycle. Large expanded porphyrins are known to curl into a twisted conformation due to their highly flexible nature.17,81−84 On the other hand, they also display inversion of a few heterocyclic rings. Both these features are generally mutually exclusive to each other. It can be inferred that, possibly, ring inversions in large porphyrinoids/isophlorinoids are crucial to avert nonplanar conformation by inducing steric hindrance at the center of the macrocycle. In fact, a similar feature was observed by Osuka and co-workers with an octaphyrin.85 Similar to hexaphyrin, octaphyrin, 81 (twisted 36π), can have multiple π configurations varying from 32π to 40π electrons. However, the 36π and 38π are the most predominant structures for the eight pyrrole macrocycles. Recently, they were successful

Scheme 37. Synthesis of Hexapyrrole 30π Expanded Isophlorin with Diethylsulfanyl Substitutents78

3.3. Antiaromatic Expanded Isophlorins

Since the acid catalyzed reaction of thiophene or pyrrole with pentafluoro benzaldehyde yielded a variety of π conjugated macrocycles, it could be considered as a general synthetic methodology between a five membered heterocyclic unit and the aryl aldehyde.

Scheme 38. Synthesis of Monobenzo 20π Isophlorin, 77, and Dibenzo 30π Expanded Isophlorin, 7879

P


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Scheme 39. One-Pot Acid Catalyzed Condensation of Furan and Pentafluoro Benzaldehyde To Yield 30π (79) and 40π (80) Expanded Isophlorins80

Scheme 40. Planar Octapyrrole Dianion Expanded Isophlorin, 83, Obtained by the Deprotonation of 36π Octaphyrin, 8185

Scheme 41. Synthesis of Monophosphorous Complex, 84, and Bis-phosphorous Complex, 85, of Twisted Isophlorin86

in the identification of a 36π octaphyrin dianion, 83, with four inverted pyrrole rings (Scheme 40). This structural feature is in stark contrast to the figure-of-eight conformation for a majority of octaphyrins and further supports the ring-inversion induced stabilization of planarity. It was observed that the addition of a strong base leads to either mono or bis deprotonation of the pyrrole NH, depending the stoichiometry of the added base. With 40 equiv of TBAF, they were able to identify only the

monodeprotonated octaphyrin, 82, which revealed the characteristics of a Mobius band. Addition of excess TBAF (7000 equiv) led to the double deprotonation and the uncurling of the macrocycle into a planar structure. X-ray diffraction analysis of 83 revealed the inversion of four alternate pyrrole rings, similar to that observed for 40π octa furan, 80. Due to the planarity of this 36π macrocycle, it was expected to be antiaromatic in nature, which was substantiated by the estimated NICS value of δ + 22.6 ppm. Q


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the resonances of the ethylene bridge protons, which displayed two doublets at δ 12.83 and 5.37 ppm for the inner and outer protons, respectively. A similar macrocycle, 87, with β substituted thiophenes also displayed characteristics of paratropic ring current effects. X-ray diffraction analysis of the 87 revealed a rectangular geometry; however, it displayed lack of ring inverted thiophene rings. It could be observed that the insertion of the ethylene bridge had elongated the macrocycle by compressing the distance between the opposite thiophenes, leading to insufficient space for accommodating the β carbons. The estimated NICS values of δ +11.8 and +11.99 ppm for 86 and 87 reaffirmed the paratropic ring current effects in these 4nπ macrocycles. Yet, this orientation could be altered to a squarish framework by replacing both the thiophenes of the acetylene by furan units. Acid catalyzed condensation of bis-furan acetylene with thiophene/selenophene/furan diol yielded the expected 32π expanded isophlorins, 88−90 (Scheme 43).88 Their proton

Prior to this report, the same research group was successful in the isolation of 40π isophlorin, 85, albeit in its twisted conformation (Scheme 41).86 Treating the 36π octaphyrin, 81, with PCl3 and triethyl amine yielded the 38π monophosphorus complex (84) and the 40π di phosphorus (85) complexes. They observed that the yield of 85 was significant when the reaction was carried out in the presence of water. This complexation is accompanied by simultaneous fourelectron reduction of the 36π octaphyrin to the 40π expanded isophlorin. However, they were quick to observe the two-electron redox transformation between the 38π and 40π states for both 84 and 85, with very little stability for the 40π state of 84. They could alter between the two states by employing MnO2 as the oxidizing agent for the reduced form and NaBH4 as the reducing agent for the oxidized form. Since the macrocycle adopted a twisted conformation, two different pockets are available for metal complexation. X-ray crystallographic analysis revealed +3 and +5 oxidation states for the phosphorus atoms in the complex. In one of the pockets, phosphorus was oxidized to phosphine oxide along with the two P−N bonds with the nitrogens of the pyrrole rings and a P−C bond with a β carbon of a pyrrole ring. However, the phosphorus in the +3 oxidation state is formed only from P−N bonds. Even though they account for the 40π electrons, the proton NMR spectrum did not display the significant paratropic ring currents expected of 4nπ systems. Their nonplanar conformation is not only aided by inherent flexibility, but also in addition to phosphorus complexation, which prevents it from uncurling to planarity. Hence, the expected antiaromatic feature of this macrocycle is lost by structure induced loss of paratropicity.

Scheme 43. Synthesis of 32π Expanded Isophlorins from Difuranyl Ethylene88

3.4. Expanded Isophlorins with Ethylene Bridges

Apart from the inclusion of additional heterocyclic rings to expand the π network of isophlorin, additional meso carbon bridges can also be employed to increase the conjugated pathway. Even though such instances are very few, yet they exemplify the unknown chemistry of antiaromatic systems. Incorporating two additional meso carbons into an isophlorin framework can change the electron count from (4n+2)π to 4nπ systems and vice versa. This was demonstrated by inserting two additional meso bridges into the 30π expanded hexa thia isophlorin 70 (Scheme 42).87 Scheme 42. Synthesis of 32π Expanded Isophlorins from Dithienyl Ethylene87 NMR spectrum revealed significant paratropic ring current effects at low temperature. Of particular interest was the observation of two doublets at δ 12.42 and 4.91 ppm for the inner and outer hydrogens of the ethylene bridge in 88. A coupling constant of 16 Hz for these two signals further confirmed the E conformation of the double bond between the heterocyclic units. Ring inverted heterocyclic rings were confirmed from X-ray diffraction studies. It became apparent that the reduced atomic size of oxygen provided sufficient space for accommodating the ring inverted β carbons inside the cavity of the macrocycle. When a 32π expanded isophlorin with six furan rings was synthesized, its molecular structure revealed an unexpected twisted confirmation. TFA was added to enhance its poor solubility in common organic solvents. Suddenly, the color of the solution in methylene chloride changed from brownish-red to deep blue color. The resulting product was crystallized to observe a planar 30π dication with two triflate ions, one each above and below the place of the macrocycle. Similar changes were observed for other

The synthesis of ethylene bridged expanded isophlorin, 86, was achieved by the acid catalyzed condensation of bis-thiophene ethylene with thiophene diol followed by subsequent oxidation. As expected, the insertion of two additional meso carbons transformed the aromatic 30π macrocycle to the antiaromatic 32π expanded isophlorin. Its proton NMR spectral features were in tune with the expected paratropic ring current effects, although observed only at low temperatures. Of particular interest were R


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Scheme 44. McMurry Coupling of Dithienyl Dialdehyde into 22π Expanded Isophlorins90,91

Scheme 45. Anti-aromatic Tetraepoxy Annulenes with a π-Framework Analogous to Expanded Isophlorins

by DDQ oxidation yielded the corresponding 22π expanded isophlorin. Its molecular structure revealed a planar conformation, with the ethylene bridge adopting a cis-like conformation. The proton NMR spectrum revealed the diatropic ring current effects expected of the 4nπ system. Surprisingly, they could predict the possibility of 20π antiaromatic dication [91]++ upon the addition of H2SO4 to 91.

32π macrocycles, and similar results were obtained by oxidizing with Meerwien salt [(SbCl6)−(Et3O)+].89 The significant change in their electronic properties was confirmed by proton NMR spectroscopy and electronic spectroscopy. Of particular interest were the large ring current shifts for the ethylene bridge protons upon switching from antiaromatic to the aromatic state. The hydrogen of the ethylene bridge in [90]++ that was oriented away from the center of the macrocycle was found to resonate as a doublet at δ 14.04 ppm, corresponding to a downfield shift by more than 10 ppm. Similarly, the ethylene bridge hydrogen inside the macrocycle cavity resonated at δ −9.93 ppm, an upfield shift by more than 20 ppm. In general, a huge change in Δδ value from 7.42 ppm for 88 to 24 ppm for [90]++signified a major transformation in the electronic property of the macrocycle. The estimated NICS value of δ +11.24 and −14.01 ppm for [90] and [90]++, respectively, confirmed the oxidation induced transformation from 4nπ to a (4n+2)π system. Further investigations revealed the reduction of these aromatic dications to the corresponding antiaromatic free base upon the addition of reducing agents such as FeCl2, Zn, or triethyl amine. Similar structural modifications to the isophlorin structure, 43, were reported by the groups of Kamljit Singh90 and Daoben Zhu.91 They synthesized an aromatic 22π expanded isophlorin, 91, with four thiophene units by replacing two meso carbons with equal ethylene bridges (Scheme 44). McMurry coupling of (phenylmethylene)dithiophene/selenophene dialdehyde followed

4. ISOPHLORIN-LIKE MACROCYCLES 4.1. Tetraepoxy Annulenes

π-Conjugated systems with a close resemblance to the π skeleton were synthesized with multiple ethylene bridges between thiophene or furan units. Markl and co-workers92 reported the synthesis of tetraepoxy annulenes by connecting two bifuran units through lengthy alkene bridges. They could be ideally considered as the expanded version of tetraoxa porphycene, 20. They were successful in the synthesis of 32π, 36π, and 40π macrocycles, 92−94, through Witting type cyclization from appropriate precursors (Scheme 45). Due to the large size of the macrocycles from numerous carbon bridges, authors could detect multiple isomers in the proton NMR spectrum for these systems. From the observed chemical shift values, they could confirm the paratropic ring current effect expected of 4nπ systems. By rearranging the carbon bridges with suitable precursors, they were able to synthesize S


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Scheme 46. Ethylene Bridged Macrocycles Synthesized from McMurry Coupling of Thiophene, Bithiophene, and Terthiophene Dialdehyde95

20π tetrathiophene, 100, bears a structural resemblance to porphycene, 19, and the authors could not oxidize it further to its corresponding 18π dication, while another group could electrochemically reduce it to the 22π dianion. Hexathiophene, 101, can be considered as a structural isomer of 30π expanded isophlorin 70, since both contain six thiophene units and six bridging meso carbon atoms. Yet, 101 was found to be devoid of significant ring current effects, since two doublets for the thiophene protons were observed at δ 7.05 and 6.98 ppm along with a singlet for the bridging ethylene protons at δ 6.60 ppm. In contrast to 70, the chemical shift values are much more upfield shifted to suggest the absence of diatropic ring current effects. Ellinger and co-workers could prove the nonplanar structure of both 100 and 101 by X-ray diffraction studies in support of the spectroscopic features of these annulenes. Further, the cyclization of terthiophene dialdehyde by McMurry coupling yielded the 28π hexathiophene, 102, with two ethylene bridges, which had moderate stability. The observation of signals in the region between δ 7.00 and 6.00 ppm in its proton NMR spectrum convinced the authors about its non-antiaromatic behavior. But they could successfully oxidize to its corresponding dication by the addition of sulfuric acid. The purple colored dication displayed downfield chemical shift values (recorded in D2SO4) for all its protons between δ 11.00 and 12.50 ppm to validate the diatropic ring current effects expected of the 26π system. Finally, they were successful at the synthesis of tetrathia[22]annulene[2.1.2.1], 103, by subjecting the dialdehyde of dithienylmethane. From NMR spectroscopy, they could identify the downfield chemical values to indicate the aromatic character of a macrocycle which could be considered as an aromatic expanded isophlorin.

isomers of 32π and 36π tetraepoxy annulenes. Particularly, for tetraepoxy[32]annulene(8.0.8.0),93 92 two different isomers tetraepoxy[32]annulene(6.2.6.2), 95, and tetarepoxy[32]annulene(4.4.4.4), 96, were synthesized and identified as antiaromatic from their spectral characteristics. Similarly, tetraepoxy[36]annulene(10.0.10.0),94 93, and tetraepoxy[36]annulene(6.4.6.4), 97, corresponded to 36π macrocycles. The only 40π macrocycle tetraepoxy[40]annulene(12.0.12.0), 94, synthesized had poor solubility characterization by NMR spectroscopy. All these macrocycles were readily oxidized to their corresponding aromatic dications. Similar tetraexpoxy annulenes with (4n+2)π electrons were also synthesized that displayed characteristic features of aromatic systems. 4.2. Sulfur Bridged Annulenes

Cava and co-workers reported the synthesis of sulfur bridged annulenes by McMurry coupling of dialdehydes derived from thiophene and its oligomers (Scheme 46).95 Intermolecular coupling of 2,5-thiophenedicarboxaldehyde yielded trisulfide 98 and the tetrasulfide 99, respectively. They both represent a typical annulene-like π-framework with cis-type ethylene bridges in between the thiophene units. 98 is perhaps the smallest of the isophlorin-like macrocycles, and it accounts for 18π-electrons with six carbon bridges between the three thiophene units. Yet, its proton NMR spectrum did not reveal significant diatropic ring currents as expected of (4n+2)π electron systems. Even though the observation of only two signals at δ 6.84 and 6.81 ppm highlighted the symmetrical nature of the macrocycle, the authors identified its nonplanar structure from X-ray diffraction analysis. All three thiophene units were out of the mean plane of the macrocycle, which could be the probable reason for the lack of significant ring current effects. Similarly, they could cyclize the dialdehyde of bithiophene to synthesize 20π and 30π macrocycles, 100 and 101, respectively.

4.3. Oxidized Porphyrins

The scope of iosphlorin chemistry originated mainly due to the possibility of a 20π intermediate in the synthesis of porphyrin. T


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Scheme 47. Two-Electron Oxidation of 18π Porphyrin, 104, into 16π Macrocycle, 105, and Synthesis of Cationic Metal Complex, 10696,97

However, it can also be envisaged that the 18π porphyrin can be oxidized to a 16π macrocycle, which should be devoid of any NH in the core of the macrocycle. Yamamoto and co-workers were successful in oxidation of the β-substituted meso phenyl porphyrin, 104, into a 16π electron species, 105 (Scheme 47). In a two step process, 104 was bis-lithiated by n-BuLi followed by the addition of SOCl2 to yield the unstable 16π 105.96 Its absorption spectrum displayed a significant blue shift in comparison to the 18π porphyrin, 104. From single crystal X-ray diffraction studies, it was confirmed to adopt a highly distorted structure with clear bond alternation between the single and double bonds. With four imine-like nitrogen donors, it can be expected to act as an efficient ligand for low oxidation states of metal ions. However, they observed that salts such as SnCl2 were capable of reducing the 16π macrocycle 105 to an 18π porphyrin core.97 It was observed that the monolithiated complex of 105 could be reduced by metals such as zinc and copper to yield the corresponding metal porphyrin complexes. However, they were successful to identify a cationic metal complex, 106, with [ZnCl3]− as the counteranion upon reacting 105 directly with zinc chloride (Scheme 47). The structure of this metal complex as elucidated by single crystal X-ray diffraction displayed a ruffled structure similar to the neutral ligand 105. The estimated NICS values of +0.5 and +4.5 for 105 and 106, respectively, revealed the weak antiaromatic character. This can be attributed to the severe distortion from the highly planar geometry of the porphyrin.

enhance the resistance to further oxidation. This has been exemplified by highly electronegative metalloids such as Si(IV) and Ge(IV), who possess the ability to pull π electron density toward the metal center when complexed by tetrapyrrole isophlorin. At the same time, the diverse structural features of these antiaromatic systems such as planar, ruffled, and figure-of-eight conformations, highlight the importance of planarity for π-conjugation even in 4nπ macrocycles. Ruffled and twisted conformations highlight the structure induced loss of diatropic/paratropic ring current effects. On the contrary, heterocyclic ring inversion prevents twisting of the macrocycle into a nonplanar conformation to sustain effective conjugation of the π circuit. It has been observed that 4nπ systems are distinctly different in their reactivity with oxidizing agents in comparison to the aromatic counterparts. Reversible two-electron oxidation of isophlorinoids to their corresponding aromatic states has been the hallmark of these antiaromatic macrocycles that exude the potential to be employed as a source of electrons in organic redox transformations. There are many unexplored factors of antiaromatic isophlorinoids, which ideally could be explored in parallel to porphyrinoids. 4nπ systems are expected to have a doubly degenerate HOMO with one electron each. Hence, they can be anticipated to be better organic conductors in comparison to diamagnetic aromatic species. However, Jahn−Teller distortions lead to reduced symmetry and the subsequent loss of the doubly degenerate HOMO, resulting in diamagnetic species. By sustaining the triplet ground state, antiaromatic systems can be harnessed as potential materials for organic ferromagnets.24 A prominent disability of isophlorin appears in the form of its ability to complex metal ions. The coordination chemistry of metal−isophlorin complexes does not appear to be as significant as observed with porphyrin. It can be expected that synthetic advances toward metal ligation by antiaromatic systems can open up new avenues for applications based on paramagnetic materials.

5. SUMMARY AND OUTLOOK In this review, we have highlighted the synthetic aspects of stable isophlorin and its modified derivatives. It has been more than half a decade since the concept of isophlorin was introduced and has been pivotal to the chemistry of antiaromaticity, apart from cyclobutadiene and cyclcooctatetraene. Even though the chemistry of isophlorin has yet to bloom, it has already disclosed the diversity in terms of structure and reactivity. The synthesis of modified 20π isophlorins and their expanded derivatives contradicts the suspected instability of antiaromatic systems. The choice of heteroatoms and substituents on the meso carbons of modified isophlorins is crucial to the stability under ambient conditions. In addition, strong electronegative substituents

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. ORCID

Venkataramanarao G. Anand: 0000-0002-7110-7994 U


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Notes

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The authors declare no competing financial interest. Biographies Kiran Reddy Baddigam was born in Thumuluru village, Andhra Pradesh, India. He received his M.Sc. degree in Organic Chemistry from the Acharya Nagarjuna University, India, in 2008, and he received his Ph.D. degree from the Indian Institute of Science Education and Research, Pune, India, in 2016 with Prof. Anand. His Ph.D. dissertation was based on the synthesis of novel π-conjugated isophlorinoids and their host− guest interaction studies with fullerene-C60. Ashokkumar Basavrajappa received his B.Sc. in 2011 and his M.Sc. in Chemistry in 2013 from University of Mysore, Karnataka, India. Then he joined Indian Institute of Science Education and Research (IISER), Pune, India, for his doctoral studies in 2014. Presently, he is pursuing doctoral research under the guidance of Prof. V. G. Anand. His research mainly focuses on the synthesis of stable expanded isophlorins with unique optical, electronic, and magnetic properties. Madan Digambar Ambhore was born in Nanded, Maharashtra state, India, in 1990. He received his Bachelor’s degree (2011) and Master’s (2013) in Organic Chemistry from Yeshwant Mahavidyalaya, Nanded, affiliated with S.R.T.M. University Nanded, Maharashtra, India. Currently, he is pursuing his doctoral studies under the supervision of Prof. V. G. Anand, at Indian Institute of Science Education and Research (IISER), Pune. His research work is focused on the synthesis of coremodified porphyrins and isophlorins. Venkataramanarao G. Anand was born in 1974 and hails from Bengaluru, Karnataka, India. He completed his M.Sc. from St. Joseph’s College, Bengaluru (affiliated with Bangalore University), in 1996 and received his Ph.D. from IIT Kanpur, India, in 2002 for research on expanded porphyrins with Prof. Tavarekere K. Chandrashekar. From 2002−2004, he was a JSPS postdoctoral fellow with Prof. Atsuhiro Osuka at Kyoto University, Japan. Later, he joined CSIR-NIIST, Thiruvananthapuram, India, as a Scientist in 2004 and then moved to IISER Pune as an assistant professor in June 2007. Since 2013, he has been an associate professor at the same institute. His research interests are in synthesis, spectroscopic characterization, computational studies, and magnetic and structural properties of antiaromatic macrcocyles, π radicals, and fused π-conjugated systems.

ACKNOWLEDGMENTS VGA thanks DST, New Delhi, India, for the Swarnajayanti Fellowship. BKR thanks the UGC for a research fellowship. AKB and MDA thank IISER Pune for their respective research fellowships. REFERENCES (1) Kadish, K. M.; Smith, K. M.; Guilard, R. The Porphyrin Handbook: Inorganic, organometallic and coordination chemistry; Elsevier: 2000. (2) Dolphin, D. The Porphyrins; Academic Press: 1978. (3) Kadish, K. M.; Smith, K. M.; Guilard, R. The Porphyrin Handbook; Academic Press: San Diego, 2000; Vols. 1−10. (4) Furuta, H.; Asano, T.; Ogawa, T. N-Confused Porphyrin - a New Isomer of Tetraphenylporphyrin. J. Am. Chem. Soc. 1994, 116, 767−768. (5) Chmielewski, P. J.; Latos-Grażyński, L.; Rachlewicz, K.; Glowiak, T. Tetra-p-tolylporphyrin with an Inverted Pyrrole Ring: A Novel Isomer of Porphyrin. Angew. Chem., Int. Ed. Engl. 1994, 33, 779−781. (6) Woodward, R. B. Totalsynthese des Chlorophylls. Angew. Chem. 1960, 72, 651−662. (7) Furuta, H.; Maeda, H.; Osuka, A. Confusion, inversion, and creation–a new spring from porphyrin chemistry. Chem. Commun. 2002, 1795−1804. V


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Isophlorinoids: The Antiaromatic Congeners of Porphyrinoids

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