Metalloporphyrin Model Research Articles

Interaction of Iron(III)-5,10,15,20-Tetrakis (4-Sulfonatophenyl) Porphyrin with Chloroquine, Quinine and Quinidine

Iron(III)-5,10,15,20-tetrakis(4-sulfonatophenyl) porphyrin (FeTPPS) is used as non-physiological metalloporphyrin model for the natural iron (III)-protoporphyrin IX (FePPIX) resulting from hemoglobin degradation to investigate ligand binding reactions in aqueous solution. Studies were conducted on the interaction of FeTPPS with Chloroquine, Quinine, and Quinidine, which are historically the most common quinoline-based drugs used to treat malaria, an infectious disease afflicting several hundred millions every year worldwide, mainly in tropical regions. Using UV-Visible spectrophotometry, the binding reaction was studied at pH 7.40 in purely aqueous solution, and in aqueous solution containing NaNO3 at concentration of 0.1 M. Fitted titration curves obtained were in agreement with experimental data according to a formation scheme of 1:1 complex (1 FeTPPS μ-oxo-dimer: 1 Antimalarial). Values of apparent binding constant (K) obtained were between 4.3 × 103 M-1 to 7.59 × 104 M-1, demonstrating that FeTPPS and the antimalarials formed stable complexes. The stability of the complex decreased when NaNO3 was added to the solution. This ionic strength dependence was ascribed to electrostatic effects. Quinine and Chloroquine interacted with FeTPPS stronger than Quinidine did. Chloroquine showed the strongest affinity to FeTPPS. These findings revealed the influence of steric and stereochemical factors. Molecular electrostatic potentials (MEP) calculated with Hartree-Fock theory argue in favor of π-π and electrostatic interactions between reaction partners as driving forces for the complex formation. In the case of FeTPPS: Chloroquine interaction, it is suggested that an intramolecular hydrogen bond is formed between phenyl and quinuclidine N-H+ as additional force stabilizing the complex. Analysis of crystallographic data using the Cambridge Structural Database (CSD) gave evidence of the hydrogen bond formation between phenyl and N-H+ groups in 370 structures.

ChemInform Abstract: Manganese Catalyzed C‐H Halogenation

AbstractReview: 64 refs.

Manganese Catalyzed C-H Halogenation.

The remarkable aliphatic C-H hydroxylations catalyzed by the heme-containing enzyme, cytochrome P450, have attracted sustained attention for more than four decades. The effectiveness of P450 enzymes as highly selective biocatalysts for a wide range of oxygenation reactions of complex substrates has driven chemists to develop synthetic metalloporphyrin model compounds that mimic P450 reactivity. Among various known metalloporphyrins, manganese derivatives have received considerable attention since they have been shown to be versatile and powerful mediators for alkane hydroxylation and olefin epoxidation. Mechanistic studies have shown that the key intermediates of the manganese porphyrin-catalyzed oxygenation reactions include oxo- and dioxomanganese(V) species that transfer an oxygen atom to the substrate through a hydrogen abstraction/oxygen recombination pathway known as the oxygen rebound mechanism. Application of manganese porphyrins has been largely restricted to catalysis of oxygenation reactions until recently, however, due to ultrafast oxygen transfer rates. In this Account, we discuss recently developed carbon-halogen bond formation, including fluorination reactions catalyzed by manganese porphyrins and related salen species. We found that biphasic sodium hypochlorite/manganese porphyrin systems can efficiently and selectively convert even unactivated aliphatic C-H bonds to C-Cl bonds. An understanding of this novel reactivity derived from results obtained for the oxidation of the mechanistically diagnostic substrate and radical clock, norcarane. Significantly, the oxygen rebound rate in Mn-mediated hydroxylation is highly correlated with the nature of the trans-axial ligands bound to the manganese center (L-Mn(V)═O). Based on the ability of fluoride ion to decelerate the oxygen rebound step, we envisaged that a relatively long-lived substrate radical could be trapped by a Mn-F fluorine source, effecting carbon-fluorine bond formation. Indeed, this idea led to the discovery of the first Mn-catalyzed direct aliphatic C-H fluorination reactions utilizing simple, nucleophilic fluoride salts. Mechanistic studies and DFT calculations have revealed a trans-difluoromanganese(IV) species as the key fluorine transfer intermediate. In addition to catalyzing normal (19)F-fluorination reactions, manganese salen complexes were found to enable the incorporation of radioactive (18)F fluorine via C-H activation. This advance represented the first direct Csp(3)-H bond (18)F labeling with no-carrier-added [(18)F]fluoride and facilitated the late-stage labeling of drug molecules for PET imaging. Given the high reactivity and enzymatic-like selectively of metalloporphyrins, we envision that this new Heteroatom-Rebound Catalysis (HRC) strategy will find widespread application in the C-H functionalization arena and serve as an effective tool for forming new carbon-heteroatom bonds at otherwise inaccessible sites in target molecules.

Spectroscopic observation of iodosylarene metalloporphyrin adducts and manganese(V)-oxo porphyrin species in a cytochrome P450 analogue

Different metalloporphyrin model compounds have been synthesized to study the mechanisms of cytochrome P450s with various terminal oxidants, and numerous intermediates have been reported. However, the detailed mechanism of the oxygen atom transfer from iodosylarene to the substrates remains unclear. Here we report the direct ultraviolet-visible spectroscopic observation of the soluble iodosylarene-manganese porphyrin adduct following catalytic oxidation using 2,4,6-tri-tert-butylphenol as the reductant. When the reductant is changed to cis-stilbene, the rate-determining step also changes. Both the iodosylarene-manganese porphyrin adduct and [(porphyrin)Mn(V)=O] species may be simultaneously observed. In the absence of reductant, the adduct of iodosylarene with sterically hindered [Mn(meso-tetrakis(2,6-dichlorophenyl)porphinato)Cl] is immediately formed, and smoothly converted into a high-valent [(porpyrinato)Mn=O]. Electrospray ionization mass spectrometry analysis of the reaction further confirms the transformation between these species. This study provides an insight into the mechanism of oxygen transfer within the haem-containing enzymatic systems.

A brief history of the contribution of metalloporphyrin models to cytochrome P450 chemistry and oxidation catalysis

Since their discovery in the 1960s, cytochrome P450-dependent monooxygenases have very much attracted the interest of chemists because of their ability to catalyze the selective transfer of an oxygen atom from O2 to very diverse substrates including alkanes. The huge number of studies performed during these last 30 years on P450s themselves and on iron porphyrin models has led to a detailed understanding of the oxidations catalyzed by iron porphyrins and hemeproteins in general, and to the design of many bioinspired oxidation catalysts. This article gives an overview of what were the main contributions of metalloporphyrin model studies to the fields of P450 chemistry and oxidation catalysis, through a brief comparative history of the development of our knowledge on cytochrome P450 and on the development and use of metalloporphyrin models. Depuis leur découverte autour de 1960, les monooxygenases à cytochrome P450 ont beaucoup attiré l'attention des chimistes du fait de leur capacité à catalyser le transfert sélectif d'un atome d'oxygène d'O2 sur des substrats très divers, y compris des alcanes. Le nombre énorme d'études réalisées au cours de ces 30 dernières années sur les P450s eux-mêmes et sur des porphyrines de fer modèles a conduit à une connaissance détaillée des oxydations catalysées par ces métalloporphyrines et les hémoprotéines en général, ainsi qu'à la mise au point d'un grand nombre de catalyseurs d'oxydation bioinspirés. Cet article donne un survol de ce qu'ont été les principales contributions des études utilisant des métalloporphyrines modèles aux domaines de la chimie des P450s et de la catalyse d'oxydation, à travers une brève histoire comparative du développement de nos connaissances sur les cytochromes P450 et du développement et de l'utilisation de métalloporphyrines modèles.

Metalloporphyrins as Biomimetic Models for Cytochrome P-450 in the Oxidation of Atrazine

The aim of this work was to evaluate whether metalloporphyrin models could mimic the action of cytochrome P-450 in the oxidation of atrazine, a herbicide. The commercially available second-generation metalloporphyrins 5,10,15,20-tetrakis(2,6-dichlorophenyl)porphyrin metal(III) chloride [M(TDCPP)Cl] and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin metal(III) chloride [M(TFPP)Cl] (metal = Fe or Mn) and the oxidants iodosylbenzene and metachloroperbenzoic acid were employed in this study. Results showed that the metalloporphyrins used here can oxidize atrazine. Yields as high as 32% were obtained for the Mn(TFPP)Cl/PhIO system, which shows that these catalysts can mimic both the in vivo and the in vitro action of cytochrome P-450, with formation of the metabolites DEA and DIA. The formation of five other unknown products was also detected, but only one of them could be identified, since the other four were present in very low concentrations. The compound COA, identified by mass spectrometry, was the main product in most of the oxidation reactions.

Effects of systematic peripheral group deuteration on the low-frequency resonance Raman spectra of myoglobin derivatives.

Resonance Raman spectra are reported for a series of systematically deuterated analogues of myoglobin in its deoxy state as well as for its CO and O(2) adducts. Specifically, the myoglobin samples studied are those that have been reconstituted with deuterated protoheme analogues. These include the methine deuterated, protoheme-d4; analogue bearing C(2)H(3) groups at the 1, 3, 5, and 8 positions, protoheme-d12; the species bearing C(2)H(3) groups at the 1 and 3 positions only, 1,3-protoheme-d6; and the species bearing C(2)H(3) groups at the 5 and 8 positions only, 5,8-protoheme-d6. While the results are generally consistent with previously reported data for synthetic metalloporphyrin models and previous studies of labeled heme proteins, the high-quality low-frequency RR data reported here reveal several important aspects of these low-frequency modes. Of special interest is the fact that, using the two d6-protoheme analogues, it is shown that certain modes are apparently localized on particular pyrrole rings, while others are localized on different rings; i.e., several of these low-frequency modes are localized on one side of the heme.

Porphyrin xanthene amides: anchoring distal H-bonding in heme models

Distal H-bonding to axial ligand is strategically introduced in metalloporphyrin models by modifying porphyrin xanthene acid in which the carboxyl proton is preferentially H-bonded to the xanthene oxygen. Xanthene carboxamide is able to deliver intramolecular H-bonding and simultaneously lock into a well-defined conformation. Multipoint recognition of ligand is demonstrated in an amidinium–acetate–Zn porphyrin complex, mimicking a structural feature found in sulfite reductase.

Radical cation intermediates in N-dealkylation reactions.

1. A number of mechanistic possibilities exist for P450-catalysed N-dealkylation and have been considered over the years, including C- and N-hydroxylation and sequential electron transfer (SET). With peroxidases the evidence strongly favours SET and free radicals can be detected. Any mechanism must account for lack of incorporation of label from H218O into product by P450s and the high kinetic deuterium isotope effects that are seen in N-dealkylation reactions catalysed by peroxidases but not P450s. 2. Several lines of evidence support a role for SET in P450 amine oxidations, including Hammett analysis, products of dihydropyridine oxidations, and products of mechanism-based inhibition by strained cycloalkylamines. 3. The hypothesis was considered that the P450s act via base catalysis to deprotonate the aminium radical generated by SET, since the pKa has been estimated to be approximately 9. Dihydropyridine aminium radicals have low pKa (< 4) and are generally considered to have considerable kinetic acidity. None of the haemoproteins under consideration (including the peroxidases and haemoglobin) showed high kinetic hydrogen isotope effects for the oxidation of [4-2H]- or [4-3H]-labelled 1,4-dihydropyridines. These results are consonant with the view that P450s catalyse the deprotonation of N,N-dialkylaniline aminium radicals. 4. Since low isotope effects were seen with biomimetic metalloporphyrin models as well as P450s, the deprotonation is attributed to the (FeO)2+ entity, expected to be a strong base, and not the apoprotein. Thus, the FeO moiety of peroxidases is shielded, consistent with evidence by others that SET occurs through the porphyrin edge. Both P450s and peroxidases catalysed the oxidative N-demethylation of aminopyrine and N,N-dimethylaminothioanisole; however, only the peroxidases generated the stable coloured aminium radicals. 5. The rates of N-demethylation of variously para-substituted N,N-dimethylanilines can be used to undertake Hammett or Marcus analysis. The former yields rho = -0.6 and the latter an apparent E1/2 of approximately 1.8 for the formal (FeO)3+ entity of P4502B1. 6. Even in the oxidation of N,N-dialkylanilines, a finite rate of N-oxidation is seen (approximately 0.1% of N-dealkylation). The simplest paradigm has N-oxygenation and N-dealkylation both proceeding from a common aminium radical intermediate.

Herzberg–Teller coupling and configuration interaction in a metalloporphyrin model: 1,3,5,7-tetramethylcyclo-octatetraene dianion

1,3,5,7-tetramethylcyclo-octatetraene dianion (TMCOT−2) is employed as a metalloporphyrin model. Its UV-VIS absorption spectrum shows two electronic bands, an intense band (Soret or B) at ∼215 nm and a weaker state (Q band) at 382 nm, while cyclo-octatetraene dianion (COT−2) only has a B band at 236 nm. An exact Pariser–Parr–Pople (PPP) calculation of COT−2 predicts a strong Soret band at 231 nm and a vanishing Q band intensity at 366 nm. Resonance Raman spectrum with excitation near the Q and Soret bands of TMCOT−2 shows enhancement patterns remarkably similar to those of metalloporphyrins. Nontotally symmetric modes are enhanced in resonance with the Q band, while the totally symmetric modes are enhanced in resonance with the B state. The cyclic polyene TMCOT−2 spectrum thus provides direct evidence for Herzberg–Teller coupling of the Q band and B state.

Cytochromes P-450 and model systems: great diversity of catalyzed reactions

Abstract

Hydroxylation by cytochrome P-450 and metalloporphyrin models. Evidence for allylic rearrangement

Hydroxylation by cytochrome P-450 and metalloporphyrin models. Evidence for allylic rearrangement