Robert Pollice

#RobSelects paper of the week #ScienceMagazine: Intramolecular peptide-catalyst-controlled stereoselective Michael addition between the enamine of an aldehyde and a ketovinylester. #catalysis https://doi.org/10.1126/science.aec8992

#RobSelects paper of the week #ScienceMagazine: Single-molecule vibrational spectroscopy via tunable femtosecond infrared excitation and cryogenic ultra-high vacuum scanning tunneling microscopy. #physchem https://doi.org/10.1126/science.adz6643

#RobSelects paper of the week #ChemicalScience: Electrochemical one-pot method for rhodium(II)-catalyzed cyclopropanation via in situ oxidation of tert-butyl hydrazones to diazo compounds. #catalysis https://doi.org/10.1039/D5SC08940A

#RobSelects paper of the week #ACSCentSci: Systematic statistical analysis of 66,000 organic reactions from high-throughput experiments representative of pharmaceutical drug discovery. #orgchem https://doi.org/10.1021/acscentsci.5c02031

#RobSelects paper of the week #J_A_C_S: Excited-state triplet thiazole-2-thione biradicals as radical covalent catalysts for skeletal reorganization of N-sulfonyl vinylaziridines. #catalysis https://doi.org/10.1021/jacs.5c20284

#RobSelects paper of the week #J_A_C_S: Iridium-catalyzed reduction of beta-boryl amides triggers stereospecific cyclization to form aminocyclopropanes. #catalysis https://doi.org/10.1021/jacs.5c21144

#RobSelects paper of the week #ACSCatalysis: Nickel-catalyzed dehydroxylative cross-coupling of 1-substituted cyclopropanols and boronic acids via gamma-carbon-carbon activation. #catalysis https://doi.org/10.1021/acscatal.5c07422

#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

Are you interested in any aspect of molecular chemistry? Come and joins us for the first Groningen Molecular Chemistry Symposium (GroMoChem): https://gromochem.web.rug.nl/ We have an excellent line-up of speakers, covering a broad range of topics. Additionally, if you are within 4 years of […]

#RobSelects paper of the week #ChemicalScience: Real-space analysis and visualization of steric repulsion based on the Pauli kinetic energy excess. #compchem https://doi.org/10.1039/D5SC07952G

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: Photochemical isomerization of N-substituted pyrazoles to imidazoles. #orgchem https://doi.org/10.26434/chemrxiv-2026-68vcj

#RobSelects paper of the week #J_A_C_S: Comprehensive investigation of regio- and stereoselectivity of iridium-catalyzed carbon-hydrogen borylation of small substituted aliphatic carbocycles. #catalysis https://doi.org/10.1021/jacs.5c18839

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.

#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

#RobSelects paper of the week #ACSCatalysis: Accelerating automated reaction pathway exploration through the incorporation of ontological constraints and structural reasoning. #compchem https://doi.org/10.1021/acscatal.5c06298

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: Utilizing simulated descriptors from catalytically relevant structures for enantioselectivity prediction and optimization. #catalysis https://doi.org/10.26434/chemrxiv-2025-f5ddv-v2

#RobSelects paper of the week #J_A_C_S: Enantioselective cycloaddition of cyclopropanes across alkynes via diamine phosphine oxide-ligated nickel-aluminum bimetallic catalysts. #catalysis https://doi.org/10.1021/jacs.5c18087

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: 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

#RobSelects paper of the week #J_A_C_S: Pd-Catalyzed Buchwald-Hartwig amination with a mild and solube potassium alkyl carboxylate salt and a phosphorinane ligand. #catalysis https://doi.org/10.1021/jacs.5c07790

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.

#RobSelects preprint of the week #ChemRxiv: Photocatalytic decarboxylative trifluoroethylation of aliphatic carboxylic acids. #catalysis https://doi.org/10.26434/chemrxiv-2025-9jfwq

#RobSelects paper of the week #J_A_C_S: Synthesis of substituted cycloheptatrienes through insertion of a chromium fluorocarbyne into the adduct of a nucleophile and benzene. #inorgchem https://doi.org/10.1021/jacs.5c16875

Metallaphotoredox Iron Catalysis Enables Direct Carbonyl-to-Carbene Conversion Metallocarbenes are powerful intermediates for constructing complex molecular architectures, yet their generation typically relies on hazardous diazo or ylide precursors. We report a photocatalytic strategy for direct carbene formation from unmodified carbonyl compounds using a low-valent iron system. The reaction proceeds through net oxidative addition of Fe(I) into the carbonyl bond, followed by α-protonation and α-elimination to generate a reactive Fe–carbene intermediate. This platform enables stereospecific cyclopropanation of diverse alkenes—including complex, drug-like, and peptide-derived substrates—under mild conditions, delivering highly functionalized, sp³-rich products. Mechanistic studies reveal direct carbonyl activation rather than free radical intermediacy, with a concerted–asynchronous olefin insertion pathway. These findings establish a general strategy for carbonyl-to-carbene conversion, expanding the scope of base-metal catalysis and providing a blueprint for redefining carbonyl activation in synthetic chemistry.

#RobSelects preprint of the week #ChemRxiv: Metallaphotoredox iron-catalyzed cyclopropanation of alkenes with both aldehydes and ketones through iron-carbene generation. #catalysis https://doi.org/10.26434/chemrxiv-2025-lsdnn

#RobSelects paper of the week #J_A_C_S: Frustrated Lewis pair catalyst for coupling formate esters with vinyl and aryl organoboranes. #catalysis https://doi.org/10.1021/jacs.5c17878

Reaction Database for Catalysis and Organometallics via Freely Available Supplementary Information Chemical reaction databases have become core scientific infrastructure. Most prominent datasets focus on or- ganic reactions, or only include reactants and product rather than full reaction pathways, leaving organometallic chemistry particularly underserved despite its centrality to homogeneous catalysis. This gap limits the develop- ment of machine learning models for organometallic reactions and limits applications in mechanism discovery, selectivity prediction, and catalyst design. This work introduces an open, reaction-centric resource derived from XXX SI across 50+ journals from seven publishers through 2025 using the Gold-DIGR (Gold-Data Integration for Generalized Reactions) workflow. Reported organometallic reactions are aggregated and reaction properties extracted or recalculated, including reactant, product, and transition-state geometries, intrinsic reaction coor- dinate (IRC) traces, reaction classes, and ligand/metal descriptors (coordination, valence-electron counts, bond orders). Bond–electron matrices enable electron-flow analyses along reaction coordinates, visualized as Sankey diagrams connecting local electron rearrangements to class-level patterns. The resulting corpus spans canoni- cal classes—oxidative addition, reductive elimination, migratory insertion, β-hydride elimination, C–H activation, transmetalation, and σ-bond metathesis—enabling quantitative mechanistic analyses at scale. As a demonstration of the meta-analyses enabled by this broad-based data generation, the relationship between bond-breaking/forming events and the transition states are studied to investigate concerted versus sequential scenarios. Class-specific tim- ing asymmetries emerge, with reductive elimination and β-atom elimination events skewed pre-transition-state, oxidative addition and migratory insertion skewed post-transition-state, and transmetallation showing the broad- est dispersion. By releasing both tooling and data, this work provides a foundation for mechanistic benchmarking and data-driven catalyst design.

#RobSelects preprint of the week #ChemRxiv: Extracting organometallic reactivity data from openly available electronic supplementary information documents. #cheminf https://doi.org/10.26434/chemrxiv-2025-ccgfs

#RobSelects paper of the week #ChemicalScience: Computational design of a carbon allotrope exhibiting altermagnetic semiconductor properties. #matchem https://doi.org/10.1039/D5SC05194K

OMNI-P2x: A Universal Neural Network Potential for Excited-State Simulations Photo-active molecular systems play an essential role in modern science and technology, finding applications in solar cells, organic light-emitting diodes (OLEDs), reaction catalysis, photodynamic therapy, and beyond. The rational design of photo-responsive molecules requires understanding of the photophysical and photochemical processes underlying their operation. This understanding can be gained via the first-principles quantum-mechanical (QM) calculations which, however, turn out prohibitively expensive for high-throughput investigations. To break through this limitation, here we introduce OMNI-P2x: the first universal neural network potential for molecular excited and ground electronic states. OMNI-P2x can be used, directly or after fine-tuning, in place of quantum-mechanical methods to perform a wide range of photophysical and photochemical simulations. OMNI-P2x is approaching the accuracy of time-dependent density functional theory (TD-DFT) methods at a fraction of the cost. Remarkably, this universal potential is more accurate and faster than established semiempirical QM methods, marking the watershed moment in theoretical method development for excited-state simulations. Here, we demonstrate its use in UV/Vis absorption spectroscopy, in real-time photodynamical simulations, and in the rational design of the visible-light-absorbing azobenzene systems.

#RobSelects preprint of the week #ChemRxiv: Universal neural network potential for modeling molecular excited states at the accuracy of TD-DFT approaches. #compchem https://doi.org/10.26434/chemrxiv-2025-j207x-v2

#RobSelects paper of the week #J_A_C_S: Photochemical generation of carbon radicals from organoboron starting materials enabled via catalyst-borate complexes. #catalysis https://doi.org/10.1021/jacs.5c17266

Accurate Density Functional Theory for Non-Covalent Interactions in Charged Systems Accurately modeling non-covalent interactions (NCIs) involving charged systems remains an outstanding challenge in Density Functional Theory (DFT), with implications across natural and life sciences, engineering, e.g., in biochemistry, catalysis, and materials science. For these interactions, the interplay between electrostatics, polarization, and dispersion leads to systematic errors of up to tens of kcal/mol in standard dispersion-enhanced DFT methods. We solve this problem by introducing (r2SCAN+MBD)@HF, a DFT method without empirically fitted parameters that combines the r2SCAN functional and many-body dispersion, both evaluated on Hartree-Fock densities. We show that the unique synergy of these three components enables balanced treatment of short- and long-range correlation, which is crucial for accurate description of NCIs involving charged systems. Evaluations on standard benchmarks and a new Metal Ion Protein Clusters dataset introduced here show that (r2SCAN+MBD)@HF significantly improves accuracy for NCIs involving charged systems while maintaining robust performance for neutral systems. Given the ubiquity of such interactions, (r2SCAN+MBD)@HF is broadly applicable from biochemistry and materials science, including for generating high-quality data to train machine-learning force fields.

#RobSelects preprint of the week #ChemRxiv: Modeling non-covalent interactions in both neutral and charged systems with the r²SCAN functional plus many-body dispersion evaluated on Hartree-Fock electron densities. #compchem https://doi.org/10.26434/chemrxiv-2025-jx112-v2

#RobSelects paper of the week #angew_chem: Mapping the reactivities of 7-electron-4-center neutral radicals via quantum chemistry and data science. #inorgchem https://doi.org/10.1002/anie.202511509

Solvated Electron-Driven Hydroamination of Olefins We report a transition metal-free method for the intermolecular hydroamination of olefins using solvated electrons, generated in situ from granulated lithium under sonication in 2-methyltetrahydrofuran (2-MeTHF). This additive-free protocol enables rapid formation of mixed secondary and tertiary amines under ambient conditions with broad substrate scope and functional group tolerance. Mechanistic studies support an SET and HAT pathway, with lithium amide intermediates acting as both reductants and nucleophiles. The method offers excellent atom economy, sustainability, and synthetic utility, exemplified by the selective synthesis of the racemic version of the pharmaceutical benzphetamine in high yield.

#RobSelects preprint of the week #ChemRxiv: Intermolecular alkene hydroamination promoted by single electron reduction. #orgchem https://doi.org/10.26434/chemrxiv-2025-fblsl

#RobSelects paper of the week #J_A_C_S: Deriving a model for estimating rates of C-X reductive elimination from palladium(II) derived via causal inference. #catalysis https://doi.org/10.1021/jacs.5c06124