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Journal ArticleDOI

Development and Molecular Understanding of a Pd-catalyzed Cyanation of Aryl Boronic Acids Enabled by High-Throughput Experimentation and Data Analysis

TL;DR: In this article, a synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic Ncyanosuccinimide has been developed.
Abstract: A synthetic method for the palladium-catalyzed cyanation of aryl boronic acids using bench stable and non-toxic Ncyanosuccinimide 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 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.
Citations
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01 Sep 2010
TL;DR: In this paper, the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations for Pd-catalyzed amination reactions is discussed.
Abstract: Dialkylbiaryl phosphines are a valuable class of ligand for Pd-catalyzed amination reactions and have been applied in a range of contexts. This perspective attempts to aid the reader in the selection of the best choice of reaction conditions and ligand of this class for the most commonly encountered and practically important substrate combinations.

966 citations

Journal ArticleDOI
TL;DR: Kraken as mentioned in this paper is a discovery platform covering monodentate organophosphorus(III) ligands providing comprehensive physicochemical descriptors based on representative conformer ensembles.
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.

53 citations

Journal ArticleDOI
TL;DR: In this article , the integration of statistical principles into homogeneous catalysis can streamline not only reaction optimization protocols but also mechanistic investigation procedures, highlighting how different aspects of molecular modeling, data set design, data visualization, and nuanced data restructuring can contribute to improving chemical reactivity and selectivity, while furthering our understanding of reaction mechanisms.
Abstract: The chemical sciences are witnessing an influx of statistics into the catalysis literature. These developments are propelled by modern technological advancements that are leading to fast and reliable data production, mining, and management. In organic chemistry, models encoded with information-rich parameters have facilitated the formulation of mechanistic hypotheses across different data-size regimes. Herein, we aim to demonstrate through selected examples that the integration of statistical principles into homogeneous catalysis can streamline not only reaction optimization protocols but also mechanistic investigation procedures. Namely, we highlight how different aspects of molecular modeling, data set design, data visualization, and nuanced data restructuring can contribute to improving chemical reactivity and selectivity, while furthering our understanding of reaction mechanisms. By mapping out these techniques at different data set sizes, we hope to encourage the broad application of data-driven approaches for mechanistic studies regardless of the accessible amount of data.

6 citations

Journal ArticleDOI
TL;DR: In this article , a machine learning workflow for the multi-objective optimization of catalytic reactions that employ chiral bisphosphine ligands was described through the optimization of two sequential reactions required in the asymmetric synthesis of an active pharmaceutical ingredient.
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.

5 citations

BookDOI
01 Jan 2004
TL;DR: The Science of Synthesis is a quality reference work developed by a highly esteemed editorial board to provide a comprehensive and critical selection of reliable organic and organometallic synthetic methods.
Abstract: Science of Synthesis: Houben-Weyl Methods of Molecular Transformations is the entirely new edition of the acclaimed reference series Houben-Weyl, the standard synthetic chemistry resource since 1909. This new edition is published in English and will comprise 48 volumes published between the years 2000 and 2008. Science of Synthesis is a quality reference work developed by a highly esteemed editorial board to provide a comprehensive and critical selection of reliable organic and organometallic synthetic methods. This unique resource is designed to be the first point of reference when searching for a synthesis strategy. Contains the expertise of presently 400 leading chemists worldwide. Critically evaluates the preparative applicability and significance of the synthetic methods. Discusses relevant background information and provides detailed experimental procedures For full information on the Science of Synthesis series, visit the Science of Synthesis Homepage Series Editors: D. Bellus, S. V. Ley, R. Noyori, M. Regitz, E. Schaumann, I. Shinkai, E. J. Thomas, B. M. Trost, P. J. Reider

2 citations

References
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Book
01 Jan 1966
TL;DR: In this article, the Straight Line Case is used to fit a straight line by least squares, and the Durbin-Watson Test is used for checking the straight line fit.
Abstract: Basic Prerequisite Knowledge. Fitting a Straight Line by Least Squares. Checking the Straight Line Fit. Fitting Straight Lines: Special Topics. Regression in Matrix Terms: Straight Line Case. The General Regression Situation. Extra Sums of Squares and Tests for Several Parameters Being Zero. Serial Correlation in the Residuals and the Durbin--Watson Test. More of Checking Fitted Models. Multiple Regression: Special Topics. Bias in Regression Estimates, and Expected Values of Mean Squares and Sums of Squares. On Worthwhile Regressions, Big F's, and R 2 . Models Containing Functions of the Predictors, Including Polynomial Models. Transformation of the Response Variable. "Dummy" Variables. Selecting the "Best" Regression Equation. Ill--Conditioning in Regression Data. Ridge Regression. Generalized Linear Models (GLIM). Mixture Ingredients as Predictor Variables. The Geometry of Least Squares. More Geometry of Least Squares. Orthogonal Polynomials and Summary Data. Multiple Regression Applied to Analysis of Variance Problems. An Introduction to Nonlinear Estimation. Robust Regression. Resampling Procedures (Bootstrapping). Bibliography. True/False Questions. Answers to Exercises. Tables. Indexes.

18,952 citations

Journal ArticleDOI
TL;DR: In this paper, a cross-coupling reaction is proposed for coupling 1 -Alkenylboron Derivatives: Synthesis of Conjugated Dienes 6.
Abstract: B. Other Catalyti; Process by Transition-Metal Complexes IV. Cross-Coupling Reaction A. Coupling of 1 -Alkenylboron Derivatives: Synthesis of Conjugated Dienes 6. Coupling of Arylboron Derivatives: Synthesis of Biaryls C. Coupling of Alkylboron Derivatives D. Coupling with Triflates E. Synthesis of Vinylic Sulfides F. Coupling with lodoalkanes: Alkyl-Alkyl CouDlino G. Coupling with Other Organic Halides and Boron Reagents V. Head-to-Tail Coupling VI. Carbonylative Coupling VII. Alkoxycarbonylation and Dimerization VIII. Conclusion 2457 2458 2458

10,937 citations

Journal ArticleDOI
TL;DR: In this article, the representative (E)-1-alkenyldisiamylboranes and 1-alkenyl-1,3,2-benzodioxaboroles readily obtainable via hydroboration of 1 -alkynes react with (1) halides or (1)-alkynyl halides in the presence of a catalytic amount of tetrakis(triphenylphosphine)palladium and base to give corresponding conjugated (E-dienes or (E-)enynes with high regio-and

1,731 citations

Journal ArticleDOI
TL;DR: Structural studies of various 1.Pd complexes are presented along with computational data that help elucidate the efficacy that 1 imparts on Suzuki-Miyaura coupling processes, and a comparison of the reactions is presented that is informative in determining the relative importance of ligand bulk and electron-donating ability in the high activity of catalysts derived from ligands of this type.
Abstract: Suzuki−Miyaura coupling reactions of aryl and heteroaryl halides with aryl-, heteroaryl- and vinylboronic acids proceed in very good to excellent yield with the use of 2-(2‘,6‘-dimethoxybiphenyl)dicyclohexylphosphine, SPhos (1). This ligand confers unprecedented activity for these processes, allowing reactions to be performed at low catalyst levels, to prepare extremely hindered biaryls and to be carried out, in general, for reactions of aryl chlorides at room temperature. Additionally, structural studies of various 1·Pd complexes are presented along with computational data that help elucidate the efficacy that 1 imparts on Suzuki−Miyaura coupling processes. Moreover, a comparison of the reactions with 1 and with 2-(2‘,4‘,6‘-triisopropylbiphenyl)diphenylphosphine (2) is presented that is informative in determining the relative importance of ligand bulk and electron-donating ability in the high activity of catalysts derived from ligands of this type. Further, when the aryl bromide becomes too hindered, an ...

1,562 citations