247 results on '"Matthew S. Sigman"'
Search Results
2. Data-Driven Multi-Objective Optimization Tactics for Catalytic Asymmetric Reactions Using Bisphosphine Ligands
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Jordan J. Dotson, Lucy van Dijk, Jacob C. Timmerman, Samantha Grosslight, Richard C. Walroth, Francis Gosselin, Kurt Püntener, Kyle A. Mack, and Matthew S. Sigman
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Colloid and Surface Chemistry ,General Chemistry ,Biochemistry ,Article ,Catalysis - Abstract
Optimization of the catalyst structure to simultaneously improve multiple reaction objectives (e.g., yield, enantioselectivity, and regioselectivity) remains a formidable challenge. Herein, we describe a machine learning workflow for the multi-objective optimization of catalytic reactions that employ chiral bisphosphine ligands. This was demonstrated through the optimization of two sequential reactions required in the asymmetric synthesis of an active pharmaceutical ingredient. To accomplish this, a density functional theory-derived database of >550 bisphosphine ligands was constructed, and a designer chemical space mapping technique was established. The protocol used classification methods to identify active catalysts, followed by linear regression to model reaction selectivity. This led to the prediction and validation of significantly improved ligands for all reaction outputs, suggesting a general strategy that can be readily implemented for reaction optimizations where performance is controlled by bisphosphine ligands.
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- 2022
3. Exploring Structure–Function Relationships of Aryl Pyrrolidine-Based Hydrogen-Bond Donors in Asymmetric Catalysis Using Data-Driven Techniques
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Mohammad H. Samha, Julie L. H. Wahlman, Jacquelyne A. Read, Jacob Werth, Eric N. Jacobsen, and Matthew S. Sigman
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General Chemistry ,Article ,Catalysis - Abstract
Hydrogen bond-based organocatalysts rely on networks of attractive noncovalent interactions (NCIs) to impart enantioselectivity. As a specific example, aryl pyrrolidine substituted urea, thiourea, and squaramide organocatalysts function cooperatively through hydrogen bonding and difficult-to-predict NCIs as a function of the reaction partners. To uncover the synergistic effect of the structural components of this catalyst class, we applied data science tools to study various model reactions using a derivatized, aryl pyrrolidine-based, hydrogen-bond donor (HBD) catalyst library. Through a combination of experimentally collected data and data mined from previous reports, statistical models were constructed, illuminating the general features necessary for high enantioselectivity. A distinct dependence on the identity of the electrophilic reaction partner and HBD catalyst is observed, suggesting that a general interaction is conserved throughout the reactions analyzed. The resulting models also demonstrate predictive capability by the successful improvement of a previously reported reaction using out-of-sample reaction components. Overall, this study highlights the power of data science in exploring mechanistic hypotheses in asymmetric HBD catalysis and provides a prediction platform applicable in future reaction optimization.
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- 2022
4. Data Science-Driven Analysis of Substrate-Permissive Diketopiperazine Reverse Prenyltransferase NotF: Applications in Protein Engineering and Cascade Biocatalytic Synthesis of (−)-Eurotiumin A
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Samantha P. Kelly, Vikram V. Shende, Autumn R. Flynn, Qingyun Dan, Ying Ye, Janet L. Smith, Sachiko Tsukamoto, Matthew S. Sigman, and David H. Sherman
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Biological Products ,Data Science ,Diketopiperazines ,General Chemistry ,Dimethylallyltranstransferase ,Protein Engineering ,Biochemistry ,Article ,Carbon ,Catalysis ,Indole Alkaloids ,Mixed Function Oxygenases ,Substrate Specificity ,Colloid and Surface Chemistry ,Flavins ,Chemical Sciences ,Solvents ,Animals - Abstract
Prenyltransfer is an early-stage carbon-hydrogen bond (C-H) functionalization prevalent in the biosynthesis of a diverse array of biologically active bacterial, fungal, plant, and metazoan diketopiperazine (DKP) alkaloids. Toward the development of a unified strategy for biocatalytic construction of prenylated DKP indole alkaloids, we sought to identify and characterize a substrate-permissive C2 reverse prenyltransferase (PT). As the first tailoring event within the biosynthesis of cytotoxic notoamide metabolites, PT NotF catalyzes C2 reverse prenyltransfer of brevianamide F. Solving a crystal structure of NotF (in complex with native substrate and prenyl donor mimic dimethylallyl S-thiolodiphosphate (DMSPP)) revealed a large, solvent-exposed active site, intimating NotF may possess a significantly broad substrate scope. To assess the substrate selectivity of NotF, we synthesized a panel of 30 sterically and electronically differentiated tryptophanyl DKPs, the majority of which were selectively prenylated by NotF in synthetically useful conversions (2 to >99%). Quantitative representation of this substrate library and development of a descriptive statistical model provided insight into the molecular origins of NotF's substrate promiscuity. This approach enabled the identification of key substrate descriptors (electrophilicity, size, and flexibility) that govern the rate of NotF-catalyzed prenyltransfer, and the development of an "induced fit docking (IFD)-guided" engineering strategy for improved turnover of our largest substrates. We further demonstrated the utility of NotF in tandem with oxidative cyclization using flavin monooxygenase, BvnB. This one-pot, in vitro biocatalytic cascade enabled the first chemoenzymatic synthesis of the marine fungal natural product, (-)-eurotiumin A, in three steps and 60% overall yield.
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- 2022
5. Noncovalent Stabilization of Radical Intermediates in the Enantioselective Hydroamination of Alkenes with Sulfonamides
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Eve Y. Xu, Jacob Werth, Casey B. Roos, Andrew J. Bendelsmith, Matthew S. Sigman, and Robert R. Knowles
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Ions ,Sulfonamides ,Kinetics ,Colloid and Surface Chemistry ,Free Radicals ,Stereoisomerism ,General Chemistry ,Alkenes ,Biochemistry ,Catalysis - Abstract
Noncovalent interactions (NCIs) are critical elements of molecular recognition in a wide variety of chemical contexts. While NCIs have been studied extensively for closed-shell molecules and ions, very little is understood about the structures and properties of NCIs involving free radical intermediates. In this report, we describe a detailed mechanistic study of the enantioselective radical hydroamination of alkenes with sulfonamides and present evidence suggesting that the basis for asymmetric induction in this process arises from attractive NCIs between a neutral sulfonamidyl radical intermediate and a chiral phosphoric acid (CPA). We describe experimental, computational, and data science-based evidence that identifies the specific radical NCIs that form the basis for the enantioselectivity. Kinetic studies support that C-N bond formation determines the enantioselectivity. Density functional theory investigations revealed the importance of both strong H-bonding between the CPA and the
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- 2022
6. Leveraging Regio- and Stereoselective C(sp3)–H Functionalization of Silyl Ethers to Train a Logistic Regression Classification Model for Predicting Site-Selectivity Bias
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Yannick T. Boni, Ryan C. Cammarota, Kuangbiao Liao, Matthew S. Sigman, and Huw M. L. Davies
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Colloid and Surface Chemistry ,General Chemistry ,Biochemistry ,Catalysis - Published
- 2022
7. Design and Application of a Screening Set for Monophosphine Ligands in Cross-Coupling
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Tobias Gensch, Sleight R. Smith, Thomas J. Colacot, Yam N. Timsina, Guolin Xu, Ben W. Glasspoole, and Matthew S. Sigman
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General Chemistry ,Catalysis - Published
- 2022
8. Interrogating the Mechanistic Features of Ni(I)-Mediated Aryl Iodide Oxidative Addition Using Electroanalytical and Statistical Modeling Techniques
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Tianhua Tang, Avijit Hazra, Daniel S. Min, Wendy L. Williams, Eli Jones, Abigail G. Doyle, and Matthew S. Sigman
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Colloid and Surface Chemistry ,General Chemistry ,Biochemistry ,Catalysis - Published
- 2023
9. A Physical Organic Approach towards Statistical Modeling of Tetrazole and Azide Decomposition**
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Jonas Rein, Jonathan M. Meinhardt, Julie L. Hofstra Wahlman, Matthew S. Sigman, and Song Lin
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General Chemistry ,General Medicine ,Catalysis - Published
- 2023
10. Mechanistically Guided Workflow for Relating Complex Reactive Site Topologies to Catalyst Performance in C–H Functionalization Reactions
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Ryan C. Cammarota, Wenbin Liu, John Bacsa, Huw M. L. Davies, and Matthew S. Sigman
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Kinetics ,Colloid and Surface Chemistry ,Coordination Complexes ,Thermodynamics ,Rhodium ,Stereoisomerism ,General Chemistry ,Methane ,Biochemistry ,Carbon ,Catalysis ,Hydrogen - Abstract
Leveraging congested catalyst scaffolds has emerged as a key strategy for altering innate substrate site-selectivity profiles in C-H functionalization reactions. Similar to enzyme active sites, optimal small molecule catalysts often feature reactive cavities tailored for controlling substrate approach trajectories. However, relating three-dimensional catalyst shape to reaction output remains a formidable challenge, in part due to the lack of molecular features capable of succinctly describing complex reactive site topologies in terms of numerical inputs for machine learning applications. Herein, we present a new set of descriptors, "Spatial Molding for Approachable Rigid Targets" (SMART), which we have applied to quantify reactive site spatial constraints for an expansive library of dirhodium catalysts and to predict site-selectivity for C-H functionalization of 1-bromo-4-pentylbenzene via donor/acceptor carbene intermediates. Optimal site-selectivity for the terminal methylene position was obtained with Rh
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- 2022
11. Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036
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Jie Xu, Samantha Grosslight, Kyle A. Mack, Sierra C. Nguyen, Kyle Clagg, Ngiap-Kie Lim, Jacob C. Timmerman, Jeff Shen, Nicholas A. White, Lauren E. Sirois, Chong Han, Haiming Zhang, Matthew S. Sigman, and Francis Gosselin
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Proto-Oncogene Proteins p21(ras) ,Colloid and Surface Chemistry ,Pyridines ,Linear Models ,Quinazolines ,Antineoplastic Agents ,General Chemistry ,Biochemistry ,Catalysis - Abstract
An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 (
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- 2022
12. Mechanistic Guidance Leads to Enhanced Site-Selectivity in C–H Oxidation Reactions Catalyzed by Ruthenium bis(Bipyridine) Complexes
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David B. Vogt, Matthew S. Sigman, Jeremy D. Griffin, and J. Du Bois
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Bipyridine ,chemistry.chemical_compound ,Chemistry ,Site selectivity ,chemistry.chemical_element ,General Chemistry ,Combinatorial chemistry ,Redox ,Catalysis ,Ruthenium - Published
- 2021
13. Theoretical and Experimental Investigation of Functionalized Cyanopyridines Yield an Anolyte with an Extremely Low Reduction Potential for Nonaqueous Redox Flow Batteries
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Thomas P. Vaid, Monique E. Cook, Jessica D. Scott, Marino Borjesson Carazo, Jonathan Ruchti, Shelley D. Minteer, Matthew S. Sigman, Anne J. McNeil, and Melanie S. Sanford
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Organic Chemistry ,General Chemistry ,Catalysis - Abstract
Cyanopyridines and cyanophenylpyridines were investigated as anolytes for nonaqueous redox flow batteries (RFBs). The three isomers of cyanopyridine are reduced at potentials of -2.2 V or lower vs. ferrocene
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- 2022
14. Investigating Oxidative Addition Mechanisms of Allylic Electrophiles with Low-Valent Ni/Co Catalysts Using Electroanalytical and Data Science Techniques
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Tianhua Tang, Eli Jones, Thérèse Wild, Avijit Hazra, Shelley D. Minteer, and Matthew S. Sigman
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Kinetics ,Oxidative Stress ,Colloid and Surface Chemistry ,Data Science ,General Chemistry ,Biochemistry ,Oxidation-Reduction ,Catalysis - Abstract
The catalysis by a π-allyl-Co/Ni complex has drawn significant attention recently due to its distinct reactivity in reductive Co/Ni-catalyzed allylation reactions. Despite significant success in reaction development, the critical oxidative addition mechanism to form the π-allyl-Co/Ni complex remains unclear. Herein, we present a study to investigate this process with four catalysis-relevant complexes: Co(
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- 2022
15. Leveraging Regio- and Stereoselective C(sp
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Yannick T, Boni, Ryan C, Cammarota, Kuangbiao, Liao, Matthew S, Sigman, and Huw M L, Davies
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Logistic Models ,Catalysis ,Ethers - Abstract
The C-H functionalization of silyl ethers via carbene-induced C-H insertion represents an efficient synthetic disconnection strategy. In this work, site- and stereoselective C(sp
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- 2022
16. Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines
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Mark D. Levin, Matthew S. Sigman, Balu D. Dherange, Patrick Q Kelly, and Jordan P Liles
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Steric effects ,Indole test ,Indoles ,Molecular Structure ,Cyclopropanation ,Azirines ,Aryl ,Communication ,Quinoline ,General Chemistry ,Biochemistry ,Combinatorial chemistry ,Catalysis ,Carbon ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,chemistry ,Torquoselectivity ,Pyridine ,Pyrroles ,Density Functional Theory ,Pyrrole - Abstract
Herein, we report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores, respectively. By employing α-chlorodiazirines as thermal precursors to the corresponding chlorocarbenes, the traditional haloform-based protocol central to the parent Ciamician-Dennstedt rearrangement can be modified to directly afford 3-(hetero)arylpyridines and quinolines. Chlorodiazirines are conveniently prepared in a single step by oxidation of commercially available amidinium salts. Selectivity as a function of pyrrole substitution pattern was examined, and a predictive model based on steric effects is put forward, with DFT calculations supporting a selectivity-determining cyclopropanation step. Computations surprisingly indicate that the stereochemistry of cyclopropanation is of little consequence to the subsequent electrocyclic ring opening that forges the pyridine core, due to a compensatory homoaromatic stabilization that counterbalances orbital-controlled torquoselectivity effects. The utility of this skeletal transform is further demonstrated through the preparation of quinolinophanes and the skeletal editing of pharmaceutically relevant pyrroles.
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- 2021
17. N-Ammonium Ylide Mediators for Electrochemical C–H Oxidation
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Pengfei Hu, Tianhua Tang, Chi He, Moses G. Gichinga, Phil S. Baran, Sameer Tyagi, Shelley D. Minteer, Rafael Navratil, Debora Chiodi, Masato Saito, Massimiliano Lamberto, Michael Meanwell, Matthew S. Sigman, Mayank Tanwar, Matthew Neurock, Martin D. Eastgate, Bruce P. McKillican, Michael A. Schmidt, Longrui Chen, Sagar Udyavara, Christian A. Malapit, Ethan Carlson, Cian Kingston, and Yu Kawamata
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chemistry.chemical_classification ,2019-20 coronavirus outbreak ,General Chemistry ,010402 general chemistry ,Electrochemistry ,Directed evolution ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Article ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,chemistry ,Ylide ,Reagent ,Organic synthesis ,Reactivity (chemistry) ,Selectivity - Abstract
The site-specific oxidation of strong C(sp(3))–H bonds is of uncontested utility in organic synthesis. From simplifying access to metabolites and late-stage diversification of lead compounds to truncating retrosynthetic plans, there is a growing need for new reagents and methods for achieving such a transformation in both academic and industrial circles. One main drawback of current chemical reagents is the lack of diversity with regard to structure and reactivity that prevents a combinatorial approach for rapid screening to be employed. In that regard, directed evolution still holds the greatest promise for achieving complex C–H oxidations in a variety of complex settings. Herein we present a rationally designed platform that provides a step toward this challenge using N-ammonium ylides as electrochemically driven oxidants for site-specific, chemoselective C(sp(3))–H oxidation. By taking a first-principles approach guided by computation, these new mediators were identified and rapidly expanded into a library using ubiquitous building blocks and trivial synthesis techniques. The ylide-based approach to C–H oxidation exhibits tunable selectivity that is often exclusive to this class of oxidants and can be applied to real-world problems in the agricultural and pharmaceutical sectors.
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- 2021
18. Rate Profiling the Impact of Remote Functional Groups on the Redox-Relay Heck Reaction
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Samantha L. Kraus, Matthew S. Sigman, and Sean P. Ross
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Profiling (computer programming) ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Organic Chemistry ,Stereoisomerism ,Alkenes ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,Redox ,Article ,Catalysis ,0104 chemical sciences ,law.invention ,Stereocenter ,Relay ,law ,Heck reaction ,Physical and Theoretical Chemistry ,Oxidation-Reduction - Abstract
The redox-relay Heck reaction is a powerful method for the construction of enantioenriched quaternary stereocenters remote from existing functional groups. However, there has been little success in the design of site-selective alkene functionalization based on these methods. Herein, we show that experimentally determined rates can be used to train a multivariate linear regression model capable of predicting the rate of a specific relay Heck reaction, allowing for the site-selective functionalization of diene substrates.
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- 2021
19. Analyzing mechanisms in Co(<scp>i</scp>) redox catalysis using a pattern recognition platform
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Matthew S. Sigman, Christopher Sandford, Shelley D. Minteer, and Tianhua Tang
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Electrolysis ,010405 organic chemistry ,Chemistry ,business.industry ,Ligand ,Pattern recognition ,General Chemistry ,Overpotential ,010402 general chemistry ,Electrochemistry ,01 natural sciences ,Redox ,0104 chemical sciences ,Catalysis ,law.invention ,chemistry.chemical_compound ,Benzyl bromide ,law ,Artificial intelligence ,Cyclic voltammetry ,business ,Bond cleavage - Abstract
Redox catalysis has been broadly utilized in electrochemical synthesis due to its kinetic advantages over direct electrolysis. The appropriate choice of redox mediator can avoid electrode passivation and overpotential, which strongly inhibit the efficient activation of substrates in electrolysis. Despite the benefits brought by redox catalysis, establishing the precise nature of substrate activation remains challenging. Herein, we determine that a Co(i) complex bearing two N,N,N-tridentate ligands acts as a competent redox catalyst for the reduction of benzyl bromide substrates. Kinetic studies combining electroanalytical techniques with multivariable linear-regression analysis were conducted, disclosing an outer-sphere electron-transfer mechanism, which occurs in concert with C–Br bond cleavage. Furthermore, we apply a pattern recognition platform to distinguish between mechanisms in the activation of benzyl bromides, found to be dependent on the ligation state of the cobalt(i) center and ligand used., Through kinetic studies combining electroanalytical techniques with multivariable linear-regression (MLR) analysis, a pattern recognition platform is established to determine the electron-transfer mechanism (inner-sphere or outer-sphere) of an electrochemical reduction of benzyl bromides, mediated by different cobalt complexes.
- Published
- 2021
20. Mechanistic Studies Inform Design of Improved Ti(salen) Catalysts for Enantioselective [3 + 2] Cycloaddition
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Sophia G. Robinson, Song Lin, Binyang Jiang, Xiangyu Wu, and Matthew S. Sigman
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Molecular Conformation ,Stereoisomerism ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Catalysis ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Coordination Complexes ,Diamine ,Density Functional Theory ,Titanium ,Cycloaddition Reaction ,Enantioselective synthesis ,General Chemistry ,Ethylenediamines ,Combinatorial chemistry ,Cycloaddition ,0104 chemical sciences ,chemistry ,Salicylaldehyde ,Thermodynamics ,Density functional theory ,Selectivity - Abstract
Ti(salen) complexes catalyze the asymmetric [3 + 2] cycloaddition of cyclopropyl ketones with alkenes. While high enantioselectivities are achieved with electron-rich alkenes, electron-deficient alkenes are less selective. Herein, we describe mechanistic studies to understand the origins of catalyst and substrate trends in an effort to identify a more general catalyst. Density functional theory (DFT) calculations of the selectivity determining transition state revealed the origin of stereochemical control to be catalyst distortion, which is largely influenced by the chiral backbone and adamantyl groups on the salicylaldehyde moieties. While substitution of the adamantyl groups was detrimental to the enantioselectivity, mechanistic information guided the development of a set of eight new Ti(salen) catalysts with modified diamine backbones. These catalysts were evaluated with four electron-deficient alkenes to develop a three-parameter statistical model relating enantioselectivity to physical organic parameters. This statistical model is capable of quantitative prediction of enantioselectivity with structurally diverse alkenes. These mechanistic insights assisted the discovery of a new Ti(salen) catalyst, which substantially expanded the reaction scope and significantly improved the enantioselectivity of synthetically interesting building blocks.
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- 2020
21. Catalytic Enantioselective Synthesis of Difluorinated Alkyl Bromides
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Eric N. Jacobsen, Matthew S. Sigman, Jacquelyne A. Read, John M. Ovian, and Mark D. Levin
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Halogenation ,Stereoisomerism ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Catalysis ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Bromide ,Molecule ,Hydrocarbons, Iodinated ,Alkyl ,chemistry.chemical_classification ,Molecular Structure ,fungi ,Enantioselective synthesis ,General Chemistry ,Combinatorial chemistry ,Hydrocarbons, Brominated ,0104 chemical sciences ,Transformation (genetics) ,chemistry - Abstract
We report an iodoarene-catalyzed enantioselective synthesis of β,β-difluoroalkyl halide building blocks. The transformation involves an oxidative rearrangement of α-bromostyrenes, utilizing HF–pyridine as the fluoride source and m-CPBA as the stoichiometric oxidant. A catalyst decomposition pathway was identified, which, in tandem with catalyst structure–activity relationship studies, facilitated the development of an improved catalyst providing higher enantioselectivity with lower catalyst loadings. The versatility of the difluoroalkyl bromide products was demonstrated via highly enantiospecific substitution reactions with suitably reactive nucleophiles. The origins of enantioselectivity were investigated using computed interaction energies of simplified catalyst and substrate structures, providing evidence for both CH–π and π–π transition state interactions as critical features.
- Published
- 2020
22. Enantioselective Intramolecular Allylic Substitution via Synergistic Palladium/Chiral Phosphoric Acid Catalysis: Insight into Stereoinduction through Statistical Modeling
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F. Dean Toste, Christopher Sandford, Cheng-Che Tsai, Tao Wu, Buyun Chen, and Matthew S. Sigman
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inorganic chemicals ,Allylic rearrangement ,statistical modeling ,allylic substitution ,chemistry.chemical_element ,010402 general chemistry ,01 natural sciences ,Article ,Catalysis ,noncovalent interactions ,chemistry.chemical_compound ,Nucleophile ,Models ,Reactivity (chemistry) ,Phosphoric Acids ,Phosphoric acid ,Substitution reaction ,Models, Statistical ,010405 organic chemistry ,Chemistry ,organic chemicals ,Organic Chemistry ,technology, industry, and agriculture ,Enantioselective synthesis ,asymmetric catalysis ,Stereoisomerism ,General Medicine ,General Chemistry ,Statistical ,palladium ,Asymmetric induction ,Combinatorial chemistry ,0104 chemical sciences ,Intramolecular force ,Chemical Sciences ,Palladium - Abstract
The mode of asymmetric induction in an enantioselective intramolecular allylic substitution reaction catalyzed by a combination of palladium and a chiral phosphoric acid was investigated by a combined experimental and statistical modeling approach. Experiments to probe nonlinear effects, the reactivity of deuterium-labeled substrates, and control experiments revealed that nucleophilic attack to the π-allylpalladium intermediate is the enantio-determining step, in which the chiral phosphate anion is involved in stereoinduction. Using multivariable linear regression analysis, we determined that multiple noncovalent interactions with the chiral environment of the phosphate anion are integral to enantiocontrol in the transition state. The synthetic protocol to form chiral pyrrolidines was further applied to the asymmetric construction of C–O bonds at fully substituted carbon centers in the synthesis of chiral 2,2-disubstituted benzomorpholines.
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- 2020
23. Electrochemical Ruthenium-Catalyzed C–H Hydroxylation of Amine Derivatives in Aqueous Acid
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James B. C. Mack, Matthew S. Sigman, Sophia G. Robinson, J. Du Bois, and Sara N. Alektiar
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chemistry.chemical_element ,Hydroxylation ,010402 general chemistry ,Electrochemistry ,01 natural sciences ,Biochemistry ,Catalysis ,Ruthenium ,chemistry.chemical_compound ,Polymer chemistry ,Amines ,Physical and Theoretical Chemistry ,Amine derivatives ,Aqueous solution ,Molecular Structure ,010405 organic chemistry ,Organic Chemistry ,Water ,0104 chemical sciences ,chemistry ,Solvents ,Protons ,Oxidation-Reduction ,Hydrogen - Abstract
The development of an electrochemically driven, ruthenium-catalyzed C-H hydroxylation reaction of amine-derived substrates bearing tertiary C-H bonds is described. The reaction is performed under constant current electrolysis in a divided cell to afford alcohol products in yields comparable to those of our previously reported process, which requires the use of stoichiometric H
- Published
- 2020
24. Enantioselective Allenoate-Claisen Rearrangement Using Chiral Phosphate Catalysts
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Javier Miró, F. Dean Toste, Tobias Gensch, Seo-Jung Han, Mario Ellwart, Hsin-Hui Lin, and Matthew S. Sigman
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Models, Molecular ,Naphthalenes ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Catalysis ,Phosphates ,Stereocenter ,Colloid and Surface Chemistry ,Models ,Computational chemistry ,Non-covalent interactions ,Amino Acids ,chemistry.chemical_classification ,Enantioselective synthesis ,Diastereomer ,Molecular ,Stereoisomerism ,General Chemistry ,Asymmetric induction ,0104 chemical sciences ,Claisen rearrangement ,chemistry ,Chemical Sciences ,Selectivity - Abstract
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 β-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.
- Published
- 2020
25. Electrochemical cobalt-catalyzed selective carboxylation of benzyl halides with CO2 enabled by low-coordinate cobalt electrocatalysts
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Henry S. White, Tanner Stone, Matthew Neurock, Andrew Pendergast, Ryan E. Smith, Matthew S. Sigman, Ding Wu, Tommy Primo, Sagar Udyavara, Wesley Beck, Christian A. Malapit, Selma Kadic, Shelley D. Minteer, and Mayank Tanwar
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inorganic chemicals ,Halide ,chemistry.chemical_element ,Electrosynthesis ,Combinatorial chemistry ,Catalysis ,chemistry.chemical_compound ,chemistry ,Carboxylation ,13. Climate action ,Electroanalytical method ,Organic synthesis ,Selectivity ,Cobalt - Abstract
The direct, transition metal-catalyzed carboxylation of organohalides with carbon dioxide is a highly desirable transformation in organic synthesis as it utilizes feedstock chemicals and delivers carboxylic acids –among the most utilized class of organic molecules. Phenyl acetic acids, in particular, are privileged motifs that appear in many pharmaceuticals and biologically active compounds. This article reports the development of a sustainable and selective cobalt-catalyzed electrochemical carboxylation of benzyl halides with CO2 to generate phenyl acetic acids. The success of this transformation is enabled by the development of low-coordinate cobalt/pyrox complexes as electrocatalysts to convert various benzyl chlorides and bromides to their corre-sponding phenyl/heteroaryl acetic acids with high selectivity over undesired homocoupling of the benzyl halides. The combina-tion of electroanalytical methods, simulation studies, control reactions, and first-principles density functional theory (DFT) calculations informed the mechanistic analysis of this reaction. An EC’C-type activation mechanism of benzyl halides, which is unique to Co(II)/pyrox electrocatalysts, provides the rationalization of the exceptional observed selectivity for carboxylation. Specifically, the Co(II)/pyrox catalyst undergoes reduction to Co(I) followed by halogen abstraction and a favorable radical rebound to Co(II)/pyrox to form alkyl–Co(III) intermediates. Although voltammetry only shows a single electron transfer step, bulk electrolysis shows a two electron process and using DFT calculations, the intermediates are proposed to undergo two-electron reduction to alkyl–Co(I) followed by a ZnCl2-assisted CO2 insertion to form the carboxylated adducts with regenera-tion of Co(I)/pyrox.
- Published
- 2021
26. Stereoconvergent and -divergent Synthesis of Tetrasubstituted Alkenes by Nickel-Catalyzed Cross-Couplings
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Chong Han, Haiming Zhang, Jana Wassmer, Cian Kingston, Sleight R. Smith, Natalie Seeger, Matthew S. Sigman, Daniel Zell, Francis Gosselin, Lauren E. Sirois, and Janis Jermaks
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Ligand ,Diastereomer ,General Chemistry ,Biochemistry ,Combinatorial chemistry ,Enol ,Catalysis ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,chemistry ,Stereoselectivity ,Divergent synthesis ,Isomerization ,Boronic acid - Abstract
We report the development of a method to diastereoselectively access tetrasubstituted alkenes via nickel-catalyzed Suzuki-Miyaura cross-couplings of enol tosylates and boronic acid esters. Either diastereomeric product was selectively accessed from a mixture of enol tosylate starting material diastereomers in a convergent reaction by judicious choice of the ligand and reaction conditions. A similar protocol also enabled a divergent synthesis of each product isomer from diastereomerically pure enol tosylates. Notably, high-throughput optimization of the monophosphine ligands was guided by chemical space analysis of the kraken library to ensure a diverse selection of ligands was examined. Stereoelectronic analysis of the results provided insight into the requirements for reactive and selective ligands in this transformation. The synthetic utility of the optimized catalytic system was then probed in the stereoselective synthesis of various tetrasubstituted alkenes, with yields up to 94% and diastereomeric ratios up to 99:1 Z/E and 93:7 E/Z observed. Moreover, a detailed computational analysis and experimental mechanistic studies provided key insights into the nature of the underlying isomerization process impacting selectivity in the cross-coupling.
- Published
- 2021
27. Linear Regression Model Development for Analysis of Asymmetric Copper-Bisoxazoline Catalysis
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Jacob Werth and Matthew S. Sigman
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010405 organic chemistry ,Ligand ,Chemistry ,Cyclopropanation ,Enantioselective synthesis ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Catalysis ,Chemical space ,Article ,0104 chemical sciences ,chemistry.chemical_compound ,Computational chemistry ,Bayesian multivariate linear regression ,Linear regression ,Lewis acids and bases ,Organometallic chemistry - Abstract
Multivariate linear regression analysis (MLR) is used to unify and correlate different categories of asymmetric Cu-bisoxazoline (BOX) catalysis. The versatility of Cu-BOX complexes has been leveraged for several types of enantioselective transformations including cyclopropanation, Diels-Alder cycloadditions and difunctionalization of alkenes. Statistical tools and extensive molecular featurization has guided the development of an inclusive linear regression model, providing a predictive platform and readily interpretable descriptors. Mechanism-specific categorization of curated datasets and parameterization of reaction components allows for simultaneous analysis of disparate organometallic intermediates such as carbenes and Lewis acid adducts, all unified by a common ligand scaffold and metal ion. Additionally, this workflow permitted the development of a complementary linear regression model correlating analogous BOX-catalyzed reactions employing Ni, Fe, Mg, and Pd complexes. Comparison of ligand parameters in each model reveals the relevant structural requirements necessary for high selectivity. Overall, this strategy highlights the utility of MLR analysis in exploring mechanistically driven correlations across a diverse chemical space in organometallic chemistry and presents an applicable workflow for related ligand classes.
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- 2021
28. Univariate classification of phosphine ligation state and reactivity in cross-coupling catalysis
- Author
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Ellyn Peters, Tobias Gensch, Abigail G. Doyle, Matthew S. Sigman, Sleight R. Smith, Samuel H. Newman-Stonebraker, Heather C. Johnson, and Julia E. Borowski
- Subjects
chemistry.chemical_compound ,Multidisciplinary ,Computational chemistry ,Chemistry ,Molecular descriptor ,Univariate ,Statistical analysis ,Reactivity (chemistry) ,Phosphine ,Catalysis - Abstract
Which phosphines squeeze together? Phosphine ligands coordinated to palladium and nickel are essential tools for assembling the backbones of pharmaceutical compounds. For decades, descriptors that characterize spatial bulk have helped to guide phosphine optimization. However, these descriptors tend to apply to ideal geometries of a single ligand. Newman-Stonebraker et al . introduce a descriptor that considers how the ligand conformation might change in a crowded environment. Specifically, they found that the minimum percentage buried volume accurately predicts when one or two of a particular ligand will coordinate to a metal center, frequently a key determinant of successful catalysis. —JSY
- Published
- 2021
29. Development of High Energy Density Diaminocyclopropenium-Phenothiazine Hybrid Catholytes for Non-Aqueous Redox Flow Batteries
- Author
-
David B. Vogt, Matthew S. Sigman, Yichao Yan, Melanie S. Sanford, and Thomas P. Vaid
- Subjects
Aqueous solution ,Flow (psychology) ,Inorganic chemistry ,Substituent ,chemistry.chemical_element ,General Medicine ,General Chemistry ,Redox ,Nitrogen ,Catalysis ,chemistry.chemical_compound ,chemistry ,Phenothiazine ,Molecule ,Solubility - Abstract
This report describes the design of diaminocyclopropenium-phenothiazine hybrid catholytes for non-aqueous redox flow batteries. The molecules are synthesized in a rapid and modular fashion by appending a diaminocyclopropenium (DAC) substituent to the nitrogen of the phenothiazine. Combining a versatile C-N coupling protocol (which provides access to diverse derivatives) with computation and structure-property analysis enabled the identification of a catholyte that displays stable two-electron cycling at potentials of 0.64 and 1.00 V vs. Fc/Fc+ as well as high solubility in all oxidation states (≥0.45 M in TBAPF6 /MeCN). This catholyte was deployed in a high energy density two-electron RFB, exhibiting >90 % capacity retention over 266 hours of flow cell cycling at >0.5 M electron concentration.
- Published
- 2021
30. Simultaneously Enhancing the Redox Potential and Stability of Multi-Redox Organic Catholytes by Incorporating Cyclopropenium Substituents
- Author
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Matthew S. Sigman, Yichao Yan, Melanie S. Sanford, Sophia G. Robinson, and Thomas P. Vaid
- Subjects
Phenazine ,General Chemistry ,Resonance (chemistry) ,Photochemistry ,Biochemistry ,Redox ,Catalysis ,chemistry.chemical_compound ,Delocalized electron ,Colloid and Surface Chemistry ,chemistry ,Ferrocene ,Phenothiazine ,Molecule ,Spin density - Abstract
High redox potential, two-electron organic catholytes for nonaqueous redox flow batteries were developed by appending diaminocyclopropenium (DAC) substituents to phenazine and phenothiazine cores. The parent heterocycles exhibit two partially reversible oxidations at moderate potentials [both at lower than 0.7 V vs ferrocene/ferrocenium (Fc/Fc+)]. The incorporation of DAC substituents has a dual effect on these systems. The DAC groups increase the redox potential of both couples by ∼300 mV while simultaneously rendering the second oxidation (which occurs at 1.20 V vs Fc/Fc+ in the phenothiazine derivative) reversible. The electron-withdrawing nature of the DAC unit is responsible for the increase in redox potential, while the DAC substituents stabilize oxidized forms of the molecules through resonance delocalization of charge and unpaired spin density. These new catholytes were deployed in two-electron redox flow batteries that exhibit voltages of up to 2.0 V and no detectable crossover over 250 cycles.
- Published
- 2021
31. Design and Application of a Screening Set for Monophosphine Lig-ands in Metal Catalysis
- Author
-
Tobias Gensch, Guolin Xu, Yam Timsina, Thomas Colacot, Matthew S. Sigman, Ben Glasspoole, and Sleight R. Smith
- Subjects
Set (abstract data type) ,chemistry.chemical_compound ,chemistry ,Basis (linear algebra) ,Computer science ,Dimensionality reduction ,Context (language use) ,Cluster analysis ,Combinatorial chemistry ,Phosphine ,Chemical space ,Catalysis - Abstract
In reaction discovery, the search space of discrete reaction parameters such as catalyst structure is often not explored systematical-ly. We have developed a tool set to aid the search of optimal catalysts in the context of phosphine ligands. A virtual library, kra-ken, that is representative of the monodentate P(III)-ligand chemical space was utilized as the basis to represent the discrete lig-ands as continuous variables. Using dimensionality reduction and clustering techniques, we suggested a Phosphine Optimization Screening Set (PHOSS) of 32 commercially available ligands that samples this chemical space completely and evenly. We present the application of this screening set in the identification of active catalyst for various cross-coupling reactions and how well-distributed sampling of the chemical space facilitates identification of active catalysts. Furthermore, we demonstrate how proximi-ty in ligand space can be a useful guide to further explore ligands when very few active catalysts are known.
- Published
- 2021
32. Data Science Meets Physical Organic Chemistry
- Author
-
Jennifer M. Crawford, F. Dean Toste, Cian Kingston, and Matthew S. Sigman
- Subjects
Computer science ,Enantioselective synthesis ,Statistical model ,Context (language use) ,General Medicine ,General Chemistry ,Data science ,Article ,Transition state ,Catalysis ,Workflow ,Mechanism (philosophy) ,Chemical Sciences ,Physical organic chemistry - Abstract
ConspectusAt the heart of synthetic chemistry is the holy grail of predictable catalyst design. In particular, researchers involved in reaction development in asymmetric catalysis have pursued a variety of strategies toward this goal. This is driven by both the pragmatic need to achieve high selectivities and the inability to readily identify why a certain catalyst is effective for a given reaction. While empiricism and intuition have dominated the field of asymmetric catalysis since its inception, enantioselectivity offers a mechanistically rich platform to interrogate catalyst-structure response patterns that explain the performance of a particular catalyst or substrate.In the early stages of an asymmetric reaction development campaign, the overarching mechanism of the reaction, catalyst speciation, the turnover limiting step, and many other details are unknown or posited based on related reactions. Considering the unclear details leading to a successful reaction, initial enantioselectivity data are often used to intuitively guide the ultimate direction of optimization. However, if the conditions of the Curtin-Hammett principle are satisfied, then measured enantioselectivity can be directly connected to the ensemble of diastereomeric transition states (TSs) that lead to the enantiomeric products, and the associated free energy difference between competing TSs (ΔΔG⧧ = -RT ln[(S)/(R)], where (S) and (R) represent the concentrations of the enantiomeric products). We, and others, speculated that this important piece of information can be leveraged to guide reaction optimization in a quantitative way.Although traditional linear free energy relationships (LFERs), such as Hammett plots, have been used to illuminate important mechanistic features, we sought to develop data science derived tools to expand the power of LFERs in order to describe complex reactions frequently encountered in modern asymmetric catalysis. Specifically, we investigated whether enantioselectivity data from a reaction can be quantitatively connected to the attributes of reaction components, such as catalyst and substrate structural features, to harness data for asymmetric catalyst design.In this context, we developed a workflow to relate computationally derived features of reaction components to enantioselectivity using data science tools. The mathematical representation of molecules can incorporate many aspects of a transformation, such as molecular features from substrate, product, catalyst, and proposed transition states. Statistical models relating these features to reaction outputs can be used for various tasks, such as performance prediction of untested molecules. Perhaps most importantly, statistical models can guide the generation of mechanistic hypotheses that are embedded within complex patterns of reaction responses. Overall, merging traditional physical organic experiments with statistical modeling techniques creates a feedback loop that enables both evaluation of multiple mechanistic hypotheses and future catalyst design. In this Account, we highlight the evolution and application of this approach in the context of a collaborative program based on chiral phosphoric acid catalysts (CPAs) in asymmetric catalysis.
- Published
- 2021
33. Development and Molecular Understanding of a Pd-catalyzed Cyanation of Aryl Boronic Acids Enabled by High-Throughput Experimentation and Data Analysis
- Author
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Niccolò Bartalucci, Antonio Togni, Paul C. J. Kamer, Tobias Gensch, Claas Schünemann, Matthew S. Sigman, Samantha Grosslight, Bernd H. Müller, Benson J. Jelier, Jordan De Jesus Silva, and Christophe Copéret
- Subjects
inorganic chemicals ,Steric effects ,chemistry.chemical_compound ,chemistry ,Ligand ,Aryl ,Yield (chemistry) ,Functional group ,chemistry.chemical_element ,Cyanation ,Combinatorial chemistry ,Catalysis ,Palladium - Abstract
A synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic N-cyanosuccinimide has been developed. High-throughput experimentation facilitated the screen of 90 different ligands and the resultant statistical data analysis identified that ligand σ–donation, π–acidity and sterics are key drivers that govern yield. Categorization into three ligand groups – monophosphines, bisphosphines and miscellaneous – was performed before the analysis. For the monophosphines, the yield of the reaction increases for strong σ–donating, weak π–accepting ligands, with flexible pendant substituents. For the bisphosphines, the yield predominantly correlates with ligand lability. The applicability of the designed reaction to a wider substrate scope was investigated, showing good functional group tolerance in particular with boronic acids bearing electron-withdrawing substituents. This work outlines the develop-ment of a novel reaction, coupled with a fast and efficient workflow to gain understanding of the optimal ligand properties for the design of improved palladium cross-coupling catalysts.
- Published
- 2021
34. Nickel-catalyzed asymmetric reductive cross-coupling of α-chloroesters with (hetero)aryl iodides
- Author
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Sarah E. Reisman, Sara E. Dibrell, Leah Cleary, Caitlin R. Lacker, Adam R. Pancoast, Kelsey E. Poremba, Travis J. DeLano, and Matthew S. Sigman
- Subjects
Coupling ,Chemistry ,Ligand ,Aryl ,Enantioselective synthesis ,Substrate (chemistry) ,chemistry.chemical_element ,General Chemistry ,Combinatorial chemistry ,Catalysis ,chemistry.chemical_compound ,Nickel ,Polymer chemistry - Abstract
An asymmetric reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. This nickel-catalyzed reaction proceeds with a chiral BiOX ligand under mild conditions, affording α-arylesters in good yields and enantioselectivities. The reaction is tolerant of a variety of functional groups, and the resulting products can be converted to pharmaceutically-relevant chiral building blocks. A multivariate linear regression model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity., A Ni-catalyzed enantioselective reductive cross-coupling of α-chloroesters and (hetero)aryl iodides is reported. A MLR model was developed to quantitatively relate the influence of the α-chloroester substrate and ligand on enantioselectivity.
- Published
- 2021
35. Linking Mechanistic Analysis of Catalytic Reactivity Cliffs to Ligand Classification
- Author
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Tobias Gensch, Matthew S. Sigman, Julia E. Borowski, Abigail G. Doyle, Heather C. Johnson, Peters E, Newman-Stonebraker S, and Sleight R. Smith
- Subjects
Steric effects ,Denticity ,Computational chemistry ,Chemistry ,Ligand ,Molecular descriptor ,Feature (machine learning) ,Reactivity (chemistry) ,Representation (mathematics) ,Catalysis - Abstract
Statistical analysis of reaction data with molecular descriptors can enable chemists to identify reactivity cliffs that result from a mechanistic dependence on a specific structural feature. In this study, we develop a broadly applicable and quantitative classification workflow that identifies reactivity cliffs in eleven Ni- and Pd-catalyzed cross-coupling datasets employing monodentate phosphine ligands. A unique ligand steric descriptor, %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. Taken together, we expect that this strategy will be of broad value in mechanistic investigation of structure-reactivity relationships, while providing a means to rationally partition datasets for data-driven modeling.
- Published
- 2021
36. Enantioselective Synthesis of Alkyl Allyl Ethers via Palladium‐Catalyzed Redox‐Relay Heck Alkenylation of O ‐Alkyl Enol Ethers
- Author
-
Matthew B. Prater and Matthew S. Sigman
- Subjects
chemistry.chemical_classification ,010405 organic chemistry ,organic chemicals ,education ,Enantioselective synthesis ,chemistry.chemical_element ,General Chemistry ,Bond formation ,010402 general chemistry ,01 natural sciences ,Enol ,Medicinal chemistry ,Redox ,Article ,0104 chemical sciences ,Catalysis ,chemistry.chemical_compound ,chemistry ,Heck reaction ,Alkyl ,Palladium - Abstract
Herein we report a transformation that generates an array of enantiomerically enriched, alkyl allyl ethers. Cyclic, acyclic, and heteroatom-bearing alkenyl triflates undergo an enantioselective, palladium-catalyzed C–C bond formation with diverse acyclic O-alkyl enol ethers in good yields and excellent enantioselectivities.
- Published
- 2019
37. Mechanism-Based Design of a High-Potential Catholyte Enables a 3.2 V All-Organic Nonaqueous Redox Flow Battery
- Author
-
Yichao Yan, Melanie S. Sanford, Sophia G. Robinson, and Matthew S. Sigman
- Subjects
Colloid and Surface Chemistry ,Chemical engineering ,Chemistry ,Mechanism based ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Flow battery ,Redox ,Catalysis ,Energy storage ,0104 chemical sciences - Abstract
Nonaqueous redox flow batteries (RFBs) represent a promising technology for grid-scale energy storage. A key challenge for the field is identifying molecules that undergo reversible redox reactions at the extreme potentials required to leverage the large potential window of organic solvents. In this Article, we use a combination of computations, chemical synthesis, and mechanistic analysis to develop thioether-substituted cyclopropenium derivatives as high potential electrolytes for nonaqueous RFBs. These molecules exhibit redox potentials that are 470-500 mV higher than those of known electrolytes. Strategic variation of the alkyl substituent on sulfur afforded a derivative that undergoes charge-discharge cycling at +1.33 V vs ferrocene/ferrocenium in acetonitrile/tetrabutylammonium hexafluorophosphate. This electrolyte was paired with a phthalimide derivative to achieve a proof-of-principle 3.2 V all-organic RFB.
- Published
- 2019
38. A Physical Organic Approach to Tuning Reagents for Selective and Stable Methionine Bioconjugation
- Author
-
Wendy Cao, Matthew S. Sigman, Christopher J. Chang, Arismel Tena Meza, Alec H. Christian, F. Dean Toste, Shang Jia, and Patricia Zhang
- Subjects
Aziridines ,Chemical biology ,010402 general chemistry ,Peptides, Cyclic ,01 natural sciences ,Biochemistry ,Redox ,Article ,Catalysis ,Adduct ,chemistry.chemical_compound ,Methionine ,Colloid and Surface Chemistry ,Thioether ,Humans ,Bioconjugation ,General Chemistry ,Oxaziridine ,Combinatorial chemistry ,0104 chemical sciences ,HEK293 Cells ,chemistry ,Molecular Probes ,Reagent ,Chemical Sciences ,Indicators and Reagents - Abstract
We report a data-driven, physical organic approach to the development of new methionine-selective bioconjugation reagents with tunable adduct stabilities. Statistical modeling of structural features described by intrinsic physical organic parameters was applied to the development of a predictive model and to gain insight into features driving the stability of adducts formed from the chemoselective coupling of oxaziridine and methionine thioether partners through Redox Activated Chemical Tagging (ReACT). From these analyses, a correlation between sulfimide stabilities and sulfimide ν (C═O) stretching frequencies was revealed. We exploited the rational gains in adduct stability exposed by this analysis to achieve the design and synthesis of a bis-oxaziridine reagent for peptide stapling. Indeed, we observed that a macrocyclic peptide formed by ReACT stapling at methionine exhibited improved uptake into live cells compared to an unstapled congener, highlighting the potential utility of this unique chemical tool for thioether modification. This work provides a template for the broader use of data-driven approaches to bioconjugation chemistry and other chemical biology applications.
- Published
- 2019
39. Enantioselective construction of remote tertiary carbon–fluorine bonds
- Author
-
F. Dean Toste, Jian-Bo Liu, Qianjia Yuan, and Matthew S. Sigman
- Subjects
General method ,010405 organic chemistry ,Chemistry ,Extramural ,General Chemical Engineering ,Bond ,Organic Chemistry ,Enantioselective synthesis ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,Article ,0104 chemical sciences ,Catalysis ,Heck reaction ,Chemical Sciences ,Carbon–fluorine bond ,Reactivity (chemistry) - Abstract
The carbon-fluorine bond engenders distinctive physicochemical properties and significant changes to general reactivity, which have impacted molecular design in material science, agrochemicals, and pharmaceutical research. These unique features are generally derived from fluorine having the highest electronegativity coupled to an enhanced bond strength of the C‒F bond compared to a C‒H bond. As a result, C‒F bonds are often leveraged as replacements for C‒H bonds when the latter presents a liability at a saturated (sp(3)) carbon centre especially for benzylic C‒H bonds prone to metabolic oxidation. In this context, the development of catalytic, enantioselective methods to set stereocenters containing a benzylic C‒F bond has been an important and rapidly evolving goal in synthetic chemistry. There have been notable advances enabling the construction of secondary stereocenters containing both a C‒F and a C‒H bond on the same carbon. In contrast, there are significantly fewer synthetic strategies defined for accessing stereocenters that incorporate a tertiary C‒F bond, especially those remote from pre-existing activating groups. Herein, we report a general method that establishes C‒F tertiary, benzylic stereocenters by forging a C‒C bond via a Pd-catalyzed enantioselective Heck reaction of acyclic alkenyl fluorides with arylboronic acids. This method provides a platform to rapidly incorporate significant functionality about the benzylic tertiary fluoride by virtue of the diversity of both reaction partners as well as the ability to install the stereocenters remotely from pre-existing functional groups.
- Published
- 2019
40. Holistic Prediction of Enantioselectivity in Asymmetric Catalysis
- Author
-
Jolene P. Reid and Matthew S. Sigman
- Subjects
Multidisciplinary ,Nucleophilic addition ,010405 organic chemistry ,Computer science ,Enantioselective synthesis ,010402 general chemistry ,01 natural sciences ,Asymmetric induction ,Chemical synthesis ,Chemical space ,Article ,0104 chemical sciences ,Catalysis ,Workflow ,Reagent ,Biochemical engineering - Abstract
Summary: When faced with unfamiliar reaction space, synthetic chemists typically apply reported conditions (reagents, catalyst, solvent, additives) from closely-related reactions to new substrate types. Unfortunately, this approach often fails due to subtle, albeit important, differences in reaction requirements. Consequently, a significant goal in synthetic chemistry is the ability to transfer chemical observations from one reaction to another, quantitatively. Here, we present such a platform by developing a holistic, data-driven workflow for deriving statistical models for one set of reactions that can be applied to predict out-of-sample examples. As a validating case study, published enantioselectivity data sets that employ BINOL-derived chiral phosphoric acids for a range of nucleophilic addition reactions to imines were combined and statistical models developed. These models reveal the general interactions imparting asymmetric induction and allow the quantitative transfer of this information to new reaction components. The disclosed techniques create opportunities for translating comprehensive reaction analysis to diverse chemical space, streamlining both catalyst and reaction development., Methods Summary: After the database of the reactions is constructed, the experimental output, enantiomeric ratios, were mathematically modelled through linear regression techniques to reveal which of the proposed parameters allow for the prediction of new outcomes. The detailed acquisition of parameters can be found in the Supplementary Information and the descriptor tables attached as an accompanying spreadsheet. The models produced were evaluated for their goodness of fit, R2, and their robustness is demonstrated by external validations’ goodness of fit, predR2. The nearer the R2 and slope values are to one (indicating a tight, one-to-one correlation between predicted and measured outcomes) and the nearer the intercept is to zero (indicating minimal systematic error), the more robust the model. Potential models were refined through number of parameters, because this allows for a mechanistically informative interrogation and cross-validation scores. Leave one reaction out (LORO) analysis was performed to probe general mechanistic principles, which provides the basis for mechanistic transfer of experimental observations and tested further by predicting out-of-sample.
- Published
- 2019
41. Noncovalent Interactions Drive the Efficiency of Molybdenum Imido Alkylidene Catalysts for Olefin Metathesis
- Author
-
Alexey Fedorov, Jordan De Jesus Silva, Christophe Copéret, Samantha Grosslight, Matthew S. Sigman, and Marco A. B. Ferreira
- Subjects
chemistry.chemical_classification ,Chemistry ,Ligand ,Aryl ,General Chemistry ,010402 general chemistry ,Metathesis ,01 natural sciences ,Biochemistry ,Medicinal chemistry ,Catalysis ,0104 chemical sciences ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Electronic effect ,Salt metathesis reaction ,Phenol ,Non-covalent interactions - Abstract
High-throughput experimentation and multivariate modeling allow identification of noncovalent interactions (NCIs) in monoaryloxy-pyrrolide Mo imido alkylidene metathesis catalysts prepared in situ as a key driver for high activity in a representative metathesis reaction (homodimerization of 1-nonene). Statistical univariate and multivariate modeling categorizes catalytic data from 35 phenolic ligands into two groups, depending on the substitution in the ortho position of the phenol ligand. The catalytic activity descriptor TON1h correlates predominantly with attractive NCIs when phenols bear ortho aryl substituents and, conversely, with repulsive NCIs when the phenol has no aryl ortho substituents. Energetic span analysis is deployed to relate the observed NCI and the cycloreversion metathesis step such that aryloxide ligands with no ortho aryls mainly impact the energy of metallacyclobutane intermediates (SP/TBP isomers), whereas aryloxides with pendant ortho aryls influence the transition state energy for the cycloreversion step. While the electronic effects from the aryloxide ligands also play a role, our work outlines how NCIs may be exploited for the design of improved d0 metathesis catalysts.
- Published
- 2019
42. Enantioselective N-Alkylation of Indoles via an Intermolecular Aza-Wacker-Type Reaction
- Author
-
Jamie R. Allen, Yukino Furukawa, Matthew S. Sigman, and Ana Bahamonde
- Subjects
Allylic rearrangement ,Indoles ,Alkylation ,Stereochemistry ,Chemistry ,Prevention ,Intermolecular force ,Enantioselective synthesis ,Stereoisomerism ,Alcohol ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Catalysis ,0104 chemical sciences ,Stereocenter ,Enamine ,chemistry.chemical_compound ,Colloid and Surface Chemistry ,Chemical Sciences - Abstract
The development of an intermolecular and enantioselective aza-Wacker reaction is described. Using indoles as the N-source anda selection of alkenols as the coupling partnersselective β-hydride elimination toward the alcohol was achieved. This strategy preserves the newly formed stereocenter by preventing the formation of traditionally observed enamine products. Allylic and homoallylic alcohols with a variety of functional groups are compatible with the reaction in high enantioselectivity. Isotopic-labeling experiments support a syn amino-palladation mechanism for this new class of aza-Wacker reactions.
- Published
- 2019
43. Disparate Catalytic Scaffolds for Atroposelective Cyclodehydration
- Author
-
Jennifer M. Crawford, F. Dean Toste, Scott J. Miller, Roxane Jacob, Jolene P. Reid, Yongseok Kwon, Junqi Li, and Matthew S. Sigman
- Subjects
Chemistry ,Stereoisomerism ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Chemical synthesis ,Article ,Catalysis ,0104 chemical sciences ,Colloid and Surface Chemistry ,Organic chemistry ,Phosphoric Acids ,Density Functional Theory - Abstract
Catalysts that control stereochemistry are prized tools in chemical synthesis. When an effective catalyst is found, it is often explored for other types of reactions, frequently under the auspices of different mechanisms. As successes mount, a unique catalyst scaffold may become viewed as “privileged”. However, the mechanistic hallmarks of privileged catalysts are not easily enumerated, nor readily generalized to genuinely different classes of reactions or substrates. We explored the concept of scaffold uniqueness with two catalyst types for an unusual atropisomer-selective cyclodehydration: (a) C(2)-symmetric chiral phosphoric acids, and (b) phosphothreonine-embedded, peptidic phosphoric acids. Pragmatically, both catalyst scaffolds proved fertile for enantioselective/atroposelective cyclodehydrations. Mechanistic studies revealed that the determinants of often equivalent and high atroposelectivity are different for the two catalyst classes. A data-descriptive classification of these asymmetric catalysts reveals an increasingly broad set of catalyst chemotypes, operating with different mechanistic features, that creates new opportunities for broad and complementary application of catalyst scaffolds in diverse substrate space.
- Published
- 2019
44. Mechanistic Study of Ruthenium-Catalyzed C–H Hydroxylation Reveals an Unexpected Pathway for Catalyst Arrest
- Author
-
James B. C. Mack, Matthew S. Sigman, J. Du Bois, Katherine L. Walker, Richard N. Zare, Robert M. Waymouth, and Sophia G. Robinson
- Subjects
Substituent ,chemistry.chemical_element ,General Chemistry ,Electrochemistry ,Biochemistry ,Combinatorial chemistry ,Catalysis ,Dissociation (chemistry) ,Turnover number ,Ruthenium ,Hydroxylation ,chemistry.chemical_compound ,Bipyridine ,Colloid and Surface Chemistry ,chemistry - Abstract
We have recently disclosed [(dtbpy)2RuCl2] as an effective precatalyst for chemoselective C-H hydroxylation of C(sp3)-H bonds and have noted a marked disparity in reaction performance between 4,4'-di- tert-butyl-2,2'-bipyridine (dtbpy)- and 2,2'-bipyridine (bpy)-derived complexes. A desire to understand the origin of this difference and to further advance this catalytic method has motivated the comprehensive mechanistic investigation described herein. Details of this reaction have been unveiled through evaluation of ligand structure-activity relationships, electrochemical and kinetic studies, and pressurized sample infusion high-resolution mass spectrometry (PSI-MS). Salient findings from this investigation include the identification of more than one active oxidant and three disparate mechanisms for catalyst decomposition/arrest. Catalyst efficiency, as measured by turnover number, has a strong inverse correlation with the rate and extent of ligand dissociation, which is dependent on the identity of bipyridyl 4,4'-substituent groups. Dissociated bipyridyl ligand is oxidized to mono- and bis- N-oxide species under the reaction conditions, the former of which is found to act as a potent catalyst poison, yielding a catalytically inactive tris-ligated [Ru(dtbpy)2(dtbpy N-oxide)]2+ complex. Insights gained through this work highlight the power of PSI-MS for studies of complex reaction processes and are guiding ongoing efforts to develop high-performance, next-generation catalyst systems for C-H hydroxylation.
- Published
- 2019
45. Palladium-catalyzed enantioselective alkenylation of alkenylbenzene derivatives
- Author
-
Ryan J. DeLuca, Zhi-Min Chen, Jing-Yao Guo, Maximillan Loch, Matthew S. Sigman, and Jian-Bo Liu
- Subjects
010405 organic chemistry ,Aryl ,Enantioselective synthesis ,chemistry.chemical_element ,Regioselectivity ,General Chemistry ,010402 general chemistry ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Catalysis ,Stereocenter ,chemistry.chemical_compound ,chemistry ,Rapid access ,Palladium - Abstract
A regioselective and enantioselective palladium-catalyzed relay Heck alkenylation of alkenylbenzene derivatives to construct remote stereocenters is disclosed. Various β-substituted styrenes were readily obtained in moderate yields with good to excellent levels of enantioselectivity. This strategy provides rapid access to enantioenriched δ, e, ζ, and η-alkenyl aryl compounds from simple starting materials. Mechanistic studies suggest that termination of the relay reaction is controlled by affinity of the arene for the Pd complex during migration.
- Published
- 2019
46. Catalytic Carbonyl-Olefin Metathesis of Aliphatic Ketones: Iron(III) Homo-Dimers as Lewis Acidic Superelectrophiles
- Author
-
Matthew S. Sigman, Christopher C. McAtee, Paul M. Zimmerman, Haley Albright, Jolene P. Reid, Jacob R. Ludwig, Lindsey A. Karp, Corinna S. Schindler, and Paul S. Riehl
- Subjects
Models, Molecular ,Iron ,Molecular Conformation ,Aryl ketone ,Alkenes ,Metathesis ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Article ,Catalysis ,Colloid and Surface Chemistry ,Salt metathesis reaction ,Organic chemistry ,Lewis acids and bases ,Lewis Acids ,Olefin metathesis ,Chemistry ,General Chemistry ,Ketones ,Bond formation ,Combinatorial chemistry ,Lewis acid catalysis ,0104 chemical sciences ,Dimerization - Abstract
Catalytic carbonyl-olefin metathesis reactions have recently been developed as a powerful tool for carbon-carbon bondformation. However, currently available synthetic protocols rely exclusively on aryl ketone substrates while the corresponding aliphatic analogs remain elusive. We herein report the development of Lewis acid-catalyzed carbonyl-olefin ring-closing metathesis reactions for aliphatic ketones. Mechanistic investigations are consistent with a distinct mode of activation relying on the in situ formation of a homobimetallic singly-bridged iron(III)-dimer as the active catalytic species. These “superelectrophiles” function as more powerful Lewis acid catalysts that form upon association of individual iron(III)-monomers. While this mode of Lewis acid activation has previously been postulated to exist, it has not yet been applied in a catalytic setting. The insights presented are expected to enable further advancement in Lewis acid catalysis by building upon the activation principle of “superelectrophiles” and broaden the current scope of catalytic carbonyl-olefin metathesis reactions.
- Published
- 2018
47. Enantiodivergent Pd-catalyzed C–C bond formation enabled through ligand parameterization
- Author
-
Tobias Gensch, Benjamin Murray, Shibin Zhao, Matthew S. Sigman, Mark R. Biscoe, and Zachary L. Niemeyer
- Subjects
Multidisciplinary ,010405 organic chemistry ,Ligand ,Stereochemistry ,Bond formation ,010402 general chemistry ,01 natural sciences ,Article ,0104 chemical sciences ,Catalysis ,Transmetalation ,chemistry.chemical_compound ,Stereospecificity ,chemistry ,Nucleophile ,Molecular descriptor ,Phosphine - Abstract
The staying power of electron-poor ligands The venerable Suzuki coupling reaction originally used palladium to pair up unsaturated carbon centers. The protocol has been widely extended to chiral saturated alkyl carbons, but control over product stereochemistry is a pressing challenge. Zhao et al. systematically studied how the properties of the phosphine ligands that are coordinated to the catalyst influence the stereochemical outcome. Certain electron-withdrawing phosphines favored retention of the initial configuration in chiral alkyltrifluoroborate reactants. Conversely, bulky electron-rich phosphines lead to inverted configurations in the products. Science , this issue p. 670
- Published
- 2018
48. A Comprehensive Discovery Platform for Organophosphorus Ligands for Catalysis
- Author
-
Kjell Jorner, AkshatKumar Nigam, Alán Aspuru-Guzik, Robert Pollice, Matthew S. Sigman, dos Passos Gomes G, Tobias Gensch, Pascal Friederich, Peters E, Lindner D'Addario M, and Gaudin T
- Subjects
Workflow ,Colloid and Surface Chemistry ,Computer science ,Ligand ,Kraken ,Pruning (decision trees) ,Biochemical engineering ,General Chemistry ,Biochemistry ,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 1,558 ligands, including commercially available examples, and trained machine learning models to predict properties of over 300,000 new ligands. We demonstrate the application of kraken to systematically explore the property space of organophosphorus ligands and how existing datasets in catalysis can be used to accelerate ligand selection during reaction optimization.
- Published
- 2021
49. Interrogation of 2,2'-Bipyrimidines as Low-Potential Two-Electron Electrolytes
- Author
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Matthew S. Sigman, Jeremy D. Griffin, and Adam R. Pancoast
- Subjects
Steric effects ,Molecular Structure ,Chemistry ,Protonation ,Electrons ,General Chemistry ,Electrolyte ,Electrochemistry ,Biochemistry ,Redox ,Combinatorial chemistry ,Catalysis ,Article ,Electrolytes ,Colloid and Surface Chemistry ,Electric Power Supplies ,Pyrimidines ,Molecule ,Density functional theory ,Solubility ,Electrodes ,Oxidation-Reduction ,Density Functional Theory - Abstract
As utilization of renewable energy sources continues to expand, the need for new grid energy storage technologies such as redox flow batteries (RFBs) will be vital. Ultimately, the energy density of a RFB will be dependent on the redox potentials of the respective electrolytes, their solubility, and the number of electrons stored per molecule. With prior literature reports demonstrating the propensity of nitrogen containing heterocycles to undergo multi-electron reduction at low potentials, we focused on the development of a novel electrolyte scaffold based upon a 2,2’-bipyrimidine skeleton. This scaffold is capable of storing two electrons per molecule while also exhibiting a low (~ −2.0 V vs Fc/Fc(+)) reduction potential. A library of 24 potential bipyrimidine anolytes were synthesized and systematically evaluated to unveil structure-function relationships through computational evaluation. Through analysis of these relationships, it was unveiled that steric interactions disrupting the planarity of the system in the reduced state could be responsible for higher levels of degradation in certain anolytes. The major decomposition pathway was ultimately determined to be protonation of the dianion by solvent; which could be reversed by electrochemical or chemical oxidation. To validate the hypothesis of strain-induced decomposition, two new electrolytes with minimal steric encumbrance were synthesized, evaluated, and found to indeed exhibit higher stability than their sterically hindered counterparts.
- Published
- 2021
50. Development and Molecular Understanding of a Pd-Catalyzed Cyanation of Aryl Boronic Acids Enabled by High-Throughput Experimentation and Data Analysis
- Author
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Jordan De Jesus Silva, Antonio Togni, Benson J. Jelier, Claas Schünemann, Paul C. J. Kamer, Christophe Copéret, Bernd H. Müller, Matthew S. Sigman, Niccolò Bartalucci, Samantha Grosslight, and Tobias Gensch
- Subjects
inorganic chemicals ,ligand design ,Aryl ,Organic Chemistry ,data analysis ,chemistry.chemical_element ,Cyanation ,aryl boronic acids ,cyanation ,high-throughput experimentation ,palladium ,Biochemistry ,Combinatorial chemistry ,Catalysis ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Physical and Theoretical Chemistry ,Throughput (business) ,Palladium - Abstract
A synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic N-cyanosuccinimide has been developed. High-throughput experimentation facilitated the screen of 90 different ligands and the resultant statistical data analysis identified that ligand sigma-donation, pi-acidity and sterics are key drivers that govern yield. Categorization into three ligand groups - monophosphines, bisphosphines and miscellaneous - was performed before the analysis. For the monophosphines, the yield of the reaction increases for strong sigma-donating, weak pi-accepting ligands, with flexible pendant substituents. For the bisphosphines, the yield predominantly correlates with ligand lability. The applicability of the designed reaction to a wider substrate scope was investigated, showing good functional group tolerance in particular with boronic acids bearing electron-withdrawing substituents. This work outlines the development of a novel reaction, coupled with a fast and efficient workflow to gain understanding of the optimal ligand properties for the design of improved palladium cross-coupling catalysts., Helvetica Chimica Acta, 104 (12), ISSN:0018-019X, ISSN:1522-2675
- Published
- 2021
- Full Text
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