Transfer Learning-Enabled Ligand Prediction for Ni-Catalyzed Atroposelective Suzuki-Miyaura Cross-Coupling Based on Mechanistic Similarity: Leveraging Pd Knowledge for Ni Discovery.

The rational design of novel molecular catalysts often confronts challenges due to complex structure-performance relationships. Emerging data-driven approaches provide revolutionary solutions, yet the application of machine learning to new catalyst development inevitably faces a low-data regime with limited effective structure-performance modelings available. In this study, we present a transfer learning strategy to facilitate knowledge transfer from well-documented Pd catalysis to a novel, underexplored Ni system.

QM9star, two Million DFT-computed Equilibrium Structures for Ions and Radicals with Atomic Information.

Ions and radicals serve as key intermediates in molecular transformation, with their chemical properties being essential for understanding and predicting reaction reactivity and selectivity. In this data descriptor, we report a quantum chemical dataset named QM9star, comprising cations, anions, and radicals. This dataset is derived from the molecular structures of the QM9 dataset, created by removing terminal hydrogens followed by optimization using B3LYP-D3(BJ)/6-311 + G(d,p) level of density functional theory.

Post-Transition State Bifurcation Controls Torsional Selectivity in Radical Addition of Allenes.

Post-transition state bifurcation (PTSB) has received wide attention in the field of reaction mechanism research due to its role in producing nonstatistical reaction selectivity, which cannot be solely explained by transition state theory. Particularly, even subtle molecular motions such as bond torsion can precipitate PTSB, thereby significantly complicating the quantitative understanding of dynamic selectivity. In this work, we found that the radical addition of allenes is an elementary transformation that generally exhibits PTSB stereoselectivity, where a single radical addition transition state can lead to both Z- and E-allylic radicals via the post-transition state allylic single bond torsion.

Reaction performance prediction with an extrapolative and interpretable graph model based on chemical knowledge.

Accurate prediction of reactivity and selectivity provides the desired guideline for synthetic development. Due to the high-dimensional relationship between molecular structure and synthetic function, it is challenging to achieve the predictive modelling of synthetic transformation with the required extrapolative ability and chemical interpretability. To meet the gap between the rich domain knowledge of chemistry and the advanced molecular graph model, herein we report a knowledge-based graph model that embeds the digitalized steric and electronic information.

Data-driven design of new chiral carboxylic acid for construction of indoles with C-central and C-N axial chirality via cobalt catalysis.

Challenging enantio- and diastereoselective cobalt-catalyzed C-H alkylation has been realized by an innovative data-driven knowledge transfer strategy. Harnessing the statistics of a related transformation as the knowledge source, the designed machine learning (ML) model took advantage of delta learning and enabled accurate and extrapolative enantioselectivity predictions. Powered by the knowledge transfer model, the virtual screening of a broad scope of 360 chiral carboxylic acids led to the discovery of a new catalyst featuring an intriguing furyl moiety.

An Asynchronous Concerted Mechanism and Its Origin in Lewis Acid-Mediated Carbonyl-Olefin [2+2] Cycloaddition.

The concerted mechanism of thermal BBr -mediated [2+2] carbonyl-olefin cycloaddition is intriguing considering the conflict against the Woodward-Hoffmann rule. In this work, we report a mechanistic study of the titled reaction using density functional theory calculations. The concerted [2+2] cycloaddition mechanism is operative even for the truncated model system of 2-methyl-2-butene and butanone.

Unsymmetric N-heterocyclic carbene ligand enabled nickel-catalysed arylation of bulky primary and secondary amines.

The arylation of sterically hindered amines represents one of the long-standing challenges in synthetic chemistry. Herein, we report a highly efficient Ni-catalysed arylation of sterically hindered primary and secondary amines with aryl chlorides or phenol derivatives enabled by an unsymmetric N-heterocyclic carbene (NHC) ligand. The protocol provides general, efficient, and scalable access to various sterically demanding anilines in excellent yields under mild conditions.

Direct Incorporation of Dinitrogen into an Aliphatic C-H Bond.

The activation of dinitrogen (N) and direct incorporation of its N atom into C-H bonds to create aliphatic C-N compounds remains unresolved. Incompatible conditions between dinitrogen reduction and C-H functionalization make this process extremely challenging. Herein, we report the first example of dinitrogen insertion into an aliphatic C-H bond on the ligand scaffold of a 1,3-propane-bridged [NN]-type dititanium complex.

Exploring Spectrum-based Molecular Descriptors for Reaction Performance Prediction.

Despite the availability and accuracy of modern spectroscopic characterization, the utilization of spectral information in chemical machine learning is still primitive. Here, we report an optical character recognition-based automatic process to utilize spectral information as molecular descriptors, which directly transforms experimental spectrum images to readable vectors. We demonstrate its machine learning application in the reaction yield dataset of Pd-catalyzed Buchwald-Hartwig cross-coupling with aryl halides.

Identification of Alkoxy Radicals as Hydrogen Atom Transfer Agents in Ce-Catalyzed C-H Functionalization.

The intermediacy of alkoxy radicals in cerium-catalyzed C-H functionalization via H-atom abstraction has been unambiguously confirmed. Catalytically relevant Ce(IV)-alkoxide complexes have been synthesized and characterized by X-ray diffraction. Operando electron paramagnetic resonance and transient absorption spectroscopy experiments on isolated pentachloro Ce(IV) alkoxides identified alkoxy radicals as the sole heteroatom-centered radical species generated via ligand-to-metal charge transfer (LMCT) excitation.

Bridging Chemical Knowledge and Machine Learning for Performance Prediction of Organic Synthesis.

Recent years have witnessed a boom of machine learning (ML) applications in chemistry, which reveals the potential of data-driven prediction of synthesis performance. Digitalization and ML modelling are the key strategies to fully exploit the unique potential within the synergistic interplay between experimental data and the robust prediction of performance and selectivity. A series of exciting studies have demonstrated the importance of chemical knowledge implementation in ML, which improves the model's capability for making predictions that are challenging and often go beyond the abilities of human beings.

(-Bu)NBr-Promoted N Splitting to Molybdenum Nitride.

Splitting of N via six-electron reduction and further functionalization to value-added products is one of the most important and challenging chemical transformations in N fixation. However, most N splitting approaches rely on strong chemical or electrochemical reduction to generate highly reactive metal species to bind and activate N, which is often incompatible with functionalizing agents. Catalytic and sustainable N splitting to produce metal nitrides under mild conditions may create efficient and straightforward methods for N-containing organic compounds.

Towards Data-Driven Design of Asymmetric Hydrogenation of Olefins: Database and Hierarchical Learning.

Asymmetric hydrogenation of olefins is one of the most powerful asymmetric transformations in molecular synthesis. Although several privileged catalyst scaffolds are available, the catalyst development for asymmetric hydrogenation is still a time- and resource-consuming process due to the lack of predictive catalyst design strategy. Targeting the data-driven design of asymmetric catalysis, we herein report the development of a standardized database that contains the detailed information of over 12000 literature asymmetric hydrogenations of olefins.

Carboxylate breaks the arene C-H bond a hydrogen-atom-transfer mechanism in electrochemical cobalt catalysis.

Combined computational and experimental studies elucidated the distinctive mechanistic features of electrochemical cobalt-catalyzed C-H oxygenation. A sequential electrochemical-chemical (EC) process was identified for the formation of an amidylcobalt(iii) intermediate. The synthesis, characterization, cyclic voltammetry studies, and stoichiometric reactions of the related amidylcobalt(iii) intermediate suggested that a second on-cycle electro-oxidation occurs on the amidylcobalt(iii) species, which leads to a formal Co(iv) intermediate.

Mechanism and Selectivity Control in Ni- and Pd-Catalyzed Cross-Couplings Involving Carbon-Oxygen Bond Activation.

Transition-metal-catalyzed C-O bond activation provides a useful strategy for utilizing alcohol- and phenol-derived electrophiles in cross-coupling reactions, which has become a research field of active and growing interest in organic chemistry. The synergy between computation and experiment elucidated the mechanistic model and controlling factors of selectivities in these transformations, leading to advances in innovative C-O bond activation and functionalization methods.Toward the rational design of C-O bond activation, our collaborations with the Jarvo group bridged the mechanistic models of C(sp)-O and C(sp)-O bond activations.

Divergent rhodium-catalyzed electrochemical vinylic C-H annulation of acrylamides with alkynes.

α-Pyridones and α-pyrones are ubiquitous structural motifs found in natural products and biologically active small molecules. Here, we report an Rh-catalyzed electrochemical vinylic C-H annulation of acrylamides with alkynes, affording cyclic products in good to excellent yield. Divergent syntheses of α-pyridones and cyclic imidates are accomplished by employing N-phenyl acrylamides and N-tosyl acrylamides as substrates, respectively.

Understanding the mechanism and reactivity of Pd-catalyzed C-P bond metathesis of aryl phosphines: a computational study.

Transition metal-catalyzed single bond metathesis has recently emerged as a useful strategy for functional group transfer. In this work, we explored the mechanism and reactivity profile of Pd/PhI-cocatalyzed C-P bond metathesis between aryl phosphines using density functional theory (DFT) calculations. The overall single bond metathesis involves two Pd(ii)-catalyzed C-P reductive eliminations and two Pd(0)-catalyzed C-P oxidative additions, which allows the reversible C-P bond cleavage and formation of the phosphonium cation.

Catalytic and Photochemical Strategies to Stabilized Radicals Based on Anomeric Nucleophiles.

Carbohydrates, one of the three primary macromolecules of living organisms, play significant roles in various biological processes such as intercellular communication, cell recognition, and immune activity. While the majority of established methods for the installation of carbohydrates through the anomeric carbon rely on nucleophilic displacement, anomeric radicals represent an attractive alternative because of their functional group compatibility and high anomeric selectivities. Herein, we demonstrate that anomeric nucleophiles such as C1 stannanes can be converted into anomeric radicals by merging Cu(I) catalysis with blue light irradiation to achieve highly stereoselective C(sp)-S cross-coupling reactions.

Predicting Regioselectivity in Radical C-H Functionalization of Heterocycles through Machine Learning.

Radical C-H bond functionalization provides a versatile approach for elaborating heterocyclic compounds. The synthetic design of this transformation relies heavily on the knowledge of regioselectivity, while a quantified and efficient regioselectivity prediction approach is still elusive. Herein, we report the feasibility of using a machine learning model to predict the transition state barrier from the computed properties of isolated reactants.

Computation-Guided Development of the "Click" -Quinone Methide Cycloaddition with Improved Kinetics.

We report here a deep mechanistic study of the "click" -quinone methide (QM) cycloaddition between -quinolinone quinone methide (QQM) and thio-vinyl ether (TV), named as TQ-ligation. DFT calculations revealed the unexpected fact that dehydration of QQM precursors is the rate-determining step of this transformation, and two highly reactive QQM precursors were predicted. Guided by the calculations, a new "click" QM cycloaddition which shows significantly improved kinetics and remarkable efficiency on protein labeling was developed.

Divergent pathway and reactivity control of intramolecular arene C-H vinylation by vinyl cations.

Vinyl cations exhibit remarkable reactivity towards arene C-H functionalizations. This computational study revealed the key mechanistic details of intramolecular C-H vinylation through a vinyl cation intermediate. Based on the reaction mechanism, the effects of substitution, ring strain and tether length on the reactivity of the vinyl cation were elucidated.

Computational studies on Ni-catalyzed amide C-N bond activation.

Recently, remarkable advances in the mechanistic understanding of Ni-catalyzed amide C-N bond activation have been achieved by computational chemists. These computational studies revealed the key mechanistic processes of Ni-catalyzed amide C-N bond cleavage, providing the molecular basis for the rationalization of reactivities and selectivities. This review summarizes the general mechanistic models of Ni-catalyzed amide C-N bond activation, and discusses their applications in the understanding and design of Ni-catalyzed cross coupling reactions involving amides.

Rhodium(III)-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Dienes: An Experimental and DFT Study.

Because of the inherent difficulty in differentiating two olefins, the development of metal-catalyzed asymmetric cyclization of 1,6-dienes remains challenging. Herein, we describe the first rhodium(III)-catalyzed asymmetric borylative cyclization of cyclohexadienone-tethered mono-, 1,1-di-, and ()-1,2-disubstituted alkenes (1,6-dienes), affording optically pure -bicyclic skeletons bearing three or four contiguous stereocenters with high yields (25-93%), and excellent diastereoselectivities (>20:1 dr) and enantioselectivities (90-99% ee). This mild catalytic approach is generally compatible with a wide range of functional groups, which allows several facile conversions of the cyclization products.

Engineered Cytochrome -Catalyzed Lactone-Carbene B-H Insertion.

Previous work has demonstrated that variants of a heme protein, cytochrome ( cyt ), catalyze abiological carbene boron-hydrogen (B-H) bond insertion with high efficiency and selectivity. Here we investigated this carbon-boron bondforming chemistry with cyclic, lactone-based carbenes. Using directed evolution, we obtained a cyt variant that shows high selectivity and efficiency for B-H insertion of 5- and 6-membered lactone carbenes (up to 24,500 total turnovers and 97.

C-H Acidity and Arene Nucleophilicity as Orthogonal Control of Chemoselectivity in Dual C-H Bond Activation.

We discovered a cooperative gold/silver catalysis mechanism in the oxidative cross-coupling reaction between 1,2,4,5-tetrafluorobenzene and N-TIPS-indole, using DFT calculations. A silver(I)-catalyzed CMD mechanism is responsible for the C-H activation of 1,2,4,5-tetrafluorobenzene, and C-H acidity determines the chemoselectivity. A gold(III)-catalyzed S2Ar mechanism is responsible for the C3-H activation of N-TIPS-indole, and arene nucleophilicity determines the chemo- and regioselectivity.