LG

An automated electrochemical flow platform for operator-free data generation is presented, leveraging slug-based reaction mixtures for low material consumption. This platform was employed in the context of library synthesis of 44 medicinal chemistry-relevant compounds. The platform was also used to optimize one previously unsuccessful target via DoE, leading to a 6-fold yield increment.

Abstract

Automated batch and flow setups are well-established for high throughput experimentation in both thermal chemistry and photochemistry. However, the development of automated electrochemical platforms is hindered by cell miniaturization challenges in batch and difficulties in designing effective single-pass flow systems. In order to address these issues, we have designed and implemented a new, slug-based automated electrochemical flow platform. This platform was successfully demonstrated for electrochemical C−N cross-couplings of E3 ligase binders with diverse amines (44 examples), which were subsequently transferred to a continuous-flow mode for confirmation and isolation, showing its applicability for medicinal chemistry purposes. To further validate the versatility of the platform, Design of Experiments (DoE) optimization was performed for an unsuccessful library target. This optimization process, fully automated by the platform, resulted in a remarkable 6-fold increase in reaction yield.

A catalytic methodology for the direct cross-coupling of gaseous alkanes with (hetero)aryl bromides through the combination of metallaphotoredox-mediated hydrogen atom transfer and nickel catalysis is reported. The method provides an efficient platform for the conversion of these abundant chemical feedstocks into high-value alkyl(hetero)arenes and bypasses the longstanding need of using preactivated alkylating agents in C(sp²)-C(sp³) cross-couplings.

Abstract

Gaseous alkanes represent the most abundant carbon-based chemical feedstocks in our planet. However, the intrinsic inertness of their C−H bonds has rendered the use of these alkanes very difficult for purposes beyond aerobic combustion and energy intensive processes. Thus, clean and energy-efficient transformations for their use in synthetic organic chemistry are still rare. Here we report a catalytic methodology for the direct cross-coupling of gaseous alkanes with (hetero)aryl bromides through the combination of metallaphotoredox-mediated hydrogen atom transfer and nickel catalysis. This protocol provides an efficient platform for the addition of short alkyl groups into diverse (hetero) aromatic rings, providing a wide range of high-value alkyl(hetero)arenes, and bypassing the longstanding need of using preactivated alkylating agents in C(sp²)-C(sp³) cross-couplings. The method features high chemoselectivity, regioselectivity and a remarkable functional group tolerance, operates under mild conditions, and exhibits operational simplicity

The performance of 5-hydroxymethylfurfural oxidation reaction was improved by depositing Ni-based co-catalyst on the Fe₂O₃ photoanode. Compared to alcohol, Ni-based co-catalyst has a higher bond dissociation free energy, which ensures the transfer of α-H from the alcohol molecule to the co-catalyst through proton-coupled electron transfer process.

Abstract

Using biomass oxidation reactions instead of water oxidation reactions is optimal for accomplishing biomass conversion and effective hydrogen generation. Here, we report that α-Fe₂O₃ photoanodes with a NiOOH cocatalyst exhibit excellent performance for photoelectrochemical oxidation of 5-hydroxymethylfurfural (HMF) to 2,5-furandicarboxylic acid (FDCA). The conversion efficiency for HMF reaches 98.5 %, while the selectivity for FDCA is 94.2 %. We revealed that HMF is oxidized through a spontaneous proton-coupled electron transfer (PCET) process with the high-valent phase of the Ni-based catalyst. The dangling oxygen and bridging oxygen of the high-valent phase species serve as proton-accepting sites. Furthermore, we pointed out that the deprotonated bond dissociation free energy difference between the catalysts and alcohols is the thermodynamic trigger for the PCET process. This study provides a reasonable explanation for the alcohol oxidation reaction, which is beneficial for designing biomass conversion systems.

Machine learning models trained on mechanistic datasets created using expert reaction templates demonstrate the ability to successfully predict known reaction mechanisms. This study illustrates how such mechanistic models can explain how reaction outcomes are produced, recapitulate the roles of catalysts and reagents, and suggest potential side products and impurities.

Abstract

Mechanistic understanding of organic reactions can facilitate reaction development, impurity prediction, and in principle, reaction discovery. While several machine learning models have sought to address the task of predicting reaction products, their extension to predicting reaction mechanisms has been impeded by the lack of a corresponding mechanistic dataset. In this study, we construct such a dataset by imputing intermediates between experimentally reported reactants and products using expert reaction templates and train several machine learning models on the resulting dataset of 5,184,184 elementary steps. We explore the performance and capabilities of these models, focusing on their ability to predict reaction pathways and recapitulate the roles of catalysts and reagents. Additionally, we demonstrate the potential of mechanistic models in predicting impurities, often overlooked by conventional models. We conclude by evaluating the generalizability of mechanistic models to new reaction types, revealing challenges related to dataset diversity, consecutive predictions, and violations of atom conservation.

A novel green solvent, γ-valerolactone (GVL), efficiently facilitates the photocatalytic activation of C−H bonds in benzylic compounds. Mechanistic studies reveal that GVL′s high dielectric constant (ϵ) increases the driving force (−ΔG), and its large refractive index (n) reduces reorganization energy (λ), collectively reducing the reaction barrier (ΔG ^≠). This research advances the overlooked solvent effects in semiconductor photocatalysis.

Abstract

Solvents can significantly influence chemical reactions in condensed phases. Their critical properties are increasingly recognized in various research domains such as organic synthesis and biomass valorization. However, in semiconductor photocatalysis, solvents are primarily viewed as mediums for dissolving and diffusing substances, with their potential beneficial effects on photocatalytic conversions often overlooked. Additionally, common photocatalysis solvents like acetonitrile (ACN) pose serious safety and environmental concerns. In this study, we demonstrate that novel and safe green solvents, such as γ-valerolactone (GVL), can significantly enhance the performance of semiconductor photocatalysis for C−H bond activation. Non-specific solvent-solute interactions are the primary contributors to increased photocatalytic activity in the self-coupling of benzylic compounds. Specifically, GVL′s large dielectric constant and high refractive index lower the energy barrier for the rate-determining C−H bond activation step, facilitating a faster coupling reaction. The versatility of GVL is further demonstrated in reactions with multiple reagents and in various oxidation and reduction photocatalytic systems beyond classic C−H bond activation. This work not only pioneers the use of green solvents but also provides comprehensive insights for proper solvent selection in semiconductor photocatalysis.

Early-career chemists highlight the challenges and opportunities for their generation in working towards a sustainable future. They showcase how contributions can be made towards more sustainable education, outreach to society and policymakers, better research culture, equity, and better accessibility to science, particularly in scientific publishing.

Abstract

The concepts of sustainability and sustainable chemistry have attracted increasing attention in recent years, being of great importance to the younger generation. In this Viewpoint Article, we share how early-career chemists can contribute to the sustainable transformation of their discipline. We identify ways in which they can engage to catalyse action for change. This article does not attempt to answer questions about the most promising or pressing areas driving research and chemical innovation in the context of sustainability. Instead, we want to inspire and engage early-career chemists in pursuing sustainable actions by showcasing opportunities in education, outreach and policymaking, research culture and publishing, while highlighting existing challenges and the complexity of the topic. We want to empower early-career chemists by providing resources and ideas for engagement for a sustainable future globally. While the article focuses on students and early-career chemists, it provides insights to further stimulate the engagement of scientists from diverse backgrounds.

This Minireview examines a selection of case studies that showcase distinctive and enabling electrochemical approaches that have allowed for the generation and reaction of carbocation intermediates under mild conditions. Particular emphasis is placed on the progress that has been made in this area of organic synthesis and polymer chemistry over the past decade.

Abstract

This Minireview examines a selection of case studies that showcase distinctive and enabling electrochemical approaches that have allowed for the generation and reaction of carbocation intermediates under mild conditions. Particular emphasis is placed on the progress that has been made in this area of organic synthesis and polymer chemistry over the past decade.

The controlled and beneficial degradation of a cyanoarene-based photocatalyst (PC) is accomplished. The pre-PC, tailored for rapid degradation, resulted in formation of an alkylated PC with proper redox potentials and an extended triplet lifetime. This facilitates the efficient catalysis of halogen-atom-transfer (XAT) reactions of alkyl halides.

Abstract

We present the strategic design of donor-acceptor cyanoarene-based photocatalysts (PCs) aiming to augment beneficial PC degradation for halogen atom transfer (XAT)-induced dehalogenation reactions. Our investigation reveals a competitive nature between the catalytic cycle and the degradation pathway, with the degradation becoming dominant, particularly for less activated alkyl halides. The degradation behavior of PCs significantly impacts the efficiency of the XAT process, leading to exploration into manipulating the degradation behavior in a desirable direction. Recognizing the variation in the nature and rate of PC degradation, as well as its influence on the reaction across the range of PC structures, we carefully engineered the PCs to develop a pre-catalyst, named 3DP-DCDP-IPN. This pre-catalyst undergoes rapid degradation into an active form, 3DP-DCDP-Me-BN, exhibited an enhanced reducing ability in its radical anion form to induce better PC regeneration and consequently effectively catalyzes the XAT reaction, even with a challenging substrate.

Chemistry is vital for society , but its practices must align with sustainable development. While attention often focuses on individual pillars—environment, economy, or equity—true sustainability requires alignment across all three. The cover image depicts a sustainability compass, symbolizing the integration of diverse principles into a unified set of triple E priorities proposed by Javier Pérez-Ramírez et al. in their Scientific Perspective (e202318676) to guide efforts in the chemical sciences.

A range of d2-labeled alkanes can be synthesized via nickel-catalyzed hydrodeuterioalkylation of deuterated alkyl thianthrenium (TT) salts with unactivated alkenes. The deuterated alkyl reagents effectively integrate deuterium from D₂O via pH-dependent hydrogen isotope exchange (HIE). Our method enables high deuterium incorporation and precise control over insertion site, essential for drug synthesis.

Abstract

Isotopically labeled alkanes play a crucial role in organic and pharmaceutical chemistry. While some deuterated methylating agents are readily available, the limited accessibility of other deuteroalkyl reagents has hindered the synthesis of corresponding products. In this study, we introduce a nickel-catalyzed system that facilitates the synthesis of various deuterium-labeled alkanes through the hydrodeuteroalkylation of d2-labeled alkyl TT salts with unactivated alkenes. Diverging from traditional deuterated alkyl reagents, alkyl thianthrenium (TT) salts can effectively and selectively introduce deuterium at α position of alkyl chains using D₂O as the deuterium source via a single-step pH-dependent hydrogen isotope exchange (HIE). Our method allows for high deuterium incorporation, and offers precise control over the site of deuterium insertion within an alkyl chain. This technique proves to be invaluable for the synthesis of various deuterium-labeled compounds, especially those of pharmaceutical relevance.