Probing the hydride transfer process in the lumiflavine–1-methylnicotinamide model system using group softness

Catalytic Cycle of Human Glutathione Reductase Near 1 Å Resolution

“…Finally, a fourth factor favoring catalysis is that the nicotinamide C4 hydride and Cys63-SG are on opposite sides of the flavin plane and roughly in line with the N5-C4a bond (Figure 8), in position for good HOMO-LUMO overlap20,54–55 and also consistent with optimal geometry for 1,2-addition of the hydride and the sulfur across a double bond47,56–57. This optimal geometry for a 1,2-addition raises the interesting possibility that the reduction of GR is not a distinct two-step process with hydride transfer to the flavin occurring first, followed by disulfide reduction, but instead is concerted, with hydride transfer linked to and enhanced by disulfide reduction.…”

Electrophilicity Index

“…Apart from these major types of reactions, the electrophilicity concept at both the global and the local levels has been used to analyze a wide variety of chemical processes. They include oxidation of thiophenes, catalytic olefination of carbonyl compounds and polyhaloalkanes, reduction of formylchromones, hydride transfer reaction in 1-methyl nicotinamide-lumiflavine, formaldehyde decomposition, intermolecular ligand exchange in alkyltin trihalides, nucleophilic addition to carbon−carbon double bonds, Friedel−Crafts benzylation and acylation reactions, metalation of oxazolines, oxidation of thiols, alkaline hydrolysis of N -phenylacetamides, ene reactions of nitroso compounds, aminolysis of thiocarbonates, etc. The main theme of these studies is to identify a reactant which will act as an electrophile (larger ω value) or another to behave as a nucleophile (smaller ω value).…”

“…290 Quantitative linear relationships between the experimental rate constants and the Maynard-Parr electrophilicity index and/ or its local counterpart have been obtained for the Friedel -Crafts reactions, 289 nucleophilic addition involving the Cd C double bond, 288 and aminolysis of thiolcarbonates and dithiocarbonates. 294 The reactivity patterns associated with formaldehyde decomposition, 287 intermolecular ligand exchange in alkyltin trihalides, 287 hydride ion transfer, 286 etc. have been properly analyzed in terms of the electrophilicity index or its variants.…”

Studies of regioselectivity of large molecular systems using DFT based reactivity descriptors

“…On the basis of the group softness (sum of the local softness 143 of the involved atomic centers), 344,346,349,362 conceptual DFT studies by Rivas et al have led to the suggestion of a direct hydride transfer between the reactive regions in nicotinamide and lumiflavine. 363,364 Different atomic centers of lumiflavine and nicotinamide were tested, but the smallest difference in group softness was found between the C3, Ht, and C5 atoms of nicotinamide and the C4a, N1, and N5 atoms of lumiflavine, supporting the hydride transfer [365][366][367][368][369][370][371] between these regions (Fig. 9) 363 In the lumiflavine molecule, the local electrophilicity 255 (i.e., w + (k); eqn (75)) of the N5 atom is higher than the local electrophilicity of the N1 and C4a atoms.…”

“…363,364 Different atomic centers of lumiflavine and nicotinamide were tested, but the smallest difference in group softness was found between the C3, Ht, and C5 atoms of nicotinamide and the C4a, N1, and N5 atoms of lumiflavine, supporting the hydride transfer [365][366][367][368][369][370][371] between these regions (Fig. 9) 363 In the lumiflavine molecule, the local electrophilicity 255 (i.e., w + (k); eqn (75)) of the N5 atom is higher than the local electrophilicity of the N1 and C4a atoms. So, the N5 atom will most likely receive the hydride ion.…”