Are one-step aromatic nucleophilic substitutions of non-activated benzenes concerted processes?

Analysis of the mechanism of one-step SNAr reactions of non-activated benzenes shows the presence of structures similar to those of Meisenheimer intermediates, thus accounting for the non-concerted nature of these reactions.

QM/MM MD and free energy simulations of the methylation reactions catalyzed by protein arginine methyltransferase PRMT3

Protein arginine N-methyltransferases (PRMTs) catalyze the transfer of methyl group(s) from S-adenosyl-l-methionine (AdoMet) to the guanidine group of arginine residue in abundant eukaryotic proteins. Two major types of PRMTs have been identified in mammalian cells. Type I PRMTs catalyze the formation of asymmetric ω-NG, NG-dimethylarginine (ADMA), while Type II PRMTs catalyze the formation of symmetric ω-NG, N′G-dimethylarginine (SDMA). The two different methylation products (ADMA or SDMA) of the substrate could lead to different biological consequences. Although PRMTs have been the subject of extensive experimental investigations, the origin of the product specificity remains unclear. In this study, quantum mechanical/molecular mechanical (QM/MM) molecular dynamics (MD) and free energy simulations are performed to study the reaction mechanism for one of Type I PRMTs, PRMT3, and to gain insights into the energetic origin of its product specificity (ADMA). Our simulations have identified some important interactions and proton transfers involving the active site residues. These interactions and proton transfers seem to be responsible, at least in part, in making the Nη2 atom of the substrate arginine the target of the both 1st and 2nd methylations, leading to the asymmetric dimethylation product. The simulations also suggest that the methyl transfer and proton transfer appear to be somehow concerted processes and that Glu326 is likely to function as the general base during the catalysis.

Surface electrochemistry of N,N',N″,N‴-tetramethyl-tetra-3,4-pyridinoporphyrazinocobalt(II)

The complex N,N',N″,N‴ -tetramethyl-tetra-3,4-pyridinoporphyrazinocobalt(II) ([ Co II TMPz [4+])4+ adsorbed on a graphite electrode undergoes spontaneous reduction, forming a surface containing Co I. Five reversible surface peaks are observed at low pH, two of which are two-electron concerted processes. At high pH, one of these two-electron processes splits into two one-electron waves. Both oxidation and reduction of the central metal can be observed, along with successive reduction steps involving the porphyrazine ligand. Notable is the marked shift to positive potentials of these processes, relative to unsubstituted cobalt phthalocyanine, due to the positive charge localized on the porphyrazine. The electrocatalytic activity of this complex modified electrode toward the reduction of hydrogen peroxide is also reported. We demonstrate that a series of different surfaces exist which are obtained by variation of pH and polarization potential and that these surfaces possess differing electrocatalytic activity. Surfaces inactive to hydrogen peroxide can exist at potentials more negative than active surfaces even though the driving force for peroxide reduction will be greater for the former.

Paradoxical coronary microcirculatory constriction during ischemia: a synergic function for nitric oxide and endothelin

A paradoxical microcirculatory constriction has been observed in hearts of patients with ischemia, secondary to coronary stenosis. Here, using the isolated mouse heart (Langendorff), we examined the mechanism of this response, assuming involvement of nitric oxide (NO) and endothelin-1 (ET-1) systems. Perfusion pressure was maintained at 65 mmHg for 70 min ( protocol 1), or it was reduced to 30 mmHg over two intervals, between the 20- and 40-min marks ( protocol 2) or from the 20-min mark onward ( protocol 3). In protocol 1, coronary resistance (CR) remained steady in untreated heart, whereas it progressively increased during treatment with the NO synthesis inhibitor NG-nitro-l-arginine methyl ester (l-NAME) (2.7-fold) or the ETA antagonist BQ-610 (2.8 fold). The ETB antagonist BQ-788 had instead no effect by itself but curtailed vasoconstriction to BQ-610. In protocol 2, hypotension raised CR by 2.2-fold. This response was blunted by reactive oxygen species (ROS) scavengers (mannitol and superoxide dismutase plus catalase) and was converted into vasodilation by l-NAME, BQ-610, or BQ-788. Restoration of normal pressure was followed by vasodilation and vasoconstriction, respectively, in untreated and treated preparations. In protocol 3, CR progressively increased with hypotension in the absence but not presence of l-NAME or BQ-610. We conclude that the coronary vasculature is normally relaxed by two concerted processes, a direct action of NO and ET-1 curtailing an ETB2-mediated tonic vasoconstriction through ETA activation. The negative feedback mechanism on ETB2 subsides during hypotension, and the ensuing vasoconstriction is ascribed to ET-1 activating ETA and ETB2 and reactive nitrogen oxide species originating from ROS-NO interaction.

A career in phthalocyanine chemistry – the Linstead Award 2002

A stroll through memory lane highlighting the author's contributions to phthalocyanines, including synthetic aspects especially of binuclear species, manganese oxygen breathing chemistry, mixed valence species, solution and surface electrochemistry, electrocatalysis, two-electron concerted processes, charge transfer spectroscopy, ligand electrochemical parameter applications and phthalocyanine design.