skip to main content


Title: Tailored quinones support high-turnover Pd catalysts for oxidative C–H arylation with O 2
Palladium(II)-catalyzed C–H oxidation reactions could streamline the synthesis of pharmaceuticals, agrochemicals, and other complex organic molecules. Existing methods, however, commonly exhibit poor catalyst performance with high Pd loading (e.g., 10 mol %) and a need for (super)stoichiometric quantities of undesirable oxidants, such as benzoquinone and silver(I) salts. The present study probes the mechanism of a representative Pd-catalyzed oxidative C–H arylation reaction and elucidates mechanistic features that undermine catalyst performance, including substrate-consuming side reactions and sequestration of the catalyst as inactive species. Systematic tuning of the quinone co-catalyst overcomes these deleterious features. Use of 2,5-di- tert -butyl- p -benzoquinone enables efficient use of molecular oxygen as the oxidant, high reaction yields, and >1900 turnovers by the palladium catalyst.  more » « less
Award ID(s):
1700982
NSF-PAR ID:
10232035
Author(s) / Creator(s):
; ; ; ; ;
Date Published:
Journal Name:
Science
ISSN:
0036-8075
Page Range / eLocation ID:
eabd1085
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. null (Ed.)
    Palladium(II)-catalyzed allylic acetoxylation has been the focus of extensive development and investigation. Methods that use molecular oxygen (O2) as the terminal oxidant typically benefit from the use of benzoquinone (BQ) and a transition-metal (TM) cocatalyst, such as Co(salophen), to support oxidation of Pd0 during catalytic turnover. We previously showed that Pd(OAc)2 and 4,5-diazafluoren-9-one (DAF) as an ancillary ligand catalyze allylic oxidation with O2 in the absence of cocatalysts. Herein, we show that BQ enhances DAF/Pd(OAc)2 catalytic activity, nearly matching the performance of reactions that include both BQ and Co(salophen). These observations are complemented by mechanistic studies of DAF/Pd(OAc)2 catalyst systems under three different oxidation conditions: (1) O2 alone, (2) O2 with cocatalytic BQ, and (3) O2 with cocatalytic BQ and Co(salophen). The beneficial effect of BQ in the absence of Co(salophen) is traced to the synergistic roles of O2 and BQ, both of which are capable of oxidizing Pd0 to PdII. The reaction of O2 generates H2O2 as a byproduct, which can oxidize hydroquinone to quinone in the presence of PdII. NMR spectroscopic studies, however, show that hydroquinone is the predominant redox state of the quinone cocatalyst in the absence of Co(salophen), while inclusion of Co(salophen) maintains oxidized quinone throughout the reaction, resulting in better reaction performance. 
    more » « less
  2. null (Ed.)
    Palladium catalyzed cross-coupling reactions represent a significant advancement in contemporary organic synthesis as these reactions are of strategic importance in the area of pharmaceutical drug discovery and development. Supported palladium-based catalysts are highly sought-after in carbon–carbon bond forming catalytic processes to ensure catalyst recovery and reuse while preventing product contamination. This paper reports the development of heterogeneous Pd-based bimetallic catalysts supported on fumed silica that have high activity and selectivity matching those of homogeneous catalysts, eliminating the catalyst's leaching and sintering and allowing efficient recycling of the catalysts. Palladium and base metal (Cu, Ni or Co) contents of less than 1.0 wt% loading are deposited on a mesoporous fumed silica support (surface area SA BET = 350 m 2 g −1 ) using strong electrostatic adsorption (SEA) yielding homogeneously alloyed nanoparticles with an average size of 1.3 nm. All bimetallic catalysts were found to be highly active toward Suzuki cross-coupling (SCC) reactions with superior activity and stability for the CuPd/SiO 2 catalyst. A low CuPd/SiO 2 loading (Pd: 0.3 mol%) completes the conversion of bromobenzene and phenylboronic acid to biphenyl in 30 minutes under ambient conditions in water/ethanol solvent. In contrast, monometallic Pd/SiO 2 (Pd: 0.3 mol%) completes the same reaction in three hours under the same conditions. The combination of Pd with the base metals helps in retaining the Pd 0 status by charge donation from the base metals to Pd, thus lowering the activation energy of the aryl halide oxidative addition step. Along with its exceptional activity, CuPd/SiO 2 exhibits excellent recycling performance with a turnover frequency (TOF) of 280 000 h −1 under microwave reaction conditions at 60 °C. Our study demonstrates that SEA is an excellent synthetic strategy for depositing ultra-small Pd-based bimetallic nanoparticles on porous silica for SCC. This avenue not only provides highly active and sintering-resistant catalysts but also significantly lowers Pd contents in the catalysts without compromising catalytic activity, making the catalysts very practical for large-scale applications. 
    more » « less
  3. Palladium(II) catalysts promote oxidative dehydrogenation and dehydrogenative coupling of many organic molecules. Oxidations of alcohols to aldehydes or ketones are prominent examples. Hydroquinone (H2Q) oxidation to benzoquinone (BQ) is conceptually related to alcohol oxidation, but it is significantly more challenging thermodynamically. The BQ/H2Q redox potential is sufficiently high that BQ is often used as an oxidant in Pd-catalyzed oxidation reactions. A recent report (J. Am. Chem. Soc.2020, 142, 19678–19688) showed that certain ancillary ligands can raise the PdII/0 redox potential sufficiently to reverse this reactivity, enabling (L)PdII(OAc)2 to oxidize hydroquinone to benzoquinone. Here, we investigate the oxidation of tert-butylhydroquinone (tBuH2Q) and 4-fluorobenzyl alcohol (4FBnOH), mediated by (bc)Pd(OAc)2 (bc = bathocuproine). Although alcohol oxidation is thermodynamically favored over H2Q oxidation by more than 400 mV, the oxidation of tBuH2Q proceeds several orders of magnitude faster than 4FBnOH oxidation. Kinetic and mechanistic studies reveal that these reactions feature different rate-limiting steps. Alcohol oxidation proceeds via rate-limiting β-hydride elimination from a PdII-alkoxide intermediate, while H2Q oxidation features rate-limiting isomerization from an O-to-C-bound PdII-hydroquinonate species. The enhanced rate of H2Q oxidation reflects the kinetic facility of O–H relative to C–H bond cleavage. 
    more » « less
  4. Metal-mediated cross-coupling reactions offer organic chemists a wide array of stereo- and chemically-selective reactions with broad applications in fine chemical and pharmaceutical synthesis.1 Current batch-based synthesis methods are beginning to be replaced with flow chemistry strategies to take advantage of the improved consistency and process control methods offered by continuous flow systems.2,3 Most cross-coupling chemistries still encounter several issues in flow using homogeneous catalysis, including expensive catalyst recovery and air sensitivity due to the chemical nature of the catalyst ligands.1 To mitigate some of these issues, a ligand-free heterogeneous catalysis reaction was developed using palladium (Pd) loaded into a polymeric network of a silicone elastomer, poly(hydromethylsiloxane) (PHMS), that is not air sensitive and can be used with mild reaction solvents (ethanol and water).4 In this work we present a novel method of producing soft catalytic microparticles using a multiphase flow-focusing microreactor and demonstrate their application for continuous Suzuki-Miyaura cross-coupling reactions. The catalytic microparticles are produced in a coaxial glass capillary-based 3D flow-focusing microreactor. The microreactor consists of two precursors, a cross-linking catalyst in toluene and a mixture of the PHMS polymer and a divinyl cross-linker. The dispersed phase containing the polymer, cross-linker, and cross-linking catalyst is continuously mixed and then formed into microdroplets by the continuous phase of water and surfactant (sodium dodecyl sulfate) introduced in a counter-flow configuration. Elastomeric microdroplets with a diameter ranging between 50 to 300 micron are produced at 25 to 250 Hz with a size polydispersity less than 3% in single stream production. The physicochemical properties of the elastomeric microparticles such as particle swelling/softness can be tuned using the ratio of cross-linker to polymer as well as the ratio of polymer mixture to solvent during the particle formation. Swelling in toluene can be tuned up to 400% of the initial particle volume by reducing the concentration of cross-linker in the mixture and increasing the ratio of polymer to solvent during production.5 After the particles are produced and collected, they are transferred into toluene containing palladium acetate, allowing the particles to incorporate the palladium into the polymer network and then reduce the palladium to Pd0 with the Si-H functionality present on the PHMS backbones. After the reduction, the Pd-loaded particles can be washed and dried for storage or switched into an ethanol/water solution for loading into a micro-packed bed reactor (µ-PBR) for continuous organic synthesis. The in-situ reduction of Pd within the PHMS microparticles was confirmed using energy dispersive X-ray spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS) and focused ion beam-SEM, and TEM techniques. In the next step, we used the developed µ-PBR to conduct continuous organic synthesis of 4-phenyltoluene by Suzuki-Miyaura cross-coupling of 4-iodotoluene and phenylboronic acid using potassium carbonate as the base. Catalyst leaching was determined to only occur at sub ppm concentrations even at high solvent flow rates after 24 h of continuous run using inductively coupled plasma mass spectrometry (ICP-MS). The developed µ-PBR using the elastomeric microparticles is an important initial step towards the development of highly-efficient and green continuous manufacturing technologies in the pharma industry. In addition, the developed elastomeric microparticle synthesis technique can be utilized for the development of a library of other chemically cross-linkable polymer/cross-linker pairs for applications in organic synthesis, targeted drug delivery, cell encapsulation, or biomedical imaging. References 1. Ruiz-Castillo P, Buchwald SL. Applications of Palladium-Catalyzed C-N Cross-Coupling Reactions. Chem Rev. 2016;116(19):12564-12649. 2. Adamo A, Beingessner RL, Behnam M, et al. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science. 2016;352(6281):61 LP-67. 3. Jensen KF. Flow Chemistry — Microreaction Technology Comes of Age. 2017;63(3). 4. Stibingerova I, Voltrova S, Kocova S, Lindale M, Srogl J. Modular Approach to Heterogenous Catalysis. Manipulation of Cross-Coupling Catalyst Activity. Org Lett. 2016;18(2):312-315. 5. Bennett JA, Kristof AJ, Vasudevan V, Genzer J, Srogl J, Abolhasani M. Microfluidic synthesis of elastomeric microparticles: A case study in catalysis of palladium-mediated cross-coupling. AIChE J. 2018;0(0):1-10. 
    more » « less
  5. A highly selective palladium-catalyzed carbonylative arylation of weakly acidic benzylic C(sp 3 )–H bonds of azaarylmethylamines with aryl bromides under 1 atm of CO gas has been achieved. This work represents the first examples of use of such weakly acidic pronucleophiles in this class of transformations. In the presence of a NIXANTPHOS-based palladium catalyst, this one-pot cascade process allows a range of azaarylmethylamines containing pyridyl, quinolinyl and pyrimidyl moieties and acyclic and cyclic amines to undergo efficient reactions with aryl bromides and CO to provide α-amino aryl-azaarylmethyl ketones in moderate to high yields with a broad substrate scope and good tolerance of functional groups. This reaction proceeds via in situ reversible deprotonation of the benzylic C–H bonds to give the active carbanions, thereby avoiding prefunctionalized organometallic reagents and generation of additional waste. Importantly, the operational simplicity, scalability and diversity of the products highlight the potential applicability of this protocol. 
    more » « less