Inverted and fused expanded heteroporphyrins.

Expanded heteroporphyrins are a class of porphyrin macrocycles containing pyrrole, thiophene, furan, selenophene and other heterocyclic rings that are connected to form an internal ring pathway containing a minimum of 17 atoms and more than 18 delocalized π electrons in their conjugated macrocyclic framework. Considering that expanded heteroporphyrins are large in size, these macrocycles are structurally flexible and prefer to adopt various conformations in which one or more pyrrole(s)/heterocycle(s) tend to be in an inverted conformation and pointed outward from the centre of the macrocyclic core. The inverted expanded heteroporphyrins are divided into two classes as follows: (1) N-inverted expanded heteroporphyrins and (2) hetero-atom inverted expanded heteroporphyrins. Both inverted expanded heteroporphyrins show quite unique features in terms of their structure, aromaticity, and electronic and coordination properties. Sometimes, inverted expanded heteroporphyrins lead to the formation of fused expanded heteroporphyrins because of the intramolecular fusion of the pyrrole "N" with the "C" of the inverted heterocycle ring, which also exhibit unique features compared to inverted expanded heteroporphyrins. In this review, we attempt to describe the synthesis, structure, and aromatic, electronic and coordination properties of inverted and fused expanded heteroporphyrins. This review covers the synthesis, structure and properties of inverted and fused expanded heteroporphyrins containing a combination of pyrrole/heterocycle rings starting with five pyrrole/heterocycle-containing pentaphyrins, and then expanded heteroporphyrins containing six, seven, eight and more pyrrole/heterocyclic rings in their porphyrin macrocyclic framework.

Protonation-Triggered Hückel and Möbius Aromatic Transformations in Nonaromatic Core-Modified [30]Hexaphyrin(2.1.1.2.1.1) and Annulated [28]Hexaphyrin(2.1.1.0.1.1).

Two 1,2-diphenyl-1,2-dithienylethene-embedded hexaphyrins 6 and 8 containing 30π and 28π electrons, respectively, in conjugation exhibit nonaromatic characteristics. Compound 6 shows an unusual bond length equalization in its electronic structure. However, on protonation, 6 exhibits Hückel aromatic characteristics while 8 shows Möbius aromatic characteristics. The changes in aromaticity are accompanied by change in conformation from a figure-eight/twisted structure to an open extended structure.

Two non-identical twins in one unit cell: characterization of 34π aromatic core-modified octaphyrins, their structural isomers and anion bound complexes.

Four different core-modified planar 34π octaphyrins (10, 11, 13, and 15) which exhibit rotational isomerism have been synthesized and characterized both in solution and solid states. Octaphyrins 10, 11 and 13 show two inseparable isomers A and B which crystallize in the same unit cell. However, 15 forms two identical isomers of A. Structurally, the two isomers in 10, 11 and 13 (A and B) are different only in the ring inversion of one of the thiophene or selenophene rings present in the terthiophene subunit of the macrocycle. In isomer A, the middle thiophene or selenophene rings are inverted, while in isomer B, the terminal thiophene rings are inverted. The 1H NMR spectrum of these macrocycles shows peaks assignable to protons of both the isomers in toluene D8. The single crystal structure analysis of 10 reveals the presence of both isomers 10A and 10B in a single unit cell with the P21/n space group. Both the isomers exhibit aromatic behaviour in the freebase form. Protonation of pyrrole nitrogens leads to exclusive formation of isomer B for 10 and 11. However, both the isomers are present upon protonation of 13 where the central heterocyclic ring of terthiophene subunits has thiophene and selenophene rings. Octaphyrin 15 crystallizes in the P21/c space group and exclusively isomer A was formed in the reaction. Protonation of pyrrole nitrogens leads to significant increases in aromaticity as revealed by 1H NMR chemical shift data. The NICS values calculated for the individual heterocyclic rings before and after protonation support such a conclusion. The AICD plots exhibit clockwise orientation of current density vectors suggesting the presence of diatropic ring current in the octaphyrins. Energy calculations at the M06L/CC-pVTZ//M06L/6-31G** level qualitatively account for exclusive stabilization of a particular isomer relative to the other upon protonation. To the best of our knowledge 10 represents the first example in expanded porphyrin chemistry where two different structural isomers crystallize in a single unit cell.

24π Core-Modified Nonfused Pentaphyrin with Möbius Aromaticity.

Syntheses of core-modified 24π pentaphyrin 7 and 20π homoporphyrin 8 are reported. The freebase form of 7 exhibits optical and 1 H NMR spectroscopic behavior corresponding to a 4nπ nonaromatic topology at 298 K. However, upon lowering the temperature to 188 K, 7 exhibits weak aromaticity because of a small conformational change. Protonation of the imine pyrrolic nitrogen atoms results in sharpening of the absorption band with more than 100 nm red shift and two-fold increase in ϵ values. The 1 H NMR spectra show large shielding and deshielding of specific protons accompanied by twisting of pyrrole and thiophene rings from the mean plane of the macrocycle. These observations suggest a major structural change upon protonation. The single-crystal X-ray structure of protonated 7 a reveals a severe twisting of the macrocycle, especially at the ethene bridge, and the two thiophene rings adjacent to the ethene bridge are pointed above and below the plane of the ethene bridge (49.07° and 49.08°). The nucleus-independent chemical shift (NICS) values calculated at the center of the macrocycle for the freebase and protonated derivatives of 7 a and 7 b are -5.6, -8.3 ppm and -5.3, -8.4 ppm, respectively. The anisotropy-induced current density (AICD) plots suggest a clockwise circulation of π electrons. Taken together, the changes occurring in the optical spectra, 1 H NMR spectra, single-crystal X-ray structure and NICS calculation reflect a Möbius aromatic topology for protonated 7. However, the homoporphyrin 8 remains nonaromatic both in the freebase and protonated form.

In Vitro and In Vivo Demonstration of Human-Ovarian-Cancer Necrosis through a Water-Soluble and Near-Infrared-Absorbing Chlorin.

With the objective of developing efficient sensitizers for therapeutic applications, we synthesized a water-soluble 5,10,15,20-tetrakis(3,4-dihydroxyphenyl)chlorin (TDC) and investigated its in vitro and in vivo biological efficacy, comparing it with the commercially available sensitizers. TDC showed high water solubility (6-fold) when compared with that of Foscan and exhibited excellent triplet-excited-state (84%) and singlet-oxygen (80%) yields. In vitro photobiological investigations in human-ovarian-cancer cell lines SKOV-3 showed high photocytotoxicity, negligible dark toxicity, rapid cellular uptake, and specific localization of TDC in neoplastic cells as assessed by flow-cytometric cell-cycle and propidium iodide staining analysis. The photodynamic effects of TDC include confirmed reactive-oxygen-species-induced mitochondrial damage leading to necrosis in SKOV-3 cell lines. The in vivo photodynamic activity in nude-mouse models demonstrated abrogation of tumor growth without any detectable pathology in the skin, liver, spleen, or kidney, thereby demonstrating TDC application as an efficient and safe photosensitizer.

Bicyclic Baird-type aromaticity.

Classic formulations of aromaticity have long been associated with topologically planar conjugated macrocyclic systems. The theoretical possibility of so-called bicycloaromaticity was noted early on. However, it has yet to be demonstrated by experiment in a simple synthetic organic molecule. Conjugated organic systems are attractive for studying the effect of structure on electronic features. This is because, in principle, they can be modified readily through dedicated synthesis. As such, they can provide useful frameworks for testing by experiment with fundamental insights provided by theory. Here we detail the synthesis and characterization of two purely organic non-planar dithienothiophene-bridged [34]octaphyrins that permit access to two different aromatic forms as a function of the oxidation state. In their neutral forms, these congeneric systems contain competing 26 and 34 π-electronic circuits. When subject to two-electron oxidation, electronically mixed [4n+1]/[4n+1] triplet biradical species in the ground state are obtained that display global aromaticity in accord with Baird's rule.

[40]π Fused and Nonfused Core-Modified Nonaphyrins: Syntheses and Structural Diversity.

The synthesis of fused and nonfused core-modified 40π nonaphyrins are reported. Spectroscopic and X-ray structural studies reveal a twisted figure-eight conformation in the freebase form that is nonaromatic. Structural changes occur, from figure-eight to open extended conformation, upon protonation, thereby adopting 4nπ Hückel antiaromatic character, which is reflected in spectroscopic and theoretical studies. Such a structural change also induces ring inversions of specific heterocyclic rings by 180°.

Phenylene-Bridged Core-Modified Planar Aromatic Octaphyrin: Aromaticity, Photophysical and Anion Receptor Properties.

The synthesis of a planar expanded meso porphyrin with an intramolecular para-phenylene-bridged core is reported. The planarity of the octaphyrin macrocycle was confirmed by single-crystal X-ray structural analysis, in which the bridged para-phenylene unit deviated by 27° from the mean macrocyclic plane. Spectroscopic analyses and theoretical calculations suggested that the macrocycle was Hückel aromatic and followed a major [34 π] single-conjugation pathway, which indicated that the bridging para-phenylene unit was not involved in the macrocyclic conjugation. Analysis of the photophysical properties of this system by steady-state absorption/fluorescence spectroscopy and transient absorption spectroscopy revealed moderate enhancement in the parameters of the octaphyrin as compared to its non-bridged octaphyrin congeners, which was attributed to the planarity and rigidity of the macrocycle as imposed by the bridging para-phenylene unit. Preliminary anion-binding studies revealed that the protonated macrocycle bound selectively with chloride ions through N-H⋅⋅⋅Cl hydrogen-bonding interactions.

[32]π Fused Core-Modified Heptaphyrin with Möbius Aromaticity.

A new fused core-modified 32π heptaphyrin with Möbius aromatic character is reported. The (1)H NMR data indicated a weak Möbius aromaticity at 298 K; however, at 213-183 K, the molecule predominates [4n]π Möbius conformation with strong diatropic ring current, which was further confirmed by X-ray analysis. The protonation experiment led to preservation of the Möbius aromaticity at 298 K. Nevertheless, the experimental results were further supported by theoretical studies. Overall, this study represents the first example of Möbius aromatic fused core-modified expanded porphyrin.

Fused core-modified planar antiaromatic 32π heptaphyrins: unusual synthesis and structural diversity.

The condensation reaction of fused dithienothiophene (DTT) diol with a core-modified tripyrrane led to the formation of acid and its concentration dependent products, sapphyrin and heptaphyrin. The single crystal X-ray analysis of sulphur and selenium heptaphyrin exhibits planar conformation owing to fusion. The experimental and theoretical calculations revealed the antiaromatic electronic structure of Hückel 4nπ.

meso-Aryl core-modified fused sapphyrins: syntheses and structural diversity.

Two new, fused core-modified expanded porphyrins, sapphyrins 3 and 4, were synthesized by a simple acid-catalyzed condensation of electron-rich and rigid precursor, dithienothiophene (DTT) diol, and core-modified tripyrrane. These sapphyrins exhibit structural diversity depending upon the heteroatom present in the macrocyclic framework, where the thiophene ring is inverted in 3, while the selenophene ring in 4 exists in normal and inverted form in the free base and addition of two protons shifts the equilibrium to inverted form.

Photophysical properties of bridged core-modified hexaphyrins: conjugational perturbation of thiophene bridges.

The role of thiophene bridges in determining the photophysical properties of bridged core-modified hexaphyrins is investigated. Depending on the substituted chalcogen atoms and conjugational perturbation across the thiophene bridges, the bridged core-modified hexaphyrins reveal unique photophysical properties.

Conformational change from a twisted figure-eight to an open-extended structure in doubly fused 36π core-modified octaphyrins triggered by protonation: implication on photodynamics and aromaticity.

Two examples of core-modified 36π doubly fused octaphyrins that undergo a conformational change from a twisted figure-eight to an open-extended structure induced by protonation are reported. Syntheses of the two octaphyrins (in which Ar=mesityl or tolyl) were achieved by a simple acid-catalyzed condensation of dipyrrane unit containing an electron-rich, rigid dithienothiophene (DTT) core with pentafluorobenzaldehyde followed by oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The single-crystal X-ray structure of the octaphyrin (in which Ar=mesityl) shows a figure-eight twisted conformation of the expanded porphyrin skeleton with two DTT moieties oriented in a staggered conformation with a π-cloud distance of 3.7 Å. Spectroscopic and quantum mechanical calculations reveal that both octaphyrins conform to a [4n]π nonaromatic electronic structure. Protonation of the pyrrole nitrogen atoms of the octaphyrins results in dramatic structural change, which led to 1) a large redshift and sharpening of absorption bands in electronic absorption spectrum, 2) a large change in chemical shift of pyrrole ß-CH and -NH protons in the (1)H NMR spectrum, 3) a small increase in singlet lifetimes, and 4) a moderate increase in two-photon absorption cross-section values. Furthermore, nucleus-independent chemical shift (NICS) values calculated at various geometrical positions show positive values and anisotropy-induced current density (AICD) plots indicate paratropic ring-currents for the diprotonated form of the octaphyrin (in which Ar=tolyl); the single-crystal X-ray structure of the diprotonated form of the octaphyrin shows an extended structure in which one of the pyrrole ring of each dipyrrin subunit undergoes a 180° ring-flip. Four trifluoroacetic acid (TFA) molecules are bound above and below the molecular plane defined by meso-carbon atoms and are held by N-H···O, N-H···F, and C-H···F intermolecular hydrogen-bonding interactions. The extended-open structure upon protonation allows π-delocalization and the electronic structure conforms to a [4n]π Hückel antiaromatic in the diprotonated state.

Calix[2]thia[4]phyrin: an expanded calixphyrin with aggregation-induced enhanced emission and anion receptor properties.

The synthesis of calix[2]thia[4]phyrin 3, a core-modified expanded calixphyrin, by an efficient synthetic route is reported. 3 exhibits an aggregation-induced enhanced emission (AIEE) phenomenon upon addition of increasing amounts of water. This is attributed to the restricted intramolecular rotation of the meso-aryl rings present on the sp(3) bridging carbons. SEM studies revealed the formation of aggregation in an acetonitrile/water mixture with an average diameter of the aggregate in the range 0.38-2.08 µm. The photoluminescence quantum yield of 3 in 9:1 water/acetonitrile is 5-fold higher than the quantum yield in acetonitrile alone. Single-crystal X-ray analysis of 3 revealed a chairlike conformation stabilized by N-H···N and C-H···π intramolecular hydrogen-bonding interactions. Fluorine atoms on the meso-pentafluorophenyl groups are involved in C-H···F intermolecular hydrogen-bonding interactions to generate a two-dimensional supramolecular assembly in the solid state. In the diprotonated state, 3 has affinity for anions and forms 1:1 complexes with SO4(2-), NO3(-), Cl(-), and ClO4(-) in solution. The tetrahedral anions bind more strongly than the other anions. Single-crystal X-ray structure studies of the ClO4(-) anion complex with 3 revealed the formation of both 1:1 and 1:2 complexes in the solid state, with the host and the guest being held together by N-H···O hydrogen-bonding interactions.

Core-modified meso-aryl hexaphyrins with an internal thiophene bridge: structure, aromaticity, and photodynamics.

Take the shortcut: The synthesis of core-modified meso aryl hexaphyrins with an internal thiophene bridge is reported. Introduction of the thiophene bridge alters the electronic structure as well as the π-electron circuit, resulting in increases in singlet lifetime (τ(s)) and the two-photon absorption (TPA) cross-section. Furthermore, for the sulfur derivative, the internal bridging thiophene participates in a π-electron conjugation pathway.

In vitro demonstration of apoptosis mediated photodynamic activity and NIR nucleus imaging through a novel porphyrin.

We synthesized a novel water-soluble porphyrin THPP and its metalated derivative Zn-THPP having excellent triplet excited state quantum yields and singlet oxygen generation efficiency. When compared to U.S. Food and Drug Administration approved and clinically used sensitizer Photofrin, THPP showed ca. 2-3-fold higher in vitro photodynamic activity in different cell lines under identical conditions. The mechanism of the biological activity of these porphyrin systems has been evaluated through a variety of techniques: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, comet assay, poly(ADP-ribose)polymerase (PARP) cleavage, CM-H(2)DCFDA assay, DNA fragmentation, flow cytometric analysis, fluorescence, and confocal microscopy, which confirm the apoptotic cell death through predominantly reactive oxygen species (ROS). Moreover, THPP showed rapid cellular uptake and are localized in the nucleus of the cells as compared to Hoechst dye and Photofrin, thereby demonstrating its use as an efficient sensitizer in photodynamic therapy and live cell NIR nucleus imaging applications.

Meso-tetrakis(p-sulfonatophenyl)N-confused porphyrin tetrasodium salt: a potential sensitizer for photodynamic therapy.

A water-soluble derivative of N-confused porphyrin (NCP) was synthesized, and the photodynamic therapeutic (PDT) application was investigated by photophysical and in vitro studies. High singlet oxygen quantum yield in water at longer wavelength and promising IC(50) values in a panel of cancer cell lines ensure the potential candidacy of the sensitizer as a PDT drug. Reactive oxygen species (ROS) generation on PDT in MDA-MB 231 cells and the apoptotic pathway of cell death was illustrated using different techniques.

Modified 26 and 28 pi hexaphyrins with five meso-links: optical, redox, and structural properties.

The syntheses of new aromatic 26pi and non-aromatic 28pi hexaphyrins through a [4+2] acid catalyzed condensation of easily available and air-stable precursors are reported. Both 26pi and 28pi hexaphyrins are reversibly transformed into one another by two-electron reduction with NaBH(4) or two-electron oxidation with dichlorodicyanobenzoquinone (DDQ) respectively. Detailed optical and NMR spectral studies suggests that the [26]hexaphyrin is aromatic and possesses a diatropic ring current, while [28]hexaphyrin exhibits non-aromatic characteristics. The structural characterization has been done with extensive (1)H and 2D NMR studies. Theoretical calculations performed with various conformational possibilities tested for the unsubstituted hexaphyrin, at semiempirical level, suggest that the most stable conformation takes an inverted structure with one pyrrole ring inversion. The energy optimization for the final geometry of the unsubstituted hexaphyrin, performed at the B3LYP/6-31G* level of DFT, shows excellent agreement with the structure derived from the solution NMR data. Electrochemical data reveals HOMO destabilization with increasing pi-electron conjugation consistent with the large red shifts of the absorption bands.

Photophysical properties of core-modified expanded porphyrins: nature of aromaticity and enhancement of ring planarity.

We have investigated the excited-state dynamics and nonlinear optical properties of representative core-modified expanded porphyrins, tetrathiarubyrin, tetraselenarubyrin, pentathiaheptaphyrin, tetrathiaoctaphyrin, and tetraselenaoctaphyrin, containing 26, 30, and 34 pi electrons using steady-state and time-resolved absorption and fluorescence spectroscopic measurements along with femtosecond Z-scan method, with a particular attention to the photophysical properties related to molecular planarity and aromaticity. Core-modification of macrocycles by sulfur and selenium leads to NIR-extended steady-state absorption and fluorescence spectra and short-lived excited-state due to the heavy-atom effect in time-resolved spectroscopic experiments. Large negative nucleus-independent chemical shift values ranging from -13 to -15 ppm indicate that all molecular systems are highly aromatic. The observed enhancement of two-photon absorption cross-section values over 10 (4) GM for core-modified hepta- and octaphyrins is mainly attributable to their rigid and planar structures as well as their aromaticity. Overall, the observed spectroscopic and theoretical results consistently demonstrate the enhanced molecular planarity of core-modified expanded porphyrins compared with their corresponding all-aza expanded porphyrins.

Structural diversity in expanded porphyrins.

Inspired by the chemistry of porphyrins, in the last decade, a new research area where porphyrin analogues such as expanded, isomeric, and contracted porphyrins have been synthesized, and their chemistry has been exploited extensively. Expanded porphyrins are macrocyclic compounds where pyrrole or heterocyclic rings are connected to each other through meso carbon bridges. Depending on the number of pyrrole rings in conjugation or the number of double bonds linking the four pyrrole rings expanded porphyrins containing up to 64 pi electrons are reported in the literature. The interest in these systems lies in their potential applications as anion binding agents, as photosensitizers for photodynamic therapy (PDT), in antisensing applications, as MRI contrasting agents, and more recently, as material for nonlinear optical application. Expanded porphyrins containing more than four pyrrole or heterocyclic rings, such as sapphyrin (five pyrrole), rubyrin (six pyrrole), heptaphyrin (seven pyrrole), and octaphyrin (eight pyrrole), are reported in the literature. Furthermore, substituents on expanded porphyrins can be attached either at the meso carbons or at beta-pyrrole positions. beta-substituted expanded porphyrins generally adopt normal structure where all the pyrrole nitrogens point inward in the cavity 1, while the meso-substituted expanded porphyrins exhibit normal 2, inverted 3, fused 4, confused 5, and figure eight 6 conformations. The conformation of expanded porphyrin is dependent on the nature of the linkage of the heterocyclic rings, the nature and the number of the heteroatoms present in the cavity, and the state of protonation. It is possible to change one conformation to another by varying temperature or by simple chemical modification, such as protonation by acids. An understanding of the structure-function correlation in expanded porphyrins is an important step for designing these molecules for their potential applications. In this context, even though several meso aryl expanded porphyrins are reported in literature, there is no comprehensive understanding of structural diversity exhibited by them. In this Account, an attempt has been made to provide a systematic understanding of the conditions and circumstances that lead to various conformations and structures. Specifically, the structural diversities exhibited by five pyrrolic macrocycles to ten pyrrolic macrocycles are covered in this Account. In pentapyrrolic systems, sapphyrins, N-fused, and N-confused pentaphyrins are described. It has been shown that the positions of the heteroatom affect the conformation and in turn the aromaticity. In hexapyrrolic systems, rubyrins and hexaphyrins are covered. The conformation of core-modified rubyrins was found to be dependent on the number and nature of the heteroatom present inside the core. Further, in the hexapyrrolic systems, an increase in the number of meso carbons from four (rubyrin) to six (hexaphyrin) increases the conformational flexibility, where different types of conformations are observed upon going from free base to protonated form. Heptapyrrolic and octapyrrolic expanded porphyrins also exhibit rich structural diversity. Octaphyrins are known to exhibit figure eight conformation, where the macrocycle experiences a twist at the meso carbon, losing aromatic character. By suitable chemical modification, it is possible to avoid the twist, and planar 34 pi core-modified octaphyrins have been reported that show aromatic character and obey the (4 n + 2) Hückel rule. The structural diversity exhibited by nine pyrrolic macrocycles (nonaphyrins) and ten pyrrolic macrocycles (decaphyrins) are also described.