Quantitative Reactivity Models for Oxidative Addition to L2Pd(0): Additional Substrate Classes, Solvents, and Mechanistic Insights DOI Creative Commons

Jingru Lu,

Holly Celuszak,

Irina Paci

et al.

Chemistry - A European Journal, Journal Year: 2024, Volume and Issue: 30(62)

Published: Aug. 20, 2024

Abstract Quantitative molecular structure‐reactivity models are useful for generating predictions to guide synthesis design, and in formulating testing mechanistic hypotheses. We report an expanded multivariate linear regression (MLR) model the rate of (hetero)aryl ( pseudo )halide oxidative addition L 2 Pd(0), here exemplified by Pd(PCy 3 ) . This builds on a prior from our group, with additional substrate classes (aryl chlorides iodides) reaction solvents (THF, toluene, THF/DMF mixture). Overall solvent effects across entire set minimal under these conditions, enabling unified MLR without introduction new descriptors beyond original five. Examining origin two electrostatic potential ESP led generation simpler, four descriptor that is suitable aryl halides, but not 2‐halopyridines. Using this we identified outlier, 2‐pyridyl triflate, which undergoes nucleophilic displacement does involve adjacent nitrogen atom. Finally, discuss relationship between C−X bond strength rates, compare intrinsic index IBSI dissociation enthalpy BDE as descriptor.

Language: Английский

Regioselective Suzuki–Miyarua Cross-Coupling for Substituted 2,4-Dibromopyridines Catalyzed by C3-Symmetric Tripalladium Clusters DOI

Zhixin He,

Meng Chen,

Yingrui Song

et al.

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: 90(5), P. 1895 - 1904

Published: Jan. 24, 2025

Multipalladium clusters possess peculiar structures and synergistic effects for reactivity selectivity. Herein, C3-symmetric tripalladium (1, 0.5 mol %) afford C2-regioselective SMCC of 2,4-dibromopyridine with phenylboronic acids or pinacol esters (C2:C4 up to 98:1), in contrast Pd(OAc)2 ligand-free conditions. In addition, similar C2-selectivity was achieved Sonogashira, Negishi, Kumada coupling reactions. This method highlights their powerful catalytic ability, exclusive C2-selectivity, broad substrate scope, efficient amplification, multiple ligand-exchange feasibility demonstrates that the conventional sites could be successfully regulated even reversed by catalysts.

Language: Английский

Citations

0
Mechanisms and Site Selectivity of (Het)Ar–X Oxidative Addition to Pd(0) Are Controlled by Frontier Molecular Orbital Symmetry DOI Creative Commons

Jingru Lu,

Nathan D. Schley, Irina Paci

et al.

Published: April 1, 2024

We report how the reaction mechanism and site-selectivity of 2-halopyridine oxidative addition to L2Pd(0) are both controlled by frontier molecular orbital symmetry. Comparing rates for pairs 2-chloro-3-EDG-pyridines / 2-chloro-5-EDG-pyridines (EDG = electron-donating group: NH2, OMe F) Pd(PCy3)2 reveals 3-EDG isomers undergo ~100 times faster than their 5-EDG counterparts (∆ΔG‡OA 10.4-11.6 kJ mol-1). Experimental computational mechanistic studies reveal that LUMO symmetries substrates control mechanism. For derivatives, high coefficients at reactive C2 position, antibonding symmetry through C2=N bond pyridine lead a nucleophilic displacement oxida-tive Conversely, derivatives has node C5–C2 plane, lead-ing minimal contribution carbon. The higher energy LUMO+1 substantial density C2, but nitrogen. This leads undergoing 3-centered insertion These effects also multihalogenated pyridines, which we investigate electron-withdrawing substituents. Incorporating simple fron-tier based descriptors quantitative multivariate linear model im-proved prediction accuracy relative substituted L2Pd(0).

Language: Английский

Citations

3
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 2, 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

Citations

3
Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights DOI
Geraldo Duran-Camacho,

Douglas C. Bland,

Fangzheng Li

et al.

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(9), P. 6404 - 6412

Published: April 11, 2024

This report describes a detailed study of Ni phosphine catalysts for the Suzuki–Miyaura coupling dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most ligands, these transformations afford mixtures mono- and diarylated cross-coupling products as well competing oligomerization acid. However, ligand screen revealed that PPh2Me PPh3 high yield selectivity monoarylation over diarylation minimal Several key observations were made regarding reactions, including: (1) ligands fall within narrow range Tolman cone angles (between 136 157°); (2) more electron-rich trialkylphosphines predominantly products, while less di- triarylphosphines favor monoarylation; (3) proceeds via intramolecular oxidative addition; (4) solvent (MeCN) plays crucial role in achieving selectivity. Experimental density functional theory studies suggest all data can be explained based on reactivity intermediate: Ni0–π complex monoarylated product. larger, trialkylphosphine this π undergoes addition faster than substitution by MeCN solvent, leading to selective diarylation. In contrast, relatively small triarylphosphine associative is competitive addition, resulting formation products. The generality method demonstrated variety chloro-substituted aryl Furthermore, optimal (PPh2Me) are leveraged achieve Ni-catalyzed broader set dichloroarene substrates.

Language: Английский

Citations

3
Heterocyclic Suzuki–Miyaura coupling reaction of metalla-aromatics and mechanistic analysis of site selectivity DOI Creative Commons
Zuzhang Lin, Yapeng Cai, Yaowei Zhang

et al.

Chemical Science, Journal Year: 2023, Volume and Issue: 14(5), P. 1227 - 1233

Published: Jan. 1, 2023

We describe unique polyhalogenated heteroarene candidates for site-selective cross-coupling, which shows high catalytic performances in the functionalization of polycyclic metalla-aromatics with excellent photophysical properties.

Language: Английский

Citations

8
Mechanistic Origin of Ligand Effects on Exhaustive Functionalization During Pd-Catalyzed Cross-Coupling of Dihaloarenes DOI
Nathaniel G. Larson, Jacob P. Norman, Sharon R. Neufeldt

et al.

ACS Catalysis, Journal Year: 2024, Volume and Issue: 14(9), P. 7127 - 7135

Published: April 23, 2024

We describe a detailed investigation into why bulky ligands-those that enable catalysis at "12e -" Pd0-tend to promote overfunctionalization during Pd-catalyzed cross-couplings of dihalogenated substrates. After one cross-coupling event takes place, PdL initially remains coordinated the π system nascent product. Selectivity for mono- vs. difunctionalization arises from relative rates π-decomplexation versus second oxidative addition. Under Suzuki coupling conditions in this work, direct dissociation 12e - π-complex cannot outcompete Instead, Pd must be displaced as 14e PdL(L') by incoming ligand L'. The is another molecule dichloroarene if reaction do not include π-coordinating solvents or additives. More tends result when increased substrate sterics raises energy bimolecular transition state separating mono-cross-coupled This work has practical implications optimizing selectivity involving multiple halogens. For example, we demonstrate small coordinating additives like DMSO can largely suppress and precatalyst structure also impact selectivity.

Language: Английский

Citations

3
Mechanisms and Site Selectivity of (Het)Ar–X Oxidative Addition to Pd(0) Are Controlled by Frontier Molecular Orbital Symmetry DOI

Jingru Lu,

Nathan D. Schley, Irina Paci

et al.

Organometallics, Journal Year: 2024, Volume and Issue: unknown

Published: July 16, 2024

Language: Английский

Citations

3
A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry DOI
James T. Brewster,

Samuel D. Randall,

John P. Kowalski

et al.

Organic Letters, Journal Year: 2022, Volume and Issue: 24(49), P. 9123 - 9129

Published: Dec. 7, 2022

Photoredox-transition metal dual catalysis provides a unique platform for constructing sp3-rich chemical matter. Here, we report nickel-catalyzed cross-coupling of commercially available or easily prepared redox-active NHP azetidine-2-carboxylates with heteroaryl iodides to yield 2-heteroaryl azetidines. This "off-the-shelf" approach yielded products amenable diversification giving access novel saturated heterocyclic scaffolds useful medicinal chemistry programs. An alternative mechanism Hantzsch ester within halides and α-amino radicals is also presented.

Language: Английский

Citations

13
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

Citations

2
Computational analysis of R–X oxidative addition to Pd nanoparticles DOI Creative Commons
Mikhail V. Polynski, Yulia S. Vlasova, Yaroslav V. Solovev

et al.

Chemical Science, Journal Year: 2024, Volume and Issue: 15(26), P. 9977 - 9986

Published: Jan. 1, 2024

Oxidative addition (OA) is a necessary step in mechanisms of widely used synthetic methodologies such as the Heck reaction, cross-coupling reactions, and Buchwald-Hartwig amination. This study pioneers exploration OA aryl halide to palladium nanoparticles (NPs), process previously unaddressed contrast activity well-studied Pd(0) complexes. Employing DFT modeling semi-empirical metadynamics simulations, oxidative phenyl bromide Pd was investigated detail. Energy profiles NPs were analyzed compared those involving complexes forming under both ligand-stabilized (phosphines) ligandless (amine base) conditions. Metadynamics simulations highlighted edges (1 1 1) facets key element activity. We demonstrate that not only kinetically facile at ambient temperatures but also thermodynamically favorable. finding accentuates necessity incorporating future investigations, thus providing more realistic view involved catalytic mechanisms. These results enhance understanding (cross-)coupling reinforcing concept "cocktail". posits dynamic interconversions between diverse active inactive centers, collectively affecting outcome reaction. High direct C-X activation paves way for novel approaches catalysis, potentially enhancing field offering new pathways consider.

Language: Английский

Citations

2