Computer-Driven Development of Ylide Functionalized Phosphines for Palladium-Catalyzed Hiyama Couplings.

Palladium-catalyzed couplings of silicon enolates with aryl electrophiles are of great synthetic utility, but often limited to expensive bromide substrates. A comparative experimental study confirmed that none of the established ligand systems allows to couple inexpensive aryl chlorides with α-trimethylsilyl alkylnitriles. In contrast, ylide functionalized phosphines (YPhos) led to encouraging results. A statistical model was developed that correlates the reaction yields with ligand features. It was employed to predict catalyst structures with superior performance. With this cheminformatics approach, YPhos ligands were tailored specifically to the demands of Hiyama couplings. The newly synthesized ligands displayed record-setting activities, enabling the elusive coupling of aryl chlorides with α-trimethylsilyl alkyl nitriles. The preparative utility of the catalyst system was demonstrated by the synthesis of pharmaceutically meaningful α-aryl alkylnitriles, α-arylcarbonyls and biaryls.

A negative-solvatochromic fluorescent probe for visualizing intracellular distributions of fatty acid metabolites.

Metabolic distribution of fatty acid to organelles is an essential biological process for energy homeostasis as well as for the maintenance of membrane integrity, and the metabolic pathways are strictly regulated in response to environmental stimuli. Herein, we report a fluorescent fatty acid probe, which bears an azapyrene dye that changes its absorption and emission features depending on the microenvironment polarity of the organelle into which it is transported. Owing to the environmental sensitivity of this dye, the distribution of the metabolically incorporated probe in non-polar lipid droplets, medium-polarity membranes, and the polar aqueous regions, can be visualized in different colors. Based on density scatter plots of the fluorophore, we demonstrate that the degradation of triacylglycerols in lipid droplets occurs predominantly via lipolysis rather than lipophagy in nutrition-starved hepatocytes. This tool can thus be expected to significantly advance our understanding of the lipid metabolism in living organisms.

A Comprehensive Discovery Platform for Organophosphorus Ligands for Catalysis.

The design of molecular catalysts typically involves reconciling multiple conflicting property requirements, largely relying on human intuition and local structural searches. However, the vast number of potential catalysts requires pruning of the candidate space by efficient property prediction with quantitative structure-property relationships. Data-driven workflows embedded in a library of potential catalysts can be used to build predictive models for catalyst performance and serve as a blueprint for novel catalyst designs. Herein we introduce kraken, a discovery platform covering monodentate organophosphorus(III) ligands providing comprehensive physicochemical descriptors based on representative conformer ensembles. Using quantum-mechanical methods, we calculated descriptors for 1558 ligands, including commercially available examples, and trained machine learning models to predict properties of over 300000 new ligands. We demonstrate the application of kraken to systematically explore the property space of organophosphorus ligands and how existing data sets in catalysis can be used to accelerate ligand selection during reaction optimization.

A Striking Mode of Activation of Carbon Disulfide with a Cooperative Bis(silylene).

The reactivity of the 1,4-substituted bis(silylenyl)terphenylene 1, 1,4-[ortho-(LSi)C6 H4 ]2 C6 H4 , (L=RC(NtBu)2 , R=Ph, Mes) towards CS2 is reported. It results in a dearomatization of the phenylene ring, affording the 1,3-substituted cyclohexadiene derivative 2. According to DFT calculations, a transient silene containing a Si=C bond capable of π(C=C) addition at the aromatic phenylene ring is a key intermediate. In contrast, addition of CS2 to the biphenyl-substituted mono-silylene ortho-(LSi)C6 H4 -C6 H5 3 leaves the aromatic π-system intact and forms, in a [1+2] cycloaddition reaction, the corresponding thiasilirane 4 with a three-membered SiSC ring. Further experimental studies led to the isolation of the novel mesoionic five-membered Si2 S2 C heterocycle 6, which reacts with CS2 under C-C bond formation. All isolated new compounds were fully characterized and their molecular structures determined by single-crystal X-ray diffraction analyses.

The Evolution of Data-Driven Modeling in Organic Chemistry.

Organic chemistry is replete with complex relationships: for example, how a reactant's structure relates to the resulting product formed; how reaction conditions relate to yield; how a catalyst's structure relates to enantioselectivity. Questions like these are at the foundation of understanding reactivity and developing novel and improved reactions. An approach to probing these questions that is both longstanding and contemporary is data-driven modeling. Here, we provide a synopsis of the history of data-driven modeling in organic chemistry and the terms used to describe these endeavors. We include a timeline of the steps that led to its current state. The case studies included highlight how, as a community, we have advanced physical organic chemistry tools with the aid of computers and data to augment the intuition of expert chemists and to facilitate the prediction of structure-activity and structure-property relationships.

Univariate classification of phosphine ligation state and reactivity in cross-coupling catalysis.

Chemists often use statistical analysis of reaction data with molecular descriptors to identify structure-reactivity relationships, which can enable prediction and mechanistic understanding. In this study, we developed a broadly applicable and quantitative classification workflow that identifies reactivity cliffs in 11 Ni- and Pd-catalyzed cross-coupling datasets using monodentate phosphine ligands. A distinctive ligand steric descriptor, minimum percent buried volume [%Vbur (min)], is found to divide these datasets into active and inactive regions at a similar threshold value. Organometallic studies demonstrate that this threshold corresponds to the binary outcome of bisligated versus monoligated metal and that %Vbur (min) is a physically meaningful and predictive representation of ligand structure in catalysis.

Data-science driven autonomous process optimization.

Autonomous process optimization involves the human intervention-free exploration of a range process parameters to improve responses such as product yield and selectivity. Utilizing off-the-shelf components, we develop a closed-loop system for carrying out parallel autonomous process optimization experiments in batch. Upon implementation of our system in the optimization of a stereoselective Suzuki-Miyaura coupling, we find that the definition of a set of meaningful, broad, and unbiased process parameters is the most critical aspect of successful optimization. Importantly, we discern that phosphine ligand, a categorical parameter, is vital to determination of the reaction outcome. To date, categorical parameter selection has relied on chemical intuition, potentially introducing bias into the experimental design. In seeking a systematic method for selecting a diverse set of phosphine ligands, we develop a strategy that leverages computed molecular feature clustering. The resulting optimization uncovers conditions to selectively access the desired product isomer in high yield.

Twofold C-H Activation Enables Synthesis of a Diazacoronene-Type Fluorophore with Near Infrared Emission Through Isosteric Replacement.

The synthesis and photophysical properties of a soluble amide-embedded coronene is reported. The key step in this synthesis is the twofold C-H activation of diazaperylene by a rhodium(III)Cp* catalyst. This unprecedented structural motif shows intense fluorescence in the near infrared region with a small Stokes shift and a distinct vibronic structure, which exhibits a slight extent of negative solvatochromism. Comparison of this compound with some relevant compounds revealed the importance of the amide incorporation in the peripheral concave region including an angular position to retain high aromaticity reflecting that of parent coronene. Treatment of this compound with Lewis acid B(C6 F5 )3 formed a bis-adduct, which exhibited enhanced aromaticity as a consequence of the increased double bond character of the amide C-N bonds.

Enantioselective Allenoate-Claisen Rearrangement Using Chiral Phosphate Catalysts.

Herein we report the first highly enantioselective allenoate-Claisen rearrangement using doubly axially chiral phosphate sodium salts as catalysts. This synthetic method provides access to ß-amino acid derivatives with vicinal stereocenters in up to 95% ee. We also investigated the mechanism of enantioinduction by transition state (TS) computations with DFT as well as statistical modeling of the relationship between selectivity and the molecular features of both the catalyst and substrate. The mutual interactions of charge-separated regions in both the zwitterionic intermediate generated by reaction of an amine to the allenoate and the Na+-salt of the chiral phosphate leads to an orientation of the TS in the catalytic pocket that maximizes favorable noncovalent interactions. Crucial arene-arene interactions at the periphery of the catalyst lead to a differentiation of the TS diastereomers. These interactions were interrogated using DFT calculations and validated through statistical modeling of parameters describing noncovalent interactions.

Investigating the Role of Ligand Electronics on Stabilizing Electrocatalytically Relevant Low-Valent Co(I) Intermediates.

Cobalt complexes have shown great promise as electrocatalysts in applications ranging from hydrogen evolution to C-H functionalization. However, the use of such complexes often requires polydentate, bulky ligands to stabilize the catalytically active Co(I) oxidation state from deleterious disproportionation reactions to enable the desired reactivity. Herein, we describe the use of bidentate electronically asymmetric ligands as an alternative approach to stabilizing transient Co(I) species. Using disproportionation rates of electrochemically generated Co(I) complexes as a model for stability, we measured the relative stability of complexes prepared with a series of N, N-bidentate ligands. While the stability of Co(I)Cl complexes demonstrates a correlation with experimentally measured thermodynamic properties, consistent with an outer-sphere electron transfer process, the set of ligated Co(I)Br complexes evaluated was found to be preferentially stabilized by electronically asymmetric ligands, demonstrating an alternative disproportionation mechanism. These results allow a greater understanding of the fundamental processes involved in the disproportionation of organometallic complexes and have allowed the identification of cobalt complexes that show promise for the development of novel electrocatalytic reactions.

Enantiodivergent Pd-catalyzed C-C bond formation enabled through ligand parameterization.

Despite the enormous potential for the use of stereospecific cross-coupling reactions to rationally manipulate the three-dimensional structure of organic molecules, the factors that control the transfer of stereochemistry in these reactions remain poorly understood. Here we report a mechanistic and synthetic investigation into the use of enantioenriched alkylboron nucleophiles in stereospecific Pd-catalyzed Suzuki cross-coupling reactions. By developing a suite of molecular descriptors of phosphine ligands, we could apply predictive statistical models to select or design distinct ligands that respectively promoted stereoinvertive and stereoretentive cross-coupling reactions. Stereodefined branched structures were thereby accessed through the predictable manipulation of absolute stereochemistry, and a general model for the mechanism of alkylboron transmetallation was proposed.

Increasing Catalyst Efficiency in C-H Activation Catalysis.

C-H activation reactions with high catalyst turnover numbers are still very rare in the literature and 10 mol % is a common catalyst loading in this field. We offer a representative overview of efficient C-H activation catalysis to highlight this neglected aspect of catalysis development and inspire future effort towards more efficient C-H activation. Examples ranging from palladium catalysis, Cp*RhIII - and Cp*CoIII -catalysis, the C-H borylation and silylation to methane C-H activation are presented. In these reactions, up to tens of thousands of catalyst turnovers have been observed.

Approach to Comparing the Functional Group Tolerance of Reactions.

Herein, we describe an approach to quantifying and comparing functional group (FG) tolerance of synthetic reactions. Additive-based reaction screening is utilized as a tool for the objective comparison of reaction conditions as demonstrated in four case studies. This contributes to an understanding of factors limiting a reaction's FG tolerance and the identification of truly mild reactions.

Reductive Eliminations from Diarylpalladium(II) Complexes: A Combined Experimental and Computational Investigation.

The diverse mechanisms for the reductive elimination of biaryl compounds from diarylpalladium(II) complexes with a tetradentate ligand were investigated through a combined experimental and computational study. At least four distinct chemical triggers with specific regioselectivity exist for this elimination. Heating of the complexes in inert solvents (e.g., para-xylene) reveals their relatively high thermal stability as reflected by a very high barrier for a unimolecular reductive elimination. In contrast, electron-donor ligands like triphenylphosphine induce a facile reductive elimination via twofold associative ligand exchange as confirmed by kinetic experiments, which are in good agreement with the computational results. Oxidants, such as H2 O2 , can trigger an oxidation-induced reductive elimination via palladium(IV) intermediates at room temperature. Rearrangement of the diarylpalladium(II) complexes can occur in organic acids, facilitating a reductive elimination with distinct regiochemical outcome.

Cp*Rh(III)/Bicyclic Olefin Cocatalyzed C-H Bond Amidation by Intramolecular Amide Transfer.

A bicyclic olefin was discovered as a cocatalyst in a Cp*Rh(III)-catalyzed C-H bond amidation proceeding by an intramolecular amide transfer in N-phenoxyacetamide derivatives. Combining experimental and theoretical studies, we propose that the olefin promotes a Rh(III) intermediate to undergo oxidative addition into the O-N bond to form a Rh(V) nitrenoid species and subsequently direct the nitrenoid to add to the ortho position. The amide directing group plays a dual role as a cleavable coordinating moiety as well as an essential coupling partner for the C-H amidation. This methodology was successfully applied to the late-stage diversification of natural products and a marketed drug under mild conditions.

Combination of Cp*RhIII -Catalyzed C-H Activation and a Wagner-Meerwein-Type Rearrangement.

A combination of Cp*RhIII -catalyzed C-H activation and Wagner-Meerwein-type rearrangement was successfully achieved for the first time. Thus, bridged polycyclic molecules that are not readily accessible by other means were accessed under mild conditions with high efficiency (as low as 0.5 mol % Rh catalyst) in the coupling of N-phenoxyacetamide with 7-azabenzonorbornadiene.

Cobalt-Catalyzed C-H Thiolation through Dehydrogenative Cross-Coupling.

A cobalt-catalyzed dehydrogenative cross-coupling of thiols and indoles is reported. Using a cooperative reaction system, a new mode of action for the cobalt-catalyzed C-heteroatom bond formation was found. The directed C-H activation catalysis overrides an undirected thiolation of indole in the 3-position that occurs in the absence of cobalt. Mechanistic studies indicate a sequence of C-H activation, thiolate transfer, and reductive elimination.

Synthesis of Stable Diarylpalladium(II) Complexes: Detailed Study of the Aryl-Aryl Bond-Forming Reductive Elimination.

The synthesis of diarylpalladium(II) complexes by twofold aryl C-H bond activation was developed. These intermediates of oxidative cyclization reactions are stabilized by chelation with acetyl groups while still maintaining sufficient reactivity to study their reductive elimination. Four distinct triggers were found for the reductive elimination of these complexes to dibenzofurans and carbazoles. Thermal elimination occurs at very high temperatures, whereas ligand-promoted and oxidatively induced reductive eliminations proceed readily at room temperature. Under these conditions, no isomerization occurs. In contrast, weak Brønsted acids, such as acetic acid, lead to a sequence of proto-demetalation, isomerization to a κ(3) -diarylpalladium(II) complex, and reductive elimination to non-symmetrical cyclization products.

Cobalt(III)-Catalyzed Directed C-H Allylation.

The cobalt(III)-catalyzed allylation was developed for amide-directed C-H activation of arenes, heteroarenes, and olefins. A variety of allyl sources can be employed to introduce this useful functional group.