Synthesis of new azido porphyrins and their reactivity in copper(I)-catalyzed Huisgen 1,3-dipolar cycloaddition reaction with alkynes

We report herein the preparation of two novel porphyrins substituted with an azido group born either on the para-position of one phenyl meso-susbtituent of a tetraaryl zinc porphyrin (1) or directly on the meso-position of a trisaryl nickel porphyrin (2). We studied the scope and the limitation the Huisgen cycloaddition reaction of these two porphyrins using different catalytic conditions. We observed that the carbene (SIMes)CuBr in THF/H₂O 3:1 at 45 °C for 60 h gives almost quantitative yields for the reaction between 1 and different alkynes, but significantly lower yields with 2 probably due to its thermal instability.     

Sc(III) porphyrins. The molecular structure of two Sc(III) porphyrins and a re-evaluation of the parameters for the molecular mechanics modelling of Sc(III) porphyrins

The crystal structures of two new Sc(III) porphyrins, [Sc(TPP)Cl]·2.5(1-chloronaphthalene), (5,10,15,20-tetraphenylporphyrin)-chloro-scandium(III)·2.5(1-chloronaphthalene) solvate, (Mo Kα, 0.71073 Å, triclinic system  = 9.9530(2) Å, b = 15.4040(3) Å, c = 17.7770(3) Å, α = 86.5190(10)°, β = 89.7680(10)°, γ = 86.9720(10)°, 13101 independent reflections, R₁ = 0.0712) and the dimeric [μ₂-(OH)₂(Sc(TPP))₂], bis-(μ-hydroxo)-(5,10,15,20-tetraphenylporphyrin) scandium(III) (Mo Kα, 0.71073 Å, monoclinic system C2, a = 24.2555(16) Å, b = 11.1598(7) Å, c = 25.6468(17) Å, β = 91.980(2)°, 13084 independent reflections, R₁ = 0.0485) are reported. In [Sc(TPP)Cl] the metal is five-coordinate and the porphyrin is domed with the metal displaced by 0.63 Å from the mean porphyrin towards the axial Cl⁻ ligand. The average Sc-N bond length is 2.143(3) Å, which is shorter than the average bond length of previously reported structures. Two of the phenyl rings are nearly orthogonal to the porphyrin core and the other two are significantly tilted because of contacts with 1-chloronaphthalene solvent molecules, and the phenyl rings of neighbouring porphyrins. In [μ₂-(OH)₂(Sc(TPP))₂] both porphyrins are domed, with the metal displaced from the mean porphyrin plane towards the bridging hydroxo ligands. The average Sc-N bond length is 2.197(12) Å, which is in the upper range of Sc-N bond lengths in known Sc(III) porphyrins but not dissimilar to the average Sc-N bond lengths in another other bis-μ₂-hydroxo Sc(III) porphyrin, [μ₂-(OH)₂(Sc(OEP))₂]. One porphyrin is rotated relative to the upper porphyrin by 25° due to steric contacts between the phenyl substituents. We have used these new structures to re-evaluated our previously reported molecular mechanics force field parameters for modelling Sc(III) porphyrins using the MM2 force field; the training set was augmented from two to seven structures by using all available Sc(III) porphyrin structures and the two new structures. The modelling reproduces the porphyrin core very accurately; bond lengths are reproduced to within 0.01 Å, bond angles to within 0.5° and torsional angles to within 2°. The optimum parameters for modelling the Sc(III)-N bond lengths, determined by finding the minimum difference between the crystallographic and modelling mean bond lengths with the aid of artificial neural network architectures, were found to be 0.90 ± 0.03 mdyn Å⁻¹ for the bond force constant and2.005 ± 0.005 Å for the strain-free bond length. Modelling the seven Sc(III) porphyrins with the new parameters gives an average Sc-N bond length of 2.182 ± 0.018 Å, indistinguishable from the crystallographic mean of 2.181 ± 0.024 Å.     

Porphyrins with exocyclic rings. Part 19: Efficient syntheses of phenanthrolinoporphyrins

5-Nitro-1,10-phenanthrolines react with isocyanoacetate esters in the presence of DBU in THF to give excellent yields of the corresponding phenanthrolinopyrroles. These were condensed with acetoxymethylpyrroles using catalytic quantities of p-toluenesulfonic acid in acetic acid to give dipyrrylmethanes, but these structures proved to be poorly suited for porphyrin synthesis due to the electron-withdrawing nature of the fused phenanthroline unit. However, phenanthrolinopyrrole ethyl esters could be converted to the corresponding α-unsubstituted pyrroles with KOH in ethylene glycol at 180-190 °C, and these condensed with 2 equiv of acetoxymethylpyrroles in refluxing acetic acid-isopropyl alcohol to give tripyrranes. In a one pot procedure, tripyrrane di-tert-butyl esters were treated with TFA at room temperature to cleave the protective groups, diluted with dichloromethane, reacted with pyrrole dialdehydes and oxidized to afford phenanthrolinoporphyrins in 52-83% yield. These conditions also allow the synthesis of porphyrins with additional fused acenaphthylene or phenanthrene rings. Although the UV-vis spectra for these porphyrins are unexceptional, the presence of an external coordination site allows many potential applications to be considered. Porphyrins with two phenanthroline units could not be prepared by the ‘3+1’ strategy. Instead, α-unsubstituted phenanthrolinopyrroles were reacted with a bis(dimethylaminomethyl)pyrrole in refluxing acetic acid to give moderate yields of the corresponding opp-diphenanthrolinoporphyrins. In one case, a triphenanthrolinoporphyrin and trace amounts of an adj-diphenanthrolinoporphyrin were formed as by-products.     

Convenient synthesis of porphine from β-tetra(tert-butyl)porphyrin

β-Tetra(tert-butyl)porphyrin was prepared from 2-dimethylaminomethyl-4-tert-butylpyrrole and converted into porphine, the mother compound of porphyrins, in 64% yield. The dealkylation smoothly proceeded in aqueous sulfuric acid over 15 min at 190 °C under nitrogen.     

Porphyrins with exocyclic rings. Part 20: Synthesis and spectroscopic characterization of porphyrins with fused 2,1,3-benzoxadiazole and 2,1,3-benzoselenadiazole moieties

Porphyrins with fused 2,1,3-benzoxadiazole and 2,1,3-benzoselenadiazole units were prepared by the ‘3+1’ MacDonald-type methodology. 4-Nitro-2,1,3-benzoxadiazole, 6-chloro-4-nitro-2,1,3-benzoxadiazole and 4-nitro-2,1,3-benzoselenadiazole condensed with isocyanoacetates in the presence of the non-nucleophilic base DBU to give tricyclic pyrrole derivatives in excellent yields. Further cleavage of the ester moieties and decarboxylation afforded α-unsubstituted pyrroles and these were further condensed with 2 equiv of an acetoxymethylpyrrole tert-butyl ester to give crude preparations of tripyrranes. The tert-butyl ester protective groups were cleaved with TFA and following dilution with dichloromethane, ‘3+1’ condensation with a pyrrole dialdehyde, and oxidation with ferric chloride, the heterocyclic ring fused porphyrins were obtained in moderate yields. The yields were lower than expected because of difficulties in preparing required tripyrranes due to the reduced reactivity of the pyrrolic intermediates. The UV-vis spectra of these new porphyrin systems were highly modified showing broadened split Soret bands. In addition, the nickel(II), copper(II) and zinc complexes gave unusual UV-vis spectra with weakened split Soret bands and strong Q-type absorptions above 600 nm. These modified structures show some potential for applications as photosensitizers in photodynamic therapy.     

Synthesis of π-expanded BODIPYs and their fluorescent properties in the visible-near-infrared region

A series of π-expanded boron-dipyrromethenes (BODIPYs) fused with aromatic rings at β,β-positions, such as benzene, acenaphthylene, and benzofluoranthene were prepared by the reaction of BF₃·OEt₂ with bicyclo[2.2.2]octadiene-fused dipyrromethene and the subsequent retro Diels-Alder reaction. These BODIPYs exhibited the absorptions and the fluorescence emissions over wide range of visible-near-infrared region at 500-800 nm. BODIPYs composed of two fluorantho[8,9-f]isoindoles absorbed and emitted at red-region over 750 nm with absolute fluorescence quantum yield (Φ_f) of ca. 0.3, although they are unstable under air in room light. BODIPY composed fluorantho[8,9-f]isoindole and acenaphtho[1,2-c]pyrrole was stable and showed a bright fluorescence emission at 695 nm with high Φ_f of 0.70.     

Stacking and separation of urinary porphyrins in capillary electrophoresis: optimization of concentration efficiency and resolution

We demonstrated that anionic porphyrins could be stacked and separated in micellar electrokinetic chromatography (MEKC) and microemulsion electrokinetic chromatography (MEEKC) by applying acetonitrile and high salt content in human urine sample matrix. The introduction of sample containing acetonitrile and sodium chloride into the CE capillary at more than 10% of the total capillary volume resulted in the improvement of peak resolution and the enhancement of detection sensitivity. The achieved acetonitrile stacking enrichment factors of six porphyrins ranged from 12 to 32 in MEKC and from 28 to 33 in MEEKC, respectively. The stacking technique was successfully applied for analyzing porphyrins present in urine samples that were deproteinized with acetonitrile. For the analysis of coproporphyrin isomers, addition of the sodium cholate (SC) into micelle and microemulsion solutions provided adequate resolution. Calibration curves obtained for the determination of coproporphyrin isomers were found linear between 30 and 400 nmol L⁻¹, and the limit of detection (LOD) was 20 nmol L⁻¹ in MEEKC. Intra- and interday precisions (n = 11) in the microemulsion separation system for the isomers at spiked concentrations of 40-400 nmol L⁻¹ in urine were in the range of 0.1-0.4% and 0.7-7.6% for migration time and peak area, respectively. Coproporphyrin III, coproporphyrin I and uroporphyrin were detected at levels of 80.7 nmol L⁻¹, 32.3 nmol L⁻¹ and 19.8 nmol L⁻¹, respectively, in the urine samples collected from healthy individuals. Different porphyrin profiles, however, were observed in urine samples from porphyria cutanea tarda (PCT) patients.     

A novel and efficient synthesis of porphine

meso-Tetra(n-hexyloxycarbonyl)porphyrin was found to be converted into porphine, the mother compound of porphyrins, in a 77% yield when heated in aqueous sulfuric acid at 180 °C over 30 min under an inert atmosphere. The observation demonstrates that the substituted porphyrin serves as a novel and useful precursor for porphine.     

Non-covalent assemblies of negatively charged boronated porphyrins with different cationic moieties

A unique approach to non-covalent electron and energy transfer is described that is based on the formation of salt bridges between oppositely charged porphyrin units. A new class of electrostatically linked dimeric and pentameric porphyrins was synthesized by interaction of novel anionic boron containing porphyrins such as 5-(benzamidodecahydro-closo-dodecaborate)-10,15,20-triphenylporphyrin (N1) and meso-tetrakis-benzamidodecahydro-closo-dodecaborate)porphyrin (N2) and a variety of cationic meso-tetraarylporphyrin units. A bipyridine linked dimer (N1 · bpy · N1) was also prepared by employing N,N′-dimethyl-4,4′-bipyridinium (bpy) as a spacer between two mono-anionic species. A quinone-porphyrin dyad was also prepared for electron or energy transfer demonstration. All the synthesized assemblies were characterized by NMR, IR, UV-Vis, and mass spectroscopy. Significant spectral changes occurred in the absorption spectra of these non-covalent porphyrin assemblies compared to those of the reference monomers, indicating the presence of electronic interaction between the adjacent porphyrin units. Resonance light scattering was also used to study the formation of these assemblies in solution.     

Novel D-π-A system based on zinc-porphyrin derivatives for highly efficient dye-sensitised solar cells

We have designed and synthesised novel zinc porphyrin dyes that have a D-π-A system based on porphyrin derivatives containing a carbazole linked triphenylamine (TPA) electron-donating group as the second electron donor and a meso-substituted phenyl carboxyl anchoring group attached at the meso position of the porphyrin ring, yielding push-pull porphyrins as the most efficient green dye for DSSC applications. Under photovoltaic performance measurements, a maximum photon-to-electron conversion efficiency of 5.01% was achieved with the DSSC based on the dye HKK-Por1 (J_SC = 10.7 mA/cm², V_OC = 0.67 V, FF = 0.70) under AM1.5 irradiation (100 mW/cm²).     

One-pot synthesis of triazole-fused isoindoles from o-alkynylbenzaldehydes and trimethylsilyl azide

An efficient one-pot synthesis of 1,2,3-triazole-fused isoindoles from o-alkynylbenzaldehydes and trimethylsilyl azide (TMSN₃) is reported. The reaction proceeds through the formation of a diazide intermediate and a subsequent intramolecular azide-alkyne cycloaddition, providing a novel access to a variety of 8-azido-8H-[1,2,3]triazolo[5,1-a]isoindoles in high yields.     

Design and synthesis of water-soluble bioconjugatable trans-AB-porphyrins

Three free base porphyrins have been prepared that bear a polar and facially encumbering 2,4,6-tris-(carboxymethoxy)phenyl motif at one meso (5-) position. The only other substituent (15-position) comprises phenyl, formyl, or p-aminophenyl. The porphyrins exhibit solubility in water (or aqueous buffer solutions) at pH ≥7 and concentrations >1 mM at room temperature. The concise syntheses, water solubility, and bioconjugatable handle make these porphyrin constructs suitable for biological applications.     

New N,N-amino-diphosphonate-containing methacrylic derivatives, their syntheses and radical copolymerizations with MMA

Hydroxy-amino-diphosphonates HO-C_n-NH₂, with 2 ? n ? 11, have been successfully synthesized via the Kabachnick-Field reaction at 70 °C with high yields. These hydroxy compounds are then reacted with methacryloyl chloride to lead to novel amino-diphosphonate methacrylates MAC_nNP₂ (with 2 ? n ? 11). These highly pure methacrylate monomers were obtained with yields higher than 75%. Radical copolymerizations of MAC_nNP₂ (with 2 ? n ? 11) with MMA have been conducted and the r₁ values (related to MAC_nNP₂) are in the range of 1.1-1.3, and r₂ values (related to MMA) about 0.8; this shows that the diphosphonate groups are statistically bonded to the methacrylic backbone.     

Microwave-assisted cycloadditions of 2-alkynylbenzonitriles with sodium azide: selective synthesis of tetrazolo[5,1-a]pyridines and 4,5-disubstituted-2H-1,2,3-triazoles

Under microwave irradiation (75 W), treatment of 2-alkynylbenzonitriles with 1.5 equiv of sodium azide in DMSO at 140 °C gave 4,5-disubstituted-2H-1,2,3-triazoles in 60-99% yields. Additionally, adding 8 equiv of ZnBr₂ and using 8 equiv of sodium azide in DMF at 100 °C lead to the formation of tetrazolo[5,1-a]isoquinolines up to 87% yield.     

Amphiphilic meso(sulfonate ester fluoroaryl)porphyrins: refining the substituents of porphyrin derivatives for phototherapy and diagnostics

A set of amphiphilic fluorinated porphyrins appended with sulfonate ester groups were synthesized and fully characterized. The reaction proceeds efficiently, with high yields, with an improved methodology. Their potential use as imaging and phototherapeutic agents was assessed measuring relevant photophysical properties. It is shown that these porphyrins have good photostability, long triplet lifetimes (between 47 μs and 102 μs), high singlet oxygen quantum yields (0.74≤FD≤1.00), low fluorescence quantum yields (<0.04) and sharp 19F NMR peaks. The data on the new meso(sulfonate ester fluoroaryl)porphyrins illustrate the potential of perfluorinated sulfonate esters to improve physical properties relevant for cancer imaging and photodynamic therapy.     

Microwave-assisted arylation of rac-(E)-3-acetoxy-1,3-diphenylprop-1-ene with arylboronic acids

The palladium-catalyzed arylation of rac-(E)-3-acetoxy-1,3-diphenylprop-1-ene with arylboronic acids was studied under controlled microwave irradiation conditions. A variety of different catalysts, bases, and solvents were explored in order to achieve optimum yields in the shortest possible reaction times. The best isolated yields were obtained using Pd₂(dba)₃·CHCl₃/PPh₃ as the catalytic system, potassium phosphate monohydrate as the base, and toluene/H₂O as a solvent system. Microwave irradiation using 5 mol % of the palladium catalyst for 90 s (max. temp 170 °C) generally afforded the cross-coupling products in good to excellent yields.     

Enantioselective Access to 1H‐Isoindoles with Quaternary Stereogenic Centers by Palladium(0)‐Catalyzed C−H Functionalization

A catalytic enantioselective method for the synthesis of chiral 1H‐isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)‐catalyzed C?H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H‐isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.     

Lead structures for applications in photodynamic therapy. Part 2: Synthetic studies for photo-triggered release systems of bioconjugate porphyrin photosensitizers

Photodynamic therapy (PDT) selectivity and specificity can be improved by binding the photosensitizers to target receptors. One approach is to cross-link porphyrins to a biological target receptor via the photocleavable o-nitrobenzyl linker, where a controlled released of the porphyrin can be monitored upon irradiation. The synthetic pathways involved esterification of a porphyrin-carboxylic acid and a unit containing the o-nitrobenzyl alcohol moiety and the bioconjugate. Reactions of a model porphyrin and o-nitrobenzyl alcohol using the carbonyl activating carbodiimide reagent DCC gave a stable N-acyl urea porphyrin, whereas use of EDAC (1-ethyl-3-(3-dimethyl aminopropyl)carbodiimide hydrochloride) gave the desired compounds. Further studies were carried out on the attachment of carbohydrates (i.e., potentially receptor binding ligands) through such a linker to porphyrins. Preliminary irradiation experiments of such a compound show that upon UV irradiation (350 nm) for 80 min, approximately 50% of the porphyrin was cleaved to release the carboxylic acid porphyrin photosensitizer indicating the utility of such systems as photosensitizers delivery systems.     

[3+2] Dipolar cycloadditions of an unstabilised azomethine ylide under continuous flow conditions

The [3+2] dipolar cycloaddition reactions of the unstabilised azomethine ylide precursor benzyl(methoxymethyl)(trimethylsilylmethyl)amine with 12 electron-deficient alkenes in the presence of catalytic trifluoroacetic acid are examined under continuous flow conditions (20-100 °C, 10-60 min residence time). The more reactive and hazardous alkenes such as ethyl acrylate, N-methylmaleimide and (E)-2-nitrostyrene afford substituted N-benzylpyrrolidine products in 77-83% yields, whereas less reactive dipolarophiles such as (E)-crotononitrile and ethyl methacrylate give lower yields (59-63%). Under optimised conditions, the reaction with ethyl acrylate is scaled up to afford ethyl N-benzylpyrrolidine-3-carboxylate (30 g, 87%) in 1 h.     

Effect of aldehyde and methoxy substituents on nucleophilic aromatic substitution by [F]fluoride

For a series of benzaldehydes only with a leaving group or with both a leaving group and a single methoxy substituent ¹⁸F-fluorination via nucleophilic aromatic substitution (S_NAr) was studied in DMF and Me₂SO. In general, the radiochemical yields were clearly higher in DMF than in Me₂SO. In the fluorodehalogenation reaction (leaving group: halogen = Br, Cl), extremely low radiochemical yields were observed in Me₂SO (<1%). By monitoring labeling reactions using HPLC, oxidation of the aldehyde function of the precursor was detected. Especially, 2-bromobenzaldehyde was oxidized fastest in Me₂SO (within 3 min reaction time, 90% of the precursor was consumed; radiochemical yield = 1.0 ± 0.5%); however, in DMF oxidation was always kept at a low level during the entire reaction (<5% of the precursor was oxidized; radiochemical yield = 73.0 ± 0.2%). In DMF, nitrobenzaldehydes with a methoxy substituent (methoxy group in meta-position to the nitro group) were labeled with good radiochemical yields (4-methoxy-2-nitrobenzaldehyde: 87 ± 3%; 2-methoxy-4-nitrobenzaldehyde: 83 ± 3%; 2-methoxy-6-nitrobenzaldehyde: 79 ± 4%) comparable to the non-substituted nitrobenzaldehydes (2-nitrobenzaldehyde: 84 ± 3%; 4-nitrobenzaldehyde: 81 ± 5%). Moreover, for structurally similar compounds, radiochemical yields showed a good correlation with ¹³C-NMR ppm values of the aromatic carbon atom bearing the leaving group.