Porphyrins with exocyclic rings. Part 24. Synthesis and spectroscopic properties of pyrenoporphyrins, potential building blocks for porphyrin molecular wires

Porphyrins with fused pyrene units have been prepared by ‘2+2’ and ‘3+1’ methodologies. Nitration of 1,2,3,6,7,8-tetrahydropyrene, followed by oxidation with DDQ, gave 4-nitropyrene and this condensed with ethyl isocyanoacetate in the presence of DBU or a phosphazene base to generate a pyrenopyrrole ethyl ester. Ester saponification and decarboxylation with KOH in ethylene glycol at 190 °C gave the parent pyreno[4,5-c]pyrrole and this was further condensed with 2 equiv of acetoxymethylpyrroles to afford the corresponding tripyrranes protected at the terminal positions with tert-butyl esters. In a one pot procedure, the ester protective groups were cleaved with TFA and following dilution with dichloromethane, ‘3+1’ condensation with a pyrrole dialdehyde, and dehydrogenation with DDQ, the targeted pyrenoporphyrins were generated in good overall yields. A dialdehyde was also prepared from the pyrenopyrrole intermediate and this reacted to give an opp-dipyrenoporphyrin. The pyrenopyrrole ethyl ester reacted with dimethoxymethane in the presence of an acid catalyst to give a dipyrenopyrrolylmethane, and this was used to prepare an adj-dipyrenoporphyrin using the MacDonald ‘2+2’ approach. The pyrenopyrrole dialdehyde was also used to prepare a porphyrin with fused pyrene and phenanthroline moieties. Although the UV-vis spectra of these new porphyrin systems are unexceptional, pyrenoporphyrins show many of the features necessary for the construction of porphyrin molecular wires.     

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.     

Molecular and crystal structures of 5,7-dichloro-4-nitro-2,1,3-benzoxadiazole and products of its reactions with secondary amines

The molecular and crystal structures of 5,7-dichloro-4-nitro-2,1,3-benzoxadiazole and products of its reactions with hexamethyleneimine and dimethylamine were established by X-ray diffraction analysis. The molecular structures and the systems of hydrogen bonds in the crystals of these compounds are discussed.     

Synthetic access to 5,10-disubstituted porphyrins

A simple acid-catalyzed condensation of unsubstituted tripyrranes with pyrrole and various aldehydes affords 5,10-disubstituted-β-unsubstituted porphyrins by the ‘3+1’ approach in low to moderate yields. A complementary synthesis of similar compounds involves reaction of unsubstituted porphyrin (porphine) with organolithium reagents in good yields.     

Porphyrins with exocyclic rings. 15.(1) synthesis of quino- and isoquinoporphyrins, aza analogues of the naphthoporphyrins

Porphyrins with fused isoquinoline and quinoline units have been prepared by the "3 + 1" methodology. 5-Nitroisoquinoline and 6-nitroquinoline condensed with ethyl isocyanoacetate in the presence of a phosphazene base to give isoquino- and quinopyrroles, respectively. Ester saponification and decarboxylation with KOH in ethylene glycol at 190 degrees C gave the parent azatricycles, and these were further condensed with 2 equiv of an acetoxymethylpyrrole to give the corresponding tripyrranes protected at the terminal positions as their tert-butyl esters. In a one-pot procedure, the ester protective groups were cleaved with TFA, and following dilution with dichloromethane, "3 + 1" condensation with a pyrrole dialdehyde and dehydrogenation of the phlorin intermediate with DDQ gave the targeted azanaphthoporphyrins in excellent yields. Although the UV-vis spectra of these new porphyrin systems are unexceptional, they show promise for further functionalization and applications in the development of porphyrin arrays. In addition, a zinc chelate of the isoquinoporphyrin system shows a high degree of regioselective intermolecular interaction/aggregation in chloroform solution that may lead to selectivity in molecular recognition studies.     

Porphyrins with exocyclic rings. 16. Synthesis and spectroscopic characterization of fluoranthoporphyrins, a new class of highly conjugated porphyrin chromophores

Porphyrins with fused aromatic rings are under detailed investigation due to their unique spectroscopic properties. To gain more insights into the effects due to ring annealation on the porphyrin chromophore, a series of fluoranthoporphyrins have been synthesized. Reaction of 3-nitrofluoranthene with isocyanoacetate esters in the presence of a phosphazene base afforded good yields of the fluorantho[2,3-c]pyrrole esters 8. Cleavage of the ester moiety with KOH in ethylene glycol afforded the parent heterocycle 9, and this condensed with 2 equiv of acetoxymethylpyrroles 10 in refluxing acetic acid-2-propanol to afford tripyrranes 11. Following cleavage of the tert-butyl ester protective groups with TFA, "3 + 1" condensation with pyrrole dialdehyde 12 gave the fluoranthoporphyrins 13 in good overall yields. In addition, reaction of tripyrrane 11 with acenaphthopyrrole dialdehyde 16 gave the mixed acenaphthofluoranthoporphyrin 17 in excellent yields. A difluoranthoporphyrin 18 was also prepared via a "2 + 2" MacDonald condensation. Reaction of fluoranthopyrrole 8a with dimethoxymethane in the presence of p-toluenesulfonic acid gave the symmetrical dipyrrylmethane 19, and following ester saponification, this was condensed with a dipyrrylmethane dialdehyde to afford the adj-difluoranthoporphyrin 18. The UV--vis spectra for these fluoranthoporphyrins gave a series of three broadened absorptions in the Soret band region, although the Q-bands were little effected by ring fusion. The nickel(II), copper(II), and zinc chelates were more unusual, showing strong absorptions near 600 nm. Difluoranthoporphyrin 18 showed many of the same spectroscopic features, although the presence of two ring fusions gave rise to an increase in the spectroscopic shifts. The mixed system 17 gave spectra that showed larger red shifts due to the acenaphthylene unit combined with the features due to the fluoranthene rings. This work further demonstrates the utility of aromatic ring fusion in altering the properties of porphyrinoid systems.     

Crystal engineering with 2,1,3-benzoselenadiazole and mercury(II) chloride

The reactions of HgCl₂ with 2,1,3-benzoselenadiazole (bsd) in methanol afforded the polymeric complexes [HgCl₂(bsd)₂]_n (1) and [HgCl₂bsd]_n (2) in good yields. The crystal structures of 1 and 2 have been determined by single-crystal X-ray crystallography. Complex 1 is an one-dimensional (1D) polymer and consists of (HgCl₂)_n chains running parallel to the c-axes. Complex 2 is a two-dimensional (2D) polymer and consists of (HgCl₂)_n chains running parallel to the a-axes and being further bridged by bsd molecules to create a layer lying parallel to the ab plane. Both crystal structures are dominated by π···π interactions between the bsd molecules, while the presence of N···Se interactions increases the dimensionality in 1. Characteristic IR data are discussed in terms of the nature of bonding in the structures of the two complexes.     

Application of 9-ethyl[1,2,5]selenadiazolo[3,4-h]quinolones in the synthesis of tricyclic azoloquinolones

A series of tricyclic azoloquinolones was prepared by a novel approach based on the protection of a benzene-1,2-diamine moiety as 2,1,3-benzoselenadiazole ring. A new reductive deselenation of 9-ethylselenadiazolo[3,4-h]quinolones using zinc powder in acetic acid afforded 7,8-diamino-1-ethylquinolones in high yields. The obtained diaminoquinolones were employed as useful substrates in cyclocondensation reactions leading to azoloquinolone derivatives.     

Synthesis and spectroscopic characterization of meso-tetraarylporphyrins with fused phenanthrene rings

A series of meso-tetraaryl porphyrins with fused phenanthrene rings have been synthesized from boron trifluoride-catalyzed Lindsey condensation of phenanthro[9,10-c]pyrrole with various para-substituted arylaldehydes at low temperature. Their structures were characterized by UV-vis, ¹H NMR, and mass spectroscopies. The UV-vis spectra of these compounds showed remarkable bathochromic shift of the Soret band to the wavelength around 577 nm and Q-bands into the near-infrared region.     

Porphyrins with exocyclic rings. Part 23: Synthesis of porphyrins with large exocyclic rings—cyclohexadeca[b]pyrroles and porphyrins therefrom

Knorr-type condensation of cyclododecanone, cyclopentadecanone, and cyclohexadecanone with phenylhydrazones derived from acetoacetate esters in the presence of zinc dust at elevated temperatures gave the corresponding large ring cycloalka[b]pyrroles in excellent yields. A cyclohexadeca[b]pyrrole was reacted with lead tetraacetate to give an acetate derivative, and this condensed with α-unsubstituted pyrroles in the presence of p-toluenesulfonic acid in acetic acid to give a series of related dipyrrolic structures. Hydrogenolysis of the benzyl ester protective groups, followed by ‘2+2’ condensations with dipyrrylmethane dialdehydes, gave unusual cycloalkanoporphyrins with 16-membered exocyclic rings. When an alkyl group is situated next to the carbocyclic ring, proton NMR spectroscopy indicates that the conformational mobility of the carbocyclic unit is severely restricted.     

Application of the Gould-Jacobs reaction to 4-amino-2,1,3-benzoselenadiazole

An effective method for the synthesis of 4-amino-2,1,3-benzoselenadiazole (4) has been described. Reduction of readily available 4-nitrobenzothiadiazole 6 with SnCl₂·2H₂O afforded 1,2,3-triaminobenzene dihydrochloride 2. The latter upon treatment with aqueous SeO₂ solution provided desired amine 4. Nucleophilic vinylic substitution of activated enol ethers 7 with amine 4 led to (benzoselenadiazol-4-ylamino)methylene derivatives 8. Thermal cyclization of derivatives 8a-c, e, f under Gould-Jacobs reaction conditions gave angularly annelated 7-(non)substituted selenadiazolo[3,4-h]quinolones 9. Acid hydrolysis of etyl ester 9c afforded corresponding acid 10. All prepared selenadiazoloquinolones were tested for antimicrobial activity.     

Use of 4-(N,N-dimethylaminosulphonyl)-7-fluoro-2,1,3-benzoxadiazole as a labelling reagent for peroxyoxalate chemiluminescence detection and its application to the determination of the beta-blocker metoprolol in serum by high-performance liquid chromatography.

Fluorogenic reagents having a benzofurazan moiety, viz., 4-(N,N-dimethylaminosulphonyl)-7-fluoro-2,1,3-benzoxadiazole (DBD-F), 7-fluoro-4-nitro-2,1,3-benzoxadiazole and 4-(aminosulphonyl)-7-fluoro-2,1,3-benzoxadiazole, were compared for the sensitive analysis of their derivatives by high-performance liquid chromatography with peroxyoxalate chemiluminescence detection. Of the proline derivatives, DBD-proline was the most sensitive with a detection limit of 2 fmol. The optimum concentrations of bis[4-nitro-2-(3,6,9-trioxadecyloxycarbonyl)phenyl] oxalate and H2O2 for the post-column reaction were 0.5 and 75 mmol dm-3 respectively and amino acids and beta-blockers derivatized with DBD-F were detected in the range 0.2-40 fmol (signal-to-noise ratio = 3) using the proposed method. The lower detection limit of metoprolol (a beta-blocker having an isopropylamino group) spiked in serum was 0.8 ng ml-1 using 20 microl of serum (signal-to-noise ratio = 5).     

Porphyrins with exocyclic rings. Part 21: Influence of pyrrolic and carbocyclic ring alkyl substituents on the synthesis of porphyrins bearing six-membered exocyclic rings

A series of 5-substituted 4,5,6,7-tetrahydroindoles were prepared by reacting 4-substituted cyclohexanones with phenylhydrazones derived from esters of acetoacetic acid under Knorr-type reaction conditions. Related 6,6-dimethyltetrahydroindoles were also prepared by reacting dimedone with oximes by the Knorr pyrrole syntheses, followed by selective reduction of the remaining ketone moiety with diborane. The substituted tetrahydroindoles were regioselectively oxidized with lead tetraacetate to give the related 7-acetoxy derivatives, and these reacted with 5-unsubstituted pyrrole esters to give pyrrolyltetrahydroindoles. In one case, a bromo substituent was used to protect the β-position of the pyrrole reactant. Cleavage of the benzyl ester protective groups with hydrogen over Pd/C, which also removes the bromo-protective group, gave four dipyrrole carboxylic acids. These were condensed with a dipyrrylmethane dialdehyde using the MacDonald ‘2+2’ condensation to give substituted porphyrins with six-membered exocyclic rings. These structures are useful for comparison to porphyrin samples found in organic-rich sediments such as oil shales and petroleum. The presence of methyl substituents on the six-membered ring for the tetrahydroindole precursors slightly decreases the yields for porphyrin synthesis, and this effect is enhanced when the system becomes more sterically crowded due to the presence of an ethyl group of the adjacent pyrrole ring. 5-Alkyl substituted tetrahydroindoles were also converted to tetrapropanoporphyrins via a cyclotetramerization procedure. The alkyl substituents again decreased the yields, although 5-alkyl substituents were found to have a far less deleterious effect than 6-alkyl groups. In addition to providing samples to help assign the vibrational spectra of geoporphyrin samples, these results demonstrate that highly substituted porphyrin systems can be prepared from tetrahydroindole derivatives.     

荧光分光光度法研究酶在非水相体系中的转酯化反应活性

以4-肼基-7-硝基-2,1,3-苯并氧杂二唑肼为荧光底物,乙烯基羧酸酯、伯醇为转酯化反应底物通过荧光分光光度法比较了几种能以固体聚合物为底物的商品化酶制剂在有机溶剂中催化转酯化反应的性质.该方法使用微量溶剂和底物进行反应,测定快捷,具有很高的直观性.实验所用4种酶制剂均可在异辛烷、甲苯和乙腈中催化转酯化反应,催化能力是脂肪酶LPL-3>蛋白酶Alcalase 3.0 T>蛋白酶subtilisin Carhberg>蛋白酶bacillolysin,但有机溶剂的疏水性对转酯化反应影响较大,疏水性高的有机溶剂比较适合做酶催化转酯化反应的溶剂.和月桂酸乙烯酯相比,小分子的丙酸乙烯酯更有利于酶催化转酯化反应的进行.     

Amino acid composition analysis of minute amounts of cysteine-containing proteins using 4-(aminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole and 4-fluoro-7-nitro-2,1,3-benzoxadiazole in combination with HPLC

The simultaneous determination of amino acid composition including cysteine of egg albumin, a model protein containing a/s cysteine residue, is reported. All the thiol groups of the cysteine residue(s) of egg albumin were labelled with 4-(aminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole, a fluorogenic reagent for thiol groups. The labeled egg albumin was hydrolyzed in 6N HCl at 110 degrees C for 24 h. The hydrolysate was lyophilized, derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole, a fluorogenic reagent for amines, and subjected to HPLC. 18 derivatized amino acids including double labelled cysteine were separated within 90 min on a Nucleosil ODS column (150 mm X 4.6 mm i.d.; 5 microns), and detected at 530 nm (ex. 470 nm) in a range from 90 fmol (aspartic acid) to 1.3 pmol (cysteine) (S/N = 3). Composition ratios of amino acids of egg albumin were similar to theoretical values except for methionine, which would be destroyed under the present acid hydrolysis condition. Analytical methods for cysteine residues are reviewed, and the availability of fluorogenic reagents having the benzofurazan structure is also discussed.     

Determination of fluvoxamine in rat plasma by HPLC with pre-column derivatization and fluorescence detection using 4-fluoro-7-nitro-2,1,3-benzoxadiazole

A sensitive, simple and reliable method using high-performance liquid chromatographic (HPLC) assay of fluvoxamine (FLU), a selective serotonin reuptake inhibitor (SSRI), in rat plasma after pre-column derivatization with 4-fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was developed in this study. Extracted plasma samples were mixed with NBD-F at 60 degrees C for 5 min and injected into HPLC. Retention times of FLU and an internal standard (propafenone) derivative were 15.5 and 13.5 min, respectively. The calibration curve was linear over the range 0.015-1.5 microg/mL (r2 = 0.9985) and the lower limits of detection and quantification of FLU were 0.008 and 0.015 microg/mL, respectively, in 100 microL of plasma. The derivative sample was stable at 4 degrees C for 1 day. The coefficients of variation for intra-day and inter-day assay of FLU were less than 8.3 and 9.6%, respectively. Other SSRIs and centrally acting drugs did not interfere with the peak of the FLU derivative. The method was applied for analysis of the plasma samples from rats treated with FLU. These results indicate that the method presented is useful to determine the FLU levels in rat plasma of volumes as small as 100 microL and can be applied to pharmacokinetic studies.     

Catecholamines derivatized with 4-fluoro-7-nitro-2,1,3-benzoxadiazole: characterization of chemical structure and fluorescence properties

4-Fluoro-7-nitro-2,1,3-benzoxadiazole (NBD-F) was evaluated as a fluorogenic derivatization reagent for the analysis of the catecholamines, dopamine, epinephrine, norepinephrine, and their naturally occurring metabolites, metanephrine and normetanephrine, homovanillic acid, 3,4-dihydroxyphenyl acetic acid. These compounds reacted rapidly with NBD-F under mild conditions to form stable derivatives. The optimal reaction conditions were found to be 12.5 mM borate buffer pH 8.0 in water:acetonitrile (1:1) at 50 °C for 5 min. New NBD derivatives of all the catecholamines and metabolites were prepared and purified and were shown by electrospray mass spectrometry to be fully reacted at all available catechol and amine sites, resulting in di- or tri-substituted derivatives. Homovanillic acid and 3,4-dihydroxyphenyl acetic acid reacted with NBD-F but gave non-fluorescent derivatives. The fluorescence excitation wavelength maximum demonstrated a red shift for the derivatives with increasing polarity of the solvent and the fluorescence intensity increased linearly with increasing organic ratio in the solvent-aqueous buffer complex. The presence of electrolyte in the solvent and the electrolyte concentration in the solvent-electrolyte complex had little effect on the fluorescent intensity. The fluorescence quantum yields in acetonitrile were also obtained. The separation behavior of the NBD-catecholamines was determined by high-performance liquid chromatography (HPLC). The studies demonstrated good potential for the application of NBD-F derivatization to the quantitative analysis of catecholamines and related compounds in biological matrices.     

Organocatalytic conjugate addition of α-nitroacetates to β,γ-unsaturated α-keto esters and subsequent decarboxylation: synthesis of optically active δ-nitro-α-keto esters

Organocatalytic asymmetric conjugate addition of tert-butyl nitroacetates to β,γ-unsaturated α-keto esters has been developed. The subsequent in situ hydrolysis-decarboxylation of the adducts provided 5-nitro-2-oxopentanoates. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst. A number of γ-aryl, γ-alkyl, and γ-heteroaryl β,γ-unsaturated α-keto esters and α-substituted tert-butyl nitroacetates were examined in the transformation. Generally 5-nitro-2-oxopentanoates were obtained in good yields (up to 97%) and enantioselectivities (up to 94% ee). The products were readily transformed to chiral proline derivatives by catalytic hydrogenation.     

Palladium(II)-catalyzed arylation of unactivated C(sp3)-H bonds by using 2,1,3-benzoselenadiazole-4-amine as directing ligand

A modified bidentate directing ligand derived from 2,1,3-benzoselenadiazole (BSeD) was designed and synthesized. It exhibited high regioselectivity in the catalytic activation of unactivated C(sp³)-H bonds with aryl iodides in the presence of palladium catalyst in yields up to 94%.     

Kinetics of proton transfer from tetra(4-nitro-5-tert-butyl)phthalocyanine to nitrogen-containing bases in benzene

The acid-basic interaction between tetra(4-nitro-5-tert-butyl)phthalocyanine and pyridine, 2-methylpyridine, morpholine, piperidine, n-butylamine, diethylamine, and triethylamine in benzene is studied. It is found that the intermolecular transfer of protons of NH groups from tetra(4-nitro-5-tert-butyl)phthalocyanine to morpholine and diethylamine is characterized by unusually low values of the reaction constant rates. The effect of the structure of tetra(4-nitro-5-tert-butyl)phthalocyanine and tetra(3-nitro-5-tert-butyl)phthalocyanine, and of the nature of the base on the kinetic parameters of acid-base interaction is demonstrated. A structure is proposed for complexes with the transfer of displaced phthalocyanines’ protons. It is found that they undergo decomposition over time.