Ubiquitous Intermediates Research Articles

Electrocatalytic metal hydride generation using CPET mediators.

Transition metal hydrides (M-H) are ubiquitous intermediates in a wide range of enzymatic processes and catalytic reactions, playing a central role in H+/H2 interconversion1, the reduction of CO2 to formic acid (HCOOH)2 and in hydrogenation reactions. The facile formation of M-H is a critical challenge to address to further improve the energy efficiency of these reactions. Specifically, the easy electrochemical generation of M-H using mild proton sources is key to enable high selectivity versus competitive CO and H2 formation in the CO2 electroreduction to HCOOH, the highest value-added CO2 reduction product3. Here we introduce a strategy for electrocatalytic M-H generation using concerted proton-electron transfer (CPET) mediators. As a proof of principle, the combination of a series of CPET mediators with the CO2 electroreduction catalyst [MnI(bpy)(CO)3Br] (bpy = 2,2'-bipyridine) was investigated, probing the reversal of the product selectivity from CO to HCOOH to evaluate the efficiency of the manganese hydride (Mn-H) generation step. We demonstrate the formation of the Mn-H species by in situ spectroscopic techniques and determine the thermodynamic boundary conditions for this mechanism to occur. A synthetic iron-sulfur cluster is identified as the best CPET mediator for the system, enabling the preparation of a benchmark catalytic system for HCOOH generation.

Dichloromethylation of enones by carbon nitride photocatalysis

Small organic radicals are ubiquitous intermediates in photocatalysis and are used in organic synthesis to install functional groups and to tune electronic properties and pharmacokinetic parameters of the final molecule. Development of new methods to generate small organic radicals with added functionality can further extend the utility of photocatalysis for synthetic needs. Herein, we present a method to generate dichloromethyl radicals from chloroform using a heterogeneous potassium poly(heptazine imide) (K-PHI) photocatalyst under visible light irradiation for C1-extension of the enone backbone. The method is applied on 15 enones, with γ,γ-dichloroketones yields of 18–89%. Due to negative zeta-potential (−40 mV) and small particle size (100 nm) K-PHI suspension is used in quasi-homogeneous flow-photoreactor increasing the productivity by 19 times compared to the batch approach. The resulting γ,γ-dichloroketones, are used as bifunctional building blocks to access value-added organic compounds such as substituted furans and pyrroles.

Isolation and characterization of a lithiated pyridine - aggregation in the solid state and in solution.

Pyridyllithiums are ubiquitous intermediates used for the electrophilic functionalization of pyridines. In this work, the isolation of a pyridyllithium is reported. Single crystal XRD revealed a dimer in the solid state. In THF solution it was identified as a monomer using DOSY NMR spectroscopy. Calculations showed that the pyridyllithium is a very electron rich pyridine superbase, which may account for its high reactivity.

Metal Olefin Complexes: Revisiting theDewar−Chatt−DuncansonModel and Deriving Reactivity Patterns from Carbon‐13 NMR Chemical Shift

AbstractMetal olefin complexes that are ubiquitous intermediates in catalysis are investigated by a detailed analysis of their13C‐NMR chemical shift tensors. This analysis allows evidencing specific electronic features, namely the olefin‐to‐metalσ‐donation and the metal‐to‐olefinπ‐backdonation as proposed in theDewar−Chatt−Duncansonmodel. Apart from these interactions, the chemical shift tensor analysis reveals an additional ligand‐to‐metalπ‐donation of the olefinσ(C=C) orbital in systems with suitably oriented vacant d‐orbitals. This interaction which is not accounted for in theDewar−Chatt−Duncansonmodel explains the reactivity of this type of metal olefin complexes towards oxidative cyclization (olefin insertion) and protonolysis.

Stabilized Ru[(H2O)6]3+ in Confined Spaces (MOFs and Zeolites) Catalyzes the Imination of Primary Alcohols under Atmospheric Conditions with Wide Scope

Imines are ubiquitous intermediates in organic synthesis, and the metal–mediated imination of alcohols is one of the most direct and simple methods for their synthesis. However, reported protocols lack compatibility with many other functional groups since basic supports/media, pure oxygen atmospheres, and/or released hydrogen gas are required during reaction. Here we show that, in contrast to previous metal-catalyzed methods, hexa-aqueous Ru(III) catalyzes the imination of primary alcohols with very wide functional group tolerance, at slightly acid pH and under low oxygen atmospheres. The inorganic metal complex can be supported and stabilized, integrally, within either faujasite-type zeolites (Y and X) or a metal organic framework (MOF), to give a reusable heterogeneous catalyst which provides an industrially viable process well below the flammability limit of alcohols and amines.

Direct Characterization of a Reactive Lattice-Confined Ru2 Nitride by Photocrystallography.

Reactive metal-ligand (M-L) multiply bonded complexes are ubiquitous intermediates in redox catalysis and have thus been long-standing targets of synthetic chemistry. The intrinsic reactivity of mid-to-late M-L multiply bonded complexes renders these structures challenging to isolate and structurally characterize. Although synthetic tuning of the ancillary ligand field can stabilize M-L multiply bonded complexes and result in isolable complexes, these efforts inevitably attenuate the reactivity of the M-L multiple bond. Here, we report the first direct characterization of a reactive Ru2 nitride intermediate by photocrystallography. Photogeneration of reactive M-L multiple bonds within crystalline matrices supports direct characterization of these critical intermediates without synthetic derivatization.

Lithium Enolates in the Enantioselective Construction of Tetrasubstituted Carbon Centers with Chiral Lithium Amides as Noncovalent Stereodirecting Auxiliaries.

Lithium enolates derived from carboxylic acids are ubiquitous intermediates in organic synthesis. Asymmetric transformations with these intermediates, a central goal of organic synthesis, are typically carried out with covalently attached chiral auxiliaries. An alternative approach is to utilize chiral reagents that form discrete, well-defined aggregates with lithium enolates, providing a chiral environment conducive of asymmetric bond formation. These reagents effectively act as noncovalent, or traceless, chiral auxiliaries. Lithium amides are an obvious choice for such reagents as they are known to form mixed aggregates with lithium enolates. We demonstrate here that mixed aggregates can effect highly enantioselective transformations of lithium enolates in several classes of reactions, most notably in transformations forming tetrasubstituted and quaternary carbon centers. Easy recovery of the chiral reagent by aqueous extraction is another practical advantage of this one-step protocol. Crystallographic, spectroscopic, and computational studies of the central reactive aggregate, which provide insight into the origins of selectivity, are also reported.

ChemInform Abstract: Use of EPR Spectroscopy to Unravel Reaction Mechanisms in (Catalytic) Bond Activation Reactions: Some Selected Examples

AbstractReview: 92 refs.

Use of EPR Spectroscopy to Unravel Reaction Mechanisms in (Catalytic) Bond Activation Reactions: Some Selected Examples

Paramagnetic species are ubiquitous intermediates in many different reactions involving chemical bond activation and catalysis. Despite this fact, the use of electron paramagnetic resonance (EPR) spectroscopy for unraveling reaction mechanisms for homogeneous catalytic reactions has been rather limited. This overview article details several areas dealing with small molecule activation in the homogeneous medium where EPR spectroscopy is potentially useful and has sometimes been used. We will present various examples from the literature to show the usefulness of this method in studying the activation and possible fixation of small molecules such as H2, O2, and N2. Additionally, some examples related to nitridyl radicals and their relation with carbene radicals will also be discussed with a focus on their detection through EPR spectroscopy. We will present the usefulness and the limitations of this method by discussing selected examples from the literature. This is not meant to be a comprehensive review.

Extending the Kynurenine Pathway to an Aldehyde Disarming Enzyme: Mechanistic Study of Bacterial AMSDH and Identification of the Correct Human Enzyme

Aldehydes are ubiquitous intermediates in metabolic pathways, and their innate reactivity can often make them quite unstable. There are several aldehydic intermediates in the metabolic pathway for tryptophan degradation which can decay into neuroactive compounds that have been associated with numerous neurological diseases, such as quinolinic acid (QUIN). An enzyme of this pathway, 2-aminomuconate-6-semialdehyde dehydrogenase, which is responsible for ‘disarming’ the final aldehydic intermediate, has yet to be studied at the molecular level. Its activity steers the vast majority of metabolic flux to further catabolism and prevents overproduction of a metabolic dead-end, picolinic acid. In this presentation we will show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms, two of which are covalently-bound, substrate-enzyme adducts. The crystal- and solution-state spectroscopic data along with the crystal structures also reveal that the substrate must undergo an isomerization reaction prior to oxidation. This study provides an in-depth mechanistic understanding of an anticipated dehydrogenase in the kynurenine pathway.

Crystallographic and spectroscopic snapshots reveal a dehydrogenase in action.

Aldehydes are ubiquitous intermediates in metabolic pathways and their innate reactivity can often make them quite unstable. There are several aldehydic intermediates in the metabolic pathway for tryptophan degradation that can decay into neuroactive compounds that have been associated with numerous neurological diseases. An enzyme of this pathway, 2-aminomuconate-6-semialdehyde dehydrogenase, is responsible for ‘disarming’ the final aldehydic intermediate. Here we show the crystal structures of a bacterial analogue enzyme in five catalytically relevant forms: resting state, one binary and two ternary complexes, and a covalent, thioacyl intermediate. We also report the crystal structures of a tetrahedral, thiohemiacetal intermediate, a thioacyl intermediate and an NAD+-bound complex from an active site mutant. These covalent intermediates are characterized by single-crystal and solution-state electronic absorption spectroscopy. The crystal structures reveal that the substrate undergoes an E/Z isomerization at the enzyme active site before an sp3-to-sp2 transition during enzyme-mediated oxidation.

The role of preadaptations or evolutionary novelties for the evolution of sexually deceptive orchids.

The role of preadaptations or evolutionary novelties for the evolution of sexually deceptive orchids.

Hydrogen Forms in Water by Proton Transfer to a Distorted Electron

Solvated electrons are ubiquitous intermediates in radiation-induced processes, with their lifetime being determined by quenching processes, such as the direct reaction with protons under acidic conditions. Ab initio molecular dynamics simulations allow us to unravel with molecular resolution the ultrafast reaction mechanism by which the electron and proton react in water. The path to a successful reaction involves a distortion and contraction of the hydrated electron and a rapid proton motion along a chain of hydrogen bonds, terminating on the water molecule most protruding into the electron cloud. This fundamental reaction is thus decidedly shown to be of a proton-transfer rather than electron-transfer character. Due to the desolvation penalty connected with breaking of the hydration shells of these charged particles, the reaction is, however, not diffusion-limited, in agreement with the interpretation of kinetics measurements.

The role and characterization of phospholipase A1 in mediating lysophosphatidylcholine synthesis in Trypanosoma brucei

Lysophospholipids are ubiquitous intermediates in a variety of metabolic and signalling pathways in eukaryotic cells. We have reported recently that lysoglycerophosphatidylcholine (lyso-GPCho) synthesis in the insect form of the ancient eukaryote Trypanosoma brucei is mediated by a novel phospholipase A1 (TbPLA1). In the present study, we show that despite equal levels of TbPLA1 gene expression in wild-type insect and bloodstream trypomastigotes, both TbPLA1 enzyme levels and lysoGPCho metabolites are approx. 3-fold higher in the bloodstream form. Both of these parasite stages synthesize identical molecular species of lysoGPCho. TbPLA1 null mutants in the bloodstream form of the parasite are viable, but are deficient in lysoGPCho synthesis, a defect that can be overcome by the expression of an ectopic copy of TbPLA1. The biochemical attributes of TbPLA1-mediated lysoGPCho synthesis were examined in vitro using recombinant TbPLA1. Although TbPLA1 possesses an active-site serine residue, it is insensitive to serine-modifying reagents, such as di-isopropyl fluorophosphate and PMSF, a characteristic shared by lipases that possess lid-sheltered catalytic triads. TbPLA1 does not require metal co-factors for activity, but it does require interfacial activation prior to catalysis. Results from size-exclusion chromatography and binding kinetics analysis revealed that TbPLA1 activation by Triton X-100/GPCho mixed micelle surfaces was not specific and did not require the pre-formation of a specific enzyme-substrate complex to achieve surface binding.

Recognition of Isopentenylpyrophosphate and Daudi Tumor Cells By Distinct Subsets of Vγ2/Vδ2 T Cells

Gammadelta (γδ) T cells account for 1–10% of CD3+ lymphocytes in the peripheral blood and mostly express a heterodimeric T cell receptor (TCR) with Vγ2+ and Vδ2+ chains. Although the Vγ2/Vδ2 subset is defined by the shared expression of common TCR gene segments, these TCRs are highly diverse due to characteristic N nucleotide insertion and deletion at the complementarity-determining region 3 (CDR3) of both γand δ-chains. Vγ2/Vδ2 T cells recognize alkylphosphates that are ubiquitous intermediates in isoprenoid biosynthesis and tumor cells derived from hematopoietic malignancies in a non MHCrestricted, TCR-dependent manner. Previous work from our lab demonstrated that a model alkylphosphate, isopentenylpyrophosphate (IPP), specifically selects Jγ1.2+ chains and selectively skews the Vγ2 repertoire toward longer chain lengths. We assumed that Vγ2/Vδ2 recognition of alkylphosphates and tumor cells was common and hypothesized that Daudi B cells, the model tumor target for Vγ2/Vδ2 T cells, would similarly promote the outgrowth of Vγ2/Vδ2 lymphocytes with longer, Jγ1.2 Vγ2 TCRs. Peripheral blood mononuclear cells (PBMC) from 6 donors were stimulated in vitro with interleukin-2 (IL2) alone, IL2 and IPP, or IL2 and irradiated (120 Gy) Daudi tumor cells. The frequency of Vγ2/Vδ2 lymphocytes increased from 5.8 ± 7.8% on Day 0 to 5.5 ± 5.9%, 34 ± 32%, 47 ± 27% after 2 weeks in culture with IL2, IL2+IPP or IL2+Daudi, respectively. RNA was extracted before and after stimulation, Vγ2 and ζδ2 chains were amplified from reverse transcribed cDNA, and spectratype analysis was performed to assess changes in the distribution of Vg2 CDR3 lengths. IPP and Daudi similarly skewed the Vγ2 repertoire toward longer chain lengths, while not affecting the overall distribution of Vδ2 chain lengths. Comparison of Vγ2 CDR3 sequences from three donors suggest that recognition of IPP and Daudi is mediated by two distinct subsets of Vγ2/Vδ2 T cells, thus overturning the prevailing model for gd T cell recognition of tumors. Collectively, these experiments help clarify the role of Vγ2 CDR3 specificity in alkylphosphate and tumor recognition and demonstrate that discrete subsets of Vγ2/Vδ2 T cells mediate alkylphosphate and tumor responsiveness. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

Single-crystal neutron diffraction on sigma complexes: recent results from IPNS

E-mail: tkoetzle@anl.gov For a number of years we have been employing single-crystal neutron diffraction to investigate structures of sigma complexes of transition metals. Sigma complexes are of special interest because they are ubiquitous intermediates in metal-catalyzed reactions including hydrogenations, activation and functionalization of hydrocarbons, and hydroborations. Here we will report on some recent results obtained using the SCD instrument at Argonne’s Intense Pulsed Neutron Source, which has been upgraded with two new position-sensitive Anger detectors to achieve increased data collection efficiency. In the future, we hope to be able to dramatically extend these studies at the Spallation Neutron Source (SNS) using the single-crystal diffractometer (Topaz) that is currently under development there.

Single-crystal neutron diffraction: a valuable tool for probing bond activation in transition metal σ complexes

Transition metal σ complexes are ubiquitous intermediates in metal-catalyzed reactions, including hydrogenations, activation and functionalization reactions of hydrocarbons, and hydroborations. For over 20 years, single-crystal neutron diffraction has been exploited to investigate bond activation in these systems. Topics investigated include H–H activation in H 2 complexes, C–H activation in agostic systems and, most recently, B–H activation in a catecholborane metal complex. These results are illustrated here drawing upon studies carried out at both pulsed neutron sources and steady-state reactors. Despite notable successes such as those that we highlight, however, single-crystal neutron diffraction has seen somewhat limited application here to date primarily due to the need for large crystals. Revolutionary improvements are anticipated with the advent of a new generation of sources including the Spallation Neutron Source (SNS) that is scheduled to become operational at Oak Ridge, TN in 2006. At the SNS, it will be possible to work with crystals approaching the size commonly used in X-ray studies employing laboratory sources and to greatly expand the range of materials that are open to investigation.

Physical organic photochemistry

Physical organic photochemistry has been concerned with the systematic investigation of structure-reactivity relationships involved in the photophysics and photochemistry of organic molecules. The field relies heavily on the use of physical and computational methods to elucidate mechanistic pathways that allow an understanding of the molecular basis of observed or predicted structure-reactivity relationships. Determination of rate laws through kinetic analysis, syntheses of “tailor made” structures to test theories or mechanisms, and the use of product structure has been the dominant tool in physical organic chemistry and has shown similar validity in physical organic photochemistry. Reactive intermediates, which were postulated to explain observed products, have played an important role in the development of physical organic chemistry. In physical organic photochemistry these reactive intermediates have often been directly detected by time resolved spectroscopic methods. During the 1960s the methods of physical organic photochemistry typically involved steady state kinetics, product analysis and the assumption of triplets as ubiquitous intermediates. During the 1970s time resolved methods became available and traditional reactive intermediates (carbenes, ylides, radicals, biradicals etc.) became accessible to direct spectroscopic observation, characterization and investigation. In addition, singlet states, exciplexes and radical ions were added to the list of commonly occurring reactive intermediates. There was a shift in the theoretical framework for thinking about photochemical reactions from the state diagram level to the energy surface level. During the 1980s the use of sophisticated instrumentation and time resolution of the order of nanoseconds became more common. During this period the pervasive occurrence of electron transfer processes in organic photochemical reactions became apparent, and reactive intermediates such as contact ion pairs and solvent separated ion pairs became familiar in a variety of reactions. A major change occurred as photochemists began to investigate photoprocesses occurring in microheterogeneous systems such as micelles, cyclodextrins, polymers, and porous solids. It was discovered that weak magnetic fields can strongly modify photoprocesses which occur in microheterogeneous media if radical pairs or biradicals are involved . Since my last review in 1984, the basic paradigms for investigating organic photochemistry have not changed very much, but advances in instrumentation have continued to have a major impact on the field. For example