Search

Borondipyrrins (BODIPYs) have found wide-spread application in bioimaging and material sciences. These applications require the tuning of the chemical and photophysical properties of the fluorophore through the introduction of functional groups at the BODIPY core. In this context, an approach to bisfunctionalized BODIPYs has been explored. The oxidative nucleophilic substitution of hydrogen (ONSH) in the 3-(alpha)-position of BODIPYs has been combined with the nucleophilic substitution (SNAr) at the aryl unit of pentafluorophenyl (PFP)-substituted BODIPYs and their dipyrrane precursors. In an alternative approach, alpha-alkoxy-substituted BODIPYs have been prepared starting from the corresponding dipyrrin. In this case, the alpha-methoxy group of the BODIPY is susceptible to a hitherto unreported methoxy-amino exchange. The compounds were investigated with respect to their optical spectroscopic properties revealing the influence of the different substitution patterns on their absorption and emission spectra.

The antibacterial photodynamic activity of hyperbranched polyglycerol (hPG) loaded with zinc porphyrin photosensitizers and mannose units was investigated. hPG, with a MW of 19.5 kDa, was functionalized with about 15 molecules of the photosensitizer {5,10,15-tris(3-hydroxyphenyl)-20-[4-(prop-2-yn-1-ylamino)tetrafluorophenyl]porphyrinato}-zinc(II) by using copper(I)-catalyzed 1,3-dipolar cycloaddition (CuAAC). These nanoparticle conjugates were functionalized systematically with increasing loadings of mannose in the range of approximately 20 to 110 groups. With higher mannose loadings (ca. 58–110 groups) the water-insoluble zinc porphyrin photosensitizer could thus be transferred into a water-soluble form. Targeting of the conjugates was proven in binding studies to the mannose-specific lectin concanavalin A (Con A) by using surface plasmon resonance (SPR). The antibacterial phototoxicity of the conjugates on Staphylococcus aureus (as a typical Gram-positive germ) was investigated in phosphate-buffered saline (PBS). It was shown that conjugates with approximately 70–110 mannose units exhibit significant antibacterial activity, whereas conjugates with approximately 20–60 units did not induce bacterial killing at all. These results give an insight into the multivalency effect in combination with photodynamic therapy (PDT). On addition of serum to the bacterial cultures, a quenching of this antibacterial phototoxicity was observed. In fluorescence studies with the conjugates in the presence of increasing bovine serum albumin (BSA) concentrations, protein-conjugate associations could be identified as a plausible cause for this quenching.

The copper(I)-catalyzed 1,3-dipolar cycloaddition of 4-azido(tetrafluorophenyl)boron-dipyrrin (azido-BODIPY) with diverse terminal alkynes, varying from simple alkyl-substituted derivatives to alkynes with functional groups and carbohydrates, was successfully employed to obtain meso-functionalized BODIPY derivatives through the 1,2,3-triazole linkage. The scope of this reaction was extended to the preparation of di- and trivalent BODIPY systems through the use of appropriate alkynyl linkers. Moreover, the synthesis of hydroxyl- and pentafluorothio-(SF5)-substituted, 1,2,3-triazole-linked array systems consisting of porphyrins and corroles as the central scaffold, in combination with a BODIPY, was investigated. These covalently connected tetrapyrrole-BODIPY arrays exemplify a versatile approach to the construction of multichromophore systems: the combination of 1,3-dipolar cycloaddition and nucleophilic substitution on pentafluorophenyl-substituted porphyrinoids. The systems designed herein could serve in various light-harvesting applications and electron-transfer studies.

A detailed study of the nucleophilic aromatic substitution reaction of meso-pentafluorophenyl-substituted tetrapyrrole systems with different alcohols is presented. The systematic investigation of various alcohols and bases in two different solvents led to optimized reaction conditions, allowing the selective substitution of the p-fluorine atoms of meso-pentafluorophenyl-substituted porphyrins, their zinc complexes, and a meso-tris(pentafluorophenyl)corrole with alcohols and a simple base in high yields. When applied to A3B porphyrins in combination with suitable protecting groups, functionalized, polar A3B porphyrins can be prepared in a simple two-step one-pot procedure. By using the nucleophilic aromatic substitution reaction, a dimeric porphyrin system was synthesized. In addition, the copper(I)-catalyzed 1,3-dipolar cycloaddition of properly functionalized meso-pentafluorophenyl-substituted porphyrins led to the corresponding porphyrin dimer with a 1,2,3-triazole linker. The method described herein allows a simple and fast approach towards multifunctionalized porphyrinoids based on meso-pentafluorophenyl-substituted tetrapyrroles.

meso-Substituted trans-A2B2-porphyrins bearing specific patterns of substituents are crucial building blocks in porphyrin-based biomimetic systems and molecular materials and can be used for the construction of well-defined porphyrin-based architectures. A new stepwise and rational synthesis of functionalized trans-A2B2-porphyrins is reported in which for the first time donor–acceptor-substituted cyclopropane precursors (d–a cyclopropanes) are exploited. The three presented d–a cyclopropanes are readily accessible in a multi-gram scale and serve as aldehyde equivalents in the reaction with an excess of pyrrole to afford the corresponding dipyrromethanes (DPMs). The three DPMs were synthesized in yields of 60–74%. They are stable in purified form in the absence of light and air and were subsequently condensed with a wide range of aliphatic and aromatic aldehydes bearing electron-donating or electron-withdrawing substituents followed by oxidation to form the corresponding trans-A2B2-porphyrins. Fourteen functionalized porphyrins were synthesized in yields of 14–31%, indicating the broad scope of the synthetic procedure. The possibility to introduce key functional groups is emphasized, which enables subsequent modification of these porphyrins with moieties inducing biological activity. Modification of the tetrapyrroles may occur by addition to one of the porphyrin peripheral double bonds, the use of substituents of the aryl groups or via the methoxycarbonyl group at two of the meso-substituents. Three examples of porphyrins were converted into the corresponding 7,8-dihydroxychlorins by osmium-mediated dihydroxylation and one of the resulting chlorins was subjected to saponification to give a highly polar chlorin dicarboxylic acid. A 4-bromophenyl-substituted d–a cyclopropane was prepared by rhodium-catalyzed cyclopropanation and then transformed into a DPM which was subsequently condensed to a porphyrin. Its Zn complex allowed a Heck reaction to afford the functionalized bis(alkenyl)-substituted trans-A2B2-Zn-porphyrin.

Congest and conjugate: The application of a sterically congested dipyrromethane in an acid-catalyzed [2+2+2] building-block approach was studied for the first time, resulting in the formation of two stable calix[6]phyrin(1.1.1.1.1.1) diastereomers (see scheme). The calix[n]phyrins were further functionalized at their pentafluorophenyl residues, allowing the first synthesis of a calix[4]phyrin(1.1.1.1) dimer.

Calix[4]phyrins are an important class of hybrid macrocyclic systems at the interface between porphyrins and calixpyrroles (porphyrinogens). A new stepwise synthesis of oxidation-resistant meso-hydrogenated calix[4]phyrins is reported, which allows variable substitution in the residues of their sp2-meso-centers without the need for a porphyrin intermediate. It relies on the acid-catalyzed condensation of a sterically hindered donor–acceptor-substituted cyclopropane precursor with pyrrole to form a sterically congested dipyrromethane. This was subsequently condensed with a wide range of alkyl and aryl aldehydes bearing electron-donating or electron-withdrawing substituents followed by an oxidation step to form stable calix[4]phyrin(1.1.1.1)s with bridging meso-CH hydrogen atoms through an acid-promoted dehydrative condensation. The methodology avoids any need for premetallation of the macrocycle and/or the use of organometallic catalysts or reagents and allows the incorporation of the bulky cyclopropane-derived substituents specifically into the 5,15-meso-like positions. The resulting regioisomerically pure products display conformational features that reflect their mixed nature between porphyrins and calixpyrroles and they were assessed by X-ray diffraction analysis, NMR techniques and UV/Vis spectroscopy. The possibility to introduce key functional groups enables subsequent modification of these calix[4]phyrins and allows their connection to other groups such as biologically active moieties. Of special interest is an unprecedented example of an acid-driven lactonization that results in the incorporation of a mono-meso-spirolactone into a calix[4]phyrin(1.1.1.1). Moreover, it is demonstrated that this approach to calix[4]phyrins is also applicable to other sterically congested dipyrromethanes.

The reaction of alcohols with (pentafluorophenyl)dipyrromethane (PFP-DPM) under basic conditions has been studied, giving access to the corresponding alkoxy-substituted DPMs. This method represents the first high-yielding substitution of PFP-DPM carried out with oxygen nucleophiles. Condensation of these prefunctionalized DPMs with aldehydes led to the respective trans-A2B2 porphyrins. This pathway allows a simple synthesis of multifunctionalized tetrapyrroles. Oxidation and boron complexation of these DPMs, on the other hand, led to meso-functionalized difluoroboraindacenes (BODIPYs). In addition, nucleophilic substitution of PFP-BODIPY with sodium azide led to a 4-azidophenyl derivative, thus further enhancing the scope of reactive sites suitable for subsequent transformations.

General syntheses have been developed for meso-substituted por- phyrins with one or two substituents in the 5,10-positions and no b substitu- ents. 5-Substituted porphyrins with only one meso substituent are easily prepared by an acid-catalyzed conden- sation of dipyrromethane, pyrrole-2- carbaldehyde, and an appropriate alde- hyde using a "(2+1+1)" approach. Sim- ilarly, 5,10-disubstituted porphyrins are accessible by simple condensation of unsubstituted tripyrrane with pyrrole and various aldehydes using a "(3+1)" approach. The yields for these reac- tions are low to moderate and addi- tional formation of either di- or mono- substituted porphyrins due to scram- bling of the intermediates is observed. However, the reactions can be per- formed quite easily and the desired target compounds are easily removed due to large differences in solubility. A complementary and more selective syn- thesis involves the use of organolithium reagents for SNAr reactions. Reaction of in situ generated porphyrin (por- phine) with 1.1-8 equivalents of RLi gave the monosubstituted porphyrins, while reaction with 3-6 equivalents of RLi gave the 5,10-disubstituted por- phyrins in yields ranging from 43 to 90 %. These hitherto almost inaccessi- ble compounds complete the series of different homologues of A-, 5,15-A2-, 5,10-A2-, A3-, and A4-type porphyrins and allow an investigation of the grad- ual influence of type, number, and re- giochemical arrangement of substitu- ents on the properties of meso-substi- tuted porphyrins. They also present im- portant starting materials for the syn- thesis of ABCD porphyrins and are potential synthons for supramolecular materials requiring specific substituent orientations.

A comprehensive crystallographic analysis of 10 porphyrin quinone precursors (dimethoxybenzene derivatives), and six porphyrin quinones has been performed. The free bases and zinc(II) complexes of the porphyrin quinones are of the 5,10,15-triaryl/alkyl-20-quinone-porphyrin type and carry various bridging and quinone units. The structural and conformational parameters were determined for all compounds; the donor-acceptor separation distances range from 6.3 to 10.9 A. Knowledge of these data is a prerequisite for a detailed interpretation of theoretical and spectroscopic studies on such systems. Despite the obvious influence of the type and geometry of the bridging unit and quinone on the spatial arrangement of the donor and acceptor components, a large variety of different packing arrangements in the crystal were observed. These include π stacking, aggregate formation and axial ligation in the zinc(II) porphyrins. The latter often utilized the quinone (or dimethoxy) oxygen atoms for coordination to zinc(II) centers leading to porphyrin quinone dimers and even polymers.

The synthesis of appropriate porphyrin-quinone electron-transfer complexes as model compounds for photosynthesis requires access to functionalized triptycene quinone aldehydes with different redox potentials. A synthetic strategy involving a classical Diels-Alder reaction, tautomerization and oxidation was only of limited utility for preparing the desired compounds. Thus, an alternative approach was required and for this purpose a strategy involving the reaction of excess quinone with appropriate anthracene derivatives in acetic acid has been developed. This method affords the target compounds in a single synthetic step in good yields and with high purity. The aldehyde functionality required for the subsequent porphyrin synthesis can be incorporated into either the anthracene or the quinone starting component. Fifteen different triptycene quinones have been synthesized, eight of which have been studied in detail by single crystal X-ray crystallography to provide insight into their structural chemistry and solid-state aggregation properties. Additionally, the synthesis of two porphyrin-quinone target compounds is described.

meso-Substituted trans-A2B2-porphyrins bearing specific patterns of substituents are crucial building blocks in porphyrin-based biomimetic systems and molecular materials and can be used for the construction of well-defined porphyrin-based architectures. A new stepwise and rational synthesis of functionalized trans-A2B2-porphyrins is reported in which for the first time donor–acceptor-substituted cyclopropane precursors (d–a cyclopropanes) are exploited. The three presented d–a cyclopropanes are readily accessible in a multi-gram scale and serve as aldehyde equivalents in the reaction with an excess of pyrrole to afford the corresponding dipyrromethanes (DPMs). The three DPMs were synthesized in yields of 60–74%. They are stable in purified form in the absence of light and air and were subsequently condensed with a wide range of aliphatic and aromatic aldehydes bearing electron-donating or electron-withdrawing substituents followed by oxidation to form the corresponding trans-A2B2-porphyrins. Fourteen functionalized porphyrins were synthesized in yields of 14–31%, indicating the broad scope of the synthetic procedure. The possibility to introduce key functional groups is emphasized, which enables subsequent modification of these porphyrins with moieties inducing biological activity. Modification of the tetrapyrroles may occur by addition to one of the porphyrin peripheral double bonds, the use of substituents of the aryl groups or via the methoxycarbonyl group at two of the meso-substituents. Three examples of porphyrins were converted into the corresponding 7,8-dihydroxychlorins by osmium-mediated dihydroxylation and one of the resulting chlorins was subjected to saponification to give a highly polar chlorin dicarboxylic acid. A 4-bromophenyl-substituted d–a cyclopropane was prepared by rhodium-catalyzed cyclopropanation and then transformed into a DPM which was subsequently condensed to a porphyrin. Its Zn complex allowed a Heck reaction to afford the functionalized bis(alkenyl)-substituted trans-A2B2-Zn-porphyrin.

A crucial factor in choosing a porphyrin or analogous photosensitizer for photodynamic therapy (PDT) is its ability to incorporate into the cells. For hydrophobic compounds that partition passively into the cytoplasmic membrane, a partition coefficient between an organic solvent and water, P, is one factor that could be used to predict the molecule's ability to diffuse into biomembranes. We synthesized several porphyrins, modified with two, three or four meso-substituents and studied their spectroscopic and photophysical properties. The octanol-water partitioning coefficients, log P, were calculated as a parameter for hydrophobicity. We found these porphyrins to be very hydrophobic, with log P values in the range of 8.9-11.8. These were correlated with the binding constants of these porphyrins into liposomes, K(b), as well as to their uptake by cells. The correlation between the estimated log P and K(b) is nearly linear but negative, indicating, apparently, that there is lesser binding to liposomes with increased hydrophobicity. On the other hand, all of the studied porphyrins are taken up by cells, but there is no clear correlation between cellular uptake and the log P or K(b). Lipinski's pharmacological "rule of 5" predicts poor permeation of drugs into cells when log P is greater than five. This may be relevant for diffusional binding to liposomes, where aqueous aggregation can interfere strongly with cellular uptake. In such extreme conditions, neither liposome binding nor other rules seem to predict porphyrin behavior in vitro.