Abnormal interactions of Cu and Zn ions with the amyloid β (Aβ) peptide are proposed to play an important role in the pathogenesis of Alzheimer’s disease (AD). Disruption of these metal–peptide interactions using chemical agents holds considerable promise as a therapeutic strategy to combat this incurable disease. Reported herein are two bifunctional compounds (BFCs) L1 and L2 that contain both amyloid-binding and metal-chelating molecular motifs. Both L1 and L2 exhibit high stability constants for Cu2+ and Zn2+ and thus are good chelators for these metal ions. In addition, L1 and L2 show strong affinity toward Aβ species. Both compounds are efficient inhibitors of the metal–mediated aggregation of the Aβ42 peptide and promote disaggregation of amyloid fibrils, as observed by ThT fluorescence, native gel electrophoresis/Western blotting, and transmission electron microscopy (TEM). Interestingly, the formation of soluble Aβ42 oligomers in presence of metal ions and BFCs leads to an increased cellular toxicity. These results suggest that for the Aβ42 peptide – in contrast to the Aβ40 peptide, the previously employed strategy of inhibiting Aβ aggregation and promoting amyloid fibril dissagregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aβ42 oligomers.

Organometallic Pd(III) complexes have been implicated as intermediates in a number of catalytic and stoichiometric transformations. While a few dinuclear organometallic Pd(III) complexes have been characterized, no mononuclear organometallic Pd(III) complexes have been isolated to date. Reported herein is the synthesis and characterization of a series of Pd(III) complexes supported by the tetradentate ligand N,N'-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane (N4). Chemical or electrochemical oxidation of the Pd(II) complexes (N4)Pd(II)(R)(X) (R = Me, X = Cl: 1; R = Ph, X = Cl: 2; R = X = Me: 3) generates [(N4)Pd(III)MeCl](+) (1(+)), [(N4)Pd(III)PhCl](+) (2(+)), and [(N4)Pd(III)Me(2)](+) (3(+)). These stable Pd(III) complexes were isolated and characterized by X-ray diffraction, cyclic voltammetry, UV-vis, EPR, magnetic moment measurements, and DFT to confirm the presence of paramagnetic d(7) Pd(III) centers. Moreover, these Pd(III) complexes undergo light-induced C-C bond formation to give the corresponding homocoupled products ethane or biphenyl. Particularly remarkable is the observation for the first time of ethane formation from monomethyl Pd complexes.

Oxidation of the Pd(II) complex (N4)Pd(II)Me(2) (N4 = N,N'-di-tert-butyl-2,11-diaza[3.3](2,6)pyridinophane) with O(2) or ROOH (R = H, tert-butyl, cumyl) produces the Pd(III) species [(N4)Pd(III)Me(2)](+), followed by selective formation of ethane and the monomethyl complex (N4)Pd(II)Me(OH). Cyclic voltammetry studies and use of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap suggest an inner-sphere mechanism for (N4)Pd(II)Me(2) oxidation by O(2) to generate a Pd(III)-superoxide intermediate. In addition, reaction of (N4)Pd(II)Me(2) with cumene hydroperoxide involves a heterolytic O-O bond cleavage, implying a two-electron oxidation of the Pd(II) precursor and formation of a transient Pd(IV) intermediate. Mechanistic studies of the C-C bond formation steps and crossover experiments are consistent with a nonradical mechanism that involves methyl group transfer and transient formation of a Pd(IV) species. Moreover, the (N4)Pd(II)Me(OH) complex formed upon ethane elimination reacts with weakly acidic C-H bonds of acetone and terminal alkynes, leading to formation of a new Pd(II)-C bond. Overall, this study represents the first example of C-C bond formation upon aerobic oxidation of a Pd(II) dimethyl complex, with implications in the development of Pd catalysts for aerobic oxidative coupling of C-H bonds.

Two structurally related and photoresponsive cyanide-bridged Fe/Co square complexes, {Fe2Co2}, are reported: {[(Tp(Me))Fe(CN)3]2[Co(bpy)2]2[(Tp(Me))Fe(CN)3]2}·12H2O (2) and {[(Tp(Me))Fe(CN)3]2[Co(bpy)2]2[BPh4]2}·6MeCN (3), where Tp(Me) and bpy are hydridotris(3-methylpyrazol-1-yl)borate and 2,2'-bipyridine, respectively. Through electrochemical and spectroscopic studies, the Tp(Me) ligand appears to be a moderate σ donor in comparison to others in the [NEt4][(Tp(R))Fe(III)(CN)3] series [where Tp(R) = Tp, hydridotris(pyrazol-1-yl)borate; Tp(Me) = hydridotris(3-methylpyrazol-1-yl)borate; pzTp = tetrakis(pyrazol-1-yl)borate; Tp* = hydridotris(3,5-dimethylpyrazol-1-yl)borate; Tp*(Me) = hydridotris(3,4,5-trimethylpyrazol-1-yl)borate]. The spectroscopic, structural, and magnetic data of the {Fe2Co2} squares indicate that thermally-induced intramolecular electron transfer reversibly converts {Fe(II)LS(μ-CN)Co(III)LS} pairs into {Fe(III)LS(μ-CN)Co(II)HS} units near ca. 230 and 244 K (T1/2) for 2 and 3, respectively (LS: low spin; HS: high spin). These experimental results show that 2 and 3 display light-induced {Fe(III)LS(μ-CN)Co(II)HS} metastable states that relax to thermodynamic {Fe(II)LS(μ-CN)Co(III)LS} ones at ca. 90 K. Ancillary Tp(R) ligand donor strength appears to be the dominant factor for tuning electron transfer properties in these {Fe2Co2} complexes.

Nickel complexes have been widely employed as catalysts in C-C and C-heteroatom bond formation reactions. In addition to Ni(0) and Ni(II) intermediates, several Ni-catalyzed reactions are proposed to also involve odd-electron Ni(I) and Ni(III) oxidation states. We report herein the isolation, structural and spectroscopic characterization, and organometallic reactivity of Ni(III) complexes containing aryl and alkyl ligands. These Ni(III) species undergo transmetalation and/or reductive elimination reactions to form new C-C or C-heteroatom bonds and are also competent catalysts for Kumada and Negishi cross-coupling reactions. Overall, these results provide strong evidence for the direct involvement of organometallic Ni(III) species in cross-coupling reactions and oxidatively induced C-heteroatom bond formation reactions.