Unconventional mechanism and selectivity of the Pd-catalyzed C–H bond lactonization in aromatic carboxylic acid

The search for more effective and highly selective C–H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission. The elucidating of mechanism and controlling factors will, undoubtedly, help to broaden scope of these synthetic protocols, and enable discovery of more efficient, environmentally benign, and highly practical new C–H oxidation reactions. Here, we reveal the stepwise intramolecular SN2 nucleophilic substitution mechanism with the rate-limiting C–O bond formation step for the Pd(II)-catalyzed C(sp3)–H lactonization in aromatic 2,6-dimethylbenzoic acid. We show that for this reaction, the direct C–O reductive elimination from both Pd(II) and Pd(IV) (oxidized by O2 oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the η3-(π-benzylic)–Pd and K+–O(carboxylic) interactions. The controlling factors of the benzylic vs ortho site-selectivity of this reaction are the: (a) difference in the strains of the generated lactone rings; (b) difference in the strengths of the η3-(π-benzylic)–Pd and η2-(π-phenyl)–Pd interactions, and (c) more pronounced electrostatic interaction between the nucleophilic oxygen and K+ cation in the ortho-C–H activation transition state. The presented data indicate the utmost importance of base, substrate, and ligand in the selective C(sp3)–H bond lactonization in the presence of C(sp2)–H.

Design principles for site-selective hydroxylation by a Rieske oxygenase

Rieske oxygenases exploit the reactivity of iron to perform chemically challenging C–H bond functionalization reactions. Thus far, only a handful of Rieske oxygenases have been structurally characterized and remarkably little information exists regarding how these enzymes use a common architecture and set of metallocenters to facilitate a diverse range of reactions. Herein, we detail how two Rieske oxygenases SxtT and GxtA use different protein regions to influence the site-selectivity of their catalyzed monohydroxylation reactions. We present high resolution crystal structures of SxtT and GxtA with the native β-saxitoxinol and saxitoxin substrates bound in addition to a Xenon-pressurized structure of GxtA that reveals the location of a substrate access tunnel to the active site. Ultimately, this structural information allowed for the identification of six residues distributed between three regions of SxtT that together control the selectivity of the C–H hydroxylation event. Substitution of these residues produces a SxtT variant that is fully adapted to exhibit the non-native site-selectivity and substrate scope of GxtA. Importantly, we also found that these selectivity regions are conserved in other structurally characterized Rieske oxygenases, providing a framework for predictively repurposing and manipulating Rieske oxygenases as biocatalysts.

Solvent-Controlled Regioselective Arylation of Indoles and Mechanistic Explorations

The ability to manipulate the site selectivity in C–H bond functionalization reactions is an important goal in modern chemistry. Herein, we report a new reaction strategy for the regioselective arylation...

Theoretical Prediction and Explanation of Reaction Site Selectivity in the Addition of a Phenoxy Group to Perfluoropyrimidine, Perfluoropyridazine, and Perfluoropyrazine

Perfluoroaromatics, such as perfluoropyridine and perfluorobenzene, are privileged synthetic scaffolds in organofluorine methodology, undergoing a series of regioselective substitution reactions with a variety of nucleophiles. This unique chemical behavior allows for the synthesis of many perfluoroaromatic derived molecules with unique and diverse architectures. Recently, it has been demonstrated that perfluoropyridine and perfluorobenzene can be utilized as precursors for a variety of materials, ranging from high performance polyaryl ethers to promising drug scaffolds. In this work, using density functional theory, we investigate the possibility of perfluoropyrimidine, perfluoropyridazine, and perfluoropyrazine participating in similar substitution reactions. We have found that the first nucleophilic addition of a phenoxide group substitution on perfluoropyrimidine and on perfluoropyridazine would happen at a site para to one of the nitrogen atoms. While previous literature points to mesomeric effects as the primary cause of this phenomenon, our work demonstrates that this effect is enhanced by the fact that the transition states for these reactions result in bond angles that allow the phenoxide to π-complex with the electron-deficient diazine ring. The second substitution on perfluoropyrimidine and on perfluoropyridazine is most likely to happen at the site para to the other nitrogen. The second substitution on perfluoropyrazine is most likely to happen at the site para to the first substitution. The activation energies for these reactions are in line with those reported for perfluoropyridine and suggest that these platforms may also be worth investigation in the lab as possible monomers for high performance polymers.

Non-directed highly para-selective C-H functionalization of TIPS-protected phenols promoted by a proton shuttle

Palladium-catalyzed non-directed C-H functionalization provides an efficient approach for direct functionalization of arenes, but it usually suffers from poor site selectivity, limiting its wide application. Herein, it is reported for the first time that the proton shuttle of 3,5-dimethyladamantane-1-carboxylic acid (1-DMAdCO2H) can affect the site selectivity during the C-H activation step in palladium-catalyzed non-directed C-H functionalization, leading to highly para-selective C-H olefination of TIPS-protected phenols. This transformation displayed good generality in realizing various other para-selective C-H functionalization reactions such as hydroxylation, halogenation, and allylation reactions. A wide variety of phenol derivatives including bioactive molecules of triclosan, thymol, and propofol, were compatible substrates, leading to the corresponding para-selective products in moderate to good yields. A preliminary mechanism study revealed that the spatial repulsion factor between proton shuttle and bulky protecting group resulted in the selective C-H activation at the less sterically hindered para-position. This new model non-directed para-selective C-H functionalization can provide a straightforward route for remote site-selective C-H activations.

A general strategy for C(sp3)–H functionalization with nucleophiles using methyl radical as a hydrogen atom abstractor

Photoredox catalysis has provided many approaches to C(sp3)–H functionalization that enable selective oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. While highly enabling, functionalization of the carbon-centered radical is largely mediated by electrophilic reagents. Notably, nucleophilic reagents represent an abundant and practical reagent class, motivating the interest in developing a general C(sp3)–H functionalization strategy with nucleophiles. Here we describe a strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover. The resulting carbocation is functionalized by a variety of nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an azide—to effect diverse bond formations. Mechanistic studies indicate that HAT is mediated by methyl radical—a previously unexplored HAT agent with differing polarity to many of those used in photoredox catalysis—enabling new site-selectivity for late-stage C(sp3)–H functionalization.

Ligand-gated ion channels as targets of neuroactive insecticides

The Cys-loop superfamily of ligand-gated ion channels (Cys-loop receptors) is one of the most ubiquitous ion channel families in vertebrates and invertebrates. Despite their ubiquity, they are targeted by several classes of pesticides, including neonicotinoids, phenylpyrazols, and macrolides such as ivermectins. The current commercialized compounds have high target site selectivity, which contributes to the safety of insecticide use. Structural analyses have accelerated progress in this field; notably, the X-ray crystal structures of acetylcholine binding protein and glutamate-gated Cl channels revealed the details of the molecular interactions between insecticides and their targets. Recently, the functional expression of the insect nicotinic acetylcholine receptor (nAChR) has been described, and detailed evaluations using the insect nAChR have emerged. This review discusses the basic concepts and the current insights into the molecular mechanisms of neuroactive insecticides targeting the ligand-gated ion channels, particularly Cys-loop receptors, and presents insights into target-based selectivity, resistance, and future drug design.

Cationic DABCO-based Catalyst for Site-Selective C−H Alkylation via Photoinduced Hydrogen-Atom Transfer

A novel class of hydrogen-atom transfer (HAT) catalysts based on the readily available and tunable 1,4-diazabicyclo[2.2.2]octane (DABCO) structure was designed, and their photoinduced HAT catalysis ability was demonstrated. The combination of the optimal HAT catalyst with an acridinium-based organophotoredox catalyst enables highly efficient and site-selective C−H alkylation of substrates ranging from unactivated hydrocarbons to complex molecules. Notably, a HAT catalyst with additional substituents adjacent to a nitrogen atom further improved the site-selectivity. Mechanistic studies suggested that the N-substituent of the catalyst plays a crucial role, assisting in the generation of a dicationic aminium radical as an active species for the HAT process.