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The current state of pharmaceutical development of porphyrin-type macrocycles in medicine is highlighted. Currently, several porphyrinoid-based drugs are under various stages of development as phototherapeutic agents, X-ray radiation enhancers and boron neutron capture agents. These compounds represent a burgeoning class of pharmacological agents that are potentially useful in an array of treatment areas.

The texaphyrins are prototypical metal-coordinating expanded porphyrins. They represent a burgeoning class of pharmacological agents that show promise for an array of medical applications. Currently, two different water-soluble lanthanide texaphyrins, namely motexafin gadolinium (Gd-Tex, 1) and motexafin lutetium (Lu-Tex, 2), are involved in multi-center clinical trials for a variety of indications. The first of these agents, XCYTRIN^® (motexafin gadolinium) Injection, is being evaluated as a potential X-ray radiation enhancer in a randomized Phase III clinical trial in patients with brain metastases. The second, in various formulations, is being evaluated as a photosensitizer for use in: (i) the photodynamic treatment of recurrent breast cancer (LUTRIN^® Injection; now in Phase IIb clinical trials); (ii) photoangioplastic reduction of atherosclerosis involving peripheral and coronary arteries (ANTRIN^® Injection; now in Phase II and Phase I clinical trials, respectively); and (iii) light-based age-related macular degeneration (OPTRIN™ Injection; currently under Phase II clinical evaluation), a vision-threatening disease of the retina. In this article, these developments, along with fundamental aspects of the underlying chemistry are reviewed.

The synthesis of an isoamethyrin-type expanded porphyrin bearing both meso- and β-substituents is presented. The diprotonated form of this macrocycle was characterized by conventional spectroscopic means and via a single crystal X-ray diffraction analysis. This species is observed to adopt a planar conformation in the solid state. Nonetheless, the inner ring current, as inferred from ¹H NMR spectroscopic studies, is found to be severely diminished as compared to isoamethyrin, by the presence of the two meso-phenyl moieties. A second crystal structure, in which a molecule of water is hydrogen-bound to a pyrrole NH, was also solved.

A new member of the cyclo[n]pyrrole class of expanded porphyrins was prepared from the corresponding thiophene-containing terpyrrole precursor through use of a mild electrochemical oxidative procedure. The isolated macrocycle, featuring nine heterocyclic subunits directly connected through their α,α′-positions, is the largest cyclo[n]pyrrole derivative reported to date. The structure obtained via synchrotron radiation-based studies revealed a dimeric arrangement involving individual macrocyclic subunits.

Iridium metalation of [26]hexaphyrin 1 and [36]octaphyrin 2 gave Ir(III) complex of [26]hexaphyrin 3 and Ir(I) complex of [36]octaphyrin 4, respectively. The complex 3 is an aromatic molecule displaying considerably electron-rich nature while the complex 4 shows weak antiaromatic nature with a small HOMO–LUMO gap of 0.82 eV.

meso–meso Directly-linked trimeric and pentameric porphyrin–hexaphyrin hybrid arrays 5 and 6 comprising of electron-deficient porphyrin units were prepared by cross-condensation of monomeric and dimeric electron-deficient meso-formyl porphyrins with a tripyrrane. The solid-state structures of 5 and 6 have been determined by single crystal X-ray diffraction analysis. The latter is the largest crystal structure of meso–meso linked multiporphyrinic array analogues reported to date.

Triphenylphosphine was added regioselectively at the C(3) position of bis-Au(III) complex of [26]hexaphyrin 5 in the presence of trifluoroacetic acid to produce [28]hexaphyrin triphenylphosphine adduct 6 in 62% yield, which has been fully characterized by NMR, UV-vis/NIR absorption, and MS spectroscopies, and X-ray diffraction analysis. The rigid planar structure forces 6 to take Hückel antiaromaticity, which has been supported by its ¹H NMR spectrum. Curiously, the detailed structural analysis elucidated that the triphenylphosphine moiety exists as a phosphorane form in the solid state. A plausible mechanism via a double protonated 5 is proposed, which can explain the observed regioselectivity.

The $N$-methylated 25-oxasmaragdyrins were synthesized by reacting 25-oxasmaragdyrins with CH₃I in presence of KOH in THF at reflux temperature. Although the reactions were carried out in presence of excess CH₃I, we obtained only dimethyl-25-oxasma ragdyrins, where $N$-methylations occurred at 24 and 26 “N”s of pyrrole rings of tripyrrane moiety of smaragdyrin core as confirmed by X-ray crystallography. The $N$-methylated-25-oxasmaragdyrins were characterized in detail by 1D and 2D NMR spectroscopy, absorption, fluorescence and electrochemical techniques. The effect of distortion induced by methylation, clearly reflected in structural and electronic properties of the macrocycle. All the pyrrole and furan protons experienced upfield shifts in the ¹H NMR and maximum upfield shifts were noted for the $N$-methylated pyrrole ring protons. The absorption spectra showed broad Soret band and four ill-defined Q-bands with significant reduction in extinction coefficients. The $N$-methylated 25-oxasmaragdyrins were comparatively less fluorescent. The redox studies indicated that they are difficult to oxidize and easier to reduce.

Skeletally recombined $N$-fused pentaphyrin bromide underwent aromatic nucleophilic substitution-like reactions when treated with several amine reagents. As a result, an irregular bond such as a vinylene or phenylene linkage was formed between the inside of the macrocycle and the amine nitrogen. This linkage extended the conjugation network and created a “switchback $\pi$-plane” in the product, achieving a new kind of three-dimensional zigzag-like delocalization of $\pi$-electrons.

Phosphorus complexes of porphyrinoids such as porphyrins, corroles, $N$-fused porphyrins, $N$-fused expanded porphyrins and expanded porphyrins can be prepared readily by treating the porphyrinoid with phosphorylating agents such as PX₃, PX₅ and POX₃ (X $=$ Cl or Br) under standard reaction conditions. In phosphorus porphyrinoids, the phosphorus is generally high valent $+$5 oxidation state and the coordination number is varied from four to six. The insertion of P(V) into porphyrinoids alters the structure and electronic properties of the macrocycle significantly. Specially, the phosphorus binding mode is different from one porphyrinoid to another. The oxophilicity nature of P(V) in P(V) porphyrinoids is very useful to change variety of axial ligands and also helps to synthesize multi-porphyrin arrays by axial bonding approach. This review summarizes the phosphorus complexes of five different porphyrinoids and discusses their structure and electronic properties as well as their applications in the synthesis of more elaborate P(V) porphyrinoid based architectures.

meso-Aryl dipyrromethanes are important building blocks to create various practical molecules, and the electron-withdrawing effect of the meso-aryls can play an important role in improving/controlling their reactivities in further reactions: meso-Pentafluorophenyl and meso-(2,6-dichlorophenyl) substituted dipyrromethanes towards the associating dipyrrins and other derivatives have been investigated, in which coordination with different transition metals followed by the dissociation of the metal coordination by interruption of proton and halide ions have been verified. Furthermore, simple DDQ-oxidations of the dipyrromethanes have afforded DDQ-dipyrrin adducts which were delivered to distinctly advanced molecular rearrangements in the presence of acid and base. Vinylene bisdipyrrin compounds, obtained in the reactions of DDQ-dipyrrin adducts with a Lewis base triethylamine, have produced expanded porphyrinoid bis-nickel complexes during the metalation procedure with nickel acetate, while a cobalt metalation of the vinylene bisdipyrrin compounds resulted in an isolation of diamagnetic octahedral cobalt(III) complex. Moreover, meso-pentafluorophenyl and meso-(2,6-dichlorophenyl) dipyrromethanes have been useful platforms to accomplish size-controlled series of meso-aryl-substituted expanded porphyrins and easy separation/purification of selective meso-aryl expanded porphyrins, in which advanced metal complexes and various fascinating properties and reactivities admitting moderate functional molecules have arisen.

The dumbbell-shaped type-I conformation is the inherent structure of the [26]hexaphyrin(1.1.1.1.1.1) framework without any perturbations from its peripheral substituents. Conversely, the rectangular type-II conformation can be regarded as a more general structure seen in stable [26]hexaphyrins(1.1.1.1.1.1) because of not only the synthetic limitations but also the steric influences related to the meso-aryl substituents. In this study, the synthesis of [26]hexaphyrins(1.1.1.1.1.1) bearing a series of electron-withdrawing groups and their conformational characterizations were investigated. The ¹H NMR spectra showed that [26]hexaphyrin with 3,5-dinitrophenyl groups at the 5,20-positions was obtained as the sole type-I conformer, whereas most other [26]hexaphyrins are in equilibrium between type-I, type-II, and type-II$\prime$ conformers. Moreover, UV-vis absorption measurements revealed that type-I conformations can utilize the electronic features of their 5,20-substituents owing to their relatively co-planar arrangements with the macrocycles.

Presented here is the stepwise and one-pot synthesis of a dipyridazinamethyrin, 1. In either synthetic route, a proper metal cation template was found necessary. ¹H NMR and UV-Vis absorption studies suggest this macrocycle exhibits a non-aromatic nature. DFT calculations suggest that the optimized structure of this macrocycle is slightly ruffled rather than planar.

1,4-Phenylene-incorporated decaphyrin(1.0.1.0.0.1.0.1.0.0) 1 has been previously synthesized and optically resolved in the free-base form; however, it undergoes racemization at elevated temperature. In this study, we fixed the figure-of-eight conformation by means of rhodium(I) coordination. The resulting tetranuclear Rh(I) complex 1-Rh${}_4$, which is scarcely reported to date, exhibited considerable conformational stability. Accordingly, it could be readily resolved by high-performance liquid chromatography (HPLC) on a chiral stationary phase, and no racemization was observed even at 110${}^{\circ }$C. Importantly, the tetranuclear porphyrinoid complex bearing a unique edge-to-edge alignment of the two 1,4-phenylene spacers revealed a relatively large molar circular dichroism (CD) with an absorption dissymmetry factor ($g_{\mathrm{\text{abs}}})$ of 0.018. While a two-fold larger $g_{\mathrm{\text{abs}}}$ of up to 0.036 was seen for the structural congener 1, wherein the 1,4-phenylene spacers adopt a face-to-face orientation. Thus, it serves to be an attractive basis to explore the structural effect on the chiroptical properties of the expanded porphyrinoid.