Discovery Of Reactions Research Articles

Organic and Organometallic Chemistry at the Single-Molecule, -Particle, and -Molecular-Catalyst-Turnover Level by Fluorescence Microscopy.

Mechanistic studies have historically played a key role in the discovery and optimization of reactions in organic and organometallic chemistry. However, even apparently simple organic and organometallic transformations may have surprisingly complicated multistep mechanisms, increasing the difficulty of extracting this mechanistic information. The resulting reaction intermediates often constitute a small fraction of the total reaction mixture, for example, creating a long-term analytical challenge of detection. This challenge is particularly pronounced in cases where the positions of intermediates on the reaction energy surface mean that they do not "build up" to the quantities needed for observation by traditional ensemble analytical tools. Thus, their existence and single-step elementary reactivity cannot be studied directly. New approaches for obtaining this otherwise-missing mechanistic information are therefore needed. Single-turnover, single-molecule, single-particle, and other subensemble fluorescence microscopy techniques are ideally suited for this role because of their sensitivity and spatiotemporal resolution. Inspired by the robust development of single-molecule fluorescence microscopy tools for studying enzyme catalysis, our laboratory has developed analogous fluorescence microscopy techniques to overcome mechanistic challenges in synthetic chemistry, with sensitivity as high as the single-complex, single-turnover, and single-molecule level. These techniques free the experimenter from the previous restriction that intermediates must "build up" to quantities needed for detection by ensemble analytical tools and are suited to systems where synchronization through flash photolysis or stopped flow would be inconvenient or inaccessible. In this process, the techniques transform certain previously "unobservable" intermediates and their elementary single-step reactivities into "observable" ones through sensitive and selective spectral handles. Our program has focused on imaging reactions in small-molecule, organic, and polymer synthetic chemistry with an accent on the reactivity of molecular transition metal complexes and catalysts. Our laboratory initiated studies in this area in 2008 with the imaging of individual palladium complexes that were tagged with spectator fluorophores. To enable imaging, we started with fluorophore selection and development, overcame challenges with imaging in organic solvents, and developed strategies compatible with air-sensitive chemistry and concentrations of reagents generally used in small-molecule synthesis. These studies grew to include characterization of previously unknown organometallic intermediates in the synthesis of organozinc reagents and the direct study of their elementary-step reactivity. The ability to directly observe this behavior generated predictive power for selecting salts that accelerated organozinc reagent formation in synthesis, including salts that had not yet been reported synthetically. In 2017 we also developed the first single-turnover imaging of molecular (chemo)catalysts, which through the technique's spatiotemporal resolution revealed abruptly time-variable polymerization kinetics wherein molecular ruthenium ring-opening metathesis polymerization (ROMP) catalysts changed rates independently from other catalysts less than 1 μm away. Individual catalytic turnovers, each corresponding to one single-chain-elongation reaction arising from insertion of single ROMP or enyne monomers at individual Grubbs II molecular ruthenium catalysts, were spatiotemporally resolved as green flashes in growing polymers. In this Account, we discuss the development of this technique from idea to application, including challenges overcome and strategies created to image synthetic organic and organometallic molecular chemistry at the highest levels of detection sensitivity. We also describe challenges not yet solved and provide an outlook for this growing field at the intersection of microscopy and synthetic/molecular chemistry.

Application of Complexes of Group 13 Elements in Synthetic Organic Chemistry for Activation of Carbonyl Compounds

The main aspects of modern organic chemistry of the Group 13 elements – aluminum (Al), gallium (Ga), indium (In), and thallium (Tl) – are considered. Herewith, the main emphasis is placed on their use for the various carbonyl compounds activation in organic synthesis and reactions, which are specific for these elements. The 21th century marked a new era in the development of chemistry of the Group 13 elements; it is connected with the discovery of surprising and unexpected reactions and new compounds (primarily in the area of organic and coordination chemistry), defining various fields of these elements application.

The Emergence of Carbon Isotope Exchange.

Significant progress in C-C bond activation with transition metals has recently enabled the development of several carbon isotope exchange reactions. These methods are based on C-C bond decarboxylative carboxylation reactions in the presence of selected transition metals and labelled carbon monoxide or carbon dioxide.

Interactive molecular dynamics in virtual reality from quantum chemistry to drug binding: An open-source multi-person framework.

As molecular scientists have made progress in their ability to engineer nanoscale molecular structure, we face new challenges in our ability to engineer molecular dynamics (MD) and flexibility. Dynamics at the molecular scale differs from the familiar mechanics of everyday objects because it involves a complicated, highly correlated, and three-dimensional many-body dynamical choreography which is often nonintuitive even for highly trained researchers. We recently described how interactive molecular dynamics in virtual reality (iMD-VR) can help to meet this challenge, enabling researchers to manipulate real-time MD simulations of flexible structures in 3D. In this article, we outline various efforts to extend immersive technologies to the molecular sciences, and we introduce "Narupa," a flexible, open-source, multiperson iMD-VR software framework which enables groups of researchers to simultaneously cohabit real-time simulation environments to interactively visualize and manipulate the dynamics of molecular structures with atomic-level precision. We outline several application domains where iMD-VR is facilitating research, communication, and creative approaches within the molecular sciences, including training machines to learn potential energy functions, biomolecular conformational sampling, protein-ligand binding, reaction discovery using "on-the-fly" quantum chemistry, and transport dynamics in materials. We touch on iMD-VR's various cognitive and perceptual affordances and outline how these provide research insight for molecular systems. By synergistically combining human spatial reasoning and design insight with computational automation, technologies such as iMD-VR have the potential to improve our ability to understand, engineer, and communicate microscopic dynamical behavior, offering the potential to usher in a new paradigm for engineering molecules and nano-architectures.

Enabling Two-Electron Pathways with Iron and Cobalt: From Ligand Design to Catalytic Applications.

Homogeneous catalysis with Earth-abundant, first-row transition metals, including iron and cobalt, has gained considerable recent attention as a potentially cost-effective and sustainable alternative to more commonly and historically used precious metals. Because fundamental organometallic transformations, such as oxidative addition and reductive elimination, are two-electron processes and essential steps in many important catalytic cycles, controlling redox chemistry-in particular overcoming one-electron chemistry-has been as a central challenge with Earth-abundant metals. This Perspective focuses on approaches to impart sufficiently strong ligand fields to generate electron-rich metal complexes able to promote oxidative addition reactions where the redox changes are exclusively metal-based. Emphasis is placed on how ligand design and exploration of fundamental organometallic chemistry coupled with mechanistic understanding have been used to discover iron catalysts for the hydrogen isotope exchange in pharmaceuticals and cobalt catalysts for C(sp2)-H borylation reactions. A pervasive theme is that first-row metal complexes often promote unique chemistry from their precious-metal counterparts, demonstrating that these elements offer a host of new opportunities for reaction discovery and for more sustainable catalysis.

Geodesic interpolation for reaction pathways.

The development of high throughput reaction discovery methods such as the ab initio nanoreactor demands massive numbers of reaction rate calculations through the optimization of minimum energy reaction paths. These are often generated from interpolations between the reactant and product endpoint geometries. Unfortunately, straightforward interpolation in Cartesian coordinates often leads to poor approximations that lead to slow convergence. In this work, we reformulate the problem of interpolation between endpoint geometries as a search for the geodesic curve on a Riemannian manifold. We show that the perceived performance difference of interpolation methods in different coordinates is the result of an implicit metric change. Accounting for the metric explicitly allows us to obtain good results in Cartesian coordinates, bypassing the difficulties caused by redundant coordinates. Using only geometric information, we are able to generate paths from reactants to products which are remarkably close to the true minimum energy path. We show that these geodesic paths are excellent starting guesses for minimum energy path algorithms.

Pyridine-Based PCP-Ruthenium Complexes: Unusual Structures and Metal-Ligand Cooperation.

Metal-ligand cooperation (MLC) by dearomatization/aromatization provides a unique way for bond activation, which has led to the discovery of various acceptorless dehydrogenative coupling reactions. However, most of the studies are based on pincer complexes with a central nitrogen donor. Aiming at exploration of the possibility of MLC by PCP-type pincer complexes, we report herein the synthesis, characterization, structure, and reactivity of pyridine-based PCP-Ru complexes. X-ray structures and DFT calculations indicate a carbenoid character of quaternized pyridine-based PCP-Ru complexes. These complexes undergo dearomatization by direct deprotonation, and the dearomatized complex can react with hydrogen, alcohols, or nitriles to regain aromatization via MLC.

Predictive Model for the [Rh2(esp)2]-Catalyzed Intermolecular C(sp3)–H Bond Insertion of β-Carbonyl Ester Carbenes: Interplay between Theory and Experiment

Intermolecular C(sp3)–H insertions of β-carbonyl ester dirhodium-carbenes are extremely rare. Toward developing efficient reactions of these carbenes, a model for their insertion into C(sp3)–H bonds is described using density functional theory (DFT) calculations. In this study, the relevant electronic and steric components of β-carbonyl ester dirhodium-carbenes that affect intermolecular C(sp3)–H activation energies are explored, parametrized, and used to construct an intuitive model for predicting propensity for C–H insertion. The resulting insights from the theoretical investigation are actualized through experiments to establish reactivity trends for these species and reaction discovery. On the basis of these integrated computational and experimental efforts, examples of intermolecular C(sp3)–H insertions featuring secondary α-diazo-β-amide esters are reported. The resulting carbenes feature an intramolecular 1,6-hydrogen bond that affords increased stability and enhanced reactivity for C(sp3)–H insertion as compared to other β-carbonyl ester dirhodium-carbenes. The reactivity of these carbenes is also highlighted through (1) an example of a cyclopropanation reaction and (2) the use of a chiral dirhodium catalyst system.

Direct aqueous carbonation of heat activated serpentine: Discovery of undesirable side reactions reducing process efficiency

This work discloses a possible explanation for the relatively low efficiency and yield observed in direct aqueous carbonation of heat activated serpentine which remained a critical unanswered question during three decades of ex-situ mineral carbonation research and development. The discovery of undesirable side reactions, occurring during direct aqueous carbonation of heat activated serpentine has been reported and investigated in detail. These reactions result in the reformation of crystalline serpentine and precipitation of amorphous magnesium silicate hydroxide phase/s on the surface of reacting feed particles. Reformation of serpentine occurs under relatively mild conditions (in terms of pressure and temperature) and after only a few minutes of reaction which is in stark contrast to the conditions and rates which occur during geological serpentinisation and other laboratory studies. Scanning Electron Microscopy and Energy Dispersive X-ray spectroscopy analyses showed precipitation of amorphous magnesium silicate hydroxide phase/s during carbonation process. Fourier Transform Infrared Spectroscopy and Thermogravimetric analyses identified and quantified free and hydrogen bonded hydroxyls of silanol groups in the structure of the reaction products when heat activated lizardite and antigorite were carbonated. The growth of a crystalline serpentine phase was confirmed and quantified by X-ray Diffraction and Thermogravimetric analyses in the reaction products when heat activated antigorite was used a feed.

Hemoprotein-Catalyzed Cyclopropanation En Route to the Chiral Cyclopropanol Fragment of Grazoprevir.

Reactions that were once the exclusive province of synthetic catalysts can increasingly be addressed using biocatalysis. Through discovery of unnatural enzyme reactions, biochemists have significantly expanded the reach of enzymatic catalysis to include carbene transfer chemistries including olefin cyclopropanation. Here we describe hemoprotein cyclopropanation catalysts derived from thermophilic bacterial globins that react with diazoacetone and an unactivated olefin substrate to furnish a cyclopropyl ketone, a previously unreported reaction for enzyme catalysts. We further demonstrate that the resulting cyclopropyl ketone can be converted to a key cyclopropanol intermediate that occurs en route to the anti-hepatitis C drug grazoprevir.

Protein Substrates for Reaction Discovery: Site-Selective Modification with Boronic Acid Reagents.

Chemical modification of natural proteins must navigate difficult selectivity questions in a complex polyfunctional aqueous environment, within a narrow window of acceptable conditions. Limits on solvent mixtures, pH, and temperature create challenges for most synthetic methods. While a protein's complex polyfunctional environment undoubtedly creates challenges for traditional reactions, we wondered if it also might create opportunities for pursuing new bioconjugation reactivity directly on protein substrates. This Account describes our efforts to date to discover and develop new and useful reactivity for protein modification by starting from an open-ended screen of potential transition-metal catalysts for boronic acid reactivity with a model protein substrate. By starting from a broad screen, we were hoping to take advantage of the very many potential reactive sites on even a small model protein. And perhaps more importantly, whole proteins as reaction screening substrates might exhibit uniquely reactive local environments, the results of a dense combination of functional groups that would be nearly impossible to mimic in a small-molecule context. This effort has resulted in the discovery of four new protein modification reactions with boronic acid reagents, including a remarkable modification of specific backbone N-H bonds. This histidine-directed Chan-Lam coupling, based on specific proximity of an imidazole and two amide groups, is one important example of powerful reactivity that depends on a combination of functional groups that proteins make possible. Other bioconjugation reactions uncovered include a three-component tyrosine metalation with rhodium(III), a nickel-catalyzed cysteine arylation, and an unusual ascorbate-mediated oxidative process for N-terminal modification. The remarkably broad scope of reactivity types encountered in this work is a testament to the breadth of boronic acid reactivity. It is also a demonstration of the diverse reactivities that are possible by the combined alteration of boronic acid structure and metal promoter. The discovery of specific backbone modification chemistry has been a broadly empowering reactivity. Pyroglutamate, a naturally occurring posttranslational modification, exhibits remarkably high reactivity in histidine-directed backbone modification, which allows us to treat pyroglutamate as a reactive bioorthogonal handle that is readily incorporated into proteins of interest by natural machinery. In another research direction, the development of a vinylogous photocleavage system has allowed us to view backbone modification as a photocaging modification which is released by exposure to light.

Automatic discovery of adverse reactions through Chinese social media

Despite tremendous efforts made before the release of every drug, some adverse drug reactions (ADRs) may go undetected and thus, cause harm to both the users and to the pharmaceutical companies. One plausible venue to collect evidence of such ADRs is online social media, where patients and doctors discuss medical conditions and their treatments. There is substantial previous research on ADRs extraction from English online forums. However, very limited research was done on Chinese data. In this paper, we try to use the posts from two popular Chinese social media as the original dataset. We propose a semi-supervised learning framework that detects mentions of medications and colloquial ADR terms and extracts lexicon-syntactic features from natural language text to recognize positive associations between drug use and ADRs. The key contribution is an automatic label generation algorithm, which requires very little manual annotation. This bootstrapping algorithm could also be further applied on English data. The research results indicate that our algorithm outperforms the hidden Markov model and conditional random fields. With this approach, we discovered a large number of side effects for a variety of popular medicines in real world scenarios. [ABSTRACT FROM AUTHOR]

Transition Metal Vinylidene- and Allenylidene-Mediated Catalysis in Organic Synthesis.

With their mechanistic novelty and various modalities of reactivity, transition metal unsaturated carbene (alkenylidene) complexes have emerged as versatile intermediates for new reaction discovery. In particular, the past decade has witnessed remarkable advances in the chemistry of metal vinylidenes and allenylidenes, leading to the evolution of a diverse array of new catalytic transformations that are mechanistically distinct from those developed in the previous two decades. This review aims to provide a survey of the recent achievements in the development of organic reactions that make use of transition metal alkenylidenes as catalytic intermediates and their applications to organic synthesis.

Enantioselective N‐Heterocyclic Carbene Catalysis that Exploits Imine Umpolung

AbstractThe catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza‐Stetter reaction that proceeds via imine umpolung using N‐heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover‐limiting addition of the NHC to the imine.

Enantioselective N-Heterocyclic Carbene Catalysis that Exploits Imine Umpolung.

The catalytic umpolung of imines remains an underdeveloped approach to reaction discovery. Herein we report an enantioselective aza-Stetter reaction that proceeds via imine umpolung using N-heterocyclic carbene catalysis. The reaction proceeds with high levels of enantioselectivity (all ≥96:4 er) and good generality (21 examples). Mechanistic studies are reported and are consistent with turnover-limiting addition of the NHC to the imine.

Discovery and Development of Metal-Catalyzed Coupling Reactions in the Synthesis of Dasabuvir, an HCV-Polymerase Inhibitor.

Dasabuvir (1) is an HCV polymerase inhibitor which has been developed as a part of a three-component direct-acting antiviral combination therapy. During the course of the development of the synthetic route, two novel coupling reactions were developed. First, the copper-catalyzed coupling of uracil with aryl iodides, employing picolinamide 16 as the ligand, was discovered. Later, the palladium-catalyzed sulfonamidation of aryl nonaflate 33 was developed, promoted by electron-rich palladium complexes, including the novel phosphine ligand, VincePhos (50). This made possible a convergent, highly efficient synthesis of dasabuvir that significantly reduced the mutagenic impurity burden of the process.

Well-Defined Pre-Catalysts in Amide and Ester Bond Activation.

Over the past few decades, transition metal catalysis has witnessed a rapid and extensive development. The discovery and development of cross-coupling reactions is considered to be one of the most important advancements in the field of organic synthesis. The design and synthesis of well-defined and bench-stable transition metal pre-catalysts provide a significant improvement over the current catalytic systems in cross-coupling reactions, avoiding excess use of expensive ligands and harsh conditions for the synthesis of pharmaceuticals, agrochemicals and materials. Among various well-defined pre-catalysts, the use of Pd(II)-NHC, particularly, provided new avenues to expand the scope of cross-coupling reactions incorporating unreactive electrophiles, such as amides and esters. The strong σ-donation and tunable steric bulk of NHC ligands in Pd-NHC complexes facilitate oxidative addition and reductive elimination steps enabling the cross-coupling of broad range of amides and esters using facile conditions contrary to the arduous conditions employed under traditional catalytic conditions. Owing to the favorable catalytic activity of Pd-NHC catalysts, a tremendous progress was made in their utilization for cross-coupling reactions via selective acyl C–X (X=N, O) bond cleavage. This review highlights the recent advances made in the utilization of well-defined pre-catalysts for C–C and C–N bond forming reactions via selective amide and ester bond cleavage.

En route to metal-mediated and metal-catalysed reactions in water.

This perspective report presents the key approaches for the development of various organometallic reactions in aqueous media. In view of future sustainability, the efficient use of natural resources, such as renewable biomass-based feedstocks, constitutes an important aspect for sustainable chemical industry. The exploration and discovery of efficient organometallic reactions or equivalents in water enrich the toolbox of organic chemists for the direct conversion of biomass-derived feedstocks into high-valued chemicals and the direct modification of biomolecules in their native aqueous environment, which contributes to future sustainability.

Exploring the sequence, function, and evolutionary space of protein superfamilies using sequence similarity networks and phylogenetic reconstructions.

Integrative computational methods can facilitate the discovery of new protein functions and enzymatic reactions by enabling the observation and investigation of complex sequence-structure-function and evolutionary relationships within protein superfamilies. Here, we highlight the use of sequence similarity networks (SSNs) and phylogenetic reconstructions to map the functional divergence and evolutionary history of protein superfamilies. We exemplify this approach using the nitroreductase (NTR) flavoenzyme superfamily, demonstrating that SSN investigations can provide a rapid and effective means to classify groups of proteins, expose sequence similarity relationships across the global scale of a protein superfamily, and efficiently support detailed phylogenetic analyses. Integration of such approaches with systematic experimental characterization will expand our understanding of the functional diversity of enzymes, their evolution, and their associated physiological roles.

Recent Progress on Cyclic Nitrenoid Precursors in Transition-Metal-Catalyzed Nitrene-Transfer Reactions.

Nitrene-transfer reactions are powerful synthetic tools for the direct incorporation of nitrogen atoms into organic molecules. The discovery of novel nitrene-transfer reactions has been dominantly supported not only by improvements in transition-metal catalysts but also by the employment of novel precursors of nitrenoids. Since pioneering work involving the use of organic azides and iminoiodinanes as practical synthetic tools for nitrogen-containing compounds was reported, a new approach using various N-heterocycles containing strain energy or a weak bond has emerged. In this review, we briefly summarize the history of nitrene-transfer chemistry from the viewpoint of its precursors. In particular, the use of N-heterocycles such as 2H-azirines, 1,4,2-dioxazol-5-ones, 1,2,4-oxadiazol-5-ones, isoxazol-5(4H)-ones, and isoxazoles is comprehensively described, showing the recent remarkable progress in this chemistry.