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Marjorie A Jones - One of the best experts on this subject based on the ideXlab platform.
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normal and abnormal heme biosynthesis part 7 synthesis and metabolism of coproporphyrinogen iii analogues with acetate or butyrate side chains on rings c and d development of a modified model for the active site of coproporphyrinogen oxidase
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Timothy D Lash, Teresa R Lamm, Andy J Schaber, Wenhsiang Chung, Eric K Johnson, Marjorie A JonesAbstract:Abstract Analogues of coproporphyrinogen-III have been prepared with acetate or butyrate groups attached to the C and D pyrrolic subunits. The corresponding porphyrin methyl esters were synthesized by first generating a,c-biladienes by reacting a dipyrrylmethane with pyrrole aldehydes in the presence of HBr. Cyclization with copper(II) chloride in DMF, followed by demetalation with 15% H 2 SO 4 –TFA and reesterification, gave the required porphyrins in excellent yields. Hydrolysis with 25% hydrochloric acid and reduction with sodium-amalgam gave novel diacetate and dibutyrate Porphyrinogens 9 . Diacetate 9a was incubated with chicken red cell hemolysates (CRH), but gave complex results due to the combined action of two of the enzymes present in these preparations. Separation of uroporphyrinogen decarboxylase (URO-D) from coproporphyrinogen oxidase (CPO) allowed the effects of both enzymes on the diacetate substrate to be assessed. Porphyrinogen 9a proved to be a relatively poor substrate for CPO compared to the natural substrate coproporphyrinogen-III, and only the A ring propionate moiety was processed to a significant extent. Similar results were obtained for incubations of 9a with purified human recombinant CPO. Diacetate 9a was also a substrate for URO-D and a porphyrinogen monoacetate was the major product in this case; however, some conversion of a second acetate unit was also evident. The dibutyrate porphyrinogen 9b was only recognized by the enzyme CPO, but proved to be a modest substrate for incubations with CRH. However, 9b was an excellent substrate for purified human recombinant CPO. The major product for these incubations was a monovinylporphyrinogen, but some divinyl product was also generated in incubations using purified recombinant human CPO. The incubation products were converted into the corresponding porphyrin methyl esters, and these were characterized by proton NMR spectroscopy and mass spectrometry. The results extend our understanding of substrate recognition and catalysis for this intriguing enzyme and have allowed us to extend the active site model for CPO. In addition, the competitive action of both URO-D and CPO on the same diacetate porphyrinogen substrate provides additional perspectives on the potential existence of abnormal pathways for heme biosynthesis.
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use of di and tripropionate substrate analogs to probe the active site of human recombinant coproporphyrinogen oxidase
Medical Science Monitor, 2008Co-Authors: Justin B. Morgenthaler, Timothy D Lash, Reyna L Barto, Marjorie A JonesAbstract:Background: Defects in the enzyme coproporphyrinogen oxidase result in accumulation of porphyrins which may affect the severity of a subset of porphyrias. Thus evaluation of this enzyme for substrate selectivity is of value. Kinetic evaluations of recombinant human coproporphyrinogen oxidase have been undertaken using six di- and tripropionate analogs of the natural substrate coproporphyrin-ogen-III. These substrate analogs were modified by having alkyl groups in place of one or both of the ring 13- or 17-propionate moieties. Material/Methods: Cloned human enzyme was incubated with analogs under apparent first order conditions and with various substrate concentrations. The kinetic values, K m and V max , were determined. Results: Relative to the authentic substrate, the K m values for the 13-ethyl, dimethyl and diethyl Porphyrinogens were very comparable whereas the K m values were much higher using dipropyl and dibutyl porphyrinogen and much lower for the 17-ethyl analog. For the dipropionate analogs, the V max values were an apparent function of the carbon length of the substituent on the C and D rings, with longer carbon length severely reducing product formation by some 4-5 orders of magnitude. Also, the two isomeric tripropionates that were tested indicated that it was more detrimental to have an ethyl group at the 13-position for both binding and catalysis. Conclusions: This work extends our understanding of porphyrin ring substituent effects reported by Cooper et al. (2005). The substituents on both the C and D rings have significant effects on both the substrate binding and catalysis by this important enzyme.
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metabolism of pentacarboxylate Porphyrinogens by highly purified human coproporphyrinogen oxidase further evidence for the existence of an abnormal pathway for heme biosynthesis
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Christopher L. Cooper, Marjorie A Jones, Christian M Stob, Timothy D LashAbstract:Abstract An abnormal series of porphyrin tetracarboxylic acids known as the isocoproporphyrins, are commonly excreted by patients suffering from the disease porphyria cutanea tarda (PCT). These porphyrins appear to arise by bacterial degradation of dehydroisocoproporphyrinogen that is generated by the premature metabolism of the normal pentacarboxylate intermediate (5dab) by coproporphyrinogen oxidase (copro’gen oxidase). This porphyrinogen can be further metabolized by uroporphyrinogen decarboxylase to give harderoporphyrinogen, one of the usual intermediates in heme biosynthesis. Therefore, it is possible that some of the heme formed under abnormal conditions may originate from the ‘isocopro-type’ porphyrinogen intermediate. In order to investigate the feasibility of alternative pathways for heme biosynthesis, the four type III pentacarboxylate isomeric Porphyrinogens were incubated with purified, cloned human copro’gen oxidase at 37 °C with various substrate concentrations under initial velocity conditions. Of the four isomers, only 5dab was a substrate for copro’gen oxidase and this gave dehydroisocoproporphyrin. The structure of the related porphyrin tetramethyl ester was confirmed by proton NMR spectroscopy and mass spectrometry. The K m value for proto’gen-IX formation from copro’gen, an indicator of molecular recognition, was similar to the K m value for monovinyl product formation with 5dab, although copro’gen-III has an approximately twofold higher K cat value. Although 5dab is a slightly poorer substrate than copro’gen-III, these results support the hypothesis that an abnormal route for heme biosynthesis is possible in humans suffering from PCT or related syndromes such as hexachlorobenzene poisoning.
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unprecedented overmetabolism of a porphyrinogen substrate by coproporphyrinogen oxidase
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Timothy D Lash, Annasigrid I M Keck, Ukti N Mani, Marjorie A JonesAbstract:Abstract Harderoporphyrinogen-I is metabolized by avian hemolysate preparations of coproporphyrinogen oxidase to give a trivinylic product; this unprecedented ‘overmetabolism’ of the porphyrinogen substrate provides strong support for a proposed model of the active site of this poorly understood enzyme.
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metabolism of analogues of coproporphyrinogen iii with modified side chains implications for binding at the active site of coproporphyrinogen oxidase
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Timothy D Lash, Todd A Kaprak, Lan Shen, Marjorie A JonesAbstract:Porphyrinogens with modified propionate side chains bearing methyl substituents were found to be modest substrates for coproporphyrinogen oxidase; the results indicate that alteration of the substituents involved in secondary binding interactions has a comparable affect to modifying the side chain that undergoes degradation at the catalytic site.
Timothy D Lash - One of the best experts on this subject based on the ideXlab platform.
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normal and abnormal heme biosynthesis part 7 synthesis and metabolism of coproporphyrinogen iii analogues with acetate or butyrate side chains on rings c and d development of a modified model for the active site of coproporphyrinogen oxidase
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Timothy D Lash, Teresa R Lamm, Andy J Schaber, Wenhsiang Chung, Eric K Johnson, Marjorie A JonesAbstract:Abstract Analogues of coproporphyrinogen-III have been prepared with acetate or butyrate groups attached to the C and D pyrrolic subunits. The corresponding porphyrin methyl esters were synthesized by first generating a,c-biladienes by reacting a dipyrrylmethane with pyrrole aldehydes in the presence of HBr. Cyclization with copper(II) chloride in DMF, followed by demetalation with 15% H 2 SO 4 –TFA and reesterification, gave the required porphyrins in excellent yields. Hydrolysis with 25% hydrochloric acid and reduction with sodium-amalgam gave novel diacetate and dibutyrate Porphyrinogens 9 . Diacetate 9a was incubated with chicken red cell hemolysates (CRH), but gave complex results due to the combined action of two of the enzymes present in these preparations. Separation of uroporphyrinogen decarboxylase (URO-D) from coproporphyrinogen oxidase (CPO) allowed the effects of both enzymes on the diacetate substrate to be assessed. Porphyrinogen 9a proved to be a relatively poor substrate for CPO compared to the natural substrate coproporphyrinogen-III, and only the A ring propionate moiety was processed to a significant extent. Similar results were obtained for incubations of 9a with purified human recombinant CPO. Diacetate 9a was also a substrate for URO-D and a porphyrinogen monoacetate was the major product in this case; however, some conversion of a second acetate unit was also evident. The dibutyrate porphyrinogen 9b was only recognized by the enzyme CPO, but proved to be a modest substrate for incubations with CRH. However, 9b was an excellent substrate for purified human recombinant CPO. The major product for these incubations was a monovinylporphyrinogen, but some divinyl product was also generated in incubations using purified recombinant human CPO. The incubation products were converted into the corresponding porphyrin methyl esters, and these were characterized by proton NMR spectroscopy and mass spectrometry. The results extend our understanding of substrate recognition and catalysis for this intriguing enzyme and have allowed us to extend the active site model for CPO. In addition, the competitive action of both URO-D and CPO on the same diacetate porphyrinogen substrate provides additional perspectives on the potential existence of abnormal pathways for heme biosynthesis.
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use of di and tripropionate substrate analogs to probe the active site of human recombinant coproporphyrinogen oxidase
Medical Science Monitor, 2008Co-Authors: Justin B. Morgenthaler, Timothy D Lash, Reyna L Barto, Marjorie A JonesAbstract:Background: Defects in the enzyme coproporphyrinogen oxidase result in accumulation of porphyrins which may affect the severity of a subset of porphyrias. Thus evaluation of this enzyme for substrate selectivity is of value. Kinetic evaluations of recombinant human coproporphyrinogen oxidase have been undertaken using six di- and tripropionate analogs of the natural substrate coproporphyrin-ogen-III. These substrate analogs were modified by having alkyl groups in place of one or both of the ring 13- or 17-propionate moieties. Material/Methods: Cloned human enzyme was incubated with analogs under apparent first order conditions and with various substrate concentrations. The kinetic values, K m and V max , were determined. Results: Relative to the authentic substrate, the K m values for the 13-ethyl, dimethyl and diethyl Porphyrinogens were very comparable whereas the K m values were much higher using dipropyl and dibutyl porphyrinogen and much lower for the 17-ethyl analog. For the dipropionate analogs, the V max values were an apparent function of the carbon length of the substituent on the C and D rings, with longer carbon length severely reducing product formation by some 4-5 orders of magnitude. Also, the two isomeric tripropionates that were tested indicated that it was more detrimental to have an ethyl group at the 13-position for both binding and catalysis. Conclusions: This work extends our understanding of porphyrin ring substituent effects reported by Cooper et al. (2005). The substituents on both the C and D rings have significant effects on both the substrate binding and catalysis by this important enzyme.
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metabolism of pentacarboxylate Porphyrinogens by highly purified human coproporphyrinogen oxidase further evidence for the existence of an abnormal pathway for heme biosynthesis
Bioorganic & Medicinal Chemistry, 2005Co-Authors: Christopher L. Cooper, Marjorie A Jones, Christian M Stob, Timothy D LashAbstract:Abstract An abnormal series of porphyrin tetracarboxylic acids known as the isocoproporphyrins, are commonly excreted by patients suffering from the disease porphyria cutanea tarda (PCT). These porphyrins appear to arise by bacterial degradation of dehydroisocoproporphyrinogen that is generated by the premature metabolism of the normal pentacarboxylate intermediate (5dab) by coproporphyrinogen oxidase (copro’gen oxidase). This porphyrinogen can be further metabolized by uroporphyrinogen decarboxylase to give harderoporphyrinogen, one of the usual intermediates in heme biosynthesis. Therefore, it is possible that some of the heme formed under abnormal conditions may originate from the ‘isocopro-type’ porphyrinogen intermediate. In order to investigate the feasibility of alternative pathways for heme biosynthesis, the four type III pentacarboxylate isomeric Porphyrinogens were incubated with purified, cloned human copro’gen oxidase at 37 °C with various substrate concentrations under initial velocity conditions. Of the four isomers, only 5dab was a substrate for copro’gen oxidase and this gave dehydroisocoproporphyrin. The structure of the related porphyrin tetramethyl ester was confirmed by proton NMR spectroscopy and mass spectrometry. The K m value for proto’gen-IX formation from copro’gen, an indicator of molecular recognition, was similar to the K m value for monovinyl product formation with 5dab, although copro’gen-III has an approximately twofold higher K cat value. Although 5dab is a slightly poorer substrate than copro’gen-III, these results support the hypothesis that an abnormal route for heme biosynthesis is possible in humans suffering from PCT or related syndromes such as hexachlorobenzene poisoning.
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the enigma of coproporphyrinogen oxidase how does this unusual enzyme carry out oxidative decarboxylations to afford vinyl groups
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: Timothy D LashAbstract:A new mechanism is proposed to explain how coproporphyrinogen oxidase performs two oxidative decarboxylations on a porphyrinogen substrate without the aid of cofactors or metal ions in the presence of molecular oxygen.
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unprecedented overmetabolism of a porphyrinogen substrate by coproporphyrinogen oxidase
Bioorganic & Medicinal Chemistry Letters, 2002Co-Authors: Timothy D Lash, Annasigrid I M Keck, Ukti N Mani, Marjorie A JonesAbstract:Abstract Harderoporphyrinogen-I is metabolized by avian hemolysate preparations of coproporphyrinogen oxidase to give a trivinylic product; this unprecedented ‘overmetabolism’ of the porphyrinogen substrate provides strong support for a proposed model of the active site of this poorly understood enzyme.
Jonathan P. Hill - One of the best experts on this subject based on the ideXlab platform.
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Stable pseudotetrahedral supermolecules based on an oxoporphyrinogen
Tetrahedron Letters, 2010Co-Authors: Jan Labuta, Jonathan P. Hill, Mark R. J. Elsegood, Katsuhiko ArigaAbstract:Abstract Topologically asymmetric compounds, important as chiral nanoscale building blocks, were synthesized using stepwise N-alkylation on tetrakis (3,5-di- t -butyl-4-oxocyclohexadien-2,5-yl) porphyrinogen as revealed by X-ray crystallographic studies on a porphyrinogen molecule bearing four different N-substituents.
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Chromogenic indicator for anion reporting based on an N-substituted oxoporphyrinogen.
Inorganic Chemistry, 2006Co-Authors: Jonathan P. Hill, Amy Lea Schumacher, Francis D'souza, Jan Labuta, Carl Redshaw, Mark R. J. Elsegood, Masaru Aoyagi, Takashi Nakanishi, Katsuhiko ArigaAbstract:5,10,15,20-Tetrakis-3,5-di-tert-butyl-4-oxocyclohexadienylidene porphyrinogen and its di-N-benzylated derivative are solvatochromic dyes capable of binding anionic species. The influence of solvent polarity and hydrogen bonding on their electronic absorption spectra was observed. Hydrogen bonding by the porphyrinogen amine protons of acetone solvent molecules could be observed in the solid state. The acetone solvate of N21N23-dibenzyl-5,10,15,20-tetrakis-3,5-di-tert-butyl-4-oxocyclohexadienylidene porphyrinogen crystallized under anhydrous conditions in the space group P1 with cell dimensions a = 12.1693(11) A, b = 17.5849(13) A, c = 21.0965(17) A, α = 69.870(4)°, β = 78.140(4)°, γ = 82.865(5)°. These Porphyrinogens are capable of binding a variety of anions and can be used to distinguish fluoride chromogenically from the other halide anions. Solvatochromism was combined with anion binding in an attempt to provide more selective tests for anions. The anion binding properties were investigated using UV/vi...
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cover picture structures spectral and electrochemical properties of n naphth 2 ylmethyl appended Porphyrinogens eur j org chem 14 2005
European Journal of Organic Chemistry, 2005Co-Authors: Jonathan P. Hill, Katsuhiko Ariga, Amy L Mccarty, Wolfgang Schmitt, Francis D SouzaAbstract:The cover picture shows the X-ray crystal structures of the compounds obtained by the alkylation of a conjugated porphyrinogen precursor at its macrocyclic nitrogen atoms with 2-(methylenenaphthyl) groups. The presence of the N-alkyl groups introduces intermolecular π−π stacking interactions which culminate in a 1-dimensional stacked array for the fully N-substituted derivative. The N-alkylation enhances the ability of the compounds to form anion radical and cation radical species and permits “tuning” of the electrochemical properties of the core porphyrinogen. Details are discussed in the article by J. P. Hill et al. on p. 2893 ff.
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Cover Picture: Structures, Spectral and Electrochemical Properties of N‐(Naphth‐2‐ylmethyl)‐Appended Porphyrinogens (Eur. J. Org. Chem. 14/2005)
European Journal of Organic Chemistry, 2005Co-Authors: Jonathan P. Hill, Katsuhiko Ariga, Amy L Mccarty, Wolfgang Schmitt, Francis D′souzaAbstract:The cover picture shows the X-ray crystal structures of the compounds obtained by the alkylation of a conjugated porphyrinogen precursor at its macrocyclic nitrogen atoms with 2-(methylenenaphthyl) groups. The presence of the N-alkyl groups introduces intermolecular π−π stacking interactions which culminate in a 1-dimensional stacked array for the fully N-substituted derivative. The N-alkylation enhances the ability of the compounds to form anion radical and cation radical species and permits “tuning” of the electrochemical properties of the core porphyrinogen. Details are discussed in the article by J. P. Hill et al. on p. 2893 ff.
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structures spectral and electrochemical properties of n naphth 2 ylmethyl appended Porphyrinogens
European Journal of Organic Chemistry, 2005Co-Authors: Jonathan P. Hill, Katsuhiko Ariga, Amy L Mccarty, Wolfgang Schmitt, Francis DsouzaAbstract:Alkylation of 5,10,15,20-tetrakis(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)porphyrinogen at its macrocyclic nitrogen atoms results in four multiply N-substituted products, which were isolated and characterized. The electrochemical and spectroelectrochemical properties of these compounds were determined. Molecular structures of the N-alkylated compounds are influenced strongly by intermolecular π-π stacking interaction between naphthyl groups leading to formation of dimers or stacked arrays of the macrocycle depending on multiplicity of substituents. The redox and spectral properties of the compounds are related to the increasing multiplicity of N-substitution. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
Amy L Mccarty - One of the best experts on this subject based on the ideXlab platform.
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Cover Picture: Structures, Spectral and Electrochemical Properties of N‐(Naphth‐2‐ylmethyl)‐Appended Porphyrinogens (Eur. J. Org. Chem. 14/2005)
European Journal of Organic Chemistry, 2005Co-Authors: Jonathan P. Hill, Katsuhiko Ariga, Amy L Mccarty, Wolfgang Schmitt, Francis D′souzaAbstract:The cover picture shows the X-ray crystal structures of the compounds obtained by the alkylation of a conjugated porphyrinogen precursor at its macrocyclic nitrogen atoms with 2-(methylenenaphthyl) groups. The presence of the N-alkyl groups introduces intermolecular π−π stacking interactions which culminate in a 1-dimensional stacked array for the fully N-substituted derivative. The N-alkylation enhances the ability of the compounds to form anion radical and cation radical species and permits “tuning” of the electrochemical properties of the core porphyrinogen. Details are discussed in the article by J. P. Hill et al. on p. 2893 ff.
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cover picture structures spectral and electrochemical properties of n naphth 2 ylmethyl appended Porphyrinogens eur j org chem 14 2005
European Journal of Organic Chemistry, 2005Co-Authors: Jonathan P. Hill, Katsuhiko Ariga, Amy L Mccarty, Wolfgang Schmitt, Francis D SouzaAbstract:The cover picture shows the X-ray crystal structures of the compounds obtained by the alkylation of a conjugated porphyrinogen precursor at its macrocyclic nitrogen atoms with 2-(methylenenaphthyl) groups. The presence of the N-alkyl groups introduces intermolecular π−π stacking interactions which culminate in a 1-dimensional stacked array for the fully N-substituted derivative. The N-alkylation enhances the ability of the compounds to form anion radical and cation radical species and permits “tuning” of the electrochemical properties of the core porphyrinogen. Details are discussed in the article by J. P. Hill et al. on p. 2893 ff.
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structures spectral and electrochemical properties of n naphth 2 ylmethyl appended Porphyrinogens
European Journal of Organic Chemistry, 2005Co-Authors: Jonathan P. Hill, Katsuhiko Ariga, Amy L Mccarty, Wolfgang Schmitt, Francis DsouzaAbstract:Alkylation of 5,10,15,20-tetrakis(3,5-di-tert-butyl-4-oxo-2,5-cyclohexadienylidene)porphyrinogen at its macrocyclic nitrogen atoms results in four multiply N-substituted products, which were isolated and characterized. The electrochemical and spectroelectrochemical properties of these compounds were determined. Molecular structures of the N-alkylated compounds are influenced strongly by intermolecular π-π stacking interaction between naphthyl groups leading to formation of dimers or stacked arrays of the macrocycle depending on multiplicity of substituents. The redox and spectral properties of the compounds are related to the increasing multiplicity of N-substitution. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)
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highly nonplanar electron deficient n substituted tetra oxocyclohexadienylidene Porphyrinogens structural computational and electrochemical investigations
Journal of Organic Chemistry, 2004Co-Authors: Jonathan P. Hill, Ian J Hewitt, Christopher E Anson, Annie K Powell, Amy L Mccarty, Paul A Karr, Melvin E Zandler, Francis DsouzaAbstract:The structures and electrochemistry of N-benzylated meso-tetrakis (3,5-di-tert-butyl-4-oxo-cyclohexa-2,5-dienylidene) Porphyrinogens have been investigated. Structural determinations reveal the isomeric identity of the products obtained from the N-alkylation of the parent meso-tetra (oxo-cyclohexadienylidene) porphyrinogen. The compounds are subject to increased macrocyclic deformations upon increasing N-substitution culminating in the tetra-N-benzyl derivative, which has a buckling superimposed on the already highly puckered macrocycle. The electrochemical analyses emphasize the electron deficiency of the N-benzylated meso-tetra(oxo-cyclohexadienylidene) Porphyrinogens and indicate that they can be considered as quinones conjugated via the unsaturated tetrapyrrolic macrocycle. The N-benzylated compounds studied form stable and well-defined π-cation radical and π-anion radical species because of their highly conjugated nature. Ab initio molecular orbital calculations at the B3LYP/3-21G(*) level confirmed ...
S M S Chauhan - One of the best experts on this subject based on the ideXlab platform.
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synthesis of 5 10 15 20 meso unsubstituted and 5 10 15 20 meso substituted 21 23 ditellura diselena core modified Porphyrinogens oxidation and detection of mercury ii
RSC Advances, 2014Co-Authors: Sohail Ahmad, Kumar Karitkey Yadav, Sarangthem Joychandra Singh, S M S ChauhanAbstract:Tellurium and selenium incorporated 5,10,15,20-meso-unsubstituted-21,23-ditellura/diselena core-modified Porphyrinogens (N2Te2 and N2Se2), 5,10,15,20-meso-unsubstituted-21-tellura/selena core-modified Porphyrinogens (N3Te and N3Se) and fully substituted meso-carbons Porphyrinogens (N2Te2, N2Se2 and higher analogs) are synthesized by 3 + 1 condensation of tellurophene/selenophene dipyrranes and their corresponding diols in the presence of BF3–etharate or BF3–methanol. The meso-unsubstituted and substituted Porphyrinogens were oxidized with chloranil/0.1% aqueous FeCl3 in CHCl3 at room temperature to obtain the corresponding porphines and porphyrins which are further reduced to corresponding chlorin and bacteriochlorin, whereas the fully meso-substituted Porphyrinogens were found to be good ligands for Hg2+. The structures of the products were characterized by IR, 1H, 13C, 125Te, 77Se NMR, CHN analysis, mass spectrometry and single-crystal XRD.
