Dehydrogenative Coupling Reactions with Guanidino-Functionalized Aromatics.

Dehydrogenative coupling (DC) reactions are of importance for the construction of new carbon-element bonds in synthetic organic chemistry. In this work, we report on the synthesis and characterization of several redox-active guanidino-functionalized aromatic molecules (GFAs) for use in DC (C-C and C-O) reactions. In a systematic approach, we first characterize the new DC reagents in all relevant redox and protonation states, and compare their performance in competitive test proton-coupled electron transfer (PCET) reactions. Then, their use in four different DC reactions with different mechanisms is evaluated.

Coupling Photocatalytic Hydrogen Production with Key Oxidation Reactions.

Hydrogen represents a clean and sustainable energy source with wide applications in fuel cells and hydrogen energy storage systems. Photocatalytic strategies emerge as a green and promising solution for hydrogen production, which still reveals several critical challenges in enhancing the efficiency and stability and improving the whole value. This review systematically elaborates on various coupling approaches for photocatalytic hydrogen production, aiming to improve both efficiency and value through different oxidation half-reactions. Firstly, the fundamental mechanism is discussed for photocatalytic hydrogen production. Then, the advances, challenges, and opportunities are expanded for the coupling of photocatalytic hydrogen production, which focuses on the integration of value-added reactions including O2 production, H2O2 production, biomass conversion, alcohol oxidation, and pollutants treatment. Finally, the challenges and outlook of photocatalytic H2 production technology are analyzed from the aspects of coupling hydrogen production value, photocatalyst design and reaction system construction. This work presents a holistic view of the field, emphasizing the synergistic benefits of coupled reactions and their practical application potential, rather than focusing on catalysts or single reaction systems. This review provides valuable references for the development and application of photocatalytic hydrogen production in energy conversion and environmental conservation through sustainable, eco-friendly and economic pathways.

C-C Bonding in Molecular Systems via Cross-Coupling-like Reactions Involving Noncovalently Bound Constituent Ions.

Carbon-based molecules are of universal importance for a huge variety of chemical and biological processes. The complication of the structure of such molecules proceeds via the bonding of carbon atoms. An efficient mechanism for such reactions proceeds via cross-coupling, related to the association of bond-terminating counter-ions. Here, an uncommon version of such a process is investigated, with at least some ions bound in the system noncovalently and/or switching the bonding mode in due course. The analyzed sample reactions involve a single C-C bond formation in environmentally relevant halocarbon species and involve alkali-halide ion-pair components. A consistent ab initio computational study predicts the related energy barriers to alter significantly in the presence of the ion pair. Different channels are checked, with the carbon-halogen bond cleavage preceding or following the actual C-C bonding and with the counter-ions located closely or farther apart. The relative heights of the corresponding energy barriers are found to be switched by the ion pair. The above results suggest a possibility of facilitating such reactions without expensive catalysts.

Recent Applications of Sulfonium Salts in Synthesis and Catalysis.

The use of sulfonium salts in organic synthesis has experienced a dramatic increase during the last years that can arguably be attributed to three main factors; the development of more direct and efficient synthetic methods that make easily available sulfonium reagents of a wide structural variety, their intrinsic thermal stability, which facilitates their structural modification, handling and purification even on large scale, and the recognition that their reactivity resembles that of hypervalent iodine compounds and therefore, they can be used as replacement of such reagents for most of their uses. This renewed interest has led to the improvement of already existing reactions, as well as to the discovery of unprecedented transformations; in particular, by the implementation of photocatalytic protocols. This review aims to summarize the most recent advancements on the area focusing on the work published during and after 2020. The scope of the methods developed will be highlighted and their limitations critically evaluated.

Ubiquitous Role of Phosphine-Based Water-Soluble Ligand in Promoting Catalytic Reactions in Water.

Catalysis has been at the forefront of the developments that has revolutionised synthesis and provided the impetus in the discovery of platform technologies for efficient C-C or C-X bond formation. Current environmental situation however, demands a change in strategy with catalysis being promoted more in solvents that are benign (Water) and for that the development of hydrophilic ligands (especially phosphines) is a necessity which could promote catalytic reactions in water, allow recyclability of the catalytic solutions and make it possible to isolate products using column-free techniques that involve lesser usage of hazardous organic solvents. In this review, we therefore critically analyse such catalytic processes providing examples that do follow the above-mentioned parameter.

UPCYCLING OF CHITIN TO CROSS-COUPLING CATALYSTS: TAILORED SUPPORTS AND OPPORTUNITIES IN MECHANOCHEMISTRY.

In this study chitin derived from shrimp shells was used in the design of heterogeneous Pd-based catalysts for Heck and Suzuki-Miyaura cross-coupling reactions. The synthesis of Pd nanoparticles supported on N-doped carbons was performed through different approaches, including a sustainable mechanochemical approach, by using a twin-screw extruder. All catalytic systems were characterized by a multitechnique approach and the effect of nanoparticles size, N-doping on the support, and their synergistic interactions were elucidated. Specifically, Kelvin Probe Atomic Force Microscopy provided valuable insights on charge transfer and metal-support interactions. The catalytic behaviour of the samples was investigated in cross-coupling reactions under batch conditions and under semi-continuous flow solvent-free conditions, respectively obtaining a quantitative yield and a noteworthy productivity of 8.7 mol/(gPdh).

Selective Synthesis of Organonitrogen Compounds via Electrochemical C-N Coupling on Atomically Dispersed Catalysts.

The C-N coupling reaction demonstrates broad application in the fabrication of a wide range of high value-added organonitrogen molecules including fertilizers (e.g., urea), chemical feedstocks (e.g., amines, amides), and biomolecules (e.g., amino acids). The electrocatalytic C-N coupling pathways from waste resources like CO2, NO3-, or NO2- under mild conditions offer sustainable alternatives to the energy-intensive thermochemical processes. However, the complex multistep reaction routes and competing side reactions lead to significant challenges regarding low yield and poor selectivity toward large-scale practical production of target molecules. Among diverse catalyst systems that have been developed for electrochemical C-N coupling reactions, the atomically dispersed catalysts with well-defined active sites provide an ideal model platform for fundamental mechanism elucidation. More importantly, the intersite synergy between the active sites permits the enhanced reaction efficiency and selectivity toward target products. In this Review, we systematically assess the dominant reaction pathways of electrocatalytic C-N coupling reactions toward various products including urea, amines, amides, amino acids, and oximes. To guide the rational design of atomically dispersed catalysts, we identify four key stages in the overall reaction process and critically discuss the corresponding catalyst design principles, namely, retaining NOx/COx reactants on the catalyst surface, regulating the evolution pathway of N-/C- intermediates, promoting C-N coupling, and facilitating final hydrogenation steps. In addition, the advanced and effective theoretical simulation and characterization technologies are discussed. Finally, a series of remaining challenges and valuable future prospects are presented to advance rational catalyst design toward selective electrocatalytic synthesis of organonitrogen molecules.

Electrochemical Decarboxylative Cross-Coupling with Nucleophiles.

Decarboxylative cross-coupling reactions are powerful tools for carbon-heteroatom bonds formation, but typically require pre-activated carboxylic acids as substrates or heteroelectrophiles as functional groups. Herein, we present an electrochemical decarboxylative cross-coupling of carboxylic acids with structurally diverse fluorine, alcohol, H2O, acid, and amine as nucleophiles. This strategy takes advantage of the ready availability of these building blocks from commercial libraries, as well as the mild and oxidant-free conditions provided by electrochemical system. This reaction demonstrates good functional-group tolerance and its utility in late-stage functionalization.

Palladium anchored to BisPyP@bilayer-SiO2@NMP organic-inorganic hybrid as an efficient and recoverable novel nanocatalyst in suzuki and stille C-C coupling reactions.

The palladium anchored to BisPyP@bilayer-SiO2@NMP organic-inorganic hybrid was employed as an effective and recyclable organometallic catalyst in Suzuki and Stille C-C coupling reactions. The structure of this magnetic nanocatalyst was determined using various techniques such as SEM, TEM, FT-IR, EDS, ICP-OES, VSM, N2 adsorption-desorption isotherms, XRD, and TGA. In both of the mentioned coupling paths, the yields of the products were very favorable and ranged from 90 to 98%. Also, they had significant features compared to previous reports, such as very short reaction time (5-15 and 7-20 min respectively in the Suzuki and Stille reactions), easy work-up, broad substrate scope, ease of separation of the catalyst using a magnet, suitable reproducibility of the catalyst in 6 runs, heterogeneous nature of the catalyst and not washing it during consecutive runs with confirmation of hot filtration and ICP-OES methods.

Organophosphates as Versatile Substrates in Organic Synthesis.

This review summarizes the applications of organophosphates in organic synthesis. After a brief introduction, it discusses cross-coupling reactions, including both transition-metal-catalyzed and transition-metal-free substitution reactions. Subsequently, oxidation and reduction reactions are described. In addition, this review highlights the applications of organophosphates in the synthesis of natural compounds, demonstrating their versatility and importance in modern synthetic chemistry.

A Structure-Activity Relationship Study of Amino Acid Derivatives of Pterostilbene Analogues Toward Human Breast Cancer.

Pterostilbene is the dimethylated analogue of Resveratrol, a compound with well-known biological activities, such as antioxidant, chemopreventive, anti-diabetic, anti-obesity, and cardioprotective. Despite many studies on the general effect of such polyphenolic molecules and their derivatives, a deep comprehension of their action and systematic structure-activity relationship studies are still rare. Herein, three different analogues of functionalizable Pterostilbene were efficiently synthesized and derivatized with a selected library of antioxidant amino acids, allowing for a highly diversified exploration of the chemical space. The library was analyzed towards cancer cells. Collectively, our data demonstrated the enhanced anti-proliferative activity of Tryptophan-conjugated compounds. In breast cancer cells, the treatment with Tryptophan-conjugated analogues induced the activation of cellular stress pathways, including autophagy signaling.

Alkylphenols disrupt estrogen homeostasis via diradical cross-coupling reactions: A novel pathway of endocrine disruption.

Estrogen, being an essential class of sex hormone, is an important target of endocrine disruption chemicals. It is well known that environmental disruptors could activate or inhibit estrogen receptors, acting as agonists or antagonists, and thus affect the circulating estrogen concentrations. Here, we report enzyme-mediated diradical cross-coupling reactions between alkylphenols (e.g., 2,4-di-tert-butylphenol [DBP], 4-nonylphenol [4-NP], and 4-tert-octylphenol [4-t-OP]) and estrogens (e.g., estradiol [E2]) that generate coupling metabolites and disrupt estrogen homeostasis. Among the phenolic xenobiotics, the screening of metabolic products revealed that alkylphenols had the highest reaction activities and generated coupling metabolites with high abundances (DBP-O-E2, 4-t-OP-O-E2, and 4-NP-O-E2). The coupling reactions were catalyzed by cytochrome P450 3A4 (CYP3A4) and verified by the detection of the coupling products in general populations. In vitro and in vivo exposures together with CYP3A4 inhibition demonstrated that cross-coupling reactions of phenols and E2 significantly reduced the normal levels of E2. We further established a unique spin-trapping-based high-throughput screening method to show the existence of diradicals in the coupling reaction. Density functional theory calculations revealed that spin aromatic delocalization was the fundamental cause of the high rebound barrier and sufficient lifetime of phenoxy radicals that enabled phenolic cross-coupling triggered by cytochrome P450. The identified mechanistic details for diradical cross-coupling reactions provide a novel pathway for phenolic chemicals to disrupt estrogen homeostasis.

Bottom-Up Construction of Ni(II)-Incorporated Covalent Organic Framework for Metallaphotoredox Catalysis.

The construction of an all-in-one catalyst, in which the photosensitizer and the transition metal site are close to each other, is important for improving the efficiency of metallaphotoredox catalysis. However, the development of convenient synthetic strategies for the precise construction of an all-in-one catalyst remains a challenging task due to the requirement of precise installation of the catalytic sites. Herein, we have successfully established a facile bottom-up strategy for the direct synthesis of Ni(II)-incorporated covalent organic framework (COF), named LZU-713@Ni, as a versatile all-in-one metallaphotoredox catalyst. LZU-713@Ni showed excellent activity and recyclability in the photoredox/nickel-catalyzed C-O, C-S, and C-P cross-coupling reactions. Notably, this catalyst displayed a better catalytic activity than its homogeneous analogues, physically mixed dual catalyst system, and, especially, LZU-713/Ni which was prepared through post-synthetic modification. The improved catalytic efficiency of LZU-713@Ni should be attributed to the implementation of bottom-up strategy, which incorporated the fixed, ordered, and abundant catalytic sites into its framework. This work sheds new light on the exploration of concise and effective strategies for the construction of multifunctional COF-based photocatalysts.

Oxazaborolidinones: Steric Coverage Effect of Lewis Acidic Boron Center in Suzuki-Miyaura Coupling Reactions.

It was demonstrated that α-hydroxycarboxamide is an excellent boron-protecting group. The reaction between α-hydroxycarboxamide and organoboronic acids produced stable oxazaborolidinones (OxBs), in which the sp 2 ${{_{{\rm sp}{^{2}}}}}$ -hybridized boron atom was sterically protected by α-hydroxycarboxamide. The alkyl groups of the α-hydroxycarboxamide moiety can dynamically cover the p-orbital of the sp 2 ${{_{{\rm sp}{^{2}}}}}$ -hybridized boron center, creating a small space around the boron atom, allowing for smooth transmetalation by a Pd catalyst and easy deprotection by water. This protecting phenomenon is effective for readily purification, Suzuki-Miyaura coupling reactions with unstable boronic acids and iterative cross-couplings.

Aiming for More Sustainable Cross-Coupling Chemistry by Employing Single-Atom Catalysis on Scale.

Scaling up syntheses from mg to kg quantities is a complex endeavor. Besides adapting laboratory protocols to industrial processes and equipment and thorough safety assessments, much attention is paid to the reduction of the process' environmental impact. For processes including transition metal catalyzed steps, e.g. cross-coupling chemistry, this impact strongly depends on the identity of the metal used. As such, a key approach is the replacement of single-use with reusable heterogeneous catalysts. Transition metal single-atom heterogeneous catalysts (SAC), a novel class of catalytic materials, might exhibit all the necessary properties to step up to this task. This article shall discuss current applications of SAC in cross-coupling chemistry from the point of a process chemist and shed light on the NCCR Catalysis contribution to the field. Investigations of the stability-activity-selectivity relationship of SACs in combination with early-stage life-cycle assessments (LCA) of potential processes lay the foundation for large-scale application tailored catalyst synthesis. Ultimately, prevailing challenges are highlighted, which need to be addressed in future research.

High-Performance Near-Infrared Chlorinated Rylenecarboximide Fluorophores via Consecutive C-N and C-C Bond Formation.

A new class of near-infrared (NIR) fluorophores, PAI, is obtained by consecutive C-N/C-C bond formation between diphenylamines and 9,10-dibromoperylenecarboximide. Owing to the rigid structure, extended π-conjugation and pronounced push-pull substitution, these fluorophores show emission maxima up to 804 nm and large Stokes shifts. The extraordinarily high fluorescence quantum yields from 47 % to 70 % are attributed to chloro substitution in the bay positions of the perylene core. These characteristics, together with high photostability, qualify them as useful NIR emitters for applications as biomarkers and security inks.

Phenoxythiazoline (FTz)-Cobalt(II) Precatalysts Enable C(sp2 )-C(sp3 ) Bond-Formation for Key Intermediates in the Synthesis of Toll-like Receptor 7/8 Antagonists.

Evaluation of the relative rates of the cobalt-catalyzed C(sp2 )-C(sp3 ) Suzuki-Miyaura cross-coupling between the neopentylglycol ester of 4-fluorophenylboronic acid and N-Boc-4-bromopiperidine established that smaller N-alkyl substituents on the phenoxyimine (FI) supporting ligand accelerated the overall rate of the reaction. This trend inspired the design of optimal cobalt catalysts with phenoxyoxazoline (FOx) and phenoxythiazoline (FTz) ligands. An air-stable cobalt(II) precatalyst, (FTz)CoBr(py)3 was synthesized and applied to the cross-coupling of an indole-5-boronic ester nucleophile with a piperidine-4-bromide electrophile that is relevant to the synthesis of reported toll-like receptor (TLR) 7/8 antagonist molecules including afimetoran. Addition of excess KOMe⋅B(Oi Pr)3 improved catalyst lifetime due to attenuation of alkoxide basicity that otherwise resulted in demetallation of the FI chelate. A first-order dependence on the cobalt precatalyst and a saturation regime in nucleophile were observed, supporting turnover-limiting transmetalation and the origin of the observed trends in N-imine substitution.

Conjugation-Induced Spin Delocalization in Helical Chiral Carbon Radicals via Through-Bond and Through-Space Effects.

A class of highly stable hydrocarbon radicals with helical chirality are synthesized, which can be isolated and purified by routine column chromatography on silica gel. These carbon-centered radicals are stabilized by through-bond delocalization and intramolecular through-space conjugation, which is evidenced by Density Functional Theory (DFT) calculation. The high stability enables to directly modify the carbon radical via palladium-catalyzed cross-coupling with the radical being untapped. The structures and optoelectronic properties are investigated with a variety of experimental methods, including Electron Paramagnetic Resonance (EPR), Ultraviolet Visisble Near Infrared (UV-vis-NIR) measurements, Cyclic Voltammetry (CV), Thermogravimetry Analysis (TGA), Circular Dichroism (CD) spectra, High-Performance Liquid Chromatography (HPLC), and X-ray crystallographic analysis. DFT calculations indicated that the 9-anthryl helical radical is more stable than its tail-to-tail σ-dimer over 13.2 kJ mol-1 , which is consistent with experimental observations.

Synthesis of phenylethanoid glycosides from acrylic esters of glucose and aryldiazonium salts via palladium-catalyzed cross-coupling reactions and evaluation of their anti-Alzheimer activity.

Cinnamic acid-containing sugar compounds such as phenylethanoid glycosides are widely present in nature and display various biological activities. In this work, the synthesis of trans-cinnamic acid containing phenylethanoid glycosides was achieved via palladium-catalyzed cross-coupling reactions between glycosyl acrylic esters and aryldiazonium salts. A wide range of functionalized aryldiazonium salts were successfully coupled with 6-O- and 4-O-acrylic esters of glucose under optimized conditions. The reactions proceeded at room temperature in the absence of additives and base. The desired products were obtained in good to excellent yields. Selected compounds from the library were screened for anti-Alzheimer activity, while compound 16 displayed significant inhibitory activities against butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) enzymes.

Photocatalytic 2-Iodoethanol Coupling to Produce 1,4-Butanediol Mediated by TiO2 and a Catalytic Nickel Complex.

Photocatalytic 2-iodoethanol (IEO) coupling provides 1,4-butanediol (BDO) of particular interest to produce degradable polyesters. However, the reduction potential of IEO is too negative (-1.9 vs NHE) to be satisfied by most of the semiconductors, and the kinetics of transferring one electron for IEO coupling is slow. Here we design a catalytic Ni complex, which works synergistically with TiO2 , realizing reductive coupling of IEO powered by photo-energy. Coordinating by terpyridine stabilizes Ni2+ from being photo-deposited to TiO2 , thereby retaining the steric configuration beneficial for IEO coupling. The Ni complex can rapidly extract electrons from TiO2 , generating a low-valent Ni capable of reducing IEO. The photocatalytic IEO coupling thus provides BDO in 72 % selectivity. By a stepwise procedure, BDO is obtained with 70 % selectivity from ethylene glycol. This work put forward a strategy for the photocatalytic reduction of molecules requiring strong negative potential.