Speciation and Reactivity of Mono- and Binuclear Ni Intermediates in Aminoquinoline-Directed C-H Arylation and Benzylation.

This paper describes detailed organometallic studies of the aminoquinoline-directed Ni-catalyzed C-H functionalization of 2,3,4,5-tetrafluoro--(quinolin-8-yl)benzamide with diaryliodonium reagents. A combination of F NMR spectroscopy and X-ray crystallography is used to track and characterize diamagnetic and paramagnetic intermediates throughout this transformation. These provide key insights into both the cyclometalation and oxidative functionalization steps of the catalytic cycle.

Characterization and Reactivity of Copper(II) and Copper(III) σ-Aryl Intermediates in Aminoquinoline-Directed C-H Functionalization.

Over the past decade, numerous reports have focused on the development and applications of Cu-mediated C-H functionalization reactions; however, to date, little is known about the Cu intermediates involved in these transformations. This paper details the observation and characterization of Cu and Cu intermediates in aminoquinoline-directed C(sp)-H functionalization of a fluoroarene substrate. An initial C(sp)-H activation at Cu occurs at room temperature to afford an isolable anionic cyclometalated Cu complex.

Nickel(IV) Intermediates in Aminoquinoline-Directed C(sp)-C(sp) Coupling.

We use a ligand design strategy to isolate a cyclometalated nickel(IV) complex that is directly analogous to a key intermediate proposed in aminoquinoline-directed C-H functionalization catalysis. This nickel(IV) complex is formed by oxidative addition of a diaryliodonium reagent to an anionic nickel(II)-picolinate precursor. The nickel(IV) σ-aryl complex is stable at room temperature but undergoes C(sp)-C(sp) bond-forming reductive elimination under mild conditions (70 °C, 120 min).

Tunable Optical Molecular Thermometers Based on Metallacrowns.

The effect of ligands' energy levels on thermal dependence of lanthanide emission was examined to create new molecular nanothermometers. A series of LnGaLL metallacrowns (shorthand LnL), where Ln = Gd, Tb, or Sm (HL' = salicylhydroxamic acid (Hshi), 5-methylsalicylhydroxamic acid (Hmshi), 5-methoxysalicylhydroxamic acid (Hmoshi), and 3-hydroxy-2-naphthohydroxamic acid (Hnha)) and HL″ = isophthalic acid (Hiph), was synthesized and characterized. Within the series, ligand-centered singlet state (S) energy levels ranged from 23,300 to 27,800 cm, while triplet (T) energy levels ranged from 18,150 to 21,980 cm.

Tuning the photophysical properties of lanthanide(iii)/zinc(ii) 'encapsulated sandwich' metallacrowns emitting in the near-infrared range.

A family of ZnLn(HA) metallacrowns (MCs; Ln = Yb, Er, and Nd; HA = picoline- (picHA), pyrazine- (pyzHA), and quinaldine- (quinHA) hydroximates) with an 'encapsulated sandwich' structure possesses outstanding luminescence properties in the near-infrared (NIR) and suitability for cell imaging. Here, to decipher which parameters affect their functional and photophysical properties and how the nature of the hydroximate ligands can allow their fine tuning, we have completed this ZnLn(HA) family by synthesizing MCs with two new ligands, naphthyridine- (napHA) and quinoxaline- (quinoHA) hydroximates. ZnLn(napHA) and ZnLn(quinoHA) exhibit absorption bands extended into the visible range and efficiently sensitize the NIR emissions of Yb, Er, and Nd upon excitation up to 630 nm.

Synthesis and characterization of a model complex for flavodiiron NO reductases that stabilizes a diiron mononitrosyl complex.

Flavodiiron NO reductases (FNORs) are important enzymes in microbial pathogenesis, as they equip microbes with resistance to the human immune defense agent nitric oxide (NO). DFT calculations predict that a network of second coordination sphere (SCS) hydrogen bonds is critical for the key NN coupling step in the NO reduction reaction catalyzed by FNORs. In this study, we report the synthesis of a model complex of FNORs with pendant hydrogen bond donors.

Modulation of H/H exchange in iridium-hydride 2-hydroxypyridine complexes by remote Lewis acids.

A series of iridium hydride complexes featuring dihydrogen bonding are presented and shown to undergo rapid H/H exchange (1240 s at 25 °C). We demonstrate that the H/H exchange rate can be modified by post-synthetic modification at a remote site using BH, Zn(CF), and [MeO][BF]. This route provides a complementary strategy to traditional methods that rely on pre-metalation modifications to a metal's primary sphere.

Isolable Pyridinium Trifluoromethoxide Salt for Nucleophilic Trifluoromethoxylation.

An isolable pyridinium trifluoromethoxide salt is prepared from the reaction of 4-dimethylaminopyridine with the commercially available liquid 2,4-dinitro(trifluoromethoxy)benzene. The salt is an effective trifluoromethoxide source for S2 reactions to form trifluoromethyl ethers.

Visible, Near-Infrared, and Dual-Range Luminescence Spanning the 4f Series Sensitized by a Gallium(III)/Lanthanide(III) Metallacrown Structure.

Lanthanide(III) ions (Ln) in coordination compounds exhibit unique luminescence properties with narrow and characteristic f-f transitions throughout the visible and near-infrared (NIR) ranges. In addition, some Ln such as Pr, Sm, Dy, Ho, Er, and Tm possess an exceptional ability, although less explored, to exhibit dual-range emissions. Such remarkable features allow highly specific use in materials science and biology, for example, for the creation of sophisticated barcode modules or for the next generation of optical imaging applications.

Defluorinative Functionalization of Pd(II) Fluoroalkyl Complexes.

When subjected to arylboranes, anionic trifluoromethyl and difluorobenzyl palladium(II) complexes undergo fluoride abstraction followed by 1,1-migratory insertion. The resulting intermediate fluoroalkyl species can be induced to undergo a subsequent transmetalation and reductive elimination from either an formed fluoroboronate (FB(Ar)) or an exogenous boronic acid/ester (ArB(OR)) and nucleophilic activator, representing a net defluorinative arylation reaction. The latter method enabled a structurally diverse substrate scope to be prepared from either an isolated palladium-CF complex, or from Pd(PPh) and other commercially available reagents.

Iodinated Metallacrowns: Toward Combined Bimodal Near-Infrared and X-Ray Contrast Imaging Agents.

Multimodal probes capable of combining imaging modalities within a single molecule are in high demand today as they can provide information at both molecular and anatomical levels. Herein, a study was conducted on a series of gallium(III)/lanthanide(III) bis(12-MC-4) metallacrowns (MCs) with the general composition {Ln[12-MC -4]} (iph) (Ln-I , x=0, 4, 8, 12), where shi and iph are salicylhydroximate and isophthalate ligands, respectively, or their iodinated derivatives. For Yb-I , the attenuation in X-ray computed tomography (XCT) imaging and near-infrared (NIR) luminescence properties can be finely tuned by controlled structural modifications based on iodo groups.

Nickel(II/IV) Manifold Enables Room-Temperature C(sp)-H Functionalization.

This Article demonstrates a mild oxidatively induced C(sp)-H activation at a high-valent Ni center. In contrast with most C(sp)-H activation reactions at Ni, the transformation proceeds at room temperature and generates an isolable Ni σ-alkyl complex. Density functional theory studies show two plausible mechanisms for this C-H activation process involving triflate-assisted C-H cleavage at either a Ni or a Ni intermediate.

Catalytically Relevant Intermediates in the Ni-Catalyzed C(sp)-H and C(sp)-H Functionalization of Aminoquinoline Substrates.

This Article describes the synthesis and characterization of cyclometalated aminoquinoline Ni σ-aryl and σ-alkyl complexes that have been proposed as key intermediates in Ni-catalyzed C-H functionalization reactions. These Ni complexes serve as competent catalysts for the C-H functionalization of aminoquinoline derivatives with I. They also react stoichiometrically with I to form either aryl iodides or β-lactams within minutes at room temperature.

Aryl-Fluoride Bond-Forming Reductive Elimination from Nickel(IV) Centers.

The treatment of pyridine- and pyrazole-ligated Ni σ-aryl complexes with Selectfluor results in C(sp)-F bond formation under mild conditions. With appropriate design of supporting ligands, diamagnetic Ni σ-aryl fluoride intermediates can be detected spectroscopically and/or isolated during these transformations. These studies demonstrate for the first time that Ni σ-aryl fluoride complexes participate in challenging C(sp)-F bond-forming reductive elimination to yield aryl fluoride products.

Structure-Based Discovery of M-89 as a Highly Potent Inhibitor of the Menin-Mixed Lineage Leukemia (Menin-MLL) Protein-Protein Interaction.

Inhibition of the menin-mixed lineage leukemia (MLL) protein-protein interaction is a promising new therapeutic strategy for the treatment of acute leukemia carrying MLL fusion (MLL leukemia). We describe herein our structure-based design, synthesis, and evaluation of a new class of small-molecule inhibitors of the menin-MLL interaction (hereafter called menin inhibitors). Our efforts have resulted in the discovery of highly potent menin inhibitors, as exemplified by compound (M-89).

Connecting Organometallic Ni(III) and Ni(IV): Reactions of Carbon-Centered Radicals with High-Valent Organonickel Complexes.

This paper describes the one-electron interconversions of isolable Ni and Ni complexes through their reactions with carbon-centered radicals (R•). First, model Ni complexes are shown to react with alkyl and aryl radicals to afford Ni products. Preliminary mechanistic studies implicate a pathway involving direct addition of a carbon-centered radical to the Ni center.

Synthetic Model Complex of the Key Intermediate in Cytochrome P450 Nitric Oxide Reductase.

Fungal denitrification plays a crucial role in the nitrogen cycle and contributes to the total NO emission from agricultural soils. Here, cytochrome P450 NO reductase (P450nor) reduces two NO to NO using a single heme site. Despite much research, the exact nature of the critical "Intermediate I" responsible for the key N-N coupling step in P450nor is unknown.

Stable, Well-Defined Nickel(0) Catalysts for Catalytic C-C and C-N Bond Formation.

The synthesis and catalytic activity of several classes of NHC-Ni(0) pre-catalysts stabilized by electron-withdrawing alkenes are described. Variations in the structure of fumarate and acrylate ligands modulate the reactivity and stability of the NHC-Ni(0) pre-catalysts and lead to practical and versatile catalysts for a variety of transformations. The catalytic activity and efficiency of representative members of this class of catalysts have been evaluated in reductive couplings of aldehydes and alkynes and in -arylations of aryl chlorides.

Structure-Based Discovery of CF53 as a Potent and Orally Bioavailable Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitor.

We report the structure-based discovery of CF53 (28) as a highly potent and orally active inhibitor of bromodomain and extra-terminal (BET) proteins. By the incorporation of a NH-pyrazole group into the 9H-pyrimido[4,5- b]indole core, we identified a series of compounds that bind to BRD4 BD1 protein with K values of <1 nM and achieve low nanomolar potencies in the cell growth inhibition of leukemia and breast cancer cells. The most-promising compound, CF53, possesses excellent oral pharmacokinetic properties and achieves significant antitumor activity in both triple-negative breast cancer and acute leukemia xenograft models in mice.

Solid-State Insight Into the Action of a Pharmaceutical Solvate: Structural, Thermal, and Dissolution Analysis of Indinavir Sulfate Ethanolate.

The crystal structure of indinavir sulfate, a pharmaceutical administered as an ethanol solvate, is presented, revealing a unique channel/ionic solvate structure to be characteristic of the compound. The properties of the material with regard to thermal treatment and water adsorption follow closely from the structure. The in situ amorphization of the pharmaceutical upon contacting liquid water is observed and highlights the unique dissolution enhancement of marketing the crystalline solvate dosage.

A Unique Ln {[3.3.1]Ga Metallacryptate} Series That Possesses Properties of Slow Magnetic Relaxation and Visible/Near-Infrared Luminescence.

A new family of [3.3.1] metallacryptates with the general composition [LnGa (H shi)(Hshi)(shi) (C H N)] (Ln-1; shi =salicylhydroximate; Ln = Pr, Nd, Sm-Yb) has been synthesized and characterized.