The rate of living ring-opening metathesis polymerization (ROMP) of N-hexyl-exo-norbornene-5,6-dicarboximide initiated by Grubbs third-generation catalyst precursors [(HIMes)(py)(Cl)Ru═CHPh] and [(HIMes)(3-Br-py)(Cl)Ru═CHPh] is measured to be independent of catalyst concentration. This result led to the development of a rate law describing living ROMP initiated by a Grubbs third-generation catalyst that includes an inverse first-order dependency in pyridine. Additionally, it is demonstrated that one of the two pyridines coordinated to the solid catalyst is fully dissociated in solution. The monopyridine adduct formation is confirmed in solution by H DOSY (diffusion-ordered NMR spectroscopy), and a Van't Hoff analysis of the equilibrium between mono- and dipyridine adducts (extrapolated K ∼ 0.5 at 25 °C). Finally, the difference in polymerization rates between two catalyst precursors is demonstrated to correspond to the difference in coordination strength between the two pyridines, suggesting that the catalytic species involved in the polymerization's rate-determining step is not coordinated to pyridine.

We report the development of an open-source experimental design via Bayesian optimization platform for multiobjective reaction optimization. Using high-throughput experimentation (HTE) and virtual screening data sets containing highdimensional continuous and discrete variables, we optimized the performance of the platform by fine-tuning the algorithm components such as reaction encodings, surrogate model parameters, and initialization techniques. Having established the framework, we applied the optimizer to real-world test scenarios for the simultaneous optimization of the reaction yield and enantioselectivity in a Ni/photoredox-catalyzed enantioselective crosselectrophile coupling of styrene oxide with two different aryl iodide substrates. Starting with no previous experimental data, the Bayesian optimizer identified reaction conditions that surpassed the previously human-driven optimization campaigns within 15 and 24 experiments, for each substrate, among 1728 possible configurations available in each optimization. To make the platform more accessible to nonexperts, we developed a graphical user interface (GUI) that can be accessed online through a web-based application and incorporated features such as condition modification on the fly and data visualization. This web application does not require software installation, removing any programming barrier to use the platform, which enables chemists to integrate Bayesian optimization routines into their everyday laboratory practices.

A Ni/photoredox-catalyzed enantioselective reductive coupling of styrene oxides and aryl iodides is reported. This reaction affords access to enantioenriched 2,2-diarylalcohols from racemic epoxides via a stereoconvergent mechanism. Multivariate linear regression (MVLR) analysis with 29 bioxazoline (BiOx) and biimidazoline (BiIm) ligands revealed that enantioselectivity correlates with electronic properties of the ligands, with more electron-donating ligands affording higher ee's. Experimental and computational mechanistic studies were conducted, lending support to the hypothesis that reductive elimination is enantiodetermining and the electronic character of the ligands influences the enantioselectivity by altering the position of the transition state structure along the reaction coordinate. This study demonstrates the benefits of utilizing statistical modeling as a platform for mechanistic understanding and provides new insight into an emerging class of chiral ligands for stereoconvergent Ni and Ni/photoredox cross-coupling.

The amination of aryl halides has become one of the most commonly practiced C−N bond-forming reactions in pharmaceutical and laboratory syntheses. The widespread use of strong or poorly soluble inorganic bases for amine activation nevertheless complicates the compatibility of this important reaction class with sensitive substrates as well as applications in flow and automated synthesis, to name a few. We report a palladium-catalyzed C−N coupling using Et 3 N as a weak, soluble base, which allows a broad substrate scope that includes bromoand chloro(hetero)arenes, primary anilines, secondary amines, and amide type nucleophiles together with tolerance for a range of base-sensitive functional groups. Mechanistic data have established a unique pathway for these reactions in which water serves multiple beneficial roles. In particular, ionization of a neutral catalytic intermediate via halide displacement by H 2 O generates, after proton loss, a coordinatively unsaturated Pd−OH species that can bind amine substrate triggering intramolecular N−H heterolysis. This water-assisted pathway operates efficiently with even weak terminal bases, such as Et 3 N. The use of a simple, commercially available ligand, PAd 3 , is key to this water-assisted mechanism by promoting coordinative unsaturation in catalytic intermediates responsible for the heterolytic activation of strong element-hydrogen bonds, which enables broad compatibility of carbon-heteroatom crosscoupling reactions with sensitive substrates and functionality.

A Ni/photoredox-catalyzed enantioselective reductive coupling of styrene oxides and aryl iodides is reported. This reaction affords access to enantioenriched 2,2-diarylalcohols from racemic epoxides via a stereoconvergent mechanism. Multivariate linear regression (MVLR) analysis with 29 bioxazoline (BiOx) and biimidazoline (BiIm) ligands revealed that enantioselectivity correlates with electronic properties of the ligands, with more electron-donating ligands affording higher ee’s. Mechanistic studies were conducted, lending support to the hypothesis that the electronic character of the ligands influences the enantioselectivity by altering the position of the transition state structure along the reaction coordinate. This study demonstrates the benefits of utilizing statistical modeling as a platform for mechanistic understanding and provides new insight into an emerging class of chiral ligands for stereoconvergent Ni and Ni/photoredox cross-coupling.

Zerovalent palladium complexes are ubiquitous active species in modern cross-coupling reactions that comprise many premier methods for the construction of C–C and C–heteroatom bonds in organic synthesis. While palladium(0) complexes stabilized by two or more dative ligands are widely known, the most active form of Pd(0) coordinated by a single ancillary ligand (“monoligated Pd(0)”) has long eluded direct characterization. We report the synthesis and unambiguous solution- and solid-state characterization of functionally 12-electron Pd(0) complexes coordinated by a single tri(1-adamantyl)phosphine (PAd3) ligand. Access to these fleeting intermediates was achieved by enabling B-to-Pd transmetalation reactions that occur at cryogenic temperature. This work opens new avenues to experimentally interrogate highly reactive on-cycle Pd(0) catalysts and their structure-dependent reactivity and speciation, which should be broadly informative in continuing studies of catalytic processes featuring the prevalent Pd(0)/Pd(II) redox couple.

Novel Au-PAd3 complexes have been synthesized from the known [Au(PAd3)Cl]. A number of derivatives were deployed as catalysts and compared with NHC and tertiary phosphine congeners.

Zerovalent palladium complexes are ubiquitous active species in modern cross-coupling reactions that comprise many premier methods for the construction of C–C and C–heteroatom bonds in organic synthesis. While palladium(0) complexes stabilized by two or more dative ligands are widely known, the most active form of Pd(0) coordinated by a single ancillary ligand (“monoligated Pd(0)”) has long eluded direct characterization. We report the synthesis and unambiguous solution- and solid-state characterization of functionally 12-electron Pd(0) complexes coordinated by a single tri(1-adamantyl)phosphine (PAd3) ligand. Access to these fleeting intermediates was achieved by enabling B-to-Pd transmetalation reactions that occur at cryogenic temperature. This work opens new avenues to experimentally interrogate highly reactive on-cycle Pd(0) catalysts and their structure-dependent reactivity and speciation, which should be broadly informative in continuing studies of catalytic processes featuring the prevalent Pd(0)/Pd(II) redox couple.