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An analogue of the mitochondrial calcium uniporter (MCU) inhibitor Ru265 containing axial ferrocenecarboxylate ligands is reported. This new complex exhibits enhanced cellular uptake compared to the parent compound Ru265.

A new method to tune solubility of ZrMOPs via node-modification.

Camphorsultam-based lithium enolates referred to colloquially as Oppolzer enolates are examined spectroscopically, crystallographically, kinetically, and computationally to ascertain the mechanism of alkylation and the origin of the stereoselectivity. Solvent- and substrate-dependent structures include tetramers for alkyl-substituted enolates in toluene, unsymmetric dimers for aryl-substituted enolates in toluene, substrate-independent symmetric dimers in THF and THF/toluene mixtures, HMPA-bridged trisolvated dimers at low HMPA concentrations, and disolvated monomers for the aryl-substituted enolates at elevated HMPA concentrations. Extensive analyses of the stereochemistry of aggregation are included. Rate studies for reaction with allyl bromide implicate an HMPA-solvated ion pair with a (+)Li(HMPA)(4) counterion. Dependencies on toluene and THF are attributed to exclusively secondary shell (medium) effects. Aided by density functional theory (DFT) computations, a stereochemical model is presented in which neither chelates nor the lithium gegenion serve roles. The stereoselectivity stems from the chirality within the sultam ring and not the camphor skeletal core.

Addition of NO to a nonheme dithiolate-ligated iron(II) complex, Fe

Herein, a synthetic method was developed to prepare a series of tris(dialkylamino)sulfonium and sulfoxonium cations from sulfur monochloride. Alkaline stability studies of these two cation families in 2 M KOH/CD

Cofacial porphyrin catalysts for the Oxygen Reduction Reaction (ORR) formed via coordination-driven self-assembly have so far been limited to designs with fourfold symmetry, where four molecular clips bridge two porphyrin sites. We have synthesized six Py

SCS pincer ligands have an interesting combination of strong-field and weak-field donors, a coordination environment that is also present in the nitrogenase active site. Here, we explore the electronic structures of iron(II) and iron(III) complexes with such a pincer ligand, bearing a monodentate phosphine, thiolate S donor, amide N donor, ammonia, or CO. The ligand scaffold features a proton-responsive thioamide site, and the protonation state of the ligand greatly influences the reduction potential of iron in the phosphine complex. The N–H bond dissociation free energy, derived from a square scheme, is 56 ± 2 kcal/mol. EPR spectroscopy and SQUID magnetometry measurements show that the iron(III) complexes with S and N as the fourth donors have an intermediate spin (S = 3/2) ground state with large zero field splitting, and X-ray absorption spectra show high Fe–S covalency. The Mössbauer spectrum changes drastically with the position of a nearby alkali metal cation in the iron(III) amido complex, and DFT calculations explain this phenomenon through a change between having the doubly-occupied orbital as d(z)2 or d(yz), as the former is more influenced by the nearby positive charge.

The quest for homoleptic Cr TEMPO species has led to the preparation of pseudo-pentagonal planar (η2-TEMPO)2CrX (X = Cl, TEMPO), with perturbations from TEMPO(−) lone pairs at roughly 0°, 90°, 135°, 225° and 270°.

The radionuclides (225)Ac(3+) and (213)Bi(3+) possess favorable physical properties for targeted alpha therapy (TAT), a therapeutic approach that leverages α radiation to treat cancers. A chelator that effectively binds and retains these radionuclides is required for this application. The development of ligands that can be used for this purpose, however, is challenging because the large ionic radii and charge-diffuse nature of these metal ions give rise to weaker metal-ligand interactions. In this study, we evaluated two 18-membered macrocyclic chelators, macrodipa and py-macrodipa, for their ability to complex (225)Ac(3+) and (213)Bi(3+). Their coordination chemistry with Ac(3+) was probed computationally and with Bi(3+) experimentally via NMR spectroscopy and X-ray crystallography. Furthermore, radiolabeling studies were conducted, revealing the efficient incorporation of both (225)Ac(3+) and (213)Bi(3+) by py-macrodipa that matches or surpasses the well-known chelators macropa and DOTA. Incubation in human serum at 37 °C showed that ~90% of the (225)Ac(3+)–py-macrodipa complex dissociates after 1 d. The Bi(3+)–py-macrodipa complex possesses remarkable kinetic inertness in an EDTA transchelation challenge study, surpassing that of Bi(3+)–macropa. This work establishes py-macrodipa as a valuable candidate for (213)Bi(3+) TAT, providing further motivation for its implementation within new radiopharmaceutical agents.

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The C-alkylation of secondary nitroalkanes with electrophiles is a straightforward strategy for constructing tertiary nitroalkanes; however, controlling the stereoselectivity of this type of reaction remains challenging. Here, we report a highly chemo- and stereoselective C-alkylation of nitroalkanes with alkyl halides catalyzed by an engineered flavin-dependent “ene”-reductase (ERED). Directed evolution of the old yellow enzyme from Geobacillus kaustophilus provided a triple mutant, GkOYE-G7, capable of synthesizing tertiary nitroalkanes in high yield and enantioselectivity. Mechanistic studies indicate that the excitation of an enzyme-templated charge-transfer complex formed between the substrates and cofactor is responsible for radical initiation. Moreover, a single-enzyme two-mechanism cascade reaction was developed to prepare tertiary nitroalkanes from simple nitroalkenes, highlighting the potential to use one enzyme for two mechanistically distinct reactions., This work was supported by the NIH National Institute of General Medical Sciences (R01GM127703). This work made use of the Cornell University NMR Facility, which is supported, in part, by the NSF through MRI award CHE-1531632. J.M.C. acknowledges the Margarita Salas grant from the Ministerio de Universidades, Universitat Politécnica de Valencia, Spain, funded by the European Union-Next Generation EU (2021-2023). The authors thank Yucong Zheng for his assistance with docking.

Tertiary nitroalkanes and the corresponding α-tertiary amines represent important motifs in bioactive molecules and natural products. The

The chemistry of zirconium-based metal-organic polyhedra (ZrMOPs) is often limited by their poor solubilities. Despite their attractive features-including high yielding and facile syntheses, predictable topologies, high stability, and tunability-problematic solubilities have caused ZrMOPs to be under-studied and under-applied. Although these cages have been synthesized with a wide variety of carboxylate-based bridging ligands, we explored a new method for ZrMOP functionalization

We examine the effects of fusing two benzofurans to s-indacene (indacenodibenzofurans, IDBFs) and dicyclopenta[b,g]naphthalene (indenoindenodibenzofurans, IIDBFs) to control the strong antiaromaticity and diradical character of these core units. Synthesis via 3-functionalized benzofuran yields syn-IDBF and syn-IIDBF. syn-IDBF possesses a high degree of paratropicity, exceeding that of the parent hydrocarbon, which in turn results in strong diradical character for syn-IIDBF. In the case of the anti-isomers, synthesized via 2-substituted benzofurans, these effects are decreased; however, both derivatives undergo an unexpected ring-opening reaction during the final dearomatization step. All the results are compared to the benzothiophene-fused analogues and show that the increased electronegativity of oxygen in the syn-fused derivatives leads to enhancement of the antiaromatic core causing greater paratropicity. For syn-IIDBF increased diradical character results from rearomati-zation of the core naphthalene unit in order to relieve this paratropicity.

The mitochondrial calcium uniporter (MCU) is a transmembrane protein that resides on the inner membrane of the mitochondria and mediates calcium uptake into this organelle. Given the critical role of mitochondrial calcium trafficking in cellular function, inhibitors of this channel have arisen as tools for studying the biological relevance of this process and as potential therapeutic agents. In this study, four new analogues of the previously reported Ru-based MCU inhibitor [ClRu(NH

Inhibitors of the mitochondrial calcium uniporter (MCU) are valuable tools for studying the role of mitochondrial Ca

Aldehyde and ketone hydrosilylation turnover frequencies of up to 330 s−1 have been achieved using a phosphine-substituted aryl diimine cobalt catalyst.

The complex [MnCl

A new nonheme iron(II) complex, FeII (Me3 TACN)((OSiPh2 )2 O) (1), is reported. Reaction of 1 with NO(g) gives a stable mononitrosyl complex Fe(NO)(Me3 TACN)((OSiPh2 )2 O) (2), which was characterized by Mossbauer (δ=0.52 mm s-1 , |ΔEQ |=0.80 mm s-1 ), EPR (S=3/2), resonance Raman (RR) and Fe K-edge X-ray absorption spectroscopies. The data show that 2 is an {FeNO}7 complex with an S=3/2 spin ground state. The RR spectrum (λexc =458 nm) of 2 combined with isotopic labeling (15 N, 18 O) reveals ν(N-O)=1680 cm-1 , which is highly activated, and is a nearly identical match to that seen for the reactive mononitrosyl intermediate in the nonheme iron enzyme FDPnor (ν(NO)=1681 cm-1 ). Complex 2 reacts rapidly with H2 O in THF to produce the N-N coupled product N2 O, providing the first example of a mononuclear nonheme iron complex that is capable of converting NO to N2 O in the absence of an exogenous reductant.

The radionuclide 213Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10-7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.

Dinuclear manganese hydride complexes of the form [Mn

Actinium-225 ((225)Ac) is one of the most promising radionuclides for targeted alpha therapy (TAT). With a half-life of 9.92 days and a decay chain that emits four high energy α particles, (225)Ac is well-suited for TAT when conjugated to macromolecular targeting vectors that exhibit extended in vivo circulation times. The implementation of (225)Ac in these targeted constructs, however, requires a suitable chelator that can bind and retain this radionuclide in vivo. Previous work has demonstrated the suitability of a diaza-18-crown-6 macrocyclic chelator H(2)macropa for this application. Building upon these prior efforts, in this study, two rigid variants of H(2)macropa, which contain either one (H(2)BZmacropa) or two (H(2)BZ(2)macropa) benzene rings within the macrocyclic core, were synthesized and investigated for their potential use for (225)Ac TAT. The coordination chemistry of these ligands with La(3+), used as a non-radioactive model for Ac(3+), was carried out. Both NMR spectroscopic and X-ray crystallographic studies of the La(3+) complexes of these ligands revealed similar structural features as those found for the related complex of H(2)macropa. Thermodynamic stability constants of the La(3+) complexes, however, were found to be one and two orders of magnitude lower than those of H(2)macropa for H(2)BZmacropa and H(2)BZ(2)macropa, respectively. The decrease in thermodynamic stability was rationalized via the use of density functional theory calculations. (225)Ac radiolabeling and serum stability studies with H(2)BZmacropa showed that this chelator compares favorably with H(2)macropa. Based on these promising results, a bifunctional version of this chelator, H(2)BZmacropa-NCS, was synthesized and conjugated to the antibody codrituzumab (GC33), which targets the liver cancer biomarker glypican-3 (GPC3). The resulting GC33-BZmacropa conjugate and an analogous GC33-macropa were evaluated for their (225)Ac radiolabeling efficiencies, antigen-binding affinity, and in vivo biodistribution in HepG2 liver cancer tumor-bearing mice. Although both conjugates were comparably effective in their radiolabeling efficiencies, [(225)Ac]Ac-GC33-BZmacropa showed slightly poorer serum stability and biodistribution than [(225)Ac]Ac-GC33-macropa. Together, these results establish H(2)BZmacropa-NCS as a new bifunctional chelator for the preparation of (225)Ac radiopharmaceuticals.

Herein, we report a bulky variant of a bis-benzimidazole carboxylate ligand. The five-position of the benzimidazole groups were substituted with tertiary butyl groups with the intention of preventing bis-ligation and oligomerization, as was observed in other studies using similar ligands. Unfortunately, even with the bulkier substituents, the new ligand still formed a bis-ligated structure. Although the new ligand did not afford the desired mono-ligated species under the conditions studied here, the preparation of the new ligand and coordination compounds provides an added design principle in the ongoing efforts of preparing structurally faithful 2-histidine-1-carboxylate model ligands in biomimetic chemistry.

Advances in radical-based catalytic reactions have created a demand for understanding their mechanistic underpinnings. Here, we present the isolation, structural elucidation, and theoretical analysis of a catalytically relevant charge-transfer species formed between the azidyl radical and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO). The unusual bond angles and pancake bonding between these two fragments highlight the weak bonding interactions present in this complex. This X-ray structure validates computational predictions as well as mechanistic proposals of TEMPO-mediated radical azidation reactions.

[Image: see text] A high-spin, mononuclear Ti(II) complex, [(Tp(tBu,Me))TiCl] [Tp(tBu,Me–) = hydridotris(3-tert-butyl-5-methylpyrazol-1-yl)borate], confined to a tetrahedral ligand-field environment, has been prepared by reduction of the precursor [(Tp(tBu,Me))TiCl(2)] with KC(8). Complex [(Tp(tBu,Me))TiCl] has a (3)A(2) ground state (assuming C(3v) symmetry based on structural studies), established via a combination of high-frequency and -field electron paramagnetic resonance (HFEPR) spectroscopy, solution and solid-state magnetic studies, Ti K-edge X-ray absorption spectroscopy (XAS), and both density functional theory and ab initio (complete-active-space self-consistent-field, CASSCF) calculations. The formally and physically defined Ti(II) complex readily binds tetrahydrofuran (THF) to form the paramagnetic adduct [(Tp(tBu,Me))TiCl(THF)], which is impervious to N(2) binding. However, in the absence of THF, the Ti(II) complex captures N(2) to produce the diamagnetic complex [(Tp(tBu,Me))TiCl](2)(η(1),η(1);μ(2)-N(2)), with a linear Ti=N=N=Ti topology, established by single-crystal X-ray diffraction. The N(2) complex was characterized using XAS as well as IR and Raman spectroscopies, thus establishing this complex to possess two Ti(III) centers covalently bridged by an N(2)(2–) unit. A π acid such as CNAd (Ad = 1-adamantyl) coordinates to [(Tp(tBu,Me))TiCl] without inducing spin pairing of the d electrons, thereby forming a unique high-spin and five-coordinate Ti(II) complex, namely, [(Tp(tBu,Me))TiCl(CNAd)]. The reducing power of the coordinatively unsaturated Ti(II)-containing [(Τp(tBu,Me))TiCl] species, quantified by electrochemistry, provides access to a family of mononuclear Ti(IV) complexes of the type [(Tp(tBu,Me))Ti=E(Cl)] (with E(2–) = NSiMe(3), N(2)CPh(2), O, and NH) by virtue of atom- or group-transfer reactions using various small molecules such as N(3)SiMe(3), N(2)CPh(2), N(2)O, and the bicyclic amine 2,3:5,6-dibenzo-7-azabicyclo[2.2.1]hepta-2,5-diene.

The preparation of a series of dibenzo- and tetrabenzo-fused fluoreno[3,2-b]fluorenes is disclosed, and the diradicaloid properties of these molecules are compared with those of a similar, previously reported series of anthracene-based diradicaloids. Insights on the diradical mode of delocalization tuning by constitutional isomerism of the external naphthalenes has been explored by means of the physical approach (dissection of the electronic properties in terms of electronic repulsion and transfer integral) of diradicals. This study has also been extended to the redox species of the two series of compounds and found that the radical cations have the same stabilization mode by delocalization that the neutral diradicals while the radical anions, contrarily, are stabilized by aromatization of the central core. The synthesis of the fluorenofluorene series and their characterization by electronic absorption and vibrational Raman spectroscopies, X-ray diffraction, SQUID measurements, electrochemistry, in situ UV-vis-NIR absorption spectroelectrochemistry, and theoretical calculations are presented. This work attempts to unify the properties of different series of diradicaloids in a common argument as well as the properties of the carbocations and carbanions derived from them.

Poly(pivalolactone) (PPVL) is a crystalline polyester with attractive physical and mechanical properties; however, prohibitively expensive syntheses of pivalolactone have thwarted efforts to produc...

Ru-PNN pincer catalysts of the general form [{PNN}Ru(H)(Cl)(CO)] can dehydrogenate alcohols through inner- and outer-sphere mechanisms, but determining the favored path is challenging. To address t...

High-energy resolution fluorescence-detected Cu K-edge X-ray absorption spectroscopy (XAS) and single-crystal polarized XAS data are presented toward refining the assignments of bands assigned as excitations from Cu 1s to ligand-localized molecular orbitals. These have been previously dubbed "XAS-metal-ligand charge transfer" (XAS-MLCT) bands. Data are presented for a series of [Cu(xbpy)2]n+ complexes (xbpy = 2,2'-bipyridine (1n+), 4,4'-bisamino-2,2'-bipyridine (2n+), and 4,4'-dimethoxy-2,2'-bipyridine (3n+); n = 1 and 2). Dipolar dependencies of these "XAS-MLCT" bands in both Cu1+ and Cu2+ species lead to reassignment of these features as owing their intensities primarily to Cu 1s → Cu 4p excitations. The transition densities are Cu-localized, highlighting that XAS-MLCT features in Cu XAS spectra are not "charge transfer" transitions but rather quasi-atomic transitions. Although scrutiny of the acceptor orbitals supports assignment as Cu 1s → ligand π* transitions, it ultimately appears that while the ligand orbital energetics govern the positions of these bands the intensity is conferred through a small degree of metal 4p mixing into otherwise ligand-dominated acceptor molecular orbitals.

Lanthanides (Ln(3+)) are critical materials used for many important applications, often in the form of coordination compounds. Tuning the thermodynamic stability of these compounds is a general concern, which is not readily achieved due to the similar coordination chemistry of lanthanides. Herein, we report two 18-membered macrocyclic ligands called macrodipa and macrotripa that show for the first time a dual selectivity towards both the light, large Ln(3+) ions and the heavy, small Ln(3+) ions, as determined by potentiometric titrations. The lanthanide complexes of these ligands were investigated by NMR spectroscopy and X-ray crystallography, revealing the occurrence of a significant conformational toggle between a 10-coordinate Conformation A and an 8-coordinate Conformation B that accommodates Ln(3+) ions of different sizes. The origin of this selectivity pattern was further supported by density functional theory (DFT) calculations, which show the complementary effects of ligand strain energy and metal-ligand binding energy that contribute to this conformational switch. This work demonstrates how novel ligand design strategies can be applied to tune the selectivity pattern for the Ln(3+) ions.

The ability to alter optoelectronic and magnetic properties of molecules at a late stage in their preparation is in general a nontrivial feat. Here, we report the late-stage oxidation of benzothiop...

The synthesis of 1,2-dihydroquinolines by the hydrazine-catalyzed ring-closing carbonyl-olefin metathesis (RCCOM) of N-prenylated 2-aminobenzaldehydes is reported. Substrates with a variety of substitution patterns are shown. With an acid-labile protecting group on the nitrogen atom, in situ deprotection and autoxidation furnish quinoline. In comparison with related oxygen-containing substrates, the cycloaddition step of the catalytic cycle is shown to be slower, but the cycloreversion is found to be more facile.

Structural, spectroscopic, and reactivity studies are presented for an electron transfer series of copper hydroxide complexes supported by a tridentate redox-active ligand. Single crystal X-ray crystallography shows that the mononuclear [CuOH](1+) core is stabilized via intramolecular H-bonds between the H-donors of the ligand and the hydroxide anion when the ligand is in its trianionic form. This complex undergoes two reversible oxidation processes that produce two metastable “high-valent” CuOH species, which can be generated by addition of stoichiometric amounts of 1e(−) oxidants. These CuOH species are characterized by an array of spectroscopic techniques including UV–vis absorption, electron paramagnetic resonance (EPR), and X-ray absorption spectroscopies (XAS), which together indicate that all redox couples are ligand-localized. The reactivity of the complexes in their higher oxidation states toward substrates with modest O─H bond dissociation energies (e.g., 4-substitued-2,6-di-tert-butylphenols) indicates that these complexes act as 2H(+)/2e(−) oxidants, differing from the 1H(+)/1e(−) reactivity of well-studied [CuOH](2+) systems.

Reactions facilitating inversion of alkene stereochemistry are rare, sought-after transformations in the field of modern organic synthesis. Although a number of isomerization reactions exist, most methods require specific, highly activated substrates to achieve appreciable conversion without side product formation. Motivated by stereoinvertive epoxide carbonylation reactions, we developed a two-step epoxidation/deoxygenation process that results in overall inversion of alkene stereochemistry. Unlike most deoxygenation systems, carbon monoxide was used as the terminal reductant, preventing difficult postreaction separations, given the gaseous nature of the resulting carbon dioxide byproduct. Various alkyl-substituted cis- and trans-epoxides can be reduced to trans- and cis-alkenes, respectively, in >99:1 stereospecificity and up to 95% yield, providing an alternative to traditional, direct isomerization approaches.

This work details the synthesis, characterization, and catalytic activity of reactive low-coordinate organozinc complexes. The complexes activate hydrogen and they appear to be more active in hydrogenation of ketones and imines than their tridentate pincer analogs. This is thought, in part, to be due to the lack of trailing third phosphorus arm present in previous work. DFT computations reveal a sigma-bond metathesis mechanism is comparable to an alternative aromatization/dearomatization metal-ligand cooperative mechanism.

Inclusion of a second nitrogen atom in the aromatic core of phosphorus-nitrogen (PN) heterocycles results in unexpected tautomerization to a nonaromatic form. This tautomerization, initially observed in the solid state through X-ray crystallography, is also explained by computational analysis. We prepared an electron deficient analogue (2 e) with a fluorine on the pyridine ring and showed that the weakly basic pyridine resisted tautomerization, providing key insights to why the transformation occurs. To study the difference in solution vs. solid-state heterocycles, alkylated analogues that lock in the quinoidal tautomer were synthesized and their different

SCS pincer ligands have an interesting combination of strong-field and weak-field donors that is also present in the nitrogenase active site. Here, we explore the electronic structures of iron(II) and iron(III) complexes with such a pincer ligand, bearing a monodentate phosphine, thiolate S donor, amide N donor, ammonia, or CO. The ligand scaffold features a protonresponsive thioamide site, and the protonation state of the ligand greatly influences the reduction potential of iron in the phosphine complex. The N–H bond dissociation free energy can be quantitated as 56 ± 2 kcal/mol. EPR spectroscopy and SQUID magnetometry measurements show that the iron(III) complexes with S and N as the fourth donors have an intermediate spin (S = 3/2) ground state with large zero field splitting, and X-ray absorption spectra show high Fe–S covalency. The Mössbauer spectrum changes drastically with the position of a nearby alkali metal cation in the iron(III) amido complex, and DFT calculations explain this phenomenon through a change between having the doubly-occupied orbital as dz2 or dyz, as the former is more influenced by the nearby positive charge.