Acridine/Lewis Acid Complexes as Powerful Photocatalysts: A Combined Experimental and Mechanistic Study.

A class of generated Lewis acid (LA) activated acridine complexes is reported, which act as potent photochemical catalysts for the oxidation of a variety of protected secondary amines. Acridine/LA complexes exhibit tunable excited state reduction potentials ranging from +2.07 to 2.

Transition State Analysis of Key Steps in Dual Photoredox-Cobalt-Catalyzed Elimination of Alkyl Bromides.

A combination of inter- and intramolecular C kinetic isotope effects and density functional theory analysis is used to evaluate the key mechanistic events of sequentially operating catalytic cycles in the dual photoredox-cobalt-catalyzed elimination of alkyl bromides. The results point to a mechanism proceeding via irreversible halogen-atom transfer (XAT) from the alkyl halide, resulting in an alkyl radical, which undergoes hydrogen-atom transfer (HAT) to a Co(II) intermediate to deliver the product olefin. Alternative pathways involving nucleophilic substitution by a Co(I) species and by -hydride elimination are discounted based on the poor agreement of experimental and predicted C KIEs.

Resolving Conflicting Mechanisms for Photoredox Allylic sp-CH Arylation Using Deuterium-Labeling and Isotope Effects.

Two conflicting mechanisms have emerged for the direct arylation of allylic C-H bonds enabled by the combined use of thiol and photoredox catalysis. In the original report ( , , 74-77), a radical coupling step-between a radical anion of an arene and an allylic radical-is proposed to be the key C-C bond-forming step. A recent mechanistic study (.

An Arm-to-Disarm Strategy to Overcome Phenotypic AMR in .

Most front-line tuberculosis drugs are ineffective against hypoxic non-replicating drug-tolerant () contributing to phenotypic antimicrobial resistance (AMR). This is largely due to the poor permeability in the thick and waxy cell wall of persister cells, leading to diminished drug accumulation and reduced drug-target engagement. Here, using an "arm-to-disarm" prodrug approach, we demonstrate that non-replicating persisters can be sensitized to Moxifloxacin (MXF), a front-line TB drug.

Altering the Localization of an Unpaired Spin in a Formal Ni(V) Species.

The participation of both ligand and the metal center in the redox events has been recognized as one of the ways to attain the formal high valent complexes for the late 3d metals, such as Ni and Cu. Such an approach has been employed successfully to stabilize a Ni(III) bisphenoxyl diradical species in which there exist an equilibrium between the ligand and the Ni localized resultant spin. The present work, however, broadens the scope of the previously reported three oxidized equivalent species by conveying the approaches that tend to affect the reported equilibrium in CH CN at 233 K.

Copper-Catalyzed Hydroamination: Enantioselective Addition of Pyrazoles to Cyclopropenes.

Chiral -cyclopropyl pyrazoles and structurally related heterocycles are prepared using an earth-abundant copper catalyst under mild reaction conditions with high regio-, diastereo-, and enantiocontrol. The observed N:N regioselectivity favors the more hindered nitrogen of the pyrazole. Experimental and DFT studies support a unique mechanism that features a five-centered aminocupration.

Copper-Phosphido Catalysis: Enantioselective Addition of Phosphines to Cyclopropenes.

We describe a copper catalyst that promotes the addition of phosphines to cyclopropenes at ambient temperature. A range of cyclopropylphosphines bearing different steric and electronic properties can now be accessed in high yields and enantioselectivities. Enrichment of phosphorus stereocenters is also demonstrated via a Dynamic Kinetic Asymmetric Transformation (DyKAT) process.

Stereospecific Nickel-Catalyzed Cross-Electrophile Coupling Reaction of Alkyl Mesylates and Allylic Difluorides to Access Enantioenriched Vinyl Fluoride-Substituted Cyclopropanes.

Cross-electrophile coupling reactions involving direct C-O bond activation of unactivated alkyl sulfonates or C-F bond activation of allylic -difluorides remain challenging. Herein, we report a nickel-catalyzed cross-electrophile coupling reaction between alkyl mesylates and allylic -difluorides to synthesize enantioenriched vinyl fluoride-substituted cyclopropane products. These complex products are interesting building blocks with applications in medicinal chemistry.

Synthesis of Silicon-Substituted Hemicyanines for Multimodal SWIR Imaging.

SWIR dyes offer many advantages over their more common NIR congeners; however, the available options are limited. New SWIR imaging agents can be accessed by remodeling existing NIR molecules (, hemicyanines (HDs)). In this study, we synthesized SWIR-HD, a modified HD featuring dimethylsilicon and benzo[]indolium groups that are designed to red-shift the absorbance and emission to 988 and 1126 nm, respectively.

Enzymatic Nitrogen Insertion into Unactivated C-H Bonds.

Selective functionalization of aliphatic C-H bonds, ubiquitous in molecular structures, could allow ready access to diverse chemical products. While enzymatic oxygenation of C-H bonds is well established, the analogous enzymatic nitrogen functionalization is still unknown; nature is reliant on preoxidized compounds for nitrogen incorporation. Likewise, synthetic methods for selective nitrogen derivatization of unbiased C-H bonds remain elusive.

Probing the Free Energy Landscape of Organophotoredox-Catalyzed Anti-Markovnikov Hydrofunctionalization of Alkenes.

Experimental C kinetic isotope effects (KIEs) provide unprecedented mechanistic insight into three intermolecular anti-Markovnikov alkene hydrofunctionalization reactions─hydroesterification, hydroamination, and hydroetherification─enabled by organophotoredox catalysis. All three reactions are found to proceed via initial oxidation of the model alkenes to form a radical cation intermediate, followed by sequential nucleophilic attack and hydrogen-atom transfer to deliver the hydrofunctionalized product. A normal C KIE on the olefinic carbon that undergoes nucleophilic attack provides qualitative evidence for rate-limiting nucleophilic attack in all three reactions.

Mechanism and Origin of Remote Stereocontrol in the Organocatalytic Enantioselective Formal C(sp)-H Alkylation Using Nitroalkanes as Alkylating Agents.

Experimental C kinetic isotope effects (KIEs) and density functional theory (DFT) calculations are used to evaluate the mechanism and origin of enantioselectivity in the formal C(sp)-H alkylative desymmetrization of cyclopentene-1,3-diones using nitroalkanes as the alkylating agent. An unusual combination of an inverse (∼0.980) and a normal (∼1.

Isotope Effects Reveal the Catalytic Mechanism of the Archetypical Suzuki-Miyaura Reaction.

Experimental and theoretical C kinetic isotope effects (KIEs) are utilized to obtain atomistic insight into the catalytic mechanism of the Pd(PPh)-catalyzed Suzuki-Miyaura reaction of aryl halides and aryl boronic acids. Under catalytic conditions, we establish that oxidative addition of aryl bromides occurs to a 12-electron monoligated palladium complex (Pd-(PPh)). This is based on the congruence of the experimental KIE for the carbon attached to bromine (KIE = 1.

Probing Catalyst Function - Electronic Modulation of Chiral Polyborate Anionic Catalysts.

Boroxinate complexes of VAPOL and VANOL are a chiral anionic platform that can serve as a versatile staging arena for asymmetric catalysis. The structural underpinning of the platform is a chiral polyborate core that covalently links together alcohols (or phenols) and vaulted biaryl ligands. The polyborate platform is assembled in situ by the substrate of the reaction, and thus a multiplex of chiral catalysts can be rapidly assembled from various alcohols (or phenols) and bis-phenol ligands for screening of catalyst activity.

Rapid Evaluation of the Mechanism of Buchwald-Hartwig Amination and Aldol Reactions Using Intramolecular C Kinetic Isotope Effects.

A practical approach is introduced for the rapid determination of C kinetic isotope effects that utilizes a "designed" reactant with two identical reaction sites. The mechanism of the Buchwald-Hartwig amination of -butylbromobenzene with primary and secondary amines is investigated under synthetically relevant catalytic conditions using traditional molecular C NMR methodology at natural abundance. Switching to 1,4-dibromobenzene, a symmetric bromoarene as the designed reactant, the same experimental C KIEs are determined using an molecular KIE approach.

Biocatalytic, Intermolecular C-H Bond Functionalization for the Synthesis of Enantioenriched Amides.

Directed evolution of heme proteins has opened access to new-to-nature enzymatic activity that can be harnessed to tackle synthetic challenges. Among these, reactions resulting from active site iron-nitrenoid intermediates present a powerful strategy to forge C-N bonds with high site- and stereoselectivity. Here we report a biocatalytic, intermolecular benzylic C-H amidation reaction operating at mild and scalable conditions.

A General Approach to Convert Hemicyanine Dyes into Highly Optimized Photoacoustic Scaffolds for Analyte Sensing*.

Most photoacoustic (PA) imaging agents are based on the repurposing of existing fluorescent dye platforms that exhibit non-optimal properties for PA applications. Herein, we introduce PA-HD, a new dye scaffold optimized for PA probe development that features a 4.8-fold increase in sensitivity and a red-shift of the λ from 690 nm to 745 nm to enable ratiometric imaging.

Boosting NAD with a small molecule that activates NAMPT.

Pharmacological strategies that boost intracellular NAD are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production of nicotinamide mononucleotide (NMN), the predominant NAD precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT.

Transition state analysis of an enantioselective Michael addition by a bifunctional thiourea organocatalyst.

The mechanism of the enantioselective Michael addition of diethyl malonate to trans-β-nitrostyrene catalyzed by a tertiary amine thiourea organocatalyst is explored using experimental 13C kinetic isotope effects and density functional theory calculations. Large primary 13C KIEs on the bond-forming carbon atoms of both reactants suggest that carbon-carbon bond formation is the rate-determining step in the catalytic cycle. This work resolves conflicting mechanistic pictures that have emerged from prior experimental and computational studies.

Allosteric Activation Shifts the Rate-Limiting Step in a Short-Form ATP Phosphoribosyltransferase.

Short-form ATP phosphoribosyltransferase (ATPPRT) is a hetero-octameric allosteric enzyme comprising four catalytic subunits (HisG) and four regulatory subunits (HisZ). ATPPRT catalyzes the Mg-dependent condensation of ATP and 5-phospho-α-d-ribosyl-1-pyrophosphate (PRPP) to generate N-(5-phospho-β-d-ribosyl)-ATP (PRATP) and pyrophosphate, the first reaction of histidine biosynthesis. While HisG is catalytically active on its own, its activity is allosterically enhanced by HisZ in the absence of histidine.

C Kinetic Isotope Effects as a Quantitative Probe To Distinguish between Enol and Enamine Mechanisms in Aminocatalysis.

A combination of experimental C kinetic isotope effects (KIEs) and high-level density functional theory (DFT) calculations is used to distinguish between "enamine" and "enol" mechanisms in the Michael addition of acetone to trans-β-nitrostyrene catalyzed by Jacobsen's primary amine thiourea catalyst. In light of the recent findings that the widely used O-incorporation probe for these mechanisms is flawed, the results described in this communication demonstrate an alternative probe to distinguish between these pathways. A key advantage of this probe is that quantitative mechanistic information is obtained without modifying experimental conditions.

Asymmetric Induction via a Helically Chiral Anion: Enantioselective Pentacarboxycyclopentadiene Brønsted Acid-Catalyzed Inverse-Electron-Demand Diels-Alder Cycloaddition of Oxocarbenium Ions.

An enantioselective catalytic inverse-electron-demand Diels-Alder reaction of salicylaldehyde acetal-derived oxocarbenium ions and vinyl ethers to generate 2,4-dioxychromanes is described. Chiral pentacarboxycyclopentadiene (PCCP) acids are found to be effective for a variety of substrates. Computational and X-ray crystallographic analyses support the unique hypothesis that an anion with point-chirality-induced helical chirality dictates the absolute sense of stereochemistry in this reaction.

Formation of hydrazones and stabilized boron-nitrogen heterocycles in aqueous solution from carbohydrazides and ortho-formylphenylboronic acids.

A recent addition to the suite of fast bioorthogonal reactions combines hydrazines and hydroxylamines with ortho-carbonyl substituted phenylboronic acids. Carbohydrazides are easily incorporated into biomolecules, making them appealing substrates in these reactions. Here we show that simple alkyl carbohydrazides form a single product with ortho-formylphenylboronic acid in an organic solvent and in the solid state.

A Designed Approach to Enantiodivergent Enamine Catalysis.

The rational design and implementation of enantiodivergent enamine catalysis is reported. A simple secondary amine catalyst, 2-methyl-l-proline, and its tetrabutylammonium salt function as an enantiodivergent catalyst pair delivering the enantiomers of α-functionalized aldehyde products in excellent enantioselectivities. This novel concept of designed enantiodivergence is applied to the enantioselective α-amination, aldol, and α-aminoxylation/α-hydroxyamination reactions of aldehydes.