Franziska Schoenebeck

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Organization: RWTH Aachen University , Germany

Department: Institute of Organic Chemistry

Title: (PhD)

TOPICS

Organic Chemistry

Trifluoromethylation Phosphine Ligands C-H Activation

Chemicals
References

When Weaker Can Be Tougher: The Role of Oxidation State (I) in P- vs N-Ligand-Derived Ni-Catalyzed Trifluoromethylthiolation of Aryl Halides

Co-reporter:Indrek Kalvet, Qianqian Guo, Graham J. Tizzard, and Franziska Schoenebeck

ACS Catalysis March 3, 2017 Volume 7(Issue 3) pp:2126-2126

Publication Date(Web):January 31, 2017

DOI:10.1021/acscatal.6b03344

The direct introduction of the valuable SCF3 moiety into organic molecules has received considerable attention. While it can be achieved successfully for aryl chlorides under catalysis with Ni0(cod)2 and dppf, this report investigates the Ni-catalyzed functionalization of the seemingly more reactive aryl halides ArI and ArBr. Counterintuitively, the observed conversion triggered by dppf/Ni0 is ArCl > ArBr > ArI, at odds with bond strength preferences. By a combined computational and experimental approach, the origin of this was identified to be due to the formation of (dppf)NiI, which favors β-F elimination as a competing pathway over the productive cross-coupling, ultimately generating the inactive complex (dppf)Ni(SCF2) as a catalysis dead end. The complexes (dppf)NiI–Br and (dppf)NiI–I were isolated and resolved by X-ray crystallography. Their formation was found to be consistent with a ligand-exchange-induced comproportionation mechanism. In stark contrast to these phosphine-derived Ni complexes, the corresponding nitrogen-ligand-derived species were found to be likely competent catalysts in oxidation state I. Our computational studies of N-ligand derived NiI complexes fully support productive NiI/NiIII catalysis, as the competing β-F elimination is disfavored. Moreover, N-derived NiI complexes are predicted to be more reactive than their Ni0 counterparts in catalysis. These data showcase fundamentally different roles of NiI in carbon–heteroatom bond formation depending on the ligand sphere.Keywords: cross-coupling; DFT; fluorine; ligand; mechanisms; nickel;

A Holy Grail in Chemistry: Computational Catalyst Design: Feasible or Fiction?

Co-reporter:Carl Poree and Franziska Schoenebeck

Accounts of Chemical Research March 21, 2017 Volume 50(Issue 3) pp:605-605

Publication Date(Web):March 21, 2017

DOI:10.1021/acs.accounts.6b00606

Efficient and selective catalysis lies at the heart of much of chemistry, enabling the synthesis of molecules and materials with enormous societal and technological impact. Modern in silico tools should allow us to develop new catalysts faster and better than ever before; this contribution discusses the feasibility and potential of computational catalyst design.

Understanding the Unusual Reduction Mechanism of Pd(II) to Pd(I): Uncovering Hidden Species and Implications in Catalytic Cross-Coupling Reactions

Co-reporter:Carin C. C. Johansson Seechurn, Theresa Sperger, Thomas G. Scrase, Franziska Schoenebeck, and Thomas J. Colacot

Journal of the American Chemical Society April 12, 2017 Volume 139(Issue 14) pp:5194-5194

Publication Date(Web):March 16, 2017

DOI:10.1021/jacs.7b01110

The reduction of Pd(II) intermediates to Pd(0) is a key elementary step in a vast number of Pd-catalyzed processes, ranging from cross-coupling, C–H activation, to Wacker chemistry. For one of the most powerful new generation phosphine ligands, PtBu3, oxidation state Pd(I), and not Pd(0), is generated upon reduction from Pd(II). The mechanism of the reduction of Pd(II) to Pd(I) has been investigated by means of experimental and computational studies for the formation of the highly active precatalyst {Pd(μ-Br)(PtBu3)}2. The formation of dinuclear Pd(I), as opposed to the Pd(0) complex, (tBu3P)2Pd was shown to depend on the stoichiometry of Pd to phosphine ligand, the order of addition of the reagents, and, most importantly, the nature of the palladium precursor and the choice of the phosphine ligand utilized. In addition, through experiments on gram scale in palladium, mechanistically important additional Pd- and phosphine-containing species were detected. An ionic Pd(II)Br3 dimer side product was isolated, characterized, and identified as the crucial driving force in the mechanism of formation of the Pd(I) bromide dimer. The potential impact of the presence of these side species for in situ formed Pd complexes in catalysis was investigated in Buchwald–Hartwig, α-arylation, and Suzuki–Miyaura reactions. The use of preformed and isolated Pd(I) bromide dimer as a precatalyst provided superior results, in terms of catalytic activity, in comparison to catalysts generated in situ.

Divergent Reactivity of a Dinuclear (NHC)Nickel(I) Catalyst versus Nickel(0) Enables Chemoselective Trifluoromethylselenolation

Co-reporter:Alexer B. Dürr;Dr. Henry C. Fisher;Indrek Kalvet;Khai-Nghi Truong; Dr. Franziska Schoenebeck

Angewandte Chemie 2017 Volume 129(Issue 43) pp:13616-13620

Publication Date(Web):2017/10/16

DOI:10.1002/ange.201706423

AbstractWe herein showcase the ability of NHC-coordinated dinuclear NiI–NiI complexes to override fundamental reactivity limits of mononuclear (NHC)Ni0 catalysts in cross-couplings. This is demonstrated with the development of a chemoselective trifluoromethylselenolation of aryl iodides catalyzed by a NiI dimer. A novel SeCF3-bridged NiI dimer was isolated and shown to selectively react with Ar−I bonds. Our computational and experimental reactivity data suggest dinuclear NiI catalysis to be operative. The corresponding Ni0 species, on the other hand, suffers from preferred reaction with the product, ArSeCF3, over productive cross-coupling and is hence inactive.

Palladium(I) Dimer Enabled Extremely Rapid and Chemoselective Alkylation of Aryl Bromides over Triflates and Chlorides in Air

Co-reporter:M. Sc. Indrek Kalvet;M. Sc. Theresa Sperger;M. Sc. Thomas Scattolin;M. Sc. Guillaume Magnin; Dr. Franziska Schoenebeck

Angewandte Chemie 2017 Volume 129(Issue 25) pp:7184-7188

Publication Date(Web):2017/06/12

DOI:10.1002/ange.201701691

AbstractDisclosed herein is the first general chemo- and site-selective alkylation of C−Br bonds in the presence of COTf, C−Cl and other potentially reactive functional groups, using the air-, moisture-, and thermally stable dinuclear PdI catalyst, [Pd(μ-I)PtBu3]2. The bromo-selectivity is independent of the substrate and the relative positioning of the competing reaction sites, and as such fully predictable. Primary and secondary alkyl chains were introduced with extremely high speed (<5 min reaction time) at room temperature and under open-flask reaction conditions.

Palladium(I) Dimer Enabled Extremely Rapid and Chemoselective Alkylation of Aryl Bromides over Triflates and Chlorides in Air

Co-reporter:M. Sc. Indrek Kalvet;M. Sc. Theresa Sperger;M. Sc. Thomas Scattolin;M. Sc. Guillaume Magnin; Dr. Franziska Schoenebeck

Angewandte Chemie International Edition 2017 Volume 56(Issue 25) pp:7078-7082

Publication Date(Web):2017/06/12

DOI:10.1002/anie.201701691

Mechanistic insights on the Pd-catalyzed addition of C–X bonds across alkynes – a combined experimental and computational study

Co-reporter:Theresa Sperger;Christine M. Le;Mark Lautens

Chemical Science (2010-Present) 2017 vol. 8(Issue 4) pp:2914-2922

Publication Date(Web):2017/03/28

DOI:10.1039/C6SC05001H

The Pd-catalyzed intramolecular addition of carbamoyl chlorides and aryl halides across alkynes is investigated by means of DFT calculations and mechanistic test experiments. The data suggest a mechanistic pathway that involves oxidative addition, alkyne insertion, cis → trans isomerization and reductive elimination. Our data indicate that oxidative addition is the reactivity limiting step in the addition of aryl chlorides and bromides across alkynes. However, for the corresponding addition of carbamoyl chlorides, alkyne insertion is found to be limiting. Full energetic reaction pathways for the intramolecular additions across alkynes are presented herein and the role of ligands, alkyne substituents and tether moieties are discussed. Notably, the calculations could rationalize a pronounced effect of the alkyne substituent, which accounts for the exceptional reactivity of TIPS-substituted alkynes. In particular, the bulky silyl moiety is shown to significantly destabilize the formed Pd(II)-intermediates, thus facilitating both cis → trans isomerization and reductive elimination, which overall results in a flatter energetic landscape and a therefore increased catalytic efficiency.

Mild and selective base-free C–H arylation of heteroarenes: experiment and computation

Co-reporter:Hannes P. L. Gemoets;Indrek Kalvet;Alexander V. Nyuchev;Nico Erdmann;Volker Hessel;Timothy Noël

Chemical Science (2010-Present) 2017 vol. 8(Issue 2) pp:1046-1055

Publication Date(Web):2017/01/30

DOI:10.1039/C6SC02595A

A mild and selective C–H arylation strategy for indoles, benzofurans and benzothiophenes is described. The arylation method engages aryldiazonium salts as arylating reagents in equimolar amounts. The protocol is operationally simple, base free, moisture tolerant and air tolerant. It utilizes low palladium loadings (0.5 to 2.0 mol% Pd), short reaction times, green solvents (EtOAc/2-MeTHF or MeOH) and is carried out at room temperature, providing a broad substrate scope (47 examples) and excellent selectivity (C-2 arylation for indoles and benzofurans, C-3 arylation for benzothiophenes). Mechanistic experiments and DFT calculations support a Heck–Matsuda type coupling mechanism.

Computation and Experiment: A Powerful Combination to Understand and Predict Reactivities

Co-reporter:Theresa Sperger, Italo A. Sanhueza, and Franziska Schoenebeck

Accounts of Chemical Research 2016 Volume 49(Issue 6) pp:1311

Publication Date(Web):May 12, 2016

DOI:10.1021/acs.accounts.6b00068

Computational chemistry has become an established tool for the study of the origins of chemical phenomena and examination of molecular properties. Because of major advances in theory, hardware and software, calculations of molecular processes can nowadays be done with reasonable accuracy on a time-scale that is competitive or even faster than experiments. This overview will highlight broad applications of computational chemistry in the study of organic and organometallic reactivities, including catalytic (NHC-, Cu-, Pd-, Ni-catalyzed) and noncatalytic examples of relevance to organic synthesis. The selected examples showcase the ability of computational chemistry to rationalize and also predict reactivities of broad significance. A particular emphasis is placed on the synergistic interplay of computations and experiments. It is discussed how this approach allows one to (i) gain greater insight than the isolated techniques, (ii) inspire novel chemistry avenues, and (iii) assist in reaction development. Examples of successful rationalizations of reactivities are discussed, including the elucidation of mechanistic features (radical versus polar) and origins of stereoselectivity in NHC-catalyzed reactions as well as the rationalization of ligand effects on ligation states and selectivity in Pd- and Ni-catalyzed transformations. Beyond explaining, the synergistic interplay of computation and experiments is then discussed, showcasing the identification of the likely catalytically active species as a function of ligand, additive, and solvent in Pd-catalyzed cross-coupling reactions. These may vary between mono- or bisphosphine-bound or even anionic Pd complexes in polar media in the presence of coordinating additives. These fundamental studies also inspired avenues in catalysis via dinuclear Pd(I) cycles. Detailed mechanistic studies supporting the direct reactivity of Pd(I)–Pd(I) with aryl halides as well as applications of air-stable dinuclear Pd(I) catalysts are discussed. Additional combined experimental and computational studies are described for alternative metals, these include the discussion of the factors that control C–H versus C–C activation in the aerobic Cu-catalyzed oxidation of ketones, and ligand and additive effects on the nature and favored oxidation state of the active catalyst in Ni-catalyzed trifluoromethylthiolations of aryl chlorides. Examples of successful computational reactivity predictions along with experimental verifications are then presented. This includes the design of a fluorinated ligand [(CF3)2P(CH2)2P(CF3)2] for the challenging reductive elimination of ArCF3 from Pd(II) as well as the guidance of substrate scope (functional group tolerance and suitable leaving group) in the Ni-catalyzed trifluoromethylthiolation of C(sp2)–O bonds. In summary, this account aims to convey the benefits of integrating computational studies in experimental research to increase understanding of observed phenomena and guide future experiments.

Stereoselective Synthesis of Methylene Oxindoles via Palladium(II)-Catalyzed Intramolecular Cross-Coupling of Carbamoyl Chlorides

Co-reporter:Christine M. Le, Theresa Sperger, Rui Fu, Xiao Hou, Yong Hwan Lim, Franziska Schoenebeck, and Mark Lautens

Journal of the American Chemical Society 2016 Volume 138(Issue 43) pp:14441-14448

Publication Date(Web):October 4, 2016

DOI:10.1021/jacs.6b08925

We report a highly robust, general and stereoselective method for the synthesis of 3-(chloromethylene)oxindoles from alkyne-tethered carbamoyl chlorides using PdCl2(PhCN)2 as the catalyst. The transformation involves a stereo- and regioselective chloropalladation of an internal alkyne to generate a nucleophilic vinyl PdII species, which then undergoes an intramolecular cross-coupling with a carbamoyl chloride. The reaction proceeds under mild conditions, is insensitive to the presence of moisture and air, and is readily scalable. The products obtained from this reaction are formed with >95:5 Z:E selectivity in nearly all cases and can be used to access biologically relevant oxindole cores. Through combined experimental and computational studies, we provide insight into stereo- and regioselectivity of the chloropalladation step, as well as the mechanism for the C–C bond forming process. Calculations provide support for a mechanism involving oxidative addition into the carbamoyl chloride bond to generate a high valent PdIV species, which then undergoes facile C–C reductive elimination to form the final product. Overall, the transformation constitutes a formal PdII-catalyzed intramolecular alkyne chlorocarbamoylation reaction.

Nickel-catalyzed trifluoromethylthiolation of Csp2–O bonds

Co-reporter:Alexander B. Dürr, Guoyin Yin, Indrek Kalvet, François Napoly and Franziska Schoenebeck

Chemical Science 2016 vol. 7(Issue 2) pp:1076-1081

Publication Date(Web):30 Oct 2015

DOI:10.1039/C5SC03359D

While nickel catalysts have previously been shown to activate even the least reactive Csp2–O bonds, i.e. aryl ethers, in the context of C–C bond formation, little is known about the reactivity limits and molecular requirements for the introduction of valuable functional groups under homogeneous nickel catalysis. We identified that due to the high reactivity of Ni-catalysts, they are also prone to react with existing or installed functional groups, which ultimately causes catalyst deactivation. The scope of the Ni-catalyzed coupling protocol will therefore be dictated by the reactivity of the functional groups towards the catalyst. Herein, we showed that the application of computational tools allowed the identification of matching functional groups in terms of suitable leaving groups and tolerated functional groups. This allowed for the development of the first efficient protocol to trifluoromethylthiolate Csp2–O bonds, giving the mild and operationally simple C–SCF3 coupling of a range of aryl, vinyl triflates and nonaflates. The novel methodology was also applied to biologically active and pharmaceutical relevant targets, showcasing its robustness and wide applicability.

Computational Studies of Synthetically Relevant Homogeneous Organometallic Catalysis Involving Ni, Pd, Ir, and Rh: An Overview of Commonly Employed DFT Methods and Mechanistic Insights

Co-reporter:Theresa Sperger, Italo A. Sanhueza, Indrek Kalvet, and Franziska Schoenebeck

Chemical Reviews 2015 Volume 115(Issue 17) pp:9532

Publication Date(Web):July 24, 2015

DOI:10.1021/acs.chemrev.5b00163

Factors That Control C–C Cleavage versus C–H Bond Hydroxylation in Copper-Catalyzed Oxidations of Ketones with O2

Co-reporter:Althea S.-K. Tsang; Ajoy Kapat

Journal of the American Chemical Society 2015 Volume 138(Issue 2) pp:518-526

Publication Date(Web):December 16, 2015

DOI:10.1021/jacs.5b08347

The Cu-catalyzed oxidation of ketones with O2 has recently been extensively utilized to cleave the α-C–C bond. This report examines the selective aerobic hydroxylation of tertiary α-C–H bonds in ketones without C–C cleavage. We set out to understand the underlying mechanisms of these two possible reactivity modes. Using experimental, in situ IR spectroscopic, and computational studies, we investigated several mechanisms. Our data suggest that both C–C cleavage and C–H hydroxylation pathways proceed via a common key intermediate, i.e., an α-peroxo ketone. The fate of this peroxide dictates the ultimate product selectivity. Specifically, we uncovered the role of hppH [= 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine] to act not only as a base in the transformation but also as a reductant of the peroxide to the corresponding α-hydroxy ketone. This reduction may also be accomplished through exogenous phosphine additives, therefore allowing the tuning of reduction efficiency toward higher driving forces, if required (e.g., for more-activated substrates). The likely competitive pathway is the cleavage of peroxide to the α-oxy radical (likely catalyzed by Cu), which is computationally predicted to spontaneously trigger C–C bond cleavage. Increasing the susceptibility of this deperoxidation step via (i) the removal of reductant (use of different base, e.g., DBU) or the modulation of (ii) the substitution pattern toward greater activation (substrate control) and (iii) the nature of Cu catalyst (counterion and solvent dependence) will favor the C–C cleavage product.

Fundamental Studies and Development of Nickel-Catalyzed Trifluoromethylthiolation of Aryl Chlorides: Active Catalytic Species and Key Roles of Ligand and Traceless MeCN Additive Revealed

Co-reporter:Guoyin Yin; Indrek Kalvet; Ulli Englert

Journal of the American Chemical Society 2015 Volume 137(Issue 12) pp:4164-4172

Publication Date(Web):March 19, 2015

DOI:10.1021/jacs.5b00538

A catalytic protocol to convert aryl and heteroaryl chlorides to the corresponding trifluoromethyl sulfides is reported herein. It relies on a relatively inexpensive Ni(cod)2/dppf (cod = 1,5-cyclooctadiene; dppf = 1,1′-bis(diphenylphosphino)ferrocene) catalyst system and the readily accessible coupling reagent (Me4N)SCF3. Our computational and experimental mechanistic data are consistent with a Ni(0)/Ni(II) cycle and inconsistent with Ni(I) as the reactive species. The relevant intermediates were prepared, characterized by X-ray crystallography, and tested for their catalytic competence. This revealed that a monomeric tricoordinate Ni(I) complex is favored for dppf and Cl whose role was unambiguously assigned as being an off-cycle catalyst deactivation product. Only bidentate ligands with wide bite angles (e.g., dppf) are effective. These bulky ligands render the catalyst resting state as [(P–P)Ni(cod)]. The latter is more reactive than Ni(P–P)2, which was found to be the resting state for ligands with smaller bite angles and suffers from an initial high-energy dissociation of one ligand prior to oxidative addition, rendering the system unreactive. The key to effective catalysis is hence the presence of a labile auxiliary ligand in the catalyst resting state. For more challenging substrates, high conversions were achieved via the employment of MeCN as a traceless additive. Mechanistic data suggest that its beneficial role lies in decreasing the energetic span, therefore accelerating product formation. Finally, the methodology has been applied to synthetic targets of pharmaceutical relevance.

Hoch effiziente C-SeCF3-Kupplung von Aryliodiden durch einen luftbestndigen zweikernigen PdI-Katalysator

Co-reporter:Marialuisa Aufiero;Theresa Sperger;Dr. Althea S.-K. Tsang;Dr. Franziska Schoenebeck

Angewandte Chemie 2015 Volume 127( Issue 35) pp:10462-10466

Publication Date(Web):

DOI:10.1002/ange.201503388

Abstract

Aufbauend auf unseren jüngsten Entdeckungen bei zweikernigen Pd^I-Komplexen beschreiben wir hier die Anwendung dieses Konzeptes zur Realisierung der ersten katalytischen Umwandlung von Aryliodiden zu ArSeCF₃-Verbindungen. Durch die Verwendung eines luft-, feuchtigkeits- und temperaturbeständigen Pd^I-Zweikernkomplexes konnte die hoch effiziente C-SeCF₃-Kupplung einer Reihe von Aryliodiden erreicht werden. Ein neuer SeCF₃-verbrückter zweikerniger Pd^I-Komplex 3 wurde isoliert, auf seine katalytische Kompetenz untersucht und als Katalysator wiederverwendet. Sowohl experimentelle als auch berechnete Resultate lassen auf einen Zweikern-Pd^I-Katalysemodus schließen.

Highly Efficient CSeCF3 Coupling of Aryl Iodides Enabled by an Air-Stable Dinuclear PdI Catalyst

Co-reporter:Marialuisa Aufiero;Theresa Sperger;Dr. Althea S.-K. Tsang;Dr. Franziska Schoenebeck

Angewandte Chemie International Edition 2015 Volume 54( Issue 35) pp:10322-10326

Publication Date(Web):

DOI:10.1002/anie.201503388

Abstract

Building on our recent disclosure of catalysis at dinuclear Pd^I sites, we herein report the application of this concept to the realization of the first catalytic method to convert aryl iodides into the corresponding ArSeCF₃ compounds. Highly efficient CSeCF₃ coupling of a range of aryl iodides was achieved, enabled by an air-, moisture-, and thermally stable dinuclear Pd^I catalyst. The novel SeCF₃-bridged dinuclear Pd^I complex 3 was isolated, studied for its catalytic competence and shown to be recoverable. Experimental and computational data are presented in support of dinuclear Pd^I catalysis.

Palladium/Phosphaadamantan-Katalysator ermglicht die trans-selektive Chlorcarbamoylierung von Alkinen

Co-reporter:Christine M. Le;Xiao Hou;Theresa Sperger;Dr. Franziska Schoenebeck;Dr. Mark Lautens

Angewandte Chemie 2015 Volume 127( Issue 52) pp:16127-16131

Publication Date(Web):

DOI:10.1002/ange.201507883

Abstract

Eine intramolekulare Palladium(0)-katalysierte Chlorcarbamoylierung von Alkinen zur Synthese pharmazeutisch relevanter Methylenoxindole wird beschrieben. Dabei wird eine weitgehend unerforschte Klasse von Phosphanliganden verwendet, die sich als besonders geeignet für diese Umwandlung herausstellte und sowohl hohe Reaktivität als auch ausschließliche trans-Selektivität ermöglicht. Dieser Bericht zeigt die erste übergangsmetallkatalysierte atomeffiziente Addition eines Carbamoylchlorids an ein Alkin.

Trifluoromethylthiolation of Aryl Iodides and Bromides Enabled by a Bench-Stable and Easy-To-Recover Dinuclear Palladium(I) Catalyst

Co-reporter:Dr. Guoyin Yin;Indrek Kalvet ;Dr. Franziska Schoenebeck

Angewandte Chemie 2015 Volume 127( Issue 23) pp:6913-6917

Publication Date(Web):

DOI:10.1002/ange.201501617

Abstract

While palladium catalysis is ubiquitous in modern chemical research, the recovery of the active transition-metal complex under routine laboratory applications is frequently challenging. Described herein is the concept of alternative cross-coupling cycles with a more robust (air-, moisture-, and thermally-stable) dinuclear Pd^I complex, thus avoiding the handling of sensitive Pd⁰ species or ligands. Highly efficient CSCF₃ coupling of a range of aryl iodides and bromides was achieved, and the recovery of the Pd^I complex was accomplished via simple open-atmosphere column chromatography. Kinetic and computational data support the feasibility of dinuclear Pd^I catalysis. A novel SCF₃-bridged Pd^I dimer was isolated, characterized by X-ray crystallography, and verified to be a competent catalytic intermediate.

Dispersion Makes the Difference: Bisligated Transition States Found for the Oxidative Addition of Pd(PtBu3)2 to Ar-OSO2R and Dispersion-Controlled Chemoselectivity in Reactions with Pd[P(iPr)(tBu2)]2

Co-reporter:Eirik Lyngvi, Italo A. Sanhueza, and Franziska Schoenebeck

Organometallics 2015 Volume 34(Issue 5) pp:805-812

Publication Date(Web):December 11, 2014

DOI:10.1021/om501199t

The manipulation of the steric nature of ligands is a key design principle in organometallic reactivity. While general intuition assumes steric effects to be repulsive, recent reports counterintuitively suggested that highly crowded hydrocarbon molecules may be stabilized more strongly than their less bulky analogues as a consequence of dispersion interactions. With the objective of investigating the significance of such attractive intramolecular dispersion forces in organometallic catalysis, we herein studied the effect of dispersion on the accessible geometries and reactivities for two trialkylphosphine ligands of different sizes in Pd-catalyzed cross-coupling reactions: i.e., L = PtBu3 and its smaller analogue L = P(iPr)(tBu2). Those methods that account well for dispersion (e.g., ωB97XD, B3LYP-D3) allowed the first location of bisphosphine-ligated transition states for the oxidative addition of Pd0L2 to aromatic C–O bonds, involving the bulky and widely employed ligand L = PtBu3. DFT methods without dispersion gave rise to dissociation of one phosphine ligand in all cases examined. To probe whether dispersion may even be a reactivity-controlling factor, we also examined the favored site selectivity of the reaction of Pd0L2 with 4-chlorophenyl triflate, for which the selectivity has previously been shown to be dependent on the ligation state of the reactive palladium species. Various DFT methods (PBE, B3LYP, M06L) and basis sets and different solvent models (COSMO-RS, CPCM) were assessed. While for Pd(PtBu3)2 dispersion-free and dispersion-containing methods predicted the monophosphine pathway via PdL and reaction at C–Cl to be favored, striking differences were observed for Pd[P(iPr)(tBu2)]2. Dispersion-free DFT predicted C–OTf addition by Pd[P(iPr)(tBu2)]2 to be disfavored by ΔΔG⧧ ≈ 20 kcal/mol, despite being experimentally accessible. In stark contrast, the involvement of dispersion adequately described the selectivity. The attractive dispersion forces of the crowded trialkyl substituents are therefore a key controlling factor in the competition between mono- and bisligated pathways.

An Exclusively trans-Selective Chlorocarbamoylation of Alkynes Enabled by a Palladium/Phosphaadamantane Catalyst

Co-reporter:Christine M. Le;Xiao Hou;Theresa Sperger;Dr. Franziska Schoenebeck;Dr. Mark Lautens

Angewandte Chemie International Edition 2015 Volume 54( Issue 52) pp:15897-15900

Publication Date(Web):

DOI:10.1002/anie.201507883

Abstract

Pharmaceutically relevant methylene oxindoles are synthesized by a palladium(0)-catalyzed intramolecular chlorocarbamoylation reaction of alkynes. A relatively underexplored class of caged phosphine ligands is uniquely suited for this transformation, enabling high levels of reactivity and exquisite trans selectivity. This report entails the first transition-metal-catalyzed atom-economic addition of a carbamoyl chloride across an alkyne.

Trifluoromethylthiolation of Aryl Iodides and Bromides Enabled by a Bench-Stable and Easy-To-Recover Dinuclear Palladium(I) Catalyst

Co-reporter:Dr. Guoyin Yin;Indrek Kalvet ;Dr. Franziska Schoenebeck

Angewandte Chemie International Edition 2015 Volume 54( Issue 23) pp:6809-6813

Publication Date(Web):

DOI:10.1002/anie.201501617

Abstract

Air-Stable Dinuclear Iodine-Bridged Pd(I) Complex - Catalyst, Precursor, or Parasite? The Additive Decides. Systematic Nucleophile-Activity Study and Application as Precatalyst in Cross-Coupling

Co-reporter:Marialuisa Aufiero, Thomas Scattolin, Fabien Proutière, and Franziska Schoenebeck

Organometallics 2015 Volume 34(Issue 20) pp:5191-5195

Publication Date(Web):October 6, 2015

DOI:10.1021/acs.organomet.5b00766

Dinuclear Pd(I) complexes were recently shown to potentially adopt various possible roles in catalysis, being capable of functioning as catalyst via dinuclear catalysis cycles, precatalyst for Pd(0), or inhibitor. This report examines the factors that control the mechanistic role in catalysis. Our data suggest that the transformation to Pd(0) occurs via nucleophile-induced fragmentation of Pd(I)–Pd(I). A systematic study examining the nucleophilicity of additive versus activity was undertaken that revealed the minimum nucleophilicity necessary to activate two structurally very similar Pd(I) dimers, [Pd(μ-X)(PtBu3)]2 (X = I or Br). While the more labile bromine-bridged Pd(I) dimer is converted to Pd(0) with nucleophiles N ≥ 10.5, the iodine-bridged analogue requires N ≥ 16.1 (N according to Mayr’s scale). Too strong nucleophiles generate a high concentration of unstable monoligated Pd(0) rapidly, leading to Pd loss (i.e., Pd black). On the other hand, careful tuning of nucleophilicity allows for a controlled release of well-defined Pd(0) species. These insights have led to the first application of the air-stable and previously thought unreactive iodine-bridged dimer [Pd(μ-I)(PtBu3)]2 as a precatalyst for monoligated Pd(0) in cross-coupling reactions. The reactions were performed without exclusion of oxygen—all reagents were handled in air without special precautions. Highly efficient Kumada couplings of aryl iodides and bromides were achieved in <5 min at room temperature.

Experiment and computation: a combined approach to study the reactivity of palladium complexes in oxidation states 0 to IV

Co-reporter:Karl J. Bonney and Franziska Schoenebeck

Chemical Society Reviews 2014 vol. 43(Issue 18) pp:6609-6638

Publication Date(Web):24 Apr 2014

DOI:10.1039/C4CS00061G

As the accuracy of computational chemistry increases, and the advent of more powerful computers decreases the amount of time required to perform complex calculations, the use of this to investigate chemical systems becomes increasingly attractive. Particularly in combination with practical lab-based experimental and spectroscopic studies the application of in silico studies is a powerful tool for mechanistic investigations. In this review we demonstrate how a combined experimental and computational approach can yield mechanistic insight that could frequently not have been accessible to this high degree of certainty by utilising one of these two approaches alone. After an introduction describing the challenges of studying palladium-based chemistry, and how this combined approach can help to tackle these challenges (Section 1), we provide examples in which experiments have been used in tandem with computational chemistry. This discussion is categorised by palladium oxidation state for convenience: Pd(0) chemistry comprises discussion on oxidative addition in traditional Pd(0)/Pd(II) cross-coupling (Section 2); a section on odd oxidation state chemistry includes oxidation of Pd(0) to Pd(I) dimers, oxidative addition to Pd(I) dimers, oxidation of Pd(II) to Pd(III) dimers and subsequently reductive elimination from these Pd(III) dimers (Section 3); Pd(II) chemistry includes transmetallation, reductive elimination and the field of C–H activation relating to palladium catalysis (Section 4); and finally, a section on Pd(IV) chemistry focusses on reductive elimination from these complexes (Section 5).

Mechanistic Insight into the Spirocyclopropane Isoxazolidine Ring Contraction

Co-reporter:Stefan Diethelm, Franziska Schoenebeck, and Erick M. Carreira

Organic Letters 2014 Volume 16(Issue 3) pp:960-963

Publication Date(Web):January 21, 2014

DOI:10.1021/ol403693t

A mechanistic study of the ring contraction of spirocyclopropane isoxazolidines to form β-lactams is reported. Based on experimental and computational investigations, we propose a concerted mechanism that proceeds with retention of configuration during cyclopropane cleavage.

Computational Ligand Design for the Reductive Elimination of ArCF3 from a Small Bite Angle PdII Complex: Remarkable Effect of a Perfluoroalkyl Phosphine

Co-reporter:Dr. Mads C. Nielsen;Dr. Karl. J. Bonney;Dr. Franziska Schoenebeck

Angewandte Chemie 2014 Volume 126( Issue 23) pp:6013-6016

Publication Date(Web):

DOI:10.1002/ange.201400837

Abstract

To date only three ligands are known to trigger the challenging reductive elimination of ArCF₃ from Pd^II. We report the computational design of a bidentate trifluoromethylphosphine ligand that although exhibiting a generally ineffective small bite angle is predicted to give facile reductive elimination. Our experimental verification gave quantitative formation of ArCF₃ at 80 °C within 2 h. This highlights the distinct effect of P-CF₃ in organometallic reactivity and constitutes a proof-of-principle study of computational reactivity design.

Combining the Reactivity Properties of PCy3 and PtBu3 into a Single Ligand, P(iPr)(tBu)2. Reaction via Mono- or Bisphosphine Palladium(0) Centers and Palladium(I) Dimer Formation

Co-reporter:Fabien Proutiere, Eirik Lyngvi, Marialuisa Aufiero, Italo A. Sanhueza, and Franziska Schoenebeck

Organometallics 2014 Volume 33(Issue 23) pp:6879-6884

Publication Date(Web):November 25, 2014

DOI:10.1021/om5009605

Trialkylphosphine ligands are ubiquitous in catalysis. Via modulation of the steric bulk of these ligands, two central aspects that dictate reactivity and selectivity in catalysis can be controlled: i.e., the coordination sphere and favored oxidation state of the reactive metal center. Within this class of ligands, tricyclohexylphosphine (PCy3) and tri-tert-butylphosphine (PtBu3) are most widely used in catalysis. While the smaller PCy3 favors reactivity via Pd bisphosphine species with the test substrate 4-chlorophenyl triflate 1 and does not form dinuclear Pd(I) complexes upon oxidation of Pd(0), PtBu3 reacts via a monophosphine-ligated Pd complex with 1 and forms dinuclear Pd(I) complexes on oxidation. We herein report that the hybrid ligand P(iPr)(tBu)2, characterized by a cone angle that is between those of PCy3 and PtBu3, features all of these reactivity properties in a single scaffold. This is exemplified in chemoselectivity studies with test system 1, in which the site selectivity could be readily modulated. The novel Pd(I) dimer {[P(iPr)(tBu)2]PdI}2 has also been synthesized.

Computational Ligand Design for the Reductive Elimination of ArCF3 from a Small Bite Angle PdII Complex: Remarkable Effect of a Perfluoroalkyl Phosphine

Co-reporter:Dr. Mads C. Nielsen;Dr. Karl. J. Bonney;Dr. Franziska Schoenebeck

Angewandte Chemie International Edition 2014 Volume 53( Issue 23) pp:5903-5906

Publication Date(Web):

DOI:10.1002/anie.201400837

Abstract

Combining Experimental and Computational Studies to Understand and Predict Reactivities of Relevance to Homogeneous Catalysis

Co-reporter:Dr. Althea S.-K. Tsang;Italo A. Sanhueza;Dr. Franziska Schoenebeck

Chemistry - A European Journal 2014 Volume 20( Issue 50) pp:16432-16441

Publication Date(Web):

DOI:10.1002/chem.201404725

Abstract

This article showcases three major uses of computational chemistry in reactivity studies: the application after, in combination with, and before experiment. Following a brief introduction of suitable computational tools, challenges and opportunities in the implementation of computational chemistry in reactivity studies are discussed, exemplified with selected case studies from our and other laboratories.

Kinetic and Computational Studies on Pd(I) Dimer-Mediated Halogen Exchange of Aryl Iodides

Co-reporter:Indrek Kalvet, Karl J. Bonney, and Franziska Schoenebeck

The Journal of Organic Chemistry 2014 Volume 79(Issue 24) pp:12041-12046

Publication Date(Web):September 23, 2014

DOI:10.1021/jo501889j

Building on our previous discovery and reactivity explorations of the Pd(I) dimer [(PtBu3)PdBr]2-mediated halogen exchange of aryl iodides [ Chem. Sci. 2013, 4, 4434], this report presents kinetic studies of this process, giving first-order kinetic dependence in the Pd(I) dimer and aryl iodide. An activation free energy barrier of ΔG⧧ = 24.9 ± 3.3 kcal/mol was experimentally determined. Extensive computational studies on the likely reaction pathway were subsequently carried out. A variety of DFT methods were assessed, ranging from dispersion-free methods to those that better account for dispersion (M06L, ωB97XD, D3-DFT). While significant discrepancies in the quantitative prediction of activation barriers were observed, all computational methods consistently predicted the analogous qualitative reactivity that is in agreement with all spectroscopic and reactivity data collected. Overall, these data provide compelling additional support of the direct reactivity of Pd(I)–Pd(I) with aryl iodides.

Dinuclear Pd(I) complexes—solely precatalysts? Demonstration of direct reactivity of a Pd(I) dimer with an aryl iodide

Co-reporter:Karl J. Bonney, Fabien Proutiere and Franziska Schoenebeck

Chemical Science 2013 vol. 4(Issue 12) pp:4434-4439

Publication Date(Web):03 Sep 2013

DOI:10.1039/C3SC52054D

This report provides experimental, computational and spectroscopic data in support of the direct reactivity of a Pd(I) dimer with an aryl iodide, resulting in Br/I halogen exchange between the complex and the aryl iodide. The reactivity could not be achieved through analogous Pd(0) conditions, demonstrating the distinct reactivities at such multiple Pd-sites. Computational studies support that the direct oxidative addition to ArI by the dinuclear metal complex is energetically feasible.

Trifluoromethylation of Ketones and Aldehydes with Bu3SnCF3

Co-reporter:Italo A. Sanhueza, Karl J. Bonney, Mads C. Nielsen, and Franziska Schoenebeck

The Journal of Organic Chemistry 2013 Volume 78(Issue 15) pp:7749-7753

Publication Date(Web):July 8, 2013

DOI:10.1021/jo401099e

The (trifluoromethyl)stannane reagent, Bu3SnCF3, was found to react under CsF activation with ketones and aldehydes to the corresponding trifluoromethylated stannane ether intermediates at room temperature in high yield. Only a mildly acidic extraction (aqueous NH4Cl) is required to release the corresponding trifluoromethyl alcohol products. The protocol is compatible with acid-sensitive functional groups.

Mild and selective base-free C–H arylation of heteroarenes: experiment and computation

Co-reporter:Hannes P. L. Gemoets, Indrek Kalvet, Alexander V. Nyuchev, Nico Erdmann, Volker Hessel, Franziska Schoenebeck and Timothy Noël

Chemical Science (2010-Present) 2017 - vol. 8(Issue 2) pp:NaN1055-1055

Publication Date(Web):2016/09/05

DOI:10.1039/C6SC02595A

Mechanistic insights on the Pd-catalyzed addition of C–X bonds across alkynes – a combined experimental and computational study

Co-reporter:Theresa Sperger, Christine M. Le, Mark Lautens and Franziska Schoenebeck

Chemical Science (2010-Present) 2017 - vol. 8(Issue 4) pp:NaN2922-2922

Publication Date(Web):2017/01/27

DOI:10.1039/C6SC05001H

Nickel-catalyzed trifluoromethylthiolation of Csp2–O bonds

Co-reporter:Alexander B. Dürr, Guoyin Yin, Indrek Kalvet, François Napoly and Franziska Schoenebeck

Chemical Science (2010-Present) 2016 - vol. 7(Issue 2) pp:NaN1081-1081

Publication Date(Web):2015/10/30

DOI:10.1039/C5SC03359D

Dinuclear Pd(I) complexes—solely precatalysts? Demonstration of direct reactivity of a Pd(I) dimer with an aryl iodide

Co-reporter:Karl J. Bonney, Fabien Proutiere and Franziska Schoenebeck

Chemical Science (2010-Present) 2013 - vol. 4(Issue 12) pp:NaN4439-4439

Publication Date(Web):2013/09/03

DOI:10.1039/C3SC52054D

Experiment and computation: a combined approach to study the reactivity of palladium complexes in oxidation states 0 to IV

Co-reporter:Karl J. Bonney and Franziska Schoenebeck

Chemical Society Reviews 2014 - vol. 43(Issue 18) pp:NaN6638-6638

Publication Date(Web):2014/04/24

DOI:10.1039/C4CS00061G

Methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), min. 98% [RuPhos Palladacycle Gen. 3]

CAS:1445085-77-7

Methanesulfonato(2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II), min. 98% [RuPhos Palladacycle Gen. 3]