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

Опубликована: Апрель 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).

Язык: Английский

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Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms

Опубликована: Апрель 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.

Язык: Английский

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Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights

ACS Catalysis, Год журнала: 2024, Номер 14(9), С. 6404 - 6412

Опубликована: Апрель 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.

Язык: Английский

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Mechanistic Origin of Ligand Effects on Exhaustive Functionalization During Pd-Catalyzed Cross-Coupling of Dihaloarenes

ACS Catalysis, Год журнала: 2024, Номер 14(9), С. 7127 - 7135

Опубликована: Апрель 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.

Язык: Английский

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

Organometallics, Год журнала: 2024, Номер unknown

Опубликована: Июль 16, 2024

Язык: Английский

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ortho‐Selective Suzuki Coupling of Dichlorophenol and Dichlorobenzylalcohol in Water under Palladium Catalysis Directed by Noncovalent Interactions and Computational Analysis

Asian Journal of Organic Chemistry, Год журнала: 2025, Номер unknown

Опубликована: Янв. 14, 2025

Abstract The use of attractive noncovalent interactions is emerging as a versatile approach to address site‐selectivity challenges. Herein, we report ortho‐selective Suzuki coupling reactions in water 2,3‐dichloroarenes and 2,4‐dichloroarenes bearing hydroxy group the presence palladacycle catalyst directed by interactions. Various ortho‐substituted arylphenols arylbenzyl alcohols were obtained good excellent yields with high selectivity. Density functional theory (DFT) calculations ab initio molecular dynamics (AIMD) simulations suggested that ortho ‐selective dichlorophenols dichlorobenzyl occurred through electrostatic hydrogen bonding interactions, respectively.

Язык: Английский

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A Decarboxylative Cross-Coupling Platform To Access 2-Heteroaryl Azetidines: Building Blocks with Application in Medicinal Chemistry

Organic Letters, Год журнала: 2022, Номер 24(49), С. 9123 - 9129

Опубликована: Дек. 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.

Язык: Английский

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Heterocyclic Suzuki–Miyaura coupling reaction of metalla-aromatics and mechanistic analysis of site selectivity

Chemical Science, Год журнала: 2023, Номер 14(5), С. 1227 - 1233

Опубликована: Янв. 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.

Язык: Английский

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Sequential One-Pot (Het)arene Thioetherification and Amination with Nickel and Visible Light

ACS Catalysis, Год журнала: 2023, Номер 13(20), С. 13618 - 13625

Опубликована: Окт. 9, 2023

The development of predictable methods to increase molecular complexity is paramount importance in modern organic chemistry, especially the context synthesizing multifunctionalized (het)arenes active pharmaceutical ingredients (APIs) and materials. While considerable progress has been made using various protocols, sequential one-pot carbon–heteroatom cross-coupling reactions remain challenging. Herein, we report reaction conditions under adaptive dynamic homogeneous catalysis (AD-HoC) that offer a facile introduction functional groups onto (het)aromatic scaffolds, resulting significantly increased controlled construction diverse library molecules. Moreover, photoredox employed AD-HoC introduce layer versatility, as distinct selectivity involving pyrimidines. Manipulating tremendous value designing targeted synthesis routes for specific molecules APIs. simplicity predictability conditions, along with benefits make this approach an appealing choice researchers aiming create complex

Язык: Английский

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Oxidative Addition of (Hetero)aryl (Pseudo)halides at Palladium(0): Origin and Significance of Divergent Mechanisms

Опубликована: Апрель 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.

Язык: Английский

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