Cationic Transition State Research Articles

Electric-Field Catalysis on Carbon Nanotubes in Electromicrofluidic Reactors: Monoterpene Cyclizations.

The control over the movement of electrons during chemical reactions with oriented external electric fields (OEEFs) has been predicted to offer a general approach to catalysis. Recently, we suggested that many problems to realize electric-field catalysis in practice under scalable bulk conditions could possibly be solved on multiwalled carbon nanotubes in electromicrofluidic reactors. Here, we selected monoterpene cyclizations to assess the scope of our system in organic synthesis. We report that electric-field catalysis can function by stabilizing both anionic and cationic transition states, depending on the orientation of the applied field. Moreover, electric-field catalysis can promote reactions which are barely accessible by general Brønsted and Lewis acids and field-free anion-π and cation-π interactions, and drive chemoselectivity toward intrinsically disfavored products without the need for pyrene interfacers attached to the substrate to prolong binding to the carbon nanotubes. Finally, interfacing with chiral organocatalysts is explored and evidence against contributions from redox chemistry is provided.

Electric‐Field Catalysis on Carbon Nanotubes in Electromicrofluidic Reactors: Monoterpene Cyclizations

AbstractThe control over the movement of electrons during chemical reactions with oriented external electric fields (OEEFs) has been predicted to offer a general approach to catalysis. Recently, we suggested that many problems to realize electric‐field catalysis in practice under scalable bulk conditions could possibly be solved on multiwalled carbon nanotubes in electromicrofluidic reactors. Here, we selected monoterpene cyclizations to assess the scope of our system in organic synthesis. We report that electric‐field catalysis can function by stabilizing both anionic and cationic transition states, depending on the orientation of the applied field. Moreover, electric‐field catalysis can promote reactions which are barely accessible by general Brønsted and Lewis acids and field‐free anion‐π and cation‐π interactions, and drive chemoselectivity toward intrinsically disfavored products without the need for pyrene interfacers attached to the substrate to prolong binding to the carbon nanotubes. Finally, interfacing with chiral organocatalysts is explored and evidence against contributions from redox chemistry is provided.

Highly Acidic Electron-Rich Brønsted Acids Accelerate Asymmetric Pictet-Spengler Reactions by Virtue of Stabilizing Cation-π Interactions.

Electron-rich heteroaromatic imidodiphosphorimidates (IDPis) catalyze the asymmetric Pictet-Spengler reaction of N-carbamoyl-β-arylethylamines with high stereochemical precision. This particular class of catalysts furthermore provides a vital rate enhancement compared to related Brønsted acids. Here we present experimental studies on the underlying reaction kinetics that shed light on the specific origins of rate acceleration. Analysis of Hammett plots, kinetic isotope effects, reaction orders, Eyring plots, and isotopic scrambling experiments, allowed us to gather insights into the molecular interactions between the chiral Brønsted acid and catalytically formed intermediates. Based on rigorously determined pKa values as well as the experimental evidence, we propose that attractive intermolecular forces offered by electron-rich π-surfaces of the chiral counteranion enthalpically stabilize cationic intermediates and transition states by way of cation-π interactions. This view is furthermore supported by in-depth density functional theory calculations. Our deepened understanding of the reaction mechanism allowed us to develop a method for accessing 1-aryltetrahydroisoquinolines from aromatic dimethyl acetals, a substrate class that was thus far inaccessible via catalytic asymmetric Pictet-Spengler reactions.

Reference-Quality Free Energy Barriers in Catalysis from Machine Learning Thermodynamic Perturbation Theory.

For the first time, we report calculations of the free energies of activation of cracking and isomerization reactions of alkenes that combine several different electronic structure methods with molecular dynamics simulations. We demonstrate that the use of a high level of theory (here Random Phase Approximation-RPA) is necessary to bridge the gap between experimental and computed values. These transformations, catalyzed by zeolites and proceeding via cationic intermediates and transition states, are building blocks of many chemical transformations for valorization of long chain paraffins originating, e.g., from plastic waste, vegetable oils, Fischer-Tropsch waxes or crude oils. Compared with the free energy barriers computed at the PBE+D2 production level of theory via constrained ab initio molecular dynamics, the barriers computed at the RPA level by the application of Machine Learning thermodynamic Perturbation Theory (MLPT) show a significant decrease for isomerization reaction and an increase of a similar magnitude for cracking, yielding an unprecedented agreement with the results obtained by experiments and kinetic modeling.

Reference‐Quality Free Energy Barriers in Catalysis from Machine Learning Thermodynamic Perturbation Theory

AbstractFor the first time, we report calculations of the free energies of activation of cracking and isomerization reactions of alkenes that combine several different electronic structure methods with molecular dynamics simulations. We demonstrate that the use of a high level of theory (here Random Phase Approximation—RPA) is necessary to bridge the gap between experimental and computed values. These transformations, catalyzed by zeolites and proceeding via cationic intermediates and transition states, are building blocks of many chemical transformations for valorization of long chain paraffins originating, e.g., from plastic waste, vegetable oils, Fischer–Tropsch waxes or crude oils. Compared with the free energy barriers computed at the PBE+D2 production level of theory via constrained ab initio molecular dynamics, the barriers computed at the RPA level by the application of Machine Learning thermodynamic Perturbation Theory (MLPT) show a significant decrease for isomerization reaction and an increase of a similar magnitude for cracking, yielding an unprecedented agreement with the results obtained by experiments and kinetic modeling.

Late-Stage Halogenation of Peptides, Drugs and (Hetero)aromatic Compounds with a Nucleophilic Hydrazide Catalyst.

Unlike its other halogen atom siblings, chlorination of a bioactive compound can change its physiological characteristics, improve its pharmacological profile, and function as a point of diversification through cross-coupling reactions. As a result, it has been a crucial strategy for drug discovery and development. However, functional groups such as amines, amides, hydroxy groups, or carboxylic acids trap the Cl+ , severely limiting the reactivity and making direct chlorination far too difficult to be practical. Herein, we introduce a nucleophilic sulfonohydrazide catalyst for late-stage halogenation of peptides and drugs. This direct, mild and metal-free protocol shows high functional-group tolerance and is compatible with a range of structurally diverse peptides, drugs and aromatic compounds. Furthermore, DFT studies indicate that the reaction most likely proceeds via a cationic transition state. The gram-scale synthesis, high stability and efficiency of the catalyst provide a facile route for late-stage functionalization and intermediates for further derivatization.

Late‐Stage Halogenation of Peptides, Drugs and (Hetero)aromatic Compounds with a Nucleophilic Hydrazide Catalyst

AbstractUnlike its other halogen atom siblings, chlorination of a bioactive compound can change its physiological characteristics, improve its pharmacological profile, and function as a point of diversification through cross‐coupling reactions. As a result, it has been a crucial strategy for drug discovery and development. However, functional groups such as amines, amides, hydroxy groups, or carboxylic acids trap the Cl+, severely limiting the reactivity and making direct chlorination far too difficult to be practical. Herein, we introduce a nucleophilic sulfonohydrazide catalyst for late‐stage halogenation of peptides and drugs. This direct, mild and metal‐free protocol shows high functional‐group tolerance and is compatible with a range of structurally diverse peptides, drugs and aromatic compounds. Furthermore, DFT studies indicate that the reaction most likely proceeds via a cationic transition state. The gram‐scale synthesis, high stability and efficiency of the catalyst provide a facile route for late‐stage functionalization and intermediates for further derivatization.

Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications

Cyclobutanone is a strained motif with broad applications, while direct assembly of the aromatic ring fused cyclobutanones beyond benzocyclobutenone (BCB) skeletons remains challenging. Herein, we report a Rh-catalyzed formal [3+2] annulation of diazo group tethered alkynes involving a 4-exo-dig carbocyclization process, providing a straightforward access to furan-fused cyclobutanones. DFT calculations disclose that, by comparison to the competitive 5-endo-dig process, 4-exo-dig carbocyclization is mainly due to lower angle strain of the key sp-hybridized vinyl cationic transition state in the cyclization step. Using less reactive catalysts Rh2(carboxylate)4 is critical for high selectivity, which is explained as catalyst-substrate hydrogen bonding interaction. This method is proved successful to direct access previously inaccessible and unknown furan-fused cyclobutanone scaffolds, which can participate in a variety of post-functionalization reactions as versatile synthetic blocks. In addition, preliminary antitumor activity study of these products indicates that some molecules exhibite significant anticancer potency against different human cancer cell lines.

Ruthenium nickel bimetallic nanoparticles embedded in nitrogen-doped carbon mesoporous spheres as a superior catalyst for the hydrogenation of toxic nitroarenes

In this work, the ruthenium nickel bimetallic nanoparticles embedded in nitrogen-doped carbon mesoporous spheres (RuNi@ N-CMS) as a novel catalyst were designed and prepared. Hydrogenation of toxic p-nitrophenol into p-aminophenol was carried out in an aqueous medium using the prepared nanostructure. The as-synthesized RuNi@ N-CMS nanostructure displayed a better catalytic activity in comparison to both Ni@ N-CMS and Ru@ N-CMS nanostructures which can be ascribed to synergistic effects of ruthenium-nickel. In contrast to the nitrogen-doped catalyst, RuNi@CMS showed less activity, possibly because nitrogen acts as a secondary active site. The rate constant and TOF values were found to be 6.77 × 10-3 and 0.825 s−1 for hydrogenation of p-nitrophenol, respectively. Furthermore, RuNi@ N-CMS nanostructure was investigated in the reduction of nitroarene derivatives bearing electron-donating and electron-withdrawing groups. According to the kinetics study and Hammett plot of the reduction of nitroarenes, the cationic transition state is involved in the catalytic reaction. Most importantly, the catalyst could be recovered and reused after five consecutive runs without significantly deactivating.

A Water‐ and Base‐Stable Iminopyridine‐Based Cage That Can Bind Larger Organic Anions

AbstractCatalysis inside molecular cages and capsules has attracted an increasing amount of attention over the last decade. While many examples of the catalysis of reactions with cationic intermediates and transition states are known, those with anionic counterparts are scarce. One limiting factor is access to suitably sized cationic iminopyridine‐based cages that are stable towards water and anionic/nucleophilic guest molecules. This study aimed at identifying such suitable cages. In this full paper, we describe the journey that finally led to the synthesis of a novel iminopyridine‐based tetrahedron that can bind larger organic anions with binding constants of up to 850 M−1 in MeCN−d3/H2O=9 : 1. Importantly, it also displays stability in basic aqueous acetonitrile. Surprisingly, investigations towards catalysis of reactions with anionic transition states did not indicate rate accelerations in the presence of the cage.

Aromatic Interactions in Glycochemistry: From Molecular Recognition to Catalysis.

Aromatic platforms are ubiquitous recognition motifs occurring in protein carbohydrate- binding domains (CBDs), RNA receptors and enzymes. They stabilize the glycoside/ receptor complexes by participating in stacking CH/π interactions with either the α- or β- face of the corresponding pyranose units. In addition, the role played by aromatic units in the stabilization of glycoside cationic transition states has started being recognized in recent years. Extensive studies carried out during the last decade have allowed the dissection of the main contributing forces that stabilize the carbohydrate/aromatic complexes, while helping delineate not only the standing relationship between the glycoside/ aromatic chemical structures and the strength of this interaction but also their potential influence on glycoside reactivity.

Organoselenium ligand-stabilized copper nanoparticles: Development of a magnetically separable catalytic system for efficient, room temperature and aqueous phase reduction of nitroarenes

Herein, we report the synthesis of a novel selenoether ligand L1 (pyren-1-yl-CH2-NH-CH2-CH2-SePh) and the first example of organoselenium compound stabilized-copper nanoparticles (NPs) with long term stability. Such stabilized nanoparticles (NPs) have been immobilised non-covalently on a chitosan-layered magnetic support to obtain Fe3O4@CS@L1-stabilized-CuNPs, characterized very well by various techniques. It has been explored as an extremely efficient and recyclable catalytic system for cost effective and green borohydride reduction reactions of a variety of nitroarenes (4-nitrophenol, nitrobenzene, 2-nitrophenol, 4-nitroaniline, 2-nitroaniline, 4-nitrotoluene, 1-chloro-4-nitrobenzene and 4-nitroanisole) in an eco-friendly solvent i.e. water at room temperature with ≥99% conversions into aminoarenes in very short reaction times. Additional advantages, offered by the catalyst, are its magnetic separability and recyclability. A very high value of rate constant (0.350 per minute) and a very low value (31.7 KJ per mol) of activation energy (Ea) have been found. Catalyst is very robust and does not let the copper species and ligand leach into the solution during the course of reduction reaction. Kinetics and Hammett plot of the catalytic reaction have been studied. It appears that the catalysis proceeds via a cationic transition state.

Rigid Arrangements of Ionic Charge in Zeolite Frameworks Conferred by Specific Aluminum Distributions Preferentially Stabilize Alkanol Dehydration Transition States

AbstractZeolite reactivity depends on the solvating environments of their micropores and the proximity of their Brønsted acid sites. Turnover rates (per H+) for methanol and ethanol dehydration increase with the fraction of H+ sites sharing six‐membered rings of chabazite (CHA) zeolites. Density functional theory (DFT) shows that activation barriers vary widely with the number and arrangement of Al (1–5 per 36 T‐site unit cell), but cannot be described solely by Al–Al distance or density. Certain Al distributions yield rigid arrangements of anionic charge that stabilize cationic intermediates and transition states via H‐bonding to decrease barriers. This is a key feature of acid catalysis in zeolite solvents, which lack the isotropy of liquid solvents. The sensitivity of polar transition states to specific arrangements of charge in their solvating environments and the ability to position such charges in zeolite lattices with increasing precision herald rich catalytic diversity among zeolites of varying Al arrangement.

Rigid Arrangements of Ionic Charge in Zeolite Frameworks Conferred by Specific Aluminum Distributions Preferentially Stabilize Alkanol Dehydration Transition States.

Zeolite reactivity depends on the solvating environments of their micropores and the proximity of their Brønsted acid sites. Turnover rates (per H+ ) for methanol and ethanol dehydration increase with the fraction of H+ sites sharing six-membered rings of chabazite (CHA) zeolites. Density functional theory (DFT) shows that activation barriers vary widely with the number and arrangement of Al (1-5 per 36 T-site unit cell), but cannot be described solely by Al-Al distance or density. Certain Al distributions yield rigid arrangements of anionic charge that stabilize cationic intermediates and transition states via H-bonding to decrease barriers. This is a key feature of acid catalysis in zeolite solvents, which lack the isotropy of liquid solvents. The sensitivity of polar transition states to specific arrangements of charge in their solvating environments and the ability to position such charges in zeolite lattices with increasing precision herald rich catalytic diversity among zeolites of varying Al arrangement.

The Importance of Kinetic and Thermodynamic Control when Assessing Mechanisms of Carboxylate-Assisted C-H Activation.

The reactions of substituted 1-phenylpyrazoles (phpyz-H) at [MCl2Cp*]2 dimers (M = Rh, Ir; Cp* = C5Me5) in the presence of NaOAc to form cyclometalated Cp*M(phpyz)Cl were studied experimentally and with density functional theory (DFT) calculations. At room temperature, time-course and H/D exchange experiments indicate that product formation can be reversible or irreversible depending on the metal, the substituents, and the reaction conditions. Competition experiments with both para- and meta-substituted ligands show that the kinetic selectivity favors electron-donating substituents and correlates well with the Hammett parameter giving a negative slope consistent with a cationic transition state. However, surprisingly, the thermodynamic selectivity is completely opposite, with substrates with electron-withdrawing groups being favored. These trends are reproduced with DFT calculations that show C-H activation proceeds by an AMLA/CMD mechanism. H/D exchange experiments with the meta-substituted ligands show ortho-C-H activation to be surprising facile, although (with the exception of F substituents) this does not generally lead to ortho-cyclometalated products. Calculations suggest that this can be attributed to the difficulty of HOAc loss after the C-H activation step due to steric effects in the 16e intermediate that would be formed. Our study highlights that the use of substituent effects to assign the mechanism of C-H activation in either stoichiometric or catalytic reactions may be misleading, unless the energetics of the C-H cleavage step and any subsequent reactions are properly taken into account. The broader implications of our study for the assignment of C-H activation mechanisms are discussed.

Cyclizations catalyzed inside a hexameric resorcinarene capsule.

The self-assembled, hydrogen-bonded hexameric resorcin[4]arene capsule represents one of the most readily accessible host systems for the study of container catalysis. This assembly can stabilize cationic intermediates and transition states through cation-π interactions with the aromatic walls and several reactions have been successfully performed in its cavity. This highlight focuses mainly on the applications of this host system for the catalysis of cyclization reactions such as terpene cyclizations, intramolecular hydroalkoxylation and carbonyl-olefin metathesis.

The Emergence of Anion-π Catalysis.

The objective of this Account is to summarize the first five years of anion-π catalysis. The general idea of anion-π catalysis is to stabilize anionic transition states on aromatic surfaces. This is complementary to the stabilization of cationic transition states on aromatic surfaces, a mode of action that occurs in nature and is increasingly used in chemistry. Anion-π catalysis, however, rarely occurs in nature and has been unexplored in chemistry. Probably because the attraction of anions to π surfaces as such is counterintuitive, anion-π interactions in general are much younger than cation-π interactions and remain under-recognized until today. Anion-π catalysis has emerged from early findings that anion-π interactions can mediate the transport of anions across lipid bilayer membranes. With this evidence for stabilization in the ground state secured, there was no reason to believe that anion-π interactions could not also stabilize anionic transition states. As an attractive reaction to develop anion-π catalysis, the addition of malonic acid half thioesters to enolate acceptors was selected. This choice was also made because without enzymes decarboxylation is preferred and anion-π interactions promised to catalyze selectively the disfavored but relevant enolate addition. Concerning anion-π catalysts, we started with naphthalene diimides (NDIs) because their intrinsic quadrupole moment is highly positive. The NDI scaffold was used to address questions such as the positioning of substrates on the catalytic π surface or the dependence of activity on the π acidity of this π surface. With the basics in place, the next milestone was the creation of anion-π enzymes, that is, enzymes that operate with an interaction rarely used in biology, at least on intrinsically π-acidic or highly polarizable aromatic amino-acid side chains. Electric-field-assisted anion-π catalysis addresses topics such as heterogeneous catalysis on electrodes and remote control of activity by voltage. On π-stacked foldamers, anion-(π) n-π catalysis was discovered. Fullerenes emerged as the scaffold of choice to explore contributions from polarizability. On fullerenes, anionic transition states are stabilized by large macrodipoles that appear only in response to their presence. With this growing collection of anion-π catalysts, several reactions beyond enolate addition have been explored so far. Initial efforts focused on asymmetric anion-π catalysis. Increasing enantioselectivity with increasing π acidity of the active π surface has been exemplified for enamine and iminium chemistry and for anion-π transaminase mimics. However, the delocalized nature of anion-π interactions calls for the stabilization of charge displacements over longer distances. The first step in this direction was the formation of cyclohexane rings with five stereogenic centers from achiral acyclic substrates on π-acidic surfaces. Moreover, the intrinsically disfavored exo transition state of anionic Diels-Alder reactions is stabilized selectively on π-acidic surfaces; endo products and otherwise preferred Michael addition products are completely suppressed. Taken together, we hope that these results on catalyst design and reaction scope will establish anion-π catalysis as a general principle in catalysis in the broadest sense.

Enantioselective Enzymatic Naphthoyl Ring Reduction

Birch reductions of aromatic hydrocarbons by means of single-electron-transfer steps depend on alkali metals, ammonia, and cryogenic reaction conditions. In contrast, 2-naphthoyl-coenzyme A (2-NCoA) and 5,6-dihydro-2-NCoA (5,6-DHNCoA) reductases catalyze two two-electron reductions of the naphthoyl-ring system to tetrahydronaphthoyl-CoA at ambient temperature. Using a number of substrate analogues, we provide evidence for a Meisenheimer complex-analogous intermediate during 2-NCoA reduction, whereas the subsequent reduction of 5,6-dihydro-2-NCoA is suggested to proceed via an unprecedented cationic transition state. Using vibrational circular dichroism (VCD) spectroscopy, we demonstrate that both enzymatic reductions are highly stereoselective in D2 O, providing an enantioselective pathway to products inaccessible by Birch reduction. Moreover, we demonstrate the power of VCD spectroscopy to determine the absolute configuration of isotopically engendered alicyclic stereocenters.

New Class of Glycoside Hydrolase Mechanism-Based Covalent Inhibitors: Glycosylation Transition State Conformations.

The design of covalent inhibitors in glycoscience research is important for the development of chemical biology probes. Here we report the synthesis of a new carbocyclic mechanism-based covalent inhibitor of an α-glucosidase. The enzyme efficiently catalyzes its alkylation via either an allylic cation or a cationic transition state. We show this allylic covalent inhibitor has different catalytic proficiencies for pseudoglycosylation and deglycosylation. Such inhibitors have the potential to be useful chemical biology tools.

ChemInform Abstract: Self‐Assembled Supramolecular Structures as Catalysts for Reactions Involving Cationic Transition States

AbstractReview: [40 refs.