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1. Controlling Catalyst Speciation to Achieve Room Temperature Pd‐Catalyzed Aminations with Aryl and Heteroaryl Chlorides

   https://doi.org/10.1002/adsc.202401337  

   Rodriguez_Moreno, Mariur; Setelin, Mary_L; Hansen, Joshua_D; Corey, James_L; Noble, Kirt_L; Stillwell, Lillian_R; Angell, Emily; Stubbs, Olivia_A; Kumawat, Jugal; Muñoz_Gomez, Carlos_S; et al (January 2025, Advanced Synthesis & Catalysis)

   Abstract The amination of aryl halides with palladium catalysts (Buchwald‐Hartwig amination) is a widely used transformation in synthetic and drug discovery chemistry. In this report, we demonstrate that a monometallic 2‐phosphinoimidazole Pd catalyst exhibits comparable or enhanced reactivity when compared to all ligands screened for room temperature amination of aryl chlorides with secondary amines. The di‐tert‐butylphosphine derivative showed extremely high reactivity while the di‐isopropyl variant led to almost complete loss of catalytic activity. Computational and experimental mechanistic and kinetic studies indicate that a monometallic Pd structure rather than a bimetallic Pd structure is key to fast catalysis. The di‐tert‐butylphosphine ligand has fast catalysis because it thermodynamically disfavors the formation of a much less active bimetallic Pd complex. A wide substrate scope is demonstrated for the arylation of secondary amines with aryl chlorides using our new catalyst system. 

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2. Transition-State Stabilization by Secondary Orbital Interactions between Fluoroalkyl Ligands and Palladium During Reductive Elimination from Palladium(aryl)(fluoroalkyl) Complexes

   https://doi.org/10.1021/acscatal.3c02648  

   Kalkman, Eric D.; Qiu, Yehao; Hartwig, John F. (October 2023, ACS Catalysis)

   Palladium-catalyzed fluoroalkylations of aryl halides are valuable reactions for the synthesis of fluorinated, biologically active molecules. Reductive elimination from an intermediate Pd(aryl)(fluoroalkyl) complex is the step that forms the C(aryl)–C(fluoroalkyl) bond, and this step typically requires higher temperatures and proceeds with slower rates than the reductive elimination of nonfluorinated alkylarenes from the analogous Pd(aryl)(alkyl) complexes. The experimental rates of this step correlate poorly with common parameters, such as the steric property or the electron-withdrawing ability of the fluoroalkyl ligand, making the prediction of rates and the rational design of Pd-catalyzed fluoroalkylations difficult. Therefore, a systematic study of the features of fluoroalkyl ligands that affect the barrier to this key step, including steric properties, electron-withdrawing properties, and secondary interactions, is necessary for the future development of fluoroalkylation reactions that occur under milder conditions and that tolerate additional types of fluoroalkyl reagents. We report computational studies of the effect of the fluoroalkyl (RF) ligand on the barriers to reductive elimination from Pd(aryl)(RF) complexes (RF = CF2CN, CF2C(O)Me, etc.) containing the bidentate ligand di-tert-butyl(2-methoxyphenyl)phosphine (L). The computed Gibbs free-energy barriers to reductive elimination from these complexes suggest that fluoroalkylarenes should form quickly at room temperature for the fluoroalkyl ligands we studied, excluding RF = CF3, CF2Me, C2F5, CF2CFMe2, CF2Et, CF2iPr, or CF2tBu. Analyses of the transition-state structures by natural bond orbital (NBO) and independent gradient model (IGMH) approaches reveal that orbital interactions between the Pd center and a hydrogen atom or π-acid bonded to the α-carbon atom of the RF ligand stabilize the lowest-energy transition states of Pd(aryl)(RF) complexes. Comparisons between conformers of transition-state structures suggest that the magnitude of such stabilizations is 4.7–9.9 kcal/mol. In the absence of these secondary orbital interactions, a more electron-withdrawing fluoroalkyl ligand leads to a higher barrier to reductive elimination than a less electron-withdrawing fluoroalkyl ligand. Computations on the reductive elimination from complexes containing para-substituted aryl groups on palladium reveal that the barriers to reductive elimination from complexes containing more electron-rich aryl ligands tend to be lower than those to reductive elimination from complexes containing less electron-rich aryl ligands when the fluoroalkyl ligands of these complexes can engage in secondary orbital interactions with the metal center. However, the computed barriers to reductive elimination do not depend on the electronic properties of the aryl ligand when the fluoroalkyl ligands do not engage in secondary orbital interactions with the metal center. 

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3. gem-Difluoroallylation of Aryl Halides and Pseudo Halides with Difluoroallylboron Reagents in High Regioselectivity

   https://doi.org/10.1002/anie.202111476  

   Sakamoto, Shu; Butcher, Trevor W.; Yang, Jonathan L.; Hartwig, John F. (October 2021, Angewandte Chemie)

   We report the palladium-catalyzed gem-difluoroallylation of aryl halides and pseudo halides with 3,3-difluoroallyl boronates in high yield with high regioselectivity, and we report the preparation of the 3,3-difluoroallyl boronate reactants by a copper-catalyzed defluorinative borylation of inexpensive gaseous 3,3,3-trifluoropropene with bis(pinacola-to) diboron. The gem-difluoroallylation of aryl and heteroaryl bromides proceeds with low catalyst loading (0.1 mol% [Pd]) and tolerates a wide range of functional groups, including primary alcohols, secondary amines, ethers, ketones, esters, amides, aldehydes, nitriles, halides, and nitro groups. This protocol extends to aryl iodides, chlorides, and triflates, as well as substituted difluoroallyl boronates, providing a versatile synthesis of gem-difluoroallyl arenes that we show to be valuable intermediates to a series of fluorinated building blocks 

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4. Amine-functionalized carbon nanotubes supported palladium nanoparticles in Buchwald-Hartwig amination

   Winkleman, Harlee B; Eweama, Marykristy; Picinich, Lacey; Siamaki, Ali R (October 2023, American Chemical Society (ACS))

   NA (Ed.)

   Buchwald-Hartwig amination is a cross-coupling reaction between aryl halides or pseudohalides and primary or secondary amines to produce aryl amines. The reaction has become a fundamental tool in organic synthesis for the formation of carbon-nitrogen bonds in a variety of biologically active molecules, natural products, pharmaceuticals, and material science. These reactions usually employ a palladium complex in homogeneous form along with a ligand to stabilize the metal center. In this regard, there are many disadvantages for using homogeneous catalysis including the potential contamination of the metal in the final product and lack of recyclability of the catalyst. Heterogeneous catalysis is an alternative attractive approach to construct carbon-nitrogen bonds in which the metal is fixed on variety of solid supports such as zeolites, polymers, mesoporous silica, and carbon materials. This would allow for ease of separation of the catalyst from the reaction and reusability for the subsequent runs. In this presentation, we will introduce the synthesis of amine-functionalized carbon nanotubes (CNTs) supported Pd nanoparticles (Pd/MWCNTs-NH2) via simple dry mixing of the corresponding palladium salts and amine-functionalized CNTs using the mechanical energy of a ball-mill mixer. The method is very straightforward and rapid and does not require any solvent or reducing agents, a feature that allows for large-scale preparation of these materials. The as-prepared catalyst demonstrated excellent catalytic activity for the Buchwald-Hartwig carbon–nitrogen cross-coupling reactions of variety of aryl halides and functionalized amines under microwave irradiation conditions and short reaction time. The Pd/MWCNTs-NH2 nanoparticles prepared by this simple, solventless, and inexpensive preparation provide a more direct, cost-efficient, and streamlined means to accomplish often-challenging Buchwald-Hartwig amination reactions. 

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5. Pushing steric limits in osmium(IV) tetraaryl complexes

   https://doi.org/10.1039/D2DT01706G  

   Parr, Joseph Michael; Olivar, Clarissa; Saal, Thomas; Haiges, Ralf; Inkpen, Michael Stephen (July 2022, Dalton Transactions)

   Investigations into the reactivity, properties, and applications of osmium(IV) tetraaryl complexes have been hampered by their low yielding syntheses from volatile and toxic OsO4 (typically ≤34%). Here we show that known air-stable M(aryl)4 compounds (M = Os, Ru; aryl = 2-tolyl, 2,5-xylyl) can be prepared in ≤73% yields using new, less hazardous (Oct4N)2[MX6] precursors (M = Os, Ru; X = Cl, Br). This approach also facilitates the preparation of Os(mesityl)4 (Os3) for the first time, a complex comprising bulky 2,6-dimethyl substituted aryl ligands, albeit in low yield (5%). To better understand these yield extremes, we track, by synthesizing two additional new complexes with different 2-substituted σ-aryl ligands, a clear relationship between the yields of Os(aryl)4 and ligand steric bulk. Single-crystal X-ray structures of these compounds indicate that the observed yield trend reflects the ease of accommodating aryl substituents into an open pocket that lies directly opposite each M-aryl coordination site. We perform variable-temperature 1H NMR studies of Os3, utilize a "tetrahedricity" metric to assess geometric distortion in Ru(aryl)4 and Os(aryl)4 materials, and calculate cone angle and percentage buried volume metrics to further illustrate and help quantify -aryl ligand steric properties. Solution cyclic voltammograms of Os(aryl)4 show that the potentials of their reversible 1−/0 and 0/1+ redox features can be fine-tuned by varying aryl substituents, and that Os3 exhibits an additional 1+/2+ redox event not previously observed in this class of compounds. Taken together, this work helps to advance the potential application of these relatively underexplored organometallic complexes in established and emerging areas of molecular materials science, such as extended molecular frameworks and self-assembled monolayers, where analogous tetraphenylmethane and silane species (M = C, Si) have been frequently targeted. 

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