Co-reporter:Stephen J. Tereniak and Shannon S. Stahl
Journal of the American Chemical Society October 18, 2017 Volume 139(Issue 41) pp:14533-14533
Publication Date(Web):September 24, 2017
DOI:10.1021/jacs.7b07359
A recently reported Pd-catalyzed method for oxidative imidoylation of C–H bonds exhibits unique features that have important implications for Pd-catalyzed aerobic oxidation catalysis: (1) The reaction tolerates heterocycles that commonly poison Pd catalysts. (2) The site selectivity of C–H activation is controlled by an N-methoxyamide group rather than a suitably positioned heterocycle. (3) A Pd0 source, Pd2(dba)3 (dba = dibenzylideneacetone), is superior to Pd(OAc)2 as a precatalyst, and other PdII sources are ineffective. (4) The reaction performs better with air, rather than pure O2. The present study elucidates the origin of these features. Kinetic, mechanistic, and in situ spectroscopic studies establish that PdII-mediated C–H activation is the turnover-limiting step. The tBuNC substrate is shown to coordinate more strongly to PdII than pyridine, thereby contributing to the lack of heterocycle catalyst poisoning. A well-defined PdII–peroxo complex is a competent intermediate that promotes substrate coordination via proton-coupled ligand exchange. The effectiveness of this substrate coordination step correlates with the basicity of the anionic ligands coordinated to PdII, and Pd0 catalyst precursors are most effective because they selectively afford the PdII–peroxo in situ. Finally, elevated O2 pressures are shown to contribute to background oxidation of the isonitrile, thereby explaining the improved performance of reactions conducted with air rather than 1 atm O2. These collective results explain the unique features of the aerobic C–H imidoylation of N-methoxybenzamides and have important implications for other Pd-catalyzed aerobic C–H oxidation reactions.
Co-reporter:Yu-Heng Wang, Michael L. Pegis, James M. Mayer, and Shannon S. Stahl
Journal of the American Chemical Society November 22, 2017 Volume 139(Issue 46) pp:16458-16458
Publication Date(Web):October 17, 2017
DOI:10.1021/jacs.7b09089
A series of mononuclear pseudomacrocyclic cobalt complexes have been investigated as catalysts for O2 reduction. Each of these complexes, with CoIII/II reduction potentials that span nearly 400 mV, mediate highly selective two-electron reduction of O2 to H2O2 (93–99%) using decamethylferrocene (Fc*) as the reductant and acetic acid as the proton source. Kinetic studies reveal that the rate exhibits a first-order dependence on [Co] and [AcOH], but no dependence on [O2] or [Fc*]. A linear correlation is observed between log(TOF) vs E1/2(CoIII/II) for the different cobalt complexes (TOF = turnover frequency). The thermodynamic potential for O2 reduction to H2O2 was estimated by measuring the H+/H2 open-circuit potential under the reaction conditions. This value provides the basis for direct assessment of the thermodynamic efficiency of the different catalysts and shows that H2O2 is formed with overpotentials as low as 90 mV. These results are compared with a recently reported series of Fe-porphyrin complexes, which catalyze four-electron reduction of O2 to H2O. The data show that the TOFs of the Co complexes exhibit a shallower dependence on E1/2(MIII/II) than the Fe complexes. This behavior, which underlies the low overpotential, is rationalized on the basis of the catalytic rate law.
Co-reporter:Alireza Rahimi, Ali Azarpira, Hoon Kim, John Ralph, and Shannon S. Stahl
Journal of the American Chemical Society May 1, 2013 Volume 135(Issue 17) pp:6415-6418
Publication Date(Web):April 9, 2013
DOI:10.1021/ja401793n
An efficient organocatalytic method for chemoselective aerobic oxidation of secondary benzylic alcohols within lignin model compounds has been identified. Extension to selective oxidation in natural lignins has also been demonstrated. The optimal catalyst system consists of 4-acetamido-TEMPO (5 mol %; TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) in combination with HNO3 and HCl (10 mol % each). Preliminary studies highlight the prospect of combining this method with a subsequent oxidation step to achieve C–C bond cleavage.
Co-reporter:Aristidis Vasilopoulos, Susan L. Zultanski, and Shannon S. Stahl
Journal of the American Chemical Society June 14, 2017 Volume 139(Issue 23) pp:7705-7705
Publication Date(Web):May 30, 2017
DOI:10.1021/jacs.7b03387
A Cu-catalyzed method has been identified for selective oxidative arylation of benzylic C–H bonds with arylboronic esters. The resulting 1,1-diarylalkanes are accessed directly from inexpensive alkylarenes containing primary and secondary benzylic C–H bonds, such as toluene or ethylbenzene. All catalyst components are commercially available at low cost, and the arylboronic esters are either commercially available or easily accessible from the commercially available boronic acids. The potential utility of these methods in medicinal chemistry applications is highlighted.
Co-reporter:Andrei V. Iosub and Shannon S. Stahl
ACS Catalysis December 2, 2016 Volume 6(Issue 12) pp:8201-8201
Publication Date(Web):October 24, 2016
DOI:10.1021/acscatal.6b02406
Catalytic dehydrogenation of saturated or partially saturated six-membered carbocycles into aromatic rings represents an appealing strategy for the synthesis of substituted arenes. Particularly effective methods have been developed for the dehydrogenation of cyclohexanones and cyclohexenes into substituted phenol, aniline, and benzene derivatives, respectively. In this Perspective, we present the contributions of our research group to the discovery and development of palladium-based catalysts for aerobic oxidative dehydrogenation methods, including general methods for conversion of cyclohexanones and cyclohexenones into substituted phenols and a complementary method for partial dehydrogenation of cyclohexanones to cyclohexenones. The mechanistic basis for chemoselective conversion of cyclohexanones to phenols or enones is presented. These results are presented within the context of recent methods developed by others for the synthesis of aryl ethers, anilines, and other substituted arenes. Overall, Pd-catalyzed dehydrogenation methods provide a compelling strategy for selective synthesis of aromatic and related unsaturated molecules.Keywords: aerobic; aromatic; catalysis; dehydrogenation; oxidation; palladium;
Co-reporter:Dian Wang and Shannon S. Stahl
Journal of the American Chemical Society April 26, 2017 Volume 139(Issue 16) pp:5704-5704
Publication Date(Web):April 11, 2017
DOI:10.1021/jacs.7b01970
Copper salts find widespread use in Pd-catalyzed oxidation reactions, and they are typically used as oxidants or redox-active cocatalysts. Here, we probe the origin of a dramatic acceleration effect of Cu(OTf)2 in the C–H/C–H aerobic oxidative coupling of o-xylene. NMR spectroscopic analysis of the PdII catalyst in the presence of Cu(OTf)2, together with other experimental and DFT computational studies of the catalytic reaction, show that Cu(OTf)2 activates the PdII catalyst for C–H activation via a non-redox pathway and has negligible impact on catalyst reoxidation. These observations led to the testing of other metal triflate salts as cocatalysts, the results of which show that Fe(OTf)3 is even more effective than Cu(OTf)2.
Co-reporter:Scott D. McCann, Jean-Philip Lumb, Bruce A. Arndtsen, and Shannon S. Stahl
ACS Central Science April 26, 2017 Volume 3(Issue 4) pp:314-314
Publication Date(Web):February 24, 2017
DOI:10.1021/acscentsci.7b00022
A homogeneous Cu-based catalyst system consisting of [Cu(MeCN)4]PF6, N,N′-di-tert-butylethylenediamine (DBED), and p-(N,N-dimethylamino)pyridine (DMAP) mediates efficient aerobic oxidation of alcohols. Mechanistic study of this reaction shows that the catalyst undergoes an in situ oxidative self-processing step, resulting in conversion of DBED into a nitroxyl that serves as an efficient cocatalyst for aerobic alcohol oxidation. Insights into this behavior are gained from kinetic studies, which reveal an induction period at the beginning of the reaction that correlates with the oxidative self-processing step, EPR spectroscopic analysis of the catalytic reaction mixture, which shows the buildup of the organic nitroxyl species during steady state turnover, and independent synthesis of oxygenated DBED derivatives, which are shown to serve as effective cocatalysts and eliminate the induction period in the reaction. The overall mechanism bears considerable resemblance to enzymatic reactivity. Most notable is the “oxygenase”-type self-processing step that mirrors generation of catalytic cofactors in enzymes via post-translational modification of amino acid side chains. This higher-order function within a synthetic catalyst system presents new opportunities for the discovery and development of biomimetic catalysts.
Co-reporter:David S. Mannel, Maaz S. Ahmed, Thatcher W. RootShannon S. Stahl
Journal of the American Chemical Society 2017 Volume 139(Issue 4) pp:1690-1698
Publication Date(Web):January 6, 2017
DOI:10.1021/jacs.6b12722
In the present study, we demonstrate the utility of “admixture screening” for the discovery of new multicomponent heterogeneous Pd catalyst compositions that are highly effective for aerobic oxidative methyl esterification of primary alcohols. The identification of possible catalysts for this reaction was initiated by the screening of simple binary and ternary admixtures of Pd/charcoal in combination with one or two metal and/or metalloid components as the catalyst. This approach permitted rapid evaluation of over 400 admixture combinations for the oxidative methyl esterification of 1-octanol at 60 °C in methanol. Product yields from these reactions varied widely, ranging from 2% to 88%. The highest yields were observed with Bi-, Te-, and Pb-based additives, and particularly from those containing both Bi and Te. Validation of the results was achieved by preparing specific PdBiTe catalyst formulations via a wet-impregnation method, followed by application of response surface methodology to identify the optimal Pd-Bi-Te catalyst stoichiometry. This approach revealed two very effective catalyst compositions: PdBi0.47Te0.09/C (PBT-1) and PdBi0.35Te0.23/C (PBT-2). The former catalyst was used in batch aerobic oxidation reactions with different primary alcohols and shown to be compatible with substrates bearing heterocycle and halide substituents. The methyl ester products were obtained in >90% yield in nearly all cases. Implementation of the PBT-2 catalyst in a continuous-flow packed-bed reactor achieved nearly 60 000 turnovers with no apparent loss of catalytic activity.
Co-reporter:Zachary K. Goldsmith;Aparna K. Harshan;James B. Gerken;Márton Vörös;Sharon Hammes-Schiffer;Giulia Galli
PNAS 2017 Volume 114 (Issue 12 ) pp:3050-3055
Publication Date(Web):2017-03-21
DOI:10.1073/pnas.1702081114
NiFe oxyhydroxide materials are highly active electrocatalysts for the oxygen evolution reaction (OER), an important process
for carbon-neutral energy storage. Recent spectroscopic and computational studies increasingly support iron as the site of
catalytic activity but differ with respect to the relevant iron redox state. A combination of hybrid periodic density functional
theory calculations and spectroelectrochemical experiments elucidate the electronic structure and redox thermodynamics of
Ni-only and mixed NiFe oxyhydroxide thin-film electrocatalysts. The UV/visible light absorbance of the Ni-only catalyst depends
on the applied potential as metal ions in the film are oxidized before the onset of OER activity. In contrast, absorbance
changes are negligible in a 25% Fe-doped catalyst up to the onset of OER activity. First-principles calculations of proton-coupled
redox potentials and magnetizations reveal that the Ni-only system features oxidation of Ni2+ to Ni3+, followed by oxidation to a mixed Ni3+/4+ state at a potential coincident with the onset of OER activity. Calculations on the 25% Fe-doped system show the catalyst
is redox inert before the onset of catalysis, which coincides with the formation of Fe4+ and mixed Ni oxidation states. The calculations indicate that introduction of Fe dopants changes the character of the conduction
band minimum from Ni-oxide in the Ni-only to predominantly Fe-oxide in the NiFe electrocatalyst. These findings provide a
unified experimental and theoretical description of the electrochemical and optical properties of Ni and NiFe oxyhydroxide
electrocatalysts and serve as an important benchmark for computational characterization of mixed-metal oxidation states in
heterogeneous catalysts.
Co-reporter:Damian P. Hruszkewycz;Kelsey C. Miles;Oliver R. Thiel
Chemical Science (2010-Present) 2017 vol. 8(Issue 2) pp:1282-1287
Publication Date(Web):2017/01/30
DOI:10.1039/C6SC03831J
A simple cobalt(II)/N-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C–H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C–H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90–100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate (AMG 579) under process-relevant reaction conditions.
Co-reporter:Dr. Amit Das; Dr. Shannon S. Stahl
Angewandte Chemie 2017 Volume 129(Issue 30) pp:9018-9023
Publication Date(Web):2017/07/17
DOI:10.1002/ange.201704921
AbstractElectrocatalytic methods for organic synthesis could offer sustainable alternatives to traditional redox reactions, but strategies are needed to enhance the performance of molecular catalysts designed for this purpose. The synthesis of a pyrene-tethered TEMPO derivative (TEMPO=2,2,6,6-tetramethylpiperidinyl-N-oxyl) is described, which undergoes facile in situ noncovalent immobilization onto a carbon cloth electrode. Cyclic voltammetry and controlled potential electrolysis studies demonstrate that the immobilized catalyst exhibits much higher activity relative to 4-acetamido–TEMPO, an electronically similar homogeneous catalyst. In preparative electrolysis experiments with a series of alcohol substrates and the immobilized catalyst, turnover numbers and frequencies approach 2 000 and 4 000 h−1, respectively. The synthetic utility of the method is further demonstrated in the oxidation of a sterically hindered hydroxymethylpyrimidine precursor to the blockbuster drug, rosuvastatin.
Co-reporter:Dr. Amit Das; Dr. Shannon S. Stahl
Angewandte Chemie International Edition 2017 Volume 56(Issue 30) pp:8892-8897
Publication Date(Web):2017/07/17
DOI:10.1002/anie.201704921
AbstractElectrocatalytic methods for organic synthesis could offer sustainable alternatives to traditional redox reactions, but strategies are needed to enhance the performance of molecular catalysts designed for this purpose. The synthesis of a pyrene-tethered TEMPO derivative (TEMPO=2,2,6,6-tetramethylpiperidinyl-N-oxyl) is described, which undergoes facile in situ noncovalent immobilization onto a carbon cloth electrode. Cyclic voltammetry and controlled potential electrolysis studies demonstrate that the immobilized catalyst exhibits much higher activity relative to 4-acetamido–TEMPO, an electronically similar homogeneous catalyst. In preparative electrolysis experiments with a series of alcohol substrates and the immobilized catalyst, turnover numbers and frequencies approach 2 000 and 4 000 h−1, respectively. The synthetic utility of the method is further demonstrated in the oxidation of a sterically hindered hydroxymethylpyrimidine precursor to the blockbuster drug, rosuvastatin.
Co-reporter:Mioy T. Huynh, Colin W. Anson, Andrew C. Cavell, Shannon S. Stahl, and Sharon Hammes-Schiffer
Journal of the American Chemical Society 2016 Volume 138(Issue 49) pp:15903-15910
Publication Date(Web):November 10, 2016
DOI:10.1021/jacs.6b05797
Quinones participate in diverse electron transfer and proton-coupled electron transfer processes in chemistry and biology. To understand the relationship between these redox processes, an experimental study was carried out to probe the 1 e– and 2 e–/2 H+ reduction potentials of a number of common quinones. The results reveal a non-linear correlation between the 1 e– and 2 e–/2 H+ reduction potentials. This unexpected observation prompted a computational study of 134 different quinones, probing their 1 e– reduction potentials, pKa values, and 2 e–/2 H+ reduction potentials. The density functional theory calculations reveal an approximately linear correlation between these three properties and an effective Hammett constant associated with the quinone substituent(s). However, deviations from this linear scaling relationship are evident for quinones that feature intramolecular hydrogen bonding, halogen substituents, charged substituents, and/or sterically bulky substituents. These results, particularly the different substituent effects on the 1 e– versus 2 e–/2 H+ reduction potentials, have important implications for designing quinones with tailored redox properties.
Co-reporter:Paul B. White; Jonathan N. Jaworski; Charles G. Fry; Brian S. Dolinar; Ilia A. Guzei
Journal of the American Chemical Society 2016 Volume 138(Issue 14) pp:4869-4880
Publication Date(Web):March 11, 2016
DOI:10.1021/jacs.6b01188
4,5-Diazafluoren-9-one (DAF) has been identified as a highly effective ligand in a number of Pd-catalyzed oxidation reactions, but the mechanistic basis for its utility has not been elucidated. Here, we present the complex coordination chemistry of DAF and palladium(II) carboxylate salts. Multiple complexes among an equilibrating mixture of species have been characterized by 1H and 15N NMR spectroscopy and X-ray crystallography. These complexes include monomeric and dimeric PdII species, with monodentate (κ1), bidentate (κ2), and bridging (μ:κ1:κ1) DAF coordination modes. Titration studies of DAF and Pd(OAc)2 reveal the formation of two dimeric DAF/Pd(OAc)2 complexes at low [DAF] and four monomeric species at higher [DAF]. The dimeric complexes feature two bridging acetate ligands together with either a bridging or nonbridging (κ1) DAF ligand coordinated to each PdII center. The monomeric structures consist of three isomeric Pd(κ1-DAF)2(OAc)2 complexes, together with Pd(κ2-DAF)(OAc)2 in which the DAF exhibits a traditional bidentate coordination mode. Replacing DAF with the structurally related, but more-electron-rich derivative 9,9-dimethyl-4,5-diazafluorene (Me2DAF) simplifies the equilibrium mixture to two complexes: a dimeric species in which the Me2DAF bridges the two Pd centers and a monomeric species with a traditional κ2-Me2DAF coordination mode. The use of DAF in combination with other carboxylate ligands (CF3CO2– or tBuCO2–) also results in a simplified collection of equilibrating PdII–DAF complexes. Collectively, the results highlight the ability of DAF to equilibrate rapidly among multiple coordination modes, and provide valuable insights into the utility of DAF as a ligand in Pd-catalyzed oxidation reactions.
Co-reporter:Colin W. Anson; Soumya Ghosh; Sharon Hammes-Schiffer
Journal of the American Chemical Society 2016 Volume 138(Issue 12) pp:4186-4193
Publication Date(Web):February 29, 2016
DOI:10.1021/jacs.6b00254
Macrocyclic metal complexes and p-benzoquinones are commonly used as co-catalytic redox mediators in aerobic oxidation reactions. In an effort to gain insight into the mechanism and energetic efficiency of these reactions, we investigated Co(salophen)-catalyzed aerobic oxidation of p-hydroquinone. Kinetic and spectroscopic data suggest that the catalyst resting-state consists of an equilibrium between a CoII(salophen) complex, a CoIII-superoxide adduct, and a hydrogen-bonded adduct between the hydroquinone and the CoIII–O2 species. The kinetic data, together with density functional theory computational results, reveal that the turnover-limiting step involves proton-coupled electron transfer from a semi-hydroquinone species and a CoIII-hydroperoxide intermediate. Additional experimental and computational data suggest that a coordinated H2O2 intermediate oxidizes a second equivalent of hydroquinone. Collectively, the results show how Co(salophen) and p-hydroquinone operate synergistically to mediate O2 reduction and generate the reactive p-benzoquinone co-catalyst.
Co-reporter:Susan L. Zultanski; Jingyi Zhao
Journal of the American Chemical Society 2016 Volume 138(Issue 20) pp:6416-6419
Publication Date(Web):May 12, 2016
DOI:10.1021/jacs.6b03931
A modular Cu/ABNO catalyst system has been identified that enables efficient aerobic oxidative coupling of alcohols and amines to amides. All four permutations of benzylic/aliphatic alcohols and primary/secondary amines are viable in this reaction, enabling broad access to secondary and tertiary amides. The reactions exhibit excellent functional group compatibility and are complete within 30 min–3 h at rt. All components of the catalyst system are commercially available.
Co-reporter:Paul B. White, Jonathan N. Jaworski, Geyunjian Harry Zhu, and Shannon S. Stahl
ACS Catalysis 2016 Volume 6(Issue 5) pp:3340
Publication Date(Web):April 11, 2016
DOI:10.1021/acscatal.6b00953
2,2′-Bipyridine (bpy), 1,10-phenanthroline (phen), and related bidentate ligands often inhibit homogeneous Pd-catalyzed aerobic oxidation reactions; however, certain derivatives, such as 4,5-diazafluoren-9-one (DAF), can promote catalysis. In order to gain insight into this divergent ligand behavior, eight different bpy- and phen-derived chelating ligands have been evaluated in the Pd(OAc)2-catalyzed oxidative cyclization of (E)-4-hexenyltosylamide. Two of the ligands, DAF and 6,6′-dimethyl-2,2′-bipyridine (6,6′-Me2bpy), support efficient catalytic turnover, while the others strongly inhibit the reaction. DAF is especially effective and is the only ligand that exhibits “ligand-accelerated catalysis”. Evidence suggests that the utility of DAF and 6,6′-Me2bpy originates from the ability of these ligands to access κ1-coordination modes via dissociation of one of the pyridyl rings. This hemilabile character is directly observed by NMR spectroscopy upon adding 1 equiv of pyridine to solutions of 1/1 L/Pd(OAc)2 (L = DAF, 6,6′-Me2bpy) and is further supported by the X-ray crystal structure of Pd(py)(κ1-DAF)OAc2. DFT computational studies illuminate the influence of three different chelating ligands (DAF, 6,6′-Me2bpy, and 2,9-dimethyl-1,10-phenanthroline (2,9-Me2phen)) on the energetics of the aza-Wacker reaction pathway. The results show that DAF and 6,6′-Me2bpy destabilize the corresponding ground-state Pd(N∼N)(OAc)2 complexes, while stabilizing the rate-limiting transition state for alkene insertion into a Pd–N bond. Interconversion between κ2 and κ1 coordination modes facilitates access to open coordination sites at the PdII center. The insights from these studies introduce new ligand concepts that could promote numerous other classes of Pd-catalyzed aerobic oxidation reactions.Keywords: aerobic; catalysis; diazafluorenone; mechanism; oxidation; palladium; Wacker
Co-reporter:Kyle Clagg, Haiyun Hou, Adam B. Weinstein, David Russell, Shannon S. Stahl, and Stefan G. Koenig
Organic Letters 2016 Volume 18(Issue 15) pp:3586-3589
Publication Date(Web):July 12, 2016
DOI:10.1021/acs.orglett.6b01592
A direct oxidative C–H amination affording 1-acetyl indolecarboxylates starting from 2-acetamido-3-arylacrylates has been achieved. Indole-2-carboxylates can be targeted with a straightforward deacetylation of the initial reaction products. The C–H amination reaction is carried out using a catalytic Pd(II) source with oxygen as the terminal oxidant. The scope and application of this chemistry is demonstrated with good to high yields for numerous electron-rich and electron-poor substrates. Further reaction of selected products via Suzuki arylation and deacetylation provides access to highly functionalized indole structures.
Co-reporter:Kelsey C. Miles, M. Leigh Abrams, Clark R. Landis, and Shannon S. Stahl
Organic Letters 2016 Volume 18(Issue 15) pp:3590-3593
Publication Date(Web):July 13, 2016
DOI:10.1021/acs.orglett.6b01598
A method for aerobic oxidation of aldehydes to carboxylic acids has been developed using organic nitroxyl and NOx cocatalysts. KetoABNO (9-azabicyclo[3.3.1]nonan-3-one N-oxyl) and NaNO2 were identified as the optimal nitroxyl and NOx sources, respectively. The mildness of the reaction conditions enables sequential asymmetric hydroformylation of alkenes/aerobic aldehyde oxidation to access α-chiral carboxylic acids without racemization. The scope, utility, and limitations of the oxidation method are further evaluated with a series of achiral aldehydes bearing diverse functional groups.
Co-reporter:Fei Wang;Dinghai Wang;Scott D. McCann;Wen Zhang;Pinhong Chen;Guosheng Liu
Science 2016 Volume 353(Issue 6303) pp:
Publication Date(Web):
DOI:10.1126/science.aaf7783
Abstract
Direct methods for stereoselective functionalization of sp3-hybridized carbon–hydrogen [C(sp3)–H] bonds in complex organic molecules could facilitate much more efficient preparation of therapeutics and agrochemicals. Here, we report a copper-catalyzed radical relay pathway for enantioselective conversion of benzylic C–H bonds into benzylic nitriles. Hydrogen-atom abstraction affords an achiral benzylic radical that undergoes asymmetric C(sp3)–CN bond formation upon reaction with a chiral copper catalyst. The reactions proceed efficiently at room temperature with the benzylic substrate as limiting reagent, exhibit broad substrate scope with high enantioselectivity (typically 90 to 99% enantiomeric excess), and afford products that are key precursors to important bioactive molecules. Mechanistic studies provide evidence for diffusible organic radicals and highlight the difference between these reactions and C–H oxidations mediated by enzymes and other catalysts that operate via radical rebound pathways.
Co-reporter:Scott D. McCann and Shannon S. Stahl
Accounts of Chemical Research 2015 Volume 48(Issue 6) pp:1756
Publication Date(Web):May 28, 2015
DOI:10.1021/acs.accounts.5b00060
Selective oxidation reactions have extraordinary value in organic chemistry, ranging from the conversion of petrochemical feedstocks into industrial chemicals and polymer precursors to the introduction of heteroatom functional groups into pharmaceutical and agrochemical intermediates. Molecular oxygen (O2) would be the ideal oxidant for these transformations. Whereas many commodity-scale oxidations of simple hydrocarbon feedstocks employ O2 as an oxidant, methods for selective oxidation of more complex molecules bearing diverse functional groups are often incompatible with existing aerobic oxidation methods. The latter limitation provides the basis for our interest in the development of new catalytic transformations and the elucidation of mechanistic principles that underlie selective aerobic oxidation reactions. One challenge inherent in such methods is the incommensurate redox stoichiometry associated with the use of O2, a four-electron oxidant, in reactions that achieve two-electron oxidation of organic molecules. This issue is further complicated by the use of first-row transition-metal catalysts, which tend to undergo facile one-electron redox steps. In recent years, we have been investigating Cu-catalyzed aerobic oxidation reactions wherein the complexities just noted are clearly evident. This Account surveys our work in this area, which has emphasized three general classes of reactions: (1) single-electron-transfer reactions for oxidative functionalization of electron-rich substrates, such as arenes and heterocycles; (2) oxidative carbon–heteroatom bond-forming reactions, including C–H oxidations, that proceed via organocopper(III) intermediates; and (3) methods for aerobic oxidation of alcohols and amines that use CuII in combination with an organic redox-active cocatalyst to dehydrogenate the carbon–heteroatom bond. These reaction classes demonstrate three different pathways to achieve two-electron oxidation of organic molecules via the cooperative involvement of two one-electron oxidants, either two CuII species or CuII and a nitroxyl cocatalyst. They show the ability of Cu to participate in traditional organometallic steps commonly associated with precious-metal catalysts, such as C–H activation and reductive elimination, but also demonstrate the accessibility of reaction steps not typically associated with precious-metal catalysts, such as single-electron transfer. Many of the Cu-catalyzed reactions offer advantages over analogous two-electron oxidation reactions mediated by palladium or other noble metals. For example, carbon–heteroatom oxidative coupling reactions in the first two reaction classes noted above are capable of using O2 as the terminal oxidant, while analogous reactions with Pd commonly require less desirable oxidants, such as hypervalent iodine or electrophilic halogen sources. In addition, the alcohol and amine oxidations in the third reaction class are significantly more efficient and show much broader scope and functional group tolerance than related Pd-catalyzed reactions. The mechanistic basis for these differences are described herein.
Co-reporter:Xiaomin Xie
Journal of the American Chemical Society 2015 Volume 137(Issue 11) pp:3767-3770
Publication Date(Web):March 9, 2015
DOI:10.1021/jacs.5b01036
Cu/nitroxyl catalysts have been identified that promote highly efficient and selective aerobic oxidative lactonization of diols under mild reaction conditions using ambient air as the oxidant. The chemo- and regioselectivity of the reaction may be tuned by changing the identity of the nitroxyl cocatalyst. A Cu/ABNO catalyst system (ABNO = 9-azabicyclo[3.3.1]nonan-N-oxyl) shows excellent reactivity with symmetrical diols and hindered unsymmetrical diols, whereas a Cu/TEMPO catalyst system (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl) displays excellent chemo- and regioselectivity for the oxidation of less hindered unsymmetrical diols. These catalyst systems are compatible with all classes of alcohols (benzylic, allylic, aliphatic), mediate efficient lactonization of 1,4-, 1,5-, and some 1,6-diols, and tolerate diverse functional groups, including alkenes, heterocycles, and other heteroatom-containing groups.
Co-reporter:Andrei V. Iosub
Journal of the American Chemical Society 2015 Volume 137(Issue 10) pp:3454-3457
Publication Date(Web):March 3, 2015
DOI:10.1021/ja512770u
A palladium(II) catalyst system has been identified for aerobic dehydrogenation of substituted cyclohexenes to the corresponding arene derivatives. Use of sodium anthraquinone-2-sulfonate (AMS) as a cocatalyst enhances the product yields. A wide range of functional groups are tolerated in the reactions, and the scope and limitations of the method are described. The catalytic dehydrogenation of cyclohexenes is showcased in an efficient route to a phthalimide-based TRPA1 activity modulator.
Co-reporter:Ravi Pokhrel; McKenna K. Goetz; Sarah E. Shaner; Xiaoxia Wu
Journal of the American Chemical Society 2015 Volume 137(Issue 26) pp:8384-8387
Publication Date(Web):June 18, 2015
DOI:10.1021/jacs.5b05093
Manganese oxides are a highly promising class of water-oxidation catalysts (WOCs), but the optimal MnOx formulation or polymorph is not clear from previous reports in the literature. A complication not limited to MnOx-based WOCs is that such catalysts are routinely evaluated by different methods, ranging from the use of a chemical oxidant such as Ce4+, photoactive mediators such as [Ru(bpy)3]2+, or electrochemical techniques. Here, we report a systematic study of nine crystalline MnOx materials as WOCs and show that the identity of the “best” catalyst changes, depending on the oxidation method used to probe the catalytic activity.
Co-reporter:Scott D. McCann
Journal of the American Chemical Society 2015 Volume 138(Issue 1) pp:199-206
Publication Date(Web):December 22, 2015
DOI:10.1021/jacs.5b09940
Cooperative catalysis between CuII and redox-active organic cocatalysts is a key feature of important chemical and enzymatic aerobic oxidation reactions, such as alcohol oxidation mediated by Cu/TEMPO and galactose oxidase. Nearly 20 years ago, Markó and co-workers reported that azodicarboxylates, such as di-tert-butyl azodicarboxylate (DBAD), are effective redox-active cocatalysts in Cu-catalyzed aerobic alcohol oxidation reactions [Markó, I. E., et al. Science 1996, 274, 2044], but the nature of the cooperativity between Cu and azodicarboxylates is not well understood. Here, we report a mechanistic study of Cu/DBAD-catalyzed aerobic alcohol oxidation. In situ infrared spectroscopic studies reveal a burst of product formation prior to steady-state catalysis, and gas-uptake measurements show that no O2 is consumed during the burst. Kinetic studies reveal that the anaerobic burst and steady-state turnover have different rate laws. The steady-state rate does not depend on [O2] or [DBAD]. These results, together with other EPR and in situ IR spectroscopic and kinetic isotope effect studies, reveal that the steady-state mechanism consists of two interdependent catalytic cycles that operate in sequence: a fast CuII/DBAD pathway, in which DBAD serves as the oxidant, and a slow CuII-only pathway, in which CuII is the oxidant. This study provides significant insight into the redox cooperativity, or lack thereof, between Cu and redox-active organic cocatalysts in aerobic oxidation reactions.
Co-reporter:Jamie Y. C. Chen; Lianna Dang; Hanfeng Liang; Wenli Bi; James B. Gerken; Song Jin; E. Ercan Alp
Journal of the American Chemical Society 2015 Volume 137(Issue 48) pp:15090-15093
Publication Date(Web):November 17, 2015
DOI:10.1021/jacs.5b10699
Nickel–iron oxides/hydroxides are among the most active electrocatalysts for the oxygen evolution reaction. In an effort to gain insight into the role of Fe in these catalysts, we have performed operando Mössbauer spectroscopic studies of a 3:1 Ni:Fe layered hydroxide and a hydrous Fe oxide electrocatalyst. The catalysts were prepared by a hydrothermal precipitation method that enabled catalyst growth directly on carbon paper electrodes. Fe4+ species were detected in the NiFe hydroxide catalyst during steady-state water oxidation, accounting for up to 21% of the total Fe. In contrast, no Fe4+ was detected in the Fe oxide catalyst. The observed Fe4+ species are not kinetically competent to serve as the active site in water oxidation; however, their presence has important implications for the role of Fe in NiFe oxide electrocatalysts.
Co-reporter:Mohammad Rafiee; Kelsey C. Miles
Journal of the American Chemical Society 2015 Volume 137(Issue 46) pp:14751-14757
Publication Date(Web):October 27, 2015
DOI:10.1021/jacs.5b09672
Bicyclic nitroxyl derivatives, such as 2-azaadamantane N-oxyl (AZADO) and 9-azabicyclo[3.3.1]nonane N-oxyl (ABNO), have emerged as highly effective alternatives to TEMPO-based catalysts for selective oxidation reactions (TEMPO = 2,2,6,6-tetramethyl-1-piperidine N-oxyl). Their efficacy is widely attributed to their smaller steric profile; however, electrocatalysis studies described herein show that the catalytic activity of nitroxyls is more strongly affected by the nitroxyl/oxoammonium redox potential than by steric effects. The inexpensive, high-potential TEMPO derivative, 4-acetamido-TEMPO (ACT), exhibits higher electrocatalytic activity than AZADO and ABNO for the oxidation of primary and secondary alcohols. Mechanistic studies provide insights into the origin of these unexpected reactivity trends. The superior activity of ACT is especially noteworthy at high pH, where bicyclic nitroxyls are inhibited by formation of an oxoammonium hydroxide adduct.
Co-reporter:Changwu Zheng and Shannon S. Stahl
Chemical Communications 2015 vol. 51(Issue 64) pp:12771-12774
Publication Date(Web):03 Jul 2015
DOI:10.1039/C5CC05312A
Branched-selective oxidative Heck coupling reactions have been developed between arylboronic acids and electronically unbiased terminal alkenes. The reactions exhibit high catalyst-controlled regioselectivity favoring the less common branched isomer. The reactions employ a catalyst composed of Pd(TFA)2/dmphen (TFA = trifluoroacetate, dmphen = 2,9-dimethyl-1,10-phenanthroline) and proceed efficiently at 45–60 °C under 1 atm of O2 without requiring other additives. A broad array of functional groups, including aryl halide, allyl silane and carboxylic acids are tolerated.
Co-reporter:Andrei V. Iosub and Shannon S. Stahl
Organic Letters 2015 Volume 17(Issue 18) pp:4404-4407
Publication Date(Web):September 2, 2015
DOI:10.1021/acs.orglett.5b01790
Dehydrogenation of (partially) saturated heterocycles provides an important route to heteroaromatic compounds. A heterogeneous cobalt oxide catalyst, previously employed for aerobic oxidation of alcohols and amines, is shown to be effective for aerobic dehydrogenation of various 1,2,3,4-tetrahydroquinolines to the corresponding quinolines. The reactions proceed in good yields under mild conditions. Other N-heterocycles are also successfully oxidized to their aromatic counterparts.
Co-reporter:Paul M. Osterberg, Jeffry K. Niemeier, Christopher J. Welch, Joel M. Hawkins, Joseph R. Martinelli, Thomas E. Johnson, Thatcher W. Root, and Shannon S. Stahl
Organic Process Research & Development 2015 Volume 19(Issue 11) pp:1537-1543
Publication Date(Web):December 6, 2014
DOI:10.1021/op500328f
Applications of aerobic oxidation methods in pharmaceutical manufacturing are limited in part because mixtures of oxygen gas and organic solvents often create the potential for a flammable atmosphere. To address this issue, limiting oxygen concentration (LOC) values, which define the minimum partial pressure of oxygen that supports a combustible mixture, have been measured for nine commonly used organic solvents at elevated temperatures and pressures. The solvents include acetic acid, N-methylpyrrolidone, dimethyl sulfoxide, tert-amyl alcohol, ethyl acetate, 2-methyltetrahydrofuran, methanol, acetonitrile, and toluene. The data obtained from these studies help define safe operating conditions for the use of oxygen with organic solvents.
Co-reporter:Janelle E. Steves, Yuliya Preger, Joseph R. Martinelli, Christopher J. Welch, Thatcher W. Root, Joel M. Hawkins, and Shannon S. Stahl
Organic Process Research & Development 2015 Volume 19(Issue 11) pp:1548-1553
Publication Date(Web):June 30, 2015
DOI:10.1021/acs.oprd.5b00179
An improved Cu/nitroxyl catalyst system for aerobic alcohol oxidation has been developed for the oxidation of functionalized primary and secondary alcohols to aldehydes and ketones, suitable for implementation in batch and flow processes. This catalyst, which has been demonstrated in a >50 g scale batch reaction, addresses a number of process limitations associated with a previously reported (MeObpy)CuI/ABNO/NMI catalyst system (MeObpy = 4,4′-dimethoxy-2,2′-bipyridine, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl, NMI = N-methylimidazole). Important catalyst modifications include the replacement of [Cu(MeCN)4]OTf with a lower-cost Cu source, CuI, reduction of the ABNO loading to 0.05–0.3 mol%, and use of NMI as the only ligand/additive (i.e., without a need for MeObpy). Use of a high flash point solvent, N-methylpyrrolidone, enables safe operation in batch reactions with air as the oxidant. For continuous-flow applications compatible with elevated gas pressures, better performance is observed with acetonitrile as the solvent.
Co-reporter:Jodie F. Greene, Yuliya Preger, Shannon S. Stahl, and Thatcher W. Root
Organic Process Research & Development 2015 Volume 19(Issue 7) pp:858-864
Publication Date(Web):May 29, 2015
DOI:10.1021/acs.oprd.5b00125
A “tube-in-shell” membrane flow reactor has been developed for aerobic oxidation reactions that permits continuous delivery of O2 to a liquid-phase reaction along the entire length of the flow path. The reactor uses inexpensive O2-permeable PTFE (“Teflon”) tubing that is compatible with elevated pressures and temperatures and avoids hazardous mixtures of organic vapor and oxygen. Several polymeric materials were tested, and PTFE exhibits a useful combination of low cost, chemical stability and gas diffusion properties. Reactor performance is demonstrated in the aerobic oxidation of several alcohols with homogeneous Cu/TEMPO and Cu/ABNO catalysts (TEMPO = 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl and ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl). Kinetic studies demonstrate regimes where the overall rate is controlled by the kinetics of the reaction or the transport of oxygen through the tube wall. Near-quantitative product yields are achieved with residence times as low as 1 min. A parallel, multitube reactor enables higher throughput, while retaining good performance. Finally, the reactor is demonstrated with a heterogeneous Ru(OH)x/Al2O3 catalyst packed in the tubing.
Co-reporter:Janelle E. Steves and Shannon S. Stahl
The Journal of Organic Chemistry 2015 Volume 80(Issue 21) pp:11184-11188
Publication Date(Web):October 12, 2015
DOI:10.1021/acs.joc.5b01950
Two solutions, one consisting of bpy/TEMPO/NMI and the other bpy/ABNO/NMI (bpy =2,2′-bipyridyl; TEMPO = 2,2,6,6-tetramethylpiperidine N-oxyl, ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl; NMI = N-methylimidazole), in acetonitrile are shown to have good long-term stability (≥1 year) under air at 5 °C. The solutions may be combined in appropriate quantities with commercially available [Cu(MeCN)4]OTf to provide a convenient catalyst system for the aerobic oxidation of primary and secondary alcohols.
Co-reporter:Jinho Kim and Shannon S. Stahl
The Journal of Organic Chemistry 2015 Volume 80(Issue 4) pp:2448-2454
Publication Date(Web):January 16, 2015
DOI:10.1021/jo5029198
Cu-catalyzed aerobic oxidative three-component coupling of a terminal alkyne, secondary amine, and sulfonamide enables efficient synthesis of amidines. The use of Cu(OTf)2 (5 mol %) produces amidines selectively without Glaser–Hay alkyne homocoupling products. Preliminary studies suggest that the reaction pathway involves initial oxidative coupling of the terminal alkyne with the secondary amine, followed by hydroamidation of the ynamine intermediate with the sulfonamide.
Co-reporter:Dr. Alison E. Wendlt ; Shannon S. Stahl
Angewandte Chemie International Edition 2015 Volume 54( Issue 49) pp:14638-14658
Publication Date(Web):
DOI:10.1002/anie.201505017
Abstract
Quinones are common stoichiometric reagents in organic chemistry. Para-quinones with high reduction potentials, such as DDQ and chloranil, are widely used and typically promote hydride abstraction. In recent years, many catalytic applications of these methods have been achieved by using transition metals, electrochemistry, or O2 to regenerate the oxidized quinone in situ. Complementary studies have led to the development of a different class of quinones that resemble the ortho-quinone cofactors in copper amine oxidases and mediate the efficient and selective aerobic and/or electrochemical dehydrogenation of amines. The latter reactions typically proceed by electrophilic transamination and/or addition-elimination reaction mechanisms, rather than hydride abstraction pathways. The collective observations show that the quinone structure has a significant influence on the reaction mechanism and has important implications for the development of new quinone reagents and quinone-catalyzed transformations.
Co-reporter:Dr. Alison E. Wendlt ; Shannon S. Stahl
Angewandte Chemie 2015 Volume 127( Issue 49) pp:14848-14868
Publication Date(Web):
DOI:10.1002/ange.201505017
Abstract
Chinone sind gebräuchliche, stöchiometrisch eingesetzte Reagentien in der organischen Chemie. para-Chinone mit hohem Reduktionspotential wie DDQ und Chloranil werden verbreitet angewendet und fördern normalerweise die Hydridabstraktion. In den letzten Jahren wurden viele katalytische Anwendungen dieser Methoden entwickelt, wobei das oxidierte Chinon in situ mithilfe von Übergangsmetallen, O2 oder Elektrochemie regeneriert wird. Ergänzende Studien haben zur Entdeckung einer anderen Klasse von Chinonen geführt, die den ortho-Chinon-Cofaktoren in Kupfer-Amin-Oxidasen ähneln und effiziente und selektive aerobe und/oder elektrochemische Dehydrierungen von Aminen vermitteln. Letztgenannte Reaktionen laufen gewöhnlich über elektrophile Transaminierungs- und/oder Additions-Eliminierungs-Reaktionsmechanismen anstelle von Hydridabstraktionspfaden ab. Die gesammelten Beobachtungen zeigen, dass die Chinonstruktur einen signifikanten Einfluss auf den Reaktionsmechanismus ausübt und somit bedeutende Auswirkungen auf die Entwicklung neuer Chinonreagentien und Chinon-katalysierter Umwandlungen hat.
Co-reporter:Rishi Parajuli;James B. Gerken;Kunttal Keyshar;Ian Sullivan
Topics in Catalysis 2015 Volume 58( Issue 1) pp:57-66
Publication Date(Web):2015 February
DOI:10.1007/s11244-014-0345-x
A fully integrated electrochemical cell for co-production of formate (HCOO−) and oxygen (O2) from carbon dioxide (CO2) and water using only earth-abundant elements has been developed. The process converts CO2 to formate using electrons derived from anodic water oxidation. A novel cathodic catalyst system, consisting of a tin (Sn) cathode in combination with the soluble heterocycle 2-picoline, was identified for CO2 reduction. Water oxidation takes place at a fluorine-doped tin oxide electrode coated with an electrodeposited cobalt oxide (CoOx) electrocatalyst. Use of 2-picoline as a soluble cathodic co-catalyst lowered the overpotential and enhanced the stability of the Sn-mediated CO2 reduction process. Fluorophosphate served as a redox-stable electrolyte to buffer the anode compartment at mildly acidic pH (~ 5 to 5.5), thereby stabilizing the CoOx electrocatalyst and supporting efficient water oxidation. The complete electrochemical cell maintained a stable cell voltage of less than 3 V over 5 days, with an average formate faradaic yield of 34 %. These results are presented together with an economical analysis of large-scale solar-driven production of formate/formic acid from CO2 and water.
Co-reporter:James B. Gerken and Shannon S. Stahl
ACS Central Science 2015 Volume 1(Issue 5) pp:234
Publication Date(Web):July 15, 2015
DOI:10.1021/acscentsci.5b00163
Efficient reduction of O2 to water is a central challenge in energy conversion and many aerobic oxidation reactions. Here, we show that the electrochemical oxygen reduction reaction (ORR) can be achieved at high potentials by using soluble organic nitroxyl and nitrogen oxide (NOx) mediators. When used alone, neither organic nitroxyls, such as 2,2,6,6-tetramethyl-1-piperidinyl-N-oxyl (TEMPO), nor NOx species, such as sodium nitrite, are effective ORR mediators. The combination of nitroxyl/NOx species, however, mediates sustained O2 reduction with overpotentials as low as 300 mV in acetonitrile containing trifluoroacetic acid. Mechanistic analysis of the coupled redox reactions supports a process in which the nitrogen oxide catalyst drives aerobic oxidation of a nitroxyl mediator to an oxoammonium species, which then is reduced back to the nitroxyl at the cathode. The electrolysis potential is dictated by the oxoammonium/nitroxyl reduction potential. The overpotentials accessible with this ORR system are significantly lower than widely studied molecular metal-macrocycle ORR catalysts and benefit from the mechanism-based specificity for four-electron reduction of oxygen to water mediated by NOx species, together with kinetically efficient reduction of oxidized NOx species by TEMPO and other organic nitroxyls.
Co-reporter:Jamie Y. C. Chen, Jeffrey T. Miller, James B. Gerken and Shannon S. Stahl
Energy & Environmental Science 2014 vol. 7(Issue 4) pp:1382-1386
Publication Date(Web):17 Feb 2014
DOI:10.1039/C3EE43811B
Ni:Fe:Al mixed oxides were identified as highly active water oxidation electrocatalysts. A systematic investigation of these materials has led to the characterization of a well-defined NiFeAlO4 inverse spinel catalyst. Electrochemical characterization of NiFeAlO4 shows activity exceeding previously reported catalysts of similar composition and/or structure, including NiO, NiFe (9:1), and NiFe2O4.
Co-reporter:James B. Gerken, Sarah E. Shaner, Robert C. Massé, Nicholas J. Porubsky and Shannon S. Stahl
Energy & Environmental Science 2014 vol. 7(Issue 7) pp:2376-2382
Publication Date(Web):29 May 2014
DOI:10.1039/C4EE00436A
Mixed metal oxides comprise a diverse class of materials that are appealing as potential water oxidation electrocatalysts. Here we report combinatorial screening of nearly 3500 trimetallic AxByCzOq mixed metal oxide compositions that led to the discovery of electrocatalysts with enhanced activity relative to, inter alia, the well-studied pure oxides, ABO3, and AB2O4 stoichiometries of those metals. Using a fluorescence-based parallel screening method, we directly detect electrolytic oxygen-evolution activity of catalyst arrays under alkaline conditions. From these data, composition–activity relationships amongst mixed oxides composed of earth-abundant elements have been determined. Significant sustained activity is observed only in the presence of Co or Ni, and the data draw attention to synergistic interactions between these redox-active ions and Lewis-acidic cations, such as Fe, Al, Ga, and Cr. The best activities are observed with oxides composed of Ni and Fe, together with another element.
Co-reporter:Alison E. Wendlandt
Journal of the American Chemical Society 2014 Volume 136(Issue 34) pp:11910-11913
Publication Date(Web):August 11, 2014
DOI:10.1021/ja506546w
Quinolines are common pharmacophores present in numerous FDA-approved pharmaceuticals and other bioactive compounds. Here, we report the design and development of new o-quinone-based catalysts for the oxidative dehydrogenation of tetrahydroquinolines to afford quinolines. Use of a Co(salophen) cocatalyst allows the reaction to proceed efficiently with ambient air at room temperature. The utility of the catalytic method is demonstrated in the preparation of a number of medicinally relevant quinolines.
Co-reporter:Dian Wang ; Yusuke Izawa
Journal of the American Chemical Society 2014 Volume 136(Issue 28) pp:9914-9917
Publication Date(Web):June 25, 2014
DOI:10.1021/ja505405u
Pd-catalyzed aerobic oxidative coupling of arenes provides efficient access to biaryl compounds. The biaryl product forms via C–H activation of two arenes to afford a PdIIArAr′ intermediate, which then undergoes C–C reductive elimination. The key PdIIArAr′ intermediate could form via a “monometallic” pathway involving sequential C–H activation at a single PdII center, or via a “bimetallic” pathway involving parallel C–H activation at separate PdII centers, followed by a transmetalation step between two PdII–aryl intermediates. Here, we investigate the oxidative coupling of o-xylene catalyzed by a PdX2/2-fluoropyridine catalyst (X = trifluoroacetate, acetate). Kinetic studies, H/D exchange experiments, and kinetic isotope effects provide clear support for a bimetallic/transmetalation mechanism.
Co-reporter:Bradford L. Ryland ; Scott D. McCann ; Thomas C. Brunold
Journal of the American Chemical Society 2014 Volume 136(Issue 34) pp:12166-12173
Publication Date(Web):August 4, 2014
DOI:10.1021/ja5070137
2,2′-Bipyridine-ligated copper complexes, in combination with TEMPO (2,2,6,6-tetramethylpiperidine-N-oxyl), are highly effective catalysts for aerobic alcohol oxidation. Considerable uncertainty and debate exist over the mechanism of alcohol oxidation mediated by CuII and TEMPO. Here, we report experimental and density functional theory (DFT) computational studies that distinguish among numerous previously proposed mechanistic pathways. Oxidation of various classes of radical-probe substrates shows that long-lived radicals are not formed in the reaction. DFT computational studies support this conclusion. A bimolecular pathway involving hydrogen-atom-transfer from a CuII–alkoxide to a nitroxyl radical is higher in energy than hydrogen transfer from a CuII–alkoxide to a coordinated nitroxyl species. The data presented here reconcile a collection of diverse and seemingly contradictory experimental and computational data reported previously in the literature. The resulting Oppenauer-like reaction pathway further explains experimental trends in the relative reactivity of different classes of alcohols (benzylic versus aliphatic and primary versus secondary), as well as the different reactivity observed between TEMPO and bicyclic nitroxyls, such as ABNO (ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl).
Co-reporter:Adam B. Weinstein and Shannon S. Stahl
Catalysis Science & Technology 2014 vol. 4(Issue 12) pp:4301-4307
Publication Date(Web):01 Aug 2014
DOI:10.1039/C4CY00764F
(DAF)Pd(OAc)2 (DAF = 4,5-diazafluorenone) catalyzes aerobic intramolecular aryl C–H amination with N-benzenesulfonyl-2-aminobiphenyl in dioxane to afford the corresponding carbazole product. Mechanistic studies show that the reaction involves in situ generation of peroxide species from 1,4-dioxane and O2, and the reaction further benefits from the presence of glycolic acid, an oxidative decomposition product of dioxane. An induction period observed for the formation of the carbazole product correlates with the formation of 1,4-dioxan-2-hydroperoxide via autoxidation of 1,4-dioxane, and the in situ-generated peroxide is proposed to serve as the reactive oxidant in the reaction. These findings have important implications for palladium-catalyzed aerobic oxidation reactions conducted in ethereal solvents.
Co-reporter:David S. Mannel, Shannon S. Stahl, and Thatcher W. Root
Organic Process Research & Development 2014 Volume 18(Issue 11) pp:1503-1508
Publication Date(Web):September 23, 2014
DOI:10.1021/op5002676
Ru(OH)x/Al2O3 is among the more versatile catalysts for aerobic alcohol oxidation and dehydrogenation of nitrogen heterocycles. Here, we describe the translation of batch reactions to a continuous-flow method that enables high steady-state conversion and single-pass yields in the oxidation of benzylic alcohols and dehydrogenation of indoline. A dilute source of O2 (8% in N2) was used to ensure that the reaction mixture, which employs toluene as the solvent, is nonflammable throughout the process. A packed bed reactor was operated isothermally in an up-flow orientation, allowing good liquid–solid contact. Deactivation of the catalyst during the reaction was modeled empirically, and this model was used to achieve high conversion and yield during extended operation in the aerobic oxidation of 2-thiophene methanol (99+% continuous yield over 72 h).
Co-reporter:Tianning Diao, Shannon S. Stahl
Polyhedron 2014 84() pp: 96-102
Publication Date(Web):
DOI:10.1016/j.poly.2014.06.038
Co-reporter:Bradford L. Ryl ; Shannon S. Stahl
Angewandte Chemie International Edition 2014 Volume 53( Issue 34) pp:8824-8838
Publication Date(Web):
DOI:10.1002/anie.201403110
Abstract
Oxidations of alcohols and amines are common reactions in the synthesis of organic molecules in the laboratory and industry. Aerobic oxidation methods have long been sought for these transformations, but few practical methods exist that offer advantages over traditional oxidation methods. Recently developed homogeneous Cu/TEMPO (TEMPO=2,2,6,6-tetramethylpiperidinyl-N-oxyl) and related catalyst systems appear to fill this void. The reactions exhibit high levels of chemoselectivity and broad functional-group tolerance, and they often operate efficiently at room temperature with ambient air as the oxidant. These advances, together with their historical context and recent applications, are highlighted in this Minireview.
Co-reporter:Bradford L. Ryl ; Shannon S. Stahl
Angewandte Chemie 2014 Volume 126( Issue 34) pp:8968-8983
Publication Date(Web):
DOI:10.1002/ange.201403110
Abstract
Oxidationen von Alkoholen und Aminen sind häufige Reaktionen in der Synthese organischer Moleküle im Labor und in der Industrie. Nach aeroben Oxidationsmethoden für diese Umwandlungen wurde lange geforscht, aber es existieren nur einige wenige praktische Verfahren, die Vorteile gegenüber klassischen Oxidationsmethoden bieten. Kürzlich entwickelte homogene Cu/TEMPO- und verwandte Katalysatorsysteme scheinen nun diese Lücke zu füllen. Die Reaktionen sind hoch chemoselektiv, tolerieren eine Bandbreite von funktionellen Gruppen und laufen oftmals schon bei Raumtemperatur mit der Umgebungsluft als Oxidationsmittel ab. Die Vorteile dieser aeroben Oxidationsmethoden werden in diesem Kurzaufsatz diskutiert, zusammen mit dem historischen Kontext und neueren Anwendungen.
Co-reporter:Alison E. Wendlandt
Journal of the American Chemical Society 2013 Volume 136(Issue 1) pp:506-512
Publication Date(Web):December 12, 2013
DOI:10.1021/ja411692v
Copper amine oxidases are a family of enzymes with quinone cofactors that oxidize primary amines to aldehydes. The native mechanism proceeds via an iminoquinone intermediate that promotes high selectivity for reactions with primary amines, thereby constraining the scope of potential biomimetic synthetic applications. Here we report a novel bioinspired quinone catalyst system consisting of 1,10-phenanthroline-5,6-dione/ZnI2 that bypasses these constraints via an abiological pathway involving a hemiaminal intermediate. Efficient aerobic dehydrogenation of non-native secondary amine substrates, including pharmaceutically relevant nitrogen heterocycles, is demonstrated. The ZnI2 cocatalyst activates the quinone toward amine oxidation and provides a source of iodide, which plays an important redox-mediator role to promote aerobic catalytic turnover. These findings provide a valuable foundation for broader development of aerobic oxidation reactions employing quinone-based catalysts.
Co-reporter:Tianning Diao ; Doris Pun
Journal of the American Chemical Society 2013 Volume 135(Issue 22) pp:8205-8212
Publication Date(Web):May 13, 2013
DOI:10.1021/ja4031648
The dehydrogenation of cyclohexanones affords cyclohexenones or phenols via removal of 1 or 2 equiv of H2, respectively. We recently reported several PdII catalyst systems that effect aerobic dehydrogenation of cyclohexanones with different product selectivities. Pd(DMSO)2(TFA)2 is unique in its high chemoselectivity for the conversion of cyclohexanones to cyclohexenones, without promoting subsequent dehydrogenation of cyclohexenones to phenols. Kinetic and mechanistic studies of these reactions reveal the key role of the dimethylsulfoxide (DMSO) ligand in controlling this chemoselectivity. DMSO has minimal kinetic influence on the rate of Pd(TFA)2-catalyzed dehydrogenation of cyclohexanone to cyclohexenone, while it strongly inhibits the second dehydrogenation step, conversion of cyclohexenone to phenol. These contrasting kinetic effects of DMSO provide the basis for chemoselective formation of cyclohexenones.
Co-reporter:Doris Pun ; Tianning Diao
Journal of the American Chemical Society 2013 Volume 135(Issue 22) pp:8213-8221
Publication Date(Web):May 13, 2013
DOI:10.1021/ja403165u
We have carried out a mechanistic investigation of aerobic dehydrogenation of cyclohexanones and cyclohexenones to phenols with a Pd(TFA)2/2-dimethylaminopyridine catalyst system. Numerous experimental methods, including kinetic studies, filtration tests, Hg poisoning experiments, transmission electron microscopy, and dynamic light scattering, provide compelling evidence that the initial PdII catalyst mediates the first dehydrogenation of cyclohexanone to cyclohexenone, after which it evolves into soluble Pd nanoparticles that retain catalytic activity. This nanoparticle formation and stabilization is facilitated by each of the components in the catalytic reaction, including the ligand, TsOH, DMSO, substrate, and cyclohexenone intermediate.
Co-reporter:Janelle E. Steves
Journal of the American Chemical Society 2013 Volume 135(Issue 42) pp:15742-15745
Publication Date(Web):October 7, 2013
DOI:10.1021/ja409241h
Cu/TEMPO catalyst systems promote efficient aerobic oxidation of sterically unhindered primary alcohols and electronically activated substrates, but they show reduced reactivity with aliphatic and secondary alcohols. Here, we report a catalyst system, consisting of (MeObpy)CuI(OTf) and ABNO (MeObpy =4,4′-dimethoxy-2,2′-bipyridine; ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl), that mediates aerobic oxidation of all classes of alcohols, including primary and secondary allylic, benzylic, and aliphatic alcohols with nearly equal efficiency. The catalyst exhibits broad functional group compatibility, and most reactions are complete within 1 h at room temperature using ambient air as the source of oxidant.
Co-reporter:Alison M. Suess ; Mehmed Z. Ertem ; Christopher J. Cramer
Journal of the American Chemical Society 2013 Volume 135(Issue 26) pp:9797-9804
Publication Date(Web):June 10, 2013
DOI:10.1021/ja4026424
Copper(II)-mediated C–H oxidation is the subject of extensive interest in synthetic chemistry, but the mechanisms of many of these reactions are poorly understood. Here, we observe different products from CuII-mediated oxidation of N-(8-quinolinyl)benzamide, depending on the reaction conditions. Under basic conditions, the benzamide group undergoes directed C–H methoxylation or chlorination. Under acidic conditions, the quinoline group undergoes nondirected chlorination. Experimental and computational mechanistic studies implicate an organometallic C–H activation/functionalization mechanism under the former conditions and a single-electron-transfer mechanism under the latter conditions. This rare observation of divergent, condition-dependent mechanisms for oxidation of a single substrate provides a valuable foundation for understanding CuII-mediated C–H oxidation reactions.
Co-reporter:Jessica M. Hoover ; Bradford L. Ryland
Journal of the American Chemical Society 2013 Volume 135(Issue 6) pp:2357-2367
Publication Date(Web):January 14, 2013
DOI:10.1021/ja3117203
Homogeneous Cu/TEMPO catalyst systems (TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) have emerged as some of the most versatile and practical catalysts for aerobic alcohol oxidation. Recently, we disclosed a (bpy)CuI/TEMPO/NMI catalyst system (NMI = N-methylimidazole) that exhibits fast rates and high selectivities, even with unactivated aliphatic alcohols. Here, we present a mechanistic investigation of this catalyst system, in which we compare the reactivity of benzylic and aliphatic alcohols. This work includes analysis of catalytic rates by gas-uptake and in situ IR kinetic methods and characterization of the catalyst speciation during the reaction by EPR and UV–visible spectroscopic methods. The data support a two-stage catalytic mechanism consisting of (1) “catalyst oxidation” in which CuI and TEMPO–H are oxidized by O2 via a binuclear Cu2O2 intermediate and (2) “substrate oxidation” mediated by CuII and the nitroxyl radical of TEMPO via a CuII-alkoxide intermediate. Catalytic rate laws, kinetic isotope effects, and spectroscopic data show that reactions of benzylic and aliphatic alcohols have different turnover-limiting steps. Catalyst oxidation by O2 is turnover limiting with benzylic alcohols, while numerous steps contribute to the turnover rate in the oxidation of aliphatic alcohols.
Co-reporter:Wan Pyo Hong ; Andrei V. Iosub
Journal of the American Chemical Society 2013 Volume 135(Issue 37) pp:13664-13667
Publication Date(Web):August 29, 2013
DOI:10.1021/ja4073172
Homogeneous Pd catalysts have been identified for the conversion of cyclohexenone and tetralone O-pivaloyl oximes to the corresponding primary anilines and 1-aminonaphthalenes. This method is inspired by the Semmler–Wolff reaction, a classic method that exhibits limited synthetic utility owing to its forcing conditions, narrow scope, and low product yields. The oxime N–O bond undergoes oxidative addition to Pd0(PCy3)2, and the product of this step has been characterized by X-ray crystallography and shown to undergo dehydrogenation to afford the aniline product.
Co-reporter:Jessica M. Hoover, Bradford L. Ryland, and Shannon S. Stahl
ACS Catalysis 2013 Volume 3(Issue 11) pp:2599
Publication Date(Web):September 30, 2013
DOI:10.1021/cs400689a
Combinations of homogeneous Cu salts and 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) have emerged as practical and efficient catalysts for the aerobic oxidation of alcohols. Several closely related catalyst systems have been reported, which differ in the identity of the solvent, the presence of 2,2′-bipyridine as a ligand, the identity of basic additives, and the oxidation state of the Cu source. These changes have a significant influence on the reaction rates, yields, and substrate scope. In this report, we probe the mechanistic basis for differences among four different Cu/TEMPO catalyst systems and elucidate the features that contribute to efficient oxidation of aliphatic alcohols.Keywords: aerobic; alcohol oxidation; copper; kinetics; mechanism; TEMPO
Co-reporter:Markus B. Lauber and Shannon S. Stahl
ACS Catalysis 2013 Volume 3(Issue 11) pp:2612
Publication Date(Web):September 30, 2013
DOI:10.1021/cs400746m
New highly practical methods are presented for aerobic oxidation of secondary alcohols with a nitroxyl radical in combination with HNO3, NaNO2, or both as cocatalysts. Diverse nitroxyls are compared, including several novel bicyclic derivatives. Catalyst systems with the readily available nitroxyls, 9-azabicyclo[3.3.1]nonane-N-oxyl (ABNO) and 9-azabicyclo[3.3.1]nonan-3-one-N-oxyl (keto-ABNO), are optimized in acetic acid or acetonitrile as the solvent. The reactions are compatible with substrates bearing diverse functional groups and proceed efficiently under mild conditions at ambient pressure and temperature.Keywords: ABNO; aerobic oxidation; keto-ABNO; nitroxyl radical; secondary alcohols
Co-reporter:Jinho Kim and Shannon S. Stahl
ACS Catalysis 2013 Volume 3(Issue 7) pp:1652
Publication Date(Web):June 13, 2013
DOI:10.1021/cs400360e
An efficient catalytic method has been developed for aerobic oxidation of primary amines to the corresponding nitriles. The reactions proceed at room temperature and employ a catalyst consisting of (4,4′-tBu2bpy)CuI/ABNO (ABNO = 9-azabicyclo[3.3.1]nonan-3-one-N-oxyl). The reactions exhibit excellent functional group compatibility and substrate scope and are effective with benzylic, allylic, and aliphatic amines. Preliminary mechanistic studies suggest that aerobic oxidation of the Cu catalyst is the turnover-limiting step of the reaction.Keywords: aerobic oxidation; amine oxidation; copper; nitrile; nitroxyl
Co-reporter:Adam B. Powell and Shannon S. Stahl
Organic Letters 2013 Volume 15(Issue 19) pp:5072-5075
Publication Date(Web):September 19, 2013
DOI:10.1021/ol402428e
Efficient aerobic oxidative methyl esterification of primary alcohols has been achieved with a heterogeneous catalyst consisting of 1 mol % Pd/charcoal (5 wt %) in combination with bismuth(III) nitrate and tellurium metal. The Bi and Te additives significantly increase the reaction rate, selectivity, and overall product yields. This readily accessible catalyst system exhibits a broad substrate scope and is effective with both activated (benzylic) and unactivated (aliphatic) alcohols bearing diverse functional groups.
Co-reporter:James B. Gerken, Matthew L. Rigsby, Rose E. Ruther, Riviam J. Pérez-Rodríguez, Ilia A. Guzei, Robert J. Hamers, and Shannon S. Stahl
Inorganic Chemistry 2013 Volume 52(Issue 6) pp:2796-2798
Publication Date(Web):March 4, 2013
DOI:10.1021/ic302827s
A modular synthetic method has been developed for the preparation of Ru polypyridyl complexes bearing a terminal alkyne. This method proceeds through a readily accessible intermediate with a silyl-protected alkyne and allows access to a variety of five- and six-coordinate Ru complexes. These complexes can be easily attached to azide-functionalized electrode surfaces with only slight perturbation of the redox properties of the parent complex.
Co-reporter:Jodie F. Greene, Jessica M. Hoover, David S. Mannel, Thatcher W. Root, and Shannon S. Stahl
Organic Process Research & Development 2013 Volume 17(Issue 10) pp:1247-1251
Publication Date(Web):September 7, 2013
DOI:10.1021/op400207f
A scalable, continuous-flow process has been developed to implement a homogeneous CuI/TEMPO catalyst system for aerobic oxidation of primary alcohols to aldehydes. This catalyst system is compatible with a wide range of alcohols bearing diverse functional groups. A dilute oxygen source (9% O2 in N2) is used to avoid flammable oxygen/organic mixtures. Residence times in the heated reaction zone can be as low as 5 min with activated (e.g., benzylic) alcohols. The method has been demonstrated with nine different alcohols, including one up to 100 g scale. This flow-based catalytic method exhibits significant advantages for aerobic oxidation of alcohols, including substantially shorter residence times and broader substrate scope relative to a Pd-catalyzed method that we reported recently.
Co-reporter:Nicholas J. Hill, Jessica M. Hoover, and Shannon S. Stahl
Journal of Chemical Education 2013 Volume 90(Issue 1) pp:102-105
Publication Date(Web):November 12, 2012
DOI:10.1021/ed300368q
Modern undergraduate organic chemistry textbooks provide detailed discussion of stoichiometric Cr- and Mn-based reagents for the oxidation of alcohols, yet the use of such oxidants in instructional and research laboratories, as well as industrial chemistry, is increasingly avoided. This work describes a laboratory exercise that uses ambient air as the source of oxidant and a readily available CuI/TEMPO catalyst system to convert benzyl alcohols to the corresponding aldehydes in standard glassware at room temperature. The procedure is well suited for a high-enrollment undergraduate course, and the complete exercise fits easily within a 3-h lab period. The structures of the organic starting materials and products are determined by NMR spectroscopy and EI-MS. The protocol is adapted from the contemporary research literature and provides students with practical experience of a modern, “green” oxidation method. In addition to the practical aspects, the experiment encourages student discussion and exploration of transition-metal-catalyzed reactions, a topic that is underrepresented in the contemporary undergraduate organic chemistry curriculum.Keywords: Alcohols; Catalysis; Green Chemistry; Hands-On Learning/Manipulatives; Inorganic Chemistry; Inquiry-Based/Discovery Learning; Laboratory Instruction; Organic Chemistry; Oxidation/Reduction; Second-Year Undergraduate;
Co-reporter:Xuan Ye, Paul B. White, and Shannon S. Stahl
The Journal of Organic Chemistry 2013 Volume 78(Issue 5) pp:2083-2090
Publication Date(Web):November 16, 2012
DOI:10.1021/jo302266t
The stereochemical course of the amidopalladation of alkenes has important implications for the development of enantioselective Pd-catalyzed “Wacker-type” oxidative amidation of alkenes. We have recently shown that the addition of base (Na2CO3) can alter the stereochemical course of amidopalladation in the (IMes)Pd(TFA)2(H2O)-catalyzed aerobic oxidative amidation of alkene. In this study, the mechanism of (IMes)Pd(TFA)2(H2O)-catalyzed oxidative heterocyclization of (Z)-4-hexenyltosylamide was investigated in the presence and absence of exogenous base Na2CO3. The results reveal two parallel pathways in the absence of base: a cis-amidopalladation pathway with turnover-limiting deprotonation of the sulfonamide nucleophile and a trans-amidopalladation pathway with turnover-limiting nucleophilic attack of sulfonamide on the coordinated alkene. The addition of base (Na2CO3) lowers the energy barrier associated with the proton transfer, leading to an overall faster turnover rate and exclusive cis-amidopalladation of alkene.
Co-reporter:Claudio Martínez, Yichen Wu, Adam B. Weinstein, Shannon S. Stahl, Guosheng Liu, and Kilian Muñiz
The Journal of Organic Chemistry 2013 Volume 78(Issue 12) pp:6309-6315
Publication Date(Web):May 15, 2013
DOI:10.1021/jo400671q
A modified protocol has been identified for Pd-catalyzed intermolecular aminoacetoxylation of terminal and internal alkenes that enables the alkene to be used as the limiting reagent. The results prompt a reassessment of the stereochemical course of these reactions. X-ray crystallographic characterization of two of the products, together with isotopic labeling studies, show that the amidopalladation step switches from a cis-selective process under aerobic conditions to a trans-selective process in the presence of diacetoxyiodobenzene.
Co-reporter:Adam B. Weinstein;David P. Schuman;Zhi Xu Tan ; Shannon S. Stahl
Angewandte Chemie 2013 Volume 125( Issue 45) pp:12083-12086
Publication Date(Web):
DOI:10.1002/ange.201305926
Co-reporter:Yusuke Izawa;Dr. Changwu Zheng; Shannon S. Stahl
Angewandte Chemie 2013 Volume 125( Issue 13) pp:3760-3763
Publication Date(Web):
DOI:10.1002/ange.201209457
Co-reporter:Adam B. Weinstein;David P. Schuman;Zhi Xu Tan ; Shannon S. Stahl
Angewandte Chemie International Edition 2013 Volume 52( Issue 45) pp:11867-11870
Publication Date(Web):
DOI:10.1002/anie.201305926
Co-reporter:Yusuke Izawa;Dr. Changwu Zheng; Shannon S. Stahl
Angewandte Chemie International Edition 2013 Volume 52( Issue 13) pp:3672-3675
Publication Date(Web):
DOI:10.1002/anie.201209457
Co-reporter:Alison N. Campbell and Shannon S. Stahl
Accounts of Chemical Research 2012 Volume 45(Issue 6) pp:851
Publication Date(Web):January 23, 2012
DOI:10.1021/ar2002045
Oxidation reactions are key transformations in organic chemistry because they can increase chemical complexity and incorporate heteroatom substituents into carbon-based molecules. This principle is manifested in the conversion of petrochemical feedstocks into commodity chemicals and in the synthesis of fine chemicals, pharmaceuticals, and other complex organic molecules. The utility and function of these molecules correlate directly with the presence and specific placement of oxygen and nitrogen heteroatoms and other functional groups within the molecules.Methods for selective oxidation of C–H bonds have expanded significantly over the past decade, and their role in the synthesis of organic chemicals will continue to increase. Our group’s contributions to this field are linked to our broader interest in the development and mechanistic understanding of aerobic oxidation reactions. Molecular oxygen (O2) is the ideal oxidant. Its low cost and lack of toxic byproducts make it a highly appealing reagent that can address key “green chemistry” priorities in industry. With strong economic and environmental incentives to use O2, the commmodity chemicals industry often uses aerobic oxidation reactions. In contrast, O2 is seldom used to prepare more-complex smaller-volume chemicals, a limitation that reflects, in part, the limited synthetic scope and utility of existing aerobic reactions.Pd-catalyzed reactions represent some of the most versatile methods for selective C–H oxidation, but they often require stoichiometric transition-metal or organic oxidants, such as CuII, AgI, or benzoquinone. This Account describes recent strategies that we have identified to use O2 as the oxidant in these reactions. In Pd-catalyzed C–H oxidation reactions that form carbon-heteroatom bonds, the stoichiometric oxidant is often needed to promote difficult reductive elimination steps in the catalytic mechanism. To address this challenge, we have identified new ancillary ligands for Pd that promote reductive elimination, or replaced Pd with a Cu catalyst that undergoes facile reductive elimination from a CuIII intermediate. Both strategies have enabled O2 to be used as the sole stoichiometric oxidant in the catalytic reactions. C–H oxidation reactions that form the product via β-hydride or C–C reductive elimination steps tend to be more amenable to the use of O2. The use of new ancillary ligands has also overcome some of the limitations in these methods. Mechanistic studies are providing insights into some (but not yet all) of these advances in catalytic reactivity.
Co-reporter:Changwu Zheng ; Dian Wang
Journal of the American Chemical Society 2012 Volume 134(Issue 40) pp:16496-16499
Publication Date(Web):September 21, 2012
DOI:10.1021/ja307371w
Pd-catalyzed aerobic oxidative coupling of vinylboronic acids and electronically unbiased alkyl olefins provides regioselective access to 1,3-disubstituted conjugated dienes. Catalyst-controlled regioselectivity is achieved by using 2,9-dimethylphenanthroline as a ligand. The observed regioselectivity is opposite to that observed from a traditional (nonoxidative) Heck reaction between a vinyl bromide and an alkene. DFT computational studies reveal that steric effects of the 2,9-dimethylphenanthroline ligand promote C–C bond formation at the internal position of the alkene.
Co-reporter:Tianning Diao, Tyler J. Wadzinski and Shannon S. Stahl
Chemical Science 2012 vol. 3(Issue 3) pp:887-891
Publication Date(Web):31 Oct 2011
DOI:10.1039/C1SC00724F
The direct α,β-dehydrogenation of aldehydes and ketones represents an efficient alternative to stepwise methods to prepare enal and enone products. Here, we describe a new Pd(TFA)2/4,5-diazafluorenone dehydrogenation catalyst that overcomes key limitations of previous catalyst systems. The scope includes successful reactivity with pharmaceutically important cyclopentanone and flavanone substrates, as well as acyclic ketones. Preliminary mechanistic studies compare the reactivity of this catalyst to previously reported dehydrogenation catalysts and reveal that cleavage of the α-C–H bond of the ketone is the turnover-limiting step of the catalytic mechanism.
Co-reporter:Matthew L. Rigsby, Sukanta Mandal, Wonwoo Nam, Lara C. Spencer, Antoni Llobet and Shannon S. Stahl
Chemical Science 2012 vol. 3(Issue 10) pp:3058-3062
Publication Date(Web):16 Jul 2012
DOI:10.1039/C2SC20755A
Several binuclear cobalt(III) complexes that mimic Ru-based water oxidation catalysts have been prepared. The initial complexes exhibited thermodynamic instability and kinetic lability that complicated efforts to use these cobalt complexes as electrocatalysts for water oxidation. Binuclear cobalt(III) complexes supported by a bridging bispyridylpyrazolate (bpp) ligand overcome these limitations. Two bpp-ligated dicobalt(III)-peroxo complexes were prepared and structurally characterized, and electrochemical investigation of these complexes supports their ability to serve as molecular electrocatalysts for water oxidation under acidic conditions (pH 2.1).
Co-reporter:Alison E. Wendlandt and Shannon S. Stahl
Organic Letters 2012 Volume 14(Issue 11) pp:2850-2853
Publication Date(Web):May 17, 2012
DOI:10.1021/ol301095j
Biomimetic aerobic oxidation of primary benzylic amines has been achieved by using a quinone catalyst. Excellent selectivity is observed for primary, unbranched benzylic amines relative to secondary/tertiary amines, branched benzylic amines, and aliphatic amines. The exquisite selectivity for benzylic amines enables oxidative self-sorting within dynamic mixtures of amines and imines to afford high yields of cross-coupled imine products.
Co-reporter:Jihua Zhang, Matthew J. Markiewicz, Bernard Weisblum, Shannon S. Stahl, and Samuel H. Gellman
ACS Macro Letters 2012 Volume 1(Issue 6) pp:714
Publication Date(Web):May 23, 2012
DOI:10.1021/mz300172y
A new family of β-lactams is described that enables anionic ring-opening polymerization (AROP) to prepare nylon-3 materials bearing diverse appended functionality, including carboxylic acid, thiol, hydroxyl, and secondary amine groups. Nylon-3 copolymers generated with the new β-lactams are shown to display distinctive self-assembly behavior and biological properties.
Co-reporter:Tianning Diao, Paul White, Ilia Guzei, and Shannon S. Stahl
Inorganic Chemistry 2012 Volume 51(Issue 21) pp:11898-11909
Publication Date(Web):October 23, 2012
DOI:10.1021/ic301799p
Recent studies have shown that Pd(DMSO)2(TFA)2 (TFA = trifluoroacetate) is an effective catalyst for a number of different aerobic oxidation reactions. Here, we provide insights into the coordination of DMSO to palladium(II) in both the solid state and in solution. A crystal structure of Pd(DMSO)2(TFA)2 confirms that the solid-state structure of this species has one O-bound and one S-bound DMSO ligand, and a crystallographically characterized mono-DMSO complex, trans-Pd(DMSO)(OH2)(TFA)2, exhibits an S-bound DMSO ligand. 1H and 19F NMR spectroscopic studies show that, in EtOAc and THF-d8, Pd(DMSO)2(TFA)2 consists of an equilibrium mixture of Pd(S-DMSO)(O-DMSO)(TFA)2 and Pd(S-DMSO)2(TFA)2. The O-bound DMSO is determined to be more labile than the S-bound DMSO ligand, and both DMSO ligands are more labile in THF relative to EtOAc as the solvent. DMSO coordination to PdII is substantially less favorable when the TFA ligands are replaced with acetate. An analogous carboxylate ligand effect is observed in the coordination of the bidentate sulfoxide ligand, 1,2-bis(phenylsulfinyl)ethane to PdII. DMSO coordination to Pd(TFA)2 is shown to be incomplete in AcOH-d4 and toluene-d8, resulting in PdII/DMSO adducts with <2:1 DMSO/PdII stoichiometry. Collectively, these results provide useful insights into the coordination properties of DMSO to PdII under catalytically relevant conditions.
Co-reporter:Alison E. Wendlandt and Shannon S. Stahl
Organic & Biomolecular Chemistry 2012 vol. 10(Issue 19) pp:3866-3870
Publication Date(Web):23 Mar 2012
DOI:10.1039/C2OB25310K
The copper(II)-mediated oxidative cyclization of enamides to oxazoles is reported. A range of 2,5-disubstituted oxazoles were prepared in moderate to good yields in two steps from simple amide and alkyne precursors.
Co-reporter:Amanda E. King, Bradford L. Ryland, Thomas C. Brunold, and Shannon S. Stahl
Organometallics 2012 Volume 31(Issue 22) pp:7948-7957
Publication Date(Web):August 24, 2012
DOI:10.1021/om300586p
We previously reported a preliminary mechanistic study of aerobic Cu(OAc)2-catalyzed methoxylation of 4-tolylboronic ester (King et al. J. Am. Chem. Soc., 2009, 131, 5044–5045), which revealed that aryl transmetalation from the boronic ester to CuII is the turnover-limiting step. In the present study, more thorough kinetic and spectroscopic studies provide additional insights into the transmetalation pathway and identity of the CuII catalyst resting state(s). EPR spectroscopic studies show that at least two copper(II) species are present under catalytic conditions, and their relative populations vary as a function of reaction time and acidity of the arylboronic ester and are influenced by addition of acetic acid or acetate to the reaction mixture. Analysis of kinetic data and 11B NMR and EPR spectra under diverse reaction conditions suggests that aryl transmetalation occurs from a tetracoordinate, anionic boronate to a cationic CuII species, mediated by a methoxide bridge.
Co-reporter:Adam B. Weinstein ; Shannon S. Stahl
Angewandte Chemie 2012 Volume 124( Issue 46) pp:11673-11677
Publication Date(Web):
DOI:10.1002/ange.201206702
Co-reporter:Adam B. Weinstein ; Shannon S. Stahl
Angewandte Chemie International Edition 2012 Volume 51( Issue 46) pp:11505-11509
Publication Date(Web):
DOI:10.1002/anie.201206702
Co-reporter:Dr. James B. Gerken;Jamie Y. C. Chen;Robert C. Massé;Dr. Adam B. Powell ; Shannon S. Stahl
Angewandte Chemie International Edition 2012 Volume 51( Issue 27) pp:6676-6680
Publication Date(Web):
DOI:10.1002/anie.201201999
Co-reporter:Jihua Zhang, Matthew J. Markiewicz, Brendan P. Mowery, Bernard Weisblum, Shannon S. Stahl, and Samuel H. Gellman
Biomacromolecules 2012 Volume 13(Issue 2) pp:
Publication Date(Web):December 14, 2011
DOI:10.1021/bm2013058
Nylon-3 polymers contain β-amino-acid-derived subunits and can be viewed as higher homologues of poly(α-amino acids). This structural relationship raises the possibility that nylon-3 polymers offer a platform for development of new materials with a variety of biological activities, a prospect that has recently begun to receive experimental support. Nylon-3 homo- and copolymers can be prepared via anionic ring-opening polymerization of β-lactams, and use of an N-acyl-β-lactam as coinitiator in the polymerization reaction allows placement of a specific functional group, borne by the N-acyl-β-lactam, at the N-terminus of each polymer chain. Controlling the unit at the C-termini of nylon-3 polymer chains, however, has been problematic. Here we describe a strategy for specifying C-terminal functionality that is based on the polymerization mechanism. After the anionic ring-opening polymerization is complete, we introduce a new β-lactam, approximately 1 equiv relative to the expected number of polymer chains. Because the polymer chains bear a reactive imide group at their C-termini, this new β-lactam should become attached at this position. If the terminating β-lactam bears a distinctive functional group, that functionality should be affixed to most or all C-termini in the reaction mixture. We use the new technique to compare the impact of N- and C-terminal placement of a critical hydrophobic fragment on the biological activity profile of nylon-3 copolymers. The synthetic advance described here should prove to be generally useful for tailoring the properties of nylon-3 materials.
Co-reporter:James B. Gerken ; J. Gregory McAlpin ; Jamie Y. C. Chen ; Matthew L. Rigsby ; William H. Casey ; R. David Britt
Journal of the American Chemical Society 2011 Volume 133(Issue 36) pp:14431-14442
Publication Date(Web):August 1, 2011
DOI:10.1021/ja205647m
Building upon recent study of cobalt-oxide electrocatalysts in fluoride-buffered electrolyte at pH 3.4, we have undertaken a mechanistic investigation of cobalt-catalyzed water oxidation in aqueous buffering electrolytes from pH 0–14. This work includes electrokinetic studies, cyclic voltammetric analysis, and electron paramagnetic resonance (EPR) spectroscopic studies. The results illuminate a set of interrelated mechanisms for electrochemical water oxidation in alkaline, neutral, and acidic media with electrodeposited Co-oxide catalyst films (CoOxcfs) as well as for a homogeneous Co-catalyzed electrochemical water oxidation reaction. Analysis of the pH dependence of quasi-reversible features in cyclic voltammograms of the CoOxcfs provides the basis for a Pourbaix diagram that closely resembles a Pourbaix diagram derived from thermodynamic free energies of formation for a family of Co-based layered materials. Below pH 3, a shift from heterogeneous catalysis producing O2 to homogeneous catalysis yielding H2O2 is observed. Collectively, the results reported here provide a foundation for understanding the structure, stability, and catalytic activity of aqueous cobalt electrocatalysts for water oxidation.
Co-reporter:Paul B. White
Journal of the American Chemical Society 2011 Volume 133(Issue 46) pp:18594-18597
Publication Date(Web):October 18, 2011
DOI:10.1021/ja208560h
Alkene insertion into Pd–N bonds is a key step in Pd-catalyzed oxidative amidation of alkenes. A series of well-defined Pd(II)-sulfonamidate complexes have been prepared and shown to react via insertion of a tethered alkene. The Pd–amidate and resulting Pd–alkyl species have been crystallographically characterized. The alkene insertion reaction is found to be reversible, but complete conversion to oxidative amination products is observed in the presence of O2. Electronic-effect studies reveal that alkene insertion into the Pd–N bond is favored kinetically and thermodynamically with electron-rich amidates.
Co-reporter:Jessica M. Hoover
Journal of the American Chemical Society 2011 Volume 133(Issue 42) pp:16901-16910
Publication Date(Web):August 23, 2011
DOI:10.1021/ja206230h
Aerobic oxidation reactions have been the focus of considerable attention, but their use in mainstream organic chemistry has been constrained by limitations in their synthetic scope and by practical factors, such as the use of pure O2 as the oxidant or complex catalyst synthesis. Here, we report a new (bpy)CuI/TEMPO catalyst system that enables efficient and selective aerobic oxidation of a broad range of primary alcohols, including allylic, benzylic, and aliphatic derivatives, to the corresponding aldehydes using readily available reagents, at room temperature with ambient air as the oxidant. The catalyst system is compatible with a wide range of functional groups and the high selectivity for 1° alcohols enables selective oxidation of diols that lack protecting groups.
Co-reporter:Tianning Diao
Journal of the American Chemical Society 2011 Volume 133(Issue 37) pp:14566-14569
Publication Date(Web):August 18, 2011
DOI:10.1021/ja206575j
α,β-Unsaturated carbonyl compounds are versatile intermediates in the synthesis of pharmaceuticals and biologically active compounds. Here, we report the discovery and application of Pd(DMSO)2(TFA)2 as a catalyst for direct dehydrogenation of cyclohexanones and other cyclic ketones to the corresponding enones, using O2 as the oxidant. The substrate scope includes heterocyclic ketones and several natural-product precursors.
Co-reporter:Nattawan Decharin ; Brian V. Popp
Journal of the American Chemical Society 2011 Volume 133(Issue 34) pp:13268-13271
Publication Date(Web):July 26, 2011
DOI:10.1021/ja204989p
(Sp)PdCl2 [Sp = (−)-sparteine] catalyzes a number of different aerobic oxidation reactions, and reaction of O2 with a PdII–hydride intermediate, (Sp)Pd(H)Cl (1), is a key step in the proposed catalytic mechanism. Previous computational studies suggest that O2 inserts into the PdII–H bond, initiated by abstraction of the hydrogen atom by O2. Experimental and computational results obtained in the present study challenge this conclusion. Oxygenation of in-situ-generated (Sp)Pd(H)Cl exhibits a zero-order dependence on [O2]. This result is inconsistent with a bimolecular H-atom-abstraction pathway, and DFT computational studies identify a novel “reductive elimination” mechanism, in which the chelating nitrogen ligand undergoes intramolecular deprotonation of the PdII–hydride. The relevance of this mechanism to other PdII oxidation catalysts with chelating nitrogen ligands is evaluated.
Co-reporter:Rose E. Ruther ; Matthew L. Rigsby ; James B. Gerken ; Stephanie R. Hogendoorn ; Elizabeth C. Landis ; Shannon S. Stahl ;Robert J. Hamers
Journal of the American Chemical Society 2011 Volume 133(Issue 15) pp:5692-5694
Publication Date(Web):March 25, 2011
DOI:10.1021/ja200210t
We demonstrate a modular “click”-based functionalization scheme that allows inexpensive conductive diamond samples to serve as an ultrastable platform for surface-tethered electrochemically active molecules stable out to ∼1.3 V vs Ag/AgCl. We have cycled surface-tethered Ru(tpy)2 to this potential more than 1 million times with little or no degradation in propylene carbonate and only slightly reduced stability in water and acetonitrile.
Co-reporter:Nattawan Decharin
Journal of the American Chemical Society 2011 Volume 133(Issue 15) pp:5732-5735
Publication Date(Web):March 25, 2011
DOI:10.1021/ja200957n
Benzoquinone (BQ) and O2 are among the most common stoichiometric oxidants in Pd-catalyzed oxidation reactions. The present study provides rare insights into mechanistic differences between BQ and O2 in their reactivity with a well-defined Pd−hydride complex, Pd(IMes)2(H)(O2CPh) (1). BQ promotes the reductive elimination of PhCO2H from 1 and catalyzes the formation of a PdII−OOH complex when this reaction is carried out under aerobic conditions. These results have important implications for Pd-catalyzed oxidation reactions.
Co-reporter:Michael M. Konnick, Nattawan Decharin, Brian V. Popp and Shannon S. Stahl
Chemical Science 2011 vol. 2(Issue 2) pp:326-330
Publication Date(Web):13 Oct 2010
DOI:10.1039/C0SC00392A
The reaction of molecular oxygen with palladium(II)–hydrides is a key step in Pd-catalyzed aerobic oxidation reactions, and the mechanism of such reactions has been the focus of considerable investigation and debate. Here we describe the reaction of O2 with a series of electronically varied PdII–H complexes of the type trans-(IMes)2Pd(H)(O2CAr), with different para-substituted benzoates as the ArCO2− ligand. Analysis of the oxygenation rates of these complexes revealed a non-linear Hammett plot, and further kinetic studies demonstrated that reaction of O2 with the most electron-rich para-methoxybenzoate derivative proceeds via two parallel mechanisms, one initiated by rate-limiting reductive elimination of the carboxylic acid (HXRE) and the other involving hydrogen-atom abstraction by O2 (HAA). DFT computational studies support these conclusions and reveal that the preferred mechanism for the O2insertion reaction changes from HAA to HXRE as the para substituent on the benzoate ligand shifts from electron-donating to electron-withdrawing.
Co-reporter:Richard I. McDonald, Paul B. White, Adam B. Weinstein, Chun Pong Tam, and Shannon S. Stahl
Organic Letters 2011 Volume 13(Issue 11) pp:2830-2833
Publication Date(Web):May 2, 2011
DOI:10.1021/ol200784y
Enantioselective intramolecular oxidative amidation of alkenes has been achieved using a (pyrox)Pd(II)(TFA)2 catalyst (pyrox = pyridine-oxazoline, TFA = trifluoroacetate) and O2 as the sole stoichiometric oxidant. The reactions proceed at room temperature in good-to-excellent yields (58–98%) and with high enantioselectivity (ee = 92–98%). Catalyst-controlled stereoselective cyclization reactions are demonstrated for a number of chiral substrates. DFT calculations suggest that the electronic asymmetry of the pyrox ligand synergizes with steric asymmetry to control the stereochemical outcome of the key amidopalladation step.
Co-reporter:Alison N. Campbell, Eric B. Meyer and Shannon S. Stahl
Chemical Communications 2011 vol. 47(Issue 37) pp:10257-10259
Publication Date(Web):22 Aug 2011
DOI:10.1039/C1CC13632A
Palladium-catalyzed aerobic oxidative cross-couplings of indoles and benzene have been achieved by using 4,5-diazafluorene derivatives as ancillary ligands. Proper choice of the neutral and anionic ligands enables control over the reaction regioselectivity.
Co-reporter:Lauren M. Huffman and Shannon S. Stahl
Dalton Transactions 2011 vol. 40(Issue 35) pp:8959-8963
Publication Date(Web):05 May 2011
DOI:10.1039/C1DT10463B
A net trans C–N reductive elimination reaction is observed from a macrocyclic aryl-CuIII complex, and a mechanistic study of this reaction indicates that coordinating ligands play a role in mediating this unusual transformation.
Co-reporter:Alison E. Wendlt;Alison M. Suess
Angewandte Chemie International Edition 2011 Volume 50( Issue 47) pp:11062-11087
Publication Date(Web):
DOI:10.1002/anie.201103945
Abstract
The selective oxidation of CH bonds and the use of O2 as a stoichiometric oxidant represent two prominent challenges in organic chemistry. Copper(II) is a versatile oxidant, capable of promoting a wide range of oxidative coupling reactions initiated by single-electron transfer (SET) from electron-rich organic molecules. Many of these reactions can be rendered catalytic in Cu by employing molecular oxygen as a stoichiometric oxidant to regenerate the active copper(II) catalyst. Meanwhile, numerous other recently reported Cu-catalyzed CH oxidation reactions feature substrates that are electron-deficient or appear unlikely to undergo single-electron transfer to copper(II). In some of these cases, evidence has been obtained for the involvement of organocopper(III) intermediates in the reaction mechanism. Organometallic CH oxidation reactions of this type represent important new opportunities for the field of Cu-catalyzed aerobic oxidations.
Co-reporter:Alison E. Wendlt;Alison M. Suess
Angewandte Chemie 2011 Volume 123( Issue 47) pp:11256-11283
Publication Date(Web):
DOI:10.1002/ange.201103945
Abstract
Die selektive Oxidation von C-H-Bindungen und der Einsatz von O2 als stöchiometrisches Oxidationsmittel stellen zwei wesentliche Herausforderungen in der organischen Chemie dar. Kupfer(II) ist ein vielseitiges Oxidationsmittel für verschiedene oxidative Kupplungen, die durch Einelektronen-Transfer (SET) von elektronenreichen organischen Molekülen ausgelöst werden. Viele dieser Reaktionen können mit Kupfer katalytisch durchgeführt werden, wenn molekularer Sauerstoff als Oxidationsmittel eingesetzt wird, um den aktiven Kupfer(II)-Katalysator zu regenerieren. Daneben wurden auch zahlreiche neue Cu-katalysierte C-H-Oxidationen mit elektronenarmen Substraten beschrieben, von denen ein SET zum Kupfer(II) unwahrscheinlich scheint. In einigen dieser Fälle konnte die Beteiligung von Organokupfer(III)-Intermediaten im Reaktionsmechanismus nachgewiesen werden. Metallorganische C-H-Oxidationen dieser Art eröffnen neue bedeutende Möglichkeiten für das Gebiet der Cu-katalysierten aeroben Oxidationen.
Co-reporter:Dr. Lauren M. Huffman;Alicia Casitas;Marc Font;Mercè Canta;Dr. Miquel Costas;Dr. Xavi Ribas;Dr. Shannon S. Stahl
Chemistry - A European Journal 2011 Volume 17( Issue 38) pp:10643-10650
Publication Date(Web):
DOI:10.1002/chem.201100608
Abstract
A well-defined macrocyclic aryl–CuIII complex (2) reacts readily with a variety of oxygen nucleophiles, including carboxylic acids, phenols and alcohols, under mild conditions to form the corresponding aryl esters, biaryl ethers and alkyl aryl ethers. The relationship between these reactions and catalytic CO coupling methods is demonstrated by the reaction of the macrocyclic aryl–Br species with acetic acid and p-fluorophenol in the presence of 10 mol % CuI. An aryl-CuIII-Br species 2Br was observed as an intermediate in the catalytic reaction. Investigation of the stoichiometric CO bond-forming reactions revealed nucleophile-dependent changes in the mechanism. The reaction of 2 with carboxylic acids revealed a positive correlation between the log(kobs) and the pKa of the nucleophile (less-acidic nucleophiles react more rapidly), whereas a negative correlation was observed with most phenols (more-acidic phenols react more rapidly). The latter trend resembles previous observations with nitrogen nucleophiles. With carboxylic acids and acidic phenols, UV-visible spectroscopic data support the formation of a ground-state adduct between 2 and the oxygen nucleophile. Collectively, kinetic and spectroscopic data support a unified mechanism for aryl-O coupling from the CuIII complex, consisting of nucleophile coordination to the CuIII center, deprotonation of the coordinated nucleophile, and CO (or CN) reductive elimination from CuIII.
Co-reporter:Yusuke Izawa;Doris Pun
Science 2011 Volume 333(Issue 6039) pp:209-213
Publication Date(Web):08 Jul 2011
DOI:10.1126/science.1204183
Phenol derivatives are prepared from nonaromatic ring compounds that can bear a wide variety of substitutents.
Co-reporter:Michelle T. Dohm ; Brendan P. Mowery ; Ann M. Czyzewski ; Shannon S. Stahl ; Samuel H. Gellman ;Annelise E. Barron
Journal of the American Chemical Society 2010 Volume 132(Issue 23) pp:7957-7967
Publication Date(Web):May 20, 2010
DOI:10.1021/ja909734n
Non-natural oligomers have recently shown promise as functional analogues of lung surfactant proteins B and C (SP-B and SP-C), two helical and amphiphilic proteins that are critical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restricted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Here we present an alternative approach to SP-B mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, are prepared by ring-opening polymerization of β-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B. Attachment of an N-terminal octadecanoyl unit to the nylon-3 copolymers, inspired by the post-translational modifications found in SP-C, affords further improvements by reducing the percent surface area compression to reach low minimum surface tension. Cytotoxic effects of the copolymers are diminished relative to that of an SP-B-derived peptide and a peptoid-based mimic. The current study provides evidence that sequence-random copolymers can mimic the in vitro surface-active behavior of lung surfactant proteins in a mixed lipid film. These findings raise the possibility that random copolymers might be useful for developing a lung surfactant replacement, which is an attractive prospect given that such polymers are easier to prepare than are sequence-specific oligomers.
Co-reporter:Alison N. Campbell ; Paul B. White ; Ilia A. Guzei
Journal of the American Chemical Society 2010 Volume 132(Issue 43) pp:15116-15119
Publication Date(Web):October 7, 2010
DOI:10.1021/ja105829t
Pd-catalyzed C−H oxidation reactions often require the use of oxidants other than O2. Here we demonstrate a ligand-based strategy to replace benzoquinone with O2 as the stoichiometric oxidant in Pd-catalyzed allylic C−H acetoxylation. Use of 4,5-diazafluorenone (1) as an ancillary ligand for Pd(OAc)2 enables terminal alkenes to be converted to linear allylic acetoxylation products in good yields and selectivity under 1 atm O2. Mechanistic studies have revealed that 1 facilitates C−O reductive elimination from a π-allyl−PdII intermediate, thereby eliminating the requirement for benzoquinone in this key catalytic step.
Co-reporter:Amanda E. King ; Lauren M. Huffman ; Alicia Casitas ; Miquel Costas ; Xavi Ribas
Journal of the American Chemical Society 2010 Volume 132(Issue 34) pp:12068-12073
Publication Date(Web):August 6, 2010
DOI:10.1021/ja1045378
Recent studies have highlighted the ability of CuII to catalyze the aerobic oxidative functionalization of C−H bonds; however, very little is known about the mechanisms of these reactions. Here, we describe the CuII-catalyzed C−H methoxylation and amidation of a macrocylic arene substrate with O2 as the stoichiometric oxidant. Kinetic and in situ spectroscopic studies demonstrate the involvement of three different oxidation states of Cu in the catalytic mechanism, including an aryl-CuIII intermediate. These observations establish a novel mechanistic pathway that has implications for numerous other Cu-catalyzed aerobic oxidation reactions.
Co-reporter:Alicia Casitas, Amanda E. King, Teodor Parella, Miquel Costas, Shannon S. Stahl and Xavi Ribas
Chemical Science 2010 vol. 1(Issue 3) pp:326-330
Publication Date(Web):15 Jun 2010
DOI:10.1039/C0SC00245C
A series of aryl–copper(III)-halide complexes have been synthesized and characterized by NMR and UV-visible spectroscopy, cyclic voltammetry and X-ray crystallography. These complexes closely resemble elusive intermediates often invoked in catalytic reactions, such as Ullmann–Goldberg cross-coupling reactions, and their preparation has enabled direct observation and preliminary characterization of aryl halide reductive elimination from CuIII and oxidative addition to CuI centers. In situ spectroscopic studies (1H NMR, UV-visible) of a Cu-catalyzed C–N coupling reaction provides definitive evidence for the involvement of an aryl-copper(III)-halide intermediate in the catalytic mechanism. These results provide the first direct observation of the CuI/CuIII redox steps relevant to Ullmann-type coupling reactions.
Co-reporter:Xuan Ye, Martin D. Johnson, Tianning Diao, Matthew H. Yates and Shannon S. Stahl
Green Chemistry 2010 vol. 12(Issue 7) pp:1180-1186
Publication Date(Web):16 Jun 2010
DOI:10.1039/C0GC00106F
The synthetic scope and utility of Pd-catalyzed aerobic oxidation reactions has advanced significantly over the past decade, and these reactions have the potential to address important green-chemistry challenges in the pharmaceutical industry. This potential has not been realized, however, because safety concerns and process constraints hinder large-scale applications of this chemistry. These limitations are addressed by the development of a continuous-flow tube reactor, which has been demonstrated on several scales in the aerobic oxidation of alcohols. Use of a dilute oxygen gas source (8% O2 in N2) ensures that the oxygen/organic mixture never enters the explosive regime, and efficient gas-liquid mixing in the reactor minimizes decomposition of the homogeneous catalyst into inactive Pd metal. These results provide the basis for large-scale implementation of palladium-catalyzed (and other) aerobic oxidation reactions for pharmaceutical synthesis.
Co-reporter:Yusuke Izawa
Advanced Synthesis & Catalysis 2010 Volume 352( Issue 18) pp:3223-3229
Publication Date(Web):
DOI:10.1002/adsc.201000771
Abstract
An improved method for the direct oxidative coupling of o-xylene could provide streamlined access to an important monomer used in polyimide resins. The use of 2-fluoropyridine as a ligand has been found to enable unprecedented levels of chemo- and regioselectivity in this palladium-catalyzed aerobic oxidative coupling reaction. Preliminary insights have been obtained into the origin of the effectiveness of 2-fluoropyridine as a ligand.
Co-reporter:Brian V. Popp ; Christine M. Morales ; Clark R. Landis
Inorganic Chemistry 2010 Volume 49(Issue 18) pp:8200-8207
Publication Date(Web):July 6, 2010
DOI:10.1021/ic100806w
The reaction of molecular oxygen with palladium(0) centers is a key step in Pd-catalyzed aerobic oxidation reactions. The present study provides a density functional theory (DFT) computational analysis of the mechanism and electronic structural features of the reversible, associative exchange between O2 and ethylene at an ethylenediamine (en)-coordinated palladium(0) center. Salient features of the mechanism include: (1) the near thermoneutrality of the O2-alkene exchange reaction, consistent with experimentally observed reversible exchange between O2 and alkenes at well-defined Pd centers, (2) end-on activation of triplet O2 at an apical site of the trigonal Pd0 center, resulting in formation of a PdI(η1-superoxide) species, (3) rearrangement of the PdI(η1-superoxide) species into a pseudo-octahedral (en)Pd(η2-O2)(η2-C2H4) species with concomitant crossing from the triplet to singlet energy surfaces, and (4) release of alkene from an axial face of (en)PdII(η2-peroxo) with a geometry in which the alkene leaves with an end-on trajectory (involving an interaction of the Pd dz2 and alkene π* orbitals). This study highlights the similar reactivity and reaction pathways of alkenes and O2 with an electron-rich metal center, despite the different ground-state electronic configurations of these molecules (closed-shell singlet and open-shell triplet, respectively).
Co-reporter:Alicia Casitas, Albert Poater, Miquel Solà, Shannon S. Stahl, Miquel Costas and Xavi Ribas
Dalton Transactions 2010 vol. 39(Issue 43) pp:10458-10463
Publication Date(Web):01 Oct 2010
DOI:10.1039/C0DT00284D
Well-defined aryl–CuIII–halide species undergo reductive elimination upon acid addition resulting in the formation of strong aryl–halide bonds. The computationally studied mechanism points towards ligand protonation as the rate-determining step, in agreement with previous experimental data.
Co-reporter:RichardI. McDonald ;ShannonS. Stahl
Angewandte Chemie International Edition 2010 Volume 49( Issue 32) pp:5529-5532
Publication Date(Web):
DOI:10.1002/anie.200906342
Co-reporter:RichardI. McDonald ;ShannonS. Stahl
Angewandte Chemie 2010 Volume 122( Issue 32) pp:5661-5664
Publication Date(Web):
DOI:10.1002/ange.200906342
Co-reporter:Dr. James B. Gerken;Elizabeth C. Lis; Robert J. Hamers ; Shannon S. Stahl
ChemSusChem 2010 Volume 3( Issue 10) pp:1176-1179
Publication Date(Web):
DOI:10.1002/cssc.201000161
Co-reporter:Jihua Zhang, Samuel H. Gellman and Shannon S. Stahl
Macromolecules 2010 Volume 43(Issue 13) pp:5618-5626
Publication Date(Web):June 11, 2010
DOI:10.1021/ma1010809
Nylon-3 copolymers generated via ring-opening polymerization of β-lactams have recently been shown to function as selective antibacterial agents or as chemoattractants that can induce fibroblasts to attach to surfaces. Understanding the molecular basis of these activities and developing improved materials requires knowledge of the relative reactivities of different β-lactams, which influence subunit distribution patterns within polymer chains. The homopolymerization of a cyclooctyl β-lactam (2) in the presence of a strong base and imide co-initiator was studied using both gas chromatography (GC) and in situ infrared (IR) spectroscopy. The rate of this anionic ring-opening polymerization reaction exhibits a first-order dependence on the β-lactam and co-initiator concentrations and a zero-order dependence on the base concentration. Analogous studies of four other β-lactams, bearing various substituents [cyclohexyl (1), cyclododecyl (3), and Boc-protected amino groups (4, 5)], revealed that different monomers exhibit significantly different homopolymerization rates. Binary copolymerizations of four β-lactam pairs (1 + 4, 2 + 3, 2 + 4, and 2 + 5), several of which lead to biologically active amphiphilic copolymers, were investigated by GC. In each of the copolymerizations, except for 2 + 3, the two β-lactams were consumed at different rates, leading to compositional drift within the resulting polymers (i.e., variable subunit distribution along the length of the polymer chains). The copolymerization rates of 2 + 3 and 2 + 4 exhibited a monotonic dependence on the starting β-lactam composition, whereas the copolymerization of 1 + 4 and 2 + 5 was slower than either of the respective β-lactam homopolymerizations. Three methods (Fineman−Ross, Kelen−Tudos, and Mayo−Lewis) were employed to determine the reactivity ratios of these β-lactam pairs at low conversions. This analysis confirms that the copolymers obtained from 1 + 4, 2 + 4, or 2 + 5 are characterized by some extent of compositional drift, while poly(2 + 3) is an ideally random copolymer. These results provide valuable insights pertinent to the molecular structure of amphiphilic nylon-3 copolymers that exhibit bioactivity.
Co-reporter:Nickeisha A. Stephenson, Jiang Zhu, Samuel H. Gellman and Shannon S. Stahl
Journal of the American Chemical Society 2009 Volume 131(Issue 29) pp:10003-10008
Publication Date(Web):July 6, 2009
DOI:10.1021/ja8094262
The carbon−nitrogen bond of carboxamides is extremely stable under most conditions. The present study reveals that simple zirconium− and hafnium−amido complexes are highly efficient catalysts for equilibrium-controlled transamidation reactions between secondary amines and tertiary amides. In a number of cases, transamidation proceeds rapidly at room temperature. We find that these new catalysts are sufficiently active to promote the metathesis of tertiary amides, which arises from successive transamidation cycles. The catalytic activities we observe are unprecedented and represent a substantial step toward a long-range goal of conducting equilibrium-controlled reactions with carboxamides.
Co-reporter:Lujuan Yang, Zhan Lu and Shannon S. Stahl
Chemical Communications 2009 (Issue 42) pp:6460-6462
Publication Date(Web):18 Sep 2009
DOI:10.1039/B915487F
Electron-rich aromatic C–H bonds undergo regioselective chlorination and bromination in the presence of CuX2, LiX (X = Cl, Br) and molecular oxygen. Preliminary mechanistic insights suggest that the bromination and chlorination reactions proceed by different pathways.
Co-reporter:Christopher C. Scarborough, Ilia A. Guzei and Shannon S. Stahl
Dalton Transactions 2009 (Issue 13) pp:2284-2286
Publication Date(Web):13 Feb 2009
DOI:10.1039/B902460C
A chiral seven-membered N-heterocyclic carbene (NHC) has been synthesized from its phenol adduct (NHC-HOPh) by a novel base-induced α-elimination method, and its donor strength has been determined from the IR stretching frequencies of the NHC-Rh(CO)2Cl complex.
Co-reporter:BrianV. Popp Dr. ;ShannonS. Stahl
Chemistry - A European Journal 2009 Volume 15( Issue 12) pp:2915-2922
Publication Date(Web):
DOI:10.1002/chem.200802311
Co-reporter:Christopher C. Scarborough, Ana Bergant, Graham T. Sazama, Ilia A. Guzei, Lara C. Spencer, Shannon S. Stahl
Tetrahedron 2009 65(26) pp: 5084-5092
Publication Date(Web):
DOI:10.1016/j.tet.2009.04.072
Co-reporter:Brian V. Popp;Johanna E. Wendlt;Clark R. Lis and;Shannon S. Stahl
Angewandte Chemie 2007 Volume 119(Issue 4) pp:
Publication Date(Web):8 DEC 2006
DOI:10.1002/ange.200603667
O2-Aktivierung: Bei der Umsetzung von molekularem Sauerstoff mit einem [Pd0(NHC)2]-Komplex (NHC=N-heterocyclisches Carben) ist die Triebkraft für die Bildung des PdII(η2-O2)-Produkts Berechnungen zufolge unerwartet gering. Entsprechend konnte experimentell eine reversible Koordination von O2 an die Pd(NHC)2-Einheit nachgewiesen werden. Rechnerisch wurde eine schrittweise Reaktion von O2 mit Pd0 über einen η1-O2-Übergangszustand ermittelt.
Co-reporter:Brian V. Popp;Johanna E. Wendlt;Clark R. Lis and;Shannon S. Stahl
Angewandte Chemie International Edition 2007 Volume 46(Issue 4) pp:
Publication Date(Web):8 DEC 2006
DOI:10.1002/anie.200603667
O2activation: Computational studies of the reaction of O2 with an [(NHC)2Pd0] (NHC=N-heterocyclic carbene) complex reveal an unexpectedly small driving force for formation of a PdII(η2-O2) product. This result led to experimental demonstration of reversible O2 coordination to the (NHC)2Pd center. Computational analysis of the reaction coordinate reveals that O2 reacts with Pd0 through a stepwise mechanism involving an η1-O2 transition state.
Co-reporter:Christen M. Bell;Denis A. Kissounko;Samuel H. Gellman ;Shannon S. Stahl
Angewandte Chemie International Edition 2007 Volume 46(Issue 5) pp:
Publication Date(Web):13 DEC 2006
DOI:10.1002/anie.200603588
Trading places: The metathesis of secondary amides through a transacylation mechanism has been achieved by employing catalytic quantities of an organic imide and a Brønsted base (see scheme). Equilibrium-controlled exchange between various amide pairs is demonstrated for substrates bearing N-alkyl and N-aryl substituents.
Co-reporter:Christen M. Bell;Denis A. Kissounko;Samuel H. Gellman ;Shannon S. Stahl
Angewandte Chemie 2007 Volume 119(Issue 5) pp:
Publication Date(Web):13 DEC 2006
DOI:10.1002/ange.200603588
Platztausch: Die Metathese sekundärer Amide über eine Transacylierung gelang durch die Verwendung katalytischer Mengen eines organischen Imids und einer Brønsted-Base (siehe Schema). Der gleichgewichtsgesteuerte Austausch zwischen einer Reihe von Amidpaaren wird für Substrate mit N-Alkyl- und N-Arylsubstituenten gezeigt.
Co-reporter:Michael M. Konnick;Bhavesh A. Ghi;Ilia A. Guzei
Angewandte Chemie International Edition 2006 Volume 45(Issue 18) pp:
Publication Date(Web):28 MAR 2006
DOI:10.1002/anie.200600532
A critical step: The reaction of molecular oxygen with a reduced palladium species represents the key step in Pd-catalyzed aerobic oxidation reactions. New PdII–hydride complexes 1 have been prepared which react with molecular oxygen to produce PdII–hydroperoxide adducts 2. Carboxylic acid catalysis of this reaction has important implications for Pd-catalyzed aerobic oxidation reactions.
Co-reporter:Michael M. Konnick;Bhavesh A. Ghi;Ilia A. Guzei
Angewandte Chemie 2006 Volume 118(Issue 18) pp:
Publication Date(Web):28 MAR 2006
DOI:10.1002/ange.200600532
Der entscheidende Schritt: Die Reaktion von molekularem Sauerstoff mit einer reduzierten Palladiumspezies bildet den Schlüsselschritt in palladiumkatalysierten aeroben Oxidationen. Mit molekularem Sauerstoff reagieren die neuen Palladium(II)-Hydrid-Komplexe 1 zu den Palladium(II)-Hydroperoxid-Addukten 2. Die katalytische Wirkung von Carbonsäuren führt zu Rückschlüssen über palladiumkatalysierte aerobe Oxidationen.
Co-reporter:Christopher C. Scarborough, Brian V. Popp, Ilia A. Guzei, Shannon S. Stahl
Journal of Organometallic Chemistry 2005 Volume 690(24–25) pp:6143-6155
Publication Date(Web):1 December 2005
DOI:10.1016/j.jorganchem.2005.08.022
We recently reported the first example of a seven-membered N-heterocyclic carbene (NHC) ligand for transition metals. These ligands are attractive because the heterocyclic framework, derived from 2,2′-diaminobiphenyl, exhibits a torsional twist that results in a chiral, C2-symmetric structure. The present report outlines the synthetic efforts that led to the development of these ligands together with the synthesis and structural characterization of metal complexes bearing seven-membered NHCs as ancillary ligands. The identity of nitrogen substituent, neopentyl versus 2-adamantyl, influences the synthetic accessibility and stability of the seven-membered amidinium salts and the NHC–metal complexes obtained via in situ deprotonation/metallation. Computational analysis of the seven-membered ring structures reveals the Hückel antiaromatic 8π electron system achieves significant Möbius aromatic stabilization upon undergoing torsional distortion of the heterocyclic ring.The syntheses of metal complexes bearing seven-membered N-heterocyclic carbenes are described, including X-ray characterization of one amidinium salt carbene precursor, one silver(I)–carbene complex, and two palladium(II)–carbene complexes. Computational analyses reveal a Möbius aromatic stabilization of the formally antiaromatic seven-membered framework.
Co-reporter:Christopher C. Scarborough;Michael J. W. Grady;Ilia A. Guzei Dr.;Bhavesh A. Ghi;Emilio E. Bunel Dr.
Angewandte Chemie International Edition 2005 Volume 44(Issue 33) pp:
Publication Date(Web):20 JUL 2005
DOI:10.1002/anie.200501522
Carbenes with a twist: A seven-membered N-heterocyclic carbene (NHC) ligand is prepared from an amidinium precursor, derived from 2,2′-dinitrobiphenyl, and yields the NHC–PdII complex [PdCl(allyl)(NHC)] (see scheme). This carbene framework exhibits a tortional twist that results in axial symmetry. This ligand class can be readily modified and is attractive for future application in asymmetric catalysis.
Co-reporter:Shannon S. Stahl
Angewandte Chemie 2004 Volume 116(Issue 26) pp:
Publication Date(Web):22 JUN 2004
DOI:10.1002/ange.200300630
Die selektive aerobe Oxidation organischer Verbindungen ist eines der fundamentalsten Probleme der modernen organischen Chemie. Effektive Lösungen müssen die spezifische Reaktivität und Selektivität von molekularem Sauerstoff berücksichtigen und unterschiedliche Klassen von Oxidationsreaktionen abdecken. Die Palladiumoxidasekatalyse kombiniert die Vielseitigkeit Palladium(II)-vermittelter Oxidationen organischer Substrate mit der Oxidation des reduzierten Palladium-Katalysators durch Disauerstoff und ermöglicht so einen Zugang zu einer breiten Auswahl an selektiven aeroben Oxidationsreaktionen. Neuere Ergebnisse zeigen, dass Cokatalysatoren wie Kupfer(II), Polyoxometallate und Benzochinone in der Oxidation von Palladium(0) durch molekularen Sauerstoff verzichtbar sind. Eine große Bedeutung für diese Reaktionen haben oxidativ stabile Liganden, die die Katalysatorzersetzung minimieren, die direkte Reaktion von Palladium mit Disauerstoff fördern, die Reaktivität des organischen Substrats regulieren und asymmetrische Katalysen ermöglichen.
Co-reporter:Shannon S. Stahl
Angewandte Chemie 2004 Volume 116(Issue 26) pp:
Publication Date(Web):22 JUN 2004
DOI:10.1002/ange.200490083
Co-reporter:Shannon S. Stahl
Angewandte Chemie International Edition 2004 Volume 43(Issue 26) pp:
Publication Date(Web):22 JUN 2004
DOI:10.1002/anie.200300630
Selective aerobic oxidation of organic molecules is a fundamental and practical challenge in modern chemistry. Effective solutions to this problem must overcome the intrinsic reactivity and selectivity challenges posed by the chemistry of molecular oxygen, and they must find application in diverse classes of oxidation reactions. Palladium oxidase catalysis combines the versatility of PdII-mediated oxidation of organic substrates with dioxygen-coupled oxidation of the reduced palladium catalyst to enable a broad range of selective aerobic oxidation reactions. Recent developments revealed that cocatalysts (e.g. CuII, polyoxometalates, and benzoquinone) are not essential for efficient oxidation of Pd0 by molecular oxygen. Oxidatively stable ligands play an important role in these reactions by minimizing catalyst decomposition, promoting the direct reaction between palladium and dioxygen, modulating organic substrate reactivity and permitting asymmetric catalysis.
Co-reporter:Shannon S. Stahl
Angewandte Chemie International Edition 2004 Volume 43(Issue 26) pp:
Publication Date(Web):22 JUN 2004
DOI:10.1002/anie.200490083
Co-reporter:Shannon R. Fix;Jodie L. Brice
Angewandte Chemie International Edition 2002 Volume 41(Issue 1) pp:
Publication Date(Web):2 JAN 2002
DOI:10.1002/1521-3773(20020104)41:1<164::AID-ANIE164>3.0.CO;2-B
Facile and efficient: a palladium-catalyzed intramolecular oxidative amination reaction [Eq. (1)] that uses molecular oxygen as a stoichiometric oxidant. These reactions require no cocatalyst for efficient reoxidation of the palladium, they operate in solvents ranging from heptane to dimethylsulfoxide, and achieve up to 250 turnovers (TO) and rates of 70 TO h−1.
Co-reporter:Shannon R. Fix;Jodie L. Brice
Angewandte Chemie 2002 Volume 114(Issue 1) pp:
Publication Date(Web):4 JAN 2002
DOI:10.1002/1521-3757(20020104)114:1<172::AID-ANGE172>3.0.CO;2-Y
Einfach und effizient: eine Palladium-katalysierte intramolekulare oxidative Aminierung [Gl. (1)] mit molekularem Sauerstoff als stöchiometrischem Oxidationsmittel. Reaktionen dieses Typs kommen ohne Cokatalysator zur Reoxidation des Palladiums aus, sie können in unterschiedlich polaren Lösungsmitteln (von Heptan bis Dimethylsulfoxid) durchgeführt werden, und es lassen sich bis zu 250 Turnovers bei Geschwindigkeiten von 70 TO h−1 erreichen.
Co-reporter:Alireza Rahimi ; Ali Azarpira ; Hoon Kim ; John Ralph
Journal of the American Chemical Society () pp:
Publication Date(Web):April 9, 2013
DOI:10.1021/ja401793n
An efficient organocatalytic method for chemoselective aerobic oxidation of secondary benzylic alcohols within lignin model compounds has been identified. Extension to selective oxidation in natural lignins has also been demonstrated. The optimal catalyst system consists of 4-acetamido-TEMPO (5 mol %; TEMPO = 2,2,6,6-tetramethylpiperidine-N-oxyl) in combination with HNO3 and HCl (10 mol % each). Preliminary studies highlight the prospect of combining this method with a subsequent oxidation step to achieve C–C bond cleavage.
Co-reporter:Zhan Lu
Organic Letters () pp:
Publication Date(Web):February 22, 2012
DOI:10.1021/ol300030w
Use of a base-free Pd(DMSO)2(TFA)2 catalyst system enables the synthesis of six-membered nitrogen heterocycles via a Wacker-type aerobic oxidative cyclization of alkenes bearing tethered sulfonamides. Various heterocycles, including morpholines, piperidines, piperazines, and piperazinones, are accessible by this method.
Co-reporter:Joanne E. Redford ; Richard I. McDonald ; Matthew L. Rigsby ; Joshua D. Wiensch
Organic Letters () pp:
Publication Date(Web):February 21, 2012
DOI:10.1021/ol3000519
Palladium(II)-catalyzed aerobic oxidative cyclization of alkenes with tethered tert-butanesulfinamides furnishes enantiopure 2,5-disubstituted pyrrolidines, originating from readily available and easily diversified starting materials. These reactions are the first reported examples of metal-catalyzed addition of sulfinamide nucleophiles to alkenes.
Co-reporter:Adam B. Weinstein and Shannon S. Stahl
Catalysis Science & Technology (2011-Present) 2014 - vol. 4(Issue 12) pp:NaN4307-4307
Publication Date(Web):2014/08/01
DOI:10.1039/C4CY00764F
(DAF)Pd(OAc)2 (DAF = 4,5-diazafluorenone) catalyzes aerobic intramolecular aryl C–H amination with N-benzenesulfonyl-2-aminobiphenyl in dioxane to afford the corresponding carbazole product. Mechanistic studies show that the reaction involves in situ generation of peroxide species from 1,4-dioxane and O2, and the reaction further benefits from the presence of glycolic acid, an oxidative decomposition product of dioxane. An induction period observed for the formation of the carbazole product correlates with the formation of 1,4-dioxan-2-hydroperoxide via autoxidation of 1,4-dioxane, and the in situ-generated peroxide is proposed to serve as the reactive oxidant in the reaction. These findings have important implications for palladium-catalyzed aerobic oxidation reactions conducted in ethereal solvents.
Co-reporter:Changwu Zheng and Shannon S. Stahl
Chemical Communications 2015 - vol. 51(Issue 64) pp:NaN12774-12774
Publication Date(Web):2015/07/03
DOI:10.1039/C5CC05312A
Branched-selective oxidative Heck coupling reactions have been developed between arylboronic acids and electronically unbiased terminal alkenes. The reactions exhibit high catalyst-controlled regioselectivity favoring the less common branched isomer. The reactions employ a catalyst composed of Pd(TFA)2/dmphen (TFA = trifluoroacetate, dmphen = 2,9-dimethyl-1,10-phenanthroline) and proceed efficiently at 45–60 °C under 1 atm of O2 without requiring other additives. A broad array of functional groups, including aryl halide, allyl silane and carboxylic acids are tolerated.
Co-reporter:Lujuan Yang, Zhan Lu and Shannon S. Stahl
Chemical Communications 2009(Issue 42) pp:NaN6462-6462
Publication Date(Web):2009/09/18
DOI:10.1039/B915487F
Electron-rich aromatic C–H bonds undergo regioselective chlorination and bromination in the presence of CuX2, LiX (X = Cl, Br) and molecular oxygen. Preliminary mechanistic insights suggest that the bromination and chlorination reactions proceed by different pathways.
Co-reporter:Tianning Diao, Tyler J. Wadzinski and Shannon S. Stahl
Chemical Science (2010-Present) 2012 - vol. 3(Issue 3) pp:NaN891-891
Publication Date(Web):2011/10/31
DOI:10.1039/C1SC00724F
The direct α,β-dehydrogenation of aldehydes and ketones represents an efficient alternative to stepwise methods to prepare enal and enone products. Here, we describe a new Pd(TFA)2/4,5-diazafluorenone dehydrogenation catalyst that overcomes key limitations of previous catalyst systems. The scope includes successful reactivity with pharmaceutically important cyclopentanone and flavanone substrates, as well as acyclic ketones. Preliminary mechanistic studies compare the reactivity of this catalyst to previously reported dehydrogenation catalysts and reveal that cleavage of the α-C–H bond of the ketone is the turnover-limiting step of the catalytic mechanism.
Co-reporter:Matthew L. Rigsby, Sukanta Mandal, Wonwoo Nam, Lara C. Spencer, Antoni Llobet and Shannon S. Stahl
Chemical Science (2010-Present) 2012 - vol. 3(Issue 10) pp:NaN3062-3062
Publication Date(Web):2012/07/16
DOI:10.1039/C2SC20755A
Several binuclear cobalt(III) complexes that mimic Ru-based water oxidation catalysts have been prepared. The initial complexes exhibited thermodynamic instability and kinetic lability that complicated efforts to use these cobalt complexes as electrocatalysts for water oxidation. Binuclear cobalt(III) complexes supported by a bridging bispyridylpyrazolate (bpp) ligand overcome these limitations. Two bpp-ligated dicobalt(III)-peroxo complexes were prepared and structurally characterized, and electrochemical investigation of these complexes supports their ability to serve as molecular electrocatalysts for water oxidation under acidic conditions (pH 2.1).
Co-reporter:Michael M. Konnick, Nattawan Decharin, Brian V. Popp and Shannon S. Stahl
Chemical Science (2010-Present) 2011 - vol. 2(Issue 2) pp:NaN330-330
Publication Date(Web):2010/10/13
DOI:10.1039/C0SC00392A
The reaction of molecular oxygen with palladium(II)–hydrides is a key step in Pd-catalyzed aerobic oxidation reactions, and the mechanism of such reactions has been the focus of considerable investigation and debate. Here we describe the reaction of O2 with a series of electronically varied PdII–H complexes of the type trans-(IMes)2Pd(H)(O2CAr), with different para-substituted benzoates as the ArCO2− ligand. Analysis of the oxygenation rates of these complexes revealed a non-linear Hammett plot, and further kinetic studies demonstrated that reaction of O2 with the most electron-rich para-methoxybenzoate derivative proceeds via two parallel mechanisms, one initiated by rate-limiting reductive elimination of the carboxylic acid (HXRE) and the other involving hydrogen-atom abstraction by O2 (HAA). DFT computational studies support these conclusions and reveal that the preferred mechanism for the O2insertion reaction changes from HAA to HXRE as the para substituent on the benzoate ligand shifts from electron-donating to electron-withdrawing.
Co-reporter:Alicia Casitas, Amanda E. King, Teodor Parella, Miquel Costas, Shannon S. Stahl and Xavi Ribas
Chemical Science (2010-Present) 2010 - vol. 1(Issue 3) pp:NaN330-330
Publication Date(Web):2010/06/15
DOI:10.1039/C0SC00245C
A series of aryl–copper(III)-halide complexes have been synthesized and characterized by NMR and UV-visible spectroscopy, cyclic voltammetry and X-ray crystallography. These complexes closely resemble elusive intermediates often invoked in catalytic reactions, such as Ullmann–Goldberg cross-coupling reactions, and their preparation has enabled direct observation and preliminary characterization of aryl halide reductive elimination from CuIII and oxidative addition to CuI centers. In situ spectroscopic studies (1H NMR, UV-visible) of a Cu-catalyzed C–N coupling reaction provides definitive evidence for the involvement of an aryl-copper(III)-halide intermediate in the catalytic mechanism. These results provide the first direct observation of the CuI/CuIII redox steps relevant to Ullmann-type coupling reactions.
Co-reporter:Lauren M. Huffman and Shannon S. Stahl
Dalton Transactions 2011 - vol. 40(Issue 35) pp:NaN8963-8963
Publication Date(Web):2011/05/05
DOI:10.1039/C1DT10463B
A net trans C–N reductive elimination reaction is observed from a macrocyclic aryl-CuIII complex, and a mechanistic study of this reaction indicates that coordinating ligands play a role in mediating this unusual transformation.
Co-reporter:Alicia Casitas, Albert Poater, Miquel Solà, Shannon S. Stahl, Miquel Costas and Xavi Ribas
Dalton Transactions 2010 - vol. 39(Issue 43) pp:NaN10463-10463
Publication Date(Web):2010/10/01
DOI:10.1039/C0DT00284D
Well-defined aryl–CuIII–halide species undergo reductive elimination upon acid addition resulting in the formation of strong aryl–halide bonds. The computationally studied mechanism points towards ligand protonation as the rate-determining step, in agreement with previous experimental data.
Co-reporter:Alison E. Wendlandt and Shannon S. Stahl
Organic & Biomolecular Chemistry 2012 - vol. 10(Issue 19) pp:NaN3870-3870
Publication Date(Web):2012/03/23
DOI:10.1039/C2OB25310K
The copper(II)-mediated oxidative cyclization of enamides to oxazoles is reported. A range of 2,5-disubstituted oxazoles were prepared in moderate to good yields in two steps from simple amide and alkyne precursors.
Co-reporter:Damian P. Hruszkewycz, Kelsey C. Miles, Oliver R. Thiel and Shannon S. Stahl
Chemical Science (2010-Present) 2017 - vol. 8(Issue 2) pp:NaN1287-1287
Publication Date(Web):2016/10/07
DOI:10.1039/C6SC03831J
A simple cobalt(II)/N-hydroxyphthalimide catalyst system has been identified for selective conversion of benzylic methylene groups in pharmaceutically relevant (hetero)arenes to the corresponding (hetero)aryl ketones. The radical reaction pathway tolerates electronically diverse benzylic C–H bonds, contrasting recent oxygenation reactions that are initiated by deprotonation of a benzylic C–H bond. The reactions proceed under practical reaction conditions (1 M substrate in BuOAc or EtOAc solvent, 12 h, 90–100 °C), and they tolerate common heterocycles, such as pyridines and imidazoles. A cobalt-free, electrochemical, NHPI-catalyzed oxygenation method overcomes challenges encountered with chelating substrates that inhibit the chemical reaction. The utility of the aerobic oxidation method is showcased in the multigram synthesis of a key intermediate towards a drug candidate (AMG 579) under process-relevant reaction conditions.
Co-reporter:Christopher C. Scarborough, Ilia A. Guzei and Shannon S. Stahl
Dalton Transactions 2009(Issue 13) pp:NaN2286-2286
Publication Date(Web):2009/02/13
DOI:10.1039/B902460C
A chiral seven-membered N-heterocyclic carbene (NHC) has been synthesized from its phenol adduct (NHC-HOPh) by a novel base-induced α-elimination method, and its donor strength has been determined from the IR stretching frequencies of the NHC-Rh(CO)2Cl complex.
Co-reporter:Alison N. Campbell, Eric B. Meyer and Shannon S. Stahl
Chemical Communications 2011 - vol. 47(Issue 37) pp:NaN10259-10259
Publication Date(Web):2011/08/22
DOI:10.1039/C1CC13632A
Palladium-catalyzed aerobic oxidative cross-couplings of indoles and benzene have been achieved by using 4,5-diazafluorene derivatives as ancillary ligands. Proper choice of the neutral and anionic ligands enables control over the reaction regioselectivity.
![2-Azatricyclo[3.3.1.13,7]dec-2-yloxy, 1-methyl-](http://img.cochemist.com/ccimg/872600/872598-44-2.png)
![2-Azatricyclo[3.3.1.13,7]dec-2-yloxy, 1-methyl-](http://img.cochemist.com/ccimg/872600/872598-44-2_b.png)
![BENZENE, 1-METHYL-4-[(1E)-3-METHYL-1,3-BUTADIENYL]-](http://img.cochemist.com/ccimg/847700/847661-16-9.png)
![BENZENE, 1-METHYL-4-[(1E)-3-METHYL-1,3-BUTADIENYL]-](http://img.cochemist.com/ccimg/847700/847661-16-9_b.png)
![Acetamide, N-[(1R)-1-methyl-2-oxoethyl]-](http://img.cochemist.com/ccimg/466700/466682-18-8.png)
![Acetamide, N-[(1R)-1-methyl-2-oxoethyl]-](http://img.cochemist.com/ccimg/466700/466682-18-8_b.png)
![Piperidine, 1-[4-(trifluoromethyl)benzoyl]-](http://img.cochemist.com/ccimg/411300/411209-38-6.png)
![Piperidine, 1-[4-(trifluoromethyl)benzoyl]-](http://img.cochemist.com/ccimg/411300/411209-38-6_b.png)
![2(3H)-Furanone, 4-[bis(phenylmethyl)amino]dihydro-, (4S)-](http://img.cochemist.com/ccimg/137500/137428-36-5.png)
![2(3H)-Furanone, 4-[bis(phenylmethyl)amino]dihydro-, (4S)-](http://img.cochemist.com/ccimg/137500/137428-36-5_b.png)
![1,4-Butanediol, 2-[bis(phenylmethyl)amino]-, (S)-](http://img.cochemist.com/ccimg/137500/137428-32-1.png)
![1,4-Butanediol, 2-[bis(phenylmethyl)amino]-, (S)-](http://img.cochemist.com/ccimg/137500/137428-32-1_b.png)
![1H,3H-NAPHTHO[1,8-CD]PYRAN-1-OL](http://img.cochemist.com/ccimg/58400/58335-51-6.png)
![1H,3H-NAPHTHO[1,8-CD]PYRAN-1-OL](http://img.cochemist.com/ccimg/58400/58335-51-6_b.png)
![Naphtho[2,3-c]furan-1(3H)-one, 4-phenyl-](http://img.cochemist.com/ccimg/50600/50558-51-5.png)
![Naphtho[2,3-c]furan-1(3H)-one, 4-phenyl-](http://img.cochemist.com/ccimg/50600/50558-51-5_b.png)
![[3-(hydroxymethyl)-4-pyridyl]methanol](http://img.cochemist.com/ccimg/38100/38070-80-3.png)
![[3-(hydroxymethyl)-4-pyridyl]methanol](http://img.cochemist.com/ccimg/38100/38070-80-3_b.png)
![Benzamide,N-[(1R)-1-phenylethyl]-](http://img.cochemist.com/ccimg/20900/20826-48-6.png)
![Benzamide,N-[(1R)-1-phenylethyl]-](http://img.cochemist.com/ccimg/20900/20826-48-6_b.png)
![Naphtho[2,3-c]furan-1(3H)-one, 9-phenyl-](http://img.cochemist.com/ccimg/10600/10568-29-3.png)
![Naphtho[2,3-c]furan-1(3H)-one, 9-phenyl-](http://img.cochemist.com/ccimg/10600/10568-29-3_b.png)
![(1H-Benzo[d]imidazol-2-yl)(phenyl)methanone](http://img.cochemist.com/ccimg/1000/955-41-9.png)
![(1H-Benzo[d]imidazol-2-yl)(phenyl)methanone](http://img.cochemist.com/ccimg/1000/955-41-9_b.png)
![5H-Cyclopenta[2,1-b:3,4-b']dipyridine, 5,5-dimethyl-](/data/chemimg/3355500/675599-96-9.png)
![5H-Cyclopenta[2,1-b:3,4-b']dipyridine, 5,5-dimethyl-](/data/chemimg/3355500/675599-96-9_b.png)
![PYRROLIDINE, 2-METHYL-1-[(4-METHYLPHENYL)SULFONYL]-](http://img.cochemist.com/ccimg/6500/6435-79-6.png)
![PYRROLIDINE, 2-METHYL-1-[(4-METHYLPHENYL)SULFONYL]-](http://img.cochemist.com/ccimg/6500/6435-79-6_b.png)
![N-{[(4-methylphenyl)sulfonyl]oxy}-3,4-dihydronaphthalen-1(2H)-imine](http://img.cochemist.com/ccimg/6400/6339-09-9.png)
![N-{[(4-methylphenyl)sulfonyl]oxy}-3,4-dihydronaphthalen-1(2H)-imine](http://img.cochemist.com/ccimg/6400/6339-09-9_b.png)
![Furo[3,4-c]pyridin-3(1H)-one](http://img.cochemist.com/ccimg/5700/5657-52-3.png)
![Furo[3,4-c]pyridin-3(1H)-one](http://img.cochemist.com/ccimg/5700/5657-52-3_b.png)
![(6E)-6-{[(5-tert-butyl-2-hydroxyphenyl)amino]methylidene}-2-ethoxy-4-nitrocyclohexa-2,4-dien-1-one](http://img.cochemist.com/ccimg/5400/5302-77-2.png)
![(6E)-6-{[(5-tert-butyl-2-hydroxyphenyl)amino]methylidene}-2-ethoxy-4-nitrocyclohexa-2,4-dien-1-one](http://img.cochemist.com/ccimg/5400/5302-77-2_b.png)
![1,2,3,4-TETRAHYDROBENZO[H]QUINOLINE](http://img.cochemist.com/ccimg/5300/5223-80-3.png)
![1,2,3,4-TETRAHYDROBENZO[H]QUINOLINE](http://img.cochemist.com/ccimg/5300/5223-80-3_b.png)
![Benzamide, N-[(1Z)-2-phenylethenyl]-](http://img.cochemist.com/ccimg/5300/5202-77-7.png)
![Benzamide, N-[(1Z)-2-phenylethenyl]-](http://img.cochemist.com/ccimg/5300/5202-77-7_b.png)
![Furo[3,4-c]pyridin-1(3H)-one](http://img.cochemist.com/ccimg/4800/4741-42-8.png)
![Furo[3,4-c]pyridin-1(3H)-one](http://img.cochemist.com/ccimg/4800/4741-42-8_b.png)
![furo[3,4-b]pyridin-5(7H)-one](http://img.cochemist.com/ccimg/4800/4733-69-1.png)
![furo[3,4-b]pyridin-5(7H)-one](http://img.cochemist.com/ccimg/4800/4733-69-1_b.png)
![Dibenzo[c,e]oxepin-5(7H)-one](http://img.cochemist.com/ccimg/4500/4445-34-5.png)
![Dibenzo[c,e]oxepin-5(7H)-one](http://img.cochemist.com/ccimg/4500/4445-34-5_b.png)
![Benzo[d][1,3]dioxole-5-carbonitrile](http://img.cochemist.com/ccimg/4500/4421-09-4.png)
![Benzo[d][1,3]dioxole-5-carbonitrile](http://img.cochemist.com/ccimg/4500/4421-09-4_b.png)
![1,1'-(1,6-HEXANEDIYL)BIS(3-BENZYL-1-AZONIABICYCLO[2.2.2]OCTANE) D<WBR />ICHLORIDE](http://img.cochemist.com/ccimg/4000/3913-80-2.png)
![1,1'-(1,6-HEXANEDIYL)BIS(3-BENZYL-1-AZONIABICYCLO[2.2.2]OCTANE) D<WBR />ICHLORIDE](http://img.cochemist.com/ccimg/4000/3913-80-2_b.png)
![1-(4-METHOXYPHENYL)-2,3,4,9-TETRAHYDRO-1H-PYRIDO[3,4-B]INDOLE](http://img.cochemist.com/ccimg/3400/3380-73-2.png)
![1-(4-METHOXYPHENYL)-2,3,4,9-TETRAHYDRO-1H-PYRIDO[3,4-B]INDOLE](http://img.cochemist.com/ccimg/3400/3380-73-2_b.png)
![Acetamide,N-[1,1'-biphenyl]-3-yl-](http://img.cochemist.com/ccimg/2200/2113-54-4.png)
![Acetamide,N-[1,1'-biphenyl]-3-yl-](http://img.cochemist.com/ccimg/2200/2113-54-4_b.png)
![[1,1'-Biphenyl]-2,2'-dicarboxaldehyde](http://img.cochemist.com/ccimg/1300/1210-05-5.png)
![[1,1'-Biphenyl]-2,2'-dicarboxaldehyde](http://img.cochemist.com/ccimg/1300/1210-05-5_b.png)
![Benzene, [(1E)-2-bromoethenyl]-](/data/chemimg/1476700/588-72-7.png)
![Benzene, [(1E)-2-bromoethenyl]-](/data/chemimg/1476700/588-72-7_b.png)
![Bicyclo[2.2.1]heptan-1-ol](http://img.cochemist.com/ccimg/500/497-36-9.png)
![Bicyclo[2.2.1]heptan-1-ol](http://img.cochemist.com/ccimg/500/497-36-9_b.png)
![3-Oxa-9-azabicyclo[3.3.1]nonane](http://img.cochemist.com/ccimg/300/280-99-9.png)
![3-Oxa-9-azabicyclo[3.3.1]nonane](http://img.cochemist.com/ccimg/300/280-99-9_b.png)
![9-Azabicyclo[3.3.1]nonane](http://img.cochemist.com/ccimg/300/280-97-7.png)
![9-Azabicyclo[3.3.1]nonane](http://img.cochemist.com/ccimg/300/280-97-7_b.png)
![Pyridine, 2-[(4S)-4,5-dihydro-4-phenyl-2-oxazolyl]-6-methyl-](/data/chemimg/3721600/1308311-03-6.png)
![Pyridine, 2-[(4S)-4,5-dihydro-4-phenyl-2-oxazolyl]-6-methyl-](/data/chemimg/3721600/1308311-03-6_b.png)
![[1,1'-Biphenyl]-4-carboxylicacid, 3'-hydroxy-, methyl ester](http://img.cochemist.com/ccimg/579600/579511-01-6.png)
![[1,1'-Biphenyl]-4-carboxylicacid, 3'-hydroxy-, methyl ester](http://img.cochemist.com/ccimg/579600/579511-01-6_b.png)
![3H-Pyrido[3,4-b]indole, 1-(4-chlorophenyl)-4,9-dihydro-](http://img.cochemist.com/ccimg/499200/499109-65-8.png)
![3H-Pyrido[3,4-b]indole, 1-(4-chlorophenyl)-4,9-dihydro-](http://img.cochemist.com/ccimg/499200/499109-65-8_b.png)
![3-[4-(TRIFLUOROMETHYL)PHENYL]PHENOL](http://img.cochemist.com/ccimg/365500/365426-93-3.png)
![3-[4-(TRIFLUOROMETHYL)PHENYL]PHENOL](http://img.cochemist.com/ccimg/365500/365426-93-3_b.png)
![Carbamic acid,N-[(1S)-1-formyl-2,2-dimethylpropyl]-, 1,1-dimethylethyl ester](http://img.cochemist.com/ccimg/335700/335627-99-1.png)
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![1H-Pyrido[3,4-b]indole, 1-(4-chlorophenyl)-2,3,4,9-tetrahydro-](http://img.cochemist.com/ccimg/139700/139655-03-1.png)
![1H-Pyrido[3,4-b]indole, 1-(4-chlorophenyl)-2,3,4,9-tetrahydro-](http://img.cochemist.com/ccimg/139700/139655-03-1_b.png)
![Pyrrolidine, 2-ethenyl-1-[(4-methylphenyl)sulfonyl]-](http://img.cochemist.com/ccimg/116700/116699-99-1.png)
![Pyrrolidine, 2-ethenyl-1-[(4-methylphenyl)sulfonyl]-](http://img.cochemist.com/ccimg/116700/116699-99-1_b.png)
![3,7,11-Triazabicyclo[11.3.1]heptadeca-1(17),13,15-triene, 7-methyl-](http://img.cochemist.com/ccimg/106100/106088-12-4.png)
![3,7,11-Triazabicyclo[11.3.1]heptadeca-1(17),13,15-triene, 7-methyl-](http://img.cochemist.com/ccimg/106100/106088-12-4_b.png)
![4'-Chloro-[1,1'-biphenyl]-3-ol](http://img.cochemist.com/ccimg/28100/28023-90-7.png)
![4'-Chloro-[1,1'-biphenyl]-3-ol](http://img.cochemist.com/ccimg/28100/28023-90-7_b.png)
![4'-Fluoro-[1,1'-biphenyl]-3-ol](http://img.cochemist.com/ccimg/10600/10540-41-7.png)
![4'-Fluoro-[1,1'-biphenyl]-3-ol](http://img.cochemist.com/ccimg/10600/10540-41-7_b.png)
![2-[2-(hydroxymethyl)phenyl]ethanol](http://img.cochemist.com/ccimg/6400/6346-00-5.png)
![2-[2-(hydroxymethyl)phenyl]ethanol](http://img.cochemist.com/ccimg/6400/6346-00-5_b.png)
![9-Azabicyclo[3.3.1]nonan-3-one](http://img.cochemist.com/ccimg/4400/4390-39-0.png)
![9-Azabicyclo[3.3.1]nonan-3-one](http://img.cochemist.com/ccimg/4400/4390-39-0_b.png)
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![5,6-Dihydro[1,1'-biphenyl]-3(4H)-one](http://img.cochemist.com/ccimg/10400/10345-87-6.png)
![5,6-Dihydro[1,1'-biphenyl]-3(4H)-one](http://img.cochemist.com/ccimg/10400/10345-87-6_b.png)
![9-WEI <SUP>1</SUP>-OXIDANYL-9-AZABICYCLO[3.3.1]NONAN-3-ONE](http://img.cochemist.com/ccimg/7200/7123-92-4.png)
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![Benzenemethanamine, 4-methoxy-N-[(4-methoxyphenyl)methylene]-](/data/chemimg/3746400/3261-60-7.png)
![Benzenemethanamine, 4-methoxy-N-[(4-methoxyphenyl)methylene]-](/data/chemimg/3746400/3261-60-7_b.png)
![2-Azatricyclo[3.3.1.1<sup>3,7</sup>]dec-2-yloxidanyl](http://img.cochemist.com/ccimg/57700/57625-08-8.png)
![2-Azatricyclo[3.3.1.1<sup>3,7</sup>]dec-2-yloxidanyl](http://img.cochemist.com/ccimg/57700/57625-08-8_b.png)
![9-Azabicyclo[3.3.1]non-9-yloxy](/data/chemimg/1187500/31785-68-9.png)
![9-Azabicyclo[3.3.1]non-9-yloxy](/data/chemimg/1187500/31785-68-9_b.png)