The geometric and electronic structure of an oxidized Cu complex ([CuSal] + ; Sal = N, N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-(1R,2R)-diamine) with a non-innocent salen ligand has been investigated both in the solid state and in solution. Integration of information from UV-vis-NIR spectroscopy, magnetic susceptibility, electrochemistry, resonance Raman spectroscopy, X-ray crystallography, X-ray absorption spectroscopy, and density functional theory calculations provides critical insights into the nature of the localization/delocalization of the oxidation locus. In contrast to the analogous Ni derivative

The cooperativity of transition-metal ions and proradical ligands in metalloenzyme active sites is of current research interest. [1] In an effort to understand the intricacies of the interaction of metal ions with organic radicals, many transition-metal complexes with one or more organic radical ligands have been studied. [2][3][4] Depending on the relative energies of the redox-active orbitals, metal complexes with proradical ligands can exist in a limiting description as a metal-ligand-radical (M n+ (LC)) or a high-valent metal complex (M (n+1)+ (L À )). Given favorable energetics, valence tautomerism can occur through variation of the ligand field or temperature. [2,[5][6][7][8][9] In particular, much recent interest exists in nickel(II) bis(salicylidene)diamine complexes (Scheme 1), [6][7][8][9][10] ) forms.Although extensive spectroscopic and electrochemical data exists for such oxidized complexes, structural data is lacking. Herein we report the X-ray crystal structure of a Ni IIligand-radical complex (1 + ), which has a contracted coordination sphere relative to its neutral analogue 1. The difference between the first two oxidation waves in the cyclic voltammogram of 1 (DE = 500 mV) and those of the Cu (DE = 205 mV) and Zn (DE = 175 mV) analogues [11] indicates that 1

Dysfunctional interactions of metal ions, especially Cu, Zn, and Fe, with the amyloid-beta (A beta) peptide are hypothesized to play an important role in the etiology of Alzheimer's disease (AD). In addition to direct effects on A beta aggregation, both Cu and Fe catalyze the generation of reactive oxygen species (ROS) in the brain further contributing to neurodegeneration. Disruption of these aberrant metal-peptide interactions via chelation therapy holds considerable promise as a therapeutic strategy to combat this presently incurable disease. To this end, we developed two multifunctional carbohydrate-containing compounds N,N'-bis[(5-beta-D-glucopyranosyloxy-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL1) and N,N'-bis[(5-beta-D-glucopyranosyloxy-3-tert-butyl-2-hydroxy)benzyl]-N,N'-dimethyl-ethane-1,2-diamine (H2GL2) for brain-directed metal chelation and redistribution. Acidity constants were determined by potentiometry aided by UV-vis and 1H NMR measurements to identify the protonation sites of H2GL1,2. Intramolecular H bonding between the amine nitrogen atoms and the H atoms of the hydroxyl groups was determined to have an important stabilizing effect in solution for the H2GL1 and H2GL2 species. Both H2GL1 and H2GL2 were found to have significant antioxidant capacity on the basis of an in vitro antioxidant assay. The neutral metal complexes CuGL1, NiGL1, CuGL2, and NiGL2 were synthesized and fully characterized. A square-planar arrangement of the tetradentate ligand around CuGL2 and NiGL2 was determined by X-ray crystallography with the sugar moieties remaining pendant. The coordination properties of H2GL1,2 were also investigated by potentiometry, and as expected, both ligands displayed a higher affinity for Cu2+ over Zn2+ with H2GL1 displaying better coordinating ability at physiological pH. Both H2GL1 and H2GL2 were found to reduce Zn2+- and Cu2+- induced Abeta1-40 aggregation in vitro, further demonstrating the potential of these multifunctional agents as AD therapeutics.

This tutorial review will highlight recent advances in medicinal inorganic chemistry pertaining to the use of multifunctional ligands for enhanced effect. Ligands that adequately bind metal ions and also include specific targeting features are gaining in popularity due to their ability to enhance the efficacy of less complicated metal-based agents. Moving beyond the traditional view of ligands modifying reactivity, stabilizing specific oxidation states, and contributing to substitution inertness, we will discuss recent work involving metal complexes with multifunctional ligands that target specific tissues, membrane receptors, or endogenous molecules, including enzymes.

The neutral and one-electron oxidized Cu(II) six-membered chelate 1,3-Salcn (1,3-Salcn = N,N'-bis(3,5-di-tert-butylsalicylidene)-1,3-cyclohexanediamine) complexes have been investigated and compared with the five-membered chelate 1,2-Salcn (N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-(1R,2R)-diamine) complexes. Cyclic voltammetry of Cu(1,3-Salcn) showed two reversible redox waves at 0.48 and 0.68 V, which are only 0.03 V higher than those of Cu(1,2-Salcn). Reaction of Cu(1,3-Salcn) with 1 equiv of AgSbF6 afforded the oxidized complex which exists as a ligand-based radical species in solution and in the solid state. The X-ray crystal structure of the oxidized complex, [Cu(1,3-Salcn)]SbF6, exhibited an asymmetric metal binding environment with a longer Cu-O bond and quinoid distortion in the phenolate moiety on one side, demonstrating at least partial ligand radical localization in the solid state. The ligand oxidation is also supported by XPS and temperature dependent magnetic susceptibility. The electronic structure of the [Cu(1,3-Salcn)](+) complex was further probed by UV-vis-NIR, resonance Raman, and electron paramagnetic resonance (EPR) measurements, and by theoretical calculations, indicating that the phenoxyl radical electron is relatively localized on one phenolate moiety in the molecule. The reactivity of [Cu(1,3-Salcn)](+) with benzyl alcohol was also studied. Quantitative conversion of benzyl alcohol to benzaldehyde was observed, with a faster reaction rate in comparison with [Cu(1,2-Salcn)](+). The kinetic isotope effect (KIE = k(H)/k(D)) of benzyl alcohol oxidation by [Cu(1,3-Salcn)](+) was estimated to be 13, which is smaller than the value reported for [Cu(1,2-Salcn)](+). The activation energy difference between [Cu(1,2-Salcn)](+) and [Cu(1,3-Salcn)](+) was in good agreement with the energy calculated from KIE. This correlation suggests that the Cu(II)-phenoxyl radical species, characterized for [Cu(1,2-salcn)](+) is more reactive for hydrogen abstraction from benzyl alcohol in comparison to the 1:1 mixture of Cu(III)-phenolate and Cu(II)-phenoxyl radical species, [Cu(1,2-Salcn)](+). Thus, the Cu(II)-phenoxyl radical species accelerates benzyl alcohol oxidation in comparison with the Cu(III)-phenolate ground state complex, in spite of the similar activated intermediate and oxidation pathway.

The geometric and electronic structures of a series of one-electron oxidized group 10 metal salens (Ni, Pd, Pt) have been investigated in solution and in the solid state. Ni (1) and Pd (2) complexes of the tetradentate salen ligand N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediamine (H2Salcn) have been examined along with the Pt (3) complex of the salen ligand N,N’-bis(3,5-di-tert-butylsalicylidene)-1,2-ethylenediamine (H2Salen). All three oxidized compounds exist as ligand radical species in solution and in the solid state. The solid state structures of [1]+ and [3]+ exhibit a symmetric coordination sphere contraction relative to the neutral forms. By contrast, the coordination sphere of the Pd derivative [2]+ exhibits a pronounced asymmetry in the solid state. In solution, the oxidized derivatives display intense low-energy NIR transitions consistent with their classification as ligand radical compounds. Interestingly, the degree of communication between the phenolate moieties depends strongly on the central metal ion, within the Ni, Pd, and Pt series. Electrochemical measurements and UV-Vis-NIR spectroscopy, in conjunction with DFT calculations provide insights into the degree of delocalization of the one-electron hole in these systems. The Pd complex [2]+ is the least delocalized and is best described as a borderline Class II/III intervalence complex based on the Robin-Day classification system. The Ni [1]+ and Pt [3]+ analogues are Class III (fully delocalized) intervalence compounds. Delocalization is dependent on the electronic coupling between the redox-active phenolate ligands, mediated by overlap between the formally filled metal dxz orbital and the appropriate ligand molecular orbital. The degree of coupling increases in the order Pd < Ni < Pt for the one-electron oxidized group 10 metal salens.

The neutral and one-electron oxidized group 10 metal, Ni(II), Pd(II) and Pt(II), six-membered chelate Salpn (Salpn = N,N'-bis(3,5-di-tert-butylsalicylidene)-1,3-propanediamine) complexes have been investigated and compared to the five-membered chelate Salen (N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-ethanediamine) and Salcn (N,N'-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexane-(1R,2R)-diamine) complexes. Reaction of the Salpn complexes with 1 equivalent of AgSbF(6) affords the oxidized complexes which exist as ligand radical species in solution and in the solid state. The solid state structures of the oxidized complexes have been determined by X-ray crystal structure analysis. While the Ni and Pt analogues exhibit an essentially symmetric coordination sphere contraction upon oxidation, the oxidized Pd derivative exhibits an asymmetric metal binding environment demonstrating at least partial ligand radical localization. In comparison to the oxidized Salen and Salcn complexes, the propyl backbone of the Salpn complexes leads to a larger deviation from a planar geometry in the solid state. The electronic structure of the oxidized Salpn complexes was further probed by UV-vis-NIR measurements, electrochemistry, EPR spectroscopy, and theoretical calculations. The intense NIR band for the one-electron oxidized Salpn complexes shifts to lower energy in comparison to the 5-membered chelate analogues, which is attributed to lower metal d(xz) character in the β-LUMO for the Salpn series. The reactivity of the one-electron oxidized Salpn complexes with exogenous ligands was also studied. In the presence of pyridine, the oxidized Ni analogue exhibits a shift in the locus of oxidation to a Ni(III) species. The oxidized PtSalpn complex rapidly decomposes in the presence of pyridine, even at low temperature. Interestingly, electronic and EPR spectroscopy suggests that the addition of pyridine to the oxidized Pd analogue results in initial dissociation of the phenoxyl radical ligand, likely due to the increased flexibility of the propyl backbone.

Investigation of a series of oxidized nitridomanganese (V) salen complexes with different para-ring substituents (R = CF 3 , tBu and NMe 2 ) demonstrates that nitride activation is dictated by remote ligand electronics. For R = CF 3 and tBu, oxidation affords a Mn(VI) species and nitride activation, with dinitrogen homocoupling accelerated by the more electron withdrawing CF 3 substituent. Employing an electron-donating substituent (R = NMe 2 ) results in a localized ligand radical species that is resistant to N-coupling of the nitrides, and is stable in solution at both 195 and 298 K.Transition metal complexes bearing terminal nitride (N 3-) ligands are of significant interest due to the key role they may play in the nitrogen fixation process, 1 their importance in stoichiometric nitrene transfer reactions, 2 and their utility as catalysts. 3 In the context of industrial (and biological) nitrogen fixation, 4 there have been a number of important reports of Fe nitride complexes in oxidation states IV, 5 V, 6 and VI, 7 and their reactivities are well documented. 8 In many cases the reactivity of terminal nitride complexes can be rationalized by the nucleophilicity (or electrophilicity) of the nitride ligand, which is determined by both metal and oxidation state, as well as ancillary ligands. 9 Group 8 nitrides of Ru(VI) and Os(VI) react with a variety of nucleophiles 10 due to population of MN  * -antibonding orbitals in the transition state. In addition, reactive electrophilic group 9 terminal nitride complexes of Co, 11 Rh,12 and Ir 13 have been reported, and a transient terminal nitride of Ni has recently been described. 14 In contrast to the reactivity of late metal nitrides, early metal nitrides are generally more stable, and are often a product of N 2 activation reactions. 15 In some cases, early transition metal nitrides react as nucleophiles. 16 Terminal nitrides of Mn(V) exhibit intermediate reactivity between their early and late transition metal analogues, and have found utility as nitrene transfer reagents. 2b Early work by Groves demonstrated nitrene transfer from a nitridomanganese(V) porphyrin complex to cyclooctene upon activation with trifluoroacetic anhydride (TFAA). 17 This reactivity was extended to nitridomanganese(V) salen complexes as a means of nitrene transfer to other electron rich alkenes, as well as silyl enol ethers. 18 Despite their synthetic utility, all examples require the addition of Lewis acids such as TFAA or tosic anhydride; likely to activate the nitride by conversion to the corresponding imide before group transfer to the substrate. 19 Nitridomanganese(V) salen complexes have also been employed as a reagent in the synthesis of other metalnitrido fragments. 20 Herein, we investigate the oxidative activation of a series of Mn(V) nitrides in which the resulting reactivity is tuned by the electronic properties of the ancillary ligand (Scheme 1). We employ the tetradentate salen due to its facile and highly modular synthesis, allowing for changes in the electr...