Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms DOI Creative Commons
Matthew J. Kania, Albert Reyes, Sharon R. Neufeldt

et al.

Published: April 1, 2024

Two limiting mechanisms are possible for oxidative addition of (hetero)aryl (pseudo)halides at Pd(0): a 3-centered concerted and nucleophilic displacement mechanism. Until now, there has been little understanding about when each mechanism is relevant. Prior investigations to distinguish between these pathways were limited few specific combinations substrate ligand. Here, we computationally evaluated over 150 transition structures in order determine mechanistic trends based on substrate, ligand(s), coordination number. Natural abundance 13C kinetic isotope effects provide experimental results consistent with computational predictions. Key findings include that (1) differences HOMO symmetries dictate that, although 12e– PdL strongly biased toward mechanism, 14e– PdL2 often prefers mechanism; (2) ligand electronics sterics, including bite angle, influence the preferred reaction PdL2; (3) phenyl triflate always reacts through regardless catalyst structure due stability anion inability oxygen effectively donate electron density Pd; (4) high reactivity C—X bonds adjacent nitrogen pyridine substrates relates stereoelectronic stabilization state. This work implications controlling rate selectivity catalytic couplings, demonstrate application insight chemodivergent cross-couplings bromochloroheteroarenes.

Language: Английский

Interrogating the Mechanistic Features of Ni(I)-Mediated Aryl Iodide Oxidative Addition Using Electroanalytical and Statistical Modeling Techniques DOI
Tianhua Tang, Avijit Hazra, Daniel S. Min

et al.

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(15), P. 8689 - 8699

Published: April 4, 2023

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

Language: Английский

Citations

48
Rapid planning and analysis of high-throughput experiment arrays for reaction discovery DOI Creative Commons
Babak Mahjour, Rui Zhang, Yuning Shen

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 3, 2023

High-throughput experimentation (HTE) is an increasingly important tool in reaction discovery. While the hardware for running HTE chemical laboratory has evolved significantly recent years, there remains a need software solutions to navigate data-rich experiments. Here we have developed phactor™, that facilitates performance and analysis of laboratory. phactor™ allows experimentalists rapidly design arrays reactions or direct-to-biology experiments 24, 96, 384, 1,536 wellplates. Users can access online reagent data, such as inventory, virtually populate wells with produce instructions perform array manually, assistance liquid handling robot. After completion array, analytical results be uploaded facile evaluation, guide next series All metadata, are stored machine-readable formats readily translatable various software. We also demonstrate use discovery several chemistries, including identification low micromolar inhibitor SARS-CoV-2 main protease. Furthermore, been made available free academic 24- 96-well via interface.

Language: Английский

Citations

30
Cross-Electrophile Coupling of Benzyl Halides and Disulfides Catalyzed by Iron DOI Creative Commons
Julius Semenya,

Yuan-Jie Yang,

Elias Picazo

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(7), P. 4903 - 4912

Published: Feb. 12, 2024

Cross-electrophile couplings are influential reactions that typically require a terminal reductant or photoredox conditions. We discovered an iron-catalyzed reaction couples benzyl halides with disulfides to yield thioether products in the absence of and under The disclosed platform proceeds without sulfur-induced catalyst poisoning use exogenous base, supporting broad scope circumventing undesired elimination pathways. applied developed chemistry new mode disulfide bioconjugation, drug synthesis, gram-scale product derivatization. Lastly, we performed mechanistic experiments better understand stereoablative between two electrophiles. Disulfides benzylic thioethers imperative for biological pharmaceutical applications but remain severely understudied comparison their ethereal amino counterparts. Hence, expect this iron catalysis downstream be interest greater scientific community.

Language: Английский

Citations

14
Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms DOI
Matthew J. Kania, Albert Reyes, Sharon R. Neufeldt

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(28), P. 19249 - 19260

Published: July 3, 2024

Two limiting mechanisms are possible for oxidative addition of (hetero)aryl (pseudo)halides at Pd(0): a 3-centered concerted and nucleophilic displacement mechanism. Until now, there has been little understanding about when each mechanism is relevant. Prior investigations to distinguish between these pathways were limited few specific combinations the substrate ligand. Here, we computationally evaluated over 180 transition structures in order determine mechanistic trends based on substrate, ligand(s), coordination number. Natural abundance

Language: Английский

Citations

10
Different Oxidative Addition Mechanisms for 12- and 14-Electron Palladium(0) Explain Ligand-Controlled Divergent Site Selectivity DOI
Jacob P. Norman, Nathaniel G. Larson, Sharon R. Neufeldt

et al.

ACS Catalysis, Journal Year: 2022, Volume and Issue: 12(15), P. 8822 - 8828

Published: July 8, 2022

In cross-coupling reactions, dihaloheteroarenes are usually most reactive at C─halide bonds adjacent to a heteroatom. This selectivity has been previously rationalized. However, no mechanistic explanation exists for anomalous reports in which specific ligands effect inverted with dihalopyridines and -pyridazines. Here we provide evidence that these uniquely promote oxidative addition 12e- Pd(0). Computations indicate 14e- Pd(0) can favor different mechanisms due differences their HOMO symmetries. These shown lead site preferences, where an atypical distal nitrogen.

Language: Английский

Citations

34
Recent Expedition inPd‐CatalyzedSonogashira Coupling and Related Processes† DOI
Pui Ying Choy, Kin Boon Gan, Fuk Yee Kwong

et al.

Chinese Journal of Chemistry, Journal Year: 2022, Volume and Issue: 41(9), P. 1099 - 1118

Published: Dec. 13, 2022

Comprehensive Summary Sonogashira cross‐coupling protocol, typically showing the reaction between aryl/vinyl halide and terminal alkyne, has been a widely used protocol for constructing C(sp 2 )‐C(sp) bond. The resulting internal alkynes are highly versatile reaching differently functionalized alkyne‐containing scaffolds or serving as valuable synthetic synthons to many other functional groups. It is worth noting that products originated from this coupling mostly applicable be transformed into corresponding Z ‐alkene, alkane, heterocyclic moieties in natural product syntheses. conditions catalyst systems able tweaked order facilitate activation of steric hindered and/or electron‐rich electrophiles. Pd‐catalyzed copper‐free caught increasing attention improved method can more environmentally friendly. What more, readily amended allow fusion carbonylation decarboxylation step catalytic cycle, thus complex yet convergent synthesis proceed an operationally simple one‐pot manner.

Language: Английский

Citations

33
Mechanistic Inference from Statistical Models at Different Data-Size Regimes DOI
Danilo M. Lustosa, Anat Milo

ACS Catalysis, Journal Year: 2022, Volume and Issue: 12(13), P. 7886 - 7906

Published: June 17, 2022

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

Language: Английский

Citations

29
We Already Know Everything about Oxidative Addition to Pd(0): Do We? DOI
Jordan Rio,

Haosheng Liang,

Lionel Perrin

et al.

ACS Catalysis, Journal Year: 2023, Volume and Issue: 13(17), P. 11399 - 11421

Published: Aug. 15, 2023

The oxidative addition (OA) of organic electrophiles to Pd(0) is a fundamental step in organopalladium chemistry and plays key role palladium-catalyzed cross-coupling reactions. This perspective summarizes selected mechanistic studies the Pd(0)-to-Pd(II) OA process involving halides pseudohalides with focus on systems relevant catalytic results are organized according nature supporting ligands, extracting general trends, describing most examples. formation active species from precatalysts surveyed, as well influence different that could be present under conditions process, providing guidelines facilitate understanding improvement

Language: Английский

Citations

19
The Road Less Traveled: Unconventional Site Selectivity in Palladium-Catalyzed Cross-Couplings of Dihalogenated N-Heteroarenes DOI
Jacob P. Norman, Sharon R. Neufeldt

ACS Catalysis, Journal Year: 2022, Volume and Issue: 12(19), P. 12014 - 12026

Published: Sept. 19, 2022

The vast majority (≥90%) of literature reports agree on the regiochemical outcomes Pd-catalyzed cross-coupling reactions for most classes dihalogenated N-heteroarenes. Despite a well-established mechanistic rationale typical selectivity, several examples reveal that changes to catalyst can switch site leading unconventional product. In this Perspective, we survey these unusual cases in which divergent selectivity is controlled by ligands or speciation. some cases, origin inverted has been established, but others mechanism remains unknown. This Perspective concludes with discussion remaining challenges and opportunities field site-selective cross-coupling. These include developing better understanding oxidative addition mechanisms, role speciation establishing an explanation influence ring substituents outcome, inverting "stubborn" substrates, minimizing unwanted over-reaction di- polyhalogenated substrates.

Language: Английский

Citations

24
A broadly applicable quantitative relative reactivity model for nucleophilic aromatic substitution (SNAr) using simple descriptors DOI Creative Commons

Jingru Lu,

Irina Paci, David C. Leitch

et al.

Chemical Science, Journal Year: 2022, Volume and Issue: 13(43), P. 12681 - 12695

Published: Jan. 1, 2022

A model for S N Ar reactivity is reported, built from relative rate data obtained by competition studies. Based only on molecular descriptors of the electrophile, predicts and site selectivity many complex substrates.

Language: Английский

Citations

24