Robert Pollice#RobSelects preprint of the week #ChemRxiv: Integrating deep generative models into automated transition state discovery workflows. #aichem https://doi.org/10.26434/chemrxiv.15002135/v1
#RobSelects preprint of the week #ChemRxiv: Methylbutyl boronate salt as methylation reagent in Suzuki-Miyaura cross couplings. #catalysis https://doi.org/10.26434/chemrxiv.15001572/v1
TIB#ChemRxiv, der internationale Preprint-Server für die chemische Forschung, ist erfolgreich auf eine neue technische Plattform umgezogen. Was genau das bedeutet und welche Rolle wir als #TIB dabei haben, erfahrt ihr hier: https://www.tib.eu/de/aktuelles/detail/chemrxiv-auf-neuer-technischer-plattform
#RobSelects preprint of the week #ChemRxiv: Photochemical conversion of aryl azides into pyridines via triplet aryl nitrenes. #orgchem https://doi.org/10.26434/chemrxiv-2026-jn9zb
#RobSelects preprint of the week #ChemRxiv: Photochemical isomerization of N-substituted pyrazoles to imidazoles. #orgchem https://doi.org/10.26434/chemrxiv-2026-68vcj
A photochemical strategy for pyrazole to imidazole conversion
Heteroaromatic scaffolds are central to modern medicinal chemistry. Methods that can reconfigure the core heterocycle of a molecule while preserving its substitution pattern would greatly streamline analogue synthesis and bioisosteric replacement. Yet, direct heterocycle-to-heterocycle interconversions remain rare. Here we report a photochemical strategy that converts pyrazoles into imidazoles in a single step with broad functional-group tolerance and full retention of peripheral substitution. The reaction is effective across densely substituted and annulated systems and extends to pyrazolo[1,5-a]azines, a class of high-value heteroaromatics that have never previously been reconfigured. We show that selective photoexcitation of the pyrazole unit enables clean, predictable rearrangement even in the presence of competing absorption pathways. Mechanistic studies support an N–N bond homolysis pathway in which solvent-dependent conformational changes govern the reactivity of the ensuing biradical intermediates. This photochemical strategy is readily translated to continuous flow, confirming its potential for scalable applications. Overall, this work establishes a practical platform for direct core reconfiguration, providing modular access to imidazole analogues of pyrazoles that are otherwise difficult to prepare or very expensive.
#RobSelects preprint of the week #ChemRxiv: Designing a hemilabile bisphosphine ligand for sterically hindered nickel-catalyzed Suzuki-Miyaura cross couplings. #catalysis https://doi.org/10.26434/chemrxiv-2025-q7td5
DiploPhos: A Hemilabile Bisphosphine for Sterically Hindered Ni-Catalyzed Suzuki–Miyaura Couplings
Pharmaceutically relevant Suzuki–Miyaura cross-couplings (SMCs) often require designer phosphine ligands and palladium loadings above 1 mol% to couple Lewis basic, sterically congested substrates. Recent work has demonstrat-ed that nickel is an attractive alternative to palladium for facile SMCs, but further ligand development is required for Ni catalysis to rival Pd for more challenging couplings. We applied prior work on monophosphine ligand design for Ni to develop a bisphosphine, DiploPhos, that outperforms state-of-the-art ligands for Ni to achieve sterically hin-dered Ni SMCs. Catalyst speciation studies revealed the hemilabile nature of DiploPhos, which improves reactivity relative to stronger chelating ligands but also leads to the formation of less-active DiploPhos-bridged aggregates. Lew-is basic functionality (present on substrates or additives) was found to promote the disaggregation of these species and led to increased SMC yields. This observation is contrary to most other systems in which Lewis basic substrates inhibit Ni-catalyzed SMC reactions. Ligand exchange studies demonstrated that despite its hemilability, DiploPhos is more resistant to displacement by heterocycles than similar bisphosphines. Together, these properties led to best-in-class reactivity for sterically hindered, Lewis base-rich Ni SMCs.
Horacio Pérez-SánchezLooking forward to comparisons, experiences, and pointers to similar tools. #ComputationalChemistry #Enzymology #QMMM #MachineLearning #MolecularSimulation #MLforScience #ReactionMechanisms #DrugDiscovery #HPC #ChemRxiv 🧵 12/12
#RobSelects preprint of the week #ChemRxiv: Utilizing simulated descriptors from catalytically relevant structures for enantioselectivity prediction and optimization. #catalysis https://doi.org/10.26434/chemrxiv-2025-f5ddv-v2
Low-Cost Mechanism-Informed Features Enable Transferable Enantioselectivity Predictions from Sparse Data
Identifying a catalyst class to optimize the enantioselectivity of a new reaction, either involving a different combination of known substrate types or an entirely unfamiliar class of compounds, is a formidable challenge. Statistical models trained on a reported set of reactions can help predict out-of-sample transformations but often face two challenges: (1) only sparse data are available i.e., limited information on catalyst–substrate interactions, and (2) simple stereoelectronic parameters may fail to describe mechanistically complex transformations. Here we report a descriptor generation strategy that accounts for changes in the enantiodetermining step with catalyst or substrate identity, allowing us to model reactions involving distinct ligand and substrate types. As validating case studies, we collected data on enantioselective nickel-catalyzed C(sp3)-couplings and trained statistical models with features extracted from the transition states and intermediates involved in asymmetric induction. These models allow for the optimization of poorly performing examples reported in a substrate scope and are applicable to unseen ligands and reaction partners. This approach offers the opportunity to streamline catalyst and reaction development, quantitatively transferring knowledge learned on sparse data to novel chemical spaces.
#RobSelects preprint of the week #ChemRxiv: Three-step one-pot protocol for cycloaddition-cycloreversion metathesis of ketenes and nitroso benzene to form ketones and phenyl isocyanate. #catalysis https://doi.org/10.26434/chemrxiv-2025-b0fgk
C=C/N=O Metathesis Enables Oxidative Decarboxylation
Metathesis reactions proceeding through a (2+2) cycloaddition – (2+2) cycloreversion sequence are of great importance in synthetic chemistry. However, to date, this type of reactivity has only been demonstrated for a limited set of compatible sub-strate classes. We present herein the design and development of a novel reaction of this class, an iron (II)-catalyzed C=C/N=O metathesis, and its application to the mild oxidative decarboxylation of carboxylic acids. The reaction proceeds under air in a one-pot fashion, utilizing readily available, inexpensive reagents, and features an earth-abundant, environmentally benign iron catalyst. The reaction exhibits broad functional group tolerance, is efficiently scalable, and its late-stage applicability was showcased through the streamlined oxidative decarboxylation of 12 drug molecules. Divergent and convergent reactivity was demonstrated relying on the complementary C=C/O=N metathesis counterpart providing access to imines instead of ketones, and the method was extended to the synthesis of esters from α-aryloxy and α-alkoxy carboxylic acids. Results of preliminary mechanistic experiments, reaction profile analysis with ReactIR, and computational studies are presented to provide further insight into the transformation.
#RobSelects preprint of the week #ChemRxiv: Photocatalytic decarboxylative trifluoroethylation of aliphatic carboxylic acids. #catalysis https://doi.org/10.26434/chemrxiv-2025-9jfwq
A C₁-Homologative Trifluoromethylation: Light-Driven Decarboxylative Trifluoroethylation of Carboxylic Acids
The incorporation of fluorinated alkyl groups is a powerful strategy to fine-tune the physicochemical and biological properties of organic molecules. In particular, the trifluoroethyl (–CH₂CF₃) substituent offers a valuable C₁-homologated analogue of trifluoromethylated motifs, yet methods for its direct introduction at sp³-hybridized carbon centers remain scarce. Here we report a general and practical approach for the decarboxylative trifluoroethylation of aliphatic carboxylic acids under visible-light irradiation. The transformation proceeds via photoinduced generation of a carbon-centered radical that adds to a bench-stable sulfonyl hydrazone reagent derived from trifluoroacetaldehyde, followed by light-driven fragmentation to furnish the desired trifluoroethylated products. The reaction operates under mild conditions, exhibits broad substrate scope, including primary, secondary, and tertiary acids, and tolerates diverse functional groups. Conceptually, the process can be viewed as a C₁-homologative trifluoromethylation, offering a distinct retrosynthetic disconnection for the synthesis of trifluoroethyl-containing building blocks. Mechanistic studies combining experimental and computational analysis provide insight into the fragmentation behavior of the key alkylated sulfonyl hydrazide intermediate.