LG

In this study, we integrate machine learning (ML) and large language models (LLMs) to accelerate the exploration of electrochemical C−H oxidation reactions. A rapid screening platform is developed for experimental screening, while LLMs assist in literature mining and generate Python code to train ML models for reactivity prediction and synthesis optimization. This human-AI collaboration enables synthetic chemists to streamline discovery processes and optimize reaction conditions efficiently.

Abstract

Electrochemical C−H oxidation reactions offer a sustainable route to functionalize hydrocarbons, yet identifying suitable substrates and optimizing synthesis remain challenging. Here, we report an integrated approach combining machine learning and large language models to streamline the exploration of electrochemical C−H oxidation reactions. Utilizing a batch rapid screening electrochemical platform, we evaluated a wide range of reactions, initially classifying substrates by their reactivity, while LLMs text-mined literature data to augment the training set. The resulting ML models for reactivity prediction achieved high accuracy (>90 %) and enabled virtual screening of a large set of commercially available molecules. To optimize reaction conditions for selected substrates, LLMs were prompted to generate code that iteratively improved yields. This human-AI collaboration proved effective, efficiently identifying high-yield conditions for 8 drug-like substances or intermediates. Notably, we benchmarked the accuracy and reliability of 12 different LLMs–including LLaMA series, Claude series, OpenAI o1, and GPT-4-on code generation and function calling related to ML based on natural language prompts given by chemists to showcase potentials for accelerating research across four diverse tasks. In addition, we collected an experimental benchmark dataset comprising 1071 reaction conditions and yields for electrochemical C−H oxidation reactions.

Methods enabling direct C-H alkylation of heterocycles are of fundamental importance in the late-stage modification of natural products, bioactive molecules, and medicinally relevant compounds. However, there is a scarcity of a general strategy for the direct C-H alkylation of a variety of heterocycles using commercially available alkyl surrogates. We report an operationally simple palladium-catalyzed direct C-H alkylation of heterocycles using alkyl halides under the visible light irradiation with good scalability and functional group tolerance. Our studies suggest that the photoinduced alkylation proceeds through cascade of events comprising, site-selective alkyl radical addition, base-assisted deprotonation, and oxidation. A combination of experiments and computations was employed for the generalization of this strategy, which was successfully translated towards the modification of natural products and pharmaceuticals.

This novel platform for automated electrochemical synthesis of compound libraries in flow enabled the C−X arylation of>30 aryl halide scaffolds in the presence of diverse amines (including sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid electrode passivation.

Abstract

Etherification and amination of aryl halide scaffolds are commonly used reactions in parallel medicinal chemistry to rapidly scan structure–activity relationships with abundant building blocks. Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale-transferable workflows for electrochemical compound library synthesis. Herein we describe a platform for automated electrochemical synthesis of C−X arylation (X=NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across>30 aryl halide scaffolds, diverse amines (including electron-deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolyte and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C−X arylation compound libraries using flow electrochemistry.

Despite the long and rich history of photoinduced direct hydrogen atom transfer (d-HAT) catalysis, the primary structures of existing catalysts rely on molecular entities containing oxo groups, particularly with aromatic ketones and inorganic polyoxometalates. Here, we disclose zwitterionic acridinium amidate as a photoreactive nitrogen-centered radical precursors, which exhibit prominent reactivity to cleave aliphatic C−H bonds.

Abstract

The development of small organic molecules that can convert light energy into chemical energy to directly promote molecular transformation is of fundamental importance in chemical science. Herein, we report a zwitterionic acridinium amidate as a catalyst for the direct functionalization of aliphatic C−H bonds. This organic zwitterion absorbs visible light to generate the corresponding amidyl radical in the form of excited-state triplet diradical with prominent reactivity for hydrogen atom transfer to facilitate C−H alkylation with a high turnover number. The experimental and theoretical investigations revealed that the noncovalent interactions between the anionic amidate nitrogen and a pertinent hydrogen-bond donor, such as hexafluoroisopropanol, are crucial for ensuring the efficient generation of catalytically active species, thereby fully eliciting the distinct reactivity of the acridinium amidate as a photoinduced direct hydrogen atom transfer catalyst.

Weakly-coordinating anions based on Si are reported. These anions support a variety of cations relevant to organometallic and catalytic applications. The methyl-substituted anion has a wide electrochemical window and supports reversible Mg electrochemistry.

Abstract

Weakly-coordinating anions (WCAs) are employed in a wide range of applications, but limitations remain, including high reactivity, limited redox window, complicated synthesis, high cost, low solublity, and low structural tunabililty. Herein, we report a new class of WCA based on alkyl or aryl (R) substituted si licates bearing f luorinated pinacolate ligands, “[^R Si^F ₂₄ ]⁻”. Anions bearing a variety of R groups were prepared, enabling facile tuning of sterics and solubility. A range of cations employed in chemical reactivity has been supported by these anions, including ether-free alkali cations, Ag⁺, Ph₃C⁺, Fc⁺, [Ni^I(COD)₂]⁺. [Pd(dppe)(NCMe)Me]⁺ has been generated by salt metathesis or protonation of a metal-alkyl bond, showcasing the ability of the [^RSi^F ₂₄]⁻ anions to support applications in coordination chemistry and catalysis. Electrochemical studies on the [Bu₄N]⁺ variant show an exceptionally wide stability window for the [^MeSi^F ₂₄]⁻ anion of 7.5 V in MeCN. CV experiments demonstrate reversible Mg deposition and stripping.

An iron(II)-catalyzed α-selective C−H amination of N-heterocycles is reported. It employs the N-heterocycle as the limiting reagent and presumably involves the formation of a reactive Fe-nitrene/imidyl radical species. This operationally simple method is amenable to the late-stage functionalization of natural products and APIs.

Abstract

Nitrogen-heterocycles are privileged structures in both marketed drugs and natural products. On the other hand, C−H amination reactions furnish unconventional and straightforward approaches for the construction of C−N bonds. Yet, most of the known methods rely on precious metal catalysts. Herein we report a site-selective intermolecular C(sp³)−H amination of N-heterocycles, catalyzed by inexpensive FeCl_2, which allows the functionalization of a wide range of pharmaceutically relevant cyclic amines. The C−H amination occurs site-selectively in α-position to the nitrogen atom, even when weaker C−H bonds are present, and furnishes Troc-protected aminals or amidines. The method employs the N-heterocycle as limiting reagent and is applicable to the late-stage functionalization of complex molecules. Its synthetic potential was further illustrated through the derivatization of α-aminated products and the application to a concise total synthesis of the reported structure for senobtusin. Mechanistic studies allowed to propose a plausible reaction mechanism involving a turnover-limiting Fe-nitrene generation followed by fast H atom transfer and radical rebound.

Cathodic reduction of 2-cinnamyl-substituted nitroarenes under constant current electrolysis affords a broad array of substituted quinoline N-oxides through a mechanism involving a 1,5-hydrogen atom abstraction.

Abstract

Electrochemical reduction of 2-allyl-substituted nitroarenes using a simple, undivided electrochemical cell with non-precious electrodes to generate nitroarene radical anions was developed. The nitroarene radical anion intermediates participate in 1,5-hydrogen atom transfer reactions to construct quinoline N-oxides bearing aryl-, heteroaryl-, alkenyl-, benzyl-, sulfonyl-, or carboxyl groups.

A direct anodic oxidative coupling process for α-heteroarylation using ferrocene-assisted asymmetric nickel electrocatalysis has been developed, enabling the synthesis of a diverse range of chiral heteroaromatic carbonyl compounds with high enantioselectivity and functional group tolerance, which can be applied to the synthesis of valuable frameworks like (−)-COX-2 inhibitor, (+)-acremoauxin A, and (+)-pemedolac.

Abstract

Oxidative cross-dehydrogenative C−H/C−H functionalizations represent an exemplary approach for synthesizing carbonyl compounds via α-heteroarylation. Here we present the development of a direct anodic oxidative coupling process between 2-acylimidazoles and divergent heterocyclic systems including indole, pyrrole, and furan, facilitated by ferrocene-assisted asymmetric nickel electrocatalysis with high levels of enantioselectivity. Mechanistic investigations indicate that the reaction initially involves the formation of a chiral Ni-bound α-carbonyl radical, which is then captured by the heteroarene radical cation via intermolecular stereoselective radical/radical cation coupling. The mild, scalable, and robust reaction conditions allow for a broad substrate scope and excellent functional group tolerance, enabling access to a wide range of chiral hetero-compounds. The consequential α-heteroaromatic carbonyl products can potentially be transformed into a plethora of synthetically valuable frameworks, as exemplified by their application in the asymmetric total synthesis of (−)-COX-2 inhibitor, (+)-acremoauxin A, and (+)-pemedolac.

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.

Reductive coupling of perimidine based N-heterocyclic germylene and 4-iodophenyl isocyanide afforded a highly colored and luminescent bis-spirogerma species with unprecedented simultaneous C−N and C−C coupling. The compound is also successfully integrated as a hole transport material in a solar cell.

Abstract

We have demonstrated a unique reductive coupling of 4-iodophenyl isocyanide, facilitated by a perimidine-based N-heterocyclic germylene (NHGe), which yields a bis-spirogerma compound featuring simultaneous C−C and C−N bond formation. This reaction, which leads to the oxidation of germanium from +2 to +4, represents a significant departure from previously documented isocyanide-germylene interactions. The product exhibits extensive conjugation across its bicyclic C₄Ge₂N₂ framework, conferring distinct photophysical properties, including prominent orange luminescence in both solution and solid states. The photophysical properties are supported by the TD-DFT calculations confirming an n→π* transition. The potential application of this compound in optoelectronic devices, particularly as a hole transport layer in PbS quantum dot solar cells, is also explored, with promising preliminary results.