Single-electron Steps Research Articles

Unlocking carbene reactivity by metallaphotoredox α-elimination.

The ability to tame high-energy intermediates is important for synthetic chemistry, enabling the construction of complex molecules and propelling advances in the field of synthesis. Along these lines, carbenes and carbenoid intermediates are particularly attractive, but often unknown, high-energy intermediates1,2. Classical methods to access metal carbene intermediates exploit two-electron chemistry to form the carbon-metal bond. However, these methods are usually prohibitive because of reagent safety concerns, limiting their broad implementation in synthesis3-6. Mechanistically, an alternative approach to carbene intermediates that could circumvent these pitfalls would involve two single-electron steps: radical addition to metal to forge the initial carbon-metal bond followed by redox-promoted α-elimination to yield the desired metal carbene intermediate. Here we realize this strategy through a metallaphotoredox platform that exploits iron carbene reactivity using readily available chemical feedstocks as radical sources and α-elimination from six classes of previously underexploited leaving groups. These discoveries permit cyclopropanation and σ-bond insertion into N-H, S-H and P-H bonds from abundant and bench-stable carboxylic acids, amino acids and alcohols, thereby providing a general solution to the challenge of carbene-mediated chemical diversification.

A Germapyramidane Switches Between 3D Cluster and 2D Cyclic Structures in Single-Electron Steps.

Reaction of the imidazolium-substituted iphosphate-diide, (Ipr)2 C2 P2 (IDP), with GeCl2 ⋅ dioxane and KBArF24 [(BarF24 )- =tetrakis[(3,5-trifluoromethyl)phenyl]borate)] afforded the dicationic spherical-aromatic nido-cluster [Ge(η4 -IDP)]2+ ([1]2+ ) (Ipr=1,3-bis(2,6-diisopropylphenyl)imidazolium-2-ylidene). This complex is a rare heavy analogue of the elusive pyramidane [C(η4 -C4 H4 )]. [1]2+ undergoes two reversible one-electron reductions, which yield the radical cation [2]⋅+ and the neutral GeII species 3. Both [2]⋅+ and 3 rearrange in solution forming the 2D aromatic and planar imidazolium-substituted digermolide [4]2+ and germole-diide 5, respectively. Both planar species can be oxidized back to [1]2+ using AgSbF6 . These redox-isomerizations correspond to the fundamental transformation of a 3D aromatic cluster into a 2D aromatic ring compound upon reduction and vice versa. The mechanism of these reactions was elucidated using DFT calculations and cyclic voltammetry experiments.

Kinetics and mechanism of oxidation of hypophosphite by tetrabutylammonium tribromide

The reaction between tetrabutylammonium tribromide and hypophosphite was studied in 50% (v/v) acetic acid under second order conditions. The overall order of reaction was found to be two, unity each in both the reactants. The reaction was found to involve direct two electron transfer step as the test for formation of free radicals due to single electron step was negative. The hypophosphorous acid (H3PO2) in aqueous solution dissociates to give H2PO2- and in the present study, as the acetic acid content increases, the rate of the reaction decreases. The plot of 1/ks against [H+] was found to be linear with an intercept. These observations suggest that the undissociated phosphorus acid is the active reductant species whose concentration decreases as the pH of the solution increases, thus resulting in a decrease of the rate constant. The activation parameters for the reaction were also determined by the studying the reaction at different temperature and it was found that there is considerable decrease in the entropy of the reaction. Such a decrease in the entropy is the explained by considering an ordered transition state between the reactants.

A Guide to Low‐Valent Titanocene Complexes as Tunable Single‐Electron Transfer Catalysts for Applications in Organic Chemistry

AbstractLow‐valent titanocene catalysts are a versatile tool for organic synthesis. They promote inter‐ and intramolecular reactions ranging from homolytic bond cleavages to reductive umpolung reactions to additions and cyclizations in single electron steps. These reactions heavily depend on the redox potential of an in situ formed titanium(III) center, which can be adjusted by the choice of appropriate ligands. We herein review various chiral and achiral ligand‐modified titanocene catalysts and their reduction potentials Ep/2 obtained via cyclic voltammetry. The latter are found to correlate with the Hammett parameters σp of the cyclopentadienyl substituents and to the pKa values of the corresponding acids of the Ti−X ligands. For selected examples, we further discuss how the adjustment of the redox properties through modifications of the titanocene ligands can lead to greatly improved reaction outcomes in titanium(III) catalyzed single‐electron transfer reactions.

Catalytic reductive ring opening of epoxides enabled by zirconocene and photoredox catalysis

Catalytic reductive ring opening of epoxides enabled by zirconocene and photoredox catalysis

Merging Carbonyl Addition with Photocatalysis.

The carbonyl group stands as a fundamental scaffold and plays a ubiquitous role in synthetically important chemical reactions in both academic and industrial contexts. Venerable transformations, including the aldol reaction, Grignard reaction, Wittig reaction, and Nozaki-Hiyama-Kishi reaction, constitute a vast and empowering synthetic arsenal. Notwithstanding, two-electron mechanisms inherently confine the breadth of accessible reactivity and topological patterns.Fostered by the rapid development of photoredox catalysis, combing well-entrenched carbonyl addition and radicals can harness several unique and increasingly sustainable transformations. In particular, unusual carbon-carbon and carbon-heteroatom disconnections, which are out of reach of two-electron carbonyl chemistry, can be conceived. To meet this end, a novel strategy toward the utilization of simple carbonyl compounds as intermolecular radical acceptors was developed. The reaction is enabled by visible-light photoredox-initiated hole catalysis. In situ Brønsted acid activation of the carbonyl moiety prevents β-scission from occurring. Furthermore, this regioselective alkyl radical addition reaction obviates the use of metals, ligands, or additives, thus offering a high degree of atom economy under mild conditions. On the basis of the same concept and the work of Schindler and co-workers, carbonyl-olefin cross-metathesis, induced by visible light, has also been achieved, leveraging a radical Prins-elimination sequence.Recently, dual chromium and photoredox catalysis has been developed by us and Kanai, offering a complementary approach to the revered Nozaki-Hiyama-Kishi reaction. Leveraging the intertwined synergy between light and metal, several radical-to-polar crossover transformations toward eminent molecular motifs have been developed. Reactions such as the redox-neutral allylation of aldehydes and radical carbonyl alkylation can harvest the power of light and enable the use of catalytic chromium metal. Overall, exquisite levels of diastereoselectivity can be enforced via highly compact transition states. Other examples, such as the dialkylation of 1,3-dienes and radical carbonyl propargylation portray the versatile combination of radicals and carbonyl addition in multicomponent coupling endeavors. Highly valuable motifs, which commonly occur in complex drug and natural product architectures, can now be accessed in a single operational step. Going beyond carbonyl addition, seminal contributions from Fagnoni and MacMillan preconized photocatalytic HAT-based acyl radical formation as a key aldehyde valorization strategy. Our group articulated this concept, leveraging carboxy radicals as hydrogen atom abstractors in high regio- and chemoselective carbonyl alkynylation and aldehyde trifluoromethylthiolation.This Account, in addition to the narrative of our group and others' contributions at the interface between carbonyl addition and radical-based photochemistry, aims to provide core guiding foundations toward novel disruptive synthetic developments. We envisage that extending radical-to-polar crossovers beyond Nozaki-Hiyama-Kishi manifolds, taming less-activated carbonyls, leveraging multicomponent processes, and merging single electron steps with energy-transfer events will propel eminent breakthroughs in the near future.

High-resolution longitudinal profile diagnostics for ultralow charges stored in a ring

Observations of optical synchrotron radiation emitted over millions of passes from a few electrons circulating in the particle accumulator ring at the Advanced Photon Source were performed with a digital CMOS camera and a synchroscan streak camera operating at 117.3 MHz. Discrete changes of integrated counts in the CMOS image region of interest are ascribed to single electron steps in a 10-s sensor integration time. Circulations of a single electron at 375 and at 425 MeV were demonstrated in the 12-bit digital CMOS camera images. The streak camera operating at the 12th harmonic of the fundamental revolution frequency at 9.77 MHz was used to measure the bunch length from 0.5-nC circulating charge down to tens of electrons or $<10\text{ }\text{ }\mathrm{aC}$. The measurements were performed with $\ensuremath{\sim}8\text{\ensuremath{-}}\mathrm{ps}$ temporal resolution uniquely at such ultralow charges. These results also serve as a proof-of-principle longitudinal profile diagnostic for the predicted effects of optical stochastic cooling at low charge in commissioning experiments at the Fermilab Integrable Optics Test Accelerator ring.

From Enantioselective to Regiodivergent Epoxide Opening and Radical Arylation – Useful or Just Interesting?

It is shown how the simple titanocene(III)-catalyzed reductive opening of epoxides has developed from a highly selective desymmetrizing opening of meso-epoxides. The combination of the origins of regioselectivity with atom-economic catalysis in single electron steps results in a highly selective regiodivergent epoxide opening (REO).1 Introduction2 Regiodivergent Epoxide Opening3 Atom Economy and Epoxide Arylation4 REO Arylation5 Words about the Wording6 Conclusion

Electrocatalysis of the first electron transfer in hydrogen evolution reaction with an atomically precise CuII-organic framework catalyst

Developing atomically precise catalysts for hydrogen evolution reaction (HER) will help understand the catalytic reaction mechanisms for guiding the synthesis of new HER catalysts. A Cu-based metal-organic framework (CuII-MOF) consisting of trinuclear mixed-ligand units was prepared under hydrothermal conditions, and the structure, morphology, and elemental composition were characterized by (single crystal) XRD, TEM, SEM, XPS, BET, TGA and ATR-FTIR. Doping of 9.2 wt% CuII-MOF powder into the carbon paste electrode caused a roughly 440 mV positive shift of the HER potential at 10 mA cm−2 in 1.0 M H2SO4. The CuII-MOF showed a high working stability due to the dual-ligand-protected Cu active centers. The intrinsic catalytic mechanism was investigated by Tafel slope analysis, solid state electrochemistry and electrochemical impedance spectroscopy. The CuII ions in the CuII-MOF are successively reduced through two single-electron steps over a potential range of 0.7 to 0.1 V vs. RHE to form single-atom Cu0 active centers, on which adsorbed H atoms can be generated with a positive onset potential of about 100 mV vs. RHE through a following chemical redox reaction. The mechanistic findings point out the necessity and feasibility of developing bicomponent or bifunctional MOF-based catalysts to efficiently accelerate both the first and second electron transfer steps of HER.

Condition Screening for Sustainable Catalysis in Single-Electron Steps by Cyclic Voltammetry: Additives and Solvents.

Cyclic voltammetry-based screening method for Cp2 TiX-catalyzed reactions is extended to the screening of solvents other than tetrahydrofuran for bulk electrolysis of the catalyst and radical arylation. It was found that CH3 CN can be used as a solvent for both processes without additives. Furthermore, in tetrahydrofuran, squaramide L2 is more efficient than the previously reported supramolecular halide binder, Schreiner's thiourea L1. The results extend the usefulness of the proposed time and resource-efficient screening method for designing catalysis reactions in single-electron steps.

Merging Catalysis in Single Electron Steps with Photoredox Catalysis—Efficient and Sustainable Radical Chemistry

We describe a combination of catalysts that allows the coupling of titanocene(III) catalysis with photoredox catalysis. Oxidation of radical intermediates by a photoredox catalyst opens novel catal...

Electrochemistry of Iodide in LiCl-KCl Molten Salts and Chemla Effect: An Overview

Several radioactive iodine isotopes are formed as fission products in the nuclear fuel, and retained within the fuel matrix by the fuel cladding as containment. During reprocessing of the used fuels by the pyroprocessing route, a significant fraction of iodine is reported to be retained in the molten salt as iodide (I-). The oxidation of I- is strongly influenced by the Cl-. When Cl- concentration is in excess of I-, the iodide oxidizes to [ICl2]- in two single electron steps via an [I2Cl]- intermediate. The presence of chloride leads to oxidation of I3 - to occur at less positive potentials. Chemla effect of type 1 has been observed in the LiCl-KCl molten salt systems wherein the mobility of the K+ is larger than that of Li+ when the fraction of KCl is higher than 0.325 at 723 K. The Chemla effect could lead to accumulation of KCl near the cathode and adversely influence the electrolytic parameters.

Mechanism‐Based Condition Screening for Sustainable Catalysis in Single‐Electron Steps by Cyclic Voltammetry

A cyclic-voltammetry-based screening method for Cp2 TiX-catalyzed reactions is introduced. Our mechanism-based approach enables the study of the influence of various additives on the electrochemically generated active catalyst Cp2 TiX, which is in equilibrium with catalytically inactive [Cp2 TiX2 ]- . Thioureas and ureas are most efficient in the generation of Cp2 TiX in THF. Knowing the precise position of the equilibrium between Cp2 TiX and [Cp2 TiX2 ]- allowed us to identify reaction conditions for the bulk electrolysis of Cp2 TiX2 complexes and for Cp2 TiX-catayzed radical arylations without having to carry out the reactions. Our time- and resource-efficient approach is of general interest for the design of catalytic reactions that proceed in single-electron steps.

Cp2TiX Complexes for Sustainable Catalysis in Single‐Electron Steps

AbstractInvited for the cover of this issue are the groups of Robert Flowers at Lehigh University and Andreas Gansäuer at Universität Bonn. The image depicts a titanocene complex picking the best “fruit” from a selection of anions for catalysis. Read the full text of the article at 10.1002/chem.201705707.

Cp2 TiX Complexes for Sustainable Catalysis in Single-Electron Steps.

We present a combined electrochemical, kinetic, and synthetic study with a novel and easily accessible class of titanocene catalysts for catalysis in single-electron steps. The tailoring of the electronic properties of our Cp2 TiX-catalysts that are prepared in situ from readily available Cp2 TiX2 is achieved by varying the anionic ligand X. Of the complexes investigated, Cp2 TiOMs proved to be either equal or substantially superior to the best catalysts developed earlier. The kinetic and thermodynamic properties pertinent to catalysis have been determined. They allow a mechanistic understanding of the subtle interplay of properties required for an efficient oxidative addition and reduction. Therefore, our study highlights that efficient catalysts do not require the elaborate covalent modification of the cyclopentadienyl ligands.

Electron Accumulative Molecules.

With the goal to produce molecules with high electron accepting capacity and low reorganization energy upon gaining one or more electrons, a synthesis procedure leading to the formation of a B-N(aromatic) bond in a cluster has been developed. The research was focused on the development of a molecular structure able to accept and release a specific number of electrons without decomposing or change in its structural arrangement. The synthetic procedure consists of a parallel decomposition reaction to generate a reactive electrophile and a synthesis reaction to generate the B-N(aromatic) bond. This procedure has paved the way to produce the metallacarboranylviologen [M(C2B9H11)(C2B9H10)-NC5H4-C5H4N-M'(C2B9H11)(C2B9H10)] (M = M' = Co, Fe and M = Co and M' = Fe) and semi(metallacarboranyl)viologen [3,3'-M(8-(NC5H4-C5H4N-1,2-C2B9H10)(1',2'-C2B9H11)] (M = Co, Fe) electron cumulative molecules. These molecules are able to accept up to five electrons and to donate one in single electron steps at accessible potentials and in a reversible way. By targeted synthesis and corresponding electrochemical tests each electron transfer (ET) step has been assigned to specific fragments of the molecules. The molecules have been carefully characterized, and the electronic communication between both metal centers (when this situation applies) has been definitely observed through the coplanarity of both pyridine fragments. The structural characteristics of these molecules imply a low reorganization energy that is a necessary requirement for low energy ET processes. This makes them electronically comparable to fullerenes, but on their side, they have a wide range of possible solvents. The ET from one molecule to another has been clearly demonstrated as well as their self-organizing capacity. We consider that these molecules, thanks to their easy synthesis, ET, self-organizing capacity, wide range of solubility, and easy processability, can find important application in any area where ET is paramount.

ChemInform Abstract: Active Species and Mechanistic Pathways in Iron‐Catalyzed C—C Bond‐Forming Cross‐Coupling Reactions

AbstractReview: 81 refs.

Active Species and Mechanistic Pathways in Iron-Catalyzed C–C Bond-Forming Cross-Coupling Reactions

Over the past decade, considerable progress on iron-catalyzed C–C bond-forming cross-coupling reactions has been made, leading to the successful development of several new catalytic systems. This perspective presents the proposed mechanistic pathways of iron-mediated cross-coupling reactions of organohalides and Grignard reagents and discusses the evidence documented in the literature that distinguishes whether such pathways proceed via single- or double-electron processes. When cross-coupling reactions are conducted in the presence of ligands, there is still much discussion in the literature as to whether the lowest iron oxidation state responsible for catalytic activity is Fe(I) or Fe(II). However, when ligand-free conditions are employed, it has been shown that iron reaches an Fe(I) oxidation state, allowing an Fe(I)/Fe(III) catalytic cycle. Moreover, for cross-couplings using alkyl halide electrophiles, evidence suggests that the reaction proceeds through single-electron steps, with the generation of ...

Cationic Titanocene(III) Complexes for Catalysis in Single-Electron Steps.

By exploiting solvent and anion effects, [Cp2Ti](+) complexes for atom-economical catalysis in single-electron steps were developed and applied for the first time. These complexes constitute remarkably stable and active catalysts for radical arylations. The reaction kinetics and catalyst composition were studied by cyclic voltammetry and in situ IR spectroscopy.

Cytomics of the tumour microenvironment: therapeutic targeting (keynote lecture)

There is a growing appreciation of the influence of both the tumour microenvironment and the dynamic nature of the cellular micro-community in determining tumour progression and therapeutic resistance. Changes in cell heterogeneity, resulting from time-varying changes in the microenvironment, present complex challenges for cancer therapy. For example, the tumour micro-community comprises multiple levels of cellular interactions overlaid with pervading influences such as variation in the levels of oxygenation. Molecular targeting combined with agents that target the microenvironment offer novel approaches. The presentation focused on two examples supported by cytometric techniques. First, dissecting the influences of cellular interactions on tumour progression-related cell behavior. An in vitro, non-adherent small cell lung cancer (SCLC) cell model system enabled the engineering of cellular micro-communities. SCLC cells show surface expression of a potential drug target, polysialylated neural cell adhesion molecule (NCAM; NCAM1 or CD56). The extensive addition of polysialic acid (polySia) to NCAM in SCLC decreases membrane apposition, cell adhesion and enables cell migration. Cytometric studies reveal heterogeneity in the expression of polySia in SCLC cell populations that can be related to proliferation potential both in vitro and in vivo. In constructed 3-D micro-communities, polySia expression was driven in non-expressing variants by the presence of over-expressing subpopulations. This suggests that a degree of homeostasis operates with implications for polySia-NCAM-targeted therapies. The second example addressed the targeting of hypoxia for therapeutic advantage using a novel hypoxia activated prodrug (HAP) technology. Hypoxia in tumour regions, arising from loss of vascularity, generates drug resistant phenotypes. Targeting hypoxic tumour cells using HAPs has been previously attempted using a diverse group of chemicals based mainly on structures with alkylating functionality. Crucially most of these agents are reduced in single electron steps by a number of enzymes including cytochrome P450 reductase. This produces prodrug conversion to species that bind covalently to DNA. Critically, the cytotoxins generated do not persist such that targeted cells upon re-oxygenation may contribute to tumour regrowth. We have developed the concept of a unidirectional hypoxia activated prodrug (uHAP), building upon experience with di-N-oxides of tertiary amine anthraquinones, to develop the novel agent OCT1002. The uHAP represents a distinct class of HAP, reduced to a cytotoxic species through an irreversible two-step process, each involving a two-electron reduction. The bioactive reduction products inhibit DNA processing and topoisomerase II activity, selectively causing cancer cell death. The presentation explored the application of cytometric methods to reveal the mechanisms of action of OCT1002 and to provide an insight into the targeting of hypoxic regions of prostate and pancreatic cancers. The above examples highlight the importance of cell-based approaches in the development of therapeutic strategies that address changing patterns of target presentation in different cellular microenvironments. [PJS acknowledges the contributions of Prof. Rachel Errington (Cardiff University); Prof. Stephanie McKeown (University of Ulster) and Robert Falconer (Bradford University)].