skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Computational Methods Enable the Prediction of Improved Catalysts for Nickel-Catalyzed Cross-Electrophile Coupling
Cross-electrophile coupling has emerged as an attractive and efficient method for the synthesis of C(sp2)–C(sp3) bonds. These reactions are most often catalyzed by nickel complexes of nitrogenous ligands, especially 2,2’-bipyridines. Precise prediction, selection, and design of optimal ligands remains challenging, despite significant increases in reaction scope and mechanistic understanding. Molecular parame-terization and statistical modeling provide a path to the development of improved bipyridine ligands that will enhance the selectivity of existing reactions and broaden the scope of electrophiles that can be coupled. Herein, we describe the generation of a computational lig-and library, correlation of observed reaction outcomes with features of the ligands, and in silico design of improved bipyridine ligands for Ni-catalyzed cross-electrophile coupling. The new nitrogen-substituted ligands display a fivefold increase in selectivity for product formation versus homodimerization when compared to the current state of the art. This increase in selectivity and yield was general for several cross-electrophile couplings, including the challenging coupling of an aryl chloride with an N-alkylpyridinium salt.  more » « less
Award ID(s):
1900366 2154502
PAR ID:
10489752
Author(s) / Creator(s):
; ; ; ; ; ; ;
Publisher / Repository:
American Chemical Society
Date Published:
Journal Name:
Journal of the American Chemical Society
Volume:
146
Issue:
5
ISSN:
0002-7863
Page Range / eLocation ID:
3043 to 3051
Subject(s) / Keyword(s):
organic chemistry catalysis modeling
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; ; ; (, Journal of the American Chemical Society)
    Nickel-catalyzed cross-electrophile coupling (XEC) reactions of (hetero)aryl electrophiles represent appealing alternatives to palladium-catalyzed methods for biaryl synthesis, but they often generate significant quantities of homocoupling and/or proto-dehalogenation side products. In this study, an informer library of heteroaryl chloride and aryl bromide coupling partners is used to identify Ni-catalyzed XEC conditions that access high selectivity for the cross-product when using equimolar quantities of the two substrates. Two different catalyst systems are identified that show complementary scope and broad functional-group tolerance, and time-course data suggest the two methods follow different mechanisms. A NiBr2/terpyridine catalyst system with Zn as the reductant converts the aryl bromide into an aryl-zinc intermediate that undergoes in situ coupling with 2-chloropyridines, while a NiBr2/bipyridine catalyst system with tetrakis(dimethylamino)ethylene as the reductant uses FeBr2 and NaI as additives to achieve selective cross-coupling. 
    more » « less
  2. ; (, Advanced Synthesis & Catalysis)
    Abstract Direct preparation of alkylated amide‐derivatives by cross‐coupling chemistry using sustainable protocols is challenging due to sensitivity of the amide functional group to reaction conditions. Herein, we report the synthesis of alkyl‐substituted amides by iron‐catalyzed C(sp2)−C(sp3) cross‐coupling of Grignard reagents with aryl chlorides. The products of these reactions are broadly used in the synthesis of pharmaceuticals, agrochemicals and other biologically‐active molecules. Furthermore, amides are used as versatile intermediates that can participate in the synthesis of valuable ketones and amines, providing access to motifs of broad synthetic interest. The reaction is characterized by its good substrate scope, tolerating a range of amide substitution, including sterically‐bulky, sensitive and readily modifiable amides. The reaction is compatible with challenging organometallics possessing β‐hydrogens, and proceeds under very mild, operationally‐simple conditions. Optimization of the catalyst system demonstrated the beneficial effect of O‐coordinating ligands on the cross‐coupling. The reaction was found to be fully chemoselective for the mono‐substitution at the less sterically‐hindered position. Mechanistic studies establish the order of reactivity and provide insight into the role of amide to control mono‐selectivity of the alkylation. The protocol provides the possibility for convenient access to alkyl‐amide structural building blocks using sustainable cross‐coupling conditions with high efficiency. magnified image 
    more » « less
  3. ; (, Molecules)
    Aryl benzoates are compounds of high importance in organic synthesis. Herein, we report the iron-catalyzed C(sp2)–C(sp3) Kumada cross-coupling of aryl chlorobenzoates with alkyl Grignard reagents. The method is characterized by the use of environmentally benign and sustainable iron salts for cross-coupling in the catalytic system, employing benign urea ligands in the place of reprotoxic NMP (NMP = N-methyl-2-pyrrolidone). It is notable that high selectivity for the cross-coupling is achieved in the presence of hydrolytically-labile and prone to nucleophilic addition phenolic ester C(acyl)–O bonds. The reaction provides access to alkyl-functionalized aryl benzoates. The examination of various O-coordinating ligands demonstrates the high activity of urea ligands in promoting the cross-coupling versus nucleophilic addition to the ester C(acyl)–O bond. The method showcases the functional group tolerance of iron-catalyzed Kumada cross-couplings. 
    more » « less
  4. ; ; ; (, Reaction Chemistry & Engineering)
    This perspective describes Auto-QChem, an automatic, high-throughput and end-to-end DFT calculation workflow that computes chemical descriptors for organic molecules. Tailored toward users without extensive programming experience, Auto-QChem has facilitated more than 38 000 DFT calculations for 17 000 molecules as of January 2022. Starting from string representations of molecules, Auto-QChem automatically (a) generates conformational ensembles, (b) submits and manages DFT calculations on a high-performance computing (HPC) cluster, (c) extracts production-ready features that are suitable for statistical analysis and machine learning model development, and (d) stores resulting calculations in a cloud-hosted and web-accessible database. We describe in detail the design and implementation of Auto-QChem, as well as its current functionalities. We also review three case studies where Auto-QChem was applied to our recent efforts in combining data science approaches in organic chemistry methodology development: (a) the design of a diverse and unbiased aryl bromide substrate scope for a Ni/photoredox catalyzed alkylation reaction, (b) mechanistic studies on the effect of bioxazoline (BiOx) and biimidazoline (BiIm) ligands on enantioselectivity in a Ni/photoredox catalyzed cross-electrophile coupling of epoxides and aryl iodides, (c) the development of a reaction condition optimization framework using Bayesian optimization. In addition, we discuss limitations and future directions of Auto-QChem and similar automated DFT calculation systems. 
    more » « less
  5. ; (, Catalysis Science & Technology)
    null (Ed.)
    Although palladium-catalyzed cross-coupling of aryl halides and reactive pseudohalides has revolutionized the way organic molecules are constructed today across various fields of chemistry, comparatively less progress has been made in the palladium-catalyzed cross-coupling of less reactive C–O electrophiles. This is despite the fact that the use of phenols and phenol derivatives as bench-stable cross-coupling partners has been well-recognized to bring about major advantages over aryl halides, such as natural abundance of phenols, (2) avoidance of toxic halides, (3) orthogonal cross-coupling conditions, (4) prefunctionalization of phenolic substrates by electrophilic substitution or C–H functionalization, (5) ready availability of phenols from a different pool of precursors than aryl halides. In this review, we present an overview of recent advances made in the field of palladium-catalyzed cross-coupling of C–O electrophiles with a focus on catalytic systems, (2) reaction type, and (3) class of C–O coupling partners. Although the field has been historically dominated by nickel catalysis, it is now evident that the use of more versatile, more functional group tolerant and highly active palladium catalysts supported by appropriately designed ancillary ligands enables the cross-coupling with improved substrate scope and generality, and likely represents a practical solution to the broadly applicable cross-coupling of various C–O bonds across diverse chemical disciplines. The review covers the period through June 2020. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email