Cluster dynamics of heterometallic trinuclear clusters during ligand substitution, redox chemistry, and group transfer processes.

Stepwise metalation of the hexadentate ligand tbsLH6 (tbsLH6 = 1,3,5-C6H9(NHC6H4-o-NHSiMe2tBu)3) affords bimetallic trinuclear clusters (tbsL)Fe2Zn(thf) and (tbsL)Fe2Zn(py). Reactivity studies were pursued to understand metal atom lability as the clusters undergo ligand substitution, redox chemistry, and group transfer processes. Chloride addition to (tbsL)Fe2Zn(thf) resulted in a mixture of species including both all-zinc and all-iron products. Addition of ArN3 (Ar = Ph, 3,5-(CF3)2C6H3) to (tbsL)Fe2Zn(py) yielded a mixture of two trinuclear products: (tbsL)Fe3(µ3-NAr) and (tbsL)Fe2Zn(µ3-NAr)(py). The two imido species were separated via crystallization, and outer sphere reduction of (tbsL)Fe2Zn(µ3-NAr)(py) resulted in the formation of a single product, [2,2,2-crypt(K)][(tbsL)Fe2Zn(µ3-NAr)]. These results provide insight into the relationship between heterometallic cluster structure and substitutional lability and could help inform both future catalyst design and our understanding of metal atom lability in bioinorganic systems.

Lewis Acid Supported Nickel Nitrenoids.

Metalation of the polynucleating ligand F,tbs LH6 (1,3,5-C6 H9 (NC6 H3 -4-F-2-NSiMe2 t Bu)3 ) with two equivalents of Zn(N(SiMe3 )2 )2 affords the dinuclear product (F,tbs LH2 )Zn2 (1), which can be further deprotonated to yield (F,tbs L)Zn2 Li2 (OEt2 )4 (2). Transmetalation of 2 with NiCl2 (py)2 yields the heterometallic, trinuclear cluster (F,tbs L)Zn2 Ni(py) (3). Reduction of 3 with KC8 affords [KC222 ][(F,tbs L)Zn2 Ni] (4) which features a monovalent Ni centre. Addition of 1-adamantyl azide to 4 generates the bridging µ3 -nitrenoid adduct [K(THF)3 ][(F,tbs L)Zn2 Ni(µ3 -NAd)] (5). EPR spectroscopy reveals that the anionic cluster possesses a doublet ground state (S = 1 / 2 ${{ 1/2 }}$ ). Cyclic voltammetry of 5 reveals two fully reversible redox events. The dianionic nitrenoid [K2 (THF)9 ][(F,tbs L)Zn2 Ni(µ3 -NAd)] (6) was isolated and characterized while the neutral redox isomer was observed to undergo both intra- and intermolecular H-atom abstraction processes. Ni K-edge XAS studies suggest a divalent oxidation state for the Ni centres in both the monoanionic and dianionic [Zn2 Ni] nitrenoid complexes. However, DFT analysis suggests Ni-borne oxidation for 5.

Revealing redox isomerism in trichromium imides by anomalous diffraction.

In polynuclear biological active sites, multiple electrons are needed for turnover, and the distribution of these electrons among the metal sites is affected by the structure of the active site. However, the study of the interplay between structure and redox distribution is difficult not only in biological systems but also in synthetic polynuclear clusters since most redox changes produce only one thermodynamically stable product. Here, the unusual chemistry of a sterically hindered trichromium complex allowed us to probe the relationship between structural and redox isomerism. Two structurally isomeric trichromium imides were isolated: asymmetric terminal imide (tbsL)Cr3(NDipp) and symmetric, µ3-bridging imide (tbsL)Cr3(µ3-NBn) ((tbsL)6- = (1,3,5-C6H9(NC6H4-o-NSi t BuMe2)3)6-). Along with the homovalent isocyanide adduct (tbsL)Cr3(CNBn) and the bisimide (tbsL)Cr3(µ3-NPh)(NPh), both imide isomers were examined by multiple-wavelength anomalous diffraction (MAD) to determine the redox load distribution by the free refinement of atomic scattering factors. Despite their compositional similarities, the bridging imide shows uniform oxidation of all three Cr sites while the terminal imide shows oxidation at only two Cr sites. Further oxidation from the bridging imide to the bisimide is only borne at the Cr site bound to the second, terminal imido fragment. Thus, depending on the structural motifs present in each [Cr3] complex, MAD revealed complete localization of oxidation, partial localization, and complete delocalization, all supported by the same hexadentate ligand scaffold.

Exposing the inadequacy of redox formalisms by resolving redox inequivalence within isovalent clusters.

In this report we examine a family of trinuclear iron complexes by multiple-wavelength, anomalous diffraction (MAD) to explore the redox load distribution within cluster materials by the free refinement of atomic scattering factors. Several effects were explored that can impact atomic scattering factors within clusters, including 1) metal atom primary coordination sphere, 2) M-M bonding, and 3) redox delocalization in formally mixed-valent species. Complexes were investigated which vary from highly symmetric to fully asymmetric by 57Fe Mössbauer and X-ray diffraction to explore the relationship between MAD-derived data and the data available from these widely used characterization techniques. The compounds examined include the all-ferrous clusters [ n Bu4N][(tbsL)Fe3(µ3-Cl)] (1) ([tbsL]6- = [1,3,5-C6H9(NC6H4-o-NSi t BuMe2)3]6-]), (tbsL)Fe3(py) (2), [K(C222)]2[(tbsL)Fe3(µ3-NPh)] (4) (C222 = 2,2,2-cryptand), and the mixed-valent (tbsL)Fe3(µ3-NPh) (3). Redox delocalization in mixed-valent 3 was explored with cyclic voltammetry (CV), zero-field 57Fe Mössbauer, near-infrared (NIR) spectroscopy, and X-ray crystallography techniques. We find that the MAD results show an excellent correspondence to 57Fe Mössbauer data; yet also can distinguish between subtle changes in local coordination geometries where Mössbauer cannot. Differences within aggregate oxidation levels are evident by systematic shifts of scattering factor envelopes to increasingly higher energies. However, distinguishing local oxidation levels in iso- or mixed-valent materials can be dramatically obscured by the degree of covalent intracore bonding. MAD-derived atomic scattering factor data emphasize in-edge features that are often difficult to analyze by X-ray absorption near edge spectroscopy (XANES). Thus, relative oxidation levels within the cluster were most reliably ascertained from comparing the entire envelope of the atomic scattering factor data.

Ligand-Based Control of Single-Site vs. Multi-Site Reactivity by a Trichromium Cluster.

The trichromium cluster (tbs L)Cr3 (thf) ([tbs L]6- =[1,3,5-C6 H9 (NC6 H4 -o-NSit BuMe2 )3 ]6- ) exhibits steric- and solvation-controlled reactivity with organic azides to form three distinct products: reaction of (tbs L)Cr3 (thf) with benzyl azide forms a symmetrized bridging imido complex (tbs L)Cr3 (µ3 -NBn); reaction with mesityl azide in benzene affords a terminally bound imido complex (tbs L)Cr3 (µ1 -NMes); whereas the reaction with mesityl azide in THF leads to terminal N-atom excision from the azide to yield the nitride complex (tbs L)Cr3 (µ3 -N). The reactivity of this complex demonstrates the ability of the cluster-templating ligand to produce a well-defined polynuclear transition metal cluster that can access distinct single-site and cooperative reactivity controlled by either substrate steric demands or reaction media.

Antitrypanosomal lead discovery: identification of a ligand-efficient inhibitor of Trypanosoma cruzi CYP51 and parasite growth.

Chagas disease is caused by the intracellular protozoan parasite Trypanosomal cruzi , and current drugs are lacking in terms of desired safety and efficacy profiles. Following on a recently reported high-throughput screening campaign, we have explored initial structure-activity relationships around a class of imidazole-based compounds. This profiling has uncovered compounds 4c (NEU321) and 4j (NEU704), which are potent against in vitro cultures of T. cruzi and are greater than 160-fold selective over host cells. We report in vitro drug metabolism and properties profiling of 4c and show that this chemotype inhibits the T. cruzi CYP51 enzyme, an observation confirmed by X-ray crystallographic analysis. We compare the binding orientation of 4c to that of other, previously reported inhibitors. We show that 4c displays a significantly better ligand efficiency and a shorter synthetic route over previously disclosed CYP51 inhibitors, and should therefore be considered a promising lead compound for further optimization.