Wendy L. Williams

Bio: Wendy L. Williams is an academic researcher from Princeton University. The author has contributed to research in topics: Chemistry & Aryl. The author has an hindex of 1, co-authored 2 publications receiving 10 citations. Previous affiliations of Wendy L. Williams include University of California, Los Angeles.

The Evolution of Data-Driven Modeling in Organic Chemistry.

Abstract: 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.

Oxidative Addition of Aryl Halides to a Ni(I)-Bipyridine Complex.

Abstract: The oxidative addition of aryl halides to bipyridine- or phenanthroline-ligated nickel(I) is a commonly proposed step in nickel catalysis. However, there is a scarcity of complexes of this type that both are well-defined and undergo oxidative addition with aryl halides, hampering organometallic studies of this process. We report the synthesis of a well-defined Ni(I) complex, [(CO2Etbpy)NiICl]4 (1). Its solution-phase speciation is characterized by a significant population of monomer and a redox equilibrium that can be perturbed by π-acceptors and σ-donors. 1 reacts readily with aryl bromides, and mechanistic studies are consistent with a pathway proceeding through an initial Ni(I) → Ni(III) oxidative addition to form a Ni(III) aryl species. Such a process was demonstrated stoichiometrically for the first time, affording a structurally characterized Ni(III) aryl complex.

Role of Electron-Deficient Olefin Ligands in a Ni-Catalyzed Aziridine Cross-Coupling To Generate Quaternary Carbons.

Abstract: We previously reported the development of an electron-deficient olefin (EDO) ligand, Fro-DO, that promotes the generation of quaternary carbon centers via Ni-catalyzed Csp3–Csp3 cross-coupling with...

Interrogating the Mechanistic Features of Ni(I)-Mediated Aryl Iodide Oxidative Addition Using Electroanalytical and Statistical Modeling Techniques.

Abstract: While the oxidative addition of Ni(I) to aryl iodides has been commonly proposed in catalytic methods, an in-depth mechanistic understanding of this fundamental process is still lacking. Herein, we describe a detailed mechanistic study of the oxidative addition process using electroanalytical and statistical modeling techniques. Electroanalytical techniques allowed rapid measurement of the oxidative addition rates for a diverse set of aryl iodide substrates and four classes of catalytically relevant complexes (Ni(MeBPy), Ni(MePhen), Ni(Terpy), and Ni(BPP)). With >200 experimental rate measurements, we were able to identify essential electronic and steric factors impacting the rate of oxidative addition through multivariate linear regression models. This has led to a classification of oxidative addition mechanisms, either through a three-center concerted or halogen-atom abstraction pathway based on the ligand type. A global heat map of predicted oxidative addition rates was created and shown applicable to a better understanding of the reaction outcome in a case study of a Ni-catalyzed coupling reaction.

Oxidative Addition of Aryl Halides to a Ni(I)-Bipyridine Complex

Abstract: The oxidative addition of aryl halides to bipyridine- or phenanthroline-ligated nickel(I) is a commonly proposed step in nickel catalysis. However, there is a scarcity of complexes of this type that both are well-defined and undergo oxidative addition with aryl halides, hampering organometallic studies of this process. We report the synthesis of a well-defined Ni(I) complex, [(CO2Etbpy)NiCl]4 (1). Its solution-phase speciation is characterized by a significant population of monomer and a redox equilibrium that can be perturbed by π-acceptors and σ-donors. 1 reacts readily with aryl bromides, and mechanistic studies are consistent with a mechanism proceeding through an initial Ni(I) → Ni(III) oxidative addition. Such a process was demonstrated stoichiometrically for the first time, affording a structurally characterized Ni(III) aryl complex.

Nickel-catalyzed formation of quaternary carbon centers using tertiary alkyl electrophiles.

Abstract: Transformation of sterically hindered tertiary alkyl electrophiles under nickel-catalyzed conditions to forge C(sp3)-C bonds and simultaneously create challenging all-carbon quaternary centers has received growing attention in the recent years. The unique nature of nickel featuring flexible oxidation states ranging from Ni0 to NiIV, allows the effective activation of tertiary alkyl electrophiles through ionic (2e) or radical pathways. In nickel-catalyzed coupling of tertiary alkyl electrophiles, the competitive β-H elimination upon the resulting alkyl-Ni intermediate is relatively slow, thus benefiting the C-C bond forming process. Meanwhile, nickel-catalyzed radical addition of tertiary alkyl electrophiles to unsaturated C-C bonds has also advanced rapidly due to the successful incorporation of carboxylic acid and alcohol derivatives as radical precursors, and more importantly due to further interception of the intermediate radical adducts with nucleophiles and electrophiles to accomplish three-component cascade reactions. This review highlights these state-of-the-art nickel-catalyzed transformations of tertiary electrophiles, organized by reaction types with emphasis on the reaction mechanisms.

A Comprehensive Discovery Platform for Organophosphorus Ligands for Catalysis

Abstract: 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.

Sulfonamide Directivity Enables Ni-Catalyzed 1,2-Diarylation of Diverse Alkenyl Amines

Abstract: 1,2-Diarylation of alkenyl sulfonamides with aryl iodides and aryl boronic esters under nickel catalysis is reported. The developed method tolerates coupling partners with disparate electronic prop...

Multicomponent alkene azido-arylation by anion-mediated dual catalysis

Abstract: β-Arylethylamine-containing molecules display important indications in the modulation of pain, treatment of neurological disorders and management of opioid addiction, amongst others, making it a privileged scaffold in drug discovery1,2. De novo methods for their assembly are reliant on transformations that convert a small class of feedstocks into the target compounds via time consuming multi-step syntheses3–5. Synthetic invention can drive investigation of the chemical space around this scaffold in order to further expand its capabilities in biology6–9. Here, we report the development of a dual catalysis platform that enables a multi-component coupling of alkenes, aryl-electrophiles and a simple nitrogen-nucleophile, providing single-step access to synthetically versatile and functionally diverse β-arylethylamines. Driven by visible-light, two discrete copper-catalysts orchestrate aryl-radical formation and azido-group transfer, which underpin an alkene azido-arylation process. The process exhibits broad scope in alkene and aryl components and an azide-anion performs a multifaceted role as both nitrogen source and in mediating the redox-neutral dual-catalysis via inner-sphere electron transfer10,11. The synthetic capabilities of this anion-mediated alkene functionalization process are likely to be of use in a variety of pharmaceutically-relevant and wider synthetic applications.