Tomas Horsten

Electrocatalytic hydrogenation (ECH) of furfural under acidic conditions is examined using Pd/C and Pd-TiON_x/GO catalysts. Differences in redox behavior and adsorption properties are observed. Pd/C exhibits higher selectivity toward furfuryl alcohol, while Pd-TiON_x/GO favors 2-methylfuran formation. Metal–support interactions and surface properties are shown to play a key role in tuning ECH activity and selectivity.

Electrocatalytic hydrogenation (ECH) offers a sustainable alternative to conventional hydrogenation of biomass-derived compounds by using cathodic potential instead of heat and molecular hydrogen. This study explores the ECH of furfural under acidic conditions, focusing on how metal–support interactions influence the performance of Pd-based catalysts. Two systems are compared: Pd on carbon (Pd/C) and Pd supported on titanium oxynitride-graphene oxide (Pd–TiONx/GO). Pd–TiONx/GO exhibits lower oxophilicity and a higher proton adsorption tendency than Pd/C. Additionally, its surface shows a more negative charge, indicated by a cathodic shift (≈10 mV) in the potential of zero total charge measured via N₂O reduction. These differences significantly affect catalytic behavior. While Pd/C shows roughly twice the activity for converting furfural to furfuryl alcohol (FA), Pd–TiONx/GO is over 100 times more active in producing 2-methylfuran (2-MF) and also enhances the competitive hydrogen evolution reaction. This suggests Pd–TiONx/GO has lower surface coverage by furfural and FA, allowing for more hydrogen adsorption and favouring 2-MF formation. Overall, the study demonstrates that Pd's electrosorptive and catalytic properties can be tuned via electronic effects from the TiONx support, enabling selective manipulation of ECH pathways.

An electrochemical approach has been developed for late-stage direct trideuteromethyl incorporation into thioethers by using stoichiometric methanol-d ₄ as the trideuteromethyl isotopic source. Mechanistic studies showed that the sulfonium salt generated in situ is the key intermediate. Control experiments revealed that in situ generation of the sulfonium and its subsequent reduction at the cathode is the key to alkyl displacement and precise late-stage trideuteration.

Abstract

Deuterated compounds exhibit significant pharmacokinetic advantages and have been widely applied in drug discovery. Trideuteromethyl-containing compounds represent a substantial portion of both approved deuterated drugs and those in development. Traditional approaches to incorporate trideuterated methyl group with trideuterated methyl sources (such as iodomethane-d ₃, dimethyl sulfate-d ₆) require preactivated synthetic precursor, limiting the application for the late-stage trideuteromethyl group incorporation of pharmaceutical molecules. Herein, we develop an electrochemical approach for late-stage trideuteromethyl incorporation of thioether by using stoichiometric methanol-d ₄ as the trideuteromethyl isotopic source via a sulfide alkyl displacement. This protocol features operational simplicity, selectivity, and scalability, enabling direct alkyl modification of various aryl alkyl sulfides as well as gram-scale production of trideuteromethyl drugs without the need for synthetic precursors. Mechanistic studies show that the in-situ generated sulfonium salt was the key intermediate. A series of control experiments reveals that alkanes as the departing moiety are the key to alkyl displacement and precise late-stage trideuteration.

The intensification of electrochemical hydrocarboxylation reaction employing a spinning cylinder electrode reactor is presented. The optimized system provides high reaction scale for the synthesis of valuable compounds, incorporating CO₂ gas in organic molecules in an efficient way.

There is an increasing attention in developing reactions that can incorporate CO₂ into organic molecules. In this context, electrochemistry offers a sustainable and mild approach to utilize this valuable yet elusive C1 building block in a scalable fashion. Herein, the intensification of the electrochemical hydrocarboxylation of activated alkenes is presented. The study covers the evaluation of critical chemical and electrochemical parameters to maximize the efficiency of the process in standardized small-scale batch cells, followed by the transfer to a spinning cylinder electrochemical reactor. Leveraging the enhanced mass transfer of this reactor design, the reaction can be further optimized, leading to a more efficient process. After validating the transformation across different substrates, the regioselective addition of CO₂ is further improved by tuning the current density of the process. Finally, a scale-up in recirculation mode is performed, achieving a productivity of 55 g day⁻¹ and demonstrating its potential for the efficient and scalable utilization of the electrochemical hydrocarboxylation reaction.

Nature, Published online: 09 June 2025; doi:10.1038/d41586-025-01775-9

We present a photochemical strategy for transforming 1H- and 2H-indazoles into benzimidazoles, enabling heteroaromatic interconversion under mild conditions. This approach, grounded in a two-step mechanism of excited-state tautomerization and photochemical rearrangement, offers broad scope, high yields, and functional group tolerance, expanding the diversity of heterocycle-based libraries for fragment-based drug discovery.

Abstract

Fragment-based drug discovery relies on preparing diverse libraries of advanced building blocks, often incorporating heteroaromatic motifs. Altering the core of heteroaromatics to maximize library diversity typically requires de novo synthesis of each system. This can be often challenging when specific substitution patterns are needed. Here, we introduce a photochemical strategy for the direct permutation of 1H- and 2H-indazoles into benzimidazoles. This transformation exploits the distinct photochemical properties of these heteroaromatics and proceeds under mild conditions. Through systematic experimental and computational studies, we have elucidated a two-step mechanism involving excited-state tautomerization of 1H-indazoles, followed by photochemical rearrangement of the resulting 2H-isomers. This approach demonstrates broad substrate scope, high yields, and compatibility with a variety of functional groups. This method can expand the structural diversity of heterocycle-based libraries through the concept of chemical permutation for heteroaromatic interconversion.

Herein, we report the use of bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane (DABAl-Me₃) as practical source of radicals for the introduction of valuable methyl groups to aryl bromides via a Nickel/metallaphotocatalytic cross coupling strategy.

Abstract

We report a metallaphotocatalytic strategy for the selective methylation of (hetero)aryl bromides via nickel-catalyzed cross-coupling with bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane (DABAl-Me₃), as a commercially available, air-stable, and non-pyrophoric aluminum-based reagent. The method enables a fast, robust, and scalable methylation protocol that broadly accommodates various functional groups while preventing protodehalogenation. Mechanistic studies confirm the unprecedented generation of methyl radicals from an organo-aluminum precursor under photoredox conditions, bypassing the limitations of conventional two-electron pathways. This work expands the toolbox of practical radical precursors and provides a streamlined approach for selective C(sp²)─CH₃ bond formation.

This study analyzes the electrochemical reduction pathways of 5-hydroxymethylfurfural (HMF) on Cu electrodes. Our findings show that 2,5-bis(hydroxymethyl)furan (BHMF) and 5-methylfurfural (5-MF) occurs through direct HMF reduction. Additionally, 5-methylfurfural alcohol (MFA) can be produced either from HMF or 5-MF, while 2,5-dimethylfuran is derived from 5-MF as intermediate.

The electroreduction of 5-hydroxymethylfurfural (HMF) offers promising opportunities for the synthesis of valuable chemical precursors. However, achieving high selectivity in this process remains challenging due to the complexity of the reaction mechanisms involved. Here, this study employs different electrochemical techniques to analyze each of the HMF electroreduction pathways. These findings demonstrate that the primary products of HMF electroreduction are 2,5-bis(hydroxymethyl)furan (BHMF) and 5-methylfurfural alcohol (MFA), with lower formation of 5-methylfurfural (5-MF) and 2,5-dimethylfuran. This study identifies a significant competition between hydrogen evolution reaction and the reduction of HMF and 5-MF that affect the faradaic efficiencies of the organic transformation. In contrast, BHMF and MFA display a reduced reactivity, behaving as terminal molecules. Through impedance analysis, it is possible to follow the reaction pathways by associating each reaction step with the changes observed in charge transfer and accumulation phenomena. These are key parameters for understanding the reaction mechanisms in the system as they allow to distinguish between adsorption, absorption and reaction of the organic molecules onto the electrode surface. This approach helps to accurately select the optimal potential for the reduction reactions. The results obtained in this study facilitate the design of efficient and selective electrocatalytic systems for biomass conversion.

Publication date: 1 July 2025

Source: Chemical Engineering Journal, Volume 515

Author(s): Zhenyu Bao, Chen Wang, Zhengyu Wang, Xinwen Bai, Yujuan Zhao, Xiaowei Shi, Lingxia Zheng

A straightforward two-step synthesis to bifunctional precursors of N-heterocyclic carbenes (NHCs) is developed. Based on this, a library of imidazolium-based NHCs, with a variety of hydrogen bond donor groups in the backbone is prepared. The utility of the bifunctional NHC ligands is demonstrated in transition metal catalysis with the resulting palladium(II) and copper(I) complexes.

Bifunctional N-heterocyclic carbenes (NHCs) with additional hydrogen bond donor groups in the backbone are important organocatalysts and ligands for transition metal complexes. Herein, a straightforward synthetic approach to a library of bifunctional imidazolium salts, precursors for the respective NHCs with amidine, squaramide, and (thio)urea moieties as hydrogen bond donors, is reported. The preparation of bifunctional palladium(II) and copper(I) NHC complexes and their application in catalysis is presented.

A two-step protocol is developed for the efficient oxidative degradation of Kraft lignin. This method utilizes a highly concentrated peroxodicarbonate solution at moderate temperatures, followed by thermal treatment, significantly enhancing monoaromatic yield up to 15.6 wt%. Cogenerated carbonates in this transformation represent the make-up chemical of pulping plants.

The oxidative degradation of technically relevant types of Kraft lignin is efficiently accomplished by a significantly improved two-step protocol. The key is the use of highly concentrated peroxodicarbonate solution which selectively oxidizes the lignin particles at moderate temperature which are thermally treated in a subsequent step. The liberation of low-molecular-weight phenols occurs when the oxidizer is already consumed enhancing the yield of target compounds strongly up to 15.6 wt%. Co-generated carbonates in this transformation represent the make-up chemical of pulping plants. This makes this approach suitable and attractive to be implemented as a bolt-on or integrated into the Kraft pulping process. The green metrics clearly indicate the sustainable and superior features of the method established.

We present a metal-free method for aromatic deuterium labeling via photoexcitation in deuterated HFIP. This approach leverages the enhanced basicity of excited-state aromatics to achieve selective hydrogen isotope exchange at challenging positions. Demonstrated on complex drug molecules, this efficient strategy provides a valuable tool for isotope labeling, with mechanistic insights confirmed by transient absorption spectroscopy.

Abstract

Isotope labeling, particularly with deuterium (²H), plays a critical role in drug discovery due to its ease of incorporation and its potential to switch unwanted metabolic transformations. Deuterium incorporation can enhance drug stability, affect pharmacokinetics, and alter metabolism pathways. Current deuterium labeling methods focus on hydrogen isotope exchange (HIE), and typically rely on the use of transition metal catalysis. Herein, we present a metal-free approach for aromatic HIE, utilizing photoexcitation in deuterated hexafluoroisopropanol (HFIP-d ₁). By exploiting the enhanced basicity of excited-state aromatics, this method achieves selective deuteration at positions often inaccessible by traditional methods. The approach is efficient and was demonstrated across a broad number of complex drug molecules. Transient absorption spectroscopy confirms the formation of deuterated arenium ions.