Electrochemically-Driven 1,4-Aryl Migration via Radical Fluoromethylation of N-Allylbenzamides: a Straightforward Access to Functionalized ß-Arylethylamines.

An electrochemical radical Truce Smiles rearrangement of N-allylbenzamides is documented herein. The selective 1,4-aryl migration was triggered by the radical fluoromethylation of the alkene providing a direct route to fluoro derivatives of the highly privileged ß-arylethylamine pharmacophore. This practical transformation utilizes readily available starting materials and employs an electrical current to drive the oxidative process under mild reaction conditions. It accommodates a variety of migratory aryl groups with different electronic properties and substitution patterns. Careful selection of the protecting group on the nitrogen atom of the N-allylbenzamide is crucial to outcompete the undesired 6-endo cyclization and achieve high level of selectivity towards the 1,4-aryl migration. DFT calculations support the reaction mechanism and unveil the origin of selectivity between the two competitive pathways.

Photocatalytic Asymmetric Acyl Radical Truce-Smiles Rearrangement for the Synthesis of Enantioenriched α-Aryl Amides.

The radical Truce-Smiles rearrangement is a straightforward strategy for incorporating aryl groups into organic molecules for which asymmetric processes remains rare. By employing a readily available and non-expensive chiral auxiliary, we developed a highly efficient asymmetric photocatalytic acyl and alkyl radical Truce-Smiles rearrangement of α-substituted acrylamides using tetrabutylammonium decatungstate (TBADT) as a hydrogen atom-transfer photocatalyst, along with aldehydes or C-H containing precursors. The rearranged products exhibited excellent diastereoselectivities (7 : 1 to >98 : 2 d.r.) and chiral auxiliary was easily removed. Mechanistic studies allowed understanding the transformation in which density functional theory (DFT) calculations provided insights into the stereochemistry-determining step.

Regime Switch in the Dual-Catalyzed Coupling of Alkyl Silicates with Aryl Bromides.

Metallaphotoredox catalyzed cross-coupling of an arylbromide (Ar-Br) with an alkyl bis(catecholato)silicate (R-Si⊖ ) has been analyzed in depth using a continuum of analytical techniques (EPR, fluorine NMR, electrochemistry, photophysics) and modeling (micro-kinetics and DFT calculations). These studies converged on the impact of four control parameters consisting in the initial concentrations of the iridium photocatalyst ([Ir]0 ), nickel precatalyst ([Ni]0 ) and silicate ([R-Si⊖ ]0 ) as well as light intensity I0 for an efficient reaction between Ar-Br and R-Si⊖ . More precisely, two regimes were found to be possibly at play. The first one relies on an equimolar consumption of Ar-Br with R-Si⊖ smoothly leading to Ar-R, with no side-product from R-Si⊖ and a second one in which R-Si⊖ is simultaneously coupled to Ar-Br and degraded to R-H. This integrative approach could serve as a case study for the investigation of other metallaphotoredox catalysis manifolds of synthetic significance.

Phenyl Silicates with Substituted Catecholate Ligands: Synthesis, Structural Studies and Reactivity.

While the generation of aryl radicals by photoredox catalysis under reductive conditions is well documented, it has remained challenging under an oxidative pathway. Because of the easy photo-oxidation of alkyl bis-catecholato silicates, a general study of phenyl silicates bearing substituted catecholate ligands has been achieved. The newly synthesized phenyl silicates have been fully characterized, and their reactivity has been explored. It was found that, thanks to the substitution of the catecholate moiety, notably with the 4-cyanocatecholato ligand, the phenyl radical could be generated and trapped. Computational studies provided a rationale for these findings.

Hierarchical Self-Assembly of Polyoxometalate-Based Organo Palladium(II) Metallomacrocycles via Electrostatic Interactions.

The design and synthesis of a supramolecular square composed of polyoxometalate-based hybrid donors and ethylenediamine palladium(II) nodes are reported. The structure of the metallomacrocycle scaffold was inferred by diffusion NMR, small-angle X-ray scattering (SAXS), and molecular modeling. The metallomacrocycle scaffold that contains negatively and positively charged subunits can further self-assemble owing to a competition between the solvation energy of the discrete species and intermolecular electrostatic interactions. When the dissociating character of the solvent was lowered or when in the presence of a protic solvent, different types of multiscale organizations (vesicles and pseudo-1D structures) were selectively formed and were characterized by SAXS and transmission electron microscopy.

Capturing the Monomeric (L)CuH in NHC-Capped Cyclodextrin: Cavity-Controlled Chemoselective Hydrosilylation of α,ß-Unsaturated Ketones.

The encapsulation of copper inside a cyclodextrin capped with an N-heterocyclic carbene (ICyD) allowed both to catch the elusive monomeric (L)CuH and a cavity-controlled chemoselective copper-catalyzed hydrosilylation of α,ß-unsaturated ketones. Remarkably, (α-ICyD)CuCl promoted the 1,2-addition exclusively, while (ß-ICyD)CuCl produced the fully reduced product. The chemoselectivity is controlled by the size of the cavity and weak interactions between the substrate and internal C-H bonds of the cyclodextrin.

Molecular Cobalt Complexes with Pendant Amines for Selective Electrocatalytic Reduction of Carbon Dioxide to Formic Acid.

We report here on a new series of CO2-reducing molecular catalysts based on Earth-abundant elements that are very selective for the production of formic acid in dimethylformamide (DMF)/water mixtures (Faradaic efficiency of 90 ± 10%) at moderate overpotentials (500-700 mV in DMF measured at the middle of the catalytic wave). The [CpCo(PR2NR'2)I]+ compounds contain diphosphine ligands, PR2NR'2, with two pendant amine residues that act as proton relays during CO2-reduction catalysis and tune their activity. Four different PR2NR'2 ligands with cyclohexyl or phenyl substituents on phosphorus and benzyl or phenyl substituents on nitrogen were employed, and the compound with the most electron-donating phosphine ligand and the most basic amine functions performs best among the series, with turnover frequency >1000 s-1. State-of-the-art benchmarking of catalytic performances ranks this new class of cobalt-based complexes among the most promising CO2-to-formic acid reducing catalysts developed to date; addressing the stability issues would allow further improvement. Mechanistic studies and density functional theory simulations confirmed the role of amine groups for stabilizing key intermediates through hydrogen bonding with water molecules during hydride transfer from the Co center to the CO2 molecule.

On the Influence of the Protonation States of Active Site Residues on AChE Reactivation: A QM/MM Approach.

Acetylcholinesterase (AChE), an enzyme of the serine hydrolase superfamily, is a mediator of signal transmission at cholinergic synapses by catalyzing acetylcholine cleavage into acetate and choline. This enzyme is vulnerable to covalent inhibition by organophosphate compounds (like VX). Covalent inhibition of AChE does not revert spontaneously. Known reactivator compounds have limited action in restoring catalytic activity. QM/MM simulations of VX-inhibited AChE reactivation by pralidoxime (2-PAM), a classical reactivator, were performed. These afforded a broad view of the effect of protonation states of active-site residues, and provide evidence for the role of Glu202, which needs to be protonated for reactivation to occur. In situ deprotonation of 2-PAM for both protonation states of Glu202 showed that His447 is able to deprotonate 2-PAM with the assistance of Glu202. Because the active site of serine hydrolases is highly conserved, this work provides new insights on the interplay between the catalytic triad residues and this glutamate, newly identified as protonatable.

Cyclodextrin Cavity-Induced Mechanistic Switch in Copper-Catalyzed Hydroboration.

N-heterocyclic carbene-capped cyclodextrin (ICyD) ligands, α-ICyD and ß-ICyD derived from α- and ß-cyclodextrin, respectively give opposite regioselectivities in a copper-catalyzed hydroboration. The site-selectivity results from two different mechanisms: the conventional parallel one and a new orthogonal mechanism. The shape of the cavity was shown not only to induce a regioselectivity switch but also a mechanistic switch. The scope of interest of the encapsulation of a reactive center is therefore broadened by this study.

Photochromism and Dual-Color Fluorescence in a Polyoxometalate-Benzospiropyran Molecular Switch.

The photophysical properties of a Keggin-type polyoxometalate (POM) covalently bounded to a benzospiropyran (BSPR) unit have been investigated. These studies reveal that both closed and open forms are emissive with distinct spectral features (λem (closed form)=530 nm, λem (open form)=670 nm) and that the fluorescence of the BSPR unit of the hybrid is considerably enhanced compared to BSPR parent compounds. While the fluorescence excitation energy of the BSPR reference compounds (370 nm) is close to the intense absorption responsible of the photochromic character (350 nm), the fluorescence excitation of the hybrid is shifted to lower energy (400 nm), improving the population of the emissive state. Combined NOESY NMR and theoretical calculations of the closed form of the hybrid give an intimate understanding of the conformation adopted by the hybrid and show that the nitroaryl moieties of the BSPR is folded toward the POM, which should affect the electronic properties of the BSPR.